Solitary cutaneous infantile myofibroma as a hallmark of myofibromatosis: Two cases and review of the literature.

Infantile myofibroma (IM) commonly presents as a benign cutaneous fibrous tumor in infancy. Although the majority of solitary IM regress without any morbidity, some cases have underlying bone or visceral involvement that can lead to both morbidity and mortality. In this report with review of the literature, we present two cases of solitary cutaneous IM with internal involvement and discuss screening cases of solitary IM with full body imaging.

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.

Undifferentiated pleomorphic sarcoma: Factors predictive of adverse outcomes.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) encompasses rare neoplasms that can arise either in the dermis or in the subfascial soft tissue. The behavior of UPS ranges from indolent to aggressive, but data predicting outcomes are limited. OBJECTIVE: Identify predictors of poor outcomes by analyzing a large collection of UPS cases. METHODS: We evaluated all available cases of UPS (including those termed atypical fibroxanthoma, malignant fibrous histiocytoma, pleomorphic dermal sarcoma, and subfascial UPS) across 3 tertiary care centers. RESULTS: Among the 319 patients, 45 experienced recurrence, 33 experienced metastasis, and 96 died of any cause. Risk factors for recurrence were clinical tumor size larger than 5 cm and invasion beyond subcutaneous fat. Risk factors for distant metastases were tumor site, tumor size larger than 2 cm, invasion beyond subcutaneous fat, and lymphovascular invasion. Risk factors for overall mortality were age, immunosuppression, tumor size larger than 2 cm, and lymphovascular invasion. History of skin cancer was associated with a lower risk of recurrence and metastasis. LIMITATIONS: This was a retrospective study. CONCLUSIONS: Using the unbiased approach of pooling all UPS cases regardless of terminology, we identified clinical and histologic factors predicting poor outcomes. We propose subcategorization of UPS (into superficial versus deep UPS), which is consistent with the American Joint Committee on Cancer staging of soft-tissue sarcoma.

Non-tuberculous mycobacterial infections following cosmetic laser procedures: a case report and review of the literature.

Skin infections are not uncommon after cosmetic laser procedures. Infection rates following ablative laser resurfacing procedures are reported to be as high as 7.6%, compared to 1.9% for fractional ablation. An infrequent yet important infectious complication of ablative laser treatment is that caused by non-tuberculous mycobacteria (NTM).

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.

Reactive eccrine syringofibroadenomatosis secondary to primary cutaneous amyloidosis: a novel association.

We report the unprecedented case of reactive eccrine syringofibroadenoma (ESFA) secondary to primary cutaneous amyloidosis. A 62-year-old woman of Asian ethnicity presented with a pruritic rash on the back of long-standing duration. Physical examination revealed diffuse hyperpigmentation localized to the interscapular region; there were a multitude of hyperpigmented macules merged in a rippled pattern intermixed with scattered papules and cobblestone-like areas. A punch biopsy from a papule was taken. Histopathological examination revealed a network of epithelial strands and cords hanging from the epidermis and harboring foci of ductal differentiation. Eosinophilic collections of amorphous material were found between the epithelial strands, obscuring the superficial dermis. The microscopic picture was consistent with primary cutaneous amyloidosis associated with reactive ESFA. Results of histochemical and immunohistochemical staining confirmed the diagnosis. We speculate that pathogenetic mechanisms intrinsic to primary cutaneous amyloidosis, in addition to unknown genetic factors, resulted in clinical changes of lichen amyloidosus associated with an abnormal hyperplastic epithelial response with histopathological features of ESFA rather than the common epidermal change of acanthosis and hyperkeratosis.

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.

Novel SOX10 indel mutations drive schwannomas through impaired transactivation of myelination gene programs.

BACKGROUND: Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas. METHODS: We performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10. RESULTS: We identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs. CONCLUSIONS: We thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.

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.

The 7th edition AJCC staging system for cutaneous squamous cell carcinoma accurately predicts risk of recurrence for heart and lung transplant recipients.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the most common malignancy after solid organ transplantation, with an increased risk of recurrence and metastasis over the general population. The newly updated 7th edition American Joint Committee on Cancer (AJCC) staging system for cSCC is based on consensus expert opinion and requires validation in large cohort studies and in specific patient subpopulations. OBJECTIVE: Our objective was to evaluate the risk of cSCC recurrence in a high-risk population of heart and lung transplant recipients, based on the 7th edition AJCC staging system. METHODS: We performed a 10-year retrospective cohort study of all primary cSCC diagnosed in heart and lung transplant recipients at a tertiary care academic dermatology center. RESULTS: The cumulative incidence of local recurrence was 4% for cSCC in situ and 19% for stage I cSCC at 5 years, and 54% for stage II cSCC at 3 years. Stage II tumors had a 10-fold greater risk of recurrence than stage I, and a 43-fold greater risk of recurrence than in situ tumors. LIMITATIONS: This study is limited to a specific patient subgroup at a tertiary care center, and may not be generalizable to all populations. CONCLUSIONS: Heart and lung transplant recipients are at high risk for local recurrence of cSCC. These data substantiate the prognostic accuracy of the newly updated 7th edition AJCC staging system for stage 0, I, and II cSCC in this population and demonstrate the aggressive behavior of this cancer in immunosuppressed patients.

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.

Alpha-interferon induced sarcoidosis mimicking metastatic melanoma.

Despite its modest potential benefit, alpha-interferon is one of the most frequently employed therapies for melanoma. With the increasing incidence of melanoma, a parallel increase in interferon use and the associated adverse reactions that accompany interferon therapy should be expected. We present a case of an interferon-induced sarcoidosis-like reaction in a melanoma patient that was initially misinterpreted clinically and radiographically as metastatic melanoma. The etiology of sarcoidosis remains a mystery, but appears to involve Th-1 cytokines such as interferon and interleukin-2. Observance of a sarcoidosis-like reaction induced by interferon therapy lends additional support to the importance of this cytokine in the pathogenesis of sarcoidosis. It is important for pathologists to be aware of this entity when interpreting biopsies from melanoma patients treated with interferon.

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.

A20 and ABIN1 Suppression of a Keratinocyte Inflammatory Program with a Shared Single-Cell Expression Signature in Diverse Human Rashes.

Genetic variation in the NF-κB inhibitors, ABIN1 and A20, increase risk for psoriasis. While critical for hematopoietic immune cell function, these genes are believed to additionally inhibit psoriasis by dampening inflammatory signaling in keratinocytes. We dissected ABIN1 and A20's regulatory role in human keratinocyte inflammation using an RNA sequencing-based comparative genomic approach. Here we show subsets of the IL-17 and tumor necrosis factor-α signaling pathways are robustly restricted by A20 overexpression. In contrast, ABIN1 overexpression inhibits these genes more modestly for IL-17, and weakly for tumor necrosis factor-α. Our genome-scale analysis also indicates that inflammatory program suppression appears to be the major transcriptional influence of A20/ABIN1 overexpression, without obvious influence on keratinocyte viability genes. Our findings thus enable dissection of the differing anti-inflammatory mechanisms of two distinct psoriasis modifiers, which may be directly exploited for therapeutic purposes. Importantly, we report that IL-17-induced targets of A20 show similar aberrant epidermal layer-specific transcriptional upregulation in keratinocytes from diseases as diverse as psoriasis, atopic dermatitis, and erythrokeratodermia variabilis, suggesting a contributory role for epidermal inflammation in a broad spectrum of rashes.

Transcriptional Programming of Normal and Inflamed Human Epidermis at Single-Cell Resolution.

Perturbations in the transcriptional programs specifying epidermal differentiation cause diverse skin pathologies ranging from impaired barrier function to inflammatory skin disease. However, the global scope and organization of this complex cellular program remain undefined. Here we report single-cell RNA sequencing profiles of 92,889 human epidermal cells from 9 normal and 3 inflamed skin samples. Transcriptomics-derived keratinocyte subpopulations reflect classic epidermal strata but also sharply compartmentalize epithelial functions such as cell-cell communication, inflammation, and WNT pathway modulation. In keratinocytes, ∼12% of assessed transcript expression varies in coordinate patterns, revealing undescribed gene expression programs governing epidermal homeostasis. We also identify molecular fingerprints of inflammatory skin states, including S100 activation in the interfollicular epidermis of normal scalp, enrichment of a CD1C+CD301A+ myeloid dendritic cell population in psoriatic epidermis, and IL1ßhiCCL3hiCD14+ monocyte-derived macrophages enriched in foreskin. This compendium of RNA profiles provides a critical step toward elucidating epidermal diseases of development, differentiation, and inflammation.

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.