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.

Malignant syphilis: ostraceous, ulceronecrotic lesions in a patient with human immunodeficiency virus.

We present a 36-year-old HIV-positive man with a sixweek history of spreading, ulcerative, and necroticcutaneous lesions. Laboratory and histopathologicexamination revealed syphilis. This case of malignantsyphilis, also known as lues maligna, is an uncommonvariant of this sexually transmitted infection. This casehighlights the importance of including malignantsyphilis in the differential diagnosis of patientspresenting with a disseminated ulcerative andnecrotic rash, especially in individuals with HIV.

Challenges in Treating Secondary Syphilis Osteitis in an Immunocompromised Patient with a Penicillin Allergy: Case Report and Review of the Literature.

Syphilis is a sexually transmitted infection that remains fairly commonplace. The introduction of penicillin aided in curbing the incidence of disease; however, with the advent of the human immunodeficiency virus (HIV), syphilis is now on a resurgence with sometimes curious presentations. We present a case of a 36-year-old Caucasian gentleman with untreated HIV who complained of a skin eruption and joint pains for 6 weeks, prompting the diagnosis of secondary syphilis osteitis. Skin lesions were reminiscent of "malignant" syphilis. CD4 count was 57 cells/µL. RPR was elevated with 1 : 64 titer and positive confirmatory TP-PA. Radiography of the limbs revealed polyostotic cortical irregularities corroborated on bone scintigraphy. The patient had an unknown penicillin allergy and was unwilling to conduct a trial of penicillin-based therapy. He was subsequently treated with doxycycline 100 mg twice daily for 6 weeks and commenced antiretroviral therapy, noting dramatic improvement in both the skin lesions and joint pains. Unfortunately, he defaulted on follow-up, precluding serial RPR and bone imaging. Penicillin allergies have proven to be quite a conundrum in such patients, without much recourse for alternative therapy. Doxycycline with/without azithromycin is other options worth considering.

Histopathologic Variants of Cutaneous Squamous Cell Carcinoma In Situ With Analysis of Multicentric Subtypes: Possible Relationship to Human Papillomavirus.

Squamous cell carcinoma in situ (SCCIS) of the skin is relatively common. When the authors reviewed 3846 cutaneous SCCIS cases over an 18-month period, they found 6 distinct histopathologic subtypes of SCCIS, 5 of which demonstrated multicentric variants. Multicentric variants of SCCIS were noted on nongenital and nonmucosal skin. All of the multicentric cases that were studied with p16 immunohistochemistry were positive in the tumor cells, suggesting a possible role of human papillomavirus in tumorigenesis. The authors believe that human papillomavirus likely plays a part in the development of these multicentric cutaneous SCCIS.

Metastatic hepatocellular carcinoma to the skin staining positive with HMB-45.

Hepatocellular carcinoma (HCC) is uncommonly observed as a cutaneous metastasis. We report a 76-year-old man with metastatic HCC to the skin of the nasal ala, diagnosed antecedent to the primary tumor. HCC was confirmed by positive immunostaining with Hep Par 1 in tissue from the metastasis and from a needle biopsy of the primary lesion. In addition, tumor cells from both the metastasis and liver stained positive with HMB-45. To our knowledge, HMB-45 positive staining has not been reported in either primary or metastatic HCC.

Fulminant group A streptococcal necrotizing fasciitis: clinical and pathologic findings in 7 patients.

BACKGROUND: Necrotizing fasciitis is a rapidly progressive soft tissue infection with high morbidity and mortality rates. Examination of deep incisional biopsy specimens can provide prompt diagnosis and improve survival. We describe 7 patients with necrotizing fasciitis caused by group A Streptococcus species. OBJECTIVE: Our purpose was to describe the unique dermatopathology and clinical features in 7 patients with necrotizing fasciitis caused by group A Streptococcus. METHODS: We conducted a retrospective review. RESULTS: The average age of the patients was 47 years. Fasciitis occurred on an extremity in all cases. All 5 patients with streptococcal toxic shock syndrome died of their disease. The histopathologic findings from early fascial disease revealed superficial epidermal necrosis, edema, and hemorrhage with few inflammatory cells, whereas clinically advanced, necrotic skin lesions revealed diffuse necrosis, thrombosis, neutrophilia, and numerous gram-positive diplococci. CONCLUSIONS: Patients with clinical features of necrotizing fasciitis should have a deep incisional biopsy specimen obtained from the central area of ecchymotic, necrotic plaques to confirm the diagnosis. Immediate surgical intervention is necessary to reduce the morbidity and mortality rates associated with necrotizing fasciitis.

Livedo (livedoid) vasculitis and the factor V Leiden mutation: additional evidence for abnormal coagulation.

We report the case of a patient with livedo vasculitis associated with the factor V Leiden mutation. This association provides additional support for abnormalities of coagulation in patients with this disorder. The spectrum of platelet, coagulation, and fibrinolytic disorders reported with livedo vasculitis is reviewed.