Tumor markers are grouped into diagnostic and prognostic markers. Specific diagnostic markers appear extensively in cells of a particular neoplasm and not in other tumors. These markers can be used to assess the cellular lineage and histogenic origin of various neoplasms. Thus, diagnostic markers can be used for the confirmatory diagnosis of various tumors. This paper reviews the literature on various diagnostic markers and aims to group them based on the cellular lineage of neoplasms.
Tumor markers are proteins produced by the tumor cells or by other cells of the body in response to cancer or certain benign (noncancerous) conditions. These substances can be found in the blood, in the urine, in the tumor tissue, or in other tissues. Different tumor markers are found in different types of cancer, and levels of the same tumor marker can be altered in more than one type of cancer [
Tumor markers can be categorized into diagnostic and prognostic markers. Antigens or clusters of antigens expressed by the tumors can be detected with the help of specific diagnostic investigations [
Desmin is a type III intermediate filament found near the Z line in sarcomeres. It is a 52 kD protein that is a subunit of intermediate filaments in skeletal muscle tissue, smooth muscle tissue, and cardiac muscle tissue. Its presence in vascular smooth muscle is variable [
Desmin is detected in rhabdomyosarcoma of all subtypes, benign smooth muscle tumours, benign skeletal muscle tumours and leiomyosarcoma (50%) [
Actins are family of contractile proteins of molecular weight (42 kd) which are divided into alpha, beta, and gamma subtypes depending on electrophoretic mobility. There are three isoforms of alpha actin (alpha-skeletal, alpha-cardiac, and alpha-smooth muscle) and two forms of gamma-actin (gamma-smooth muscle and gamma-cytoplasmic).
Actin is also expressed in normal tissues like skeletal muscle, cardiac muscle, pericytes, smooth muscle, myofibroblast and myoepithelial cells. Antibodies directed against alpha smooth muscle actin show positivity for smooth muscle cells and myofibroblasts, but not cardiac and skeletal muscle. Actin plays an important role in carcinogenesis. The cell transformation is accompanied by a loss of actin filaments. Alterations of actin polymerization or actin remodeling played a pivotal role in regulating the morphologic and phenotypic events of a malignant cell [
The actin antibody (HHF-35) can be used for immunostaining of myofibroblastic cells within granulation tissue, scar tissue, nodular fasciitis, and fibromatosis. Muscle specific actin antibody can express rhabdomyosarcoma, and the intensity of staining depends on the differentiation of the tumour [
MyoD1 is a protein with a key role in regulating muscle differentiation. MyoD1 is expressed in activated satellite cells and myoblast. Myogenin is a member of a family of myogenic regulatory genes, which includes MyoD1 and MRF4. These genes encode a set of transcription factors, which are essential for muscle development. MyoD1 is involved in skeletal muscle differentiation. It is therefore a useful marker for tumors of the muscle lineage, being strongly expressed in alveolar rhabdomyosarcomas [
Myoglobulin is found in cardiac and skeletal muscles. This protein appears in early muscle differentiation but is not found in sufficient amount in tumours. Myoglobulin was found to be expressed only in 50% of the rhabdomyosarcomas [
The protein is called “S100” because the constituents were soluble in 100% saturated ammonium sulphate neutral Ph. Schwann cells, glial cells, skeletal muscle, chondrocytes, lipocytes, macrophage subsets, and myoepithelial cells express S-100 normally [
S100 protein is widely distributed in central and peripheral nervous systems. S100 protein is readily demonstrable in astrocytes, oligodendrocytes, schwann cells, folliculostellate cells of adenohypophysis, satellite cells of adrenal medulla, chondrocytes, adipocytes, myoepithelial cells, and various histiocytes which include Langerhans cells of epidermis and interdigitating reticulum cells of the lymph nodes. It is not present in perineurial cells [
In mixed tumour of salivary gland myoepithelial cells demonstrate S100 proteins [
GFAP is an intermediate filament protein of glial cells. It can be used to distinguish glial hamartomas of soft tissue from nonglail lesions. GFAP is a constituent of glial cells of the astrocytic lineage and is also present in primary glial brain tumors. Neurilemomas show occasional expression of GFAP. Neuroblastoma also shows positivity for this marker [
Enolase is an enzyme involved in glycolytic pathway. It exists as three immunological subunits (alpha, beta, and gamma). Beta-beta is found in skeletal muscle, alpha-alpha in glial cells of brain, and gamma-gamma and gamma-alpha in neurons. The gamma subunit can be identified in neuronal and neuroendocrine cells, although the intensity of the immunoreactivity varies with the type of cells. It can also be identified in neuronal and neuroendocrine cells and is also identified in plasma cells and megakaryocytes. Fifty percent of neuroblastomas, paragangliomas, and neuroendocrine tumours express neuron specific enolase. About one-third of the malignant melanomas also produce the enzyme [
Neurofilament protein has been identified within neuroblastomas, ganglioneuroma, and paraganglioma. The amount of staining is proportional to the amount of cytoplasm [
Factor VIII is a complex of two components that have different biochemical, functional, and immunological properties. Factor-VIII-associated antigen (Von Willebrand factor) is synthesized by endothelial cell. It is also found in platelets and megakaryocyte. It is considered as a good marker for endothelial differentiation. This antigen can be demonstrated in normal endothelium and endocardium and in most of the benign vascular tumours (hemangiomas, pyogenic granuloma) [
The CD-34 antigen is expressed on hematopoietic progenitor cells of lymphoid and myeloid linage in the bone marrow and in some acute leukemias. It is also expressed in vascular endothelial cells and dentritic cells. It is detected in most of the benign vascular tumours. About 80–90% of malignant tumours including Kaposi’sarcoma contain this antigen [
CD-31 antigen is a transmembrane glycoprotein expressed by endothelial cells as well as various hematopoietic cells, including megakaryocytic, plasma cells, and platelets. All benign vascular tumours express this antigen and in addition about 80–100% of angiosarcomas have identifiable immunoreactivity [
Enzymes alpha-1 antitrypsin, alpha-1 antichymotrypsin, and muramidase (lysozyme) are the three most common substances utilized in the diagnosis of histiocytic and presumed histiocytic lesion.
CD-68 is a constituent of lysosomes. Among the neoplasms, it is expressed in some histiocytic, myeloid, and myelomonocytic malignant tumours and is also present in lymphomas of B-cell lineage. It is also expressed in certain carcinomas and granular cell tumours which are characterized by a superabundance of larger phagolysosomes. It is used to detect malignant fibrous histiocytoma and presents in half of the angiomatoid fibrous histiocytoma [
Vimentin is the intermediate filament traditionally associated with mesenchymal cells and mesenchymal tumours which is present in a wide variety of cells during early embryological development and is replaced by a type of specific intermediate filament in the course of differentiation. Vimentin is the major IF protein in mesenchymal cells, and it is frequently used as developmental marker of cells and tissues. Vimentin is normally expressed in fibroblast, chondroblast, smooth muscle cells, mesothelium, pericytes, melanocytes, and endothelial cells [
In nodular fascitis and fibrosarcoma, spindle cells show the expression of vimentin [
Cytokeratins (CK) make up the largest subgroup of IF proteins and represent the most abundant proteins in epithelial cells. Their expression is site specific and differentiation dependent. At present, more than 60 CK genes have been identified from the human genome sequence. Out of them fifty-four are functional genes. CK are subgrouped into Type I (acidic) of 40–56.5 kDa and Type II (basic) of 53–67 kDa. Type I and Type II cytokeratins are varied in their immuoreactivities and charge [
Depending on their tissue expression pattern, cytokeratins are grouped into simple epithelia specific cytokeratins (7, 8, 18, 19, and 20), stratified epithelia specific cytokeratins (4, 5, 13, 14, 1, 6, 10, and 19), keratinized stratified squamous epithelium cytokeratins (5, 14, 1, 6, 10, and 16), non keratinized epithelium having cytokeratins (4, 13, 19, 5, and 14), squamous epithelial cytokeratins (2, 56, and 10) and odontogenic epithelium expressing cytokeratins 8 and 19 [
It is also a valuable adjunct in the diagnosis of spindle cell tumours of the skin fibroxanthoma, spindle cell carcinoma and malignant melanoma. Paranuclear distribution of Keratin in Merkel cell carcinoma may be helpful in distinguishing this lesion from round cell sarcomas and lymphomas.
Cytokeratin has been expressed in leiomyosarcoma and Ewing’s sarcoma. It is sporadically seen in malignant fibrohistiocytoma, liposarcoma, rhabdomyosarcoma, MPNST, hemangioendotheliomas, hemangiopericytoma, and angiosarcomas [
In mixed tumour of salivary gland, ductal epithelial cells and solid cellular nests with tubular structure strongly express cytokeratin [
The diagnostic markers discussed can be summarized by classifying them as shown in Table
Proposed classification of diagnostic markers.
Markers for tumors with muscle differentiation | Muscle specific actin |
Desmin | |
Myogenin | |
Myoglobin | |
MyoD1 | |
| |
Markers for tumors with neural differentiation | S100 |
CD57 | |
P75NTR | |
Neurofilament | |
GFAP | |
Neuron specific enolase | |
Leu-7 | |
Myelin basic protein | |
| |
Markers for tumors with Vascular cell differentiation | Von Willibrand-Factor |
CD-34 | |
CD-31 | |
Type 1V collagen | |
Ulex europaeus | |
| |
Markers for histiocytes | CD-68 |
| |
Marker for mesenchymal tumors | Vimentin |
| |
Marker for epithelial tumors | Cytokeratin |
Integrin | |
Filaggrin | |
Involucrin | |
Desmosomal proteins | |
| |
Markers for melanin | S1OO |
HMB-45 | |
Melanin A | |
Microphthalmia factor | |
| |
Markers for chondrocytes | Leu-6 |
Leu-7 | |
Leu-8 | |
S100 | |
| |
Markers for bone | Alkaline Phosphatase |
Type 1 collagen | |
Type 5 collagen | |
BMP-2 | |
BMP-7 | |
TG F |
|
PDGF | |
IGF | |
Bone sialoprotein | |
Osteopontin | |
Osteocalcin | |
Osterix | |
Receptor activated nuclear factor |