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 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 5  |  Issue : 2  |  Page : 89-94

Emerging applications of immunohistochemistry in head and neck pathology


1 Department of Dentistry, Walawalkar Rural Medical College and Hospital, Chiplun, Maharashtra, India
2 Department of Orthodontics, Dr. Rajesh Ramdasji Kambe Dental College and Hospital, Akola, Maharashtra, India
3 Department of Orthodontics, ACPM Dental College and Hospital, Dhule, Maharashtra, India
4 Department of Oral and Maxillofacial Surgery, Dr. Rajesh Ramdasji Kambe Dental College and Hospital, Akola, Maharashtra, India

Date of Web Publication25-Oct-2016

Correspondence Address:
Pawankumar Dnyandeo Tekale
Department of Orthodontics, Dr. Rajesh Ramdasji Kambe Dental College and Hospital, Akola, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2277-4696.192981

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  Abstract 

Immunohistochemistry is important in diagnosis, investigation, and determining the behavior and pathogenesis of oral tumors. Immunohistochemistry protocols were developed using antibodies tagged with chromogens to identify specific markers. In these protocols, antigen-antibody reactions using nonfluorescent chromogens are analyzed in an optical microscope. 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. This paper reviews the literature on Emerging Applications of Immunohistochemistry in Head and Neck Pathology.

Keywords: Head and neck pathology, immunohistochemistry, tumor markers


How to cite this article:
Patil DB, Tekale PD, Patil HA, Padgavankar PH. Emerging applications of immunohistochemistry in head and neck pathology. J Dent Allied Sci 2016;5:89-94

How to cite this URL:
Patil DB, Tekale PD, Patil HA, Padgavankar PH. Emerging applications of immunohistochemistry in head and neck pathology. J Dent Allied Sci [serial online] 2016 [cited 2021 Jun 18];5:89-94. Available from: https://www.jdas.in/text.asp?2016/5/2/89/192981


  Introduction Top


The application of immunologic research methods to histopathology has been resulted in marked improvement in the microscopic diagnosis of neoplasms. Although histologic analysis of hematoxylin and eosin stained tissue sections remains at the core of the practice of head and neck surgical pathology, immunohistochemistry had become a powerful tool in the armamentarium of the pathologist.[1] It affords a significant advantage in the diagnosis of difficult and equivocal tumors. Immunohistochemistry has also provided insight into tumor histopathogenesis and has contributed to more accurate determination of patient prognosis. Predictable tumor expression of many of the same antigens (a macromolecular protein or polysaccharide that can bind to an antibody molecule) as their cells of origin or normal tissue counterparts validates the principle of tumor classification by immunohistochemistry. Application of immunohistochemistry in distinguishing undifferentiated oral neoplasms of different origins was achieved through the detection of tumor antigens using known antibodies.[2] Thus, immunohistochemistry is important in diagnosis, investigation, and determining the behavior and pathogenesis of oral tumors.


  Oral Squamous Cell Carcinoma Top


Squamous cell carcinoma is by far the most important form of oral cancer. Immunohistochemical markers of interest in squamous cell carcinoma are keratins (the cytoskeletal proteins of epithelial cells), other squamous cell carcinoma antigens, and markers applicable in the evaluation of the biologic potential of tumors, such as proliferation antigen.[3]


  Keratin Top


Keratins are the cytoskeletal intermediate filament proteins typical of all epithelial cells. More than 20 different keratins are known to be located in epithelial cells.[3],[4] These are the polypeptides numbered 1 through 20, comprise the type II (basic) keratins and the type I (acidic) keratins. This family of intermediate filaments is crucial in diagnostic immunohistochemistry for the identification of specific carcinoma subtypes.[5] The normal oral squamous epithelium contains predominantly high molecular weight keratins. Keratins 5, 14, and 19 are present in the basal cell layer; and keratin 4 and 13 in the upper layer, together with other keratins.[1]

Oral squamous cell carcinomas typically contain high molecular weight keratins (5 and 14) and keratin 19 in most cells in contrast to the basal distribution in normal squamous epithelia. The low molecular weight keratins 8 and 18 which are only focally present in normal oral epithelia are often present in squamous cell carcinomas. Keratin 19 expression is increased in oral premalignancy but also in hyperplastic lesions and is therefore not specific for premalignancy.[3],[4]

Poorly differentiated carcinoma that may resemble sarcoma can be identified by its content of keratins of high and low molecular weights. Reactivity with antibodies to high molecular weight keratins suggests squamous cell differentiation of a carcinoma, whereas adenocarcinomas typically show a keratin limited to low molecular weight keratins.[3] To differentiate adenocarcinomas from the adenoid squamous cell carcinomas keratin 20 can be used since it is negative in squamous cell carcinoma.[5]

Along with tumor typing various immunohistochemical markers can be used to assess the proliferation potential of the tumors.

Markers of cellular proliferation and biologic potential

Among oral tumors, squamous cell carcinomas have been the main objects of immunohistochemical studies evaluating the markers of cell proliferation and their possible prognostic correlations.

Proliferation of a cell is dependent on the cell cycle. Several nuclear proteins are differently expressed in various stages of the cell cycle that includes duplication of DNA during the cellular replication. Ki-67 antigen, a nuclear protein, was originally isolated from Reed–Sternberg's cell line. It is expressed in all cells except for those in G0 phase (resting, noncycling cells).[5] Ki-67 staining produces less background staining and more contrast hence easier to interpret.[5] Proliferating cell nuclear antigen (PCNA), a member of the cyclin family, is an auxiliary component of DNA-polymerase-δ. It appears in all cycling (proliferating) cells; therefore, it detects a higher number of cycling cells than Ki-67. Furthermore, it has long half-life (20 h) which results in staining of cells which have recently left the cell cycle and influenced by primary antibody dilution and fixation conditions. Hence, Ki-67 is a reliable tool for measuring proliferative activity in human tissue.[3] The immunoreactivity of these proliferation markers appears limited to the proliferating basal cells in the normal and hyperplastic mucosa, but it increases and also appears in suprabasal layers in the dysplastic mucosa. One study suggested that the PCNA score decreased after chemotherapy, suggesting that, this marker might be useful in monitoring the response to therapy.[5]


  Immunohistochemical Features of Oral Salivary Gland Tumors Top


The salivary glands host an extraordinarily diverse array of neoplasms. Most are proliferations of ductal and myoepithelial cells in various combinations; acinar cells participate infrequently. Interpretation of histologic material is further complicated by the fact that a variety of secondary alterations is common to several different entities. They include clear cell change, cystic change, oncocytic cytologic features, sebaceous differentiation, and prominent lymphoid stroma. To some extent, immunohistochemistry can solve the confusion regarding the typing of salivary gland tumors and aid in correct diagnosis and prognosis in few cases.[4]

Pleomorphic adenoma is the most common benign salivary gland tumor. The components of pleomorphic adenoma-like ductal cells and myoepithelial cells show immune-reactivity to various markers; staining for glial fibrillary acidic protein (GFAP) has been localized to the myoepithelial calls that appear to be the most undifferentiated ultrastructurally, in a pattern similar to neoplastic cartilage. This marker has proved diagnostically useful in both histopathologic and in fine-needle aspiration cytologic studies.[5] The majority of pleomorphic adenomas are positive, whereas normal salivary gland tissue, chronic sialadenitis, basal cell adenomas, adenoid cystic carcinomas, and low-grade mucoepidermoid carcinomas give negative results. This marker has utility in differentiating the pleomorphic adenomas from the polymorphous low-grade adenocarcinomas.[6] As it can be confused with the pleomorphic adenoma, polymorphous low-grade adenocarcinomas may simulate histologically with adenoid cystic carcinoma. Adenoid cystic carcinoma is different immunohistochemically by showing extensive immunoreactivity for S-100 protein, muscle actins, and epithelial membrane antigen; these antigens are seen in a more limited pattern in adenoid cystic carcinoma.[6] Furthermore, Ki-67 immunostaining can be helpful in their differentiation.[7]

Thus, the role of immunohistochemistry in salivary gland tumors is limited but important.[8]


  Oral Melanoma Top


Malignant melanoma can present as a primary tumor in oral mucosa or as a metastasis in adjacent soft tissues and jaw bones. The histologic diagnosis may be difficult, especially in cases in which the biopsy shows no junctional connection with the surface epithelium and the tumor is amelanotic. Histologic patterns of melanoma also are variable and may include epithelioid, spindle cell sarcomatous, or round cell appearances that must be distinguished from carcinoma, sarcoma, and lymphoma, respectively.[9]

Malignant melanoma has a typical antigenic profile, and this diagnosis usually can be confirmed easily by immunohistochemistry.[10] S-100 protein is present in almost 95% cases. They are also positive for neuron-specific enolase (NSE) and vimentin and usually are negative for keratin. Melanoma-specific antigen identified with monoclonal antibody homatropine methylbromide-45 (HMB-45) is present in about 70-80% of melanomas, especially the so-called desmoplastic (neurotropic) melanomas that may simulate soft tissue sarcomas.[5] Furthermore, 75% melanomas are positive for MELAN-A or anti-tyrosinase. Among these S-100 protein is highly sensitive but not specific, whereas HMB-45 is highly specific and moderately sensitive.[11]

Clear cell sarcomas, or melanoma of the soft parts, are unique tumors that may produce melanin and are intimately associated with tendons or aponeuroses. They express S-100 and often HMB-45, NSE, and Leu-7. The absence of mucin and the presence of melanin distinguish them from synovial sarcomas.[12]


  Benign Mesenchymal Tumors of Oral Cavity Top


Among the mesenchymal tumors, certain tumors require immunohistochemistry for identification and differentiation from other tumors. Among these are the granular cell tumor, granular cell epulis, melanotic neuroectodermal tumor of infancy and schwannoma.

Granular cell tumor (formerly granular cell myoblastoma) occurs within the oral cavity, predominantly in the tongue of the adult patient. This tumor is believed to be related to Schwann cell neoplasms and is positive for S-100 protein and vimentin, similar to schwannoma, but negative for the muscle cell markers desmin and muscle actins, consistent with its Schwann cell, and nonmuscular nature.[3] Granular cells are also positive for NSE, laminin, and myelin basic proteins. Staining is negative for neurofilament proteins and GFAP.[11]

Granular cell tumor of gingiva of newborns (granular cell epulis) which usually presents in the anterior alveolar ridge of newborns differs from granular cell tumor of adults and is believed to be of fibroblastic origin.[6] This tumor is positive for vimentin but in contrast to granular cell tumor of adults is negative for S-100 protein.[1],[6]

Melanotic neuroectodermal tumor of infancy (melanotic prognoma) is a rare, usually benign tumor that occurs in the jawbones, predominantly in infants. This tumor consists of small neural-like cells and large, pigmented epithelial-like cells and shows a complex immunohistochemical profile reflecting its divergent differentiation properties. The large cell (cuboidal cell) component is positive for keratins and melanoma-specific antigen (HMB-45), but they are usually negative for S-100. Some small cell component is also positive for vimentin, epithelial membrane antigen, GFAP, NSE, and synaptophysin.[1],[6]


  Oral Sarcomas Top


Both soft tissue sarcomas of different types and bone sarcomas arising in jaw bones may present in the oral cavity. Among the various sarcomas many sarcomas occur in the oral cavity, but before oral sarcoma is diagnosed, it is important to exclude the possibility of sarcomatoid spindle cell carcinoma and malignant melanoma. Most of the sarcomas contain vimentin, the intermediate filament protein typical of mesenchymal cells and negative for keratins. Moreover as described previously, melanoma is positive for S-100 protein and melanoma-specific antigen (HMB-45).[13]

Rhabdomyosarcomas

Among the soft tissue sarcomas, embryonal rhabdomyosarcomas represent one of the most common soft tissue sarcoma affecting the maxillofacial region. They are usually present in children in the first decade of life and most often presents histologically as a “small round blue cell neoplasm.”[14] The morphology of embryonal rhabdomyosarcoma varies widely depending on the degree of cellular differentiation, cellularity and pattern of growth. The diagnostic considerations include neuroblastoma, Ewing's sarcoma, synovial sarcoma, melanoma, melanotic neuroectodermal tumor, and malignant lymphoma. Further, it might be confused with the solid variant of alveolar rhabdomyosarcoma, with which it has prognostic implications. Being the mesenchymal tumor vimentin is uniformly present, but it has minimal utility. Among myogenic selective markers, desmin is the most consistently detectable in paraffin-embedded specimens showing appreciable staining in virtually all cases of embryonal rhabdomyosarcoma as well as in the alveolar and pleomorphic histologic types.[15] Other small round cell tumors lack desmin. Because a large number of tumor cells in rhabdomyosarcoma are normally stained, desmin is particularly helpful in small biopsy material in which the diagnosis is often the most challenging.[16] In addition to desmin, myglobin has been a marker that has been traditionally used for the diagnosis of these tumors. Unfortunately, despite its high specificity, this antibody displays poor sensitivity and is generally not very helpful in undifferentiated tumor cells. More recently, a family of myogenic proteins has been defined that plays a crucial role in the commitment of primitive mesenchymal cells toward a skeletal myogenic lineage. These proteins include MyoD1, myogenin, Myf-5, and Myf-6. Because these regulatory proteins are expressed at an earlier stage of differentiation than structural proteins, these antibodies have been used with much success for the diagnosis poorly differentiated rhabdomyosarcomas.[17]

Osteosarcoma

One of the greatest challenges in the bone and soft tissue tumor pathology is the reliable recognition of osseous matrix production in malignant lesions. Because the presence of true osteoid equates with a diagnosis of osteosarcoma, this is an important issue. Since the late 1990s, number of putatively osteoblast-specific markers have been developed including bone morphogenetic protein, type I collagen, COL-I-C peptide, decorin, osteocalcin, osteonectin, osteopontin, proteoglycans I and II, bone sialoprotein, and bone glycoprotein 75. Among these, only two-osteonectin and osteocalcin (OCN) have been associated with sufficiently good performance in paraffin section to merit their inclusion in diagnostic immunohistologic studies. OCN is one of the most prevalent noncollagenous intra-osseous proteins and is predominantly localized to osteoblasts. OCN generally has a reasonable level of sensitivity for osteoblastic differentiation (approximately 70%) and is, for practical purposes, virtually completely specific for bone-forming cells and tumors. However, sometimes fibroblasts can also cross-react with the polyclonal anti-OCN reagents therefore; monoclonal antibodies with selective peptide recognition are preferred for diagnostic work. Thus, it can be used with reasonable success as a single marker to detect such neoplasms.[2]

Ewing's tumor and primitive neuroectodermal tumor

Ewing's tumor and primitive neuroectodermal tumors (PNETs) are closely related — if not identical — neoplasms. They share similar chromosomal translocations, predominantly t(11;22) translocations, that result in a novel fusion gene encoding for a chimeric oncoprotein that appears to act as a transcription factor. These tumors also express cell surface glycoprotein p30/32 (CD99) encoded by the MIC2 gene. O13, the monoclonal antibody that binds this glycoprotein, is helpful in the identification of this rare group of tumors when analyzing formalin-fixed tissues. Interpretation of round-cell tumors should be carried out with the knowledge that some lymphomas and rhabdomyosarcomas may also stain positive with this antibody although leukocyte common antigen (LCA) and muscle markers can be used for separating these cases. It should be noted that solitary fibrous tumors also stain positive for CD99. Definitive diagnosis of Ewing's tumor/PNETs can be made with either cytogenetic, fluorescence in situ hybridization, or reverse transcriptase polymerase chain reaction analyses to identify the characteristic chromosomal/molecular defects in these tumors.[18]

Leiomyosarcomas

Among the muscle cell tumors, malignant smooth muscle cell tumors are also seen in the oral cavity although with some rarity. It probably arises from smooth muscle cells, especially those found in blood vessel walls and from undifferentiated mesenchymal cells.[16] Some of the tumor cells may be metastases from the distant sites such as the uterus. They are usually positive for muscle cell markers such as desmin and actin but may also contain keratin. However, these are not the specific markers and can also be seen in other lesions. Apart from these, α-smooth muscle fraction of actin filaments has been developed with much success.[17] It is expressed in smooth muscle neoplasms and in nonsmooth muscle lesions with myoid differentiation such as nodular fasciitis and myofibroblastic lesions. Another novel marker, caldesmon a protein involved in cell contraction that is widely distributed in both smooth and nonsmooth muscle cells has been recently used for the diagnosis of leiomyosarcoma and tumors with smooth muscle cell-like differentiation. One isoform of this protein, the high molecular weight h-caldesmon, has been reported to be specific for smooth muscle cells. It is unreactive in rhabdomyosarcoma, malignant fibrous histiocytoma, desmoid tumors and inflammatory myofibroblastic tumors.[17]

Vascular malignancies

Malignancies of vascular tissue are the next one although rare but can pose definitive diagnostic difficulties due to a wide spectrum of morphologic appearances. Angiosarcoma is the rare malignant tumors recapitulating the features of endothelial cells. Although well-differentiated tumors can be identified histologically by the vasoformative nature of the tumor cells, poorly differentiated variants are difficult to identify. Furthermore, may tumors other than angiosarcomas can show slit-like structures and pools of extravasated erythrocytes, causing differential diagnostic difficulties. Thus, the endothelial markers can be useful in such neoplasms.[17] Among the antigens most useful in identification of angiosarcomas is CD31, the platelet-endothelium cell adhesion molecule-1. This antigen is present in endothelial cells and platelets but is practically absent in carcinomas and is detectable in about 90% of angiosarcomas and also in Kaposi's sarcoma.[17] CD34 (hematopoietic progenitor cell antigen) is present in endothelial cells and in some fibroblasts. CD34 is present in about 80-90% of angiosarcomas and Kaposi's sarcoma, but is also present in other sarcomas, especially in epithelioid sarcoma, dermatofibrosarcoma protuberans, and leiomyosarcoma.[5] A new marker FLI1, a nuclear transcription factor appears to be expressed in almost 100% of different vascular tumors, including Kaposi's sarcoma.[18]


  Hematological Malignancies Top


Lymphomas

These are often diagnosed as undifferentiated malignant neoplasms. Immunohistochemistry plays a decisive role in oral lymphomas. The main problem in the instance of small cell lesions is to differentiate them from reactive lymphoid proliferations, which is done by documenting the clonal nature of the proliferations. Large cell lymphomas, in turn, must be differentiated from other undifferentiated-appearing malignant neoplasms, such as carcinomas and melanomas using antibodies to LCA (LCA, CD45), keratin and S-100 protein.[3] LCA is an excellent screening marker for lymphoid cells, including the non-Hodgkin's lymphomas. LCA positive cells can be further delineated by more specific lymphoid markers, including those for T-lymphocytes (UCHL-1, CD3, L60, and MT1), B-lymphocytes (L26, LN1, LN2, LMB1, and MB2).[19] Most of the small lymphomas are or B-cell origin and show monotypic immunoglobulin light chains (κ or λ), which can be identified consistently on acetone fixed frozen sections. Mucosa-associated lymphoid tissue lymphomas are often composed of clear-cytoplasmic, small, cleaved cells that show phenotypic markers of B-cells and monotypic light chains and may originate from the minor salivary glands in the oral mucosa. The most important pan-B-cell marker that can be identified in paraffin sections is CD20 (L26 antibody). Most other pan-B-cell antigens (CD19, CD22) and B-cell subset antigens can be identified only in acetone fixed frozen sections. Burkitt's lymphoma, a common cancer of the jaws of children in equatorial Africa, is a B-cell neoplasm that carries the B-cell antigens and is CD10 positive, consistent with its origin from B-cells of the germinal center phenotype.[3] Immunohistochemistry is also helpful in identification of Hodgkin's disease. Markers for Reed–Sternberg cells include CD15, CD30, and BLA36. In lymphocyte predominant Hodgkin's disease and the Reed–Sternberg cells differ in phenotype and are CD15, CD30 negative but CD45, CD20 and BLA36 positive.[19]

Plasmacytoma

Tissue manifestation of multiple myeloma or solitary plasmacytoma can be typically identified by the presence of monotypic immunoglobulin light-chain (κ/λ) pattern.[1]


  Peripheral Nerve Tumors Top


In contrast to neurofibromas, which contain a mixture of cells, neurilemmomas consist predominantly of Schwann cells (schwannoma) and, therefore, express S-100 protein, variably Leu-7, and occasionally GFAP. Leiomyosarcomas may show some histological resemblance, but they generally do not express S-100 protein. Neurofilament protein helps in the distinction of neurilemmomas and neurofibromas. Malignant tumors arising from nerves or showing nerve sheath differentiation are better designated as “malignant peripheral nerve sheath tumors” since they often recapitulate Schwann cells, perineural fibroblasts, or fibroblasts. Nerve sheath differentiation can be identified using markers such as S-100 protein, Leu-7, and myelin-basic protein. S-100 is expressed, albeit focally, in 50-90% of malignant peripheral nerve sheath tumors, Leu-7 in approximately 50%, and myelin-basic protein in 40%. None of these markers is specific; therefore, it is better to use the entire panel. With the exception of rare forms of glandular schwannomas, CK is not expressed. A potential confusion may arise with synovial sarcomas, but these tumors only rarely express S-100. S-100 is only focally expressed in neurilemmomas, while neurofibromas express S-100 diffusely.[20]


  Organ Specific Antigens in the Identification of Metastatic Carcinomas Top


Differentiated carcinomas of some organs sometimes can be identified by the presence of narrowly distributed organ-specific antigens.[21] Following are the antigens and antibodies of value in the determination of specific tumor type cell origin.[18],[22]

Use of protein functional pathways and modifications and protein cell type specificity may be needed when markers are proposed for use in diagnostic pathology.[23] Furthermore evidence-based methods, minimum criteria for diagnostic accuracy (STARD), will help in selecting antibodies for use in diagnostic pathology.[24]


  Conclusion Top


This Review provides a brief overview of the role of immunohistochemistry in various oral lesions, benign as well as malignant. However, many new antibodies are being commercialized the basic ones are discussed for the differentiation of various oral lesions. In the future, the pathologist will continue to play a central role in diagnosis and immunohistochemistry as the routine armamentarium in diagnostic tests. Thus, these changes likely will improve the understanding of diseases that affect the head and neck and the ability of the pathologist to render a correct diagnosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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  In this article
Abstract
Introduction
Oral Squamous Ce...
Keratin
Immunohistochemi...
Oral Melanoma
Benign Mesenchym...
Oral Sarcomas
Hematological Ma...
Peripheral Nerve...
Organ Specific A...
Conclusion
References

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