To our knowledge, this is the first paper examining the role of anatomic site of ARMM on prognosis. Clinical differences between primary site of disease in this series do exist. In our study, anal melanoma was more common in the Caucasian population. While it is interesting to note that racial differences exist by anatomic site, due to the fact that patient numbers are small, it is difficult to draw many conclusions from this finding. It is known that although the absolute incidence of mucosal melanoma is greatest in Caucasians, the proportion of anorectal mucosal melanoma in African Americans, Hispanics, and Asians, similar to other types of mucosal melanoma, is greater than that observed in Caucasians.1,17
Additionally, patterns of racial distribution may be reflective of an institutional referral bias. Differences in Breslow thickness can be seen between primary tumor sites and thinner lesions are observed in the anal melanoma group. Anal melanoma tumors are also diagnosed at earlier stages. This may be due to the fact that some anal lesions are identified by visual inspection of the anal verge, whereas anorectal and rectal tumors are often diagnosed only when patients are symptomatic from disease. Despite some anal tumors being thinner at the time of diagnosis, diagnosis at an earlier pathologic stage does not significantly alter survival outcomes when compared with anorectal or rectal primary sites.
Patterns of surgical management differ by primary location. While the majority of patients with anal melanoma underwent transanal excision, in part owing to the facts that no surgical operation has shown a survival benefit and transanal excision has a lower morbidity than APR, patients with anorectal or rectal melanoma were more likely to undergo APR. APR is often reserved for cases not amenable to local excision or for palliation. Due to the fact that ARMM can often be multifocal and amelanotic in up to 20–25% of cases, achieving curative resection by WLE can be challenging.5
Additionally, the radial growth phase component of a melanoma may extend beyond the visible tumor. These factors likely also contributed to our margin positivity rate.
Sentinel lymph node biopsy was performed in more anal melanoma patients, perhaps due to its distal location and technical feasibility compared to more proximal tumors. Of note, sentinel lymph node biopsy had been performed on mucosal melanoma tumors as part of a prior institutional protocol. As lymph node status has not proven to be prognostic in anorectal melanoma, and given that no therapy has demonstrated an improvement in survival, there was no standardization of management based upon the results of these biopsies.
There was no improvement in survival for those patients who received adjuvant systemic or radiation therapy in our study. As no level 1 or 2 evidence exists to direct the physician in the management of ARMM in the adjuvant setting, the standard of care is observation. If a patient develops systemic metastases or the risk of systemic metastases is considered high, adjuvant therapy is administered or patients are enrolled in clinical trials at our institution in which they receive it.
Patterns of recurrence differed between these groups. Anal melanomas more frequently recurred in the lymph nodes initially, either alone or in combination with distant disease, compared to more proximal tumors. This recurrence pattern may be a reflection of initial surgical intervention; patients with anorectal or rectal melanoma undergoing APR have their draining lymph node basin removed in the mesorectum at initial operation, whereas those with anal lesions, who mostly underwent transanal excision, had their nodal basin left intact. This pattern may also reflect a difference in the ability to detect lymph node metastases by anatomic location. Inguinal adenopathy is more readily detected on physical examination, whereas mesorectal lymph node metastases require radiographic imaging for discovery. Therefore, inguinal adenopathy may be more easily recognized and diagnosed for anal lesions, while mesorectal lymphadenopathy may not be apparent until cross-sectional imaging is performed to assess for systemic disease.
Despite these differences in tumor thickness, surgical resection, and recurrence patterns, overall survival is not significantly different among ARMM of distinct primary sites. These findings reinforce the need for continued research in this disease. Because of the uniformly poor prognosis of ARMM, efforts centering on combining surgical excision with systemic therapy as first-line treatment are ongoing and effective systemic therapy is required for the successful treatment of this disease.
Recently, significant advances have been made in the field of both immunotherapy and targeted therapy in the treatment of cutaneous metastatic melanoma. Ipilimumab, a new human monoclonal antibody that targets cytotoxic T-lymphocyte antigen 4 (CTLA-4), was the first agent to show improvement in overall survival in patients with metastatic melanoma in a phase III, randomized, control trial.22–23
Additionally, vemurafenib, an inhibitor of mutant BRAF, has demonstrated a significant impact on both progression-free and overall survival in a phase III trial in patients with melanoma containing the V600E BRAF mutation. Lastly, various inhibitors of KIT, such as imatinib mesylate, sunitinib, nilotinib and dasatinib, have also demonstrated activity in a subset of patients with metastatic melanoma harboring KIT alterations.24
It is known that certain mucosal melanomas, including ARMM, contain these BRAF and KIT mutations at varying rates according to anatomic site.25–26
Thus, it can be hypothesized that some ARMM may represent better targets for drugs such as ipilimumab which function through immune system modulation, while those which demonstrate a specific actionable mutation may respond more optimally to targeted inhibitors, such as imatinib and vemurafenib. Currently there is no data available on these new effective immune therapeutic agents and targeted drugs in the treatment of ARMM specifically. However, new trials utilizing these agents, including Ipilimumab, BRAF- and KIT-inhibitors, for the treatment of all mucosal melanomas, are underway.
There are a few limitations of our study. For the purpose of this study, we excluded patients with distant metastases who were not considered for curative resection. In doing so, our data represent outcomes for patients considered good surgical risk, most of whom were referred to our institution for surgical treatment and therefore contain a certain selection bias. Because anorectal melanoma is a rare disease, our total population is relatively small with our anatomic subsets including a limited number of patients, increasing the possibility of type II error. Also, given that some patients were lost to follow-up, there were limitations in our ability to accurately assess dates of recurrence and, therefore, recurrence free survival. Lastly, when defining primary anatomic location not all anal tumors could be definitively confirmed as mucosal melanomas. Two anal tumors may have been located on perianal skin. However, description of these lesions as documented by physical examination was consistent with anal verge melanoma. Therefore, we have chosen to include these 2 anal patients due to the likelihood that these tumors were mucosal melanomas.
This study represents the only series describing the outcomes of anorectal melanoma by anatomic location of the primary lesion. 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, long-term prognosis remains poor for all cases of anorectal mucosal melanoma; however, progress in the development of systemic therapy for this disease holds the promise for improved outcomes in the future.