Case Report: Primary Duodenal Melanoma with Brain Metastasis



 

Sonha Nguyen, MD1,2; Naila Khan, MD1,2; Christine Duong, MD1,2; Mary Le, MD3; Vishal Ranpura, MD1,2,4

Perm J 2021;25:20.252

https://doi.org/10.7812/TPP/20.252
E-pub: 05/19/2021

Malignant duodenal tumors can be primary or secondary. Although the most common primary tumor involving the duodenum is an adenocarcinoma, primary malignant melanomas arising in the small intestine are exceedingly rare and remain a controversial clinical entity. In this report, we present a unique case of primary duodenal melanoma with brain metastasis managed successfully by surgical excision, stereotactic radiation, and adjuvant immunotherapy.

CASE PRESENTATION

A 61-year-old white man was sent to the emergency department at Kaiser Permanente Riverside by his primary care doctor because of decreased hemoglobin levels and fatigue for 1 month. His medical history was significant for restless leg syndrome, a history of peptic ulcer disease more than 20 years earlier, and remote tobacco use disorder (0.8 pack-years, quit 30 years previously). Medication use included ibuprofen 800 mg twice daily for the past 3 months for chronic low back pain. One year before presentation, he had a positive screening fecal test. Subsequently, he underwent diagnostic colonoscopy, which was unremarkable. The patient did not have a prior personal or family history of bleeding diseases or cancer. He denied fevers, unintentional weight loss, skin lesions, hematuria, hematochezia, or melena. He also denied excessive sun or occupational exposures.

On admission, his vital signs and physical examination were unremarkable. Laboratory studies confirmed microcytic anemia with a hemoglobin level of 6.3 g/dL (baseline hemoglobin, 14.5 g/dL 3 years prior). Anemia workup revealed ferritin < 8 ng/mL, consistent with iron-deficiency anemia. A stool screening for Helicobacter pylori antigen was negative. He received 3 U of red blood cell transfusions. Contrast-enhanced chest–abdomen–pelvis computed tomography (CT) showed a 10.5 × 7.6 × 6.6-cm duodenal mass with a few mildly enlarged mesenteric lymph nodes, the largest measuring 1.3 cm (Figure 1A). Subsequently, the patient underwent urgent esophagogastroduodenoscopy, which revealed a 10-cm friable and circumferential ulcerated mass around the third portion of the duodenum with no sign of obstruction or active hemorrhage (Figure 1B). The duodenal biopsy of the lesion showed poorly differentiated neoplastic cells, with immunohistochemistry staining positive for HMB-45, S100, Melan-A, and SOX10 (Figure 2). In addition, the tumor cells were negative for pancytokeratin, CK7, CK20, CDX2, CD117, CD34, CD45, CD3, and CD20. These findings were consistent with melanoma. Additional molecular testing was negative for the BRAF V600 mutation. A positron emission tomographic scan showed a large, hypermetabolic duodenal mass with adjacent small mesenteric nodes and no other distant avid disease (Figure 1E). At this time, the patient was not deemed a surgical candidate because of the location of his tumor and was therefore discharged home in stable condition with outpatient medical oncology follow-up.

tpj20252f1

Figure 1. Computed tomographic scan of the abdomen in axial plane, esophagogastroduodenoscopy findings, and positron emission tomographic scan of the whole body. (A) A computed tomographic scan of the abdomen at admission showed a 10.5 × 7.6 × 6.6-cm duodenal mass (arrow) with few mildly enlarged mesenteric lymph nodes. (B) Esophagogastroduodenoscopy showed an approximately 10-cm friable and circumferential ulcerated mass (arrow) around the third position of the duodenum with no sign of obstruction or active hemorrhage. (C) A computed tomographic scan of the abdomen showed a high-grade partial obstruction at the fourth portion of the duodenum with the air-fluid level (arrow). (D) Esophagogastroduodenoscopy showed the stomach and duodenum filled with particles; we were unable to reach the site of obstruction. (E) A positron tomographic scan showed a large hypermetabolic duodenal mass (arrow) with adjacent small mesenteric nodes and no other distant avid disease.

tpj20252f2

Figure 2. Histological examination of the duodenal lesion (hematoxylin–eosin) with immunohistochemical stains. (A) The histological section shows a cohesive sheet of poorly differentiated tumor cells within the duodenal submucosa (×10 magnification). (B) The tumor cells were positive for HMB-45 in cytoplasm (×10 magnification). (C) The tumor cells were positive for Melan-A in cytoplasm (×10 magnification). (D) The tumor cells were positive for S100 in cytoplasm (×10 magnification). (E) The tumor cells were positive for SOX10 in the nucleus (×10 magnification).

At the outpatient visit, a detailed full-body dermatological and ophthalmological examination revealed no cutaneous or choroidal lesions suspicious of a primary source. Two weeks after discharge, magnetic resonance imaging (MRI) of the brain as a part of the malignancy workup showed 2 foci of intraaxial metastatic disease involving the right parietal cortex and the left occipital lobe measuring up to 9 mm, consistent with metastatic disease (Figure 3A). Otherwise, the patient did not have any focal neurological deficits. Radiation oncology was consulted and he underwent 1 dose of stereotactic radiosurgery at 22.5 Gy to both lesions of the brain. Subsequent MRI of the brain showed improvement of the lesions (Figure 3B). He was then started on combination immunotherapy with nivolumab 1 mg/kg and ipilimumab 3 mg/kg intravenously every 3 weeks. Unfortunately, he developed grade 4 colitis after 1 cycle of combination immunotherapy. Further treatment was held, and the patient was started on high-dose prednisone 90 mg daily with a slow taper.

tpj20252f3

Figure 3. Magnetic resonance imaging of the sagittal plain of the brain. (A) Magnetic resonance imaging of the brain 2 weeks after diagnosis of duodenal melanoma showed 2 foci of intraaxial metastatic disease involving the right parietal cortex and the left occipital lobe (arrow) measuring up to 9 mm. (B) Magnetic resonance imaging of the brain after 1 dose of stereotactic radiosurgery at 22.5 Gy showed improvement of the previous 2 foci (arrow). (C) Magnetic resonance imaging of the brain 26 months after the initial diagnosis showed no recurrence.

A 2-month follow-up CT scan of the abdomen after completing the first cycle of nivolumab/ipilimumab showed focal wall thickening at the proximal jejunum and marked improvement of the adjacent subcentimeter mesenteric lymph nodes. When the patient’s diarrhea resolved and his prednisone was tapered to 5 mg daily, he resumed single-agent nivolumab 3 mg/kg intravenously every 2 weeks. However, the following week, he developed postprandial epigastric abdominal pain with emesis. Repeat CT scan of the abdomen showed high-grade partial obstruction at the fourth portion of the duodenum (Figure 1C), which was then confirmed by esophagogastroduodenoscopy (Figure 1D). The patient underwent successful surgical management with exploratory laparotomy and intestinal resection of the duodenal mass. Two weeks postoperatively, nivolumab was resumed. The patient tolerated treatment well except for hypothyroidism, which was treated with levothyroxine.

The patient is currently doing well 38 months after surgery without any further evidence of recurrence or distant metastasis despite the initial aggressive presentation of the tumor. His most recent CT scan of the chest–abdomen–pelvis and MRI of the brain (Figure 3C) revealed no new masses or lymphadenopathy. He continues to be on treatment with nivolumab. Figure 4 summarizes the course of events since his initial diagnosis to the present.

tpj20252f4 copy copy

Figure 4. Timeline of hospitalization admission leading to initial diagnosis of primary duodenal melanoma until presence. CT = computed tomography; EGD = esophagogastroduodenoscopy; Hgb = hemoglobin; MRI = magnetic resonance imaging; PET = positron emission tomography; TSH = thyroid-stimulating hormone.

DISCUSSION

Melanoma is a malignant tumor that develops from melanocytes, a pigmented, dendritic-like cell, present mainly in the skin and less commonly in the eyes, meninges, and gastrointestinal (GI) mucosa. Melanomas account for 1% to 3% of all malignancies.1 The incidence has been increasing globally and an estimated 48,000 patients die each year from this malignancy. Although the GI tract is the most common site of metastatic involvement, given its rich blood and lymphatic supply,2 primary malignant melanomas arising in the small intestine, particularly the duodenum, are exceedingly rare and remain controversial. Current literature is limited to only a few case reports.3

There are several theories regarding the origin of primary malignant melanoma in the small intestine. One theory argues that GI melanoma without a primary visible skin lesion may represent either an undiagnosed or spontaneous regression of a cutaneous malignancy caused by infection or changes in the immune system.4,5 However, there is growing literature on primary melanoma in the small intestine without evidence of a cutaneous source.6-9 Some experts have postulated that GI melanomas arise from the migration of multipotent neural crest cells into the bowel and differentiate into specialized cells. As such, melanoblasts in the small bowel may serve as precursors to malignant melanoma.10-12 Histological and immunohistochemical studies have been shown to support this hypothesis by showing the presence of normal melanocytes in the mucosa of the GI tract.13-16

Often, primary duodenal melanoma may be asymptomatic or may manifest with nonspecific clinical symptoms.17 In the advanced stage, it may present with upper GI tract bleeding or intestinal obstruction. Therefore, the diagnosis of primary intestinal melanoma has been a challenge, in combination with its rarity. Several criteria have been proposed.2,11 Among them, Sachs et al defined primary malignant melanoma in the small bowel with the following criteria: 1) biopsy-proved melanoma from the intestine at a single focus; 2) no evidence of disease in any other organs, including the skin, eye, and lymph nodes outside the region of drainage at the time of diagnosis; and 3) disease-free survival of at least 12 months after diagnosis. Our patient fits the 3 criteria of diagnosis. He was diagnosed with solitary biopsy-proved duodenal melanoma with absence of a cutaneous or choroidal lesion from thorough dermatological and ophthalmological examination performed by the experts. Moreover, the patient has been doing well 38 months after initial diagnosis.

Upper GI endoscopy and CT scanning remain the crucial modalities for the detection of lesions and diagnosis. Ultimately, immunohistochemical staining is needed to confirm the diagnosis. It is important to note that the sensitivity of S100 ranges between 33% and 100% whereas HMB-45 antibodies have a sensitivity of 80% to 97% and a specificity of 100%,13 respectively. To date, the incidence of metastasis in primary duodenal melanoma is not clear. Positron emission tomography is helpful for staging and identifying the sites of metastasis. There are few case reports in the literature of primary duodenal melanoma with liver and gallbladder metastasis.3,9,18,19 Our patient had asymptomatic brain metastasis on MRI, with a positron emission tomographic scan confirming no other avid disease after initial diagnosis of duodenal melanoma.

Surgical excision is the treatment of choice for duodenal melanoma. There is no standardized surgical strategy because of the overall low incidence and the complex anatomy of the duodenum, given its rich supply of blood vessels. Therefore, the surgical approach is tailored individually based on the expertise of the surgeons.20 Pancreaticoduodenectomy is applicable in all cases. For nonampullary lesions, partial duodenal resection and subtotal gastrectomy are deemed appropriate. Meanwhile, other methods, such as adjuvant radiotherapy and chemotherapy have not been shown to have concrete evidence of survival benefit. In addition, the presence of BRAF, NRAS, PTEN, and KIT mutations warrant the emergence of newer anticancer drugs for the treatment of melanoma. This option did not apply in this case because our patient had a BRAF-negative tumor.

Since 2011, immune checkpoint inhibitors have been approved for advanced melanoma treatment. Ipilimumab is a monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4. The newer immune checkpoint inhibitor is nivolumab, which is an antiprogram cell death 1 monoclonal antibody. In phase 3 of the CheckMate 067 trial, the median overall survival was 19.9 months with ipilimumab monotherapy and 36.9 months with nivolumab monotherapy, although the median overall survival of nivolumab plus ipilimumab was not reached at a minimum follow-up of 48 months.21-23 In our case, the patient developed grade 4 colitis after the first cycle of combined nivolumab and ipilimumab. Therefore, ipilimumab was discontinued. He continued to do well on nivolumab only, with an adverse effect of hypothyroidism that was subsequently controlled with levothyroxine.

Overall, the prognosis of duodenal melanoma is poor, mainly because of the delay in diagnosis. The 5-year survival of untreated primary GI melanoma is reported to be 14%, with a typical duration of survival of only 12.5 months.24,25 Among published case reports, Li et al26 reported a case of primary duodenal melanoma treated successfully by surgical excision, with the longest survival duration of more than 46 months with no reported relapse. Similarly, our patient has been doing well with no signs of relapse 22 months after curative resection.

CONCLUSION

Primary duodenal tumors are exceedingly rare; thus, they remain a controversial clinical entity. To our knowledge, our report is the first of its kind to report a case of primary duodenal melanoma with brain metastasis treated successfully by surgical excision, stereotactic radiosurgery, and immunotherapy with nivolumab.

Disclosure Statement

The author(s) have no conflicts of interest to disclose.

Funding

No funding was requested or required for this case report.

Author Affiliations

1Department of Internal Medicine, University of California Riverside, Riverside, CA

2Department of Internal Medicine, Kaiser Permanente, Riverside, CA

3Department of Pathology, Kaiser Permanente, Riverside, CA

4Department of Hematology and Oncology, Kaiser Permanente, Riverside, CA

Corresponding Author

Sonha Nguyen, MD (sonhanguyen29@gmail.com)

Author Contributions

Sonha Nguyen, MD and Naila Khan, MD performed a literature search and drafted the manuscript. Mary Le, MD assisted with histological images and revised the manuscript. Christine Duong, MD and Vishal Ranpura, MD supervised with patient care and revised the manuscript.

References

1. Elsayed AM, Albahra M, Nzeako UC, Sobin LH. Malignant melanomas in the small intestine: A study of 103 patients. Am J Gastroenterol 1996 May;91(5):1001–6. PMID:8633538.

2. Blecker D, Abraham S, Furth EE, Kochman ML. Melanoma in the gastrointestinal tract. Am J Gastroenterol 1999 Dec;94(12):3427–33. DOI: https://doi.org/10.1111/j.1572-0241.1999.01604.x, PMID:10606298.

3. Kilambi R, Singh AN, Dash NR, Madhusudhan KS, Das P. Primary giant aggressive amelanotic duodenal melanoma. Ann R Coll Surg Engl 2017 May;99(5):e131–4. DOI: https://doi.org/10.1308/rcsann.2016.0323, PMID:28462646.

4. McGovern VJ. Spontaneous regression of melanoma. Pathology 1975 Apr;7(2):91–9. DOI: https://doi.org/10.3109/00313027509092702, PMID:1153228.

5. Khalid U, Saleem T, Imam A, Khan M. Pathogenesis, diagnosis and management of primary melanoma of the colon. World J Surg Oncol 2011 Feb;9(1):14. DOI: https://doi.org/10.1186/1477-7819-9-14

6. Sanyal S, Kaman L, Behera A, Kakkar N. Primary small bowel melanoma: A case report. Trop Gastroenterol 2004 Oct–Dec;25(4):187–8. PMID:15912983.

7. Krüger S, Noack F, Blöchle C, Feller AC. Primary malignant melanoma of the small bowel: A case report and review of the literature. Tumori 2005 Jan–Feb;91(1):73–6. DOI: https://doi.org/10.1177/030089160509100114, PMID:15850009.

8. Atmatzidis KS, Pavlidis TE, Papaziogas BT, Papaziogas TB. Primary malignant melanoma of the small intestine: Report of a case. Surg Today 2002 Sept;32(9):831–3. DOI: https://doi.org/10.1007/s005950200161, PMID:12203066.

9. Kadivar TF, Vanek VW, Krishnan EU. Primary malignant melanoma of the small bowel: A case study. Am Surg 1992 Jul;58(7):418–22. PMID:1616187.

10. Bloch T, Tejada E, Brodhecker C. Malignant melanoma in Meckel’s diverticulum. Am J Clin Pathol 1986 Aug;86(2):231–4. DOI: https://doi.org/10.1093/ajcp/86.2.231, PMID:3739973.

11. Sachs DL, Lowe L, Chang AE, CarsonE, JohnsonTM. Do primary small intestinal melanomas exist? Report of a case. J Am Acad Dermatol 1999 Dec;41(6):1042–4. DOI: https://doi.org/10.1016/s0190-9622(99)70273-2

12. Krausz MM, Ariel I, Behar AJ. Primary malignant melanoma of the small intestine and the APUD cell concept. J Surg Oncol 1978;10(4):283–8. DOI: https://doi.org/10.1002/jso.2930100402, PMID:29168.

13. Clemmensen OJ, Fenger C. Melanocytes in the anal canal epithelium. Histopathology 1991 Mar;18(3):237–41. DOI: https://doi.org/10.1111/j.1365-2559.1991.tb00831.x, PMID:2045074.

14. de la Pava S, Nigogosyan G, Nigogosyan G, Pickren JW, Cabrera A. Melanosis of the esophagus. Cancer 1963 Jan;16(1):48–50. DOI: https://doi.org/10.1002/1097-0142(196301)16:1<48::aid-cncr2820160107>3.0.co;2-m

15. Stranks GJ, Mathai JT, Rowe-Jones DC. Primary malignant melanoma of the oesophagus: Case report and review of surgical pathology. Gut 1991 Jul;32(7):828–30. DOI: https://doi.org/10.1136/gut.32.7.828, PMID:1855693.

16. Joob AW, Haines GK 3rd, Kies MS, Shields TW. Primary malignant melanoma of the esophagus. Ann Thorac Surg 1995 Jul;60(1):217–22. DOI: https://doi.org/10.1016/s0003-4975(95)00084-4, PMID:7598604.

17. Lens M, Bataille V, Krivokapic Z. Melanoma of the small intestine. Lancet Oncol 2009 May;10(5):516–21. DOI: https://doi.org/10.1016/S1470-2045(09)70036-1, PMID:19410196.

18. Bendic A, Durdov MG, Stipic R, Karaman I. Melanoma in the ampulla of Vater. Hepatobiliary Pancreat Dis Int 2013 Feb;12(1):106–8. DOI: https://doi.org/10.1016/s1499-3872(13)60016-8

19. Anvari K, Gharib M, Jafarian AH, Saburi A, Javadinia SA. Primary duodenal malignant melanoma: A case report. Caspian J Intern Med 2018 Summer;9(3):312–5. DOI: https://doi.org/10.22088/cjim.9.3.312s, PMID:30197780.

20. Popivanov G, Tabakov M, Mantese G, et al. Surgical treatment of gastrointestinal stromal tumors of the duodenum: A literature review. Transl Gastroenterol Hepatol 2018 Sep;3:71. DOI: https://doi.org/10.21037/tgh.2018.09.04, PMID:30363779.

21. Hodi FS, Chiarion-sileni V, Gonzalez R, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-Year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol 2018 Nov;19(11):1480–92. DOI: https://doi.org/10.1016/s1470-2045(18)30700-9

22. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010 Aug;363(8):711–23. DOI: https://doi.org/10.1056/nejmoa1003466

23. Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015 Apr;16(4):375–84. DOI: https://doi.org/10.1016/s1470-2045(15)70076-8

24. Darouichi M. Invagination intestinale sur métastases multiples d’un mélanome malin [Intussusception on multiple metastases of malignant melanoma]. J Radiol. 2011 May;92(5):437–40. French. DOI: https://doi.org/10.1016/j.jradio.2011.03.015. Epub 2011 May 7. PMID: 21621111.

25. Patel JK, Didolkar MS, Pickren JW, Moore RH. Metastatic pattern of malignant melanoma. A study of 216 autopsy cases. Am J Surg 1978 Jun;135(6):807–10. DOI: https://doi.org/10.1016/0002-9610(78)90171-x, PMID:665907.

26. Li H, Fan Q, Wang Z, et al. Primary malignant melanoma of the duodenum without visible melanin pigment: A mimicker of lymphoma or carcinoma. Diagn Pathol 2012 Jun;7:74. DOI: https://doi.org/10.1186/1746-1596-7-74, PMID:22735126.

Keywords: brain metastasis, duodenal melanoma, nivolumab, stereotactic surgery

ETOC

Click here to join the eTOC list or text ETOC to 22828. You will receive an email notice with the Table of Contents of The Permanente Journal.

CIRCULATION

2 million page views of TPJ articles in PubMed from a broad international readership.

Indexing

Indexed in MEDLINE, PubMed Central, EMBASE, EBSCO Academic Search Complete, and CrossRef.


                                             

 

 

ISSN 1552-5775 Copyright © 2021 thepermanentejournal.org

All Rights Reserved