Case 6 -

Invasive Adenocarcinoma Versus Pseudoinvasion in Colonic Adenomas Lisa Yerian, John Hart and Amy Noffsinger

The histologic assessment of colonic adenomas is frequently complicated by the interpretation of epithelial elements in the submucosa, which may either represent benign "misplaced" epithelium of the adenoma (also termed "pseudoinvasion") or submucosally invasive adenocarcinoma. This common diagnostic dilemma can be quite difficult and carries huge therapeutic and prognostic implications [1, 2, 3, 4, 5]. Benign Misplaced Epithelium, Pseudoinvasion, or Pseudo-carcinoma Misplaced epithelium, or "pseudoinvasion," is most frequently seen in large pedunculated polyps from the left colon, usually the sigmoid colon [3]. The pathogenesis of this phenomenon is related to repeated twisting and torsion of the polyp causing vascular compromise, ischemic injury, hemorrhage, and herniation of epithelium through the muscularis mucosae into the submucosa [3, 4]. Pseudoinvasion is a common finding in colonic adenomas that is clinically insignificant when accurately recognized. In contrast, submucosally invasive adenocarcinoma is a biologically malignant lesion, carrying a risk of lymph node or distant metastasis. The diagnosis of submucosally invasive adenocarcinoma and its distinction from benign but dysplastic glands that are misplaced into the submucosa is thus an important and sometimes difficult distinction with therapeutic and prognostic consequences [2]. Invasive Adenocarcinoma In order for a colonic polyp to be biologically malignant, there must be invasion of carcinoma into the submucosa [5, 7]. Unlike the esophagus and the stomach, intramucosal carcinoma in the colon carries no risk of lymph node metastasis. This is attributed to the lack of lymphatic channels in the colonic mucosa [6, 7]. Hence, in the colon a diagnosis of invasive carcinoma indicates that tumor has invaded through the muscularis mucosae into the submucosa. Clinical Implications The definitive therapy for non-malignant colonic adenomas is complete removal, if possible. In the absence of submucosally invasive adenocarcinoma, no further therapy is required for a completely removed colonic adenoma, irrespective of the presence of pseudoinvasion [3]. In contrast, the presence of submucosally invasive adenocarcinoma in a polyp carries a risk of lymph node and distant metastasis and may therefore require further intervention. This decision is complex and requires assessment of tumor invasion within the polypectomy specimen, completeness of excision, the histologic grade of the tumor, and the presence of lymphatic or blood vessel invasion [5], as these factors (high-grade or poorly differentiated tumor, presence of angiolymphatic space invasion) have been associated with an increased risk of lymph node metastasis [8, 9]. The decision to pursue surgical resection depends on the estimated risk of lymph node metastasis weighed against the risk of operative morbidity and mortality from a surgical resection. If surgery is pursued for a completely endoscopically resected adenocarcinoma that is well to moderately differentiated and without angiolymphatic invasion, then all parties must be aware of the high probability that nothing will be found in the resection specimen. Key Distinguishing Histologic Features Architecture: The low-power assessment of the polyp may be the most helpful histologic feature [5]. Benign misplaced epithelium usually has a rounded, lobular configuration, consisting of a well-circumscribed "bolus" of glands. Invasive adenocarcinoma, on the other hand, commonly exhibits an irregular, jagged, or infiltrative profile with angulated or poorly formed glands. Single cells or small clusters of cells without lamina propria (see below) are features of invasive adenocarcinoma. Benign misplaced epithelium should show no architectural features of invasive adenocarcinoma. Epithelium: The epithelium may exhibit low-grade or high-grade dysplasia but typically is similar to the intramucosal portion of the polyp. Cytologically malignant cells, or higher grade cytology than that seen elsewhere in the polyp is concerning, although not diagnostic, for invasive adenocarcinoma. Lamina propria: The glands of benign misplaced epithelium are typically surrounded by a rim of lamina propria that includes abundant inflammatory cells and is similar to that seen in other, not worrisome portions of the polyp. Definite intramucosal "benign" areas of the polyp can be extremely helpful for comparison of the stroma. Although lamina propria has a characteristic appearance, it can vary between polyps and usually that seen in herniated glands is extremely similar to that seen in other areas of the polyp. The stroma often contains hemorrhage and hemosiderin [1, 4], but importantly, there is no stromal desmoplasia [3]. Invasive adenocarcinoma is not surrounded by lamina propria, and stromal desmoplasia is a characteristic feature of true submucosal invasion. Mucin pools: Benign misplaced epithelium and invasive adenocarcinoma may both be associated with mucin pools within the submucosa [2, 3]. The mucin pools associated with pseudoinvasion tend to be smooth, regular, and associated with ruptured crypts. They are either acellular or lined by dysplastic epithelium similar to that seen at the surface of the polyp [3]. The mucin pools of invasive adenocarcinoma, in contrast, are irregular, jagged pools dissecting through submucosa and may contain floating cytologically malignant cells. A practical rule regarding the nature of acellular mucin collections is to assign the same biologic significance as that of the associated epithelium. If the associated epithelium consists of benign misplaced glands surrounded by lamina propria, then the mucin pools are also benign, but if the associated epithelium is cytologically malignant (like that of invasive adenocarcinoma), then the mucin pools should be regarded as part of the malignant process [2, 3, 5]. Vascular invasion: The presence of true vascular invasion is not a feature of benign misplaced epithelium and should prompt a diligent search for invasive adenocarcinoma. In rare cases, additional deeper sections may be required to identify a small focus of invasive cancer. What if You Can't Tell? 1. Compare the epithelium to epithelium you are confident is adenoma in the same polyp. 2. Compare the stroma to stroma you are confident is the benign stroma of adenoma in the same polyp. 3. Look for evidence of definite vascular or lymphatic space invasion. 4. Cut levels. This will at least buy you a little time, and you may find more definitive evidence of submucosal invasion in the deeper sections. 5. Show it to your colleagues. 6. Call the clinician to discuss the endoscopic findings and management plan. Benign misplaced epithelium is extremely uncommon in sessile lesions [2]. If the polyp was not completely excised and is not endoscopically resectable, then the patient may need to undergo a resection irrespective of your assessment of the submucosal epithelium. In this scenario, a diagnosis of "atypical" or "suspicious" may be acceptable. 7. Does immunohistochemistry help? Some investigators have attempted to utilize immunohistochemical stains to assist in the distinction between pseudoinvasion and submucosally invasive adenocarcinoma occurring in a colonic adenoma [10, 11]. Expression of stromelysin-3 was documented in invasive carcinoma, but lack of expression did not exclude an invasive lesion [10]. Submucosally invasive adenocarcinomas have also been found to exhibit increased expression of the tumor suppressor gene p53 as compared to intramucosal portions of the same polyp [11], and all of the adenomas studied (23/23) exhibited preserved E-cadherin and collagen IV staining [11]. 8. Occasionally a definite distinction between invasion and pseudoinvasion is not possible, and consensus cannot be reached even among experienced GI pathologists [12]. In these cases a descriptive diagnosis is warranted, and a phone call to the clinician may be helpful. The pathologist may choose to describe the finding ("deep neoplastic glands of uncertain significance"), and elaborate in a comment as to the diagnostic problems. References: Quizilbash AH, Meghji M, Castelli M. Pseudocarcinomatous invasion in adenomas of the colon and rectum. Dis Colon Rectum 1980;23:529-535. Sobin LH. Pseudoinvasive intestinal polyps. Dig Dis Pathol 1989;2:1-l2. Greene FL. Epithelial misplacement in adenomatous polyps of the colon and rectum. Cancer 1974;33:206-217. Muto T, Bussey HJR, Morson BC. Pseudo-carcinomatous invasion in adenomatous polyps of the colon and rectum. J Clin Pathol 1973;26:25-31. Cooper HS, Deppisch LM, Kahn EI, Lev R, et al. Pathology of the malignant colorectal polyp. Hum Pathol 1998;29:15-26. Fenoglio CM, Kaye GI, Lane N. Distribution of human colonic lymphatics in normal, hyperplastic, and adenomatous tissue: its relationship to metastasis from small carcinomas in pedunculated adenomas, with two case reports. Gastroenterology 1973;64:51-66. Compton C, Fenoglio-Preiser CM, Pettigrew N, Fielding LP. American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group. Cancer 2000;88:1739-1757. Jass JR. Malignant colorectal polyps. Gastroenterology 1995;109:2034-2035. Volk EE, Goldblum JR, Petras RE, Carey WD, Fazio VW. Management and outcome of patients with invasive carcinoma arising in colorectal polyps. Gastroenterology 1995;109:1801-1807. Mueller J, Mueller E, Arras E, Bethke B, et al. Stromelysin-3 expression in early (pT1) carcinomas and pseudoinvasive lesions of the colorectum. Virch Arch 1997;430:213-219. Yantiss RK, Bosenberg MW, Antonioli DA, Odze RD. Utility of MMP-1, p53, E-cadherin, and collagen IV immunohistochemical stains in the differential diagnosis of adenomas with misplaced epithelium versus adenomas with invasive adenocarcinoma. Am J Surg Path 2002;26:206-215. Cooper HS, Deppisch LM, Gourley WK, et al. Endoscopically removed malignant colorectal polyps: clinicopathologic correlations. Gastroenterology 1995;108:1657-1665.