Mesenchymal skin tumors - Novel entities in the 5th edition of WHO classification of skin tumors.

The section on mesenchymal tumors in 5th edition of WHO classification of skin tumors has undergone several changes, the most important of which, as usual, is the inclusion of newly identified tumor entities, which will be the main focus of this review article. These specifically include three novel cutaneous mesenchymal tumors with melanocytic differentiation, and rearrangements of the CRTC1::TRIM11, ACTIN::MITF, and MITF::CREM genes. In addition, EWSR1::SMAD3-rearranged fibroblastic tumors, superficial CD34-positive fibroblastic tumors, and NTRK-rearranged spindle cell neoplasms were newly included. Of the other changes, only the most important ones will be briefly mentioned.

Novel CRTC1::MRTFB(MKL2) Gene Fusion detected in Myxoid Mesenchymal Neoplasms with Myogenic Differentiation involving Bone and Soft Tissue.

Appropriate classification of fusion-driven bone and soft tissue neoplasms continues to evolve, often relying on the careful integration of morphologic findings with immunohistochemical, molecular, and clinical data. Herein, we present three cases of a morphologically distinct myxoid mesenchymal neoplasm with myogenic differentiation and novel CRTC1::MRTFB (formerly MKL2) gene fusion. Three tumors occurred in 2 female and 1 male patient with a median age of 72 (range: 28-78). Tumors involved the left iliac bone, the right thigh, and the left perianal region with a median size of 4.0 cm (4.0-7.6 cm). While one tumor presented as an incidental finding, the other two tumors were noted given their persistent growth. At the time of last follow-up, one patient was alive with unresected disease at 6 months, one patient was alive without evidence of disease at 12 months after surgery and one patient died of disease 24 months after diagnosis. On histologic sections, the tumors showed multinodular growth and were composed of variably cellular spindle to round-shaped cells with distinct brightly eosinophilic cytoplasm embedded within a myxoid stroma. One tumor showed overt smooth muscle differentiation. Cytologic atypia and mitotic activity ranged from minimal (2 cases) to high (1 case). By immunohistochemistry, the neoplastic cells expressed focal smooth muscle actin, h-caldesmon, and desmin in all tested cases. Skeletal muscle markers were negative. Next-generation sequencing detected nearly identical CRTC1::MRTFB gene fusions in all cases. We suggest that myxoid mesenchymal tumors with myogenic differentiation harboring a CRTC1::MRTFB fusion may represent a previously unrecognized, distinctive entity that involves soft tissue and bone. Continued identification of these novel myxoid neoplasms with myogenic differentiation will be important in determining appropriate classification, understanding biologic potential, and creating treatment paradigms.

Molecular analysis of apocrine mixed tumors and cutaneous myoepitheliomas: a comparative study confirming a continuous spectrum of one entity with near-ubiquitous PLAG1 and rare mutually exclusive HMGA2 gene rearrangements.

Myoepithelial neoplasms of the skin and soft tissue still represent a confusing and somewhat controversial field in pathology as it appears that this category includes several different entities. However, recent studies have suggested that both apocrine mixed tumors (AMT) and cutaneous myoepitheliomas (CM) harbor identical chromosomal rearrangements involving the PLAG1 gene and hence may represent a morphological spectrum. The aim of the present study was to share our institutional experience with these tumors and specifically focus on studying their immunohistochemical and molecular features to further assess their relatedness. Eleven cases of AMT and 7 cases of CM were collected and analyzed using immunohistochemistry (IHC), PLAG1 FISH, and Archer FusionPlex assay. There were 14 male and 4 female patients with ages ranging from 26 to 85 years (median 55.8 years, mean 58.5 years). AMTs were mainly located in the head and neck (n = 10), while CMs were mainly located in the acral sites (n = 5). PLAG1 IHC was diffusely strongly positive in 14/17 (82%) cases, whereas a single case of AMT diffusely expressed HMGA2. Both tumor groups showed PLAG1 gene fusions which were detected in 6/13 analyzable samples (AMT, n = 4 and CM, n = 2), and included TRPS1::PLAG1 (n = 3), NDRG1::PLAG1 (n = 1), CTNNB1::PLAG1 (n = 1) and a novel PXDNL::PLAG1 fusion (n = 1). The remaining 5 cases were negative, 5 were not analyzable and the single case positive for HMGA2 by IHC revealed a potential HMGA2 gene rearrangement. The cases were further studied by FISH, with 12/17 cases showing PLAG1 gene rearrangement (AMT, n = 8 and CM, n = 4). Altogether, 14/18 cases showed PLAG1 gene rearrangement by at least one of the methods. PLAG1 immunohistochemistry had a 92% specificity and sensitivity. Our study provided additional data to suggest that AMT and CM share overlapping morphological and immunohistochemical features as well as molecular background characterized by PLAG1 gene fusions and thus represent a morphological spectrum. In addition, we identified a novel PXDNL::PLAG1 fusion and suggested that rare cases may harbor HMGA2 gene alterations which seem to be mutually exclusive with PLAG1 gene fusions. The relatedness of these tumors to salivary gland myoepithelial neoplasms and distinctness from eccrine mixed tumors and other skin and soft tissue myoepithelial neoplasms with EWSR1/FUS fusions is discussed.

Familial syndromes associated with testicular and paratesticular neoplasms: a comprehensive review.

A syndromic association between a subset of testicular/paratesticular neoplasms is well established. Such examples include Carney complex and large cell calcifying Sertoli cell tumor, Peutz-Jeghers syndrome and intratubular large cell hyalinizing Sertoli cell neoplasia, and VHL syndrome and clear cell papillary cystadenoma of the epididymis.However, recent studies proposed potential novel links between some testicular and paratesticular neoplasms with certain tumor syndromes. While more studies are still needed to solidify these associations, recent research suggests that a subset of Leydig cell tumors may arise in patients with hereditary leiomyomatosis and renal cell carcinoma syndrome or that some seminomas may occur in Lynch syndrome patients. Additionally, an association between testicular sex cord stromal tumors and paratesticular sarcomas with Familial adenomatous polyposis syndrome and DICER1 syndrome, respectively, has been proposed as well. This review provides a comprehensive overview of the intricate relationship between familial syndromes and associated testicular and paratesticular tumors, shedding light on their clinicopathological and molecular characteristics.

Comprehensive clinicopathological, molecular, and methylation analysis of mesenchymal tumors with NTRK and other kinase gene aberrations.

Alterations in kinase genes such as NTRK1/2/3, RET, and BRAF underlie infantile fibrosarcoma (IFS), the emerging entity 'NTRK-rearranged spindle cell neoplasms' included in the latest WHO classification, and a growing set of tumors with overlapping clinical and pathological features. In this study, we conducted a comprehensive clinicopathological and molecular analysis of 22 cases of IFS and other kinase gene-altered spindle cell neoplasms affecting both pediatric and adult patients. Follow-up periods for 16 patients ranged in length from 10 to 130 months (mean 38 months). Six patients were treated with targeted therapy, achieving a partial or complete response in five cases. Overall, three cases recurred and one metastasized. Eight patients were free of disease, five were alive with disease, and two patients died. All cases showed previously reported morphological patterns. Based on the cellularity and level of atypia, cases were divided into three morphological grade groups. S100 protein and CD34 were at least focally positive in 12/22 and 14/22 cases, respectively. Novel PWWP2A::RET, NUMA1::RET, ITSN1::RAF1, and CAPZA2::MET fusions, which we report herein in mesenchymal tumors for the first time, were detected by RNA sequencing. Additionally, the first uterine case with BRAF and EGFR mutations and CD34 and S100 co-expression is described. DNA sequencing performed in 13 cases uncovered very rare additional genetic aberrations. The CNV profiles showed that high-grade tumors demonstrate a significantly higher percentage of copy number gains and losses across the genome compared with low- and intermediate-grade tumors. Unsupervised clustering of the tumors' methylation profiles revealed that in 8/9 cases, the methylation profiles clustered with the IFS methylation class, irrespective of their clinicopathological or molecular features. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Vascular Neoplasms With NFATC1/C2 Gene Alterations : Expanding the Clinicopathologic and Molecular Characteristics of a Distinct Entity.

Despite significant advances in their molecular pathogenesis, skeletal vascular tumors remain diagnostically challenging due to their aggressive radiologic appearance and significant morphologic overlap. Within the epithelioid category and at the benign end of the spectrum, recurrent FOS/FOSB fusions have defined most epithelioid hemangiomas, distinguishing them from epithelioid hemangioendothelioma and angiosarcoma. More recently, the presence of EWSR1/FUS :: NFATC1/2 fusions emerged as the genetic hallmark of a novel group of unusual vascular proliferations, often displaying epithelioid morphology, with alternating vasoformative and solid growth, variable atypia, reminiscent of composite hemangioendothelioma. In this study, we further our understanding and morphologic spectrum of NFATC -fusion positive vascular neoplasms by describing 9 new cases, including soft tissue locations and novel fusion partners. Combining with the initial cohort of 5 cases, a total of 14 patients were analyzed, showing slight female predilection and an age range of 10 to 66 (mean 42 y). Twelve patients had solitary lesions, while 2 had multifocal polyostotic (pelvic bones) disease. Overall, 12 lesions were intra-osseous and 2 in soft tissue. By targeted RNA Fusion panels or FISH, there were 6 cases of EWSR1::NFATC1 , 4 EWSR1::NFATC2 , 2 FUS::NFATC2 , 1 EWSR1 rearrangement, and 1 with a novel FABP4::NFATC2 fusion. Follow-up was available in 4 patients. One patient experienced 2 local recurrences, 11 and 15 years postdiagnosis, and one patient experienced progressive disease despite multimodality treatment (curettings, embolization, radiation) over 3 years. In summary, our extended investigation confirms that NFATC -related fusions define a distinct group of vascular neoplasms with variable architecture, epithelioid phenotype, and cytologic atypia, commonly located in the bone, occasionally multifocal and with potential for local recurrence and aggressive behavior but no metastatic potential. Molecular analysis is recommended in diagnostically challenging cases with atypical histology to exclude malignancy.

Molecular pathology in diagnosis and prognostication of head and neck tumors.

Classification of head and neck tumors has evolved in recent decades including a widespread application of molecular testing in tumors of the salivary glands, sinonasal tract, oropharynx, nasopharynx, and soft tissue. Availability of new molecular techniques allowed for the definition of multiple novel tumor types unique to head and neck sites. Moreover, the expanding spectrum of immunohistochemical markers facilitates a rapid identification of diagnostic molecular abnormalities. As such, it is currently possible for head and neck pathologists to benefit from a molecularly defined classifications, while making diagnoses that are still based largely on histopathology and immunohistochemistry. This review highlights some principal molecular alterations in head and neck neoplasms presently available to assist pathologists in the practice of diagnosis, prognostication and prediction of response to treatment.

Inflammatory Rhabdomyoblastic Tumor: From a Nebulous Smooth Muscle Neoplasm to a Novel Skeletal Muscle Tumor Subtype.

Inflammatory rhabdomyoblastic tumor is a recently introduced name for neoplasms currently included in the World Health Organization classification of soft tissue tumors under the rubric inflammatory leiomyosarcoma. Inflammatory rhabdomyoblastic tumor is an excellent example of how surgical pathologists working in conjunction with tumor biologists can greatly improve tumor classification to the benefit of patients. Over the last 28 years, understanding of this entity has undergone a fascinating evolution. This review serves as a summary of the latest findings in inflammatory rhabdomyoblastic tumor research and a diagnostic manual for the practicing surgical pathologist.

Sarcomas Harboring EWSR1::PATZ1 Fusions: A Clinicopathologic Study of 17 Cases.

Soft tissue sarcomas harboring EWSR1::PATZ1 are a recently recognized entity with variable morphology and a heterogeneous immunohistochemical profile. We studied 17 such tumors. The tumors occurred in 12 men and 5 women (median age, 50 years; range, 15-71 years), involved the thoracoabdominal soft tissues (14 cases; 82%), lower extremities (2 cases; 12%), and tongue (1 case; 6%), and ranged from 0.7 to 11.3 cm (median, 4.7 cm). All but 1 patient received complete surgical resection; 7 were also treated with neoadjuvant chemo/radiotherapy. All cases showed typical features of EWSR1::PATZ1 sarcoma, including uniform round to spindled cells, fibromyxoid matrix, fibrous bands, hyalinized vessels, and pseudoalveolar/microcystic spaces. Unusual features, seen in a subset of cases, included degenerative-appearing nuclear atypia, epithelioid cytomorphology, mature fat, abundant rhabdomyoblasts, high mitotic activity, and foci with increased cellularity and nuclear atypia. Positive immunohistochemical results were desmin (16/17, 94%), MyoD1 (13/14, 93%), myogenin (6/14, 43%), GFAP (10/10, 100%), S100 protein (15/17, 88%), SOX10 (7/13, 54%), keratin (10/17, 59%), CD99 (4/11, 36%), H3K27me3 (retained expression 9/9, 100%), p16 (absent expression 1/4, 25%), and p53 (wild type 3/3, 100%). Fusion events included EWSR1 exon 8::PATZ1 exon 1 (14/17, 82%), EWSR1 exon 9::PATZ1 exon 1 (2/17, 12%), and EWSR1 exon 7::PATZ1 exon 1 (1/17, 6%). No evaluated tumor had alterations of CDKN2A/B and/or TP53, or MDM2 amplification. Clinical follow-up (16 patients: median, 13.5 months; range, 1-77 months) showed distant metastases in 3 patients (1/3 at time of presentation) and no local recurrences. At the time of last follow-up, 14 patients were disease free, 1 was alive with disease, 1 was dead of disease (at 13 months), and 1 had an indeterminant pulmonary nodule. We conclude that the morphologic spectrum of EWSR1::PATZ1 is broader than has been previously appreciated. Although more long-term follow-up is needed, the prognosis of these very rare sarcomas may be more favorable than previously reported.

Branchioma: immunohistochemical and molecular genetic study of 23 cases highlighting frequent loss of retinoblastoma 1 immunoexpression.

Branchioma is an uncommon benign neoplasm with an adult male predominance, typically occurring in the lower neck region. Different names have been used for this entity in the past (ectopic hamartomatous thymoma, branchial anlage mixed tumor, thymic anlage tumor, biphenotypic branchioma), but currently, the term branchioma has been widely accepted. Branchioma is composed of endodermal and mesodermal lineage derivatives, in particular epithelial islands, spindle cells, and mature adipose tissue without preexistent thymic tissue or evidence of thymic differentiation. Twenty-three branchiomas were evaluated morphologically. Eighteen cases with sufficient tissue were assessed by immunohistochemistry, next-generation sequencing (NGS) using the Illumina Oncology TS500 panel, and fluorescence in situ hybridization (FISH) using an RB1 dual-color probe. All cases showed a biphasic morphology of epithelial and spindle cells with intermingled fatty tissue. Carcinoma arising in branchioma was detected in three cases. The neoplastic cells showed strong AE1/3 immunolabeling (100%), while the spindle cells expressed CD34, p63, and SMA (100%); AR was detected in 40-100% of nuclei (mean, 47%) in 14 cases. Rb1 showed nuclear loss in ≥ 95% of neoplastic cells in 16 cases (89%), while two cases revealed retained expression in 10-20% of tumor cell nuclei. NGS revealed a variable spectrum of likely pathogenic variants (n = 5) or variants of unknown clinical significance (n = 6). Loss of Rb1 was detected by FISH in two cases. Recent developments support branchioma as a true neoplasm, most likely derived from the rudimental embryological structures of endoderm and mesoderm. Frequent Rb1 loss by immunohistochemistry and heterozygous deletion by FISH is a real pitfall and potential confusion with other Rb1-deficient head and neck neoplasms (i.e., spindle cell lipoma), especially in small biopsy specimens.

Utility of Immunohistochemistry With Antibodies to SS18-SSX Chimeric Proteins and C-Terminus of SSX Protein for Synovial Sarcoma Differential Diagnosis.

Synovial sarcoma is a relatively common soft tissue tumor characterized by highly specific t(X;18)(p11;q11) translocation resulting in the fusion of SS18 with members of SSX gene family. Typically, detection of SS18 locus rearrangement by fluorescence in situ hybridization or SS18 :: SSX fusion transcripts confirms the diagnosis. More recently, immunohistochemistry (IHC) for SS18-SSX chimeric protein (E9X9V) and C-terminus of SSX (E5A2C) showed high specificity and sensitivity for synovial sarcoma. This study screened a cohort of >1000 soft tissue and melanocytic tumors using IHC and E9X9V and E5A2C antibodies. Three percent (6/212) of synovial sarcomas were either negative for SS18-SSX or had scattered positive tumor cells (n=1). In these cases, targeted RNA next-generation sequencing detected variants of SS18 :: SSX chimeric transcripts. DNA methylation profiles of 2 such tumors matched with synovial sarcoma. A few nonsynovial sarcoma tumors (n=6) revealed either focal SS18-SSX positivity (n=1) or scattered positive tumor cells. However, targeted RNA next-generation sequencing failed to detect SS18 :: SSX transcripts in these cases. The nature of this immunopositivity remains elusive and may require single cell sequencing studies. All synovial sarcomas showed positive SSX IHC. However, a mosaic staining pattern or focal loss of expression was noticed in a few cases. Strong and diffuse SSX immunoreactivity was also seen in epithelioid sclerosing osteosarcoma harboring EWSR1 :: SSX1 fusion, while several sarcomas and melanocytic tumors including cellular blue nevus (5/7, 71%) revealed focal to diffuse, mostly weak to intermediate SSX staining. The SS18-SSX and SSX IHC is a useful tool for synovial sarcoma differential diagnosis, but unusual immunophenotype should trigger molecular genetic testing.

Malignant female genital tract smooth muscle tumors with adipocytic differentiation: A morphologic, immunohistochemical, MDM2 fluorescence in situ hybridization and molecular genetic study of 6 lipoleiomyosarcomas.

Leiomyosarcoma with adipocytic differentiation or lipoleiomyosarcoma is an uncommon sarcoma of the female genital tract with only a few individual reports in the literature. We therefore performed a morphologic, immunohistochemical, MDM2 gene amplification and RNA and DNA sequencing analysis of a series of gynecologic lipoleiomyosarcoma to better define the clinicopathologic spectrum. Six tumors from 6 patients were identified and classified as spindled lipoleiomyosarcoma (n = 2), mixed spindled and myxoid lipoleiomyosarcoma (n = 1), epithelioid lipoleiomyosarcoma with focal myxoid features (n = 1) and mixed spindled and epithelioid lipoleiomyosarcoma (n = 2). Patient age ranged from 41 to 64 years (mean: 49; median: 50). Primary location included uterine corpus (3), uterine corpus/cervix (2) and broad ligament (1). Tumor size ranged from 4.5 to 22 cm (mean: 11.2; median: 9.8). Four patients had metastasis at presentation or subsequently developed recurrent or distant disease. Patient status was known for 5: 2 dead of disease, 2 alive with disease and 1 alive without evidence of disease. Immunohistochemical expression of smooth muscle markers, ER, PR and WT-1 showed patterns similar to non-adipocytic gynecologic leiomyosarcomas. MDM2 amplification fluorescence in situ hybridization performed on 2 tumors was negative in 1 and equivocal in 1. Sequencing studies performed on 3 tumors found TP53 mutations in 3, with 1 tumor also having an ATRX alteration. No gene fusions were identified. Although lipoleiomyosarcomas have a diverse morphologic spectrum, our findings suggest the smooth muscle component shares morphologic and immunohistochemical features with female genital tract non-adipocytic leiomyosarcomas. Lipoleiomyosarcomas also have genetic alterations associated with non-adipocytic gynecologic leiomyosarcomas.

Spindle cell rhabdomyosarcomas: With TFCP2 rearrangements, and novel EWSR1::ZBTB41 and PLOD2::RBM6 gene fusions. A study of five cases and review of the literature.

AIMS: Spindle-cell/sclerosing rhabdomyosarcomas (SS-RMS) are clinically and genetically heterogeneous. They include three well-defined molecular subtypes, of which those with EWSR1/FUS::TFCP2 rearrangements were described only recently. This study aimed to evaluate five new cases of SS-RMS and to perform a clinicopathological and statistical analysis of all TFCP2-rearranged SS-RMS described in the English literature to more comprehensively characterize this rare tumour type. METHODS AND RESULTS: Cases were retrospectively selected and studied by immunohistochemistry, fluorescence in situ hybridization with EWSR1/FUS and TFCP2 break-apart probes, next-generation sequencing (Archer FusionPlex Sarcoma kit and TruSight RNA Pan-Cancer Panel). The PubMed database was searched for relevant peer-reviewed English reports. Five cases of SS-RMS were found. Three cases were TFCP2 rearranged SS-RMS, having FUSex6::TFCP2ex2 gene fusion in two cases and triple gene fusion EWSR1ex5::TFCP2ex2, VAX2ex2::ALKex2 and VAX2intron2::ALKex2 in one case. Two cases showed rhabdomyoblastic differentiation and spindle-round cell/sclerosing morphology, but were characterized by novel genetic fusions including EWSR1ex8::ZBTB41ex7 and PLOD2ex8::RBM6ex7, respectively. In the statistical analysis of all published cases, CDKN2A or ALK alterations, the use of standard chemotherapy and age at presentation in the range of 18-24 years were negatively correlated to overall survival. CONCLUSION: EWSR1/FUS::TFCP2-rearranged SS-RMS is a rare rhabdomyosarcoma subtype, affecting predominantly young adults with average age at presentation 34 years (median 29.5 years; age range 7-86 years), with a predilection for craniofacial bones, rapid clinical course with frequent bone and lung metastases, and poor prognosis (3-year overall survival rate 28%).

Nasal and sinonasal tumors formed by atypical adenomatous lesions arising in respiratory epithelial adenomatoid hamartoma/seromucinous hamartoma.

Two benign adenomatous lesions are commonly recognized within the sinonasal tract, namely respiratory epithelial adenomatoid hamartoma (REAH) and seromucinous hamartoma (SH). We present 10 hitherto unrecognized benign polypoid nasal and sinonasal tumoriform lesions having in average 3.6 cm in largest dimension, which are histogenetically related to SH and REAH. In addition to typical structures of REAH and SH, these lesions contained an additional characteristic and slightly atypical adenomatous component, which we termed atypical sinonasal glands arising in SH (ASGSH). ASGSH often produced deep red colored secretion with peripheral clearing similar to that seen in thyroid follicles. In contrast to SH, ASGSH was endowed by both secretory and myoepithelial layers and had mostly angulated shapes with snout-like protrusions into the lumens. Both layers were formed by an irregular, disorganized, and often incomplete cell lining, which had slightly atypical cytological features without mitoses. In 3 cases, ASGSHs revealed sebaceous differentiation, and in 3 cases the stroma produced a well-differentiated cartilage. Neoplastic nature of ASGSH was supported by finding of various mutations as revealed by next generation sequencing in five cases. In two cases each, we found identical mutations in BRAF gene (Val600Glu), and RET gene (Arg912Trp), respectively and in one case FAT1 gene alteration (Pro1665Leu).

Benign female genital tract smooth muscle tumors with adipocytic differentiation: A morphologic, immunohistochemical and MDM2 fluorescence in situ hybridization study of 44 conventional lipoleiomyomas and lipoleiomyoma variants.

Leiomyomas with adipocytic differentiation typically occur in the uterus although they may arise at several sites in the female genital tract. While these are most commonly spindled leiomyomas with a component of adipocytic tissue ("conventional lipoleiomyomas"), there is a relatively ill-defined assortment of leiomyoma variants with adipocytic differentiation. We performed a morphologic, immunohistochemical and MDM2 gene amplification analysis of a large series of gynecologic leiomyomas with adipocytic differentiation to better define the clinicopathologic spectrum. Forty four tumors from 44 patients were identified and classified as conventional lipoleiomyoma (n = 21), adipocyte-rich lipoleiomyoma (defined as tumor volume >80 % adipocytes, n = 9); cellular lipoleiomyoma (n = 9); hydropic lipoleiomyoma (n = 3); and lipoleiomyoma with bizarre nuclei (n = 2). Patient age ranged from 32 to 83 years (mean 63; median 63). Primary location included uterine corpus (35), uterine cervix (3), uterine corpus/cervix (1), broad ligament (2), parametrium (2), and round ligament (1). Tumor size was 0.6-30 cm (mean 8; median 6). None of the 34 patients with follow up developed further disease (range 1-311 months; mean 65; median 41). Immunohistochemical expression of ER, PR, HMB45, Melan A, Cathepsin K and WT-1 in lipoleiomyomas and variants was similar to patterns in non-adipocytic gynecologic leiomyomas. MDM2 amplification fluorescence in situ hybridization performed on 14 tumors was negative in all. Our findings suggest female genital tract conventional lipoleiomyomas and lipoleiomyoma variants largely parallel their non-adipocytic counterparts in morphology and immunophenotype, and may be categorized using non-adipocytic leiomyoma histologic criteria.

The value of GLI1 and p16 immunohistochemistry in the premolecular screening for GLI1-altered mesenchymal neoplasms.

Mesenchymal neoplasms with GLI1 alterations have recently been reported in several anatomic locations. Their morphology and immunohistochemistry (IHC) are nonspecific, making their recognition a true challenge. To assess the diagnostic value of GLI1 and p16 IHC for identifying GLI1-altered neoplasms, we evaluated 12 such neoplasms (6 GLI1-amplified and 6 with GLI1-fusions) using the GLI1 IHC. Additionally, we evaluated some of their morphological and molecular mimickers, including glomangiomas, Ewing sarcomas (ES), myxoid liposarcomas, and MDM2/CDK4-amplified sarcomas (well-differentiated liposarcoma/WDLPS, dedifferentiated liposarcoma/DDLPS, and intimal sarcoma). All successfully tested GLI1-altered tumors (11/11) demonstrated at least moderate/strong nuclear and/or cytoplasmic GLI1 IHC positivity. GLI1-amplified tumors exhibited a moderate/strong predominantly nuclear staining, compared to a moderate, patchy, and predominantly cytoplasmic GLI1 positivity in GLI1-fusion tumors. Among their mimics, GLI1 immunoreactivity, either cytoplasmic or nuclear, was observed in intimal sarcoma (3/3) and WDLPS/DDLPS (22/25). GLI1 IHC demonstrated 92% sensitivity and 90.8% specificity in diagnosing GLI1-altered neoplasms. Strong/moderate nuclear/cytoplasmic p16 immunoexpression was noted in all GLI1-amplified tumors compared to none of fused cases. Overall, the GLI1/p16 combination demonstrated a sensitivity and specificity of 100% and 93% for GLI1-amplified tumors. In conclusion, we confirm that GLI1 IHC represents a good, quick, and cheap helpful screening tool. The inclusion of p16 may aid in pre-screening for potential GLI1-amplified neoplasms and provide insights on which tumors warrant further molecular testing.

EWSR1::POU2AF3(COLCA2) Sarcoma: An Aggressive, Polyphenotypic Sarcoma With a Head and Neck Predilection.

EWSR1::POU2AF3 (COLCA2) sarcomas are a recently identified group of undifferentiated round/spindle cell neoplasms with a predilection for the head and neck region. Herein, we report our experience with 8 cases, occurring in 5 men and 3 women (age range, 37-74 years; median, 60 years). Tumors involved the head/neck (4 cases), and one each the thigh, thoracic wall, fibula, and lung. Seven patients received multimodal therapy; 1 patient was treated only with surgery. Clinical follow-up (8 patients; range, 4-122 months; median, 32 months) showed 5 patients with metastases (often multifocal, with a latency ranging from 7 to 119 months), and 3 of them also with local recurrence. The median local recurrence-free and metastasis-free survival rates were 24 months and 29 months, respectively. Of the 8 patients, 1 died of an unknown cause, 4 were alive with metastatic disease, 1 was alive with unresectable local disease, and 2 were without disease. The tumors were composed of 2 morphologic subgroups: (1) relatively bland tumors consisting of spindled to stellate cells with varying cellularity and fibromyxoid stroma (2 cases) and (2) overtly malignant tumors composed of nests of "neuroendocrine-appearing" round cells surrounded by spindled cells (6 cases). Individual cases in the second group showed glandular, osteogenic, or rhabdomyoblastic differentiation. Immunohistochemical results included CD56 (4/4 cases), GFAP (5/8), SATB2 (4/6), keratin (AE1/AE3) (5/8), and S100 protein (4/7). RNA sequencing identified EWSR1::POU2AF3 gene fusion in all cases. EWSR1 gene rearrangement was confirmed by fluorescence in situ hybridization in 5 cases. Our findings confirm the head/neck predilection and aggressive clinical behavior of EWSR1::POU2AF3 sarcomas and widen the morphologic spectrum of these rare lesions to include relatively bland spindle cell tumors and tumors with divergent differentiation.

Non-cutaneous syncytial myoepitheliomas are identical to cutaneous counterparts: a clinicopathologic study of 24 tumors occurring at diverse locations.

AIMS: Cutaneous syncytial myoepithelioma (CSM) is a rare myoepithelioma variant of skin, characterized by intradermal syncytial growth of spindle cells with a distinct immunophenotype of EMA and S100 positivity and infrequent keratin expression. While CSM was first described as a cutaneous tumor, singular non-cutaneous cases have since been reported in bone. We aimed to investigate the clinicopathological features of this variant across all anatomic sites through a large multi-institutional study. METHODS AND RESULTS: We complied a total of 24 myoepitheliomas with syncytial growth from our files. The tumors occurred in 12 male and 12 female patients (M:F = 1:1), with a median age of 31 years (range, 9-69 years). While the majority of tumors (75%, n = 18) occurred in skin, a significant subset (25%, n = 6) arose in non-cutaneous sites, including bone (n = 3), bronchus/trachea (n = 2), and interosseous membrane of tibia/fibula (n = 1). Tumor size ranged from 0.4 to 5.9 cm. Clinical follow-up (7 patients; range 14-202 months; median 56.5 months) showed a single local recurrence 8 years after incomplete skin excision but no metastases; all patients were alive at the time of last follow-up without evidence of disease. Histologically, all tumors were pink at low-power and characterized by a syncytial growth of bland ovoid, spindled, or histiocytoid cells with eosinophilic cytoplasm and prominent perivascular lymphoplasmacytic inflammation. One-third displayed adipocytic metaplasia (8/24). Rare cytologic atypia was seen but was not associated with increased mitotic activity. All tumors expressed S100, SMA, and/or EMA. Keratin expression was absent in most cases. Molecular analysis was performed in 16 cases, all showing EWSR1-rearrangments. In total, 15/15 (100%) harbored an EWSR1::PBX3 fusion, whereas 1 case EWSR1 FISH was the only molecular study performed. CONCLUSION: Syncytial myoepithelioma is a rare but recognizable morphologic variant of myoepithelioma which may have a predilection for skin but also occurs in diverse non-cutaneous sites. Our series provides evidence supporting a reappraisal of the term "cutaneous syncytial myoepithelioma," as 25% of patients in our series presented with non-cutaneous tumors; thus, we propose the term "syncytial myoepithelioma" to aid pathologist recognition and avoidance of potentially confusing terminology when referring to non-cutaneous examples. The behavior of syncytial myoepithelioma, whether it arises in cutaneous or non-cutaneous sites, is indolent and perhaps benign with a small capacity for local recurrence.