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* Context.--Melanotic schwannoma (MS) is a nerve sheath tumor with a uniform composition of variably melanin-producing Schwann cells and metastatic potential. The MS is an uncommon neoplasm, accounting for less than 1% of all nerve sheath tumors, with a predilection for spinal nerve involvement. Microscopically, the tumors are characterized by spindle and epithelioid cells arranged in interlacing fascicles, with marked accumulation of melanin in neoplastic cells and associated melanophages. The MSs are frequently associated with Carney complex, showing features of psammoma bodies and adipose-like cells. Strict criteria of malignancy in MS are not well developed, although a combination of worrisome histologic features (large, vesicular nuclei, with macronucleoli, brisk mitotic activity, and necrosis) raises concern for aggressive behavior.Objective.--To review the current status of the MS literature, discussing putative etiology, histopathology, current genetics, and differential diagnoses, including overlap with other pigmented tumors.Data Sources.--Search of PubMed (National Center for Biotechnology Information, Bethesda, Maryland) and the authors' own experiences.Conclusions.--The occurrence of MS at several unusual anatomic sites and its spectrum of morphologic patterns can result in significant diagnostic difficulty, and correct diagnosis is particularly important because of its high tendency to recur locally and to metastasize, which highlights the importance of diagnostic recognition, ancillary molecular genetic testing, and close clinical follow-up of patients with MS.(Arch Pathol Lab Med. 2018;142:1517-1523; doi: 10.5858/arpa.2017-0162-RA), Melanotic schwannoma (MS) is a nerve sheath tumor with a uniform composition of variably melaninproducing Schwann cells and metastatic potential. (1-44) MS is an uncommon neoplasm, accounting for less than [...]

Context.--Fluorescence in situ hybridization (FISH) and brightfield in situ hybridization (ISH) are 2 clinically approved laboratory methods for detecting ERBB2 (HER2) amplification in breast cancer. Objective.--To compare the performance of FISH and brightfield ISH on proficiency testing administered by the College of American Pathologists Laboratory Accreditation Program. Design.--Retrospective review was performed on 70 tissue core samples in 7 separate proficiency testing surveys conducted between 2009 and 2013. Results.--The samples included 13 consensus-amplified tissue cores, 53 consensus-nonamplified cores, and 4 cores that did not reach consensus for FISH and/or brightfield ISH. There were 2552 individual responses for FISH and 1871 individual responses for brightfield ISH. Consensus response rates were comparable for FISH (2474 of 2524; 98.0%) and brightfield ISH (2135 of 2189; 97.5%). The FISH analysis yielded an average HER2 copy number per cell that was significantly higher (by 2.86; P = .02) compared with brightfield ISH for amplified cores. For nonamplified cores, FISH yielded slightly, but not significantly, higher (by 0.17; P = .10) HER2 copy numbers per cell. There was no significant difference in the average HER2 to control ratio for either consensus-amplified or consensus-nonamplified cores. Participants reported 'unable to analyze' more frequently for brightfield ISH (244 of 2453; 9.9%) than they did for FISH (160 of 2684; 6.0%). Conclusions.--Our study indicates a high concordance rate in proficiency testing surveys, with some significant differences noted in the technical performance of these assays. In borderline cases, updated American Society of Clinical Oncology/College of American Pathologists cutoff thresholds that place greater emphasis on HER2 copy number per cell could accentuate those differences between FISH and brightfield ISH. doi: 10.5858/arpa.2017-0457-CP, Amplification or overexpression of the human epidermal growth factor receptor 2 (ERBB2, HER2) gene is an important oncogenic driver in up to 20% to 25% of breast cancers. Breast cancers [...]

* Context.--Recurrent epidermal growth factor receptor (EGFR) mutations are seen in a subset of pulmonary adenocarcinomas. These mutations are targeted by EGFR inhibitors and are a biomarker for response to EGFR inhibitor therapies. Initial data have indicated an increased frequency of activating EGFR mutations in nonsmoking Asian females. However, there are very few studies of global scope that address the question of mutation distribution across the population of lung cancer. Objective.--To determine the frequency of EGFR mutations in exons 18 through 21 detected in clinical laboratories participating in the College of American Pathologists proficiency testing program for EGFR in calendar year 2013. Design.--We reviewed the surveys from 170 clinical laboratories from 20 countries that participated in the College of American Pathologists EGFR proficiency testing program. The proficiency testing includes questions regarding the total numbers of tests performed at each common mutation site, including both activating and resistance mutations, and their frequency. Countries were grouped into regional groups in order to assess frequency of mutation by type, and to indirectly assess ethnic differences in mutation frequencies. Results.--Among the treatment-sensitive activating mutations, the most common are exon 19 mutations (n = 10 802 of 136 533 cases; 7.9% of total cases tested) and the exon 21 L858R mutation (n = 10 351 of 136 533 cases; 7.6% of total cases tested) and the least common are exon 20 mutations (n = 466 of 136 533 cases; 0.3% of total cases tested). The T790M mutation in exon 20 is the more common resistance mutation (n = 1010 of 136 533 cases; 0.7% of all cases tested). The highest activating mutation frequency is seen in southern Asia (n = 4260 of 9337 cases; 46%) and the lowest activating mutation frequencies are in South and North America (n = 113 of 1439 cases and 7926 of 86 654 cases; 8% and 9%, respectively). Conclusions.--Our data confirm that activating EGFR mutations are more common in southern Asia and that the distribution of activating EGFR mutations varies significantly across the regions. Similarly, the frequency and distribution of resistance mutations also show significant variation when comparing southern Asia with other regions. (Arch Pathol Lab Med. 2018;142:163-167; doi: 10.5858/arpa.2016-0579-CP), Recurrent epidermal growth factor receptor (EGFR) mutations characterize a subset of pulmonary adenocarcinomas and represent an effective therapeutic target for some tyrosine kinase inhibitors. (1,2) In patients whose tumors harbor [...]

Background: The conventionally understood pathogenesis of agminated Spitz nevi includes a mosaic HRAS mutation followed by copy number gains in 11p. However, we have recently observed agminated presentations of fusion‐driven melanocytic neoplasms. Methods: We retrieved cases from our database of benign fusion‐induced melanocytic neoplasms with an agminated presentation. Both the primary lesion and the secondary lesion were sequenced. TERT‐promoter mutational testing and the melanoma fluorescence in situ hybridization assay were also performed. Results: Three cases were included. Two had a PRKCA fusion (partners ATP2B4 and MPZL1) and one had a ZCCHC8::ROS1 fusion. None of the cases met morphologic or molecular criteria for malignancy. There was no evidence of tumor progression in secondary lesions. The same fusion was identified in the primary and secondary lesions. None of the patients developed evidence of nodal or systemic metastasis. Conclusions: We present accumulating evidence that fusion‐driven melanocytic neoplasms can present with an agminated presentation. The differential diagnosis of an agminated presentation versus a locally recurrent or potentially locally metastatic tumor is critical, and accurate diagnosis has significant prognostic and therapeutic consequences for the patient. As with HRAS mutations, fusion‐driven melanocytic tumors may have an agminated presentation. [ABSTRACT FROM AUTHOR]

Context.--Detection of acquired variants in cancer is a paradigm of precision medicine, yet little has been reported about clinical laboratory practices across a broad range of laboratories. Objective.--To use College of American Pathologists proficiency testing survey results to report on the results from surveys on next-generation sequencing-based oncology testing practices. Design.--College of American Pathologists proficiency testing survey results from more than 250 laboratories currently performing molecular oncology testing were used to determine laboratory trends in next-generation sequencing-based oncology testing. Results.--These presented data provide key information about the number of laboratories that currently offer or are planning to offer next-generation sequencing-based oncology testing. Furthermore, we present data from 60 laboratories performing next-generation sequencing-based oncology testing regarding specimen requirements and assay characteristics. The findings indicate that most laboratories are performing tumor-only targeted sequencing to detect single-nucleotide variants and small insertions and deletions, using desktop sequencers and predesigned commercial kits. Despite these trends, a diversity of approaches to testing exists. Conclusions.--This information should be useful to further inform a variety of topics, including national discussions involving clinical laboratory quality systems, regulation and oversight of next-generation sequencing-based oncology testing, and precision oncology efforts in a data-driven manner. (Arch Pathol Lab Med. 2017;141:1679-1685; doi: 10.5858/arpa.2016-0542-CP), Clinical testing for somatic or acquired variants in cancer specimens is a common modality of precision, or personalized, medicine. Detection of somatic variants in cancer specimens can be used for [...]

Context.--With enormous growth in the field of molecular pathology, the reporting of results gleaned from this testing is essential to guide patient care. Objective.--To examine molecular reports from laboratories participating in proficiency testing for required elements to convey molecular laboratory test results to clinicians and patients. Design.--Molecular laboratories participating in the College of American Pathologists (CAP) proficiency testing program for BRAF mutation analysis were solicited to submit examples of final reports from 2 separate proficiency testing reporting cycles. Reports were reviewed for the presence or absence of relevant components. Results.--A total of 107 evaluable reports were received (57 demonstrating a positive result for the BRAF V600E mutation and 50 negative). Methods for BRAF testing varied, with 95% (102 of 107) of reports adequately describing their assay methods and 87% (93 of 107) of reports adequately describing the target(s) of their assays. Information on the analytic sensitivity of the assay was present in 74% (79 of 107) of reports and 83% (89 of 107) reported at least 1 assay limitation, though only 34% (36 of 107) reported on variants not detected by their assays. Analytic and clinical interpretive comments were included in 99% (106 of 107) and 90% (96 of 107) of reports, respectively. Of participants that perform a laboratory-developed test, 88% (88 of 100) included language addressing the development of the assay. Conclusions.--Laboratories participating in BRAF proficiency testing through the CAP are including most of the required reporting elements to unambiguously convey molecular results. Laboratories should continue to strive to report these results in a concise and comprehensive manner. (Arch Pathol Lab Med. 2017;141:658-665; doi: 10.5858/arpa.2016-0280-CP), The fields of genomics and molecular pathology are evolving rapidly with increasing complexity of available technologies. Reporting the results of molecular testing must be comprehensive and yet concise so that [...]

Objectives: To determine maternal vs fetal origin for blood in placental intervillous thrombi (IVTs).Methods: We used comparative analysis of microsatellites (short tandem repeats [STRs]), sex chromosome fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC) for fetal (ɑ-fetoprotein [AFP]) and maternal (immunoglobulin M [IgM]) serum proteins to distinguish the origin of IVTs. Using an informatics approach, we tested the association between IVTs and fetomaternal hemorrhage (FMH).Results: In 9 of 10 cases, the preponderance of evidence showed that the thrombus was mostly or entirely maternal in origin. In 1 case, the thrombus was of mixed origins. STR testing was prone to contamination by entrapped fetal villi. FISH was useful but limited only to cases with male fetuses. IgM showed stronger staining than AFP in 9 cases, supporting maternal origin. By informatics, we found no association between IVTs and FMH.Conclusions: Evidence supports a maternal origin for blood in IVTs. IHC for IgM and AFP may be clinically useful in determining maternal vs fetal contribution to IVTs. [ABSTRACT FROM AUTHOR]

Context.--The distinction between well-differentiated epithelial favorable-histology Wilms tumor (EFHWT) and metanephric adenoma (MA) in children has historically been determined by the required absence of both a fibrous pseudocapsule and mitotic activity in MA. More recently these features have been allowed in adult MA. Mutations in exon 15 of the BRAF gene are reported in up to 88% of MAs but have not been reported in EFHWTs in children lacking MA features. Objective.--To clarify the pathologic and molecular features used to distinguish between pediatric MA and EFHWT. Design.--Stage I epithelial tumors classified as EFHWT on central review (36 patients) were identified from the Children's Oncology Group AREN03B2 study. Thirteen tumors had morphologic features overlapping those of MA and 23 lacked such features; 35 of 36 had tissue available for sequencing of BRAF. Results.--Patients with EFHWTs with MA features (13) were older (mean, 8.4 versus 1.9 years; P < .001), had smaller tumor diameters (mean, 6.0 versus 9.7 cm; P < .001), and had fewer mitoses (mean, 1 versus 48 mitoses per 10 high-power fields; P < .001) than patients with EFHWT lacking MA features (23). All EFHWTs with MA features contained at least a partial fibrous pseudocapsule; 7 of 12 (58%) had a BRAF exon 15 mutation. No BRAF exon 15 mutations were identified in 23 EFHWTs lacking MA features. None of the 13 EFHWT patients with MA features have experienced relapse (median follow-up 5.9 years). Conclusions.--Pediatric epithelial neoplasms with features of MA that show partial encapsulation and/or modest mitotic activity may be classified as MAs. Although BRAF mutation supports the diagnosis of MA, it is not required for the diagnosis. [ABSTRACT FROM AUTHOR]

Context.--The College of American Pathologists surveys are the largest laboratory peer comparison programs in the world. These programs allow laboratories to regularly evaluate their performance and improve the accuracy of the patient test results they provide. Proficiency testing is offered twice a year to laboratories performing microsatellite instability testing. These surveys are designed to emulate clinical practice, and some surveys have more challenging cases to encourage the refinement of laboratory practices. Objective.--This report summarizes the results and trends in microsatellite instability proficiency testing from participating laboratories from the inception of the program in 2005 through 2012. Design.--We compiled and analyzed data for 16 surveys of microsatellite instability proficiency testing during 2005 to 2012. Results.--The number of laboratories participating in the microsatellite instability survey has more than doubled from 42 to 104 during the 8 years analyzed. An average of 95.4% of the laboratories correctly classified each of the survey test samples from the 2005A through 2012B proficiency challenges. In the 2011B survey, a lower percentage of laboratories (78.4%) correctly classified the specimen, possibly because of overlooking subtle changes of microsatellite instability and/or failing to enrich the tumor content of the specimen to meet the limit of detection of their assay. Conclusions.--In general, laboratories performed well in microsatellite instability testing. This testing will continue to be important in screening patients with colorectal and other cancers for Lynch syndrome and guiding the management of patients with sporadic colorectal cancer. (Arch Pathol Lab Med. 2014; 138:363-370; doi: 10.5858/arpa.2013-0159-CP), Although most cases of colorectal cancer (CRC) are sporadic, approximately 2% to 3% are due to the hereditary CRC syndrome known as hereditary nonpolyposis CRC (1) or Lynch syndrome (LS). [...]

* Context.--The fraction of malignant cells in tumor tissue submitted for tests of genetic alterations is a critical variable in testing accuracy. That fraction is currently determined by pathologist visual estimation of the percentage of malignant cells. Inaccuracy could lead to a false-negative test result. Objective.--To describe a prospective, multi-institutional study to determine pathologist estimation accuracy. Design.--Ten X20 magnification images of hematoxylin-eosin-stained colon tissue specimens were sent as an educational component of the College of American Pathologists KRAS-B 2011 Survey. Data from 194 labs were analyzed and compared to a criterion standard with comprehensive manual nuclear counts. Results.--Survey responses indicated low interlaboratory precision of pathologist estimation, but mean estimates were fairly accurate. A total of 5 of the 10 cases assessed showed more than 10% of respondents overestimating in a manner that could lead to false-negative test results. Conclusions.--The significance of estimation errors resulting in molecular testing failures with implications for patient care is unknown, but the current study suggests false-negative test results may occur. (Arch Pathol Lab Med. 2013;137:1545-1549; doi: 10.5858/arpa.2012-0561-CP), Successful molecular oncology testing depends on accurate assessment of the percentage of malignant cells in the analyzed tissue specimen. Although sensitivity is highly variable, depending on the individual technical approach, [...]