Original contributionGlypican 3 expression in tumors with loss of SMARCB1/INI1 protein expression☆,☆☆
Introduction
Glypican 3 (GPC3), which is located in Xq26, is a member of the glypican family of heparin-sulfate proteoglycans. This protein is linked to the cell surface through a glycosylphosphatidylinositol anchor, and is thought to regulate cell growth and apoptosis through interactions with morphogenic or growth factors such as Wnt5a, fibroblast growth factor 2, bone morphogenic protein 7, and tissue factor pathway inhibitor [1], [2], [3]. Loss-of-function mutations in the human GPC3 gene result in Simpson-Golabi-Behmel syndrome, an X-linked condition characterized by severe malformations and pre- and postnatal overgrowth. Furthermore, these patients have a high risk of developing embryonal tumors, mostly Wilms kidney tumor and neuroblastoma [4].
Malignant rhabdoid tumor (MRT), which was originally described in 1978 as a rhabdomyosarcomatoid variant of Wilms tumor, is a rare and highly aggressive embryonal tumor in infancy or childhood [5]. SMARCB1/INI1 (INI1) immunohistochemical expression has not been detected in any MRT cases except in rare examples, and this feature has been reported to be useful for the correct diagnosis of MRT [6], [7], [8]. However, loss of INI1 protein expression has also been demonstrated in all renal medullary carcinomas, almost all epithelioid sarcomas, half of epithelioid malignant peripheral nerve sheath tumors, about half of pediatric myoepithelial carcinomas, and some extraskeletal myxoid chondrosarcomas [9], [10], [11], [12], [13].
In the present study, we analyzed the frequency of GPC3 protein expression in a large series of MRT cases and other tumors with loss of INI1 protein expression. Furthermore, we examined mRNA expressions of GPC3 in frozen samples by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and serum-soluble GPC3 protein in preoperative blood samples by enzyme-linked immunosorbent assay (ELISA).
Section snippets
Patients
Tumors with loss of INI1 protein expression in the present study were selected from among more than 15 000 cases of bone and soft-tissue tumors registered in the Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, between 1955 and 2010. The primary monoclonal antibodies used in the case selection were BAF47, an antibody to the SMARCB1/INI1 gene product (clone 25; 1:250; 20-minute microwave; BD Transduction Laboratories, San Diego, CA). As a
Glypican 3 immunoreactivity
The results of the immunohistochemical analysis are summarized in Table 3. In 6 of the 14 MRTs (42.9%), 1 (2.1%) of the 48 epithelioid sarcomas and 3 of the 5 pediatric undifferentiated soft-tissue sarcomas (60%), overexpression of more than 10% of LI was recognized (Fig. 1A-D). However, all the remaining cases showed absent expression of less than 1% of LI (Fig. 1E-H). GPC3 immunoreactivity was found significantly more frequently in MRT than in epithelioid sarcoma (P = .0003) or proximal-type
Discussion
MRT is characterized by rhabdoid cells having a globoid, and hyaline or eosinophilic intracytoplasmic inclusions [8], [16]. However, the existence of rhabdoid cells is recognized in a wide variety of tumors, such as epithelioid sarcoma, synovial sarcoma, extraskeletal myxoid chondrosarcoma, leiomyosarcoma, malignant mesothelioma and desmoplastic small round-cell tumors [8]. The histological features of proximal-type epithelioid sarcoma particularly resemble those of MRT, especially extrarenal
References (26)
- et al.
Glypican-3 expression in clear cell adenocarcinoma of the ovary
Mod Pathol
(2009) - et al.
Infrequent SMARCB1/INI1 gene alteration in epithelioid sarcoma: a useful tool in distinguishing epithelioid sarcoma from malignant rhabdoid tumor
Hum Pathol
(2009) - et al.
Loss of INI1 expression defines a unique subset of pediatric undifferentiated soft tissue sarcomas
Mod Pathol
(2009) - et al.
Glypican-3, overexpressed specifically in human hepatocellular carcinoma, is a novel tumor marker
Biochem Biophys Res Commun
(2003) - et al.
Glypican-3 is overexpressed in human hepatocellular carcinoma
Cancer Sci
(2003) - et al.
Glypican 3: a novel marker in testicular germ cell tumors
Am J Surg Pathol
(2006) - et al.
Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome
Nat Genet
(1996) - et al.
Histopathology and prognosis of Wilms tumors: results from the First National Wilms' Tumor Study
Cancer
(1978) - et al.
Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression
Am J Surg Pathol
(2011) - et al.
Highly aggressive behavior of malignant rhabdoid tumor: a special reference to SMARCB1/INI1 gene alterations using molecular genetic analysis including quantitative real-time PCR
J Cancer Res Clin Oncol
(2007)
Extrarenal rhabdoid tumors of soft tissue: clinicopathological and molecular genetic review and distinction from other soft-tissue sarcomas with rhabdoid features
Pathol Int
Epithelioid sarcoma: a clinicopathologic and immunohistochemical analysis of 106 cases from the French sarcoma group
Am J Clin Pathol
INI1-deficient tumors: diagnostic features and molecular genetics
Am J Surg Pathol
Cited by (25)
Poorly differentiated chordoma showing loss of SMARCB1/INI1: Clinicopathological and radiological spectrum of 9 cases, including uncommon features of a relatively under-recognized entity
2021, Annals of Diagnostic PathologyCitation Excerpt :Germ cell tumor (GCT) constitutes another differential diagnosis for a poorly differentiated chordoma, especially because of glypican 3 staining, noted in some of these cases, including two cases of this study (Case 6 and 7) and focal brachyury staining reported in GCTs [9,19]. Glypican 3, a membrane-bound heparin sulfate proteoglycan, is mutated in Simpson-Golabi-Behmel syndrome, which is associated with an increased risk of Wilm's tumor and MRT, the latter tumor displays loss of SMARCB1/INI1 and initially designated as a rhabdomyosarcomatoid variant of Wilms tumor [20]. Therefore, it is imperative to know its expression in poorly differentiated chordomas, especially during the consideration of GCT as one of the differential diagnoses.
Uncommon and peculiar soft tissue sarcomas: Multidisciplinary review and practical recommendations. Spanish Group for Sarcoma research (GEIS –GROUP). Part II
2021, Cancer Treatment ReviewsCitation Excerpt :Immunophenotype shows characteristically, loss of SMARCB1 (INI-1). Most tumors also express epithelial markers (keratins and EMA) and could also express CD99, synaptophysin, ERG, SALL4 and glypican-3 among others [93,94]. All these tumors are related to tumor suppressor role for the SWI/SNF (SWItch/Sucrose Non-Fermenting) complex involved in the remodeling of chromatin.
The heparanase/heparan sulfate proteoglycan axis: A potential new therapeutic target in sarcomas
2016, Cancer LettersCitation Excerpt :Other studies reported variable percentage of GPC3 immunoreactivity in rhabdomyosarcomas and malignant rhabdoid tumors [80,81]. Interestingly, in the latter malignancies, originally described as rhabdomyosarcomatoid variants of Wilms tumors, GPC3 overexpression has been suggested as a useful diagnostic tool and a candidate target for immunotherapy [82]. Immunohistochemical analyses on a multitumor array revealed also consistent GPC3 expression in liposarcomas [83].
All things rhabdoid and SMARC: An enigmatic exploration with Dr. Louis P. Dehner
2016, Seminars in Diagnostic PathologyCitation Excerpt :That being said, several recent studies have proposed a variety of potential tools to help in this situation. For instance, Kohashi et al.119 detected glypican 3 overexpression in over 40% of MRT versus only 2% of proximal ES, and subsequently demonstrated differential microRNA expression between MRT and ES as well.120 SALL4 immunoexpression has likewise been shown to be demonstrable in two thirds of MRT but only rarely in ES.121
ERG and SALL4 expressions in SMARCB1/INI1-deficient tumors: A useful tool for distinguishing epithelioid sarcoma from malignant rhabdoid tumor
2015, Human PathologyCitation Excerpt :Malignant rhabdoid tumor, which has been classified as a tumor of uncertain differentiation, is a rare and highly aggressive embryonal tumor in infancy or childhood [14]. The histologic and immunohistochemical features of this tumor, including the absence of SMARCB1/INI1 protein expression, resemble those of epithelioid sarcoma, especially of proximal type [1,4,19]. Some data exist regarding the histologic and immunohistochemical differences between proximal-type epithelioid sarcoma and malignant rhabdoid tumor, but these findings are not yet conclusive.
Current advances in immunotherapy for atypical teratoid rhabdoid tumor (ATRT)
2023, Neuro-Oncology Practice
- ☆
Disclosure/conflict of interest: The authors declare that there are no conflicts of interest to disclose.
- ☆☆
This study was supported in part by a Grant-in-Aid for Scientific Research (B) (No. 21390107) and Young Scientists (B) (No.21790356) from the Japan Society for the Promotion of Science, the National Cancer Center Research and Development Fund (23-B-12), and Health and Labor Science Research Grants for Clinical Research from the Ministry of Health, Labor and Welfare, Tokyo, Japan. The English used in this manuscript was revised by KN International (http://www.kninter.com/).