You are here

Colonic small cell neuroendocrine carcinoma in a patient with long-standing ulcerative colitis treated with azathioprine

Digestive and Liver Disease, In Press, Corrected Proof, Available online 7 April 2016, Available online 7 April 2016

Dear Editor,

We report the case of a patient with long-standing ulcerative colitis (UC) treated with Azathioprine (AZA) who developed a neuroendocrine small cell carcinoma arising from the sigmoid colon.

A 61-year old man was diagnosed with extensive UC in 2002. After initial response to oral and topical mesalazine, azathioprine (AZA) 2.5 mg/kg/day was added five years after diagnosis because of steroid-dependency. After AZA introduction the patient achieved sustained steroid-free remission but, 3 years later, he was diagnosed with idiopathic autoimmune hemolytic anemia requiring repeated steroid courses despite concomitant immunosuppression. Eight years after diagnosis the patient was in remission off-steroids and endoscopic surveillance for long-standing disease was started. At index colonoscopy (2010) erythema and decreased vascular pattern were observed in the whole colon except for the sigmoid which showed also mild friability and small erosions. Histological examination was consistent with UC in remission with features of mild activity in the sigmoid colon. No dysplasia was observed. Endoscopic surveillance was then planned every 2 years and the subsequent colonoscopy (2012) showed a similar pattern. In 2014 the patient was symptom-free but a routine abdominal ultrasound prescribed by the general practitioner showed multiple liver metastasis. A total body CT scan confirmed metastatic liver disease without any evidence of primitive neoplasm. A bowel wall thickness of the sigmoid colon and pericolic enlarged lymphnodes (12 mm) were also detected. Colonoscopy showed a narrowed sigmoid colon with nodular mucosa and confluent deep ulcerations: histologic examination of endoscopic biopsies showed a small cell neuroendocrine carcinoma with high proliferative index (Ki67 > 90%). Immunohistochemical analysis showed expression of thyroid transcription factor-1 (TTF-1), pool of cytokeratins and synaptophysin and absence of CDX2 and CD20 antigens. These immunohistochemical findings were confirmed by histological examination of a percutaneous liver biopsy (Fig. 1). An intestinal origin of the neoplasia was supposed considering the absence of any lesion in the lung. In the subsequent weeks a clinical deterioration occurred with rapidly progressive liver failure. Death occurred within 2 months from diagnosis.

gr1

Fig. 1 (A) Bioptic fragment of colonic mucosa infiltrated by small cell carcinoma (white arrow). The surrounding mucosa shows crypt distortion and increased chronic inflammatory infiltrate (black arrow). (B) The neoplasia shows positivity for synaptophysin (white arrow) and (C) shows a high proliferative index by Ki67 staining. (D) Bioptic fragment from liver metastasis: the neoplastic cells express nuclear TTF-1.

Neuroendocrine neoplasms (NENs) account for less than 1% of all colorectal malignancies and are characterized by a high rate of liver metastasis: the prognosis is particularly poor compared to colorectal adenocarcinoma [1]. NENs occur infrequently in the setting of inflammatory bowel disease (IBD), and the vast majority are clinically indolent, well-differentiated carcinoids found incidentally after surgery. Rarely NENs other than carcinoids have been reported in IBD and a neuroendocrine differentiation from multipotential cells in dysplastic epithelium has been suggested [2].

The case we have described shows some interesting peculiarities. Firstly the neoplasia was diagnosed at an advanced stage despite biannual endoscopic examination: this may reflect the rapid rate of malignant progression and/or the suboptimal negative predictive value of endoscopic surveillance.

Secondly the immunohistochemical finding of TTF-1 expression. TTF-1 is a tissue specific transcription factor that plays a critical role in the normal development of embryonic epithelial cells of the thyroid and lung and it is commonly used to assist in the differential diagnosis of carcinomas of the lung and thyroid. Recent studies, however, have reported that TTF-1 can infrequently be found to be expressed in some NENs arising in other organs, including the colon [3]. The prognostic significance of TTF-1 expression is controversial. In small cell lung cancer TTF-1 has no prognostic value but it may be associated to improved outcome in non-small cell lung cancer [4].

Finally, a potential role of AZA in promoting tumor occurrence or its rapid progression cannot be excluded. The patient had been receiving AZA for 7 years because of steroid dependency and the development of malignancy as a late complication of thiopurine-use is of major concern. Although an increased risks of lymphoproliferative disorders and non melanoma skin cancer is well established, data on the overall cancer risk are limited and controversial. Recently, an historical cohort study showed that AZA use in IBD patients is associated with an increased risk of overall cancer although causality cannot be established [5]. However, a specific association with thiopurine exposure and NENs has never been reported.

Conflict of interest

None declared.

References

  • [1] P.E. Bernick, D.S. Klimstra, J. Shia, et al. Neuroendocrine carcinomas of the colon and rectum. Diseases of the Colon and Rectum. 2004;47:163-169 Crossref
  • [2] J.E. Sigel, J.R. Goldblum. Neuroendocrine neoplasms arising in inflammatory bowel disease: a report of 14 cases. Modern Pathology. 1998;11:537-542
  • [3] N.G. Ordonez. Value of thyroid transcription factor-1 immunostaining in tumor diagnosis: a review and update. Applied Immunohistochemistry and Molecular Morphology. 2012;20:429-444 Crossref
  • [4] D. Misch, T. Blum, C. Boch, et al. Value of thyroid transcription factor (TTF)-1 for diagnosis and prognosis of patients with locally advanced or metastatic small cell lung cancer. Diagnostic Pathology. 2015;10:21 Crossref
  • [5] B. Pasternak, H. Svanström, K. Schmiegelow, et al. Use of azathioprine and the risk of cancer in inflammatory bowel disease. American Journal of Epidemiology. 2013;177:1296-1305 Crossref

Footnotes

Digestive and Liver disease Unit, “La Sapienza” University S. Andrea Hospital, Rome, Italy

Department of Clinical and Molecular Medicine, “La Sapienza” University, S. Andrea Hospital, Rome, Italy

Gastroenterology Unit, S. Filippo Neri Hospital, Rome, Italy

Corresponding author.