Preneoplastic Lesions and Gallbladder Cancer: An Estimate of the Period Required for Progression

Transcription

1 GASTROENTEROLOGY 1996;111: Preneoplastic Lesions and Gallbladder Cancer: An Estimate of the Period Required for Progression IVÁN ROA,* JUAN C. ARAYA,* MIGUEL VILLASECA,* XABIER DE ARETXABALA, PABLO RIEDEMANN, KAZUO ENDOH, and JUAN ROA* Departments of *Pathology, Surgery, and Internal Medicine, Faculty of Medicine, Hospital Temuco, Universidad de la Frontera, Temuco, Chile; and Department of Hygiene and Preventive Medicine, Niigata University School of Medicine, Niigata, Japan Background & Aims: Scarce biological information ex- the gallbladder lesions considered as preneoplastic 2 12 has ists about the importance of preneoplastic lesions in not been clearly shown except that dysplasia is intimately gallbladder cancer. The aim of this study was to esti- associated with carcinoma. 3 The differences in the age mate the time required for the sequence of dysplasia at diagnosis observed between preneoplastic lesions and (DY) to carcinoma of the gallbladder. Methods: Eighty- carcinomas (early and advanced) would permit a first four cases of DY, 60 cases of early carcinomas (ECs), approach to determine their evolution and would provide 181 cases of advanced carcinomas (ACs), and 121 an approximation of the time required for the transition. cases of metastatic (ME) gallbladder cancer were ana- The pathology of gallbladder tumors in Chile is particlyzed. Age was used as the main parameter. Statistical analysis was performed using analysis of variance and ularly important because of its high incidence and mormultiple regression analysis. Results: Among all cases, tality rate Large geographical variation in the inci- the mean age of female patients was lower than the dence of gallbladder cancer has been shown throughout mean age of male patients (P Å 0.001). A significant the world, and Chile had the highest gallbladder cancer difference in mean age between sexes by specific type standardized mortality rate for both sexes between 1981 of lesion was also observed (P õ 0.001). The mean and Cases are generally advanced at diagnosis, age was 46.3 years (SD, 16) in the DY group, 57.5 resulting in survival that rarely exceeds 12 months. The years (SD, 16.7) in the EC group, 59 (SD, 13.7) in the high association in Chile between gallstones and gall- AC group, and 61.1 (SD, 12.1) in the ME group. Multi- bladder carcinoma represents an advantage for the study ple regression analysis showed statistically significant of this type of cancer. The clinical manifestations of the differences (r Å 0.386; P õ 0.001) in the mean age tumor in most of the cases are produced by inflammatory of patients with dysplastic lesions compared with the conditions or lithiasis; thousands of gallbladders are recarcinoma group. Conclusions: According to these obmoved each year because of nontumoral conditions. 14 servations, the period required to progress from dysplasia to advanced gallbladder carcinoma would be around Cholecystectomy is the most common surgical procedure 15 years, observing a continuum in the progression of in Chilean hospitals after cesarean sections. 27 The majorthe lesions. ity of the cases of gallbladder dysplasia and carcinoma are first diagnosed by cholecystectomy. 15,24 n important aspect of the biology of malignant The aim of this study was to estimate the period re- Aneoplasms is their natural evolution, particularly quired for a lesion considered as preneoplastic to undergo the period required for the transition from a preneoplastic transformation into gallbladder carcinoma by examining lesion to an advanced form of the disease. Knowledge stage-specific mean age at diagnosis. of the most important characteristics of proliferation is Materials and Methods essential for intervention during the period considered All cases of gallbladder mucosal dysplasia and gallbladto be critical. der carcinomas diagnosed at the Hospital Temuco (Temuco, In organs such as the uterine cervix, clinical and cyto- Chile) between January 1987 and December 1990 were inlogical examination has allowed this period to be deter- cluded in this study. This institution provides all inpatient mined with precision, and the natural history has been medical care for the population. The dysplastic lesions were determined. 1 However, in other organs such as the gall- defined according to histological criteria previously reported. 3 bladder, no such information is currently available, and All cases of dysplasia or carcinoma diagnosed in cholecystecit is not possible to develop screening programs for early detection of gallbladder carcinoma by the American Gastroenterological Association On the other hand, the exact biological meaning of /96/$3.00

2 July 1996 PRENEOPLASTIC LESIONS AND GALLBLADDER CANCER 233 Figure 1. Mean age at cholecystectomy in the control group (n Å 3773 cases)., Male patients;, female patients. Figure 2. Dysplasia and tumor lesions., Male patients;, female patients. DY, dysplasia; EC, early carcinoma; AC, advanced carcinoma; ME, metastasis. tomy samples were studied by serial sections (mapping). The 2.2 in acute and 3.7 in chronic cholecystitis. In these tumors with infiltration into the mucosa or muscular layer were groups, 27.6% of the patients were Chilean Indians (Maconsidered as early carcinomas. The diagnosis of metastasis was puche), and no difference in ethnic background was obestablished in those cases in which it was not possible to perform the cholecystectomy because of the extensive tumoral served. compromise of the liver, peritoneum, or lymph nodes and Table 1 summarizes the general features of the patients when the principal tumoral mass was located at the gallbladder with dysplastic lesions and carcinomas. The female/male area. As a control group, all 3773 nontumoral cholecystectogroups ratio in the dysplasia and in the advanced carcinoma mies, performed between 1992 and 1993 in this same institution, was two times higher than in the early carcinoma were included. and metastasis groups. A somewhat higher proportion of The information recorded in each case included age, sex, advanced carcinoma cases were female patients compared and race. Patients were divided in two groups according to with the early carcinoma series, but the difference was ethnic origin: Mapuche (Chilean Indians) and non-mapuche not significant. The proportion of the patients of Ma- (Spanish or other European ancestry). For statistical analysis, puche origin (Chilean Indians) increased by severity of depending on the homogeneity of the variances according to lesion from 21.4% in the dysplastic lesions group to the Bartlett test, analysis of variance or Kruskall Wallis tests 30.5% in the metastatic group. were used. Multiple regression analysis was performed using categorical or ordinal data as explanatory (independent) varifemale patients is shown in Figure 2. In all groups, the The mean age for each type of lesion in male and ables for continuous data (dependent) variables. Age at diagnomean age for female patients was lower than for male sis was the dependent variable, whereas race, sex, and type of lesions were the explanatory variables. patients (11.3 years younger in the dysplasia group, 7.1 Results years younger in early carcinoma group, 6.2 years younger in advanced carcinoma group, and 9.6 years The mean age of patients with cholecystectomy younger in the metastasis group). The difference in the due to inflammatory disease or gallstones was 43.4 years mean age between the dysplasia and advanced carcinoma (SD, 16.8 years). The gallbladder was resected 7.1 years groups was 9.3 years in male patients (P Å 0.007) and earlier in the female group than in the male group (P Å 14.4 years in female patients (P Å ; Table 2) ) (Figure 1). The difference in the mean age of There was a statistically significant difference in both cholecystectomy between patients with acute and chronic sexes for the non-indian population in the mean age cholecystitis was 3.2 years. This difference was significant of diagnosis between dysplastic and neoplastic lesions. only in women (P Å 0.001). The female/male ratio was However, in the Mapuche group, the difference in the Table 1. General Characteristics of Cases (Number of Cases) Dysplasia Early carcinoma Advanced carcinoma Metastasis Sex Female Male % Female Ratio F/M Race Non-Mapuche Mapuche % Mapuche Total

3 234 ROA ET AL. GASTROENTEROLOGY Vol. 111, No. 1 Table 2. Mean of Age and Type of Lesion by Sex and Race Non-Mapuche Mapuche Total DY EC AC ME DY EC AC ME DY EC AC ME Female 44 a a 49 c c 45 a a Male 53 b b 60 c c 56 b b Total 45 a a 52 c c 46 a a NOTE. Numbers were rounded for tabulation purposes. DY, dysplasia; EC, early carcinoma; AC, advanced carcinoma; ME, metastasis. a P Å , Kruskall Wallis test (one-way analysis of variance) (P õ 0.05, Bartlett s test for homogeneity of variance). b P õ 0.05 (analysis of variance). c Not significant. mean age between the dysplasia and the advanced carci- the incidence of gallbladder cancer worldwide have been noma groups was only 8 years in female patients and 11 shown. 26,28 The Chilean population has the highest stan- years in male patients (P Å NS). The age at diagnosis dardized mortality ratio in both sexes due to gallbladder for all neoplastic lesions was younger for Indian than for cancer. 26 non-indian patients. However, the reverse was observed Before commenting further on the findings, it is imamong patients with dysplasia. Overall, the difference in portant to consider the validity of these observations. the mean age of patients with dysplasia and early carci- First, the time of progression suggested in this report is noma lesions was 12 years, ranging from 2 years in Indian based on the average age at which the different lesions women to 13 years in non-mapuche women. The differ- are detected. This age does not necessarily correspond to ence between early carcinoma and advanced carcinoma that of the true onset of a specific lesion. Therefore, lesions was 2 years in the total series (3 years in female a difference probably exists between the real time of patients and 2 years in male patients). beginning of the lesion and the time of histological detec- In multiple regression analysis in the general group tion. Therefore, the time course of tumor progression and in both sexes, a significant difference in the mean from preneoplastic lesions towards carcinoma may be age in all types of lesions was shown (Table 3). Race, longer. however, did not show differences in multiple regression In this study, more than 95% of the cases were cholecysanalysis, and a significant difference only in the analysis tectomy for gallstones or cholecystitis. A preoperative diof variance test was observed, in which the different types agnosis of gallbladder cancer was quite rare (õ5%). Our of lesions and race were considered independent variables. study includes all such cases drawn from the same population source as the controls. All patients with each type of Discussion lesions (control, preneoplastic, and neoplastic) were symp- Gallbladder cancer is currently a common disease tomatic, and the extrapolation of these findings to the in Chile. 14 The incidence and mortality rate are the high- asymptomatic population is not necessarily appropriate. est in the world, and the trend is increasing. 13,14,26 Since Access to the public health system is universal for all 1987, gallbladder cancer has been the most common inhabitants in the area under study, including the Indian cause of cancer death in women in Chile, ahead of gastric population. Given the above, the average age at diagnosis and uterine cervix cancer. In the coming decades, gall- of these lesions represents a preliminary estimate of the bladder cancer is expected to be the most frequent malig- period of progression from one stage to the next. nant tumor in Chile. Marked geographical variations in We found that patients with dysplastic lesions were younger than patients with early carcinomas, and both Table 3. Multiple Regression Analysis were younger than patients with advanced carcinomas. This observation provides indirect evidence in support Coefficient Partial of the progressive evolution of the lesions. This fact has of correlation Variants regression coefficient F value Significance been shown in other organs, and gallbladder cancer should not be an exception. The present data represent Mapuche NS Sex P õ the cross-sectional mean age for each type of lesion and Type of lesion P õ do not necessarily represent the average time required for Fixed one type of lesion to advance to the next one. However, NOTE. Multiple correlation coefficient (r Å 0.386; P õ 0.001). demonstration of increasing age with increasingly ad-

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5 236 ROA ET AL. GASTROENTEROLOGY Vol. 111, No. 1 Covarrubia C, Valdivieso V, Torres MI, Uizua A. Frequency of De Aretxabala X. DNA content in gallbladder carcinoma: a flow gallbladder cancer in Chile, a high risk area. Int J Cancer 1988; cytometric study of 96 cases. Histopathology 1993;23:459 41: De Aretxabala X, Roa I, Araya J, Flores P, Burgos L. Operative 35. Roa I, Araya J, Wistuba I, Villaseca M, De Aretxabala X. Gallfindings in early forms of gallbladder carcinoma. Br J Surg 1990; stones in the IX region of Chile, autopsy study in an area with 77: high proportion of Mapuche people. Rev Med Chile 1991;119: 30. De Aretxabala X, Roa I, Burgos L, Araya J, Fonseca L, Wistuba I, Flores P. Gallbladder cancer in Chile. A report on 54 potentially 36. Armitage P, Doll R. The age distribution of cancer and a multiresectable tumors. Cancer 1992;69: stage theory of carcinogenesis. Br J Cancer 1954;8: Roa I, Araya J, Wistuba I. Villaseca M. Carcinoembryonic antigen 37. Farber E, Cameron C. The sequential analysis of cancer developexpression in gallbladder cancer. Rev Med Chile 1991;119:129 ment. Adv Cancer Res 1980;31: Roa I, Araya J, Shiraishi T, Yatani R, Wistuba I, Villaseca M, De Aretxabala X. Immunohistochemical expression of Ca19-9, Received November 29, Accepted February 26, epithelial membrane antigen, Dupan-2 and carcinoembryonic antigen Address requests for reprints to: Iván Roa, M.D., Department of in gallbladder carcinoma. Rev Med Chile 1992;120:1218 Pathology, Faculty of Medicine, Universidad de la Frontera, P.O. Box D, Temuco, Chile. 33. Roa I, Araya J, Shiraishi T, Yatani R, Wistuba I, Villaseca M, De Supported by grants Fondecyt and 9508 Direccion de Aretxabala X. Immunohistochemical expression of the pepsinogen Investigacion Universidad de la Frontera. I and II in gallbladder. Rev Med Chile 1992;129:1351 The authors thank Dr. Arthur Evans from the Clinical Epidemiology Roa I, Araya J, Shiraishi T, Yatani R, Wistuba I, Villaseca M, Unit, North Carolina University, for his valuable suggestions and comments.