Immunohistochemical analysis is of value in the diagnosis of various clinical subtypes of primary cutaneous melanoma and metastatic melanoma from unknown primary. Moreover, it can be utilized to assess the prognosis of individual tumors. Important markers of melanoma cells are as follows:[ 4 , 7 , 8 ]. Some variants e. It is a helpful marker in frozen sections for delineating surgical margins for residual or recurrent melanoma during Mohs surgery. It may also be present in some benign melanocytic lesions.
Desmoplastic melanoma is the only type, consistently negative for this marker. Mel-5 : An antibody detecting a kDa glycoprotein expressed by normal and neoplastic melanocytes. Ki67 detectable by MIB1antibody : It is a proliferation marker for melanoma cells.
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Microphthalmia transcription factor MiTF : This is a melanocytic nuclear protein crucial for growth, development and viability of melanocytes in embryonic and postnatal life. It also plays a role in synthesis of melanin. It is not a specific marker and the specificity is much lower in spindle cell variant of melanoma. However, its specificity is less as it stains melanocytic nevi equally strongly and hence its utility is limited. It is not effective to detect desmoplastic melanoma.
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Non specific markers : Vimentin, epithelial membrane antigen, cytokeratin, muscle-specific actin, neuron-specific enolase; cytokeratins may be positive in some metastatic melanoma. The clinical and histopathological features of melanoma may often be overlapping with melanocytic nevi. IHC may help in differentiating these difficult to diagnose cases.
Following are some of the recently recognized immunohistochemical markers which show differential expressivity in melanocytic neoplasms; e. CD99 expression is focally positive for some cases of spitz nevi whereas spitzoid melanoma shows predominantly diffuse staining pattern. Nucleolin protein is a major nucleolar argyrophilic protein involved in carcinogenesis. Minichromosome maintainance proteins MCM3 and MCM4 ,[ 11 ] Microtubule-associated protein-2 MAP-2 ,[ 12 ] Versican; [ 13 ] phospho-Histone H3 pHH3 :[ 14 ] expressed differentially in benign and malignant melanocytic tumors enhanced expression in dysplastic nevi and superficial spreading melanoma.
Heat shock protein HSP :[ 15 ] Expression in melanocytic nevi is equivalent to normal skin. There is overexpression in melanoma cells, especially in metastatic melanoma. Glucose transporters Glut-1, Glut-3 :[ 16 ] play role in glucose metabolism of melanocytes. Glut-1 is expressed in benign melanocytic nevi, which is downregulated in majority of the melanoma cells.
Ki67 is associated with vertical growth phase of the tumor and hence is a prognostic marker. Nucleolin protein is the second powerful prognostic indicator after melanoma thickness. MAP-2 expression is a predictor of disease progression and significantly correlates with Breslow vertical tumor thickness, Clark level and stage of disease.
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Fatty acid-binding protein 7 FABP7 expression may be associated with tumor progression and invasion; it is associated with Ki67 score. Expression of HSP on melanoma cells is associated with widespread metastasis and poor prognosis. Phospho-histone H3 pHH3 rapidly assesses the mitotic activity of malignant cells and is considered as a mitotic marker. Dysregulation of cell adhesion molecules is associated with progression of melanoma.
Carcinoembryonic antigen cell adhesion molecule-1 CEACAM-1 may have a role in progression of melanoma and serves as a potential prognostic marker in melanoma.
RUNX3 is an important tumor suppressor playing role in cell proliferation, apoptosis and tumor metastasis. Positive RUNX3 expression in human melanoma is an important prognostic factor in patient outcome. Expression of these markers shows a strong correlation with the BCC subtype; a lower expression is seen in morphoeic and more aggressive form of BCC, as compared to nodular, micronodular and superficial variants. Immunostaining for p63 is positive in the cells of SCC, and helps in diagnosis of the cases with atypical presentation. The different tumors in this group are as follows:[ 24 ].
These tumors are mainly composed of a variable proportion of the components like fibroblasts and myofibroblasts, histiocytes, dermal dendrocytes, collagen, elastin and mucin. Immunohistochemical analysis for the above components includes detection of vimentin vm , CD34, muscle-specific actin msa , factor XIIIa, and histiocytic markers. Usually these are the tumors of adults and elderly, located mostly on extremities. These occur as solitary, well-circumscribed papule or nodule Some lesions like fibrosarcoma have a deeper location.
Clinically, it is important to differentiate these lesions from other entities like cysts, lipoma and cutaneous fibroma or acrochordon. Epithelioid cell histiocytoma has a vascular component and frequently mistaken as pyogenic granuloma. Some of these lesions have the potential of local recurrence following excision and tendency to deeper invasion. Some others present with atypical cells and mitotic figures histopathologically. The classical histopathological features of dermatofibrosarcoma protuberans are evident at the mature nodular stage.
The initial plaque stage may bear histopathological resemblance to many other fibrohistiocytic tumors and may cause diagnostic difficulty. Help of IHC is occasionally required in differentiating these conditions if diagnostic confusion arises. In addition, the predominant immunohistochemical staining pattern of the constituent cells helps in understanding the histogenesis of such tumors e.
Distinguishing features of different benign and malignant fibrous tumors of the skin[ 24 ]. Though most of these tumors present with classical clinical and histopathological pictures, overlapping features may pose diagnostic difficulty at times. Desmoplastic trichoepithelioma DT may show morphological and histopathological similarities with morpheiform BCC. Syringoma and DT can be differentiated by CEA positivity and involucrin negativity in the former and vice versa.
This is the most common skin lesion showing neurofilament immunostaining. Minichromosome maintenance nuclear protein expression is a helpful marker in detecting cell proliferation in Merkel cell carcinoma. Metastatic cutaneous nodules may be the first indicator of an internal malignancy. Clinical symptoms related to the primary organ, if present, may be helpful. Some metastatic tumors may retain the characteristics of parent organ cells thyroid acini, renal tubular cells and help in diagnosis.
If such clinical and histopathological indicators are absent, immunohistochemical staining methods may be of diagnostic help. Table 4 lists some of the markers helpful in identifying the source organ for unknown cutaneous metastasis. Some immunohistochemical markers for unknown cutaneous metastasis[ 7 ].
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CD10 antigen a kDa zinc metalloendopeptidase , is expressed in dermal sheath cells of hair follicles, which are involved in regeneration of dermal papillae and thus key factor in hair growth. Immunological alteration play major role in the pathogenesis of alopecia areata. Some adhesion molecule receptors play important role in the pathogenesis of alopecia areata by enhancing adhesion of leukocytes to endothelial cells and thereafter their trafficking to dermis. These include ICAM-1, endothelial leukocyte adhesion molecule-1 and lymphocyte function associated molecule In the progressive stage of alopecia areata, these are over expressed in both affected and unaffected skin, whereas these are only weakly positive in the stable phase of the disease.
In scarring alopecia, there is inflammation involving the permanent portion of the hair follicle, resulting in irreversible hair loss. Immunohistochemical staining may help to establish the underlying etiology in a case of scarring alopecia;. In discoid lupus erythematosus causing scarring alopecia, there is a T-lymphocytic infiltrate involving the dermoepidermal junction, extending along the hair follicle and its appendages.
There are apoptotic basal keratinocytes, which show abnormal expression of certain antigens like Ki67, p53 and bcl In graft vs. In this malignant disorder of the hair follicle, patient presents with non-specific features; clinical pictures simulating follicular mucinosis or dissecting cellulitis have been reported. Other presenting skin lesions include alopecia, papules, cysts or comedones.
Because of the deep perifollicular location of the neoplastic cell infiltrate, the disorder is less accessible to skin-targeted therapy. Primary cutaneous lymphomas are a group of disorders characterized by localization of neoplastic lymphocytes T cells and B-cells to the skin.
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Skin is the second most common extranodal site of lymphoma first being gastrointestinal tract. The different types of cutaneous lymphomas vary widely in clinical features, histopathological characteristics, immunophenotypic features and therapeutic outcome. IHC play an important role in diagnosis of primary cutaneous lymphomas.
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Each type expresses multiple antigen markers on the surface of cells and there are several subclassifications based upon these. Table 5 lists the different types of primary CTCLs and their immunophenotypic expressions. Cutaneous T-cell lymphomas and their immunophenotypes[ 28 , 29 ]. Immunophenotypical abnormalities; e. To differentiate from lymphoblastic or myeloblastic neoplasms, CD3 and myeloperoxidase immunostaining should be performed, negativity of which exclude these cases.
Lymphoproliferative malignancies of regulatory T-cells Treg cells with aggressive course, necessitating polychemotherapy have been reported. There is consistent expression of bcl CD5 and CD43 expression are not seen. Primary cutaneous diffuse large B-cell lymphoma, leg type PCLBCL ; this is a tumor common in elderly females with unfavorable prognosis and tendency to disseminate. The cells are positive for CD20 and CD79a and there is strong expression of bcl Expression of bcl-6 is seen in most cases and CD10 is usually negative.
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