Background

Breast cancer causes 20% of cancer deaths in women and is increasing in incidence. There appears to be a leveling off in the incidence of breast cancer but up to 1988, the incidence had been increasing. A typical pathology report should indicate the type of breast cancer, the histologic grade, the size, and a comment on the surgical margins. In addition, depending upon the case, ancillary studies examining for estrogen and progesterone receptors and Her2-neu may be ordered. The pathologist should also strive to correlate the histologic findings to the clinical and radiologic findings. For example, if the biopsy was originally performed for suspicious calcifications, the surgical pathology report should indicate whether microcalcifications were present and the location of these changes, that is, within benign breast tissue or tumor. Prognosis for breast cancer and treatment for breast cancer are discussed in other sections.

Breast cancer genes (BRCA1 and BRCA2)
CA15-3
Colloid Carcinoma (Mucinous Carcinoma)
Ductal carcinoma in situ (DCIS)
Herceptin
Lobular carcinoma in situ (LCIS)
Invasive ductal carcinoma with Paget's disease
Invasive lobular carcinoma
Medullary carcinoma
Paget's disease
Tubular carcinoma

Outline

Epidemiology	Synonyms Incidence Age Antibiotics Diet Estrogen Geography Genetics Lactation Reproductive Life Obesity Parity Race Radiation Sex
Disease Associations	Cowden's syndrome Endometrial carcinoma Granular cell tumor Hodgkin Disease Ovarian adenofibromas Prolactinoma Thyroid cancer
Pathogenesis	Animal Model Apoptosis Estrogen Receptor Loss of Heterozygosity Progression Oncogenes
Laboratory/ Radiologic/ Other Diagnostic Testing	Screening mammography Breast Ductal Lavage Imaged guided biopsies MRI CA15-3 Her2-neu
Gross Appearance and Clinical Variants	Bilateral Inflammatory breast cancer Non-palpable breast cancer
Histopathological Features and Variants	Adequacy of biopsy Adenoid cystic carcinoma Adenosquamous cell carcinoma Apocrine carcinoma Centrally necrotizing carcinoma Choriocarcinomatous Clear cell carcinoma Colloid carcinoma Estrogen receptor negative carcinoma Histiocytoid carcinoma Invasive micropapillary carcinoma Metaplastic carcinoma Myoepithelial tumors Papillary carcinoma Pigmented (melanin) Pleomorphic carcinoma Sarcomatoid carcinoma Secretory carcinoma Small cell carcinoma
Special Stains/ Immunohistochemistry/ Electron Microscopy	Tissue Microarrays Her2-neu Cadherins CD10 Epidermal growth factor receptor Estrogen Receptor GCDFP-15 GLUT-1 Melatonin receptors p63
Differential Diagnosis	Benign Mechanical Transport Carcinoid tumor, metastatic Cylindromas Ectopic breast tissue Homologous carcinomas Intramammary lymph nodes Lymphoma, anaplastic Megakaryocytes Ovarian Carcinoma, Metastatic Xanthomatous Pseudotumor
Prognosis
Treatment
Commonly Used Terms	Estrogen and progesterone receptors Pagetoid Scarff-Bloom-Richardson Grading
Internet Links	Gross and Microscopic pictures

EPIDEMIOLOGIC ASSOCIATIONS
SYNONYMS	Duct carcinoma with productive fibrosis Scirrhous carcinoma Carcinoma simplex Invasive duct carcinoma, not otherwise specified (NOS)
INCIDENCE/ PREVALENCE	One in nine women will develop breast cancer within her lifetime 27 per 100,000 in USA 44,000 women dying yearly 60-80% of all malignant breast tumors
Trends in incidence rates of invasive lobular and ductal breast carcinoma. Li CI, Anderson BO, Daling JR, Moe RE. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, MP 381, PO Box 19024, Seattle, WA 98109-1024.	JAMA 2003 Mar 19;289(11):1421-4 Abstract quote CONTEXT: Research has suggested that use of combined estrogen and progestin hormone replacement therapy (CHRT) increases breast cancer risk and that CHRT use is more strongly associated with the risk of invasive lobular breast carcinoma than that of invasive ductal carcinoma. Lobular carcinoma is less common than ductal carcinoma but can be more difficult to diagnose because of its subtle elusive infiltrative pattern. OBJECTIVE: To evaluate trends in invasive lobular and ductal carcinoma incidence rates from 1987 through 1999, during which time use of CHRT increased in the United States. DESIGN: Descriptive epidemiologic study. SETTING: Nine cancer registries that participate in the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute and that cover Atlanta, Ga; Detroit, Mich; San Francisco-Oakland, Calif; Seattle, Wash; and Connecticut, Hawaii, Iowa, New Mexico, and Utah. POPULATION: Women 30 years of age and older residing in the areas covered by the 9 SEER registries. MAIN OUTCOME MEASURES: Proportional changes in incidence rates of invasive lobular and ductal carcinoma among women with no prior history of breast cancer. RESULTS: A total of 190 458 women were included in this analysis who were identified through the registries as having invasive breast cancer; 7682 of the 198 140 potentially eligible women (ie, those identified as not having in situ breast cancer) were excluded from this analysis because stage of cancer was unknown. Invasive breast cancer incidence rates adjusted for age and for SEER historic stage increased 1.04-fold (95% confidence interval [CI], 1.004-1.07) from 1987-1999 (206.7/100 000 to 214.1/100 000, age-adjusted). However, incidence rates of tumors classified as lobular increased 1.52-fold (95% CI, 1.42-1.63), and those classified as mixed ductal-lobular increased 1.96-fold (95% CI, 1.80-2.14); rates of these types combined increased 1.65-fold (95% CI, 1.55-1.78) (19.8/100 000 to 33.4/100 000, age-adjusted). In contrast, ductal carcinoma rates remained largely constant (153.8/100 000 to 155.3/100 000, age-adjusted; proportional change, 1.03 [95% CI, 0.99-1.06]). The proportion of breast cancers with a lobular component increased from 9.5% in 1987 to 15.6% in 1999. CONCLUSIONS: Ductal carcinoma incidence rates remained essentially constant from 1987-1999 while lobular carcinoma rates increased steadily. This increase presents a clinical challenge given that lobular carcinoma is more difficult to detect than ductal carcinoma by both physical examination and mammography.
AGE	Steady rise to menopause Average age of diagnosis is 64 yrs
ANTIBIOTICS
Antibiotic use in relation to the risk of breast cancer. Velicer CM, Heckbert SR, Lampe JW, Potter JD, Robertson CA, Taplin SH. Department of Epidemiology, University of Washington, Seattle, USA.	JAMA. 2004 Feb 18;291(7):827-35 Abstract quote.   CONTEXT: Use of antibiotics may be associated with risk of breast cancer through effects on immune function, inflammation, and metabolism of estrogen and phytochemicals; however, clinical data on the association between antibiotic use and risk of breast cancer are sparse. OBJECTIVE: To examine the association between use of antibiotics and risk of breast cancer. DESIGN, SETTING, AND PARTICIPANTS: Case-control study among 2266 women older than 19 years with primary, invasive breast cancer (cases) enrolled in a large, nonprofit health plan for at least 1 year between January 1, 1993, and June 30, 2001, and 7953 randomly selected female health plan members (controls), frequency-matched to cases on age and length of enrollment. Cases were ascertained from the Surveillance, Epidemiology, and End Results cancer registry. Antibiotic use was ascertained from computerized pharmacy records. MAIN OUTCOME MEASURE: Association between extent of antibiotic use and risk of breast cancer. RESULTS: Increasing cumulative days of antibiotic use were associated with increased risk of incident breast cancer, adjusted for age and length of enrollment. For categories of increasing use (0, 1-50, 51-100, 101-500, 501-1000, and > or =1001 days), odds ratios (95% confidence intervals) for breast cancer were 1.00 (reference), 1.45 (1.24-1.69), 1.53 (1.28-1.83), 1.68 (1.42-2.00), 2.14 (1.60-2.88), and 2.07 (1.48-2.89) (P<.001 for trend). Increased risk was observed in all antibiotic classes studied and in a subanalysis having breast cancer fatality as the outcome. Among women with the highest levels of tetracycline or macrolide use, risk of breast cancer was not elevated in those using these antibiotics exclusively for acne or rosacea (indications that could be risk factors for breast cancer due to altered hormone levels), compared with those using them exclusively for respiratory tract infections, adjusted for age and length of enrollment (odds ratio, 0.91; 95% confidence interval, 0.44-1.87). CONCLUSIONS: Use of antibiotics is associated with increased risk of incident and fatal breast cancer. It cannot be determined from this study whether antibiotic use is causally related to breast cancer, or whether indication for use, overall weakened immune function, or other factors are pertinent underlying exposures. Although further studies are needed, these findings reinforce the need for prudent long-term use of antibiotics.
DIET	Moderate or heavy alcohol consumption No association with coffee or cigarette smoking
EXOGENOUS ESTROGEN	Controversial but may have a slightly increased risk
ENDOGENOUS ESTROGEN EXCESS	Functioning ovarian tumors producing estrogen and postmenopausal women with high circulating levels of estrogen
GEOGRAPHY	4-7x more common in US than Asia
Predominance of high-grade pathway in breast cancer development of Middle East women. Al-Kuraya K, Schraml P, Sheikh S, Amr S, Torhorst J, Tapia C, Novotny H, Spichtin H, Maurer R, Mirlacher M, Simon R, Sauter G. [1] 1King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia [2] 2Institute of Pathology, University Hospital Eppendorf, Hamburg, Germany.	Mod Pathol. 2005 Jul;18(7):891-7 Abstract quote.   Recent data have suggested considerable molecular differences in cancers from various ethnical groups. As molecular features are increasingly used for predicting cancer prognosis and response to therapy, better knowledge of ethnic molecular features is important. To identify potential molecular differences between breast cancers in Europe and the Middle East, we analyzed consecutive breast cancer series from Switzerland (n=2197) and Saudi Arabia (n=204). Tissue microarrays were analyzed by fluorescence in situ hybridization for HER2, CCND1, MYC, and EGFR amplification. The data revealed marked differences between Saudi and Swiss patients. Saudi breast cancers had a markedly higher frequency of HER2 (31 vs 17%; P<0.0001) and MYC (16 vs 5%; P<0.0001) amplifications than Swiss breast cancers. Remarkably, this was partly due to a much higher incidence of grade 3 cancers in the Saudi than in the Swiss population (65 vs 32%; P<0.0001). However, differences in amplification frequency hold also true within grade 3 cancers (HER2: 40 vs 30%, P<0.05; MYC: 22 vs 11%, P=0.002). Interestingly, in combination with known age standardized incidence rates of breast cancer in Saudi Arabia (21.6/100 000) and Switzerland (70.1/100 000), these data suggest that the incidence of high-grade breast cancer is comparable for Saudi and Swiss women, while the incidence of low-grade breast cancers is about 14 times lower in Saudi than for Swiss women. These observations suggest that a difference in genetic susceptibility and/or lifestyle between Saudi and Swiss women has a substantial and much higher than expected impact on the risk of low-grade breast cancer.
Proliferation in african breast cancer: biology and prognostication in nigerian breast cancer material. Ikpatt OF, Kuopio T, Collan Y. Department of Pathology (OFI, University of Calabar Teaching Hospital, Nigeria.	Mod Pathol 2002 Aug;15(8):783-9 Abstract quote Three hundred cases of invasive breast carcinoma from the University of Calabar Teaching Hospital, Nigeria were subjected to evaluation of proliferative activity by mitotic counts. The prognostic significance and association with other prognostic factors were evaluated. The mitotic activity was expressed as mitotic activity index (MAI), and standardized mitotic index (SMI). Pearson's correlation and univariate and multivariate Cox's regression were used. The mean follow-up time was 25.9 months. The mean values of SMI and MAI were 42.6 mitotic figures per square millimeter and 30.5 mitotic figures per 10 high-power fields, respectively, and these were much higher than values reported for Europe or other Western countries. The SMI had a positive correlation with tumor size (r = 0.31, P <.0001), histologic grade (r = 0.68, P <.0001), nuclear area (r = 0.45, P <.0001), and negative correlation with fraction of fields with tubular differentiation (FTD; r = -0.56, P = <0.0001). There was no statistically significant difference in the mitotic activity between the postmenopausal and the premenopausal patients. Also, lymph node-positive patients had higher counts than did lymph node-negative patients. Earlier determined grading associated decision thresholds divided the patients into groups of favorable and unfavorable prognosis. However, the statistically optimal thresholds for Nigerian material were different (32 and 92 mitotic figures per square millimeter for SMI). Tumor size of 5 cm, SMI, and MAI were independent prognostic factors. Nigerian breast cancers are high-grade, high-stage, and high-proliferating cancers occurring in a younger population than those of the Western countries. Proliferation is also more active. Evaluation of SMI or MAI can improve the distinction between aggressive and less aggressive variants of breast cancer.
GENETICS	5-10% of women have inheritance of a mutation in the breast cancer gene (BRCA1 and BRCA2) 1.5-2x risk for women with first degree relatives with breast CA 4-6x risk with two affected relatives Familial syndromes (Li-Fraumeni syndrome, Cowden's syndrome, Ataxia-Telangiectasia)
HORMONE REPLACEMENT THERAPY
LACTATION
Lactation and breast carcinoma risk in a South African population. Coogan PF, Rosenberg L, Shapiro S, Hoffman M. Slone Epidemiology Unit, Boston University School of Medicine, Brookline, Massachusetts 02446, USA.	Cancer 1999 Sep 15;86(6):982-9 Abstract quote BACKGROUND: A number of epidemiologic studies have reported a reduced risk of breast carcinoma among women who have lactated but others have not. The current study presents data regarding lactation and breast carcinoma risk from a hospital-based case-control study of black and colored South African women. METHODS: Incident breast carcinoma cases treated between January 1994 and October 1997 (n = 446) at 2 major hospitals in Cape Town and hospital patients admitted for conditions unrelated to breast carcinoma (controls, n = 1471) were queried regarding the duration of breast-feeding each liveborn child and breast carcinoma risk factors. Multivariate logistic regression models were used to calculate odds ratios (ORs) for various categories of lactation compared with a reference category of never having breast-fed among women who had had at least one full term live birth. RESULTS: Approximately 83% of cases and 85% of controls had ever breast-fed (OR = 0.9; 95% confidence interval [95% CI], 0.7-1.3). Among all subjects, the ORs for those who lactated for <3 years were near or at unity. Beyond 3 years, ORs extending up to >/=7 years were less than unity, but the 95% CIs included 1.0 (OR for duration of >/=7 years = 0.7; 95% CI, 0.4-1.3). ORs did not vary by menopausal status. Breast carcinoma risk was not found to be related to the duration of breast-feeding the first child, the number of children breast-fed, or the patient's age at first lactation. CONCLUSIONS: The results of the current study suggest lactation has little or no protective effect on breast carcinoma risk.
LENGTH OF REPRODUCTIVE LIFE	Early menarche (start of menstruation) and late menopause increases risk
OBESITY	Increased risk due to excess estrogen synthesis from peripheral fat in postmenopausal women Decreased risk in obese women <40 yrs
ORAL CONTRACEPTIVES
Oral contraceptives and the risk of breast cancer. Marchbanks PA, McDonald JA, Wilson HG, Folger SG, Mandel MG, Daling JR, Bernstein L, Malone KE, Ursin G, Strom BL, Norman SA, Wingo PA, Burkman RT, Berlin JA, Simon MS, Spirtas R, Weiss LK. Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, USA.	N Engl J Med 2002 Jun 27;346(26):2025-32 Abstract quote BACKGROUND: It is uncertain whether the use of an oral contraceptive increases the risk of breast cancer later in life, when the incidence of breast cancer is increased. We conducted a population-based, case-control study to determine the risk of breast cancer among former and current users of oral contraceptives. METHODS: We interviewed women who were 35 to 64 years old. A total of 4575 women with breast cancer and 4682 controls were interviewed. Conditional logistic regression was used to calculate odds ratios as estimates of the relative risk (incidence-density ratios) of breast cancer. RESULTS: The relative risk was 1.0 (95 percent confidence interval, 0.8 to 1.3) for women who were currently using oral contraceptives and 0.9 (95 percent confidence interval, 0.8 to 1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. The results were similar among white and black women. Use of oral contraceptives by women with a family history of breast cancer was not associated with an increased risk of breast cancer, nor was the initiation of oral-contraceptive use at a young age. CONCLUSIONS: Among women from 35 to 64 years of age, current or former oral-contraceptive use was not associated with a significantly increased risk of breast cancer.
PARITY	Increased risk if first child born after 30 yrs of age Increased risk in nulliparous than multiparous women
RACE	Overall incidence is lower in black women but do present with more advanced stage with increased mortality as compared to white women
AFRICAN-AMERICAN
Impact of breast carcinoma on African-American women: the Detroit experience. Newman LA, Carolin K, Simon M, Kosir M, Hyrniuk W, Demers R, Grossbart Schwartz A, Visscher D, Peters W, Bouwman D. Department of Surgery, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, Michigan 48230, USA.	Cancer 2001 May 1;91(9):1834-43 Abstract quote BACKGROUND: National and regional population-based data have demonstrated substantially worse outcome in African-American patients with breast carcinoma when compared with white patients, as well as a younger age distribution among African-American patients with breast carcinoma. The extent to which various socioeconomic, environmental, lifestyle, and genetic factors interact to account for this ethnicity-related disparity in survival is poorly understood. Greater than one-half of the inner-city population of Detroit, Michigan is African American, and greater metropolitan Detroit has been one of the contributing registries for the Surveillance, Epidemiology, and End Results (SEER) program since its inception in 1973. The impact of breast carcinoma on African Americans in the Detroit area is therefore well documented and provides significant insight into the history, epidemiology, and biology of this major public health care problem. METHODS: A review of the medical literature published over the past 20 years regarding African-American patients with breast carcinoma was performed. The pertinent findings were summarized in the context of advances made in breast carcinoma screening, treatment, and risk reduction during that period. RESULTS: The large African-American population of Detroit is a major factor contributing to the excessive breast carcinoma mortality rate reported for this city, which is one of the highest in the United States. Improvements in early detection of breast carcinoma by using screening mammography have been apparent in the earlier stage distributions of breast carcinoma observed in both white and African-American patients; however, progress has lagged substantially for the latter group. Detroit SEER registry data also have shown a younger age distribution of African-American patients with breast carcinoma and higher rates of estrogen receptor negative tumors. Finally, preliminary data from health maintenance organizations have suggested improved breast carcinoma outcome for African Americans who possess greater socioeconomic benefits, but disparities in disease stage at presentation persist. CONCLUSIONS: The diverse Detroit community is ideally suited for breast carcinoma screening programs and clinical investigations that seek to address and overcome ethnicity-related survival disparities and barriers to health care. Findings from these studies can be correlated with results from similar projects in other geographic areas.
MEXICAN
Breast carcinoma presents a decade earlier in Mexican women than in women in the United States or European countries. Rodriguez-Cuevas S, Macias CG, Franceschi D, Labastida S. Department of Surgery, Hospital de Oncologia, CMN, IMSS, Mexico City, Rebsamen 1142, col. del Valle, Mexico D.F. 03100.	Cancer 2001 Feb 15;91(4):863-8 Abstract quote BACKGROUND: In Mexico, breast carcinoma is the second most frequent malignancy, representing 10.6% of all cases and 16.4% of all cancers in women, with an increase in breast carcinoma mortality rates from 3.6 per 100,000 women in 1985 to 6 per 100,000 women in 1994. Most of the tumors are diagnosed in advanced stages with little chance of cure. METHODS: To determine the age of patients in Mexico at presentation of breast carcinoma, the authors analyzed the cases registered from 1993 to 1996 from the database of the Histopathological Registry of Malignant Neoplasms in Mexico. RESULTS: There were 29,075 cases of breast carcinoma. The median age of Mexican women with breast carcinoma is 51 years, and 45.5% of all breast carcinomas develop before patients reach age 50 years. The most frequently affected age group is that of 40-49 years (29.5%), whereas the groups from 30 to 39 and from 60 to 69 years of age have a similar percentage (14%) of frequency. This contrasts with women from the United States, as well as with women from European countries, where the median age at presentation is 63 years, and only one-fourth of the patients are younger than 50 years of age, and three-fourths are postmenopausal. Similar to Mexico, in Venezuela and in Japan nearly one-half of women with breast carcinoma are younger than 50 years of age, and this resembles rates in many Latin American countries. CONCLUSIONS: It is necessary to change the guidelines of breast carcinoma screening in Mexican women, to increase the possibility of early diagnosis and better survival.
RADIATION EXPOSURE	Risk increases with younger age of exposure and higher radiation doses Mantle radiation for Hodgkin's disease have 20-30% increased risk 10-20 yrs following radiation
SEX
Male Versus Female Breast Cancers. Muir D, Kanthan R, Kanthan SC. Departments of Pathology (Drs Muir and R. Kanthan) and Surgery (Dr S. C. Kanthan), College of Medicine, University of Saskatchewan, Saskatoon.	Arch Pathol Lab Med 2003 Jan;127(1):36-41 Abstract quote Context.-The rate of male breast cancer is a small fraction of that observed in females, thus severely limiting our understanding of the pathogenesis of this condition. It remains unclear whether the biological behavior and tumor progression associated with male breast cancer parallel that of the female form. Objectives.-To evaluate the immunohistochemical profile of male breast carcinomas and to compare this profile with that of stage-matched female breast cancers. Design.-Seventy-five cases of primary male breast cancer were identified using the records of the Saskatchewan Cancer Foundation over a period of 26 years (1970-1996). Fifty-nine of these cases had formalin-fixed, paraffin-embedded tissue blocks available for the purposes of this study. All cases were reviewed and a standardized modified Bloom-Richardson grading criterion was applied. Estrogen receptor status, progesterone receptor status, c-Erb-B2 expression, p53 expression, and Bcl-2 expression were evaluated by immunohistochemistry. Results from 240 consecutive cases of stage-matched female breast cancers analyzed in the same laboratory were used as a standard set for comparison. Results.-Male breast cancers tended to be high grade (85% grade 3) in comparison with the female breast cancers (50% grade 3). In descriptive analysis across all stages of disease, male carcinomas were more frequently estrogen receptor positive (81% vs 69%) than their female counterparts. Despite their high grade, they were less likely to overexpress p53 (9% vs 28%) and Erb-B2 (5% vs 17%) than the female counterparts. There was no significant difference in either progesterone receptor (63% vs 56%) or Bcl-2 (79% vs 76%) overexpression. Stratified analysis by stage-matched controls showed no statistically significant differences among the men and women with stage I disease. However, in stage II-matched samples, statistically significant differences were observed between the 2 groups. The male cancers were more likely to overexpress estrogen receptor (81.6% vs 64.4%, P =.04), progesterone receptor (71.1% vs 47.5%, P =.01), and Bcl-2 (78.9% vs 69.4%, P =.20). They also showed statistically significant lower expression of p53 (7.9% vs 36.3%, P =.001) and Erb-B2 (5.3% vs 23.8% P =.01). Conclusion.-Male breast cancers display distinct immunophenotypic differences from those occurring in women, implying a different pathogenesis in the evolution and progression of this disease. Such differences may play key roles in therapeutic management, warranting different treatment strategies in comparison to female breast cancers.

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
ANGIOSARCOMA
Cutaneous angiosarcoma following breast-conserving surgery and radiation: an analysis of 27 cases. Billings SD, McKenney JK, Folpe AL, Hardacre MC, Weiss SW. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA	Am J Surg Pathol. 2004 Jun;28(6):781-8. Abstract quote   Iatrogenic angiosarcomas (AS), following treatment of breast carcinomas and attributed to chronic lymphedema, were first described by Stewart and Treves. With emphasis on breast-conserving therapy combined with adjuvant radiation, a recently recognized form of cutaneous postradiation angiosarcoma of the breast (CPRASB) has emerged. To more completely characterize CPRASB, 27 cases were analyzed. Histologic features studied included pattern of growth (vasoformative, sieve-like, or solid), nuclear grade, necrosis, and mitotic rate. Clinical and follow-up information was obtained. The patients received relatively standard radiation treatment. The median interval to diagnosis of CPRASB was 59 months; 5 occurred in less than 3 years. Lymphedema was largely absent, and when present was only mild in nature. CPRASB was frequently multifocal at presentation (13 of 27). All tumors had a vasoformative pattern of growth; the majority (16 of 27) had areas with a sieve-like pattern. The solid pattern was less frequent (7 of 27). The majority had high-grade nuclear features (16 grade 3, 8 grade 2, 3 grade1). The mean mitotic rate was 9/10 HPF. Necrosis was rare (2 of 27). All were treated with wide excision or mastectomy. Follow-up was available on 22 of 27 cases (median 44 months). Fourteen experienced local recurrence and 6 had multiple recurrences. Metastasis was documented in 9 of 22 patients and involved lungs (6), contralateral breast (3), skeleton (2), lymph nodes (1), and soft tissue (1). Eight patients died of disease, 2 died with disease, 4 were alive with disease, and 8 are alive without disease. The median interval to death was 33.5 months. All 4 patients with disease have documented metastasis. CPRASB differs from Stewart-Treves AS by its shorter latency period and lack of association with lymphedema.
COWDEN'S SYNDROME
Clinical and pathological features of breast disease in Cowden's syndrome: an underrecognized syndrome with an increased risk of breast cancer. Schrager CA, Schneider D, Gruener AC, Tsou HC, Peacocke M. Department of Pathology, Tufts University School of Medicine, Boston, MA, USA.	Hum Pathol 1998 Jan;29(1):47-53 Abstract quote Cowden's syndrome (CS), or multiple hamartoma syndrome, is an autosomal dominant disorder associated with benign skin tumors and an increased risk of breast cancer. In an effort to understand the basic mechanisms regulating the development of breast cancer in this patient population, as well as to define diagnostic aspects of the disorder, we describe for the first time the clinical and pathological spectrum of breast disease in CS. We obtained the clinical histories and examined the histopathology of 59 cases from 19 women with CS sent to us from a variety of institutions. The 19 women showed a spectrum of benign histopathological findings, including ductal hyperplasia, intraductal papillomatosis, adenosis, lobular atrophy, fibroadenomas, and fibrocystic change. Seventeen (89%) showed features suggestive of a breast hamartoma. Fourteen women (74%) showed malignant disease, most of which was ductal carcinoma. Twelve patients (86%) showed ductal carcinoma in situ (DCIS), and 12 (86%) showed infiltrating ductal carcinoma. One patient had only DCIS and another patient showed both infiltrating tubular carcinoma and lobular carcinoma in situ. Ten patients (71%) actually showed foci of tumor involving densely fibrotic, hamartomatous areas. In summary, we show that women with CS have a spectrum of exuberant benign and malignant breast pathology. A common benign breast lesion in CS is a densely fibrotic hyalinized nodule, whereas the most frequent breast malignancy is ductal carcinoma.
ENDOMETRIAL CARCINOMA	Increased risk of breast cancer
GRANULAR CELL TUMOR
Colocalized granular cell tumor and infiltrating ductal carcinoma of the breast. Al-Ahmadie H, Hasselgren PO, Yassin R, Mutema G. Departments of Pathology (Drs Al-Ahmadie, Yassin, and Mutema) and Surgery (Dr Hasselgren), University of Cincinnati Medical Center, Cincinnati, Ohio.	Arch Pathol Lab Med 2002 Jun;126(6):731-3 Abstract quote A 57-year-old woman presented with a 2-year history of a palpable mass in the upper inner quadrant of the right breast. A 1.1-cm, poorly circumscribed, firm tumor nodule was noted, consisting of 2 histologically distinct lesions in the same location, with some areas showing purely well-differentiated invasive ductal carcinoma and others composed of granular cell tumor. In 1 area, the 2 tumors collided and infiltrated each other. The invasive ductal carcinoma was admixed with ductal carcinoma in situ of solid and cribriform types. To our knowledge, this is the first case report demonstrating colocalization of these 2 neoplasms, which raises questions regarding causal relationship. We also review the literature on granular cell tumor of the breast.
HODGKIN DISEASE
Breast cancer following radiotherapy and chemotherapy among young women with hodgkin disease. Travis LB, Hill DA, Dores GM, Gospodarowicz M, Van Leeuwen FE, Holowaty E, Glimelius B, Andersson M, Wiklund T, Lynch CF, Van't Veer MB, Glimelius I, Storm H, Pukkala E, Stovall M, Curtis R, Boice JD Jr, Gilbert E. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Md.	JAMA. 2003 Jul 23;290(4):465-75. Abstract quote CONTEXT: Second cancer is the leading cause of death in long-term survivors of Hodgkin disease (HD), with exceptionally high risks of breast cancer among women treated at a young age. Quantitative associations between radiotherapy dose delivered to the breast and administered chemotherapy have not been reported to date in large series, nor has the influence of ovarian exposures on subsequent risk. OBJECTIVE: To quantify the long-term risk of breast cancer associated with use of radiotherapy and chemotherapy to treat young women with HD. DESIGN, SETTING, AND SUBJECTS: Matched case-control study of breast cancer within a cohort of 3817 female 1-year survivors of HD diagnosed at age 30 years or younger, between January 1, 1965, and December 31, 1994, and within 6 population-based cancer registries. The study was conducted March 1, 1996, through September 30, 1998. MAIN OUTCOME MEASURES: Relative risk (RR) of breast cancer associated with radiation dose delivered to site of breast cancer or to ovaries and with cumulative dose of alkylating agents. RESULTS: Breast cancer occurred in 105 patients with HD who were matched to 266 patients with HD but without breast cancer. A radiation dose of 4 Gy or more delivered to the breast was associated with a 3.2-fold (95% confidence interval [CI], 1.4-8.2) increased risk, compared with the risk in patients who received lower doses and no alkylating agents. Risk increased to 8-fold (95% CI, 2.6-26.4) with a dose of more than 40 Gy (P<.001 for trend). Radiation risk did not vary appreciably by age at exposure or reproductive history. Increased risks persisted for 25 or more years following radiotherapy (RR, 2.3; 95% CI, 0.5-16.5; P =.03 for trend with dose). Treatment with alkylating agents alone resulted in a reduced risk (RR, 0.6; 95% CI, 0.2-2.0) of breast cancer, and combined alkylating agents and radiotherapy in a 1.4-fold (95% CI, 0.6-3.5) increased risk. Risk of breast cancer decreased with increasing number of alkylating agent cycles (P =.003 for trend). Risk also was low (RR, 0.4; 95% CI, 0.1-1.1) among women who received 5 Gy or more delivered to ovaries compared with those who received lower doses. CONCLUSIONS: Hormonal stimulation appears important for the development of radiation-induced breast cancer, as evidenced by the reduced risk associated with ovarian damage from alkylating agents or radiation. The high radiation-related risk, which did not diminish at the highest doses or the longest follow-up, however, suggests the need for lifetime surveillance and programs of patient and public awareness.
OVARIAN ADENOFIBROMAS
The association of benign and malignant ovarian adenofibromas with breast cancer and thyroid disorders. Silva EG, Tornos C, Malpica A, Deavers MT, Tortolero-Luna G, Gershenson DM. Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.	Int J Surg Pathol 2002 Jan;10(1):33-9 Abstract quote An unexpected association with breast cancer and thyroid disorders was found during a review of 91 cases of benign and malignant ovarian adenofibromas. Sixty-three tumors were benign, 11 had areas of borderline neoplasms, and 17 had a component of carcinoma. Such tumors were divided into glandular/cystic (61 cases) and papillary (30 cases) according to their gross and microscopic appearance. Among the 61 patients with glandular/cystic adenofibromas, 13 (21%) had breast cancer and 19 (31%) also had thyroid disorders. Among the 30 patients with papillary adenofibromas there were no cases of breast cancer and only 2 patients had thyroid disorders. The average age of the patients with ovarian adenofibroma and breast cancer or thyroid disorders was higher (66 years) than that of patients without breast cancer or thyroid disorders (55 years). More patients with breast cancer and thyroid disorders had bilateral adenofibromas than patients without breast cancer or thyroid disorders. We also reviewed the medical records of 100 patients with ovarian cancer without adenofibroma component, 100 patients with breast cancer, and 100 patients with ovarian and breast cancer. Six percent of patients with ovarian cancer had breast cancer and 16% of each one of these groups had thyroid disorders. This unexpected association found between glandular/cystic adenofibromas, breast cancer, and thyroid disorders might be explained by defects common to these organs. Disorders of some of these organs have been linked by common genetic changes and it is known that these organs are under the influence of similar hormones. Mutations of PTEN have been found in breast and thyroid cancer. The thyroid and ovaries are controlled by glycoprotein hormones of the pituitary gland, which have common alpha subunits.
PROLACTINOMA
Two case reports of breast carcinoma associated with prolactinoma. Strungs I, Gray RA, Rigby HB, Strutton G. Department of Pathology, Toowoomba Base Hospital, Qld, Australia.	Pathology 1997 Aug;29(3):320-3 Abstract quote Two cases of breast carcinoma associated with prolactinoma are presented. Literature review reveals only five previous case reports of this association. Both of our cases occurred in women, aged 55 and 34. Both were typical of the reported cases in that they had long histories of amenorrhea before diagnosis of prolactinomas and breast carcinomas. One patient had a three and a half year history of atypical ductal hyperplasia and a prominent intraduct component in the invasive tumor. Both had axillary lymph node metastases. The significance of the association of breast carcinoma with prolactinoma is discussed. Whereas studies in animals have shown prolactin to be an initiator and promoter of breast carcinoma, studies in humans have been inconclusive. Some studies have shown raised levels of prolactin in patients with breast carcinoma and their daughters, while others have not. The paucity of case reports linking breast carcinoma and prolactinoma may indicate that the association is mere coincidence, but studies evaluating the relationship between breast carcinoma and all forms of hyperprolactinemia need to be conducted before a causal link is dismissed. Prolactin may act as a cofactor with, for example, estrogen or stress, to induce breast carcinoma.
THYROID CANCER
The development of breast carcinoma in women with thyroid carcinoma. Chen AY, Levy L, Goepfert H, Brown BW, Spitz MR, Vassilopoulou-Sellin R. Department of Head and Neck Surgery, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.	Cancer 2001 Jul 15;92(2):225-31 Abstract quote BACKGROUND: Breast carcinoma and thyroid carcinoma are two malignancies that occur most commonly in women. An association between the incidence rates of thyroid and breast carcinoma in women after a diagnosis of the other malignancy has been suggested in a retrospective analysis of a single institution's tumor registry. In that study, an increased incidence of breast carcinoma in premenopausal women previously treated for thyroid carcinoma was observed. METHODS: The purpose of this study was to investigate further this relation utilizing a large database, the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database. The SEER database is maintained by the National Cancer Institute, and it represents 11 population-based cancer registries covering approximately 14% of the United States population. The study was a population-based retrospective cohort analysis using external comparisons. From 1973 to 1994, 365 women in the SEER database were identified as having both thyroid and breast carcinomas. The SEER database from 1973 to 1994 was utilized to calculate age specific and calendar year specific incidence rates for each year for thyroid and breast carcinomas. The expected number of second cancers for each age group, calendar year, and follow-up period were determined by multiplying these incidence rates by the age specific and calendar year specific number of person-years at risk. The risk ratio (RR) was calculated by dividing the observed by the expected number of second cancers. Statistical significance was determined by the Poisson test. RESULTS: A total of 1,333,115 person-years were available for analysis. One hundred thirteen thyroid carcinoma cases were diagnosed after breast carcinoma cases (RR, 0.99; P = 0.576). Two hundred fifty-two breast carcinoma cases were diagnosed after thyroid carcinoma cases (RR, 1.18; P = 0.007). Premenopausal women (age 20-49 years) with an index thyroid carcinoma have a significantly increased risk of developing subsequent breast carcinoma (RR, 1.42; P = 0.001). Black premenopausal women with an index thyroid carcinoma do not have an increased risk of developing breast carcinoma, but the statistical power is lower due to low numbers. No women with index breast carcinoma have an increased risk of developing thyroid carcinoma. CONCLUSIONS: Women with a history of thyroid carcinoma have a greater than expected risk of developing breast carcinoma. This risk is most pronounced in premenopausal white women. The implications of this observation with respect to breast carcinoma screening guidelines and thyroid carcinoma treatment guidelines deserve further investigation.

 

PATHOGENESIS	CHARACTERIZATION
ANIMAL MODEL
Histopathologic Characterization of Mammary Neoplastic Lesions Induced With 7,12 Dimethylbenz(alpha)anthracene in the Rat. Costa I, Solanas M, Escrich E. Department of Pathology, Hospital General de Granollers, Barcelona, Spain (Dr Costa); and the Department of Cell Biology, Physiology and Immunology, Medical Physiology Unit, Universitat Autonoma de Barcelona, Barcelona, Spain (Drs Costa, Solanas, and Escrich).	Arch Pathol Lab Med 2002 Aug;126(8):915-927 Abstract quote Context.-The dimethylbenz(alpha)anthracene (DMBA) breast cancer model induced in the rat is used for the study of mammary carcinogenesis because it closely mimics human breast disease. Objective.-To analyze the histopathologic features of mammary carcinomas induced in the DMBA experimental model, in a manner similar to that used in human pathology, to allow a comparative analysis between both systems. Design.-Three experimental series of 20 animals were used. At 53 days of age, a single dose of 5 mg of DMBA per rat was given. Mammary tumors were collected when the rats were killed. Several histopathologic parameters were studied. For grading, the parameters described in the modified Scarff-Bloom-Richardson scheme were used, adapted to rat mammary tumors. Results.-More than 50% of the carcinomas presented a pattern grade I, a nuclear grade I or II, and fewer than 10 mitoses/10 high-power fields (P <.05). Although the tumors were generally well differentiated, they showed a range of differentiation. More than 85% of carcinomas did not display tumoral necrosis (P <.05). This feature was observed mostly in high-grade carcinomas. There was no or scanty lymphoplasmacytic infiltration in more than 70% of carcinomas (P <.05). The degree of infiltration increased with the histologic grade. Microcalcifications were found rarely (P <.05). The carcinomas exhibited a mixed structural pattern, most with a predominant cribriform pattern (P <.05). No or light (+) stromal response was seen in most cases (P <.05). Some carcinomas, especially when poorly differentiated, presented a desmoplastic reaction. Most carcinomas presented scanty mast cell infiltration (P <.05), no features of secretion (P <.05), and absence of microcribriform pattern (P <.05). These features were seen more often in low-grade carcinomas. Conclusions.-Despite the presence of some structural differences, rat mammary adenocarcinomas and the most common human breast carcinomas share several morphologic similarities. Moreover, some features could be related to the aggressive behavior of the tumor. The analysis carried out in this study, similar to that done in human pathology, allows a more extensive understanding of mammary tumors in rats, as well as a more accurate use of this animal model, and has made it possible to develop an innovative classification of rat mammary lesions.
APOPTOSIS
Major histocompatibility complex status in breast carcinogenesis and relationship to apoptosis. Redondo M, Garcia J, Villar E, Rodrigo I, Perea-Milla E, Serrano A, Morell M. Department of Biochemistry, Hospital Costa del Sol, Marbella, Spain.	Hum Pathol. 2003 Dec;34(12):1283-9 Abstract quote.   Major histocompatibility complex (MHC) molecules are of central importance in regulating the immune response against tumors. In this study we used immunohistochemistry to study human leukocyte antigen (HLA) class I and II antigen expression in normal breast tissues and benign, preneoplastic, primary, and metastatic breast lesions using antibodies against beta-2-microglobulin (beta2-m), heavy-chain, and HLA-DR antigens. Whereas all normal tissues and benign lesions were positive for beta2-m and HLA-A, -B, and -C antigens, total loss of HLA class I antigens was found in 37% (11 of 30) of in situ carcinomas, in 43% (56 of 131) of the primary tumors, and in 70% (31 of 45) of the lymph node metastases. HLA-DR was also underexpressed in breast cancer cells; thus 20% (6 of 30) of in situ carcinomas, 15% of invasive carcinomas (20 of 131), and only 1 metastatic case were positive for this antigen. Both HLA class I and II antigen expression were more frequently down-regulated in metastatic lesions than in primary breast lesions (P <0.05), and a tendency toward a simultaneous defective expression of HLA class I and II antigens was observed in primary carcinomas (P = 0.07). However, no correlation was found between the expression of any of the aforementioned molecules and pathological parameters or survival. Interestingly, HLA class I expression was expressed more frequently in tissues with high apoptotic activity and was significantly associated with the expression of the proapoptotic bax gene (P = 0.02), and was inversely associated with expression of the antiapoptotic bcl-2 gene (P = 0.03). We conclude that alterations in HLA class I and II antigen expression are early events in breast carcinogenesis and play significant roles in metastatic progression. In addition, their expression is correlated with apoptosis-regulating proteins, which may influence the cytotoxicity of T cells against HLA class I-specific tumor antigens.
ESTROGEN RECEPTOR BETA EXPRESSION
Declining estrogen receptor-beta expression defines malignant progression of human breast neoplasia. Shaaban AM, O'Neill PA, Davies MP, Sibson R, West CR, Smith PH, Foster CS. Department of Cellular and Molecular Pathology, University of Liverpool, UK.	Am J Surg Pathol. 2003 Dec;27(12):1502-12. Abstract quote   It has been shown that the risk of breast cancer developing in certain morphologically identifiable benign breast lesions correlates with expression of estrogen receptor alpha (ER-alpha). Although ER-alpha and ER-beta genes share a large degree of homology, it is generally thought that their distribution and functions are substantially different in many tissues. Recent development of reliable antibodies to ER-beta has provided this first opportunity to test the hypothesis that the likelihood of malignant transformation in morphologically benign breast lesions can be accurately defined by the distribution and level of ER-beta expression relative to that of ER-alpha. Using a monoclonal antibody, ER-beta protein expression has been analyzed in 53 normal breasts and compared with a cohort of histologically distinct breast lesions of different prognostic risk (54 hyperplasia of usual type, 35 ductal carcinoma in situ, and 141 invasive cancers). All of these tissues were also assessed for ER-alpha. Expression of ER-beta protein was also analyzed in an additional spectrum of benign breast lesions with low or negligible risk of progression to malignancy. The median proportion of cells expressing ER-beta was highest in normal breast lobules (median 94.33%, interquartile range 78.25-99.00) but declined significantly through usual ductal hyperplasia (median 76.67, interquartile range 49.17-95.00, P = 0.002) and ductal carcinoma in situ (median 70.00, interquartile range 59.00-85.00, P = 0.009) to invasive cancer (median 60.00, interquartile range 50.00-80.00, P < 0.001). An appreciable proportion (33.81%) of ER-alpha-negative invasive cancers expressed ER-beta. A high but variable level of ER-beta expression occurred in the benign lesions. The data from the intact histologic tissues were evaluated with respect to the relative expression of ER-alpha and ER-beta in five mammary cell lines of different behavioral phenotype (MCF7, ZR-75, T47D, MDAMB231, HUMA121). The highly significant differences in expression and distinct tissue distributions of ER-alpha and ER-beta within the histologic lesions of defined risk, together with the data from the cell lines, support the original hypothesis that the tissue concentration, relative occurrence, and/or interaction of these two types of estrogen receptor may play an important role in modulating mammary tumorigenesis.
LOSS OF HETEROZYGOSITY
Loss of heterozygosity associated with uniparental disomy in breast carcinoma. Murthy SK, DiFrancesco LM, Ogilvie RT, Demetrick DJ. Departments of Pathology and Laboratory Medicine (SKM, LMD, RTO, DJD), Oncology (LMD, RTO, DJD), and Biochemistry and Molecular Biology (DJD), The University of Calgary.	Mod Pathol 2002 Dec;15(12):1241-50 Abstract quote Loss of heterozygosity is commonly assumed to be due to deletion of the appropriate genomic region in one chromosome within a neoplastic cell but may be due to other mechanisms such as mitotic non-disjunction or somatic recombination leading to uniparental heterodisomy. We chose to study the genomic regions surrounding the p53 and RB1 tumor suppressor genes in breast carcinoma to evaluate the different mechanisms that could mediate loss of heterozygosity. A microsatellite analysis of polymorphic markers in 50 breast cancer samples showed loss of heterozygosity for at least 1 of the 10 markers analyzed in 50% of the tumors studied, and an overall 8.47% of the informative loci showed loss of heterozygosity. All of the cases with loss of heterozygosity were further analyzed for gene copy number of the tumor suppressor genes RB1 and p53 by fluorescence in situ hybridization of either tumor touch preparations or microdissected tumor nuclei with specific genomic probes. Surprisingly, all samples showed the presence of both copies of tumor suppressor genes, including 4/50 cases showing loss of heterozygosity of tumor suppressor gene-spanning markers. One of the 4 cases showed loss of heterozygosity of markers spanning a distance of 6 cM over the RB1 gene, with normal copy numbers of the gene. Three other cases showed loss of heterozygosity of markers within the tumor suppressor gene (RBI or p53) and at least one other spanning marker. No cases showed a simultaneous reduction to homozygosity of markers both near the tumor suppressor gene and distal loci. We suggest that the presence of both copies of the tumor suppressor gene in the cases with loss of heterozygosity of spanning markers and internal markers for that tumor suppressor gene could be explained by somatic recombination resulting in uniparental disomy, but not mitotic nondisjunction or deletion. As the mechanism for physical deletion of a chromosome may be different from those mediating somatic recombination, study of this phenomenon may identify different pathways of genomic instability that may be of diagnostic or treatment significance in breast or other cancers, particularly in those treatments based upon DNA-altering agents.
PROGRESSION
Different proliferative activity of the glandular and myoepithelial lineages in benign proliferative and early malignant breast diseases. Bankfalvi A, Ludwig A, De-Hesselle B, Buerger H, Buchwalow IB, Boecker W. Institute of Pathology, Munster University Hospital, Munster, Germany.	Mod Pathol. 2004 Sep;17(9):1051-61. Abstract quote   The aim of the present study was to explore cell biological characteristics of normal breast, benign proliferative breast diseases and noninvasive breast malignancies based on the recently published adult progenitor cell concept from our group. Here, we investigated the proliferative activity of CK5/14(+), CK8/18/19(+) and alpha-smooth muscle actin(+) cellular phenotypes encountered in normal mammary gland, in a series of usual ductal hyperplasias and early malignant breast diseases, such as atypical ductal and lobular hyperplasias, as well as ductal and lobular in situ carcinomas. Immunohistochemical double labeling was performed on frozen sections from diagnostic breast biopsies by using antibodies to basal cytokeratins (CK5/14), glandular cytokeratins (CK8/18/19), smooth muscle actin and the Ki-67 antigen (MIB1). Normal breast tissues and usual ductal hyperplasias were characterized by a heterogeneous cellular composition of the growth fraction. The proliferative cell compartment consisted of CK8/18/19(+) glandular and, in a variable proportion, CK5/14(+) progenitor phenotypes. In contrast, noninvasive breast malignancies were composed of a monotonous proliferation of CK 8/18/19(+) neoplastic glandular cells. These findings indicate a significant role of progenitor cells in the development of benign proliferative breast diseases and lend support to the view that malignant transformation in the human breast usually occurs in a cell committed to the glandular lineage. Our results provide cell kinetic support to the functional progenitor cell hypothesis, and we propose this concept as an operative model for understanding benign proliferative and malignant breast diseases.
Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer. Kuukasjarvi T, Karhu R, Tanner M, Kahkonen M, Schaffer A, Nupponen N, Pennanen S, Kallioniemi A, Kallioniemi OP, Isola J. Department of Pathology, Tampere University Hospital, University of Tampere, Finland.	Cancer Res 1997 Apr 15;57(8):1597-604 Abstract quote To understand the genetic basis and clonal evolution underlying metastatic progression of human breast cancer in vivo, we analyzed the genetic composition of 29 primary breast carcinomas and their paired asynchronous metastases by comparative genomic hybridization and fluorescence in situ hybridization. The mean number of genetic changes by comparative genomic hybridization was 8.7 +/- 5.3 in primary tumors and 9.0 +/- 5.7 in their metastases. Although most of the genetic changes occurred equally often in the two groups, gains of the Xq12-q22 region were enriched in the metastases. According to a statistical analysis of shared genetic changes and breakpoints in paired specimens, 20 of the metastases (69%) showed a high degree of clonal relationship with the corresponding primary tumor, whereas the genetic composition of 9 metastases (31%) differed almost completely from that of the paired primary tumors. In both groups, however, chromosome X inactivation patterns suggested that the metastatic lesions originated from the same clone as the primary tumor. Fluorescence in situ hybridization analysis with probes specific to metastatic clones usually failed to find such cells in the primary tumor sample. In conclusion, detailed characterization of the in vivo progression pathways of metastatic breast cancer indicates that a linear progression model is unlikely to account for the progression of primary tumors to metastases. An early stem line clone apparently evolves independently in the primary tumor and its metastasis, eventually leading to multiple, genetically almost completely different, clones in the various tumor locations in a given patient. The resulting heterogeneity of metastatic breast cancer may underlie its poor responsiveness to therapy and explain why biomarkers of prognosis or therapy responsiveness measured exclusively from primary tumors give a restricted view of the biological properties of metastatic breast cancer.
	Am J Clin Pathol 2001;115:362-369 A linear stepwise progression of breast tumorigenesis has been postulated, from usual ductal hyperplasia through atypical hyperplasia, ductal carcinoma in situ (DCIS), and invasive carcinoma Likely that at least 2 pathways for the development of invasive breast carcinoma exist Low-grade invasive carcinoma may arise from low-grade DCIS, which in turn is related closely to atypical ductal hyperplasia (ADH) Or, high-grade invasive carcinoma may arise from high-grade DCIS, but the immediate precursor of high-grade DCIS is not clear
Quantitative Study of Breast Cancer Progression: Different Pathways for Various In Situ Cancers L. Mariuzzi, M.D., A. Mombello, M.D., G. Granchelli, M.D., V. Rucco, M.D., E. Tarocco, M.D., D. Frank, Ph.D., J. Davis, M.D., D. Thompson, M.Sc., H. Bartels, M.SIE., G. M. Mariuzzi, M.D. and P. H. Bartels, Ph.D., F.I.A.C.(Hon), M.D. (Hon) Departments of Pathology of the University of Udine (LM) and the University of Verona (AM, GG, VR, ET, GMM), Verona, Italy; and Department of Pathology (JD), Arizona Cancer Center (DF), and Optical Sciences Center (DT, HB, PHB), University of Arizona, Tucson, Arizona	Mod Pathol 2002;15:18-25 Abstract quote The chromatin pattern in nuclei from breast ductal proliferative lesions was quantitatively evaluated with the objective of deriving measures of tumor progression. A total of 110 cases were analyzed. There were 38 cases of normal tissue or benign proliferative lesions, 41 cases of ductal carcinoma in situ (DCIS), and 31 cases of microinfiltrating DCIS and of infiltrating cancer. A total of 9424 nuclei were analyzed. High-resolution images were digitally recorded. For each nucleus, 93 karyometric features descriptive of the spatial and statistical distribution of the nuclear chromatin were computed. Data analysis included establishing a profile of relative deviations of each feature from "normal," called the nuclear signature, and of lesion signatures as well as of trends of lesion progression. Two trends of evolution could be discerned: one from normal to hyperplasia, atypical hyperplasia, and comedo DCIS as representative of high-grade lesions; and the other from normal to hyperplasia to cribriform DCIS, solid DCIS, and infiltrating cancer, representing lower grade lesions. The nuclei in microinfiltrating foci are distinctly different from nuclei in high-grade comedo DCIS. The nuclei in microinfiltrating foci have a statistically significantly lower nuclear abnormality. They may represent outgrowing clones.
ONCOGENES
ras oncogene	Mutations present in 10-30%
Her2-neu
BRCA1 and BRCA2
c-myc	Ampflication of 17% of cancers Altered expression had significantly shorter disease free survival
Immunohistochemical Expression of Human Erythrocyte Glucose Transporter and Fatty Acid Synthase in Infiltrating Breast Carcinomas and Adjacent Typical/Atypical Hyperplastic or Normal Breast Tissue Piero L. Alò, MD, Paolo Visca, MD, Claudio Botti, MD, Gregorio M. Galati, MD, Valeria Sebastiani, MD, Tiziana Andreano, MD, Ugo Di Tondo, MD, and Ellen S. Pizer, MD, PhD	Am J Clin Pathol 2001;116:129-134 Abstract quote To evaluate the immunohistochemical expression of GLUT1, human erythrocyte glucose transporter 1, and fatty acid synthase (FAS), 66 human breast carcinomas and adjacent peritumoral tissue were studied. GLUT1 and FAS were expressed in 53 and 61 carcinomas, in 17 and 14 typical/atypical hyperplastic tissues, and in 16 and 13 tissues adjacent to tumor normal breast tissue, respectively. Statistical analysis revealed association between invasive carcinomas, invasive carcinomas with in situ component and GLUT1 immunostaining. GLUT1 staining was associated with tumor grade, FAS with tumor stage, and GLUT1 and FAS coexpression with tumor grade. Controls expressed no immunostaining. GLUT1 and FAS are new markers involved in the biologic activities of cancer cells. GLUT1 and FAS coexpression may indicate increased use of energy by the neoplastic cells correlated with poorly differentiated features and aggressive behavior. The innovative finding that GLUT1 and FAS are observed in mammary carcinoma adjacent nonneoplastic tissues may suggest a role in detecting initial phases of breast carcinogenesis.
Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study. Antoniou AC, Pharoah PD, McMullan G, Day NE, Ponder BA, Easton D. CRC Genetic Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.	Genet Epidemiol 2001 Jul;21(1):1-18 Abstract quote We used data from a population based series of breast cancer patients to investigate the genetic models that can best explain familial breast cancer not due to the BRCA1 and BRCA2 genes. The data set consisted of 1,484 women diagnosed with breast cancer under age 55 registered in the East Anglia Cancer registry between 1991-1996. Blood samples taken from the patients were analysed for mutations in BRCA1 and BRCA2. The genetic models were constructed using information on breast and ovarian cancer history in first-degree relatives and on the mutation status of the index patients. We estimated the simultaneous effects of BRCA1, BRCA2, a third hypothetical gene BRCA3, and a polygenic effect. The models were assessed by likelihood comparisons and by comparison of the observed numbers of mutations and affected relatives with the predicted numbers. BRCA1 and BRCA2 could not explain all the familial clustering of breast cancer. The best-fitting single gene model for BRCA3 was a recessive model with a disease allele frequency 24% and penetrance 42% by age 70. However, a polygenic model gave a similarly good fit. The estimated population frequencies for BRCA1 and BRCA2 mutations were similar under both recessive and polygenic models, 0.024 and 0.041%, respectively. A dominant model for BRCA3 gave a somewhat worse fit, although the difference was not significant. The mixed recessive model was identical to the recessive model and the mixed dominant very similar to the polygenic model. The BRCA3 genetic models were robust to the BRCA1 and BRCA2 penetrance assumptions. The overall fit of all models was improved when the known effects of parity on breast and ovarian cancer risks were included in the model-in this case a polygenic model fits best. These findings suggest that a number of common, low-penetrance genes with additive effects may account for the residual non-BRCA1/2 familial aggregation of breast cancer, but Mendelian inheritance of an autosomal recessive allele cannot be ruled out.
PTEN
Reduced expression of PTEN correlates with breast cancer progression. Bose S, Crane A, Hibshoosh H, Mansukhani M, Sandweis L, Parsons R. Department of Pathology, University of California, Los Angeles, California 90048, USA.	Hum Pathol 2002 Apr;33(4):405-9 Abstract quote PTEN is a tumor-suppressor gene with phosphatase activity that is mutated in a variety of cancers. We analyzed a series of 34 invasive and 18 in situ breast cancers with known molecular status of the PTEN genotype using immunohistochemistry. Reduced PTEN protein expression was seen in 38% of invasive cancers and in 11% of in situ cancers. The frequency of reduced expression was highest in stage II and III cancers. Reduced expression also correlated with aneuploidy. In addition, in tumors with both in situ and invasive components, expression within the ductal carcinoma in situ portion tended to reflect the expression pattern of the invasive component. These data suggest that PTEN expression is frequently reduced in advanced breast cancers.

 

LABORATORY/ RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
SCREENING MAMMOGRAPHY	Yearly screening for women over 40 years of age
Influence of annual mammography from age 40 on breast cancer pathology. Anderson TJ, Waller M, Ellis IO, Bobrow L, Moss S.	Hum Pathol. 2004 Oct;35(10):1252-9 Abstract quote.   The objective of this study was to determine the influence of annual mammography on pathology features of breast cancers in an invited population. We conducted a randomized trial of 53,890 invited and 106,971 control United Kingdom women who were recruited only from those aged 40 years, with central review of cancer histology. We compare the invasive cancer distribution for the categories of size, histological type, grade, and node status in subgroups of the invited population with that of controls. Among 1287 cancers identified in the total population through the end of December 1999, there are major differences among prevalence, incidence, interval, and lapsed-attender and nonattender subgroups for the distribution of cancer numbers in categories of chosen qualitative histological features. These reflect the biases known to affect a population exposed to screening. Comparing cancers from the unbiased group of the invited population with controls shows significant differences in distributions for size, grade, and node status but not histological type. Multivariate logistic regression shows significant reduction (odds ratio, 0.73; P = 0.043) in node-positive status for the unbiased group. We conclude that annual mammography from age 40 years significantly reduces size and positive-node status of invasive cancers in the invited population. The potential for phenotypic drift of grade emphasizes the relevance of screen detection of all grades at sizes smaller than 10 mm.
Breast cancers in women 35 years of age and younger: mammographic findings. Shaw de Paredes E, Marsteller LP, Eden BV. Department of Radiology, University of Virginia Health Sciences Center, Charlottesville 22908.	Radiology 1990 Oct;177(1):117-9 Abstract quote During an 8-year period, 74 breast cancers were diagnosed in 66 patients 35 years of age and younger who underwent preoperative mammography. Mammograms and clinical data in these women were reviewed retrospectively to evaluate the mammographic findings and the efficacy of mammography. In 58 cases the cancer was detected by means of both clinical examination and mammography; in eight cases, mammography alone enabled readers to find the lesion; in seven cases, the lesion was found by means of clinical examination, but mammograms were negative; and in one case a cancer was found by means of incidental biopsy of the contralateral breast. Although 34 patients (52%) had dense breasts, mammography demonstrated the lesion in 66 cases (89%); the most common mammographic finding was microcalcifications, with or without associated masses (n = 28 [38%]). The authors do not suggest that screening of women younger than 35 years be performed routinely, but they believe that mammography can be valuable in screening young women at high risk for breast cancer or in confirming and suggesting prompt biopsy of a suspicious lesion.
Relationship between mammographic and histological risk factors for breast cancer. Boyd NF, Jensen HM, Cooke G, Han HL. Division of Epidemiology and Statistics, Ontario Cancer Institute, Canada.	J Natl Cancer Inst 1992 Aug 5;84(15):1170-9 Abstract quote BACKGROUND: Information on breast cancer risk can be obtained both from the histological appearance of the breast epithelium in biopsy specimens and from the pattern of parenchymal densities in the breast revealed by mammography. It is not understood, however, how parenchymal densities influence breast cancer risk or whether these densities are associated with histological risk factors. PURPOSE: We have estimated, in a large cohort of women, the relative risk of detecting carcinoma in situ, atypical hyperplasia, hyperplasia without atypia, or nonproliferative disease in biopsy specimens from women with different extents of mammographic density. We also examined the association between these histological classifications and radiological features present specifically at the biopsy site. METHODS: The source of study material was a population of women aged 40-49 years who were enrolled in the Canadian National Breast Screening Study (NBSS). Mammograms from women who had undergone a biopsy (n = 441) and from a comparison group of women (n = 501) randomly selected from the mammography arm of the NBSS were classified according to the extent of mammographic density. The corresponding histological slides were independently classified by a review pathologist. RESULTS: Compared with women showing no mammographic densities, women with the most extensive densities (i.e., occupying greater than 75% of the breast volume) had a 9.7 times greater risk of developing carcinoma in situ or atypical hyperplasia (95% confidence interval [CI] = 1.75-53.97), a 12.2 times greater risk of developing hyperplasia without atypia (95% CI = 2.97-50.14), and a 3.1 times greater risk of developing non-proliferative disease (95% CI = 1.20-8.11). The gradients in risk were not monotonic across the five classifications of mammographic density. The association could not be explained by the presence of mammographic densities at the biopsy site, but calcification at the biopsy site was strongly associated with high-risk histological changes (relative risk = 24; 95% CI = 5.0-156.0). CONCLUSIONS: These results suggest that the radiological patterns referred to as mammographic dysplasia may influence breast cancer risk by virtue of their association with high-risk histological changes in the breast epithelium. IMPLICATIONS: Identification of the factors responsible for high-risk histological changes may offer new insights into the etiology of breast cancer and potentially lead to the development of methods for its prevention.
National Institutes of Health Consensus Development Conference Statement: Breast Cancer Screening for Women Ages 40-49, January 21-23, 1997. National Institutes of Health Consensus Development Panel.	J Natl Cancer Inst 1997 Jul 16;89(14):1015-26 Abstract quote OBJECTIVE: To provide health care providers, patients, and the general public with a responsible assessment of currently available data regarding the effectiveness of mammography screening for women ages 40-49. PARTICIPANTS: A non-Federal, nonadvocate, 12-member panel representing the fields of oncology, radiology, obstetrics and gynecology, geriatrics, public health, and epidemiology and including patient representatives. In addition, 32 experts in oncology, surgical oncology, radiology, public health, and epidemiology, presented data to the panel and to a conference audience of 1,100. EVIDENCE: The literature was searched through Medline and an extensive bibliography of references was provided to the panel and the conference audience. Experts prepared abstracts with relevant citations from the literature. Scientific evidence was given precedence over clinical anecdotal experience. CONSENSUS PROCESS: The panel, answering predefined questions, developed its conclusions based on the scientific evidence presented in open forum and the scientific literature. The panel composed a draft statement that was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised draft statement at the end of the conference. The final statement with a minority report was completed within several weeks after the conference. CONCLUSIONS: The Panel concludes that the data currently available do not warrant a universal recommendation for mammography for all women in their forties. Each woman should decide for herself whether to undergo mammography. Her decision may be based not only on an objective analysis of the scientific evidence and consideration of her individual medical history, but also on how she perceives and weighs each potential risk and benefit, the values she places on each, and how she deals with uncertainty. However, it is not sufficient just to advise a woman to make her own decision about mammograms. Given both the importance and the complexity of the issues involved in assessing the evidence, a woman should have access to the best possible relevant information regarding both benefits and risks, presented in an understandable and usable form. Information should be developed for women in their forties regarding potential benefits and risks to be provided to enable each woman to make the most appropriate decision. In addition, educational material to accompany this information should be prepared that will lead women step by step through the process of using such information in the best possible way for reaching a decision. For women in their forties who choose to have mammography performed, the costs of the mammograms should be reimbursed by third-party payors or covered by health maintenance organizations so that financial impediments will not influence a woman's decision. Additionally, a woman's health care provider must be equipped with sufficient information to facilitate her decisionmaking process. Therefore, educational material for physicians should be developed to assist them in providing the guidance and support needed by the women in their care who are making difficult decisions regarding mammography. The two panel members writing a minority report believed the risks of mammography to be overemphasized by the majority and concluded that the data did support a recommendation for mammography screening for all women in this age group and that the survival benefit and diagnosis at an earlier stage outweigh the potential risks.
Women with breast cancer: histologic findings in the contralateral breast. Roubidoux MA, Helvie MA, Wilson TE, Lai NE, Paramagul C. Department of Radiology, University of Michigan Medical Center, Ann Arbor 48109-0326, USA.	Radiology 1997 Jun;203(3):691-4 Abstract quote PURPOSE: To investigate contralateral breast biopsy histologic findings in women with breast cancer. MATERIALS AND METHODS: Histologic findings in 237 patients with breast cancer who underwent contralateral breast biopsy for clinically or mammographically detected abnormalities were retrospectively reviewed. Malignant findings were categorized by histologic type. Benign findings were categorized by risk of breast cancer. Comparison was made with mammographically guided breast biopsy results in 1,294 patients without breast cancer. RESULTS: Of the 237 patients, 168 (70.9%) had either malignancy or high-risk histologic findings. One hundred thirty-nine patients (58.6%) had malignant findings; 98 (41.4%) had benign findings. Of the 98 with benign findings, 29 (30%) had high-risk histologic findings. Thirty (33%) of the 91 patients with invasive cancer had invasive lobular carcinoma. Forty-seven (45.6%) of the 103 patients with malignant lesions at mammographically guided biopsies had ductal carcinoma in situ alone. CONCLUSION: Compared with biopsy in women without breast cancer, contralateral biopsy in women with breast cancer was more likely to show malignancy, invasive lobular carcinoma, or ductal carcinoma in situ alone (P < .001) or to show high-risk histologic benign findings (P < .001). Mammographic and clinical findings in the contralateral breast should be regarded as more suspicious than those in patients without known breast cancer.
BREAST DUCTAL LAVAGE
Assessment of utility of ductal lavage and ductoscopy in breast cancer-a retrospective analysis of mastectomy specimens. Badve S, Wiley E, Rodriguez N. Northwestern University Medical School, Chicago, Illinois (SB, EW, NR) and Indiana University School of Medicine, Indianapolis, Indiana (SB).	Mod Pathol 2003 Mar;16(3):206-9 Abstract quote Early detection of breast lesions continues to be an important goal in the management of breast cancer. At present, mammographic imaging in addition to physical examination is the main screening method for the detection of cancer. Fiberoptic ductoscopy and duct lavage are being recently used to evaluate patients at risk for breast cancer. Both techniques examine the nipple and central duct area to identify intraductal lesions. In this study, we examined the frequency of involvement of these structures in mastectomy specimens as a surrogate marker to estimate the utility of these methods in breast cancer patients. The presence and type of involvement of the nipple and central duct area was retrospectively evaluated in 801 mastectomy specimens from a 4-year period that had been performed for infiltrating or in situ carcinoma. Atypical proliferation or cells, when seen in the ducts of this region, was considered as evidence of nipple involvement, even if definite evidence of malignancy was lacking. The review of 801 mastectomies showed nipple and central duct involvement in 179 (22%) cases. Among the 665 cases of infiltrating carcinoma, 17% did not have an intraductal component. The relative rarity of nipple and central duct in mastectomy specimens and the lack of an in situ component in many cases raise questions about the utility of fiberoptic ductoscopy and duct lavage as methods for screening of breast cancer. Additionally, as these methods examine only 1-2 ducts of the 15-20 ducts that open at the nipple, they might fail to detect focal abnormalities.
Cellular characteristics of nipple aspiration fluid during the menstrual cycle in healthy premenopausal women. Mitchell G, Trott PA, Morris L, Coleman N, Sauter E, Eeles RA. Section of Cancer Genetics, Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK.	Cytopathology 2001 Jun;12(3):184-96 Abstract quote Cellular characteristics of nipple aspiration fluid during the menstrual cycle in healthy premenopausal women. Fifteen healthy premenopausal female volunteers underwent weekly nipple aspiration of ductal fluid from both breasts during two menstrual cycles to investigate the variability of the cellular profile of the ductal fluid. Ductal fluid was successfully obtained using breast massage and nipple-areolar suction from 247/280 (89%) breasts. 83% of samples available for cytological analysis were cellular and 30% of cellular aspirates contained ductal epithelial cells identified using standard morphological criteria. No significant variation in cell number or cell type was identified during the menstrual cycle. All samples tested had an 'H' score of zero for oestrogen receptor. Seven out of 14 women expressed the proliferation marker Mcm-2 in the cells of at least one of the specimens, with no evidence of a menstrual cycle influence on expression. In conclusion, the cellular profile of breast ductal fluid did not vary consistently during the menstrual cycle, permitting future breast cancer screening studies incorporating serial nipple aspirations to be performed independent of the phase of the cycle.
Breast cancer risk in women with abnormal cytology in nipple aspirates of breast fluid. Wrensch MR, Petrakis NL, Miike R, King EB, Chew K, Neuhaus J, Lee MM, Rhys M. Dept. of Epidemiology and Biostatistics, School of Medicine, Box 1215, University of California San Francisco, San Francisco, CA 94143, USA.	J Natl Cancer Inst 2001 Dec 5;93(23):1791-8 Abstract quote BACKGROUND: We previously showed that women with abnormal cytology in breast fluid obtained by nipple aspiration had an increased relative risk (RR) of breast cancer compared with women from whom fluid was not obtained and with women whose fluid had normal cytology. This study extends the follow-up in the original study group (n = 4046) and presents the first follow-up for a second group of women (n = 3627). METHODS: We collected nipple aspirate fluid from women in the San Francisco Bay Area during the period from 1972 through 1991, classified the women according to the most severe epithelial cytology observed in fluid specimens, and determined breast cancer incidence through March 1999. We estimated RRs for breast cancer using Cox regressions, adjusting for age and year of study entry. All statistical tests were two-sided. RESULTS: For women in the first and second study groups, the median years of follow-up were 21 years and 9 years, respectively, and breast cancer incidences were 7.8% (285 cases in the 3633 women for whom breast cancer status could be determined) and 3.5% (115 of 3271), respectively. Compared with women from whom no fluid was obtained, whose incidences of breast cancer were 4.7% (39 of 825) and 3.3% (65 of 1950) for those in group 1 and group 2, respectively, incidences and adjusted RRs were 8.1% (34 of 422), with RR = 1.4 (95% confidence interval [CI] = 0.9 to 2.3), and 0% (0 of 31), respectively, for those with unsatisfactory aspirate specimens and 8.2% (148 of 1816), with RR = 1.6 (95% CI = 1.1 to 2.3), and 3.1% (25 of 811), with RR = 1.2 (95% CI = 0.8 to 2.0), respectively, for those with normal cytology in aspirates. Compared with women from whom no fluid was obtained, incidences and adjusted RRs for women in group 1 with epithelial hyperplasia and atypical hyperplasia in aspirates were 10.8% (52 of 483), with RR = 2.4 (95% CI = 1.6 to 3.7), and 13.8% (12 of 87), with RR = 2.8 (95% CI = 1.5 to 5.5), respectively, while those for women in group 2 were 5.5% (25 of 457) and 0% (0 of 22), respectively, with a combined RR = 2.0 (95% CI = 1.3 to 3.3). CONCLUSION: The results obtained with the newly followed women independently confirmed previous findings that women with abnormal cytology in nipple aspirates of breast fluid have an increased risk of breast cancer.
Ductal lavage for detection of cellular atypia in women at high risk for breast cancer. Dooley WC, Ljung BM, Veronesi U, Cazzaniga M, Elledge RM, O'Shaughnessy JA, Kuerer HM, Hung DT, Khan SA, Phillips RF, Ganz PA, Euhus DM, Esserman LJ, Haffty BG, King BL, Kelley MC, Anderson MM, Schmit PJ, Clark RR, Kass FC, Anderson BO, Troyan SL, Arias RD, Quiring JN, Love SM, Page DL, King EB. Institute for Breast Health, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, USA.	J Natl Cancer Inst 2001 Nov 7;93(21):1624-32 Abstract quote BACKGROUND: Breast cancer originates in breast epithelium and is associated with progressive molecular and morphologic changes. Women with atypical breast ductal epithelial cells have an increased relative risk of breast cancer. In this study, ductal lavage, a new procedure for collecting ductal cells with a microcatheter, was compared with nipple aspiration with regard to safety, tolerability, and the ability to detect abnormal breast epithelial cells. METHODS: Women at high risk for breast cancer who had nonsuspicious mammograms and clinical breast examinations underwent nipple aspiration followed by lavage of fluid-yielding ducts. All statistical tests were two-sided. RESULTS: The 507 women enrolled included 291 (57%) with a history of breast cancer and 199 (39%) with a 5-year Gail risk for breast cancer of 1.7% or more. Nipple aspirate fluid (NAF) samples were evaluated cytologically for 417 women, and ductal lavage samples were evaluated for 383 women. Adequate samples for diagnosis were collected from 111 (27%) and 299 (78%) women, respectively. A median of 13,500 epithelial cells per duct (range, 43-492,000 cells) was collected by ductal lavage compared with a median of 120 epithelial cells per breast (range, 10-74,300) collected by nipple aspiration. For ductal lavage, 92 (24%) subjects had abnormal cells that were mildly (17%) or markedly (6%) atypical or malignant (<1%). For NAF, corresponding percentages were 6%, 3%, and fewer than 1%. Ductal lavage detected abnormal intraductal breast cells 3.2 times more often than nipple aspiration (79 versus 25 breasts; McNemar's test, P<.001). No serious procedure-related adverse events were reported. CONCLUSIONS: Large numbers of ductal cells can be collected by ductal lavage to detect atypical cellular changes within the breast. Ductal lavage is a safe and well-tolerated procedure and is a more sensitive method of detecting cellular atypia than nipple aspiration.
IMAGE GUIDED BIOPSIES
Diagnostic Agreement in the Evaluation of Image-guided Breast Core Needle Biopsies: Results from a Randomized Clinical Trial. Collins LC, Connolly JL, Page DL, Goulart RA, Pisano ED, Fajardo LL, Berg WA, Caudry DJ, McNeil BJ, Schnitt SJ. Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; dagger Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee; double dagger Department of Radiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina; section sign Department of Radiology, University of Virginia Health Sciences Center, Charlottesville, Virginia; paragraph sign Department of Radiology, University of Maryland School of Medicine, Baltimore, Maryland; and Department of Health Care Policy, Harvard Medical School, and Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts.	Am J Surg Pathol. 2004 Jan; 28(1): 126-131. Abstract quote   SUMMARY: BACKGROUND Image-guided core needle biopsies (CNBs) are commonly used as the initial sampling method for nonpalpable, mammographically detected breast lesions. Although prior studies have shown that this procedure is a highly sensitive and accurate method for the detection of breast cancer, the level of diagnostic agreement between pathologists in the analysis of CNB has not been previously studied in detail.METHODS To address this, we reviewed the pathologic findings in 2004 CNB from patients enrolled in the Radiologic Diagnostic Oncology Group 5 study, a randomized, multicenter trial designed to determine the role of CNB and fine needle aspiration biopsy in the evaluation of nonpalpable breast lesions. Slides of CNB specimens were initially diagnosed by pathologists at the 22 participating institutions (local diagnosis) and were then sent to the study pathologists for central review (central diagnosis). Local and central diagnoses were compared.RESULTS Overall, the central diagnosis and local diagnosis were concordant in 1925 cases (96%), indicating an excellent level of agreement by kappa statistic analysis (kappa = 0.90; 95% confidence interval 0.88-0.92). The level of agreement between local and central pathologists did not vary with the image guidance system (stereotactic mammography vs. ultrasound) or with the mammographic findings (soft tissue density vs. microcalcifications). The level of diagnostic agreement observed for CNB was comparable to that observed among 596 open surgical biopsies obtained from patients in this study and subjected to central pathology review (93% agreement; kappa = 0.89, 95% confidence interval 0.86-0.92). CONCLUSIONS The level of diagnostic agreement in interpretation of breast CNB is extremely high among pathologists and is comparable to that seen for open surgical biopsy.
MRI
Human breast lesions: characterization with contrast-enhanced in vivo proton MR spectroscopy--initial results. Yeung DK, Cheung HS, Tse GM. Department of Clinical Oncology, Medical Physics Division, Prince of Wales Hospital, 30-32 Ngan Shing St, Shatin, Hong Kong, China.	Radiology 2001 Jul;220(1):40-6 Abstract quote PURPOSE: To assess the clinical usefulness of localized proton (hydrogen 1) magnetic resonance (MR) spectroscopy in the characterization of contrast material-enhanced breast lesions on the basis of choline detection. MATERIALS AND METHODS: Examinations were performed at 1.5 T with use of a standard breast coil. Contrast-enhanced MR imaging was performed in 30 consecutive patients (mean age, 50 years; age range, 20--80 years) who had nonspecific lesions (>1.5 cm in diameter) on sonograms or mammograms. Single-voxel (1)H MR spectroscopy was performed in the enhancing lesions by using a point-resolved spectroscopic sequence with echo times of 38, 135, and 270 msec. MR spectroscopic and histopathologic findings were determined in blinded fashion and compared. RESULTS: Twenty-four patients had carcinoma of the breast (tumor size, 2.0--11.2 cm; mean, 4.7 cm), and six had benign lesions (lesion size, 1.8--3.8 cm; mean, 2.7 cm). Choline was detected in 22 patients with carcinoma. Choline was not detected in five patients with benign lesions and in two patients with carcinoma. The preliminary results indicate that this technique had a sensitivity of 92%, specificity of 83%, and accuracy of 90%. CONCLUSION: Choline can be reliably detected in less than 45 minutes in large contrast-enhanced breast lesions by using a multiecho point-resolved spectroscopic protocol. The presence of water-soluble choline metabolites obtainable with (1)H MR spectroscopy could complement MR imaging findings to improve specificity and to reduce the number of unnecessary biopsies.
Occult Contralateral Breast Carcinoma Incidentally Detected by Breast Magnetic Resonance Imaging Priscilla J. Slanetz, MD, MPH,* Whitney B. Edmister, AB, Eren D. Yeh, MD, Anjali C. Talele, AB, and Daniel B. Kopans, MD	Breast J 2002;8:145 Abstract quote The incidence of synchronous bilateral breast cancers has been reported to be between 3.4 and 7.4, as detected on mammography, physical examination, or both. We undertook a study to determine how often magnetic resonance (MR) imaging detects a contralateral abnormality in patients with known breast carcinoma. As part of an institutional review board (IRB) -approved research protocol, 17 patients with pathologically proven invasive carcinoma underwent preoperative MR imaging of both breasts using a T1-weighted, high-resolution gradient echo sequence (precontrast and postcontrast), an echo-planar sequence during administration of gadolinium, and a T2-weighted, fast-spin echo sequence. The morphology and dynamic enhancement of lesions in both breasts were assessed. Biopsy was recommended for any lesion meeting set criteria. MR imaging identified all 17 known invasive cancers in the breast of concern on mammography or physical examination. Five of 17 patients (29) had 10 contralateral lesions identified on MR, for which biopsy was recommended. One of these lesions proved to represent a fibroadenoma. The other 9 lesions proved to represent a malignancy (6 invasive lobular, 2 infiltrating ductal, and 1 tubular). Four of the 17 patients (24) with invasive cancer had contralateral synchronous cancers occult to physical examination, mammography, and ultrasonography. In this series, breast MR imaging of the breasts was more sensitive than mammography or physical examination in the detection of early breast cancer. Breast MR imaging of the contralateral breast may be of value as a routine screen in those patients with a known or suspected malignancy.
Ultrasound or CT scan	Ultrasound may identify solid versus cystic lesions
Occult cancer in women with dense breasts: detection with screening US--diagnostic yield and tumor characteristics. Kolb TM, Lichy J, Newhouse JH. Department of Radiology, Columbia_Presbyterian Medical Center, College of Physicians and Surgeons Columbia University, New York, NY, USA	Radiology 1998 Apr;207(1):191-9 Abstract quote PURPOSE: To evaluate bilateral screening ultrasound (US) in the detection of otherwise occult masses and cancer in women with dense breasts and normal mammographic and physical examination findings. MATERIALS AND METHODS: Of 11,220 consecutive patients prospectively examined, all 3,626 women with dense breasts and normal mammographic and physical examination findings underwent physician-performed screening US. The size and stage of cancers detected with US alone were compared with those of cancers detected on mammograms, at physical examination, or both, in the remainder of the patients. RESULTS: In the group of 3,626 women, 11 surgically proved cancers in 11 women (prevalence, 0.30%) were identified with US alone. These cancers were not statistically significantly different in mean surgical size and stage from those of 61 nonpalpable, mammographically detected cancers and were smaller and lower in stage than 64 palpable cancers (P < .01) that were diagnosed in the remainder of the population. In the women with dense breasts, overall cancer detection increased by 17% (from 63 to 74 tumors), and the number of tumors detected only with imaging increased by 37% (from 30 to 41 tumors). CONCLUSION: Screening US can depict small, early-stage, otherwise occult cancers similar in size and stage to mammographically identified nonpalpable cancers and smaller and lower in stage than palpable cancers in dense breasts.
Palpable breast thickening: role of mammography and US in cancer detection. Kaiser JS, Helvie MA, Blacklaw RL, Roubidoux MA. Department of Radiology, University of Michigan Health Systems, 1500 E Medical Center Dr, Taubman Center 2910N, Ann Arbor, MI 48109-0326, USA.	Radiology 2002 Jun;223(3):839-44 Abstract quote PURPOSE: To determine the frequency of breast carcinoma and ascertain the diagnostic yield of mammography and breast ultrasonography (US) in the detection of breast carcinoma in women with palpable breast thickening. MATERIALS AND METHODS: One hundred twenty-three consecutive cases of breast thickening (103 patients) during a 1-year period were reviewed. Experienced breast examiners prospectively identified patients with breast thickening. Results of diagnostic mammographic work-up, breast US, breast biopsy, and clinical follow-up were retrospectively reviewed. RESULTS: Six (5%) of 123 cases had a diagnosis of breast carcinoma; five (83%) of the six had invasive carcinoma. Mammography was performed in all cases, US in 77 (63%) cases. Mammographic sensitivity for invasive cancer detection was 60% (three of five cases), specificity was 94% (102 of 108 cases), and negative predictive value was 97% (102 of 105 cases). Sensitivity of US alone was 100% (two of two cases), specificity was 96% (65 of 68 cases), and negative predictive value was 100% (65 of 65 cases). The combined negative predictive value of mammography and US was 100%. Patients with prior biopsies at the site of palpable thickening accounted for most false-negative mammograms. Median time to initiate follow-up of patients in whom biopsy was not performed was 14 months. CONCLUSION: Breast cancer was discovered in 5% of women with palpable breast thickening. Women with negative mammograms and US scans are at low risk for cancer but should, in our opinion, be followed up at short-term intervals with clinical examination and imaging if biopsy is not elected by their surgeon or clinician.
Flow cytometry	Diploid tumors with a high S phase fraction (SPF) have a significantly reduced disease-free survival rate when compared to diploid tumors with a low SPF
Evaluation of Multiparameter Flow Cytometry for the Detection of Breast Cancer Tumor Cells in Blood Samples Ignacio Cruz, MD, etal.	Am J Clin Pathol 2005;123:66-74 Abstract quote We comparatively evaluated different cytokeratin (CK) reagents analyzed by flow cytometry (FCM) for the identification of the best combination of DNA/CK staining for detecting minimal numbers of breast cancer cells in peripheral blood (PB). In 59 primary breast cancer tumors, we comparatively analyzed the reactivity for up to 6 different anti-CK reagents using multiparameter FCM: anti-CK7, anti-CK20, anti–pan-CK, anti-CK8/CK18, anti-CK8, and anti-CK18. Afterward, dilutional experiments of Michigan Cancer Foundation (MCF)7 breast cancer cells in PB were performed, and the sensitivity of a DNA/CK18 staining was evaluated. Our results showed that anti-CK18 reagents were those providing the brightest and more sensitive staining for primary breast cancer tumor cells by FCM. Dilutional experiments of MCF cells in PB showed that the DNA/anti-CK18 double staining was highly specific for the identification of epithelial cells; its sensitivity ranged between 10–6 and 10–7 (detection of 1 tumor cell among 106 to 107 nucleated blood cells). Combined assessment of DNA cell contents and reactivity for CK18 by FCM is a sensitive method for the specific identification of breast cancer cells in PB.
LABORATORY MARKERS
CA15-3
her2-neu

 

GROSS OR CLINICAL VARIANTS	CHARACTERIZATION
Sites	Slightly more common in the left than right breast (110:100) Bilateral or sequential in 4% of cases 50%arise in the upper outer quadrant 20% in the central or subareolar region 10% each in the remaining three quadrants
Appearance	Stellate or circumscribed appearance Usually a solid tumor with a firm gray to white cut surface Chalky white streaks correspond to necrosis, calcification, or elastosis
BILATERAL CANCERS
Clonal Analysis of Bilateral Mammary Carcinomas by Clinical Evaluation and Partial Allelotyping Gary M.K. Tse, FRCPC, Fred Y.L. Kung, MBChB, Amy B.W. Chan, MBChB, Bonita K.B. Law, FRCS, Alexander R. Chang, FRCPA, and Kwok-Wai Lo, PhD	Am J Clin Pathol 2003;120:168-174 Abstract quote Bilateral breast carcinomas may represent contralateral metastases or new primary tumors. The presence of carcinoma in situ, a lower grade, or a different histotype in the second tumor is considered a clinical criterion for a second primary tumor. In this study, 26 bilateral breast carcinomas from 13 patients were analyzed based on clinical criteria, and the results were compared with those obtained by partial allelotyping using 47 markers at 7 chromosomal arms. Of the 8 synchronous tumors, 5 were concluded to be distinct primary tumors using clinical criteria; some were confirmed by partial allelotyping. In the remaining 3 cases, partial allelotyping showed distinct primary tumors. Five patients had metachronous carcinomas with 3 distinct primary tumors, 1 metastasis, and 1 that was uncertain by clinical criteria. Three cases were confirmed by partial allelotyping, and the uncertain case was shown to be distinct primary tumors. No discrepant results were noted. Stringent application of clinical criteria is accurate for differentiating second primary tumors from metastases.
Metachronous bilateral mammary metaplastic and infiltrating duct carcinomas: A molecular study for clonality. Kung FY, Tse GM, Lo KW, Law BK, Chang AR, Chen MH. Departments of Anatomical and Cellular Pathology and Surgery, Prince of Wales Hospital and P.H. Chan Medical Laboratories Limited, Hong Kong SAR.	Hum Pathol 2002 Jun;33(6):677-9 Abstract quote Mammary metaplastic carcinoma is uncommon. In this study, both carcinoma and sarcoma components of a metaplastic carcinoma and a subsequent metachronous contralateral infiltrating ductal carcinoma were analyzed by microsatellite analysis for the loss of heterozygosity (LOH) patterns at multiple sites on chromosome arms 3p, 6q, 8, 9p, 11, 13q, 14q, 16q, and 17p. The LOH patterns between the carcinoma and sarcoma components in the first tumor were similar, indicating clonality. The LOH patterns between the first and second tumors were different at all chromosome arms, indicating different clonality and a second primary. We demonstrated a second primary carcinoma in a patient with previous metaplastic carcinoma rather than a metastasis with carcinoma component only.
INFLAMMATORY BREAST CANCER	Clinical-pathologic correlation of a breast with cellulitis-like clinical picture secondary to extensive dermal lymphatic spread by an underlying breast carcinoma
MULTIFOCAL MULTICENTRIC CANCERS
Multicentric and multifocal cancer: whole-breast US in preoperative evaluation. Berg WA, Gilbreath PL. Department of Radiology, Greenebaum Cancer Center, University of Maryland, Baltimore 21201, USA.	Radiology 2000 Jan;214(1):59-66 Abstract quote PURPOSE: To evaluate preoperative whole-breast ultrasonography (US) in the management of breast cancer. MATERIALS AND METHODS: The ipsilateral breast in 40 patients with known breast cancer or in whom there was high suspicion of breast cancer was evaluated with whole-breast US. Biopsy was performed on all discrete solid lesions. RESULTS: US depicted 45 (94%) of 48 invasive tumor foci and seven (44%) of 16 foci of ductal carcinoma in situ (DCIS). Mammography depicted 39 (81%) of 48 invasive tumor foci and 14 (88%) of 16 foci of DCIS. The nine (14%) of 64 malignant foci seen only at US included three infiltrating ductal carcinomas, two mixed infiltrating and intraductal carcinomas, two infiltrating lobular carcinomas, and two foci of DCIS. Two (18%) of 11 foci of infiltrating lobular carcinoma were missed at both US and mammography. Of 20 patients mammographically suspected of having unifocal disease, three (15%) required wider excision on the basis of US findings. Two additional foci were depicted only at US in one of 16 patients mammographically suspected of having multicentric or multifocal disease. Of four patients with mammographically occult disease, US correctly depicted the diffuse (n = 2) or unifocal (n = 2) extent of the cancer. CONCLUSION: Whole-breast US complements mammography in the preoperative evaluation of patients with breast cancer, particularly when breast conservation is contemplated.
A case-control study of unilateral and bilateral breast carcinoma patients. Newman LA, Sahin AA, Cunningham JE, Bondy ML, Mirza NQ, Vlastos GS, Whitman GJ, Brown H, Buchholz TA, Lee MH, Singletary SE. Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.	Cancer 2001 May 15;91(10):1845-53 Abstract quote BACKGROUND: Women with unilateral breast carcinoma are at increased risk for developing contralateral disease. The clinical significance of bilateral breast carcinoma has not been fully defined, and the subset of patients who may benefit from medical or surgical risk-reduction intervention has not yet been characterized. The purpose of this study was to evaluate risk factors and outcomes for bilateral breast carcinoma. METHODS: A subject group of 70 bilateral breast carcinoma patients (62% metachronous) was matched by age and survival interval with a control group of 70 unilateral breast carcinoma patients. Median follow-up was 103 months. RESULTS: Eighty-two percent of the unilateral patients and 80% of the bilateral patients had Stage I or II disease at diagnosis. Median age at presentation was 53 years. In the bilateral group, the contralateral cancer was diagnosed at the same or earlier stage than the first cancer in 87% of cases. Bilateral patients were significantly more likely to have multicentric disease and to have a positive family history for breast carcinoma compared with the unilateral group. There were no significant differences regarding history of exogenous hormone exposure, lobular histology, hormone-receptor status, or HER-2/neu expression. Five-year disease-free survival was 94% for the unilateral breast carcinoma patients and 91% for the bilateral breast carcinoma patients (P = 0.16). CONCLUSIONS: Survival for patients with bilateral breast carcinoma is similar to that of patients with unilateral disease; however, prophylactic risk-reduction intervention for the contralateral breast should be considered in patients who have multicentric unilateral disease or a positive family history for breast carcinoma.
Multifocal, Multicentric, and Contralateral Breast Cancers: Bilateral Whole-Breast US in the Preoperative Evaluation of Patients. Moon WK, Noh DY, Im JG. Departments of Radiology (W.K.M., J.G.I.) and Surgery (D.Y.N.), Clinical Research Institute, Seoul National University Hospital and the Institute of Radiation Medicine, Seoul National University Medical Research Center, 28 Yongon-Dong, Chongno-Gu, Seoul 110-744, Korea. From the 2000 RSNA scientific assembly.	Radiology 2002 Aug;224(2):569-576 Abstract quote PURPOSE: To evaluate the efficacy of preoperative bilateral whole-breast ultrasonography (US) in the detection of additional multifocal, multicentric, and contralateral cancers and the effect of US information on therapeutic decisions. MATERIALS AND METHODS: Two hundred one patients who had newly diagnosed breast cancer or who were suspected of having breast cancer underwent US examination of the ipsilateral and contralateral breasts with a 10-, 12-, or 13-MHz transducer. All solid lesions found at US alone were classified according to level of suspicion and were selected for biopsy. The US results were compared with mammographic findings. Sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: In ipsilateral breasts, US depicted 194 (97%) of 201 foci of invasive cancer and 52 (75%) of 69 foci of ductal carcinoma in situ (DCIS), whereas mammography and physical examination depicted 173 (86%) foci of invasive cancer and 56 (81%) foci of DCIS. In the contralateral breast, US depicted 11 (92%) of 12 foci of invasive cancer and four (57%) of seven foci of DCIS, whereas mammography and physical examination depicted six (50%) foci of invasive cancer and five (71%) foci of DCIS. Overall, US depicted mammographically and clinically unsuspected multifocal or multicentric cancers in 28 patients (14%) and contralateral cancer in eight patients (4%). On the basis of these US findings, therapy was correctly changed in 32 patients (16%). The sensitivity, specificity, and positive and negative predictive values of prospective classification of 77 solid lesions detected at US alone were 100% (36 of 36), 51% (21 of 41), 64% (36 of 56), and 100% (21 of 21), respectively. CONCLUSION: Bilateral whole-breast US complements mammography in the preoperative evaluation of patients with breast cancer.
Pathologic analysis of tumor size and lymph node status in multifocal/multicentric breast carcinoma. Andea AA, Wallis T, Newman LA, Bouwman D, Dey J, Visscher DW. Department of Pathology, Harper Hospital, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, Michigan 48201, USA.	Cancer 2002 Mar 1;94(5):1383-90 Abstract quote BACKGROUND: For unifocal invasive breast carcinoma, increasing tumor diameter predictably correlates with a greater frequency of lymph node involvement, thereby facilitating treatment decisions. In invasive breast tumors presenting with multiple nodules, however, it is unclear whether tumor size correlates with lymph node dissemination in a similar manner. METHODS: The authors analyzed a series of 101 invasive breast carcinomas presenting with multiple macroscopically apparent lesions (2 foci: n = 77; 3: n = 20; 4: n = 4). Two different assessments of the tumor size (diameter of largest focus and combined diameter of all the foci) were then correlated with the status of axillary lymph nodes. For comparison with unifocal tumors, the authors used both external and internal control series (the latter consisting of 469 patients from their institution). The associations between lymph node status, tumor size, and multifocality were modeled using univariate and multivariate logistic regression, for each modality of tumor size assessment. RESULTS: The logistic curves for multifocal and unifocal tumors were significantly different when the largest diameter was used as a tumor size estimate. Multifocal cases had higher frequencies of lymph node involvement than unifocal lesions of similar size category. In a multivariate logistic regression, the odds ratio of positive lymph node status in multifocal versus unifocal cases was 2.8 using largest diameter as a tumor size estimate (P < 0.0001). When the combined diameter assessment was used, however, the regression curve of multifocal cases was similar to that of unifocal cases, and the frequency of lymph node positivity was not significantly different in multifocal versus unifocal cases of the same size (odds ratio, 1.4; P = 0.13). CONCLUSIONS: The authors' results show that, if aggregate diameters are used, unifocal and multifocal breast carcinomas are similar with respect to frequency of regional lymph node metastasis. Currently used algorithms, which use the diameter of the largest nodule, result in understaging of multifocal breast carcinomas due to underestimation of actual tumor size.
Multicentric mammary carcinoma: evidence of monoclonal proliferation. Middleton LP, Vlastos G, Mirza NQ, Eva S, Sahin AA. Department of Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA	Cancer 2002 Apr 1;94(7):1910-6 Abstract quote BACKGROUND: Both the widespread use of screening mammography and emphasis on breast conservation have raised many questions regarding the clinical and therapeutic management of multicentric mammary carcinoma (MMC). MMC has been postulated to be either a clonal proliferation of a single mammary carcinoma or multiple independent synchronous primary tumors in the same breast. The goal of the current study was to evaluate the histologic features and immunohistochemical profile of MMC. We also compared the clinical outcomes of the patients in the current study with stage-matched and treatment-matched groups of patients with unicentric mammary carcinoma. METHODS: The authors studied 32 patients with T1-T2, N0-1, M0 multicentric invasive mammary carcinomas diagnosed between 1983-1988 and treated at The University of Texas M. D. Anderson Cancer Center. The histologic features of each tumor (including tumor type, nuclear grade, presence of in situ carcinoma, pattern of in situ carcinoma, and lymphovascular invasion) were evaluated. The authors performed immunohistochemical analysis of estrogen receptor (ER), progesterone receptor (PR), HER-2/neu, and Ki-67 in 25 cases, including 14 from which > 1 tumor was available to perform comparative immunohistochemical analysis. The clinical parameters of each case were compared with those of the unicentric breast carcinoma controls. RESULTS: The median age of the patients with MMC was 45 years (range, 28-69 years). Twelve patients had a family history of breast carcinoma (37.5%). The maximum tumor dimension ranged from 0.2-3.2 cm in the index lesion (median, 2.0 cm) and 0.1-2.5 cm in the second lesion (median, 0.9 cm). Twelve patients were clinically classified as having Stage I disease and 20 patients were considered to have Stage II disease at the time of presentation. Follow-up data were available for all the patients and follow-up ranged from 4.5-16 years (median, 6 years). The disease-free survival was 84% at 5 years and 73% at 10 years in the MMC patients and 78% and 70%, respectively, in patients with unicentric breast carcinoma (P = 0.4368). Histologically, 24 of the multicentric tumors were found to be infiltrating ductal tumors and 8 were found to be infiltrating lobular carcinomas. The nipple was involved in 10 cases. The histology of the multicentric invasive tumor was nearly identical in 31 cases (97%). Approximately 72% of the cases had in situ carcinoma in both tumors and 44% had lymphovascular invasion. Comparative immunohistochemical analysis of separate tumors was equivalent with regard to ER, PR, and HER-2/neu. The quantitative immunohistochemical staining for the proliferative marker Ki-67 differed between tumors in two cases. CONCLUSIONS: The near-identical morphologic and immunohistochemical patterns in the MMC cases in the current study support the hypothesis that early-stage synchronous tumors are a clonal proliferation of a single mammary carcinoma. Furthermore, the results of the current study support evaluating prognostic markers in only one tumor per MMC patient. There was no appreciable difference in the disease-free survival of patients with unicentric and multicentric breast carcinoma.
NON-PALPABLE CANCER
Non palpable breast carcinomas. Histological and immunohistochemical studies of 160 cases. Charpin C, Bonnier P, Khouzami A, Andrac L, Habib M, Vacheret H, Lavaut MN, Piana L. Department of Pathology, (Hopital de la Timone), Marseille, France.	Pathol Res Pract 1993 Apr;189(3):267-74 Abstract quote A series of 160 impalpable breast carcinomas was collected from 1979 to 1991. Mammographs showed microcalcifications (64%), or opaque images (36%). Surgical specimens were X-rayed during the intervention in order (i) to ascertain that the lesions detected on mammographs were removed, and (ii) to guide the pathologist in sampling tissue fragment for an appropriate microscopic evaluation of the lesions. During the intervention, the peroperation histological diagnosis was correct in 63% of the cases, whereas malignancies were underscored in 37%. No false positive diagnosis was recorded. A large majority (92%) of false diagnoses stated during surgery were in situ carcinomas diagnosed as epitheliosis and invasive carcinomas diagnosed as in situ carcinomas. In 63% of the cases the axillary lymph node could be removed during the first intervention. In 91% of the cases "in sano" margins of resection were evaluated as such during the intervention. The size of tumors ranged from 1 to 60 mm (m = 10 mm - SD = 8.45), 70% measuring less than 10 mm. Carcinomas were in situ (23.75%), microinvasive (13.75%) and invasive (62.5%). Carcinomas were ductal (78.1%), lobular (18.7%) and of other types (14.2%). A majority of intraductal carcinoma (68%) were comedocarcinomas. Invasive carcinomas accounted for grade I in 37% of the cases, grade II in 56%, grade III in 7%, ductal carcinomas and for tubular carcinomas in 15%. Immunodetection could be performed on frozen sections in 78 cases. Tumors were receptor positive in 58% of the cases. The greater growth fraction (Ki-67) and higher detection of HER-2/neu oncogene product were observed in comedocarcinomas. Diploid tumors accounted for 52% of those evaluated (n = 48).

 

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
ADEQUACY OF BIOPSY
Adequate Histologic Sampling of Breast Core Needle Biopsies Andrew A. Renshaw, MD From the Department of Pathology, Baptist Hospital of Miami, Miami, Fla.	Arch Pathol Lab Med 2001;125:1055–1057. Abstract quote Objective.—To determine the degree of histologic sampling necessary for adequate examination of breast core needle biopsy specimens. Design. —The results of all breast core needle biopsies (11 and 14 gauge) with a diagnosis of atypical small acinar proliferation or atypical ductal hyperplasia and subsequent excisional biopsies, for a 50-month period were reviewed. Blocks of all cores were sectioned entirely in 8 slides to determine the amount of sectioning needed to detect these foci, and the results were correlated with those from the excision specimen. Setting.—Large community hospital practice. Results. —Of 3026 cases, 216 (7.1%) were diagnosed as atypical ductal hyperplasia or atypia not otherwise specified. Subsequent resections were available in 105 (49%) cases, and after review, 95 (92%) qualified as atypical ductal hyperplasia and 2 were determined to be atypical small acinar proliferations. The 2 small acinar proliferations were first detected on the second and fourth slides. Of the atypical ductal hyperplasia cases, 43% were detected on the first slide, 17% on the second, 23% on the third, 8% on the fourth, and 8% on the fifth. No lesions were initially detected after this level. Ductal carcinoma in situ was detected in the excision specimens from 1 case each of those detected initially on the fourth and fifth slides. Conclusion. —Five sections of breast core needle biopsy specimens are necessary to ensure that all atypical small acinar proliferations and atypical ductal hyperplasia lesions are sampled.
CONCORDANCE
Implications of pathologist concordance for breast cancer assessments in mammography screening from age 40 years. Anderson TJ, Sufi F, Ellis IO, Sloanedagger JP, Moss S. Department of Pathology, University of Edinburgh, Edinburgh, Scotland; Nottingham City Hospital, Nottingham, UK; University of Liverpool, UK; and Cancer Screening Evaluation Unit, Institute of Cancer Research, Sutton, UK., daggerDeceased.	Hum Pathol 2002 Mar;33(3):365-71 Abstract quote Three pathologists reviewed slides and reports of cancers arising in both the study and control populations of the U.K. trial of annual mammography screening from age 40 years. A total of 875 cases were scored independently as noninvasive, microinvasive, or invasive cancer, with the last also evaluated for histology grade, type, and lymphatic vascular invasion. Of these, 870 (99.2%) were confirmed malignant, 1 case had cytology only, and 5 were judged by all reviewers as benign. Reviewer complete concordance for the three classes of malignancy was achieved in 826 (95%) and majority agreement in 31 (3.6%) of 870 with complete data. All three readers recorded grade in 736 cancers, giving a kappa statistic of 0.69, 0.52, and 0.66 for grades I, II, and III, respectively, and 0.61 overall. Agreement that the cancer was special type or not was obtained in 671 (89.0%) with complete concordance in the nature of the type in 504 and majority view in 167; another 58 (7.7%) were characterised as "part special" pattern, with type disagreement in 23 (3%). The kappa statistic for single type subcategories in those cancers was substantial, at 0.68 overall. This improved to 0.76 for the last 230 invasive cancers after the pathologists agreed more explicit criteria for type discrimination. There was almost perfect agreement between original and review diagnosis of breast malignancy for both noninvasive/microinvasive and invasive cancer (kappa 0.84 and 0.91, respectively), justifying confidence in the diagnosis of breast cancer by U.K. pathologists. The specialists agreed substantially on qualitative histology features of type and grade of cancers, and improved further for typing by defining criteria. These consensus data, along with invasive size and node status, are reliable for use as surrogate measures of outcome, and to enhance interpretation of effect, when the trial case population sources are disclosed.
Correlation of histologic prognostic factors in core biopsies and therapeutic excisions of invasive breast carcinoma. Harris GC, Denley HE, Pinder SE, Lee AH, Ellis IO, Elston CW, Evans A.	Am J Surg Pathol 2003 Jan;27(1):11-5 Abstract quote Breast core biopsy is one of the major nonoperative methods of diagnosis. Increasingly, there is also a need to provide prognostic data to facilitate timely patient management. We present the results from 500 patients with invasive breast carcinoma, who underwent core biopsy followed by a therapeutic surgical procedure. Grade and type of the invasive and in situ carcinoma, together with the presence or absence of vascular invasion, were determined in both biopsy and definitive surgical excision and the results compared. There was 67% agreement with overall grade (kappa value 0.48), with scores for tubule formation, pleomorphism, and mitotic scoring achieving values of 82%, 73%, and 58%, respectively. Only 60% of grade 1 and 2 carcinomas showed concordance, but 84% of grade 3 tumors showed agreement between core and excision results. Tumor typing, vascular invasion, and grading of ductal carcinoma in situ had agreement values of 74%, 69%, and 65%, respectively. The major problem with assessing prognostic factors on needle biopsy specimens is undersampling of the most informative areas. However, in those patients in whom preoperative assessment of prognostic factors is most likely to be beneficial, i.e., those with grade 3 carcinomas, a high level of agreement was achieved in this large study.
Grading	See Commonly Used Terms Scarf-Bloom-Richardson Grading
Extratumoral lymphatic tumor emboli	25% of cases Majority will have accompanying lymph node metastases
Blood vessel invasion	Identified in 13% of T1N0M0 patients In these patients, recurrence was more frequent
Perineural invasion	10% of invasive carcinomas Usually in high grade tumors and associated with lymphatic tumor emboli
Elastosis	Abundant changes usually associated with estrogen receptor positivity
VARIANTS
ADENOID CYSTIC CARCINOMA
KIT is highly expressed in adenoid cystic carcinoma of the breast, a basal-like carcinoma associated with a favorable outcome. Azoulay S, Lae M, Freneaux P, Merle S, Al Ghuzlan A, Chnecker C, Rosty C, Klijanienko J, Sigal-Zafrani B, Salmon R, Fourquet A, Sastre-Garau X, Vincent-Salomon A. 1Department of Pathology, Institut Curie, Paris Cedex, France.	Mod Pathol. 2005 Dec;18(12):1623-31. Abstract quote   Recent biological studies have classified breast carcinomas into HER2-overexpressing, estrogen receptor-positive/luminal, basal- and normal-like groups. According to this new biological classification, the objectives of our study were to assess the clinical, morphologic and immunophenotypic characteristics of adenoid cystic carcinoma of the breast in order to classify this subtype of breast carcinoma. A total of 18 cases of adenoid cystic carcinoma were identified from the Institut Curie files. Clinical information was available for 16 patients with a median follow-up of 6.5 years. Morphologically, all tumors were graded according to the system defined by Kleer and Oberman (histologic and nuclear grade). Immunophenotype was assessed with anti-ER, PR, HER-2, KIT, basal (CK5/6) and luminal cytokeratins (CK8/18) and p63 antibodies. One out of 18 tumors was nuclear grade 1 (16%), nine were nuclear grade 2 (50%) and eight were nuclear grade 3 (44%). All cases were estrogen receptor, progesterone receptor and HER-2 negative. Epithelial cells were strongly positive around glandular lumina with one or both cytokeratins, identifying the coexistence of CK5/6+ cells, CK5/6 and CK8/18+ cells, CK8/18+ cells and p63+ cells. All cases (100%) were also KIT positive. In all, 15 patients were treated by surgery. Nine of them received adjuvant radiotherapy. Follow-up was available for 16 patients. In all, 14 patients were alive. Two of them, initially treated by surgery only, presented a local recurrence. Two patients died (one of them treated by radiation therapy only died from her disease). Our study shows that adenoid cystic carcinoma of the breast is a special, estrogen receptor, progesterone receptor, HER-2 negative and highly KIT-positive, basal-like breast carcinoma, associated with an excellent prognosis. This highly specific immunophenotype could be useful to differentiate adenoid cystic carcinoma of the breast from other subtypes of breast carcinoma such as cribriform carcinoma.
Expression of c-kit in adenoid cystic carcinoma of the breast. Crisi GM, Marconi SA, Makari-Judson G, Goulart RA. Department of Pathology, Baystate Medical Center/Tufts University School of Medicine, Springfield, MA 01199, USA.	Am J Clin Pathol. 2005 Nov;124(5):733-9. Abstract quote   Breast adenoid cystic carcinoma (BACC) is a biologically distinct tumor with morphologic mimickers, which might make accurate classification problematic. Because c-kit expression has been reported in adenoid cystic carcinoma of various anatomic sites, we evaluated BACC for c-kit by immunohistochemical analysis, comparing the findings to similarly stained mimickers. Tested cases included 6 BACCs, 15 low-grade infiltrating ductal carcinomas (LGIDCs) chosen as potential mimickers, and 15 head-neck adenoid cystic carcinomas (HNACCs). All BACCs showed plasma membranous and cytoplasmic staining equal to or greater than that of adjacent benign epithelium. Five BACCs (83%) expressed c-kit in more than 50% of tumor cells. Only 2 of 15 LGIDCs expressed low-intensity, focal c-kit staining. Of the 15 HNACCs, 10 (67%) expressed c-kit. Hormone receptors were consistently negative in BACCs. All BACCs expressed c-kit, whereas LGIDCs infrequently expressed low-intensity c-kit. Immunohistochemical evaluation for c-kit might aid in accurately classifying carcinomas with histologic features overlapping adenoid cystic carcinoma and LGIDC.
Adenoid cystic carcinoma arising in a fibroadenoma. Blanco M, Egozi L, Lubin D, Poppiti R. The Arkadi M Rywlin MD, Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA.	Ann Diagn Pathol. 2005 Jun;9(3):157-9. Abstract quote   Adenoid cystic carcinoma (ACC) of the breast is a rare neoplasm, accounting for only 0.1 % of all breast carcinomas. An intriguing factor of ACC in the breast is its good prognosis compared to ACC in other locations, mainly in the minor salivary glands. The incidence of axillary lymph node involvement is also very low compared to that of other breast tumors, and distant metastases are uncommon. We report the case of a 65-year-old woman with a 2-year history of a well-circumscribed breast nodule sonographically thought to be a lymph node which was later excised because of rapid growth. Histologic examination showed an adenoid cystic carcinoma with squamous differentiation originating in a fibroadenoma. A review of the literature reveals no previous report of such a case.
Microglandular adenosis with transition into adenoid cystic carcinoma of the breast. Acs G, Simpson JF, Bleiweiss IJ, Hugh J, Reynolds C, Olson S, Page DL.	Am J Surg Pathol. 2003 Aug;27(8):1052-60 Abstract quote Microglandular adenosis (MGA) is a well-recognized, if rare and incompletely characterized, entity in which carcinoma is rarely thought to develop. We report 17 cases in which patterns of adenoid cystic carcinoma (ACC) coexisted with MGA. Immunocharacterization with beta-catenin, E-cadherin, cytokeratins (AE1/AE3), epithelial membrane antigen, S-100 protein, smooth muscle actin, and vimentin was also performed. Most cases had areas of invasive ACC characterized by its defining dual-lumen types. Some cases of ACC appeared to have expanded glands intermingled within the MGA, whereas in other cases ACC formed a transition with the characteristic small, gland-like spaces of MGA. MGA and "atypical MGA" stained irregularly and similarly to that seen in myoepithelium with the three markers of myoepithelial cells in breast: S-100 protein, smooth muscle actin, and vimentin. These markers were also positive in the more solid elements of the ACC. Our study suggests that ACC may develop in a background of and in continuity with MGA. Altered myoepithelial cells appear to be the major neoplastic element in both ACC and "atypical MGA." "Atypical MGA" with transition to ACC may show histologic patterns and an immunohistochemical profile similar to that of ACC. These lesions might be best interpreted as ACC in situ. Both MGA and ACC of the breast grow in an expansile and diffusely infiltrative pattern without having significant metastatic capacity. Their unusual interaction with the surrounding stroma may play a role in this benign biologic behavior.
Solid variant of mammary adenoid cystic carcinoma with basaloid features: a study of nine cases. Shin SJ, Rosen PP. Department of Pathology, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, NY, U.S.A.	Am J Surg Pathol 2002 Apr;26(4):413-20 Abstract quote Adenoid cystic carcinoma of the breast is a rare neoplasm that represents <1% of breast carcinomas. The tumors are histologically indistinguishable from examples in other sites, and they have a generally favorable prognosis. Several studies have investigated the possible correlation between histologic grade in adenoid cystic carcinoma (largely determined by cytology and growth pattern) and prognosis. Some earlier reports concluded that a solid variant of mammary adenoid cystic carcinoma had a more aggressive clinical course, but others did not confirm this impression. This report describes nine patients with a solid variant of mammary adenoid cystic carcinoma that has a striking basaloid appearance. All were women ranging in age from 37 to 83 years. A solitary mass was evident in all patients. Tumor size was 1.1-15 cm (mean 3.7 cm). The tumors exhibited a predominantly solid architecture comprised of basaloid appearing cells with moderate to marked nuclear atypia. Five tumors had >5 mitotic figures per 10 high power microscopic fields. Intercalated ducts were found in all tumors, being well formed in six and poorly formed in three. Immunohistochemical stains for cytokeratins, basement membranes, and vimentin were consistently positive. Surgery was performed in all cases consisting of excision in seven and mastectomy in two. Axillary lymph node metastases were found in two of six axillary dissections and four had negative lymph nodes. The lymph nodes were not examined in three patients. Follow-up information was available for seven patients. Six women had no evidence of disease after follow-up of 2-88 months (mean 32 months), one patient died of unknown causes, and one patient was lost to follow-up. It is concluded that the solid variant of mammary carcinoma with basaloid features is a histologically distinct tumor that is capable of axillary metastases. Long-term follow-up of a larger series of cases will be needed to determine whether the prognosis of these patients differs significantly from that of women with conventional adenoid cystic carcinoma. Presently, these patients are candidates for axillary staging by sentinel lymph node mapping or low axillary dissection if there is no clinical evidence of axillary metastases. Systemic adjuvant treatment would be prudent when axillary nodal metastases are present. Breast-conserving surgery with radiation is an option if negative margins can be achieved because this appears to be a unicentric form of carcinoma.
ADENOSQUAMOUS CELL CARCINOMA
The pathology of low-grade adenosquamous carcinoma of the breast. An immunohistochemical study. Drudis T, Arroyo C, Van Hoeven K, Cordon-Cardo C, Rosen PP. Department of Cancer and Metastasis, Hospital Durani Reynals, Hospitalet de LLogregat, Barcelona, Spain.	Pathol Annu 1994;29 ( Pt 2):181-97 Abstract quote Low-grade adenosquamous carcinoma of the breast is a variant of metaplastic mammary carcinoma characterized by a locally invasive growth pattern and a low risk for metastases. In this study none of the carcinomas exhibited greater than 5 percent nuclear immunoreactivity for estrogen or progesterone receptors, and as a result they were classified as negative for these receptors. Reactivity for cathepsin D was found in 39 percent of the tumors, largely limited to areas of epidermoid differentiation. Membrane immunoreactivity for HER-2/neu oncogenes was present in glandular components of 46 percent of the carcinomas. Immunoreactivity for p53 (greater than 10 percent of nuclei) was present in 13 percent of the tumors, also in glandular elements. Six different patterns of coexpression of p53, HER-2/neu and cathepsin D were found, the most frequent being the following: HER-2/neu(+), p53(-), cathepsin D(-) (9 cases, 39%); cathepsin D(+), p53(-), HER-2/neu(-) (5 cases, 22%); and the three markers negative (5 cases, 22 percent). Coexpression of the two oncogenes was found in only one tumor which was also positive for cathepsin D. These results indicate that the expression of various immunohistochemical prognostic markers may be heterogeneous and that there may not be a specific pattern of marker coexpression within a carefully defined histologic subtype of mammary carcinoma. Furthermore, characteristics reported to be associated with an unfavorable prognosis (negative hormone receptors, presence of cathepsin D, and expression of oncogenes such as HER-2/neu) may be found in a substantial proportion of tumors that comprise this clinically and histologically low-grade variant of mammary carcinoma. This disassociation between expected prognosis based on expression of current prognostic markers and observed prognosis occurs in other forms of mammary carcinoma. Medullary carcinoma, when diagnosed on the basis of rigorously defined criteria, has an excellent prognosis despite the fact that these tumors are characterized by absence of estrogen and progesterone receptors and a high proliferative rate. The histological classification of mammary carcinomas is itself an important prognostic variable that may take precedence over selected biochemical markers.
APOCRINE CARCINOMA
Apocrine carcinoma of the breast. A morphologic and immunocytochemical study. Eusebi V, Millis RR, Cattani MG, Bussolati G, Azzopardi JG.	Am J Pathol 1986 Jun;123(3):532-41 Abstract quote The mode of recognition and hence the frequency of apocrine differentiation in breast carcinomas, assessed on purely morphologic grounds, remains uncertain. One hundred consecutive cases of breast carcinoma were studied in order to establish the incidence of this type of tumor. With the use of an immunocytochemical method for the detection of GCDFP-15, a protein present in apocrine epithelium and in the fluid of tension cyst of the breast, the presence of apocrine differentiation was confirmed in 4 cases initially diagnosed as apocrine carcinomas on histologic grounds. Eight additional cases contained immunoreactive cells: 1 contained 10% of positive cells scattered throughout the tumor, and the other 7 cases were only focally positive. In 4 of these latter cases positive staining was confined to the in situ component. The ultrastructural findings in 2 cases of apocrine carcinoma are discussed in order to link the morphologic features for recognizing this tumor type and the presence of the antigenic apocrine marker.
Apocrine adenocarcinoma of the bilateral axillae. Yoshida A, Kodama Y, Hatanaka S, Takasaki T, Kuriwaki K, Yoshida H. First Department of Pathology, Kagoshima University, Faculty of Medicine, Japan.	Acta Pathol Jpn 1991 Dec;41(12):927-32 Abstract quote A case of apocrine adenocarcinoma arising in the bilateral axillae is reported. The patient was an 88-year-old Japanese male who complained of a mass lesion and pus-like discharge in the right axilla. Another mass was also noticed in the left axilla. No other neoplastic lesion was found in other sites of the body. The histologic appearances of the bilateral axillary tumors were almost identical. Both were adenocarcinoma with varying degrees of differentiation, composed of glands and nests of atypical epithelial cells with abundant eosinophilic cytoplasm. Some neoplastic cells exhibited cytoplasmic projections on their apical surface. Foci of in situ carcinoma were observed within the neoplastic tissue in the bilateral axillae. The neoplastic cells were immunohistochemically positive for epithelial membrane antigen (EMA) and gross cystic disease fluid protein (GCDFP-15), but negative for carcinoembryonic antigen (CEA). On the basis of their histologic and immunohistochemical features and distinctive location, the tumors were diagnosed as apocrine adenocarcinoma.
Bilateral apocrine carcinoma of the breast. Molecular and immunocytochemical evidence for two independent primary tumours. Schmitt FC, Soares R, Seruca R. Institute of Molecular Pathology and Immunology of Porto University, IPATIMUP, Portugal.	Virchows Arch 1998 Dec;433(6):505-9 Abstract quote Apocrine carcinoma is an uncommon variant of breast cancer. The frequency of bilaterality in patients who have apocrine carcinoma in one breast is not significantly different from that for bilateral mammary carcinomas in general, but bilateral apocrine carcinomas are very uncommon. We report on a bilateral apocrine carcinoma of the breast in a 74-year-old woman. The apocrine differentiation in both tumours was confirmed by the positivity of the cytoplasmic granules for PAS after diastase digestion and immunoreactivity for GCDFP-15 and sialyl-Tn. The tumour in the right breast showed immunohistochemical expression of p53, and a mutation was demonstrated by PCR-SSCP; the tumour in the left breast was negative for p53 on immunohistochemistry, and no mutation was found at the molecular level. c-erbB2 expression was not detected in the right tumour but there was overexpression (at the cell membrane) in the left tumour. Both tumours were aneuploid: the right tumour displayed multiple stemlines, whereas the left tumour had a triploid profile. Using the fluorescence in situ hybridization technique we demonstrated that both tumours displayed chromosome 17 polysomy and numerical abnormalities of chromosome 1, polysomy in the right and monosomy in the left tumour. We conclude that the two tumours are probably independent, as are most bilateral carcinomas of the breast.
Molecular cytogenetic comparison of apocrine hyperplasia and apocrine carcinoma of the breast. Jones C, Damiani S, Wells D, Chaggar R, Lakhani SR, Eusebi V. Breast Molecular Pathology Group, Department of Histopathology, Royal Free and University College Medical School, University College London, London, United Kingdom.	Am J Pathol 2001 Jan;158(1):207-14 Abstract quote The relationship of apocrine metaplasia to invasive breast cancer is controversial. Different authors have reported that apocrine differentiation in proliferative lesions may be a risk factor, a precursor lesion, or have no association with malignancy. The aim of this study was to compare the genetic alterations in benign apocrine hyperplasia with apocrine ductal carcinoma in situ (DCIS) and invasive apocrine carcinomas of the breast using comparative genomic hybridization. The mean number of alterations in apocrine hyperplasia was 4.1 (n = 10) compared to 10.2 in apocrine DCIS (n = 10) and 14.8 (n = 4) in invasive carcinoma. The most common alterations in apocrine hyperplasia were gains of 2q, 13q, and 1p and losses of 1p, 17q, 22q, 2p, 10q, and 16q. Apocrine DCIS and invasive carcinomas showed gains of 1q, 2q, 1p, and losses of 1p, 22q, 17q, 12q, and 16q as their most common DNA copy number changes. Apocrine hyperplasia is considered to be a benign lesion and its relationship to invasive carcinoma remains unclear. Our data suggest that some apocrine hyperplasias may be clonal proliferations. The mean number of alterations are lower in apocrine hyperplasia, however the changes show considerable overlap with those identified in in situ and invasive apocrine carcinoma. These alterations are also commonly seen in nonapocrine breast cancer. The data are consistent with apocrine hyperplasia as a putative nonobligate precursor of apocrine carcinoma.
CENTRALLY NECROTIZING CARCINOMA
Centrally Necrotizing Carcinomas of the Breast A Distinct Histologic Subtype With Aggressive Clinical Behavior	Am J Surg Pathol 2001;25:331-337 (Abstract directly quoted) This report describes a distinctive subtype of breast carcinoma that we have termed centrally necrotizing carcinoma (CNC; in this study, N = 34), which is characterized by an unusual and aggressive natural history. Centrally necrotizing carcinomas are composed of well-circumscribed, unicentric nodules with extensive central necrosis that are surrounded by a narrow rim of viable high-grade tumor cells. These tumor cells show minimal ductal differentiation (i.e., tubule formation), but are usually associated with focal ductal carcinoma in situ. The mean age of the patients in this study was 57.5 ± 11.6 years, and the mean tumor size was 2.5 ± 1.2 cm. Twenty-eight percent of the patients had positive axillary lymph nodes (mean number of lymph nodes involved, 2.1 ± 1.2). Ninety-four percent of cases were negative for estrogen and progesterone receptors. In 21 patients (62%), local and/or distant recurrences developed (median time to recurrence, 16.2 months), and, to date, 20 have died from breast cancer (median time to death, 22.5 months). Progression of disease (defined as the development of either a recurrence or death resulting from disease) occurred in 24 patients (71%). Comparison with a set of 26 poorly differentiated ductal carcinomas with (nonextensive, patchy) necrosis matched for age, tumor size, and lymph node status showed a significantly worse progression-free survival rate for the CNC group (p <0.004). Conclusion: CNC is an uncommon but readily identifiable subtype of breast carcinoma and is characterized by early systemic metastasis and an accelerated clinical course.
CHORIO-CARCINOMATOUS
Breast carcinoma with choriocarcinomatous features. Resetkova E, Sahin A, Ayala AG, Sneige N.	Ann Diagn Pathol. 2004 Apr;8(2):74-9. Abstract quote Although breast carcinomas have been shown to produce various ectopic substances, including human chorionic gonadotropin, it is rare to identify morphologic differentiation compatible with the hormone produced by a tumor. Presently, only eight cases of breast carcinoma with focal choriocarcinomatous differentiation have been reported in the literature.     This article describes the pathologic findings, immunohistochemical profile, and clinical course in two additional cases of this unusual variant of breast carcinoma. In the first case, the tumor had morphologic features suggestive of medullary carcinoma, and the patient is doing well 12 months after presentation. In the second case, the tumor was locally advanced at presentation with histologic features consistent with metaplastic carcinoma having squamous, sarcomatoid, and choriocarcinomatous elements. The patient presented with extensive multifocal metastases 6 months after the initial presentation and is not responding well to standard or experimental treatment regimen. Immunostaining for the beta subunit of human chorionic gonadotropin was localized mostly, but not entirely, to multinucleated syncytiotrophoblast-like giant cells within both tumors.
CLEAR CELL CARCINOMA
Clear cell carcinoma of the breast with immunohistochemical evidence of divergent differentiation. Shirley SE, Escoffery CT, Titus IP, Williams EE, West AB. Departments of Pathology and Surgery, University of the West Indies, Mona, Jamaica; and the Department of Pathology, New York University, New York, NY.	Ann Diagn Pathol 2002 Aug;6(4):250-6 Abstract quote Primary clear cell carcinoma of the breast is a rare tumor. The clear cell morphology of the neoplastic population in these tumors has been ascribed to the presence of intracellular lipid, mucin or glycogen, or to myoepithelial, apocrine, or neuroendocrine differentiation. However, a clear cell neoplasm exhibiting evidence of a range of differentiation has not been previously reported. We describe a case of a glycogen-rich primary clear cell breast carcinoma occurring in a 59-year-old woman that showed positivity for apocrine and neuroendocrine markers, as well as possible myoepithelial differentiation. The tumor was a 4-cm mass composed predominantly of periodic acid-Schiff-positive clear cells arranged in a solid, infiltrative pattern. Immunohistochemical staining of the tumor cells was variably positive for cytokeratin, progesterone receptors, gross cystic disease fluid protein-15, neuron specific enolase, chromogranin, and S-100 protein and negative for estrogen receptors, smooth muscle actin, CD31, and CD34. The patient refused any form of further investigation or treatment, but shows no evidence of recurrence or metastatic disease after 18 months of follow-up.
COLLOID CARCINOMA
CYLINROMA
Cylindroma of the Breast of Skin Adnexal Type: A Study of 4 Cases. Nonaka D, Rosai J, Spagnolo D, Fiaccavento S, Bisceglia M. *Department of Pathology, National Cancer Institute, Milan, Italy; daggerWestern Australian Centre for Pathology and Medical Research, Nedlands, Australia; double daggerAnatomic Pathology Service, Casa di Cura Poliambulanza, Brescia, Italy; and the section signDepartment of Pathology, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy	Am J Surg Pathol. 2004 Aug;28(8):1070-1075. Abstract quote   Four cases of solitary cylindroma of the breast of skin adnexal type are described. The tumors were morphologically and immunophenotypically identical to their dermal counterparts. They arose in close proximity to the nipple, such as the retroareolar area of the breast and in intimate association with the lactiferous ducts, suggesting an origin from the latter structures. One case occurred in a woman with hereditary multiple cylindromatosis (Brooke-Spiegler syndrome). This is the second reported case of this hereditary syndrome with extracutaneous manifestations and the first case in which the breast is involved.
ESTROGEN RECEPTOR NEGATIVE CARCINOMA
Estrogen receptor-negative breast carcinomas: a review of morphology and immunophenotypical analysis. Putti TC, El-Rehim DM, Rakha EA, Paish CE, Lee AH, Pinder SE, Ellis IO. 1Department of Pathology, National University of Singapore, Singapore.	Mod Pathol. 2005 Jan;18(1):26-35 Abstract quote. Estrogen receptor (ER)-negative breast cancers are a group of tumors with poor prognosis and fewer cancer prevention and treatment strategies compared to ER-positive tumors. The aim of this study was to assess the morphological characteristics and immunohistochemical profile of ER-negative tumors and thus to understand the biological behavior and unique nature. In total, 291 consecutive ER-negative cases available from our primary breast cancer series were examined. Hematoxylin- and eosin-stained sections of all the cases were studied for several morphological parameters and their immunophenotype profile. These findings were correlated with patient and tumor characteristics and survival data. ER-negative tumors constituted 30% of the primary operable breast cancer series. The majority of tumors were grade 3 (94%) and the commonest histological types were ductal/no specific type (85%), and atypical medullary carcinoma (8%). High-grade comedo-type necrosis, lymphoid stroma, central necrosis/fibrosis and pushing margins were the most common morphological features. The presence of a pushing margin showed a significant relation to androgen receptor negativity, absence of epidermal growth factor receptor expression and negative lymph nodes. Lymphoid stroma and comedo-necrosis correlated with higher tumor grade. ER-negative breast cancers are a distinct group of tumors with several common morphological features. Grade 3 histology, pushing margin, lymphoid stroma, comedo-type necrosis and central fibrosis/necrosis are the dominant morphological findings. The presence of a pushing margin appears to have a significant correlation with negative lymph node status. ER-negative tumors show a higher expression of p53, CerbB2 and epidermal growth factor receptor compared to ER-positive breast cancer. These unique features support the concept that ER-negative tumors are a morphologically and phenotypically distinct entity and provide a rationale for the study and use of newer promising agents in the treatment of ER-negative breast cancer.
FAMILIAL
Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium.	Lancet 1997 May 24;349(9064):1505-10 Abstract quote BACKGROUND: A few breast cancer cases are attributable to a hereditary predisposition to the disease. We aimed to compare the histological features of breast cancer in women carrying mutations in the susceptibility genes BRCA1 and BRCA2 with controls unselected for family history. METHODS: The morphological characteristics of specimens from 440 patients with familial breast cancer, including 118 in carriers of BRCA1 mutations and 78 in carriers of BRCA2 mutations, were compared with those from 547 age-matched controls, unselected for family history, by seven pathologists. FINDINGS: Cancers in carriers of BRCA1 (p < 0.0001) and BRCA2 mutations (p = 0.04) were, on average, of a higher overall grade than in controls. For example, the proportions in grade 3 were 66% of 139, 41% of 58 and 36% of 368 specimens, respectively. However, when the three grade indices were considered independently, breast cancers in BRCA1-mutation carriers showed more pleomorphism (p = 0.006), a higher mitotic count (p < 0.0001), and less tubule formation than controls (p = 0.006), whereas cancers in BRCA2-mutation carriers showed less tubule formation (p = 0.003), but no difference in pleomorphism or mitotic count. The occurrence of invasive lobular carcinoma and invasive ductal carcinoma was not significantly different between carriers of BRCA1 or BRCA2 mutations and controls. Medullary or atypical medullary carcinoma was, however, found more often in BRCA1 (13%, p < 0.0001) than in BRCA2-mutation carriers (3%) or controls (2%). Tubular carcinoma was less common in BRCA2-mutation carriers. The few mucoid carcinomas were all in familial cases. Carriers of BRCA1 mutations showed less ductal carcinoma in situ around the invasive lesion than controls (41 vs 56%, p = 0.001). Lobular carcinoma in situ was less common in familial cancers (p = 0.013), but differences were not significant for BRCA1-mutations or BRCA2-mutation carriers, separately. INTERPRETATION: The histology of breast cancers in predisposed women differs from that in sporadic cases, and there are differences between breast cancers in carriers of BRCA1 and BRCA2 mutations. The findings suggest that breast cancer due to BRCA1, has a different natural history to BRCA2 or apparently sporadic disease, which may have implications for screening and management.
HISTIOCYTOID CARCINOMA
Histiocytoid breast carcinoma: an apocrine variant of lobular carcinoma. Walford N, ten Velden J. Department of Pathology, University of Amsterdam, The Netherlands.	Histopathology 1989 May;14(5):515-22 Abstract quote Two cases of in situ and invasive histiocytoid breast carcinoma are described. The invasive components of both tumours showed architectural and cytological similarities to lobular carcinoma. The in situ components showed areas of classical lobular carcinoma in situ, areas of lobular carcinoma with apocrine features and areas with transitional features. It is concluded that histiocytoid carcinoma represents an apocrine variant of lobular carcinoma. Differentiation of this tumour from chronic sclerosing inflammation may be difficult in both primary and secondary lesions.
Histiocytoid breast carcinoma: histological, immunohistochemical, ultrastructural, cytological and clinicopathological studies. Shimizu S, Kitamura H, Ito T, Nakamura T, Fujisawa J, Matsukawa H. Department of Pathology, Yokohama Minami Kyosai Hospital, Japan.	Pathol Int 1998 Jul;48(7):549-56 Abstract quote Histiocytoid breast carcinoma (HBC) is a rare variant of breast carcinoma and often causes a diagnostic dilemma because of its histological similarities to some types of breast cancer and benign lesions. To elucidate the incidence of HBC and its biological properties, histological specimens from 1010 breast cancer patients treated at Yokohama Minami Kyosai Hospital between 1972 and 1996 were reviewed. Three cases of pure HBC and three cases of combined HBC (two with pleomorphic lobular carcinoma and one with apocrine ductal carcinoma) were found, yielding an incidence of 0.3% for each. Two of the three pure HBC cases contained foci of in situ lobular carcinoma. Targetoid and Indian file invasive patterns, the features characteristic of lobular carcinoma, were present in all three pure HBC cases and in two of the three combined HBC with pleomorphic lobular carcinoma. These results, together with those of previous studies, suggested that the majority of HBC are of lobular origin, although the apocrine ductal origin is also possible in a small number of HBC. Diastase-resistant periodic acid-Schiff-positive granules and granular immunoreactivities for gross cystic disease fluid protein-15 (GCDFP-15) were characteristic of the histiocytoid tumor cells in both the pure and combined HBC, suggesting the apocrine differentiation of tumor cells. All three pure HBC cases were in stage 1 and were free of the disease for up to 5 years and 1 month after the lumpectomy. Thus, the prognosis of HBC appears to be dependent on the stage of the disease and may not always be poor, as indicated by the original report mentioning a preferential eyelid metastasis.
E-cadherin immunohistochemical analysis of histiocytoid carcinoma of the breast. Gupta D, Croitoru CM, Ayala AG, Sahin AA, Middleton LP. Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center, Houston; and the Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.	Ann Diagn Pathol 2002 Jun;6(3):141-7 Abstract quote Histiocytoid carcinoma is a rare type of invasive breast carcinoma. It has been considered to be a variant of lobular carcinoma, a variant of apocrine ductal carcinoma, and an apocrine variant of lobular carcinoma and to resemble lipid-rich carcinoma. In attempts to elucidate its histogenesis, investigators have used mucin and oil red O histochemical analysis and GCDFP-15 immunostaining. E-cadherin is a relatively recent addition to the armamentarium of immunohistochemical markers used for cell differentiation and is a member of a family of transmembrane glycoproteins that has been shown to have a strong correlation with the histologic phenotypes of breast carcinoma. Most ductal carcinomas show diffuse membrane expression of E-cadherin, and lobular carcinomas are characterized by complete lack of membrane staining of E-cadherin. The object of this study was to use E-cadherin immunohistochemical analysis to help clarify the histogenesis of histiocytoid carcinoma. Fourteen cases containing the diagnosis of histiocytoid carcinoma of the breast were identified at M. D. Anderson Cancer Center (Houston, TX) from 1988 to 2001. All cases were rereviewed, histologic features were evaluated, and immunohistochemical staining with E-cadherin and GCDFP-15 was performed. Clinical information was extracted from the patients' medical records. Eleven cases met published histologic criteria for histiocytoid carcinoma. The remaining three cases were apocrine carcinoma. The pattern of tumor infiltration was solid, without secondary lumen formation in all cases of histiocytoid carcinoma. Lobular carcinoma in situ was identified in eight cases, but was absent in three. There was no E-cadherin immunohistochemical staining in eight of the 11 cases of histiocytoid carcinoma (72.7%). GCDFP-15 was immunoreactive in all 10 cases of histiocytoid carcinoma where it was performed. Follow-up data was available for nine of the 11 cases of histiocytoid carcinoma: six patients were alive with disease at 1.5 to 48 months, one patient had died of disease at 60 months, and two patients had no evidence of disease at 32 and 45 months. We conclude that histiocytoid carcinoma has an immunophenotypical profile consistent with both ductal and lobular differentiation. Moreover, the lack of consistent morphologic features, a specific clinical profile, and a distinct immunohistochemical pattern lead us to hypothesize that histiocytoid carcinoma is not a special type of breast cancer.
INVASIVE MICROPAPILLARY CARCINOMA
Invasive micropapillary carcinoma of the breast : association of pathologic features with lymph node metastasis. Guo X, Chen L, Lang R, Fan Y, Zhang X, Fu L. Department of Breast Cancer Pathology and Research Laboratory, State Key Laboratory of Breast Cancer Research, Cancer Hospital of Tianjin Medical University, Tianjin, China.	Am J Clin Pathol. 2006 Nov;126(5):740-6 Abstract quote Invasive micropapillary carcinoma (IMPC) of the breast is characterized by a high incidence of axillary lymph node metastasis. To investigate the relationship between pathologic features and lymph node metastasis, 51 cases of breast carcinoma with IMPC components were studied. Immunohistochemical analysis for vascular endothelial growth factor (VEGF)-C and VEGF receptor (VEGFR)-3 was performed, and lymphatic vessel density was measured. The main findings included a significantly increased number of positive lymph nodes and/or an increased rate of lymph node metastasis in IMPC with a higher histologic grade, prominent stromal infiltration of lymphocytes, and higher VEGF-C expression and lymphatic vessel density. The percentage of IMPC component in the tumor was not associated with the incidence of lymph node metastasis. The results suggest that the histologic grade, lymphatic vessel density, and lymphocyte infiltration of IMPC are the key factors that influence lymph node metastasis. Further studies are required to elucidate the mechanisms underlying the lymphotropism of this distinct variant of breast carcinoma.
Immunohistochemical and clinicopathologic characteristics of invasive ductal carcinoma of breast with micropapillary carcinoma component. Kim MJ, Gong G, Joo HJ, Ahn SH, Ro JY. Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.	Arch Pathol Lab Med. 2005 Oct;129(10):1277-82. Abstract quote   CONTEXT: A micropapillary carcinoma (MC) component is generally considered to behave aggressively. Although several reports have described the prognostic significance of MC in breast carcinomas, immunohistochemical findings of MC, especially as compared to non-MC, are rarely described. OBJECTIVE: We compared clinicopathologic and immunohistochemical findings between 38 cases of invasive breast carcinoma with an MC component (IMC) and 217 cases of invasive breast carcinoma without an MC component (NIMC). DESIGN: We constructed a tissue microarray from 38 cases of IMC and performed immunohistochemical stainings for cytokeratin (CK) 7, CK20, estrogen receptor, progesterone receptor, p53, c-Erb-B2, CD34, CK5, epidermal growth factor receptor, and c-Kit in both MC and non-MC components. RESULTS: Cases with IMC were associated with greater tumor size, more frequent lymphovascular invasion, nodal metastases, greater mean numbers of positive lymph nodes, and higher stage than those with NIMC, but were not associated with poorer survival rates. On immunohistochemistry, only p53 reactivity was statistically different between MC and non-MC components in IMC cases. Estrogen receptor positivity tended to be lower in MC than non-MC, but the difference was not significant. Most of the MCs and non-MCs in IMC cases were positive for CK7, but none of them were positive for CK20, CK5, epidermal growth factor receptor, or c-Kit. CONCLUSIONS: Based on the frequent nodal metastases and association with higher stage found in IMC as compared with NIMC cases, as well as higher p53 positivity and lower frequency of estrogen receptor expression, MC could be considered an aggressive histologic type of breast carcinoma. In both MC and non-MC components in IMC cases, no basallike immunostaining pattern was detected.
Pathogenesis of invasive micropapillary carcinoma: role of MUC1 glycoprotein. Nassar H, Pansare V, Zhang H, Che M, Sakr W, Ali-Fehmi R, Grignon D, Sarkar F, Cheng J, Adsay V. Department of Pathology, Wayne State University, Harper University Hospital Detroit, MI 48201, USA.	Mod Pathol. 2004 Sep;17(9):1045-50. Abstract quote   Invasive micropapillary carcinoma, a tumor with highly infiltrative characteristics is defined by a distinctive cleft formation around the neoplastic cell clusters which is presumably a result of the detachment of the cells from the stroma due to as yet undetermined factors. Ultrastructural examination performed on a handful of cases demonstrated an unexpected secretory activity in the stroma-facing surface of the cells. MUC1 is a glycoprotein typically expressed in the apical surface of normal epithelial cells, responsible for maintaining lumen formation. In conventional adenocarcinomas, MUC1 expression is largely intracytoplasmic, intercellular, or apical (in glandular areas). The MUC1 expression pattern was investigated by immunohistochemical staining in invasive micropapillary carcinoma of breast (n=11), pancreas (n=5), gynecologic tract (n=11) and urinary bladder (n=10). The results were contrasted with the staining pattern in conventional carcinomas of the same organs (n=202). In all invasive micropapillary carcinoma, MUC1 expression was predominantly in the stroma-facing surface of the cell clusters (basal), accentuating the outlines of the micropapillary units by forming a distinct band on this surface. In conventional carcinoma the labeling was mostly apical in areas with lumen formation and intracytoplasmic and intercellular in the poorly differentiated areas. In conclusion, in the micropapillary pattern of invasive carcinoma, the expression of MUC1, is largely limited to the basal surface of the cells in contrast to conventional carcinomas in which MUC1 is largely apical, intracytoplasmic or intercellular. This provides support for the reversal of cell orientation as an important factor of the morphogenesis and possibly the pathogenesis of invasive micropapillary carcinoma. Since MUC1 is known to have a role in lumen formation, and has an inhibitory role in the cell to stroma interaction, it is conceivable that it is a key factor in the detachment of cells from stroma allowing for the dissection of the connective tissue and easing the spread of cells.
Invasive Micropapillary Carcinoma of the Breast Clinicopathologic Study of 62 Cases of a Poorly Recognized Variant With Highly Aggressive Behavior Guido Pettinato, MD, etal.	Am J Clin Pathol 2004;121:857-866 Abstract quote We report 62 cases of invasive micropapillary carcinoma of the breast characterized by delicate pseudopapillary structures lacking a fibrovascular core and by tubuloalveolar structures freely floating in clear, empty spaces. All patients but 1 were women (median age, 57 years; range, 25-89 years). Tumor size ranged from 0.7 to 10 cm (median, 2.8 cm); 54 (87%) were grade 3. Psammoma bodies were identified in 29 (47%). Focal to massive lymphatic permeation was present in 39 (63%). Architectural features were retained in the node metastases, dermal lymphatics, and recurrences. Fifty-six patients (90%) had metastatic axillary nodes: 18 tumors were estrogen receptor–positive (32%); 11 were progesterone receptor–positive (20%); HER2/neu was overexpressed in 53 (95%) and p53 in 39 (70%). A peculiar immunoreactivity for MUC1 limited to the cytoplasmic membrane oriented toward the stroma and an absence of immunoreactivity for E-cadherin in the same side of the cytoplasmic membrane indicated inversion of cell polarization and a disturbance in the cell adhesion molecules. Of 41 patients with available follow-up, 29 (71%) had local recurrence (mean, 30 months) and 20 (49%) died of disease. These results underscore the aggressive behavior and poor prognosis of this breast carcinoma variant. Aggressive preoperative neoadjuvant chemotherapy should be considered.
Invasive micropapillary carcinoma of the breast: Eighty cases of an underrecognized entity Mary M. Walsh, MD and Ira J. Bleiweiss, MD	Hum Pathol 2001;32:583-589. Abstract quote Eighty cases of infiltrating duct carcinoma of the breast with a pure or partial micropapillary component are reported. The cases were analyzed using various parameters, including age at presentation, tumor size, tumor grade, presence of lymphatic invasion, and axillary lymph node status. The patients' age at presentation ranged from 36 to 92 years (mean, 58.8 years). Tumor size ranged from 0.1 to 10 cm (mean, 2.0 cm); 67.5% (54 of 80) were poorly differentiated, and 32.5% (26 of 80) were moderately differentiated; 62.5% (50 of 80) of the cases had lymphatic invasion; 72.3% (47 of 65) of cases with axillary dissections had positive lymph nodes; and 25% (20 of 80) of the tumors were 1.0 cm and 7.5% (6 of 80) were 0.5 cm. The characteristics of these small tumors with an invasive micropapillary component have not previously been reported. Despite their minute size, these small micropapillary carcinomas seem to show the same proclivity for lymphatic spread and nodal dissemination as larger tumors with this unique histologic pattern.
Clinicopathologic Analysis of Invasive Micropapillary Differentiation in Breast Carcinoma Hind Nassar, M.D., Tracy Wallis, B.S., Aleodor Andea, M.D., Jyotirmoy Dey, Ph.D., Volkan Adsay, M.D. and Daniel Visscher, M.D. Departments of Pathology and BiostatisticsHarper Hospital, Wayne State University and the Karmanos Cancer Institute, Detroit, Michigan	Mod Pathol 2001;14:836-841 Abstract quote Invasive micropapillary carcinoma (IMPCa) of breast is histologically characterized by growth of cohesive tumor cell clusters within prominent clear spaces resembling dilated angiolymphatic vessels. In this study, eighty three breast carcinomas with IMPCa differentiation were identified by review of the invasive carcinoma cases in our institution and correlated retrospectively with standard clinicopathologic parameters and survival status relative to a control series of cases (mean follow up 7 years). IMPCa growth pattern was present in 6% of all breast carcinomas; it was generally a focal component in otherwise typical invasive ductal carcinoma. It comprised more than 80% of the total neoplasm in only 10 cases (12%), 50–80% of the neoplasm in 7 cases (8%), 20–50% of the neoplasm in 22 cases (26%) and less than 20% in 44 cases (53%). The mean tumor size was 4 cm, 22% invaded skin, and 58% were poorly differentiated, but 71% were ER positive. Axillary node metastases were present in 77% of cases, were typically multiple (51% had three or more positive), and usually contained an IMPCa component (81% of the cases). There was no significant difference in node status, ER status, size, tumor grade, or peritumoral angiolymphatic invasion between tumors with predominant (more than 50%) v/s focal IMPCa components. In both groups 46% of the patients died from their disease (mean interval to death = 36m). Skin involvement and nodal status were the only parameters which predicted poor survival (P = .01). The outcome of patients with IMPCa did not differ significantly from infiltrating ductal carcinomas of similar node status. In conclusion, our results suggest that IMPCa growth pattern may be a manifestation of aggressive behavior, as shown by frequent skin invasion and extensive nodal involvement. However, clinicopathologic features and outcome of IMPCa are not strongly dependent on the relative amount of micropapillary component.
Invasive micropapillary carcinoma of the breast is associated with chromosome 8 abnormalities detected by comparative genomic hybridization. Thor AD, Eng C, Devries S, Paterakos M, Watkin WG, Edgerton S, Moore DH 2nd, Etzell J, Waldman FM. Department of Pathology, University of Oklahoma Health Science Centers, Oklahoma City, USA.	Hum Pathol 2002 Jun;33(6):628-31 Abstract quote Invasive micropapillary carcinoma (IMC) of the breast is a rare variant of invasive ductal carcinoma (IDC) characterized by unique histology and an extremely high incidence of lymph node metastases (approximately 95%). Comparative genomic hybridization (CGH) was used to characterize DNA extracted from 16 archival IMC cases to identify clonal genetic changes associated with this unique and highly metastatic cancer subtype. The average number of chromosomal alterations per IMC tumor was 7.4 +/-2.9 (3.4 gains and 3.9 losses), fewer than the number that we have observed in IDCs not otherwise specified (9.5 +/-6.6), IDCs with erbB-2 gene amplification (12.6 +/-5.9), and invasive lobular carcinomas (8.2 +/-5.5). The mean number of changes in IMC was significantly higher than we have observed in the rarely metastasizing tubular subtype of IDC (3.9 +/-2.3, P = 0.001), but less than the more aggressive subset of erbB-2-amplified IDC (P = 0.02). Remarkably, 100% of IMCs demonstrated loss involving the short arm of chromosome 8 (8p). Six cases showed loss of the entire 8p arm, whereas in 10 cases the loss was limited to the distal portion (8p21-pter) with localized gain of proximal 8p (8p11-p12). A reciprocal gain of 8q was detected in 14 cases (88%). Other common alterations included loss of 17p in 50% of tumors and loss of 16q in 50% of IMC cases. Gains of 17q (38%), 1q (31%), and 16p (25%) were also commonly detected. In comparison, IDCs (not otherwise specified), IDCs of the tubular subtype, and invasive lobular carcinomas showed only modest 8p loss (33%, 28%, and 13%, respectively). This region of chromosome 8 may contain 1 or more genes whose loss leads to this particular histology and/or the lymphotrophic phenotype associated with this histopathologic pattern.
Invasive micropapillary carcinoma of the breast: a prognostic study. Paterakos M, Watkin WG, Edgerton SM, Moore DH 2nd, Thor AD. Department of Pathology, Evanston Northwestern Healthcare and Northwestern University Medical School, IL 60201, USA.	Hum Pathol. 1999 Dec;30(12):1459-63. Abstract quote Invasive micropapillary carcinoma (IMC) of the breast is a rare variant of infiltrating ductal carcinoma that has been associated with an extremely high incidence of lymph node metastases. Follow-up studies on patients with pure IMC breast cancer histology have been limited by low patient numbers, short duration of follow-up, and a lack of multivariate analyses. Using invasive breast cancers from 1,287 patients (median follow-up, 13.8 years), histological review showed 21 cases (1.7%) with pure IMC histology. Pure IMC histology was associated with high-grade histology (P = .04), metastases to regional lymph nodes (P < .001), a high mitotic index (P = .02), and erbB-2 immunopositivity (P = .007). Univariate analyses showed a strong association between IMC histology and shortened survival (disease-free survival [DFS], P = .0052; median, 44 months for IMC and 63 months for non-IMC; disease-specific survival [DSS], P = .014; medians, 71 and 78 for IMC and non-IMC, respectively) only in an analysis of all patients. Because only 1 case of node-negative IMC histology was available, univariate analysis of IMC histology was performed only on node-positive patients without significance. Multivariate analyses comparing IMC histology with either node-positive or all other breast cancers failed to show independent prognostic significance. In summary, breast cancer patients with pure IMC histology showed survival rates similar to those of other patients with equivalent numbers of lymph node metastases.
METAPLASTIC CARCINOMA
Metaplastic Sarcomatoid Carcinoma of the Breast With Absent or Minimal Overt Invasive Carcinomatous Component: A Misnomer. Davis WG, Hennessy B, Babiera G, Hunt K, Valero V, Buchholz TA, Sneige N, Gilcrease MZ. From the Departments of *Pathology, daggerMedical Oncology, double daggerSurgical Oncology, and section signRadiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX.	Am J Surg Pathol. 2005 Nov;29(11):1456-1463. Abstract quote   Metaplastic carcinomas of the breast are a heterogeneous group of neoplasms ranging from tumors with a predominant component of overt carcinoma and focal mesenchymal differentiation to keratin-positive tumors with pure sarcomatoid morphology. We examined the clinicopathologic features of 22 patients previously diagnosed at M.D. Anderson Cancer Center with metaplastic carcinoma of the breast with pure or almost pure sarcomatoid morphology. Patients were included in the study if their tumors had sarcomatoid morphology and: 1) an invasive carcinomatous component identifiable on hematoxylin and eosin stains comprising less than 5% of the invasive tumor; or 2) associated ductal carcinoma in situ; or 3) immunohistochemical expression of keratin in the sarcomatoid areas. Patients with low-grade fibromatosis-like metaplastic tumors and those who received neoadjuvant chemotherapy were excluded. Axillary lymph node dissection or limited axillary node excision was performed in 17 patients, including 1 patient who had a sentinel lymph node biopsy. Lymph node involvement occurred in only 1 patient and consisted of a single 3.5-mm metastasis. Clinical follow-up was available for 21 patients and ranged from 4 months to 155 months (median follow-up, 35 months). Ten patients experienced local relapse, including 7 of 11 patients treated with breast-conserving surgery, and 9 developed distant metastases, most frequently to the lungs. These findings suggest that metaplastic sarcomatoid carcinomas that lack or have only a minimal overt invasive carcinomatous component have a biologic behavior similar to that of sarcomas. In addition to systemic treatment, early aggressive local therapy is recommended, as these patients have a high rate of local relapse.
Metaplastic breast carcinomas: are they of myoepithelial differentiation?: immunohistochemical profile of the sarcomatoid subtype using novel myoepithelial markers. Leibl S, Gogg-Kammerer M, Sommersacher A, Denk H, Moinfar F. From the Department of Pathology, Medical University of Graz, Graz, Austria.	Am J Surg Pathol. 2005 Mar;29(3):347-53. Abstract quote   We investigated 20 spindle cell (sarcomatoid) metaplastic carcinomas (MCs) without squamous differentiation. In addition, five high-grade phyllodes tumors were assessed for comparison. Our immunohistochemical antibody panel included pan-cytokeratin (CK), low molecular weight CK (CK8/18), four basal cell type CKs (34betaE12, CK5/6, CK14, and CK17), vimentin antibodies, as well as antibodies to established (SMA, CD10, p63, S-100, maspin, calponin, GFAP, SM-myosin), and novel (CD29, 14-3-3sigma) myoepithelial markers. Sixteen of the 20 tumors (80%) expressed at least two markers of the combination CD10/p63/SMA. S-100 detected 1 case negative for CD10/p63/SMA and 3 cases that only expressed one marker of this combination. While 18 MCs (90%) were positive for CD29, 14-3-3sigma (11 cases) and maspin (9 cases) were observed in 55% and 45%, respectively. Antibodies to pan-CK and the basal cell type CKs were strongly reactive in 12 tumors (60%), but in 6 cases (30%) positivity for these markers was weak and only focal; 2 MCs showed no positivity for CK. The stromal component of all phyllodes tumors was positive for vimentin, whereas all other investigated markers were absent except for focal p63 and CD10 expression in 1 case each. Our findings convincingly show a myoepithelial immunophenotype in sarcomatoid MCs, which is demonstrated by the presence of basal cell type CKs and the combination of the established myoepithelial markers CD10, p63, SMA, and S-100. We conclude that tumors with weak or even absent CK expression should only be diagnosed as primary sarcomas of the breast after exclusion of a myoepithelial immunophenotype. CD29 and 14-3-3sigma represent valuable novel myoepithelial markers in these diagnostically difficult cases.
Metaplastic Carcinoma of the Breast: p53 Analysis Identified the Same Point Mutation in the Three Histologic Components Xiaojuan Wang, M.D., Ichiro Mori, M.D., Ph.D., Weihua Tang, M.D., Qifeng Yang, M.D., Misa Nakamura, Ph.D., Yasushi Nakamura, M.D., Ph.D., Misako Sato, B.S., Takeo Sakurai, M.D., Ph.D. and Kakudo Kennichi, M.D., Ph.D. Department of Pathology (XW, IM, WT, MN, YN, MS, KK), Wakayama Medical University, Japan; and Department of Surgery (QY, TS), Affiliated Kihoku Hospital, Wakayama Medical University, Japan	Mod Pathol 2001;14:1183-1186 Abstract quote A rare case of metaplastic carcinoma of the breast with both squamous metaplasia and cartilaginous metaplasia was reported. Histologically, the neoplasm revealed complex features, which were consisting of invasive ductal carcinoma, squamous carcinomatous component and chondrosarcomatoid component. Gradual transition of each component was recognized microscopically. p53 mutation analysis disclosed the same point mutation in three histologically different components, but not in the normal epithelium. Based on the morphologic findings, immunohistochemical findings and the p53 mutation analysis, we concluded that these three components in the tumor originated from the same duct progenitor cells.
MINIMAL
Minimal (< or =0.1 cm) invasive carcinoma in breast core needle biopsies. Incidence, sampling, associated findings, and follow-up. Renshaw AA. Department of Pathology, Baptist Hospital of Miami,	Arch Pathol Lab Med. 2004 Sep;128(9):996-9. Abstract quote   CONTEXT: Although minimally invasive (microinvasive) carcinoma (< or =0.1 cm) of the breast is a well-known and well-characterized entity in excision specimens, the significance of small foci of invasion in breast core needle biopsies has not been well described. OBJECTIVE: To define the significance of minimally invasive carcinoma in breast core needle biopsies. DESIGN: Review of a large series of core needle biopsies for invasive carcinomas measuring 0.1 cm or less and correlation of the results with those of subsequent excision. SETTING: Large community hospital. RESULTS: From approximately 8500 biopsies, a total of 18 cases of minimally invasive carcinoma from 16 women aged 42 to 80 years were identified. All were present on only 1 of 8 slides made from the block. Overall, the incidence was approximately 0.1% of all biopsies and 1% of all invasive carcinomas. Six cases were invasive lobular carcinomas, 1 was tubulolobular carcinoma, 3 were tubular carcinomas, and the remaining 8 were ductal carcinomas. Eight cases were associated with high-grade comedo ductal carcinomas, 2 with low-grade ductal carcinoma in situ, 3 with atypical ductal hyperplasia, 3 with atypical ductal hyperplasia and lobular carcinoma in situ, and 2 with no other lesion. From a total of 8 sections done entirely through the block, the lesion was present on the first level in 4 cases and the fifth level in 5 cases. No cases were identified in the last 3 levels. Subsequent pathology was available for 16 of the 18 cases. Invasive carcinomas measuring more than 1 cm were present in 9 cases (64%; along with 2 positive lymph nodes), invasive carcinomas less than 1 cm in 2 cases (14%), ductal carcinoma alone in 4 cases (29%), and no carcinoma in 1 case (7%). No pathologic or radiologic features were associated with the finding of invasive carcinoma at excision. CONCLUSION: Invasive carcinoma measuring 0.1 cm or less is a rare finding in breast core needle biopsies, is commonly associated with in situ carcinomas and atypical hyperplasias, and is often associated with larger invasive foci at excision. However, invasive carcinomas smaller than 0.1 cm can occur without any other significant findings and may require relatively extensive sampling to identify.
MYOEPITHELIAL TUMORS
Mammary NOS-Type Sarcoma With CD10 Expression: A Rare Entity With Features of Myoepithelial Differentiation. Leibl S, Moinfar F. Institute of Pathology, Medical University of Graz, Graz, Austria.	Am J Surg Pathol. 2006 Apr;30(4):450-6. Abstract quote   We present an extensive immunohistochemical analysis of 7 mammary sarcomas that did not fit into any specific soft tissue sarcoma category. Histologically, they were composed of spindle cells with highly pleomorphic nuclei and abundant mitoses. Our immunohistochemical antibody panel included pan-cytokeratin (CK), basal cell type CKs (34betaE12, CK5/6, CK14, CK17) and vimentin antibodies, antibodies to established (SMA, CD10, p63, S-100, maspin, calponin, GFAP, SM-myosin), and novel (CD29, 14-3-3sigma) myoepithelial markers, as well as antibodies to CD34, desmin, h-caldesmon, steroid receptors (estrogen, progesterone, androgen), and EGFR (Her-1). Whereas CKs, CD34, desmin, and h-caldesmon were not expressed, all tumors were positive for CD10 and vimentin. CD29 and SMA were observed in 3 cases each (43%), and p63 and calponin in 2 cases each (29%). Other myoepithelial markers and steroid receptors were absent, except androgen receptors, which were expressed in one sarcoma. Five sarcomas showed positivity for EGFR. The distinction of specific, histogenetically defined sarcoma entities (such as leiomyosarcoma, angiosarcoma, liposarcoma) from NOS-type sarcoma with CD10 expression is usually clear-cut because the former exhibit a characteristic histomorphology and immunoprofile. Phyllodes tumors with stromal overgrowth or recurrent phyllodes tumors lacking epithelial structures as well as periductal stromal sarcomas can be ruled out by their frequent expression of CD34 and negativity for myoepithelial markers. The most important differential diagnosis is sarcomatoid metaplastic carcinoma because its treatment includes axillary lymphadenectomy. Since some NOS-type sarcomas with CD10 expression and most metaplastic carcinomas show positivity for CD29, SMA, and p63, differential diagnosis can be extremely difficult and requires extensive immunohistochemical evaluation for CKs and additional myoepithelial markers such as S-100, 14-3-3sigma, and maspin. The immunophenotype of NOS-type sarcomas with CD10 expression suggests that these neoplasms represent a mammary sarcoma variant with myoepithelial features.
Benign Myoepithelial Tumors of the Breast Have Immunophenotypic Characteristics Similar to Metaplastic Matrix-Producing and Spindle Cell Carcinomas Nikolay K. Popnikolov, MD, PhD,1* Alberto G. Ayala, MD,2 Kerry Graves,1 and Zoran Gatalica, MD, DSc	Am J Clin Pathol 2003;120:161-167 Abstract quote We immunohistochemically compared benign myoepithelial tumors (adenomyoepitheliomas [AMEs]) and metaplastic matrix-producing (MMP-CA) and spindle cell (MSC-CA) carcinomas of the breast to identify helpful diagnostic markers. Normal myoepithelial cells (MECs) consistently expressed cytokeratin, a-smooth muscle actin (SMA), myosin, S-100, CD10, and maspin. They were variably positive for vimentin and negative for epithelial membrane antigen (EMA), steroid receptors, p53, and HER-2/neu. MECs in AMEs less frequently expressed CD10 (4/8 [50%]) and myosin (6/8 [75%]) but frequently acquired characteristics of luminal cells, such as expression of EMA (5/8 [63%]) and steroid receptors (5/8 [63%]). No abnormal p53 or HER-2/neu expression was seen in AMEs. MMP-CA and MSC-CA were similar to AMEs in cytokeratin, vimentin, S-100, maspin, and HER-2/neu expression. MMP-CAs expressed less a-SMA (2/8 [25%]) and myosin (2/7 [29%]) and lacked estrogen receptor (0/9 [0%]). MSC-CAs were consistently CD10+ (4/4 [100%]) yet failed to express myosin (0/3 [0%]). p53 overexpression was seen frequently in MMP-CAs (4/8 [50%]) and MSC-CAs (1/3 [33%]). Benign myoepithelial mammary tumors differ immunophenotypically from normal MECs; a panel of immunohistochemical markers may be required to establish their myoepithelial origin. A similarly altered myoepithelial phenotype also is characteristic of metaplastic mammary carcinomas. The abnormal expression of oncogenes or antioncogenes, such as p53, may be more useful for distinguishing between those entities than the expression of the classic myoepithelial markers.
PAPILLARY
Intracystic Papillary Carcinomas of the Breast: A Reevaluation Using a Panel of Myoepithelial Cell Markers. Collins LC, Carlo VP, Hwang H, Barry TS, Gown AM, Schnitt SJ. *Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA daggerPhenoPath Laboratories, Seattle, WA.	Am J Surg Pathol. 2006 Aug;30(8):1002-1007 Abstract quote Intracystic papillary carcinomas (IPC) of the breast have traditionally been considered to be variants of ductal carcinoma in situ (DCIS). However, it is not clear if all lesions categorized histologically as IPC are truly in situ carcinomas, or if some such lesions might represent circumscribed or encapsulated nodules of invasive papillary carcinoma. Given that the demonstration of a myoepithelial cell (MEC) layer around nests of carcinoma cells is a useful means to distinguish in situ from invasive carcinomas of the breast in problematic cases, assessment of the presence or absence of a MEC layer at the periphery of the nodules that comprise these lesions could help resolve this issue. We studied the presence and distribution of MEC at the periphery of the nodules of 22 IPC and, for comparison, 15 benign intraductal papillomas using immunostaining for 5 highly sensitive markers that recognize various MEC components: smooth muscle myosin heavy chain, calponin, p63, CD10, and cytokeratin 5/6. All 22 lesions categorized as IPC showed complete absence of MEC at the periphery of the nodules with all 5 markers. In contrast, a MEC layer was detected around foci of conventional DCIS present adjacent to the nodules of IPC. Furthermore, all benign intraductal papillomas, including those of sizes comparable to those of IPC, showed a MEC layer around virtually the entire periphery of the lesion with all 5 MEC markers. In conclusion we could not detect a MEC layer at the periphery of the nodules of any of 22 lesions categorized histologically as IPC. One possible explanation for this observation is that these are in situ lesions in which the delimiting MEC layer has become markedly attenuated or altered with regard to expression of these antigens, perhaps due to their compression by the expansile growth of these lesions within a cystically dilated duct. Alternatively, it may be that at least some lesions that have been categorized as IPC using conventional histologic criteria actually represent circumscribed, encapsulated nodules of invasive papillary carcinoma. Regardless of whether these lesions are in situ or invasive carcinomas, available outcome data indicate that they seem to have an excellent prognosis with adequate local therapy alone. Therefore, we believe it is most prudent to continue to manage patients with these lesions as they are currently managed (ie, similar to patients with DCIS) and to avoid categorization of such lesions as frankly invasive papillary carcinomas. Given our observations, we favor the term "encapsulated papillary carcinoma" over "intracystic papillary carcinoma" for circumscribed nodules of papillary carcinoma surrounded by a fibrous capsule in which a peripheral layer of MEC is not identifiable.
Clinicopathologic Analysis of Solid Papillary Carcinoma of the Breast and Associated Invasive Carcinomas. Nassar H, Qureshi H, Volkanadsay N, Visscher D. *Wayne State University/Harper Hospital and the Karmanos Cancer Institute, Detroit, MI daggerMayo Clinic, Rochester, MN.	Am J Surg Pathol. 2006 Apr;30(4):501-507. Abstract quote Solid papillary carcinomas (SPCs) are uncommon tumors composed of circumscribed large cellular nodules separated by bands of dense fibrosis. The aim of this study was to further elucidate the characteristics of SPC, the types and significance of invasive carcinomas associated with these tumors, and the long-term clinical outcome. Fifty-eight SPCs were analyzed (mean follow-up, 9.4 years). Cases were divided into three groups: 1) SPC only (32.7%), 2) SPC with extravasated mucin (8.6%), and 3) SPC with invasive components (58.7%) consisting of neuroendocrine-like (29.5%), colloid (23.5%), ductal not otherwise specified (14.5%), lobular (3%), tubular (3%), or mixed (26.5%). The mean age was 72 years. All were estrogen receptor positive and 86% were histologic grade 1. The total size of the tumor measured 0.3 to 15 cm. In the group with invasive carcinoma, the size of invasion was 0.1 to 4 cm. Axillary nodes were involved in 13% of the cases (6 of 46); all of these had an invasive component in the primary tumor. Local recurrence was seen in 5 patients, all from the group with invasive carcinoma. Overall, 11.7% died of their tumor, 1 to 4 years after diagnosis (mean, 2.3 years); none of them belongs to the group of noninvasive SPC. Five of the 6 patients who died of tumor had invasive components. The sixth patient who died with "metastatic signet-ring cell carcinoma" at 10 years was in the group of patients with SPC with extravasated mucin where the SPC lesion had prominent signet-ring cell features. In conclusion, SPCs are heterogeneous lesions that arise in older women and have an indolent behavior. Lymph node and distant metastases are uncommon and generally limited to cases with (conventional) invasive components.
Cytokeratins in Papillary Lesions of the Breast: Is There a Role in Distinguishing Intraductal Papilloma From Papillary Ductal Carcinoma In Situ? Tan PH, Aw MY, Yip G, Bay BH, Sii LH, Murugaya S, Tse GM. From the *Department of Pathology, Singapore General Hospital, Singapore; daggerDepartment of Anatomy, National University of Singapore, Singapore; and double daggerDepartment of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong.	Am J Surg Pathol. 2005 May;29(5):625-632. Abstract quote   We studied 50 papillary lesions (25 papillomas and 25 papillary ductal carcinomas in situ, DCIS) diagnosed at Singapore General Hospital, for immunohistochemical expression of cytokeratin (CK) 5/6, CK14, and 34betaE12. The immunoscore (proportion of stained cells multiplied by staining intensity) was compared between the two groups. Cytokeratin expression was corroborated by confocal microscopy. Results were applied to a separate series of 43 papillary tumors from Hong Kong (HK). CK5/CK6, CK14, and 34betaE12 showed higher immunoscores in papillomas (mean values, 107.6, 186.6, and 113.1, respectively) than papillary DCIS (mean values, 12, 29.6, and 34.5, respectively; P < 0.0001, P < 0.001, and P < 0.02, respectively). A cutoff immunoscore threshold of 50 appeared discriminatory between papilloma and papillary DCIS, and this value was applied to the HK cases, with CK5/CK6, CK14, and 34betaE12 correctly predicting 25 (89.3%), 26 (92.9%), and 27 (96.4%), respectively, of 28 HK lesions labeled as papillomas; while they corroborated 13 (86.7%), 13 (86.7%), and 5 (33.3%), respectively, of 15 HK cases diagnosed as papillary DCIS. Review of discordant cases showed that lesions were small, derived from core biopsies, or disclosed accompanying invasive carcinoma. When both SGH and HK cases were combined as a group, the sensitivity of an immunoscore of 50 or less in the diagnosis of papillary DCIS was 95%, 85%, and 62.5% for CK5/CK6, CK14, and 34betaE12, respectively, while the specificity was 86.8%, 94.3%, and 86.8%, respectively. CK immunohistochemistry can aid in evaluating papillary breast lesions. 34betaE12 does not appear as useful in identifying papillary DCIS.
Myoepithelial Cell Staining Patterns of Papillary Breast Lesions From Intraductal Papillomas to Invasive Papillary Carcinomas Cheryl B. Hill, MD, and I-Tien Yeh, MD	Am J Clin Pathol 2005;123:36-44 Abstract quote We evaluated 25 intraductal papillomas and 18 papillary carcinomas (invasive, 4; micropapillary ductal carcinoma in situ [DCIS], 5; cases originally classified as intracystic/intraductal papillary carcinoma, 9) by calponin, smooth muscle myosin heavy chain (SMM-HC), and p63 immunostains. Calponin, SMM-HC, and p63 labeled myoepithelial cells (MECs) in all intraductal papillomas and all micropapillary DCIS cases. The invasive papillary carcinoma cases were uniformly negative for all stains. The 9 cases originally diagnosed as intracystic/intraductal papillary carcinoma showed more variable results, with identification of an MEC layer in only 4 cases. Comparison of staining of MECs by these 3 stains showed that calponin was more sensitive and intense than SMM-HC; however, there was cross-reactivity with myofibroblastic cells. Staining with p63 was discontinuous, making interpretation of an intact myoepithelial layer difficult. Of 9 cases originally classified as intraductal papillary carcinoma, 5 showed absence of a basal MEC layer by immunohistochemical analysis. The lack of a basal MEC layer in these cases suggests a spectrum of progression from in situ to invasive disease and might help explain distant metastases from previously reported "intraductal papillary carcinoma."
Papillary Lesions of the Breast With and Without Atypical Ductal Hyperplasia Can We Accurately Predict Benign Behavior From Core Needle Biopsy? S. Nicholas Agoff, MD, and Thomas J. Lawton, MD	Am J Clin Pathol 2004;122:440-443 Abstract quote Evaluation of papillary lesions of the breast can be difficult, and in core needle biopsy specimens, accurate diagnosis is challenging. Initial studies suggested that all papillary lesions revealed by core biopsy required surgical excision. Recent data suggest that only papillary lesions with atypical ductal hyperplasia (ADH) revealed by core biopsy need surgical excision. We evaluated our experience at the University of Washington Medical Center, Seattle, with papillary lesions with and without ADH on core biopsy to determine whether diagnostic accuracy can be achieved. In 51 core biopsy specimens, we evaluated the presence or absence of ADH: 25 were benign papillomas; 26 were papillomas with ADH. Surgical follow-up was available for 36 cases (11 papillomas and 25 papillomas with ADH). Clinical (radiologic) follow-up was available in 5 papilloma cases (average follow-up, 35.6 months). Follow-up revealed that all papillomas on core biopsy were benign. Excisional biopsy revealed ductal carcinoma in situ or invasive carcinoma in 12 (48%) of 25 papillary lesions with ADH. Benign papillomas can be adequately diagnosed with core biopsy. All papillary lesions with ADH require surgical excision owing to the high rate of associated neoplasia.
Papillomas and Atypical Papillomas in Breast Core Needle Biopsy Specimens Risk of Carcinoma in Subsequent Excision Andrew A. Renshaw, MD, Robert P. Derhagopian, MD, Dolores M. Tizol-Blanco, MD, and Edwin W. Gould, MD	Am J Clin Pathol 2004;122:217-221 Abstract quote We sought to define the risk associated with papillomas and atypical papillomas in breast core needle biopsy specimens from a series of approximately 8,500 biopsies performed during 8 years. From a total of 62 papillary lesions (including papillomas and atypical papillomas), 40 (65%) had histologic follow-up. Overall, 15 (38%) of 40 patients had ductal carcinoma in situ (12 cases) or invasive carcinoma at excision (3 cases). Eight cases diagnosed as papilloma had benign follow-up. Slides were available for review in 38 cases and reclassified into benign papilloma with florid hyperplasia and no or minimal atypia (18 cases), papilloma with separate foci of atypical ductal hyperplasia (7 cases), and severely atypical papillomas "suspicious" for papillary carcinoma (13 cases). Carcinoma was identified in 0 (0%), 2 (29%), and 12 (92%) cases, respectively. We conclude that while atypical papillary lesions and papillomas with associated atypical ductal hyperplasia in breast core needle biopsy specimens are associated with a risk of carcinoma, lesions diagnosed as papilloma or papilloma with no or minimal atypia are benign and do not need to be excised.
Accuracy of core needle biopsy diagnosis in assessing papillary breast lesions: histologic predictors of malignancy. Ivan D, Selinko V, Sahin AA, Sneige N, Middleton LP. Department of Pathology, The University of Texas-Houston, Houston, TX, USA.	Mod Pathol. 2004 Feb;17(2):165-71 Abstract quote.   The purpose of this study was to determine the accuracy of core needle biopsy (CNB) diagnosis of papillary breast lesions and to identify histologic features that can predict malignancy. We retrospectively reviewed 2876 CNB performed at MD Anderson Cancer Center (01/95-08/02) and identified 50 papillary lesions: 30 papillomas, eight atypical papillomas and 12 papillary carcinomas. Histopathological parameters were evaluated and radiographic findings were reviewed. When available, the CNB was compared with the excisional biopsy (EB) material. Carcinoma was confirmed by EB in 11/12 cases and invasion was correctly assessed in 67% of them. In EB, 6/8 (75%) atypical papillomas revealed carcinoma in situ or atypia and the remaining two (25%) were benign, six out of 30 (20%) papillomas had been excised and none had shown atypia; the remaining patients had clinical and radiological follow-up with no evidence of disease progression. We conclude that CNB is effective for assessing papillary breast lesions and that EB is more accurate in determining invasion. Cellular monotony, lack of myoepithelial cells, and cytologic atypia are more accurate predictors of malignancy (P<0.0001) than is the presence of mitoses (P<0.053). A diagnosis of carcinoma or atypical papilloma by CNB should warrant an EB, whereas benign papillomas may be followed if imaging findings are concordant.
PIGMENTED
Pigmented Mammary Paget Disease and Pigmented Epidermotropic Metastases From Breast Carcinoma Luis Requena, M.D.; Martín Sangueza, M.D.; Omar P. Sangueza, M.D.; Heinz Kutzner, M.D.	Am J Dermatopathol 2002; 24(3):189-198 Abstract quote Pigmented mammary Paget disease is a rare clinicopathologic variant of mammary Paget disease. It has been described in female and male patients with intraductal mammary carcinoma extending to the epidermis of the nipple and areola through a lactiferous duct. Pigmented cutaneous metastases from breast carcinoma are uncommon variants of epidermotropic metastatic breast carcinoma. All these lesions may mimic malignant melanoma clinically and histopathologically. From a histopathologic point of view, involvement of the dermoepidermal junction by neoplastic cells of the mammary carcinoma seems to be a prerequisite for development of the clinical pigmentation. We report three examples of pigmented mammary Paget disease and six cases of pigmented epidermotropic metastases from breast carcinoma, which were studied from both the histopathologic and immunohistochemical points of view. Two cases of pigmented mammary Paget disease and all cases of pigmented epidermotropic metastatic breast carcinoma showed the proliferation of dendritic melanocytes arranged as solitary units along the dermoepidermal junction and intermingled with the neoplastic cells of the mammary carcinoma in the superficial dermis. In one case of pigmented mammary Paget disease, there was abundant melanin within the cytoplasm of the Paget cells, but an increased number of melanocytes could not be demonstrated. Local production of melanocytic chemotactic factor by neoplastic cells of the mammary carcinoma when they reach the dermoepidermal junction has been postulated as the cause of the melanocytic proliferation and clinical hyperpigmentation of these epidermotropic breast carcinomas. Another possibility is the phagocytosis or transfer of melanin from melanocytes to the intraepidermal neoplastic cells of the breast carcinoma. Pigmented mammary Paget disease and pigmented epidermotropic metastatic breast carcinoma should be differentiated from melanoma clinical and histopathologically.
PLEOMORPHIC
Pleomorphic carcinoma of the breast: clinicopathological analysis of 26 cases of an unusual high-grade phenotype of ductal carcinoma. Silver SA, Tavassoli FA. Department of Gynecologic and Breast Pathology, Armed Forces Institute of Pathology, Washington, DC, USA.	Histopathology 2000 Jun;36(6):505-14 Abstract quote AIMS: Pleomorphic carcinoma is a poorly described entity whose phenotype is not well recognized as within the morphological spectrum of breast carcinoma. The purpose of this report is to describe the clinicopathological features of this tumour, and to promote its recognition as an unusual high-grade morphological variant of mammary ductal carcinoma. METHODS AND RESULTS: Histological slides of breast carcinomas (N = 64) coded between 1978 and 1995 as having pleomorphic or anaplastic features were reviewed. Pleomorphic carcinoma (N = 26) was diagnosed when > or = 50% of the tumour manifested a pleomorphic cell population (> sixfold variation in nuclear size). Tumours of lobular origin were excluded. All neoplasms occurred in women with a mean age of 53 years. Patients underwent biopsy and/or mastectomy (n = 24) or lumpectomy (n = 2). The tumours' mean size was 54 mm. All were high-grade neoplasms. The pleomorphic cell population comprised 50-100% of the tumour; 31% had a prominent spindled morphology. Fifty-eight per cent of the tumours were initially misclassified by referring pathologists as sarcomas or carcinomas, possibly metastatic. Adjacent DCIS or a transition to classic ductal carcinoma was present in 73%. Five (19%) patients were stage I and three (12%) had stage IV disease. Axillary dissections yielded > or = 3 (mean 7.2) positive lymph nodes in 52%. Most (68%) tumours were aneuploid; a high S-phase (> 10%) was present in 63%. All neoplasms were ER negative and all but one were PR negative. p53 expression was present in 71%; none expressed bcl-2. c-erbB-2 was detected in four (19%) node-positive and in 0 (0%) node-negative cases (P = 0.01). Of 16 patients with follow-up, 6 (38%) were disease-free (mean, 74 months), four (25%) alive with disease (mean, 33 months) and six (38%) dead of disease at a mean of 22 months. CONCLUSIONS: Pleomorphic carcinoma is a prognostically unfavourable lesion and represents the extreme end of the morphological spectrum of grade III infiltrating ductal carcinoma.
SARCOMATOID CARCINOMA
Spindle Cell (Sarcomatoid) Carcinoma of the Breast: A Clinicopathologic and Immunohistochemical Analysis of 29 Cases. Carter MR, Hornick JL, Lester S, Fletcher CD. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.	Am J Surg Pathol. 2006 Mar;30(3):300-309. Abstract quote   Spindle cell (sarcomatoid) carcinoma of the breast is a rare variant of breast cancer that has been classified under the broad rubric of metaplastic carcinoma. Because the term "metaplastic carcinoma" comprises a heterogeneous group of tumors, it has been difficult to reliably predict biologic potential or to determine optimal therapy. To better characterize the spindle cell subset of metaplastic breast carcinomas, we reviewed 29 cases. All patients were adult females ranging from 40 to 96 years of age (median, 68 years). Tumor size ranged from 1.5 to 15 cm (median, 4 cm). Treatment was by excision and/or mastectomy with axillary node evaluation in most cases, often combined with postoperative radiation and/or chemotherapy. All cases were clinically of breast origin, showed >/=80% spindled/sarcomatoid morphology, and demonstrated keratin positivity and/or close association with ductal carcinoma in situ. Immunohistochemical studies showed evidence suggesting myoepithelial differentiation as exhibited by immunoreactivity for smooth muscle actin, cytokeratin 14, and p63 in a subset of cases (39%). Twenty-seven cases exhibited pure spindled or sarcomatoid morphology of variable appearance and nuclear grade, whereas 2 contained high-grade invasive ductal carcinoma comprising </=20% of the tumor mass. Two cases exhibited heterologous elements (1 rhabdomyosarcoma and 1 with both chondrosarcoma and osteosarcoma) and 4 were associated with ductal carcinoma in situ. Follow-up data were available on 24 of 29 patients (range, 1-120 months; median, 20 months). Of 20 cases in which axillary nodes were biopsied, definitive nodal metastases were identified in only 1 (5%), and this was in a case with a significant component of invasive ductal carcinoma. Three patients developed local recurrences. Extranodal metastases occurred in 11 of 24 patients (46%), most commonly to the lungs. Ten of 24 patients (42%) died of disease at a median interval of 11.5 months (range, 1-46 months) and 3 patients were alive with metastatic disease. Eight patients were alive with no evidence of recurrent or metastatic disease (median, 29.5 months). Based on this series, spindle cell/sarcomatoid carcinoma of the breast is a highly aggressive neoplasm with a high rate of extranodal metastases. Purely spindled/sarcomatoid tumors have a significantly lower rate of nodal metastases than conventional ductal and lobular breast carcinomas.
An immunohistochemical study of metaplastic spindle cell carcinoma, phyllodes tumor and fibromatosis of the breast. Dunne B, Lee AH, Pinder SE, Bell JA, Ellis IO.	Hum Pathol. 2003 Oct;34(10):1009-15 Abstract quote.   The diagnosis of metaplastic (sarcomatoid) carcinoma (MSC) of breast often requires immunohistochemistry with a cytokeratin (CK) panel to distinguish them from phyllodes tumors (PT), primary sarcomas, and fibromatoses. CK staining may be heterogeneous in metaplastic carcinomas. The aim of the study was to investigate the theory that MSCs show evidence of myoepithelial differentiation and to evaluate immunohistochemical markers that may be helpful in distinguishing MSCs from PT and fibromatosis. We reviewed histology and performed immunohistochemistry for AE1/AE3, 34betaE12, CK5 and CK14, Cam5.2, CK7 and CK19, epithelial membrane antigen (EMA) (B55), smooth muscle actin (SMA), S100, desmin, vimentin, CD31, CD34, and bcl-2 on paraffin-embedded tissue from 18 MSCs, 26 PTs, and 8 fibromatoses. We assessed staining by using a semiquantitative method. Sarcomatous areas in MSCs were positive for 34betaE12 in 11 cases; for SMA in 10; for CK5 in 7; for CK14 in 6; for Cam5.2, AE1/AE3, and S100 in 5; and for CK7 and CK19 in 3. No CK expression was seen in stromal areas in PT or in fibromatoses. CD34 and bcl-2 were more frequently expressed in spindle cell areas in PTs (18 and 12 of 26, respectively) than in MSCs (0 and 2 of 18, respectively). MSCs show strong evidence of myoepithelial differentiation. CD34 and, to a lesser extent, bcl-2 positivity in PTs may be helpful in differentiating these two lesions from MSCs, particularly in small biopsies, because CK staining in MSCs may be heterogeneous. In our hands, 34betaE12 was the CK most frequently expressed in sarcomatoid areas in MSCs.
SECRETORY CARCINOMA
Secretory carcinoma of the breast: a distinct variant of invasive ductal carcinoma assessed by comparative genomic hybridization and immunohistochemistry. Diallo R, Schaefer KL, Bankfalvi A, Decker T, Ruhnke M, Wulfing P, Jackisch C, Luttges J, Sorensen PH, Singh M, Poremba C. Institute of Pathology, Heinrich-Heine-University, Dusseldorf, Germany.	Hum Pathol. 2003 Dec;34(12):1299-305. Abstract quote   Secretory carcinomas (SCA) are distinguished from infiltrating ductal carcinomas (IDC) of the breast by their characteristic histomorphology and more favorable prognosis and by the expression of a chimeric tyrosine kinase that is encoded by the ETV6-NTRK3 fusion gene. On this basis, we evaluated 13 SCAs (12 of them with ETV6-NTRK3 gene fusion) by molecular and immunohistochemical (IHC) methods. DNA was obtained from 8 of 13 microdissected SCAs and was analyzed for genetic alterations (GA) by comparative genomic hybridization (CGH). IHC staining was performed for estrogen receptor (ER), progesterone receptor (PR), HER2/neu, and Ki-67 (MIB1) in all 13 cases. Molecular and immunohistochemical results in SCAs were compared with previous data regarding immunohistochemical and molecular characteristics of IDCs. An average of 2.0 GAs (range: 0 to 6) were detected, including recurrent gains of chromosome 8q (37.5%) and 1q (25%) and losses of 22q (25%). Four of 13 (31%) SCAs were positive for ER, and 2 were positive for PR. The mean MIB1-labeling index was 11.4% (range: <1 to 34%). Her-2/neu protein overexpression was detected in 2 cases, including 1 with strong (score 3+) and 1 with weak HER2/neu expression (score 2+). Fluorescence in situ hybridization analysis of the latter case showed no evidence of HER-2/neu-gene amplification. Compared with previous findings in IDCs, SCAs are characterized by a relatively low number of GAs, a low proliferative rate, infrequent HER2/neu protein overexpression, decreased steroid hormone receptor expression, and expression of ETV6-NTRK3 fusion gene. These results support the hypothesis that SCAs have immunohistochemical and genetic features that distinguish them from IDCs of the usual type.
Invasive secretory (juvenile) carcinoma arising in ectopic breast tissue of the axilla. Shin SJ, Sheikh FS, Allenby PA, Rosen PP. Department of Pathology, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, NY 10021, USA.	Arch Pathol Lab Med 2001 Oct;125(10):1372-4 Abstract quote Mammary carcinoma arising in ectopic breast tissue is an uncommon occurrence. Most reported cases have involved ductal carcinoma, but other types, such as medullary, papillary, and lobular carcinomas, have been described. For pathologists, the diagnosis of mammary carcinoma arising in ectopic breast tissue can be difficult, especially in the axilla, where carcinoma of adnexal origin must be excluded. We describe a 46-year-old woman who developed invasive (juvenile) secretory carcinoma in ectopic right axillary breast tissue and micrometastatic carcinoma in an ipsilateral axillary lymph node. The carcinoma arose in a right axillary mass that had been present for 8 years, from which she had secreted fluid during prior breast-feeding. To our knowledge, this is the first report of secretory carcinoma arising in axillary breast tissue to be documented in the current literature.
Secretory carcinoma of the breast: a tumour analogous to salivary gland acinic cell carcinoma? Hirokawa M, Sugihara K, Sai T, Monobe Y, Kudo H, Sano N, Sano T. Department of Pathology, University of Tokushima School of Medicine, Tokushima, Japan.	Histopathology 2002 Mar;40(3):223-9 Abstract quote AIMS: Acinic cell-like breast carcinoma is a newly recognized entity, and few acinic cell-like breast carcinoma cases have been reported. All reported acinic cell-like breast carcinomas were counterparts of the solid type of acinic cell carcinoma of the salivary gland. We report here three cases of secretory breast carcinoma with acinic cell differentiation, and discuss the similarity between secretory breast carcinoma and acinic cell carcinoma of the salivary gland. METHODS AND RESULTS: The cases were histologically identical to acinic cell carcinoma of the salivary gland: papillary-cystic type in case 1, a mixture of papillary-cystic, microcystic and follicular type in case 2, and microfollicular type in case 3. Immunohistochemically, the tumour cells were positive for salivary-type amylase, lysozyme, S100 protein and alpha 1-antitrypsin, and negative or less reactive for gross cystic disease fluid protein-15 and oestrogen receptor. All three cases did not reveal metastasis or recurrence. CONCLUSIONS: These cases were typical of secretory breast carcinoma, and were clinically, histologically and immunohistochemically analogous to acinic cell carcinoma of the salivary gland. We emphasize that secretory breast carcinoma and acinic cell carcinoma of the salivary gland may be identical lesions.
SMALL CELL CARCINOMA
E-Cadherin–Negative Primary Small Cell Carcinoma of the Breast Report of a Case and Review of the Literature Simon Bergman, MD, Syed A. Hoda, MD, Kim R. Geisinger, MD, Andrew J. Creager, MD, and Jacqueline K. Trupiano, MD	Am J Clin Pathol 2004;121:117-121 Abstract quote Primary small cell carcinoma of the breast is exceedingly rare, with fewer than 25 reported cases. The case presented herein is that of a 61-year-old woman with a 2.5-cm mass of the left breast. She underwent mastectomy with axillary node dissection. Histologic examination revealed sheets and nests of small, hyperchromatic, malignant cells with indistinct nucleoli and scant cytoplasm. High-grade solid and comedo ductal carcinoma in situ also was present. Two of 5 axillary lymph nodes contained metastatic disease. Immunohistochemical analysis demonstrated weak immunoreactivity for cytokeratin, neuron-specific enolase, and bcl-2. This histologic and immunohistochemical profile was consistent with that of a primary small cell carcinoma. Interestingly, this neoplasm lacked immunoreactivity for E-cadherin. E-cadherin expression has been documented in all 11 (100%) of 11 previously reported cases of primary small cell carcinoma of the breast, suggesting that this tumor is a form of ductal carcinoma. To our knowledge, this is the first reported case of E-cadherin–negative small cell carcinoma of the breast, which raises the question of a possible lobular histogenesis in some of these neoplasms.
Small Cell Carcinoma of the Breast A Clinicopathologic and Immunohistochemical Study of Nine Patients Sandra J. Shin, M.D.; Ronald A. DeLellis, M.D.; Liang Ying, B.A.; Paul Peter Rosen, M.D. From the Pathology Department, New York Presbyterian Hospital–Weill Medical College of Cornell University, New York, NY, U.S.A.	Am J Surg Pathol 2000;24:1231-1238 Abstract quote Small cell carcinoma of the breast is an uncommon neoplasm that has been reported rarely in the literature. The aim of this study was to characterize better the pathologic and immunohistochemical features of this neoplasm. Nine examples of mammary small cell carcinoma were retrieved from the authors' consultation files and reviewed. The patients ranged in age from 43 to 70 years. Two patients had a previous history of cutaneous malignant melanoma and one had prior lobular carcinoma in situ and atypical duct hyperplasia in the same breast as the small cell carcinoma. Eight patients presented with a mass in the breast; one patient had an axillary tumor. Tumor size ranged from 1.3 to 5.0 cm (mean, 2.6 cm). Histologically, the nine tumors had characteristics of small cell carcinoma with high mitotic activity and necrosis. A dimorphic histologic appearance was observed in four tumors. In one instance, this consisted of small cell carcinoma merging with invasive lobular carcinoma. In three cases, small cell carcinoma was present together with invasive, poorly differentiated duct carcinoma; invasive carcinoma with ``lobular and gland-forming elements''; and focal squamous differentiation, respectively. Lymphatic tumor emboli were identified in four instances. An in situ component was seen in seven tumors; five were of the small cell type in ducts and two were of the ductal type with high nuclear grade. Immunohistochemical analysis showed consistent staining for cytokeratin markers but variable staining with neuroendocrine markers. Sixty-six percent of the tumors (six of nine) were reactive for chromogranin, synaptophysin, or peptide hormones, including four positive for chromogranin and synaptophysin, one positive for synaptophysin and calcitonin, and one positive for calcitonin alone. One tumor that was reactive for chromogranin and synaptophysin also contained calcitonin immunoreactive cells, whereas gastrin-releasing peptide was present in two other tumors that were also positive for chromogranin. Leu 7 was positive in three cases that were reactive for either chromogranin or synaptophysin. Five tumors were estrogen and progesterone receptor-positive. All tumors were positive for bcl-2 and negative for HER2/neu. Patients were treated by mastectomy (n = 3) or lumpectomy (n = 6). Eight underwent an axillary dissection that revealed metastatic carcinoma in four patients. Seven patients received adjuvant chemotherapy and four patients received radiation. Two patients also received tamoxifen treatment. Metastases developed in two patients (22%) with a follow-up period of 11 and 32 months. All patients were alive at last follow up 3 to 35 months after treatment. When compared with published reports of mammary small cell carcinoma, our results show that the prognosis in these patients may not be as poor as previously suggested.
THYROID CARCINOMA, TALL CELL VARIANT OF PAPILLARY CARCINOMA
Breast tumor resembling the tall cell variant of papillary thyroid carcinoma: report of 5 cases. Eusebi V, Damiani S, Ellis IO, Azzopardi JG, Rosai J.	Am J Surg Pathol. 2003 Aug;27(8):1114-8. Abstract quote Five cases of a hitherto undescribed breast tumor having histologic features similar to those of the tall cell variant papillary thyroid carcinoma are described. They were composed of columnar mitochondrion-rich to oxyphilic cells arranged in nests, papillae, and follicle-like structures. In addition, the neoplastic cells showed numerous nuclear grooves and, in two cases, nuclear pseudo-inclusions. None of the patients had previous concomitant or subsequent evidence of a thyroid tumor. Immunohistochemistry further excluded a metastasis from the thyroid in the four cases tested, as they were consistently thyroglobulin and thyroid transcription factor 1 negative.

 

SPECIAL STAINS/ IMMUNO- PEROXIDASE/ OTHER	CHARACTERIZATION
TISSUE MICROARRAYS
Reliability of tissue microarrays in detecting protein expression and gene amplification in breast cancer. Zhang D, Salto-Tellez M, Putti TC, Do E, Koay ES. Molecular Diagnosis Centre (DHZMS-T, ED, ES-CK), National University Hospital, and Department of Pathology (DHZ, MS-T, TCP, ED, ES-CK), National University of Singapore, Singapore.	Mod Pathol 2003 Jan;16(1):79-85 Abstract quote Tissue microarrays allow high throughput molecular profiling of diagnostic or predictive markers in cancer specimens and rapid validation of novel potential candidates identified from genomic and proteomic analyses in a large number of tumor samples. To validate the use of tissue microarray technology for all the main biomarkers routinely used to decide breast cancer prognostication and postsurgical adjuvant therapy, we constructed a tissue microarray from 97 breast tumors, with a single 0.6 mm core per specimen. Immunostaining of tissue microarray sections and conventional full sections of each tumor were performed using well-characterized prognostic markers (estrogen receptor ER, progesterone receptor PR and c-erbB2). The full section versus tissue microarray concordance for these stains was 97% for ER, 98% for PR, and 97% for c-erbB2, respectively, with a strong statistical association (kappa value more than 0.90). Fluorescence in situ hybridization analysis for HER-2/neu gene amplification from the single-core tissue microarray was technically successful in about 90% (87/97) of the cases, with a concordance of 95% compared with parallel analyses with the full sections. The correlation with other pathological parameters was not significantly different between full-section and array-based results. It is concluded that the constructed tissue microarray with a single core per specimen ensures full biological representativeness to identify the associations between biomarkers and clinicopathological parameters, with no significant associated sampling bias.
Her2-neu	See her2-neu
CADHERINS	Am J Clin Pathol 2001;115:85-98 Moderate to strong membrane expression found in all invasive (100/100) and in situ ductal carcinomas (131/131) 41/42 invasive and 50/53 in situ lobular carcinomas showed complete loss of expression Invasive carcinomas with both features (41) showed three staining patterns: Complete or almost complete lack of membrane staining similar to lobular CA Uniform membrane expression througout the tumor similar to ductal CA Focal loss of staining
Cadherins as Predictive Markers of Nodal Metastasis in Breast Cancer Maya Madhavan, etal.	Mod Pathol 2001;14:423-427 Abstract quote Adhesion molecules, particularly cadherins play a pivotal role in cancer invasion and metastasis. Because the therapeutic management of tumors with and without nodal metastasis differs considerably, our idea was to identify tumors with metastatic potential. We studied the expression of E-cadherin and P-cadherin immunohistochemically in 51 cases of breast cancer that included 29 node-negative and 22 node-positive cases. Expression of the cadherins was mainly membranous, with cytoplasmic staining in a few lesions. Both E-cadherin and P-cadherin showed significant down-regulation of their expression in node-positive tumors in comparison to node-negative tumors. Logistic regression analysis revealed that the positive expression of E-cadherin and P-cadherin showed low odds ratios of 0.1 and 0.2, respectively, and were statistically significant. On multivariate analysis, both the cadherins were found to be of independent prognostic value. This suggests that cadherin expression could be a marker of nodal metastasis. An observation of interest was that the expression of E-cadherin and P-cadherin were highly correlated (correlation coefficient = 0.5873), which requires further evaluation for confirmation of a common regulatory pathway that could be activated in the early onset of nodal metastasis.
Persistent E-Cadherin Expression in Inflammatory Breast Cancer Celina G. Kleer, etal.	Mod Pathol 2001;14:458-464 Abstract quote E-cadherin is a transmembrane glycoprotein that mediates epithelial cell-to-cell adhesion. Because loss of E-cadherin expression results in disruption of cellular clusters, it has been postulated that E-cadherin functions as a tumor suppressor protein. The role of E-cadherin in inflammatory breast cancer (IBC), a distinct and highly aggressive form of breast cancer, is largely unknown. The aim of our study was to elucidate whether E-cadherin expression contributes to the development and progression of the IBC phenotype and to investigate any differences in E-cadherin expression between IBC and stage-matched non-IBC. Forty-two breast cancer cases (20 IBC and 22 non-IBC) were identified. Strict and well-accepted criteria were used for the diagnosis of IBC. Clinical and pathologic features were studied, and formalin-fixed, paraffin-embedded tissue sections were immunostained for E-cadherin, estrogen and progesterone receptors (ER and PR, respectively), and HER2/neu. Statistical analysis was performed using Fisher’s exact test. All IBC uniformly expressed E-cadherin, whereas 15 of the 22 (68%) of the non-IBC expressed the protein (P = .006). Intralymphatic tumor emboli in the IBC cases were also all E-cadherin positive. Two IBC tumors demonstrated invasive lobular histology, and both cases were positive for E-cadherin. Of the non-IBC cases, three were invasive lobular carcinomas, and all were positive for E-cadherin. No association was found between E-cadherin expression and ER, PR status, or HER2/neu overexpression. Our study demonstrates that there is a strong association between E-cadherin expression and IBC and suggests that E-cadherin may be involved in the pathogenesis of this form of advanced breast cancer. In our study, we demonstrate that circulating IBC tumor cells strongly express E-cadherin, thereby providing an important exception to the positive association between E-cadherin loss and poor prognosis in breast cancer.
The Prognostic Significance of P-Cadherin in Infiltrating Ductal Breast Carcinoma Carlos Gamallo, M.D., Gema Moreno-Bueno, Ph.D., David Sarrió, Ph.D., Francisco Calero, M.D., David Hardisson, M.D. and José Palacios, M.D. Servicio de Anatomía PatológicaHospital Universitario de La Princesa (CG), Programa de Patología Molecular, Centro Nacional de Investigaciones Oncológicas (CNIO) Carlos III (GMB, DS, JP), and Departamentos de Obstetricia y Ginecología (FC) and Anatomía Patológica (DH), Hospital Universitario La Paz, Madrid, Spain	Mod Pathol 2001;14:650-654 Abstract quote We have immunohistochemically investigated P-cadherin (P-CD) expression in a series of 210 infiltrating ductal carcinomas (IDC) in an attempt to assess the biological and prognostic relevance of P-CD in patients harboring IDCs. Although only 74/210 (35%) of IDCs expressed P-CD in >5% of tumor cells (P-CD–positive carcinomas), categorical analyses revealed that P-CD–positive IDCs were larger (26 ± 21 cm versus 22 ± 11 cm, P = .0568), of higher histological grade (P = .0001), and had more lymph node metastases (P = .0327) than P-CD–negative breast carcinomas. In addition, P-CD–positive tumors were negative for estrogen (P = .0001) and progesterone receptors (P = .0001) and showed reduced E-cadherin expression (P = .0276) more frequently than P-CD–negative tumors. Univariate analysis carried out in 171 patients demonstrated that P-CD expression was also an indicator of poor prognosis ( [{chi}] 2 = 8.292, P = .004), extent of lymph node metastasis ( [{chi}] 2 = 20.854, P = .0000), histological grade ( [{chi}] 2 = 12.908, P = .0016), and negative progesterone receptors ( [{chi}] 2 = 4.116, P = .042). However, only histological grade and nodal metastases emerged as independent prognostic markers in the multivariate analysis. These results suggest that although P-CD expression may be involved in the progression of IDCs, its value as an independent prognostic factor remains to be established.
Does the level of E-cadherin expression correlate with the primary breast carcinoma infiltration pattern and type of systemic metastases? Goldstein NS. Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI 48073, USA.	Am J Clin Pathol 2002 Sep;118(3):425-34 Abstract quote Relationships between membrane E-cadherin reactivity of invasive carcinoma, a dyshesive growth pattern, and lobular carcinoma-type systemic metastases were studied in 295 breast carcinomas and 57 patients with lobular carcinoma systemic metastases. There were 143 pure lobular carcinomas, 80 mixed (lobular and ductal) carcinomas, and 72 pure ductal carcinomas. Two (7%) of 30 mixed, predominantly lobular carcinomas, 23 (61%) of 38 mixed carcinomas, and 8 (67%) of 12 mixed, predominantly ductal carcinomas had E-cadherin staining in more than 10% of the lobular carcinoma cells. Lobular carcinoma-type systemic metastases were identified in 45 cases (38 [84%], pure lobular; 5 (11%], mixed; 2 [4%], pure ductal). No E-cadherin staining was found in 42 (98%) of 43 lobular carcinomas in cases of lobular carcinoma-type systemic metastases and all 57 cases of lobular carcinoma systemic metastases. Absent cell-to-cell adhesion seems to be a necessary property of carcinoma cells to facilitate permeation through tissue planes and produce characteristic lobular carcinoma-type systemic metastases. The level of decreased E-cadherin expression at which a dyshesive growth pattern emerges in primary breast carcinomas may be less than the level associated with lobular carcinoma-type systemic metastases.
CD10
Myoepithelial markers are expressed in at least 29% of oestrogen receptor negative invasive breast carcinoma. Kesse-Adu R, Shousha S. 1Department of Histopathology, Charing Cross Hospital and Faculty of Medicine, Imperial College, London, UK.	Mod Pathol. 2004 Jun;17(6):646-52. Abstract quote   Around 20% of invasive breast carcinoma are oestrogen receptor alpha (ER) negative. Theoretically, this negativity could be either due to the result of downregulation of ER expression in the tumour cells, or the result of the tumour being derived from or differentiating towards cells which normally lack that expression. Normal basal, including myoepithelial, cells of the breast are ERnegative. CD10, smooth muscle actin and S100 are markers of these basal cells that can be used for their demonstration in routinely processed sections. This study was aimed at comparing the incidence of positivity for three myoepithelial markers in ER-negative and ER-positive invasive breast carcinoma. We have examined sections of 117 cases of breast carcinoma, including 77 ER-negative and 40 ER-positive cases, for the expression of CD10, smooth muscle actin and S100, using the avidin-biotin complex immunoperoxidase technique. A tumour was considered positive if more than 10% of the tumour cells were positively stained. In all, 36 (47%) ER-negative tumours were positive for one or more of these myoepithelial markers. The percentage of positively stained tumour cells varied between 30 and 100%. Of the 40 ER-positive tumours, only three (8%) were positive; two for S100 and one for actin, with none being positive for CD10. If cases stained only with S100 are excluded, as some of these may represent luminal differentiation, definite myoepithelial differentiation seems to be present in 29% (22/77) of ER-negative tumours as compared with 2.5% (1/40) of ER-positive tumours; a difference which is highly significant (P<0.001). It is suggested that at least 29% of ER-negative invasive breast carcinomas may be derived from or differentiating along the direction of basal nonconventional luminal epithelial breast cells that normally lack the expression of ER but totally or partially express various myoepithelial markers. Such tumours might need a different therapeutic approach.
Availability of CD10 immunohistochemistry as a marker of breast myoepithelial cells on paraffin sections. Moritani S, Kushima R, Sugihara H, Bamba M, Kobayashi TK, Hattori T. Department of Pathology, Shiga University of Medical Science, Seta-tsukinowa-cho, Ohtsu, Japan.	Mod Pathol 2002 Apr;15(4):397-405 Abstract quote CD10, also called common acute lymphoblastic leukemia antigen (CALLA), was recently found to be expressed in nonhematopoietic tissues. Although CD10 was also identified in human breast myoepithelial cells, its availability of immunohistochemistry on paraffin sections has not been examined so far. In the present study, we demonstrated CD10 immunohistochemically on paraffin sections of both normal and pathological breast tissues, comparing its staining patterns to those of smooth muscle actin (SMA), which is now commonly used to highlight myoepithelium. CD10 was consistently positive in normal breast myoepithelial cells. CD10 also clearly highlighted myoepithelial cells in intraductal papilloma, adenosis, ductal hyperplasia, fibroadenoma, and phyllodes tumor as well as SMA did. In atypical ductal hyperplasia and ductal carcinoma in situ, continuous, discontinuous, and totally negative stainings of both CD10 and SMA were noted, depending on foci of neoplastic cell nests. However, both stainings clearly demonstrated myoepithelial cells of cancerized acini, being useful in differentiating lobular cancerization from microinvasion. Because SMA was also positive in normal vessels and spindle-shaped stromal cells, CD10, which was negative in vessels, was useful in differentiating myoepithelial cells from thin vascular wall in intracystic lesions with delicate papillae. Although background staining of spindle-shaped stromal cells was also noted in CD10, the positive cell number was less, and the signal was weaker than that of SMA. The absence of myoepithelial cells in invasive ductal carcinomas was more clearly highlighted by CD10 than SMA. We concluded that CD10 could be another useful marker of breast myoepithelial cells on paraffin sections. Combination of CD10 and SMA will provide more sophisticated information about presence or absence of myoepithelial cells in confusing breast lesions.
EPIDERMAL GROWTH FACTOR RECEPTOR
Radioimmunohistochemistry of Epidermal Growth Factor Receptor in Breast Cancer Kevin W. Robertson, MD, Jonathon R. Reeves, PhD, Alison K. Lannigan, MD, James J. Going, PhD, Timothy G. Cooke, MD, and Peter D. Stanton, PhD From the Lister Department of Surgery (Drs Robertson, Reeves, Lannigan, and Cooke) and Department of Pathology (Dr Going), Royal Infirmary, Castle Street, Glasgow, Scotland, UK; and Department of Surgery, Clinical School of Medicine, Collins St, Hobart, Tasmania, Australia (Dr Stanton)	Arch Pathol Lab Med 2002;Vol. 126, No. 2, pp. 177–181. Abstract quote Context.—Conflicting reports of epidermal growth factor receptor (EGFR) expression in breast cancer and inconstant relationships with established prognostic indicators and outcomes suggest difficulties with EGFR measurement. Objective.—To compare EGFR measurement in a panel of cell lines and in breast carcinomas by radioimmunohistochemistry (R-IHC), conventional immunohistochemistry (IHC), and a ligand binding (LB) assay. Design.—Eight EGFR-expressing cell lines and 50 primary breast carcinoma specimens were analyzed for EGFR by IHC, R-IHC, and LB assays. A further 153 primary breast cancer specimens were analyzed by R-IHC alone. Results.—All 3 assays were in good agreement for the cell lines. In the subset of the 50 carcinoma specimens, EGFR was detected by LB assays in 19 (38%) and by IHC in 24 (48%). However, R-IHC detected EGFR in 46 (92%) of 50 and in 186 (92%) of all 203 carcinoma specimens. The LB assay agreed poorly with R-IHC of carcinomas, possibly because the LB assay is sensitive to EGFR-expressing nontumor breast parenchyma in the tissue analyzed. Both IHC and R-IHC on carcinoma specimens agreed better, but 26 carcinoma specimens (52%) in which EGFR was not detectable by IHC had a 10-fold range in receptor level detectable by R-IHC. Conclusion.—To elucidate the role of EGFR or other growth factor receptors in breast cancer requires accurate, sensitive receptor assays. With its dynamic range, R-IHC returned meaningful results over the entire range of expression actually present in breast cancer, which LB assays and IHC failed to do.
ESTROGEN RECEPTOR
Immunohistochemistry of Estrogen and Progesterone Receptors Reconsidered Experience With 5,993 Breast Cancers Mehrdad Nadji, MD, Carmen Gomez-Fernandez, MD, Parvin Ganjei-Azar, MD, and Azorides R. Morales, MD	Am J Clin Pathol 2005;123:21-27 Abstract quote Paraffin sections or fine-needle aspiration smears from 5,993 cases of invasive mammary carcinomas were assessed immunohistochemically for estrogen receptor (ER; 1D5) and progesterone receptor (PR; 636) expression. Staining pattern and intensity were correlated with histologic subtypes and nuclear grades of tumors. Positive nuclear staining for ER and PR was observed in 75% and 55% of invasive carcinomas, respectively. In 92% of ER+ cases, diffuse and uniform staining of most tumor cells was observed. In the remaining 8%, a focal ER reaction was seen, usually because of inadequate fixation. In 21% of PR+ tumors, the reaction was heterogeneous or focal but unrelated to fixation. There were no ER–, PR+ tumors. All pure tubular, colloid, and infiltrating lobular carcinomas were ER+. All medullary, apocrine, and metaplastic and most high-nuclear-grade carcinomas were ER–. With monoclonal antibody 1D5 and antigen retrieval, immunohistochemical reaction for ER in breast cancer usually is an all-or-none phenomenon; therefore, quantitation of results is unnecessary. Despite antigen retrieval, inadequate fixation can cause false-negative results; evaluation of internal positive control samples is imperative. ER positivity and negativity are predictable in certain histologic types and nuclear grades of breast cancer. The reaction for PR can be heterogeneous or focal.
Bimodal Frequency Distribution of Estrogen Receptor Immunohistochemical Staining Results in Breast Cancer An Analysis of 825 Cases Laura C. Collins, MD, Maria L. Botero, MD, and Stuart J. Schnitt, MD	Am J Clin Pathol 2005;123:16-20 Abstract quote Immunohistochemical analysis is used routinely to determine the estrogen receptor (ER) status of breast cancers in paraffin sections. However, lack of standardization has raised concerns that weakly ER+ tumors often are classified erroneously as ER–. To determine the frequency of weakly ER+ tumors, we reviewed ER immunostains of 825 breast cancers. For each case, we estimated the proportion of ER+ tumor cells and also determined an Allred score (which results in scores of 0 or 2 through 8, based on staining intensity and proportion of positive cells). In 817 cases (99.0%), tumor cells showed complete absence of staining or staining in 70% or more of the cells. Similarly, 818 cases (99.2%) exhibited Allred scores of 0 or of 7 or 8. Thus, with the immunohistochemical method used in our laboratory, ER staining is essentially bimodal. The overwhelming majority of breast cancers are either completely ER– or unambiguously ER+, and cases with weak ER immunostaining are rare.
Minimum Formalin Fixation Time for Consistent Estrogen Receptor Immunohistochemical Staining of Invasive Breast Carcinoma Neal S. Goldstein, MD, Monica Ferkowicz, MT(ASCP), PathA(AAPA), Eva Odish, HTL(IHQ), Anju Mani, MD, and Farnaz Hastah, MD	Am J Clin Pathol 2003;120:86-92 Abstract quote To identify the minimum time necessary for consistent immunohistochemical estrogen receptor (ER) results in our laboratory, we evaluated results in timed fixation blocks and cases with disparate and similar needle core biopsy and partial mastectomy specimens. Tissue sections of 24 ER-positive, invasive breast carcinomas were fixed for 3, 6, 8, and 12 hours and 1, 2, and 7 days. ER values were quantified using the Q score (0-7). In timed fixation blocks, the mean Q score per block was 2.46 for blocks fixed for 3 hours, 5.75 for blocks fixed for 6 hours, and 6.70 for blocks fixed for 8 hours (P < .001). The difference between the case maximum and mean block Q scores was a plateau of almost 0 at 6 to 8 hours of formalin fixation. For needle core biopsy specimen fixation times, the means for specimens with ER-disparate and ER-similar results were 1.2 and 6.3 hours, respectively (P = .01). The minimum formalin fixation time for reliable immunohistochemical ER results is 6 to 8 hours in our laboratory, regardless of the type or size of specimen.
Assessment of Interlaboratory Variation in the Immunohistochemical Determination of Estrogen Receptor Status Using a Breast Cancer Tissue Microarray Robin L. Parker, MD David G. Huntsman, MD David W. Lesack, MD James B. Cupples, MD Dennis R. Grant, MD Majid Akbari, MD C. Blake Gilks, MD	Am J Clin Pathol 2002;117:723-728 Abstract quote The determination of tumor cell estrogen receptor (ER) expression status by immunohistochemical analysis has become standard practice, yet assay reproducibility has not been assessed adequately. By using a breast cancer tissue microarray, we examined interlaboratory variability in ER reporting. A 2-fold redundant tissue microarray block was created from 29 breast cancers. Unstained slides were distributed to 5 laboratories, and each laboratory immunostained and scored 1 slide for ER. Interlaboratory agreement ranged from moderate to high (overall kappa = 0.54 for 0-3+ grading; overall kappa = 0.84 for negative vs positive assessment of ER status). When 1 observer scored each of the 5 slides, interlaboratory agreement was slightly better (kappa = 0.63 for 0-3+ scoring; kappa = 0.96 for negative vs positive scoring). One laboratory, which had used an antibody and antigen retrieval method different from the others, demonstrated only fair concordance with the other 4 laboratories, but there was substantial intralaboratory interobserver agreement and excellent agreement with an outside observer reviewing the slide stained in that laboratory. The tissue microarray was an efficient and effective tool for identifying variability in ER reporting and should prove valuable in other external quality assurance programs.
GCDFP-15
Expression of Apocrine Differentiation Markers in Neuroendocrine Breast Carcinomas of Aged Women Anna Sapino, M.D., Luisella Righi, M.D., Paola Cassoni, M.D., Mauro Papotti, M.D., Patrizia Gugliotta, Bsc and Gianni Bussolati, M.D., Frc Path Department of Biomedical Sciences and Human OncologyUniversity of Torino, Torino, Italy	Mod Pathol 14:768-776 Abstract quote Neuroendocrine (NE) breast carcinomas are a rare entity in young women; however, their frequency increases in aged patients. The present work demonstrates that NE breast carcinomas in elderly women can also express an apocrine immunophenotype and analyzes the histological and clinical aspects of such differentiation. A selected series of 50 NE tumors (positive for NE markers in 50% of the cells) was tested for the immunocytochemical expression of gross cystic disease fluid protein-15 (GCDFP-15). The results demonstrated that about 50% of moderately (G2) and well-differentiated (G1) NE breast carcinomas (mucinous, solid papillary, and solid cohesive histotypes) coexpressed the apocrine marker. In these cases, specific mRNA for GCDFP-15 (PIP) and for chromogranin A (ChA) was demonstrated using in situ hybridization (ISH). Carcinomas of the alveolar subtype (G2) and poorly differentiated carcinomas (G3), including one case of atypical carcinoid, were pure NE carcinomas, devoid of apocrine differentiation. The steroid receptor status of these lesions was evaluated to test a possible involvement of androgen receptors in apocrine differentiation. We demonstrated that the level of AR and the mean age of patients at diagnosis were significantly higher in apocrine than in nonapocrine differentiated tumors. The histological grade and the expression of estrogen receptor (ER) significantly influenced the prognosis of these NE carcinomas, either pure or NE-apocrine differentiated. The most original result of our study is therefore the demonstration of a possible divergent apocrine differentiation of NE breast carcinomas that might be regulated by the activation of androgen receptors in elder patients. In addition, the possibility for using Chs or GCDFP-15 serum values in the follow-up of these patients, as demonstrated in two cases of the present series, can justify the immunophenotyping of the tumors.
GLUT-1
Glucose Transporter Glut-1 Is of Limited Value for Detecting Breast Carcinoma in Serous Effusions Robert L. Zimmerman, M.D., Shanth Goonewardene, M.D. and Franz Fogt, Dr. med., M.R.C.P., M.B.A. Department of PathologyPresbyterian Medical Center, University of Pennsylvania Health System (RLZ, FF); and Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania (SG), Philadelphia, Pennsylvania	Mod Pathol 2001;14:748-751 Abstract quote Diagnosing breast carcinoma that has metastasized to body cavity fluids can be difficult. Recently, immunostaining for the facultative glucose transporter Glut-1 has been described as a sensitive and specific means of detecting carcinomas in effusions. However, only five cases of breast carcinoma were studied. We examined Glut-1 specifically as a means of detecting breast carcinoma in effusion cytology. Using avidin-biotin immunocytochemistry, cell block material from 31 cases of breast carcinoma metastatic to body cavity effusions and 33 cases of benign effusions were studied. All cases were immunostained with the Glut-1 antibody. An additional set of slides from these same cases was stained for mucin using the Mayer’s mucicarmine technique. Slides were graded for percentage of cells exhibiting immunoreactivity for Glut-1 or for the presence of mucin. Results of staining for both Glut-1 alone and in combination with mucicarmine were compared between the benign and malignant groups. Of the breast cancer cases, 19 of 31 (61%) were immunoreactive for Glut-1, and 25 of 31 (81%) were positive for either Glut-1 or mucicarmine. One of the 33 (3%) benign cases was immunoreactive for Glut-1, and none were positive for mucin. These data suggest that using Glut-1 as a single immunostain or in conjunction with mucicarmine is a specific but modestly sensitive means of detecting breast carcinoma in this cytologic setting.
MELATONIN RECEPTORS
Differential expression of high-affinity melatonin receptors (MT1) in normal and malignant human breast tissue. Dillon DC, Easley SE, Asch BB, Cheney RT, Brydon L, Jockers R, Winston JS, Brooks JS, Hurd T, Asch HL. State University of New York at Buffalo School of Medicine, USA.	Am J Clin Pathol 2002 Sep;118(3):451-8 Abstract quote Melatonin is a pineal hormone that strongly inhibits the growth of breast cancer cells in vitro and in vivo. We report thefirst use of immunohistochemical analysis to determine the distribution of the high-affinity melatonin receptor subtype, MTI, in human breast tissue, the hypothalamic suprachiasmatic nucleus, and skin. The MT1 antibody, which is specific for the cytoplasmic portion of the receptor, produced cytoplasmic staining in normal-appearing breast epithelial cells and ductal carcinoma cells; stromal cells, myoepithelial cells, and adipocytes were nonreactive. The majority of nonneoplastic samples (13/19 [68%]) were negative to weakly positive, while moderate to strong reactivity was seen in most cancer samples (49/65 [75%]). Thus, although MT1 receptors were detectable in normal and malignant breast epithelium, high receptor levels occurred more frequently in tumor cells (P < .001), and tumors with moderate or strong reactivity were more likely to be high nuclear grade (P < .045). These findings may have implications for the use of melatonin in breast cancer therapy.
p63
p63 Expression in Breast Cancer: A Highly Sensitive and Specific Marker of Metaplastic Carcinoma. Koker MM, Kleer CG. From the Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI.	Am J Surg Pathol. 2004 Nov;28(11):1506-12. Abstract quote   p63, a member of the p53 gene family, is involved in cellular differentiation and is expressed in the nuclei of myoepithelial cells of normal breast ducts and lobules. Although p63 has been reported in metaplastic carcinomas of the breast, its expression pattern in breast carcinomas and sarcomas has not been fully characterized, and its potential diagnostic utility has not been defined. In this study, we determined p63 expression in a large number of breast carcinomas, including metaplastic carcinomas, and in Phyllodes tumors and sarcomas. We examined 189 invasive breast carcinomas, including 15 metaplastic carcinomas, as well as 10 Phyllodes tumors, and 5 pure sarcomas of the breast for pattern and intensity of p63 staining using an anti-p63 antibody (clone 4A4, Neomarkers). p63 was strongly expressed in 13 of 15 metaplastic carcinomas (86.7%). p63 was positive in all the metaplastic carcinomas with spindle cell and/or squamous differentiation (12 of 12), and in 1 of 3 metaplastic carcinomas with cartilage foci. In stark contrast, only 1 of 174 (0.6%) nonmetaplastic invasive carcinomas was positive for p63. All Phyllodes tumors and sarcomas were consistently negative for p63 expression. The sensitivity and specificity of p63 as a diagnostic marker for metaplastic carcinoma was 86.7% and 99.4%, respectively. We propose the inclusion of p63 as part of the diagnostic workup of challenging spindle cell tumors of the breast as a highly specific marker for metaplastic carcinomas.
Immunohistochemical Distinction of Invasive From Noninvasive Breast Lesions: A Comparative Study of p63 Versus Calponin and Smooth Muscle Myosin Heavy Chain. Werling RW, Hwang H, Yaziji H, Gown AM.	Am J Surg Pathol 2003 Jan;27(1):82-90 Abstract quote Identification of myoepithelial cells using antibodies to cytoskeletal proteins, such as smooth muscle myosin heavy chain (SMM-HC) and calponin, can play an important role in distinguishing invasive carcinoma from its histologic mimics. However, antibodies to these proteins may also cross-react with stromal myofibroblasts and vascular smooth muscle cells. It has recently been demonstrated that myoepithelial cells express the nuclear protein, p63, a member of the p53 gene family. We compared the patterns of reactivity of antibodies with p63, calponin, and SMM-HC on 85 breast lesions, including 11 cases of sclerosing adenosis, 33 cases of ductal carcinoma in situ, including 10 that showed microinvasion, 6 cases of lobular carcinoma in situ, and 35 cases of infiltrating ductal carcinoma. All three antibodies were positive on the vast majority of myoepithelial cells in all cases. A small minority of cases showed focal gaps in the revealed myoepithelial cell layer, reflected in discontinuous positive immunostaining around noninvasive epithelial nests (including ductal carcinoma in situ). No case showed p63 expression by myofibroblasts or vascular smooth muscle cells, whereas myofibroblasts expressed, in 8% and 76% of cases, SMM-HC and calponin, respectively. Although no tumor cell reactivity was noted with antibodies to calponin or SMM-HC, tumor cells in 11% of cases showed at least focal p63 expression. And although antibodies to p63 offer excellent sensitivity and increased specificity for myoepithelial detection relative to antibodies to calponin and SMM-HC, they have the following diagnostic limitations: 1) they occasionally demonstrate an apparently discontinuous myoepithelial layer, particularly around ductal carcinoma in situ, and 2) they react with a small but significant subset of breast carcinoma tumor cells. p63 may represent a myoepithelial marker that can complement or replace SMM-HC and/or calponin in the analysis of difficult breast lesions.
p63 staining of myoepithelial cells in breast fine needle aspirates: a study of its role in differentiating in situ from invasive ductal carcinomas of the breast. Reis-Filho JS, Milanezi F, Amendoeira I, Albergaria A, Schmitt FC. IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, 4200 Porto, Portugal Hospital de Sao Joao, Porto Medical Faculty, University of Porto, 4200 Porto, Portugal.	J Clin Pathol 2002 Dec;55(12):936-9 Abstract quote AIMS: One of the limitations of fine needle aspiration biopsy (FNAB) of the breast is in distinguishing invasive carcinoma (IDC) from ductal carcinoma in situ (DCIS). It has been proposed that the presence of myoepithelial cells overlying epithelial malignant cell clusters suggests DCIS. However, the recognition of myoepithelial cells in aspirates may be difficult. The aim of this study was to investigate a new nuclear myoepithelial cell marker, p63, a p53 homologue nuclear transcription factor, in a series of breast FNABs in an attempt to distinguish IDC from DCIS. METHODS: Papanicolaou stained smears from eight cases of pure DCIS and 15 cases of pure IDC with a histologically confirmed diagnosis were submitted to immunocytochemical analysis using the antibody 4A4 against p63. Two pathologists evaluated the presence of p63 positive cells overlying malignant cell clusters and admixed with malignant cells. The frequency of p63 positive cells in DCIS and IDC was compared using Fisher's exact test. RESULTS: p63 consistently stained the nuclei of myoepithelial cells, either overlying malignant cell clusters and/or admixed with malignant cells. p63 positive myoepithelial cells were seen in all DCIS cases and in nine of the 15 cases of IDC (p = 0.0375). In eight cases (three DCIS and five IDC), scattered p63+ epithelial malignant cells were seen. CONCLUSIONS: Although p63 positive myoepithelial cells are found more frequently in DCIS cases, their presence cannot be used as a criterion to rule out invasion in breast FNABs because they are present in up to 60% of invasive cases.
p63, a p53 homologue, is a selective nuclear marker of myoepithelial cells of the human breast. Barbareschi M, Pecciarini L, Cangi MG, Macri E, Rizzo A, Viale G, Doglioni C. Department of Pathology, San Martino Hospital, Trento, Italy.	Am J Surg Pathol 2001 Aug;25(8):1054-60 Abstract quote Myoepithelial cells (MCs) constitute the basal cell layer of normal mammary epithelia, and their identification is of particular diagnostic value because they are retained in most benign lesions while being lost in malignancy. Several MC immunocytochemical markers are currently available for diagnostic purposes, with special reference to smooth muscle-related antigens. p63 is a member of the p53 gene family, and its germline mutations are associated with severe mammary developmental defects in both rodents and humans. Different p63 isoforms have been identified, some of which (DeltaNp63) are preferentially expressed in the epithelial basal cells of different organs and have been considered as possible markers of stem cells/reserve cells. We investigated immunohistochemically 384 samples of normal and diseased human breast, including 300 invasive carcinomas, using four antibodies recognizing all p63 isoforms, or the DeltaNp63 isoforms. Twenty cytologic specimens were also investigated. Furthermore, snap-frozen tissue samples from three fibroadenomas and 10 invasive ductal carcinomas with their paired non-neoplastic tissues and three corresponding lymph node metastases were evaluated for the expression of p63 mRNA by RT-PCR. In normal breast tissue p63 immunoreactivity was confined to the nuclei of MCs. In all benign lesions p63-immunoreactive cells formed a continuous basal rim along the epithelial structures. Stromal cells, and in particular myofibroblasts, were consistently unreactive. Adenomyoepitheliomas showed nuclear staining in most neoplastic cells. A peripheral rim of p63-immunoreactive cells was retained surrounding lobular and ductal carcinoma in situ, although it was discontinuous as opposed to the normal structures. Invasive breast carcinomas were consistently devoid of nuclear p63 staining, with the exception of the two adenoid-cystic carcinomas, of the two ductal carcinomas with squamous metaplasia, and of 11 (4.6%) ductal carcinomas not otherwise specified, showing p63 immunoreactivity in a minor fraction (5-15%) of the neoplastic cells. In comparison with other MC markers, p63 was the most specific, being restricted exclusively to MCs, whereas antibodies to smooth muscle actin and, to a lesser extent, calponin also decorated stromal myofibroblasts. In the cytologic preparations p63 immunoreactivity was a consistent feature of "naked nuclei" and of a subset of cells surrounding benign epithelial clusters. RT-PCR experiments with primers specific for different p63 isoforms documented that normal tissues and fibroadenomas preferentially expressed the DeltaNp63 isoforms. Our study demonstrates that in normal and pathologic breast tissues MCs consistently express the DeltaNp63 isoforms. We suggest p63 as a reliable, highly specific, and sensitive MC marker in both histologic and cytologic preparations. Furthermore, because p63 immunoreactivity in adult epithelia is normally restricted to progenitor cells, it can be speculated that it might be a clue for the identification of the still elusive breast progenitor cells.

 

DIFFERENTIAL DIAGNOSIS	CHARACTERIZATION
BENIGN MECHANICAL TRANSPORT
Breast epithelial cells in dermal angiolymphatic spaces: A manifestation of benign mechanical transport. Diaz NM, Mayes JR, Vrcel V.	Hum Pathol. 2005 Mar;36(3):310-3. Abstract quote   Summary Evidence suggesting that breast epithelial cells may reach axillary lymph nodes by benign mechanical transport (BMT), rather than metastatic means, has been recently reported. We report a case of a patient with ductal carcinoma in situ of the breast, who had displaced epithelial elements in the mastectomy specimen, dermal angiolymphatic spaces, and a sentinel lymph node. We attribute the epithelial aggregates in the dermal angiolymphatic spaces and a single cell in the sentinel lymph node to BMT, based on the clinicopathological findings of the case. We, therefore, suggest that the effects of BMT be considered in the differential diagnosis of epithelial aggregates in dermal angiolymphatic spaces in the appropriate clinicopathological setting.
CARCINOID TUMOR, METASTATIC FROM GI TRACT
Primary small bowel carcinoid tumor with bilateral breast metastases: report of 2 cases with different clinical presentations. Mosunjac MB, Kochhar R, Mosunjac MI, Lau SK. Department of Pathology and Laboratory Medicine, Emory University, Grady Memorial Hospital, Atlanta, Ga, USA.	Arch Pathol Lab Med. 2004 Mar;128(3):292-7. Abstract quote   CONTEXT: Carcinoid tumor metastatic to the breast is uncommon and can closely mimic a mammary carcinoma. The differentiation of metastatic carcinoid tumor from primary breast tumor is important, however, owing to different clinical management and prognosis. OBJECTIVE: The purpose of this study was to describe 2 patients with bilateral metastatic carcinoid tumors to the breast with different clinical manifestations. DESIGN: We examined the radiological, clinical, cytologic, histologic, immunohistochemical, and ultrastructural features of these 2 cases. RESULTS: In case 1, the tumor presented initially as a stellate mass on mammogram and was diagnosed as grade II infiltrating ductal carcinoma. It was only after the discovery of small intestinal, liver, ovarian, and contralateral breast masses, as well as careful morphologic and immunohistochemical evaluations, that the true nature of the tumor was realized. In case 2, the tumor initially presented as a small intestinal tumor with liver metastases and bilateral breast masses. The breast masses were diagnosed accurately as metastatic carcinoid tumor by morphologic and immunohistochemical evaluations. CONCLUSIONS: Metastatic carcinoid tumor to the breast is uncommon, but poses a diagnostic challenge in that morphologically it can closely mimic a primary breast tumor. Careful attention to clinical features and the use of auxiliary immunohistochemical studies can help in arriving at the correct diagnosis.
CYLINDROMA
Solitary Cylindroma (Dermal Analog Tumor) of the Breast A Previously Undescribed Neoplasm at This Site S. Tunc Gokaslan, M.D.; Brian Carlile, M.D; M. Dudak, M.D.; Jorge Albores–Saavedra, M.D. From the Department of Pathology, Division of Anatomic Pathology (S.T.G., B.C., J.A.-S.), and Department of Surgery (M.D.), The University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.	Am J Surg Pathol 2001;25:823-826 Abstract quote The authors report a previously undescribed small, well-demarcated breast tumor similar to a dermal cylindroma in a 63-year-old woman. The tumor was an incidental finding in a lumpectomy specimen for infiltrating lobular carcinoma. The cylindroma was surrounded by normal-appearing breast parenchyma and had the typical ``jigsaw'' pattern of epithelial basaloid islands. The islands showed focal squamous and myoepithelial differentiation. A notable number of reactive dendritic Langerhans cells permeated the epithelial cell islands, a feature considered to be characteristic of dermal cylindroma. There was also ductal differentiation. Thick bands of hyaline periodic acid–Schiff (PAS) stain and collagen IV-positive basement membrane material bordered the cell islands, and PAS–collagen IV-positive hyaline globules were seen within the cell islands. There was no nuclear pleomorphism or mitotic figures. The cylindroma did not express gross cystic disease fluid protein 15, carcinoembryonic antigen, estrogen and progesterone receptors, or cytokeratin 20 (CK20). There was diffuse and strong immunoreactivity to CK AE1/AE3, and focal reactivity for CK7 and smooth muscle actin. Cylindroma of the breast should be distinguished from adenoid cystic carcinoma and basal cell carcinoma. Although clearly epithelial, the exact histogenesis and cell phenotype of this unusual dermal type cylindroma of the breast are unknown.
ECTOPIC BREAST TISSUE
Ectopic breast tissue as a possible cause of false-positive axillary sentinel lymph node biopsies. Maiorano E, Mazzarol GM, Pruneri G, Mastropasqua MG, Zurrida S, Orvieto E, Viale G.	Am J Surg Pathol 2003 Apr;27(4):513-8 Abstract quote Epithelial inclusions representing ectopic breast tissue are uncommonly seen in axillary lymph nodes. The extensive histopathologic examination of axillary sentinel lymph nodes of patients with breast carcinoma may increase the chances to encounter tiny foci of ectopic breast tissue, which may be misinterpreted as (micro)metastatic disease and lead to unwarranted completion of axillary dissection and to inaccurate staging and improper adjuvant treatments for the patients. Here we report on seven cases of ectopic breast tissue in axillary sentinel lymph nodes. In three cases there were coexistent micrometastases, and in the remaining cases the ectopic tissue was not associated with metastatic disease. The ectopic breast tissue showed remarkably varied morphologic features, including apocrine metaplasia and proliferative changes indistinguishable from those occurring in sclerosing adenosis and florid epithelial hyperplasia of the breast. A peripheral layer of myoepithelial cells was consistently detected in the ectopic glands and ducts. Besides awareness and purely morphologic criteria, a false-positive identification of these inclusions as metastatic carcinoma may be avoided by the use of immunohistochemical reactions for the localization of specific markers of the myoepithelial cell component, which is associated with the ectopic breast tissue.
HOMOLOGOUS CARCINOMAS
Homologous carcinomas of the breasts, skin, and salivary glands. A histologic and immunohistochemical comparison of ductal mammary carcinoma, ductal sweat gland carcinoma, and salivary duct carcinoma. Wick MR, Ockner DM, Mills SE, Ritter JH, Swanson PE. Division of Surgical Pathology, Washington University Medical Center, St Louis, MO 63110, USA.	Am J Clin Pathol 1998 Jan;109(1):75-84 Abstract quote Morphologic mimicry among human malignant neoplasms is a well-known phenomenon in surgical pathology; both undifferentiated and "committed" neoplasms may exhibit this trait. One particularly common group of histologic simulants includes ductal carcinomas of the breasts, the cutaneous appendages, and the salivary glands. One hundred three tumors in this structural cluster were analyzed microscopically and immunohistologically to codify points of potential pathologic similarity and difference. All the lesions were typified by irregularly permeative clusters and cords of atypical polygonal cells with variable luminal differentiation. A proportion of primary neoplasms in each site demonstrated in situ ductal components; in the absence of the latter elements, however, it was not possible to make topography-related morphologic distinctions among them. Immunostains for gross cystic disease fluid protein-15 (GCDFP-15), carcinoembryonic antigen, S100 protein, c-erbB-2 oncoprotein, estrogen receptor protein, and progesterone receptor protein also showed largely overlapping phenotypes in each of the three tumor categories, with selected exceptions. These differences were elucidated through paired chi 2 analysis and included a statistically significant infrequency of GCDFP-15 in eccrine sweat gland carcinomas, a paucity of carcinoembryonic antigen in breast cancers, and an absence of estrogen receptor protein in salivary duct carcinomas. Such findings may be useful in predefined differential diagnostic settings involving the distinction between primary and metastatic ductal cancers of the breasts, skin, and salivary glands. Nevertheless, because of the striking homologies between such tumors at structural and protein-synthetic levels of comparison, it is mandatory that all available clinicopathologic information be used in this context.
INTRAMAMMARY LYMPH NODES
Intramammary Lymph Nodes	Hum Pathol 2001:32:178-187. Abstract quote 26 such specimens from 26 patients amongst 3,096 breast biopsy and mastectomy specimens; approximately 8% of 38,931 total surgical specimens Of the 26 specimens containing intramammary lymph nodes, 23 were biopsies, 2 were mastectomy specimens, and 1 was a fine-needle aspiration (FNA). A qualified mammographer (A.T.) reviewed radiographic records on the 5 patients who underwent breast biopsy based on a mammographically visible nodule, which turned out to be a lymph node when examined histologically. Slides from paraffin-embedded tissue were reviewed by 3 pathologists Following specimen types and sources were used to survey the presence of intramammary lymph nodes in the human female breast mound: (1) cadaver breasts; (2) community hospital breast specimens; and (3) university and VA hospital specimens Defined as a lymphoid tissue aggregate with a distinct capsule and germinal centers True lymph nodes within and associated with breast specific tissue (ie, tissue that includes duct and gland structures) were identified Conclusion: Lymph nodes occur in any quadrant of the breast mound Recognizing the possibility of intramammary lymph nodes is important when choosing between patient management options Intramammary lymph nodes can be sampled by FNA Intramammary lymph nodes can contain various disease processes Intramammary lymph nodes are commonly identified by imaging methods and are more likely to be sampled by FNA than either by core or excisional biopsy
LYMPHOMA, ANAPLASTIC
Sarcomatoid variant of anaplastic large cell lymphoma mimicking a primary breast cancer. Pereira EM, Maeda SA, Reis-Filho JS. Salomao & Zoppi Associated Pathologists (Drs Pereira and Maeda), Porto, Portugal; and the Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal (Dr Reis-Filho).	Arch Pathol Lab Med 2002 Jun;126(6):723-6 Abstract quote The sarcomatoid variant of anaplastic large cell lymphoma is one of the rarest histologic variants of this neoplasm. Due to its sarcomatoid features, it is frequently misdiagnosed as a poorly differentiated sarcoma, anaplastic carcinoma, or melanoma. We report the case of a 92-year-old woman with a sarcomatoid anaplastic large cell lymphoma mimicking a primary breast neoplasm. The patient presented with a rapidly enlarging lump in the left breast and nodules in the right axilla. The immunohistochemical profile showed reactivity for leukocyte common antigen, UCHL-1, vimentin, and CD30, but immunoexpression of anaplastic lymphoma kinase was lacking. Anaplastic large cell lymphomas are lymphoid neoplasms of T-cell/null-cell lineage that consistently express the activation marker CD30 and usually carry a gene rearrangement of the anaplastic lymphoma kinase gene. To the best of our knowledge, this is the first reported case of sarcomatoid anaplastic large cell lymphoma presenting as a primary breast neoplasm in which anaplastic lymphoma kinase expression was assessed.
MEGAKARYOCYTES
Megakaryocytes mimicking metastatic breast carcinoma. Hoda SA, Resetkova E, Yusuf Y, Cahan A, Rosen PP. Department of Pathology, Weill Medical College of Cornell University & New York Presbyterian Hospital-Weill Cornell Medical Center, New York, NY 10021, USA.	Arch Pathol Lab Med 2002 May;126(5):618-20 Abstract quote False-positive diagnosis of lymph nodes occurs when a benign element in a lymph node, or in its capsule, is interpreted as metastatic carcinoma. This report describes a patient with breast carcinoma who had megakaryocytes in axillary sentinel lymph nodes mimicking metastatic carcinoma. The patient had no history of a hematologic disease, and we found no evidence of a concurrent hematopoietic disorder. The megakaryocytes were reactive for CD31, CD61, and von Willebrand factor, but not for cytokeratin (AE1/AE3). Megakaryocytes should be added to the list of benign histologic abnormalities that may simulate metastatic carcinoma in a sentinel lymph node.
OVARIAN CARCINOMA, METASTATIC
Serous carcinoma of the ovary and peritoneum with metastases to the breast and axillary lymph nodes: a potential pitfall. Recine MA, Deavers MT, Middleton LP, Silva EG, Malpica A. From the Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX.	Am J Surg Pathol. 2004 Dec;28(12):1646-51. Abstract quote Metastasis of ovarian or peritoneal serous carcinoma to the breast and/or axillary lymph nodes is a rare event. Nevertheless, its recognition and distinction from mammary carcinoma are of great clinical importance because the treatment and prognosis differ significantly. Eighteen cases of ovarian or peritoneal serous carcinoma metastatic to the breast and/or axillary LNs from a 14-year period (1990-2003) were retrieved from our files. Clinical information was obtained from the patients' charts. The age of the patients ranged from 21 to 67 years (median, 55 years). The primary tumors included 14 ovarian serous carcinomas (11 high grade and 3 low grade; 2 of the low-grade tumors presented as serous tumors of low malignant potential and recurred as low-grade serous carcinoma) and 4 peritoneal serous carcinomas (3 high grade and 1 low grade). Of the ovarian neoplasms, 1 was stage I and 10 were stage III tumors; the breast and/or axillary lymph node metastases were discovered on average 30 months after presentation (range, 7-135 months). Three of the ovarian serous carcinomas were stage IV tumors; in 1 case, there were axillary lymph node metastases at initial presentation; and in 2 cases, breast and/or axillary lymph node metastases developed at 18 and 102 months. Two of the 4 patients with peritoneal serous carcinoma presented with stage IV disease, having synchronous breast and axillary lymph node metastases; the other 2 patients developed them at 11 and 16 months after presentation. Four patients had multiple breast lesions and 8 patients had a single metastasis. In 4 cases, the breast metastases were initially interpreted as infiltrating ductal carcinoma. The remaining 6 patients had axillary lymph node involvement only. The metastases in 17 of the cases had papillary features, with psammoma bodies present in 4. Immunoperoxidase studies for GCDFP-15 and WT-1 were performed in 4 cases; all 4 were positive for WT-1 and negative for GCDFP-15. Follow-up was available for 17 patients, with 7 patients known to be dead from disease (survival range, 2-31 months) after the development of metastatic disease to the breast or axillary lymph nodes. Ten patients were alive with disease at their last follow-up, which ranged from 1 to 30 months after the breast or axillary LN metastasis developed. Metastases to the breast or axillary lymph nodes from ovarian and/or peritoneal serous carcinomas are uncommon. Most of the patients in whom metastatic disease develops have a known history of advancedstage ovarian or peritoneal carcinoma. Breast and/or axillary LN involvement at initial presentation can occur but is rare. Differentiation between metastatic and primary tumors of the breast is of great importance because treatment and prognosis differ significantly. Clinical history, the presence of papillary architecture, and WT-1 expression are useful in establishing the correct diagnosis.
XANTHOMATOUS PSEUDOTUMOR
Xanthomatous pseudotumor. Tan KB, Thamboo TP, Raju GC. Department of Pathology, National University Hospital, National University of Singapore, Singapore.	Arch Pathol Lab Med 2003 Jun;127(6):739-41 Abstract quote Neoadjuvant chemotherapy has become an integral part of the treatment for locally advanced breast cancer. It facilitates tumor resectability and also provides an opportunity for the assessment of therapeutic response and prognosis. We report a case in which a large primary breast carcinoma was significantly reduced in size clinically and replaced by a mass lesion that was composed almost entirely of foamy histiocytes. This peculiar phenomenon is described in detail, together with a brief review of the other known postchemotherapy histologic features that include tumor necrosis, tumor cell cytoplasmic vacuolation and marked nuclear atypia, accompanying chronic inflammatory cellular infiltrate, fibrosis, and ductal-lobular atrophy.

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Estrogen and Progesterone Receptors-These are receptors present on normal ductal epithelium and frequently present on breast cancer cells.  Special stains can detect their presence and if present, are a favorable prognostic indicator.

Pagetoid-This is a descriptive term derived from the disease of the same name, Paget's disease of the breast.  In this cancer, the cells exhibit a peculiar pattern of growth predominately limited to nipple and skin epithelium.

Scarf-Bloom-Richardson Grading (Nottingham Revision)-A common method of grading breast cancers.  It combines scores of  the tumor grade, degree of glandular differentiation, and number of mitotic figures.  The higher the grade, the poorer the prognosis.  Thus, tumors can have a range of 3 (well differentiated) to
9 (poorly differentiated).

Feature	Score
Tubule formation (extent within tumor)
>75%	1
10-75%	2
<10%	3
Nuclear pleomorphism
Small regular uniform	1
Moderate variation	2
Marked variation	3
Mitotic Count per 10 high power fields (hpf)
0-9	1
10-19	2
>20	3

Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation

Commonly Used Terms
This is a glossary of terms often found in a pathology report.

Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscope

Surgical Pathology Report
Examine an actual biopsy report to understand what each section means

Special Stains
Understand the tools the pathologist utilizes to aid in the diagnosis

How Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurate

Got Path?
Recent teaching cases and lectures presented in conferences

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• Fine Needle Aspiration Cytology
• National Alliance of Breast Cancer Organizations
• Pathologists Who Make A Difference
• Search for a Physician Specialist

Last Updated November 7, 2006

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