Melanoma in infants, caused by a gene fusion involving the anaplastic lymphoma kinase (ALK).

We describe the first cases of pediatric melanoma with ALK fusion gene arising within giant congenital melanocytic nevi. Two newborn boys presented with large pigmented nodular plaques and numerous smaller satellite nevi. Additional expansile nodules developed within both nevi and invasive melanomas were diagnosed before 10 months of age in both boys. Oncogenic driver mutations in NRAS and BRAF were absent in both cases. Instead, oncogenic ZEB2::ALK fusion genes were identified in both the nevus and melanoma developing within the nevus. In both cases, tumors were noted by ultrasound in utero, demonstrated significant nodularity at birth, and progressed to melanoma in the first year of life suggesting that congenital nevi with ALK fusion genes may behave more aggressively than those with other mutations. As ALK kinase inhibitors are effective against a range of tumors with similar ALK fusion kinases, identifying ALK fusion genes in congenital melanocytic nevi may provide an opportunity for targeted therapy.

Spiny Keratoderma in Association with Melanoma.

Spiny keratoderma (SK) was first described by Brown in 1871 and is characterized by numerous 1-2 mm spines of keratin on the palms and soles, usually sparing the dorsal surfaces, or disseminated over the trunk. Histologically, the "spine" represents a column of hyperkeratosis. Several different forms are known, including familial, sporadic, post-inflammatory and paraneoplastic. Although an association of SK with melanoma has been reported, the significance of such co-occurrence remains unclear due to the limited number of cases. To increase the body of knowledge and shed further light on this rare condition, we present a case of SK in a patient with a recent history of melanoma in situ.

Review of 189 Consecutive Female Genital Skin and Mucosal Biopsies Submitted to an Academic Dermatopathology Practice.

OBJECTIVES: To describe consecutive vulvar biopsy cases and to create an educational template for pathology trainees and practicing pathologists. METHODS: We reviewed 189 consecutive biopsies from the female genital area skin and mucosa. We classified them based on etiologies and examined limited clinical information. RESULTS: We classified diagnoses as squamous intraepithelial neoplasia (21.5%), melanocytic neoplasia (17.9%), lichenoid dermatoses (15.9%), nonlichenoid dermatoses (11.3%), infectious (6.2%), reparative (4.6%), or miscellaneous (22.6%). The miscellaneous diagnoses included common entities (polyps and cysts) and rarer entities (calcinosis cutis, adnexal neoplasms, or basal cell carcinoma) and nonspecific descriptive diagnoses. Clinicians most often included the actual diagnosis in their differential for melanocytic lesions (83%) and least often for inflammatory lesions (32%). However, some cases included a clinical description without a differential diagnosis (14%) or no helpful clinical information (4%). The distribution of whether correct diagnoses were included in the clinical differential was similar between submitting physicians and midlevel providers. CONCLUSIONS: Understanding squamous and melanocytic pathology and the various lichenoid and other inflammatory diagnoses is critical for signing out female genital tract skin pathology. The cases examined in this report can serve as an educational template for trainees and practicing pathologists.

Genomic and Clinicopathologic Characteristics of PRKAR1A-inactivated Melanomas: Toward Genetic Distinctions of Animal-type Melanoma/Pigment Synthesizing Melanoma.

Melanocytic tumors with inactivation of protein kinase A regulatory subunit-α (PRKAR1A) have large oval nuclei and intense pigmentation. Historically, these tumors have been categorized under various names, including epithelioid blue nevus, pigmented epithelioid melanocytoma (PEM) and animal-type melanoma. Although a subset of PEM harbor BRAF activating mutations and biallelic inactivation of PRKAR1A, there are only a few reports of melanomas, or of tumors with genomic alterations beyond those of PEMs. Herein, we describe the clinicopathologic and genetic features of 8 melanomas and tumors that lack PRKAR1α expression by immunohistochemistry but do not fit with conventional PRKAR1A-inactivated melanocytomas. These tumors tended to affect younger patients than conventional melanomas (median age=38 y) and presented as dark brown/black papules and nodules. Histopathologically, they demonstrated nodularity, sometimes in a background of conventional melanoma, and large vesicular nuclei with prominent nucleoli. With the exception of 1 case, the mitotic index was not significantly elevated. Immunohistochemically, all cases showed loss of PRKAR1α and of p16 expression. Seven tumors underwent massively parallel short read (next-generation) sequencing of a panel of 480 cancer-associated genes. Five tumors demonstrated truncating mutations of PRKAR1A and the 2 in which such mutations were not identified demonstrated loss of heterozygosity of the PRKAR1A locus. Four of the tumors harbored BRAF V600E mutations, and 1 harbored a FAM39B-BRAF gene fusion. Another harbored a GNA11 activating mutation. A MAP kinase activating mutation was not identified in the remaining case. Four tumors displayed TERT promoter mutations and chromosomal copy number changes supporting the diagnosis of melanoma. Two cases without these alterations and were classified as "high-grade PRKAR1A-inactivated melanocytomas". The 1 case with widespread metastases demonstrated mutations in TP53 and RB1. Overall, we provide the first genetic characterization of PRKAR1A-inactivated melanomas, discuss the differential diagnosis of heavily pigmented epithelioid melanocytic neoplasms, and propose a new nomenclature for such tumors.

Spitz melanoma is a distinct subset of spitzoid melanoma.

Melanomas that have histopathologic features that overlap with those of Spitz nevus are referred to as spitzoid melanomas. However, the diagnostic concept is used inconsistently and genomic analyses suggest it is a heterogeneous category. Spitz tumors, the spectrum of melanocytic neoplasms extending from Spitz nevi to their malignant counterpart Spitz melanoma, are defined in the 2018 WHO classification of skin tumors by the presence of specific genetic alterations, such as kinase fusions or HRAS mutations. It is unclear what fraction of "spitzoid melanomas" defined solely by their histopathologic features belong to the category of Spitz melanoma or to other melanoma subtypes. We assembled a cohort of 25 spitzoid melanomas diagnosed at a single institution over an 8-year period and performed high-coverage DNA sequencing of 480 cancer related genes. Transcriptome wide RNA sequencing was performed for select cases. Only nine cases (36%) had genetic alterations characteristic of Spitz melanoma, including HRAS mutation or fusion involving BRAF, ALK, NTRK1, or MAP3K8. The remaining cases were divided into those with an MAPK activating mutation and those without an MAPK activating mutation. Both Spitz melanoma and spitzoid melanomas in which an MAPK-activating mutation could not be identified tended to occur in younger patients on skin with little solar elastosis, infrequently harbored TERT promoter mutations, and had a lower burden of pathogenic mutations than spitzoid melanomas with non-Spitz MAPK-activating mutations. The MAPK-activating mutations identified affected non-V600 residues of BRAF as well as NRAS, MAP2K1/2, NF1, and KIT, while BRAF V600 mutations, the most common mutations in melanomas of the WHO low-CSD category, were entirely absent. While the "spitzoid melanomas" comprising our cohort were enriched for bona fide Spitz melanomas, the majority of melanomas fell outside of the genetically defined category of Spitz melanomas, indicating that histomorphology is an unreliable predictor of Spitz lineage.

Genomic analysis of atypical fibroxanthoma.

Atypical fibroxanthoma (AFX), is a rare type of skin cancer affecting older individuals with sun damaged skin. Since there is limited genomic information about AFX, our study seeks to improve the understanding of AFX through whole-exome and RNA sequencing of 8 matched tumor-normal samples. AFX is a highly mutated malignancy with recurrent mutations in a number of genes, including COL11A1, ERBB4, CSMD3, and FAT1. The majority of mutations identified were UV signature (C>T in dipyrimidines). We observed deletion of chromosomal segments on chr9p and chr13q, including tumor suppressor genes such as KANK1 and CDKN2A, but no gene fusions were found. Gene expression profiling revealed several biological pathways that are upregulated in AFX, including tumor associated macrophage response, GPCR signaling, and epithelial to mesenchymal transition (EMT). To further investigate the presence of EMT in AFX, we conducted a gene expression meta-analysis that incorporated RNA-seq data from dermal fibroblasts and keratinocytes. Ours is the first study to employ high throughput sequencing for molecular profiling of AFX. These data provide valuable insights to inform models of carcinogenesis and additional research towards tumor-directed therapy.

A case of hair re-pigmentation from a scalp melanoma.

Hair re-pigmentation in adults is a rare phenomenon. We describe a 58-year-old woman who developed hair re-pigmentation on her vertex scalp as a marker of underlying melanoma. Histopathology revealed a nodular melanoma that was surrounding but not invading follicular epithelium. To our knowledge, there have only been 4 other previously published cases describing hair re-pigmentation in the setting of scalp melanoma. Focal hair re-pigmentation in adults should prompt a thorough evaluation for an underlying melanoma.

Activating MET kinase rearrangements in melanoma and Spitz tumours.

Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy. Here we identify six different melanocytic tumours with genomic rearrangements of MET fusing the kinase domain of MET in-frame to six different N-terminal partners. These tumours lack activating mutations in other established melanoma oncogenes. We functionally characterize two of the identified fusion proteins (TRIM4-MET and ZKSCAN1-MET) and find that they constitutively activate the mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase (PI3K) and phospholipase C gamma 1 (PLCγ1) pathways. The MET inhibitors cabozantinib (FDA-approved for progressive medullary thyroid cancer) and PF-04217903 block their activity at nanomolar concentrations. MET fusion kinases thus provide a potential therapeutic target for a rare subset of melanoma for which currently no targeted therapeutic options currently exist.

Clinical, histopathologic, and genomic features of Spitz tumors with ALK fusions.

Activating kinase fusions have recently been described as early oncogenic events that are mutually exclusive with HRAS and BRAF mutations in Spitz tumors. Here, we report a series of 32 Spitz tumors with ALK fusions (6 Spitz nevi, 22 atypical Spitz tumors, and 4 spitzoid melanomas) in patients ranging from 5 months to 64 years (median=12 y) of age. The tumors typically presented as exophytic papules on the extremities and were occasionally darkly pigmented. In addition to ALK fusions previously described in other tumor types (NPM1-ALK, TPR-ALK), we identified 2 novel ALK fusions (CLIP1-ALK and GTF3C2-ALK) in our cohort of Spitz tumors. Array comparative genomic hybridization of 19 of these tumors demonstrated a high frequency of chromosome 2 aberrations (where ALK resides, 63%) and chromosome 1p loss in 37% of the cases. Spitz tumors with ALK fusions demonstrated unique histopathologic features. Clefts and small vesicle-like spaces were arrayed between plump spindled melanocytes with fibrillar cytoplasm and enlarged nuclei. These melanocytes were typically arrayed in elongated and fusiform nests with radial orientation. The tumors often had extension into the dermis or subcutis with a wedge-shaped or bulbous lower border (45% and 17%, respectively). An infiltrative growth pattern was often present at the periphery of the tumor and was highlighted by ALK immunohistochemistry. In conclusion, Spitz tumors with ALK rearrangement show distinct histopathologic features that should aid in improving classification of these diagnostically challenging tumors.

Ambiguous melanocytic tumors with loss of 3p21.

Germline loss-of-function mutations in BAP1 are associated with the development of cutaneous melanocytic tumors with some histopathologic characteristics seen in Spitz nevi. Similar melanocytic tumors occurring in a sporadic setting have been demonstrated to have biallelic loss of BAP1. In some of these sporadic tumors, loss of BAP1 occurs through mutation of 1 allele and genomic loss of the other. We screened our database of comparative genomic hybridization profiles of ambiguous melanocytic tumors to identify cases with a single genomic event involving loss of the BAP1 locus. The prevalence of tumors with a single genomic event involving loss of BAP1 was 6.7% in our study population. We further characterized the BAP1 status in 17 of these tumors with available additional material, confirming loss of BAP1 in all cases. We describe BAP1 loss in a blue nevus-like melanoma and further expand the histopathologic spectrum of spitzoid melanocytic neoplasms with BAP1 loss.

Absence of peripheral blood chimerism in graft-vs-host disease following orthotopic liver transplantation: case report and review of the literature.

BACKGROUND: Graft-vs-host disease (GVHD) is a rare and often fatal complication of orthotopic liver transplantation (OLT). The skin is frequently involved early in disease progression, but clinical and histopathological features may be nonspecific, presenting a diagnostic challenge. While the detection of peripheral blood chimerism has been proposed as a diagnostic criterion for post-OLT GVHD, it is not known whether peripheral blood chimerism is an absolute requirement for the diagnosis. MATERIALS AND METHODS: We report a case of a 57-year-old man who developed post-OLT GVHD with cutaneous, enteric, and bone marrow involvement. We also review the epidemiology, pathogenesis, clinical presentation, histopathology, molecular diagnostic techniques, and treatment of GVHD following liver transplantation. RESULTS: In our patient, analysis of the peripheral blood by short-tandem repeat polymerase chain reaction did not detect circulating donor lymphocytes. Donor lymphocytes were detected in the buccal mucosa, however, confirming the diagnosis. A review of chimerism patterns in 63 previously published cases of post-OLT GVHD reveals that this is the first reported case in which chimerism was absent in the peripheral blood but present in another site. CONCLUSIONS: Peripheral blood chimerism may be absent in cases of post-OLT GVHD. A combination of clinical, histopathological, and molecular features is therefore required to make this challenging diagnosis.

Diffuse neonatal hemangiomatosis: an evidence-based review of case reports in the literature.

BACKGROUND: The term "diffuse neonatal hemangiomatosis" has been used historically to describe multifocal vascular lesions affecting the skin and viscera in infants. OBJECTIVE: We hypothesized that many cases reported as diffuse neonatal hemangiomatosis did not have infantile hemangiomas (IH), but represented more recently described neonatal vascular diseases. METHODS: A literature search was performed using PubMed database (1950-2009) with the terms "neonatal hemangiomatosis," "benign hemangiomatosis," and "diffuse hemangiomatosis." A total of 180 articles were identified. Exclusion criteria included disease onset later than 3 years of age and absence of multifocal skin involvement. In all, 73 cases were selected and categorized into 3 groups: IH/probable IH; multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT)/probable MLT; and multifocal vascular lesions, not otherwise specified. RESULTS: Of the 73 cases, 43 had IH/probable IH, 17 had MLT/probable MLT, and 13 had multifocal vascular lesions, not otherwise specified. The clinical outcomes of these groups differed in that two of 43 (5%) patients with IH died whereas 11 of 17 (65%) patients with MLT died (odds ratio 37.6, confidence interval 5.6-387.6, P value < .0001). LIMITATIONS: This was a literature-based meta-analysis, which inherently has limitations of incomplete and inconsistently presented information. CONCLUSIONS: Many cases reported in the literature as diffuse neonatal hemangiomatosis represent newly described multifocal vascular anomalies such as MLT, which has a strikingly higher mortality than IH. We propose the term "multifocal infantile hemangioma-with or without extracutaneous disease" instead of "diffuse neonatal hemangiomatosis" for multiple cutaneous IH. Accurate diagnosis of multifocal neonatal vascular lesions is imperative to facilitate appropriate evaluation, treatment, and prognosis.

Basal cell carcinoma on the ear is more likely to be of an aggressive phenotype in both men and women.

BACKGROUND: We observed that basal cell carcinoma (BCC) on the ear demonstrates a more aggressive phenotype compared with other body sites. OBJECTIVE: We sought to determine if it is statistically significant that BCC on the ear is more aggressive. METHODS: We queried our 2009 database for all BCCs biopsied from the ear. Multiple data points, including tumor subtype and risk level, were analyzed for 100 BCCs on the ear and 100 BCCs on the cheek. RESULTS: BCC on the ear was diagnosed 471 times. Of the first 100 occurrences of BCC on the ear, 57% were high risk compared with 38% on the cheek (odds ratio 2.16, 95% confidence interval 1.23-3.81, P = .01). Men were more likely to have BCC on the ear: 79% male on the ear and 53% male on the cheek (P < .001). However, BCC on the ear in women is also more likely to be aggressive (57%, 12 of 21). LIMITATIONS: The data were retrieved from a single year at our institution, and there could potentially be regional bias given that the population of data is from a single institution. Many of the specimens we evaluate are reviewed in consultation and may thus represent a selection bias. CONCLUSION: BCC on the ear presents as an aggressive phenotype in the majority of cases for both men and women, and it occurs much more frequently in men. Knowledge of this information can help guide physicians and ensure that these tumors are adequately biopsied and treated.

Giant clear-cell acanthoma with keratoacanthoma-like changes: a case report.

Clear cell acanthoma is a benign epidermal lesion with a variable clinical appearance and distinct histopathology features. Although, it is considered an entirely benign entity, few case reports describe unusual or atypical variants of clear cell acanthoma. We observed a case of a large clear cell acanthoma that also has features of a keratoacanthoma.

Successful bilateral transaortic renal endarterectomy after failed renal artery angioplasty and stenting: a case report.

Restenosis after renal angioplasty and stenting is usually treated with repeat angioplasty or surgery. Because development of substantial postangioplasty periarterial fibrosis is thought to preclude transaortic endarterectomy, renal artery bypass grafting has been the operation of choice in this setting. This report describes successful bilateral transaortic renal thromboendarterectomy undertaken for the treatment of restenosis after percutaneous angioplasty and stenting for renovascular hypertension caused by bilateral renal artery nonostial stenosis.