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VHA Diagnostic Electron Microscopy Program

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Diagnostic Electron Microscopy Overview

The appropriate use of ultrastructural study adds a new dimension to diagnostic pathology.  Its value in difficult diagnostic situations has been demonstrated repeatedly in VA hospitals, particularly when there is close coordination between pathologists and clinicians.  

Ultrastructural study may be applied to a variety of substances including biological materials. By examination of specially prepared tissue sections, changes not perceived by light microscopy can be identified leading to improved diagnostic interpretations. For instance, in certain kidney diseases, the correct diagnosis can be made only by these means and this in turn affects the prognosis and selection of therapy. Similarly, certain neoplasms can be identified definitively only through ultrastructural study with obvious implications for prognosis and selection of therapy. Many other examples include studies of diseases of the liver, muscle, nervous and gastrointestinal systems. Another area of growing importance is the identification of viral particles in biological material. In some instances, ultrastructural study is the only way to establish the presence of a viral infection and in other instances a diagnosis may be made earlier than by serological methods. The use of electron microscopy is a vital part of the modern diagnostic armamentarium. The costs of diagnostic EM are relatively small in light of the benefits to patient care.

The role of electron microscopy in diagnostic pathology was reviewed by Rosai and Erlandson (American Journal of Surgical Pathology, 19: 247-250, 1995). They concluded that electron microscopy remains “... an important and sometimes essential tool in diagnostic pathology.”  In this article they compared electron microscopy with immunohistochemistry: “...The techniques of electron microscopy and immunohistochemistry should be viewed not as competing with each other but rather as complementary methods for achieving the same goal (i.e., the recognition of diagnostic structures, features of differentiation in neoplasms, or microorganisms). When comparing these procedures, it becomes apparent that the detailed fine structure of cellular and extracellular constituents can be resolved only by high resolution transmission electron microscopy. Examples of such diagnostic structures include ciliary abnormalities in immotile cilia syndrome, bands of Bungner (rows of Schwann cell processes) in axonal atrophy, Weibel-Palade bodies in endothelial cells, Birbeck granules in Langerhans cells, melanosomes in amelanotic malignant melanoma, and myosin/ribosome complexes or rudimentary sarcomeres in poorly differentiated rhabdomyosarcoma.

Using immunohistochemical stains, we can only assume the presence of these potentially diagnostic structures in neoplasms;  as with all other techniques, there are pitfalls and limitations associated with immunohistochemistry. These include the failure of attempts to standardize methodology and institute quality control; the paucity of absolute tissue- or tumor-specific antibodies; the lack of a distinct diagnostic immunophenotype in many tumors; the occurrence of anomalous (aberrant or unexpected) immunostaining; and the fact that small amounts of antigens may not be detectable by immunostaining methods, notably in neuroendocrine carcinomas. A false diagnostic impression by the pathologist may also result in the selection of an inappropriate panel of antibodies. These limitations sometimes require extensive (and expensive) panels of antibodies for the evaluation of a given neoplasm. Similar considerations apply to other special techniques such as cytogenetics and molecular analysis.

“Only the most appropriate and cost-effective ancillary diagnostic procedure should be employed in the evaluation of cases that cannot be resolved using routine methods. The choice of the initial procedure should be based on the specific problem and the resources available to the laboratory. For instance, the first approach for the elucidation and subclassification of hematopoietic neoplasms should be immunohistochemical. Conversely, whenever possible, the initial approach to the adenocarcinoma versus epithelial mesothelioma (not sarcomatoid variants) diagnostic dilemma should be electron microscopy, in view of the fact that long, thin, nonrigid, nonintestinal-type microvilli devoid of a glycocalyx and actin rootlets are diagnostic for epithelial mesotheliomas, whereas none of the antibodies presently advocated for this differential diagnosis is specific. Ultrastructural studies also may be preferable to immunophenotyping for the evaluation of percutaneous fine-needle aspiration specimens.

Electron microscopy should also be used as a first approach or conjointly with other procedures for the diagnosis of a select number of nonneoplastic diseases. Examples include glomerular diseases (currently the most widely used diagnostic application of electron microscopy), notably the idiopathic nephrotic syndrome, benign familial recurrent hematuria (thin basement membrane syndrome), and hereditary nephropathy [i.e., Alport's syndrome]; bullous skin disorders such as epidermolysis bullosa; diseases due to ciliary dysmorphology; and the rapid diagnosis of viral diseases.”  Another excellent review article on the role of electron microscopy in diagnostic pathology is by Dr. Andra R. Frost, et al at the Department of Pathology, The George Washington University Medical Center, Washington, DC. (Archives of Pathology & Laboratory Medicine, 1994;118:922-926).