Small-cell carcinoma of the rectum

Small-Cell Carcinoma of the R e c t u m Report of t w o Cases Javier Cebrian, M.D., Sergio W. Larach, M.D., Andrea Ferrara, M.D., Paul R. Williamson, M.D., Michael F. Trevisani, M.D., Henry J. Lujan, M.D., Andrew Kassir, M.D. From the Colon a n d Rectal Clinic of Orlando, Orlando, Florida Small-cell carcinoma of the rectum is an ingrequent pathologic finding, and its precise incidence is u n k n o w n . Its incidence is less than 0.2 percent among all colorectal cancers. This tumor manifests highly aggressive behavior. The treatment of choice is combination chemotherapy similar to that used for small-cell carcinoma of the lung, but in small localized tumors surgery plus c h e m o t h e r a p y is an alternative. We present two cases of small-cell carcinoma of the l o w e r rectum and a review o f the literature. [Key words: Oat-cell carcinoma; Rectal cancer; Extrapulmonary smallcell cancer] REPORT OF CASES Case 1 A 46-year-old female patient was evaluated for complaints of rectal pain, rectal bleeding, and discomfort after evacuation. Her past medical history was significant for a hysterectomy followed by pelvic radiation therapy for a Stage II cervical squamous-cell carcinoma in 1984. Physical examination revealed a firm mass originating at the dentate line and extending 8 cm proximal in the lower rectum. Flexible sigmoidoscopy was performed and a friable mucosa was seen in the lower rectum and anal canal. Otherwise, the rectum was healthy'. Multiple biopsies were performed to rule out tumor vs. radiation proctitis. The mucosa demonstrated changes consistent with radiation proctitis. There were no other pathologic findings. CT scan of the pelvis (Fig. 1) s h o w e d a mass, 4 X 6 cm, located at the left lateral aspect of the pelvis and extending from the rectum superiorly into the presacral space on the left. The rectum and sigmoid were displaced laterally. The rest of the pelvis showed only multiple hemostatic clips. Results of a CT scan of the a b d o m e n were normal. Pathology (Fig. 2) showed a small-cell carcinoma that stained positive for chromogranin, synaptophysin, and neuron-specific enolase. The patient underwent surgical exploration, and findings s h o w e d multiple liver metastases, massive periaortic and peri-iliac metastatic nodes, and an unresectable lesion in the pelvis. Diverting colostomy was performed. The patient refused any further treatment. Cebrian J, Larach SW, Ferrara A, Williamson PR, Trevisani MF, Lujan HJ, Kassir A. Small-cell carcinoma of the rectum: report of two cases. Dis Colon Rectum 1999;42:274-277. E xtrapulmonary oat-cell or small-cell cancer (SCC) is a rare tumor w h o s e precise incidence is unknown. ~ Although the first SCC of extrapulmonary origin was described in 1926, 2, 3 it remains an unusual finding. In a review of 203 cases of SCC seen between 1973 and 1979 at the National Cancer Institute, Levenson et al. 4 found only eight (4 percent) cases of extrapulmonary origin. SCCs are malignancies derived from the cells of the neuroendocrine system. Neuroendocrine ceils are distributed throughout the gastrointestinal tract, pancreas, lung, thyroid, adrenal gland, and m a n y other organs. The gastrointestinal tract has the largest population of neuroendocrine cells. Despite this, neuroendocrine malignancies are rare in the colon or rectum, 5 accounting for less than 1 percent of all colorectal cancers. In fact, only 94 cases have b e e n reported in the English literature. 6 Here we describe two cases of SCC of the lower rectum. The first case was in a patient w h o developed an SCC (oat-celD of the rectum 12 years after irradiation for a Stage II cervical cancer. The other case was a male patient w h o had b e e n diagnosed with moderately differentiated prostate cancer seven months before with periaortic and liver involvement and was undergoing h o r m o n e therapy. Case 2 A mate patient, 74 years old, had a history of lower abdominal pain and constipation. He had b e e n diagnosed with a well-differentiated adenocarcinoma of the prostate with pelvic lymph-node and liver involvement seven months before. He also underwent an aortic bifemoral graft three months before. A Address reprint requests to Dr. Larach: Colon and Rectal Clinic of Orlando, 110 Underwood Street, Orlando, Florida 32806. 274 Vol. 42, No. 2 SMALL-CELLCARCINOMA OF THE RECTUM 275 Figure 3. Laparoscopic view of the liver in Patient 2, demonstrating extensive metastatic disease. Figure 1. Computed tomography scan of the pelvis in Patient 1. Figure 2. Microscopic features of oat-cell cancer of the rectum. (Chromogranin A; ×40 to 400). colonoscopy was performed and s h o w e d a large obstructing tumor in the low rectum with extensive ulceration of the mucosa. Multiples biopsies were performed. A C T scan of the a b d o m e n and pelvis s h o w e d a large rectal mass consistent with neoplasm, diffuse metastatic disease in the liver, iliac adenopathy, and a small left adrenal mass, possibly a metastatic focus. The pathology report indicated a diffuse malignant cellular infiltrate consistent with small-cell undifferentiated (neuroendocrine) carcinoma. Stains were positive for synaptophysin and keratin. The patient underwent surgery (Fig. 3), and a colostomy was performed. The patient died of his disease two months after surgery. DISCUSSION Extrapulmonary SCC occurs most often in the minor salivary glands or esophagus, although it has b e e n reported to occur in the gallbladder, tonsil, endometrium, and vagina, 7-1° with an incidence of 1,000 n e w cases diagnosed in the United States each year. I Colorectal SCC is a relatively rare tumor with an overall incidence of less than 1 percent a m o n g all colorectal cancers. 6 The most c o m m o n location for this type of cancer is the rectum, followed b y the c e c u m and sigmoid colon. The cell origin of extrapulmonary SCC was originally thought to be derived from the amine precursor uptake and decarboxylation system; however, most recent experimental and clinical observations support the theol T that these tumors developed on divergent differentiation from pluri potential cells derived from the endoderm, which undergo progressive malignant differentiation under certain influences. 2 These changes are not restricted to the gastrointestinal tract. There are d o c u m e n t e d cases of these neoplasms in the prostate 3 and in the female genital tract, including the vagina, cervix, and ovary. 1° Most articles suggest that neuroendocrine cancers of the gastrointestinal tract manifest a highly aggressive behavior, 1, z, 5, 11 even more than their adenocarcinoma counterpart of the same stage 6 or other tumors that have no features of neuroendocrine differentiation. 1 Peak incidence of these tumors is in the sixth and seventh, decades of life. Liver and l y m p h - n o d e involvement are found in 70 to 80 percent of patients early in their evolution, and neither size, location, nor multiplicity of primary lesions have demonstrated prognostic value in these tumors.12 Survival time is short, with life expectancy limited to six to eleven months, according to some articles.<12 Saclarides e t al. 13 reported a six-month survival rate of 58 percent and a five-year survival rate of only 6 276 CEBRIAN E T A L percent. In our patients the tumors exhibited this highly aggressive behavior. Both patients developed earlier extensive lymph-node and liver metastases, and one patient died only two months after surgery. Extrapulmonary SCC posses the same light microscopic, immunocytochemical, and ultrastmctural characteristics as its counterpart of the lung, including the high malignant potential. 3 Despite this, its precise diagnosis remains a challenge for the pathologist, because it must be distinguished from lymphoma, amelanotic melanoma, carcinoid, undifferentiated adenocarcinoma, and anal canal cloacogenic carcinomas. There are three degrees of histologic differentiation of these tumors: 1) the oat-cell variant, characterized by small, undifferentiated tumor cells, 2) the moderately differentiated neuroendocrine carcinoma, composed of a mature ceil type, histologically intermediate between the undifferentiated SCC and the carcinoid tumors, and 3) the intermediate variant, which is a transitional histologic type between the two others. In their review of 988 patients who underwent a resection for colorectal cancer, Saclarides e t al. ~3 found only 39 (3.9 percent) cases of neuroendocrine cancers. Approximately 50 percent of colorectal cancers that were initially classified as poorly differentiated carcinomas proved to have neuroendocrine differentiation w h e n further evaluated by immunohistochemical studies. In their review only 15 (1.5 percent) cases were SCC, and only 9 of the 988 cases (0.9 percent) were in the rectum. In other important studies of neuroendocrine carcinomas of the colon and rectum, Gaffey et al. 14 reported 24 cases. Of them, only six were small-cell cancer, and only two of them were located in the rectum. Clinical characteristics of their patients were similar to ours. Gender ratio was equal; ages ranged from 55 to 68 years; and clinical symptoms included altered bowel habits, gastrointestinal hemorrhage, and abdominal pain. Moreover, five of their six patients had lymph-node involvement and hepatic metastasis at surgery, tn the immunoreactivity evaluation of their biopsy specimens, four were positive for neuron-specific enolase and only one was positive for synaptophysin. In Saclarides and colleagues' study .3 all biopsy specimens were stained with antibodies to neuron-specific enolase, serotonin, vasoactive intestinal polypeptide, somatostatin, and human chromogranin. To be classified as a neuroendocrine carcinoma, immunoreactivity to at least two antibodies was required. The chance of immunopositivity for neuroendocrine markers is higher in the Dis Colon Rectum, February 1999 differentiated variant. ~ In our first patient the specimen was stained for chromogranin, synaptophysin, and neuron-specific enolase, and in the second case, synaptophysin and keratin stain were positive. Diagnostic workup is similar to that used for patients with SCC of the lung. It includes clinical examination; CT scan of the chest, abdomen and pelvis; and endoscopy and biopsy of suspicious lesions. Fine-needle aspiration cytology and ultrasound or CT-guided biopsies play a role in the diagnosis of metastatic lesions of the liver or other accessible places. 12,15 Combination chemotherapy similar to that used in lung SCC is generally recommended; however, the rarity of these tumors does not allow for a standardized protocol. Systemic chemotherapy consisting of cisplatin and etoposide (VP-16) achieved good results in the treatment of this lesion. ~6 Other chemotherapeutic regimens include cyclophosphamide, doxorubicin, or vincristine. 13 Khansur e t al. 2 suggested that for localized tumors, surgical resection with or without chemotherapy- is the treatment of choice, but for advanced disease, they suggest a plan of intensive chemotherapy in combination with radiotherapy. Review of the literature disclosed five reported cases of rectal tumors developing at varying times after pelvic irradiation for cervical c a n c e r s -~9 Patients developed adenocarcinoma of the rectum between 12 and 20 years after radiation treatment. This is the basis for classifying a tumor as a radiation-induced tumor, according to the article by Black and Ackerman. 2° Although Nakatsuka et al. 21 could not find differences in the histologic types of colorectal cancer among Japanese atomic b o m b survivors, Land and colleagues 22 demonstrated that in cases of radiation-induced lung cancers, the small cell was the most frequent type. We could not find references in the literature to radiation-induced small-cell cancer of the rectum. In our first case we do not k n o w whether there were changes caused by radiation in the mucosa adjacent to the tumor. REFERENCES 1. Lederman JA. Extrapulmonary small cell carcinoma. Postgrad Med J 1992;68:79-81. 2. Khansur TK, Routh A, Mihas TA, Underwood JA, Smith GF, Mihas AA. Syndrome of inappropriate ADH secretion and diplopia: Oat cell (small cell) rectal carcinoma metastatic to the central nervous system. Am J Gastroenterol 1995;90:1173-4. 3. Oesterling JE, Hauzeur CG, Farrow GM. 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