| Japanese Journal of Clinical Oncology | Pages |
Characteristics in Primary Signet-ring Cell Carcinoma of the Colorectum, from Clinicopathological Observations.
Introduction
Materials And Methods
Samples and DNA Preparation
Mutational Analysis of K-ras
Results
Discussion
Acknowledgment
References
Characteristics in Primary Signet-ring Cell Carcinoma of the Colorectum, from Clinicopathological Observations.
Background: The biological behavior of signet-ring cell carcinomas in colorectum tends to be worse than that of mucinous carcinomas. However, in previous studies, clinicopathological features of this disease have been somewhat ill-defined because various histological criteria of this disease were adopted.
Methods: We selected 11 cases of signet-ring cell carcinomas and 29 cases of mucinous carcinomas among 1595 consecutive colorectal carcinomas on defined criteria and compared clinicopathological and molecular biological features between these two types of carcinomas.
Results: Clinical stagings of signet-ring cell carcinomas were far advanced and their prognosis tended to be worse than that of mucinous carcinomas. Furthermore, the incidence of K-ras mutations in signet-ring cell and mucinous carcinomas showed no difference between these two types of carcinomas. However, the incidence of K-ras mutation in these diseases was slightly lower than that in 30 ordinary colorectal carcinomas examined as a comparison.
Conclusions: These results suggest that the carcinogenesis of signet-ring cell and mucinous carcinomas are different from that of ordinary colorectal carcinomas and that there may exist other genes related to malignancy of signet-ring cell carcinomas.
INTRODUCTION
Signet-ring cell and mucinous carcinomas are similar in possessing an extensive mucinous component (1). In signet-ring cell carcinomas, especially, this intracytoplasmic mucinous component pushes its nucleus to the peripheral side, showing its characteristic morphological appearance. However, there are some clinicopathological differences between these two variants of colorectal adenocarcinomas. Previous studies showed that the biological behavior of signet-ring cell carcinomas tends to be worse than that of mucinous carcinomas (1-3). As various histological criteria of signet-ring cell carcinomas were adopted in previous studies, clinicopathological features of this disease have been somewhat ill-defined. For instance, in some studies signet-ring cell carcinomas were considered to be linitis plastica. However, Laufman and Saphir (4) reported that primary linitis plastica carcinoma should be classified into several groups according to the histologic growth pattern. Furthermore, Nakahara et al. (5) and Shirouzu et al. (3) reported that one fifth or sixth of linitis plastica carcinomas were signet-ring cell carcinomas. In this study we adopted the histological criteria directed by the World Health Organization (6), in the same way as several reports by Messerini et al. (2) and other authors (7-9), and compared clinicopathological features between signet-ring cell and mucinous carcinomas.
Mucinous and signet-ring cell carcinomas are of much higher prevalence in patients with long-standing, extensive ulcerative colitis than in the general population (10), and the non-polypoid morphology is assumed to be characteristic in this setting (11). Chaubert et al. (12) reported that the prevalence of K-ras and p53 mutations found in ulcerative colitis-associated colonic carcinomas appears to be lower than in sporadic carcinomas, and Yamagata et al. (13) also reported that the macroscopically flat type of carcinoma complicating ulcerative colitis had no K-ras mutation. These results suggested that the incidence of K-ras mutation would be low in mucinous and signet-ring cell carcinomas. However, there have been no previous reported studies on this point. We therefore examined K-ras mutations in all samples of mucinous and signet-ring cell carcinomas in our series.
MATERIALS AND METHODS
Samples and DNA Preparation
Among 1595 consecutive colorectal carcinomas surgically resected at the First Department of Surgery, the University of Tokyo from January 1963 to December 1996, we selected 40 cases in which the tumor contained [ge]50% of mucinous component as revealed by HE staining. Furthermore, we differentiated signet-ring cell carcinomas from mucinous carcinomas according to the following criteria defined by Laufman and Saphir (4). Their pathologic criteria of primary signet-ring cell carcinoma of the colorectum were as follows: 1, presence of signet-ring cells; 2, formation of immature or abortive glands; and 3, occurrence of anaplastic cells with monocytoid features. Furthermore, in accordance with World Health Organization directives (6), we added the following restrictions to clarify the feature of signet-ring cell carcinoma and to deny the possibility of metastasis from other cancers: 4, the presence of another primary cancer was excluded; and 5, the proportion of signet-ring cells among neoplastic cells was >50%. Ultimately, we selected 11 cases (0.69%) with signet-ring cell carcinomas and 29 cases (1.82%) with mucinous carcinomas.
The patient records and pathological reports were reviewed according to the Rules of the Japanese Society for Cancer of the Colon and Rectum (14). DNAs were extracted from archival formalin-fixed, paraffin embedded tissue blocks, and purified as described previously (15).
The [chi]2 test was used to analyze clinical differences between signet-ring cell and mucinous carcinomas but not for the mean age and duration of symptoms, for which Student's t-test was used, while the Kaplan-Meier method was used to produce survival curves. The log rank test was used to analyze differences in probability of survival.
Mutational Analysis of K-ras
Because most K-ras mutations in colorectal carcinomas occur at codon 12, we screened for mutations at this site in all samples and in 30 ordinary advanced colorectal carcinomas as a control. Mutational analysis was performed using the 2-step sensitive PCR method as described by Yamagata et al. (16)
RESULTS
The mean age of patients with signet-ring cell carcinomas was 46.3 years and that of patients with mucinous carcinomas was 60.2 years (Table 1 and
Table 1. .
| No. | Sex | Age (yr) | Chief complaint | Site | Size (mm) | Duration of symptoms (months) | P | H | Stage | Operation | Survival after operation (days) |
| 1 | F | 26 | Abd. pain, mass | T | 90 | 6 | 0 | 0 | II | RHC | 693 |
| 2 | M | 24 | Abd. pain | S | 80 | 0.5 | 0 | 0 | II | Sigmoidectomy | 797 |
| 3 | F | 38 | Abd. pain, hematochezia | S | 150 | 4 | 3 | 0 | IV | Colostomy | 68 |
| 4 | F | 78 | Abd. pain, mass, vomit | D | 100 | 2 | 0 | 0 | IV | Bypass | 63 |
| 5 | F | 40 | Abd. pain | Rb | >80 | 2 | 3 | 0 | IV | Colostomy | 112 |
| 6 | M | 34 | Hematochezia | S | >80 | 5 | 2 | 0 | IV | Colostomy | 108 |
| 7 | M | 57 | Abd. pain, constipation | S | 80 | 3 | 1 | 3 | IV | Colostomy | 64 |
| 8 | F | 56 | Abd. pain | C | 120 | 3 | 3 | 0 | IV | Explatory lapa. | 151 |
| 9 | F | 67 | Abd. fullness, constipation | Rb | 100 | 1 | 3 | 3 | IV | Colostomy | 149 |
| 10 | F | 47 | Abd. pain, abd. fullness | D | >80 | 2 | 3 | 0 | IV | Ileostomy | D.O. |
| 11 | F | 42 | Abd. pain, hematochezia | S | 145 | 2 | 2 | 0 | IV | Sigmoidectomy | 351 |
Table 2.
| Signet-ring cell carcinoma (11 cases) | Mucinous carcinoma (29 cases) | Statistics (P) | |
| Mean age (years) | 46.3 ± 16.8 | 60.2 ± 12.6 | <0.01 |
| Ratio of male to female | 0.38 | 1.23 | 0.11 |
| Chief complaint | |||
| Abdominal pain | 9 (81.8%) | 11 (37.9%) | |
| Bowel habit abnormalities | 5 (45.5) | 13 (44.8) | |
| Abdominal fullness | 2 (18.2) | 2 (6.9) | |
| Abdominal mass | 2 (18.2) | ||
| Duration of symptoms (months) | 2.8 ± 1.7 | 7.6 ± 5.5 | <0.01 |
| Site | |||
| Distal | 9 (81.8%) | 16 (55.2%) | |
| Proximal | 2 (18.2) | 13 (44.8) | 0.12 |
| Size | |||
| [ge]8cm | 11 (100%) | 6 (21.4%) | |
| <8cm | 0 | 22 (78.6) | <0.00001 |
| P | |||
| P0 | 3 (27.3%) | 22 (78.6%) | |
| P1 | 1 (9.1) | 1 (3.6) | |
| P2 | 2 (18.2) | 1 (3.6) | |
| P3 | 5 (45.4) | 4 (14.2) | |
| P0/P1-3 | <0.01 | ||
| H | |||
| H0 | 9 (81.8%) | 28 (96.6%) | |
| H3 | 2 (18.2) | 1 (3.4) | 0.11 |
| n | |||
| n0 | 4 (40.0%) | 17 (58.6%) | |
| n1 | 0 | 4 (13.8) | |
| n2 | 0 | 8 (27.6) | |
| n3 | 2 (20.0) | 0 | |
| n4 | 4 (40.0) | 0 | <0.00001 |
| n0-2/n3,4 | |||
| Stage | |||
| I | 0 | 1 (3.4%) | |
| II | 2 (18.2%) | 11 (38.0) | |
| III | 0 | 9 (31.0) | |
| IV | 9 (81.8) | 8 (27.6) | |
| Stage I-III/Stage IV | <0.01 | ||
K-ras mutations at codon 12 were detected in four out of 11 cases (36.4%) of signet-ring cell carcinomas (Fig.
DISCUSSION
Figure 1. The Kaplan-Meier survival curve of 11 signet-ring cell carcinoma patients([squ]) and 29 mucinous carcinoma patients ([cir]). There was a significant difference in survival rates between the two groups (P < 0.0001). Figure 2. Mutational analysis of K-ras using the 2-step sensitive PCR method. Templates are DNA extracted from signet-ring cell carcinoma patients (S1-S8). Four of these samples (S1-S4) exhibited a band of mutant allele as well as a band of normal allele. Marker: [phis] × 174/HaeIII DNA marker.
In our study the frequency of signet-ring cell carcinoma was 0.69%, which was consistent with the figures in several previous studies (2,17,18). However, its frequency was >10% in other studies (19,20). This discrepancy was assumed to be unavoidable because histological criteria of signet-ring cell carcinoma were extremely variable in these studies. Hence, clinical data of this disease have been very variable. We diagnosed in accordance with World Health Organization directives (6), whose histologic criterion was that a signet-ring cell carcinoma contained >50% typical signet-ring cells. Two out of 11 signet-ring cell carcinomas selected in this study contained a component of poorly differentiated adenocarcinomas and the others were mainly composed of signet-ring cell and mucinous carcinomas. Shirouzu et al. (3) classified the former as scirrhous type and the latter as lymphangiosis type, and reported that these two types of signet-ring cell carcinomas exhibited different growth patterns and that their biological behavior was different. Furthermore, there was the possibility of conversion of colorectal carcinomas from signet-ring cell to mucinous carcinomas. However, in this study, we defined signet-ring cell carcinomas according to the World Health Organization directives without dividing them into subgroups. Although the proportion of mucinous carcinoma patients who were followed up (59%) was smaller than that of signet-ring cell carcinoma patients (91%), our study based on this criterion revealed that the prognosis of signet-ring cell carcinomas in the colorectum tended to be worse than that of mucinous carcinomas, as reported in previous studies. This was because tumor size of signet-ring cell carcinomas was so large and clinical stagings so advanced that curative operations for this disease were almost impossible. High frequency of peritoneal dissemination and central node involvement were especially noteworthy. Although Almagro (1) stressed the need for awareness and recognition of this disease at an earlier stage, it would be extremely difficult in clinical settings because most of the symptoms in signet-ring cell carcinomas were nonspecific, and the average duration of symptoms was only 2.8 months. Little has been known about the prevalence of inflammatory bowel disease among signet-ring cell and mucinous carcinomas. In our study there was no mucinous carcinoma associated with ulcerative colitis. However, two out of 11 signet-ring cell carcinoma cases (18.2%) were associated with long-standing and extensive ulcerative colitis. Conversely, Choi and Zelig (10) reported that mucinous or signet-ring cell carcinomas were associated with much higher prevalence in patients with long-standing, extensive ulcerative colitis than in the general population. Furthermore, Tytgat et al. (11) pointed out that non-polypoid morphology was assumed to be characteristic in carcinomas derived from inflammatory bowel disease. From this evidence, we concluded that signet-ring cell carcinomas and mucinous carcinomas might be derived from non-polypoid type of carcinomas, which exhibit low incidence of K-ras mutation (13,16). To test this hypothesis, we screened K-ras mutation in all samples and in 30 ordinary advanced colorectal carcinomas. As a result, we detected K-ras mutations at codon 12 in four cases (36.4%) of signet-ring cell carcinomas, 11 cases (37.9%) of mucinous carcinomas and 18 cases (60.0%) of ordinary carcinomas. There was no difference between signet-ring cell carcinomas and mucinous carcinomas. However, the incidence of K-ras mutation in these diseases was slightly lower than that in the ordinary colorectal carcinomas. These results suggest that the carcinogenesis of signet-ring cell and mucinous carcinomas may be different from that of ordinary colorectal carcinomas. This study suggested the possibility that signet-ring cell carcinomas in the colorectum grow more rapidly than mucinous carcinomas. From the genetic aspect, some alterations relating to rapid growth of signet-ring cell carcinomas may happen during a tumor's growth. Further study is needed to identify genetic alterations involved in carcinogenesis of signet-ring cell carcinomas.
Acknowledgment
This study was supported in part by a grant-in-aid from the Ministry of Health and Welfare of Japan.
References
For reprints and all correspondence: Shin Sasaki, First Department of Surgery, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113, Japan
E-mail: SASAKI-1SU@h.u-tokyo.ac.jp
This page is run by Oxford University Press, Great Clarendon Street, Oxford OX2 6DP, as part of the OUP Journals
Comments and feedback: www-admin{at}oup.co.uk
Last modification: 19 May 1998
Copyright© Japanese Journal of Clinical Oncology, 1998.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E. T. Park, H. K. Oh, J. R. Gum Jr., S. C. Crawley, S. Kakar, J. Engel, C. C. Leow, W.-Q. Gao, and Y. S. Kim HATH1 Expression in Mucinous Cancers of the Colorectum and Related Lesions. Clin. Cancer Res., September 15, 2006; 12(18): 5403 - 5410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. I. Wistuba, C. Behrens, J. Albores-Saavedra, R. Delgado, F. Lopez, and A. F. Gazdar Distinct K-ras Mutation Pattern Characterizes Signet Ring Cell Colorectal Carcinoma Clin. Cancer Res., September 1, 2003; 9(10): 3615 - 3619. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||