Cullen’s Research at Johns Hopkins Hospital

A History of Endometriosis

5. Cullen’s Research at Johns Hopkins Hospital

Ronald E. Batt¹

(1)

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

Abstract

From available evidence, Thomas Cullen remained unaware of the active role Robert Meyer played in resolving Cullen’s differences with Professor Friedrich von Recklinghausen. However, Cullen may have relieved von Recklinghausen’s embarrassment with his discussion of the origin of the glands in his case of adeno-myoma of the round ligament: “While admitting the probability of the glands in our case being due to remains of the Wolffian body, we cannot, from their striking resemblance to those of the uterine mucosa, and from the fact that their stroma resembles that of the mucosa, refrain from suggesting the possibility that they may be due to an abnormal embryonic deposit of a portion of Müller’s duct.”¹ Heartened by the “peace offering” he received from Strassburg, von Recklinghausen and Cullen would continue their professional exchange for a decade. Cullen returned to the daily routine of the pathology laboratory of analyzing gynecologic surgical specimens. He focused his attention on completing a study of uterine cancer.² Notwithstanding all the work he would do on adenomyomas, Cullen’s real interest lay in the pathology and early detection of uterine cancer.

Cullen’s Research at Johns Hopkins Hospital 1898–1906

Two years later, in 1898, William W. Russell operated on a postmenopausal patient for cystic adenocarcinoma of the left ovary.³ The woman had experienced a natural menopause. Russell removed a normal size right ovary “enveloped in adhesions on the posterior surface of the broad ligament, while the tube was free and patent.”⁴ In the January-February-March 1899 issue of the Johns Hopkins Hospital Bulletin, Russell published the results of his analysis. On microscopic examination of longitudinal serial sections of the ovary, Russell reported: “we were astonished to find areas which were an exact prototype of the uterine glands and interglandular connective tissue.”⁵Plate III of Max Broedel’s illustrations shows a portion of a wall surrounding a cystic space with what might be interpreted as an organoid structure within the substance of the ovary. “The whole [of the organoid structure] formed an exact reproduction of a portion of the uterine mucous membrane and muscle. The arrangement of these structures gave the impression that they were a continuous system from the groove on the posterior surface to a cystic space on the anterior face.”⁶ He stipulated: “accepting the studies of Nagel, that the epithelial elements of the Müllerian duct are derived from the germinal epithelium, as correct, I believe we are able to explain the condition found in this instance as due to an anomalous point of development of portions of the Müllerian duct in the germinal epithelium.”⁷ Russell then reviewed contemporary explanations “in reference to the origin of the epithelium of the Müllerian duct.” Russell drew the conclusion “that the epithelium of the Müllerian duct is exclusively derived from true germinal epithelium.” ⁸ Russell contended that his specimen supplied “direct proof that the germinal epithelium is capable of producing glands analogous to those of the uterine mucosa.”⁹ In other words, Russell believed the germinal epithelium of the right ovary differentiated into aberrant portions of the Müllerian duct by metaplasia. He did not argue for a pathogenesis from mesonephric rests. Nor did he believe the aberrant endometrial tissue of the right ovary originated from müllerian rests.¹⁰

Years later, Howard Kelly spoke of this case of W. W. Russell. “Without any doubt, his most important contribution was a carefully made objective study of a case, the first one reported, of endometrial tissue in the ovary, far reaching in its consequences in view of the later studies of Thomas S. Cullen and John A. Sampson.”¹¹ Kelly was unaware of Rokitansky’s contribution. More than a century later, Benagiano and Brosens also would credit Russell of Johns Hopkins as the first to describe what is now known as an ovarian endometrioma.¹² However, Russell’s case was no ordinary endometrioma as defined by Hughesdon.¹³ First, the ovary was normal size. Second, the lesion was strikingly different from the ovarian cystic and solid lesions encountered at Johns Hopkins Hospital at that time. Third, the lesion extended from one surface of the ovary to the other as a solid seam of adenomyomatous tissue with small cystic cavities evidencing some bleeding. “The whole formed an exact reproduction of a portion of the uterine mucous membrane and muscle. The arrangement of these structures gave the impression that they were a continuous system from the groove on the posterior surface to a cystic space in the anterior face.”¹⁴ Arguably this lesion may have been Sampson’s developmentally misplaced endometrium,¹⁵ a choristoma,¹⁶ and an example of müllerianosis.¹⁷

An editorial appeared in the September 30, 1899 issue of the Journal of the American Medical Association, without reference to Cullen or Russell. It stated flatly that the work of Leopold Landau of Berlin settled the issue of pathogenesis of adenomyomata of the female sexual apparatus and proved von Recklinghausen’s theory of origin from Wolffian canals.¹⁸ At this time in North America, there was only one journal devoted to obstetrics and gynecology, the Journal of Obstetrics and the Diseases of Women and Children. So it was not unusual for a subject of general interest to general practitioners and general surgeons to appear in a general interest medical journal such as the Journal of the American Medical Association. What was unusual, perhaps, was the lack of any reference to Cullen’s articles on the subject, articles published by the leading American medical school of the time.

Early in his career Cullen decided to follow the Johns Hopkins idea to write definitive books on a subject¹⁹ rather than medical textbooks that required successive editions.²⁰ This practice cost Cullen between 50 and 60 thousand dollars for the five books he published. He deliberately took the losses rather than profits from textbooks. Cullen clarified: “With each major book I wrote, I took the same course. Insofar as I could, I assembled all the knowledge on that subject available at that date, presented it in as complete a manner as possible and published. That was definitive and I was through. The next man could take on from there.”²¹

By 1900 Cullen had finished his cancer research. He wrote his first monograph, Cancer of the Uterus, the equivalent of a PhD dissertation. In the dedication, Cullen acknowledged his teacher-advisors, Howard A. Kelly and William H. Welch.²² Yale offered him the chairmanship of its department of gynecology with the rank of full professor. Johns Hopkins met this challenge with a counter offer of associate professor and Cullen remained at Johns Hopkins.²³ Reflecting in his later years, Cullen said that Cancer of the Uterus “was probably the most important book I ever published.”²⁴ Karl Martzloff, his student and biographer agreed: “Cullen’s first book…remained the single great unchallenged monograph on uterine cancer until the voluminous and excellent German monograph of Schottlaender and Kermauner appeared 12 years later.”²⁵ Cullen now had an international reputation based on his work with cancer, not adenomyomas.

In 1901, William Welch was consulted for a second opinion on a case with a presumptive diagnosis of osteo-fibromyoma of the uterus.²⁶ He was given an unusual specimen to examine and found in it smooth muscle, true bone, and embryonic connective tissue. He agreed with the diagnosis, but with qualifications: “The tumor must, I think, be referred to embryonic remnants, and there is no objection to considering it as a teratoid formation, although not a very complex one. Besides the bone and smooth muscle, there is a great deal of peculiar embryonic connective tissue in the growth, partly mucoid in character, and partly more cellular, and this tissue is quite unlike any found in ordinary myomatous tumors.”²⁷ This was an example of a non-müllerian tissue (bone) in müllerian tissue (uterus); a choristoma, a developmental anomaly. Recall that Robert Meyer had identified endometrial islands in the uterus of a 9 month fetus: developmental adenomyosis. W. W. Russell had identified what may have been a choristoma, i.e., developmentally misplaced endometrial tissue in the ovary. Recall also, that Robert Meyer discovered a giant uterine adenofibromyoma that resembled epididymis, misplaced mesonephric tissue in the uterus, a non-müllerian tissue in müllerian tissue – a choristoma. In sum, by the turn of the twentieth century, developmental uterine adenomyosis, a non-mullerian choristoma of the uterus composed of embryonic bone, and possibly developmentally misplaced endometriosis of the ovary had been identified.

Baldy and Longscope reviewed the pertinent literature on uterine adenomyomas in 1902, before resolution of the debate between Cullen and von Recklinghausen. They strongly supported Cullen’s mucosal pathogenesis and thought the mesonephric theory of von Recklinghausen “improbable.”²⁸ Baldy and Longscope made no mention of Iwanoff.²⁹ However, they seemed better informed than the author of the editorial in the Journal of the American Medical Association of 1899 who settled on von Recklinghausen’s theory of origin from the Wolffian body.³⁰ Six years later, Cullen opined that the review by Baldy and Longscope was “probably the best article written in this country on adenomyoma of the uterus.”³¹ Undoubtedly, their favorable review of his work encouraged Cullen.

In 1903 Cullen published a supplement in German to the Festschrift for his friend, Professor Johannes Orth of Berlin. On this momentous occasion Cullen reported all the cases of diffuse benign uterine adenomyomata that he had accumulated since 1896.³² The 22 cases supported his earlier demonstration of the mucosal pathogenesis of diffuse uterine adenomyomas. Because the adenomyomatous process was confined to the uterus in most of his cases, Cullen stated that he could “definitely determine ‘in most cases’ the origin of the glands from the mucous membrane of the uterine cavity.”³³ Cullen must have experienced a sense of pride in his newfound professional stature, contributing to the Festschrift of the successor to Virchow’s chair, because he distributed hard cover copies of the Festschrift to his friends.³⁴

Cullen received further support from Whitridge Williams, Professor of Obstetrics at Johns Hopkins. In 1904, Williams performed an autopsy on a woman who had tragically died 2 h postpartum. The stroma within diffuse islands of adenomyosis throughout the uterine musculature had been converted to decidua.³⁵ Arguing by analogy, Cullen used this case as proof that the decidual transformation of islands of mucosa was identical to uterine mucosa, a case that “would certainly tend to convince the most skeptical.”³⁶

In 1906, while in Germany for the fourth time, Cullen telephoned von Recklinghausen and made an appointment to visit him in Strassburg. After 10 years of correspondence the two finally met face-to-face. Cullen had anticipated that their meeting would provide an opportunity for discussion about their mutual interest, the pathogenesis of adenomyomas. Instead, Cullen witnessed a performance.³⁷ “Though an old man then, von Recklinghausen was still doing original work in pathology and had just published some results of his recent researches in bone infection that were perfectly fascinating. But do you think I could get him talking about them or showing the work going on in his laboratory? Not a bit of it. What he wanted to talk about and show off was an autopsy table his son had sent him from Pittsburgh. We spent nearly all the time I had with him admiring it; just an ordinary American-made autopsy table.”³⁸ Von Recklinghausen’s allegorical performance went right over Cullen’s head. Despite a “decade of maturing experience” resulting from his correspondence with the great German pathologist,³⁹ Cullen simply could not fathom the embarrassment that von Recklinghausen had experienced in 1896, an embarrassment that Robert Meyer had seen as tragic. Nor could Cullen seem to grasp that the performance he was witnessing in 1906 was a reenactment of that earlier embarrassment over an American-made microtome. Ironically, what Meyer had perceived in 1898 as tragedy, Cullen perceived in 1906 as comedy.⁴⁰

One might consider von Recklinghausen’s reaction to Cullen’s article as a four-act play performed episodically between 1896 and 1908. The young German scientist Emil Ries attended the first act of the performance in von Recklinghausen’s laboratory in 1896 where he witnessed the body language and ironic verbal reaction of the Professor upon reading Cullen’s article.⁴¹ In 1898 the mature German scientist, Robert Meyer, attended the second act of the play in von Recklinghausen’s laboratory. Meyer saw his old professor tragically performing familiar old techniques of tissue preparation from both of their student days. Thomas Cullen saw in 1896 the comical performance of von Recklinghausen in the third act, also set in the latter’s laboratory, a performance that might better be called a tragicomedy.⁴²The fourth act was performed in 1908 on a split stage, the eastern half representing the study of von Recklinghausen, the western half the study of Cullen. Both the older and younger protagonists were writing letters that discussed pathological material for the younger man’s forthcoming book, Adenomyoma of the Uterus.Perhaps each had observed correctly the performances they attended; the observers were not seeing the same text because each saw a different act.⁴³

Of course von Recklinghausen’s message appears obvious in historical hindsight: had he had a microtome, his minor thesis of mucosal invasion would have been his major thesis. He would have seen with thinner microscopic preparations just what Cullen had seen. And, he would not have been embarrassed by an apprentice pathologist. Even when Cullen visited von Recklinghausen in his laboratory in Strassburg in 1906, the Herr Professor could not bring himself to discuss adenomyomas. Instead he acted out his lingering humiliation in a performance that Cullen could recall clearly many years later, but never with complete understanding.⁴⁴

The Mutual Legacy of Friedrich von Recklinghausen and Thomas Cullen

Friedrich von Recklinghausen (1833–1910) retired in 1906 after a long and distinguished career. He is best remembered for his description of lymph channels (canals of Recklinghausen) in connective tissue (1862), of multiple neurofibromatosis (1882), and osteitis fibrosa cystica (1891), but not for adenomyomas.⁴⁵ Nonetheless, his monograph Die Adenomyome und Cystadenome der Uterus- und Tubenwandung catalyzed the careers of both Robert Meyer and Thomas Cullen. Not without a further touch of irony, Hans Chiari (1851–1916) – assistant to Rokitansky – was called to von Recklinghausen’s chair of pathological anatomy at Strassburg in 1906.⁴⁶ Chiari honored the memory of von Recklinghausen with a biographical essay.⁴⁷

Cullen honored von Recklinghausen in Adenomyoma of the Uterus published in 1908.⁴⁸ He credited the “masterly work of von Recklinghausen”⁴⁹ for bringing the subject to prominence.⁵⁰ Cullen mentioned the “considerable controversy” that followed upon the publication of Die Adenomyome und Cystadenome der Uterus- und Tubenwandung ihre Abkunft von Resten des Wolff’schen Korpers.⁵¹ To his everlasting credit, von Recklinghausen graciously accepted the consensus of the scientific community regarding the correctness of Cullen’s work on uterine adenomyomas. Similarly, Robert Meyer thought von Recklinghausen’s work a pedagogic success because it brought adenomyosis to the attention of the medical profession.⁵² Lockyer concurred saying that full interest in the subject of adenomyomas was aroused only in 1896 with the appearance of von Recklinghausen’s magnificent work, Die Adenomyome und Cystadenomyome der Uterus und Tubenwandung. Lockyer cited other strengths of von Recklinghausen’s monograph; he classified uterine adenomyomas morphologically into two classes and four varieties and “the description he gives of his second variety, i.e. the centrally situated growth holds good to this day.”⁵³ Retirement notwithstanding, von Recklinghausen continued to review microscopic slides and offer “valuable criticism” as Cullen prepared his definitive monograph, Adenomyoma of the Uterus.⁵⁴ This was an example of professionalism at its finest. In a footnote, Cullen referenced Die Adenomyome und Cystadenome der Uterus- und Tubenwandung ihre Abkunft von Resten des Wolff’schen Korpers. Then he added: “I wish to express my deep sense of obligation to Professor v. Recklinghausen⁵⁵ for his kindness in examining sections from several of the cases and for his valuable criticism of the same.”⁵⁶ In short, Rokitansky discovered uterine adenomyosis, von Recklinghausen popularized it, and Cullen wrote the definitive monograph on all the permutations of its pathology, diagnosis, treatment, and malignant transformation.

Cullen used von Recklinghausen’s unhyphenated Adenomyoma in the title of his 1908 monograph. In prior publications on the subject from 1896 to 1903, Cullen had hyphenated Adenomyoma, the descriptive name that von Recklinghausen had first used in 1893.⁵⁷ Why had Cullen preferred Adeno-myoma? Did insertion of the hyphen emphasize his conception of the chronological separation of events in the formation of adenomyomas? Was it to emphasize that glacial endometrial mucosa “flowed” into chinks and crevices in preexisting Laurentian myomas?⁵⁸ Or was the hyphen simply a declaration of independence? Finally, what caused Cullen to revert to the original unhyphenated Adenomyoma of von Recklinghausen in the title of his 1908 monograph?

The visit to Strassburg in 1906 changed Cullen’s perception of von Recklinghausen. When he saw the 73-year-old professor face-to-face for the first and only time, Cullen observed more than a comical performance. Like Emil Ries a decade earlier, Cullen observed not only the words and body language of von Recklinghausen, the eminent professor of pathology; he also observed his department and his laboratory. Cullen would recall: “Though an old man then, von Recklinghausen was still doing original work in pathology and had just published some results of his recent researches in bone infection that were perfectly fascinating.”⁵⁹ Cullen departed Strassburg with a new found respect for the old German master who at 73 was still conducting original research. Undoubtedly in Strassburg, Cullen experienced the formidable presence and disciplined formality characteristic of a Germanic Vorstand (University Department Chairman), quite unlike the congeniality he experienced with Professor Orth in Göttingen.⁶⁰

Considering Cullen’s personal experience with von Recklinghausen, with whom he had corresponded for more than a decade,⁶¹ and the expression of his “deep sense of obligation to him,” one may argue with some justification that von Recklinghausen served on a symbolic level as an academic advisor for Cullen’s Habilitation, his monograph on Adenomyomas of the Uterus.⁶² Moreover, in expressing his “deep sense of obligation,” Cullen also acknowledged his indebtedness to von Recklinghausen for having awakened him in 1896 to Adeno-myoma uteri diffusum benignum. Due to the professionalism of both men, in 1908 Cullen could accept that “on all material points there was no difference between them.”

In Adenomyoma of the Uterus, Cullen concentrated on analyzing the surgical material from Johns Hopkins Hospital. He explicitly stated he did not do a search of the literature. This may explain why he did not cite Rokitansky in 1908 when he had done so in the article of 1896 and his monograph on cancer in 1900.⁶³ However, Cullen did not neglect the work of von Recklinghausen. He restated his position of 1896 that he agreed with von Recklinghausen⁶⁴ that uterine adenomyomas are benign “perfectly normal endometrial glands…surrounded by the normal stroma of the mucosa.”⁶⁵ Cullen also addressed the pathogenesis of tubal adenomyomas so important to von Recklinghausen in 1896. Referring to the work of von Franque,⁶⁶ Robert Meyer,⁶⁷ Gottschalk,⁶⁸ and Lockstaedt,⁶⁹ Cullen explained that in salpingitis isthmica nodosa [tubal adenomyosis] the tubal mucosa protrudes into the muscle of the tube creating “gland-like spaces” without underlying stroma because “in the tubal mucosa the characteristic stroma of the uterine mucosa is wanting.”⁷⁰ Cullen also related his understanding of von Recklinghausen’s reasoning with regard to the pathogenesis of uterine adenomyomata. Von Recklinghausen reasoned from the “supposed close analogy between elements of the Wolffian duct and the glandular structures” present in uterine adenomyomata and opined that in the “vast majority” of cases the “glandular elements were derivatives of the Wolffian duct.” ⁷¹ Cullen did not go into details. Whereas von Recklinghausen developed a morphological classification of uterine adenomyomas, Cullen classified adenomyomas clinically:

Adenomyomatous uterus with a relatively⁷² normal contour

Subperitoneal⁷³ or intraligamentary adenomyomata⁷⁴

Submucous adenomyomata⁷⁵

Interestingly, Cullen continued the tradition started by Rokitansky⁷⁶ of using colorful non-medical words as “walnut, hen’s egg, hazelnuts, bean, pea, cherry ” to describe the size of cysts, tumors, and other lesions.⁷⁷ He commented on the two large intraligamentary cystic adenomyomas described by Breus; the cavity of one communicated directly with the endometrial cavity of the uterus⁷⁸; and notably, the other specimen that contained 7 L of thick brownish fluid.⁷⁹ Cullen explained the pathophysiology of the latter case.

It is natural that the cysts in the uterine wall should remain small [miniature uterine cavities], as they are compressed by the muscle, on the other hand, when they have once become subperitoneal [and intraligamentary] they may dilate until they can contain several liters of [chocolate-colored] blood.⁸⁰

Cullen recommended scanning the uterine musculature with a magnifying loupe to “discover small, round, irregular, triangular or oblong areas composed of a waxy, fairly homogeneous tissue, lying between myomatous bundles” in order to differentiate adenomyomas from common myomas (fibroids); sometimes he identified “miniature uterine cavities.” ⁸¹ Cullen found the need for magnification – as had Rokitansky decades before. It is noteworthy also that in 1908, when he wrote the preface to his book, Cullen still used the metaphorical term flowing: “the uterine mucosa was at many points flowinginto the diffuse myomatous tissue.”⁸² Likely, Cullen was inspired to use this metaphor by recollections of his Canadian vacation experience. Early in his medical career, he vacationed in September in the lovely region of Parry Sound, Ontario, Canada.⁸³ Parry Sound lies on Georgian Bay which was formed when the glaciers receded over the Canadian Shield, also known as the Laurentian Plateau. The Canadian Shield is a large geographic area in eastern and central Canada composed of bare rock dating to the Precambrian era. Thousands of years ago, during the last ice age, the glaciers ground the hard Canadian Shield smooth and in the process gouged out the Great Lakes of North America and many smaller lakes. When lake water is driven by wind or ship’s wake it flows and ebbs in the hard smooth crevices of the rocky shorelines. In this northern landscape, glaciations formed the surface contours of the rock, flowing water from the melting glaciers came after. Cullen envisioned rocky myomas as “pre-existing” pathologic entities into the crevices of which the glacial uterine mucosa “flowed” to cause adenomyomas.⁸⁴ In Myomata of the Uterus, published in 1909, Cullen described the mechanism by which he envisioned uterine mucosa entering chinks in myomatous tissue. “In cases of adenomyoma of the uterus we usually find a diffuse myomatous thickening of the uterine muscle. This thickening may be confined to the inner layers of the anterior, posterior, or lateral walls, but in other cases the myomatous tissue completely encircles the uterine cavity. This diffuse myomatous tissue contains large or small chinks, and into these the normal uterine mucosa flows. If the chinks are small, there is only room for isolated glands, but where the spaces are goodly in size, large masses of mucosa flow into and fill them. We accordingly have a diffuse myomatous growth with normal mucosa flowing in all directions through it. The mucosa lining the uterine cavity is perfectly normal.”⁸⁵ Benagiano and Brosens captured the essence of this passage.⁸⁶ In Cullen’s conception, cancer invaded, but benign endometrial mucosa flowed.

Cullen reported that women were usually between 30 and 60 years of age when they sought medical attention for adenomyomata. They complained of increasingly heavy periods to outright continuous hemorrhaging and menstrual cramps. Occasionally a patient would complain of “grinding pain in the uterus.”⁸⁷ Cullen always attempted to explain the pathophysiology of disease when he could. He attributed the “grind pain” to “increased tension, since all the islands of mucosa scattered throughout the diffuse myoma naturally swell up at the menstrual period, and thus increase the size of the uterus.”⁸⁸What remains unspoken but implied in that reasoning was the “grinding pain” resulted from muscular contractions compressing the islands of mucosa in the adenomyoma. Cullen believed clinicians should easily diagnosis symptomatic uterine adenomyomata because (1) usually bleeding was confined to the menstrual period and (2) usually menstrual pain was midline, “referred to the uterus.”⁸⁹

The years between 1896 and 1908 – when Freund first described the clinical symptoms and signs of adenomyosis and Cullen described the Johns Hopkins’ clinical experience with patients operated for adenomyosis – are nearly synonymous with the emergence of gynecologic surgical pathology. From Rokitansky through von Recklinghausen, virtually all progress resulted from observations on morbid tissues removed at autopsy. By Cullen’s time, aseptic surgery, long experience with general anesthesia, and improved surgical technique resulted in consistent low operative mortality and the necessity for clinico-pathologic correlation to arrive at a correct preoperative diagnosis, tissue diagnosis, and prognosis. Physicians began to record the symptoms and the signs of patient with adenomyosis. During the long decade between 1896 and 1908, the voice of the patient was heard, interpreted, and recorded by physicians as personal medical history in clinic and hospital charts and in the medical literature.

Between 1894 and 1909 Cullen concentrated on diseases of the uterus: cancer, adenomyomas, and myomas (fibroids). He wrote four books, all profusely and beautifully illustrated: Cancer of the Uterus in 1900⁹⁰; Adenomyoma of the Uterus in 1908⁹¹; and Myomata of the Uterus⁹² and Cancer of the Uterus in 1909.⁹³ They earned for Cullen the admiration of historians of pathology such as Robert H. Young.⁹⁴ However, for gynecologists, Cullen’s reputation with regard to endometriosis has been overshadowed by John Sampson’s theory of retrograde menstruation and implantation. Ivo Brosens declared in 2004 that “It is a cruel trick of history that the great contribution of Cullen to the knowledge of the nosographic entity of endometriosis is usually ignored.”⁹⁵ A cruel trick of history indeed. Thomas Cullen’s monumental Adenomyomas of the Uterus with its clinical pathologic correlation firmly established the nosography of adenomyosis.

Cullen’s monograph Adenomyoma of the Uterus, for which von Recklinghausen may be said to have acted as academic advisor, not only served as the equivalent of a German Habilitation, it may be viewed also as the second and revised edition of von Recklinghausen’s Die Adenomyome und Cystadenome der Uterus- und Tubenwandung ihre Abkunft von Resten des Wolff’schen Korpers. And von Recklinghausen lived to see it published. Whereas the genealogy of ideas on adenomyosis flowed from Rokitansky to Chiari to von Recklinghausen to Cullen, the spirit of Wissenschaft emanated from Goethe to Müller to Virchow and through Orth and von Recklinghausen to Cullen.

In conclusion, from Rokitansky’s description in 1860 until late in the nineteenth century, all scientific investigation of adenomyomas occurred in Europe. For American gynecologists and surgeons, adenomyoma was an unknown disease until Cullen studied the surgical specimens excised by Howard Kelly at the Johns Hopkins Hospital. Since initially gynecological surgical pathology existed nowhere in North America except Johns Hopkins Hospital, virtually all surgeons and gynecologists had to depend on their own naked eye examination of surgical specimens at the operating table. Consequently, until Cullen began publishing his work on adenomyomas, all that American gynecologists had perceived at abdominal surgery were ovarian cysts, fibroids, massive pelvic and abdominal adhesions from infection, and cancer. Cullen made them aware of the existence of uterine adenomyoma, but still they could not diagnose it accurately until they developed gynecologic pathology in their own departments.

Uterine Cancer to Flexner Report to Cancer Prevention

Thomas Cullen maintained a lifelong interest in uterine cancer and its early diagnosis and treatment. As an aspiring academic in 1898, he published on the early diagnosis of carcinoma of the uterus.⁹⁶ In the first line of the preface of his first book, Cancer of the Uterus: Its Pathology, Symptomatology, Diagnosis, and Treatment (1900), Cullen revealed the origin of his crusade for early diagnosis and treatment of uterine cancer. “The number of cases of cancer of the genital tract coming too late for operation is so appalling that the surgeon is ever seeking to devise ways and means by which the dread malady may be more generally detected at the earliest possible moment – at a time when complete removal of the malignant tissue is still possible.”⁹⁷

He also revealed the embryonic state of the specialty of gynecology in 1900 when he addressed his volume to family physicians. “In the present volume it has been my aim to give the family physician a clear idea of the early signs of carcinoma, in order that he may always be on his guard, and may not treat too lightly any suspicious indications which may be present.”⁹⁸ To put Cullen’s statement in context it must be realized that, except in large cities, most gynecologic and obstetric care was in the hands of general practitioners and general surgeons until after World War II. In the first decade of the twentieth century Cullen published additional articles, mostly related to the cause and early diagnosis of cancer.⁹⁹ He began duplicate publication in an effort to impress upon the medical profession the need for early diagnosis.¹⁰⁰

Cullen took an active interest in the etiology of uterine cancer. In 1900, he evaluated both the parasitic theory and the older embryonic inclusion theory of origin of uterine cancer and concluded neither was of value, though he delayed final judgment regarding the parasitic theory for another decade. His evaluation is worth reading as it reveals the depth of his knowledge of the cancer literature.

[Embryonic origin of cancer] “Origin of carcinoma from embryonic inclusion of epithelial elements…This theory, generally attributed to Cohnheim, had previously (as was pointed out by Pianese*) been advanced by Durante in 1874, one year before the appearance of Cohnheim’s publication. According to these two authorities, during foetal life portions of the epithelium become nipped off and included in the connective tissue. In after years these isolated colonies of cells are in some manner stimulated to activity, and give rise to carcinomata. This theory had many advocates, but in recent years it has gradually been abandoned.”¹⁰¹

[Parasitic origin of cancer] “Our work has been essentially along histological lines, the chief aim in view being concerned with the early recognition of carcinoma, in order that the organ involved be may be removed at the earliest possible moment….We have become most interested in the so-called parasitic origin of carcinoma, especially in its relation to cancer of the uterus.”¹⁰² [Cullen concludes] “Neither the theory of Cohnheim [embryonic rests] nor that of Ribbert¹⁰³ explain its origin; and the weight of evidence is against the parasitic theory.”¹⁰⁴

Cullen seemed much more concerned with the cause of cancer than the cause of adenomyomas, and rightly so, because cancer killed while adenomyomas only wounded. Cancer theory provides a window to Cullen’s mental compartmentalization of adenomyomas and cancer. While Cullen was interested in the infectious parasitic theory of the origin of cancer and early on dismissed the embryonic theory of cancer causation, he never believed in an infectious origin for uterine or extrauterine adenomyoma but readily accepted and championed an embryonic theory of origin for extrauterine adenomyomata. From bitter experience early in his career, he considered cancer a lethal invasive disease, pondered its cause, and campaigned for its early diagnosis and treatment. Contrarily, an adenomyoma was a disease of a lesser order of magnitude. After all, cancer had been known since antiquity, but no one in North America even knew uterine adenomyomas existed until he differentiated adenomyomas from the ubiquitous, benign uterine fibroid. Furthermore, the surgical treatment of uterine adenomyoma was straight-forward and successful, unlike the surgical treatment of advanced uterine corpus cancer and cervical cancer.

Compared to his early and bitter experience with cancer, Cullen had a heady initial experience with uterine adenomyoma that brought him instant recognition at Johns Hopkins, led to an exchange with von Recklinghausen, and found expression in his writings in idyllic metaphors from the wilds of the Canadian Bush. Cullen used metaphors – such as flowing and springing from – in his scientific writing, the latter suggestive of mushrooms “springing from” the floor of the virgin forest of his youth, the former reminiscent of the “flowing” waters of the Magnetawan River and Lake Ahmic where he vacationed “many happy summers” with Howard Kelly, Max Broedel, and Simon Flexner.¹⁰⁵

In 1909 Cullen published Myomata of the Uterus with Howard A. Kelly as the first author.¹⁰⁶ At the time, Kelly was Professor of Gynecology in the Johns Hopkins University and Gynecologist-in-Chief to the Johns Hopkins Hospital, Cullen an Associate Professor of Gynecology and Associate Gynecologist.¹⁰⁷Myomata of the Uterus consisted entirely of myomatous material from the Johns Hopkins University and Hospital. Because of the large number of original cases he had examined, Cullen reported only the Hopkins experience and made no effort to review the “vast amount of current literature” on the disease.¹⁰⁸ Recall that Kelly had assigned Cullen to study the pathology of uterine myomas in 1893, during the course of which Cullen recognized that uterine adenomyomas differed from myomas.

Cullen changed publishers in 1909 when he released a minimally updated Cancer of the Uterus.¹⁰⁹ Despite his disclaimer of 1900, Cullen maintained an active interest in the parasitic theory of cancer.¹¹⁰ In the 1909 edition, Cullen cited WT Councilman¹¹¹ and consulted H. Gaylord regarding the parasitic theory of cancer.¹¹² Councilman had trained under Welch at Johns Hopkins and later served as Shattuck Professor of Pathological Anatomy at Harvard Medical School.¹¹³ Harvey Gaylord was the director of the Gratwick Clinic in Buffalo, New York, an institute dedicated to the study and treatment of cancer. Founded by Roswell Park, it was later designated the Roswell Park Cancer Institute. As in 1900, Cullen considered the “weight of evidence against the parasitic theory” and concluded the etiology of cancer remained “an unsettled question.”¹¹⁴

1908 and 1909 were banner years for Cullen. He had published three books and held the rank of associate professor of gynecology at the most prestigious medical school in North America. He felt secure academically.¹¹⁵ The department chairman, Howard Kelly, was busy and happy in his position at Hopkins, though his close friend and associate Osler had departed for Oxford in 1905. Then a revolution in medical education – an insistence on full-time clinical faculty – intervened to disrupt the enormously productive rhythm of the department of gynecology and changed the lives of both men. In the end, Cullen assumed increasing administrative responsibilities, sought outside interests, and ultimately ceased significant gynecological research.

In 1910, 6 years after the American Medical Association founded its Council on Medical Education, Abraham Flexner published a report of his survey of 155 medical schools in the USA, of which “50, or a little less than a third, were integral parts of universities.”¹¹⁶Medical Education in the United States and Canada,¹¹⁷ referred to as the “Flexner report,” was officially Bulletin Number Four prepared for the Carnegie Foundation for the Advancement of Teaching.¹¹⁸

Frederick T. Gates, of the Rockefeller Institute, invited Flexner to lunch and “asked him what he would do with $1,000.000 to be used for medical education.” Flexner replied that “I should give it to Dr. Welch.”¹¹⁹ When Flexner was sent to make a detailed investigation of medical education at Johns Hopkins, Welch took the occasion to invite Flexner to dinner with Franklin Mall and William Halsted. At dinner “Mall argued eloquently that every penny of any new funds that might be obtained should be spent on putting the heads of the clinical departments on full-time [salary].”¹²⁰ This proposal for salaried full-time professors in clinical departments, thought radical in America by most physicians, was strongly supported by the German physiologist, Carl Ludwig, as well as other German full-time clinicians. Mall had studied under Ludwig and accepted his ideas on clinical reform.¹²¹ Welch, who also had studied under Ludwig, fully supported Mall’s position.¹²²

Flexner presented three alternative plans for Johns Hopkins, but favored Plan One: “that the school should be endowed and reduced to 250 students, and the main clinical chairs placed on a university, or full-time, basis.”¹²³Welch’s biographers, Flexner and Flexner, recalled that: “This suggestion, involving as it did full-time, contained dynamite, as everyone saw.”¹²⁴ They continued: “On June 11, 1911, Welch finally reported to Gates that ‘the opinion prevails in our medical faculty and among the trustees of the University’ that the proposition involving full-time, ‘if it can be carried out upon an adequate financial basis, is the one which meets the most urgent needs and promises the largest benefits not to the Johns Hopkins School alone but to medical education in general.’”¹²⁵

According to Howard Kelly’s biographer, Flexner’s assessment of the clinical faculty at Johns Hopkins “had been grossly unfair. The report brought about heated argument and discord ensued.”¹²⁶ Kelly was vehemently opposed to full-time clinical faculty, as was his friend Osler. Osler, then at Oxford, wrote: “Against the sin of prosperity which looms large in Mr. Flexner’s report the clinical professor must battle hard. I was myself believed to be addicted to it. … The truth is there is much misunderstanding in the minds and not a little nonsense on the tongues of the people about the large fortunes made by members of the clinical staff. At any rate, let the University and Hospital always remember with gratitude the work of one ‘prosperous’ surgeon, whose department is so irritatingly misunderstood by Mr. Flexner. I do not believe the history of medicine presents a parallel to the munificence of our colleague Kelly to his clinic. Equal in bulk, in quality and in far-reaching practical value to the work from any department of the University, small wonder that his clinic became the Mecca for surgeons from all parts of the world, and that his laboratory methods, perfected by Drs. Cullen and Hurdon, have become general models, while through the inspiration of Mr. Max Broedel, a new school of artistic illustration in medical works has developed in the United States. And, shades of Marion Sims, Goodell and Gaillard Thomas! this (sic) is the department which the Angel of Bethesda, in the fullness of his ignorance, suggests should be, if not wiped out, at any rate merged with that of Obstetrics!”¹²⁷

The first rumor of Kelly’s impending resignation circulated in 1911.¹²⁸ By 1912, in line with his deep interest in cancer and cancer prevention, Cullen diverted some of his energy from research to patient education on a national scale. In response to his inquiry concerning cancer education for the public, he was invited to present a paper at the Fourth Clinical Congress of Surgeons of North America in November 1912. Elected chairman of a newly formed cancer campaign committee, he initiated cancer education of the public and endorsed the first popular article on cancer written by a layman, Samuel Hopkins Adams.¹²⁹ Adam’s article, entitled “What Can We Do About Cancer” appeared in the May 1913 issue of The Ladies Home Journal.¹³⁰ Many in the medical profession criticized Cullen for endorsing Adam’s article. Nonetheless, he persevered in his crusade because he had seen that many patients at Johns Hopkins were diagnosed too late for surgery to cure their disease.¹³¹ Cullen believed firmly that education of the public would lead to early diagnosis and successful surgical treatment.¹³² Cullen launched the crusade for early cancer detection and treatment, a crusade that would catch the imagination of the nation and result in ever expansive private and public funding for cancer research that ultimately resulted in the founding of the American Cancer Society.¹³³ He related the story of “How cancer education of the public got started” in a letter to Dr. Joseph Bloodgood published many years later in the Bulletin of the American College of Surgeons.¹³⁴ The diagnosis and treatment of the benign invasive diseases, adenomyosis and endometriosis, did not share the public spotlight now shining on the malignant invasive disease, cancer.

Cancer education was the first among many extracurricular activities that would distract Cullen from his hitherto total immersion in academic work. In 1913 Johns Hopkins University decided to phase in the full-time plan but left Kelly, Cullen and the Department of Gynecology outside the new arrangement for the time being.¹³⁵ Howard A. Kelly, the consummate academic entrepreneur and problem solver, an applied scientist who financed his research and his department with relatively token compensation from Johns Hopkins, was not cut out to be a Flexnerian full-time academic. Another rumor of Kelly’s impending resignation surfaced in 1916. He went on indefinite leave early in 1917 and officially tendered his resignation as professor and chairman of the Department of Gynecology at Johns Hopkins on February 12, 1919. Kelly reentered private practice to continue clinical research that he had begun in 1904 into the therapeutic uses of radium for benign and malignant gynecologic diseases.¹³⁶ With reluctance, The Board of Trustees accepted Kelly’s resignation “to take effect at the end of the present school year.”¹³⁷Kelly recommended Cullen as his successor to “head of the Department of Gynecology with the title of Professor of Clinical Gynecology.”¹³⁸

Despite all that had transpired, Cullen accepted the full-time position at Johns Hopkins. Long before, in 1896, he had declined the invitation from Vanderbilt University to the chair of pathology and in 1900 he had declined the invitation from Yale to the chair of gynecology with the rank of full professor.¹³⁹ As early as 1915, Cullen had adopted Kelly’s position that gynecology and abdominal surgery belonged together in one department.¹⁴⁰ When Kelly took an indefinite leave of absence in 1917, Cullen became acting Gynecologist-in-Chief, and declined the invitation to the chair of gynecology at Jefferson Medical College in Philadelphia.¹⁴¹ With Kelly’s formal resignation in 1919, Cullen became head of the division of gynecology within the Department of Surgery.¹⁴² But the tensions from years of controversy regarding full-time clinical faculty and the uncertain fate of the Department of Gynecology combined to take a toll on Cullen. His research output diminished as he took on many outside interests.¹⁴³ Before he retired as professor of gynecology in 1939, the Flexnerian reforms had brought forth the modern medical schools and teaching hospitals in the USA, although not all with full-time clinical faculty as at Johns Hopkins.¹⁴⁴ The “[Flexnerian] revolution called for medical schools to be university-based, for faculty to be engaged in original research, and for students to participate in ‘active’ learning through laboratory study and real clinical work.”¹⁴⁵

Looking back, Cullen the pathologist-surgeon proved a steady and reliable academic colleague for Kelly the quintessential clinician-surgeon.¹⁴⁶ Kelly had a genius for recognizing young physicians with the requisite talents to accomplish the objectives he envisioned. Following Cullen’s suggestion, Kelly made pathology a foundational experience of his 5-year residency program of clinical and surgical training and research in gynecology.¹⁴⁷Ambidextrous, Kelly operated with lightening speed, dexterity, and confidence. Cullen, by his own admission, operated step by step, in a deliberate teaching mode reminiscent of an organ recital in the pathology laboratory. At the completion of each step of the operation, Cullen would ask the resident “Satisfied?”¹⁴⁸ Ever loyal and steadfast, and sharing the humanitarian spirit of Kelly, Cullen was perhaps the ideal associate professor. They complemented each other. Each respected the other’s talents. Not without a touch of irony, Kelly may be viewed as a quintessential clinical professor and Cullen an early exemplar of a full-time professor of gynecology. In retrospect, Charles Noble and Hunter Robb, former assistants of Kelly, were too much like Kelly to have filled the niche that Cullen fashioned for himself. The very talents and mindset that made Osler and Kelly so valuable in founding the clinical departments of medicine and gynecology at Johns Hopkins were the least appreciated by Abraham Flexner, the medical educational reformer. Cullen – not Kelly or Osler – more nearly fitted the new academic model and it was Cullen who stayed on to maintain the teaching and research tradition at Johns Hopkins.

***

The reader will find Chaps. 6 and 7 to be ahistorical in the sense that they represent pure analysis and synthesis of Cullen’s scientific thought and medical practice during the last years of his scientifically productive career, though far from the end of his long academic career at Johns Hopkins. Set within an international historical context of emergent surgical pathology and more aggressive surgical treatment of deep pelvic adenomyomas, Chap. 6presents the tortuous history that led to the recognition, surgical management, serious complications of surgery, and efforts to understand the pathogenesis and natural history of adenomyomas (deeply invasive endometriosis) of the rectovaginal septum by constructing meaningful classifications of the disease.

Cullen addressed the problem of uterine mucosa in the ovary late in his investigative career; 70 years after its discovery by Rokitansky, and nearly 15 years after Ludwig Pick confirmed Rokitansky’s discovery. It took the unique case of DeWitt Casler to spark investigation into the differential diagnosis of the myriad causes of chocolate cysts of the ovary, and the recognition by John Sampson that ovarian endometriomas could be distinguished from other chocolate cysts of the ovary, by careful histologic examination of surgical specimens. Casler’s unique case, which will be described in full, finally brought Cullen out of his 25-year descriptive pathology mode of analysis of surgical specimens to rethink his classification of extrauterine adenomyomas in terms of misplaced uterine mucosa. This mental readjustment prepared Cullen to accept Sampson’s theory of pathogenesis of implantation endometriosis.

Chapter 7 is set in the aftermath of World War I, when Cullen lamented the sad and debilitated state of his German colleagues and the downgrading of the independent status of the Department of Gynecology to a division in the Department of Surgery. It analyzes Cullen’s last major synthesis of his research into uterine and extrauterine adenomyomas and his fascination with pathogenesis. It recounts the state-of-the-art surgical management of deeply invasive extrauterine adenomyomas at Johns Hopkins Hospital at the end of the second decade of the twentieth century and Cullen’s personal struggle to manage adenomyomas of the bowel. By this time, Cullen’s work had stimulated improved patient care and clinical research at several universities and at the Mayo Clinic. No longer would Cullen and Johns Hopkins be the epicenter of endometriosis research; soon the torch would pass to John Sampson and the Albany Medical College.

Footnotes

Cullen, TS. Adeno-myoma of the round ligament. Bulletin Johns Hopkins Hospital 1896;7:112–114:114. See also: Thomas Stephen Cullen, Adenomyoma of the Uterus [Philadelphia: WB Saunders, 1908], 253.

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.” Thomas Stephen Cullen, Cancer of the Uterus: Its Pathology, Symptomatology, Diagnosis, and Treatment. Also the Pathology of Diseases of the Endometrium [New York: D. Appleton and Company, 1900].

Russell, Cullen’s senior at Johns Hopkins, was the same William Wood Russell who reclaimed the residency position promised to Cullen in 1894. He was a resident under Howard Kelly and later became an associate professor of gynecology at Johns Hopkins.

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

Russell, William Wood. 1899; 10:8–10:8. Plates I, II, and III are appended to the article.

Russell, William Wood. 1899; 10:8–10.

Russell, William Wood. 1899; 10:8–10:8.

Russell, William Wood, 1899; 10:8–10;9.

Russell, William Wood. 1899; 10:8–10:9–10. “In the specimen which I have described there is a collection of glands in a groove on the surface of the ovary. The epithelium covering them is continuous with a single layer of columnar cells at the margin of the groove and extends a short distance over the surrounding surface. Thus we have direct proof that the germinal epithelium is capable of producing glands analogous to those of the uterine mucosa.”

Wolffian or mesonephric 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. 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 that has become displaced and lies embedded in tissue of another character that persists as an embryonic remnant in the adult. Müllerian duct, also known as the paramesonephric duct, arises from the urogenital ridge in the fetus to form the fallopian tubes, uterus, cervix and upper vagina. Germinal epithelium of the ovary consists of low flat mesothelial cells on the surface of the ovary, similar to those lining the peritoneal cavity. Mesothelial cells are derived from the mesoderm which gives rise to the gastrointestinal and reproductive organs. Metaplasia is the abnormal transformation of an adult, fully differentiated tissue of one kind into a differentiated tissue of another kind; metaplasia is an acquired condition in contrast to heteroplasia. Coelomic metaplasia is a general term that refers to the abnormal transformation of adult, fully differentiated tissue lining the peritoneal cavity into a differentiated tissue of another kind, such as endometrial tissue. Serosal metaplasia is a more restricted term that refers to the abnormal transformation of adult, fully differentiated tissue covering the surface of pelvic and abdominal organs – such as the uterus – into a differentiated tissue of another kind, such as endometrial tissue. Heteroplasia, on the other hand, is the development of cytologic and histologic elements that are not normal for the organ or part in question, as the growth of bone in a site where there is normal fibrous connective tissue. Heterotopiameans cells or tissue displaced to an abnormal location.

Howard Kelly did not credit von Franque whom WW Russell had cited as reference #11. Russell, William Wood. Aberrant portions of the müllerian duct found in an ovary. Johns Hopkins Hospital Bulletin 1899; 10:8–10:10. “…von Franque has published the preliminary report of an ovary which apparently confirms the Wolffian theory. His remarks are so brief that one is not justified in criticism, but it would seem that he has in his case positive evidence that the parovarial tubules can, as we have already suggested, enter the ovary through the hilum and produce these glandular formations.” Ref. No. 11: Von Franque. Uber Urnierenreste im Ovarium, etc. Sitzungs-Berichte der physikalich-medicinischen Gesellschaft zu Würzburg, July 7, 1898.

Benagiano G, Brosens I. History of adenomyosis. Best Pract Res Clin Obstet Gynecol 2006;20:449–63:450–1.

Hughesdon PE. The structure of the endometrial cyst of the ovary. J Obstet Gynaecol Brit Emp 1957;44:481–487.

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

Sampson JA. Heterotopic or misplaced endometrial tissue. Am J Obstet Gynecol 1925;10:649–664.

Choristoma. In Stedman’s Medical Dictionary. 28^th ed. [Philadelphia: Lippincott Williams & Wilkins, 2006], 371. A choristoma is a mass of histologically normal tissue that is “not normally found in the organ or structure in which it is located.” Müllerian choristomas are a subset of non-müllerian choristomas found throughout the body.

Ronald E. Batt, Smith RA, Buck Louis GM, Martin DC, Chapron C, Koninckx PR, Yeh J. Müllerianosis. Histol Histopathol 2007;22:1161–1166.

Editorial. Adenomyomata of the female sexual apparatus. Journal American Medical Association 1899;33:863–4.

Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 327. “The Hopkins idea is to publish and to publish adequately; to do so thorough a job when you undertake to deal with a subject that it won’t be worth anyone’s time to touch it again for twenty or thirty years.”

Judith Robinson, Tom Cullen, 159.

Thomas Stephen Cullen, Cancer of the Uterus: Its Pathology, Symptomatology, Diagnosis, and Treatment. Also the Pathology of Diseases of the Endometrium [New York: D. Appleton and Company, 1900], 535–536.

Judith Robinson, Tom Cullen, 159.

Judith Robinson, Tom Cullen, 139.

Martzloff, KH. Thomas Stephen Cullen [Presidential Address]. Am J Obstet Gynecol 1960;80:833–843:837.

Johnston, George B. Osteo-Fibromyoma of the Uterus. Am Gynaec & Obst. J., N.Y., 1901, XVIII, 307–308. William Henry Welch, Pathology, Preventive Medicine, vol. 1 of Papers and Addresses by William Henry Welch [Baltimore, MD: Johns Hopkins Press, 1920], 432–3.

Baldy JM and Longscope WT. Adenomyomata Uteri. Am J Obstetrics and Diseases of Women and Children 1902;xlv:788–802.

Iwanoff NS. Drusiges cystenhaltiges Uterusfibromyom compliciert durch Sarcom und Carcinom. Monatsschr. Geburtsh u. Gynak. 1898;7:295. See: Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment [London: Macmillan and Company, 1918], 297. Iwanoff postulated that an adenomyoma complicated with carcinoma and sarcoma originated from the uterine serosa. See also: 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:539–57:540. Iwanoff’s theory would later gained support of Pick Aschoff, Robert Meyer, Emil Novak, and many others.

Editorial. Adenomyomata of the female sexual apparatus. Journal American Medical Association 1899;33:863–4.

Thomas Stephen Cullen, Adenomyoma of the Uterus [Philadelphia: WB Saunders, 1908], 2. Fn. No. 2.

Thomas S. Cullen. Adeno-Myome des Uterus. [Berlin: Verlag von August Hirsch, 1903].

Cuthbert Lockyer, Fibroids and Allied Tumours, 289.

The author has a hard bound copy from the Library of Dr. John B. Murphy of Chicago, thanks to Dr. Ronald Cyr.

J. Whitridge Williams. Decidual formation through the uterine muscularis: a contribution to the origin of adenomyoma of the uterus. Transactions of the Southern Surgical Association 1904;17:119.

Thomas Stephen Cullen, Adenomyoma of the Uterus [Philadelphia: WB Saunders, 1908], 197.

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: 17. The theatre metaphor has been used in referring to the Paris surgeon Philippe-Joseph Pelletan. Ibid: 22. “Reviewing Paris Medicine from the vantage point of forty years, Bowditch articulated several themes:…Andral, Chomel, and Louis, and the theatrical nature of Paris Medicine; each leading physician had his theatre in which he regularly performed: Andral at the Faculty of Medicine, Chomel at the Charite hospital, and Louis at the Pitie Hospital.”

Judith Robinson, Tom Cullen, 127.

Judith Robinson, Tom Cullen, 127. Nearly 30 years later, Cullen recalled this meeting as “one of the most comical experiences of my life.”

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.

Roger Chartier, “Texts, Printing, Readings,” in The New Cultural History, ed. Lynn Hunt [Berkeley, CA: University of California Press, 1989],154–175: 166–67. “The final remarks of Rojas in the prologue of the Celestina concern the very genre of the text: ‘Others have made quite a to-do about the name of the play, saying it was not a comedy but a tragedy, since it ended so sadly. The first author wished to give it a description that would reflect what happens in the beginning, and so he called it a comedy. I have found myself in a dilemma, and I have cut the Gordian knot by calling the play a tragicomedy.’”

Roger Chartier, “Texts, Printing, Readings,” in The New Cultural History, ed. Lynn Hunt [Berkeley, CA: University of California Press, 1989], 154–175: 154. The question was not simple because each was reading a different text, seeing a difference act, attending a different performance. Most plays do not enjoy a twelve year run.

Judith Robinson, Tom Cullen, 127. Nearly thirty years later, Cullen recalled this meeting as “one of the most comical experiences of my life.”

Editorial. Friedrich von Recklinghausen (1833–1910). German Pathologist. JAMA 1968 Aug 26;205(9):640–1.

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

Chiari H. Friedrich Daniel v. Recklinghausen. Vehr Deutsch Path Ges 1912;15:478–488.

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

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.]

Thomas Stephen Cullen, Adenomyoma of the Uterus, 1.

Thomas Stephen Cullen, Adenomyoma of the Uterus, v–vi.

Robert Meyer, Autobiography, 33.

Cuthbert Lockyer, Fibroids and Allied Tumours, 266–271.

Thomas Stephen Cullen, Adenomyoma of the Uterus [Philadelphia: WB Saunders, 1908], 1–2. On page 2, footnote No. 1, Cullen wrote: “I wish to express my deep sense of obligation to Professor v. Recklinghausen for his kindness in examining sections from several of the cases and for his valuable criticism of the same.”

The author’s italic to emphasize the formal address.

Thomas Stephen Cullen, Adenomyoma of the Uterus, 2, FN. No. 1. The original quotation was in parentheses: “(I wish to express my deep sense of obligation to Professor v. Recklinghausen for his kindness in examining sections from several of the cases and for his valuable criticism of the same.)”

Cullen, TS. Adeno-myoma uteri diffusum benignum. Bulletin Johns Hopkins Hospital 1896;6:133–157. Cullen, TS. Adeno-myoma of the round ligament. Bulletin Johns Hopkins Hospital 1896;7:112–114. Thomas S. Cullen. Adeno-Myoma des Uterus. [Berlin: Verlag von August Hirsch, 1903].

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

Judith Robinson, Tom Cullen, 127. As mention before, there are so many direct quotations from interviews, that Tom Cullen of Baltimore is more than a biography; in many places it is autobiographical.

Thomas Stephen Cullen (1868–1953) was 38 years old and an associate professor when he visited von Recklinghausen. Coincidently, the author spent his 38th birthday in Austria in 1971 on a six week mini-sabbatical to study pelvic surgery. He witnessed the austere formality and presence of Professor Hüsslein, Vorstand (chairman) of the Department of Obstetrics and Gynecology, Second Frauenklinik, University of Vienna.

Judith Robinson, Tom Cullen, 127. Thirty years later, Cullen would tell his biographer that this decade of correspondence with the famous von Recklinghausen of Strasbourg, “the survivor of the age of giants [had been for him] a decade of maturing experience.”

Donald Fleming, William H. Welch and the Rise of Modern Medicine [Boston, MA: Little Brown and Company, 1954], 37. “The sense that with advanced students only the lightest kind of supervision could be tolerated went very deep in the greater German scientists and characterized most if not all of the men who succeeded in arousing creativity in others.”

Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment [London: Macmillan and Company, 1918]. Lockyer’s monograph is an invaluable reference resource for professional and clinician historians. He was an authority of the subject, knew the contemporary principals involved, and analyzed the literature at hand in England during World War I. Ironically, Lockyer did not cite Rokitansky either. It was left to Cullen’s English friend and colleague, Cuthbert Lockyer, to publish the first major review of uterine and extrauterine adenomyomas.

Thomas Stephen Cullen, Adenomyoma of the Uterus [Philadelphia: WB Saunders, 1908], 187. Cuthbert Lockyer, Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment [London: Macmillan and Company, 1918], 423–4. However, as Lockyer pointed out, three of von Recklinghausen’s cases were malignant.

Von Franque O. Salpingitis nodosa isthmica und Adenomyoma Tubae. Centralbl. F. Gynaek., 1900, Bd. xxv, S. 660.

Meyer R. Ztschr. f. Geburtshülfe und Gynaekologie, Bd. xlii, H. 1.

Gottschalk. Demonstration zur Enstehung der Adenome des Tubenisthmus. Ztschr. F. Geburtshülfe und Gynaekologie, 1900, Bd. xlii, S. 616.

Lockstaedt P. Ueber Vorkommen und Bedeutung von Drusenschlauchen in Myomen des Uterus. Monatsschr. f. Geb. u. Gyn., 1898, Bd. vii, S. 188.

Thomas Stephen Cullen, Adenomyoma of the Uterus [Philadelphia: WB Saunders, 1908], 236.

Thomas Stephen Cullen, Adenomyoma of the Uterus, 193.

Thomas Stephen Cullen, Adenomyoma of the Uterus, 2. Cullen qualified his use of the word relatively: “I use the word ‘relatively’ because if operative interference be long delayed some of the discrete myomata so frequently found may assume large proportions and almost completely overshadow the adenomyoma, while at the same time greatly altering the contour of the uterus.”

Thomas Stephen Cullen, Adenomyoma of the Uterus, 125. When the adenomyomatous growth extends from the endometrium to the outer surface of the upper half of the uterus it will tend to form a subperitoneal adenomyoma.

Thomas Stephen Cullen, Adenomyoma of the Uterus, 125. When the adenomyomatous growth extends from the endometrium to the outer surface of the lower half of the uterus it will tend to “spread out between the fold of the broad ligament” and form an intraligamentary adenomyoma.

When the adenomyomatous growth extends from the endometrium into the uterine cavity it will form a submucous adenomyoma.

Erna Lesky, The Vienna Medical School of the 19^thCentury [Baltimore, MD: Johns Hopkins University Press, 1976], 106. “Starting with the year…1836, the Medical Yearbooks of the Imperial Royal Austrian State carried ‘essays which in their form, tendencies and contents differed strikingly not only from the majority of other articles contained in the same publications, but also from almost all the other usually published in Germany’…They were permeated by a ‘particular, logical spirit,’ using ‘impressive, original language.’ They were Treatises by Carl Rokitansky (1804–1878).” Among the treatises was the 1838 publication Uber die sogenannten Verdoppelungen des Uterus (On the So-Called Duplications of the Uterus.)

Thomas Stephen Cullen, Adenomyoma of the Uterus [Philadelphia: WB Saunders, 1908], 127, 157, 197.

Thomas Stephen Cullen, Adenomyoma of the Uterus, 197. Cullen believed “beyond doubt” that the lining of this communicating intraligamentary cystic adenomyoma derived from the uterine mucosa.

Carl Breus, ueber wahre epithelführende Cystenbildung in Uterusmyomen. Leipzig und Wien: Franz Deuticke, 1894. See also Thomas Stephen Cullen, Adenomyoma of the Uterus, 147–8, 197.

Thomas Stephen Cullen, Adenomyoma of the Uterus, 196.

Thomas Stephen Cullen, Adenomyoma of the Uterus, 3. See also page 126. Some miniature uterine cavities were filled with “chocolate-colored contents,” old menstrual blood.

Thomas Stephen Cullen, Adenomyoma of the Uterus, v.

Judith Robinson, Tom Cullen, 169. This is beautiful country for vacationing; the author has fished, canoed, and camped in this region often as it lies within easy driving distance from Buffalo, New York.

Cuthbert Lockyer, Fibroids and Allied Tumours, 302.

Howard A. Kelly and Thomas S. Cullen, Myomata of the Uterus [Philadelphia: WB Saunders, 1909].

Benagiano G and Brosens I. History of adenomyosis. Best Practice & Research Clinical Obstetrics and Gynaecology 2006;20:449–463:451. “Three points in this description are worthy of mention: first, a clear identification of the epithelial tissue as ‘uterine mucosa’; second, an equally clear definition of the mechanism through which the mucosa invades the underlying tissue (through the presence in the myometrium of chinks or fissures); third, the existence of a sort of prerequisite for the formation of what we call adenomyosis, namely a ‘myomatous’ thickening of the uterine muscle. Also noticeable is the claim that ‘sometimes its direct connection with the mucosa of the uterine cavity can be traced’.”

Thomas Stephen Cullen, Adenomyoma of the Uterus [Philadelphia: WB Saunders, 1908], 261.

Thomas Stephen Cullen, Adenomyoma of the Uterus, 261.

Thomas Stephen Cullen, Cancer of the Uterus: Its Pathology, Symptomatology, Diagnosis, and Treatment, also The Pathology of Diseases of the Endometrium [New York: Appleton, 1900].

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

Howard A. Kelly and Thomas S. Cullen, Myomata of the Uterus [Philadelphia: WB Saunders, 1909].

Thomas Stephen Cullen, Cancer of the Uterus: Its Pathology, Symptomatology, Diagnosis, and Treatment, also The Pathology of Diseases of the Endometrium [Philadelphia: WB Saunders, 1909]. In the 1900 and 1909 editions of Cancer of the Uterus, Cullen acknowledged his intellectual debt to von Rokitansky and von Recklinghausen and the other Austrian and German scholars for their contributions to the study of adenomyomas of the uterus.

Young RH. The rich history of gynaecological pathology: brief notes on some of its personalities and their contributions. Pathology 2007;39:6–25. Young RH. Dusting off old books: comments on classic gynecologic pathology books of yesteryear. Int J Gynecol Pathol2000;19:67–84. Young RH. History of gynecological pathology. I. Dr. Thomas S. Cullen. Int J Gynecol Pathol 1996;15:181–6.

Brosens I. Endometriosis rediscovered? Hum Reprod 2004;19:1679–80. See also: Benagiano G and Brosens I. History of adenomyosis. Best Practice & Research Clinical Obstetrics and Gynaecology 2006;20:449–463.

Cullen TS. The early diagnosis of carcinoma of the uterus. Memphis Lancet 1898; December.

Thomas Stephen Cullen, Cancer of the Uterus: Its Pathology, Symptomatology, Diagnosis, and Treatment [New York: Appleton, 1900]. Cullen intended this remarkable work with three hundred and ten illustrations to be a definitive treatise on the subject, as he did all his books. He did not want to write textbooks that required periodic updating.

Cullen TS. A rare variety of adeno-carcinoma of the uterus. John Hopkins Hospital Reports 1900 IX:401. Cullen TS. The cause of cancer. American Medicine 1901;1:298. Cullen TS. The early diagnosis of cancer of the uterus: operative technic. International Clinics 1909; 4 (19th series): 193. Cullen TS. The early diagnosis of cancer of the uterus: operative technic. Pennsylvania Medical Journal 1909–10; vol. 13:110.

100

Later in the twentieth century, editors frowned on duplicate publication as a tactic of padding the number of publications in curriculum vitae. However, Cullen’s motives were honest: to educate physicians to listen to patients who complained of vaginal bleeding and to make every effort to diagnosis cancer of the uterus early when it was curable by surgery.

101

Cullen, Thomas Stephen. Cancer of the Uterus: Its Pathology, Symptomatology, Diagnosis, and Treatment. Also the Pathology of Diseases of the Endometrium. New York: D. Appleton and Company, 1900:652. *Pianese C. Beitrag zur Histologie und Aetiologie des Carcinomas. Ziegler’s Beitrage (Supplementheft), Jena, 1896.

102

103

Cullen, Thomas Stephen. Cancer of the Uterus, 1900:653–654. “According to this author [Ribbert], then, the connective-tissue cells increase to such an extent that they invade the epithelial layer and nip off epithelial cells or groups of cells; this isolated epithelium at a later period is capable of producing carcinoma.” See also: Lockyer, Cuthbert. Fibroids and Allied Tumours (Myoma and Adenomyoma): Their Pathology, Clinical Features and Surgical Treatment. London: Macmillan and Co., 1918:1. “Cohnheim’s theory of embryonic ‘rests’ has been applied to myoma, and corresponds with the view of Ribbert.”

104

Cullen, Thomas Stephen. Cancer of the Uterus, 1900:657. Roswell Park had secured a grant from the New York State Legislature to investigate the parasitic theory of endometriosis. Cullen was in personal communication with Harvey Gaylord, who with Pease “have for several years been carrying on extensive investigations as to the origin of cancer, and have brought forward some very suggestive data in support of the parasitic theory.” Gaylord became the Director of the Gratwick Clinic in Buffalo, New York, now the Roswell Park Cancer Institute.

105

Te Linde RW. In Memoriam: Thomas Stephen Cullen, 1868–1953. Transactions American Gynecological Society 1953;76:227–229.

106

Howard A. Kelly and Thomas S. Cullen, Myomata of the Uterus [Philadelphia: WB Saunders Company, 1909].

107

Howard A. Kelly and Thomas S. Cullen. Myomata of the Uterus, 1909:title page.

108

Kelly, Howard A. and Thomas S. Cullen. Myomata of the Uterus, 1909:v. This volume was meant to be definitive.

109

Thomas Stephen Cullen, Cancer of the Uterus: Its Pathology, Symptomatology, Diagnosis, and Treatment; also The Pathology of Diseases of the Endometrium [Philadelphia: W. B. Saunders, 1909].

110

Cullen, Thomas Stephen. Cancer of the Uterus, 1909:657.

111

Cullen, Thomas Stephen. Cancer of the Uterus, 1909:657.

112

Cullen and Gaylord, personal communication.

113

Young RH. Dr. Thomas S. Cullen. International Journal Gynecological Pathology 1996;15:181–186:181.

114

Cullen, Thomas Stephen. Cancer of the Uterus, 1909:657.

115

Kelly, Howard A. and Thomas S. Cullen. Myomata of the Uterus. Philadelphia: WB Saunders Company, 1909:title page. In 1909, Howard A. Kelly was the Professor of Gynecology in the Johns Hopkins University and Gynecologist-in-Chief to the Johns Hopkins Hospital. Thomas S. Cullen was an Associate Professor of Gynecology in Johns Hopkins University and Associate Gynecologist to the Johns Hopkins Hospital. Young RH. Dr. Thomas S. Cullen. International Journal Gynecological Pathology 1996;15:181–186:182. Cullen was advanced from associate in gynecology to associate professor of gynecology in 1900 following the publication of his monograph Cancer of the Uterus and the offer from Yale University of the chair of the department of gynecology. See also: Judith Robinson, Tom Cullen of Baltimore[London, Toronto, New York: Oxford University Press, 1949], 160.

116

Simon Flexner and James Thomas Flexner, William Henry Welch and the Heroic Age of American Medicine [Baltimore, MD: Johns Hopkins University Press, 1993], 307.

117

Abraham Flexner, Medical Education in the United States and Canada [New York: Carnegie Foundation for the Advancement of Teaching, 1910]. Kenneth M. Ludmerer, Time to Heal: American Medical Education from the Turn of the Century to the Era of Managed Care[Oxford: Oxford University Press, 1999], 79. “Abraham Flexner’s 1910 report did not even mention internship or other hospital training for medical graduates, reflecting the prevailing orthodoxy that the four years of medical school provided sufficient preparation for general practice.”

118

Judith Robinson, Tom Cullen, 229.

119

Simon Flexner and James Thomas Flexner, William Henry Welch, 308.

120

Simon Flexner and James Thomas Flexner, William Henry Welch, 308.

121

Simon Flexner and James Thomas Flexner, William Henry Welch and the Heroic Age of American Medicine [Baltimore, MD: Johns Hopkins University Press, 1993], 300. Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 228.

122

Simon Flexner and James Thomas Flexner, William Henry Welch, 141–2.

123

Simon Flexner and James Thomas Flexner, William Henry Welch, 308.

124

Simon Flexner and James Thomas Flexner, William Henry Welch, 309.

125

Simon Flexner and James Thomas Flexner, William Henry Welch, 309.

126

Audrey W. Davis. Dr. Kelly of Hopkins: Surgeon, Scientist, Christian [Baltimore, MD: Johns Hopkins Press, 1959], 99.

127

Osler quoted in Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 232.

128

Audrey W. Davis. Dr. Kelly of Hopkins: Surgeon, Scientist, Christian [Baltimore, MD: Johns Hopkins Press, 1959], 101.

129

Young RH. Dr. Thomas S. Cullen. International Journal Gynecological Pathology 1996;15:181–186:184.

130

Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 241, 248.

131

Judith Robinson, Tom Cullen 243.

132

Cullen TS. Report of cancer campaign committee. Surg Gynecol Obstet 1913; November.

133

Cullen, Thomas S. How cancer education of the public got started. Bull Am Coll Surg 1963;48:87.

134

Cullen TS. How cancer education of the public got started. Bull Am Coll Surg 1963;48:87.

135

Audrey W. Davis. Dr. Kelly of Hopkins: Surgeon, Scientist, Christian [Baltimore, MD: Johns Hopkins Press, 1959], 100.

136

Audrey W. Davis. Dr. Kelly of Hopkins, 102–103, 127. From the dust jacket, we learn that Audrey Davis was a close friend and editor of his published works for over twenty years. “Before his death, Dr. Kelly asked Miss Davis to write his biography and left her the wealth of material used to write this story.” Judith Robinson, Tom Cullen, 279.

137

Audrey W. Davis. Dr. Kelly of Hopkins: Surgeon, Scientist, Christian [Baltimore, MD: Johns Hopkins Press, 1959], 104.

138

Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 295. Thomas S. Cullen. The Distribution of Adenomyomas Containing Uterine Mucosa. Chicago, IL: American Medical Association Press, 1920, title page. In 1920, Cullen was officially a “Professor of Clinical Gynecology in the Johns Hopkins University and Visiting Gynecologist to the Johns Hopkins Hospital.” Audrey W. Davis. Dr. Kelly of Hopkins: Surgeon, Scientist, Christian [Baltimore, MD: Johns Hopkins Press, 1959], 105. However, Cullen assumed direction of gynecology, not as an independent department, but as a division of general surgery under Halsted.

139

Judith Robinson, Tom Cullen, 133, 159.

140

Judith Robinson, Tom Cullen, 262–264.

141

Judith Robinson, Tom Cullen, 279, 281.

142

Judith Robinson, Tom Cullen, 295.

143

Judith Robinson, Tom Cullen, 312. “President of the Medical and Chirurgical Faculty of Maryland; a director of the transportation company that linked the eastern and western shores of Maryland with Chesapeake Bay ferries; trustee, chosen by the Episcopal bishop of Maryland, of the Hannah More Academy for girls; deacon in the Presbyterian church of his own choice; thirty-third degree mason; writer still – four papers by Thomas S. Cullen were published in American medical journals in 1927, two in 1928, two in 1929 – speaker by special invitation at the 1929 meeting of the British Medical Association in Manchester; elected by the House of Delegates of the American Medical Association to be one of its nine trustees…member of the Maryland State Board of Health and vice-president of Baltimore’s public library system.” Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 313. Nonetheless, Cullen continued teaching full time and his due diligence was rewarded in 1932 with the designation Professor of Gynecology, a position he had filled since 1919.

144

Te Linde RW. In Memoriam: Thomas Stephen Cullen, 1868–1953. Transactions American Gynecological Society 1953;76:227–229. Cullen was promoted from Professor of Clinical Gynecology (1919) to Professor of Gynecology in 1932.

145

Kenneth M. Ludmerer, Time to Heal: American Medical Education from the Turn of the Century to the Era of Managed Care [Oxford: Oxford University Press, 1999], xxii.

146

Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 316. “It was in the laboratory that the men in the gynecological service came to know their chief best.”

147

Judith Robinson, Tom Cullen, 315. Cullen designed the five-year residency program for Kelly.

148

Judith Robinson, Tom Cullen, 409.

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