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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. Genetic testing for a PTEN mutation can confirm a diagnosis of PHTS.
PTEN 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 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, which is usually follicular carcinoma, is approximately 35%. The risk for endometrial cancer is not well defined, but may approach 28%. A 2012 study included 3399 prospectively recruited individuals who met relaxed International Cowden Consortium PHTS criteria; 368 were found to have deleterious PTEN mutations. 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 deleterious PTEN mutation were found to have 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 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
(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 on 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 on Genetic/Familial High Risk Assessment of breast and ovarian (v2.2015).
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. Most 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.
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.
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.
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 Act (CLIA). Laboratory testing for PTEN mutations is available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by 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.
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, which detects mutations in approximately 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.
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. 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 Nervous/Mental Conditions, 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 Medically Necessary, “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.
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.
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 added.
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.