SPECIAL CONTRIBUTION Section Editor: Claire W. Michael, M.D.
Cytopathology: Why Did It Take So Long To Thrive? James R. Wright, Jr. M.D., Ph.D.*
Lionel S. Beale of London made some of the earliest contributions to Cytopathology in the 1850–1860s. Cytopathology then experienced a 601 year hiatus during which few advances were made. In 1927, Londoner Leonard S. Dudgeon published his wet film method for rapid intraoperative diagnosis and in 1928 Greek-American George Papanicolaou and Romanian Aurel A. Babes¸ independently discovered that cervical cancer can be diagnosed using vaginal smears; these were huge advancements. Yet, there was another hiatus where little progress was made which lasted until the publications of Papanicolaou and Trout in the early 1940s. After that, the field of exfoliative Cytopathology immediately flourished. None of the standard histories of Cytopathology explain these two gaps. Primary and secondary historical sources were examined to explain this pattern. The author concludes that the first hiatus is explained by the 19th Century pathology establishment’s strong opposition to the doctrine of the uniqueness of cancer cells that was being pushed by only a few maverick pathologists; in fact, for many mainstream pathologists, cancer was rigidly defined by cell behavior (metastases and invasion) and not cell morphology well into the 20th Century. Biopsy-based diagnosis faced similar opposition but advanced more rapidly as it was possible to examine increased numbers of cells in a pattern that partially maintained their normal adjacencies and architecture. The second hiatus is explained by economic pressures supporting intraoperative frozen section diagnoses and, in the instance of vaginal smears, the embryonic state of the public campaign supporting the importance of early cancer diagnosis. Diagn. Cytopathol. 2015;43:257–263. VC 2015 Wiley Periodicals, Inc. Key Words: medical history; cytopathology; histopathology; clinical pathology; cancer biology; cancer diagnosis Department of Pathology & Laboratory Medicine, the University of Calgary Cumming School of Medicine and Calgary Laboratory Services, Calgary, Alberta, Canada *Correspondence to: Dr. James R. Wright, Jr, Professor and Head, Department of Pathology & Laboratory Medicine, University of Calgary/Alberta Health Services, Diagnostic and Scientific Centre, 9, 3535 Research Road NW, Calgary, Alberta, Canada T2L 2K8. E-mail: [email protected] Received 2 December 2014; Accepted 16 December 2014 DOI: 10.1002/dc.23246 Published online 21 January 2015 in Wiley Online Library (wileyonlinelibrary.com). C 2015 WILEY PERIODICALS, INC. V
There have been many fine articles and books written over the past 65 years on the history of cytopathology, each describing the general sequence of events and discoveries.1–9 Most start with a very brief mention of F.-A. Pouchet (1847), W.H. Walshe (1851), F. Donaldson (1853), M. Lancereaux (1858), and/or W.H. Dickinson (1869), but all of them then quickly focus on Lionel Smith Beale (Fig. 1) who published several influential books on microscopy,10–13 which according to William Osler, those in the English speaking world who knew anything about microscopes at the time he was beginning his career and thereafter learned it from reading Beale’s books; according to Osler in his obituary for Beale: “as practical physicians we must always be thankful to him for the stimulating work which he did in medical microscopy. His . . . well known books . . . were of the greatest service to two generations of medical students. Both in Canada and in the United States, there are scores of men of my day who, like myself, knew Dr. Beale only through his writings, who will hear of the death of their old teacher with sincere regret and who will recall with gratitude labors which so often helped to lighten their own.”14,15 In the context of cytopathology, Beale advocated the routine microscopic examination of vaginal discharges and urine whenever cancer of the uterus is suspected as early as 185414 and reported the presence of cancer cells in the sputum in 1860.16 Historians consider Beale to be the “Father of Clinical Pathology” and a founder of Cancer Cytopathology.17,18 After Beale, most describe occasional reports but note that no real progress was made until the late 1920s when there was virtually a total rebirth of clinical cytology after a 60 year hiatus. For instance, according to Bernard Naylor: “The late 1920s saw the beginning of a new era in exfoliative cytology. Before that time the literature was sprinkled with isolated case reports of cytologic diagnosis which were regarded as impractical curiosities, or occasional small series which were regarded with some Diagnostic Cytopathology, Vol. 43, No 3
257
Diagnostic Cytopathology DOI 10.1002/dc
WRIGHT
Fig. 1. Lionel Smith Beale portrait by Henry Tanworth Wells 1828–1903.
Fig. 2. Leonard S. Dudgeon portrait by Dr. Douglas C. L. Derry, c. 1930s, Guy’s and St. Thomas’ Charity, C20T collection. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
C Royal College of Physicians (http://www.bbc.co.uk/arts/yourpaintings/ V
paintings/lionel-smith-beale-8281906-192468). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
skepticism by most pathologists.”4 The review articles and books generally agree that the next critically important contribution to cytopathology was Leonard S. Dudgeon’s wet film method first described in 192719–21 and he developed some disciples, especially in the UK.22,23 Cytopathology historians agree that Dudgeon (Fig. 2) made important contributions2–5,7,9,24 and his method actually competed with the frozen section for intraoperative diagnostic methodological pre-eminence,25 as did another cytopathologic method, albeit to a much lesser extent, that involved teasing tissue apart, mounting it on a slide in a drop of 1% acetic acid, cover-slipping, and viewing under a microscope introduced in 1929 by German pathologist Reinhold Dengler.25,26 A year after Dudgeon in 1928, both George Papanicolaou and Romanian Aurel A. Babes¸ reported that cancer of the cervix could be diagnosed with vaginal smears.27 Although both published their work immediately,27–30 neithers work was widely embraced at that time. However, the work of Dudgeon, Papanicolaou, and Babes¸ in the late 1920s jump-started cytopathologic research after 601 years of little progress. Yet, still there was another brief gap. In fact, Naylor calls all the entire opus of cytopathology research from its beginning until 1941 the “early historic era” and then notes this “gave way abruptly to the era of development and expansion in 1941 with the publications by Drs. George Papanicolaou and Herbert Trout, of Cornell University, of the seminal paper in the American Journal of Obstetrics and Gynecology, ‘The Diagnostic Value of Vaginal Smears in the Carci258
Diagnostic Cytopathology, Vol. 43, No 3
noma of the Uterus’, which was followed in 1943 by their famous monograph Diagnosis of Uterine Cancer by the Vaginal Smear with its magnificent drawings by Hashime Muryama of exfoliated cells and tissues.”8 Why was there such a long gap between Beale and Dudgeon and what accounted for the additional delay from Papanicolaou and Babes¸ to Papanicolaou and Trout? None of the above-mentioned historical reviews have addressed these fundamental questions head on.
Methods Available primary and secondary historical resources were reviewed and analyzed.
Analysis and Discussion Beale’s textbooks which promoted cancer cytopathology also described other uses for the microscope that would today fall into the realm of Clinical Pathology (e.g., analysis of crystal morphology, etc.) and these applications continued to progress. In the latter half of the 19th Century, much of this clinical microscopy was performed by the clinician directly caring for the patient31–33 but by the early 20th Century, it became part of the expanding field of Clinical Pathology.34–36 A sampling of turn of the 20th Century textbooks of Clinical Pathology such as Chemical and Microscopical Diagnosis published in 1905 by Columbia University pathologist Frances Carter Wood shows the breath of testing utilizing a microscope to have exponentially expanded over what Beale had envisioned.37 Lionel Beale started both Clinical Pathology and Cytopathology. Why did the former continue to flourish and the later experience a 601 year hiatus?
Diagnostic Cytopathology DOI 10.1002/dc
WHY DID IT TAKE SO LONG?
When Beale did his cytopathologic original work, histology and cytology were both on equally shaky footing. Johannes M€ uller, a pioneer of cell theory and cancer biology in the 1830s and 1840s,; (1) trained cell theory founder Theodor Schwann, (2) first determined that cancer tissue was composed of cells, and (3) trained many of the prominent figures, such as Rudolph Virchow, who would later become the leading pathologists of the mid-to-late 19th Century. M€uller was adamant that the microscope was useful for cancer research but would never be useful for cancer diagnosis or cancer patient care.38–40 Why did histopathologic diagnosis of cancer forge ahead and leave cytopathologic diagnosis of cancer to stagnate for 601 years? The remainder of this essay will focus on addressing these questions. The microscope improved greatly in the 19th century with innovations such as the Abbe condenser and the achromatic objective lens,41,42 but I am unaware of any evidence that during the period from the time of Beale to the time of Dudgeon, microscope improvements favored histology over cytology. Guido Majno and Isabelle Joris have done an interesting analysis of why the microscope took so long to become a tool for medical research, noting that early versions were available in the early 1600s and that microscopic anatomy made little progress until the early 1800s and that “between the birth of the microscope and the birth of microscopic pathology there is a puzzling gap of almost 250 years.”43 They further note that Morgagni wrote his 1761 masterpiece De Sedibus et Causis morborum per Anatomem indagatis, the cornerstone of modern pathology, and that Bichat, wrote his 1799 treatise on tissue pathology without its use. Majno and Joris identified eight barriers: (1) secrecy, (2) price, (3) technical difficulty, (4) misuse as a toy by the very wealthy, (5) lack of ideas, (6) neglect by universities, (7) poor optics, and (8) distrust (i.e., “the fear of studying optical artefacts, of chasing shadows instead of dealing with reality”) [n.b., these concerns are echoed in other papers14,44]. In their “experimental history” paper, Majno and Joris specifically explored no. 7 (poor optics) by trying to study acute inflammation in a transparent tissue (fresh, unfixed, and unstained omentum) using only early 19th century techniques and technology and they reported that the resolution of the Culpeper-type microscope (a model produced in London until 1830) proved inadequate.43 Although cytology and histology were equally challenged by microscope optical limitations, clearly, innovations in later half of the 19th century such as the development of fixatives, embedding materials, stains, and microtomes were critical developments advancing histopathologic diagnosis ahead of cytopathology,6,25 as significant fixation and staining improvements related to cytopathology were slower to develop. For instance, cytologists were usually viewing unstained preparations
for much of the 19th century.4,6 Even wet fixation, used by Dudgeon, was not possible until Giemsa described this method in 1909 to make protozoa preparations.4
Setbacks Described in the Cytopathology Historical Literature Interestingly, Francis Donaldson of Baltimore blames distrust of the microscope, a fear he debunks at great length in his 1853 paper “The practical application of the microscope to the diagnosis of cancer.”45 Donaldson notes: “If those who think there is no reliance to be placed on appearances in the field of the microscope would take any crystal, such as that of the beautiful octohedra of the oxalate of lime visible already to the naked eye, and magnify it by degrees, they would see that, no matter what the power of the glass used, it possesses the same number of sides, angles, etc.; the only difference being that the minute details, not visible before, would be brought out. They ought to remember that no matter how high the magnifying power of a lens, it cannot render visible things which do not really exist—it cannot create.” However, this cannot be the primary issue as it should have equally exerted an adverse effect on the progression of histopathologic cancer diagnosis. Even advances in cytopathology prevented further advances. In 1896, L.P.H. Bahrenberg of Cleveland published his technique of centrifuging serous fluids, fixing, sectioning, and staining the sediment. By the late 1920s, it was a fairly standard technique in America.7,46 According to Naylor: “the author, Bahrenberg, had a certain amount of success with his method as did others after him, but his approach to the study of cells was essentially that of the tissue pathologist: and it was this approach, both technically and mentally, which retarded the advancement of exfoliative cytology. Cells cannot be examined with the grossness of tissue sections; they require special methods which bring out the fineness of detail, especially of nuclei. Such techniques were not generally applied until the 1940s.”4 Early authors warned that microscopic cancer diagnosis was not an exact science and that it was prone to errors. For instance, George Adams1 notes that Dickenson47 wrote: “in cases, indeed, in which malignant disease of the bladder or kidney is suspected, the microscope is often a source of error. Under circumstances of irritation and disturbance large cells, presenting quite the idea of cancer cells, of all shapes and characters, regular and irregular, rounded, angular, and elongated, are occasionally thrown off in abundance from various parts of the urinary membrane. Patients who on the evidence of urine presenting such appearances have been convicted of cancer have been known to get well and remain so.”1 George Adams further notes that “it need hardly be emphasized that the early history of the subject has been Diagnostic Cytopathology, Vol. 43, No 3
259
Diagnostic Cytopathology DOI 10.1002/dc
WRIGHT
discontinuous. There were sporadic reports by isolated investigators that awakened an alertness in others. Variants of fixing, embedding, and staining methods were reported by different men in different countries, often without knowledge of similar work in progress or completed elsewhere. This is, of course, a familiar phenomenon in the history of science.”1 Likely, cytopathology would have been somewhat more prone to this problem than histopathology as there were many more practitioners of the latter. While agreeing that all of the above-mentioned observations are true and played a role, another phenomenon characteristic of the history of science played a much more important role. Historian of science Thomas Kuhn, in his classic book The Structure of Scientific Revolutions, has observed that science advances through a series of paradigm shifts (i.e., shared basic assumptions).48 For cytology to advance into the mainstream, several paradigm shifts were required including the acceptance of the doctrine of the uniqueness of cancer cells and a change in definition of cancer.
Reasons for the 601 Year Hiatus As a pathologist-historian who has written extensively on the history of other areas of pathology but never cytopathology, I see several fundamental reasons that explain the afore-mentioned 601 year hiatus. First of all, there needed to be a paradigm shift in the definition of cancer.49 Cell theory was established in 1838–1839 by Matthias Schleiden and Theodor Schwann; in 1839, Johannes M€ uller proclaimed that cancers were also comprised of cells but almost all prominent cancer researchers and pathologists, including Rudolf Virchow, strongly opposed the idea that the cells which in aggregate composed cancers were morphologically different than normal cells. Dogma, which persisted well into the 20th Century, held that cancer was defined by cell behavior (i.e., the ability to invade and metastasize) and not cell morphology.49 Therefore, prior to the publication of Beale’s first book in 1854, there were only seven mavericks world-wide who believed in the uniqueness of cancer cells. According to cancer historian and pathologist Leland J. Rather, Danish pathologist Adolph Hannover published the first microscopic description of a cancer cell in 1843. Contemporaries who came to support the premise of a morphologically specific cancer cell prior to 1850 included three Frenchmen (Hermann Lebert in 1845, Sur geon Charles Emmanuel Sedillot, and Emile K€uss in 1846), two Germans (Heinrich Meckel in 1846 and Carl Bruch in 1847), a Scottish pathologist (John Hughes Bennett in 1849), and Hannover.40 Although some prominent experts in pathology and cancer research generally supported the use of the microscope for cancer research, 260
Diagnostic Cytopathology, Vol. 43, No 3
many did not believe that the microscope would ever be useful for the diagnosis of cancer.40,50 To understand the hiatus, one first needs to recognize the difficulty in accepting the validity of biopsy-based diagnosis and then understand that cytology-based diagnosis stretched the 19th century imagination even further and required an additional paradigm shift beyond acceptance of biopsy-based diagnosis. The series of transitions for biopsy-based diagnosis included acceptance: (1) that magnification of tissue/cells under the microscope does not alter reality, (2) that cancer is not ultimately defined entirely by its behavior in situ (i.e., invasion or metastases), and (3) malignant behavior can be predicted by a tumor’s histologic appearance; acceptance of these three tenets was beyond all but a few. However, at least in the situation of biopsy, it was possible to examine the histologic appearance of putative cancer cells in very large groups and, in some instance, see some elements of behavior; in stark contrast, cytology provided only an opportunity to examine individual cells or small clumps of cells without the same ability to gauge how they interact with each other. The early adopters of biopsy were willing to ignore dogma and advance science based on their own observations; furthermore, they had to withstand ridicule by the mainstream pathology establishment. In the world of biopsies, Emile K€uss, along with Surgeon Charles Emmanuel Sedillot, of Strasbourg were mavericks not only for immediately embracing the doctrine of the uniqueness of cancer cells in 1846 but also for putting this belief to practical use by developing the first punch biopsy tool, performing the first three cancer biopsies, and making diagnoses that were used to guide clinical management.50,51 However, most consider German Carl Ruge, a gynecologist at the Women’s Hospital in Berlin, to be the Father of Biopsy,25,50,52,53 even though K€uss predated him by 30 years. Ruge started performing biopsies in the early 1880s when he noted that he could confirm the presence of cancer in
Cytopathology: Why Did It Take So Long To Thrive? James R. Wright, Jr. M.D., Ph.D.*
Lionel S. Beale of London made some of the earliest contributions to Cytopathology in the 1850–1860s. Cytopathology then experienced a 601 year hiatus during which few advances were made. In 1927, Londoner Leonard S. Dudgeon published his wet film method for rapid intraoperative diagnosis and in 1928 Greek-American George Papanicolaou and Romanian Aurel A. Babes¸ independently discovered that cervical cancer can be diagnosed using vaginal smears; these were huge advancements. Yet, there was another hiatus where little progress was made which lasted until the publications of Papanicolaou and Trout in the early 1940s. After that, the field of exfoliative Cytopathology immediately flourished. None of the standard histories of Cytopathology explain these two gaps. Primary and secondary historical sources were examined to explain this pattern. The author concludes that the first hiatus is explained by the 19th Century pathology establishment’s strong opposition to the doctrine of the uniqueness of cancer cells that was being pushed by only a few maverick pathologists; in fact, for many mainstream pathologists, cancer was rigidly defined by cell behavior (metastases and invasion) and not cell morphology well into the 20th Century. Biopsy-based diagnosis faced similar opposition but advanced more rapidly as it was possible to examine increased numbers of cells in a pattern that partially maintained their normal adjacencies and architecture. The second hiatus is explained by economic pressures supporting intraoperative frozen section diagnoses and, in the instance of vaginal smears, the embryonic state of the public campaign supporting the importance of early cancer diagnosis. Diagn. Cytopathol. 2015;43:257–263. VC 2015 Wiley Periodicals, Inc. Key Words: medical history; cytopathology; histopathology; clinical pathology; cancer biology; cancer diagnosis Department of Pathology & Laboratory Medicine, the University of Calgary Cumming School of Medicine and Calgary Laboratory Services, Calgary, Alberta, Canada *Correspondence to: Dr. James R. Wright, Jr, Professor and Head, Department of Pathology & Laboratory Medicine, University of Calgary/Alberta Health Services, Diagnostic and Scientific Centre, 9, 3535 Research Road NW, Calgary, Alberta, Canada T2L 2K8. E-mail: [email protected] Received 2 December 2014; Accepted 16 December 2014 DOI: 10.1002/dc.23246 Published online 21 January 2015 in Wiley Online Library (wileyonlinelibrary.com). C 2015 WILEY PERIODICALS, INC. V
There have been many fine articles and books written over the past 65 years on the history of cytopathology, each describing the general sequence of events and discoveries.1–9 Most start with a very brief mention of F.-A. Pouchet (1847), W.H. Walshe (1851), F. Donaldson (1853), M. Lancereaux (1858), and/or W.H. Dickinson (1869), but all of them then quickly focus on Lionel Smith Beale (Fig. 1) who published several influential books on microscopy,10–13 which according to William Osler, those in the English speaking world who knew anything about microscopes at the time he was beginning his career and thereafter learned it from reading Beale’s books; according to Osler in his obituary for Beale: “as practical physicians we must always be thankful to him for the stimulating work which he did in medical microscopy. His . . . well known books . . . were of the greatest service to two generations of medical students. Both in Canada and in the United States, there are scores of men of my day who, like myself, knew Dr. Beale only through his writings, who will hear of the death of their old teacher with sincere regret and who will recall with gratitude labors which so often helped to lighten their own.”14,15 In the context of cytopathology, Beale advocated the routine microscopic examination of vaginal discharges and urine whenever cancer of the uterus is suspected as early as 185414 and reported the presence of cancer cells in the sputum in 1860.16 Historians consider Beale to be the “Father of Clinical Pathology” and a founder of Cancer Cytopathology.17,18 After Beale, most describe occasional reports but note that no real progress was made until the late 1920s when there was virtually a total rebirth of clinical cytology after a 60 year hiatus. For instance, according to Bernard Naylor: “The late 1920s saw the beginning of a new era in exfoliative cytology. Before that time the literature was sprinkled with isolated case reports of cytologic diagnosis which were regarded as impractical curiosities, or occasional small series which were regarded with some Diagnostic Cytopathology, Vol. 43, No 3
257
Diagnostic Cytopathology DOI 10.1002/dc
WRIGHT
Fig. 1. Lionel Smith Beale portrait by Henry Tanworth Wells 1828–1903.
Fig. 2. Leonard S. Dudgeon portrait by Dr. Douglas C. L. Derry, c. 1930s, Guy’s and St. Thomas’ Charity, C20T collection. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
C Royal College of Physicians (http://www.bbc.co.uk/arts/yourpaintings/ V
paintings/lionel-smith-beale-8281906-192468). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
skepticism by most pathologists.”4 The review articles and books generally agree that the next critically important contribution to cytopathology was Leonard S. Dudgeon’s wet film method first described in 192719–21 and he developed some disciples, especially in the UK.22,23 Cytopathology historians agree that Dudgeon (Fig. 2) made important contributions2–5,7,9,24 and his method actually competed with the frozen section for intraoperative diagnostic methodological pre-eminence,25 as did another cytopathologic method, albeit to a much lesser extent, that involved teasing tissue apart, mounting it on a slide in a drop of 1% acetic acid, cover-slipping, and viewing under a microscope introduced in 1929 by German pathologist Reinhold Dengler.25,26 A year after Dudgeon in 1928, both George Papanicolaou and Romanian Aurel A. Babes¸ reported that cancer of the cervix could be diagnosed with vaginal smears.27 Although both published their work immediately,27–30 neithers work was widely embraced at that time. However, the work of Dudgeon, Papanicolaou, and Babes¸ in the late 1920s jump-started cytopathologic research after 601 years of little progress. Yet, still there was another brief gap. In fact, Naylor calls all the entire opus of cytopathology research from its beginning until 1941 the “early historic era” and then notes this “gave way abruptly to the era of development and expansion in 1941 with the publications by Drs. George Papanicolaou and Herbert Trout, of Cornell University, of the seminal paper in the American Journal of Obstetrics and Gynecology, ‘The Diagnostic Value of Vaginal Smears in the Carci258
Diagnostic Cytopathology, Vol. 43, No 3
noma of the Uterus’, which was followed in 1943 by their famous monograph Diagnosis of Uterine Cancer by the Vaginal Smear with its magnificent drawings by Hashime Muryama of exfoliated cells and tissues.”8 Why was there such a long gap between Beale and Dudgeon and what accounted for the additional delay from Papanicolaou and Babes¸ to Papanicolaou and Trout? None of the above-mentioned historical reviews have addressed these fundamental questions head on.
Methods Available primary and secondary historical resources were reviewed and analyzed.
Analysis and Discussion Beale’s textbooks which promoted cancer cytopathology also described other uses for the microscope that would today fall into the realm of Clinical Pathology (e.g., analysis of crystal morphology, etc.) and these applications continued to progress. In the latter half of the 19th Century, much of this clinical microscopy was performed by the clinician directly caring for the patient31–33 but by the early 20th Century, it became part of the expanding field of Clinical Pathology.34–36 A sampling of turn of the 20th Century textbooks of Clinical Pathology such as Chemical and Microscopical Diagnosis published in 1905 by Columbia University pathologist Frances Carter Wood shows the breath of testing utilizing a microscope to have exponentially expanded over what Beale had envisioned.37 Lionel Beale started both Clinical Pathology and Cytopathology. Why did the former continue to flourish and the later experience a 601 year hiatus?
Diagnostic Cytopathology DOI 10.1002/dc
WHY DID IT TAKE SO LONG?
When Beale did his cytopathologic original work, histology and cytology were both on equally shaky footing. Johannes M€ uller, a pioneer of cell theory and cancer biology in the 1830s and 1840s,; (1) trained cell theory founder Theodor Schwann, (2) first determined that cancer tissue was composed of cells, and (3) trained many of the prominent figures, such as Rudolph Virchow, who would later become the leading pathologists of the mid-to-late 19th Century. M€uller was adamant that the microscope was useful for cancer research but would never be useful for cancer diagnosis or cancer patient care.38–40 Why did histopathologic diagnosis of cancer forge ahead and leave cytopathologic diagnosis of cancer to stagnate for 601 years? The remainder of this essay will focus on addressing these questions. The microscope improved greatly in the 19th century with innovations such as the Abbe condenser and the achromatic objective lens,41,42 but I am unaware of any evidence that during the period from the time of Beale to the time of Dudgeon, microscope improvements favored histology over cytology. Guido Majno and Isabelle Joris have done an interesting analysis of why the microscope took so long to become a tool for medical research, noting that early versions were available in the early 1600s and that microscopic anatomy made little progress until the early 1800s and that “between the birth of the microscope and the birth of microscopic pathology there is a puzzling gap of almost 250 years.”43 They further note that Morgagni wrote his 1761 masterpiece De Sedibus et Causis morborum per Anatomem indagatis, the cornerstone of modern pathology, and that Bichat, wrote his 1799 treatise on tissue pathology without its use. Majno and Joris identified eight barriers: (1) secrecy, (2) price, (3) technical difficulty, (4) misuse as a toy by the very wealthy, (5) lack of ideas, (6) neglect by universities, (7) poor optics, and (8) distrust (i.e., “the fear of studying optical artefacts, of chasing shadows instead of dealing with reality”) [n.b., these concerns are echoed in other papers14,44]. In their “experimental history” paper, Majno and Joris specifically explored no. 7 (poor optics) by trying to study acute inflammation in a transparent tissue (fresh, unfixed, and unstained omentum) using only early 19th century techniques and technology and they reported that the resolution of the Culpeper-type microscope (a model produced in London until 1830) proved inadequate.43 Although cytology and histology were equally challenged by microscope optical limitations, clearly, innovations in later half of the 19th century such as the development of fixatives, embedding materials, stains, and microtomes were critical developments advancing histopathologic diagnosis ahead of cytopathology,6,25 as significant fixation and staining improvements related to cytopathology were slower to develop. For instance, cytologists were usually viewing unstained preparations
for much of the 19th century.4,6 Even wet fixation, used by Dudgeon, was not possible until Giemsa described this method in 1909 to make protozoa preparations.4
Setbacks Described in the Cytopathology Historical Literature Interestingly, Francis Donaldson of Baltimore blames distrust of the microscope, a fear he debunks at great length in his 1853 paper “The practical application of the microscope to the diagnosis of cancer.”45 Donaldson notes: “If those who think there is no reliance to be placed on appearances in the field of the microscope would take any crystal, such as that of the beautiful octohedra of the oxalate of lime visible already to the naked eye, and magnify it by degrees, they would see that, no matter what the power of the glass used, it possesses the same number of sides, angles, etc.; the only difference being that the minute details, not visible before, would be brought out. They ought to remember that no matter how high the magnifying power of a lens, it cannot render visible things which do not really exist—it cannot create.” However, this cannot be the primary issue as it should have equally exerted an adverse effect on the progression of histopathologic cancer diagnosis. Even advances in cytopathology prevented further advances. In 1896, L.P.H. Bahrenberg of Cleveland published his technique of centrifuging serous fluids, fixing, sectioning, and staining the sediment. By the late 1920s, it was a fairly standard technique in America.7,46 According to Naylor: “the author, Bahrenberg, had a certain amount of success with his method as did others after him, but his approach to the study of cells was essentially that of the tissue pathologist: and it was this approach, both technically and mentally, which retarded the advancement of exfoliative cytology. Cells cannot be examined with the grossness of tissue sections; they require special methods which bring out the fineness of detail, especially of nuclei. Such techniques were not generally applied until the 1940s.”4 Early authors warned that microscopic cancer diagnosis was not an exact science and that it was prone to errors. For instance, George Adams1 notes that Dickenson47 wrote: “in cases, indeed, in which malignant disease of the bladder or kidney is suspected, the microscope is often a source of error. Under circumstances of irritation and disturbance large cells, presenting quite the idea of cancer cells, of all shapes and characters, regular and irregular, rounded, angular, and elongated, are occasionally thrown off in abundance from various parts of the urinary membrane. Patients who on the evidence of urine presenting such appearances have been convicted of cancer have been known to get well and remain so.”1 George Adams further notes that “it need hardly be emphasized that the early history of the subject has been Diagnostic Cytopathology, Vol. 43, No 3
259
Diagnostic Cytopathology DOI 10.1002/dc
WRIGHT
discontinuous. There were sporadic reports by isolated investigators that awakened an alertness in others. Variants of fixing, embedding, and staining methods were reported by different men in different countries, often without knowledge of similar work in progress or completed elsewhere. This is, of course, a familiar phenomenon in the history of science.”1 Likely, cytopathology would have been somewhat more prone to this problem than histopathology as there were many more practitioners of the latter. While agreeing that all of the above-mentioned observations are true and played a role, another phenomenon characteristic of the history of science played a much more important role. Historian of science Thomas Kuhn, in his classic book The Structure of Scientific Revolutions, has observed that science advances through a series of paradigm shifts (i.e., shared basic assumptions).48 For cytology to advance into the mainstream, several paradigm shifts were required including the acceptance of the doctrine of the uniqueness of cancer cells and a change in definition of cancer.
Reasons for the 601 Year Hiatus As a pathologist-historian who has written extensively on the history of other areas of pathology but never cytopathology, I see several fundamental reasons that explain the afore-mentioned 601 year hiatus. First of all, there needed to be a paradigm shift in the definition of cancer.49 Cell theory was established in 1838–1839 by Matthias Schleiden and Theodor Schwann; in 1839, Johannes M€ uller proclaimed that cancers were also comprised of cells but almost all prominent cancer researchers and pathologists, including Rudolf Virchow, strongly opposed the idea that the cells which in aggregate composed cancers were morphologically different than normal cells. Dogma, which persisted well into the 20th Century, held that cancer was defined by cell behavior (i.e., the ability to invade and metastasize) and not cell morphology.49 Therefore, prior to the publication of Beale’s first book in 1854, there were only seven mavericks world-wide who believed in the uniqueness of cancer cells. According to cancer historian and pathologist Leland J. Rather, Danish pathologist Adolph Hannover published the first microscopic description of a cancer cell in 1843. Contemporaries who came to support the premise of a morphologically specific cancer cell prior to 1850 included three Frenchmen (Hermann Lebert in 1845, Sur geon Charles Emmanuel Sedillot, and Emile K€uss in 1846), two Germans (Heinrich Meckel in 1846 and Carl Bruch in 1847), a Scottish pathologist (John Hughes Bennett in 1849), and Hannover.40 Although some prominent experts in pathology and cancer research generally supported the use of the microscope for cancer research, 260
Diagnostic Cytopathology, Vol. 43, No 3
many did not believe that the microscope would ever be useful for the diagnosis of cancer.40,50 To understand the hiatus, one first needs to recognize the difficulty in accepting the validity of biopsy-based diagnosis and then understand that cytology-based diagnosis stretched the 19th century imagination even further and required an additional paradigm shift beyond acceptance of biopsy-based diagnosis. The series of transitions for biopsy-based diagnosis included acceptance: (1) that magnification of tissue/cells under the microscope does not alter reality, (2) that cancer is not ultimately defined entirely by its behavior in situ (i.e., invasion or metastases), and (3) malignant behavior can be predicted by a tumor’s histologic appearance; acceptance of these three tenets was beyond all but a few. However, at least in the situation of biopsy, it was possible to examine the histologic appearance of putative cancer cells in very large groups and, in some instance, see some elements of behavior; in stark contrast, cytology provided only an opportunity to examine individual cells or small clumps of cells without the same ability to gauge how they interact with each other. The early adopters of biopsy were willing to ignore dogma and advance science based on their own observations; furthermore, they had to withstand ridicule by the mainstream pathology establishment. In the world of biopsies, Emile K€uss, along with Surgeon Charles Emmanuel Sedillot, of Strasbourg were mavericks not only for immediately embracing the doctrine of the uniqueness of cancer cells in 1846 but also for putting this belief to practical use by developing the first punch biopsy tool, performing the first three cancer biopsies, and making diagnoses that were used to guide clinical management.50,51 However, most consider German Carl Ruge, a gynecologist at the Women’s Hospital in Berlin, to be the Father of Biopsy,25,50,52,53 even though K€uss predated him by 30 years. Ruge started performing biopsies in the early 1880s when he noted that he could confirm the presence of cancer in
