Genetic Testing for PTEN Hamartoma Tumor Syndrome

POLICY NUMBER

A.2.04.88

DESCRIPTION

The PTEN hamartoma tumor syndrome (PHTS) includes several syndromes with heterogeneous clinical symptoms, which may place individuals at an increased risk for the development of certain types of cancer. Genetic testing for PTEN can confirm a diagnosis of PHTS.

PTEN Hamartoma Tumor Syndromes

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

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 age late 20s. The lifetime risk of developing breast cancer is 85%, with an average age of diagnosis between 38 and 46 years. The lifetime risk for thyroid cancer, usually follicular carcinoma, is approximately 35%. The risk for endometrial cancer is not well-defined, but may approach 28%. A 2012 study included 3,399 prospectively recruited individuals who met relaxed International Cowden Consortium PHTS criteria; 368 were found to have PTEN disease-associated variants. Estimated lifetime cancer risks were: 85.2% for breast (95% confidence interval [CI], 71.4% to 99.1%); 35.2% for thyroid (95% CI, 19.7% to 50.7%); 28.2% for endometrium (95% CI, 17.1% to 39.3%); 9.0% for colorectal (95% CI, 3.8% to 14.1%); 33.6% for kidney (95% CI, 10.4% to 56.9%); and 6% for melanoma (95% CI, 1.6% to 9.4%). A 2013 study of 154 individuals with a PTEN disease-associated variant found cumulative cancer risks at age 70 of 85% for any cancer (95% CI, 70% to 95%), 77% for female breast cancer (95% CI, 59% to 91%), and 38% for thyroid cancer (95% CI, 25% to 56%).

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%).

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 is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS.

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 variants should be assumed to have cancer risks similar to CS.

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 disease-associated variant is identified.

Diagnostic Criteria for Cowden Syndrome

The International Cowden Consortium has developed criteria for diagnosing Cowden Syndrome.

Diagnostic Criteria for Cowden Syndromeª

Pathognomonic Criteria

• Lhermitte-Duclos disease adult defined as the presence of a cerebellar dysplastic gangliocytoma

  • Mucocutaneous lesions:

  • Trichilemmomas, facial

  • Acral keratoses

  • Papillomatous lesions

Major criteria

• Breast Cancer

• Thyroid Cancer (papillary or follicular)

• Macrocephaly (occipital frontal circumference ≥97th percentile)

• Endometrial cancer

Minor criteria

• Other structural thyroid lesions (e.g., adenoma, multinodular goiter)

• Mental retardation (i.e., IQ ≤75)

• Gastrointestinal hamartomas

• Fibrocystic disease of the breast

• Lipomas

• Fibromas

• Genitourinary tumors (e.g., uterine fibroids, renal cell carcinoma) or

• 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

2. Two or more major criteria, but one must include macrocephaly or Lhermitte-Duclos disease; or

3. One major and three minor criteria; or

4. Four minor criteria.

Operational diagnosis in a family with a diagnosis of Cowden syndrome

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

ªThese criteria for diagnosing Cowden syndrome have been adopted by the National Comprehensive Cancer Network

In 2013, a systematic review assessed the clinical features reported in individuals with a PTEN disease-associated variant and proposed revised diagnostic criteria. Reviewers concluded that there was insufficient evidence to support inclusion of benign breast disease, uterine fibroids, or genitourinary malformations as diagnostic criteria. There was sufficient evidence to include autism spectrum disorders, colon cancer, esophageal glycogenic acanthosis, penile macules, renal cell carcinoma, testicular lipomatosis, and vascular anomalies, and many of these clinical features are included in Cowden syndrome testing minor criteria in the National Comprehensive Cancer Network guidelines on genetic/familial high-risk assessment of breast and ovarian (v.2.2024).

Bannayan-Riley-Ruvalcaba Syndrome (BRRS)

Diagnostic criteria for BRRS have not been established. Current diagnostic practices 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)

PS 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 is listed below.

Diagnostic Criteria for Proteus Syndrome

Additional Diagnostic Criteria

Connective tissue nevi (pathognomonic) OR 2 of the following:

Epidermal nevus

• Disproportionate overgrowth (one or more):

  • Limbs: arms/legs; hands/feet/digits

  • Skull: hyperostoses

  • External auditory meatus: hyperostosis

  • Vertebrae: megaspondylodysplasia

  • Viscera: spleen/thymus

• Specific tumors before end of second decade (either one)

  • Bilateral ovarian cystadenomas

  • 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 down slanting of palpebral fissures and/or minor ptosis

  • Low nasal bridge

  • Wide or anteverted nares

  • Open mouth at rest

Proteus-Like Syndrome

Proteus-Like Syndrome (PLS) is undefined but describes individuals with significant clinical features of PS not meeting the diagnostic criteria.

Molecular Diagnosis

PTEN (phosphatase and tens in homolog deleted on chromosome 10) is a tumor suppressor gene on chromosome 10q23 and is a dual-specificity phosphatase with multiple but incompletely understood roles in cellular regulation. PTEN is the only gene for which disease-associated variants are known to cause PHTS. PTEN disease-associated variants are inherited in an autosomal dominant manner.

Most CS cases are simplex. However, because CS is likely underdiagnosed, the actual proportion of simplex cases (ie, individuals with no obvious family history) and familial cases (ie, ≥2 related affected individuals) cannot be determined. It is estimated that 50% to 90% of cases of CS are de novo and approximately 10% to 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 disease-associated variant 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 disease-associated variant. Some data have suggested that up to 20% of patients with Proteus syndrome and up to 50% of patients with a Proteus-like syndrome have PTEN disease-associated variants.

Most of these disease-associated variants can be identified by sequence analysis of the coding and flanking intronic regions of genomic DNA. A smaller number of variants are detected by deletion/duplication or promoter region analysis.

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.

Management

TreatmentTreatment of the benign and malignant manifestations of PHTS is the same as for their sporadic counterparts (ie, chemotherapy, surgery, and/or radiotherapy as per usual guidelines and clinical practice).

SurveillanceThe most serious consequences of a diagnosis of PHTS relates to the increased risk of cancers, including breast, thyroid and endometrial, and to a lesser extent, renal. Therefore, the most important aspect of management of an individual with a PTEN disease-associated variant is increased cancer surveillance to detect tumors at the earliest, most treatable stages.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratory testing for PTEN variants is available under the auspices of the CLIA. Laboratories that offer LDTs must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

POLICY

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

Targeted genetic testing for a PTEN familial variant may be considered medically necessary in a first-degree relative of a proband with a known PTEN pathogenic variant.

Genetic testing for PTEN is considered investigational for all other indications.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Testing Strategy to Confirm a Diagnosis in a Proband

The order of testing to optimize yield would be 1) Sequencing of PTEN exons 1-9 and flanking intronic regions. If no disease-associated variant is identified, perform 2) deletion/duplication analysis. If no disease-associated variant is identified, consider, 3) promoter analysis, which detects disease-associated variants in approximately 10% of individuals with Cowden Syndrome who do not have an identifiable disease-associated variant in the PTEN coding region.

Testing a First-Degree Relative

When a PTEN disease-associated variant has been identified in the proband, testing of asymptomatic at-risk relatives can identify those family members who have the familial variant, for whom an initial evaluation and ongoing surveillance should be performed.

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). The Society's nomenclature is recommended by the Human Variome Project, the HUman Genome Organization (HUGO), and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification

Genetic Counseling

Experts recommend formal genetic counseling for patients who are at risk of inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients. Genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

07/18/2013: New policy added. Approved by Medical Policy Advisory Committee.

03/21/2014: Policy reviewed; description updated regarding the proposal of revised diagnostic criteria based on a review related to the clinical features reported in individuals with a PTEN mutation. Removed "including, but not limited to, prenatal testing" from the investigational policy statement.

03/13/2015: Policy reviewed; description updated. Policy statements unchanged. Policy guidelines updated regarding testing in a first-degree relative.

08/18/2015: Medical policy revised to add ICD-10 codes.

03/30/2016: Policy description updated regarding Cowden Syndrome and laboratory-developed tests. Policy statements unchanged. Policy guidelines updated to add genetic counseling information and medically necessary and investigative definitions.

06/07/2016: Policy number A.2.04.88 added.

02/24/2017: Policy updated to change "mutation" to "disease-associated variant" throughout policy. Policy statement revised to state that targeted genetic testing for a PTEN familial variant may be considered medically necessary in a first-degree relative of a proband with a known PTEN pathogenic variant. Policy guidelines updated regarding standard terminology.

02/27/2018: Policy reviewed. Policy statement unchanged. Policy Guidelines updated regarding variant classification and genetic counseling information.

03/19/2019: Policy reviewed; no changes.

03/06/2020: Policy reviewed; no changes.

12/17/2020: Code Reference section updated to add new CPT code 0235U, effective 01/01/2021.

04/01/2021: Policy description updated. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

04/07/2022: Policy reviewed; no changes.

09/30/2022: Code Reference section updated to add new ICD-10 diagnosis codes Q85.81, Q85.82, and Q85.89, effective 10/01/2022.

03/15/2023: Policy description updated. Policy statement updated with minor wording change.

09/29/2023: Code Reference section updated to revise the code description for ICD-10 diagnosis code Q85.81, effective 10/01/2023.

03/19/2024: Policy description updated. Policy statements unchanged. Code Reference section updated to remove deleted ICD-10 diagnosis code Q85.8.

04/09/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.88

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

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