The patient underwent wide local excision of the primary lesion, preceded by a sentinel lymph node (SLN) mapping with a submucosal injection of 99mTC-Nanocoll. A single pre-sacral SLN was found and biopsied.

The final pathology from the resection specimen demonstrated spindle-shaped, melanotic cells invading into the muscularis propria. The cells demonstrated a high mitotic index, with evidence of vascular invasion. Immunohistochemical (IHC) staining showed strongly positive staining with HMB-45, MART-1, and S100. Additionally, the SLN was found to harbor micrometastases.

Considerable dispute exists regarding the cell of origin for ARMM. While the presence of melanocytes has been relatively well described in the mucosa of the head and neck ^{13, 14} and the esophagus ^{15, 16}, its presence in the intestinal mucosa from the stomach to distal rectum is controversial ¹⁷. Historically, melanocytes have been found within the transition zone beneath the dentate line and increases in number distally toward the anoderm ^{18, 19}. This has led to the presumption that anorectal melanoma arises from normal melanocytes distal to the dentate line that extend proximally into the rectum ²⁰. Staining for melanoma markers using various techniques for HMB-45 and S100 have demonstrated that melanocytes present rarely in the mucosal epithelium above the dentate line in normal patients ²¹. Additionally, a proliferation of normal melanocytes within the colorectal epithelium proximal to the dentate line has been seen in patients with melanoma arising within the proximal anal canal ^{21, 22}. This has led to the conclusion that ARMM can arise directly from melanocytes located in the intestinal epithelium of the proximal anus or distant rectum hence, primary anorectal melanoma ²³.

Embryologically, cells migrating from the neural crest that enter the dorsolateral pathway differentiate into melanocytes that eventually populate their eventual sites of colonization, while cells entering the ventral pathway are the neurogenic precursors of the peripheral and enteric nervous system ²⁴. Neural crest cells are typified by a characteristic set of transcription factors including Snail2 (Slug), Sox10, FoxD3, and Sox9 ²⁵. Melanocyte migration and differentiation involves a complex interplay of cell signaling pathways ²⁶. Specific mutations in the c-Kit/stem cell factor (SCF) pathway, the endothelin receptor type B/endothelin pathway, and the Sox10 transcription factor pathway being associated with a variety of related pigment and enteric nervous system disorders including piebaldism, Waardenburg syndrome, and Hirschprung's disease ^27-32.

Exposure to ultraviolet (UV) rays, especially UV-B rays at a wavelength of 290 to 320 nm, is clearest risk factor for the development of cutaneous malignancies, including melanoma ^{33, 34}. While cumulative exposure increases the risk of the more common basal cell (BCC) and squamous cell carcinomas (SCC) of the skin, CM is associated with intense, intermittent exposure to UV rays ³⁵. Two well described nucleic acid lesions caused by UV-B include 6-4 photoproducts (6-4PP) and cyclobutane pyramidine dimers (CPD) ³⁶. Accumulation of these signature mutations are seen in BCC and SCC, including p16/INK4A and p53 ³⁷. Mutations in BRAF is the most common driver mutation in malignant melanoma, found in upwards of 60% of all CMs and 80% of melanocytic nevi, the vast majority being the V600E amino acid substitution at exon 15 ^38-40. While the signature UV-associated 6-4PP and CPD nucleic acid mutations are not found to be the etiology of BRAF mutations, there is evidence that faulty repair of UV-A associated oxidative damage and other UV-B associated mutations may be the etiology of BRAF mutations in CM ⁴¹.

The role of photocarcinogenesis in CM is highlighted by the different patterns of mutations associated with MM. Edwards et al evaluated primary MM tumors from varying anatomical locations and found no evidence of BRAF mutation, in stark contrast to the prevalence of this mutation in CM ⁴². Along with a paucity of BRAF mutations ⁴³, similar studies have shown decreased NRAS mutations in MM compared to CM ^{44, 45}, while KIT driver mutations are increased in MM ^{46, 47}. Other mechanisms of pathogenesis for MM have been investigated, including viral infections ⁴⁸ and the use of tobacco ⁴⁹, but no clear etiology of MM has been elucidated.

Due to its relative rarity, the treatment of ARMM is controversial. While it is clear that surgical resection is favored, the extent of surgery has been called into question as upwards of 25% of patients with ARMM present with inoperable tumors, either because of distant metastases or aggressive locoregional disease ^{2, 3}. 60% of patients present with local lymphatic spread ². This aggressive local disease led to the suggestion that an abdominoperineal resection (APR) be the treatment of choice in order to address local lymph nodes ^50-53. Brady et al reported on 71 patients with ARMM treated with either abdominoperineal resection (APR), wide local excision (WLE), or biopsy and/or fulgration only ⁵⁴. While no significant difference in survival was found regardless of operative approach, the local recurrence rate was 8% for APR versus 20% for local therapies.

Given the morbidity of APR and the clear quality of life advantages of WLE ⁵⁵, there has been persistent concerns regarding an aggressive surgical approach with no clearly demonstrated survival advantage ^{5, 56}. Iddings et al reported on patterns of treatment and outcomes in patients with ARMM from the SEER database and found no significant different in five-year survival between patients undergoing APR versus WLE (17% and 19%, respectively) ⁵⁷. Nilsson et al found that margins of resection significantly predicted long-term advantage, with 5-year survivals of 19% for patients receiving an R0 resection, compared to 6% for patients with R+ resections, regardless of the type of surgery ⁵⁸. Of note, patients undergoing APR were significantly more likely to receive an R0 resection (76%) compared to those undergoing WLE (26%). Our patient did undergo WLE, but notably had an R1 resection, with microscopic involvement of the margins of resection. The role of reoperation for margins after an initial WLE has not been addressed in the literature.

As was the case in our patient, distant metastases areoverwhelmingly the cause of mortality in patients with ARMM, leading to the suggestion that WLE be the initial procedure of choice ⁵⁹. However, as demonstrated in our case, patients with local recurrence often require repeat excisions, occasionally including salvage APR ⁶⁰. With reports of local recurrence rates as high as 65% with WLE alone ⁶¹, investigations into improved local control with the addition of radiation have been undertaken. Kelly et al reported on 54 patients undergoing WLE followed by adjuvant radiation, and showed a local recurrence rate of 18% at 5 years ⁶².

A lingering question in the treatment of ARMM involves the approach to nodal disease. The use of sentinel lymph node (SLN) mapping has been reported, with subclinical nodal disease found in the inguinal and pelvic nodal basin SLNs ^62-66. No series large enough has been reported to draw conclusions on the effect of SLN biopsy on recurrence or survival, leading some to conclude that the procedure should not be performed ⁶⁷. The presence of regional lymph node metastases has not been shown to affect recurrence patterns ⁴, lending further support to the avoidance of lymphadenectomy. In our patient, with a positive mesorectal SLN, we opted to avoid pelvic exploration as there is no evidence supporting an improved outcome with extended lymphadenectomy.