From von Rokitansky to von Recklinghausen to Cullen

A History of Endometriosis

4. From von Rokitansky to von Recklinghausen to Cullen

Ronald E. Batt¹

(1)

State University of New York at Buffalo, Buffalo, New York, USA

Abstract

At the top of the hierarchy of the Vienna Medical School in the 1860s, Rokitansky was aware of the growing academic sentiment that macroscopic morbid pathological anatomy was no longer at the cutting edge of medical research.¹ By mid-nineteenth century, the precision, control, and reproducibility of experimental science “had greatly increased scientists’ understanding of the laws governing chemical, physiological, and physical processes…For this reason physicians viewed experimental physiology, more than pathological anatomy or the clinical sciences, as the cornerstone of scientific medicine.”²Publication of Virchow’s Cellularpathologie in 1858 had opened the era of physiologic pathology and sounded the death knell of macroscopic pathologic anatomy.³ Though he did not embrace experimentation or routine microscopic examinations of tissues in his own research, in his ministerial position at the University, Rokitansky had prepared himself, his department, and the University for this important transition.⁴

Rokitansky’s Interest in Developmental Pathology

Then, in 1861, came a call from within the University of Vienna, a demand for a paradigm shift in academic pathology from the “morphologically-organicistically” French school approach that Rokitansky had “deepened and perfected” to the German “experimental–physiological” approach. This was a more fundamental change than a call for microscopic analysis of pathological specimens. Together, experimental medicine and cellular pathology represented a “shift in the center of gravity of European medicine” toward “therapy as the ultimate purpose of the entire medical science.”⁵ Rokitansky found himself and his department in a position not unlike that of anatomy in 1786 when Emperor Joseph II demoted the department to a position inferior to physiology. Shortly after he discovered uterine and ovarian endometriosis, Rokitansky turned his attention to developmental pathology. Despite the assertion that his macromorphologic approach to anatomy was obsolete, Rokitansky still had much to contribute using this approach for developmental pathology.

Years earlier, following a debate with Virchow on the development of neoplasms, the “importance of ontogenetic development for the understanding of congenital malformations became increasingly clear” to Rokitansky.⁶Stemming from his early work on vaginal agenesis, Rokitansky generated a decided interest in developmental biology in his later years, an interest focused on the study of midline organs of mesodermal origin. He published on cardiovascular malformations, “Persistence of the Ductus arteriosus” and “The Defects of the Septa of the Heart.”⁷ Undoubtedly, this work in developmental pathology, late in his career, not only motivated his assistant, Hans Kundrat (1845–1893),⁸ to concentrate in this field but also contributed to Rokitansky’s reputation and the naming of partial müllerian agenesis as the Rokitansky Syndrome.

Kundrat not only mastered morbid macroscopic anatomical pathology but also took a keen interest in developmental pathology. Rokitansky, nearing the end of his own career, actively promoted Kundrat’s rapid academic advancement. Kundrat had graduated from medical school in 1868 and immediately became Rokitansky’s assistant. He was promoted to lecturer in 1873, titular associate professor in 1875, and in 1877 to full professor to succeed Heschl in the Chair of Pathology at Graz, Austria. In 1882, Kundrat was called to Rokitansky’s Chair of Pathological Anatomy in Vienna on the death of Richard Heschl (1824–1881).⁹

A colleague and friend of Kundrat from student days described the characteristics that had attracted the attention of Rokitansky. “Kundrat was without doubt a great and important morphologist. His formative concepts of observation were most extraordinary. He visualized the very complicated processes of developmental history so exactly and explained the disturbances of these processes so easily, that this in itself made him the most outstanding expert in the field of congenital malformations.”¹⁰

In effect, Rokitansky had reinvented himself in the last decade and a half of his career, but apparently not without a cost to his department. William Osler studied in Vienna for the first 5 months of 1874 and observed the deteriorated state of medicine and pathology relative to surgery, obstetrics, and dermatology.¹¹ In a letter dated March 1, 1874, Allgemeines Krankenhaus, Osler wrote: “Altogether, midwifery and skin diseases are specialties in Vienna, while in general medicine and pathology it is infinitely below Berlin…After having seen Virchow it is absolutely painful to attend postmortems here, they are performed in so slovenly a manner, and so little use is made of the material.”¹² Such was the state of pathologic anatomy on Rokitansky’s retirement in 1874, seen from the perspective of a Canadian physician.¹³

The near simultaneous observations of William Osler in Vienna make a telling comparison with those of William Welch in Strassburg. According to Welch, when he visited Strassburg in 1876, von Recklinghausen was “perhaps the most celebrated teacher of pathology in Germany.”¹⁴ Welch was astonished at the volume of pathological material available. Because he did not know normal tissue histology, Welch was not able to take von Recklinghausen’s pathological histology course. However, he did attend von Recklinghausen’s demonstration course in gross pathology and found it “unsurpassed” by anything he had seen.¹⁵ Welch observed that autopsies – postmortem examinations –conducted by German medical students were “thorough beyond anything I have ever seen.”¹⁶ Welch’s observation of the high level of the academic practice of pathology in Strassburg in 1876 contrasted sharply with Osler’s observation of the poor state of pathological anatomy in Vienna in 1874, at the time of the celebration of Rokitansky’s seventieth birthday. Among the differences, von Recklinghausen was a master microscopic pathologist and Rokitansky was not; furthermore, von Recklinghausen was 43 years old and entering the peak years of his career in 1876, while von Rokitansky was an infirm 70-year-old man on the threshold of retirement.¹⁷

Rokitansky’s Legacy

Nosographic Classification of Human Disease Based on Pathologic Anatomy

Carl Freiherr von Rokitansky, the founder of modern anatomic pathology, devoted his entire professional life to the specialty of anatomic pathology to the exclusion of all other medical practice.¹⁸ In 1875, Rokitansky wrote of his career and his academic legacy: “In accordance with a pressing need of my time…I have pursued pathological anatomy first of all in the sprit of investigation fruitful for clinical medicine.”¹⁹ Two powerful examples of his success were his collaboration with the internist Skoda and his influence on the remarkable career of the internist Kussmaul as well as the hundreds of students from foreign countries he attracted to his dissecting table.²⁰ A quotation from Rokitansky’s final lecture sums up his thinking. “Pathological Anatomy is the essential basis for pathological physiology, to be supplemented further by pathological histology, chemical pathology, and experimental pathology.”²¹

While Virchow had severely criticized the hematohumoral theory of Rokitansky contained in the first volume of the first edition of his three-volume magnum opus published in 1846, he lauded Rokitansky as the Linne of anatomical pathology for the second edition – expunged of the discredited theory – published in 1855.²² Ironically, 1855 marked the year of publication of the second German edition of Rokitansky’s Handbook as well as publication of the Sydenham Society’s honorific English translation of the first [1846] edition.²³ Due, largely, to this unfortunate coincidence, Rokitansky’s reputation suffered in the eyes of some historians who read only the English translation of the first edition [1855] and not the revised second German edition [1855]. Some chose the fluent English in the Sydenham Society’s translation of the first edition of the Handbook of Pathological Anatomyrather than coping with the Rokitansky’s idiosyncratic German in the revised and more praiseworthy second edition.²⁴Those readers of the English translation who judged Rokitansky unfavorably based their judgment on the discredited hematohumoral theory, thereby giving Rokitansky virtually no credit for his life’s work organizing and categorizing anatomical pathology.²⁵

The German physician–historian, Karl Sudhoff, came to Rokitansky’s defense. “From the past of our science, modern investigation may take its guide-posts, while, on the other hand, the most recent scientific findings will shed light upon the scientific life of the past, thus enabling us better to understand and more justly estimate the significance of the mental struggles and honest endeavors of seekers after truth in bygone days. Thus, today one might ask: ‘The great Rokitansky, the real creator of modern pathological anatomy in its essential parts as well as in its total conception, was he in his doctrine of crases [hematohumoral theory] nothing more than a victim of atavistic notions, which he could not get rid of, an impractical dreamer, in comparison with whom the sober-sided localistic clinician gained all the more admiration?’ Just for this reason, perhaps, we may learn to admire Rokitansky’s genial, far-seeing vision; he did not want to throw overboard the intuitive conclusions of the past because they had begun to seem improbable by comparison with the ever-advancing triumphs of the localistic gospel, of which he was the most successful standard-bearer himself. And we are bound to admire him all the more in that the unparalleled successes in one trend of investigation did not prevent him from envisaging basic pathological problems that could get no satisfactory answer from ‘localistic’ doctrine.”²⁶

The American historian, Robert Miciotto, also defended Rokitansky by explaining the ideas of prominent scientists who influenced the formulation of his rather extreme theory of disease. “…as late as 1853 (seven years after the review, and two years prior to omnis cellula a cellula), Virchow himself was still expressing the belief in intracellular blastemas as a productive source of cellular contents. In fact, one of the ironies of Virchow’s depiction of many of Rokitansky’s ideas as outmoded and unproven occurs in his negative response to the Rokitansky suggestion that an alternative method of cellular production may be, ‘The propagation of nuclei and cells…within a parent cell.’ It is a concept which the father of cellular pathology derides as having been concluded ‘by means of the most arbitrary playing with facts and explanations…’”²⁷

Many knowledgeable physicians, who were contemporaries of Rokitansky, attested to his legacy as scientist and educator. When Carl Wunderlich (1815–1877), whose seminal treatise on the relation of disease and body heat became the basis for the use of the thermometer in clinical medicine, visited the University of Vienna autopsy house in 1840, he wrote that Rokitansky labored on the cutting edge of medical science.²⁸ In 1878, the year of Rokitansky’s death, Klebs expressed appreciation for Rokitansky’s teaching: “[He] taught us to think anatomically at the bedside and to weave at the autopsy table the individual phases of the morbid process into the pattern of the clinical progress.”²⁹ Based on his immense experience in the autopsy house, Rokitansky taught clinicians to analyze the morbid finding and to reconstruct the evolution of the pathological process. This enabled clinicians to analyze the patient’s symptoms and signs and detect disease patterns, thus leading to earlier and more accurate diagnosis in the living.³⁰ It was the constant feedback from pathology laboratory to clinic, from autopsy to hospital that developed diagnostic skills. Robert Meyer recalled that his “most brilliant teacher” was the internist, Adolf Kussmaul, who had been instructed in pathology by Rokitansky. Meyer related that Kussmaul’s “diagnoses were not far from infallible.” At a retirement banquet for Kussmaul in 1887, von Recklinghausen said “that he had not once been able to reverse a diagnosis after dissecting one of his patients.” Meyer continued, “It was always astonishing how carefully [Kussmaul] examined his patients in order to arrive at a diagnosis.”³¹

In 1895, 40 years after its second edition, Virchow spoke of Rokitansky’s Handbook as the “unsurpassed treatise of pathological anatomy.”³² At the turn of the century, Virchow credited Rokitansky for helping to “emancipate” pathological anatomy in the German-speaking lands and for having brought pathological anatomy into closer harmony with clinical medicine.³³ The American Roswell Park, considered “Baron von Rokitansky…one of the most famous men in modern times.”³⁴ By 1933, Sigerist opined that Rokitansky’s great contributions had become the common property of medicine; his contributions had become timeless and thus “nameless.”³⁵ Commenting on Rokitansky’s Autobiography and Inaugural Address, Paul Klemperer contributed a mid-twentieth century assessment of Rokitansky’s legacy. Klemperer noted that “for many a pathologist of today [1961] Rokitansky might appear as an almost legendary figure reminiscent of a period referred to euphemistically as classical but appraised as outmoded in terms of modern pathology.”³⁶ Reference to classical has more currency among musicians and historians than physicians and scientists, as Klemperer asserted.

Historians, such as Roy Porter, assess Rokitansky and his department from an entirely different perspective. “Rokitansky had a superb mastery of anatomy and pathological science, and left notable studies of congenital malformations and reports on numerous conditions, including pneumonia, peptic ulcer, and valvular heart disease.”³⁷ Porter, nonetheless, as virtually every other historian of medicine and science, did not include endometriosis among conditions Rokitansky reported, undoubtedly because Rokitansky did not give the disease a proper name. Nor have historians included endometriosis or adenomyosis in their historical compendiums of disease.

Developmental Pathology to Evolutionary Developmental Biology

From Rokitansky though Kundrat and his students, one stream of scientific investigation flowed and blended with similar streams and eventually with the field of evolutionary biology. Only in the 1990s did the field of evolutionary biology evolve into the interdisciplinary field of evolutionary developmental biology, a field that has given new direction to the study and history of endometriosis.³⁸

Mayer-Rokitansky-Küster-Hauser Syndrome and Developmental Pathology

In the late stage of his career, Rokitansky developed a special interest in developmental pathology of the genitourinary and cardiovascular systems, two midline organ systems of mesodermal origin. In medical school, his interest in embryology had been ignited by the works of Johan Friedrich Meckel (1781–1833),³⁹ and by actually holding in his hands the specimen jar containing the anomalous “sexual organs of the 60-year-old Magdalena Fischer” from the Vienna pathology museum.⁴⁰ One has only to recall the stifling lectures and rote memorization of Rokitansky’s student days to appreciate the experience of visualizing a pathological specimen and thinking of its embryological development and how it affected the life of the very woman whose identify had been preserved with her anomalous body parts. This interest was stoked by Müller’s treatise on embryology in 1830,⁴¹ and first reported in 1838 as a case series: “Concerning the so-called duplication of the uterus.”⁴² Furthermore, Paris hospital medicine informed Rokitansky’s clinicopathologic perspective: physicians and pathologists no longer thought in terms of sick individuals; “they saw diseases,” diseases they could study at autopsy.⁴³

A physician never forgets an observation early in his career that so captures his interest that he publishes the case in the medical literature.⁴⁴ Rokitansky’s description of those specimens added to the importance and recognition of uterovaginal malformations.⁴⁵ Rokitansky must have had an intense interest in malformations because he imparted this interest to Kussmaul, an internist, who later published a book entitled The Malformations of the Uterus.⁴⁶ Rokitansky’s report of 1838 has resounded into the twenty-first century as an integral part of the Mayer-Rokitansky-Küster-Hauser syndrome.⁴⁷ The very name of the syndrome embodies the sense of scientific continuity, of a community of scholars who influenced one another in the search for pathogenesis, etiology, diagnosis, and treatment.⁴⁸

In sum, being steeped in embryology, Rokitansky’s early publications on uterovaginal anomalies (Mayer-Rokitansky-Küster-Hauser syndrome) made him more conscious of midline developmental abnormalities. This interest led, in later years, to Rokitansky’s intensive study of the cardiovascular⁴⁹ and genitourinary systems,⁵⁰ and in the interim, may have been one more factor in his recognition of endometriosis. Rokitansky published lasting contributions not only to the understanding of diseases characterized by excessive müllerian tissue, such as endometriosis and adenomyosis,⁵¹ but also to the congenital anomaly characterized by deficient müllerian tissue, partial müllerian aplasia.⁵² The Mayer-Rokitansky-Küster-Hauser syndrome illustrates precisely the author’s argument that gynecologic diseases apparent on the body surface or on cursory examination of the body interior were diagnosed much earlier than more subtle chronic diseases – like endometriosis and adenomyosis – in the body interior.

From Rokitansky to von Recklinghausen

“Conflicts in theories are common and can be settled satisfactorily only by experiment and critical observations rather than by speculative thinking. And yet, the latter approach has been the common one because the human brain craves understanding and aims at bringing everything under a single system of laws for the sake of making prediction safer and easier…This common pitfall is well demonstrated by the history of the evolution of theories aiming to explain the etiology of adenomyosis.”

Emge⁵³

According to the Austrian gynecologist Carl Breus – who dedicated his pamphlet on cystic adenomyomas to Hans Kundrat, assistant to Rokitansky and second successor to his chair of pathological anatomy in Vienna – Carl Schroeder, Herr, and Grosskopf had by 1884 collected more than 100 references to adenomyomata from the medical literature for a dissertation.⁵⁴ At the end of World War I, Cuthbert Lockyer, a reliable English authority on the subject of adenomyomas accepted the authenticity of the 100 references.⁵⁵ In 1924 a third authority, the Englishman K. Vernon Bailey writing primarily on extrauterine adenomyomas, did not reference any literature before the 1880s.⁵⁶ In 1962 a fourth authority Ludwig Emge, an American with a life-long interest in uterine adenomyosis, stated endometrial stromatosis “was first described by Virchow.” This was in 1863, just 3 years after Rokitansky’s initial report on uterine adenomyosis.⁵⁷ However, Emge had been unable to locate the “some hundred cases [that] had been collected by Carl Schroeder, Herr (sic), and Grosskopf.”⁵⁸

How to explain the discrepancy? What circumstances would explain the loss of interest in the more than 100 cases of cystic adenomyomas described by Breus in 1884?⁵⁹ Lockyer offered an explanation: “until the year 1894 (sic) there [were] very few reliable records of myomas containing cysts lined by epithelium.”⁶⁰ Lockyer attributed to Babes (1882) the first description of an adenomyoma – in a 91-year-old woman – a hazelnut size intramural myoma lying in the fundus of the uterus [which] contained cysts lined with low cuboidal epithelium “derived from embryonic germs.”⁶¹ This also appears to be the first mention in the literature of the theory of embryonic (congenital) müllerian rests proposed for the pathogenesis of uterine adenomyomas. According to Lockyer, “Up to 1896 the müllerian origin of adenomyoma had been generally accepted. The supporters of this view included Diesterweg, Schroeder, C. Ruge, Babes, Schottlander, Hauser, Strauss, Orloff, Ricker (for the uterus), and A. Martin, Orthmann, Chiari, Baraban, Pilliet (for the tube).”⁶² Significantly, the German pathologist Friedrich von Recklinghausen in his monograph of 1896 made no reference to adenomyomas before 1882, other than references to Rokitansky (1860 and 1861) and Virchow (1863).⁶³ Von Recklinghausen’s first reference was also to Babes in 1882. From this, we may conclude there was nothing of significance in the medical literature on adenomyomas before 1882, other than the works of Rokitansky and Virchow.⁶⁴ In sum, Friedrich Daniel von Recklinghausen remains the decisive authority on what constitutes the significant literature on adenomyomas between 1860 and 1896.⁶⁵

What happened in the 1880s to make that literature memorable? It was then, as we have seen in the article by Babes that investigators began to postulate the pathogenesis of tumors from embryonic rests.⁶⁶As early as 1854, Robert Remak, a student of Johannes Müller, suggested that tumors might originate “at an early developmental stage of the human embryo.” Remak anticipated the hypothesis of Julius Cohenheim that tumors originated from embryonic rests.⁶⁷ In the first edition of his book Vorlesungen published in 1877, Cohenheim, a student of Virchow,⁶⁸ put forth the idea that “the growth as well as the structure of tumors might be accounted for on the assumption of an origin from embryonal cells…from residual embryonal rudiments [rests].”⁶⁹

The search for pathogenesis and etiology was stimulated further when, after meticulous experimentation, Robert Koch announced to a select audience in Berlin in 1882 that he had discovered the bacillus that caused human tuberculosis.⁷⁰ Using tuberculosis as the model, Michael Worboys described the evolution of theories of disease in the nineteenth century as developing in three stages. Worboys contended “at its simplest [theories of disease] can be seen as moving from defining diseases by their symptoms and results to defining them in terms of processes and causes.”⁷¹ [Stage I] In the early nineteenth century, the disease was known as consumption, or phthisis, from the Greek word for “wasting.” This characterization was based on a holistic view of the symptoms and results; patients wasted away as their body literally consumed itself. [Stage II] “In the first half of the nineteenth century, the term ‘tuberculosis’ came to be used, referring to the localized pathological process of tubercle (nodule) formation in the lungs. Thus the disease was defined by process and results, but these were now described at the tissue and cellular level.” [Stage III] “However, the identification and acceptance of the Tubercule bacillus in the 1880s as the essential cause, over an extended period it must be said, led to the creation of an aetiological definition of the disease.”⁷²

Uterine and ovarian endometriosis were defined by Rokitansky in 1860 by the second-stage theory of disease, as a localized pathological process in the uterus and ovary. Rokitansky offered a theory of inflammatory pathogenesis. K. Codell Carter’s observation is pertinent: “While the medical profession accepted new discoveries only as evidence was forthcoming, everyone was open to the idea that universal necessary causes could be found even for non-bacterial diseases.”⁷³ For the next 7 decades, investigators offered other theories of pathogenesis, but were not able to identify the aetiology, the universal necessary cause of endometriosis, a chronic disease with many characteristics of cancer.

Greaves summarized the complexity of cancer causation, a summary directly applicable to the pathogenesis and etiology of endometriosis. “The composite and probabilistic nature of risk for cancer, plus its extended time frame of evolutionary development, poses the major intellectual obstacle in understanding causation for the public and professionals alike. The ingredients and pattern of the composite are different for each type of cancer and, even for a single type of cancer, risk factors can vary in weight or importance. This is not intuitively easy to grasp given past false assumptions about disease causality. There is often a tacit assumption that not only can and should causation in cancer be formally and indisputably provable but that singular causes must exist and these are both necessary and sufficient for the disease. This is simplistic and it is wrong. Causation can be inferred as ‘the most probable explanation’ but it is extraordinarily difficult, if not impossible, to prove culpability beyond doubt. Moreover, since all cancers are multifactorial in origin and can arise via alternative causal mechanism, the necessary and sufficient criterion is entirely inappropriate for cancer – as it is for the causation of most of our aliments.”⁷⁴

The Austrian gynecologist Breus published a pamphlet in 1883 in which he documented a 7-L cystic uterine myoma lined with ciliated epithelium.⁷⁵ Lockyer noted that in 1883, Diesterweg described two polypoid lesions located on the posterior uterine wall that contained blood-filled cysts lined with ciliated epithelium.⁷⁶ And, 2 years later, Diesterweg removed a fist-sized cystic tumor lined by ciliated epithelium from the same patient.⁷⁷Diesterweg theorized the pathogenesis of uterine adenomyomas resulted from invasive idiopathic stromal hyperplasia, a theory supported by “Carl Ruge (1889), Carl Schroeder (1892), and Hauser (1893).”⁷⁸ In 1887, Hans Chiari described the inflammatory pathogenesis of salpingitis isthmica nodosa, i.e., invasion of the muscular wall of the fallopian tube by its mucosal lining.⁷⁹ Lockyer explained Chiari’s reasoning based on observations of postmortem specimens of thickened fallopian tubes: “these swellings were the outcome of a chronic salpingitis, which he explained by stating that during an acute inflammation there was sufficient intratubal tension to force portions of the mucous membrane into the oedematous muscle-wall. The extruded portions of mucosa at first retain their communication with the lumen of the tube, but later on they become isolated, and form the gland-spaces which are found in the wall of the tube. These ‘adenomas,’ by setting up irritation, produce hypertrophy and hyperplasia of the muscle-tissue; and to this inflammatory histoid node the name Salpingitis isthmica nodosa was given by Chiari.”⁸⁰

Chiari’s Salpingitis isthmica nodosa (tubal adenomyosis) was directly analogous to uterine adenomyosis; invasion of the muscular wall of the uterus by its mucosal lining that was described by Chiari’s mentor Rokitansky in 1860. Neither uterus nor fallopian tube has a submucosa to retard invasion, such as the bowel possesses. Interestingly, Chiari and Rokitansky attributed mucosal invasion of the tube and uterus, respectively, to an inflammatory process. Chiari’s inflammatory theory of pathogenesis of tubal adenomyosis did not go unchallenged.

Von Recklinghausen postulated a different theory of pathogenesis of cystic uterine adenomyomas in a one and a quarter page note published in 1893. He believed they originated from “Ueberresten der Wolff’schen Canale,” that is, from embryonic rests of the Wolffian duct. The fact that von Recklinghausen specifically cited “Rokitansky’s Cystosarcoma adenoids uterinum” by name in his 1893 article indicates that he was familiar with the literature on uterine adenomyomas and the chronological limits of the literature dating back to Rokitansky’s original article in 1860.⁸¹ Other authors cited by von Recklinghausen included Babes, Diesterweg, and Hauser. In 1895, von Recklinghausen published a short but illuminating note entitled “Concerning the adenomyomas of the uterus and tube.”⁸² Therein, he described microscopic pseudoglomeruli that resembled the glomeruli of the kidney; the basis for his theory of mesonephric embryonic rests – Wolffian rests.

After reviewing the literature on adenomyomas, Von Recklinghausen wrote a monograph on the subject in 1896 entitled: Adenomyomas and Cystadenomyomas of the Uterus and Fallopian tubes and Their Origin from the Wolffian Body.⁸³ In 1918, two decades after its publication, the English surgeon Cuthbert Lockyer, a contemporary of von Recklinghausen, evaluated the medical and historical importance of von Recklinghausen’s monograph. “It was in the year 1896 that full interest in the subject [adenomyoma] was aroused by the publication of Friedrich von Recklinghausen’s magnificent work, Die Adenomyome und Cystadenomyome der Uterus und Tubenwandung.”⁸⁴According to Lockyer, the American investigator Rabinovitz recorded that von Recklinghausen “attempted completely to overthrow the inflammatory theory [of Chiari], and enunciated the congenital origin of salpingitis nodosa.”⁸⁵ Recall that there were three theories of pathogenesis of uterine adenomyomas at this time; the 1860 Rokitansky hypothesis of chronic inflammation,⁸⁶ the 1854–1877–1882 Remak-Cohenheim-Babes theory of embryonic rests,⁸⁷ and the 1883 Diesterweg theory of hyperplastic endometrial invasion of the uterus.⁸⁸ In the introduction to his article, Rabinovitz stated that the subject of “salpingitis nodosa” (or as he preferred “adenomyosalpingitis”) was subject to “copious, and at times, even acrimonious debate” among proponents of three conflicting views of the pathogenesis of the disease: inflammatory, congenital, or some compromise between the two.⁸⁹ This statement of Rabinovitz goes to the heart of von Recklinghausen’s motivation for studying adenomyomas in the first place.

Recall that von Recklinghausen’s interest in the pathogenesis of uterine and tubal adenomyomas began in 1893, when he published his first short note on the subject. If Rabinovitz was correct, then one might conclude, as did Lockyer, that von Recklinghausen’s major work on the pathogenesis of adenomyomas of the uterus and fallopian tubes was undertaken to disprove the inflammatory hypothesis of Chiari, a former assistant of Rokitansky.⁹⁰ Thus, one may trace intellectual continuity from Rokitansky through Chiari to von Recklinghausen.

However, there appears to be more to the story. In 1883, Diesterweg had hypothesized the pathogenesis of uterine adenomyomas resulted from invasive idiopathic stromal hyperplasia; Diesterweg’s hypothesis was supported by others.⁹¹ As Lockyer pointed out, in 1894 Pilliet expressed “the view that cysts and glands of adenomyoma were of mucosal origin.”⁹² The articles by Diesterweg and Pilliet may have alerted von Recklinghausen to the idea of mucosal origin, for he cited both among the 107 references in his 1896 monograph.⁹³ But far more importantly, Pilliet’s article of 1889 may also have been the source for von Recklinghausen’s theory that the vast majority of uterine and tubal adenomyomas were derived from Wolffian rests.⁹⁴ Like Bichat, Rokitansky, and Virchow before him, von Recklinghausen read widely in the medical literature when formulating his theory.⁹⁵ In this case, he was searching for alternatives to the inflammatory theory postulated by Chiari. In his 1896 monograph, Von Recklinghausen postulated that adenomyomas were organoid tumours derived from Wolffian rests originating from the mesonephros – Wolffian body – as he had first postulated in 1893.⁹⁶ He divided uterine adenomyomas into two classes, those arising peripherally in the uterus and fallopian tube from Wolffian remnants and the rare central lesions arising from the endometrium.⁹⁷ Lockyer transcribed von Recklinghausen’s classification of uterine adenomyomas by morphology into four varieties:

Hard, in which the muscle tissue is in excess of the gland elements

Cystic, with spaces visible to the naked eye, possessing gland tissue and muscle in equal amounts

Soft, in which the gland tissue appears microscopically as islands and is the predominating feature

Telangiectatic, soft, very vascular growths, which are almost devoid of cysts⁹⁸

This first pathological classification of uterine adenomyomas was important because it had diagnostic significance for pathologists and for any surgeon sufficiently curious to incise and examine a growth in situ or after its removal.

Von Recklinghausen’s colleague, the gynecologist Wilhelm A. Freund, wrote an afterward to von Recklinghausen’s monograph in which he attempted to define the clinical signs and symptoms by which uterine adenomyomas could be diagnosed. Viewed from the perspective of the twenty-first century, the critical clinical features were profuse and painful periods, pelvic peritonitis, and severe anemia.⁹⁹Lockyer presented the full clinical picture presented by Freund. “There was a history of debilitated childhood. Menstruation appeared late; puberty was postponed. The periods were profuse and painful. Irregular haemorrhage was common; there was pelvic peritonitis and marked anaemia. Body-functions were impaired, and the growth led eventually to complete incapacity for work. Objectively there were signs of general hypoplasia and infantilism. The tumour had its situation in the dorsal wall of the uterus. Pelvic peritonitis and fixation of the pelvic organs was a marked feature. The site of election was the cornu uteri, from whence the growth spread downwards towards the cervix.”¹⁰⁰ Freund’s “clinical picture” was considered too general to make an exact preoperative diagnosis of uterine adenomyomas. The aforementioned symptoms and objective signs were contested by many investigators and were found wanting to differentiate uterine adenomyomas from uterine fibroids. Investigators concluded that only a tentative preoperative diagnosis was possible; positive diagnosis could only be made at surgery and many times only by histologic examination.¹⁰¹

Notwithstanding, von Recklinghausen’s macro-, micro-morphologic classification of adenomyomas combined with Freund’s description of symptoms and signs was a major first effort to establish clinical–pathological correlation and give adenomyomas a name and nosographic significance for clinicians and pathologists. Von Recklinghausen’s prestige guaranteed that the monograph would be influential and widely read. Recall that most investigators had accepted the theory of müllerian rests to explain the origin of pelvic adenomyomas until 1896. After 1896, von Recklinghausen’s theory of mesonephric origin of adenomyomas from Wolffian rests displaced the müllerian theory.¹⁰² Von Recklinghausen’s challenge to the older müllerian theory started a “Streitfrage,”¹⁰³ a great controversy in Europe over the pathogenesis of uterine and tubal adenomyomata. When von Recklinghausen’s monograph crossed the Atlantic Ocean in 1896 to North America, it ignited a mini-Streitfrage at Johns Hopkins Hospital.

From von Recklinghausen to Cullen

At the time that Friedrich von Recklinghausen, the first and most brilliant assistant of Rudolf Virchow, published his brief note on uterine adenomyoma on May 19, 1893,¹⁰⁴ Thomas Cullen was studying at the Pathological Institute of the University of Göttingen under Johannes Orth.¹⁰⁵ Under Orth’s direction, Cullen became thoroughly indoctrinated in German Scientific methods and the concept of Wissenschaft, self-directed scholarship and research.¹⁰⁶ Cullen studied under Orth while waiting to begin a residency in gynecologic surgery under Howard A. Kelly at Johns Hopkins Hospital in Baltimore, Maryland. Cullen was befriended by Orth who taught him the “root fact” of teaching: “You can’t teach a man anything worth knowing. You can only show him what there is to learn.”¹⁰⁷ Cullen made Orth’s aphorism his own; it shaped Cullen’s method of teaching gynecologic pathology and surgery.¹⁰⁸ In Göttingen, Cullen became a Germanophile.¹⁰⁹

When Cullen returned to Baltimore in October 1893, the residency position Kelly had promised him had been reclaimed by William W. Russell. Inspired, Howard Kelly arranged for Cullen to be given charge of gynecological pathology. As if endowed with foresight, Cullen had returned from Germany with his own microscope.¹¹⁰ A small room was set aside for gynecologic pathology, one floor below Welch’s pathological anatomy laboratory, referred to as the Pathological. There, Cullen, the assistant of Howard Kelly, stayed for 3 years studying and examining fresh surgical specimens under the influence of William H. Welch and Simon Flexner, Welch’s assistant.¹¹¹ Unlike German laboratories where the professor assigned a subject for investigation, at the Pathological, each person was free to choose the subject.¹¹² Thus, Cullen’s opportunity for independent research on a subject of his own choosing was made possible by Welch’s liberal philosophy of research. Welch came to the “Hopkins eager to establish the German system of laboratory education there, but the result was very different. In Germany, a laboratory entered on the investigation of a large subject which presented a variety of separate problems that were parceled out among the advanced students, the professor keeping the many threads in his own hands. The nature and comprehensiveness of the general subject reflected the inventiveness, fertility, and technical skill of the professor, which also determined the results achieved. This was not Welch’s way. He never devoted his laboratory to the investigation of any single subject, nor did he show any special fertility in the choice of problems for himself or others; his own choices…were determined by fortuitous circumstances, not any plan. And he never set a student to work on a concrete problem, seeming rather to avoid any such commitment; he held that men do not work well on assigned tasks.”¹¹³ In September 1895, after just 2 years in charge of gynecological pathology, Cullen sent reprints of his first publications to Welch, who responded with a note of encouragement to the young investigator.¹¹⁴ Cullen recalled many years later that his experience in pathology under Welch was “priceless.”¹¹⁵

In 1893, the same year Cullen started research in pathology under Welch, Frederick Jackson Turner read a paper before the American Historical Association entitled “The Significance of the Frontier in American History.”¹¹⁶According to Turner, the 1890s marked the end of an era in American history when the Superintendent of the United States Census declared the American Frontier closed.¹¹⁷ Turner argued persuasively the grand concept of American exceptionalism; a hypothesis that Americans were shaped by the harsh environment of the frontier into self-reliant, rugged individuals. The quick actions of Howard Kelly and William Welch to found gynecologic pathology at Johns Hopkins Hospital and the equally quick action of Thomas Cullen to respond – thus becoming the first gynecologic pathologist in North America – represent nothing less than actions of self-reliant individuals; exemplars of American – and Canadian – exceptionalism.

And their decisiveness paid off handsomely.¹¹⁸ On October 31, 1894, during his second year in the laboratory, Cullen received an unusual fresh surgical specimen that piqued his curiosity¹¹⁹ – a scene reminiscent of the freshsurgical specimen that caught the attention of Rokitansky 34 years earlier in the old Leichenhaus in Vienna. Cullen examined a “uniformly enlarged uterus about four times normal size…caused by a diffuse thickening of the whole anterior wall.” Unsure how to process the specimen, Cullen walked upstairs for a consultation with Dr. Welch. Welch, too, had never seen anything like it. He recommended that histologic sections be cut through the full thickness of the anterior wall of the uterus.¹²⁰ Cullen followed Welch’s advice and cut giant serial sections with a microtome. “Examination of these sections showed that the increase in thickness was due to the presence of a diffuse myomatous tumor occupying the inner portion of the uterine wall, and that the uterine mucosa was at many points flowing into the diffuse myomatous tissue.” In March 1895, Cullen reported this case to a meeting of the Johns Hopkins Medical Society.¹²¹ On April 6, 1895, Cullen received his second specimen, an adenomyoma that involved the posterior uterine wall. He duly processed the second specimen as he had the first. And there the matter rested until 1896.

In 1896, Friedrich von Recklinghausen published a monograph entitled: Die Adenomyome und Cystadenome der Uterus- und Tubenwandung ihre Abkunft von Resten des Wolff’schen Korpers; Adenomyomas and Cystadenomas of the Uterus and Tubal Wall, their Origin from Embryonic Rests of the Wolffian body.¹²²Die Adenomyome und Cystadenome der Uterus- und Tubenwandung¹²³ fully documented von Recklinghausen’s theory of the pathogenesis of adenomyomas from remnants of the Wolffian body; only in the Anhang or appendix did the author include one case whose pathogenesis he attributed to mucosal invasion. With the publication of von Recklinghausen’s monograph, the disease “adenomyoma uteri,” virtually leapt over the Atlantic Ocean – from the German University of Strassburg in Alsace to the German – oriented Johns Hopkins University in Baltimore, Maryland; from the laboratory of Friedrich Daniel von Recklinghausen (1833–1910)¹²⁴ to the laboratory of William Henry Welch (1850–1934), who had studied under von Recklinghausen.¹²⁵ Or more poetically, the European experience with adenomyomas was transferred from von Rokitansky to Chiari to von Recklinghausen to Cullen.

When the 27-year-old Johns Hopkins’ instructor in gynecologic pathology, Thomas Stephen Cullen, read von Recklinghausen’s monograph, he experienced an awakening.¹²⁶ The famous German pathologist, the 63-year-old Professor Friedrich von Recklinghausen, had theorized the pathogenesis of uterine and tubal adenomyomas from embryonic mesonephric rests. Suddenly, Cullen realized the significance of his own work. His microscopic findings differed from those of the great German pathologist. In two cases of uterine adenomyomas, he had demonstrated the endometrial mucosa invaded the underlying uterine muscle. Until that moment, Cullen had had no idea of the significance of his own microscopic analysis. Cullen’s awakening by von Recklinghausen is reminiscent of Schwann’s dramatic awakening by Schleiden.¹²⁷

Cullen pulled the large microscopic slides of his two cases and restudied them in the light of von Recklinghausen’s research. In hindsight, Cullen realized he had demonstrated the mucosal origin of benign diffuse uterine adenomyomas in 1894 and 1895. His mucosal invasion pathogenesis of uterine adenomyomas conflicted directly with von Recklinghausen’s mesonephric theory of origin from Wolffian remnants. Confident of his microscopic analysis, he sought consultation.

Armed with his giant microscopic slides, Cullen took his case to Welch. He too had read Die Adenomyome und Cystadenome der Uterus und Tubenwandung. Welch defended his old teacher, saying to Cullen: “You’re wrong in your interpretation.” Cullen recalled his retort to Welch: “I don’t care a hoot what von Recklinghausen says…look down the barrel of that microscope.” Welch examined the slides without comment.¹²⁸ But, Welch’s lack of comment to Cullen was not lack of concern or involvement. Welch, affectionately and quietly known among his admirers as “Popsy,”¹²⁹ suspected – as Cullen could not – that he knew the basis for the difference of opinion between Cullen and von Recklinghausen.¹³⁰

From Welch’s active defense of von Recklinghausen to silence was confirmation enough for Cullen. He determined to write up his findings. Cullen would take issue with von Recklinghausen. Von Recklinghausen had developed a theory to explain the pathogenesis of uterine adenomyomas in the periphery of the uterus and in the proximal fallopian tube: adenomyomas remote from the uterine cavity and its mucosa. Cullen developed no theory. Instead, he demonstrated – by technology unavailable to von Recklinghausen – the pathogenesis of benign diffuse uterine adenomyoma from the uterine mucosa.¹³¹ Herein lay the crux of the forthcoming debate.

However, Cullen had no dispute with Wilhelm Alexander Freund, the gynecologist who first described the clinical aspects of uterine adenomyoma in an appendix to von Recklinghausen’s pathological anatomy.¹³² By 1896, the advantages of surgical pathology enabled researchers, like Freund, to correlate the clinical and pathological aspects of chronic diseases hidden in the interior of the living human body. By so doing, Freund elevated the pathological entity adenomyosis to a clinical entity. He demonstrated that a practitioner could diagnose adenomyosis – Die Adenomyome und Cystadenome der Uterus – by its signs and symptoms. This empowered him and others to prescribe specific medical or surgical treatment as indicated.¹³³ Nearly 2 decades earlier in 1878, Freund had published a new method for the removal of the entire uterus, a publication that a century later the medical historian Larry Longo considered among the classic pages in obstetrics and gynecology.¹³⁴

Rokitansky had viewed Sarcoma adenoids uterinum, (benign uterine adenomyosis) Cystosarcoma adenoids uterinum, (benign cystic uterine adenomyosis), and Ovarial-Cystosarcoma (benign ovarian endometriosis) as distinct ontologic disease entities and he gave them descriptive Latin names. In other words, Rokitansky viewed adenomyosis and endometriosis as ontological diseases, distinguishable from healthy bodily tissues and organs.¹³⁵ In the ontological view, disease is seen as an independent entity with a history of its own.¹³⁶ Pathologists and surgeons tended to adhere to the ontological view of disease; disease was something they excised and separated from the body.¹³⁷ By the end of the nineteenth century, the Berlin gynecologist W. A. Freund viewed Die Adenomyome und Cystadenome der Uterus of von Recklinghausen, the Sarcoma adenoids uterinum of Rokitansky, as a distinct benign clinical entity – an ontological disease with a triad of symptoms and signs that enabled him to diagnose the disease clinically – before surgery.

Louis Pasteur and Robert Koch hastened identification of the role of bacteria as specific external invaders in the causation of specific diseases.¹³⁸ The technological inventions of these scientists and their followers strengthened the ancient ontological view that disease was caused by outside factors. The ontological view perceived disease as “essentially external in its causation.”¹³⁹ In the nineteenth century, Claude Bernard in France and Virchow in Germany became exponents of the physiological concept of disease, a concept that expressed doubt about a clear demarcation between health and disease. Claude Bernard’s Introduction to the Study of Experimental Medicine (1836) “became the classical philosophical exposition of the new concept.” Bernard wrote: “The words, life, death, health, disease, have no objective reality.”¹⁴⁰ Around the time of the Franco-Prussian War of 1870–1871, the dispute over disease theory turned nationalistic in character. The German Virchow espoused a physiological or “internal” concept of disease and held that the French Pasteurian bacteriology represented the “external” causation of disease.¹⁴¹

Georges Canguilhem offered a nuanced explanation in his doctoral thesis written during World War II.¹⁴² “Medical thought has never stopped alternating between these two representations of disease, between these two kinds of optimism, always finding some good reason for one or the other attitude in a newly explained pathogenesis. Deficiency diseases and all infectious or parasitic diseases favor the ontological theory, while endocrine disturbances and all diseases beginning with dys- support the dynamic or functional [physiologic] theory. However, these two conceptions do have one point in common: in disease, or better, in the experience of being sick, both envision a polemical situation: either a battle between the organism and a foreign substance, or an internal struggle between opposing forces. Disease differs from a state of health, the pathological from the normal, as one quality differs from another, either by the presence or absence of a definitive principle or by an alternation of the total organism.”¹⁴³ Note the nuanced definitions of Canguilhem; physiologic theory means a struggle between opposing forces [internal concept of disease], and ontological theory means a battle between the body and a foreign substance [external concept of disease]; without mention that disease is an independent entity with a history of its own.¹⁴⁴

Owsei Temkin broadened the concept of ontological disease when he related the concept of an internal ontological orientation: “The ontologist thus avoids a difficulty which the radical physiologist must face. The difference in attitude between the two is expressed in the encounter between Michel Peter and Pasteur as told by Rene Dubos. Peter claimed that ‘Disease is in us, of us, by us’, whereas ‘Pasteur emphasized that contagion and disease could be the expression of the living processes of foreign microbial parasites, introduced from the outside, descending from parents identical to themselves, and incapable of being generated de novo.’ Pasteur made it clear that contagious disease was the expression of a foreign life. But if disease has to be looked for in our own nature it has to be accounted for differently. If we attribute it to genes [or shed endometrium in the case of endometriosis] we still have recourse to ontology, as I indicated previously, an ‘internal’ ontological orientation in contrast to the external of the bacteriologist. It is probably neither possible nor advisable to renounce ontology completely.”¹⁴⁵ Still to be realized for the chronic müllerian (endometriotic) diseases is a classification founded on etiologic causation.¹⁴⁶

Learning from von Recklinghausen’s inclusion of Freund’s clinical description of the signs and symptoms of uterine adenomyomas, Cullen integrated clinical picture and pathological anatomy in his response to von Recklinghausen. The medical history of patients and their families reported by Cullen illustrate the background of serious infectious diseases prevalent at the end of the nineteenth century. Such diseases as tuberculosis, diphtheria, influenza, malaria, pneumonia, typhoid fever, and meningitis were endemic. Women with a history of any of these diseases were further weakened by the profuse uterine bleeding and uterine pain and tenderness that accompanied diffuse adenomyosis of the uterus.

Before writing up his scientific report, Cullen carefully reexamined his thinly sliced, microscopic sections mounted in celloidin. They were giant full-thickness serial sections that included the diffuse inner muscular thickening of the anterior uterine wall in the first specimen and of the posterior uterine wall in the second specimen. In both specimens, Cullen clearly demonstrated that the adenomyomatous tissue originated from direct invasion of the uterine musculature by stroma and glands of the uterine mucosa. Cullen’s detailed report of his two cases of mucosal invasion included a third case of “pseudo-invasion.” The third case revealed the sophistication of his response. Max Broedel’s explicit illustrations of the gross and microscopic pathology proved beyond question the origin in the two cases of uterine adenomyomas from endometrial mucosa.¹⁴⁷ “Adeno-myoma Uteri Diffusum Benignum” by Thomas S. Cullen, MB (Toronto) appeared in the Johns Hopkins Hospital Reports, volume 6, 1896.¹⁴⁸

Cullen’s observations benefited from the application of scientific advances to the processing of tissue, improvements in microscopy, and the emergence of surgical pathology following wider use of aseptic surgery and decreased surgical mortality during the late nineteenth century. He processed his surgical specimens by first hardening them in Müller’s solution, a legacy from Johannes Müller via Virchow to von Recklinghausen to Welch to Cullen.¹⁴⁹ “Thereafter, the tissue to be examined had to be immersed for fixed periods in alcohols of varying strength and in celloidin, before it could be blocked, sectioned, stained, and mounted for microscopic examination.”¹⁵⁰Celloidin, a solution of pyroxylin in ether and alcohol, used for embedding histological specimens, was in wide use by 1890 as were the giant histologic sections of an entire organ such as a kidney or a large specimen such as a uterine adenomyoma.¹⁵¹ Cullen used Weigert’s hematoxylin stain for his study of uterine adenomyomas in 1896.¹⁵²Having bought a microscope in Germany in 1893 while studying with Orth, Cullen examined his specimens through an instrument with the latest refinements introduced by the German optical genius Ernst Abbe (1840–1905) between the years 1872 and 1886: the Abbe condenser and apochromatic objectives with compensating eyepieces.¹⁵³ And critically, Cullen had access to a microtome to cut thin tissue slices.¹⁵⁴

However, compared to Virchow’s academic stature when he had criticized Rokitansky 50 years earlier, Cullen possessed neither a Ph.D. nor a Habilitation when he challenged von Recklinghausen in 1896. Eschewing his aggressive rhetoric with Welch, Cullen cautiously invited debate with von Recklinghausen by distinguishing adenomyomata “situated in the uterine muscle at some distance from the mucosa” from the variety “situated in the inner layers of the uterine wall.” Cullen invoked the research of Rokitansky and von Recklinghausen to bolster his argument. To accurately frame the debate, the introduction is presented as Cullen wrote it: “Glandular elements in myomata of the uterus are not at all infrequent, and numerous cases have been reported. There is a difference of opinion as to the source of the glands, some believing that they originate from remains of the Wolffian body, others that they are due to down-growths from the uterine mucosa. In the majority of the reported cases the adeno-myomata have been situated in the uterine muscle at some distance from the mucosa, or have been subperitoneal. From these cases one has only been able to deduce theories as to the origin of the glands, but has not been in a position to make any definitive statement. In this article I propose briefly discussing a variety of adeno-myomata which is diffuse in character, is situated in the inner layers of the uterine wall, and which is dependent on the uterine mucosa for its glandular elements. “Tumours of this nature have been mentioned by Rokitansky,¹⁵⁵ Schatz,¹⁵⁶ and Schroeder,¹⁵⁷ and Diesterweg¹⁵⁸reports a case which was probably of this character. v. Recklinghausen,¹⁵⁹ in the ‘Nachtrag’¹⁶⁰ accompanying his recent work ‘Die Adenomyome und Cystadenome der Uterus- und Tubenwandung,’ carefully depicts a case belonging to this group.”¹⁶¹

Mindful that he was a young apprentice in pathology¹⁶² compared to the great German Master, Cullen allowed for their differences of opinion regarding the pathogenesis of uterine adenomyomata by diplomatically, but correctly, stating that most of the lesions previously described had been “situated in the uterine muscle at some distance from the mucosa, or have been subperitoneal.” Having established the basis for the difference of opinion, Cullen then cited the case that von Recklinghausen had appended in the Nachtrag, as well as cases by Rokitansky, Schatz, Schroeder, and “probably” Diesterweg that supported his observation that the glands and stroma of uterine adenomyomata originate from the uterine mucosa. Finally, Cullen described minutely the gross and microscopic picture of adenomyoma uteri diffusum benignum (diffuse adenomyosis). In the first case, the uterine wall was “divided into two distinct portions: an outer, 1 cm. thick which resembles normal uterine muscle; the remainder of the wall presents a coarsely striated appearance, the striae running in all directions…the diffuse growth as a whole is much paler [‘watered silk appearance’ of von Recklinghausen] than the outer covering of uterine muscle.” Microscopically, “the diffuse thickening is composed of non-striped muscle bundles which run in all directions. They occur as long bands of fibres, which follow a straight or serpiginous course and do not show much tendency to arrange themselves concentrically as in ordinary myomata….At numerous points the longitudinal glands are seen penetrating the growth for a distance of 1 cm. or more. These glands present exactly the same appearance as those on the surface of the mucosa, and are accompanied by the characteristic stroma of the mucosa….The glands are most abundant near the uterine mucosa, diminish in number as one passes outward, and in the normal uterine muscle are entirely wanting…The stroma surrounding these glands resembles identically that of the uterine mucosa.”¹⁶³

Cullen then carefully described von Recklinghausen’s and his own interpretation of the microscopic findings. “v. Recklinghausen was in places able to make out a definite arrangement of the muscle around the glands. He believes that the growth of the glands and of the muscle go hand in hand. I was unable to detect any special relation of the muscle to the glands. In both cases it looked as if the mucosa had penetrated into the spaces between the muscle bundles. I am constrained to believe that the muscular growth commenced in the inner zone just beneath the mucosa, and that the bundles of these fibres have been loosely united with one another and have allowed the uterine glands to penetrate into the depth.”¹⁶⁴ Thus, Cullen presented his side of the debate with von Recklinghausen.

In sum, Cullen wrote his article on benign diffuse adenomyoma of the uterus as an immediate response to the totality of von Recklinghausen’s monograph. He introduced the term diffuse to describe adenomyomas with stroma and glands derived by endometrial invasion of the uterine musculature. Cullen’s diffuse adenomyomatous lesions were the antithesis of the organoid structures described by von Recklinghausen. As adenomyosis originates from the uterine mucosa and invades the myometrium, the lesion is diffuse. However, some lesions become cut off from their site of origin as they invade and appear macroscopically more compact or organoid, though microscopically they appear similar. Cullen’s histologic descriptions augmented by Max Broedel’s illustrations would give rise to a private debate with von Recklinghausen over the pathogenesis of uterine adenomyomata.

Mindful that Cullen wrote “Adeno-myoma uteri diffusum benignum” ¹⁶⁵ as a response to von Recklinghausen’s monograph, Welch sent a copy to his old teacher in Strassburg.¹⁶⁶ Von Recklinghausen had seen mucosal invasion but interpreted his findings quite differently than Cullen; von Recklinghausen thought that what appeared as mucosal invasion to Cullen was instead erosion of the mucosa by the expanding organoid adenomyoma, just the opposite of what Cullen demonstrated. Years later, Cullen told his biographer: “I soon heard from von Recklinghausen and I answered him and we had a long and interesting correspondence on our subject. I sent him large sections of my tumors – ones I had described in my paper – and it ended with something as near an admission of error as an old and famous Herr Professor could be expected to make: ‘On all material points there is no difference between us.’”¹⁶⁷ From the German professor’s perspective, he had demonstrated mucosal invasion in one case as Cullen had in two cases. In other words, Cullen had merely confirmed von Recklinghausen’s minor thesis, that of mucosal invasion, which he had reported in the Nachtrag or appendix to his monograph.¹⁶⁸ Hence: “On all material points there is no difference between us.”¹⁶⁹ Furthermore, Cullen had not disproved his major theory, the origin from remnants of the Wolffian body. Cullen’s dissatisfaction arose from the belief that he had disproved the German professor’s major theory of origin from remnants of the Wolffian body. Dissatisfied with the outcome, Cullen began to collect more surgical cases to prove his point.

Cullen’s “awakening” conformed to the historical germ theory of Herbert Baxter Adams.¹⁷⁰ Adams’ theory related American history as an outgrowth of Anglo-Saxon and Germanic antecedents.¹⁷¹ The Adamsonian “intellectual germ” that awakened Thomas Stephen Cullen in 1896 was a direct outgrowth of Germanic antecedents transmitted and transplanted onto American soil in the form of Friedrich von Recklinghausen’s monograph.¹⁷²While reviewing a historical monograph by James V. Ricci,¹⁷³ Martzloff casually divulged a 50-year-old first-hand-account of von Recklinghausen’s reaction on reading Cullen’s article Adenomyoma uteri diffusum benignum in 1896.¹⁷⁴ “Chapter 31 discusses the once highly controversial subject of adenomyomatous changes. It would have been interesting to the reader to know that Cullen, in showing that the adenomyomas he studied were of endometrial (Müllerian) origin and not of Wolffian origin, as espoused by Recklinghausen, did so by means of studying serial sections. This he was able to do accurately because he had a microtome! When the great Recklinghausen read Cullen’s article he turned somewhat chagrinned to Emil Ries (as told to me by the late E. R.) who was in Recklinghausen’s laboratory at that time, and said ‘Cullen has proven his point. This merely shows what this young ingenious American (junger künstlicher Amerikaner), (Cullen was born a Canadian) has been able to accomplish with the aid of a mechanical device (Ein mechanisches werkzeug) while we still putter around making sections with razor and amyloid liver.’”¹⁷⁵

Emil Ries was a young German scientist working in von Recklinghausen’s laboratory who witnessed first-hand the Professor’s body language and verbal reaction to Cullen’s article. Years later, Ries related the story to Karl H. Martzloff who not only recorded it in the Western Journal of Surgery, Obstetrics, and Gynecology but undoubtedly, having studied under Cullen, also related the story to Cullen.¹⁷⁶Cullen told his biographer his version of the same incident that resulted in von Recklinghausen’s comment: “On all material points there is no difference between us:” Cullen explained: “There was a difference, of course, and the real reason for it was that von Recklinghausen had obtained his material from autopsies, after the changes due to death had occurred. I was working on living tissue, or on tissue so lately removed from living patients as to be the next thing. So I knew I was right. It is the difference between trying to find the cause of a fire after the house has burned down, and getting there while it is still burning. The earlier you get to a fire, the better your chance of discovering how it began.”¹⁷⁷

That same year 1896, Cullen identified what he claimed was the first adenomyoma of the round ligament, which he promptly published with illustrations by Max Broedel in the Bulletin of the Johns Hopkins Hospital.¹⁷⁸Cullen sent a copy of “Adeno-myoma of the round ligament” and microscopic sections to “Professor von Recklinghausen in Strasbourg.”¹⁷⁹ In the article, Cullen described the histologic findings: “In many places the glands present a peculiar arrangement and correspond to von Recklinghausen’s pseudo-glomeruli.” Then, Cullen explained: “These pseudo-glomeruli consist of stroma resembling that of the uterine mucosa…What corresponds to Bowman’s capsule consists of a layer of cells resting directly upon the muscle fibres…In other words, the space between the capsule and the so-called glomerulus is nothing more than a dilatation of the gland cavity.”¹⁸⁰ In sum, Cullen explained to von Recklinghausen – complete with microscopic slides – how endometrial glands and stroma could appear to be pseudo-glomeruli. This time, Cullen was not dissatisfied with the response. Von Recklinghausen wrote to Cullen thanking him and said that he had used Cullen’s slides to illustrate his talk at a medical meeting in Frankfurt, Germany. Cullen considered this reply a “peace offering” from the eminent German Professor, a “peace offering,” which he “graciously received.”¹⁸¹ It was after this second communication between the two that “an amicable pathological correspondence passed between Strasburg and Baltimore as matters of interest arose,”¹⁸² a scholarly exchange that continued for more than a decade.¹⁸³

Robert Meyer Disproves von Recklinghausen’s Wolffian Theory

Learning to see was never, is never, will never prove effortless…

Daston and Galison ¹⁸⁴

The 1890s marked the end of an era in the discipline of human pathology, a paradigm shift from morbid pathological anatomy practiced at the autopsy table to surgical pathology practiced with fresh specimens.¹⁸⁵ Surgical pathology laboratories were often improvised as was Cullen’s laboratory at Johns Hopkins Hospital in 1893 and Robert Meyer’s “closet” sized laboratory in his Berlin apartment in 1895.¹⁸⁶ Meyer bought a small microtome and so was able to make thin microscopic tissue preparations for Johannes Veit, professor of gynecology at the University of Berlin, as Cullen did for Howard Kelly, professor of gynecology at Johns Hopkins University.¹⁸⁷ Once again, technology played a key role in scientific advancement, a generation earlier it had been the microscope of Rokitansky; now it was the microtome of Cullen and Meyer.¹⁸⁸

Later, makeshift laboratories were replaced by laboratories in universities and university hospitals equipped with the latest technology. Medical scientists had the choice between medical illustrations “able to capture the meaning and essence of a situation,” and photographs “which could serve as a form of ‘raw material’.”¹⁸⁹

Daston and Galison described the hazards of negotiating the slippery slope of scientific objectivity. “The persistent visual ambiguities of microscopy demanded photographic illustration, to forestall the observer’s tendency ‘to insert involuntarily his hypothetical explanation into the depiction.’ A photograph was deemed scientifically objective because it countered a specific kind of scientific subjectivity: intervention to aestheticize or theorize the seen.¹⁹⁰ Current usage allows a too easy slide among senses of objectivity that are by turns ontological, epistemological, methodological, and moral. Yet these various senses of the objective cohere neither in precept nor in practice. ‘Objective knowledge,’ understood as ‘a systematized theoretical account of how the world really is,’ comes as close to truth as today’s timorous metaphysics will permit. But even the most fervent advocate of ‘objective methods’ in the sciences - be those methods statistical, mechanical, numerical, or otherwise - would hesitate to claim that they guarantee the truth of a finding.”¹⁹¹

The parallelism between Meyer and Cullen continued. Coincidently in 1896, Robert Meyer was already studying the pathogenesis of a uterine myoma “in which some almond-sized nodules of endometrium were encapsulated…when von Recklinghausen published his work on the mesonephric origin of ‘adenomyomata’ of the uterus (1896), which were in reality adenomyosis.”¹⁹² Like Welch and Cullen, Robert Meyer read von Recklinghausen’s monograph. Unlike Welch the conciliator and Cullen the debater, Meyer played the role of a scientific detective. In response to von Recklinghausen’s Die Adenomyome und Cystadenome der Uterus- und Tubenwandung, he began embryological studies to either corroborate or disprove his old professor’s theory. In 1897, Meyer took a practical course in embryology from the Oscar Hertwig, famous for the first microscopic description of fertilization in the sea urchin.¹⁹³ That same year, he requested the uteri of fetuses and adults. With these specimens, Meyer began extensive embryological studies to test von Recklinghausen’s mesonephric theory.¹⁹⁴Meyer published six cases of adenomyoma of the cornual–tubal angle of the uterus.¹⁹⁵ Torn between the mucosal theory of Cullen and the mesonephric (Wolffian duct) theory of von Recklinghausen, Meyer assigned the pathogenesis of three cases to each of the theories.¹⁹⁶ In the process, Meyer became an outstanding embryologist comparable to Fischel, Keibel, Felix, and Mall. Emil Novak attributed Robert Meyer’s preeminence in pathology to his profound knowledge of embryology.¹⁹⁷ Indicative of a latent interest in embryology, Meyer had squirreled away in his desk “an extremely rare specimen, an osteoid tissue in the uterus of a fetus.”¹⁹⁸

In 1897, R. Kossmann of Berlin vigorously opposed the Wolffian rest theory of von Recklinghausen, arguing for the origin of adenomyomas from accessory müllerian ducts.¹⁹⁹ Cuthbert Lockyer, a contemporaneous observer of the events, recorded that Kossmann’s “destructive criticism…was instrumental in destroying the enthusiasm” for von Recklinghausen’s theory, but not the enthusiasm of Robert Meyer.²⁰⁰ A great controversy arose as to the origin of the gland elements in adenomyomata, a great “Streitfrage” between supporters and detractors of v. Recklinghausen’s Wolffian theory. Lockyer commented on the universal respect for the judgment of Robert Meyer: “In this great Streitfrage it is particularly interesting to watch the evolution of the important part played by Professor Meyer of Berlin, and his final conclusions carry the great weight from the fact that all through the controversy, he kept an open mind, ready to receive new impressions, and to accord fresh findings their full value; being untrammeled by prejudice, he was candid enough to admit a change of view as occasion required, and he seemed able to do this without loss of dignity or prestige.”²⁰¹

Meyer made an informal visit to Alsace in 1898 to see his old professor. Alsace was a Germanic province of the Holy Roman Empire lost to France during the 30-Years War (1618–1648) and recaptured from France during the Franco-Prussian War of 1870–1871. There, in Strasbourg, in 1819, the French founded the first chair of pathological anatomy in Europe.²⁰² But unfortunately, the French deprived provincial universities “of all local initiative and deliberately subordinated [them] to the Sorbonne and the College de France.”²⁰³ After the Franco-Prussian War, the Germans sent Friedrich Daniel von Recklinghausen, the very first assistant of Rudolph Virchow and one of their ablest pathologists, to the chair of pathological anatomy at the German University of Strassburg. The Germans set high standards of scholarship. In that era, standards of Wissenschaft were so high that German professors, such as von Recklinghausen, were regarded as virtual academic deities.

As a medical student in Strassburg in the mid-1880s, Robert Meyer studied pathological anatomy under von Recklinghausen.²⁰⁴ In his autobiography, Meyer wrote: “I learned from him the fundamentals of pathology and the art of dissection and of cutting sections by hand. For staining we used the natural dyestuffs known at the time, cochenille and carmine. Both were excellent and durable, even up to the present.”²⁰⁵ Meyer knew that Friedrich von Recklinghausen was a master morbid pathologist and, as a student of Virchow, a skilled microscopist. But he wanted to find out whether von Recklinghausen was still using the same techniques he had taught him in medical school. Meyer related that von Recklinghausen “was kind enough to demonstrate his sections to me, which he still cut by hand. So it was a matter of chance that he did not find the connection of adenomyosis with the endometrium. Only in later cases did he see it and have to admit in a supplement the possibility of the endometrial histogenesis. That was tragic.”²⁰⁶

Meyer wondered how it had been possible for von Recklinghausen to have overlooked direct endometrial invasion of the uterine muscle as Cullen had demonstrated so clearly in two cases.²⁰⁷ Meyer was unaware that von Recklinghausen, expert microscopist that he was, had set out to disprove Chiari’s inflammatory theory of the pathogenesis of adenomyomas, a theory that postulated mucosal invasion of the muscular wall of the fallopian tube caused by inflammation.²⁰⁸ Armed with multiple observations of pseudo-glomeruli, von Recklinghausen appears to have thrown out mucosal invasion with inflammation.²⁰⁹ With respect to pseudo-glomeruli and von Recklinghausen’s mesonephric theory, Meyer speculated that it was “perhaps the influence of the times which found it interesting to look for the unusual in ‘embryonal’ histogenesis.”²¹⁰ Meyer intimated that von Recklinghausen may have learned embryology from books, which Meyer believed was impossible.²¹¹ He continued: “one can understand von Recklinghausen’s misconception when one considers his deficient technique.”²¹² The hand-cut histologic sections were just too thick. Consequently, as he focused up and down, he saw histologic structures that resembled kidney glomeruli, from which he deduced his theory of mesonephric rests. The renowned German professor had been upstaged in the later years of his career by a young pathologist using a superior piece of technical equipment – a microtome.²¹³ Though Meyer recognized von Recklinghausen’s technical error, he had not proved the error of his theory. That would take 5 more years of persistent research by a prepared mind open to the serendipitous finding of rare embryological anomalies.

Meanwhile in 1898, Iwanoff suggested metaplasia of the uterine serosa to explain the pathogenesis of adenomyomas located under the smooth peritoneal covering of the uterus – distant from the uterine endometrial cavity and its mucosa.²¹⁴ Iwanoff’s theory later gained the support of Pick, Aschoff, Robert Meyer, Emil Novak, and many others.²¹⁵ Thus, by 1898, there were five theories of pathogenesis of uterine adenomyomas; (1) from inflammation, (2) from müllerian rests, (3) from mesonephric rests, (4) from direct mucosal invasion of the myometrium, and (5) from metaplasia of the coelomic epithelium.

In 1899, in the course of his embryological research on human fetuses, Meyer described “various kinds of adenomyoma, adenomyosis of the uterus and islands of endometrium in the uterine wall of a fetus of nine months.”²¹⁶What Meyer observed was misplaced embryonic müllerian–endometrial tissue. For the first time ever, Meyer demonstrated – unequivocally – developmentally misplaced endometrium, embryonic adenomyosis. This unusual congenital adenomyosis in the unborn was histologically the same as the common acquired adenomyosis of Rokitansky, von Recklinghausen, and Cullen. Contemporaneously, unaware of Robert Meyer’s embryological work, William Wood Russell of Johns Hopkins Hospital postulated developmentally misplaced endometrium in the adult ovary that same year, 1899.²¹⁷

At the Berlin Gynecological Society meeting in 1900, Meyer “remarked that von Franque’s work had had the effect of shaking his faith in von Recklinghausen’s theory.”²¹⁸ Heretofore, he had defended the mesonephric theory of von Recklinghausen. Earlier that year, von Franque had demonstrated that the “epithelial features” of adenomyomas resulted from inflammatory changes in “mature mucous membrane” of the fallopian tube.²¹⁹ Like the uterine mucosa, the tubal mucosa had no submucosa to limit invasion. One month before the Berlin meeting, Meyer had gone to Carl Ruge with 2 years worth of research and requested additional uteri of fetuses and adults. Ruge was so “enchanted” with Meyer’s embryological research that he persuaded Meyer to give a lecture on “The Genesis of the Cystadenomata and Adenomyomata of the Uterus,” before the Berlin Gynecological Society.²²⁰ Meyer brought his microscopic slides of “islands of endometrium in the uterine wall of a fetus of nine months” to illustrate his lecture.”²²¹ He used a “brand-new projector, an epidiascope” made by Carl Zeiss of Jena.²²² This was the first time that Meyer was able to project actual microscopic slides, in effect achieving enlargement of the image without sacrifice of detail. Before that he could only project microphotographs.²²³ In the epidiascope, Meyer found a new instrument vital for his embryologic and pathologic research.

During the years 1900 and 1901, Robert Meyer published articles on the mucosal origin of uterine adenomyomas.²²⁴ Both Lockyer and Meyer²²⁵ would champion inflammation of mature mucous membranes as the pathogenesis of uterine adenomyomas.²²⁶ Lester King traced the theory of inflammation to ancient authors. Celsus in the first century AD “explicitly” described the characteristic signs of inflammation caused by a foreign body, a cinder in the eye: “dolor, tumor, rubor, and calor – pain, swelling, redness, and heat.” A second cause of inflammation also recognized since antiquity was produced by “bad” food [or drink]; “abdominal pain, fever, and diarrhea…The whole theory of inflammation, constantly expanding like the universe, can be intercalated between terms A and B, between ‘the’ cause (the cinder [or bad food]) and ‘the’ effect (the full-blown inflammation).”²²⁷In the early eighteenth century, Herman Boerhaave (1668–1738) believed that “inflammation resulted principally from a mechanical obstruction of vessels…from a contraction of the vessel, an impaction of…red blood cells, or a thickening…of the blood [which could be relieved by] diminishing the force of the arterial blood by bleeding and purging.” William Cullen (1710–1790) succeeded Boerhaave as the leading theorist on inflammation of the eighteenth century. Cullen theorized that inflammation arose from a functional obstruction of the blood vessels resulting from spasm, not a mechanical obstruction as theorized by Boerhaave. But the treatment was the same.²²⁸John Hunter (1728–1793) in his classic Treatise on the Blood, Inflammation, and Gunshot Wounds described three types of inflammation, “the adhesive, the suppurative, and the ulcerative.”²²⁹ In Traite des membranes published at the turn of the nineteenth century, Marie-Francois-Xavier Bichat (1771–1802) distinguished simple membranes tissues from pathological membranes. “He considered mucous membrane a protective barrier against foreign bodies, comparable to the skin. A mucous membrane exposed to air, he noted, will have a protective power against inflammation, although a serous membrane, similarly exposed, will not.”²³⁰Thomas Hodgkin (1798–1878) of Guy’s Hospital in London who praised the English and French – especially Bichat and Laennec – for the study of tissues, realized that serous and mucous membranes “afford[ed] the best opportunity for observing the varieties in the modes of inflammation, in the products to which they give rise, and in the stages through which they pass.” But of paramount importance, Hodgkin linked inflammation and disease: the serous and mucous tissues were subject not only to inflammation but also to an “overwhelming frequency of disease.”²³¹ He accused the followers of Broussaisism, the “so-called physiological doctrine” of Francois-Joseph- Victor Broussais (1772–1838), of seeing nothing but inflammation, “inflammation everywhere.”²³² Broussais theorized that disease was the result of inflammation resulting from chemical, mechanical, or emotional stimuli; Laennec opposed the idea.²³³ Relating the theory of inflammation to the müllerian diseases; Rokitansky mentioned inflammation several times when he discussed endometriotic lesions in 1860 and Chiari specifically postulated inflammation as the pathogenesis of endosalpingiosis in 1887.

Only von Recklinghausen challenged the inflammatory theory of pathogenesis during the nineteenth century. Lockyer and Robert Meyer held fast to the inflammatory theory. From the historical distance of mid-twentieth century, Robert Meyer reassessed the inflammatory theory as an explanation of the pathogenesis of adenomyosis: “In the Zeitschrift für Gynakologie (1924) in Virchows Archiv (1924), and in Deutsche Pathologische Gesellshaft (1925) I published articles on adenomyosis and endometriosis. As early as 1909 I had observed that it was the stroma of the endometrium which had the ability to destroy other tissue, especially elastic tissues (Virchows Archiv). At that time it was not known that one tissue could dissolve another without being malignant. There was a similarity between inflammation and this dissolving potentiality that induced me to call it adenomyometritis. This was an error and I had to struggle with myself for a long time until I was at length persuaded that it was an adenomyohyperplasia and accepted the expression adenomyosis uteri et tubae (Frankl) and endometriosis from the Americans for the identical ectopic proliferation of the endometrium without musculature. This mostly occurs independently of adenomyosis of the uterus. I found that the histolytic quality is not only responsible for the destruction of the interfascicular connective tissue but also for the musculature which undergoes necrosis to a greater or lesser degree.”²³⁴

Von Franque’s theory of the inflammatory pathogenesis of tubal adenomyoma²³⁵ (a theory put forth earlier by Chiari in 1887) and the inflammatory theory of pathogenesis of uterine adenomyoma postulated by “Felix Legueu and Marien of Montreal” had influenced Lockyer.²³⁶ In the years 1901 and 1902, Meyer commented on adenomyomas at the tubal angle of the uterus that von Recklinghausen contended originated from mesonephric (Wolffian) rests. “It is a definitely post-foetal phenomenon: all stages are present, from the cutting off of a single cyst in the mucosa (salpingitis pseudo-follicularis) and the intrusion of a single short follicles in the muscularis (salpingitis follicularis) to an enormous adenomatous branching through all the layers of the tube-wall and into the broad ligament…It was true that the normal tube had no glands, but the pathological tube was different – it could make them.”²³⁷ Meyer spoke of the “sprouting-faculty” of the epithelium of the fallopian tube, likening it to “water under a high pressure bursting out in jets to form a fountain; the epithelium of an inflamed tube is under such a pressure, and is ready to make use of the smallest aperture for proliferation and for spreading through countless interstices.”²³⁸ Speaking about the pathogenesis of uterine adenomyosis, Meyer continued: “The stroma of the invading mucosa is of great significance: it clothes all the epithelial spaces; it is spindle-celled and thick, but never sarcomatous…The invasion is post-foetal; it is a disease of the adult uterus.”²³⁹ As with the fallopian tube, absence of a true submucosa favored mucosal invasion of the uterine musculature.

1902 was an eventful year for Robert Meyer’s research. That year, Rudolf Virchow accepted an article from Meyer describing an “extremely rare specimen, an osteoid tissue in the uterus of a fetus.” It was the specimen he had squirreled away in his desk years before. During the negotiations for publication, Meyer requested and received from Virchow the genitals of a 6-year-old orangutan. On examination, he found “an island of endometrium in the middle of the posterior wall of the fundus” in exactly the same place that he had found a similar lesion in the uterus of the 9 month fetus 3 years previously.²⁴⁰Meyer thus had documented developmental adenomyosis in a nonhuman primate and in a human fetus.

Also in 1902, Meyer obtained another unique uterine specimen, this one human. With the Zeiss epidiascope,²⁴¹ he studied a “new kind of giant adenofibromyoma proceeding from a horn of the uterus…an organoid structure [that] in no way resemble[d] adenomyosis but strikingly resemble[d] epididymis.”²⁴² Meyer had demonstrated a “real adenomyoma of mesonephric origin imitating the epoophoron or epididymis of the adults.”²⁴³ This adenomyoma was not composed of endometrial glands and stroma. Meyer stated that this case was decisive for his renunciation of von Recklinghausen’s mesonephric theory of pathogenesis of uterine and tubal adenomyomas.²⁴⁴When he published his findings in 1903, he criticized the mesonephric theory “point by point” after which it was “generally and definitely abandoned.”²⁴⁵ Meyer achieved with his embryological expertise what Cullen was unqualified to do; he scientifically refuted von Recklinghausen’s mesonephric theory.²⁴⁶ Meyer could only refute von Recklinghausen by demonstrating an actual Wolffian mesonephric rest in a fetal uterus; he had had to prove that it did not resemble a pseudo-glomeruli; in fact, it resembled epididymis. Recall also that Meyer had taken a practical course in embryology from Oscar Hertwig in 1897 and subsequently devoted years to embryological research.²⁴⁷ Cullen had no such training in embryology; he simply accepted the müllerian theory of pathogenesis of uterine and extrauterine adenomyomas, relying on their histologic identity.

Refuting the theory was one thing, but explaining it to von Recklinghausen was another. Meyer convinced his old professor “of this faulty reasoning” based on misinterpretation of thick, hand-cut histologic sections.²⁴⁸ While Cullen had demonstrated an alternative pathogenesis by mucosal invasion, he had not disproved von Recklinghausen’s theory. It took Robert Meyer’s embryological research in fetal uteri and the uteri of children and adults to definitively disprove von Recklinghausen’s Wolffian theory of origin of uterine and tubal adenomyomas. The meeting in 1903 between von Recklinghausen and Robert Meyer must have been painful for both men.

Footnotes

Erna Lesky, The Vienna Medical School of the 19th Century [Baltimore, MD: Johns Hopkins University Press, 1976], 274, 397: According to Erna Lesky, historian of the Second Vienna Medical School, “Around 1860…the idea gained ground … that the potentialities of the anatomical-diagnostic trend of the Rokitansky and Skoda school had been exhausted.”

Arleen Marcia Tuchman, Science, Medicine, and the State of Germany: The Case of Baden, 1815–1871 [New York: Oxford University Press, 1993], 10.

Erna Lesky, 112.

Erna Lesky, 264. “The fact than an associate professorship for experimental pathology was created in 1868, and that it was raised to the rank of a chair in 1873, is related to the close contact of this subject and its representative, Salomon Stricker, with the pathological anatomist and ministerial consultant Rokitansky.” Lesky, 349. “The first edition of Moriz Rosenthal’s Klinik der Nervenkrankheiten (Clinical Aspects of Nervous Diseases) appeared in 1870, and a completely new edition was published in 1875. The book was dedicated to Carl von Rokitansky, and in its solid pathological basis as well as in the careful and surprisingly complete review of the results of contemporary research in neurophysiology and neuropathology, it demonstrates the work of an indefatigable scientist who could rightly be called a student of Rokitansky and of Türck.” The same may be said of several other books by Rosenthal.

Erna Lesky, 145.

Erna Lesky, 112–113.

“Kundrat’s interest was a direct continuation of the developmental trend of research of Rokitansky’s late period; it was concerned with malformations due to arrested development, and had found its expression in the last work Die Defecte der Scheidewande des Herzens (Defects of the Inter-Ventricular Septa) (Vienna, 1875).” Kundrat included etiology in his theories of congenital malformations. Erna Lesky, The Vienna Medical School of the 19^thCentury [Baltimore, MD: Johns Hopkins University Press, 1976], 516. Edward Albert, a friend and colleague of Kundrat from his student days, “characterized the main field of interest of Kundrat…‘Kundrat was without doubt a great and important morphologist. His formative concepts of observation were most extraordinary. He visualized the very complicated processes of developmental history so exactly and explained the disturbances of these processes so easily, that this in itself made him the most outstanding expert in the field of congenital malformations.’”

Erna Lesky, 515.

Erna Lesky, 516. “Kundrat’s interest was a direct continuation of the developmental trend of research of Rokitansky’s late period.”

Harvey Cushing, The Life of Sir William Osler [Oxford, UK: Clarendon Press, 1926], 113–114. In a letter dated “March 1^st, 1874. Allgemeines Krankenhaus,” Osler wrote “Altogether, midwifery and skin diseases are specialties in Vienna, while in general medicine and pathology it is infinitely below Berlin…After having seen Virchow it is absolutely painful to attend postmortems here, they are performed in so slovenly a manner, and so little use is made of the material.”

Harvey Cushing, 113–114.

Harvey Cushing, 114. Osler explained. “Carl Rokitansky, at his best merely a descriptive pathologist, was at this time near the end of his career, and indeed the group of other Bohemians, the great masters who had made the ‘new Vienna School’ and turned the eyes of the medical world towards Austria, had most of them, with the exception of Billroth, been born in the first decade of the century. The Berlin School, with Virchow as its chief figure, represented a group fifteen years younger.” Michael Bliss. William Osler: A Life in Medicine[Oxford, UK: Oxford University Press, 1999], 78.

Simon Flexner and James Thomas Flexner, William Henry Welch and the Heroic Age of American Medicine [Baltimore, MD: Johns Hopkins University Press, 1993], 78.

Simon Flexner and James Thomas Flexner, 78.

Robert Joseph Miciotto, “Carl Rokitansky: Nineteenth-Century Pathologist and Leader of the New Vienna School” [PhD dissertation.] The Johns Hopkins University, 1979], 273–274.

Schaller, Anton. Reflexionen des Frauenarztes der Gegenwart auf das pathologisch-anatomische Lebenswerk Carl Freiherr v. Rokitanskys. Wien Med Wochenschr 2004;154:477–481. (Reflections of a present –day gynaecologist on the work of Carl Freiherr v. Rokitansky in the fields of pathology and anatomy).

R.J. Rather, Eva R. Rohl. An English Translation of the Hitherto Untranslated Part of Rokitansky’s Einleitung to volume 1 of the Handbuch der allgemeinen Pathologie (1846), with a Bibliography of Rokitansky’s Published Works. Clio medica 1972;7:215–227:216. Rather and Rohl quoted from Rokitansky’s farewell address: Carl von Rokitansky, Abschiedsrede des Professors Carl Freiherr von Rokitansky [Vienna, 1875].

Venita Jay, “The legacy of Karl Rokitansky,” Arch Pathol Lab Med 2000;124:345–346. See also: Erna Lesky, The Vienna Medical School of the 19th Century [Baltimore, MD: Johns Hopkins University Press, 1976], 498–499. “In professional circles in Germany, the old master of pathological anatomy, Carl von Rokitansky, caused quite a stir when he established a separate Chair for General and Experimental Pathology in Vienna in 1873.” He himself had stated, as early as 1846, in the introduction to Volume 1 of his manual: “pathological anatomy should be the basis not only of medical knowledge but also of medical practice, and it should include all the knowledge and fundamentals of the science and practice in medicine. Subsequently, however, Rokitansky…was [un]able to incorporate in pathological anatomy the microscopic and experimental methods which had developed so vigorously from the forties. In Vienna these methods were employed and developed outside the realm of pathological anatomy: microscopy in the laboratories of Brücke and Wedl, and animal experiments in Carl Ludwig’s laboratory.”

Erna Lesky, The Vienna Medical School of the 19th Century [Baltimore, MD: Johns Hopkins University Press, 1976], 107–108. Referring to Virchow, Lesky wrote: “No one was able to evaluate this achievement better than the man who continued to work on the basis thereof. Rudolph Virchow (1821–1902) referred to Rokitansky as the Linne of pathological anatomy.” Lesky cited: Rudolph Virchow, WMW 5, 417 (1855). Owsei Temkin, The Double Face of Janus and Other Essays in the History of Medicine [Baltimore and London: Johns Hopkins University Press, 1977], 273. Temkin noted that 1855 marked the year that Virchow published his article entitled “Cellular Pathology,” in which he enunciated his “famous formula, omnis cellula a cellula.” See Rudolph Virchow, Zellular-Pathologie. Virchows Archiv 1855;8:23.

Carl Rokitansky, A Manual of Pathological Anatomy, Volume II. The Abdominal Viscera. trans. Edward Sieveking [Philadelphia, PA: Blanchard & Lea, 1855], ix. Editor’s Preface. “The fact of the Work having been selected for translating by the Council of the Sydenham Society, is in itself a proof that it is deserving of the high estimation in which it has been held by all pathologists acquainted with continental literature; but it may not be superfluous to state that the value of the Professor’s remarks is enhanced by his being entirely unfettered by preconceived notions or prejudiced views, as to the disease of the individual brought to the dead-house for examination.” Carl Rokitansky, A Manual of Pathological Anatomy, Volume I. General Pathological Anatomy. trans. William Edward Swaine [Philadelphia, PA: Blanchard & Lea, 1855]. American Publisher’s Notice, Philadelphia, August 1855. “The world-wide reputation of the author and of his work render eulogy superfluous, while the appearance of the translation under the auspices of the Sydenham Society is a guarantee of its fidelity.”

Carl Rokitansky, A Manual of Pathological Anatomy, Volume II. vii–ix. Editor’s Preface. “Owing to the acknowledged difficulty of the author’s style, it has however been thought advisable to divide the translation into four volumes, each of which is entrusted to a different editor.” “Of the difficulties connected with the translation, I will only say that they are much increased by the figurative style of the author. He constantly uses terms in a sense peculiar to himself, and his total disregard for the ordinary rules of composition is an additional and frequent source or obscurity.”

Robert J. Miciotto, “Carl Rokitansky: A Reassessment of the Hematohumoral Theory of Disease,” Bulletin of the History of Medicine 53, no. 2 [Summer 1978]: 183. Rokitansky’s reputation gradually declined, undeservedly tarnished by his hematohumoral theory of disease, which compared unfavorably to Virchow’s theory of cellular pathology, especially when the latter evolved into molecular biology.

Karl Sudhoff, “What is history of medicine?” in Essays in the History of Medicine trans. by various hands and ed. Fielding H. Garrison [New York: Medical Life Press, 1926], 71, 72.

Robert J. Miciotto, “Carl Rokitansky: A Reassessment of the Hematohumoral Theory of Disease,” Bulletin of the History of Medicine 53, no. 2 [Summer 1978]: 183–199: 185–186.

Paul Klemperer, Notes on Carl von Rokitansky’s Autobiography and Inaugural Address. Bulletin History of Medicine 1961;35:364–380:376–377. Klemperer quoted Wunderlich: “Wunderlich, an enthusiastic visitor in 1840, wrote: ‘The Vienna Institute no more counts the number of autopsies in the hundreds, and Rokitansky can consult thousands of protocols in reference to more than one disease.’ I do not believe that any other institute can match this proportion.”

Paul Klemperer, Notes on Carl von Rokitansky’s Autobiography and Inaugural Address. Bulletin History of Medicine 1961;35:364–380:379.

Paul Klemperer, 1961;35:364–380:379.

Robert Meyer, Autobiography of Dr. Robert Meyer (1864–1947): A Short Abstract of a Long Life [New York: Henry Schuman, 1949], 17.

Paul Klemperer, 1961;35:364–380:379. Klemperer cited Rudolph Virchow, Hundred Jahre allgemeiner Pathologie [Berlin: August Hirschwald, 1895].

R.J. Rather, Eva R. Rohl. An English Translation of the Hitherto Untranslated Part of Rokitansky’s Einleitung to volume 1 of the Handbuch der allgemeinen Pathologie (1846), with a Bibliography of Rokitansky’s Published Works. Clio medica 1972;7:215–227: 216. Rather and Rohl quoted from : Rudolph Virchow, “Ein alter Berichte ueber die Gestaltung der pathologischen Anatomie in Deutschland, wie sie is und wie sie widen muss,” Virchows Archiv 1900;159:24–39.

Park, Roswell. An Epitome of the History of Medicine. 2nd Ed. Philadelphia: FA Davis Company, 1908: 250.

Paul Klemperer, Notes on Carl von Rokitansky’s Autobiography and Inaugural Address. Bulletin History of Medicine 1961;35:364–380:379. Klemperer quoted Sigerist from: Henry E. Sigerist, Grosse Aerzte [Muenchen: J.F. Lehmann, 1933].

Paul Klemperer, 1961;35:364–380:376, 379. Referring to Rokitansky’s Handbook of Pathological Anatomy, Klemperer, a pathologist, stated in 1961: “Today its contents are inadequate for the second year medical student.”

Roy Porter, “Medical Science,” in The Cambridge Illustrated History of Medicine, ed. Roy Porter [Cambridge: Cambridge University Press, 1996], 154–201:177.

Brosens IA, Brosens JJ. Endometriosis. Eur J Obstet Gynecol Reprod Biol 2000;414:105–112. Ronald E. Batt, Smith RA, Buck Louis GM, Martin DC, Chapron C, Koninckx PR, Yeh J. Müllerianosis. Histol Histopathol 2007;22:1161–1166. Bloom MS, Buck Louis GM, Schisterman EF, Liu A, Kostyniak PJ. Maternal serum polychlorinated biphenyl concentrations across critical windows of human development. Environ Health Perspect 2007; 115:1320–1324. Buck Louis GM, Hediger ML, Pena JB. Intrauterine exposures and risk of endometriosis. Hum Reprod 2007;22:3232–3236. Buck Louis GM, Gray LE Jr, Marcus M, Ojeda SR, Pescovitz OH, Witchel SF, Sippell W, Abbott DH, Soto A, Tyl RW, Bourguignon JP, Skakkeback NE, Swan SH, Golub MS, Wabitsch M, Toppari J, Euling SY. Environmental factors and puberty timing: expert panel research needs. Pediatrics 2008;121 Suppl 3:S192-207.

Venita Jay, “The legacy of Karl Rokitansky,” Arch Pathol Lab Med 2000;124:345–346. “Rokitansky was profoundly influenced…by the concepts of comparative anatomy and embryology” of Johan Friedrich Meckel. Meckel published Handbuch der pathologischen Anatomie(1812–1816) and System der vergleichenden [comparative] Anatomie (1821–1831).

See specimen one [Magdalena Fischer], first seen by Rokitansky in 1828 and described in 1838 in: Von Prof. Dr. Rokitansky, Uber die sogenannten Verdoppelungen des Uterus. Medicinische Jahrbucher des kaiserl. konigl osterreichischen Staates 1838;26:S39-S77:40.

Johannes Müller, Bildungsgeschichte der Genitalien aus anatomischen Untersuchungen an Embryonen des Menschen and der Thiere, nebst einem Anhang über die chirurgische Behandlung der Hypospadia. [Düsseldorf, 1830]. Goethe, the poet-scientist, inspired Johannes Müller to a lifetime of meticulous basic science research and teaching that in turn motivated investigators in the German speaking world. In that scientific atmosphere, Rokitansky investigated müllerian anomalies.

Von Prof. Dr. Rokitansky, Uber die sogenannten Verdoppelungen des Uterus. Medicinische Jahrbucher des kaiserl. konigl osterreichischen Staates 1838;26:S39-S77.

Ann La Berge and Caroline Hannaway, “Paris Medicine: Perspectives Past and Present,” in Constructing Paris Medicine, ed. Caroline Hannaway and Ann La Berge [Amsterdam, NL: Editions Rodopi B. V., 1998], 1–69:5.

The author is referring to the 1828 case of partial müllerian agenesis that was retrieved in a specimen jar on 30 July 1838. See: Von Prof. Dr. Rokitansky, Uber die sogenannten Verdoppelungen des Uterus. Medicinische Jahrbucher des kaiserl. konigl osterreichischen Staates 1838;26:S39–S77. For the importance of case reports in medicine, see Owsei Temkin, “The Scientific Approach to Disease: Specific Entity and Individual Sickness,” in The Double Face of Janus and Other Essays in the History of Medicine [Baltimore, MD: Johns Hopkins University Press, 1977], 441–455:452–453. Temkin notes: “It is not immediately clear why the anatomical interpretation of disease had to follow the road from case histories to disease entities….The role of the case history in a particular phase of medical development elucidates further the notion of the abnormal in medicine…The case history is the form in which the physician links the science, which does not deal with the unique directly, and the patient, who requires attention as an individual.”

Ghirardini G, Popp LW. The Mayer-von Rokitansky-Küster-Hauser syndrome (uterus bipartitus solidus rudimentarius cum vagina solida): the development of gynecology through the history of a name. Clin Exp Obstet Gynecol 1995;22:86–91.

Robert Meyer, Autobiography of Dr. Robert Meyer (1864–1947): A Short Abstract of a Long Life. With a Memoir of Dr. Meyer by Emil Novak, MD. [New York: Henry Schuman, 1949], 16–17.

Roland Sedivy, “200 Jahre Rokitansky – sein Vermachtnis fur die heutige Pathologie,” Wiener Klinische Wochenschrift 2004;116/23: 779–787. This article contains a bust and a photograph of Rokitansky executed in 1874 on the occasion of his retirement at age 70. In February 2004, Roland Sedivy conducted a PubMed search of “Rokitansky”; 238 citations (47%) were in reference to the Mayer-Rokitansky-Küster-Hauser syndrome, the next nearest citation, 138 (27%), was in reference to history. Table 1 gives a list of seventeen of Rokitansky’s discoveries by surname or scientific name. Item 7 in the list is: “Endometriose.” See also: Ottokar Rokitansky, “Carl Freiherr von Rokitansky – zum 200, Geburtstag: Eine Jubilaumsgedenkschrift, Wiener Klinische Wochenschrift 2004;116/23: 773–788.

Venita Jay, “The legacy of Karl Rokitansky,” Arch Pathol Lab Med 2000;124:345–346. Rokitansky published On some of the Most important Diseases of the Arteries (1852) and The Defects in the Septum of the Heart (1875). See also: Davies MK, Hollman A. Karl Freiherr von Rokitansky (1804–1878). Heart 1997;78(5):425.

Park, Roswell. An Epitome of the History of Medicine. 2nd Ed. Philadelphia: FA Davis Company, 1908:250–251. Roswell Park wrote: “for fourteen years he studied the defects of the septum of the heart and the comparative anatomy of the uterus and genito-urinary organs.”

Rokitansky C. Ueber Uterusdrüsen-Neubildung in Uterus- und Ovarial-Sarcomen. Zeitschift Gesellschaft der Aerzte in Wien. 1860;16:577–581. See also: Simpson JL. Genetics of the female reproductive ducts. Am J Med Genet 1999;89:224–239. Simpson reports two cases of a rare condition of excessive müllerian tissue: true duplication of the müllerian ducts: “affected women must have two separate uteri, each of which can have two fallopian tubes.” Simpson believes it may result from division of one or both müllerian ducts early in embryogenesis. Recall the spectacular case of true duplication with two vaginas, two uteri each with two fallopian tubes, in which the woman conceived and carried a normal male child until a therapeutic abortion had to be performed to preserve the life of the mother due to deficient pelvic capacity to carry the child further.

Von Prof. Dr. Rokitansky, Uber die sogenannten Verdoppelungen des Uterus. Medicinische Jahrbucher des kaiserl. konigl osterreichischen Staates 1838;26:S39–S77. Partial müllerian agenesis, the Mayer-Rokitansky-Küster-Hauser syndrome.

Emge LA. The elusive adenomyosis of the uterus: its historical past and its present state of recognition. Am J Obstet Gynecol 1962;83:1541–1563.

Carl Breus, Uber Wahre Epithel Führende Cystenbildung in Uterusmyomen [Leipzig und Wien: Franz Deuticke, 1894], 6. “Oskar Schroeder, O. Heer und C. Grosskopf haben die Mühe nicht gescheut, in ihren Dissertationsschriften alle in der Literatur mitgetheilten Falle von solchen Cystomyomen zu sammeln und haben so bis 1884 über 100 derselben zusammengestellt.” See also Breus, page 10, where he cites the 1860 article of Rokitansky. See: Erna Lesky, The Vienna Medical School of the 19th Century [Baltimore, MD: Johns Hopkins University Press, 1976], 424. Carl Breus (1852–1914) and the pathologist Alexander Kolisko, a student of Kundrat – second successor to Rokitansky’s chair of pathological anatomy in Vienna, wrote the classical book Pathological Shapes of the Pelvis (3 Vols. Vienna, 1900–1912). Leopold G. Koss and Philip H. Lieberman, “Surgical Pathology at Memorial Sloan-Kettering Cancer Center,” in Guiding the Surgeon’s Hand: The History of American Surgical Pathology, ed. Juan Rosai [Washington, DC: Armed Forces Institute of Pathology, 1997], 66. Alexander Kolisko, Carl Breus’s coauthor, was the third successor to Rokitansky’s chair of pathological anatomy in Vienna. See also: Thomas Stephen Cullen, Adenomyoma of the Uterus [Philadelphia: WB Saunders, 1908], 1. Thomas Cullen, who was conversant with the Austrian and German literature, also recorded that Breus had credited Schroeder, Herr, and Grosskopf with having collected 100 cases of myomata containing glandular elements up to the year 1884.

Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment [London: Macmillan and Company, 1918], 265. Lockyer did not refer to the original report of Breus of 1884. Instead, he cited Cullen and gave the incorrect year. Lockyer wrote: “Cullen mentions that about one hundred had been recorded under various titles up to 1896.”

Bailey KV. The etiology, classification, and life history of tumors of the ovary and other female pelvic organs containing aberrant müllerian elements, with suggested nomenclature. J Obstet Gynaecol Brit Emp 1924;xxxi:539–573:540. Bailey made only passing reference to the first two authorities, Cullen and Lockyer.

Emge LA. The elusive adenomyosis of the uterus: its historical past and its present state of recognition. Am J Obstet Gynecol 1962;83:1541–1563:1554. Emge may have stated the date incorrectly when he wrote: “stromatosis was first described by Virchow in 1864.” Additionally, Emge did not cite the reference to Virchow; he was probably recalling a reference he had read years before. However, von Recklinghausen did reference Virchow in 1863, not 1864. See: Friedrich v. Recklinghausen, Die Adenomyome und Cystadenome der Uterus- und Tubenwandung ihre Abkunft von Resten des Wolff’schen Korpers. Im Anhang: Von W. A. Freund, Klinische Notizen zu den voluminosen Adenomyomen des Uterus [Berlin: Verlag von August Hirschwald, 1896.], 96. Referring to Virchow’s description of endometrial stromatosis, von Recklinghausen stated: “So by the first look under the microscope at the simple construction of the histology of this organoid tumor of Virchow we arrive at the conviction that we must separate this special tumor from the usual spherical myoma.” See: Reference 60: R. Virchow, Die krankhaften Geschwulste. 1863. I. 263–286, III. 150. (The pathological tumors)

Emge LA. 1962;83:1541–1563:1542. It is possible that the dissertation to which Breus referred was located in a university library or archive in Austria. That might explain Emge’s failure to find it.

Erna Lesky, The Vienna Medical School of the 19th Century [Baltimore, MD: Johns Hopkins University Press, 1976], 424. Breus was a reliable authority who was promoted to associate professor in 1894.

Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment [London: Macmillan and Company, 1918], 265. “1894” Instead of 1884 in all probability represents a typographic or type-setting error. Lockyer states that “Cullen mentions that about one hundred [myomas containing cysts lined by epithelium] had been recorded under various titles up to 1896, but only a few of the most important need here be given [in Lockyer’s monograph of 1918].”

Cuthbert Lockyer, 265. Babes G. Uber epitheliale Geschwulste in Uterusmyomen Allgem. Wiener med Ztschr 1882;27:36–48. Lockyer never mentioned the contributions of Rokitansky. 1882 was the year that Koch announced his discovery of the tuberculosis bacillus which stimulated investigators to search for the cause of disease. For chronic diseases, the search began for pathogenesis, for an explanation of the pathway taken by the disease process.

Cuthbert Lockyer, 274–275.

Friedrich v. Recklinghausen, Die Adenomyome und Cystadenome der Uterus- und Tubenwandung ihre Abkunft von Resten des Wolff’schen Korpers. Im Anhang: Von W. A. Freund, Klinische Notizen zu den voluminosen Adenomyomen des Uterus [Berlin: Verlag von August Hirschwald, 1896.] Von Recklinghausen most certainly was aware of the entire German and Austrian literature on the subject of adenomyomas as well as contributions from England and the other countries on the Continent of Europe.

Von Recklinghausen, Cullen, and Lockyer all picked Babes (1882) as the first reliable reference to “myomas containing cysts lined by epithelium.”

Friedrich v. Recklinghausen, Die Adenomyome und Cystadenome der Uterus- und Tubenwandung ihre Abkunft von Resten des Wolff’schen Korpers. Im Anhang: Von W. A. Freund, Klinische Notizen zu den voluminosen Adenomyomen des Uterus [Berlin: Verlag von August Hirschwald, 1896.] Bailey KV. The etiology, classification and life history of tumours of the ovary and other female pelvic organs containing aberrant müllerian elements, with suggested nomenclature. J Obstet Gynaecol Brit Emp 1924;xxxi:539–573:540. Writing two decades after von Recklinghausen, Bailey considered articles on the pathology of adenomyomas by Breus, Chiari, Martin, Orthmann, Werth, and Schauta worthy of mention.

Illustrated Stedman’s Medical Dictionary. 24th ed. [Baltimore, MD: Williams & Wilkins, 1982], 1224. Embryonic rest: “[From the Latin restare, to remain]. A group of cells or a portion of fetal tissue that has become displaced and lies embedded in tissue of another character.”

LJ Rather, The Genesis of Cancer: A Study in the History of Ideas [Baltimore, MD: Johns Hopkins University Press, 1978], 122.

LJ Rather, The Genesis of Cancer, 170–171. See also: David Cantor, “Cancer.” In Companion Encyclopedia of the History of Medicine. Vol. 1. ed. W. F. Bynum and Roy Porter [London: Routledge, 1997], 537–561:540–544. David Cantor, “Cancer.” In Companion Encyclopedia of the History of Medicine. Vol. 1. ed. W. F. Bynum and Roy Porter [London: Routledge, 1997], 537–561:540–542. The search for the cause of malignant as well as benign tumors constitutes an interesting chapter in the history of science and medicine. Until Bichat argued at the turn of the nineteenth century that for the seat of cancer in body tissues, “the history of cancer was part of a broader history of inflammation.” Subsequently Laennec distinguished between gangrene and cancer. David Cantor, 542. In the late 1830s, Johannes Müller integrated Schwann’s cell theory into the genesis of cancer. Müller believed that “both normal and pathological cells were structured aggregates of transformed cells, developed for the most part de novo from an amorphous blastema ultimately derived from circulating blood.” Later, “Virchow believed that tumour cells developed from ‘embryonic’ cells, scattered throughout the omnipresent connective tissue.” Cantor, 543. In 1867, Wilhelm Waldeyer argued that “normal epithelium was the sole source of epithelial cells contained in a given carcinoma. The sole mechanism of local spread was the active or passive movement of cancer cells into adjacent tissue, while the sole mechanism of metastatic spread was through the transport of cancer cells to the metastatic sites via the blood, lymph, or other body fluids.” Cantor, 544. In the twentieth-century, the cause of cancer has shifted between two polarities “explanations favouring the action of exogenous factors such as viruses, parasites, environmental chemicals, or physical agents such as radiation; and those favouring endogenous factors such as genetic mutation.” Alexander Berglas, Cancer: Nature, Cause, and Cure [Paris: Institute Pasteur, 1957] 6–7. Berglas from the Pasteur Institute compared cancer to a “runaway healing attempt.” Once the cancer cells dedifferentiates to a functionally more primitive cell, “control mechanisms of the body no longer have any influence on the constantly dividing ‘malignant’ cells; they no longer submit to the regulatory processes of the organism.”

K. Codell Carter, The Rise of Causal Concepts of Disease: Case Histories [Burlington, VT: Ashgate, 2003], 134. Carter quotes Paul Ehrlich’s recollection of that meeting: “all who were present were deeply moved and that evening has remained my greatest experience in science.”

Michael Worboys, Spreading Germs: Disease Theories and Medical Practice in Britain, 1865–1900. [Cambridge, UK: Cambridge University Press, 2000], 4.

Michael Worboys, 4.

K. Codell Carter, The Rise of Causal Concepts of Disease: Case Histories [Burlington, VT: Ashgate, 2003], 143.

Mel Greaves, “Finale: Cause, Complexity, and the Evolutionary Rub,” in Cancer: The Evolutionary Legacy [Oxford: Oxford University Press, 2000], 213–220:213.

Carl Breus, Uber Wahre Epithel Führende Cystenbildung in Uterusmyomen [Leipzig und Wien, Franz Deuticke, 1894], 1–36

Diesterweg B. Ein Fall von Cystofibrom uteri verum Zeitschr f Geb 1883:9:191.

Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment [London: Macmillan and Company, 1918], 265–266.

Emge LA. The elusive adenomyosis of the uterus: its historical past and its present state of recognition. Am J Obstet Gynecol 1962;83:1541–1563:1543.

Chiari H. Zur pathologischen Anatomie des Eileiter-Catarrhs. Pager Ztschr. Heilkunde 1887;8:457–473. That same year, Martin reported cases similar to Chiari. Martin. Uber Tubenkrankung. Zeitschr für Geb und Gynak 1887;13. S. 299. Martin cited by: Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment [London: Macmillan and Company, 1918], 284.

Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment [London: Macmillan and Company, 1918], 307.

Von Recklinghausen F. Ueber die Adenocysten der Uterustumoren und Ueberreste des Wolff’schen Organs. Deutsche Medicinische Wochenschrift 1893;xix:325–326.

Von Recklinghausen F. Ueber die Adenomyome des Uterus und der Tuba. Wiener Klinische Wochenschrift 1895;29:530.

Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment [London: Macmillan and Company, 1918], 266. Cuthbert Lockyer, MD, BS, FRCP, FRCS was Vice-President Obstetrical and Gynaecological Section, Royal Society of Medicine; Corresponding member of the Societe d’Obstetrique Belge; Surgeon to In-Patients, Samaritan Hospital for Women; Obstetric Physician to Out-Patients Charing Cross Hospital; Joint-Lecturer on gynaecology and Obstetrics, Charing Cross Hospital Medical School; Examiner to the Royal College of Physicians and Surgeons; Late Examiner in Midwifery and Diseases of Women to the University of London.

Cuthbert Lockyer, 307–308. The theories of pathogenesis and etiology of cancer and endometriosis have been discussed earlier in this chapter.

Carl Rokitansky, Ueber Uterusdrüsen-Neubildung in Uterus- und Ovarial-Sarcomen. Zeitschift Gesellschaft der Aerzte in Wien. 1860;16:577–581. “Of the existing connective tissue tumors of the uterus, the round fibroids are to be differentiated from the so called fibrous polyps of the uterus in which glandular tubules are found. These are connective tissue tumors rooted in the basal stroma of the uterus and cannot be shelled out (Paget’s continuous growth) in contrast to the well circumscribed fibrous tumors. They commonly develop within or from the submucosal stratum and grow into the uterine cavity as so called polyps of various shapes (cylindric, pear-club shaped) and are covered by an adherent uterine mucosa. The various changes in its texture may appear identical to the changes seen as a result of chronic inflammation. [Italics added]. In contrast to the easily removable fibrous tumors, we commonly consider these connective tissue tumors as sarcoma [benign], here specifically as uterus sarcoma. These tumors growing into a mucosal cavity generally retain their old name of polyp and uterus polyp and, according to the discussion above, would be distinguished from the round fibroids prolapsed into the uterine cavity. As round fibroids may develop within the inner tissue layers of the uterus, so can sarcomas on rare occasion develop from a mucosal-free outer layer. In view of the above discussion, it is important to recognize the changes occurring in the mucosa and the submucosal stratum of the uterus as consequences of chronic inflammation.” [Italics added]. When Rokitansky stated: “As round fibroids may develop within the inner tissue layers of the uterus, so can sarcomas on rare occasion develop from a mucosal-free outer layer,” did he anticipate Iwanoff’s serosal theory of metaplasia of 1898?

LJ Rather, The Genesis of Cancer: A Study in the History of Ideas [Baltimore, MD: Johns Hopkins University Press, 1978], 122. As early as 1854, Robert Remak, a student of Johannes Müller, suggested that tumors might originate “at an early developmental stage of the human embryo.” Remak anticipated the hypothesis of Julius Cohenheim that tumors originated from embryonic rests.

Emge LA. The elusive adenomyosis of the uterus: its historical past and its present state of recognition. Am J Obstet Gynecol 1962;83:1541–1563:1543. Diesterweg theorized the pathogenesis of uterine adenomyomas resulted from invasive idiopathic stromal hyperplasia, a theory supported by “Carl Ruge (1889), Carl Schroeder (1892), and Hauser (1893).”

Rabinovitz M. The pathogenesis of adenomyosalpingitis (salpingitis nodosa): report of ten cases. American Journal of Obstetrics and Diseases of Women and Children 1913; lxviii;711–752.

Erna Lesky, The Vienna Medical School of the 19th Century [Baltimore, MD: Johns Hopkins University Press, 1976], 115, 558.

A. Pilliet. Fibromyome de la trompe uterine. Bull de la Soc Anat de Paris 1894:554. Cited by Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment [London: Macmillan and Company, 1918], 284. Sampson, JA. Ovarian hematomas of endometrial type (perforating hemorrhagic cysts of the ovary) and implantation adenomas of endometrial type. Boston Medical and Surgical Journal 1922;186:445–456. Sampson wrote, without direct citation, “In 1894, Pilliet took the view that the cysts and glands of adenomyoma were of mucosal origin.” Undoubtedly, Sampson’s information came from Lockyer whom he acknowledged in the opening sentence of this paper.

A. Pilliet, Les debris du corps de Wolff et leur role dans la pathogenie des tumours. Tribune medicale. 1889. See: Friedrich v. Recklinghausen, Die Adenomyome und Cystadenome der Uterus- und Tubenwandung ihre Abkunft von Resten des Wolff’schen Korpers. Im Anhang: Von W. A. Freund, Klinische Notizen zu den voluminosen Adenomyomen des Uterus [Berlin: Verlag von August Hirschwald, 1896.]: Ref. No 20.

Erwin H. Ackerknecht, A Short History of Medicine [New York: Ronald Press, 1968], 166. Bichat and Virchow were fortunate, their theories endured. But Ackerknecht’s assessment of Rokitansky would apply to von Recklinghausen: “But unfortunately his factual foundation was insufficient.”

Harold Speert, Obstetric & Gynecologic Milestones: Illustrated [New York: Parthenon Publishing Group, 1996], 89. “The female genital tact, from the ovary to the hymen, contains a mine of embryonic remnants, vestiges of the primitive urogenital system, which provides a yield of never-ending interest to the clinical gynecologist as well as the student of embryology.” The mesonephros – the primitive vertebrate kidney – comprises two elongated masses in the early vertebrate embryo. The mesonephros was named the Wolffian body to honor Caspar Wolff who discovered these primitive kidneys in 1759. A Wolffian rest represents a group of cells or a portion of the mesonephros (Wolffian body) that has become displaced and lies embedded in tissue of another character that persists as an embryonic remnant in the adult.

Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment [London: Macmillan and Company, 1918], 266. Von Recklinghausen’s four varieties of adenoma are taken directly from Lockyer. See: Friedrich v. Recklinghausen, Die Adenomyome und Cystadenome der Uterus- und Tubenwandung ihre Abkunft von Resten des Wolff’schen Korpers. Im Anhang: Von W. A. Freund, Klinische Notizen zu den voluminosen Adenomyomen des Uterus [Berlin: Verlag von August Hirschwald, 1896]. My copy of this monograph obtained online from the Center for Research Libraries, Identifier: m-r-000252-f3, Scan Date: September 26, 2007 contained only text, no illustrations.

Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment [London: Macmillan and Company, 1918], 267–268.

100

Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment [London: Macmillan and Company, 1918], 437.

101

Cuthbert Lockyer, 438–439.

102

Cuthbert Lockyer, 274–275. Lockyer named the supporters of the Müllerian origin of adenomyomas as: “Diesterweg, Schroeder, C. Ruge, Babes, Schottlander, Hauser, Strauss, Orloff, Ricker (for the uterus), and A. Martin, Orthmann, Chiari, Baraban, Pilliet (for the tube).” Müllerian rest: The paired müllerian tubes – primitive vertebrate fallopian tubes, uterus, cervix, and upper vagina – comprise two elongated masses in the early vertebrae embryo. A müllerian rest represents a group of cells or a portion of the müllerian anlage that has become displaced and lies embedded in tissue of another character that persists as an embryonic remnant in the adult. Wolffian rest: The mesonephros – the primitive vertebrate kidney – comprises two elongated masses in the early vertebrate embryo. A Wolffian rest represents a group of cells or a portion of the mesonephros (Wolffian body) that has become displaced and lies embedded in tissue of another character that persists as an embryonic remnant in the adult.

103

Cuthbert Lockyer, 281.

104

Von Recklinghausen F. Ueber die Adenocysten der Uterustumoren und Ueberreste des Wolff’schen Organs. Deutsche Medicinische Wochenschrift 1893;xix:325–326.

105

Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 106. Orth was Virchow’s favorite assistant and future successor to his chair.

106

Andreas W. Daum, “Wissenschaft and knowledge,” in The Short Oxford History of Germany: Germany 1800–1870 [Oxford: Oxford University Press, 2004], 137–161:137. Daum equated the German term Wissenschaft with scholarship and research, which included “the sciences, social sciences, and humanities.” See Martzloff KH. Thomas Stephen Cullen. Am J Obstet Gynecol 1960;80:833–843:835: Cullen spent 6 months in the laboratory of Johannes Orth. The tradition of Wissenschaft was strong in the laboratory of Johannes Orth; it was based on an intellectual genealogy directly traceable to Goethe himself. Goethe profoundly influenced Johannes Müller who, in turn, became the great German medical educator of the nineteenth century. Müller trained Virchow, who trained Orth who directly influenced Cullen in his early and formative 6 months spent in Orth’s pathology laboratory.

107

Judith Robinson, Tom Cullen of Baltimore, 108–109.

108

Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 404–411.

109

Judith Robinson, 216. Soon after he returned to Johns Hopkins Hospital, Cullen began a lifelong friendship with Max Broedel, Howard Kelly’s master medical illustrator. The two made a pact; Broedel would write and converse with Cullen in English and Cullen would reciprocate in German. To his biographer, Cullen recalled: “All his life I don’t think I spoke two hours of English to him, or wrote fifty words that were not German.” See also Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 168. This practice facilitated Cullen’s lectures in Germany and his communication with von Recklinghausen.

110

Judith Robinson, 113.

111

Judith Robinson, 113, 117.

112

Judith Robinson, 118. Simon Flexner & James Flexner, William Henry Welch and the Heroic Age of American Medicine [Baltimore: Johns Hopkins University Press, 1993], 163. See also: Kenneth M. Ludmerer, Learning to Heal: The Development of American Medical Education [New York: Basic Books, 1985], 41. William H. Welch maintained in 1886 that medicine had become a model of experimental research and that if a university wished to achieve creditability as a research university, it had to accommodate scientific medicine.

113

Simon Flexner & James Flexner, William Henry Welch and the Heroic Age of American Medicine [Baltimore: Johns Hopkins University Press, 1993], 163.

114

Simon Flexner & James Flexner, William Henry Welch and the Heroic Age of American Medicine [Baltimore: Johns Hopkins University Press, 1993], 245. “You are to be congratulated upon the excellent way in which you have written up and discussed these interesting cases. The drawings are works of art and make everything clear. You are taking the right way to build up a scientific reputation.” See also: Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 119.

115

Judith Robinson, 113. Howard A. Kelly was so impressed with Cullen’s foundation in gynecological pathology that, after his residency in gynecologic surgery, he took Cullen as his assistant with the rank of Instructor in Gynecology in the Johns Hopkins University and Assistant Resident Gynecologist in the Johns Hopkins Hospital. Kelly had recognized that Cullen’s talents in gynecological pathology complemented his own extraordinary talents as a gynecological surgeon; they made a good team for research and teaching. Furthermore, subsequent to Cullen’s experience, Kelly made a year of gynecologic pathology requisite before beginning the residency in gynecologic surgery. Judith Robinson, 136. Howard Kelly later remarked to Cullen that “he would give fifty thousand dollars to have had [Cullen’s] experience in pathology.” Judith Robinson, 113.

116

Frederick Jackson Turner, “The Significance of the Frontier in American History,” in The Early Writings of Frederick Jackson Turner, ed. Frederick Jackson Turner [Madison WI, [1893] 1938], 185–229. The essence of Turner’s Frontier Thesis is contained in the last sentence of the first paragraph of his famous 1893 essay: “The existence of an area of free land, its continuous recession, and the advance of American settlement westward explain American development.” Turner was one of the first American professional historians; he trained at Johns Hopkins University.

117

There was no territory within the United States that had fewer than two inhabitants per square mile.

118

Thomas Stephen Cullen, Adenomyoma of the Uterus [Philadelphia: WB Saunders, 1908], v. Cullen recounted the story of his first encounter with an adenomyoma in the opening paragraph of the preface. Ironically, the first case that Cullen encountered was the less common variety, an adenomyoma of the anterior wall of the uterus; the more common site being the posterior wall.

119

Cullen discovered his first case of diffuse uterine adenomyomas in October 1894 while engaged in a study of uterine myomata with his surgical mentor, Howard A. Kelly. He had just returned from Europe where he spent 6 months in the pathology laboratory of Carl Orth in Berlin. See: Howard A. Kelly and Thomas S. Cullen, Myomata of the Uterus [Philadelphia: WB Saunders, 1909], v. “In 1894 we commenced a careful study of uterine myomata and contemplated publishing the results of our findings. A year later, however, the work was temporarily laid aside, as it was deemed wiser to take up the subject of carcinoma of the uterus. After the publication of that work in 1900 we again turned our attention to uterine myomata, and since that time we have been continually gathering data on that subject.”

120

Thomas Stephen Cullen, Adenomyoma of the Uterus [Philadelphia: WB Saunders, 1908], v. Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 195.

121

Thomas Stephen Cullen, Adenomyoma of the Uterus [Philadelphia: WB Saunders, 1908], v.

122

123

Friedrich v. Recklinghausen, Die Adenomyome und Cystadenome der Uterus.

124

In 1862, 2 years after Rokitansky’s description of endometriosis, von Recklinghausen described lymph channels, known as canals of Recklinghausen.

125

Owsei Temkin, “Basic Science, Medicine, and the Romantic Era,” in The Double Face of Janus and Other Essays in the History of Medicine [Baltimore, MD: Johns Hopkins University Press, 1977], 254. In 1877 in Strassburg, Welch studied gross pathology with von Recklinghausen, normal histology with Waldeyer, and physiological chemistry with Hoppe-Seyler. Page 258. It was von Recklinghausen who pointed out to Welch the significance of bacteria.

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Cullen, Thomas Stephen. Adeno-myoma of the round ligament. Johns Hopkins Hospital Bulletin. 1896;7:112–114. In a carefully crafted understatement, Cullen recorded his reaction. “Recently our interest in these cases has been awakened by the excellent work of v. Recklinghausen.” In the references, see: Cullen: Adeno-myoma uteri diffusum benignum. Johns Hopkins Hospital Reports, Vol. VI (in press). That Volume 7 of the Johns Hopkins Hospital Bulletin was published before Volume 6 was not the first time the Hospital reports were published out of sequence. See: Simon Flexner and James Thomas Flexner, William Henry Welch and the Heroic Age of American Medicine [Baltimore, MD: Johns Hopkins University Press, 1993], 243. Volume II written by William Osler was published 7 years before Volume I written by William Welch.

127

Laura Otis, Müller’s Lab [Oxford: Oxford University Press, 2007], 63. Otis quotes Schwann’s dramatic awakening, which illustrates the role of analogy in the formulation of his biological cell theory: “One day when I was having dinner with Schleiden [in October 1837] that illustrious botanist indicated to me the important role that the nucleus plays in the development of plant cells. Suddenly, I remembered having seen a similar structure [un organe pareil] in cells of the chorda dorsalis, and at that very instant I grasped the extreme importance the discovery would have if I succeeded in showing that, in the cells of the chorda dorsalis, the nucleus plays the same role that it plays in the development of plant cells…This fact, if solidly established through observation, would imply the negation of a vital force common to animals and would make it necessary to admit the individual life of the elementary parts of other tissues and a common means of formation through cells. This recognition of a principle, later verified by observation, constitutes the discovery I had the good fortune to make…I invited Schleiden to accompany me to the Anatomical Theater, where I showed him the nuclei in the chorda dorsalis cells. He saw [reconnut] a perfect resemblance to the nuclei of plants.”

128

Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 125.

129

Simon Flexner and James Thomas Flexner, William Henry Welch and the Heroic Age of American Medicine [Baltimore, MD: Johns Hopkins University Press, 1993], 170.

130

Donald Fleming, William H. Welch and the Rise of Modern Medicine [Boston, MA: Little Brown and Company, 1954], 33–34. From December 1877 to February 1878, Welch had performed a “piece of scientific investigation under von Recklinghausen” in Strassburg. Hence, Welch was familiar with von Recklinghausen’s microscopic techniques from that period. Welch also knew that von Recklinghausen was a skilled microscopist as would be expected of an assistant trained by Rudolf Virchow, who was an assistant of Johannes Müller. See also: Simon Flexner and James Thomas Flexner, William Henry Welch and the Heroic Age of American Medicine [Baltimore, MD: Johns Hopkins University Press, 1993], 108. Welch might also have remembered the experiment that von Recklinghausen had had him perform nearly 20 years before regarding the origin of pus cells. When it came to interpretation of the experiment, “Welch recognized [von Recklinghausen’s] reasoning as fallacious and reserved judgment, assuming there must be some other explanation.”

131

Cullen cut his tissue sections with a microtome, an instrument that von Recklinghausen did not have.

132

Anhang. Klinische Notizen zu den voluminosen Adenomyomen des Uterus. Von W. A. Freund. [The complete clinical picture of adenomyomas of the uterus.] Friedrich v. Recklinghausen, Die Adenomyome und Cystadenome der Uterus- und Tubenwandung ihre Abkunft von Resten des Wolff’schen Korpers. Im Anhang: Von W. A. Freund, Klinische Notizen zu den voluminosen Adenomyomen des Uterus [Berlin: Verlag von August Hirschwald, 1896.] Robert Meyer, Autobiography of Dr. Robert Meyer: (1864–1947): A Short Abstract of a Long Life[New York: Henry Schuman, 1949], 33. Robert Meyer confirmed that W. A. Freund first identified the classical clinical symptoms of uterine adenomyoma/adenomyosis.

133

134

Freund, Wilhelm Alexander. Eine neue Methode der Extirpation des ganzen Uterus. Sammlung Klinischer Vortage no. 133, Gynkologie, vol. 41, pp. 911–924, 1878. Longo LD. Classic pages in obstetrics and gynecology. Am J Obstet Gynecol 1977;128:117.

135

Owsei Temkin, “Health and Disease,” in The Double Face of Janus and Other Essays in the History of Medicine [Baltimore, MD: Johns Hopkins University Press, 1977], 426. “The ontological view of disease, i.e., thinking of them as real, distinct entities, was nothing new. Even the comparison of a disease with an animal was old-Plato (Timaeus 89B) had used it, and Varro (116-27B.C.) had actually spoken of animals, too small to be seen by the eye, ‘which by mouth and nose through the air enter the body and cause severe diseases.’ (Rerum rusticarium 1, 2).”

136

Robert P. Hudson, Disease and Its Control: The Shaping of Modern Thought [Westport, CT: Greenwood Press, 1983], 231.

137

Robert P. Hudson, 229.

138

Owsei Temkin, “Health and Disease,” in The Double Face of Janus and Other Essays in the History of Medicine [Baltimore, MD: Johns Hopkins University Press, 1977], 435.

139

Roy Porter, Blood and Guts: A Short History of Medicine [New York: W. W. Norton & Company, 2002], 82.

140

Owsei Temkin, “Health and Disease,” 434–435.

141

Roy Porter, Blood and Guts: A Short History of Medicine [New York: W. W. Norton & Company, 2002], 82.

142

Georges Canguilhem, The Normal and the Pathological. Trans. Carolyn R. Fawcett in collaboration with Robert S. Cohen [New York: Zone Books, 1991], 29. In the Preface to the Second Edition (1950), Canguilhem wrote: “This second edition of my doctoral thesis in medicine exactly reproduces the text of the first, published in 1943.” The text quoted above was originally published in 1966 as Le normal et le pathologique and copyrighted by Presses Universitaires de France. It was originally published in English and copyrighted in 1978 by D. Reidel Publishing Company, Dordrecht, Holland.

143

Georges Canguilhem, The Normal and the Pathological. Trans. Carolyn R. Fawcett in collaboration with Robert S. Cohen [New York: Zone Books, 1991], 41.

144

Robert P. Hudson, Disease and Its Control: The Shaping of Modern Thought [Westport, CT: Greenwood Press, 1983], 231.

145

Owsei Temkin, “The Scientific Approach to Disease: Specific Entity and Individual Sickness,” in The Double Face of Janus and Other Essays in the History of Medicine [Baltimore, MD: Johns Hopkins University Press, 1977], 450.

146

Knud Faber, Nosography in Modern Internal Medicine [New York: Paul B. Hoeber, Inc., 1923], 98.

147

Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 196. Years later, Cullen recalled: “Microscopic examination of large sections of the first two specimens had clearly shown the glandular element in adenomyomata… originated in a flowing outward of the normal uterine mucosa.”

148

Cullen TS. Adeno-myoma uteri diffusum benignum. Johns Hopkins Hospital Reports 1896;6:133–157. Cullen was unaware of two brief notes on the subject that von Recklinghausen had published, the first on May 19, 1893, the second on June 14, 1895. Von Recklinghausen F. Ueber die Adenocysten der Uterustumoren und Ueberreste des Wolff’schen Organs. Deutsche Medicinische Wochenschrift 1893;xix:325–326. Von Recklinghausen F. Ueber die Adenomyome des Uterus und der Tuba. Wiener Klinische Wochenschrift 1895;29:530.

149

Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 120.

150

Judith Robinson, 120.

151

Robert Meyer, Autobiography of Dr. Robert Meyer (1864–1947): A Short Abstract of a Long Life. With a Memoir of Dr. Meyer by Emil Novak, MD. [New York: Henry Schuman, 1949], 29.

152

Cullen TS. Adeno-myoma uteri diffusum benignum. Johns Hopkins Hospital Reports 1896;6:133–157:136. Fielding H. Garrison, An Introduction to the History of Medicine. 4th edition, reprinted [Philadelphia: W. B. Saunders, 1914], 859. Weigert introduced hematoxylin staining in 1885. Fielding H. Garrison, An Introduction to the History of Medicine. 4th edition, reprinted [Philadelphia: W. B. Saunders, 1914], 522. “Virchow did practically all his work with carmine [tissue stain].”

153

RM Allen, The Microscope [New York: D. Van Nostrand Company, 1940], 10–12.

154

Fielding H. Garrison, An Introduction to the History of Medicine. 4th edition, reprinted [Philadelphia: W. B. Saunders, 1914], 522. Purkinje (1787–1869 had a microtome. “The microtome was definitely introduced by Wilhelm His in 1866, but was not perfected until about 1875, after which it became an important labor-saving device.” Another source gives a later date. Alexander Hellemans and Bryan Bunch, The Timetables of Science: A Chronology of the Most Important People and Events in the History of Science, Touchtone Edition [New York: Simon & Schuster], 362–364. However, some advances such as the microtome to slice thin tissue sections were not invented until 1885. The microtome was invented by Charles Darwin, son of Charles Darwin, author of The Origin of Species.

155

Rokitansky. Ueber Uterusdrüsen-Neubildung in Uterus u. s. w. Zeitsch. der k. k. Gesellsch. der Aerzte zu Wien, 1860, S. 577. Also: Rokitansky. (klob.) Gusserow in Billroth u. Luecke, 1886, Bd. II, S. 15.

156

Schatz. Ein Fall von Fibro-adenome cysticum diffusum et polyposum corporis et colli uteri. Archiv f. Gyn., 1884, XXII, S. 456.

157

Schroder. Handbuch der Krankheiten der weiblichen Geschlechtsorgane. 7. Auflage, Leipzig, 1886, S. 228.

158

Diesterweg. Ein Fall von Cystofibroma uteri verum. Zeitschr. F. Geb. u. Gyn., Bd. IX, 1883, S. 191.

159

von Recklinghausen. Ueber die Adenocysten der Uterustumoren und Ueberreste des Wolff’schen Organs. Deutsche Med. Woch., XIX. 1893, S. 825. Also: Von Recklinghausen. Die Adenomyome und Cystadenome der Uterus und Tubenwandung. Berlin, 1896.

160

Nachtrag means supplement to the main text.

161

Cullen TS. Adeno-myoma uteri diffusum benignum. Johns Hopkins Hospital Reports 1896;6:133–157:133.

162

To more fully appreciate the fruit of Welch’s philosophy to allow assistants in his laboratory to learn and discover by plunging into the work of the laboratory, consider the early achievement of Cullen with his demonstration of the pathogenesis of uterine adenomyomas. Cullen’s short career in pathology at the time of his discovery is summarized: Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 78. Cullen started at Johns Hopkins Hospital in late September, 1891. Ibid: 81. Cullen spent the next months in the “Pathological,” the pathology laboratory of William Henry Welch. Ibid: 103. Following a year long internship, Cullen spent several months studying pathology in the laboratory of Johannes Orth at Göttingen, Rudolf Virchows “chosen disciple.” Ibid: 113–114. Cullen returned to Johns Hopkins Hospital expecting to start his residency in Gynecology only to find that the more senior William Russell had decided to take the gynecologic residency. Unexpectedly, Cullen would spend October 1893 until October 1896 in Welch’s Pathological. He would become a well-trained gynecological pathologist before he started his residency in gynecology.

163

Cullen TS. Adeno-myoma uteri diffusum benignum. Johns Hopkins Hospital Reports 1896;6:133–157: 149–150.

164

Cullen TS. Adeno-myoma uteri diffusum benignum. Johns Hopkins Hospital Reports 1896;6:133–157:150.

165

Cullen, TS. Adeno-myoma uteri diffusum benignum. Bulletin Johns Hopkins Hospital 1896;6:133–157.

166

Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 125.

167

Judith Robinson, 125.

168

Cullen TS. 1896;6:133–157:133. On the first page of his article, Cullen states “v. Recklinghausen in the ‘Nachtrag’ accompanying his recent work, ‘Die Adenomyome und Cystadenome der Uterus-und Tubenwandung,’ carefully depicts a case belong to this group [diffuse adenomyomata].”

169

Judith Robinson, 125. What Cullen long remembered as v. Recklinghausen’s expression of “scientific equivalency” may have been tinged with “chagrin;” the German professor’s mental distress caused by humiliation at the hands of an apprentice armed with a microtome.

170

Adams was Frederick Jackson Turner’s dissertation advisor at Johns Hopkins University late in the nineteenth century.

171

Frederick Jackson Turner, “The Significance of the Frontier in American History,” in The Early Writings of Frederick Jackson Turner, ed. Frederick Jackson Turner [Madison WI, [1893] 1938], 185–229. The essence of Turner’s Frontier Thesis is contained in the last sentence of the first paragraph of his famous 1893 essay: “The existence of an area of free land, its continuous recession, and the advance of American settlement westward explain American development.” See also: Harry Ritter, Dictionary of Concepts in History [New York: Greenwood Press, 1986], 170–178.

172

Martzloff, KH. Thomas Stephen Cullen [Presidential Address]. Am J Obstet Gynecol 1960;80:833–843. In 1960, Karl Martzloff gave his presidential address before the American Gynecological Society; a biographical essay entitled “Thomas Stephen Cullen.” Martzloff, a former student of Cullen, confirmed that v. Recklinghausen and Cullen enjoyed a long and cordial professional relationship. “They corresponded for years” contrary to the opinion of some that it was a “long period of ill will.”

173

James V. Ricci. One Hundred Years of Gynaecology 1800–1900. A Comprehensive Review of the Specialty during it Greatest Century with Summaries and Case Reports of All Diseases Pertaining to Women [Philadelphia: Blakiston, 1945.] Professor James V. Ricci trained Edward J. Winkler, who was my professor of obstetrics and gynecology during medical school, internship and my first year of residency at the University of Buffalo School of Medicine, 1954–1960.

174

Martzloff, KH. Views and Reviews. Western J Surgery, Obstetrics, and Gynecology 1946;54 (August):338. The pagination is confusing. On the top of the page, immediately it reads: VIEWS and REVIEWS (Continued from page IX). On the bottom of the page, it reads: 338.

175

Martzloff ended with “Although Recklinghausen had his forthcoming book in press, he added a footnote, according to Dr. Ries, (not Reis, p. 510), recognizing Cullen’s work.” This last sentence seems counterfactual. Von Recklinghausen had published his book before Cullen published his article. Recall that both Welch and Cullen had read the monograph before Cullen walked up to Welch’s laboratory with his giant slides from the 1894 and 1895 cases. Recall also that it was von Recklinghausen’s monograph, with the appendix containing the one case of mucosal invasion (von Recklinghausen’s minor thesis), that “awakened” Cullen to the significance of his two cases.

176

Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 125.

177

Judith Robinson, 125. See also: Martzloff, KH. Thomas Stephen Cullen [Presidential Address]. Am J Obstet Gynecol 1960;80:833–843:833–834. Martzloff offered an insight into Cullen’s personality that may tangentially shed some light on Cullen’s apparent ambiguity toward von Recklinghausen at this early period. Referring to Cullen, Martzloff said: “These comments are designed to be neither fault-finding nor critical, but only to afford an interesting side light to a distinguished, though not a particularly popular individual. It may seem strange that a man so generous, kind, and thoughtful, who always enjoyed the confidence and loyalty of his staff, should lack popular appeal. Always genuinely appreciative and punctilious in acknowledging a kindness or a favor, he nevertheless gave the impression of being constantly pressed for time and of being self-sufficient to the point of apparent brusqueness.” Martzloff, KH. 1960;80:833–843:836. I believe Martzloff’s assessment of Cullen may be taken at face value. He described his own relationship with Cullen as follows: “One whom it has been my privilege to know, one who encouraged me in my early years.”

178

Cullen, TS. Adeno-myoma of the round ligament. Bulletin Johns Hopkins Hospital 1896;7:112–114.

179

Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 126.

180

Cullen, TS. 1896;7:112–114:113.

181

Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 126.

182

Judith Robinson, 126.

183

Martzloff, KH. Thomas Stephen Cullen [Presidential Address]. Am J Obstet Gynecol 1960;80:833–843.

184

Lorraine Daston and Peter Galison, Objectivity [New York: Zone Books, 2007], 161, 49, 27–28. “Learning to see was never, is never, will never prove effortless…We always return to our central question: how does the right depiction of the working objects of science join scientific sight to the scientific self?…However dominant scientific objectivity may have become in the sciences since circa 1860, it never had, and still does not have, the epistemological field to itself. Before objectivity, there was truth-to-nature; after the advent of objectivity came trained judgment…The relationship between epistemic virtues may be one of quiet compatibility, or it may be one of rivalry and conflict. In some cases, it is possible to pursue several simultaneously; in others, scientists must choose between truth and objectivity, or between objectivity and judgment. Contradictions exist.”

185

Robert E. Fechner, “The Birth and Evolution of American Surgical Pathology,” in Guiding the Surgeon’s Hand: The History of American Surgical Pathology, ed. Juan Rosai [Washington, DC: Armed Forces Institute of Pathology, 1997], 1.

186

Robert Meyer, Autobiography of Dr. Robert Meyer (1864–1947): A Short Abstract of a Long Life [New York: Henry Schuman, 1949], 29. Robert Meyer met Viet, Professor of Gynecology, at his uncle’s home in 1895. In response to this meeting with Viet, Meyer began his work as a pathologist in a “closet” sized laboratory in his apartment so he could be close to the hospital.

187

Robert Meyer, Autobiography, 29. circa 1895–1896: “I had a microscope, bought a small microtome, and learned in a short time to make sections and diagnoses with the help of Veit and books. Soon I was a virtuoso who could make sections through a whole kidney in celloidin, some of which I still have. I learned to bring the unstained sections from the knife into diluted alcohol onto the slide and to observe them with low power in comparing them with stained sections under high power. That technique I needed in order to look for anomalies in the uterus of many fetuses and adults. I stained and preserved only the positive findings. It required the patience and perseverance of a mule, which I had.” Later Meyer trained a technician for this work. Meanwhile, unbeknownst to Meyer, his old professor of pathology von Recklinghausen was still cutting tissue sections by hand using a knife as he had taught Meyer in medical school.

188

Lorraine Daston and Peter Galison, Objectivity [New York: Zone Books, 2007], 325. “By the end of the nineteenth century…The perfection of the microscope made it possible to go from the organ pathology of Morgagni and the tissue pathology of Xavier Bichat to the cellular concepts of Rudolf Virchow, and the later introduction of the oil immersion lens greatly aided the development of microbiology. The discovery of anesthesia made vivisection practical, thereby providing the physiologist with his most important tool. The microscope and developments in chemistry made it possible to study the morphological and molecular elements of body fluids. …a huge growth in the size of the scientific community was facilitated by a remarkable expansion and transformation of scientific pedagogy in Europe and North America during the period roughly between 1880 and 1914, especially in Germany, France, Great Britain, and the United States.”

189

Lorraine Daston and Peter Galison, Objectivity, 164.

190

Lorraine Daston and Peter Galison, Objectivity, 135.

191

Lorraine Daston and Peter Galison, Objectivity, 51.

192

Robert Meyer, Autobiography of Dr. Robert Meyer: (1864–1947): A Short Abstract of a Long Life [New York: Henry Schuman, 1949], 32.

193

Robert Meyer, Autobiography, 32.

194

Robert Meyer, Autobiography, 32.

195

Meyer R. Uber Genese der Cystadenome und Adenomyome des Uterus, mit Demonstrationen. Zeitschr Geburtsh und Gyn 1897; 37: 327–337.

196

Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment [London: Macmillan and Company, 1918], 281–282.

197

Emil Novak, A memoir of Dr. Meyer in Robert Meyer, Autobiography of Dr. Robert Meyer: (1864–1947): A Short Abstract of a Long Life [New York: Henry Schuman, 1949], xii. “In my own judgment the one factor above all others which made possible Meyer’s preeminence in the field of pathology was his profound knowledge of embryology. He was really one of the great embryologists of his time, the recognized peer of such men as Fischel, Keibel, Felix, and Mall. It was this great asset which gave him a fundamental approach in the interpretation of problems of pathology which was not possessed by any other pathologist of his day.”

198

Robert Meyer, Autobiography, 32. Ibid: 38. Meyer wrote: “I had, on occasion, seen and heard Virchow as the President of the Berliner Medizinische Gesellschaft and was deeply impressed by his clarity. He had accepted from me a short article on osteoid tissue in the cervix of the uterus (Virchows Archiv 167 [1902]).”

199

Kossmann R. Die Abstammung der Drüseneinschlüsse in der Uterus und der Tuben. Archiv für Gynak 1897; Bd. liv. S:359, 381. See Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment[London: Macmillan and Company, 1918], 277.

200

Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment [London: Macmillan and Company, 1918], 278–279.

201

Cuthbert Lockyer, Fibroids and Allied Tumours, 281.

202

Esmond B. Long, A History of American Pathology [Springfield, IL: Charles C. Thomas, 1962], 54.

203

Donald Fleming, William H. Welch and the Rise of Modern Medicine [Boston, MA: Little Brown and Company, 1954], 35.

204

This was approximately the same time when William Henry Welch worked on a project supervised by v. Recklinghausen.

205

Robert Meyer, Autobiography of Dr. Robert Meyer: (1864–1947): A Short Abstract of a Long Life [New York: Henry Schuman, 1949], 16.

206

Robert Meyer, Autobiography of Dr. Robert Meyer: (1864–1947): A Short Abstract of a Long Life [New York: Henry Schuman, 1949], 33.

207

Robert Meyer, Autobiography, 33. Meyer wrote: “Not that theory is almost forgotten but in retrospect one wonders how von Recklinghausen could in thirty cases have overlooked the connection of the adenomyosis with the endometrium, which is now quite clear…Only in later cases did he see it and have to admit in a supplement the possibility of the endometrial histogenesis.”

208

Rabinovitz M. The pathogenesis of adenomyosalpingitis (salpingitis nodosa): report of ten cases. American Journal of Obstetrics and Diseases of Women and Children 1913; lxviii;711–752.

209

To paraphrase the hackneyed expression: thrown out the baby with the bathwater.

210

Robert Meyer, Autobiography, 64. Meyer quoted the physicist Mack to that effect; “The observation is already influenced by the theory.”

211

Robert Meyer, Autobiography, 33.

212

Robert Meyer, Autobiography, 33.

213

Robert Meyer, Autobiography, 33.

214

Iwanoff NS. Drusiges cystenhaltiges Uterusfibromyom compliciert durch Sarcom und Carcinom. Monatsschr. Geburtsh u. Gynak. 1898;7:295. Cited by Emge LA. The elusive adenomyosis of the uterus: its historical past and its present state of recognition. Am J Obstet Gynecol 1962;83:1541–1563. See also Pick L. Ueber Neubildungen am Genitale bei Zwittern nebst Beitragen zur Lehre von den Adenomen des Hodens und Eierstockes. Arch f Gynaek 1905;lxxvi:251–275. In reference 34, Pick gives the bibliographic reference for Iwanoff’s dissertation. Iwanoff, Adeno-myome de l’uterus. Inaug.-Diss. Petersburg. (Russisch.) Vergl. auch Frommel’s Jahresberichte für 1897. S. 103 u.

215

216

Robert Meyer, Autobiography, 33.

217

Russell, William Wood. Aberrant portions of the müllerian duct found in an ovary. Johns Hopkins Hospital Bulletin 1899; 10:8–10.

218

Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment [London: Macmillan and Company, 1918], 282. See: Franque OV. Salpingitis nodosa isthmica und Adenomyoma tubae. Zeitschr f. Geb 1900; Bd. xlii: S. 42. “Von Franque’s conclusions were that a pre-existing inflammation explained the origin of most of the ‘growths,’ but that von Recklinghausen’s hypothesis must be held as the elucidation of the few.”

219

Cuthbert Lockyer, Fibroids and Allied Tumours, 279. Lockyer cited Franque OV. Salpingitis nodosa isthmica und Adenomyoma tubae. Zeitschr f. Geb 1900; Bd. xlii: S. 41.

220

Robert Meyer, Autobiography, 32.

221

Robert Meyer, Autobiography, 33.

222

Illustrated Stedman’s Medical Dictionary. 24^th ed. [Baltimore, MD: Williams & Wilkins, 1982], 474. The epidiascope is a “projector by which images are reflected by a mirror through a lens, or lenses, onto a screen, using reflected light for opaque objects and transmitted light for translucent or transparent ones.” Carl Zeiss was the company for which Ernst Abbe worked.

223

Robert Meyer, Autobiography, 32–33.

224

Meyer R. Uber Drüsen, Cysten und Adenome in Myometrium bei Erwachsenen. Zietschr f. Geb und Gynak 1900–1901; xlii, xliii, xliv.

225

Robert Meyer, Autobiography, 70–71.

226

Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment [London: Macmillan and Company, 1918], 279. Lockyer cited Franque OV. Salpingitis nodosa isthmica und Adenomyoma tubae. Zeitschr f. Geb 1900; Bd. xlii: S. 41. Robert Meyer believed that inflammation might initiate basal endometrial invasion characteristic of diffuse adenomyosis, a concept harbored by Chiari for initiation of salpingitis isthmica nodosa (endosalpingiosis). Meyer abandoned the inflammatory theory in favor of the hormonal theory introduced by Lauche in 1923. See Emge LA. The elusive adenomyosis of the uterus: its historical past and its present state of recognition. Am J Obstet Gynecol 1962;83:1541–1563. Emge cited Arnold Lauche. Virchow’s Arch Path Anat 1923;243:298.

227

Lester S. King, Medical Thinking: A Historical Preface [Princeton, NJ: Princeton University Press, 1982], 197–198.

228

Lester S. King, Medical Thinking: A Historical Preface [Princeton, NJ: Princeton University Press, 1982], 229–233.

229

Lester S. King, The Medical World of the Eighteenth Century [Huntington, NY: Robert E. Krieger Publishing Co., 1958, Reprint 1971], 284, 287.

230

Lester S. King, The Medical World of the Eighteenth Century, 291–292.

231

Russell C. Maulitz, Morbid Appearances: The Anatomy of Pathology in the Early Nineteenth Century [New York: Cambridge University Press, 1987], 207.

232

Russell C. Maulitz, Morbid Appearances, 205.

233

Jacalyn Duffin, “Laennec and Broussais: The ‘Sympathetic’ Duel” in Constructing Paris Medicine, ed. Caroline Hannaway and Ann La Berge [Amsterdam, NL: Editions Rodopi B. V., 1998], 251–274: 254, 262.

234

Robert Meyer, Autobiography, 70–71.

235

Franque OV. Salpingitis nodosa isthmica und Adenomyoma tubae. Zeitschr f. Geb 1900; Bd. xlii: S. 41.

236

237

Cuthbert Lockyer, Fibroids and Allied Tumours, 285–286.

238

Cuthbert Lockyer, Fibroids and Allied Tumours, 285–286. Meyer R. Uber Drüsen, Cysten und Adenome in Myometrium bei Erwachsenen. Zietschr f. Geb und Gynak 1900–1901; xlii, xliii, xliv.

239

Cuthbert Lockyer, Fibroids and Allied Tumours, 288. Meyer R. Uber Drüsen, Cysten und Adenome in Myometrium bei Erwachsenen. Zietschr f. Geb und Gynak 1900–1901; xlii, xliii, xliv.

240

Robert Meyer, Autobiography, 38.

241

Illustrated Stedman’s Medical Dictionary, 24^th ed. [Baltimore, MD: Williams & Wilkins, 1982], 474. A projector by which images are reflected by a mirror through a lens, or lenses, onto a screen, using reflected light for opaque objects and transmitted light for translucent or transparent one.

242

Robert Meyer, Autobiography, 35. See also: Robert Meyer, Eine unbekannte Art von Adenomyom des Uterus mit einer kritischen Besprechung der Urnierenhypothese v. Recklinghausen’s. Zeitschr. f. Geburtsh. Gyn. 1903;49:464–507.

243

Robert Meyer, Autobiography, 33.

244

Robert Meyer, Autobiography, 35.

245

Robert Meyer, Eine unbekannte Art von Adenomyom des Uterus mit einer kritischen Besprechung der Urnierenhypothese v. Recklinghausen’s. Zeitschr. f. Geburtsh. Gyn. 1903;49: 464–507.

246

Emil Novak, “A Memoir of Dr. Meyer,” in Robert Meyer, Autobiography of Dr. Robert Meyer (1864–1947): A Short Abstract of a Long Life [New York: Henry Schuman, 1949], xii. Novak opined: “In my judgment the one factor above all others which made possible Meyer’s preeminence in the field of pathology was his profound knowledge of embryology. He was really one of the great embryologists of his time, the recognized peer of such men as Fischel, Keibel, Felix, and Mall. It was this great asset which gave him a fundamental approach in the interpretation of problems of pathology which was not possessed by any other pathologist of his day.”

247

Robert Meyer, Autobiography, 32.

248

Emge LA. The elusive adenomyosis of the uterus: its historical past and its present state of recognition. Am J Obstet Gynecol 1962;83:1541–1563:1543.

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