Metastatic Malignant Melanoma from Unknown Origin to the Jejunum: A Case Report

Introduction. A 66-year-old man presented to the emergency department (ED) with mid and left upper quadrant abdominal pain and shortness of breath.

History. The patient had been complaining of coughing and increased shortness of breath with exertion that became progressively worse over 6 months. He had an episode of vomiting 2 days before arriving at the emergency department. He also complained of abdominal pain and cramping. His past medical history included lung and liver tumors, which were incidental findings on positron emission tomography-computed tomography (PET-CT) scans. The patient also had tobacco use disorder, however, he quit smoking in 1981. Other details of his smoking history are not known. The patient’s mother was previously diagnosed with myeloid dysplasia. There was no family history of skin-related cancer.

Diagnostic testing. Abdominal CT scan showed two large, ulcerated masses in the jejunum suspicious for malignancy as well as several enlarged mesenteric lymph nodes (Figure 1).

Figure 1. CT scan with oral contrast. Oral contrast-enhanced CT image of the abdomen shows enlarged mesenteric lymph nodes and ulcerated masses.

Pelvic CT scan showed a right iliac bone with irregular sclerotic and lytic areas. Colonoscopy also revealed significant wall thickening and dilation. Biopsy of the jejunal mass revealed a malignant neoplasm involving unremarkable small bowel mucosa (Figure 2).

Figure 2. Representative histological section of the jejunal mass biopsy (H&E stain).

The tumor cells were negative for cytokeratin (Figure 3) and strongly positive for melanocytic markers SOX10, S100, HMB45, and Melan A (Figure 4).

Figure 3. Immunohistochemistry for cytokeratin AE1/AE3 showed that the tumor cells were negative for cytokeratin.

Figure 4. Immunohistochemistry for melanocytic marker SOX10 revealed strong and diffuse positivity in tumor cells.

In situ hybridization was negative for a rearrangement involving the EWSR1 gene, excluding gastrointestinal clear cell sarcoma. The overall findings were diagnostic of stage IV (cTX(2), cN2b, pM1c) melanoma.

Differential diagnoses. When the patient first arrived at the ED for his abdominal symptoms, initial consult notes identified colonic diverticulitis, lymphoma, and metastatic disease as top differentials. For a jejunal mass, differential diagnoses include benign tumors such as adenomas and stromal tumors as well as malignant tumors including adenocarcinomas, lymphomas, and carcinoids. Potential diagnoses may also include granulomas, hemangiomas, diverticula, Crohn’s disease, and foreign bodies.¹ These differentials were based on the initial presentation of the patient as well as consideration of the overall timeline of symptom onset. Acutely, the patient’s abdominal pain and emesis suggested diverticulitis, whereas progressive shortness of breath suggested an underlying chronic condition such as lymphoma or metastatic disease. Gastric tumors are rarely diagnosed as primary melanoma. Diagnosis can be challenging in the absence of a cutaneous lesion and disease can progress to a late stage if not identified early.

Treatment and management. Between April 2019 and June 2020, the patient received 16 rounds of chemotherapy. Nivolumab 200 mg in 100 mL 0.09% sodium chloride (NaCl) and ipilimumab 67.2 mg in 50 mL 0.09% NaCl were selected as chemotherapy treatment due to their clinical efficacy in treating numerous tumors including melanoma.¹⁵ Melena, abdominal pain, and night sweats resolved after the first infusion. Five days after the third infusion, the patient reported to the ED with sharp, severe pain in bilateral lower extremities, and muscle spasms in his legs and shoulders, raising suspicion for bone metastasis. Despite sclerotic/lytic processes of the right iliac bone, PET-CT scans detected no suspicious fluorodeoxyglucose avid osseous foci. The patient declined to be admitted to the ED for pain control. Worsening symptoms and leg swelling resulted in a repeat trip to the ED in July 2019. Chemotherapy was halted after the 7th round due to nivolumab-induced pneumonitis and replaced by a prednisone regimen with slow tapering for 7 weeks. Nivolumab infusions continued again after this point but were then indefinitely discontinued after the 16th round due to treatment-related orthopnea. The patient was finally restarted on a prednisone treatment.

Outcome and follow-up. Repeated full-body CT scans displayed no neoplastic processes of melanoma until March 2023. Nuclear medicine PET-CT scan revealed metabolic activity in the liver, raising suspicion of liver metastasis. Although follow-up with MRI imaging showed no discrete hepatic mass, there was slightly heterogeneous activity with a focus in the anterior segment of the liver. This was a non-neoplastic process unrelated to melanoma that eventually normalized. The patient underwent follow-up with yearly nuclear medicine PET-CT scans. However, these were negative for cancer.

Discussion. Malignant melanoma is among the most aggressive skin malignancies and is responsible for 50-70% of all skin tumor deaths.² Primary intestinal melanoma is often diagnosed late due to lesions and signs of disease that are not so obviously recognized by patients and physicians. Thus, prognosis tends to be low. Diagnosing this condition is challenging and involves careful consideration of primary intestinal melanoma versus metastatic melanoma. Metastatic melanoma originates cutaneously, where most melanocytes are located. Primary intestinal melanoma originates within the gastrointestinal tract which may also contain a limited number of melanocytes.³ Primary intestinal melanoma is rare and is associated with a worse prognosis than cutaneous melanoma due to the lack of early detection.⁴ Multiple cases have reported evidence of metastatic melanoma present in the gastrointestinal tract, however, few, such as this case, have reported primary melanoma originating in this region.⁵

Presentation of this tumor typically includes abdominal pain, obstruction, nausea, vomiting, and bleeding.⁶ Typical cutaneous melanoma presentation includes an asymmetrical, irregularly shaped growth with a diameter greater than 6 mm.⁷ 

Advanced melanoma can be treated with a combination of checkpoint inhibitors such as nivolumab and ipilimumab that focus on different targets including PD-1 and CTLA-4, respectively.⁸ These agents are anticancer monoclonal antibodies that neutralize extracellular targets and stimulate immune system recognition. One study has shown that nivolumab has a one-year survival rate of 73% compared to 26% before the introduction of these agents and has a favorable safety profile in patients with advanced melanoma.⁹ The effectiveness of these drugs has been studied more extensively in patients diagnosed with advanced cutaneous melanoma, however, this remains an area to be further studied for cases of primary intestinal melanoma. This case report supports evidence that checkpoint inhibitors can be effective in treating primary melanoma originating from the jejunum.

Within the last decade, significant advancements have been made in the treatment of melanoma. Before the development of combination checkpoint inhibitors, patients commonly underwent surgical removal of affected intestinal areas. Up to 2016, there were 32 published cases of primary small bowel melanoma and, among those patients with regular follow-ups, only half obtained a disease-free status.¹⁰ With the recent rise in use of immune checkpoint inhibitors, more patients diagnosed with advanced melanoma can achieve higher overall survival rates.¹¹  In this patient, immunotherapy was recommended on the basis of symptom reduction, enhancement of quality of life, and prolonged survival. With treatment, the patient’s CT scans eventually showed stable disease. Wall thickening in the gastrointestinal tract subsided and the jejunal mass disappeared. After his initial stage IV diagnosis, the patient ultimately achieved disease-free status. 

It is imperative to obtain tissue samples for a cancer work-up. This case illustrates primary cancer in an unusual site. Early biopsy and histopathology of tumor mass cells are necessary to differentiate between benign and metastatic tumors. In primary care settings, referral to tissue biopsy with appropriate immune staining is required to make a definitive diagnosis of primary small bowel melanoma. Patients should be referred for melanoma biopsy using evidence-based guidelines. Pigmented lesions on the skin that are suspicious of melanoma should be characterized using the ABCDE rule, which assesses the shape, color, diameter, borders, and evolving nature of the lesion.¹² Patients should consult their physicians if any of these changes are noticed. Those with signs and symptoms of metastatic disease including cough, fatigue, and pain may be considered for PET and MRI imaging.¹³ Once characterized, tissue containing the lesion may undergo excisional biopsy to determine depth of invasion and determine what additional laboratory studies are indicated for diagnosis. Different stains may be used to evaluate tumoral thickness and invasion including HE, S-100, SOX10, Melan-A, and HMB-45, however, the latter three have demonstrated a more precise assessment.¹⁴

Conclusion. In conclusion, this case emphasizes the uncommon incidence of primary gastrointestinal melanoma, highlighting the difficulties in diagnosis and the requirement for increased awareness among medical professionals. Even though it is uncommon, individuals who report gastrointestinal symptoms should have gastrointestinal melanoma taken into consideration in their differential diagnosis. Improving patient outcomes requires multidisciplinary management and early detection in order to prevent complications of disease, which may include metastasis and multi-organ involvement. This case emphasizes how crucial it is to carry out more research to comprehend this unusual illness and establish effective treatment plans.