TUMOR MARKERS

Dr. Asifa Iqbal

Oral And Maxillofacial Surgery ,KEMU Mayo Hospital,Lahore.

Contents• What are tumor markers?• History• Ideal tumor markers• Clinical application• How to detect tumor markers • Broad classification• Specific classes of tumor markers• Specific tumor markers implicated in head & neck neoplasia• Drawbacks• New frontiers• Conclusion

Tumor Markers？• Biological substances synthesized and released by

cancer cells themselves or

• Produced by the host in response to the presence of tumor

• Most tumor markers are proteins

• Detected in a solid tumor, in circulating tumor cells in blood, serum, lymph nodes, bone marrow or in other body fluids (urine, stool, ascites)

Brief history of Tumor Markers

Ideal Tumor Marker

• Be specific to the tumor.• Level should change in response to tumor size.• An abnormal level should be obtained in the presence of

micro metastases.• Levels in healthy individuals should be lower in

concentrations than those found in cancer patients.• Predict recurrences before they are clinically detectable.• Test should be cost effective.

Ideal Tumor Marker????

Clinical Application

• Screening To identify early cancer risk

• Diagnosis To corroborate the diagnosis

• Staging To assess & stratify the risk

• Prognosis To predict the outcome

• Localization To locate the primary

• Therapy To target the therapy

• Surveillance To detect recurrence in FU

• Monitoring To evaluate response to Rx.

How to Detect Tumor Markers?

• ELISA • Immuno-histochemistry (IHC)• Polymerase chain reaction (PCR)• Fluorescence in situ hybridization (FISH)• Cluster Kits ( All-in-One Kit)

– Detects profiles– Patterns– Prototypes– Constellations

Tumor MarkersAntigens

Hormones

Enzymes

Tissue Specific

TUMOR

DIAGNOSIS• FNAC (CYTOPATHOLOGY)

• FROZEN SECTIONS

• INCISIONAL BIOPSY FOLLOWED BY EXCISION

• LIGHT MICROSCOPY– H/E

DIAGNOSIS, CONT• ELECTRON MICROSCOPY

• IMMUNOHISTOCHEMISTRY

• ENZYME HISTOCHEMISTRY– ALK. PHOSPHATASE IN OSTEOSARCOMA AND VAS. ENDOTHELIAL

TUMORS– ACID PHOS. IN GIANT CELL TUMOR AND HISTIOCYTIC TUMORS

• CYTOGENETICS AND MOLECULAR METHODS

MORPHOLOGY OF CELLS

• SPINDLE CELL

• EXAMPLES– FIBROUS TUMORS – FIBROUS HISTIOCYTOMA – SMOOTH MUSCLE – SCHWANNOMA– NUROFIBROMA

• SMALL ROUND CELL– SIZE OF A LYMPHOCYTE – WITH LITTLE CYTOPLASM

• EXAMPLES– RHABDOMYOSARCOMA – PRIMITIVE NEUROECTODERMAL TUMOR (PNET)

• EPITHELIOD CELL– POLYHEDRAL – WITH CENTRAL NUCLEUS – ABUNDANT CYTOPLASM

• EXAMPLES– SMOOTH MUSCLE – ENDOTHELIAL, – SCHWANN CELL – EPITHELIOD SARCOMA

ARCHITHECTURAL PATTERNS• FASCICLES OF EOSINOPHILIC SPINDLE CELLS INTERSECTING AT

RIGHT ANGLES– SMOOTH MUSCLE

• STORIFORM -SHORT FASCICLES OF SPINDLE CELLS RADIATING FROM A CENTRAL POINT,LIKE SPOKES OF A WHEEL.– FIBROHISTOCYTIC TUMORS

• NUCLEI ARRANGED IN COLUMNS -PALISADING– SCHWANN CELL

• HERRING BONE– FIBROSARCOMA

• MIXTURE OF SPINDLE CELL AND EPITHELIOD CELLS– SYNOVIAL SARCOMA

IMMUNO-HISTOCHEMISTRY

• CYTOKERATIN,– EPITHELIAL CELLS– SARCOMATOID CARCINOMA – SYNOVIAL SARCOMA– EPITHELIOD SARCOMA– MESOTHELIOMAS– CHONDROSARCOMA

• VIMENTIN– GENERAL MARKER OF CONNECTIVE TISSUE

• DESMIN– SMOOTH MUSCLE AND SKELETAL MUSCLE

• CHROMOGRANIN, SYNAPTOPHYSIN– NEUROBLASTOMA– PNET– PARAGANGLIOMA

• EMA (Epithelial membrane antigen)– SARCOMATOID CARCINOMA – SYNOVIAL SARCOMA– MPNST– LEIOMYOSARCOMA– MESENCHYMAL TUMOR– EPITHELIOD SARCOMA– CHONDROSARCOMA

• S100 PROTEIN– NERVOUS TUMORS– MELANOCYTIC TUMORS– PNET– LIPOSARCOMA– CHONDROSARCOMAS

• DESMIN,– MUSCLE TUMORS – MYOFIBROBLASTIC LESIONS– SOME NEURAL TUMORS

• SMOOTH MUSCLE ACTIN – MUSCLE TUMORS – MYOFIBROBLASTIC LESIONS

• CD34– VASCULAR TUMORS– SOLITARY FIBROUS TUMOR– FIBROHISTIOCYTIC TUMORS– SPINDLE CELL/ PLEOMORPHIC LIPOMAS– SOME NERVOUS TUMORS– EPITHELIOID SARCOMA

• CD99– PNET– SYNOVIAL SARCOMA– EWING`S SARCOMA– LYMPHOBLASTIC LYMPHOMA– ALVEOLAR RHABDOMYOSARCOMA

• SMOOTH MUSCLE ACTIN :– SMOOTH MUSCLE AND MYOFIBROBLASTS

• HHV8– KAPOSI SARCOMA

• CD31– NORMAL AND MALIGNANT ENDOTHELIAL CELLS

• ANTICHYMOTRYPSIN/ANTI TRYPSIN– FIBROHISTIOCYTIC MARKER– HISTIOCYTIC LYMPHOMA– OSTIOSARCOMA

• MYOGLOBIN/MYOD-1– IMMATURE SKELETAL MUSCLE FIBERS

• NEURONE SPECIFIC ENOLASE(NSE)– NEURAL MARKER

RHABDOMYOSARCOMA

• DESMIN• MYOGLOBIN• SK.MUSCLE MYOSIN• SK.MUSCLE ACTIN• CREATINE KINASE-M

LEIOMYOSARCOMA

• SMOOTH MUSCLE ACTIN• DESMIN• MYOSIN

NEURAL MARKERS

• S-100• NEUROFILAMENT• NSE• SYNAPTOPHYSIN• CHROMOGRANIN• CD 57• LEU-7• CD 99

VASCULAR SARCOMAS• CD 31 +• CD 34 +• FACTOR 8 +• FLI 1 +• HHV 8 +/ -• CYTOKERATIN +/ -• EMA +/ -• C- KIT +/-• UEA 1

Immunohistochemistry of GIST• CD117

– 95%• CD34

– 60- 70%• H- caldesmon

– 80%• SMA

– 15- 60%• S100 protein

– 5- 10%

How to proceed

PLAN• CYTOKERATIN +VE AND VIMENTIN –VE

– EPITHELIAL TUMORS

• CYTOKERATIN + VE AND VIMENTIN+VE• SYNOVIAL SARCOMA• EPITHELIOD SARCOMA• MESOTHELIOMA

• CYTOKERATIN – VE AND VIMENTIN -VE• NEURONE SPECIFIC ENOLASE(NSE) +

• GANGLIO-NEUROBLASTOMA

CYTOKERATIN -VE AND VIMENTIN +VE

• DESMIN +– MYOGLOBIN+– SK.MUS.MYOSIN +– SK.MUS. ACTIN +

• RHABDOMYOSARCOMA

– SMOOTH MUSCLE MYOSIN +• LEIOMYOMA

CYTOKERATIN - AND VIMENTIN +

• FACTOR VIII RELATED ANTIGEN +/ULEX EUROPEUS AGGULTININS +– VASCULAR TUMORS

• S100 +– NERVE TUMORS – LIPOSARCOMA– MELANOMA– GRANULAR CELL TUMOR

CYTOKERATIN - AND VIMENTIN +

LC +• LYMPHOMA

– ALPHA 1 ANTI TRYPSIN (AAT)+– AACT +– LYSOZYME +– PEANUT AGG +

• HISTIOCYTIC LYMPHOMA

CYTOKERATIN - AND VIMENTIN +

• ACT +– OSTEOSARCOMA– FIBRO HISTIOCYTIC TUMORS

• GFAP +• GLIOMAS• ASTEROCYTOMA

Specific tumor markers implicated in oral neoplasms

• Alpha-1-Antichymotrypsin (1-ACT) & Factor XIIIa antibodies

• BCL-2• Beta 2-Microglobulin• CD44, CD80, CD105 • Cytokeratins• Cathepsin-D• CEA, CA19-9, CA125

• Carbohydrate associated antigens

• Calretinin• C-erb2• Cyclin, MIB• Growth factors• P-53

Keratin and proliferation staining in the oral epithelium mice. Oral epithelium (lips) were immunostained for cytokeratin 13 (A–D), cytokeratin 6 (E–H), Ki-67 (I–L)

Figure 1: (a) H and E-stained section of a case of Burkitt lymphoma (note typical morphology with starry sky appearance); (b) a higher magnification of the same as in (a); (c) Bcl2 immunostaining on a case of BL (note focal weak cytoplasmic staining); and (d) Bcl2 immunostaining on a case of BL (note strong diffuse cytoplasmic staining)

Beta 2-Microglobulin:

Tumor Markers - Drawbacks

• Cancer heterogeneity

• Lack of Specificity – false positives

• Lack of Sensitivity - false negatives

• Benign diseases - positive CA 125 or CEA

• Smokers have raised CEA

• Normal persons also have small amounts

• Higher levels only with large tumor volume

• Some cancers never have higher levels

New Frontiers• Genomics: Gene structure.• Proteonomics: Protein structure.• Pharmacogenomics: Gene-based drugs structuring

and delivery.• G-scan: Human genome mapping.• New treatment modalities.• Individualised treatment modalities.• Early detection of malignant change.• Greater sensitivity and specificity.• Better monitoring and follow-up care.

Conclusion• Tumor markers can’t be primary modalities for the

diagnosis of cancer. • Main utility in clinical medicine is a laboratory test to

support the diagnosis. • With the evolving understanding of genetics and

molecular basis of human malignancies, there has been much interest in determining whether specific molecular changes in different premalignant & malignant tumors might guide treatment decisions.