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Put simply, cancer is the uncontrolled growth of cells that can invade nearby structures as well as migrate to remote organs (metastasis).  Due to the invasive  nature of cancer, it can result     in death. Generally, a patient might develop malignancy if the required genetic and environmental disorders are fulfilled.3 In general, the malignancy in a patient is usually due to a single cancer (with or without metastasis). This means there is only one primary focus of the malignancy that causes the disease in the patient. However, in some uncommon cases, there might be more than one foci in a patient. This is called multiple cancers.

Table 1: Some interesting reports on multiple cancers

Multiple cancers is an interesting pathology. Below are some pathological descriptions of multiple cancers:10, 11

- Primary cancers that appear in a patient in different organs at the same time

- Cancer found in both sides of paired organs such as breast and kidney is not considered as a cancer in different organs

- Different kinds of malignancies in the same organ are considered as a cancer in the same organ

- The uterus with adnexa and the lower intestine are each classified as single organs

- There must be histological confirmation of malignant nature

- Metastatic lesions are not considered as a new primary cancer

- The malignancy must not be the result of previous cancer therapy (chemotherapy or radiotherapy)

These criteria are called “Werthamer criteria”.10 Multiple cancers is classified as a rare syndrome that   can be seen in less than 1 % of cancerous patients. Some rare combinations are sporadically reported in  literature12-16  (Table 1). Focusing on the natural history of multiple cancers, Schoenberg17 analyzed the Connecticut data during 1935-1964 and concluded that “individuals with one malignant neoplasm have 1.29 times the risk of developing a new independent primary tumor when compared to individuals who never had cancer”.  However, the increased risk seems to be site  depen-dent. According to another  newer  study   by  Ray  et  al.18, no increased risk could be observed for prostate cancer. Similar findings were also reported for laryn- geal cancer.19  Also, in this work19,  the size and site of   the laryngeal tumor was shown to have  no relationship  to the occurrence of other primary  cancers.  Patients  with multiple cancers usually have a family history of cancers. However, no family history can also be seen.16

As noted, genetic defects is an important basic requirement for carcinogenesis. For some cancers such  as retinoblastoma, there is already copious information on the underlying gene mutations that cause the cancers. For multiple cancers, the genes that have correlation are of interest. There are several, specific groups of multiple cancers that have strong evidence of genetic inheritance. The so called hereditary multiple cancer syndrome is the name of those disorders.20-22 Indeed, one-twentieth of overall cancers have a clear hereditary pattern. Those cancers are proved for passing from one to the next generation. Hence, the role of gene defect can be proven. Well-known hereditary syndromes include hereditary breast and ovarian cancer syndrome, Cowden syndrome and multiple endocrine neoplasia. The details of some important hereditary multiple cancer syndrome will be further discussed.

A. Von Hippel-Lindau disease

Von Hippel-Lindau disease (VHL) is a rare disease that involves many organ systems. The main disorders can be seen in the vascular system.It can be benign or malignant. In benign cases,the abnormalities might be angiomas.  In malignant cases, hemangioblastomas can be seen. The malignant hemangioblastomas in VHL are common at retina, brain and spinal cord.23-25 The concomitant primary tumors include adrenal tumor, kidney  cancer and pancreas cancer.23-25 Hence, it is a rule to com-  pletely investigate for these possible cancers in patients presenting with the VHL.

Focusing on the genetic defect in the VHL, the widely mentioned gene is the VHL gene. Mutations within the VHL gene can be seen in almost all patients with VHL. Generally, the VHL gene is responsible for the production of a specific protein, namely pVHL (213 amino acid residues, molecular weight of 24 to 30 kDa).26 Normally, this derived protein helps inhibit the hypoxia-inducible factor (HIF) via post-translational prolyl hydroxylation with use of a conserved family of Egl-nine enzymes and further targeting HIF for ubiquitin-mediated degradation.26-27 Aberration of the protein function is believed to be the starting point of carcinogenesis.26 This is well observed in the case of renal cell carcinoma.26, 28, 29

B. Cowden syndrome

Cowden syndrome(CS) is another rare multiple cancer syndrome whereby its underlying genetic pathology has been proven. The nature of this disease is the development of multiple tumor-like growths (hamartomas) of the skin and mucous membranes. Sometimes, abnormal growth can also be seen at the gastrointestinal tract or central nervous system. There are also reports on the increased risk of breast, uterus and thyroid cancers.30-33

Focusing on the genetic defect in CS, the widely mentioned gene is PTEN gene.34,35 The mutations within PTEN gene can be seen in almost all patients with  PTEN. Generally, PTEN is  a  tumor  suppressor  gene  on 10q23.3 which corresponds to encoding a lipid phosphatase that lies upstream of protein kinase B (Akt).35,36 PTEN negatively regulates  cell  interactions with the extracellular matrix and the aberration of this normal function can result in carcinogenesis.35

C. Li-Fraumeni Syndrome

Li-Fraumeni Syndrome (LFS) is another rare disorder with onset in the young. Increased risk of many cancers is observed in LFS. The problematic cancers include soft tissue sarcomas, breast cancer, leukemia, lung cancer, adrenocortical cancer and brain cancer.37-39

Focusing on the genetic defect in CS, the widely mentioned gene is the TP53 gene.40,41 The mutations within the TP53 gene can be seen in approximately 50% of the cases and common mutations are missense mutations, located between exon 5 and exon 8, within the DNA-binding domain of TP53.41 At present, the investigation for TP53 is more widely available. It is recommended for testing in any case with a tumor in the general population, belonging to LFS.41

D. Lynch syndrome

Lynch syndrome or hereditary non-polyposis colorectal cancer syndrome is another rate genetic disorder presenting with early age onset colorectal cancer, endometrial cancer and other extracolonic malignancies.42-44 The mutations in DNA mismatch repair genes (MLH1, MSH2,  MSH6  or  PMS2)  have  a  proven  relationship to Lynch syndrome.42-44 Due to the high incidence of colorectal cancer in the West, attempts to launch the screening investigation for Lynch syndrome have been widely mentioned and have been approved for their cost effectiveness.45 For screening, a combination of various genetic and immunohistochemical tests are used.46

E. Muir Torre syndrome

Muir Torre syndrome is a variant of Lynch syndrome. It is strongly related to skin cancers. The genetic disorder is usually within one of the DNA mismatch repair genes and can be seen in up to 70 % of the cases.47,48

F. Turcot syndrome

Turcot syndrome is another variant of Lynch  syndrome. It is strongly related to brain cancer (glioblastoma or astrocytoma).49, 50

G. Hereditary breast and ovarian cancer syndrome

Hereditary  breast  and   ovarian   cancer   syndrome is a genetic disorder that has a proven relationship to mutations in the BRCA1 and  BRCA2  genes.  It  is related to the increased risk of many cancers including breast cancer (in both sexes), ovarian cancer and prostate cancer. Also, there are some reports of a risk for pancreatic cancer and melanoma.51,52

Focusing on the risk, an 85% lifetime risk of breast cancer and up to a 46% lifetime risk ovarian cancer are reported.53 Preconception counseling is recommended for this syndrome.54

Gene defects is an important underlying pathology   in multiple cancers. There is already confirming evidence on the underlying abnormality of some genes  in several multiple cancers. Investigation into those problematic genes can be a basic screening tool for early detection and recognition of the possible occurrence of multiple cancers in a cancerous patient. There is no doubt that many primary cancers might be concurrent in a patient but only one cancer might be initially detected.   If it is affordable, screening should be performed in any cancerous patient as early as possible. Early diagnosis is the core concept in any cancer therapy, whether multiple or not.55