Melanoma in a patient with DNMT3A overgrowth syndrome.

Alterations in epigenetic regulators are increasingly recognized as early events in tumorigenesis; thus, patients with acquired or inherited variants in epigenetic regulators may be at increased risk for developing multiple types of cancer. DNMT3A overgrowth syndrome (DOS), caused by germline pathogenic variants in the DNA methyltransferase gene DNMT3A, has been associated with a predisposition toward development of hematopoietic and neuronal malignancies. DNMT3A deficiency has been described to promote keratinocyte proliferation in mice. Although altered DNA methylation patterns are well-recognized in melanoma, the role of DNA methyltransferases in melanoma pathogenesis is not clear. We report the case of an adult DOS patient with a germline DNMT3A loss-of-function mutation, who developed an early-onset melanoma with regional lymph node metastatic disease. Exome sequencing of the primary tumor identified an additional acquired, missense DNMT3A mutation in the dominant tumor clone, suggesting that the loss of DNMT3A function was relevant for the development of this tumor.

Combined Kdm6a and Trp53 Deficiency Drives the Development of Squamous Cell Skin Cancer in Mice.

Cutaneous squamous cell carcinoma (cSCC) has among the highest mutation burdens of all cancers, reflecting its pathogenic association with the mutagenic effects of UV light exposure. Although mutations in cancer-relevant genes such as TP53 and NOTCH1 are common in cSCC, they are also tolerated in normal skin and suggest that other events are required for transformation; it is not yet clear whether epigenetic regulators cooperate in the pathogenesis of cSCC. KDM6A encodes a histone H3K27me2/me3 demethylase that is frequently mutated in cSCC and other cancers. Previous sequencing studies indicate that roughly 7% of cSCC samples harbor KDM6A mutations, including frequent truncating mutations, suggesting a role for this gene as a tumor suppressor in cSCC. Mice with epidermal deficiency of both Kdm6a and Trp53 exhibited 100% penetrant, spontaneous cSCC development within a year, and exome sequencing of resulting tumors reveals recurrent mutations in Ncstn and Vcan. Four of 16 tumors exhibited deletions in large portions of chromosome 1 involving Ncstn, whereas another 25% of tumors harbored deletions in chromosome 19 involving Pten, implicating the loss of other tumor suppressors as cooperating events for combined KDM6A- and TRP53-dependent tumorigenesis. This study suggests that KDM6A acts as an important tumor suppressor for cSCC pathogenesis.

Eosinophilic Dermatosis of Malignancy Involving the Eyelid.

A 72-year-old man with history of chronic lymphocytic lymphoma presented with a tender, ulcerated cutaneous eyelid lesion. Excisional biopsy revealed a diagnosis of eosinophilic dermatosis of malignancy. This rare paraneoplastic eruption is associated with hematologic malignancies and characterized histopathologically by lymphocytic infiltration accompanied by numerous eosinophils. To our knowledge, eosinophilic dermatosis of malignancy involving the eyelid has not been previously reported.

Eosinophilic folliculitis, eosinophilic dermatosis of hematologic malignancy and acneiform follicular mucinosis: Two case reports and a review of the literature highlighting the spectrum of histopathology.

Within the literature, there is overlap in the histopathological features described in eosinophilic folliculitis associated with chronic lymphocytic leukemia (CLL), eosinophilic dermatosis of hematologic malignancy, and acneiform follicular mucinosis. These disorders are described with varying degrees of superficial and deep lymphocytic and eosinophilic inflammation demonstrating perivascular, perifollicular, and folliculocentric involvement with or without follicular mucin deposition. Given significant histopathological overlap, these diagnoses may represent a continuum on a spectrum of dermatoses. Here, we present two cases with histopathological elements that reflect components of this clinicopathological spectrum and compare our findings with previously reported cases to compare and contrast reported features. Our first case is a 71-year-old African American man with long-standing CLL who developed a pruritic erythematous papular eruption on the face and chest with biopsy revealing a dense folliculotropic lymphocytic infiltrate with conspicuous eosinophils and follicular mucinosis. Our second case is a 70-year-old Caucasian man recently diagnosed with CLL/small lymphocytic lymphoma who developed an erythematous papular rash on the neck and face with biopsy revealing superficial and deep perivascular and periadnexal lymphocytic inflammation with scattered eosinophils. Characterization of our two cases and comparison with available literature suggest that these disorders may represent a continuum of dermatoses.

Reduced Wide Local Excision Margins are Associated with Increased Risk of Relapse and Death from Merkel Cell Carcinoma.

INTRODUCTION: Current recommendations regarding the size of wide local excision (WLE) margins for Merkel cell carcinoma (MCC) are not well established. METHODS: WLE and pathologic margins were respectively reviewed from 79 patients with stage I or II MCC, who underwent WLE at Washington University in St Louis from 2005 to 2019. Outcomes included local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant recurrence-free survival (DRFS), disease-free survival (DFS), and disease-specific survival (DSS). RESULTS: Thirty-two percent of patients received adjuvant radiotherapy (aRT). At 1 year, DFS was 51.3%, 71.4%, and 87.8% for patients with WLE margins < 1 cm, 1-1.9 cm, and ≥ 2 cm, respectively (p = 0.02). At 3 years, the DSS was 57.7%, 82.6%, and 100% for patients with WLE margins < 1 cm, 1-1.9 cm, and ≥ 2 cm, respectively (p = 0.02). Multivariable Cox analysis demonstrated that every 1-cm increase in WLE margins was associated with improved RRFS [hazard ratio (HR) = 0.28, 95% confidence interval (CI): 0.11-0.75], DRFS (HR 0.30, CI 0.08-0.99), DFS (HR 0.42, CI 0.21-0.86), and DSS (HR 0.16, CI 0.04-0.61). WLE and pathologic margin size were moderately-to-strongly correlated (r = 0.66). Close or positive pathologic margins (< 3 mm) were associated with reduced DRFS (HR 6.83, CI 1.80-25.9), DFS (HR 2.98, CI 1.31-6.75), and DSS (HR 3.52, CI 1.14-10.9). CONCLUSION: Reduced WLE and pathologic margins were associated with higher risk of relapse and death from MCC. Larger WLE margins are important in populations with lower rates of adjuvant radiation.

Symptomatic vulvar demodicosis: A case report and review of the literature.

Demodex folliculorum is a mite that commonly inhabits the pilosebaceous units of facial skin, particularly in a perioral and periorbital distribution. While typically an incidental and asymptomatic parasite, Demodex spp. are proposed to contribute to the pathogenesis of facial folliculitis, chronic blepharitis and papulopustular rosacea. Reports of demodicosis in anatomic locations other than the face are exceedingly rare. Here we report a 36-year-old woman with symptomatic Demodex spp. infestation of Fordyce spots of the labia minora. She was referred to dermatology after a 9-month history of tender red bumps on the vulva that would arise and drain over a 24 to 72 hours period, several times per week. Physical examination revealed erythema of the labia minora and introitus with a 4 mm, pink, dome-shaped soft papule on the left labium minus. Wet mount, microbiologic cultures and sexually transmitted infection (STI) screenings were unremarkable. Histopathologic examination revealed a well-circumscribed nodule of suppurative granulomatous inflammation arising in a background of mucosa with Fordyce spots, the majority of which were infiltrated by Demodex spp. Treatment with oral ivermectin and topical metronidazole cream resulted in a symptom-free period of 22 months. This case represents an unusual presentation of symptomatic Demodex infestation.

Dermatomyositis Presenting as Vulvovaginitis.

BACKGROUND: Dermatomyositis is an inflammatory myopathy that has an increased risk of malignancy, warranting aggressive health maintenance screenings. Dermatomyositis can rarely present with vulvovaginitis, thus clinical suspicion is important in early diagnosis. CASE: We present the case of a 31-year-old woman with a 10-year history of vulvovaginitis as her presenting symptom of dermatomyositis. On further investigation, she had a history of joint pain, muscle pain, fatigue, and leukopenia. On examination, she was found to have a rash and mucopurulent vulvovaginitis. Biopsies from the chest, axilla, and vulva were compatible with dermatomyositis. Evaluation for malignancy was negative, and her symptoms resolved with treatment of the dermatomyositis. CONCLUSION: Dermatomyositis is an inflammatory disease that can be associated with malignancy. This particular patient presented with vulvovaginitis. This case is important because the diagnosis was delayed. Early recognition is important to evaluate for malignancy.

Eruptive squamous atypia (also known as eruptive keratoacanthoma): Definition of the disease entity and successful management via intralesional 5-fluorouracil.

BACKGROUND: Eruptive squamous atypia (ESA), which is an idiopathic, sometimes koebnerizing, proliferation of atypical but well-differentiated keratinocytes (also termed eruptive keratoacanthoma), is often misdiagnosed as cancer and managed by excisional surgery, provoking further koebnerization. A clear definition of this phenomenon and treatment outcome data are lacking. OBJECTIVE: To define ESA and evaluate efficacy of intralesional (IL) 5-fluorouracil (5-FU) treatment. METHODS: A retrospective cohort study examined patients with ESA that arose spontaneously or within a recent surgical scar and was treated with IL 5-FU at a tertiary academic center between January 2008 and December 2016. Complete clearance, partial clearance, and number of surgical excisions performed were tabulated. RESULTS: Of 30 patients with 136 ESA lesions, 20 (67%) had resolution of ESA with IL 5-FU monotherapy. In all, 10 patients (33%) required additional therapy (topical 5-FU, steroids, cryotherapy, or acitretin). No IL 5-FU-treated ESA lesions required surgical excision. The number of excisional procedures decreased significantly (P = .006), with 27 patients (90%) needing fewer excisions 12 months after versus 12 months before initiation of IL 5-FU therapy. Dyspigmentation was the only adverse event. LIMITATIONS: Limitations include retrospective analysis and use of data from a single institution. CONCLUSION: With close clinical monitoring, IL 5-FU can be used to successfully treat ESA.

Advances in the Genetic Characterization of Cutaneous Mesenchymal Neoplasms: Implications for Tumor Classification and Novel Diagnostic Markers.

Cutaneous mesenchymal neoplasms often pose significant diagnostic challenges; many such entities are rare or show clinical and histologic overlap with both other mesenchymal and non-mesenchymal lesions. Recent advances in the genetic classification of many cutaneous mesenchymal neoplasms have not only helped define unique pathologic entities and increase our understanding of their biology, but have also provided new diagnostic markers. This review details these recent discoveries, with a focus on their implications for tumor classification and diagnosis.

Diagnostic Immunohistochemistry in Cutaneous Neoplasia: An Update.

Immunohistochemistry (IHC) is an important adjunct in the diagnosis of neoplastic skin diseases. In addition to the many established IHC markers currently in use, new markers continue to emerge, although their general acceptance and routine application requires robust validation. Here, we summarize the most well-established and commonly used biomarkers along with an array of newer ones reported in the past several decades that either demonstrate or hold high clinical promise in the field of cutaneous pathology. We also highlight recent applications of novel IHC markers in melanoma diagnosis including genetic mutation status markers [e.g. BRAF (v-raf murine sarcoma viral oncogene homolog B) and NRAS (neuroblastoma RAS viral oncogene homolog)] and an epigenetic alteration marker (e.g. 5-hydroxymethylcytosine). We specifically focus on the role of IHC in the differential diagnosis of cutaneous lesions that fall under the following categories: melanoma, epidermal tumors with an intraepidermal epitheliomatous pattern, spindle cell lesions of the dermis, small round blue cell tumors of the dermis, and cutaneous adnexal tumors. While IHC is a valuable tool in diagnostic dermatopathology, marker selection and interpretation must be highly informed by clinical context and the histologic differential diagnosis. With rapid progress in our understanding of the genetic and epigenetic mechanisms of tumorigenesis, new IHC markers will continue to emerge in the field of diagnostic dermatopathology.

Anticancer therapy SMRT-ens up: targeting the BCL6-SMRT interaction in B cell lymphoma.

Transcription factors have proven to be difficult targets for the development of small-molecule drugs. In this issue of Cancer Cell, Cerchietti et al. identify and characterize a specific, small-molecule inhibitor of BCL6, an oncogenic transcriptional repressor, that has high clinical promise for treating diffuse large B cell lymphoma.

Primary and immortalized mouse epicardial cells undergo differentiation in response to TGFbeta.

Cells derived from the epicardium are required for coronary vessel development. Transforming growth factor beta (TGFbeta) induces loss of epithelial character and smooth muscle differentiation in chick epicardial cells. Here, we show that epicardial explants from embryonic day (E) 11.5 mouse embryos incubated with TGFbeta1 or TGFbeta2 lose epithelial character and undergo smooth muscle differentiation. To further study TGFbeta Signaling, we generated immortalized mouse epicardial cells. Cells from E10.5, 11.5, and 13.5 formed tightly packed epithelium and expressed the epicardial marker Wilm's tumor 1 (WT1). TGFbeta induced the loss of zonula occludens-1 (ZO-1) and the appearance of SM22alpha and calponin consistent with smooth muscle differentiation. Inhibition of activin receptor-like kinase (ALK) 5 or p160 rho kinase activity prevented the effects of TGFbeta while inhibition of p38 mitogen activated protein (MAP) kinase did not. These data demonstrate that TGFbeta induces epicardial cell differentiation and that immortalized epicardial cells provide a suitable model for differentiation.

Coronary vessel development is dependent on the type III transforming growth factor beta receptor.

Transforming growth factor (TGF)beta receptor III (TGFbetaR3), or beta-glycan, binds all 3 TGFbeta ligands and inhibin with high affinity but lacks the serine/threonine kinase domain found in the type I and type II receptors (TGFbetaR1, TGFbetaR2). TGFbetaR3 facilitates signaling via TGFbetaR1/TGFbetaR2 but also has been suggested to play a unique and nonredundant role in TGFbeta signaling. Targeted deletion of Tgfbr3 revealed a requirement for Tgfbr3 during development of the coronary vessels. Coronary vasculogenesis is significantly impaired in null mice, with few vessels evident and numerous, persistent blood islands found throughout the epicardium. Tgfbr3-null mice die at embryonic day 14.5, the time when functional coronary vasculature is required for embryo viability. However, in null mice nascent coronary vessels attach to the aorta, form 2 coronary ostia, and initiate smooth muscle recruitment by embryonic day 14. Analysis of earlier developmental stages revealed defects in the epicardium. At embryonic day 13.5, these defects include an irregular and hypercellular epicardium with abundant subepicardial mesenchyme and a thin compact zone myocardium. Tgfbr3-null mice also displayed other defects in coronary development, including dysmorphic and distended vessels along the atrioventricular groove and subepicardial hemorrhage. In null mice, vessels throughout the yolk sac and embryo form and recruit smooth muscle in a pattern indistinguishable from heterozygous or wild-type littermates. These data demonstrate a requirement for Tgfbr3 during coronary vessel development that is essential for embryonic viability.