RB1-deficient squamous cell carcinoma: the proposed source of combined Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine (NE) carcinoma arising from integration of Merkel cell polyomavirus (MCPyV) DNA into a host cell or from ultraviolet light-induced genetic damage (proportions vary geographically). Tumors in the latter group include those with "pure" NE phenotype and those "combined" with other elements, most often squamous cell carcinoma (SCC). We performed comprehensive genomic profiling (CGP) of MCPyV+ and MCPyV- (pure and combined) tumors, to better understand their mutational profiles and shed light on their pathogenesis. Supplemental immunohistochemistry for Rb expression was also undertaken. After eliminating low quality samples, 37 tumors were successfully analyzed (14 MCPyV+, 8 pure MCPyV- and 15 combined MCPyV-). The SCC and NE components were sequenced separately in 5 combined tumors. Tumor mutational burden was lower in MCPyV+ tumors (mean 1.66 vs. 29.9/Mb, P < 0.0001). MCPyV- tumors featured frequent mutations in TP53 (95.6%), RB1 (87%), and NOTCH family genes (95.6%). No recurrently mutated genes were identified in MCPyV+ tumors. Mutational overlap in the NE and SCC components of combined tumors was substantial ('similarity index' >24% in 4/5 cases). Loss of Rb expression correlated with RB1 mutational (P < 0.0001) and MCPyV- status (P < 0.0001) in MCCs and it was observed more frequently in the SCC component of combined MCC than in a control group of conventional cutaneous SCC (P = 0.0002). Our results (i) support existing evidence that MCPyV+ and MCPyV- MCCs are pathogenetically distinct entities (ii) concur with earlier studies linking the NE and SCC components of combined MCCs via shared genetic profiles and (iii) lend credence to the proposal that an Rb-deficient subset of SCC's is the source of phenotypically divergent combined MCCs.

Endocrine Mucin-Producing Sweat Gland Carcinoma: Emerging Evidence of Multicentric Cutaneous Origin and Occasional Concurrence With Analogous Breast Tumors.

INTRODUCTION: Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a low-grade carcinoma with predilection for the eyelid. It is analogous to solid papillary carcinoma of the breast with both expressing neuroendocrine markers and the potential to progress to invasive mucinous carcinoma (IMC). Although over 80 cases of EMPSGC have been reported, few multicentric cases have been described in the literature. In this article, we report 9 cases of EMPSGC including 3 with multicentric disease. METHODS: A computerized search was performed for EMPSGC and IMC of the eyelid from January 2000 to February 2021. Records were reviewed for age, sex, tumor location, and clinical impression. RESULTS: Eight EMPSGC (7 associated with IMC) and 1 IMC of the eyelid were identified. Lesions were slightly more common in men (55%) than women. The mean age of presentation was 76 years (range, 59-98 years). Lesions ranged from 2.5 to 12 mm. Three cases had multicentric synchronous lesions on the skin. Histologically, these were well-circumscribed dermal tumors with solid or partially cystic nodules. Tested tumors expressed at least 1 neuroendocrine marker and were positive for CK7, ER/PR, 1 or more of GCDFP-15, mammaglobin, and GATA-3. One case had an associated IMC of the breast, and another case was associated with an intraductal papilloma of the breast in a man. There was no evidence of metastasis. CONCLUSION: EMPSGC is a low-grade adnexal neoplasm, commonly affecting the eyelid of the elderly. Lesions often progress to IMC, metastases being exceptionally rare. EMPSGC can be bilateral and multicentric. Concurrence with breast neoplasms has been observed and deserves investigation.

Plexiform Melanocytic Schwannoma: Report of a Second Case and Overview of a Rare Entity.

ABSTRACT: The seminal case report of plexiform melanocytic schwannoma, published a decade ago, indicated that this is a rare variant of schwannoma demonstrating immunohistochemical expression of melanocytic markers, electron microscopic evidence of melanosome formation, and genetic features of a benign schwannoma. We report herein, a second example of this entity. Of added interest, our case showed pseudoglandular features, as previously recorded in other variants of schwannoma. A 66-year-old man presented with a cutaneous papule on the abdomen. Histopathologically, a vertically oriented, exoendophytic, folliculocentric, dermal tumor with a plexiform architecture was observed. This was composed of nodules and diverging fascicles of bland spindle-shaped cells. Notable interstitial mucin deposition conveyed a pseudoglandular appearance to the lesion. The spindled cells co-expressed S100, SOX10, and HMB45. A minority of cells expressed Melan-A and MiTF. EMA and claudin-1 stained capsular and perifascicular perineurial cells. Melanin was absent. Plexiform melanocytic schwannoma represents one of several nerve sheath tumors that peculiarly display evidence of melanocytic differentiation. These include melanocytoneuroma, pigmented neurofibroma (or melanocytic neurofibroma), and malignant melanotic schwannian tumor. Of importance, these proliferations can be mistaken for melanocytic tumors, including melanoma. In expanding the literature on this topic, we discuss steps required to distinguish plexiform melanocytic schwannoma from melanoma and other nerve sheath tumors with melanocytic differentiation. The possible pathogenesis of these unusual neoplasms is also addressed.

Epithelioid Fibrous Histiocytoma With Chondroblastoma-Like Features: A Report of a Rare Entity and Discussion of Related Diagnostic Challenges.

ABSTRACT: Epithelioid fibrous histiocytoma (EFH) is an uncommon benign skin lesion. It is distinct from FH by virtue of its recurrent anaplastic lymphoma kinase (ALK) gene rearrangements and immunohistochemical expression of ALK protein. It often poses a challenge in interpretation. Clinically, it is characterized by a flesh-colored papule/nodule on an extremity of a young to middle-aged individual. Microscopically, it is represented by a circumscribed dermal papule/nodule composed of sheets of plump epithelioid cells, forming whorled aggregates around numerous intralesional vessels. Immunohistochemistry, notably ALK positivity and relevant negative stains, serves to distinguish EFH from its morphological mimics. Rare examples of chondroblastoma-like EFH and EFH with osseous metaplasia are recorded in the literature. Our case is of a 58-year-old man who attended an oculoplastic surgeon because of an exophytic cutaneous nodule on the right upper eyelid. The lesion was excised. Microscopically, it displayed morphological and immunohistochemical features of EFH. Of interest, discrete foci of chondro-osseous change, including chondroblastoma-like pericellular calcification, osteoid formation, and osteoclast-like giant cells, were noted throughout the lesion. A diagnosis of EFH with chondroblastoma-like features was made. Of interest, the changes observed in this EFH serve to link the previously reported examples of pure chondroblastoma-like EFH and EFH with osseous metaplasia. This morphological variant of EFH adds to the existing diagnostic challenge presented by these lesions, particularly in the distinction from other calcifying tumors of the skin.

The use of noninvasive imaging techniques in the diagnosis of melanoma: a prospective diagnostic accuracy study.

BACKGROUND: Early detection of melanoma is crucial to improving the detection of thin curable melanomas. Noninvasive, computer-assisted methods have been developed to use at the bedside to aid in diagnoses but have not been compared directly in a clinical setting. OBJECTIVE: We conducted a prospective diagnostic accuracy study comparing a dermatologist's clinical examination at the bedside, teledermatology, and noninvasive imaging techniques (FotoFinder, MelaFind, and Verisante Aura). METHODS: A total of 184 patients were recruited prospectively from an outpatient dermatology clinic, with lesions imaged, assessed, and excised. Skin specimens were assessed by 2 blinded pathologists, providing the gold standard comparison. RESULTS: Fifty-nine lesions from 56 patients had a histopathologic diagnosis of melanoma, whereas 150 lesions from 128 patients were diagnosed as benign. Sensitivities and specificities were, respectively, MelaFind (82.5%, 52.4%), Verisante Aura (21.4%, 86.2%), and FotoFinder Moleanalyzer Pro (88.1%, 78.8%). The sensitivity and specificity of the teledermoscopist (84.5% and 82.6%, respectively) and local dermatologist (96.6% and 32.2%, respectively) were also compared. LIMITATIONS: There are inherent limitations in using pathology as the gold standard to compare sensitivities and specificities. CONCLUSION: This study demonstrates that the highest sensitivity and specificity of the instruments were established with the FotoFinder Moleanalyzer Pro, which could be a valuable tool to assist with, but not replace, clinical decision making.

Merkel cell carcinoma: A review.

Merkel cell carcinoma has been a focus of active scientific investigation in recent years and new information on the topic has emerged. Although uncommon, this primary cutaneous neuroendocrine carcinoma, usually involving the head/neck of elderly individuals, has a poor prognosis. Within the past two decades, an increase in the incidence of the tumor and the discovery of its link to the Merkel cell polyomavirus have focused medical attention on the lesion. The resulting studies have improved our understanding of the biology of the neoplasm and contributed to clinical care. Specifically, two pathogenic subsets of the tumor have come to light, the majority due to Merkel cell polyomavirus and the minority caused by ultraviolet radiation-induced genetic damage. This dichotomy carries prognostic implications favoring the former subset. In addition, having capitalized on the known susceptibility of the tumor to immune influences, investigators have recently discovered its responsiveness to immune checkpoint inhibition. This revelation has constituted a therapeutic milestone at the clinical level. Herein we provide an overview of the topic, outline updates in the field and place an emphasis on dermatopathologic aspects of Merkel cell carcinoma.

Independent primary cutaneous and mammary apocrine carcinomas with neuroendocrine differentiation: Report of a case and literature review.

Cutaneous apocrine carcinomas share common features with their counterparts in the breast; hence, metastatic mammary carcinoma must be excluded before such lesions can be designated primary cutaneous neoplasms. Primary tumors from either source rarely exhibit neuroendocrine differentiation. We report a case of a 72-year-old female with a painless 1.2-cm scalp nodule. An incisional biopsy revealed dermal involvement by an invasive apocrine carcinoma juxtaposed to a benign apocrine cystic lesion. Immunohistochemically, the carcinoma expressed neuroendocrine proteins including synaptophysin, chromogranin, and CD56. A primary cutaneous apocrine carcinoma with neuroendocrine differentiation was favored, but additional investigations to exclude breast origin were recommended. These revealed a 1.1-cm nodule in the right breast, which proved to be an invasive ductal carcinoma, morphologically and immunophenotypically similar to the scalp lesion. This confounded the case, yet factors militating against metastatic breast carcinoma to skin included (a) the small size of the mammary tumor, (b) absence of other metastatic disease, and (c) juxtaposition of the scalp carcinoma to a putative benign precursor. Molecular studies were undertaken to resolve the diagnostic quandary. Single nucleotide polymorphism microarray analysis revealed distinct patterns of chromosomal copy number alterations in the two tumors, supporting the concept of synchronous and unusual primary neoplasms.

A Case of Whipple Disease With Cutaneous Manifestations.

ABSTRACT: Whipple disease (WD) is a rare bacterial infectious disease that is classically characterized by years of arthralgia, followed by malabsorption, diarrhea, and weight loss. However, WD may manifest in virtually any organ system, and patients with WD rarely develop subcutaneous erythema nodosum-like lesions. We report a case of a 51-year-old man diagnosed with WD who subsequently developed widely distributed erythematous subcutaneous nodules after 5 months of antibiotic therapy.

Apocrine Hidradenoma and Adenomyoepithelioma: Entities on a Biological Continuum of Adnexal Neoplasia.

Apocrine hidradenomas (AH) once believed to harbor myoepithelial cells are now considered pure epithelial neoplasms. They are categorized separately from adenomyoepitheliomas which consist of apocrine epithelial and myoepithelial components. Reports of myoepithelial tumors arising in AH have suggested a link between the 2. Our goal was to explore whether cases diagnosed on routine microscopy as AH harbored occult myoepithelial elements, which would be disclosed by an immunohistochemical evaluation. Twenty-nine such cases, derived from a teaching collection of one of the authors, formed the basis of the study. Clinical and demographic data were documented, and morphological details of the cases were recorded. A panel of immunohistochemistry (AE1AE3, CK8/18, epithelial membrane antigen, p63, S100 protein, glial fibrillary acid protein, calponin, alpha actin, and others), designed to identify myoepithelial cells, was used. The population consisted of 14 women and 15 men (mean age 55.8; range 26-82 years). The tumors, located on the head/neck (14), limbs (10), and trunk (5), were solid (2) and solid/cystic (27). They exhibited varied (often combined) cytological elements (clear, squamoid, polygonal, and mucinous cells). On immunohistochemistry, aggregates of myoepithelial cells were identified in 5 (17%) cases. Four were calponin+ and AE1AE3+; they occupied ≤30% of tumor volumes and exhibited fusiform cytomorphology. One was S100 protein+ and AE1AE3+; it occupied 70% of tumor volume and exhibited polygonal cytomorphology. The gradation in the volume of myoepithelial elements disclosed by immunohistochemistry in a subset of our cases suggests that AH and adenomyoepitheliomas exist on a biological continuum of adnexal neoplasia. The diagnostic categorization of lesions with dual elements requires further study, but we propose that the term adenomyoepithelioma be restricted to those in which myoepithelial cells constitute ≥25% of tumor volume.

Plasmacytic cutaneous pathology: A review.

We review the spectrum of cutaneous disorders associated with inflammatory and neoplastic plasmacytic pathology. Because plasma cells are derived from B-lymphocytes our overview includes discussion of certain lymphoplasmacytic proliferations. It is structured along histopathological lines, addressing conditions characterized by (a) cutaneous plasma cell infiltrates, (b) deposits of plasma cell products or their derivatives in the skin and (c) miscellaneous, poorly understood cutaneous complications of plasmacytic disorders. Lesions arising primarily in the skin and those due to cutaneous involvement by multisystem disorders are addressed. The range includes a spectrum of tumefactive and circulatory manifestations. We highlight key clinical and pathological features of the different conditions and outline recent advances in our understanding of these entities. By emphasizing the dermatopathological characteristics of this spectrum of disorders we hope to hone the diagnostic accuracy of practitioners in the field.

Bowen disease with invasive mucin-secreting sweat gland differentiation: Report of a case and review of the literature.

Bowen disease (BD) with divergent adnexal differentiation is a rare composite cutaneous tumor featuring different phenotypic elements. Sebaceous, poroid and trichilemmal invasive components have been described in this setting and very infrequent reports of mucinous glandular differentiation are extant. Clinically, these tumors are not sufficiently distinctive to enable recognition without histopathological evaluation. From a microscopic perspective, care must be taken to exclude a collision tumor as well as other combined cutaneous neoplasms featuring squamous and glandular differentiation. Direct continuity between the two epithelial phenotypes helps to establish the correct diagnosis and generates interesting speculation about the pathogenesis of these and other epithelial skin tumors. We describe a case of BD in continuity with an invasive adenocarcinoma exhibiting mucinous sweat gland differentiation on the face of an elderly man. Details of the case are outlined with the objective of adding to a scant literature on this topic.

EWSR1-PBX3 gene fusion in cutaneous syncytial myoepithelioma.

Cutaneous syncytial myoepithelioma (CSM) is a recently recognized, histopathological variant of myoepithelial (ME) tumors of the skin. It is characterized by a syncytial arrangement of spindled, ovoid, and/or epithelioid cells forming a well-circumscribed, unencapsulated dermal nodule. There is a paucity of intervening stroma, and absent duct or gland formation. Strong immunohistochemical staining for S100 and epithelial membrane antigen (EMA) has been described, while cytokeratin expression has been uncommon. The majority of CSMs harbor a rearrangement involving the EWSR1 gene. Although various fusion partner genes have been discovered in ME tumors at other anatomic sites, none has yet been described in CSM. We present a case of CSM represented clinically by a papule on the mid-upper back of a healthy 44-year-old female. It exhibited morphological and immunohistochemical features of a CSM with strong, diffuse S100 and alpha-actin expression, and focal positivity for EMA and cytokeratin AE1/AE3. Fluorescence in-situ hybridization showed an EWSR1 gene rearrangement. Massively parallel next-generation RNA sequencing revealed PBX3 as the fusion partner. The EWSR1-PBX3 gene fusion has been previously identified in three cases of ME tumors of bone and soft tissue, and in a case of retroperitoneal leiomyoma. This is the first report of an EWSR1-PBX3 fusion in CSM.

Global PD-L1 Signals and Tumor-Infiltrating Lymphocytes: Markers of Immunogenicity in Different Subsets of Merkel Cell Carcinoma and Potential Therapeutic Implications.

We previously studied the genetic and immunohistochemical profiles of subsets of Merkel cell carcinoma (MCC) stratified by morphology and Merkel cell polyomavirus (MCPyV) status. Recent advances in the immunotherapy of this disease prompted us to examine markers of immunogenicity [PD-L1 expression and tumor-infiltrating lymphocytes (TILS) in these subsets]. The observed clinical responses to checkpoint inhibition of the PD-1/PD-L1 pathway have not correlated with PD-L1 expression by MCC cells, and recent evidence suggests that functions of this pathway within the immune tumor microenvironment may be relevant. We conducted a semiquantitative (high, moderate, and minimal) immunohistochemical evaluation of the global PD-L1 signal in 52 cases of MCC, segregated in 3 subsets [pure MCPyV-positive (n = 28), pure MCPyV-negative (n = 9), and combined MCPyV-negative (n = 15)]. TILS were categorized as brisk, nonbrisk, or absent. Intersubset comparisons revealed that high global PD-L1 signals were exclusively associated with pure MCPyV-positive MCCs contrasted with virus-negative cases (P = 0.0003). Moderate signals were seen across all 3 groups. Brisk TILS were significantly associated with MCPyV-positive MCCs compared with MCPyV-negative cases (P = 0.029). Neither parameter (PD-L1 or TILS) was significantly different between the MCPyV-negative groups. Of potential clinical relevance, MCPyV seems to convey greater immunogenicity to MCCs than the high mutational burden/greater neoantigen load of MCPyV-negative cases. Interesting too is the fact that subset-related profiles of these markers mirrored those noted at genetic and immunohistochemical levels, separating pure MCPyV-positive MCCs from the virus-negative subsets.

Leprosy in Nonimmigrant Canadian Man without Travel outside North America, 2014.

In Canada, Hansen disease (leprosy) is rare and not considered in diagnoses for nonimmigrant patients. We report Mycobacterium leprae infection in a Canadian man whose sole travel was to Florida, USA. The M. leprae isolate was identified as armadillo-associated genotype 3I-2-v1. Travelers to the southern United States should avoid contact with armadillos.

Primary large cell neuroendocrine carcinoma of the skin: An under-recognized entity and a mimic of metastatic disease.

Primary large cell neuroendocrine carcinomas of the skin are exceptionally rare and can be diagnosed only when a metastasis from another organ has been excluded. We report the case of a 62-year-old woman with a cutaneous papule on the mid-chest which generated a differential diagnosis of vascular lesion and basal cell carcinoma. Following excision, microscopic evaluation revealed a dermal large cell undifferentiated carcinoma, with a brisk mitotic rate and focal geographic necrosis. Mucin production was absent. On immunohistochemistry, the lesion expressed CK7, AE1AE3, CK8/18, chromogranin, synaptophysin, CD56, calcitonin (patchy) and TTF-1 (minimal focal). Stains for neurofilament, CK20, CK5/6, p40, p63, SOX10, MART-1, EMA, CEA, ER/PR, GATA3, GCDFP, mammoglobin, PAX-8, CDX2, napsin, ERG and MCPyV proved negative. The histopathological diagnosis was of a large cell neuroendocrine carcinoma, probably metastatic. The patient underwent comprehensive clinical, laboratory and radiographic investigations and no underlying primary carcinoma was detected. During a 20-month follow-up period with an oncologist, the patient remains well and free of any apparent carcinoma. This suggests a primary large cell neuroendocrine carcinoma of skin. To date, 3 such cases have been reported in Japanese patients. This is the first in a Caucasian resident of North America.

Postirradiation pseudosclerodermatous panniculitis with involvement of breast parenchyma: a dramatic example of a rare entity and a pitfall in diagnosis.

Postirradiation pseudosclerodermatous panniculitis is a rare complication of external beam radiotherapy. This inflammatory process typically presents as an erythematous indurated plaque in a previously irradiated region of skin. To date, 13 cases have been reported worldwide. We present a case of a 70-year-old female who received breast irradiation following conservation surgery for invasive breast carcinoma. In her third year of follow-up, she developed an enlarging mass, involving the subcutis and underlying breast tissue, associated with mammographically detected coarse calcifications and density, at the surgical site. This was deemed highly suspicious of recurrent malignancy. Following several benign needle core biopsies, she had an excision of the mass. This revealed a lobular panniculitis and irradiation-induced vascular changes affecting subcutaneous fat and underlying breast tissue. This is the 14th reported case of this rare entity. It is unique in the degree of involvement, affecting breast parenchyma as well as subcutaneous fat, and in its corresponding dramatic clinical and radiographic manifestations.

A Case of Nonuremic Calciphylaxis Treated Effectively With Systemic Corticosteroids.

Calciphylaxis is a syndrome of systemic calcification of the arteries leading to painful tissue necrosis and ulceration. The disease has a high mortality rate with no clear etiology. There is a strong correlation of calciphylaxis with end-stage renal disease, but it can also affect people with normal renal function. Treatment of the disease has been successful at times with various modalities, but in the case of systemic corticosteroids, there is conflicting evidence. In this case report, the authors present a patient with acute nonuremic calciphylaxis who responded very positively to systemic corticosteroids.

Plasmacytoid dendritic cells in hypertrophic discoid lupus erythematosus: an objective evaluation of their diagnostic value.

BACKGROUND: Hypertrophic discoid lupus erythematosus (HDLE), a rare variant of lupus skin disease, is difficult to distinguish from squamous neoplasms and certain dermatoses microscopically. Recently, recognition of the pathogenetic significance of plasmacytoid dendritic cells (PDCS) in cutaneous lupus erythematosus (LE) and of their patterns of distribution in different manifestations of the disease prompted us to study their diagnostic value in the context of HDLE. METHODS: Using immunohistochemistry (CD123) to label the cells, we examined their quantities and patterns of distribution in 27 tissue samples of HDLE from nine patients compared with 39 inflammatory and neoplastic control samples from 36 patients. RESULTS: Using three parameters pertaining to PDCs: (i) their representation of 10% or more of the inflammatory infiltrate, (ii) their arrangement in clusters of 10 cells or more and (iii) their presence at the dermoepidermal junction, we found them to have significant diagnostic value, with accuracies of 77%, 74% and 71%, respectively. CONCLUSIONS: This study supports the careful descriptive observations of previous authors in the field. It also lends validity to the diagnostic step of mapping, immunohistochemically, the density and distribution of PDCs in suspected cases of HDLE.