Ductal carcinoma in situ or DCIS has been elevated to a very important status in breast pathology. As sophisticated tests such as mammography and stereotactic core biopsies become increasingly commonplace, this diagnosis is made with more frequency. It is an in situ malignancy, a cancer which has not spread beyond the confines of the duct from which it arises. It most commonly presents as a non-palpable lesion, usually visualized by mammography. It may also be an incidental finding found on a breast biopsy taken for another lesion.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Intraductal carcinoma, DCIS INCIDENCE
Autopsy study of 77 adult women found 14 cases of DCIS for an incidence of occult cancer in 25%
30% of all new breast cancer cases in institutions with mammographic surviellance
DISEASE ASSOCIATIONS CHARACTERIZATION INVASIVE CARCINOMA
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.
PATHOGENESIS CHARACTERIZATION DCIS and cancer
If cancer arises, is usually occurs in the area occupied by the DCIS
DCIS is present in 80% of invasive breast cancers
Morphological similarities to invasive carcinoma
Shares highly abnormal molecular abnormalities such as DNA aneuploidy and Her2-neu gene amplification
Loss of heterozygosity studies of microdissected DCIS and invasive components of the same tumor reveal identical genetic abnormalities
BRCA1 AND BRCA2
- Prevalence of BRCA1 and BRCA2 mutations in women diagnosed with ductal carcinoma in situ.
Claus EB, Petruzella S, Matloff E, Carter D.
Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Conn 06520-8034, USA.
JAMA. 2005 Feb 23;293(8):964-9. Abstract quote
CONTEXT: The distribution of BRCA1 and BRCA2 mutations in women diagnosed with noninvasive breast carcinoma is unknown.
OBJECTIVE: To estimate the BRCA1 and BRCA2 mutation prevalence in women with ductal carcinoma in situ (DCIS), unselected for age, family history, or ethnicity.
DESIGN, SETTING, AND PARTICIPANTS: The data were 369 DCIS cases diagnosed among female residents aged 20 to 79 years from the state of Connecticut between September 15, 1994, and March 14, 1998. These women were participants in a large population-based case-control study of breast carcinoma in situ. Telephone interviews were used to collect risk factor information and blood or buccal specimens were collected for BRCA1 and BRCA2 mutation testing.
MAIN OUTCOME MEASURES: Prevalence of disease-associated mutations of BRCA1 and BRCA2 in women diagnosed with DCIS.
RESULTS: Three (0.8%) and 9 (2.4%) of 369 DCIS cases had disease-associated mutations in BRCA1 or BRCA2, respectively. One woman had a mutation in both genes (BRCA1 W321X and BRCA2 3398del5). Carriers were significantly more likely than noncarriers to report a first-degree (mother, sister, or daughter) family history of breast cancer (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.1-12.4), as well as a personal history of ovarian cancer. In addition, carriers were more likely than noncarriers to be diagnosed at an early age (<50 years) (OR, 3.4; 95% CI, 1.0-11.7), as well as to report at least 1 first-degree relative diagnosed with breast cancer before 50 years (OR, 10.6; 95% CI, 3.0-37.0).
CONCLUSIONS: Ductal carcinoma in situ is a part of the breast/ovarian cancer syndromes defined by BRCA1 and BRCA2, with mutation rates similar to those found for invasive breast cancer. These findings suggest that patients with breast cancer with an appropriate personal or family history of breast and/or ovarian cancer should be screened and followed according to high-risk protocols, regardless of whether they are diagnosed with in situ or invasive breast cancer.
CLONAL PROCESS Molecular studies have revealed a single clonal process even if multifocal
Heterogeneous versus homogeneous genetic nature of multiple foci of in situ carcinoma of the breast.
Volante M, Sapino A, Croce S, Bussolati G.
Department of Biomedical Sciences and Oncology, University of Turin, Italy.
Hum Pathol. 2003 Nov;34(11):1163-9. Abstract quote
The vast majority of in situ breast cancers represent focal lesions all derived from a single clone and requiring local treatment alone.
We focused our attention on rare cases of multicentric in situ carcinomas affecting different quadrants, which required mastectomy. Defining the origin from single- or multiple-cell clones of separate independent neoplastic foci in the breast may be of pathogenetic interest and of importance in deciding the type of therapy to be administered.
We employed a molecular assay based on loss of heterozygosity (LOH) and human androgen receptor assay (HUMARA) analysis of microdissected samples from 19 mastectomies. Two or more tissue samples were obtained from 7 patients with multicentric lobular in situ carcinoma (LCIS), either classical or large-cell variety; and 12 patients with multicentric ductal in situ carcinomas (DCIS), either low-grade (7 cases) or high-grade (5 cases) variety. Separate foci of high-grade (comedonic) DCIS were found to be monoclonal in nature. On the contrary, definite evidence favoring the origin from different cell clones of separate carcinomatous foci within the same breast was obtained in 2 cases of low-grade DCIS and in 6 cases of LCIS.
A genetic imbalance might be the factor favoring the development of multifocal heterogeneous foci of in situ breast cancer. Such a small subgroup of in situ cancers affecting diffusely the entire breast and originating from independent foci presents both clinical and pathogenetic interest.
Correlation of Nuclear Morphometry with Pathologic Parameters in Ductal Carcinoma In Situ of the Breast
Puay Hoon Tan, F.R.C.P.A., Boon Bee Goh, Gilbert Chiang, F.R.C.P.A. and Boon Huat Bay, Ph.D.
Department of Pathology (PHTGC), Singapore General Hospital, Singapore; United Medical and Dental School of Guy’s and St. Thomas’ Hospital, University of London (BBG), London, United Kingdom; and Department of Anatomy, Faculty of Medicine (BHB), National University of Singapore, Singapore
Mod Pathol 2001;14:937-941 Abstract quote
Morphometric features of nuclear perimeter, nuclear area, feret ratio, and feret circle were studied in a series of 64 cases of ductal carcinoma in situ (DCIS) of the breast in Singapore women.
The results were compared with pathologic parameters of tumor size, nuclear grade, necrosis, cell polarization, and architectural pattern. There was statistically significant correlation between nuclear perimeter and area with all the pathologic parameters, with the strongest association observed for nuclear grade (P < .0001). Higher grade nuclei as assessed histologically were associated with larger nuclear area (44.14 µm2 in low-grade lesions, 47.77 µm2 in intermediate-grade lesions, and 72.05 µm2 in high-grade lesions) and perimeter (25.94 µm in low-grade nuclei, 27.12 µm in intermediate-grade nuclei, and 33.66 µm in high-grade nuclei). DCIS lesions with necrosis and absence of polarization also revealed increased nuclear area and perimeter (P < .05). Comedo architecture was associated with larger nuclear area and perimeter (65.97 µm2, 31.7 µm) than the papillary subtype (42.17 µm2, 25.29 µm), with the mixed morphologic pattern disclosing intermediate values (54.83 µm2, 29.43 µm). There was direct correlation for tumor size with nuclear area and perimeter (P < .01).
No similar relationship was found between pathologic parameters and feret ratio or circle, indicating that nuclear roundness or lack of it did not factor as a significant component in the pathologic assessment.
GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION Appearance Most cases do not have distinctive gross findings Comedocarcinoma This is the exception with necrotic cores expressed from the cut surface as thin, soft cylinders Extensive intraductal component (EIC)
Defined as DCIS within an invasive carcinoma-the DCIS occupies 25% or more of the overall tumor mass and extends beyond the confines of that main mass
Presence is powerful predictor of local recurrence
In general, it has a segmental distribution, confirmed by radial rather than serial sectioning of the breast
Foci of carcinoma in more than one quadrant of the breast
Estimated at 32%
Low grade tumors more likely to be inadequately excised due to increased discontinous or multifocal growth
High grade tumors more likely to be associated with microcalcifications
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
Histological margin assessment for breast ductal carcinoma in situ: precision and implications.
Sigal-Zafrani B, Lewis JS, Clough KB, Vincent-Salomon A, Fourquet A, Meunier M, Falcou MC, Sastre-Garau X.
1Departments of Pathology, Institut Curie, 26 rue d'Ulm, 75248 Paris, France.
Mod Pathol. 2004 Jan;17(1):81-8 Abstract quote.
Local recurrence after lumpectomy for ductal carcinoma in situ (DCIS) is a major concern and is related to residual disease in the breast.
We studied the predictive value of lumpectomy margins for residual DCIS and compared our results and pathological processing techniques with those published in the literature. Margin status was determined for 89 patients with screen-detected DCIS who had lumpectomy and re-excision, for the presence and extent of residual disease. Margin width was defined as the narrowest distance between tumor and any inked margin or, where margins were positive, classified into focal involvement (<1 mm of the inked surface involved), minimal (>/=1<15 mm) and extensive (>/=15 mm). The amount of residual tumor was quantified according to the number of ducts involved with tumor: small (fewer than 10 ducts) or large (10 or more ducts) residuum. The initial margin status was a significant predictor for the presence of residual tumor in re-excision specimens (P=0.006). There was residual tumor in 44 and 45% of close non-involved (>1 and </=1 mm width) margins, 67% of focally, 71% of moderately and 94% of extensively positive margins. The pathologic tumor size was also a predictor for the presence of residual tumor with 27, 68 and 74% of lesions measuring </=10, 11-25, >25 mm,respectively, showing residual disease.
The presence of residual tumor was not significantly related to age, mammographic appearance, nuclear grade or intraductal necrosis. The initial margin status was found to predict for the amount of residual tumor.
With careful margin assessment, margin status after lumpectomy for DCIS can be used to predict for the presence and amount of residual tumor in the breast and is a guide to further management decisions. A standard for margin status reporting and pathological processing of screen-detected DCIS in situ lesions will help in the interpretation of data from different institutions.
Pathologists' Agreement With Experts and Reproducibility of Breast Ductal Carcinoma-in-Situ Classification Schemes
Wendy A. Wells, M.D.; Patricia A. Carney, Ph.D.; M. Scottie Eliassen, M.S.; Margaret R. Grove, M.S.; Anna N. A. Tosteson, Sc.D.
From the Department of Pathology (W.A.W.), Center for the Evaluative Clinical Sciences (M.R.G., A.N.A.T.), Department of Community and Family Medicine (P.A.C., M.S.E., M.R.G.), and Department of Medicine (A.N.A.T.), Dartmouth Medical School, Hanover, New Hampshire, U.S.A.
Am J Surg Pathol 2000;24:651-659
Several histologic classifications for breast ductal carcinoma in situ (DCIS) have been proposed.
This study assessed the diagnostic agreement and reproducibility of three DCIS classifications (Holland [HL], modified Lagios [LA], and Van Nuys [VN]) by comparing the interpretations of pathologists without expertise in breast pathology with those of three breast pathology experts, each a proponent of one classification. Seven nonexpert pathologists in New Hampshire and three experts evaluated 40 slides of DCIS according to the three classifications. Twenty slides were reinterpreted by each nonexpert pathologist. Diagnostic accuracy (nonexperts compared with experts) and reproducibility were evaluated using inter-and intrarater techniques (kappa statistic). Final DCIS grade and nuclear grade were reported most accurately among nonexpert pathologists using HL (kappa = 0.53 and 0.49, respectively) compared with LA and VN (kappa = 0.29 and 0.35, respectively, for both classifications). An intermediate DCIS grade was assessed most accurately using HL and LA, and a high grade (group 3) was assessed most accurately using VN. Diagnostic reproducibility was highest using HL (kappa = 0.49). The VN interpretation of necrosis (present or absent) was reported more accurately than the LA criteria (extensive, focal, or absent; kappa = 0.59 and 0.45, respectively), but reproducibility of each was comparable (kappa = 0.48 and 0.46, respectively). Intrarater agreement was high overall.
Comparing all three classifications, final DCIS grade was reported best using HL. Nuclear grade (cytodifferentiation) using HL and the presence or absence of necrosis were the criteria diagnosed most accurately and reproducibly. Establishing one internationally approved set of interpretive definitions, with acceptable accuracy and reproducibility among both pathologists with and without expertise in breast pathology interpretation, will assist researchers in evaluating treatment effectiveness and characterizing the natural history of DCIS breast lesions.
GENERAL Divided into low, intermediate, and high grade nuclei Low Monomorphic evenly spaced cells with roughly spherical, centrally placed nuclei and inconsipicuous nucleoli
Few mitoses and little necrosis
Intermediate Changes intermediate between low and high grade High Pleomorphic, irregularly spaced cells with large nuclei and marked variation in size and shape, coarse chromatin, and prominent nucleoli
VARIANTS APOCRINE Will show usual criteria of DCIS but composed of apocrine cells
Cytologically should have marked nuclear atypia
Apocrine ductal carcinoma in situ of the breast: histologic classification and expression of biologic markers.
Leal C, Henrique R, Monteiro P, Lopes C, Bento MJ, De Sousa CP, Lopes P, Olson S, Silva MD, Page DL.
Department of Pathology and Epidemiology, Instituto Portugues de Oncologia, Centro Regional do Porto, Portugal.
Hum Pathol 2001 May;32(5):487-93 Abstract quote
Apocrine ductal carcinoma in situ (ADCIS) has been called a special type of ductal carcinoma in situ (DCIS) because the histologic grading is considered difficult using the classification schemes that have been proposed for common DCIS. However, ADCIS encompasses a spectrum of lesions with different morphologic aspects ranging from minimally atypical to overtly malignant.
To define a classification scheme for ADCIS, 35 cases (22 pure and 13 associated with invasive carcinoma) were selected on the basis of conventional morphology on hematoxylin and eosin (H&E)-stained sections. Each case was assigned to 1 of 3 histologic grades (low, intermediate, and high) based on nuclear morphology and the presence of necrosis. In addition, the expression of hormone receptors p53, bcl-2, c-erbB-2, and Ki-67 was evaluated by immunohistochemistry, and the DNA ploidy was determined by image cytometry. Fifteen cases were classified as high histologic grade, 10 as low histologic grade, and the other 10 as intermediate grade. All but 4 cases, irrespective of grade, had the same hormonal immunophenotype: androgen receptor positivity (97.1%) and estrogen receptor and progesterone receptor negativity (94.3% and 97.1% respectively). Twenty-one cases (61.8%) showed p53 expression, and 47.1% of the cases were positive for c-erbB-2. The median positivity for Ki-67 was 5.2%. ADCIS has a unique morphologic and hormonal profile, distinct from common DCIS, deserving a specific classification.
The proposed classification scheme allows for categorization of ADCIS according to the most important morphologic features already seen in common DCIS, ie, nuclear grade and necrosis. The expression of biologic markers other than hormonal receptors and bcl2 in ADCIS seems in general to be similar to that in common DCIS. Ki-67 and c-erbB-2 are expressed more frequently in intermediate and high histologic grade ADCIS.
- Hum Pathol. 2007 Feb;38(2):197-204. Abstract quote
Microarray profiling of invasive breast carcinomas has identified subtypes including luminal A, luminal B, HER2-overexpressing, and basal-like. The poor-prognosis, basal-like tumors have been immunohistochemically characterized as estrogen receptor (ER)-negative, HER2/neu-negative, and cytokeratin 5/6-positive and/or epidermal growth factor receptor (EGFR)-positive.
The aim of this study was to determine the prevalence of basal-like ductal carcinoma in situ in a population-based series of cases using immunohistochemical surrogates. A total of 245 pure ductal carcinoma in situ cases from a population-based, case-control study were evaluated for histologic characteristics and immunostained for ER, HER2/neu, EGFR, cytokeratin 5/6, p53, and Ki-67. The subtypes were defined as: luminal A (ER+, HER2-), luminal B (ER+, HER2+), HER2 positive (ER-, HER2+), and basal-like (ER-, HER2-, EGFR+, and/or cytokeratin 5/6+). The prevalence of breast cancer subtypes was basal-like (n = 19 [8%]); luminal A, n = 149 (61%); luminal B, n = 23 (9%); and HER2+/ER-, n = 38 (16%). Sixteen tumors (6%) were unclassified (negative for all 4 defining markers).
The basal-like subtype was associated with unfavorable prognostic variables including high-grade nuclei (P < .0001), p53 overexpression (P < .0001), and elevated Ki-67 index (P < .0001).
These studies demonstrate the presence of a basal-like in situ carcinoma, a potential precursor lesion to invasive basal-like carcinoma.
Mod Pathol. 2006 May;19(5):617-21. Abstract quote
Basal-like carcinomas have recently been identified in gene expression profiling studies as a subtype of invasive breast cancer. These lesions are estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative (triple negative), and typically express basal cytokeratins, epidermal growth factor receptor (EGFR), and/or c-kit. As poorly differentiated invasive ductal carcinomas, they presumably have a ductal carcinoma in situ (DCIS) precursor with similar cytologic and immunophenotypic features. However, the frequency and even the existence of a DCIS lesion with an immunophenotype analogous to that of invasive basal-like carcinomas have not been previously evaluated.
We studied 66 cases of high nuclear grade DCIS using antibodies to ER, PR, HER2, three basal cytokeratins, EGFR, and c-kit to determine the frequency of the triple negative phenotype, and to determine the relationship between the triple negative phenotype and expression of basal cytokeratins and other biomarkers characteristically expressed by invasive basal-like carcinomas. Four cases (6%) exhibited the triple negative phenotype; the remaining cases showed other combinations of ER, PR, and HER2 expression (nontriple negative). Basal cytokeratins, EGFR, or both were expressed by all four triple negative lesions, but by only 21 of 51 (42%) nontriple negative cases (P=0.04).
We conclude that a small proportion of high-grade ductal carcinomas in situ exhibit an ER-negative/PR-negative/HER2-negative (triple negative) phenotype, and these lesions more commonly show expression of basal cytokeratins and/or EGFR than nontriple negative high-grade DCIS. Given that invasive breast cancers typically share immunophenotypic features with the ductal carcinoma in situ from which they arise, our findings raise the possibility that the triple-negative, basal cytokeratin and/or EGFR-positive DCIS lesions we identified represent a precursor lesion to invasive basal-like carcinomas.
CANCERIZATION OF THE LOBULES
Cancerization of lobules and atypical ductal hyperplasia adjacent to ductal carcinoma in situ of the breast.
Goldstein NS, Lacerna M, Vicini F.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.
Am J Clin Pathol 1998 Sep;110(3):357-67 Abstract quote
Recurrent carcinoma develops in approximately 10% of patients with ductal carcinoma in situ (DCIS) of the breast treated with local excision and radiation therapy. Cancerization of lobules (COL) and atypical ductal hyperplasia (ADH)frequently occur at the edge of DCIS.
We postulated that recurrent carcinoma is associated with ADH or COL near the DCIS excision margin, and the amount of DCIS left in the breast may be too large for eradication by radiation therapy.
To identify histologic features associated with recurrence, we retrospectively studied specimens of 94 patients with DCIS treated by local excision and radiation. We analyzed the rim of tissue near the final margin for the amount of COL, ADH, and DCIS. During a median follow-up of 78 months, local recurrence developed in 9 patients. COL or ADH with DCIS near the final margin was associated with recurrence; the strongest relationship was with recurrences in the same site as the lumpectomy bed. DCIS with ADH was significantly associated with recurrence in the low-grade DCIS group; DCIS with COL was associated with recurrence in the high-grade group. Other features were not associated with outcome.
We believe that ADH composed of cells identified as those of DCIS should be considered part of the DCIS lesion. DCIS may be inadequately excised if ADH and DCIS or COL and DCIS are near the margin.
CANCERIZATION OF SMALL DUCTS
Cancerization of small ectatic ducts of the breast by ductal carcinoma in situ cells with apocrine snouts: a lesion associated with tubular carcinoma.
Goldstein NS, O'Malley BA.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.
Am J Clin Pathol 1997 May;107(5):561-6 Abstract quote
Small ectatic ducts lined by atypical ductal cells with apocrine snouts occasionally have been observed in association with tubular carcinoma; some pathologists have considered these carcinomas to be a form of ductal carcinoma in situ (DCIS).
Thirty-two cases of tubular carcinoma, 41 of invasive grade 1 ductal carcinoma with DCIS, 40 of invasive grade 1 ductal carcinoma without DCIS, 40 of invasive grade 3 ductal carcinoma, 40 of invasive lobular carcinoma, 20 of well-differentiated DCIS, and 80 of fibrocystic changes were examined to determine the relationship between the lesion formed by atypical ductal cells with apocrine snouts and invasive carcinoma, DCIS, and benign breast changes.
Seventeen cases contained lesions formed by atypical ductal cells with apocrine snouts: 14 were associated with tubular carcinoma (43.7%), and 3 with invasive grade 1 ductal carcinoma (3.7%). In six invasive carcinomas, the associated DCIS was formed by cells identical to those within the lesion. These lesions were found at the periphery of the invasive carcinoma and adjacent to the DCIS. The lesions were probably composed of low-grade intraductal malignant epithelial cells, which partially involve small ectatic ducts and are often adjacent structures as a form of cancerization.
This cytologic and architectural form of DCIS appears to be related to an invasive carcinoma that is usually of tubular subtype. Attention to this form of cancerization by malignant intraductal cells, especially with regard to specimen surgical margins, is imperative when a tubular carcinoma is encountered.
If a pathologist encounters only this lesion in a partially sampled breast biopsy specimen, additional (or all) tissue should be submitted for histologic evaluation to ensure that an invasive carcinoma is not missed. This lesion needs to be distinguished from the frequent, benign, columnar alteration within lobules and small ectatic ducts.
Clear cell Cells with optically clear cytoplasm Clinging Single or few layers of neoplastic cells lining the lumen of the duct Comedonecrosis Coagulative necrosis within nests of usually solid DCIS
Cribriform Rigid fenestrations with punched out spaces Cystic hypersecretory Variant of micropapillary type with prominent mucinous secretions distending involved duct spaces resulting in cystic appearance
Mucous may be extruded into surrounding tissue
INDETERMINATE Carcinomas In Situ of the Breast With Indeterminate Features
Rosen's breast pathology. Philadelphia, PA: Lippincott-Raven, 1997.
Diagnostic histopathology of the breast. Edinburgh, Scotland: Churchill Livingstone, 1987.
Pathology of the breast. 2nd ed. Stamford, CT: Appleton and Lange, 1999.
Rosen favors a combined ductal and lobular category
Fisher favors ductolobular carcinoma in situ (DLCIS) for their cases with small monomorphic cells with foci of cribriform or necrosis indicating such lesions should be managed as DCIS
Page and Anderson advise that in most cases an attempt should be made to categorize lesions as DCIS or LCIS but note that on rare occasions this may not be possible, necessitating the diagnosis of carcinoma in situ of both lobular and ductal type
Tavassoli advises that LCIS cases with necrosis should be managed similarly to intermediate-grade DCIS, believing that this is a reflection of ``far-advanced lobular neoplasia.''
Micropapillary Neuroendocrine Organoid appearance with prominent argyrophilia resembling a carcinoid tumor Papillary carcinoma in situ, encysted Older women
Circumscribed papillary structures with fibrovascular cores
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.
Hum Pathol. 2006 Jul;37(7):787-93. Epub 2006 May 26. Abstract quote
The solid papillary variant of ductal carcinoma in situ is an uncommon entity, which usually presents in the seventh or eighth decade and may be associated with invasive mucinous carcinoma. Solid papillary ductal carcinoma in situ (SP-DCIS) shares many morphological features with usual ductal hyperplasia (UDH) involving a papilloma: papillary architecture, solid growth, cellular streaming, and low-grade nuclear features. These similarities can make the distinction between these 2 entities challenging.
Recent studies have demonstrated that immunohistochemical staining for cytokeratin 5/6 can distinguish UDH from conventional forms of ductal carcinoma in situ. Most of the epithelial cells of UDH express cytokeratin 5/6, but the tumor cells of ductal carcinoma in situ do not.
We tested the hypothesis that the results of staining for cytokeratin 5/6 can distinguish UDH from the solid papillary variant of ductal carcinoma in situ. Immunohistochemical staining of 14 cases of SP-DCIS and 9 cases of UDH (4 involving papillomas) was performed using cytokeratin 5/6 antibody clone D5/16 B4. Strong cytoplasmic or membrane staining was considered positive. The hyperplastic cells in all cases of UDH showed strong staining for cytokeratin 5/6. The percentage of positive cells ranged from 50% to 80%. None of the SP-DCIS tumor cells stained for cytokeratin 5/6; however, many cases did show staining of occasional entrapped, benign epithelial, and myoepithelial cells. We conclude that the absence of strong cytokeratin 5/6 expression by SP-DCIS distinguishes it from its morphological mimic, UDH.
Pathologists must guard against misinterpreting SP-DCIS as UDH in those cases in which the carcinoma cells engulf cytokeratin 5/6-expressing residual, native epithelial cells.
Small cell solid Uniform population of cells with low grade features Solid SIGNET RING SQUAMOUS CELL CARCINOMA IN SITU
- Squamous Cell Carcinoma In Situ of the Breast: A Light Microscopic and Immunohistochemical Study of a Previously Undescribed Lesion.
*Department of Pathology, BC Cancer Agency, Vancouver, Canada †Department of Pathology, Netherlands Cancer Institute, Amsterdam ‡Department of Anatomical Pathology, Istanbul Tip Fakultesi, Capa, Topkapi, Istanbul, Turkey §Department of Pathology Lionʼs Gate Hospital, Vancouver, British Columbia, Canada ∥Section of Anatomical Pathology, Department of Oncological Sciences, University of Bologna, Bellaria Hospital, Bologna, Italy
- Am J Surg Pathol. 2007 Sep;31(9):1414-1419. Abstract quote
Three cases of squamous carcinoma in situ of the breast, one with an invasive component are described in women aged 35, 51, and 59 years. Two cases were detected by screening mammography. In 1 case, the squamous ductal carcinoma in situ was extensive. All cases showed obvious squamous features on standard hematoxylin and eosin sections.
The in situ component of the lesions and the squamous differentiation were supported by immunohistochemistry. In 2 cases, the neoplastic cells showed actin positivity indicating myoepithelial cell differentiation. One case showed trilineage differentiation into luminal, squamous, and myoepithelial cells.
These cases illustrate a variant of duct carcinoma in situ that has not been described in the current literature and provide insights into the dual epithelial-myoepithelial differentiation of some breast neoplasms.
- Basal phenotype of ductal carcinoma in situ: recognition and immunohistologic profile.
1Department of Pathology, Magee-Women's Hospital of UPMC, Pittsburgh, PA, USA.
- Mod Pathol. 2006 Nov;19(11):1506-11. Epub 2006 Aug 25. Abstract quote
The basal phenotype of breast carcinoma was demonstrated from a study of gene expression profiles, which demonstrated five carcinoma phenotypes with differing immunohistologic profiles and outcomes. The basal phenotype, so-named because of an immunohistologic profile that is similar to myoepithelial cells of the breast, has poor outcomes. While the invasive basal phenotype has been described, there is a paucity of literature regarding the existence or recognition of a precursor lesion.
We searched our CoPath database for breast carcinomas in the age group of 37 years or less, and this yielded 98 cases from the years 2001 to April 2006. Pathology reports were screened for those cases that were negative for estrogen and progesterone receptors and HER-2/neu (triple negative). A total of 16 cases (16/98, 16%) fulfilled these criteria. Histology was reviewed and immunostains were performed for Cytokeratins 14, 17, and 5/6, vimentin, EGFR, c-kit, smooth muscle actin and p63. All 16 cases had a high-grade invasive ductal carcinoma, Nottingham score 9/9, with geographic necrosis, good circumscription and lymphoid infiltrates.
Of the 16 cases, 13 exhibited at least one area of ductal carcinoma in situ (DCIS). The DCIS types were solid, flat or micropapillary, high nuclear grade, with comedonecrosis and invariably associated with intense lymphoid inflammatory cell infiltration.
Of 16 invasive cases, 14 (88%) were positive for CK14, CK17, CK5/6 and EGFR; 94% were vimentin positive, while half or less of cases were positive for smooth muscle actin, c-kit or p63. All of the DCIS components demonstrated the same immunohistologic profile as the invasive component.
A DCIS component of solid, flat or micropapillary type exists in the basal phenotype of breast carcinoma, and it demonstrates the same immunophenotype as the invasive carcinoma, typically positive for CK5/6, CK14, CK17, vimentin and EGFR, but negative for ER/PR and HER-2/neu.
DIFFERENTIAL DIAGNOSIS CHARACTERIZATION COLLAGENOUS SPHERULOSIS
Am J Surg Pathol. 2006 Jan;30(1):20-7. Abstract quote
Collagenous spherulosis is a rare benign lesion that can microscopically mimic atypical ductal hyperplasia, cribriform ductal carcinoma in situ, or adenoid cystic carcinoma. Seventy-nine cases of collagenous spherulosis in women aged 36 to 90 years (mean age, 52 +/- 11 years) were identified from the University of Texas M. D. Anderson Cancer Center pathology files from the last 10 years. The pathology reports and slides from 59 patients were reviewed.
This study does not attempt to evaluate the overall incidence of collagenous spherulosis because only cases with an actual diagnosis of collagenous spherulosis in pathology report were reviewed.
The aim of this study was to investigate the underlying pathology within collagenous spherulosis and its relation to other pathologic findings within the specimen. Collagenous spherulosis was present as multiple foci ranging in size from 0.1 to 0.3 cm in 44 (75%) of the 59 cases. Collagenous spherulosis was associated with benign lesions of the breast in 41 cases, with atypical ductal hyperplasia in 3 cases, and with lobular carcinoma in situ in 15 cases. Microcalcifications were found in lesions involved by collagenous spherulosis in 15 cases. In summary, although collagenous spherulosis was mostly associated with benign breast lesions, in our study it was also frequently seen in association with lobular carcinoma in situ.
Collagenous spherulosis could present as a mammographically suspicious mass or density and could be associated with microcalcifications. Increased numbers of cases of collagenous spherulosis may be expected in the future as a result of breast cancer-screening programs. Caution is needed not to overinterpret collagenous spherulosis as atypical or ductal carcinoma in situ, especially on core needle biopsy specimens.
METASTATIC CARCINOMA Metastases to breast simulating ductal carcinoma in situ: Report of two cases and review of the literature
Ann Diagn Pathol 2001;5:15-20
We report two examples of tumors with a papillary histologic pattern metastasing to the breast. One of the cases occurred in a 31-year-old woman with a primary renal cell carcinoma, the other was in a 42-year-old woman with an ovarian papillary serous adenocarcinoma. In the first case, the patient's previous history of cancer was not known to the pathologist. The cases highlight the difficulty in distinguishing primary from metastatic tumors in the breast. In both cases the tumors infiltrated in a pattern that mimicked in situ ductal carcinoma changes. Additionally, in both cases, the metastasing tumor was unusual with the tumor cells diffusely permeating the lymphatic spaces, not in a solid mass.
These cases and a review of the literature indicated that breast metastases, although rare, must be recognized and differentiated from primary breast tumors to avoid unnecessary radical surgery to the breast. Moreover, the presence of changes similar to in situ carcinoma of the breast are not conclusive evidence that one is evaluating a primary breast carcinoma. When there is any unusual histomorphology, a good degree of suspicion is necessary.
Diagnosed by disruption of the basement membrane with foci of invasive cancer having maximum diameter of 1 mm or less
Some also designate minimally invasive cancer with larger areas of invasive growth
Atypical ductal hyperplasia (ADH) This is the most important and difficult distinction to be made by the pathologist. Even expert pathologists disagree on the diagnosis of these borderline lesions. The following table highlights some of the most important differentiating features.
Adopted from: The Breast in Systemic Pathology. Third Edition. Volume 13. Churchill Livingstone 1998.
CRITERIA ADH LOW GRADE DCIS Size <2-3 mm >2-3 mm Cellular composition May have uniform population but merges with areas of usual type hyperplasia within same duct space
Spindle cells may be prominent
Myoepithelial cells always present around periphery of duct spaces
Single population of cells
Spindle cells rare
Myoepithelial cells usually present around periphery of duct spaces
Architecture Micropapillary, cribriform, solid Well developed micropapillayr, cribriform, or solid patterns Lumina May be distinct and well formed ovoid or rounded spaces in cribriform type Well formed, regular punched out lumina in cribriform type often with cells oriented towards the luminal space Cell orientation May be regular, even placement at least focally
Cells may be at right angles to bridges in cribriform types
Micropapillary structures with indiscernible fibrovascular cores or smooth geometric spaces and rigid Nuclear spacing May be even Even Epithelial tumor cell character Small, uniform or medium sized monotonous cell populations focally Small, uniform monotonous cell population Nucleoli Single and small Single and small Mitoses Infrequent, abnormal forms rare Infrequent, abnormal forms rare Necrosis/apoptosis Rare May be present Myoepithelial cells Present Present, rarely attenuated in thickness Calcification May be present May be present
CHARACTERIZATION Hormone receptor staining 50% positivity in micropapillary, solid, and cribriform types
20% in comedocarcinoma
- C-KIT expression in ductal carcinoma in situ of the breast: co-expression with HER-2/neu.
Diallo R, Rody A, Jackisch C, Ting E, Schaefer KL, Kissler S, Karn T, Geddert H, Engels K, Kaufmann M, Gabbert HE, Shroyer KR, Poremba C.
Institute of Pathology, Heinrich-Heine-University of Dusseldorf, 40225 Dusseldorf, Germany.
Hum Pathol. 2006 Feb;37(2):205-11. Abstract quote
The proto-oncogene c-KIT (CD117) is highly expressed in normal breast epithelium and is decreased in invasive breast cancer.
In this study, we analyzed the protein expression and the mutational status of c-KIT in ductal carcinoma in situ (DCIS) of the breast and correlated these findings with nuclear grade, architectural pattern, and expression of HER-2, estrogen receptor (ER)-alpha, and progesterone receptor (PR). C-KIT, HER-2, ER, and PR expression were analyzed immunohistochemically in 106 cases of paraffin-embedded DCIS (85 pure DCIS and 21 DCIS with concurrent carcinoma). Direct sequencing of exons 9 and 11 of the c-KIT gene was performed to analyze the hot spot mutational regions in representative cases. C-KIT expression was found in 55 (52.8%) of all DCIS, correlating with high nuclear grade (P < .0001), comedonecrosis (P < .0001), and solid growth pattern (P = .001). Furthermore, c-KIT expression was strongly associated with HER-2 positivity (P < .0001) and was significantly lower in ER- or PR-positive cases (P = .001 and P = .006, respectively). C-KIT expression alone or co-expression with HER-2 in pure DCIS did not differ significantly from DCIS with invasive component (P = .09). Mutational analysis in 6 c-KIT-positive DCIS revealed no activating mutations in exons 9 or 11.
- Our findings suggest that the expression of c-KIT protein might define a subset of poorly differentiated, HER-2-positive DCIS with decreased expression of steroid hormone receptors, comedonecrosis, and a solid growth pattern. The implications of c-KIT and HER-2 co-expression for breast carcinogenesis should be further evaluated.
Her2-neu Present in most cases of comedocarcinoma and in mixed cases with comedonecrosis
- HER2 protein overexpression in estrogen receptor-positive ductal carcinoma in situ of the breast: frequency and implications for tamoxifen therapy.
Collins LC, Schnitt SJ.
1Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Mod Pathol. 2005;18:615-620 Abstract quote
Recent clinical data have suggested that the efficacy of tamoxifen in reducing the risk of local recurrence following lumpectomy and radiation therapy in patients with ductal carcinoma in situ (DCIS) is limited to patients with estrogen receptor (ER)-positive lesions. However, it is currently not known if HER2 protein overexpression might be associated with reduced tamoxifen benefit in patients with ER-positive DCIS, as has been suggested in patients with ER-positive invasive breast cancer and in preclinical models. Moreover, the frequency of HER2 overexpression in ER-positive ductal carcinoma in situ has not been previously evaluated in detail.
To address this issue, we studied ER expression and HER2 overexpression in 148 cases of DCIS using a sensitive double immunostaining technique and assessed the frequency of ER expression and HER2 overexpression in relation to each other and in relation to DCIS grade. Overall, ER expression was seen in 114 cases (77%) and HER2 protein overexpression was seen in 42 cases (28%). Of 114 ER-positive ductal carcinoma in situ, 14 (12%) showed concurrent HER2 protein overexpression, and all 14 of these DCIS lesions were of high nuclear grade. In addition, in all 14 ER-positive DCIS cases that showed HER2 overexpression, double immunostaining demonstrated that ER and HER2 protein were coexpressed by the same neoplastic cells.
We conclude that a subset of ER-positive DCIS show concomitant overexpression of HER2 protein. Whether or not HER2 overexpression is associated with a diminished response to tamoxifen in patients with ER-positive DCIS will require investigation in clinical outcome studies.
J Pathol 1997;183:404–11
Am J Pathol 1993;143:1731–42.
E-cadherin protein expression is lost in invasive lobular carcinoma and in LCIS but not in invasive ductal carcinoma or DCIS
Am J Surg Pathol 2001;25:229-236
89 cases of breast CIS
(28 LCIS, 33 DCIS, 28 CIS-IF)
CIS-IF cases were divided into three groups based on histology:
Group 1-Cytologic and architectural features typical of LCIS but showed areas of comedo-type necrosis (n = 6)
Group 2-CIS lesions characterized by small, uniform neoplastic cells either growing in a solid pattern with focal microacinar-like structures but with cellular dyshesion, or growing in a cohesive mosaic pattern but with occasional intracytoplasmic vacuoles (n = 17)
Group 3-Marked cellular pleomorphism and nuclear atypia but had the dyshesive growth pattern characteristic of LCIS (n = 5).
All 28 cases of LCIS were E-cadherin negative
All 33 DCIS cases were E-cadherin positive by immunohistochemistry
All cases from CIS-IF group 1 and group 3 were negative for E-cadherin
In contrast, CIS-IF group 2 cases were heterogeneous with respect to E-cadherin staining:
Six (35.3%) cases were E-cadherin negative (more akin to LCIS)
5 (29.4%) cases were E-cadherin positive (akin to DCIS)
6 (35.3%) cases had both E-cadherin–positive and E-cadherin–negative tumor cells, suggesting a mixed DCIS/LCIS phenotype
Am J Surg Pathol 2001;25:237-244
12 cases of in situ carcinomas with equivocal features and correlated their histologic attributes with those of the associated invasive carcinomas
E-cadherin–positive in situ lesions were invariably associated with invasive carcinomas of the ductal type
In situ carcinomas that were E-cadherin negative were associated with invasive carcinomas of the lobular type in five of six cases
In all cases, the invasive carcinomas showed the same pattern of E-cadherin reactivity as the in situ lesions
Sharply defined cellular membranes, necrosis, and occasional microacini were seen in both E-cadherin—positive and negative in situ carcinomas
Intracytoplasmic lumina and a noncohesive appearance were seen only in E-cadherin—negative lesions
E-Cadherin Reactivity of 95 Noninvasive Ductal and Lobular Lesions of the Breast Implications for the Interpretation of Problematic Lesions
Neal S. Goldstein, etal.
Am J Clin Pathol 2001;115:534-542 Abstract quote
Studies suggest that E-cadherin is useful to classify epithelial breast lesions as ductal or lobular, but extensive experience with this antibody is lacking.
We studied reactivity of lesions with classic and indeterminate morphologic features. We reviewed 95 lesions and divided them into unanimous and nonunanimous diagnosis groups; the unanimous group served as benchmark lesions to which E-cadherin reactivity could be standardized and compared.
All 37 ductal lesions in the unanimous group had strong, diffuse E-cadherin reactivity. Two of 22 classic lobular carcinoma in situ (LCIS) lesions had sparse E-cadherin–reactive lobular cells within a few terminal duct lobular units. Neither displayed transition from nonreactive to reactive cells.
Of 36 lesions in the nonunanimous group, 19 had insufficient morphologic features for definitive classification. Only 6 of 19 were E-cadherin reactive, including several minimally proliferative lesions. The other 17 lesions in the nonunanimous group had LCIS and ductal carcinoma in situ (DCIS) features. All had no E-cadherin, or strong membrane reactivity of constituent cells in varying proportions, without a transition between reactive and nonreactive cells.
Results suggest that the majority of morphologically nondiagnostic atypical lesions are lobular, including those associated with DCIS. E-cadherin seems to be absent in most lobular lesions.
Biologic Markers in Ductal Carcinoma In Situ and Concurrent Infiltrating Carcinoma A Comparison of Eight Contemporary Grading Systems
Anthony S.-Y. Leong, etal.
Am J Clin Pathol 2001;115:709-718 Abstract quote
The relevance of 8 contemporary classification and grading systems for ductal carcinoma in situ (DCIS) of the breast was examined in 100 tumors by comparing DCIS grade with grade of the concurrent infiltrating ductal carcinoma (IDC). Besides tumor size and nodal status, the immunohistochemical parameters in both lesions were compared, including estrogen receptor, progesterone receptor, c-erbB-2 protein, E-cadherin, vimentin, Ki-67 (MIB1), and p27.
Nuclear grading of DCIS alone or in combination with architectural pattern and necrosis showed the best correlation with grade of the invasive component. There also was a positive correlation between every biologic marker expressed in DCIS and in the concurrent IDC, supporting a clonal relationship.
Biologic markers varied between the different grades of DCIS. DCIS is heterogeneous, and the progression of DCIS to IDC may be from low-grade DCIS to low-grade IDC and high-grade DCIS to high-grade IDC. This concept is different from the conventional model held for intraepithelial neoplasia in the cervix, vulva, vagina, and skin, in which there is increasing severity of in situ atypia (dysplasia) before the development of stromal invasion.
Expression of CD31 by cells of extensive ductal in situ and invasive carcinomas of the breast.
Sapino A, Bongiovanni M, Cassoni P, Righi L, Arisio R, Deaglio S, Malavasi F.
Department of Biomedical Sciences and Human Oncology, University of Torino Medical School, Torino, Italy.
J Pathol 2001 Jun;194(2):254-61 Abstract quote
CD31, an adhesion molecule expressed by endothelial cells, leukocytes, and platelets, is used in surgical pathology as a marker of normal and neoplastic vascularization. During the assessment of angiogenesis in breast carcinomas, CD31 expression was observed in a single case of large (5.2 cm diameter) high nuclear grade ductal carcinoma in situ (HG-DCIS) associated with poorly differentiated invasive ductal carcinoma (G3-IDC). Expression was limited to the cell membrane.
This study focused on 32 HG-DCIS> or = 2 cm, either pure or associated with IDC. Cancer cells wereCD31(+) in 11 cases. Double staining using anti-CD31 monoclonal antibody (MAb) and anti-CD44 MAb, the anti-hyaluronate receptor, showed that foci of CD31(+) and CD44(-) tumour cells could be traced throughout the glandular tree, marking the intraductal diffusion of tumour up to Paget's cells at the nipple. The associated G3-IDC and their lymph node metastases were instead CD31(+) and CD44(+). CD31(+) tumours were oestrogen receptor (ER)(-), frequently p53(+) and c-erb-B2(+), and infiltrated by CD4(+) T lymphocytes. Normal and hyperplastic epithelia were constantly CD31(-). Other endothelial markers (e.g Factor VIII-RA and CD34) were not expressed by carcinoma cells, as was CD38, the CD31 ligand.
In conclusion, CD31 expression is a feature acquired by breast cancer cells in the DCIS model. CD31 expression mainly correlates with tumour cells spreading within the ductal system. Finally, the invasive phenotype requires the co-expression of CD31 and CD44.
Combined E-cadherin and high molecular weight cytokeratin immunoprofile differentiates lobular, ductal, and hybrid mammary intraepithelial neoplasias.
Bratthauer GL, Moinfar F, Stamatakos MD, Mezzetti TP, Shekitka KM, Man YG, Tavassoli FA.
Department of Gynecologic and Breast Pathology, Armed Forces Institute of Pathology, Washington, DC.
Hum Pathol 2002 Jun;33(6):620-7 Abstract quote
The terminal duct-lobular unit is the origin of 2 distinct variants of intraepithelial neoplasia traditionally separated into ductal and lobular types based on a combination of cytologic and architectural features.
In general, distinction of the fully developed or classic lobular intraepithelial neoplasia (LIN) from various grades of ductal intraepithelial neoplasia (DIN) is not a problem. An increasing number of lesions that appear to have intermediate, overlapping ductal and lobular features are being sent to us for consultation because of the distinctly different clinical implication of the 2 diagnoses.
We have separated and designated these as MIN (mammary intraepithelial neoplasia, not otherwise specified), whereas others have categorized them into either a definitive ductal or lobular subtype. The recent findings that LIN lacks immunoreaction for E-cadherin coupled with significantly diminished to absent expression of the high molecular weight (HMW) cytokeratins in more than 90% of grade 1b or higher DIN prompted us to evaluate intraepithelial neoplasias for a possibly more precise immunohistochemical categorization. One hundred and ten examples of intraepithelial neoplasias, consisting of 40 classic LIN, 20 unequivocal DIN 1c to DIN 3 (ductal carcinoma in situ), and 50 MIN, were acquired from the files of the Armed Forces Institute of Pathology.
These specimens were tested with an antibody to E-cadherin and with antibody 34ssE12 reactive against HMW cytokeratins 1, 5, 10 and 14. All samples of LIN showed complete absence of reactivity with anti-E-cadherin, whereas all cases of DIN displayed a positive immunoreaction. In contrast, the DIN lesions displayed little or no reactivity with 34ssE12, whereas the lobular lesions showed cytoplasmic reactivity, often in a distinct perinuclear pattern. Twenty-three of the morphologically indeterminate cases could be classified as either ductal or lobular based on the immunoprofile, and 27 demonstrated an immunoprofile that differed from either typical DIN or classic LIN. Among the 27 MIN, 11 were negative for both markers (negative hybrids), whereas 16 were positive for both markers (positive hybrids). These 2 antibodies in combination are extremely useful in distinguishing lobular and ductal lesions and clarifying the nature of some of the morphologically intermediate cases. Also, they have confirmed the presence of a group of intraepithelial lesions (MIN) with not only overlapping morphologic features, but also immunoprofiles distinctly different from either DIN or LIN.
These MIN lesions may reflect either a transient stage in the development of DIN and LIN (the immediate post-stem cell stage) or a plastic group in transition from one type to the other. This group needs further evaluation for better understanding of its significance, pattern of progression, and behavior.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS Van Nuys Prognostic Index (VNPI) seeks to correlate nuclear features, necrosis, and size to form a prognostic index-See table below GENERAL In general, volume of DCIS, grade, and margin status are the most important prognostic variables
- Prognostic and Predictive Molecular Markers in DCIS: A Review.
Nofech-Mozes S, Spayne J, Rakovitch E, Hanna W.
From the *Department of Pathology, Sunnybrook and Women's College Health Sciences Center, Toronto, Ontario, Canada; and daggerDepartment of Radiation Oncology, Toronto Sunnybrook Regional Cancer Centre, Toronto, Ontario, Canada.
Adv Anat Pathol. 2005 Sep;12(5):256-264. Abstract quote
Eighteen percent of all new breast cancers detected on screening mammography are ductal carcinoma in situ (DCIS), a preinvasive lesion that is highly curable. However, some women with DCIS will develop life-threatening invasive breast cancer. Because the determinants of invasive recurrence are unknown, all women with DCIS require the same treatment (usually with surgery and radiation).
Therefore, there is a need to identify biologic markers and create a profile that will provide prognostic information that is more accurate than the currently used van Nuys Index to predict invasive recurrence.
In the present review, we examined the many biologic markers studied in breast cancer, describe their main biologic role and their expression in DCIS, and review the various studies regarding their ability to serve as prognostic factors in breast cancer with an emphasis on predicting invasive recurrence in patients with DCIS.
This review covers established markers, namely, ER, PR and HER2/neu, that are used routinely to make treatment decisions as well as investigative biologic factors involved in cell proliferation, cell cycle regulation, extracellular molecules, factors involved in extracellular matrix degradation, and angiogenesis.
However, controversies exist regarding the value of these prognostic factors, their interrelationship, and their advantages over morphologic evaluation.
Continued local recurrence of carcinoma 15-25 years after a diagnosis of low grade ductal carcinoma in situ of the breast treated only by biopsy.
Page DL, Dupont WD, Rogers LW, Jensen RA, Schuyler PA.
Vanderbilt University School of Medicine, Department of Pathology, Nashville, Tennessee, USA.
Cancer 1995 Oct 1;76(7):1197-200 Abstract quote
BACKGROUND. The stratification of ductal carcinoma in situ (DCIS) of the human breast into prognostically relevant categories by size and histologic pattern is a current concern. Few studies have been able to follow women after the identification of any type of DCIS when they have had biopsy only.
METHODS. This is an extension of a follow-up study of a group of 28 women with small, noncomedo ductal carcinomas in situ that were excised by biopsy only, published in 1982. All these women have now been successfully followed for an average of almost 30 years.
RESULTS. The overall risk of development of invasive carcinoma for these women over almost 30 years is nine times that of the general population (95% confidence interval, 4.7-17). This is similar to the 11-fold elevation in relative risk that was determined after about 15 years of follow-up. All invasive carcinomas have developed in the same area in the same breast. There were two women in whom invasive carcinoma developed between 20 and 30 years after initial biopsy. One other woman had an extensive noncomedo DCIS that was identified 25 years after her initial biopsy, but had no evidence of invasive disease.
CONCLUSIONS. The natural history of small, noncomedo DCIS can last over at least 2 decades, with invasive carcinoma developing at the same site in which DCIS was previously discovered in a significant percentage of women (broadly, between 25%-50%). This is quite different from the natural history of comedo DCIS or any type of DCIS treated purposefully by surgery alone.
Ductal carcinoma in situ detected in the mammographic era: an analysis of clinical, pathologic, and treatment-related factors affecting outcome with breast-conserving therapy.
Vicini FA, Lacerna MD, Goldstein NS, Horwitz EM, Dmuchowski CF, White JR, Gustafson GS, Ingold JA, Martinez AA.
Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI 48073, USA.
Int J Radiat Oncol Biol Phys 1997 Oct 1;39(3):627-35 Abstract quote
PURPOSE: We reviewed our institution's experience treating predominantly mammographically detected ductal carcinoma in situ (DCIS) with breast-conserving therapy (BCT) to determine if any clinical, pathologic, or treatment-related factors affected outcome.
METHODS AND MATERIALS: From January 2, 1980 to January 6, 1992, 107 breasts in 105 patients were treated with BCT at William Beaumont Hospital, Royal Oak, MI. All patients underwent at least an excisional biopsy and 70 patients (65%) were reexcised. All patients received whole-breast irradiation to a median dose of 50.4 Gy (range 43.1 to 56.0 Gy). Ninety-nine patients (93%) received a supplemental boost to the tumor bed for a median total dose of 60.4 Gy (range 59.1 to 71.8 Gy) using either photons (2 patients), electrons (69 patients), or an interstitial implant (28 patients).
RESULTS: With a median follow-up of 78 months, 10 patients have failed in the treated breast for a 5- and 10-year actuarial local control rate of 91.2 and 89.8%, respectively. Thirteen percent of the population have been followed for 10 years or more. Three recurrences were pure DCIS, and seven were invasive. All patients were salvaged with mastectomy. Nine patients remain without evidence of disease a median of 30.6 months after surgery. One patient failed distantly 36 months after local recurrence for an ultimate cause specific survival of 99%. Potential clinical (age, mammographic findings, method of detection, etc.), pathologic (nuclear grade, margins, etc.), and treatment-related factors (dose, boost technique, reexcision status, etc.) affecting outcome were analyzed. No variable was found to be associated with an ipsilateral breast tumor recurrence. However, when only recurrences that occurred within or immediately adjacent to the lumpectomy cavity were analyzed, both margin status and the extent of cancerization of lobules (COL) near the surgical margin were associated with the development of a local recurrence.
CONCLUSIONS: Patients treated with BCT for predominantly mammographically detected DCIS achieve excellent rates of local control and overall survival. Both margin status and the extent of COL near the surgical margin appear to be associated with recurrences within or immediately adjacent to the lumpectomy cavity. These data suggest that careful attention to the completeness of surgical resection of DCIS is an important determinant of outcome.
Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma.
Fisher ER, Dignam J, Tan-Chiu E, Costantino J, Fisher B, Paik S, Wolmark N.
National Surgical Adjuvant Breast and Bowel Project Pathology Center, Pittsburgh, Pennsylvania, USA.
Cancer 1999 Aug 1;86(3):429-38 Abstract quote
BACKGROUND: This report is an 8-year update of the authors' previous findings from National Surgical Adjuvant Breast Project (NSABP) Protocol B-17, which relates to the influence of pathologic characteristics on the natural history and treatment of intraductal carcinoma (DCIS).
METHODS: Nine pathologic features observed in a pathologic subset of 623 of 814 evaluable women enrolled in this randomized clinical trial were assessed for their role in the prediction of second ipsilateral breast tumors (IBT), other events, and selection of breast irradiation (XRT) following lumpectomy.
RESULTS: The frequency of subsequent IBT was reduced from 31% to 13% (P = 0.0001) by XRT. The average annual hazard rates for IBT were reduced by XRT for all pathologic features examined. Four characteristics were individually noted to be significantly related to IBT, but only moderate-to-marked and absent-to-slight comedo necrosis were found to be independent high and low risk predictors, respectively, for such an event in patients of both treatment groups. XRT effected a 7% absolute reduction at 8 years in the low risk group. Despite a relatively high incidence (approximately 40%) of IBT consisting of invasive cancer, mortality due to breast carcinoma after DCIS for the entire cohort was found to be only 1.6% at 8 years.
CONCLUSIONS: The degree of comedo necrosis in patients with DCIS appears to be sufficient for discriminating between high and low risks for IBT following lumpectomy for DCIS. Although margin status, unlike in our previous report, was found to have only a slight or borderline influence on the frequency of IBT at 8 years, excision of DCIS with free margins is advised. The low risk group exhibits a statistically significant reduction of IBT from XRT. The decision to forgo XRT in the treatment of this singular subset of patients would appear to depend on clinical considerations and the input of informed patients rather than being standard practice.
Pathologic and technical considerations in the treatment of ductal carcinoma in situ of the breast with lumpectomy and radiation therapy.
Vicini FA, Goldstein NS, Kestin LL.
Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI, USA.
Ann Oncol 1999 Aug;10(8):883-90 Abstract quote
BACKGROUND: Lumpectomy and radiation therapy is considered a standard treatment option for ductal carcinoma in situ (DCIS) of the breast. The incidence of locally recurrent carcinoma using this therapeutic approach ranges from 6%-19%. Multiple studies have attempted to identify factors associated with the development of local recurrences in these patients. Despite extensive reports examining this issue, no factor(s) has consistently been correlated with outcome.
METHODS: This review examines the criteria that various authors have proposed as being associated with recurrence, including DCIS grade, size, histologic subtype, status of surgical margins, and technical factors to help clarify their roles in optimizing treatment outcome. The issue of the definition of the type of recurrence is also addressed.
RESULTS: Though multiple studies have examined the impact of grade, histologic subtype, necrosis, and DCIS size on outcome, no consistent results have been observed to suggest that these factors can be routinely used to guide therapy. The adequacy of excision appears to correlate with local control but is imprecisely defined by margin status alone. Based upon recent data, it appears that atypical ductal hyperplasia and cancerization of lobules in the context of coexistent DCIS, may need to be considered as part of the DCIS lesion that should be excised. This issue may account for some of the disparate results of different studies of DCIS. For statistical purposes, recent studies also suggest that only recurrences developing within or adjacent to the bed of the initial DCIS lesion should be considered when analyzing factors associated with outcome. Recurrences developing elsewhere in the breast may include new DCIS and invasive lesions that bear no biologic relationship with the initial DCIS lesion. Finally, since it is impossible to insure that all DCIS has been removed, it may be more appropriate to consider DCIS lesions as adequately or inadequately excised instead of completely or incompletely excised. Since DCIS is essentially a microscopic disease, pathologists should have a primary role in helping to define the adequacy of excision.
CONCLUSIONS: Additional studies with complete pathology review and longer follow-up are needed to reach a consensus on which prognostic factors are consistently associated with recurrence for patients with DCIS treated with lumpectomy and radiation therapy. At the present time, adequacy of excision appears to correlate with outcome. However, more precise and consistent methods need to be developed to assist in the determination of adequate DCIS extirpation.
Pathologic features of initial biopsy specimens associated with residual intraductal carcinoma on reexcision in patients with ductal carcinoma in situ of the breast referred for breast-conserving therapy.
Goldstein NS, Kestin L, Vicini F.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI 48073-6769, USA.
Am J Surg Pathol 1999 Nov;23(11):1340-8 Abstract quote
The histologic criteria for determining which patients require a reexcision after an initial excisional biopsy for ductal carcinoma in situ (DCIS) of the breast are poorly defined. The authors examined the initial biopsy specimens of 98 patients with inked margins and determined the amount of DCIS on reexcision to help clarify which histologic criteria are useful in judging the need for reexcision.
Features in initial biopsy specimens that were associated with an increasing number of slides with DCIS on reexcision were an increasing number of slides with DCIS, an increasing number of DCIS ducts or terminal duct lobular units (TDLUs) with "cancerization" of lobules (COL) within 0.42 cm of the inked margin, and multifocal positive margins. In patients with negative (>0.2 cm) initial biopsy specimen margins, an increasing number of DCIS ducts or TDLUs with COL near the initial biopsy specimen margin were also associated significantly with an increasing number of slides with DCIS on reexcision. Six or more slides with DCIS or 11 or more DCIS ducts or TDLUs with COL within 0.42 cm of the inked margin in the initial biopsy specimens were associated with 6 or more slides with DCIS on reexcision.
These results suggest that the amount of DCIS in initial biopsy specimens and the amount of DCIS near the margin are associated with the quantity of DCIS remaining in the breast after an initial excisional biopsy. Pathologists can use these factors when assisting clinicians in evaluating the need for a reexcision.
Factors associated with local recurrence of mammographically detected ductal carcinoma in situ in patients given breast-conserving therapy.
Kestin LL, Goldstein NS, Lacerna MD, Balasubramaniam M, Martinez AA, Rebner M, Pettinga J, Frazier RC, Vicini FA.
Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI 48073, USA.
Cancer 2000 Feb 1;88(3):596-607 Abstract quote
BACKGROUND: The authors reviewed their institution's experience treating patients with mammographically detected ductal carcinoma in situ (DCIS) of the breast with breast-conserving therapy (BCT) to determine 10-year rates of local control and survival and to identify factors associated with local recurrence.
METHODS: From January 1980 to December 1993, 132 breasts in 130 patients were treated with BCT for mammographically detected DCIS at William Beaumont Hospital, Royal Oak, Michigan. All patients underwent an excisional biopsy, and 64% were reexcised. All patients received postoperative whole-breast irradiation to a median dose of 45.0 Gray (Gy) (range: 43.1-56.0 Gy). One hundred twenty-four cases (94%) received a boost to the tumor bed for a median total dose of 60.4 Gy (range: 45.0-71.8 Gy). All cases underwent complete pathologic review by one pathologist. The median follow-up was 7.0 years.
RESULTS: Of the entire study group, 13 patients developed recurrence within the ipsilateral breast, for 5- and 10-year actuarial rates of 8.9% and 10.3%, respectively. Nine of the 13 recurrences (69%) occurred within or immediately adjacent to the lumpectomy cavity and were designated as true recurrences or marginal misses (TR/MM). Four patients (31%) had recurrence elsewhere in the breast. Ten of the 13 recurrences (77%) were invasive, whereas 3 (23%) were pure DCIS. Only 1 patient died of disease, corresponding to 5- and 10-year actuarial cause specific survival rates of 100% and 99.0%, respectively. Multiple clinical, pathologic, and treatment-related factors were analyzed for association with ipsilateral breast failure or TR/MM. In multivariate analysis, only the absence of pathologic calcifications was significantly associated with ipsilateral breast failure. When specifically analyzed for TR/MM, younger age at diagnosis, number of slides with DCIS, number of DCIS and cancerization of lobules (COL) foci within 5 mm of the margin, and the absence of pathologic calcifications demonstrated a statistically significant association. Close or positive margin status did not significantly predict for either TR/MM (P = 0.14) or ipsilateral breast failure (P = 0.19).
CONCLUSIONS: In patients with mammographically detected DCIS treated with BCT, adequate excision of all DCIS prior to RT can result in improved rates of local control. However, margin status may not adequately predict complete tumor extirpation. The volume of DCIS within 5 mm of the margin appears to be a more reliable surrogate for the adequacy of excision. In addition, young patient age and the absence of pathologic calcifications are independent risk factors for the development of local recurrence.
Intraductal Carcinoma of the Breast Pathologic Features Associated With Local Recurrence in Patients Treated With Breast-Conserving Therapy
Neal S. Goldstein, M.D.; Larry Kestin, M.D.; Frank Vicini, M.D.
From the Departments of Anatomic Pathology and Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan
Am J Surg Pathol 2000;24:1058-1067 Abstract quote
Local excision and radiation therapy is a standard treatment option for duct carcinoma in situ (DCIS) of the breast. There is no consensus regarding the significant histologic features associated with recurrence.
The authors studied a large group of patients with mammographically detected DCIS treated with breast-conserving therapy to explore DCIS volume relationships, DCIS features, specimen characteristics, and the effect of patient age at diagnosis.
Thirteen patients (10%) developed a recurrent carcinoma in the ipsilateral breast, resulting in 5-and 10-year actuarial recurrence rates of 8.9% and 10.3%, respectively. Local recurrences were identified as a true recurrence/marginal miss (TR/MM) in nine patients, and elsewhere in the breast in four patients.
The notable features associated with TR/MM recurrences on univariate analysis included patient age less than 45 years old, six or more slides with DCIS, no microscopic calcifications within DCIS ducts, and five or more DCIS ducts or terminal duct lobular units (TDLUs) with cancerization of lobules (COL) within 0.42 cm of the final surgical margin. DCIS tumor size, nuclear grade, amount of central necrosis, and margin status were not associated with outcome.
Multivariate analysis found that the absence of microcalcifications within DCIS ducts, patient age, number of slides with DCIS or TDLUs with COL, and the number of DCIS ducts or TDLUs with COL within 0.42 cm of the final margin were related significantly to TR/MM recurrence. Patients with a total of six or more slides with DCIS, or who have 11 or more DCIS ducts or TDLUs with COL near the final margin are at increased risk of having a substantial volume of residual DCIS in the adjacent unexcised breast.
These results suggest that the volume of DCIS in the specimen, and the volume of DCIS near the margin are associated with local recurrence. These features can be used to identify those patients with a higher chance of local recurrence.
Relationship between excision volume, margin status, and tumor size with the development of local recurrence in patients with ductal carcinoma-in-situ treated with breast-conserving therapy.
Vicini FA, Kestin LL, Goldstein NS, Baglan KL, Pettinga JE, Martinez AA.
Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.
J Surg Oncol 2001 Apr;76(4):245-54 Abstract quote
BACKGROUND AND OBJECTIVES: We reviewed our institution's experience treating patients with ductal carcinoma-in-situ (DCIS) with breast-conserving therapy (BCT) to help define the interrelationship between excision volume, margin status, and tumor size with local recurrence.
METHODS: From January 1980 to December 1993, 146 patients received BCT for DCIS. All patients underwent excisional biopsy and 95 cases (64%) underwent re-excision. Each patient received whole breast radiation to a median dose of 45 Gy. An additional 139 cases (94%) received a supplemental boost to the tumor bed (median total dose 60.4 Gy). The median follow-up is 7.2 years.
RESULTS: Seventeen patients developed an ipsilateral breast failure for a 5- and 10-year actuarial rate of 10.2 and 12.4%, respectively. On multivariate analysis, patient age, margin status, the number of slides containing DCIS, the number of DCIS/cancerization of lobules (COL) foci near (< 5 mm) the margin, and a smaller volume of excision (< 60 cm(3)) were all independently associated with outcome. Although the local recurrence rate generally decreased as margin distance increased, these differences did not achieve statistical significance unless the volume of excision was taken into consideration.
CONCLUSIONS: These findings suggest that the success of BCT is directly related to the degree of surgical removal of DCIS and that margin status alone may be suboptimal in defining excision adequacy.
Predicting Invasion in the Excision Specimen From Breast Core Needle Biopsy Specimens With Only Ductal Carcinoma In Situ
Andrew A. Renshaw, MD
From the Department of Pathology, Baptist Hospital of Miami, Miami, Fla.
Arch Pathol Lab Med 2002;Vol. 126, No. 1, pp. 39–41. Abstract quote
Objective.—Some patients with ductal carcinoma in situ on breast core needle biopsy will have invasion at excision. The aim of this study was to determine if patients at increased risk for invasion could be identified.
Methods.—The results of all breast core needle biopsies with a diagnosis of ductal carcinoma in situ during a 50-month period were reviewed. A variety of histologic features were identified and correlated with the presence of invasion at excision.
Results.—Of 3026 cases, 152 (5%) were diagnosed as ductal carcinoma in situ; excisional biopsies were available for 91 (60%) of these 152 cases, and 17 (19%) showed invasive tumor. Neither the radiographic findings, presence of comedonecrosis, comedo histology, lobular extension, size of the largest focus, nor aggregate size was significantly associated with an increased incidence of invasion (all P > .05). However, comedo histology with a cribriform/papillary architecture was significantly associated with an increased risk of invasion (5/7 [72%] cases with invasion, P = .002), as were tumors greater than 4 mm with lobular extension (6/15 [40%], P = .03).
Conclusion.—Patients with comedo ductal carcinoma in situ with a cribriform/papillary pattern or tumor involving more than 4 mm with lobular extension in breast core needle specimens are at increased risk for invasion at excision.
Impact of young age on outcome in patients with ductal carcinoma-in-situ treated with breast-conserving therapy.
Vicini FA, Kestin LL, Goldstein NS, Chen PY, Pettinga J, Frazier RC, Martinez AA.
Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI 48073, USA.
J Clin Oncol 2000 Jan;18(2):296-306 Abstract quote
PURPOSE: We reviewed our institution's experience treating patients with ductal carcinoma-in-situ (DCIS) with breast-conserving therapy (BCT) to determine the impact of patient age on outcome.
PATIENTS AND METHODS: From 1980 to 1993, 146 patients were treated with BCT for DCIS. All patients underwent excisional biopsy, and 64% underwent re-excision. All patients received whole-breast irradiation to a median dose of 45 Gy. Ninety-four percent of patients received a boost to the tumor bed, for a median total dose of 60.4 Gy. All slides on every patient were reviewed by one pathologist. The median follow-up period was 7.2 years.
RESULTS: Seventeen patients developed an ipsilateral local recurrence, for 5- and 10-year actuarial rates of 10.2% and 12.4%, respectively. The 10-year rate of ipsilateral failure was 26.1% in patients younger than 45 years of age versus 8.6% in older patients (P =.03). On multivariate analysis, young age was independently associated with recurrence of the index lesion (true recurrence/marginal miss ?TR/MM failures), regardless of how it was analyzed (eg, < 45 years of age or as a continuous variable). In addition, young patients had a dramatically higher 10-year rate of invasive TR/MM failures (19.9% v 3.2%). In a separate multivariate analysis for the development of invasive TR/MM failures, only patient age and predominant nuclear grade were independently associated with recurrence. The relationship between excision volume and outcome was analyzed in the 95 patients who underwent re-excision. The 5-year actuarial rate of TR/MM failure was significantly worse only in young patients with smaller (< 40 mL) re-excision volumes (33.3% v 9.1%; P =.02). In a separate multivariate analysis of only these 95 patients (25 of whom were < 45 years of age), the volume of re-excision had the strongest association with outcome (P =.05). Patient age was no longer associated with local recurrence.
CONCLUSION: These findings suggest that young patients with DCIS have a significantly greater risk of local recurrence after BCT that is independent of other previously defined risk factors. Our data also suggest that the extent of resection may in part be related to the less optimal results that are observed in these patients.
Differences in the pathologic features of ductal carcinoma in situ of the breast based on patient age.
Goldstein NS, Vicini FA, Kestin LL, Thomas M.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.
Cancer 2000 Jun 1;88(11):2553-60 Abstract quote
BACKGROUND: Young patient age at diagnosis has been reported as a risk factor for recurrence in patients with ductal carcinoma in situ (DCIS) of the breast treated with breast-conserving therapy (BCT). The authors examined pathologic features of DCIS in three different age groups of patients to identify differences that might explain why young patient age at the time of diagnosis is a risk factor for recurrence.
METHODS: Excised specimens from 177 breasts of 172 patients with DCIS treated with BCT were studied. All slides from all specimens were reviewed. Patients were divided into 3 age groups: those age < 45 years, those ages 45-59 years, and those age >/= 60 years. The histologic features that were quantified included most common and highest nuclear grades, DCIS architectural pattern, amount of central necrosis (quartiles), calcifications, amount of DCIS, and number of terminal duct lobular units (TDLUs) with cancerization of lobules (COL) within 0.42 cm of the margin, margin status, and size and volume of excision specimens.
RESULTS: Patients age < 45 years at the time of diagnosis more frequently had higher nuclear grade DCIS (highest nuclear Grade 3: 69%, 60%, and 39%; P = 0.003), respectively and central necrosis (72%, 62%, and 44%; P = 0. 01), respectively. Although not statistically significant, younger patients tended to have comedo subtype DCIS more often (31%, 23%, and 19%; P = 0.35), respectively. Younger patients also more often had smaller initial biopsy specimen maximum dimensions (4.3 cm, 5.2 cm, and 5.7 cm; P = 0.004), respectively, with close or positive margins (89%, 61%, and 64%; P = 0.03), and more TDLUs with COL in the 0.42-cm rim of tissue adjacent to the margin (5.2, 3.6, and 1.9; P = 0.23), respectively. No other features including the amount of DCIS when classified as > 50% or > 75% of ducts, calcifications within DCIS ducts, pattern of DCIS involvement, number of slides examined, number of slides with DCIS, and mean number of DCIS ducts near the margin were found to occur more frequently in younger patients.
CONCLUSIONS: Younger patients with DCIS may have an increased risk of local recurrence when treated with BCT due to smaller initial excision volumes, a greater proportion of high nuclear grade DCIS, and central necrosis.
Effect of time interval on residual disease in breast cancer.
Wiley EL, Diaz LK, Badve S, Morrow M.
Am J Surg Pathol 2003 Feb;27(2):194-8 Abstract quote
The histologic responses of breast tissue to injury are limited. Needle core biopsies of the breast are associated with displacement of tumor cells, and the incidence of tumor displacement decreases as the time interval between needle core biopsy and subsequent excision increases. This suggests that displaced tumor cells are destroyed by reparative processes induced by tissue injury. Residual tumor in a lumpectomy site may also be subjected to the same destructive processes associated with tissue repair.
A total of 259 consecutive cases of infiltrating ductal carcinoma with margin-positive lumpectomies and their associated reexcision specimens obtained over a 7-year period were analyzed for the presence, type, and quantity of residual disease.
The overall incidence of residual disease was 69%. Residual infiltrating ductal carcinoma was present in 35% of cases, and residual ductal carcinoma in situ was present in 50%. An increased time interval between lumpectomy and reexcision was associated with a decreased incidence of residual infiltrating carcinoma (p <0.0043); this decrease was not found associated with ductal carcinoma in situ.
These findings suggest that the host response to injury may destroy residual infiltrating carcinoma cells in some margin-positive cases.
CONTRALATERAL BREAST CANCER RISK
Risk of contralateral breast cancer among women with carcinoma in situ of the breast.
Habel LA, Moe RE, Daling JR, Holte S, Rossing MA, Weiss NS.
Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, Washington, USA.
Ann Surg 1997 Jan;225(1):69-75 Abstract quote
BACKGROUND: Information is limited on the risk of contralateral breast cancer after a diagnosis of breast carcinoma in situ (BCIS). METHODS: In western Washington, between 1974 and 1993, 1929 women with a first primary ductal carcinoma in situ (DCIS) and 282 women with a first primary lobular carcinoma in situ (LCIS) were followed for contralateral breast cancer. Rates of contralateral invasive breast cancer and BCIS were compared with population rates of first primary breast cancer using Poisson regression to adjust for age and calendar year.
RESULTS: The rate of contralateral invasive disease after BCIS was approximately twice the population rate for women with DCIS and three times the population rate for women with LCIS; relative rates decreased somewhat with increasing time since diagnosis of LCIS, but were fairly stable after DCIS. The relative rate of contralateral DCIS after BCIS was substantially higher than for contralateral invasive disease, but dropped dramatically after the first year after the initial BCIS, especially among women with LCIS. Contralateral BCIS usually was of the same histologic type as the initial BCIS; histologic concordance of BCIS was 71% for women with an initial LCIS and 78% for women with DCIS.
CONCLUSIONS: Data suggest that the rate of contralateral invasive breast cancer is elevated for at least 5 years after a diagnosis of BCIS compared with the rate of first primary breast cancer in the population, and that the rate is only slightly higher for women with LCIS than for women with DCIS. The markedly elevated rate of contralateral DCIS may result in large part from increased medical surveillance of women diagnosed with BCIS, especially during the first year after the initial diagnosis.
INVASIVE CARCINOMA PROGRESSION
7/28 women with DCIS treated only with biopsy developed invasive carcinoma in the same breast after an average interval of 6.1 years
Risk of subsequent invasive cancer in the contralateral breast is 3.4%
The clinical behavior of breast carcinoma is probably determined at the preinvasive stage (ductal carcinoma in situ).
Gupta SK, Douglas-Jones AG, Fenn N, Morgan JM, Mansel RE.
Department of Surgery, University of Wales College of Medicine, Cardiff, South Glamorgan, United Kingdom.
Cancer 1997 Nov 1;80(9):1740-5 Abstract quote
BACKGROUND: Mammography has greatly increased the number of women diagnosed with ductal carcinoma in situ (DCIS) of the breast. New classifications of DCIS recently have been proposed. In this study, these classifications were applied to DCIS associated with invasive tumors and correlated with patient prognosis.
METHODS: Three hundred cases of infiltrating ductal carcinoma of the breast in which there was associated DCIS in the surrounding breast were studied. The DCIS was classified as well, moderately, or poorly differentiated, according to two recently published systems using the cytonuclear features of the malignant cells (Holland classification) and cytology and the presence of necrosis (Van Nuys classification).
RESULTS: The differentiation of DCIS was significantly correlated with the grade of the invasive carcinoma (P < 0.0001), the Nottingham prognostic index (P < 0.0001), and the clinical outcomes of the patients (P < 0.0001).
CONCLUSIONS: These findings indicate that a model in which there is increasing in situ dysplasia before the development of stromal invasion is incorrect for breast carcinoma. Rather, in most cases, well-differentiated DCIS probably gives rise to low grade invasive breast carcinoma with a better long term clinical outcome. These data suggest that many of the important prognostic biologic and genetic characteristics of breast carcinoma are already established in the neoplastic clones of malignant cells at the preinvasive stage of the disease.
Histologic and Radiographic Analysis of Ductal Carcinoma In Situ Diagnosed Using Stereotactic Incisional Core Breast Biopsy
Michelle Bonnett, M.D., Tracy Wallis, B.S., Michelle Rossmann, M.D., Nat L. Pernick, M.D., Kathryn A. Carolin, M.D., Mark Segel, M.D., David Bouwman, M.D. and Daniel Visscher, M.D.
Departments of Pathology (MB, TW, NLP, DV), Surgery (KC, DB), and Radiology (MR, MS), Karmanos Cancer Institute and Wayne State University School of Medicine, Detroit, Michigan
Mod Pathol 2002;15:95-101 Abstract quote
Background: Stereotactic incisional core breast biopsy (SCBB) is a highly specific technique for diagnosing ductal carcinoma in situ (DCIS) in patients with suspicious mammographic microcalcifications. However, its sensitivity for excluding the presence of coexisting occult invasive disease in this setting is not fully established.
Design: We correlated SCBB findings to subsequent lumpectomy/mastectomy (lx/mx) results in 122 cases of DCIS. In 29 of these cases, the SCBB showed microscopic invasion (n = 15) or foci that were suspicious for invasion (n = 14). Likelihood for invasive disease in subsequent lx/mx samples from each case then was compared with various parameters, including DCIS grade, extent and mammographic findings.
Results: Overall, 13% of cases in which the SCBB showed DCIS only (i.e., without any evidence of invasion), had invasive disease in the subsequent excision. This finding was significantly correlated with DCIS grade (low: 0/26 [0%], intermediate: 2/31 [6%], high: 10/36 [28%], P < .001). Invasive lesions were usually small (nine T1a, one T1b, and two T1c) and typically present within more extensive fields of DCIS (no invasion: 1.5 cm DCIS size; invasion: 2.8 cm mean DCIS size, P = .01). This was reflected by greater extent of involvement in the SCBB (5/8 cases with invasion had >15 ducts involved, versus 4/23 with <15 ducts involved, P = .03). SCBB that were suspicious or positive for microinvasion demonstrated invasion in most subsequent excision (susp: 7/14 [50%], microinv: 11/15 [73%]), generally of significant extent (11/18 T1b-c).
Conclusions: 1. Patients with SCBB showing high grade DCIS and DCIS suspicious or positive for microinvasion have a significant and high likelihood, respectively, of harboring occult invasive neoplasm. They should accordingly be carefully evaluated radiographically, and possibly with sentinel node biopsy to facilitate axillary staging. 2. Likelihood of occult invasion is correlated with overall DCIS size/extent.
Ductal Carcinoma In Situ of the Breast: A Comparative Analysis of Histology, Nuclear Area, Ploidy, and Neovascularization Provides Differentiation Between Low- and High-Grade Tumors
Amparo Ruiz, MD,* Sergio Almenar, MD, Miguel Cerdá, MD,* Juan José Hidalgo, MD,* Alfonso Puchades, MD, and Antonio Llombart-Bosch, MD
Breast J 2002;8:139 Abstract quote
Ductal carcinoma in situ (DCIS) is a heterogeneous group of lesions that has been subdivided into three types: well differentiated (grade I), moderately differentiated (grade II), and poorly differentiated (grade III). Forty-five cases of DCIS were analyzed for image analysis: nuclear area, DNA ploidy, and vascularization in order to establish a more precise correlation between the histologic grade and these morphometric parameters.
Our results confirm that the mean nuclear area, DNA ploidy, and microvessel density (MVD) progressively increased from DCIS grade I to DCIS grade III. The analysis of the nuclear area in relationship to DCIS grading demonstrated a progressive increase of values between grades I/II to grade III, but these data have no statistical significance. An analysis of DNA ploidy demonstrated significant differences between grades I/III (p < 0.05), but there was no statistical significance between grades I/II, grades II/III, or both (p > 0.005). The analysis of MVD was extremely significant between grades I/III (p < 0.001) and grades II/III (p < 0.001), but between grades I/II, these values showed no significant differences (p > 0.05).
Based on this study, it can be concluded that image analysis techniques confirm how DCIS presents morphometric values that increase from DCIS grade I to DCIS grade III and that within this spectrum, DCIS grade III can be identified as a group of tumors presenting a large nuclear area, aneuploid DNA, and abundant vascular neogenesis, confirming that this neoplasm displays more aggressive patterns than the other two types. These criteria should justify a higher rate of tumor progression to DCIS grade III.
Although by definition, this tumor has not spread beyond the confines of the duct, there are cases of metastases to local axillary regional lymph nodes
These cases may represent a missed focus of microinvasion
TREATMENT Dependent upon the VNPI stage
Am J Surg Pathol. 2005 Dec;29(12):1625-1632. Abstract quote
In breast conservation therapy, the margin status of the specimen predicts local recurrence and determines the need for reexcision. Many surgeons now take, at the time of lumpectomy, multiple separate "cavity margins" (CM) (the entire wall of the residual cavity) as final margins that supersede the oriented lumpectomy margins (LMs).
We studied the efficacy of this method in 126 patients (23 with ductal carcinoma in situ [DCIS] only and 103 with invasive carcinoma with or without DCIS) who had an oriented lumpectomy specimen and also had four to six additional CMs. The tumors were evaluated for the following: size, grade, LM status (distance of tumor from margin and, if involved, extent of involvement), vascular invasion, lymph node status, and presence or absence of extensive intraductal component. The additional CM specimens were evaluated for residual carcinoma (if any) and its distance from the inked true margins, and the results were correlated with the corresponding LMs.
Only approximately 50% of patients (52 of 103) with histologically positive LMs (defined as carcinoma within 2 mm of the inked surface) had residual carcinoma in their CMs. Additional CM sampling rendered the overall final margin status histologically negative in 61 of 103 (59%) cases with histologically positive LMs, therefore significantly reducing the need for reexcision.
Younger patient age, higher number of positive LMs, high tumor grade, and the presence of extensive intraductal component were predictive of residual carcinoma in CM specimens, whereas the distance of carcinoma from the inked surface and the extent of tumor involvement of histologically positive LMs were not. Because CM specimens taken from patients with histologically positive LMs usually lack tumor, we suspect that many positive LMs are likely false positives.
Possible factors accounting for false-positive LMs include seepage of ink into crevices of the specimen promoted by excessive inking, tumor friability promoting displacement of tumor into ink, manipulation of specimens for radiographs, and retraction artifact.
Mammographically detected ductal carcinoma in situ treated with conservative surgery with or without radiation therapy: patterns of failure and 10-year results.
Kestin LL, Goldstein NS, Martinez AA, Rebner M, Balasubramaniam M, Frazier RC, Register JT, Pettinga J, Vicini FA.
Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.
Ann Surg 2000 Feb;231(2):235-45 Abstract quote
OBJECTIVE: The authors reviewed their institution's experience treating mammographically detected ductal carcinoma in situ (DCIS) of the breast with breast-conserving therapy (BCT) to determine 10-year rates of local control and survival, patterns of failure, and factors associated with outcome.
SUMMARY BACKGROUND DATA: From January 1980 to December 1993, 177 breasts in 172 patients were treated with BCT for mammographically detected DCIS of the breast at William Beaumont Hospital, Royal Oak, Michigan.
METHODS: All patients underwent an excisional biopsy, and 65% were reexcised. Thirty-one breasts (18%) were treated with excision alone, whereas 146 breasts (82%) received postoperative radiation therapy (RT). All patients undergoing RT received whole-breast irradiation to a median dose of 50.0 Gy. One hundred thirty-six (93%) received a boost to the tumor bed for a median total dose of 60.4 Gy. Median follow-up was 5.9 years for the lumpectomy alone group and 7.2 years for the lumpectomy + RT group.
RESULTS: In the entire population, 15 patients had an ipsilateral breast recurrence. The 5- and 10-year actuarial rates of ipsilateral breast recurrence were 7.8% and 7.8% for lumpectomy alone and 8.0% and 9.2% for lumpectomy + RT, respectively. Eleven of the 15 recurrences developed within or immediately adjacent to the lumpectomy cavity and were designated as true recurrences or marginal misses (TMM). Four recurred elsewhere in the breast. Eleven of the 15 recurrences were invasive, whereas 4 were pure DCIS. Only one patient died of disease, yielding 5- and 10-year actuarial cause-specific survival rates of 100% and 99.2%, respectively. Eleven patients were diagnosed with subsequent contralateral breast cancer, yielding 5- and 10-year actuarial rates of 5.1% and 8.3%, respectively. Clinical, pathologic, and treatment-related factors were analyzed for an association with ipsilateral breast failure or TR/MM. No factors were significantly associated with ipsilateral breast failure. In the entire population, the omission of RT and younger age at diagnosis were significantly associated with TR/MM. Patients younger than 45 years at diagnosis had a significantly higher rate of TR/MM in both the lumpectomy + RT and lumpectomy alone groups. None of the 37 patients who received a postexcisional mammogram had an ipsilateral breast failure versus 15 in the patients who did not receive a postexcisional mammogram.
CONCLUSIONS: Patients diagnosed with mammographically detected DCIS of the breast appear to have excellent 100-year rates of local control and overall survival when treated with BCT. These results suggest that the use of RT reduces the risk of local recurrence and that patients diagnosed at a younger age have a higher rate of local recurrence with or without the use of postoperative RT.
Salvage treatment for local recurrence after breast-conserving surgery and radiation as initial treatment for mammographically detected ductal carcinoma in situ of the breast.
Solin LJ, Fourquet A, Vicini FA, Haffty B, Taylor M, McCormick B, McNeese M, Pierce LJ, Landmann C, Olivotto IA, Borger J, de La Rochefordiere A, Schultz DJ.
Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Cancer 2001 Mar 15;91(6):1090-7 Abstract quote
BACKGROUND: The purpose of the current study is to evaluate the outcome of salvage treatment for local recurrence after breast-conserving surgery and radiation as initial treatment for mammographically detected ductal carcinoma in situ (DCIS; intraductal carcinoma) of the breast.
METHODS: An analysis was performed of 42 patients with local only first failure (n = 41) or local-regional only first failure (n = 1) after breast-conserving surgery and radiation treatment had been given for DCIS of the breast. Surgical treatment at the time of local recurrence included mastectomy (n = 37; 88%) or excision (n = 5; 12%). Adjuvant systemic therapy at the time of local recurrence was chemotherapy (n = 3; 7%), tamoxifen (n = 8; 19%), both (n = 1; 2%), none (n = 29; 69%), or unknown (n = 1; 2%). The median interval from the time of initial treatment to local recurrence was 4.8 years (range = 1.0-15.2 yrs). The median follow-up after salvage treatment was 4.5 years (range = 0.2-12.8 yrs).
RESULTS: At the time of the local recurrence, 22 patients (52%) had invasive ductal carcinoma, 18 patients (43%) had DCIS, 1 patient (2%) had invasive lobular carcinoma, and 1 patient (2%) had angiosarcoma. After salvage treatment, the rate of overall survival and the rate of cause specific survival for all 42 patients were 92% at both 5- and 8-years after treatment. The rate of freedom from distant metastases was 89% at 5 and 8 years. Favorable prognostic factors after salvage treatment were DCIS as the histology of the local recurrence and mammography only as the method of detection of the local recurrence.
CONCLUSIONS: The results of salvage treatment in the current study demonstrated that local recurrences were salvaged with high rates of survival and freedom from distant metastases. These results support the use of breast-conserving surgery and radiation for initial management of DCIS of the breast.
Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the national surgical adjuvant breast and bowel project experience.
Fisher B, Land S, Mamounas E, Dignam J, Fisher ER, Wolmark N.
National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA, USA.
Semin Oncol 2001 Aug;28(4):400-18 Abstract quote
The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted two sequential randomized clinical trials to aid in resolving uncertainty about the treatment of women with small, localized, mammographically detected ductal carcinoma in situ (DCIS).
After removal of the tumor and normal breast tissue so that specimen margins were histologically tumor-free (lumpectomy), 818 patients in the B-17 trial were randomly assigned to receive either radiation therapy to the ipsilateral breast or no radiation therapy.
B-24, the second study, which involved 1,804 women, tested the hypothesis that, in DCIS patients with or without positive tumor specimen margins, lumpectomy, radiation, and tamoxifen (TAM) would be more effective than lumpectomy, radiation, and placebo in preventing invasive and noninvasive ipsilateral breast tumor recurrences (IBTRs), contralateral breast tumors (CBTs), and tumors at metastatic sites.
The findings in this report continue to demonstrate through 12 years of follow-up that radiation after lumpectomy reduces the incidence rate of all IBTRs by 58%. They also demonstrate that the administration of TAM after lumpectomy and radiation therapy results in a significant decrease in the rate of all breast cancer events, particularly in invasive cancer.
The findings from the B-17 and B-24 studies are related to those from the NSABP prevention (P-1) trial, which demonstrated a 50% reduction in the risk of invasive cancer in women with a history of atypical ductal hyperplasia (ADH) or lobular carcinoma in situ (LCIS) and a reduction in the incidence of both DCIS and LCIS in women without a history of those tumors.
The B-17 findings demonstrated that patients treated with lumpectomy alone were at greater risk for invasive cancer than were women in P-1 who had a history of ADH or LCIS and who received no radiation therapy or TAM. Although women who received radiation benefited from that therapy, they remained at higher risk for invasive cancer than women in P-1 who had a history of LCIS and who received placebo or TAM.
Thus, if it is accepted from the P-1 findings that women at increased risk for invasive cancer are candidates for an intervention such as TAM, then it would seem that women with a history of DCIS should also be considered for such therapy in addition to radiation therapy. That statement does not imply that, as a result of the findings presented here, all DCIS patients should receive radiation and TAM. It does suggest, however, that, in the treatment of DCIS, the appropriate use of current and better therapeutic agents that become available could diminish the significance of breast cancer as a public health problem.
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Proliferative Breast Disease
Van Nuys Prognostic Index-This is a commonly used grading system which stratifies DCIS into different risk and treatment strategies.
GRADE MARGINS SIZE NUCLEAR GRADE 1 >/= 10 mm </=15 mm Low grade, Intermediate grade without necrosis 2 1-9 mm 16-40 mm Low grade, Intermediate grade with necrosis 3 <1 mm >41 mm High grade with or without necrosis
SCORE TREATMENT OUTCOME (After 8 years) 3-4 Excision with negative margins 97-100% recurrence free 5-7 Excision with radiation (Leads to 17% decrease in recurrence) 85% recurrence free when treated with radiation after excision 8-9 Excision with radiation Local recurrence >60%
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