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Aims: Chondromyxoid fibroma (CMF) is a rare, benign bone tumour which arises primarily in young adults and is occasionally diagnostically challenging. Glutamate metabotropic receptor 1 (GRM1) gene encodes a metabotropic glutamate receptor and was recently shown to be up‐regulated in chondromyxoid fibroma through gene fusion and promoter swapping. The aim of this study was to interrogate cases of CMF for the presence of GRM1 gene rearrangements, gene fusions and GRM1 protein overexpression. Methods and results: Selected cases were subjected to testing by fluorescent in‐situ hybridisation (FISH) with a GRM1 break‐apart probe, a targeted RNA sequencing method and immunohistochemical study with an antibody to GRM1 protein. Two cases were subjected to whole transcriptomic sequencing. In 13 of 13 cases, GRM1 protein overexpression was detected by immunohistochemistry using the GRM1 antibody. Of the 12 cases successfully tested by FISH, nine of 12 showed GRM1 rearrangements by break‐apart probe assay. Targeted RNA sequencing analysis did not detect gene fusions in any of the eight cases tested, but there was an increase in GRM1 mRNA expression in all eight cases. Two cases subjected to whole transcriptomic sequencing (WTS) showed elevated GRM1 expression and no gene fusions. Conclusion: GRM1 gene rearrangements can be detected using FISH break‐apart probes in approximately 75% of cases, and immunohistochemical detection of GRM1 protein over‐expression is a sensitive diagnostic method. The gene fusion was not detected by targeted RNA sequencing, due most probably to the complexity of fusion mechanism, and is not yet a reliable method for confirming a diagnosis of CMF in the clinical setting. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cyst cytology evaluates for neoplastic mucin and epithelial grade. This study describes cytological features of low‐ and high‐grade mucinous neoplasms (MNs) using gastrointestinal contaminants for comparison. Methods: Histologically confirmed pancreatic cystic neoplasms were reviewed by a panel of cytopathologists to identify which, among 26 selected cytologic features, correlate significantly with low‐ and high‐grade MN. A test for greater than or equal to four of eight high‐grade features (three‐dimensional architecture, high nuclear:cytoplasmic ratio, moderate nuclear membrane abnormalities, loss of nuclear polarity, hyperchromasia, >4:1 nuclear size variation in one cluster, karyorrhexis, and necrosis) was assessed for identifying a high‐grade neoplasms. Additional characteristics of the cohort such as cyst fluid carcinoembryonic antigen results, molecular testing, Papanicolaou Society of Cytopathology classification, and select high‐risk clinical features are described. Results: Endoscopic ultrasound fine‐needle aspirations from 134 MN and 17 serous cystadenomas containing gastrointestinal contaminants were included. The MN consisted of 112 (84%) intraductal papillary MNs (low‐grade = 69, 62%; high‐grade = 24, 21%; and invasive = 19, 17%) and mucinous cystic neoplasms (low‐grade = 20, 90%; high‐grade = 2, 10%). Half had greater than five clusters of epithelium for analysis. Compared with gastrointestinal contaminants, mucin from MN was thick and colloid‐like (40% vs. 6%, p <.01), covered >20% of the smear area (32% vs. none, p <.01), and contained histiocytes (46% vs. 18%, p =.04). Greater than or equal to four of eight select high‐grade features was present in 36% of high‐grade MN with sensitivity 37% and 98% specificity. Conclusion: Colloid‐like features, >20% of smear, and histiocytes correlated with MN. Testing for greater than or equal to four high‐grade features had low sensitivity and high specificity for high‐grade MN. In a multi‐institutional cohort, the features of mucin, low‐, and high‐grade mucinous neoplasms are described. [ABSTRACT FROM AUTHOR]

Aims: Primary intraosseous rhabdomyosarcoma (RMS) is a rare entity defined by EWSR1/FUS–TFCP2 or, less commonly, MEIS1–NCOA2 fusions. The lesions often show a hybrid spindle and epithelioid phenotype, frequently coexpress myogenic markers, ALK, and cytokeratin, and show a striking propensity for the pelvic and craniofacial bones. The aim of this study was to investigate the clinicopathological and molecular features of 11 head and neck RMSs (HNRMSs) characterised by the genetic alterations described in intraosseous RMS. Methods and results: The molecular abnormalities were analysed with fluorescence in‐situ hybridisation and/or targeted RNA/DNA sequencing. Seven cases had FUS–TFCP2 fusions, four had EWSR1–TFCP2 fusions, and none had MEIS1–NCOA2 fusions. All except one case were intraosseous, affecting the mandible (n = 4), maxilla (n = 3), and skull (n = 3). One case occurred in the superficial soft tissue of the neck. The median age was 29 years (range, 16–74 years), with an equal sex distribution. All tumours showed mixed epithelioid and spindle morphology. Immunohistochemical coexpression of desmin, myogenin, MyoD1, ALK, and cytokeratin was seen in most cases. An intragenic ALK deletion was seen in 43% of cases. Regional and distant spread were seen in three and four patients, respectively. Two patients died of their disease. Conclusions: We herein present the largest series of HNRMSs with TFCP2 fusions to date. The findings show a strong predilection for the skeleton in young adults, although we also report an extraosseous case. The tumours are characterised by a distinctive spindle and epithelioid phenotype and a peculiar immunoprofile, with coexpression of myogenic markers, epithelial markers, and ALK. They are associated with a poor prognosis, including regional or distant spread and disease‐related death. [ABSTRACT FROM AUTHOR]

Abstract: Extraskeletal osteosarcoma (ESOSA) is a rare soft tissue neoplasm representing <5% of osteosarcomas and <1% of all soft‐tissue sarcomas. Herein, we investigate the clinicopathological and molecular features of ESOSA and explore potential parameters that may affect outcome. Thirty‐two cases were retrieved and histomorphology was reviewed. Clinical history and follow‐up were obtained through electronic record review. DNA from formalin‐fixed paraffin‐embedded (FFPE) tissue was extracted and processed from 27 cases. Genome‐wide DNA copy number (CN) alterations and allelic imbalances were analyzed by single nucleotide polymorphism array using Affymetrix OncoScan FFPE Assay. Massive high‐throughput deep parallel sequencing was performed using a customized panel targeting 410 cancer genes. Log rank, Fisher's exact test and Cox proportional hazards were used for statistical analysis. In this series of 32 patients (male n = 12, female n = 20), the average age was 66 years (19–93) and median follow up was 24 months (range 6–120 months). Frequent genomic alterations included CN losses in tumour suppressor genes including CDKN2A (70%), TP53 (56%) and RB1 (49%). Mutations affecting methylation/demethylation, chromatin remodeling and WNT/SHH pathways were identified in 40%, 27%, and 27%, respectively. PIK3CA and TERT promoter variant mutations were identified in 11% of the cases. Cases harbouring simultaneous TP53 and RB1 biallelic CN losses were associated with worse overall survival and local recurrence (p = 0.04, p = 0.02, respectively). CDKN2A losses and positive margins were also associated with worse overall survival (p = 0.002; p = 0.03, respectively). Our findings suggest that age above 60, positive margin status, simultaneous biallelic TP53 and RB1 losses and CDKN2A loss are associated with a worse outcome in ESOSA. Comparison between conventional paediatric osteosarcoma and ESOSA shows that, while both share genetic similarities, there are notable dissimilarities and mechanistic differences in the molecular pathways involved in ESOSA. [ABSTRACT FROM AUTHOR]

Phosphaturic mesenchymal tumor, mixed connective tissue variant (PMT-MCT) is a rare, largely benign, mesenchymal neoplasm almost invariably associated with oncogenic osteomalacia. It is generally found in the soft tissue and bone of the extremities. We report a case of a 61-year-old female with long-standing osteomalacia who was found to have PMT-MCT of the thoracic spine. There have been very few previously reported cases of PMT involving the spinal vertebrae and neuropathologists should be aware of this lesion. Recognition of PMT-MCT is critical for optimal patient care since complete surgical resection without additional therapy is curative. [ABSTRACT FROM AUTHOR]

Activating mutations in either BRAF or NRAS are seen in a significant number of malignant melanomas, but their incidence appears to be dependent to ultraviolet light exposure. Thus, BRAF mutations have the highest incidence in non-chronic sun damaged (CSD), and are uncommon in acral, mucosal and CSD melanomas. More recently, activating KIT mutations have been described in rare cases of metastatic melanoma, without further reference to their clinical phenotypes. This finding is intriguing since KIT expression is downregulated in most melanomas progressing to more aggressive lesions. In this study, we investigated a group of anal melanomas for the presence of BRAF, NRAS, KIT and PDGFRA mutations. A heterozygous KIT exon 11 L576P substitution was identified in 3 of 20 cases tested. The 3 KIT mutation-carrying tumors were strongly immunopositive for KIT protein. No KIT mutations were identified in tumors with less than 4+ KIT immunostaining. NRAS mutation was identified in one tumor. No BRAF or PDGFRA mutations were identified in either KIT positive or negative anal melanomas. In vitro drug testing of stable transformant Ba/F3 KIT [ABSTRACT FROM AUTHOR]

The article presents a study which showed that it is not cost effective to have routine endometrial sampling of asymptomatic premenopausal women shedding normal endometrial cells in Papanicolaou tests. The high cost of unnecessary procedures and limited clinical benefits are reportedly associated with the new reporting format. Little, if any, significant endometrial pathology is detected after Papanicolaou test reporting of normal endometrial cells (nEMC) in cycling women in their 40s.