von Hippel-Lindau disease-related neoplasia with an emphasis on renal manifestations.

von Hippel-Lindau (VHL) disease is characterized by biallelic inactivation of the VHL gene leading to abnormal or absent VHL protein function, and constitutive activation of hypoxia-inducible factors (HIF) that leads to pro-tumorigenic signaling. Individuals with VHL disease develop numerous cysts and tumors involving multiple organs including the kidneys, central nervous system, endolymphatic sac, lungs, pancreatobiliary system, adrenal glands, epididymis, and/or broad ligament. On histologic examination, these lesions show morphologic overlap as they are frequently characterized by cells with clear cytoplasm and prominent vascularity. In addition to distinguishing non-renal tumors from metastatic clear cell renal cell carcinoma, understanding site-specific histopathologic and immunophenotypic features of these tumors has several applications. This includes distinguishing VHL-related tumors from those that arise sporadically and lack VHL gene alterations, guiding further genetic workup, and helping distinguish between different genetic predisposition syndromes. In this context, immunohistochemical studies for markers such as paired box 8 (PAX-8), carbonic anhydrase 9 (CA9), and glucose transporter 1 (GLUT-1) have an important role in routine clinical practice and represent cost-effective diagnostic tools. The recent development of targeted therapeutics directed against HIF-mediated signaling represents a significant milestone in the management of VHL disease and highlights the importance of accurately diagnosing and characterizing the wide spectrum of VHL disease-associated lesions.

Cutaneous Malignant Mixed Tumor With Pulmonary Metastasis: A Case Report and Literature Review.

BACKGROUND: Cutaneous malignant mixed tumor (MMT) is a rare sweat gland-derived tumor characterized by admixed malignant epithelial cells and chondromyxoid stroma. Approximately 50 cases have been described in the literature. Metastasis, which may occur in more than one-third of cases, is most common in the lung. METHODS: We summarized the clinicopathologic features of a patient with cutaneous MMT metastatic to the lungs. A literature review of similar cases was completed using Web of Science, Scopus, and PubMed databases. RESULTS: A woman in her 70s presented with an enlarging mass on her left eyebrow; histopathologic examination showed large islands of atypical cells with increased mitotic activity, admixed with necrosis on a background of fibrotic and chondromyxoid stroma. Multiple lung nodules were identified during follow-up. Examination of a pulmonary core needle biopsy specimen was consistent with metastatic cutaneous MMT. Literature review identified 10 cases published between 1980 and 2017. Most primary tumors were large (≥4 cm). Local recurrence was uncommon, and the lung was the only metastatic site in 5 cases. Histopathologically, metastatic tumors were described as more cellular, with diminished stromal tissue compared with the primary lesion. CONCLUSION: This is 1 of the 11 reports of cutaneous MMT with metastasis to the lungs found in the English-language literature published after 1980. Of note, most reports were published before 1990, making this case study one of the few contemporary descriptions of cutaneous MMT with pulmonary metastases. We think that the present case report will increase the awareness of this rare tumor.

Renal Tubular Epithelial Subnuclear Vacuolization in Hypothermia and Diabetic Ketoacidosis-A Retrospective Autopsy Study.

ABSTRACT: Subnuclear vacuolization of the renal tubular epithelium refers to discrete lipid vacuoles displacing the nuclei toward the lumen. This phenomenon has been associated with conditions sharing fatal ketoacidosis as a common denominator. This retrospective study aimed to investigate renal tubular epithelial subnuclear vacuolization and other postmortem examination findings in fatal hypothermia and diabetic ketoacidosis (DKA) cases.Fourteen cases with hypothermia and 19 cases with DKA were included. More cases with DKA had focal or diffuse subnuclear vacuolization compared with hypothermia cases (89% vs 43%; P = 0.007). In 6 cases with DKA, formalin pigment was detected within subnuclear vacuoles, whereas no case with hypothermia had formalin pigment deposition. Comparative analyses of hypothermia and DKA cases revealed further differences: Vitreous beta-hydroxybutyrate was higher in the DKA group compared with the hypothermia group (P = 0.044), whereas blood ethanol concentrations were higher in the latter (P = 0.008). Hypothermia cases were older compared with the DKA cases (P = 0.022).When all cases were included in the statistical analysis, cases with subnuclear vacuolization had higher vitreous beta-hydroxybutyrate and blood ethanol concentrations (P = 0.029 and 0.023, respectively). The findings corroborate the results of previous studies suggesting a link between subnuclear vacuolization and increased levels of ketoacidosis.

Viral panniculitis in a patient with disseminated opportunistic Enterovirus infection.

Infection-induced panniculitis has been described in association with a broad range of microorganisms. Among those, viral panniculitis represents a minor category, with only a few anecdotal reports in the literature documenting viral infection in the subcutaneous fat. Herein, we report a woman in her 30s with seropositive rheumatoid arthritis on rituximab and prednisone, who presented with a 6-month history of progressive multisystem manifestations, including unintentional weight loss, fever, fatigue, myopathy, pancreatitis, and sensorineural hearing loss. She had indurated plaques on her thighs characterized by predominantly lobular panniculitis with chronic lymphohistiocytic inflammation. Molecular studies performed at the Centers for Disease Control and Prevention identified evidence of Enterovirus group with the highest identity of Coxsackievirus A9. Enterovirus RNA was also detected in the cerebrospinal fluid and muscle. Based on the findings, a diagnosis of disseminated enteroviral infection in the setting of B-cell depletion was rendered. To the best of our knowledge, this represents the first reported case of viral panniculitis with documentation of Coxsackievirus A9 in the skin. Since rituximab may be used for the treatment of autoimmune dermatological diseases, familiarity of the potential occurrence of severe enteroviral infections in the setting of immunosuppressive treatment is important for dermatopathologists.

Erythema Migrans and Interface Changes: More Than a Fortuitous Association.

The histology of erythema (chronicum) migrans (ECM) is classically described as a nonspecific perivascular infiltrate with a variable number of plasma cells and eosinophils. However, deviations from this pattern were described, such as focal interface changes or spongiosis, potentially posing a clinicopathological challenge. In this study, cases submitted with a serologically confirmed, clinically unequivocal, or highly suspicious diagnosis of ECM/Lyme disease between January 01, 2016, and September 01, 2018, were retrieved from the electronic database system and reviewed to delineate the histopathologic features of ECM. The series consisted of 14 cases. A superficial perivascular lymphocytic infiltrate was noted in all biopsies, accompanied by a deep and/or interstitial inflammatory infiltrate in 9 cases (64%). The inflammation ranged from relatively sparse to dense and prominent. At least focal interface changes were noted in 12 biopsies (86%). Eosinophils and plasma cells were noted in 7 (50%) and 10 (71%) cases, respectively. From a histologic standpoint, ECM is a protean entity and may manifest with a variable density of perivascular and/or interstitial lymphocytic infiltrate admixed with eosinophils and/or plasma cells and accompanied by focal interface dermatitis. Within the appropriate clinical context, ECM should be considered in the differential diagnosis of focal interface and/or sparse perivascular dermatitis.

Assessment of quality of life in Turkish children with psoriasis and their caregivers.

BACKGROUND/OBJECTIVES: The effect of pediatric psoriasis on quality of life has been demonstrated, but data regarding its influence on caregiver quality of life are scarce. The objective was to investigate how psoriasis affects quality of life of children and their caregivers. METHODS: This multicenter study included 129 children with psoriasis and their caregivers, who were family members accompanying patients to the clinic. Patient quality of life was measured using the Child Dermatology Life Quality Index. Caregiver quality of life was assessed using Dermatological Family Impact Scale, a 15-item questionnaire validated for use in the Turkish language. RESULTS: Mean Child Dermatology Life Quality Index score was 7.6, indicating a moderate effect on patient quality of life. Symptoms and feelings were the most severely impaired domains of patient quality of life, and emotions was the most severely impaired domain of caregiver quality of life. Dermatological Family Impact Scale score was significantly correlated with Child Dermatology Life Quality Index (correlation coefficient [r] = .554, P < .001) and Psoriasis Area and Severity Index (r = .350, P < .001). Caregivers of patients receiving systemic agents or phototherapy had relative impairment of multiple domains of quality of life compared to caregivers of patients receiving topical treatment only. CONCLUSION: Psychosocial effect of pediatric psoriasis was shown to extend beyond the individual, highlighting the importance of addressing patient and caregiver quality of life concerns in an integrated approach.

Alopecia, palmoplantar keratoderma, skin fragility and follicular hyperkeratoses due to compound heterozygous mutations in desmoplakin.

Inherited mutations in desmosome genes can present with a spectrum of skin, hair and cardiac abnormalities. Here we describe a 4-year-old Turkish boy with a cardio-cutaneous syndrome resulting from compound heterozygous nonsense mutations in desmoplakin. Early recognition of such cases by clinical awareness of the dermatological features and molecular diagnostics can improve patient management through early cardiac support, although the risk of cardiomyopathy and arrhythmias poses a major health concern.

Prevalence of obesity in paediatric psoriasis and its impact on disease severity and progression.

BACKGROUND/OBJECTIVES: The current literature suggests there is a possible connection between paediatric psoriasis and obesity. However, there is a paucity of research on the influence of increased adiposity on the severity of paediatric psoriasis and disease progression. We aimed to compare the prevalence of being overweight or obese in paediatric psoriasis patients and controls and assess the potential impact of being overweight/obese on disease severity and progression of disease. METHODS: This multicentre prospective case-control study included 289 psoriasis patients (aged < 18 years) treated and followed up by one of the four university hospitals in Turkey. The control group consisted of 151 consecutive age-matched and sex-matched children who lacked a personal or family history of psoriasis. The participants' characteristics, psoriasis-related parametres (e.g., initial subtype, psoriasis area and severity index, presence of psoriatic arthritis) and body mass index were determined. RESULTS: The difference between the prevalence of being overweight/obese among psoriatics (28%) and the control group (19%) was significant (P = 0.024). Being overweight/obese had no significant impact on disease severity and unresponsiveness to topical treatment. Within a median follow-up time of 12 months, 23% of our patients with localised disease at disease onset progressed to generalised disease. The impact of being overweight/obese on disease progression was found to be non-significant; however, disease duration was found to have a significant impact on disease progression (P = 0.026). CONCLUSIONS: Although it is not associated with disease severity and course, increased bodyweight may be a health problem for psoriatic children.

Interstitial Mycosis Fungoides With Lichen Sclerosus-Like Clinical and Histopathological Features.

Mycosis fungoides (MF) simulates a variety of dermatologic disorders histopathologically and clinically, well deserving the designation of a great mimicker. Interstitial MF is a rare, but well-recognized histopathological variant resembling the interstitial form of granuloma annulare or the inflammatory phase of morphea. From a clinical standpoint, MF can have a wide array of manifestations, including an anecdotal presentation with lesions clinically suggestive of lichen sclerosus (LS). We herein report a 25-year-old man with a history of patch-stage MF who later developed widespread LS-like lesions histopathologically consistent with interstitial MF. In some biopsies, additional features resembling LS were discerned. We think that our case might represent a unique variant of interstitial MF presenting with LS-like lesions. The diagnostic challenge arising from this uncommon presentation is discussed together with review of the literature.

Infantile Bullous Pemphigoid Treated Using Intravenous Immunoglobulin: Case Report and Review of the Literature.

We report a 5-month-old girl diagnosed with bullous pemphigoid who initially did not respond to systemic corticosteroids and dapsone but rapidly improved after the addition of intravenous immunoglobulin (IVIG) infusions. A literature search revealed anecdotal cases of infantile bullous pemphigoid treated with IVIG, although variable treatment regimens were used, and some resistant cases required additional medications such as rituximab for clinical remission.

Gómez-López-Hernández Syndrome: A Rare Cause of Bilateral Nonscarring Alopecia.

Gómez-López-Hernández syndrome is a rare neurocutaneous disorder characterized by the triad of rhombencephalosynapsis, parietal alopecia, and trigeminal anesthesia. We report a 16-year-old girl with bilateral parietotemporal alopecia in whom cranial magnetic resonance imaging revealed rhombencephalosynapsis, suggesting a diagnosis of Gómez-López-Hernández syndrome. Neurologic examination and neuroimaging may be warranted in select patients with parietal alopecia to exclude this uncommon entity.

Coexistence of aplasia cutis and nevus psiloliparus--report of a novel case.

Nevus psiloliparus is a type of mesodermal nevus of the scalp classically seen with encephalocraniocutaneous lipomatosis. The close association between nevus psiloliparus and aplasia cutis congenita is called didymosis aplasticopsilolipara. Although typically associated with neurologic, ocular, and skeletal findings, didymosis aplasticopsilolipara can be seen without the context of encephalocraniocutaneous lipomatosis.

A novel association of an uncommon pigmentation pattern: coexistence of cutis tricolor with intracranial teratoma and holoprosencephaly.

Cutis tricolor was first described in a 17-year-old male patient by Happle et al. as a rare coexistence of circumscribed hyperpigmentation and hypopigmentation close to each other on a background of normally pigmented skin. Cutis tricolor has been reported as an isolated cutaneous finding or in various associations. To the best of our knowledge, cutis tricolor in association with teratoma and holoprosencephaly has not been reported in the literature. Herein, we report a male patient who presented with a teratoma and a combination of whorl-like hypopigmentation together with hyperpigmented patches adjacent to each other on intermediately pigmented skin. This case report supports the view that cutis tricolor may be a marker of an underlying neurological abnormality.

Therapeutic Targets in Advanced Penile Cancer: From Bench to Bedside.

Discovery of effective systemic therapies for patients with advanced penile cancer has been slow to occur. Comprehensive genomic profiling from several studies shed light on the molecular oncogenesis of penile squamous cell carcinoma (PSCC) and differences between HPV-related and unrelated tumors. While these two subsets of PSCC appear distinct in their biology, there are not yet specific treatment strategies recommended on that basis. Cell surface proteins have been identified that may potentially serve as drug targets for monoclonal antibodies or small molecule inhibitors. Here, we review some of the new biological insights regarding PSCC that could lead to improved therapies, as well as the related clinical trials recently completed or in progress. We conclude that antibody-drug conjugates are especially promising, as are the combinations of immune checkpoint inhibitors with other types of drugs.

NTRK3-Rearranged Prostatic Acinar Adenocarcinoma: Report of a Patient and Review of the Literature.

Molecular investigations have led to increased therapeutic options for prostatic adenocarcinoma. A single case report of a PRPSAP1::NTRK3 gene fusion occurring in prostate cancer was previously reported. A review of the literature revealed that NTRK gene rearrangements are exceedingly rare molecular events in prostate cancer. NTRK gene fusions can be oncogenic drivers or develop as resistance mechanisms. The tumor-agnostic approvals of TRK inhibitors by the FDA provide additional rationale for molecular investigations of aggressive prostatic adenocarcinomas. This may prove to be an additional therapeutic option for patients with aggressive prostatic carcinomas refractory to initial therapy. We report a case of an aggressive castrate-resistant prostatic adenocarcinoma with a BMP6::NTRK3 gene fusion.

Genomic attributes of prostate cancer across primary and metastatic noncastrate and castrate resistant disease states: a next generation sequencing study of 183 patients.

Primary prostatic adenocarcinoma (pPC) undergoes genomic evolution secondary to therapy-related selection pressures as it transitions to metastatic noncastrate (mNC-PC) and castrate resistant (mCR-PC) disease. Next generation sequencing results were evaluated for pPC (n = 97), locally advanced disease (involving urinary bladder/rectum, n = 12), mNC-PC (n = 21), and mCR-PC (n = 54). We identified enrichment of TP53 alterations in high-grade pPC, TP53/RB1 alterations in HGNE disease, and AR alterations in metastatic and castrate resistant disease. Actionable alterations (MSI-H phenotype and HRR genes) were identified in approximately a fifth of all cases. These results help elucidate the landscape of genomic alterations across the clinical spectrum of prostate cancer.