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Year : 2020  |  Volume : 63  |  Issue : 1  |  Page : 90-95
Clear cell sarcoma like tumor of gastrointestinal tract: Experience of three cases and review of literature

1 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
2 Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
3 Radiology, All India Institute of Medical Sciences, New Delhi, India

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Date of Web Publication31-Jan-2020


Clear cell sarcoma-like tumor of the gastrointestinal tract (CCSGT) is a rare, aggressive tumor with many histological mimickers. Herein, we have documented our experience of three cases of CCSGT and reviewed the literature. The index cases were identified in male patients in their twenties, one in jejunum and two in the distal colon. Histomorphological examination revealed the characteristic heterogeneous histomorphology with patchy immunohistochemical positivity with S100 protein and negative melanocytic markers. The fluorescence in-situ hybridization test showed translocation of the EWSR1 (22q12) gene in >80% tumor cells. While one of our patients died after 2 years with lung metastasis, the other two patients are still alive on 1.5 years and 3 months follow up, respectively. CCSGT is a rare malignant tumor of the gastrointestinal tract. Although characteristic morphology, use of a judicial panel of immunohistochemical stains, and translocation study for EWSR1 gene can establish the diagnosis, experience in adjuvant therapy is still limited.

Keywords: Clear cell sarcoma-like tumor, EWSR1, gastrointestinal tract, mesenchymal, S100

How to cite this article:
Sonai MK, Rastogi S, Madhusudhan K S, Gupta SD, Das P. Clear cell sarcoma like tumor of gastrointestinal tract: Experience of three cases and review of literature. Indian J Pathol Microbiol 2020;63:90-5

How to cite this URL:
Sonai MK, Rastogi S, Madhusudhan K S, Gupta SD, Das P. Clear cell sarcoma like tumor of gastrointestinal tract: Experience of three cases and review of literature. Indian J Pathol Microbiol [serial online] 2020 [cited 2022 Jan 28];63:90-5. Available from: https://www.ijpmonline.org/text.asp?2020/63/1/90/277367

   Introduction Top

Enzinger initially reported clear cell sarcoma (CCS) of soft tissue in 1965.[1] CCS of soft tissue differs from that of melanoma by lack of BRAF mutations and the presence of EWSR related fusions or translocation. Clear cell sarcoma-like tumor of the gastrointestinal tract (CCSGT) differs from that of a CCS of soft tissue by the presence of osteoclastic giant cells, absence of melanin pigment in tumor cells, and patchy strong S100 positivity with absence of melanocytic differentiation. Ekfors in 1993, reported the first case of CCSGT in the duodenum.[2] In the literature, while a few case reports are available, larger case series are sparse owing to the rarity of this lesion. Herein, we report three cases of CCSGT.

   Case Presentation Top

Patient 1

A 29-year-old male patient presented with anemia and headache for 3 months duration and consulted a private hospital. A contrast-enhanced computed tomography (CECT) scan of the abdomen and pelvis revealed a well-defined mass in the infra-umbilical region, which was in contact with a loop of the small bowel. Similar nodules were noted in the left iliac region and mesentery. Resected intestine revealed a mid-jejunal 5 cm ulcero-proliferative mass extending upto the serosa. It was reported as a case of an undifferentiated mesenchymal tumor and was referred to our hospital.

Patient 2

A 24-year-old male patient, presented to OPD with a prior history of right hemicolectomy, was diagnosed with a case of a high-risk type gastrointestinal stromal tumor (GIST). The patient initially was presented with bleeding per rectum. Non-contrast Computed Tomography (NCCT)-Contrast-enhanced Computed Tomography (CECT) whole abdomen showed a sigmoid colon thickening measuring 2 cm [Figure 1]a along with enlarged paracaval and mesenteric lymph nodes with a maximum dimension of 1.5 cm. The serum CEA level was 2 ng/ml. Right hemicolectomy was performed and a diagnosis of a high-risk type gastrointestinal stromal tumor, with the presence of a few osteoclast-like giant cells, was given in another hospital. During his visit to our hospital, blocks from the right hemicolectomy specimen were reviewed, which revealed diagnosis of a CCSGT. Though, there was no mention regarding the cause of lower GI bleed in this patient in the clinical sheet received along with the blocks, we supposed that being a large polypoidal intraluminal growth with ulceration of the overlying mucosa resulted in GI bleed. The disease recurred in the form of multiple, oval, peripherally enhancing, hypodense, centrally necrotic lesions in the right lobe of liver with nodular opacities.
Figure 1:(a) Axial contrast-enhanced CT scan of patient 2 showing a polypoidal mass (arrow) in the sigmoid colon. (b) Gross photomicrograph of the polypoidal sigmoid colon tumor (arrows) in patient 3 almost obliterating the lumen. (c) Coronal contrast-enhanced CT images of patient 3 showing polypoidal soft tissue mass in the proximal sigmoid colon (arrows)

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Patient 3

A 28-year male patient presented with bleeding per rectum for 8 months. Colonoscopy showed an ulcerated lesion, restricted in the sigmoid colon. Biopsy showed features suggestive of CCSGT. Later, the resection specimen showed a transmural polypoidal growth measuring 5.5 cm in its largest dimension, invading the mucosa to form an ulcer and occluding the lumen partially [Figures 1]b and [Figures 1]c.

Histological analysis in three cases

All the three cases showed lobulated tumors, with heterogeneity of pattern of tumor cell arrangements; comprising of epithelioid to spindle-shaped cells arranged in nests, sheets, and focal pseudopapillary pattern, separated by thin collagen septa, and infiltrated by few lymphocytes and plasma cells [Figure 2]a. The pseudopapillary pattern of the tumor cells was formed due to necrosis of tumor cells away from vessels and viable perivascular tumor cells [Figure 2]b. The tumor cells showed oval to elongated plump nuclei with conspicuous nucleoli and mild nuclear pleomorphism. In all the three cases an admixture of the spindled cells and epithelioid cells with clear cytoplasm were noted [Figures 2]c and [Figures 2]d. On an average 6–10 mitotic figures/10hpf were identified, including atypical mitoses. Scattered osteoclast-like multinucleate giant cells were noted in all the three cases [Figure 2]d. Excised tumor from patient 3 showed a sizeable polypoidal tumor, almost occluding the whole lumen [Figure 2]e. The tumor cells showed patchy immunopositivity for S100 protein [Figures 2]f and [Figures 2]g, while they were negative for melanocytic differentiation markers including cytokeratin, Melan A, and HMB 45. The S100 positivity was noted both in tumor cell nuclei and cytoplasm [Figures 2]e and [Figures 2]g. The tumor cells were also negative for CD117, DOG1, CD34, and smooth muscle actin. While chromogranin stain in all our three cases was negative, tumor cells from patient 1 showed focal positivity for CD56 [Figure 2]h. CD68 stain positivity was noted in the osteoclastic-like giant cells and in approximately 10% to 15% tumor areas scattered throughout the tumors. Fluorescence-in-situ hybridization (FISH) was performed in all the three cases from sections cut from the formalin-fixed paraffin-embedded tissues, using the Cytotest LSP EWSR1 5' CytoOrange/LSP EWSR1 3' CytoGreen probes to detect EWSR1 translocation. In all three cases, EWSR1 gene rearrangement was detected with percentage of cells showing translocation more than 80% (>15% of cells showing translocation was considered as positive), confirming a diagnosis of CCSGT [Figure 2]i.
Figure 2: Photomicrographs show a heterogeneous, lobulated tumor (arrows) [a ×40], comprising of epithelioid cells with clear cytoplasm (b ×200 [arrows]) and spindled cells, along with a few osteoclastic giant cells [c ×100]. In one patient, a large polypoidal intraluminal mass was noted (arrows) [d ×40]. The tumor showed patchy nuclear and cytoplasmic positivity for S100 protein (arrows) [e ×100; f ×200] and negativity for HMB45 stain [g ×40]. Focally CD56 stain was positive (arrow) [h ×200]. The nuclei in figue I shows EWSR1 (22q12) translocation

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Treatment and follow-up

Patient 1 was treated by Pazopanib (tyrosine kinase inhibitor) 400 mg OD for 3 months, postsurgery. The dose could not be escalated due to toxic myalgia. At 6 months follow up, he showed progressive disease, therefore, methotrexate was started and surgery was repeated in another hospital. The patient died after 25 months following initial diagnosis with lung metastasis.

Patient 2 had received chemotinib (400 mg/day). After the revision of diagnosis and surgical excision at our center, no further adjuvant therapy was given. The patient, however, started herbal medicines of his own. Till the last follow up after 1.5 years of initial diagnosis, he is still alive doing all routine chores.

Patient 3 came to follow-up 3 months after surgery with no evidence of relapse or new lesions. His general condition markedly improved.

   Discussion and Conclusions Top

CCSGT is a distinct tumor compared with its soft tissue counterpart by the lack of melanocytic differentiation while retaining the neurogenic differentiation and characteristic histomorphology. While the CCSGT shows the presence of osteoclastic giant cells, the giant cells present in CCS of soft tissue is usually not osteoclastic (number of nuclei <50/cell). So far sixty-seven cases of CCSGT have been reported in the English literature, described predominantly in young adults with symptoms of bleeding, anemia, and intestinal obstruction [Table 1]. In our study, all three patients were male ranged from 24 to 29 years. CCSGT presents as a mass arising in the muscular layer with recurrent ulceration through overlying mucosa.[2] The most common sites of initial presentation are small bowel, colon, and stomach. One of the index cases showed a jejunal mass, while the other two cases were noted in descending colon and sigmoid colon.
Table 1: All reported cases of Clear cell sarcoma.like tumor of the gastrointestinal tract and their characteristics

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CCSGT is characterized by the hallmark EWSR related rearrangements including EWSR-CREB and EWSR-ATF gene fusions.[3] Microscopically, CCSGT shows monotonous epithelioid cells arranged in various patterns including solid, nests, and pseudopapillary architectures. Osteoclast-type giant cells are frequently seen.[4] No melanin pigment or melanocytic differentiation was identified in all the three index cases, as described previously.[4] Previous ultrastructure studies demonstrated premelanosomes, atypical melanosomes, and melanosome like structures in CCSGT, along with long interdigitating processes noted in these tumor cells.[2],[3],[4] Articles published post–2006 demonstrated only melanosomes. It is customary to look for expression of GIST markers (CD117, DOG1, or CD34), in tumors of the gastrointestinal tract (GIT) showing spindled to epithelioid morphology. Sometimes the pseudopapillary arrangement can mimic a solid pseudopapillary tumor of the pancreas, which can be differentiated by immunopositivity for β-catenin, CD10, SOX11, vimentin, and progesterone receptors. Sometimes CCSGT can show the focal expression of neuroendocrine markers, as was seen with CD56 in only one of our cases; however, this positivity is never diffuse. SOX10 positivity has been described in CCSGT, which also suggests a neuroectodermal differentiation. Both CCS and CCSGT show similar fusions involving EWSR-ATF1 and EWSR-CREB1; however, as described previously, histomorphology and immunophenotype of CCS and CCSGT are different.[4] CCSGT is different from that of the melanoma by the absence of pleomorphic tumor cells, the absence of CD117 positivity (65% of melanoma cases), the absence of a known skin primary, lack of BRAF and other driver mutations of melanoma, and presence of EWSR-ATF1 and EWSR-CREB1 fusions in CCSGT.

CCSGT, in general, has an aggressive course with potential for distant metastasis to liver, lymph nodes, lung, pancreas, and brain, regardless of the type of fusion.[2],[4],[5],[6],[7] Metastasis can be the initial presentation or can develop later in the disease course, months after the initial diagnosis.[5] Out of the three index cases, in patient 2 metastases to the liver and lung were noted. Progression of disease and lung metastasis was noted later in patient 1.

Few of the patients with CCSGT in literature had a history of exposure to chemotherapy and radiotherapy due to other diseases during their childhood period including neuroblastoma, hepatoblastoma, acute lymphoblastic leukemia, and Ewing's sarcoma.[8],[9],[10],[11],[12] Hence, exposure to radiotherapy and chemotherapy has also been regarded as an etiology for the development of CCSGT and the same needs to be investigated further. Surgery is the mainstay of treatment. Reports on the effect of chemotherapy and radiotherapy on CCSGT is limited.[6] In patient 1, a tyrosine kinase inhibitor was used in low dosage postoperatively. However, the disease progressed and metastasis took place later, followed by the demise of the patient. Patient 3 showed optimal improvement after surgical excision and no adjuvant therapy was instituted.

In summary, we herein have described three cases of CCSGT, all of which showed classical histomorphology, immunophenotype, and EWSR rearrangement, with evidence of metastasis to the lung in two cases. While one of them died due to metastasis, the other two are still alive, one with metastasis under adjuvant treatment and the other symptom-free. Adjuvant therapy is not standardized and the experience is limited.

Ethics Approval

Approval of the Institute's ethics committee was taken.

Declaration of patient consent

Informed consent was taken for all surgical and therapeutic procedures and for using the archival material for academic and research purposes as per the routine protocol.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Enzinger FM. Clear-cell sarcoma of tendons and aponeuroses. An analysis of 21 cases. Cancer 1965;18:1163-74.  Back to cited text no. 1
Ekfors TO, Kujari H, Isomaki M. Clear cell sarcoma of tendons and aponeuroses (malignant melanoma of soft parts) in the duodenum: The first visceral case. Histopathology 1993;22:255-9.  Back to cited text no. 2
Donner LR, Trompler RA, Dobin S. Clear cell sarcoma of the ileum: The crucial role of cytogenetics for the diagnosis. Am J Surg Pathol 1998;22:121-4.  Back to cited text no. 3
Antonescu CR, Nafa K, Segal NH, Dal Cin P, Ladanyi M. EWS-CREB1: A recurrent variant fusion in clear cell sarcoma--association with gastrointestinal location and absence of melanocytic differentiation. Clin Cancer Res 2006;12:5356-62.  Back to cited text no. 4
Mehta A BK, Massarani R, Esposito T, Abood G, Shoup M. Clear cell sarcoma of the jejunum—Surgical management in two patients with review of the literature. Case Rep Clin Med 2013;2:272-6.  Back to cited text no. 5
Libertini M, Thway K, Noujaim J, Puls F, Messiou C, Fisher C, et al. Clear cell sarcoma-like tumor of the gastrointestinal tract: Clinical outcome and pathologic features of a molecularly characterized tertiary center case series. Anticancer Res 2018;38:1479-83.  Back to cited text no. 6
Hui M, Uppin S, Mehta J, Krishnamani K, Gandhi LV. An unusual case of clear cell sarcoma presenting as multiple abdominal masses confirmed by RT-PCR. South Asian J Cancer 2013;2:152.  Back to cited text no. 7
[PUBMED]  [Full text]  
Zambrano E, Reyes-Mugica M, Franchi A, Rosai J. An osteoclast-rich tumor of the gastrointestinal tract with features resembling clear cell sarcoma of soft parts: Reports of 6 cases of a GIST simulator. Int J Surg Pathol 2003;11:75-81.  Back to cited text no. 8
Yang JC, Chou AJ, Oeffinger KC, La Quaglia MP, Wolden SL. Clear cell sarcoma of the gastrointestinal tract after very low-dose therapeutic radiation therapy: A case report. J Pediatr Surg 2012;47:1943-5.  Back to cited text no. 9
Balkaransingh P, Saad SA, Govil SC, Thind PK, Ballance CM, Weiss AR. Clear cell sarcoma of the gastrointestinal tract presenting as a second malignant neoplasm following neuroblastoma in infancy. Pediatr Blood Cancer 2012;58:481-2.  Back to cited text no. 10
Thway K, Judson I, Fisher C. Clear cell sarcoma-like tumor of the gastrointestinal tract, presenting as a second malignancy after childhood hepatoblastoma. Case Rep Med 2014;2014:984369.  Back to cited text no. 11
Insabato L, Guadagno E, Natella V, Somma A, Bihl M, Pizzolorusso A, et al. An unusual association of malignant gastrointestinal neuroectodermal tumor (clear cell sarcoma-like) and Ewing sarcoma. Pathol Res Pract 2015;211:688-92.  Back to cited text no. 12

Correspondence Address:
Prasenjit Das
Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_195_19

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