Figure 3 - uploaded by Jun Zhou
Content may be subject to copyright.
Relatively solid area of GNET composed of the relatively monomorphic epithelioid or polygonal cells with eosinophilic cytoplasm and vesicular nu- clei.
Source publication
A malignant gastrointestinal neuroectodermal tumor (GNET), a distinctive entity covering the characteristics of clear cell sarcoma (CCS) of gastrointestinal tract described recently, arising primarily in the ileum of a 33-year-old woman is reported. Histologically, the neoplasm involved the full thickness of the intestinal wall. Tumor cells, mainly...
Citations
... In 2012, Stockman et al. [3] proposed to redesignate this tumor class as GNET instead of 'clear-cell sarcoma-like tumor of the gastrointestinal tract' (CCSLTGT), and this term has been increasingly accepted by pathologists [1][2][3][4][5][6]. Furthermore, GNET can be histologically misdiagnosed as another epithelioid and/or spindle cell neoplasm [7]. ...
... Most cases have been described in the small intestine in addition to the stomach and the colon [1][2][3][4], following an aggressive clinical behavior with local recurrence and metastatic disease to lymph nodes or hematogenous spread early at the time of diagnosis [4][5][6]. ...
Malignant gastrointestinal neuroectodermal tumor (GNET) is an infrequent soft-tissue sarcoma, formerly referred to as clear-cell sarcoma-like gastrointestinal tumor (CCSLGT) and frequently reported in the literature as clear-cell sarcoma of the gastrointestinal tract (CCS-GI); it is characterized by an absence of melanocytic differentiation and the presence of nontumoral osteoclast-like giant cells (OLGCs). The current study reports a case of a 79 year old woman admitted to the emergency department (ED) with symptoms of constipation and intestinal obstruction; a mass was found within the ileal wall necessitating of surgical approach. Immunohistochemically, tumor cells surprisingly had the hallmark of GNETs. Unfamiliarity with tumors with the features of GNETs can easily lead to a misdiagnosis by surgical pathologist. Therefore, comprehensive evaluation, including morphology and additional studies, is required for an appropriated diagnosis. Furthermore, without a high index of suspicion, there is actually no consensus on staging or treatment.
... GNET and GIST share some characteristics where both tumors arise in the gastrointestinal tract wall and microscopically show spindle and/or epithelioid cells. However, GIST does not typically show osteoclast-like multinucleated giant cells [12]. Malignant giant cell tumors and leiomyosarcoma are also included within the list of differentials that need to be excluded. ...
Gastrointestinal neuroectodermal tumors (GNETs) are malignant tumors frequently arising within the muscularis propria of the gastrointestinal tract and often extend into the submucosa and subserosa. The stomach is the second most common site of incidence of GNETs after the small intestine. The most important differential of GNET is the clear cell sarcoma-gastrointestinal (CCS-GI). Both share similar morphological as well as molecular features and show S100 positivity; however, the lack of melanocytic differentiation in GNET distinguishes it from CCS-GI. Both typically show rearrangements of the EWSR1 gene, with t(12;22) (q13;q12) EWSR1-ATF1 or t(2;22) (q34;q12) EWSR1-CREB1 fusions. We present a case of a 71-year-old man with an incidentally discovered GNET in the gastric cardia and fundus.
... Stockman et al. suggests that GNET tumors "may arise 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", supporting the Antonescu et al. theory of GNET arising from neuroectodermal precursor cells with lost differentiating potential [3,10]. Additionally, it is notable that mitotic rate and Ki-67 of reported GNET cases spanned a wide range between 1-30 (most cases around 10-12) of 10 High Power Field and 5-90% (most cases around 20%) respectively [1,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. This observation is consistent with our reported cases. ...
... Singh et al. reported a 61-year-old African American patient with a resected GNET of the right colon harboring a EWSR1-CREB1 fusion that experienced a DFS of 7 years before metastatic recurrence after adjuvant platinum and etoposide chemotherapy [22]. Other adjuvant sarcoma-based systemic treatments such as doxorubicin or epirubicin and ifosfamide, doxorubicin and dacarbazine, dacarbazine and cisplatin, vincristine, doxorubine and cyclophosphamide have been used in some case reports with variable outcomes and follow up [1,14,15,18,25,40,41]. Some reports did not specify the type of adjuvant chemotherapy [2,13,24,42,43]. ...
Malignant gastrointestinal neuroectodermal tumor (GNET) is an ultra-rare soft tissue sarcoma, therefore often misdiagnosed and has no available standard treatment. Here, we report 3 cases of metastatic GNET with variable clinical courses. Our small case series as well as extensive literature review, further support that GNET is a spectrum of diseases with variable inherent biology and prognosis. Surgical management in the setting of recurrent/metastatic disease may be appropriate for GNET with indolent nature. Response to systemic treatments including chemotherapy and targeted treatments is variable, likely related to heterogenous biology as well. Furthermore, we retrospectively identified 20 additional GNET cases from Foundation Medicine’s genomic database and expanded on their clinicopathological and genomic features. Comprehensive genomic profiling (CGP) with DNA and RNA sequencing of this cohort, in the course of clinical care, demonstrated recurrent EWSR1 chromosomal rearrangements and a sparsity of additional recurrent or driver genomic alterations. All cases had low tumor mutational burden (TMB) and were microsatellite stable.
... The most common site of involvement of GNET is the small intestine (72%). Ileum is the most common site (24 cases) [4,5,[7][8][9][10][12][13][14][19][20][21][22][23][24][25] followed by stomach in 12 cases [5,7,8,11,15,16,[26][27][28] and jejunum in 12 cases. [5,7,8,12,17,[29][30][31] In seveb cases, [5,6,18,22,32] the exact site of involvement was not specified, though all these cases were located in the small bowel. ...
... [38] Although there is no consensus for chemotherapy after the surgical excision, three patients received chemotherapy. [11,13,24] ...
Malignant gastrointestinal (GI) neuroectodermal tumor is an extremely rare entity that was first described by Zambrano et al. in 2003 as "clear cell sarcoma (CCS)-like tumor of the GI tract." It shares some of the histopathological features of CCS but lacks the immunohistochemical (IHC) reactivity for melanocytic markers. Most mesenchymal neoplasms of the GI tract belong to the category of GI stromal tumors and are characterized by the IHC expression of c-KIT. In cases, without detectable KIT receptor expression, several differential diagnoses have to be taken into consideration. In this article, we describe such a case and present a review of all the reported cases till date. We also present the current available knowledge on its pathology and molecular genetics along with the limitations in its diagnosis. Here, we report a case of a 32-year-old man with a tumor of the small bowel composed of polygonal tumor cells arranged in solid nests, alveolar pattern, and pseudopapillary and admixed with numerous osteoclast-like multinucleated giant cells. Immunohistochemically, the tumor cells strongly expressed S-100 protein only. HMB-45, melan-A, CD117, cytokeratin, desmin, smooth muscle actin, and CD-34 were absent. Ki-67 index was 15%. The diagnosis was further confirmed by fluorescence in situ hybridization (FISH) demonstrating the presence of EWSR1 (22q12) translocation. A final diagnosis of malignant gastroneuroectodermal tumor was rendered. The patient is disease-free for 20 months of postsurgery. The diagnosis of this entity should be considered in the presence of S-100-positivity and multinucleated osteoclastic giant cells and the absence of melanocytic differentiation in a tumor arising from GI tract. Further confirmation can be done by performing FISH analysis.
... CCSLGTs mostly affect young adults and children without a sex predilection [1,25]. These often arise from the wall of the small intestine, rarely from the wall of stomach, colon, and peritoneum. ...
... In contrast to CCS of the soft tissue (previously known as melanoma of the soft tissue), CCSLTGT was initially described as a distinct entity by Zambrano et al (2) in 2003 from a series of 6 cases that were characterized histologically by the presence of osteoclast-like giant cells (OLGCs) and immunohistochemically by the absence of melanocyte-specific markers. An increasing number of cases support that CCSLTGT is a distinctive tumor entity, and not a variant of CCS of the soft tissue (3)(4)(5)(6)(7)(8)(9)(10). However, the pathological nature of CCSLTGT is distinguishable from CCS of the soft tissue in that it always arises in tendons and aponeuroses, and shows melanocytic differentiation at the light microscopic, ultrastructural and protein levels (1,10). ...
... However, the pathological nature of CCSLTGT is distinguishable from CCS of the soft tissue in that it always arises in tendons and aponeuroses, and shows melanocytic differentiation at the light microscopic, ultrastructural and protein levels (1,10). In 2012, Stockman et al (6) proposed to re-designate this tumor entity as a 'malignant Primary malignant gastrointestinal neuroectodermal tumor occurring in the ileum with intra-abdominal granulomatous nodules: A case report and review of the literature gastrointestinal neuroectodermal tumor' (GNET) instead of a CCSLTGT, and this term has been increasingly accepted by pathologists (7)(8)(9)(11)(12)(13). Based on recent studies, cases that were previously reported as soft tissue-type CCS of the gastrointestinal tract (CCS-GI) lacking melanocytic differentiation may be appropriately categorized as CCSLTGT or GNET, although a GNET remains a controversial tumor entity (1)(2)(3)(4)(6)(7)(8)(9)(10)(11)13). ...
... In 2012, Stockman et al (6) proposed to re-designate this tumor entity as a 'malignant Primary malignant gastrointestinal neuroectodermal tumor occurring in the ileum with intra-abdominal granulomatous nodules: A case report and review of the literature gastrointestinal neuroectodermal tumor' (GNET) instead of a CCSLTGT, and this term has been increasingly accepted by pathologists (7)(8)(9)(11)(12)(13). Based on recent studies, cases that were previously reported as soft tissue-type CCS of the gastrointestinal tract (CCS-GI) lacking melanocytic differentiation may be appropriately categorized as CCSLTGT or GNET, although a GNET remains a controversial tumor entity (1)(2)(3)(4)(6)(7)(8)(9)(10)(11)13). To the best of our knowledge, only 47 cases that may represent a GNET have been reported in the English or Chinese languages, including 31 of which appear to be reported as a CCSLTGT or GNET and 16 that correspond to CCS-GI lacking melanocytic differentiation. ...
Malignant gastrointestinal neuroectodermal tumors (GNETs) are rare aggressive malignant neoplasms that exclusively occur within the wall of the gastrointestinal tract. The GNET was first described as an ‘osteoclast-rich tumor of the gastrointestinal tract with features resembling clear cell sarcoma (CCS) of soft parts’ in 2003. Although the GNET shares certain histological features with CCS, it is characterized by a lack of melanocytic differentiation and the presence of non-tumoral osteoclast-like giant cells (OLGCs). The present study reports a case of a GNET of the ileum with intra-abdominal granulomatous nodules, an uncommon accompanying finding, and summarizes the current literature. A 30-year-old woman presented with the symptoms of intestinal obstruction, and a mass was found within the ileum wall. Multiple grey-white nodules were found adhering to the omentum and serosa of the ileum. Histologically, the tumor was located in the muscularis propria and infiltrated the mucosa and the serosa. Tumor cells presented with oval or polygonal nuclei and prominent nucleoli, and were predominantly arranged in nested and pseudopapillary patterns, with the presence of cluster of differentiation (CD)68-positive, scattered OLGC. Immunohistochemically, it was determined that the tumor cells expressed Vimentin, CD56, S-100 and transcription factor SOX-10, while being negative for pan-cytokeratin, cytokeratin (CK)7, CK20, synaptophysin, chromogranin-A, CD117, anoctamin-1, CD34, human melanoma black-45, Melan-A, smooth muscle actin, CD3 and CD20 expression. Ewing sarcoma breakpoint region 1 gene rearrangement was identified by fluorescence in situ hybridization analysis. Ultrastructurally, no typical melanosomes were identified. In addition, the intra-abdominal grey-white nodules were microscopically identified as chronic granulomatous inflammation. The patient received four cycles of adjuvant chemotherapy following routine tumor resection. Due to its rarity and histological similarity with other neoplasms, unfamiliarity with the features of GNETs by surgical pathologists can easily lead to a misdiagnosis. Therefore, comprehensive assessments, including morphology and ancillary studies, are required for an accurate diagnosis of GNET.
... With less than 50 cases reported in the English language literature, GNET is now recognized as a rare neoplasm that predominantly arises from the small intestine [10,11], followed by the stomach [12], esophagus [13], and the colon [14]. Patients commonly complain of abdominal pain and weight loss, and some also experience fever, anemia, and melena [7,12]. ...
... Patients commonly complain of abdominal pain and weight loss, and some also experience fever, anemia, and melena [7,12]. GNET is usually treated by surgical excision, followed by chemotherapy if metastatic disease is present [11]. Indeed, almost half of the patients showed lymph node involvement at the time of diagnosis, and many had metastatic liver disease [12]. ...
... Some GNETs showed predominantly epithelioid morphology whereas others were mostly spindled with or without osteoclast-like giant cells [7]. Pseudopapillary [11] and oncocytic [17] variants were also described as potential diagnostic pitfalls. ...
With less than 50 reported cases, Gastrointestinal Neuroectodermal Tumor (GNET) is a rare malignant neoplasm. Here we report an unusual case of GNET with indolent clinical behavior. The patient is a 59-year-old Caucasian man whose 2 cm sigmoid colon mass did not increase significantly in size during a 10-year surveillance colonoscopy. This mass was recently resected due to change in bowel habits. H&E sections revealed a polypoid, low-grade spindle cell neoplasm, arising from the submucosa and infiltrating the muscularis propria. Negative CD117 and DOG-1 stains excluded a diagnosis of Gastrointestinal Stromal Tumor (GIST). The tumor cells were positive for vimentin, S-100, synaptophysin, and CD56. Pertinent negative stains included Melan-A, HMB-45, smooth muscle actin, CD34, and cytokeratin. Electronmicroscopy showed no obvious sign of differentiation. A presumptive diagnosis of GNET was made. FISH for rearrangement of the EWSR1 gene was, however, negative. There was no evidence of metastatic disease at the time of surgery. One year after surgical removal of this tumor, the patient is asymptomatic. We propose that a subset of GNET may follow an indolent clinical course.
... The authors concluded that this entity shares some but not all the features of clear cell sarcoma (CCS) [2]. Up to our knowledge, only 44 cases that may represent GNET were described in the English literature, 29 of which reported as GNET or CCSLTGT [1][2][3][4][5][6][7][8][9] and 15 as CCS in GI but lacked melanocytic differentiation [10][11][12][13][14][15][16][17][18][19]. The clinical, morphologic, immunohistochemical and molecular/cytogenetic features of previously reported GNET cases are presented in (Table 1). ...
... Rosettelike structures and myxoid stroma have been described. Metastatic tumors resemble the primary tumor in morphologic features including the presence of osteoclastlike multinucleated giant cells [1,2,5,7,9]. Our case occurred in the small intestine and followed an aggressive course of disease with local recurrence and unfortunate death of the patient 4 years after initial presentation. ...
Background
Malignant gastrointestinal neuroectodermal tumor (GNET) is an extremely rare entity that was first described by Zambrano et al. in 2003 as “Clear cell sarcoma-like tumor of the gastrointestinal tract”. It shares some of the histological features of clear cell sarcoma (CCS) but lacks the immunohistochemical reactivity for melanocytic markers. We report a case of GNET that was initially misdiagnosed as gastrointestinal stromal tumor (GIST). Recognizing this entity is important to avoid misdiagnosis. Case presentationA case of an 18-year-old male presented with a small intestinal tumor. Histologically it was characterized by polygonal cells arranged in pseudoalveolar pattern and situated in the muscularis propria. Scattered osteoclast-like multinucleated giant cells were also noted. The neoplastic cells were positive for S-100 protein and negative for HMB-45, Melan A, smooth muscle actin, desmin and CD117. EWSR1 gene rearrangement was detected by fluorescence in situ hybridization (FISH) analysis. The patient returned with recurrence after 36 months’ management by surgical resection and died one year later. ConclusionsGNET can be mistaken histologically for other non-epithelial gastrointestinal tumors. Awareness of its existence and diagnostic criteria by the pathologist is necessary to avoid misdiagnosis, particularly as GIST, CCS or malignant peripheral nerve sheath tumor (MPNST).
Malignant gastrointestinal neuroectodermal tumor (GNET) is an extremely rare neoplasm. Immunohistochemically, GNET typically demonstrates neural differentiation but lacks melanocytic differentiation, making it distinct from clear cell sarcoma of the soft tissues (CCS). Herein we report for the first time the cytomorphologic features of lymph node metastasis from presumably liver GNET. A 36-year-old female presented with fevers, night sweats, loss of appetite, and a 20-lbs weight loss. Radiographic imaging showed a 13 cm heterogeneously enhancing mass in the right lobe of the liver and a hypermetabolic 0.9 cm periportal lymph node on positron emission tomography-computed tomography (PET/CT). Initially, a CT-guided liver biopsy was performed followed by right hepatic lobectomy and portal lymphadenectomy. The liver biopsy and resection showed an S100-protein and SOX10 positive malignant neoplasm and genomic profiling of liver biopsy revealed EWSR1-CREB1gene rearrangement. These findings in conjunction with the morphologic and immunohistochemical profile were diagnostic of GNET. Two months later, she presented with recurrent lymphadenopathy in the upper abdomen. Fine needle aspiration of the periportal nodal mass revealed single and clusters of primitive, large to medium-sized neoplastic cells with round to oval nuclei, high nuclear-cytoplasmic ratio, vesicular chromatin, and prominent nucleoli. The tumor cells were S100 protein and SOX10 positive, consistent with metastasis of the patient's recently diagnosed malignant digestive system GNET. Palliative chemotherapy was administered but the patient died a few days later, 4 months from the initial diagnosis. Awareness of this entity and judicial use of ancillary studies including molecular testing are essential for achieving accurate diagnosis.
