Endometrial Cancer – Hereditary/genetic factors

Endometrial Cancer, Cancer of the Uterine Corpus

1. What every clinician should know

Uterine cancer is the most common gynecologic malignancy in the United States with an estimated 52,630 new cases and 8,590 deaths expected in 2014. Hereditary endometrial cancer makes up approximately 2% to 5% of all cases. Lynch syndrome and Cowden syndrome are the two most common inherited syndromes known to increase a woman’s lifetime risk of endometrial cancer.

Women with hereditary endometrial cancer are at risk for many nongynecologic malignancies, increasing the importance of identification and counseling for these women and their relatives. Identification of these women may allow for the early detection of cancer and strategic measures to reduce development of subsequent cancer through risk reducing surgery. Women impacted by these inherited susceptibility syndromes benefit from reproductive counseling with implications for offspring and extended family.

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominant genetic disorder that increases a woman’s lifetime risk of endometrial cancer between 17% and 60%. Based on estimates, Lynch syndrome occurs between 1 in 600 and 1 in 3000 people. These patients make up 10% of new endometrial cancer cases per year in women under the age of 50. Patients have at least one germline mutation in specific DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2).

In addition, deletions in the EPCAM gene result in Lynch syndrome through hypermethylation of the MSH2 promoter and subsequent MSH2 silencing. Uterine cancer is the sentinel malignancy in approximately 40% to 60% of patients with Lynch syndrome. Along with uterine cancer, Lynch syndrome patients are at significantly increased risk of colon, ovarian, pancreatic, stomach, and ureteral/renal pelvis cancers.

Cowden syndrome is an autosomal dominant genetic disorder characterized clinically by hamartomas, macrocephaly, mucocutaneous lesions, and an increased lifetime risk of various malignancies including breast, endometrial, thyroid, renal, skin, brain, and colorectal cancer. It is part of a larger group of disorders referred to as PTEN hamartoma tumor syndrome (PHTS) based on a common association with germline mutations in the PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumor suppressor gene.

Cowden syndrome is estimated to be present in at least 1 in 200,000 people. The lifetime risk for development of endometrial cancer is between 19% and 28%. Women with Cowden syndrome are at high risk of developing breast cancer with the most recent evidence indicating a cumulative risk between 81% and 85%.

Physicians should be aware of the hallmarks of hereditary cancer syndromes:

• early age of onset

• multiple affected family members

• presence of multiple and/or bilateral primary cancers

These hallmarks represent important signs that a person may be at risk for an inherited cancer syndrome. Women may warrant further evaluation through genetic counseling and/or referral to an oncologic specialist if they were diagnosed with endometrial cancer at a young age (less than 50 years old), have a strong family history of malignancies, or a personal history of bilateral or multiple cancers.

2. Diagnosis and differential diagnosis

My patient has a history of endometrial cancer – how do I evaluate her for an inherited predisposition to endometrial cancer?

To determine whether a patient should be evaluated for an inherited predisposition to endometrial cancer, certain information will be needed:

• At what age was she diagnosed with endometrial cancer?

• Does she have a history of any other malignancies (i.e., colon or breast cancer)? If so, when were they diagnosed in relation to her endometrial cancer? Was there bilaterality associated with those cancers (i.e., breast)?

• In her family history, does she have any relatives with cancer of the endometrium, breast, thyroid, colon, ureter, small bowel, stomach, pancreas, brain, biliary tract, renal pelvis, or other malignancies?

• If she is an established patient, remember to ask an updated family history as family members may be diagnosed with additional cancers over time.

• Physical examination findings may raise suspicion for Cowden syndrome including changes in the oral mucosa, decreased head circumference, or thyroid changes (enlarged or nodular on palpation)

Patients may not have the necessary information to determine genetic risk. It may be important to lower the threshold for initiating genetic risk assessment in the following situations:

• Presence of adoption in the lineage, as this may lead to an unknown cancer history in multiple genetic relatives

• Families with a small number of female relatives, potentially leading to underrepresentation of gynecologic malignancies

• History of hysterectomy and/or oophorectomy at a young age in multiple family members, as this may secondarily reduce the risk of subsequent gynecologic malignancies

If a patient has a 5-10% chance risk of an inherited predisposition to malignancy, further evaluation is warranted unless the patient chooses not to undergo additional counseling. Prior to this referral, a patient should understand the reason for further evaluation and potential risks, which include emotional or psychological stress, as well as potential health consequences for her family. Informed consent is vital as patients move forward in this process.

Who should I refer for genetic counseling and/or to an oncologic specialist?

Based on the information obtained through patient history, a determination will need to be made as to whether a patient should be referred to a genetic counselor and/or an oncologic specialist. Various organizations have developed criteria for quantification of genetic risk.

Historically, Lynch syndrome families were identified based on specific clinical criteria. The initial criteria (Amsterdam I) in 1991 focused on colon cancer alone; however, this was then revised with the Amsterdam II criteria in 1999 to include Lynch syndrome-associated extracolonic tumors.

The Amsterdam II criteria incorporated the following: (1) at least three relatives must have a cancer associated with Lynch syndrome (colorectal, endometrial, ureter, small bowel, or renal-pelvis), (2) must affect at least two relatives in successive generations, (3) at least one affected relative must be a first-degree relative of the other two, and (4) at least one relative with a Lynch syndrome-associated cancer must have been diagnosed before age 50. The Amsterdam II criteria can be remembered with the “3-2-1 rule” (3 affected members, 2 generations, 1 under age 50): 50% of patients who meet these criteria will not have Lynch syndrome, while 50-68% of patients with Lynch syndrome will fail to be diagnosed based on these criteria.

A separate set of guidelines designed to identify patients with colorectal cancer who need further evaluation was put forth as the Bethesda Guidelines in 1997. These were subsequently revised in 2004 to better delineate which colorectal tumors indicate that patients should undergo molecular testing for Lynch syndrome. Evidence for Lynch syndrome was detected in 29% of patients who met these criteria with 65% found to have a mutation in MLH1 or MSH2.

More recently, the Society of Gynecologic Oncology developed guidelines directed toward patients with endometrial cancer. These guidelines recommend that any woman with a 20-25% risk of having an inherited predisposition to endometrial, colorectal, or related cancers should undergo risk assessment. A patient who fits into one of the following five categories would meet this risk criteria:

1. Patients with endometrial or colorectal cancer with the following history:

• At least three relatives with a Lynch/HNPCC-associated cancer (colorectal, endometrial, small bowel, ureter, or renal pelvis) in one lineage.

• One affected individual should be a first-degree relative of the other two.

• At least two successive generations should be affected.

• At least one Lynch/HNPCC-associated cancer should be diagnosed before age 50.

2. Patients with synchronous or metachronous endometrial and colorectal cancer with the first cancer diagnosed prior to age 50

3. Patients with synchronous or metachronous ovarian and colorectal cancer with the first cancer diagnosed prior to age 50

4. Patients with colorectal or endometrial cancer with evidence of a mismatch repair defect (i.e., microsatellite instability (MSI) or immunohistochemical loss of expression of MLH1, MSH2, MSH6, or PMS2)

5. Patients with a first- or second-degree relative with a known mismatch repair gene mutation

The Society of Gynecologic Oncology has also developed criteria to identify women with a 5-10% risk of having an inherited predisposition to endometrial, colorectal, or related cancers. For these women, it may be helpful to undergo genetic risk assessment.

1. Patients with endometrial or colorectal cancer diagnosed prior to age 50.

2. Patients with endometrial or ovarian cancer with a synchronous or metachronous colon or other Lynch/HNPCC-associated tumor* at any age.

3. Patients with endometrial or colorectal cancer and a first-degree relative with a Lynch/HNPCC-associated tumor* diagnosed prior to age 50.

4. Patients with colorectal or endometrial cancer diagnosed at any age with two or more first- or second-degree relatives with a Lynch/HNPCC-associated tumor,* regardless of age.

5. Patients with a first- or second-degree relative who meets the above criteria.

*Lynch/HNPCC-related tumors include colorectal, endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, and biliary tract.

Differential diagnosis

Given that 2-5% of endometrial cancers are due to hereditary susceptibility syndromes, it is important to consider a genetic cause when a patient is diagnosed with this malignancy. Lynch syndrome, also known as HNPCC, results in the vast majority of endometrial cancers due to inherited susceptibility. Cowden syndrome is a less common genetic disorder, but an important one to consider given the implications not only for the increased risk of endometrial cancer but also for many other malignancies.

Diagnosis of Lynch Syndrome

Lynch syndrome is associated with an increased lifetime risk of cancers related to the endometrial, colon, stomach, ovary, hepatobiliary tract, central nervous system, urinary tract, pancreas, and sebaceous neoplasms. Notably, these patients have significant lifetime risks of colon (30-80%), endometrial (40-60%), and ovarian cancer (4-38%). Please see Table I , which provides cancer risk based on genetic mutation.

Table I.n

With genomic advancements, it has been determined patients with Lynch syndrome have at least one germline mutation in specific DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2) or deletions in the EPCAM gene resulting in hypermethylation of the MSH2 promoter. Diagnosis can be initiated through clinical criteria or tumor testing criteria. The Amsterdam criteria are imperfect, especially in the setting of limited family history, but clinical criteria such as these can be useful, especially if tumor is not available for testing.

If endometrial cancer is diagnosed, the tumor can be tested to determine if the patient has Lynch syndrome. The tumor can be evaluated for microsatellite instability (MSI), immunohistochemical (IHC) expression of mismatch repair proteins and methylation of the MLH1 gene promoter. The diagnosis of Lynch syndrome is made definitively by identifying a deleterious germline mutation in a mismatch repair gene. Germline mutations are present in every cell of the body from birth. This is in contrast to somatic mutations, which occur over time in a subset of cells due to environmental exposure or other causes.

The BRAF V600E mutation can be useful in the evaluation of colorectal tumors. BRAF V600Emutations are strongly associated with MLH1promoter methylation in sporadic colorectal tumors, which all but eliminates the likelihood that a patient has Lynch syndrome. The BRAF V600E mutation is uncommon in endometrial cancer. As such, its clinical utility in the workup for Lynch syndrome is limited.

Deficiencies in DNA mismatch repair proteins cause the phenomenon of microsatellite instability (MSI). MSI results when there is expansion or contraction of short repetitive DNA sequences known as microsatellites. This is due to deficiencies in at least one DNA mismatch repair protein. MSI is found in up to 35% of endometrial cancers. Mononucleotide and dinucleotide repeat (i.e., CGCGCG or CCCCCC) regions often demonstrate MSI in these settings. Specific genomic sites can be tested for MSI based on allelic shift in tumor compared to normal DNA. There are panels of markers to test MSI ranging from 5 to 10 sites. The most commonly used panel was designated by the National Cancer Institute in 1998: BAT25, BAT26, D2S123, D5S346, and D173250.

This panel is used to define the level of MSI if present. If a tumor has allelic shift in two or more microsatellites in the panel, the tumor is categorized as MSI-high (MSI-H). A tumor is classified as MSI-low (MSI-L) if there is allelic shift in only one microsatellite. If there is no evidence of allelic shift in the panel, the tumor is considered microsatellite-stable (MSS). MSI-H is seen commonly in Lynch syndrome patients; however, it is also found in endometrial cancers with promoter hypermethylation of MLH1. In those tumors categorized as MSI-H, if there is loss of MLH1expression on IHC, a methylation-specific polymerase chain reaction for MLH1 proximal promoter region -248 to -178 is performed to detect methylation of the MLH1promoter. The presence of MLH1 promoter methylation indicates a likely sporadic tumor instead of Lynch syndrome.

Immunohistochemical staining uses antibodies to mismatch repair (MMR) proteins to determine if tumors express MMR gene products. Immunohistochemistry (IHC) is another triage tool to evaluate for Lynch syndrome. Endometrial cancer tissue can be stained for the panel of mismatch repair proteins MLH1, MSH2, MSH6, and PMS2. Absent staining is considered abnormal. Because the mismatch repair proteins dimerize together, specific patterns of staining loss can be seen. MLH1 and PMS2 are often absent together and MSH2 and MSH6 are often lost together. The specific staining patterns can direct the genetic testing strategy. As an example, if a patient’s tumor fails to express MSH6 by IHC, initial genetic evaluation can be targeted to MSH6.

Both MSI and IHC testing can be performed with formalin-fixed, paraffin-embedded tissue. Each of these tests can serve as an initial evaluation for endometrial cancer patients when there is concern for Lynch syndrome. MSI testing has a sensitivity of 77-89% and specificity of 89%, while IHC has a sensitivity and specificity of 83% and 89%, respectively. If one or both of these results are abnormal, the patient should be referred to a genetic counselor. The results may be due to Lynch syndrome but may also result with epigenetic silencing.

Patients will be counseled and, once fully informed, may choose to undergo genetic testing with germline DNA sequencing and testing for large rearrangements and deletions in MMR genes. Germline testing will include evaluation of MLH1, MSH2, MSH6, or PMS2 unless directed more specifically by absence of expression with IHC. In cases where there is a loss of expression of MSH2 without a germline mutation found, the EPCAM gene should be evaluated. Deletions in the EPCAM gene result in hypermethylation of the MSH2 promoter and silencing of MSH2 in 20-25% of patients where no germline MSH2 mutation is found. Of note, there is a 5-10% false-negative rate with IHC as well as MSI testing.

If MSI testing is done initially and MSI-H is found, consider IHC testing to direct genetic evaluation or proceed with germline testing. If IHC testing is done initially and all MMR repair proteins are expressed, no further evaluation is needed if the patient is over 50 at time of endometrial cancer diagnosis and has no significant family history. If the patient is under 50 at the time of diagnosis, has multiple primary cancers, or has a family history including Lynch syndrome-associated cancers, she should still be referred for genetic evaluation.

If there is absent expression of MLH1, PMS2, MSH2, or MSH6 with IHC evaluation, then the patient should be referred for genetic evaluation. If there is absent expression of MLH1 and PMS2 on IHC evaluation, consider evaluation for MLH1 hypermethylation. If the hypermethylation is present, this indicates a likely sporadic tumor. If there is a history of early onset of malignancy or significant family history, then consider MLH1 genetic testing; otherwise, no further testing is needed. If the hypermethylation is negative, the patient should be referred for genetic evaluation.

In addition to the Amsterdam II and revised Bethesda Guidelines, risk models have been developed to quantify risk of a genetic mutation in the MMR genes and/or subsequent risk of malignancy. These models include PREMM (http://premm.dfci.harvard.edu), MMRpro (http://utsouthwestern.edu/breasthealth/cagene/), and HNPCC predict model (http://hnpccpredict.hgu.mrc.ac.uk/. These models may be useful when tumor testing is not available.

Currently, there is ongoing debate as to how best to screen patients with endometrial cancer for Lynch syndrome. Universal testing of all colorectal tumors has been found to be cost effective and is now recommend by the National Comprehensive Cancer Network. Although various institutions have moved to universal screening of tumors with a new diagnosis of endometrial cancer, more data are needed to determine if this is a cost-effective approach. Lynch syndrome patients with MSH6 mutations have made development of selective screening modalities challenging given the clinicopathologic characteristics of these tumors are different from those associated with other MMR mutations.

These patients tend to develop endometrial cancer at a later age (mean 50-61) compared to women with other MMR mutations. In addition, most patients with MSH6 mutations do not have a personal/family history indicative of Lynch syndrome, and some of these tumors are MSS or MSI-L. All patients with endometrial cancer should undergo screening for inherited susceptibility syndromes based on personal and family history. Unfortunately, patients with Lynch syndrome may be missed due to a lack of family history.

Ideally, universal tumor testing for all tumors or patients less than age 60 diagnosed with endometrial cancer should take place. If universal testing is not currently performed at your medical center, practitioners should make a decision to initiate tumor testing or refer to a genetics counselor/oncologist if there is at least a 5% chance the patient has an inherited cancer predisposition.

Diagnosis of Cowden Syndrome

Cowden syndrome is associated with germline mutations in the PTEN tumor suppressor gene. PTEN is involved with apoptosis, cell cycle arrest, and various cell survival pathways. A person with Cowden syndrome who has a germline mutation in one allele of PTEN will have loss or reduction in PTEN activity with loss of the other allele through a second hit. This will lead to increased phosphorylation of many important cellular proteins and impact signaling pathways related to migration, invasion, cell cycle progression, translation, metabolism, apoptosis, and angiogenesis.

Cowden syndrome is part of a larger group referred to as the PTEN hamartoma tumor syndrome (PHTS), which includes Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus-like syndrome, and Proteus syndrome. BRRS is a congenital disorder with primary clinical features that include hamartomatous intestinal polyps, macrocephaly, pigmented macules on the penis, and lipomas. Of these syndromes, Cowden syndrome is the only one known to be directly associated with a predisposition to cancer. However, there is a belief that patients with other disorders in the PHTS group should be assumed to have cancer risks.

The penetrance of PTEN mutations in Cowden syndrome is estimated to be 80%. The same pathogenic PTEN mutations in Cowden syndrome have been observed in other syndromes within the spectrum of PHTS. The genotypes or, in this case, the different PTEN mutations do not appear to align with specific phenotypes within the PHTS group. In addition, not all patients who meet clinical criteria for Cowden or other syndromes within PHTS have been found to have germline PTENmutations. These findings are likely due to other genetic and/or epigenetic processes that affect phenotype.

Patients with Cowden syndrome have an increased lifetime risk of breast, thyroid, endometrial, renal, skin, brain, and colorectal cancer. Please see Table II for lifetime risk of various cancers associated with Cowden syndrome. Hallmarks of Cowden syndrome include multiple hamartomas and elevated risk of malignancy. Clinical features include mucocutaneous papillomatous papules, trichilemmomas, acral keratoses, and palmoplantar keratoses. Both adult Lhermitte-Duclos disease, a dysplastic gangliocytoma of the cerebellum, and an autism spectrum disorder characterized by macrocephaly are associated with Cowden syndrome. Cowden syndrome can be variable in expression with many features that occur within the general population.

Table 2.n

Estimates of PTEN mutation frequency in individuals meeting criteria for Cowden syndrome established by the International Cowden Consortium in 1996 have ranged from 34% to 80%. The clinical criteria generated through the International Cowden Consortium were created before the discovery of PTEN in 1997. These clinical criteria were based on case reports and expert opinion with selection bias.

Since that time, these clinical guidelines have been reevaluated based on findings in patients with known PTEN mutations. These new guidelines, proposed by Pilarksi et al, group Cowden syndrome with the other syndromes that make up the PHTS. The National Comprehensive Cancer Network has used these updated guidelines to establish criteria for both the diagnosis of Cowden syndrome/PHTS and identification of patientswho should undergo testing for PTEN mutations.

Clinical diagnostic criteria have major and minor characteristics. A person is given an operational diagnosis of PHTS if she has either of the following: (1) three or more major criteria, but one must include macrocephaly, Lhermitte-Duclos disease, or gastrointestinal hamartomas, or (2) two major and three minor criteria. In a family with one individual who meets criteria for PHTS clinically or has a PTEN mutation, a patient is given an operation diagnosis of PHTS if she meets any of the following three criteria: (1) any two major criteria with or without minor criteria, (2) one major and two minor criteria, or (3) three minor criteria. Major criteria are breast cancer, endometrial cancer (epithelial), thyroid cancer (follicular), Lhermitte-Duclos disease (adult), gastrointestinal hamartomas (including ganglioneuromas, excluding hyperplastic polyps; 3 or more), macrocephaly (97th percentile or higher: 58 cm for females, 60 cm for males), macular pigmentation of the glans penis, and multiple mucocutaneous lesions.

The mucocutaneous lesions can be any of the following: (1) three or more trichilemmomas with at least one biopsy proven, (2) three or more palmoplantar keratotic pits and/or acral hyperkeratotic papules, (3) at least three mucocutaneous neuromas, or (4) oral papillomas (particularly on the tongue and gingiva) that are biopsy proven, dermatologist diagnosed, or at least three present. Minor criteria are autism spectrum disorder, colon cancer, at least three esophageal glycogenic acanthoses, at least three lipomas, mental retardation (i.e., IQ 75 or less), thyroid cancer (papillary or follicular variant of papillary), renal cell carcinoma, testicular lipomatosis, vascular anomalies (including multiple intracranial developmental venous anomalies), and thyroid structural lesions (i.e., adenomas or multinodular goiter).

Guidelines through the National Comprehensive Cancer Network are available to help determine which patients with Cowden syndrome/PTHS should undergo genetic testing. Refer your patient for genetic testing if she meets one of the following criteria:

• Individual from a family with a known PTENmutation.

• Individual meeting clinical diagnostic criteria for CS/PHTS as above.

• At-risk individuals with a first-degree relative with a clinical diagnosis of CS/PHTS or BRRS for whom testing has not been done

• Individuals with a personal history of one of the following:

• Bannayan-Riley-Ruvalcaba syndrome (BRRS)

• Adult Lhermitte-Duclos disease

• Autism spectrum disorder and macrocephaly

• Two or more biopsy-proven trichilemmomas

• Two or more major criteria (one must be macrocephaly)

• Three or more major criteria, without macrocephaly

• One major and at least three minor criteria

• At least four minor criteria

Major and minor criteria for genetic testing vary from those used to make a clinical diagnosis. Major criteria for genetic testing referral are the following: breast cancer, endometrial cancer, follicular thyroid cancer, multiple GI hamartomas or ganglioneuromas, macrocephaly (megalocephaly, 97% or greater, 58 cm in adult women, 60 cm in adult men), macular pigmentation of the glans penis, mucocutaneous lesions (one biopsy proven trichilemmoma, multiple palmoplantar keratoses, and multifocal or extensive oral mucosal papillomatosis, multiple cutaneous facial papules – commonly verrucous).

Minor criteria for genetic testing referral are the following: autism spectrum disorder, lipomas, at least three esophageal glycogenic acanthoses, colon cancer, mental retardation (i.e., 75 or less), papillary or follicular variant of papillary thyroid cancer, renal cell carcinoma, single GI hamartomas or ganglioneuroma, thyroid structural lesions (i.e., adenoma, nodules, goiter), vascular anomalies (including muttiple development venous anomalies), testicular lipomatosis, single GI hamartoma, or ganglioneuroma.

If patients do not meet criteria for genetic testing, individualized health recommendations should be based on personal and family history. Patients with a history of an allogeneic bone marrow transplant should discuss with a genetic counselor the most appropriate testing sample to be used given the theoretical risk of contamination from donor.

3. Management

Counseling recommendations

A patient who is diagnosed with Lynch syndrome or Cowden syndrome will need to undergo specific follow-up, which includes:

• Discussion of risk-associated malignancies and other diagnoses linked to the inherited syndrome.

• Further genetic testing if indicated through individual and familial characteristics.

• Psychosocial assessment with support.

• Assessment of familial impact and potential benefits of alerting relatives.

• If childbearing age, discuss potential effects on reproductive health (i.e., preimplantation genetic diagnosis).

• Review of risk-reducing interventions (medical and surgical).

My patient has Lynch syndrome – what do I do?

Lynch syndrome is associated with a mutation in at least one of the following genes: MLH1, MSH2, MSH6, PMS2, and EPCAM. Each of these mutations confers different risks associated with malignancy. The National Comprehensive Cancer Network has developed guidelines for management of these patients based on risk of cancer associated with the identified genetic mutation. These guidelines have been adapted below:

For patients with MLH1, MSH2, and EPCAM mutations

Uterine and ovarian cancer risk

• Prophylactic hysterectomy with bilateral salpingo-oophorectomy (BSO) is a risk-reducing option that should be considered by women who have completed child-bearing.

• Educate patients that dysfunctional uterine bleeding warrants evaluation.

• No clear evidence supports screening for endometrial cancer; however, annual office endometrial sampling is an option.

• Data do not support routine ovarian cancer screening; however, clinicians may find screening helpful in certain circumstances.

• Transvaginal ultrasound for endometrial and ovarian cancer has not been shown to be sufficiently sensitive or specific to support a positive recommendation but may be considered at the discretion of the clinician.

Risk of other cancers

• Colonoscopy at age 20-25 or 2-5 years prior to the earliest colon cancer if it is diagnosed before age 25 and repeated every 1-2 years.

• No clear evidence to support screening for gastric, duodenal, or small bowel cancer; however, selected individuals or families or those of Asian descent may consider EGD with extended duodenoscopy (to distal duodenum or into the jejunum) every 3-5 years beginning at age 30-35.

• Consider annual urinalysis starting at 25-30 years of age due to risk of urothelial cancer.

• Annual physical/neurological examination starting at age 25-30 due to risk of central nervous system cancer.

Additional considerations

• Initial data suggest aspirin may decrease the risk of colon cancer in patients with Lynch syndrome; however, recommendation for standard use cannot be made at this time.

• Despite an increased risk of pancreatic cancer, no screening recommendations exist at this time.

• Patients may be at increased risk of breast cancer, but due to limited data screening recommendations cannot be made at this time.

Mental health, quality of life, familial risk

• Address psychosocial and quality of life aspects undergoing risk reducing hysterectomy/BSO.

• Discuss risk of inherited cancer to relatives, options for evaluation, and subsequent care.

• Recommend genetic counseling and consideration of genetic testing for relatives at risk.

For patients with MSH6 or PMS2 mutations

Uterine and ovarian cancer risk

• Prophylactic hysterectomy with bilateral salpingo-oophorectomy (BSO) is a risk-reducing option that should be considered by women who have completed child-bearing.

• Educate patients that dysfunctional uterine bleeding warrants evaluation.

• No clear evidence supports screening for endometrial cancer; however, annual office endometrial sampling is an option.

• Data do not support routine ovarian cancer screening; however clinicians may find screening helpful in certain circumstances.

• Transvaginal ultrasound for endometrial and ovarian cancer has not been shown to be sufficiently sensitive or specific to support a positive recommendation but may be considered at the discretion of the clinician.

Risk of other cancers

• Colonoscopy at age 25-30 or 2-5 years prior to the earliest colon cancer if it is diagnosed before age 30 and repeated every 1-2 years

• With limited data available to determine age of onset and penetrance among MSH6 and PMS2 carriers, colonoscopies starting at younger or later ages may be considered in some families.

• Risk of other Lynch syndrome-related cancer is low based on available data, but given the limited data available, no screening recommendation can be made at this time for these various malignancies.

Mental health, quality of life, familial risk

• Address psychosocial and quality of life aspects undergoing risk-reducing hysterectomy/BSO.

• Discuss risk of inherited cancer to relatives, options for evaluation, and subsequent care.

• Recommend genetic counseling and consideration of genetic testing for relatives at risk.

My patient has Cowden syndrome – what do I do?

The National Comprehensive Cancer Network guidelines

Uterine and breast cancer risk

• Educate patients regarding symptoms of endometrial cancer and encourage prompt notification of concerning symptoms.

• Consider annual random endometrial biopsies and/or ultrasound beginning at age 30-35.

• Discuss risk reducing mastectomy and hysterectomy, counsel regarding degree of protection, cancer risk, and reconstruction options

• Oophorectomy is not indicated in the setting of Cowden syndrome alone but may be indicated for other reasons.

• Breast awareness starting at age 18.

• Clinical breast exam every 6-12 months starting at age 25 or 5-10 years before the earliest known breast cancer in the family.

• Annual mammography and breast MRI screening starting at age 30-35 or individualized based on the earliest age of onset in the family

• For reproductive age women, advise about prenatal diagnosis and assisted reproduction including preimplantation for genetic diagnosis.

Risk of other cancers

• Annual comprehensive physical exam starting at age 18 or 5 years before the youngest age of diagnosis of a component cancer in the family (whichever comes first), with particular attention to the thyroid.

• Annual thyroid ultrasound starting at age 18 or 5-10 years before the earliest known thyroid cancer in the family, whichever is earlier.

• Colonoscopy, starting at age 35, then every 5 years or more frequently if the patient is symptomatic or polyps are found

• Consider renal ultrasound starting at age 40, then every 1-2 years..

• Dermatologic management may be indicated for patients.

Mental health, quality of life, familial risk

• Address psychosocial and quality of life aspects undergoing risk reducing mastectomy and/or hysterectomy.

• Consider psychomotor assessment in children at diagnosis and brain MRI if there are symptoms.

• Discuss risk of inherited cancer to relatives, options for evaluation and subsequent care.

• Recommend genetic counseling and consideration of genetic testing for relatives at-risk.

Pathology

Lynch Syndrome

Lynch syndrome-associated endometrial cancers have a range of histologic subtypes including endometrioid, clear cell, uterine papillary serous, and malignant mixed mullerian tumor, with the most common subtype being endometrioid (approximately 86%). Tumor morphology associated with abnormal expression of mismatch repair proteins with IHC include the following: tumor-infiltrating lymphocytes, peritumoral lymphocytes, synchronous ovarian and endometrial tumors, undifferentiated tumor histology, and/or lower uterine segment origin of tumor. Lower uterine segment endometrial cancers are rare; however, women with Lynch syndrome appear to have a higher prevalence compared to general endometrial cancer patients and endometrial cancer patients younger than age 50.

Lynch syndrome-associated epithelial ovarian cancers were diagnosed at stage I in 47% of patients, in comparison to 80% of general ovarian cancer patients who have advanced stage disease (stage III or IV) at time of diagnosis. Approximately 70-80% of epithelial ovarian cancers in the general population are high grade serous, while 28% of Lynch syndrome-associated epithelial ovarian cancers were serous with 35% endometrioid, 17% clear cell, and 5% mucinous in a cohort of patients.

In comparison to the other MMR genes associated with Lynch syndrome, some endometrial cancers with MSH6 mutations are MSS or MSI-L. This in addition to the clinical differences associated with endometrial cancer patients with MSH6 mutations has made it more challenging to develop screening guidelines to identify all patients with Lynch syndrome that do not incorporate universal screening.

Cowden Syndrome[|#BLINK#|

Data are limited when characterizing breast cancer or endometrial cancer tumor type in patients with Cowden syndrome. Within the general population, PTEN is the most commonly mutated gene in endometrial cancer, making it impossible to identify patients with Cowden syndrome or PHTS on this alone. There is strong evidence to link somatic PTEN mutations to endometrial carcinogenesis; however, the role of germline PTEN mutations continues to be investigated.

Previously, uterine fibroids or leiomyomata had been identified as a clinical feature of patients with Cowden syndrome. These reports do not provide diagnostic criteria as to how patients were identified as having Cowden syndrome. As such, these reports do not clarify if the rate of uterine fibroids (21-38%) is increased in patients with Cowden syndrome. It is unlikely the prevalence of uterine fibroids is drastically different in patients with Cowden syndrome compared to the general population.

Available literature does not indicate histopathologic differences in the breast cancer of patients with Cowden syndrome compared to the general population. Further study is required to better quantify potential differences. Patients with Cowden syndrome do appear to have a high risk of benign fibrocystic breast disease in additional to their increased lifetime risk of breast cancer.

4. Complications

Complications of genetic evaluation

Undergoing genetic evaluation has potential disadvantages patients must be aware of beyond the apparent pyschological and emotional stress. Limitations of current genetic testing including false negatives. Patients who undergo genetic evaluation may, unfortunately, have more questions than answers if a genetic variant of unknown significance is found. These are genetic variants that may be part of a normal spectrum or potentially concerning mutations without enough data to determine risk.

If a known mutation associated with Cowden syndrome or Lynch syndrome is discovered, patients will be encouraged to discuss this with family members. Individual choice may have a direct impact on the health decisions of other family members. Patients have to make challenging decisions regarding reproduction including timing of prophylactic surgery if desired and potential pregestational diagnosis.

In addition, patients may fear discrimination in employment settings or with health insurance if they are found to have an inherited susceptibility syndrome. These patients should be assured that the Genetic Information Non-Discrimination Act bans the use of predictive genetic information in enrollment, underwriting and coverage decisions by individual and group health insurers. It also bans this information from being used in employment decisions.

Complications of prophylactic surgery

Prophylactic surgery may include hysterectomy, bilateral salpingo-oophorecomy, and/or bilateral mastectomy depending on the respective inherited susceptibility syndrome. Each of these procedures has inherent surgical risks. Undergoing hysterectomy limits the ability of a patient to carry a pregnancy. Bilateral mastectomy is associated both with physical changes and emotional/psychosocial stress. Prophylactic bilateral salpingo-oophorectomy prior to menopause is likely associated with increased risk of fractures, dementia, increased risk of heart disease, cognitive impairment, and decreased overall survival. Quality of life may be impacted with decrease in libido and vaginal dryness in addition to other symptoms of menopause such as hot flashes and insomnia.

However, the risk of malignancy associated with Lynch syndrome and Cowden syndrome is significant, and these prophylactic surgeries can reduce aspects of that risk considerably. A detailed discussion with your patient and referral to an oncologic specialist will allow her to make an informed decision based on risk assessment.

5. Prognosis and Outcome

"What if" scenarios

My patient has a family member with Lynch syndrome or Cowden syndrome – what do I do?

If a patient has a family history of Lynch syndrome or Cowden syndrome, she should undergo genetic counseling. The Society of Gynecologic Oncology recommends against genetic testing for Lynch/HNPCC under the age of 21 in absence of extremely early onset of cancer in the family. Prior to referral to genetic counseling, the patient should understand the reason for referral and potential impact on her personal health. She can be tested directly for the specific mutation if it is known. If the mutation is not known and the person in the family who was diagnosed with the inherited susceptibility syndrome is still alive, it would be prudent to have this person tested prior to anyone else in the family. However, if this affected family member is no longer alive, your patient may desire to be tested for mutations in MLH1, MSH2, MSH6, PMS2, and the EPCAM gene.

If a germline mutation is found, the patient is diagnosed with Lynch syndrome and should undergo surveillance and counseling as appropriate. The patient should be managed with individualized surveillance based on personal and familial risk if the genetic testing is negative or a mutation of unknown significance is found. For a woman with a family member with only a clinical diagnosis of Cowden syndrome/PTEN hamartoma tumor syndrome (PTHS), the woman must have one major or two minor criteria (as listed above) to be recommended for genetic testing. If the woman has a relative with a known PTEN mutation, she should undergo testing for that mutation after appropriate counseling. PTEN testing should include full sequence analysis, promoter analysis, and deletion/duplication analysis.

If no mutation is found, other hereditary cancer syndromes such as hereditary breast and/or ovarian cancer syndrome and/or Li-Fraumeni syndrome should be considered. Assuming all genetic testing is negative but the patient meets clinical criteria for Cowden syndrome/PTHS, she should undergo appropriate counseling and surveillance. If all testing is negative or a variant of unknown significance is found, and she does not meet clinical criteria for an inherited susceptibility syndrome, she should undergo individualized screening based on personal and familial history.

If my patient has a BRCA mutation, does she have an increased risk of uterine cancer?

Women with genetic mutations in BRCA1 and/or BRCA2 may have an association with uterine serous carcinomas. The majority of data have been found in small cohorts of patients with BRCA mutations who developed uterine serous cancers. There is not enough evidence to develop standardized recommendations based on these studies. At this time, there are no recommended interventions with regard to uterine surveillance or prophylactic hysterectomy in women with BRCA mutations. Patients should be encouraged to report concerning symptoms such as abdominal bloating, pain, and vaginal bleeding to their providers expeditiously.

6. What is the evidence for specific management and treatment recommendations?

Lancaster, JM, Powell, CB, Kauff, ND. “Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions”. Gynecologic Oncology. vol. 107. 2007. pp. 159-62. (Society of Gynecologic Oncology committee statement reviewing risk of inherited predispositions to gynecologic cancers.)

Bonadona, V, Bonaiti, B, Olschwang, S. “Cancer risks associated with germline mutations in , , and genes in Lynch syndrome”. Journal of the American Medical Association. vol. 305. 2011. pp. 2304-10. (Study with evaluation of cancer risk for specific Lynch syndrome associated genes.)

“NCCN: Practice Guidelines in Oncology”. Genetic/Familial High-Risk Assessment: Colorectal. 2014. (NCCN guidelines for evaluation, referral, and surveillance in setting of Lynch syndrome.)

Barakat, RR, Berchuk, A, Markman, M, Randall, E. “Principles and Practice of Gynecologic Oncology”. 2013. (Textbook with chapter that includes review of hereditary gynecologic cancers.)

Barrow, E, Robinson, L, Alduai, W. “Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations”. Clinical Genetics. vol. 75. 2009. pp. 141-9. (Study with evaluation of cancer risk for specific Lynch syndrome-associated genes.)

Barrow, E, Alduai, W, Robinson, L. “Colorectal cancer in HNPCC: cumulative lifetime incidence, survival, and tumour distribution. A report of 121 families with proven mutations”. Clinical Genetics. vol. 74. 2008. pp. 233-42. (Study with evaluation of cancer risk for specific Lynch syndrome-associated genes.)

Senter, L, Clendenning, M, Sotamaa, K. “The clinical phenotype of Lynch syndrome due to germ-line mutations”. Gastroenterology. vol. 135. 2008. pp. 419-28. (Study with evaluation of cancer risk for PMS2 mutations in Lynch syndrome.)

Watson, P, Vasen, HF, Meckli, J. “The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome”. International Journal of Cancer. vol. 123. 2008. pp. 444-9. (Study with evaluation of cancer risk for specific Lynch syndrome-associated genes.)

Rabban, JT, Calins, SM, Kamezis, AN. “Assocation of tumor morphology with mismatch-repair protein status in older endometrial cancer patients: implicationsfor universal versus selective screening strategies for Lynch syndrome”. American Journal of Surgical Pathology Epub ahead of print. 2014. (Study evaluating specific screening modality for Lynch syndrome in endometrial cancer patients.)

Westin, SN, Lacour, RA, Urbauer, DL. “Carcinoma of the lower uterine segment: a newly described association with Lynch syndrome”. Journal of Clinical Oncology. vol. 26. 2008. pp. 5965-71. (Pathologic evaluation of lower uterine segment tumors and association with Lynch syndrome.)

Broaddus, R, Lynch, HT, Chen, L. “Pathologic features of endometrial carcinoma associated with HNPCC: a comparison with sporadic endometrial carcinoma”. Cancer. vol. 106. 2006. pp. 87-94. (Retrospective review comparing tumors of Lynch syndrome patients with other cohorts of endometrial cancer patients.)

Ketabi, Z, Batuma, K, Bernstein, I. “Ovarian cancer linked to Lynch syndrome typically presents as early-onset, non-serous epithelial tumors”. Gynecologic Oncology. vol. 121. 2011. pp. 462-5. (Retrospective review of Lynch syndrome patients with ovarian cancer.)

Schmeler, KM, Lynch, HT, Chen, L. “Prophylacticsurgery to reduce the risk of gynecologic cancers in the Lynch syndrome”. New England Journal of Medicine. vol. 354. 2006. pp. 261-9. (Study comparing cancer occurrence in Lynch syndrome patients based on history of prophylactic surgery.)

Umar, A, Boland, CR, Terdiman, JP. “Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability”. Journal of the National Cancer Institute. vol. 96. 2004. pp. 261-8. (Revised Bethesda Criteria for Lynch syndrome with review of microsatellite categories designated by the NCI.)

Farooq, A, Walker, LJ, Bowling, J. “Cowden syndrome”. Cancer Treatment Reviews. vol. 36. 2010. pp. 577-83. (Review addressing diagnosis, genetics, and surveillance.)

Pilarski, R, Burt, R, Kohlman, W. “Cowden syndrome and the hamartoma tumor syndrome: systematic review and revised diagnostic crietria”. Journal of the National Cancer Institute. vol. 105. 2013. pp. 1607-16. (Revised diagnostic criteria for Cowden syndrome/PHTS based on clinical findings in patients with PTEN mutations.)

“NCCN: Practice Guidelines in Oncology:Genetic/Familial High-Risk Assessment: Breast and Ovarian”. 2014. (NCCN guidelines for evaluation, referral, and surveillance in setting of Cowden syndrome.)

Pilarski, R. “Cowden syndrome: a critical review of the clinical literature”. Journal of Genetic Counseling. vol. 18. 2009. pp. 13-27. (Review addressing diagnosis, genetics and surveillance.)

Lavie, O, Ben Arie, A, Segev, Y. “germline mutations in women with uterine serous carcinoma-still a debate”. International Journal of Gynecological Cancer. vol. 20. 2010. pp. 1531-4. (Retrospective study of BRCA patients with uterine serous cancer.)

Pilarski, R, Stephens, JA, Noss, R. “Predicting mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features”. Journal of Medical Genetics. vol. 48. 2011. pp. 505-12. (Review of clinical features of Cowden syndrome and BRRR.)

Tan, M, Mester, JL, Ngeow, J. “Lifetime cancer risks in individuals with germline mutations”. Clinical Cancer Research. vol. 18. 2012. pp. 400-7. (Study evaluating risk of cancer in patients with Cowden syndrome.)

Riegert-Johnson, DL, Gleeson, FC, Roberts, M. “Cancer and Lhermitte-Duclos disease are common in Cowden syndrome patients”. Hereditary Cancer in Clinical Practice. vol. 8. 2010. pp. 6(Study evaluating risk of cancer in patients with Cowden syndrome.)

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