The Third Most Prevalent Form of Cancer in Kashmir

Syed Sameer provides a technical update of his research in colorectal cancer in Kashmir

(Aga Syed Sameer, 26, was born in Srinagar. He passed his matriculation (10th grade) from the Islamia Public School and his 12th grade from the Iqbal Memorial Instiute, both in Srinagar. He completed his Bachelor's degree from the Sri Partap College, Srinagar, and his master's Degree in Biochemistry from the University of Kashmir in Srinagar. He is presently a Ph.D. Scholar in the Department of Clinical Biochemistry, Immunology and Molecular Medicine in the Sher-i-Kashmir Istitute of Medical Sciences (SKIMS) in Soura Srinagar. He has published numerous articles and conducted research in a variety of fields related to his graduate studies. He has a diploma in computer applications, and is a certified Civil Defense cadet, and won state level gymnastic competition for floor exercises. He takes pride in his perseverence, patience and problem solving skills.)

Colorectal Cancer in Kashmir

Colorectal cancer (CRC) also called colon cancer or large bowel cancer includes cancerous growths in the colon, rectum and appendix. It is the third most common cause of cancer-related death in the western world. The annual incidence of CRC worldwide has been estimated to be at least half a million. It is a commonly diagnosed cancer in both men and women. In 2008, about 148,810 new cases were diagnosed, and almost 49,960 deaths from colorectal cancer were speculated world wide. High incidence rates are found in western world populations, i.e. Western Europe, North America, and Australia. The lowest rates of CRC are found in the sub-Saharan Africa, South America and Asia, but are increasing in countries adopting western life-style and dietary habits. And the scenario in the Kashmir valley is not different from that of the world. In Kashmir too, it is the most prevalent form of cancer after esophageal and gastric.

TYPES

Colon cancer is usually observed in one of three specific patterns: sporadic, inherited, or familial. Sporadic disease, with no familial or inherited predisposition, accounts for approximately 70% of CRC in the population. Sporadic colon cancer is common in persons older than 50 years of age, probably as a result of dietary and environmental factors as well as normal aging. Fewer than 10% of patients have an inherited predisposition to colon cancer. The inherited syndromes include those in which colonic polyps are a major manifestation of disease and those in which they are not. The polyposis syndromes are subdivided into familial adenomatous polyposis (FAP) and the hamartomatous polyposis syndromes. The nonpolyposis predominant syndromes include hereditary nonpolyposis CRC (HNPCC) (Lynch syndrome I) and the cancer family syndrome (Lynch syndrome II). Although uncommon, these syndromes provide insight into the biology of all types of CRC. The third and least understood pattern of colon cancer development is known as familial colon cancer. In affected families, colon cancer develops too frequently to be considered sporadic colon cancer but not in a pattern consistent with an inherited syndrome. Up to 25% of all cases of colon cancer may fall into this category.

ETIOLOGY

No one knows the exact causes of colorectal cancer. Doctors often cannot explain why one person develops this disease and another does not. However, it is clear that colorectal cancer is not contagious. No one can catch this disease from another person. Research has shown that people with certain risk factors are more likely than others to develop colorectal cancer. A risk factor is something that may increase the chance of developing a disease. The most important of these are the age, diet, obesity, diabetes & smoking, personal cancer history, alcohol consumption, large intestinal polyps, family history of colon cancer, race and ethnic background, genetic or family predisposition.

• Colorectal cancer is more likely to occur as people get older. More than 90 percent of people with this disease are diagnosed after age 50.
• Studies suggest that diets high in fat (especially animal fat) and low in calcium, folate, and fiber may increase the risk of colorectal cancer.
• Also, some studies suggest that people who eat adiet very low in fruits and vegetables may have a higher risk of colorectal cancer.
• A person who smokes cigarettes may be at increased risk of developing polyps and colorectal cancer.
• A person who has already had colorectal cancer may develop colorectal cancer a second time.

Two kinds of observations indicate a genetic contribution to CRC risk: a) increased incidence of CRC among persons with a family history of CRC; and b) families in which multiple family members are affected with CRC, the pattern indicates an autosomal dominant inheritance of cancer susceptibility. The molecular basis of CRC is multifactorial, and is likely to involve the actions of genes at multiple levels along the multistage carcinogenesis process. Examples of genes involved in pathogenesis of CRC include p53, Transforming Growth Factor (TGF)-β, SMADs, K-RAS, p16, p14, APC, β-catenin, E-cadherin, MLH1, MSH2, MSH6, PMS2, AXIN, STK11, and PTEN.

HISTOPATHOLOGY

Colorectal tumors present with a broad spectrum of neoplasms, ranging from benign growths to invasive cancer, and are predominantly epithelial-derived tumors (i.e., adenomas or adenocarcinomas). Pathologists have classified the lesions into three groups: nonneoplastic polyps, neoplastic polyps (adenomatous polyps, adenomas), and cancers. More than 95% of CRCs are carcinomas and among them 95% are adenocarcinomas. While there is no direct proof that most CRCs arise from adenomas, adenocarcinomas are generally considered to arise from adenomas based upon these two important observations: a) benign and malignant tissue occur within colorectal tumors; and b) when patients with adenomas were followed for 20 years, the risk of cancer at the site of the adenoma was 25%, a rate much higher than that expected in the normal population.

SYMPTOMS

A common symptom of colorectal cancer is a change in bowel habits. Symptoms include:
• Having diarrhea or constipation
• Feeling that your bowel does not empty completely
• Finding blood (either bright red or very dark) in your stool
• Finding your stools are narrower than usual
• Frequently having gas pains or cramps, or feeling full or bloated
• Losing weight with no known reason
• Feeling very tired all the time
• Having nausea or vomiting

Most often, these symptoms are not due to cancer. Other health problems can cause the same symptoms. Anyone with these symptoms should see a doctor to be diagnosed and treated as early as possible. Usually, early cancer does not cause pain. It is important not to wait to feel pain before seeing a doctor.

SCREENING TESTS

Because CRC develops slowly from removable precancerous lesions, screening & detection of the disease at an early stage during regular health examinations can reduce both the incidence and mortality of the disease. Some of the most commonly screening tests employed for the detection of CRC are:
Fecal occult blood test (FOBT): Fecal hemoglobin Stool-based screening for CRC is simple, inexpensive and the least invasive method of screening available. FOBT, which is the most widely used screening modality for CRC, detects hemoglobin enzymatically or immunologically. If this test detects blood, other tests are needed to find the source of the blood. Benign conditions (such as hemorrhoids) also can cause blood in your stool.

Sigmoidoscopy or Colonoscopy: A lighted tube called a sigmoidoscope a colonoscope is inserted inside the rectum and the lower part of the colon to check for any malignant growth. Sigmoidoscopy offers significant improvements in detection rates for CRC. However, the diagnostic value of both is limited with regards to costs, risks, and inconvenience.

Double-contrast barium enema: An enema with a barium solution and air is pumped into the rectum. Several x-ray pictures are taken of the colon and rectum. The barium and air help the colon and rectum show up on the pictures and help in detection of any unusual growth.

Who Should Get Them Done?
• People who have a family history of cancers
• People in their 40s and older
• People who are at higher-than-average risk of CRC (High Risk Groups)

All of these screening tests are done on regular basis in almost all health centres across the valley including SKIMS. If tests show an abnormal area (such as a polyp) of growth, a biopsy to check for cancer cells may be necessary. Often, the abnormal tissue can be removed during colonoscopy or sigmoidoscopy. A pathologist checks the tissue for cancer cells using a microscope to ascertain the malignant nature of the tissue. The patient is also simultaneously asked to perform the marker tests; serum markers -CEA, CA19-9, prolactin or gene markers – kras, APC, P53 etc.

KASHMIR CHAPTER

In Kashmir valley the trends of the lifestyle in both urban and rural areas are changing drastically and so are the trends of the cancers. Colorectal cancer now represents the third most common cancer in the valley closely following esophageal and gastric cancer. Almost 200 odd patients suffering from CRC are treated annually in SKIMS alone. And about 30% of these cases come in late advanced stage with complications and have to be operated in emergency.

As all of these cancers affect the Gastro Intestinal Tract (GIT), the link between the dietary habits of the people and the cancers is immediately speculated. In three landmark studies conducted by Siddiqi et al in Kashmiri population an association between the presence of nitrosamines in various food stuffs used in Kashmir was shown (1991-1998). His studies also associated the consumption of noon chai with the progression and development of GIT related cancers. Mir et al (2005) also speculated the role of nitroso amines in the development of GIT related cancers, in addition the found females to be at increased risk of developing esophageal cancer.
In a study conducted by Me and Dr. Shakeel (2008) in CRC patients of the Kashmir we found the mutations of the p53 gene to be associated with the development & progression of CRC. Out of fourty two CRC patients 19 (45%) had mutations in p53 gene. This study also revealed the significant association in the incidence of p53 mutations in smokers rather than non-smokers and in Dukes Stage C and D than in A and B. A significantly higher frequency of p53 mutations was seen in rectal (75%) compared with colon (18.1%) cancers. However the comparison did not show significant association with age, sex, and dwelling. In another study on CRC for Kras gene mutations (2009), I found out that out of 53 patients studied 22% patients had mutations in this gene. These K-ras mutations were significantly associated with advanced Dukes’ stage, positive lymph node status and mucinous histotype. These studies mark the importance that both these genes can be used as the prognostic tools for the early detection of the CRC in conjunction with the other screening methods for better management of the disease. Further more, my year long study also observed that male & female sexes were being affected equally by CRC, although the CRC cases were more from rural areas than from urban ones. Also most of the CRC patients were from poor socio-economic background.