Clinical Colorectal Cancer February 2002 • 243 Colorectal Cancer Images in Introduction Carcinoma of the large bowel is a common and deadly dis- ease with approximately 130,000 new cases per year, and it accounts for approximately 15% of all cancer-related deaths in the United States. 1 The prevalence of colorectal cancer in- creases with age and most tumors are discovered during a pa- tient’s sixth decade. The etiology of colon cancer is still un- known; however, environmental and genetic factors appear to play an important role. The prognosis of colorectal carcinoma is mainly determined by the tumor stage, as deeply invading tumors with lymph node invasion are associated with a high incidence of distant metastases and poor survival. However, tumor grade and specific histopathologic subtype also affect prognosis. Histologically, the vast majority of colorectal cancers are well to moderately differentiated, mucin-producing ade- nocarcinomas. However, other rare types of colorectal cancer include signet ring carcinomas, squamous and adenosqua- mous carcinomas, basaloid (cloacogenic) carcinoma, and small-cell carcinomas. In some instances, tumors may show dual or multidirectional differentation. For example, a squa- mous component has been reported, usually in cecal tumors, either in combination with the usual adenocarcinoma subtype (adenosquamous carcinoma), or as a pure squamous cell car- cinoma. 2 Similarly, mucin-producing adenocarcinomas ex- hibiting neuroendocrine differentiation or admixed with a neuroendocrine component are a known phenomenon. 3,4 Car- cinomas exhibiting more than two lines of differentiation are unusual, and only sporadic reports of this phenomenon are described in the literature. 5-10 These tumors tend to be ag- gressive and usually have metastatic spread at the time of presentation. Four cases of colonic adenocarcinoma exhibiting dual or multidirectional differentiation are reported herein. Their his- tologic and immunohistochemical features are discussed, the- ories about their pathogenesis are presented, and the potential clinical importance of these unusual pathologic variants is emphasized. Diagnostic and Pathogenetic Implications of Colorectal Carcinomas with Multidirectional Differentiation: A Report of 4 Cases Abstract Multidirectional differentiation in colorectal carcinomas is a rare phenomenon. Four cases are reported herein, and their clinical and pathologic characteristics are discussed. Two men and 2 women between the ages of 56 and 76 years who presented with abdominal symptoms are included in this report.Two tumors were located in the right colon, one in the splenic flexure, and one in the descending colon. Distant metastases were evident at presentation in 3 of 4 cases. Histologically, two tumors exhibited neuroendocrine and glandular differentiation; the third tumor was an adenocarcinoma with a sarcomatous component and the fourth tumor showed 3 lines of differentiation (glandu- lar, squamous, and sarcomatoid). In all tumors evaluated, areas of adenocarcinomas were positive for low-molecular weight cytokeratin (CAM 5.2) and mucicarmine, but negative for high-molecular weight cytokeratin (AE3).The squa- mous cell component was AE3 positive and CAM 5.2 negative.The neuroendocrine component was highlighted by neuroendocrine markers and the sarcomatoid component revealed smooth muscle differentiation. All tumors (except one mucinous tumor) were negative for cytokeratin-20 staining.One patient was on supportive care for ter- minal metastatic carcinoma,and 2 patients were being treated with adjuvant chemotherapy at the time of this report. Colon carcinoma with multidirectional differentiation is a rare event and may originate from stem cells within the gastrointestinal mucosa, and/or represent the convergence of multiple tumors arising at the same site.This type of tumor should be considered in the differential diagnosis of a bowel biopsy with multiple histopathologic variants. Clinical Colorectal Cancer, Vol. 1, No. 4, 243-248, 2002 Key words: Sarcomatoid differentiation, Immunohistochemistry, Adenocarcinoma, Squamous cell carcinoma, Neuroendocrine antigen, Cytokeratin Submitted: Jan. 15, 2002; Revised: Feb. 7, 2002; Accepted: Feb. 11, 2002 Address for correspondence: Domenico Coppola, MD, Department of Pathology, College of Medicine and H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida 33612 Fax: 813-632-1708; e-mail: coppola@moffitt.usf.edu 1 Department of Pathology 2 Department of Pathology and Oncology H. Lee Moffitt Cancer Center and Research Institute 3 VAMC Bay Pines University of South Florida, Tampa Abderrahman Ouban, 1 Rehana A. Nawab, 3 Domenico Coppola 2