Role of Surgery in Cancer Prevention

José G. Guillem

Andrew Berchuck

Jeffrey F. Moley

Jeffrey A. Norton

Sheryl G. A. Gabram-Mendola

Vanessa W. Hui

INTRODUCTION

Since the heritable component of some cancer predispositions has been linked to mutations in specific genes, clinical interventions have been formulated for mutation carriers within affected families. The primary interventions for mutation carriers for highly penetrant syndromes, such as multiple endocrine neoplasia (MEN), familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (CRC), and hereditary breast and ovarian cancer syndromes, are primarily surgical. This chapter is divided into five sections addressing breast (S.G.A.G.), gastric (J.N.), ovarian and endometrial (A.B.), and MENs (J.F.M.) and colorectal (J.G.G., V.W.H.). For each, the clinical and genetic indications and timing of prophylactic surgery and its efficacy, when known, are provided.

Prophylactic surgery in hereditary cancer is a complex process, requiring a clear understanding of the natural history of the disease and variance of penetrance, a realistic appreciation of the potential benefit and consequence of a risk-reducing procedure in an otherwise potentially healthy individual, and the long-term sequelae of such surgical intervention, as well as the individual patient’s and family’s perception of surgical risk and anticipated benefit.

PATIENTS AT HIGH RISK FOR BREAST CANCER

Identification of Patients at Risk

A detailed family history is the most important tool for identifying individuals at increased risk for hereditary cancers. The US Preventive Services Task Force updated their recommendation for risk assessment, genetic counseling, and genetic testing for asymptomatic women who have not been diagnosed with a BRCA-related cancer. In this update, the use of a risk screening tool is highly recommended to identify appropriate patients for referral for genetic counseling.¹ The American Society of Clinical Oncology has also updated the policy on genetic and genomic testing for cancer susceptibility, and this update includes information on genetic tests of uncertain clinical utility and direct-to-consumer marketing, both of which impact the practice of oncology and preventive medicine.² Historically, genetic counseling and testing were offered by health-care providers. However, with the advent of direct-to-consumer marketing, individuals may obtain tests and receive results directly from a company. The American Society of Clinical Oncology still endorses pre- and posttest counseling for thorough disclosure of the impact of testing. Before any woman considers risk-reduction surgery such as bilateral mastectomy or salpingo-oophorectomy, referral to a high-risk or genetic screening program is desirable, as women often overestimate their actual breast cancer risk.³

The most common cancer syndromes that place women at risk for breast cancer are BRCA1⁴ and BRCA2⁵ gene mutations. Other less common syndromes are listed in Table 32.1.⁶^,⁷

Following referral for genetic assessment, three groups of patients emerge.⁸ The first consists of those women who have undergone genetic testing and have been found to harbor a mutated gene associated with high penetrance for breast cancer. Given that the possibility of developing breast cancer in this group may be as high as 90%, there is a role for enhanced surveillance or risk-reduction surgery. The American Cancer Society has published guidelines for magnetic resonance imaging (MRI) screening as a method for enhanced surveillance.⁹ Women in this first group qualify for such screening, which can be offered annually but scheduled at 6-month intervals with screening mammography to increase the rate of identifying interval cancers. Alternatively, simultaneous screening with MRI and mammography to compare one modality with the other on an annual basis may also be offered. Another choice for this group of women is to pursue bilateral risk-reduction mastectomy with an option for immediate reconstruction. Bilateral salpingo-oophorectomy for BRCA1 and BRCA2 mutation carriers may also be considered, as this procedure has been shown to reduce breast cancer risk by almost 50%.⁸^,¹⁰ This is especially true for BRCA2 mutation carriers, who tend to develop hormone receptor-positive breast cancers.

The second group consists of women with strong family histories suggestive of hereditary breast cancer who test negative for both the BRCA1 and BRCA2 mutations as well as the other described syndromes. In this group, there may not have been a family member with cancer who was tested for the mutation. Therefore, a negative test does not necessarily indicate that a woman’s risk is equivalent to that of the general population.⁷ There may also be an undetected mutation in such a family, indicating the possibility of higher-than-average risk for that particular woman. These women may or may not qualify for enhanced surveillance with MRI screening,⁹ and accurate assessment of their risk may require the use of other risk prediction tools,³ in addition to evaluating for the presence of lobular carcinoma in situ, atypical lobular hyperplasia, or atypical ductal hyperplasia, and determining if a more intensive surveillance regimen is necessary based on heterogeneously or extremely dense breast tissue on mammography.

The third group consists of women with a strong family history of breast cancer, who for various reasons, have chosen not to pursue genetic testing. These individuals may have other healthrelated problems, psychological concerns, cost issues, or they may fear perceived medical insurance discrimination. Women in all groups can be educated that with passage of the Genetic Information Nondiscrimination Act in 2008, significant advances have occurred that protect patients from discrimination by employers and health insurers.¹¹

Women in the second and third groups may still qualify for bilateral risk-reduction mastectomy and immediate reconstruction. Often, women who elect this path are influenced by their family history or by witnessing breast and/or ovarian cancer deaths in close family members, giving them a significant fear of a breast or ovarian cancer diagnosis. For women in all three groups, the decision of whether to pursue risk-reducing surgery is difficult. Often, the expertise of a cancer clinical psychologist or psychiatrist
is enlisted, as risk-reduction mastectomy involves an irreversible procedure with body image and sexual implications.⁸

TABLE 32.1 Hereditary Carcinoma Syndromes Including Breast Cancer

Syndrome	Chromosome/Gene	Primary Carcinoma	Secondary Carcinoma	Breast Cancer Penetrance
Familial breast cancer/ovarian cancer syndrome	17g21; BRCA1 Autosomal dominant	Breast cancer, ovarian cancer	Colon, prostate	60%-80%
Familial breast cancer/ovarian cancer syndrome	13q12; BRCA2 Autosomal dominant	Breast cancer, ovarian cancer	Male breast cancer, endometrial, prostate, oropharyngeal, pancreatic	60%-80%
Li-Fraumeni syndrome	17p13.1 and 22q12.1; TP53 and CHEK2 Autosomal dominant	Soft tissue cancers (including breast)	Soft tissue sarcoma, leukemia, osteosarcoma, melanoma, colon, pancreas, adrenal syndrome, cortex, and brain tumors	50%-85% (for all types of cancers in this syndrome)
PTEN hamartoma syndrome (Cowden’s)	10q23.31; PTEN mutation Autosomal dominant	Breast cancer	Thyroid (follicular) and endometrial carcinoma	25%-50%
Peutz-Jeghers syndrome	19p13.3; STK11 Autosomal dominant	Gastrointestinal cancers	Esophagus, stomach, small intestine, large bowel, pancreas, lung, ovary, endometrial	29%
Diffuse gastric cancer	16q22.1; CDH1 Autosomal dominant	Diffuse gastric cancer	Colorectal, lobular breast cancer	39% (lobular breast cancer)
Louis-Bar syndrome	11q22.3; ATM Autosomal recessive	Leukemia and lymphoma	Ovarian, breast, gastric, melanoma, leiomyomas, sarcomas	38% (for all types of cancers in the syndrome)
PTEN, phosphatase and tensin homolog. Data from Lux MP, Fasching PA, Beckmann MW. Hereditary breast and ovarian cancer: review and future perspectives. J Mol Med 2006;84:16-28; and Shannon KM, Chittenden A. Genetic testing by cancer site: breast. Cancer J 2012;18:310-319.

Updated in 2007, the Society of Surgical Oncology published a position statement on the role of prophylactic mastectomy for patients at high risk for breast cancer, as well as those patients recently diagnosed with breast cancer who are considering contralateral prophylactic breast surgery.¹² For women at high risk, indications fall into three broad categories: presence of a mutation in BRCA or other susceptible genes, strong family history with no demonstrable mutation, and histologic risk factors (biopsy-proven atypical ductal hyperplasia, atypical lobular hyperplasia, or lobular carcinoma in situ especially in patients with a strong family history of breast cancer). Recommendations for patients with recently diagnosed breast cancer are similar in that they include the indications for high-risk individuals previously noted, as well as future surveillance challenges for the opposite breast (clinically and mammographically dense breast tissue or diffuse, indeterminate microcalcifications in the contralateral breast). Another important consideration is the need for symmetry in patients with large, ptotic, or disproportionately sized contralateral breasts.

Surgical Issues and Technique

In a single institution’s 33-year experience,¹³ the risk for breast cancer in both moderate- and high-risk groups of women based on family history was reduced by at least 89% for women who underwent bilateral prophylactic mastectomy. From a technical perspective, in this study, women either had a subcutaneous mastectomy (removal of the majority of breast tissue with sparing of the nipple-areola complex) or total mastectomy (removal of the entire breast through the nipple-areola complex). Most of the recurrences occurred in women undergoing a subcutaneous mastectomy. However, this was the most frequent procedure performed at that time and thus may have contributed to the number of increased recurrences.

Another surgical option for high-risk women is bilateral salpingooophorectomy. Among a cohort of women with BRCA1 and BRCA2 mutations, this procedure has been associated with a lower risk of mortality from both breast and ovarian cancer.¹⁰ As an additional benefit, this procedure also decreases the risk of breast cancer in this patient population, likely through the mechanism of decreasing hormonal exposure at a younger age.

Contemporary surgical procedures for risk-reducing bilateral mastectomy include total mastectomy, skin-sparing mastectomy (preservation of the skin envelope by removal of the entire breast through a circumareolar incision around the nipple-areola complex), subcutaneous mastectomy, areola-sparing mastectomy (removal of the nipple while sparing the areola), and nipple-sparing mastectomy (removal of entire breast and nipple core tissue but preservation of nipple-areolar skin).¹⁴ Given advances in reconstructive nipple-areolar techniques, it appears that total mastectomy with or without skin-sparing methods reduces the risk of breast cancer to the greatest extent with reasonable cosmesis. More limited and long-term follow-up data are available on areola- and nipple-sparing techniques. The potential limitations of these procedures are distortion of the nipple-areola complex and lack of sensitivity after breast tissue has been completely removed.⁸

Immediate reconstruction is offered to patients and performed in the vast majority undergoing bilateral risk-reduction mastectomy. Choices of reconstruction include a bilateral pedicled or free tissue transverse rectus abdominis muscle flap, a free bilateral deep inferior epigastric perforator flap or superficial inferior epigastric artery flap, bilateral latissimus flaps with or without implant or expanders, or bilateral implant or expander placement alone.¹⁴ Although tissue flap transfer gives a more natural appearance and texture to the reconstructed site, individual body contour drives the ultimate plan for reconstruction. The decision about the type
of reconstruction should be made by the plastic surgeon with input from the surgical oncologist, especially for the group of women with breast cancer desiring bilateral mastectomies who may require adjuvant radiation for treatment.

Although the risk reduction is dramatic for bilateral mastectomy, residual breast tissue may be left behind, especially with skinsparing procedures. Patients should be educated that careful chest wall surveillance is recommended after such a procedure. Local recurrences after bilateral implant reconstruction are reliably detected by clinical examination. Recurrences after reconstruction with autologous tissue present most commonly on the skin 50% to 72% of the time and are detectable by physician examination.¹⁵ Nonpalpable deeper recurrences in this setting are less common, and use of mammography image surveillance may be indicated, especially if significant breast tissue was left behind unintentionally during the bilateral mastectomy procedure. At times, an initial “screening” mammogram may be performed, if significant residual breast tissue is suspected; this should occur well after all healing has taken place to delineate the amount of visible breast tissue on imaging. This drives future decisions of whether to follow a patient with imaging. Finally, all patients should be instructed to return for clinical breast examination with the health provider if any change is noted on the reconstructed breasts, regardless of imaging plan.

Although risk-reduction bilateral mastectomy may be exceedingly beneficial for high-risk women, especially for those testing positive for BRCA1, BRCA2, or other deleterious mutations, or belonging to a family afflicted with a cancer syndrome, they are never emergent procedures. Along with risk-reduction bilateral salpingo-oophorectomy, risk-reduction bilateral mastectomy resides at the far end of the spectrum of an individual’s choices.¹⁶ These procedures should be offered only after appropriate genetic counseling and accurate assessment of a woman’s actual risk for breast and ovarian cancer. An in-depth consultation with the patient and her family members is necessary prior to proceeding with an operative plan.

HEREDITARY DIFFUSE GASTRIC CANCER

Gastric cancer is the fourth most common cause of cancer worldwide and is the second leading cause of cancer mortality.¹⁷ Although environmental agents, including Helicobacter pylori and diet, are the primary risk factors for this disease, approximately 10% of gastric cancers are a result of familial clustering.¹⁸^,¹⁹ Histologically, gastric cancers may be classified as either intestinal or diffuse types. The intestinal type histopathology is linked to environmental factors and advanced age. The diffuse type occurs in younger patients and is associated with a familial predisposition. Because of a decrease in intestinal-type gastric cancers, the overall incidence of gastric cancer has declined significantly in the past 50 years. However, the incidence of diffuse gastric cancer (DGC), which is also called signet ring cell or linitis plastica, has remained stable and, by some reports, may be increasing.

Figure 32.1 A family pedigree showing autosomal dominant inheritance of gastric cancer. Individual mutation testing results for the codon 1003 CDH1 mutation are indicated by + or -. Individuals affected with gastric cancer are shaded. (From Norton JA, Ham CM, Van Dam J, et al. CDH1 truncating mutations in the E-cadherin gene: an indication for total gastrectomy to treat hereditary diffuse gastric cancer. Ann Surg 2007;245:873.)

Hereditary DGC (HDGC) is a genetic cancer susceptibility syndrome defined by one of the following: (1) two or more documented cases of DGC in first- or second-degree relatives, with at least one diagnosed before the age of 50; or (2) three or more cases of documented DGC in first- or second-degree relatives, independent of age of onset. The average age of onset of HDGC is 38, and the pattern of inheritance is autosomal dominant.²⁰ Figure 32.1 shows a pedigree with HDGC.

In 1998, inactivating germline mutations in the E-cadherin gene CDH1 were identified in three Maori families, each with multiple cases of poorly differentiated DGC.²¹ The CDH1 mutations in these families were inherited in an autosomal dominant pattern, with incomplete but high penetrance. Onset of clinically apparent cancer was early, with the youngest affected individual dying of DGC at the age of 14.²¹ Since then, germline mutations of CDH1 have been identified in 30% to 50% of all patients with HDGC.¹⁹^,²² More than 50 mutations have been recognized across diverse ethnic backgrounds, including European, African American, Pakistani, Japanese, Korean, and others.¹⁹ In addition to gastric cancers, germline CDH1 mutations are associated with increased risk of lobular carcinoma of the breast, and this was the first manifestation of a CDH1 mutation in one series.²³ CDH1 is, to date, the only gene implicated in HDGC. Penetrance of DGC in patients carrying a CDH1 mutation is estimated at 70% to 80%, but may be higher. The need for a systematic study of specimens is supported by recent work by Gaya et al.²⁴ in which initial total gastrectomy specimens were reported as negative, but detailed sectioning and analysis showed invasive carcinoma.

CDH1 is localized on chromosome 16q22.1 and encodes the calcium-dependent cell adhesion glycoprotein E-cadherin. Functionally, E-cadherin impacts maintenance of normal tissue morphology and cellular differentiation. It is hypothesized that CDH1 acts as a tumor suppressor gene in HDGC, with loss of function leading to loss of cell adhesion and subsequently to proliferation, invasion, and metastases. Figure 32.2 shows the CDH1 mutation for the pedigree depicted in Figure 32.1.

The germline CDH1 mutation is most frequently a truncating mutation. Germline missense mutations are causative in a few HDGC kindreds, but are more often clinically insignificant. In vitro assays for cellular invasion and aggregation may predict the functional impact of missense mutations to aid in this distinction.²² Within the gastric mucosa, the “second hit” leading to complete loss of E-cadherin function results from CDH1 promoter methylation, as has been described in sporadic gastric cancer.²⁵

Figure 32.2 The mutation in this kindred is located in the central region of the E-cadherin gene that codes for the extracellular cadherin domains of the protein containing calcium-binding motifs important in the adhesion process. The C → T transition in exon 7 of nucleotide 1003 results in a premature stop codon (R335X), producing truncated peptides that lack the transmembrane and cytoplasmic β-catenin-binding domains essential for tight cell-cell adhesion. Black area indicates truncated portion of peptide. N, N-terminus; C, C-terminus; S, signal peptide; PRE, precursor sequence; TM, transmembrane domain; CP, cytoplasmic domain. (From Norton JA, Ham CM, Van Dam J, et al. CDH1 truncating mutations in the E-cadherin gene: an indication for total gastrectomy to treat hereditary diffuse gastric cancer. Ann Surg 2007;245:873.)

It remains unclear whether specific CDH1 mutations are associated with distinctive phenotypic characteristics or rates of penetrance, although this may become apparent as more recurrent mutations are recognized. To date, most mutations identified have been novel and distributed throughout CDH1. Recognition of recurrent mutations has usually resulted from independent events; however, there is evidence for the role of founder effects in certain kindreds.²² At present, it is also unclear whether patients with HDGC without detectable CDH1 mutations have mutation of a different gene or merely a CDH1 mutation that has gone unrecognized.

New recommended screening criteria for CDH1 mutations are as follows:

Families with one or more cases of DGC
Individuals with DGC before the age of 40 years without a family history
Families or individuals with cases of DGC (one case below the age of 50 years) and lobular breast cancer
Cases where pathologists detect in situ signet ring cells or pagetoid spread of signet ring cells adjacent to diffuse type gastric cancer¹⁸^,²⁶

As in other familial cancer syndromes, genetic counseling should take place prior to genetic testing so that the family understands the potential impact of the results. After obtaining informed consent, a team comprising a geneticist, gastroenterologist, surgeon, and oncologist should discuss the possible outcomes of testing and the management options associated with each. Genetic testing should first be performed on a family member with HDGC or on a tissue sample if no affected relative is living. In addition to direct sequencing, multiplex ligation-dependent probe amplification is recommended to test for large genomic rearrangements. If a CDH1 mutation is identified, asymptomatic family members may proceed with genetic testing, preferably by the age of 20.¹⁹ If no mutation is identified in the family member with DGC, the value of testing asymptomatic relatives is low.

Among individuals found to carry a germline CDH1 mutation, clinical screening is problematic. Histologically, DGC is characterized by multiple infiltrates of malignant signet ring cells, which may underlie normal mucosa.²⁷ Because these malignant foci are small in size and widely distributed, they are difficult to identify via random endoscopic biopsy. Chromoendoscopy and positron emission tomography have reportedly been used, but the clinical utility of these tools in early detection remains unproven. Lack of a sensitive screening test for HDGC makes early diagnosis extremely challenging. By the time patients are symptomatic and present for treatment, many have diffuse involvement of the stomach or linitis plastica, and rates of mortality are high. Published case reports describe patients who have presented with extensive DGC despite recent normal endoscopy and negative biopsies.²⁸ The 5-year survival rate for individuals who develop clinically apparent DGC is only 10%, with the majority dying before age 40.

Because of high cancer penetrance, poor outcome, and inadequacy of clinical screening tools for HDGC, prophylactic total gastrectomy is recommended as a management option for asymptomatic carriers of CDH1 mutations.¹⁸ Although total gastrectomy is performed with prophylactic intent in these cases, most specimens have been found to contain foci of diffuse signet ring cell cancer.¹⁹^,²⁸^,²⁹ Foci of DGC have been identified even in patients who have undergone extensive negative screening, including high-resolution computed tomography, positron emission tomography scan, chromoendoscopy-guided biopsies, and endoscopic ultrasonography.¹⁹ However, HGDC in asymptomatic CDH1 carriers is usually completely resected by prophylactic gastrectomy, as pathologic analyses of resected specimens have shown only T1N0 disease.

Because these signet ring cell cancers are multifocal and distributed throughout the entire stomach, especially in the cardia,³⁰ prophylactic gastrectomy should include the entire stomach, and the surgeon must transect the esophagus and not the proximal stomach. Furthermore, it should be performed by a surgeon experienced in the technical aspects of the procedure and familiar with HDGC. In asymptomatic patients, lymph node metastases have not been observed; therefore, D2 lymph node resection is not necessary. The optimal timing of prophylactic gastrectomy in individuals with CDH1 mutations is unknown, but recent consensus recommendations indicate that age 20 is reasonable.¹⁸

Although it is a potentially lifesaving procedure, prophylactic gastrectomy for CDH1 mutation carries significant risks that must be considered. Overall mortality for total gastrectomy is estimated to be as high as 2% to 4%, although it is estimated to be 1% when performed prophylactically. Patients must also be aware that there is a nearly 100% risk of long-term morbidity associated with this procedure, including diarrhea, dumping, weight loss, and difficulty eating.¹⁹ A recent study of the effects of prophylactic gastrectomy for CDH1 mutation demonstrated that physical and mental function were normal at 12 months, but specific digestive issues were recognized. Overall, 70% had diarrhea, 63% fatigue, 81% eating discomfort, 63% reflux, 45% eating restrictions, and 44% had altered body image, suggesting that this operation impacted negatively on quality of life.³¹ Because of these complications and the fact that lymph node spread has not been observed, some recommend vaguspreserving gastrectomy done either open or laparoscopically. In addition, because the penetrance of CDH1 mutations is incomplete, some patients who undergo prophylactic gastrectomy would never have gone on to develop clinically significant gastric cancer. Prophylactic gastrectomy has, in fact, been performed on several patients reported to show no evidence of gastric cancer on pathology.²⁹

Some individuals with CDH1 mutations choose not to pursue prophylactic gastrectomy. These individuals should undergo careful surveillance, including biannual chromoendoscopy with biopsies, beginning when they are at least 10 years younger than
the youngest family member with DGC was at time of diagnosis. It is recommended that any endoscopically visible lesion is targeted and that six random biopsies are taken from the following regions: antrum, transitional zone, body, fundus, and cardia. Careful white-light examination with targeted and random biopsies combined with detailed histopathology can identify early lesions and help to inform decision making with regard to gastrectomy.³² Additionally, because women with CDH1 mutations have a nearly 40% lifetime risk of developing lobular breast carcinoma, they should be carefully screened with annual mammography and breast MRI starting at age 35.²³ They should also do monthly self-examinations and have a breast examination by a physician every 6 months. The same surveillance recommendations are probably appropriate for HDGC families without identifiable CDH1 mutations, although no current guidelines for this exist.

The emergence of gene-directed gastrectomy as a treatment strategy for patients with HDGC represents the culmination of a successful collaboration between molecular biologists, geneticists, oncologists, gastroenterologists, and surgeons. It is anticipated that the recognition of similar molecular markers in other familial cancer syndromes will transform the approach to the early diagnosis and treatment of a variety of tumors.

SURGICAL PROPHYLAXIS OF HEREDITARY OVARIAN AND ENDOMETRIAL CANCER

Hereditary Ovarian Cancer (BRCA1, BRCA2)

Inherited mutations in BRCA1 and BRCA2 strongly predispose women to breast cancer and to high-grade serous cancers of the ovary, fallopian tube, and peritoneum.³³^,³⁴ About two-thirds are due to BRCA1 mutations and one-third BRCA2 mutations, and these account for about 15% to 20% of high-grade serous cases. The lifetime risk of these gynecologic cancers increases from a baseline of 1.5% to about 15% to 25% in BRCA2 carriers and 30% to 60% in BRCA1 carriers.³³^,³⁴ BRCA1/2 mutations are rare in most populations (<1 in 500 individuals); one notable exception is the Ashkenazi Jewish population, in which the carrier frequency is 1 in 40.³⁵ BRCA1-associated cases peak in the 50s and BRCA2-associated cancers in the 60s.³⁶ In addition to BRCA1/2 mutations, germline mutations in a number of other genes in the homologous recombination DNA repair pathway confer high penetrance susceptibility to ovarian cancer (e.g., RAD51C, RAD51D, BRIP1, PALB2).³⁷ This has led to the development of more comprehensive cancer genetic testing panels that are increasingly being used to identify women who are candidates for risk-reducing salpingooophorectomy (RRSO).

Genetic testing for inherited high-penetrance mutations in BRCA1/2 and other genes should be discussed with women who have a significant family history of early onset breast cancer and/or cancers of the ovary, fallopian tube, or peritoneum. Involvement of a genetic counselor prior to testing is helpful, as they have expertise in managing the inherent clinical and social issues. Most BRCA1/2 mutations involve base deletions or insertions in the coding sequence or splice sites that encode truncated protein products that are clearly dysfunctional. Less frequently, disease-causing mutations may occur that alter a single amino acid, though most of these missense variants represent innocent polymorphisms. The clinical significance of missense mutations can sometimes be elucidated by determining whether they segregate with cancer in other family members. In addition, genomic rearrangements may occur that inactivate BRCA1 or BRCA2, and identification of such alterations requires molecular testing beyond sequencing.

Penetrance of ovarian cancer is not 100% in those with clearly deleterious BRCA1/2 mutations, but presently it is not possible to provide more precise personalized risk estimates to guide the use of RRSO. However, common variants have been discovered in other genes that appear to affect the risk of ovarian cancer in BRCA1/2 carriers.³⁸ Based on the known ovarian cancer risk-modifying loci, it has been reported that the 5% of BRCA1 carriers at lowest risk have a lifetime risk of ≤28% of developing ovarian cancer, whereas the 5% at highest risk have a ≥63% lifetime risk. In the future, when modifier loci are more completely catalogued, more precise estimates of cancer risk may be provided to individual patients who are considering RRSO.

As about 20% of women with high-grade serous ovarian cancers have BRCA1/2 mutations, it has been suggested that all of these women undergo genetic testing regardless of family history.³⁹ Mutational analysis in women with these cancers may increasingly become standard practice as the cost of genetic testing declines. Testing may also be driven by the availability of poly(ADP-ribose) polymerase inhibitor therapy for women whose cancers have germline or sporadic mutations in genes such as BRCA1/2 and others that are involved in homologous recombination DNA repair.

RRSO is strongly recommended in women who carry BRCA1/2 mutations because of the high mortality rate of ovarian cancer and the lack of effective screening and prevention approaches. Although screening with pelvic ultrasound and serum CA125 is generally recommended for BRCA1/2 carriers during their 20s and 30s, it is not proven to reduce ovarian cancer mortality because even early stage high-grade cancers have a very high mortality. Oral contraceptives reduce the risk of ovarian cancer in the general population and appear to have a similar effect in BRCA1/2 carriers, but this must be balanced against concerns regarding increased breast cancer risks.

The past practice of performing RRSO based solely on family history has been replaced by reliance on genetic testing. Clinical management of women with a strong family history in whom a deleterious germline mutation is not found, or those with variants of uncertain significance, should be resolved on a case-by-case basis. RRSO may be deemed appropriate in some cases, despite the absence of a clearly deleterious mutation. Fortunately, the risk of hereditary ovarian cancer does not rise dramatically until the mid-30s in women with BRCA1 mutations and the 40s for women with BRCA2 mutations.³⁶ As a result, most women are able to complete childbearing prior to undergoing RRSO. It is advisable for BRCA1 carriers to undergo RRSO around age 35, as there is a 4% risk of ovarian cancer being discovered clinically or at the time of RRSO by age 40.¹⁰ BRCA2 carriers may choose to delay surgery into their 40s due to their lower risk of ovarian cancer, but this could diminish the protection against breast cancer that is afforded by RRSO. If a mutation carrier, particularly a BRCA1 carrier, chooses to pursue fertility into her 40s, then she should be counseled that she is at considerable risk of developing a life-threatening cancer that is largely preventable.

Several studies have provided evidence of the efficacy of RRSO. In one early study of BRCA1/2 carriers, RRSO reduced the rate of breast and ovarian cancer by 75% over several years of follow-up.⁴⁰ A separate study in 2002 examined outcome in 551 BRCA1/2 carriers from various registries.⁴¹ Among 259 women who had undergone RRSO, 6 (2.3%) were found to have stage I ovarian cancer at the time of the procedure and 2 (0.8%) subsequently developed serous peritoneal carcinoma. Among the controls, 58 (20%) women developed ovarian cancer after a mean follow-up of 8.⁸ years. With the exclusion of the six women whose cancers were diagnosed at surgery, RRSO reduced ovarian cancer risk by 96%. More recently, in 2014, an international registry study of over 5,783 subjects with median follow-up of 5.⁶ years found that RRSO reduced ovarian, tubal, and peritoneal cancer risk by 80%.³⁶ There was an estimated lifetime risk of primary peritoneal cancer after RRSO of about 4% for BRCA1 carriers and 2% for BRCA2 carriers.³⁶ The risk of death from all causes was reduced by 77%. A prospective cohort study noted that RRSO was associated with reduction in breast cancer-specific (hazard ratio [HR] = 0.44; 95% confidence interval [CI] = 0.26 to 0.76), ovarian cancer-specific (HR = 0.21; 95% CI = 0.06 to 0.80), and all-cause mortality (HR = 0.40; 95% CI = 0.26 to 0.61).¹⁰

Figure 32.3 Hematoxylin and eosin (A) and immunohistochemical staining (B) demonstrating overexpression of mutant TP53 in serous carcinoma in situ of the fallopian tube from a BRCA1 mutation carrier who underwent risk-reducing bilateral salpingo-oophorectomy.

Removal of the ovaries, as internal organs, usually has little effect on body image and self-esteem, and most BRCA1/2 mutation carriers elect to undergo RRSO. Insurance payers will almost always pay for RRSO in proven mutation carriers.

RRSO can be performed laparoscopically in most women, with discharge to home the same day. If a laparoscopic approach is problematic due to obesity or adhesions, the surgery can be performed through a small lower abdominal incision. Morbidity including bleeding, infection, and damage to the urinary or gastrointestinal tracts can occur, but the incidence of serious complications is very low. As the fallopian tubes and ovaries are small discrete organs, they are relatively easy to remove completely. Attention should be paid to transecting the ovarian artery and vein proximal to the ovary and tube so that remnants are not left behind. This involves opening the pelvic sidewall peritoneum, visualizing the ureter, and then isolating the ovarian blood supply. If there are adhesions between the adnexa and adjacent structures, careful dissection should be performed to ensure complete removal of the ovaries and fallopian tubes. If the uterus is not removed, care should be taken to remove the entire fallopian tube. A small portion of the tube inevitably will be left in the cornu of the uterus, but the risk of fallopian tube cancer developing in such remnants appears to be negligible.

Though there is not strong evidence that BRCA1/2 mutations increase uterine cancer risk, many women elect to have the uterus removed as part of the surgical procedure because they have completed their family or have other gynecologic indications. Although the addition of a hysterectomy may increase operative time, blood loss, surgical complications, and hospital stay, it usually can be performed laparoscopically and serious adverse outcomes are infrequent. Furthermore, the likelihood of future exposure to tamoxifen in the context of breast cancer prevention or treatment, which increases endometrial cancer risk two- to three-fold, also argues for concomitant hysterectomy. Women who receive hormone replacement therapy after surgery will require a progestin along with estrogen to protect against the development of endometrial cancer if the uterus is not removed.

In younger women, surgical menopause after RRSO is associated with vasomotor symptoms, vaginal atrophy, decreased libido, and an accelerated onset and incidence of osteoporosis and cardiovascular disease. In premenopausal women who do not have a personal history of breast cancer, estrogen replacement can be administered to ameliorate many of the deleterious effects of premature menopause. Systemic estrogen levels are lower in oophorectomized premenopausal women taking hormone replacement than if the ovaries had been left in place. The therapeutic benefit of oophorectomy in women with breast cancer has long been appreciated, and more recent studies support the contention that RRSO reduces the risk of breast cancer by about half in BRCA1/2 carriers.⁴² However, a meta-analysis showed that while RRSO was strongly protective against estrogen receptor-positive breast cancer (HR = 0.22), there was no protection against estrogen receptor-negative breast cancer.⁴² Many carriers are identified after developing early onset breast cancer, and this group represents the most difficult in which to balance the potential risks and benefits of estrogen replacement therapy.

Early stage high-grade serous cancers and in situ lesions with TP53 mutations have been identified in the fallopian tubes of some RRSO specimens (Fig. 32.3). This has led to a paradigm shift in which it is now thought that most high-grade serous cancers found in the ovary, fallopian tube, and peritoneum are derived from cells that originate in the tubal fimbria.⁴³ The frequency of occult malignancies has varied between reports, but appears to be about 3%.⁴³ In view of this, the pelvis and peritoneal cavity should be examined carefully. Malignant cells also have been found in peritoneal cytologic specimens, and washings of the pelvis should be obtained when performing RRSO. The pathologist should be informed of the indication for surgery and serial sections of the fallopian tubes should be performed to look for the presence of early lesions. Patients found to have occult invasive high-grade serous cancers should be treated with chemotherapy after surgery. Those with in situ lesions appear to have a good outcome without chemotherapy.⁴⁴

Cases of peritoneal serous carcinoma indistinguishable from ovarian cancer have been observed years after RRSO, but the origin of these cancers is unclear. Some may represent recurrences of occult ovarian or tubal cancers. In this regard, retrospective examination of the ovaries and fallopian tubes sometimes has revealed primary cancers that were not originally recognized. In contrast, some of these cancers likely arise directly from fallopian tube cells that have implanted in the peritoneum and subsequently become malignant. Patients who undergo RRSO should be made aware of their residual risk of peritoneal cancer, but there is no evidence that continued surveillance using CA125 and/or ultrasound is beneficial.

HEREDITARY ENDOMETRIAL CANCER (LYNCH SYNDROME)

Although Lynch syndrome (LS, also known as hereditary nonpolyposis CRC syndrome) typically manifests as familial clustering of early onset CRC, there is also an increased incidence of several other types of cancers—most notably endometrial cancer in women.⁴⁵ About 3% of endometrial cancers are attributable to
inherited mutations in the DNA mismatch repair (MMR) genes that cause LS. Most often, MSH2 and MLH1 are implicated, but mutations in MSH6 and PMS2 also occur.⁴⁵ The risk of ovarian cancer is also significantly increased in LS, but to a lesser degree than in BRCA1/2 mutation carriers, and accounts for only about 1% of all ovarian cancers.

Cells in which one of the LS genes have been inactivated exhibit a phenomenon called microsatellite instability (MSI).⁴⁶ This occurs as DNA mismatches cause shortening or lengthening of repetitive DNA sequences and these mismatches go unrepaired. This results in generation of alleles in the cancer that contain a greater or lesser number of repeats than are present in normal cells from that individual. MSI occurs in most LS-associated colorectal and endometrial cancers.⁴⁶ However, MSI is found in about 20% of sporadic cancers that arise in these organs, and in most cases is caused by silencing of the MLH1 gene due to promoter hypermethylation. Screening strategies for identification of MMR gene alterations in families with LS-associated cancers include analysis of tumor tissue for MSI and/or loss of DNA MMR gene expression using immunohistochemistry (IHC).⁴⁶ In cancers with MSI or loss of expression of one of the MMR genes, or in families with pedigrees suggestive of LS, these genes can be sequenced to identify disease-causing mutations, most of which cause truncated protein products.⁴⁷ Although it has been suggested that it may be costeffective to do these tests on all endometrial cancers, this approach has not been widely adopted.⁴⁷

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