Here’s how to make your way through the CPT® molecular pathology code set. “The genetic testing code set is really unlike anything else in CPT®,” explained Larry Simon, MD, MBA, Blue Cross and Blue Shield of Louisiana, Member CPT® Editorial Panel, in his presentation “More Than Denim — Understanding Genes, Biomarkers, and Molecular Pathology” with Aaron D. Bossler, MD, PhD, Moffitt Cancer Center, Tampa, Member CPT® Editorial Panel at HEALTHCON 2024. So, if you are performing any genetic testing in your practice, and you’re bewildered by the ever-growing number of molecular pathology tests available to analyze a patient’s genetic makeup, you’ve come to the right place, as many of your questions will be answered here. What Is Genetic Testing? Essentially, our bodies’ DNA or RNA, “encodes all the proteins that make up our cells that make up our tissues that make up our bodies that make us, ‘us’,” Bossler explained. DNA or RNA — also known as biomarkers, molecular markers, or signature molecules — are subject to different types of mutations: one nucleotide in a sequence can change to another, for example, or a DNA sequence can be deleted or inserted in both small and large ways. All of these things can affect a patient’s propensity to a given disease as well as their ability to fight it. Genetic testing, then, enables providers to do a number of things for their patients: Providers can use the tests to confirm a diagnosis; predict how a patient’s genetics will affect their response to treatments; counsel a patient on the genetic etiology of a disease so they can make decisions about treatments or disease management; and predict the progression of a disease.
In the oncology arena specifically, genetic testing is used to identify inherited gene mutations which can put a person at higher risk of developing certain types of cancer. The American Cancer Society indicates this type of predictive genetic testing is best used for patients with a strong family history of certain cancers, patients who have already been diagnosed with cancer, and patients who have family members known to have an inherited gene mutation. Additionally, genetic testing can provide an insight into how a patient with cancer will respond to treatments. For example, a deletion in the EGFR gene removes some key amino acids, a mutation that makes lung cancer patients sensitive to tyrosine kinase inhibitors. Somatic testing — testing that looks for acquired mutations in an individual and is used to detect such conditions as cancer or neoplasia — allows such patients to see if they will, or will not, respond to tyrosine kinase inhibitors, a targeted cancer therapy that attacks certain cancer cells while leaving other cells alone, Bossler explained. How Are the Genetic Testing Codes Structured in CPT®? “There are codes for essentially single genes, then codes for a bunch of genes tested at one time, codes for a bunch of genes tested at one time plus a bunch of other stuff thrown in like a gumbo, then a separate set of codes that are for your lab, and no one else can use them but you,” explained Simon. Tier 1 codes (81161-81383) are specific to single genes. For example, 81205 (BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (eg, maple syrup urine disease) gene analysis, common variants (eg, R183P, G278S, E422X)) tests for mutations in the BCKDHB gene, which can “disrupt the normal function of the BCKD enzyme complex, preventing it from effectively breaking down leucine, isoleucine, and valine … leading to seizures, developmental delay, and the other health problems associated with maple syrup urine disease,” according to Medline Plus. These tests must “demonstrate clinical usefulness,” and must have widespread and high volume of utilization in labs across the U.S., according to Simon. Tier 2 codes (81400-81408, 81479) cover a wide range of genes. For example, 81400 (Molecular pathology procedure, Level 1 (eg, identification of single germline variant [eg, SNP] by techniques such as restriction enzyme digestion or melt curve analysis) …) lists 23 different genes that can be tested using this methodology. However, these tests are usually performed at a much lower volume than the tier 1 tests. Essentially, the two tiers reflect the resources involved in performing and interpreting the tests. Multianalyte assays with algorithmic analyses (MAAA) codes (81490-81599) and administrative MAAA codes (0002M-0019M) describe procedures that use multiple results and an algorithmic analysis from the testing of genes, proteins, lipids, and carbohydrates, and are usually unique to a single laboratory or manufacturer, Simon explained. Administrative MAAA codes are similar to Category III CPT® codes, in that the tests have lower utilization and literature support than Category I codes. Examples include 81521 (Oncology (breast), mRNA, microarray gene expression profiling of 70 content genes and 465 housekeeping genes, utilizing fresh frozen or formalin-fixed paraffin-embedded tissue, algorithm reported as index related to risk of distant metastasis), which is unique to MammaPrint®, Agendia, Inc., and 0006M (Oncology (hepatic), mRNA expression levels of 161 genes, utilizing fresh hepatocellular carcinoma tumor tissue, with alpha-fetoprotein level, algorithm reported as a risk classifier), which is unique to HeproDXTM, GoPath Laboratories, LLC. Genomic sequencing procedure codes (81410-81471) are used to report tests performed on nucleic acids from germline or neoplastic samples to analyze DNA or RNA sequencing “relevant to a clinical situation,” according to Simon. An example of these codes would be 81435 (Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include sequencing of at least 10 genes, including APC, BMPR1A, CDH1, MLH1, MSH2, MSH6, MUTYH, PTEN, SMAD4, and STK11). Proprietary laboratory assay (PLA) codes (0001U-0449U) describe codes that are unique to a lab or manufacturer that wants to specifically identify their test, and must be used over a Category I code for the same service because the PLA code is more specific, Simon noted.
An example of a PLA code is 0162U (Hereditary colon cancer (Lynch syndrome), targeted mRNA sequence analysis panel (MLH1, MSH2, MSH6, PMS2) (List separately in addition to code for primary procedure), a test proprietary to CustomNext + RNA: Lynch (MLH1, MSH2, MSH6, PMS2), Ambry Genetics®. Reminder: All the genetic testing codes must fulfill the CPT® criteria for Category I codes, meaning the service must: When Does CPT® Update the Molecular Pathology Codes? “The lab CPT® code set is changed multiple times a year. It’s really important to keep up with this release calendar in order to configure your systems and code for things properly,” cautioned Simon. This means paying attention to more than just the annual CPT® updates that are released at the end of September every year and that become effective on Jan. 1 of the following year. That’s because these updates only affect the tier 1 molecular pathology test codes. The AMA updates the PLA codes on a quarterly basis, however, while the tier 2 and MAAA codes are updated three times a year per the schedule found in the Code Changes Beyond the Annual Code Set Release Cycle chart located on page 1330 of the 2024 CPT® book.