The life history of the various techniques that have been applied over the years to diagnostic pathology shows a remarkable variation in staying power. Some, like formalin fixation, paraffin embedding, and hematoxylin–eosin staining, have remained indispensable for close to a century. Others, such as enzyme histochemistry and tissue culture, have come and gone without leaving a trace, except perhaps in a few highly specialized fields. The case of electron microscopy is particularly telling. First developed by physicists and masterfully applied to basic cell biology issues by eminent scientists such as George Palade, Marylin Farquhar, Guido Majno, Don Fawcett, and others, it was eventually discovered by diagnostic pathologists, who used it with the hope of detecting organelles and other structures not identifiable by light microscopy that would assist them in their diagnostic quests. A period of unrestrained enthusiasm for the technique ensued in the 1960s, with the description of numerous features that were regarded as being highly associated with—and sometimes apparently specific of—certain cell types and the tumors arising from them. Well-known examples are the Weibel–Palade bodies of endothelial cells, the alternating thin and thick filaments of skeletal muscle cells, the melanosomes of melanin-producing cells, the complex desmosomes of epithelial cells, the Birbeck’s granules of Langerhans’ cells, and many others. In a strikingly short time, nearly all major pathology departments equipped themselves with one or more electron microscopes. Some organizations (eg, the Veterans Administration) went as far as choosing the electron microscope as their main research tool, and hardly any pathology article was published or a pathology presentation made without a set of electron micrographs being included (alas, sometimes merely as window dressings). Individuals like Hector Battifora, Robert Erlandson, the Bruce McKay, Jerome Taxy, Feroze Ghadially, and others acquired a welldeserved reputation for the groundbreaking studies they carried out with this technique on human tumors, whereas similarly gifted individuals did likewise in the field of renal and other medical diseases. But then a new technique arrived in the mid 1970s, called immunohistochemistry, which essentially wiped out electron microscopy as a diagnostic tool, particularly in the field of neoplastic diseases. Its advantages over electron microscopy seemed obvious: It did not require a considerable initial investment or a dedicated suite, the observer did not have to lock himself or herself in a claustrophobic environment, there was the promise of a greater degree of specificity, and it featured a substantially larger catalog of tissue-related markers. This led to a progressive disenchantment with the use of electron microscopy as a diagnostic tool. Electron microscopes were not longer bought, and many of the existing ones were discarded. A picture that made the rounds during that period featured an electron microscope with a big sign “On sale” attached to it, ironically shown by one of the best diagnostic electron microscopists of his time. Having been a witness of the many contributions made by electron microscopy in its halcyon days and having personally benefited from its use on many occasions, it was sad for me to watch this violent rejection, feeling that it was grossly unfair and not totally justified. There are still tumors in which electron microscopy plays an important diagnostic role (such as interdigitating dendritic cell tumors, for which there are no specific immunohistochemical markers at present). Ultrastructural evaluation can also play an important role in the teaching of pathology by providing a basis for the understanding of disease processes and for explaining many of the observations made with the light microscope (as somebody put it, doing electron microscopy makes you a better light microscopist). Yet the technique seemed doomed, and so it appears at present to most. But wait. Now, all of a sudden and totally unexpectedly, at the moment that the switch of the last electron microscope is being turned off, an article appears that might—it just might—reverse the trend. It comes from the Department of Pathology of Queen Elizabeth Hospital in Hong Kong, is authored by Drs K-c Lee and L-s Mak, and is presented as a new paradigm in ultrastructural examination. The article, published in this issue of the journal, describes the technique of virtual electron microscopy, which is refreshingly simple in its conception. It simply consists in adapting at the
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Mar 8, 2012
Xiaolu Wang 
Open Access