Faculty Bibliography

BACKGROUND:Acral lentiginous melanoma is associated with worse survival than other subtypes of melanoma. Understanding prognostic factors for survival and recurrence can help better inform follow-up care. OBJECTIVES/OBJECTIVE:To analyze the clinicopathologic features, melanoma-specific survival, and recurrence-free survival by substage in a large, multi-institutional cohort of primary acral lentiginous melanoma patients. METHODS:Retrospective review of the United States Melanoma Consortium database, a multi-center prospectively collected database of acral lentiginous melanoma patients treated between January 2000 and December 2017. RESULTS:= .001) were also prognostic factors for recurrence-free survival. CONCLUSION/CONCLUSIONS:In this cohort of patients, acral lentiginous melanoma was associated with poor outcomes even in early stage disease, consistent with prior reports. Stage IIB and IIC disease were associated with particularly low melanoma-specific and recurrence-free survival. This suggests that studies investigating adjuvant therapies in stage II patients may be especially valuable in acral lentiginous melanoma patients.

PURPOSE/OBJECTIVE:We hypothesized that initial biopsy may understage acral lentiginous melanoma (ALM) and lead to undertreatment or incomplete staging. Understanding this possibility can potentially aid surgical planning and improve primary tumor staging. METHODS:A retrospective review of primary ALMs treated from 2000 to 2017 in the US Melanoma Consortium database was performed. We reviewed pathology characteristics of initial biopsy, final excision specimens, surgical margins, and sentinel lymph node biopsy (SLNB). RESULTS:We identified 418 primary ALMs (321 plantar, 34 palmar, 63 subungual) with initial biopsy and final pathology results. Median final thickness was 1.8 mm (range 0.0-19.0). There was a discrepancy between initial biopsy and final pathology thickness in 180 (43%) patients with a median difference of 1.6 mm (range 0.1-16.4). Final T category was increased in 132 patients (32%), including 47% of initially in situ, 32% of T1, 39% of T2, and 28% of T3 lesions. T category was more likely to be increased in subungual (46%) and palmar (38%) melanomas than plantar (28%, p = 0.01). Among patients upstaged to T2 or higher, 71% had ≤ 1-cm margins taken. Among the 27 patients upstaged to T1b or higher, 8 (30%) did not have a SLNB performed, resulting in incomplete initial staging. CONCLUSIONS:In this large series of ALMs, final T category was frequently increased on final pathology. A high index of suspicion is necessary for lesions initially in situ or T1 and consideration should be given to performing additional punch biopsies, wider margin excisions, and/or SLNB.

Melanoma disseminates to the skeletal system where it is then difficult to treat. Yet, there remains limited research investigating metastatic bone disease (MBD) in melanoma. Here, we evaluate whether there are distinct clinicopathologic variables at the time of primary melanoma diagnosis that predispose metastases to engraft bone, and we test the hypothesis that patients with MBD have different responses to treatment. Cutaneous melanoma patients enrolled in a prospective database were studied. Individuals with metastatic melanoma and bone metastases (M-Bone) were compared to those with metastatic disease but no M-Bone. Of the 463 (42.7%) patients, 198 with unresectable metastatic melanoma had M-Bone and 98 developed bone metastasis (bone mets) as first site. Progression-free survival and overall survival were significantly worse in patients with M-Bone compared to those without M-Bone (P < 0.001) independent of treatment modalities, and in patients whose melanoma spread to bone first, compared to those who developed first mets elsewhere (P < 0.001). Interestingly, patients with bone mets presented with primary tumors that had more tumor infiltrating lymphocytes (P < 0.001) and less often a nodular histologic subtype compared to patients without M-Bone (P < 0.001). Our data suggest that melanoma bone metastasis is a distinct clinical and biological entity that cannot be explained by generalized metastatic phenotype in all patients. The observed dichotomy between more favorable primary histopathologic characteristics and a grave overall prognosis requires more studies to elucidate the molecular processes by which melanomas infiltrate bone and to build a mechanistic understanding of how melanoma bone metastases yield such detrimental outcomes.

BACKGROUND:The American Joint Committee on Cancer (AJCC) maintains that the eighth edition of its Staging Manual (AJCC8) has improved accuracy compared to the seventh (AJCC7). However, there are concerns that implementation may disrupt analysis of active clinical trials for stage III patients. We used an independent cohort of melanoma patients to test the extent to which AJCC8 has improved prognostic accuracy compared to AJCC7. METHODS:We analyzed a cohort of 1,315 prospectively enrolled patients. We assessed primary tumor and nodal classification of stage I-III patients using AJCC7 and AJCC8 to assign disease stages at diagnosis. We compared recurrence-free (RFS) and overall survival (OS) using Kaplan-Meier curves and log-rank tests. We then compared concordance indices of discriminatory prognostic ability and area under the curve (AUC) of 5-year survival to predict RFS/OS. All statistical tests were two-sided. RESULTS:Stage IIC continued to have worse outcomes than those for stage IIIA patients, with 5-year RFS of 26.5% (95%CI=12.8-55.1%) vs. 56.0% (95%CI=37.0-84.7%) by AJCC8 (P = 0.002). For stage I, removing mitotic index as T classification factor decreased its prognostic value, although not statistically significantly (RFS C-index=0.63 [95%CI=0.56-0.69] to 0.56 [95%CI=0.49-0.63], P = 0.07; OS C-index=0.48 [95%CI=0.38-0.58] to 0.48 [95%CI=0.41-0.56], P = 0.90). For stage II, prognostication remained constant (RFS C-index=0.65 [95%CI=0.57-0.72]; OS C-index=0.61 [95%CI=0.50-0.72]), and. For stage III, AJCC8 yielded statistically significantly enhanced prognostication for RFS (C-index=0.65 [95%CI=0.60-0.70] to 0.70 [95%CI=0.66-0.75], P = 0.01). CONCLUSIONS:Compared with AJCC7, we demonstrate that AJCC8 enables more accurate prognosis for patients with stage III melanoma. Restaging a large cohort of patients can enhance the analysis of active clinical trials.

OBJECTIVE:To describe and evaluate trends of general surgery residency applicants, matriculants, and graduates over the last 13 years. SUMMARY OF BACKGROUND DATA/BACKGROUND:The application and matriculation rates of URMs to medical school has remained unchanged over the last three decades with Blacks and Hispanics representing 7.1% and 6.3% of matriculants, respectively. With each succession along the surgical career pathway, from medical school to residency to a faculty position, the percentage of URMs decreases. METHODS:The Electronic Residency Application Service to General Surgery Residency and the Graduate Medical Education Survey of residents completing general surgery residency were retrospectively analyzed (2005-2018). Data were stratified by race, descriptive statistics were performed, and time series were charted. RESULTS:From 2005 to 2018, there were 71,687 Electronic Residency Application Service applicants to general surgery residencies, 26,237 first year matriculants, and 24,893 general surgery residency graduates. Whites followed by Asians represented the highest percentage of applicants (n = 31,197, 43.5% and n = 16,602, 23%), matriculants (n = 16,395, 62.5% and n = 4768, 18.2%), and graduates (n = 15,239, 61% and n = 4804, 19%). For URMs, the applicants (n = 8603, 12%, P < 0.00001), matriculants (n = 2420, 9.2%, P = 0.0158), and graduates (n = 2508, 10%, P = 0.906) remained significantly low and unchanged, respectively, whereas the attrition was significantly higher (3.6%, P = 0.049) when compared to Whites (2.6%) and Asians (2.9%). CONCLUSION/CONCLUSIONS:Significant disparities in the application, matriculation, graduation, and attrition rates for general surgery residency exists for URMs. A call to action is needed to re-examine and improve existing recommendations/paradigms to increase the number of URMs in the surgery training pipeline.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Metastasectomy for melanoma provides durable disease control in carefully selected patients. Similarly, BRAF-targeted and immune checkpoint inhibition has improved median overall survival (OS) in metastatic patients. We hypothesized that there is an increasing role for metastasectomy in melanoma patients responding to these therapies. METHODS:Retrospective analysis of a prospectively maintained database identified 128 patients with stage IV melanoma who received targeted molecular and/or checkpoint inhibitors at an academic institution from 2006 to 2017. Records were reviewed to characterize clinicopathologic characteristics, response to treatment, and intent of surgery for those who underwent metastasectomy. OS was analyzed by the Kaplan-Meier method. RESULTS:Median OS from stage IV diagnosis was 31.3 months. A total of 81 patients received checkpoint inhibitors, 11 received targeted inhibitors, and 36 received both. A total of 73 patients underwent metastasectomy. Indications for surgery included the intent to render disease-free (54%), palliation (34%), and diagnostic confirmation (11%). Responders to systemic therapy who underwent metastasectomy had improved OS compared to responders who did not (84.3 vs. 42.9 months, P = .018). CONCLUSIONS:Metastasectomy for melanoma is associated with improved OS in patients that respond to targeted molecular or immunotherapy. Resection should be strongly considered in this cohort as multimodality treatment results in excellent OS.

Mutational heterogeneity can contribute to therapeutic resistance in solid cancers. In melanoma, the frequency of inter- and intra-tumoral heterogeneity is controversial. We examined mutational heterogeneity within individual melanoma patients using multi-platform analysis of commonly mutated driver and non-passenger genes. We analyzed paired primary and metastatic tumors from 60 patients, and multiple metastatic tumors from 39 patients whose primary tumors were unavailable (n=271 tumors). We used a combination of multiplex SNaPshot assays, Sanger Sequencing, Mutation-specific PCR, or droplet digital PCR to determine the presence of BRAF^V600, NRAS^Q61, and TERT^-124C>T and TERT^-146C>T mutations. Mutations were detected in BRAF (39%), NRAS (21%) and/or TERT (78%). Thirteen patients had TERT^mutant discordant tumors; seven of these had a single tumor with both TERT^-124C>T and TERT^-146C>T mutations present at different allele frequencies. Two patients had both BRAF and NRAS mutations; one in different tumors and the other had a single tumor with both mutations. One patient with a BRAF^mutant primary lacked mutant BRAF in least one of their metastases. Overall, we identified mutational heterogeneity in 18/99 (18%) patients. These results suggest that some primary melanomas may be comprised of subclones with differing mutational profiles. Such heterogeneity may be relevant to treatment responses and survival outcomes.

Noncutaneous melanomas are rare subtypes of melanoma with high rates of metastatic disease and poor overall survival. One-third to one-half of cases are amelanotic, which may contribute to a delay in diagnosis. Immunohistochemistry staining with typical melanoma markers helps confirm the diagnosis. There is no standard staging system across mucosal melanomas. Elective nodal dissection is not recommended and there is a paucity of data to support use of sentinel lymph node biopsy. Mutational analysis should be routinely performed. Systemic therapy options include targeted inhibitors, immunotherapy, and cytotoxic chemotherapy, although further studies are needed to confirm their efficacy.

In 2011, the American Board of Surgery announced a new specialty board certification for Complex General Surgical Oncology. The development of a 2-year fellowship training curriculum was based on the core values of multidisciplinary care, surgical management of oncologic disease, education in basic research and clinical trial design, community outreach, patient counseling, and leadership in oncology. This article highlights the elements necessary for developing a fellowship training program in the context of these core values.

Surgery with or without radiation has always been the mainstay of treatment for patients with non-melanoma skin cancers, including basal cell carcinoma, squamous cell carcinoma, and Merkel cell carcinoma. Until recently, there were no effective systemic therapies for patients with advanced disease. This review will focus on the landmark clinical trials that led to Food and Drug Administration (FDA) approval of Vismodegib for advanced basal cell carcinoma (ERIVANCE BCC) and pembrolizumab for advanced Merkel cell carcinoma (KEYNOTE-017). These trials have not only changed the landscape for patients with metastatic disease but also notably for patients with locally advanced disease that is either unresectable or resectable with high morbidity. Additional mention is made for the clinical trial that led to FDA approval of cemiplimab for advanced cutaneous squamous cell carcinoma (EMPOWER-CSCC-1), which is already changing practice patterns, but for which longer-term data are still needed.