International Journal of Colorectal Disease

, Volume 25, Issue 9, pp 1087–1092

Clinicopathological characteristics of rectal carcinoids

Authors

  • Sang Nam Yoon
    • Department of SurgeryUniversity of Ulsan College of Medicine and Asan Medical Center
  • Chang Sik Yu
    • Department of SurgeryUniversity of Ulsan College of Medicine and Asan Medical Center
  • Ui Sup Shin
    • Department of SurgeryUniversity of Ulsan College of Medicine and Asan Medical Center
  • Chan Wook Kim
    • Department of SurgeryUniversity of Ulsan College of Medicine and Asan Medical Center
  • Seok-Byung Lim
    • Department of SurgeryUniversity of Ulsan College of Medicine and Asan Medical Center
    • Department of SurgeryUniversity of Ulsan College of Medicine and Asan Medical Center
Original Article

DOI: 10.1007/s00384-010-0949-y

Cite this article as:
Yoon, S.N., Yu, C.S., Shin, U.S. et al. Int J Colorectal Dis (2010) 25: 1087. doi:10.1007/s00384-010-0949-y

Abstract

Purposes

Carcinoids are heterogeneous neuroendocrine tumors with malignant potential. The rectum is the third most common location for gastrointestinal carcinoids. We assessed the clinicopathological characteristics of rectal carcinoids.

Methods

A retrospective study of 203 patients treated for rectal carcinoids at the Asan Medical Center, Seoul, Republic of Korea from 1991 to 2007.

Results

The patients were on average 51 (18–83) years old. The male-to-female ratio was 1.48:1. Over half (62.1%) of the patients were asymptomatic. The most frequent symptoms in the symptomatic patients were abdominal pain (11.1%) and hematochezia (10.7%). Local excision was applied to 92.1%, low anterior resection to 4.9%, and biopsy only to 3.0% of total patients. Initially, 4.4% presented with distant metastasis. Distant metastasis rates for tumors ≤1 cm, >1 to ≤2 cm, and >2 cm were 1.7% (3/177), 15.0% (3/20), and 50.0% (3/6), respectively. In the follow-up period, three patients showed recurrences. The size, lymphovascular invasion, perineural invasion, and T and N stages were associated with distant metastasis. The overall 5-year survival rate was 94.0%. The TNM stage and presence of lymphovascular invasion were associated with lower survival.

Conclusions

The chance that a rectal carcinoid will develop distant metastases increases as the tumor increases in size, lymphovascular invasion or perineural invasion is present, and T and N stages increase. The TNM stage and presence of lymphovascular invasion were associated with lower survival. Treatment plan should be chosen carefully considering above factors.

Keywords

Rectal carcinoidsTumor sizeDepth of invasionLymph node metastasisLymphovascular invasionPerineural invasionDistant metastasis

Introduction

Carcinoids arise from the Kulchitsky’s cells in the crypts of Lieberkűhn and are morphologically and biologically heterogeneous neuroendocrine tumors that have a malignant potential. In 1867, Langhans [1] first described a gut carcinoid tumor, and in 1907, Oberndorfer differentiated carcinoid tumors from carcinomas of the gastrointestinal tract [2]. However, it was not until the work of Gosset and Mason [3] in 1914 that it was understood that carcinoids are endocrine-related tumors. Gastrointestinal carcinoids are currently referred to as gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Despite several reclassifications of GEP-NETs by the World Health Organization, the term “carcinoid” is still used as a synonym of “well differentiated NET” and the term “malignant carcinoid” is used as a synonym of “well differentiated neuroendocrine carcinoma” [4]. Patients who develop carcinoid tumors have a higher risk (approximately 55%) for developing synchronous and metachronous nonendocrine malignancies, most commonly adenocarcinomas of the gastrointestinal and genitourinary system [5].

The rectum is the third most common location for gastrointestinal carcinoids next to the small bowel and colon (including the appendix) [6], but rectal carcinoids comprise only 1–2% of all rectal tumors [7]. Rectal carcinoids are epithelial tumors that develop in the deep portion of glands. They typically invade through the muscularis mucosa into the submucosa and resemble submucosal tumors [8]. Carcinoid syndrome (cutaneous flushing, gut hypermotility, and diarrhea) occurs only very rarely in patients with rectal carcinoids [9].

Compared to other carcinoids of the gastrointestinal tract, rectal carcinoids are the smallest. The Surveillance Epidemiology and End Results database has shown that the median size of primary tumors in the rectum is 0.6 cm (which is also what we observed in this study), while the median size for tumors in the other organs is somewhat greater exhibiting 1–3 cm [10]. However, rectal carcinoids that are less than 1 cm in size can still have a significant malignant potential, as the recorded incidence of metastasis for these tumors ranges from 1.7% to 3.4% [11, 12].

Some factors, including tumor size, have been reported to be associated with distant metastasis and lower survival rates. While clearly metastasis becomes more common as the size of the primary tumor increases, it is currently difficult to decide between treatments such as local excision and radical surgery, especially for tumors that are <1 to ≥2 cm in diameter. The aim of this study was to summarize our experiences with rectal carcinoids and to identify factors that are associated distant metastasis and lower survival.

Patients and methods

Patients

Two hundred and six consecutive patients were treated for rectal carcinoids endoscopically or surgically at the Asan Medical Center, Seoul, Republic of Korea from February 1991 to February 2007. Three patients who underwent surgery for synchronous colorectal carcinoma were excluded. A total of 203 rectal carcinoid patients were retrospectively reviewed. The demographic data, symptoms, the procedures performed, the presence of metastases at presentation, the gross and histological findings of the tumors, and the survival status at follow-up were recorded.

The diagnosis of rectal carcinoids was usually made by endoscopy and confirmed by routine hematoxylin and eosin staining and immunohistochemistry for the presence of synaptophysin and chromogranin. Endoscopic ultrasound (EUS) and somatostatin receptor scintigraphy (SRS) were not performed routinely.

Local excision included endoscopic snare polypectomy, transanal excision (TAE), and transsphincteric resection (TSR). Low anterior resection (LAR) was performed as a radical surgery, except for unresectable liver metastasis in some cases. Snare polypectomy was performed for most of the patients endoscopically treated. Endoscopic submucosal dissection (ESD) or transanal endoscopic microsurgery (TEM) were not performed in this series.

The median values of the actual follow-up period and follow-up period for survival were 20 (0–179) months and 53 (6–213) months, respectively. The median actual follow-up periods for local excision, LAR, and biopsy-only cases were 19.3 (0–179), 39.5 (3–65), and 13.3 (3–48) months, respectively. The patients who were treated surgically were followed up at least once a year with abdominal and pelvic computed tomography and sigmoidoscopy or colonoscopy. Although most of the patients who were treated endoscopically were lost from follow-up and disease status was unknown, the survival status of them was accurate because we took it from the database of the National Health Institute Corporation, and in result, follow-up period for survival analysis is different from the actual follow-up period. Accordingly, the authors dealt with overall survival rather than disease-free survival.

TNM staging system

The TNM staging system proposed by Landry et al. [10] was used to predict prognosis. T1 includes primary tumor’s depth of invasion up to and into muscularis propria in ≤1-cm-sized tumor and up to muscularis propria >1- to ≤2-cm-sized tumor. T2 indicates beyond muscularis propria in ≤1 cm, into muscularis propria in >1 to ≤2 cm, and up to and into muscularis propria in >2-cm-sized tumor. T3 is invasion beyond muscularis propria in >1-cm-sized tumor. N0 is no lymph node metastasis, and N1 indicates regional lymph node metastasis present. M0 is no distant metastasis, and M1 indicates distant metastasis present.

Statistics

Factors that were significantly associated with distant metastasis, including tumor size, depth of invasion, lymphovascular invasion (LVI), perineural invasion (PNI), and T and N stages were identified by binary logistic regression. Survival was estimated by the Kaplan–Meier method, and the factors associated with lower survival were evaluated by using the log rank test. A P value of less than 0.05 was considered statistically significant, and all calculations were performed by using SPSS software (version 12.0, SPSS Inc., Chicago, IL, USA).

Results

Treatment algorithm for all patients is shown in Fig. 1. At diagnosis, 4.4% presented with distant metastasis; 3.4% had hepatic metastases only and 1% had multiple metastases, including the liver. Seven of nine patients with distant metastasis received chemotherapy, namely, a combination of cisplatin and etoposide (four patients) or cisplatin only (three patients). Local excision was applied to 92.1% (snare polypectomy 78.3%, TAE 12.8%, and TSR 1.0%, LAR to 4.9%, and biopsy only to 3.0% of total patients due to unresectable distant metastasis. The distant metastasis rates for tumors on the basis of size ≤1 cm, >1 to ≤2 cm, and >2 cm were 1.7% (3/177), 15.0% (3/20), and 50.0% (3/6), respectively. Noticeably, three tumors ≤1 cm in size presented together with distant metastases.
https://static-content.springer.com/image/art%3A10.1007%2Fs00384-010-0949-y/MediaObjects/384_2010_949_Fig1_HTML.gif
Fig. 1

Treatment algorithm for all patients. LAR low anterior resection, CRC colorectal cancer, TAE transanal excision, TSR transsphincteric resection. Asterisk means that of nine patients with distant metastasis, seven (3.4%) had hepatic metastases only and two (1%) had multiple metastases, including the liver. The dagger sign means that the patient with 3.0-cm-sized rectal carcinoids underwent TAE rather than LAR because she had underlying Child C liver cirrhosis. The sizes in each box indicate a median value with minimum to maximum range of the sizes of rectal carcinoids

Total nine patients had lymph node metastasis; lymph node metastasis was identified on a histological examination in six patients who underwent low anterior resection, and it was suspected by computed tomography in three patients who underwent biopsy only due to unresectable distant metastasis. Among seven LAR cases without distant metastasis, four cases had lymph node metastasis identified on a histological examination. However, in the other three patients, LAR was performed because their rectal carcinoids showed a nonlifting sign on endoscopy. Of three LAR cases with distant metastasis, two cases were identified to have lymph node metastasis on a histological examination, and the other one was not.

The mean age of the patients was 50 (18–83) years, and the male-to-female ratio was 1.48:1. Over half (62.1%) of the patients were asymptomatic. The rest of the patients suffered from abdominal pain (11.3%), hematochezia (9.8%), diarrhea (6.4%), rectal pain (3.0%), and so on. One patient with liver metastasis who underwent palliative low anterior resection presented facial flushing. The median size and distance from the anal verge of the rectal carcinoids were 0.6 (0.1–4.3) cm and 7 (1–15) cm, respectively. The TNM stage of rectal carcinoids was the system proposed by Landry et al. [10]. Fifty patients (24.6%) had synchronous colorectal adenoma (Table 1). In immunohistochemistry for the presence of synaptophysin and chromogranin, 99% (99/100) and 46.2% (42/91) expressed these markers, respectively (Fig. 2).
Table 1

Clinicopathologic characteristics of 203 patients with rectal carcinoids

 

n (%)

Median (range)

Age

 

51.0 (18–83)

Male–Female

121:82 (59.6:40.4)

 

Distance from anal verge (cm)

 

7.0 (1–15)

Size (cm)

 

0.6 (0.1-4.3)

Depth of invasion

 Up to but not into MP

190 (93.6)

 

 Into MP

7 (3.4)

 

 Beyond MP

6 (3.0)

 

Lymphovascular invasion (yes/no)

7/196 (3.4/96.6)

 

Perineural invasion (yes/no)

4/199 (2.0/98.0)

 

Synaptophysin (positive/negative)

99/1 (99/1)

 

Chromogranin (positive/negative)

42/49 (46.2/53.8)

 

Synchronous colorectal adenoma (yes/no)

50/153 (24.6/75.4)

 

T1/2/3a

190/8/5 (93.6/3.9/2.5)

 

N0/1a

194/9 (95.6/4.4)

 

M0/1a

194/9 (95.6/4.4)

 

Stage I/II/III/IVa

188/5/1/9 (92.6/2.5/0.5/4.4)

 

MP muscularis propria

aProposed staging system by Landry et al. [10]

https://static-content.springer.com/image/art%3A10.1007%2Fs00384-010-0949-y/MediaObjects/384_2010_949_Fig2_HTML.gif
Fig. 2

Representative examples of tumors that show positive results upon immunohistochemical analysis. a Synaptophysin (×200): diffusely immunoreactive. b Chromogranin (×200): focally immunopositive

During follow-up period, three patients showed recurrences. One of these, a 60-year-old female, underwent LAR for a 1.5-cm-sized rectal carcinoid. The biopsy revealed invasion of the proper muscle layer and seven of nine lymph nodes were positive for metastasis. Her tumor recurred in the liver 1 year later, and she expired 5 years after the first operation. The second patient with recurrence was a 64-year-old male who underwent LAR and right lobectomy for a 2.8-cm-sized rectal carcinoid that was associated with a huge single hepatic metastasis; his tumor recurred in intra-abdominal lymph nodes 2 years later. Analysis of the biopsies revealed that two of eight lymph nodes were positive for metastasis, and LVI and PNI were present. The last patient with recurrence was a 39-year-old female who underwent TAE for her 3.0-cm-sized rectal carcinoid because she had Child C liver cirrhosis. The resection margin was focally positive. Local recurrence occurred 7 years later, and this necessitated two more TAE procedures. Of 187 patients who underwent local excision, 20 patients had positive resection margin, but only one case (the last above) recurred.

The size categories, LVI, PNI, T stage, and N stage were significantly associated with distant metastasis (Table 2). Depth of invasion had no significant association with distant metastasis. Multivariate analysis could not be calculated because of small number in each subgroup. The overall 5-year survival rate was 94.0%, and the TNM stage and presence of lymphovascular invasion were associated with lower survival (Fig. 3).
Table 2

Univariate analysis of factors associated with distant metastasis

Factors

OR

95% CI

P value

Size categories

≤1 cm (n = 177)

1

  

>1 to ≤2 cm (n = 20)

10.2

1.92–54.7

0.007

>2 cm (n = 6)

58.0

8.12–414

<0.001

Lymphovascular invasion

Absent (n = 196)

1

  

Present (n = 7)

23.8

4.32–130

<0.001

Perineural invasion

Absent (n = 199)

1

  

Present (n = 4)

27.4

3.36–224

0.002

T

T1 (n = 190)

1

  

T2 (n = 8)

56.4

7.652–416

<0.001

T3 (n = 5)

376

28.0–5045

<0.001

N

N0 (n = 194)

1

  

N1 (n = 9)

59.4

11.4–308

<0.001

OR odds ratio, CI confidence interval

https://static-content.springer.com/image/art%3A10.1007%2Fs00384-010-0949-y/MediaObjects/384_2010_949_Fig3_HTML.gif
Fig. 3

a Overall survival rate for all patients and overall survival rates according to the b TNM stage and c presence of lymphovascular invasion. LVI lymphovascular invasion

Discussion

The present study found that larger primary tumors are associated with a worse prognosis, which is consistent with previous reports [1113]. Overall 5-year survival rates were 96.7%, 87.7%, and 50.0% for tumors ≤1 cm, >1 to ≤2 cm, and >2 cm, respectively. However, the overall survival is not governed by size of the primary tumor alone. The TNM system proposed by Landry et al. [10] and presence of LVI were significantly associated with survival in this study.

EUS and SRS are the most recommended pretreatment investigational methods. It was suggested that most gastrointestinal carcinoids can be accurately diagnosed by EUS and conventional endoscopy [14]. Octreoscan (Mallinckrodt, Inc., St. Louis, MO, USA) is a commercially available kit for the preparation of 111-In pentetreotide. The overall sensitivity of scintigraphy using Octreoscan is reported to be 80–91% for neuroendocrine tumors [4, 15]. However, as a matter of fact, a few cases took these exams in this series. EUS has been recently introduced and performed for rectal carcinoids, especially with more than 1 cm in size. Regarding SRS in the current study, it appeared hard to obtain a specific radioactive reagent timely with its high cost in Republic of Korea, only a few patients have been examined with SRS.

Recently, ESD and TEM were introduced for local excision of rectal carcinoids. It was reported that the size and shape of the excised tissue are better controlled, and en bloc resection is possible even with large tumors [16]. TEM is a minimally invasive procedure that can be used to excise small rectal lesions, which may be inaccessible or difficult to resect by TAE [17]. Endoscopic snare polypectomy was usually performed for small rectal carcinoids less than 1 cm in this series. ESD has been mostly performed for polyps in our hospital, but it is recently indicated for rectal carcinoids as well. TEM was not available during the study period.

There was only one recurrence among 20 patients with positive resection margin after local excision. The reason for very low recurrence rate cannot be clearly identified in patients with local excision, possibly assumed to be relatively short follow-up periods and cautery effect at the margin despite positive result on a biopsy.

Distant metastasis becomes clearly more commonly as the size of the primary tumor increases. However, rectal carcinoids that are less than 1 cm in size can still have a significant malignant potential ranging from 1.7% to 3.4% [11, 12]. Concurrently in our study, three of the 177 rectal carcinoids (1.7%) that were ≤1 cm in size were associated with distant metastasis upon initial presentation. Thus, one should remember that relatively small rectal carcinoids are also associated with the possibility of distant metastasis.

The results of LVI were reported to be associated with poor outcomes. Fahy et al. [11] showed that distant metastasis was significantly associated with LVI as with our study. Six of six patients with metastasis had LVI, while eight of 44 patients without metastasis had LVI. Koura et al. [12] revealed the negative impact of LVI and PNI on behavior of rectal carcinoids. “Typical” carcinoids, in their study, had no or rare mitotic cells and did not invade the lymphatics, blood vessels, perineurium, or muscularis propria. “Atypical” carcinoids, in contrast, had at least one of these features present. Five-year metastasis-free survival was 100% in 16 patients with “typical” carcinoids versus 50% in four patients with “atypical” carcinoids.

Some efforts have been made to clarify a treatment plan for rectal carcinoids. Kim et al. [18] reported that for tumors 1–1.9 cm in diameter, atypical endoscopic features (semipedunculated, ulcerofungating, hyperemia, central depression, erosion, and ulceration) are associated with metastasis [19]. This observation may help to determine adequate operations, namely, local excision or radical operation. Most of the endoscopic and pathologic reports did not mention above atypical endoscopic features, so the authors could not review these. In addition, Fahy et al. [11] proposed “carcinoid of the rectum risk stratification (CaRRs)” to predict outcome. CaRRs was graded high, intermediate, and low according to size, depth, LVI, and mitotic rate, and it correlated well with survival. In this study, mitotic rate was not reviewed due to limited availability of the tumor slides.

We were unable to draw specific treatment recommendations based upon the results of the current study, due to its retrospective nature and small numbers in each subgroup. However, it appears that small rectal carcinoids <1 cm in size can be safely managed by local excision. For tumors >1 to ≤2 cm, local excision is usually recommended, but radical surgery should be considered if there is evidence of lymph node metastasis or LVI on a biopsy. In contrast, for tumors >2 cm, radical surgery must be performed. Imaging studies such as computed tomography or magnetic resonance imaging is recommended for all patients with rectal carcinoids to rule out distant metastasis.

Conclusions

The chance that a rectal carcinoid will develop distant metastasis increases as the tumor increases in size, lymphovascular invasion or perineural invasion is present, and T and N stages increase. The TNM stage and presence of lymphovascular invasion were associated with lower survival. Treatment plan should be chosen carefully considering above factors.

Copyright information

© Springer-Verlag 2010