Friday, March 15, 2019

CPT 81201 - 81210, 81288, 81292 - 81299 , 81300, 81317, 81318, 81406

Code Description CPT

81201 APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; full gene sequence

81202 APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; known familial variants

81203 APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; duplication/deletion variants

81210 BRAF (v-raf murine sarcoma viral oncogene homolog B1) (eg, colon cancer), gene analysis, V600E variant

81288 MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis 

81292 MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis

81293 MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants

81294 MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants

81295 MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis

81296 MSH2 (muts honolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary nonpolyposis colorectal cancer, lynch syndrome) gene analysis, known familial variants

81297 MSH2 (muts honolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary nonpolyposis colorectal cancer, lynch syndrome) gene analysis, duplication/deletion variants

81298 MSH2 (muts honolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary nonpolyposis colorectal cancer, lynch syndrome) gene analysis, full sequence analysis

81299 MSH6 (muts honolog 6 [e. coli]) (eg, hereditary non-polyposis colorectal cancer, lynch syndrome) gene analysis, known familial variants

81300 MSH6 (muts honolog 6 [e. coli]) (eg, hereditary non-polyposis colorectal cancer, lynch syndrome) gene analysis, duplication/deletion variants

81301 Microsatellite instability analysis (eg, hereditary non-polyposis colorectal cancer, lynch syndrome) of markers for mismatch repair deficiency (eg, BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed

81317 PMS2 (postmeiotic segregation increased 2 [ s. cerevisiae]) (eg, hereditary nonpolyposis colorectal cancer, lynch syndrome) gene analysis, full sequence analysis

81318 PMS2 (postmeiotic segregation increased 2 [ s. cerevisiae]) (eg, hereditary nonpolyposis colorectal cancer, lynch syndrome) gene analysis, known familial variants

81319 PMS2 (postmeiotic segregation increased 2 [ s. cerevisiae]) (eg, hereditary nonpolyposis colorectal cancer, lynch syndrome) gene analysis, duplication/deletion variants

81406 Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia)

81435 Hereditary colon cancer syndromes (eg, Lynch syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include analysis of at least 7 genes, including APC, CHEK2, MLH1, MSH2, MSH6, MUTYH, and PMS2

81436 Hereditary colon cancer syndromes (eg, Lynch syndrome, familial adenomatosis polyposis); duplication/deletion gene analysis panel, must include analysis of at least 8 genes, including APC, MLH1, MSH2, MSH6, PMS2, EPCAM, CHEK2, and MUTYH


Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes


Introduction


Five to ten percent of all cancers may be inherited. Several genes have been identified that are associated with colon cancer and are passed from parents to children. Genetic testing may help determine the risk of colon cancer in family members and guide the frequency of colon cancer screening tests. This policy describes when those tests are covered based on the latest scientific studies. Some of these tests need to be pre-approved by the health plan. See Coverage Criteria for more specific information.

Note:  The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.


Testing Medical Necessity Lynch Syndrome(Also known as hereditary non-polyposis colorectal cancer or HNPC)
Initial screening Screening for Lynch syndrome as an initial evaluation of tumor tissue: * ALL cases of colorectal cancer, regardless of age screened for
Genetic testing  (eg, COLARIS® (Myriad))

Lynch Syndrome using either microsatellite instability (MSI) or immunohistochemical (IHC), with or without BRAF/MLH1 promoter methylation testing, may be considered medically necessary as an initial evaluation of tumor tissue .

Note: MSI/IHC testing prior to actual genetic testing for Lynch syndrome is recommended, but not required.
Genetic testing for Lynch syndrome (MLH1, MSH2, MSH6, PMS2 sequence analysis) may be considered medically necessary when the member meets ANY ONE of the following criteria: * A colon cancer diagnosis with a positive result from MSI/IHC
test (see Lynch syndrome initial screening, above) OR * Colorectal carcinoma (CRC) diagnosed in a patient who is less
than 50 years old OR * Endometrial cancer diagnosed in a patient who is less than 50
years old OR * All of the Amsterdam II clinical criteria are met (see below) OR * One of the revised Bethesda guidelines are met (seebelow) OR * One first-degree or second-degree relative* with a Lynch
syndrome mutation (genes MLH1, MSH2, MSH6, PMS2) OR * Personal history of endometrial cancer diagnosed at age 51-60

and one first-degree relative diagnosed with a Lynchassociated cancer.**
*For the purposes of familial assessment, first- or second-degree relatives are blood relatives on the same side of the family (maternal or paternal). The maternal and paternal sides of the


Testing Medical Necessity

family should be considered independently for familial patterns of cancer. *First-degree relatives are parents, siblings, and offspring. Second-degree relatives are aunts, uncles, grandparents, niece, nephews or half-siblings.
**Lynch-associated cancers include colorectal, endometrial, gastric, ovarian, pancreas, bladder, ureter and renal pelvis, brain (usually glioblastoma as seen in Turcot syndrome), and small intestinal cancers, as well as sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome.
 Genetic testing for Lynch syndrome is considered investigational when the member has not met at least one of the criteria listed above.
Familial Adenomatous Polyposis (FAP) and Associated Variants
Adenosis polyposis coli (APC) (eg, Colaris AP® (Myriad))
MYH/MUTYH-Associated Polyposis (MAP)
Adenosis polyposis coli (APC) genetic testing is considered medically necessary for ANY ONE of the following indications: * Personal history of greater than 10 cumulative colonic
adenomatous polyps OR * One first-degree relative diagnosed with familial adenomatous

polyposis (FAP) or with a documented APC mutation.  o If feasible, the specific APC mutation should be identified in
the affected first-degree relative with FAP prior to testing the member see (see below).
o “Full sequence” APC genetic testing is considered medically necessary only when the affected family member is unavailable or unwilling to be tested.
Note: First-degree relatives are parents, siblings, and offspring.
 APC genetic testing is considered investigational when the member has not met at least one of the criteria listed above.
MYH/MUTYH-Associated Polyposis (MAP) Genetic Testing may be considered medically necessary for ANY ONE of the following indications: * Personal history of 10 to 20 cumulative adenomatous polyps,
OR
with negative APC mutation testing and no family history of adenomatous polyposis




Genetic Counseling

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.

General Guidelines for Lynch and FAP Syndromes

1. Testing may be done to distinguish between a diagnosis of Lynch syndrome versus Familial Adenomatous Polyposis (FAP). Whether testing begins with the “MLH1, MSH2, MSH6, PMS2” mutations or the “APC” mutations depends upon the clinical presentation. 

2. In ideal situations, initial genetic testing for FAP or Lynch syndrome is performed in an affected family member so that testing in unaffected family members can focus on the mutation found in the affected family member. When this was not done, the following guidelines apply.

Lynch-Specific Guidelines


1. For patients with colorectal cancer being evaluated for Lynch syndrome, it is recommended that either the microsatellite instability (MSI) test, or the immunohistochemistry (IHC) test,  with or without BRAF gene mutation testing, be used as an initial evaluation of tumor tissue prior to MLH1, MSH2, MSH6, PMS2 sequence analysis. (Note that MSI/IHC testing may not be feasible if no tumor tissue is available.) Consideration of proceeding to MLH1, MSH2, MSH6, PMS2 sequencing would depend on the results of MSI or IHC testing. IHC testing in particular may help direct which Lynch syndrome gene likely contains a mutation, if any, and may also provide some additional information if Lynch syndrome genetic testing is inconclusive.


2. Several Clinical Laboratory Improvement Amendments (CLIA)*licensed clinical laboratories offer gene mutation testing for Lynch syndrome. The GeneTests website (available online at: http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/2622*db=genete sts) lists 21 U.S.-located laboratories that offer this service. Lynch syndrome mutation testing is packaged under a copyrighted name by at least one of these. The COLARIS® test from Myriad Genetic Laboratories includes sequence analysis of MLH1, MSH2, MSH6, and PMS2; large rearrangement analysis for MLH1, MSH2, PMS2, and MSH6 large deletions/ duplications; and analysis for large deletions in the EPCAM gene near MSH2. Two versions of this test, the COLARIS (excludes PMS2 testing) and COLARIS Update (includes PMS2 testing) are available. Testing is likely done in stages, beginning with the most common types of mutations. Individualized testing (e.g., targeted testing for a family mutation) can also be requested.

3. Amsterdam II clinical criteria are the most stringent criteria for defining families at high risk for Lynch syndrome. ALL of the following criteria must be fulfilled:

o 3 or more relatives have been diagnosed with an associated cancer (colorectal cancer, or cancer of the endometrium, small intestine, ureter or renal pelvis)
o 1 of the 3 should be a first-degree relative of the other 2
o 2 or more successive generations are affected
o 1 or more relatives were diagnosed before the age of 50 years
o Familial adenomatous polyposis (FAP) should be excluded in cases of colorectal carcinoma
o Tumors should be verified by pathologic examination
o Modifications:
* EITHER: very small families, which cannot be further expanded, can be considered to have HNPCC with only 2 colorectal cancers in first-degree relatives if at least 2 generations have the cancer and at least 1 case of colorectal cancer was diagnosed by the age of 55 years;
OR
* In families with 2 first-degree relatives affected by colorectal cancer, the presence of a third relative with an unusual early-onset neoplasm or endometrial cancer is sufficient.

4. The revised Bethesda guidelines are less strict than the Amsterdam criteria and are intended to increase the sensitivity of identifying at-risk families. The Bethesda guidelines are also felt to be more useful in identifying which patients with colorectal cancer should have their tumors tested for microsatellite instability and/or immunohistochemistry. Fulfillment of any of the following criterion meets guidelines:
o Colorectal carcinoma (CRC) diagnosed in a patient who is less than 50 years old
o Presence of synchronous (at the same time) or metachronous (at another time, i.e., a recurrence of) CRC or other Lynch syndrome*associated tumors, regardless of age
o CRC with high microsatellite instability histology diagnosed in a patient less than 60 years old
o CRC diagnosed in 1 or more first-degree relatives with a Lynch syndrome-associated tumor,( colorectal, endometrial, gastric, ovarian, pancreas, bladder, ureter and renal pelvis, brain (usually glioblastoma as seen in Turcot syndrome), and small intestinal cancers, as well as sebaceous gland adenomas and keratoacanthomas in Muir- Torre syndrome) with one of the cancers being diagnosed at younger than 50 years of age

o CRC diagnosed with 1 or more first-degree relatives with an HNPCC-related tumor (colorectal, endometrial, stomach, ovarian, pancreas, bladder, ureter and renal pelvis, biliary tract, brain [usually glioblastoma as seen in Turcot syndrome], sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome, and carcinoma of the small bowel), with one of the cancers being diagnosed at younger than age 50 years, OR CRC diagnosed in 2 or more first- or second-degree relatives  with HNPCC-related tumor, regardless of age

Description

Genetic testing is available for both affected individuals and those at risk for various types of hereditary cancer. This review evaluates genetic testing for hereditary colorectal cancer and polyposis syndromes, including familial adenomatous polyposis, Lynch syndrome (formerly known as hereditary nonpolyposis colorectal cancer), MUTYH-associated polyposis, and Lynch syndrome*related endometrial cancer.


Background  Hereditary Colorectal Cancers

There are currently 2 well-defined types of hereditary colorectal cancer, familial adenomatous polyposis (FAP) and Lynch syndrome (formerly hereditary nonpolyposis colorectal cancer or HNPCC).

Familial Adenomatous Polyposis (FAP) and Associated Variants

FAP typically develops by age 16 years and can be identified by the appearance of hundreds to thousands of characteristic, precancerous colon polyps. If left untreated, all affected individuals will go on to develop colorectal cancer. The mean age of colon cancer diagnosis in untreated individuals is 39 years. FAP accounts for 1% of colorectal cancer and may also be associated with osteomas of the jaw, skull, and limbs; sebaceous cysts; and pigmented spots on the retina, referred to as congenital hypertrophy of the retinal pigment epithelium (CHRPE). FAP associated with these collective extra-intestinal manifestations is sometimes referred to as Gardner syndrome. FAP may also be associated with central nervous system (CNS) tumors, referred to as Turcot syndrome.

Germline mutations in the adenomatous polyposis coli (APC) gene, located on chromosome 5, are responsible for FAP and are inherited in an autosomal dominant manner. Mutations in the APC gene result in altered protein length in about 80% to 85% of cases of FAP. A specific APC gene mutation (I1307K) has been found in subjects of Ashkenazi Jewish descent that may explain a portion of the familial colorectal cancer occurring in this population. 

A subset of FAP patients may have attenuated FAP (AFAP), characterized by fewer than 100 cumulative colorectal adenomas occurring later in life than in classical FAP.
In AFAP, colorectal cancer occurs at an average age of 50-55 years, but there is a high lifetime risk of colorectal cancer of about 70% by age 80 years. The risk of extra-intestinal cancer is lower in AFAP compared to classical FAP, but it is still high at an estimated cumulative lifetime risk of 38% compared to the general population.

Only 30% or fewer of AFAP patients have APC mutations. Instead, some of these patients have mutations in the MUTYH (formerly MYH) gene and are then diagnosed with MUTYH-associated polyposis (MAP). MAP occurs with a frequency approximately equal to FAP, with some variability among prevalence estimates for both. While clinical features of MAP are similar to FAP or AFAP, a strong multigenerational family history of polyposis is absent. Bi-allelic MUTYH mutations are associated with a cumulative colorectal cancer risk of about 80% by age 70, whereas mono-allelic MUTYH mutation-associated risk of


colorectal cancer appears to be relatively minimal, although it is still under debate.

Thus, inheritance for high-risk colorectal cancer predisposition is autosomal recessive in contrast to FAP. When relatively few (i.e., between 10 and 99) adenomas are present and family history is unavailable, the differential diagnosis may include both MAP and Lynch syndrome. Genetic testing in this situation could include APC, MUTYH if APC is negative for mutations, and screening for mutations associated with Lynch syndrome.

It is important to distinguish among classical FAP, attenuated FAP, and MAP (mono- or bi-allelic) by genetic analysis because recommendations for patient surveillance and cancer prevention vary according to the syndrome

Lynch Syndrome

Patients with Lynch syndrome have a predisposition to colorectal cancer and other malignancies as a result of an inherited mutation in a DNA mismatch repair (MMR) gene. Lynch syndrome includes those with an existing cancer and those who have not yet developed cancer. The term “HNPCC” originated prior to the discovery of explanatory MMR mutations for many of these patients, and now includes some who are negative for MMR mutations and likely have mutations in as-yet unidentified genes.

For purposes of clarity and analysis, the use of Lynch syndrome in place of HNPCC has been recommended in several recent editorials and publications.

Lynch syndrome is estimated to account for 3% to 5% of colorectal cancer and is also associated with an increased risk of other cancers such as endometrial, ovarian, urinary tract, and biliary tract cancer. Lynch syndrome is associated with an increased risk of developing colorectal cancer by age 70. After correction for ascertainment bias, the risk is approximately 27% to 45% for men, and 22% to 38% for women.

Lynch syndrome patients who have colorectal cancer also have an estimated 16% risk of a second primary within 10 years.

Lynch syndrome is associated with any of a large number of possible mutations in 1 of several MMR genes, known as MLH1, MSH2, MSH6, PMS2, and rarely MLH3. Risk of all Lynch syndromerelated cancers is markedly lower for carriers of a mutation in the MSH6 and PMS2 genes, although for most cancers it is still significantly higher than that of the general population.

Friday, February 15, 2019

CPT 81200, 81223, 81255, 81257, 89290, 89291, 89398 - Preimplantation Genetic Testing in Embryos

Code Description CPT

81200 ASPA (aspartoacylase) (eg, Canavan disease) gene analysis, common variants (e.g., E285A, Y231X)

81223 CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; full gene sequence

81255 HEXA (hexosaminidase A [alpha polypeptide]) (eg, Tay-Sachs disease) gene analysis, common variants (eg, 1278insTATC, 1421+1G>C, G269S)

81257 HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis, for common deletions or variant (eg, Southeast Asian, Thai, Filipino, Mediterranean, alpha3.7, alpha4.2,

81599 Unlisted multianalyte assay with algorithmic analysis

89290 Biopsy, oocyte polar body or embryo blastomere, microtechnique (for preimplantation genetic diagnosis); less than or equal to 5 embryos

89291 Biopsy, oocyte polar body or embryo blastomere, microtechnique (for preimplantation genetic diagnosis); greater than 5 embryos

89398 Unlisted reproductive medicine laboratory procedure

Specific CPT codes describe the embryo biopsy procedure (89290-89291). Additional CPT codes will be required for the genetic analysis and will vary by technique used to perform the genetic analysis. 




Preimplantation Genetic Testing in Embryos


Introduction

In vitro fertilization is the process of combining eggs and sperm in a lab dish to create a fertilized egg (an embryo) and later implanting it into the uterus to complete the pregnancy. Before implantation, one or more cells from the embryo may be tested to see if there are problems with its genes or chromosomes. “Preimplantation genetic diagnosis” testing looks at the genes to see if the embryo carries a genetic disease such as cystic fibrosis. “Preimplantation genetic screening” looks to see if there are too few or too many chromosomes. This policy describes when either type of preimplantation genetic testing may be considered medically necessary.  

Note:   The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered. 



Policy Coverage Criteria 

Procedure Medical Necessity

Preimplantation genetic diagnosis (PGD)


The procedure to obtain the cell sample for PGD (ie, the embryo biopsy) is considered medically necessary when the criteria below for PGD are met. However, the IVF procedure (ie, the procedures and services, including intracytoplasmic sperm injection [ICSI], required to create the embryos to be tested and the transfer of the appropriate embryos back to the uterus after testing) is covered only for persons with assisted fertility benefits for IVF. Please check the member contract and benefit descriptions for coverage of assisted fertility techniques such as IVF.  Preimplantation genetic diagnosis (PGD) may be considered medically necessary as an alternative to amniocentesis or chorionic villus sampling in couples undergoing IVF who meet one of the following criteria: * For evaluation of an embryo at an identified elevated risk of a
genetic disorder such as when: o Both partners are known carriers of a single-gene
autosomal recessive disorder o One partner is a known carrier of a single-gene autosomal
recessive disorder and the partners have an offspring who has been diagnosed with that recessive disorder 
o One partner is a known carrier of a single-gene autosomal dominant disorder
o One partner is a known carrier of a single X-linked disorder OR * For evaluation of an embryo at an identified elevated risk of
structural chromosomal abnormality such as if one parent has a balanced or unbalanced chromosomal translocation.


Procedure Medical Necessity
Preimplantation genetic screening (PGS), gender selection


Note: When the specific criteria noted above are met, the Plan will cover the embryo biopsy procedure to obtain the cell and genetic test associated with PGD under the medical benefit.

Preimplantation genetic screening (PGS) is considered not medically necessary when testing embryos solely for nonmedical gender selection or selection of other nonmedical traits.
Procedure Investigational
Preimplantation genetic diagnosis (PGD)
Preimplantation genetic screening (PGS)

Coding 
 

Preimplantation genetic diagnosis (PGD) as an alternative to amniocentesis or chorionic villus sampling is considered investigational in patients/couples who are undergoing IVF in all situations other than those specified above.

Preimplantation genetic screening (PGS) as an alternative to amniocentesis or chorionic villus sampling is considered investigational in patients/couples who are undergoing IVF in all situations when used to screen for potential genetic abnormalities in couples without a specific known inherited disorder.


Related Information 

Additional Information

In some cases involving a single X-linked disorder, determination of the gender of the embryo provides sufficient information for excluding or confirming the disorder.
The severity of the genetic disorder is also a consideration. At present, many cases of preimplantation genetic diagnosis (PGD) have involved lethal or severely disabling conditions with limited treatment opportunities, such as Huntington chorea or Tay-Sachs disease. Cystic fibrosis is another condition for which PGD has been frequently performed. However, cystic fibrosis has a variable presentation and can be treatable. The range of genetic testing that is performed on amniocentesis samples as a possible indication for elective abortion may serve as a guide.

This policy does not address the myriad ethical issues associated with preimplantation genetic testing (PGT) that, it is hoped, have involved careful discussion between the treated couple and the physician. For some couples, the decision may involve the choice between the risks of an in vitro fertilization procedure and deselection of embryos as part of the PGT treatment versus normal conception with the prospect of amniocentesis and an elective abortion.



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 (see Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology 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  Previous  Updated  Definition
Mutation Disease-associated variant Disease-associated change in the DNA sequence  Variant Change in the DNA sequence 
Familial variant Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification Definition
Pathogenic Disease-causing change in the DNA sequence
Likely pathogenic Likely disease-causing change in the DNA sequence 
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.


Genetic Counseling

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.

Evidence Review 

Description

Preimplantation genetic testing (PGT) involves analysis of biopsied cells as part of an assisted reproductive procedure. It is generally considered to be divided into 2 categories:
1. Preimplantation genetic diagnosis (PGD) is used to detect a specific inherited disorder in conjunction with in vitro fertilization (IVF) and aims to prevent the birth of affected children to couples at high risk of transmitting a disorder
2. Preimplantation genetic screening (PGSin conjunction with in vitro fertilization (IVF)  involves testing for potential genetic abnormalities for couples without a specific known inherited disorder.

Background
Preimplantation Genetic Testing


Preimplantation genetic testing (PGT) describes various adjuncts to an assisted reproductive procedure in which either maternal or embryonic DNA is sampled and genetically analyzed, thus permitting deselection of embryos harboring a genetic defect before implantation of an embryo into the uterus. The ability to identify preimplantation embryos with genetic defects before implantation provides an alternative to amniocentesis, chorionic villus sampling(CVS), and selective pregnancy termination of affected fetuses. Preimplantation genetic testing  is generally categorized as either diagnostic (preimplantation genetic diagnosis [PGD]) or screening (preimplantation genetic screening [PGS]). PGD is used to detect genetic evidence of a specific inherited disorder, in the oocyte or embryo, derived from mother or couple, respectively, that has a high risk of transmission. PGS is not used to detect a specific abnormality but instead uses similar techniques to identify a number of genetic abnormalities in the absence of a known heritable disorder. This terminology, however, is not used consistently (eg, some authors use PGD when testing for a number of possible abnormalities in the absence of a known disorder).

Biopsy

Biopsy for PGD can take place at 3 stages: the oocyte, cleavage stage embryo, or the blastocyst. In the earliest stage, both the first and second polar bodies are extruded from the oocyte as it completes the meiotic division after ovulation (first polar body) and fertilization (second polar body). This strategy thus focuses on maternal chromosomal abnormalities. If the mother is a known carrier of a genetic defect and genetic analysis of the polar body is normal, then it is assumed that the genetic defect was transferred to the oocyte during meiosis.

Biopsy of cleavage stage embryos or blastocysts can detect genetic abnormalities arising from either the maternal or paternal genetic material. Cleavage stage biopsy takes place after the first few cleavage divisions when the embryo is composed of 6 to 8 cells (ie, blastomeres). Sampling involves aspiration of one and sometimes 2 blastomeres from the embryo. Analysis of 2 cells may improve diagnosis but may also affect the implantation of the embryo. In addition, a potential disadvantage of testing at this phase is that mosaicism might be present. Mosaicism refers to genetic differences among the cells of the embryo that could result in an incorrect interpretation if the chromosomes of only a single cell are examined.

The third option is sampling the embryo at the blastocyst stage when there are about 100 cells. Blastocysts form 5 to 6 days after insemination. Three to 10 trophectoderm cells (outer layer of the blastocyst) are sampled. A disadvantage is that not all embryos develop to the blastocyst phase in vitro and, when they do, there is a short time before embryo transfer needs to take place. Blastocyst biopsy has been combined with embryonic vitrification to allow time for test results to be obtained before the embryo is transferred.



Analysis and Testing


The biopsied material can be analyzed in a variety of ways. Polymerase chain reaction or other amplification techniques can be used to amplify the harvested DNA with subsequent analysis for single genetic defects. This technique is most commonly used when the embryo is at risk for a specific genetic disorder such as Tay-Sachs disease or cystic fibrosis. Fluorescent in situ hybridization (FISH) is a technique that allows direct visualization of specific (but not all) chromosomes to determine the number or absence of chromosomes. This technique is most commonly used to screen for aneuploidy, sex determination, or to identify chromosomal translocations. FISH cannot be used to diagnose single genetic defect disorders. However, molecular techniques can be applied with FISH (eg, microdeletions, duplications) and, thus, single-gene defects can be recognized with this technique. Performing PGS using FISH is known as PGS version 1.

Another more recent approach is array comparative genome hybridization testing at either the 8-cell or, more often, the blastocyst stage, also known as PGS version 2. Unlike FISH analysis, hybridization allows for 24 chromosome aneuploidy screening, as well as more detailed screening for unbalanced translocations and inversions and other types of abnormal gains and losses of chromosomal material. Other PGS version 2 methods include single nucleotide variant microarrays and quantitative polymerase chain reaction.

Next-generation sequencing such as massively parallel signature sequencing has potential applications to prenatal genetic testing and is grouped with PGS version 2 techniques in some literature and referred to as PGS version 3 in other literature.

Embryo Classification

Three general categories of embryos have undergone preimplantation genetic testing, which are discussed in the following subsections.

Embryos at Risk for a Specific Inherited Single Genetic Defect 
Inherited single-gene defects fall into 3 general categories: autosomal recessive, autosomal dominant, and X-linked. When either the mother or father is a known carrier of a genetic defect, embryos can undergo PGD to deselect embryos harboring the defective gene. Sex selection of a female embryo is another strategy when the mother is a known carrier of an X-linked disorder for which there is no specific molecular diagnosis. The most common example is female carriers of fragile X syndrome.
In this scenario, PGD is used to deselect male embryos, half of which would be affected. PGD could also be used to deselect affected male embryos. While there is a growing list of single genetic defects for which molecular diagnosis is possible, the most common indications include cystic fibrosis, ß-thalassemia, muscular dystrophy, Huntington disease, hemophilia, and fragile X disease. It should be noted that when PGD is used to deselect affected embryos, the treated couple is not technically infertile but is undergoing an assisted reproductive procedure for the sole purpose of PGD. In this setting, PGD may be considered an alternative to selective termination of an established pregnancy after diagnosis by amniocentesis or chorionic villus sampling.

Embryos at a Higher Risk of Translocations

Balanced translocations occur in 0.2% of the neonatal population but at a higher rate in infertile couples or in those with recurrent spontaneous abortions. PGD can be used to deselect embryos carrying the translocations, thus leading to an increase in fecundity or a decrease in the rate of spontaneous abortion.

Identification of Aneuploid Embryos 

Implantation failure of fertilized embryos is common in assisted reproductive procedures; aneuploidy of embryos is thought to contribute to implantation failure and may also be the cause of recurrent spontaneous abortion. The prevalence of aneuploid oocytes increases in older women. These age-related aneuploidies are mainly due to nondisjunction of chromosomes during maternal meiosis. Therefore, PGS has been explored as a technique to deselect aneuploid oocytes in older women and is also known as PGD for aneuploidy screening. FISH analysis of extruded polar bodies from the oocyte or no blastomeres at day 3 of embryo development was  initially used to detect aneuploidy (PGS version 1). A limitation of FISH is that analysis is limited to a restricted number of proteins. More recently, newer PGS methods have been developed and are known collectively as PGS version 2. These methods allow for all chromosomes analysis with genetic platforms including array comparative genomic hybridization and single-nucleotide variant chain reaction analysis. Moreover, in addition to older women, PGS has been proposed for women with repeated implantation failures.

Thursday, January 17, 2019

CPT 86152, 86153 - Liquid Biopsy - Circulating Tumor DNA

Coding 

The use of circulating tumor DNA and/or circulating tumor cells is considered investigational for all indications (see Table 1 for examples of liquid biopsy tests).

Code Description CPT

81479 Unlisted molecular pathology procedure

86152 Cell enumeration using immunologic selection and identification in fluid specimen (eg, circulating tumor cells in blood);

86153 Cell enumeration using immunologic selection and identification in fluid specimen (eg, circulating tumor cells in blood); physician interpretation and report, when required





Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy)

Introduction

Liquid biopsy is a when a blood sample (rather than a piece of tissue) is used to test for cancer cells or small genetic cancer pieces mixing in the blood. The blood sample is taken from the arm and is tested for cells or genetic pieces that cancers shed into the bloodstream. Identifying tumor cell material in the blood might help to diagnose cancer, track changes in a cancer over time or help select the right type of cancer treatment. However, there is not enough information from clinical studies to be certain that this works as well as a tissue biopsy in most people, because we don’t yet know that this works as well as tissue biopsy. This treatment is not yet proven.

Note:   The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered. 
Policy Coverage Criteria 

Procedure Investigational

Circulating Tumor DNA, Circulating Tumor Cells 



Related Information 

This policy does not address the use of blood-based testing for epidermal growth factor receptor variants in non-small-cell lung cancer or the use of AR-V7 circulating tumor cells for metastatic prostate cancer.


Description

Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) in peripheral blood, referred to as “liquid biopsy,” have several potential uses for guiding therapeutic decisions in patients with cancer or being screened for cancer. This policy evaluates uses for liquid biopsies not addressed in a separate policy. If a separate policy exists, then conclusions reached there supersede conclusions here.

Background
Liquid biopsy refers to analysis of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) as methods of noninvasively characterizing tumors and tumor genome from the peripheral blood.

Circulating Tumor DNA

Normal and tumor cells release small fragments of DNA into the blood, which is referred to as cell-free DNA (cfDNA). cfDNA from nonmalignant cells is released by apoptosis. Most cell-free tumor DNA is derived from apoptotic and/or necrotic tumor cells, either from the primary tumor, metastases, or CTCs.

Unlike apoptosis, necrosis is considered a pathologic process, and generates larger DNA fragments due to incomplete and random digestion of genomic DNA. The length or integrity of the circulating DNA can potentially distinguish between apoptotic and necrotic origin. ctDNA can be used for genomic characterization of the tumor.

Circulating Tumor Cells 

Intact CTCs are released from a primary tumor and/or a metastatic site into the bloodstream. The half-life of a CTC in the bloodstream is short (1-2 hours), and CTCs are cleared through extravasation into secondary organs.

Most assays detect CTCs through the use of surface epithelial markers such as EpCAM and cytokeratins. The primary reason for in detecting CTCs is prognostic, through quantification of circulating levels.


Detecting ctDNA and CTCs

Detection of ctDNA is challenging because ctDNA is diluted by nonmalignant circulating DNA and usually represents a small fraction (<1 approaches="" are="" cfdna.="" eg="" methods="" more="" nbsp="" needed.="" of="" p="" sanger="" sensitive="" sequencing="" standard="" than="" the="" therefore="" total="">
Highly sensitive and specific methods have been developed to detect ctDNA, for both singlenucleotide mutations (eg, BEAMing [which combines emulsion polymerase chain reaction [PCR] with magnetic beads and flow cytometry] and digital PCR) and copy-number variants. Digital genomic technologies allow for enumeration of rare mutant variants in complex mixtures of DNA.

Approaches to detecting ctDNA can be considered targeted, which includes the analysis of known genetic mutations from the primary tumor in a small set of frequently occurring driver mutations, which can impact therapy decisions or untargeted without knowledge of specific variants present in the primary tumor, and include array comparative genomic hybridization, next-generation sequencing, and whole exome and genome sequencing.

CTC assays usually start with an enrichment step that increases the concentration of CTCs, either by biologic properties (expression of protein markers) or physical properties (size, density, electric charge). CTCs can then be detected using immunologic, molecular, or functional assays.


Summary of Evidence

For individuals who have advanced cancer who receive testing of ctDNA to select targeted treatment, the evidence includes observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, morbid events, and medication use. Given the breadth of methodologies available to assess ctDNA, the clinical validity of each commercially available test must be established independently, and these data are lacking. Published studies reporting clinical outcomes and/or clinical utility are lacking. The uncertainties concerning clinical validity and clinical utility preclude conclusions about whether variant analysis of ctDNA can replace variant analysis of tissue. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have advanced cancer who receive testing of CTCs to select targeted treatment, the evidence includes observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, morbid events, and medication use. Given the breadth of methodologies available to assess CTCs, the clinical validity of each commercially available test must be established independently, and these data are lacking. Published studies reporting clinical outcomes and/or clinical utility are lacking. The uncertainties concerning clinical validity and clinical utility preclude conclusions about whether the use of CTCs can replace variant analysis of tissue. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have cancer who receive testing of ctDNA to monitor treatment response, the evidence includes observational studies. Relevant outcomes are overall survival, diseasespecific survival, test accuracy and validity, morbid events, and medication use. Given the breadth of methodologies available to assess ctDNA, the clinical validity of each commercially available test must be established independently, and these data are lacking. Published studies reporting clinical outcomes and/or clinical utility are lacking. The uncertainties concerning clinical validity and clinical utility preclude conclusions about whether the use of ctDNA should be used to monitor treatment response. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have cancer who receive testing of CTCs to monitor treatment response, the evidence includes a randomized controlled trial, observational studies, and systematic reviews of observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, morbid events, and medication use. Given the breadth of methodologies available to assess CTCs, the clinical validity of each commercially available test must be established independently, and these data are lacking. The available randomized controlled trial found no effect on overall survival when patients with persistently increased CTC levels after first-line chemotherapy were switched to an alternative cytotoxic therapy. Other studies reporting clinical outcomes and/or clinical utility are lacking.

The uncertainties concerning clinical validity and clinical utility preclude conclusions about whether the use of CTCs should be used to monitor treatment response. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have received curative treatment for cancer who receive testing of ctDNA to predict risk of relapse, the evidence includes observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, morbid events, and medication use. Given the breadth of methodologies available to assess ctDNA, the clinical validity of each commercially available test must be established independently, and these data are lacking. Published studies reporting clinical outcomes and/or clinical utility are lacking. The uncertainties concerning clinical validity and clinical utility preclude conclusions about whether the use of ctDNA should be used to predict relapse response. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have received curative treatment for cancer who receive testing of CTCs to predict risk of relapse, the evidence includes observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, morbid events, and medication use. Given the breadth of methodologies available to assess CTCs, the clinical validity of each commercially available test must be established independently, and these data are lacking. Published studies reporting clinical outcomes and/or clinical utility are lacking. The uncertainties concerning clinical validity and clinical utility preclude conclusions about whether the use of CTCs should be used to predict relapse response. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who are asymptomatic and at high risk for cancer who receive testing of ctDNA to screen for cancer, no evidence was identified. Relevant outcomes are overall survival, diseasespecific survival, test accuracy, and test validity. Published data on clinical validity and clinical

Wednesday, December 19, 2018

CPT 0078U, 81225, 81226, 81227, 81291 - Pharmacogenetic Testing for Pain Management

Code Description CPT

0078U Pain management (opioid-use disorder) genotyping panel, 16 common variants (ie, ABCB1, COMT, DAT1, DBH, DOR, DRD1, DRD2, DRD4, GABA, GAL, HTR2A, HTTLPR, MTHFR, MUOR, OPRK1, OPRM1), buccal swab or other germline tissue sample, algorithm reported as positive or negative risk of opioid-use disorder (new code effective 10/1/18)

81225 CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *8, *17)

81226 CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN)

81227 CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *5, *6)

81291 MTHFR (5,10-methylenetetrahydrofolate reductase) (eg, hereditary hypercoagulability) gene analysis, common variants (eg, 677T, 1298C)

81479 Unlisted molecular pathology procedure



Pharmacogenetic Testing for Pain Management

Introduction

When it comes to treating pain, there are a lot of different choices. These include things like over-the-counter remedies like acetaminophen and ibuprofen, medications that are rubbed onto the skin, and prescription drugs known as opioids. Antidepressants and antiseizure medications are also sometimes used to help with pain. Managing acute (sudden and intense) and chronic (long lasting) pain can be challenging.  Each person not only has a different response to pain, but they may also have a different response to pain medication. In short, what works for one person may not work for another. A person’s genetics may affect pain perception and how the body processes medications. Genetic tests have been developed to try to find out how a person might respond to drugs to treat pain. These genetic tests are investigational (unproven). There is not enough medical evidence in published studies to show whether these genetic tests will improve overall health results.

Note:   The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered. 



Policy Coverage Criteria 

Service Investigational
Genetic testing for pain management

Genetic testing for pain management is considered investigational for all indications.
This policy does not address testing for congenital insensitivity to pain.
This policy is not intended to address testing that is limited to cytochrome P450 genotyping, which is addressed in a separate medical policy, (see Related Policies).
Commercially-available genetic tests for pain management consist of single-nucleotide variants (SNVs) or (less commonly) individual SNV testing. SNVs implicated in pain management include the following (see also Table 1):

* 5HT2C (serotonin receptor gene)
* 5HT2A (serotonin receptor gene)
* SLC6A4 (serotonin transporter gene)
* DRD1 (dopamine receptor gene)
* DRD2 (dopamine receptor gene)
* DRD4 (dopamine receptor gene)
* DAT1 or SLC6A3 (dopamine transporter gene)
* DBH (dopamine beta-hydroxylase gene)
* COMT (catechol O-methyltransferase gene)

* MTHFR (methylenetetrahydrofolate reductase gene)
* *-aminobutyric acid (GABA) A receptor gene
* OPRM1 (µ-opioid receptor gene)
* OPRK1 (*-opioid receptor gene)
* UGT2B15 (uridine diphosphate glycosyltransferase 2 family, member 15)
* Cytochrome p450 genes: CYP2D6, CYP2C19, CYP2C9, CYP3A4, CYP2B6, CYP1A2


 Evidence Review 

Description 


While multiple pharmacologic therapies are available for the management of acute and chronic pain, there is a lot of variability in the person’s response to pain, particularly in the management of chronic pain, and in the presence of adverse events (AEs). This has prompted interest in better targeting pain therapies through the use of pharmacogenetic testing of genes relevant to analgesic pharmacokinetics or pharmacodynamics. A number of panels of genetic tests for genes that have shown some association with the pharmacokinetics or pharmacodynamics of analgesic medications have been developed to aid in the management of pain.

Background

Pain is a universal human experience and an important contributor to outpatient and inpatient medical visits. The Institute of Medicine (IOM) reported in 2011 that common chronic pain conditions affect at least 116 million adults in the United States.
1
 Chronic pain may be due to cancer or chronic noncancer conditions. These noncancer conditions may include migraines, low back pain, or fibromyalgia. Multiple therapeutic options exist to manage pain, including pharmacotherapies, behavioral modifications, physical and occupational therapy, and complementary/alternative therapies. Nonetheless, the IOM has reported that many individuals receive inadequate pain prevention, assessment, and treatment. Given that pain is an individual and subjective experience, assessing and predicting response to pain interventions, including pain medications, is challenging.

Pain Management


A variety of medication classes are available to manage pain. These include non-opioid analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), and opioid analgesics which target central nervous system pain perception. Adjuvant medications such as antiepileptic drugs (eg, gabapentin, pregabalin), antidepressants (eg, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors), and topical analgesics have also been used. The management of chronic pain has been driven, in part, by the World Health Organization’s analgesic ladder for pain management, which was developed for the management of cancer-related pain but has been applied to the management of other forms of pain. The ladder outlines a stepped approach to pain management, beginning with non-opioid analgesia and proceeding to a weak opioid (eg, codeine), with or without an adjuvant for persisting pain. If these fail to control pain, the next step is a strong opioid (eg, fentanyl, morphine), with or without an adjuvant for persisting or worsening pain. Various opioids are available in short- and long-acting preparations and administered through variety of routes, including oral, intramuscular, subcutaneous, sublingual, and transdermal.



Pharmacologic Treatment

For acute pain management, particularly postoperative pain, systemic opioids and non-opioid analgesics remain the mainstay of therapy. However, there has been growing interest in using alternative, nonsystemic treatments in addition to or instead of systemic opioids. These options include neuraxial anesthesia, a type of regional anesthesia including epidural or intrathecal opioid injection. This type of anesthesia may be managed by a patient-controlled anesthesia pump. Postoperative peripheral nerve blocks may also be used.

While available pain management therapies are effective for many patients, there is a great deal of variability in pain response, particularly in the management of chronic pain. In addition, many opioids have a significant risk of adverse events (AEs), ranging from mild (eg, constipation) to severe (eg, respiratory depression) and are associated with a risk of dependence, addiction, and abuse. Limitations in currently available pain management techniques have led to interest in the use of pharmacogenetics to improve the targeting of therapies in order to predict and avoid AEs.

Genetics of Pain Management

Genetic factors may influence many aspects of pain and pain control, including predisposition to conditions that lead to pain, pain perception, and the development of comorbid conditions that may affect pain perception. The currently available genetic tests relevant to pain management look at single-nucleotide variants (SNVs) in single genes potentially related to pharmacokinetic or pharmacodynamic processes. 

Broadly speaking, genes related to these clinical scenarios include those involved in neurotransmitter uptake, clearance, and reception; opioid reception; and hepatic drug metabolism. Panels of genetic tests have been developed and have been proposed for use in the management of pain. Genes identified as being relevant to pain management and that are included in currently available panels are summarized in Table 1.



Commercially Available Genetic Tests for Pain Management
Several test labs market panels of tests or individual tests designed to address one or more aspects of pain management, including but not limited to drug selection, drug dosing, or prediction of AEs. Specific variants included in the panels are shown in Table 2.
* GeneSight® Analgesic (Assurex Health, Mason, OH) is a genetic panel test that is intended to analyze “how patients’ genes can affect their metabolism and possible response to FDA [U.S. Food and Drug Administration]-approved opioids, NSAIDs and muscle relaxants commonly used to treat chronic pain.”

Results are provided with a color-coded report based on efficacy and tolerability, which displays which medications should be used as directed, used with caution, or used with increased caution and more frequent monitoring.


The company’s website does not specify the testing methods. Publications describing other tests provided by the company specify that testing is conducted via SNP sequencing performed via multiplex polymerase chain reaction.

* Proove Biosciences (Irvine, CA) offers several genetic panels that address pain control. The Proove® Opioid Risk Panel is a panel of 11 genes that is intended to predict opioid abuse and failure of opioid therapy. Genetic testing results are provided along with an overall “Dependence Risk Index.”

The company also markets the Proove® Pain Perception panel, which is a panel test for SNPs in several genes related to pain perception, including COMT and at least 3 other genes. Results are provided with a report which stratifies patients’ pain sensitivity based on COMT haplotype.

In addition, Proove offers panels designed to predict good and poor responders to opioid therapies and non-opioid pain therapies. These are the Proove® Opioid Response


Tuesday, November 27, 2018

CPT 0301T,32998, 32999, 47382, 76940 -Microwave Tumor Ablation


CPT Code - Description

0301T Destruction/reduction of malignant breast tumor with externally applied focused microwave, including interstitial placement of disposable catheter with combined temperature monitoring probe and microwave focusing sensocatheter under ultrasound thermotherapy guidance

19499 Unlisted procedure, breast

32998 Ablation therapy for reduction or eradication of 1 or more pulmonary tumor(s) including pleura or chest wall when involved by tumor extension, percutaneous, radiofrequency, unilateral

32999 Unlisted procedure, lungs and pleura

47382 Ablation, 1 or more liver tumor(s), percutaneous, radiofrequency

47399 Unlisted procedure, liver

49999 Unlisted procedure, abdomen, peritoneum and omentum

50592 Ablation, 1 or more renal tumor(s), percutaneous, unilateral, radiofrequency

53899 Unlisted procedure, urinary system (for renal tumors)

60699 Unlisted procedure, endocrine system (for adrenal or thyroid tumors)

76940 Ultrasound guidance for, and monitoring of, parenchymal tissue ablation





Microwave Tumor Ablation

Introduction

Ablation refers to destroying tumors without removing them. Microwave ablation is a method of trying to treat tumors using microwave energy. A small probe is placed into the tumor. The probe sends out microwave energy. The microwaves cause enough heat to kill tumor cells. Medical studies show that while this technique can destroy tumors at a particular location, cancer recurrence at other sites is common, depending on the stage and type of cancer. More studies are needed to show which patients would benefit the most from this treatment, as well as explaining why this treatment should be used instead of other proven methods. For these reasons, microwave ablation of tumors is considered investigational (unproven).

Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.

Policy Coverage Criteria Service Investigational Microwave ablation (MWA) Microwave ablation (MWA) of primary and metastatic tumors is considered investigational. Coding

According to an American Medical Association publication (Clinical Examples in Radiology, 2012, 8, [3}), “microwave is part of the radiofrequency spectrum, and simply uses a different part of the radiofrequency spectrum to develop heat energy to destroy abnormal tissue.” Therefore, AMA recommends that microwave ablation should be reported using the CPT codes for radiofrequency ablation as noted in the coding table below.

Related Information
This policy does not address MWA for the treatment of splenomegaly or ulcers or as a surgical coagulation tool. Evidence Review

Description

Microwave ablation (MWA) is a technique that is used to destroy tumors and soft tissue. It generates microwave energy to create thermal coagulation and localized tissue necrosis, and has been used to treat tumors not amendable to resection. It has also been used to treat patients ineligible for surgery due to age, comorbidities, or poor general health. MWA may be performed as an open procedure, laparoscopically, percutaneously, or thoracoscopically under image guidance (eg, ultrasound, computed tomography, magnetic resonance imaging) with sedation, or local or general anesthesia. This technique is also referred to as microwave coagulation therapy.

Background
MWA is a technique that uses microwave energy to induce an ultra-high speed, 915 MHz or 2.450 MHz (2.45 GHz), alternating electric field, which causes water molecules to rotate and create heat. This results in thermal coagulation and localized tissue necrosis. In MWA, a single microwave antenna or multiple antennas connected to a generator are inserted directly into the tumor or tissue to be ablated; energy from the antennas generates friction and heat. The local heat coagulates the tissue adjacent to the probe, resulting in a small, 2- to 3 -cm elliptical area  (5 x 3 cm) of tissue ablation. In tumors greater than 2 cm in diameter, 2 to 3 antennas may be used simultaneously to increase the targeted area of MWA and shorten operative time. Multiple antennas may also be used simultaneously to ablate multiple tumors. Tissue ablation occurs quickly, within 1 minute after a pulse of energy, and multiple pulses may be delivered within a treatment session, depending on tumor size. The cells killed by MWA are typically not removed but are gradually replaced by fibrosis and scar tissue. If there is local recurrence, it occurs at the margins. Treatment may be repeated as needed. MWA may be used to:

1. Control local tumor growth and prevent recurrence
2. Palliate symptoms
3. Extend survival duration

MWA is similar to radiofrequency (RFA) and cryosurgical ablation. However, MWA has potential advantages over RFA and cryosurgical ablation. In MWA, the heating process is active, which produces higher temperatures than the passive heating of RFA and should allow for more complete thermal ablation in less time. The higher temperatures reached with MWA (>100°C) can overcome the “heat sink” effect in which tissue cooling occurs from nearby blood flow in large vessels, potentially resulting in incomplete tumor ablation. MWA does not rely on the conduction of electricity for heating and, therefore, does not flow electrical current through patients and does not require grounding pads, because there is no risk of skin burns. Additionally, MWA does not produce electric noise, which allows ultrasound guidance during the procedure without interference, unlike RFA. Finally, MWA can take less time than RFA, because multiple antennas can be used simultaneously.

Adverse Events

Complications from MWA are usually considered mild and may include pain and fever. Other potential complications associated with MWA include those caused by heat damage to normal tissue adjacent to the tumor (eg, intestinal damage during MWA of the kidney or liver), structural damage along the probe track (eg, pneumothorax as a consequence of procedures on the lung), liver enzyme elevation, liver abscess, ascites, pleural effusion, diaphragm injury or secondary tumors if cells seed during probe removal. MWA should be avoided in pregnant women because potential risks to the patient and/or fetus have not been established. It should also be avoided in patients with implanted electronic devices such as implantable pacemakers that may be adversely affected by microwave power output.

Applications

MWA was first used percutaneously in 1986 as an adjunct to liver biopsy. Since then, MWA has been used to ablate tumors and other tissues in order to treat many conditions. These have included hepatocellular carcinoma, breast cancer, colorectal cancer metastatic to the liver, renal cell carcinoma, renal hamartoma, adrenal malignant carcinoma, non-small-cell lung cancer, intrahepatic primary cholangiocarcinoma, secondary splenomegaly and hypersplenism, abdominal tumors, and other tumors not amenable to resection. Well-established local or systemic treatment alternatives are available for each of these malignancies. The potential advantages of MWA for these cancers include improved local control and other advantages common to any minimally invasive procedure (eg, preserving normal organ tissue, decreasing morbidity, shortening length of hospitalization). MWA also has been investigated as primary and/or palliative treatment for unresectable hepatic tumors, and also as a bridge to liver transplantation. In the latter setting, MWA is being assessed to determine whether it can reduce the incidence of tumor progression while awaiting liver transplantation and thus maintain a patient’s candidacy for the transplant.

Summary of Evidence

For individuals who have an unresectable primary or metastatic tumor (eg, breast, hepatic [primary or metastatic], pulmonary, renal) who receive MWA, the evidence includes case series, observational studies, cohort studies, randomized controlled trials (RCTs), and systematic reviews. Relevant outcomes are overall survival, disease-specific survival, symptoms, quality of life, and treatment-related mortality and morbidity. Available studies have shown that MWA results in a wide range of complete tissue ablation (50%-100%) depending on tumor size, with complete ablation common and nearing 100% with smaller tumors (eg, less than or equal to 3 cm). Tumor recurrence rates at ablated sites are very low. However, tumor recurrence at nonablated sites is common and may correlate with disease state (eg, in hepatocellular carcinoma). Intraoperative and postoperative minor and major complications are low, especially when tumors are smaller and accessible. Patient selection criteria and rationale for using MWA over other established techniques (eg, surgical resection, radiofrequency ablation) are needed. The evidence is insufficient to determine the effects of the technology on health outcomes. Ongoing and Unpublished Clinical Trials

Thursday, November 1, 2018

Plastic Surgery, cosmetic, reconstructive CPT codes list


Introduction

There are generally two types of plastic surgery, cosmetic and reconstructive. Cosmetic surgery is performed to improve appearance, not to improve function or ability. The plan does not cover cosmetic surgery. Reconstructive surgery focuses on reconstructing defects of the body or face due to trauma, burns, disease, or birth disorders. Reconstructive surgery is designed to restore or improve function associated with the presence of a defect. This policy outlines when reconstructive surgery may be covered

Note:

The Introduction section is for your general knowledge and is not to be  taken as policy coverage criteria . The  rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for  providers . A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered

Coding Code Description Medically Necessary Services  CPT
17106 Destruction of cutaneous vascular proliferative lesions (eg,laser technique; less than 10 sq cm
17107 Destruction of cutaneous vascular proliferative lesions (eg , laser technique; 10.0 to 50.0  sq cm
17108 Destruction of cutaneous vascular proliferative lesions (eg , laser technique); over 50.0 sq cm
21125 Augmentation, mandibular body or angle; prosthetic material
21127 Augmentation, mandibular body or angle; with bone graft,  onlay or interpositional (includes obtaining autograft)
21137 Reduction forehead; contouring only
21138 Reduction forehead; contouring and application of prosthetic material or bone graft  (includes obtaining autograft)
21139 Reduction forehead;  contouring and setback of anterior frontal sinus wall
65760 Keratomileusis
65765 Keratophakia
65767 Epikeratoplasty

Cosmetic Services CPT
11920 Tattooing, intradermal introduction of insoluble opaque pigments to correct color  defects of skin, including micropigmentation; 6.0 sq cm or less
11921 Tattooing, intradermal introduction of insoluable opaque pigments to correct color  defects of skin, including micropigmentation; 6.1 sq cm to 20.0 sq cm
11922 Tattooing, intradermal introduction of insoluable opaque pigments to correct color  defects of skin, including micropigmentation; each additional 20.0 sq cm, or part  thereof (List separately in addition to code for primary procedure)
11950 Subcutaneous injection of filling material (eg , collagen); 1cc or less
11951 Subcutaneous injection of filling material (eg , collagen); 1.1 to 5.0 cc
11952 Subcutaneous injection of filling material (eg , collagen); 5.1 to 10.0 cc
11954 Subcutaneous injection of filling material (eg, collagen); over 10.0 cc
11960 Insertion of tissue expander(s) for other than breast, including subsequent expansion
15780 Dermabrasion; total face (eg, for acne scarring, fine wrinkling, rhytids, general  keratosis)
15781 Dermabrasion;  segmental, face
15782 Dermabrasion; regional, other than face
15783 Dermabrasion; superficial, any site, (eg, tattoo removal)
15786 Abrasion; single lesion (eg keratosis, scar)
15787 Abrasion; each additional four lesions or less (List separately in  addition to code for  primary procedure)
15819 Cervicoplasty
15824 Rhytidectomy; forehead
15825 Rhytidectomy; neck with platysmal tightening (platsymal flap, P - flap)
15826 Rhytidectomy; glabellar frown lines
15828 Rhytidectomy; cheek, chin, and neck
15829 Rhytidectomy; superficial musculoapneurotic system SMAS flap
15832 Excision, excessive skin and subcutaneous tissue (includes lipectomy); thigh
15833 Excision, excessive skin and subcutaneous tissue (includes lipectomy); leg
15834 Excision, excessive skin and subcutaneous tissue (includes lipectomy); hip
15835 Excision, excessive skin and subcutaneous tissue (includes lipectomy); buttock
15836 Excision, excessive skin and subcutaneous tissue (includes lipectomy); arm
15837 Excision, excessive  skin and subcutaneous tissue (includes lipectomy); forearm or hand
15838 Excision, excessive skin and subcutaneous tissue (includes lipectomy); submental fat pad
15839 Excision excessive skin and subcutaneous tissue (includes lipectomy); other areas
15847 Excision, excessive skin and subcutaneous tissue (includes lipectomy), abdomen (eg , abdominoplasty) (includes umbilical transposition and fascial plication) (List separately  in addition to code for primary procedure)
15876 Suction assisted lipectomy;  head and neck
15877 Suction assisted lipectomy; trunk
15878 Suction assisted lipectomy; upper extremity
15879 Suction assisted lipectomy; lower extremity
19355 Correction of inverted nipples
21120 Genioplasty; augmentation (autograft, allograft,  prosthetic material)
21121 Genioplasty; sliding osteotomy, single piece
21122 Genioplasty; sliding osteotomies, 2 or more osteotomies (eg , wedge excision or bone  wedge reversal for asymmetrical chin)
21123 Genioplasty; sliding, augmentation with  interpositional bone grafts (includes obtaining  autografts)
40500 Vermilionectomy (lip shave), with mucosal advancement
54360 Plastic operation on penis to correct angulation
56620 Vulvectomy simple; partial
69300 Otoplasty, protruding ear, with or  without size reduction

HCPCS
Q2026 Injection, Radiesse, 0.1 ml
Q2028 Injection, sculptra, 0.5 mg

Cosmetic / Reconstructive CPT

11970 Replacement of tissue expander with permanent prosthesis
11971 Removal of tissue expander(s)  without insertion of prosthesis
19316 Mastopexy
19324 Mammaplasty, augmentation; without prosthetic implant
19325 Mammaplasty, augmentation; with prosthetic implant
19328 Removal of intact mammary implant
19330 Removal of mammary implant material
19340 Immediate insertion of breast prosthesis following mastopexy, mastectomy or in  reconstruction
19342 Delayed insertion of breast prosthesis following mastopexy, mastectomy or in  reconstruction
19350 Nipple/areola reconstruction
19357 Breast reconstruction, immediate or delayed, with tissue expander, including subsequent expansion
19366 Breast reconstruction with other technique
19370 Open periprosthetic capsulotomy, breast
19371 Periprosthetic capsulectomy, breast
19380 Revision of reconstructed breast
21088 Impression and custom preparation; facial prosthesis
21188 Reconstruction midface, osteotomies (other than LeFort type) and bone grafts  (includes obtaining autografts)
21280 Medial canthopexy (separate procedure)
21282 Lateral canthopexy

Non - covered Services
CPT
17380 Electrolysis epilation, each 30 minutes
69090 Ear piercing

Note :
CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA) . HCPCS  codes, descriptions and materials are copyrighted by Centers for Medicare Services (CMS).

Definition of Terms

When specific definitions are not present in a member’s plan, the following definitions will be  applied.

Cosmetic:
In this policy, cosmetic services are those which are primarily intended to preserve or  improve appearance. Cosmetic surgery is performed to reshape normal structures of the body in  order to improve the patient’s appearance or self- esteem.

Physical functional impairment:In this policy, physical functional impairment means a limitation from normal (or baseline level) of physical functioning that may include, but is not  limited to, problems with ambulation, mobilization, communication, respiration, eating,  swallowing, vision, facial expression, skin integrity, distortion of nearby body part(s) or obstruction of an orifice. The physical functional impairment can be due to structure, congenital  deformity, pain, or other causes. Physical functional impairment excludes social, emotional and psychological impairments or potential impairments

Reconstructive surgery:

In this policy, reconstructive surgery refers to surgeries performed on abnormal structures of the body, caused by congenital defects, developmental a bnormalities, trauma, infection, tumors or disease. It is generally performed to improve function. Determination of Eligibility for Coverage The final determination of eligibility for coverage should be based on application of the specific contract language based on the etiology of the defect and the presence or absence of documented physical functional impairment .

Administering the Contract Language ( also seeBenefit Application)

The  following general principles describe the issues to be determined in properly administering  the contract language.

1.The eligibility of a service for coverage may be based on either a specific benefit addressing cosmetic or reconstructive services or on its specific exemption or exclusion for cosmetic or  reconstructive services or both.

2. Cosmetic services are usually considered to be those that are primarily to restore  appearance and that otherwise do not meet the definition of reconstructive.

The definition  of reconstructive may be based on two distinct factors:

o Whether the service is primarily indicated to improve or correct a functional impairment or is primarily to improve appearance; and
o The etiology of the defect (eg, congenital anomaly, anatomic variant, result of trauma, post-therapeutic intervention, disease process).

3.  The presence or absence of a functional impairment is a critical point in interpreting coverage eligibility. For musculoskeletal conditions, the concept of a functional impairment is straightforward. However, when considering dermatologic conditions, the function of the skin is more difficult to define. Procedures designed to enhance the appearance of the skin are typically considered cosmetic
 

Wednesday, May 30, 2018

Billing Guideline for experimental or investigations procedure

EXPERIMENTAL OR INVESTIGATIONAL PROCEDURES


Any drug, device or medical treatment or procedure and related services that are experimental or investigational as defined by BCBSKS are non-covered services.

Experimental or investigational refers to the status of a drug, device or medical treatment or procedure:

A. if the drug or device cannot be lawfully marketed without approval of the U.S. Food and Drug Administration and approval for marketing has not been given at the time the drug or device is furnished and the drug or device is not Research-Urgent as defined except for prescription drugs used to treat cancer when the prescription drug is recognized for treatment of the indication in one of the standard reference compendia or in substantially accepted peer-reviewed medical literature; or
B. if Credible Evidence shows that the drug, device or medical treatment or procedure is the subject of ongoing phase I, II, or III clinical trials or under study to determine its maximum tolerated dose, its toxicity, its safety, its efficacy, or its efficacy as compared with the standard means of treatment or diagnosis and the trials are not Research-Urgent as defined except for prescription drugs used to treat cancer when the prescription drug is recognized for treatment of the indication in one of the standard reference compendia or in substantially accepted peer-reviewed medical literature; or

C. if Credible Evidence shows that the consensus among experts regarding the drug, device or medical treatment or procedure is that further studies or clinical trials are necessary to determine its maximum tolerated dose, its toxicity, its safety, its efficacy or its efficacy as compared with the standard means of treatment or diagnosis and the trials are not Research-Urgent as defined except for prescription drugs used to treat cancer when the prescription drug is recognized for treatment of the indication in one of the standard reference compendia or in substantially accepted peer-reviewed medical literature; or

D. if there is no Credible Evidence available that would support the use of the drug, device, medical treatment or procedure compared to the standard means of treatment or diagnosis except for prescription drugs used to treat cancer when the prescription drug is recognized for treatment of the indication in one of the standard reference compendia or in substantially accepted peer-reviewed medical literature.

Credible evidence shall mean only published reports and articles in the authoritative medical and scientific literature; the written protocol(s) used by the treating facility or the protocol(s) of another facility studying substantially the same drug, device or medical treatment or procedure; or the written informed consent used by the treating facility or by another facility studying substantially the same drug, device or medical treatment or procedure.

Research-Urgent shall mean a drug, device, medical treatment or procedure that may be covered (even though otherwise excluded by the contract as experimental or investigational) providing the specified criteria outlined in the contract is met.

Contracting providers shall notify the patient when services to be rendered are considered experimental or investigational and may not be covered under the member’s contract. Any patient being billed for services considered experimental or investigational must have a signed waiver in his/her file. The provider must discuss this with the patient in advance, document this in the medical record, and include the GA modifier (waiver on file) on the claim form (electronic or paper). (See Section X. WAIVER FORM) Failure to discuss and obtain a signed waiver in advance of the service will result in provider write-off.

UNIFORM PROVIDER CHARGING PRACTICES


Occasionally BCBSKS receives questions about what constitutes a provider’s usual charge when a provider offers cash customers a discount and what amount to bill BCBSKS. The term “usual charge” is defined in our Contracting Provider Agreements, but to specifically address this question, our policy is as follows:

A. Provider discounts or charging practices based upon individual patients’ situations (for example: patient hardship or professional courtesy) are acceptable and are not considered the provider’s usual charge. If a provider gives a patient a discount for cash, they must bill BCBSKS the same amount.

B. If a provider gives a lower charge to every patient who does not have health insurance, we consider that lower charge to be the “usual charge.”

Because a contracting provider agrees to not bill a BCBSKS member at the time of service, there should never be a circumstance in which a BCBSKS member pays anything other than a deductible, copayment, coinsurance, or non-covered procedure at the time of service. As an additional matter in regard to this point, our payments are timely enough that they are essentially cash for all practical purposes. If we are in fact late with payments, then the remedy is stated under the Prompt Payment law.

C. Agencies such as community mental health centers and county health departments would be allowed to use a sliding scale for charging practices due to agency regulations.

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