Anatomic pathology selected abstracts

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Editors: Rouzan Karabakhtsian, MD, PhD, professor of pathology and director of the Women’s Health Pathology Fellowship, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Rachel Stewart, DO, PhD, assistant professor, Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington; Nicole Panarelli, MD, associate professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center; and Shaomin Hu, MD, PhD, pathology resident, Albert Einstein College of Medicine, Montefiore Medical Center.

Markers for differentiating triple-negative breast cancer from TTF1-negative 
lung adenocarcinoma

June 2019—Triple-negative breast cancer patients have an increased risk of developing visceral metastases and other primary nonbreast cancers, particularly lung cancer. The differential diagnosis of triple-negative breast cancer (TNBC) metastases and primary cancers from other organs can be difficult due to lack of a TNBC standard immunoprofile. The authors analyzed the diagnostic value of estrogen receptor, progesterone receptor, human epidermal growth factor receptor, thyroid transcription factor-1 (TTF1), napsin A, mammaglobin, gross cystic disease fluid protein 15 (GCDFP15), Sry-related HMG-box gene 10 (SOX10), GATA-binding protein 3 (GATA3), and androgen receptor in a series of 207 TNBC and 152 primary lung adenocarcinomas. All tested TNBCs were TTF1 and napsin A negative. When comparing TNBC- and TTF1-positive or -negative lung adenocarcinoma, SOX10 had the best sensitivity (62.3 percent) and specificity (100 percent) as a marker in favor of TNBC compared with lung adenocarcinoma, irrespective of TTF1 status (P < .0001). GATA3 had moderate sensitivity (30.4 percent) and excellent specificity (98.7 percent) and misclassified only two of 152 (1.3 percent) lung adenocarcinomas. GCDFP15 had moderate sensitivity (20.8 percent) and excellent specificity (98 percent) and misclassified only three of 152 (two percent) lung adenocarcinomas. Mammaglobin and androgen receptor had moderate sensitivities (38.2 and 30 percent, respectively), good specificities (81.6 and 86 percent, respectively), and misclassified 28 of 152 (18 percent) and 21 of 152 (14 percent) lung adenocarcinomas, respectively. In multivariate analysis, the best markers for distinguishing between SOX10-negative TNBC and TTF1- and napsin A-negative lung adenocarcinoma were GATA3 (odds ratio [OR], 33.5; 95 percent confidence interval [CI], 7.3–153.5; P < .0001) and GCDFP15 (OR, 31.7; 95 percent CI, 6.9–145.6; P < .0001). Only 13 of 207 (6.3 percent) TNBC cases did not express any of the aforementioned markers. On the basis of the authors’ results, the best sequential immunohistochemical analysis to differentiate TNBC from TTF1-negative lung adenocarcinoma is SOX10, followed by GATA3, and, finally, GCDFP15. This order is important in the diagnostic workup of small biopsies from lung nodules in women with a previous history of TNBC.

Laurent E, Begueret H, Bonhomme B, et al. SOX10, GATA3, GCDFP15, androgen receptor, and mammaglobin for the differential diagnosis between triple-negative breast cancer and TTF1-negative lung adenocarcinoma. Am J Surg Pathol. 2019;43(3):293–302.

Correspondence: Dr. Gaëtan MacGrogan at g.macgrogan@bordeaux.unicancer.fr

Novel gene fusions in secretory carcinoma of the salivary gland

Secretory carcinoma of the salivary gland is a low-grade malignancy associated with a well-defined clinical, histologic, immunohistochemical, and cytogenetic signature. Although the t(12;15) (p13;q25) translocation resulting in an ETV6-NTRK3 gene fusion is well documented, advances in molecular profiling in salivary gland tumors have led to the discovery of RET as another ETV6 gene fusion partner in secretory carcinoma. The authors applied an RNA-based next-generation sequencing approach for fusion detection to 14 presumed 
secretory carcinomas. The cases included seven secretory carcinomas with classic ETV6-NTRK3 gene fusion and three secretory carcinomas harboring an ETV6-RET gene fusion. Two cases revealed a NCOA4-RET gene fusion and were subsequently reclassified as intraductal carcinomas. One case with an unusual dual-pattern morphology revealed a novel translocation involving ETV6, NTRK3, and MAML3 gene rearrangements. Interestingly, no ETV6-NTRK3 or ETV6-RET secretory carcinoma was ever documented to have this unique dual-pattern morphology or harbor a MAML3 mutation. The remaining case had no detected chromosomal abnormalities. The authors concluded that advances in molecular profiling of secretory carcinoma have led to the discovery of novel fusion partners such as RET and now MAML3. Additional molecular characterization of salivary gland neoplasms is needed as these mutations may present alternative therapeutic targets in patients with these tumors.

Guilmette J, Dias-Santagata D, Nosé V, et al. Novel gene fusions in secretory carcinoma of the salivary glands: enlarging the ETV6 family. Hum Pathol. 2018;83:50–58.

Correspondence: Dr. P. M. Sadow at psadow@mgh.harvard.edu

Impact of updated ASCO/CAP guidelines on HER2 FISH testing in breast cancer

Human epidermal growth factor receptor 2 (HER2, ERBB2) is a valuable prognostic and predictive biomarker for breast cancer. Accurate assessment of HER2 status is essential in selecting patients with invasive breast cancer who will likely respond to HER2-targeted therapies. Major modifications in the diagnostic recommendation for FISH have been made in the updated 2018 American Society of Clinical Oncology/College of American Pathologists guideline on HER2 testing for invasive breast cancer. According to the revised guideline, concomitant immunohistochemistry assays are required to arrive at the most accurate HER2 status designation after HER2 FISH equivocal results. The authors conducted a study to evaluate the impact of the revised 2018 ASCO/CAP guideline on HER2 status designation. They retrospectively reviewed the HER2 FISH testing results from 2,233 cases of invasive breast cancer between January 2014 and December 2017. Concomitant IHC was performed on the same tissue blocks that were used for FISH testing. Compared with the 2013 guidelines, the HER2 status in 183 (8.2 percent) cases were redefined in the 2018 guidelines. Among those 183 cases, 175 cases that were equivocal according to the 2013 guidelines were redefined as HER2 negative (n = 173) or HER2 positive (n = 2). Eight cases previously classified as HER2 positive were converted to negative in the 2018 guidelines, all of which had HER2 IHC scores of 1+ or 2+. The number of cases in the negative category was 1,705 according to the 2018 guidelines, as opposed to 1,524 by the 2013 guidelines. The updated 2018 ASCO/CAP guideline eliminated the FISH equivocal category, which can be attributed to reflex HER2 IHC. Reflex IHC for FISH equivocal cases is of prime importance. Furthermore, HER2 FISH results were converted from positive to negative based on the concomitant IHC results in a small percentage of cases. The authors concluded that the 2018 ASCO/CAP guidelines provide much clearer instructions and recommendations for HER2 status designation than the 2013 guidelines and, therefore, reduce the risk of misdiagnosis.

Liu ZH, Wang K, Lin DY, et al. Impact of the updated 2018 ASCO/CAP guidelines on HER2 FISH testing in invasive breast cancer: a retrospective study of HER2 FISH results of 2233 cases. Breast Cancer Res Treat. 2019;175(1):51–57.

Correspondence: Dr. Fang-Ping Xu at xfpraider@163.com

Reappraisal of HER2 status in the spectrum of advanced urothelial carcinoma

Although HER2 may be a therapeutic target, its evaluation in urothelial carcinoma of the bladder does not rely on a standardized scoring system by immunohistochemistry or FISH, as reflected by various methodologies in the literature and clinical trials. The authors conducted a study to improve and standardize HER2 amplification detection in bladder cancer. They assessed immunohistochemical criteria derived from the 2013 American Society of Clinical Oncology/College of American Pathologists guidelines for breast cancer and investigated intratumoral heterogeneity in a retrospective multicentric cohort of 188 patients with locally advanced urothelial carcinoma of the bladder. Immunohistochemistry was performed on 178 primary tumors and 126 lymph node metastases; eligible cases (moderate/strong, complete/incomplete membrane staining) were assessed by FISH. HER2 overexpression was more frequent with 2013 ASCO/CAP than 2007 ASCO/CAP guidelines (P < .0001). The rates of positive HER2 FISH were similar between primary tumor and lymph node metastases (eight percent). Among positive FISH cases, 48 percent were associated with moderate/strong incomplete membrane staining that were not scored eligible for FISH by the 2007 ASCO/CAP criteria. Among 3+ immunohistochemistry score cases, 67 percent were associated with HER2-positive FISH. Concordance between primary tumors and matched lymph node metastases was moderate for immunohistochemistry (κ = 0.54; 95 percent confidence interval [CI], 0.41–0.67) and FISH (κ = 0.50; 95 percent CI, 0.20–0.79). HER2-positive FISH was more frequent in micropapillary carcinomas (12 percent) and carcinoma with squamous differentiation (11 percent) than in pure conventional carcinoma (six percent). Intratumoral heterogeneity for HER2 immunohistochemistry was observed in seven percent of primary tumors and six percent of lymph node metastases; 24 percent of positive HER2 FISH cases presented intratumoral heterogeneity. The study suggests that HER2 evaluation should incorporate an immunohistochemistry screening step with eligibility for FISH including incomplete/complete and moderate/strong membrane staining. To take into account the potential impact of spatial or temporal intratumoral heterogeneity, the evaluation should be performed on tumor and lymph node and for each histological variant observed.

Moktefi A, Pouessel D, Liu J, et al. Reappraisal of HER2 status in the spectrum of advanced urothelial carcinoma: a need of guidelines for treatment eligibility. Mod Pathol. 2018;31:1270–1281.

Correspondence: Dr. Yves Allory at yves.allory@curie.fr

Analysis of cancer-associated fibroblasts and epithelial-mesenchymal transition

Activated cancer-associated fibroblasts and fibroblasts that have undergone epithelial-mesenchymal transition in cancer stroma contribute to tumor progression and metastasis. However, no published reports have investigated the cancer-associated fibroblast (CAF) phenotype and its clinicopathological relevance in cutaneous malignant tumors, including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. The authors conducted a study in which they investigated the CAF phenotype in cutaneous malignant tumors based on the tumors’ histology and immunohistochemical expression of CAF-related markers, including adipocyte enhancer-binding protein 1 (AEBP1), podoplanin, platelet-derived growth factor receptor α (PDGFRα), PDGFRβ, fibroblast-activating protein (FAP), CD10, S100A4, α-smooth muscle actin (α-SMA), and the EMT-related markers ZEB1, Slug, and Twist. They also assessed the role of the CAF phenotype in cutaneous malignant cancers using hierarchical cluster analysis. Consequently, three subgroups were stratified based on the expression pattern of CAF- and EMT-related markers. Subgroup one was characterized by low expression of AEBP1, PDGFRα, PDGFRβ, FAP, and Slug. Subgroup two was closely associated with high expression of PDGFRβ, S100A4, and Twist. Subgroup three had high expression levels of podoplanin, PDGFRβ, CD10, S100A4, α-SMA, ZEB1, Slug, and Twist. High expression of CD10 was commonly found in all three subgroups. These subgroups were correlated with histologic subtypes—that is, subgroup one, malignant melanoma; subgroup two, basal cell carcinoma; and subgroup three, squamous cell carcinoma. The authors suggested that the expression pattern of CAF- and EMT-related proteins plays crucial roles in the progression of these three cutaneous malignant tumors.