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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. PHTS can be diagnosed with the identification of a PTEN mutation.
The PTEN (‘phosphatase and tensin homologue on chromosome 10’) hamartoma tumor syndrome (PHTS) 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).
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%.
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 mutations should be assumed to have cancer risks similar to CS.
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
Operational diagnosis in an Individual
Any of the following:
Operational diagnosis in a family where one individual is diagnostic for Cowden
1. One pathognomonic criterion; or
(International Cowden Consortium diagnostic criteria for the diagnosis of Cowden syndrome have been adopted by National Comprehensive Cancer Network)
In 2013, a systematic review was conducted related to the clinical features reported in individuals with a PTEN mutation, and revised diagnostic criteria were proposed. The authors 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 these clinical features are included in Cowden syndrome testing minor criteria in NCCN guidelines Genetic/Familial High Risk Assessment: Breast and Ovarian (v2.2014).
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:
OR two of the following:
OR three of the following:
Proteus-like syndrome is undefined but describes individuals with significant clinical features of PS but who do not meet the diagnostic criteria.
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 that 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.
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.
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.
Genetic testing for a PTEN mutation may be considered medically necessary in a first -degree relative of a proband with a known PTEN mutation. (see Policy Guidelines)
Genetic testing for a PTEN mutation is considered investigational for all other indications.
Testing Strategy for Confirming the Diagnosis in a Proband
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 (research). Promoter analysis detects mutations in ~10% of individuals with CS who do not have an identifiable mutation in the PTEN coding region.
Testing in a First-Degree Relative
When a PTEN mutation has been identified in the proband, testing of asymptomatic at-risk relatives can identify those family members who have the family-specific mutation, for whom an initial evaluation and ongoing surveillance should be performed.
Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
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.
Blue Cross and Blue Shield Association Policy # 2.04.88
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.