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Background
Prognostic factors in breast cancer have exploded over the past several years. Pathologists have played a major role in identifying different histological and immunohistochemical markers that have a direct bearing on both the treatment and behavior of breast cancer.
OUTLINE
GENERAL AGE BILATERAL CANCERS CHROMOSOMAL ABNORMALITIES DNA PLOIDY DCIS ASSOCIATED FIBROTIC FOCUS HORMONAL RECEPTOR STATUS LCIS ASSOCIATED LYMPH NODE STATUS LYMPHOVASCULAR INVASION ONCOGENES p53 PREGNANCY RACE SECOND PRIMARY BREAST CANCER SIZE OF TUMOR TOPOISOMERASES TREATMENT INADEQUACIES TUMOR ASSOCIATED ANTIGENS TUMOR STAGING
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS The prognosis of breast cancer is influenced by a number of factors Tumors <1 cm with negative nodes have 98% survival at 5 yrs
Tumors <2 cm with negative nodes have 96% survivalSingle most important factor in determining prognosis for early breast cancer
10 yr disease free survival is 70-80% with negative nodes
One to three positive nodes 35-40%
Ten or more positive nodes 10-15%
Micrometastasis <0.2 cm are associated with better prognosis
NOTE: 20-30% of node-negative women will have a recurrence and die within 10 yrsBetter for tubular, papillary, colloid, medullary versus NOS types
>80% of women with Grade I tumors survive 16 yrs50-85% of tumors have estrogen receptors
70% of tumors with estrogen receptors regress after hormone treatment
Only 5% of receptor negative tumors respondHigher proliferation rates have poorer prognosis
High S-phase fraction by flow cytometrySee her2-neu High correlation with increased vessel density and metastasis Strong association with lymph node metastasis
Dermal lymphatic invasion (inflammatory carcinoma) has 3 yr survival of 3-10%GENERAL
Histopathologic types of benign breast lesions and the risk of breast cancer: case-control study.Shaaban AM, Sloane JP, West CR, Moore FR, Jarvis C, Williams EM, Foster CS.
Department of Cellular and Molecular Pathology (A.M.S., J.P.S., F.R.M., C.J., C.S.F.), Department of Public Health (C.R.W.), Merseyside and Cheshire Cancer Registry Office (E.M.W.), University of Liverpool, Liverpool, U.K.
Am J Surg Pathol 2002 Apr;26(4):421-30 Abstract quote The hypothetical multistep model of carcinogenesis indicates that breast cancer develops via a series of intermediate hyperplastic lesions through in situ to invasive carcinoma.
To identify the risk inherent within the different morphologic lesions, we have analyzed the data from 674 benign biopsy specimens comprising 120 cases who subsequently developed breast cancer and 382 controls (matched for age and date of biopsy) spanning a period up to 20 years of follow-up (mean 66.95 months). In this series we have confirmed an increased risk associated with certain types of benign breast lesions.
Atypical lobular hyperplasia was the most significant risk factor for breast cancer with more unfavorable outcome in patients <50 years of age (p = 0.003) and a relative risk (RR) of 4.55 (confidence interval [CI] 1.77-11.69). Hyperplasia of usual type showed an RR of 1.53 (CL 1.10-2.13) with a statistically worse probability of survival (cancer-free time) for patients >50 years. For atypical ductal hyperplasia the RR was 2.03 (CI 0.80-1.39). Blunt duct adenosis was significantly more common in cases progressing to breast cancer compared with controls, showing an RR of 2.08 (CI 1.12-2.85).
We describe in detail the criteria of morphologic changes observed in blunt duct adenosis and define, for the first time, the level of risk associated with each of its six subtypes. Improved knowledge of breast carcinogenesis will provide insight for defining high-risk groups thus resulting in improved screening and management regimens.
AGE Pathology and heredity of breast cancer in younger women.
Marcus JN, Watson P, Page DL, Lynch HT.
Department of Pathology, Creighton University, Omaha, Neb.
J Natl Cancer Inst Monogr 1994;(16):23-34 Abstract quote
The pathology of early-age onset breast cancer is considered here from three perspectives: 1) benign proliferative disease, 2) the cancers themselves, and 3) familial and hereditary breast cancer.
Hereditary breast cancer, a subset of familial breast cancer featuring a strong autosomal dominant pedigree pattern and multiple primary cancers, has a strong predilection for younger women, accounting for about one half of breast cancers under age 30.
With respect to benign proliferative disease, the increased relative risk of breast cancer associated with proliferative disease with atypia, about fourfold to fivefold for all ages, is doubled by the presence of a family history of breast cancer and amplified by young age.
With respect to the carcinomas, the relative incidences of medullary carcinoma and ductal carcinoma in situ are increased in young women, while lobular and tubular carcinomas are decreased. Invasive breast cancer is higher grade and more proliferative in younger women, as measured by thymidine-labeling index, DNA flow cytometric S-phase fraction, and proliferation-associated proteins. The increased fraction of ductal carcinoma in situ and higher grade invasive cancers may help to account, respectively, for increased recurrence rates with conservative therapy, and more aggressive natural history in younger women.
Familial breast cancers show trends for increased medullary type, but the effect is not independent of age. Weak associations of family history with tubular carcinoma have been reported, but data for associations with lobular carcinoma in situ and invasive lobular carcinoma are conflicting.
Hereditary breast cancer as a class has higher tumor proliferation rates, an effect independent of age. Knowledge of the pathology and biomarker characteristics of BRCA1 gene-linked hereditary breast cancers, which account for a substantial fraction of breast cancers in younger women, should shed light on the nature of the responsible gene(s) and guide approaches to therapy and prophylaxis.
The histologic phenotypes of breast carcinoma occurring before age 40 years in women with and without BRCA1 or BRCA2 germline mutations: a population-based study.
Armes JE, Egan AJ, Southey MC, Dite GS, McCredie MR, Giles GG, Hopper JL, Venter DJ.
Molecular Pathology Laboratory, Victorian Breast Cancer Research Consortium, Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia.
Cancer 1998 Dec 1;83(11):2335-45 Abstract quote
BACKGROUND: Women with breast carcinoma diagnosed before age 40 years have a greater prevalence of germline BRCA1 and BRCA2 mutations than women with breast carcinoma diagnosed at older ages. Several recognizable histologic characteristics have been identified in breast carcinoma from studies of BRCA1/2 mutation carriers who belong to multiple-case families. The authors attempted to determine whether breast carcinoma occurring before age 40 years in BRCA1 or BRCA2 mutation carriers who were not selected for family history could be distinguished histologically from one another and from breast carcinoma in women of a similar age without a germline BRCA1 or BRCA2 mutation.
METHODS: The study undertook a histologic assessment of breast carcinomas diagnosed before age 40 years identified from a population-based study.
RESULTS: Breast carcinoma in BRCA1 mutation carriers was associated with a distinct histologic appearance; these tumors were high grade, and had exceptionally high mean mitotic counts, a syncytial growth pattern, pushing margins, and confluent necrosis. Atypical medullary carcinoma was overrepresented in BRCA1 mutation carriers. All low grade tumors and tumors with low mitotic rates belonged to the group without BRCA1 or BRCA2 mutations. Pleomorphic lobular carcinomas and extensive intraduct carcinomas were more common in BRCA2 mutation carriers.
CONCLUSIONS: Breast carcinoma occurring in women with a germline BRCA1 or BRCA2 mutation have recognizable histologic phenotypes, which may be useful in identifying individuals more likely to carry germline mutations. Histologic examination of breast carcinoma should become an important part of the evaluation of women seeking genetic testing for germline mutations in these breast carcinoma susceptibility genes.
Breast cancer in young women: clinicopathologic correlation.
Bertheau P, Steinberg SM, Cowan K, Merino MJ.
Laboratory of Surgical Pathology, Saint-Louis Hospital, Paris, France.
Semin Diagn Pathol 1999 Aug;16(3):248-56 Abstract quote
It has been suggested that early-onset breast carcinomas may be different from those that occur in older women.
The clinicopathologic characteristics of 191 young female patients (under 40 years of age) diagnosed with breast carcinoma (BC) were studied. Clinical history, staging, treatment and outcome were reviewed. Histology was assessed for tumor subtypes, invasive and in situ components, nuclear and histologic grades and lymph node status. Adjacent nontumoral breast tissue was evaluated.
Clinically, 11 patients were stage 0, 21 stage I, 94 stage II, 38 stage III, 6 stage IV, and in 21 no information was obtained. Sixty five percent of patients had positive lymph nodes at diagnosis; 102 patients (54%) relapsed at a median of 29 months after diagnosis.
Histologically, 180 cases were infiltrating BC, 150 ductal (83%), 19 lobular (11%) and 11 of special types (6%); 11 cases were ductal carcinoma in situ. We found no cases of medullary carcinoma. High nuclear grade and vascular invasions were frequent (68% and 67%, respectively) even in patients who remained disease-free at least 5 years after diagnosis (61% and 60%, respectively).
Our study demonstrates that the histologic types of early-onset breast cancer are not different from other BC. However, BC in young women is often associated with histologic features of high-grade malignancy even in patients with better survival.
Our results suggest that BCs in young women are different from those that occur in older women.
BILATERAL CANCERS Multicentricity and bilaterality in invasive breast carcinoma.
Lesser ML, Rosen PP, Kinne DW.
Surgery 1982 Feb;91(2):234-40 Abstract quote
Multicentricity and bilaterality are well-established characteristics of breast carcinoma, but little is known about the relationship of these variables with each other. This question was explored by analyzing the data pertaining to 880 women with invasive breast carcinoma.
Patients with multicentric carcinoma had bilateral disease more often than those whose carcinoma was apparently limited to a single quadrant. Among women who had lobular carcinoma in situ coexisting with infiltrating duct carcinoma or infiltrating lobular carcinoma, bilaterality and multicentricity were significantly more common than they were among patients whose only lesion was infiltrating duct or medullary cancer. Other variables associated with bilaterality and multicentricity were degree of ductal differentiation, tumor size, nodal status, type of tumor margin, intensity of lymphoid infiltrate, and menstrual status. Age at diagnosis and estrogen receptors were related to bilaterality but not to multicentricity.
The following variables proved to be unrelated to bilaterality and multicentricity: family history of breast carcinoma, height, weight, and parity.
The data obtained in this study tend to support a conclusion that multicentricity and bilaterality are manifestations of similar factors involved in the neoplastic transformation of mammary gland epithelium leading to the development of breast cancer.
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.
A case-control study of unilateral and bilateral breast carcinoma patients.
Newman LA, Sahin AA, 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.
CHROMOSOMAL ABNORMALITIES
Aneuploidy of chromosome 20 in invasive breast cancer correlates with poor outcome.Nakopoulou L, Tsirmpa I, Giannopoulou I, Trafalis D, Katsarou S, Davaris P.
Department of Pathology, Medical School, The National and Kapodistrian University of Athens, Greece.
Cancer Genet Cytogenet 2002 Apr 15;134(2):127-32 Abstract quote Breast carcinoma is a genetically and phenotypically heterogeneous disease and is frequently associated with nonrandom chromosomal alterations.
The aim of this study was to investigate the numerical aberrations of chromosome 20 in breast cancer. The observed chromosome-specific numerical abnormalities were evaluated along with the established clinicopathological parameters, the immunohistochemical expression of ER, PR, p53, c-erbB-2, Ki-67 and patients' survival. Nonisotopic in situ hybridization was applied to interphase cell nuclei on paraffin embedded tissue sections. Polysomy of chromosome 20 was the prevalent alteration in 45 of 50 (90%), monosomy in 2 of 50 (4%) and disomy in 3 of 50 (6%) cases. Invasive ductal carcinomas displayed a higher percentage of polysomy than lobular ones. A statistical significant association was demonstrated between Ki-67 immunohistochemical expression and polysomy of chromosome 20. Disomy was inversely correlated with Ki-67, while monosomy was suggestively associated with PR positive expression.
Among the patients, those with the highest levels of polysomy showed the worst survival. In conclusion, the gain of chromosome 20 is the prevalent aberration in patients with breast carcinomas and may be useful prognostic marker in breast cancer.
DNA PLOIDY DNA ploidy, S-phase, and steroid receptors in more than 127,000 breast cancer patients.
Wenger CR, Beardslee S, Owens MA, Pounds G, Oldaker T, Vendely P, Pandian MR, Harrington D, Clark GM, McGuire WL.
University of Texas Health Science Center, Department of Medicine/Medical Oncology, San Antonio 78284-7884.
Breast Cancer Res Treat 1993 Oct;28(1):9-20 Abstract quote
Several potential prognostic factors are available today for patients with breast cancer, and many more are being identified and studied. To evaluate the clinical utility of these factors, it will be necessary to measure them on a large number of patients, and then follow these patients so that multivariate survival analyses can be performed.
The Oncology Research Network was established in 1986 by the University of Texas Health Science Center at San Antonio and Nichols Institute Reference Laboratories in order to evaluate the clinical utility of new prognostic factors for patients with primary breast cancer. The first generation of prognostic factors included steroid receptors, along with DNA ploidy and S-phase fraction determined by flow cytometry. Currently, laboratory results have been obtained from more than 127,000 patients, and follow-up information is available on a subset of more than 25,000 of these patients. S-phase fraction was related to the ploidy status of the tumor.
An increased incidence of aneuploidy and higher S-phase fractions were found in estrogen and progesterone receptor negative tumors, tumors from patients with positive axillary lymph nodes, tumors greater than 2 cm in diameter, and patients younger than 35 years of age.
Preliminary survival analyses suggest that S-phase fraction and DNA ploidy, in combination with other prognostic factors, are powerful predictors of early disease relapse. The Oncology Research Network provides an important resource for examining the clinical significance of new laboratory assays and for expediting improvements in existing laboratory techniques.
DCIS ASSOCIATED (EXTENSIVE INTRADUCTAL COMPONENT) An assessment of extensive intraductal component as a risk factor for local recurrence after breast-conserving therapy.
Jacquemier J, Kurtz JM, Amalric R, Brandone H, Ayme Y, Spitalier JM.
Department of Anatomic Pathology, Marseille Cancer Institute, France.
Br J Cancer 1990 Jun;61(6):873-6 Abstract quote
The influence of extensive intraductal component (EIC) on local recurrence risk was studied for 496 patients with stage I-II infiltrating ductal cancers treated by conservative surgery and irradiation.
EIC was diagnosed in 65 of 231 (28%) premenopausal and 41 of 265 (15.5%) post-menopausal patients. Local recurrence risk was markedly increased in EIC+ patients (5-year actuarial risk 18% versus 8% without EIC, P less than 0.001), but this effect appeared limited to premenopausal patients. Local recurrence risk increased with increasing degree of EIC. EIC with more than 50% intraductal carcinoma was more prevalent in patients younger than 40, perhaps accounting to some degree for the higher local recurrence rates observed in younger patients.
The presence of EIC had no influence on overall survival, on median time to local recurrence, or on short-term survival after local failure. The usefulness of EIC as a risk factor for local recurrence is discussed.
Intraductal carcinoma associated with invasive carcinoma of the breast. A comparison of the two lesions with implications for intraductal carcinoma classification systems.
Goldstein NS, Murphy T.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.
Am J Clin Pathol 1996 Sep;106(3):312-8 Abstract quote
Intraductal carcinoma (DCIS) is a useful marker for predicting which women will develop a recurrent breast malignancy.
The authors examined 150 consecutive, mammographically detected, T1 invasive carcinomas associated with DCIS to study the DCIS and compare it to its associated invasive carcinoma.
Intraductal carcinoma nuclear grades were assigned to each duct on a scale of 1 to 3. The percentage of DCIS ducts that were involved by each grade was quantitated into quartiles for cases with more than one DCIS nuclear grade. The predominant architectural pattern corresponding to each DCIS nuclear grade was recorded. Ninety-two percent of the 150 invasive carcinomas were of ductal type, 4% were tubular, and the remainder were various other subtypes. Nine percent of the DCIS cases were nuclear grade 1. The remaining 91% of cases were almost evenly distributed between mixed DCIS nuclear grades 1 and 2 (19%), pure DCIS nuclear grade 2 (24%), mixed DCIS nuclear grade 2 to 3 (25%), and pure DCIS nuclear grade 3 (22%). Two percent of cases were a mixture of DCIS nuclear grades 1 and 3 or 1, 2, and 3. All pure DCIS nuclear grade 1 or mixed 1 and 2 were associated with well or moderately differentiated invasive carcinomas, whereas the majority (61%) of the pure DCIS nuclear grade 3 cases were associated with poorly differentiated invasive carcinomas. There was no relation between the DCIS architectural pattern and the invasive carcinoma grade. In general, the DCIS nuclear grade correlates with the grade of the invasive carcinoma.
Unlike DCIS architecture, nuclear grade heterogeneity within DCIS associated with invasive carcinoma is minimal. DCIS classification systems based on nuclear grade have merit because there is little variation in nuclear grade within a given patient's lesion.
Extensive and predominant in situ component in breast carcinoma: their influence on treatment results after breast-conserving therapy.
Sinn HP, Anton HW, Magener A, von Fournier D, Bastert G, Otto HF.
Department of Pathology, University of Heidelberg, Germany.
Eur J Cancer 1998 Apr;34(5):646-53 Abstract quote
Intramammary tumour recurrence is one of the most important problems in breast-conserving therapy.
We reviewed a series of 957 patients treated with breast-conserving therapy for primary invasive breast carcinomas between 1 January 1985 and 31 December 1992 at the University of Heidelberg. All histological slides were re-evaluated for risk factors with special emphasis on the extent and subclassification of the in situ tumour and the margin status.
Six parameters were identified as significant risk factors for intramammary recurrence in the univariate analysis, including extensive or predominant in situ component (EIC, with at least twice the greatest dimension of the invasive tumour component), histological grade, angioinvasion, lobular tumour type, involved resection margin and lymph node status.
The presence of an EIC was statistically correlated with low tumour grade, tumour at the resection margins and in re-excision specimens and with multifocal tumour invasion. Multivariate logistic regression analysis revealed that EIC (relative risk (RR) = 1.9), tumour grade (RR = 1.76), angioinvasion (RR = 1.34), lobular tumour type (RR = 1.65) and young age (< or = 40 years, RR = 1.39) were independent predictors of local recurrence.
When combining these factors in a linear model, the simultaneous presence of at least two of the five risk factors predicted a 5-year risk of intramammary recurrence of 20.9% compared with a risk of only 1-5% when none or one of these risk factors were identifiable.
We conclude that the risk of subsequent intramammary recurrence after breast-conserving therapy can be estimated from a scoring system that includes four histological risk factors and the patient's age.
FIBROTIC FOCUS
Fibrotic focus in invasive ductal carcinoma: an indicator of high tumor aggressiveness.Hasebe T, Tsuda H, Hirohashi S, Shimosato Y, Iwai M, Imoto S, Mukai K.
Pathology Division, National Cancer Center Research Institute, East, Chiba, Japan.
Jpn J Cancer Res 1996 Apr;87(4):385-94 Abstract quote Histological examination of invasive ductal carcinoma of the breast often demonstrates the presence of an extensive central fibrotic focus (FF). The clinicopathological significance of the FF, or scar, in primary invasive ductal carcinoma is still ambiguous.
One hundred and fifty-three cases of invasive ductal carcinoma (IDC) were classified into two groups, those with and those without FF. The differences in frequency of immunohistochemically detected overexpression of c-erbB-2 protein and nuclear accumulation of p53 protein, and the labeling index of proliferating cell nuclear antigen (PCNA), as well as histopathological parameters were compared between these two groups. IDCs smaller than 50 mm with FF showed a higher frequency of high-grade tumors, a higher frequency of lymph node metastasis, and a significantly higher frequency of c-erbB-2 protein overexpression than those without FF. In tumors of 20 mm or less, the incidence of nuclear accumulation of p53 protein was significantly higher in tumors with than those without FF. Tumors with FF showed a significantly higher PCNA labeling index than those without FF, regardless of tumor size.
The present results indicate that the presence of FF is an important clinicopathological parameter associated with a higher degree of malignancy in IDCs, especially those smaller than 50 mm. Therefore, dividing IDCs into those with and those without FF appears to be meaningful clinicopathologically.
Fibrotic focus in invasive ductal carcinoma of the breast: a histopathological prognostic parameter for tumor recurrence and tumor death within three years after the initial operation.Hasebe T, Tsuda H, Tsubono Y, Imoto S, Mukai K.
Pathology Division, National Cancer Center Research Institute, East, Tokyo.
Jpn J Cancer Res 1997 Jun;88(6):590-9 Abstract quote We investigated whether the presence of a fibrotic focus (FF) in the primary lesion and in lymph node metastasis is a good predictor of early tumor recurrence or death in patients with invasive ductal carcinoma (IDC).
Multivariate relative risk (RR) of tumor recurrence and death according to the presence of FF in the primary tumor was estimated using the Cox proportional hazards regression model with adjustment for other prognostic factors (histologic grade, T classification, nodal status, tumor necrosis, DNA ploidy, c-erbB-2 protein expression, p53 protein expression, and labeling index of proliferating cell nuclear antigen). For the evaluation of the metastatic status in the axillary lymph nodes, RR of multivariate analysis was adjusted for the presence of FF in the metastatic tumor and the number of lymph nodes involved (1-3 and > 3). The presence of FF increased the RR of tumor recurrence significantly for the cases in all stages, and especially for those in stages I and II (RR = 6.9, P < 0.05 and RR = 25.0, P < 0.005, respectively).
All cases that died of disease had FF. Among IDCs with FF, 24 cases had FF in lymph node metastasis. Significantly higher RRs of tumor recurrence and death were observed in cases with FF in lymph node metastasis than in those without it (RR = 2.0, P < 0.001 and RR = 5.9, P < 0.05, respectively). It was suggested that the presence of FF is an important predictor of early tumor recurrence or death in patients with IDCs.
The presence of FF in lymph node metastatic lesions is also a significant prognostic parameter.
New prognostic histological parameter of invasive ductal carcinoma of the breast: clinicopathological significance of fibrotic focus.Hasebe T, Mukai K, Tsuda H, Ochiai A.
Pathology Division, National Cancer Center Research Institute East, Chiba, Japan.
Pathol Int 2000 Apr;50(4):263-72 Abstract quote Immunohistochemistry, DNA ploidy analysis and molecular genetics have made it possible to predict the outcome of breast cancer more precisely than routine histological examination alone. However, in routine practice, it is difficult to incorporate these methodologies in all cases. If certain histological parameters can accurately predict the outcome of patients with breast cancer, they would be more practical for routine use.
We showed that the presence of fibrotic focus (FF) in invasive ductal carcinoma (IDC) is closely associated with c-erbB-2 or p53 protein expression, high proliferative activity, and high angiogenesis of the tumors. Furthermore, multivariate analyses with well-known prognostic parameters for IDC demonstrated that the presence of FF is the most useful independent parameter to predict IDC patient outcome. In addition, our data suggested that the interaction between tumor cells and stromal fibroblasts may play an important role in the formation of FF in IDC based on growth factor and growth factor receptor protein expression in the tumor cells and fibroblasts forming FF.
Based on the results of our clinicopathological studies, we propose a new prognostic classification scheme for the prediction of IDC patient outcome, which consists of FF, nuclear atypia, and fat invasion. This classification has superior predicting power to existing prognostic classifications.
Prognostic significance of fibrotic focus in invasive ductal carcinoma of the breast: a prospective observational study.Hasebe T, Sasaki S, Imoto S, Mukai K, Yokose T, Ochiai A.
Pathology Division (TH, TY, AO).
Mod Pathol 2002 May;15(5):502-16 Abstract quote We have already reported invasive ductal carcinomas (IDCs) with fibrotic focus (FF) to be associated with significantly poorer survival than IDCs without FF. The purpose of this study was to prospectively investigate the effect of the presence of FF on the outcomes of 439 patients with IDCs to confirm the prognostic significance of FF, by the multivariate analysis, employing the Cox proportional hazard regression model, as compared with well-known clinicopathological parameters.
We also precisely evaluated the prognostic significance of FF from the viewpoint of FF characteristics. The present study demonstrated that the presence of FF is a very useful parameter predicting tumor recurrence (TR), as well as initial distant organ metastasis (IDOM), in lymph node-negative IDCs (P =.024 and P =.026) and in IDCs positive for either or both estrogen receptor (ER) or progesterone receptor (PR) (P =.007 and P =.015), respectively. In addition, FF of >8 mm in diameter was found to be an independent prognostic parameter for TR and IDOM in lymph node-negative patients and patients with IDC positive for either or both ER or PR (P =.005 and P =.018).
We conclude that the presence of FF is a very important histologic prognostic parameter for patients with IDCs of the breast.
HORMONE RECEPTOR STATUS
Morphologic spectrum of estrogen receptor-negative breast carcinoma.Scawn R, Shousha S.
Department of Histopathology, Charing Cross Hospital and Imperial College of Science, Technology and Medicine, London, United Kingdom.
Arch Pathol Lab Med 2002 Mar;126(3):325-30 Abstract quote Context.-Estrogen receptor (ER)-negative breast carcinomas are a heterogeneous group of breast cancers that are generally thought to be aggressive.
Objective.-To determine the morphologic and immunohistochemical spectrum of a consecutive series of ER-negative breast carcinomas, in an attempt to understand the pathogenesis and behavior of these lesions.
Design.-Seventy-four consecutive cases of ER-negative invasive carcinomas were studied. Hematoxylin-eosin-stained sections were reviewed, and new sections were stained for c-erbB-2, p53, vimentin, and androgen and prolactin receptors. The findings were correlated with the axillary lymph node status as a measure of tumor aggressiveness.
Setting.-The histopathology department of a tertiary referral teaching hospital.
Results.-The tumors included 50 (68%) invasive ductal carcinomas, 21 (28%) medullary/atypical medullary carcinomas, and 1 each of invasive lobular, apocrine, and papillary carcinoma. Some of the invasive ductal cases had distinctive features that are described in this report. Maximum tumor diameter varied between 5 and 100 mm. Sixty tumors (81%) were grade 3, 13 (18%) were grade 2, and 1 (1%) was grade 1. Of the 60 cases in which the axillary node status was known, 34 (57%) had metastases, and 26 did not. Tumors associated with positive nodes were significantly larger than those associated with negative nodes (37.2 vs 17.8 mm, P <.001). A higher percentage of node-negative tumors were c-erbB-2 positive (42% vs 21%, P <.05). There were no differences between the 2 groups with regard to histologic type, tumor grade, or the expression of p53, vimentin, or androgen or prolactin receptors
Conclusions.-Many ER-negative breast carcinomas have distinctive microscopic features. Not all ER-negative tumors are aggressive, as judged by the absence of lymph node metastases in 43% of cases in this series. Tumor size is the most important indicator for the likelihood of the presence of lymph node metastases. The wide range of tumor sizes encountered in this series suggests that the ER status of a tumor is determined early in its natural history and supports the existence of 2 separate pathways for the development of ER-negative and ER-positive breast carcinomas.
LOBULAR CARCINOMA IN SITU The relation between the presence and extent of lobular carcinoma in situ and the risk of local recurrence for patients with infiltrating carcinoma of the breast treated with conservative surgery and radiation therapy
Abner AL, Connolly JL, Recht A, Bornstein B, Nixon A, Hetelekidis S, Silver B, Harris JR, Schnitt SJ.
Joint Center for Radiation Therapy, Harvard Medical School, Boston, MA 02215, USA
Cancer 2000 Mar 1;88(5):1072-7 Abstract quote
BACKGROUND: When found in an otherwise benign biopsy, lobular carcinoma in situ (LCIS) has been associated with an increased risk of development of a subsequent invasive breast carcinoma. However, the association between LCIS and the risk of subsequent local recurrence in patients with infiltrating carcinoma treated with conservative surgery and radiation therapy has received relatively little attention.
METHODS: Between 1968 and 1986, 1625 patients with clinical Stage I-II invasive breast carcinoma were treated at the Joint Center for Radiation Therapy at Harvard Medical School with breast-conserving surgery (CS) and radiation therapy (RT) to a total dose to the primary site of > or =60 grays. Analysis was limited to 1181 patients with infiltrating ductal carcinoma, infiltrating lobular carcinoma, or infiltrating carcinoma with mixed ductal and lobular features who, on review of their histologic slides, had sufficient normal tissue adjacent to the tumor to evaluate for the presence of LCIS and also had a minimum potential follow-up time of 8 years. The median follow-up time was 161 months.
RESULTS: One hundred thirty-seven patients (12%) had LCIS either within the tumor or in the macroscopically normal adjacent tissue. The 8-year crude risk of recurrence was not significantly increased for patients with LCIS associated with invasive ductal, invasive lobular, or mixed ductal and lobular carcinoma. Among the 119 patients with associated LCIS adjacent to the tumor, the 8-year rate of local recurrence was 13%, compared with 12% for the 1062 patients without associated LCIS. For the 70 patients with moderate or marked LCIS adjacent to the tumor, the 8-year rate of local recurrence was 13%. The extent of LCIS did not affect the risk of recurrence. The risks of contralateral disease and of distant failure were similarly not affected by the presence or extent of LCIS.
CONCLUSIONS: Breast-conserving therapy involving limited surgery and radiation therapy is an appropriate method of treating patients with invasive breast carcinoma with or without associated LCIS. Neither the presence nor the extent of LCIS should influence management decisions regarding patients with invasive breast carcinoma.
Lobular carcinoma in situ increases the risk of local recurrence in selected patients with stages I and II breast carcinoma treated with conservative surgery and radiation.
Sasson AR, Fowble B, Hanlon AL, Torosian MH, Freedman G, Boraas M, Sigurdson ER, Hoffman JP, Eisenberg BL, Patchefsky A.
Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19104, USA
Cancer 2001 May 15;91(10):1862-9 Abstract quote
BACKGROUND: Lobular carcinoma in situ (LCIS) is a known risk factor for the development of invasive breast carcinoma. However, little is known regarding the impact of LCIS in association with an invasive carcinoma on the risk of an ipsilateral breast tumor recurrence (IBTR) in patients who are treated with conservative surgery (CS) and radiation therapy (RT). The purpose of this study was to examine the influence of LCIS on the local recurrence rate in patients with early stage breast carcinoma after breast-conserving therapy.
METHODS: Between 1979 and 1995, 1274 patients with Stage I or Stage II invasive breast carcinoma were treated with CS and RT. The median follow-up time was 6.3 years.
RESULTS: LCIS was present in 65 of 1274 patients (5%) in the study population. LCIS was more likely to be associated with an invasive lobular carcinoma (30 of 59 patients; 51%) than with invasive ductal carcinoma (26 of 1125 patients; 2%). Ipsilateral breast tumor recurrence (IBTR) occurred in 57 of 1209 patients (5%) without LCIS compared with 10 of 65 patients (15%) with LCIS (P = 0.001). The 10-year cumulative incidence rate of IBTR was 6% in women without LCIS compared with 29% in women with LCIS (P = 0.0003). In both groups, the majority of recurrences were invasive. The 10-year cumulative incidence rate of IBTR in patients who received tamoxifen was 8% when LCIS was present compared with 6% when LCIS was absent (P = 0.46). Subsets of patients in which the presence of LCIS was associated with an increased risk of breast recurrence included tumor size < 2 cm (T1), age < 50 years, invasive ductal carcinoma, negative lymph node status, and the absence of any adjuvant systemic treatment (chemotherapy or hormonal therapy) (P < 0.001). LCIS margin status, invasive lobular carcinoma histology, T2 tumor size, and positive axillary lymph nodes were not associated with an increased risk of breast recurrence in these women.
CONCLUSIONS: The authors conclude that the presence of LCIS significantly increases the risk of an ipsilateral breast tumor recurrence in certain subsets of patients who are treated with breast-conserving therapy. The risk of local recurrence appears to be modified by the use of tamoxifen. Further studies are needed to address this issue.
LYMPH NODE STATUS Prognostic features in patients with stage T1 breast carcinoma and a 0.5-cm or less lymph node metastasis. Significance of lymph node hilar tissue invasion.
Goldstein NS, Mani A, Vicini F, Ingold J.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.
Am J Clin Pathol 1999 Jan;111(1):21-8 Abstract quote
Trends in surgical practice suggest that pathologists will encounter increased numbers of patients with small invasive ductal adenocarcinomas; small, if any, metastatic deposits in axillary lymph nodes (ALNs); and possibly fewer ALN specimens to examine. New prognostic histologic features may be needed in this environment.
We studied histologic features of primary breast carcinoma and ALN metastasis from 86 patients who had stage T1 ductal carcinomas with only 1 ALN metastasis that was 0.5 cm or less and correlated these features with the development of distant metastases to evaluate their potential usefulness as prognostic indicators.
The median follow-up period was 5.3 years. Distant metastases developed in 12 patients. Features significantly associated with 10-year distant metastases-free survival were lymph node hilar tissue invasion (HTI) and ALN metastasis size (stage N1a vs N1b). Tumor grade 1 vs grades 2 or 3 approached significance. The presence of HTI also was related significantly to a decreased 10-year distant metastases-free survival in the stage N1b group.
Our study suggests that HTI, along with other well-known parameters, is a useful prognostic feature. In addition, it supports the opinion that ALN dissection may provide limited additional information for patients with grade 1, stage Tla, invasive ductal carcinomas. Additional studies are needed to confirm our findings.
The risk of nodal metastases in breast cancer patients with clinically negative lymph nodes: a population-based analysis.Voogd AC, Coebergh JW, Repelaer van Driel OJ, Roumen RM, van Beek MW, Vreugdenhil A, Crommelin MA.
Comprehensive Cancer Center South, Eindhoven, The Netherlands.
Breast Cancer Res Treat 2000 Jul;62(1):63-9 Abstract quote A population-based study was performed to assess the likelihood of axillary lymph node metastases in patients with clinically negative lymph nodes, according to patient age, tumor size and site, estrogen receptor status, histologic type and mode of detection. Data were obtained from the population-based Eindhoven Cancer Registry.
During the period 1984-1997, 7680 patients with invasive breast cancer were documented, 6663 of whom underwent axillary dissection. Of the 5125 patients who were known to have clinically negative lymph nodes and underwent axillary dissection, 1748 (34%) had positive lymph nodes at pathological examination.
After multivariate analysis, histologic type, tumor size, tumor site and the number of lymph nodes in the axillary specimen remained as independent predictors of the risk of nodal involvement (P < 0.001). Lower risks were found for patients with medullary or tubular carcinoma, smaller tumors, a tumor in the medial part of the breast and patients with less than 16 nodes examined.
This study gives reliable estimates of the risk of finding positive lymph nodes in patients with a clinically negative axilla. Such information is useful when considering the need for axillary dissection and to predict the risk of a false-negative result when performing sentinel lymph node biopsy.
LYMPHOVASCULAR INVASION
Characteristics of tumors in lymph vessels play an important role in the tumor progression of invasive ductal carcinoma of the breast: a prospective study.Hasebe T, Sasaki S, Imoto S, Ochiai A.
Pathology Division (TH, AO) and Epidemiology and Biostatistics Division (SS), National Cancer Center Research Institute East.
Mod Pathol 2002 Sep;15(9):904-13 Abstract quote It is unknown whether the characteristics of tumor cells in lymph vessels play an important role in the tumor progression of invasive ductal carcinoma (IDC) of the breast.
The purpose of this study was to investigate the significance of the characteristics of tumor cells in the lymph vessels in relation to the tumor progression in 393 IDC patients in comparison with well-known histological parameters. The dimensions of lymph vessel tumor emboli were measured, and their structural features, nuclear atypia, and numbers of mitotic and apoptotic figures were also assessed. Multiple regression analysis showed the dimension, the distance, the number of mitotic figures, the number of apoptotic figures, and papillary features of lymph vessel tumor emboli to be significantly associated with the increased number of cells invading the lymph vessels (P<.05).
The Cox proportional hazard multivariate analyses showed that more than six apoptotic figures in lymph vessel tumor emboli significantly increased the hazard rates (HRs) of tumor recurrence and death in IDCs without nodal metastasis and that more than four mitotic figures in lymph vessel tumor emboli significantly increased the HRs of tumor recurrence and death in IDCs with nodal metastasis (P <.05). The present study showed that the histological characteristics of tumor cells in lymph vessels play a very important role in the tumor progression of IDCs.
METALLOPROTEINASE Correlation of Tissue Inhibitor of Metalloproteinase-2 with Proliferative Activity and Patients’ Survival in Breast Cancer
Lydia Nakopoulou, M.D., Sophia Katsarou, M.D., Ioanna Giannopoulou, Paraskevi Alexandrou, M.D., Ioanna Tsirmpa, Effie Panayotopoulou, Johnny Mavrommatis and Antonios Keramopoulos, M.D.
Department of Pathology (LN, SK, IG, PA, IT, EP, JM) and First Department of Gynaecology and Obstetrics (AK), Medical School, The National and Kapodistrian University of Athens, Athens, Greece
Mod Pathol 2002;15:26-34 Abstract quote
Tissue inhibitors of metalloproteinases (TIMPs) are endogenous regulators of matrix metalloproteinases (MMPs). They are believed to possess several distinct cellular functions, particularly the contradictory activities of inhibiting MMPs and promoting tumor cell growth.
Immunohistochemistry was performed to detect TIMP-2 protein in 136 infiltrative breast carcinomas. TIMP-2 protein was analyzed in parallel with clinicopathologic features (tumor size, histologic type, nuclear and histologic grade, stage), patients’ overall survival and ER, PR, Ki-67, topo II, c-erbB-2, p53 and bcl-2 proteins. Statistical analysis was performed using univariate and multivariate models analysis.
Immunoreactivity for TIMP-2 was observed in cancer cells and stromal fibroblasts in 106 (77.94%) and 104 (76.47%) of 136 cases, respectively. TIMP-2 protein expression in stromal fibroblasts showed a statistically significant inverse correlation with tumor size (P = .014). An inverse correlation was also observed between TIMP-2 epithelial immunoreactivity and nuclear and histologic grade (P = .036 and P = .007, respectively). TIMP-2 protein reactivity showed statistically significant positive associations with topo II and bcl-2 in stromal and cancer cells, respectively (P = .032 and P = .001, respectively). TIMP-2 protein expression in cancer and stromal cells was associated with better patients’ overall survival (P = .002 and P = .038, respectively). When evaluated by the Cox’s proportional hazard regression model, this association was further established, but only as far as TIMP-2 expression in tumor epithelium was concerned (P = .019).
Our results support the multifunctional potential of TIMP-2 through its correlation on the one hand to a favorable outcome, due to its MMP inhibitory activity and on the other to topo II contributing to its growth factor activity.
NEUROENDOCRINE DIFFERENTIATION
Neuroendocrine differentiation and prognosis in breast adenocarcinoma.Miremadi A, Pinder SE, Lee AH, Bell JA, Paish EC, Wencyk P, Elston CW, Nicholson RI, Blamey RW, Robertson JF, Ellis IO.
Department of Histopathology, Nottingham City Hospital, Nottingham, UK.
Histopathology 2002 Mar;40(3):215-22 Abstract quote Aims: Neuroendocrine differentiation has been detected, and its prognostic value studied, in a number of common human carcinomas. To date there are few detailed studies examining its relevance in breast carcinoma.
In this study we evaluate the frequency and prognostic importance of neuroendocrine differentiation in breast adenocarcinoma.Methods and results: The presence of neuroendocrine differentiation, defined as positive reactivity for three markers, neuron-specific enolase (NSE), chromogranin A and/or synaptophysin, has been evaluated in 99 patients with primary operable breast cancer using standard immunocytochemical techniques. A consecutive cohort of patients were selected from the Nottingham/Tenovus series. Comprehensive patient and tumour records have been maintained, and patients were followed up according to a defined protocol. Eighteen cases were positive for NSE, 10 for chromogranin A and 13 for synaptophysin. Eleven percent were positive with more than one neuroendocrine marker. No significant association was found between neuroendocrine differentiation and tumour size, grade, stage or the prevalence of vascular invasion. There was no significant difference in either overall or disease-free survival between patients with or without neuroendocrine differentiation.
Conclusions: In this study we confirm that neuroendocrine differentiation can be identified in a subset (10-18%) of human breast carcinomas. This phenomenon appears to have no relationship to established prognostic factors or patient outcome.
ONCOGENES Concurrent overexpression of p53 and c-erbB-2 correlates with accelerated cycling and concomitant poor prognosis in node-negative breast cancer
Pierre Rudolph, etal.
Hum Pathol 2001;32:311-319 (Abstract quote)
Simultaneous overexpression of c-erbB-2 and p53 has been reported to be prognostically unfavorable in breast cancer. Herein, we show that concurrent overexpression of these 2 proteins is associated with a marked reduction in the relative fraction of cells in G1 phase of the cell cycle, indicating an accelerated cell cycle progression.
Using an immunohistochemical approach, we examined 261 cases of node-negative infiltrating ductal carcinomas of the breast with respect to c-erbB-2 and p53 expression and to the proliferative activity measured by the Ki-67 index. By means of a novel monoclonal antibody, Ki-S2, which exclusively recognizes proliferating cells in the S, G2, and M phases of the reproductive cycle, we were further able to calculate the relative fraction of the cells having passed the restriction point at the G1/S boundary, thus defining a cycling ratio (CR). The results were correlated with clinical outcome; median follow-up time was 96 months. Tumors that simultaneously overexpressed c-erbB-2 and p53 had a high median CR and followed an unfavorable course. However, increased CRs were also observed independently of c-erbB-2 and p53 overexpression, suggesting that other molecular mechanisms may contribute to acceleration of cell cycle progression. In a multivariate analysis that included patient age, tumor size, hormone receptor status, c-erbB-2 and p53 expression, and the Ki-67 index, CR emerged as the most significant independent predictor of overall and disease-free survival (P < .0001).
It is concluded that the CR is a gauge of cell cycle deregulation and therefore may be a powerful indicator of the biologic behavior of cancers.
Loss of Expression of the PTEN Gene Protein Product Is Associated with Poor Outcome in Breast Cancer
Peter L. Depowski, M.D., Seth I. Rosenthal, M.D. and Jeffrey S. Ross, M.D.
Department of Pathology and Laboratory MedicineAlbany Medical College, Albany, New York
Mod Pathol 2001;14:672-676 Abstract quote
The PTEN gene, a candidate tumor suppressor, is localized to chromosome 10q23 and shares extensive homology with cytoskeletal proteins auxilin and tensin. A high frequency of mutations at the PTEN locus has been described in a variety of neoplasms including breast cancer. However, the role of PTEN alternations and its association with outcome variables in breast neoplasia is not well established.
DESIGN: Formalin-fixed paraffin embedded tissues from 151 women (mean age 62 years, range 26–98) with primary diagnosis of invasive breast cancer were evaluated for PTEN protein expression by automated immunohistochemical methods. Slides were scored semi-quantitatively based on staining intensity and distribution, and results were compared with clinical pathologic parameters. The mean follow-up was 56 months (range 1–169).
RESULTS: Seventy-three (48%) of 151 breast tumors had loss of PTEN protein expression. On univariate analysis, loss of PTEN expression (P = .034), stage (P < .0001), node positive (P < .0001), and tumor grade (P = .002) were associated with disease-related death. Loss of PTEN expression also predicted lymph node metastasis (P < .0001), and correlated with loss of estrogen receptor staining (P = .040). Loss of PTEN did not correlate with stage, tumor grade, disease recurrence, or loss of progesterone receptor [although a trend was seen (P = .092). On multivariate analysis, stage (P < .0001), lymph node metastasis (P < .0001), and tumor grade (P = .002) correlated with survival.
CONCLUSION: Loss of PTEN protein expression occurs commonly in breast cancer and correlates with disease related death, lymph node metastasis, and loss of estrogen receptor staining. Our results support the proposed role of PTEN as a candidate tumor suppressor in breast cancer and suggest a need for further study of this marker.
Amplification of c-myc by Fluorescence In Situ Hybridization in a Population-Based Breast Cancer Tissue Array
Jaana K. Rummukainen, M.D., Tiina Salminen, M.D., Johan Lundin, M.D., Ph.D., Soili Kytölä, Ph.D., Heikki Joensuu, MD Ph.D. and Jorma J. Isola, MD Ph.D.
Laboratory of Cancer Genetics (JKRSK, JJI), Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere Finland; and Department of Oncology (TS, JL, HJ), Helsinki University Central Hospital, Helsinki, Finland
Mod Pathol 2001;14:1030-1035 Abstract quote
A total of 261 primary breast carcinomas were analyzed for amplification of the c-myc oncogene by fluorescence in situ hybridization performed on tumor tissue array samples.
Results were compared with individual clinicopathologic and follow-up data. Thirty-eight (14.6%) of the tumors showed c-myc gene amplification (defined as two or more additional copies of c-myc gene in relation to the number of chromosome 8 centromere). The reproducibility of fluorescence in situ hybridization assay (defined by hybridization with two different myc probes) was good (kappa coefficient 0.402). Statistically significant associations were found between c-myc amplification and DNA aneuploidy (P = .0011), and progesterone receptor negativity (P = .0071), and c-myc amplification also tended to be associated with high histologic grade (P = .064), positive axillary nodal status (P = .080), and a high S-phase fraction (P = .052). c-myc amplification was not significantly associated with overall survival of patients with invasive cancer (P = .32).
These data from a population-based tumor material suggest that c-myc amplification is a feature of aggressive breast cancers, but that it is unlikely to be a clinically useful prognostic factor.
p53 p53 in node-negative breast carcinoma: an immunohistochemical study of epidemiologic risk factors, histologic features, and prognosis.
Rosen PP, Lesser ML, Arroyo CD, Cranor M, Borgen P, Norton L.
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
J Clin Oncol 1995 Apr;13(4):821-30 Abstract quote
PURPOSE: The present study explores p53 in relation to the following four aspects of node-negative breast carcinoma: epidemiologic risk factors, tumor histopathology, prognosis, and HER2/neu (HER) expression.
MATERIALS AND METHODS: Immunohistochemical (IH) staining for p53 was performed on formaldehyde-fixed, paraffin-embedded primary invasive carcinomas from 440 node-negative patients with a median follow-up duration of 119 months.
RESULTS: The IH expression, or lack thereof, of p53 separately or in combination with HER did not prove to be prognostically significant and there was no consistent association of p53 with epidemiologic risk factors. p53 was expressed in 68% of medullary carcinomas (MEDs), which is a significantly higher frequency (P < .001) than in lobular (9%) and duct (23%) carcinomas. p53 was not found in some types of low-grade carcinomas (tubular and papillary), and was observed in a minority of mucinous carcinomas. p53 was present significantly more often in carcinomas with high-grade or poorly differentiated nuclear grade than in low- or intermediate-grade tumors. There was an inverse statistically significant relationship between estrogen receptor (ER) positivity and p53 expression. Tumors with the p53(+)/HER(-) immunophenotype tended to be MEDs or duct carcinomas with a marked lymphoplasmacytic reaction. Infiltrating lobular carcinomas (IFLCs) were largely p53(-)/HER(-). p53(+)/HER(+) carcinomas had the best prognosis. The poorest outcome was associated with the p53(-)/HER(+) immunophenotype. This trend was statistically significant for recurrence-free and overall survival in patients with T1NOMO infiltrating duct carcinoma (IFDC).
CONCLUSION: The IH demonstration of p53 was not a reliable prognostic indicator in the node-negative breast carcinoma patients studied and it was not associated with major epidemiologic risk factors. The combined immunophenotypic expression of p53 and HER was significantly associated with some histologic types of breast carcinoma and with prognosis in T1NOMO breast carcinoma.
Validation of p53 Immunohistochemistry as a Prognostic Factor in Breast Cancer in Clinical Practice
Angela N. Bartley, MBS and Dennis W. Ross, MD, PhDFrom Wake Forest University School of Medicine (Ms Bartley); and the Department of Pathology, Forsyth Medical Center, Winston-Salem, NC (Dr Ross)
Arch Pathol Lab Med 2002;Vol. 126, No. 4, pp. 456–458. Abstract quote Context.—Abnormal p53 tumor suppressor gene expression as detected by immunohistochemistry is a possible prognostic factor in breast cancer. The difference in techniques used to evaluate the expression of mutated p53 protein is under intense scrutiny, as well as its uses either independently or in conjunction with other prognostic factors in breast cancer.
Objective.—To determine whether p53 immunohistochemistry can be used as a reliable indicator of the presence of mutated nuclear p53 protein, and whether this method can be performed reliably in a community hospital's clinical practice.
Design.—One hundred twenty-two cases of breast carcinoma were stained and analyzed for the presence of p53 protein using DO-7 (Dako Corporation, Carpinteria, Calif) p53 antibody.
Results.—Of the 122 cases of invasive carcinoma studied, 23 (18.7%) were positive for p53, and 16 (16.3%) of 98 cases with coexisting ductal carcinoma in situ were positive for p53. This finding is in agreement with comparable published studies.
Conclusions.—Based on the results of this study, we conclude that p53 immunohistochemistry qualifies as a diagnostic technique suitable for clinical practice in a community hospital. Its detection may be particularly promising in clinical trials of new molecular therapies directed at the p53 tumor suppressor gene.
PREGNANCY ASSOCIATED Breast carcinoma presenting during or shortly after pregnancy and lactation.
Shousha S.
Department of Histopathology, Imperial College School of Medicine and Charing Cross Hospital, London, England.
Arch Pathol Lab Med 2000 Jul;124(7):1053-60 Abstract quote
CONTEXT: Much has been written about the clinical management and prognosis of breast carcinomas presenting during pregnancy and lactation, yet little is known about the detailed histopathology of these tumors.
OBJECTIVE: To determine whether these carcinomas have any specific diagnostic features.
DESIGN: A detailed histologic and immunohistochemical study of 14 cases of breast carcinoma presenting during or shortly after pregnancy or lactation was conducted. The findings were compared with a control group of 13 tumors developing in age-matched women with no recent history of pregnancy or lactation.
SETTING: The histopathology department of a tertiary referral teaching hospital.
RESULTS: Tumors in the pregnancy/lactation group had a significantly higher incidence of cancerization of lobules (79% vs 15%) and of grade III invasive ductal carcinomas (80% vs 33%). Tumors occurring during lactation were either totally or partly mucinous and were MUC2 positive. Tumors occurring during pregnancy, but not during lactation, were mostly estrogen and progesterone receptor negative (4/5 and 5/5, respectively). All tumors occurring during pregnancy and lactation that were tested for c-erbB-2 overexpression were negative, whereas all 4 tumors tested that occurred shortly after delivery or cessation of lactation were positive for c-erbB-2 overexpression. The incidence of axillary lymph node metastasis was high in both the study and control groups, although it was slightly higher in the control group (78% and 90%, respectively).
CONCLUSIONS: Although breast carcinomas diagnosed during or shortly after pregnancy and lactation have features in common with those developing in women of similar ages, particularly with respect to a high incidence of lymph node metastasis, the findings of this study suggest that they may also have distinct morphologic and immunohistochemical features of their own. Such features may vary according to whether the patient was pregnant, lactating, or had recently terminated her pregnancy or lactation at the time of surgical excision. Examination of more cases would help confirm these findings.
Pregnancy-associated breast cancer: a case-control study in a young population with a high-fertility rate.Ibrahim EM, Ezzat AA, Baloush A, Hussain ZH, Mohammed GH.
Department of Oncology, King Faisal Specialist Hospital and Research Centre, Kingdom of Saudi Arabia.
Med Oncol 2000 Nov;17(4):293-300 Abstract quote Pregnancy-associated breast cancer (PABC) is not a rare event. The association frequently imposes a management challenge.
We intended to review the clinical features, therapy, and outcome of patients with PABC seen at a single institution over a five-year period and to compare those with that seen in a matched control group. Data of all patients with PABC diagnosed during pregnancy were retrospectively reviewed (Group I). For each patient in Group I, three matched controls with breast cancer without pregnancy were identified (matched for age, stage, and year of diagnosis, Group II). 72 patients in Group I and 216 in Group II were identified. Their median age was similar (34 vs 35 y, respectively). The median number of prior pregnancies for patients in Groups I and II was 5. Patients had shorter duration of symptoms prior to diagnosis as compared with their controls (5.6 vs 9.4 months, P < 0.0001). 3%, 31%, 40%, and 26% of patients had Stage I to IV, respectively. A pattern that was similar to that seen in our breast cancer population. Pregnancy was terminated in 34 patients (47%), while 38 (53%) had normal spontaneous vaginal delivery. 47 patients in Group I had surgery; 37 (52%) had modified radical mastectomy and 10 (14%) had conservative surgery. In 37 patients surgery was performed after termination of pregnancy and 10 had surgery performed during pregnancy. The median number of positive lymph nodes in Group I was 4 as compared with 2 for patients in Group II. No patients in Group I had systemic chemotherapy during first trimester, while only 4 (6%) and 3 (4%) received adjuvant or neoadjuvant during second and third trimester, respectively. No congenital malformation in the newborns was diagnosed. None of the patients in Group I received radiotherapy during pregnancy. Over a median of 47.5 months, 48 (67%) patients in Group I were alive as compared to 126 (58%) in Group II, with no difference in the median survival (P= 0.79).
Comparing overall survival (OS) between the two groups stage for stage also showed no significant difference. Also there was no difference in progression-free survival between the two groups. Cox proportional hazard model identified advanced stage as the only independent adverse prognostic variable that influenced OS in Group I. Despite that this series included a relatively young population with a high fertility rate, the study confirmed the lack of a survival difference between patients with PABC and their matched controls.
PREGNANCY, CONCURRENT Chemotherapy for breast carcinoma during pregnancy: A French national survey.
Giacalone PL, Laffargue F, Benos P.
Department of Obstetrics and Gynecology, Hopital Arnaud de Villeneuve, Montpellier, France.
Cancer 1999 Dec 1;86(11):2266-72 Abstract quote
BACKGROUND: During pregnancy, the need for maternal chemotherapy for breast carcinoma must be balanced against the fetal risk because modification of cancer therapy to assure the birth of a healthy infant may affect maternal prognosis adversely. To the authors' knowledge few studies have documented the oncologic and obstetric management of this association.
METHODS: A retrospective nationwide survey was used to identify women treated with chemotherapy for breast carcinoma during pregnancy. Each member of the Societe Francaise d'Oncologie Gynecologique and the Societe Francaise de Senologie et de Pathologie Mammaire completed a postal questionnaire regarding cancer staging, oncologic treatment, obstetric details, pregnancy outcome, fetal behavior, and postdelivery follow-up. Twenty women were accrued to the study.
RESULTS: The mean gestational age at the first cycle of treatment was 26 weeks. A total of 38 cycles were administered during pregnancy, with a median of 2 cycles. Delivery was performed at a mean of 34.7 weeks. Two pregnancies that were exposed to chemotherapy during the first trimester resulted in spontaneous abortion. One pregnancy exposed in the second trimester resulted in intrauterine death. The remaining 17 pregnancies resulted in live births, although 3 women had complications related to chemotherapy (anemia, leukopenia, and fetal growth retardation) and 1 newborn died 8 days after birth without apparent etiology. Two newborns had complications related to prematurity (transient respiratory distress). At a mean follow-up of 42.3 months, all live infants were reported to have reached normal developmental milestones.
CONCLUSIONS: The current study found that even when chemotherapy was initiated after the first trimester, 95% of the pregnancies resulted in live births with low related morbidity in the newborns.
PREGNANCY, SUBSEQUENT, IN BREAST CANCER SURVIVORS Childbearing issues in breast carcinoma survivors.
Surbone A, Petrek JA.
Department of Surgery and Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cancer 1997 Apr 1;79(7):1271-8 Abstract quote
BACKGROUND: The issue of the subsequent pregnancy after breast carcinoma treatment is of paramount importance to young survivors and their oncologists. Matters related to having children, whether biologic or not, are analyzed.
METHODS: Available evidence on the role of estrogen in the carcinogenesis and promotion of breast carcinoma is summarized. The scanty literature on pregnancy in breast carcinoma survivors is reviewed and evaluated. With reference to infertility as the result of adjuvant treatment, studies on therapy-induced amenorrhea are cited.
RESULTS: The survival of women with breast carcinoma is not decreased by subsequent pregnancy in any of the published series. Nevertheless, several biases may be present, making the results less than conclusive; no prospective studies exist. Theoretic concern of tumor promotion may be justified when considering the long term exposure to intense gestational hormones in the presence of established breast carcinoma with possible micrometastases. As a separate issue, the common situation of chemotherapy-induced amenorrhea may not permit pregnancy. Information for the breast carcinoma survivor on assisted conception and adoption is limited.
CONCLUSIONS: Further research on the safety of subsequent pregnancy after breast carcinoma treatment is needed; the authors report that they are initiating a multicenter prospective study to address these issues.
Pregnancy after breast carcinoma: outcomes and influence on mortality.
Velentgas P, Daling JR, Malone KE, Weiss NS, Williams MA, Self SG, Mueller BA.
Department of Biostatistics, University of Washington, Seattle, USA.
Cancer 1999 Jun 1;85(11):2424-32 Abstract quote
BACKGROUND: To the authors' knowledge, no previous studies have identified an adverse effect of pregnancy on patient survival after breast carcinoma. However, results are difficult to interpret because of failure to control for stage of disease at the time the pregnancy occurred.
METHODS: Study participants were women diagnosed with invasive breast carcinoma between 1983-1992 who previously had participated in a population-based case-control study or, if deceased, proxy respondents. Information regarding subsequent pregnancies was obtained by self-administered questionnaire or telephone interview. Information regarding breast carcinoma recurrences was obtained by questionnaire and from cancer registry abstracts. Women who became pregnant after a diagnosis of breast carcinoma (n = 53) were matched with women without subsequent pregnancies based on stage of disease at diagnosis and a recurrence free survival time in the comparison women greater than or equal to the interval between breast carcinoma diagnosis and onset of pregnancy in the women with a subsequent pregnancy.
RESULTS: Sixty-eight percent of women who became pregnant after being diagnosed with breast carcinoma delivered one or more live-born infants. Miscarriages occurred in 24% of the patients who became pregnant compared with 18% of the controls (women without breast carcinoma) of similar ages from the case-control study. Five of the 53 women who had been pregnant after breast carcinoma died of the disease. The age-adjusted relative risk (RR) of death associated with any subsequent pregnancy was 0.8 (95% confidence interval [95% CI], 0.3-2.3). All five deaths occurred among the 36 women who had a live birth (age-adjusted RR = 1.1; 95% CI, 0.4-3.7).
CONCLUSIONS: The findings of the current study are based on a small number of deaths but do not suggest that pregnancy after a diagnosis of breast carcinoma has an adverse effect on survival.
RACE Racial differences in breast carcinoma survival.
\Joslyn SA, West MM.
University of Northern Iowa, Cedar Falls, Iowa 50614-0241, USA.
Cancer 2000 Jan 1;88(1):114-23 Abstract quote
BACKGROUND: Survival after breast carcinoma diagnosis is significantly worse among African American women for reasons unknown. The purpose of this study was to update reports on the National Surveillance, Epidemiology, and End Results Program and to examine the effect of race on breast carcinoma survival.
METHODS: Subjects were 135,424 women diagnosed with primary breast carcinoma between 1988-1995. Patient age, tumor stage at the time of diagnosis, hormone receptor status, tumor histology, menopausal status, and survival were compared by race category.
RESULTS: African American women diagnosed with breast carcinoma (n = 11,159) had a significantly increased risk of death from breast carcinoma and from all cancers compared with white women (n = 124,265), independent of the effects of other predictor variables. African American women were significantly younger at the time of diagnosis, with approximately 33% of the population age
CONCLUSIONS: The results of the current study show that race is an independent predictor of survival from breast carcinoma. These findings are consistent with other large, population-based studies of racial differences in breast carcinoma survival and have been comported by studies of racial differences in the molecular biology of breast carcinoma, thus providing support for the epidemiologic credibility of the independence of the association.
SECOND PRIMARY BREAST CANCERS Breast carcinoma after cancer at another site: method of detection, tumor characteristics, and surgical treatment.
Nissen MJ, Lazovich D, Jolitz G.
Oncology Research, Park Nicollet Institute, Minneapolis, Minnesota, USA.
Cancer 2000 Nov 1;89(9):1999-2005Abstract quote
BACKGROUND: As the number of cancer survivors increases, so will the number of second primary cancers, including breast carcinoma after cancer at another site. Limited information is available regarding the clinical characteristics of breast carcinoma after a primary at another site.
METHODS: TUMORS (The Upper Midwest Oncology Registry Services) was used to identify 937 women with breast carcinoma occurring as a second primary after a first primary at a known site other than the breast. They were compared with a sample of 1874 women with first primary breast carcinoma, frequency-matched by age to the second primary group, for method of detection, tumor characteristics, and type of surgery.
RESULTS: Women with breast carcinoma after cancer at another site tended to have smaller tumors and less extensive disease than women with first primary breast carcinoma and were somewhat more likely than first primary cases to have had their breast carcinoma detected by mammogram or clinical breast exam rather than detecting it themselves. Differences in method of detection accounted for differences in tumor size and extent. Second primary breast carcinoma was less likely to be lobular or mixed ductolobular carcinoma compared with first primary breast carcinoma. Surgical treatment (mastectomy vs. breast-conserving surgery) did not differ for first and second primary breast carcinoma.
CONCLUSIONS: Clinical characteristics of breast carcinoma after cancer at another site were by and large similar to those of first primary breast carcinoma. The more favorable prognostic characteristics among women with a history of cancer were accounted for by increased medical surveillance.
SIZE OF TUMOR
Axillary lymph node metastases in patients with small carcinomas of the breast: is accurate prediction possible?Anan K, Mitsuyama S, Tamae K, Nishihara K, Iwashita T, Abe Y, Ihara T, Toyoshima S.
Department of Surgery, Kitakyushu Municipal Medical Centre, Japan.
Eur J Surg 2000 Aug;166(8):610-5 Abstract quote OBJECTIVES: To find out whether macroscopic classification of the tumour margin is predictive of axillary lymph node metastases and to identify a combination of clinical and pathological findings by which axillary node status can be predicted accurately in small carcinomas (T1) of the breast.
DESIGN: Retrospective study.
SETTING: Municipal referral centre, Japan.
SUBJECTS: All 1003 patients with T1 invasive carcinoma of the breast who had axillary lymph node dissection between January 1970 and December 1996 as part of their treatment.
MAIN OUTCOME MEASURES: The association between the incidence of axillary lymph node metastases and 10 clinical and pathological factors (age, palpability and size of tumour, macroscopic classification of tumour margin, clinical axillary status, radiating spiculation on a mammogram, histological type, lymphatic invasion, oestrogen and progesterone receptor status) were analysed.
RESULTS: Clinical axillary node status, macroscopic classification of tumour margin, lymphatic invasion, and age of the patient were significant predictors of axillary lymph node metastases (p < 0.01 in each case). Among 47 patients aged 65 or more whose tumours had well-defined margins and with a clinical N0 status in the axillae, the incidence of histological axillary lymph node metastasis was only 6% (n = 3) whereas it was 65% in 57 patients with tumours of ill-defined margins whose axillae were N1 or N2.
CONCLUSIONS: Macroscopic classification of tumour margins is an independent predictor of axillary lymph node metastases for patients with small carcinomas of the breast. However, even with combinations of the examined predictors of axillary node metastases, the subgroup of patients at minimal risk of metastasis was less than 5% in T1 breast cancer, whereas three-quarters of the patients had clear axillary lymph nodes. Most patients with T1 breast cancer will need surgical staging of the axillae by methods such as sentinel node biopsy.
TOPOISOMERASES
Topoisomerase II-alpha Expression in Different Cell Cycle Phases in Fresh Human Breast Carcinomas.Villman K, Stahl E, Liljegren G, Tidefelt U, Karlsson MG.
Departments of Oncology (KV), Pathology (ES, MGK), Surgery (GL), and Medicine (UT), Orebro University Hospital, Orebro, Sweden.
Mod Pathol 2002 May;15(5):486-91 Abstract quote Topoisomerase II-alpha (topo IIalpha) is the key target enzyme for the topoisomerase inhibitor class of anti-cancer drugs. In normal cells, topo IIalpha is expressed predominantly in the S/G2/M phase of the cell cycle. In malignant cells, in vitro studies have indicated that the expression of topo IIalpha is both higher and less dependent on proliferation state in the cell.
We studied fresh specimens from 50 cases of primary breast cancer. The expression of topo IIalpha in different cell cycle phases was analyzed with two-parameter flow cytometry using the monoclonal antibody SWT3D1 and propidium iodide staining. The expression of topo IIalpha was significantly higher in the S/G2/M phase of the cell cycle than in the G0/G1 phase in both DNA diploid and DNA nondiploid tumors. In 18 of 21 diploid tumors, and in 25 of 29 nondiploid tumors, >50% of the topo IIalpha-positive cells were in the G0/G1 phase.
This significant expression of topo IIalpha in the G0/G1 phase of the cell cycle may have clinically important implications for treatment efficacy of topoisomerase II inhibitors.
TREAMENT INADEQUACIES The effect of less than definitive care on breast carcinoma recurrence and mortality.
Lash TL, Silliman RA, Guadagnoli E, Mor V.
Department of Epidemiology and Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
Cancer 2000 Oct 15;89(8):1739-47 Abstract quote
BACKGROUND: Risk factors for breast carcinoma offer few opportunities for prevention; thus, the reduction of morbidity and mortality among breast carcinoma patients must remain a priority. The objective of this study was to measure the effects of less than definitive care for patients with breast carcinoma on disease recurrence and mortality.
METHODS: The prognostic evaluation and treatment received by an inception cohort of 494 women was characterized. Three hundred ninety women ages 45-90 years with local or regional breast carcinoma who were diagnosed between 1984 and 1986 and were treated at one of eight Rhode Island hospitals comprised the final cohort. Disease recurrence and mortality were ascertained through December 31, 1996. Candidate determinants of outcomes were a less than definitive prognostic evaluation and less than definitive primary therapy-adjusted for confounding by patient age, extent of disease, and comorbid diseases.
RESULTS: During the first 5 years of follow-up, patients who received a less than definitive prognostic evaluation had an adjusted relative hazard of recurrence of 1.7 (95% confidence interval, 1.0-2.7) and an adjusted relative hazard for breast carcinoma mortality of 2.2 (95% confidence interval, 1.2-3.9). Patients who received less than definitive therapy had an adjusted relative hazard of recurrence of 1.6 (95% confidence interval, 1.0-2.5), and an adjusted relative hazard of breast carcinoma mortality of 1.7 (95% confidence interval, 1.0-2.8).
CONCLUSIONS: Breast carcinoma patients who receive less than definitive care are at excess risk for disease recurrence and mortality. Women with early stage breast carcinoma should be treated in accordance with existing guidelines.
TUMOR ASSOCIATED ANTIGENS Expression of MAGE tumour-associated antigens is inversely correlated with tumour differentiation in invasive ductal breast cancers: an immunohistochemical study.
Kavalar R, Sarcevic B, Spagnoli GC, Separovic V, Samija M, Terracciano L, Heberer M, Juretic A.
Maribor General Hospital, Slovenia.
Virchows Arch 2001 Aug;439(2):127-31 Abstract quote
MAGE (Melanoma antigen E) family gene products encompass tumour-associated antigens (TAAs) recognised by human leukocyte antigen (HLA)-restricted specific T-cells. Agents inducing DNA demethylation, an event typically detectable in cellular de-differentiation processes, were shown to induce the expression of MAGE genes.
By using a monoclonal antibody specific for MAGE family gene products, we have studied the expression of these TAAs in a group of 144 patients with invasive ductal breast cancers. Immunohistochemical data were correlated with tumour differentiation, lymphatic vessel invasion, oestrogen receptor expression, intratumoural necrosis, lymphocytic infiltration, perineural invasion, tumour microcalcifications and axillary lymph node metastases.
MAGE immunoreactivity was undetectable in non-neoplastic cells. In poorly differentiated cancers positive staining was observed in 30/63 cases (47.6%) as compared with 13/51 (25.4%) and 5/30 (16.6%) in moderately and well-differentiated tumours, respectively (P<0.05). In addition, MAGE immunoreactivity was significantly correlated with lymphatic vessel invasion and intratumoural necrosis. Moreover, a significant inverse relationship with oestrogen receptor expression was also observed. However, no significant correlation could be established between MAGE immunoreactivity and defined phenotypic characteristics of tumour infiltrating lymphocytes, including expression of CD3, CD4, CD8, CD20 or granzyme B. Thus, expression of MAGE family gene products in invasive ductal breast cancers appears to be associated with poorly differentiated histological phenotypes.
These data support the concept of specific immunotherapy in highly aggressive forms of breast neoplasms. Furthermore, they suggest that MAGE immunoreactivity could represent a tumour marker of potential prognostic relevance.
Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
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