Clinicopathologic Observations on Primary Malignant Melanoma of the Digestive Tract

Introduction

Primary malignant melanoma of the digestive tract represents a rare clinical entity, with approximately 50% of tumors arising in the rectal/anal verge region. Primary malignant melanoma of the digestive tract frequently poses diagnostic challenges due to its morphological overlap with conventional rectal adenocarcinoma. Given the aggressive biological behavior and dismal prognosis associated with this malignancy, heightened diagnostic vigilance is warranted during histopathological evaluation. Through retrospective analysis of 21 confirmed primary malignant melanoma of the digestive tract tumors, this study performs a comprehensive clinicopathological analysis to enhance recognition and optimize diagnostic accuracy for this underdiagnosed disease entity.

Data and Methods

Results

Pathological Morphology

(1) Gross examination: Seventeen patients presented with elevated masses (Figure 1), while four patients exhibited ulcerated-infiltrated masses. Eighteen patients featured solitary masses, with maximum diameters ranging from 1.3 to 13.5 cm (mean: 4.91 cm). Three patients demonstrated multiple masses, with the number of tumors ranging from two to four. (2) Microscopic observation: The tumors display diverse architectural patterns, including diffuse (Figure 2), trabecular (Figure 3), papillary (Figure 4), and vesicular arrangements (Figure 5). Pigmentation was evident in 11 tumors, while 10 tumors were non-pigmented. Tumor morphology was heterogeneous, featuring spindle-shaped (Figure 6) and epithelioid forms (Figure 7). In two tumors, tumor cells exhibited clear cytoplasm with eccentrically displaced nuclei, resembling signet-ring cell morphology (Figure 8). High-power examination revealed distinct cellular pleomorphism, with round, vacuolated nuclei containing prominent eosinophilic nucleoli. Mitotic figures were readily observable. Analysis of tumor invasion depth revealed that seven tumors infiltrate the submucosa, six tumors infiltrated the muscularis propria, and eight tumors infiltrated the entire wall. Lymph node metastasis was detected in six patients (Figure 9). Immunohistochemical Findings: Tumor cells showed diffuse positivity for vimentin (Figure 10), S-100 (Figure 11), and SOX10 (Figure 12), with positive staining for HMB45 and melan-A. Tumor cells were uniformly negative for keratin 5/6, keratin (Figure 13), p63, CHGA, SYP (Figure 14), desmin, CDX2, CD20, and PAX-5. One tumor demonstrated focal DOG-1 positivity in approximately 10% of tumor cells, while DOG-1 was negative in the tumor cells of the remaining cases. The Ki-67 proliferation index ranges from 10% to 70%. Among the three patients with multiple tumors, the first patient was a 66-year-old man, who presented with two esophageal tumors measuring 1 cm and 3 cm in maximum diameter, both appearing as bulging masses. Histopathological analysis demonstrated full-thickness infiltration of the esophageal wall, with no evidence of lymph node metastasis. The second patient was a 68-year-old woman presenting with four tumors, all situated within the ileum. The specimens were submitted for pathological examination as follows: A segment of the intestine measuring 23 cm in length with a maximum diameter of 7.0 cm was received. The intestinal lumen was dilated, with focal thinning of the intestinal wall and intussusception involving an approximately 11.0 cm segment. The intestinal mucosa exhibited marked edema, covering an area of 11 cm × 6 cm. A protruding mass (Mass 1), measuring 8 cm × 5 cm × 4.5 cm, was identified 8 cm from the intussuscepted end (21 cm from the opposite cut edge). Another protruding mass (Mass 2), measuring 4.5 cm × 4 cm × 3 cm, was noted 12 cm from the intussuscepted end (15 cm from the opposite cut edge). The cut surfaces of both masses appeared grayish-white to grayish-brown and were soft in texture. Two polypoid protrusions, measuring 2 cm and 2.7 cm in diameter, respectively, were observed 13 cm from the masses. Pathological diagnosis: Both masses and the two polyps were confirmed as malignant melanoma with ulceration of the mucosal surface. Mass 1 infiltrated into the muscularis propria, Mass 2 infiltrated into the submucosa, and the two polyps infiltrate into the submucosal layer. The third patient was a 68-year-old man, who presented with two rectal tumors measuring 4.5 cm and 3.5 cm in maximum diameter, both appearing as bulging masses. Histological examination revealed tumor infiltration into the rectal muscular layer with associated lymph node metastasis.

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Figure 1.

Melanin deposits are present around the tumor.

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Figure 2.

Tumor cells are diffusely arranged. (H&E, × 100).

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Figure 3.

Tumor cells are arranged in a trabecular pattern. (H&E, × 100).

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Figure 4.

Tumor cells are arranged in a papillary pattern. (H&E, × 100).

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Figure 5.

Tumor cells are arranged in an acinar pattern. (H&E, × 100).

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Figure 6.

Tumor cells are spindle-shaped. (H&E, × 400).

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Figure 7.

Tumor cells are epithelioid. (H&E, × 400).

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Figure 8.

Tumor cells with transparent cytoplasm, pushing the nucleus to one side (H&E, × 400).

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Figure 9.

Tumor lymph node metastasis (H&E, × 200).

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Figure 10.

Tumor cells are vimentin positive (IHC, × 200).

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Figure 11.

Tumor cells are S100 positive (IHC, × 400).

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Figure 12.

Tumor cells are SOX10 positive (IHC, × 400).

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Figure 13.

Tumor cells are keratin negative (IHC,×200).

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Figure 14.

Tumor cells are SYP negative (IHC, × 400).

Discussion

Primary mucosal malignant melanoma is an exceedingly rare neoplasm, constituting merely 1% of all malignant melanomas. Within the digestive tract, primary malignant melanoma is particularly uncommon, with a predilection for the rectum and esophagus. Notably, 50% of these digestive tract melanomas arise in the anorectal region. Anorectal malignant melanoma represents approximately 1% of all malignant rectal tumors and 0.3%–1% of all malignant melanomas. These tumors are characterized by their highly aggressive nature, poor prognosis, and elevated mortality rates. Epidemiological studies indicate that women have a 1.6-fold higher risk of developing this condition compared to men, with a mean age at diagnosis of 71 years. Common clinical presentations include hematochezia and altered bowel habits.^1–3

Esophageal primary malignant melanoma is even more rare, accounting for only 0.1% to 0.2% of esophageal neoplasms and 0.5% of all non-cutaneous melanomas. Current literature primarily consists of case reports, with Wang et al ⁴ providing a comprehensive analysis in 2019 by summarizing clinicopathological data from 76 patients. Their findings revealed a male predominance with a male-to-female ratio of 2.17:1 and a mean age of onset at 60.5 years. Interestingly, most patients were asymptomatic at diagnosis, though some presented with dysphagia. Macroscopic examination showed that 92.1% of tumors were located in the middle and lower thirds of the esophagus, with microscopic analysis revealing that over half of the tumors infiltrated beyond the muscularis propria. Surgical intervention, particularly subtotal esophagectomy or esophagogastrectomy with lymph node dissection, was the primary treatment modality, performed in 77.6% of tumors.^5,6

Primary malignant melanoma of the small intestine represents an exceptionally rare and highly aggressive variant. Its insidious nature, compounded by the organ's concealed anatomical location and the absence of early symptoms, often results in advanced-stage presentation at diagnosis, leading to an exceptionally poor prognosis. ⁷ While small bowel involvement typically occurs as a secondary site from cutaneous lesions, primary small intestinal melanoma itself is extraordinarily rare, with only a handful of documented tumors in medical literature.

Regarding the pathogenesis of primary malignant melanoma of the digestive tract, three main hypotheses have been proposed. The first suggests that while melanocytes are not typically present in the small and large intestines, they can occasionally be found in the mucosal epithelium of the gastrointestinal tract and in lymph nodes. These sporadic melanocytes may give rise to primary malignant melanoma at these sites. ⁸ The second hypothesis posits that primary malignant melanoma of the digestive tract originates from Schwann cells associated with the autonomic innervation of the gut. ⁹ The third hypothesis proposes that these melanomas may arise from neural crest cells that migrate to the digestive tract mucosa during embryonic development. Specifically, these cells migrate through the umbilical-gut pathway and differentiate into amine precursor uptake and decarboxylation (APUD) cells. These APUD cells have the potential to undergo malignant transformation, leading to the development of tumors such as gastrinomas, carcinoid tumors, and malignant melanomas. ¹⁰

In terms of histomorphology, primary malignant melanoma of the digestive tract exhibits a wide range of morphological variants, which can resemble epithelial, hematopoietic, neural, and mesenchymal tissues. Tumor cells may form various structures, including nested clusters, trabecular, glandular, swirling, and papillary patterns. Additionally, they can differentiate into diverse cell types such as Schwann cells, fibroblasts, myofibroblasts, rhabdomyoblasts, osteoblasts, chondroblasts, ganglion cells, and smooth muscle cells.^11–13 Microscopically, the tumor cells can display significant morphological diversity, appearing either epithelioid or spindle-shaped. The cytoplasm may also exhibit various features, including imprinted cells, clear cells, balloon-like cells, rhabdomyoblasts, and a plasma cell-like appearance. ¹⁴

Signet-ring cell-like primary malignant melanoma of the digestive tract is an exceptionally rare histomorphological pattern. This pattern was first described by Sheibani and Battifora in 1988 in the context of malignant melanoma. To date, only 22 tumors have been reported, with just two involving the signet-ring cell-like variant in primary malignant melanoma of the digestive tract. This rarity makes diagnosis particularly challenging. ¹⁵ Consequently, confirming the diagnosis of primary malignant melanoma of the digestive tract often requires immunohistochemical staining. Tumor cells typically show positive expression of HMB45 and S100 proteins, while being negative for keratin and carcinoembryonic antigen. S100 is highly sensitive for diagnosing primary malignant melanoma of the digestive tract, with a sensitivity of 90%, as reported by Khalid et al ¹⁵ HMB45, on the other hand, is highly specific due to its ability to recognize pre-melanosomal glycoproteins associated with the tyrosinase system. Khalid et al ¹⁵ found that 100% of primary malignant melanoma of the digestive tract specimens were positive for HMB45, underscoring its diagnostic utility.

On preoperative biopsy, primary malignant melanoma of the digestive tract is frequently misdiagnosed as poorly differentiated carcinoma. A study by Sabanathan et al ¹⁶ highlighted that the diagnostic accuracy of biopsy for this tumor type is only 80%, with 20% to 50% of tumors being misdiagnosed due to the absence of visible melanin granules under microscopy. Sun et al ¹⁷ identified several reasons for these misdiagnoses: (1) some tumors lack melanin, making melanin granules invisible microscopically; (2) melanocytes may be focally distributed, leading to biopsy samples that miss melanocyte-containing areas; and (3) primary malignant melanoma of the digestive tract may be obscured by overlying normal epithelium. For instance, Endo et al ¹⁸ reported a tumor where a patient was initially misdiagnosed with poorly differentiated squamous cell carcinoma on biopsy. The patient presented with a bulging mass in the lower thoracic esophagus, which appeared white and lacked melanin deposits. Histopathological examination of the biopsy specimen suggested poorly differentiated squamous cell carcinoma. Notably, the patient's tumor marker levels for carcinoembryonic antigen and squamous cell carcinoma antigen were within normal limits, and no cutaneous melanoma or hyperpigmentation was detected elsewhere in the body. Based on the UICC eighth edition TNM classification (2017), the patient was diagnosed with esophageal squamous cell carcinoma (ESCC) staged as T3N1M0, stage IIIA. The patient underwent triple chemotherapy with docetaxel, cisplatin, and 5-fluorouracil, followed by thoracoscopic esophagectomy with two-field lymph node dissection via the posterior mediastinum and gastric reconstruction. Intraoperatively, metastatic lymph nodes along the celiac and common hepatic arteries were black and invaded the hepatic plexus, which was resected curatively. Postoperative pathological examination of the specimen revealed intratumoral pigmentation, and further analysis of H&E and immunohistochemical sections confirmed the diagnosis of primary malignant melanoma of the digestive tract.

It is important to note that the diagnosis of primary malignant melanoma of the digestive tract requires the exclusion of metastatic lesions. Therefore, a thorough evaluation of the patient, including physical examination, imaging studies, and gastrointestinal endoscopy, is essential to confirm the absence of primary lesions in other sites, such as the skin and eyes.^15,19 The diagnostic criteria for primary malignant melanoma of the digestive tract, as proposed by Blecker et al, ²⁰ include: (1) no evidence of metastatic spread on physical examination, (2) no history of excised malignant melanoma or cutaneous malignant melanoma, and (3) Presence of melanocytic hyperplasia or melanoma in situ within the basal layer of the mucosa.

The differential diagnosis of primary malignant melanoma of the digestive tract typically includes the following: (1) Poorly differentiated adenocarcinoma of the gastrointestinal tract: This tumor lacks eosinophilic nuclei and pigmentation. Immunohistochemically, it expresses epithelial markers such as Pan-keratin, keratin 7, and keratin 20. (2) Carcinosarcoma: Microscopically, this tumor consists of both epithelial and sarcomatoid components, often with spindle cells resembling fibrosarcoma or pleomorphic undifferentiated sarcoma. It exhibits significant heterogeneity, with frequent nuclear atypia and bizarre tumor giant cells. Heterologous elements such as bone and cartilage may be present. The epithelial component is usually squamous cell carcinoma or basal-like squamous cell carcinoma, but adenocarcinoma can also occur. Both the epithelial and some sarcomatoid components express epithelial markers (eg, keratin, p40, p63, keratin 5/6), while the sarcomatoid component may also express vimentin. (3) Gastrointestinal stromal tumor (GIST): This is the most common mesenchymal tumor of the gastrointestinal tract, predominantly found in the stomach, followed by the small intestine, colorectum, and esophagus. Grossly, it is well-demarcated and usually solitary. Microscopically, it may appear spindle-shaped or epithelioid. Immunohistochemically, it is positive for KIT, DOG1, and CD34, but negative for SMA and S100. (4) Neuroendocrine carcinoma (NEC): This includes small-cell neuroendocrine carcinoma (SCNEC) and large-cell neuroendocrine carcinoma (LCNEC). NEC often exhibits sheet-like or nodular growth with “geographic” necrosis. SCNEC cells are small to medium-sized with high nuclear-to-cytoplasmic ratios, hyperchromatic nuclei, and inconspicuous nucleoli. LCNEC cells are larger with abundant cytoplasm, vesicular nuclei, coarse chromatin, and prominent nucleoli.

(5) Malignant gastrointestinal neuroectodermal tumor (GNET): This is a rare tumor with neuroectodermal differentiation. Morphologically, it resembles clear cell sarcoma and often contains osteoclast-like giant cells. Tumor cells are small to medium-sized, arranged in sheets, nests, or trabeculae, with clear or eosinophilic cytoplasm and prominent nucleoli. Immunohistochemically, they express neural crest and neuroendocrine markers (eg, CHGA, SYP, CD56, S100, SOX10) but not melanocytic markers (eg, HMB45, MelanA). Molecularly, GNET is characterized by t(12;22)(q13;q12) and t(2;22)(q34;q12), resulting in EWSR1::ATF1 and EWSR1::CREB1 fusions, respectively. (6) Diffuse large B-cell lymphoma (DLBCL): This is the most common subtype of primary gastrointestinal lymphoma. Tumor cells express pan-B-cell markers such as CD20, CD22, CD79a, and PAX5. (7) Ewing sarcoma: This highly aggressive small round cell tumor primarily affects children and adolescents, with a peak incidence at 15 years. It usually arises in bones but is extremely rare in the gastrointestinal tract. Histologically, it is divided into nests by fibrous septa, with small, uniform tumor cells showing fine chromatin and inconspicuous nucleoli. Necrosis is common. Immunohistochemically, CD99 shows diffuse membrane positivity, and NKX2.2 is positive. Molecularly, it is characterized by t(12;22)(q24;q12) and t(21;22)(q22;q12), resulting in EWSR1::FLI1 and EWSR1::ERG fusions, respectively. (8) Synovial sarcoma: This tumor is extremely rare in the digestive tract. It can be monophasic (composed of spindle cells) or biphasic (composed of spindle and epithelial cells). The epithelial component may form glands or nests with eosinophilic secretions. Immunohistochemically, it expresses epithelial markers in the biphasic type. (9) Alveolar soft part sarcoma: This uncommon tumor in the gastrointestinal tract consists of nests of cells separated by fibrous septa. Tumor cells have central or eccentric nuclei, vesicular chromatin, and prominent nucleoli. Immunohistochemically, they express TFE3, cathepsin K, calretinin, and desmin but are negative for S100, HMB45, and SYP. (10) Histiocytic sarcoma: This rare tumor is even rarer in the digestive tract. Tumor cells are round or oval, large, and diffusely distributed, with pleomorphism, abundant eosinophilic cytoplasm, and vesicular nuclei. They express histiocytic markers (eg, CD68, CD163, lysozyme) but are usually negative for S-100. (11) Pleomorphic rhabdomyosarcoma: This is rare in the gastrointestinal tract. Tumor cells are large, polygonal, round, or spindle-shaped, often multinucleated, with marked pleomorphism and necrosis. Immunohistochemically, they express desmin, MyoD1, and myogenin.

Common treatments for primary malignant melanoma of the digestive tract include radical resection, chemotherapy, and immunotherapy. However, standardized treatment protocols have not yet been established due to the rarity of this tumor type. Approximately 80% to 90% of patients experience symptomatic relief after palliative surgical resection, and studies have shown that surgical resection also improves patient prognosis. ²¹ Current research suggests that chemotherapy may be used for patients with primary malignant melanoma of the digestive tract, but the efficacy of cytotoxic agents such as dacarbazine, nimustine, vincristine, vindesine, tamoxifen, and cisplatin remains limited.^22,23

The National Comprehensive Cancer Network (NCCN) guidelines recommend the current treatment strategy for unresectable malignant melanoma, which includes first-line immunotherapy such as PD-1 inhibitors (eg, nivolumab) and anti-CTLA-4 antibodies (eg, ipilimumab). For patients with BRAF gene mutations, a combination of molecularly targeted therapies, such as BRAF inhibitors and MEK inhibitors, is recommended. ²⁴ Notably, the introduction of novel therapies, including immune checkpoint inhibitors (immunotherapy) and BRAF/MEK inhibitors (targeted therapy), has significantly improved the survival of patients with advanced primary malignant melanoma of the digestive tract in recent years.

Nivolumab, a PD-1 immune checkpoint inhibitor, has shown promising results in treating primary malignant melanoma of the digestive tract. For example, Endo et al ¹⁸ reported an example of retroperitoneal recurrence in a patient with primary malignant melanoma of the esophagus, which was successfully treated with nivolumab 16 months after radical esophagectomy. Abdominal CT revealed a 36-mm retroperitoneal mass adjacent to the ascending colon, later confirmed as recurrent primary malignant melanoma of the esophagus. After 41 courses of nivolumab treatment, PET-CT confirmed the complete disappearance of the retroperitoneal mass. Similarly, Ito et al ²⁵ reported an example of recurrent primary malignant melanoma of the digestive tract with lymph node and bone metastases that responded well to nivolumab, showing significant reduction in metastatic lesions after 16 months of treatment without further progression. Wang et al ⁴ also observed a 75% treatment response rate in 12 patients with primary malignant melanoma of the digestive tract treated with nivolumab, with a median response duration of 11.4 months. These studies suggest that immune checkpoint inhibitors may improve the prognosis of patients with primary malignant melanoma of the digestive tract. However, due to the rarity of this tumor, further studies with larger sample sizes are needed to confirm these findings. ²⁶

In conclusion, primary malignant melanoma of the digestive tract is a rare and highly aggressive tumor. The possibility of this diagnosis should be considered when endoscopic examination reveals pigmentation on the tumor surface. Definitive diagnosis requires histopathological examination (H&E staining), immunohistochemical staining, and imaging to rule out metastatic disease. Early detection and radical resection are critical for ensuring a favorable prognosis. The efficacy of adjuvant chemotherapy and radiotherapy remains uncertain, while newer therapies such as immunotherapy and targeted therapy may improve overall survival in patients with this tumor type.