Breast Neoplasms: Dabbs DJ

Yaziji H, Taylor CR, Goldstein NS, Dabbs DJ, Hammond EH, Hewlett B, Floyd AD, Barry TS, Martin AW, Badve S, Baehner F, Cartun RW, Eisen RN, Swanson PE, Hewitt SM, Vyberg M, Hicks DG, Anonymous00020. · Vitro Molecular Laboratories, Miami, FL daggerKeck School of Medicine, University of Southern California, Los Angeles, USA. · Appl Immunohistochem Mol Morphol. · Pubmed #18931614 No free full text.

Abstract: Estrogen receptor (ER) status in breast cancer is currently the most important predictive biomarker that determines breast cancer prognosis after treatment with endocrine therapy. Although immunohistochemistry has been widely viewed as the gold standard methodology for ER testing in breast cancer, lack of standardized procedures, and lack of regulatory adherence to testing guidelines has resulted in high rates of "false-negative" results worldwide. Standardized testing is only possible after all aspects of ER testing--preanalytical, analytical, and postanalytical, have been closely controlled. A meeting of the "ad-hoc committee" of expert pathologists, technologists, and scientists, representing academic centers, reference laboratories, and various agencies, issued standardization testing recommendations, aimed at optimization of clinical ER testing environment, as a step toward improved standardized testing.

Chivukula M, Striebel JM, Erşahin C, Dabbs DJ. · Department of Pathology, Magee Women's Hospital of UPMC, Pittsburgh, PA 15213, USA. · Appl Immunohistochem Mol Morphol. · Pubmed #18542031 No free full text.

Abstract: The basal-like phenotype (BLP) subtype of breast carcinoma has been identified as 1 of 5 tumor subtypes first revealed by microarray profiling. This phenotype tends to be more aggressive, is more often associated with BRCA1 mutations, and carries a poor prognosis. Few studies have morphologically characterized BLP on resected breast specimens (RS), and no studies have evaluated these diagnostic parameters in core needle biopsies (CNB) of breast. We identified a group of 35 RS that demonstrated BLP by morphology and/or immunophenotype based on the criteria used in the literature. Retrospectively, we reviewed the CNB of these RS for the following morphologic features: growth pattern, nuclear grade, mitotic rate, presence of ductal carcinoma in situ, necrosis, and lymphocytic response. Of these histologic features, solid growth pattern [88.6% (31/35)] with nuclear grade 3 [100% (35/35)], marked lymphocytic infiltrate [74.3% (26/35)], and absence or <5% of ductal carcinoma in situ [91.4% (32/35)] were seen most consistently in all the CNB. Geographic necrosis was seen in almost half of the cases [48.6% (17/35)]. Lymphovascular invasion and squamoid differentiation were limited to a small number of cases. On the basis of our results, we propose using certain morphologic features (solid growth pattern, high nuclear grade, presence of marked lymphocytic infiltrate, and geographic necrosis) in recognizing BLP on CNB. Triple negativity of estrogen receptor, progesterone receptor, and HER2/neu combined with positive BLP immunohistochemical markers such as the cytokeratins (CK): CK17, CK14, CK5/6, and epidermal growth factor receptor, help to further confirm the diagnosis.

Bhargava R, Dabbs DJ. · Department of Pathology, Magee-Women Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. · Adv Anat Pathol. · Pubmed #17471116 No free full text.

Abstract: In recent years, the use of immunohistochemistry (IHC) in breast pathology has increased tremendously. It is not because the new genre of breast pathologists are less well trained than their "experienced" counterparts; it is mainly because of the demands of more accurate and precise diagnoses, identification of new entities and availability of novel antibodies. The main purpose of this review is to discuss the use of best available antibodies in diagnoses of breast epithelial lesions. The following items are discussed: assessment of invasion, IHC in papillary lesions, identification of breast tumor subtypes, IHC in proliferative breast lesions, assessment of lymphatic space invasion, diagnosis of metaplastic breast carcinoma, IHC in Paget disease, use of cytokeratins in sentinel lymph node assessment, and diagnosis of breast carcinoma at metastatic sites. Because the main focus of this review is on diagnosis, receptor studies on breast carcinoma are briefly discussed and only a few general comments are made.

Dabbs DJ. · Department of Pathology, Allegheny General Hospital, Pittsburgh, PA, USA. · Am J Clin Pathol. · Pubmed #11993711 No free full text.

Abstract: Fine-needle aspiration of the breast is one of the most common procedures performed on patients with a palpable breast mass. The pathologist needs to be aware of the diagnostic and prognostic parameters that must be included in the cytopathology report of breast carcinomas. These fundamental parameters include tumor type, nuclear grade of the carcinoma, and hormone receptor status.

Chivukula M, Bhargava R, Tseng G, Dabbs DJ. · Dept of Pathology, Magee Women's Hospital of UPMC, University of Pittsburgh, PA 15213, USA. · Am J Clin Pathol. · Pubmed #19461086 No free full text.

Abstract: Flat epithelial atypia (FEA) is an emerging entity of uncertain clinical significance, and outcome data are sparse. The aim of this study was to evaluate the clinicopathologic significance of this entity for proper management. All core needle biopsy (CNB) specimens diagnosed as atypical ductal hyperplasia (ADH) from January 2006 to April 2008 were retrieved. H&E-stained slides of 5 levels on each case were reviewed. The differences in upstaging in subsequent excisions in the FEA and ADH group (31/189 [16.4%]) vs the pure FEA group (5/35 [14%]) and pure FEA (5/35 [14%]) vs pure ADH (5/45 [11%]) were not statistically significant. We observed that FEA evolved into ADH at the same site at an average of 3 to 4 levels. Our study concludes that there is an association of FEA with ADH on multiple levels of CNB specimens, and follow-up surgical excision findings for FEA are clinically significant.

Esposito NN, Dabbs DJ, Bhargava R. · Department of Pathology, Magee-Womens Hospital of the University of Pittsburgh, Pittsburgh, PA, USA. · Am J Clin Pathol. · Pubmed #19141383 No free full text.

Abstract: Encapsulated papillary carcinoma (EPC) of the breast is traditionally considered a variant of ductal carcinoma in situ (DCIS). However, recent studies show EPCs lack myoepithelial cells at their periphery, leading some to conclude that EPCs are invasive. We used a robust collagen type IV immunohistochemical procedure to assess invasion in 21 cases of pure EPC and 6 EPCs with adjacent invasive ductal carcinoma (IDC) and compared these results with those for papilloma, DCIS, and IDC. Moderate to intense collagen type IV expression was seen in all EPCs and was absent or decreased in all IDCs. All patients with pure EPC had negative axillary nodes with the exception of 1 who had a micrometastasis, and all were alive with no evidence of disease at follow-up (mean, 40.4 months). EPCs are in situ carcinomas with an excellent prognosis and can be managed with local therapy with or without sentinel lymph node biopsy.

Bhargava R, Beriwal S, McManus K, Dabbs DJ. · Department of Pathology, Magee-Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. · Am J Clin Pathol. · Pubmed #18854264 No free full text.

Abstract: Multiple immunohistochemical stains, including cytokeratin (CK)5/6, are used in a panel format to identify "basal-like" carcinomas. We set out to determine the sensitivity and specificity of the CK5 antibody (clone XM26) and compared its expression with that of CK5/6 (clone D5/16B4) in a variety of breast carcinoma cases. The study was performed on 3 breast carcinoma tissue microarrays (TMAs). TMA-1 consisted of 59 consecutive breast carcinoma cases. TMA-2 (n = 16) and TMA-3 (n = 11) consisted of basal-like breast carcinomas previously characterized morphologically and immunohistochemically at our institution. Of the 86 total cases, 20 were positive for CK5 and CK5/6, 14 were positive for CK5 only, and 52 were negative for both. The sensitivity of CK5 for identifying basal-like tumors was 97% compared with 59% for CK5/6. Both antibodies had comparable specificity of more than 95%. For positive cases, the percentage and intensity of staining was much higher with CK5 than with CK5/6 (P = .0001).

Chivukula M, Haynik DM, Brufsky A, Carter G, Dabbs DJ. · Department of Pathology, Magee-Women's Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. · Am J Surg Pathol. · Pubmed #18769331 No free full text.

Abstract: Pleomorphic lobular carcinoma in situ (PLCIS) is a more recently characterized entity that mimics high-grade ductal carcinoma in situ (DCIS). PLCIS is sometimes treated similar to high-grade DCIS, but no consensus has been reached for the most appropriate treatment. The aim of this study is to evaluate the histologic and immunohistologic profile of pure PLCIS on core needle biopsies and present follow-up clinical data. We reviewed 12 cases of pure PLCIS diagnosed on core needle biopsies of the breast along with subsequent surgical resections. Histologically, all cases showed dyscohesive cells with grade 3 nuclei, prominent nucleoli, and moderate to abundant eosinophilic cytoplasm. A panel of immunohistochemical stains to study this entity included E-cadherin, P120 catenin, estrogen receptor, progesterone receptors, HER2/neu, and Ki-67 (MIB-1). Residual PLCIS was found on excisional biopsies in 83% (10/12) cases. Invasive lobular carcinoma was found in 25% (3/12) cases. The lobular nature of all cases was confirmed by negative E-cadherin and cytoplasmic-dominant staining with P120 catenin. PLCIS was positive for estrogen receptor in 92% (11/12); progesterone receptor in 50% (6/12), and Her2/neu was positive in 25% (3/12). A moderate to high proliferation activity was observed with MIB (Ki-67) staining in 92% (11/12) cases. We conclude that PLCIS has a lobular immunostaining pattern for P120 catenin and E-cadherin indicating disruption of the E-cadherin/P120 catenin complex. This entity has aggressive parameters similar to high-grade DCIS including grade 3 nuclei, high Ki-67 (MIB-1) index, and HER2/neu positivity. PLCIS has a significant association with other high-risk lesions and invasive lobular carcinoma.

Monaco SE, Dabbs DJ, Kanbour-Shakir A. · Department of Pathology, University of Pittsburgh Medical Center-Shadyside Hospital, 5230 Centre Avenue, WG02.1, Pittsburgh, PA 15232, USA. · Diagn Cytopathol. · Pubmed #18677762 No free full text.

Abstract: Pleomorphic lobular carcinoma (PLC) is a subtype of infiltrating lobular carcinoma because of its dyscohesiveness, linear infiltration pattern, and lack of membranous E-cadherin staining. However, it differs from classic lobular carcinoma because of its high-grade cytology and more aggressive clinical behavior. In breast fine-needle aspiration biopsies, PLC can be confused with invasive ductal carcinoma, particularly the apocrine variant. In this report, we illustrate how metastatic PLC in body fluid specimens shows many of the same cytomorphologic changes that occur in reactive/atypical mesothelial cells. Fortunately, the immunohistochemical staining pattern of PLC can help to distinguish it from other possible diagnoses in the differential, such as reactive/atypical mesothelial cells and other metastatic neoplasms. However, the frequent apocrine features seen in this variant of breast carcinoma can cause nonspecific immunohistochemical positivity that may make the interpretation difficult. This is the first report illustrating the cytopathology and immunohistochemical findings of pleomorphic lobular carcinoma in body cavity fluid cytology. Our case highlights the important issues and pitfalls to be aware of when making this diagnosis.

Carley AM, Chivukula M, Carter GJ, Karabakhtsian RG, Dabbs DJ. · Department of Pathology, Magee Women's Hospital of UPMC, Pittsburgh, PA 15213, USA. · Am J Clin Pathol. · Pubmed #18628095 No free full text.

Abstract: Lobular neoplasia (LN) and columnar cell alterations (CCAs) may share similar genetic abnormalities, but there is no appreciable literature that addresses the simultaneous occurrence of these lesions in breast core biopsy (CNB) specimens or resection specimens. Three groups of breast tissue were examined: group 1, 68 CNB specimens targeted for "suspicious" microcalcifications (Breast Imaging Reporting and Data System [BI-RADS] 4) and diagnosed with LN; group 2, 2,516 CNB reports for a 1-year period; and group 3, 400 consecutive breast carcinoma resection specimens analyzed for LN and CCAs within the vicinity of carcinoma. In group 1, LN was associated with CCAs in 54% of cases (37/68). In group 2, LN was found in association with CCA in 1.3% of cases (32/2,516). In group 3, 13.0% of cases of CCAs (52/400) were associated with LN. Our study suggests the association of these two lesions in breast tissue is nonrandom and that they may have a common progenitor pathway of neoplastic development.

Onuma K, Dabbs DJ, Bhargava R. · Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. · Int J Gynecol Pathol. · Pubmed #18580321 No free full text.

Abstract: Mammaglobin (MGB), a secretory protein belonging to the uteroglobin/Clara cell protein family, is a sensitive marker for breast carcinoma, but is also reported to be expressed in the female genital tract and its neoplasms. Details of MGB expression pattern and its pathologic significance in the female genital tract have not been systematically studied. To investigate the potential use of MGB in gynecologic pathology practice, we tested MGB expression by immunohistochemistry on 47 endocervical adenocarcinomas (whole tissue sections of 13 invasive and 35 in situ) and 55 endometrial carcinomas (39 endometrioid and 16 nonendometrioid represented on a single tissue microarray). Nonneoplastic endocervical and endometrial tissues were also evaluated for MGB expression. MGB expression was detected in thirty (77%) of 39 of endometrioid endometrial adenocarcinomas compared with 4 (31%) of 13 endocervical adenocarcinomas. MGB was mostly negative in nonendometrioid endometrial carcinoma (negative in 14 [88%] of 16). Endocervical adenocarcinoma in situ (AIS) showed either weak (predominantly) or moderate (occasionally) expression in about 40% of the cases in comparison with strong positivity in benign endocervical glandular epithelium. Reduction of MGB staining was seen in transition from benign epithelium to AIS. These results confirm that MGB is not specific for breast carcinoma, but is also variably expressed in nonneoplastic and neoplastic endocervical and endometrial tissues. Frequent MGB expression in endometrioid endometrial adenocarcinoma is significantly different from nonendometrioid carcinoma. Hormone receptor status is not associated with MGB expression in endometrial carcinomas. Most endocervical adenocarcinomas are negative for MGB, in contrast to mostly positive endometrioid endometrial adenocarcinomas, however, MGB expression alone is not specific enough to distinguish these 2 tumor types. MGB expression is altered in neoplastic endocervical epithelium compared with normal, and may indicate its decreased expression in the process of early carcinogenesis. MGB may be a promising new adjunctive marker in gynecologic pathology.

Flanagan MB, Dabbs DJ, Brufsky AM, Beriwal S, Bhargava R. · Department of Pathology, Magee-Women's Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. · Mod Pathol. · Pubmed #18360352 No free full text.

Abstract: Oncotype DX is a commercially available reverse transcriptase-polymerase chain reaction based assay that provides a Recurrence Score (RS) and has been shown to provide prognostic and predictive information in estrogen receptor-positive lymph node-negative breast cancers. Independent studies of its utility in routine practice are lacking. Slides and surgical pathology reports from 42 cases of breast carcinomas evaluated by Oncotype DX were retrospectively reviewed to determine patient age, tumor size, histologic grade, estrogen and progesterone receptor (ER and PR) and ERBB2 (HER-2/neu) data, with ER and PR reported as a semi-quantitative score reflecting both intensity of staining and proportion of positive cells. We show here that Recurrence Score is significantly correlated with tubule formation, nuclear grade, mitotic count, ER immunohistochemical score, PR immunohistochemical score, and HER-2/neu status, and that the equation RS=13.424+5.420 (nuclear grade) +5.538 (mitotic count) -0.045 (ER immunohistochemical score) -0.030 (PR immunohistochemical score) +9.486 (HER-2/neu) predicts the Recurrence Score with an R2 of 0.66, indicating that the full model accounts for 66% of the data variability. Although the Oncotype DX Recurrence Score holds potential, further validation of its independent value beyond that of histopathologic analysis is necessary before it can be implemented in clinical decision making.

Striebel JM, Bhargava R, Horbinski C, Surti U, Dabbs DJ. · Department of Pathology, Magee-Womens Hospital, Pittsburgh, PA 15213, USA. · Am J Clin Pathol. · Pubmed #18285260 links to  free full text

Abstract: To our knowledge, there are no universally accepted, evidence-based guidelines for how to resolve the HER2 status of tumors demonstrating equivocal amplification. The present study was based on 17 breast core biopsy specimens demonstrating invasive carcinoma with equivocal HER2 amplification, defined as an HER2/chromosome 17 centromere ratio of 1.8 to 2.2. Each case had a corresponding resection specimen, on which HER2 immunohistochemical and repeated fluorescence in situ hybridization analyses were performed. A definitive change in HER2 status based on the resection specimen occurred in 10 (59%) of 17 cases, with 4 patients (24%) becoming eligible for trastuzumab therapy and 6 (35%) triaged as ineligible. These results suggest that genetic and protein expression heterogeneity exists in tumors that show low-level HER2 gene copy numbers. For the purposes of uniform clinical management, HER2 status should be evaluated on a larger tumor sample if the core biopsy specimen demonstrates an equivocal result. These results support the recent American Society of Clinical Oncology/College of American Pathologists recommendations for further testing in cases with equivocal HER2 results.

Chivukula M, Bhargava R, Brufsky A, Surti U, Dabbs DJ. · Department of Pathology, Magee Women's Hospital of UPMC, Pittsburgh, PA 115213, USA. · Mod Pathol. · Pubmed #18246053 links to  free full text

Abstract: HER2 oncoprotein is overexpressed in 15-20% of breast carcinomas and is associated with poor outcome. The 2+ group is considered equivocal, since gene amplification is observed in some but not others. The aim of our study is to ascertain if there is clinical significance to heterogeneity of HER2 immunohistologic expression in breast core-needle biopsies vs surgical resection specimens. A total of 37 invasive breast carcinomas diagnosed on core-needle biopsies and scored 2+ by HER2 immunohistochemical assay were selected from our files. The results were obtained on these selected cases, of which 19 cases were nonamplified and 18 cases were amplified. The follow-up resection specimens were reviewed and two additional tumor blocks were selected in each case for HER2 immunostaining. The 74 tissue blocks were examined for HER2 using antibody clone CB11 on the Benchmark XT and scored as negative (score 0 or 1+), weakly positive (2+) or strongly positive (3+). Results within the amplified group, 56% (11/18) showed significant areas with 3+ score in both blocks, 28% (5/18) remained as 2+, 11% (2/18) showed score 0-1+. In the nonamplified group, 42% (8/19) had score 0-1+, 37% (7/19) remained as 2+, 0% (0/19) had score 3+. Five (5) cases showed heterogeneous staining in both the groups. In the amplified group, 56% of cases showed strong 3+ in both the blocks of which half of these cases had areas of 2+. Fluorescence in situ hybridization was performed on a representative resection specimen block. In the amplified group 72% (13/18) cases were amplified, 22% (4/18) were nonamplified. In the nonamplified group, no amplification is detected in a great majority of cases 89% (17/19). HER2 immunohistochemistry on core-needle biopsies is usually predictive of tumor HER2 status. However, performing fluorescence in situ hybridization on core-needle biopsies almost completely resolves the issue of heterogeneous expression of HER2.

Dabbs DJ, Kaplai M, Chivukula M, Kanbour A, Kanbour-Shakir A, Carter GJ. · Department of Pathology, Magee-Women's Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. · Appl Immunohistochem Mol Morphol. · Pubmed #17721269 No free full text.

Abstract: Pleomorphic lobular carcinoma of the breast is a high nuclear grade variant of lobular carcinoma. E-cadherin, a tumor-invasion suppressor gene, codes for a transmembrane protein that functions in intercellular adhesion. The E-cadherin protein internal domain binds with alpha, beta, gamma, and p120 catenins to anchor the E-cadherin complex to the actin cytoskeleton of the cell. The E-cadherin gene is routinely mutated in lobular neoplasia. This study examines the morphomolecular spectrum of the components of the E-cadherin-catenin complex in lobular neoplasia. Fifteen cases of pleomorphic lobular neoplasia, 8 cases of classic lobular neoplasia and 4 ductal carcinomas were studied. Normal breast epithelium and invasive ductal carcinomas all showed intense linear cell membrane immunostaining with antibodies to E-cadherin, alpha, beta, gamma, and P120 catenins. Membrane immunostaining of the catenin antibodies in lobular neoplasia was negative, except for rare cases that displayed beaded or dotlike patterns. Cytoplasmic immunostaining patterns for all lobular lesions included coarse paranuclear granules of beta catenin or diffuse intense cytoplasmic staining for P120 catenin. These immunostaining patterns demonstrate that catenins alpha, beta, gamma, and p120 are routinely dislocated from the cell membrane into the cytoplasm in lobular neoplasia and that the disrupted catenin patterns parallel absence of membrane E-cadherin in all cases. The diffuse cytoplasmic immunostaining of p120 in lobular neoplasia may be useful diagnostically as a positive marker for lobular neoplasia.

Powell WC, Hicks DG, Prescott N, Tarr SM, Laniauskas S, Williams T, Short S, Pettay J, Nagle RB, Dabbs DJ, Scott KM, Brown RW, Grogan T, Roche PC, Tubbs RR. · Ventana Medical Systems Inc,; Tucson, AZ, USA. · Appl Immunohistochem Mol Morphol. · Pubmed #17536315 No free full text.

Abstract: The 2 methodologies in current clinical use to assess HER2 status in breast cancer are: fluorescence in situ hybridization (FISH) (gene amplification) and immunohistochemistry (protein over-expression). A consistent finding has been that 3% to 15% of breast cancers over-express HER2 protein without evidence for gene amplification. Accurate determination of the HER2 status has implications for selecting patients most likely to respond to trastuzumab. We report here our preliminary experience with a new anti-HER2 rabbit monoclonal antibody, 4B5. The evaluation of HER2 status in 2 different cohorts of breast cancer cases (Single Institution (SI) and Multinational (MN)) with a total of 322 breast cancer cases was performed on an automated staining system (Ventana Medical Systems, Inc, Tucson, AZ) and scored by 3 pathologists (0-3+), for comparison with CB11 staining results (PATHWAY) and FISH (PathVysion). Interlaboratory reproducibility of automated staining results and interpretation was determined on a subset of the SI cohort at 3 separate laboratories. Rabbit monoclonal 4B5 demonstrated sharper membrane staining with less cytoplasmic and stromal background staining than CB11. In the SI cohort, the staining results for 4B5 were highly comparable with those obtained for CB11 with an overall concordance of 93.3%. In the multinational cohort, the overall concordance with CB11 was 84.7%. This lower level of concordance was associated with a much higher overall agreement of 4B5 with FISH (89.5%), compared with agreement of CB11 with FISH (81.2%). The difference in the performance of CB11 in the MN cohort versus the SI cohort may be due to differences in tissue fixation and processing in a centralized, high volume laboratory in an academic medical center versus multiple sites in the international community with potentially nonstandardized techniques. The staining results with 4B5 indicate that it has a more robust performance than CB11 because the correlation of 4B5 with FISH was nearly equivalent (88.2% MN; 89.3% SI) in both cohorts. Interlaboratory reproducibility was also excellent (kappa 1.0). RMoAb 4B5 provides excellent sensitivity, specificity, and interlaboratory reproducibility for the detection of HER2 status in breast cancer.

Karabakhtsian RG, Johnson R, Sumkin J, Dabbs DJ. · Department of Pathology, Magee-Women's Hospital of UPMC, Pittsburgh, PA 15213, USA. · Am J Surg Pathol. · Pubmed #17460455 No free full text.

Abstract: A core biopsy diagnosis of atypical ductal epithelial hyperplasia is upstaged on follow-up excisional biopsy (FUEB) to in situ or invasive carcinoma in about 20% of cases, thus prompting a FUEB. In contrast, upstaging information for a core biopsy diagnosis of pure lobular neoplasia (LN), without mass lesions or other risk-associated lesions is less clear. In this retrospective study, we report the largest consecutive series of patients who had a breast core biopsy diagnosis of LN and a FUEB. Core needle breast biopsies with a diagnosis of LN were retrieved from our files for the period 1999 to 2005, yielding 110 patients. One hundred and one patients had a follow-up surgical excision. Cases of LN with coexisting high-risk lesions (n=9, 10%) were excluded from the study. Patients with associated mass lesions all had benign findings (n=15, 16%) and had no impact on the study results. The remaining 77 core biopsies had no masses or risk lesions and were mammographically Breast Imaging Reporting and Data System 4 (BIRADS) for microcalcifications. Overall, 8/77 (10%) of patients with a radiographic BIRADS 4 image with calcifications and a core biopsy diagnosis of LN on core biopsy were upstaged on FUEB to ductal carcinoma in situ or invasive carcinoma. The numbers upstaged from core biopsies were as follows: atypical lobular hyperplasia (ALH) 4/52 (8%), mixed ALH/lobular carcinoma in situ (LCIS) 1/9 (10%), and pure LCIS 3/16 (19%). A core biopsy of LCIS with neoplastic epithelial calcifications was nearly 3 times more likely to be upstaged on FUEB compared with ALH. We conclude that a finding of LN on breast core biopsy in a patient with a BIRADS 4 image and calcifications is associated with a risk of 8% to 19% of upstaging to a treatable disease on FUEB.

Dabbs DJ, Bhargava R, Chivukula M. · Department of Pathology, Magee-Women's Hospital of the University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. · Am J Surg Pathol. · Pubmed #17325485 No free full text.

Abstract: The distinction between lobular and ductal lesions of the breast is important in several circumstances. Diagnostic reproducibility of lobular versus ductal lesions, based on histology alone, is less than optimal. The proper distinction between atypical lobular hyperplasia, lobular carcinoma in situ and low-grade ductal carcinoma in situ is critical for patient management. Patients who have a core biopsy of invasive lobular carcinoma often have preoperative magnetic resonance imaging to prepare the surgeon for proper margin attainment. E-cadherin, a negative membrane marker for lobular neoplasia, is useful in the distinction of lobular versus ductal neoplasia, but as a negative marker, can be difficult to interpret in particularly challenging cases. In this study, we surveyed primary and metastatic ductal lesions (62) and lobular lesions (64) of the breast to determine if P120 catenin is useful in the diagnostic distinction between lobular and ductal neoplasia. Primary breast ductal and lobular preneoplastic and neoplastic lesions were immunostained with E-cadherin and P120ctn and independently classified as ductal or lobular lesions. In addition, a wide array of carcinomas of different types were surveyed with P120ctn in tissue microarrays to ascertain whether the cytoplasmic P120ctn immunostaining pattern observed in lobular neoplasia was unique. Accurate categorization of ductal versus lobular neoplasia in the breast with P120ctn immunostaining was effective in all cases. Separation of low-grade ductal carcinoma in situ from lobular neoplasia was efficient. Diagnostically, P120ctn was particularly useful in identifying early lesions of lobular neoplasia. Of the other tumors that may morphologically mimic lobular carcinoma, only the diffusely infiltrating variants of rectal and gastric carcinomas showed diffuse cytoplasmic P120ctn immunostaining. Caution should be exercised when examining tumors in metastatic sites with P120ctn, with the incorporation of an appropriate panel of immunostains.

Bhargava R, Beriwal S, Dabbs DJ. · Department of Pathology, Magee-Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. · Am J Clin Pathol. · Pubmed #17145637 links to  free full text

Abstract: There are limited data that compare the usefulness of mammaglobin with gross cystic disease fluid protein-15 (GCDFP-15) in the identification of breast carcinomas. Whole tissue sections of 29 breast carcinomas with matched lymph node metastases and 63 breast carcinomas on tissue microarray were stained with mammaglobin cocktail and GCDFP-15 antibodies. In addition, tissue microarrays (US Biomax, Rockville, MD) containing 544 different human tumors were also stained with the mammaglobin antibody cocktail. Positive staining was seen in 67 (55.4%) of 121 breast carcinomas with mammaglobin and in 28 cases (23.1%) with GCDFP-15. In the majority of cases, the staining intensity and number of cells staining were higher with mammaglobin than with GCDFP-15. Positive mammaglobin staining was also seen in 44 (8.1%) of 544 nonbreast tumors. Mammaglobin is a more sensitive marker than GCDFP-15 for breast carcinoma; however, it lacks the specificity of GCDFP-15.

Esposito NN, Chivukula M, Dabbs DJ. · Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA. · Mod Pathol. · Pubmed #17143261 links to  free full text

Abstract: Tubulolobular carcinoma is a type of mammary carcinoma that displays an admixture of invasive tubules and lobular-like cells. Previous reports have shown it to share clinical similarities to lobular carcinoma, whereas more recent studies have shown it to be E-cadherin positive. The aim of the current study was to further explore the immunophenotype of tubulolobular carcinoma, and to document its natural behavior. Nineteen cases of tubulolobular carcinoma and 10 cases each of tubular and lobular carcinoma were retrieved for comparison analysis. Immunohistochemistry was performed with antibodies against estrogen receptor, progesterone receptor, HER2/neu, 34betaE12, E-cadherin, and the catenins. Twenty-five percent of patients with tubulolobular carcinoma presented with greater than stage I disease, compared to 0 and 60% of patients with tubular and lobular carcinoma, respectively. Two patients with tubulolobular carcinoma had tumor recurrence, one of whom also developed metastasis. The majority of all carcinomas were estrogen and progesterone receptor positive. E-cadherin displayed membranous staining in all tubular and tubulolobular carcinomas, and was negative in all lobular carcinomas. Half of each carcinoma subtype displayed granular cytoplasmic 34betaE12 immunoreactivity. alpha-Catenin exhibited partial or complete membranous staining in all tubulolobular and tubular carcinomas, and was negative in all lobular carcinomas. beta-Catenin displayed membranous staining in tubulolobular and tubular carcinomas, whereas all lobular carcinomas had coarse cytoplasmic immunoreactivity. p120 and gamma-catenin displayed membranous staining in 100% of tubulolobular and tubular carcinomas and cytoplasmic staining in 100% of lobular carcinomas. Tubulolobular carcinoma of the breast is thus a distinct type of mammary carcinoma that displays both tubular and lobular patterns histologically but displays the membranous E-cadherin/catenin complex characteristic of the ductal immunophenotype. Tubulolobular carcinoma appears to be more aggressive than tubular carcinoma, as 16% of patients had lymph node metastases, although all were alive at a mean follow-up of 40 months.

Esposito NN, Mohan D, Brufsky A, Lin Y, Kapali M, Dabbs DJ. · Department of Pathology, University of Pittsburgh, Pittsburgh, Pa 15213, USA. · Arch Pathol Lab Med. · Pubmed #17090194 No free full text.

Abstract: CONTEXT: Phyllodes tumors (PTs) of the breast are biphasic neoplasms composed of epithelium and a spindle-cell stroma. Currently, PTs are classified as benign, borderline, or malignant based on histopathologic features. However, histologic classification does not always predict outcome. Objective.-To determine the prognostic value of a variety of clinicopathologic features and immunoreactivities in PTs. DESIGN: Sixteen benign, 8 borderline, and 6 malignant PTs with follow-up were examined for reactivity across a panel of immunohistochemical stains, including c-Kit, endothelin 1, p16, p21, p53, and Ki-67. Clinicopathologic features, including stromal cellularity, mitotic rate, and margin status, were also assessed. Tumor variables were compared among tumor subgroups and between tumors that did and did not recur. RESULTS: Of the 30 PTs, 4 recurred (1 benign, 2 borderline, 1 malignant). One patient with a malignant tumor died of metastatic disease 34 months after initial diagnosis. The overall positive rate of c-Kit immunoreactivity was 13% in benign, 63% in borderline, and 67% in malignant PTs. Endothelin 1 epithelial cytoplasmic staining was seen in 100% of benign, 50% of borderline, and 17% of malignant PTs. Additionally, p16, p21, p53, and Ki-67 were differentially expressed among benign, borderline, and malignant tumors. Positive surgical resection margins was the only variable that significantly predicted recurrent disease (P = .02). CONCLUSIONS: Stromal c-Kit positivity and epithelial endothelin 1 negativity are more often associated with malignant PTs; however, only positive margin status is significantly associated with tumor behavior.

Dabbs DJ, Chivukula M, Carter G, Bhargava R. · Department of Pathology, Magee-Women's Hospital of UPMC, Pittsburgh, PA 15213, USA. · Mod Pathol. · Pubmed #16941011 links to  free full text

Abstract: 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.

Dabbs DJ, Carter G, Fudge M, Peng Y, Swalsky P, Finkelstein S. · Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA. · Mod Pathol. · Pubmed #16400324 links to  free full text

Abstract: Columnar cell lesions of the breast include a morphologic spectrum of simple columnar cell change, columnar cell hyperplasia, columnar cell hyperplasia with atypia and ductal carcinoma in situ of micropapillary/cribriform type. Invasive carcinomas of low grade are often seen in association with this spectrum. The biologic significance of these lesions that are commonly found on breast biopsies is unknown. Three cases of formalin-fixed, paraffin-embedded breast tissues, each displaying the entire spectrum of columnar cell lesions through ductal carcinoma in situ and including foci of invasive carcinoma were microdissected at multiple sites to evaluate neoplasia progression. Minute tissue targets were microdissected (4-8/case) from unstained 4-microm thick recut paraffin sections and included non-neoplastic breast and sites of columnar cell change, hyperplasia, atypia, ductal carcinoma in situ and invasive carcinoma. Allelic imbalance for a broad panel of microsatellite markers in proximity to known tumor suppressor genes was quantitated using automated polymerase chain reaction/gel electrophoresis. Genomic loci evaluated 1p, 3p, 5q, 9p, 9q, 10q, 17p, 17q, 19q, 22q. The presence, topographic relationship and time course of mutational damage was correlated with columnar morphologic features. Detailed allelic imbalance information was obtained from each microdissection tissue target producing a detailed fingerprint of mutational damage in each case. Allelic damage was targeted predominately at 9q, 10q, 17p and 17q. Simple columnar cell change was without mutational changes and only present in one case of columnar cell hyperplasia. The remainder of the cases all show progressive accumulation of allelic damage in columnar cell changes with atypia, ductal carcinoma in situ and invasive carcinoma. The fractional mutation percentage increased progressively from columnar cell hyperplasia through invasive carcinoma. Low level of allelic imbalance was demonstrable in columnar cell lesions by the microdissection approach. A gradient of progressive mutational change could be delineated in each case manifesting allelic loss damage. Allelic loss damage appeared to preferentially target loci at 9q, 10q, 17p and 17q. The findings are consonant with the hypothesis that a select group of atypical columnar cell lesions are morphologic precursors to invasive carcinoma. Integrated molecular pathology analysis used here can help define the significance of columnar cell lesions and its role in breast cancer tumorigenesis on an individual patient basis.

Klepchick PR, Dabbs DJ, Bonaventura M, Falk J, Keenan D, Landsittel D, Johnson R. · Department of Surgery, Magee-Womens Hospital, 300 Halket St., Pittsburgh, PA 15213, USA. · Am J Surg. · Pubmed #15474442 No free full text.

Abstract: BACKGROUND: Routine intraoperative evaluation of sentinel lymph nodes (SLNs) in breast cancer suffers from lack of sensitivity and consumes both time and resources. Failure to perform immediate consultation requires node-positive patients to return for delayed dissection. METHODS: We sought to determine whether selective use of intraoperative pathology consultation (IOC), based on the surgeon's clinical suspicion for metastases, would be accurate, avoid unnecessary consultations, and have a similar rate of delayed axillary dissection. We performed a retrospective chart review of two cohorts of clinically node-negative patients with invasive breast cancer undergoing axillary lymph node dissection (ALND). Selective pathology evaluation was performed in the study group and mandatory evaluation in the control group. RESULTS: The axillary basins of 327 patients undergoing routine IOC were compared with those of 91 patients in whom selective IOCs were requested. Twenty-eight consultations (31%) were obtained in the selective group. Selective consultation changed intraoperative management in 11 of 28 patients (39%) compared to 46 of 327 (14%) in the routine group (P = 0.005). The mean SLN metastasis size was 9.6 mm compared to 1.5 mm in patients in whom consultation was deferred (P = 0.003). The need for delayed ALND (17% vs. 14%) was similar in both groups, and was determined by occult metastases that were not detected by either method. CONCLUSIONS: Selective use of IOC detects the majority of SLN macrometastases, avoids consultation that does not alter intraoperative management, and is not associated with an increased need for delayed ALND.

Dabbs DJ, Fung M, Johnson R. · Department of Pathology, Magee-Women's Hospital, University of Pittsburgh Medical Center Health Services, Pittsburgh, Pennsylvania 15213, USA. · Breast J. · Pubmed #15125743 No free full text.

Abstract: The sentinel lymph node (SLN) procedure is a method for ascertaining the axillary lymph node status in patients with breast cancer. Intraoperative examination of the SLN may be important, because a positive result directs surgery to a complete axillary lymph node dissection. Intraoperative cytologic examination (IOCE) is a method of intraoperative evaluation, although little data are available regarding the sensitivity of the method with respect to tumor size and the size of the SLN metastasis. All SLN cases for the years 1997-2002 at Magee-Womens Hospital were tabulated for primary breast carcinoma size, IOCE result, final histologic result, and size of the SLN metastasis. All SLNs had IOCE with touch imprints. Scrape SLN preparations and frozen sections were strongly discouraged. There were 748 SLN cases comprising 1576 SLNs that had IOCE, and there were 247 true positive SLN cases comprising 522 SLNs. Of the 247 true positive SLN cases, 111 had a positive IOCE (111/247; 45% sensitivity overall) and there were 136 false negatives. Of the 247 cases, 164 were SLN micrometastases < or =2.0 mm in size, and 44 (27%) of these were detected by IOCE, while the remaining 120 cases were false negative. Of the 83 SLN macrometastases (>2.0 mm), 66 (80%) were detected by IOCE, with 17 false negatives. In this series, 15 cases (2%) were given the IOCE diagnosis of atypical/defer, and all of these permanent sections were histologically positive. There were five IOCE-positive cases that were histologically negative. Of the 164 SLNs with micrometastases < or =2.0 mm, 17.6% (29/164) were < or =0.5 mm (6/29 [21.4%] were IOCE positive), 5.5% (9/164) were 0.51-1.0 mm (3/9 [33%] were IOCE positive), and 3.6% (6/164) were 1.1-2.0 mm (2/6 [33%] were IOCE positive). There were 83 SLNs with macrometastases larger than 2.0 mm, and 66/83 (80%) were detected by IOCE. In this group, 22% (18/83) were 2.1-5.0 mm (8/18 [44.4%] were IOCE positive) and 57.8% (48/83) were larger than 5.0 mm (41/48 [85%] were IOCE positive). The mean primary breast tumor size was 15.4 mm, with a mean SLN tumor size of 1.4 mm. There was a significant correlation with tumor size and the presence of SLN metastasis, and a significant correlation with tumor size and size of the SLN metastasis. There was a significant t correlation of primary tumor size and positive IOCE, with the group of negative IOCE cases having a mean tumor size of 14 mm and the positive IOCE group having a mean tumor size of 22 mm. The overall sensitivity of the method was 45%, specificity 99%, positive predictive value 0.99, and negative predictive value 0.80. Sensitivity of the IOCE procedure based on SLN tumor size is as follows: < or =0.5 mm, 21.4%; 0.51-1.0 mm, 33%; 1.1-2.0 mm, 33%; 2.1-5.0 mm, 44.4%; and >5.0 mm, 85%. Primary tumor size correlates with a positive SLN status and size of the SLN metastasis. Most false-negative IOCEs are due to micrometastases. Positive IOCE cases had a significantly larger SLN metastasis size (mean 8.0 mm) than the false-negative IOCE group (mean 1.4 mm). The IOCE of SLNs has a high negative predictive value, but this is a poor test for the detection of micrometastases, as this group accounts for the majority of false-negative IOCEs of breast SLNs.