Danielle M. Bello

Anal versus rectal melanoma: does site of origin predict outcome?

BACKGROUND: Anatomic site is a predictive factor in subtypes of cutaneous and mucosal melanoma. OBJECTIVE: The aim of this study was to examine the clinical relevance of location of origin of anorectal melanoma as a prognostic factor. DESIGN: With the use of a prospectively maintained database, clinical characteristics, management, and outcomes were compared according to the site of origin. SETTINGS, PATIENTS, INTERVENTIONS: A retrospective review was conducted of patients diagnosed with anorectal melanoma from 1994 to 2010. Tumors were defined as anal, anorectal, or rectal melanoma according to their anatomic relationship to the dentate line. MAIN OUTCOME MEASURES: Clinicopathologic factors were compared by &khgr;2 test. Time-to-event analysis was performed by Kaplan-Meier analysis. RESULTS: Of the 96 patients included (41 with anal melanoma, 32 with anorectal melanoma, 23 with rectal melanoma), patients with rectal and anorectal mucosal melanoma had advanced primary tumors (median Breslow thickness, 12 mm and 8 mm, p = 0.002), whereas anal lesions could be found at earlier depths (median thickness, 6.5 mm). Patients with anal tumors more commonly underwent transanal excision (p < 0.02) and sentinel lymph node biopsy (p = 0.004) versus anorectal and rectal tumors. Patterns of recurrence were also distinct; nearly two-thirds of anorectal and rectal tumors recurred systemically, whereas anal melanoma more often recurred within the lymph nodes first (63%; p < 0.02). Recurrence occurred in 24 (59%) patients with anal tumors, 23 (72%) patients with anorectal tumors, and 16 (70%) patients with rectal tumors. Median overall survival was 22 months for anal melanoma, 28 months for anorectal melanoma, and 27 months for rectal melanoma. Recurrence and survival were not statistically different between the groups. LIMITATIONS: This study is limited by small sample size and its retrospective nature. CONCLUSIONS: This study represents the only series describing the outcomes of anorectal melanoma by anatomic location. Lesions at or proximal to the dentate line present with more advanced disease, possibly related to a delay in diagnosis. Lesions distal to the dentate line more commonly recur within lymph nodes, which may represent differences in nodal drainage. Irrespective of location, the long-term prognosis remains poor for all cases of anorectal melanoma.

Melanoma Mutagenesis and Aberrant Cell Signaling

BACKGROUND Malignant melanoma is the most fatal type of skin cancer. Traditional melanoma classification has been based on histological subtype or anatomical location. However, recent evidence suggests that melanoma comprises a group of diseases characterized by distinct molecular mutations. These mutations affect disease behavior but provide unique opportunities for targeted therapy. METHODS In this review, several signaling pathways in melanoma are described as well as how mutations of BRAF, NRAS, KIT, GNAQ, and GNA11 genes cause aberrant signaling and malignant transformation. RESULTS Multiple genes affecting both the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathway are mutated in melanoma. Melanomas harboring the BRAF V600E mutation have demonstrated sensitivity to both RAF and MAPK/extracellular signal regulated kinase (ERK) inhibitors in vitro and in vivo. In addition, KIT-mutant melanomas, often arising from mucosal, acral, and chronically sun-damaged skin surfaces, have shown clinical response to several inhibitors of the type III transmembrane receptor tyrosine kinase KIT. Uveal melanoma, which often harbors GNAQ or GNA11 mutations, may also be sensitive to MAPK/ERK or protein kinase C/PI3K pathway inhibition. CONCLUSIONS Emerging knowledge of these molecular alterations has led to clinical advances in patients with melanoma. The study of known mutations and identification of new potential targets must continue in an effort to develop more effective therapies for this disease.

Robust Antitumor Responses Result from Local Chemotherapy and CTLA-4 Blockade

Immunotherapy success depends on inflamed tumor microenvironments. In tumor models, inflammation induced by chemotherapy, combined with CTLA-4 blockade, improved survival rates. In a clinical trial, patients with melanoma showed a durable response to such combined therapy. Clinical responses to immunotherapy have been associated with augmentation of preexisting immune responses, manifested by heightened inflammation in the tumor microenvironment. However, many tumors have a noninflamed microenvironment, and response rates to immunotherapy in melanoma have been <50%. We approached this problem by utilizing immunotherapy (CTLA-4 blockade) combined with chemotherapy to induce local inflammation. In murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8+ and CD4+ T cells increasing the CD8/Foxp3 T-cell ratio. These changes were associated with improved survival of the mice. To translate these findings into a clinical setting, 26 patients with advanced melanoma were treated locally by isolated limb infusion with the nitrogen mustard alkylating agent melphalan followed by systemic administration of CTLA-4 blocking antibody (ipilimumab) in a phase II trial. This combination of local chemotherapy with systemic checkpoint blockade inhibitor resulted in a response rate of 85% at 3 months (62% complete and 23% partial response rate) and a 58% progression-free survival at 1 year. The clinical response was associated with increased T-cell infiltration, similar to that seen in the murine models. Together, our findings suggest that local chemotherapy combined with checkpoint blockade–based immunotherapy results in a durable response to cancer therapy. Cancer Immunol Res; 6(2); 189–200. ©2018 AACR.

Adjuvant Therapy in the Treatment of Melanoma

Melanoma is an aggressive form of cutaneous malignancy, with over 10,000 deaths in the US in 2016. In the past 10 years, treatment for stage IV disease with targeted therapy and immune therapy has changed the trajectory of the disease. While the median survival of patients with stage IV disease was historically \ 1 year, there are now patients alive without disease recurrence for more than 10 years. The successful treatment of stage IV patients raises the question as to whether patients with high-risk features (stage II or III) can be administered the treatment in a ‘prophylactic’ or ‘adjuvant’ setting in order to prevent disease recurrence and treat micrometastatic disease. Immunotherapy has been the most tested adjuvant therapy in melanoma and will be the focus of this review.

Correction to: Lymph Node Status in Breast Cancer Does Not Predict Tumor Biology

In the “Results” section third paragraph, second sentence, there is an error. The corrected sentence is as follows.