Primary Gastric Malignant Melanoma in a 68-Year-Old Woman: A Case Report and Review of the Literature.

Non-cutaneous melanoma is a very rare clinical entity. Gastric melanoma can be primary or secondary, but determining their nature is in most cases very challenging. To date, very few cases of primary gastric melanoma have been described in the literature. We report the first case of primary gastric melanoma documented in a Romanian patient, confirmed through clinical, imagistic, and pathological diagnosis. A 68-year-old female patient presented to our hospital with complaints of dyspepsia, abdominal pain, and weight loss. Esophagogastroduodenoscopy revealed two large sessile masses in the gastric fundus, which was histologically compatible with melanoma; immunohistochemistry staining was positive for vimentin, S100 protein, HMB45 antibody and Melan A/MART1, and negative for pan-CKAE1/AE3, leukocyte common antigen and DOG1. Extensive dermatological and ophthalmological examinations did not identify a primary lesion. The patient was therefore diagnosed with primary melanoma of the stomach. At the time of the diagnosis, multiple bone and pulmonary metastases were detected and considering the poor general status of the patient, surgery was not recommended. She died three months following diagnosis. A review of the literature identified only 32 other reported cases of primary gastric melanoma, all in individuals ≥50 years of age and most of them in male patients. Partial or total gastrectomy was the usual treatment of choice, but prognosis was overall poor. Awareness of this rare condition must be increased among healthcare providers, as early detection can improve survival chances.

Introduction

Gastric cancer is one of the most common malignancies worldwide, accounting for 26% of the global cancer incidence and 35% of all cancer-associated deaths [1].

While malignant gastric metastases of cutaneous origin are a common occurrence, non-cutaneous melanoma of the gastrointestinal tract, termed primary gastrointestinal melanoma, can rarely arise from the mucosal membrane lining the digestive tract [2].

The prevalence of primary gastrointestinal melanomas is of 0.5-1 case per million.

The greatest incidence is in the anorectal (31.4% in the anal canal, and 22.2% in the rectum) and oropharyngeal (32.8%) region, whereas the esophagus (5.9%), stomach (2.7%), small bowel (2.3%), gallbladder (1.4%), and large bowel (0.9) are low-incidence sites of occurrence [3].

Primary gastric melanoma is a rare clinical condition, with less than 50 cases documented so far [4,5], that has an aggressive behavior and poor prognosis at diagnosis.

We present the case of a 68-year-old woman with two large stomach tumors, which were shown to be malignant melanomas.

Detailed clinical, laboratory and imaging investigations did not identify an alternative primary site.

To our knowledge, this is the first case of primary gastric melanoma documented in a patient in Romania.

Case presentation

A 68-year old woman presented to the department of gastroenterology at the Lotus Image Hospital from Targu Mures complaining of nausea and vomiting, abdominal pain, more pronounced in the left hypochondrium and lumbar division, and recent weight loss.

The patient had a history of diabetes mellitus type II requiring insulin administration, arterial hypertension, and discopathy of the thoracic and lumbar segments.

She denied smoking and reported occasional use of alcohol, and her family’s history was deemed noncontributory.

Physical examination revealed epigastric tenderness.

We specify that patient tutor expressed her informed consent for data processing and publication.

Esophagogastroduodenoscopy was performed, and demonstrated two sessile masses in the gastric fundus (Figure 1) ranging from 2.5 to 3cm, with ulcerated overlying mucosa.

Figure 1

Upper endoscopy revealed two large, crater-like ulcerated lesions in the gastric fundus, ranging from 2.5 to 3cm (A, B)

Two biopsy samples were collected.

An abdominal and pelvic magnetic resonance imaging (MRI), performed later in our clinic, demonstrated the endoscopically visualized masses, measuring 1.45×1.9cm and 2.8×2.4cm (Figure 2).

Figure 2

Magnetic resonance images showing two wall thickening enhancing masses in the gastric fundus, measuring 1.45×1.9cm (A) and 2.8×2.4cm (B): The tumors are irregular, with restricted diffusion. (A) The mass exhibited a heterogeneous mild hypointensity on T2-weighted imaging. (B) On enhanced imaging, the lesion was unevenly enhanced

The MRI also revealed secondaries in the pelvic gridle, left and right adrenal adenomas, and fibromatous nodules on the uterus.

The patient was soon after hospitalized at the Oncology Department of a local hospital, under suspicion of gastrointestinal stromal tumor.

While hospitalized, the results of the histological examination became available.

The histologic examination revealed sheets or individual cells infiltrating the mucosa and submucosa of stomach.

The tumor cells were pleomorphic rounded-epithelioid with hyperchromatic nuclei or vesicular chromatin and eosinophilic, prominent nucleoli.

A low quantity of stroma with reduced desmoplasia and minimal lymphocytic and neutrophilic infiltrate was evidenced.

Some of the cells were dyscohesive, with no identifiable pigment.

No necrosis was observed in the examined slides (Figure 3).

Figure 3

Hematoxylin and eosin sections of the endoscopic biopsy, at 40×magnification: sheets or individual cells infiltrating the mucosa and submucosa of stomach. Tumor cells are pleomorphic rounded-epithelioid with hyperchromatic nuclei or vesicular chromatin and eosinophilic, prominent nucleoli. Some cells are dyscohesive, lacking pigmentation. No necrosis was identified in the examined mass.

Immunohistochemical (ICH) staining was performed to identify the origin of the tumor cells and allow differential diagnosis.

Initial ICH showed that tumor cells were negative for pan-CKAE1/AE3 and leukocyte common antigen, and positive for vimentin (Figure 4A) and S100 protein (Figure 4B).

Figure 4

Photomicrograph of endoscopic biopsy showing staining of large tumor cells, at 40×magnification: (A) vimentin with cytoplasmatic expression; (B) S100 protein-nuclear and cytoplasmatic expression in tumor cells; (C)HMB45 antibody-cytoplasmatic positive tumor cells; (D) Melan A/MART1-membranous and cytoplasmatic staining in tumor; (40x).

Subsequent ICH examination revealed negative reaction for DOG1 and positive for HMB45 (Figure 4C) and Melan A/MART1 (Figure 4D), leading to a diagnosis of malignant melanoma.

Further genetic analysis detected a V600E mutation of the BRAF gene.

The histological, ICH and genetic analysis were performed in "Radusan" histology and cytopathology laboratory from Cluj Napoca.

While hospitalized, subsequent examination by thoracic, abdominal and pelvic computer tomography confirmed previous MRI findings and also showed multiple bone and pulmonary secondaries.

Thorough hematological, gynecological, dermatological and ophthalmological consults were also conducted.

The patient was released after three weeks, with a diagnosis of primary melanoma of the stomach.

In view of her deteriorated health status, the patient received pain-management treatment in outpatient setting.

Two weeks after release from the hospital, the patient was admitted in the emergency department due to hematemesis.

Severe secondary anemia was detected (hemoglobin 7.10g/dL; hematocrit 22%).

Endoscopy revealed laminar bleeding of one of the tumors, which could not be stopped upon administration of adrenalin (1:10000 solution) and surgical consult was requested.

Due to the poor general health state, the surgeon recommended conservative treatment.

Hemostatic treatment was administered for a week, with the patient’s condition (including the anemia) improving slightly (hemoglobin 9.40g/dL; hematocrit 27.6%).

After release from the emergency department, one week later, the patient continued to undergo palliative therapy.

Unfortunately, she subsequently died from disease progression at three months from diagnosis.

Discussions

Primary gastric melanomas are very rare occurrences, with very few cases reported in female patients worldwide so far.

Following a search on PubMed using the terms "primary gastric melanoma", “primary gastric malignant melanoma", “primary melanoma of the stomach” and "primary gastric mucosal melanoma" we identified 32 cases [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37] in the literature.

All cases except one were reported in patients aged ≥50 years and most in male patients. Only 10 of the 32 cases were described in women.

These data seem to indicate a higher risk of primary gastric melanoma in men than in women, although this interpretation is limited by the apparent extremely low incidence of the disease.

Nevertheless, a higher risk of developing melanoma was identified for men than for women, with the relative incidence ratio between genders increasing with age [38].

A recent systematic literature review on surgically treated cases only, identified 25 cases and estimated a 5-month period for recurrence, with only 12% of patients surviving after five years from diagnosis [5].

Another systematic literature review on cases comparing the 1-year survival in patients who underwent surgery with patients who did not receive treatment, also identified 34 cases, and showed that 1-year survival was 56.5% with surgery, rising to 66% with adjuvant therapy [4]

The timely diagnosis of primary gastric melanoma is challenging.

Initial symptoms can be misleading, with some patients reporting only severe fatigue and/or weight loss [8,10,12,16,21,23,26,34], although laboratory analyses often indicate severe anemia as an underlying condition.

These non-specific symptoms may lead to a delayed presentation to the physician, which impacts the overall survival.

However, in the literature, melena, gastric pain, vomiting and/or hematemesis were more often reported [6,13,14,20,22,27,28,29,30,35,37] as the initial cause for contacting a healthcare provider and all these symptoms suggest gastric involvement.

In the cases identified in the literature, gastric endoscopy was reported as the most frequent means used to detect the tumor and collect a biopsy sample.

Due to the limited number of cases of primary gastric melanomas, the physicians’ awareness is no doubt low, and it is likely that initial misdiagnosis as gastrointestinal stromal tumor or adenocarcinoma occurs, especially if pigmentation is not present [21,27,32].

In the absence of melanin, diagnosis based on histopathology findings only can prove challenging.

Very often, for primary gastrointestinal melanomas, tumor cells from the basal layer of epithelium are observed to extend in the more superficial epithelium in pagetoid manner [39,40].

However, there is no typical presentation of the tumor cells.

In advanced melanomas, different cell types (spindled, plasmacytoid and epithelioid) in various arrangements (sheet-like, organoid/alveolar, neutrophic or desmoplastic) can be present [5,32].

Morphologically, gastric melanomas can mimic poorly differentiated adenocarcinomas, gastrointestinal stromal tumors, or lymphomas [5,12,41].

However, immunostaining methods can help in establishing the correct nature of the tumor.

Melanomas are positive for S100 protein, HMB45 antibody, and MART-1/Melan A, with negative staining in the presence of vimentin being used to rule out melanoma [42].

In our case, all these markers were positive, leading to the initial suspicion of melanoma.

Moreover, negative markers in our case were panCKAE1/AE3, excluding epithelial origin of the tumor, and leukocyte common antigen, excluding lymphoid proliferation.

Subsequent analysis also excluded gastrointestinal stromal tumor, as the samples were DOG1 negative.

While all these findings indicate the primary nature of the tumor, an exhaustive examination was carried out in order to fully exclude a cutaneous source.

Previously proposed criteria for diagnosis of mucosal melanoma include the absence of concurrent lesions and no history of melanoma or removal of atypical melanocytic lesions from the skin or other organs, lack of other organ involvement, or a 12-month timeline for disease-free survival following diagnosis [39].

In our case, two lesions were detected; multiple tumors were reported only for four other cases in the literature [13,15,25,28].

Detailed examination of our patient excluded another primary tumor, but the disease was already advanced at the time of diagnosis and multiple metastases were present.

Our case is also one of the few reported in the literature where a BRAF mutation was identified.

While fairly common for cutaneous melanomas, BRAF mutations are rare in mucosal melanomas [43] and have a different profile from that detected in skin tumors [44].

Among the case reports identified through our literature search, three described a V600E BRAF mutation [9,14,29], as in our case, and another, an even rarer V600R one [10].

However, testing was not performed for most reviewed cases, while in one instance, it returned negative results [31].

So far, there are no clear guidelines for the treatment of primary gastric melanoma.

Even if the condition is detected in its incipient phase, surgical resection is preferred when possible.

In our case, the patient’s poor general health and the fact that the tumor had already metastasized in multiple organs ruled out surgical intervention and only palliative care was offered.

In 22 out of the 32 cases of primary gastric melanoma reviewed, partial or total gastrectomy was performed.

The outcome was not always reported.

However, for eight of these cases, the patient was disease-free at last follow-up, which varied between four months and six years post-surgery [7,12,22,26,32,33,34,37].

In other eight cases, the patients died within 12 days to one year due to disease progression [6,8,10,11,13,14,16,35].

Chemotherapy, immunotherapy, radiotherapy or lesion resection combined with immunotherapy were also attempted, with mixed survival outcomes [9,15,18,20,21,23,25,31].

Treatment with a BRAF-inhibitor (vemurafenib) for a patient with V600 mutation led to no disease progression for six months, and ipilimumab was used as second line therapy.

However, the patient died within 12 months from diagnosis [9].

For a patient with multiple gastric melanomas, surgery followed by immunotherapy was successful, with the patient in good general health at two years post-last surgical intervention [25].

In the absence of established guidelines, the most suitable treatment for primary gastric melanoma must currently be identified on a case-by-case basis and no outcome prognosis is available.

Conclusions

The late detection of a primary gastric melanoma, which had already metastasized at the time of the diagnosis, led to a lack of treatment options and eventually resulted in the patient’s death within three months from diagnosis.

A review of the literature indicated an overall poor prognosis for primary gastric melanoma, even if gastrectomy is performed.

Accurate diagnosis relies on histopathology findings and IHC staining for melanoma markers such as SOX10, S100, and HMB-45.

To improve survival, early detection is critical, and therefore awareness on this very rare cancer must be risen among gastroenterologists and oncologists.

Conflict of interests

The authors declare that they have no competing interest.