PROSTATIC ACID PHOSPHATASE

Clinical significance:

PAP is  a member of the group of acid phosphatases (an enzyme found primarily in men in the prostate gland and semen ) to determine the health of the prostate gland. Prostate dysfunction results in the release of PAP into the blood. High concentrations are found in the prostate gland. Significant amounts are also found in platelets, bone, spleen, kidney and liver. PAP is a major constituent in seminal fluid and is also secreted in urine. PAP is normally presents in the serum at low levels. The alternative tests are as follows: Prostatic acid phosphatase test; Serum acid phosphatase; Male PAP test.
The acid phosphatases are a diverse group of isoenzymes which are classified on the basis of their increasing electrophoretic mobility. These isoenzymes are capable of hydrolyzing phosphate esters in an acidic media. The major PAP fraction is isoenzyme 2, glycoproteins synthesized by the prostate gland with a molecular mass of approximately 1000,000 daltons. This test is most often performed to determine  prostate cancer, and for the prognosis of treatment. This test is no longer used routinely. The availability of the more sensitive and specific PSA assay has largely replaced the PAP test's clinical use.

what abnormal results mean

Abnormal PAP values can be obtained for many reasons. The most common reasons for abnormal PAP values include, but are not limited to:

• Prostate cancer
• Prostate cancer that has spread outside the prostate (particularly to bone
• Decreased blood flow to prostate
• Paget's disease (bones become thicker and softer)
• Anemia
• Infection (usually severe)
• Thrombophlebitis
• Goucher's disease 
• Hyperparathyroidism
• Heart attack 
• Kidney disease 
• Physical stimulation of the prostate (colonoscopy, enemas, prostate examination)
• Multiple myeloma 
• Prostatitis

CARCINOEMBRYONIC ANTIGEN

CLINICAL SIGNIFICANCE:

Carcinoembryonic antigen (CEA) is a protein found in many types of cells but associated with tumors and the developing fetus . CEA is a protein that normally occurs in fetal gut tissue. After birth, detectable serum levels essentially disappear. However, CEA may increase in the presence of various disorders such as colon cancer. This test may also be used to determine the responsiveness of cancer patients to treatment  (to determine if cancer is spreading or going into remission). The CEA was one of the first oncofetal antigens to be described and exploited clinically. It is a complex glycoprotein of molecular weight 20,000, that is associated with the plasma membrane of tumor cells, from which it may be released into the blood .

Although CEA was first identified in colon cancer,  and abnormal CEA blood level is specific neither for  colon cancer nor for malignancy in general. Elevated CEA levels are found in a variety of cancers other than colonic, including pancreatic, gastric, lung, and breast. It is also detected in benign conditions including cirrhosis, inflamatory bowel disease, chronic lung disease, and pancreatitis. The CEA was found to be elevated in up to 90 per cent of smokers and in 3 per cent of a healthy control population. Thus, the test for CEA cannot substitute for a pathological diagnosis.

Since cancer prevalence in a healthy population is low, an elevated CEA has an unacceptably low positive predictive value, with excess false positives. Also, since elevated CEA occurs in the advanced stage of incurable cancer but is low in the early, curable disease, the likelihood of a positive result affecting a patient's survival is diminished. The CEA has been sugested as having prognostic value for patients with colon cancer. Preoperative CEA values have been positively correlated with stage and negatively correlated with disease free survival.

Although not satisfactory for screening  a healthy population, CEA has been used to monitor recurrence. Early data suggested that CEA predicted clinical relapse by several months. Subsequently, several investigators have examined intensive, serial CEA monitoring as an indicator for second look surgery in the hope that relapse could be detected at a time when surgical resection for cure was still possible. Criteria for reoperation included a significant rise of CEA above a base line level on serial determinations and absence of obvious unrespectable disease on staging workup. Determinations of CEA should be done frequently: at a minimum of every 3 months and if possible every 1month to 2 months. Elevations above baseline should be verified rapidly to exclude laboratory error.

The CEA is of some use as a monitor in treatment. Usually the CEA returns to normal within 1 to 2 months of surgery, but if it returns elevated persistent disease may be indicated. The test is not infallible in patients treated with radiotherapy and chemotherapy but can be useful in those whose tumor is not measurable. The CEA is often positve in malignancies other than colonic. In cancer of the breast, lung, pancreas, stomach and ovary the CEA may be elevated and can be used to monitor the progress of disease or response to treatment.

What abnormal result mean:

Elevated levels:

• Colon cancer
• Breast cancer 
• Lung cancer
• Pancreatic cancer 
• Thyroid cancer
• Genitourinary carcinomas
• Inflammatory gastrointestinal diseases (for example, ulcerative colitis, diverticulitis, cholecystitis, pancreatitis) 
• Cirrhosis
• Other liver disease 
• Peptic ulcer
• Heavy smoking 
• Pulmonary infections

A single abnormal CEA value may be significant, but must be regarded cautiously. In general, very high CEA levels indicate more serious cancer, with a poorer chance for cure. But  some benign diseases and certain cancer treatments may produce an elevated CEA test. Cigarette smoking will also cause the CEA level to be abnormally high.

FREE- PROSTRATE SPECIFIC ANTIGEN (PSA)

Clinical Significance :

PSA is  a 340000 dalton monomeric  glycoprotein  related to the proteses enzyme family. PSA has been found to form stable complexes with two of the major extracellular protease inhibitors in blood, alpha antichymotrypsin (ACT) and alpha macroglobulin (AMG). A small fraction of PSA remains free in blood. In prostate cancer  patients PSA complexed with ACT (PSA-ACT) is typically the major form in circulation for about 50% of these patients PSA-ACT accounts for 85% of the total PSA present. Some 12-15% of prostate cancer  patients on the other hand present with free  (that is, uncomplexed) PSA as the predominant form.

A. Incidence of BPH increases with age:

1. Men aged 60 years : 50%

2. Men aged 80 years : 88%

B. Incidence of symptomatic onset is related to ethhnicity:

1. African American men : onset at age 60 years

2. Caucasian men : onset at age 65 years

Clinical Application:

1. Free PSA is found to comprise significantly (p<0.0001) smaller fraction in patients with untreated prostate cancer than in patients with  benign prostatic hypetrophy (BPH).

2. In many men with serum PSA levels less than 10 ng/ml comprising dital PSA levels to free PSA fractions has been proposed as a way to facilitate discrimination between prostate cancer and BPH.

3. The ratio, free PSA/total PSA has been found to be a superior diagnostic indicator than total PSA.

Disadvantage/Limitation

Complex formation with ACT results in exposure of a limited no of antigenic epitopes of PSA, where as complex formation with AMG encapsulates the antigenic epitopes of PSA. Difference in recognition of these multiple forms of PSA by reagent antibodies have contributed to discrepancies between commercial PSA assays

CA-125 (OV) Test

CLINICAL SIGNIFICANCE:

CA125 is a mucin like glycoprotein. It is a surface antigen associated with nonmucinous epithelial  ovarian  cancer. The protein is sloughed or secreted from the surface of the ovarian cancer cells into the serum or ascites also made by inflamed normal cells that line body parts. This substance is shed in body fluids and finds it's way into the bloodstream. It is a useful tumor marker for evaluating therapy and monitoring disease status in patients under treatment for ovarian cancer.

CLINICAL APPLICATIONS:

1.It is a marker for ovarian and endometrial carcinoma.

2.To monitor for persistent or recurrent serious carcinoma of ovary in post –operative period or during chemotherapy.

3.To monitor therapy in patients with endometriosis.

4.CA 125 is useful in differentiating benign from malignant disease in patients with palpable ovarian masses.

5.Postoperatively the level of CA 125 correlates with the tumor bulk and is a prognostic indicator of clinical outcome.

6.It has been reported that patients with  levels>35 U/ml have the highest risk of clinical recurrence .

7.The rate of change in CA 125 is also highly prognostic. A rapid decrease in the level of CA 125 indicates positive response to therapy.

8.Elevated levels after the third course of primary chemotherapy indicate poor outcome.

9.CA 125 is not increased in mucinous adenocarcinoma.

ELEVATED IN:

Malignant diseases:

1.Nonmucinous epithelial  ovarian carcinoma.

2.Fallopian tube tumors.

3.Cervical  adenocarcinoma.

4.Endometrial adenocarcinoma.

5.Trophoblastic tumors.

6.Squamous cell carcinoma of vulva or cervix.

ACCUARACY OF CA 125 TEST

• The  CA 125 test only returns a true positive result for about 50% of stage I ovarian cancer patients.
• The  CA 125 test has an 80% chance of returning true positive results from stage II, III, and IV ovarian cancer patients .

LIMITATIONS:

• Before treatment, patients with confirmed ovarian carcinoma frequently have levels of CA 125 within the range observed in healthy individuals.

• Elevated levels can be observed in  patients with nonmalignant diseases.

• However several gynaecological disorders can cause a false positive result. Endometriosis, benign ovarian cysts, first trimester of pregnancy, and pelvic inflammatory disease all produce higher levels of CA 125.

• CA 125 test has a lower specificity in premenopausal women than postmenopausal women.

• Approximately 20 percent of women who have ovarian cancer do not ever have elevated CA 125. That is why it is critical to use CA 125 only as a part of a diagnostic regime that includes transvaginal sonography and a rectovaginal pelvic exam.

INTERFERENCES:

Heterophilic antibodies in human serum can react with reagent immunoglobulin, interfering with in-vitro immunoassays. Patients routinely exposed to animals or to animal serum products can be prone to this interference and anomalous values may be observed.

CA 19.9 Test

     CA 19.9  represents the most important and basic  carbohydrate tumor marker. Usually very little of CA19.9 is detectable  in the blood of normal individuals. The immunohistologic  distribution of CA 19.9 in tissues is consistent with the quantitative determination of higher CA 19.9 concentrations in cancer than in normal or inflamed tissues. Recently reports indicates that the serum CA 19. 9 level is frequently elevated in the serum of subjects with various gastrointestinal malignancies, such as pancreatic, colorectal, gastric and hepatic carcinomas. Together with CEA, elevated CA 19.9 is suggestive of gallbladder neoplasm in the setting of inflammatory gallbladder disease. This tumor-associated antigen may also be elevated in some non-malignant conditions. Research studies demonstrate that serum CA19.9 values may have utility in monitoring subjects with the above-mentioned diagnosed malignancies.

It has been shown that a persistent elevation in serum CA19.9 value following treatment may be indicative of occult metastatic and/or residual disease.A persistently rising serum CA 19.9 value may be associated with progressive malignant disease and poor therapeutic response. A declining CA 19.9 value may be indicative of a favourable prognosis and good response to treatment. A group of mucin type glycoprotien Sialosyl Lewis Antigens (SLA), such as CA 19.9 and CA 19.5, has come to be recognized as circulating cancer-associated antigens for gastrointestinal cancer.

Clinical Application

To diagnose pancreatic cancer (in conjunction with other diagnostic modalities like CT, USG).

1. To monitor therapy and  recurrences.
2. Levels correlate well with pancreatic cancer staging. With the cut off of 37 U/ml, 67% of patients with respectable and 87 % of those with unrespectable pancreatic cancer have elevated levels. With 1000 U/ml as cut off, 35 % of patients with unrespectable and 5% of respectable pancreatic cancer have elevated values.
3. Pancreatic cancer in the non-jaundiced patients can be difficult to diagnose, even with the aid of modern scanning techniques. The detection and quantification of CA 19.9 can be used in serological diagnosis of disease.
4. As an aid in serological diagnosis of cystic fibrosis patients.
5. May indicate development of cholangiocarcinoma in patients with primary sclerosing cholangitis.

Decreased levels

Low amounts of CA 19.9 can be detected in a certain percentage of healthy people, and many conditions that affect the liver or pancreas can cause temporary elevations.

Increased levels

1. Moderate to high levels are found in pancreatic cancer, other cancers, and in several other diseases and conditions.
2. The highest levels of CA 19.9 are seen excretory ductal pancreatic cancer- cancer that is found in the pancreas tissues that produce food- digesting enzymes and in the ducts that carry those enzymes into the small intestine.  This tissue is where 95% of pancreatic cancers are found.
3. Hepatobiliary cancer.
4. Colon cancer.

CA 15.3 Test

CA 15.3 molecule is a mucin, being a product of the MUC1 gene. Other names for this mucin include polymorphic epithelial mucin (PEM), epithelial membrane antigen (EMA) or episalin. The MUC1 antigen is a transmembrane Glyco-protein containing a large extra cellular domain, a hydrophobic membrane -spanning domain of 31 amino acids and a cytoplasmic domain of 69. amino acids. CA 15.3 is a highly polymorphic glycoprotein expressed at the apical surface of normal epithelial cells.

The most common type of breast cancer begins in the lining of the ducts and is called ductal carcinoma. Another type, called lobular carcinoma, arises in the lobules. When breast cancer spread outside the breast, cancer cells are often founded in lymph nodes under the arm. If the cancer has reached these nodes, it may mean that cancer cells have spread to other parts of the body -other lymph nodes and other organs, such as bones , liver, or lungs-via the lymphatic system or the blood stream. Cancer that spreads is the same disease and has the same name as the original (primary) cancer. When breast cancer spreads, it is called metastatic breast cancer, even though the secondary tumor is in another organ. Doctors sometimes call "distant" disease.

The risk of breast cancer increases gradually as a woman gets older. This disease is uncommon in women under the age of 35. All women age 40 and older are at risk for breast cancer. However, most breast cancer occur in women over the age of 50, and the risk is  especially high for women over age 60. The risk factors of breast cancer are personal history of breast cancer, genetic alternations, family history, certain breast changes, breast density, radiation therapy, and late child bearing.  Also at a somewhat increased for developing breast cancer are women who started menstruating at an early age (before age 12), experienced menopause late (after age 55), never had children, or took hormone replacement therapy or birth control pills for long period of the time. Each of these factors increases the amount of time a woman's body is  exposed to estrogen. The longer this exposure, the more likely she is to develop breast cancer.