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. 2024 Jun 1;48(6):652-661.
doi: 10.1097/PAS.0000000000002222. Epub 2024 Apr 8.

Genomic and Pathologic Profiling of Very Well-Differentiated Gastric Adenocarcinoma of Intestinal Type: A Study With Emphasis on Diffuse-Type Transformation

Hirofumi Rokutan  1 , Yasuhito Arai  2 , Akiko Kunita  1 , Satoshi Yamasaki  3 , Hiromi Nakamura  2 , Natsuko Hama  2 , Atsuhito Nakayama  1 , Fumie Hosoda  2 , Yasushi Totoki  2   4 , Mitsuhiro Fujishiro  5 , Yasuyuki Seto  6 , Tatsuhiro Shibata  3   2 , Tetsuo Ushiku  1
Affiliations

Genomic and Pathologic Profiling of Very Well-Differentiated Gastric Adenocarcinoma of Intestinal Type: A Study With Emphasis on Diffuse-Type Transformation

Hirofumi Rokutan et al. Am J Surg Pathol. .

Abstract

Very well-differentiated adenocarcinoma of intestinal type is a distinct subtype of gastric cancer characterized by anastomosing glands with a hand-in-hand pattern and low-grade cytologic atypia resembling intestinal metaplasia. This is a slow-growing neoplasm with an indolent clinical course; however, a subset demonstrates transformation into adenocarcinoma with higher-grade histology, typically diffuse-type carcinoma, and behaves aggressively. This study aimed to better characterize the genomic and pathologic features, with a focus on factors associated with diffuse-type transformation. A total of 58 cases with (n=31) and without (n=27) diffuse-type transformation were analyzed for molecular and pathologic features. First, comprehensive deep DNA sequencing was conducted in 18 cases (discovery cohort), followed by a digital droplet polymerase chain reaction of hot spot RHOA mutations in 40 cases (validation cohort). In total, RHOA mutations were the most common alteration (34%), followed by loss of ARID1A (12%), p53 alterations (10%), and CLDN18 :: ARHGAP26/6 fusions (3.4%). FGFR2 amplification was identified in an advanced case with a p53 alteration. Altered p53 expression was recognized only in higher-grade components and was significantly associated with advanced disease ( P =0.0015) and diffuse-type transformation ( P =0.026). A mixed mucin phenotype was also strongly correlated with advanced disease ( P <0.001) and diffuse-type transformation ( P <0.001). Decreased E-cadherin expression was frequently observed (74%) in poorly cohesive components. This study demonstrated that a subset of RHOA -mutant diffuse-type gastric cancers develops through the transformation of very well-differentiated adenocarcinoma of intestinal type. Our observations suggest a mixed mucin phenotype as a risk factor and alterations in p53 and E-cadherin as drivers of diffuse-type transformation.

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Conflict of interest statement

Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Figures

FIGURE 1
FIGURE 1
Representative histology of very well-differentiated gastric adenocarcinoma of intestinal type and its transformation into diffuse-type advanced tumors. A, Hand-in-hand pattern (arrows) is seen in this typical example of very well-differentiated gastric adenocarcinoma. Tumor cells show low-grade cytologic atypia mimicking intestinal metaplasia. B, Another example of an intramucosal, very well-differentiated adenocarcinoma composed of tortuous neoplastic glands in the left, with signet-ring cell transformation in the right. This tumor had an RHOA p.G17E mutation. C, Frame in (B) a high-power view of a signet-ring cell component. D–G, An advanced case with the RHOA p.G17E mutation. D, A low-power view. E, Intramucosal component of very well-differentiated gastric adenocarcinoma. F, Tubule-forming component with high-grade cytologic atypia was also seen in the intramucosal layer. G, Poorly cohesive carcinoma component invading into the submucosal layer, exhibiting diffuse-type histology with stromal fibrosis.
FIGURE 2
FIGURE 2
Genetic and pathologic landscape of 58 very well-differentiated gastric adenocarcinomas of intestinal type. Recurrent RHOA mutations were identified in both the discovery cohort and the validation cohort. Advanced tumors frequently harbor p53 aberrations. CLDN18::ARHGAP fusions were detected in RHOA-wild-type tumors. ARID1A loss and p53 aberration did not coexist. IHC indicates immunohistochemistry; M, intramucosal tumor; PCC, poorly cohesive carcinoma; SM, tumor with submucosal invasion.
FIGURE 3
FIGURE 3
A representative case with abnormal p53 expression and another case with ARID1A loss. Very well-differentiated component with typical low-grade histology (A) shows a wild-type pattern of p53 staining (B), whereas the accompanying high-grade tubular component (C) demonstrates diffuse and strong p53 staining (D). E and F, Biopsy pictures of another case with typical low-grade histology and ARID1A loss. Nuclear expression of ARID1A is lost in cells forming tortuous neoplastic glands. Note the retained expression in non-neoplastic glands and stromal cells.
FIGURE 4
FIGURE 4
A case with FGFR2 amplification. (A) A representative image of invasive area showing diffuse-type histology. In this advanced tumor with FGFR2 amplification, overexpression by immunohistochemistry (B) and amplification by FISH (C, red signals) was confirmed in diffuse-type components but not in very well-differentiated component. This tumor showed diffuse positivity for p53 (D).
FIGURE 5
FIGURE 5
Schematic illustration of the natural history of very well-differentiated gastric adenocarcinoma of intestinal type. RHOA mutation, CLDN18::ARHGAP fusion, and ARID1A loss are early events because they are present in the intramucosal low-grade components. TP53 mutation/p53 alteration is the major secondary event significantly associated with high-grade or diffuse-type transformation. Decreased E-cadherin expression is also associated with diffuse-type transformation. Tumor with mixed mucin phenotype is more likely to develop high-grade or diffuse-type transformation. Our analysis of the G17E/Y42C ratio suggested that diffuse-type gastric cancer more frequently develops from precursors other than very well-differentiated gastric adenocarcinoma. MM indicates muscularis mucosae.
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