Pigmented intraepithelial Merkel cell carcinoma mimicking melanoma in situ.

Merkel cell carcinoma (MCC) is a rare neoplasm that arises in the skin of elderly patients on sun-exposed areas such as the head, neck, and extremities. Involvement of the epidermis by tumor cells is a relatively uncommon phenomenon. However, a few cases have been reported of Merkel cell carcinoma in situ (MCCIS) in which tumor cells are confined exclusively to the epidermis without dermal involvement. Herein, we present a peculiar MCCIS lesion in a 66-year-old man composed of tumor cells in a nested and lentiginous growth pattern, exhibiting variable quantities of intracytoplasmic dusty brown pigment consistent with melanin, thus closely mimicking melanoma in situ. In addition, the lesion was associated with invasive squamous cell carcinoma, which has not been previously reported in the literature. An extensive search of the PubMed-indexed, English-language literature yielded only 17 case reports of MCCIS without documented invasion in which clinical data were available. Out of the cases with available clinical information, individuals with strict MCCIS (n = 13) showed no evidence of recurrence or metastases. The median follow-up time in the cases with available data (n = 9) was 12 months (mean 12.8 months, range 6-21). Thus, MCCIS without invasion may have a favorable clinical course in contrast to invasive MCC tumors.

A Case of Anastomosing Hemangioma of the Breast During Pregnancy.

Anastomosing hemangiomas (AH) are rare benign masses. We report an occurrence of AH in the breast during pregnancy, its pathological analysis, and clinical management. Key in the evaluation of these rare vascular lesions is differentiating AH from angiosarcoma. A low proliferative Ki-67 index and small size on imaging and final pathology will confirm AH from angiosarcoma. Clinical management of AH requires surgical resection and standard interval mammography and clinical breast examination.

An Unusual Benign Uterine Stromal Spindle Cell Tumor Harboring JAZF1::BCORL1.

Uterine mesenchymal lesions demonstrate various underlying genomic alterations involving MED12 , JAZF1 , YWHAE , BCOR , and ALK genes, among others. Recent publications describe a subset of high-grade endometrial stromal sarcoma lesions harboring BCORL1 gene aberrations including JAZF1::BCORL1 . Herein, we present an unusual benign endomyometrial spindle cell lesion that defies classificatory efforts by demonstrating mixed histomorphologic and immunohistochemical features of endometrial stromal nodule, leiomyoma, and uterine inflammatory myofibroblastic tumor while harboring a JAZF1::BCORL1 . The lesion was found in a 43-yr-old woman with pelvic pain and heavy menses as a 5.5 cm well-circumscribed ulcerated mass fungating from the cervical os. Microscopic examination revealed a polypoid, well-circumscribed, moderately cellular endomyometrial tumor composed by bland spindle cells haphazardly disposed within a slightly edematous stroma enriched by a delicate network of thin-walled vessels that were occasionally encircled by the tumor cells. Unequivocal evidence of tongue-like growth pattern into the myometrium, tumor-type necrosis or increased mitotic activity was not identified after sampling the entire lesion. The lesion showed patchy immunoreactivity for both smooth muscle actin-alpha and desmin while negative for CD10, HMB45, ALK (D5F3), and BCOR. An Archer FusionPlex panel assay demonstrated a fusion involving both exons 4 from the JAZF1 and BCORL1 genes. The JAZF1::BCORL1 has not, to the best of our knowledge, been previously reported in a benign/low-grade mesenchymal uterine lesion.

Benign Neurofibroma/Schwannoma Hybrid Peripheral Nerve Sheath Tumor of the Ulnar Nerve Harboring a Metastatic Papillary Thyroid Carcinoma Deposit: A Case Report of Tumor-to-Tumor Metastasis.

A 74-year-old man with a medical history significant for papillary thyroid cancer (PTC) presented with a rapidly enlarging grape-sized mass in his right medial arm with paresthesia in the ulnar nerve distribution. Imaging was suspicious for a peripheral nerve sheath tumor (PNST), but an ultrasound-guided biopsy was equivocal. The mass was excised with final histopathology demonstrating a benign neurofibroma/schwannoma hybrid nerve sheath tumor (N/S HNST) harboring a metastatic PTC deposit, ultimately mimicking the rare glandular schwannoma subtype. Next-generation sequencing (NGS) of the lesion demonstrated somatic variants in BRAF and TERT (common in PTC) and NF2 (common in PNSTs). After excision, the patient's nerve symptoms improved. A postsurgical PET/CT scan also showed progression in the lungs/mediastinum. Due to the metastatic nature of his PTC, he was treated with 14 mg of Lenvima (lenvatinib) daily, and his PET/CT surveillance was performed at more frequent intervals. Tumor-to-tumor metastasis (TTM) is a rare occurrence. To our knowledge, this is the first case reported on PTC metastasizing into a benign (hybrid) PNST, which mimicked glandular schwannoma. Symptomatology, imaging characteristics, NGS, and histopathological characteristics that can decipher between different benign PNST subtypes (schwannoma, neurofibroma, glandular, hybrid, etc.), malignant PNSTs (MPNSTs), and TTM are described.

Discordance Between Immunohistochemistry and In Situ Hybridization to Detect HER2 Overexpression/Gene Amplification in Breast Cancer in the Modern Age: A Single Institution Experience and Pooled Literature Review Study.

BACKGROUND: Human epidermal growth factor 2 (HER2) amplification and/or overexpression occurs in 12% to 25% of breast cancers. Accurate detection of HER2 is critical in predicting response to HER2-targeted therapy. Both immunohistochemistry (IHC) and in situ hybridization (ISH) are FDA-approved methods for detecting HER2 status because its protein overexpression is largely attributable to gene amplification. However, variable discordant results between IHC and ISH have been reported. METHODS: We determined the frequency of HER2 IHC/ISH discordance in these patients and also performed a pooled literature review analysis. RESULTS: Of the 1125 consecutive primary or metastatic breast cancers with HER2 IHC and ISH performed simultaneously between 2015 and 2020, 84.6% had an unequivocal HER2 status. Discordance was found in 30 cases from 26 patients, including 13 IHC-/ISH+ and 17 IHC+/ISH-, representing 1.6% and 11.9% of IHC- and IHC+ cases, respectively. Review of the literature between 2001 and 2020 identified 46 relevant studies, with a total of 43,468 cases with IHC and ISH performed. The IHC-/ISH+ and IHC+/ISH- discordances were seen in all antibody clones and ISH methods used. The IHC+/ISH- discordance was significantly higher than IHC-/ISH+ (13.8% vs. 3%, P < .0001). The overall discordance constituted 4% of all cases and 5.4% of those with an unequivocal IHC status. Significantly lower incongruities for both IHC-/ISH+ and IHC+/ISH- were found in those published after 2018. The discordances probably reflect altered biology of HER2 oncogene/oncoprotein. Routinely performing both IHC and ISH may uncover such cases to prevent denial of potentially beneficial targeted therapy.

Round cell tumor with a myxoid matrix harboring a PHF1-TFE3 fusion: Myoepithelial neoplasm or ossifying fibromyxoid tumor?

Myoepithelial tumors arising in soft tissue are uncommon and mostly manifest a benign clinical course, although a malignant form does exist. An EWSR1 gene rearrangement is a common event in these tumors. Ossifying fibromyxoid tumor, a rare soft tissue neoplasm of uncertain differentiation, may have overlapping histologic and immunophenotypic features with myoepithelial tumors, but frequently harbors a PHF1 gene rearrangement. Interestingly, a PHF1-TFE3 fusion has been recently reported in both entities. Here we report a case of a malignant soft tissue tumor demonstrating myoepithelial differentiation and harboring a PHF1-TFE3 fusion. Despite being slow-growing and lacking significant cytologic atypia at initial presentation, the patient deteriorated rapidly with local recurrence and distant metastases. A discussion of the potential clinicopathologic implications of a PHF1-TFE3 fusion in these entities is also developed.

Clinicopathologic features and outcome of head and neck mucosal spindle cell squamous cell carcinoma.

Spindle cell squamous cell carcinoma (SpC-SCC) is rare, accounting for 0.4-4% of head and neck (HN) SCCs. Better understanding of HN SpC-SCC clinicopathologic characteristics, especially features that predict outcome, is needed. We present a clinicopathologic review of 71 HN mucosal SpC-SCC from three tertiary centers. The patient population showed a median age of 63 years (range 20-91), slight male predominance (M:F = 1.6:1), and a preponderance of smokers/ex-smokers (45/71, 64%). Most lesions involved oral cavity (42/71, 59%), especially oral tongue (n = 18), and larynx (n = 20, 28%). Polypoid/exophytic growth and surface ulceration were seen in 60% and 86% of cases, respectively. Histologically, most tumors showed sarcoma-like pattern (65/70, 93%), the remaining exhibiting granulation tissue-like or fibromatosis-like patterns, and 5 lesions showed osteosarcomatous/chondrosarcomatous elements. Most tumors (53/71, 74%) showed a conventional SCC (C-SCC) component, keratinizing (86%) or non-keratinizing/basaloid (14%). Nodal metastases, seen in 22 (31%) of resection specimens, showed SpC-SCC and/or C-SCC histomorphology. By immunohistochemistry, 76% of lesions showed immunoreactivity for keratin and 62/60% of lesions were p40/p63 positive. Ki-67 proliferation index ranged from 5 to 70%. Follow-up was available on 69 patients, median of 1.1 years from the time of SpC-SCC diagnosis. The 3-, 5-, and 10-year disease-specific survival (DSS) was 62, 37, and 12%, respectively. AJCC pN stage was an independent prognostic factor for DSS and distant metastasis-free survival (DMFS), whereas the presence of C-SCC was independently associated with improved DMFS. HN SpC-SCC is rare and might be diagnostically challenging. AJCC pN stage and co-existing C-SCC component appear to be prognostically relevant.

Clear cell papillary neoplasm of the breast with MAML2 gene rearrangement: Clear cell hidradenoma or low-grade mucoepidermoid carcinoma?

Clear cell hidradenoma (CCH) is an uncommon adnexal tumor usually arising from eccrine glands and commonly seen on the face and the upper extremities. CCH occurring in the breast is extremely rare. Herein we report a case of MAML2-rearranged CCH of breast with a papillary architecture closely mimicking intraductal papilloma, adenomyoepithelioma and low-grade mucoepidermoid carcinoma, thus representing a source of diagnostic confusion. An overview of salient histologic features and immunophenotypes to distinguish CCH and low-grade mucoepidermoid carcinoma is also integrated into the report.

Rare MDM2 amplification in a fat-predominant angiomyolipoma.

Angiomyolipomas (AMLs) are triphasic tumors (smooth muscle, vascular and adipocytic components) with myomelanocytic differentiation, arising most commonly in the kidneys, which can show predominant epithelioid morphology and fat-predominant or fat-poor variants. Fat-predominant AMLs can show areas of hypercellularity and lipoblast-like cells, and these features can mimic well-differentiated liposarcoma (WDLS). To date, only one documented metastatic epithelioid AML showed unequivocal MDM2 amplification by fluorescence in situ hybridization. We describe our findings in a series of 35 AMLs including epithelioid, fat-poor, and fat-predominant variants, following interrogation of the MDM2 locus by FISH and CISH assays. MDM2 amplification was detected in 1 fat-predominant AML. Our findings demonstrate that rare MDM2 amplifications can occur in AMLs. We favor that this finding likely represents a "molecular bystander" event since these tumors are mainly driven by aberrations in the TSC1/TSC2 genes. Nevertheless, the presence of MDM2 amplification in a fat-predominant AML could present a potential diagnostic pitfall, particularly when confronted with the differential diagnosis of fat-predominant AML and WDLS in limited material from the retroperitoneum.

GLI1-amplifications expand the spectrum of soft tissue neoplasms defined by GLI1 gene fusions.

GLI1 fusions involving ACTB, MALAT1, and PTCH1 genes have been recently reported in a subset of malignant soft tissue tumors with characteristic monomorphic nested epithelioid morphology and frequent S100 positivity. However, we encountered a group of morphologically similar soft tissue tumors lacking the canonical GLI1 gene fusions and sought to investigate their genetic abnormalities. A combined approach including RNA sequencing, targeted exome sequencing and FISH methodologies were used to identify potential novel genetic abnormalities. Ten patients (five females, five males) with an age range of 4-65 years (median 32.5) were identified. Tumors were located in the soft tissues of the limbs, trunk and head and neck, with one each in the tongue and lung. Histologically, tumors revealed ovoid to epithelioid cells arranged in a distinctive nested-trabecular pattern, separated by thin septa and a delicate vascular network. Two cases showed areas of increased nuclear pleomorphism and focal fascicular spindle cell growth. Four tumors showed a high mitotic count (≥15/10 HPFs), with necrosis seen in three of them. Lymphovascular invasion was noted in two cases. No consistent immunoprofile was detected, with positivity for CD56 (six cases), S100 (four cases), SMA (two cases), and pan-CK (one case). FISH showed GLI1 (12q13.3) gene amplification in all 10 cases, with co-amplification of CDK4 (12q14.1) in nine (90%) and MDM2 (12q15) in eight (80%) cases. Targeted exome sequencing performed in three cases confirmed the GLI1, CDK4, and MDM2 co-amplification. Only one case showed the presence of both GLI1 break-apart and amplification, although no gene partner was detected. Our findings suggest that GLI1 amplification, often associated with co-amplifications of CDK4 and MDM2 genes, may represent an alternative genetic mechanism of GLI1 oncogenic activation akin to GLI1 fusions, defining the pathogenesis of an emerging group of malignant soft tissue tumors with a distinctive nested growth pattern and variable immunoprofile.

Spindle Epithelial Tumor with Thymus-Like Differentiation (SETTLE): A Next-Generation Sequencing Study.

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a malignant biphasic neoplasm of the thyroid or neck with propensity for late metastasis. Unlike synovial sarcoma, its main morphologic mimic, SETTLE lacks synovial sarcoma-associated translocations. A single case of SETTLE has shown a KRAS mutation but to date no comprehensive next generation sequencing studies of this rare neoplasm have been undertaken. Herein, we subjected 5 well defined cases of SETTLE to direct sequence analysis of 592 genes and fusion gene analysis of 52 genes frequently rearranged in human cancers. We identified one case with two pathogenic variants in the KMT2D gene, one being in an intron splice site (c.674-1A>G) and the other being a frameshift variant (p.M2829fs). This same case also had a pathogenic nonsense variant in the KMT2C gene (p.R1237*). A second case of SETTLE carried a pathogenic NRAS missense variant, Q61R. No other molecular alterations, microsatellite instability, gene fusions or amplifications were identified.

PAX8 Expression in Solitary Fibrous Tumor: A Potential Diagnostic Pitfall.

PAX8 is used as a diagnostic aid in classifying retroperitoneal (RP) spindle cell tumors. PAX8 positivity in a spindled RP tumor is typically associated with sarcomatoid renal cell carcinoma (SRCC). However, PAX8 expression in solitary fibrous tumor (SFT), a tumor not uncommon to the RP, has not been extensively studied. We investigated the expression of PAX8 in SFTs and other spindle cell RP tumors. We collected 30 SFT, 23 SRCC, 11 gastrointestinal stromal tumors, 2 synovial sarcomas, 6 dedifferentiated liposarcomas (DDLS), 4 well differentiated liposarcomas (WDLS), and select other tumors. We identified nuclear PAX8 expression in 13 of 30 (43%) SFT, 0 of 6 (0%) DDLS, and 1 of 4 (25%) WDLS. Twenty-eight of 30 (93%) SFT, 0 of 23 (0%) SRCC, 2 of 6 (33%) DDLS, and 1 of 4 (25%) WDLS showed nuclear STAT6 expression. All gastrointestinal stromal tumors were negative for both PAX8 and STAT6. Of the 13 SFT showing PAX8 expression, 8 showed diffuse expression and 5 expressed PAX8 focally. Extrapleural SFTs were more likely to express PAX8 compared with pleural SFTs (10/13; 77% vs. 3/17; 18%, respectively; P=0.00117). Twenty of 23 (87%) SRCC expressed PAX8; the sarcomatoid component of all 23 SRCC was negative for STAT6. Of the other spindle cell tumors studied, 1 of 2 synovial sarcomas and 1 of 2 histiocytic sarcomas showed PAX8 expression. Pathologists should be aware of the potential pitfall of the relatively frequent expression of PAX8 by SFT and STAT6 expression in liposarcoma. PAX8 expression by a spindle cell lesion of RP would not allow distinction between SFT, SRCC, or sclerosing liposarcoma by itself. A STAT6/PAX8 phenotype excludes SRCC.

Primary Pulmonary Myxoid Sarcoma: A Newly Described Entity-Report of a Case and Review of the Literature.

Primary pulmonary myxoid sarcoma (PPMS) is a recently described, exceedingly rare low-grade lung sarcoma that tends to present in young females as an endobronchial mass and shows evidence of an EWSR1- CREB1 fusion. Herein, we present a case of PPMS with fluorescence in situ hybridization (FISH) analysis for EWSR1 and CREB1 rearrangements. An 80-year-old woman presented with an endobronchial, multinodular tumor exhibiting spindle, ovoid and epithelioid cells arranged in reticular/lattice-like and alveolar-like patterns in a myxoid background. The tumor showed focal epithelial membrane antigen immunoreactivity as well as an Alcian blue-positive stroma that was sensitive to digestion with hyaluronidase. EWSR1 and CREB1 rearrangements were detected by break-apart FISH probes. The patient showed persistence of disease 36 months after diagnosis and was discharged to hospice care. We contribute with a report of an additional case of this very unusual entity and perform a brief review of the literature published so far on the subject.

Primary cutaneous adenoid cystic carcinoma with MYB aberrations: report of three cases and comprehensive review of the literature.

Adenoid cystic carcinoma (ACC) is a relatively rare slow-growing and often-aggressive epithelial-myoepithelial neoplasm that arises in multiple organs including the skin. The t(6;9) (q22-23;p23-24) translocation, resulting in a MYB-NFIB gene fusion has been found in ACCs from the salivary glands and other organs. Recently, MYB aberrations occurring in a subset (40%) of primary cutaneous ACC (PCACC) examples was described. Herein, we report three additional cases of PCACC harboring MYB aberrations. The tumors presented in three males aged 43, 81 and 55 years old and affected the extremities in the first two patients and the scalp in the third one. None of the patients had history of prior or concurrent ACC elsewhere. Lesions exhibited the classic ACC morphology of nests of basaloid cells arranged in cribriform and adenoid patterns. Sentinel lymph node biopsy was performed in two cases with one case showing lymph node positivity. Fluorescence in situ hybridization with break-apart probes for MYB and NFIB loci revealed that two cases showed MYB rearrangements while one case showed loss of one MYB signal. None of the cases showed NFIB rearrangements. We contribute with three additional cases of PCACC exhibiting MYB aberrations, the apparent driving genetic abnormality in these tumors.