Late presentation of esophageal cancer: Observations in a multiracial South East Asian population

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1 Journal of Digestive Diseases 2010; 11; doi: /j x Late presentation of esophageal cancer: Observations in a multiracial South East Asian population Muhammad ABDULLAH*, Adil Abdel KARIM* & Khean-Lee GOH *Department of Surgery, and Division of Gastroenterology, Faculty of Medicine, University of Malaya, Malaysia OBJECTIVE: Esophageal cancer (ECA) is an important cancer in Malaysia. The aim of the study is to review the demographic data and clinical presentation of patients with ECA seen at the University of Malaya Medical Centre, Kuala Lumpur.cdd_ METHODS: Patients with histologically proven ECA were recruited for the study. Patients case notes, endoscopy and operating theater records were reviewed. All cases were histologically confirmed. RESULTS: A total of 143 patients with ECA was diagnosed between 1998 and The mean age of the patients was years with a male : female ratio of 1.8:1. Of these 50.3 percent were Indians, 32.9 percent, Chinese and 16.8 percent Malays. The overall hospital-based prevalence rates per admissions according to races were: Malay; 23.5, Chinese; 57.4 and Indian; The location of the tumors was: upper; 16 (11.2%) middle; 52 (36.4%) and lower; 75 (52.4%). The histological type of ECA were: squamous cell carcinomas; 113 (79.0%) and adenocarcinomas; 30 (21.0%). The ECA stage at diagnosis, was: II; 18 (12.6%), III; 23 (16.1%) and IV; 102 (71.3%). Only 24 (16.8%) patients underwent surgery and13 (9.1%) were considered curative. Overall 114 (79.7%) patients underwent palliative endoscopic stenting and six (4.2%) were given other palliative therapy including radiotherapy. CONCLUSIONS: Squamous cell cancer was the predominant type. ECA presents late in our patients and only a minority of patients underwent curative surgery. KEY WORDS: esophageal cancer, late presentation, multiracial, Asian population. INTRODUCTION Although it is often overshadowed by gastric cancer and colorectal cancer, esophageal cancer remains an important cancer in the Asia Pacific region. Its late presentation makes it a difficult and challenging Correspondence to: Khean-Lee Goh, Head of Gastroenterology and Hepatology, Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia. klgoh56@tm.net.my No conflicts of interest exist with any of the authors. No source of funding was sought for in this study. Journal compilation 2010 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology and Blackwell Publishing Asia Pty Ltd. medical problem. Cancer statistics show that Asian countries have some of the highest age-standardized incidence rates (ASR) of esophageal cancers in the world with a very high concentration of cases in the Caspian littoral in Iran and in several provinces in China. 1 4 However, the cancer incidence vary greatly within a diverse continent, with some countries like the Philippines and Thailand reporting a very low ASR. 5 Esophageal cancer is also not common in Malaysia. The ASR of esophageal cancer from two cancer registries in Penang and Sarawak in Malaysia show a relatively low ASR of 2.5 and 2.2 per population in males. 5 Further sub-analysis of the ASR national cancer registry of Peninsula Malaysia and 28

2 Journal of Digestive Diseases 2010; 11; Esophageal cancer in an Asian population 29 neighboring Singapore 5 by race shows a higher incidence among Chinese and Indians. In Malaysia, where three major Asian races: Malay, Chinese and Indian co-exist, marked ethnic difference in various other gastrointestinal cancers have previously been observed and reported. 7,8 Esophageal adenocarcinoma is reportedly the fastest growing gastrointestinal cancer in the developed world. 9 However, it appears that the squamous cell carcinoma is still the predominant histological type in Asia. 10 The objective of this study is to review our experience with esophageal cancer (ECA) in a major tertiary hospital in Malaysia with respect to ethnic differences, clinical presentation, histological type, types of treatment and outcomes. MATERIALS AND METHODS The admission records of patients presenting to the University of Malaya Medical Center, Kuala Lumpur, over a 6-year period (January 1998 to December 2003) were carefully reviewed. Data were counterchecked and verified with additional review of endoscopy and operating theater records. All cases of ECA were histologically confirmed and were divided into squamous cell carcinomas (SCC) or adenocarcinomas (AC). The hospital-based prevalence of disease by ethnic groups was determined by the number of cases divided by the number of hospital admissions by ethnic group over the same period of time and the prevalence per hospital admissions was calculated. Social class was arbitrarily classified according to the level of education, in which patients with no or primary school education only were classified as lower class, those with secondary school education as middle class and those with college or university education as of a high social class. Statistical analysis The record was entered into a Microsoft Access database and analyzed using SPSS (Statistical Package for Solution and Services), version 11.5 (SPSS Chicago, IL). Comparison of proportions were carried out using the c 2 test and Fisher s exact tests where appropriate. A two-tailed test was used for all calculations. A P-value of <0.05 was taken as significant. RESULTS Overall 143 patients were diagnosed as having ECA over the period of the study. The basic demographic characteristics of the patients are as shown in Table 1. Table 1. Basic demography of esophageal cancer patients n 143 Mean age (years) (mean SD) Male : Female 92:51 Ethnicity n (%) Malay 24 (16.8) Chinese 47 (32.9) Indian 72 (50.3) Histological type and location of tumor Most of the ECA patients had SCC; 113 (79.0%). The remaining 30 patients (21%) were diagnosed as having AC. The location of these tumors was: upper; 16 (11.2%), middle; 52 (36.4%) and lower 75 (52.4%) and were all located distally at the cardioesophageal junction. Ethnic distribution of cases The predominant race affected was Indian, which accounted for half of all the cases seen (Table 1). The overall hospital-based prevalence rates per admissions according to races were: Malay; 23.5, Chinese; 57.4 and Indian; The breakdown of cases according to races and gender is as shown in Tables 2 and 3, where cases of SCC and AC are considered separately. The prevalence of SCC was: Indian men and women; and per hospital admissions, respectively; Chinese men and women; 74.8 and 22.3 per , respectively, and Malay men and women; 8.4 per and 12.8 per , respectively. For both men and women, Indians had significantly higher prevalence compared to all other racial groups (men: Indians vs Malays; P < 0.001; Indians vs Chinese; P = 0.026, women: Indians vs Malays and Chinese; P < 0.001). Amongst Indians, the prevalence amongst men although numerically significant, was not statistically higher compared to women (P = 0.305). The prevalence among Chinese men was significantly higher than among women (P < 0.001). No difference was seen between Malays men and women (P = 0.819). There were fewer patients with AC, particularly when subdivided into the different ethnic groups. Again, Indian men had the highest prevalence of 33.6 per hospital admissions, followed by Malay men and Chinese men. Owing to the small numbers, the difference between Indian men and Malay and Chinese men did not achieve statistical significance.

3 30 M Abdullah et al. Journal of Digestive Diseases 2010; 11; Table 2. Race Distribution of squamous cell carcinoma by race and gender Male Female n Admissions Prevalence* n Admissions Prevalence* Malay Chinese Indian Total *Per hospital admissions within the racial group. Table 3. Race Distribution of adenocarcinomas by race and gender Male Female n Admissions Prevalence* n Admissions Prevalence* Malay Chinese Indian Total 25 5 *Per hospital admissions within the racial group. Table 4. Distribution of squamous cell carcinomas (SCC) and adenocarcinomas (AC) by level of education Social class However, its prevalence among men was significantly higher in all ethnic groups (men vs women: Malay = 0.056, Chinese = 0.016, Indian = 0.027). Social class Social class was considered for SCC and AC separately. The distribution for SCC and AC according to social class is shown in Table 4. For SCC, 92 of 113 patients (81.4%) were considered to be of a lower social class with little or no education, 11 (9.7%) were middle class and 10 (8.8%) were considered to be in the upper class. For the patients with AC, a wider distribution of social class was seen, although most patients (63.3%) were still of a lower social class, with 23.3% middle class and 13.3% upper class. Risk factors SCC (n = 113) AC (n = 30) n % n % Low Middle High Risk factors for both SCC and AC are shown in Table 5. Most patients (71.7%) with SCC gave a history of smoking. A small percentage (2.7%) gave a history of chewing raw tobacco. A history of significant alcohol consumption was seen in only 18.6% of patients. Betel nut chewing was found in only seven (6.2%) and tobacco chewing in three (2.7%), all in Indian patients. Caustic soda ingestion was reported in three (2.7%), all Chinese patients. In contrast, only one-third of patients with AC had a history of smoking and an even lower percentage had a history of alcohol ingestion. A minority of patients had a known history of gastroesophogeal reflux disease (GERD) and only one patient was diagnosed as having a previous Barrett s esophagus. Staging of disease The staging of disease according to the American Joint Committee on Cancer classification is shown in Table 6. Most patients presented with an advanced stage of disease: 71.3% of patients were already in stage IV at the time of diagnosis. Treatment and disease outcome A total of 24 (16.8%) patients were subjected to surgery (Table 7). Curative surgery was possible only in 13 (9.1%), of whom only five (4.5%) were longterm survivors. Of the latter, all were diagnosed to have stage II disease. The median survival was 26 months (25 75% interquartile range [IQR]: months. Eleven (7.7%) patients who underwent surgery with curative intent were found not to be operable at surgery. They were then referred for the place-

4 Journal of Digestive Diseases 2010; 11; Esophageal cancer in an Asian population 31 Table 5. Risk factors Prevalence of risk factors for squamous cell carcinomas (SCC) and adenocarcinomas (AC) SCC (n = 113) AC (n = 30) n % n % P value Smoking <0.001 Alcohol Betel nut chewing Caustic soda ingestion Raw tobacco Known history of GERD <0.001 Barrett s esophagus GERD, gastroesophogeal reflux disease. Table 6. Staging of tumor according to American Joint Committee on Cancer Stage Frequency Percentage II III IV ment of endoscopic stents. A total of 114 (79.7%) patients underwent palliative stenting. Their median survival was 5 months (25 75% IQR: 5 13 months). Six (4.2%) patients underwent palliative radiotherapy and chemotherapy following endoscopic dilatation. The median survival of this group of patients was 10 months (25 75% IQR 6 27 months). Ten patients received no definitive palliative treatment following endoscopic dilatation owing to advanced stage of the disease with a median survival of 3.5 months (25 75% IQR: months). DISCUSSION Over a 5-year period we have seen a fairly large number of patients with ECA in our medical centre which is a tertiary hospital in a suburban area of the capital city of Malaysia, Kuala Lumpur. As ECA is a complex disease and almost always referred to a major hospital, we feel that we have been able to capture most of the cases in this area, which is reflective of the suburban population of the country. We have found in our study that SCC is the predominant type of ECA, accounting for almost 80% of all cases. This is in keeping with the experience from Asia where a rise in AC has not yet been observed Based on hospital admission statistics and calculated according to race we have also found that SCC was far more common in Indians than in Malays and Chinese. It is interesting to note that the Malays have the lowest burden of disease. This is in keeping with cancer statistics of the National Cancer Registry of Malaysia, 6 where Indian men and women were found to have the highest ASR of ECA of 6.3 and 4.5 compared to Chinese men and women (3.0 and 1.0) and Malay men and women (1.6 and 0.5) per population, respectively. Ethnic differences in a multiracial population have always been intriguing and point to host genetic susceptibility or environmental factors peculiar to a particular race. Amongst the well-recognized environmental risk factors, only cigarette smoking was found in most patients with SCC. A lower proportion of patients with AC were reported to be smokers. Betel nut and tobacco chewing, which have been associated with SCC, 14 were uncommonly reported in our patients. These two habits were common practices amongst the Indian migrant population who were brought over as indentured labor by the British colonial government in the early 20th century. 15,16 Caustic soda ingestion was a common form of attempted suicide in young Chinese women about years ago but, again, was reported in very few patients with SCC. Alcohol ingestion was also uncommon in our study population. Genetic studies have identified numerous mutations which may be putative in esophageal SCC. 17 Of recent interest however, are polymorphisms involving alcohol and aldehyde dehydrogenase. Mutations in these genes result in accumulation of acetaldehyde, which is thought be toxic and carcinogenic to the body. 18,19 In a recent study by Cui et al. the interaction of these mutations with alcohol and tobacco smoking was reported. 20 Although less common than SCC, AC was still seen in 20% of our patients. AC has been closely linked to the rise in GERD in the developed world, where it has increased exponentially While reports have also

5 32 M Abdullah et al. Journal of Digestive Diseases 2010; 11; Table 7. Treatment and survival Treatment Frequency Percent Median survival (months) 25 75% IQR None Stent Radio- and chemotherapy Curative surgery IQR, interquartile range. shown the emergence of GERD in the Asia Pacific region, 25,26 a similar experience with AC has not yet been seen. In our patients, a history of GERD was not commonly reported and the known presence of Barrett s esophagus was reported in only one patient. A greater percentage of patients smoked and drank alcohol in the SCC compared to AC patients. Comparison between SCC and AC patients was difficult because of the small numbers of patients with the known risk factors in both groups. The association of lower social class (>80%) was well seen in patients with SCC. The association of GERD with obesity and a more affluent lifestyle predisposing to AC may affect patients in the higher social classes. However, in our study more than half of our patients with AC (63.3%) belonged to the lower social class. The most striking problem with our patients with ECA is the late presentation of disease, with almost 90% of patients presenting in stage III or IV. Only a minority of patients was operable and an even smaller percentage cured. This reflects the natural history of the disease which is often silent until dysphagia sets in. Utilization of heath facilities is also low among poorer and less educated patients who often resort to traditional cures before seeking a medical consultation. Furthermore, no screening strategy is available for ECA. For AC, screening patients with Barrett s esophagus will allow the detection of early cancers but problems still exist with the detection and diagnosis of Barrett s esophagus in the Asia Pacific region. The late presentation of disease has made treatment difficult. It is thus confined to supportive or palliative treatment. The choice of palliation used in our patients; predominantly endoscopic stenting, reflects the availability of facilities and expertise and therefore a bias for therapeutic endoscopy. With obstructive esophageal cancers the advent of self-expanding metallic stents has been a major step forward and has made stenting much easier and safer. However, in several specialized centers in Asia the advent and use of multimodality treatment with neoadjuvant chemoradiation and newer surgical approaches have resulted in better cure rates. 10,27 The management of esophageal surgery requires a dedicated center where careful pre-operative assessment and assiduous postoperative care together with skillful surgery will result in the best results for the patient with esophageal cancer. The marked improvement in living conditions in the Asia Pacific region over the past two decades has been associated with a decline in SCC. 13,28,29 Fernandes et al. in Singapore showed a decreased prevalence of SCC with a numerical but non-statistically significant increase in AC. 13 In our own endoscopy-based study comparing findings over a 10-year period of time, SCC has declined but with as yet no discernible increase in AC. 30 REFERENCES 1 Mahboubi E, Kmet J, Cook PJ, Day NE, Ghadirian P, Salmasizadeh S. Oesophageal cancer studies in the Caspian littoral of Iran: the Caspian cancer registry. Br J Cancer 1973; 28: Kamangar F, Malekzadeh R, Dawsey SM, Saidi F. Esophageal cancer in Northeastern Iran: a review. Arch Iran Med 2007; 10: Yang CS. Research on esophageal cancer in China: a review. Cancer Res 1980; 40 (8 Pt 1): Ke L. Mortality and incidence trends from esophagus cancer in selected geographic areas of China c Int J Cancer 2002; 102: Curado MP, Edwards B. Shin HR et al., eds. Cancer Incidence in Five Continents, Vol. IX. Lyon: IARC, IARC Scientific Publications no Lim GCC, Rampal S, Halimah Y. Cancer Incidence in Peninsular Malaysia Kuala Lumpur: National Cancer Registry, Goh KL, Cheah PL, Md N, Quek KF, Parasakthi N. Ethnicity and H. pylori as risk factors for gastric cancer in Malaysia: a prospective case control study. Am J Gastroenterol 2007; 102: Goh KL, Quek KF, Yeo GTS et al. Colorectal cancer in Asians a demographic and anatomic survey in Malaysian patients undergoing colonoscopy. Aliment Pharmacol Ther 2005; 22: Blot WJ, McLaughlin JK. The changing epidemiology of esophageal cancer. Semin Oncol 1999; 26 (5 Suppl 15): Law S, Wong J. Changing disease burden and management issues for esophageal cancer in the Asia Pacific region. J Gastroenterol Hepatol 2002; 17:

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