A 76-year-old white man presented with abdominal pain localized to the right upper quadrant. He had alteration in bowel habits, with some increase in bowel movements during the previous 6 to 7 months. Past medical history was significant for bilateral nephrolithiasis, cholecystectomy, and appendectomy. Imaging studies, including computed tomography and magnetic resonance imaging with gadolinium, revealed multiple solid lesions in the liver too numerous to be counted, compatible with diffuse metastatic nodules. There was a suspicious area of bowel wall thickening in the cecum. Complete blood cell count showed the following values: hemoglobin, 151 g/L; platelets, 300 × 10^9/L; and absolute neutrophil count, 11.2 × 10^9/L. Stool was positive for occult blood. The results of viral hepatitis studies were negative. Tumor marker studies, including serum prostate-specific antigen (0.2 ng/mL), α-fetoprotein (3.8 ng/mL), and carcinoembryonic antigen (1.7 ng/mL) were within normal reference ranges. However, his serum alkaline phosphatase level was significantly raised to 456 U/L. A computed tomography–guided fine-needle biopsy of the liver lesions was performed to confirm the nature of the lesion (Figure 1). A few days later, the patient developed bilateral lung infiltrates, hyperpyrexia, and enterococcal septicemia followed by severe hypotension, and he died. Permission for autopsy was obtained.
Autopsy revealed diffuse involvement of the liver by multiple tumor nodules ranging from 0.5 to 3.5 cm. The periportal, peripancreatic, and mesenteric lymph nodes appeared to be involved. A 4.1 × 3.5 × 1.2-cm, firm, infiltrative mass was identified in the cecum, extending up to the serosa and focally infiltrating through the lateral wall. Hematoxylin-eosin–stained sections from the cecal mass, liver nodules, and the involved lymph nodes showed similar morphologic features, including nests as well as diffuse sheets of cells with hyperchromatic nuclei and negligible to scanty amounts of cytoplasm (Figure 2). Nuclear molding, high mitotic activity, apoptosis, and foci of necrosis could be seen (Figure 3). Immunostaining was performed, including cytokeratin, neuron-specific enolase, synaptophysin (Figure 4), leukocyte common antigen, and prostate-specific antigen. The neoplastic cells in the cecum, liver, and lymph nodes were strongly positive for neuron-specific enolase, synaptophysin, and cytokeratin.
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Pathologic Diagnosis: Small Cell Carcinoma of the Large Intestine
Small cell carcinoma of the large intestine is a highly malignant neoplasm; these tumors are rare and comprise less than 1% of colorectal cancers. They resemble their lung counterparts in terms of histologic characteristics and behavior. By light microscopy, small cell carcinomas are undifferentiated, but special techniques show neuroendocrine differentiation. The small cell carcinoma is mainly a tumor of older people, with the mean age of occurrence being 63 years. Topographically, they have a predilection for the right side of the colon and most commonly the cecum (as in the present case). Symptoms are related to intestinal obstruction and include crampy abdominal pain, malaise, weight loss, and alteration of bowel habits. Typically the duration of symptoms is short (running only a few weeks), indicating the aggressive nature of this tumor. Most patients at the time of presentation have metastasis, mostly to the liver. The frequency of hepatic metastasis at the time of surgery is much higher (71%) compared to that of poorly differentiated carcinoma (7%) or non–small cell undifferentiated carcinomas of large gut (50%).1–5
The gross features of small cell carcinoma of colon do not distinguish it from adenocarcinoma. It may appear as a bulky mass projecting into the bowel lumen or perforating the bowel wall. Occasionally it can appear as a tiny focus in an adenomatous polyp. By light microscopic examination, small cell carcinoma of colon resembles small cell carcinoma of lung (oat cell carcinoma). The tumor is composed of sheets and nests of densely packed, round to ovoid cells with hyperchromatic nuclei, stippled nuclear chromatin, inconspicuous nucleoli, and scant cytoplasm. Pleomorphism is minimal. Numerous mitoses, apoptotic cells, foci of necrosis, and vascular invasion are usually obvious. The characteristic pattern of encrustation of the nuclear material around blood vessels (Azzopardi effect) has been reported at the site of metastasis in 2 cases.6 Trabecular and rosettelike patterns indicative of neuroendocrine differentiation may be seen. Not uncommonly, squamous differentiation and abortive gland formation is noted. An associated adenoma is seen in one third of cases.2,4 Burke et al,3 in a series of 38 cases, found an overlying adenoma in as many as 45% of their cases and squamous differentiation in 21%. However, when associated with adenoma, the adenomatous portion had no special features and the interface of adenoma and small cell carcinoma was abrupt. Absence of an associated adenoma may be due to overgrowth of a large tumor, as in the present case. These tumors usually show at least some evidence of neuroendocrine differentiation either by electron microscopy or by immunohistochemistry. Ultrastructurally, membrane-bound dense core granules are seen in 81% of cases. Immunostains are very helpful. Positivity for neuron-specific enolase, chromogranin, synaptophysin, cytokeratin, and Leu-7 antigens is the most common finding. The highest rates of positivity are reported with neuron-specific enolase (87%) and synaptophysin (56%).3 The features of the metastatic lesions in the liver or the lymph nodes are similar to those of the primary lesion, and the morphologic and immunohistochemical characteristics can be readily identified. Differentiating from carcinoids of colon poses few diagnostic difficulties. Typically, carcinoids show a characteristic growth pattern, less than 1 mitosis per high-power field, and lack of necrosis.
Small cell carcinomas are believed to arise from uncommitted stem cells or the reserve cells of colonic crypts in probable preexisting adenomas. These are believed to be capable of differentiating into a number of types of neoplastic cells, including neuroendocrine tumor triggered by genetic alteration from an unidentified stimulus. Few cases of primary small cell undifferentiated carcinoma of the rectum associated with ulcerative colitis have been reported in literature.7
Colorectal small cell carcinomas carry an extremely poor prognosis, as almost all cases have lymph node and liver metastases. Of the 20 colonic tumors reviewed by Redman et al,8 widespread metastasis was present in 85%. In the follow-up of their cases, Burke et al3 found that most patients did not respond to therapy, despite a variety of regimens. Two thirds of the patients with small cell carcinoma of colon were dead at 5 months. Occasional reports of remission in response to multidrug chemotherapy, meant for treating pulmonary small cell carcinoma, do occur in the literature. However, the remissions were short-lived, the longest lasting up to 12 months.3,7,9
