doi:10.1111/codi.12760

Original article

Ileocaecal junction carcinoma: a clinicopathological study of 199 cases L. H. Lee*, A. R. MacLean†, V. G. Falck* and X. Gui* *Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada and †Department of Surgery, University of Calgary, Calgary, AB, Canada Received 16 April 2014; accepted 10 July 2014; Accepted Article online 26 August 2014

Abstract Aim The ileocaecal junction (ICJ) region is an epithelial transition zone in which carcinomas are frequently diagnosed. However, it is currently unknown whether ICJ carcinomas (ICJ-CAs) have distinctive features. This study aimed to characterize the clinicopathological features of ICJ-CAs. Method All ileal and colorectal resections for carcinoma, performed in Calgary, Canada between January 2009 and June 2012, were reviewed. Carcinomas in which the epicentre was within 5 cm of the ileocaecal valve (ICV) were defined as ICJ-CAs. Of 1003 carcinomas studied, 199 (19.8%) were ICJ-CAs, including 93 (9.3%) that crossed the ICV. Comparison of clinicopathological features with carcinomas of the other ileocolorectal regions was made. Survival was also assessed. Results Clinically, ICJ-CAs were more common in female than male patients (56.3% female) compared with left-colonic (42.9% female) and rectal (37.9% female) carcinomas, and were more common in older age-groups of patients (71.8  12.7 years) compared with appendiceal (62.6  11.3 years), left-colonic (69.4  12.3 years) and rectal (67.1  11.9 years) carcinomas. Macroscopically, ICJ-CAs were similar to other colorectal carcinomas and were mostly described as ulcerated (63.3%). Histologically, ICJ-CAs had more mucinous, signet-ring cell and/or neuroendocrine features (39.7%, 8.0% and 7.5%,

Introduction Epithelial transition zones (TZs), regions where different epithelia meet, are often associated with unique or increased cancer susceptibility. Most studies have focused on squamo-columnar junctions, including the Correspondence to: Xianyong Gui, MD, PhD, FRCPC, University of Calgary and Calgary Laboratory Services, Department of Pathology and Laboratory Medicine, 1403 29 Street NW, Calgary, Alberta T2N 2T9, Canada. E-mail: [email protected]

respectively) than did carcinomas of the left colon (16.8%, 1.6% and 1.1%, respectively) and the rectum (14.1%, 1.0% and 0.0%, respectively). They were higher grade (20.1% were high grade) than those of the leftcolon (10.3%) and the rectum (9.8%). ICJ-CAs presented at a higher T-stage (25.6% were T4) compared with rectal carcinomas (11.6%). Most significantly, ICJ-CAs presented at a higher N-stage (25.6% were N2) than did right-colonic (14.1%) and rectal (16.2%) carcinomas. Although survival of patients with ICJ-CAs did not differ from those with right-colonic carcinomas, those with carcinomas directly involving the ICV did show a significantly decreased survival. Conclusion ICJ-CAs display several distinct clinicopathological features that may require special diagnostic, prognostic and management attention. Keywords Ileocaecal valve, colorectal neoplasms, caecal neoplasms, ileal neoplasms What does this paper add to the literature? This paper is the first systematic study of the clinicopathological features of carcinomas of the ileocaecal junction. The ileocaecal junction is a unique epithelial transition zone, and carcinomas here display important features that may require special diagnostic, prognostic and management attention.

endo-ectocervix junction, cornea-conjunctiva junction, gastro-oesophageal junction and the ano-rectal junction, all of which show high levels of carcinogenesis [1–4]. Furthermore, carcinomas arising in TZs present some unique features. For example, carcinoma of the gastro-oesophageal junction is distinct from carcinoma of the stomach and the oesophagus in aetiology, epidemiology, pathology and prognosis. This has resulted in the requirement for unique classification and treatment [5].

Colorectal Disease ª 2014 The Association of Coloproctology of Great Britain and Ireland. 17, O1–O9

O1

L. H. Lee et al.

Ileocaecal junction carcinomas

time and cause of death were recorded. Cases of peritoneal carcinomatosis were excluded because of the uncertainty of the primary tumour in some cases. Metastatic cancer from nonintestinal sites was also excluded. Patients who received preoperative chemoradiation therapy were considered separately because of the difficulty in determining the pre-/post-treatment TNM staging [8,9] and the common effects of therapy on tumour histology [10]. A carcinoma with its epicentre within 5 cm proximal or distal to the ICV was arbitrarily defined as an ICJCA. This was determined through the combination of gross descriptions, surgical reports and slide reviews. The distance of 5 cm was chosen for agreement with the Siewert definition of oesophagogastric junction tumours [5]. The remainder of the tumours were subgrouped, based on their location of origin, into the following categories: terminal ileum (excluding tumours designated as ICJ-CAs), appendix (without direct extension to the ICV or involving bowel within 5 cm of the ICV), right colon (caecum, ascending colon, hepatic flexure and transverse colon, and excluding tumours designated as ICJ-CAs), left colon (splenic flexure, descending colon and sigmoid colon) and rectum (rectosigmoid and rectum). The TNM staging was reported according to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 7th edition [9]. The clinicopathological findings of ICJ-CAs were compared with those of carcinomas in other ileo-colorectal regions. Continuous data were compared using the two-tailed Student’s t-test. Categorical variables were compared using Fisher’s exact test. P < 0.05 was considered statistically significant. Multiple-testing correction for each category of comparison was performed using the Benjamini–Hochberg procedure with a false-

The ileocaecal junction (ICJ) is a TZ in which the small and the large intestinal mucosa merge, separating quite different bowel luminal environments. The biology and pathology of this particular TZ has not been well studied. Limited reports in the literature regarding ICJ tumours were focused on carcinoid tumours [6]. It has been suggested that carcinomas at the ICJ are rare and are usually diagnosed late when complications occur [7]. In current clinical pathology practice, however, carcinomas in the ICJ area do not appear to be uncommon. Whether the carcinomas in this region have any unique clinicopathological characteristics, compared with those of the other intestinal regions, is an interesting question but has never been studied. The present study attempts to answer this question and to define the ileocaecal junction carcinoma (ICJ-CA).

Method We conducted a retrospective review of all ileal and colorectal malignancies resected between January 2009 and June 2012 in all nonpaediatric hospitals of the Calgary metropolitan area. Cases were identified through the centralized laboratory information system. Original pathology and surgical reports, and histopathology slides, were reviewed. Representative slides containing tumour were reassessed by a gastrointestinal pathologist and diagnoses were reclassified if found to be inaccurate. Histology sections of tumours close to the ileocaecal valve (ICV) were also reassessed to determine their precise location relative to the ICV. The clinical information and the pathological features of each tumour, including location, gross appearance, histological type, grade, depth of invasion (T-stage), nodal metastasis (N-stage), pre-existing adenomas, follow-up/survival

Table 1 Clinical data of the reviewed cases. Age Location Terminal ileum Appendix ICJ Right colon Left colon Rectal Total

n (%) 7 12 199 205 184 396 1003

(0.7) (1.2) (19.8)‡ (20.4) (18.3) (39.5)

Gender

Mean  SD 63.0 62.6 71.8 71.6 69.4 67.1 69.3

      

15.0 11.3 12.7 12.3 12.3 11.9 12.4

P†

Male n (%)

Female n (%)

P†

0.0739 0.0146*

3 2 87 105 105 246 548

4 10 112 100 79 150 455

1.0 0.0768

0.8600 0.0620 0.0001* 0.0023*

(42.9) (16.7) (43.7) (51.2) (57.1) (62.1) (54.6)

(57.1) (83.3) (56.3) (48.8) (42.9) (37.9) (45.4)

0.1363 0.0106* 0.00003* 0.0051*

ICJ, ileocaecal junction; ICV, ileocaecal valve. †Compared with the ICJ. ‡93 (9.3%) crossed the ICV. *Significant difference from the ICJ (Student’s t-test for age, Fisher’s exact test for gender, P < 0.05).

O2

Colorectal Disease ª 2014 The Association of Coloproctology of Great Britain and Ireland. 17, O1–O9

L. H. Lee et al.

Ileocaecal junction carcinomas

(a)

(b)

Histology

*

100%

100%

80%

80%

60%

60%

40%

* *

*

*

40%

**

20%

20%

**

*

0%

Grade

**

Adenocarcinoma Mucinous Features Signet Ring NOS Features

(c)

* *

* 0%

Neuroendocrine Features

Other

Low grade

High grade

(d)

Gross Description

100%

100%

80%

80%

60%

T-Stage

60%

*

40%

40% 20%

* 20%

*

ke

e

-li

us

g

ue aq

0% Tx

Pl

D

at ng

iff

in

id po Fu

ed

(e)

Po ly

s

ck er

as

Pu

lc U

M

ed

on

er at

si Le

An nu la r

0%

Ti

T1

T3

T4

Pre-existing Adenomo (among those identified)

(f)

N-Stage

T2

100% 100% 80%

80%

*

60% 40%

60% 40%

* * *

20%

* N0

Ileum

0% Tubular Adenoma

0% Nx

20%

N1

Appendix

Tubulovillous Adenoma

Villous Adenoma

N2

ICJ-CA

Right Colon

Left Colon

Sessile Serrated Adenoma

Traditional Serrated Adenoma

Rectum

Figure 1 Distribution of tumour characteristics among tumours identified at each anatomical site. Each bar represents the percentage of tumours at the given anatomical site that contains the identified feature. More than one feature may be present in each tumour, and therefore the percentage may add up to more than 100%. An asterisk (*) above a bar signifies that the proportion of tumours with the feature at the specified anatomical site is significantly different compared with the proportion of ileocaecal junction carcinomas (ICJCAs) (Fisher’s Exact Test with the Benjamini–Hochberg procedure for multiple test correction, false discovery rate = 0.05).

discovery rate of 0.05. Total survival and disease-specific survival were compared between ICJ-CAs and rightsided colon carcinomas using Kaplan–Meier survival

analysis with log-rank and Wilcoxon tests. Statistical analyses were performed using Excel 2010 (Microsoft Corp., Redmond, WA, USA) and SPSS 19.0 (IBM

Colorectal Disease ª 2014 The Association of Coloproctology of Great Britain and Ireland. 17, O1–O9

O3

L. H. Lee et al.

Ileocaecal junction carcinomas

Corp, Armonk, NY, USA). The study was approved by the local Institutional Research Board.

Results One-thousand and three cases qualified for inclusion in our review. Location distribution, and differences in age and gender are summarized in Table 1. One-hundred and ninety-nine (19.8%) tumours qualified as ICJ-CAs according to our definition, including 93 (9.3%) that crossed the ICV. Patients with ICJ-CAs were older by approximately 10 years compared with those with appendiceal or terminal ileum carcinomas, although the difference from the latter did not reach statistical significance (P = 0.074), probably because of the small numbers of ileal carcinomas. Patients with ICJ-CAs were also older than those with rectal carcinomas by approximately 5 years. A significantly higher percentage of patients with ICJ-CAs were women compared with leftcolonic and rectal carcinoma patients. The distributions of histology, grade, macroscopic description, T-stage, N-stage and pre-existing adenoma are summarized in Fig. 1. ICJ-CAs displayed some unique histological features. First, compared with the adjacent ileal and appendiceal tumours, ICJ-CAs do not appear to be merely extensions of ileal or appendiceal carcinomas, although in some cases it should be a concern. Most ICJ-CAs were adenocarcinomas not otherwise specified (NOS), whereas appendiceal carcinomas (i.e. carcinomas confined to the appendix) were less often considered adenocarcinoma NOS and more often showed signet-ring cell features. All ileal carcinomas

(a)

(c)

O4

were of neuroendocrine histology. Second, ICJ-CAs showed some differences from left-sided and rectal tumours. ICJ-CAs had more carcinomas with mucinous, signet-ring and/or neuroendocrine features (Fig. 2) and had a higher proportion of high-grade tumours. Grossly, ICJ-CAs were generally similar to all other colonic carcinomas, but a higher number of ICJ-CAs were fungating (24.1%) compared with rectal tumours (12.1%). Overall, there was a trend for decreasing T-stage at presentation towards the distal colon. A significant difference existed between ICJ-CAs and rectal carcinomas in that ICJ-CAs were of higher stage, with more at stage T4 (25.6% for ICJ-CAs vs 11.6% for rectal carcinomas). The rectal cancer results may be biased because many locally advanced rectal cancers (clinical T3, T4 or node positive) would receive neoadjuvant treatment [11]. However, when estimating the difference in stage by including treated carcinomas that may be T3/T4, there remained a trend that ICJ-CAs were more advanced than rectal carcinomas [ICJ-CA at T3/T4 = 161 (80.9%); rectal carcinoma at T3/T4 = 383 (73.9%); P = 0.052]. Although ICJ-CAs are located at the start of the right colon, ICJ-CAs still showed some differences from the other right-colonic carcinomas. ICJ-CAs were of significantly higher N-stage. Whilst not statistically significant, ICJ-CAs tended to have more T4 carcinomas (25.6% for ICJ-CAs vs 18.5% for right-colonic carcinomas) and fewer T3 carcinomas (55.3% for ICJ-CAs vs 63.4% for right-colonic carcinomas). Moreover, again, whilst not statistically significant, fewer ICJ-CAs

(b)

(d)

Figure 2 Common histology of ileocaecal junction carcinomas (ICJ-CAs). (a) Adenocarcinoma not otherwise specified (NOS) at the ileocaecal valve [haematoxylin and eosin (H&E) stain, 20 9magnification]. (b) Adenocarcinoma with mucinous features (H&E stain, 40 9magnification). (c) Adenocarcinoma with signet-ring cell features (H&E stain, 400 9magnification). (d) Adenocarcinoma with both mucinous and signet-ring cell features (H&E stain, 200 9magnification).

Colorectal Disease ª 2014 The Association of Coloproctology of Great Britain and Ireland. 17, O1–O9

L. H. Lee et al.

Ileocaecal junction carcinomas

Total survival, ICJ-CA on ICV

Total survival, ICJ-CA (b) 1.0

1.0

0.8

0.8 Total survival (%)

Total survival (%)

(a)

0.6

0.4

0.2

0.6

0.4

0.2 ICJ-CA Right colon

ICJ-CA-censored Right colon-censored

0.0

0.0 0

10

20

30

40

50

60

0

10

20

30

40

50

60

Time (months)

Time (months) Disease survival, ICJ-CA

Disease survival, ICJ-CA on ICV (d)

(c)

1.0

Disease-specific survival (%)

1.0 Disease-specific survival (%)

ICJ-CA on ICV-censored Right colon*-censored

ICJ-CA on ICV Right colon*

0.8

0.6

0.4

0.2 ICJ-CA Right colon

ICJ-CA-censored Right colon-censored

0.0 0

10

20

30

40

50

60

0.8

0.6

0.4

0.2 ICJ-CA on ICV Right colon*

0.0 0

10

20

ICJ-CA on ICV-censored Right colon*-censored

30

40

50

60

Time (months)

Time (months)

Figure 3 Kaplan–Meier survival analysis. (a) Total survival is the same between ileocaecal junction carcinomas (ICJ-CAs) and rightsided colon cancers (log-rank, P = 0.51; and Wilcoxon, P = 0.73). (b) ICJ-CAs involving the ileocaecal valve (ICV) show decreased early total survival compared with the remainder of right-colon cancers (log-rank, P = 0.08; Wilcoxon, P = 0.02). (c) Diseasespecific survival between ICJ-CA and right-colon cancers is also the same (log-rank, P = 0.73; Wilcoxon, P = 0.79). (d) Again, ICJ-CAs involving the ICV show decreased early disease-specific survival compared with the remainder of right-colon cancers (log-rank, P = 0.09; Wilcoxon, P = 0.03). Mean follow-up time is 31.7  14.5 months. Asterisk (*) indicates thay the right-colon cancer definition includes ICJ-CAs that do not involve the ICV.

were associated with sessile-serrated adenomas compared with the carcinomas of the right colon (1.9% vs 5.0%, respectively). ICJ-CAs tended to have more mucinous, signet-ring and neuroendocrine features. Furthermore, ICJ-CAs had a trend for lower histological grade (low grade in 79.9% of ICJ-CAs vs 77.1% of right-colon cancers). This goes against the trend in the

left colon and rectum in which lower grades were seen more distally. Regarding patient survival, patients with ICJ-CA and right-colonic carcinoma showed no significant difference in overall or disease-specific survival. However, using a more specific definition of ICJ-CA, by including only those that also involved the ICV, a significant early total

Colorectal Disease ª 2014 The Association of Coloproctology of Great Britain and Ireland. 17, O1–O9

O5

L. H. Lee et al.

Ileocaecal junction carcinomas

Table 2 Comparison between ileal-centred and caecal-centred ileocaecal junction carcinomas (ICJ-CAs)*. All ICJ-CAs

ICJ-CAs that cross the ICV

Type

Ileal-centred (n = 17) n (%)

Caecal-centred (n = 182) n (%)

Ileal-centred (n = 7) n (%)

Caecal-centred (n = 86) n (%)

Adenocarcinoma NOS Mucinous features Signet-ring features Neuroendocrine features Other

5 3 0 10 0

150 76 16 5 5

4 2 0 2 0

72 39 10 3 2

(29.4) (17.6) (0.0) (58.8) (0.0)

(82.4) (41.8) (8.8) (2.7) (2.7)

(57.1) (28.6) (0.0) (28.6) (0.0)

(83.7) (45.3) (11.6) (3.5) (2.3)

*No significant difference between distributions of all ICJ-CAs and those that cross the ileocaecal valve (ICV) (Fisher’s exact test with the Benjamini–Hochberg procedure; false discovery rate = 0.05).

and disease-specific survival difference was shown (Fig. 3). A further breakdown of ICJ-CAs, according to epicentre in relation to the ICV (i.e. located on the ileal or the caecal side of the ICV) and according to histology, is summarized in Table 2. Table 2 also shows a comparison with only the ICJ-CAs crossing the ICV. The histology classified as ‘others’ includes those with medullary features and micropapillary features. A small number of ICJ-CAs had coexisting appendiceal tumours. Nine had continuous extension of tumour between the appendix and caecal mucosa, four invaded the appendix through the appendiceal serosa and one had evidence of appendiceal invasion only within lymphovascular channels. ICJ-CAs involving the appendix showed similar histology to ICJ-CAs that did not involve the appendix. Whether these cases had an appendiceal origin could not be confirmed.

Discussion The ICJ is a TZ between the ileum and the colon. Although glandular epithelia line both sides of the ICJ, they differ in structure and function, resulting in different luminal environments. Ileal mucosa is exposed to high flow rates and bile acids, whereas colonic mucosa is exposed to many more bacteria. Architecturally, the ileum contains villi, structures that are absent in the colon. The cell composition of ileal mucosa has more endocrine and Paneth cells compared with colonic mucosa, and goblet cells of ileal mucosa contain primarily sialomucins rather than the sulfomucins of colonic goblet cells. Immunologically, the ileum has higher concentrations of lymphoid tissue including prominent Peyer’s patches. Furthermore, the flora differs between the ileum and the colon [12]. Regional differences in microflora have been implicated in many intestinal diseases, including cancer and inflammatory bowel disease.

O6

There are few case reports of adenocarcinomas at the ICJ, and no study of these carcinomas in general. Previous studies have found differences between right- and left-colonic carcinomas, including epidemiological, clinical, molecular and biological differences [13–15]. The present study attempted to characterize carcinomas at the ICJ and compare them with carcinomas of the terminal ileum and colon. Our findings suggest that ICJCAs differ significantly from carcinomas of the distal colon. More enlightening, however, is that ICJ-CAs have some differences from right-colonic carcinomas. Perhaps the most important finding that may impact clinical management is the statistically significant finding of higher N-stage in ICJ-CAs compared with rightcolonic carcinomas. Previous studies indicate that right-sided tumours are generally of higher stage than left-sided tumours [15]; however, our finding that ICJCAs are higher stage than other right-sided cancers has not been previously described. This may be a result of slower tumour growth in that location and/or because the local larger luminal space allows the tumours to grow for longer before presentation. Whilst ICJ-CAs might be expected to cause earlier clinical symptoms by obstructing the ICV, the fluidity of ileal contents may allow easy flow through a partially obstructed ICV. Notably, ICJ-CAs do not have a worse overall or disease-specific prognosis compared with right-sided carcinomas, according to our current definition of ICJ-CAs (i.e. epicentre within 5 cm of the ICV). However, if a more stringent definition of ICJ-CA (to include only those carcinomas that actually involve the ICV) is used, a difference in prognosis is shown, primarily focused in the early time frame of approximately 2 years. Here, there is dramatic survival drop-off of patients with ICV cancers compared with those with cancers of the remainder of the right colon. After this time period, patients with ICV cancers primarily die of unrelated causes. The reason for this appears to be the higher Nstage (i.e. more lymph node metastasis) of these ICV

Colorectal Disease ª 2014 The Association of Coloproctology of Great Britain and Ireland. 17, O1–O9

L. H. Lee et al.

cancers as it is the only measure of aggressiveness that is significantly different between ICV cancers and those of the right colon (P = 0.005). Although this more stringent definition of ICJ-CA provides a prognostic difference, it would be debatable whether it is biased. Logically, adding the stipulation that ICJ-CAs should involve the ICV would bias towards larger cancers (tumour length: 4.8  2.1 cm for ICJ-CA on ICV vs 4.1  1.9 cm for other right cancers, P = 0.003). However, the T-stage (i.e. depth of invasion) of carcinoma, which is an established prognostic indicator, was not different (P = 0.092) and thus one may argue that this definition is nevertheless useful. There may be additional reasons for more advanced carcinomas at the ICJ. Incomplete colonoscopy has been an issue because the right colon is more difficult to visualize fully and has less effective bowel preparation. Furthermore, right-sided adenomas are more often sessile and thus are more easily missed [16]. The number of cancers at the ICJ is also higher than would be expected if there was an even distribution throughout the colon. There were 19.9 cancers/cm in the ICJ region (199 cancers, 10 cm). Considering only the caecal-centred cancers, there were 36.4 cancers/cm (182 cancers, 5 cm). Using the US National Cancer Institute [17] estimates of the average colon component lengths, the carcinoma density is 3.3 cancers/cm (208 cancers, 63 cm) in the right colon, 3.0 cancers/cm (192 cancers, 65 cm) in the left colon and 39.8 cancers/cm (518 cancers, 13 cm) in the rectum (including the cancers that received neoadjuvant therapy). Thus, ICJ-CAs occur at a much higher density than do those of the right colon and left colon and at a similar rate as those in the rectum. This increased rate may be the result of the ICJ being a TZ, as increased rates are seen in other TZs. Compared with squamo-columnar junctions, however, the ICJ is a columnar-columnar junction in which metaplasia is not readily observed. The most well-studied columnar-columnar junction is the periampullary region, defined as within 2 cm of the ampulla of vater [18]. This region has the highest incidence of carcinoma in its vicinity and contains the majority of duodenal and biliary carcinomas [19]. Similarly to the ICJ, it includes the border of two glandular mucosas and is exposed to different secretions. Although periampullary adenocarcinomas can be subdivided into intestinal and pancreatobiliary types [20], they are grouped as one entity with a unique staging system because their prognosis is better than cancers of the same mucosa away from the ampulla [18]. Why this is so remains uncertain; it may be a result of early symptom occurrence or of differences in tumour biology. Our ICJ-CA data are

Ileocaecal junction carcinomas

similar, with two major populations of tumours: adenocarcinomas and neuroendocrine carcinomas concentrated on the caecal and ileal sides, respectively (Table 2). Whether ICJ-CAs should be segregated as an entity distinct from right-sided colon cancers and terminal ileum cancers requires further investigation. However, the ICJ region is more complex because the appendiceal orifice is frequently in close proximity (within 5 cm) to the ICV. Although the caecal and appendiceal mucosa is considered to be the same, and so the region not generally thought of as a TZ, differences still exist, especially because unique cancer types arise from the appendix. In this study, although ICJCAs differed from appendiceal tumours in several ways (Table 1), a proportion of ICJ-CAs may have originated from the appendix. It is not possible to state firmly that the nine (4.5%) cases with tumour involving both appendix and caecum originate from caecal, rather than appendiceal, mucosa. Thus, some ICJ-CAs may originate from the appendix and contribute to some ICJ-CA features, such as the increased prevalence of mucinous, signet-ring and neuroendocrine features. The biology of why TZs have increased cancer rates is unclear, is probably multifactorial and may be site specific [21]. TZs, such as the gastro-oesophageal junction, are a niche location for stem cells that are subject to tumour formation in response to changes in the microenvironment [22]. In squamo-columnar junctions, the TZ possesses signalling pathways, some similar to that of epidermal wound healing, that also predispose to carcinoma development [23]. These factors would need to be studied in detail at the ICJ. Whether ICJ-CAs have distinct molecular pathways compared with right-colonic carcinomas has not been studied, and no literature exists regarding the molecular pathology of cancers around the ICV. It is known that colorectal cancers generally arise from two distinct pathways, namely the serrated pathway and the adenoma– carcinoma sequence [24]; however, our data do not show any significant difference in pre-existing adenomas between ICJ-CAs and carcinomas of other colonic regions, including the right colon. Furthermore, the trend for increased mucinous and signet-ring features compared with right-colonic carcinomas may suggest an increased proportion of microsatellite instability (MSI) tumours [24]. It would be interesting to study whether Lynch syndrome or CpG island methylator phenotype (CIMP) tumours are over-represented in patients with ICJ-CAs. We have not yet pursued further studies at the molecular level. Nevertheless, our data would hopefully provide some clues to draw the attention of researchers to this particular region of bowel. More generally, whilst current understanding of colon cancer

Colorectal Disease ª 2014 The Association of Coloproctology of Great Britain and Ireland. 17, O1–O9

O7

L. H. Lee et al.

Ileocaecal junction carcinomas

molecular pathology divides them into right- and leftsided cancers, new research is suggesting that it may be more a continuum, with molecular changes gradually shifting from across the colon [25,26]. ICJ-CAs may be even more distinct because of their location at a TZ, but this requires targeted molecular investigation. There are limitations to our study. There is currently no other established definition of what should be classified as ICJ-CA, and the ICJ is a difficult region to define. Another limitation is our general exclusion of patients who received neoadjuvant therapy, although this primarily affects our comparisons with rectal cancers. We did account for these treated carcinomas by including them in appropriate areas of our analyses. Finally, we did not adjust for confounders, such as ethnicity, that are known factors affecting the type and location of intestinal cancers.

3

4 5

6

7

8

Conclusion 9

Carcinomas of the ICJ region appear to have some distinct features. They differ from left-colonic carcinomas in several aspects, and they are of higher N-stage than the other right-colonic carcinomas. As defined in this study, ICJ-CAs do not have a survival difference from right-colonic cancers. However, a survival difference is seen when looking at the subset of ICJ-CAs that involves the ICV, with a particularly early onset of death. Whether unique clinical management is required remains unknown and would be an important future study. Owing to the trend of increased mucinous and signet-ring features compared with right-colon carcinomas, it would be important to study whether MSI or CIMP tumours are over-represented in ICJ-CAs.

10

11 12

13

14

Acknowledgements We would like to acknowledge Jianguo Zhang for his statistical consult in the data analysis.

15

Author contributions Study conception and design: VF, XG. Acquisition of data: LHL, ARM, XG, VF. Analysis and interpretation of data: LHL, ARM, XG. Writing manuscript: LHL, XG.

16

17

References

18

1 Fluhmann CF. Carcinoma in situ and the transitional zone of the cervix uteri. Obstet Gynecol 1960; 16: 424–37. 2 Trudgill NJ, Suvarna SK, Royds JA, Riley SA. Cell cycle regulation in patients with intestinal metaplasia at the

O8

19

gastro-oesophageal junction. Mol Pathol 2003; 56: 313–7. McKelvie PA, Daniell M, McNab A, Loughnan M, Santamaria JD. Squamous cell carcinoma of the conjunctiva: a series of 26 cases. Br J Ophthalmol 2002; 86: 168–73. Grodsky L. Transitional cell cancer of the anus and rectum. Calif Med 1961; 95: 386–90. Siewert JR, Stein HJ. Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg 1998; 85: 1457–9. Soga J. Carcinoids of the colon and ileocecal region: a statistical evaluation of 363 cases collected from the literature. J Exp Clin Cancer Res 1998; 17: 139–48. Y€ or€ uk G, Aks€ oz K, Buyracß Z, Unsal B, Nazli O, Ekinci N. Adenocarcinoma of the ileocecal valve: report of a case. Turk J Gastroenterol 2004; 15: 268–9. Puppa G, Sonzogni A, Colombari R, Pelosi G. TNM staging system of colorectal carcinoma: a critical appraisal of challenging issues. Arch Pathol Lab Med 2010; 134: 837–52. American Joint Committee on Cancer. AJCC cancer staging manual, 7th edn. New York: Springer, 2010. Shia J, Tickoo SK, Guillem JG et al. Increased endocrine cells in treated rectal adenocarcinomas: a possible reflection of endocrine differentiation in tumor cells induced by chemotherapy and radiotherapy. Am J Surg Pathol 2002; 26: 863–72. Aklilu M, Eng C. The current landscape of locally advanced rectal cancer. Nat Rev Clin Oncol 2011; 8: 649–59. Ahmed S, Macfarlane GT, Fite A, McBain AJ, Gilbert P, Macfarlane S. Mucosa-Associated Bacterial Diversity in Relation to Human Terminal Ileum and Colonic Biopsy Samples. Appl Environ Microbiol 2007; 73: 7435–42. Benedix F, Schmidt U, Mroczkowski P et al. Colon carcinoma–classification into right and left sided cancer or according to colonic subsite? –Analysis of 29,568 patients. Eur J Surg Oncol 2011; 37: 134–9. Fazeli MS, Adel MG, Lebaschi AH. Colorectal carcinoma: a retrospective, descriptive study of age, gender, subsite, stage, and differentiation in Iran from 1995 to 2001 as observed in Tehran University. Dis Colon Rectum 2007; 50: 990–5. Benedix F, Kube R, Meyer F et al. Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum 2010; 53: 57–64. Bianco MA, Cipolletta L, Rotondano G et al. Prevalence of nonpolypoid colorectal neoplasia: an Italian multicenter observational study. Endoscopy 2010; 42: 279–85. SEER Training: Anatomy of Colon and Rectum. http:// training.seer.cancer.gov/colorectal/anatomy/. Sarmiento JM, Nagomey DM, Sarr MG, Farnell MB. Periampullary cancers: are there differences? Surg Clin North Am 2001; 81: 543–55. Beger HG, Treitschke F, Gansauge F, Harada N, Hiki N, Mattfeldt T. Tumor of the ampulla of Vater: experience

Colorectal Disease ª 2014 The Association of Coloproctology of Great Britain and Ireland. 17, O1–O9

L. H. Lee et al.

with local or radical resection in 171 consecutively treated patients. Arch Surg 1999; 134: 526–32. 20 Schirmacher P, B€ uchler MW. Ampullary adenocarcinoma differentiation matters. BMC Cancer 2008; 8: 251. 21 Mcnairn AJ, Guasch G. Epithelial transition zones: merging microenvironments, niches, and cellular transformation. Eur J Dermatol 2011; 21(Suppl 2): 21–8. 22 Ishimoto T, Oshima H, Oshima M et al. CD44+ slow-cycling tumor cell expansion is triggered by cooperative actions of Wnt and prostaglandin E2 in gastric tumorigenesis. Cancer Sci 2010; 101: 673–8.

Ileocaecal junction carcinomas

23 Sch€afer M, Werner S. Transcriptional control of wound repair. Annu Rev Cell Dev Biol 2007; 23: 69–92. 24 Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 2007; 50: 113–30. 25 Kaz AM, Wong C-J, Dzieciatkowski S, Luo Y, Schoen RE, Grady WM. Patterns of DNA methylation in the normal colon vary by anatomical location, gender, and age. Epigenetics 2014; 9: 492–502. 26 Kim H-S. Site-specific colorectal cancer; how is it different? Korean J Gastroenterol 2013; 61: 63–70.

Colorectal Disease ª 2014 The Association of Coloproctology of Great Britain and Ireland. 17, O1–O9

O9

Ileocaecal junction carcinoma: a clinicopathological study of 199 cases.

The ileocaecal junction (ICJ) region is an epithelial transition zone in which carcinomas are frequently diagnosed. However, it is currently unknown w...
717KB Sizes 0 Downloads 3 Views