EPITHELIAL TUMOR MARKERS

Presented by

Dr. VARUN SURYA• P.G student • Dept. of oral & maxillofacial

pathology• Government dental college

Mumbai -01

Guided by

Dr. J.V.TUPKARI• HOD & professor • Dept. of oral & maxillofacial

pathology• Government dental college

Mumbai -01

Introduction

• Earlier the most common determinant or marker of carcinomatous transformation in a tissue was the histopathologic presence or absence of epithelial dysplasia.

• However the expanding field of oncology has revealed new and more specific markers that would help to determine the degree of cell alteration and enable a better understanding of the degree of malignant transformation of these cells.

• Several abnormal cellular products are produced by the neoplastic cells and also by the body in the presence of such an abnormal situation.

• Such cellular products can be detected in the various body fluids and on the surface of the cancer cells either by biochemical methods or by immunochemistry.

• These products that are detected and measured are known as ‘tumor markers’.

Definition

• A tumor marker is a substance present in or produced by a tumor or by the tumor’s host in response to the tumor’s presence that can be used to differentiate a tumor from normal tissue or to determine the presence of a tumor based on measurement in the blood or secretions.

• Tumor markers can be found in cells, tissues or body fluids.

• They can be measured quantitatively or qualitatively by chemical, immunological or molecular biological methods to determine the presence of neoplasia

• The distinguishing biological characteristics of tumor cells, such as their capacity for invasion, metastasis, unlimited proliferation, evasion of apoptosis and angiogenesis, are all mediated by complex molecular pathways, any of the components of which are potential tumor markers.

Types

• Few markers are specific for a single individual tumor (tumor specific markers).

• Most are found with different tumors of the same tissue type (tumor associated markers)

IDEAL TUMOR MARKER

• It should be highly sensitive and should have low false negatives

• It should be highly specific and should have low false positive • It should have high positive and negative predictive value • 100% accuracy in differentiating between healthy individuals

and tumor patients • It should be able to differentiate between neoplastic and

non neoplastic disease and show positive correlation with ‑tumor volume and extent

• It should predict early recurrence and have prognostic value

• It should be clinically sensitive i.e., measurable at early stage of tumor

• Its levels should be preceding the neoplastic process, so that it should be useful for screening early cancer

• It should be either a universal marker for all types of malignancies or specific to one type of malignancy

• It should be easily assayable and be able to indicate all changes in cancer patients receiving treatment.

• But ideal tumor markers does not exist………….

1st Classification• Cell surface markers

1. Carbohydrates—particularly blood group antigens 2. Squamous carcinoma antigens Ca-1, TA-4, SQM1 and 3H-1 3. Histocompatibility antigens—HLA class I and HLA class II 4. Growth factors and receptors

• Intracellular markers 1. Cytoskeletal components—Cytokeratins 2. Markers of abnormal keratinization— Filaggrin, Involucrin, Desmosomal proteins 3. Carcinoma antigen 17, 13 4. Silver binding nucleolar organizing regions 5. Oncogenes 6. Tumor suppressor genes 7. Arachidonic acid products- PGE2, leukotrine B4 and 5,12, and 15 hydroxyeicosatetraenoic acids 8. Enzymes—Gamma- glutamyltranspeptidase, LDH 9. Basement membrane markers— fibronectin, laminin 10. Matrix markers—Tenascin

Scully & burkhardt (1993)

2nd Classification• Tumor growth markers

1. Epithelial growth factor (EGF) 2. Cyclins 3. Nuclear cell proliferation antigens 4. AgNORs (Agryophilic nucleolar organizer region) 5. Skp2 (S-phase kinase-interacting protein 2) 6. HSP 27 and 70 (Heat shock proteins) 7. Telomerase

• Markers of tumor suppression and anti-tumor response 1. Retinoblastoma protein (pRb) 2. Cyclin dependant kinase inhibitors 3. p53 4. bax 5. Fas/FasL

• Angiogenesis markers 1. VEGF/VEGF-R (Vascular endothelial growth factor/ receptor) 2. PD- ECGF (Platelet-derived endothelial cell growth factor) 3. FGFs (Fibroblast growth factor)

• Markers of tumor invasion and metastatic potential 1. MMPs (matrix-metallo proteases) 2. Cathepsins 3. Cadherins and catenins 4. Desmoplakin

• Cell surface markers 1. Carbohydrates 2. Histocompatibility antigen (HLA) 3. CD57 antigen

• Intracellular markers 1. Cytokeratins

• Markers of anomalous keratinization 1. Filagrins 2. Invoulcrin 3. Desmosomal proteins 4. Intercellular substance antigen 5. Nuclear analysis

• Arachidonic acid products 1. Prostaglandin E2 2. Leucotriene B4

• Enzymes 1. Glutathione S-transferase

Epithelial markers

• Cytokeratins (CK) • Epithelial membrane antigen (EMA) • Oncofetal antigens

a. Alpha fetoprotein (AFP) ‑b. Carcinoembryonic antigen (CEA)

• Desmoplakin

Mesenchymal markers• Muscle antigens

1. Desmin 2. Actin 3. Myoglobin 4. Myosin

• Vascular antigen1. CD 34 2. CD 31

• Neural antigens 1. S 100 2. Neuron specific enolase (NSE) 3. Glial fibrillary acidic protein (GFAP) 4. Synaptophysin 5. Nerve growth factor receptor

Prognostic markers

• Cell adhesion molecules 1. Cadherins 2. Integrins 3. Selectins

• Proliferation markers 1. PCNA 2. Ki67 3. AgNORs

Biochemical markers

• Enzymes and isoenzymes 1. Prostatic acid phosphatase (PAP) 2. Prostate Specific Antigen (PSA) 3. Placental Alkaline Phosphatase (PALP) 4. Lysozyme

• Protein 1. Ferritin 2. Glycoprotein 3. Beta protein 4. Immuno globulins 5. Albumin

Hormone receptors

1. Estrogen receptor (ER) 2. Progesterone receptor (PR)

USES OF TUMOR MARKERS

1.Screening in General Population

• The concept of screening an apparently healthy population is to find out the presence of occult disease at an early stage, wherein effective therapeutic intervention is likely to be beneficial.

• However, inadequate test sensitivity and specificity in discrimination of a low prevalence situation, limits the role of these markers to smaller confines

2.Diagnosis

• The identification of primary disease is an important function of any tumor marker.

• For definitive results it is essential that the marker be 100% specific and 100% sensitive.

• For example, the presence of Bence Jones proteins in the urine remains one of the strongest diagnostic indicators of multiple myeloma.

• In the vast majority of diagnostic situations, circulating tumor markers are used. If appropriate, in conjunction with diagnostic imaging and tissue biopsy, perhaps coupled with immuno-histochemical staining of tumor-specific antigens.

3.Differential Diagnosis

• Most of the tumor markers are present in normal, benign and cancerous tissue and are usually ambiguous.

• However, they can still be used in differential diagnosis of suspicious lesions.

• The tumor markers are commonly employed to decide the histogenetic origin of oral cavity neoplasms and therefore help ruling out atleast some of the entities on the differential diagnosis list

4.Clinical Staging of Cancer

• Clinical staging of the cancer is aided by quantitation of the marker, that is, the serum level of the marker reflects the tumor burden present.

• Markers can also detect microscopic metastasis with radioimmune detection

5.Nuclear Scanning of Injected Radioactive Antibodies

• Radioactive labeled antibody specific tumor marker is injected into patients suspected of having undetected tumor metastasis.

• Accumulation of specific antibody in tumor cells may be visualized by isotope scanning with appropriate subtraction techniques to overcome background activity or by emission tomographic scanning.

• The labeled antibody can be injected intravenously or into the lymphatic circulation for more efficient binding to metastatic site

6.Prognostic Indicators for Disease Progression

• Tumor markers can provide prognostic information, which may include indications for choice of therapy and likelihood of response.

• The estimate of survival time based on evidence of metastatic disease can also be predicted

7. Evaluating the Success of Treatment / Monitoring the Response to Therapy

• After successful initial treatment, such as surgery, the marker value should alter.

• The rate of the alteration can be predicted by using the half-life of the marker.

• For e.g. If the marker is supposed to be decreased after t/t, but the observed half-life of the marker after treatment is longer than the expected half-life, then the treatment has not been successful in completely eliminating the tumorous tissue.

• The magnitude of marker alteration may, however, reflect the degree of success of the treatment or the extent of disease involvement.

• Most tumor marker values correlate with the effectiveness of treatment and responses to therapy.

• Sometimes, however, the values may show an initial delay before demonstrating the expected pattern of change.

8.Detecting the Recurrence of Cancer

• It is of utmost importance to precede and to predict recurrence so that relapse can be picked up as soon as possible and appropriate measures may be undertaken.

• A clinically sensitive tumor marker will reflect the amount of viable tumor burden, assuring homogeneity of production in tumor cell population.

• This quantitative relationship is of great importance not only to monitor response to therapy, but also to alert the clinician to the onset of drug resistance.

EPITHELIAL MARKERS

Cytokeratin

• Cytokeratins are also known as keratins and they are classified as intermediate filament proteins and are found with in the cytoplasm of all epithelial cells

• Cytokeratins are a family of 20 members which are present in normal epithelial cells and their tumors.

• They are divided in to two broad groups according to their isoelectric point

Basic group (type 1) Acidic group (type 2)

Keratin 1-8 Keratin 9-20

MW: 52-67 kD MW: 40-56 kD

• The keratins are broadly divided into• 1. Primary keratins are those keratins which are always

synthesized by the epithelial cells on a regular basis, e.g., K8/18 in simple epithelia, K5/14 in stratified epithelia.

• 2. Secondary keratins are those types of keratins which are produced by the epithelial cells in addition to or instead of primary keratins, e.g., K7/19 in simple epithelia, K15, and K6/16 in stratified epithelia.

• During epidermal differentiation, low molecular weight keratins 5/14 of the basal layer are replaced by high molecular weight keratins 1/10,11 which can be used as a marker of keratinization

Based on molecular weight

•molecular weight of 40kDa. •mainly distributed in glandular and simple epithelia.

Low molecular weight keratins:

•molecular weight between 40kDa and 57kDa•found in stratified epithelia.

Intermediate molecular weight

keratins:

•molecular weight of 57kDa•seen in keratinized stratified epithelia

High molecular weight keratins:

Functions of Keratins• Keratins fundamentally influence the architecture and mitotic

activity of the epithelial cells. • Keratins and associated filaments provide a scaffold for

epithelial cells and tissues to sustain mechanical stress, maintain their structural integrity, ensure mechanical resilience, to protect against variations in hydrostatic pressure and establish cell polarity.

• Keratins and its filaments are involved in cell signalling , cell transport, cell compartmentalization and cell differentiation.

• Keratin filaments also influence cell metabolic processes by regulating protein synthesis and cell growth.

• Keratins may also be involved in the transport of membrane bound vesicles in the cytoplasm of the epithelial cells.

• Keratins are usually found in pairs, with one type I co existing with one type II , each ‑encoded by its own gene.

• In the absence of pairing , they are unstable & vulnerable to degradation by proteases.

• Cytokeratin profile reflects both cell type & differentiation status in different types & different layers of epithelia.

Cytokeratin expression in normal oral mucosa

Basal cells

• Keratinised sites : k5 & k14• Non-keratinised sites : k19

Supra-basal cells

• Keratinised sites : k1 & k10• Non-keratinised sites : k4 & k13

CK in basal layer

CYTOKERATIN 5&14 Cytokeratin 19

CK in supra-basal layer

Cytokeratin 10 Cytokeratin 4 in human leukoplakia lesions

Simple epithelial keratins • K8 & k18• Not normally found in stratified squamous

epithelium, but rather in single cells, such as glandular tissue (e.g., salivary glands).

Cytokeratin expression in pathology

low molecular weight keratins appear early in development

seen in more simple

non stratified ‑epithelia and

tumors derived from them

(i.e., breast carcinomas or

gastrointestinal carcinomas

derived from cuboidal or

simple columnar epithelia)

higher molecular weight keratins appear

later

Associated with the formation of more complex stratified

epithelia

seen in more complex stratified squamous epithelia and their

corresponding tumors (i.e., squamous cell

carcinomas).

• In epithelial tumors, some keratin polypeptides are either not expressed or are over expressed.

• After their release from proliferating or apoptotic cells, cytokeratins act as useful markers for epithelial malignancies.

• Therefore, keratins have gained importance as marker proteins useful in diagnosis of tumors of epithelial origin.

• It should be remembered that cytokeratin expression is not strictly restricted to epithelia and their tumors.

• Some non epithelial derived tumors, such as ‑synovial sarcoma, epitheliod sarcoma, myosarcoma, ewing’s tumor, malignant melanoma, schwannoma, glial tumors, large cell anaplastic lymphoma and malignant mesothelioma may also express immunoreactivity for cytokeratins.

Three most applied cytokeratin markers1. tissue polypeptide antigen (TPA)- broad

spectrum test, and it measures cytokeratins 8, 18, and 19.

2. tissue polypeptide specific antigen (TPS)3. CYFRA 21 1‑• TPS and CYFRA 21 1 assays are more specific ‑

and they measure cytokeratin 18 and cytokeratin 19

•best IHC marker for Merkel cell ‑carcinomasCk 20•markers for poorly differentiated squamous cell carcinomaCk 13 •a marker for odontogenic epithelial originCk 14 & 19

Ck in odontogenic tumors

• Odontogenic tumors with epithelial component frequently express CK 14 and 19.

• Numerous studies have shown that AOT and ameloblastomas express CKs 5, 14 and 19.

• IHC studies by Martínez- Mata et al. proved that most of tumors of mesenchymal origin like odontogenic myxoma (OM) do not express CK 14 and 19.

• Thus, CK 14 and 19 can be used as markers for tumors of odontogenic epithelial origin.

Clinical Significance• Keratin expression patterns are characteristic for distinct

stages during cellular epithelial differentiation from embryonal to adult and of the internal maturation program during development.

• Epithelial tumors including metastasis most widely retain their keratin patterns of their normal origin; thus the determination of the keratin patterns of tumors is widely exploited for cell and tumor typing.

• Therefore keratins have evolved to be one of the most potent epithelial differentiation and tumor markers in cell biology, embryology, and surgical pathology.

• Specific antibodies against several keratins are routinely used for immunohistochemical typing of carcinoma in tumor diagnostics

• Keratins can be used as differentiation markers in normal oral epithelia.

K8/18

• markers for simple epithelial differentiation

K1/10

• markers for keratinized epithelium

K4/13

• markers for non-keratinized epithelium.

K6/16

• considered as hyperproliferative markers• expressed in sites of high epidermal keratinocyte turnover and in pathological hyperproliferative conditions affecting the skin

K8/18 : •strongly stained in most adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, and neuroendocrine carcinoma. •monitoring of fragments of these keratins in the serum as serological tumor markers to monitor cancer load, cancer progression, and response to therapy.

K19 : •The detection of soluble K19 fragments in the serum released by carcinoma cells by the CYFRA 21-1 has found broad clinical application as a marker to monitor treatment and evaluate response to therapy.

K20: •K20 is a potent immunohistochemical marker in tumor pathology since its peculiar expression spectrum is essentially maintained in the corresponding primary and metastatic carcinoma.•K20 positivity is seen in majority of gastric adenocarcinoma, transitional cell carcinoma, and Merkel cell carcinoma. •K20 is considered to be a consistent marker for Merkel cell carcinoma

CYFRA-21.1

• Cyfra 21-1 is a soluble fragments of Ck 19 generated by necrosis of tumor cells.

• This marker is recognized by two monoclonal antibodies against fragments of CK 19 in the serum.

• The assumption is that Cyfra 21-1 is released into the bloodstream during cell death, and therefore its level correlates very well with the tumour mass, or more specifically with the necrosis in the tumour, which is a function of the tumour mass.

• Ilana Doweck et al (1995) measured Cyfra 21-1 (cytokeratin fraction 21-1) in OSCC patients and found Cyfra 21-1 levels were in good correlation with the tumor stage .

K6 and 16 : typically and strongly expressed in squamous cell carcinoma of different sites.

K6, 16 and 17 : inducible keratin upon stress, injury and inflammation and therefore increased expression is seen in squamous cell carcinoma.

The increased expression of K17 which is usually absent in normal epithelia could be attributed to neo-expression during tumorigenesis.

A unique feature of K17 is its inducibility after skin injury.

After K6/16, K17 is switched on in regenerating and migrating epidermal keratinocytes upon wound healing

• A study of 18 fine needle aspiration biopsies obtained by traversing the cyst cavity and contacting the opposite cyst wall, compared the CK10 expression of sampled epithelial cells with CK10 expression of the postoperative biopsies .

• The authors reported that this technique accurately distinguished OKCs from non-keratinised dentigerous and radicular cysts in the entire sample

• Another paper reported strong expression of cytokeratin 17 in all layers of the epithelium in all of six OKCs from patients with the NBCCS.

• In a sample of seven sporadic OKCs – two cases : strong expression of cytokeratin 17 – other 5 : showed weaker and irregular staining

• Dentigerous cysts showed weak positivity for cytokeratins 13, 17 and 18.

• It was suggested that cytokeratin 17 might be a useful marker – to distinguish OKCs from other jaw cysts – to distinguish syndrome from sporadic OKCs

Ck in oral squamous cell carcinomas

Well -differentiated oral squamous cell carcinomas.

• increased expression of K1/10, K4/13

Less well-differentiated oral squamous cell carcinoma

• express neither of these keratin pairs to any significant extent but do express K19.

Moderated and poor oral squamous cell carcinoma

• May express K8 and sometimes K7 and 18. • The expression of K8 and K18 in oral squamous cell carcinoma is considered to be an independent prognostic marker .• Also K5 and K6 are considered as useful markers for squamous cell carcinomas in histologically uncertain, poorly differentiated or metastatic tumor cases.

OSCC vs mucoepidermoid carcinoma

Mucoepidermoid carcinoma

• also expresses CK7, 8, and 19 and negative for CK10.

CK10

• usually absent in these tumors, reflecting that true keratinization is an uncommon finding in mucoepidermoid carcinoma.

CK13

• found to be useful in differentiating mucoepidermoid carcinoma from other salivary gland tumors.

OSCC (grade III) mucoepidermoid carcinoma (high grade)

CK 14 strikingly positive focally positive

areas of squamous metaplasia

positive for CK10 positive for CK13

• Consistent expressions of K13 and K19 may provide a useful marker of odontogenic epithelium in general.

• K19 scores are found to reflect histological differentiation as well as predicting the clinical outcome.

• Combining K19 immunostaining with regular H & E stain may be helpful to facilitate and assure assigning a more accurate grade for oral epithelial dysplasia

DESMOPLAKIN

Desmoplakins are highly conserved proteins present within the desmosomal plaques of epithelial cells. Utilizing antibodies directed against desmoplakin I and II, immunoreactivity can be localized to peripheral punctate regions in a wide variety of epithelial cells, meningeal cells, and mesothelium.

• Desmoplakins can also be identified within the glandular component of synovial sarcomas but not in other sarcomas.

• Thus desmoplakins represent an additional marker of epithelial differentiation independent of keratin.

• Mutations in this gene are the cause of several cardiomyopathies and keratodermas as well as the autoimmune disease paraneoplastic pemphigus

Desmoplakin I/II . Immunoperoxidase staining of formalin fixed, paraffin-embedded human skin tissue showing cytoplasmic

staining of epidermal cells.

Alpha fetoprotein

• AFP is a very popular and extensively studied carcinoembryonic glycoprotein / Oncofetal antigen. Alpha fetoprotein (AFP) is a 70kD ‑glycoprotein.

• AFP is normally produced during fetal development by the liver and yolk sac. After birth, the levels drop off rapidly, and by the second year only trace amounts are detectable in serum.

• Serum AFP measurement is of valuable clinical aid in diagnosis, prognosis and monitoring primary hepatocellular carcinoma, hepatoblastoma, non seminomatous ‑testicular germ cell tumors the embryonal carcinoma, teratoma, choriocarcinoma and yolk sac carcinoma etc., germ cell tumors of ovary and extragonadal germ cell tumors

Human fetal liver tissue stained with alpha Fetoprotein antibody

Carcinoembryonic antigen (CEA)

• CEA is an oncofetal glycoprotein. • It is expressed in normal mucosal cells . • Elevated levels of CEA is seen in malignancies such

as salivary gland tumors i.e. carcinomas with glandular differentiation and can also be observed in squamous cell carcinomas.

• Non neoplastic conditions associated with elevated ‑CEA levels include cigarette smoking, peptic ulcer disease, inflammatory bowel disease, pancreatitis, hypothyroidism, biliary obstruction, and cirrhosis.

Lesion CEA

OKC Weakly +ve

Dentigerous cyst -ve rxn

Radicular cyst -ve rxn

Epithelial membrane antigen (EMA)

• High molecular weight protein (265 to 400)• Shows apical staining on a wide variety of

normal & neoplastic epithelial cells.

• Expression of CEA and EMA, as with that of keratin 10/11, appeared to be dependent on epithelial structure and differentiation.

• Their expression by OKC epithelium was restricted to weak and patchy staining of the surface layers, although areas with ’disordered structure’ showed cytoplasmic staining of most cells particularly for EMA.

• In the dentigerous cysts both antigens, more so EMA, were found in most epithelial cells and in the radicular cyst their distribution was variable.

• Differences in cytokeratin, EMA and CEA between the parakeratinised OKC and the orthokeratinised variety have demonstrated that the latter, having a considerably less aggressive behaviour, is a different entity and should bear a different name, ’orthokeratinised odontogenic cyst’ (OOC) .

• Keratins associated with squamous differentiation or cornified epithelium showed pronounced staining in all but the basal cell layer of the OOC whereas in the parakeratinised OKC staining was found only in the upper and surface parakeratin layers.

• Both EMA and CEA were consistently present in the surface parakeratin layer of the OKC but completely absent in the orthokeratinised linings.

Leu M1 (CD15)

• Useful in identifying carcinomas & distinguishing them from mesotheliomas.

• It is also granulocytic marker & stains reed-sternberg cells of hodgkin’s disease.

•

Ber-EP4

• Ber –EP4 is another widely distributed epithelial cell antigen which react with a pair of glycoprotein (34 & 49 kD).

• Many carcinomas are +ve ,whereas mesothelial cells & mesotheliomas are usually -ve

B72.3

• TAG-72 (tumor associated glycoprotein)• Helpful in distinction between carcinoma &

mesotheliomas.

Limitations of Tumor Marker Use

1. Too many markers

• Each year clinicians are faced with the discovery of a multitude of new molecular markers, often with claims that they will provide new information that is important for determining prognosis or improving cancer treatment.

• The clinician is then faced with the arduous task of trying to keep with the technology and sorting through the literature to determine which of these tumor markers are relevant to the care of their individual patients

2. Creates un-necessary confusion

• The relevant question that needs to be answered is whether the tumor marker in question will alter the clinical decision-making to result in a favorable outcome for the patient and unfortunately most often it does not!

• The absence of large, prospective, multicenter trials to assess the utility of any of the tumor markers only adds to the confusion.

• Despite the specificity of some tumor markers, a negative marker value does not rule out recurrent disease and other diagnostic modalities such as imaging still have to be performed as part of the surveillance program.

3. Technique is not fully developed

• Despite the advent of monoclonal antibody and immunoassay technologies, which have dramatically increased our ability with a high degree of reproducibility to identify minute quantities of particular substances in serum, there are currently no tests for tumor markers of adequate sensitivity and specificity to permit routine screening or early diagnosis of a particular type of cancer.

4. Inadequate sensitivity and specificity

• The lack of adequately sensitive and specific test can be attributed to a multifactorial situation.

• Most tumor markers are substances produced by some types of non-neoplastic cells; although perhaps in much lower quantities than they are produced by tumor cells.

• Varying levels of these markers may be present at all times in different tumor free individuals and varying levels of the particular marker may be present in different individuals with a particular tumor type.

• Most tumor markers show some overlap between the levels seen in controls and in cancer-affected individuals. Thus it becomes necessary to choose a threshold at which level particular marker is considered abnormal and suggestive of the presence of that tumor type.

• Setting the threshold lower increases sensitivity by including a higher number of patients with a particular tumor, but decreases the specificity by also including more tumor free individuals, while raising the threshold will have the reverse effect

• If a tumor marker assay was 95% sensitive or 95% specific and were to be applied to population containing 5,00,000 cases in a population of 100 million people, it would yield 4,75,000 true positive and 5 million false positive results.

• Thus for every cancer case detected there would be 10 cancer free individuals who would needlessly undergo further work up and psychological stress resulting from a false positive test. These numbers in reality would become even worse because tumor marker in current use have sensitivity and specificity below 95% particularly for small lesions.

5. Financial and psychological cost

• Knowledge by the patient of a rising tumor marker may cause significant anxiety, particularly, if this information does not alter the treatment plan as patients equate rising tumor marker levels with worsening disease.

• Thus the financial and psychological cost to the society , of routine screening for early cancers using currently available tumor marker would be unreasonable.

References

• Shear M. The aggressive nature of the odontogenic keratocyst: Is it a benign cystic neoplasm? Part 3. Immunocytochemistry of cytokeratin and other epithelial cell markers. Oral Oncol 2002; 38(5): 407-15.

• Ajay G Nayak, Laxmikanth Chatra. Tumor Markers: An Overview. Journal of Indian Academy of Oral Medicine and Radiology, July-September 2010;22(3):147-150

• Babu GS, Supriya AN, Raj Kumar NG, Swetha P. Tumor markers: An overview. J Orofac Sci 2012;4:87-95.

• Sanjay Reddy B , Madhavi Reddy B , Shyam NDVN. Tumour Markers in Oral Neoplasia. IJDA, 2(1), 2010

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