Multiomics Profiling Distinguishes Sebaceous Carcinoma from Benign Sebaceous Neoplasms and Provides Insight into the Genetic Evolution of Sebaceous Carcinogenesis.

PURPOSE: Sebaceous carcinoma is the third most common nonkeratinocyte skin cancer in the United States with 1,000 cases per year. The clinicopathologic features of sebaceous carcinoma and benign sebaceous neoplasms (adenomas, sebaceomas) can overlap, highlighting the need for molecular biomarkers to improve classification. This study describes the genomic and transcriptomic landscape of sebaceous neoplasms in order to understand tumor etiology and biomarkers relevant for diagnosis and treatment. EXPERIMENTAL DESIGN: We performed whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS) of sebaceous neoplasms from six academic and two federal healthcare facilities in the United States diagnosed between January 1, 1999, and December 31, 2021. RESULTS: We evaluated 98 sebaceous neoplasms: 64 tumors (32 adenomas, 2 sebaceomas, 5 atypical sebaceous neoplasms, 25 carcinomas) had sufficient material for WGS, 96 tumors (42 adenomas, 11 sebaceomas, 8 atypical sebaceous neoplasms, 35 carcinomas) had sufficient material for WTS, and 62 tumors (31 adenomas, 2 sebaceomas, 5 atypical sebaceous neoplasms, 24 carcinomas) had sufficient material for combined WGS and WTS. Overall, we found decreased cholesterol biosynthesis and increased TP53 mutations, copy number gains (chromosome 6, 8q, and/or 18), and tumor mutation burden-high (>10 mutations/MB) in carcinomas compared to adenomas. Although diminished compared to adenomas, most carcinomas still had higher cholesterol biosynthesis than nonmalignant skin. Multiomics profiling also supported a precancerous model of tumor evolution with sebaceomas and atypical sebaceous neoplasms being likely intermediate lesions. CONCLUSIONS: The study findings highlight key diagnostic biomarkers for sebaceous carcinoma and suggest that immunotherapy and modulation of cholesterol biosynthesis could be effective treatment strategies.

Multiple Onychopapillomas and BAP1 Tumor Predisposition Syndrome.

Importance: BRCA1-associated protein (BAP1) tumor predisposition syndrome (TPDS) is a cancer genodermatosis associated with high risk of uveal and cutaneous melanoma, basal cell carcinoma, and multiple internal malignant neoplasms, including mesothelioma and renal cell carcinoma. Early detection of the syndrome is important for cancer surveillance and genetic counseling of family members who are at risk. Objective: To determine the prevalence of nail abnormalities in individuals with pathogenic germline variants in BAP1. Design, Setting, and Participants: In this prospective cohort study, individuals who were known carriers of pathogenic BAP1 germline variants were consecutively enrolled between October 10, 2023, and March 15, 2024. Dermatologic evaluation for nail abnormalities was performed, including a history of nail abnormalities and associated symptoms, physical examination, medical photography, and nail biopsy for histopathology. This was a single-center study conducted at the National Institutes of Health Clinical Center. Main Outcomes and Measures: Primary outcomes were the prevalence and spectrum of nail changes and histopathologic characterization. Results: Among 47 participants (30 female [63.8%]; mean [SD] age, 46.4 [15.1] years) ranging in age from 13 to 72 years from 35 families, nail abnormalities were detected in 41 patients (87.2%) and included leukonychia, splinter hemorrhage, onychoschizia, and distal nail hyperkeratosis. Clinical findings consistent with onychopapilloma were detected in 39 patients (83.0%), including 35 of 40 individuals aged 30 years or older (87.5%). Nail bed biopsy was performed in 5 patients and was consistent with onychopapilloma. Polydactylous involvement with onychopapillomas was detected in nearly all patients who had nail involvement (38 of 39 patients [97.4%]). Conclusions and Relevance: This study found that BAP1 TPDS was associated with a high rate of nail abnormalities consistent with onychopapillomas in adult carriers of the disease. Findings suggest that this novel cutaneous sign may facilitate detection of the syndrome in family members who are at risk and patients with cancers associated with BAP1 given that multiple onychopapillomas are uncommon in the general population and may be a distinct clue to the presence of a pathogenic germline variant in the BAP1 gene.

Cutaneous Gamna-Gandy bodies: An unusual case of dystrophic calcification.

Dystrophic calcification is a common histopathologic finding that can be concomitant with a plethora of diseases, ranging from self-limited infections to insidious malignancies. Gamna-Gandy bodies (GGBs) are a form of dystrophic calcification associated with chronic hemolysis and are typically observed in the spleen. In this report, we present the case of a 92-year-old man who presented with a 4-mm blue papule that was biopsied given the concern for a blue nevus. The subsequent histopathologic examination of the biopsy specimen showed a dermal organizing hematoma adjacent to pale-yellow to brown, refractile material within fibrotic collagen consistent with GGBs. Scanning electron microscopy with energy-dispersive x-ray analysis (SEM/EDXA) revealed that the structures were composed of carbon (39%), oxygen (32%), iron (16%), phosphorus (7%), calcium (5%), and sodium (1%). Fourier transform infrared spectroscopy identified amorphous calcium phosphate. GGBs have not been previously described in the skin and have been rarely characterized with SEM/EDXA in other sites.

NRAS Mutation Detected in a Melanoma With Chondroid Stroma: A Case Report With Molecular Evaluation and Literature Review of a Rare Form of Melanoma.

Melanoma with cartilaginous differentiation is a rare histologic subtype that has been reported in the literature. It often presents clinically different than conventional melanomas and can be diagnostically challenging. Molecular alterations in previously reported cases have not been published. We present a case of melanoma with chondroid stroma from a 70-year-old man that was found to contain an NRAS mutation (c.182A>G (p.Q61R)) via Illumina TruSight Tumor 15 (TST15) next generation sequencing assay.

Squamous cell carcinoma with perineural involvement in nevus sebaceus.

Nevus sebaceus (NS), also known as an organoid nevus, is a congenital skin hamartoma involving the pilosebaceous unit, epidermis, and adnexa, frequently occurring in the scalp area. During childhood, the lesion remains unchanged but may subsequently increase in size during puberty in response to hormonal release, with possible tumor development. We report a case of squamous cell carcinoma (SCC) development in an NS with histologic evidence of perineural involvement on the anterior central scalp of a 13-year-old adolescent girl. We also review the management and prognosis.

Deep Penetrating Fibrous Histiocytoma: A Case Report and Implications for Surgical Management.

Deep penetrating fibrous histiocytoma (DPFH) is a rare variant of fibrous histiocytoma that can arise in the subcutis and deep soft tissues with different clinical implications from dermatofibromas. Dermatofibromas are mainly cosmetic annoyances and do not require surgical management. However, the DPFH does require that negative surgical margins be achieved because of the possibility of local recurrence and distant metastasis. We describe a case of a 24-year-old man diagnosed with DPFH through histologic examination and immunohistochemistry. The lesion displayed diffuse, strong D2-40 positivity and a minority of cells were highlighted with factor XIIIa. The lesion was negative for CD34. The patient's lesion was incompletely excised and a repeat excision was required.

Granular cell basal cell carcinoma: report of a case and review of the literature.

Granular cell basal cell carcinoma (BCC), characterized by large cells with abundant eosinophilic cytoplasm and conspicuous granularity, is an extremely rare variant of BCC with only 14 cases reported in the literature to date. A case of an 82-year-old man with clinically suspected BCC of the face is presented. Microscopic examination demonstrated characteristic morphologic and immunophenotypic features of granular cell BCC, as well as novel expression of p16 and lack of bcl-2 expression, both of which are previously undescribed in granular BCCs in the literature to date. Although very rare, this entity is important to include in the differential of any nodular cutaneous neoplasm with granular features. The rarity of this lesion makes immunohistochemistry especially helpful. As in other BCCs, granular cell BCCs typically strongly express Ber-EP4 and cytokeratins. The granular BCCs are characteristically periodic acid-Schiff positive, but show no expression of S100 protein. The rarity of the granular cell BCC and the aggressive biological behavior of the entities that may share similar histologic features make arriving at the correct diagnosis paramount to appropriate clinical management. The fifteenth case of granular cell BCC with subsequent review of the literature is reported, with particular focus on the immunohistochemical characteristics.

Cutaneous deciduosis: a report of two cases of an unusual pseudomalignancy.

Cutaneous deciduosis represents a rare manifestation of cutaneous endometriosis in which typical endometrial glands and stroma are morphologically and physiologically transformed under hormonal influence. The transformed glands and stroma usually take on the microscopic appearance of uterine decidua but may mimic malignancy. We describe two cases of cutaneous deciduosis that presented in the post-partum period, but biopsies were not performed until a much later date. The first lesion arose on the perineum of a 31-year-old female after vaginal delivery, but a biopsy was not performed until 6 years after presentation. The second lesion grew in a cesarean section scar of a 26-year-old female with a history of ovarian adnexal endometriosis. Clinically described as a persistent post-operative hematoma, the lesion throbbed in synchrony with her menstrual cycles; a biopsy was also performed 6 years after presentation. Histopathologically, both specimens showed similar findings. Sections showed a multinodular proliferation of pale-staining epithelioid cells without significant nuclear atypia or conspicuous mitotic figures. Both showed focal glands that ranged from slit-like to slightly dilated and that contained a flattened epithelial lining without atypia. These unusual cases are presented to instruct about the pathologic findings of this entity in order to prevent the unnecessary diagnosis of malignancy.

Pure apocrine nevus: a report of 4 cases.

Apocrine nevus is a rare tumor composed of increased mature apocrine glands and ductal structures within a fibrous stroma, located predominantly in the reticular dermis. They have been reported in association with apocrine carcinoma, extramammary Paget disease, and syringocystadenoma papilliferum; less commonly a pure apocrine nevus is identified, unassociated with another apocrine proliferation. Clinically apocrine nevi may appear as solitary or multiple nodules or plaques on the scalp, presternal skin, though they are seen most commonly in the axillae. We describe 4 cases of pure apocrine nevus, all of which appeared clinically as painless or mildly tender skin-colored axillary masses, 2 of which were bilateral. In each case, the lesions appeared in adulthood, and patients denied knowledge of congenital or childhood presence. Patients denied pruritis, discharge, bleeding, or antecedent trauma. Grossly, the specimens consisted of subcutaneous, multicystic ill-defined nodules. Biopsy showed prominent apocrine glands composed of irregularly columnar luminal cells with eosinophilic cytoplasm arranged in a somewhat organoid pattern filling the reticular dermis and extending into the subcutaneous adipose tissue. The glandular luminal cells displayed decapitation secretion. There was a paucity of pilosebaceous units. In one case, the overlying epidermis was papillomatous. The deepest portion of one specimen had lactational change simulating a lactational adenoma. No atypia was seen in either the glandular structures or the stroma. The adjacent sebaceous and eccrine structures were normal. The histologic features and immunohistochemical profile in relation to other apocrine lesions will be reviewed.

Rapid onset of argyria induced by a silver-containing dietary supplement.

We describe a 53-year-old man in good general health who presented with an 8-month history of progressive gray hyperpigmentation of the face. He denied using any prescription medications; however, he admitted to taking a herbal supplement. Clinically, the differential diagnosis included hemochromatosis, Wilson's disease and hyperpigmentation secondary to supplement use. Punch biopsies from the left forehead and preauricular region showed heavily sun-damaged skin with a minimal inflammatory infiltrate. Closer inspection, however, revealed minute scattered black/brown particles distributed in the basement membrane zone of eccrine and sebaceous glands. Similar particles were also present in hair follicles, blood vessels and arrector pili muscles. The particles did not stain with Gomori methenamine silver, Fontana-Masson or iron stains. Electron microscopy with energy-dispersive x-ray analysis showed numerous particles, less than 1 µm in greatest dimension, which showed peaks for silver and sulfur. This analytical result confirmed the impression of argyria. Further history revealed that the patient had indeed been taking a silver supplement for several months under the premise that it would boost his immune system. This case is unique in that the patient's hyperpigmentation developed in a short period of time as compared with other reports in the medical literature.

Lupus mastitis: a clinicopathologic review and addition of a case.

Lupus mastitis (LM) is a rare presentation of lupus erythematosus profundus or lupus panniculitis, an unusual and rare clinical variant of lupus erythematosus itself in which the inflammatory reaction occurs primarily in the deep subcutaneous adipose. Although not required for diagnosis, essentially all cases of LM present with systemic or discoid lupus. The etiology is uncertain. Histologically it is defined by a lymphocytic lobular panniculitis and a characteristic hyaline sclerosis of the adipose tissue. Treatment is primarily medical due to exacerbation of disease by surgical intervention. A high index of suspicion, and familiarity of the histologic findings, is therefore required to make an accurate diagnosis and prevent further unwarranted diagnostic procedures. Herein, we provide a literature-based review of the clinical, radiologic, and pathologic findings of LM and its treatment and prognosis with the addition of a case for the literature.

Atypical chromhidrosis: a case report of orange sweat.

Chromhidrosis is a rare sweat gland disorder that produces pigmented sweat. The etiology of this disorder often is unknown and the clinical presentation can vary. We describe a previously asymptomatic patient who presented with bronzing of the skin and complained of orange stains on her clothing. The patient's symptoms began after a prophylactic hysterectomy with bilateral oophorectomy. She is the first reported patient with orange-pigmented sweat in chromhidrosis. She also is the first postmenopausal patient with chromhidrosis.

Hepatocellular carcinoma presenting as a precocious cutaneous metastasis.

The authors report a case of hepatocellular carcinoma (HCC) diagnosed by evaluation of a cutaneous metastasis in a patient without a prior diagnosis of HCC. Subsequent evaluation confirmed the presence of additional widespread metastatic disease. The medical literature is reviewed with regards to cutaneous metastasis, including precocious metastasis, of HCC. The pathologic evaluation of HCC is reviewed, including a discussion of the immunohistochemical profile of this malignancy and the utility of hepatocyte paraffin 1, CD10, and polyclonal carcinoembryonic antigen (pCEA) immunohistochemical stains.

Splitting hairs: the 'hamburger sign' in trichotillomania.

BACKGROUND: A 43-year-old male presented with the clinical findings of patchy alopecia that contained persistent hair and re-growth of hairs of various lengths, consistent with trichotillomania. A biopsy was performed to confirm the diagnosis.. RESULTS: Histologic evaluation revealed findings consistent with trichotillomania, including trichomalacia. Several hair shafts also showed a vertically oriented split, which contained proteinaceous material and erythrocytes. Morphologically, these were reminiscent of a hamburger within a bun. CONCLUSIONS: The unusual finding reported in this case has not been previously reported. The "hamburger bun sign" provides an additional clue to traumatic injury in the evaluation of biopsies for trichotillomania.