Distribution of Pelvic and Abdominal Adenomyomas

A History of Endometriosis

7. Distribution of Pelvic and Abdominal Adenomyomas

Ronald E. Batt¹

(1)

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

Abstract

By 1920, Cullen accepted three models for the pathogenesis of extrauterine adenomyomas: (1) from embryonic müllerian rests, (2) “springing from” the posterior wall of the cervix or body of the uterus and invading the rectum, and (3) from overflow of uterine mucosa – shed from an adenomyoma of the rectovaginal septum onto tube and ovary – the same flowing metaphor that he used to explain the pathogenesis of diffuse uterine adenomyomas. Cullen came tantalizingly close to – and yet so far from – Sampson’s later observations when he wrote: “One gathers the impression that the uterine mucosa from the diffuse adenomyoma on the posterior surface of the cervix and uterus has overflowed upon the adherent tube [and ovary].”¹ Cullen had the implantation pathogenesis in reverse.

The Distribution of Adenomyomas Containing Uterine Mucosa

In 1920, Cullen published a major review of uterine and extrauterine adenomyomas containing misplaced uterine mucosa.² This 69 page scientific article represented the apotheosis of Cullen’s research on all phenotypes of adenomyomata. In a comprehensive review of his experience with extrauterine adenomyomata, Cullen emphasized adenomyoma of the rectovaginal septum and included a cursory summary of adenomyomas of the uterus.³ The article contains the definitive illustration by Max Broedel of a sagittal section of abdomen and pelvis, showing all ten anatomic locations where Cullen had personally observed misplaced uterine mucosa.⁴ Whereas in 1919 Cullen had enumerated seven sites,⁵ only 1 year later he listed ten locations in which he had “found uterine mucosa” within the pelvis and abdomen.⁶ Cullen’s classification appears to be an expansion of Lockyer’s 1918 classification by organ.⁷

Figure 1 – The various points at which I have found uterine mucosa:⁸

Adenomyoma of the body of the uterus⁹

Adenomyoma of the rectovaginal septum¹⁰

Adenomyoma of the uterine horn, or of the fallopian tube¹¹

Adenomyoma of the round ligament

Uterine mucosa in [the hilum of] the ovary¹²

Adenomyoma of the utero-ovarian ligament

Adenomyoma of the uterosacral ligament

Adenomyoma of the sigmoid flexure

Adenomyoma of the rectus muscle

10.

Adenomyoma of the umbilicus¹³

By labeling Figure 1 as various sites where he had observed “uterine mucosa,” instead of various sites where he had observed adenomyomata, Cullen gave inordinate emphasis to the ovary, the one location where cystic lesions did not fit neatly into his categorization of solid uterine and extrauterine adenomyomas.¹⁴ Furthermore by so labeling, Cullen identified an outlier – uterine mucosa – as the defining characteristic of both uterine and extrauterine disease. To grasp Cullen’s thinking, one may consider the game of billiards. Cullen racked his solid and striped adenomyomas only to find the odd ovarian ball did not fit, so he devised a larger more inclusive rack, relabeled the billiard balls and found that all ten uterine mucosa balls fitted neatly into the new rack. This proved to be the first tentative break from von Recklinghausen’s “adenomyoma” terminology.

In Cullen’s review of the distribution of adenomyomas containing uterine mucosa, Broedel captured Cullen’s classification in a famous sagittal view of the female pelvis and abdomen that showed all ten anatomical sites where Cullen had personally observed uterine mucosa.¹⁵ Broedel’s illustration, which included a depiction of a large intraluminal adenomyoma of the sigmoid colon, was last reproduced in textbooks in 1958.¹⁶ Uterine mucosa in the hilum of the ovary, in the rectus muscle, and the sigmoid colon was illustrated for the first time.¹⁷,¹⁸

Analysis reveals a glaring discontinuity between Broedel’s illustrations and Cullen’s operative findings and histology recorded in the captions. In the exquisite composite illustration drawn in 1918, Broedel depicted a large spherical polyp with a broad base – originating in the musculature of the wall of the sigmoid colon.¹⁹ Broedel’s broad based spherical polyp projects far into the lumen of the sigmoid colon causing a blockage analogous to a tennis ball obstructing the downspout on a gutter.²⁰ First of all, adenomyomas of the bowel – be they of the sigmoid colon, rectum, ileum, or appendix – originate on the serosa, not from within the musculature of the bowel wall. Second, as adenomyomatous tissue invades from outside inward it puckers and gathers the serosa, distorting and kinking the bowel and causing partial to complete obstruction. This kinking and distortion of the bowel, the “accordion effect,” was observed by Kellogg²¹ and subsequently by all pelvic surgeons treating obstructive endometriotic bowel lesions. In Broedel’s illustration, there is no evidence of Kellogg’s accordion effect, no puckering and gathering of the serosa.²² In Broedel’s illustration, the serosa of the sigmoid colon – in the area where the broad based polyp originates – is completely normal! For emphasis, there is no sign of puckering of the serosa, no accordion effect so well described by Kellogg. In other words, Broedel’s large spherical polyp with a broad base, originating in the musculature of the wall of the sigmoid colon, was not an adenomyoma. If not an adenomyoma, what was it? More than likely the large spherical polyp was a gastrointestinal stromal tumor such as a myoma, leiomyoma, or neurofibroma of the wall of the sigmoid colon.²³

Whereas Broedel illustrated an obstructive intraluminal spherical polyp of the sigmoid colon with normal bowel serosa, at surgery Cullen described a “puckered area [serosa of sigmoid colon] at the pelvic brim.”²⁴Furthermore, “a photomicrograph of a [histologic] section taken from the sigmoid growth” shows no evidence of the large spherical intraluminal tumor depicted by Broedel. On the contrary, the histology shows a normal rectal (sic) mucosa with great thickening of the underlying muscular wall.²⁵ “Scattered throughout the muscular tissue were uterine glands surrounded by the characteristic stroma.”²⁶ In other words, the operative description and the histologic findings indicated typical adenomyoma that had invaded through the serosa into the muscularis of the sigmoid colon.

For years these two illustrations have been accepted as representing an adenomyoma of the sigmoid colon; accepted without question on the authority of Cullen and his premier medical illustrator, Broedel. One can only speculate how this error happened. The explanation may lie in the stressful circumstances at Johns Hopkins Hospital and Medical School in 1918 when Broedel drew this illustration. First of all, following the effective date of Howard Kelly’s resignation as chairman of the Department of Gynecology, Cullen’s status was diminished twice: from the unqualified rank of associate professor to the higher but qualified rank of professor of clinical gynecology, and, when his responsibilities were formalized Cullen was appointed head of the new division of gynecology in Halsted’s Department of Surgery, not chairman of Kelly’s Department of Gynecology. Secondly, Cullen was distracted by extramural obligations such as preparation of a paper on “Cullen sign” for inclusion in a gift volume to celebrate Osler’s 70th birthday.²⁷ Cullen also endured “deepening loneliness” due to the absence of “Popsy” Welch and Cullen’s brother Ernst in military service in World War I and the suffering and death of his wife Emma Beckwith Cullen from a brain tumor in 1918.²⁸ Finally, he found himself unable to comfort his dear friend Broedel, who was “bereft of the Germany he loved.”²⁹ All of these difficulties were compounded by the outbreak of the influenza pandemic of 1918. “All Baltimore, all of the East Coast, was erupting in flames. The virus struck the Hopkins itself so hard that the university closed its hospital to all but its own staff and students. Three Hopkins medical students, three Hopkins nurses, and three Hopkins doctors would die.”³⁰ In short, under such stress Cullen had little time to devote to details of medical illustration, which he left to Broedel.³¹ The normal two-way flow of communications between collaborators was disrupted by events beyond their control. The disconnect between illustration and caption went into print without being detected. Thus the error entered the medical literature in 1920³² and proceeded from there into gynecologic textbooks.³³

Uterus

Though he devoted less than two pages of text to adenomyomas of the body of the uterus, several points are clinically relevant. “The line of demarcation between the normal outer uterine muscle wall and the diffuse myomatous growth just beneath the mucosa is invariably sharply defined, but the two are nevertheless so closely blended that it would be absolutely impossible to separate them.”³⁴ Gynecologic surgeons experienced in performing conservative uterine and pelvic surgery will immediately recognize why they must “cut out” adenomyomas which do not have a capsule while they can “shell out” fibroids because they do have a capsule. Cullen went on to say that “the histologic picture in a typical case [of diffuse uterine adenomyoma – adenomyosis] is very characteristic: the uterine mucosa is often of normal thickness and looks perfectly natural, but as we approach the underlying diffuse myomatous tissue, the mucosa is seen to penetrate it in all directions.”³⁵ And perhaps with a final unreferenced nod to Rokitansky, Cullen wrote: “In the course of time, portions of the diffuse adenomyoma may project into the uterine cavity and be expelled through the cervix as submucous adenomyomas.”³⁶ He also expressed his opinion of the pathophysiology of uterine hemorrhage and uterine crampy pain associated with diffuse uterine adenomyomata. With onset of menstruation, “the patient will not only lose her normal quota of blood, but this will be greatly increased by the flow coming from the large areas of mucosa which are scattered throughout the diffuse myomatous growth….There will, as a rule, be a great deal of pain in the uterus at the period due primarily to the swelling of the mucosa which is scattered throughout the uterine walls.”³⁷

The most “widespread” and extensive adenomyoma of the uterus that Cullen ever saw was located in the right horn of a bicornuate uterus, an anomalous uterus.³⁸ “Islands of normal-appearing uterine mucosa are seen scattered everywhere throughout the diffusely thickened uterine walls, and the glands extend right up to the peritoneal surface.”³⁹ In the same anomalous specimen, Cullen described a 1 cm adenomyoma of the left tube located 2 cm “beyond the [left] uterine horn,” an “adenomyoma of the uterine type.”⁴⁰ This particular lesion was unique in his experience and is worth describing in some detail. “Even with low power it is noted that it is almost solid… Its center is occupied by diffuse myomatous tissue, and scattered everywhere throughout this are glands which resemble in every particular uterine glands. The majority of these lie in direct contact with the muscle, but here and there are several glands embedded in the characteristic stroma of the uterine mucosa. Some of the glands are dilated and at one or two points we can see miniature uterine cavities. We have in this tube an adenomyoma of the uterine type, and I am totally at a loss to explain its mode of origin.”⁴¹

Nonetheless, Cullen may have given a clue to its origin. “In this case, we have a most unusual combination; a bicornuate uterus, the right horn of which presents a most beautiful example of diffuse adenomyoma; a right tubal ectopic pregnancy; adenomyoma of the inner end of the left tube and a hydrosalpinx of its outer end.”⁴² Could the “adenomyoma of the inner end of the left tube” represent “salpingitis nodosum isthmica” of Chiari⁴³ that had undergone metaplasia under the hormonal stimulus associated with the tubal pregnancy? Another clue to the original tubal morphology is that the majority of the glands had no stroma and lay in direct contact with the muscle, a characteristic of tubular epithelium.

Rectovaginal Septum

The substance of this article rests in the long section on adenomyoma of the rectovaginal septum. Cullen wished to lay “unusual emphasis” on these lesions because of their “unusual importance,” describing in some detail pervasive invasiveness with the risk of chronic invalidism or even death if not diagnosed and treated in time.⁴⁴ Death was no stranger to Cullen, as we shall see when we come to discussion of adenomyomas of the sigmoid colon. This socially conscious physician wanted to caution his audience that they might avoid his terrible experience. He retold the 1913 story of Dr. Jessup sending him specimens of two adenomyomas of the rectovaginal septum and of receiving the “Proceedings of the Royal Medicaland Chirurgical Society of London, containing Cuthbert Lockyer’s article on ‘Adenomyoma of the Rectovaginal Septum.’”⁴⁵ Compared to his first awakening and “gotcha” experience in 1896,⁴⁶ the second awakening must have deeply impressed Cullen, for he had told the story several times before: in 1914,⁴⁷ 1916,⁴⁸ and again in Syracuse in 1919.⁴⁹

Returning to the seriousness of “widespread” adenomyomas of the rectovaginal septum, Cullen exhorted surgeons to perform a “preliminary permanent colostomy… Later the pelvic structures can be removed en bloc.” For added emphasis he reminded his readers of the difficulty of this surgery: “The removal of an extensive adenomyoma of the rectovaginal septum is infinitely more difficult than a hysterectomy for carcinoma of the cervix.”⁵⁰ This prudent advice – prudent for the era before antibiotics, safe blood transfusion and better knowledge of body fluid dynamics – was based on personal experience: one patient who developed vesicovaginal and rectovaginal fistulas⁵¹and two patients with adenomyomas of the sigmoid colon, both of whom died.⁵² Cullen had presented his ninth case of adenomyoma of the rectovaginal septum in 1916. In the interim, he had accumulated ten more cases for a total personal experience with 19 cases.⁵³ In comparison, the Mayo Clinic experience comprised four cases.⁵⁴

Cullen’s septum case 10, published as Case 2 in 1920,… illustrates a small adenomyoma of the rectovaginal septum in which the legend describes the lesion thusly: “just posterior to the cervix is a slightly bluish black cystic area about 6 mm. in diameter. This bluish black appearance is, of course, due to the accumulation of old menstrual blood in a small cystic area in the adenomyoma.”⁵⁵ Cullen also illustrates a sagittal section through the entire uterus, cervix, and a generous portion of the upper vagina, the vaginal cuff.⁵⁶ Both illustrations show the adenomyoma high in the posterior vaginal fornix.⁵⁷ To emphasize the point, Broedel’s illustration unambiguously shows a small lesion in the wall of the posterior vaginal fornix behind the cervix (retrocervical); a location distant from the floor of the rectovaginal pouch of Douglas, distant from the rectum, and distant from the anatomic rectovaginal septum of Denonvilliers.⁵⁸ Cullen and Broedel appear to have been unacquainted with the description of the anatomic rectovaginal septum by Denonvilliers in 1836.⁵⁹ Cullen described the site of origin of adenomyomatous lesions of the rectovaginal septum. “Adenomyoma of the rectovaginal septum usually starts just behind the cervix, and on bimanual examination, one can feel in this region a small, somewhat moveable nodule scarcely more than a centimeter in diameter.”⁶⁰ Cullen repeatedly used such phrases as: “a small nodule is felt directly behind the cervix⁶¹…may break into the vagina⁶²…a small nodule directly behind the cervix⁶³…in the posterior vaginal wall near the cervix⁶⁴…appears to have begun in the posterior vaginal wall⁶⁵…a small lump was felt in the vaginal wall behind the cervix⁶⁶…behind the cervix was a nodule about 1.5 cm. in diameter.”⁶⁷ He described endometriotic invasion of the posterior vaginal vault, a lesion associated with deep dyspareunia. “Occasionally, as the growth progresses, the polypoid condition in the vaginal vault directly behind the cervix becomes very prominent, and in those cases in which the growth breaks through the vaginal mucosa, there may be a menstrual flow from the vaginal vault even when a supravaginal hysterectomy has been performed some years before for uterine myomas.”⁶⁸

The crucial point to be emphasized is that Cullen relied for diagnosis on detecting a palpable hard lesion that “usually starts just behind the cervix.”⁶⁹ The nodule distorted the posterior vaginal fornix, was readily palpable vaginally, and sometimes was visible as a bluish lesion in the posterior fornix. Hence, when Cullen had Broedel illustrate adenomyoma of the rectovaginal septum, the illustrations depicted neither rectal involvement nor involvement of the true anatomic rectovaginal septum; instead the illustrations showed, very precisely, an adenomyotic nodule beneath the mucosa of the posterior vaginal fornix, located in the tissue that forms a “septum” between the posterior vaginal fornix and the anterior rectovaginal pouch of Douglas.

Cullen illustrated an adenomyoma that invaded the broad ligament and compressed the right ureter causing partial ureteral obstruction.⁷⁰ When the author examined this illustration closely he could understand – for the first time – how Cullen could describe an adenomyoma as “springing from the cervix.” By “springing from” Cullen meant the growth of a pedunculated subperitoneal adenomyoma extending well beyond the outer contour of the uterus.⁷¹ Importantly, the accompanying large histologic section of the right broad ligament and adenomyoma demonstrates that fatty tissue has been invaded and replaced by connective tissue and adenomyomatous elements. “(Case 10). Discrete adenomyoma of the right broad ligament pressing on and partially obstructing the ureter…At the left, where the nodule was attached to the right side of the cervix, most of the tissue consists of fat. As we pass toward the right the adipose tissue is found to be replaced in part by connective tissue. At the extreme right the tissue consists of nonstriped muscle and fibrous tissue, and scattered throughout it are a moderate number of glands resembling those of the uterine mucosa.”⁷²

Over the years Cullen constantly equated pathogenesis and morphology.⁷³ Under the heading “cause of adenomyoma of the rectovaginal septum,” Cullen stated in 1916: “The source of origin of their glands is also clear, namely, from the uterine mucosa.”⁷⁴ Cullen continued: “When discussing cervical adenomyomas, in my work on ‘Adenomyoma of the Uterus,’ several years ago, I pictured an island of perfectly normal mucosa of the body of the uterus situated near the outer surface of the cervix. Subsequent studies may possibly show that this is no great rarity. If so, this growth might readily become the starting point for those adenomyomas found in the rectovaginal septum.”⁷⁵

Nowhere perhaps may Cullen’s argument by analogy be more clearly demonstrated than in his statement: “The glands in the adenomyomas of the rectovaginal septum look like, and act exactly like, those of the mucosa of the body of the uterus, and they undoubtedly arise from uterine glands or from remnants of Müller’s duct.”⁷⁶ In this either–or argument, Cullen would not admit the Meyer-Iwanoff heterotopic-coelomic metaplasia theory or the inflammatory theory of Meyer.⁷⁷ He was bound to the müllerian origin of all adenomyomas in all locations and demanded their origin from either post-embryonic or embryonic müllerian tissues. Compare the pastoral metaphors that Cullen used to describe adenomyoma of the uterus: “flow, flowing, and rivers”; with the military metaphors with which he described adenomyomas of the rectovaginal septum: “the growth has invaded all parts of the pelvic floor⁷⁸…The mass in question was about 3 cm. long and densely adherent to the side of the rectum, to the posterior vaginal wall, and also to the lateral wall of the pelvis. It really had to be dug out.”⁷⁹

In cases where disease obliterated the rectovaginal pouch of Douglas, rectal examination or combined rectal–vaginal examination was preferable to vaginal examination. Cullen believed adenomyomas of the rectovaginal septum originated by “growing from the posterior surface of the cervix” or “springing from the posterior surface of the cervix” ⁸⁰ Importantly, Cullen’s fundamental belief was based on the appearance of small adenomyoma in the surgical specimens. Thanks to the beautiful illustrations of Broedel, we can reconstruct Cullen’s reasoning. Thus, when Cullen wanted Broedel to illustrate the “hard nodular” adenomyotic lesion in extensive cases, where the rectovaginal pouch of Douglas was obliterated, he chose to depict the nodule as “springing” from the back of the cervix⁸¹. Only in Fig. 42 was adenomyoma of the rectovaginal septum depicted as involving the rectum. I believe that the determining factor, in so depicting the adenomyotic “hard nodule,” was the operative technique used for its removal. Rather ingeniously, Cullen and his associates overcame the problem of rectal involvement by mobilizing the disease en bloc. They exposed the ureters to prevent injury, and then freed the uterus with adherent rectum and cuff of vagina by cutting the vagina anteriorly and laterally. “One can then lift the uterus and vaginal cuff up and with more ease separate the adherent vaginal cuff from the rectum. Sometimes it will be necessary to remove a wedge of the adherent anterior rectal wall with the uterus.”⁸² In extensive cases of adenomyomata of the rectovaginal septum, this technique facilitated dissecting the rectum from the adenomyoma, which remained adherent to the posterior aspect of the cervix.

Having operated the most difficult cases of deep pelvic endometriosis imaginable, Cullen again gave voice to the difficulty of the surgery for extensive adenomyomas involving the vagina, cervix and uterus, and rectum. He reminded his readers again that excision of an extensive adenomyoma of the rectovaginal septum was, in his experience, “infinitely more difficult than a hysterectomy for carcinoma of the cervix.”⁸³

Uterosacral Ligament

WW Russell had called Cullen’s attention to adenomyoma of the uterosacral ligament “years ago, [which] on histologic examination…presented a typical adenomyomatous picture.” Since then, Cullen had seen “a cyst 1.5 cm. in diameter apparently springing from the right uterosacral ligament,” a lesion that resembled grossly the adenomyoma of Russell, though the histologic picture “was not very definite.”⁸⁴ What is particularly interesting is Cullen’s phrase expressing pathogenesis, the extrauterine adenomyoma “apparently springing from the right uterosacral ligament.” Cullen’s strength lay in description and synthesis, not analysis or theory.

Sigmoid Colon

Cullen encountered his first case of adenomyoma of the sigmoid colon unexpectedly at laparotomy on a poor risk patient on 4 April 1918, a poor risk patient who also had an adenomyoma that had penetrated the posterior fornix of the vagina.⁸⁵ Unfortunately, Lockyer’s treatise of 1918 that contained a section on adenomyomas of the sigmoid colon was published too late to alert Cullen to their existence. And from available evidence, though Casler’s case of obstruction of the sigmoid colon was successfully operated before Cullen’s case, the obstruction was not attributed to adenomyotic invasion of the sigmoid colon.⁸⁶ Thus, Cullen was not forewarned. He diagnosed the rectovaginal adenomyoma penetrating into the posterior fornix before surgery. At surgery – completely unaware of the presence of an adenomyoma of the sigmoid colon – Cullen mobilized the rectovaginal septal lesion vaginally before he began the abdominal operation. Only then did he discover the adenomyoma in the sigmoid colon. Thinking it was a carcinoma, Cullen explored the liver and upper abdomen for evidence of metastases. Unexpectedly faced with a possible carcinoma in a poor risk patient, Cullen mobilized the sigmoid colon and displaced it low in the pelvis. Then he exteriorized the sigmoid colon from the peritoneal cavity by sewing the peritoneum over it. Cullen anticipated performing a definitive second stage operation later when the patient was in better condition. Unfortunately the patient died in the interim. Only at autopsy was the true nature of the sigmoid lesion revealed to be a benign adenomyoma.

Cullen consulted Lockyer’s book, Fibroids and Allied Tumors and observed that Lockyer “gives us the best résumé of the literature on adenomyoma.”⁸⁷ He also found a case reported by Robert Meyer in 1919.⁸⁸ That patient had been operated in 1907 by Professor Mackenrodt, after whom Mackenrodt’s ligament was named.

Cullen encountered his second case of adenomyoma of the sigmoid colon at surgery in late June or early July 1919. “On opening the abdomen the first thing which attracted one’s attention was a mass the size of a large lemon which was situated in the upper part of the rectum or lower sigmoid colon.”⁸⁹ He did not attempt to resect the sigmoid lesion. Instead, with considerable difficulty, he performed a total abdominal hysterectomy. In the process he excised a walnut sized adenomyoma located in the posterior vaginal vault that was “intimately connected with the cervix, rectum and broad ligament…It was a difficult operation on account of the fixation of the uterus. In attempting to separate the growth from the rectum, an opening was made in the bowel after which the whole involvement of the rectum by the tumor was cut away and the rectum was sutured.”⁹⁰ His second patient also died postoperatively.

These were pioneering days in the diagnosis and surgical treatment of adenomyomas of the colon. Again Cullen reviewed the literature. He found the article by Mahle and MacCarty from the Mayo Clinic in which they reported their experience with one case of adenomyoma of the sigmoid colon and cited an earlier case of Leitch.⁹¹ The patient of Mahle and MacCarty had been referred to them for treatment of a tumor of the “lower bowel” found at laparotomy.⁹² Forewarned, they studied the colon before surgery with an “X-ray of the colon and a proctosigmoidoscopic examination,” but both proved negative.⁹³This was an example of the early use of diagnostic radiology.⁹⁴ At surgery, a “tumor mass was found encircling the sigmoid, involving a segment of the bowel 4 cm. in length. The sigmoid and the bladder were adherent to a mass around the uterus.”⁹⁵ The sigmoid colon was dissected from the uterine mass and Mahle and MacCarty resected a 12 cm length of sigmoid colon along with “tarry cysts” of both ovaries; they did not perform a hysterectomy.⁹⁶ Mahle and MacCarty’s patient survived the limited operation apparently without complications. Cullen reported his third and last case of adenomyoma of the sigmoid colon without citing the case of Leitch reported by Mahle and MacCarty.

One’s respect for Cullen soars when one realizes that he provided sufficient evidence for the historian to reconstruct his personal learning curve for recognizing and treating adenomyomas containing uterine mucosa. This historical reconstruction is possible only because of Cullen’s honesty and his full and meticulous recording of exactly what happened. Early in his career, Cullen recommended reporting all clinical experience, both good and adverse, so that other surgeons could learn from the Johns Hopkins experience and avoid complications when treating their patients.⁹⁷

Rectus Muscle

Cullen presented a fascinating case of adenomyoma in the left rectus muscle, fascinating for its pathogenesis and because it provides a window on the practice of gynecology before widespread use of hospitals for surgery and before rigorous residency training and certification.⁹⁸ Following an incomplete abortion, “curettage was performed for retained membranes and the dilator passed through the retroflexed uterus at the cervical uterine junction. The body of the uterus was torn half loose from the cervix before the accident was discovered. The patient evidenced considerable shock, was rushed to the hospital, the abdomen was opened and the damage repaired.”⁹⁹ Nine and one half years later, the patient noticed a “little soreness in the lower abdomen just to the left of the lower angle of the abdominal scar.”¹⁰⁰ The same surgeon, who had saved the patient’s life nine and a half years before, was again consulted and he removed the “entire lower end of the left rectus” muscle which contained a tumor without capsule approximately 2.5–3 cm long and 1.5 cm wide and 1.5 cm “thick.” Cullen examined sections from the tumor and confirmed the diagnosis of an adenomyoma. Cullen’s illustration, does not show the scar, and neither the referring physician nor Cullen mention the type of incision made at the emergency surgery. Nevertheless, based on the patient’s localization of the lesion, “just to the left of the lower angle of the abdominal scar, the incision was probably midline.”¹⁰¹ Supporting this assumption, a midline incision is generally employed for emergency laparotomy, especially with a patient in shock.

The case begs for analysis. Apparently, neither Cullen nor the referring surgeon appreciated the pathogenesis of this lesion. The referring surgeon mused that the adenomyoma “did not seem to be associated with the scar of the incision” from the emergency surgery. Cullen reached for an explanation, citing two cases of adenomyoma of the abdominal wall reported by Mahle and MacCarty from the Mayo Clinic.¹⁰² Both cases were examples of iatrogenic transplantation of uterine mucosa. In the first case, the adenomyoma was located in the lower abdominal wall, “under a previous laparotomy scar.” In the second case, an 8 cm adenomyoma extended from the uterus to the abdominal wall at the site of a previous ventral uterine suspension. Fortunately, Cullen supplied sufficient data to reconstruct the pathogenesis of the adenomyoma in this unusual case. In all probability a family practitioner, working under trying circumstances in the patient’s home around 1909, curetted the uterus to complete the miscarriage, but failed to recognize the retroflexed position of the uterus before curettage. The operator unknowingly perforated the anterior wall of the uterus with the instrument and curetted the lower anterior abdominal wall vigorously. When he pressed the sharp curette upward, thinking the instrument was inside the uterus, the curette engaged and lacerated the abdominal wall. As the operator drew the curette downward and outward, the abdominal wall tissue caught by the curette remained attached at its lower end and the bleeding continued. Undoubtedly, the operator curetted harder and harder in an effort to retrieve all products of conception and stop the bleeding. In the process, he not only lacerated the left rectus muscle with its artery and vein, but also enlarged the uterine perforation tearing the “body of the uterus…half loose from the cervix.” The patient bled profusely from lacerated blood vessels in the abdominal wall and uterine wall and went into shock from blood loss. By repeated manipulation of the curette, uterine mucosa was caught in the curette and transferred to the traumatized left rectus muscle where the transplanted tissue developed into an adenomyoma. Many years later Cullen and Broedel wrote an article thoroughly describing the anatomy of the rectus abdominis muscle, an article that adds credence to the traumatic pathogenesis of this adenomyoma of the rectus muscle.¹⁰³

Ovary

In all, Cullen operated one patient and reported five other patients who had uterine mucosa in an ovary.¹⁰⁴ The first patient was reported by Russell from the Johns Hopkins Hospital in 1899.¹⁰⁵ Cullen reported the second case from the archives of Johns Hopkins Pathology Laboratory (GYN. Path. No. 22505, Sept. 19, 1916.) The patient had a myomatous uterus and a small left ovarian cyst “partially filled with blood [and] containing uterine mucosa in its walls.”¹⁰⁶ Cullen continued: “The cyst wall is lined by one layer of cylindric epithelium. In places, this lies in direct contact with the ovarian tissue, but here and there is separated by a definite stroma. Near the right, the stroma is very evident, and embedded in it is a gland resembling those of the body of the uterus.”¹⁰⁷

Cullen’s third patient was operated by Casler in 1917.¹⁰⁸ Cullen summarized Casler’s case. From Cullen’s remarks it is obvious that he had reviewed the microscopic slides. The specimen was remarkable because scattered throughout a diffuse myomatous thickening [of the uterus] “were quantities of stroma identical with that of the uterine mucosa…This stroma however contained no glands. The tumor resembled in every particular the picture of an ordinary adenomyoma of the uterus except for the fact that the glands were missing from the stroma.”¹⁰⁹ Cullen examined the ovary and uterus and opined that the histologic sections explained the ectopic menstruation. “On histologic examination great quantities of typical uterine mucosa were found scattered throughout the ovarian tumor, thus clearly explaining why the patient had continued to menstruate without any uterus. The ovary contained all the essential elements, normal ova, and practically normal uterine mucosa, and the small tract left where the uterus had been removed supplied the necessary avenue along which the menstrual flow escaped.”¹¹⁰

Curiously, Cullen did not elaborate on the difference between the misplaced uterine mucosa within the uterine wall, the uterine polyp, and that found in the ovary. Histologic sections of the adenomyoma near the uterine serosa showed uterine stroma – without glands – “infiltrating and dividing the uterine muscle into a course mesh-work.”¹¹¹ The large uterine polyp was also composed of aggressively infiltrating uterine stoma with few glands. In contrast, the ovarian cyst was lined by broad-based polyps; some were composed of uterine stroma only, while other polyps were composed of “masses of stroma but with many large atypical uterine glands,¹¹² many of the glands filled with degenerated blood.”¹¹³

Casler had described within the ovarian cyst other “liver-colored polypi, irregular in size, generally with a broad base, each…made up of uterine tissue, glands, stroma and muscle.”¹¹⁴ In his opening remarks, Casler addressed tangentially Cullen’s concept of the pathogenesis of diffuse uterine adenomyoma. “Adenomyoma…has generally been regarded as a benign tumor, characterized in the main by invasion of the muscle columns, or, as some pathologist regard it, by a ‘flowing in’ of the glandular tissue into the crevices of the muscle bands, the glandular tissue always accompanied by a larger or smaller amount of interglandular stroma.”¹¹⁵ Furthermore Casler questioned Cullen’s passive “flowing in” metaphor. “The structure of the tumor and the remarkable way in which the stroma has invaded from the mucosa to the serosal surface of the growth, suggests an active process of an infiltrating character on the part of the stroma and not a passive ‘flowing in,’ between the muscle columns, and at once brings up the question in cases of adenomyoma as to whether the stroma is not as active an agent in these growths as the glands and possible a more active agent.”¹¹⁶ Referring to his own case, Casler used such active and aggressive words as “exterminated…strangulation… [and] attacked,”¹¹⁷ to explain the pathogenesis of uterine adenomyomata. However at this late date in his career, Cullen did not deign to respond to Casler’s not so subtle challenge regarding the finer points of pathogenesis of diffuse uterine adenomyoma.

Cullen’s fourth case consisted of a histologic slide of a “relatively small ovary containing a large island of normal uterine mucosa” sent to him from Philadelphia by Dr. Charles Norris.¹¹⁸ An “area of typical uterine mucosa [was] embedded in the substance of the ovary…connected with an irregular cyst cavity.”¹¹⁹

On May 12, 1919, Cullen operated ovarian Case 5, his one and only patient with uterine mucosa in the ovary, also his Septum Case 14.¹²⁰ At surgery Cullen found “the most wide-spread distribution of an adenomyoma of the rectovaginal septum that I have ever seen [and] it was one of the most difficult hysterectomies I ever attempted.”¹²¹ The rectovaginal pouch of Douglas was obliterated completely. However, the pathology of the tube and ovary was the more interesting aspect of the case. Cullen described an: “Extension of an adenomyoma of the rectovaginal septum to the surface of the adherent fallopian tube…On the surface of the tube is an area of typical uterine mucosa…It really looks as if the widespread adenomyoma of the rectovaginal septum has literally flowed over on the surface of the tube.”¹²² Cullen found histologic proof also of “uterine mucosa on the surface of the ovary…The mucosa of the adenomyoma of the rectovaginal septum seems to have overflowed to the surface of the adherent ovary.”¹²³

Characteristically, Cullen described minutely the gross as well as microscopic pathology: “The [right] tube and ovary form a conglomerate mass which has been densely adherent to the side of the uterus as well as to the surrounding structures. Notwithstanding this the fimbriated end of the tube is patent and appears relatively normal.”¹²⁴ In this case Cullen postulated the pathogenesis of uterine mucosa on the tube and ovary. He pictured the extensive adenomyoma of the rectovaginal septum “flowing” onto ovary and tube.¹²⁵ Cullen came tantalizingly close to – and yet so far from – Sampson’s later observations when he wrote: “One gathers the impression that the uterine mucosa from the diffuse adenomyoma on the posterior surface of the cervix and uterus has overflowed upon the adherent tube [and ovary].”¹²⁶Cullen had the pathogenesis in reverse.

Cullen’s sixth and final ovarian case, consisting of a letter and specimen, was sent to him from St. Louis by Dr. Otto Schwarz. Such was Cullen’s thoroughness that he later visited St. Louis and reviewed other slides from the case with Dr. Schwarz in the latter’s laboratory. So perfect was the analogy that Cullen commented on the microscopic features: “a photomicrograph that I have had made from one of Dr. Schwarz’ sections…It is a beautiful example of an ovary containing miniature uterine cavities.” In the very next sentence, Cullen repeated his invitation for others to take up the research, an invitation first made in Syracuse in 1919. “From the foregoing it is evident that in due time a sufficient number of cases will undoubtedly be reported, and then we shall possibly be able to give a composite picture of both the clinical course and of the histologic changes that occur in this most unusual group of cases.”¹²⁷

By 1920, Cullen was the undisputed North American authority on uterine and extrauterine adenomyomas. He was self confident to the point of being completely self referential in his “bird’s eye” review of 1919,¹²⁸ and except for three citations, self referential in his major review of 1920.¹²⁹ Lack of references to the work of other colleagues, domestic and foreign, also reflected his declining interest in the subject.¹³⁰ Cullen was tired when he wrote this final major article on adenomyomata and he did not attempt “to cover the literature on the subject.”¹³¹ This is the same man who for years had spent “three afternoons a week in the Surgeon General’s Library.”¹³² In other circumstances, Cullen would have written a book. In his “fragmentary article” of 1919¹³³ as well as in this review of 1920,¹³⁴ Cullen invited others to study uterine mucosal lesions in the ovary and adenomyoma of the sigmoid colon. After studying adenomyomas for 25 years, he was ready to pass the baton of authority to a successor.¹³⁵

Nonetheless, Cullen managed to write one more short case series in 1921 on a relatively rare condition, subperitoneal pedunculated adenomyoma, a topic he had discussed thoroughly in his monograph on uterine adenomyomas in 1908. Cullen expressed the main reason that he revisited this topic. “These three cases are such beautiful examples of a relative rare condition that we may with profit consider them in detail.” What struck the author with considerable force was Cullen’s use of the expressions “springing from” and “which sprang from” 20 times to express the origin of uterine adenomyomas. He had used these same expressions elsewhere with extrauterine adenomyomas.¹³⁶ Cullen concluded this article with his last formal statement on adenomyomas. “The more we study adenomyomas the more fully are we convinced that they should, if possible, be removed as soon as they have been diagnosed.”¹³⁷ As a final caveat, recall that Cullen came to the belief that hormone-resistant endometriosis would continue to invade the bowel and cause problems even after hysterectomy and removal of both tubes and ovaries.

***

Chapters 8 and 9 that follow present pure analysis and synthesis of John A. Sampson’s scientific articles during his most creative period in a long and productive academic career. To put these chapters in historical context: this was the period when European countries lay devastated by the most ghastly war yet fought in world history, compounded by the further loss of young men and women from the Asian influenza epidemic of 1918 that swept from a military installation in the United States to engulf and kill millions of civilians worldwide. During the post-war years medical research in Europe ground to a snail’s pace – a Europe plagued by inflation and loss of a whole generation of young men. Meanwhile relatively unscathed, medical research continued virtually unabated in some former European colonies, especially the United States of America and Canada where the era came to be known as the roaring twenties, a time of economic prosperity. Paradoxically, research into endometriosis at Johns Hopkins seemed to grind to a snail’s pace, but for a different reason – loss of interest by its leading investigator, Thomas Cullen.

For John A. Sampson, Professor of Gynecology at Albany Medical College on the eastern end of the Erie Canal in upstate New York – time stood still in those immediate postwar years as he immersed himself totally in endometriosis research. Sampson, with two decades experience studying all aspects of cervical cancer and a budding interest in endometriosis, was inspired initially by an insight derived from DeWitt Casler’s case of the menstruating ovary. During the feverish pace of research that followed, Sampson generated the second of three insights, retrograde menstruation and implantation, that would ultimately lead to his mature theory of implantation endometriosis. The third insight, spread by lymphatic and venous metastases, came from his realization that endometriosis shared many characteristics of cervical, endometrial, and ovarian cancer. Such must have been the pace and the exhilaration of discovery that in 1923 Sampson unwittingly expressed the foundation for his success in academic medicine and medical research. In a semi-autobiographical presidential address before the American Gynecological Society, Sampson disclosed that his childhood role model was President Theodore Roosevelt and his adult professional role model none other than Howard A. Kelly, his professor at Johns Hopkins Hospital.

Put into medical historical context, Chaps. 8 and 9 represent the first in-depth analysis of Sampson’s classic theory for the pathogenesis of external endometriosis. Whereas the theories of pathogenesis from embryonic rests, serosal and coelomic metaplasia, and direct invasion of the uterine and tubal muscle were all derived from observations in the laboratory, Sampson’s theory could only have been conceived by a seasoned surgeon steeped in biological field research and cross-trained in human pathology. In sum, Sampson’s theory required the composite scientific and creative talents of a field biologist, a master cancer surgeon, and a mature gynecologic pathologist. Chapters 8 and 9 provide the window through which we may observe Sampson’s scientific creativity.

Equally important they reveal the first theory of pathogenesis of endometriosis amenable to experimental testing to prove or disprove its validity. Furthermore, Sampson’s theory of pathogenesis: by implantation of endometrial tissue shed from ruptured endometrial chocolate ovarian cysts, from endometrial tissue shed directly through the fallopian tubes onto the ovaries and other pelvic organs, and from venous and lymphatic metastases is the only theory that has the power to explain the precise anatomical distribution of all but the most esoteric endometriotic lesions.

Footnotes

Cullen, TS. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery. 1920;1:215–283: 244.

Cullen TS. Archives of Surgery 1920;1:215–283.

Scholars with a deep interest in this subject may wish to read this chapter with a copy of Cullen’s 1920 article in hand so they can compare the illustrations in the article with the text of this chapter.

Cullen TS. Archives of Surgery 1920;1:215–283;217. Fig. 1.

Cullen TS. The distribution of adenomyomata containing uterine mucosa. American Journal of Obstetrics and Diseases of Women and Children. 1919;180:130–138:136. “Figure 1. The abnormal distribution of uterine mucosa. 1. In the wall of the uterus and at the uterine horn. 2. I the rectovaginal septum. 3. In the round ligament. 4. In the ovary. 5. In the utero-ovarian ligament. 6. In the uterosacral ligament. 7. At the umbilicus.”

Cullen, Thomas S. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery. 1920;1:215–283.

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

Cullen, TS. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery. 1920;1:215–283:217.

Cullen, Thomas S. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery. 1920;1:215–283: 217, Fig. 1. The illustration shows extensive “diffuse adenomyoma” or adenomyosis of the uterus involving not only the anterior and posterior walls but also the fundus of the uterus. Young, RH. Dusting of old books: Comments on classic gynecologic pathology books of yesteryear. International Journal of Gynecological Pathology. 2000;19:67–84. As Robert H. Young pointed out, Cullen used the term adenomyoma of the uterus to include both “diffuse adenomyoma” (adenomyosis) and “discrete adenomyoma” (adenomyoma). This lesion was treated exhaustively in a separate monograph. Thomas Stephen Cullen, Adenomyoma of the Uterus [Philadelphia: WB Saunders, 1908].

Cullen, Thomas S. Archives of Surgery. 1920;1:215–283: 217, Fig. 1. Note the discrepancy between terminology and illustration: the lesion labeled adenomyoma of the rectovaginal septum is shown in a retrocervical location involving the tissue between the posterior vaginal fornix and anterior portion of the rectovaginal pouch of Douglas.

Cullen, Thomas S. Archives of Surgery. 1920;1:215–283: 222 Cullen noted: “We have in this tube an adenomyoma of the uterine type, and I am totally at a loss to explain its mode of origin.”

Cullen, Thomas S. Archives of Surgery. 1920;1:215–283: 243, Fig. 21. The legend reads: “Uterine mucosa on the surface of the ovary in a case of adenomyoma of the rectovaginal septum…The miniature uterine cavity on the surface of e the right ovary is represented by a. The lining mucosa resembles in every particular that of the body of the uterus. Some of the glands show hypertrophy. The mucosa of the adenomyoma of the rectovaginal septum seems to have overflowed to the surface of the adherent ovary. The same condition was noted on the surface of the corresponding tube.” This is an important addition to his classification and the first evidence of his attention directed to the ovary, other than a prior acknowledgement of the case of WW Russell published in 1899.

This lesion was treated exhaustively in a separate monograph. Thomas S. Cullen. Embryology, Anatomy, and Diseases of the Umbilicus [Philadelphia: W. B. Saunders, 1916].

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives Surgery 1920;1:215–283. In Figure 1, Cullen labeled the various sites at which he had found uterine mucosa, (1) was the body of the uterus; (2) rectovaginal septum, (3) uterine horn or fallopian tube, (4) round ligament, (5) hilum of the ovary, (6) utero-ovarian ligament, (7) uterosacral ligament, (8) sigmoid colon, (9) rectus muscle, and (10) umbilicus.

Cullen TS. Archives of Surgery 1920;1:215–283;217. Figure. 1. As evidence that Cullen valued this contribution, he had it published as a hard cover sixty-nine page monograph in 1920. Thomas S. Cullen. The Distribution of Adenomyomas Containing Uterine Mucosa.Chicago, IL: American Medical Association Press, 1920. The author has a copy in his library, thanks to Dr. Ronald Cyr.

E. Stewart Taylor, Essentials of Gynecology [Philadelphia: Lea & Febiger, 1958], 256. Figure 194. “The usual locations for endometriosis. (Cullen, courtesy of Arch. Surg.)”

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives Surgery 1920;1:215–283:269. Figure 42 (Case 16, rectovaginal septum Case 19). See also Figure 1, page 217; sagittal view of the female pelvis and abdomen.

Cullen TS. Archives Surgery 1920;1:215–283:271, Figure 43 (Case 16, rectovaginal septum Case 19).

Cullen TS. Archives Surgery 1920;1:215–283:269. Figure 42 (Case 16, rectovaginal septum case 19) inset showing “independent adenomyoma of the sigmoid almost completely blocking the lumen of the bowel.” This beautiful illustration depicts deeply invasive endometriosis (adenomyoma) of the rectovaginal pouch of Douglas that has penetrated the posterior fornix of the vagina. It also purports to show an adenomyoma partially obstructing the sigmoid colon.

In the illustration the mucosa – though distended over the intraluminal spherical polyp – is normal.

Kellogg FS. Adenomyoma of the recto-vaginal septum. Boston Medical and Surgical Journal 1917; 176 or 177: 22–24:24. Puckering and gathering of bowel serosa is a universally recognized phenotypic feature of advanced bowel adenomyomas that surgeons routinely observe with adenomyomas of the rectum, sigmoid colon, descending colon, ascending colon, and ileum. On numerous occasions of partial to complete obstruction of the sigmoid colon or the ileum, the author has observed an “Omega deformation of the bowel segment” where the adenomyoma (endometriosis) has invaded.

Cullen TS Archives Surgery 1920;1:215–283:269. Figure 42 (Case 16) inset showing “independent adenomyoma of the sigmoid almost completely blocking the lumen of the bowel.” This illustration depicts deeply invasive adenomyoma (endometriosis) that has penetrated through the anterior rectovaginal pouch of Douglas into the posterior fornix of the vagina. It also purports to show an adenomyoma obstructing the sigmoid colon.

Stacey E. Mills, ed., Sternberg’s Diagnostic Surgical Pathology, 4^th ed., vol. 2. [Philadelphia: Lippincott Williams & Wilkins, 2004], 1589–1591. Juan Rosai, ed., Ackerman’s Surgical Pathology, 8^th ed., vol. 1. [St. Louis: Mosby, 1996], 645–647:645. “Gastrointestinal stromal tumors, (GISTs) constitute the largest category of primary nonepithelial neoplasms of the stomach and small intestine.” Dr. Salvador Udagawa, my colo-rectal surgical colleague with whom I have worked closely for 25 years has removed gastrointestinal stromal tumors from the large intestine including the sigmoid colon; the largest GIST he removed was obstructing the distal transverse colon. See also Ancel Blaustein, “Pelvic endometriosis,” in Pathology of the Female Genital Tract, ed. Ancel Blaustein [New York: Springer-Verlag, 1977], 404–419. See figure 22.29, page 416. “Napkin-ringlike constriction of the [bowel] wall, intramural endometriosis present.” See figure 22.30, page 417. “Sigmoid colon. Endometrial implants in the smooth muscle layer. There is a hypertrophy of muscle about the implants.” See Figure 22.31 “Sigmoid colon. Lesions of endometriosis that on gross inspection have a high index of suspicion for carcinoma. There is a raised submucosal lesion and puckering on the serosal surface.”

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives Surgery 1920;1:215–283:269–270. See caption under Figure 42 (Case 16, rectovaginal septum Case 19), page 269 that is titled “Adenomyoma of the rectovaginal septum, independent adenomyoma of the sigmoid almost completely blocking the lumen of the bowel.”

Cullen labeled the specimen rectal mucosa instead of mucosa of sigmoid colon.

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives Surgery 1920;1:215–283:271. See caption under Figure 43 (Case 16, rectovaginal septum Case 19) labeled “Adenomyoma of the sigmoid flexure totally independent of a coexisting adenomyoma of the rectovaginal septum.”

Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 330.

Judith Robinson, Tom Cullen, 280, 282.

Judith Robinson, Tom Cullen, 279–80.

John M. Barry, The Great Influenza: The Epic Story of the Deadliest Plague in History. [New York: Penguin Books, 2005], 258.

Martzloff KA. Thomas Stephen Cullen. Am J Obstet Gynecol 1960;80:833–843:837. “The artistry of Max Broedel was a priceless adjunct to the books written by Kelly and by Cullen; Broedel was, in fact, an indispensable collaborator. While it was his judgment that frequently decided the type and form of illustration to be used in a given situation, of equal importance were some of his dissections and microscopic studies.”

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives Surgery 1920;1:215–283:269. Figure 42 (Case 16, rectovaginal case 19).

Ancel Blaustein, “Pelvic endometriosis,” in Pathology of the Female Genital Tract, ed. Ancel Blaustein [New York: Springer-Verlag, 1977], 404–419. See Blaustein illustration 22.2, on page 405, labeled “Pelvic and abdominal sites of endometriosis.” It is a reproduction of Broedel’s sagittal illustration of abdomen and pelvis, showing all ten anatomic locations where Cullen had personally observed misplaced uterine mucosa: Cullen TS. The distribution of adenomyomata containing uterine mucosa. Archives of Surgery 1920;1:215–283;217. However, it was not attributed to Cullen. Instead it was reprinted in Blaustein by permission from C. Javert, Pathogenesis of endometriosis, Cancer 1949;2:399. In other words, Broedel’s sagittal illustration of abdomen and pelvis showing the sites of misplaced uterine mucosa had taken on a life of its own; the original reference to Cullen was not mentioned, another “disconnect” helped to perpetuate the error.

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery 1920;1:215–283:216.

Cullen TS. Archives of Surgery 1920;1:215–283:216.

Cullen TS. Archives of Surgery 1920;1:215–283:216–17.

Cullen TS. Archives of Surgery 1920;1:215–283:221. Figure 4 (Case 1). Adenomyoma of the right uterine horn.

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery 1920;1:215–283:221.

Cullen TS. Archives of Surgery 1920;1:215–283:222.

Cullen TS. Archives of Surgery 1920;1:215–283:224. See Figure 6, Case I. Adenomyoma of the left fallopian tube.

Cullen TS. Archives of Surgery 1920;1:215–283:222.

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.

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery 1920;1:215–283:223–224.

Cullen TS. Archives of Surgery 1920;1:215–283:222.

Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 125. Quotation of Cullen: “Popsy had read von Recklinghausen and he wanted to pull me out. ‘You’re wrong in your interpretation, Cullen,’ he told me, ‘von Recklinghausen says…’ But I had brought the evidence with me, sectioned and mounted for examination. ‘I don’t care a hoot what von Recklinghausen says,’ I said, ‘Look down the barrel of that microscope.’ ”

Cullen TS. Adenomyoma of the rectovaginal septum. JAMA 1914;62:835–839.

Cullen TS. Adenomyoma of the rectovaginal septum. JAMA 1916;LXVII:401–406.

Cullen TS. The distribution of adenomyomata containing uterine mucosa. Am J Obstetrics Diseases Women and Children 1919;180:130–138.

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery 1920;1:215–283:225.

Cullen TS. Adenomyoma of the recto-vaginal septum. Johns Hopkins Hospital Bulletin 1917;28:343–349:348.

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery 1920;1:215–283.

Cullen’s total personal experience with adenomyomas of the rectovaginal septum at the time his 1920 paper went to press: 1913 – 2 cases, 1915–1 case, 1916–2 cases, 1917 – 4 cases, 1920 – 10 cases for total of 19 personal cases of adenomyoma of the rectovaginal septum.

Mahle AE, MacCarty WC. Ectopic adenomyoma of uterine type (A report of ten cases). J Lab & Clin Med 1920;5:218–228:226.

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery 1920;1:215–283. Figure 7, labeled “Adenomyoma of the rectovaginal wall as seen on vaginal inspection.”

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery 1920;1:215–283: Figure 8, labeled “Adenomyoma of the rectovaginal septum. This is a longitudinal section of the uterus and vaginal cuff seen in Figure 7.”

Cullen TS. Archives of Surgery. 1920;1:215–283.

Cullen TS. Archives of Surgery. 1920;1:215–283. Page 227, Fig. 8 (case 2). Denonvilliers, CPD. Bull Soc Anatomy of Paris (Series 3) 1836:20:105.

Denonvilliers, CPD. Bull Soc Anatomy of Paris (Series 3) 1836:20:105. This basic anatomic problem was clarified by the research of Nichols and Milley. Nevertheless, the misnomer perpetuated by Cullen, has persisted into the twenty-first century and has created much confusion as has the persistence of Cullen’s controversial theory of pathogenesis of these invasive lesions from müllerian embryonic rests.

Cullen TS. Archives of Surgery. 1920;1:215–283:223.

Cullen TS. Archives of Surgery. 1920;1:215–283:225.

Cullen TS. Archives of Surgery. 1920;1:215–283:227. Figure 8.

Cullen TS. Archives of Surgery. 1920;1:215–283:229.

Cullen TS. Archives of Surgery. 1920;1:215–283:233.

Cullen TS. Archives of Surgery. 1920;1:215–283:235.

Cullen TS. Archives of Surgery. 1920;1:215–283:223.

Cullen TS. Archives of Surgery 1920;1:215–283:223.

Cullen TS. Archives of Surgery. 1920;1:215–283:250. Figure 27 (Case 10).

Cullen TS. Three cases of subperitoneal pedunculated adenomyoma. Archives Surgery 1921;2:443–454. In this one article alone, Cullen employed the term “springing from” 13 times and “which sprang from” three times. In 1920, he had used the terms 20 times.

Cullen, Thomas S. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery. 1920;1:215–283:252. Figure 29 (Case 10).

Cullen TS. Adenomyoma of the rectovaginal septum. JAMA 1916;LXVII:401–406:405.

Cullen TS. JAMA 1916;LXVII:401–406:404.

Cullen TS. JAMA 1916;LXVII:401–406:404. Thomas Stephen Cullen, Adenomyoma of the Uterus [Philadelphia: WB Saunders, 1908], 169, Figure 49.

Cullen TS. JAMA 1916;LXVII:401–406:405.

Cullen TS. Adenomyoma of the rectovaginal septum. JAMA 1916;LXVII:401–406. In an abstract of the discussion to Cullen’s paper, Dr. Carey Culbertson stated: “It is not difficult to understand how inflammatory pressure might produce such a squeezing out of the mucosa into the wall of the tube; but in the case of the rectovaginal septum or postcervical space, the distance from the uterine cavity is too great to admit of the presence here of typical uterine mucosa as the result of inflammatory pressure.”

Cullen TS. JAMA 1916;LXVII:401–406:403.

Cullen TS. JAMA 1916;LXVII:401–406:401–2.

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery 1920;1:215–283.

Cullen TS. Archives of Surgery 1920;1:215–283:236. See: Cullen’s septum case 14, illustrated in Fig. 16 (Case 6) on page 238. Cullen described this case as “This is the most widespread distribution of an adenomyoma of the rectovaginal septum that I have ever seen.” On page 240, Cullen stated this supravaginal (subtotal hysterectomy) “was one of the most difficult hysterectomies I ever attempted.”

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery 1920;1:215–283:225. See also pages 229, 230, 236, 239–40 etc. under operation for each case.

Cullen, Thomas S. Archives of Surgery. 1920;1:215–283:225.

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery 1920;1:215–283:265. See Case 16, page 272: Septum Case 19; Gyn. No. 23764; Gyn. Path. No. 23891.

Cullen TS. Archives of Surgery 1920;1:215–283. Surgery was performed on 4 April 1918. Analysis of this paper is somewhat frustrating because the illustrations are out of sequence with the text they illustrate. That it was an article in the first volume of a new journal may explain the situation.

Casler DB. A unique, diffuse uterine tumor, really an adenomyoma, with stroma, but no glands. Menstruation after complete hysterectomy due to uterine mucosa in remaining ovary. Transactions of the American Gynecological Society. 1919;44:69–84:76–7. Casler’s patient was operated 3 January 1917 with Gyn. Path. No. 22897 ½. Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery 1920;1:215–283:272–3. Cullen’s patient was operated 4 April 1918 with Gyn. Path. No. 23891.

Lockyer, Cuthbert. Fibroids and Allied Tumours. New York: Macmillan Company, 1918.

Meyer, Robert. Ueber entzündliche heterotope Epithelwucherungen im weiblichen Genitalgebiete und uber eine bis in die Wurzel des Mesocolon ausgedehnte benigne Wucherung des Darmepithels. Virchows Arch. f. path Anat. 1919:195:487.

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery 1920;1:215–283:276.

Mahle AE, MacCarty WC. Ectopic adenomyoma of uterine type (A report of ten cases). J Lab & Clin Med 1920;5:218–228:221–225. Leitch A. Migratory adenomyomata f the uterus. Proc Roy Soc Med 1913;vii, Pt. ii, Obst and Gynec Sec: 393–398,

Mahle AE, MacCarty WC. J Lab & Clin

Med 1920;5:218–228:221.

Mahle AE, MacCarty WC. J Lab & Clin Med 1920;5:218–228:221.

Had this been a cancer originating in the mucosa of the sigmoid colon, the proctosigmoidoscopy would have been diagnostic, and probably the barium enema study also. However, adenomyomas originate on the serosal or outer surface of the sigmoid colon. While the adenomyomatous mass within the wall of the sigmoid colon might have indented the lumen, the bowel mucosa overlying the adenomyoma would have been smooth and normal appearing.

Mahle AE, MacCarty WC. J Lab. & Clin Med. 1920;5:221. The authors referred to a similar case of adenomyoma of the sigmoid colon observed by Leitch.

Mahle AE, MacCarty WC. Ectopic adenomyoma of uterine type (A report of ten cases). J Lab & Clin Med 1920;5:218–228:221.

Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 122–23. The Gynecological Service lost four of five patients from postoperative septic peritonitis in 1 week; one patient was infected before surgery and survived, the four clean cases did not. At the weekly staff meeting in January 1895, Cullen recommended the cases be reported in detail. Kelly assigned the task to Cullen. See Cullen TS. Post-operative septic peritonitis. Johns Hopkins Hospital Reports 1895;IV:411.

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery 1920;1:215–283:272. See Figure 44, on page 272 an anatomical illustration labeled: “Adenomyoma in the left rectus muscle.” See also Figures 45, on page 273, a histologic section labeled: “The nodule consisted of nonstriped muscle and fibrous tissue, and scattered throughout it were areas of typical uterine mucosa.” Figure 46, on page 274 (also a microscopic section) shows islands of normal uterine mucosa “scattered throughout the myoma.”

Cullen TS. Archives of Surgery 1920;1:215–283:278. Subsequently the patient had a normal pregnancy, normal labor and delivery at term. However, a hematoma of the left broad ligament and left vaginal wall developed postpartum. It was successfully drained vaginally.

100

Cullen TS. Archives of Surgery 1920;1:215–283:272. Figure 44, Adenomyoma of the left rectus muscle. See Figure 45 on page 273 and Figure 46 on page 274 for the histology.

101

Cullen TS. Archives of Surgery 1920;1:215–283:272. Figure 44, Adenomyoma of the left rectus muscle. See Figure 45 on page 273 and Figure 46 on page 274 for the histology.

102

Mahle AE, MacCarty WC. Ectopic adenomyoma of uterine type (A report of ten cases). J Lab. & Clin Med. 1920;5:221.

103

Cullen TS, Broedel M. Lesions of the rectus abdominis muscle simulating an acute intra-abdominal emergency. Bulletin Johns Hopkins Hospital 1937;lxi:295–315.

104

Cullen, Thomas S. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery. 1920;1:215–283:258. William Wood Russell was the same man who reconsidered his withdrawal and accepted the residency position that Kelly had offered to Cullen in the interim. This resulted in Cullen spending three precious years in the pathology laboratory.

105

Russell WW. Aberrant portions of the müllerian duct found in an ovary. Johns Hopkins Hospital Bulletin. 1899;8–10 with an additional three pages labeled Plate I, Plate II, and Plate III each with illustrations of whole-ovary microscopic sections drawn by Max Broedel.

106

Cullen, Thomas S. Archives of Surgery. 1920;1:215–283:260, 262.

107

Cullen, Thomas S. Archives of Surgery. 1920;1:215–283:260, 263, Figure 36 (Case 13).

108

Cullen, Thomas S. Archives of Surgery. 1920;1:215–283:259–60.

109

Cullen, Thomas S. Archives of Surgery. 1920;1:215–283:259.

110

Cullen, Thomas S. Archives of Surgery. 1920;1:215–283:250–60.

111

112

The glands were atypical only in the sense of being dilated, they resembling Swiss cheese hyperplasia of the uterine endometrium.

113

Casler DB. Transactions of the American Gynecological Society. 1919;44:69–84.

114

Casler DB. Transactions of the American Gynecological Society. 1919;44:69–84. See Figure 7.

115

Casler DB. Transactions of the American Gynecological Society. 1919;44:69–84:69.

116

Casler DB. Transactions of the American Gynecological Society. 1919;44:69–84:70.

117

Casler DB. Transactions of the American Gynecological Society. 1919;44:69–84:74. “The pathological process beginning in the polyp is really an orderly overgrowth of the stroma, which has gradually exterminated the uterine glands by strangulation, and then in the same manner has attacked the uterine musculature.”

118

Cullen, Thomas S. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery. 1920;1:215–283:259–60:258.

119

Cullen TS. Archives of Surgery 1920;1:215–283:259–260. Figures 33 and 34.

120

Cullen TS. Archives of Surgery 1920;1:215–283:237.

121

Cullen TS. Archives of Surgery 1920;1:215–283:238–240. See supra-vaginal hysterectomy specimen, amputated through the cervix: Cullen’s septum case #14, Figure 16, page 238.

122

Cullen TS. Archives of Surgery 1920;1:215–283:242. Cullen’s septum case #14 See: Fig. 20, page 242. Here, Cullen extended the use of his “flow” metaphor for describing adenomyoma of the tube.

123

Cullen TS. Archives of Surgery 1920;1:215–283:243. Cullen’s septum case #14. Fig. 21, page 243. The legend reads: “Uterine mucosa on the surface of the ovary in a case of adenomyoma of the rectovaginal septum…The miniature uterine cavity on the surface of the right ovary is represented by a. The lining mucosa resembles in every particular that of the body of the uterus. Some of the glands show hypertrophy. The mucosa of the adenomyoma of the rectovaginal septum seems to have overflowed to the surface of the adherent ovary. The same condition was noted on the surface of the corresponding tube.”

124

Cullen TS. Archives of Surgery. 1920;1:215–283: 242.

125

Cullen TS. Archives of Surgery 1920;1:215–283:262. See Cullen’s septum case 14 (Gyn.-Path. No. 25003) on page 237 and endometriosis of the tube: Figure 20 on page 242. See also endometriosis of the ovary: Figure 21 on page 243.

126

Cullen TS. Archives of Surgery. 1920;1:215–283: 244.

127

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery 1920;1:215–283:264,

128

Cullen TS. The distribution of adenomyomata containing uterine mucosa. American Journal of Obstetrics and Diseases of Women and Children 1919;180:130–138.

129

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives Surgery 1920;1:215–283.

130

Cullen TS. Thomas S. Cullen, Henry Mills Hurd, the First Superintendent of the Johns Hopkins Hospital [Baltimore, MD: Johns Hopkins Press, 1920]. In 1920, Cullen published a small biography honoring Henry Mills Hurd, the first superintendent of the Johns Hopkins Hospital, the man who had so encouraged publication by members of the faculty. Three cases of subperitoneal, pedunculated adenomyoma. Arch Surgery 1921;2:443–454. Cullen TS. Further remarks on diseases of the umbilicus Surg Gynecol Obstet 1922;35:257–283. Cullen TS, Broedel M. Lesions of the rectus abdominis muscle simulating an acute intra-abdominal condition. Bull Johns Hopkins Hospital, November, 1937.

131

Cullen TS. Archives Surgery 1920;1:215–283:215.

132

Judith Robinson, Tom Cullen of Baltimore [London, Toronto, New York: Oxford University Press, 1949], 117.

133

Cullen TS. The distribution of adenomyomata containing uterine mucosa. Am J Obstetrics Diseases Women and Children 1919;180:130–138.

134

Cullen TS. The distribution of adenomyomas containing uterine mucosa. Archives of Surgery 1920;1:215–283.

135

Cullen TS. Archives of Surgery 1920;1:215–283. Cullen began his classification of adenomyomata with adenomyoma of the body of the uterus and ended with adenomyoma of the umbilicus, subjects on which he had written books.

136

Cullen TS. Archives of Surgery 1920;1:215–283:250. Figure 27 (Case 10). Cullen illustrated an adenomyoma [springing from the cervix] that invaded the broad ligament and compressed the right ureter causing partial ureteral obstruction.

137

Cullen TS. Three cases of subperitoneal pedunculated adenomyoma. Archives Surgery 1921;2:443–454:454. Mahle AE, MacCarty WC. Ectopic adenomyoma of uterine type (A report of ten cases). J Lab & Clin Med 1920;5:218–228:218. Cogently, Mahle and MacCarty from the Mayo Clinic had observed in 1920: “It is evident, regardless of the amount of literature which has been written on the subject, that the importance of adenomyoma has not been recognized either clinically or surgically.”

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