characteristics in primary signet-ring cell carcinoma of the.pdf

7/27/2019 Characteristics in Primary Signet-ring Cell Carcinoma of the.pdf

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Jpn J Clin OncoI1998;28(3)202-206

Characteristics in Primary Signet-ring Cell Carcinoma of theColorectum, from Clinicopathological Observations.Shin Sasaki, Tadahiko Masaki, Naoyuki Umetani, Noriaki Futakawa, Hidehiko Ando and Tetsuichiro MutoFirst Department of Surgery, University of Tokyo, Tokyo, Japan

Background: Thebiological behavior of signet-ring cell carcinomas in colorectum tendstobeworse than thatofmucinous carcinomas. However, inprevious studies, clinicopathological features of this disease have been somewhat ill-defined because varioushistological criteria of thisdisease were adopted.Methods: We selected 11 cases of signet-ring cell carcinomas and 29 cases of mucinouscarcinomas among 1595 consecutive colorectal carcinomasondefined criteria and comparedclinicopathological andmolecular biological features between these twotypes ofcarcinomas.Results: Clinical stagings of signet-ring cell carcinomas were far advanced and theirprognosis tended to be worse than that of mucinous carcinomas. Furthermore, theincidence of K-ras mutations in signet-ring cell andmucinous carcinomas showed nodifference between these two types of carcinomas. However, the incidence of K-rasmutation in these diseases was slightly lower than that in 30 ordinary colorectalcarcinomas examined as a comparison.Conclusions: These results suggest that the carcinogenesis of signet-ring cell andmucinous carcinomas aredifferent from that of ordinary colorectal carcinomas andthatthere mayexist othergenes related tomalignancy of signet-ring cellcarcinomas.Key words: signet-ring cell carcinoma - mucinous carcinoma - K-rasmutation - colorectal neoplasm

INTRODUCTIONSignet-ring cell andmucinous carcinomas aresimilar in possessingan extensive mucinous component (1). In signet-ring cell carcinomas, especially, this intracytoplasmic mucinous componentpushes its nucleus to the peripheral side, showing its characteristicmorphological appearance. However, there are some clinicopathological differences between these two variants of colorectaladenocarcinomas. Previous studies showed that the biologicalbehavior of signet-ring cell carcinomas tends to be worse than thatof mucinous carcinomas (1-3). As various histological criteria ofsignet-ring cell carcinomas were adopted in previous studies,clinicopathological features of this disease have been somewhatill-defmed. For instance, in some studies signet-ring cell carcinomas were considered to be linitis plastica. However, Laufmanand Saphir (4) reported that primary linitis plastica carcinomashould be classified into several groups according to the histologicgrowth pattern. Furthermore, Nakahara et al. (5) and Shirouzu etal. (3) reported that one fifth or sixth of linitis plastica carcinomaswere signet-ring cell carcinomas. In this study we adopted thehistological criteria directed by theWorldHealth Organization (6),

Received August 4, 1997; accepted October 13, 1997For reprints and all correspondence: Shin Sasaki, First Department of Surgery,University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113, JapanE-mail: [email protected]

in the same way asseveral reports byMesserini et al. (2) and otherauthors (7-9), and compared clinicopathological features betweensignet-ring cell and mucinous carcinomas.Mucinous and signet-ring cell carcinomas are of much higher

prevalence in patients with long-standing, extensive ulcerativecolitis than in the general population (10), and the non-polypoidmorphology is assumed to be characteristic in this setting (11).Chaubert et al. (12) reported that the prevalence of K-ras and p53mutations found in ulcerativecolitis-associated colonic carcinomasappears to be lower than in sporadic carcinomas, and Yamagata etal. (13) also reported that the macroscopically flat type ofcarcinoma complicating ulcerative colitis had no K-ras mutation.These results suggested that the incidence ofK-ras mutation wouldbe low in mucinous and signet-ring cell carcinomas. However,there have been no previous reported studies on this point. Wetherefore examined K-ras mutations in all samples of mucinousand signet-ring cell carcinomas in our series.MATERIALS AND METHODSSAMPLES AND DNA PREPARATIONAmong 1595 consecutive colorectal carcinomas surgically resected at the First Department of Surgery, the University ofTokyofrom January 1963 to December 1996, we selected 40 cases inwhich the tumor contained ::::50% of mucinous component asrevealed by HE staining. Furthermore, we differentiated signetring cell carcinomas from mucinous carcinomas according to the


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following criteria defmed by Laufman and Saphir (4). Theirpathologic criteria of primary signet-ring cell carcinoma of thecolorectum were as follows: 1, presence of signet-ring cells; 2,formation of immature or abortive glands; and 3, occurrence ofanaplasticcells with monocytoid features. Furthermore, in accordance with World Health Organization directives (6), we added thefollowing restrictions to clarify the feature of signet-ring cellcarcinoma and to deny the possibility of metastasis from othercancers: 4, the presence of another primary cancer was excluded;and 5, theproportion of signet-ringcells among neoplasticcellswas>50%.Ultimately,we selected 11cases (0.69%)withsignet-ringcellcarcinomas 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 theColon and Rectum (14). DNAs were extracted from archivalformalin-fixed, paraffm embedded tissue blocks, and purified asdescribed previously (15).The X2 test was used to analyze clinical differences between

signet-ring cell and mucinous carcinomas but not for the mean ageand duration of symptoms, for which Student's r-test was used,while the Kaplan-Meier method was used to produce survivalcurves. The log rank test was used to analyze differences inprobability of survival.MUTATIONAL ANALYSIS OF K-RASBecause most K-ras mutations in colorectal carcinomas occur atcodon 12, we screened for mutations at this site in all samples andin 30 ordinary advanced colorectal carcinomas as a control.Mutational analysis was performed using the 2-step sensitivePCRmethod as described by Yamagata et al. (16)

RESULTSThe mean age of patients with signet-ring cell carcinomas was46.3 years and that of patients with mucinous carcinomas was60.2 years (Table 1 and 2). Patients with signet-ring cellcarcinomaswere significantly younger than those with mucinouscarcinomas (P < 0.01). The male:female ratios of signet-ring cell

JpnJ Clin OncoI1998;28(3) 203and mucinous carcinoma were 0.38 and 1.23 respectively. Twocases out of 11 signet-ring cell carcinomas (18.2%) wereassociated with extensive ulcerative colitis, which had lasted 26and 18 years respectively. No mucinous carcinoma was associated with ulcerative colitis. Abdominal pain and abnormalitiesof bowel habit were the main symptoms in both types ofcarcinoma. The average duration of symptoms in signet-ring cellcarcinomas was 2.8 months, much shorter than that of mucinouscarcinomas (7.6 months) (P < 0.01). In all signet-ring cellcarcinoma cases the tumor size was >8cm, significantly largerthan that of mucinous carcinoma cases 8cm, 22 cases; ~ 8 c m ,six cases) (P < 0.00001). Eight of the signet-ring cell carcinomasrevealed extramural growth patterns, and macroscopic configurations were classified as type 2 in five cases, type 3 in three andtype 4 in two among 10 noted signet-ring cell carcinoma cases.On the other hand, macroscopic configurations were classified astype 1 in one case, type 2 in 10, type 3 in five, type 4 in one andtype 5 in five among 22 informative mucinous carcinoma cases.Peritoneal dissemination was significantly more frequent insignet-ring cell carcinomas (eight cases, 72.7%) than inmucinouscarcinomas (six cases, 21.4%) (P < 0.01). Synchronous livermetastasis was found in one out of 29mucinous carcinoma cases(3.4%) and two out of 11 signet-ring cell carcinoma cases(18.2%). In these three cases liver metastases were multiple.Lymph node metastases were graded as nOin 17, n1 in four andn2 in eight among mucinous carcinomas, and as nO in four, n3 intwo and n4 in four among signet-ring cell carcinomas. Centralnode involvement (n3 and n4) was significantly more frequent insignet-ring cell carcinomas (six cases, 60.0%) than in mucinouscarcinomas (no cases) (P < 0.00001). Clinical stagings ofsignet-ring cell carcinoma cases were more advanced andresection was evaluatedas non-curative in ninecases (81.8%). Allof 10follow-up cases died of this disease with a mean survival ofonly 256 days. On the other hand, 13 cases (76.5%) among 17follow-up mucinous carcinoma patients were alive withoutrecurrence with a follow-up duration from 3 months to 7 yearsand 1 month (Fig. I). There was a significant difference in thesurvival rates between these two groups (P < 0.000l).

Table1. Clinical findings in signet-ring cell carcinoma patientsNo. Sex Age Chief complaint Site Size Duration of P H Stage Operation Survival after

(yr) (mm) symptoms operation(months) (days)

1 F 26 Abd. pain, mass T 90 6 0 0 II RHC 6932 M 24 Abd. pain S 80 0.5 0 0 II Sigmoidectomy 7973 F 38 Abd. pain, hematochezia S 150 4 3 0 IV Colostomy 684 F 78 Abd. pain, mass, vomit D 100 2 0 0 IV Bypass 635 F 40 Abd. pain Rb >80 2 3 0 IV Colostomy 1126 M 34 Hematochezia S >80 5 2 0 IV Colostomy 1087 M 57 Abd. pain, constipation S 80 3 I 3 IV Colostomy 648 F 56 Abd. pain C 120 3 3 0 IV Explatory lapa. 1519 F 67 Abd. ful lness , cons tipa tion Rb 100 1 3 3 IV Colostomy 14910 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

P,Peritoneal dissemination; H, Hepatic metastasis; Abd., abdominal; T,Transverse colon; S, Sigmoid colon; D, Descending colon; Rb, Rectum below peritonealreflection; C, Cecum; RHC, Right hemicolectomy; lapa., laparotomy; D.O., dropped out.


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204 Signet-ring cell carcinoma in colorectumTable 2. Comparison of clinical features between signet-ring cell carcinomas and mucinous carcinomas

Signet-ring cell carcinoma (11 cases) Mucinous carcinoma (29 cases) Statistics (P)Mean age (years) 46.3 16.8 60.2 12.6


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Jpn J Clin OncoI1998;28(3) 205

References

Acknowledgment

derived from inflammatory bowel disease. From this evidence,we concluded that signet-ring cell carcinomas and mucinouscarcinomas might be derived from non-polypoid type of carcinomas, which exhibit low incidence of K-ras mutation (13 ,16). Totest this hypothesis, we screened K-ras mutation in all samplesand in 30 ordinary advanced colorectal carcinomas. As a result ,we detected K-ras mutations at codon 12in four cases (36.4%) ofsignet-ring cell carcinomas, II cases (37.9%) of mucinouscarcinomas and 18cases (60.0%) of ordinary carcinomas. Therewas no difference between signet-ring cell carcinomas andmucinous carcinomas. However, the incidence ofK-ras mutationin these diseases was slightly lower than that in the ordinarycolorectal carcinomas. These results suggest that the carcinogenesis of signet-ring cell and mucinous carcinomas may bedifferent from that of ordinary colorectal carcinomas.

This study suggested the possibili ty that signet-ring cellcarcinomas in the colorectum grow more rapidly than mucinouscarcinomas. From the genetic aspect, some alterations relating torapid growth of signet-ring cell carcinomas may happen duringa tumor's growth. Further study is needed to identify geneticalterations involved in carcinogenesis of signet-ring cell carcinomas.

This study was supported in part by a grant-in-aid from theMinistry of Health and Welfare of Japan.

I. Almagro VA . Primary signet-ring carc inoma of the colon. Cancer1983;52:1453-7.2. Messerini L,Palomba A,Zampi G. Primary signet-ring cell carcinomaof the

colon and rectum. DisColonRectum 1995;38: 1189-92.3. Shirouzu K, Isomoto H, Morodomi T, Ogata Y, Akagi Y, Kakegawa T.Primary linitis plastica carcinoma of the colon and rectum. Cancer1994;74:1863-8.4. Laufrnan H, Saphir O. Primary linitis plastica of the colon. Arch Sutg1951;62:79- 91.S. Nakahara H, Ishikawa T,ltabashi M. Diffusely infiltrating primary colorectalcarcinoma of linitis plastica and Iymphangiosis types . Cancer1992;69:901-6.6. Jass JR. Sobin LH., editors . International histological classification oftumors: histological typing of intestinal tumours. 2nd ed. Berlin: SpringerVerlag, 1989.7. H a l v ~ r s e n TB, Seim E. Influence of mucinous compoments on survival incolorectal adenocarcinomas: a multivariate analysis. J Clin Pathol1988;4]: 1068-72.8. Secco GB, Fardelli R, Campora E, Lapertosa G, Gentile R, Zoli S, et al.

Primary mucinous adenocarcinomas and signet-ringcell carcinoma of colonand rectum. Oncology 1994;51:30-4.9. Giacchero A, Aste H, Baracchini P, Conio M, Fulcheri E, Lapertosa G, et al.Primary signet-ring carcinoma of the large bowel: report of nine cases.Cancer 1985;56:2723-6.10. Choi PM, Zelig MP. Similarity of colorectal cancer in Crohn 's disease andulcerative colitis: implications for carcinogenesis and prevention. Gut1994;36:153-4.II . Tytgat GN, Dhir V, Gopinath N. Endoscopic appearance of dysplasia andcancer in inflammatory bowel disease. EuI'J Cancer 1995;31:1174-7.12. Chaubert P, Benha tta r J, Saraga E, Costa J. K-ras mutations and p53alterations in neoplastic and nonneoplastic lesions associated with longstand ing ulcerative colitis. Am J PmhoI1994;144:767-7S.13. Yamagata S, Muto T, Uchida Y, Masaki T, Higuchi Y, Sawada T. et al .Polypoid growth and K-ras codon 12mutations in coJorectal cancer. Cancer1995:75 :953-7.

7 83 4 5Yearso

20

M u t a n t ~(106bp)N o r m a l ~ L - ~ _(77bp)

Figure 1.The Kaplan-Meier survival curve of 11 signet-ling cell carcinomapatiemsrll) and 29 mucinous carcinoma patients (0 ). There was a significantdifference in survival rates between the two groups (P < 0.0001).

Figure 2. Mutation al analysis of K-ras using the 2-step sensitive PCR method.Templates areDNA extractedfrom signet-ring cell carcinomapatients (S J-SR).Four of these samples (SI-S4) exhibited a band of mutant allele as well as aband of normal allele. Marker : $ x I74/HaeIII DNA marker.

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Survival rate(%J

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40

tumor sizeof signet-ring cell carcinomas was so large and clinicalstagings so advanced that curativeoperations for this diseasewerealmost impossible. High frequency of peritoneal disseminationand central node involvement were especial ly noteworthy.Although Almagro (I ) st ressed the need for awareness andrecognition of this disease at an earlier stage, it would beextremely difficult in clinical settings because most of thesymptoms in signet-ring cell carcinomas were nonspecific, andthe average duration of symptoms was only 2.8 months.

Little has been known about the prevalence of inflammatorybowel disease among signet-ring cell and mucinous carcinomas.In our study there was no mucinous carcinoma associated withulcerative colitis. However, two out of II signet-ring cellcarcinomacases (18.2%) were associated with long-standing andextensive ulcerative colitis. Conversely, Choi and Zelig (10)repor ted that mucinous or signet-ring cell carcinomas wereassociated with much higher prevalence in patients with longstanding, extensive ulcerative colitis than in the general population .Furthermore, Tytgat et a!. (11) pointed out that non-polypoidmorphology was assumed to be characteristic in carcinomas


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206 Signet-ring cellcarcinoma in colorectum14. JapaneseSocietyfor Cancerof theColonandRectum,editors.The GeneralRulesfor ClinicalandPathological Studieson Cancerof theColon,Rectum,and Anus. 5thed. Tokyo:Kanehara-shuppan, 1994.15. Harii A,HanH-J,ShimadaM,YanagisawaA,KatoY,OhtaH,et al.Frequentreplicationerrors at micrasatellite loci in tumors of patients with multipleprimary cancers.Cancer Res 1994;54:3373-5.16. YamagataS, MutoT,UchidaY, Masaki T,SawadaT,TsunoN, et a1. Lowerincidence of K-ras codon 12mutation in flat colorectal adenomas than inpolypoid adenoma.Jpn J Cancer Res 1994;85:147-51.17. Lui 10, Kung IT, Lee JM, Boey JH. Primary colorectal signet-ring cell

carcinomain young patients:reportof 3 cases.Pathology 1985;17:31-5.

18. Wolfman EF,AstlerVB,CollerFA.Mucoidadenocarcinomaofthecolonandrectum.Surgery 1957;42:846-52.19. DajaniYF,ZayidI,Malatjalian DA,KamalME Colorectalcancerin Jordanand NovaScotia: a comparative epidemiologicand histopathologic study.Cancer 1980;46:420-8.20. Ibrahim NK, Abdul-Karim FW. Colorectal adenocarcinoma in youngLebaneseadults:the American Universityof Beirut-Medical Centerexperience with32patients.Cancer 1986;58:816-20.

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