Medical Policy: 02.01.20 

Original Effective Date: December 2000 

Reviewed: August 2020 

Revised: August 2020 

 

Notice:

This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Tumor markers are substances normally produced by cancer or by other cells in the body in response to cancer, or certain benign (noncancerous) conditions. Most tumor markers are made by normal cells but are produced at a much higher level in the presence of cancer. Tumor markers may be found in the blood, plasma, other bodily fluids (e.g., urine, saliva, cerebrospinal fluid) and/or tissue. Although an abnormal tumor marker level may suggest cancer, their presence alone does not confirm a diagnosis. Tumor makers are typically combined with other diagnostic studies (e.g. laboratory tests, biopsy, radiological imaging) to confirm the diagnosis. These markers may not be elevated in the presence of some diseases or cancers, especially in early stages of the disease, they may not be specific to a particular type of disease or cancer, and/or they may be elevated by more than one type of disease or cancer.

 

In some types of cancers, tumor marker levels may reflect the extent or stage of the disease and can be useful in determining the most effective treatment and how the disease will respond to the treatment. Typically, the primary use of tumor markers is to monitor a cancer’s response to treatment with periodic measurements following therapy. Following therapy, a decrease in the maker level may indicate a response to therapy as opposed to consistently elevated or rising marker levels which may be indicative of lack of response to treatment or recurrence of the disease. The evidence in the published peer reviewed literature and professional societies support tumor markers for the diagnosis and management of some cancers, while other tumor markers are still evolving and their clinical utility has not been proven. 

 

Summary

Recommendations and guidelines by professional societies and organizations and evidence in the published peer reviewed scientific literature support the use of defined tumor markers for the diagnosis, treatment planning, treatment monitoring and/or follow up of specific cancers. The evidence is sufficient to determine that the technology results in a meaningful improvement in net health outcomes.

 

However, improvements in meaningful health outcomes for numerous other tumor markers have not been proven and they are still under investigation to determine their clinical utility in the management of individuals with various types of cancers. Overall, clinical trials have primarily been in the form of retrospective validation studies with small heterogeneous patient populations and short term follow ups. Studies comparing the tumor markers to established treatment options are lacking and management of patients based on the results of these markers have not been published. The evidence is insufficient to determine the effects of the technology on net health outcomes. 

 

Practice Guidelines and Position Statements

The American College of Obstetricians and Gynecologists (ACOG)

In 2011 (reaffirmed in 2019), the American College of Obstetricians and Gynecologists (ACOG), issued a committee opinion Number 716 (replaces Committee Opinion Number 477), role of the obstetrician-gynecologist in the early detection of epithelial ovarian cancer which included the following recommendations:

  • Currently, there is no strategy for early detection of ovarian cancer that reduces ovarian cancer mortality.
  • The use of transvaginal ultrasonography and tumor markers (such as CA 125), alone or in combination, for the early detection of ovarian cancer in average-risk women have not been proved to reduce mortality, and harms exist from invasive diagnostic testing (e.g., surgery) resulting from false-positive test results.
  • Epithelial ovarian cancer is most commonly detected in an advanced stage (65% of cases are stage III or stage IV) when the cure rate is only 18%.
  • Early stage (localized) ovarian cancer is associated with improved survival.
  • Taking a detailed personal and family history for breast, gynecologic, and colon cancer facilitates categorizing women based on their risk (average risk or high risk) of developing epithelial ovarian cancer.
  • The patient and her obstetrician–gynecologist should maintain an appropriate level of suspicion when potentially relevant signs and symptoms of ovarian cancer are present.

 

American Society of Clinical Oncology (ASCO)

In 2012, the American Society of Clinical Oncology (ASCO) issued a clinical practice update on breast cancer follow-up and management after primary treatment which included the following recommendation: 

 

Recommendation for Breast Cancer Follow-Up and Management in Adjuvant Setting: Not Recommended:
  • The use of CA 15-3 or CA 27.29 is not recommended for routine surveillance of patients with breast cancer after primary therapy.
  • CEA testing is not recommended for routine surveillance of patients with breast cancer after primary therapy. 

 

In 2015, the American Society of Clinical Oncology (ASCO) a clinical practice guideline, use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer, to include the following recommendation:

  • CEA, CA 15-3 and CA 27.29 may be used as adjuvant assessments to contribute to decisions regarding therapy for metastatic breast cancer. Data are insufficient to recommend use of CEA, CA 15-3, and CA 27-29 alone for monitoring response to treatment. The recommendations for use is based on clinical experience and Panel informal consensus in the absence of studies designed to evaluate the clinical utility of markers. As such, it is also reasonable for clinicians to not use these markers as adjunctive assessments. (Type: informal consensus. Evidence quality: insufficient. Strength of recommendation: moderate)  

 

National Comprehensive Cancer Network (NCCN)

Breast Cancer Version 5.2020
Principles of Monitoring Metastatic Disease Findings Concerning for Progression of Disease Include Serum Tumor Markers (CEA, CA 15-3, CA 27.29)
Baseline Prior to New Therapy Chemotherapy Endocrine Therapy Restaging if Concern for Progression of Disease
Optional Optional Optional Optional

 

Rising tumor markers (e.g. CEA, CA 15-3, C 27.29) are concerning for tumor progression, but may also be seen in setting of responding disease. An isolated increase in tumor markers should rarely be used to declare progression of disease.  Changes in bone lesion are often difficult to assess on plain or cross – sectional radiology or bone scan. For these reasons, patient symptoms and serum tumor markers may be more helpful in patients with bone-dominate metastatic disease.

 

Monitoring the treatment of metastatic breast cancer involves a wide array of assessments and the need for clinician to integrate several different forms of information to make a determination of the effectiveness of treatment and the acceptability of toxicity. The information includes those from direct observations of the patient, including patient reported symptoms, performance status, change in weight, and physical examination; laboratory tests such as alkaline phosphatase, liver function, blood counts, and calcium; radiographic imaging; functional imaging; and where appropriate, tumor biomarkers.

 

Genetic/Familial High-Risk Assessment: Breast, Ovarian and Pancreatic Cancer Version 1.2020
BRCA-Related Breast and/or Ovarian Cancer Syndrome
Serum Tumor Marker (CA-125)
Clinical PresentationWork-up
BRCA Pathogenic/Likely Pathogenic Variant-Positive Management
  • Recommend risk reduction salpingo-oopherectomy (RRSO) typically between 35 and 40 years, and upon completion of child bearing.
  • Ovarian cancer onset in patients with BRCA2 pathogenic/likely pathogenic variants is an average of 8-10 years later than in patients with BRCA1 pathogenic/likely pathogenic variants, it is reasonable to delay RRSO until age 40-45 years in patients with BRCA2 pathogenic/likely pathogenic variants unless age at diagnosis in the family warrants earlier age consideration of prophylactic surgery.
For those patients who have not elected risk reduction salpingo-oopherectomy (RRSO), transvaginal ultrasound combined with serum CA-125 for ovarian cancer screening, although of uncertain benefit, may be considered at the clinician's discretion at age 30-35 years.

 

Colon Cancer Version 4.2020
Serum Tumor Marker (CEA)
Clinical PresentationWork-up
Pedunculated or sessile polyp (adenoma) with invasive cancer

Work-up shows the following findings: Fragmented specimen or margin cannot be assessed or unfavorable histologic features

Consider CBC, chemistry profile, CEA

Colon cancer appropriate for resection (non-metastatic)

CEA as part of the work-up

Suspected or proven metastatic synchronous andenocarcinoma (any T, any N, M1)

CEA as part of the work-up

 

Surveillance
Pathologic StageSurveillance
Stage II, III CEA every 3-6 months for 2 years, then every 6 months for a total of 5 years
Stage IV CEA every 3-6 months x2 years, then every 6 months for a total of 5 years

 

Rectal Cancer Version 6.2020
Serum Tumor Marker (CEA)
Clinical PresentationWork-up, and Surveillance

Pedunculated polyp or Sessile polyp (adenoma) with invasive cancer;

  • Fragmented specimin or margin cannot be assessed or unfavorable histologic features
CEA as part of work-up
Rectal cancer appropriate for resection

CEA as part of the work-up

Suspected or proven metastatic synchronous adenocarcinoma (T an, N any, M1) Work-up includes CEA

 

Surveillance
Pathologic StateSurveillance
Stage II-IV CEA every 3-6 months for 2 years then every 6 months for total of 5 years

 

Ovarian Cancer Version 1.2020
Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer
Serum Tumor Marker (CA-125 and CEA)
Clinical PresentationWork-up, Receiving Primary Chemotherapy, After Primary Treatment and Surveillance
  • Suspicious/palpable pelvic mass detected on abdominal/pelvic exam and or ascites abdominal distention, and/or
  • Symptoms without source of malignancy i.e. bloating, pelvic or abdominal pain, difficulty eating or feeling full quickly, or urinary symptoms (urgency or frequency)
CA-125 or other tumor makers as clinically indicated

 

Other tumor markers may include inhibin, beta-human chorionic gonadotropin (B-hCG), alpha-fetoprotein, lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), and CA 19-9

Newly diagnosis ovarian cancer after recent surgical procedure

CA-125 or other tumor makers as clinically indicated 

 

Other tumor markers may include inhibin, beta-human chorionic gonadotropin (B-hCG), alpha-fetoprotein, lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), and CA 19-9

Stage I, II, III and IV after primary treatment

Monitoring and follow-up:  CA-125 or other tumor markers if initially elevated

 

Other tumor markers may include inhibin, beta-human chorionic gonadotropin (B-hCG), alpha-fetoprotein, lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), and CA 19-9

Borderline Epithelial Ovarian Tumors (low malignant potential)

Monitoring and Follow-up: CA-125 or other tumor markers every visit if initially elevated

 

Other tumor markers may include inhibin, beta-human chorionic gonadotropin (B-hCG), alpha-fetoprotein, lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), and CA 19-9

Less Common Ovarian Histopathologies (malignant germ cell neoplasms and malignant sex cord stromal tumors)

 

See below chart

Mucinous Carcinoma of the Ovary Additional work-up: CEA, CA-19-9

 

Ovarian Cancer Version 1.2020
Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer

Serum Tumor Marker Surveillance for Malignant Germ Cell and Sex Cord Stromal Tumors

Malignant Germ Cell Tumors
 Year 1Year 2Year 3Years 4-5Year 5
Dysgerminoma Physical exam and serum tumor markers (CA-125; as clinically indicated CEA and CA 19-9) every 2-3 months  Physical exam and serum tumor markers (CA-125; as clinically indicated CEA and CA 19-9) every 3-4 months Physical exam and serum tumor markers (CA-125; as clinically indicated CEA and CA 19-9) every 6 months Physical exam and serum tumor markers (CA-125; as clinically indicated CEA and CA 19-9) every 6 months Physical exam and serum tumor markers (CA-125; as clinically indicated CEA and CA 19-9) annually
Non-dysgerminoma Physical exam and serum tumor markers (CA-125; as clinically indicated CEA and CA 19-9) every 2 months Physical exam and serum tumor markers (CA-125; as clinically indicated CEA and CA 19-9) every 2 months Physical exam and serum tumor markers (CA-125; as clinically indicated CEA and CA 19-9) every 4-6 months Physical exam and serum tumor markers (CA-125; as clinically indicated CEA and CA 19-9) every 6 months Physical exam and serum tumor markers (CA-125; as clinically indicated CEA and CA 19-9) annually

 

Malignant Sex-Cord Stromal Tumors
 0-2 YearsAfter 2 years
Serum Tumor Markers

Serum tumor markers as clinically indicated, if applicable (CA-125, CEA and CA 19-9)

 

If done frequency based on stage (i.e. 6-12 months if early stage, low risk disease; 4-6 months if high risk disease)

Serum tumor markers as clinically indicated, if applicable (CA-125, CEA and CA 19-9)

 

If done frequency based on stage (i.e. 6-12 months if early stage, low risk disease; 4-6 months if high risk disease)

 

Uterine Neoplasms Version 2.2020
Endometrial Carcinoma
Serum Tumor Marker CA-125
Clinical PresentationWork-up and Surveillance
Suspected extrauterine disease (endometrioid histology) Work-up
  • Consider CA-125;

Surveillance

  • CA-125 if initially elevated

Biopsy findings:

  • Serous carcinoma; or
  • Clear cell carcinoma; or
  • Undifferentiated/dedifferentiated carcinoma; or
  • Carcinosarcoma

Additional Work-up

  • Consider CA-125

 

Pancreatic Adenocarcinoma Version 1.2020
Serum Tumor Marker (CA 19-9)
Clinical PresentationWork-up, Monitoring and Surveillance

Clinical suspicion of pancreatic cancer or evidence of dilated pancreatic and/or bile duct (stricture) -

No metastatic disease on physical exam and imaging

Baseline CA 19-9 after adequate biliary drainage
Resectable disease Post treatment CA 19-9
Borderline resectable disease no metastases Work-up
  • Baseline CA 19-9

Biopsy Positive

  • Post Treatment CA 19-9
Post-operative adjuvant treatment

Baseline postoperative CA 19-9 if not previously done

 

Surveillance

  • Every 3-6 month for 2 years, then every 6-12 months as clinically indicated CA 19-9 (category 2B)

 

Hepatobiliary Cancers Version 2.2020
Serum Tumor Markers (CEA and CA 19-9)
Clinical PresentationWorkup
Biliary Tract Cancers: Intrahepatic Cholangiocarcinoma – isolated intrahepatic mass (imaging characteristics consistent with malignancy but not consistent with hepatocellular carcinoma)

Work-up: Consider CEA and CA 19-9

 

Footnote: CEA and CA 19-9 are baseline tests and should not be done to confirm diagnosis.

Biliary Tract Cancer: Extrahepatic Cholangiocarcinoma – presentation includes any of the following: pain, jaundice, abnormal LFT’s, obstruction or abnormality on imaging

Work-up: Consider CEA and CA 19-9

 

Footnote: CEA and CA 19-9 are baseline tests and should not be done to confirm diagnosis.

Biliary Tract Cancers: Gallbladder Cancer

 

Presentation

  • Mass on imaging
  • Jaundice  

 

Post resection status

 

Work-up: Consider CEA and CA 19-9

 

Footnote: CEA and CA 19-9 are baseline tests and should not be done to confirm diagnosis.

 

Surveillance: consider CEA and CA 19-9 as clinically indicated

 

Occult Primary Version 3.2020
Localized Adenocarcinoma or Carcinoma not Otherwise Specified
Serum Tumor Markers (CA-125 and CA 19-9)
Clinical PresentationWorkup
Localized adenocarcinoma or carcinoma not otherwise specified, chest (multiple nodules) or pleural effusion Additional workup for women – CA-125
Localized adenocarcinoma or carcinoma not otherwise specified, peritoneal/ascites Additional workup for women – CA-125
Localized adenocarcinoma or carcinoma not otherwise specified, retroperitoneal mass Additional workup for women – CA-125
Localized adenocarcinoma or carcinoma not otherwise specified, inguinal nodes Additional workup for women – CA-125

 

Thyroid Carcinoma Version 2.2020
Medullary Carcinoma
Serum Tumor Marker (CEA)
Clinical PresentationWork-up and Surveillance
Clinical Presentation: Medullary thyroid carcinoma on FNA Diagnostic procedures include CEA
Clinical Presentation: Medullary thyroid carcinoma diagnosed after initial thyroid surgery Additional work-up includes CEA
Clinical Presentation: Germline mutation of RET proto-oncogene – MEN 2B (RET mutations) Additional work-up includes CEA
Clinical Presentation: Germline mutation of RET proto-oncogene – MEN 2A/Familial medullary thyroid carcinoma (FMTC) (RET mutations)) Additional work-up includes CEA
Management 2-3 months postoperative; Disease Monitoring
  • Detectable basal calcitonin or elevated CEA; if imaging is negative and asymptomatic
    • Serum calcitonin, CEA every 6-12 months
  • Basal calcitonin undetectable and CEA within reference range; active surveillance
    • Annual serum calcitonoin and CEA

 

Neuroendocrine and Adrenal Tumors Version 2.2020
Serum Tumor Markers (Chromogranin A (CgA) and 24 Hour Urine or plasma 5-HIAA)
Clinical PresentationWork-up and Surveillance

 Neuroendocrine tumor of the gastrointestinal tract (jejunal/ileal/colon; duodenal; appendix; rectal; gastric), lungs (bronchopulmonary) and thymus (carcinoid tumors)

 

Clinical symptoms

  • Primary tumors in the GI tract usually are not associated with symptoms of hormone secretion unless extensive metastasis
  • Symptoms of hormone secreation may include flushing, diarrhea, cardiac valvular fibrosis and bronchoconstriction
  • Bronchial/thymic tumors may be associated with classic carcinoid syndrome as well as Cushing’s syndrome

Some neuroendocrine tumors can secrete specific neuroendocrine hormones. Hormonal workup should be guided by the presence of symptoms of the excess hormone. Screening for hormones in asymptomatic individuals is not routinely required.

  • Initial evaluation includes chromogranin A (CgA) and 24 hour urine or plasma 5-HIAA
  • Surveillance: Chromogranin A (CgA) and 24 hour urine or plasma 5-HIAA
    • 12 weeks-12 months post-resection – as clinically indicated
    • >1 year post-resection to a maximum of 10 years, every 12-24 months
    • consider as clinically indicated
Pancreatic neuroendocrine tumor (NET) Chromogranin A (CgA)
Carcinoid Syndrome Biochemical evaluation with 24 hour urine or plasma 5-HIAA

 

Non-Small Cell Lung Cancer Version 6.2020
Serum Tumor Markers (CEA)
Clinical PresentationWork-up
The distinction between pulmonary adenocarcinoma and malignant mesothelioma (epithelial type) can be made by correlation of the histology with the clinical impression, imaging studies, and a limited panel of immunomarkers if needed. Immunostatins sensitive and specific for pulmonary adenocarcinoma include pCEA

 

Small Bowel Adenocarcinoma
Serum Tumor Marker (CA 19-9 and CEA)
Clinical PresentationWork-up and Surveillance
Duodenum Work-up: CA 19-9 and CEA

Surveillance: CEA and/or CA 19-9 every 3-6 months for 2 years then every 6 months for a total of 5 years

Jejunum/Ileum Work-up: CA 19-9 and CEA

Surveillance: CEA and /or CA 19-9 every 3-6 months for 2 years then every 6 months for a total of 5 years

Metastatic adenocarcinoma Work-up: CA 19-9 and CEA

 

Prior Approval:

Not applicable

 

Policy:

See related medical policies

  • 02.04.65 Molecular Markers in Fine Needle Aspirates of the Thyroid
  • 02.04.45 Multimarker Serum Testing Related to Ovarian Cancer
  • 02.04.59 Gene Expression Profiling for the Management of Breast Cancer 

 

Measurement of the following tumor markers are considered medically necessary for the indications listed below when measurement may be used to influence the management of patients, and when these management changes will result in an improvement in patient outcomes:

 

Tumor Marker Condition(s)
Carcinoembryonic Antigen (CEA)(82378)
  • Metastatic Breast Cancer
  • Colorectal Cancer
  • Biliary Tract Cancers including:
    • Intrahepatic Cholangiocarcionoma
    • Extrahepatic Cholangiocarcinoma
    • Gallbladder Cancer
  • Medullary Thyroid Carcinoma
  • Pseudomyxoma peritonei/mucinous carcinoma of the ovary
  • Lung cancer
  • Mucinous appendiceal carcinoma
  • Small bowel adenocarcinoma
  • Ovarian cancer
Cancer Antigen 125 (CA-125) (86304)
  • Primary Peritoneal Cancer
  • Ovarian cancer
  • Ovarian cancer screening in asymptomatic women when there is a family history of hereditary ovarian cancer syndrome (a pattern of clusters of ovarian cancer within two or more generations) where testing is performed concurrently with vaginal ultrasound and prophylactic/risk reducing salpingo-oopherectomy (RRSO) has not been performed, may be considered as an additional screening test at the clinician’s discretion starting at age 30 years of age or 10 years before earliest age of first diagnosis of ovarian cancer in family.
  • Evaluation of pelvic mass
  • Endometrial cancer
  • Occult primary localized adenocarcinoma or carcinoma not otherwise specified for any of the following clinical presentations:
    • Chest (multiple nodules or pleural effusion) in women
    • Peritoneal/Ascites in women
    • Retroperitoneal mass in women
    • Inguinal nodes in women
CA 19-9 (86301)
  • Pancreatic Cancer
  • Biliary Tract Cancers including:
    • Intrahepatic Cholangiocarcionoma
    • Extrahepatic Cholangiocarcinoma
    • Gallbladder Cancer
  • To aid in the detection of cholangiocarcinoma in patients with primary sclerosing cholangitis
  • Gastric cancer
  • Pseudomyxoma peritonei/mucinous carcinoma of ovary
  • Ovarian Cancer
  • Small bowel adenocarcinoma
CA 15-3 and CA 27.29 (86300) Metastatic Breast Cancer
5-HIAA (5 Hydrocyindoleascetic Acid) (24 hour urine) (83497)
  • Neuroendocrine Tumors
  • Carcinoid syndrome
Chromogranin A (CgA) (86316) Neuroendocrine Tumors

 

Tumor markers not meeting the above medical necessity criteria will be considered not medically necessary as they have not been proven to be effective.

 

Measurement of the serum tumor markers including but not limited to the following are considered investigational:

  • Ova-1 (CA-125, apolipoprotein A1, beta 2 microglobulin transferin and pre-albumin) and ROMA (CA-125 and HE4
  • Human epididymis protein (HE4)
  • A2-PAG (pregnancy associated alpha2 glycoprotein)
  • BCM (breast cancer mucin)
  • CAM 17-1 (antimucin monoclonal antibody)
  • CAM-26 (carcinoma associated mucin antigen)
  • CAM-29 (carcinoma associated mucin antigen)
  • MCA (mucinous carcinoma associated antigen)
  • TPA (tissue polypeptide antigen)
  • TPS (tissue polypeptide specific antigen)
  • CA 72-4 (cancer antigen 72-4)
  • CA-50 (cancer antigen 50)
  • CA-242 (cancer antigen 242)
  • CA-195 (cancer antigen 195)
  • CA-549 (cancer antigen 549)
  • CA-SCC (squamous cell carcinoma antigen)
  • CAR-3 (antigenic determinant recognized by monoclonal antibody AR-3)
  • DMSA (pentavalent technetium-99mm dimercaptosuccinic acid)
  • NSE (neuron specific enolase)
  • Du-PAN-2 (sialylated carbohydrate antigen)
  • EPCA-2 (early prostate cancer antigen)
  • TAG-12 (tumor associated glycoprotein 12)
  • TAG 72 (tumor associated glycoprotein 72)
  • TAG-72-3 (tumor associated glycoprotein 72-3)
  • TNF-alpha (TNF-a) (tumor necrosis factor alpha)
  • TATI (tumor associated trypsin inhibitor)
  • P-LAP (placental alkaline phosphatase)
  • PNA-ELLA (peanut lectin bonding assay)
  • P53 (monocolonal antibody)
  • SLEX (sialylated Lewis-X antigen)
  • SLX (sialylated SSEA-1 antigen)
  • SPAN-1 (sialylated carbonated antigen SPAN-1) 

 

Recommendations and guidelines by professional societies and organizations and evidence in the published peer reviewed scientific literature support the use of defined tumor markers for the diagnosis, treatment planning, treatment monitoring and/or follow up of specific cancers. However, based on the peer reviewed medical literature, improvements in meaningful health outcomes have not been proven for the above tumor markers and are still under investigation to determine their clinical utility in the management of individuals with various types of cancers. Studies comparing the tumor markers to established treatment options are lacking and management of patients based on the results of these markers have not been published and does not support that these markers having sufficient sensitivity or specificity to define their clinical role. The evidence is insufficient to determine the effects of this testing on net health outcomes.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.

  • 82378 Carcinoembryonic antigen (CEA)
  • 83497 Hydroxyindolacetic acid 5-HIAA
  • 86300 Immunoassay for tumor antigen, quantitative; CA 15-3 (27.29)
  • 86301 Immunoassay for tumor antigen, quantitative; CA 19-9
  • 86304 Immunoassay for tumor antigen, quantitative; CA 125
  • 86305 Human epididymis protein
  • 86316 Immunoassay for tumor antigen; other antigen, quantitative (eg. CA 50, 72-4, 549), each (this code is used for CgA)
  • 81479 Unlisted molecular pathology procedure
  • 81599 Unlisted multi-analyte assay with algorithmic analysis
  • 84999 Unlisted chemistry procedure

 

Selected References:

  • Burtis C A, Ashwood Er, editors. Tietz textbook of clinical chemistry. Third edition.  Philadelphia: W.B.Saunders, c1999. Pages 735-740.
  • Gion M, Boracchi P, Dittadi R, Biganzoli E, Peloso L, Mione R, Gatti C, Paccagnella A, Marubini E.  Prognostic role of serum CA15.3 in 362 node-negative breast cancers.  An old player for a new game. European Journal of Cancer; June 2002; 38 (9): 1165-6.
  • Jacobs IJ, et al..  Screening for ovarian cancer: a pilot randomized controlled trial.  Lancet  1999 Apr 10;353(9160):1207-10.
  • Jacobs IJ, et al.  Risk of diagnosis of ovarian cancer after raised serum CA 125 concentration: a prospective cohort study.  BMJ  1996 Nov 30;313(7069):1355-8.
  • ACOG Committee Opinion: number 280, December 2002. The role of the generalist obstetrician-gynecologist in the early detection of ovarian cancer.  Obstet Gynecol  2002 Dec;100(6):1413-6.
  • Tuxen MK, Soletormos G, Dombernowsky P. Serum tumor marker CA 125 for monitoring ovarian cancer during follow-up.  Scand J Clin Lab Invest  2002;62(3):177-88.
  • Smith RA, Cokkinides V, Eyre HJ et al. American Cancer Society Guidelines for the early Detection of Cancer, 2003. CA Cancer J Clin 2003 Jan-Feb;53(1):27-43.
  • Bast RC, Ravdin P, hays D et al. 2000 update of recommendations for the use of tumor markers on breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Incol 2001;19(6):1865-78.
  • Micke O, Bruns F, Kurowski R et al. Predictive value of carbohydrate antigen 19-9 in pancreatic cancer treated with radiotherapy. Int J Radiat Oncol Biol Phys 2003; 57(1):90-7.
  • Kurebayashi J, Yamaoto Y, Tanaka K et al. Significance of serum carcinoembryonic antigen and CA 15.3 in monitoring advanced breast cancer patients treated with systemic therapy: a large-scale retrospective study. Breast Cancer 2003;10(1):38-44.
  • Harris L, Fritsche H, Mennel R et al. American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. J Clin Oncol. 2007 Nov 20;25(33):5287-312.
  • Zatelli MC, Torta M, Leon A et al. Chromogranin A as a marker of neuroendocrine neoplasia: an Italian Multicenter Study. Endocr Relat Cancer. 2007 Jun;14(2):473-82.
  • Seregni E, Ferrari L, Bajetta E et al. Clinical significance of blood chromogranin A measurement in neuroendocrine tumours. Ann Oncol. 2001;12 Suppl 2:S69-72.
  • Stirling D, Evans DGR, Pichert G et al. Screening for Familial Ovarian Cancer: Failure of Current Protocols to Detect Ovarian Cancer at an Early Stage According to the International Federation of Gynecology and Obstetrics System. J Clin Oncol 2005; 23(24):5588-5596.
  • Bast Jr. RC. Status of Tumor Markers in Ovarian Cancer Screening. J Clin Oncol 2003; 21(10s):200s-205s.
  • Karlan BY, McIntosh M. The Quest for Ovarian Cancer’s Holy Grail: Can CA-125 Still Be the Chalice of Early Detection? J Clin Oncol 2007;25(11): 1303-1304.
  • Marcos CA, Martinez DA, de Los Toyos JR et al. The usefulness of new serum tumor markers in head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg. 2009 Mar; 140(3):375-80.
  • Tsai HL, Chang YT, Chu KS et al. Carcinoembryonic antigen in monitoring of response to cetuximab plus FOLFIRI or FOLFOX-4 in patients with metastatic colorectal cancer. Int J Biol Markers. 2008 Oct-Dec; 23(4):244-8.
  • Li YG, Zhang N. Clinical significance of serum tumor M2-PK and CA 19-9 detection in the diagnosis of cholangiocarcinoma. Dig Liver Dis. 2009 Jan 23. [Epub ahead of print]
  • Andriole GL, Crawford ED, Grubb 3rd RL et al. Mortality Results from a Randomized Prostate-Cancer Screening Trial. N Engl J Med 2009; 360(13): 1310-19.
  • Brawley OW, Ankerst DP, Thompson IM. Screening for Prostate Cancer. CA Cancer J Clin 2009[Epub prior to print June 29, 2009].
  • Lin K, Lipsitz R, Miller T et al. Benefits and Harms of Prostate-specific Antigen Screening for Prostate Cancer: An Evidence Update for the U.S. Preventive Services Task Force. Ann Intern Med. 2008;149(3):192-99.
  • Lim LS, Sherin K, and the American College of Preventive Medicine (ACPM) Prevention Practice Committee. Screening for Prostate Cancer in U.S. Men: ACPM Position Statement on Preventive Practice. Am J Prev Med 2008;34(2):164-70.
  • Charatcharoenwitthaya P, Enders FB, Halling KC et al. Utility of Serum Tumor Markers, Imaging, and Biliary Cytology for Detecting Cholangiocarcinoma in Primary Sclerosing Cholangitis. Hepatology 2008;48:1106-1117.
  • Juntermanns B, radunz S, Heuer M et al. Tumor markers as a diagnostic key for hilar cholangiocarcinoma. Eur J Med Res. 2010 Aug 20; 15(8):357-61.
  • Morris-Stiff G, Teli M, Jardine N et al. CA19-9 antigen levels can distinguish between benign and malignant pancreatobiliary disease. Hepatobiliary Pancreat Dis Int. 2009 Dec; 8(6):620-6.
  • Abbas G, Lindor KD. Cholangiocarcinoma in primary sclerosing cholangitis. J Gastrointest Cancer. 2009; 40(1-2):19-25. Epub 2009 Aug 25.
  • Gilligan TD, Seidenfeld J, Basch EM et al. American Society of Clinical Oncology Practice Guideline on Uses of Serum Tumor Markers in Adult Males with Germ Cell tumors. J Clin Oncol 2010; 28(20):3388-3404.
  • Moore RG, McKeekin DS, Brown AK et al. A novel multiple marker bioassay utilizing HE4 and CA-125 for the prediction of ovarian cancer in patients with pelvic mass. Gynecol Oncol 2009; 112(1):40-6.
  • Nolen B, Velikokhatnaya L, Marrangoni A et al. Serum biomarker panels for the discrimination of benign from malignant cases in patients with an adnexal mass. Gynecol Oncol 2010; 117(3);440-5.
  • Andersen MR, Goff BA, Lowe KA et al. Use of a symptom index, CA 125 and HE4 to predict ovarian cancer. Gynecol Oncol 2010; 116(3):378-83.
  • Molina R, Escudero JM, Auge JM et al. HE4 a novel tumour marker for ovarian cancer: comparison with CA 125 and ROMA algorithm in patients with gynaecological diseases. Tumor Biol 2011; 32:1087-95. Doi: 10.007/s13277-011-0204-3.
  • Moore RG, Miller MC, Disilvestro P et al. Evaluation of the diagnostic accuracy of the risk of ovarian malignancy algorithm in women with a pelvic mass. Obstet Gynecol. 2011 Aug; 118(2 Pt 1): 280-8.
  • Sturgeon CM, Duffy MJ, Hoffmann BR et al. National Academy of Clinical Biochemistry Laboratory Medicine Clinical Practice Guidelines for use of tumor markers in liver, bladder, cervical, and gastric cancers. Clin Chem 2010 Jun;56(6): e1-48. Epub 2010 Mar 5.
  • Anderson GL, McIntosh M, Wu L et al. Assessing lead tome of selected ovarian cancer biomarkers: a nested case-control study. J Natl Cancer Inst 2010; 102(1):26-38.
  • Lenhard M, Steiber P, Hertlein L et al. The diagnostic accuracy of two human epididymis protein 4 (HE4) testing systems in combination with CA125 in the differential diagnosis of ovarian masses. Clin Chem Lab Med. 2011 Sep 16 [Epub ahead of print].
  • Holcomb K, Vucetic Z, Miller MC et al. Human epididymis protein 4 offers superior specificity in the differentiation of benign and malignant adnexal masses in premenopausal women. Am J Obstet Gynecol. 2011 Oct;205(4):358.el-6. Epub 2011 May 14.
  • American Association for the Study of Liver Disease (AASLD). ASSLD Practice Guideline. Management of Hepatocellular Carcinoma: An Update. July 2010
  • American Association for the Study of Liver Disase (AASLD). ASSLD Practice Guideline. Diagnosis and Management of Primary Sclerosing Cholangitis. February 2010.
  • The American College of Obstetrician and Gynecologists (ACOG). Committee Opinion, Number 477, March 2011. The Role of the Obstetrician-Gynecologist in the Early Detection of Epithelial Ovarian Cancer. 
  • American Society of Clinical Oncology (ASCO). Guideline for Tumor Markers for Testicular Cancer and Extragonadal Germ Cell Tumors in Teenage Boys and Men.
  • American Society of Clinical Oncology (ASCO) 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer, Journal of Clinical Oncology Volume 25, Number 33, November 2007.
  • American Society of Clinical Oncology (ASCO). ASCO 2006 Update of Recommendations for the Use of Tumor Markers for Gastrointestinal Cancers, Journal of Clinical Oncology Volume 24, Number 33, November 2006.
  • National Comprehensive Cancer Network (NCCN) Version 2.2020 Uterine Neoplasms.
  • National Comprehensive Cancer Network (NCCN) Occult Primary (Cancer of  Unknown Primary) Version 3.2020. 
  • National Comprehensive Cancer Network (NCCN) Version 4.2020 Colon Cancer.
  • National Comprehensive Cancer Network (NCCN) Version 6.2020 Rectal Cancer.
  • National Comprehensive Cancer Network (NCCN) Version 2.2020 Neuroendocrine Tumors.
  • National Comprehensive Cancer Network (NCCN) Version 3.2020 Testicular Cancer (nonseminoma and pure seminoma). 
  • National Comprehensive Cancer Network (NCCN) Version 5.2020 Hepatobiliary Cancers.
  • National Comprehensive Cancer Network (NCCN) Version 3.2017 Small Cell Lung Cancer.
  • National Comprehensive Cancer Network (NCCN) Version 1.2020 Pancreatic Adenocarcinoma.
  • National Comprehensive Cancer Network (NCCN) Version 2.2020 Prostate Cancer.
  • National Comprehensive Cancer Network (NCCN) Version 3.2020 Gastric Cancer.
  • National Comprehensive Cancer Network (NCCN) Version 5.2020 Breast Cancer.
  • National Comprehensive Cancer Network (NCCN) Version 2.2020 Thyroid Carcinoma.
  • National Comprehensive Cancer Network (NCCN) Soft Tissue Sarcoma Version 2.2020.
  • National Comprehensive Cancer Network (NCCN) Acute Myeloid Leukemia Version 3.2020.
  • National Comprehensive Cancer Network (NCCN) Vulvar Cancer Version 3.2020.
  • National Comprehensive Cancer Network (NCCN) Version 6.2020 Non-Small Cell Lung Cancer.
  • National Comprehensive Cancer Network (NCCN) Version 1.2020 Malignant Plural Mesothelioma.
  • National Comprehensive Cancer Network (NCCN) Version 1.2020 Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer.
  • National Comprehensive Cancer Network (NCCN) Version 2.2020 Small Bowel Adenocarcinoma
  • American Thyroid Association. Molecular Analysis for Mutations in Thyroid FNA Improves the Diagnosis of Malignancy for All Categories of Indeterminate Cytology. J Clin Endocrinol Metab 2011;96:3390-7, Epub August 31, 2011.
  • AACE (American College of Endocrinology)/AAES (American Association of Endocrine Surgeons) Medical/Surgical Guidelines for Clinical Practice: Management of Thyroid Carcinoma. Endocrine Practice Vol.7 No. 3 May/June 2001. 
  • UpToDate. Diagnostic Approach to and Treatment of Thyroid Nodules. Douglas S. Ross, M.D.. This Topic Last Updated January 22, 2016.
  • MedScape. Molecular Diagnosis for Indeterminate Thyroid Nodules on Fine Needle Aspiration. 2013.
  • Erik K. Alexander, M.D. et al. The New England Journal of Medicine, Preoperative Diagnosis of Benign Thyroid Nodules with Indeterminate Cytology. August 23, 2012. N Engl J Med 367;8.
  • Veracyte. Afirma Thyroid FNA Analysis.   
  • American Society of Clinical Oncology (ASCO) 2010 Clinical Practice Guideline on the Uses of Serum Tumor Markers in Adult Males with Germ Cell Tumors. JCO July 10, 2010 vol.28 no.20 3388-3404.
  • Wagner L. Patrick, Austin Frances, et. al. Significance of Serum Tumor Marker Levels in Peritoneal Carcinomatosis of Appendiceal Origin, Ann Surg Oncol, 2013 February; 20(2): doi.1245/s10434-012-2627-5
  • Koh, Ju-Li, et al. Carbohydrate Antigen 19-9 (CA 19-9) is an Independent Prognostic  Indicator in Pseudomyxoma Peritonei Post Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy, Journal of Gastrointestinal Oncology 4.2 (2013): 173
  • Salini Ritu, Backes Floor, et. al. Posttreatment Surveillance and Diagnosis of Recurrence in Women with Gynecologic Malignancies: Society of Gynecologic Oncologists Recommendations, American Journal of Obstetrics & Gynecology June 2011.
  • Khatcheressian James, Hurley Patricia, et. al. Breast Cancer Follow-Up and Management after Primary Treatment: American Society of Clinical Oncology Clinical Practice Guideline Update, Journal of Clinical Oncology 2012. J Clin Oncol 31:961-965 
  • Van Poznak Catherine, Somerfield Mark R., et. al. Use of Biomarkers to Guide Decisions on Systemic Therapy for Women with Metastatic Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline, Journal of Clinical Oncology 2015.  J Clin Oncol 33:2695-2704
  • Fallahi Poupak, Giannini Riccardo, et. al. Molecular Diagnostics of Fine Needle Aspiration for the Presurgical Screening of Thyroid Nodules. Current Genomics 2014, 15, 171-177
  • Ferris Robert, Baloch Zubair, Bernet Victor, et. al. American Thyroid Assocation Statement on Surgical Application of Molecular Profiling for Thyroid Nodules: Current Impact on Perioperative Decision Making. Thyroid Volume 25, Number 7, 2015
  • Nikiforov Yuri, Yip Linwah, Nikiforova Marina, New Strategies in Diagnosing Cancer in Thyroid Nodules: Impact of Molecular Markers. American Assocation for Cancer Research October 13, 2015.
  • Labourier Emmanuel, Shifrin Alexander, Busseniers Anne, et. al. Molecular Testing for miRNA and DNA on Fine Needle Aspiration Improves the Preoperative Diagnosis of Thyroid Nodules with Indeterminate Cytology. J Clin Endocrinol Metab May 2015.
  • Interpace Diagnostics – Value Dossier ThyGenX and ThyraMIR. Prepared by Interpace Diagnostics, LLC September 16, 2015
  • ECRI. Health Technology Assessment. Afirma Thyroid Gene Expression Classifier (Veracyte, Inc) for Evaluating Thyroid Nodules of Indeterminate Cytopathologic Diagnosis. Updated November 10, 2015/Published June 6, 2014.
  • Bernet Victor, Hupart Kenneth, et. al. AACE/ACE Disease State Commentary: Molecular Diagnostic Testing of Thyroid Nodules with Indeterminate Cytopathology. Endocrine Practice April 2014 Vol. 20. No. 4, pp. 360-363
  • CMS. National Coverage Determination (NCD) for Tumor Antigen by Immunoassay CA-125 (190.28)
  • CMS. National Coverage Determination (NCD) for Tumor Antigen by Immunoassay CA 15-3/CA 27.29 (190.29)
  • CMS. National Coverage Determination (NCD) for Tumor Antigen by Immunoassay CA 19-9 (190.30)
  • UpToDate. Cancer of the Appendix and Pseudomyxoma Peritonei. Richard Swanson M.D., Jeffrey A Meyerhardt M.D., PhD. Topic last updated December 19, 2016.
  • UpToDate. Thyroid Biopsy. Douglas S Reed, M.D., Topic last updated January 20, 2016.
  • UpToDate. Screening for Ovarian Cancer. Karen J. Carlson M.D., Topic last updated August 18, 2017.
  • UpToDate. Clinical Presentation, Diagnosis, and Staging of Colorectal Cancer. Finlay A Macrae M.D., Johanna Bendell M.D., Topic last updated August 15, 2017.
  • UpToDate. Overview of the Classification and Management of Cancers of Unknown Primary Site. John D. Hainsworth M.D., F. Anthony Greco, M.D., Topic last updated June 5, 2017.
  • UpToDate. Overview of the Management of Rectal Adenocarcinoma. David P. Ryan, M.D., Miguel A. Rodriguez-Bigas M.D., Topic last updated August 21, 2017.
  • UpToDate. Clinical Manifestations and Diagnosis of Cholangiocarcinoma. Robert C Lowe, M.D., Nezam H. Afdel M.D., FRCPI, Christopher D. Anderson M.D., FACS, Kris V. Kowdley M.D., FACP, FACG, GASGE, AGAF. Topic last updated November 30, 2016.
  • Di Fabio F, Aston W, Mohamed F, Chandrakumaran K. et. al. Elevated tumor markers are normalized in most patients with pseudomyxoma peritonei 7 days after complete tumor removal. Colorectal Dis 2015 Aug;17(8):698-703
  • National Cancer Institute. Tumor Markers. Last reviewed November 4, 2015.
  • UpToDate. Management of Patients at High Risk for Breast and Ovarian Cancer. Claudine Isaacs M.D., Beth N. Peshkin MS, CGC. Topic last updated October 11, 2016.
  • Sturgeon CM, Hoffman BR, Chan DW, et. al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for use of Tumor Markers in Clinical Practice: Quality Requirements. Clin Chem 2008 Aug;54(8):e1-e10. PMID 18606634
  • Duffy M. Tumor markers in clinical practice. A review focusing on common solid cancers. Med Princ Pract 2013;22:4-11
  • Incoronato M, Mirabelli P, Catalano O, et. al. CA 15-3 is a useful serum tumor marker for diagnostic integration of hybrid positron emission tomography with integrated computed tomography during follow-up of breast cancer patients. BMC Cancer 2014;14:356
  • Duffy M. Clinical use of tumor biomarkers: an overview. Klin Biochm Metab 25(46) 2017 No 4 p 157-161
  • National Academy of Clinical Biochemistry. Laboratory Medicine Practice Guidelines Use of Tumor Markers in Liver, Bladder, Cervical and Gastric Cancers. 2010
  • National Academy of Clinical Biochemistry. Laboratory Medicine Practice Guidelines Use of Tumor Markers in Testicular, Prostate, Colorectal, Breast and Ovarian Cancers. 2008 
  • Carmignani C, Hampton, R, Sugarbaker C, et. al. Utility of CEA and CA 19-9 tumor markers in diagnosis and prognostic assessment of mucinous epithelial cancers of the appendix. J Surg Oncol 2004 Sep 15;87(4):162-6     
  • American College of Obstetricians and Gynecologists (ACOG). Early Detection of Epithelial Ovarian Cancer in Women at Average Risk.  Committee Opinion 716 (replaces committee opinion number 477, March 2011, Reaffirmed 2019.

 

Policy History:

  • August 2020 - Annual Review, Policy Revised
  • August 2019 - Annual Review, Policy Revised
  • August 2018 - Annual Review, Policy Revised
  • August 2017 - Annual Review, Policy Revised
  • January 2017 - Interim Review, Policy Revised
  • October 2016 - Interim Review, Policy Revised
  • August 2016 - Annual Review, Policy Revised
  • December 2015 - Interim Review, Policy Revised
  • September 2015 - Annual Review, Policy Revised
  • July 2015 - Interim Review, Policy Revised
  • October 2014 - Annual Review, Policy Revised
  • March 2014 - Interim Review, Policy Revised
  • November 2013 - Interim Review, Policy Revised
  • October 2013 - Annual Review, Policy Revised
  • December 2012 - Annual Review, Policy Renewed
  • December 2011 - Annual Review, Policy Renewed
  • December 2010 - Annual Review, Policy Revised

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

*CPT® is a registered trademark of the American Medical Association.