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Year : 2021  |  Volume : 64  |  Issue : 2  |  Page : 373-375
Malignant gastrointestinal neuroectodermal tumor-A case report

1 Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, Tamil Nadu, India
2 Department of Surgical Gastroenterology, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, Tamil Nadu, India

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Date of Submission23-Mar-2020
Date of Decision09-Jun-2020
Date of Acceptance09-Jul-2020
Date of Web Publication9-Apr-2021


Malignant gastrointestinal neuroectodermal tumor (GNET) is a rare neoplasm with unknown etiology. It was previously referred to as Clear cell sarcoma of gastrointestinal tract. This tumor is characterized by a higher rate of local recurrence and metastasis. Due to its aggressive clinical course, distinguishing this entity from various other mimickers is very essential. Herein, we present a case of malignant GNET in a 33-year-old male patient.

Keywords: Clear cell sarcoma of gastrointestinal tract, EWSR1, Malignant gastrointestinal neuroectodermal tumor

How to cite this article:
Harshavardhini S, Saishalini C N, Pavithra V, Shah NM, Sankar S. Malignant gastrointestinal neuroectodermal tumor-A case report. Indian J Pathol Microbiol 2021;64:373-5

How to cite this URL:
Harshavardhini S, Saishalini C N, Pavithra V, Shah NM, Sankar S. Malignant gastrointestinal neuroectodermal tumor-A case report. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 May 16];64:373-5. Available from: https://www.ijpmonline.org/text.asp?2021/64/2/373/313277

   Introduction Top

Malignant gastrointestinal neuroectodermal tumor (GNET) is an extremely rare entity with neuroectodermal differentiation. The old nomenclature, clear cell sarcoma of gastrointestinal tract has been replaced by the term GNET. Only 50 cases of this entity have been reported in the literature so far, with minimal Indian data.[1] Clear cell sarcoma was initially described by Enzinger et al.[2] in the distal limb deep soft tissues. The first ever visceral case was reported in the duodenum by Ekfors et al.[3] Considering the sparse data available in Indian literature, reporting of this case is of paramount importance.

   Case History Top

A 33-year-old gentleman with no known comorbidities presented with complaints of continuous, dull aching, lower abdominal pain for the past one year. It was associated with vomiting, 2-3 episodes every third day, which was partly bilious. The patient was initially investigated in an outside hospital, where he was found to have severe anemia and was transfused with 4 units of packed red blood cells. During routine examination in our hospital outpatient department, patient still had severe pallor, with no significant systemic examination findings.

Routine investigations revealed hemoglobin of 8.2 gm/dl, with peripheral blood smear showing microcytic hypochromic blood picture. Serum iron studies confirmed the iron deficiency status, with low serum iron level—29.59 pg/dl (70-180 pg/dl), increased total iron binding capacity—365.30 pg/dl (155-355 pg/dl) and low transferrin saturation—8.1% (20-50%). Upper gastrointestinal endoscopy showed normal study. CECT whole abdomen showed an asymmetrical wall thickening involving a short segment of mid ileal loop of approximate length 2.5 cm with a maximum thickness of 0.9 cm, with an arterial mucosal hyper enhancement and progressive venous enhancement. Few enlarged lymph nodes were also noted in the perilesional area. The final impression suggested a possibility of malignant etiology with a differential diagnosis of adenocarcinoma/carcinoid [Figure 1]a and [Figure 1]b
Figure 1: CECT abdomen (axial view) (a) arterial phase and (b) venous phase showing short segmental wall thickening of mid- ileal loops showing hyper enhancement on arterial phase with progressive venous enhancement, (c) Gross image showing a submucosal ulcerative lesion of size 1.8 × 1 × 0.8 cm

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The patient was taken up for surgery and intraoperatively, a firm growth was noted in the jejuno-ileal junction with significant lymphadenopathy in the mesentery. Segmental resection and anastomosis with mesenteric lymphadenectomy was done and the specimen was sent for routine histopathological examination. The postoperative period was uneventful and was discharged on postoperative day 7.

Grossly we received a segment of small bowel measuring 13.5 cm in length. Examination of the specimen showed a submucosal ulcerative lesion of size 1.8 × 1 × 0.8 cm, which was 5.3 cm from proximal resected end, 6 cm from distal resected end and 0.1 cm from the radial margin [Figure 1]c. Histopathological examination revealed an ulcerated small intestinal mucosa with a submucosal lesion composed of sheets and nests of tumor cells having moderate eosinophilic cytoplasm with round to oval nucleus having vesicular chromatin and many of them showing prominent nucleoli. Atypical mitotic figures were also noted (10/10 HPF) [Figure 2]a and [Figure 2]b. Of the three lymph nodes examined, one node appeared to be infiltrated by tumor cells [Figure 2]c and [Figure 2]d. With these histopathological findings, the initial differentials considered were epithelioid gastrointestinal stromal tumor (GIST), neuroendocrine carcinoma, melanoma, and malignant gastrointestinal neuroectodermal tumor.
Figure 2: (a) H and E examination, scanner power view shows ulcerated small intestinal mucosa with a submucosal lesion. (b) Higher power view shows sheets and nests of tumor cells having moderate eosinophilic cytoplasm with round to oval nucleus having vesicular chromatin with many of them showing prominent nucleoli, (c) and (d) H and E examination of lymph node shows infiltration by tumor cells in scanner and higher power view

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A panel of Immunohistochemical markers comprising of vimentin, S-100, SOX-10, synaptophysin, chromogranin, INSM-1, DOG-1, HMB-45, and Ki67 proliferative index was suggested to arrive at a confirmatory diagnosis. The tumor cells were diffusely positive for vimentin, showed diffuse cytoplasmic positivity for S-100, diffuse nuclear positivity for SOX-10 and were also focally positive for synaptophysin. Chromogranin, INSM-1, DOG-1, and HMB-45 were negative ruling out GIST and tumors with neuroendocrine and melanocytic differentiation. Ki67 labelling index was 20%. This immunohistochemical pattern favored a diagnosis of Malignant Gastrointestinal Neuroectodermal tumor [Figure 3].
Figure 3: Immunohistochemistry shows (a) Diffuse cytoplasmic positivity for S.100; (b) Diffuse nuclear positivity for SOX.10; (c) Ki67 labelling index of 20%

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For molecular confirmation of EWSR-1 gene rearrangement, the tissue blocks were sent to a referral hospital. The analysis was performed using Interphase Fluorescent In Situ Hybridisation (FISH) technique. Of the total 55 tumor cell nuclei counted, 81% showed split signals, and fusion signals were noted in 19% of tumor cell nuclei, confirming EWSR-1 gene rearrangement.

Post-surgery, the patient was started on the chemotherapy regimen of Vincristine, Etoposide, Adriamycin, Cyclophosphamide, Mesna, and Ifosfamide. Follow up PET/CECT post 8 cycles of chemotherapy showed no residual FDG uptake. Subsequently the patient was lost to follow up.

   Discussion Top

GNETs are rare neoplasms with unknown etiology. It has a predilection for young adults, with a mean patient age of 33 years. No sex preponderance has been found so far. It often metastasizes to lymph nodes and liver at the time of presentation. Grossly, tumors form an endophytic polypoidal mass or mural lesions, often with ulceration resembling carcinomas. Histopathologically, an epithelioid or spindle cell morphology arranged in various patterns is seen.[4] Morphological differentials include metastatic melanoma, gastrointestinal stromal tumor (GIST), neuroendocrine carcinoma, leiomyosarcoma, de-differentiated liposarcoma, perivascular epithelioid cell sarcoma, synovial sarcoma, and metastatic clear cell carcinoma. Immunohistochemical studies show GNET to be positive for S-100, SOX-10, CD56 and synaptophysin.[5]This confirmation is essential to differentiate from other intramural tumors like GIST, for which effective targeted therapy is available.[6]

At molecular level, GNET is characterized by the Ewings sarcoma breakpoint region 1 gene (EWSR1) rearrangement involving t(12;22) which results in EWSR1-ATF1 fusion and t(2;22) that leads to EWSR1-CREB1 fusion.[7] Whereas this rearrangement has also been identified in other distinctive tumors like Ewings sarcoma, hyalinizing clear cell carcinoma of the salivary gland, myoepithelial carcinoma, extrasketelal myxoid chondrosarcoma, myxoid liposarcoma, angiomatoid fibrous histiocytoma, and desmoplastic small round cell tumors. Therefore, EWSR1 gene rearrangement is not a specific but a sensitive criterion that aids in confirming the diagnosis of GNET. Though being a highly aggressive tumor, because of its rarity, the prognostic data of this tumor is limited, and no staging criteria has been defined so far.[8]

Zambrano et al. described this entity as an osteoclast-rich tumor of gastrointestinal tract with features resembling clear cell sarcoma of soft parts.[9] The term malignant GNET was first designated by Stockman et al., based on its ultrastructural and immunohistochemical features and suggested that these tumors originated from an autonomic nervous system-related primitive cell of neural crest derivation that shows a neural line of differentiation with complete absence of melanocytic features This series included 16 cases, of which large proportion of cases were found to have metastasis at the time of presentation, especially to lymph nodes or liver.[10]

An article by Chang et al. is the largest case series available in the literature so far, which has reviewed 19 cases of GNET, with small intestine being the commonest site involved. Varied histological patterns were observed and IHC was positive for S100, SOX10, vimentin, synaptophysin, CD56, CD99 and CD117. EWSR1 rearrangement was observed in 14 of 15 patients tested.[11]

Antonescu et al. were the first to describe a recurrent translocation of EWSR1 resulting in EWSR1-CREB1 fusion. This study concluded that GNET expresses neuroectodermal markers and lacks melanocytic differentiation.[12]

In conclusion, GNET is an extremely rare malignant tumor of the GI tract that can be mistaken for other non-epithelial GI tumors. Based on the above findings, GNET has to be suspected and diagnosed promptly due to its aggressive clinical course in general. Awareness of its existence and diagnostic criteria by the pathologist is necessary to avoid misdiagnosis.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Prado G, Gorcey SA, Szallasi A, Maluf H. Indolent gastrointestinal neuroectodermal tumor (GNET) of the colon: A new entity. J Gastrointest Cancer Stromal Tumor 2017;2:2.  Back to cited text no. 1
Enzinger FM. Clear-cell sarcoma of tendons and aponeuroses. An analysis of 21 cases. Cancer 1965;18:1163-74.  Back to cited text no. 2
Ekfors TO, Kujari H, Isomäki M. Clear cell sarcoma of tendons and aponeuroses (malignant melanoma of soft parts) in the duodenum: The first visceral case. Histopathology 1993;22:255-60.  Back to cited text no. 3
Kong J, Li N, Wu S, Guo X, Gu C, Feng Z. Malignant gastrointestinal neuroectodermal tumor: A case report and review of the literature. Oncol Lett 2014;8:2687-90.  Back to cited text no. 4
Alyousef MJ, Alratroot JA, ElSharkawy T, Shawarby MA, Hashem TM, Alsayyah A. Malignant gastrointestinal neuroectodermal tumor: A case report and review of the literature. Diagn Pathol 2017;12:29.  Back to cited text no. 5
Jagtap SV, Nikumbh DB, Kshirsagar AY, Bohra A, Khatib W. Malignant gastrointestinal stromal tumor of the sigmoid colon with perforation and peritonitis-an unusual presentation. Int J Health Sci Res 2012;2:104-9.  Back to cited text no. 6
Toon CW, Cooper W, Selinger C, Berney CR, Tomlinson J. Malignant gastrointestinal neuroectodermal tumour (GNET): Neural mesenchymal tumours of the gastrointestinal tract with striking histology and EWSR1 gene rearrangement. Pathology 2019;51:324-7.  Back to cited text no. 7
Kansal S, Rao S. Malignant gastrointestinal neuroectodermal tumor: A unique rare neoplasm. Indian J Surg Oncol 2017;8:630-3.  Back to cited text no. 8
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. 9
Stockman DL, Miettinen M, Suster S, Spagnolo D, Dominguez-Malagon H, Hornick JL, et al. Malignant gastrointestinal neuroectodermal tumor: Clinicopathologic, immunohistochemical, ultrastructural, and molecular analysis of 16 cases with a reappraisal of clear cell sarcoma-like tumors of the gastrointestinal tract. Am J Surg Pathol 2012;36:857-68.  Back to cited text no. 10
Chang B, Yu L, Guo WW, Sheng WQ, Wang L, Lao I, et al. Malignant gastrointestinal neuroectodermal tumor: Clinicopathologic, immunohistochemical, and molecular analysis of 19 cases. Am J Surg Pathol 2020;44:456-66.  Back to cited text no. 11
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. 12

Correspondence Address:
C N Saishalini
Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai - 600 116, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_269_20

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