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Individual reprints of this article are not available. Address correspondence to Kelly V. Liang, MD, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, 200 First St SW, Rochester MN 55905
Malignant melanoma is one of the most common malignancies to metastasize to the gastrointestinal (GI) tract. Metastases to the GI tract can present at the time of primary diagnosis or decades later as the first sign of recurrence. Symptoms may include abdominal pain, dysphagia, small bowel obstruction, hematemesis, and melena. We report 2 cases of malignant melanoma metastatic to the GI tract, followed by a review of the literature. The first case is a 72-year-old man who underwent resection of superficial spreading melanoma on his back 13 years previously who presented with dysphagia. A biopsy specimen of a mucosal fold in a gastric fundus noted during endoscopy was taken and revealed metastatic malignant melanoma, which was resected 1 month later. Three weeks later, the patient was found to have an ulcerated jejunal metastatic melanoma mass, which was also resected. The second case is a 63-year-old man with an ocular melanoma involving the choroid of the left eye that had been diagnosed 4 years previously, which had been excised several times, who presented with anorexia, dizziness, and fatigue. He was found to have cerebellar and stomach metastases. He underwent adjuvant radiation therapy, chemotherapy, and surgical resection of the gastric melanoma metastasis. In patients with a history of melanoma, a high index of suspicion for metastasis must be maintained if they present with seemingly unrelated symptoms. Diagnosis requires careful inspection of the mucosa for metastatic lesions and biopsy with special immunohistochemical stains. Management may include surgical resection, chemotherapy, immunotherapy, observation, or enrollment in clinical trials. Prognosis is poor, with a median survival of 4 to 6 months.
Malignant melanoma is one of the most common malignancies associated with metastatic disease of the gastrointestinal (GI) tract. Metastases to the GI tract can present both at the time of primary diagnosis or several years later as the first sign of recurrence. Symptoms are generally identical to those caused by other GI tumors, including abdominal pain, fatigue, dysphagia, constipation, tenesmus, small bowel obstruction, perforated bowel, hematemesis, and melena. We report 2 cases of malignant melanoma metastatic to the GI tract, followed by a review of the literature.
REPORT OF CASES
Case 1
A 72-year-old man presented with dysphagia but no odynophagia. An upper esophagogastroduodenoscopy (EGD) revealed Candida esophagitis. However, during endoscopy, the patient was noted to have a mucosal fold in a gastric fundus from which a biopsy specimen was taken. The specimen revealed metastatic malignant melanoma. Immunostains showed that the neoplastic cells were positive for Melan A, S100, and tyrosinase, focally positive for c-kit, and negative for keratin, CAM 5.2, cytokeratin 7, and cytokeratin 20. These results confirmed the diagnosis of malignant melanoma (Figure 1). The patient had a Clark level II superficial spreading melanoma (thickness, 0.6 mm) on his lower back that had been resected 13 years previously. There was no evidence of ulceration, regression, or high mitotic rate (Figure 2). He had been followed up regularly by a dermatologist and previously remained free of obvious disease recurrence.
Figure 1Case 1. Stomach biopsy specimen. Gastric mucosa with involvement by metastatic melanoma (hematoxylin-eosin, original magnificatio×400); inset, immunostain (Melan A, original magnificatio×400).
Figure 2Case 1. Specimen from left flank skin excision. Superficial spreading malignant melanoma (Clark level II, Breslow depth of 0.6 mm; hematoxylin-eosin, original magnificatio×200).
The patient underwent staging with computed tomography (CT) of the head, chest, abdomen, and pelvis, which showed no other sites of the disease. Positron emission tomography (PET) was negative for hypermetabolic activity; in particular, no evidence existed of an increased uptake in the stomach. A CT of the head was negative for brain metastases. The patient then underwent wedge resection of the gastric cardia lesion, the results of which showed 2 metastatic melanoma nodules, the larger of which measured 2.8 cm in the largest diameter. Margins of the resection were negative.
Three weeks later, the patient was admitted for evaluation of anemia and melena. He underwent colonoscopy and extended upper EGD. The colonoscopy revealed no overt bleeding source. The extended EGD revealed an ulcerated, friable, dark pink mass that occupied half of the luminal circumference in the proximal jejunum that had undergone biopsy. The biopsy specimen of the jejunal mass revealed metastatic malignant melanoma. The patient underwent a small bowel follow-through the following day, which demonstrated the 2-cm sessile mass with central ulceration in the proximal jejunum and no other lesions.
The patient underwent surgical resection of the proximal jejunal melanoma lesion with a laparoscopic exploration and wedge resection of a segment of the fourth portion of the duodenum and proximal jejunum (duodenojejunostomy, side to side, stapled). The procedure revealed metastatic melanoma that involved the wall of the jejunum. Immunohistochemical stains showed that the neoplastic cells were strongly reactive for HMB-45. Furthermore, metastatic melanoma was identified in the regional lymph nodes (2 of 4).
The patient returned to the medical oncology department for follow-up several weeks after surgery, at which time skin and lung metastases were found. He was enrolledin a clinical trial of melanoma vaccine and after disease progression was enrolled in a phase 1 study of targeted therapy. Several months later he developed slurred speech and was found to have disease metastatic to the brain. He was treated with palliative radiation treatment to the whole brain (30 Gy in 10 fractions). After completion of palliative radiation therapy, the patient chose supportive treatment, was enrolled in hospice care, and died 2 months later.
Case 2
A 63-year-old man presented with a 10-day history of gradual-onset dizziness, fatigue, positional vertigo, decreased appetite, nausea, vomiting, and lethargy. He denied headaches or visual changes. Magnetic resonance imaging of the brain revealed an enhancing 3.0 × 3.5 × 2.5-cm mass in the right hemisphere of the cerebellum with surrounding edema. He underwent excision of the mass, which revealed metastatic malignant melanoma, followed by adjuvant radiation therapy (30 Gy in 10 fractions). A PET scan performed a few weeks later revealed a focal area of thickening in the superior aspect of the greater gastric curvature. The EGD revealed a 3-cm, ulcerated, bluish-pigmented, primarily submucosal mass in the location identified by PET. The biopsy specimen revealed metastatic malignant melanoma.
The patient had a history of ocular melanoma that involved the choroid of the left eye diagnosed 4 years previously with local recurrence 1 year later, which was treated with resection 3 times. He had also undergone a biopsy of the right eye, which produced benign results. He had not had any further eye examinations on a regular basis.
The patient was evaluated for surgical resection of the stomach metastasis, but surgery was deferred until he fully recovered from the brain surgery. He subsequently received 2 cycles of temozolomide chemotherapy, complicated by loss of appetite, generalized fatigue, and weakness. He underwent gastric wedge resection of the stomach melanoma metastasis, which revealed metastatic melanoma that formed a 5.0 × 4.8 × 2.1-cm mass that extensively involved the submucosa and muscularis propria, causing ulceration of the mucosa. The mucosal resection margins were negative for tumor. Immunohistochemistry stains revealed neoplastic cells positive for S100, HMB-45, and Melan A and showed no staining for keratin (Figure 3).
Figure 3Case 2. Specimen from stomach resection. Metastatic melanoma (hematoxylin-eosin, original magnification ×400); inset, immunostain (Melan A, original magnificatio×400).
The patient did well postoperatively. Brain magnetic resonance imaging 1 month later revealed no evidence of recurrent tumor in the cerebellum but showed a new metastasis present at the left frontal operculum with moderate surrounding vasogenic edema. He subsequently underwent stereotactic radiosurgery with gamma knife for the frontal metastasis. Two months later, he developed recurrent brain and pulmonary metastases. He underwent several more gamma knife surgical procedures for progressive brain metastases and ultimately enrolled in the hospice program.
DISCUSSION
A review of the literature was performed using Ovid MEDLINE with the subject headings melanoma and gastrointestinal tract and the keyword metastatic to search for all case reports and reviews published on malignant melanoma metastatic to the GI tract. References cited in case series and case reports were hand searched to obtain all related relevant articles. Similar searches were performed using PubMed and EMBASE.
Malignant melanoma that involves the GI tract may be either primary or metastatic.
Primary GI melanoma can arise in various GI mucosal sites, including the oral cavity, esophagus, small bowel, colon, rectum, and anus, in the absence of prior cutaneous melanoma.
Primary melanomas of the GI tract are rarely diagnosed at an early stage, tend to be more aggressive, and are associated with a worse prognosis. Distinguishing between a primary GI mucosal melanoma and a melanoma metastatic to the GI tract from an unknown or regressed cutaneous primary may be difficult.
such as junctional melanocytic proliferation within the mucosa. In contrast, metastasis from spontaneous regression of primary cutaneous melanoma is characterized histologically by lymphocytic infiltration of the dermis with melanophages, vascular proliferation, and reparative fibrosis.
Clinically, a primary GI mucosal melanoma is suggested if the patient has no obvious primary cutaneous melanoma or has an isolated GI lesion without other extraintestinal metastases.
An autopsy series of 216 patients with advanced malignant melanoma at Roswell Park Memorial Institute suggested that GI metastasis is second only to the lung in sites of organ metastatic disease.
The most common sites of metastases were the lymph nodes (73.6%) and lungs (71.3%), followed by the liver (58.3%), brain (54.6%), bone (48.6%), and adrenal glands (46.8%). The incidence of GI metastases was 43.5%.
Multiple organ involvement of metastases was common (95%). The distribution of GI organ metastases in this series was as follows: liver, 58.3%; peritoneum, 42.6%; pancreas, 37.5%; small bowel, 35.6%; spleen, 30.6%; colon, 28.2%; stomach, 22.7%; oral cavity andesophagus, 9.3%; and biliary tract, 8.8%.
A large review of autopsies from Memorial Sloan Kettering Cancer Center previusly found the incidence of GI metastases to be as follows: liver, 68%; small bowel, 58%; colon, 22%; stomach, 20%; duodenum, 12%; rectum, 5%; esophagus, 4%; and anus, 1%.
In ocular malignant melanoma, the most common site of metastasis was the liver, and single organ involvement was found in almost one third of patients.
Similarly, the 7-year experience at Tianjin Medical University Cancer Hospital (1989-1996) found small bowel metastases in 7.8% of malignant melanomas detected during that period.
Because it is the most common subtype of melanoma, superficial spreading melanoma is the most common subtype to metastasize to the GI tract, although all the histological subtypes of cutaneous melanoma may metastasize to the GI tract.
They usually appear as multiple ulcerated polypoid lesions and may be either pigmented or amelanotic. Metastases may present both at the time of primary diagnosis or decades later as the first sign of recurrence. Symptoms often mimic those of other GI tumors, including abdominal pain, fatigue, dysphagia, constipation, tenesmus, small bowel obstruction, perforated bowel, hematemesis, melena, and anemia.
Presentation of small intestinal metastatic melanoma has been reported to cause intussusception that results in small bowel obstruction and a retroperitoneal mass, both requiring laparatomy.
One case report described melanoma metastatic to the ampulla of Vater, causing progressive jaundice and melanotic stools, that was treated with pancreaticoduodenectomy (Whipple procedure).
Similar to our second case, a previous case report described a man with ocular melanoma who presented with intestinal subocclusion, weight loss, and a left paraumbilical palpable mass, which was found to be melanoma metastatic to the small intestine.
Therefore, persistent nonspecific complaints, such as vague abdominal pain, weight loss, anorexia, or fatigue, should lead to suspicion of melanoma metastatic to the GI tract in patients who have a history of melanoma.
Diagnosis of metastatic melanoma is generally made by radiographic contrast studies, including CT, ultrasonography, and barium studies, and endoscopic evaluation, including EGD, endoscopic retrograde cholangiopancreatography, and colonoscopy.
Therefore, further studies should be undertaken even if CT is negative. In addition, since small intestinal metastases are more common than esophageal or stomach metastases, all patients undergoing upper GI tract series should also have a small bowel follow-through. Metastatic lesions may be intraluminal masses, ulcerating lesions, diffusely infiltrating lesions, or mesenteric implants.
Biopsy of masses either endoscopically or during surgery (laparotomy) often secures the diagnosis. Special immunohistochemical stains, including HMB-45 and S100, are particularly useful in confirming the diagnosis of metastatic melanoma.
The prognosis of patients with metastatic malignant melanoma is poor. Studies suggest a mean survival of patients with systemic metastases from melanoma to be only 6 to 8 months.
Patients with lung-only metastases and normal lactate dehydrogenase levels have better prognoses than patients with metastasis to other visceral organs, including the GI tract, or elevated lactate dehydrogenase levels. This observation has been reflected in the melanoma staging system (stage IV with M1c disease).
Cutaneous malignant melanoma (Arizona Cancer Center experience), I: natural history and prognostic factors influencing survival in patients with stage I disease [published correction appears in Cancer. 1989;63:1436].
Disease progression in patients with thin cutaneous melanomas (tumour thickness ≥0.75 mm): clinical and epidemiological data from the Tumour Center Munich 1977-98.
Among thin melanomas, superficial spreading melanoma was the most frequent subtype (76.2%) in a large retrospective study of 2302 patients with thin cutaneous melanoma lesions.
Disease progression in patients with thin cutaneous melanomas (tumour thickness ≥0.75 mm): clinical and epidemiological data from the Tumour Center Munich 1977-98.
Because of the high prevalence, superficial spreading melanoma was also most frequent among patients with recurrent thin melanoma (51 of 77 patients). In contrast, nodular melanoma, acrolentiginous melanoma, lentigo maligna melanoma, and unclassified melanoma were present in 6, 4, 10, and 6 of the 77 patients, respectively.
Disease progression in patients with thin cutaneous melanomas (tumour thickness ≥0.75 mm): clinical and epidemiological data from the Tumour Center Munich 1977-98.
Clinical characteristics associated with increased risk of disease progression in thin cutaneous melanomas included male patients and patients with lentigo maligna melanoma or acrolentiginous melanoma, which may be explained by their frequent location in the head and neck region.
Disease progression in patients with thin cutaneous melanomas (tumour thickness ≥0.75 mm): clinical and epidemiological data from the Tumour Center Munich 1977-98.
Other authors have also found axial primary tumor site, Clark level III or IV, severe histological regression, ulceration, and high mitotic rate to be significant prognostic risk factors for disease progression in thin melanomas (variably defined as <0.76 mm, <0.5 mm, or <1.0 mm).
The patient described in case 1 had initially presented with a thin (0.6-mm-thick) superficial spreading melanoma yet developed a late metastasis. The initial biopsy specimen showed no ulceration, regression, high mitotic rate, or other features that could explain an increased risk of subsequent progression.
Treatment of metastatic melanoma to the GI tract may include surgical resection, chemotherapy, immunotherapy, biochemotherapy, observation, or participation in clinical trials. However, the immunocompromised state caused by chemotherapy may cause serious complications in patients with GI tract involvement.
Several studies have reported on the efficacy and improvement in mortality associated with surgical resection for melanoma metastases in both the GI tract and other distant sites.
Using the Melanoma Registry, which contains data on more than 1100 patients with melanoma who underwent surgery at the University of Alabama at Birmingham during a 20-year period, Wornom et al
reported on the outcomes of 65 patients who underwent surgical excision of 94 metastatic lesions from the brain, lung, abdomen, distant subcutaneous sites, and distant lymph nodes. Relief of symptoms was obtained in 77% to 100% of patients in the various subgroups, with symptomatic relief in 100% of patients with abdominal metastases. Median survival ranged from 8 to 15 months in the various subgroups, and 16% of patients lived for 2 years or longer.
described 3 patients with melanoma metastatic to the small bowel, all of whom underwent surgical resection. Two patients remained well 6 and 2 years after surgery, respectively, whereas 1 patient died of metastatic melanoma within the abdomen 4 years after surgery. Ollila et al
reported on a retrospective review of 124 of 6509 melanoma patients who had GI tract metastases at the John Wayne Cancer Institute from 1971 through 1994. Of these 124 patients, 69 (56%) underwent surgical exploration of the abdomen, of which 46 (67%) had curative resection and 23 (33%) had a palliative procedure only. Almost all (97%) of the 69 surgical patients experienced symptomatic relief postoperatively. The median survival of patients undergoing curative resection was 48.9 months compared with only 5.4 months in patients undergoing palliative procedures and 5.7 months in patients undergoing nonsurgical interventions. Morbidity and mortality were minimal. On multivariate analysis, the 2 most important prognostic factors for long-term survival were resection with curative intent and the GI tract as the initial site of distant metastasis. Five-year survival in the curative resection group was 41%.
However, these survival numbers may be somewhat better because of selection bias in a specialized cancer center. Other authors have also reported improved survival and palliation of symptoms after resection of both solitary and multiple small bowel metastatic melanoma lesions.
Taking into account the results of these studies collectively, in patients with melanoma metastatic to the GI tract, particularly if the GI metastasis is the first site of stage IV disease, curative surgical resection should be strongly considered both for palliation of symptoms and improvement in mortality.
Unfortunately, most patients with completely resected melanoma metastases will experience a disease relapse. Consequently, there is an interest in developing adjuvant therapeutic strategies to prevent recurrence. Completely resected metastatic melanoma is a potential target for immune therapy. Since the bulk of the tumor is surgically removed, it is believed that the immune system, if stimulated, will be able to eliminate microscopic disease and overcome tumor-induced tolerance. Although some of the uncontrolled phase 2 studies suggest modest survival benefit with such an approach,
so far, no survival benefits of adjuvant therapy have been demonstrated in randomized trials. Other approaches that use antiangiogenesis agents are also under investigation. Therefore, eligible patients should be considered for involvement in clinical trials. In the current reported cases, the patients underwent curative resection but unfortunately their metastatic disease continued to progress to other distant sites.
CONCLUSION
In patients with a history of melanoma, a high index of suspicion for metastasis needs to be maintained if they present with seemingly unrelated symptoms. Malignant melanoma has a predisposition to metastasize to the GI tract, so metastatic disease must be strongly considered in the differential diagnosis of patients who present with anemia and melena. Diagnosis requires careful inspection of the mucosa for metastatic lesions and biopsy with special immunohistochemical stains (HMB-45 and S100). Prognosis is poor, with a median survival of only 4 to 6 months. Treatment may include surgical resection for isolated metastases or for palliation, chemotherapy, immunotherapy, biochemotherapy, observation, or participation in clinical trials. Studies have shown that surgical resection for melanoma metastatic to the GI tract may be effective for palliation and may result in long-term survival in selected patients.
REFERENCES
Schuchter LM
Green R
Fraker D
Primary and metastatic diseases in malignant melanoma of the gastrointestinal tract.
Cutaneous malignant melanoma (Arizona Cancer Center experience), I: natural history and prognostic factors influencing survival in patients with stage I disease [published correction appears in Cancer. 1989;63:1436].
Disease progression in patients with thin cutaneous melanomas (tumour thickness ≥0.75 mm): clinical and epidemiological data from the Tumour Center Munich 1977-98.
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