Peritoneal Mesothelioma in a Patient with Long-Standing Crohn’s Disease: Cause or Coincidence? Open Access

Peritoneal mesothelioma (PeM) is a rare malignancy arising from the mesothelial cells that line the peritoneal cavity [1]. Environmental or occupational contact with asbestos is the most well-established risk factor. However, unlike pleural mesothelioma, PeM is less frequently linked to asbestos exposure [2]. The pathogenesis of PeM likely involves complex genetic and molecular mechanisms, and chronic serosal inflammation – such as that seen in patients with Crohn’s disease (CD) – has been postulated as a contributing factor in PeM carcinogenesis [3]. Here, we present a case of PeM in a patient with a long-standing history of Crohn’s disease with no documented asbestos exposure.

A 46-year-old man with a history of long-standing stricturing and fistulizing ileal CD presented to our clinic with a 6-month history of recurrent episodes of intestinal subocclusion. He was first diagnosed at 19 years old after undergoing a diagnostic workup for recurrent abdominal pain and diarrhea, achieving clinical remission with steroid therapy. Five years later, he experienced a relapse with steroid dependency and was started on azathioprine. Twelve years post-diagnosis, the patient developed a perianal fistula, which was successfully treated with adalimumab (ADA) administered every other week, resulting in complete fistula closure. A decade later, the ADA dosage was optimized to weekly administration due to a relapse with abdominal cramps, vomiting, and diarrhea. While clinical improvement was noted, imaging showed persistent complex active ileal CD with transmural inflammation, serosal adhesions, stricture, and fistula formation.

At the current presentation, he reported no additional symptoms. Both physical examination and blood workup were unremarkable, with therapeutic ADA levels (8.9 µg/mL) and low fecal calprotectin (71 µg/g). Computed tomography (CT) enterography revealed significant thickening of the distal ileum wall with adhesive and fistulizing changes to the sigmoid colon, as well as new-onset ascites and peritoneal densification (Fig. 1), with no pathologic lymph nodes. After a multidisciplinary team (MDT) meeting and case review, surgical intervention was proposed due to the significant worsening of obstructive symptoms and the inability to definitively exclude a neoplastic complication, such as small bowel adenocarcinoma. Complementary chest CT showed no abnormalities. The patient had undergone a surveillance colonoscopy under deep sedation 6 months earlier, which identified a recess compatible with an internal fistula opening 20 cm from the anus. However, it was not possible to reach the right colon due to fixation, and no other mucosal abnormalities were detected. Since CT enterography identified pathological changes confined to the small bowel, with no additional colonic involvement beyond ileo-sigmoidal fistulization, it was concluded that repeating an ileocolonoscopy would offer no additional benefit as it would not alter the surgical indication.

Intraoperatively, a small bowel mass adherent to the sigmoid colon, millimetric nodules of the peritoneum, and ascites were identified. The procedure involved adhesiolysis, aspiration of abdominal fluid, ileocecal resection of 30 cm of bowel, and extraction and closure of the ileosigmoid fistula. The procedure and the postoperative period were uneventful. Histopathologic analysis of the resected stenotic segment revealed changes consistent with CD, without evidence of dysplasia. Additionally, multiple foci of epithelioid mesothelioma were identified in the small bowel serosa (Fig. 2a). These lesions exhibited a tubulopapillary pattern, invading the intestinal wall up to the muscularis propria, with immunohistochemical staining positive for calretinin (Fig. 2b) and CK7 and negative for CK20.

The patient had no history of asbestos exposure. Following MDT discussion and staging of the PeM, he underwent concurrent cytoreductive surgery – including total omentectomy, peritonectomy, anterior rectum resection, and cholecystectomy – combined with hyperthermic intraoperative peritoneal perfusion with chemotherapy. At the 15-month follow-up, the patient remains asymptomatic with no signs of recurrence and is under close monitoring.

PeM is a rare and aggressive cancer of the peritoneal lining, with incidence rates in industrialized countries estimated at 0.2–3 cases per million [1]. Pleural mesothelioma, the most common type, accounts for approximately 80% of all mesothelioma cases, while PeM comprises only 15–20% [2].

Mesothelioma is closely associated with chronic inflammation, particularly in the context of asbestos exposure. Asbestos fibers are known to induce a chronic inflammatory response and oxidative stress, leading to DNA damage in mesothelial cells [4].

The carcinogenesis of PeM is complex, multifactorial, and still poorly understood. Compared to pleural mesothelioma, PeM is less frequently associated with asbestos exposure, and many cases are considered idiopathic. While asbestos exposure is still the most significant risk factor, it is present in only about 33–50% of cases of PeM, compared to over 90% in pleural mesothelioma [3]. Other non-asbestos-related causes of PeM include genetic factors, such as germline mutations in the BRCA1-associated protein-1 (BAP1) gene, and other environmental exposures, though these account for a small proportion of cases [1, 5].

Moreover, chronic inflammation has been implicated as a risk factor in cases of non-asbestos-related PeM, suggesting that persistent serosal inflammatory states may play a role in its pathogenesis [3, 5]. This aligns with the broader understanding that chronic inflammatory states can contribute to carcinogenesis, potentially through mechanisms involving persistent cellular damage and repair. Patients with CD, a chronic inflammatory disorder characterized by inflammation of all layers of the intestinal wall and involvement of the mesentery [6, 7], are at increased risk of developing small bowel and colorectal cancer [8, 9].

To the best of our knowledge, only 3 cases of PeM arising in patients with CD have been reported in the literature (Table 1). Butnor et al. [10] reviewed approximately 3,800 cases of mesothelioma, including 500 cases of PeM, and identified 3 patients with both PeM and a prior diagnosis of CD. In all cases, CD had been diagnosed at least 3 years (ranging from 3 to 40 years) before the diagnosis of PeM. In the case with the shortest duration of established CD, the patient had a long history of prior diarrhea. Potential occupational exposure to asbestos was documented in only 1 case [10].

Remarkably, no cases of PeM have been reported in patients with ulcerative colitis, which supports a potential link between PeM and the transmural inflammation, and consequent serosal inflammation, seen in CD. There is evidence that adipocyte progenitors in the mesenteric adipose tissue of CD, the «creeping fat», exhibit increased mesothelial characteristics, which may contribute to the chronic inflammatory environment, potentially influencing mesothelial cell behavior and proliferation [11]. Wilkinson et al. [12] described a case of an exuberant mesothelial reaction in longstanding CD ileitis mimicking malignant mesothelioma, highlighting the diagnostic challenges in differentiating between benign mesothelial proliferation and malignant mesothelioma in the context of CD. Furthermore, chronic serosal inflammation from other conditions, such as familial Mediterranean fever [13], endometriosis [14, 15], and long-standing intra-abdominal catheters [16], has been described as a risk factor for PeM, supporting the potential role of chronic inflammation in mesothelial carcinogenesis.

Clinically, the disease typically progresses within the peritoneal cavity, often manifesting with nonspecific symptoms such as abdominal pain, distension, and ascites, which can contribute to delayed diagnosis and worse prognosis [2, 3]. This is particularly challenging in patients with longstanding CD due to overlapping clinical and imaging features that may be misinterpreted as an exacerbation or nonresponse to medical therapy. Table 2 summarizes the main differential diagnoses to consider. CT imaging of the abdomen and pelvis is the recommended diagnostic tool for preoperative assessment [17]. In this case, the true significance of the new-onset ascites and peritoneal lining densification was initially underestimated, even though the importance of excluding a neoplastic complication was addressed at the MDT meeting.

Similar to pleural mesothelioma, the histologic subtypes of PeM include epithelioid (about 60% of cases of all cases), sarcomatoid (around 20%), and biphasic (approximately 20%) [18]. The main prognostic factors include the histologic subtype – with epithelioid histology associated with a better prognosis – lymph node involvement, and the completeness of cytoreduction [17, 19]. Regardless of etiology, for selected patients with diffuse PeM, no extraperitoneal disease spread, good performance status, and a high likelihood of achieving complete surgical cytoreduction, cytoreductive surgery with hyperthermic intraoperative peritoneal perfusion with chemotherapy is the cornerstone of treatment and significantly improves survival [20]. Studies have demonstrated a median survival of 29.5–92 months and a 5-year survival rate of 39–63% with this approach [18, 19]. For patients who are not candidates for surgery or have recurrent disease, multiple intravenous systemic therapy options are available and are primarily based on clinical trials conducted in patients with pleural mesothelioma. In this context, immunotherapy, either alone or in combination with chemotherapy, has emerged as a significant treatment modality for PeM [19, 20].

This case report presents a rare case of non-asbestos-related PeM in a patient with long-standing active complex ileal CD. Overall, the rarity of PeM limits our understanding of its epidemiological features. There is evidence suggesting a link between chronic serosal inflammation – as illustrated in this case – and PeM. However, the precise mechanisms and clinical significance of this relationship are still unclear, and it is not possible to infer a cause-effect association. Further research is needed to better understand this relationship.

Ethics approval was not required for this study in accordance with local/national guidelines. Informed consent was obtained from the patient for the publication of this article and any accompanying images.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

All the authors made substantial contributions to the article. Rita Prata drafted the manuscript. Pedro Lages Martins, Verónica P. Borges, Pedro Botelho, António Figueiredo, and Jaime Ramos critically revised the manuscript. All the authors approved the final version of the manuscript.

The complete data of this study are not publicly available due to the patient’s privacy but are available from the corresponding author upon reasonable request.