Ever since Billroth’s report, in 1889, of a patient with multiple tumors, a gastric carcinoma that developed after the removal of a spinocellular epithelioma of the right ear, MPM have been objects of medical curiosity (5
). Until 1932, only a few such cases had been recognized, when Warren and Gates classified 1,259 such patients from literature reports and post mortem examinations and modified the diagnostic criteria for MPM, which included the following (6
): i) each tumor must present a definite picture of malignancy; ii) each tumor must be histologically distinct; and iii) the possibility that one is a metastasis of another must be excluded. A number of theories have been proposed to explain MPM but, to date, none have been proven, although the key risk factors appear to be smoking and family history (8
In review of the literature regarding MPM, several common points may be concluded (2
). First, the Japanese population appears to have a higher likelihood of developing MPM. Yamamoto et al
reported that 15 to 20% of Japanese patients with colorectal carcinoma developed MPM (9
). This may be caused by genetic susceptibility, longer average life span or medical advances in chemotherapy and radiotherapy. Second, most patients with MPM are geriatric. Third, smoking-related cancers, prostate cancers and renal cell carcinoma are most commonly associated with MPM (10
). Fourth, head and neck cancer survivors are at an increased risk of developing another cancer of the respiratory or digestive tract (11
). A ‘field cancerization effect’ was assumed to explain this phenomenon, with carcinogens to which the organ has been exposed initiating the proliferation of numerous clones of cells (12
). Carcinogenic insults, such as tobacco and alcohol, may increase the likelihood of multiple independent malignant foci developing in the mucosa epithelium. The patient (IV12, proband) described in the present study never smoked tobacco or drank alcohol, but he received chemotherapy and radiotherapy for the first primary cancer.
The frequency of MPM depends on the length of the observation period, applied diagnostic and prognostic criteria, exposure to environmental factors, genetically defined individual susceptibility, diagnostic accuracy, follow-up and administered treatment. There was no family history of FAP in this case, and two family members (IV7 and IV12) have multiple malignancies. Our patient (IV12, proband) was diagnosed with malignant histiocytoma and colonic cancer, which have different histopathological criteria. Family members in this case had a high incidence of colon cancer, suggesting that certain genetic features may induce tumorgenesis.
In 15–20% of patients with colon cancer there is evidence of a family history (13
). HNPCC is the most common form of hereditary colorectal cancers, with conservative estimates of 5–10% of the total colorectal cancer burden (14
). Predisposed individuals have an increased lifetime risk of developing colorectal, endometrial and other types of cancer. HNPCC may present with differing phenotypes and a detailed family history is required going back at least 3 generations (13
). The first report of a cancer family that represented what is now known as HNPCC was published by Aldred Scott Warthin, a renowned pathologist, in 1913 (16
). Over time, as general knowledge about HNPCC improved, more and more affected families were reported. The characteristic presentation of HNPCC is frequently right-sided localization, the presence of synchronous and metachronous colorectal carcinomas and its association with other HNPCC-related extra-colonic tumors, including gastric, endometrial and urinary and biliary tract cancers in afflicted families (13
). Pancreatic tumors have been reported in relatives with HNPCC (17
). Colorectal adenocarcinoma occurring in patients with HNPCC frequently exhibits medullary features. We report a case of MPM involving tubulovillous adenoma in the ascending colon and malignant histiocytoma in the scapular with family history of colorectal carcinoma. In this family, 11 members were diagnosed with colonic cancer. The family history is notable for a high incidence of right-sided colonic cancer with no evidence of FAP. HNPCC has an earlier age of onset, Crohn’s disease-like lymphocytic infiltration of tumor tissues, increased mucin production and a lower degree of histological differentiation compared with FAP (13
). In this case report, 11 patients were male and 3 were female, and the fourth generation was markedly younger than the third generation when their cancers were first diagnosed. This family fulfills Amsterdam criteria I, with high incidence in males and early age at onset of cancer.
We are aware of some limitations in this study. First, we report only one family history investigation with the charted family tree, which limits the ability to provide robust evidence. More cases should be investigated. Second, we were unable to demonstrate a detailed explanation for the mechanism of MPM and HNPCC. Further basic research is thus needed. Despite these limitations, we believe that the present study provides evidence to improve the recognition of MPM and HNPCC, which are not well-known among practicing physicians, leading to not recognizing families at risk.
In summary, cases with MPM have been reported more often in the recent literature, but clinicians should also keep in mind that the prevalence of MPM is increasing. The assumption of a new lesion in a patient with a previous history of cancer as metastasis could possibly change the treatment strategies and delay the management of a curable neoplasm. The early detection of additional primary malignancies will enable prompt management and is likely to increase the cure rate of the disease. Multiplicity of primary malignancies itself does not necessarily indicate a poor prognosis, as long as adequate diagnosis and management are performed (2
). This study suggests that family history may be a key risk factor for MPM and HNPCC, whose detailed molecular mechanism remains to be elucidated. This study, with an investigation of family history, may improve the clinical recognition of HNPCC and MPM, which is important for successful surgical treatment.