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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.

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.

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.

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.

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.

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.

Background Appropriate use criteria (AUC) provide patient-centered physician guidance in test selection. An initial set of AUC was reported by the American Society of Dermatopathology (ASDP) in 2018. AUC reflect evidence collected at single timepoints and may be affected by evolving evidence and experience. The objective of this study was to update and expand AUC for selected tests. Methods RAND/UCLA (RAND Corporation [Santa Monica, CA]/University of California Los Angeles) methodology used includes the following: (a) literature review; (b) review of previously rated tests and previously employed clinical scenarios; (c) selection of previously rated tests for new ratings; (d) development of new clinical scenarios; (e) selection of additional tests; (f) three rating rounds with feedback and group discussion after rounds 1 and 2. Results For 220 clinical scenarios comprising lymphoproliferative (light chain clonality), melanocytic (comparative genomic hybridization, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, telomerase reverse transcriptase promoter), vascular disorders (MYC), and inflammatory dermatoses (periodic acid-Schiff, Gomori methenamine silver), consensus by panel raters was reached in 172 of 220 (78%) scenarios, with 103 of 148 (70%) rated "usually appropriate" or "rarely appropriate" and 45 of 148 (30%), "appropriateness uncertain." Limitations The study design only measures appropriateness. Cost, availability, test comparison, and additional clinical considerations are not measured. The possibility that the findings of this study may be influenced by the inherent biases of the dermatopathologists involved in the study cannot be excluded. Conclusions AUC are reported for selected diagnostic tests in clinical scenarios that occur in dermatopathology practice. Adhering to AUC may reduce inappropriate test utilization and improve healthcare delivery.

Primary cutaneous Ewing sarcoma (EWS) is a very rare neoplasm that shares similar morphologic, immunohistochemical, and molecular features with its osseous counterpart. Herein, we present an extraordinarily rare case of PAX7-positive cutaneous EWS in a 9-year-old girl that was also diffusely positive for SOX10 and S100-protein. Next generation sequencing detected the EWSR1-FLI1 fusion supporting the diagnosis, which was further validated by break-apart EWSR1 fluorescence in situ hybridization. Diffuse S100-protein and SOX10 expression has been reported only in a handful of cases of EWS and may pose significant diagnostic challenges for dermatopathologists. PAX7 is a recently introduced marker, which is highly sensitive for EWS and can potentially have discriminatory power in the differential diagnosis of cutaneous undifferentiated round blue cell tumors.

The immunohistochemical stain ERG is a useful diagnostic marker for leukemia cutis. Translocations involving the ERG gene have been identified in acute myeloid leukemia (AML) and it plays critical roles in differentiation of hematopoietic stem cells. However, little is known about ERG expression in the bone marrow or in myeloid neoplasms. The aim of this study is to characterize ERG expression in normal bone marrow specimens, and those with various myeloid neoplasms. We performed immunohistochemical studies assessing ERG expression in bone marrow biopsies obtained over a 1-year period, in which myeloperoxidase (MPO) was used to assess granulocyte populations. Twenty-eight bone marrow biopsies (6 normal, 12 with acute myeloid leukemia (AML), 6 with myeloproliferative neoplasms (MPN), and 4 with myelodysplastic/MPN) were identified. Strong nuclear ERG staining was present within the granulocytes and precursors in near complete concordance with MPO in 26/28 (93%) cases. Fifty-eight percent of AML cases showed more staining for ERG than MPO in the leukemic cells. ERG can be useful for assessing granulocyte populations in bone marrow biopsies, and in many instances of AML, stained a proportion of myeloblasts.

Cutaneous metastases from hepatocellular carcinoma (HCC) are extremely rare and can represent a sign of an underlying malignancy or relapse/progression from an existing tumor. We report a case of a cutaneous metastasis arising in a patient with metastatic HCC following orthotopic liver transplantation. Diagnosis is a multistep process as cutaneous HCC metastases must be differentiated from primary cutaneous malignancies as well as other cutaneous metastases. Making this even more challenging, HCC metastases have heterogeneous clinical and histologic appearances. Therefore, the use of immunohistochemical stains, including hepatocyte paraffin-1, arginase-1, and glypican-3, and correlation with the clinical context are essential for a correct diagnosis.

BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene, located on chromosome 3p21, encoding BAP1 nuclear protein, which is associated with a subset of melanocytic tumors with distinct cytologic features. Single nucleotide polymorphism array (SNP-array) is a molecular karyotyping technique that can detect copy number variations and loss of heterozygosity in various fresh and formalin-fixed paraffin-embedded tissues. Herein we present a 56-year-old female, who presented with a lesion on her left nose/cheek that was growing in size and changing in color. Histopathology was characteristic of a BAP1-deficient melanocytic neoplasm, with a biphasic population of cytologically bland conventional nevomelanocytes and a proliferation of large epithelioid melanocytes with abundant eosinophilic cytoplasm. Immunohistochemistry for BAP1 showed loss of nuclear labeling in the epithelioid melanocytes. SNP-array revealed a chromosome 21q22.1 monoaberration with no chromosome 3 abnormalities. The detection of this aberration prompted a discussion as to whether the lesion was best designated as a nevus or tumor. SNP-array on the patient's blood showed the same monoaberration of chromosome 21q22.1. This case emphasizes the importance of interpreting microarray results in the context of morphology, as germline aberrations can be a pitfall when assessing the genomic stability of a melanocytic proliferation by SNP array.

Dermatofibrosarcoma protuberans (DFSP) is a translocation-associated, low-grade sarcoma with fibroblastic differentiation. It is the most common superficial sarcoma, almost exclusively arising within the dermis. In a minority of cases, there is a transition from the conventional morphology to a fibrosarcomatous pattern, known as a fibrosarcomatous DFSP (FS-DFSP). Although a number of different molecular alterations have been described to account for this transformation, it remains poorly understood. Herein we report the first case of a FS-DFSP with a fusion between ERG, an ETS family transcription factor, and MAP3K7CL, a kinase gene rarely observed in fusion gene events.

Malignant melanoma (MM) may display highly variable phenotypic diversity, sometimes associated with loss of immunohistochemical melanocytic markers and acquisition of nonmelanocytic lineage of differentiation. Primary cutaneous MM with rhabdomyosarcomatous differentiation is extremely rare with only 5 reported cases in the literature. To date, a chronological progression of a MM to rhabdomyosarcoma has not been conclusively documented. A 96-year-old man underwent a re-excision of an "atypical fibroxanthoma" of the forearm, which revealed a small lentigo maligna melanoma associated with a dominant dermal high-grade spindle cell nodule admixed with a population of malignant polygonal epithelioid cells. On immunohistochemical studies, the spindle cells were completely negative for all melanocytic markers, whereas a small population of polygonal neoplastic cells at the periphery was positive for Desmin and Myo-D1, supporting early rhabdomyosarcomatous transformation. Several subsequent re-excisions demonstrated merely nodules of malignant pleomorphic epithelioid cells with rhabdomyosarcomatous differentiation and devoid of melanocytic markers. In addition, both rhabdomyosarcomatous component and original MM displayed identical mutations. Therefore, the histologic, immunohistochemical, and molecular findings documented for the first time a chronological progression from an invasive MM to a pleomorphic rhabdomyosarcoma through an intermediate stage of undifferentiated sarcoma/atypical fibroxanthoma. Interestingly, subsequent recurrences of pure rhabdomyosarcomatous component displayed skip lesions/microsatellitosis, marked tumor-infiltrative lymphocytes, and rare junctional nests of rhabdomyosarcomatous cells in the epidermis, histologic features that were not described in primary cutaneous rhabdomyosarcoma and therefore could serve as morphologic clues to the diagnosis of rhabdomyosarcomatous transformation in an MM.

Anastomosing hemangioma (AH) is a relatively novel variant of benign vascular tumors originally described in the genitourinary tract. Although AH was subsequently documented in various anatomic locations, a primary AH of the skin has not been reported in the literature. The current case report documents a vascular lesion with histologic features reminiscent of an AH. A 41-year-old female patient underwent an excision of a painful nodule on the leg. Histologic examination showed a well-circumscribed vascular lesion composed of anastomosing sinusoidal capillary-sized vessels, several intravascular fibrin thrombi, rare intraluminal nucleated red blood cells, and focal intracytoplasmic hyaline globules. As AH was hitherto only documented in extracutaneous sites, most dermatopathologists are probably not familiar with this variant of hemangioma. The current case report details the morphologic features of a potential example of a primary cutaneous AH to increase the awareness of this distinctive hemangioma variant among dermatopathologists. Larger studies of vascular lesions with similar histologic features and immunohistochemical profiles are warranted to investigate the potential existence of primary AH in the skin.

Melanoma ex blue nevus (MEBN) is a rare, aggressive, and potentially lethal neoplasm. Distinguishing MEBN from an atypical cellular blue nevus can be very challenging. We report a diagnostically difficult case of MEBN with lymph node metastases, in which single nucleotide polymorphism array and fluorescence in situ hybridization were used to arrive at the correct diagnosis. It was also analyzed by the recently-introduced proprietary 23-gene expression signature test. To the best of our knowledge, this is the second reported case of MEBN analyzed by the 23-gene expression signature, which provided a false-negative result. More studies are needed to assess the sensitivity and specificity of this test in various melanocytic proliferations.

Perivascular epithelioid cell tumors (PEComas) are a family of mesenchymal neoplasms that have smooth muscle and melanocytic differentiation. They can be sporadic or associated with tuberous sclerosis complex and commonly present in the kidney as angiomyolipoma or in the lung as pulmonary clear cell sugar tumors or lymphangioleiomyomatosis. However, they can present at any visceral or soft tissue site. They usually have a benign clinical course, but rarely can behave in a malignant fashion. Most PEComas demonstrate abnormalities of TSC2, but a recently described subset harbor TFE3 rearrangements that seem to be mutually exclusive of TSC2 alterations. TFE3-rearranged PEComas demonstrate a distinct alveolar morphology that lacks spindle cells and smooth muscle differentiation. Distinction between these may have important therapeutic consequences. Herein, we present a case of a TFE3-rearranged PEComa without the customary morphology that required ancillary investigation with TFE3 immunohistochemistry and break-apart fluorescence in situ hybridization for proper categorization.

As the landscape of melanomagenesis becomes better refined through increasingly detailed schema grounded in distinct clinicopathologic-molecular pathways, the stepwise process and variations of molecular nevogenesis have largely remained elusive. Herein, we present a series of 8 melanocytic nevi in patients ranging from 40 to 74 years of age (median: 59.5 y), which demonstrated a reproducible constellation of histomorphologic features as well as a copy number gain of the long arm of chromosome 15 (15q). The most characteristic histologic feature was sclerosis with maturation at the base of the lesion. All cases demonstrated a dome-shaped configuration and epidermal acanthosis with hyperpigmentation. However, the cytologic features ranged in their appearances from that of a banal nevus with ovoid nuclei, inconspicuous nucleoli, and minimal cytoplasm to enlarged, epithelioid forms with central nucleoli and abundant cytoplasm. No lesions showed staining with BRAF V600E or NRAS Q61R immunohistochemistry. Single-nucleotide polymorphism-based chromosome microarray analysis revealed a monoaberrant 15q gain in all cases. The histology was sufficiently distinctive in the initial 6 cases encountered to allow for prospective identification of 2 additional cases harboring a 15q gain. The clinical follow-up did not reveal recurrence in any case. Although adverse outcomes were not observed in our cohort, future studies are needed to more adequately characterize the clinical and biological behavior of these lesions.

"Cutaneous melanocytic tumor with CRTC1-TRIM11 fusion" (CMTCT) is a newly described, potentially novel entity that typically presents as a dermal nodule on the head and neck, extremities, and trunk of adults. Histopathologically, it is reported as a nodular or multinodular tumor composed of epithelioid and spindle cells that are variably immunoreactive for S100-protein, SOX10, and MITF along with more specific melanocytic markers such as MelanA and HMB45. With only 11 cases reported in the English literature so far, the neoplasm appears to behave in a relatively indolent fashion. Nevertheless, in one case, local recurrence and synchronous distant metastasis were evident after 13 years. Additional cases with longer follow-up are essential to determine the neoplasm's biologic behavior with more accuracy. Herein, two cases of CMTCT, one arising on the lower back of a 65-year-old female and the other on the arm of a 33-year-old female in addition to a comprehensive literature review are reported.

Background Secondary AS most commonly follows breast cancer and includes postirradiation AS (PRAS) and lymphedema-associated AS. The frequent amplification of MYC (8q24.21) in secondary AS and the rising incidence of PRAS and atypical vascular lesions (AVLs) have prompted interest in the diagnostic and prognostic utility of MYC in AS. Methods Retrospective series with ≥ 2 cases of cutaneous AS and describing the use of FISH for MYC amplification or IHC for MYC overexpression were included. Results Sixteen studies met inclusion criteria. Overall, 93 percent of cases evaluated by FISH and IHC were concordant. The sensitivity of FISH in primary AS was only 6.8 percent, and protein overexpression occurred without amplification in sun-damaged skin. FISH and IHC were over 78 percent sensitive in secondary AS, but negative in over 98 percent of AVLs. MYC amplification and FLT4 coamplification were associated with shorter overall survival in secondary AS. Conclusion FISH for MYC amplification and IHC for MYC overexpression are useful in distinguishing PRAS from AVLs and may also have prognostic value in secondary AS. In contrast, these methods have little diagnostic or prognostic value in primary AS and should not be used to distinguish primary AS from benign vascular neoplasms. This article is protected by copyright. All rights reserved.

Malignant gastrointestinal neuroectodermal tumor (GNET) is an extremely rare neoplasm. Immunohistochemically, GNET typically demonstrates neural differentiation but lacks melanocytic differentiation, making it distinct from clear cell sarcoma of the soft tissues (CCS). Herein we report for the first time the cytomorphologic features of lymph node metastasis from presumably liver GNET. A 36-year-old female presented with fevers, night sweats, loss of appetite, and a 20-lbs weight loss. Radiographic imaging showed a 13 cm heterogeneously enhancing mass in the right lobe of the liver and a hypermetabolic 0.9 cm periportal lymph node on positron emission tomography-computed tomography (PET/CT). Initially, a CT-guided liver biopsy was performed followed by right hepatic lobectomy and portal lymphadenectomy. The liver biopsy and resection showed an S100-protein and SOX10 positive malignant neoplasm and genomic profiling of liver biopsy revealed EWSR1-CREB1gene rearrangement. These findings in conjunction with the morphologic and immunohistochemical profile were diagnostic of GNET. Two months later, she presented with recurrent lymphadenopathy in the upper abdomen. Fine needle aspiration of the periportal nodal mass revealed single and clusters of primitive, large to medium-sized neoplastic cells with round to oval nuclei, high nuclear-cytoplasmic ratio, vesicular chromatin, and prominent nucleoli. The tumor cells were S100 protein and SOX10 positive, consistent with metastasis of the patient's recently diagnosed malignant digestive system GNET. Palliative chemotherapy was administered but the patient died a few days later, 4 months from the initial diagnosis. Awareness of this entity and judicial use of ancillary studies including molecular testing are essential for achieving accurate diagnosis.

Low-grade endometrial stromal sarcoma (LGESS) is a rare malignant uterine tumor with the potential to metastasize years after the primary resection. There is a broad differential diagnosis for endometrial stromal sarcomas (ESS), including both benign and malignant entities. Herein, we present the case of a 64-year-old female with metastatic LGESS to the lung, diagnosed by cytology, 24 years after her initial presentation. This report discusses the cytomorphologic and histopathologic characteristics, and ancillary studies including immunohistochemical stains and recent advances in molecular diagnostics of ESS. Accurate diagnosis of spindle cell lesions in the lung can be challenging. As such, this case highlights the instrumental role of ancillary testing and molecular diagnostics to achieve a more definitive diagnosis.

Follicular dendritic cell sarcoma (FDCS) is a rare malignant neoplasm of follicular dendritic cell origin which can present a diagnostic challenge. Due to the rarity of this neoplasm, its molecular pathogenesis has not been fully elaborated. A previous series of 13 cases reported that 38% contained mutations of genes encoding proteins involved in negative regulation of NF-κB. NF-κB is a family of transcription factors regulated through multiple cellular processes known as the canonical and noncanonical pathways. Here we present the case of a 62-year-old man who presented with abdominal pain and systemic symptoms and was found to have a mass in the porta hepatis. Fine needle aspiration cytology demonstrated a spindle cell neoplasm with vesicular chromatin and prominent nucleoli with admixed lymphocytes. Surgical resection showed an intranodal, 7.3 × 5.5 × 3.5 cm, solid mass composed of plump, spindle to histiocytoid cells with ovoid nuclei and small, prominent nucleoli arranged in a whorled and fascicular pattern. The lesional cells stained positively for CD21, CD23, and CD35 by immunohistochemistry, consistent with a diagnosis of FDCS. Next-generation sequencing revealed pathologic mutations in three genes involved in NF-κB regulation pathways: NFKBIA, TNFAIP3, and TRAF3. A pathologic TP53 mutation was also identified. This case report supports prior associations of the NF-κB pathway dysregulation and FDCS. Additionally, it is the first reported FDCS case with TRAF3 mutation as well as the first reported case to suggest disruption in both the canonical and noncanonical NF-κB pathways in the same lesion.

To our knowledge, we describe the first mesenchymal tumor with a novel GLI1-FOXO4 fusion gene. This well-circumscribed kidney tumor displayed variably myxoid and epithelioid histologic features with a focally nodular growth pattern and bland, round to ovoid nuclei. No overt high-grade features were seen. Focal immunohistochemistry expression of smooth muscle actin (SMA) and Melan-A suggests a possible relationship with perivascular epithelioid cell tumor (PEComa). The clinical and morphologic features appear distinct from other reported neoplasms harboring GLI1 or FOXO4 gene rearrangements. The patient underwent surgical nephrectomy and is without evidence of disease during a relatively short clinical follow-up period. However, we feel that the features of this tumor warrant long-term follow-up to monitor for the possibility of a late recurrence or metastasis. In addition to reporting this novel fusion tumor, we also provide a brief review of GLI1 and FOXO4 gene functions in both normal and neoplastic contexts, including proposed functional outcomes of the specific fusion gene identified in this case. This article is protected by copyright. All rights reserved.

Pseudomyogenic hemangioendothelioma, an uncommon mesenchymal neoplasm composed of plump spindled and/or epithelioid endothelial cells, may present multicentrically and tends to locally recur but rarely metastasizes. Morphologic resemblance to epithelioid sarcoma and other spindle cell neoplasms may result in diagnostic confusion. Molecular characterization of pseudomyogenic hemangioendothelioma has revealed these neoplasms often harbor a rearrangement of the FOSB gene with SERPINE1 or ACTB as recurrent fusion gene partners. Herein, a case of a fibular pseudomyogenic hemangioendothelioma with minimal extension into the adjacent soft tissue arising in a 17 year-old male is presented. The neoplasm exhibited sheets of epithelioid cells with abundant eosinophilic cytoplasm and variably eccentric nuclei. RNA sequencing revealed a novel CLTC-FOSB fusion transcript that was subsequently confirmed by direct sequencing of reverse transcription-polymerase chain reaction products demonstrating an in-frame fusion between exon 17 of the clathrin heavy chain (CLTC) gene and exon 2 of the FOSB (FosB proto-oncogene, AP-1 transcription factor subunit) gene. CLTC-FOSB fusion has not been described in a neoplasm before.

Pulmonary adenofibroma (PAF) is a rare neoplasm that may be related to solitary fibrous tumor (SFT). A subset of PAFs harbor the NAB2-STAT6 fusion that is typical of SFT, but a significant proportion do not. Their distinction is clinically important as SFTs can potentially have an aggressive clinical course, while there has been no report of a PAF behaving in a malignant fashion. We report a case of a 60-year-old male who developed a SFT and PAF in the same lung. The SFT harbored a NAB2-STAT6 fusion, while the PAF did not have any identifiable fusion. This case represents the first instance of a single patient with both of these tumors occurring simultaneously in the same lung.

AIMS: The aim of this study was to identify potential driver genetic alterations in a dedifferentiated liposarcoma with rhabdomyosarcomatous differentiation. METHODS AND RESULTS: A 24-year-old female underwent resection of an abdominal mass which on a previous biopsy demonstrated rhabdomyosarcomatous differentiation concerning for embryonal rhabdomyosarcoma (ERMS). Histologically the resected tumor displayed a high-grade sarcoma with rhabdomyosarcomatous differentiation in the background of well-differentiated liposarcoma consistent with dedifferentiated liposarcoma (DDLPS). Fluorescence in situ hybridization confirmed MDM2 amplification, as did array-based copy number profiling. Whole-exome sequencing revealed a somatic FGFR1 hotspot mutation and RNA-sequencing an LMNB2-MAP2K6 fusion only within the dedifferentiated component. CONCLUSIONS: This study represents an in-depth examination of a rare dedifferentiated liposarcoma with rhabdomyosarcomatous differentiation in a young individual. Additionally, it is also instructive of a potential pitfall when assessing for MDM2 amplification in small biopsies. Despite exhaustive analysis, mutation and gene copy number analysis did not identify any molecular events that would underlie the rhabdomyoblastic differentiation. Our understanding of what causes some tumors to dedifferentiate as well as undergo divergent differentiation is limited, and larger studies are needed.

Solitary fibrous tumor (SFT) is a unique mesenchymal neoplasm that was originally believed to be of submesothelial origin. Eventually, SFT expanded to include what was previously called hemangiopericytoma in other regions of the body that had similar immunohistochemical and morphologic features. Although most are benign, many studies have tried to identify histologic features that predict which tumors will behave in an aggressive manner. Recently, dedifferentiation has been described in rare cases of SFT and does appear to correlate with a more aggressive clinical course. Dedifferentiated SFT occurs in a similar age range and location as conventional SFT and can resemble multiple different malignant entities. Utilization of ancillary studies and thorough tissue sampling is important to reach the correct diagnosis. The morphologic features, immunohistochemistry, molecular alterations, and prognosis will be discussed.

BackgroundPanniculitis occurring in dermatomyositis is uncommon, with only a few cases described in the literature, most of them as case reports. ObjectiveThis report describes the clinicopathological and immunohistochemical findings in a series of 18 patients with panniculitis associated with dermatomyositis. MethodsIn each patient, we collected the clinical data of the cutaneous lesions as well as the characteristic clinical and laboratory findings. A series of histopathologic findings was recorded in the biopsy of each patient. A panel of antibodies was used in some cases to investigate the immunophenotype of the infiltrate. Data of treatment and follow-up were also collected. ResultsOf the 18 patients, 13 were female and 5 were male, ranging in age from 13 to 74 years (median, 46.4 years). In addition to panniculitis, all patients presented pathognomonic cutaneous findings of DM and reported proximal muscle weakness prior to the diagnosis of panniculitis. Muscle biopsy was performed in 17 patients and MRI in one, all with the diagnosis of inflammatory myopathy. None of the patients presented any associated neoplasia. Panniculitis lesions were located in the upper or lower limbs. Histopathology showed a mostly lobular panniculitis with lymphocytes as the main component of the infiltrate. Most cases showed also numerous plasma cells and lymphocytes surrounding necrotic adipocytes (rimming) were frequently seen. Lymphocytic vasculitis and abundant mucin interstitially deposited between collagen bundles of the dermis were also frequent findings. Late-stage lesions showed hyaline necrosis of the fat lobule and calcification. Immunohistochemistry demonstrated that most lymphocytes of the infiltrate were T-helper lymphocytes, with some B lymphocytes in the lymphoid aggregates and small clusters of CD-123-positive plasmacytoid dendritic cells in the involved fat lobule. ConclusionPanniculitis in dermatomyositis is rare. Histopathologic findings of panniculitis dermatomyositis are identical to those of lupus panniculitis. Therefore, the final diagnosis requires clinic-pathologic correlation. Linked article: This article is commented on by A. Kuhn, pp. 1231-1232 in this issue. To view this article visit

Histopathology is the gold standard for diagnosing melanocytic lesions; however, distinguishing benign versus malignant is not always clear histologically. Single nucleotide polymorphism (SNP) microarray analysis may help in making a definitive diagnosis. Here, we share our experience with the Oncoscan FFPE Assay and demonstrate its diagnostic utility in the context of ambiguous melanocytic lesions. Eleven archival melanocytic lesions, including three benign nevi, four melanomas, three BAP1-deficient Spitzoid nevi and one nevoid melanoma were selected for validation. SNP-array was performed according to the manufacturer's protocol, using the recommended 80ng of DNA; however, as little as 15ng was used if the extraction yield was lower. Concordance was assessed with H&E and various combinations of BAP1 and p16 immunohistochemical stains (IHC) and external reference laboratory chromosomal microarray results. After validation, the SNP array was utilized to make definitive diagnoses in four challenging cases. Oncoscan SNP array findings were in concordance with H&E, IHC, and reference laboratory chromosomal microarray testing. The SNP-based microarray can accurately detect copy number changes and aid in making a more definitive diagnosis of challenging melanocytic lesions. This can be accomplished using significantly less DNA than is required by other microarray technologies.

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.

Primary intraprostatic synovial sarcoma is a rare presentation of an otherwise well-studied disease, and it is one of the few primary sarcomas to occur in the prostate. Ancillary diagnostic techniques including immunohistochemistry and molecular genetics are useful to establish a definitive diagnosis. Despite its unorthodox location, it shares histologic and molecular genetic characteristics with tumors found elsewhere in the body. Most notably, the chromosomal translocation t(X;18)(p11;q11) encodes a chimeric transcription-activating protein, SS18-SSX, which has been identified as the primary driver mutation. The SS18-SSX fusion gene provides a consistent and dependable means of establishing a definitive diagnosis via reverse transcription–polymerase chain reaction or fluorescence in situ hybridization. Recent studies have continued to provide insight into the oncogenesis of this disease. The goal of this review is to elaborate on the clinicopathologic characteristics and underline those techniques that best facilitate the diagnosis of primary intraprostatic synovial sarcoma.