Introduction

Gall Bladder Cancer (GBC) was first described by De Stoll in 1777. GBC is a rare neoplasm with marked ethnic, gender and geographical variations worldwide. Since 1980s, the mortality rate remained as such. Bolivia and Chile have had the highest incidence rate in the world. The highest mortality rate of both women (16.6/1, 00, 000) and men (7.8/1, 00, 000) was also observed in Chile ¹ . The comparison of different population based cancer registries indicated that GBC was one of the commonest causes of cancer related mortality in women in northern and north-eastern states of India ² . The reported incidence ranged from 10/1, 00, 000 in Delhi to 2-3/1, 00, 0 00 in South India ³ . The association of GBC with gall stone increased the risk from 4 to 7 times than those without gall stone ⁴ . Mention may be made of chronic cholecystitis, Salmonella typhii infection, BMI, dietary and environmental factors as some risk factors other than gall stone ^{1, 5, 6} . Blood serum alkaline phosphatase (ALP), serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT) and total bilirubin (TB) were found elevated in different cancers ^{7, 8, 9, 10} . The asymptomatic nature of the disease always remained a problem in the diagnosis and treatment. This was always being confused with other gastrointestinal problems as symptoms like abdominal pain, abdominal lump, anorexia, jaundice, nausea and vomiting are common to GI tract problems. Thus, urgent ultra-sonography followed by cytological investigations is needed to diagnose the gall bladder disease. Unfortunately, in a study area like ours, most often patients visit hospital only when the disease is in its advance stage and thus, have a poor prognosis. There is lack of an ideal civil registration system in this part of South-East Asia to estimate the morbidity and mortality rates for a particular disease. The national level data sets ^{11, 12} showing incidence of gall bladder cancer made available have clearly missed the North Central part of India (including north Madhya Pradesh, a few districts of Uttar Pradesh and Rajasthan), may be due to the remoteness, lack of availability of hospital based data and other reasons. The worst part of the malaise is the predominance of gall bladder cancer in rural population, who are either unaware of the extreme consequences or are too poor to afford the cost of diagnosis and treatment and hence, continue to suffer. The present study is first of its kind, reporting on the status of the disease in North Central Indian population especially in rural and semi-urban areas. Our observations are based on a regional cancer centre based record of two years, which admits most of the patients from the regions shown in the map (Figure 1: Geographic distribution of study area (Map not to scale).

Figure 1

Methods

A retrospective study was carried out at the Cancer Hospital and Research Institute (CHRI), Gwalior, Regional Cancer Centre (Code-08), Ministry Of Family Health and Welfare (MOFHW), Government of India from the period January 01, 2007 to December 31, 2008. The study was approved by Institutional Ethics Committee. We collected information on the medical diagnosis and demographics of all the 464 different categories of gall bladder disease patients who were admitted for treatment during the above period. Out of 464 patients, 365 had Gall Bladder Cancer with Gall stone (abbreviated as GSC onwards), 15 with Gall Stone (abbreviated as GS), 36 with Gall Bladder Cancer without stone (abbreviated as GC), 30 with Chronic Cholecystitis (abbreviated as CC) and 18 having Gall Bladder Cancer with Cholecystitis (abbreviated as GCC). We have excluded the data of patients who left the hospital after check- up at outpatient door for personal problems and studied all the comparative data available from the hospital record for those who got admitted and properly diagnosed. The cases were confirmed on the basis of clinical investigations, like X-ray, ultrasound, cytological examination (FNAC), histopathological examination and blood biochemistry reports. About 80% of the diagnosis is based on the ultrasound, chest X-ray and cytological tests (FNAC) and of remaining 20%, after post surgical histopathology. Sample t- test was carried out for the average values of the parameters in five different categories of gall bladder disease (collectively abbreviated as GBD). A total of 419 gall bladder cancer (abbreviated as GBC) with or without gall stones/ cholecystitis were included in the present study. The statistical analysis was performed using Graph Pad Prism 5 ¹³ .

Result and discussion

In our hospital based record, Gall Bladder Cancer is placed at the fourth position (419 out of 3820 cases of various cancers registered during 2007-2008), following cervix (third, 13.61%), breast (second, 18.64%) and head and neck (first, 24.7%) cancers (Fig 2A: Site wise distribution of cancer). About 11% of patients admitted at the hospital were with gall bladder cancers, being the most common amongst gastrointestinal tract cancers (53%) followed by oral cavity and colorectal cancers (Fig 2B: Distribution of gastrointestinal tract cancer patients). Most of the patients admitted were residents of north Madhya Pradesh, adjoining Uttar Pradesh and Rajasthan (Fig 1).

Figure 2

Figure 3

The area-wise contribution of number of cases is shown in Fig 3 (District-wise distribution of gall bladder cancer (GBC) patients admitted in the hospital). Significantly, about 70% of GBD patients were from rural areas but the gall stone (GS) or cholecystitis (CC) cases alone were largely from urban areas (Table 1: Distribution of patients in rural and urban areas).

Figure 4

Figure 5

Table 1: Distribution of patients in rural and urban areas

The food habit of the GBD patients was mostly vegetarian (76%). About 64% of patients admitted were having no education or only primary level education with very low income (about 70%). The annual income in about 56% of the total cases was found extremely low (

Figure 6

Table 2: Body mass index of gall bladder cancer patients

The females appeared more prone to the disease as compared to males (F/M ratio = 3.223). The average age of the patients in male was found to be 56.76 ± 1.179 (SD) (P<0.0001) and that of female was 52.13± 0.8188 (SD) (P<0.0001). The highest incidence of gall bladder cancer was found in the age group of 51-60 years (Table3: Number of different categories of gall bladder disease (N), F/M ratio and mean age of the patients). We have no strong evidence or data support to associate blood group with the incidence of GBC (Table 4: Percentage of different blood groups among the cancer patients) but, about 42.60% GBC patients were belonging to blood group B positive as compare to O positive (26.72%) or A positive (17.56%) blood groups.

Figure 7

Table 3: Number of different categories of gall bladder disease (N), F/M ratio and mean age of the patients

Figure 8

Table 4: Percentage of different blood groups among the cancer patients

The presence of gall stone was found in as high as 87% (N=365, single stone in 113 cases, multiple stones in 252 cases and 52 cases were without stones) of all the GBC cases (N=419) admitted in the hospital. The diffuse type of cancer was found most prevalent (40%), followed by occurrence in fundus (38%). The ultrasonographic pattern showed the infiltration of mass to liver (in 24.58% cases), porta hepatic (24.82% cases) and lymph node at porta (25.53%) almost equally, followed by ascites (in 18.02% cases). The post surgical histological investigations carried out on 78 cases showed that 91% of the cancers were adenocarcinomatous according to TNM classifications (Stage I, 09%; Stage II, 29%; Stage III, 31% and Stage IV, 02%). About 2% cases were colloidal carcinomas and 5% were other non small cell carcinoma. The menopausal status in most of the female cancer patients (N=301) were post menopausal (79%). The serum alkaline phosphatase (ALP), serum glutamic pyruvic transaminse (SGPT), serum glutamic oxaloacetic transaminase (SGOT) and total bilirubin (TB) levels in gall bladder diseases were found significantly elevated. The isoenzyme ALP level was found higher in male than in female patients in all the cases (P< 0.0001). The level of SGPT is more in male (212.2±56.4) than in female (149.4±16.4) (P< 0.0001). The SGOT and TB levels were 212.2±56.4 and 149.4±16.4 (P< 0.0001), 10.34± 2.8 and 8.391±1.73 (P< 0.0001) in males and females in GBC patients, respectively (Fig 4A: Comparative levels of SGOT in GSC, GS, CC and GC patients; Fig 4B: Comparative levels of total bilirubin (TB) in GSC, GS, CC and GC patients; Fig 4C: Comparative levels of ALP in GSC, GS, CC and GC patients; and Fig 4D: Comparative levels of SGPT in GSC, GS, CC and GC patients). The levels of SGPT, SGOT and TB were higher in females than in males in GS, GSC, Cholecystitis and GCC.

Figure 9

The highest worldwide incidence rates have been reported for women in Delhi, India (21.5/1,00,000), South Karachi, Pakistan (13.8/1,00,000) and Quito, Ecuador (12.9/1,00,000); the female to male ratio (F/M) being around 3, but vary from 1 in far east Asia to 5 in Spain and Colombia ¹⁴ . An increase in the incidence rate of 1/1,00,000 in male and 3.3/1,00,000 in female to 3.9/1,00,000 in male and 9.0/1,00,000 in female during the period 1987-96 was observed in a New Delhi based study ⁶ . In our hospital based records, F/M ratio was found to be 3.223 in GBC. GBC ranks at the fourth place after head and neck, breast and cervical cancers. The percentage of GBC cases is highest (53%) amongst the Gastrointestinal Tract cancers registered at CHRI. The crude incidence rate in this area (North M.P) for gall bladder cancer was estimated to be 15.0/100,000 in female and 5.9/100,000 in male during a period of two years (2007-2008). The incidence rate reported in Indian Council of Medical Research cancer registry from the other high incidence districts/cities of India, like Delhi (10.1), Kamrup (8.1), Kolakata (5.4), and Mumbai (3.2) were less than that in the north central Indian region ¹¹ . This is the first ever report on the status of gall bladder cancer from the region with a population of more than two million (20, 00, 000). The earlier studies have reported obesity and high BMI as a potential risk factor for GBD ¹⁵ . The present report, however, encountered about 68.22% of all GBC patients to be having BMI below 18.5-22.9, indicating lack of any significant association with obesity in the studied population. The highest frequency of GBC was found among women over an age of 65 years and among the patients at the time of definitive operation, it is 59.9 years ¹⁶ . In contrast, our study showed an average age among the GBC cases to be 56.76 ± 1.179 (P<0.0001) in male and 52.13 ± 0.818 (P<0.0001) in female. The reported risk factors for GBC are gall stone, chronic cholecystitis, bacterial infections (Salmonella typhii, S. paratyphii) and post-menopause of woman ^{4, 17} . In this study, about 87.11% of GBCs were found associated with Gall Stone. Our study also provides evidences to indicate that the onset of pathogenesis in women to be generally at post-menopause. Of the 262 GBC cases available at the time, who were tested for blood groups, the highest number of patients were found to be B +ve (41.60%) followed by O +ve (26.72%) and A +ve (17.56%). The levels of serum enzymes, like ALP, SGPT and SGOT were reported to be elevated in different cancers including hepatocellular, liver, colorectal, bone marrow metastasis or osteosarcoma ^{9, 10, 18} . Our present analysis also found levels of these clinically important enzymes to be consistently high, as is the case of biliary tract diseases particularly in males than in females.

The most significant revelation made by this study was the predominance of low income, socially unaware groups and rural population, being most affected by the disease. It is evident from the observation that about 75.89% of GSC cases were from rural areas and that about 63.01% affected persons were either illiterate or had education at the primary level. A huge chunk of patients were vegetarian (80.55%) with diets less in protein content and high in fat and carbohydrates. The incidence of gall bladder cancer in the study area is alarming and new cases are frequent in the hospitals with advanced stage of the disease. The major risk amongst these are, of course, gall stones but lower BMI in such patients may not be considered as a risk factor because this can be an effect of the disease rather than a cause or risk factor. The low income and lack of education prevents this major group of patients for early investigations and medical diagnosis. The average age of females affected by GBC is as low as 52.13 (SD±0.818), which seems much lower than the international average of 65 years. The age of onset of gall bladder disease, in general, and gall bladder cancer, in particular, is lowering in India as reported earlier ¹² are substantiated by our present observation.

Thus, evidence from earlier studies as well from the present study that there is lowering of age of onset is suggestive of genetic predisposition of the study population towards the disease. Alongside, a few important studies also supported familial occurrence of gall stones that includes Farmingham studies ¹⁹ and Star county study ²⁰ . In India, a New Delhi based study has shown high prevalence of gall stones in first degree relatives of gall stone patients ²¹ . The analysis of human pedigree data using a threshold model and the variance component analysis revealed that genetic factors alone explain 44% of variation in gall bladder disease ^{22, 23} .

Conclusion

The data presented in this report reflects the incidence rate of gall bladder cancer in this area, which, however, may not be the actual, since the patients admitted are self reported to a hospital, many subjects harboring the disease are expected to be missed out. But keeping in mind, the fact that CHRI is the only super-specialty cancer hospital in the region and the GBC patient admissions are increasing alarmingly (even if some? are drifted away) in comparison to other regions, the estimated incidence rate in the present study, though crude, provides a glimpse of the future state of GBC in this region. Disappointedly, the economic or educational (awareness) status as well as other life style conditions of the population from rural background is not going to be changed substantially in the near future. The positive outcomes of such studies are many, the availability of incidence data on different population and demographics are important in knowing and understanding the trend of the disease globally. This report, therefore, draws attention for a wide epidemiological survey of the rural and semi urban area of the region or the very least rural hospital and dispensary based screening that can help predict the scenario in a better way and take preventive measures and policy making to help screen and manage the disease.

Acknowledgement