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VHA Diagnostic Electron Microscopy Program

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Diagnostic Indications for Electron Microscopy

Indications for the use of transmission electron microscopy (TEM) for pathologic diagnosis fall into major categories:

  1. Renal Disease

  2. Neoplasms

  3. Infectious Disease

  4. Metabolic Disease

  5. Disease of Obscure Nature and/or Unknown Etiology

RENAL DISEASE: The very important role of TEM in diagnosis of renal disease is well documented (13,18). In many renal diseases, a diagnosis cannot be rendered without the use of TEM. In other instances, TEM contributes to refinement of the diagnosis (e.g., subclassification of lupus nephritis) or provides crucial corroborative information. From a practical standpoint, TEM is ideally suited to the analysis of percutaneous renal biopsies, which yield a limited amount of tissue. Examination of a single glomerulus by TEM may be sufficient to allow a definitive diagnosis.

TEM often plays a crucial role in the evaluation of medical renal disorders. It allows direct visualization and precise localization of a wide variety of primary and secondary abnormalities affecting the renal glomerulus and other compartments in the renal parenchyma, including:

  • Proteinaceous deposits.
  • Immune complexes (seen as electron dense deposits).
  • Subendothelial granular deposits in kappa light chain disease.
  • Amyloid fibrils · Cryoglobulins · Other fibrillary deposits (non-amyloidotic fibrillary glomerulopathy)
  • Intrinsic and acquired glomerular basement membrane abnormalities
  • Hereditary nephritis/Alport's syndrome.
  • Thin basement membrane nephropathy
  • Diabetic nephropathy
  • "Dense deposits" of membranoproliferative glomerulonephritis, type II.
  • Damage to visceral epithelial cells and their foot processes.
  • Minimal change disease
  • Focal segmental glomerulosclerosis
  • Damage to endothelial cells (e.g., thrombotic microangiopathies)
    Inclusion bodies
  • Tubuloreticular structures (most common in lupus and HIV infections)
  • Zebra bodies (Fabry's disease)
  • Crystals (e.g., cystine crystals in cystinosis)
  • Viral Inclusions

NEOPLASMS: The important role of TEM in the diagnosis of neoplasms is well documented in major surgical pathology texts such as Silverberg's Principles and Practice of Surgical Pathology (2) and Rosai's Ackerman's Surgical Pathology (18). Their indications for the use of TEM in the diagnosis of tumors include:

  • Poorly differentiated carcinomas. In these neoplasms, TEM is indicated for the identification of squamous, glandular, and neuroendocrine differentiation which may be easily missed light microscopically.
  • Poorly differentiated round cell neoplasms with the differential diagnosis of carcinoma, lymphoma/leukemia, malignant melanoma, and sarcoma.
  • Poorly differentiated neoplasms of endocrine versus non-endocrine nature.
  • Neoplasms having a differential diagnosis of adenocarcinoma versus diffuse malignant mesothelioma.
  • Poorly differentiated spindle cell neoplasms with differential diagnosis of spindle cell carcinoma, spindle cell melanoma, and soft part sarcomas, especially fibrosarcoma, leiomyosarcoma, malignant schwannoma, and malignant fibrous histiocytoma.
    The above indications are further documented in the literature (4,5)

Additional indications for use of TEM in tumor diagnosis include:

  • Poorly differentiated hematopoietic and lymphoreticular malignancies, especially where light microscopic determinations of exact cell type is very difficult (1,6). These include anaplastic plasmacytoma, lymphoplasmacytic lymphoma, granulocytic sarcoma, acute myeloblastic leukemia, and erythroleukemia. (1,6)
  • Bone marrow biopsies from patients suspected of having myelodysplastic syndrome. TEM is helpful in documenting the pathologic changes of myelodysplastic syndrome which may be difficult to discern by light microscopy (1,3).
  • Possible cutaneous T-cell lymphomas. Use of TEM is indicated for the pathologic study of skin and lymph node biopsies as well as buffy coats of peripheral blood from patients suspected of having cutaneous T-cell lymphomas, for mycosis cells and Sezary cells may be inapparent by light microscopy, but are readily seen with TEM (1,6,7,19).
  • Use of TEM also facilitates recognition of mycosis cells in the very early stage of mycosis fungoides presenting as psoriasiform dermatitis, parapsoriasis, poikiloderma, and alopecia mucinosa (7).

INFECTIOUS DISEASE: The important role of TEM in the diagnosis of infectious diseases has been reviewed by Orenstein (16). In general, use of TEM is indicated whenever the etiology of a suspected infectious disease is unknown. More specifically, use of TEM is indicated whenever the following occur:

  • An infectious disease (viral, bacterial or protozoal) is suspected, but an infectious agent is not visible in tissue sections studied by light microscopy. Examples of this situation include infections of the intestine due to microsporidia and very small, Gram negative bacteria which are barely visible or invisible light microscopically. They are readily apparent in tissue sections studied with TEM, however (11,16).
  • There are differences of opinion among pathologists using light microscopy as to the etiology of an Infectious disease. An example of this situation was published in Ultrastructural Pathology (9).
  • There is conflicting evidence (clinical, light microscopic, immunohistochemical, serologic, and cultural) for the cause of an infectious disease.

METABOLIC DISEASE: Indications for the use of TEM in the diagnosis of metabolic diseases include the following:

  • Possible amyloidosis in which histochemical stains are negative or equivocal (8)
  • Skeletal muscle biopsies possibly having mitochondrial myopathy in which light microscopic changes are absent (17,20)
  • Peripheral nerve biopsies from patients suspected of having neuropathies in which light microscopic changes are absent (17,20)
  • Liver biopsies from patients suspected of having alcoholic liver disease. Alcoholic liver disease is associated with characteristic ultrastructural findings of mitochondrial hyperplasia and gigantism and fibrillar Mallory bodies which may be present when light microscopic changes of alcoholic liver disease are minimal or absent (21). Use of TEM in the study of liver biopsies from patients suspected of having alcoholic liver disease is indicated when light microscopic changes typical of alcoholic liver disease are absent or minimal.
  • Hypersensitivity diseases of the skin. Use of TEM is indicated in the study of skin biopsies from patients suspected of having hypersensitivity diseases of the skin (including drug eruptions), for TEM may on occasion reveal dermal vascular injury (especially acute degeneration of endothelial cells and electron dense deposits in dermal vascular walls) which may be very difficult to see light microscopically and/or immunohistochemically (12,15,22).

DISEASES OF OBSCURE NATURE AND/OR UNKNOWN ETIOLOGY: Use of TEM is indicated in the study of tissues having diseases of obscure nature and/or unknown causes. An example of this situation was published in Ultrastructural Pathology (10).

MICROPROBE ANALYSIS: Microprobe analysis is currently primarily used for the pneumoconioses, especially asbestosis (23, 24). New applications using new devices such as laser probes are being detailed by Dr. Roggli, formerly of the Durham VAMC and now Professor at its affiliate institution Duke University in reference 24.



1. Diagnostic Electron Microscopy. New York: John Wiley & Sons. 1979; Vol.2:47-162

2. Principles and Practice of Surgical Pathology. New York: Churchill Livingstone. 1990:119-144 3. Neoplastic Hematopathology. Baltimore: Williams & Wilkins 1992; 1367-1404

4. Am J Surg Pathol. 1995;19:247-250

5. Arch Pathol Lab Med. 1994;118:922-926

6. Diagnostic Electron Microscopy of Tumours. Boston: Butterworths. 2nd ed. 1985

7. Cancer Treatment Reports. 1979;63:565-570

8. Oral Surg Oral Med Oral Pathol. 1989;68:618-623

9. Ultrastruct Pathol. 1995;19:95-99

10. Ultrastruct Pathol. 1996;20:195-202

11. Ann Int Med. 1996;125:523

12. Hum Pathol. 1993;24:384-390

13. EMSA Bulletin 1991;21:68-73

14. Diagnostic Electron Microscopy. New York: John Wiley & Sons. 1979;Vol 2:309-350

15. Hum Pathol. 1979;10:313:325

16. J Histotechnol. 1995;18:211-224  

17. Diag. Ultrastructure of Non-Neoplastic Diseases. New York: Churchill Livingstone 1992;594-614

18. Ackerman's Surgical Pathology. St. Louis: The C.V. Mosby Co. 1989;34-36 and 820-853

19. Cancer Treatment Reports. 1979;63:571-574

20. Muscle Biopsy: A Practical Approach. Philadelphia: Bailliere Tindall. 1985;129-183

21. Diagnostic Electron Microscopy. New York: John Wiley & Sons. 1979;Vol 2:15-46

22. J Am Acad Dermatol. 1990;22:359-361

23. Microprobe Analysis in Medicine. Washington: Hemisphere, 1989.

24. Biomedical Applications of Microprobe Analysis: Academic Press, 1999

The above is modified from a document originally prepared by Dr. John Guccion of the Washington, DC  VAMC  EM laboratory.