Past medical history was significant for a "birthmark" extending over his abdomen and lower back, for which multiple excision/grafting procedures were performed at 6 years of age. He denied any itching, bleeding, or noticeable changes in the lesion's size, texture, color, or appearance for the last 20 years. The patient did not recall a specific diagnosis but reported consistent follow-up and mole mapping with a dermatologist outside the US. Despite being born in the UK, he lived in South Africa from early childhood until his 23 years of age and then returned to his home country, where he stayed until moving to the US a few months before presentation. When he was 10 years old, his father was treated for pulmonary tuberculosis. No other relevant family history was reported. He denied excess alcohol intake, current/former smoking, illicit drug use, overexposure to UV radiation, or known occupational hazards.
During bedside evaluation, the patient was found to have heterogeneous brown-to-black patches/plaques scattered on his torso, buttocks, and lower abdomen with satellite lesions, areas of hypertrichosis, and irregular borders, consistent with partially-excised giant CMN of bathing trunk distribution (Figure 1). The skin lesions were mostly flat except for a nodular border where grafting was previously done. In addition, a 2-cm mobile, firm, non-tender and non-erythematous subcutaneous nodule was palpated in the right axillary region. His physical exam was otherwise unremarkable.
On initial workup, blood counts, basic chemistries, liver function tests, troponin levels, urinalysis, and electrocardiogram were within normal limits. Conversely, serum D-dimer was elevated (2.42 mcg/mL) and chest radiography showed a left lower lobe (LLL) density of approximately 3 cm, leading to the acquisition of thoracic computed tomography (CT) angiography. Despite a lack of pulmonary emboli, significant findings included two LLL nodules (2.7 and 1.0 cm), a left posterior pleural-based nodule (0.8 cm), and a right lower lobe nodule (0.3 cm).
The patient was admitted to the hospital for further diagnostic evaluation. While serum lactate dehydrogenase (LDH) was elevated (350 U/L), other laboratory tests resulted negative (including traditional tumor markers, hepatitis/HIV testing, QuantiFERON-TB Gold, and three sputum acid-fast bacillus smears). Contrast-enhanced CT (CECT) of the abdomen demonstrated hypodense lesions in the left and right adrenal glands (4.7 x 4.1 and 3.7 x 3.5 cm, respectively), between liver segments 2/3 (2.8 x 2.4 cm), and in the left inferior renal pole (1.4 x 1.1 cm). Brain magnetic resonance imaging (MRI) showed multiple enhancing parenchymal nodules of 0.4-1.2 cm, some of them with surrounding edema. Meanwhile, a whole spine MRI found no additional disease in the central nervous system (CNS) or vertebral bodies.
The high suspicion of metastatic cancer prompted an incisional biopsy of the right mid-back nodular area. Histopathological evaluation lacked evidence of malignancy and was consistent with reactive melanocytic proliferation to an underlying scar. As a result, the patient underwent an incisional biopsy of the right axillary nodule, with formalin-fixed paraffin-embedded (FFPE) samples revealing malignant cells within fibroadipose tissue (Figure 2). Immunohistochemistry (IHC) showed positivity for preferentially expressed antigen in melanoma (PRAME), S100, melan-A, and tyrosinase:a pattern consistent with melanoma:and negativity for BRAF V600E and NRAS Q61R. A hybridization capture-based next-generation sequencing assay (MSK-IMPACT) was also applied to the FFPE specimens. Although no microsatellite instability or structural variants were found, the tumor was positive for somatic mutations in NRAS exon 3 (c.181C>A, p.Q61K), EP300 exon 31 (c.5992G>A, p.G1998R), and MSH2 exon 12 (c.1996A>G, p.I666V). Additional findings included an estimated tumor mutation burden of 2.5 mutations/megabase and MDM2/GLI1/ERBB3/CDK4/IGF1/TERT/SDHA/EP300/MSH2 amplification.
On account of his elevated serum LDH levels and CNS metastases, M1d(1) melanoma was ultimately diagnosed. As surgical metastasectomy was not appropriate, upfront treatment consisted of ipilimumab/nivolumab (3 mg/kg and 1 mg/kg, respectively, administered intravenously once every 3 weeks) and multifraction stereotactic radiosurgery of the brain (27 Gy divided into 3 daily fractions). Low-grade adverse events (hepatitis, thyroiditis, and oral mucositis) occurred after the first cycle of ipilimumab/nivolumab, but did not require immunotherapy discontinuation. Following 6 weeks of treatment, brain MRI showed interval contraction of CNS lesions and chest CTCE demonstrated stable pulmonary lesions. On the other hand, abdominopelvic imaging revealed new mesenteric/inguinal adenopathy and increased metastatic involvement of liver, kidneys, and adrenals.
The patient's rapid disease progression led to subsequent-line treatment with CVT (cisplatin 20 mg/m2 IV on days 1-4, vinblastine 1.6 mg/m2 IV on days 1-4, and temozolomide 150 mg/m2 orally on days 1-5 administered every 21 days). Following 3 cycles of cytotoxic chemotherapy, CECT disclosed nonobstructing transient small bowel intussusceptions secondary to intra- and extraluminal metastatic lesions. As a result, the patient was transitioned to nivolumab/relatlimab (480 mg/160 mg IV once every 4 weeks). A few days after the second combination dose, he presented to the ED complaining of intractable abdominal pain. Repeat abdominal CECT showed an edematous, hypoattenuating closed-loop small bowel obstruction with twisting of the mesentery. Given the evidence of significant ischemia, exploratory laparotomy with partial small bowel resection and reanastomosis was performed. The patient recovered well, albeit with considerable weight loss related to continued anorexia and abdominal pain. Stable disease (<20% growth of target lesions) was observed after three nivolumab/relatlimab doses. However, interval imaging after the fourth dose showed progression of the thoracic and abdominopelvic masses. Figure 3 showcases a timeline with relevant data from the patient's clinical course.