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MP 2.04.88 Genetic Testing for PTEN Hamartoma Tumor Syndrome

Medical Policy    
Section
Medicine 
Original Policy Date
2/2013
Last Review Status/Date
Reviewed with literature search/2:2015
Issue
2:2015
  Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


Description

PHTS is characterized by hamartomatous tumors and PTEN germline mutations. Clinically, PHTS includes CS, 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 25% to 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% to 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.

PLS 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.

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

  • Lhermitte-Duclos disease (LDD)–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 (eg, adenoma, multinodular goiter)
  • Mental retardation (ie, IQ ≤75)
  • Gastrointestinal hamartomas
  • Fibrocystic disease of the breast
  • Lipomas
  • Fibromas
  • Genitourinary tumors (eg, uterine fibroids, renal cell carcinoma) or
  • Genitourinary structural malformations

Operational Diagnosis in an Individual
Any of the following:

  • Mucocutaneous lesions alone if:
    • There are 6 or more facial papules, of which 3 or more must be trichilemmoma, or
    • Cutaneous facial papules and oral mucosal papillomatosis, or
    • Oral mucosal papillomatosis and acral keratoses, or
    • Palmoplantar keratoses, 6 or more
  • Two or more major criteria, but one must include macrocephaly or LDD; or
  • One major and 3 minor criteria; or
  • Four minor criteria.

Operational Diagnosis in a Family Where 1 Individual Is Diagnostic for Cowden

  1. One pathognomonic criterion; or
  2. Any 1 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])

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.(1) 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 CS testing minor criteria in NCCN guidelines Genetic/Familial High Risk Assessment: Breast and Ovarian (v2.2014).(2)

Bannayan-Riley-Ruvalcaba Syndrome

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 (ie, 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: 

  • Connective tissue nevi (pathognomonic)

OR 2 of the following:

  • Epidermal nevus
  • Disproportionate overgrowth (1 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 3 of the following:

  • Dysregulated adipose tissue (either one)
    • Lipomas
    • Regional absence of fat
  • Vascular malformations (1 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

PLS 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 relate 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 mutation is increased cancer surveillance to detect tumors at the earliest, most treatable stages.

Molecular Diagnosis

PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a tumor suppressor gene on chromosome 10q23 and is dual specificity phosphatase with multiple but incompletely understood roles in cellular regulation.(3) 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. Most CS cases are simplex. 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 mutation is identified. Up to 85% of patients who meet the 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 PHTS has been made, based on clinical signs and also in first-degree relatives of a probands with a known PTEN mutation.

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.


Policy

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.

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


Policy Guidelines 

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.

There are specific CPT codes for PTEN testing:

81321 PTEN (phosphatase and tensin homolog) (eg, Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; full sequence analysis
81322 known familial variant
81323 duplication/deletion variant


Benefit Application

 BlueCard/National Account Issues

No applicable information


Rationale

This policy was created in 2013 and is based on a search of the MEDLINE database through January 31, 2015. Literature that describes the analytic validity, clinical validity, and clinical utility of genetic testing for PTEN-related disorders was sought.

Analytic Validity

Analytic validity is 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, analytic 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 multiplex ligation-dependent probe amplification is 90% and 98%, respectively.(4)

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

Clinical validity is 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 syndrome (BRRS) have been based on 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.(3)

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 (PLS). For PTEN-related deletion/duplication, it is up to 10% for BRRS and unknown for CS, PS, and PLS.(4)

Germline PTEN mutations have been identified in approximately 80% of patients meeting diagnostic criteria for CS and in 50% to 60% of patients with a diagnosis of BRRS, using PCR-based mutation analysis of the coding and flanking intronic regions of the gene.(5,6) 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.(5)

Whether the remaining patients have undetected PTEN mutations or mutations in other, unidentified genes, is not known.(7)

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.(3) 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 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.

Summary of Evidence

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 because 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

Clinical utility is 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), and (2) family members of individuals with PHTS. These situations will be discussed separately next.

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.

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 PHTS. These individuals need initial evaluation and ongoing surveillance.

Section Summary

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 of Evidence

A PTEN mutation can be identified in up to 85% of patients who meet the clinical criteria for a diagnosis of Cowden syndrome (CS) 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 PHTS has been made, based on clinical signs and also in first-degree relatives of a probands with a known PTEN mutation.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN) guidelines Genetic/Familial High Risk Assessment : Breast and Ovarian (v2.2014)(2) recommend the following for CS management:

For women:

  • Breast awareness starting at age 18 years.
  • Clinical breast exam every 6 to 12 months, starting at age 25 years or 5 to 10 years before the earliest known breast cancer in the family.
  • Annual mammography and breast MRI screening starting at age 30 to 35 years or individualized based on earliest age of onset in family.
  • For endometrial cancer screening, encourage patient education and prompt response to symptoms. Consider annual random endometrial biopsies and/or ultrasound beginning at age 30 to 35 years.
  • Discuss risk-reducing mastectomy and hysterectomy 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 (whichever comes first), with particular attention to breast and thyroid exam.
  • Annual thyroid ultrasound starting at age 18 years, or 5 to 10 years before the earliest known thyroid cancer in the family, whichever is earlier.
  • Colonoscopy, starting at age 35 years, then every 5 or more frequently if patient is symptomatic or polyps found.
  • Dermatologic management may be indicated for some patients.
  • Consider renal ultrasound starting at age 40 years, then every 1 to 2 years
  • Consider psychomotor assessment in children at diagnosis and brain MRI if there are symptoms
  • 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.

Reproductive options:

  • For women of reproductive age, advise about options for prenatal diagnosis and assisted reproduction including preimplantation genetic diagnosis. Discussion should include known risks, limitations, and benefits of these technologies.

U.S. Preventive Services Task Force Recommendations
No U.S. Preventive Services Task Force recommendations for genetic testing for PTEN hamartoma tumor syndrome have been identified.

Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.

References:

  1. Pilarski R, Burt R, Kohlman W, et al. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst. Nov 6 2013;105(21):1607-1616. PMID 24136893
  2. National Comprehensive Cancer Network (NCCN). NCCN guidelines Genetic/Familial High Risk Assessment : Breast and Ovarian (V2.2014). http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed December 15, 2014.
  3. 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. Aug 2011;48(8):505-512. PMID 21659347
  4. ARUP Laboratory Test Directory. PTEN-Related Disorder (PTEN Sequencing). http://ltd.aruplab.com/tests/pub/2002722. Accessed December 15, 2014.
  5. 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. Mar 1998;7(3):507-515. PMID 9467011
  6. 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. Aug 1999;8(8):1461-1472. PMID 10400993
  7. 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. May 2004;41(5):323-326. PMID 15121767

 

Codes

Number

Description

CPT

 

(See Policy Guidelines)

ICD-9-CM diagnosis

759.6

Other hamaroses, NEC

  V19.5 Family history of congenital anomalies
ICD-10-CM (effective 10/1/15) Q85.8

Other phakomatoses, not elsewhere classified

  Z13.71 Encounter for nonprocreative screening for genetic disease carrier status
  Z13.79 Encounter for other screening for genetic and chromosomal anomalies
ICD-10-PCS (effective 10/1/15)   Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.

 


Index

Genetic Testing, PTEN

 


Policy History

 

Date Action Reason
02/14/13 Add to Medicine section, Pathology/Laboratory subsection Policy created with literature search through January 2013. Medically necessary to confirm a diagnosis in a patient with signs of PHTS and in first degree relatives of a proband with a known PTEN mutation. Genetic testing for a PTEN mutation is considered investigational for all other indications, including, but not limited to, prenatal testing.
2/13/14 Replace policy Policy updated with literature search through January 9, 2014; reference 1 added. Prenatal testing removed from the investigational statement. Clarification of testing strategy in Policy Guidelines.
2/12/15 Replace policy Policy updated with literature search through January 31, 2015. No references added. No change in policy statements.