Modern colonoscopy allows for both diagnosis and treatment

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2007;5: CLINICAL PATHOLOGY The Malignant Colon Polyp: Diagnosis and Therapeutic Recommendations MARIE E. ROBERT Department of Pathology, Yale University School of Medicine, New Haven, Connecticut This article discusses the proper handling of the malignant colon polyp, that is, polypoid lesions that appear endoscopically to represent adenomas and histologically reveal an invasive carcinoma component, from the time of endoscopy to the pathologic diagnosis. Prognostically important pathologic features and a paradigm to guide treatment decisions are presented. Modern colonoscopy allows for both diagnosis and treatment of many colonic lesions without the necessity for subsequent surgery. Large adenomas and hyperplastic polyps often safely can be removed endoscopically, either whole or piecemeal. The task for the pathologist examining these specimens is to answer 2 questions. First, what is the diagnosis, and second, is the lesion completely excised? In adenomas removed piecemeal and in some snare polypectomy specimens, the pathologist alone cannot determine the adequacy of excision. The endoscopist, in conjunction with the pathology report, makes the best assessment of completeness of excision. While the above comments apply to most adenomas, special problems exist in the setting of malignant polyps. These are polypoid lesions that appear endoscopically to represent adenomas, but that histologically reveal an invasive carcinoma component. These lesions generate anxiety among pathologists and gastroenterologists because the issue becomes not only whether the lesion is excised completely, but also what is the risk of lymph node metastasis? Therefore, each report of a malignant polyp generates a discussion of the need for subsequent surgical resection. This review discusses the proper handling of the malignant colon polyp from the time of endoscopy to the pathologic diagnosis. Prognostically important pathologic features and a paradigm to guide treatment decisions are presented. Clinical Scenario A 57-year-old man undergoes an initial screening colonoscopy. Three separate polypoid lesions are seen. The largest is a 2.0-cm pedunculated polyp at 20 cm. The other 2 lesions each measure less than 0.4 cm and are located in the sigmoid and transverse colon. The large polyp is snared and removed in 1 piece; the base is cauterized. Endoscopically, the lesion appears to have been removed completely. The 2 smaller lesions are removed using standard biopsy forceps. On gross pathologic examination, the biopsy margin of the pedunculated polyp is identified and inked. The lesion is bisected exactly through the midpoint. Additional sections are shaved from either side (Figure 1). The entire polyp is embedded in 3 cassettes, such that the center of the stalk, showing the interface of the mucosa and submucosa including the cauterized margin, will be visualized. Microscopically, the lesion consists primarily of a villous adenoma (Figure 2). However, sections through the center of the stalk reveal moderately differentiated adenocarcinoma invading into the stalk submucosa. No vascular/lymphatic invasion is identified. The distance between the deepest focus of invasive cancer and the stalk biopsy margin is less than 1 mm. In addition, the deepest tumor focus shows cautery artifact, indicating proximity to the margin. The mucosa at the biopsy margins is free of adenoma. The 2 separately submitted polyps are tubular adenomas. Because tumor was present within the cauterized biopsy margin, a Figure 1. Optimal sectioning of intact polyps. Cutting the polyp in the center of the stalk allows the most thorough examination of the mucosa/ submucosa junction and the stalk margin. Modified from Cranley et al. 5 Abbreviations used in this paper: LN, Lymph node by the AGA Institute /07/$32.00 doi: /j.cgh

2 June 2007 MALIGNANT COLON POLYP 663 biopsy and retrieval process. Although fragmented specimens usually can be evaluated for carcinoma, they are more likely to generate reports that are unable to assess the biopsy margin, leading in some cases to a default surgical resection. On gross examination, the pathologist or technician attempts to identify the stalk margin, which is inked. Sections then are taken as described earlier in the clinical scenario (Figure 1). In fragmented specimens, the margin and other landmarks are assessed as possible and sections are similarly submitted. In all cases, the entire lesion is submitted for histology. Because a large amount of tissue is embedded in each tissue cassette, it is important that at least 3 level sections are prepared on each separate cassette. In many cases, multiple additional level sections are needed to fully visualize the invasive component and its relationship to the cauterized margin. Therapeutic Considerations The question of the need for surgery in patients with endoscopically removed malignant colon polyps has generated extensive study and discussion. Much of the important literature on this topic dates to the 1980s, and, surprisingly, little has changed regarding management since that time. In the preendoscopic era, surgical polypectomy and colectomy were the only means for diagnosis and treatment of large colonic polyps. The pathology specimens generated allowed absolute diagnostic certainty as to the depth of invasion and completeness of excision because the entire colonic wall was included. 1 Since 1970, most malignant polyps are removed at endoscopy and include only the polyp head and stalk if present, either as one Table 1. Malignant Colon Polyps Removed by Endoscopic Polypectomy Figure 2. (A) Low-power view of the center of the snared polyp. The surface is a villous adenoma. In the center of the lesion invasive carcinomatous glands are present in the submucosa (arrows) and approach the cauterized margin. (B) On high power, a tumorous gland is seen very near the cauterized biopsy margin (arrows). The tumor itself shows cautery artifact. The distance between the tumor and the margin is less than 1 mm. This is considered a positive margin. segmental colectomy is performed. No residual tumor is present in the resection and all lymph nodes are negative for tumor. Approach to Pathologic Examination of Large Colon Polyps The accurate and complete pathologic diagnosis of malignant colon polyps begins with the gross examination and sectioning of the specimen. This, in turn, depends to a great extent on the manner in which the lesion was removed and sent to the pathology laboratory by the gastroenterologist. Polyps removed in one piece allow the pathologist the greatest opportunity to identify the center of the stalk for correct sectioning. The identification of the stalk is aided further by the placement of ink or other identifying mark by the endoscopist as soon as the tissue is retrieved. In some centers, a hypodermic needle is placed in the stalk margin. By necessity, some polyps must be removed piecemeal or are prone to fragmentation during the Study Estimate of residual Disease Number of residual disease, recurrence, positive LN/total patients (%) Berci et al, /4 (0) Welch and Hedberg, /9 (55.6) Wolff and Shinya, /8 (0) Nivatvongs and Goldberg, /2 (0) Coutsoftides et al, /11 (18) Muto et al, /2 (0) Colacchio et al, /22 (22.7) Kodaira et al, /5 (40) Rossini et al, /22 (0) Cooper, /30 (13.3) Lipper et al, /11 (0) Langer et al, /13 (7.7) Morson et al, /49 (0) Cranley et al, / ) Cooper et al, /140 (12.6) Volk et al, /46 (21.7) Total 55/412 (13.3) NOTE. The vast majority of patients (in many of the studies 100% of patients) with residual disease, positive lymph nodes on resection, or recurrent tumor had unfavorable histologic findings in the original polypectomy specimens (see text for more detail). Modified from Wilcox et al. 1 LN, lymph node.

3 664 MARIE E. ROBERT CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 6 Figure 3. (A) Limitations of snare polypectomy for malignant polyps. The lesion on the left is treated adequately by polypectomy alone, whereas the lesion on the right will require colectomy because of a positive margin. Modified from Haggitt et al. 8 (B) Poorly differentiated carcinoma. This high-power view shows the cytologic detail of a malignant polyp with mucinous features (mucinous carcinoma). Notice the lack of recognizable gland formation, a feature of poorly differentiated tumors. The tumor cells form nests and float in mucin pools (arrows). (C) The same lesion as that shown in B. The mucinous carcinoma is present at the biopsy margin (arrow). fragment or as numerous pieces. The specimens generated may yield incomplete information or be subject to technical imperfections that leave an element of uncertainty to the diagnosis. In all cases, pathologists and gastroenterologists must work together to decide the next best step for the patient. For perspective, it should be remembered that the incidence of invasive carcinoma within adenomatous polyps is low, ranging from 0.2% to 8.3% of all adenomas. 2 6 Further, in patients with malignant polyps, the incidence of residual disease (including lymph node metastases) in follow-up resections or recurrent carcinoma at a later time is approximately 10% 13% based on an analysis of 16 studies (Table 1). 1,11 20 When specific histologic features are analyzed with regard to risk of residual disease, most studies agree that at least 2 features, tumor differentiation and status of biopsy margin, correlate with the likelihood of lymph node and distant metastasis (Figure 3). Thus, most patients who have residual tumor or positive lymph nodes in a resection specimen or who develop later distant metastasis had positive or equivocal biopsy margins and/or poorly differentiated tumors. 1,4 8 However, even when these ominous histologic findings are present, the majority of patients have no residual tumor in resection specimens. Therefore, although surgery is justified when the margin is positive for carcinoma or the tumor is poorly differentiated, the expected finding in these specimens is no residual tumor and negative lymph nodes. A third histologic feature, lymphatic or vascular invasion, also may have prognostic significance, but the data are less clear. Several studies have reported that finding lymphatic/ vascular invasion is associated with lymph node metastasis and recurrent disease, 5,7 9 although other studies showed no correlation. 6,10 Complicating the analysis is the fact that lymphatic/ vascular invasion is uncommonly seen in malignant polypectomy specimens. More importantly, its detection is fraught with technical and interpretative difficulty for the pathologist. Interobserver agreement on the presence of lymphatic invasion in polypectomy specimens is poor, largely because of retraction artifact, which creates an artificial space around tumor nests that simulates a vascular channel. The distribution of lymphatic channels in the colon deserves special discussion. Studies delineating the normal distribution of lymphatic channels in the colonic mucosa and submucosa have shown that lymphatic vessels are present in the submucosa and deeper in the colonic wall, but are rare to absent in normal mucosa A plexus of lymphatic channels normally is found in the superficial submucosa and within the muscularis mucosa, with rare extensions into the lamina propria (mucosa) limited to the region at the base of the crypts. The near absence of lymphatics within the mucosa has been offered as the reason for the observed lack of malignant potential (lymph node metastasis) observed in polyps showing only intramucosal carcinoma. 22 However, this theory has been complicated by recent studies using more sensitive techniques to detect lymph vessels. Studies using the relatively new antibody D2-40 (Dako, Carpenteria, CA), which stains lymphatic but not blood vessel endothelium, have shown that lymphatics undergo

4 June 2007 MALIGNANT COLON POLYP 665 of lymphatic invasion in decision making.6,7 One recommended using margin status and tumor differentiation alone7 and the other advocated the additional use of lymphatic invasion assessment in the decision of whether to resect.6 Considering all data available, the current recommendation is that lymphatic and vascular invasion should be assessed. If definitely seen, it should be noted as an unfavorable histologic finding and should prompt surgical resection. Thus, all pathology reports should comment on margin, tumor grade, and lymphatic/ vascular invasion.1,2,4 8,24,25 Gastroenterologists should discuss the pathologic findings of malignant polyps with the pathologist to ensure that the report is interpreted correctly. Differential Diagnosis An important entity in the differential diagnosis of malignant colon polyps is the adenoma with pseudoinvasion. Figure 4. (A) Lymphatic invasion is rare and difficult to identify with certainty in malignant polyp specimens. In this example, a solid nest of tumor cells is present in a space that appears to be lined by endothelial cells (arrow). This appearance is characteristic of lymphatic (or capillary) invasion and is an indication for colectomy when found. (B) This highpower view of a factor VIII stained slide reveals that the clump of tumor cells is indeed lying within a vascular space. The cells lining the structure are factor VIII positive, identifying them as endothelial cells (arrow). proliferation and are present in the stalk and mucosa of adenomas and early invasive cancers. In malignant polyps, lymphatic channels often are present near nests of infiltrating tumor.23,24 From a practical viewpoint, detecting lymphatic invasion is difficult by light microscopy (Figure 4). True lymphatic invasion is rare, although retraction of tissue creating an artificial space around tumor cells is common in paraffin sections, as mentioned earlier. The use of immunohistochemistry for D2-40 may help identify lymphatic channels. However, its use is not yet routine, and technical issues such as loss of a suspicious focus in level sections limits the usefulness of special stains in this setting. Other vascular markers, such as CD31, CD34, and factor VIII also may be used. These markers strongly stain blood vessel endothelium, and, to a lesser extent, lymphatic endothelium. The 2 most recent studies of histologic prognostic factors in malignant polyps reflect the ambivalence surrounding the use Figure 5. (A) Pseudoinvasion. This low-power view of a pedunculated adenoma reveals intramucosal carcinoma. In addition, several rounded nests of glands appear to be beneath the muscularis mucosa and lay within the superficial submucosa (arrows). (B) On high power, the nests within the submucosa are surrounded by lamina propria type inflammatory cells (arrows). In addition, the glands are identical histologically to those found in the mucosa immediately above. Note the dilated and congested vessels nearby. Other areas revealed hemosiderin-laden macrophages. These features are characteristic of pseudoinvasion.

5 666 MARIE E. ROBERT CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 6 The term pseudoinvasion refers to the presence of mucosal glandular epithelium beneath the muscularis mucosa in colonic polyps (Figure 5). Pathologists and gastroenterologists must be aware of this fairly common phenomenon because it easily can be mistaken for invasive carcinoma by an inexperienced pathologist. Pseudoinvasion usually occurs in large ( 1 cm) polyps, especially those with long stalks, and is found most commonly in polyps of the sigmoid colon. 26,27 Mechanistically, it has been postulated that large pedunculated polyps undergo twisting and torsion, leading to stalk hemorrhage, inflammation, and disorganization of the muscularis mucosa. Under these conditions, islands of adenomatous epithelium are displaced through the muscularis mucosa and lie within the stalk submucosa. Studies convincingly have shown that such lesions have no malignant potential and should be treated similar to adenomas. 26,27 Microscopically, several characteristic histologic features characterize pseudoinvasion. The displaced glandular elements usually have rounded, not infiltrative, contours, carry with them a small amount of lamina propria, and are identical cytologically to the overlying adenomatous component. Often these elements are in direct continuity with the mucosa and appear to traverse the muscularis mucosa. Hemorrhage and hemosiderin deposition are seen commonly and are a clue to the diagnosis. Inflammation and granulation tissue can be found. Cystic dilatation of the displaced glands with mucin distention is not uncommon in pseudoinvasion because mucin produced by the entrapped glands has no means to reach the lumen. Occasionally, rupture of dilated glands occurs with acellular mucin extravasation and a subsequent inflammatory response. Distinction from mucinous (colloid) carcinoma is important and can be difficult. In mucinous carcinoma, the mucin pools contain malignant cells, a feature lacking in pseudoinvasion (Figure 3B). Level sections and second opinions are highly recommended in polyps with potential pseudoinvasion. Summary Based on the literature presented above, pathology reports of malignant colon polyps should contain specific mention of the 3 prognostically significant histologic features, namely: (1) the distance between the invasive tumor and the cauterized biopsy margin (tumor within the cauterized region constitutes a positive margin), (2) tumor differentiation (well, moderately, or poorly differentiated), and (3) the status of lymphatic or vascular invasion (present or absent). In a note at the bottom of the pathology report, the lesion should be categorized as showing favorable or unfavorable histology, bearing in mind that any one unfavorable feature (tumor present at margin, poorly differentiated tumor, or positive for lymphatic or vascular invasion) constitutes an overall designation of unfavorable histology, and is an indication for surgical resection because of the increased risk of lymph node metastasis or residual disease. On the other hand, in the absence of unfavorable features, the polypectomy is considered curative. Specimens that do not lend themselves to proper analysis for any reason (piecemeal removal or poor orientation) sometimes result in a default decision to resect. In this setting, additional biopsy examinations may yield more information, at least regarding the presence of residual tumor at the prior biopsy site. Finally, proper decision making for patients with malignant colon polyps requires that clinicians and pathologists work together to ensure the best possible outcome. References 1. Wilcox GM, Anderson PB, Colacchio TA. Early invasive carcinoma in colonic polyps: a review of the literature with emphasis on the assessment of the risk of metastasis. Cancer 1986;57: Colacchio TA, Forde KA, Scantlebury VP. Endoscopic polypectomy: inadequate treatment for invasive colorectal carcinoma. Ann Surg 1981;194: Cooper HS. Surgical pathology of endoscopically removed malignant polyps of colon and rectum. Am J Surg Pathol 1983;7: Morson BC, Whiteway JE, Jones EA, et al. Histopathology and prognosis of malignant colorectal polyps treated by endoscopic polypectomy. Gut 1984;25: Cranley JP, Petras RE, Carey WD, et al. When is endoscopic polypectomy adequate therapy for colonic polyps containing invasive carcinoma? Gastroenterology 1986;91: Volk EE, Goldblum JR, Petras RE, et al. Management and outcome of patients with invasive carcinoma arising in colorectal polyps. Gastroenterology 1995;109: Cooper HS, Deppisch LM, Gourley WK, et al. Endoscopically removed malignant colorectal polyps: clinicopathologic correlations. Gastroenterology 1995;108: Haggitt RC, Glotzbach RE, Soffer EE, et al. Prognostic factors in colorectal carcinomas arising in adenomas: implications for lesions removed by endoscopic polypectomy. Gastroenterology 1985;89: Muller S, Chesner IM, Egan MJ, et al. Significance of venous and lymphatic invasion in malignant polyps of the colon and rectum. Gut 1989;30: Geraghty JM, Williams CB, Talbot IC. Malignant colorectal polyps: venous invasion and successful treatment by endoscopic polypectomy. Gut 1991;32: Berci G, Parish J, Morgenstern L. Diagnostic colonoscopy and colonoscopic polypectomy. Arch Surg 1973;106: Welch CE, Hedberg S. Polypoid lesions of the gastrointestinal tract, vol. 2: Major problems in clinical surgery, ed. 2. Philadelphia: W.B. Saunders, 1975; Wolff WI, Shinya H. Earlier diagnosis of cancer of the colon through endoscopy. Cancer 1974;34: Coutsoftides T, Sivak MV, Benjamin SP, Jagelman D. Colonoscopy and the management of polyps containing invasive carcinoma. Ann Surg 1978;188: Nivatvongs S, Goldberg SM. Management of patients who have polyps containing invasive carcinoma removed via a colonoscope. Dis Colon Rectum 1978;21: Muto T, Kamina J, Sawada T, et al. Colonoscopic polypectomy in diagnosis and treatment of early carcinoma of the large intestine. Dis Colon Rectum 1980;23: Kodaira S, Teramoto T, Ono S, et al. Lymph node metastases from carcinomas developing in pedunculated and semipedunculated colorectal adenomas. Aust NZ J Surg 1981;51: Rossini FP, Ferrari A, Spandre M, Coverlizza S. Colonoscopic polypectomy in diagnosis and management of cancerous adenomas. Endoscopy 1982;14: Lipper S, Kahn LB, Ackerman LV. The significance of microscopic invasive cancer in endoscopically removed polyps of the large bowel. Cancer 1983;52: Langer JC, Cohen Z, Taylor BR, et al. Management of patients with polyps containing malignancy removed by colonscopic polypectomy. Dis Colon Rectum 1984;27: 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 peduncu-

6 June 2007 MALIGNANT COLON POLYP 667 lated adenomas, with two case reports. Gastroenterology 1973;64: Fogt F, Zimmerman RL, Ross HM, et al. Identification of lymphatic vessels in malignant, adenomatous and normal colonic mucosa using the novel immunostain D2-40. Oncol Rep 2004;11: Walgenbach-Bruenagel G, Tolba RH, Varnai AD, et al. Detection of lymphatic invasion in early stage primary colorectal cancer with the monoclonal antibody D2-40. Eur Surg Res 2006;38: Riddell RH. Hands off cancerous large bowel polyps. Gastroenterology 1985;89: Jass JR. Malignant colorectal polyps. Gastroenterology 1995; 109: Muto T, Bussey HJR, Morson BC. Pseudo-carcinomatous invasion in adenomatous polyps of the colon and rectum. J Clin Pathol 1973;26: Greene FL. Epithelial misplacement in adenomatous polyps of the colon and rectum. Cancer 1974;33: Address requests for reprints to: Marie E. Robert, MD, Department of Pathology, Yale University School of Medicine, PO Box , 310 Cedar Street, New Haven, Connecticut marie.robert@yale.edu; fax: (203)