Amit Agrawal (1)
J.P.Shetty (2)
Rajanish Joshi (3)
1. Dr. Amit Agrawal: Associate professor in Neurosurgery, Department of Neurosurgery, K.S.Hegde Medical Academy, Mangalore.
2. Dr. J.P.Shetty: Associate Professor in Pathology, Department of Pathology, K.S.Hegde medical Academy, Mangalore
3. Dr. Rajanish Joshi: Lecturer in Medicine, Department of Medicine, Mahatma Gandhi Institute of Medical Sciences, Sevagram


Corresponding Author:
Dr. Amit Agrawal
Associate Professor in Neurosurgery
Department of Neurosurgery
K.S.Hegde Medical Academy
Deralakatte-575018
Mangalore
Karnataka (India)
e-mail-dramit_in@yahoo.com
Phone- +91-824-2204472
Fax- +91-824-2204016

Abstract-
Tumor markers are helpful for screening, determining diagnosis and prognosis, assessing response to therapy, and monitoring for cancer recurrence. Recently many technological advances in immunohistochemistry, molecular biology, genetics, and chromosomal and nuclear analysis have opened a new era of molecules to manage cancer. Tumor markers are used in the central nervous system to diagnose and monitor treatment of germ cell tumors, pituitary tumors, and metastatic disease. However in spite of development of more and more specific and sensitive markers for various central nervous system tumors there are no reliable tumor markers for certain tumors like malignant gliomas. In this article we review the various aspects of tumor markers and discuss their role in central nervous system.
Key words - central nervous system, cerebrospinal fluid, tumor marker



Introduction-
Tumor markers are the biochemical substances normally produced in low quantities by cells in the body , but secreted into the bloodstream by certain tumors or by the host in response to the cancer in very large amounts. They are helpful for screening, determining diagnosis and prognosis, assessing response to therapy, and monitoring of cancer recurrence. Tumor markers can be detected by radioimmunoassay or immunohistochemical techniques; however tumor markers are not always reliable enough to be used to detect cancer early on [1, 2.]

Historical perspective-
Sir Henry Bence Jones as early as in 1847 introduced the concept of tumor marker when he described a urinary tumor marker as a method to confirm the diagnosis of a blood-born dyscrasia that resulted in kidney failure, wasting, and death and termed this protein as Bence Jones protein. Years later this protein was identified as IgG light chain associated with multiple myeloma. In the same year, Sir Michael Foster described amylase as a marker for pancreatic cancer. Following these there were many advances in tumor marker biology and more specific molecules were identified. Among these markers were acid phosphatase (1930s) as a marker for prostate and bone cancers, urinary chorionic gonadotropins (1940s) for gestational trophoblastic neoplasms, and vanillyl mandelic acid ( 1950s) for neuroendocrine tumors. The modern era of tumor markers has been influenced by the many technological advances in immunohistochemistry, molecular biology, genetics, and chromosomal and nuclear analysis [3,4,5,6.]


Tumor marker-
Tumor marker is a molecule that is associated with a particular tumor (Table-1). The marker can reside in any body fluid or cavity (e.g., serum, urine, bile, CSF). Ideally, however, the fluid should be accessible, reproducible, and quantifiable. Tumor markers are also called onco-fetal proteins as these molecules are expressed in the fetal tissue during normal development. There are three major types of tumor markers that are released into the circulation i.e. enzymes, hormones and glycoproteins (Table-2). However increased level of these substances does not mean presence of cancer [1, 7].
 

Ideal tumor marker-
An ideal tumor marker should be able to confirm diagnosis, monitor treatments and screen for cancer relapse, screen whole populations especially high-risk groups, confirm histopathology, predict drug response, and provide a substrate target for further therapies. It should possess high specificity and sensitivity to the tumor, and it should be unique. No tumor marker now available has met these ideals. The reason for this is the relative lack of sensitivity and specificity of the available tests, given the low prevalence of cancers in most population groups. Given the low prevalence of cancer in general, even tests that are highly sensitive and specific may have low predictive values [4, 5, 6]. Prostate-specific antigen (PSA) is a prototypical serum tumor marker that has a high specificity (96%) and moderate sensitivity (23%), and it is a serologic test that is easily obtained, is reproducible across different laboratories, and can be reliably measured. A PSA level of >10 ng/mL has a high correlation with prostate cancer (67%) [3.]


Laboratory methods-
Tumor markers are measured in the clinical laboratory with specific immunoassays. The antibody reagents used in these immunoassays are directed against unique sites (epitopes) on the tumor markers being measured. Detection of tumor markers in blood or body secretions at concentrations that are significantly elevated relative to a healthy reference population may suggest the presence of a tumor. Determination of tumor markers in biopsies of suspect tissues may be used to distinguish benign from malignant neoplasms, and to identify the tissue origins of metastasized cancers.

Tumor markers and central nervous system-
Tumor markers are used in the central nervous system to diagnose germ cell tumors, pituitary tumors, and metastatic disease. However no reliable tumor markers have been described for malignant glioma. The reasons for this are numerous, including the relative low incidence of malignant glioma in the population, the lethality of most malignant gliomas (median survival for Glioblastoma Multiforme is 13.2 months), the difficulty in obtaining tissue samples to screen for potential tumor markers, and the limitations imposed by the blood-brain barrier to obtain serum samples of any potential tumor marker [8. ]

These tumor markers can be used in the central nervous system for following purposes:
· Making a diagnosis of cancer or of a specific type of cancer
· Determining the prognosis in a patient
· Monitoring the course in a patient in remission or while receiving surgery, radiation, or chemotherapy
· Screening a healthy population or a high risk population for the presence of cancer
 

Normalization of tumor marker values may indicate cure despite radiographic evidence of persistent disease as the residual tumor may be nonviable. Conversely, tumor marker levels may rise after effective treatment (possibly related to cell lysis), but the increase may not portend treatment failure. However, a consistent increase in tumor marker levels, coupled with lack of clinical improvement, may indicate treatment failure. Residual elevation after definitive treatment indicates persistent disease [9. ]

Pituitary tumors-
Hormones are natural products of pituitary gland and secreted by specific cell types (Table-3). These can be identified by the specific markers and are mainly used to identify the type of cells of pituitary adenoma including the clinically nonfunctioning adenomas. This forms the basis of diagnosis and therapy of pituitary tumors [10. ]

Germ cell tumors-
Germ cell tumors are not rare in central nervous system. The primordial germ cell disseminates most frequently in mediastinum and diencephalopineal region. They include
(1) Germinomas
(2) Malignant non-germinomatous tumors (includes embryonal carcinomas, choriocarcinomas, yolk sac tumors, and mixed types)
(3) Teratomas (immature and mature)
Thus, the germ cell tumor markers are used frequently in CNS tumors (Table-4). These markers include-

Placental alkaline phosphatase (PLAP) :
PLAP is a cell surface glycoprotein elaborated by syncytiotrophoblasts and produced by primordial germ cells. However its low secretion titer makes detection difficult. PLAP is usually seen in all geminomas and in some choriocarcinomas focally. Although placental alkaline phosphatase (PLAP) may represent a tumor marker for germinomas, it does not specifically differentiate among its subtypes. Immunohistochemically, PLAP is positive in 75 to 100% of germinomas and in 33 to 86% of nongerminomatous tumours [11] .
Alpha fetoprotein (AFP) -
Alpha-Fetoprotein is a normal fetal serum protein synthesized by the liver, yolk sac, and gastrointestinal tract that shares sequence homology with albumin. It is a major component of fetal plasma, reaching a peak concentration of 3 mg/ml at 12 weeks of gestation. Following birth, it clears rapidly from the circulation, having a half life of 3.5 days, and its concentration in adult serum is less than 20 ng/ml. The AFP is rarely elevated in healthy persons, and a rise is seen in only a few disease states. Germinomas are negative for AFP. Endodermal sinus tumor and embryonal carcinoma show strong positivity. Even the CSF level of this marker is high in these two tumours. Elevation occurs in certain liver diseases, especially acute viral or drug induced hepatitis and conditions associated with hepatic regeneration. In general, the elevations are under 500 ng/ml. however in germ cell tumors the elevation may be greater than 500 ng/ml [11].
Human Chorionic Gonadotrophin(HCG) -
HCG is a glycoprotein consisting of subunits alpha, epsilon and beta, which are nonconvalently linked. The hormone is normally produced by the syncytiotrophoblastic cells of the placenta and is elevated in pregnancy. All gestational trophoblastic tumors and few germ cell tumors produce HCG, and it is a valuable marker in these tumors, screening all cases reliably and indicating poor responses to treatment. The level correlates with tumor mass and thus has prognostic value. HCG is extremely sensitive, being elevated in women with minute amounts of tumor [11].
Neuron Specific Enolase
Neuron specific enolase is an isozyme of the glycolytic pathway that is found only in brain and neuroendocrine tissue. It is an immunohistochemical marker for tumors of the central nervous system, neuroblastomas, and APUD tumors. However according to the available literature, measurement of neuron specific enolase level cannot be correlated to the extent of the disease, the patient's prognosis, or the patient's response to treatment because of the poor sensitivity of this marker.

Immunoglobulins
Production of a monoclonal immunoglobulin molecule is characteristic of multiple myeloma. These paraproteins are usually complete antibody molecules but may be isolated light chains or, rarely, heavy chains. They may be lambda or kappa light chains and of any immunoglobulin subtype. There estimation is valuable in the staging and response to treatment in myeloma involving spine and cranium. The amount of paraprotein serves an index of tumor volume and response to treatment is indicated by a fall in paraprotein production, whereas a rise points to relapse.

The diagnostic pitfalls:
The interpretation of any immunohistochemistry results should not supercede the proper clinical and radiological correlation, as different assays for the same tumor marker may yield results that have different absolute values. Such differences may be related to assay format, calibration, antibody specificity, and how the epitopes on the tumor marker are presented in an individual patient sample. Apart from these certain other limitations are -

· Tumor marker levels can be elevated in people with benign conditions
· Tumor marker levels are not elevated in every person with cancer, especially in the early stages of the disease
· Many tumor markers are not specific to a particular type of cancer
· The level of a tumor marker can be elevated by more than one type of cancer
Recommendations-
Clinical, radiological and pathological correlation is must while interpreting the laboratory results of tumor markers. Certain guidelines can be followed while managing patients with cancer (Table-5)

Challenges and future-
According to the most recent statistics more than 18,000 new cases of brain cancer will be diagnosed in 2004 in the United States 12.In spite of development of more and more specific and sensitive markers for various central nervous system tumors there are no reliable tumor markers for certain tumors like . malignant gliomas. Recently some markers are reported with promising results. Allelic 1p chromosomal deletion has been shown to be a promising tumor marker in patients harboring anaplastic oligodendroglioma 13, 14. However, despite high specificity, this test has limited sensitivity and is expensive.15. In pituitary gland tumors also other markers like . development regulatory protein Pit-1, Keratins, receptors like estrogen receptor and transcription factor SFI are being tried in different pituitary adenomas and their exact role in the prognosis and management are being tested.

Conclusion-
Despite advances in neuroimaging, microsurgical techniques, radiotherapy, and chemotherapy, the prognosis for patients with cancer remains poor. Newer molecules are continuously being explored for detection of cancer within the very early phases. The continuing refinement and evolution of knowledge of tumor markers and application of newer techniques will result in better diagnosis and management of cancer in future.


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Table- 3 Pituitary gland hormones and their cell of origin

AFP = alpha-fetoprotein; beta-hCG = beta subunit of human chorionic gonadotropin.

*—any detectable AFP indicates the presence of a nonseminomatous component; in this situation, the malignancy should be treated as a nonseminomatous germ cell tumor.

†—Gestational trophoblastic disease is not a germ cell tumor; rather, it

is a rare gynecologic malignancy related to pregnancy.

• Never rely on the result of a single test
• When ordering serial testing, be certain to order every test from the same laboratory using the same assay kit
• Be certain that the tumor marker selected for monitoring recurrence was elevated in the patient prior to surgery
• Consider the half-life of the tumor marker when interpreting the test result
• Consider how the tumor marker is removed or metabolized from the blood circulation
• Consider ordering multiple markers to improve both the sensitivity and the specificity for diagnosis
• Order the nonspecific markers for cost-saving and for their high sensitivity
• Be aware of the presence of multiple sources of tumor markers