LT and SOX9 expression are associated with gene sets that distinguish Merkel cell polyomavirus (MCPyV)-positive and MCPyV-negative Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive malignant neuroendocrine tumour. There are two subsets of MCC, one related to Merkel cell polyomavirus (MCPyV) and the other to ultraviolet radiation (UVR). MCPyV-positive and MCPyV-negative MCCs have been considered to be different tumours, as the former harbour few DNA mutations and are not related to UVR, and the latter usually arise in sun-exposed areas and may be found in conjunction with other keratinocytic tumours, mostly squamous cell carcinomas. Two viral oncoproteins, large T antigen (LT; coded by MCPyV_gp3) and small T antigen (sT; coded by MCPyV_gp4), promote different carcinogenic pathways. OBJECTIVES: To determine which genes are differentially expressed in MCPyV-positive and MCPyV-negative MCC; to describe the mutational burden and the most frequently mutated genes in both MCC subtypes; and to identify the clinical and molecular factors that may be related to patient survival. METHODS: Ninety-two patients with a diagnosis of MCC were identified from the medical databases of participating centres. To study gene expression, a customized panel of 172 genes was developed. Gene expression profiling was performed with nCounter technology. For mutational studies, a customized panel of 26 genes was designed. Somatic single nucleotide variants (SNVs) were identified following the GATK Best Practices workflow for somatic mutations. RESULTS: The expression of LT enabled the series to be divided into two groups (LT positive, n = 55; LT negative, n = 37). Genes differentially expressed in LT-negative patients were related to epithelial differentiation, especially SOX9, or proliferation and the cell cycle (MYC, CDK6), among others. Congruently, LT displayed lower expression in SOX9-positive patients, and differentially expressed genes in SOX9-positive patients were related to epithelial/squamous differentiation. In LT-positive patients, the mean SNV frequency was 4.3; in LT-negative patients it was 10 (P = 0.03). On multivariate survival analysis, the expression of SNAI1 [hazard ratio (HR) 1.046, 95% confidence interval (CI) 1.007-1.086; P = 0.02] and CDK6 (HR 1.049, 95% CI 1.020-1.080; P = 0.001) were identified as risk factors. CONCLUSIONS: Tumours with weak LT expression tend to co-express genes related to squamous differentiation and the cell cycle, and to have a higher mutational burden. These findings are congruent with those of earlier studies.

Merkel cell carcinoma (MCC) is an aggressive form of skin tumour. There are two subtypes of MCC: one of them is related to a virus called Merkel cell polyomavirus (MCPyV); the other one is related to persistent exposure to sunlight. The aim of this research was to find differences between these subtypes in their molecular behaviour (the genes that are expressed and the mutations that may be found). To do this, we carried out two studies, one to investigate gene expression (the process cells use to convert the instructions in our DNA into a functional product such as a protein) and one to look at gene mutations (changes in the DNA sequence). We found that the tumours that were not related to MCPyV expressed genes related to epithelial differentiation (the process by which unspecialized cells gain features characteristics of epithelial cells, which, among other things, make up the outer surface of the body), which means that the origin of both MCC subtypes may be different. We also found that MCPyV-related tumours had fewer mutations. Our findings are important because they help us to understand the biology of the MCC subtypes and could help with the development of new treatments for people diagnosed with skin tumours.

Urticarial mycosis fungoides: A distinctive presentation with blood involvement and a peculiar immunophenotype.

Mycosis fungoides (MF) has been widely reported to mimick a considerable number of different dermatoses, including scarring alopecia, bullous dermatoses or cysts, and comedones. In atypical presentations, histopathology is essential for the diagnosis. We present two cases of MF with clinical urticarial lesions and a striking blood involvement that responded to mogamulizumab treatment. Histopathologically, both cases had classic MF features and shared a peculiar immunophenotype, with positivity for CD25 and FOXP3. Differential diagnoses included urticarial lymphomatoid drug reactions and other lymphomas, like T-cell prolymphocytic leukemia, atypical Sézary syndrome, or adult T-cell lymphocytic leukemia. A low suspicion threshold is necessary for the diagnosis of atypical presentations of MF.

Perineural Infiltration: A Comprehensive Review of Diagnostic, Prognostic, and Therapeutic Implications.

ABSTRACT: Perineural infiltration refers to a neoplastic cell involvement in, around, and through the nerves. It is considered as one of the neoplastic dissemination pathways. Thus, its identification is crucial to establish the prognosis of some malignant skin neoplasms, such as squamous cell carcinoma, and explains the locally aggressive behavior of cutaneous neoplasms, such as microcystic adnexal carcinoma. We have conducted a review of malignant and benign skin tumors in which perineural infiltration has been described, and we also discuss some histopathological findings that may simulate perineural infiltration.

Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages.

HIV-associated neurocognitive disorders (HAND) affect 15-55% of HIV-positive patients and effective therapies are unavailable. HIV-infected monocyte-derived macrophages (MDM) invade the brain of these individuals, promoting neurotoxicity. We demonstrated an increased expression of cathepsin B (CATB), a lysosomal protease, in monocytes and post-mortem brain tissues of women with HAND. Increased CATB release from HIV-infected MDM leads to neurotoxicity, and their secretion is associated with NF-κB activation, oxidative stress, and lysosomal exocytosis. Cannabinoid receptor 2 (CB2R) agonist, JWH-133, decreases HIV-1 replication, CATB secretion, and neurotoxicity from HIV-infected MDM, but the mechanisms are not entirely understood. We hypothesized that HIV-1 infection upregulates the expression of proteins associated with oxidative stress and that a CB2R agonist could reverse these effects. MDM were isolated from healthy women donors (n = 3), infected with HIV-1ADA, and treated with JWH-133. After 13 days post-infection, cell lysates were labeled by Tandem Mass Tag (TMT) and analyzed by LC/MS/MS quantitative proteomics bioinformatics. While HIV-1 infection upregulated CATB, NF-κB signaling, Nrf2-mediated oxidative stress response, and lysosomal exocytosis, JWH-133 treatment downregulated the expression of the proteins involved in these pathways. Our results suggest that JWH-133 is a potential alternative therapy against HIV-induced neurotoxicity and warrant in vivo studies to test its potential against HAND.

Clinical, histopathologic, immunohistochemical, and electron microscopic findings in cutaneous monkeypox: A multicenter retrospective case series in Spain.

BACKGROUND: The worldwide outbreak of monkeypox has evidenced the usefulness of the dermatologic manifestations for its diagnosis. OBJECTIVE: To describe the histopathologic and immunohistochemical findings of monkeypox cutaneous lesions. METHODS: This is a retrospective histopathologic and immunohistochemical study of 20 patients with positive Monkeypox virus DNA polymerase chain reaction and immunohistochemical positivity for Vaccinia virus in cutaneous lesions. Four cases were also examined by electron microscopy. RESULTS: The most characteristic histopathologic findings consisted of full-thickness epidermal necrosis with hyperplasia and keratinocytic ballooning at the edges. In some cases, the outer root sheath of the hair follicle and the sebaceous gland epithelium were affected. Intraepithelial cytoplasmic inclusion bodies and scattered multinucleated keratinocytes were occasionally found. Immunohistochemically, strong positivity with anti-Vaccinia virus antibody was seen in the cytoplasm of ballooned keratinocytes. Electron microscopy study demonstrated numerous viral particles of monkeypox in affected keratinocytes. LIMITATIONS: Small sample size. Electron microscopic study was only performed in 4 cases. CONCLUSION: Epidermal necrosis and keratinocytic ballooning are the most constant histopathologic findings. Immunohistochemical positivity for Vaccinia virus was mostly detected in the cytoplasm of the ballooned keratinocytes. These findings support the usefulness of histopathologic and immunohistochemical studies of cutaneous lesions for diagnosis of monkeypox.

Papillary dermal elastolysis histopathology mimicking folliculotropic mycosis fungoides.

Papillary dermal elastolysis is a rare acquired disease of the elastic tissue that mainly affects elderly women with a clinical presentation of small firm papules in the neck, the supraclavicular areas and the upper back. Histopathologically, it is characteristic to find a complete or almost complete absence of elastic fibers in the papillary dermis with stains such as orcein or Verhoeff-Van Gieson. We present the case of an adult female patient presenting a clinical picture of years of evolution of elastic skin-colored papules on her neck, occasionally pruritic. Two biopsies were performed. In one of them an inflammatory infiltrate affecting the hair follicles was observed, and she was diagnosed with mycosis fungoides. The other biopsy showed a total absence of elastic fibers in the papillary dermis and was diagnosed as elastolysis of the papillary dermis. In early stages of papillary dermal elastolysis, a perivascular and periadnexal lymphocytic inflammatory infiltrate has been described, as is the case described above. It is important for dermatopathologist to know this atypical but possible presentation, as it may require a differential diagnosis with other entities such as follicular mycosis fungoides.

Median raphe cysts: A clinico-pathologic and immunohistochemical study of 52 cases.

BACKGROUND: Median raphe cysts (MRC) are epithelial-lined cystic lesions of the genital area that do not communicate with the urethra or the overlying epidermis. Immunohistochemically, MRC show positivity for cytokeratin (CK) 5-6, CK 7, carcinoembryonic antigen, p63 and uroplakin III (URO III). GATA3 and human milk fat globulin 1 (HMFG1) are immunohistochemical markers that have been not previously studied in MRC. METHODS: We conducted a study of 52 patients diagnosed with MRC in the Pathology Departments of eight hospitals between 1990 and 2016. The monoclonal antibodies used were CK5-6, CK7, CK20, URO III, p63, GATA3, and HMFG1. HMFG1 was studied in five cases of apocrine hidrocystomas and compared with five cases of MRC from our series. RESULTS: CK 5-6, CK7, and p63 expression showed strong positivity in the urothelial epithelium of 48 cases. CK20 was focally positive in areas of mucinous differentiation in three cases. GATA3 showed intense nuclear staining in 30 cases. HMFG1 was positive in three cases of MRC and in three cases of apocrine hidrocystoma. CONCLUSION: Positivity of GATA3 and CK7 in MRC supports the urothelial origin of these cysts. We found no differences in HMFG1 expression between MRC and apocrine hidrocystomas.

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.

Concurrent Presentation of Mycosis Fungoides and Primary Cutaneous Marginal Zone LPD: Clinicopathological Study of 4 Cases and Literature Review.

BACKGROUND: Mycosis fungoides is rarely associated to B-cell malignancies, and the few reported cases are mainly internal lymphomas involving secondarily the skin (ie, chronic lymphocytic leukemia). OBJECTIVES: The aim of our study is to describe the clinical and histopathological features of 4 patients presenting with 2 concurrent primary cutaneous lymphomas and review the pertinent literature. METHODS: We identified 4 cases of concurrent primary cutaneous lymphomas in our institutions. An extracutaneous lymphoma was ruled out on the basis of a complete work out. We performed a PubMed search to identify reported cases of primary cutaneous composite or concurrent lymphomas. RESULTS: Eleven cases of primary cutaneous concurrent lymphomas have been described in the literature. Counting all together (our cases and the cases previously described in the literature), mycosis fungoides was the most frequent primary cutaneous T-cell lymphoma (TCL) (13/15), followed by 1 case of peripheral TCL-NOS and 1 case of subcutaneous panniculitis-like TCL. Regarding the associated primary cutaneous B-cell lymphomas, 8/15 cases consisted of low-grade B-cell lymphomas [that is, 5 marginal zone lymphoma (in the most recent classification reclassified as marginal zone lymphoproliferative disorder, MZLD, 2 follicular-center B-cell lymphoma (primary cutaneous follicle-center lymphoma) and 1 low-grade NOS B-cell lymphoma]; 4/15 were associated to Epstein-Barr virus; 1 case consisted of a methotrexate-associated lymphoproliferative disease, and 2 cases consisted of primary cutaneous diffuse large B-cell lymphoma-leg type. CONCLUSIONS: Primary cutaneous concurrent lymphomas are exceptional. Clinicopathological correlation and a complete workout to reach the correct diagnosis may guide the appropriate treatment in each case.

Histopathology of persistent long COVID toe: A case report.

During the 2020 coronavirus (SARS-CoV-2) pandemic, several cutaneous lesions were identified, including pseudo-chilblain, vesicular, urticarial, maculopapular, and livedo/necrosis. A 59-year-old obese man with probable COVID-19 developed painful cyanosis with histopathologic capillary thrombosis of toes, and the cyanosis persisted for nearly 22 months. Shortly after initial exposure to family members with documented SARS-CoV-2, he developed upper respiratory symptoms, yet his anti-SARS-CoV-2 antibody and nasal swab RT-PCR tests were repeatedly negative. Two family members were hospitalized and one of them succumbed with documented SARS-CoV-2 pneumonia within 10 days of exposure. Biopsy specimen of the distal toe 16 weeks after initial exposure showed papillary dermal capillary thrombosis with endothelial swelling, telangiectasia, and peri-eccrine lymphocytic infiltrates resembling pernio. Overall, this is the first case of biopsy specimen of "long COVID toe" following presumed SARS-CoV-2 exposure, with a demonstration of thrombotic vasculopathy, toe cyanosis, and pernio-like pathology.

Pigmented epidermotropic breast cancer metastases: A rare variant with a particularly unusual feature.

Pigmented epidermotropic breast cancer metastases are a rarity, often clinically misdiagnosed as melanocytic lesions. Histopathologically, they show a dermal proliferation of neoplastic metastatic cells that extend to the overlying epidermis in a pattern identical to that seen in primary Paget disease (PD). Differential diagnosis should be established with entities with a similar presentation, such as pigmented mammary PD and malignant melanoma. Immunohistochemistry may be useful for this purpose. We present a new case of pigmented epidermotropic breast cancer metastases with a particularly unusual feature: the absence of dermal infiltration by neoplastic cells, thus considered as pure epidermotropic metastatic involvement.

Bowen Disease Within a Circumscribed Palmar Hypokeratosis.

ABSTRACT: Circumscribed palmar or plantar hypokeratosis is a focal disorder of keratinization that consists of a reduction in the thickness of the corneal layer of the epidermis of palms or soles. Although it is considered a benign entity, the thinning of the stratum corneum facilitates ultraviolet damage in the affected skin, which may result in an increased risk of developing focal epidermal dysplasia. Other factors, such as immunosuppression in transplanted patients, may play a role as well. We present a case of circumscribed palmar or plantar hypokeratosis with features of Bowen disease limited to the hypokeratotic epidermis.

Double CD4/CD8-Positive, Nonpoikilodermic Mycosis Fungoides Expressing CD56 in a Young Man.

ABSTRACT: We report a case of mycosis fungoides (MF) in an 18-year-old man whose neoplastic T cells expressed CD4, CD8, and CD56, with no evidence of TCR-delta or Epstein-Barr virus (EBER) expression. Clinically, neither hypopigmentation nor hyperpigmentation nor poikilodermatous skin lesions were present, and the lesions subsided with oral corticoids and retinoids and environmental solar ultraviolet exposure. Our case represents the oldest patient reported so far with nonpoikilodermatous, CD8/CD56 MF and adds to the phenotypic diversity of MF in the pediatric population. This distinct phenotype does not seem to be linked to a more aggressive course than the classic CD-4 positive one.

Histopathology of Dermatologic Complications of Tattoos.

ABSTRACT: Tattoos are characterized by the introduction of exogenous pigments into the dermis. Tattoos usually serve cosmetic purposes, although they may have other causes, such as traumatic pigment implants in accidents or medical-related tattoos in the context of radiotherapy. Dermatologic adverse reactions are relatively uncommon, and they include infections, immune-mediated reactions, cutaneous lesions secondary to the Koebner phenomenon, exacerbation of preexisting dermatosis, benign and malignant neoplasms, and a miscellaneous group of dermatologic conditions that may appear in a preexisting tattoo. The aim of this study is to review the types of histopathologic reactions that may appear in a preexisting permanent tattoo.

Syringotropic Melanoma: A Diagnostic Challenge With Prognostic Implications.

ABSTRACT: The presence of neoplastic melanocytes within the eccrine apparatus into the reticular dermis and/or subcutaneous tissue is extremely rare. The staging of syringotropic melanomas and their biological behavior are still controversial. We present 6 new cases of syringotropic melanoma and their main histopathologic features; review the previous literature; and discuss about the origin, staging, and prognosis of this rare variant of melanoma.

Modern endoscopic skull base neurosurgery.

INTRODUCTION: Since the early use of the endoscopic view for treating simple intrasellar pituitary adenomas, the skull base surgery has experienced an unprecedented revolution elevating the treatment of skull base lesions to the next level in proficiency and excellence of care. METHODS: We have reviewed the preclinical and clinical evidence supporting the use of the endoscope in the treatment of skull base lesions. In this article, we aim to discuss and provide a wide view of the current indications and future perspectives of the endoscopic endonasal approaches (EEA) and of the endoscopic transcranial approaches. RESULTS: As in the development of any other technique, EEA have gone through a transformation process from theoretical anatomic models to a pragmatic clinical use. Along the way, EEA have required several modifications, as well as pushbacks in the application of this technique in some indications. This process has resulted in the provision of an additional tool to the current surgical armamentarium that allows the skull base surgeon to face most challenging lesions along the skull base. CONCLUSIONS: The judicious combination of transcranial and endoscopic-transnasal approaches warrants highest chances of achieving satisfactory tumors resection with a reduced risk of complications.

Microcystic adnexal carcinoma with germinative follicular differentiation.

Microcystic adnexal carcinoma (MAC) is a low-grade adnexal carcinoma with controversial lines of differentiation. We present here an example of MAC showing histopathologic findings of germinative follicular differentiation in the form of solid aggregates of trichoblastoma intermingled with neoplastic aggregates of MAC. Immunohistochemical findings, showing positivity for PHLDA1 and negativity for BerEp4 in neoplastic aggregates of trichoblastoma, also supported a germinative follicular differentiation. Follicular differentiation in MAC supports an apocrine line of differentiation for this neoplasm.

Cutaneous eruption with reactive endothelial atypia due to emerging targeted cancer therapies: Report of two cases with clinico-pathologic correlation.

Targeted anticancer therapy is being used with greater frequency and dermatologic toxicities are among the most frequent adverse events of these drugs. However, histopathological features of these adverse events are not yet well characterized. We present two cases of clinically different cutaneous toxicities on two patients with hematologic neoplasia. They were treated with different drugs and in both cases medications shared inhibition of PI3K as mechanism of action. The skin biopsy specimen showed endothelial cell atypia with large nuclei and mitotic figures. To the best of our knowledge, no other cases with these striking histopathologic findings have been reported with PI3K inhibitors or other anticancer targeted therapy.

Acral lymphomatoid papulosis: Report of five cases, differential diagnosis, and review.

Acral lymphomatoid papulosis (a-LyP) is a rare clinical variant of LyP whose diagnosis may be challenging. A case series of a-LyP was studied clinically, histopathologically, immunohistochemically, and from molecular point of view. Including ours, 25 cases of a-LyP have so far been reported. Clinically, a-LyP may present as acral involvement exclusively, in combination with mucosal lesions, (in itself a rare presentation), or in association with conventional LyP. The age of presentation was slightly higher than that of conventional LyP (55 vs 45 years) and a male predominance has been observed, as usually reported. Histopathologically, no morphological differences exclusively from conventional LyP were observed. LyP types A and E were the main variants. We describe for the first time one case of type D a-LyP. Acral LyP is a rare entity and correct diagnosis can only be reached with clinical and histopathological correlation, to avoid aggressive treatment of this indolent lymphoproliferative disorder.

Toker cell hyperplasia in Zuska disease: A tricky association.

Toker cells (TCs) are sometimes present in the nipple epidermis as oval cells with pale cytoplasm and roundish nuclei. In most cases, TCs may be easily distinguished from cancerous cells of Paget disease of the nipple (PCs). Especially in TC hyperplasia, in which mild-to-moderate atypia may be present, it may be challenging to distinguish between TCs and PCs. The combination of chronic inflammatory changes in the nipple, in the context of Zuska disease, and TC hyperplasia, may easily lead to an erroneous diagnosis of mammary Paget disease.