POLICY: PG0364 ORIGINAL EFFECTIVE: 04/22/16 LAST REVIEW: 07/26/18 MEDICAL POLICY Gene Expression Profiling for Cancers of Unknown Primary Site 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 The spread of tumor cells from the developmental site of origin in the body to other tissue locations is a process called metastasis. An estimated 2% to 5% of all cancers diagnosed may be metastasized carcinoma of unknown primary origin (CUP). Preferred treatment and prognosis is dependent on determining the site of origin of the carcinoma. The CancerTYPE ID is a real-time reverse transcription PCR (RT-PCR) profiling test that compares the RNA expression from formalin-fixed paraffin-embedded (FFPE) tumor tissue from a patient with cancer of unknown primary (CUP) to the expression patterns of a panel of 50 different tumor types and subtypes to identify the most likely primary tissue of origin. There is insufficient evidence to assess the clinical utility of the CancerTYPE ID, and limited evidence to assess its analytical and clinical validity in patients with cancer of uncertain primary to identify the most likely primary tissue of origin. The Tissue of Origin Test is a microarray-based RNA profiling test that compares the RNA expression of formalinfixed paraffin-embedded (FFPE) tumor tissue from a patient with CUP to the expression patterns of a panel of 15 known characterized tumor types (bladder, breast, colorectal, gastric, hepatocellular, kidney, melanoma, non- Hodgkin s lymphoma, non-small cell lung, ovarian, pancreas, prostate, sarcoma, testicular germ cell, and thyroid) to identify the most likely primary tissue of origin. ProOnc TumorSourceDX uses mirview mets technology to identify tissue of origin for a metastatic tumor. RNA is extracted from samples of FFPE tumor sections of unknown primary origin. Developmental origin of tumor is determined using microarray-based mirna expression profiling and a decision tree classification algorithm. The patient population that may be considered for mirview mets testing includes patients with CUP to diagnosis primary origin. In addition, patients with carcinomas of suspected or known primary origin may be considered for mirview mets testing to confirm diagnosis. The RosettaGX Reveal test is a quantitative reverse transcription PCR (qrt-pcr)-based profiling test that measures microrna expression levels in RNA extracted from stained thyroid fine-needle aspiration (FNA) biopsy smears or cell blocks. A proprietary algorithm classifier combines linear discriminant analysis steps and a K Nearest Neighbor classifier step to differentiate thyroid nodules as benign or suspicious for malignancy. In addition, the test measures the hsa-mir-375 marker for medullary carcinoma. To date, the majority of the available studies fail to provide sufficient evidence that gene expression profiling to identify the tissue of origin for cancers lead to improved health outcomes (i.e., clinical utility). Well-designed randomized controlled trials (RCTs) are needed to determine the clinical utility of gene expression profiling to identify the tissue of origin for cancers of unknown primary site compared with traditional clinicopathologic factors to guide medical management and improve clinical outcomes. POLICY HMO, PPO, Individual Marketplace, & Advantage Gene expression profiling to identify the tissue of origin for cancers of unknown primary site (81504, 81540) is non-covered, including but not limited to: CancerTYPE ID ResponseDX Tissue of Origin Test ProOnc TumorSourceDX RosettaGX Cancer Origin Elite
o o o CancerTYPE ID (81540) does not require prior authorization. ResponseDX Tissue of Origin Test (81504) does not require prior authorization. All other tests for gene expression profiling to identify the tissue of origin for cancers of unknown primary site are non-covered, including but not limited to: ProOnc TumorSourceDX RosettaGX Cancer Origin HMO, PPO, Individual Marketplace, Advantage Gene expression profiling is considered investigational and not medically necessary as a technique to identify the tissue of origin for cancers of unknown primary site for all indications, including but not limited to: Determining the tissue of origin for a primary tumor; or Determining the tissue of origin for a metastatic tumor. Elite While there is insufficient evidence in the published medical literature to demonstrate the safety, efficacy and longterm outcomes of CancerTYPE ID, CMS requires this test be covered for Elite members with cancer of unknown primary (CUP). To bill for CANCER TYPE ID, please provide the following claim information: For services use CPT code 81540 Enter 1 in the Days/Unit field Select the appropriate ICD-10-CM code as listed below (ICD-10 CODES THAT ARE COVERED FOR CANCER TYPE ID FOR ELITE ONLY) While there is insufficient evidence in the published medical literature to demonstrate the safety, efficacy and longterm outcomes of ResponseDX Tissue of Origin Test, CMS requires this test be covered for Elite members with cancer of unknown primary (CUP). To bill for ResponseDX Tissue of Origin Test, please provide the following claim information: For services use CPT code 81504 Enter 1 in the Days/Unit field Select the appropriate ICD-10-CM code as listed below (ICD-10 CODES THAT ARE COVERED FOR RESPONSEDX TISSUE OF ORIGIN FOR ELITE ONLY) Paramount expects these tests to ONLY be ordered by the treating physician. CODING/BILLING INFORMATION The appearance of a code in this section does not necessarily indicate coverage. Codes that are covered may have selection criteria that must be met. Payment for supplies may be included in payment for other services rendered. CPT CODES Oncology (tissue of origin), microarray gene expression profiling of > 2000 genes, utilizing formalin-fixed paraffinembedded tissue, algorithm reported as tissue similarity scores 81504 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, 81540 algorithm reported as a probability of a predicted main cancer type and subtype ICD-10 CODES THAT ARE COVERED FOR CANCER TYPE ID FOR ELITE ONLY C18.1 Malignant neoplasm of appendix C18.9 Malignant neoplasm of colon, unspecified C22.0 Liver cell carcinoma C22.2 Hepatoblastoma C22.3 Angiosarcoma of liver C22.4 Other sarcomas of liver C22.7 Other specified carcinomas of liver C22.8 Malignant neoplasm of liver, primary, unspecified as to type C22.9 Malignant neoplasm of liver, not specified as primary or secondary C25.2 Malignant neoplasm of tail of pancreas C25.7 Malignant neoplasm of other parts of pancreas C25.8 Malignant neoplasm of overlapping sites of pancreas C25.9 Malignant neoplasm of pancreas, unspecified C33 Malignant neoplasm of trachea C34.01 Malignant neoplasm of right main bronchus
C34.02 Malignant neoplasm of left main bronchus C34.11 Malignant neoplasm of upper lobe, right bronchus or lung C34.12 Malignant neoplasm of upper lobe, left bronchus or lung C34.2 Malignant neoplasm of middle lobe, bronchus or lung C34.31 Malignant neoplasm of lower lobe, right bronchus or lung C34.32 Malignant neoplasm of lower lobe, left bronchus or lung C34.81 Malignant neoplasm of overlapping sites of right bronchus and lung C34.82 Malignant neoplasm of overlapping sites of left bronchus and lung C34.91 Malignant neoplasm of unspecified part of right bronchus or lung C34.92 Malignant neoplasm of unspecified part of left bronchus or lung C43.51 Malignant melanoma of anal skin C43.52 Malignant melanoma of skin of breast C43.59 Malignant melanoma of other part of trunk C45.9 Mesothelioma, unspecified C47.0 Malignant neoplasm of peripheral nerves of head, face and neck C47.9 Malignant neoplasm of peripheral nerves and autonomic nervous system, unspecified C48.0 Malignant neoplasm of retroperitoneum C49.0 Malignant neoplasm of connective and soft tissue of head, face and neck C49.9 Malignant neoplasm of connective and soft tissue, unspecified C50.411 Malignant neoplasm of upper-outer quadrant of right female breast C50.412 Malignant neoplasm of upper-outer quadrant of left female breast C50.511 Malignant neoplasm of lower-outer quadrant of right female breast C50.512 Malignant neoplasm of lower-outer quadrant of left female breast C50.811 Malignant neoplasm of overlapping sites of right female breast C50.812 Malignant neoplasm of overlapping sites of left female breast C50.911 Malignant neoplasm of unspecified site of right female breast C50.912 Malignant neoplasm of unspecified site of left female breast C56.1 Malignant neoplasm of right ovary C56.2 Malignant neoplasm of left ovary C61 Malignant neoplasm of prostate C64.1 Malignant neoplasm of right kidney, except renal pelvis C64.2 Malignant neoplasm of left kidney, except renal pelvis C67.5 Malignant neoplasm of bladder neck C67.9 Malignant neoplasm of bladder, unspecified C76.0 Malignant neoplasm of head, face and neck C77.0 Secondary and unspecified malignant neoplasm of lymph nodes of head, face and neck C77.1 Secondary and unspecified malignant neoplasm of intrathoracic lymph nodes C77.2 Secondary and unspecified malignant neoplasm of intra-abdominal lymph nodes C77.3 Secondary and unspecified malignant neoplasm of axilla and upper limb lymph nodes C77.4 Secondary and unspecified malignant neoplasm of inguinal and lower limb lymph nodes C77.5 Secondary and unspecified malignant neoplasm of intrapelvic lymph nodes C77.8 Secondary and unspecified malignant neoplasm of lymph nodes of multiple regions C77.9 Secondary and unspecified malignant neoplasm of lymph node, unspecified C78.01 Secondary malignant neoplasm of right lung C78.02 Secondary malignant neoplasm of left lung C78.5 Secondary malignant neoplasm of large intestine and rectum C78.6 Secondary malignant neoplasm of retroperitoneum and peritoneum C78.7 Secondary malignant neoplasm of liver and intrahepatic bile duct C79.01 Secondary malignant neoplasm of right kidney and renal pelvis C79.02 Secondary malignant neoplasm of left kidney and renal pelvis C79.2 Secondary malignant neoplasm of skin C79.31 Secondary malignant neoplasm of brain C79.49 Secondary malignant neoplasm of other parts of nervous system C79.51 Secondary malignant neoplasm of bone C79.52 Secondary malignant neoplasm of bone marrow C79.61 Secondary malignant neoplasm of right ovary C79.62 Secondary malignant neoplasm of left ovary C79.89 Secondary malignant neoplasm of other specified sites C80.0 Disseminated malignant neoplasm, unspecified C80.1 Malignant (primary) neoplasm, unspecified C82.57 Diffuse follicle center lymphoma, spleen C84.A7 Cutaneous T-cell lymphoma, unspecified, spleen
C84.Z7 Other mature T/NK-cell lymphomas, spleen C84.97 Mature T/NK-cell lymphomas, unspecified, spleen C85.17 Unspecified B-cell lymphoma, spleen C85.27 Mediastinal (thymic) large B-cell lymphoma, spleen C85.87 Other specified types of non-hodgkin lymphoma, spleen C85.97 Non-Hodgkin lymphoma, unspecified, spleen C86.1 Hepatosplenic T-cell lymphoma D01.5 Carcinoma in situ of liver, gallbladder and bile ducts D01.7 Carcinoma in situ of other specified digestive organs D01.9 Carcinoma in situ of digestive organ, unspecified D02.21 Carcinoma in situ of right bronchus and lung D02.22 Carcinoma in situ of left bronchus and lung D03.51 Melanoma in situ of anal skin D03.52 Melanoma in situ of breast (skin) (soft tissue) D03.59 Melanoma in situ of other part of trunk D49.0 Neoplasm of unspecified behavior of digestive system D49.1 Neoplasm of unspecified behavior of respiratory system D49.2 Neoplasm of unspecified behavior of bone, soft tissue, and skin D49.3 Neoplasm of unspecified behavior of breast D49.4 Neoplasm of unspecified behavior of bladder D49.511 Neoplasm of unspecified behavior of right kidney D49.512 Neoplasm of unspecified behavior of left kidney D49.59 Neoplasm of unspecified behavior of other genitourinary organ D49.6 Neoplasm of unspecified behavior of brain D49.7 Neoplasm of unspecified behavior of endocrine glands and other parts of nervous system D49.89 Neoplasm of unspecified behavior of other specified sites D49.9 Neoplasm of unspecified behavior of unspecified site J91.0 Malignant pleural effusion ICD-10 CODES THAT ARE COVERED FOR RESPONSEDX TISSUE OF ORIGIN FOR ELITE ONLY C18.1 Malignant neoplasm of appendix C18.9 Malignant neoplasm of colon, unspecified C22.0 Liver cell carcinoma C22.2 Hepatoblastoma C22.3 Angiosarcoma of liver C22.4 Other sarcomas of liver C22.7 Other specified carcinomas of liver C22.8 Malignant neoplasm of liver, primary, unspecified as to type C22.9 Malignant neoplasm of liver, not specified as primary or secondary C25.2 Malignant neoplasm of tail of pancreas C25.7 Malignant neoplasm of other parts of pancreas C25.8 Malignant neoplasm of overlapping sites of pancreas C25.9 Malignant neoplasm of pancreas, unspecified C33 Malignant neoplasm of trachea C34.00 Malignant neoplasm of unspecified main bronchus C34.01 Malignant neoplasm of right main bronchus C34.02 Malignant neoplasm of left main bronchus C34.10 Malignant neoplasm of upper lobe, unspecified bronchus or lung C34.11 Malignant neoplasm of upper lobe, right bronchus or lung C34.12 Malignant neoplasm of upper lobe, left bronchus or lung C34.30 Malignant neoplasm of lower lobe, unspecified bronchus or lung C34.31 Malignant neoplasm of lower lobe, right bronchus or lung C34.32 Malignant neoplasm of lower lobe, left bronchus or lung C34.80 Malignant neoplasm of overlapping sites of unspecified bronchus and lung C34.81 Malignant neoplasm of overlapping sites of right bronchus and lung C34.82 Malignant neoplasm of overlapping sites of left bronchus and lung C43.51 Malignant melanoma of anal skin C43.52 Malignant melanoma of skin of breast C43.59 Malignant melanoma of other part of trunk C45.9 Mesothelioma, unspecified C47.0 Malignant neoplasm of peripheral nerves of head, face and neck C47.9 Malignant neoplasm of peripheral nerves and autonomic nervous system, unspecified C48.0 Malignant neoplasm of retroperitoneum
C49.0 Malignant neoplasm of connective and soft tissue of head, face and neck C49.9 Malignant neoplasm of connective and soft tissue, unspecified C50.411 Malignant neoplasm of upper-outer quadrant of right female breast C50.419 Malignant neoplasm of upper-outer quadrant of unspecified female breast C50.511 Malignant neoplasm of lower-outer quadrant of right female breast C50.512 Malignant neoplasm of lower-outer quadrant of left female breast C50.519 Malignant neoplasm of lower-outer quadrant of unspecified female breast C50.811 Malignant neoplasm of overlapping sites of right female breast C50.812 Malignant neoplasm of overlapping sites of left female breast C50.819 Malignant neoplasm of overlapping sites of unspecified female breast C50.911 Malignant neoplasm of unspecified site of right female breast C50.912 Malignant neoplasm of unspecified site of left female breast C50.919 Malignant neoplasm of unspecified site of unspecified female breast C56.1 Malignant neoplasm of right ovary C56.2 Malignant neoplasm of left ovary C56.9 Malignant neoplasm of unspecified ovary C61 Malignant neoplasm of prostate C64.1 Malignant neoplasm of right kidney, except renal pelvis C64.2 Malignant neoplasm of left kidney, except renal pelvis C64.9 Malignant neoplasm of unspecified kidney, except renal pelvis C67.5 Malignant neoplasm of bladder neck C67.9 Malignant neoplasm of bladder, unspecified C76.0 Malignant neoplasm of head, face and neck C77.0 Secondary and unspecified malignant neoplasm of lymph nodes of head, face and neck C77.1 Secondary and unspecified malignant neoplasm of intrathoracic lymph nodes C77.2 Secondary and unspecified malignant neoplasm of intra-abdominal lymph nodes C77.3 Secondary and unspecified malignant neoplasm of axilla and upper limb lymph nodes C77.4 Secondary and unspecified malignant neoplasm of inguinal and lower limb lymph nodes C77.5 Secondary and unspecified malignant neoplasm of intrapelvic lymph nodes C77.8 Secondary and unspecified malignant neoplasm of lymph nodes of multiple regions C77.9 Secondary and unspecified malignant neoplasm of lymph node, unspecified C78.00 Secondary malignant neoplasm of unspecified lung C78.01 Secondary malignant neoplasm of right lung C78.02 Secondary malignant neoplasm of left lung C78.5 Secondary malignant neoplasm of large intestine and rectum C78.6 Secondary malignant neoplasm of retroperitoneum and peritoneum C78.7 Secondary malignant neoplasm of liver and intrahepatic bile duct C79.00 Secondary malignant neoplasm of unspecified kidney and renal pelvis C79.01 Secondary malignant neoplasm of right kidney and renal pelvis C79.02 Secondary malignant neoplasm of left kidney and renal pelvis C79.2 Secondary malignant neoplasm of skin C79.31 Secondary malignant neoplasm of brain C79.51 Secondary malignant neoplasm of bone C79.52 Secondary malignant neoplasm of bone marrow C79.60 Secondary malignant neoplasm of unspecified ovary C79.61 Secondary malignant neoplasm of right ovary C79.62 Secondary malignant neoplasm of left ovary C79.89 Secondary malignant neoplasm of other specified sites C79.9 Secondary malignant neoplasm of unspecified site C80.0 Disseminated malignant neoplasm, unspecified C80.1 Malignant (primary) neoplasm, unspecified C82.57 Diffuse follicle center lymphoma, spleen C84.A7 Cutaneous T-cell lymphoma, unspecified, spleen C84.97 Mature T/NK-cell lymphomas, unspecified, spleen C85.17 Unspecified B-cell lymphoma, spleen C85.27 Mediastinal (thymic) large B-cell lymphoma, spleen C85.87 Other specified types of non-hodgkin lymphoma, spleen C85.97 Non-Hodgkin lymphoma, unspecified, spleen C86.1 Hepatosplenic T-cell lymphoma D01.5 Carcinoma in situ of liver, gallbladder and bile ducts D01.7 Carcinoma in situ of other specified digestive organs D01.9 Carcinoma in situ of digestive organ, unspecified
D02.20 Carcinoma in situ of unspecified bronchus and lung D02.21 Carcinoma in situ of right bronchus and lung D02.22 Carcinoma in situ of left bronchus and lung D03.51 Melanoma in situ of anal skin D03.52 Melanoma in situ of breast (skin) (soft tissue) D03.59 Melanoma in situ of other part of trunk D49.0 Neoplasm of unspecified behavior of digestive system D49.1 Neoplasm of unspecified behavior of respiratory system D49.2 Neoplasm of unspecified behavior of bone, soft tissue, and skin D49.3 Neoplasm of unspecified behavior of breast D49.4 Neoplasm of unspecified behavior of bladder D49.511 Neoplasm of unspecified behavior of right kidney D49.512 Neoplasm of unspecified behavior of left kidney D49.6 Neoplasm of unspecified behavior of brain D49.7 Neoplasm of unspecified behavior of endocrine glands and other parts of nervous system D49.89 Neoplasm of unspecified behavior of other specified sites D49.9 Neoplasm of unspecified behavior of unspecified site J91.0 Malignant pleural effusion TAWG REVIEW DATES: 04/22/2016, 11/14/2017, 07/26/2018 REVISION HISTORY EXPLANATION 04/22/16: Policy created to reflect most current clinical evidence per The Technology Assessment Working Group (TAWG). 11/14/17: Policy reviewed and updated to reflect most current clinical evidence per The Technology Assessment Working Group (TAWG). 07/26/18: Changed title from PG0364 Cancer Type ID to Gene Expression Profiling for Cancers of Unknown Primary Site. Added code 81504. Added ResponseDX Tissue of Origin Test (81504) as covered without prior authorization for Elite per CMS guidelines, & non-covered for HMO, PPO, Individual Marketplace, & Advantage. Added ProOnc TumorSourceDX & RosettaGX Cancer Origin tests to policy as non-covered for all product lines. Added required ICD-10 diagnoses codes per CMS guidelines A54188 for CancerTYPE ID. Added required ICD-10 diagnoses codes per CMS guidelines A54198 for ResponseDX Tissue of Origin Test. Policy reviewed and updated to reflect most current clinical evidence per The Technology Assessment Working Group (TAWG). REFERENCES/RESOURCES Centers for Medicare and Medicaid Services, CMS Manual System and other CMS publications and services Ohio Department of Medicaid http://jfs.ohio.gov/ American Medical Association, Current Procedural Terminology (CPT ) and associated publications and services Industry Standard Review Hayes, Inc.