Introduction
Eosinophilic gastroenteritis (EG) is a heterogeneous disorder characterized by the presence of an eosinophilic infiltrate on histopathology involving one or multiple segments of the gastrointestinal (GI) tract from esophagus to the rectum.[1] It can involve all layers of GI tract (mucosa, submucosa, muscularis, and serosa).[2] Clinical features are dependent on the site and layer of GI tract involved. EG has a remitting and relapsing course in about 45% patients.[3], [4], [5] Stricture formation has been reported with EG.[6] Inflammatory conditions with remitting and relapsing course such as ulcerative colitis and Crohn's disease predispose to carcinoma. Despite being remitting relapsing inflammatory disease EG, there is only one case report of association of EG with gastric cancer.[7]
We report a case of EG leading to adenocarcinoma colon. This is the first case report suggesting an association between EG and adenocarcinoma of colon.
Case Report
This 42-year-old male who had undergone exploratory laparotomy a month ago for acute abdomen for suspected appendicular perforation presented to us with complaints of passage of small amount (<50 ml/day) of feculent discharge from lower margin of previous laparotomy site. A computed tomography sinogram was done [Figure 1] which showed thickening of anterior abdominal wall at surgical site with small bowel loops adherent to the abdominal wall and contrast lined tract extending from terminal ileal loop to skin suggestive of enterocutaneous fistula. Colonoscopy was done which showed multiple nodules in the cecum with narrowing of ileocecal junction [Figure 2]. Biopsy showed eosinophilia in lamina propria (>30/hpf) with focal cryptitis with absence of any epithelioid cells, granuloma, or malignant cells [Figure 3]. Except mild anemia, other hematological and biochemical parameters were normal. On review of history, he had intermittent small-volume diarrhea without blood, pain abdomen, poor appetite, and weight loss for the past 4 years. There was no history of allergy, atopy, or asthma. Mantoux test was positive (26 mm of induration at 48 h) but GENE probe assay for tuberculosis was negative. Antisaccharomyces cerevisiae antibody was negative.
Figure: Computed tomography sinogram showing thickening of anterior abdominal wall with loops adherent to the abdominal wall and contrast lined tract extending from terminal ileal loop to the skin (red arrow) suggestive of enterocutaneous fistula
Figure: Preoperative colonoscopic picture showing multiple nodules in the cecal area (blue arrow) with narrowing of ileocecal junction
Figure: High.power view of preoperative biopsy from cecal nodules showing dense eosinophilic infiltrates (black arrow) (>30/hpf) and focal eosinophilic cryptitis (red arrow)
In view of ileocecal stricture and persistent fistula, he was operated and right hemicolectomy with ileotransverse anastomosis was done. Histopathology of the resected specimen showed a well-differentiated adenocarcinoma with tumor infiltrating the muscularis (pT2), proximal and distal margins were tumor free, and lymph nodes were free of any malignancy. Eosinophil counts were raised in the muscularis layer of the resected specimen (>30/hpf) [Figure 4]a and [Figure 4]b.
Figure: (a) Microscopic examination of surgical resected specimen showing disorganized glandular architecture (black arrow) with well.differentiated tumor extending into muscle coat (red arrow). (b) High.power view of surgical resected specimen showing eosinophilic infiltrates in muscle layer (black arrows)
The diagnosis considered was colonic malignancy with perforation and subsequently fecal fistula formation and stricture. Postoperatively, the patient recovered well and received 12 cycles of chemotherapy comprising oxaliplatin and 5-fluorouracil.
Six months postsurgery, surveillance colonoscopy was done which showed ulcers at the anastomotic site with normal colonic mucosa [Figure 5]. Biopsy from these ulcers showed a dense inflammation of lymphocytes, plasma cells, and eosinophils (>20/hpf) in lamina propria, with no evidence of any granuloma or malignancy [Figure 6]. His peripheral eosinophil count was normal. In view of persistent tissue eosinophilia in the absence of any other underlying cause, a diagnosis of EG was made. He was started on prednisolone and showed a good clinical response in the symptoms of intermittent diarrhea which he had previously.
Figure: Surveillance colonoscopy after ileotransverse anastomosis and chemotherapy showing superficial ulcers (black arrow) at the anastomotic site
Figure: Histological sections of anastomotic site ulcers showing numerous eosinophilic infiltrates (black arrows) up to lamina propria
The presence of eosinophils in cecal stricture before surgery, demonstration of eosinophils in operated specimen, and recurrence of anastomotic ulcers with features of EG suggests that EC was the underlying predisposing factor, leading to carcinoma colon in this patient.
Discussion
First reported by Kaijser in 1937,[8] EG is rare, with an approximate incidence of 1/100,000. It commonly occurs between the second and sixth decades of life.[9] The stomach (26%–81%) and small intestine (28%–100%) are the predominantly affected areas, but the esophagus, large intestine, and rectum are also affected.[10] EG has been classified on the basis of depth of infiltration by Klein into mucosal EG, muscular EG, and serosal EG.[11] Mucosal involvement is the most common (57.5%), followed by muscular (30%) and serosal (12.5%).[9] Another study has reported the distribution of EG as 44% (19/43) mucosal, 12% (5/43) muscular, and 39% (31/43) serosal.[12]
The current accepted criteria for diagnosis of EG are as follows:
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Presence of recurrent GI symptoms
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Biopsies with a histopathology showing predominant eosinophilic infiltration with sheets of eosinophils
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Absence of parasitic or extraintestinal diseases that may cause eosinophilia.[9]
Clinical presentation depends on the layer of GI tract and the site involved. Mucosal EG presents with abdominal pain, nausea, diarrhea, anemia, or protein-losing enteropathy. Muscular EG presents as intestinal obstruction, intussusception, and gastric outlet obstruction. Rarely, it may present as intestinal strictures. Serosal EG typically presents as ascites.[13]
Klein et al. postulated that direct contact of the allergen with the mucosa initiates an antigen–antibody reaction, which leads to release of various cytokines and particularly eotaxin which acts as a chemotactic signal for eosinophils. Thus, the disease initiation occurs primarily in the mucosal layer and as the disease activity progresses, deeper layers get involved and there is transmural involvement. However, in some patients, it is seen that the mucosal layer may not be involved and other layers show involvement. It is hypothesized that initially all layers may be involved but after a point of time due to undefined immunological preference the eosinophils remain limited to a particular layer/layers. Thus, although the term mucosal, muscular, and serosal layers are used, it does not indicate a specific or limited involvement of a particular layer but signifies the predominant layer of involvement of the disease and the inflammatory process with the possibility that transmural involvement may exist.[11], [12] In a recent study of 59 patients, the distribution of mucosal, muscular, and serosal disease was 52, 3, and 4, respectively.[14] To explain the predominant mucosal involvement, it is postulated that EG involves an inward–outward pathway in which there is initial involvement of the mucosa, and as the disease progresses the deeper layers of the gut wall get involved. Earlier, the clinical suspicion for this disease entity was low, and the diagnosis was usually made on surgically resected biopsies when specimens were removed for features of obstruction or when patients presented with ascites. In view of higher suspicion now and ease of taking endoscopic biopsies which are predominantly mucosal likely the disease spectrum is shifting toward mucosal disease.[14]
Our patient had involvement of both mucosal and muscular layer as both endoscopic and operative biopsies showed eosinophilic infiltrate. Stricture formation and obstruction is the hallmark of muscular layer involvement.
Endoscopic findings in patients with EG are not specific and include erythema, focal erosions, ulcerations, and pseudopolyps. Endoscopic abnormalities in EG are most striking in the mucosal form and include thickening of folds, erythema, and friability.[15] Histological criteria for diagnosis in terms of number of eosinophils/hpf may vary according to the site of disease. Eosinophilic esophagitis (EE) is defined as eosinophil count more than 15/hpf, but in small bowel, a higher cutoff is taken as eosinophil count may be up to 30 eosinophils/hpf in the appendix, terminal ileum, cecum, and proximal colon.[16] Degranulated eosinophils are noted in the intestinal mucosa accompanying histologic damage in EG. Diagnosis of EG may be elusive because of patchy disease distribution or the mucosa being spared altogether in muscular EG. Laparoscopy or open surgical exploration may be required for establishing the diagnosis of muscular disease. Serosal EG may be diagnosed by ascitic fluid examination. The fluid composition in serosal eosinophilic enteritis is mostly protein rich (median, 43 g/L; range, 30–86 g/L), with high leukocyte count (median, 6200/mm3; range, 1300–20,500/mm3) and a large proportion of eosinophils (median, 78%; range, 39%–96%).[13]
EG is associated with asthma and allergies in 40%–50% of the cases. Association with peripheral eosinophilia is seen in about 80% of the cases but is not a prerequisite for diagnosis. In the mucosal and serosal types of the disease, a history of atopy is common and does not occur in the muscular type.[17] Mucosal eosinophilic infiltrates can be seen in parasitic infections, Helicobacter pylori infestation, connective tissue disorders, vasculitis, intestinal polyps, hypereosinophilia syndrome, inflammatory bowel disease, celiac disease, and post solid organ transplantation with immunosuppression. Our patient did not have any history of allergies or asthma. There was no peripheral eosinophilia. Antinuclear antibodies were negative. Immunoglobulin A tissue transglutaminase was negative. Serology testing for H. pylori was negative.
EG is a chronic inflammatory relapsing and remitting disease. Three different patterns of disease course are observed – (1) single flare, (2) recurrent flares, and (3) continuous disease activity. Reported relapse rates vary among studies from 18% to 45%.[3], [4], [5] In a study of 43 patients and a median follow-up of 13.1 years, spontaneous remission was observed in 40%, and relapse rates were 33% of all patients and 60% of patients who required corticosteroid therapy.[12] Risk of clinical relapse is lower with patients who have an initial spontaneous remission as compared with patients who need treatment at diagnosis. Hypereosinophilia at diagnosis is associated with increased risk of clinical relapses. Higher risks of relapses are associated with mucosal disease, proximal small intestinal disease, and extensive disease. It has been observed that mucosal disease has a more continuous course, and muscular disease has a recurring course and serosal usually present with a single flare.[12]
Chronic inflammation in GI tract is a known risk factor for carcinogenesis.[18] It plays a major role in the development of colorectal cancer (CRC) in inflammatory bowel diseases.[19] The severity of inflammation correlates with risk of development of dysplastic changes.[20] Various case reports of coexistence of tuberculosis with colonic carcinoma have been reported in literature.[21], [22], [23] The proposed pathogenic mechanism is chronic inflammatory state due to ulcerated lesions of intestinal tuberculosis which leads to carcinogenesis. Schistosomiasis has been implicated in the development of colon cancer. The cause of tumorigenesis is postulated to be due to the either endogenously produced carcinogens, impairment of immunological surveillance by chronic immune modulation, symbiotic action of other infective agents, and the presence of schistosomal toxins.[24]
Muscular type of EE due to its recurrent nature and stricture formation may serve as a risk factor of GI cancer. Probably due to rarity of disease, there is only one case of cancer reported with EG. This is, to the best of our knowledge, the first case of carcinoma colon associated with EG. Our patient had eosinophils in the colonoscopic biopsies taken preoperatively. In the resected specimen there was infiltration of the eosinophils in the muscle layer and in the post surgical anastomotic site there were ulcerations which demonstrated tissue eosinophilia. These factors indicate that this patient had EG which lead to development of carcinoma colon.
Eosinophils are a rich source of proinflammatory cytokines which play both protective and pathological effects in the GI tract.[25] Eosinophil granules contain a crystalloid core composed of major basic protein-1 and 2 and a matrix composed of eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase. These cationic proteins have proinflammatory properties and are known to exert cytotoxic effects on epithelium.[26] Eosinophil-derived transforming growth factor-β is linked with epithelial growth, fibrosis, and tissue remodeling. Eosinophils also generate large amounts of the leukotriene C4, which is metabolized to LTD4 and LTE4. These three lipid mediators increase vascular permeability.[27]
In experiments with suspensions of cells from colonic carcinomas, it has been seen that colonic carcinomas contain large numbers of eosinophils.[28] The infiltration of tumors with eosinophils does not necessarily parallel peripheral blood eosinophilia, although the two phenomenons can occur together. Eosinophilic infiltration is an independent favorable prognostic influence on outcome of CRC.[29] Eosinophils play a role in the host interaction with the tumor, perhaps by promoting angiogenesis and connective tissue formation adjacent to the cancer.[30]
Conclusion
EG is a rare disorder with a wide spectrum of clinical presentation. A high index of clinical suspicion is required for its diagnosis. Increasing luminal assessment due to ease of GI endoscopy and colonoscopy has led to increased diagnosis of mucosal EG. Like other inflammatory disorders, EG may be a predisposing factor development of GI malignancy. This is the first case report of carcinoma colon in EG and the second published case report of GI malignancy with EG.
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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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