Predictors of invasive cancer of large laterally spreading colorectal tumors: A multicenter study in Japan

Introduction

Laterally spreading tumor (LST), a term describing one growth pattern of colorectal tumors, refers to colorectal tumors with a maximum diameter of 10 mm or greater and lower vertical growth than horizontal growth. The underlying disease concept was proposed by Kudo.1 LSTs can be classified into two types: LST granular type (LST-G), with granules and nodules on the tumor surface, and LST nongranular type (LST-NG), with a flat, smooth surface.2 LST-G can be classified into two subgroups: LST-G homogenous type (LST-G-H), with uniform granules or nodules on the tumor surface, and LST-G nodular mixed type (LST-G-M), with coarse nodules on the tumor surface. LST-NG can be classified into two subtypes: LST-NG pseudodepressed type (LST-NG-PD), with a poorly demarcated, basin-like depression in the tumor center, and LST-NG flat-elevated type (LST-NG-F), with no depression.2

Most colorectal LSTs are large and are associated with a low incidence of invasive carcinoma for the size. Endoscopic resection is therefore likely to be indicated for treatment. However, because LSTs are large and sessile, en bloc endoscopic mucosal resection (EMR) is difficult to perform, and endoscopic submucosal dissection (ESD) is usually carried out in Japan. Because the colon wall is thin with many curves, ESD is technically difficult to perform. Therefore, to standardize endoscopic treatment in patients with large colorectal LSTs and other tumors, the Japanese Society for Cancer of the Colon and Rectum (JSCCR) conducted a project study entitled “a multicenter collaborative study of local curability and adverse events after various endoscopic resection procedures for colorectal tumors with a maximum diameter of 20 mm or greater (prospective questionnaire survey): a cohort study of colorectal polyps measuring more than 20 mm in diameter.” The results have been reported.3-6 That study focused on local curability and adverse events associated with the endoscopic resection of large colorectal tumors. Data on the endoscopic findings and histopathological characteristics of colorectal tumors measuring 20 mm or more in diameter were also collected.

The prediction of invasive cancer before treatment plays an important role in determining whether endoscopic resection is an appropriate treatment for large colorectal LSTs and is considered clinically useful. Therefore, the main objective of the present study was to clarify whether the risk of invasive cancer can be predicted on the basis of endoscopic findings in patients with large colorectal LSTs who were enrolled in a “cohort study of colorectal polyps measuring more than 20 mm in diameter.” In addition, a validation study was conducted to confirm the reliability of the results obtained in the main study.

Methods

Subjects

Main study

Eighteen middle- and high-volume specialized institutions affiliated with the Colorectal Endoscopic Resection Standardization Implementation Working Group of the JSCCR participated in a cohort study of colorectal polyps measuring more than 20 mm in diameter. A total of 1845 colorectal tumors with a maximum diameter of 20 mm or greater that were resected using EMR, ESD, or snare polypectomy were registered from October 2008 to December 2010. Endoscopic resection was indicated for the treatment of intramucosal colorectal neoplasia or carcinomas with a submucosal shallow invasion of <1000 μm because the risk of lymph node metastasis is very low in such cases. Endoscopic resection is not indicated for the treatment of submucosal invasive (T1) carcinoma that is suspected to be deeper than 1000 μm, other invasive carcinomas in the colorectum, and lesions that are technically difficult to resect endoscopically and therefore require surgical resection because of factors such as the presence of circumferential tumors with a risk of stenosis after endoscopic treatment. Before endoscopic resection, the depth of invasion of large colorectal LSTs was estimated based on conventional endoscopic findings. Most lesions were also examined through chromoendoscopy, performed by spraying the mucosa with 0.2% indigo carmine dye, in combination with, if possible, pit pattern diagnosis on magnifying chromoendoscopy and endoscopic ultrasonography.7-11 We focused on factors such as an expansive appearance of the tumor, the presence of ulceration or erosion, converging folds toward the tumor, and poor extension of the tumor and the surrounding colorectal wall as endoscopic findings suggesting deep invasion of the submucosa by a colorectal LST. In lesions where pit patterns of the tumor site were evaluated on magnifying chromoendoscopy, we focused on the presence of an invasive pattern.10

Among large colorectal tumors that were registered in a cohort study of colorectal polyps measuring more than 20 mm in diameter, 1236 lesions classified to have LST growth patterns were studied (Fig. 1). The inclusion criteria of the main study required LSTs measuring at least 20 mm in diameter that were histopathologically diagnosed to be adenomas or early cancers (Tis cancer or T1 cancer). LSTs that measured 20 mm or more in diameter with T2 or deeper histopathological invasion were excluded (Fig. 1).

Validation study

Among the institutions participating in the cohort study of colorectal polyps measuring more than 20 mm in diameter, a validation study of an independent series of colorectal LSTs that measured more than 20 mm in diameter and were resected endoscopically was conducted in two hospitals (K hospital and H hospital). The inclusion and exclusion criteria of the validation study were the same as those of the main study. As for the registration period and the number of registered lesions according to hospital, 131 consecutive lesions were registered in K hospital from January 2011 to December 2014, and 259 consecutive lesions were registered in H hospital from January 2003 to December 2009.

Results

Discussion

Colorectal LST is not a macroscopic classification but is widely acknowledged because of its characteristic appearance and histopathological characteristics.13 The detection rate of colorectal LSTs on colonoscopy has been reported to be 1.3 and 4.5%.14, 15 LSTs have been reported to account for 5.8% of early colorectal cancers.1

Among colorectal LSTs, LST-G lesions and LST-NG lesions both predominantly develop in horizontal directions but have different histopathological characteristics. As for lesion site, LST-G lesions most commonly arise in the rectum and the proximal colon. LST-NG lesions are most commonly found in the transverse colon.2, 16 Compared with LST-G lesions, LST-NG lesions have been reported to be associated with a high incidence of cancer invading the submucosa despite a smaller tumor diameter.17-19 LST-G and LST-NG lesions are associated with different patterns of genetic abnormalities and are thus recognized as histopathologically distinct types of LSTs.20-22

In the main study, colorectal LSTs measuring 20 mm or greater in diameter were subclassified to compare histopathological characteristics among the subclassifications. Among the LSTs, LST-G-M lesions were most frequently found in the rectum, whereas other types of LSTs were most commonly located in the proximal colon. Many LST-G-M lesions were large, measuring 40 mm or greater in diameter. As for the histological type, the incidence of pathological T1 cancer was the highest among LST-NG-PD lesions. More than half of all LST-G-H lesions were adenomas, despite the fact that large lesions with a diameter of 20 mm or greater were studied. In the results of the main study, the incidence of pathological T1 carcinoma was only 3% of LST-G-H lesions. As for predictive factors for the risk of pathological T1 carcinoma, the results of logistic regression analysis showed that LST subclassification and tumor diameter were significantly related to the risk of pathological T1 carcinoma. The AUC of the statistical model was high. In particular, compared with LST-G-H lesions, an LST subclassification of LST-NG-PD was associated with an odds ratio of 30.35 for the risk of pathological T1 carcinoma, indicating high risk. In our study, a validation study was performed to evaluate the external validity of the statistical model used in the main study. A high AUC was obtained, confirming the validity of the results of the main study.

An accurate preoperative evaluation of the invasion depth of early colorectal cancer plays an important role in determining the indication for endoscopic resection and in selecting the treatment procedure of choice. Among early colorectal carcinomas, endoscopic resection is indicated for the treatment of pathological Tis cancer because there is no risk of metastasis. The clinical management is the same as that for adenomas. Therefore, the distinction of pathological Tis cancer from adenoma based on endoscopic findings is considered to be not so meaningful. Among early colorectal cancers, pathological T1 cancer can metastasize to lymph nodes and other organs. Surgery should thus be considered. Therefore, before treatment, it is extremely important to accurately differentiate adenoma and pathological Tis cancer, indications for endoscopic treatment, from pathological T1 cancer,for which surgery should be considered. The results of the main study showed that not only tumor diameter but also LST subclassifications are important indicators that can be used to predict the invasion depth of LSTs. Investigators in other studies reported that the incidence of invasive carcinoma is the highest among LSTs with a subclassification of LST-NG-PD.2, 23-26 Kudo et al.2 and Oka et al.23 reported that all large LST-NG-PD lesions with a diameter of more than 30 mm were pathological T1 carcinomas. In patients with LST-NG-PD lesions, cancer might multifocally invade the submucosa (Fig. 2a,b). When endoscopic resection is selected for the treatment of LST-NG-PD lesions, en bloc resection using procedures that can completely resect even large lesions, such as ESD, should be performed.18, 23, 26

More than half of the LST-G-H lesions were adenomas, and even if cancer was present, most cases were pathological Tis carcinomas. Other studies have reported that invasive carcinoma is rarely found among LST-G-H lesions.2, 23, 25-28 Investigators in other studies have reported that the invasion depth of LSTs is related to tumor diameter.2, 13, 23 However, LST-G-H lesions were associated with a low incidence of pathological T1 cancer, irrespective of tumor diameter.2, 23, 25 Therefore, among LSTs, LST-G-H lesions were considered candidate lesions for piecemeal EMR regardless of the tumor diameter. Shigita et al.29 classified LST-G into three subtypes according to the size and uniformity of granules and nodules on the tumor surface to compare the histological types among the subtypes. Many LST-G lesions with a uniform surface were adenomas. About 10% of lesions with nodules that were 5–10 mm in diameter or with coarse nodules measuring 10 mm or greater were pathological T1 carcinomas. In our study, although the lesion size differed, 11% of LST-G-M lesions were pathological T1 carcinomas, indicating similar results. Therefore, ESD should be selected to endoscopically resect large LST-G-M lesions that have coarse nodules because it enables en bloc resection.

Our study had several limitations. First, a limitation of the main study and the validation study was that large colorectal LSTs that were evaluated to be free of submucosal deep invasion by endoscopists were resected endoscopically. The large colorectal LSTs that were examined in each study did not include lesions resected by surgical operation. Therefore, selection bias is considered a limitation of our study. The lesions that were suspected to have submucosal or deeper invasion and were resected surgically might have included lesions that were adenomas or pTis cancers on histopathological evaluation. A second limitation was that endoscopic resection is considered an acceptable procedure for the treatment of pathological T1 cancer confined to the shallow layer of the submucosa because such lesions are rarely associated with lymph node metastasis.30 However, in our study, the invasion depth of pathological T1 carcinomas, including the degree of submucosal invasion, could not be analyzed in detail. Although our study methods had these limitations, more than 1600 colorectal LSTs measuring 20 mm or more in diameter were included in the main and validation studies combined, and we believe that this is the first multicenter study to perform logistic regression analysis to determine predictors of the risk of pathological T1 carcinoma associated with large colorectal LSTs.

In conclusion, the results of logistic regression analysis indicate that the risk of pathological T1 carcinomas among large colorectal LSTs resected endoscopically can be predicted based on the LST subclassification and tumor diameter. The results of our study will hopefully facilitate the selection of the optimal treatment procedure for large colorectal LSTs.