Pneumatosis cystoides intestinalis: six case reports and a review of the literature

Pneumatosis cystoides intestinalis (PCI) is characterized by gas-filled cysts in the intestinal submucosa and subserosa. It is a rare disease with reported incidence of 0.03% and can occur in any age group [1]. PCI was first described by DuVernoi in 1783 and later subcategorized by Koss in 1952 [2]. It can be divided into primary or idiopathic (15%) type, which refers to air pockets that are cystic in appearance and imply to a chronic, benign idiopathic etiology [3], and secondary type (85%), which refers to radiological findings of linear, microvesicular, or more circumferential appearing intramural gas caused by various predisposing factors [3, 4]. The pathogenesis of PCI remains unclear; however, six pathophysiologic mechanisms have been proposed including inflammation, physical damage of intestinal mucosa, nutritional imbalance and dysbacteriosis, gastrointestinal dysmotility, and immune dysfunction [5, 6]. PCI can occur anywhere within the gastrointestinal tract from the esophagus to the rectum. It was previously reported that mainly involve the terminal ileum, but Morris later reported that PCI localized to large intestine in 46% of the cases, the small intestine in 27% of the cases, the stomach in 5% of the cases and the large combined with small intestine in 7% of the cases [7]. PCI can be found incidentally in asymptomatic patients, while some cases presented as abdominal pain, diarrhea, abdominal distention, constipation, bloody stool, flatus, loss of appetite, weight loss, and even life-threatening illnesses including bowel necrosis and perforation [8].

Several reports of endoscopic ultrasonography (EUS) in the evaluation of bumps in the colon have clarified the diagnosis of PCI [9, 10], while computed tomography scan is regarded as the most sensitive imaging modality for detection. However, some patients who frequently presented with non-specific gastrointestinal symptoms were often prone to be misdiagnosed or maltreated and even underwent surgical resection, which resulted in several adverse events. Herein, we reported the etiological characteristics, endoscopic features, treatment and prognosis of 6 PCI cases to recognize the endoscopic characteristics and investigate the proper treatment methods for PCI.

PCI is a rare condition characterized by gas-filled cysts in the intestinal submucosa and subserosa. Various predisposing factors have been associated with PCI: postsurgery [11], chemotherapy [12], Acarbose [13], Trichloroethylene (TCE) [14], scleroderma [15], and pulmonary illness [16]. In this report, there were total 6 patients studied, which included one case of idiopathic, one case induced by TCE, one case with UCTD, one case induced by emphysema, one case caused by diabetes and one case with PPC. Exposure to TCE results in primary PCI that previously reported in Japan, and the pathogenesis may be related to intestinal mucosal toxicity [14]. Patients with UCTD can be combined with PCI, including systemic sclerosis (SS), systemic lupus erythematosus (SLE), etc., which may be related to abnormal immune function regulation [17] and long-term use of glucocorticoids resulted in intestinal mucosal atrophy and defects, which promoted the formation of cysts in the intestinal submucosa. PCI has been associated with pulmonary disease in the absence of gastrointestinal disorder [16]. Recently, several reports have mentioned that the α-GI, voglibose or Acarbose, might be a causative factor for PCI [13, 18, 19]. It is generally understood that α-GI causes flatulence, because it suppresses absorption of carbohydrates in the colon, and intestinal bacteria then generates a large volume of gas by carbohydrate fermentation [20]. Recently, application of rituximab in patients with squamous cell carcinoma [21], sunitinib in patients with renal cell carcinoma, gefitinib in patients with lung adenocarcinoma and chemotherapy drugs, such as fluorouracil in patients with colorectal cancer were suggested to be associated with the development of PCI [22]. In this study, one of patient was suffering from peritoneal cancer, but did not use chemotherapy drugs, so the relationship between the tumor and the intestinal gas cyst requires further study. Recently, molecular-targeted agents such as anti-vascular endothelial growth factor (VEGF) agents and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been suspected to increase intestinal toxicity as well, which is interrelated to PCI [23].

Patients with PCI can be asymptomatic or present with non-specific gastrointestinal symptoms such as abdominal distention, diarrhea, constipation, abdominal pain and weight loss [5]. Although PCI was previously reported to occur more frequently in the terminal ileum of the gastrointestinal tract, Horiuchi A’s studies showed that PCI occurred 61.8% in colon,15.4% in the small intestine, which was more common in the sigmoid colon [24]. In this study, in 4 (66.7%) patients, PCI occurred in the colon, especially the sigmoid colon, while in other two (33.3%) patients, it occurred in duodenum and rectum, which was relatively rare. We looked up a lot of literature and found that there were fewer reports of PCI occurred in duodenum and rectum, so more clinical evidence needed further study. Since the lack of specificity in clinical manifestations, it should be differentiated from the duodenal diverticulum when PCI occurred in that duodenum. It has been reported that PCI can be found in mesentery, omentum, ligamentum hepatogastricum, but rarely found in esophagus and stomach. Endoscopic findings were divided into bubble-like pattern, grape or beaded circular forms, linear or cobblestone gas formation and irregular forms. The bubble-like lesion was often idiopathic, which needed to be distinguished from polyps. The grape-like or beaded subepithelial lesions should be differentiated from intestinal tuberculosis. Irregular shapes need attention to distinguish from tumors and Crohn’s disease. In previously described cases, linear gas formations were an ominous sign [25]. The radiological findings of diffuse and extensive intraluminal cysts within the walls of the colon are classic for PCI. Contrast-enhanced CT has an advantage in revealing gas within the portal venous system [26]. Endoscopic ultrasonography findings of the mucosal layer low echo below the cystic in the diagnosis of PCI is superior [27], which can avoid the risk of CT examination and distinguish from other diseases, such as polyps, carcinoma, lymphoma, liquid cysts, Gardner syndrome, Cronkhite-Canada syndrome, Peutz-Jehers syndrome, Crohn’s disease, etc. [28]. Overall, the diagnosis of PCI and its adverse events including bowel perforation, portal venous gas (PVG) [29], intestinal hemorrhage, sepsis or peritonitis is very important.

PCI is a benign lesion and very few patients face cancer risk. There is no unified standard for treatment of PCI. The most of PCI cases are usually managed conservatively, while exploratory laparotomy is considered if peritoneal irritation or persistent bowel obstruction occurs in PCI. Joseph D. Feuerstein proposed that PCI could be effectively alleviated with hyperbaric oxygen therapy at 2.5 atmospheres for 2.5 h for at least three sessions [30, 31]. In our cases, we gave oxygen therapy to PCI patients with emphysema, but without hyperbaric oxygen, which can alleviate the patient’s COPD, meanwhile regarded as the treatment methods of PCI associated with emphysema. Electronic colonoscopy forceps can facilitate the treatment of bubble-like pattern PCI, however blindly using argon knife excision may cause an explosion considering the possible existence of methane and other combustible gases. In addition, ornidazole and Bifidobacterium can be used to regulate intestinal flora, which can obviously improve the symptoms. The mechanism of antibiotic therapy is to inhibit the growth of harmful intestinal bacteria and thus to inhibit the production of hydrogen. The application of Bifidobacterium is to regulate the dysbacteriosis and improve the function of gastrointestinal tract. Knechtle reported that low pH (< 7.3), low serum bicarbonate (< 20 mmol/L) and elevated serum lactic acid (LA) (> 2 mmol/L) are associated with poor prognosis [32]. Alexander J found that surgical treatment of PCI patients with PVG could decrease the risk of death as compared to other PCI patients, so he recommended that surgical treatment was needed if the patient was not responsive to conservative treatment or had developed serious adverse events. Through the study of 123 cases of PCI, Ho-Su Lee et al. concluded that patients with both peritoneal irritation and decreased or absent enhancement of bowel wall on CT should be observed, and we should establish a simple and novel risk score that predicted mortality in patients with PCI [33]. The treatment of primary diseases is imperative for secondary PCI. Long-term follow-up of patients with PCI will facilitate understanding of the disease prognosis.

In this article, we demonstrated 6 cases of PCI with varied causes and 3 of 6 cases with intestinal stricture all were successfully managed by medical conservative treatment. PCI endoscopic manifestations were varied, and radiology combined with endoscopy could avoid misdiagnosis. The primary bubble-like pattern can be cured with endoscopic resection, while removal of etiology combined with drug therapy can resolve majority of secondary cases, thereby avoiding the adverse risks of surgery.