Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome.

AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1-/- mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC [p.Asn490_Met495delins(40)] and c.1743C>A [p.Cys581∗]) in the first individual, a homozygous variant (c.1320_1326del [p.Arg440Serfs∗3]) in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that bi-allelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.

Cutaneous lesions of angioimmunoblastic T-cell lymphoma: Clinical, pathological, and immunophenotypic features.

BACKGROUND: Angioimmunoblastic T-cell lymphoma (AITL) is a systemic peripheral T-cell lymphoma with a follicular helper T-cell (TFH ) immunophenotype that frequently involves the skin. However, the histopathology of cutaneous involvement by AITL has not been fully established. METHODS: We reviewed the clinicopathological features of 19 patients seen at our institution with AITL involving the skin. Pan-T-cell and TFH marker expression was evaluated by immunohistochemistry. Epstein-Barr virus (EBV) was detected using in situ hybridization (ISH) for Epstein-Barr virus-encoded small RNA (EBER). T-cell receptor (TCR) gene rearrangement was evaluated by PCR. RESULTS: AITL affected both trunk and extremities in 15/19 cases (79%). Perivascular infiltration by small and/or medium-sized lymphocytes was seen in 18/19 (95%). Granulomatous inflammation was identified in 4/19 (21%). Aberrant loss of CD2, CD5, or CD7 was identified in 1/18 (6%), 2/18 (11%), or 7/19 (37%) cases, respectively. Seventeen of eighteen evaluable cases (95%) expressed 2 to 3 TFH markers: PD-1 in 19/19 (100%), BCL6 in 94% (17/18), and CD10 in 37% (7/19). EBV-positive cells were detected in 3/18 (17%) with varying density. Clonal TCR gene rearrangement was identified in 9/11 (82%). CONCLUSIONS: Cutaneous involvement by AITL shows relatively non-specific histopathological features. However, an immunohistochemical panel including TFH markers and EBER ISH is useful in differential diagnosis.

Persistent dermatomal eruption on a leg.

Unilateral linear capillaritis (ULC) is a rare variant of pigmented purpuric dermatoses (PPD) that is characterized by a linear or pseudo-dermatomal eruption on a single extremity. Although clinically distinct from the other PPD, it shares histopathologic features with this group. Herein, we present a man in his 50s who presented with asymptomatic macules and scaly papules on the left lower extremity in a linear distribution. The eruption persisted despite treatment with topical triamcinolone 0.1% and oral rutocide.

Intraoperative Immunostaining for Cytokeratin-7 During Mohs Micrographic Surgery Demonstrates Low Local Recurrence Rates in Extramammary Paget's Disease.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare intraepithelial malignancy with high recurrence rates following standard surgical treatments, ranging from 22% to 60% in large retrospective reviews. OBJECTIVE: To evaluate the local recurrence rate of Mohs micrographic surgery (MMS) supplemented with intraoperative immunohistochemistry for cytokeratin-7 (MMS + CK-7) for primary and recurrent EMPD. MATERIALS AND METHODS: Retrospective, multi-center, cross-sectional study of patients treated using MMS + CK-7. Demographic, clinicopathologic, treatment, and follow-up data were obtained by chart review. RESULTS: The observed local recurrence rate for MMS + CK-7 is 3.3% (2/61 tumors) with a mean follow-up of 43.5 months (1-120 months). Local recurrence occurred in 2.3% (1/43) of primary tumors and 5.6% (1/18) of recurrent tumors. Kaplan-Meier 5-year tumor-free rates are 94.6% overall, 97.1% for primary tumors, and 80.0% for recurrent tumors. The Kaplan-Meier 5-year tumor-free rates for all EMPD tumors treated with MMS + CK-7 versus a historical cohort of MMS alone are 94.6% versus 72.0% (p = .012). CONCLUSION: MMS + CK-7 is an effective treatment for EMPD, demonstrating improved outcomes compared with historical controls.

A clinical scoring system to identify patients with sebaceous neoplasms at risk for the Muir-Torre variant of Lynch syndrome.

PURPOSE: The Muir-Torre syndrome variant of Lynch syndrome is characterized by the presence of sebaceous neoplasms (adenoma, epithelioma/sebaceoma, carcinoma) and Lynch syndrome-associated cancers (colon, endometrial, and others). Several clinical scoring systems have been developed to identify patients with colon cancer at high risk of Lynch syndrome. However, no such system has been described for patients presenting with sebaceous neoplasms. METHODS: Based on logistic regression analysis, a scoring system was developed for patients with sebaceous neoplasm to identify those with the highest likelihood of having Muir-Torre syndrome. The final version of the scoring system included variables such as age at presentation of initial sebaceous neoplasm, total number of sebaceous neoplasms, personal history of a Lynch-related cancer, and family history of Lynch-related cancers. RESULTS: Patients with a score of 3 or more were more likely to have Muir-Torre syndrome (28 of 29 patients), those with a score of 2 had intermediate likelihood (12 of 20 patients), and no patient with a score of 0 or 1 was diagnosed with Muir-Torre syndrome. CONCLUSION: The Mayo Muir-Torre syndrome risk scoring system appears to identify whether patients who present with sebaceous neoplasms are in need of further Lynch syndrome evaluation using easily ascertained clinical information. Abnormal mismatch repair gene immunohistochemistry of a sebaceous neoplasm is a poor predictor in regard to diagnosing Lynch syndrome.

Histiocytoid Sweet syndrome may indicate leukemia cutis: a novel application of fluorescence in situ hybridization.

BACKGROUND: In patients with malignancy-associated Sweet syndrome, a thorough evaluation for leukemia cutis should be considered. OBJECTIVE: We sought to describe the clinicopathologic characteristics of histiocytoid Sweet syndrome. METHODS: We retrospectively identified patients with histiocytoid Sweet syndrome at our institution from January 1992 through December 2010. We evaluated the underlying cutaneous infiltrate using immunohistochemistry and fluorescence in situ hybridization. RESULTS: We re-evaluated all 22 patients with hematologic malignancy-associated Sweet syndrome. Six patients had a monocytoid infiltrate that was consistent with histiocytoid Sweet syndrome; subsequent evaluation of these patients demonstrated cytogenetic abnormalities on prior bone-marrow biopsy specimens. Fluorescence in situ hybridization analysis was feasible in cutaneous specimens from 5 of the 6 patients and demonstrated the same cytogenetic abnormalities that were identified on prior bone-marrow biopsy specimens in 4 patients. Therefore, these 4 patients may have had a form of leukemia cutis. LIMITATIONS: This was a retrospective study. CONCLUSION: For patients with histiocytoid Sweet syndrome, an underlying hematologic malignancy, and a monocytoid infiltrate on biopsy specimen, fluorescence in situ hybridization of the cutaneous infiltrate may be beneficial to identify cytogenetic abnormalities that may indicate leukemia cutis.

Sweet syndrome: clinical presentation, associations, and response to treatment in 77 patients.

BACKGROUND: Sweet syndrome is a neutrophilic dermatosis with cutaneous tender lesions that can be associated with malignancies, infections, systemic inflammatory disorders, and medications. Although numerous studies have described Sweet syndrome, few studies have systematically investigated Sweet syndrome. OBJECTIVE: We sought to describe characteristics and treatments of patients with Sweet syndrome and evaluate clinical differences depending on the underlying cause. METHODS: A retrospective study was conducted to identify patients with Sweet syndrome evaluated at Mayo Clinic from 1992 to 2010. RESULTS: Of 77 patients with Sweet syndrome (mean age of onset 57 years), 43 (56%) were male. Eighteen patients (23%) reported a preceding infection. A total of 41 (53%) patients were classified as having classic Sweet syndrome, 27 (35%) patients had malignancy-associated Sweet syndrome, and in 9 (12%) patients drug-induced Sweet syndrome was considered. In all, 21 patients had a hematologic malignancy or myeloproliferative/myelodysplastic disorder, whereas 6 patients had solid tumors. The mean hemoglobin level, in both male and female patients (P < .0443 and P < .0035, respectively), was significantly lower in malignancy-associated versus classic and drug-induced Sweet syndrome. Systemic corticosteroids were the most frequently used treatment (70%). LIMITATIONS: This is a retrospective study and represents patients from a single academic center. CONCLUSIONS: Sweet syndrome is a distinctive disorder with certain clinical and histologic characteristics, which usually has a complete response to systemic corticosteroids. It is important to evaluate Sweet syndrome patients who have laboratory evidence of anemia for an underlying malignancy.

Comparison of virtual microscopy and glass slide microscopy among dermatology residents during a simulated in-training examination.

BACKGROUND: Virtual microscopy is increasingly being used in dermatopathology educational settings. OBJECTIVE: The objective is to evaluate diagnostic accuracy and attitudes between virtual microscopy and traditional glass slide microscopy among dermatology residents. METHODS: A 48-question dermatopathology examination was administered to 35 dermatology residents at three different dermatology residency training sites during the 2011-2012 academic year with half (n = 24) of the questions using the gold standard of glass slide microscopy and half (n = 24) using whole, scanned virtual slides. Correct number of questions using glass slides and virtual slides was evaluated. Participants were surveyed regarding previous experience with digital slide imaging; quality, ease of use, and speed of slide review; and overall microscopy preferences. RESULTS: Overall, diagnostic accuracy was better with glass slides than virtual slides (p = 0.01). However, no statistically significant difference was found in diagnostic accuracy of first-year trainees (p > 0.99) or trainees with exposure to virtual microscopy greater than two times per month (p = 0.27). There was no overall personal preference for glass slide vs. virtual microscopy. LIMITATIONS: Different cases and questions were used for glass slides and virtual microscopy. CONCLUSIONS: Diagnostic accuracy with virtual microscopy is dependent on year of residency training and prior experience with virtual microscopy.

Screening for Muir-Torre syndrome using mismatch repair protein immunohistochemistry of sebaceous neoplasms.

Screening for the Muir-Torre variant of Lynch Syndrome (LS) using Mismatch Repair (MMR) gene immunohistochemistry (IHC) on sebaceous neoplasms (SNs) is technically feasible. To date, research into the clinical utility of MMR IHC for this indication is limited. We conducted a retrospective chart review of 90 patients with MMR IHC completed on at least one SN from January 2005 to May 2010. SNs included were adenomas, epitheliomas, carcinomas and basal and squamous cell carcinomas with sebaceous differentiation. Of the 90 patients, 13 (14 %) had genetically confirmed or fulfilled clinical criteria for a diagnosis of MTS and 51 patients (57 %) presented with an abnormal MMR IHC result (loss of one or more MMR proteins) on at least one SN. Abnormal IHC had a sensitivity of 85 %, specificity of 48 %, positive predictive value (PPV) of 22 % and negative predictive value (NPV) of 95 % when evaluating for MTS. When personal or family history of colorectal cancer (≥2 family members with a history of colorectal cancer) was taken into consideration, ignoring IHC results, sensitivity was 92 %, specificity was 99 %, PPV was 92 % and NPV was 99 %. MMR IHC on SNs when used to screen for MTS has poor diagnostic utility. We recommend that MMR IHC not be performed routinely on SNs when the patient does not have either personal or family history of colorectal cancer.

Congenital and infantile benign skin lesions affecting the hand and upper extremity, part 2: nonvascular neoplasms.

This article is part 2 of a 2-part series presented to aid the hand surgeon in becoming familiar with dermatological lesions that may be present on the upper extremity during infancy. The discussion focuses on nonvascular neoplasms grouped into the following categories: epithelial, melanocytic, histiocytic, dermal, fibroblastic, and adipocytic neoplasms. Diagnostic tips are offered, including clinical photographs, to help differentiate between these lesions. In addition, the recommended treatment for each is discussed.

Congenital and infantile skin lesions affecting the hand and upper extremity, part 1: vascular neoplasms and malformations.

Many dermatologic conditions may be present on a newborn infant's upper extremity that can evoke concern for parents and/or primary caregivers. Although the pediatrician typically remains the first care provider, often these children are referred to specialists to diagnose and treat these lesions. Hand surgeons should be familiar with different infantile skin lesions on an upper extremity. Some lesions are best observed, whereas others require treatment with nonoperative measures, lasers, or surgical interventions. A 2-part series is presented to aid the hand surgeon in becoming familiar with these lesions. This part 1 article focuses on vascular neoplasms and malformations. Particular attention is paid to the multiple types of hemangiomas and hemangioendotheliomas, telangiectasias, angiokeratomas, as well as capillary, venous, and lymphatic malformations. Diagnostic tips and clinical photographs are provided to help differentiate among these lesions. In addition, the recommended treatment for each is discussed.

Benign acquired superficial skin lesions of the hand.

Numerous dermatologic conditions may be visualized by the hand surgeon during office hours, including when examining patients for an alternative chief problem. Although the primary focus of the visit may be unrelated to a skin lesion, it is important for the hand surgeon to be familiar with these lesions to address patient inquiries and determine which lesions may require some form of treatment. This article reviews some of the most common benign acquired superficial skin lesions of the hand. Particular attention will be paid to epidermal lesions, pigmented lesions, vascular lesions, dermal fibrous/fibrohistiocytic lesions, and infections that can be confused with skin neoplasms or tumor-like conditions. Diagnostic clues, including photographs, will be provided for each lesion described, as well as the recommended treatment.

Benign subungual tumors.

A variety of benign and malignant processes may affect the subungual region; however, most are relatively rare lesions. We present a review of the current literature regarding benign tumors affecting the subungual region.

Pernio (Chilblains), SARS-CoV-2, and COVID Toes Unified Through Cutaneous and Systemic Mechanisms.

Pernio or chilblains is characterized by erythema and swelling at acral sites (eg, toes and fingers), typically triggered by cold exposure. Clinical and histopathologic features of pernio are well described, but the pathogenesis is not entirely understood; vasospasm and a type I interferon (IFN-I) immune response are likely involved. During the coronavirus disease 2019 (COVID-19) pandemic, dermatologists have observed an increase in pernio-like acral eruptions. Direct causality of pernio due to COVID-19 has not been established in many cases because of inconsistent testing methods (often negative results) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a form of COVID-19‒associated pernio (also called COVID toes) is probable because of increased occurrence, frequently in young patients with no cold exposure or a history of pernio, and reports of skin biopsies with positive SARS-CoV-2 immunohistochemistry. PubMed was searched between January 1, 2020, and December 31, 2020 for publications using the following keywords: pernio, chilblain, and acral COVID-19. On the basis of our review of the published literature, we speculate that several unifying cutaneous and systemic mechanisms may explain COVID-19‒associated pernio: (1) SARS-CoV-2 cell infection occurs through the cellular receptor angiotensin-converting enzyme 2 mediated by transmembrane protease serine 2, subsequently affecting the renin-angiotensin-aldosterone system with an increase in the vasoconstricting, pro-inflammatory, and prothrombotic angiotensin II pathway. (2) Severe acute respiratory syndrome coronavirus 2 cell infection triggers an immune response with robust IFN-I release in patients predisposed to COVID-19‒associated pernio. (3) Age and sex discrepancies correlated with COVID-19 severity and manifestations, including pernio as a sign of mild disease, are likely explained by age-related immune and vascular differences influenced by sex hormones and genetics, which affect susceptibility to viral cellular infection, the renin-angiotensin-aldosterone system balance, and the IFN-I response.

Cutaneous mesenchymal tumors treated with Mohs micrographic surgery: a comprehensive review.

Cutaneous mesenchymal tumors (CMT) are rare tumors with wide clinicopathologic heterogeneity. Treatment of malignant cutaneous mesenchymal tumors traditionally includes wide local excision (WLE), though Mohs micrographic surgery (MMS) has been increasingly used. A PubMed literature review of articles from inception until September 2019 related to malignant CMT and surgical treatment with MMS or WLE was completed. Dermatofibrosarcoma protuberans treated with MMS recurred in 1.2% of patients with no reported metastasis. Atypical fibroxanthoma treated with MMS recurred and metastasized in 2.7 and 2.5%, respectively. Undifferentiated pleomorphic sarcoma treated with MMS recurred in 32% with an unknown metastatic rate. Superficial leiomyosarcoma treated with MMS recurred in 3.8% with no reported metastasis. Cutaneous angiosarcoma and myofibrosarcoma treated with MMS have shown no recurrence or metastatic disease, but literature is sparse. The rarity of malignant CMT and the lack of comparative data on treatment make conclusive treatment recommendations difficult. However, recent literature suggests MMS is a useful option and potentially a superior treatment for primary cutaneous mesenchymal tumors.

Leprosy as a Diagnostic Challenge in the United States.

A 63-year-old woman from Central Florida presented to an outside clinic with a 2-year history of a progressive, asymptomatic cutaneous eruption and arthralgias. Her past medical history was significant for reported seronegative rheumatoid arthritis, for which adalimumab, methotrexate, and low-dose prednisone therapy were initiated 5 years prior. The skin eruption occurred shortly after a 4-week hospitalization during which these medications were withheld. At her initial outside evaluation, a biopsy was performed and interpreted as subacute cutaneous lupus erythematosus (SCLE). She was treated with hydroxychloroquine without improvement. A repeat biopsy was reported as consistent with interstitial granulomatous dermatitis (IGD). There was no improvement with potent topical corticosteroids.

Acute generalized exanthematous pustulosis.

Acute generalized exanthematous pustulosis is a cutaneous reaction pattern typically precipitated by medication exposure. It has an estimated incidence of 1 to 5 cases per million per year and can occur in all age groups. Diagnosis is based on typical rash morphology, histopathology, and clinical course. Treatment consists of withdrawing the causative agent and providing supportive care. Prognosis for full recovery is excellent. Patients should be counseled to avoid any future use of the causative medication.

Identification of stage I/IIA melanoma patients at high risk for disease relapse using a clinicopathologic and gene expression model.

PURPOSE: Patients with stage I/IIA cutaneous melanoma (CM) are currently not eligible for adjuvant therapies despite uncertainty in relapse risk. Here, we studied the ability of a recently developed model which combines clinicopathologic and gene expression variables (CP-GEP) to identify stage I/IIA melanoma patients who have a high risk for disease relapse. PATIENTS AND METHODS: Archival specimens from a cohort of 837 consecutive primary CMs were used for assessing the prognostic performance of CP-GEP. The CP-GEP model combines Breslow thickness and patient age, with the expression of eight genes in the primary tumour. Our specific patient group, represented by 580 stage I/IIA patients, was stratified based on their risk of relapse: CP-GEP High Risk and CP-GEP Low Risk. The main clinical end-point of this study was five-year relapse-free survival (RFS). RESULTS: Within the stage I/IIA melanoma group, CP-GEP identified a high-risk patient group (47% of total stage I/IIA patients) which had a considerably worse five-year RFS than the low-risk patient group; 74% (95% confidence interval [CI]: 67%-80%) versus 89% (95% CI: 84%-93%); hazard ratio [HR] = 2.98 (95% CI: 1.78-4.98); P < 0.0001. Of patients in the high-risk group, those who relapsed were most likely to do so within the first 3 years. CONCLUSION: The CP-GEP model can be used to identify stage I/IIA patients who have a high risk for disease relapse. These patients may benefit from adjuvant therapy.

Model Combining Tumor Molecular and Clinicopathologic Risk Factors Predicts Sentinel Lymph Node Metastasis in Primary Cutaneous Melanoma.

PURPOSE: More than 80% of patients who undergo sentinel lymph node (SLN) biopsy have no nodal metastasis. Here we describe a model that combines clinicopathologic and molecular variables to identify patients with thin and intermediate thickness melanomas who may forgo the SLN biopsy procedure due to their low risk of nodal metastasis. PATIENTS AND METHODS: Genes with functional roles in melanoma metastasis were discovered by analysis of next generation sequencing data and case control studies. We then used PCR to quantify gene expression in diagnostic biopsy tissue across a prospectively designed archival cohort of 754 consecutive thin and intermediate thickness primary cutaneous melanomas. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. A penalized maximum likelihood estimation algorithm was used to train logistic regression models in a repeated cross validation scheme to predict the presence of SLN metastasis from molecular, clinical and histologic variables. RESULTS: Expression of genes with roles in epithelial-to-mesenchymal transition (glia derived nexin, growth differentiation factor 15, integrin ß3, interleukin 8, lysyl oxidase homolog 4, TGFß receptor type 1 and tissue-type plasminogen activator) and melanosome function (melanoma antigen recognized by T cells 1) were associated with SLN metastasis. The predictive ability of a model that only considered clinicopathologic or gene expression variables was outperformed by a model which included molecular variables in combination with the clinicopathologic predictors Breslow thickness and patient age; AUC, 0.82; 95% CI, 0.78-0.86; SLN biopsy reduction rate of 42% at a negative predictive value of 96%. CONCLUSION: A combined model including clinicopathologic and gene expression variables improved the identification of melanoma patients who may forgo the SLN biopsy procedure due to their low risk of nodal metastasis.

Clinical, pathologic, and immunologic features of pemphigus herpetiformis: a literature review and proposed diagnostic criteria.

Pemphigus herpetiformis (PH), a rare type of pemphigus, is characterized by immunologic findings consistent with pemphigus but with a unique clinical and pathologic presentation. PH was first described as resembling dermatitis herpetiformis clinically, but because of its variable presentation, it can also resemble linear immunoglobulin A bullous dermatosis and bullous pemphigoid. We reviewed reported cases to analyze the most frequent clinical, pathologic, and immunologic characteristics and to propose corresponding diagnostic criteria. Through a comprehensive review of Medline and PubMed databases, 96 publications and 158 cases were identified. After reviewing the reported characteristics of PH, we suggest the following diagnostic criteria: Clinical: 1) pruritic herpetiform intact blisters with/without erosions; and/or 2) pruritic annular or urticarial erythematous plaques with/without erosions; Pathologic: 1) intraepidermal eosinophils or neutrophils, or both; and/or 2) intraepidermal split with/without acantholysis; Immunologic: 1) direct immunofluorescence showing immunoglobulin G with/without C3 intercellular deposits; and/or 2) indirect immunofluorescence showing immunoglobulin G to epithelial cell surface; and/or 3) detection of serum autoantibodies against desmogleins (1,3) or desmocollins (1,2,3), or both. Diagnosis requires one clinical, one pathologic, and one immunologic feature. We also report three new cases diagnosed at our institution to demonstrate the applicability of the suggested criteria.