Clear cell sarcoma of the pancreas, an unusual cancer with unusual metastatic site or unusual primary site?

Abstract

Clear cell sarcoma (CCS) is a type of malignant tumor that can arise from tendons and aponeuroses. This malignant proliferation of cells with melanocytic lineage normally occurs in young patients, and it is normally identified in extremities. However, different sites including gastrointestinal organs are also described. Due difficulties in the molecular and histopathology evaluation, the diagnosis is often confused with malignant melanoma. Most cases are treated with surgical resection, but overall, the prognosis is poor. In this editorial, we will discuss a very interesting case of CCS identified in the pancreas. We will discuss the literature and controversies in the management of this type of cancer. Furthermore, we will address molecular strategies to be incorporated in those cases to better understand the primary location of the tumor. Finally, future perspectives of the field and new strategies of treatment will be described.

Key Words: Clear cell sarcoma; Soft tissue sarcoma; Metastatic cancer; Pancreatic cancer; Pancreatectomy

Core Tip: Clear cell sarcoma is a rare type of malignant tumor that can arise from tendons and aponeuroses. However, different primary sites including gastrointestinal organs are also described. Next generating sequencing evaluation can help identify molecular biomarkers that can help with the diagnosis and treatment. Although surgical resection is the mainstream treatment for most patients, the recurrence of the disease is common and normally is refractory to standard treatments including chemotherapy.

INTRODUCTION

We read with great interest the article from Liu et al[1] addressing a case of advanced clear cell sarcoma (CCS) with an unusual metastatic site, the pancreas[1]. CCS is a rare entity. It is a tumor that can arise from tendons and aponeuroses; however, the true lineage is still unclear till nowadays[2]. This malignant proliferation of cells with melanocytic lineage normally occurs in young patients and could be characterized by the translocation t (12; 22) (q13; q12) that results in a fusion of the EWS and ATF1 genes[2]. It is also important to note that primary gastrointestinal (GI) CCS are also described in the literature. Those GI or primary abdominal cases may have identified variant fusions genes including EWSR1-CREB1 or BCOR-CCNB3 through next generating sequencing (NGS)[3]. Due to difficulties in the molecular and histopathology evaluation, the diagnosis is often confused with malignant melanoma or other malignant melanocytic neoplasms (MMN)[4,5].

CASE REPORT

In the article from Liu et al[1], a patient with pancreatic CCS is submitted to surgery. It was a young patient 47 y/o, that after a resection of a primary CCS, about three years ago, presented with abdominal pain and a mass in the pancreas. Initial workout identified the solid mass in the pancreas, localized in the pancreatic tail. The patient was submitted to a distal pancreatectomy with lymphadenectomy, with good recuperation after the surgery[1].

On April 2024 we did a MESH term search on PubMed, ‘’clear cell sarcoma AND pancreas’’, with 22 articles identified. Most articles identified are discussed in this editorial.

DISCUSSION

Rare cases of CCS of the pancreas have been described in literature[5,6]. In one case, similarly, a patient with 58 y/o was diagnosed with abdominal pain[5]. The patient was diagnosed with CCS/MMN on the pancreatic tail[5]. The patient underwent distal pancreatectomy and splenectomy. Interestingly, about 6 months later this patient had a metastatic liver lesion that was further resected as well[5]. Another case was diagnosed in a young patient as well, 36 y/o[6]. In that case, the disease was localized on the head of the pancreas and the patient was treated with a Whipple procedure[6]. Further pathological evaluation showed polygonal cells arranged in a uniform nested to fascicular growth pattern with thin fibrous septa. After a fluorescence in situ hybridization testing, a translocation involving the EWSR1 gene region was identified[6]. No BRAF or NRAS mutation was detected. The patient underwent transcatheter arterial chemoembolization six times and eventually died of diffuse liver metastasis about a year later[6].

Most cases of GI CCS can have the diagnosis confirmed with molecular or NGS evaluation (Table 1). It is identified in literature multiple GI primary sites including colorectal[7], stomach[8], duodenum[9] and jejunum[10]. The diagnosis can be very challenging due to inconsistent expression of melanocytic markers by immunohistochemistry[6]. Multiple alternative diagnosis can be considered in cases of CCS including perivascular epithelioid cell tumors, MMN, GI stromal tumors and other sarcomas[6].

Table 1 Most common genomic aberrations identified in clear cell sarcoma.

Genes	Genomic alterations
EWS	Fusions or rearrangements
ATF1	Fusions or rearrangements
BCOR	Fusions or rearrangements
MET	Amplifications or Mutations

The most challenging differential for a primary GI CCS is a metastatic CCS or MMN[6]. In the case of MMN, CCS presents similar phenotypic and structural findings, some immunohistochemical characteristics can also overlap. Generally, to correctly identify the type of malignant tumor, molecular analysis should be used. BRAF and NRAS mutations are normally identified in melanomas[6]. In the majority cases CCS harbors a chromosomal translocation t (12; 22) (q13; q12), which leads to the formation of ESWR1/ATF1 fusion transcript, which is absent in MMN[6].

CCS is a highly aggressive high grade soft sarcoma, with an overall high recurrence incidence on lymph nodes and liver metastasis[11]. The diagnosis is somewhat challenging considering the overlap with melanocytic lesions and about 50% of the cases already have positive lymph nodes at diagnosis[11]. And overall, although scarce, data suggests that this type of tumor is highly resistant to chemotherapy and radiotherapy[1-11]. After a review on PubMed in April 2024 of articles related to subject, no data about effective systemic treatments were identified, furthermore, no data with immunotherapy or newer agents were also identified[4,6]. Surgery is the optimal treatment, and molecular investigation could play an important role in the diagnosis and management of this disease, however little is known of this intriguing entity.

CONCLUSION

The case reported by Liu et al[1] is important to address the potential and unusual diagnosis of CCS in pancreas and shows the challenging diagnosis involving the disease.