Foveolar Dysplasia Research Articles

An Uncommon Type of Gastric Adenoma: Pyloric Gland Adenoma with Foveolar Dysplasia.

An Uncommon Type of Gastric Adenoma: Pyloric Gland Adenoma with Foveolar Dysplasia.

1725 A Case of Latin American Female Diagnosed With Esophageal Adenocarcinoma on Brush Cytology Biopsies

INTRODUCTION: In 1975, the incidence of esophageal adenocarcinoma (EAC) was 0.4 cases per 100,000. In 2009, the incidence had risen by 5 fold to 2.58 cases per 100,000, making it one of the fastest growing cancers at this time. Esophagoduodenoscopy (EGD) is the gold standard for diagnosing Barrett’s esophagus (BE), which is a precursor to EAC. With the advent of new techniques of brush cytology sampling, there is potential to broaden our technology and our screening criteria for prevention. We present a rare case of a Latin female who was diagnosed with EAC after goblet cells were incidentally found on brush cytology. CASE DESCRIPTION/METHODS: A 73 year old Latin female with history of hiatal hernia, and H. Pylori presented with heartburn and abdominal pain. The EGD showed foveolar dysplasia at the gastric-esophageal junction. Wide Area Transepithelial Sample Biopsy With 3-Dimensional Computer-Assisted Analysis (WATS3D) showed goblet cell metaplasia. Repeat WATS3D confirmed these results and repeat forceps biopsy showed high grade dysplastic glands consistent with a well differentiated EAC. She underwent endoscopic ultrasound with biopsy and it was staged as T3N2Mx. She had a mucosal resection performed which showed poorly differentiated EAC and was referred to oncology. DISCUSSION: It is predicted that between 2011 and 2030, deaths related to EAC will double the number of those that died between 1991 to 2010. Some studies have shown increased detection rates of EAC precursors including those of BE and esophageal dysplasia (ED). For example, a 2010 study concluded that WATS3d brush biopsy allowed for substantial increases in the detection rates of BE by 39.8% and ED by 87.5%. Another 2017 study revealed an increase of 83% for BE and 88.5% for ED. Thus, cytology brush biopsies can help to diagnose high grade dysplasia and/or cancer with greater than 80% sensitivity and 95% specificity. It is also important to note that for women, the future incidence and mortality rates are also expected to rise in 2030 by approximately 9 times. The population we screen for BE is in white males over 50 who are symptomatic and with risk factors for BE or EAC. However, this is a rare case of a latin female that would not have fallen under these screening guidelines. Because of the rising incidence with worsening mortality contributing to the overall rise in EAC cases, we believe that it is imperative to broaden our screening criteria and to implement new tools such as brush cytology biopsies to a broader population as well.

A Rare Case of Hyperplastic Proximal Esophageal Polyps With Foveolar Dysplasia

A 62-year-old male with long-standing esophageal reflux underwent endoscopy at an outside institution that reported multiple polypoid lesions in upper esophagus and a small focal area of nodular mucosa at the gastroesophageal junction(GEJ). Biopsies of the proximal esophageal polyps demonstrated hyperplastic mucosa with ulceration, reactive epithelial changes, and focal intestinal metaplasia. Biopsies from the nodular GEJ mucosa were described as Barrett’s esophagus with low grade dysplasia. An upper endoscopy performed at our medical center found multiple semi-pedunculated esophageal polyps between 18-24 cm from the incisors (Figure A).Endosonographically the polypoid lesions were confined to the mucosa with normal underlying wall layers (Figure B). Patient underwent endoscopic mucosal resection (EMR) using a multi-band mucosectomy technique. Hematoxylin and eosin staining of the EMR specimens showed gastric and intestinal metaplasia, featuring cubital to columnar cells with pale clear to light eosinophilic cytoplasm and round to oval nuclei (Figure C). MUC5AC (a marker of gastric foveolar mucin) was positive in the specimen (Figure D); whereas intestinal markers MUC2, CDX-2 and Villin, were negative. The impression of the gastrointestinal pathologists was hyperplastic polyp with foveolar dysplasia. At a follow-up endoscopy 3 months later, smooth mucosal scarring was noted with no residual polypoid tissue or gastric heterotopia.

Unusual findings in Peutz-Jeghers syndrome: endoscopic and histologic appearance of gastric hamartomatous polyposis with foveolar dysplasia

Unusual findings in Peutz-Jeghers syndrome: endoscopic and histologic appearance of gastric hamartomatous polyposis with foveolar dysplasia

Gastric foveolar dysplasia: a survey of reporting habits and diagnostic criteria

This study aimed to ascertain views, incidence of reporting and diagnostic criteria for gastric foveolar dysplasia. A questionnaire, a post-questionnaire discussion and microscopic assessment of selected cases was conducted by gastrointestinal pathologists to explore the above-stated aims. Fifty-four percent of respondents never or rarely diagnosed gastric foveolar-type dysplasia. The general consensus was that round nuclei, lack of nuclear stratification, presence of inflammation/damage and surface maturation favoured reactive change; while architectural abnormalities/complexity and nuclear enlargement mainly were used to separate low-grade from high-grade foveolar dysplasia. Immunohistochemistry was rarely used to make the diagnosis of dysplasia and was thought not to be of help in routine practice. Inter-observer agreement in grading of dysplasia versus reactive, and the type of dysplasia (foveolar versus adenomatous), was substantial/almost perfect amongst 35.7% and 21.4% of participants, respectively. This reflects low reproducibility in making these diagnoses. In conclusion, foveolar dysplasia was a rarely made diagnosis among 14 gastrointestinal pathologists, there are no uniform criteria for diagnosis and there is poor inter-observer agreement in separating low-grade foveolar dysplasia from reactive gastric mucosa and low-grade adenomatous dysplasia. Greater awareness and agreed criteria will prevent misdiagnosis of low-grade foveolar dysplasia as reactive, and vice versa.

Mutational analysis by next generation sequencing of gastric type dysplasia occurring in hyperplastic polyps of the stomach: Mutations in gastric hyperplastic polyps

Gastric hyperplastic polyps (GHP) are the most common type of polyps occurring in the stomach. Although GHP are broadly interpreted as benign lesions, they may progress to dysplasia and adenocarcinoma. Objective: In this study, we aimed to identify genomic mutations that characterize and may drive malignant transformation in GHP by using next-generation sequencing. Eight GHP (2 with dysplasia, 1 indefinite for dysplasia and 5 without dysplasia) were studied. Only large polyps (>1cm) with gastric differentiation were included in this study, while adenomatous polyps (intestinal-type) were excluded. Immunohistochemistry for MUC2, MUC5A, MUC6, CDX2, p53, and Ki67 was performed. DNA was extracted from formalin-fixed paraffin-embedded sections and sequenced for the detection of somatic mutations. Multiplex sequencing was done with the TrueSeq Amplicon Cancer Panel in the MiSeq platform. Variant annotation and visualization were performed using NextGENe (SoftGenetics) software. No pathogenic mutations were detected in GHP without dysplasia. TP53 gene mutations were the most common alteration in dysplastic GHP (2 of 2 dysplastic cases). PIK3CA mutation was identified in a GHP with pyloric-type dysplasia, whereas foveolar-type dysplasia carried TP53 mutations. In conclusion, TP53 gene mutations are a common alteration in the early dysplastic stage during malignant transformation of GHP. GHP with dysplasia may show dual differentiation. In our study, pyloric-type dysplasia was associated with a PIK3CA alteration whereas foveolar dysplasia carried TP53 mutations. The identification of carcinoma-associated mutations in large GHP provides additional evidence of their neoplastic potential and emphasizes the need for their complete resection and follow-up.

Gastric Polyps—To Worry or Not?

A 15-year-old white boy underwent upper endoscopy for persistent dyspepsia for which he had been receiving a proton pump inhibitor (PPI) (lansoprazole) for several years. The esophagus and duodenum were visually and histologically normal. Small, sessile polyps were seen on the gastric body (Fig. 1A). Biopsies of the gastric mucosa were normal; the polyps showed dilatation and hyperplasia of oxyntic glands (Fig. 1B) consistent with fundic gland polyps secondary to PPI therapy.FIGURE 1: Endoscopic (A) and histological (B) findings of fundic gland hyperplasia caused by long-term use of a protein pump inhibitor.Gastric polyps may be found at endoscopy as a spontaneous benign condition, part of an adenomatous polyp syndrome (familial adenomatous polyposis [FAP]), part of a hamartomatous polyp syndrome (juvenile polyposis syndrome, Peutz-Jegher syndrome, and PTEN hamartoma syndrome), or a result of medication (PPIs). Although patient history is important for developing a differential diagnosis of gastric polyps, diagnosis is confirmed by histological findings. Fundic gland polyps (FGPs) are seen in 2% to 12% of patients with no PPI exposure, 26% to 36% of patients on long-term (>12 months) PPI therapy, and in up to 81% of adults and 51% of children with FAP (1–5). FGPs are characterized by cystically dilated and irregularly budded fundic glands, which are lined by normal parietal cells, chief cells, or mucous neck cells. FGPs in FAP (Fig. 2A) are distinguished by foveolar dysplasia and may develop adenomatous transformation (Fig. 2B). Incipient hamartomatous polyps can mimic FGP endoscopically. These polyps are characterized by an edematous lamina propria with inflammatory cells and cystically dilated glands lined by cuboidal to columnar epithelium with reactive changes; Peutz-Jegher polyps are differentiated by arborization of smooth muscle.FIGURE 2: Endoscopic (A) and histological (B) findings of gastric polyps in a patient with familial adenomatous polyposis.FGPs in FAP carry a risk of malignant transformation necessitating surveillance endoscopy. Consensus as to when to initiate surveillance does not exist; recommendations are included at the time of initial colonoscopy or around age 20 years. Interval of surveillance endoscopy for gastric FAP is every 1 to 3 years (5,6). Although there is no need to worry about malignancy related to PPI-induced FGPs, long-term use (>5 years) of PPIs has been associated with osteopenia and osteoporosis-related fractures. Conflicting data are found regarding the role of PPIs in predisposing to small bowel bacterial overgrowth. The patient was informed of the risks of long-term PPI use, received dietary counseling; the PPI was discontinued and an H2-receptor antagonist started. No further surveillance was performed as the polyps regress with cessation of PPIs.

Distinguishing Barrett gastric foveolar dysplasia from reactive cardiac mucosa in gastroesophageal reflux disease

Morphologic dysplasia remains the criterion standard of cancer risk in Barrett esophagus but poses many challenges including distinction from reactive inflammatory change. Gastric foveolar dysplasia, a newly described subtype comprising 15% to 20% of Barrett dysplasia, overlaps with reactive cardiac mucosa in gastroesophageal reflux disease (GERD). Despite the clinical importance of accurate distinction, the issue has not been studied. Review of 3698 biopsies from 461 Barrett patients yielded 160 biopsies with Barrett gastric foveolar dysplasia (74 low grade and 86 high grade). These were compared with inflamed cardia from 80 patients with GERD. Immunohistochemistry was performed for Lgl2, MUC2, MUC5AC, and MUC6. Comparing GERD with Barrett gastric foveolar dysplasia, surface nuclear stratification (85% versus 0%, P < .00001), upper mucosa-limited atypia (80% versus 0%, P < .0001), villiform architecture (52% versus 4%; P < .0001), full-thickness mucosal atypia (0% versus 100%, P < .00001), and crowded glandular architecture (0% versus 75%, P < .00001) all proved useful. Cytologic features were less helpful. Comparing low-grade gastric dysplasia alone, because its distinction from reactive cardia may be even more challenging, the listed features all remained significant. Loss or aberrant Lgl2 expression was much more typical of dysplasia (12% versus 99%; P = .0001). MUC proteins did not distinguish the groups. Surface nuclear stratification, "top-heavy" atypia, and noncrowded, villiform architecture were highly characteristic of reactive cardiac atypia in GERD, in comparison with the monolayered nuclei in crowded glands occupying the full mucosal thickness in Barrett gastric foveolar dysplasia. Loss or aberrant Lgl2 staining was useful in identifying Barrett gastric foveolar dysplasia.

Barrett’s oesophagus: past, present and future

Barrett's oesophagus (BE) is the most common cause of oesophageal adenocarcinoma. Adenocarcinoma develops through a meta-plasia-dysplasia-carcinoma sequence, but there are many unknown and controversial issues related to the diagnosis, classification, pathological criteria, molecular progression, natural history and treatment of metaplastic and dysplastic precursor lesions in BE. The purpose of this lecture (review) is to provide an evidence-based summary of the diagnosis and classification of BE-associated metaplasia and dysplasia, to provide a summary of the key pathological features of the most common types of precursor lesions, to outline common areas of diagnostic difficulties, and to evaluate adjunctive markers of cancer progression in BE. The current American College of Gastroenterologists (ACG) definition of BE is partially flawed, since not all cases of BE are endoscopically recognisable, non-goblet epithelium is biologically intestinalised and genetically abnormal, and determination of the presence or absence of goblet cells is susceptible to sampling error and variability with time. Metaplastic epithelium in BE shows clonal molecular abnormalities that precede morphological expression of dysplasia. Dysplasia in BE begins in the crypt bases and then extends more superficially to include the upper portion of the crypts and surface epithelium with time and progression. Low and high grade dysplasia are distinguished by the presence of marked cytological and/or architectural abnormalities in the latter compared to the former, but there are newly discovered subtypes of dysplasia, such as the foveolar and serrated type, in which differentiation of low from high grade dysplasia is difficult and the significance of grading dysplasia is unknown. For instance, one type of dysplasia (foveolar dysplasia) may occur in non-goblet metaplastic columnar epithelium and shows a high progression rate to carcinoma compared to conventional (intestinal type) dysplasia. There are few, if any, reliable adjunctive diagnostic techniques that can help differentiate non-dysplastic from dysplastic epithelium in BE, but α-methylacyl coenzyme A racemase (AMACR) staining has been shown to be useful in several different studies. Both low and high grade dysplasia are progressive lesions, and in general, the extent of dysplasia is a strong risk factor for progression to carcinoma. Of all the biological and genetic biomarkers studied to date, evaluation of DNA content is the most reliable and specific marker of progression in BE. The management of patients with dysplasia is variable between institutions, and ranges from aggressive surveillance, endoscopic mucosal resection, either with or without mucosal ablation, or total oesophagectomy. Recent data on radiofrequency ablation in BE is promising.

Foveolar type dysplasia in Barrett esophagus

Adenocarcinoma of the lower esophagus and esophagogastric junction is increasing in incidence in Western countries. A metaplasia (Barrett esophagus)—dysplasia—carcinoma sequence induced by gastroesophageal reflux disease is established. Two patterns of Barrett dysplasias have been described—adenomatous (type 1) and non-adenomatous (type 2 or foveolar/hyperplastic type). Interestingly, little is known about non-adenomatous dysplasia. Esophagogastrectomy cases from 41 patients with glandular dysplasia with and without associated invasive adenocarcinoma of the lower esophagus were evaluated for expression of MUC2, MUC5AC, CDX2, villin, Ki67 and p53. Results were correlated with sub-classification of the dysplasia into morphologic patterns of adenomatous vs foveolar vs hybrid type. In addition, clinicopathological parameters including the presence and extent of background intestinal metaplasia were also evaluated. Foveolar type dysplasia was present in 46% of the cases and thus, was more common than adenomatous type or hybrid type (both ∼27%) dysplasia. Immunohistochemistry confirmed the histological stratification in all cases. Foveolar type dysplasia commonly expressed MUC5AC (P<0.12) but was consistently negative for markers of intestinal differentiation, MUC2, CDX2 and villin (all P<0.01). By contrast, adenomatous type dysplasia frequently displayed intestinal differentiation markers (all P<0.0001) Hybrid-type dysplasia was similar to adenomatous type dysplasia in showing expression of intestinal differentiation markers (P<0.01) and therefore could not be sustained as a separate category. In conclusion, our study provides evidence for a non intestinal pathway to neoplastic development in Barrett esophagus, that is, gastric metaplasia—foveolar dysplasia—adenocarcinoma.

Fundic Gland Polyps in Familial Adenomatous Polyposis: Neoplasms with Frequent Somatic Adenomatous Polyposis Coli Gene Alterations

Fundic gland polyps (FGPs) are the most common gastric polyps in patients with familial adenomatous polyposis (FAP). FGPs have traditionally been regarded as nonneoplastic, possibly hamartomatous lesions, but the pathogenesis of FGPs in both FAP and sporadic patients remains unclear. FGPs in FAP can show foveolar dysplasia, and rarely invasive gastric adenocarcinoma has been reported in patients with FAP and fundic gland polyposis. Using direct gene sequencing and allelic loss assays at 5q, we analyzed somatic adenomatous polyposis coli (APC) gene alterations in 41 FAP-associated FGPs (20 with foveolar dysplasia, six indefinite for dysplasia, and 15 nondysplastic) and 13 sporadic FGPs. The foveolar epithelium and dilated fundic glands of the polyps were separately microdissected and analyzed in 25 of 41 FAP-associated FGPs and 13 of 13 sporadic FGPs. Somatic APC gene alterations were identified frequently (21 of 41 cases, 51%) in FAP-associated FGPs. Both the foveolar epithelium and the dilated fundic gland epithelium comprising the FGPs were shown to carry the same somatic APC gene alteration in 24 (96%) of 25 cases. Furthermore, there was no difference in the frequency of somatic APC gene alterations between FGPs with foveolar dysplasia (10 of 20, 50%), indefinite for dysplasia (four of six, 67%), and nondysplastic (seven of 15, 47%) in FAP patients (P: = 0.697). In contrast, FGPs from non-FAP patients showed infrequent (one of 13, 8%) APC gene alterations (P: = 0.008). These results show that FGPs in FAP patients are pathogenetically distinct from sporadic FGPs. Somatic, second-hit APC gene alterations, which precede morphological dysplasia in many FAP-associated FGPs, indicate that FGPs arising in the setting of FAP are neoplastic lesions.