Histopathologic upgrading of cutaneous squamous cell carcinomas during Mohs micrographic surgery: A retrospective cohort study.

BACKGROUND: Initial biopsies of cutaneous squamous cell carcinomas (cSCCs) may not reveal aggressive histologic features, which would otherwise inform appropriate surgical management and patient education. OBJECTIVE: To assess the incidence of, and risk factors for, histopathologic upgrading of cSCC during Mohs micrographic surgery (MMS). METHODS: This was a retrospective cohort study of invasive cSCCs treated with MMS between 2017 and 2019 at 1 academic institution. An "upgrade" was defined as a lesser degree of differentiation (poor or moderate) and/or bony or perineural invasion identified during MMS that was not reported in histopathologic evaluation of the initial biopsy. RESULTS: Of the 1558 tumors studied, 115 (7.4%) were upgraded during MMS. In multivariate logistic regression analysis, male sex, prior field treatment, location on the ear/lip, rapid growth of cSCC, and tumor diameter ≥2 cm were significant predictors of tumor upgrading. Upgraded tumors were more likely to require ≥3 MMS stages to clear, complicated closure (flap or graft), or outside (referral) repairs. LIMITATIONS: Single-center study, retrospective, and inter-rater variability. CONCLUSIONS: A significant proportion of cSCCs is histopathologically upgraded with more aggressive features during MMS. Routinely documented patient and tumor characteristics can predict tumor upgrading and assist clinicians in directing the management of potentially high-risk cSCC patients.

Histopathologic and immunophenotypic features of cutaneous solid organ transplant-associated graft-vs-host disease: Comparison with acute hematopoietic cell transplant-associated graft-vs-host disease and cutaneous drug eruption.

BACKGROUND: Although it is relatively common after hematopoietic cell transplant (HCT), graft-vs-host disease (GVHD) is a rare complication following solid organ transplantation (SOT). METHODS: This study evaluated skin biopsy specimens from five cases of SOT GVHD, 15 cases of HCT GVHD, and 15 cases of cutaneous drug eruption. Immunohistochemical staining for CD3, CD4, CD8, T-bet, and GATA-3 was performed to examine the density and immune phenotype of skin-infiltrating lymphocytes. RESULTS: Similar to HCT GVHD, the predominant histopathologic findings in skin biopsy specimens of SOT GVHD were widespread vacuolar interface dermatitis with scattered necrotic keratinocytes. However, the density of dermal inflammation was considerably higher in SOT GVHD. Features that were more predictive of a cutaneous drug eruption over GVHD included spongiosis, confluent parakeratosis, and many eosinophils. Involvement of the hair follicle epithelium was seen in all three disorders. Both forms of cutaneous GVHD showed a predominance of Th1 (CD3+/T-bet+) lymphocytes within the inflammatory infiltrates. This shift was more pronounced in SOT GVHD, particularly among intraepidermal T-cells. CONCLUSIONS: SOT GVHD shares many histopathologic features with HCT GVHD. However, SOT GVHD has a greater tendency to develop brisk lichenoid inflammation.

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.

Chronic Itch of Unknown Origin Is Associated With an Enhanced Th2 Skin Immune Profile.

ABSTRACT: Chronic pruritus of unknown origin (CPUO) is described as chronic itch lasting longer than 6 weeks in the absence of a defined skin rash and any known causative disease process. A retrospective study was performed on biopsy samples from patients with CPUO and normal controls to compare the immune profiles of these patients with healthy individuals. We used dual CD3/T-bet and CD3/GATA3 immunohistochemical staining to assess for T-cells expressing Th1 versus Th2 transcription factors, respectively. Our data showed that CD3+ cells of patients with CPUO co-express significantly more GATA3 compared with normal controls. Meanwhile, the normal control skin showed a much more balanced T-bet/GATA3 ratio of co-expression. Our data suggest an enrichment of Th2 cells in CPUO skin by T cell/GATA3 co-staining, supporting that CPUO is increasingly considered a type 2/Th2 cell-associated disease. We thus speculate that type 2 cytokine blockade-based therapies may represent effective treatments for CPUO.

Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma.

The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet. Although exome sequencing revealed several of the KDSR mutations, we employed genome sequencing to discover a pathogenic 346 kb inversion in multiple probands, and cDNA sequencing and a splicing assay established that two mutations, including a recurrent silent third base change, cause exon skipping. Immunohistochemistry and yeast complementation studies demonstrated that the mutations cause defects in KDSR function. Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation.

Metastatic pancreatic adenosquamous carcinoma to the scalp: A case report and review of the literature.

Metastatic carcinoma to the skin occurs in only a minority of patients with a visceral or internal malignancy, with breast, lung, and colorectum accounting for the majority of cases. We present the case of a 66-year-old man with a recent violaceous nodule of the left scalp (1.2 × 1.0 × 0.2 cm) that was a metastatic pancreatic adenosquamous carcinoma, representing a seemingly rare event. Two months prior, after complaining of right hip pain, an image revealed a right femoral lesion. A biopsy of that lesion showed moderately differentiated adenocarcinoma. Subsequent imaging showed a mass in the pancreatic tail and also markedly elevated serum tumor markers, CA 19-9 and carcinoembryonic antigen (5325 and 111.5 U/mL, respectively). Before the appearance of the scalp nodule, the patient received radiotherapy and was started on chemotherapy, which was continued after diagnosis and resection of the nodule. Subsequent metastases developed in the liver, lung and additional cutaneous lesions. He died 11 months after initial presentation with right hip pain. As this case shows, cutaneous metastases confer a poor prognosis, often with less than a year survival following their appearance.

Neutrophil-predominant bullous pemphigoid induced by checkpoint inhibitors: A case series.

Checkpoint inhibitors have been revolutionary in the treatment of metastatic melanoma, non-small-cell lung cancer, and renal cell carcinoma. By restricting negative feedback of T-cells, checkpoint inhibitors allow the immune system to identify and destroy malignant cells. This enhanced immune response is efficacious in the treatment of the aforementioned malignancies; however, it may lead to immune-related adverse events. Bullous pemphigoid (BP) is a well-documented cutaneous adverse reaction of checkpoint inhibitors, with a majority of cases reporting an eosinophil-predominant or mixed inflammatory infiltrate. We report two cases of neutrophil-predominant BP presenting in patients on checkpoint inhibitors.

Metachronous cutaneous squamous cell carcinoma in a young patient as the only presenting symptom to uncover Lynch syndrome with MLH1 Germline mutation.

BACKGROUND: Cutaneous malignancies are rare complications of Lynch syndrome and can include Muir-Torre and Turcot syndromes that are associated with sebaceous gland tumors and keratoacanthomas. The incidence and clinical course of cutaneous squamous cell carcinoma have not been well documented in Lynch syndrome due to its rarity. CASE PRESENTATION: A 49-year male presented with an enlarging groin skin lesion that was biopsed and demonstrated cutaneous squamous cell carcinoma for which he underwent a surgical resection. The patient experienced later a recurrence of cutaneous squamous cell carcinoma around the resected margins. Next generation sequencing of tumor tissue revealed mutations in MSH6 and MLH1, in addition to high microsatellite instability. The patient underwent pembrolizumab treatment with complete resolution of the cutaneous lesion in the groin, but subsequently developed a new mass in the right antecubital fossa shortly after discontinuation of pembrolizumab. Repeat biopsy of the antecubital fossa lesion revealed a recurrence of cutaneous squamous cell carcinoma. Germline mutation testing revealed MLH1 mutation, compatible with Lynch syndrome, and the patient restarted pembrolizumab which was associated with a complete response. The patient was referred for genetic counseling and cancer screening. CONCLUSIONS: Cutaneous squamous cell carcinoma, although rare, can be the initial presenting symptom in patients with Lynch syndrome. This association has been described in patients with germline mutations in MLH1. Lynch syndrome should be considered when evaluating young patients presenting with recurrent cutaneous squamous cell carcinoma with positive family history of malignancy and/ or without any identifiable risk factors for skin cancers, including those with a durable and rapid response to immunotherapy.

Pemphigus foliaceus in a patient with gastrointestinal stromal tumor treated with adjuvant imatinib mesylate.

Pemphigus is an autoimmune bullous disease with a number of described associations, including medications, which have been grouped into three structural categories - thiol drugs, phenol drugs, and drugs with neither functional group [1]. Discontinuation of the offending medication is considered a mainstay of therapy. We report a patient in whom the onset of pemphigus foliaceus was associated with initiation of imatinib mesylate adjuvant therapy in a patient with resected gastrointestinal stromal tumor (GIST). Imatinib was continued because of the survival benefit to the patient with a resected, high risk GIST. Treatment with rituximab resulted in near resolution of his blistering rash and follow up enzyme-linked immunosorbent assay (ELISA) demonstrated reference range immunoreactivity for both desmoglein 1 and desmoglein 3. After dose increase of imatinib therapy owing to tumor growth, the patient subsequently again developed a similar eruption. Re-biopsy and ELISA were consistent with recurrence of pemphigus. In conclusion, although the patient's pemphigus was cleared with a single cycle of rituximab infusions while continuing imatinib therapy, the disease returned after imatinib dose was increased a year later, suggesting a dose-response relationship.

Atypical Fibroxanthoma: The Washington University Experience.

BACKGROUND: Atypical fibroxanthoma (AFX) is a rare dermal neoplasm typically occurring on sun-exposed skin in the elderly. As AFX remains a diagnosis of exclusion, updated characterization and treatment assessments are necessary to support informed diagnosis and management. OBJECTIVE: Characterization of contemporary AFX and surgical outcomes by Mohs micrographic surgery (MMS) and conventional local excision (LE). METHODS: Retrospective cohort analysis of all cases of AFX at our institution from January 2000 through July 2016. RESULTS: Among 75 cases with median age at diagnosis 73 years, most occurred on the head and neck (68) independent of age. Most treated cases (42) underwent MMS alone, with median tissue removal greater for LE (2.6 cm, 4.5 cm) than MMS (0.6 cm, 1.2 cm). Over a median 26 months of follow-up, 6 recurrences were observed among 50 cases, with metastases in 2 cases. Intent-to-treat recurrence rates were 3.4% for MMS and 25% for LE. One nonrecurrent and 2 recurrent cases received revised diagnoses after initial treatment, yielding a true recurrence rate of 8.5%. CONCLUSION: Despite diagnostic confounding by similar pathologies, surgical treatment of AFX remains effective. Tissue-sparing resection by MMS affords the potential for cosmetic and reconstructive advantage, without compromising recurrence compared with conventional excision.

Acute graft-versus-host disease following lung transplantation in a patient with a novel TERT mutation.

Familial pulmonary fibrosis is associated with loss-of-function mutations in telomerase reverse transcriptase (TERT) and short telomeres. Interstitial lung diseases have become the leading indication for lung transplantation in the USA, and recent data indicate that pathogenic mutations in telomerase may cause unfavourable outcomes following lung transplantation. Although a rare occurrence, solid organ transplant recipients who develop acute graft-versus-host disease (GVHD) have very poor survival. This case report describes the detection of a novel mutation in TERT in a patient who had lung transplantation for familial pulmonary fibrosis and died from complications of acute GVHD.

A tale of two clones: Caldesmon staining in the differentiation of cutaneous spindle cell neoplasms.

BACKGROUND: We sought to compare the sensitivity and specificity of 2 different caldesmon antibodies in differentiating leiomyosarcoma from other cutaneous spindle cell neoplasms. METHODS: Representative cutaneous spindle cell neoplasms were identified, including leiomyosarcoma, atypical fibroxanthoma, dermatomyofibroma and spindle cell squamous cell carcinoma. Immunohistochemistry was performed with antibodies directed toward caldesmon, smooth-muscle actin (SMA) and desmin. Sensitivity and specificity were calculated using grades from 3 independent observers. RESULTS: The sensitivity of caldesmon (Ventana) was 100% (95% CI 78.2%-100%) and the specificity was 8.3% (2.8%-18.4%). Because this stain appeared to be non-specific, additional testing was performed on the same set of specimens using a second caldesmon clone (H-caldesmon, Dako), which had a sensitivity of 53.9% (25.1%-80.8%) and specificity of 96.6% (88.1%-99.6%). The sensitivity and specificity of SMA were 85.7% (57.2%-98.2%) and 84.5% (72.6%-92.7%), respectively. The sensitivity of desmin was 53.3% (26.6%-78.7%) with a specificity of 100% (94.0%-100%). CONCLUSIONS: The Ventana caldesmon clone is not specific to smooth muscle, a potential pitfall to laboratories using this clone. The staining pattern, sensitivity and specificity of the Dako H-caldesmon antibody clone are similar to results from prior studies. The sensitivity and specificity of the Dako clone support its use in smooth muscle identification as an additional marker in challenging cases.

Microcystic Adnexal Carcinoma: A Review of the Literature.

BACKGROUND: Microcystic adnexal carcinoma (MAC) is a rare, locally aggressive cutaneous neoplasm that commonly occurs on the face. OBJECTIVE: The purpose of this article is to comprehensively review the current literature on MAC pertaining to epidemiology, pathogenesis, clinical presentation, histology, immunohistochemistry, prognosis, follow-up, and treatment. MATERIALS AND METHODS: An extensive literature review was conducted using OVID MEDLINE and PubMed to identify articles relating to MAC. RESULTS: Microcystic adnexal carcinoma typically presents as a skin-colored nodule on the face. The pathogenesis is mostly related to pilar and eccrine differentiation. Histologically, MAC can mimic syringoma, desmoplastic trichoepithelioma, and infiltrative basal cell carcinoma. Diagnosis is challenging because superficial shave biopsies may reveal only benign findings that do not warrant further management. A deep biopsy is mandatory for the correct diagnosis, and Mohs micrographic surgery provides the highest cure rate. CONCLUSION: Microcystic adnexal carcinoma is a locally aggressive disease with histological margins that often far surpass what is clinically suspected. Mohs micrographic surgery is the standard of care for removal of these lesions. Patients with a history of MAC should be examined at least every 6 months for recurrence, metastasis, and development of additional skin cancers.

p53 Is a Helpful Marker in Distinguishing Langerhans Cell Histiocytosis From Langerhans Cell Hyperplasia.

Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cells that can be challenging to distinguish histologically from Langerhans cell (LC) hyperplasia, seen in a variety of inflammatory dermatoses. Lesional cells in both entities demonstrate positive staining for CD1a and S100. Previous studies have demonstrated positive staining of fascin, CD31, and p53 in cases of LCH, but currently, no studies have compared the staining profiles of these markers between LCH and LC hyperplasia. The authors compared immunohistochemical staining profiles of LCH (n = 15) and various inflammatory dermatoses with LC hyperplasia (n = 15) using fascin, CD31, and p53. Fascin, CD31, and p53 were graded as a percentage of CD1a staining cells in the epidermis and dermis of each specimen. Fascin showed no significant differences in staining between the 2 entities. CD31 was positive in the dermal infiltrate in 40% of cases of LCH and negative in all cases of LC hyperplasia. p53 was positive in the epidermal infiltrate in 50% of cases of LCH, and positive in the dermal infiltrate in 93% of cases of LCH, whereas negative in all cases of LC hyperplasia. Fascin was not a helpful marker in distinguishing LCH from LC hyperplasia. CD31, if positive in the dermal infiltrate, is suggestive of a diagnosis of LCH, but exhibits a relatively low sensitivity for this purpose. p53 proved to be a helpful and accurate diagnostic immunohistochemical stain when distinguishing between LCH and LC hyperplasia.

Omenn Syndrome Presenting with Striking Erythroderma and Extreme Lymphocytosis in a Newborn.

Omenn syndrome is an autosomal recessive form of "leaky" severe combined immune deficiency resulting in distinct phenotypic features. The patient described herein had an atypical presentation of Omenn syndrome, with conspicuous erythroderma and extreme lymphocytosis at birth, in contrast to the typical evolution of rash seen during the first few weeks of life. In addition, the skin findings were secondary to infiltration of CD8+ (cytotoxic) T-cells in contrast to the CD4+ (helper) T-cells typically seen, which broadens the Omenn syndrome phenotype.

Cutaneous squamous cell carcinoma progression is associated with decreased GATA-3 immunohistochemical staining.

BACKGROUND: The GATA family of transcription factors is an essential regulator of cellular proliferation and differentiation. In the skin, GATA-3 is critical for epidermal stratification and maintenance of barrier function. A role for GATA-3 in the development of human cutaneous squamous cell carcinoma (SCC) is not known. Here, we investigated GATA-3 immunohistochemical staining in premalignant and invasive cutaneous SCC from sun-exposed and sun-protected skin. METHODS: GATA-3 immunohistochemistry was performed on actinic keratoses (AK) (n = 19), in situ squamous cell carcinomas with actinic [SCCIS (A)] (n = 9) or bowenoid features [SCCIS (B)] (n = 17), well-, moderately and poorly differentiated SCC (n = 36), Bowenoid papulosis of the perineum (n = 15) and penile SCC (pSCC) (n = 10). RESULTS: We found that GATA-3 immunohistochemical staining is progressively lost in sun-exposed skin as neoplasia progresses from pre-cancerous AK to SCCIS (A), and ultimately, to SCC, which shows near absent GATA-3 staining. This reduction in GATA-3 staining is independent of histological grade in SCC. Only slight down-regulation of GATA-3 was seen in all cases of SCCIS (B) and Bowenoid papulosis, while near absent GATA-3 expression was seen in pSCC. CONCLUSION: We propose that decreased GATA-3 immunohistochemical staining is associated with cutaneous SCC progression on both sun-exposed and sun-protected sites.