Essential role of postoperative follow-up in the management of clear cell sarcoma

Abstract

Clear cell sarcoma (CCS) is a rare melanocytic soft tissue sarcoma known for its propensity to metastasize to the lymph nodes and typically has an unfavorable prognosis. Currently, surgical resection is the primary treatment for localized CCS, while radiotherapy and chemotherapy are preferred for metastatic cases. The roles of adjuvant chemotherapy, radiotherapy, and lymph node dissection are controversial. Although immunotherapy has emerged as a promising avenue in CCS treatment research, there are no established clinical standards for postoperative follow-up. This editorial discusses a recent article by Liu et al, with a focus on current diagnostic modalities, treatment approaches, and the challenging prognosis associated with CCS. Our aim is to underscore the importance of long-term patient follow-up in CCS management.

Key Words: Clear cell carcinoma; Diagnosis; Treatment; Prognosis; Follow-up

Core Tip: Clear cell sarcoma (CCS) is a rare subtype of melanocytic soft tissue sarcoma distinguished by its propensity for metastasis and recurrence. Survival rates markedly diminish in patients with advanced CCS compared with those with early-stage disease. The insidious nature of early occult onset and the limited responsiveness of CCS to chemoradiotherapy underscore the critical importance of routine postoperative follow-up for early detection of recurrent cases, which is crucial for enhancing patient prognosis.

INTRODUCTION

Clear cell sarcoma (CCS) is an uncommon and highly aggressive malignant soft tissue sarcoma (STS) it is characterized by melanocytic differentiation and is believed to originate in tendons and aponeuroses. Due to its insidious onset and slow growth in its early stages, CCS is frequently misdiagnosed as a benign lesion or is identified at an advanced stage. It poses a significant diagnostic challenge. Predominantly affecting the lower extremities, particularly the feet and ankles, CCS exhibits aggressive behavior, marked by local recurrence, lymph node metastasis, and distant metastasis[1,2]. At diagnosis, the majority of patients already present with lymph node or distant metastasis[3], contributing to the generally poor prognosis, with notably lower 5-year survival rates in advanced stages compared to those in early stages. Metastasis primarily occurs in the lungs, followed by the bones and brain[3]. While CCS of the gastrointestinal system is exceedingly rare[4], clear cell sarcoma-like gastrointestinal tumor (CCSLGT), initially reported by Zambrano et al[5] in 2003, is characterized by robust diffuse immunoreactivity of S-100 protein, negative melanocyte-specific markers, and the presence of osteoclast-like multinucleated giant cells. It primarily affects the walls of the small intestine, stomach, or large intestine. Although only two cases of primary pancreatic CCS have been reported to date[4,6], CCSLGT has a more aggressive phenotype compared with traditional CCS, often presenting with metastasis at diagnosis, particularly to the lymph nodes or liver[7].

Despite advancements in understanding the pathogenesis of STS, agreement on the management of CCS is lacking because it is a rare disease. This editorial sheds light on the latest developments in CCS diagnosis and treatment, underscoring the necessity of postoperative follow-up of patients with CCS.

CURRENT DIAGNOSTIC METHODS FOR CCS

The diagnosis of CCS typically relies on a combination of medical history, clinical presentation, and imaging findings. Many patients are already at an advanced stage at symptom onset. CCSLGT predominantly affects the intestinal wall, manifesting as abdominal pain, intestinal obstruction, and occasionally nonspecific symptoms such as anorexia, night sweats, weight loss, or anemia[7]. Patients with pancreatic CCS commonly present with symptoms such as anorexia, jaundice, or other gastrointestinal symptoms[4,6].

Computed tomography (CT) is a primary diagnostic tool for identifying suspected cases, offering insights into sarcoma size and location[8]. Magnetic resonance imaging (MRI) aids in assessing tumor depth and its relationship with surrounding structures and is needed for preoperative planning. Liu et al[9] reported a rare case of CCS with pancreatic metastasis, elucidating the imaging features of pancreatic CCS. CT imaging revealed a round, mildly enhanced, heterogeneous lesion in the pancreatic tail and MRI depicted a vague boundary between the lesion and pancreatic body, with an equal to slightly lower signal on T1 and slightly higher signal on T2, along with progressive uneven enhancement. Given CCS's propensity for hematological or lymphatic metastasis, staging typically involves preoperative assessment with whole-body CT, positron emission tomography-CT, or bone scintigraphy[10]. Recent reports underscore the possibility of peripheral blood transmission of CCS, highlighting the utility of blood smears for rapid diagnosis[11].

A histological examination is imperative to confirm the diagnosis of CCS[12]. Additionally, preoperative confirmation through percutaneous biopsy is essential to ensure negative margins[13]. Multinucleated giant cells that have a wreath-like nuclear appearance are often present in CCS[14]. In contrast, CCSLGT typically lacks conspicuous nucleoli and multinucleated giant cells, replaced instead by CD68-positive multinucleated osteoclast-like giant cells[15]. Immunohistochemical analysis of CCS demonstrates striking similarities to malignant melanoma, commonly expressing S100 protein and melanocyte-specific markers such as HMB-45, melanin-A, and microphthalmia-associated transcription factor (MITF)[16-18]. While S100 protein is expressed in nearly all cases of CCSLGT, melanoma markers (melan A, HMB45) are typically negative[15].

Differential diagnosis is critical in distinguishing CCS from S100 protein-positive and/or melanocyte marker-positive tumors, including malignant melanoma, epithelioid malignant peripheral nerve sheath tumors, melanotic schwannomas, and perivascular epithelioid cell tumors[19]. Despite having. morphological, ultrastructural, and histopathological similarities, CCS and melanoma differ in their molecular tumorigenesis[20]. Recent advancements have used fluorescence in situ hybridization and reverse transcription polymerase chain reaction to confirm CCS and distinguish it from malignant melanoma based on distinct genetic profiles[21]. Approximately 70%–90% of CCS cases are detected by the t(12;22)(q13;q12) translocation, which results in the Ewing sarcoma breakpoint region 1 (EWSR1)/activating transcription factor 1 (ATF1) chimeric gene. This translocation induces MITF expression, facilitating the acquisition of melanocytic characteristics and the expression of melanocyte markers[22]. Another specific mutation, the t(2;22)(q34;q12) translocation leading to EWSR1 and cAMP response element-binding protein (CREB1) fusion, is found in a minority of CCS cases. More recently, EWSR/cAMP responsive element modulator (CREM) fusion was identified in several CCS cases[21]. Ozenberger et al[23] used V5 labeled EWSR1/ATF1 to induce CCS in mice to observe genome distribution and found that CREM may represent an important target gene and cofactor for EWSR1/ATF1 fusion. Notably, BRAF mutations, common in melanoma, are rare in CCS[24].

CURRENT MANAGEMENT OF CCS

Currently, the preferred treatment for localized CCS is complete surgical resection with negative margins, and is often followed by local excision or partial amputation. While standards for metastasis detection remain elusive, radiation or chemotherapy is the preferred treatment modality[3]. The most frequent systemic sarcoma chemotherapy regimens include doxorubicin, sunitinib, gemcitabine, and pazopanib[25]. However, clinical trials evaluating MET inhibitors, such as tivantinib and crizotinib, have demonstrated limited antitumor activity, necessitating further research and improvement of treatment strategies[26,27]. Notably, trabectedin has recently been shown to induce cell cycle arrest in CCS cell lines, inhibit CCS tumor growth in mice, and elicit clinical and radiological tumor responses in patients[28,29].

CCS is generally regarded as unresponsive to radiotherapy and chemotherapy, with conflicting evidence of the survival advantage of adjuvant radiotherapy and chemotherapy[13,19,30,31]. A randomized prospective study by Beane et al[32] indicated that postoperative radiotherapy significantly reduced local recurrence rates in patients with STS, albeit without enhancing overall survival rates. The Japanese Orthopedic Association guidelines advocate for perioperative adjuvant radiotherapy in patients with STS, emphasizing the necessity for meticulous individual case assessment to optimize treatment outcome[33].

Recently, significant attention has been directed towards the development and application of immunotherapies for advanced sarcomas. The fundamental principle involves inhibiting the checkpoints that tumors use as a defense mechanism to evade detection by immune system. The use of immune checkpoints such as cytotoxic T-lymphocyte antigen-4 and programmed cell death-1 (PD-1) in melanoma treatment, and their parallels with CCS, have captured the interest of immunotherapists in the treatment of CCS. Marcrom et al[34] reported a case of recurrent, unresectable CCS with a complete clinical response to pembrolizumab and radiotherapy. This suggests that there is a synergistic effect between PD-1 therapy and radiotherapy. A phase I/II clinical trial conducted by Gordon et al[35] found the combined use of immune checkpoint inhibitors ipilimumab and nivolumab and the tumoricide trabectedin (the SAINT regimen) in early-stage disease significantly enhanced the survival outcomes of patients with advanced sarcoma, with CCS having a favorable responsive. However, large-scale studies are urgently needed to explore the therapeutic potential of immunotherapy in patients with CCS.

The prognosis of patients with CCS remains dismal, with 5- and 10-year survival rates ranging from 47% to 67% and 25% to 41%, respectively[19]. Notably, the 5-year overall survival rates of patients with stage III and IV CCS are substantially lower than those of patients with stage I and II CCS. Approximately one-third of patients with CCS have lymph node metastasis at diagnosis, a prevalence significantly higher than that observed in other soft tissue sarcomas[3]. In a retrospective analysis of 60 cases categorized as CCSLGT, Washimi et al[15] found that the frequency of lymph node metastasis at diagnosis was 62%, which was significantly higher. than the metastasis rate observed in CCS. Previous research has highlighted tumor size, location, and metastasis as key prognostic factors[36]. A 2023 national database study by Fujiwara et al[33] identified primary tumor resection and metastatic lymph node dissection as independent factors associated with improved prognosis.

Moreover, CCS has a recurrence rate as high as 40%[37], with reports of late recurrences occurring after more than 10 years[13]. Fujiwara et al[33] reported cumulative local recurrence rates of 11% at 3 years and 19% at 5 years postoperatively. Tumor size was found to be significantly correlated with local recurrence, in contrast to other soft tissue sarcomas, in which surgical margins and the use of chemotherapy or radiotherapy typically has a more significant role. Nonetheless, the limited patient cohort in this study raises concerns about the reliability of this conclusion, necessitating further investigation.

The high recurrence rate and aggressive nature of CCS underscore the critical importance of comprehensive long-term follow-up for all patients. However, there is currently a lack of published data outlining the optimal routine follow-up strategy for surgically treated patients with localized disease. In the case reported by Liu et al[9], the patient declined regular disease monitoring and examination after the first operation, seeking follow-up only when symptoms manifested, resulting in delayed treatment. This highlights the crucial role of regular postoperative follow-ups in patients with CCS. The clinical practice guidelines established by ESMO-EURACAN-GENTURIS recommend risk assessment and a tailored follow-up strategy based on histological type and tumor grade, size, and location. Additionally, the use of appropriate imaging modalities, such as MRI to detect local recurrence in extremities and superficial recurrence in the trunk and CT to identify lung metastases, are useful for early detection of recurrence[38].

CONCLUSION

Given the rarity of CCS, our understanding of the disease remains partial, necessitating further research to advance our understanding of its diagnosis and management. However, increased rates of metastasis and recurrence underscore the importance of prioritizing postoperative care and devising a structured follow-up regimen for patients. Early identification of at-risk individuals and prompt recognition of recurrent cases stand as crucial measures to improve patient prognosis and increase survival rates.