Primary cutaneous SMARCA4-deficient undifferentiated malignant neoplasm: A rare case report and literature review.

Primary cutaneous SMARCA4-deficient undifferentiated malignant neoplasm (SD-UMN) is a rare and recently described entity characterized by the loss of expression of the SMARCA4 (BRG1) protein, which is involved in chromatin remodeling. SD-UMN presents a diagnostic challenge due to its rarity and unique histopathological and immunohistochemical features. In this report, we present a case of primary cutaneous SD-UMN in a 67-year-old man who presented with a rapidly growing, ulcerated, and bleeding nodule on his right cheek. Histopathological examination revealed a highly cellular dermal tumor consisting of pleomorphic epithelioid cells with prominent mitotic figures and necrosis, lacking any morphological evidence of differentiation. Immunohistochemical analysis showed a complete loss of SMARCA4 and SMARCA2 expression, while INI-1 expression remained intact. p53 was diffusely expressed, and p16 was completely absent. In addition, a range of markers, including high-molecular-weight cytokeratin, p63, SOX10, INSM1, MCPyV, NKX2.2, CD99, CDX2, CD56, ERG, NUT, desmin, androgen receptor, chromogranin, CD34, and CD43 were all negative. To date, only two cases of primary cutaneous SMARCA4-deficient undifferentiated tumors have been reported in the literature. Therefore, this case report adds to the limited body of knowledge on the clinical and histopathological features of this novel entity. The report highlights the importance of considering SD-UMN in the differential diagnosis of undifferentiated cutaneous tumors.

Diagnostic discordance among histopathological reviewers of melanocytic lesions.

BACKGROUND: Histopathological examination is adequate for the diagnosis of most cutaneous melanocytic neoplasms. However, there is a subset that is either difficult to definitively diagnose or would have diagnostic disagreement upon review by multiple dermatopathologists if a more exhaustive review was performed. METHODS: Melanocytic lesions underwent an independent, blinded diagnostic histopathological review of hematoxylin and eosin-stained sections. Each lesion was reviewed by three to six dermatopathologists and categorized as benign, malignant, or unknown malignant potential (UMP). Diagnoses were grouped as concordant (all the same designation); opposing (received benign and malignant designations); majority (single designation with the highest number of diagnoses, no benign/malignant opposing designations); and non-definitive (equal number of non-opposing designations [i.e., benign/UMP or malignant/UMP]). Lesions with equivocal designations (concordant or majority UMP, opposing, majority, and non-definitive) were utilized in a patient treatment model of projected surgical treatment discrepancies. RESULTS: In total, 3317 cases were reviewed, and 23.8% of lesions received equivocal diagnoses. Of these, 7.3% were majority benign, 4.8% were majority malignant, 2.7% were majority UMP, 0.5% were concordant UMP, 6.9% were opposing, and 1.6% were non-definitive. Patient treatment models of those with equivocal lesions (n = 788) revealed a potential of overall surgical treatment variations ranging from 18% to 72%, with the highest variation amongst lesions with opposing, non-definitive, or majority UMP (40%-72%) diagnoses. CONCLUSION: Histopathologic review in this large cohort demonstrated substantial diagnostic variation, with 23.8% of cases receiving equivocal diagnoses. We identified diagnostic ambiguity even in lesions where a definitive diagnosis was previously rendered by a single real-world dermatopathologist. The combined clinical impact of diagnostic discordance or a final diagnosis of UMP is highlighted by high diagnosis-dependent treatment variation in the patient treatment model, which could be underreported in a real-world setting, where review by more than one to two dermatopathologists is relatively rare.

A plague passing over: Clinical features of the 2022 mpox outbreak in patients of color living with HIV.

INTRODUCTION: Compared with previous geographically localized outbreaks of monkeypox (MPOX), the scale of the 2022 global mpox outbreak has been unprecedented, yet the clinical features of this outbreak remain incompletely characterized. METHODS: We identified patients diagnosed with mpox by polymerase chain reaction (PCR; n = 36) from July to September 2022 at a single, tertiary care institution in the USA. Demographics, clinical presentation, infection course, and histopathologic features were reviewed. RESULTS AND CONCLUSION: Men who have sex with men (89%) and people living with HIV (97%) were disproportionately affected. While fever and chills (56%) were common, some patients (23%) denied any prodromal symptoms. Skin lesions showed a wide range of morphologies, including papules and pustules, and lesions showed localized, not generalized, spread. Erythema was also less appreciable in skin of colour patients (74%). Atypical clinical features and intercurrent skin diseases masked the clinical recognition of several cases, which were ultimately diagnosed by PCR. Biopsies showed viral cytopathic changes consistent with Orthopoxvirus infections. All patients in this case series recovered without complications, although six patients (17%) with severe symptoms were treated with tecovirimat without complication.

Superficial GLI1-amplified mesenchymal neoplasms: Expanding the spectrum of an emerging entity which reaches the realm of dermatopathology.

Mesenchymal neoplasms with GLI1 alterations (rearrangements and/or amplification) have been reported recently in several anatomic locations, which include head and neck, soft tissue, and gastrointestinal tract. Herein, to the best of our knowledge, we describe the first three cases of superficial/subcutaneous mesenchymal neoplasm with GLI1 amplification. The neoplasms exhibited low-grade cytologic features with predominant round cell morphology, glomangioma-like areas and a rich background capillary network. There were two to three mitotic figures per 10 HPF and focal necrosis in one case. The tumors exhibited variable expression of CDK4, MDM2, STAT6, D2-40, CD56 and cyclin D1. p16 had strong and diffuse nuclear and cytoplasmic expression in two cases. Numerous other stains were negative. Fluorescence in situ hybridization detected GLI1, DDIT3, and CDK4 coamplification in all cases, while next generation sequencing did not detect a GLI1 gene fusion. The overall features were compatible with a GLI1-amplified mesenchymal neoplasm. In Case 1 a new distant skin lesion appeared 1 month after the surgery exhibiting similar morphology albeit with a higher mitotic index. In Cases 2 and 3, there is no evidence of local recurrence or systemic disease after 8 years and 1 month of follow-up, respectively. These new cases of superficial GLI1-amplified neoplasm expand its clinical spectrum and enter the realm of dermatopathology. The combination of CDK4, cyclin D1, D2-40, and p16 expression with variable MDM2, STAT6, CD56, and S100 immunoreactivity in a low-grade neoplasm with round/ovoid cytomorphology resembling a vascular or adnexal neoplasm may suggest the possibility of GLI1-amplified neoplasm.

Sarcoidosis Coexisting With Distinct Forms of Alopecia on the Scalp: A Case Series.

ABSTRACT: Sarcoidosis is an idiopathic multisystem inflammatory disease that can affect virtually any part of the body. Often, it can initially present solely in the skin. Histologically, it is characterized by noncaseating, 'naked' granulomas in the dermis and subcutaneous tissue. Clinically, sarcoidosis is often referred to as a 'mimicker' of many other pathologic processes because of its wide array of presentations. Occasionally, sarcoidosis can present in the scalp as both a scarring and nonscarring alopecia. There are countless reports of sarcoidosis mimicking various other alopecias including acne keloidalis nuchae, discoid lupus erythematosus, frontal fibrosing alopecia, lichen planopilaris, and alopecia areata totalis. In this case series, we present 2 novel cases of sarcoidosis not just clinically mimicking other forms of alopecia but occurring in conjunction with a separate and histologically distinct primary alopecia.

Autoantigen microarrays reveal myelin basic protein autoantibodies in morphea.

BACKGROUND: Morphea is an autoimmune, sclerosing skin disorder. Despite the recent emphasis on immune dysregulation in morphea, the role of autoantibodies in morphea pathogenesis or utility as biomarkers are poorly defined. METHODS: Autoantigen microarray was used to profile autoantibodies from the serum of participants from the Morphea in Adults and Children (MAC) cohort. Clinical and demographic features of morphea patients with myelin basic protein (MBP) autoantibodies were compared to those without. MBP immunohistochemistry staining was subsequently performed in morphea skin to assess for perineural inflammation in areas of staining. Immunofluorescence staining on mouse brain tissue was also performed using patient sera and mouse anti-myelin basic protein antibody to confirm the presence of MBP antibodies in patient sera. RESULTS: Myelin basic protein autoantibodies were found in greater frequency in morphea (n = 50, 71.4%) compared to systemic sclerosis (n = 2, 6.7%) and healthy controls (n = 7, 20%). Patients with MBP antibodies reported pain at higher frequencies. Morphea skin biopsies, highlighted by immunohistochemistry, demonstrated increased perineural inflammation in areas of MBP expression. Immunofluorescence staining revealed an increased fluorescence signal in myelinated areas of mouse brain tissue (i.e. axons) when incubated with sera from MBP antibody-positive morphea patients compared to sera from MBP antibody-negative morphea patients. Epitope mapping revealed target epitopes for MBP autoantibodies in morphea are distinct from those reported in MS, and included fragments 11-30, 41-60, 51-70, and 91-110. CONCLUSIONS: A molecular classification of morphea based on distinct autoantibody biosignatures may be used to differentially classify morphea. We have identified anti-MBP as a potential antibody associated with morphea due to its increased expression in morphea compared to healthy controls and systemic sclerosis patients.

Appropriate use criteria for ancillary diagnostic testing in dermatopathology: New recommendations for 11 tests and 220 clinical scenarios from the American Society of Dermatopathology Appropriate Use Criteria Committee.

BACKGROUND: Appropriate use criteria (AUC) provide patient-centered physician guidance in test selection. An initial set of AUC was reported by the American Society of Dermatopathology (ASDP) in 2018. AUC reflect evidence collected at single timepoints and may be affected by evolving evidence and experience. The objective of this study was to update and expand AUC for selected tests. METHODS: RAND/UCLA (RAND Corporation [Santa Monica, CA]/University of California Los Angeles) methodology used includes the following: (a) literature review; (b) review of previously rated tests and previously employed clinical scenarios; (c) selection of previously rated tests for new ratings; (d) development of new clinical scenarios; (e) selection of additional tests; (f) three rating rounds with feedback and group discussion after rounds 1 and 2. RESULTS: For 220 clinical scenarios comprising lymphoproliferative (light chain clonality), melanocytic (comparative genomic hybridization, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, telomerase reverse transcriptase promoter), vascular disorders (MYC), and inflammatory dermatoses (periodic acid-Schiff, Gömöri methenamine silver), consensus by panel raters was reached in 172 of 220 (78%) scenarios, with 103 of 148 (70%) rated "usually appropriate" or "rarely appropriate" and 45 of 148 (30%), "appropriateness uncertain." LIMITATIONS: The study design only measures appropriateness. Cost, availability, test comparison, and additional clinical considerations are not measured. The possibility that the findings of this study may be influenced by the inherent biases of the dermatopathologists involved in the study cannot be excluded. CONCLUSIONS: AUC are reported for selected diagnostic tests in clinical scenarios that occur in dermatopathology practice. Adhering to AUC may reduce inappropriate test utilization and improve healthcare delivery.

Pilomatrical Acanthoma: An Extremely Rare Intraepidermal Variant of Pilomatricoma.

ABSTRACT: Pilomatrical differentiation can be observed in a variety of benign and malignant tumors, with the most common prototype being pilomatricoma. Pilomatricoma often presents in the deep dermis or subcutis, and the sole involvement of epidermis is extremely rare. In our current case series, specimens from 5 patients were included with an average age of 68 years. All lesions presented as solitary verrucous or keratotic papules on the extremities, with 1 lesion having a prominent horn. All lesions have a variable mixture of basaloid matrical cells and shadow cells, and all lesions express ß-catenin (strong nuclear and cytoplasmic), lymphoid enhancer-binding factor 1 within the matrical component, and pleckstrin homology-like domain family A member 1. The histomorphology and immunoprofile of all lesions are of pilomatrical differentiation, confined to the level of the epidermis. Based on these findings and analogous to the terminology used for other benign intraepidermal proliferations (hidroacanthoma simplex and epidermolytic acanthoma), we propose the term "pilomatrical acanthoma" for these rare lesions.

Melanocytic Panfolliculoma: A Case Report of a Rare Benign Follicular Tumor.

ABSTRACT: Panfolliculomas (PF) are rare, benign, follicular tumors that differentiate toward multiple components of the hair follicle, and several variants have been described. We present a case of a rare pigmented PF presenting on actinically damaged skin in an 83-year-old man, which was clinically concerning for malignancy. This tumor arose near an area of atypical squamous proliferation and has evidence of infundibular, outer root sheath, and matrical differentiation and foci of heavy melanin pigmentation and increased melanocytes. We propose the novel designation of "melanocytic PF," akin to melanocytic matricoma but with panfollicular differentiation.

A standardized approach to classifying melanocytic neoplasms? Comments on the MPATH-Dx system.

The potential benefits and limitations of the MPATH-Dx classification system for melanocytic neoplasms are presented and discussed.

Rare presentation of inflammatory myofibroblastic tumor on a digit.

Inflammatory myofibroblastic tumors (IMTs) are rare soft tissue neoplasms consisting of a mixture of spindle-shaped myofibroblasts or fibroblasts and a variable inflammatory infiltrate composed of eosinophils, plasma cells, and lymphocytes. Associations with trauma and infectious agents have been proposed, but the etiology is unknown. While IMT predominantly develops in the lungs of pediatric patients or young adults, extrapulmonary IMT is well documented and may occur anywhere. Cutaneous IMT is rare and few have been reported on the hand in the English language. The mean age of onset is 10 years, with a slight female predilection. IMT demonstrates intermediate malignant potential, with a tendency to recur locally. Metastases are rare. According to a recent review, anaplastic lymphoma kinase (ALK) positivity on immunohistochemistry is related to local recurrence, but not distant metastases. We report an unusual case of a 36-year-old male, with a lesion on the right second digit, displaying classic histopathologic and immunohistochemical features of IMT, including ALK staining, and confirmatory fluorescence in situ hybridization-proven ALK gene rearrangement.

A meissnerian neurofibroma: Case report of a rare neurofibroma variant.

Structures resembling Meissner corpuscles have been described in various nerve sheath tumors, including schwannomas and neurofibromas. When present, they are focal or scattered, and rarely a prominent feature of the lesion. Here, we report a case of a 39-year-old female who presented with an isolated lesion on her abdomen. Histopathologically, the tumor was almost exclusively composed of Meissner corpuscle-like structures (pseudo-meissnerian bodies). At a small edge of the tumor, there were features of a classic neurofibroma, with a mixture of Schwann cells, fibroblast-like cells, and interspersed mast cells. We propose the term "meissnerian neurofibroma" for this extremely rare variant of neurofibroma.

Verrucous pilar cysts infected with beta human papillomavirus.

Epidermoid cysts with histopathologic features of human papillomavirus (HPV) infection have been previously reported and are commonly termed verrucous cysts. We report a series of eight histopathologically distinct verrucous pilar cysts, distinguished from traditional verrucous epidermoid cysts by trichilemmal keratinization, as well as two verrucous hybrid pilar-epidermoid cysts. These lesions contain characteristic stratified epithelial linings with abrupt transitions to compact eosinophilic keratin, as well as areas of papillomatosis, coarse intracytoplasmic keratohyalin granules, and vacuolar structures suggestive of HPV-induced cytopathic change. HPV-24, a ß genus HPV species, was identified by degenerate polymerase chain reaction in DNA extracted from two of the lesions, and the presence of ß-HPV E4 protein was confirmed by immunohistochemistry. HPV-60, the HPV species most commonly reported in verrucous epidermoid cysts, was not detected. Verrucous pilar cysts represent histopathologically and potentially etiologically distinct lesions which may be underrecognized.

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

BACKGROUND: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy, and physician decision-making. OBJECTIVES: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology. METHODS: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience, and expert judgment, was used to develop AUC in dermatopathology. RESULTS: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate" and 52 (25%) "rarely appropriate" and 43 (20%) having "uncertain appropriateness." LIMITATIONS: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost. CONCLUSIONS: The ultimate decision to order specific tests rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-the AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.

Muir-Torre syndrome appropriate use criteria: Effect of patient age on appropriate use scores.

BACKGROUND: Muir-Torre syndrome (MTS) is a rare inherited syndrome, with an increased risk of sebaceous and visceral malignancy. Prior reports suggest screening for mismatch repair (MMR) deficiency may be warranted in patients <50 years and when sebaceous neoplasms are located on a non-head and neck location. Previously, appropriate use criteria (AUC) were developed for clinical scenarios in patients >60 years concerning the use of MMR protein immunohistochemistry (MMRP-IHC). This analysis explores the appropriateness of testing in patients ≤60 years. METHODS: Panel raters from the AUC Task Force rated the use of MMRP-IHC testing for MTS for previously rated scenarios with the only difference being age. RESULTS: Results verify the previously developed AUC for the use of MMRP-IHC in neoplasms associated with MTS in patients >60 years. Results also show that in patients ≤60 years with a single sebaceous tumor on a non-head and neck site, MMRP-IHC testing should be considered. Testing can also be considered with a 2-antibody panel on periocular sebaceous carcinoma in younger patients. CONCLUSIONS: Our findings align with known evidence supporting the need to incorporate clinical parameters in identifying patients at risk for MTS, with age being a factor when considering MMRP-IHC testing.

CDX2 and LEF-1 expression in pilomatrical tumors and their utility in the diagnosis of pilomatrical carcinoma.

BACKGROUND: The Wnt signaling pathway has been implicated in the pathogenesis of pilomatrical tumors. Lymphoid enhancer-binding factor 1 (LEF-1) is a downstream component of this pathway, and Caudal-related homeobox transcription factor 2 (CDX2) has been postulated to regulate it, but little is known about expression of these transcription factors in pilomatrical tumors. METHODS: Immunohistochemistry for CDX2, ß-catenin, LEF-1, CK19, CK5, Special AT-rich sequence- binding protein 2 (SATB2), cadherin 17 and androgen receptor was performed on pilomatricomas (PMs) (N = 12), pilomatrical carcinomas (PMCAs) (N = 12) and non-pilomatrical cutaneous tumors (N = 18). RESULTS: PMs and PMCAs were positive for CDX2 (9/12 PMs, sensitivity = 75%, specificity = 100%; 11/12 PMCAs, sensitivity = 92%, specificity = 100%; P < 0.01), ß-catenin (12/12 PMs, sensitivity = 100%, specificity = 94%; 10/12 PMCAs, sensitivity = 83%, specificity = 94%; P < 0.01) and LEF-1 (12/12 PMs, sensitivity = 100%, specificity = 56%; 12/12 PMCAs, sensitivity = 100%, specificity = 56%; P < 0.01). CDX2 expression was commonly focal, within a discrete subpopulation of squamoid cells. The LEF-1 expression pattern was different and discernable between pilomatrical tumors (strong, diffuse) and non-pilomatrical tumors (weak, patchy). CONCLUSION: This study reaffirms the importance of the Wnt signaling pathway in the tumorigenesis of pilomatrical tumors, and this introduces CDX2 as a possible regulator and marker of pilomatrical tumorigenesis. LEF-1 and CDX2 performed at least as well as ß-catenin, if not better when taking into account expression pattern, as a diagnostic marker for PMCA, and should be considered in the workup of ambiguous primitive-appearing cutaneous tumors.

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

BACKGROUND: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy and physician decision-making. OBJECTIVES: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology. METHODS: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience and expert judgment, was used to develop AUC in dermatopathology. RESULTS: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate," 52 (25%) "rarely appropriate" and 43 (20%) "uncertain appropriateness." LIMITATIONS: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost. CONCLUSIONS: The ultimate decision of when to order specific test rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.

Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses.

BACKGROUND: Human polyomavirus (HPyV)6 and HPyV7 are shed chronically from human skin. HPyV7, but not HPyV6, has been linked to a pruritic skin eruption of immunosuppression. OBJECTIVE: We determined whether biopsy specimens showing a characteristic pattern of dyskeratosis and parakeratosis might be associated with polyomavirus infection. METHODS: We screened biopsy specimens showing "peacock plumage" histology by polymerase chain reaction for HPyVs. Cases positive for HPyV6 or HPyV7 were then analyzed by immunohistochemistry, electron microscopy, immunofluorescence, quantitative polymerase chain reaction, and complete sequencing, including unbiased, next-generation sequencing. RESULTS: We identified 3 additional cases of HPyV6 or HPyV7 skin infections. Expression of T antigen and viral capsid was abundant in lesional skin. Dual immunofluorescence staining experiments confirmed that HPyV7 primarily infects keratinocytes. High viral loads in lesional skin compared with normal-appearing skin and the identification of intact virions by both electron microscopy and next-generation sequencing support a role for active viral infections in these skin diseases. LIMITATION: This was a small case series of archived materials. CONCLUSION: We have found that HPyV6 and HPyV7 are associated with rare, pruritic skin eruptions with a distinctive histologic pattern and describe this entity as "HPyV6- and HPyV7-associated pruritic and dyskeratotic dermatoses."

Congenital infantile fibrosarcoma mimicking a cutaneous vascular lesion: a case report and review of the literature.

Congenital infantile fibrosarcoma (CIFS) is a rare neoplasm of infancy that occurs most frequently in the extremities, and when presenting in the skin, may sometimes resemble infantile hemangiomas or other vascular lesions. Clinically, these tumors differ from hemangiomas in the time of onset, morphology, and growth pattern and must be evaluated histologically for definitive diagnosis. We describe an infant with a neoplasm involving the distal left forearm initially presumed to be a vascular lesion after evaluation by two separate ultrasound studies. He presented at seven weeks of life with a multinodular lesion that had enlarged significantly since birth, and the skin biopsy revealed a fibrosarcoma. This case highlights an unusual cutaneous presentation of CIFS, which varies in appearance from the previous 12 cases reported in the literature. We review the clinical manifestations of these congenital masses and emphasize early diagnosis for conservative therapy and improved prognosis.

MYC amplification in angiosarcomas arising in the setting of chronic lymphedema of morbid obesity.

BACKGROUND: Angiosarcoma is a malignancy of vascular endothelial cells which may arise secondarily as a complication of lymphedema, including chronic lymphedema of morbid obesity. Amplifications in MYC are frequently present in secondary angiosarcoma (arising in irradiated sites and chronic lymphedema) and less frequently in primary cutaneous angiosarcoma. OBJECTIVE: To describe the presence of MYC amplifications in two cases of cutaneous angiosarcoma secondary to chronic lymphedema of morbid obesity. METHODS: This study is a case series of two patients with cutaneous angiosarcoma. Clinical data was retrieved from the medical records. Histopathological analysis of the biopsy specimens was performed, including immunohistochemistry, along with fluorescence in situ hybridization. RESULTS: Angiosarcoma arose in the setting of massive chronic lymphedema complicating morbid obesity without other predisposing risk factors. Both cases exhibited epithelioid cell morphology and high-level MYC amplification. CONCLUSION: We report MYC amplification in two cases of angiosarcoma arising in massive chronic lymphedema of morbid obesity.