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From the Department of Surgery, University of Ioannina Medical School, Ioannina, Greece.
Correspondence: Address correspondence to: Dimitrios Roukos, MD, Department of Surgery, University of Ioannina Medical School, PO Box 105 Neochoropoulo, Ioannina 455 00, Greece; Fax: 30-651-48451; E-mail: droukos{at}cc.uoi.gr
Conventional surgery in the treatment of solid tumors suggests a recently declining trend. Endoscopic and laparoscopic techniques are increasingly replacing traditional surgery as both rates of early detection and minimal invasive treatment are steadily increasing. Premalignant lesions and early-stage small cancers confined to the mucosal layer along the whole gastrointestinal tract, from esophagus and stomach to the colorectum, can now curatively be resected by minimally invasive techniques substantially improving the quality of life of many patients.
In contrast, traditional surgical resection of specific organs for the protection of individuals at very high risk of developing inherited cancer in the breast, colon, and stomach is increasingly receiving considerable attention. However, although surgery is the only preventive intervention able to eliminate the risk of cancer at a specific organ, surgical prophylaxis has been controversial, for a numerous amount of reasons and questions have been raised. Here we discuss the benefits and obstacles of prophylactic surgery.
Hereditary cancer syndromes are rare. They account for less than 5% of all cases because most breast, colon, or gastric adenocarcinomas occur sporadically. These syndromes include hereditary nonpolyposis colon cancer syndrome, Peutz-Jeghers syndrome, Cowden syndrome, and some kindreds affected with Li-Fraumeni syndrome and familial adenomatous polyposis.1 Mutations in BRCA1 and BRCA2 genes have been identified, 8 years ago, to cause hereditary breast-ovarian cancer syndrome. Recently, hereditary diffuse gastric cancer (HDGC) syndrome, which is an autosomal dominantly inherited gastric cancer susceptibility syndrome caused by germ-line mutations in CDH1, the gene encoding E-cadherin, 2 has been added to the list of these syndromes.
Surgery in the prophylaxis of multiple-case family members is not an innovative approach. Prophylactic bilateral mastectomy in women with a family history of breast cancer has previously been performed and proposed as effective in reducing the risk of breast cancer.3 However, this preventive approach has been strongly criticized, particularly because surgery may be nontherapeutic and thus, unnecessarily performed in many women selected on the basis of family history and clinical criteria. By contrast, genetic testing provides a more accurate risk assessment allowing surgery to target individuals who are really at very high risk for cancer. Indeed, estimates indicate that only 25% among members of the families with hereditary breast-ovarian cancer or diffuse gastric cancer syndrome are carriers of mutations in BRCA and CDH1 genes, respectively.
The knowledge of the probability that cancer will in fact develop in a carrier of a particular mutation (i.e., the penetrance of the mutation) is essential in the clinical management of these high-risk persons. Women with mutations in BRCA1 and BRCA2 genes have a cumulative lifetime risk of 50% to 85% for breast cancer and a 10% to 40% risk for ovarian cancer.4 Carriers of a mutation in the CDH1 gene are thought to have an approximately 70% lifetime risk of gastric cancer;5,6 67% for men and 83% for women who had an additional risk of 39% for breast cancer.7
This high risk of breast-ovarian cancer and gastric cancer in carriers of mutations in BRCA and CDH1 genes, the ineffectiveness of surveillance, and the high lethality by late diagnosis are the main argues for the recommendation of prophylactic surgery as a reasonable strategy. Several current studies validate this prevention option.
In a recent study of 119 women carrying BRCA mutations, breast cancer at a 3-year period developed in 8 of 63 women who had elected close clinical surveillance but in none of the 76 carriers of such mutations who had undergone prophylactic surgery.8 In two other current and simultaneously published studies,9,10 prophylactic oophorectomy was performed in women with BRCA mutations after childbearing was complete, although the risk of ovarian cancer is considerably lower than the risk of breast cancer. In both studies salpingo-oophorectomy, as compared with intense surveillance, significantly reduced not only the risk of BRCA-related gynecologic cancer but also the risk of breast cancer.
Since the first description in 1998 of the inactivation of CDH1, a tumor suppressor gene, in three Maori families predisposed to HDGC,2 the first clinical implications of this discovery confirm the high penetrance of this gene. Microscopic foci of diffuse gastric cancer were found in all 10 gastrectomy specimens of asymptomatic carriers of CDH1 germline mutations in two recent simultaneously published studies.11,12 Surveillance with endoscopic biopsies, endoscopic ultrasonography, and/or chromoendoscopy was proven ineffective to predict the disease. Although these results support the role of prophylactic surgery in the management of CDH1 mutation carriers, they are limited by the small numbers, lack of follow-up, and the unknown natural history and biological behavior of these early lesions.11
Arguments Against Surgical Prophylaxis
Although most authors and experts advocate prophylactic surgery as a more effective preventive strategy than closed surveillance for BRCA and CDH1 mutation carriers, 4,6,8–12 there is a number of limitations and questions; none of the available studies is a randomized trial, the time to cancer rather than overall survival was selected as end point, the penetrance of these genes is incomplete, there is an additional risk of cancer at another organ, and surgery-related adverse effects on morbidity and quality of life may be substantial.
Prophylactic bilateral mastectomy had a negative effect on self-esteem, sexual relationships, and satisfaction with body appearance.13 Salpingo-oophorectomy, besides these psychosocial and sexual effects, may have additional adverse effects on the lipid profile,14 cardiovascular disease,15 and osteoposteoporosis,16 and may produce more physical symptoms than those who underwent screening.17 Similarly, prophylactic gastrectomy is associated with considerable adverse effects on morbidity and quality of life. Because of the nature of HDGC to affect the whole stomach with multifocal lesions only total gastrectomy is indicated, which, however, is associated with more adverse effects on morbidity, nutritional status, and quality of life than partial resection of the stomach. Although total gastrectomy may potentially cause death and disability the rates of postoperative morbidity and mortality have recently been drastically reduced.18 Especially for young healthy CDH1 carriers undergoing a prophylactic and thus simple total gastrectomy, without resection of neighboring organs or node dissection, this risk is minimal. Clinically relevant is the effect of total gastrectomy on quality of life. Postoperative weight loss and other metabolic and nutritional changes are considerable. However, adequate reconstruction after total gastrectomy and nutritional surveillance decreases the risk of developing severe disturbances in bone metabolisms, food intake, body composition, and quality of life.19 Although it remains controversial which reconstruction method provides the best quality of life, several reports indicate a superiority of jejunal pouch versus Roux-en-Y technique.19
The incomplete penetrance of BRCA and CDH1 mutations, estimated at approximately 70%, is another substantial limitation because prophylactic surgery will be nontherapeutic and unnecessary in 30% of the carriers. Besides this excess risk, carriers of these mutations are also at risk, although substantially lower, of cancer at another organ. This makes a medical decision more difficult. Whether prophylactic mastectomy or oophorectomy after childbearing is complete is the optimal procedure in BRCA mutation carriers is controversial and will probably remain a personal choice. Prophylactic total gastrectomy in CDH1 mutation carriers protects from stomach cancer, but these women will remain at an increased lifetime risk of breast cancer. An extremely radical approach with multiorgan surgical removal, although it offers a more complete protection, substantially increases the adverse effects on morbidity and quality of life.
Taken together all these data, genetic testing in high-risk family members is strongly recommended. In unaffected siblings prophylactic surgery should not be considered in the prevention strategy. Carriers of mutations in BRCA1, BRCA2, or CDH1 genes are at high risk of breast-ovarian cancer or gastric cancer, respectively, but the clinical management remains controversial. For medical recommendation according to the evidence-based principles, more prospective data with appropriate surveillance protocol, longer follow-up, and overall survival as end point are needed. At the present time the available current data indicate the superiority of surgical prophylaxis as compared with surveillance in reducing the risk of cancer in carriers of BRCA or CDH1 mutations. However, all the adverse effects and limitations of surgery should also be discussed in extensive preoperative counseling.
Received for publication June 19, 2002. Accepted for publication June 20, 2002.
REFERENCES
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  E. Briasoulis, D. Ziogas, and M. Fatouros Prophylactic Surgery in the Complex Decision-Making Management of BRCA Mutation Carriers Ann. Surg. Oncol., June 1, 2008; 15(6): 1788 - 1790. [Full Text] [PDF]
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