Gastric and colonic metastases of malignant melanoma diagnosed during endoscopic evaluation of symptomatic anemia presenting as angina: a case report

A 72-year-old man visited cardiology for exertional chest pain, lightheadedness, and fatigue. Six years prior, he was surgically treated for cutaneous malignant melanoma of the lower back. After a negative cardiac work-up, primary care diagnosed severe iron deficiency anemia. Emergent upper and lower gastrointestinal (GI) endoscopy revealed simultaneous melanoma metastases to the stomach and colon with discrete macroscopic features. Metastatic disease, including brain, lung, and bone, was discovered on imaging. Treatment included immunotherapy with nivolumab and stereotactic radiosurgery of the brain metastases, and our patient has remained in continued remission even after 2 years. Melanoma with GI tract (GIT) metastasis has a poor prognosis and rarely presents symptomatically or with synchronous gastric and colonic lesions. This case illustrates the importance of early primary care involvement to expedite work-up for multifocal GI metastases in patients with a remote melanoma history presenting with symptoms related to iron deficiency anemia (IDA).


Introduction
Cutaneous melanoma is among the most common malignancies to metastasize to the GIT (1), despite the GIT being the second least common location for melanoma metastasis (2).They most commonly metastasize to the GIT from extremities (15-57%), followed by the trunk (13-54%) and head/neck (5-33%) (3).GIT metastases are usually asymptomatic, with only 1-5% of melanoma patients having clinically apparent GI involvement (3) and up to 43.5% having GIT metastasis at autopsy (4).It can be difficult to determine if a GIT melanoma is metastatic or primary when there is no synchronous cutaneous primary.Metastatic GIT melanoma can present decades later as recurrence (4,5) or from a spontaneously regressed primary (6,7).
Primary GI-mucosal melanomas are typically esophageal or anorectal (8), not gastric or colonic (9), and are usually aggressive with a worse prognosis than melanoma metastatic to the GIT (4).The small bowel is the most common location for GIT metastasis (2, 3, 6, 10), and the stomach or colon is less common (2, 10).A retrospective cohort describing 55% of secondary GIT melanomas as "multifocal" probably noted a greater frequency in the upper GIT because it included small bowel (1).Here, we describe a rare case of melanoma presenting with angina from symptomatic anemia and with simultaneous gastric and colonic metastases.

Case presentation
A 72-year-old man with atrial fibrillation on apixaban presented in September 2021 (Table 1) to his cardiologist with exertional chest pressure, postural lightheadedness, and fatigue for weeks.An echocardiogram and stress test were unrevealing.Cardiac catheterization showed mild, nonobstructive coronary artery disease.Cardiology lab results showed severe microcytic anemia (hemoglobin 7.0 G/DL) and primary care lab results showed iron deficiency (ferritin 7.6 NG/ML), although there was no overt GI hemorrhage.Apixaban was held, and an emergent upper and lower endoscopy was ordered (11).
Relevant past medical history includes a cutaneous melanoma of the lower back that was diagnosed in 2015 by punch biopsy (Clark Level IV, Breslow Depth 2.25 mm, mitotic index approximately 1 mitosis/mm 2 , no significant tumor regression, epidermal ulceration, microvascular invasion, or satellite micro-metastases), which was at clinical stage IIA (T3a N0 M0) (Supplementary Figure S1).A wide local excision had negative margins, and a sentinel lymph node biopsy was negative.The pathological stage was also IIA and further staging work-up was therefore not performed based on the early stage of this typical superficial spreader.Adjuvant therapies were experimental at the time and not prescribed.Bi-annual skin and periodic ophthalmologic exams remained unremarkable.Screening colonoscopies were up to In October 2021, esophagogastroduodenoscopy and colonoscopy identified a gastric body polyp (Figure 1, Supplementary Figure S2), a partially obstructing ascending colon mass (Figure 2), and hepatic flexure polyp (Figure 3, Supplementary Figure S3).All three biopsies diagnosed metastatic melanoma (Supplementary Figures S4-S6).PET-CT found lung and right humeral head metastases, but none of the GI metastases were detectable.Abdomen/pelvis CT with contrast was non-contributory, but a chest CT demonstrated bilateral solid pulmonary nodules up to 2.5 cm, a 2.1 cm right humeral head lytic lesion, and a few left supraclavicular lymph nodes up to 1.0 cm, corresponding to PET-CT.A brain MRI showed left caudate and cerebellar metastases.Serum lactate dehydrogenase (LDH) was normal, but GI metastases harbored BRAF V600E, PTEN, and TERT mutations.The pathological stage was IV [rTX, N2b, M1d(0)] based on the American Joint Committee on Cancer (AJCC) 8th Edition staging system (13).
The patient's symptomatic anemia was successfully treated with two iron infusions.He underwent stereotactic radiosurgery for the brain metastases without complications.Twelve cycles of immunotherapy with nivolumab (480 mg monthly infused over 30 min) were completed in September 2022.Nivolumabinduced vitiligo developed at cycle 9 and guttate psoriasis on the chest, arms, and legs at cycle 11, the latter of which resolved with 0.1% triamcinolone cream twice daily.Shortly after cycle 12, he developed oral candidiasis, and preexisting seborrheic keratoses became inflamed, both thought to be nivolumab-induced.The former was treated with oral nystatin, and the latter with either a topical steroid or cryotherapy.Immunotherapy response was monitored with monthly circulating tumor DNA (ctDNA) levels and PET-CTs every 3 months.The patient went into remission after 3 months of immunotherapy and remains in continued remission as of July 2023.His surveillance has included brain MRI and whole-body PET-CT at baseline and every 3 months, along with ctDNA testing that was reduced from monthly after 6 months of diseasefree surveillance.

Discussion
Our patient's cutaneous melanoma 6 years prior is congruent with the interim average and median reported times from primary cutaneous melanoma treatment to find a GI metastasis, or 3.65 years (10) and 10 years (14), respectively.However, the locations of his metastases were very unusual.We found no reports of simultaneous upper and lower GIT lesions in metastatic GIT cases and only two reports in primary GIT cases: gastric/ileocecal (15) and esophageal/ileal (16).While our patient did have several risk factors for multiple primary GI-mucosal melanomas, including older age at diagnosis of first melanoma (66 years old), male sex, and white race (17), these were unlikely to occur in the stomach or colon (8,9), and proposed criteria for other intestinal locations require a solitary lesion (6).
Prompt diagnosis is important in symptomatic GIT metastasis because of life-threatening complications (18), which were prevented in this case.In addition to IDA, patients can present with abdominal pain, dysphagia, small bowel obstruction, and/or perforation (1,4,19).Endoscopy is superior to radiography for diagnosing GIT melanoma and its complications (19), and capsule endoscopy may be necessary (5).GIT melanoma appears as either pigmented or amelanotic ulcerated polypoid lesions (1,4,19).
GIT metastasis is a poor prognostic marker (5year survival 14%, median survival 12.5 months) (3), and autopsy often reveals multiple organ metastases (95%) (2).GI metastases are not typically the cause of death, which is usually respiratory failure from lung metastasis (2).LDH elevation is a negative predictor of survival in the AJCC staging system (13) but is not melanoma-specific.
BRAF, PTEN, and TERT mutations were present in his melanoma metastases.Half of cutaneous melanomas have BRAF mutations, and the most common V600E mutation  is associated with decreased overall survival in advanced melanoma (20).BRAF mutation testing is required for resectable or unresectable melanoma stage III or stage IV, highly recommended for stage IIC high-risk resected disease, and not recommended for stage I or stages IIA-IIB (21).His overall survival was decreased with PTEN and TERT mutations, both of which often coexist with BRAF mutations (22,23).Interestingly, however, the vitiligo he experienced during his immunotherapy has been associated with progression-free and overall survival that is significantly increased (24).

Conclusion
Melanoma often progresses to metastatic disease but can be challenging to quickly diagnose in the absence of a cutaneous lesion.GIT metastasis has a particularly poor prognosis.Synchronous gastric and colonic melanomas are extremely rare but important to consider in patients with IDA and a remote history of melanoma because of their poor prognosis and potential to cause an abdominal emergency.The patient's metastatic melanoma presented as angina, showing the importance of early primary care involvement to rapidly diagnose the cause of symptomatic IDA.The expedited upper and lower endoscopy and multidisciplinary involvement prevented abdominal complications and began timely treatment.Our patient has remained in continued remission even after 2 years.

FIGURE
FIGUREStomach polyp: Single non-melanotic, mm in diameter and .mm in height, sessile umbilicated polyp (equivalent to a Pariss classification of colonic polyps) found on the gastric body.

FIGURE
FIGUREAscending colon mass: infiltrative and ulcerated non-melanotic, partially obstructing -cm mass involving one-half of the lumen circumferences.

FIGURE
FIGUREHepatic flexure polyp: endoscopic appearance of the non-melanotic, mm in diameter and mm in height, sessile umbilicated polyp (Pariss classification of colonic polyps).
TABLE Patient care timeline.
Completes 12 cycles of nivolumab; oral thrush and inflammation of preexisting seborrheic keratoses develop shortly thereafter and are treated 10/22 Baseline surveillance imaging and ctDNA show continued complete remission 10/2022-7/2023 Remains in continued remission based on brain MRI, whole body PET-CT, and ctDNA every 3 months date (12), and a 25-mm tubular adenoma had been removed 4 years prior.