ADENOMAS WITH ADENOCARCINOMA: A STUDY EVALUATING THE RISK OF RESIDUAL CANCER AND LYMPH NODE METASTASIS

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1 253SJS / S. E. Steigen, et al.adenomas with adenocarcinomas and risk factors Scandinavian Journal of Surgery 102: 90 95, 2013 ADENOMAS WITH ADENOCARCINOMA: A STUDY EVALUATING THE RISK OF RESIDUAL CANCER AND LYMPH NODE METASTASIS S. E. Steigen 1,2, V. Isaksen 1,2, A. Skjæveland 3, B. Vonen 4,5,6 1 Department of Pathology, University Hospital of North Norway, Tromsø, Norway 2 Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway 3 Health Centre Sagvåg, Vassneset 1, Sagvåg, Norway 4 Department of Gastrointestinal Surgery, University Hospital of North Norway, Tromsø, Norway 5 Department of Clinical Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway 6 Nordland Hospital, Bodø, Norway ABSTRACT Background and Aims: The increasing number of cases with colorectal adenomas with adenocarcinoma necessitates renewed evaluation of classification systems and risk factors. The aim for this retrospective study was to evaluate the potential risk of residual cancer and lymph node metastasis in patients with colorectal adenomas with adenocarcinoma. Material and Methods: An investigation of adenomas with adenocarcinoma in 74 patients was performed on histological slides and compared with clinical characteristics. A total of 44 of the samples were from macroscopically and microscopically completely resected lesions, and cancer at extended surgery was compared with pathology reports, classifications, and histopathological features. Results: In all, 26 cases of adenomas with adenocarcinoma in the rectum and rectosigmoid were among women and 11 in men while 22 men as opposed to 15 women had primary lesions in colon, giving a significant association between gender and localization (p = 0.01). For macroscopically and microscopically fully resected lesions, Haggitt classification or submucosal invasion did not correlate with cancer at extended surgery. The lack of information on resection margins in the primary pathology reports was found to correlate significantly with residual cancer at extended surgery (p < 0.001) with residual cancer in 3 out of the 10 cases with no information, 1 out of the 5 where the resection margins were uncertain, 1 out of the 4 where the resection margins were not free, and none of the 25 cases when the resection margins were reported as free. In colon, 1 case out of the 6 with extended surgery (16.7%) was diagnosed with residual cancer compared with 4 out of the 10 (40%) from rectum. Conclusions: Haggitt or submucosal classifications were not found to be predictors for residual cancer in the remaining bowel tissue or lymph node metastasis. The only significant factor indicating increased risk of residual cancer was the lack of information on resection margins in the pathology report. Surgeons should therefore be alert when adenomas with adenocarcinomas are not confirmed as microscopically free in the pathology report. Key words: Adenoma with adenocarcinoma, Haggitt, submucosal invasion, resection margins, location, residual cancer Correspondence: Sonja E. Steigen Department for Pathology University Hospital of North Norway N-9038 Tromsø Norway Sonja.steigen@unn.no

2 Adenomas with adenocarcinomas and risk factors 91 INTRODUCTION A colorectal polyp can histologically be classified as hyperplastic or adenomatous, with only the latter being regarded as a premalignant lesion. The adenoma-carcinoma sequence is widely accepted as a model for the development of adenocarcinoma in colon and rectum (1 3). The prevalence of adenomas varies among countries but was found to be just slightly less than 20% in a large regional cohort screening study of sigmoid tumors among 50- to 64-yearolds (4). In endoscopy studies, the prevalence of adenomas in colon is somewhat higher at around 25%, and in an autopsy study, there were twice as many adenomas in colon than adenomas found in the sigmoid and rectum (5, 6). Adenomas are often classified as pendunculated or sessile ( flat, without stalk), the former being more common. In some adenomas, there is an invasive component that has penetrated the basal basement in the mucosa but is still limited to the submucosa. Such adenocarcinoma in adenomas is classified as T1 tumors in the tumor, node, metastasis (TNM) classification (7). With a biopsy from an adenoma with adenocarcinoma, a histological assessment is performed to estimate the probability of residual cancer in the bowel wall. A classification was introduced by Haggitt in 1985 (8). Adenocarcinoma confined to the upper part of the polyp head just under the mucosa is graded as level 1, while adenocarcinomas invading the submucosa in the head, neck, or stalk of a pendunculated adenoma are graded as level 2, 3, or 4 according to the depth of invasion. Adenocarcinoma invading into submucosa at the base of the stalk is classified as level 4, and so is adenocarcinoma in any sessile adenoma. If the adenocarcinoma has invaded beyond the submucosa into the muscularis propria, it is a T2 tumor, and the Haggitt classification is not applicable. Haggitt suggested that the different levels of invasiveness of the adenocarcinoma in an adenoma correlated with the presence of metastasis to regional lymph nodes. A few other reports have studied the occurrence of residual cancer, recurrent or metastatic disease on longterm follow-up of patients with adenocarcinoma in adenomas treated with polypectomy, and these showed similar correlation with the classification of levels of Haggitt (9 12). Aiming for new guidelines for management of cancer in polyps, Kikuchi et al. (13) evaluated the influence of level of invasion in the submucosa according to the previously defined criteria (14); Sm 1 when there is slight submucosal (Sm) invasion (upper third), Sm 2 with an intermediate Sm invasion (middle third), and Sm 3 with invasion near the muscularis propria (lower third). Using this classification, lesions with Haggitt level 1, 2, and 3 are all Sm 1, and level 4 (sessile or penduncular) can be Sm 1, Sm 2, or Sm 3 depending on the depth of Sm invasion. Tissue sampling is important, as a biopsy must be representative for the whole lesion. Several studies have shown that the rate of adenocarcinoma in adenomas in biopsies is underestimated when compared with later total polypectomy (15, 16). The excision margins have also been discussed. Free distance from cancer to resection margin of less than 1 mm has been regarded as a high-risk factor and a 2- to 3-mm tumorfree margin is argued as sufficient to inhibit local recurrence (17 19). The aim of this study was to evaluate adenomas with adenocarcinoma according to the established classifications and other clinicopathological factors and to estimate the probability of risk for residual cancer and lymph node metastasis. This is to ensure correct follow-up and treatment for patients with such lesions. PATIENTS AND METHODS The University Hospital of North Norway serves a population of approximately 231,500 with pathology services. The coding system is according to The Systematized Nomenclature of Medicine (SNOMED). Cases were identified by searching for colon and rectal biopsies with adeocarcinomas in adenomatous polyps and cases diagnosed as a combination of adenomatous polyps and adenocarcinoma. The archival slides were all initially stained with hematoxylin and eosin according to the standard procedures and evaluated using light microscopy. In our study, all cases were re-evaluated by two experienced pathologists in addition to one medical student. A total of 84 unique specimens were identified over the 11-year period investigated, 37 from men and 47 from women. Ten cases (four men and six women) were excluded from the study due to fragmented specimens or invasive adenocarcinoma beyond submucosa discovered at our second revision yielding 74 patients with adenomas with adenocarcinomas. A total of 25 of the cases from colon and 27 of the cases in the rectum and rectosigmoid group were first diagnosed using biopsies, while 19 had primary resections and 3 had undergone transanal endoscopic microsurgery (TEM). Among the 52 biopsied lesions, the endoscopist reported that in five cases, the lesion was not completely resected, and in three cases, the resection margins were difficult for the pathologist to interpret, giving a possibility for residual cancer in the margins. This left 44 cases for examination for residual cancer at extended surgery, which was performed on 19 cases shortly after diagnosis was given on the biopsy (92% within 2 months). The patients were recruited from five different hospitals, so endoscopic follow-up was difficult to incorporate into the study, but with one shared pathology department for all these institutions; colorectal biopsies from 38 of the patients were later evaluated. This study was approved by the regional ethics committee. All data were tabulated and analyzed with PASW statistics 18 (IBM SPSS), and the chi-squared test was used to study relations of various risk factors. Differences and correlations were considered significant at the level of p < RESULTS The basic characteristics of all the 74 patients with adenomas with adenocarcinoma are listed in Table 1.

3 92 S. E. Steigen, et al. TABLE 1 Basic characteristics of all cases. Men Women Cases Age of all cases Range Median Mean Age colon Range Median Mean Age rectum Range Median Mean Localization Ascendens 1 1 Transversum 2 0 Descendens 3 1 Sigmoideum Rectosigmoideum 2 4 Rectum 9 22 Size (mm) < > Cases/year TABLE 2 Haggitt classification correlated with findings at extended surgery and lymph node metastasis for all cases primarily diagnosed on biopsies with free resection margins. Total number of cases No resection Resection without cancer Resection with residual cancer* Lymph node metastasis Haggitt level Haggitt level Haggitt level Haggitt level *p= The follow-up time was between 25 and 346 months (median 74 months). A total of 26 cases of the adenomas with adenocarcinoma in the rectum group were among women and 11 in men while 22 men as opposed to 15 women had primary lesions in colon, giving a significant association between gender and localization (p = 0.01). Haggitt classification was evaluated on all samples, including biopsies, resections, and TEMs, except for eight cases where the interpretation was difficult due to incomplete resection margins, giving 16 graded as level 1, 20 as level 2, 11 as level 3, and 19 as level 4. For the 44 biopsies diagnosed on macroscopically and microscopically freely resected lesions, the classification was compared with residual cancer at extended surgery and lymph node metastasis (Table 2). No association was found between the Haggitt classification and the further resection with or without residual cancer or lymph node metastasis. Similarly, the total numbers of cases with Sm invasion were 53 in Sm 1, 4 in Sm 2, and 9 in Sm 3, and the depth of the invasion in the 44 biopsies compared with residual cancer and lymph node metastasis is shown in Table 3. When calculating only with regard to the 44 biopsy specimens, no significant correlation between appearance of residual cancer at extended surgery or lymph node metastasis was found. When comparing Haggitt s classification with a classification according to the Sm invasion, all cases in Haggitt level 1 3 were Sm 1, while at Haggitt level 4, one was Sm 1 and four were Sm 3. In the cases where biopsy reports did not give any information about the resection margins, there was a significantly higher incidence of residual cancer at extended surgery (p < 0.001) even if the lesions were completely removed according to the endoscopist (Table 4). Most of the cases with missing information about resection margins were reported the first 6 years of investigation with 9 cases, while 5 cases the last 5 years. There is a significant association between cases with missing information on resection margins and being from the period prior to 2004 (p = 0.04).

4 Adenomas with adenocarcinomas and risk factors 93 TABLE 3 Classification according to the submucosal invasion correlated with findings at extended surgery and lymph node metastasis for all cases primarily diagnosed on biopsies with free resection margins. Total number of cases No resection Resection without cancer Resection with residual cancer* Lymph node metastasis Sm Sm *p=0.897; Sm: submucosal. TABLE 4 Information from primary pathology reports about resection margins in biopsies correlated with finding at extended surgery and lymph node metastasis for all cases primarily diagnosed on biopsies with free resection margins. Total number of cases No resection Resection without cancer Resection with residual cancer* Lymph node metastasis Free resection margin Cancer at resection margins Uncertain resection margins No information about resection margins *p< Of the 44 cases with completely resected lesions, 6 cases with localization in colon, 3 cases from the rectosigmoid, and 10 cases from rectum received extended surgical resections. In colon, 1 case out of the 6 (16.7%) was diagnosed with residual cancer compared with 4 out of the 10 (40%) from rectum. No cases with residual cancer were found in the rectosigmoid group. The only case with a lymph node metastasis at extended surgery had primary lesion in the distal part of rectum. In all, 6 men and 13 women had extended resections performed after the diagnosis of adenocarcinoma in adenoma, with residual cancer in 3 cases in the first group and 2 in the latter without any significant increased risk with respect to gender. The diameter of colonic lesions was not significantly larger than the rectal and rectosigmoid lesions (mean vs mm). No correlation was found between size of lesion and gender. Size was found to associate neither with site of primary lesion nor with residual cancer on extended surgery or lymph node metastasis. Approximately two-thirds of the lesions were classified as adenomas with adenocarcinoma with a tubular pattern, while one-third of the lesions had tubulovillous features. Two cases were classified as villous and included in the tubulovillous group. The mean diameter of the tubular lesions was mm and the tubulovillous lesions mm. A total of 26 cases in colon and 27 cases in rectum and rectosigmoidal were classified as tubular, and 11 colon and 10 rectal and rectosigmoidal cases were classified as tubulovillous. Tubular versus tubulovillous features for only the biopsies were not associated with the risk of residual cancer at extended surgery or lymph node metastasis. Follow-up colorectal biopsies from 38 patients were evaluated after the diagnosis of adenoma with adenocarcinoma. In all, 22 of the patients had the first biopsies taken between 2 and 7 months after the primary diagnosis. No further cancer was found in any of these biopsies. DISCUSSION Management of adenomas with adenocarcinoma is complex, with achieving a balance between clinical settings and pathology reports being a challenge. Critical and renewed validation of existing classifications and evaluation of risk factors is most appropriate as more cases are likely to be found in upcoming screening programs for colorectal cancers. Haggitt classified adenomas with adenocarcinoma into four levels he and others claimed that classification into level 1 hardly ever gave residual cancer with slightly increasing incidence for level 2 and level 3. For level 4, the risk of residual cancer was described to be 15% 25% (8, 11, 12). Haggitt s study included 129 cases, later studies by Coverlizza included 31 cases and Pollard s 82 cases. In a study by Kyzer et al. (20), 44 patients out of a total of 82 had extended surgery after polypectomi with residual cancer in three cases, all being previously classified as Haggitt level 4. In a study of 151 patients by Nivatvongs et al. (21) in 1991, no incidence of lymph node metastasis was found with Haggitt level 1, 2, or 3, suggesting the distinction between levels 1 3 and level 4 was unnecessary. The other classification used is the depth of invasion in submucosa, and adenomas with adenocarcinoma are regarded as high-risk lesions for the presence of lymph node metastasis when the invasion is at the level of Sm 3 and perhaps also Sm 2 (13, 14). Our results do not support the use of Haggitt or Sm classifications as reliable predictors of finding residual cancer in the remaining regional bowel tissue or lymph nodes. Adenocarcinoma in adenomas with location in the rectum is regarded as an important factor for residual

5 94 S. E. Steigen, et al. disease and for lymph node metastasis. In our series, a higher number of lesions with residual cancer were observed at extended surgery in rectal lesions compared with colonic lesions. This is in accordance with studies done on risk for high-grade dysplasia in adenomas, where a significant higher number was found in the rectum compared to locations in colon (22). Kikuchi et al. (13) also found that location in rectum was a significant risk factor for the development of lymph node metastasis and local recurrence compared to other locations in the large bowel. The completeness and free margins after excision of premalignant and malignant lesions have previously been accepted as important risk factors (17, 23). Incomplete resection margins are most likely an important and independent factor for adverse outcomes (18), but the importance of the distance to free margins might still be discussed. In our experience, the resection margins can be difficult to judge because of heat damage from diathermy. Cells with an atypical appearance close to the resection margin can be difficult to interpret as malignant or simply damaged cells. In our study, the adenomas with adenocarcinoma where no information of the resection margins was available in the primary pathology report had the highest risk of containing residual cancer at extended surgery. This lack of information on resection margins can be due to the standard of reporting from the individual pathologist or simply just forgotten. Most of the reports with lack of information were from the first year of this study, implying that there might have been improvements over time in the routines for reporting resection margins in adenomas with adenocarcinoma. In our department, two pathologists now evaluate all new premalignant and malignant cases to ensure adequate reporting. Size is often regarded as an important risk factor, but some studies challenge this. In a smaller study by Whitlow et al. (24), the range of the size of the adenomas with adenocarcinoma was reported without commenting on size being of importance for the results on long-time survival after treatment. This suggests that size did not play a significant role. In the study by Kikutchi et al. (13) with 182 patients, the diameter was not found to be a risk factor for lymph node metastasis and local recurrence. In a study by Hermanek et al. (25) of more than 2000 adenomas, close to 200 were found to harbor adenocarcinoma with the size influencing the malignancy rate. In our study, the lesions from colon were slightly larger compared with those from rectum and rectosigmoid, but no significance was found concerning the risk of malignancy in extended resection. Thus in our study, other factors seem to weigh more than size as risk factors for the presence of residual cancer. A slight increase in the number of cases the last 5 years could be due to an increase in the occurrence of adenocarcinoma in adenomas, or just as likely due to increased awareness of the adenoma-carcinoma sequence resulting in more biopsies. Pathologists might also have been less aware of the diagnosis earlier and therefore overlooked the diagnosis or failed to report them. The average age in the population is rising, and this could account for the increase in number of cases. More lesions appear with increasing age, and the fact that a larger number of women get this disease may simply reflect that they live longer than men. For the pathologist, a frequent challenge is the lack of orientation of biopsies. Small biopsies less than 1 cm in diameter are often too small to be divided alongside the stalk, and fixation in formalin also makes the tissue curl up, making the orientation even more difficult. Fragmented and shallow biopsies can be impossible to interpret with a risk of overlooking a cancer. CONCLUSION We could not reproduce previous results where classifications based on levels of adenocarcinoma in an adenoma or depth of Sm invasion to predict the risk of residual cancer in extended resections or lymph node metastasis. In our study, the only factor indicating increased risk of residual cancer was adenomas with adenocarcinomas with lack of information on resection margins in the pathology report. It is important that the surgeons be aware of the prognostic implications of incomplete or uncertain resection margins as this should be an indication for reexcision. The pathologist should likewise be aware that description of resection margins is of clinical importance for the patient. REFERENCES 1. Stryker SJ, Wolff BG, Culp CE et al: Natural history of untreated colonic polyps. Gastroenterology 1987;93: Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. 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