Tumor Markers Media Lab

What does the presence of an estrogen receptor (ER) in the tissue sampling of a breast cancer biopsy indicate? Hormonal therapy would be completely ineffective in treating this patient A higher degree of treatment success using hormonal therapy Corresponds to the successful eradication of the breast cancer tumors Presence of a benign condition of the breast or endometrium

A higher degree of treatment success using hormonal therapy Breast cancers in which estrogen receptors (ER) or progesterone receptors (PR) are present are indicated for hormonal therapies. Those tumors that are negative for ER or PR are better suited for chemotherapy, as they lack the steroid receptors for effective hormonal therapy.

Alpha Fetoprotein (AFP)

AFP is normally produced by the yolk sac and the liver during fetal development.2 AFP is the most prevalent protein found in the blood of the human fetus and is believed to play a role similar to serum albumin, which is to transport protein of hormones and micronutrients. Normally, AFP decreases steadily during the first year or life. During pregnancy, AFP levels will rise in the blood, urine, and amniotic fluid of mothers in response to fetal development. Very high levels of AFP during pregnancy are associated with fetal malformations.2 As a tumor marker, AFP analysis is used in the post-treatment phase of previously diagnosed cancers, as well as in early surveillance of cancer survivors, where the rate of decrease of AFP has diagnostic and prognostic value. Malignant conditions associated with elevated levels of AFP in the blood include: Hepatocellular carcinoma (a liver biopsy of a hepatocellular carcinoma is shown in the image) Germ cell and yolk sac tumors Metastatic carcinomas of the liver

Cancer Prevalence and Relative Risk

According to the American Cancer Society: Lifetime risk of developing cancer varies by gender Males - 1 in 2 lifetime risk of developing cancer Females - 1 in 3 lifetime risk of developing cancer -Cancer is the second leading cause of death behind heart disease in the United States -Approximately 1 in 4 deaths is attributed to cancer -Prevention and early detection are the keys to long-term survival

The clinical utility of prostate-specific antigen (PSA) as a tumor marker includes which of the following? Detection of the recurrence of prostate cancer Staging of prostate cancer Monitoring the effectiveness of treatment of prostate cancer All of the above are clinical indications of the utility of PSA as a tumor marker

All of the above are clinical indications of the utility of PSA as a tumor marker The clinical applications of PSA as an effective tumor marker for prostate cancer include: Early detection Staging Therapeutic/treatment monitoring Identifying recurrence of prostate cancer

Which of the following statements regarding the ideal tumor marker is TRUE? An ideal tumor marker is expressed only in representative tissue samples and not in blood samples. An ideal tumor marker is 100% sensitive, even if its specificity is known to be low. An ideal tumor marker is 100% specific, even if it lacks the sensitivity required to detect cancer in all suspected cases. An ideal tumor marker has utility as an indicator of successful therapy.

An ideal tumor marker has utility as an indicator of successful therapy. Ideally, a tumor marker would have 100% sensitivity, 100% specificity, be detectable in the blood or biological fluids, have a concentration that correlates with tumor mass, and has utility in assessing therapeutic interventions and cancer recurrence.

Cancer Prevalence - New Cancer Cases by Site

Aside from skin cancers, the most commonly diagnosed cancer among men in the United States (US) is prostate cancer. Among US women, breast cancer remains the most commonly diagnosed form of cancer. Tumor markers have been characterized for both prostate cancer and breast cancer.

Breast Cancer Susceptibility Proteins

Breast cancer type 1 (BRCA1) and breast cancer type 2 (BRCA2) susceptibility proteins are normally expressed in breast tissue, where they help repair damaged DNA or destroy cells if the damaged DNA cannot be repaired. Those with genetic defects or mutations of the BRCA1 or BRCA2 genes are predisposed to developing breast or ovarian cancer. Studies have shown that carriers of the BRCA1 gene have as high as an 85% risk of developing breast cancer and a 45% risk of developing ovarian cancer by age 85.2 BRCA determination is typically performed on blood or saliva samples, which contain the DNA necessary to perform the genetic analysis. Detection of positive mutations creates dilemmas for patients, as decisions must be made about the course for prevention. In some cases, especially where family history prevails, preventive mastectomy or oophorectomy are performed to reduce the risk of developing cancers in the target organs or tissues. While not a TRUE tumor marker in the sense that BRCA is NOT detecting the growth of a malignant tumor, it has been included here since it has been used as a screening tool to assess those at risk for developing specific cancers.

CA 125

CA 125 falls short of being an ideal tumor marker in that it lacks the specificity required to be used as an effective screening tool. CA 125 is a mucin tumor marker that is produced primarily by ovarian and endothelial cells. Because CA 125 is sometimes produced by non-cancerous endothelial cells of the uterine endothelium, it is not recommended as a screening test for ovarian cancer in non-symptomatic women. CA 125 is also produced by some non-ovarian carcinomas of the pancreas, lung, breast, and colon. CA 125 is produced with an incidence of over 90% in cases of advanced ovarian cancer, and thus has been used to assist in the diagnosis of ovarian cancer in symptomatic women.6 Persistently elevated levels of CA 125 after chemotherapy are indicative of a poor prognosis. CA 125 is also used to monitor the effectiveness of ovarian cancer treatments, to assess the prognosis of a patient, and to determine recurrence or relapse from a state of remission.7

CA 15-3

CA 15-3 is a mucin tumor marker that is found in certain breast carcinomas. CA 15-3 is produced by healthy tissues of the liver and breast, but to lesser degrees than typically associated with malignancies. At a cut off level of 25 kU/L, CA 15-3 has been found to be elevated in 92% of breast carcinomas.2 CA 15-3 is also elevated in other malignancies, including the colon, ovaries, and liver. CA 15-3 is not recommended as a primary diagnostic tool for primary breast cancer, because the frequency of elevation is low and the specificity falls short of being ideal. CA 15-3 is useful in monitoring the effectiveness of therapy. CA 15-3 has been used effectively in monitoring disease progression in metastatic breast cancer.8

Which of these tetrasaccharide-rich tumor markers is derived from a blood group antigen? CEA CA 27.29 CA 19-9 CA 125

CA 19-9 Carbohydrate antigen (CA) 19-9 is derived from a blood group antigen and has utility as a tumor marker for colorectal and pancreatic carcinoma.

CA 27.29

CA 27.29 is a mucin antigen that is a marker for breast carcinoma. CA 27.29 is similar to CA 15-3 in sensitivity and specificity, and thus is not effective as a screening tool for early tumor growth. The CA 27.29 marker appears more readily in the ascitic fluid of patients with metastatic breast cancer. CA 27.29 is used to detect recurrence or metastasis of breast cancer following successful eradication of a tumor.10

CA 549

CA 549 is a mucin antigen that also serves as a marker for breast and ovarian carcinoma. CA 549 lacks the sensitivity and specificity to serve as an effective screening tool. CA 549 is also elevated in some pregnancies, in benign breast disease, and in liver disease. Some ovarian, lung, and even prostate cancers may elevate CA 549 levels. Similar to CA 15-3, CA 549 has limited utility in detecting early breast carcinoma, due to the low prevalence of individuals with elevated CA 549 during the early stages of breast cancer.9 CA 549 has strong utility as an indicator of recurrence of breast cancer after previous successful treatment to reduce tumor growth. An increasing level of CA 549 after previous successful attempts to decrease or stabilize tumor growth parallels the redevelopment or increasing growth of a breast carcinoma.9

The recurrence of which tumor marker may indicate a negative prognosis in an individual thought to be in remission with colon cancer? CA 125 CA 27.29 CA 549 CEA

CEA Carcinoembryonic antigen (CEA) is an oncofetal antigen marker that is stable during remission of gastrointestinal carcinomas. Rising CEA values may indicate the recurrence of disease or metastatic colon cancer.

Carcinoembryonic Antigen (CEA)

CEA is normally produced in the developing gastrointestinal tract of the human fetus. Production stops shortly after birth and is normally found in very low concentrations in the blood of adults. Serum levels of CEA may be elevated in heavy smokers. As a tumor marker, CEA is associated with colon cancer, in which CEA measurement is mainly used to monitor colorectal carcinoma treatment, identify recurrences after surgical resection, and for staging to determine the degree of metastasis.2 CEA may also be elevated in malignancies of other tissues, including the stomach, pancreas, breast, lung, and thyroid. Because of this relatively low specificity for a tissue or organ system, it is not recommended for use as a screening tool.

Cancer

Cancer is a group of diseases in which the uncontrolled growth and spread of abnormal cells occurs in the body. Cancerous cells are also called malignant cells. In addition to the uncontrolled overgrowth of abnormal tissues, cancerous cells may also produce a variety of both functional and abnormal products, any of which may be candidates as tumor markers.

CA 19-9

Carbohydrate antigen (CA) 19-9 is a tetrasaccharide-rich marker that is a modification of a Lewis(a) blood group antigen. CA 19-9 has been detected at increased concentrations in the blood of patients with colon cancer and pancreatic cancer. CA 19-9 is also known to be elevated in esophageal cancer and hepatocellular carcinoma. Many non-malignant conditions are known to elevate CA 19-9 in the blood, including cirrhosis, pancreatitis, and diseases of the bile duct. Because CA 19-9 is not tissue-specific and may also be elevated in non-malignant states, its utility is not as a cancer screening tool in asymptomatic individuals, but rather as a management tool in pancreatic cancers. When treating individuals who have been diagnosed with a pancreatic tumor, a baseline level of CA 19-9 may be determined. Following treatment, follow-up testing regimens are used to assess the success of the treatment, as levels of CA 19-9 should decrease in response to the treatment.11 Likewise, subsequent increases or recurrence of elevated levels of CA 19-9 in the blood following a period of remission would be a likely indication of tumor regrowth or metastasis.

Carbohydrate Tumor Markers

Carbohydrate-rich tumor markers are specific antigens found either on the surface of tumor cells or may also be secreted as products by the tumor cells. The carbohydrate tumor markers are further classified as high-molecular weight mucins and blood group antigen-related markers. Monoclonal antibodies produced against carbohydrate-rich antigens are generally more specific and less prone to cross-reactivity than antibodies developed against hormones and enzymes. In current nomenclature, the carbohydrate antigens are abbreviated "CA" and are also referred to more generally as "cancer antigens," followed by their number of discovery, such as 125, 549, and so on.

Primary and Ectopic Hormones

Certain tumor cells produce hormones, and when the hormone product is functional, may lead to a variety of endocrine disorders. The hormone-producing cells often produce excessive amounts of product, not only due to the rapidly dividing cells but also due to the lack of negative feedback mechanisms that normally exist to limit hormonal production. -The hormone source is considered primary if the endocrine tissue that normally produces the hormone, produces a hormone in excess. -When a hormone is produced at a distant site by non-endocrine tissue, the production is considered ectopic.

Components

Components produced by cancer cells include hormones, specific proteins, enzymes, carbohydrates, mucins, blood group antigens, target receptors, and oncofetal antigens. Each of these product categories will be explored in greater detail to provide an overview of the utility of several of the tumor markers within each category.

Early Detection is Crucial

Despite increased awareness of cancer's causes and predisposition, preventive measures and risk reduction are not 100% effective at avoiding cancer. The key to success in treating cancer is early detection. Unfortunately, cancer symptoms may be evasive, are often non-specific, and may be dismissed or attributed to other common ailments, aging, diet, and lifestyle. Such vague symptoms may include fatigue, loss of appetite, weight loss, transient pain, and change in bowel regularity. Tumors may grow undetected and may not cause detectable symptoms for many years in some individuals. Aggressive tumors may even begin to metastasize before the cancer is detected. When the body fails to alert individuals of a looming problem, the need for a reliable and sensitive tumor marker becomes evident.

Prostate-Specific Antigen (PSA): Controversy

Despite the decreased mortality of prostate cancer since the advent of PSA as a screening tool, a high degree of scrutiny has arisen over the number of unnecessary biopsies and subsequent testing related to false positive PSA tests.3-4 Some of this controversy relates directly to the fact that PSA also is found to be elevated in common, non-malignant conditions of the prostate, including prostatitis and benign prostatic hypertrophy (BPH). Others have argued that not all prostate cancers are associated with a high degree of mortality and that if well-contained within the prostate, are not a cause for surgical intervention to remove the tumor or perform a prostatectomy.5-6 Despite its shortcomings, PSA remains one of the most ordered cancer screening tests

Prostate-Specific Antigen (PSA): Clinical Applications in Early Detection of Prostate Cancer

Despite the high degree of specificity for prostatic tissue, PSA testing by itself is not highly effective as a screening tool for prostate cancer. PSA is also elevated in benign prostatic hyperplasia, which occurs with high frequency in men over the age of 50. PSA is used in conjunction with a digital rectal examination and followed by a transrectal ultrasound to provide a more sensitive and accurate diagnosis.3 The PSA cut-off value of 4.0 µg/L is widely used as a medical decision point to consider further diagnostic testing. The clinical sensitivity of PSA at a value of 4.0 µg/L is approximately 78%. Decreasing the cut-off level to 2.8 µg/L increases the sensitivity to approximately 92%, although this decreases the specificity to only 23%.4 To improve the diagnostic ability of PSA to detect early prostate cancer, one may use chronological measurements to determine the rate of change, also referred to as PSA velocity. A PSA velocity of >0.75 µg/L/year is more strongly associated with prostate cancer than benign conditions.

The Oncofetal Antigens

During fetal development, certain proteins are produced by the developing embryonic tissues that support the function, growth, and development of the organism. These proteins are later replaced by the proteins that play specific structural or transport roles throughout the adult life of the organism or individual. Occasionally, tumor cells develop that begin to produce these proteins that are associated with fetal development, referred to as oncofetal antigens. The most widely studied oncofetal antigens are: Alpha fetoprotein (AFP) Carcinoembryonic antigen (CEA)

In regards to hormone production, what is the term that is associated with the production of a hormone at a distant site by non-endocrine tissue? Primary Secondary Ectopic

Ectopic When a hormone is produced at a distant site by non-endocrine tissue, the production is considered ectopic. The hormone source is considered primary if the endocrine tissue that normally produces the hormone produces hormone in excess

Hormones as Tumor Markers-Human chorionic gonadotropin (hCG)

Embryonal, placenta, testicular, choriocarcinoma Normally elevated during pregnancy. hCG is produced and is highly elevated in trophoblastic or chorionic tumors of embryonic cell origin.

Estrogen and Progesterone Receptors

Estrogen receptors (ER) and progesterone receptors (PR) are normally found in the tissues where their respective target hormones play a regulatory role, such as the uterus, pituitary gland, hypothalamus, and breast. Upon hormone binding, the respective receptors form a large protein complex that activates transcription. As these receptors are tissue-based, the determination of their presence or absence requires a representative tissue sampling. Both ER and PR are used in breast cancer as indicators for hormonal therapy. Those positive for ER and PR will typically respond to hormonal treatment, while those with negative receptors will require other treatment modalities, such as chemotherapy.2 Patients with positive ER and PR typically are associated with a better prognosis and higher survival rate.

Cancer Predispositions

Exposure to toxins and chemicals, or carcinogens Cigarette smoke and tobacco products Industrial pollutants and pesticides Heavy alcohol consumption Exposure to infectious agents Hepatitis B virus (HBV) and hepatitis C virus (HCV) Human papilloma virus (HPV) Human immunodeficiency virus (HIV) Helicobacter pylori Exposure to harmful ultraviolet rays Prolonged sunlight exposure Tanning beds Obesity Lack of physical exercise Poor nutrition

The detection of an immunoglobulin clone, such as IgM, is ALWAYS associated with a malignant condition, such as a multiple myeloma. T/F

False While detection of monoclonal paraproteins is highly associated with a malignant plasma cell tumor, the appearance on non-malignant monoclonal bands increases with age, and may approach a prevalence of 5% in those over age 75. Non-malignant monoclonal bands are typically lower in concentration than in malignant cases

Hormones as Tumor Markers-Gastrin

Gastrinoma Fasting plasma gastrin is often greatly increased to several times the upper limit of normal. Considered diagnostic as a tumor marker when elevated 10 times the upper limit of normal in the presence of gastric hypersecretion.

Hormones as Tumor Markers-Glucagon

Glucagonoma (islet-cell pancreatic tumor Highly metastatic. Sustained elevated glucose levels as glucagon produced is not under control of feedback mechanisms.

Human Epidermal Growth Factor Receptor 2 (HER2/neu)

HER2/neu is found amplified in breast, ovarian, and tumors of the gastrointestinal tract. Increased amplification of the HER2/neu oncogene correlates with decreased response to hormonal and monoclonal antibody therapy in breast cancer. HER2/neu has strong prognostic value in breast cancer, and correlates with increased tumor size, positivity in adjacent lymph nodes, and higher grading scores with likelihood of metastases. HER2/neu analysis may be performed on suspicious or representative tissue samples using immunohistochemical (IHC) techniques. HER2/neu is also released into the blood, and as such, may be identified and quantified in plasma samples using commercially available immunoassay methods.2

The Ideal Tumor Marker Would Have 100% Sensitivity

Ideally, a tumor marker would be detectable as soon as cancerous cells begin to divide and would be detected in every case where the cancer exists. As such, the ideal tumor marker would have applications as a screening tool where elevations at early stages of cancer growth would most likely be localized and more likely to be curable.

The Ideal Tumor Marker Would be Detectable in Blood or Biological Fluids

Ideally, a tumor marker would be detectable in the blood or other biological fluid, either as a primary substance or as a well-defined, stable metabolite. Most clinical laboratory methods are designed to use samples collected using minimally invasive or non-invasive techniques, namely whole blood, serum, plasma, and urine. Analyte-specific assays of other biological fluids, such as stool, saliva, breast milk, and semen, have also been developed to help identify the expression of products produced by cancerous cells. The benefits of sampling such fluids over performing biopsies of suspicious tissues generally include: Reduced risk of procedural complications, including infections and injuries Reduced cost of clinical laboratory analytical procedures Robust ability to identify and quantitate a disseminated marker in the blood and body fluids over the need to pinpoint the tissue sampling of a suspicious tissue site

The Ideal Tumor Marker Would Have 100% Specificity

Ideally, a tumor marker would be detectable only in the presence of cancerous growth and would not be produced by non-cancerous cells, other healthy tissues, or non-cancerous diseases of related or unrelated tissues. As such, the false-positive incident rate would be zero.

Reference Values

Ideally, reference values could be established for a tumor marker to differentiate healthy individuals from those known to have cancer. Establishing reference intervals for tumor markers becomes essential if the tumor marker is produced by healthy tissues, or if the marker is produced in small quantities during infections, inflammation, or other benign pathologic conditions. The clinical sensitivity and specificity of a tumor marker's ability to identify cancers are highly dependent upon establishing the reference intervals. Based on the type of cancer, reference intervals or reference limits may also need to be established for tumor markers based on age and gender.

The Ideal Tumor Marker Would be Adaptable to Laboratory Analysis

Ideally, the substance produced by the cancer cells would contain identical antigenic markers in every individual where active cells are found. The purified substance would be isolated and well-characterized to permit the development of analytical methods, such as those employing immunoassay principles in which antibodies may be developed specific to epitopes or defined areas of the antigenic markers. Alternately, if purified forms of the tumor marker are amply stable to permit the preparation of calibration standards to facilitate accurate quantitation, chromatographic methods may be developed for the identification and measurement of the tumor marker in biological specimens.

The Ideal Tumor Marker Would Be Indicative of Tumor Mass

Ideally, tumor marker concentration would correlate to the mass of the tumor, where an increased measured level would correspond directly to the tumor's size or the extent of its metastasis. Along these lines, a decrease in tumor marker concentration would be able to predict tumor shrinkage. Such predictable correlations between tumor mass and expressed tumor marker concentration may be linear or exponential, as illustrated in these charts.

Specific Proteins as Tumor Markers - Monoclonal Immunoglobulins

In this agarose gel electrophoresis, the lane indicated by the arrow represents a monoclonal immunoglobulin. Monoclonal paraproteins appear as sharp bands in the globulin area of the serum electrophoresis patterns. In this particular case, the patient was subsequently diagnosed with an immunoglobulin G (IgG) multiple myeloma. A multiple myeloma is a malignant neoplasm of a single clone of plasma cells of the bone marrow. The most common monoclonal immunoglobulin in multiple myelomas is an IgG paraprotein.

Hormones as Tumor Markers-Insulin

Insulinoma Sustained increased insulin levels even in fasting state. Insulin-producing tumors are typically non-malignant.

Hormones as Tumor Markers-Parathyroid hormone (PTH)

Liver, renal, breast, lung Ectopic PTH-producing adenomas are rare, but produce PTH in excess which leads to hypercalcemia.

Hormones as Tumor Markers-Adrenocorticotropic hormone (ACTH)

Lung (small cell) ACTH normally produced by the corticotropic cells of the anterior pituitary. May be accompanied with excessive production of cortisol usually associated with Cushing's syndrome.

Hormones as Tumor Markers-Antidiuretic hormone (ADH)

Lung (small cell), adrenal cortex, pancreatic, intestine ADH helps to regulate water balance in the blood. Normally ADH is elevated in response to high blood osmolality. Measuring ADH in reference to plasma osmolality increases its sensitivity as a tumor marker.

The Mucin-Rich Carbohydrate Tumor Markers

Mucins are high molecular weight glycoproteins that are produced by specialized epithelial cells and serve as protectants and lubricants of the epithelial surface. The most common mucin tumor markers are: CA 125 CA 15-3 CA 549 CA 27.29

Following a radical prostatectomy (the removal of the prostate in men with prostate cancer), what should the patient's PSA level be? High, but within the normal range, as the cancer-producing cells have been removed. Low, but within the normal range, as PSA is produced by other healthy tissues. Persistently high, out of the normal range, if the surgery was successful. Non-detectable, since only the prostate gland produces PSA.

Non-detectable, since only the prostate gland produces PSA. Since only the prostate gland produces PSA, the complete removal of the prostate should result in the absence of PSA or the inability to detect PSA using immunoassay methods. Any PSA that remains in the blood circulation is likely indicative of a metastatic condition, where a prostatic carcinoma in a remote location (such as the bone marrow or liver) is producing PSA, indicating a poor prognosis.

Which of these tumor markers is recommended as a cancer screening test in non-symptomatic individuals? CA 15-3 CA 125 CA 19-9 None of these markers are recommended as screening tests for cancer in asymptomatic individuals.

None of these markers are recommended as screening tests for cancer in asymptomatic individuals. While each of these tumor markers has utility in assessing success of treatment and the recurrence of cancer, all lack the required specificity required to be used as a cancer screening test in asymptomatic individuals.

Prostate-Specific Antigen (PSA): Clinical Applications

PSA has been widely and successfully used as a tumor marker for prostate cancer and has utility in: Early detection of prostate cancer Staging of prostate cancer Monitoring effectiveness of treatment Monitoring for recurrence Each of these applications will be briefly discussed to provide an example of how the same component may be used at several stages of the disease process to guide a physician from diagnosis through treatment monitoring.

Prostate-Specific Antigen (PSA): Biochemistry and Genetics

PSA is known to have an enzymatic function as a serine protease. It is produced exclusively by the epithelial cells of the acini and ducts of the prostate gland. It is released into the lumina of the prostatic duct (see image on the right), where it acts to liquefy the seminal coagulum. PSA is produced in adult males by normal, benign, hyperplastic, and malignant prostate tissue but not in any other human tissues. Following its production from the acini and ducts, a small amount of PSA is taken by the capillary-rich prostate into the blood circulation, where it remains in circulation with a half-life of 3.2 days.2 The entire 240 amino acid residue sequence of PSA has been confirmed, along with its three-dimensional structure.2 Because its structure is so well characterized, specific antibodies against several of its antigenic epitopes have been developed, which has led to several specific immunoassays to detect its presence and quantitate its concentration in biological samples.

Prostate-Specific Antigen (PSA): Clinical Applications in Monitoring Recurrence

Patients in remission of prostate cancer or following a radical prostatectomy continue to be monitored on a prescribed basis using PSA. As previously discussed, ANY detection of PSA in the blood of a patient who has had a radical prostatectomy is reason for concern and warrants a more thorough investigation as to the source of the PSA production. The increase of PSA level in a patient who has been previously successfully treated for prostate cancer is also a cause for concern, as it may indicate the resurgence or regrowth of a tumor, or may indicate that the benign tissues of the prostate are producing increased amounts of PSA due to infection, benign prostatic hyperplasia (BPH), or acute urinary retention due to an obstruction. A great deal of time has been dedicated in this exercise to examining the utility of PSA, as it is one of the most widely studied, well-characterized, and analytically standardized tumor marker. Despite these facts, PSA still falls short of being the ideal tumor marker.

Hormones as Tumor Markers-Prolactin

Pituitary, renal, lung Prolactinomas are common, but benign pituitary tumors. Ectopic prolactin-producing carcinomas are very rare.

Ectopic Production of Hormone from Lung Tumor

See Image

Specific Proteins as Tumor Markers

Several specific proteins have limited utility as tumor markers. These protein products of certain tumors include: Monoclonal immunoglobulins Bence Jones protein Beta-2-microglobulin C-peptide Ferritin Thyroglobulin The immunoglobulin fragments (typically the lambda and kappa light chains excreted in urine) are among the earliest of the tumor markers. They were characterized by Dr. Henry Bence Jones in 1847.2 Bence Jones proteins are often manifestations of multiple myeloma, where a plasma cell tumor produces increased quantities of a single clone of an immunoglobulin. The image on this page is a sheet of plasma cells from a case of multiple myeloma.

Tumor Marker Receptors

The expression of receptors on the surface of cells facilitates the binding and uptake of the compound of interest. The receptors to be discussed in greater detail include: Estrogen and progesterone receptors (ER/PR) Human epidermal growth factor receptor 2 (HER2/neu) The utility of these receptors and their clinical role as tumor markers will be explored further on the pages to follow.

Enzymes as Tumor Markers

The most commonly used tumor markers with enzymatic activity are: Prostate-specific antigen (PSA) Prostatic acid phosphatase (PAP) Alkaline phosphatase Neuron-specific enolase PAP was used for many decades as a screening tool for prostate cancer; however, elevated PAP is also associated with cancers of the bone and bone marrow and benign conditions of the prostate, bones, and parathyroid. Although it lacks specificity as a tumor marker, PAP does have utility in staging prostate cancer. Among these most common enzymatic tumor markers, only PSA is specific or sensitive enough to identify specific organ involvement related to cancer.

Blood Group Antigens as Tumor Markers

The most widely used and best-characterized blood group antigen-related tumor markers include: CA 19-9 CA 50 CA 72-4 CA 242 Each of the above tumor markers has been used with limited success in identifying tumor growth in cancers of the gastrointestinal tract and digestive system, namely colorectal and pancreatic carcinomas. Among these markers, CA 19-9 has been successfully developed into commercially available immunoassays.

Prostate-Specific Antigen (PSA): Background

The prostate gland is a frequent source of urinary and urogenital maladies in adult males, including infections (prostatitis), hypertrophy (increased size), and malignant tumors. The symptoms of each of these conditions are somewhat similar, which include pain, difficulty urinating, and/or emptying the bladder. A clinical laboratory assessment to help differentiate the diagnosis is often sought. Prostate cancer, as previously indicated, is the most prevalent form of cancer in adult males.1 When prostate cancer is organ-confined and detected early, it is highly curable. Thus, a reliable and well-characterized tumor marker would seem ideally suited to assist physicians in identifying those with an undetected malignancy, even prior to the onset of symptoms.

What causes the hormones produced by malignant endocrine tissues to be highly elevated in the blood circulation? The lack of normal enzymatic activity of the healthy endocrine tissues to help maintain control of the hormones being produced by the malignant tissues. The lack of functional hormone receptors in the healthy target tissues leading to a strong and uncontrolled positive feedback mechanism. The rapid and uncontrolled growth of malignant endocrine tissues paired with the lack of an effective negative feedback mechanism. The conversion of nonfunctional hormones to functional hormones by the hormone receptors in the malignant tissues.

The rapid and uncontrolled growth of malignant endocrine tissues paired with the lack of an effective negative feedback mechanism. Malignant endocrine tumors producing functional hormones are not only rapidly dividing, they often lack functional receptors for the products being produced by the target tissues or organs, which serves as a negative feedback mechanism designed to stop further hormone production. Thus, hormone levels in cases of malignant endocrine tumors are typically elevated to several times the upper reference limit and serve as tumor markers.

Prostate-Specific Antigen (PSA): Clinical Applications in Prostate Cancer Screening (continued)

The reason that PSA must be carefully interpreted in combination with clinical symptoms is that the subsequent testing to follow up on an elevated PSA is both costly, surgically invasive, and is often met with a high degree of anxiety. The procedure to biopsy the prostate gland to confirm or rule out a diagnosis of prostate cancer is not without its risks and complications, including injury to adjacent tissues of the bladder and urethra, and may leave moderate to long term effects of impotency

The current controversy surrounding the use of prostate-specific antigen (PSA) as a tumor marker is due to which of the following? The very high incidence of false-negative results The unnecessary, expensive, and risky follow-up testing of false-positive results The lack of positivity among confined tumors of the prostate The lack of its ability to detect metastatic prostate cancer

The unnecessary, expensive, and risky follow-up testing of false-positive results While PSA is highly specific for the prostate, it is produced by healthy prostate tissue, non-malignant prostate conditions, such as prostatitis and benign prostatic hypertrophy (BPH), as well as prostatic carcinoma. Further, PSA may be increased in small prostate tumors that are well-confined and may not necessarily present an increased risk of mortality, especially in older men.

Hormones as Tumor Markers-Calcitonin

Thyroid, lung, breast, renal, liver Normally secreted in response to increased serum calcium to inhibit release of calcium from bone.

Prostate-Specific Antigen (PSA): Clinical Applications of Monitoring Treatment

Treatment of prostate cancer includes: Radiation therapy Hormonal treatment (anti-androgen therapy) Radical prostatectomy Using PSA to evaluate the effectiveness of therapy is widely employed. A decrease in PSA level in response to treatment indicates a degree of success; less tumor mass results in a lower production of PSA. A radical prostatectomy is the complete removal of the prostate. Since PSA is found ONLY in prostatic tissue, the complete removal of the prostate should result in the absence of PSA in the blood. Any residual or detectable blood levels may be indicative of a metastasis of a tumor of prostatic tissue that is producing PSA, which has a poor prognosis.

Ideally, for a tumor marker to be considered as a screening tool, it should be consistently elevated at early stages of disease so that the diagnostic sensitivity is near 100%, and elevated only when the cancer of interest is present so that the diagnostic specificity is near 100%. T/F

True While most tumor markers fall short of providing both 100% sensitivity and specificity and thus are not recommended for routine screening, ideally these are the desired characteristics of a tumor marker

Providing Diagnostic and Prognostic Support

While the "ideal tumor marker" does not exist, many markers have been identified, characterized, and developed into analytical assays to aid in the detection and prognostication of cancers. The remainder of this exercise will provide a focus on several of these tumor markers.

Specific Proteins as Tumor Markers - Diagnostic Utility

While the detection of a monoclonal paraprotein is strongly associated with the presence of a malignant plasma cell tumor, the appearance of nonmalignant monoclonal immunoglobulins increases with age, with a prevalence as high as 5% in those over age 75. In nonmalignant cases, the immunoglobulin concentrations are typically lower than observed in malignant cases.2

Prostate-Specific Antigen (PSA): Clinical Applications in Prostate Cancer Staging

You may recall that one of the desired characteristics of an ideal tumor marker is to correlate with tumor mass and degree of metastasis. In this respect, PSA serves as an effective tool to help assess the stage of prostate cancer. Higher PSA levels strongly correlate with tumor mass and metastasis. PSA levels greater than 50 µg/L are highly indicative of an advanced stage of prostate cancer. Similarly, patients with PSA levels less than 20 µg/L seldom have bone metastases.2

Which statement would NOT fit the definition of a tumor marker? A substance that actively growing cells within a malignant tumor produce in abundant quantities. A substance that the surrounding healthy tissues produces in response to active tumor growth. A substance that would ordinarily be produced in healthy tissue, but is absent due to tumor overgrowth or suppression. A functional hormone that is produced in excess by a malignant tumor.

A substance that would ordinarily be produced in healthy tissue, but is absent due to tumor overgrowth or suppression. The statement describing "a substance that would ordinarily be produced in healthy tissue, but is absent due to tumor overgrowth or suppression" does NOT meet the definition of a tumor marker. A tumor marker is generally classified as the presence of a substance produced by an actively growing tumor, or by the host in response to the presence of a tumor. A tumor marker can be defined as a detectable or measurable substance, or biomarker, produced by the cells of a tumor or by the host in response to the tumor, that provides utility in differentiating the tumor from normally dividing tissue. Some products produced by tumors may include functional compounds, such as hormones (see pg. 2, Tumor Marker, pg. 5, Cancer Predispositions, and pg. 6, Early Detection is Crucial). The following statements MEET the definition of a tumor marker: A substance that actively growing cells within a malignant tumor produce in abundant quantities. A substance that the surrounding healthy tissues produce in response to active tumor growth. A functional hormone that is produced in excess by a malignant tumor.

Tumor Marker

A tumor marker (biomarker) is a detectable or measurable substance produced by the cells of a tumor or by the host in response to the tumor. It can be used to differentiate the tumor from normally dividing tissue. Such measurable substances may be found in blood, urine, other body fluids, tissue samplings, or cellular cultures.