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Aims: Sebaceous neoplasms constitute a group of adnexal tumours, including sebaceous adenoma, sebaceoma and sebaceous carcinoma. Although mismatch repair deficiency may be observed, the nature of the genetic alterations contributing to the development of most of these tumours is still unknown. In the present study, we describe the clinical, microscopic, and molecular features of eight sebaceomas with GRHL gene rearrangement., Methods and Results: Among these sebaceomas, four occurred in women and four in men; the median age was 63 years (range = 29-89). The tumours were located in the head and neck area in all cases. Microscopic examination revealed a well-demarcated lesion located in the dermis with focal extension into the subcutaneous tissue (three cases). The neoplasms displayed macronodular (eight cases), cribriform (seven cases) and organoid (six cases) growth patterns, occurring in combination. The tumours were mainly composed of immature basophilic cells associated with scattered mature sebocytes. Numerous small infundibular cysts were present in seven cases. Mitotic activity was low (none/one to four mitoses/mm 2 ). Immunohistochemistry showed positivity for androgen receptor and p63. Preserved expression of MLH1, PMS2, MSH2 and MSH6 was observed in all cases. RNA-sequencing revealed RCOR1::GRHL2 (three cases), BCL6::GRHL1 (two cases), a BCOR::GRHL2 (one case), RCOR1::GRHL1 (one case) and TLE1::GRHL1 (one case) fusion transcript. Methylation analysis demonstrated that GRHL-fused sebaceomas form an independent cluster and highlight the proximity of such tumours with poromas with folliculo-sebaceous differentiation., Conclusions: In conclusion, we report recurrent fusions of the GRHL genes in a distinctive subset of sebaceomas harbouring infundibulocystic differentiation, a frequent organoid growth pattern and lack of mismatch repair deficiency., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

RET-fused Spitz neoplasms are rare and poorly characterized. We describe clinical, histologic and molecular findings of 31 Spitz neoplasms with RET fusion diagnosed as 16 Spitz nevus (SN), 13 atypical Spitz tumors (AST) and 2 Spitz melanoma (SM). The lesions mainly occurred in children and young adults of both sexes with predilection for the extremities. Microscopically, there were mainly symmetrical compound melanocytic neoplasms with a dome-shaped/slightly raised silhouette predominantly composed of epithelioid, spindled and/or smaller nevoid melanocytes arranged in confluent nests. Dyscohesive melanocytes within the nests in the upper part of the lesions, prominent Kamino bodies, giant multinucleated melanocytes, variable pigmentation and increased vascularity with vascular ectasia were frequent features. RNA sequencing detected 9 different 5' (N-terminus) fusion partners, including KIF5B (n= 8), LMNA (n= 7), CCDC6 (n= 6), OPTN (n= 3), MYO5A (n= 2) and NCOA4, ERC1, MYH9, AGAP3 (n= 1). Of these, OPTN::RET and AGAP3::RET represent novel fusions, and 3 further 5' fusion partners, namely NCOA4, ERC1 and MYH9 have never been reported in Spitz tumors. Although as a whole group, the tumors showed a heterogenous histopathologic presentation, correlation of the morphological features and the 5' fusion partners demonstrated certain associations. Nevoid melanocytes were exclusively encountered in cases with KIF5B fusion partner. Neuroid-like appearances with intersecting fascicles of spindled cells typified both MYO5A-fused cases. Epithelioid melanocyte population dominated cases with LMNA and CCDC6 fusion partners. Transepidermal elimination/floating intraepidermal nests of pigmented both spindled and epithelioid melanocytes were observed in the OPTN subgroup. The remaining cases with less frequent 5' fusion partners manifested in general more atypical histopathologic features, including nuclear pleomorphism, high mitotic count, atypical mitoses and sheet-like growth pattern. Melanoma fluorescence in situ hybridization (FISH) Probe Kit targeting RREB1, MYC, CDKN2A, and CCND1, was negative for copy number variation in 4 cases tested, including 2 cases with complete p16 nuclear loss on immunohistochemistry. Array comparative genomic hybridization (aCGH) performed in 3 lesions detected numerous segmental chromosomal imbalances in 2 cases diagnosed SM. DNA and RNA sequencing detected several further genomic alterations, including POU2F3 overexpression in 3 highly pigmented lesions. Further studies are needed to confirm possible correlations between the microscopic features and a particular fusion partner (or additional genetic events) in RET-fused Spitz neoplasms., (Copyright © 2025. Published by Elsevier Inc.)

Abstract: Nonmelanoma malignancies associated with congenital melanocytic nevi (CMN) are extremely rare, with only 12 reported cases of rhabdomyosarcoma (RMS) to date. We present 2 additional cases of RMS arising in giant CMN, with immunohistochemical and molecular biologic investigations. The first case was a 32-year-old woman with a personal history of melanoma in giant CMN who, after successful treatment and long remission, presented with a new 1-cm nodule within the CMN. Microscopically, the atypical areas exhibited a round cell/alveolar morphology with immunoreactivity for desmin and myogenin, and lacked PAX3/7::FOXO1 fusions typical for alveolar RMS on a reverse transcription polymerase chain reaction analysis. An identical NRAS p.Q61R mutation with comparable variant allele frequency (32% and 44%) was identified in both the nevus and the RMS tissue by next-generation sequencing. The second patient was a 5-year-old girl with a rapidly growing, bleeding, ulcerated 3 × 4 cm interscapular mass within a giant CMN that histologically seemed as a proliferation of pleomorphic spindle, polygonal and epithelioid cells with marked pleomorphism immunoreactive for myogenin, muscle-specific actin, and smooth muscle actin. Next-generation sequencing yielded an HRAS p.Q61R mutation with limited variant allele frequency (7%) in the RMS component, while ATRX p.Q2193* variant was detected in the nevus. Our study is apparently the first report of NRAS and HRAS mutations in tumors with RMS phenotype arisen in CMN., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Porocarcinoma is a malignant sweat gland tumour differentiated toward the upper part of the sweat duct and may arise from the transformation of a preexisting benign poroma. In 2019, Sekine et al. demonstrated the presence of YAP1::MAML2 and YAP1::NUTM1 fusions in most poromas and porocarcinomas. Recently, our group identified PAK2-fusions in a subset of benign poromas. Herein we report a series of 12 porocarcinoma cases harbouring PAK1/2/3 fusions., Methods and Results: Five patients were male and the median age was 79 years (ranges: 59-95). Tumours were located on the trunk (n = 7), on the thigh (n = 3), neck (n = 1), or groin area (n = 1). Four patients developed distant metastases. Microscopically, seven cases harboured a benign poroma component and a malignant invasive part. Ductal formations were observed in all, while infundibular/horn cysts and cells with vacuolated cytoplasm were detected in seven and six tumours, respectively. In three cases, the invasive component consisted of a proliferation of elongated cells, some of which formed pseudovascular spaces, whereas the others harboured a predominant solid or trabecular growth pattern. Immunohistochemical staining for CEA and EMA confirmed the presence of ducts. Focal androgen receptor expression was detected in three specimens. Whole RNA sequencing evidenced LAMTOR1::PAK1 (n = 2), ZDHHC5::PAK1 (n = 2), DLG1::PAK2, CTDSP1::PAK1, CTNND1::PAK1, SSR1::PAK3, CTNNA1::PAK2, RNF13::PAK2, ROBO1::PAK2, and CD47::PAK2. Activating mutation of HRAS (G13V, n = 3, G13R, n = 1, Q61L, n = 2) was present in six cases., Conclusion: Our study suggests that PAK1/2/3 fusions is the oncogenic driver of a subset of porocarcinomas lacking YAP1 rearrangement., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

Abstract: Close relationship between melanocytes and neural cells is accepted to reflect their common derivation from the neural crest and tumors combining both elements. We present a series of 10 patients with giant congenital melanocytic nevi (CMN) in which a secondary proliferation (11 lesions) with schwannian and/or perineuriomatous differentiation developed in the course of the disease. The age of the patients (4 male and 6 female) at the time of surgery and histological assessment varied from 3 months to 57 years. Histopathologically, the following subgroups were delineated: (1) nodular/tumoriform "neurotization" in CMN, (2) diffuse neurofibroma-like proliferation within CMN, (3) plexiform neurofibroma-like proliferation within CMN, and (4) diffuse perineuriomatous (hybrid schwannomatous-perineuriomatous) differentiation in CMN. We review the pertinent literature, including the role of recently identified Schwann cell precursors which are believed to represent the nerve-associated state of neural crest-like cells that persists into later developmental stages., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

BAP1-inactivated melanocytoma (BIM) is a novel subgroup of melanocytic neoplasm listed in the 5th edition of WHO classification of skin tumor. BIM is characterized by two molecular alterations, including a mitogenic driver mutation (usually BRAF gene) and the loss of function of BAP1, a tumor suppressor gene located on chromosome 3p21, which encodes for BRCA1-associated protein (BAP1). The latter represents a nuclear-localized deubiquitinase involved in several cellular processes including cell cycle regulation, chromatin remodeling, DNA damage response, differentiation, senescence and cell death. BIMs are histologically characterized by a population of large epithelioid melanocytes with well-demarcated cytoplasmic borders and copious eosinophilic cytoplasm, demonstrating loss of BAP1 nuclear expression by immunohistochemistry. Recently, we have published a series of 50 cases, extending the morphological spectrum of the neoplasm and highlighting some new microscopic features. In the current article, we focus on some new histological features, attempting to explain and link them to certain mechanisms of tumor development, including senescence, endoreplication, endocycling, asymmetric cytokinesis, entosis and others. In light of the morphological and molecular findings observed in BIM, we postulated that this entity unmasks a fine mechanism of tumor in which both clonal/stochastic and hierarchical model can be unified., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Abstract: We report a very unusual case of melanocytic neoplasm appearing clinically as a 0.5-cm dome-shaped pigmented papule on the chest of a 63-year-old man. Microscopically, it was an asymmetric, entirely dermally based neoplasm characterized by a multinodular, vaguely plexiform architecture composed of moderately pleomorphic spindled melanocytes with ample, dusty pigmented cytoplasm and scattered multinucleated cells. The tumor cells were strongly positive for Melan-A, HMB45, S100, and PRAME, whereas p16 showed diffuse nuclear loss. β-catenin presented a strong and diffuse cytoplasmic staining, while nuclei were negative. Despite an increased cellularity, mitotic count was low (1/mm 2 ). Fluorescence in situ hybridization revealed no copy number alteration in melanoma-related genes ( CDKN2A, MYB, MYC, CCND1 and RREB1 ). DNA and RNA sequencing identified KIT c.2458G>T and APC c.6709C>T mutations. No further genetic alteration was detected including TERT-promoter (TERT-p ) hot-spot mutation. A re-excision was performed. A sentinel lymph node biopsy was negative. Clinical investigations revealed no extracutaneous involvement. The patient is disease-free after a follow-up period of 8 months. Given the peculiar morphologic and molecular findings, we hypothesize the lesion may represent a novel subtype of an intermediate grade melanocytic tumor (melanocytoma)., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Nine species-level taxa of bat ectoparasites, three chigger mites (Trombiculidae), three hard (Ixodidae), and one soft tick (Argasidae) species, as well as two bug (Cimicidae) species from nine bat species hosts were detected in the Eastern Palaearctic. Trombiculid larvae of Leptotrombidium schlugerae, Leptotrombidium album, and Ascoschoengastia latyshevi were first recorded on bats in the temperate zone of eastern Russia. L. schlugerae was more abundant than A. latyshevi in the same study sites in Eastern Siberia, and the main hosts of both chigger species were Plecotus ognevi and Eptesicus nilssonii. Ixodid ticks Dermacentor marginatus, Ixodes simplex, and Ixodes sp. were sampled from bats in Kazakhstan, the Far East, and Eastern Siberia, respectively. Phylogenetic analysis based on Cox1, 16S rDNA, and ITS2 sequences of I. simplex showed that the specimens from the Far East grouped into a clade distributed in the Eastern Palaearctic and India. In turn, the specimen of Ixodes sp. from Eastern Siberia was most closely related to Ixodes soricis and Ixodes angustus with p-distance of 9.8-10.7% (Cox1), suggesting that this tick probably belongs to a new species. Argas vespertilionis larvae were collected from three widespread bat species in Kazakhstan. Two bug species, Cimex pipistrelli and Cimex aff. lectularius, were recorded in the Far East and Eastern Siberia, respectively. Specimens from Transbaikalia were morphologically identified as Cimex lectularius. However, they differed from the latter by 12.5-12.9% of Cox1 sequences, indicating that C. aff. lectularius may be a new species., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Spitz tumors represent a heterogeneous group of challenging melanocytic neoplasms, displaying a range of biological behaviors, spanning from benign lesions, Spitz nevi (SN) to Spitz melanomas (SM), with intermediate lesions in between known as atypical Spitz tumors (AST). They are histologically characterized by large epithelioid and/or spindled melanocytes arranged in fascicles or nests, often associated with characteristic epidermal hyperplasia and fibrovascular stromal changes. In the last decade, the detection of mutually exclusive structural rearrangements involving receptor tyrosine kinases ROS1, ALK, NTRK1, NTRK2, NTRK3, RET, MET, serine threonine kinases BRAF and MAP3K8, or HRAS mutation, led to a clinical, morphological and molecular based classification of Spitz tumors. The recognition of some reproducible histological features can help dermatopathologist in assessing these lesions and can provide clues to predict the underlying molecular driver. In this review, we will focus on clinical and morphological findings in molecular Spitz tumor subgroups.

Abstract: We report an unusual case of schwannoma with glandular elements that demonstrated apocrine decapitation secretion. The glandular structures were embedded within the tumor, varied in shape and size, and were lined by a double-to-multilayered epithelium, with the inner layer composed of monomorphous cuboidal to columnar cells, focally with apocrine decapitation secretion, and the outer layer representing myoepithelial cells. A normal eccrine unit was observed near the lesion. Immunohistochemical studies showed that all luminal cells of the glandular structures stained positive for CK7, whereas myoepithelial cells expressed S100 and p63, and epithelial membrane antigen highlighted the luminal border. CK20 and neuroendocrine markers were negative in the glandular elements.Our findings suggest that the origin of the glandular elements in our case was represented by entrapped glands. Two theories may explain the epithelial hyperplasia observed in the present case as follows: the obstructive effect theory and the inductive ability of a mesenchymal proliferation to produce epidermal or adnexal changes. We suggest that, in a subset of cases, the origin of the glandular elements might represent entrapped glands, wherein their histomorphology/cytomorphology recapitulates the elements comprising the normal adjacent tissue. Further research is necessary to elucidate the histogenesis of glandular schwannoma., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Spiradenomas are benign cutaneous adnexal neoplasms with sweat gland differentiation that can manifest a broad spectrum of histomorphologic appearances. While they show a characteristic histopathologic phenotype and clinical management involves surgical excision with a low risk of recurrence, there have been unusual histopathologic variants of spiradenoma reported, including cases with adenoid cystic carcinoma (ACC)-like changes. Primary cutaneous ACC is a low-grade malignancy presenting as a subcutaneous mass with the potential for local invasion, perineural invasion, and high rates of local recurrence after excision. The diagnosis of spiradenomas with ACC-like features can be challenging, especially when only the ACC-like component is present for evaluation. A retrospective analysis of 21 cases of spiradenoma with ACC-like changes were obtained from large academic institutions, was performed, and summarized below. All cases showed background of conventional spiradenoma, and the ACC-like areas represented a component in all lesions. The percentage of ACC-like component ranged from 5% to 40% in all cases. The ACC-like component was multifocal and without pleomorphism, perineural and/or vascular invasion, necrosis, or increased mitotic activity. MYB translocation and protein expression was studied in 16 cases by fluorescence in situ hybridization, polymerase chain reaction, and immunohistochemistry. All studied cases were negative for MYB / NFIB , MYB L1, and MYB F by fluorescence in situ hybridization and polymerase chain reaction and 3 cases were positive for MYB expression by immunohistochemistry. Our study expands on spiradenomas with ACC-like features that ought to be considered in the differential diagnosis of cutaneous neoplasms such as primary cutaneous ACC. Our results indicate that a thorough histopathologic inspection and strict application of well-defined histologic criteria are necessary to support the diagnosis of this unusual histopathologic variant. These tumors can be difficult to diagnose, and awareness of their histomorphologic spectrum will facilitate definitive diagnosis and avoid misdiagnosis with other conditions., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Spitz tumors are melanocytic neoplasms morphologically characterized by spindled and/or epithelioid cells and specific stromal and epidermal changes associated with mutually exclusive fusion kinases involving ALK, ROS1, NTRK1, NTRK2, NTRK3, MET and RET, BRAF and MAP3K8 genes or, less commonly, HRAS mutation. RAF1 fusions have been recently detected in cutaneous melanocytic neoplasms, including conventional melanoma, congenital nevus and BAP-1 inactivated tumors. We report herewith three Spitz neoplasms with a RAF1 fusion, including a previously reported CTDSPL::RAF1 fusion and two novel PPAP2B::RAF1 and ATP2B4::RAF1 fusions. Two cases were classified as Spitz nevus, while the remaining neoplasm was classified as Spitz melanoma at the time of the diagnosis, given 9p21 homozygous deletion and positive sentinel lymph node biopsy. We suggest that RAF1 fused melanocytic neoplasms can represent a novel subgroup of Spitz tumors, with a RAF1 fusion representing an oncogenic driver., Competing Interests: Declaration of competing interest Dr. Gerami has served as a consultant for DermTech Inc. and Castle Biosciences and has received royalties for textbooks from Elsevier. All other authors report no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Cuticular poroma is a rare variant of poroma composed of exclusively or predominantly cuticular cells, namely of large cells with ample eosinophilic cytoplasm. We report 7 cases of this rare tumor identified among 426 neoplasms diagnosed as poroma or porocarcinoma. The patients were 4 males and 3 females, ranging in age from 18 to 88 years. All presented with a solitary asymptomatic nodule. The location included knee (2 cases), shoulder, thigh, shin, lower arm, and neck (each 1). All lesions were surgically removed. No evidence of disease was observed in 5 patients with available follow-up (range 12-124 months).Microscopically, all neoplasms were composed of variably sized, focally closed packed, or interconnecting nodules constituted mostly of cuticular cells. Small poroid cells were a focal feature in 5 tumors, whereas in the remaining 2 cases, poroid cells with conspicuous but still in minority. Five neoplasms were somewhat asymmetric, with irregular outlines. Ductal differentiation and intracytoplasmic vacuoles were seen in 6 tumors. Other features variably encountered were conspicuous intranuclear pseudoinclusions, cystic change, occasional multinucleated cells, increased mitoses, and stromal desmoplasia. Four of the 5 tumors analyzed with next-generation sequencing yielded YAP1::NUTM1 fusions. In addition, various mutations, mostly of unknown significance were identified in one neoplasm., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The development of resistance by tumor cells to various types of therapy is a significant problem that decreases the effectiveness of oncology treatments. For more than two decades, comparative transcriptomic studies of tumor cells with different sensitivities to ionizing radiation and chemotherapeutic agents have been conducted in order to identify the causes and mechanisms underlying this phenomenon. However, the results of such studies have little in common and often contradict each other. We have assumed that a systematic analysis of a large number of such studies will provide new knowledge about the mechanisms of development of therapeutic resistance in tumor cells. Our comparison of 123 differentially expressed gene (DEG) lists published in 98 papers suggests a very low degree of consistency between the study results. Grouping the data by type of genotoxic agent and tumor type did not increase the similarity. The most frequently overexpressed genes were found to be those encoding the transport protein ABCB1 and the antiviral defense protein IFITM1. We put forward a hypothesis that the role played by the overexpression of the latter in the development of resistance may be associated not only with the stimulation of proliferation, but also with the limitation of exosomal communication and, as a result, with a decrease in the bystander effect. Among down regulated DEGs, BNIP3 was observed most frequently. The expression of BNIP3, together with BNIP3L, is often suppressed in cells resistant to non-platinum genotoxic chemotherapeutic agents, whereas it is increased in cells resistant to ionizing radiation. These observations are likely to be mediated by the binary effects of these gene products on survival, and regulation of apoptosis and autophagy. The combined data also show that even such obvious mechanisms as inhibition of apoptosis and increase of proliferation are not universal but show multidirectional changes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Tandem repeats in mitochondrial DNA control region are known to different animal taxa, including bat species of the family Vespertilionidae. The long R1-repeats in the bat ETAS-domain are often presented in a variable copy number and may exhibit both inter-individual and intra-individual sequence diversity. The function of repeats in the control region is still unclear, but it has been shown that repetitive sequences in some animal groups (shrews, cats and sheep) may include parts of ETAS1 and ETAS2 conservative blocks of mitochondrial DNA., Methods and Results: Analysis of the control region sequences for 31 Myotis petax specimens allowed the identification of the inter-individual variability and clarification of the composition of the R1-repeats. The copy number of the R1-repeats varies from 4 to 7 in individuals. The specimens examined do not exhibit a size heteroplasmy previously described for Myotis species. The unusual short 30 bp R1-repeats have been detected in M. petax for the first time. The ten specimens from Amur Region and Primorsky Territory have one or two copies of these additional repeats., Conclusions: It was determined that the R1-repeats in M. petax control region consist of parts of the ETAS1 and ETAS2 blocks. The origin of the additional repeats seems to be related to the 51 bp deletion in the central part of the R1-repeat unit and subsequent duplication. Comparison of repetitive sequences in the control region of closely-related Myotis species identified the occurrence of incomplete repeats also resulting from the short deletions, but distinct from additional repeats of M. petax., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Kissing nevus is a congenital melanocytic neoplasm arising in those parts of the body that split at some point during embryological development (i.e., eyelid; penis), resulting in two adjacent melanocytic nevi. To date, 23 cases of kissing nevus of the penis have been described, and dermatoscopic and histological findings are available in 4/23 cases. We report a dermatoscopic, histological and confocal microscopic analysis in a new case of the kissing nevus of the penis in a 57 years old man. Dermatoscopic analysis showed large globules in the central area and a peripheral pigment network; the histological examination confirmed the presence of an intradermal melanocytic nevus with minimal junctional component and congenital features. Moreover, we reported, for the first time, confocal microscopy findings in the kissing nevus of the penis, revealing the presence of dendritic cells in correspondence with the epidermis and suggesting a state of cellular activity. Considering the clinicopathological features of the lesion, a conservative approach was adopted, and a clinical follow-up was planned after six months.

Abstract: Spitz tumors are melanocytic neoplasms characterized by specific, mutually exclusive driver molecular events, namely genomic rearrangements involving the threonine kinase BRAF and the tyrosine kinase receptors ALK , NTRK1 , NTRK2 , NTRK3 , MET , RET , ROS1 , and MAP3K8 or less commonly, mutations in HRAS or MAP2K1 . We hereby report 5 Spitz tumors with a SQSTM1::NTRK2 fusion. All patients were woman with the ages at diagnosis ranging from 30 to 50 years. Locations included the lower extremity (n = 3), forearm, and back (one each). All the neoplasms were superficial melanocytic proliferation with a flat to dome-shaped silhouette, in which junctional spindled and polygonal dendritic melanocytes were mainly arranged as horizontal nests associated with conspicuous lentiginous involvement of the follicular epithelium. Only one case showed heavily pigmented, vertically oriented melanocytic nests resembling Reed nevus. A superficial intradermal component observed in 2 cases appeared as small nests with a back-to-back configuration. In all lesions, next-generation sequencing analysis identified a SQSTM1::NTRK2 fusion. A single case studied with fluorescence in situ hybridization for copy number changes in melanoma-related genes proved negative. No further molecular alterations were detected, including TERT-p hotspot mutations., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

A dynamical theory is developed of X-ray diffraction on a crystal with surface relief for the case of high-resolution triple-crystal X-ray diffractometry. Crystals with trapezoidal, sinusoidal and parabolic bar profile models are investigated in detail. Numerical simulations of the X-ray diffraction problem for concrete experimental conditions are performed. A simple new method to resolve the crystal relief reconstruction problem is proposed.

Abstract: BAP1-inactivated melanocytic tumors represent a subset of epithelioid melanocytic neoplasms resulting from biallelic inactivation of the BAP1 gene and by a driver mutation that activate the MAP kinase pathway, most commonly BRAFV600E. They occur sporadically or, less common, in the setting of BAP1 tumor predisposition syndrome caused by a BAP1 germline mutation that predisposes to several malignancies including cutaneous and uveal melanoma. To date, only few cases of BAP1-inactivated melanomas have been reported. We present a case of a 35-year-old woman presented with a melanocytic lesion microscopically composed of 3 distinct melanocytic populations, suggesting a stepwise progression model to melanoma from a conventional nevus through a melanocytoma stage. This progression was also supported from a molecular viewpoint given BRAFV600E, BAP1, and TERT-p hot spot mutations detected by targeted mutational analysis. Four atypical melanocytic lesions were removed from the patient's back, and the same A BAP1 c.856A>T, p.(Lys286Ter) mutation was detected on either tumoral or normal tissue samples. To the best of our knowledge, this is the first case of BAP1-inactivated melanoma with a documented TERT-p hot spot mutation manifesting as the first presentation of BAP1 tumor predisposition syndrome., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

BAP1-inactivated melanocytic tumor (BIMT) is a group of melanocytic neoplasms with epithelioid cell morphology molecularly characterized by the loss of function of BAP1, a tumor suppressor gene located on chromosome 3p21, and a mutually exclusive mitogenic driver mutation, more commonly BRAF. BIMTs can occur as a sporadic lesion or, less commonly, in the setting of an autosomal dominant cancer susceptibility syndrome caused by a BAP1 germline inactivating mutation. Owing to the frequent identification of remnants of a conventional nevus, BIMTs are currently classified within the group of combined melanocytic nevi. "Pure" lesions can also be observed. We studied 50 BIMTs from 36 patients. Most lesions were composed of epithelioid melanocytes of varying size and shapes, resulting extreme cytomorphological heterogeneity. Several distinctive morphological variants of multinucleated/giant cells were identified. Some hitherto underrecognized microscopic features, especially regarding nuclear characteristics included nuclear blebbing, nuclear budding, micronuclei, shadow nuclei, peculiar cytoplasmic projections (ant-bear cells) often containing micronuclei and cell-in-cell structures (entosis). In addition, there were mixed nests of conventional and BAP1-inactivated melanocytes and squeezed remnants of the original nevus. Of the 26 lesions studied, 24 yielded a BRAF mutation, while in the remaining two cases there was a RAF1 fusion. BAP1 biallelic and singe allele mutations were found in 4/22 and 16/24 neoplasms, respectively. In five patients, there was a BAP1 germline mutation. Six novel, previously unreported BAP1 mutations have been identified. BAP1 heterozygous loss was detected in 11/22 lesions. Fluorescence in situ hybridization for copy number changes revealed a related amplification of both RREB1 and MYC genes in one tumor, whereas the remaining 20 lesions studied were negative; no TERT-p mutation was found in 14 studied neoplasms. Tetraploidy was identified in 5/21 BIMTs. Of the 21 patients with available follow-up, only one child had a locoregional lymph node metastasis. Our results support a progression of BIMTs from a conventional BRAF mutated in which the original nevus is gradually replaced by epithelioid BAP1-inactivated melanocytes. Some features suggest more complex underlying pathophysiological events that need to be elucidated., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Abstract: Trichoblastoma (TB) is a benign biphasic follicular neoplasm with differentiation toward the germinative cells and a specific follicular mesenchyme. We subtyped 349 sporadic TB according to a classification proposed by Ackerman. Two hundred forty-six (246/349, 70.5%) neoplasms were comprised of mixed subtypes. TB composed exclusively of a single pattern was less common (103/349, 29.5%). The most common pure subtype was cribriform TB followed by small nodular TB. Twelve cases (12/349, 3.4%) had unique features and are reported herein as novel histopathologic subtypes of the neoplasm., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Specific alterations involving MAPK genes (MAP3K8 fusions, MAP3K3 fusions) have been recently detected in a subgroup of spitzoid neoplasms that seem to constitute a distinctive clinicopathologic group, occur mostly in younger patients (median age 18 years) and present with atypical histologic features associated with frequent homozygous deletion of CDKN2A, qualifying a high proportion of them as Spitz melanoma (malignant Spitz tumor). Apart from lesions with spitzoid morphology harboring MAP3K8 or MAP3K3 fusion, a single case with MAP2K1 deletion has been identified. The authors report herein 4 melanocytic lesions with a MAP2K1 mutation, all showing similar microscopic appearances, including spitzoid cytology and dysplastic architectural features, resembling so-called SPARK nevus, suggesting that these lesions may represent another distinctive group., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Lichen aureus is a variant of pigmented purpuric dermatoses. The usual histopathology of lichen aureus is characterized by a subepidermal dense, band-like lymphocytic infiltrate, extravasated erythrocytes, and hemosiderin deposits. We report three patients with lichen aureus on the extremities with similar clinical, dermoscopic, and histopathological findings characterized by a dense band-like relatively deep dermal infiltrate accompanied by extravasation of erythrocytes and hemosiderin deposits occasioning a resemblance to a lymphoproliferative disorder., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Backgrounds: Folate Hydrolase-1 (FOLH1; PSMA) is a type II transmembrane protein, luminally expressed by solid tumour neo-vasculature. Monoclonal antibody (mAb), J591, is a vehicle for mAb-based brachytherapy in FOLH1+ cancers. Brachytherapy is a form of radiotherapy that involves placing a radioactive material a short distance from the target tissue (e.g., on the skin or internally); brachytherapy is commonly accomplished with the use of catheters, needles, metal seeds and antibody or small peptide conjugates. Herein, FOLH1 expression in primary (p) and metastatic (m) Merkel cell carcinoma (MCC) is characterized to determine its targeting potential for J591-brachytherapy., Materials & Methods: Paraffin sections from pMCC and mMCC were evaluated by immunohistochemistry for FOLH1. Monte Carlo simulation was performed using the physical properties of conjugated radioisotope lutetium-177. Kaplan-Meier survival curves were calculated based on patient outcome data and FOLH1 expression., Results: Eighty-one MCC tumours were evaluated. 67% (54/81) of all cases, 77% (24/31) pMCC and 60% (30/50) mMCC tumours were FOLH1+. Monte Carlo simulation showed highly localized ionizing tracks of electrons emitted from the targeted neo-vessel. 42% (34/81) of patients with FOLH1+/- MCC had available survival data f or analysis. No significant differences in our limited data set were detected based on FOLH1 status ( p = 0.4718; p = 0.6470), staining intensity score ( p = 0.6966; p = 0.9841) or by grouping staining intensity scores (- and + vs. ++, +++, +++) ( p = 0.8022; p = 0.8496) for MCC-specific survival or recurrence free survival, respectively., Conclusions: We report the first evidence of prevalent FOLH1 expression within MCC-associated neo-vessels, in 60-77% of patients in a large MCC cohort. Given this data, and the need for alternatives to immune therapies it is appropriate to explore the safety and efficacy o f FOLH1-targeted brachytherapy for MCC.

Long regarded as ectopic or supernumerary breast tissue, anogenital mammary-like glands (AGMLG) are now considered a normal constituent of the anogenital area. AGMLG are presumed to be the origin for various benign and malignant lesions. Changes in AGMLG compatible with usual ductal hyperplasia and atypical ductal hyperplasia considered as precursor lesions and its presence in specimens can be explained by their role in the pathogenesis of primary extramammary Paget disease. In this report, we presented four cases of invasive squamous cell carcinoma accompanied by non-neoplastic atypical changes in ductal portions of AGMLG compatible with atypical ductal hyperplasia in breast adjacent to the carcinoma. This is a reactive phenomenon similar to that seen in apocrine/eccrine glands adjacent to squamous cell carcinoma. In a limited biopsy specimen, these areas should not be mistaken for adenocarcinoma., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 by the International Society of Gynecological Pathologists.)

Abstract: Primary cutaneous desmoplastic melanoma (DM) is a group of rare melanocytic tumors arising on severely sun-damaged skin, histologically characterized by the proliferation of spindled melanocytes in a prominent desmoplastic stroma, with a range of morphological presentations. In this article, we report a unique case of primary cutaneous DM composed of a nodular proliferation of highly pleomorphic spindled and epithelioid cells, pseudoglandular structures, clear cell change, and unusual collagen rosettes. Immunohistochemical analysis showed a strong and diffuse positivity for S-100 protein, SOX-10, nestin, p75 (nerve growth factor receptor), WT1, and p53. Molecular analysis detected a mutation in the NF1 gene [c.4084C > T, p.(Arg1362Ter)], 2 different pathogenic mutations in TP53 [c.742C > T, p.(Arg248Trp), AF:12%, COSM1640831 and c.528C > G, p.(Cys176Trp), AF:12%, COSM11114], and a mutation in GNAS [c.601C > T, p.(Arg201Cys), AF: 9%, COSM123397]. To the best of our knowledge, this is the first case reporting collagen rosettes and pseudoglandular features in primary cutaneous DM., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Sebaceous neoplasms occur sporadically or in the setting of Muir-Torre syndrome. The data regarding the correlation of pathologic features and DNA mismatch repair (MMR) staining pattern in sebaceous tumors of the skin are very scanty and based on relatively small series of patients. The goal of this study was to correlate MMR staining pattern with selected morphological features in a series of 145 sebaceous neoplasms (sebaceous adenoma, sebaceoma, and extraocular sebaceous carcinoma) from 136 patients. Cystic change, intratumoral mucin deposits, squamous metaplasia in the absence of keratoacanthoma-like changes, ulceration, intratumoral and peritumoral lymphocytes (in cases without epidermal ulceration), and intertumoral heterogeneity proved to be significantly associated with MMR deficiency. Identification of any of these changes, alone or in combination, should prompt further investigation of the patient to exclude Muir-Torre Syndrome. Our study also confirms the previously published observation that the diagnosis and tumor location are significantly associated with MMR deficiency., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Birt-Hogg-Dubé syndrome is a rare autosomal dominant disease caused by a mutation in the FLCN gene and presents with a triad of multiple fibrofolliculomas, trichodiscomas, and masses that clinically resemble fibroepithelial polyps (acrochordones), accompanied by an increased risk of kidney tumors and lung cysts. The paper provides a literature review supplemented by clinical cases and the morphological pattern of skin lesions. It presents the clinical and morphological features of cutaneous manifestations of the syndrome and gives diagnostic criteria.

Extramammary Paget disease (EMPD) is a rare neoplasm with uncertain histogenesis, usually presenting in the anogenital area, most commonly in the vulva. The disease is characterized by slow grow and high recurrence rates. This article reviews the epidemiological, clinical, morphological, genetic and treatment features of EMPD of the vulva reported in recent years., (Copyright © 2020. Published by Elsevier Inc.)

BRCA1-associated protein (BAP1)-inactivated melanocytic tumor (BIMT) is a group of epithelioid melanocytic neoplasms characterized by the loss of function of BAP1, a tumor suppressor gene located on chromosome 3p21. They occur sporadically or in the setting of an autosomal-dominant cancer susceptibility syndrome that predisposes to the development of different internal malignancies. Most of these cutaneous lesions are associated with a BRAF-mutated melanocytic nevus and therefore are included in the group of combined nevi in the last WHO classification of skin tumors. Apart from a BRAF mutation, an NRAS mutation has been reported in rare cases, whereas in some lesions no driver mutation has been detected. Here, we report 2 cases of BIMTs with a BAP1 mutation and a RAF1 fusion. Both lesions proved to be BRAF and NRAS wild type and were associated with a conventional melanocytic nevus with dysplastic junctional features. We suggest that RAF1 fusions can represent an underlying driver genetic event in these cases. Our study extends the morphological and molecular spectrum in BIMTs.

Myotis bucharensis is one of the least studied Palaearctic bat species, known from only three localities in Tajikistan and Uzbekistan and not reported since 1965. In autumn 2019, a male Myotis captured in Zerafshan river basin in Tajikistan was later identified as M. bucharensis based on tail and tibia proportions and strongly displacement of posterior small premolars. The identification was then confirmed by morphometric analyses supporting that M. bucharensis is specifically different but represents a part of the Myotis frater complex. Analyses of one mitochondrial (cyt b) and one nuclear gene (RAG2) were performed for the first time for M. bucharensis. According to these genetic results, this form is indeed a member of the «daubentonii» clade, which includes all known frater-like Myotis, and most likely represents a sister species to M. longicaudatus. Record of the alive specimen M. bucharensis has valuable implication for bat conservation in Tajikistan.

The DNA-barcoding and chromosomal study of the eastern water bat, Myotis petax Hollister, 1912, from the earlier unexplored localities in the Russian Far East are carried out. The COI barcoding obtained for 18 from a total of 19 individuals captured in five localities in the Russian Far East showed the low nucleotide variability with the prevalence of the central, the most abundant haplotype. The chromosomal characteristics of eight M. petax specimens (2n = 44, NFa = 52) in the Russian Far East are clarified. The number and localization of NOR in karyotype of M. petax is described at the first time and differ from distributional patterns of NOR in the sibling species M. daubentonii Kuhl, 1819 that can be used as diagnostic feature. The considerable intraspecific variability in the distribution of heterochromatin material revealed is not typical of the genus Myotis , but it has been found in other species of the family Vespertilionidae., (Uliana V. Gorobeyko, Irina V. Kartavtseva, Irina N. Sheremetyeva, Denis V. Kazakov, Valentin Yu. Guskov.)

ALK-fused spitzoid neoplasms represent a distinctive group of melanocytic lesions. To date, few studies addressed genetic and chromosomal alterations in these lesions beyond the ALK rearrangements. Our objective was to study genetic alterations, including ALK gene fusions, telomerase reverse transcriptase promoter (TERT-p) mutations, chromosomal copy number changes, and mutations in other genes. We investigated 29 cases of Spitz lesions (11 Spitz nevi and 18 atypical Spitz tumors), all of which were ALK immunopositive. There were 16 female and 13 male patients, with age ranging from 1 to 43 years (mean, 18.4 years). The most common location was the lower extremity. Microscopically, all neoplasms were polypoid or dome shaped with a plexiform, predominantly dermally located proliferation of fusiform to spindled melanocytes with mild to moderate pleomorphism. The break-apart test for ALK was positive in 17 of 19 studied cases. ALK fusions were detected in 23 of 26 analyzable cases by Archer FusionPlex Solid Tumor Kit. In addition to the previously described rearrangements, 3 novel fusions, namely, KANK1-ALK, MYO5A-ALK, and EEF2-ALK, were found. Fluorescence in situ hybridization for copy number changes yielded one case with the loss of RREB1 among 21 studied cases. TERT-p hotspot mutation was found in 1 of 23 lesions. The mutation analysis of 271 cancer-related genes using Human Comprehensive Cancer Panel was performed in 4 cases and identified in each case mutations in several genes with unknown significance, except for a pathogenic variant in the BLM gene. Our study confirms that most ALK fusion spitzoid neoplasms can be classified as atypical Spitz tumors, which occurs in young patients with acral predilection and extends the spectrum of ALK fusions in spitzoid lesions, including 3 hitherto unreported fusions. TERT-p mutations and chromosomal copy number changes involving 6p25 (RRB1), 11q13 (CCND1), 6p23 (MYB), 9p21 (CDKN2A), and 8q24 (MYC) are rare in these lesions. The significance of mutation in other genes remains unknown.

Inflammatory leiomyosarcoma (ILMS) is a very rare soft tissue tumor that usually follows an indolent clinical course, but long-term follow-up studies are lacking. Recent publications primarily focused on its genetic profile characterized by a near haploid genome. One study also showed these tumors to have upregulation of genes known to be crucial for skeletal muscle differentiation. Nevertheless, immunohistochemical expression of skeletal muscle markers, as well as markers that would help to distinguish ILMS from a long list of relevant differential diagnostic entities, has not been extensively studied. Nine cases of ILMS were collected and stained by a broad IHC panel which, besides others, contained MyoD1, myogenin, and PAX-7. A subset of cases was also analyzed by 2 different NGS assays and by MDM2 fluorescence in situ hybridization. Five male and 4 female patients ranged in age from 25 to 54 years (mean, 36 years). The tumors showed a predilection for intramuscular sites of the lower limbs (n = 4) and back (n = 2), whereas the remaining 3 cases affected an unspecified skeletal muscle, lung, and omentum. Follow-up with an average length of 10.6 years (range 0.5-22) was available for 8 patients. The omental tumor spread locally within the abdominal cavity, but the patient has been free of disease 7 years after treatment. None of the 5 patients with somatic soft tissue tumors (and follow-up longer than 1.5 years) had either recurrence or metastasis. Immunohistochemical studies revealed a substantial expression of skeletal muscle markers in almost all cases. This phenotype coupled with a highly characteristic genotype and significantly more indolent clinical behavior as compared with conventional leiomyosarcoma of deep soft tissue offers a strong rationale to change the current nomenclature. Based on the clinicopathological features and gene expression profile, we propose the name low-grade inflammatory myogenic tumor.

Pigmented epithelioid melanocytoma is a highly pigmented, predominantly dermal melanocytic neoplasm composed by epithelioid and spindled melanocytes. It is characterized by a limited number of specific genomic alterations principally involving protein kinase A regulatory subunit alpha (PRKAR1A) and fusion of protein kinase C alpha isoform (PRKCA). However, in some of these neoplasms, no genetic aberrations have been detected. We performed genomic analysis of a nodular heavily pigmented intradermal proliferation composed of monomorphic epithelioid melanocytes with slight cytologic atypia consisting with pigmented epithelioid melanocytoma occurring on the vulva of a 24-year-old woman. A novel fusion transcript HTT-PKN1 and an ATM (Val410Ala) missense mutation were found. No other mutations including TERT-promoter hotspot mutation analysis were detected. The data expand the spectrum of molecular alterations in pigmented epithelioid melanocytoma.

Intralymphatic histiocytosis is a rare reactive skin condition characterized by a nonspecific clinical presentation and, microscopically, by the collections of mononuclear histiocytes within the lumina of dilated lymphatic vessels. We report a rare case of intralymphatic histiocytosis associated with rosacea and prominent periocular edema (Morbihan disease). The patient is a 56-year-old woman with a 12-year history of rosacea who suddenly developed edema of the right upper eyelid that persisted 6 months before she sought medical advice. Because of an unclear clinical diagnosis, surgical excision of the edematous upper eyelid was performed. The histologic slides showed interstitial edema of the dermis with dilated vascular channels and small epithelioid cell granulomas around hair follicles. In addition, there were aggregates of cells inside numerous lymphatic vessels that were immunohistochemically positive for CD45, CD4, CD68, CD163, CD64, CD14, CD11c, and lysozyme and negative for CD3, CD20, CD30, CD56, S100, CD1a, and langerin.

We report a case of a polypoid atypical Spitz tumor with a prominent fibrosclerotic stromal component, harboring a CLIP2-BRAF fusion, which has hitherto been not reported in melanocytic lesions. The neoplasm occurred in a 78-year-old male patient and appeared microscopically as a predominantly dermal, barely symmetrical, polypoid lesion composed mainly of epithelioid cells showing moderate degree of nuclear pleomorphism with ample amphophilic cytoplasm arranged in nests, fascicles, or single units. The mitotic rate was 2/mm, and the mitoses were confined to the upper portion of the lesion. The Breslow thickness was 2.3 mm. The stroma contained conspicuous plumped fibroblasts and thickened collagen bundles associated with dilated medium-sized vessels. Focally, sclerotic areas were found. A moderately dense, lymphocyte-predominant inflammatory infiltrate scattered through the whole lesion was seen. Despite strong nuclear and cytoplasmic positivity of p16, FISH revealed homozygous loss in locus 9p21. A CLIP2-BRAF fusion was found by next-generation sequencing. No other genetic alterations including a TERT-promoter mutation was found. The patient is disease-free without recurrence or evidence of metastatic disease after 5 years and 2 months of follow-up.

Spitz tumors represent a heterogeneous group of melanocytic neoplasms with a spectrum of biological behavior ranging from benign (Spitz nevus) to malignant (spitzoid melanoma). Prediction of the behavior of these lesions based on their histological presentation is not always possible. Recently, mutually exclusive activating kinase fusions, involving ALK, NTRK1, NTRK3, RET, MET, ROS1, and BRAF, have been found in a subset of spitzoid lesions. Some of these genetic alterations were associated with specific morphological features. Here, we report the histological presentation of 6 Spitz tumors with ROS1 fusion. The age of the patients ranged from 6 to 34 years, with strong female prevalence (5:1). All neoplasms were compound melanocytic proliferations with a predominant dermal growth but a conspicuous junctional component displaying atypical microscopic features qualifying them as atypical Spitz tumor. FIP1L1 and CAPRIN1 were identified as 2 novel 5'-fusion partners of ROS1 along with the known PWWP2A-ROS1 fusion. FISH for copy number changes of 9p21, 6p25, and 11q13 was negative in all but 1 neoplasm harboring isolated gain of 8q24. TERT-promoter hotspot mutation analysis was negative in all tumors. All patients are disease-free after a mean follow-up period of 30 months. It is concluded that ROS1-fused spitzoid neoplasms seem to have no distinctive histopathological features although consistent findings were spindled melanocytes arranged in confluent whorling nests, prominent transepidermal elimination of melanocytic nests, and myxoid/mucinous changes.

Primary effusion lymphoma (PEL) is a rare form of aggressive B-cell lymphoma characterized by a malignant serous effusion involving body cavities. It usually associated with human herpes virus-8 (HHV-8) and coexpression of Epstein-Barr virus and mostly affects patients with HIV. We report a rare case of cutaneous PEL with an unusual intravascular presentation, combined with Kaposi sarcoma involving the skin, lung, and gastrointestinal tract. The molecular genetic analysis of the sarcoma and lymphoma components, using next-generation sequencing was performed. The patient was a 67-year-old man who presented with multiple cutaneous tumors and mass in the left lung. He died 17 hours after the admission to the hospital. At autopsy, in addition to the cutaneous lesions, tumors in the left lung and gastrointestinal mucosa were detected, and no effusions in the body cavities were seen. The biopsy from the cutaneous lesions, pulmonary, and intestinal tumors revealed histological and immunohistochemical features of Kaposi sarcoma. In addition, the skin biopsy specimens contained a diffuse infiltrate composed of large pleomorphic cells, with focal intravascular growth that were negative for pan B-cell markers, weakly positive for CD38 and CD138 but expressed CD3, HHV-8, and Epstein-Barr virus. Molecular genetic studies in this specimen revealed monoclonal rearrangements of the IgH gene. The diagnosis of PEL, solid variant, was made. Next-generation sequencing analysis of the tumorous and normal tissue detected a pathogenic germline mutation of the FAM175A gene and somatic mutations in BRCA2 and RAD51B (in both sarcoma and lymphoma specimens), and INPP4B and RICTOR (in lymphoma specimen only).