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Calcified chondroid neoplasms with FN1::FGFR1 or FGFR2 constitute a recently described category of mesenchymal neoplasms mostly encountered in the extremities and temporomandibular joint. Herein, we report a case of FNI1-fused calcified chondroid neoplasm of the hand with a novel FGFR3 fusion partner. The tumor exhibited a multilobulated growth pattern composed of epithelioid cells embedded in abundant stroma with myxoid, chondroid and fibrous areas and scattered osteoclast-like giant cells. RNA sequencing revealed an in-frame fusion between exon 31 of FN1 and exon 3 of FGFR3, which was subsequently confirmed by reverse transcription-polymerase chain reaction. Our findings expand on the spectrum of potential fusion partners in FN1-fused calcified chondroid neoplasms. This article is protected by copyright. All rights reserved.

BRCA1-associated protein 1 (BAP-1) is a deubiquitylase that functions as a tumor suppressor, regulating multiple cellular processes including cell cycle control, differentiation, cell death, and DNA repair. BAP-1-inactivated melanocytic tumors (BIMTs) have recently been described and are characterized by epithelioid cytomorphology, are often clonal in appearance, and typically do not recur or show malignant transformation on follow-up.To describe the histopathologic and molecular characterization of five cases of BAP-1-inactivated cutaneous malignant melanomas.The archives at two separate institutions were retrospectively searched for tumors classified as melanoma with loss of BAP-1 via immunohistochemistry. Five cases were identified. These cases were classified as malignant melanoma based on cytomorphology, immunohistochemistry, and ancillary molecular testing. The clinical demographics were recorded, along with the histomorphologic features of each case. Genomic analysis for all cases was performed via OncoScan.The five reviewed cases consisted of two females and three males ranging from 67 to 74 years in age. Molecular characterization of each case was performed using OncoScan. Microarray assay showed that there was a complete deletion of 3p in all cases, BRAF V600E mutation in two cases, NRAS missense variant in one case, and loss of 9p in three cases. All cases showed malignant copy number alterations.Herein we describe five cases of BAP-1-inactivated melanomas confirmed by histomorphology and immunohistochemistry, all of which show malignant copy number profiles including loss of 3p. In addition, we provide a case of a likely BIMT showing progression to BAP-1-inactivated melanoma on a 16-year follow-up.

Hemangioblastoma, one of the characteristic tumors associated with Von Hippel-Lindau (VHL) disease, most often presents in the central nervous system (CNS) but can uncommonly arise in extraneuraxial, or previously referred to as peripheral, locations. Without the clinical context of known VHL disease, hemangioblastoma may not enter the differential for a soft tissue mass outside the CNS. Here, we present two patients with diagnostically challenging extraneuraxial hemangioblastoma to highlight the importance of considering this entity within the differential diagnosis of soft tissue neoplasms containing clear cells and delicate vasculature. We review the relevant diagnostic features, including a suggested immunohistochemical panel, along with the potential associated clinical implications of making this diagnosis. It is recommended that affected patients be offered genetic counseling to assess for underlying VHL disease.

The overwhelming majority of cutaneous neoplasms with melanocytic differentiation are nevi, melanomas, or less commonly melanocytomas. Nevertheless, there is also a group of mesenchymal neoplasms with genuine melanocytic differentiation which can create diagnostic difficulties with significant repercussions. These can rarely present as primary or metastatic cutaneous lesions. The ones that are relevant to a dermatopathologist include malignant melanotic nerve sheath tumor, perivascular epithelioid cell neoplasm, and clear cell sarcoma. This work will provide a thorough review of clinical presentation, morphologic and immunohistochemical features as well as molecular pathogenesis of these tumors. We hope to familiarize the general dermatopathology readership with a group of neoplasms of mesenchymal lineage exhibiting melanocytic differentiation and ultimately avoid diagnostic misadventures.

Originally described in a rare subset of poorly differentiated squamous cell carcinomas termed NUT carcinomas, NUTM1 rearrangements are now known to characterize a wide spectrum of neoplasms including sarcomas, poromas/porocarcinomas, unclassified adnexal carcinomas and pediatric acute lymphoblastic leukemia. The advent of next-generation sequencing (NGS) has led to the identification of a multitude of novel fusion partners in addition to BRD4, which was initially reported in the majority of NUT carcinomas. NUTM1-rearranged sarcomas usually harbor fusions with the MAD gene family ( MXD1, MXD4, MGA) and present as spindle cell proliferations in diverse locations in patients of all ages. Herein, we present a very rare case of spindle cell sarcoma of the lung, which harbored a NUTM1::MGA fusion and offer a comprehensive update of the recent data.

Subungual melanoma can be diagnostically challenging. We evaluated the potential of PReferentially expressed Antigen for MElanoma (PRAME) immunoreactivity for differentiating benign from malignant nail melanocytic lesions.Sixty cases were identified (10 invasive melanomas, 8 melanomas in situ, 14 nevi, 12 cases of lentigo, and 16 of melanocytic activation). Percentage of PRAME-positive melanocytes was evaluated as follows: 0 no staining, 1+ 1%-25%, 2+ 26%-50%, 3+ 51%-75%, and 4+75%. A combined score of both percentage and intensity was also evaluated.The difference in PRAME expression between malignant and benign lesions was statistically significant (p 0.0001). The degree of PRAME expression significantly correlated with patients' age and clinical size. When based on percentage score, 61.1% of melanomas showed a 4+ score, 16.7% showed a 3+ score, 11.1% showed a 1+ score, and 11.1% was negative; 69.0% of the benign lesions was negative, 23.8% showed a 1+ score, 4.8% showed a 2+ score, and 2.4% showed a 4+ score. When the cutoff value for malignancy decreased from 4+ to 3+, the sensitivity increased from 61.1% to 77.8%, while specificity remained 97.6%. Combined score results were similar.PRAME is a relatively sensitive and highly specific marker in differentiating benign from malignant nail melanocytic lesions. However, correlation with morphology is imperative.

Epithelioid hemangioma of bone is a rare benign, locally aggressive vascular tumor that can be particularly challenging to diagnose given its frequent multifocality, non-specific imaging findings, and wide range of morphologic appearances. Additionally, some epithelioid hemangiomas demonstrate atypical histologic features including increased cellularity, necrosis, and moderate cytologic atypia - characteristics that may raise concern for malignancy. Molecular studies can serve as a powerful, objective tool in the differential diagnosis of diagnostically challenging epithelioid vascular tumors. Importantly

Inflammatory myofibroblastic tumor (IMT) is a distinctive fibroblastic and myofibroblastic spindle cell neoplasm with an accompanying inflammatory cell infiltrate and frequent receptor tyrosine kinase activation at the molecular level. The tumor may recur and rarely metastasizes. IMT is rare in the head and neck region, and limited information is available about its clinicopathologic and molecular characteristics in these subsites. Therefore, we analyzed a cohort of head and neck IMTs through a multi-institutional approach. Fourteen cases were included in the provisional cohort, but 1 was excluded after molecular analysis prompted reclassification. Patients in the final cohort included 7 males and 6 females, with a mean age of 26.5 years. Tumors were located in the larynx (n=7), oral cavity (n=3), pharynx (n=2), and mastoid (n=1). Histologically, all tumors showed neoplastic spindle cells in storiform to fascicular patterns with associated chronic inflammation, but the morphologic spectrum was wide, as is characteristic of IMT in other sites. An underlying fusion gene event was identified in 92% (n=11/12) of cases and an additional case was ALK-positive by IHC but could not be evaluated molecularly. ALK represented the driver in all but 1 case. Rearrangement of ALK, fused with the TIMP3 gene (n=6) was most commonly detected, followed by 1 case each of the following fusion gene partnerships: TPM3-ALK, KIF5B-ALK, CARS-ALK, THBS1-ALK, and a novel alteration, SLC12A2-ROS1. The excluded case was reclassified as spindle cell rhabdomyosarcoma after detection of a FUS-TFCP2 rearrangement and retrospective immunohistochemical confirmation of rhabdomyoblastic differentiation, illustrating an important diagnostic pitfall. Two IMT patients received targeted therapy with crizotinib, with a demonstrated radiographic response. One tumor recurred but none metastasized. These results add to the growing body of evidence that kinase fusions can be identified in the majority of IMTs and that molecular analysis can lead to increased diagnostic accuracy and broadened therapeutic options for patients.

We and others have noticed consistent staining of sebaceous glands with PReferentially expressed Antigen in MElanoma (PRAME). We aimed to determine whether PRAME was as sensitive, specific, and interpretable as adipophilin for distinguishing sebaceous neoplasms (SNs) from other neoplasms.Twenty SNs and 32 control cases were stained for PRAME and adipophilin. Extent of staining was scored as follows: 0, no staining; 1,5% positivity; 2, 5% to 50% positivity; and 3,50% positivity. Intensity was scored as negative, weak, moderate, or strong. A composite score was determined by adding the scores for extent and intensity.PRAME had positive composite scores in all 20 SNs in the more differentiated areas, whereas adipophilin had positive composite scores in 19/20 cases. PRAME showed positivity in the basaloid cells in 15/16 cases, whereas adipophilin was positive in 14. Among controls, PRAME and adipophilin had positive composite scores in 3/32 cases and 6/32 cases, respectively.PRAME and adipophilin are comparable in terms of distribution and intensity for staining sebocytes. In the basaloid cells, PRAME expression is often more diffuse and easier to detect than adipophilin. In comparing the SNs to the controls, PRAME was more sensitive and more specific than adipophilin. PRAME could be used as an additional marker of sebaceous differentiation in everyday practice.

The knowledge of clinical features and, particularly, histopathological spectrum of EWSR1-PATZ1-rearranged spindle and round cell sarcomas (EPS) remains limited. For this reason, we report the largest clinicopathological study of EPS to date. Nine cases were collected, consisting of four males and five females ranging in age from 10 to 81 years (average: 49 years). Five tumors occurred in abdominal wall soft tissues, three in the thorax, and one in the back of the neck. Tumor sizes ranged from 2.5 to 18 cm (average 6.6 cm). Five patients had follow-up with an average of 38 months (range: 18-60 months). Two patients had no recurrence or metastasis 19 months after diagnosis. Four patients developed multifocal pleural or pulmonary metastasis and were treated variably by surgery, radiotherapy, and chemotherapy. The latter seemed to have little to no clinical benefit. One of the four patients was free of disease 60 months after diagnosis, two patients were alive with disease at 18 and 60 months, respectively. Morphologically, low, intermediate, and high-grade sarcomas composed of a variable mixture of spindled, ovoid, epithelioid, and round cells were seen. The architectural and stromal features also varied, resulting in a broad morphologic spectrum. Immunohistochemically, the following markers were most consistently expressed: S100-protein (7/9 cases), GFAP (7/8), MyoD1 (8/9), Pax-7 (4/5), desmin (7/9), and AE1/3 (4/9). By next-generation sequencing, all cases revealed EWSR1-PATZ1 gene fusion. In addition, 3/6 cases tested harbored CDKN2A deletion, while CDKN2B deletion and TP53 mutation were detected in one case each. Our findings confirm that EPS is a clinicopathologic entity, albeit with a broad morphologic spectrum. The uneventful outcome in some of our cases indicates that a subset of EPS might follow a more indolent clinical course than previously appreciated. Additional studies are needed to validate whether any morphological and/or molecular attributes have a prognostic impact.

Introduction: Molecular analysis plays a growing role in the diagnosis of mesenchymal neoplasms. The aim of this study was to retrospectively apply broad, multiplex molecular assays (a solid tumor targeted next-generation sequencing [NGS]) assay and single nucleotide polymorphism [SNP] microarray) to selected tumors, exploring the current utility and limitations. Methods: We searched our database (2010-2020) for diagnostically challenging mesenchymal neoplasms. After histologic review of available slides, tissue blocks were selected for NGS, SNP microarray, or both. DNA and RNA were extracted using the AllPrep DNA/RNA FFPE Kit Protocol on the QIAcube instrument. The NGS platform used was the TruSight Tumor 170 (TST-170). For SNP array, copy number variant (CNV) analysis was performed using the OncoScanTM CNV Plus Assay. Results: DNA/RNA was successfully extracted from 50% of tumors ( n = 10/20). Specimens not successfully extracted included 6 core biopsies, 3 incisional biopsies, and 1 resection; 4 were decalcified (3 hydrochloric acid, 1 ethylenediaminetetraacetic acid). Higher tumor proportion and number of tumor cells were parameters positively associated with sufficient DNA/RNA extraction whereas necrosis and decalcification were negatively associated with sufficient extraction. Molecular testing helped reach a definitive diagnosis in 50% of tumors ( n = 5/10). Conclusions: Although the overall utility of this approach is limited, these molecular panels can be helpful in detecting a specific “driver” alteration.

Eosinophilic hyaline inclusions (EHIs) or globules have been reported in various cutaneous tumors including vascular lesions, myoepithelial neoplasms, and basal cell carcinoma. In basal cell carcinoma, the presence of intracytoplasmic inclusions is reportedly associated with myoepithelial differentiation. In this regard, EHI has not been conclusively documented in a cutaneous lesion of genuine squamous cell lineage without aberrant differentiation. In the current case, a biopsy from the right thigh of a 71-year-old male patient demonstrated a relatively well-demarcated intraepidermal squamous lesion featured an admixture of predominantly enlarged keratinocytes harboring distinct eccentric intracytoplasmic EHI and a smaller population of keratinocytes displaying pale cytoplasm. Cytologic atypia, mitotic activity, and inflammatory cells were not identified. The intracytoplasmic EHI stained red with Masson's trichrome and were negative with periodic-acid Schiff with and without diastase. Immunologically, the lesion was strongly and diffusely positive for various cytokeratins but negative for ubiquitin and myoepithelial markers. Only cytokeratin AE1 revealed a differential staining pattern as the suprabasal lesional cells displayed significantly stronger immunoreactivity in comparison with the adjacent normal keratinocytes. Polymerase chain reaction for low-risk and high-risk human papillomavirus was negative. Molecular studies did not reveal any mutations commonly encountered in seborrheic or lichenoid keratoses. As an analogous lesion has not previously reported in the literature, the term hyaline inclusion acanthoma is proposed for this peculiar lesion.

Poromas, and their malignant counterparts, porocarcinomas, harbor recurrent translocations involving YAP1-MAML2, YAP1-NUTM1, and infrequently WWTR1-NUTM1; YAP1-NUTM1 being the most common in porocarcinomas. NUT immunohistochemistry (IHC) can be used to identify NUTM1-translocated tumors. This study sought to investigate potential novel NUTM1-fusion partners among NUT IHC-positive poromas and porocarcinomas.Thirteen NUT IHC-positive poroid tumors (four poromas and nine porocarcinomas) were identified within a multi-institutional international cohort. Next-generation sequencing (NGS) assessed for NUTM1 fusion partners.NGS detected a NUTM1 fusion in 12 of 13 cases: YAP1-NUTM1 (11/12 cases) and WWTR1-NUTM1 (1/12 cases). Two of the cases (2/12) with NUTM1 fusion were not called by the NGS algorithm but had at least one read-spanning YAP1-NUTM1 break point upon manual review. A NUTM1 fusion was not identified in one case; however, the sample had low RNA quality. The following fusion events were identified: YAP1 exon 4::NUTM1 exon 3 in six cases, YAP1 exon 6::NUTM1 exon 2 in one case, YAP1 exon 3::NUTM1 exon 3 in three cases, WWTR1 exon 3::NUTM1 exon 3 in one case, and YAP1 exon 8::NUTM1 exon 3 fusion in one case.While no novel NUTM1 fusion partners were identified within our cohort, 12 of 13 cases had discoverable NUTM1 fusions; YAP1-NUTM1 fusion was detected in 11 cases (92%) and WWTR1-NUTM1 in 1 case (8%). These data corroborate findings from other recent investigations and further substantiate the utility of NUT IHC in diagnosing a subset of poroid neoplasms. In addition, two of our cases harbored fusions of YAP1 exon 6 to NUTM1 exon 3 and YAP1 exon 8 to NUTM1 exon 2, which have not been reported before in poroid neoplasms and indicate novel break points of YAP1.

Desmoplastic small round cell tumor (DSRCT) is a rare malignant tumor that occurs mainly in the retroperitoneum of children and young adults. In its prototypical form, DSCRT displays characteristic morphology with nested primitive small round cells in a desmoplastic stroma and a distinctive immunophenotype with polyphenotypic differentiation. However, DSCRT can also exhibit a broader clinical, histologic and immunohistochemical spectrum and, therefore, cause diagnostic difficulties. Given that DSCRT is an aggressive and nearly universally fatal disease, making the correct diagnosis is critically important. Herein, we report three patients with DSRCT and unusual clinical, morphologic or immunohistochemical characteristics, in order to highlight its remarkable diversity and increase awareness of this unusual, distinctive neoplasm.

Primary sarcomas of the lung are extremely uncommon. A diverse group of round cell sarcomas has been reported to originate in this location, including Ewing sarcoma, desmoplastic small round cell tumor, rhabdomyosarcoma, and poorly differentiated synovial sarcoma. The rarity of these tumors presents a potential pitfall; without careful study, they may easily be misidentified as the significantly more common poorly differentiated carcinoma. While histomorphology is a key aspect of correctly identifying a sarcoma, ancillary testing has become increasingly important in making a definitive diagnosis, as more and more recurrent genetic alterations are discovered and new entities are defined. We present three cases of primary round cell sarcomas of the lung that proved diagnostically challenging, describe the features and ancillary testing that led to the correct diagnoses, and discuss classic and evolving entities among sarcomas with round cell morphology.

Originally described in a rare subset of poorly differentiated squamous cell carcinomas termed NUT carcinomas

Epithelioid fibrous histiocytoma (EFH) is a rare cutaneous neoplasm, which is characterized by the presence of rearrangements involving the ALK gene. Although EFH was long considered a variant of fibrous histiocytoma, the identification of its unique genetic signature confirmed that it represents a distinct entity. The aim of the present study was to examine a cohort of ALK-immunoreactive EFH cases to further characterize gene fusion partners. Next generation sequencing detected ALK fusions in 11 EFH cases identified in the pathology archives of two different institutions. The most common fusion partner was DCTN1 (N = 4) followed by CLTC (N = 2) and VCL (N = 2), while the remaining cases harbored fusions involving SPECC1L, PPFIBP1, and PRKAR1A. In one case no fusion was detected by NGS and FISH despite suitable sample quality. Notably, IHC demonstrated positive ALK expression and the level of aligned ALK reads was comparable to the fusion-positive cases. To the best of our knowledge, this is the first report of CLTC as a fusion partner in EFH. The two CLTC rearranged cases in our cohort also represent the first two EFH cases in the literature that involve exon 19 of ALK, instead of exon 20. These findings underscore the remarkable plasticity of ALK as an oncogenic driver and further expand the list of its potential fusion partners in EFH. Lastly this is also the first report of ALK-immunoreactive EFH with no underlying fusion suggesting a fusion independent transcription mechanism as seen in other tumors.

Porocarcinoma is a rare malignant adnexal tumor with predilection for the lower extremities and the head and neck region of older adults. This entity may arise de novo or in association with a benign poroma. Porocarcinoma's non-specific clinical appearance, immunohistochemical profile and divergent differentiation may occasionally be diagnostically challenging. Recently, highly recurrent YAP1 and NUTM1 gene rearrangements have been described in cases of poroma and porocarcinoma. In this report, we present a case of porocarcinoma with squamous differentiation in an 81-year-old woman which harbored rearrangement of the YAP1 and NUTM1 loci and was diffusely immunoreactive for NUTM1. We discuss the recent advancements in the pathogenesis of poromas and porocarcinomas with emphasis on the clinical utility of the NUTM1 antibody. This article is protected by copyright. All rights reserved.

A small subset of cutaneous melanomas harbor oncogenic gene fusions, which could potentially serve as therapeutic targets for patients with advanced disease as novel therapies are developed. Fusions involving RAF1 are exceedingly rare in melanocytic neoplasms, occurring in less than 1% of melanomas, and usually arise in tumors that are wild type for BRAF, NRAS, and NF1. We describe herein a case of acral melanoma with two satellite metastases and sentinel lymph node involvement. The melanoma had a concomitant KIT variant and LRRFIP2-RAF1 fusion. This constellation of molecular findings has not been reported previously in melanoma. We review the existing literature on melanocytic neoplasms with RAF1 fusions and discuss the potential clinical implications of this genetic event. This article is protected by copyright. All rights reserved.

Endocrine Mucin-Producing Sweat Gland Carcinoma (EMPSGC) is a rare cutaneous adnexal malignancy with predilection for the eyelids of older adults. It must be distinguished from metastatic adenocarcinomas of extracutaneous origin and from benign adnexal proliferations on partial samples when a solid growth component and mucin production are not evident. Thus, demonstration of neuroendocrine differentiation can help to ensure a correct diagnosis. Insulinoma-associated protein 1 (INSM1) is a novel neuroendocrine marker that has recently shown greater sensitivity than synaptophysin (SYN) and chromogranin (CHR) in the diagnosis of various neuroendocrine neoplasms. We compared the performance of these three markers across ten examples of EMPSGC. All EMPSGC expressed INSM1. Eight of ten were also immunoreactive for SYN; however, INSM1 staining was generally more intense and stained a greater proportion of the tumor cells. CHR staining was weak and focal in most cases. INSM1 staining was present in hidrocystoma-like components of cystic EMPSGC. These findings suggest that INSM1 may be more sensitive than SYN and CHR and thus valuable for establishing a diagnosis of EMPSGC. This article is protected by copyright. All rights reserved.

Mammary-type myofibroblastoma (MFB) is a benign spindle cell tumor of the breast and soft tissue characterized by 13q14 alterations leading to loss of Rb-1 protein expression, a feature shared among spindle cell lipoma and cellular angiofibroma. In this article, we present a novel case of MFB arising in the left breast of a 70-year old man that microscopically showed an abrupt transition from classic MFB morphology to an area with cytologic atypia and mitotic activity, akin to sarcomatous transformation described in cellular angiofibromas. A thorough workup of the molecular underpinnings of both components using chromosomal microarray and next-generation sequencing platforms supported a clonal relationship. Nearly identical copy number changes, including a single copy loss of 13q14, were found in both components; in addition, the sarcomatous component harbored biallelic TP53 alterations. It is important for pathologists to recognize that sarcomatous features can occur in mammary-type MFB to arrive at the correct diagnosis.

Ossifying fibromyxoid tumor (OFMT) is a rare soft tissue neoplasm of uncertain differentiation and intermediate biologic potential. Up to 85% of OFMTs, including benign, atypical, and malignant forms, harbor fusion genes. Most commonly, the PHF1 gene localized to 6p21 is fused with EP400, but other fusion partners, such as MEAF6, EPC1, and JAZF1 have also been described. Herein, we present two rare cases of superficial OFMTs with ZC3H7B-BCOR and the very recently described PHF1-TFE3 fusions. The latter also exhibited moderate to strong diffuse immunoreactivity for TFE3. Reciprocally, this finding expands the entities with TFE3 rearrangements. Accumulation of additional data is necessary to determine if OFMTs harboring these rare fusions feature any reproducible clinicopathologic findings or carry prognostic and/or predictive implications.

Primary cutaneous Ewing sarcoma is a very rare entity with less than 100 cases reported in the literature, sharing the same morphological and immunohistochemical characteristics as their osseous counterparts. Herein, to the best of our knowledge, we report the first case in English literature of a molecularly confirmed Ewing sarcoma with diffuse and strong SOX10 immunoreactivity. This exceedingly rare immunohistochemical finding along with the rarity of this tumor could easily lead to a misdiagnosis with significant repercussions. Our case highlights the difficulty in diagnosing primary cutaneous Ewing sarcoma as well as the pivotal role molecular diagnostics can play in specific scenarios.

BACKGROUND Fluorescence in situ hybridization (FISH) and single nucleotide polymorphism (SNP) arrays are well-established molecular tests for the analysis of challenging melanocytic lesions. A 23-gene expression signature (GES), marketed as myPath Melanoma, is a recently introduced molecular test that categorizes melanocytic lesions as "benign," "malignant," and "indeterminate." There are few studies on the concordance between FISH, SNP, and GES in the analysis of melanocytic lesions. METHODS A single-institution retrospective analysis of 61 contiguous cases of challenging melanocytic lesions with molecular analysis by 2 or more techniques. The primary objective was to determine the intertest agreement, which was calculated as percent agreement. A secondary objective was to determine the combined-test performance, that is, the frequency of obtaining a successful test (a test with an abnormal or normal, benign or malignant result) when 2 or more molecular tests were performed. RESULTS Of the 61 cases, 58 cases were submitted for analysis using the GES assay, 44 cases were submitted for FISH analysis, and 21 cases were submitted for SNP array analysis. Percent agreement between GES and FISH array was 50.9% (18/34), which improved to 69.7% (18/23) when indeterminate/equivocal results were excluded. Similarly, percent agreement between GES and SNP array was 57.1% (8/14); this improved to 77.8% (7/9) when indeterminate/equivocal results were excluded. In 44% of cases submitted for GES and FISH and in 39% of cases submitted for GES and SNP, one test was successful and the other was not. CONCLUSION For challenging melanocytic lesions, the choice of a molecular test is consequential as the GES assay correlated with FISH and SNP arrays approximately only half of the time. This improved when cases with indeterminate/equivocal results were excluded from the calculations. The combined-test analysis supports the utility of conducting more than one molecular test, as this increased the odds of obtaining a successful test.

Pachydermodactyly is an uncommon, progressive, nontender thickening of the fingers with prominent involvement of the proximal interphalangeal joints. Pachydermodactyly mimics inflammatory arthritis but plain film radiography is normal in this condition. Pachydermodactyly has been previously described in workers performing manual labor. Mechanical stimulation has been identified as a predisposing factor in the majority of cases. We present three cases in adolescent males arising in association with excessive computer gaming.

Cutaneous metastases by solid malignancies often signify advanced disease and portend severely limited survival. Appropriate diagnosis of these lesions is particularly hampered when they closely resemble primary cutaneous tumors. In this article, we present two diagnostically challenging cases of metastatic lesions to the scalp bearing striking histologic resemblance to primary cutaneous neoplasms. One case of a metastatic urothelial carcinoma showed epidermotropism as well as histologic and immunohistochemical features virtually indistinguishable from those of a poorly differentiated squamous cell carcinoma. Next generation sequencing was performed on both the primary urothelial carcinoma and scalp malignancy revealing an identical BRAF p. S467L somatic mutation, confirming the diagnosis. Another case of metastatic renal cell carcinoma showed clinical and histomorphologic features highly reminiscent of a pyogenic granuloma. These cases demonstrate the potential of metastatic lesions to assume a myriad array of innocuous disguises and underscore the vigilance required to avoid misdiagnosis. In addition, we highlight the emerging role of molecular strategies in resolving these problematic cases.

Acral fibromyxoma (AF) is a slow growing benign soft tissue tumor with predilection to subungal and periungal region of the hands or feet. CD34 is consistently expressed whereas very recently loss of Rb1 expression was described as a possible driver molecular event for this entity. Herein we present two additional cases of AF with loss of Rb1 expression by IHC and subsequent confirmation of loss of the RB1 gene locus by fluorescence in situ hybridization (FISH). We hope to raise awareness in dermatopathology community of this new discovery, which can be diagnostically exploitable for this distinct and probably underreported neoplasm.

Desmoplastic small round-cell tumor (DSRCT) is a rare, aggressive malignant tumor, which in the great majority of cases arises at abdominal-pelvic sites. Nevertheless, rare cases of primary extra-abdominal tumors have been reported. In challenging cases, its molecular hallmark, the EWSR1-WT1 reciprocal translocation, can be exploited diagnostically by various molecular techniques. Herein, we report an extremely rare case of primary subcutaneous DSRCT in an effort to raise awareness among our dermatopathology colleagues by expanding the differential of superficial round-cell tumors.

Papillary hemangioma is a recently described benign hemangioma that typically presents on the head and neck of otherwise healthy individuals. It comprises branching papillary structures that protrude into the lumen of ectatic thin-walled vessels. Glomeruloid hemangioma (GH) is a similar, but unique, entity that occurs in patients with POEMS syndrome. The additional clinical implications of GH make distinction from papillary hemangioma critical. An additional case is herein presented and the literature on the subject reviewed. Potential differential diagnoses are discussed, with particular emphasis on the distinction from GH.

BRCA1-associated Protein 1 (BAP1)-inactivated melanocytic nevi/tumors (BIMT) have distinct morphologic features. A typical case exhibits a biphasic population of cytologically bland conventional melanocytes and a second proliferation of larger epithelioid melanocytes with abundant eosinophilic cytoplasm. The vast majority of cases harbor BRAF V600E in both components with bi-allelic inactivation of BAP1 in the epithelioid component by various molecular mechanisms resulting in loss of nuclear protein expression, which can be demonstrated by immunohistochemistry. We present a case of BIMT with histopathologic features highly suggestive of this entity but unexpected retention of nuclear expression of the BAP1 protein. Subsequent molecular tests showed heterozygous loss of the BAP1 locus on the short arm of chromosome 3 (3p21.1) by chromosomal microarray analysis (CMA) and a suspected c.505C>T p.H169Y pathogenic variant identified by DNA sequencing that was subsequently confirmed by primer-specific SNaPshot mini-sequencing. In light of the heterozygous deletion of BAP1, this variant in the remaining allele encodes a catalytically inactive BAP1 mutant protein as shown in functional studies. The presence of a nonfunctional allele within the nucleus combined with a heterozygous deletion of BAP1 explains the clear and characteristic BIMT morphology observed by histopathology. This case underlines the potential importance of molecular diagnostics when protein expression studies do not correlate with morphology.

Among sarcomas with a round-cell morphology that lack rearrangement of the EWSR1 gene, rearrangements involving the CIC gene are the most common. In comparison with Ewing Sarcoma, CIC-rearranged sarcomas present at an older average age, arise almost exclusively in soft tissues, are clinically more aggressive, and are more likely to be resistant to the chemotherapy regimens used for Ewing sarcoma. CIC-rearranged sarcomas present more commonly in a deep location, and we suspect that superficial presentations may be under-recognized. In this case series, we report three of such cases. Overall, the morphology is similar to CIC-rearranged sarcomas of deeper locations. We hope to raise awareness among the dermatopathology community by expanding the differential of superficial tumors with round cell morphology.

Objective: Tumors in the periurethral area can be a rare clinical entity with many difficulties not only in the diagnosis, as well as in the treatment plan. Skene's gland adenocarcinoma accounts for less than 0.003% of all female urethral malignant neoplasms. Case report: This report describes an extremely rare case of woman with a poorly differentiated carcinoma arising from the periurethral glands. Conclusions: Reporting of such rare cases enhance the understanding of the biological behavior of such tumors and the best treatment plan as well. This case report highlights the need for multidisciplinary approach of such rare cases, the lack of experience for such cases and the fact that the optimal treatment plan is very critical for the best prognosis of these patients. Keywords: Periurethral mass, Carcinoma, Multidisciplinary

Castleman disease is a rare benign lymphoproliferative disorder that includes a spectrum of distinct histopathological entities. The differential diagnosis of Castleman disease is broad and includes lymphomas, HIV-related lymphadenopathy, autoimmune disorders, and inflammatory liposarcoma. When Castleman disease occurs in the retroperitoneum, the distinction from the inflammatory variant of well-differentiated liposarcoma can be very challenging in small biopsies. Herein we report a case of Castleman disease that presented as a retroperitoneal mass and expressed MDM2 and CDK4 by immunohistochemistry. To our knowledge, this is the first report of Castleman disease staining positively for MDM2/CDK4, and it underscores how immunohistochemistry can potentially serve as a pitfall when differentiating this rare entity from retroperitoneal sarcomas.

Crospovidone is an insoluble pharmaceutical disintegrant that has been implicated in a rare foreign body reaction in injection drug users, classically associated with pulmonary angiothrombosis. We recently reported the first known cases of cutaneous crospovidone deposition. We herein report two additional cases with unique clinicopathologic manifestations, both in the setting of suspected injection drug abuse. Additionally, we provide a comprehensive overview of the distinct histomorphology and reproducible histochemistry of crospovidone.

Adenomyoepithelioma is an extremely rare primary cutaneous neoplasm. Although there is ample evidence on the existence of malignant adenomyoepithelioma in the breast, a malignant counterpart in the skin has not been documented. We report a primary cutaneous adenomyoepithelioma (pcAME) with malignant features arising from a spiradenoma in a 39-year-old female patient. The tumor was solid-cystic in appearance and entirely located in the subcutaneous tissue. Histologically, the tumor displayed foci of adenomatous changes and adenomyoepitheliomatous hyperplasia adjacent to a minute spiradenoma. Gradual increase of architectural complexity, cytologic atypia, mitotic activity, and infiltrative growth were observed in a significant portion of the neoplasm, indicative of transformation to adenomyoepithelioma and subsequently low- to high-grade salivary-type epithelial-myoepithelial carcinoma (EMCA). The intimate dual populations of ductal and myoepithelial cells were highlighted by a panel of immunohistochemical stains in all different components of the tumor. Molecular studies revealed a PIKCA3 mutation, a genetic aberration that has been documented in EMCA, particularly of breast origin. The current case documents for the first time a pcAME with malignant features arising from a spiradenoma and suggests adenomyoepithelioma ex spiradenoma as a possible tumorigenesis pathway of this rare cutaneous tumor.

Epithelioid fibrous histiocytoma (EFH) is a rare lesion believed to arise from dermal microvascular unit fibroblasts and dendritic histiocytes. EFH has long been considered a morphologic variant of benign fibrous histiocytoma (dermatofibroma), with prominent epithelioid cytomorphology that can mimic both vascular and melanocytic neoplasms. The molecular basis for the relationship between EFH and benign fibrous histiocytoma has remained largely unknown, with some authors suggesting that EFH represents an entity that is biologically distinct from benign fibrous histiocytoma. Recent molecular studies have identified the presence of recurrent anaplastic lymphoma kinase (ALK) gene rearrangements, a phenomenon that has not been described in benign fibrous histiocytoma. These new molecular findings highlight the uniqueness of this rare tumor and may prove useful as a diagnostic tool for differentiation from other histologic mimics.

Dedifferentiated liposarcoma is a nonlipogenic sarcoma of variable histological grade that frequently arises in association with a well-differentiated liposarcoma. Dedifferentiation occurs in approximately 10% of well-differentiated liposarcomas and is most commonly encountered in the retroperitoneum. Dedifferentiated liposarcoma of the upper respiratory tract is an extremely rare occurrence. Herein, we report a very rare case of low-grade dedifferentiated liposarcoma of the pharynx that presented as a polyp mimicking a benign process clinically and microscopically. We discuss the relevant molecular findings and review the current literature.

Malignant melanotic nerve sheath tumor (MMNST) is an exceedingly rare and aggressive neoplasm of Schwann cell origin that has seldom been described in the cytopathology literature. Herein we present a case of a 60-year-old female with a 3.8 cm presacral mass that was diagnosed as a MMNST. A molecular workup demonstrated TERT promoter -124C > T and TET2 Q891* gene mutations. Within 2 years of her initial diagnosis, she had developed widespread metastasis and pleural effusions. A cytologic workup of the pleural fluid revealed clusters of vacuolated epithelioid cells with enlarged nuclei, prominent nucleoli, and occasional multinucleation. The lesional cells were positive for SOX10, S100-protein, Melan-A, and HMB45, while negative for Calretinin, MOC31, and monoclonal CEA. In this clinicopathologic context, a diagnosis of metastatic MMNST was rendered. Awareness of this entity and its clinical presentation, along with a critical understanding of its molecular findings and that of imitators, is crucial in achieving an accurate diagnosis.

Simple Summary Molecular profiling of unclassified neoplasms has been pivotal in the characterization of new entities. Cutaneous melanocytic tumor with CRTC1::TRIM11 fusion (CMTCT) is a newly described neoplasm that falls into the broad category of diagnostically challenging dermal proliferations with melanocytic differentiation. The aim of this review is to educate colleagues about the clinical, histopathologic, and molecular features of CMTCT, and provide important information on the differential diagnosis. Abstract “Cutaneous melanocytic tumor with CRTC1::TRIM11 fusion” (CMTCT) is a recently described entity belonging to the family of superficial tumors displaying melanocytic differentiation. Thirteen cases have been reported so far, on the head and neck, extremities, and trunk of adults of all ages (12 cases) and one in an 11-year-old child. Histopathologically, it is a nodular or multilobulated tumor composed of spindle and epithelioid cells arranged in nests, fascicles, or bundles that are surrounded by thin collagenous septa. By immunohistochemistry, the tumor shows variable immunoreactivity for S100-protein, SOX10, and MITF, as well as specific melanocytic markers such as MelanA and HMB-45. The neoplasm’s biologic behavior remains uncertain since the reported cases are limited and the follow-up is short (median 12 months). However, local recurrence and synchronous distant metastasis after 13 years of initial resection has been described in one case. Herein, we present a comprehensive literature review of CMTCT hoping to raise awareness among the dermatopathologists of this potentially novel entity.