Tumor marker

A tumor marker is a biomarker found in blood, urine, or body tissues that can be elevated by the presence of one or more types of cancer. There are many different tumor markers, each indicative of a particular disease process, and they are used in oncology to help detect the presence of cancer. An elevated level of a tumor marker can indicate cancer; however, there can also be other causes of the elevation (false positive values).

Tumor markers can be produced directly by the tumor or by non-tumor cells as a response to the presence of a tumor.

Although mammography, ultrasonography, computed tomography, magnetic resonance imaging scans, and tumor marker assays help in the staging and treatment of the cancer, they are usually not definitive diagnostic tests. The diagnosis is mostly confirmed by biopsy.^[1]

Classification

On the basis of their chemical nature tumor markers can be proteins, conjugated proteins, peptides or carbohydrates. Proteins or conjugated proteins may be enzymes, hormones or fragments of proteins. Sequencing of genes for diagnostic purposes is mostly classified under the biomarker heading and is not treated here.

Uses

Tumor markers may be used for the following purposes:

• Screening for common cancers on a population basis. Broad screening for all or most types of cancer was originally suggested but has since been shown not to be a realistic goal. Screening for specific cancer types or locations requires a level of specificity and sensitivity that has so far only been reached by Example: elevated prostate specific antigen suggests that is used in some countries to screen for prostate cancer.
• Monitoring of cancer survivors after treatment, detection of recurrent disease. Example: elevated AFP in a child previously treated for teratoma suggests relapse with endodermal sinus tumor.
• Diagnosis of specific tumor types, particularly in certain brain tumors and other instances where biopsy is not feasible.
• Confirmation of diagnosis to verify the characteristics such as size and aggressiveness of a tumor and thereby to help in the evaluation of a suitable treatment schedule.
• Staging: some tumor markers are included in the staging procedures for some tumor localizations.
• Prognosis to plan the treatment when used pre-treatment and to help the patient to plan his future when used after the operation of cure.
• To verify the effect of treatment to change the treatment if ineffective.
• As companion diagnostic to verify if the treatment is suited for the type or subtype of tumor particularly in personalized medicine.

As stated in the BMJ 2009, tumor markers should not generally be used for the purpose of diagnosis of cancers, as opposed to monitoring purposes in certain cancers, or in certain cases, for screening purposes.^[2] The use of these tests without understanding their utility has resulted in inappropriate use of tumor marker blood tests, which has resulted in inappropriate over-investigation for cancers.^[3]

Techniques

Tumor markers can be determined in serum or rarely in urine or other body fluids, often by immunoassay but other techniques such as enzyme activity determination are sometimes used. Microscopic visualization in tissue by immunohistochemistry does not give quantitative results and is not considered here.

For many assays, different assay techniques are available. For monitoring it is important that the same assay is used as the results from different assays are generally not comparable. For example, for AFP many different commercial assay kits, based on different technologies, are available and for thymidine kinase there are assays for either enzyme activity or amount of substance.

If repeated measurements of tumor marker are needed, some clinical testing laboratories provide a special reporting mechanism, a serial monitor that links test results and other data pertaining to the person being tested. This requires a unique identifier for the person. In the United States commonly a Social Security number & Civil Personal Record (CPR) in Bahrain are used for this.

Interlaboratory proficiency testing for tumor marker tests, and for clinical tests more generally, is routine in Europe and an emerging field.^[4] in the United States. New York state is prominent in advocating such research.^[5]

List of commonly used markers

Tumor marker	Associated tumor types
Alpha fetoprotein (AFP)	germ cell tumor, hepatocellular carcinoma[6]
CA15-3	breast cancer[7]
CA27-29	breast cancer[8]
CA19-9	Mainly pancreatic cancer, but also colorectal cancer and other types of gastrointestinal cancer.[9]
CA-125	Mainly ovarian cancer,[10] but may also be elevated in for example endometrial cancer, fallopian tube cancer, lung cancer, breast cancer and gastrointestinal cancer.[11] May also increase in endometriosis.[12]
Calcitonin	medullary thyroid carcinoma
Calretinin	mesothelioma, sex cord-gonadal stromal tumour, adrenocortical carcinoma, synovial sarcoma[6]
Carcinoembryonic antigen	gastrointestinal cancer, cervix cancer, lung cancer, ovarian cancer, breast cancer, urinary tract cancer[6]
CD34	hemangiopericytoma/solitary fibrous tumor, pleomorphic lipoma, gastrointestinal stromal tumor, dermatofibrosarcoma protuberans[6]
CD99MIC 2	Ewing sarcoma, primitive neuroectodermal tumor, hemangiopericytoma/solitary fibrous tumor, synovial sarcoma, lymphoma, leukemia, sex cord-gonadal stromal tumour[6]
CD117	gastrointestinal stromal tumor, mastocytosis, seminoma[6]
Chromogranin	neuroendocrine tumor[6]
Chromosomes 3, 7, 17, and 9p21	bladder cancer[13]
Cytokeratin (various types: TPA, TPS, Cyfra21-1)	Many types of carcinoma, some types of sarcoma[6]
Desmin	smooth muscle sarcoma, skeletal muscle sarcoma, endometrial stromal sarcoma[6]
Epithelial membrane antigen (EMA)	many types of carcinoma, meningioma, some types of sarcoma[6]
Factor VIII, CD31 FL1	vascular sarcoma[6]
Glial fibrillary acidic protein (GFAP)	glioma (astrocytoma, ependymoma)[6]
Gross cystic disease fluid protein (GCDFP-15)	breast cancer, ovarian cancer, salivary gland cancer[6]
HMB-45	melanoma, PEComa (for example angiomyolipoma), clear cell carcinoma, adrenocortical carcinoma[6]
Human chorionic gonadotropin (hCG)	gestational trophoblastic disease, germ cell tumor, choriocarcinoma[6]
immunoglobulin	lymphoma, leukemia[6]
inhibin	sex cord-gonadal stromal tumour, adrenocortical carcinoma, hemangioblastoma[6]
keratin (various types)	carcinoma, some types of sarcoma[6]
lymphocyte marker (various types	lymphoma, leukemia[6]
MART-1 (Melan-A)	melanoma, steroid-producing tumors (adrenocortical carcinoma, gonadal tumor)[6]
Myo D1	rhabdomyosarcoma, small, round, blue cell tumour[6]
muscle-specific actin (MSA)	myosarcoma (leiomyosarcoma, rhabdomyosarcoma)[6]
neurofilament	neuroendocrine tumor, small-cell carcinoma of the lung[6]
neuron-specific enolase (NSE)	neuroendocrine tumor, small-cell carcinoma of the lung, breast cancer[6]
placental alkaline phosphatase (PLAP)	seminoma, dysgerminoma, embryonal carcinoma[6]
prostate-specific antigen (PSA)	prostate[6]
PTPRC (CD45)	lymphoma, leukemia, histiocytic tumor[6]
S100 protein	melanoma, sarcoma (neurosarcoma, lipoma, chondrosarcoma), astrocytoma, gastrointestinal stromal tumor, salivary gland cancer, some types of adenocarcinoma, histiocytic tumor (dendritic cell, macrophage)[6]
smooth muscle actin (SMA)	gastrointestinal stromal tumor, leiomyosarcoma, PEComa[6]
synaptophysin	neuroendocrine tumor[6]
thymidine kinase	lymphoma, leukemia, lung cancer, prostate cancer
thyroglobulin (Tg)	post-operative marker of thyroid cancer (but not in medullary thyroid cancer)[6]
thyroid transcription factor-1 (TTF-1)	all types of thyroid cancer, lung cancer[6]
Tumor M2-PK	colorectal cancer,[14] Breast cancer,[15][16] renal cell carcinoma[17][18] Lung cancer,[19][20] Pancreatic cancer,[21] Esophageal Cancer,[22] Stomach Cancer,[22]Cervical Cancer,[23] Ovarian Cancer,[24]
vimentin	sarcoma, renal cell carcinoma, endometrial cancer, lung carcinoma, lymphoma, leukemia, melanoma[6]

Precision and accuracy

The required precision and accuracy for different analytes varies: some analytes give small or moderate changes in concentration or activity, thereby requiring high accuracy and precision to be useful while others that show large differences between normal and pathological values may be useful even if the precision and accuracy are inferior. Therefore, the required precision and accuracy for a given assay may be different for different applications such as in different diagnoses or for different uses. This also influences the useful working range for a given assay for different diagnosis or uses. Every laboratory should verify the precision and accuracy of the assays with the instruments and personnel used.

The high dose hook effect is an artifact of immunoassay kits, that causes the reported quantity to be incorrectly low when the quantity is high. An undetected hook effect may cause delayed recognition of a tumor.^[25] The hook effect can be detected by analyzing serial dilutions. The hook effect is absent if the reported quantities of tumor marker in a serial dilution are proportional to the dilution.

Multiple Tumor marker test

As with other diagnostic tests, tumor markers have a few test characteristics that influence their usability:

• Imperfect sensitivity, which would result in false negative tests, i.e. the test result is reassuring but cancer is present or has recurred or progressed.
• Imperfect specificity, resulting in false positive tests, i.e. no cancer is present but the test result indicates the opposite, resulting in needless further testing or anxiety.

As with other tests, predictive value (the chance that a positive or negative result represents the truth), depends strongly on the pre-test probability. The predictive value may be increased if two or more tests are carried out in parallel. The condition is that the tests have in themselves similar predictive values.

Test combinations that will give more exact results are for instance:^[1]

• Colorectal: M2-PK; if M2-PK is not available, can test CEA, CA 19-9, CA 125
• Breast: CEA, CA 15-3, Cyfra 21-1
• Ovary: CEA, CA 19-9, CA 125, AFP, BHCG
• Uterine: CEA, CA 19-9, CA 125, Cyfra 21-1, SCC
• Prostate: PSA, FPSA and ratio
• Testicle: AFP, BHCG
• Pancreas/Stomach: CEA, CA 19-9, CA 72-4
• Liver: CEA, AFP
• Oesophagus: CEA, Cyfra 21-1
• Thyroid: CEA, NSE
• Lung: CEA, CA 19-9, CA 125, NSE, Cyfra 21-1 (Sensitivity at 95 percent percentile for Cyfra 21-1 is 79 percent, while for SCC and CEA are 41 and 31 percent respectively)^[26]
• Bladder: CEA, Cyfra 21-1, TPA

See also

• Tumor antigen
• List of cancer types

References

1. "Tumor markers Cancer screening". Retrieved December 28, 2013.
2. Kilpatrick, E. S; Lind, M. J (2009). "Appropriate requesting of serum tumour markers". BMJ. 339: b3111. doi:10.1136/bmj.b3111. PMID 19773324.
3. Krishnan, S T M; Philipose, Z; Rayman, G (2002). "Lesson of the week: Hypothyroidism mimicking intra-abdominal malignancy". BMJ. 325 (7370): 946–7. doi:10.1136/bmj.325.7370.946. PMC 1124444. PMID 12399347.
4. Koepke, John A. (1992). "Molecular marker test standardization". Cancer. 69 (6 Suppl): 1578–81. doi:10.1002/1097-0142(19920315)69:6+<1578::AID-CNCR2820691312>3.0.CO;2-K. PMID 1540898.
5. Promoting Safe and Effective Genetic Testing in the United States genome.gov
6. Page 746 in: Title Manual of clinical oncology Spiral manual Manual of Clinical Oncology Lippincott Manual Series Authors Dennis Albert Casciato, Mary C. Territo Editors Dennis Albert Casciato, Mary C. Territo Contributor Mary C. Territo Edition 6, illustrated Publisher Lippincott Williams & Wilkins, 2008 ISBN 0-7817-6884-5, ISBN 978-0-7817-6884-9
7. Keshaviah, A; Dellapasqua, S; Rotmensz, N; Lindtner, J; Crivellari, D; Collins, J; Colleoni, M; Thurlimann, B; et al. (2006). "CA15-3 and alkaline phosphatase as predictors for breast cancer recurrence: A combined analysis of seven International Breast Cancer Study Group trials". Annals of Oncology. 18 (4): 701–8. doi:10.1093/annonc/mdl492. PMID 17237474.
8. "Definition of CA 27-29. From MedicineNet. Last Editorial Review: 6/14/2012".
9. gpnotebook.co.uk > ca-19-9 Retrieved November 2011
10. Osman N, O'Leary N, Mulcahy E, Barrett N, Wallis F, Hickey K, Gupta R (September 2008). "Correlation of serum CA125 with stage, grade and survival of patients with epithelial ovarian cancer at a single centre". Ir Med J. 101 (8): 245–7. PMID 18990955.
11. Bast RC, Xu FJ, Yu YH, Barnhill S, Zhang Z, Mills GB (1998). "CA 125: the past and the future". Int. J. Biol. Markers. 13 (4): 179–87. PMID 10228898.
12. Bagan P, Berna P, Assouad J, Hupertan V, Le Pimpec Barthes F, Riquet M (January 2008). "Value of cancer antigen 125 for diagnosis of pleural endometriosis in females with recurrent pneumothorax". Eur. Respir. J. 31 (1): 140–2. doi:10.1183/09031936.00094206. PMID 17804443.
13. "Tumor Markers". Retrieved June 6, 2013.
14. Haug, U; Rothenbacher, D; Wente, M N; Seiler, C M; Stegmaier, C; Brenner, H (2007). "Tumour M2-PK as a stool marker for colorectal cancer: Comparative analysis in a large sample of unselected older adults vs colorectal cancer patients". British Journal of Cancer. doi:10.1038/sj.bjc.6603712.
15. Lüftner, D; Mesterharm, J; Akrivakis, C; Geppert, R; Petrides, PE; Wernecke, KD; Possinger, K (2000). "Tumor type M2 pyruvate kinase expression in advanced breast cancer". Anticancer research. 20 (6D): 5077–82. PMID 11326672.
16. Benesch, C; Schneider, C; Voelker, HU; Kapp, M; Caffier, H; Krockenberger, M; Dietl, J; Kammerer, U; Schmidt, M (2010). "The clinicopathological and prognostic relevance of pyruvate kinase M2 and pAkt expression in breast cancer". Anticancer research. 30 (5): 1689–94. PMID 20592362.
17. Oremek, GM; Sapoutzis, N; Kramer, W; Bickeböller, R; Jonas, D (2000). "Value of tumor M2 (Tu M2-PK) in patients with renal carcinoma". Anticancer research. 20 (6D): 5095–8. PMID 11326675.
18. Wechsel, HW; Petri, E; Bichler, KH; Feil, G (1999). "Marker for renal cell carcinoma (RCC): The dimeric form of pyruvate kinase type M2 (Tu M2-PK)". Anticancer research. 19 (4A): 2583–90. PMID 10470199.
19. Schneider, J; Peltri, G; Bitterlich, N; Philipp, M; Velcovsky, HG; Morr, H; Katz, N; Eigenbrodt, E (2003). "Fuzzy logic-based tumor marker profiles improved sensitivity of the detection of progression in small-cell lung cancer patients". Clinical and experimental medicine. 2 (4): 185–91. doi:10.1007/s102380300005. PMID 12624710.
20. Oremek, G; Kukshaĭte, R; Sapoutzis, N; Ziolkovski, P (2007). "The significance of TU M2-PK tumor marker for lung cancer diagnostics". Klinicheskaia meditsina. 85 (7): 56–8. PMID 17882813.
21. Hardt, PD; Ngoumou, BK; Rupp, J; Schnell-Kretschmer, H; Kloer, HU (2000). "Tumor M2-pyruvate kinase: A promising tumor marker in the diagnosis of gastro-intestinal cancer". Anticancer research. 20 (6D): 4965–8. PMID 11326648.
22. Kumar, Yogesh; Tapuria, Niteen; Kirmani, Naveed; Davidson, Brian R. (2007). "Tumour M2-pyruvate kinase: A gastrointestinal cancer marker". European Journal of Gastroenterology & Hepatology. 19 (3): 265. doi:10.1097/MEG.0b013e3280102f78.
23. Kaura, B; Bagga, R; Patel, FD (2004). "Evaluation of the Pyruvate Kinase isoenzyme tumor (Tu M2-PK) as a tumor marker for cervical carcinoma". The journal of obstetrics and gynaecology research. 30 (3): 193–6. doi:10.1111/j.1447-0756.2004.00187.x. PMID 15210041.
24. Ahmed, AS; Dew, T; Lawton, FG; Papadopoulos, AJ; Devaja, O; Raju, KS; Sherwood, RA (2007). "M2-PK as a novel marker in ovarian cancer. A prospective cohort study". European journal of gynaecological oncology. 28 (2): 83–8. PMID 17479666.
25. Leboeuf, R.; Langlois, Marie-France; Martin, Marc; Ahnadi, Charaf E.; Fink, Guy D. (2005). ""Hook Effect" in Calcitonin Immunoradiometric Assay in Patients with Metastatic Medullary Thyroid Carcinoma: Case Report and Review of the Literature". Journal of Clinical Endocrinology & Metabolism. 91 (2): 361. doi:10.1210/jc.2005-1429.
26. "Diagnostic value of SCC, CEA and CYFRA 21.1 in lung cancer: a Bayesian analysis". Retrieved August 6, 2014.

Further reading

• Lüftner, D; Mesterharm, J; Akrivakis, C; Geppert, R; Petrides, PE; Wernecke, KD; Possinger, K (2000). "Tumor type M2 pyruvate kinase expression in advanced breast cancer". Anticancer research. 20 (6D): 5077–82. PMID 11326672.

External links

• Tumor Markers, Biological at the US National Library of Medicine Medical Subject Headings (MeSH)