Malignant melanoma: An important differential diagnosis for clear cell sarcoma of the gastrointestinal tract

Abstract

A case report by Liu et al describes the characteristics of metastatic clear cell sarcoma (CCS) of the pancreas and provides valuable therapeutic insights for this rare malignancy. This case is interesting because of its rarity, suggesting that the pancreas may be a potential target organ for CCS, either primary or metastatic. At the same time, the authors also emphasize the importance of regular postoperative follow-up for timely detection of recurrent lesions, as CCS is characterized by a high degree of malignancy and a high rate of recurrent metastases. Considering that CCS of the gastrointestinal tract is easily confused with malignant melanoma (MM) of the gastrointestinal tract, here we compare the clinical features, histopathological and immunohistochemical characteristics, diagnosis, treatment, and prognosis of CCS and MM of the gastrointestinal tract, hoping to provide a reference for clinical work.

Key Words: Clear cell sarcoma; Malignant melanoma; Metastasis; Gastrointestinal tract; Differential diagnosis

Core Tip: The histological similarities and immunohistochemical overlap between clear cell sarcoma (CCS) and malignant melanoma (MM) pose a significant challenge to their diagnosis and differential diagnosis. This editorial comments on a case of metastatic CCS of the pancreas, compares in detail the histopathologic and immunohistochemical features of CCS and MM, and highlights the important role of molecular biological techniques in confirming the diagnosis of CCS and MM, providing invaluable information for the diagnosis, differentiation, and treatment of these two conditions.

INTRODUCTION

We recently read with interest a case report of metastatic clear cell sarcoma (CCS) of the pancreas by Liu et al[1]. The authors focused on the patient's clinical presentation and imaging features, as well as the individualized treatment plan; however, the authors did not mention the primary site of the tumor nor did they describe the first surgery in the patient's history, making it difficult to clarify whether the tumor was primary or metastatic. More importantly, the authors did not discuss in detail the histopathology and immunohistochemistry profile of the tumor, and whether molecular testing was performed. In fact, these features provided by the authors are insufficient to distinguish CCS from malignant melanoma (MM), this resulting in the lack of an important differential diagnosis. Because the histopathologic and immunohistochemical features of CCS and MM are so similar that they can be easily confused and misdiagnosed[2], we would like to alert authors and readers to an important differential diagnosis for CCS of the gastrointestinal tract: MM of the gastrointestinal tract.

GASTROINTESTINAL CCS AND GASTROINTESTINAL MM

CCS is a rare soft tissue sarcoma with an incidence of approximately 0.014/100000[3], accounting for less than 1% of all sarcomas, favoring young adults, and was first reported and described in detail by Enzinger[4] in 1965. Studies have shown that CCS can involve a variety of anatomical sites other than soft tissue, including the dermis[5], ears[6], penis[7], kidneys[8], and gastrointestinal tract. CCS metastatic to the gastrointestinal system is very rare, first reported by Zambrano et al[9] in 2003, and the sites of metastasis include the stomach[10], duodenum[11], jejunum[12,13], ileum[14], and transverse colon[15], while metastasis to the pancreas is extremely rare[16].

MM is a highly malignant tumor with melanocytic differentiation, accounting for 1.5% of all malignant tumors[17], and patients are predominantly middle-aged and elderly. Most MMs occur in the skin[18], and MM in the digestive tract is rare, with the first case of anorectal melanoma reported by Morson and Volkstädt[19] in 1857. It is prone to misdiagnosis or underdiagnosis due to its bidirectional differentiation characteristics, diverse pathomorphology, and the fact that some tumors do not contain melanin[20]. Table 1 shows the comparison of the tissue origin, pathologic features, immunohistochemistry profile, diagnosis, treatment, and prognosis of CCS and MM[21-32].

Table 1 Comparison of characteristics of gastrointestinal clear cell sarcoma and gastrointestinal malignant melanoma.

Tumor	Tissue origin	Imaging examination	Gross appearance	Histopathological examination	Immunohistochemistry	Molecular genetic testing	Diagnosis	Treatment	Prognosis
Clear cell sarcoma	Neural crest[21]	Hypodense mass	Grayish white, hard, ovoid	The nuclei of the tumor cells were round, uniform in size, with clear cytoplasm, scattered osteoclastic multinucleated giant cells were seen, and intracellular melanin was uncommon[23]	Most cases were positive for HMB-45, Melan-A, S-100, MiTF, PNL-2, and waveform protein, and in some cases melanin and/or melanosomes were present[26,27]	There are no BRAF or NRAS gene mutations, and most cases have the t(12;22)(q13;q12) translocation [29], which results in the EWS-ATF1 fusion gene[30]	Confirming the diagnosis relies on molecular biology	There is no consensus on a systemic treatment approach, and surgery remains the standard of care	High rate of recurrence or metastasis and poor prognosis
Malignant melanoma	Neural crest[22]	Low density occupying lesion	Grayish black, ill-defined, with infiltrative growths	The histomorphology is complex and variable, nuclear schizophrenia is common, osteoblast-like multinucleated giant cells are rare, and in most cases the tumor cells contain melanin granules that are brownish-yellow or black in color[24,25]	The rate of positivity for HMB-45, S-100, and vimentin was more than 90%, and Melan-A and PNL-2 were expressed to varying degrees[28]	Presence of BRAF gene mutations, absence of t(12;22)(q13;q12) chromosomal translocation and EWSR1 gene rearrangement[31,32]	Histopathologic examination is the gold standard for diagnosis	Comprehensive treatment including surgery, radiation, and chemotherapy	Highly malignant, highly invasive, and highly metastatic with poor clinical prognosis

It is difficult to distinguish CCS from MM based on morphologic, imaging, and immunohistochemical features, and misdiagnosis of CCS as MM has recently been reported[2]. Ultimately, molecular biological methods are required to make a definitive diagnosis of CCS. The majority of CCS cases carry the t(12;22)(q13;q12) translocation[33-36], which gives rise to the chimeric EWSR1/ATF1 fusion gene[37,38] and is therefore considered specific for CCS[39], leading many authors to emphasize the key role of cytogenetics in the diagnosis of CCS. Covinsky et al[40] used molecular techniques to identify 20 gastrointestinal tumors and confirmed the diagnosis of CCS by finding that two of them had a gene fusion transcript and the t(12;22)(q13;q12) translocation. MM with a mutation in the kinase region of the BRAF gene without the t(12;22)(q13;q12) chromosomal translocation and the EWSR1/ATF1 gene rearrangement[31]. In a previous study, Coindre et al[41] successfully identified 44 patients with CCS and 14 patients with MM using molecular biotechnology.

Therapeutically, there is no consensus regarding a systemic approach to treating CCS and surgery remains the standard. Immunotherapy has better prospects in the treatment of CCS[42]. Treatment strategies for MM involving the gastrointestinal tract mainly include a combination of surgery, radiotherapy, and chemotherapy. The choice of surgery remains controversial. In general, surgical resection with resection of the surrounding regional lymph nodes is the mainstay of treatment when the lesion is localized. Chemotherapy is the primary treatment for those who are ineligible for surgery or who experience recurrence or metastasis after surgery. Targeted drugs and immunotherapy have also been used to treat advanced MM[43,44]. With the progress of research, the mechanisms of the occurrence, development, and metastasis of CCS and MM will become clearer, and together with the clinical application of molecular genetic technology, their diagnosis rate will be greatly improved. We believe that the continuous progress of therapeutic means, especially the development of targeted therapy and immunotherapy, will definitely provide new hope for improving the prognosis of CCS and MM[43,45].

CONCLUSION

Because cases of CCS of the digestive tract are very rare, it poses a great challenge for systematic clinical research. The case of Liu et al[1] suggests that the pancreas is a potential site for CCS and that long-term postoperative follow-up is of great importance. This editorial describes in detail the clinical, pathological, and molecular characteristics of CCS and MM, emphasizing the central role of molecular techniques in their differentiation and diagnosis. Our study is significant because gastrointestinal CCS has a different management strategy than gastrointestinal MM, and the correct identification of CCS and MM is important in the diagnostic workup and treatment options.