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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, molecular genetic pathology fellow, University of Utah/ARUP Laboratories, Salt Lake City; 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.

HER2: a pan-cancer event highly enriched in AR-driven breast tumors

November 2018—Approximately one in five breast cancers is driven by amplification and overexpression of the HER2 receptor kinase, and HER2 enriched is one of four major transcriptional subtypes of breast cancer. The authors conducted a study to understand the genomics of HER2 amplification independent of subtype, as well as the underlying drivers and biology of HER2-enriched (HER2E) tumors. They investigated published genomic data from 3,155 breast tumors and 5,391 nonbreast tumors. The authors found that HER2 amplification is a distinct driver event seen in all breast cancer subtypes, rather than a subtype marker, with major characteristics restricted to amplification and overexpression of HER2 and neighboring genes. The HER2E subtype has a distinctive transcriptional landscape independent of HER2A that reflects androgen-receptor signaling as a replacement for estrogen receptor-driven tumorigenesis. HER2 amplification is also an event in 1.8 percent of nonbreast tumors. The authors concluded that their findings reveal therapeutic opportunities for combining anti-HER2 therapy with anti-androgen agents in breast cancer and highlight the potential for broader therapeutic use of HER2 inhibitors.

Daemen A, Manning G. HER2 is not a cancer subtype but rather a pan-cancer event and is highly enriched in AR-driven breast tumors. Breast Cancer Res. 2018;20:8. doi:10.1186/s13058-018-0933-y.

Correspondence: Dr. Anneleen Daemen at daemen.anneleen@gene.com or Dr. Gerard Manning at manning.gerard@gene.com

Invasive mucinous carcinoma of the breast and response patterns after neoadjuvant chemotherapy

Neoadjuvant chemotherapy is often used to treat localized invasive breast cancer. Invasive mucinous carcinoma (IMC) is considered an indolent form of invasive breast cancer and is rarely treated with this form of chemotherapy. The authors assessed seven patients who had IMC treated with neoadjuvant chemotherapy and reported a characteristic, but not well recognized, pattern of pathological response. Three patients presented with locally advanced disease; three patients had tumors that were HER2/neu positive; and four patients had tumors with admixed mucinous and micropapillary features. Clinical and imaging assessment of response showed persistent and, in some cases, progressive disease, despite evidence of significant pathological response in these cases. Pathological assessment after neoadjuvant chemotherapy demonstrated marked reduction in tumor cellularity but persistent space-occupying mucin pools, showing acellular mucin in one case, less than one percent tumor cellularity in three cases, and five to 10 percent cellularity in three cases in both the treated breast and axillary lymph nodes. The authors concluded that persistent mass-forming low-cellular or acellular mucin pools can result in discordant clinical, imaging, and pathological findings in IMC treated with neoadjuvant chemotherapy.

Didonato R, Shapiro N, Koenigsberg T, et al. Invasive mucinous carcinoma of the breast and response patterns after neoadjuvant chemotherapy (NAC). Histopathol. 2018;72(6):965–973.

Correspondence: Dr. S. Fineberg at sfineber@montefiore.org

Correlation of Oncotype DX DCIS results with histopathologic findings and clinical management decisions

Given the increased detection rates for ductal carcinoma in situ and the limited overall survival benefit from adjuvant breast irradiation after breast-conserving surgery, there is interest in identifying subsets of patients who have low rates of ipsilateral breast tumor recurrence such that they might safely forgo radiation. The Oncotype DCIS score is a reverse transcription-PCR (RT-PCR)-based assay that was validated to predict which ductal carcinoma in situ (DCIS) cases are most likely to recur. The results may be used to help identify DCIS patients who might safely forgo radiation therapy after breast-conserving surgery. However, little information is available regarding how this test is being used in practice. The authors conducted a study to examine traditional histopathologic features used in predicting DCIS risk with Oncotype DCIS results and how these results affected clinical decision-making at the authors’ academic institution. Histopathologic features and management decisions for 37 cases with Oncotype DCIS results over the past four years were collected. Necrosis, high nuclear grade, biopsy site change, estrogen receptor and progesterone receptor positivity of less than 90 percent on immunohistochemistry, and a Van Nuys prognostic index score of eight or greater were significant predictors of an intermediate–high recurrence score on multivariate regression analysis (P < .02). Low Oncotype DCIS scores and low nuclear grade were associated with lower rates of radiation therapy (P < .008). The authors considered seven (19 percent) cases with Oncotype DCIS results to be unexpected in relation to the histopathologic findings—that is, high nuclear grade with comedonecrosis and a low Oncotype score, or hormone receptor discrepancies. Overall, pathologic features correlate with Oncotype DCIS scores but unexpected results do occur, making individual recommendations challenging in some cases.

Lin CY, Mooney K, Choy W, et al. Will Oncotype DX DCIS testing guide therapy? A single-institution correlation of Oncotype DX DCIS results with histopathologic findings and clinical management decisions. Mod Pathol. 2018;31:562–568.

Correspondence: Dr. Kimberly Allison at allisonk@stanford.edu

Poorly differentiated clusters predict colon cancer recurrence: analysis of invasive-front prognostic markers

The authors conducted a study to compare common histologic markers at the invasive front of colon adenocarcinoma in terms of prognostic accuracy and interobserver agreement. They identified consecutive patients who underwent curative resection for stages I to III colon adenocarcinoma at a single institution from 2007 to 2014. They then analyzed poorly differentiated clusters (PDCs), tumor budding, perineural invasion, desmoplastic reaction, and Crohn-like lymphoid reaction at the invasive front, as well as the World Health Organization (WHO) grade of the entire tumor. The authors compared prognostic accuracies for recurrence-free survival and assessed interobserver agreement among three pathologists. The study cohort consisted of 851 patients. All of the histologic markers, except WHO grade, were significantly associated with recurrence-free survival (PDCs, tumor budding, perineural invasion, and desmoplastic reaction: P < .001; Crohn-like lymphoid reaction: P = .021). But PDCs (grade 1 [G1], n=581; G2, n=145; G3, n=125) showed the largest separation of three-year recurrence-free survival in the full cohort (G1, 94.1 percent; G3, 63.7 percent; hazard ratio [HR], 6.39; 95 percent confidence interval [CI], 4.11–9.95; P < .001) and in stage II patients (G1, 94 percent; G3, 67.3 percent; HR, 4.15; 95 percent CI, 1.96–8.82; P < .001) and stage III patients (G1, 89 percent; G3, 59.4 percent; HR, 4.50; 95 percent CI, 2.41–8.41; P < .001). PDCs had the highest prognostic accuracy for recurrence-free survival, with a concordance probability estimate of 0.642, and WHO grade had the lowest. Interobserver agreement was the highest for PDCs, with a weighted kappa of 0.824. The risk of recurrence over time peaked earlier for worse PDCs grade. The authors concluded that PDCs are the best invasive-front histologic marker in terms of prognostic accuracy and interobserver agreement. They may replace WHO grade as a prognostic indicator.

Konishi T, Shimada Y, Lee LH, et al. Poorly differentiated clusters predict colon cancer recurrence: an in-depth comparative analysis of invasive-front prognostic markers. Am J Surg Pathol. 2018;42(6):705–714.

Correspondence: Dr. Jinru Shia at shiaj@mskcc.org or Dr. Martin R. Weiser at weiser1@mskcc.org

Distinguishing appendiceal goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid from colorectal-type adenocarcinomas of appendix

The appendix gives rise to goblet cell carcinoids, which represent special carcinomas with distinct biological and histological features. Their genetic background and molecular relationship to colorectal adenocarcinoma is largely unknown. Therefore, the authors performed a next-generation sequencing analysis of 25 appendiceal carcinomas, including 11 goblet cell carcinoids, seven adenocarcinomas ex-goblet cell carcinoid, and seven primary colorectal-type adenocarcinomas, using a modified colorectal cancer-specific panel comprising 32 genes linked to colorectal and neuroendocrine tumorigenesis. The mutational profiles of these neoplasms were compared with those of conventional adenocarcinomas, mixed adenoneuroendocrine carcinomas, and neuroendocrine carcinomas of the colorectum. In addition, a large-scale pan-cancer sequencing panel covering 409 genes was applied to selected cases of goblet cell carcinoid/adenocarcinoma ex-goblet cell carcinoid (n=2, respectively). Mutations in colorectal cancer-related genes, such as TP53, KRAS, and APC, were rare to absent in goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid but frequent in primary colorectal-type adenocarcinomas of the appendix. Additional large-scale sequencing of selected goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid revealed mutations in Wnt-signaling–associated genes—USP9X, NOTCH1, CTNNA1, CTNNB1, and TRRAP. These data suggest that appendiceal goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid constitute a morphomolecular entity that is histologically and genetically distinct from appendiceal colorectal-type adenocarcinomas and its colorectal counterparts. Altered Wnt-signaling–associated genes, apart from APC, may act as potential drivers of these neoplasms. The absence of KRAS/NRAS mutations might render some of these tumors eligible for anti-EGFR–directed therapy regimens.

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