Duodenal Foveolar Adenoma: Case Presentation with Whole Exome Sequencing and Review of the Literature Open Access

Extra-ampullary duodenal adenomas are distinct lesions of the duodenal epithelium, more commonly observed in polyposis syndromes, such as familial adenomatous polyposis (FAP), and may be classified as intestinal or gastric type. The gastric type may be further subclassified into pyloric gland adenomas and foveolar adenomas, of which the latter are rare entities. Their aetiology and risk factors are currently unknown; however, gastric metaplasia might play a role in their evolution [1, 2]. In our paper, we present a case of foveolar adenoma with coexisting metaplasia and whole exome sequencing (WES), and the first review of the literature on duodenal foveolar adenomas.

Our work reports a 58-year-old male patient with a medical history of several colon polyps. In 2014, a sessile-serrated lesion was diagnosed in the ascending colon. Two years later, goblet cell-rich hyperplastic polyps with no dysplasia were diagnosed from a rectal polypectomy specimen. In 2019, a tubular adenoma with low-grade dysplasia was identified in the ascending colon, as well, and in the same location, microvesicular hyperplastic polyps with no dysplasia were diagnosed. Upper endoscopic examinations were not performed before.

The patient was admitted to hospital for a postpyloric polypectomy. During the endoscopic examination, a 13-mm, sessile polyp was found and was partially resected due to technical difficulties. The histological examination revealed a lesion composed mainly of foveolar cells with low-grade dysplasia, intermixed with solitary goblet cells, altogether forming tubulovillous structures. The lesion was concluded as foveolar adenoma, with low-grade dysplasia; however, due to the incomplete resection, a month later another endoscopy was performed, and a second polypectomy was carried out. Microscopically, similar morphology was visible, although with foci of high-grade dysplasia. Immunohistochemical analysis revealed heterogeneous, weak p53 labelling meaning wild-type TP53 gene and retained MLH1 expression. Foveolar differentiation was proven with diffuse, cytoplasmic, and membranous MUC5AC positivity. CDX2 reflected diffuse, nuclear positivity, while MUC2 remained focally positive. The second polypectomy specimen was concluded as foveolar adenoma, with high-grade dysplasia, with complete resection. Figure 1 highlights endoscopic and histologic features.

To better understand the genetic landscape, WES was carried out, according to our previous work [3], and in both lesions, KRAS (c.34G>A; p.Gly12Ser (G12S) VAF: 34.98%) and SMAD4 (c.1157G>A; p.Gly386Asp (G386D) VAF: 22.35%) mutations have been identified. Three months later, as a surveillance control examination, an upper endoscopy was performed and reported no signs of recurrence; however, an irregularity was seen in the post-bulbar and the posterior duodenal region, so 2 biopsy samples were taken. The post-bulbar sample reflected gastric foveolar metaplasia, while the other sample showed gastric corpus mucosa heterotopy. In addition, an appraising examination was performed, as well, regarding the incidence of duodenal foveolar adenomas, and between 2014 and 2023, this single patient was registered with this diagnosis (1/94 patients; 2/136 lesions; 1.5%).

Foveolar-type adenoma is an epithelial benign tumour showing foveolar differentiation that may be either sporadic or syndromic, with the latter commonly associated with FAP. Sporadic cases are rare, are characterised as solitary, low-grade lesions with negligible risk of malignancy, and in the case of syndromic association, multiplicity, or high-grade dysplasia are often observed; therefore, a low risk of cancer progression is present. Foveolar adenomas are predominantly found in the oxyntic compartment of the gastric mucosa; however, they have already been described in other locations, as well, e.g., the duodenum. Histologically, both types exhibit dysplastic columnar epithelia with distinctive mucin caps. The diagnosis relies primarily on histopathological features rather than immunophenotyping, and essential diagnostic criteria include polypoid growth with a foveolar phenotype. The current WHO classification solely defines foveolar adenomas of the stomach [1].

For our comprehensive review of the literature, we conducted search words of “duodenum,” “duodenal,” and “foveolar adenoma,” and currently 5 publications alone are available; while none of them focuses solely on duodenal foveolar adenomas, significant information about this specific localisation is lacking. Table 1 summarises the current literature.

The first publication on a duodenal foveolar adenoma case was published by Hizawa et al. [4] in 2005, and even though this article is not available in English, the authors note in the abstract that foveolar adenoma was not yet described at this localisation before. The first detailed description of gastric-type duodenal adenomas was published by Hida et al. [6] in 2017, noting the characteristics of foveolar adenomas and the differences between pyloric glands and foveolar adenomas. Namely, pyloric gland adenomas were observed to be diffusely positive for MUC6 and focally positive for MUC5AC at best, while foveolar-type adenomas were found to be complementary, displaying diffuse MUC5AC and HGM along with focal at most MUC6 positivity. When compared by mutation analysis, however, pyloric gland and foveolar adenomas commonly shared GNAS mutation and did not possess KRAS and APC mutations, suggesting the entities to be close genetically, therefore, being a part of a spectrum. Most authors agreed and used the classification of extra-ampullary duodenal adenomas, containing gastric and intestinal type, of which the former category is subdivided into pyloric gland and foveolar adenomas [2, 5‒8].

In the studies found, a total of 12 patients with foveolar adenoma of the duodenum were analysed. The average age of the patients was 64 years (median: 63.5; range: 59–70); however, it has to be emphasised that several publications did not disclose the age of the patient.

The tumours were described to have either a pedunculated or protruding appearance, and the most prevalent localisation was the first portion of the duodenum. Hijikata et al. [5] noted the difference between gastric and intestinal-type lesions included in their study; all gastric-type adenomas (n = 5/5) were pedunculated and localised to the first portion of the duodenum, while intestinal-type adenomas were less likely to be pedunculated and rather localised to the distal part of the duodenum (n = 7/39) [4, 6, 7]. The mean size of the examined lesions was 13.9 mm (median: 9.7; range: 5–27); however, it has to be emphasised again that multiple publications did not disclose the size of the lesion presented [4, 6, 7, 8].

Regarding the immunoprofile of duodenal foveolar adenomas, all presented cases have been positive with MUC5AC. MUC6 was described to be both focally positive and negative. Hijikata et al. [5] noted MUC6 to be useful in differentiating pyloric gland and foveolar adenomas, while it is most often positive in pyloric gland adenomas. Most cases noted negative staining for MUC2 and CD10, while diffuse positive staining has been observed for HGM [4‒6, 8]. Membranous expression of beta-catenin and positivity for H+/K+ ATPase and pepsinogen-I were noted, as well [2, 6, 7]. These findings confirm the tumours to be of gastric phenotype. A single case was reported to be mismatch repair deficient [8].

Molecular examination has been carried out in 2 cases. Hida et al. [6] noted GNAS mutation in both of the foveolar adenomas presented in their study. Ishizu et al. [8] reported GNAS mutation, as well, alongside KRAS mutation. In our case, consistent with the above-mentioned data, and the WHO’s mention regarding gastric foveolar adenomas, KRAS mutation was identified, as well [1].

Information regarding follow-up data is only provided by Mitsuishi et al. [7]. The article reveals that all tumours (n = 3) were completely resected in their study, and there were no cases of recurrence or progression, with no mention of the follow-up period, while in the cases presented by Hida et al. [6], the follow-up was 18 and 56 months.

Regarding differential diagnosis, the main entities that are to be distinguished when assessing a duodenal polyp are gastric-type and intestinal-type adenomas, as well as differentiating the foveolar type from the pyloric gland type in the case of the former. Immunohistochemistry may prove helpful, as intestinal adenomas display positive staining for CD10, CDX2, and/or MUC2, while gastric-type adenomas express MUC5AC and MUC6, with foveolar adenomas having a strong, diffuse positivity with MUC5AC and focal MUC6 staining and pyloric gland adenomas displaying converse tendency [2, 5‒7]. Foveolar metaplasia also has to be discerned from adenoma.

Based on morphological characteristics, and since our patient had foveolar metaplasia coexisting with the lesion, we researched whether the previous publications also reported metaplasia. Hizawa et al. [4] suspected that the tumour in their paper originated from metaplastic gastric mucosa, and Niwa et al. [2] also noted an association between gastric-type adenoma and gastric duodenal metaplasia. Mitsuishi et al. [7] reported an association between gastric duodenal metaplasia and regeneration after inflammation, as well as metaplasia and GNAS mutation [6]. Gastric duodenal metaplasia has been observed following infection, Crohn’s disease, and coeliac disease, but also in the absence of these coexisting with adenomas and gastric-type adenocarcinomas [2, 8, 9]. These findings raise the question of whether the gastric metaplasia-adenoma-adenocarcinoma sequence exists, even though no cases of progression to carcinoma have been so far described. Hida et al. [6] reported GNAS and KRAS mutations being common in foveolar metaplasia, pyloric gland adenoma, and adenocarcinoma, alongside their foveolar adenoma cases carrying GNAS mutation, thus suggesting a possible pathogenetic link. The tumourigenic pathways of gastric and intestinal-type adenocarcinoma appear to be different, and activation in the Wnt/B-catenin pathway was associated with intestinal-type adenomas but appears not to be involved in the development of gastric-type adenomas [2, 8].

Despite the WHO describing foveolar adenoma as having no malignant potential in sporadic cases and a low chance of progression to cancer in syndromic cases, several authors noted extra-ampullary duodenal adenomas in general as precancerous lesions. Hijikata et al. [5] recommended the endoscopic resection of lesions larger than 20 mm, due to the potential of progressing into adenocarcinoma [1, 2].

In summary, our paper presents a case of duodenal foveolar adenoma in a 58-year-old male patient. Microscopically, his duodenal biopsy sample revealed a polyp composed of foveolar cells with low-grade dysplasia, intermixed with solitary goblet cells, altogether forming tubulovillous structures, and the diagnosis of foveolar adenoma, with low-grade dysplasia was established. Due to incomplete resection, the patients underwent another upper endoscopic examination that justified foveolar adenoma diagnosis again, although with high-grade dysplasia and complete resection. In both samples, KRAS and SMAD4 mutations have been identified, and based on surveillance control examination, gastric foveolar metaplasia was identified, raising suspicion about its aetiological role. Based on the patient’s current and earlier histological results, the suspicion towards FAP and serrated polyposis syndrome was earlier raised; however, WES did not identify APC mutation.

Foveolar adenoma of the duodenum is a rare finding and remains a controversial mysterious entity, representing 1.5% of all duodenal benign tumours, based on our cohort. It has been mostly associated with FAP, although foveolar metaplasia has been suspected as an aetiological factor in sporadic cases. Besides typical microscopic features, MUC5AC might aid the histological diagnosis, and KRAS mutation may be identified, as well.

Written informed consent was obtained from the patient for the publication of the details of their medical case and any accompanying images. This study protocol was reviewed and approved by the Medical Research Council (BM/28834-1/2024).

The authors declare no conflict of interest.

This project was supported by the University of Szeged, Faculty of Medicine Research Fund-Hetényi Géza Grant (IV-134-62-1/2024.SZAOK).

Data collection: Ádám Ferenczi, Sofia Germano, Joana Afonso, Anita Sejben, and Levente Kuthi; interpretation of the results of whole exome sequencing: Levente Kuthi and Anita Sejben; conceptualisation: Anita Sejben, Levente Kuthi, and Tamás Lantos; writing: Ádám Ferenczi, Anita Sejben, and Levente Kuthi; funding acquisition: Anita Sejben; review and editing: Ádám Ferenczi, Anita Sejben, Levente Kuthi, and Tamás Lantos.

All data generated or analysed during this study are included in this article. Further inquiries can be directed to the corresponding author.