Development and validation of a nomogram incorporating gene expression profiling and clinical factors for accurate prediction of metastasis in patients with cutaneous melanoma following Mohs micrographic surgery.

BACKGROUND: There is a need to improve prognostic accuracy for patients with cutaneous melanoma. A 31-gene expression profile (31-GEP) test uses the molecular biology of primary tumors to identify individual patient metastatic risk. OBJECTIVE: Develop a nomogram incorporating 31-GEP with relevant clinical factors to improve prognostic accuracy. METHODS: In an IRB-approved study, 1124 patients from 9 Mohs micrographic surgery centers were prospectively enrolled, treated with Mohs micrographic surgery, and underwent 31-GEP testing. Data from 684 of those patients with at least 1-year follow-up or a metastatic event were included in nomogram development to predict metastatic risk. RESULTS: Logistic regression modeling of 31-GEP results and T stage provided the simplest nomogram with the lowest Bayesian information criteria score. Validation in an archival cohort (n = 901) demonstrated a significant linear correlation between observed and nomogram-predicted risk of metastasis. The resulting nomogram more accurately predicts the risk for cutaneous melanoma metastasis than T stage or 31-GEP alone. LIMITATIONS: The patient population is representative of Mohs micrographic surgery centers. Sentinel lymph node biopsy was not performed for most patients and could not be used in the nomogram. CONCLUSIONS: Integration of 31-GEP and T stage can gain clinically useful prognostic information from data obtained noninvasively.

Long-Term Outcomes in a Multicenter, Prospective Cohort Evaluating the Prognostic 31-Gene Expression Profile for Cutaneous Melanoma.

PURPOSE: Current guidelines for postoperative management of patients with stage I-IIA cutaneous melanoma (CM) do not recommend routine cross-sectional imaging, yet many of these patients develop metastases. Methods that complement American Joint Committee on Cancer (AJCC) staging are needed to improve identification and treatment of these patients. A 31-gene expression profile (31-GEP) test predicts metastatic risk as low (class 1) or high (class 2). Prospective analysis of CM outcomes was performed to test the hypotheses that the 31-GEP provides prognostic value for patients with stage I-III CM, and that patients with stage I-IIA melanoma and class 2 31-GEP results have metastatic risk similar to patients for whom surveillance is recommended. MATERIALS AND METHODS: Two multicenter registry studies, INTEGRATE (ClinicalTrials.gov identifier:NCT02355574) and EXPAND (ClinicalTrials.gov identifier:NCT02355587), were initiated under institutional review board approval, and 323 patients with stage I-III CM and median follow-up time of 3.2 years met inclusion criteria. Primary end points were 3-year recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). RESULTS: The 31-GEP was significant for RFS, DMFS, and OS in a univariate analysis and was a significant, independent predictor of RFS, DMFS, and OS in a multivariable analysis. GEP class 2 results were significantly associated with lower 3-year RFS, DMFS, and OS in all patients and those with stage I-IIA disease. Patients with stage I-IIA CM and a class 2 result had recurrence, distant metastasis, and death rates similar to patients with stage IIB-III CM. Combining 31-GEP results and AJCC staging enhanced sensitivity over each approach alone. CONCLUSION: These data provide a rationale for using the 31-GEP along with AJCC staging, and suggest that patients with stage I-IIA CM and a class 2 31-GEP signature may be candidates for more intense follow-up.

Interim analysis of survival in a prospective, multi-center registry cohort of cutaneous melanoma tested with a prognostic 31-gene expression profile test.

BACKGROUND: A 31-gene expression profile (GEP) test that provides risk classification of cutaneous melanoma (CM) patients has been validated in several retrospective studies. The objective of the reported study was a prospective evaluation of the GEP performance in patients enrolled in two clinical registries. METHODS: Three-hundred twenty two CM patients enrolled in the EXPAND (NCT02355587) and INTEGRATE (NCT02355574) registries met the criteria of age ≥ 16 years, successful GEP result and ≥1 follow-up visit for inclusion in this interim analysis. Primary endpoints were recurrence-free (RFS), distant metastasis-free (DMFS), and overall survival (OS). RESULTS: Median follow-up was 1.5 years for event-free patients. Median age for subjects was 58 years (range 18-87) and median Breslow thickness was 1.2 mm (range 0.2-12.0). Eighty-eight percent (282/322) of cases had stage I/II disease and 74% (237/322) had a SLN biopsy. Seventy-seven percent (248/322) had class 1 molecular profiles. 1.5-year RFS, DMFS, and OS rates were 97 vs. 77%, 99 vs. 89%, and 99 vs. 92% for class 1 vs. class 2, respectively (p < 0.0001 for each). Multivariate Cox regression showed Breslow thickness, mitotic rate, and GEP class to significantly predict recurrence (p < 0.01), while tumor thickness was the only significant predictor of distant metastasis and overall survival in this interim analysis. CONCLUSIONS: Interim analysis of patient outcomes from a combined prospective cohort supports the 31-gene GEP's ability to stratify early-stage CM patients into two groups with significantly different metastatic risk. RFS outcomes in this real-world cohort are consistent with previously published analyses with retrospective specimens. GEP testing complements current clinicopathologic features and increases identification of high-risk patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02355574  and NCT02355587.

The invasive growth potential of residual melanoma and melanoma in situ.

BACKGROUND: Residual melanoma and melanoma in situ (MIS), also referred to as marginally recurrent melanoma, continues to be a concern for all dermatologic surgeons. Little is known about the potential of these tumors to recur with a deeper invasive histology measured according to Breslow depth. OBJECTIVE: To identify the clinical features and histologic, invasive potential of marginally recurrent melanoma and MIS. By having a more accurate understanding of marginally recurrent melanoma, we can better appreciate the consequence of inadequate excision and recognize the importance of improving initial treatments. MATERIALS AND METHODS: An analysis was performed of 108 marginally recurrent melanoma and MIS cases based on prospective data collection. For each case, clinical data, including a comparison of Breslow depth from the time of primary treatment and salvage surgery for marginally recurrent tumor, were tabulated. RESULTS: Of the 84 lesions initially treated as MIS, 19 (22.6%) recurred marginally with a histologically invasive component and a mean Breslow depth of 0.94 mm. Of the 24 patients diagnosed with invasive melanoma, eight (33.3%) had a deeper Breslow depth at the time of clinical recurrence than at the time of primary treatment. The change in Breslow depth for these eight cases was 1.53 to 2.83 mm. CONCLUSIONS: Our findings demonstrate the invasive growth potential of MIS and invasive melanoma inadequately excised at the time of primary treatment. This finding illustrates the consequences of marginal recurrence and stresses the importance of accurate and complete removal of melanoma at the time of initial diagnosis and treatment.

A randomized controlled trial of high-viscosity 2-octyl cyanoacrylate tissue adhesive versus sutures in repairing facial wounds following Mohs micrographic surgery.

BACKGROUND: High-viscosity 2-octyl cyanoacrylate (HVOCA) is a rapidly polymerizing liquid topical adhesive indicated for epidermal approximation of superficial lacerations and surgical wounds. Use of HVOCA in repair of facial wounds after Mohs micrographic surgery (MMS) has not been reported. OBJECTIVE: To compare aesthetic outcome of HVOCA versus sutured epidermal closure of linearly repaired facial wounds following MMS. METHODS: Patients undergoing MMS for facial tumors with postoperative wounds >3 cm appropriate for linear closure were recruited. After placement of dermal sutures, half the wound was randomly selected for closure with HVOCA and the other half was closed with 5-0 polypropylene suture. RESULTS: Fourteen patients (13 men and 1 woman; mean age, 72+/-8.8 years; range, 52-81 years) with basal cell or squamous cell carcinoma of the face (n=12) or neck (n=2) were enrolled. The mean wound length was 4.9+/-1.9 cm (range, 3.1-10 cm). No postoperative complications, including bleeding, infection, or dehiscence, occurred. Using photographs obtained 3 months postoperatively, five dermatologists (including two Mohs surgeons) blinded to the intervention rated cosmesis using a visual analog scale from 1 (worst) to 10 (best). The mean ratings for HVOCA half (6.64+/-1.55) versus sutured half (6.77+/-1.88) were not significantly different (p=.35). Paired comparisons of rater preferences similarly showed no cosmetic differences. All 14 patients preferred OCA for ease of postoperative care. CONCLUSION: HVOCA tissue adhesive is cosmetically equivalent to epidermal sutures in the linear repair of facial wounds following MMS. This technique represents an additional option for Mohs surgeons.

Management of cutaneous angiomyolipoma and its association with tuberous sclerosis.

Although typically presenting renally, angiomyolipomas can rarely present in the skin. The tumors are composed of an admixture of blood vessels, smooth muscle and adipose tissue and are often seen in the setting of tuberous sclerosis. We describe a case of angiomyolipoma presenting on the thigh of a 50-year-old white female. This is the 17th reported case of cutaneous angiomyolipoma. As with all previously described cases, our patient did not present with the stigmata of tuberous sclerosis. Angiomyolipoma should be considered within the differential for subcutaneous nodules and work-up for tuberous sclerosis should not be pursued when presenting in the skin.

Treatment of granuloma annulare with the 585 nm pulsed dye laser.

BACKGROUND: Granuloma annulare is a chronic asymptomatic dermatosis that is typically manifested by annular papules arising on the dorsa of the hands, feet, elbows, and knees. Multiple treatment modalities have been used with variable efficacy, but no known cure exists. Obtaining long-term resolution of involved areas is often a therapeutic challenge. OBJECTIVE: We report the results of treatment of a patient with localized erythematous granuloma annulare with a 585 nm flashlamp-pumped pulsed dye laser. METHODS: A single granuloma annulare plaque present on the left wrist for 3 years was treated on three occasions with a 585 nm flashlamp-pumped pulsed dye laser initially and repeated at months 5 and 13. RESULTS: After initial pulsed dye laser treatment, significant flattening and reduction of erythema were evident within the treated area. After a second treatment at month 5 and a third treatment at month 13, further improvement was evident, and long-term remission was achieved. CONCLUSION: Localized granuloma annulare may be difficult to manage, presenting a therapeutic challenge. Thorough understanding of available treatment options, their relative efficacies, and risks of complication can facilitate successful management of this chronic disease. Pulsed dye laser therapy may be an effective and relatively safe treatment option for erythematous granuloma annulare, although prospective studies in additional patients would be desirable. Improvement of the condition in a single patient does not imply that others might improve, and variability in response is more likely.

Alpha-1-antitrypsin associated panniculitis: the MS variant.

Over 90 mutant alleles of the alpha-1-antitrypsin (AAT) gene are recognized and classified by mobility on an acid starch gel. The four major categories include: F=fast, M=medium, S=slow, Z=very slow. Among 41 reported cases of AAT panniculitis, most have the ZZ phenotype with AAT levels below normal. We report two cases of AAT panniculitis with MS phenotype and normal AAT levels. In addition, we review the pathophysiology, epidemiology, and extracutaneous manifestations of AAT disease and propose a diagnostic algorithm for ulcerative panniculitis. A 42-year-old man presented with a solitary plaque on the left thigh exacerbated by trauma or excessive activity. The lesion frequently suppurated with a yellowish oily material. Twenty years before, he had fractured his left femur which was repaired with a metal plate. X-rays, histology with special stains for organisms, and cultures were negative. AAT phenotype was MS and AAT value was normal. A 43-year-old woman presented with multiple plaques on the proximal extremities which suppurated with exercise or trauma. AAT phenotype was MS and AAT level was normal. Histologic exam for both patients showed a dense neutrophilic infiltrate with septal and lobular panniculitis and areas of necrobiosis in the lower reticular dermis.