Chapter 2
REVIEW OF LITERATURE
Cancer
Cancer is a genetic disease, arising from an accumulation of mutations that promote clonal selection of cells with increasingly aggressive behavior. The vast majorities of mutations in cancer are somatic and are found only in an individual’s cancer cells. However, about 1% of all cancers arise in individuals with an unmistakable hereditary cancer syndrome (Fearon, 1997). Cancer is a progressive disease, occurring in a series of well-defined steps, typically arising as a consequence of activating mutations (oncogenes) or deactivating mutations (tumor suppressor genes) in proliferating cells (Lisa et al., 2001). Cancer is an English term, dissimilated from Greek word 'Karakinos' (Sanskrit Karkita) for crab, the symbol for fourth zodiacal constellation (the CANCER) or Cancer is a generic term that refers to a group of chronic diseases characterized by the uncontrolled growth of abnormal cells within the body.. The word was believed to be first used by Hippocrates, who attributed this disease to an excess of black bile. Cancer was known in old ages, being described in early writings of Greeks and Romans. Pathological evidences support the bone tumors in dinosaurs and other prehistoric animals but the tumors in Egyptian mummies dating back to 5000 years represent the first known human malignancies. Later, the Roman physician Celsus (28-50 BC) used the Latin term for crab, cancer. Another Roman physician, Galen, (130-200 AD) used the Greek word for swelling, oncos, to describe tumours -the root of the modern English word, oncology. Cancer has been defined in terms of an autonomous growth that is unresponsive to normal growth factors and antigrowth signals; in provisions of irreversibility with which the cancer cells progressively lose the differentiated characteristics and functions of normal tissue of origin; on the basis of morphologic and cytogenetic features; and on the basis of reversion to growth and antigenic properties characteristics of fetal cells. Normally, cells divide and replicate to replace worn-out cells or to repair some form of injury to tissues of the body. After a predictable period, normal cells wear out and die. Cancer cells do not grow, divide and die in the same predictable fashion as normal cells. Rather, they grow, divide and create more abnormal cells, which outlive normal cells. The abnormal cells often spread to other body parts, invading other organs or systems.
Gastric cancer
Gastric cancer refers to cancer arising from any part of the stomach. Gastric cancer is often either asymptomatic (producing no noticeable symptoms) or it may cause only nonspecific symptoms (symptoms which are not specific to just gastric cancer, but also to other related or unrelated disorders) in its early stages. By the time symptoms occur, the cancer has often reached an advanced stage and may have also metastasized (spread to other, perhaps distant, parts of the body), which is one of the main reasons for its relatively poor prognosis.
Gastric cancer can cause the following signs and symptoms:
Stage 1 (Early)
Ü Indigestion or a burning sensation (heartburn)
Ü Loss of appetite, especially for meat
Ü Abdominal discomfort or irritation
Stage 2 (Middle)
Ü Weakness and fatigue
Ü Bloating of the stomach, usually after meals
Stage 3 (Late)
Ü Abdominal pain in the upper abdomen
Ü Nausea and occasional vomiting
Ü Diarrhea or constipation
Ü Weight loss
Ü Bleeding (vomiting blood or having blood in the stool)
Ü Dysphagia; this feature suggests a tumor in the cardia.
Pathology
The primary epithelial tumour of the stomach is the adenocarcinoma, and develops from the stomach mucosa, usually maintaining glandular differentiation. Other less common tumours of the stomach are the squamous cell carcinomas, and the adenosquamous carcinomas, combining characteristics of both the adenocarcinoma and the squamous cell carcinoma to approximately equal extent. Undifferentiated carcinoma lacks any differentiated features and does not fit into any of the above categories. Gastric carcinomas can be classified according to their localization in the stomach. The antral-pyloric region of the stomach is the most common site of stomach cancer, and carcinomas of the body or corpus are located along the greater or lesser curvature. Cancers of the cardia are often unable to be distinguished from cancers of the gastroesophageal junction, and are believed to be a separate entity, probably originating from the distal oesophagus. Early gastric cancers may feature protruded (Type I), elevated (Type IIa), flat (Type IIb), depressed (Type IIc) or excavated (Type III) growth (Hamilton and Aaltonen, 2000), whereas advanced gastric carcinomas are classified into polypoid (Type I), fungating (Type II), ulcerated (Type III) or infiltrative (Type IV) growth patterns (Borrmann, 1926; Hamilton and Aalton, 2000). Type II or III advanced gastric cancers are commonly ulcerating, and the risk of penetration of the submucosa is highest in early gastric cancers with a depressed growth pattern (Type IIc), and in infiltrative advanced gastric carcinomas (Type IV). The superficial spread of Type IV infiltrative (diffuse) tumours through the mucosa and submucosa result in flat, plaque-like lesions, which may exhibit shallow ulcerations. Serosal, lymphatic, and vascular invasion and lymph node metastases are most frequent in the diffusely growing tumours (Mori et al., 1995; Carneiro, 1996).
Histological classification
Various systems have been applied to the classification of gastric carcinomas, including the WHO (Laurén, 1965; Ming, 1977; Goseki and Koike, 1992; Hamilton and Aalton, 2000) classifications. The clinical significance of these classifications is limited, with only the Lauren and perhaps the Goseki classifications providing prognostic assessments (Alekseenko et al., 2004). The TNM staging of the gastric carcinoma, according to the guidelines set out by the International Union Against Cancer (UICC) (Wittekind and Sobin, 2002), is the most important prognostic factor in clinical practice (Alekseenko et al., 2004). However, the Lauren classification has been the most successful system, as it defines two distinct histological entities, which clearly exhibit different clinical and epidemiological characteristics, even in advanced gastric cancers (Satoh et al., 2007). In the Laurén classification(Laurèn, 1965), intestinal-type carcinomas maintain the glandular phenotype, with well- to moderately-differentiated tumours forming identifiable glands, often with poorly differentiated tumour cells at the invasive front. Typically arising on a background of intestinal metaplasia, these tumours exhibit an intestinal, gastric and gastrointestinal mucinous phenotype. Diffuse-type carcinomas form no or very few glandular structures, instead usually infiltrating the gastric wall, appearing diffusely distributed as small, round single cells or poorly cohesive cell clusters. They may resemble signet-ring cells, and may contain small amounts of intestinal mucin. Additionally, mixed tumours exhibit both intestinal and diffuse characteristics, and undifferentiated tumors are classified as indeterminate. The natural history of gastric carcinoma, in particular the association with environmental factors, incidence trends, and precursor lesions, is often evaluated with respect to the Laurén classification.
Descriptive epidemiology
One of the notable features of the descriptive epidemiology concerning gastric cancer is that it establishes some clear distinction between cancer localized to the gastric cardia and cancer of the rest of the stomach, as discussed below.
International variations
Despite a major decline in the incidence and mortality over several decades, gastric cancer is still the fourth most common cancer and the second to third most frequent cause of cancer death in the world (Brenner et al., 2009; Herszenyi and Tulassay, 2010). There is marked geographic variation in the incidence of gastric cancer. International Agency for Research on Cancer data for 1996, demonstrate age-standardized incidence rates in males ranging from 95.5/10.5 in Yamagata, Japan,to 7.5/10.5 in Whites in the United States. High-risk areas include China and large parts of central and South America (Parkin and Ferlay, 1997). Most of the geographic variation is accounted for by differences in the incidence of non cardia cancer. Cancer localized to the cardia has a more uniform distribution. Gastric cardia cancer accounts for only 4% of total gastric cancer cases in males in Osaka, Japan, compared to 39% in white males in the United States (Parkin and Ferlay, 1997). On a histologic level, the incidence of diffuse adenocarcinomas is reported to be similar in most populations, while the intestinal type predominates in the high-risk geographic regions and is the type that has declined significantly in incidence in many countries (Munoz and Cuello, 1968; Sipponen and Kekki, 1987). Ethnic groups who have migrated from high- to low-incidence countries have an overall risk intermediate between that of their homeland and that of their new country. First generation migrants tend to maintain their high-risk while subsequent generations have risk levels approximating that of the host country (Haenszel, 1968). The prognosis is rather poor, with a five-year survival below 30%. More than 90% of gastric cancers are adenocarcinomas, which are malignant epithelial tumors, originating from glandular epithelium of the gastric mucosa. In the Lauren classification, two major histological types of gastric adenocarcinoma can be distinguished histopathologically: the diffuse and the intestinal type (Vauhkonen et al., 2006). Intestinal metaplasia with goblet cells is considered to be a precursor lesion of the intestinal type of gastric adenocarcinoma, which shows tubular differentiation (Vauhkonen et al., 2006). The diffuse type gastric adenocarcinoma is characterized by non-cohesive single mucocellular cancer cells (signet-ring cells) diffusely infiltrating the stroma (Vauhkonen et al., 2006). The diffuse type gastric adenocarcinoma shows some predominance in the fundus and corpus of the stomach, whereas the intestinal type gastric adenocarcinoma prevails in the antrum (Vauhkonen et al., 2006). Furthermore, the remaining 10% of gastric malignancies are lymphomas or originate from gastrointestinal stromal tissue (soft tissue tumors) (Verbeke et al., 2012).
Indian variations
Cancer is one of the leading causes of adult deaths worldwide. In India, the International Agency for Research on Cancer estimated indirectly that about 635 000 people died from cancer in 2008, representing about 8% of all estimated global cancer deaths and about 6% of all deaths in India (Ferlay et al., 2010). 7137 of 122 429 study deaths were due to cancer, corresponding to 556 400 national cancer deaths in India in 2010. 395 400 (71%) cancer deaths occurred in people aged 30–69 years (200 100 men and 195 300 women). At 30–69 years, the three most common fatal cancers were oral (including lip and pharynx, 45 800 [22·9%]), stomach (25 200 [12·6%]), and lung (including trachea and larynx, 22 900 [11·4%]) in men, and cervical (33 400 [17·1%]), stomach (27 500 [14·1%]), and breast (19 900 [10·2%]) in women. Tobacco-related cancers represented 42·0% (84 000) of male and 18·3% (35 700) of female cancer deaths and there were twice as many deaths from oral cancers as lung cancers. Age-standardised cancer mortality rates per 100 000 were similar in rural (men 95·6 [99% CI 89·6–101·7] and women 96·6 [90·7–102·6]) and urban areas (men 102·4 [92·7–112·1] and women 91·2 [81·9–100·5]), but varied greatly between the states, and were two times higher in the least educated than in the most educated adults (men, illiterate 106·6 [97·4–115·7] vs most educated 45·7 [37·8–53·6]; women, illiterate 106·7 [99·9–113·6] vs most educated 43·4 [30·7–56·1]). Cervical cancer was far less common in Muslim than in Hindu women (study deaths 24, age-standardised mortality ratio 0·68 [0·64–0·71] vs 340, 1·06 [1·05–1·08] (Rajesh et al., 2012).
Kashmir variations
The valley of Kashmir is one of the divisions of Jammu and Kashmir State, situated in the Himalayas. In Kashmir valley where incidences of almost all types of organ cancers have shown a drastic increase in last couple of decades particularly gastric cancer. Gastric cancer is the leading one with an average frequency of 19.2% followed by esophagus and lung as 16.5% and 14.6%, respectively. In cancer types common to both sexes, the proportion in the men exceeds that in the women particularly in lung and bladder cancer where around 80% were males. Stomach (23%) and lung (21%) are the leading cancers in men while as esophageal cancer tops (18.3%) in women followed by breast cancer (16.6%). Those tumors affecting the stomach and extending to the esophageal lumen were considered gastric cancers. An interesting finding was the presence of around 30% adenocarcinoma of GE junction among the total frequency of stomach cancers. Around 21% of GE junction cancers were of sqamous cell carcinoma of esophageal origin while as around 8% were recorded as adenocarcinoma of esophageal origin. The age-standardized rates (ASR) of incidence of stomach cancer tops the list with 10.2 cases/100,000/year followed by esophageal cancer (9.4/100,000) and lung cancer accounts for third incident cancer (7.8 cases/100,000/year) (Arshad et al., 2012).
Age, sex and Race
The incidence of gastric cancer rises progressively with age, with most patients being between the ages of 50 and 70 years at presentation. Cases in patients younger than 30 years are very rare. Noncardia cancer is more common in males than females by a ratio of approximately 2:1. Gastric cardia cancer has a higher male-to-female ratio, of up to nearly 6:1 in U.S. Whites (Parkin and Ferlay, 1997). There are significant variations in the overall incidence of gastric cancer between different ethnic groups living in the same region (Parkin and Ferlay, 1997). The ethnic distribution for cardia cancer is different, with a preponderance in Whites over Blacks in the United States and non-Maoris over Maoris in New Zealand (Parkin and Ferlay, 1997).
Socioeconomic status
Low socioeconomic status has been consistently shown to be associated with an increased risk of gastric cancer overall (Howson and Wynder, 1986). Remarkably, the increase in incidence of cardia cancer has been predominantly in professional classes (Powell, 1992).
Aetiology and risk factors
Aetiological factors
Migrants from high- to low-incidence countries tend to maintain the high risk of the population of origin. However, subsequent generations of migrants have risk levels approximating those in the host country (Stewart BW 2003). It has been suggested that approximately 66–75% of stomach cancer risk could be reduced with high intake of fruit and vegetables and low consumption of salted foods (AICR 1997). The World Cancer Research Fund (WCRF) and Association for International Cancer Research (AICR) panel of experts reached the following conclusions:
Ü The evidence that diets high in vegetables and fruits, collectively and separately, decrease the risk of stomach cancer is convincing. There is consistent evidence that raw vegetables, allium vegetables and citrus fruits have a protective effect. A negative role has been ascribed to salted nd pickled vegetables.
Ü There is also convincing evidence that the availability of refrigeration—which facilitates year-round consumption of vegetables and fruits and may also reduce the need for salt as a preservative—protects against stomach cancer.