Cancer screening in patients with cancer.

Abstract

; Interest in multiple primary malignant neoplasms is longstanding since the Warren–Gates report (1) in 1932. We have the impression that multiple cancer cases have recently been increasing in number. Multiple primary neoplasms in the same individual are experienced more frequently as advances in cancer treatment prolong life. Improved survival rates for patients with neoplastic disease, largely due to early diagnosis, allow more patients to survive long enough to develop subsequent primary tumors. The development of more sophisticated invasive and noninvasive diagnostic tools has made it possible to detect cancer at an early stage. Furthermore, it has contributed to the detection of synchronous occult tumors which were formerly overlooked. Cases of multiple primary cancers raise questions about underlying environmental factors or host susceptibility factors. A true increase in the occurrence of additional carcinoma from an unknown cause is strongly suspected. Environmental factors are thought to play a major role in carcinogenesis. Carcinogens have a regional carcinogenic effect over an area in which multiple cell groups undergo a process toward malignancy. In individuals developing multiple primary malignancies in functionally and anatomically allied organs, environmental factors are thought to play a major role in carcinogenesis. Carcinogenesis in different organs subjected to the same carcinogens and promoting factors has led to the concept of a multicentric pathogenic process termed ‘field cancerization’ (2). In patients with multiple primary cancers, intercancer correlations were found to be statistically significant. An individual developing more than one primary tumor in anatomically and functionally unrelated organs may be considered ‘cancer-prone.’ Genetic cancer susceptibility is acquired when cancer-predisposing mutations occur. People with a family history of cancer will inherit genetic cancer susceptibility as a risk factor for cancer. Gene mutations influence cancer susceptibility through changes of metabolism and catabolism of carcinogens. Tumor suppressor genes, such as p53 and FHIT, may be candidates for target genes of these risk factors (3). Genetic instability is also considered a driving force behind carcinogenesis and the alterations of the length of single repetitive genomic sequences or microsatellite instability, implicating impaired DNA repair mechanism (4). Genetic background may influence the development of multiple primary tumors. Newly diagnosed people and survivors of earlier cancers, who have genetic cancer susceptibility, therefore, have an increased risk of multiple primary tumors. The incidence of multiple primary cancers in patients with esophageal cancer is known to be high. Subsequent other primary cancers have become a new problem for patients who survive esophageal cancer. Squamous cell carcinoma of the esophagus is associated with cancers of the upper respiratory and digestive tract. Although the reason for the high frequency of additional malignancies in esophageal cancer patients is yet to be identified, the most convincing hypothesis is the field cancerization theory. Carcinogens affecting the esophagus also affect the entire respiratory and upper digestive tracts. Alcohol and tobacco consumption are the most common risk factors in patients with esophageal carcinoma. These are also known as crucial environmental risk factors for multiple cancers of the upper aero-digestive tract. Subsequent cancers of the stomach and hypopharynx develop significantly more frequently in heavy smokers (5). Oncoprotein overexpression or gene amplification is also associated with almost all gastrointestinal tract malignancies including esophageal, gastric and colorectal cancers (6). In this issue, Kagei et al. (7) report the high incidence and relatively good outcome for patients with second primary carcinoma to justify the efficacy of screening for multiple primary cancers in patients with esophageal cancer. Patients with esophageal cancer are especially at high risk of developing squamous cell carcinoma in the head and neck. Panendoscopy is recommended on all patients with a carcinoma of the aero-digestive tract to diagnose simultaneous or synchronous primary tumors based on the field cancerization theory (8). Among carcinomas of the aero-digestive tract, esophageal squamous cell carcinoma and gastric cancer are rarely associated except in Japan. An association with adenocarcinomas of the stomach may be coincidental owing to the high frequency of gastric and esophageal tumors in Japan (9). Esophageal squamous cell carcinoma and lung cancer also appear to be rarely associated (10). The prospective study could not distinguish the patients at high risk of developing esophageal and co-existing colorectal cancer (11). Kagei et al. reported the efficacy of screening and surveillance for synchronous second primary cancer in patients with esophageal cancer (7). The efficacy of screening should be estimated in terms of cost–benefit. For improving cost–benefit, it is important to define the appropriateness of particular surveillance approaches and identify a subject with an increased risk of cancer. The significance of the high detection rates of synchronous second primary cancer should be evaluated using the observed-to-expected ratio (O/E ratio) (12). The patterns of