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Context.--Comprehensive genomic profiling has demonstrated that approximately 20% of pancreatic carcinomas with acinar differentiation harbor potentially targetable BRAF fusions that activate the MAPK pathway. Objectives.--To validate the above finding by BRAF break-apart fluorescence in situ hybridization (FISH) in a large series of pure acinar cell carcinomas (ACCs), evaluate tumors for the presence of BRAF V600E mutations, and compare clinicopathologic features of tumors with BRAF rearrangements with those without. Design.--Thirty cases of pure ACC and 6 cases of mixed acinar-neuroendocrine carcinoma (ACC-NEC) were retrieved. A break-apart FISH probe was used to detect BRAF rearrangements. Immunohistochemistry for BRAF V600E was performed. Results.--BRAF rearrangements by FISH were found in 6 of 36 cases (17%), 5 of which were pure ACC and 1 was a mixed ACC-NEC. Follow-up was available in 29 of 36 cases (81%). The median survival was 22 months for BRAFre-arranged cases and 16 months for BRAF-intact cases; the 2-year overall survival was 50% for BRAF-rearranged cases and 35% for BRAF-intact cases. No significant clinic-pathologic differences were identified in cases with BRAF rearrangement compared with those without BRAF rearrangement. BRAF V600E mutation was identified in 2 of 34 cases (6%), both of which were pure ACC and were BRAF-intact by FISH. Conclusions.--This study supports the finding that BRAF rearrangements are present in approximately 20% of cases and identified BRAF V600E mutations in approximately 5% of cases. These cases may benefit from targeted therapy., Pancreatic acinar cell carcinoma (ACC) is a rare, aggressive malignant epithelial pancreatic neoplasm that portends a grave 5-year survival of approximately 40% in resected cases and 20% in unresectable cases. [...]

* Context.--Guidelines for HER2 testing in breast cancer have changed over time, from the US Food and Drug Administration guideline to the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines published in 2007, 2013, and 2018. Objective.--To investigate the change in assignment of HER2 status in breast cancers with equivocal (2+) immunohistochemistry (IHC) results by fluorescence in situ hybridization (FISH) following implementation of the ASCO/CAP 2018 guideline. Design.--The study included 3556 invasive breast cancers that were HER2 equivocal (2+) by IHC and were submitted to our FISH laboratory after July 2018. Reflex testing (with repeat IHC staining) was performed on certain categories of FISH results known as groups 2, 3, and 4. Concomitant review of IHC and FISH was performed on these reflex cases per 2018 guideline recommendations. The FISH data were analyzed to compare US Food and Drug Administration and ASCO/CAP 2007, 2013, and 2018 interpretations. Results.--Of 3548 invasive breast cancers with complete data available, the percentage agreement for FISH according to different guidelines was highest for ASCO/ CAP 2018 versus US Food and Drug Administration (96.5%), followed by ASCO/CAP 2018 versus 2007 (93.8%), and lowest with ASCO/CAP 2018 versus 2013 (83.7%). Per the 2018 guideline, reflex IHC testing was performed on 633 breast cancers (17.8%); the majority of reflex testing results were negative (541 of 633; 85.5%). The overall distribution of HER2 FISH results (per the 2018 guideline) was 88.5% negative and 11.5% positive. Conclusions.--By eliminating the equivocal FISH category, the 2018 ASCO/CAP guideline significantly reduced the HER2 FISH-positive rate in tumors with equivocal (2+) IHC results. (Arch Pathol Lab Med. 2021;145:883-886; doi: 10.5858/arpa.2020-0273-OA), Targeted therapy has had a very favorable impact on survival for patients with HER2-positive breast cancer, and HER2-targeted therapy regimens continue to evolve. Detection of HER2 protein overexpression on the [...]

Context.--Pulmonary carcinoids are classified as typical or atypical by assessing necrosis and mitoses, which usually cannot be adequately assessed on small biopsies. Ki-67 is not currently used to grade pulmonary carcinoids, but it may be helpful to determine preliminary grade in biopsies. However, the rate at which Ki-67 could underestimate or overestimate grade on small biopsies has not been well studied. Objective.--To compare Ki-67 labeling obtained on small biopsies to subsequent resection. Design.--Ki-67 was performed on paired biopsy and resection specimens from 55 patients. Slides were scanned using Aperio ScanScope. Labeling index was determined using automated hot spot and tumor tracing methods. Results.--The study included 41 typical and 14 atypical carcinoids. Atypical carcinoids were larger and had more distant metastases. Death from disease occurred in 3 patients (all had atypical carcinoids). Median hot spot Ki67 labeling index was greater in resection compared with biopsy by 0.7% (P = .02). Median tumor tracing Ki-67 was lower in resection compared with biopsy by 0.5% (P < .001). Receiver-operating characteristic analysis showed similar hot spot Ki-67 cutoffs to predict atypical histology (3.5% for biopsy, 3.6% for resection; area under the curve [AUC], 0.75 and 0.74, respectively). Different optimal cutoffs were needed for tracing method based on biopsy (2.1%; AUC, 0.75) compared with resection (1.0%; AUC, 0.67). Conclusions.--Hot spot Ki-67 tends to underestimate grade on small biopsies, whereas grade is overestimated by tumor tracing. Hot spot Ki-67 cutoff of 3.5% predicted atypical histology for both biopsy and resection. Different biopsy and resection cutoffs were necessary for tumor tracing, which would make clinical implementation more difficult. doi: 10.5858/arpa.2019-0374-OA, Pulmonary neuroendocrine tumors are a heterogeneous group of neoplasms that includes carcinoid tumors, which have somewhat unpredictable but relatively indolent behavior, as well as small cell and large cell neuroendocrine [...]