Medical Biochemistry Tips (11): Tumor Markers

Dr. James Manos (MD)

January 5, 2016

    

       Review: Tips in Medical Biochemistry

            Volume (11)

CONTENTS

TUMOR MARKERS

Overview of tumor markers

Multiple tumor marker tests

Can tumor markers be used in cancer screening?

      TUMOR MARKERS

·         Overview of tumor markers:

·         ALK gene rearrangements (tumor): non-small cell lung cancer & anaplastic large cell lymphoma.

·         Used to help determine treatment & prognosis.

·         Alpha-fetoprotein (AFP) (blood): hepatocellular cancer & germ cell tumors. It is increased in non-seminomatous germ cell tumors, yolk sac carcinoma, neuroblastoma, and hepatoblastoma. 

·         Some correlate them also with teratomas.

·         It also rises in a mixed Mullerian tumor, Sertoli – Leydig cell tumor (rarely) and Wilms tumor (nephroblastoma) (rarely).

·         Used to help diagnose liver cancer and response to treatment; to assess stage, prognosis, and response to treatment of germ cell tumors.

·         Note: maternal serum AFP (MSAFP) varies by orders of magnitude during normal pregnancy. MSAFP increases rapidly until about 32 weeks gestation, then decreases gradually. After the pregnancy ends, it decreases rapidly, with a half-life of about 5 days. Typically, MSAFP is measured at the beginning of the second trimester (14–16 weeks). MSAFP above normal is seen in multiple gestations when there is a placental abruptio, and in some fetal abnormalities, such as neural tube defects including spina bifida and anencephaly, and abdominal wall defects. It may also increase in mothers with methylenetetrahydrofolate reductase genetic variant. Another possibility is an error in the date of the gestation. Rarely, high MSAFP is due to endodermal sinus tumor (EST) or another germ cell tumor containing EST. These tumors can occur in the pregnant woman (often as an ovarian tumor) or in the fetus. MSAFP below normal is associated with Down syndrome |& trisomy 18. Diabetic patients also have lower levels. Patients with abnormal MSAFP need to undergo detailed obstetric ultrasonography. The information is then used to decide whether to proceed with amniocentesis.

·         Beta – 2 – microglobulin (B2M) (blood, urine, or CSF (cerebrospinal fluid)): multiple myeloma, chronic lymphocytic leukemia (CLL), and some lymphomas. Used to determine prognosis & response to treatment. Note: beta-2 microglobulin levels cannot distinguish between monoclonal gammopathy of uncertain significance (MGUS), which has a better prognosis, and smoldering (low grade) myeloma.  The normal value of beta-2 microglobulin is <2 mg/L.

·    Concerning multiple myeloma, the levels of beta2-microglobulin may also be at the other end of the spectrum. Diagnostic testing for multiple myeloma includes obtaining the beta2-microglobulin level, for this level is an important prognostic indicator. A patient with a level <4 mg/L is expected to have a median survival of 43 months, while one with a level >4 mg/L has a median survival of only 12 months.

·         Beta-human chorionic gonadotropin (beta – hCG) (blood or urine): choriocarcinoma & testicular cancer. Beta - Human chorionic gonadotropin is secreted by some cancers including seminoma, choriocarcinoma, germ cell tumors, hydatidiform mole formation, teratoma with elements of choriocarcinoma, and islet cell tumor.  

·         Used to assess stage, prognosis, and response to treatment. Note: in molecular biology, human chorionic gonadotropin (hCG) is a hormone produced by the syncytioblast, a portion of the placenta following implantation.

·         The presence of hCG is detected in the pregnancy test. Some cancerous tumors produce this hormone; therefore, elevated levels measured when the patient is not pregnant can lead to a cancer diagnosis.

·         BCR – ABL fusion gene (blood; bone marrow): chronic myeloid leukemia (CML).

·         Used to confirm the diagnosis and monitor disease status.

·         BRAF mutation V600E (tumor): cutaneous melanoma & colorectal cancer.

·         Used to predict response to targeted therapies.

·         CA 15 – 3 & CA 27 – 29 (blood): breast cancer.

·         Used to assess whether treatment is working or disease has recurred. 

·         CA15-3 and associated CA27.29 (aka BR27.29) are different epitopes on the same protein antigen product of the breast cancer-associated MUC1 gene. CA27.29 has enhanced sensitivity and specificity and has therefore surpassed CA15-3 as a serum tumor marker. CA27.29 is elevated in 30% of patients with a low-stage disease and 60 to 70% of patients with advanced-stage breast cancer.

·         Both CA27.29 and CA15-3 may be elevated in patients with benign ovarian cysts, benign breast disease, and benign liver disease.

·         Elevations may also be seen in cirrhosis, sarcoidosis, and lupus. CA27.29 may be elevated in non-breast malignancies including colon, stomach, pancreas, prostate, and lung.

·         CA 19 – 9 (blood): pancreatic cancer; gallbladder cancer; bile duct cancer; and gastric cancer. Used to assess whether treatment is working.

·         Note: CA19-9 can be elevated in many types of gastrointestinal cancer, such as colorectal cancer, esophageal cancer, and hepatocellular cancer.

·         Apart from cancer, elevated levels may also occur in pancreatitis, cirrhosis, and diseases of the bile ducts (it can be elevated in people with obstruction of the bile ducts).

·         In patients who lack the Lewis antigen (a blood type antigen on red blood cells (RBCs)), which is about 10% of the Caucasian population, CA19-9 is not expressed, even in those with large tumors, because of a deficiency of a fucosyltransferase enzyme that is needed to produce CA19-9 as well as the Lewis antigen. 

·         CA – 125 (blood): ovarian cancer.

·         Used to help diagnosis, assessment of response to treatment, and evaluation of recurrence.

·         Note: Around 90% of women with advanced ovarian cancer have elevated levels of CA-125 in their blood serum, making CA-125 a useful tool for detecting ovarian cancer after the onset of symptoms. 

·         Monitoring CA-125 blood serum levels are also helpful in determining how ovarian cancer is responding to treatment and for predicting a patient’s prognosis after treatment. 

·         In one case, elevated serum levels of CA-125 were observed in a male patient with IgE myeloma, however, more trials are needed to determine the clinical significance of CA-125 in myeloma.  

·         While CA-125 is a tumor marker for ovarian cancer, it may also be elevated in other cancers, including endometrial cancer, fallopian tube cancer, lung cancer, breast cancer, and gastrointestinal cancer. 

·         CA-125 may also be raised in some relatively benign conditions, such as endometriosis, several diseases of the ovary, menstruation, and pregnancy.  

·         It also tends to be elevated in the presence of an inflammatory condition in the abdominal area, both cancerous and benign, and also in cirrhosis and diabetes mellitus. 

·         Thus, CA-125 testing is not perfectly specific for ovarian cancer and often results in false positives. The specificity of CA-125 is particularly low in premenopausal women because many benign conditions that cause fluctuations in CA-125 levels, such as menstruation, pregnancy, and pelvic inflammatory disease (PID) are seen in this population.

·         CA-125 testing is also not perfectly sensitive for detecting ovarian cancer because not every patient with cancer will have elevated levels of CA-125 in their blood, e.g., 79% of all ovarian cancers are positive for CA-125, whereas the remainder does not express this antigen at all. Also, only about 50% of patients with early-stage ovarian cancer have elevated CA-125 levels, meaning that CA-125 has particularly poor sensitivity for ovarian cancer before the onset of symptoms (that means that the use of CA-125 to detect ovarian cancer, especially in the early stages of the disease, can frequently lead to false negatives, and patients that receive false negatives are unlikely to seek further treatment for their condition).

·         Calcitonin (blood): medullary thyroid cancer.

·         Used to aid in diagnosis; check whether treatment is working, and assess recurrence.

·         Carcinoembryonic antigen (CEA) (blood): colorectal & breast cancer.

·         Used to check whether colorectal cancer has spread; to look for breast cancer recurrence and assess response to treatment.  

·         Note: carcinoembryonic antigen (CEA) describes a set of highly related glycoproteins involved in cell adhesion. CEA is typically produced in gastrointestinal tissue during fetal development, but the production stops before birth. Thus, CEA is usually present only at very low levels in the blood of healthy adults. However, the serum levels are raised in some types of cancer, which means that it can be used as a tumor marker in clinical tests. Serum levels can also be elevated in smokers. Serum from individuals with colorectal carcinoma often has higher levels of CEA than healthy individuals. 

·         CEA measurement is mainly used as a tumor marker to monitor colorectal carcinoma treatment, to identify recurrences after surgical resection, for staging, or to localize cancer spread through the measurement of biological fluids. 

·         CEA levels may also be raised in gastric carcinoma, pancreatic cancer, lung cancer, breast cancer, and medullary thyroid cancer, as well as some non-neoplastic conditions like ulcerative colitis (UC), pancreatitis, liver cirrhosis, chronic obstructive pulmonary disease (COPD), Crohn’s disease and hypothyroidism.

·         CD20 (blood): non-Hodgkin lymphoma (NHL).

·         Used to determine whether treatment with targeted therapy is appropriate.

·         Chromogranin A (CgA) (blood): Neuroendocrine tumors.

·         Used to help in diagnosis, assessment of treatment response, and evaluation of recurrence.

·         Chromosome 3, 7, 17 & 9p21 (urine): bladder cancer.

·         Used to help in monitoring for tumor recurrence.

·         Cytokeratin fragments 21 – 1 (blood): lung cancer.

·         Used to help in monitoring for recurrence.

·         EGFR mutation analysis (tumor): non – small cell lung cancer.

·         Used to help determine treatment & prognosis.

·         Estrogen receptor (ER)/ Progesterone receptor (PR) (tumor): breast cancer.

·         Used to determine whether treatment with hormonal therapy (such as tamoxifen) is appropriate.

·         Fibrin/ fibrinogen (urine): bladder cancer.

·         Used to help monitoring progression & response to treatment.

·         HE4 (blood): ovarian cancer.

·         Used to assess the progression of the disease & monitor for recurrence.

·         HER2/ neu (tumor): breast cancer; gastric cancer; and esophageal cancer.

·         Used to determine whether treatment with trastuzumab is appropriate.

·    Immunoglobulins (Ιg) (blood & urine): multiple myeloma & Waldenstrom macroglobulinemia.  Used to help diagnose disease, assess response to treatment, and monitor for recurrence.

    Note: It should be noted that immunoglobulins often can be found throughout the electrophoretic spectrum].

   The immunoglobulins (IgA, IgM, IgG, IgE, and IgD) are the only proteins present in the normal     

    gamma region.

If the gamma zone shows an increase (or spike), the first step in interpretation is to establish if the region is narrow or wide. If it is elevated in a single narrow “spike-like” manner, it could indicate monoclonal production of a single immunoglobulin (while a broad “swell-like” manner (wide) indicates polyclonal immunoglobulin production.

Immunofixation (gel electrophoresis) or immunosubtraction detects and confirms monoclonal immunoglobulins.

A broad–wide increase of gamma zone indicates polyclonal immunoglobulin production. Causes: severe infection (e.g., cirrhosis, ethanol abuse, autoimmune hepatitis, viral-induced hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis), autoimmune diseases & connective tissue diseases (e.g., rheumatoid arthritis, mixed connective tissue, temporal arteritis, systemic lupus erythematosus (SLE), sarcoid and other) and recent immunization. Also, other medical conditions that may cause a polyclonal rise in the gamma fraction include chronic viral infections (especially hepatitis, HIV, infectious mononucleosis, varicella) or bacterial infections (including endocarditis, osteomyelitis, and bacteremia), tuberculosis, various malignancies (e.g. solid tumors, ovarian tumors, lung cancer, hepatocellular cancer, renal tumors, gastric tumors, hematologic cancers), hematologic (e.g. thalassemia, sickle cell anemia) and lymphoproliferative disorders (e.g. lymphoma, leukemia), and other inflammatory conditions (e.g. gastrointestinal conditions, including ulcerative colitis and Crohn’s disease; pulmonary disorders, including bronchiectasis, cystic fibrosis, chronic bronchitis, and pneumonitis; endocrine diseases, including Graves’ disease and Hashimoto's thyroiditis).

·         KIT (tumor): gastrointestinal stromal tumor & mucosal melanoma.

·         Used to help in diagnosing and determining treatment.         

        

·         KRAS mutation analysis (tumor): colorectal cancer & non – small cell lung cancer.

·         Used to determine whether treatment with a particular type of targeted therapy is appropriate.

·         Lactate dehydrogenase (LDH) (blood): germ cell tumors (dysgerminoma) (not always it increases).

·         Used to assess stage, prognosis, and response to treatment (for further details about LDH see the specific description above that refers to LDH).

·         Nuclear matrix protein 22 (urine): bladder cancer.

·         Used to monitor response to treatment.  

·         Prostate-specific antigen (PSA) (blood): prostate cancer.

·         Used to help in diagnosis; assess response to treatment & look for recurrence.

·         Clinical practice guidelines for prostate cancer screening vary and are controversial due to uncertainty as to whether the benefits of screening ultimately outweigh the risks of overdiagnosis and overtreatment. In the USA, the FDA (foods & drug administration) has approved the PSA test for the annual detection of prostate cancer in men of age 50 and older. The patient needs to be informed of the risks and benefits of PSA testing before performing the test.

·         PSA levels between 4 and 10 ng/mL are considered to be suspicious, and consideration should be given to confirming the abnormal PSA with a repeat test.

·         If indicated, a prostate biopsy is performed to obtain a tissue sample for histopathological analysis. While PSA testing may help 1,000 in 1 000 000 avoid death due to prostate cancer, 4,000 to 5,000 in 1 000 000 would die from prostate cancer after 10 years even with screening. This means that PSA screening may reduce mortality from prostate cancer by up to 25%.

·         Expected harms include anxiety for 100 – 120 receiving false positives, biopsy pain, and other complications from the biopsy for false-positive tests. Of those found to have prostate cancer, frequent overdiagnosis is common because most cases of prostate cancer are not expected to cause any symptoms.

·         Increased levels of PSA may suggest the presence of prostate cancer. However, prostate cancer can also be present in the complete absence of an elevated PSA level, in which case the test result would be a false negative. 

·         Obesity has been reported to reduce serum PSA levels and delayed early detection may partially explain worse outcomes in obese men with early prostate cancer.

·         PSA levels can also be increased in prostatitis, irritation, benign prostatic hyperplasia (BPH), and sex/ recent ejaculation (some recommend 2 days absence from sex before a PSA test) producing a false-positive result. Digital rectal examination (dre) may also increase PSA. However, the effect is clinically insignificant, since DRE causes the most substantial increases in patients with PSA levels already elevated over 4.0 ng/mL. PSA has been shown to interact with protein C inhibitor.

·         PSA velocity:  rising PSA rate may have value in prostate cancer prognosis. Men with prostate cancer whose PSA level increased by more than 2.0 ng per milliliter during the year before the diagnosis of prostate cancer have a higher risk of death from prostate cancer despite undergoing radical prostatectomy.

·         Free PSA: Most PSA in the blood is bound to serum proteins. A small amount is not protein-bound and is called 'free PSA.'

·         In men with prostate cancer, the ratio of free (unbound) PSA to total PSA is decreased. The risk of cancer increases if the free to total ratio is less than 25%. The lower the ratio is, the higher the probability of prostate cancer. Measuring the rate of free to total PSA appears to be particularly promising for eliminating unnecessary biopsies in men with PSA levels between 4 and 10 ng/mL. Both total and free PSA increase immediately after ejaculation and return slowly to baseline levels within 24 hours.

·         Inactive PSA:  proteolytically active PSA has been shown to have an anti-angiogenic effect, and specific inactive subforms may be associated with prostate cancer. The presence of inactive proenzyme forms of PSA is another potential indicator of disease.  

·         PSA in other biologic fluids & tissues:  PSA is not specific to the prostate. Although present in large amounts in prostatic tissue and semen, it has been detected in other body fluids and tissues. In women, PSA is found in female ejaculate at concentrations roughly equal to that found in male semen. PSA is also detected in breast milk and amniotic fluid. Low levels of PSA have been identified in the urethral glands, endometrium, normal breast tissue, and salivary gland tissue. PSA also is found in the serum of women with breast, lung, or uterine cancer and in some patients with renal cancer.

·         Tissue samples can be stained for the presence of PSA to determine the origin of malignant cells that have metastasized.

·         Thyroglobulin (Tg) (tumor): follicular or papillary thyroid cancer.

·         Used to evaluate response to treatment and look for recurrence.

·         May be also increased if anti-thyroglobulin antibodies are present.

·         Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor (PAI – 1) (tumor): breast cancer.

·         Used to determine the aggressiveness of cancer and guide treatment.

·         5 – Protein signature (Ova1) (blood): ovarian cancer.

·         Used preoperatively to assess pelvic mass for suspected ovarian cancer.

·         21 – Gene signature (Oncotype DX) (tumor): breast cancer.

·         Used to evaluate the risk of recurrence.

·         70 – Gene – signature (Mammaprint) (tumor): breast cancer.

·         Used to evaluate the risk of recurrence.

·         Squamous cell carcinoma (SCC) antigen: is a marker for squamous cell cancers, which can occur in the cervix, head and neck, lung, and skin.

·         Levels of SCC can be used as an aid to stage the carcinoma and determine the response to treatment.

·         Cancer antigen 72 – 4 (CA 72 – 4): although it is slightly elevated with most carcinomas, it is mostly associated with gastric carcinoma (stomach cancer).

·         CA 74 – 2 is finding a role in the management of patients with gastric carcinoma.

·         Bence – Jones protein (urine): patients with plasmacytomas, such as patients with multiple myeloma, overproduce monoclonal immunoglobulins, called M proteins. The Bence – Jones protein refers to the immunoglobulin light chain.

·         The Bence – Jones protein is secreted into the urine where it can be measured.

·         Neuron-specific enolase (NSE): is a protein found mainly in many neurons and neuroendocrine cells. It is elevated in tumors derived from these tissues, including neuroblastoma and small cell lung cancer. 

·         It can give information about the extent of the disease, the patient's prognosis, and the patient's response to treatment. 

·         NSE can also be elevated in medullary thyroid cancers, carcinoid tumors, pancreatic endocrine tumors, and melanoma.

·         KRAS mutation: KRAS is a gene that is changed, or mutated, in 30% to 40% of colon tumors. ASCO recommends that people who have colon cancer that has spread outside the colon to other areas of the body should have a test to find out if the tumor has mutations in the KRAS gene.

·         The test helps predict which patients may benefit from specific drugs.

·         Microphthalmia transcription factor (Mitf): is essential in melanocyte development and melanoma growth. It has been investigated regarding its expression as a marker for circulating melanoma cells in the blood and to determine the correlation between disease stage and survival in melanoma patients.

·         It can detect subclinical metastatic disease and predict treatment outcomes in melanoma patients.

·         Circulating nucleic acids: may be biomarkers that could be used in the early detection of cancer. They could also be used to follow the progression of patients with cancer. Methylated DNA is one such nucleic acid-based marker. DNA is a very stable molecule and can be detected using simple polymerase chain reaction (PCR) – based approaches.

·         Bladder Tumor Antigen (BTA) (urine test): a biomarker of bladder cancer, 

cancer of kidney or ureters. It may also be elevated on invasive procedures or infection of the bladder or urinary tract.

·         NMP22  (urine): elevated on bladder cancer.

·         May also be raised on BPH (benign prostatic hypertrophy), and prostatitis.

·         5 – hydroxy – indole acetic acid (5 - HIAA) (24-hour urine collection): elevated on lymphoma, melanoma, acute leukemia, seminoma (germ cell tumors). 

·         May also be raised on hepatitis, myocardial infarction (heart attack), stroke, anemia (pernicious anemia & thalassemia), muscular dystrophy, certain medications (narcotics, aspirin, anesthetics, alcohol), and muscle injury.

·         Prostatic Acid Phosphatase (PAP): elevated on metastatic prostate cancer, multiple myeloma, lung cancer, and osteogenic sarcoma.

·         May also be elevated on prostatitis, Gaucher’s disease, osteoporosis, liver cirrhosis, hyperparathyroidism, and prostate hypertrophy.

·         Urine Catecholamines: VMA (Vanillylmandelic Acid) (24-hour collection of urine; VMA is a catecholamine metabolite): elevated on neuroblastoma, pheochromocytoma, ganglioneuroma, rhabdomyosarcoma, and PNET.

·         May be also be raised because of dietary intake (bananas, vanilla, tea, coffee, ice cream, chocolate), and medications (tetracyclines, methyldopa, MAO inhibitors).

·         Homovanillic Acid (HVA) (24-hour urine collection): it is a catecholamine metabolite, and it is elevated on neuroblastoma.

·         May also be elevated because of dietary intake (bananas, vanilla, tea, coffee, ice cream, chocolate), psychosis, major depression, and some medications (including tetracyclines, methyldopa, MAO inhibitors, and dopamine).

·         B – cell immunoglobulin gene rearrangement (bone marrow, tissue, body fluid, blood): elevated on B – cell lymphoma.

·         Des-gamma carboxyprothrombin (DCP) (blood): elevated in hepatocellular cancer (HCC).

·         Gastrin (blood): elevated on G – cell hyperplasia; and gastrinoma (gastrin-producing tumor).

·         JAK2 mutation (JAK2 V617F test) (blood, bone marrow): the JAK2 V617F test may be ordered along with other tests when a health care provider suspects that a person has a blood disorder known as a myeloproliferative neoplasm (MPN),  especially polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis (PMF). Somatic JAK2 gene mutations are also associated with several related conditions.

·         The V617F mutation is occasionally found in people with leukemia or other bone marrow disorders. Budd-Chiari syndrome, which results from a blocked hepatic vein in the liver, can also be associated with the V617F mutation when it is caused by an underlying bone marrow disorder. It is unknown how one particular mutation can be associated with several conditions.

·         Note: the JAK2 exon 12 test may be ordered when the JAK2 V617F test is negative, and the doctor still suspects polycythemia vera (PV).

·         Soluble mesothelin-related peptides (SMRP) (blood): elevated on mesothelioma (a rare type of cancer, usually in the pleura, associated with asbestos exposure).

·         T – cell receptor gene rearrangement (bone marrow, tissue, body fluid, blood): elevated on T – cell lymphoma. 

·         21 – gene signature & 70 – gene signature (tissue): breast.

·         For a detailed catalog see also:

·         https://en.wikipedia.org/wiki/Tumor_marker

·         https://en.wikipedia.org/wiki/Tumor_antigen

·         Multiple tumor marker tests:

·         Colorectal: M2-PK, if M2-PK is not available, so 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 their ratio

·         Testicle: AFP, beta-HCG

·         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)

·         Bladder: CEA, Cyfra 21-1, TPA.

·         Can tumor markers be used in cancer screening?: for a screening test, to be useful, it should have a very high sensitivity (ability to correctly identify people who have the disease) and specificity (ability to correctly identify people who do not have the disease). If a test is highly sensitive, it will detect most people with the disease, i.e., it will result in very few false–negative results. If a test is highly specific, only a small number of people who do not have the disease will test positive for it, i.e., it will result in very few false-positive results.

·         Although tumor markers are extremely useful in determining whether a tumor is responding to treatment or assessing whether it has recurred, no tumor marker identified to date is sufficiently sensitive or specific to be used on its own to screen for cancer. For example, the prostate-specific antigen (PSA) test, which measures the level of PSA in the blood, is often used to screen men for prostate cancer. However, an increased PSA level can be caused by benign prostate conditions (such as benign prostate hyperplasia (BPH)), as well as prostate cancer, and most men with an elevated PSA level do not have prostate cancer. While tumor marker tests can provide beneficial information, they do have limitations:

·         a) Many tumor markers may also be elevated in persons with diseases other than cancer.

·         b) Some tumor markers are specific for a particular type of cancer, while others are seen in several different types of cancer.

·         c) Not every person with a specific type of cancer will have an elevated level of the corresponding tumor marker.

·         d) Not every cancer has a tumor marker that has been identified as associated with it.

·         Consequently, tumor markers alone are not diagnostic for cancer; however for some types of cancer, they provide additional information that can be considered in conjunction with a patient's medical history and physical exam as well as other laboratory and/or imaging tests.