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To the Editor:

We describe a case of adenocarcinoma arising from ileal pouch mucosa 20 years after restorative proctocolectomy (RPC) performed for a severe hemorrhagic ulcerative colitis (UC), focusing on some histopathological features (acute and chronic inflammation, atrophy of the intestinal villi, proliferative activity, and the presence of dysplasia) evaluated in the several endoscopic biopsies obtained during the long follow-up period prior to cancer onset.

A 40-year-old man underwent RPC with mucosectomy and hand-sewn 18 cm J-ileal pouch–anal anastomosis (IPAA) for a severe hemorrhagic UC refractory to medical treatment. Early on he experienced a severe acute and chronic inflammation of the ileal pouch mucosa which was evident even 1 year after ileostomy closure. Pouchitis became clinically manifest 4 years after intervention, with rectal bleeding and the occurrence of substenosis of the ileal pouch inlet and of the IPAA. In the following years the patient underwent a regular endoscopic follow-up with multiple biopsies. A typical picture of severe diffuse acute and chronic mucosal inflammation with edema, granularity, and multiple ulcerations was confirmed at each endoscopy and biopsy control. In January 2005 (17 years after operation) a low-grade adenomatous dysplasia was diagnosed in an endoscopic biopsy of the ileal pouch. Because of recurrent perianal fistulas unresponsive to medical treatment, a new ileostomy was constructed in 2005. During the following year, the patient underwent multiple endoscopic dilatations of the recurrent ileal pouch inlet stenosis. In September 2008 a pouch endoscopy revealed the presence of a flat and irregular solid lesion in the posterior wall of the inflamed ileal pouch, 3–4 cm above the IPAA; the endoscopic biopsy showed the presence of “islets of adenocarcinoma within the ileal mucosa.” In order to achieve a definitive diagnosis of malignancy, we performed a transanal biopsy, which documented the lesion being an adenocarcinoma infiltrating the muscular tissue of the ileal pouch. A subsequent staging thoracic and abdominal computed tomography revealed no metastases. We therefore performed a total transabdominal excision of the ileal pouch with removal of the small rectal muscular cap; a new permanent ileostomy was constructed distally to the former one. The specimen showed a diffuse mucosal alteration typical of a chronic inflammatory process with wide ulcers; in the posterior wall of the distal portion of the pouch there was a 1.5 cm diameter solid flat area. Histology revealed this area to be a G2 adenocarcinoma invading the ileal wall and the perivisceral fat tissue, without any metastasis in the removed lymph nodes. The patient recovered uneventfully and he was discharged 8 days after surgical intervention. Then he was submitted to adjuvant chemotherapy.

Eighteen biopsies of the ileal pouch obtained from the patient during the follow-up period from 1993 to 2008 were histologically reviewed by a gastrointestinal pathologist (M.A.).

For each mucosal biopsy these histological parameters were recorded: acute and chronic inflammation, villous atrophy, proliferative activity assessed with Mib-1 immunostaining, and dysplasia. The results showed that chronic inflammation and villous atrophy developed at an early stage and they were always present during follow-up. Acute inflammation was not always present, suggesting that it was related to a response of the mucosa to some potential inflammatory agents. In our case, the ileal pouch mucosa predominantly showed type C pattern of histological adaptation (according to the classification of Veress et al1) which evolved into dysplasia and cancer 17 and 20 years after surgical intervention, respectively. Proliferative activity showed an increasing trend over time with evidence of a high index of Mib-1 positivity in the biopsies that preceded the appearance of dysplasia and cancer. It is known that Mib-1 immunostaining helps to distinguish dysplastic areas from regenerative ones. In the regenerative mucosa Mib-1 immunoreactivity is more localized at the basis of the crypts. On the contrary, in dysplastic areas immunoreactivity is present in the cells of the superficial mucosa as well as in the crypts, suggesting a complete deregulation of normal cell proliferation. Similarly, in our case Mib-1 immunostaining was diffusely distributed in the superficial epithelium of the mucosal biopsies performed before the onset of dysplasia and cancer (Fig. 1).

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Figure 1. Low-grade dysplasia as it appears with hematoxylin and eosin staining (A). Mib-1 immunostaining (B) is high and diffusely distributed in the superficial epithelium of the ileal pouch mucosa. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Few true cases of carcinoma arising in the ileal pouch mucosa following IPAA for UC have been reported in the literature so far.2–11 The peculiarity of our case is the 240-month period before the occurrence of malignancy in the ileal pouch. Thanks to the strict clinical and endoscopic follow-up with multiple biopsies, we had the advantage of studying a possible pattern of evolution from acute and chronic inflammation to dysplasia and finally to cancer. Moreover, we documented a real evolution from dysplasia to cancer in an ileal pouch excluded from stools thanks to the diverting ileostomy during a period of 3 years. This fact underlines the importance of a strict endoscopic follow-up with multiple biopsies in these patients with a severe acute and chronic pouchitis, even in the presence of an excluded ileal pouch, the mucosal inflammation being the most important factor predisposing to dysplastic and probably neoplastic evolution.

In our case the Mib-1 proliferative index appeared to be strictly related to the development of dysplasia and cancer. In particular, the diffuse distribution of Mib-1 immunoreactivity in the superficial epithelium of mucosal biopsies was a peculiar histological finding before the onset of a dysplastic and neoplastic degeneration. Further large studies are needed to evaluate the role of a careful evaluation of the proliferative activity and Mib-1 immunostaining distribution in ileal pouch biopsies obtained from patients affected by severe chronic pouchitis and villous atrophy for a prolonged time. The aim would be that of identifying a subgroup of patients at high risk for dysplastic degeneration of the ileal pouch. For these patients an intensified clinical and endoscopic follow-up with multiple biopsies should be mandatory to detect early the onset of cancer and perform a curative surgical resection.

REFERENCES

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Cristina Marmorale MD*, Pierpaolo Stortoni MD*, Walter Siquini MD*, Mario Scartozzi MD†, Rossana Berardi MD†, Alessandra Mandolesi MD‡, Italo Bearzi MD‡, Aroldo Fianchini MD*, * Department of General Surgery Ancona University Hospital Ancona, Italy, † Department of Oncology Ancona University Hospital Ancona, Italy, ‡ Department of Pathology Ancona University Hospital Ancona, Italy.