Clinicopathological differences of laterally spreading tumors of the colorectum according to gross appearance

• Introduction
• Methods
• Results
• Overall clinicopathological characteristics of LSTs
• Clinicopathological characteristics according to LST subtype
• Incidence of invasive carcinomas according to LST subtype and tumor size
• Discussion
• Acknowledgement
• References

Background and study aims: Laterally spreading tumors (LST) are classified into two subtypes, with the nongranular type harboring a higher risk of (pre)malignant changes than the granular type. Further subdifferentiation into two subgroups each has been suggested, but the clinical significance of such a subdifferentiation has not previously been studied in detail in larger numbers.

Patients and methods: Out of 6499 patients diagnosed with colorectal adenomas between January 2006 and November 2008, 153 patients (2.35 %) had 158 LSTs, 96 with a granular and 62 with a nongranular pattern. The former group was subdivided into homogeneous and nodular mixed, the latter group into flat elevated and pseudodepressed. Clinical and histopathological parameters were compared among the four subtypes.

Results: Parameters were variably distributed between the four groups, with nodular mixed tumors being larger than the other three types (P < 0.0001). As in other studies, malignant transformation and premalignant lesion (HGIN/CIS) were more frequent in nodular mixed than in homogeneous tumors (45.0 % vs. 5.6 %, P < 0.001), and also more common in pseudodepressed than in flat elevated tumors (41.7 % vs. 13.2 %, P = 0.011). Submucosal invasive cancer was present in 8.3 % of nodular mixed tumors, 7.9 % of flat elevated, and 12.5 % of pseudodepressed, while it was absent in homogeneous tumors. Serrated adenoma was identified in 10.8 % of all LSTs, and sessile serrated adenoma tended to be more common in flat elevated tumors.

Conclusions: Further subdifferentiation of the LST lesions to identify lesions at risk of malignant transformation makes most sense in the granular type. Among nongranular LSTs, both subtypes carry a significant risk.

Introduction

Laterally spreading tumors (LSTs), first described by Kudo, are a morphologically unique type of colorectal tumor characterized by laterally extending growth with a low vertical axis [1]. LSTs are defined by lateral growth of lesions larger than 10 mm in diameter and are usually classified into two types according to their surface morphology: the granular type and the nongranular type. The granular type consists of collecting nodules that form uneven granular or nodular surfaces, whereas the nongranular type exhibits a flat, smooth surface [2]. Recently, Kudo et al. subdivided LSTs further: the granular type into homogeneous and nodular mixed types; the nongranular type into flat elevated and pseudodepressed types [3].

As LSTs have been regarded as less invasive than other polypoid tumors of similar size [4] [5], and because the clinicopathological features of LSTs have not been well characterized according to tumor subtype, several studies have compared the clinicopathological features of granular and nongranular LSTs, and revealed that granular LSTs are located mainly in the rectum and proximal colon, while nongranular LSTs are common in the transverse colon [2] [3]. Histologically, 90 % of LSTs are adenomas [6]. Traditionally, the term “adenoma” has included tubular adenoma, tubulovillous adenoma, and villous adenoma. However, another distinct form of adenoma has recently been described, “serrated adenoma” – distinguished from traditional adenoma in terms of morphology and molecular tumorigenesis – which has a sawtooth appearance microscopically and is a precursor lesion of sporadic microsatellite unstable colorectal cancer [7]. Most previous studies on LSTs included exclusively “traditional” adenomas [6] [8] [9] [10]. Homogeneous-type tumors tend to be tubular adenomas, while nodular mixed tumors are more commonly associated with villous adenomas [11]. A few studies investigating LSTs have included serrated adenomas, and reported that the prevalence of serrated adenomas was about 2 % – 9 % in colon polyps [2] [3]. In the present study, we aimed firstly to investigate the clinicopathological features of specific subtypes of LST and secondly to evaluate the association of serrated adenoma with specific subtypes of LST.

Methods

Colorectal adenoma was diagnosed in 6499 patients at the National Cancer Center, Korea, between January 2006 and November 2008. In 153 of these patients (2.35 %) there were a total of 158 LSTs (5 patients had two LSTs each), and these 153 patients were enrolled in the study. Initially, four endoscopists (D.K.S., K.S.H., C.W.H., and B.C.K.) diagnosed the LST and classified its subtype. All colonoscopies were performed by four experienced endoscopists (D.K.S., K.S.H., C.W.H., and B.C.K.), each of whom had previously performed over 1000 colonoscopies per year for more than 5 years. The patients were examined using video colonoscopes (Olympus CF-240I or CF-H260; Olympus, Tokyo, Japan).

An LST is defined as a flat lesion larger than 10 mm in diameter and extending laterally and circumferentially, rather than vertically, along the interior luminal wall of the colorectum [2] [3]. LSTs are classified into two types on the basis of the endoscopic findings: a granular type and a nongranular type, according to the presence or absence of surface granularity, as described previously [2]. Granular LSTs consist of nodular aggregates with an uneven granular surface, while nongranular LSTs are flat lesions with a smooth and even surface, without granularity. In addition, the granular type, which is composed of collecting nodules, is classified grossly into homogeneous and nodular mixed types. The nongranular type is subdivided into flat elevated and pseudodepressed types, as defined by Kudo et al. [3]. The homogeneous type corresponds to Paris classification type 0-IIa with an evenly granular surface, and the nodular mixed type is a mixture of type 0-IIa and type 0-Is. The flat elevated type corresponds to type 0-IIa with a flat smooth surface, while the pseudodepressed is a mixture of type 0-IIc and type 0-IIa with a smooth surface [3].

Two endoscopists (B.C.K., K.S.H.) blindly reviewed all the cases and subdifferentiated them into four subtypes based on endoscopic images stored in a PACS (picture archiving and communication system: Marosis M-view, Infinitt Healthcare, Seoul, Korea). The level of interobserver agreement between the two endoscopists for classifying of LSTs into the two groups (granular vs. nongranular) and four subgroups (homogeneous, nodular mixed, flat elevated, pseudodepressed) was very high, with κ values of 0.85 (two groups) and 0.79 (four subgroups). When the classifications diverged, the two endoscopists discussed them and agreed on a single diagnosis.

Treatment of LSTs was by endoscopic mucosal resection (EMR), which included endoscopic piecemeal mucosal resection (EPMR), endoscopic submucosal dissection (ESD), and colectomy, according to the decision of the endoscopist during the procedure. The endoscopists examined the morphology of the LST for the presence of large nodules, a depressed area, and fold convergence and fixed shape after air insufflation in order to confirm the phenotypes of submucosal invasiveness, and also evaluated the tumors for presence or absence of the lifting sign [12] [13] [14]. Tumors that showed the lifting sign were treated endoscopically, while tumors without the lifting sign were referred for surgery [12]. Colectomy with lymph node dissection was performed as an additional treatment if the endoscopically removed tumors showed any of the histopathologic risk factors related to lymph node metastasis: i. e., positive resection margin, submucosal invasion depth 1000 µm or greater, poorly differentiated type, tumor budding, or angiolymphatic invasion [15] [16] [17]. Clinicopathological variables, which included age, sex, endoscopic findings, treatments, and histologic features, were collected from the medical records of the enrolled patients.

Pathological diagnoses were performed by a pathologist (H.J.C.). The histological type of the adenomas or carcinomas was determined using the World Health Organization (WHO) classification [18], and the pT stage of carcinomas was assessed according to American Joint Committee on Cancer (AJCC) staging [19]. Adenocarcinoma is defined as carcinoma invading through the muscularis mucosae into the submucosa, and high-grade intraepithelial neoplasia (HGIN) is defined as a lesion with the morphological characteristics of high-grade dysplasia or adenocarcinoma that is confined to the glandular epithelium or invades the lamina propria without submucosal invasion [18] [19] [20]. The submucosal invasion depth was evaluated according to Kudo’s classification as sm1, sm2, or sm3 in surgically resected specimens [1]. For endoscopically resected specimens of sessile or flat tumors, the cutoff limit between sm1 and sm2 was 1000µm of submucosal layer according to the Paris classification [21]. Serrated adenomas were subdivided histologically into traditional serrated adenoma (TSA) and sessile serrated adenoma (SSA), as described previously [7]. A pathological diagnosis of TSA was reached if nuclear dysplasia and serration were present in more than 20 % of adenoma crypts, and a diagnosis of SSA was reached on the basis of findings of sessile growth and architectural abnormalities, including dilatation, branching, or broad bases in basal crypts [22]. [Fig. 1] shows the endoscopic and histopathological findings in our study according to LST subtype.

The National Cancer Center Institutional Review Board approved this retrospective study in Korea (NCCNCS-09-286).

Statistical analysis was performed using Student’s t-test or one-way analysis of variance (ANOVA) for quantitative variables, and categorical data were analyzed by the χ² or Fisher’s exact test. Interobserver variation regarding LST subtyping was analyzed by κ value. Linear-by-linear association was used to evaluate the correlation between the size of LSTs and pathology. P values below 0.05 were considered statistically significant. All statistical analyses were performed using SPSS software version 14.0 for Windows (Chicago, Illinois, USA).

Results

Overall clinicopathological characteristics of LSTs

The mean age of the patients enrolled in the study was 62.5 years. The male-to-female ratio was 1.39 : 1. The mean tumor size was 22.9 ± 10.7 mm. The distribution of the subtypes was as follows: granular homogeneous, 36 cases (22.8 %); granular nodular mixed, 60 cases (38 %); nongranular flat elevated, 38 cases (24 %); and nongranular pseudodepressed, 24 cases (15.2 %).

The histological type of adenoma among the LSTs was most frequently tubular adenoma (73 / 158, 46.2 %). Twenty-four LSTs had a villous component (15.2 %), and 17 LSTs (10.8 %) were classified as serrated adenoma [6 TSA (3.8 %) and 11 SSA (7 %)]. Thirty-three cases (20.9 %) were diagnosed as HGIN and 11 LSTs (7.0 %) were adenocarcinoma ([Table 1]).

Initial treatment of LSTs was mainly by endoscopic resection: EMR and ESD (138/158 cases, 87.3 %) ([Table 1]). Among the 19 patients who underwent colectomy, in 9 the surgical resection was only for LSTs which were larger than 20 mm in size, while 10 patients underwent resection of combined synchronous colorectal carcinoma. Three patients with submucosal carcinomas had additional surgical resection with lymph node dissection after initial endoscopic treatment because they had the high-risk histologic features of lymph node metastasis ([Table 2]). Lymph node metastasis was not identified among the patients who had additional surgical resection after endoscopic resection.

Clinicopathological characteristics according to LST subtype

Granular nodular mixed tumors were significantly larger than the other three subtypes (P < 0.0001). LST location prevalence varied according to tumor subtype (P < 0.0001) ([Table 3]).

The adenomas in our LST series were largely of the traditional histological types (tubular adenoma, tubulovillous adenoma, or villous adenoma), irrespective of LST subtype. However, villous adenoma components were associated more frequently with granular than with nongranular LSTs (21.9 % vs. 4.8 %, respectively; P = 0.001). Serrated adenomas were identified in 10 granular LSTs (10.4 %) and 7 nongranular LSTs (11.3 %). Although 15.8 % of nongranular flat elevated tumors had SSA components and nongranular pseudodepressed tumors had no serrated adenoma component, the overall distribution of serrated adenoma did not differ significantly among the subtypes of LST ([Table 3]).

The distribution of HGIN (premalignant) and submucosal carcinomas (malignant) was more prominent in granular nodular mixed tumors than in granular homogeneous tumors (P < 0.001), and also more frequent in nongranular pseudodepressed than in nongranular flat elevated tumors (P = 0.011). However, submucosal carcinoma was not identified in granular homogeneous tumors, and the frequency or histological type of adenocarcinoma did not differ significantly between subdifferentiated types (granular homogeneous vs. granular nodular mixed, and nongranular flat elevated vs. nongranular pseudodepressed) ([Table 3]).

Incidence of invasive carcinomas according to LST subtype and tumor size

The incidence of invasive submucosal carcinomas increased with increasing tumor size, both for granular and nongranular LSTs, and for all subtypes with the exception of granular homogeneous tumors. In particular, two-thirds of nongranular LSTs larger than 30 mm were associated with invasive cancer. The rate of submucosal invasion was significantly higher in nongranular than in granular LSTs (P = 0.024), and, among the four subtypes of LST measuring 30 mm or more, especially higher in nongranular pseudodepressed than in granular nodular mixed (P = 0.009) ([Table 4]).

We also evaluated multifocal submucosal invasion according to the subtypes of LST. One out of 11 submucosal invasive cancers had multifocal submucosal invasion and this case was the granular nodular mixed type. It showed characteristic multifocal submucosal invasion especially under the large nodular portions ([Table 3]).

Nine patients with submucosal carcinoma had high risk factors for lymph node metastasis, but in only five of those patients was colectomy followed up by lymph node dissection. One patients had lymph node metastasis at diagnosis. This patient had two risk factors: more than 1000 µm depth of tumor invasion, and angiolymphatic invasion. Seven of the 11 patients with submucosal cancer were followed up and were free of recurrence or distant metastasis during the follow-up periods ([Table 2]).

Discussion

LST is a kind of superficial neoplastic lesion that has received little attention compared with other flat-type neoplasms, because its potential for malignancy is lower than that of polypoid tumors of similar size, and because it has less objective diagnostic criteria. LST is interesting for endoscopists because it is a good indication for endoscopic resection; however, its diagnosis and classification depend on endoscopic findings, and the term “laterally spreading tumor” is used to refer to heterogeneous epithelial lesions of various histological types and atypia. This may be why only a limited number of studies of LST are available. Most of the previous studies were performed in Japan [2] [3] [8] [9] and, to our knowledge, the present study is one of the largest performed to date; it included 153 non-Japanese patients. In previous studies, LST had an overall prevalence of 0.8 % – 5.2 % [23] [24]. Chiu et al. recently reported that the prevalence of LST was 0.42 % and 0.38 % in asymptomatic and average-risk Chinese groups, respectively [25], and in addition, the proportion of LST among colorectal neoplasms was 1.52 % and 1.38 % in asymptomatic and average-risk Chinese groups, respectively [25]. We confirmed that LST patients represented 2.35 % (153 of 6499) of the adenoma patients examined; the proportion of LST among colorectal neoplasms found in the present study is similar to that observed in the study of Chiu et al.

Recently, Kudo et al. classified LST into four subtypes: homogeneous, nodular mixed, flat elevated, and pseudodepressed [2] [3]. Nodular mixed tumors were associated more frequently with a villous adenoma component [11], and the giant nodules or concavities present in nodular mixed tumors were related to malignant potential [2]; however, the clinicopathological profiles of the other three subtypes have not been well characterized. Our analysis revealed that the clinicopathological characteristics of LSTs varied according to tumor subtype in terms of size, distribution, histological features, and malignant potential. Among the four subtypes, nodular mixed tumors exhibited the following characteristic findings, which were distinct from those of the other subtypes: large size (29.9±12.3mm); predominant location in the rectum (46.7 %); and a higher rate of HGIN (36.7 %), with occasional malignant transformation (submucosal carcinoma, 8.3 %). In contrast, homogeneous tumors were located predominantly in the right colon (80.6 %), and were largely low-grade adenomas (94.4 %) without an invasive carcinoma component. Flat elevated disease was also largely low-grade tubular adenoma, and associated with sessile serrated adenoma in 15.8 % of cases. Pseudodepressed disease was not associated with serrated adenoma (traditional or sessile), and relatively showed the highest rate of association with invasive carcinoma (12.5 %).

Serrated adenoma (or serrated polyp) has been recently defined as a premalignant neoplastic lesion of the serrated pathway related to microsatellite instability, in contrast with traditional adenoma which is related to chromosomal instability [7] [26]. Serrated adenoma can be classified into the traditional and the sessile types. Unlike the traditional type, which exhibits cytological atypia, the sessile type (also termed “sessile serrated polyp” or “sessile serrated lesion”) shows architectural abnormalities without cytological atypia, which is the most important histological finding for the diagnosis of adenoma [7] [26]. The differential diagnosis of sessile serrated adenoma and hyperplastic polyp may be difficult in the case of sessile lesions smaller than 0.5 cm; however, taking the size criterion for LST into consideration, sessile serrated lesions in LSTs are more reasonably regarded as sessile serrated adenoma than as hyperplastic polyp. In our study, 17 LSTs (10.8 %) had morphological serrated features on histopathological evaluation. Of those 17 LSTs, 11 were histologically sessile serrated adenomas and 6 were traditional serrated adenomas. Sessile serrated adenomas were most common in flat elevated types; however, their distribution did not differ significantly among the various subtypes ([Table 3]). In addition, flat elevated tumors, which were predominantly located in the ascending colon and had a grossly flat pattern, had features similar to those observed for sessile serrated adenomas in previous studies [7]. The present study is the first to report a correlation between LSTs and serrated adenoma.

The size and depression of polyps are good predictors of invasive cancer, and the proportion of submucosal carcinoma increases with increasing size of flat depressed types of polyps [2]. Over 50 % of flat depressed polyps larger than 11 mm have submucosal invasive carcinoma [3]. The proportion of submucosal carcinomas also increases with increasing size of LSTs of the nodular mixed and nongranular (flat elevated and pseudodepressed) types. Nongranular LSTs larger than 30 mm were submucosal invasive carcinoma in 60 % of cases. In contrast, homogeneous tumors are not associated with submucosal invasive carcinoma, even when they are larger than 30 mm ([Table 4]). In the present and previous studies [2] [3], submucosal invasive carcinoma is rare in homogeneous tumors, whereas it is frequent in pseudodepressed tumors. Uraoka et al. reported that submucosal invasion of LST was associated with large nodules (≥ 10 mm) of LST-G, and with depressed area of LST-NG [2] [5]. According to the present results and previous studies [2] [3] [5], large size, depressed phenotype, and large nodules (≥ 10 mm) are predictive markers of invasive carcinoma in LSTs.

Large flat polyps or cancers are excised endoscopically, in particular ESD for en bloc resection. ESD has the advantages of enabling precise histological evaluation and complete resection [27] [28]; however, it is associated with a higher rate of complications (e. g., hemorrhage and perforation) and requires long procedure times, and so should be performed by highly experienced endoscopists. On the basis of the present results, conventional EMR technique is suitable for the removal of large homogeneous tumors. In addition, the potential for invasive cancer of nongranular LSTs (flat elevated and pseudodepressed) increases with increasing lesion size (≥ 30 mm); therefore, it should be recommended that flat elevated and pseudodepressed tumors larger than 30 mm, and nodular mixed tumors larger than 40 mm, should be managed using ESD with en bloc resection by an endoscopist experienced in ESD. Saito et al. suggested a similar indication for ESD in the resection of LSTs: a noninvasive pattern on magnification colonoscopy, and size 20 mm or larger (nongranular LST) or 30 mm or larger (granular LST) [27]. Uraoka et al. also recommended that nongranular LSTs should be treated by ESD because of their high frequency of multifocal/lymph follicular submucosal invasion and much higher submucosal cancer rates [5]. In our study, one nodular mixed tumor had multifocal submucosal invasion. Since our findings were obtained from a small number of cases, further investigation in a large group is necessary for conclusions to be drawn. However, our results might support the association of large nodules of nodular mixed tumor and submucosal invasion. Multifocal submucosal invasion might occur in nodular mixed tumors with multiple large nodules (≥ 10 mm). Although nodular mixed tumors of 20 mm in size or larger had a lower prevalence of submucosal cancer than nongranular LSTs of similar size, submucosal invasion was identified in large nodules (≥ 10 mm) or depressed foci [5] [10]. For this reason, it is recommended that the largest nodules (≥ 10 mm) or depressed foci of nodular mixed tumors should be first resected by endoscopic piecemeal mucosal resection (EPMR) [5] [10]. EPMR for nodular mixed tumors could be done at a general hospital facility without an endoscopist experienced in ESD, and ESD might be used for large-sized superficial submucosal cancers in hospitals with endoscopists who are well experienced in ESD.

In spite of recent advances in the understanding of molecular events, previous findings regarding molecular events in specific subtypes of LST have shown some discrepancies. Several studies reported that that granular LSTs show a higher prevalence of K-ras mutation than do nongranular LSTs [4] [29] [30]. However, Noro et al. reported that the frequency of K-ras mutation does not differ between granular and nongranular LST types [31]. Regarding epigenetic characteristics, Hiraoka et al. reported that CpG island methylator phenotype-high (CIMP-high) is observed more commonly in granular than in nongranular LSTs [4]. However, Nosho et al. reported that CIMP-high was identified in 74 % of nongranular LST tumors, whereas its frequency was 8 % in granular LST lesions [32]. The variation of those results might show the presence of varied carcinogenesis among the LST subtypes. In our study, we did not perform genetic or epigenetic analyses. Although our results revealed the presence of varying clinicopathological characteristics according to LST subtype, each subtype comprised a heterogeneous group of epithelial tumors, which may also contribute to the discrepancies between the genetic and epigenetic studies.

The present study had the limitation of being retrospective. The treatment modalities were highly diverse and follow-up data were not collected. Therefore, there exists the need for further large-scale, prospective studies that include follow-up.

In conclusion, the clinicopathological characteristics of LSTs varied according to tumor subtype in terms of size, histological features, and malignant potential. Further subdifferentiation of granular LSTs makes sense to identify lesions at risk for malignant transformation. Among nongranular LSTs, both subtypes carry significant risk.

Acknowledgement

This study was supported in part by grant nos. 0910160 (H.J.C.) and 0710360 (C.W.H.) from the National Cancer Center, Korea.

Competing interests: None

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H. J. ChangMD, PhD 

Center for Colorectal Cancer Research Institute and Hospital National Cancer Center

809 Madu-dong
Ilsan-gu Goyang Gyeonggi
411–769 Korea

Fax: +82-31-9201369

Email: heejincmd@yahoo.com

References

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  Thieme ConnectPubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
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H. J. ChangMD, PhD 

Center for Colorectal Cancer Research Institute and Hospital National Cancer Center

809 Madu-dong
Ilsan-gu Goyang Gyeonggi
411–769 Korea

Fax: +82-31-9201369

Email: heejincmd@yahoo.com