Saturday, August 22, 2020

CPT code 99241, 99242, 99243, 99244, 99245

 

CPT code and Description

99241, Office consultation for a new or established patient, which requires these 3 key components: A problem focused history; A problem focused examination; and Straightforward medical decision making.


99242, Office consultation for a new or established patient, which requires these 3 components: An expanded problem focused history; An expanded problem focused examination; and Straightforward medical decision making.


99243, Office consultation for a new or established patient, which requires these 3 key components: A detailed history; A detailed examination; and Medical decision making of low complexity.


99244, Office consultation for a new or established patient, which requires these 3 key components: A comprehensive history; A comprehensive examination; and Medical decision making of moderate complexity.


99245, Office consultation for a new or established patient, which requires these 3 key components: A comprehensive history; A comprehensive examination; and Medical decision making of high complexity.


REIMBURSEMENT GUIDELINES Consultation Services


The American Medical Association (AMA) Current Procedural Terminology (CPT ®) book describes a consultation as a type of evaluation and management service provided at the request of another physician or appropriate source to either recommend care for a specific condition or problem or to determine whether to accept responsibility for ongoing management of the patient's entire care or for the care of a specific condition or problem.


Oxford will consider a claim for a consultation service for reimbursement if the requesting physician or other qualified source is identified on the claim. If the requesting entity is not identified on the claim, the consultation service will be denied because it does not meet basic AMA requirements for reporting such a code.


Services initiated by a patient and/or family and not requested by a physician or other appropriate source should not be reported using CPT consultation codes 99241-99245 or 99251-99255 or HCPCS consultation codes G0406-G0408, G0425-G0427, G0508 or G0509 but may be reported using appropriate office visit, hospital care, home service or domiciliary/rest home care codes.


Note: AMA guidelines state that only one inpatient consultation (99251-99255) should be reported by a consultant per admission. Evaluation and Management (EM) services after the initial consultation during a single admission should be reported using non-consultation EM codes.


DEFINITIONS


Consultation Service: A type of evaluation and management service provided at the request of another physician or appropriate source to either recommend care for a specific condition or problem or to determine whether to accept responsibility for ongoing management of the patient’s entire care or for the care of a specific condition or problem.

The following criteria also apply:

** A written or verbal request for consult must be made by an appropriate source

** The request must be documented in the patient’s medical record

** The consultant’s opinion must be documented in the patient’s medical record

** The consultant’s opinion must be communicated by written report to the requesting physician or other appropriate source



Payment Policy: Outpatient Consultations

Policy Overview
The American Medical Association’s (AMA) Current Procedural Terminology (CPT®) book describes a consultation as a type of evaluation and management (E&M) service provided at the request of another physicians or appropriate source to either recommend care for a specific condition or problem, or to determine whether to accept responsibility for ongoing management of the patient’s entire care or for the care of a specific condition or problem.

Furthermore, if subsequent to the completion of the consultation, the consultant assumes responsibility for the management of a portion or all of the patient’s condition(s), the appropriate E&M procedure code for the location of service should be reported.

The purpose of this policy is to outline how the health plan evaluates CPT consultation codes 99241-99245 and HCPS codes G0425-G0427 for reimbursement, particularly identifying those that should have been billed at the appropriate level of office visit, established patient or subsequent hospital care.

CMS no longer recognizes codes 99241-99245 and 99251-99255 for Medicare payment; therefore, providers should never bill these codes for Medicare members. Instead, (for Medicare members) providers should report the appropriate Evaluation and Management code payable under the fee schedule (including for visits that could be described by CPT consultations codes), that identifies where the visit occurred and the complexity of the visit performed.

Application
1. Professional
2. Outpatient Institutional Claims
3. Same member
4. Same Provider

Reimbursement

Claim lines that contain an outpatient consultation, when another outpatient consultation was billed by the same provider within six months, will be denied.

Services initiated by a parent and/or family and not requested by a physician or other appropriate source should not be reported using the CPT consultation codes 99241-99245 or HCPCS consultation codes G0425-G0427, but may be reported using appropriate office visit, hospital care, home service or domiciliary/rest home care codes. 

CPT guidelines state that only one outpatient consultation should be reported by a consultant per admission. E&M services after the initial consultation during a single admission should be reported using non consultation E&M codes.

Documentation Requirements

The following criteria apply:
** A written or verbal request for consult must be made by an appropriate source
** The request must be documented in the patient’s medical record
** The consultant’s opinion must be documented in the patient’s medical records
** The consultant’s opinion must be communicated by written report to the requesting physician or other appropriate source

Coding and Modifier Information

This payment policy references Current Procedural Terminology (CPT®). CPT® is a registered trademark of the American Medical Association. All CPT® codes and descriptions are copyrighted 2019, American Medical Association. All rights reserved. CPT codes and CPT descriptions are from current manuals and those included herein are not intended to be allinclusive and are included for informational purposes only. Codes referenced in this payment policy are for informational purposes only. 
Inclusion or exclusion of any codes does not guarantee coverage. Providers should reference the most up-to-date sources of professional coding guidance prior to the submission of claims for reimbursement of covered services.



MEDICAL POLICY Consultation Services
GUIDELINES
This policy does not certify benefits or authorization of benefits, which is designated by each individual policyholder contract. Paramount applies coding edits to all medical claims through coding logic software to evaluate the accuracy and adherence to accepted national standards. This guideline is solely for explaining correct procedure reporting and does not imply coverage and reimbursement.

DESCRIPTION
Consultations are unique evaluation and management services in which a provider has been asked for and is delivering an opinion. Patients seen in consultation may be either new patients or established patients. The intent of a consultation service is that a physician, qualified nurse practitioner, or other appropriate source is requesting advice, opinion, recommendation, suggestion, direction, or counsel, etc., in evaluating or treating a patient because that individual has expertise in a specific medical area beyond the requesting professional’s knowledge.

The medical record documentation requires three key components following the American Medical Association (AMA) Current Procedural Terminology (CPT®) guidelines for evaluation and management services; history, physical and medical decision-making. Each component has different amounts of required information ranging from low to comprehensive levels.

The following criteria must be met and documented for the service to be considered a consultation:
** Documentation of the request for consultation from the referring provider
** The reason for the consult which must be medically reasonable and necessary
** A written report by the consultant which was provided back to the referring physician

Any provider may report a consultation service as long as they follow the consultation criteria, and the AMA/CPT coding guidelines for evaluation and management (E/M) services. If documentation is not been included or has been omitted, a lower level of service must be reported. Documentation must support not only the consultation
service, but also the level of service reported.

POLICY
Consultation services (99241-99245 and 99251-99255) are non-covered for Elite.
Consultation services (99241-99245 and 99251-99255) do not require prior authorization for HMO, PPO, Individual Marketplace, & Advantage

Elite
Effective January 1, 2010, the Centers for Medicare & Medicaid Services (CMS) no longer reimburses physicians for CPT consultation codes 99241-99245 or 99251-99255 and these codes will therefore not be recognized as reimbursed services for Elite members.

Procedures codes 99241-99245 (outpatient consultations) should be reported as 99201-99205 or 99211-99215 (outpatient office services), and procedure codes 99251-99255 (inpatient consultations) should be reported as 99231-99233 (inpatient hospital services). While these services may be valid (AMA/CPT) and reportable (HIPPA) codes, it does not make them reimbursable. The AMA/CPT does not establish reimbursement guidelines; only the codes by which reimbursement is performed.

Saturday, February 29, 2020

PECOS - contact details and FAQ

PECOS TECHNICAL ASSISTANCE
CONTACT INFORMATION

ICN 903766 January 2019
PRINT-FRIENDLY VERSION

Target Audience: Medicare Fee-For-Service Providers

The Hyperlink Table, at the end of this document, provides the complete URL for each hyperlink. You may encounter problems that require technical support when using the Provider Enrollment, Chain, and Ownership System (PECOS). Knowing which Centers for Medicare & Medicaid Services (CMS) contractor to contact is the first step toward a solution. This fact sheet describes common problems and tells you who can best resolve them.

COMMON PROBLEMS AND WHOM TO CONTACT

Problem: Navigating or Accessing PECOS Website

When you experience: system-generated error messages, trouble navigating through PECOS screens, issues accessing PECOS, printing problems, or you have a valid Identity & Access Management (I&A) System user ID and password but cannot access PECOS because of a malfunction (for example, the website operates slowly or not at all, or a system-generated error message prevents data entry).

NOTE: A system-generated error message does not include messages created when you enter data incorrectly or ignore system prompts.

Solution: Contact CMS EUS Help Desk Find information on common problems, ask a question, or look up previous support history on the External User Services (EUS) website.

Phone: 866-484-8049 (TTY 866-523-4759)

Email: EUSSupport@cgi.com

Live Chat: Go to the EUS website screen, on the right side choose “Live Chat.” EUS Hours of Operation: Monday–Friday, 6 am–6 pm CT; Saturday–Sunday, closed


Problem: Accessing the PECOS System Before you log in to PECOS, you need a valid I&A System user ID and password.

NOTE: Passwords expire every 60 days. You cannot log in to the I&A System (and PECOS) until you reset your password. The I&A System tells you the number of days until your password expires. Go to the “My Profile” tab and see the password section. If you attempt to log in to PECOS with an expired password, you will be redirected to the I&A System to reset your password. Solution: Access I&A System or Contact I&A System Help

The I&A System website allows you to create an I&A System user ID and password, change your password, and recover forgotten login information. Additionally, you can access several resources:

** I&A Frequently Asked Questions (FAQs) helps you resolve common I&A System problems

** I&A System Quick Reference Guide provides step-by-step instructions, including screenshots, about I&A System features and tools

HINT: On the I&A System website, choose the “Help” button in the upper right corner of any webpage for more information on the topic of that webpage.

Problem: Enrolling in Medicare via PECOS (Non-Technical) While using PECOS, you have a question about provider enrollment or you experience problems enrolling and need guidance on completing specific sections of the PECOS enrollment application.

Solution: Read Provider Enrollment Publications or Contact Your Medicare Enrollment Contractor Browse the Medicare Learning Network® (MLN) listing of Medicare Provider-Supplier Enrollment National Educational Products. These publications focus on provider-specific Medicare enrollment and Medicare enrollment via PECOS. Refer to the Medicare Provider Enrollment Contact List to find detailed contact information on enrollment, or if you have questions, your MACs may have more information. Find their website at http://go.cms.gov/MAC-website-list.


I had an existing account I used to log in to PECOS and/or the EHR Incentive Program; can I still use it?

Yes, you can use your previous NPPES or PECOS User ID and password to login. All existing accounts used to access PECOS and EHR Incentive Program have been converted. NPPES User IDs used by Individual Providers to access all systems have also been converted.

Note that if your account has been used within the last 365 days but not in the last 180 days, you will need to reset your password. If your account has not been used in the last 365 days, you will need to re-verify your information and you will have to create a new User ID. If you are not sure if you have an account, you can check by using the forgot User ID or Password link on the I&A, PECOS, or NPPES homepage.

What do I do if my account becomes disabled?

If your account has been used within the last 365 days but not in the last 180 days, it will become disabled. When you login, the system will check your account status, and, if it is disabled, you will be required to reset your password. The system will automatically navigate you to the page to reset your password.

Why am I being told to register again if I already have an account?

If you have not accessed your account for 365 days or more, you will be required to create a new User ID to re-confirm your information. If you were previously registered as an Authorized Official or Delegated Official with your employer(s), you will need to add your employer(s) again. If you are a Staff End User, you will need to contact your employer's Authorized Official or Delegated Official to re-invite you. Important Note: Any previous connections between your employer(s) and others have been maintained in the system and will be visible after you are re-approved.

What do I do if I cannot remember my User ID?

If you cannot remember your User ID, you may select the “Retrieve Forgotten User ID” link on the I&A Sign In page and follow the instructions on the screen. You must provide either a unique email address associated with your account to receive your User ID via e mail, or enter the required User Information associated with your account to view your User ID immediately.

Note: If you retrieve your User ID without using your e-mail, you will also be required to change your password.

When did the I&A changes go into effect** October 7, 2013.

I had an existing account I used to log in to PECOS and/or the EHR Incentive Program; can I still use it?


Yes, you can use your previous NPPES or PECOS User ID and password to login. All existing accounts used to access PECOS and EHR Incentive Program have been converted. NPPES User IDs used by Individual Providers to access all systems have also been converted.

Note that if your account has been used within the last 365 days but not in the last 180 days, you will need to reset your password. If your account has not been used in the last 365 days, you will need to re-verify your information and you will have to create a new User ID. If you are not sure if you have an account, you can check by using the forgot User ID or Password link on the I&A, PECOS, or NPPES homepage.

What do I do if my account becomes disabled?

If your account has been used within the last 365 days but not in the last 180 days, it will become disabled. When you login, the system will check your account status, and, if it is disabled, you will be required to reset your password. The system will automatically navigate you to the page to reset your password.

Why am I being told to register again if I already have an account?

If you have not accessed your account for 365 days or more, you will be required to create a new User ID to re-confirm your information. If you were previously registered as an Authorized Official or Delegated Official with your employer(s), you will need to add your employer(s) again. If you are a Staff End User, you will need to contact your employer's Authorized Official or Delegated Official to re-invite you. Important Note: Any previous connections between your employer(s) and others have been maintained in the system and will be visible after you are re-approved.

What do I do if I cannot remember my User ID?

If you cannot remember your User ID, you may select the “Retrieve Forgotten User ID” link on the I&A Sign In page and follow the instructions on the screen. You must provide either a unique email address associated with your account to receive your User ID via e mail, or enter the required User Information associated with your account to view your User ID immediately. Note: If you retrieve your User ID without using your e-mail, you will also be required to change your password.

How often will I have to reset my password?

Passwords expire every 60 days. Note: there is a password section on the My Profile tab which will tell you how many days until your password expires. For example, Your Password will expire in 37 day(s).

Reminder: An expired password simply means that you cannot log in to the I&A, Electronic Health Record (EHR) Incentive Programs or the Provider Enrollment Chain and Ownership System (PECOS) until you reset your password. An expired password will not affect your NPI, Medicare enrollment, claims payments, or EHR incentive payments; and will not remove the ability for any Surrogates to attest or work on behalf of their providers if they had previously been authorized in the system. It will only prevent logging in to those systems until the password is reset. Password Reset Requirements in the Identify & Access (I&A) Management System Passwords in the I&A system, which control access to the following systems: NPPES, PECOS, and Electronic Health Record (EHR) Incentive Programs, will expire every 60 days.

Important Note: If your password expires it will NOT impact your NPI, Medicare enrollment, claims payments, or EHR incentive payments; and will NOT remove the ability for any Surrogates to attest or work on behalf of their providers if they had previously been authorized in the system. It will only prevent logging in to those systems.

In the event that your password does expire you will be prompted to reset your password the next time you attempt to login to any of the systems. You may monitor how long until your password expires by viewing the password section on the My Profile tab within I&A, which will tell you how many days until your password expires.

How does I&A work with other systems (PECOS, EHR, NPPES)?


I&A allows you to create one account to access NPPES, PECOS, and EHR Incentive Program. I&A allows Authorized Officials and Delegated Officials to:

1) Manage Staff: The ability to add staff, modify roles and provider access for existing staff associated with your employer.

2) Manage Connections: The ability to create, approve, reject, and disable connections between your employer and other Organizations (both Provider and Non-Provider organizations).

I have an NPPES account for an NPI; can I use it in I&A** Yes, if you are an Individual Provider with an NPPES account for your NPI, you can login to I&A using your NPPES User ID and password. You may also use this account to log in to PECOS and EHR Incentive Program. Note: You may need to update some account information in I&A. NPPES User IDs used to access organization NPIs (Type 2 NPIs) cannot be used in I&A and will become obsolete. You will need to create an account in I&A in order to access PECOS and EHR

Monday, December 16, 2019

CPT 0030U, G9143 - Genotype-Guided Warfarin Dosing

Code Description CPT

0030U Drug metabolism (warfarin drug response), targeted sequence analysis (ie, CYP2C9, CYP4F2, VKORC1, rs12777823) (new code effective 1/1/18)


G9143 Warfarin responsiveness testing by genetic technique using any method, any number of specimen(s)


Genotype-Guided Warfarin Dosing


Introduction

Warfarin (Coumadin) is a blood thinner that works by reducing the blood’s ability to clot. It’s often prescribed to prevent blood clot formation in people who have conditions like atrial fibrillation. Finding the correct dose can be complicated. Too high a dose can cause bleeding. Too low a dose can result in blood clots being formed. Factors such as age, weight, use of other medications, and smoking go into the calculation of how much is prescribed. Once the drug is prescribed, the doctor then adjusts the dose based on blood tests. Two genes have been associated with how well the body processes warfarin. Genetic tests have been developed to look at these genes to try to determine warfarin dosing. These genetic tests are investigational (unproven). Medical studies do not show whether genetic testing to try to adjust warfarin doses leads to better health results. More studies are needed.

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.

Test Investigational 


Testing of cytochrome p450 2C9 (CYP2C9), P450 4F2 (CYP4F2), and vitamin K epoxide reductase subunit C1 (VKORC1)

Coding Genotyping for CYP2C9, CYP4F2, and VKORC1 variants is considered investigational to manage the administration and dosing of warfarin, including: * Guiding the initial  warfarin dose  * Decreasing the time needed to achieve a stable international  normalized ratio (INR) * Reducing the risk of serious bleeding

Related Information 

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


Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Wednesday, November 13, 2019

CPT 81225, 81226, 81227 - Genotype-Guided Tamoxifen Treatment

Code Description CPT

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) 

81479 Unlisted molecular pathology procedure

81599 Unlisted multianalyte assay with algorithmic analysis



Genotype-Guided Tamoxifen Treatment

Introduction


Certain types of breast cancer are affected by hormones. Cancer cells that are said to be estrogen receptor positive (ER-positive) have receptors that attach to estrogen. Once attached, estrogen then acts like a fertilizer to help the cancer grow. Hormone therapy is used to prevent estrogen from connecting to the receptors. Tamoxifen is a type of hormone therapy that can be used for ER-positive breast cancer to prevent it from coming back and to treat breast cancer that’s already spread to other parts of the body. It’s also used for ER-positive ductal carcinoma in situ (DCIS). To process tamoxifen into its more active form, the body uses a specific, important enzyme (CYP2D6) that’s made by a particular gene. A small percentage of people (about 10%) have a form of the gene that doesn’t make as much of this important enzyme as most other people make. A genetic test has been developed to try to see if a person has the gene form that makes a smaller amount of the needed enzyme. This genetic test is investigational (unproven). Large, well-designed medical studies don’t show a strong link between this gene and tamoxifen’s effectiveness. More studies are needed. 

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  Test Investigational  Cytochrome P450 2D6 (CYP2D6) testing 

Coding 


Genotyping to determine cytochrome P450 2D6 (CYP2D6) variants is considered investigational for the purpose of managing treatment with tamoxifen for women at high risk for or with breast cancer.



Related Information 

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. It is being implemented for genetic testing medical evidence review updates starting in 2017 (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. 


Description

Tamoxifen is prescribed as a component of adjuvant endocrine therapy to prevent endocrine receptor-positive breast cancer recurrence, to treat metastatic breast cancer, and to prevent disease in high-risk populations and in women with ductal carcinoma in situ. Tamoxifen is a prodrug that undergoes extensive metabolism to yield its active form: 4-hydroxy tamoxifen and endoxifen (primary active form) via the CYP2D6 enzyme. Variants in the CYP2D6 gene are associated with significant alterations in endoxifen concentrations leading to the hypothesis that CYP2D6 variation may affect the clinical outcomes of women treated with tamoxifen but not with drugs not metabolized by CYP2D6, such as anastrozole. Gene Expression-Based Assays for Cancers of Unknown Primary

Thursday, October 17, 2019

CPT 81504, 81540, 81599 - Oncology (tissue of origin)

Coding    Code Description CPT

81479 Unlisted molecular pathology procedure

81504 Oncology (tissue of origin), microarray gene expression profiling of > 2000 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as tissue similarity scores

81540 Oncology (tumor of unknown origin), mRNA, gene expression profiling by real-time RT-PCR of 92 genes (87 content and 5 housekeeping) to classify tumor into main cancer type and subtype, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a probability of a predicted main cancer type and subtype

81599 Unlisted multianalyte assay with algorithmic analysis


Introduction

A primary site is the part of the body where cancer started. Cancers are named on this primary site, even when they spread to other parts of the body. For example, if cancer starts in the breast but spreads to the bones, lungs, or liver, it is still classified as breast cancer. Cancer treatment is often based on the primary cancer. In rare cases, a cancer may have already spread before the original cancer is found. This is known as cancer of unknown primary. Cancers of unknown primary happen in three to four percent of all cancers in the United States. Certain genetic tests are being studied as one way to try to find the original site of the cancer. There is not yet enough scientific evidence about how these genetic tests might affect overall health outcomes. These tests are considered unproven (investigational).


Policy Coverage Criteria 

Type of Test Investigational


Gene expression profiling Gene expression profiling is considered investigational to evaluate the site of origin of a tumor of unknown primary, or to distinguish a primary from a metastatic tumor.

Related Information 

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
American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology

Genetic Counseling

Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of  genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing,  including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the  utilization of genetic testing substantially and may reduce  inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Evidence Review 

Description


Cancers of unknown primary represent 3% to 4% of cancers diagnosed in the United States. These cancers are heterogeneous and many accompanied by poor prognoses. A detailed history and physical combined with imaging and tissue pathology can identify some, but not all, primary sources of secondary tumors. It is suggested that identifying the likely primary source with gene expression profiling to direct treatment may improve health outcomes.

Background

Cancers of Unknown Primary

Cancers of unknown primary (CUPs), or occult primary malignancies, are tumors that have metastasized from an unknown primary source; they make up about 3% to 4% of all cancers in the United States. Identifying the primary origin of a tumor can dictate cancer-specific treatment, expected outcome, and prognosis.

Most CUPs are adenocarcinomas or undifferentiated tumors; less commonly, they may be squamous carcinomas, melanoma, soft tissue sarcoma, or neuroendocrine tumors. Osteo- and chondrosarcomas rarely produce CUPs. The most common primary sites of CUPs are the lung and pancreas, followed by colon and stomach, then breast, ovary, prostate, and solid-organ carcinomas of the kidney, thyroid, and liver. Conventional methods used to aid in the identification of the origin of a CUP include a thorough history and physical examination; computed tomography scans of the chest, abdomen, and pelvis; routine laboratory studies; and targeted evaluation of specific signs and symptoms.

Diagnosis and Classification


Biopsy of a CUP with detailed pathology evaluation may include immunohistochemical (IHC) analysis of the tumor. IHC analysis identifies different antigens present in different types of tumors and can usually distinguish an epithelial tumor (ie, carcinoma) from melanoma or sarcoma. Detailed cytokeratin panels often allow further classification of carcinoma; however, tumors of different origins may show overlapping cytokeratin expression. Results of IHC may provide a narrow differential of possible sources of a tumor’s origin, but not necessarily a definitive answer.
Recent advances in the understanding of gene expression in normal and malignant cells have led researchers to explore molecular classification to improve the identification of the site of origin of a CUP. The molecular classification of cancers is based on the premise that, despite different degrees of differentiation, tumors retain sufficient gene expression “signatures” as to their cell of origin, even after metastasis. Theoretically, it is possible to build a gene expression database spanning many different tumor types to compare to the expression profile of very poorly differentiated tumors, or a CUP, to aid in the identification of the tumor type and organ of origin. The feasibility of using molecular classification schemes with gene expression profiling (GEP) to classify these tumors of uncertain origin has been demonstrated in several studies.

Tissue of Origin Testing, Treatment Selection, and Health Outcomes 


Patients with CUP have generally poor prognoses. For example, patients with disease limited to lymph nodes have a median survival of 6 to 9 months, and those with a disease that is extranodal 2 to 4 months.

The premise of tissue of origin testing in CUPs is that identifying a likely primary tumor site will inform treatment selection leading to improved survival and other outcomes or as a predictive test. To evaluate whether treatment selection can be improved, the ability of a test to suggest a likely site of origin (clinical validity) must be first be shown. But demonstrating clinical validity may be problematic because patients with CUPs have no identified primary tumor for a reference standard.
Imperfect reference standards must be relied on such as the available presumptive or a reference pathologic diagnosis, known tumor types, or comparisons IHC. A primary tumor diagnosed during follow-up might also be used as a reference standard, but its use would be subject to potential selection bias. Therefore, even substantial evidence supporting the ability of a test to suggest a likely site of origin will be insufficient to infer benefit. Convincing evidence for benefit requires demonstrating that using a test to select treatment will improve outcomes. 


The Tissue of Origin test (formerly known as the PathWork Tissue of Origin Test and ResponseDX: Tissue of Origin; Cancer Genetics) measures the expression of 2000 genes and compares the similarity of the GEP of a CUP to a database of known profiles from 15 tissues with more than 60 histologic morphologies. The report generated for each tumor comprises a “similarity score,” which is a measure of similarity of GEP of the specimen to the profile of the 15 known tumors in the database. Scores range from 0 (very low similarity) to 100 (very high similarity), and sum to 100 across all 15 tissues on the panel. If a single similarity score is 30 or more, it indicates that this is likely the tissue of origin. If every similarity score is between 5 and 30, the test result is considered indeterminate, and a similarity score of less than 5 rules out that tissue type as the likely origin. PathWork Diagnostics developed the test, but the company filed for bankruptcy in early 2013; Response Genetics purchased its assets, and it, in turn, was acquired by Cancer Genetics in late 2015.
An alternative method to measure gene expression is real-time quantitative polymerase chain reaction (RT-qPCR). RT-qPCR can be used at the practice level; however, it can only measure, at most, a few hundred genes, limiting tumor categorization to 7 or fewer types. Tumor classification accuracy rates using real-time polymerase chain reaction have been reported to be as high as 87%, but lower (71%) for more undifferentiated tumors.

 One assay that uses RT- qPCR is the CancerTYPE ID (Biotheranostics) assay, which measures the expression of messenger RNA in a CUP tissue sample. Samples for this are ormalin-fixed,  paraffin-embedded (FFPE) tissue sections or unstained 10 micron sections on glass slides. Expression levels of 92 genes (87 tumor-associated genes and 5 reference  genes for normalization) are used to detect 27 tumor types in a known database of 578 tumors with a range of 5 to 49 tumors per type. The report generated is the  probability for the main cancer type, possible subtypes, tumor types not able to be excluded, and those ruled out with 95% confidence calculated by K nearest neighbor  analysis.

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