Primary anorectal melanoma with BRAF V600 wild-type status presenting with widespread metastases in a 29-year-old man: a case report

Introduction

Primary anorectal malignant melanoma (ARMM) is a rare, aggressive mucosal neoplasm comprising <1% of all melanomas [1]. Typically diagnosed in the sixth or seventh decade with a female predominance, its non-specific presentation (rectal bleeding, tenesmus) is often misattributed to benign conditions, causing diagnostic delays. Up to 80% of lesions lack macroscopic pigmentation, compounding misdiagnosis risks [2, 3]. ARMM in young adults is exceptionally rare; fewer than 10 cases are reported in the literature [4]. We present a widely metastatic, BRAF wild-type primary ARMM in a 29-year-old man, highlighting the diagnostic challenges of undifferentiated anorectal masses and the necessity of rigorous immunohistochemical and molecular evaluation.

Case report

A 29-year-old man with no significant medical history presented with a 2-month history of progressive tenesmus, post-defecatory pain, and hematochezia. Serum tumor markers were normal, and human immunodeficiency virus (HIV) serology was negative. Proctoscopy revealed a friable, ulcerated, hemi-circumferential exophytic mass originating at the dentate line and extending 3 cm proximally along the anterolateral rectal wall (Fig. 1).

Figure 1.

Endoscopic visualization of the primary anorectal mass. (A) Proctoscopic view demonstrating a friable, ulcerated, hemi-circumferential exophytic mass originating at the dentate line. (B) Complementary view detailing the actively bleeding, clinically amelanotic tumor surface extending proximally along the anterolateral rectal wall.

Histopathological examination of the biopsy demonstrated a high-grade, morphologically undifferentiated neoplasm with extensive necrosis. Careful microscopic inspection revealed focal intracytoplasmic brown pigment in a minority of cells (Fig. 2). Given the anaplastic morphology, an extensive immunohistochemical panel was performed. Neoplastic cells exhibited diffuse nuclear and cytoplasmic positivity for S100 and SOX10, alongside focal expression of HMB-45 and Melan-A (Fig. 3). Epithelial, neuroendocrine, lymphoid, and mesenchymal markers were uniformly negative, confirming melanocytic lineage. Molecular testing demonstrated wild-type BRAF V600 status.

Figure 2.

Histopathologic features. (A) Low-power overview of a high-grade, extensively necrotic, and undifferentiated neoplasm infiltrating the mucosa. (B, C) Intermediate-power views displaying cohesive sheets of markedly pleomorphic tumor cells. (D) High-power detail highlighting focal intracytoplasmic brown pigment (melanin) in a minority of neoplastic cells (Hematoxylin and eosin stain).

Figure 3.

Immunohistochemical profile confirming definitive melanocytic lineage. Neoplastic cells exhibit strong, diffuse nuclear and cytoplasmic immunoreactivity for (A) S100 and (B) SOX10, alongside focal expression of (C) HMB-45 and (D) Melan-A.

Staging computed tomography and positron-emission tomography revealed extensive regional lymphadenopathy, as well as pulmonary, hepatic, adrenal, and peritoneal metastases. Comprehensive dermatologic and ophthalmologic examinations excluded cutaneous or uveal primary lesions, establishing the diagnosis of primary metastatic ARMM. The patient was referred to the multidisciplinary tumor board for palliative systemic therapy.

Discussion

Primary ARMM arises from neural crest-derived melanocytes, most frequently localizing to the transition zone near the dentate line [3, 5, 6]. Unlike its cutaneous counterpart, ARMM pathogenesis lacks an association with ultraviolet radiation. While viral etiologies (HIV, human papillomavirus) have been implicated [7], our patient was entirely immunocompetent, underscoring the enigmatic etiopathogenesis of sporadic ARMM and the need to elucidate alternative molecular drivers.

Epidemiologically, ARMM predominantly afflicts individuals in their sixth to eighth decades (median age 66) [8, 9]. Manifestation in a 29-year-old male is exceptionally rare. However, emerging data suggest a potential bimodal age distribution, with increasing incidence in young males [10]. This epidemiologic rarity inherently lowers the index of clinical suspicion, causing presenting symptoms like hematochezia and tenesmus to be misattributed to benign hemorrhoidal disease [5, 11], inevitably leading to critical diagnostic delays.

Endoscopically, ARMM frequently presents as a friable, ulcerated mass mimicking rectal adenocarcinoma. Although superficial melanin pigmentation facilitates diagnosis [12], our patient’s lesion was entirely amelanotic on gross inspection. This ambiguity shifted the diagnostic burden entirely to the histopathological evaluation.

For the surgical pathologist, ARMM poses a formidable challenge. Grossly, up to 80% of lesions are amelanotic, and microscopically, ~20% lack pigment entirely [13]. Despite identifying rare focal intracytoplasmic melanin, our case’s undifferentiated, necrotic architecture necessitated an extensive immunohistochemical workup. Distinguishing ARMM from poorly differentiated adenocarcinoma, sarcoma, small cell carcinoma, and high-grade neuroendocrine tumors [13] relies on robust expression of neural crest (S100, SOX10) and melanocytic markers (HMB-45, Melan-A), strictly coupled with negativity for alternative lineages [3, 13].

The molecular landscape of ARMM diverges significantly from cutaneous variants. While BRAF mutations drive 40%–50% of cutaneous melanomas, they are conspicuously rare in mucosal types [5]—reflected in our patient’s wild-type BRAF V600 status. Conversely, mucosal melanomas exhibit a higher prevalence of KIT aberrations and novel alterations like NRG1 deletions [3, 5]. Comprehensive molecular profiling is now mandatory to uncover actionable therapeutic targets for this inherently refractory disease.

Therapeutic management lacks standardized guidelines [1]. ARMM propagates rapidly along submucosal planes, and 26%–38% of patients harbor distant metastases at presentation [5], mirroring our patient’s fulminant dissemination, which precluded curative-intent surgery. While the 5-year survival rate remains below 20% [14], modern systemic therapies—particularly immune checkpoint inhibitors and targeted agents—offer a vital beacon of hope for prolonged survival, especially for younger patients with the physiological reserve to tolerate multi-agent regimens [3].

In conclusion, this case underscores the insidious nature and aggressive biology of ARMM. It serves as a vital reminder to consider melanoma in young adults with atypical anorectal masses, regardless of age or macroscopic pigmentation. Heightened clinical vigilance, coupled with rigorous histopathological and molecular profiling, is essential to minimize diagnostic delays and guide emerging systemic therapies.

Conflicts of interest

None declared.

Funding

None declared.