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Introduction: Solitary fibrous tumor (SFT) is a fibroblastic tumor with malignant potential that is underpinned by a recurrent inv12(q13q13)-derived NAB2::STAT6 fusion. Breast and axilla are uncommon locations for this entity. Methods: Records of two academic institutions were electronically searched for breast and axillary SFTs. Clinical and pathologic data were reviewed. Literature review for breast or axillary SFTs was performed. Present study and previously reported tumors were stratified using five SFT risk models: original and modified Demicco metastatic risk, Salas local recurrence risk, Salas metastatic risk, and Thompson local recurrence risk. Results: Five patients with breast or axillary SFT were identified. Median age was 49 years, and median follow-up (available for four patients) was 82 months. Three patients showed no evidence of disease, and one developed recurrence. Literature review identified 58 patients with breast or axillary SFT. Median age was 54 years, and median follow-up (available for 35 patients) was 24 months. Thirty-one patients showed no evidence of disease, three developed recurrence, and one developed metastasis. Original and modified Demicco models and Thompson model showed the highest sensitivity; original and modified Demicco models and Salas metastatic risk model demonstrated the highest specificity. Kaplan–Meier models were used to assess recurrence-free probability (RFP). Original and modified Demicco models predicted RFP when stratified by "low risk" and "moderate/intermediate and high risk" tumor, though sample size was small. Conclusions: While many SFTs of breast and axilla remain indolent, a subset may develop recurrence and rarely metastasize. The modified Demicco risk model demonstrated optimal performance characteristics. [ABSTRACT FROM AUTHOR]

Background: Giant cell tumor of soft tissue (GCT‐ST) is a rare soft tissue neoplasm that is morphologically similar to but genetically distinct from giant cell tumor of bone. A novel keratin‐positive GCT‐ST (KPGCT‐ST) harboring HMGA2::NCOR2 fusions was recently discovered. Fewer than 30 cases have been described; herein is reported an additional seven. Methods: Cases diagnosed as GCT‐ST were retrieved from institutional archives and consultation files. The histopathologic characteristics were assessed, and the electronic medical record was reviewed. Results: Seven tumors were identified in six women and one man with a median age of 23 years. All patients underwent excision; no recurrences or metastases were noted during a median follow‐up period of 7 months. Histopathologically, the tumors were characterized by a multinodular proliferation of keratin‐positive mononuclear cells with evenly admixed osteoclast‐like giant cells and absent neoplastic bone. A fibrous capsule with lymphoid cuffing was frequently seen. Foamy macrophages, inflammation, hemorrhage, and hemosiderin were variably present. The HMGA2::NCOR2 fusion was detected in all cases. Conclusions: Our findings support previously reported hypotheses that KPGCT‐ST is a spectrum of the same entity as the recently described xanthogranulomatous epithelial tumor. Although follow‐up data are limited, to date, KPGCT‐ST appears to follow an indolent course. [ABSTRACT FROM AUTHOR]

Microcystic/reticular schwannoma (MRS) is a benign variant of schwannoma with a predilection for the gastrointestinal tract and skin. To date, genetic characterization of this tumor is limited. Prompted by the identification of TFE3::NONO fusion and ALK overexpression in an index case of MRS, a cohort of tumors was collected from institutional and consultation archives of two institutions. Next-generation sequencing (NGS), TFE3 fluorescence in situ hybridization (FISH), and TFE3 and ALK immunohistochemistry were performed, while clinicopathologic variables were documented. Eighteen MRS cases were identified (35 to 85 years) arising in the skin (n=8), gastrointestinal tract (n=5), adrenal gland (n=3), abdominal wall (n=1), and unknown site (n=1). Tumors showed a circumscribed to multinodular to plexiform low-power architecture with variable amounts of microcystic/reticular and solid schwannian components. Mitotic figures were scarce (0-1/10 HPFs), and atypia was absent. S100 protein and/or SOX10 immunoreactivity was noted in the microcystic/reticular and schwannian areas of all cases. NGS performed on two cutaneous tumors yielded NONO exon 12 fusion with TFE3 exon 4, and these lesions also showed HMB45 and ALK expression. Two additional cases showed ALK expression (1 weak), while a third was positive for TFE3, but these cases failed to show ALK or TFE3 rearrangement by FISH/NGS. There were no morphologic variables that correlated with the presence of NONO::TFE3. We identified a subset of microcystic/reticular schwannomas with NONO::TFE3 fusions and ALK co-expression, adding to the cohort of mesenchymal neoplasms that show ALK overexpression without rearrangement of the ALK gene. [ABSTRACT FROM AUTHOR]

Background: Spitzoid melanocytic neoplasms are diagnostically challenging; criteria for malignancy continue to evolve. The ability to predict chromosomal abnormalities with immunohistochemistry (IHC) could help select cases requiring chromosomal evaluation. Methods: Fluorescence in situ hybridization (FISH)‐tested spitzoid neoplasms at our institution (2013–2021) were reviewed. p16, BRAF V600E, and preferentially expressed antigen in melanoma (PRAME) IHC results were correlated with FISH. Results: A total of 174 cases (1.9F:1M, median age 28 years; range, 5 months–74 years) were included; final diagnoses: Spitz nevus (11%), atypical Spitz tumor (47%), spitzoid dysplastic nevus (9%), and spitzoid melanoma (32%). Sixty (34%) were FISH positive, most commonly with absolute 6p25 gain (RREB1 > 2). Dermal mitotic count was the only clinicopathologic predictor of FISH. Among IHC‐stained cases, p16 was lost in 55 of 134 cases (41%); loss correlated with FISH positive (p < 0.001, Fisher exact test). BRAF V600E (14/88, 16%) and PRAME (15/56, 27%) expression did not correlate with FISH alone (p = 0.242 and p = 0.359, respectively, Fisher exact test). When examined together, however, p16‐retained/BRAF V600E‐negative lesions had low FISH‐positive rates (5/37, 14%; 4/37, 11% not counting isolated MYB loss); all other marker combinations had high rates (56%–75% of cases; p < 0.001). Conclusions: p16/BRAF V600E IHC predicts FISH results. "Low‐risk" lesions (p16+/BRAF V600E−) uncommonly have meaningful FISH abnormalities (11%). PRAME may have limited utility in this setting. [ABSTRACT FROM AUTHOR]

Aims: PRRX1–NCOA1‐rearranged fibroblastic tumour is a recently described, rare mesenchymal tumour. Only four cases have been previously reported. The aim of this article is to report six additional cases of this unusual mesenchymal neoplasm, with an emphasis on its differential diagnosis. Methods and results: The six cases were from three females and three males (age, 20–49 years; median, 42 years). Three tumours were located on the abdominal wall; two from the shoulder/axillary areas, and one on the lateral hip. All presented as slow‐growing subcutaneous nodules, ranging from 26 to 55 mm (median, 40 mm). The tumours consisted of circumscribed, variably cellular nodules composed of relatively bland plump spindled to epithelioid cells arranged singly, in cords, and occasionally in nests, embedded in hyalinised and collagenous stroma. Small hypocellular myxoid zones with ropey collagen fibres were present, as were irregularly dilated, gaping, crescent‐shaped or staghorn‐like thin‐walled vessels, best appreciated at the periphery. Immunohistochemistry for CD34, S100, MUC4 and STAT6 was consistently negative. RNA‐sequencing revealed PRRX1–NCOA1 fusions in all cases. Of the four cases with limited follow‐up (1.5–4 months), none recurred following local surgical excision. Conclusions: The morphological features of PRRX1–NCOA1‐rearranged fibroblastic tumour overlap with those of RB1‐deficient soft‐tissue tumours, solitary fibrous tumour, and low‐grade fibromyxoid sarcoma/sclerosing epithelioid fibrosarcoma. This differential diagnosis can be resolved with a combination of careful morphological study and the application of a panel of immunostains, although molecular genetic study is most definitive. The natural history of PRRX1–NCOA1‐rearranged fibroblastic tumour appears to be quite favourable, although longer‐term study of a larger number of cases is warranted. [ABSTRACT FROM AUTHOR]

Aims: Clear cell (haemangioblastoma‐like) stromal tumour of the lung is a newly described, rare pulmonary neoplasm. Recurrent YAP1–TFE3 gene fusions have recently been reported in three cases. We describe two additional cases and confirm the characteristic YAP1–TFE3 gene fusion. Methods and results: Two mesenchymal tumours of lung were identified from our soft tissue pathology consultation services and RNA sequencing was performed. Both cases were in male patients, aged 35 and 77 years. Both presented as solitary lung nodules measuring 3.9 and 7.5 cm in greatest dimension. Histopathologically, the tumours were composed of epithelioid to plump spindle cells arranged in packets and solid sheets. The cells showed fusiform to ovoid nuclei with open chromatin, variably prominent nucleoli and scant to moderate, clear to eosinophilic cytoplasm. Cytological atypia and significant mitotic activity were minimal. None of the tumours expressed lineage‐specific immunophenotypical markers. Both cases were diffusely positive for nuclear TFE3. Unlike YAP1–TFE3‐fused epithelioid haemangioendothelioma, for which the fusion breakpoint occurs in YAP1 exon 1 and TFE3 exons 4 or 6, the fusion breakpoints of these tumours were located in YAP1 exon 4 and TFE3 exon 7. Following complete surgical resection, neither of the tumours has recurred or metastasised (follow‐up period 6–7 months). Conclusions: We validate the presence of YAP1–TFE3 gene fusion in a unique primary mesenchymal tumour of lung, adding additional support for clear cell stromal tumour of the lung as a distinct entity. [ABSTRACT FROM AUTHOR]

Background: Methods for identifying gene fusion events, such as fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and transcriptome analysis, are either single gene approaches or require bioinformatics expertise not generally available in clinical laboratories. We analytically validated a customized next-generation sequencing (NGS) panel targeting fusion events in 34 genes involving soft-tissue sarcomas. Methods: Specimens included 87 formalin-fixed paraffin-embedded (FFPE) tissues with known gene fusion status. Isolated total nucleic acid was used to identify fusion events at the RNA level. The potential fusions were targeted by gene-specific primers, followed by primer extension and nested PCR to enrich for fusion candidates with subsequent bioinformatics analysis. Results: The study generated results using the following quality metrics for fusion detection: (a) ≥100 ng total nucleic acid, (b) RNA average unique start sites per gene-specific primer control ≥10, (c) quantitative PCR assessing input RNA quality had a crossing point <30, (d) total RNA percentage ≥30%, and (e) total sequencing fragments ≥500 000. Conclusions: The test validation study demonstrated analytical sensitivity of 98.7% and analytical specificity of 90.0%. The NGS-based panel generated highly concordant results compared to alternative testing methods. [ABSTRACT FROM AUTHOR]

We report the largest series to date (N = 6) of EWSR1‐SMAD3 rearranged fibroblastic tumor. Initially described in 2018, the tumor features a marked female predominance (F:M, 5:1, mean age 44‐years, median age 45.5 years; range 27‐57), with most cases (5/6, 83%) arising in acral locations (4 on foot/toe, 1 on hand). One case presented on the lower extremity. The lesions presented as nodules and were composed of short, variably cellular, intersecting fascicles of uniform spindled cells in a collagenous to myxoid stroma. In four cases, the tumor abutted the epidermis without a grenz zone. In one case, there was an abrupt transition to a central, acellular hyalinized area. Two other cases had admixed smaller collagenous areas, reminiscent of collagen rosettes. One had a concentric arrangement of tumor cells around blood vessels. Mitotic activity was low (<1/10 HPFs). All were positive for ERG by immunohistochemistry and negative for CD34 (6/6). An EWSR1‐SMAD3 fusion was identified in three cases tested by next‐generation sequencing (3/3). Rearrangement of EWSR1 by fluorescence in situ hybridization was showed in 1/1 case. Our series reaffirms prior findings and expands the known histopathologic spectrum of this emerging entity. [ABSTRACT FROM AUTHOR]

This study piloted a pan‐solid‐tumor next generation sequence (NGS)‐based laboratory developed test as a diagnostic aid in melanocytic tumors. 31 cases (4 "epithelioid" nevi, 5 blue nevi variants, 7 Spitz tumors [3 benign and 4 malignant] and 15 melanomas) were evaluated. All tumors [median diameter 7 mm (range 4‐15 mm); median thickness 2.25 mm (range 0.25‐12 mm)] yielded satisfactory results. The number of small nucleotide variants/tumor was significantly different between melanoma (median 18/tumor, range 4‐71) and all other lesions (median 8/tumor, range 3‐17) (P < 0.004) and malignant (median 16/tumor, range 4‐71) vs benign lesions (median 7/tumor, range 3‐14) (P = 0.01). BRAF, MET, NTRK1, and ROS fusions only occurred in benign Spitz tumors; EML4 fusion, BRAF, MAP2K1 and TERT mutations occurred in malignant Spitz tumors and/or melanoma. Amplifications and NRAS and NF1 mutations only occurred in melanoma. Most melanomas contained >1 pathogenic alteration. Developed NGS‐based criteria correctly classified all malignant lesions in this series. 10/12 cases showed concordance with FISH; consensus diagnosis agreed with NGS classification in FISH‐non‐concordant cases. This pilot study suggests that NGS may be an effective diagnostic adjunct comparable to FISH, but further studies with larger numbers of cases are needed. [ABSTRACT FROM AUTHOR]

CIC rearranged sarcomas have significant overlap with Ewing sarcoma, are aggressive, and typically present in deep soft tissue. They most commonly have a t(4;19)(q35;q13) with CIC‐DUX4 fusion. Superficial presentation is rare. We report eight (6F, 2M; median 45‐years‐old, range 14‐65) superficial CIC‐rearranged sarcomas, involving the extremities (n = 4), vulva (n = 2), and trunk (n = 2). The tumors were composed of nodules/sheets of round cells with necrosis and hemorrhage separated by dense hyaline bands. Tumor cells had vesicular chromatin, prominent nucleoli and frequent mitotic figures. One showed pagetoid spread. Targeted next‐generation sequencing was positive for CIC‐DUX4 fusion (6/6); fluorescence in situ hybridization (FISH) was positive for CIC rearrangement (2/3). Eight of eight had evidence of CIC‐DUX4 fusion/rearrangement by molecular techniques. Immunohistochemistry was positive for CD99+ (8/8) and DUX4+ (4/4). FISH for EWSR1 rearrangement was negative (5/5). Of five patients with at least 6 months follow‐up, three of five died of disease, all within 2 years of presentation. One is alive with disease at 48 months. One is disease free at 3 months. Superficial CIC‐rearranged sarcomas should be considered in cases exhibiting features reminiscent of Ewing sarcoma, but with increased pleomorphism and/or geographic necrosis. In contrast to superficial Ewing sarcomas, superficial CIC‐rearranged sarcomas are aggressive. [ABSTRACT FROM AUTHOR]

One-third of gastrointestinal stromal tumors (GISTs) that lack KIT or PDGFRA mutations show succinate dehydrogenase (SDH) mutations or promoter hypermethylation. Most SDH-deficient GISTs occur in the pediatric, adolescent, or young adult setting and have unique features including predilection for the stomach, multinodular plexiform architecture, epithelioid cytology, prominence of lymphovascular invasion, and predilection for nodal metastasis. Dedifferentiation in GIST is a rare histologic change which may occur de novo or secondary to imatinib therapy and is characterized by abrupt transition of well-differentiated (WD) GIST to a subclonal anaplastic process that shows loss of immunohistochemical marks (CD117, DOG1). We describe the case of a previously healthy 18-year-old man who presented with a large gastric wall mass that contained 2 distinct morphologic populations. The first was WD and characterized by sweeping fascicles of bland spindled cells. This population abruptly transitioned to dedifferentiated (DD) foci composed of large sheets of discohesive cells that displayed a spectrum of rhabdoid and epithelioid morphologies with marked pleomorphism and mitotic activity. Immunohistochemically, the tumor showed variable staining in the 2 components with diffuse DOG-1 and CD117 positivity in the WD component and complete absence in the DD foci. SDH-B staining was lost in both components. Whole exome and transcriptome analysis was performed on tissue from both components and both showed an SDHB mutation (c.286G>A) as well as unique mutational burden and copy number profiles. Herein, we describe the first case of a DD SDH-deficient GIST with morphologic, immunophenotypic, and molecular characterization. [ABSTRACT FROM AUTHOR]

Gamma delta (γδ) T-cell antigen receptor (TCR) expression and its related T-cell differentiation are not commonly reported in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). Here we report two pediatric T-ALL cases and present their clinical features, histology, immunophenotypes, cytogenetics, and molecular diagnostic findings. The first patient is a two-year-old girl with leukocytosis, circulating lymphoblasts, and a cryptic insertion of a short-arm segment at 10p12 into the long-arm segment of 11q23 resulting in an MLL and AF10 fusion transcript, which may be the first reported in γδ T-ALL. She responded to the chemotherapy protocol poorly and had persistent diseases. Following an allogeneic bone marrow transplant, she went into remission. The second patient is an eleven-year-old boy with a normal white cell count, circulating blasts, and a normal karyotype, but without any immature cellular markers by flow cytometric analysis. He responded to the chemotherapy well and achieved a complete remission. These cases demonstrate the diverse phenotypic, cytogenetic, and molecular aspects of γδ T-ALL. Early T-precursor- (ETP-) ALL and their differential diagnosis from other mature γδ T-cell leukemia/lymphomas are also discussed. [ABSTRACT FROM AUTHOR]

The article offers information on a research on the mutations at or near the splice junction for exon 14 in non-small cell lung cancer (NSCLC). Topics discussed include activation of MET receptor tyrosine kinase (RTK) and its ligand, hepatocyte growth factor (HGF) in cancers, treatment implications for the lung cancers, and clinical trials of the patients with NSCLC. Also mentioned are examining the effect of erlotinib drug and DNA sequencing analysis and staining analysis of the cancer.

We report the first genome-wide association study of habitual caffeine intake. We included 47,341 individuals of European descent based on five population-based studies within the United States. In a meta-analysis adjusted for age, sex, smoking, and eigenvectors of population variation, two loci achieved genome-wide significance: 7p21 (P = 2.4×10−19), near AHR, and 15q24 (P = 5.2×10−14), between CYP1A1 and CYP1A2. Both the AHR and CYP1A2 genes are biologically plausible candidates as CYP1A2 metabolizes caffeine and AHR regulates CYP1A2. [ABSTRACT FROM AUTHOR]

Background: Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival. [ABSTRACT FROM PUBLISHER]

The mismatch repair (MMR) genes are involved in the maintenance of genomic integrity. Recently, we showed that common variants in these genes are unlikely to contribute significantly to colorectal cancer risk. The aim of this study was to investigate the role of common variants in the mismatch repair pathway as prognostic markers in colorectal cancer patients. We genotyped 2,060 patients for 68 SNPs in 7 mismatch repair genes ( MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2), using a single nucleotide polymorphism (SNP) tagging approach. Genotypes at the tag SNPs and multi-SNP haplotypes were tested for association with overall survival (OS) and disease specific survival (DSS) using a Cox regression model. Eight SNPs and 10 haplotypes were significant at a nominal p < 0.05 in the univariate analyses. Stepwise analysis showed that haplotype effects were mainly due to associated SNPs carried by these haplotypes. After adjustment for sex, age at diagnosis and stage when using overall survival and stage only when using disease specific survival, prognostic values were unattenuated. The most significant SNP associated with disease specific survival after adjustment was rs863221, located in MSH3 (HR: 0.59, 95% confidence interval (CI) 0.42-0.82, p-value: 0.001). In conclusion, we find some evidence that common variants in mismatch repair genes may contribute to survival of patients with colorectal cancer. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]