Harikumar R, Noble Thomas, Thomas Mathew
Department of Gastroenterology,
Century Hospital,
Kerala, India.
Corresponding Author:
Dr. Harikumar R
E-mail: harikumnair@yahoo.co.in
Abstract
A 61-year-old man, with an 8-year history of ulcerative colitis, presented with bleeding per rectum for 4 weeks’ duration. Colonoscopy revealed polypoidal neoplasm at the rectosigmoid junction. Histopathology depicted small cell carcinoma. On immunohistochemical staining, chromogranin A and synaptophysin were positive. The tumour was diagnosed as undifferentiated small cell carcinoma, which is unusual since generally it is the adenocarcinoma that occurs on a background of ulcerative colitis and there are only three previous reports of small cell carcinoma occurring in UC.
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48uep6bbphidvals|193 48uep6bbphidcol2|ID 48uep6bbph|2000F98CTab_Articles|Fulltext Small cell carcinomas (SCC) are unusual tumours consisiting of different levels of neuroendocrine differentiation with oat cell carcinoma being the most primitive subtype and carcinoid tumour the most differentiated. Colorectal SCC is a rare tumour[1,2,3,4,5] with an incidence of less that 0.2% amongst all kinds of colorectal cancers.[6] The common malignancy associated with ulcerative colitis is adenocarcinoma. There are only 3 previous reports of small cell carcinoma superimposing over ulcerative colitis.[7,8]
Case Report
A 61-year-old male patient, a known case of ulcerative colitis (proctosigmoiditis) on follow up with us for 8 years, presented with a 4-week history of bleeding per rectum associated with excessive mucus in stools. He had been on oral daily mesalamine treatment. He complained of easy fatiguability, and decreased appetite but no significant loss of weight. His haemoglobin was 9 g/dL and ESR 60 mm/hr. He was initiated on oral steroids 0.75 mg/kg body weight for 3 weeks. There was no resolution of symptoms. Therefore a colonoscopy was performed. There was an elevated lesion with umbilicated ulceration in the sigmoid colon approximately 3.5 cm x 2 cm (Figure 1). The rectal and distal sigmoid colonic mucosae appeared avascular with minimal granularity. The mucosa was not edematous, erythematous or friable; there were no ulcerations either. On histopathology, the tumour tissue was composed of solid sheets and partly trabecular structures of small round or oval undifferentiated cells with hyperchromatic nuclei and scanty cytoplasm (Figure 2). There were no features suggestive of glandular or squammous elements. On immunohistochemical staining, the tumour reacted positively to chromogranin-A and synaptophysin (Figure 3). Neuron specific enolase was negative. The proliferation marker Ki-67 was diffusely stained and Ki-67 index was 78%. Based on these findings, a diagnosis of undifferentiated small cell carcinoma was made.
He had 3 metastatic lesions in the liver along with pericolic nodes. Urinary 5-hydroxyindoleacetic acid was normal. He was put on chemotherapy regimen of cyclophosphamide 50 mg/m2 and adriamycin 100 mg/m2. However, on the 4th month following diagnosis, he developed pulmonary metastasis and died.
Discussion
Colorectal SCC is a rare tumour with an incidence of less than 0.2%; the basic types include small cell undifferentiated carcinoma, neuroendocrine carcinoma and stem cell carcinoma. Some of these tumours show glandular and squammous differentiation. This morphological heterogeneity supports the theory that these tumours develop following divergent differentiation from pluripotent stem cells derived from the endoderm.
Through amine precursor uptake and the decarboxylation system, neuroendocrine cells are capable of synthesising, storing and secreting a variety of neuroamines and neuropeptides.[9] Primary SCC showing neuroendocrine differentiation has been observed in many sites including upper airway and lung, skin, thymus, kidney, breast, ovary, uterus, urinary bladder, hepatobiliary tree, pancreas, salivary gland and alimentary tract.[9] The gastrointestinal tract has the largest component of neuroendocrine cells and neoplastic proliferation of these cells occurs primarily in the appendix, ileum and rectum.[10] Neuroendocrine cells of the gut were originally thought to be of neurectodermal origin,[11] but there is another school of thought that hypothesises an endodermal origin.[12,13]
The neuroendocrine nature of these cells can be demonstrated on immunohistochemistry. Electron microscopic studies have confirmed neuroendocrine differentiation by demonstrating neurosecretory granules. For diagnosis, a positive reaction to at least two neuroendocrine markers is required.[4] These tumours usually show immunoreactivity to synaptophysin, chromogranin, neuron specific enolase (NSE) and hormones[4,5] of which synaptophysin immunoreactivity is the most reliable finding. In our case the tumour was positive to both chromogranin and synaptophysin.
Small cell neuroendocrine carcinoma is an aggressive neoplasm, which is reported to occur frequently with distant metastasis at presentation and carries a poor prognosis, even if diagnosed in the early stage.[2] The 6-month survival rate is 58% and 5-year survival rate is 6%.[1,4] Liver and lymph node involvement is found in 70-80% of patients at presentation.[14] In our case, the patient had metastasis in the liver at the time of presentation and developed lung metastasis 4 months after diagnosis while on chemotherapy. The Ki-67 index indicates proliferative activity and malignant potential; in this case the Ki-67 index was 78%.
The majority of cases of SCC present, at a stage when radical surgery is not feasible. The prognosis is poor even when the primary resection is radical.[15] Surgery should be performed only when the tumour is small and various nonsurgical treatments should be offered to patients with advanced disease.[16] Local control of SCC of the rectum can be achieved with multidrug chemotherapy and radiation therapy.[2,17] The colorectal SCC has sensitivity to chemotherapy akin to the SCC of lung.
Chemotherapy with a combination of etoposide plus cisplatin has been shown to be effective in poorly differentiated SCC.[18] Mitry et al[18] reported a response rate of 41.5% and median survival range of 15 months. Bernick et al[19] reported a median survival range of 10.4 months.
We report this case since the usual malignancy that occurs in the background of ulcerative colitis is an adenocarcinoma. Many of the molecular alterations responsible for sporadic colorectal cancer (adenocarcinoma) namely chromosomal instability, microsatellite instability and hyper-methylation also play a role in colitis associated colon carcinogenesis. There are only 3 previous reports of SCC occurring in UC.[7] Ours is the fourth case. The tumour behavior in SCC superimposing UC and de novo SCC are similar as evident by previous reports; here too the patient presented at an inoperable phase with aggressive progression associated with distant metastasis.
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