Anorectal mucosal melanoma (AMM) is a rare and aggressive malignancy, representing only 0.4–1.6% of all melanomas (1). Despite its rarity, the incidence of AMM has risen in recent decades and is higher in women than in men (2, 3). The clinical manifestations of AMM are typically nonspecific, complicating the diagnostic process (4, 5). Consequently, AMM is frequently diagnosed at an advanced stage, often with local-regional or distant metastases (2). Effective treatment options for advanced AMM are currently limited, largely due to insufficient data on prognostic factors and survival outcomes (5, 6). This case report, combined with a literature review, aims to provide a reference for the diagnosis, management, and prognosis of advanced KIT-mutated AMM.

A 66-year-old woman with a complaint of intermittent anorectal bleeding and pain for 1 month. During this period, she underwent a colonoscopy at a local hospital, which revealed the presence of a rectal tumor. Due to limited medical conditions in local hospitals, surgical treatment was not performed. Subsequently, she presented to our hospital. The patient has no history of harmful habits or significant past medical conditions, and there is no relevant family history of genetic disorders. Physical examination revealed a non-tender mass measuring 4 × 3 centimeters in the anorectal region, located approximately 4 cm from the anal margin. Colonoscopy showed a rectal lesion of about 4 cm × 3 cm × 3 cm, located within 5cm of the anal verge, with visual erosion and hemorrhage ( Figure 1A ). Biopsy was taken for the final diagnosis. Rectal magnetic resonance imaging (MRI) showed a soft tissue mass protruding from the rectal wall, with no local lymph node enlargement ( Figure 1B ). Enhanced computed tomography (CT) of the chest and abdomen detected an occupying lesion protruding from the rectal wall into the intestinal lumen, as well as a circular low-density shadow in the 4/8 liver segment along with mild enhancement. No lymph node enlargement was found in the local area. ( Figure 1C ). Hematological examinations, in review including blood count, biochemical tests, carcinoembryonic antigen, and alpha-fetoprotein levels, were within normal ranges, except that CA 199 was 29.70U/ml. Histological biopsy findings (HE staining) showed that the tumor was composed of spindle-shaped and oval-shaped cells, exhibiting significant cellular atypia and nuclear division. Immunohistochemical staining revealed positive results for HMB 45. Expression of S-100 was negative. The expression level of Ki67 was 40%. Based on the histopathological cell morphology, immunohistochemistry, and imaging examination, the patient was preliminarily diagnosed with a primary AMM with liver metastasis. After obtaining written informed consent. The patient underwent transanal local resection for primary AMM and ultrasound-guided radiofrequency ablation for liver metastases. Postoperative contrast-enhanced ultrasound demonstrated complete inactivation of the liver metastases ( Figures 2A, B ). The postoperative pathological examination results (HE staining) revealed negative margins, and the tumor cells exhibited spindle-shaped, oval-shaped, and pleomorphic types ( Figures 3A, B ). The immunohistochemical analysis showed positive staining for SOX100, S-100, HMB-45, Mela A, PRAME, p16, and ki-67 (+70%) ( Figures 3C-I ). Genetic testing identified a mutation in exon 17 of the KIT gene (D820Y), while both the BRAF and NRAS genes were found to be wild-type. The patient recovered well and was discharged on the sixth day after surgery. Three weeks post-surgery, whole-body bone imaging and enhanced CT scans of the chest and abdomen were performed. The results showed that the patient experienced no complications related to the surgery and no signs of tumor recurrence. Blood cell counts and biochemical tests were normal, with the CA 19–9 level at 31.30 U/ml. Subsequently, targeted therapy with imatinib was initiated at a dosage of 400 mg per day. CT scans of the chest, abdomen, and pelvis were performed every two months. However, after 14 weeks of imatinib treatment, the patient experienced intermittent abdominal pain. The blood routine test was normal. Biochemical tests revealed elevated levels of bilirubin, ALT, and AST, with the AST level exceeding 3-fold the upper limit of the normal reference value. The D-dimer level was measured at 4.04 µg/mL. Tumor markers: CA199 was 210.00U/ml, CA125 was 72.80U/ml. A CT scan revealed a portal vein thrombosis, along with new metastases in the liver and lungs ( Figures 2C, D ). No new lesions were found in the anorectal area. An ultrasound of both lower limb blood vessels showed no abnormalities. The patient discontinued imatinib and started receiving anticoagulant and hepatoprotective medication; however, the symptoms did not improve. As a result, the patient forwent further treatment and was discharged, dying two weeks later ( Figure 4 ).

Primary malignant melanoma can develop in various locations, including the esophagus, small intestine, anorectal region, skin, and eyes. However, some gastrointestinal melanomas may arise from metastatic cutaneous melanomas (7). In the present case, no direct evidence of cutaneous melanoma was observed; therefore, it was classified as primary AMM. Unlike cutaneous melanomas, anorectal malignant melanoma (AMM) generally exhibits a poorer prognosis owing to delayed diagnosis and its inherently aggressive behavior (3). The five-year survival rate is approximately 20% for localized disease and 0% for metastatic disease (5). Approximately 20% of patients present with distant metastasis at diagnosis, primarily as a result of delayed detection. The liver, lungs, and pelvis are the most commonly affected sites for metastasis (5, 8), consistent with the findings in this case.

AMM often presents with benign polyp-like changes or hemorrhoid-like dark red alterations (4). These features, along with potential infectious manifestations, may mimic other anorectal conditions, leading to misdiagnosis. In this case, colonoscopy revealed a lesion near the dentate line with ulceration but lacking typical pigmentation. Consequently, other differential diagnoses were considered, including gastrointestinal stromal tumors, neurogenic tumors, and various metastatic diseases. Distinguishing primary AMM from other tumors in this region remains challenging due to the lack of specific imaging characteristics (9, 10). Immunohistochemistry (IHC) is widely regarded as the most common method for diagnosing melanoma. Several key markers reported in the literature, including SOX10, HMB45, Melan-A (11, 12), as well as PRAME, p16, and Ki-67 (13, 14), aid in differentiating AMM from other lesions. The diagnosis of AMM with liver metastasis was confirmed through IHC in this case. Following transanal local excision of the primary lesion and radiofrequency ablation for liver metastases, genetic testing was performed to explore further therapeutic options, revealing a c-KIT mutation. The patient subsequently received targeted therapy with imatinib, which led to prolonged survival. Owing to the rarity and aggressive nature of this disease, coupled with the limited number of affected patients, a standard treatment regimen has not been established. Consequently, this case may serve as a valuable reference for the management of advanced KIT-mutated melanoma patients.

Currently, the American Joint Committee on Cancer (AJCC) guidelines have not established an effective staging system for assessing prognosis and guiding treatment in AMM (15). Surgical resection remains the primary treatment for localized disease (16). Decisions regarding local excision (LE) versus abdominoperineal resection (APR) should be made on a case-by-case basis (17). Both procedures aim to improve survival through R0 resection. A recent systematic review and meta-analysis indicated that LE may reduce postoperative complications and preserve sphincter function, without significant survival disadvantage compared to APR (1). In this case, R0 resection of the primary lesion was successfully achieved via LE. During follow-up, no local recurrence or surgery-related complications were observed. These findings indicate that, provided R0 resection is feasible, LE can achieve local control while preserving sphincter function. However, several studies indicate that patients with advanced AMM may not derive substantial survival benefits from surgical intervention alone (18, 19). Consequently, a multimodal treatment approach incorporating surgery has become the principal strategy for managing advanced AMM.

Activating mutations in BRAF or c-KIT have been identified in malignant melanoma, carrying significant implications for the tumor’s response to anticancer agents targeting these kinases. KIT mutations are more prevalent than NRAS or BRAF mutations, with an observed frequency of approximately 24–33% (20, 21). These mutations occur in various regions, specifically exons 9, 11, 13, 17, and 18 (22). Further studies have demonstrated that c-KIT inhibitors represent promising treatment options for patients with KIT-mutated melanoma, particularly those harboring mutations in exons 11 and 13 (23). However, a recent study indicates no significant difference in antitumor activity among the different exons affected by KIT mutations (24). In the context of targeted therapies for KIT mutations, multiple KIT inhibitors are available besides imatinib. Nevertheless, a meta-analysis indicated that bosutinib, nilotinib, and ponatinib are associated with a higher relative risk of hepatotoxicity compared to imatinib (25). In this case, a c-KIT mutation was identified in exon 17, with no BRAF or NRAS mutations detected. The patient received imatinib, achieving a survival duration of five months (from diagnosis to death). In contrast, patients with AMM and liver metastases who do not receive targeted therapy following surgery typically survive only one to two months (26). Therefore, these findings further confirm that the activating mutation in exon 17 of c-KIT is sensitive to c-KIT inhibitors, and imatinib can prolong survival in advanced AMM patients harboring this mutation. These results provide additional evidence for the management of KIT-mutated AMM patients.

Imatinib may also induce adverse effects during the treatment of solid tumors. Common adverse effects include edema, rash, and fatigue. Other adverse events include vomiting and elevated levels of ALT and AST (27). Portal vein thrombosis is exceedingly rare. Previously, only a single case of splenic vein thrombosis was reported in a patient with a gastric stromal tumor following imatinib administration (28). To our knowledge, this represents the first reported case of portal vein thrombosis in patients with advanced AMM. In this case, the patient had no hematological disorders and exhibited no radiological evidence of vascular compression that could predispose to thrombosis. Furthermore, the patient had no history of thrombosis or known genetic predisposition. Long-term use of tyrosine kinase inhibitors has been reported to induce vascular endothelial damage, potentially leading to venous thrombosis (29). However, the patient had been receiving imatinib for less than four months. Therefore, the portal vein thrombosis may be primarily attributed to paraneoplastic syndrome. Another potential adverse event of imatinib therapy is hepatotoxicity. One study indicates that approximately 1.67% of patients may develop grade 3 or 4 elevations in ALT and AST levels (25). These elevations typically occur within the first two months of treatment initiation and are generally reversible (30). It is not possible to definitively conclude that the liver injury in this patient was solely caused by imatinib, particularly considering the presence of portal vein thrombosis. Notably, these rare adverse events precluded continuation of targeted therapy in this patient. Therefore, this study highlights the potential risk of venous thrombosis in patients with advanced KIT-mutated AMM receiving imatinib. Awareness of this risk is crucial to prevent premature discontinuation of targeted therapy due to potential adverse events.

This article reports the clinical outcomes of a KIT-mutated AMM patient with concurrent liver metastasis who underwent LE and radiofrequency ablation, in addition to targeted therapy with imatinib. Our findings, supported by a review of relevant literature, suggest that this treatment strategy can effectively control local recurrence, improve quality of life, and prolong survival in patients with advanced KIT mutations. Additionally, we observed that patients with advanced AMM receiving imatinib may experience rare but severe adverse events, including portal vein thrombosis. Given the limited reports on this treatment approach and its associated adverse events, further large-scale studies with long-term follow-up are warranted to validate these findings.