Abstract
Background
Gastroblastoma is a rare gastric tumor composed of epithelial and spindle cell components. The characteristic MALAT–GLI1 fusion gene has only been identified in 5 reported cases. We report the morphological characterization of gastroblastoma with the MALAT1–GLI1 fusion gene in a young Japanese woman.
Case presentation
A 29-year-old Japanese woman visited Iwate Medical University Hospital with upper abdominal pain. Computed tomography revealed a tumor in expansive lesions involving the gastric antrum. Histologically, we observed a biphasic morphology composed of epithelial and spindle cell components. The epithelial components appeared as slit-like glandular structures with tubular or rosette-like differentiation. The spindle cell components consisted of short spindle-shaped oval cells. Immunohistochemical (IHC) analysis revealed that the spindle cell component was positive for vimentin, CD10, CD56, GLI1, and HDAC2, and focally positive for PD-L1. The epithelial component was positive for CK AE1/AE3, CAM5.2, and CK7, and negative for CK20 and EMA. Both components were negative for KIT, CD34, DOG1, SMA, desmin, S100 protein, chromogranin A, synaptophysin, CDX2, and SS18-SSX. The MALAT-GLI1 fusion gene was detected molecularly.
Conclusions
We report the following new findings with this case: (i) gastric tumors mimic the gastrointestinal mesenchyme in the embryonic period; (ii) nuclear expression of PD-L1 and HDAC2 were observed in the spindle cell component of a gastroblastoma. We speculate that histone deacetylase (HDAC) inhibitors may offer a promising treatment option for gastroblastoma.
Keywords: Gastroblastoma, MALAT1-GLI fusion gene, PD-L1
Background
Gastroblastoma, first described by Miettinen and colleagues in 2009, is a rare gastric tumor characterized by epithelial and spindle cell components [1]. To our knowledge, 16 cases have been reported in the medical literature [1–11]. However, the characteristic MALAT1–GLI1 fusion gene was identified in only 5 of those cases. Due to the rarity of this disease, its pathogenesis remains unknown. We report a case of gastroblastoma containing a MALAT1–GLI1 fusion gene in a young Japanese woman.
Case presentation
A 29-year-old Japanese woman visited Iwate Medical University Hospital with upper abdominal pain for over a week. The patient had no surgical history, drug allergies, or family history of malignancy. Her laboratory examination was unremarkable. A contrast-enhanced computed tomography (CT) scan showed a 70-mm antral expansive mass (Figs. 1A, B). A biopsy of the tumor was not performed, and she was diagnosed clinically with a gastrointestinal stromal tumor (GIST). Although a preoperative histological diagnosis was not made, a laparoscopic partial gastrectomy was performed. Eight months have passed since the surgery; however, no recurrence or metastasis has been found.
Fig. 1.
A 29-year-old Japanese woman with gastroblastoma. A Axial plane enhanced computed tomography (CT) image of the abdomen. The gastroblastoma appears as a well-circumscribed mass (arrows) showing a multi-cystic, heterogeneously enhanced mass in the lower part of the stomach; B Coronal plane enhanced CT image of the abdomen. Multi-cystic nature and heterogeneity of the gastroblastoma (arrows) arising from the bottom of the gastric wall in the upper-left quadrant
Grossly, the surgical specimen was revealed to be a nodular and well-circumscribed mass measuring 7 x 7 x 6 cm in the gastric antrum. The tumor grew as an expansive mass and involved the gastric wall structures. The cut surface showed a greyish-yellow and tan solid mass with cystic and hemorrhagic components (Fig. 2-A). Histologically, a biphasic morphology of epithelial and spindle cell components was observed. The epithelial components were slit-like glandular structures composed of low cuboidal epithelium with tubular or rosette-like differentiation with eosinophilic secretions. The spindle cell components consisted of short spindle-shaped oval cells infiltrating the smooth muscle. These cells had small round nucleoli and well-defined cell borders (Figs. 2-B, C, D). Mitotic activity was low in both components. Lymph-vascular invasion was not found. Immunohistochemical (IHC) analysis revealed that the spindle cell component was positive for vimentin, CD10 (Fig. 3-A), CD56 (Fig. 3-B), and glioma-associated oncogene homolog 1 (GLI1) (Fig. 3-C), focally positive for PD-L1 (Fig. 3-D), and histone deacetylase 2 (HDAC2) (Fig. 3-E). The epithelial component was positive for pan-cytokeratin (CK AE1/AE3), CAM5.2, and CK7, but negative for CK20 and epithelial membrane antigen (EMA). Both components were negative for KIT (Fig. 3-F), CD34 (Fig. 3-G), DOG1, smooth muscle actin (SMA), desmin, S100 protein, chromogranin A, synaptophysin, CDX2, and SS18-SSX (Fig. 3-H). Antibodies used for the IHC analysis are shown in Table 1, while results of the analysis are shown in Table 2.
Fig. 2.
Cut surface and histology of the gastroblastoma. A Cut surface of the gastroblastoma. B Most of the tumor cells were spindle cells, which appeared oval-shaped without atypia (x200). C Tubular or rosette-like differentiation (x200). D Glandular and slit-like structure (x100)
Fig. 3.
Immunohistochemical findings of the gastroblastoma. A Expression of CD10 by tumor cells (x100). B Expression of CD56 by tumor cells (x100). C Expression of GLI1 by tumor cells (x100). D Expression of PD-L1 by tumor cells (x200). E Expression of HDAC2 by tumor cells (x200). F Lack of KIT expression by tumor cells (x100). G Lack of CD34 expression by tumor cells (x100). H Lack of SS18-SSX expression by tumor cells (x100)
Table 1.
Summary of primary antibodies used in this report
| Primary antibody | Source | Clone | Dilution | Treatment |
|---|---|---|---|---|
| KIT (CD117) | DAKO | Polyclonal | Ready to use | Heat retrieval (pH6.0) |
| CD56 | DAKO | 1B6 | Ready to use | Heat retrieval (pH9.0) |
| CD10 | DAKO | 56C6 | Ready to use | Heat retrieval (pH9.0) |
| PD-L1 | DAKO | 22C3 | Ready to use | Heat retrieval (pH6.0) |
| Anti-HDAC2 | abcam | HDAC2-62 | 1:1000 | Heat retrieval (pH9.0) |
| SMA | DAKO | 1A4 | Ready to use | Heat retrieval (pH9.0) |
| CDX-2 | DAKO | DAKO-CDX2 | Ready to use | Heat retrieval (pH9.0) |
| CAM5.2 | BectonDickinson | CAM5.2 | 1:20 | Heat retrieval (pH9.0) |
| Cytokeratin | DAKO | AE1/AE3 | Ready to use | Heat retrieval (pH9.0) |
| CD34 | DAKO | NU-4A1 | Ready to use | Heat retrieval (pH9.0) |
| Desmin | DAKO | D33 | Ready to use | Heat retrieval (pH9.0) |
| Vimentin | DAKO | Vim 3B4 | Ready to use | Heat retrieval (pH9.0) |
| SS18-SSX | Cell signaling Technology | SS18-SSX | 1:500 | Heat retrieval (pH6.0) |
| GLI1 | Santa Cruz Biotechnology | C-1 | 1:500 | Heat retrieval (pH6.0) |
| CK7 | DAKO | OV-TL 12/30 | Ready to use | Heat retrieval (pH9.0) |
| CK20 | DAKO | Ks20.8 | Ready to use | Heat retrieval (pH9.0) |
| EMA | DAKO | E29 | Ready to use | Heat retrieval (pH9.0) |
| S100 | DAKO | Polyclonal | Ready to use | Heat retrieval (pH6.0) |
| Chromogranin A | abcam | Polyclonal | 1:100 | Heat retrieval (pH9.0) |
| Synaptophysin | DAKO | DAK-SYNAP | Ready to use | Heat retrieval (pH9.0) |
| DOG1 | Leica | K9 | 1:50 | Heat retrieval (pH9.0) |
Table 2.
Summary of previously published gastroblastoma cases
| Case | Author (publication year) | Age (year) | Sex | Specimen type | Locus | Size (mm) | Chief complication | IHC positive | IHC negative | Fusion gene | Treatment | Metastases | Outcome | Follow-up (month) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1-3 |
Miettinen et al. (2009) [1] |
19, 27, 30 | M, F, M | R | B, B, A | 50, 60. 150 | N/A, AP, anemia and fatigue | Vim (S), CD10 (S); CK (pan) (E); CK 18 (2/2, focally in one of the cases) (E); CK 7 (focally in E); DOG1 (focally in E, dot-like positivity in S) | CK20 (E); EMA (E); KIT (CD117) (E, S); CD34 (E, S); CD99 (E, S); SMA (E, S); Des (E, S); calretinin (E, S); p63 (E, S); S100 (E, S); CgA (E, S); Syn (E, S); CDX2 (E, S); and TTF-1 (E, S) | ND | SG, PG, antrectomy and radiation | No | ANED | 42, 60, 168 |
| 4 |
Shin et al. (2010) [2] |
9 | M | R | A | 90 | AP and palpable mass. | CD10 (S); CD56; KIT (CD117) (E); CK (pan) (E); CK (LMW) (E); EMA (E); Vim (S) | Calretinin; CD34; CEA; CgA; CK (HMW); Des; inhibin; NSE; p63; SMA; Syn | ND | R | No | ANED | 9 |
| 5 |
Wey et al. (2012) [3] |
28 | M | R | A | 38 | N/A | CD10; CD56; KIT (CD117) (E); CK (pan) (E); CK (LMW) (E); CK7 (focally in E); Vim (S) | CK20 (E); calretinin (E); CDX2 (E); Des (E); EMA (E); inhibin; p63 (E); S100 (E); SMA | ND | CHT followed by PG | LN, liver, | ANED | 3 |
| 6 |
Femandes et al. (2014) [4] |
19 | F | R | A | 105 | AP | CD10 (S, focally in E); CD56; CK AE1/AE3 (E); CK CAM5.2 (E), Vim (S) | Calretinin; CD34; KIT (CD117); CgA; Des; DOG1; S100; SMA; Syn | ND | PG | No | ANED | 20 |
| 7 |
Ma et al. (2014) [5] |
12 | M | R | A | 45 | Abdominal mass and blood in stool | CD10 (S); CD56 (S); CK AE1/AE3 (E); CK CAM5.2 (E); Vim (S) | ALK; CD34; KIT (CD117); CK5/6; Des; DOG1; PLAP; S100; SMA | ND | SG and gastroduodenostomy | No | ANED | 8 |
| 8 |
Toumi et al. (2017) [10] |
29 | F | R | U | 70 | Epigastric pain | CD10 (focally); CD99 | CK (pan); KIT (CD117); CgA; Syn | ND | R | LN | DEAD | 6 |
| 9 |
Graham et al. (2017) [6] |
28 | M | R | A | 38 | N/A | CK (pan) (E), CD56 (E), NSE (E), low Ki-67 | CgA, Syn, CEA, TTF-1, PLAP, CD30, AFP, HCG | MALAT1– GLI1 | R NOS | LN, liver, peritoneum | N/A | N/A |
| 10 |
Graham et al. (2017 [6]) |
27 | M | R | A | ND | N/A | CK (pan) (E), SMA (patchy in S) | CgA, Syn, KIT (CD117), DOG1, Des, S100, melanA, SOX10, TLE-1, CD99, CK5/6 | MALAT1– GLI1 | R NOS | No | ANED | 12 |
| 11 |
Graham et al. (2017) [6] |
9 | M | R | A | 90 | N/A | CK (pan) (E), CD10 (focally in S), KIT (CD117) (E, S), CD56 (E), Vim (S) | CgA, Syn, NSE, Des, SMA, calretinin, inhibin, CK34βE12, CD34 | MALAT1– GLI1 | R NOS | No | ANED | 93 |
| 12 |
Graham et al. (2017) [6] |
56 | F | Needle biopsy | NS | 40 | N/A | OSCAR (patchy in E), low Ki-67, Vim (S) | CK34βE12, CKT7, CK20, CDX2, CgA, Syn, CD34, CD99, KIT (CD117), DOG1, calretinin, WT1, SMA, Des, EMA, MOC31, melanA, HMB45, pCEA | MALAT1– GLI1 | Biopsy | Liver | N/A | N/A |
| 13 |
Castri et al. (2019) [7] |
79 | M | R | A | 90 | Weight loss and dysphagia | bcl2; CD10 (S> E); CD56; CK (pan) (E> S); Vim (S) | aFP, bHCG, h-caldesmon, calponin, CD31, CD99, KIT (CD117), CgA, Des, DOG1, ERG, GFAP, HMB45, melanA, PLAP, S100, STAT6, Syn | MALAT1– GLI1 | PG | Local relapse | ANED | 52 |
| 14 |
Giovanni et al. (2019) |
43 | F | R | A | 53 | Intestinal bleeding | CD10 (focally in S), EMA (focally in E), CK (pan) (E), CAM 5.2 (E), CK 7 (focally in E), Vim (S), GLI1 (E, S) | SMA (E, S), Calretinin (E, S), CgA (E, S), NSE (E, S), CD34 (E, S), CD56 (E, S), CD99 (E, S), CDX2 (E, S), Des (E, S), DOG1 (E, S), ER (E, S), CK 5/6 (E), CK 20 (E, S), Inhibin (E, S), KIT (CD117) (E, S), p63 (E, S), Syn (E, S), S100 (E, S), TTF1 (E, S), TLE1 (E, S) | ND | PG | No | ANED | 100 |
| 15 |
Koo et al. (2021) [8] |
17 | M | R | U | 63 | Intestinal bleeding | Vim (E, S), CD56 (E, S), CD10 (E, S), CK (pan) (E, S), Syn (E, S) | CD34 (E, S), KIT (CD117) (E, S), DOG1 (E, S), S100 (E, S), Des (E, S), CgA (E, S) | EWSR1-CTBP1 | PG | No | ANED | 23 |
| 16 |
Chen C et al. (2022) [11] |
58 | M | R | M | 23 | N/A | Vim (E, S), CD10 (E, S), bcl-2 (E, S), CD56 (E), CD100 (E), EMA (focal), Ki-67 (low) | KIT (CD117) (E, S), DOG1 (E, S), CD34 (E, S), SMA (E, S), Des (E, S), SOX10 (E, S), CD99 (E, S), CgA (E, S), syn (E, S), CAM5.2 (E, S), CK (pan) (E, S). | PTCH-GLI2 | ESD | No | N/A | N/A |
| 17 | Present case / Sugimoto | 28 | F | R | A | 70 | AP | CK (pan) (E), CAM5.2 (E), CD10 (S), CD56 (S), Vim (S), GLI1 (S), CK 7 (E), PD-L1 (focally in S), HDAC2 (E, S) | CK20 (E, S), EMA (E, S), CDX2 (E, S), KIT (CD117) (E, S), CD34 (E, S), SMA (E, S), Des (E, S), S100 protein (E, S), CgA (E, S), Syn (E, S), DOG1 (E, S), SS18-SSX (E, S). | MALAT1– GLI1 | PG | No | ANED | 8 |
Abbreviations: U Gastric cardia and fundus, B Gastric body, A Gastric antrum, AP Abdominal pain, IHC Immunohistochemical stain, ANED Alive no evidence of disease, CK Cytokeratin, Des Desmin, Vim Vimentin, SMA Smooth muscle actin, TTF-1 Thyroid transcription factor 1, CgA Chromogranin A, Syn Synaptophysin, S Spindle cell component, E Epithelial cell component, N/A Not available, ND Not done, SG Subtotal gastrectomy, PG Partial gastrectomy, R Resection, LN Lymph node
We performed reverse transcriptase-polymerase chain reaction (RT-PCR) analysis [6], which revealed that the tumor harbored the MALAT1–GLI1 fusion gene (Fig. 4-A, B). In addition, we developed a customized next-generation sequencing (NGS) gene panel for use in this case. The panel consisted of 28 genes (APC, TP53, CDKN2A, MET, ATM, MLH-1, PMS2, HRAS, AXIN2, BAX, DCC, MSH2, POLE, RNF43, PTEN, BRAF, EPCAM, MSH6, BUB1B, RhoA, KRAS, NRAS, SMAD4, CDK4, PIK3CA, STK11, TGFBR2, and EGFR) for exploring the genetic causes of colorectal cancer. This panel was employed for gastroblastoma in the present case to detect gene mutations. However, positive pathogenic / likely pathogenic variants were not detected with this NGS panel.
Fig. 4.
A MALAT1–GLI1 fusion gene detected by molecular analysis. A Confirmation of the presence of a MALAT1–GLI1 fusion transcript by RT-PCR analysis. B Sequencing of the cDNA-confirmed fusion of MALAT1 and GLI1
Discussion and conclusions
To our knowledge, 16 cases of gastroblastoma have been reported in the medical literature. Table 2 summarizes the clinicopathological features of these cases [1–11], as well as the clinicopathological findings associated with the present case. Nuclear PD-L1 and HDAC2 expression was observed in the spindle cell component by IHC analysis. PD-L1 is transported from the cell membrane into the nucleus and activates other checkpoint inhibition-related genes. PD-L1 transport into the nucleus was shown to be regulated by HDAC2 [12]. In the present case, PD-L1 and HDAC2 were co-expressed in tumoral nuclei. We suggest that PD-L1 migrated into the nucleus via intranuclear HDAC2 activation. As a result, we speculate that HDAC inhibitors may offer a promising treatment option for gastroblastoma. Surgical resection is the standard treatment for gastroblastoma; however, in a small number of cases, chemotherapy or radiotherapy was used [1, 10]. The postoperative course of the disease is generally favorable. However, a few cases of postoperative local recurrence, distant metastases and death have been reported [3, 6, 7, 10]. Therefore, it is valuable to mention feasible treatment options; in this case, we showed nuclear migration of PD-L1 and overexpression of HDAC2, suggesting that HDAC2 inhibitors may be helpful. However, as this was a single case report, further studies are needed to confirm this result.
The tumorigenesis of gastroblastoma is not completely understood. Although Toumi et al. reported that gastroblastoma is believed to develop from a totipotent stem cell, the relationship between gastroblastoma and stem cells is still unclear [10]. Histologically, the embryonic gastrointestinal mesenchyme is morphologically analogous to gastroblastoma (Fig. 5-A, B). In the development and differentiation of the gastrointestinal system, the epithelium and mesenchyme exhibit crosstalk via molecular signaling pathways, such as FGF, TGF-b, Wnt, Hippo, Notch and Hedgehog (Hh). In particular, the Hh signaling pathway is the common pathway for embryo and gastroblastoma development [13]. Gastroblastoma activates GLI1 transcription by the MALAT1-GLI1 fusion gene. We suggest that the morphological similarities between the tumor and the embryonic gastrointestinal mesenchyme might be due to the effect of GLI1 expression via the Hh pathway.
Fig. 5.
Histology of the fetal gastrointestinal tract (at 10 weeks). A, B Mesenchyme of the gastrointestinal tract, which resembles the spindle component of the gastroblastoma (A: x100, B: x200)
In conclusion, we report the following new findings associated with a case of gastroblastoma: (i) gastric tumors mimic the gastrointestinal mesenchyme in the embryonic period and (ii) nuclear expression of PD-L1 and HDAC2 were observed. We speculate that HDAC inhibitors may offer a promising treatment option for gastroblastoma.
Acknowledgements
The authors would like to thank Ms. E. Sugawara and Ms. C. Ishikawa for technical assistance, as well as the members of the Department of Molecular Diagnostic Pathology, Iwate Medical University, for their support.
Authors’ contributions
RS contributed to the preparation of the manuscript, Figures and Tables. TS contributed to the preparation of the manuscript, including all aspects of data collection. YA and AS provided clinical support during the preparation of the manuscript. NU, MO, NY, KI, and YO supported interpreting the pathological findings. WH helped carry out the fusion gene analysis. NY performed the immunohistochemical staining. The author(s) read and approved the final manuscript.
Funding
The authors have no funding to disclose.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ryo Sugimoto and Tamotsu Sugai contributed equally to this manuscript.
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