Gastroblastoma mimics the embryonal mesenchyme of the foregut: A case report.

doi:10.21203/rs.3.rs-2205827/v1

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Case Report

Gastroblastoma mimics the embryonal mesenchyme of the foregut: A case report.

https://doi.org/10.21203/rs.3.rs-2205827/v1

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published 17 Feb, 2023

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Background

Gastroblastoma is a rare gastric tumor composed of epithelial and spindle cell components. Identification of the characteristic MALAT–GLI1 fusion gene has only been reported in 5 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 the 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 and 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, HDAC2 and focally positive for PD-L1. The epithelial component was positive for CK AE1AE3, CAM5.2, 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. Finally, MALAT-GLI1 fusion gene was molecularly detected.

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 gastroblastoma. We speculate that HDAC (Histone Deacetylase) inhibitors may offer a promising treatment option for gastroblastoma.

Gastroblastoma

MALAT1-GLI fusion gene

PD-L1

Gastroblastoma, which was first described by Miettinen et al. 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, the tumorigenesis remains unknown. We report a case of gastroblastoma with MALAT1–GLI1 fusion gene in a young Japanese woman.

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 a malignant tumor. Laboratory examination was unremarkable. Contrast-enhanced computed tomography (CT) scan showed a 70-mm antral expansive mass (Figs. 1A, B). A biopsy examination of the tumor was not performed. The woman was diagnosed with a gastrointestinal stromal tumor (GIST) clinically. Although a preoperative histological diagnosis was not made, laparoscopic partial gastrectomy was performed. Eight months have passed since the surgery. However, no recurrence or metastasis has been found.

Grossly, the surgical specimen was revealed to be a nodular and well-circumscribed mass measuring 7 x 7 x 6 cm of the gastric antrum. The tumor grew in 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, biphasic morphology composed of epithelial and spindle cell components was observed. The epithelial components showed slit-like glandular structures composed of the low cuboidal epithelium and tubular or rosette-like differentiation with eosinophilic secreting materials. 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 invasions were 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 deacetylases 2 (HDAC2) (Fig. 3-E). The epithelial component was positive for pan-cytokeratin (CK AE1AE3), 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.

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	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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-PCR (RT-PCR) (6), which revealed that the tumor harbored the MALAT1–GLI1 fusion gene (Fig. 4-A, B). Additionally, we developed a customized Next-Generation Sequencing (NGS) gene panel for use in this case. The panel consisted of 28 genes (including 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 on this NGS panel.

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 were observed in the spindle cell components 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 regulated by HDAC2 (12). In the present case, PD-L1 and HDAC2 were co-expressed in tumoral nuclei. We suggest that PD-L1 is migrated into the nucleus intranuclear HDAC2 activation. As a result, we speculate that HDAC inhibitors may offer a promising treatment option for gastroblastoma.

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, epithelium and mesenchyme exhibit crosstalk via molecular signaling pathways, such as FGF, TGF-b, Wnt, Hippo, Notch and Hedgehog (Hh) pathways. In particular, the Hh signaling pathway is the common pathway for embryo and gastroblastoma development (14). 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.

In conclusion, we report the following new findings associated with a case of gastroblastoma: (i) we noted that gastric tumors mimic the gastrointestinal mesenchyme in the embryonic period; and (ii) nuclear expression of PD-L1 and HDAC2 were observed in gastroblastoma. 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.

Consent for publication: Written informed consent was obtained from the patient for publication of this case report.

Ethics approval and consent to participate: Not applicable.

Funding: The authors have no funding to disclose.

Competing interests: The authors declare that they have no competing interests.

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. SB, YA and AS provided clinical support during the preparation of the manuscript. NU, MO, NY, and YO supported interpreting the pathological findings. WH helped carry out the fusion gene analysis. NY performed the immunohistochemical staining.

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No competing interests reported.

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You are reading this latest preprint version

Gastroblastoma mimics the embryonal mesenchyme of the foregut: A case report.

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