Intestinal Clear Cell Sarcoma: A Rare Entity with Diagnostic and Therapeutic Dilemma: A Case Report with a Review of Literature

Abstract

Gastrointestinal clear cell sarcoma (GICCS), or malignant gastrointestinal (GI) neuroectodermal tumor, is a rare and aggressive cancer. It features malignant melanoma and is typically found in soft tissue, but it can rarely present in the GI tract. GICCS often presents with nonspecific GI symptoms, leading to a delay in diagnosis. A 44-year-old female patient presented with abdominal pain and vomiting, and on evaluation was found to have an ileal mass for which she underwent ileal resection and anastomosis at an outside hospital. Postoperative histopathology was suggestive of large cell neuroendocrine carcinoma, and she received six cycles of adjuvant chemotherapy with cisplatin and etoposide, completed in June 2021. In November 2023, she developed local recurrence with lung metastasis. The patient was rechallenged with cisplatin and etoposide for six cycles, but the disease progressed. The patient was referred to medical oncology for further management. A lung biopsy with immunohistochemistry revealed clear cell sarcoma. Fluorescent in situ hybridization for EWSR1 was positive. No targetable mutations were identified by NGS, and PDL1 was 0%. She received 4 months of sunitinib. Postsunitinib PET-CT showed progressive disease. She was not keen on further chemotherapy and had logistics for peptide receptor radionuclide therapy, and hence was offered the best supportive care. The patient passed away after 4 months. GICSS is a rare and aggressive neoplasm with limited treatment options. Surgery forms the standard of care in nonmetastatic disease, with a limited role for adjuvant treatment. Metastatic disease does not have any standard options in the first line or second line. We recommend more research into molecular targeting of genomic alterations for optimal management.

Keywords

case report - neuroectodermal tumor - clear cell sarcoma - GICCS

Introduction

Gastrointestinal clear cell sarcoma (GICCS), also known as malignant gastrointestinal (GI) neuroectodermal tumor, is an exceptionally rare and aggressive malignant mesenchymal tumor.[1] It accounts for less than 1% of soft tissue sarcoma.[2] To date, only less than 100 cases have been reported in the literature worldwide.[3] GICCS primarily occurs in the small intestine, with less frequent involvement of the stomach and colon.[2] It predominantly affects young to middle-aged adults, with an average age of 42 years.[4] There is no known sex predilection and no known etiological factors.[5] They most commonly present with abdominal pain and vomiting. Diagnosis requires a high degree of suspicion and requires a contrast-enhanced computed tomography (CECT) scan, tissue biopsy, and immunohistochemistry (IHC). It is very difficult to differentiate this tumor histologically, as it closely resembles metastatic clear cell sarcoma, GI stromal tumor, melanoma, and neuroendocrine tumor. In localized disease, the treatment of choice is surgical resection, and there is no evidence for the role of any neoadjuvant or adjuvant therapy. There are no standard treatment options available for metastatic disease. Response rates with chemotherapy and targeted agents have been dismal. All the evidence for treatment is extrapolated from the general treatment of sarcomas and clear cell sarcomas.

In this case report, we present the case of a 44-year-old female patient diagnosed with clear cell sarcoma of the small intestine, its clinical course, management, and literature review.

Case Report

A 44-year-old female patient presented to an outside hospital in January 2021 with complaints of abdominal pain and nonbilious vomiting. She had a past history of appendectomy, and there were no other known comorbidities. A CECT scan of the abdomen and Pelvis was done, which showed an irregular, thick-walled, peripherally enhanced lesion of size 4.2 cm × 4 cm on the mesenteric surface of the ileal loop, along with an enlarged mesenteric lymph node of size 10 × 11 mm. She underwent segmental ileal resection with ileoileal end-to-end anastomosis. Histopathological examination revealed a high-grade malignant neoplasm of the ileum measuring 4 cm × 3 cm × 1 cm, composed of large cells arranged in a diffuse growth pattern. The tumor infiltrated through the muscularis propria into the serosa and demonstrated a high mitotic index (>20/10 HPF) with foci of necrosis. Lymphovascular invasion was identified, while perineural invasion was absent. Surgical resection margins were free of tumor. Metastatic deposits from the same neoplasm were present in the regional lymph nodes. Immunohistochemical evaluation demonstrated diffuse positivity for synaptophysin, while chromogranin A and CD117 (c-KIT) were negative. The pathological diagnosis was neuroendocrine carcinoma of the large cell type. The AJCC TNM stage assigned was pT3 N1M0. The patient was treated with six cycles of adjuvant chemotherapy using Etoposide (100 mg per m² IV for 3 days) and Cisplatin (dose 75 mg per m² IV on day 1), completed in June 2021. There were no side effects. A Gallium Positron Emission Tomography (68Ga-DOTANOC PET CT) was done, which did not show any residual recurrent or metastatic lesion. She was kept on follow-up with 3 monthly clinical examinations and 6 monthly contrast-enhanced CT scans of the abdomen. In May 2023, the USG abdomen showed an enlarged superior mesenteric lymph node of size 0.9 × 0.8 cm, which was kept on follow-up.

The patient started complaining of mild abdominal pain and cough in November 2023. Chest X-rays showed small bilateral lung lesions, and USG abdomen showed a mesenteric lymph node of 2 × 1.5 cm in size. The DOTA PET-CT scan showed a DOTA-avid mesenteric lymph node measuring 17 × 17 mm and a right common iliac lymph node measuring 24 × 25 mm, along with bilateral pulmonary metastatic deposits, the largest measuring 21 × 14 mm in the left lower lobe. All the lesions showed avidity on the 18F-FDG PET-CT scan. The 18F-FDG PET-CT scan revealed intense metabolic activity in the mesenteric and right common iliac lymph nodes, both demonstrating an SUVmax of 30.6. Pulmonary metastases also exhibited increased tracer uptake, with SUVmax values of 20 in the left lung and 8.9 in the right lung. The patient was rechallenged with palliative chemotherapy using etoposide (100 mg per m² IV for 3 days) and cisplatin (dose 75 mg per m² IV on day 1). She completed six cycles in March 2024. Clinically, the symptoms were stable. A DOTA PET CT was taken after 4 weeks to assess response and showed progressive disease with an increase in size and metabolic activity and lung nodules and mesenteric lymph nodes, and new-onset serosal deposits in the jejunum and proximal ileum. She was referred to medical oncology for further management.

A CT-guided biopsy was taken from the lung nodule, which showed a poorly differentiated malignant neoplasm that was positive for IHC S100. IHC for synaptophysin, CD56, SOX10, HMB45, Melan A, cytokeratin, SSTRA2, INSM1, TFE3, desmin, LCA, CD117, DOG1, and CD34 were negative. A slide review of the ileal resection specimen showed ulcerated mucosa with an underlying neoplasm composed of nodular aggregates of cells arranged in nests and pseudoalveolar and papillary patterns, seen invading the submucosa. The cells showed vesicular nuclei with scattered mitosis with abundant eosinophilic/clear cytoplasm. The lymph node shows tumor metastasis. Lung biopsy review showed a similar tumor. Correlating the ileal and lung biopsies and IHC, the final report was clear cell sarcoma of the ileum. FISH analysis using the LSI EWSR1 (22q12) break apart rearrangement probe (Abbott Molecular/Vysis, Des Plaines, Illinois, United States) was performed.

Immunohistochemical studies were done for programmed cell death ligand 1 (PDL1; VENTANA PD-L1 SP263 Assay; Roche Holdings AG, Basel, Switzerland), which showed a tumor proportion score of 0%. NGS assay was done by custom hybrid capture technique to a minimum depth of 250× on Illumina NovaSeq X Plus (Illumina Inc., San Diego, California, United States) for a 76 therapeutically actionable gene panel and did not show any genomic alteration. A thorough literature review was performed, which suggested sunitinib as an active agent with maximum activity. She was started on Tab sunitinib 25 mg once daily, 2-week-on, 1-week-off protocol. The patient was clinically better and tolerating sunitinib well after two cycles, and the dose was increased to 37.5 mg once daily. She developed grade 3 mucositis, and treatment was withheld and restarted at a 25 mg dose once the toxicity was resolved to grade 1. A response assessment PET CT showed progressive disease with new onset lymph node metastasis, liver metastasis, and L1 vertebrae metastasis, with an increase in the number, size, and metabolic activity of preexisting disease. A nuclear medicine consultation was taken to evaluate the eligibility for peptide receptor radionuclide therapy (PRRT) with Lu-dotatate (Lutetium-177 DOTATATE). The therapy was suggested as a possibility on an experimental basis. However, due to financial constraints, the patient could not proceed with PRRT. The option of palliative chemotherapy with ifosfamide and doxorubicin was suggested, but the patient and relatives were not keen on any further chemotherapy and opted for the best supportive care only. Patient progressed and expired after 4 months. The patient had an overall survival (OS) of 4 years and 5 months from diagnosis. ([Fig. 1])

Fig. 1 (A) Anterior view of the maximum intensity projection, which shows the mesenteric node and lung metastasis. (B) Anterior view of the maximum intensity projection, which shows mesenteric node, serosal deposits, and enteric nodal, lung, and liver metastasis after Sunitinib. (C) The axial section of the fused image of the PET CT shows significant FDG uptake in the mesenteric node. (D) The axial section of the fused image of the PET CT shows significant FDG uptake in the mesenteric node, which has increased in size and number after Sunitinib. (E) Clusters of polygonal cells with round to oval nuclei and moderate eosinophilic cytoplasm. No differentiation features or necrosis. (F) Cell showing one green–orange (yellow) fusion, one orange signal, and one green signal, indicating positive for rearrangement of the EWSR1 gene. (G) Immunohistochemistry for S100P shows diffuse moderate cytoplasmic positivity in tumor cells.

Discussion

GICCS often presents with nonspecific GI symptoms, leading to a delay in diagnosis. Common clinical manifestations include abdominal pain, GI bleeding (melena or hematochezia), nausea, vomiting, bowel obstruction, and unintentional weight loss.[6] In some cases, a palpable abdominal mass may be detected on physical examination, particularly in advanced disease. Due to its aggressive nature, GICCS exhibits a high metastatic potential, frequently spreading through both hematogenous and lymphatic pathways. The liver and lungs are the most common sites of distant metastases, with lymph node involvement also being frequently observed. Additionally, peritoneal dissemination can occur, particularly in cases with intra-abdominal tumor rupture, and bone metastases, though rare, have been reported in advanced disease.[7] [8] The presence of metastasis at the time of diagnosis is a key prognostic factor, with localized disease having a better survival rate compared with metastatic cases.[9] Given the aggressive nature of GICCS and its tendency for early spread, timely diagnosis and a multimodal treatment approach are essential for improving patient outcomes. Due to its infrequent occurrence, effective treatment approaches are still being developed and refined.[10]

For imaging a clear cell sarcoma of the intestine, a CT scan is typically the first line of investigation, which can reveal the tumor's location, size, and potential spread to nearby lymph nodes. It shows a soft tissue mass within the intestinal wall, appearing as a thickened, irregular, or lobulated wall with potential signs of invasion into the mesentery and possible distant metastases to the liver and lymph nodes. MRI may be used for detailed soft tissue evaluation, particularly to assess the tumor's extent within the intestinal wall and surrounding structures.[11] This tumor shows FDG uptake, so FDG PET CT can be used for detecting distant metastasis after surgery and recurrence during follow-up.[12] There is no available literature to suggest Gallium DOTATATE scan positivity in GICCS, but uptake could be due to aberrant SSTR expression.[13]

Grossly appears as a large mass arising from the small bowel. The tumor often spans the entire wall. The histopathological characteristics of GICCS closely resemble those of CCS affecting tendons and aponeuroses. Microscopically, the tumor exhibits fascicles of small, rounded cells with abundant clear or eosinophilic cytoplasm and vesicular nuclei featuring prominent nucleoli. Osteoclast-like giant cells may be seen.[14] In IHC, they are usually positive for S100, SOX10, vimentin, and synaptophysin. They are negative for HMB45, Melan A, CD117, DOG 1, and cytokeratin.[8] Melanocytic markers (HMB45, A103, MITF) are frequently expressed in soft tissue CCS, whereas GICCS typically lacks expression of these markers. S-100 protein expression supports the exclusion of GIST. The histological differential diagnosis for GICSS includes metastatic clear cell sarcoma, GI stromal tumor, melanoma, and monophasic synovial sarcoma.[12]

The hallmark genetic alteration in clear cell sarcoma is the t (12; 22; q13; q12) translocation, which results in the fusion of the EWSR1 gene on chromosome 22 with the ATF1 gene on chromosome 12. This translocation is considered a defining feature of GICSS and is found in the majority of cases.[6] The EWSR1-ATF1 fusion protein is a transcription factor that likely drives tumorigenesis through dysregulation of downstream target genes involved in cellular growth, survival, and differentiation.[8] The genetic alteration is similar to clear cell sarcoma of soft parts. The next common alteration is “EWSR1-CREB1 fusion,” where the EWSR1 gene fuses with the CREB1 gene, creating a fusion protein. Other less common genetic mutations are TP53 and KIT, which may contribute to tumorigenesis and tumor progression.[9]

The treatment of GICSS is challenging due to its aggressive nature and high metastatic potential. Surgery remains the gold standard and primary curative option for localized GICSS. Complete en bloc resection with negative margins (R0 resection) is essential to reduce the risk of local recurrence.[6] Due to the infiltrative nature of the tumor, extensive resections involving the small intestine, mesentery, and adjacent structures may be necessary. Lymphadenectomy is sometimes performed due to frequent lymphatic spread. In cases of unresectable or metastatic disease, debulking surgery may be considered for symptom control, although it does not significantly improve survival. Postoperative recurrence is common, and adjuvant therapies are often required.[8]

The role of chemotherapy in GICCS remains controversial, as the tumor tends to be chemo-resistant compared with other sarcomas. Given the rarity, chemotherapy regimens are often extrapolated from broader sarcoma evidence and clear cell sarcoma of other sites. In retrospective cohorts, anthracycline-based first-line chemotherapy yields only an approximately 4% partial response rate, with a median progression-free survival (PFS) of approximately 11 weeks and OS around 39 weeks.[14] A broader analysis of 23 CCS patients treated across palliative lines found a median PFS of 2.79 months for first-line, dropping to 1.76 months in second-line. Median OS from the start of first-line chemotherapy was approximately 8.2 months. Again, responses were rare; just one partial response was noted.[15] Subsequent lines of therapy show even more limited efficacy, with stable disease observed in a few patients and disease progression predominating.[14] Some studies suggest that high-dose ifosfamide may improve outcomes in certain sarcoma histologies like synovial sarcoma; its role in GICCS is yet to be defined.[16] Gemcitabine-based regimens have been evaluated in a small cohort (n = 5), demonstrating modest activity: median time to progression was only approximately 10 weeks, and metastatic OS was reduced to approximately 28 months.[17] The most frequently used regimen includes doxorubicin with or without ifosfamide. Similar to systemic therapy, data supporting the use of radiotherapy is extrapolated from broader soft tissue sarcoma evidence. Although soft tissue sarcomas are generally considered radioresistant, radiotherapy may help improve local control in cases where surgical margins are inadequate.[9] [18] In cases of palliative treatment, radiotherapy can also be utilized to alleviate symptoms such as pain, obstruction, or bleeding. The exact role of radiotherapy in the management is yet to be defined.

An international multicenter series of 55 patients revealed that targeted therapy with sunitinib produced a modest response rate of approximately 30% and a median PFS of 4 months; however, median OS remained short at approximately 15 months.[19] Given CCS's molecular resemblance to melanoma—especially the involvement of the EWS–ATF1 fusion and melanocytic pathways—immune checkpoint inhibition combined with radiotherapy has been explored. Notably, a single case of mediastinal CCS achieved a durable complete clinical response with pembrolizumab plus radiotherapy, suggesting potential synergy warranting further clinical study.[20] The CREATE trial tested the efficacy and safety of the tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic CCS. Twenty-six out of the 28 patients had MET (+) disease. The PFS with crizotinib in MET+ CCS was similar to the results achieved with doxorubicin.[21] The NCT00557609, a phase 2 trial, has shown that disease control was obtained in 36% of patients with tivantinib, a MET inhibitor.[22]

The IMMUNOSARC II trial (NCT03277924) was a phase II master protocol exploring sunitinib in combination with nivolumab across several sarcoma subtypes, with a dedicated CCS cohort. Patients with advanced, centrally confirmed CCS received continuous daily oral sunitinib alongside nivolumab every 2 weeks. Outcomes from the CCS cohort demonstrated a 6-month PFS rate of approximately 51% (95% CI, 26–75) and a median OS of 17 months. Toxicities were manageable, with no unexpected immune-related events. These data represent the largest prospective evidence of activity for an immune checkpoint inhibitor combined with a tyrosine kinase inhibitor in CCS and suggest a potential therapeutic avenue beyond traditional cytotoxics.[23] The NCT01445379, a phase 1 clinical trial, studied CTLA-4 antibody and immune checkpoint modulator Ipilimumab in pediatric patients with advanced cancers and included two children with metastatic CCS. One of them experienced stable disease for a total duration of six cycles of this treatment.[24] A second trial, access (NCT04274023), was a phase II, single-arm European study evaluating dostarlimab (TSR-042), an anti-PD-1 antibody, specifically in advanced CCS. While enrollment was limited, the study reflects the first prospective effort exclusively targeting CCS with immunotherapy. Unfortunately, the trial was terminated early due to poor accrual, with only three patients enrolled, underscoring the rarity of the disease and the difficulty of conducting robust studies.[25] A phase I/II study sponsored by Rafael Pharmaceuticals is evaluating devimistat (CPI-613), a lipoate analog that targets mitochondrial metabolism, in combination with hydroxychloroquine. The phase I component aims to determine the maximally tolerated dose, while phase II focuses on response rates, pharmacokinetics, and safety in relapsed or refractory CCS. This approach seeks to exploit metabolic vulnerabilities by impairing oxidative phosphorylation and autophagy pathways.[26] The NCT04458922 phase II trial conducted by the National Cancer Institute is testing atezolizumab, an anti-PD-L1 antibody, in patients aged ≥ 2 years with newly diagnosed, unresectable, or metastatic CCS and chondrosarcoma. While enrollment has been challenging and the study is active but not recruiting.[27]

Beyond clinical efforts, preclinical insights are shaping therapeutic hypotheses. Epigenetic modulation with vorinostat, a histone deacetylase inhibitor, has been shown to suppress expression of the EWSR1:ATF1 fusion oncogene by reducing BRD4 (Bromodomain-containing protein 4) binding at its promoter. Combination with the BRD4 inhibitor JQ1 enhanced antiproliferative activity, suggesting that dual inhibition may have synergistic potential.[28] Separately, PRMT5 (Protein Arginine Methyltransferase 5) has been identified as a druggable vulnerability in CCS. Silencing PRMT5 markedly impaired tumor cell growth, while the small-molecule inhibitor JNJ-64619178 demonstrated activity in preclinical CCS models and completed a phase I trial in advanced solid tumors, supporting further exploration.[29] Collectively, these trials and translational studies reflect a transition from conventional cytotoxic therapy to molecularly guided strategies in CCS. Although accrual barriers limit robust clinical evidence, integrating immunotherapy, metabolic inhibitors, and epigenetic agents through collaborative rare cancer networks may represent the future of systemic therapy in this difficult-to-treat sarcoma. The interval to distant recurrence varies significantly, spanning from as short as 2 weeks to as long as 109 months.[30] The median survival is around 18 months.[5]

This case report highlights a case that was initially diagnosed as a large cell neuroendocrine carcinoma of the ileum and treated with surgery and adjuvant chemotherapy. Subsequently relapsed and received palliative chemotherapy. Slide review, repeat biopsy, and further IHC revealed GICCS. GICCS is a rare diagnosis with limited treatment options. The treatment landscape is evolving. We have presented a case with FISH, NGS, and PDL1 testing with an extensive review of the literature, which will contribute to future studies. A limitation of the study is that it is a single case report, and we could not test the fusion partner ATF or CREB due to financial constraints. We did not have any access to clinical trials that could enroll patients with such rare cancers.

Conclusion

GICCS is an extremely rare and aggressive malignant mesenchymal tumor with a poor prognosis. For localized disease, surgical resection is the standard of care. There is no known standard adjuvant treatment at present. Chemotherapy with doxorubicin-based regimens has shown very little efficacy. There is very limited data on targeted treatment and immunotherapy. Next-generation sequencing may help to identify the molecular pathogenesis and targetable pathway alterations and hence tailor the treatment accordingly.

Conflict of Interest

None declared.

Acknowledgment

The authors acknowledge DDRC Agilus Diagnostics Laboratory, Panampilly Nagar, Cochin, Kerala, and Medgenome Laboratory, Bangalore, for their laboratory services.

Patient's Consent

Written informed consent was taken from the patient for publication of this case report.

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Publication History

Article published online:
19 December 2025