BlueCross and BlueShield of Montana Medical Policy/Codes
Genetic Testing for PTEN Hamartoma Tumor Syndrome (PHTS)
Chapter: Medicine: Tests
Current Effective Date: December 27, 2013
Original Effective Date: December 27, 2013
Publish Date: September 27, 2013
Description

The phosphatase and tensin homologue on chromosome 10 hamartoma tumor syndrome (PHTS) includes several syndromes with heterogeneous clinical symptoms, which may place individuals at an increased risk of the development of certain types of cancer. PHTS can be diagnosed with the identification of a PTEN mutation.

The PTEN hamartoma tumor syndrome is characterized by hamartomatous tumors and PTEN germline mutations. Clinically, PHTS includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and Proteus-like syndrome (PLS).

Cowden syndrome (CS) is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium. Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules and present by the late 20s. The lifetime risk of developing breast cancer is 25-50%, with an average age of diagnosis between 38 and 46 years. The lifetime risk for thyroid cancer, which is usually follicular carcinoma, is approximately 10%. The risk for endometrial cancer is not well defined, but may approach 5-10%. CS is the only PHTS disorder associated with a documented predisposition to cancer; however, it has been suggested that patients with other PHTS diagnoses associated with PTEN mutations should be assumed to have cancer risks similar to CS.

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is characterized by macrocephaly, intestinal hamartomatous polyposis, lipomas, and pigmented macules of the glans penis. Additional features include high birth weight, developmental delay and mental deficiency (50% of affected individuals), a myopathic process in proximal muscles (60%), joint hyperextensibility, pectus excavatum, and scoliosis (50%).

PTEN-related Proteus syndrome (PS) is a complex, highly variable disorder involving congenital malformations and hamartomatous overgrowth of multiple tissues, as well as connective tissue nevi, epidermal nevi, and hyperostoses.

Proteus-like syndrome (PLS) is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS.

Clinical Diagnosis

A presumptive diagnosis of PHTS is based on clinical findings; however, because of the phenotypic heterogeneity associated with the hamartoma syndromes, the diagnosis of PHTS is made only when a PTEN mutation is identified.

International Cowden Consortium diagnostic criteria for the diagnosis of Cowden Syndrome:

Pathognomonic criteria

  1. Lhermitte-Duclos disease (LDD) (adult) defined as the presence of a cerebellar dysplastic gangliocytoma;
  2. Mucocutaneous lesions:
    • Trichilemmomas, facial;
    • Acral keratoses;
    • Papillomatous lesions.

Major criteria

  1. Breast Cancer;
  2. Thyroid Cancer (papillary or follicular);
  3. Macrocephaly (occipital frontal circumference ≥97th percentile);
  4. Endometrial cancer.

Minor criteria

  1. Other structural thyroid lesions (e.g., adenoma, multinodular goiter);
  2. Mental retardation (i.e., IQ ≤75);
  3. Gastrointestinal hamartomas;
  4. Fibrocystic disease of the breast;
  5. Lipomas;
  6. Fibromas;
  7. Genitourinary tumors (e.g., uterine fibroids, renal cell carcinoma); or
  8. Genitourinary structural malformations.

Operational diagnosis in an Individual

Any of the following:

  1. Mucocutaneous lesions alone if:
    • There are six or more facial papules, of which three or more must be trichilemmoma; or
    • Cutaneous facial papules and oral mucosal papillomatosis; or
    • Oral mucosal papillomatosis and acral keratoses, or
    • Palmoplantar keratoses, six or more; or
  2. Two or more major criteria, but one must include macrocephaly or LDD; or
  3. One major and three minor criteria; or
  4. Four minor criteria.

Operational diagnosis in a family where one individual is diagnostic for Cowden

  1. One pathognomonic criterion; or
  2. Any one major criterion with or without minor criteria; or
  3. Two minor criteria; or
  4. History of Bannayan–Riley–Ruvalcaba syndrome.

(International Cowden Consortium diagnostic criteria for the diagnosis of Cowden syndrome have been adopted by the National Comprehensive Cancer Network [NCCN]).

Bannayan-Riley-Ruvalcaba syndrome (BRRS). Diagnostic criteria for BRRS have not been set but are based heavily on the presence of the cardinal features of macrocephaly, hamartomatous intestinal polyposis, lipomas, and pigmented macules of the glans penis.

Proteus syndrome (PS) is highly variable and appears to affect individuals in a mosaic distribution (i.e., only some organs/tissues are affected). Thus, it is frequently misdiagnosed despite the development of consensus diagnostic criteria. Mandatory general criteria for diagnosis include mosaic distribution of lesions, progressive course, and sporadic occurrence. Additional specific criteria for diagnosis include:

  1. Connective tissue nevi (pathognomonic);

OR two of the following:

  1. Epidermal nevus;
  2. Disproportionate overgrowth (one or more);
  3. Limbs: arms/legs; hands/feet/digits;
  4. Skull: hyperostoses;
  5. External auditory meatus: hyperostosis;
  6. Vertebrae: megaspondylodysplasia;
  7. Viscera: spleen/thymus;
  8. Specific tumors before end of second decade (either one);
  9. Bilateral ovarian cystadenomas;
  10. Parotid monomorphic adenoma;

OR three of the following:

  •  Dysregulated adipose tissue (either one):
    • Lipomas;
    • Regional absence of fat;
  • Vascular malformations (one or more):
    • Capillary malformation;
    • Venous malformation;
    • Lymphatic malformation;
  • Facial phenotype:
    • Dolichocephaly;
    • Long face;
    • Minor downslanting of palpebral fissures and/or minor ptosis;
    • Low nasal bridge;
    • Wide or anteverted nares;
    • Open mouth at rest.

Proteus-like syndrome is undefined but describes individuals with significant clinical features of PS but who do not meet the diagnostic criteria.

Management

Treatment:

Treatment of the benign and malignant manifestations of PHTS is the same as for their sporadic counterparts.

Surveillance

The most serious consequences of PHTS are related to the increased risk of cancer including breast, thyroid and endometrial, and to a lesser extent, renal. The most important aspect of management of an individual with a PTEN mutation is increased cancer surveillance to detect tumors at the earliest, most treatable stages.

Molecular Diagnosis

PTEN is a tumor suppressor gene on chromosome 10q23 and is dual specificity phosphatase with multiple but incompletely understood roles in cellular regulation. (1) PTEN mutations are inherited in an autosomal dominant manner.

Because CS is likely underdiagnosed, the actual proportion of simplex cases (defined as individuals with no obvious family history) and familial cases (defined as ≥2 related affected individuals) cannot be determined. The majority of CS cases are simplex. It is estimated that 50-90% of cases of CS are de novo and approximately 10-50% of individuals with CS have an affected parent.

Because of the phenotypic heterogeneity associated with the hamartoma syndromes, the diagnosis of PHTS is made only when a PTEN mutation is identified. Up to 85% of patients who meet the clinical criteria for a diagnosis of CS and 65% of patients with a clinical diagnosis of BRRS have a detectable PTEN mutation. Some data suggest up to 20% of patients with Proteus syndrome and up to 50% of patients with a Proteus-like syndrome have PTEN mutations.

Penetrance: More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s. By the third decade, 99% of affected individuals develop the mucocutaneous stigmata, primarily trichilemmomas and papillomatous papules, as well as acral and plantar keratoses.

PTEN is the only gene in which mutations are known to cause PHTS.

Regulatory Status

No U.S. Food and Drug Administration (FDA)-cleared molecular diagnostic tests were found. Thus, molecular evaluation is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). The laboratory offering the service must be licensed by CLIA for high-complexity testing.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

Genetic testing for a PTEN mutation may be considered medically necessary to confirm the diagnosis when a patient has clinical signs* of a PTEN hamartoma tumor syndrome.

*NOTE: See Description section for clinical signs.

Genetic testing for a PTEN mutation may be considered medically necessary in a first-degree relative of a proband* with a known PTEN mutation. *NOTE: A proband is usually the first affected individual in a family who brings a genetic disorder to the attention of the medical community. A first-degree relative is any relative who is one meiosis away from a particular individual in a family; a relative with whom one-half of an individual's genes are shared, a 50% genetic link to the patient (i.e., parent, sibling, offspring).(6)

Genetic testing for a PTEN mutation is considered experimental, investigational and unproven for all other indications, including, but not limited to, prenatal testing.

Rationale

Literature Review:

The MEDLINE database was searched for literature that describes the analytic validity, clinical validity, and clinical utility of genetic testing for PTEN-related disorders.

Analytic validity (the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent)

According to a large reference laboratory, analytical sensitivity and specificity for polymerase chain reaction (PCR) sequencing PTEN-related disorders is 99%, and analytical sensitivity and specificity of testing for deletions/duplications by MLPA (multiplex ligation-dependent probe amplification) is 90% and 98%, respectively. (2)

The order of testing to optimize yield would be 1) sequencing of PTEN exons 1-9 and flanking intron regions. If no mutation is identified, perform 2) deletion/duplication analysis. If no mutation is identified, consider, 3) promoter analysis.

Clinical validity (the diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease)

Many reports on the prevalence of the features of Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba (BRRS) have been based upon data compiled from case reports and studies of small cohorts. Most of these reports were published before adoption of the International Cowden Consortium diagnostic criteria for CS in 1996, and the true frequencies of the clinical features in CS and BRRS are not known. (1)

According to a large reference laboratory, the clinical sensitivity of PTEN-related disorders sequencing is 80% for CS, 60% for BRRS, 20% for PTEN-related Proteus syndrome (PS) and 50% for Proteus-like syndrome (PSL). For PTEN-related deletion/duplication, it is up to 10% for BRRS and unknown for CS, PS, and PSL. (2)

Germline PTEN mutations have been identified in ~80% of patients meeting diagnostic criteria for CS and in 50-60% of patients with a diagnosis of BRRS, using PCR-based mutation analysis of the coding and flanking intronic regions of the gene. (3, 4) Marsh et al. screened DNA from 37 CS families and PTEN mutations were identified in 30 of 37 CS families (81%), including point mutations, insertions, and deletions. (3)

Whether the remaining patients have undetected PTEN mutations or mutations in other, unidentified genes, is not known. (5)

A 2011 study by Pilarski et al. determined the clinical features most predictive of a mutation in a cohort of patients tested for PTEN mutations. (1) Molecular and clinical data were reviewed for 802 patients referred for PTEN analysis by a single laboratory. All of the patients were classified as to whether they met revised International Cowden Consortium Diagnostic criteria. Two hundred and thirty of the 802 patients met diagnostic criteria for a diagnosis of CS. Of these, 79 had a PTEN mutation, for a detection rate of 34%. The authors commented that this mutation frequency was significantly lower than previously reported, possibly suggesting that the clinical diagnostic criteria for CS are not as robust at identifying patients with germline PTEN mutations as previously thought. In contrast, in their study, of the patients meeting diagnostic criteria for BRRS, 23 of 42 (55%) had a mutation, and 7 of 9 patients (78%) with diagnostic criteria for both CS and BRRS had a mutation, consistent with the literature.

Conclusions: Evidence from several small studies indicates that the clinical sensitivity of genetic testing for PTEN mutations may be highly variable. This may be a reflection of the phenotypic heterogeneity of the syndromes and an inherent referral bias as patients with more clinical features of CS/BRRS are more likely to get tested. The true clinical specificity is uncertain because the syndrome is defined by the mutation.

Clinical utility (how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes)

The clinical utility of genetic testing can be considered in the following clinical situations: 1) individuals with suspected PTEN hamartoma tumor syndrome (PHTS), 2) family members of individuals with PHTS, and 3) prenatal testing. These situations will be discussed separately below.

  1. Individuals with suspected PHTS. The clinical utility for these patients depends on the ability of genetic testing to make a definitive diagnosis and for that diagnosis to lead to management changes that improve outcomes. There is no direct evidence for the clinical utility of genetic testing in these patients as no studies were identified that described how a molecular diagnosis of PHTS changed patient management.

However, for patients who are diagnosed with PHTS by identifying a PTEN mutation, the medical management focuses on increased cancer surveillance to detect tumors at the earliest, most treatable stages.

  1. Family members. When a PTEN mutation has been identified in a proband, testing of at-risk relatives can identify those who also have the mutation and have PTEN hamartoma tumor syndrome (PHTS). These individuals need initial evaluation and ongoing surveillance.
  2. Prenatal screening. Prenatal diagnosis is possible for pregnancies at increased risk, by amniocentesis or chorionic villus sampling; the disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Conclusions: Direct evidence of the clinical utility of PTEN testing is lacking. However, the clinical utility of genetic testing for PTEN mutations is that genetic testing can confirm the diagnosis in patients with clinical signs and symptoms of PHTS. Management changes include increased surveillance for the cancers that are associated with these syndromes.

Summary

A PTEN mutation can be identified in up to 85% of patients who meet the clinical criteria for a diagnosis of Cowden Syndrome and 65% of patients with a clinical diagnosis of Bannayan-Riley-Ruvalcaba Syndrome. Most of these mutations can be identified by sequence analysis of the coding and flanking intronic regions of genomic DNA. A smaller number of mutations are detected by deletion/duplication or promoter region analysis.

However, the published clinical validity of testing for PTEN mutations is variable, and the true clinical validity is difficult to ascertain, as the syndrome is defined by the presence of a PTEN mutation.

The clinical utility of genetic testing for a PTEN mutation is high, in that confirming a diagnosis in a patient with clinical signs of a PTEN hamartoma tumor syndrome (PHTS) will lead to changes in clinical management by increasing surveillance to detect cancers known to be associated with PHTS at an early and treatable stage. Although most cases of a PHTS occur in individuals with no known family history of PHTS, testing of at-risk relatives will identify those who should also undergo increased cancer surveillance. Therefore, genetic testing for a PTEN mutation may be considered medically necessary when a presumptive diagnosis of a PTEN hamartoma tumor syndrome (PHTS) has been made, based on clinical signs and also in first-degree relatives of a probands with a known PTEN mutation.

Guidelines and Position Statements

2012 National Comprehensive Cancer Network (NCCN) guidelines recommend the following for CS management:

For women:

  • Breast self-exam training and education starting at age 18 years.
  • Clinical breast exam every 6-12 months, starting at age 25 years or 5-10 years before the earliest known breast cancer in the family.
  • For endometrial cancer screening, encourage patient education and prompt response to symptoms and participation in a clinical trial to determine the effectiveness and necessity of screening modalities.
  • Discuss option of risk-reducing mastectomy and hysterectomy on case-by-case basis and counsel regarding degree of protection, extent of cancer risk, and reconstructive options.

For men and women:

  • Annual comprehensive physical exam starting at age 18 years or 5 years before the youngest age of diagnosis of a component cancer in the family, with particular attention to breast and thyroid exam.
  • Baseline thyroid ultrasound at age 18 years, and consider annual thereafter.
  • Consider colonoscopy, starting at age 35 years, then every 5-10 years or more frequently if patient is symptomatic or polyps found.
  • Consider annual dermatologic exam.
  • Education regarding the signs and symptoms of cancer.

For relatives:

  • Advise about possible inherited cancer risk to relatives, options for risk assessment, and management.
  • Recommend genetic counseling and consideration of genetic testing for at-risk relatives.

Coding

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

ICD-9 Codes

759.6, v19.5, 759.5, v84.89

ICD-10 Codes

Q85.8, Z13.71, Z13.79, Z15.89, Q85.1

Procedural Codes: 81321, 81322, 81323
References
  1. Pilarski R, Stephens JA, Noss R et al. Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features. J Med Genet 2011; 48(8):505-12.
  2. ARUP Laboratories. ARUP's Laboratory Test Directory: PTEN-Related Disorders (PTEN) Sequencing : 2002722. Available online at: http://www.aruplab.com/guides/ug/tests/2002722.jsp . Last accessed February 2013.
  3. Marsh DJ, Coulon V, Lunetta KL et al. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet 1998; 7(3):507-15.
  4. Marsh DJ, Kum JB, Lunetta KL et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet 1999; 8(8):1461-72.
  5. Pilarski R, Eng C. Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet 2004; 41(5):323-6.
  6. Genetic Testing for PTEN Hamartoma Tumor Syndrome. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual, Medicine 2.04.88.
History
September 2013  New 2013 BCBSMT medical policy.
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Genetic Testing for PTEN Hamartoma Tumor Syndrome (PHTS)