Primary melanoma of the gastrointestinal tract

Table 1 Comparison between cutaneous and mucosal/gastrointestinal melanoma

Feature	Cutaneous melanoma	Mucosal/GI melanoma
Incidence	> 90% of all melanomas. Increasing global incidence (approximately 25/100000)	1%-2% of melanomas; GI primaries < 0.5%
Typical sites	Skin (trunk, extremities, head-neck)	Anorectum (55%-60%), esophagus (10%-15%), stomach (10%-12%), small bowel (5%-8%), colon (3%-5%)
Etiologic factors	Strongly related to UV exposure and intermittent sunburns; BRAF-driven oncogenesis common	Not related to UV radiation; may derive from ectopic melanocytes or APUD/Schwannian precursors
Median age at diagnosis	55-60 years	Approximately 70 years
Gender distribution	Slight male predominance	Similar or slightly male-predominant
Clinical presentation	Visible or pigmented skin lesion; early detection frequent	Non-specific GI symptoms (bleeding, anemia, obstruction, pain); diagnosis often delayed
Stage at diagnosis	Approximately 80% localized; 10%-15% metastatic	< 35% localized; majority advanced or metastatic
Median OS	Localized > 10 years; stage IV ≈ 20-30 months (immunotherapy era)	Median 14-20 months overall; < 6 months for gastric, approximately 24 months for anorectal
Prognosis	Significantly improved with immunotherapy (5-year OS ≈ 52% in CheckMate-067)	Poorer outcomes due to late diagnosis and intrinsic aggressiveness; 5-year OS < 20%
Histopathology	Often pigmented, epidermal origin, radial/vertical growth phases	Frequently amelanotic, submucosal, polypoid or ulcerated; high mitotic index
Molecular profile	BRAF (40%-50%), NRAS (15%-25%), NF1 (10%), KIT rare (< 3%)	KIT (15%-40%), NRAS (10%-20%), BRAF (5%-10%), NF1 (10%-15%), SF3B1 (5%-10%)
Tumor mutational burden	High; UV-signature mutations frequent	Low; structural/copy-number variations
Response to immunotherapy	High (ORR = 40%-60%, OS: 20 months to > 50 months)	Lower (ORR = 20%-30%, OS: 11-16 months)
Targeted therapy options	BRAF/MEK inhibitors (dabrafenib, trametinib, vemurafenib)	KIT inhibitors (imatinib, nilotinib); rare BRAF-targeted cases
Main causes of death	Distant metastases (lung, brain, liver)	Distant metastasis (liver, peritoneum)
Molecular testing recommendation	BRAF testing standard for advanced disease	Mandatory KIT, NRAS, BRAF, and NF1 sequencing for all cases

GI: Gastrointestinal; UV: Ultraviolet; OS: Overall survival; ORR: Objective response rate.

Table 2 Epidemiology and survival outcome of primary gastrointestinal melanomas

Site	Relative frequency	Median OS (months)
Anorectum	50%-60%	18-24
Esophagus	8%-12%	10-15
Stomach	7%-10%	Approximately 6
Small bowel	7%-9%	12-24
Colon	3%-5%	15-20

OS: Overall survival.