Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:
1. Describe risk factors for Lynch syndrome (LS) and indications for genetic testing.
2. Summarize screening and chemoprophylaxis for colorectal, endometrial, and ovarian cancers in women with LS.
3. Identify the role of immunohistochemical staining for LS mutations.
Lynch syndrome (LS) is a hereditary cancer syndrome caused by a pathogenic germline autosomal dominant mutation of DNA mismatch repair genes, which includes MLH1, MSH2, MSH6, PMS2, or EPCAM. It is the most common hereditary colorectal syndrome with a prevalence of 1 in 279 individuals in the United States.1 LS is diagnosed in approximately 3% of patients with newly diagnosed colorectal cancer (CRC) and 2% to 3% patients with endometrial cancer.2
History
In 1962, Dr. Henry T. Lynch studied "Family N" with multiple generations of patients with CRC without adenomas.3 Previously, in 1895, Dr. Alfred Warthin had studied "Family G" after meeting a patient who had lost many of her family members to cancer of the colon, stomach, and uterus, and he described a pattern of inheritance consistent with autosomal dominance.4 Dr. Marjorie Shaw studied a similar "Family M" in Michigan and, with Dr. Lynch, published their findings and described a "cancer family syndrome" with likely a genetic basis.3 Dr. Lynch would later go on to study Dr. Warthin's Family G, which further confirmed evidence of a similar cancer predisposition.5 Despite this body of evidence, the concept of a hereditary cancer syndrome was not widely accepted in the medical community until the 1990s, when genetic predispositions to cancer were firmly elucidated. In spite of this delay in broader acceptance, families with this disposition started to undergo increased surveillance, which led to earlier cancer diagnoses.6 In 1984, Dr. Shaw and Dr. Lynch's "cancer family syndrome" was renamed Lynch syndrome, but was also called hereditary nonpolyposis colorectal cancer (HNPCC) to contrast with familial adenomatous polyposis (FAP).7 As this syndrome confers an elevated risk of other, noncolonic malignancies, the consensus is now that it be referred to as LS.8,9 This is of particular importance in female patients, as the lifetime risk of CRC is close to the risk of endometrial cancer, and endometrial cancer is often the index LS-related cancer diagnosed in female patients.
Genetic Causes
Mismatch repair (MMR) proteins correct single base substitutions, which occur during DNA replication.10 The MMR system requires functional protein complexes of heterodimers of the products of the genes MLH1, MSH2, MSH6, and PMS2, which function as tumor suppressor genes. Individuals with LS have a germline mutation in one allele of these genes. If a somatic mutation develops in the other allele, then this leads to a 2-hit deactivation of MMR. This is then termed MMR deficiency (MMR-D), and leads to increased rates of DNA mismatches, particularly in areas of repetitive nucleotide sequences called microsatellites.11 This feature is called microsatellite instability (MSI), where there are expanded or contracted microsatellite regions within the tumor, which lead to mutations of cancer-related genes.12 Tumors can be thus classified as MSI-high or MSI-stable on the basis of their MMR status. Figure 1 provides a schematic of the mechanism of MMR-D, which frequently results in frameshift mutations.
Lynch Syndrome Phenotype
LS-related cancers include colorectal, endometrial, gastric, ovarian, renal, prostate, brain, small bowel, pancreatobiliary, and skin, in order from most to least common.13 These cancers generally have an earlier onset in patients with LS when compared with the general population due to the accelerated carcinogenesis in MMR-D.14 Lifetime cancer risk for each varies by genotype; MLH1 and MSH2 carry the highest risks.13
Muir-Torre syndrome is a variant of LS that includes characteristic skin findings of sebaceous tumors and cutaneous keratoacanthomas, particularly in carriers of MSH2 mutation.15 These skin manifestations can precede the internal malignancies, and lead to earlier diagnosis.16
Screening for Lynch Syndrome
There are 2 populations to consider when deciding who to refer for genetic screening for LS: those with a family history of LS-related cancers and those with a personal history of LS-related cancers.
The Amsterdam I criteria were proposed by the International Collaborative Group on Hereditary Non-Polyposis Colon Cancer in 1990 for those with a family history to identify carriers of LS. The Amsterdam I criteria only included consideration of CRC,17 requiring the presence of young-onset CRC and family history of 3 CRC in 2 successive generations.19 Subsequently, the Amsterdam II criteria were modified to include all LS-related cancers in view of the fact that CRC is not always the index or first cancer identified in patients with LS. The Amsterdam II criteria stated that LS should be suspected in individuals with a history of:18
* 3 or more relatives on the same side of the family with LS-related cancers, one of whom is a first-degree relative, and FAP has been excluded;
* 2 generations with LS-associated cancers; and
* 1 or more cancers diagnosed before age of 50 years.
The 3-2-1 rule can be used to remember the above criteria. However, sensitivity and specificity of the Amsterdam II criteria have been reported at 78% and 61%, respectively.19 Therefore, providers should still consider sending patients with significant family history of LS-related cancers who do not meet the above criteria for genetic testing, particularly individuals with smaller families. In the cur rent era of widespread availability of genetic testing, any patient with a first- or second-degree relative with known MMR/EPCAM mutation should have germline testing.
In patients with a personal history of LS-related cancer, germline evaluation should be considered in patients who meet any of the following criteria:
* CRC or endometrial cancer before age 50 years;
* CRC or endometrial cancer diagnosed at age more than 50 years with additional personal and family history suggestive of LS; and/or
* Identification of a pathogenic MMR variant on somatic tumor testing in any tumor type.
The Bethesda and revised Bethesda guidelines were proposed to identify individuals with CRC who should have MSI testing on the tumor (Table 1).20 Although sensitivity of the revised Bethesda guidelines is high at 94%, specificity is low at 25%.19 There are also clinical prediction models that have been created, including MMRpredict, MMRpro, and PREMM5 models, which have been shown in validation studies to have equivalent or better sensitivity and specificity compared with the revised Bethesda guidelines (Table 2).21-23 The revised Bethesda guidelines have become less clinically relevant, as standardized MMR testing on colorectal and endometrial tumors has become the standard of care.24,25
When endometrial adenocarcinoma is identified on pathology, it is reflexed for either immunohistochemistry analysis for MMR protein expression or MSI testing depending on the laboratory. Loss of MLH1/PMS2 expression further reflexes to either MLH1 promoter methylation or BRAF V600E testing. The presence of MLH1 promoter methylation indicates a low likelihood of a germline mutation in MLH1/PMS2 and instead indicates a somatic mutation. Germline mutations are typically inherited and present in all cells in the body. In contrast, somatic mutations occur during the process of tumorgenesis and are only present in tumor cells. Therefore, while germline mutations can be passed from generation to generation and lead to LS, a predisposition to specific cancers, somatic mutations are not inherited and do not indicate a concern for LS.
In the absence of methylation, germline testing is indicated. Additionally, with loss of MSH2/MSH6, germline testing is indicated. Figure 2 shows a proposed algorithm for testing in endometrial carcinoma specimens.26 In the future, standardized next-generation sequencing may be considered for all specimens.27
Testing for Lynch Syndrome
Once the decision has been made to proceed with germline testing, it is recommended to refer patients to a genetic counselor for full review of risks and benefits of testing, and to help choose which test would be most beneficial. However, given the nationwide shortage of trained genetic counselors, it is beneficial for gynecologists to be familiar with the basics of testing.28 Before testing, patients should undergo thorough counseling and informed consent, including their goals for genetic testing, the extent of results, risk of regret, unwanted findings, and a basic understanding of genetic inheritance of these conditions. A thorough history should be obtained, including a pedigree of the family, personal medical history, ethnicity, concern for consanguinity, nonpaternity, sperm or egg donor, and history of bone marrow transplant.29
If there is a known mutation in the family, then typically a single-site genetic analysis is sent. This tests only for the known familial mutation. If there is not a known mutation, then multigene panel tests are sent. A single-site genetic analysis will only identify a specific mutation within a gene and a multigene panel will use next-generation sequencing to test multiple genes simultaneously. These multigene panels contain 10 to 15 of the high-risk CRC and LS-related genes. There are 3 possible results: pathogenic or likely pathogenic mutation, variant of unknown significance (VUS), or no mutation. In individuals where these panels do not identify a mutation, but there is significant family history, either extended panel testing or whole exome sequencing can be considered. It must be emphasized that commercial genetic testing kits on the public market are not sufficient for clinical use.30
Surveillance and Risk Reduction for Lynch Syndrome Carriers
Once a patient has been diagnosed with LS, there have been proposed guidelines for surveillance of LS-related cancers, but only CRC and endometrial guidelines are evidence-based. For other cancers, the guidelines are based on expert opinion only. Here we have summarized guidelines for CRC, endometrial, and ovarian surveillance. Other LS-related cancer surveillance guidelines are dependent on which MMR gene is mutated and on family history. All patients should be counseled on healthy lifestyle habits.
Colorectal Cancer
Patients should undergo high-quality colonoscopy every 1 to 2 years starting at age 20 to 25 or 2 to 5 years before earliest CRC in the family if diagnosed before 25 years.31,32 Fecal occult blood testing or fecal immunohistochemical testing is not validated as a screening test in LS carriers due to a high risk of false-negative results.
Providers can also offer patients with LS treatment with 600 mg of aspirin daily. This was studied in the RCT CAPP2 trial and was found to significantly decrease likelihood of CRC with no increased adverse events.33
Endometrial Cancer
Providers should educate women with LS on abnormal uterine bleeding and postmenopausal bleeding, both of which should prompt endometrial evaluation.34 Providers can also offer endometrial biopsy every 1 to 2 years starting at age 30 to 35 years.35 However, the benefit of this latter diagnostic tool has been brought into question. Stuckless et al36 demonstrated in a population of LS carriers with an MSH2 mutation that gynecologic cancer screening did not result in diagnosis at earlier stage. Transvaginal ultrasound in a postmenopausal patient may be offered at the provider's discretion, but sensitivity and specificity of this test are low.37 Ultrasound should not be offered as a screening modality in premenopausal patients, given the variation of the endometrial thickness throughout the menstrual cycle.
Gynecologists can offer the option of risk-reducing total hysterectomy, as this reduces incidence of endometrial cancer.38,39 In one study, hysterectomy and bilateral salpingo-oophorectomy (BSO) reduced the risk of both endometrial and ovarian cancer in women with LS by 100%. Timing should be individualized to the patient with consideration of fertility desires, menopausal status, surgical risk, family history, and which MMR gene is mutated. Progestin-containing intrauterine devices (IUDs) have been shown in an observational study to lower risk of endometrial cancer (HR 0.39), and prospective data have shown reduced rates of endometrial proliferation.40,41
Ovarian Cancer
Female patients with LS should be counseled to present for evaluation if they develop symptoms of ovarian cancer including abdominopelvic pain, bloating, increased abdominal girth, early satiety, or urinary frequency or urgency. Transvaginal ultrasound and CA-125 have not been shown to be sensitive or specific enough to recommend use for routine screening, but could be offered to patients at the provider's discretion and with thorough counseling.35,37
Combined hormonal contraception in BRCA carriers and in the general population has been linked to a reduced risk of ovarian cancer.42 Thus, it has been extrapolated that it also lowers the risk of ovarian cancer in women with LS and can be recommended to these women. As mentioned previously, BSO may reduce the risk of ovarian cancer, and prophylactic surgery may be offered to women with LS.38 Again, timing of prophylactic surgery should be individualized to the patient with consideration of fertility desires, menopausal status, surgical risk, family history, and which MMR gene is mutated. For example, there is insufficient evidence to recommend prophylactic BSO to patients with MSH6 or PMS2 pathologic mutations, as there is low lifetime risk of ovarian cancer in these patients.
Prophylactic BSO performed for hereditary cancer risk can be performed by a generalist gynecologist so long as principles of risk reduction are observed. These include minimally invasive approach when possible, upper abdominal survey, biopsy of any abnormal peritoneal findings, collection of pelvic washings, minimized handling of tubes and peritoneum, removal of 2 cm of the proximal ovarian vasculature, and the entirety of the tube and surrounding peritoneum, and removal through an endoscopic bag.43 Both ovaries and tubes should be processed by the SEE-FIM (Sectioning and Extensively Examining the FIMbriated End) pathology protocol, where the specimen undergoes 2- to 3-mm cross-sectioning, and the pathologist should be notified of the indication for surgery.44 If a serous tubal intraepithelial carcinoma (STIC) lesion-which is a noninvasive fallopian tube precursor lesion-or occult malignancy is identified, the patient should be referred to a gynecologic oncologist.
Reproductive Considerations
Female patients with LS who are planning to conceive should be counseled regarding the 50% risk of passing this mutation to their children and should be offered the option of preimplantation genetic testing.26 It is also recommended that these patients be counseled on the rare recessive syndrome called constitutional MMR-D syndrome, which occurs when both parents pass on a pathogenic variant in the same MMR gene.45 They may consider having their reproductive partner undergo genetic screening for LS as well.
Hormone Replacement
Estrogen replacement therapy via a transdermal approach can be offered in patients with LS who have undergone prophylactic total hysterectomy and BSO, as this may help with vasomotor menopausal symptoms, and reduce risk of long-term cardiovascular outcomes and osteoporosis.46 However, in patients with estrogen receptor/progesterone receptor (ER/PR+) breast cancer, hormone replacement therapy (HRT) should be avoided, and nonhormonal options should be offered to the patient.47 As with any patient with a uterus, HRT should contain both progestin and estrogen; however, this scenario is unlikely in this patient population.26,47
In a patient with LS who has a history of endometrial or ovarian cancer, support for HRT use is unclear. A Cochrane review of the literature on HRT use in the general population after an endometrial cancer diagnosis was inconclusive on whether it can be broadly recommended.48 The available evidence seems to support use in early-stage endometrial cancers, whereas there are no data in later-stage endometrial cancer. An additional Cochrane review of HRT use in the general population after ovarian cancer was inconclusive on whether it could be recommended or advised against. This should be a discussion between the patient and provider of risks and benefits and centered on the patient's goals and quality of life.
The Role of the Obstetrician/Gynecologist
A patient with LS will require additional attention and discussion. Discussion of healthy lifestyle, menstrual awareness, and ovarian cancer-related symptoms should be reviewed in detail. An obstetrician/gynecologist can offer their patient chemoprophylaxis with hormonal contraception and/or aspirin and can also consider risk-reducing surgery at the completion of childbearing. In the post-COVID era, with limited primary care provider access, obstetricians/gynecologists may also find themselves in charge of ordering the initial genetic work-up and colonoscopies for patients with LS. All providers should be aware of the diagnostic criteria for LS and should remain vigilant regarding family history concerning for LS.
Practice Pearls
* LS is an autosomal dominant hereditary cancer syndrome in which affected individuals have a mutation in one allele of one of the MMR tumor suppressor genes that results in an elevated lifetime risk of several types of cancer, most commonly colon, endometrial, and ovarian.
* Several criteria exist for which patients should be referred for genetic testing including any individual with CRC or endometrial cancer younger than 50 years or older than 50 years with additional personal/family history concerning for LS. Additionally, identification of a pathogenic MMR variant on somatic tumor testing should trigger germline testing for LS.
* Genetic testing can be ordered as a single-site analysis if there is a known mutation in the family or, more commonly, as a multigene panel and is most often done as either a blood draw or a buccal swab.
* Cancer surveillance strategies for women with LS vary based on family history and almost always include earlier and more frequent screening for CRC.
* Women with LS can undergo risk reduction surgery with a hysterectomy and BSO to reduce their risk of endometrial and ovarian cancer, respectively.
* HRT is appropriate in most women with LS who have undergone risk reduction surgery. Decisions on HRT for women with a history of an LS-related gynecologic cancer should be individualized based on cancer history and personal goals and values.
References