Thursday, January 12, 2017

CPT CODE 81479, 81403, 81311 -Metastatic Melanoma

Procedure Codes and Description

Group 1 Codes:




Coverage Indications, Limitations, and/or Medical Necessity


This is limited coverage policy for genetic testing of tumor tissue for somatic mutations in the NRAS gene (81311). Noridian will cover NRAS testing for metastatic colorectal cancer, per NCCN guidelines (Version 3.2014). 

All other NRAS testing is non-covered.


RAS oncogene is a superfamily of signal transduction proteins, which are proteins that communicate signals between the cells. DNA mutations in the RAS family genes turns the signals on permanently such that the cells divide nonstop, leading to cancer. Three of this family’s proteins, HRAS, KRAS, and NRAS are important in tumors and encode 21kD proteins called p21s.

Previous studies have shown that targeting oncogenic NRAS-driven melanomas requires decrease in both pERK and pAKT downstream of RAS-effectors for efficacy, which could be achieved by either targeting both BRAF and CRAF or BRAF and PIK3CA simultaneously in NRAS mutant tumor cells.

Colorectal Cancer:

Multiple signaling pathways are involved in colorectal cancer pathogenesis. The epidermal growth factor receptor (EGFR) plays a key role in activation of these pathways and is commonly overexpressed in metastatic colorectal cancer (mCRC). Consequently, EGFR is a target of anticancer therapies. Two of these drugs, cetuximab and panitumumab, are monoclonal antibodies that block EGFR action. The 2013 NCCN Clinical Practice Guidelines for Colon Cancer describes a recent study by Douillard et al [2013] which reported that 17% of 641 patients from the PRIME trial without KRAS exon 2 mutations were found to have mutations in exons 3 and 4 of KRAS or mutations in exons 2, 3, and 4 of NRAS. A predefined retrospective analysis of a subset of these patients showed that progression free survival (PFS) and overall survival (OS) were decreased in those who received panitumumab plus FOLFOX compared to those who received FOLFOX alone. For this reason the FDA indication for panitumumab was recently updated to state that panitumumab is not indicated for the treatment of patients with NRAS mutation-positive disease in combination with oxaliplatin-based chemotherapy.

In chemotherapy-refractory patients, fewer than 10% of patients who harbor one of these mutations respond to EGFR immunotherapy. The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) both recommend KRAS mutation testing prior to prescribing EGFR antagonist therapy for patients with mCRC and state that alternative therapy should be prescribed when mutations are detected. 

However, NCCN Colorectal Guidelines (Version 3.2014) recommend “All patients with metastatic colorectal cancer should have tumor tissue genotyped for RAS mutations (KRAS and NRAS). At the very least, exon 2 KRAS mutation status should be determined. Whenever possible, non-exon 2 KRAS mutation status and NRAS mutation status should also be determined. Patients with any known KRAS mutation (exon 2 or non-exon-2) or NRAS mutation should not be treated with either cetuximab or panitumumab.” Consequently, Noridian is expanding coverage of NRAS to patients with metastatic colorectal cancer. 

Metastatic Melanoma:

The NRAS gene encodes a protein that helps control cell division. Approximately 15% to 20% of melanomas harbor an oncogenic NRAS mutation. NRAS mutations can occur in all melanoma subtypes, but may be slightly more common in skin with chronic sun damage or in nodular melanomas. In addition, NRAS mutations are not found in tumors with BRAF mutations.

Several studies have been carried out to examine whether mutations in BRAF and NRAS confer different pathological features and clinical behavior. The effect of these mutations on clinical outcome remains uncertain with previous studies reporting conflicting

The NRAS protein is a GTPase which can lead to the activation of other proteins (such as AKT and MEK) that are also in pathways that help regulate cell division. In theory, drugs that inhibit AKT or MEK also have the potential to counteract the effects of NRAS mutations, although NRAS targeting therapies are still in clinical trials. In addition, pathways that help regulate cell division also include other proteins that could potentially be targeted such as PI3K and mTOR.

Melanomas can be tested for NRAS mutations with targeted sequencing. There are several manufacturers of targeted genetic tests that can detect NRAS mutations in melanoma tumor samples. The prognostic significance of NRAS mutations is still not well understood and further investigation of the histologic types of melanoma with specific NRAS mutations in a larger series is necessary to validate these apparent impacts on patient outcomes. In smaller subsets of cutaneous melanoma, other activating mutations have been described, including NRAS, c­KIT, and CDK4.

Other Cancers:

Other neoplastic diseases in which NRAS mutations have been reported in the primary literature include: myeloid leukemia, bladder cancer, liver cancer, and proliferative thyroid lesions.

Schulten et al [2­013] directly sequenced mutational hotspot regions encompassing codons 12, 13, and 61 of the RAS genes in 381 cases of thyroid lesions. In addition, the putative NRAS hotspot region encompassing codon 97 was sequenced in 36 thyroid lesions. Schulten and team found mutations in 16 out of 57 patients.

Kompier et al [2010] reports that although they have been reported, NRAS mutations are not common in bladder cancer.

Although NRAS mutations have been identified in the above tumor types, evidence in the primary literature is limited with regard to the clinical utility of NRAS mutation testing and its impact on management and survival. There is currently insufficient evidence to demonstrate clinical utility of NRAS testing in these tumor types.

NRAS Testing in relation to Noonan syndrome diagnosis:

Noonan syndrome is a common autosomal dominant condition with an incidence of 1/1,000 to 1/2,500 people. Unlike the somatic tumor mutations discussed above, Noonan syndrome may be caused by a germline mutation in the NRAS gene which would be present in every cell of the body. Noonan syndrome is characterized by a number of phenotypic findings including distinctive facial features, short stature, heart defects, cryptorchidism, lymphedema, and coagulation defects, among others. Several syndromes have features that overlap clinically with Noonan syndrome including cardiofaciocutaneous syndrome, Costello syndrome, LEOPARD syndrome and Noonan-­like syndrome with loose anagen hair. The genetic etiologies of these conditions can also overlap with Noonan syndrome.

Several of these disorders have been referred to as neurocardiofacialcutaneous syndromes, RASopathies or Ras/MAPK pathway disorders and have a shared pathway of genetic function.

They are characterized by facial dysmorphism, cardiac disease, reduced growth, skeletal and ectodermal defects and variable cognitive deficits. They also share a predisposition to development of malignancies.

Overall, approximately 75% of individuals with Noonan syndrome will have an identifiable mutation with gene panel testing. To date, NRAS mutations have been found in four individual case reports which suggests that NRAS testing for Noonan syndrome is unlikely to yield positive results. The clinical features appear to be typical with no particular or distinctive phenotype observed suggesting that mutation testing targeted to select individuals is not feasible.

Genotype­phenotype correlations have emerged that can help to direct medical management for those affected with an associated condition, but not specifically for NRAS mutations. For instance, mutations in the SOS1 gene have been associated with an increased chance for ectodermal involvement, development of certain solid tumors, pulmonary stenosis, and atrial and ventricular septal defects; with an associated decreased prevalence of cognitive defects, short stature, and hypertrophic cardiomyopathy.

Medical management recommendations are available for many of the Noonan syndrome spectrum disorders. Overlapping features result in overlapping medical management recommendations, typically guided by clinical features.

RBC phenotyping

This policy provides limited-coverage for molecular phenotyping of erythrocyte antigens performed on the HEA BeadChip™ (Immucor, Warren, NJ), a single nucleotide polymorphisms (SNP)-based microarray test. This high-throughput molecular assay received FDA PMA approval in May, 2014 and is the only IVD- approved molecular test to characterize human red blood cell (RBC) antigens. 

Many clinically significant antigens are encoded by alleles defined by SNPs. This assay identifies 35 antigens and 3 phenotypic variants across 11 blood groups (Rh, Kell, Duffy, Kidd, MNS, Lutheran, Dombrock, Landsteiner-Wiener, Diego, Colton and Scianna). Genomic DNA targets isolated from whole blood are amplified and fluorescent signals are interpreted by online software as specific alleles and probable antigen phenotype. This test does not evaluate patient antibody status. 

For more than ten years, RBC genotyping has been applied mainly to mass screen donors in blood centers. American Rare Donor Program, a consortium of the American Red Cross and American Association of Blood Banks (AABB) accredited immunohematology reference laboratories have used molecular genotype information for several years to identify antigen negative blood units from donor for patients with antibodies. Blood centers also use molecular technology to genotype donors for certain antigens (eg, Dombrock) that are hard to ascertain because of antisera unavailability or weak potency. 

Hemagglutination is the most common serologic method of determining a RBC phenotype. In this technique, the patient’s RBCs are tested with antisera specific for the antigens of interest. However, hemagglutination testing cannot be used if a patient has a positive direct antiglobuin test (DAT), or if direct agglutination typing sera is not available for the antigen. In addition, serologic phenotyping is invalid in the transfused patient who may have persistent donor RBCs in circulation. Because molecular genotyping is not subject to the limitations of serologic testing, it has become a useful tool in large hospital transfusion services. 

As early as 1999, Legler et al demonstrated disparate molecular Rh phenotyping in 7 of 27 patients compared to serologic typing. Soon afterwards, Reid and others demonstrated that DNA from blood samples could be used to genotype patients who had recently been transfused. Castilho et al confirmed the unreliability of serologic testing when they showed that 6 of 40 molecular genotypes differed from serologic phenotypes in multiply transfused sickle cell anemia (SCA) patients, and in 9 of 10 alloimmunized thalassemic patients. A number of investigators have replicated these findings, most notably Bakanay et al when they demonstrated genotypic and phenotypic discrepancies in 19 or 37 multi-transfused patients in multiple alleles. The discrepancies aided in the selection of antigen-matched blood products and improved RBC survival, ultimately improving patient care. A recent case report by Wagner emphasizes the usefulness of molecular testing over serologic testing in chronically transfused patients. 

In a prospective observational study, Klapper et al. used the HEA BeadChip™ to provide extended human erythrocyte antigen (xHEA) phenotyped donor units and recipient patient samples. XHEA-typed units were assigned to pending transfusion requests using a web-based inventory management system to simulate blood order processing at four hospital transfusion services. The fraction of requests filled (FF) in 3 of 4 sites was > 95% when matching for ABO, D and known alloantibodies, with a FF of > 90% when additional matching for C, c, E, e, and K antigens. The most challenging requests came from the fourth site where the FF was 62 and 51% respectively, even with a limited donor pool. 

In a prospective observational study by Da Costa et al, 21 of 35 sickle cell anemia (SCA) patients had discrepancies or mismatches, mainly in the Rh, Duffy, Jk and MNS blood groups, between the genotype profile and the serologically-matched blood unit for multiple antigens. These authors report that their genotype-matching program resulted in elevated hemoglobin levels, increased time between transfusions and prevented the development of new alloantibodies. 

Two recently published papers have shown the feasibility of routinely applying molecular blood banking techniques in a hospital transfusion service. Routine RBC testing has been implemented in a large tertiary care hospital in Los Angeles, CA to maximize efficient use of blood units. Patients with warm or cold reacting autoantibodies, patients with SCA and patients with antibodies that could not be identified were molecularly genotyped and received molecularly matched blood from the hospital’s genotyped donor inventory. 

At a large hospital in Cleveland, OH, pre-transfusion molecular typing is performed on chronically transfused patients, patients with autoantibodies, multiple antibodies, when no antigen specific antibody is available for testing and to solve laboratory discrepancies. They authors note that the major benefit of molecular typing is its application for patients who cannot be typed by serology due to an unsuitable sample. Valid results can be obtained even when they have been transfused within a few days of testing or have been massively transfused. Samples selected for molecular testing were based on an algorithm. 

Two recent research studies have demonstrated that treatment with daratumumab, a CD38 monoclonal antibody, can bind to CD38 expressed on the surface of red blood cells (RBCs) and interferes with serologic testing, thereby preventing cross-match. False-positive reactions may persist for 2 to 6 months after infusion. 

Medicare will cover pretransfusion molecular testing using the HEA BeadChip™ assay for the following categories of patients:
Long term, frequent transfusions anticipated to prevent the development of alloantibodies (e.g. sickle cell anemia, thalassemia or other reason);

Autoantibodies or other serologic reactivity that impedes the exclusion of clinically significant alloantibodies (e.g. autoimmune hemolytic anemia, warm autoantibodies, patient recently transfused with a positive DAT, high-titer low avidity antibodies, patients about to receive or on daratumumab therapy, other reactivity of no apparent cause);

Suspected antibody against an antigen for which typing sera is not available; and

Laboratory discrepancies on serologic typing (e.g. rare Rh D antigen variants)

Medicare does not expect molecular testing to be performed on patients undergoing surgical procedures such as bypass or other cardiac procedures, hip or knee replacements or revisions, or patients with alloantibodies identifiable by serologic testing that are not expected to require long term, frequent transfusions. 

The medical necessity for molecular RBC phenotying must be documented in the patient’s medical record.


C90.00 Multiple myeloma not having achieved remission
C90.01 Multiple myeloma in remission
C90.02 Multiple myeloma in relapse
D51.0 Vitamin B12 deficiency anemia due to intrinsic factor deficiency
D53.9 Nutritional anemia, unspecified
D55.0 Anemia due to glucose-6-phosphate dehydrogenase [G6PD] deficiency
D55.1 Anemia due to other disorders of glutathione metabolism
D55.2 Anemia due to disorders of glycolytic enzymes
D55.3 Anemia due to disorders of nucleotide metabolism
D55.8 Other anemias due to enzyme disorders
D55.9 Anemia due to enzyme disorder, unspecified
D56.0 Alpha thalassemia
D56.1 Beta thalassemia
D56.2 Delta-beta thalassemia
D56.3 Thalassemia minor
D56.5 Hemoglobin E-beta thalassemia
D56.8 Other thalassemias
D56.9 Thalassemia, unspecified
D57.00 Hb-SS disease with crisis, unspecified
D57.01 Hb-SS disease with acute chest syndrome
D57.02 Hb-SS disease with splenic sequestration
D57.1 Sickle-cell disease without crisis
D57.20 Sickle-cell/Hb-C disease without crisis
D57.211 Sickle-cell/Hb-C disease with acute chest syndrome
D57.212 Sickle-cell/Hb-C disease with splenic sequestration
D57.219 Sickle-cell/Hb-C disease with crisis, unspecified
D57.3 Sickle-cell trait
D57.40 Sickle-cell thalassemia without crisis
D57.411 Sickle-cell thalassemia with acute chest syndrome
D57.412 Sickle-cell thalassemia with splenic sequestration
D57.419 Sickle-cell thalassemia with crisis, unspecified
D57.80 Other sickle-cell disorders without crisis
D57.811 Other sickle-cell disorders with acute chest syndrome
D57.812 Other sickle-cell disorders with splenic sequestration
D57.819 Other sickle-cell disorders with crisis, unspecified
D58.0 Hereditary spherocytosis
D58.1 Hereditary elliptocytosis
D58.9 Hereditary hemolytic anemia, unspecified
D59.0 Drug-induced autoimmune hemolytic anemia
D59.1 Other autoimmune hemolytic anemias
D59.9 Acquired hemolytic anemia, unspecified
D60.0 Chronic acquired pure red cell aplasia
D60.1 Transient acquired pure red cell aplasia
D60.8 Other acquired pure red cell aplasias
D60.9 Acquired pure red cell aplasia, unspecified
D61.01 Constitutional (pure) red blood cell aplasia
D61.09 Other constitutional aplastic anemia
D61.1 Drug-induced aplastic anemia
D61.2 Aplastic anemia due to other external agents
D61.3 Idiopathic aplastic anemia
D61.89 Other specified aplastic anemias and other bone marrow failure syndromes
D63.0 Anemia in neoplastic disease
D63.1 Anemia in chronic kidney disease
D63.8 Anemia in other chronic diseases classified elsewhere
D64.0 Hereditary sideroblastic anemia
D64.1 Secondary sideroblastic anemia due to disease
D64.2 Secondary sideroblastic anemia due to drugs and toxins
D64.3 Other sideroblastic anemias
D64.4 Congenital dyserythropoietic anemia
D64.89 Other specified anemias

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