Metastatic clear cell sarcoma of the pancreas: A sporadic cancer

Abstract

Primary or secondary clear cell sarcoma of the pancreas is an exceedingly rare and aggressive disease. In addition to pathology, molecular analysis is pivotal in differential diagnosis, especially with malignant melanoma. A key aspect in identifying clear cell sarcoma is specific genetic alterations, notably the translocation of t(12;22) (q13;q13), a diagnostic hallmark of this sarcoma subtype, which is absent in malignant melanoma. Treatment of primary clear cell sarcoma of the pancreas is the same as that for adenocarcinoma.

Key Words: Clear cell sarcoma; Pancreas; Rare cancer; Metastatic; Diagnosis

Core Tip: Primary or secondary clear cell sarcoma of the pancreas is an exceedingly rare and aggressive disease. In addition to pathology, molecular analysis is pivotal in differential diagnosis, especially with malignant melanoma. A key aspect in identifying clear cell sarcoma is specific genetic alterations, notably the translocation of t(12;22) (q13;q13), a diagnostic hallmark of this sarcoma subtype that is absent in malignant melanoma. Treatment of primary clear cell sarcoma of the pancreas is the same as adenocarcinoma.

INTRODUCTION

Primary or metastatic clear cell sarcoma is undoubtedly a sporadic cancer. The National Cancer Institute defines rare cancers in the United States as those occurring in fewer than 15 out of 100000 people annually[1]. Most types of tumors are considered rare, and they are often more challenging to prevent, diagnose, and treat than the more common cancers[1]. The European Society of Medical Oncology defines rare cancers as neoplastic diseases with a prevalence of fewer than 5 cases/10000 inhabitants, even if a new definition has been proposed according to changes in new-case per-year incidence rates[2]. However, the latter definition classifies neoplasms with an incidence of fewer than 6 per 100000 individuals annually as uncommon malignancies[2]. Using this definition would reduce the possibility of confusing common cancers (e.g., small-cell lung cancer, which has a short life expectancy and low prevalence) for rare cancers (e.g., testicular cancer, which is frequently cured and has a relatively high prevalence).

In 2016, the Joint Action on Rare Cancers reexamined the list of 198 rare cancers as developed by the RARECARE project. This project categorizes rare cancers into 12 families and three tiers based on the International Classification of Diseases for Oncology, which incorporates topographical and histological labels[2,3].

Here, we presented highlights on primary and secondary clear cell sarcoma of the pancreas.

PRIMARY CLEAR CELL SARCOMA OF THE PANCREAS

Most primary pancreatic tumors are epithelial cancers and primarily adenocarcinomas neurogenic malignancies or gastrointestinal stromal tumors are the most common types of stromal pancreatic tumors. Pancreatic primary sarcoma is uncommon and needs to be distinguished from gastrointestinal and retroperitoneal sarcomas that extend to the pancreas[4]. Clear cell sarcoma is an uncommon type of mesenchymal soft-tissue sarcoma that makes up less than 1% of all cases. Depending on the surveillance, epidemiology, and results databases, its incidence ranges from 0.014/100000[5,6]. Clear cell sarcoma originates from the tendon and aponeurosis. It is characterized by local invasive growth of the tendon and other soft tissues and high invasiveness, with frequent metastasis to the lungs, brain, and bones[7].

Primary pancreatic clear cell sarcoma is an infrequent clinical and pathological finding that affects young adults and has a poor prognosis[8]. The etiology of clear cell sarcoma is unknown. It has been speculated that early radiation exposure with a subsequent inflammatory cascade (e.g., due to trauma) may create an environment that allows aggressive growth. While clear cell sarcoma is well-documented in various anatomical sites such as the kidney, tendons, soft tissues, and gastrointestinal tract, its primary occurrence in the pancreas is infrequent.

Primary clear cell sarcoma of the pancreas poses a diagnostic challenge due to its extreme rarity and morphological similarities with other malignancies, particularly metastatic melanoma, because immunohistochemical studies may reveal positivity for HMB-45, Melan A, S-100, microphthalmia transcription factor (MITF), and vimentin[9-11]. Therefore, diagnosing primary clear cell sarcoma of the pancreas requires a high index of suspicion and careful differentiation from other sarcomas or metastatic lesions. This highlights the importance of utilizing advanced diagnostic techniques like cytogenetic or molecular investigations[12,13].

A key aspect in identifying clear cell sarcoma is specific genetic alterations, notably the translocation of t(12;22) (q13;q13). This translocation is a diagnostic hallmark of this sarcoma subtype and leads to the formation of the Ewing sarcoma breakpoint region 1 (ESWR1)/activating transcription factor fusion transcript (or less commonly the ESWR1/cAMP responsive element binding protein 1 fusion transcript), which is absent in malignant melanoma[14,15]. Clear cell sarcoma generally lacks the BRAF and NRAS mutations. Insulin-like growth factor 1 receptor might be a novel marker for clear cell sarcoma and treatment targets[15,16].

The therapeutic approach to non-metastatic cases is similar to pancreatic adenocarcinoma. Surgery is the cornerstone of therapy[17]. Despite the similarities in treatment to pancreatic adenocarcinoma, reporting clear cell sarcoma cases may be useful to provide oncologists with guidance for the management of rare sarcoma patients. Managing clear cell sarcoma involves a multidisciplinary treatment approach that includes surgical resection, chemotherapy, and targeted therapies. A recent study has demonstrated that the combination of anlotinib with chemotherapy in treating recurrent clear cell sarcoma is a promising therapeutic option for this rare malignancy[18]. Additionally, identifying BRAF mutations in clear cell sarcomas indicates the possibility of targeted therapeutic strategies beyond traditional sarcoma or melanoma treatments, providing a personalized approach to managing this aggressive tumor[19].

In conclusion, clear cell sarcoma of the pancreas presents diagnostic and therapeutic complexities, requiring advanced molecular techniques, targeted therapies, and interdisciplinary cooperation for effective management. Further research into the genetic and molecular features of clear cell sarcoma, particularly in uncommon locations like the pancreas, is essential to improve diagnostic accuracy and treatment outcomes for patients with this rare sarcoma.

METASTATIC CLEAR CELL SARCOMA IN THE PANCREAS

Reports of pancreatic clear cell sarcoma metastases are scarce in the medical literature. Around 2% of pancreatic cancers are caused by the pancreas, which is an uncommon metastatic site[20-22]. Most metastases in the pancreas are discovered as a part of widespread systemic disease at the time of diagnosis[22]. Renal cell carcinoma, colorectal cancer, melanoma, and lung cancer are the most frequent primary malignancies that cause pancreatic metastases; pancreatic metastases from synovial soft tissue sarcoma are extremely uncommon[23-26]. A review of pancreatic metastases of sarcomas other than clear cell sarcoma showed that the primary tumor was located in the lower limbs[27]. This observation led scientists to hypothesize that a shunt between the lower limbs and the pancreas existed. . The isolated pancreatic metastasis may be explained by abnormal vascularization that must be confirmed by autopsy. The pancreatic metastases of sarcomas are rare and preferentially propagated by the hematogenous pathway[28-30]. Metastatic dissemination can be achieved through the connective interspaces and cavities where tumor cells can become entrapped[31,32].

Because metastatic sarcoma to the pancreas is uncommon and it can be challenging to differentiate between primary and metastatic tumors using radiologic markers, it presents diagnostic and treatment challenges in clinical practice. Solitary lesions are especially difficult and are clinically mistaken as primary tumors of the pancreas in approximately one-third of cases[33]. The manifestations of metastatic sarcoma to the pancreas are similar to adenocarcinoma and may include abdominal pain, intestinal obstruction, anemia, nausea, and vomiting. Therefore, the clinical suspicion is usually late.

To definitively diagnose metastases from clear cell sarcoma, fluorescence in situ hybridization testing, real time PCR, or sequencing is necessary to show the presence of the fusion gene EWSR1/activation transcription factor 1. The pathological picture shows pale-staining or clear cells that grow in a nested or fascicular growth pattern in the tumor. The more common non-gastrointestinal variant displays phenotypic features similar to malignant melanoma (Melan-A, MITF, HMB-45) that can complicate the diagnosis. The immunohistochemical analysis of tumors consistently identifies the S-100 protein and the variable or focal expression of CD57, bcl-2, HMB45, Melan A, MITF, synaptophysin, cytokeratin, CD34, c-erbB-2, c-kit, and c-met. Alpha-smooth muscle actin, desmin, and cytokeratin are not present in the tumors.

The only therapeutic option for patients with limited sarcoma metastases is complete surgical excision, which is associated with significant disease-free survival. To date, there is no consensus regarding the benefit of chemotherapy or radiotherapy for this type of tumor. The published series on the resection of pancreatic metastases comprised few patients, although the authors reported long-term survival in many of the patients[30]. Therefore, surgery at high-volume pancreatic surgery centers is recommended whenever possible. Currently, treating clear cell sarcoma with chemotherapies designed for Ewing’s sarcoma or other sarcomas does not result in clinically meaningful results.

CONCLUSION

Why should clinicians report such a rare disease? Rare cancers are a major cause of cancer-related deaths. They are linked to several negative prognostic factors, including inequity in survival outcomes, late diagnosis, unclear prognosis, exorbitant out-of-pocket costs, limited scientific information, less expert knowledge, and limited treatment options[34]. New studies for epidemiological research on rare oncological diseases and reported case data to classify rare diseases are needed[35]. In conclusion, we remember a quip from our university mentor who would tell us that cancer is rare until you must treat an affected patient.