Introduction

Xanthoma is a tumour like lesion composed of a collection of lipid laden histiocytes/ foam cells. It is often used interchangeably with the term xanthelasma and is thought to occur as a reaction to mucosal insult. The common location where xanthomas occur are skin, tendons, and it is rarely seen in the visceral sites. Gencosmanoglu R et al(1) in their series of upper gastrointestinal xanthoma reported the overall prevalence to be 0.23% amongst all endoscopies, and a relative preponderance for stomach (76%) followed by for esophagus and duodenum (12% each). Other studies have documented the incidence of gastric xanthoma to be as high as 54% (2,3). There have been few reports of esophageal xanthomas; Hamada K et al(4) reported an incidence of 1% among endoscopies at their facility. There are only a few case reports that discuss duodenal xanthomas; the same is true for xanthomas that affect the ileo-caecal valve, colon, and rectum. Rare instances of xanthomas in the urinary bladder and prostate have also been reported(5).

Gastrointestinal xanthomas are asymptomatic lesions detected incidentally during endoscopy for other associated lesions (3). Large xanthomas in the small and large bowel may present with intestinal obstruction. On endoscopy, they are seen as flat to elevated, yellowish white mucosal plaques or nodules with granular spots and presence of tortuous micro-vessels visualized on magnifying endoscopy (4). On microscopy, clusters of lipid-filled foamy histiocytes are seen in the lamina propria or submucosa. They are mostly documented in the age group of >40 years in a background of chronic gastritis prompting a role of inflammation and ageing in the pathogenic process (1). The documentation of clinical, endoscopic and pathological features of upper gastrointestinal xanthomas are limited to case reports, and a few studies (1,4). The present study aims to bridge this caveat with a clinical, endoscopic and pathological analysis of 16 cases of xanthoma occurring in the upper gastrointestinal tract.

Material and Method

This is a retrospective, descriptive study done in a tertiary care setup. An archival search for the histopathology diagnosis of xanthoma involving the gastrointestinal tract was done from January 2012 to December 2022 (10 years). A total of 16 cases were found. The demographic details, clinical presentation, associated medical history, investigation details, endoscopic gross findings were obtained from the patient records. Histopathology slides were reviewed for microscopic features and presence of chronic gastritis, atrophy, intestinal metaplasia, granulomas, Helicobacter pylori and dysplasia/carcinoma.

Results

A total of 16 cases of xanthoma in the upper gastrointestinal tract were found. The median age of diagnosis was 61 years (range: 43-73 years). The affected gender were mostly males (M: F- 15:1). The patients most presented with abdominal pain (12/16), followed by vomiting (4/16), two patients had a prior episode of blood-tinged vomitus. Eight cases had a medical history of diabetes mellitus and only two of these have a documented hypercholesterolemia. Two cases were already diagnosed with chronic gastritis and had history of upper gastrointestinal endoscopy and biopsy. None of the cases had any history of major gastrointestinal surgery or any other site of involvement with xanthomas.

An upper gastrointestinal endoscopy was indicated in these cases to evaluate a peptic ulcer disease (12/16), acute pancreatitis (2/16) and cirrhosis (1/16). Xanthoma was an incidental detection in all the cases. Stomach was the most common affected site (gastric antrum- 11 cases, fundus- 1 case), Two cases of duodenal and one of esophageal involvement was seen. Most of the lesions were sessile nodularity (5/16), other gross presentations included polyp (4/16), erosions (2/16), ulcer (1/16) and incidentally detected flat patch (1/16). The mean size of cases presenting with polyps was 4mm in greatest dimension. Microscopically an infiltration of xanthoma cells was seen in the mucosa in 14 cases. Submucosal involvement was seen in 2/16 cases. A background of chronic gastritis was seen in 3/16 cases. Presence of helicobacter pylori and intestinal metaplasia was seen in seven and four cases respectively. Two cases showed low grade dysplasia involving the surface glands, however on follow up subsequent biopsies did not reveal any dysplasia or progress to carcinoma. A background gastric atrophy was not seen in any of the cases. A follow-up was available in 10 cases and none of them showed any recurrence of xanthoma for a mean follow up period of 12.6 months.

Figure 1: (A) Mucosal infiltration by sheets of foamy histiocytes in gastric antral mucosa. (H&E,100x) Endoscopic appearance of gastric xanthomas can be flat lesions (B), yellow elevated lesion (C) and nodule (D).

Figure 2: Ulcerated esophageal mucosal lining with mucosal sheets of foamy histiocytes (H&E, 100x), inset shows the endoscopic appearance of reddish elevated lesion.

Figure 3: Submucosal sheets of foamy histiocytes in duodenum. (H&E, 100x)

Discussion

Xanthoma is a non-neoplastic lesion found in various sites. Cutaneous xanthomas are known to be associated with abnormal lipid metabolism, while their association with gastrointestinal xanthomas (GIX) is inconclusive. GIX are common in the elderly (40-60 years) with an equal gender preponderance (6,7). Some studies have reported a male preponderance especially so in cases of esophageal xanthoma (7,8). The present study also reports a median age group of 61 years and a male preponderance in the cases.

Among the GIX, pathogenesis of gastric xanthomas is well studied. Mucosal insult can be caused by infections like Helicobacter pylori, rarely other infections like cytomegalovirus and Mycobacterium avium complex, previous radiotherapy or chemotherapy. This is followed by an inflammatory response leaving behind lipid debris from the broken cell membranes which are then phagocytosed by the macrophages thus transforming to foam cells. The evidence to this theory is given by the detection of H. pylori antigen inside the foam cells though the bacteria are not present in the gastric mucosa (6,9). The higher incidence of H. pylori infection explains the higher incidence of xanthomas in the stomach. Another plausible reason for rarer incidence of xanthomas in esophagus compared to stomach is the squamous epithelial lining of esophagus can withstand trauma and irritation better than the columnar mucosa (9). Intestinal metaplasia with bile reflux is known to cause increased cellular lipid transport, and contribute to pathogenesis of xanthomas. Inflammation and irritation of esophageal epithelium is postulated as one of the risk factors. The rare occurrence of these xanthomas in the esophagus as compared to the stomach is probably due to the esophageal epithelium being more resistant to damage as compared to gastric(8). In the present study concurrent H. pylori infection was seen in 43.7% cases, intestinal metaplasia in 31.2% and a background of chronic gastritis in 81.2% cases. A history of previous instrumentation was seen in two cases.

Xanthomas are usually small asymptomatic lesions and are incidentally detected when they are biopsied for other associated lesions or recognized at autopsy (3). In the present study, two cases were on follow up for evaluation of gastritis, two patients were suspected of pancreatitis and one was being evaluated for cirrhosis. On endoscopy, the lesions are seen as flat to elevated, yellowish white mucosal plaques or nodules with granular spots and presence of tortuous micro-vessels visualized on magnifying endoscopy (4). It can be associated with hyperplastic polyps, adenomas and adenocarcinomas (10). Rarely xanthomas can be seen as small nodules studding the mucosa forming pseudo-tumour like lesions, causing intestinal obstruction. Symptoms like vomiting, abdominal pain, distension and dysmotility are attributed to this (3,5,11). Most common endoscopic presentation in the present study was sessile nodules (41.6%) followed by small polypoidal projections (25%) and one flat lesion, associated erosions were noted in 16% cases, and an ulcer was seen in one case. Abdominal pain (75%) was the most common presenting feature followed by vomiting (20%). In a review of relationship of xanthoma with gastric cancers, Moumin F et al(2) reported a large number of patients with gastric cancer have concurrent xanthomas, with a prevalence as high as 72%, they concluded xanthomas to be a warning sign for gastric cancer along with cases showing atrophy and intestinal metaplasia. In the present study two cases (12.5%) showed low grade dysplasia in the mucosal bits, while intestinal metaplasia was noted in 31.2% cases. However, in the available follow up period, none of the cases showed any progression to a malignancy.

On microscopy, xanthomas show clusters of lipid-filled foamy histiocytes in the lamina propria or submucosa. Differential diagnosis of yellow lesions on endoscopy and foamy cells on microscopy is diverse and include ectopic sebaceous glands, clear cell carcinoid, granular cell tumour, lymphoma, signet ring cell adenocarcinoma, pseudomembranous colitis, lipoma, malakoplakia, glycogen storage disorders, Whipple’s disease and Mycobacterium avium intracellulare infection. Histochemical stains and immunohistochemistry can help achieve an accurate diagnosis (6,7). Most important is to differentiate xanthomas from signet ring cell carcinoma since both have round cells with abundant cytoplasm. In signet cell carcinoma the nucleus is eccentrically placed and filled with mucin, however in xanthomas the nucleus is centrally placed. CD68 can confirm the histiocytic origin of xanthomas (12,13). S100 can be used to rule out a granular cell tumour and pan-cytokeratin to exclude a carcinoma. Histochemical stains like Zeihl-Neelsen stain and Periodic Acid-Shiff can be used to exclude a mycobacterium avium intracellulare infection and Whipple’s disease. A detailed history and examination for a multisystem involvement can help to exclude systemic diseases like macroglobulinemia and glycogen storage disorders from the list of differential diagnosis (2,12,13).

Literature on GIX is limited largely to case reports, there are no recommendations for a definitive treatment. With the absence of long-term follow up studies on these benign, asymptomatic, incidental lesions and their relationship with premalignant lesions, a follow up is routinely advised. Proton pump inhibitors have been recommended by a few authors, postulated to be protective by promoting mucosal healing (7,14).

Conclusion

Gastrointestinal xanthoma are incidental findings detected on endoscopy. They are commonly linked to chronic gastritis, Helicobacter pylori infection, and intestinal metaplasia and are characterized by aggregation of foamy macrophages inside the lamina propria or submucosa. They have been associated with gastric malignancies, making their follow up imperative.

Compliance with ethical standards: The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. It is a retrospective study based on the archived data and does not use any personal identifiers or biological samples.

Acknowledgement: The authors acknowledge the support of the technical staff of the department for their support in retrieval of the archived slides.

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