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In Search of the Origins of Modern Surgical Pathology

Gal, Anthony A.

Advances in Anatomic Pathology: January 2001 - Volume 8 - Issue 1 - p 1-13
Review Articles And Mini Reviews
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Pathology is a relatively new specialty in the history of medicine and borrows much from the clinical and basic sciences. The clinicopathologic correlation began with deceased (autopsy) and was later extended to the living (surgical pathology). Although the roots of surgical pathology began during the first half of the 19th century, this distinctive specialty evolved through many subsequent technical and scientific discoveries. This historical review will trace the advances in microscopy, histochemistry, and surgery in the later half of the 19th century and early 20th century that led to the development of modern surgical pathology.

Deparment of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, U.S.A.

Accepted 1 October 2000.

Address correspondence to Anthony A. Gal, M.D., Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 1364 Clifton Road, N.E., Atlanta, GA 30322; E-mail: agal@emory.edu

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INTRODUCTION

The arrival of the millennium affords a splendid opportunity to explore where surgical pathology began and how it developed from other disciplines. Our rich history has many lessons worth learning from. The issues and situations of the past, although seemingly very distant and different, often reappear and stimulate one's creativity, but can also haunt or stifle one's progress. As the Roman orator Marcus Tullius Cicero (106–43 BC) wrote: “Not to know what happened before one was born is always to remain a child”(1). An awareness and appreciation of the past can lead one to better understand their story and, perhaps, impact their own destiny.

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PATHOLOGY IN THE 19TH CENTURY

Pathology, at least as one knows it in the current sense, is a relatively new specialty in the history of medicine (2,3). It is really not a distinctive subject in and of itself, and borrows so much from the clinical and basic sciences (Plate 1A) (4,5). Surgical pathology at the beginning of the 21st century is a specialty that is driven by pathologists: these are physicians who undergo specific special training in gross anatomy, autopsy dissection, histology, physiology, as well as in clinical medicine. The current practice of pathology depends on strong interactions with other clinical and research disciplines (Plate 1B).

Figure. PLATE 1.

Figure. PLATE 1.

To begin the journey into examining the origins of modern surgical pathology, we must set the clock back to the 19th C. The term “surgical pathology” appeared in the first quarter of the 19th century in the title of several monographs, lectures, and essays. In the historical collection at the National Library of Medicine, the first catalogued entry of the term “surgical pathology” is James Wilson's, Lectures of the Blood and on the Anatomy Physiology, and Surgical Pathology, of the Vascular System of the Human Body, delivered before the Royal College of Surgeons in the summer of the year 1819 (6). “Surgical pathology,” along with “morbid anatomy” and “pathologic(al) anatomy,” were frequently used in the titles of pathology books in the 19th century, although the popularity of the latter two terms has diminished more recently (Figure 2).

FIG. 2.

FIG. 2.

In the mid-to-late 19th century many surgeons performed macroscopic pathologic examination, as advances in surgical technique led to more extensive surgical operations (7–9). They were able to observe gross specimens and determine with some level of accuracy whether the lesion was diseased or not, or benign or malignant, but not much else. If a tumor or lesion was excised it was discarded and there was no documentation or minimal reporting (10). On some occasions a brief description might have been recorded in a logbook, but there certainly were no written reports as we know today. If the specimens were of teaching value or of an extraordinary nature, they might have been retained in a medical museum (7).

Unlike the practice of today, the autopsy was performed by clinicians. This was the case, particularly in Britain, France, and Italy, and also in the U.S. where the practicing physician or surgeon undertook the postmortem examination of their own patients ,and thus gained a first-hand knowledge of gross pathology (4,5,11–13). Despite their enormous interest in performing postmortem examination, many clinicians lacked thorough skills in autopsy technique (14). A few early pathologists who were not involved in direct patient care pursued more scholarly endeavors, i.e., autopsy prosection, teaching, writing, or proposing theories of disease (4,15).

In the mid 19th century through the Austrian and Germanic influences of Karl von Rokitansky (Figure 3) and Rudolf Virchov (Figure 4), autopsy pathology became the cornerstone in the science and practice of medicine (5,16). In Vienna, Rokitansky was a strong proponent of gross anatomical pathology; it is alleged that he performed over 30,000 autopsies during his 45-year career (2,4,7,8,14,16–18). He is also credited for creating the Institut für Pathologische at the Allgemeine Krankenhaus. This specialized institute was designed to centralize autopsy pathology away from the clinical practice of medicine for the purposes of postmortem analysis, research, and teaching (4,5).

FIG. 3.

FIG. 3.

FIG. 4.

FIG. 4.

In Berlin, Virchov, a younger contemporary of Rokitansky, elevated autopsy pathology to a much higher level by Virchov's incorporating microscopic tissue analysis (2,4,12,16,17,19). Published in 1858, Die Cellularpathologie is one of the most important monographs in the history of medicine (2,4). Virchov's observations formed the cell theory of disease, that is the concept still held today, in which changes at the cellular level lead to disease. Through the efforts of Virchov and his disciples, microscopy became an integral part in the practice of pathology.

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MICROSCOPY

Microscopy began in the early 17th century, but there were few scientific applications (Plate 1C) (20,21). With the simple microscope, Antony van Leeuwenhoek studied various biologic preparations, including red blood cells, protozoa, and bovine optic nerve (20,22,23). During the same era, Robert Hooke is credited with the development of one of the first compound microscopes. Hooke published Micrographia in 1665, which illustrated diverse objects with the compound microscope and from sections of cork, arose the term the “cell” (5,20,23–25).

Microscopes in the 18th century and early 19th century were very crude: they were handmade, the lenses individually polished, and impractical. During this period, there were many mechanical improvements in microscopy, but there were problems in optical resolution (21). In the 1830's Joseph Lister, the father of Lord Lister, developed the first achromatic lenses which solved the problem of spherical abberation and led microscopic optics into a new era (20,24,26).

Midcentury naturalists, such as the Reverend J. G. Wood, inspired many amateur microscopists to study and explore their world (Plate 1D) (24,27). The microscope was a toy, a folly of the wealthy, and certainly not, at this point in time, an instrument of the pathologist.

The era of “brass and glass” (24) refers to the period (mid-19th century to the turn of the century) in which major advances in microscope design and technology led to fundamental applications in the biologic sciences. The pre-eminent manufactures of microscopes were Leitz and Zeiss in Germany, and elsewhere in Britain (Figure 5A), France, and the U.S. (28). Carl Zeiss is credited with manufacturing affordable microscopes with excellent optics that were capable of high resolution. The mathematician and physicist, Ernest Abbe, who worked closely with Zeiss, was credited for several innovations, including the oil immersion lens, the apochromatic lens, and the substage condenser (Figure 6) (21,24,26,29). Towards the end of the 19th century, several manufacturers, including Ernst Leitz in Wetzlar, Germany, designed brass microscopes for use in various applications (Figure 5B) (30). After the turn of the century, microscopes were largely made from cast iron and utilized brass, primarily in the objectives or oculars (Figure 5C). A reason for this change in design was that brass was expensive, difficult to maintain, and that cast iron was cheaper and would not corrode (20,26).

FIG. 5.

FIG. 5.

Figure 5

Figure 5

Figure 5

Figure 5

FIG. 6.

FIG. 6.

The field of photomicrography began in the mid 19th century to record images seen under the microscope (31–33). William Henry Fox Talbot, the father of photography, made photomicrographs of plants as early as 1839 (34,35). Better equipment and technology became available in the following decades (Figure 7). In photography, gelatin silver bromide dry plates in the 1870s and George Eastman's Kodak nitrocellulose roll film in the 1880's led to many applications in photomicrography (32). At the Army Medical Museum, Joseph Woodward, was a pathologist, microscopist, and an early leader of American photomicrography. He devised a very elaborate photomicroscope that followed the path of the sun that required very long exposures (31,32,36,37).

FIG. 7.

FIG. 7.

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HISTOTECHNOLOGY

Many 19th century advances in histochemical stains and tissue processing techniques contributed to the rise of surgical pathology (Plate 1E) (7,38). There was a great deal of enthusiastic scientific inquiry in the mid-19th century that led to the study of various tissues with the microscope. Following careful dissection, tissues needed to be reproducibly cut and stained, as microscopy became more widely implemented in the biological sciences (Figure 8).

FIG. 8.

FIG. 8.

At this junction, there are two major types of dyes: natural and synthetic dyes. The natural dyes are derived from plant and animal substances. Amongst these dyes are carmine, saffron, hematoxylin, indigo, alizarin red, and berry and vegetable juices (38–42). Joseph Gerlach was a German histochemist who was one of the first to use histochemical stain in microscopy. In 1858 he utilized a dilute ammoniacal carmine stain, derived from the Mexican insect Dactylopius coccus, to study tissues sections of cerebellum (39,41).

The history of hematoxylin intertwines exploration in the New World with commerce in the Old World. Logwood tree (Haematoxylum campechianum) is the natural substance from which hematoxylin is derived and grows in the Campeche region of Yucatan Peninsula in Mexico, Belize (British Honduras), and Jamaica (Plate 1F) (Figure 9) (42). For centuries the Indians used a derivative of logwood for dyeing woven fabrics dark purple and black. In the early 16th century when the Spanish explored the coast of the Yucatan and Belize in search of gold and silver, they found logwood and they introduced it to European textilemakers as a competitor to indigo (42–44). For several centuries various formulations of logwood dyes were used in fabrics, but there were problems: it was unstable, it would bleach easily, and these shortcomings led to many regulations against its use in the textile industry (42,43).

FIG. 9.

FIG. 9.

The first histologic application of hematoxylin dates to 1863 when Wilhelm Waldeyer unsuccessfully applied a crude aqueous extract of logwood chips to tissue sections (39). In 1865, Franz Böhmer employed a technique with alum as a mordant, which is required to convert hematoxylin to a base, which will then combine actively and strongly stain with acidic nucleic acids (42,43). This is the first successful description of the hematoxylin-stain technique that is still used today with slight modifications (38,39,42,43).

The history of the synthetic analine dyes is as intriguing. In 1856 William Perkin, an 18-year-old chemistry student at the Royal College in London, attempted to extract quinine from coal tar, but noticed a curious black sludge at the bottom. Mixed with ethanol, the substance turned purple, which he latter called “mauve” or “analine purple,” and became the first synthetic analine dye (39–41). This accidental discovery heralded the beginning of the analine dye industry and led to the application of many commercial histochemical stains to biologic tissues. The “Dr. G. Grübler & Company” in Germany took predominance from the British in the late 19th and early 20th century (39,41,45). By 1900 there were six German dye companies manufacturing 47 different analine dyes (Figure 10) (40). Through the contributions of many histologists, the combinations of various analine dyes led to the development of innumerable histochemical stains (Figure 11) (46).

FIG. 10.

FIG. 10.

FIG. 11.

FIG. 11.

In addition to applications in tissues, various investigators used histochemical dyes to study other biological and medical samples. During the late 1870's Paul Ehrlich applied specific acid and basic analine dyes to blood smears and observed that different blood cells stained with basic dyes, but others with acidic dyes. This led to the terms “eosinophil, basophil, and neutrophil”(39). Ehrlich's stain formulation is the predecessor of the Romanovsky stain that is currently used today (39,47).

A shortcoming of histotechnique in the mid-19th century was the inability to reproducibly cut tissues. Manual methods were employed to cut tissues with a sharp knife or razor (38). The microtome, introduced in the 1830's, was an instrument that finely cut tissues prior to staining (46). The automatic rotary microtome, introduced by Charles Minot in 1885, is the forerunner of the modern electric microtome (Figure 12) (46). The hardening of tissues for cutting that began in the early 19th century with freezing in salt brine, but was rather unsuccessful (9,48). Freezing microtomes, introduced in the 1870's, eventually led to the development of the frozen section (see below)(Figure 13) (46). Paraffin wax embedding was described by Edward Klebs in 1869 and tissue fixation with formaldehyde was discovered in 1893 by Ferdinand Blum (38,46).

FIG. 12.

FIG. 12.

FIG. 13.

FIG. 13.

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THE GOLDEN AGE OF SURGERY

The dramatic technical advances in surgery from 1850 to 1900 greatly contributed to the definition of modern surgical pathology (Figure 14). At midcentury, surgical patients had a 50% chance of dying due to pain, bleeding, shock, infections, or other postoperative complications (1,49). Surgeons were very limited in what they could do for their patients. If a malignant growth was found, it was typically inoperable and the patients died soon afterwards.

FIG. 14.

FIG. 14.

Controlling pain through anesthesia was first discovered in nearby Augusta, Georgia. Crawford Long successfully applied ether during a surgical procedure in 1842, but did not publish his findings until 1849 (50,51). At the Massachusetts General Hospital, William Morton employed inhaled ether on October 16th, 1846. This well-documented event is regarded as the public demonstration of inhalational anesthesia (49,52,53).

The control of bleeding through improved hemostasis is the second major technical advance in surgery. This occurred through an increased understanding of physiology and surgical instrumentation.

The third, and perhaps most important, advancement in surgery was the control of infection. Discovery of the bacterial causation of disease led to the applications of antisepsis and asepsis. In Vienna, Ignaz Semmelweis made the observation that handwashing in chlorinated lime solutions could reduce the incidence of postpartum infections (54–56). Although he was ridiculed by his colleagues, this simple task forms one of most important principles of modern infection control (1,49,57). His cause was also championed by Oliver Wendall Holmes in the U.S.(1,49). Another originator of antisepsis was Joseph Lister who used carbolic acid soaks and sprays and markedly decreased postoperative infections (49,55,58,59). Louis Pasteur is credited with the germ theory of disease and many other observations on microbiologic fermentation and putrefaction. Following Pasteur's observations, Robert Koch isolated anthrax bacteria in 1880 and bacillus tuberculosis in 1882. Through these and many other discoveries, “the nature of infection, contagion, and wound suppuration became intelligible”(1).

Along with the applications of antisepsis / and (later) asepsis, there were many radical changes in operating room design in the late 19th century and early 20th century (60). Until the 1880's, surgeons were clad in street clothes, did not wear facemasks or gloves, and operated in dimly lit “operating theaters.” With many onlookers, surgery was more of a gladiatorial event than a veritable therapeutic procedure. To improve postoperative survival, some adventuresome surgeons applied scientific principles learned from microbiology and other disciplines.

By the mid 1880's antisepsis and the beginnings of asepsis were formally accepted into surgical practice (1,49,58). At Johns Hopkins Hospital, William Halsted implemented many aspects of modern aseptic surgical practice (i.e., sterlized gowns, masks, drapes, handwashing) to prevent infections (61). Undoubtedly other “new technologies” of the latter 19th century, such as the introduction of electricity, indoor plumbing, refrigeration, etc, contributed to the practice of modern surgery.

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THE NEAR DEATH OF SURGICAL PATHOLOGY

At the highest levels of European political and medical society, surgical pathology was nearly given a death sentence following a particular misdiagnosis of malignancy. In Germany the newly appointed 55-year-old Emperor Frederick III developed a throat lesion in the Spring of 1887 (62–64). The eminent British otolaryngologist Morell MacKenzie came to Berlin and biopsied the laryngeal lesion. This was one of the first uses of the biopsy technique, since microscopic evaluation of tissue from living patients had been largely unheard of. In this case the pathologist was Virchov who had semiretired from active practice of pathology and was more involved with various administrative, social, political, and anthropologic concerns (64). Following at least three sets of laryngeal biopsies, Virchov interpreted these hyperplastic verrucous lesions as benign (pachydermia laryngis and pachydermia verrucosa) (62,64). The Emperor's condition deteriorated and the laryngeal lesions recurred. An expectorated sputum specimen was sent to Wilhelm Waldeyer who ultimately diagnosed it as carcinoma. Within a few months, the Emperor died from the complications of advanced laryngeal carcinoma (62–64).

The consequences of these discrepancies sent shock waves throughout the medical community in Germany and Britain. Although challenged by others, Virchov remained largely unaffected (64). Following the publication of his memoirs, MacKenzie, however, received many personal and professional attacks which led to censorship and expulsion from the Royal College of Physicians (63,65). This reinforced the notion that microscopic examination of tissues from living patients was unreliable and that a knowledge of malignancy can only be obtained from the autopsy (3,66).

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DEVELOPMENT OF FROZEN SECTIONS

It has been suggested that surgical pathology began in America (4,5,8,9). Towards the end of the 19th century, the physical, political, and philosophical differences between Europe and America became more apparent. The new intellectual activity, the lack of an interest in formal academia and theory, the adventuresome pioneer spirit, and the willingness to take risks allowed many creative individuals to apply new technology that had not been previously imagined.

In a few years following the opening of the Johns Hopkins School of Medicine, William Welch was the first American pathologist to introduce the frozen section (FS) technique in surgery (9,13,67). Although FS had been used in the early 1880's at the Glasgow Infirmary for examining postmortem tissues, it had not been used during surgery (10). In 1891, using a carbon dioxide freezing microtome, Welch examined breast tissue during a surgical procedure (9,66,68,69). Halsted sent a small piece of breast tissue for analysis and Welch attempted to perform a frozen section. Unfortunately, Welch took so long to perform and interpret the FS that Halsted finished the procedure without knowledge of the results.

It is to Thomas Cullen that we can credit the first published technique for intraoperative FS in 1895 (9,70,71). Having studied in Germany with Johannes Orth, a notable pathologist and student of Virchov (72), Cullen understood the principles of tissue hardening and freezing and performed FS by prefixing tissues in formalin prior to sectioning (9). This new technique enamored Welch so much that the Bulletin of the Johns Hopkins School of Medicine was stopped at press to allow for the first published description of FS technique (9,70,71).

In the ensuing decade others claimed credit for FS technique or modified it; however, none was better publicized than the description from Louis Wilson at the Mayo Clinic (7,9,73,74). Recruited as a “full-time” pathologist at the new Pathology Department in 1905, Wilson was told by William Mayo “I wish you pathologists could tell us if a tissue is cancer or not while the patient in on the table” (73). With a background as a biology teacher and familiar with the use of botanical stains, Wilson described a very simple technique using methylene blue to stain frozen tissue samples (75). This staining method still currently used at the Mayo Clinic would allow for a diagnosis within a few minutes (76,77).

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GENERATION OF THE SURGEON-SURGICAL PATHOLOGIST

“The hybrid specialty of Surgical Pathology was born out of necessity and out of wedlock” (78).

Pathologists in academic departments of pathology were more involved with autopsies, research, and were disinterested in clinical or practical applications. It is in departments of surgery or gynecology that physicians applied their surgical and pathological skills to become the first surgical pathologists to utilize microscopic examination of the preoperative biopsy (68). The German gynecologist Carl Ruge made the diagnosis of cervical and uterine cancer by microscopic examination of currettings and published his observations in 1878 and 1880, respectively (4,7,9,66,68). In addition to being an early “surgical pathologist,” Ruge may have been one of the first true international consultants because gynecologists from other countries sent biopsy materials for his interpretation (66).

In the U.S. Cullen became the head of Gynecologic Pathology at Johns Hopkins Hospital (67). His long and illustrious career is noted for authoring several great monographs, including several devoted to cervical and uterine cancer, uterine leiomyomata, and adenomyosis (79–82). Another early surgeon-surgical pathologist was William “Wild-Bill” Clarke at Columbia University who was the Course Director of Surgical Pathology in the Department of Surgery (78,83). His nickname suggested that he was quite a character, but his legacy is most evident in his students Allen O. Whipple and Arthur Purdy Stout, who were really part of the second generation of surgeon-surgical pathologists (78,83).

At Johns Hopkins, Joseph Bloodgood was one of the most important surgeon-surgical pathologists in the first quarter of the 20th Century (67). Like Halsted and Cullen, Bloodgood studied surgery, histology, and patholgy at various European institutions and was influenced by Theodore Bilroth and Theodore Kocher (84). In 1893 he established the first Department of Surgical Pathology within the Department of Surgery and by 1897 he was one of the first surgeons to routinely use FS during surgery (13,61,66,67,84). He was an innovator, a stimulating teacher, and a strong advocate of surgical pathology (84). Bloodgood was somewhat dubious of FS at first, but later fought very hard to validate it (7,9,67,69,85). He was politically active and influenced major medical organizations, such as the American College of Surgeons to mandate that FS be employed during surgery (7,9,67).

Not every major American pathologist of this era was a supporter of FS (7,9,66). James Ewing at Memorial Hospital was not an advocate of the FS (9). In an editorial in 1925, Ewing wrote “Having made more errors by the frozen section method in breast cases than by gross examination, I have not resorted to frozen sections in this field for many years, but rely almost entirely on gross inspection of the breast tissue. Many of my colleagues report to me the same tendency”(86). Other pathologists of that era, Francis Delafield, T. Mitchell Pruden, Aldred Warthin, W. M. Late Coplin, and many others distrusted the FS (7,9). The debate continued into the 1930's: the performance of FS during surgery was thought to be a fad, folly, or fetish (Figure 15) (9,87). But it was not until the pre-World War II era that surgeons, as well as pathologists, finally realized the major significance and contributions of FS.

FIG. 15.

FIG. 15.

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THE FAMILY TREE

Nearly every practicing American surgical pathologist today can trace a strong link to at least one of four institutions (Johns Hopkins University, Columbia University, Memorial Sloan Kettering, and Washington University) where the many generations of surgeon-surgical pathologists and then surgical pathologists developed and refined their craft (3,13).

In New York City, Arthur Purdy Stout and Raphael Lattes formed one of the most comprehensive Departments of Surgical Pathology (78,83,88,89). Also in New York City at Memorial Hospital, James Ewing was followed by Fred Stewart and Frank Foote who influenced many aspiring young surgical pathologists (90–92). And finally, in St. Louis, Lauren Ackerman's spirited intensity stimulated many promising young individuals who joined him and have become many of the leaders of modern surgical pathology (93,94).

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FINAL MUSINGS

Surgical pathology essentially began at the turn of the last century from the technical contributions in microscopy, histochemistry, and surgery (9). The clinicopathological correlation began with the autopsy and later was extended to surgery. The use of the microscope enabled surgeons, and then pathologists, to translate morphologic findings present in small biopsy specimens into specific and relevant clinical information (4). The many contributions (and demands) from our surgical colleagues led to the need for precise and accurate pre-and intraoperative diagnoses, and continues to do so today.

The first three generations of surgeons-surgical pathologists were trained in surgery, but had an enormous interest in applications of pathology (13). Not until the mid-20th century did surgical pathologists gain autonomy and fiscal independence from other clinical disciplines. Divisions of Surgical Pathology were initially within Departments of Surgery, but were later incorporated into Departments of Pathology. At some institutions this union did not occur until the early 1960's (R.R. Pascal, personal communication September, 2000) (3,13,78,83).

The practice of modern surgical pathology continues the traditions of the past. That is, the integration of the technical and scientific advances of the day: in the 19th century—light microscopy, histochemical stains, and frozen sections— and in the 20th century—fluorescence microscopy, electron microscopy, and immunochemistry. As for the 21st century, the crystal ball forecasts that molecular techniques could play a very active role in diagnostic pathology. But will these “novelties de jour” supplant light microscopy? Only time will tell, but one can safely assume that a single stain, hematoxylin–which celebrates its 146th birthday in the millennium—will be here for many years to come.

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Acknowledgments:

The author would like to dedicate this manuscript to the histotechnologists at Emory University Hospital. Additional acknowledgments are to Robert Santoianni and Donna Martin for their superb assistance with the preparation of the figures.

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Keywords:

History of medicine; History of pathology; Microscopy; Histotechnique; Surgical pathology

© 2001 Lippincott Williams & Wilkins, Inc.