Metabolic heterogeneity confers differences in melanoma metastatic potential.

Metastasis requires cancer cells to undergo metabolic changes that are poorly understood1-3. Here we show that metabolic differences among melanoma cells confer differences in metastatic potential as a result of differences in the function of the MCT1 transporter. In vivo isotope tracing analysis in patient-derived xenografts revealed differences in nutrient handling between efficiently and inefficiently metastasizing melanomas, with circulating lactate being a more prominent source of tumour lactate in efficient metastasizers. Efficient metastasizers had higher levels of MCT1, and inhibition of MCT1 reduced lactate uptake. MCT1 inhibition had little effect on the growth of primary subcutaneous tumours, but resulted in depletion of circulating melanoma cells and reduced the metastatic disease burden in patient-derived xenografts and in mouse melanomas. In addition, inhibition of MCT1 suppressed the oxidative pentose phosphate pathway and increased levels of reactive oxygen species. Antioxidants blocked the effects of MCT1 inhibition on metastasis. MCT1high and MCT1-/low cells from the same melanomas had similar capacities to form subcutaneous tumours, but MCT1high cells formed more metastases after intravenous injection. Metabolic differences among cancer cells thus confer differences in metastatic potential as metastasizing cells depend on MCT1 to manage oxidative stress.

Epidermodysplasia Verruciformis and Vδ2 γδ T-cell Expansion in STK4 Deficiency.

The clinical penetrance of infectious diseases varies considerably among patients with inborn errors of immunity (IEI), even for identical genetic defects. This variability is influenced by pathogen exposure, healthcare access and host-environment interactions. We describe here a patient in his thirties who presented with epidermodysplasia verruciformis (EV) due to infection with a weakly virulent beta-papillomavirus (HPV38) and CD4+ T-cell lymphopenia. The patient was born to consanguineous parents living in the United States. Exome sequencing identified a previously unknown biallelic STK4 stop-gain mutation (p.Trp425X). The patient had no relevant history of infectious disease during childhood other than mild wart-like lesion on the skin, but he developed diffuse large B-cell lymphoma (DLBCL) and EBV viremia with a low viral load in his thirties. Despite his low CD4+ T-cell count, the patient had normal counts of CD3+ cells, predominantly double-negative T cells (67.4%), which turned out to be Vδ2+ γδ T cells. γδ T-cell expansion has frequently been observed in the 33 reported cases with STK4 deficiency. The Vδ2 γδ T cells of this STK4-deficient patient are mostly CD45RA-CD27+CCR7+ central memory γδT cells, and their ability to proliferate in response to T-cell activation was impaired, as was that of CD4+ T cells. In conclusion, γδ T-cell expansion may act as a compensatory mechanism to combat viral infection, providing immune protection in immunocompromised individuals.

Comparison of 2 T-Cell Receptor-γ Clonality Assays on Skin Biopsies Suspicious for Mycosis Fungoides.

ABSTRACT: PCR-based fragment analysis of the T-cell receptor (TCR) gene is used extensively in diagnostic labs to assess clonality in T-cell populations in multiple tissue sites. Of the numerous TCR assays that have been reported, studies assessing use on biopsies suspicious for mycosis fungoides specifically are lacking. We compared clonality findings from a previously run 2-tube/2-fluorochrome dye assay to a redesigned 1-tube/1-fluorochrome dye assay on formalin-fixed skin biopsies. Overall, the accuracy of the 2-tube assay was marginally better (75.7% vs. 71.4%), when using clinical history combined with histologic diagnosis as the gold standard. The 2-tube assay had better sensitivity (73.7% vs. 65.8%), while the 1-tube assay had superior specificity (93.8% vs. 87.5%). Clonality results were easier to interpret with the 1-tube assay. In nearly 19% of cases, a change of assays on the same biopsy resulted in a change of clonality interpretation. For laboratories that change TCR-γ clonality assays, follow-up biopsies for mycosis fungoides assessment may result in a change of diagnosis.

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.

Vulvar Lichen Sclerosus Clinical Severity Scales and Histopathologic Correlation: A Case Series.

ABSTRACT: Several vulvar lichen sclerosus (VLS) clinical severity scales have recently been proposed. In this prospective case series, we characterized histopathology in the context of clinical severity in 6 treatment-naïve postmenopausal patients with VLS. The Vulvar Quality of Life Index (VQLI) and an adaptation of the 2018 International Society for the Study of Vulvovaginal Disease Delphi consensus VLS severity score were administered. Vulvar skin punch biopsies were obtained to measure inflammatory density, constituent inflammatory cells, thickness of the stratum corneum and other epidermal layers, dermal edema, and dermal sclerosis. Clinicopathologic correlations were assessed. Two cases demonstrated sparse inflammatory densities, 1 case demonstrated patchy and nodular inflammatory density, 1 case demonstrated dense lichenoid inflammatory density, and 2 cases demonstrated dense lichenoid and epitheliotropic inflammatory densities. Those patients who reported severe pruritus demonstrated the greatest lymphocytic inflammatory densities on histopathological examination. Both cases of ulceration or erosion were associated with severe VQLI scores. Severe VQLI scores were also associated with trends for higher average thickness of the epidermal layers and of dermal sclerosis. Altogether, histopathologic grading of biopsy sites may reflect clinical severity in patients with VLS.

Cutaneous mucormycosis involving a colostomy site.

Cutaneous mucormycosis is a rapidly advancing fungal infection that most commonly occurs due to airborne spread or direct inoculation and requires early detection and prompt treatment for optimal survival. Major risk factors include diabetes, transplantations, malignancies, surgical procedures, and HIV. Diagnostic criteria are based on microscopy and culture. We present an immunocompromised patient with cutaneous mucormycosis that developed in a peristomal ulcer following a hemicolectomy procedure. Histopathologic evaluation was indicative of mucormycosis. Intravenous posaconazole treatment was initiated, but unfortunately, the patient's condition deteriorated and he passed away.

Epidermolytic Hyperkeratosis in an Epidermoid (Infundibular) Cyst.

ABSTRACT: Epidermolytic hyperkeratosis (EHK) is an uncommon histopathologic reaction pattern that may represent a primary pathological process or a coincidental finding in a variety of neoplasms. We present a case of EHK in an epidermoid (infundibular) cyst. Histopathologically, EHK demonstrates vacuolar degeneration of keratinocytes in the spinous and granular cell layers, with disrupted cellular boundaries, enlarged basophilic keratohyalin-like granules and amorphous eosinophilic inclusions, along with massive hyperkeratosis. In addition to the morphologic description of EHK, we summarize the diagnoses in which EHK has been reported. Prior cases of EHK in an epidermoid (infundibular) cyst are summarized to compare findings. The significance of incidental EHK in skin lesions is unknown.

Podophyllotoxin Cytological Effects on the Epidermis in Condyloma Acuminatum.

ABSTRACT: Podophyllotoxin (PPT) is used to treat condylomata acuminata and works by destabilizing microtubules within epithelial cells, leading to mitotic arrest in metaphase. PPT-induced changes to the epidermis can cause histological findings mimicking dysplasia. Here, we present a case of vulvar condyloma acuminatum treated with PPT, showing ballooning degeneration, necrotic keratinocytes, and mitotic figures. PPT-treated skin may resemble dysplasia or squamous cell carcinoma in situ due to dyskeratosis and frequent mitoses; however, the synchronicity of mitotic figures in early phases of mitosis, as well as the absence of cellular pleomorphism and atypical mitotic figures, allows for distinction from malignancy. This case demonstrates the importance of understanding the histological changes caused by PPT to prevent misdiagnosis and potential overtreatment.

Assessing comfort level with pediatric skin specimens among dermatopathologists and pediatric pathologists: A national cross-sectional survey.

BACKGROUND: Cutaneous histopathologic diagnoses in children often differ from those in adults. Depending on practice setting, these specimens may be evaluated by dermatopathologists or pediatric pathologists. We sought to determine whether comfort level with pediatric dermatopathology is associated with prior training, pediatric dermatopathology exposure during fellowship, career duration, or specimen subtype. METHODS: We surveyed dermatopathologists and pediatric pathologists practicing in the United States. Training and practice variables were evaluated by multivariable regression for association with comfort level. RESULTS: Of the 156 respondents, 72% were dermatopathologists (response rate 11.6%) and 28% were pediatric pathologists (response rate 9.3%). Dermatopathologists reported higher comfort overall (P < .001); this was also true for inflammatory dermatoses and melanocytic neoplasms (P < .001). Thirty-four percent and 75% of dermatopathologists and pediatric pathologists, respectively, reported lower comfort with pediatric skin specimens than their usual cases. Pediatric pathologists were 28% more likely to refer these cases to colleagues. Among dermatopathologists, dermatology-trained were more comfortable than pathology-trained colleagues interpreting inflammatory dermatoses (P < .001). CONCLUSIONS: Pathologists' comfort with pediatric dermatopathology varied significantly based upon prior training, career duration, and specimen subtype. These results suggest opportunities for improving education in this domain.

A severe presentation of acute generalized exanthematous pustulosis with non-infectious circulatory shock in an adolescent.

We present a severe case of acute generalized exanthematous pustulosis (AGEP) secondary to trimethoprim-sulfamethoxazole complicated by non-infectious circulatory shock in a 16-year-old boy. Hemodynamic instability has been reported as a complication of AGEP in adults, but is rarely observed in pediatric patients. The patient we present demonstrated characteristic cutaneous findings of AGEP including isolated non-follicular, sterile pustules on a background of erythema with involvement at intertriginous areas and subsequently developed non-infectious circulatory shock. This case expands the spectrum of possible clinical presentations for AGEP in pediatric patients.

Pink nodule of the chin: an unusual presentation of metastatic carcinoma.

Renal cell carcinoma (RCC) is the most lethal urological tumor, often because it is widely metastasized at the time of diagnosis. There are reports of cutaneous metastases, most commonly to the head and neck, presenting late after RCC is diagnosed. This case presentation explores a 45-year old female patient with a growing skin lesion on her chin, previously treated as an epidermoid cyst before presenting to dermatology clinic. We present a case of cutaneous metastatic clear cell renal cell carcinoma presenting 7 years after initial diagnosis.

Blastic plasmacytoid dendritic cell neoplasm in a young patient.

Blastic plasmacytoid dendritic cell neoplasm is a rare hematologic neoplasm originating from plasmacytoid dendritic cell precursors that has an aggressive disease course with typically poor prognosis. Herein, we report a man in his early twenties who presented with rapid onset of violaceous nodules and purpuric papules and macules that began on his chest before spreading to his arms, back, face, scalp, and legs. He also exhibited systemic symptoms including weight loss and night sweats. He was diagnosed with blastic plasmacytoid dendritic cell neoplasm and began treatment with aggressive multidrug therapy. Thus far his treatment has resulted in complete resolution of his cutaneous manifestations.

Chondrodermatitis nodularis nasi.

Chondrodermatitis nodularis helicis is a relatively common ulcerative, inflammatory condition affecting the skin, and cartilage of the ear. We present a case of chondrodermatitis affecting the skin and cartilage of the nose, designated chondrodermatitis nodularis nasi. Clinically, chondrodermatitis presents as a singular, painful, ulcerated papule or nodule that results from prolonged pressure, trauma, sun exposure, or vascular compromise. The clinical features resemble those seen in skin cancer, and a biopsy is often required to secure the diagnosis. Histopathologic analysis of chondrodermatitis demonstrates a central ulcer, beneath which there is fibrinoid necrosis of the dermis and inflammatory infiltrates. The ulcer is bordered by pseudoepitheliomatous hyperplasia with underlying granulation tissue. In addition to a clinical and morphologic description of chondrodermatitis nodularis nasi, a discussion of etiological factors and differential diagnoses is included. Increased recognition and reporting of the condition will allow for the exploration of optimal treatment strategies.

Refractory macrophage activation syndrome in the setting of adult-onset Still disease with hemophagocytic lymphohistiocytosis detected on skin biopsy treated with canakinumab and tacrolimus.

A 19-year-old Caucasian female with adult-onset Still disease (AOSD) presented for evaluation of an acute clinical decompensation and atypical annular papules and plaques with purpura on the lower extremities. A punch biopsy demonstrated histiocytes with engulfed degenerated erythrocytes and lymphocytes, consistent with hemophagocytic lymphohistiocytosis (HLH). HLH, clinically referred to as macrophage activation syndrome, is a rare complication of AOSD and is life-threatening. Relevant clinical, laboratory, and histologic features of this diagnosis are reviewed.

Pigmented fungiform papillae of the tongue: a clinical and histologic description.

A 28-year-old man with a history of mycosis fungoides presented for evaluation of multiple dark-brown macules and hyperpigmented dome-shaped papules on the distal tongue. A shave biopsy of the tongue revealed melanin pigment in the basal keratinocytes and melanophages in the lamina propria, consistent with pigmented fungiform papillae of the tongue. Relevant clinical and histologic features of this diagnosis are reviewed.

Late-stage nodular erythema elevatum diutinum mimicking sclerotic fibroma.

Erythema elevatum diutinum (EED) is a rare, cutaneous vasculitis of uncertain origin. EED can present clinically as chronic bilateral, symmetrical, periarticular papules, plaques and nodules. We report here an unusual case of EED presenting as multiple, densely fibrosing nodules on the feet of a 60-year-old human immunodeficiency virus positive woman. The initial evaluation of the patient was complicated by the strong histologic resemblance of multiple lesions to sclerotic fibroma, a cutaneous manifestation of Cowden disease. Our case highlights the important features that distinguish these 2 pathologic entities.

Self-limiting Ibrutinib-Induced Neutrophilic Panniculitis.

Neutrophilic panniculitis is a relatively rare condition, characterized by predominantly neutrophilic inflammation in the subcutaneous fat. Rarely, neutrophilic panniculitis may be induced by chemotherapeutics or targeted molecular therapies, including the Bruton tyrosine kinase inhibitor ibrutinib. Previously reported cases of ibrutinib-induced panniculitis were suppressed with sustained low-dose steroid therapy while continuing ibrutinib therapy. To our knowledge, self-limiting panniculitis during ibrutinib therapy has not yet been described. We describe a case of self-limiting, neutrophilic panniculitis which developed during ibrutinib therapy. A 78-year-old woman presented to the dermatology clinic with a 3-week history of painful erythematous nodules on her lower extremities which occurred 1 month after initiating ibrutinib therapy for chronic lymphocytic leukemia. Physical examination revealed tender erythematous poorly demarcated subcutaneous nodules on the anterior and posterior aspects of both lower legs. A panniculitis was suspected clinically, and a punch biopsy was performed. Histological evaluation revealed a lobular panniculitis with fat necrosis and infiltrates consisting predominantly of neutrophils. A diagnosis of neutrophilic panniculitis was rendered, which the patient opted not to treat. The eruption waned before resolving spontaneously over the course of 6 months despite continued ibrutinib therapy. This case illustrates panniculitis as an emerging adverse drug reaction after treatment with ibrutinib and that not all cases will require ibrutinib dose adjustment or steroid therapy but rather may be subject to spontaneous resolution.