Review

Gynecol Obstet Invest 2014;78:19

DOI: 10.1159/000358919

Received: October 21, 2013

Accepted after revision : January 20, 2014
Published online: May 16, 2014

The History of Endometriosis

Giuseppe Benagiano a Ivo Brosens c Donatella Lippi b
a

Department of Gynaecology, Obstetrics and Urology, Sapienza University, Rome, and b Department of
Experimental and Clinical Medicine, School of Sciences of Human Health, University of Florence, Florence, Italy;
c
Leuven Institute for Fertility and Embryology, Leuven, Belgium

Key Words
History Adenomyoma Adenomyosis Endometriosis

Abstract
A dispute has recently emerged whether early descriptions
exist of the condition we name endometriosis. A first question is: Who identified endometriosis? To respond, two noncomplementary methods have been employed: searching
for ancient descriptions of symptoms associated with endometriosis or, alternatively, identifying researchers who described pathological features we associate with the presence of endometriosis in its various forms. We opted for the
latter and found no evidence that in older times anyone delineated the macroscopic features of endometriosis; descriptions of menstrual or cyclic pain cannot be taken as proof of
knowledge of what caused it. During the mid-part of the
19th century, Rokitansky had a great intuition: endometrial
glands and stroma can be present in ovarian and uterine
neoplasias. However, using histological parameters of endometrial structure and activity, the first scientist to delineate
peritoneal endometriosis under the name adenomyoma
was Cullen. On the other hand, Rokitansky was the first to
describe a form of adenomyosis (an adenomatous polyp).
Early descriptions of ovarian endometrioma as haematomas
of the ovary or chocolate cysts date back to the end of the

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19th century. The first mention of an ovary containing uterine mucosa was published in 1899 by Russel, but Sampson
was the first to demonstrate specific endometrial activities,
such as desquamation at the time of menstruation and decidualization in pregnancy; subsequently, he presented a
theory on its pathogenesis.
2014 S. Karger AG, Basel

Introduction

Over the past two decades there has been an increasing interest in the history of endometriosis, and recently
Nezhat et al. [1] detailed a large number of classic texts
from antiquity to the 19th century containing descriptions of symptoms that they considered evidence of the
existence of endometriosis. Clearly, whereas some of the
women mentioned probably had endometriosis, these
descriptions cannot be taken as evidence of an early identification of the condition, and, indeed, scholars disagree
on who was the first to become aware of its existence. This
is why we have argued that to resolve the dispute, it is necessary to outline a specific methodological approach [2],
beginning with its current definition, namely the presence of functional endometrial-like tissue outside the
uterus, but in the pelvic cavity, or even outside, with eviGiuseppe Benagiano
28, chemin des Massettes
CH1218 Grand Saconnex (Switzerland)
E-Mail pinoingeneva@bluewin.ch

dence that lesions are cellularly active, or have an effect

on normal physiology [3].
The starting point for our historical journey is the definition of the expression discovering endometriosis. The
word discovery may mean: imagine its existence; name
it; provide a clinical description of its symptoms; describe
it as a separate pathophysiological entity; find histological
evidence of its nature.
In the early days, peritoneal, extraperitoneal (e.g. scar)
and deep-infiltrating endometriosis, ovarian endometrioma and adenomyosis were lumped together under
the name adenomyoma, and, initially, all these varieties were considered together [2]; only in the 1920s did
adenomyosis and endometriosis become separate entities [4, 5].
Keeping within the confines of the observation of the
presence of endometrial glands and stroma outside the
uterine cavity with the specification that this invasion
was benign (non-neoplastic) in nature [2], we will examine descriptions provided by different scholars and alleged to relate to adenomyoma, adenomyosis, endometriosis and ovarian endometrioma, critically evaluating
published information on the history of this multifaceted
condition.
In summary, we believe that there are 3 steps in the
history of the identification of endometriosis: the description of symptoms that may be attributed to the presence
of endometriosis and/or adenomyosis; the microscopic
evaluation of lesions (whether from Rokitanskys dead
house or from hysterectomy specimens), and the laparotomic/laparoscopic evaluation, with the discovery of typical (haemorrhagic) and later also subtle lesions. The latter had to be distinguished from deep endometriosis.

Ancient Descriptions of Clinical Features Suggesting

the Presence of Endometriosis

In 1999, Vincent J. Knapp [6] opened a new chapter in

the thorny debate surrounding the history of endometriosis by listing a number of old dissertations dating back
to the 18th and even the 17th century, purported to describe the characteristics of endometriosis. Then, in 2012,
Nezhat et al. [1] went much further claiming that even in
ancient times a number of classic authors described
symptoms and features of endometriosis.
The starting point to evaluate these claims is whether
any ancient author detected and described the presence
of bluish, reddish or even grey-yellow spots on the peritoneal surface or posterior fornix, or that of chocolate
2

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DOI: 10.1159/000358919

cysts in the ovary. In more recent times, such descriptions

were followed by histological confirmation of the presence of endometrial glands and stroma. The presence of
symptoms such as pain, dysmenorrhoea (whether cyclic
or not), dyspareunia, menorrhagia, etc. can be suggestive,
but they are insufficient for a correct diagnosis. Even
more so, as we have been reminded by Templeman et al.
[7] that the present dominant view of endometriosis and
adenomyosis is that they are diseases with different clinical profiles. Today, a differential diagnosis can be attempted, but such an exercise becomes extremely difficult
using only quotations from ancient physicians.
An important merit that must be ascribed to Knapp is
to have unearthed from the US National Library of Medicine many old texts dealing with female health troubles.
These important documents had been all but neglected by
contemporary medical scholars. He should be credited
with focusing our attention to the exploration of womens
diseases that began to bloom during the 18th century.
However, despite his perspicacity in highlighting this pivotal period in the history of obstetrics and gynaecology,
his approach presents some weak points.
His work is mainly based on Schrns Disputatio inauguralis medica de ulceribus uteri, which he considers the
first-known and highly detailed description of wideranging, peritoneal endometriosis [8]. From our point of
view, this enthusiastic affirmation cannot be accepted for
the following reasons: Knapp states that Schrn minutely described ulcers, that in their primary form were distributed throughout the stomach (the peritoneum) and
were located just as prominently in the bladder, the intestines, the broad ligament, and the outside of the uterus
and the cervix. First, in reading through the original text,
we find that Schrn stated that these ulcers may affect
non ... solum ... suam cavitaten ... verum etiam ... sua
orificia et vaginam (not only the inner portion of the
womb, but also the cervix and vagina); this makes them
ulcers, not endometriotic lesions. He further stated that
these inflammations were both constantly expanding in
size and vasculated, and that they could become pus-filled
[what Schrn wrote is that pus was causa mediata proximior, meaning that pus could originate or only be collected in the womb] and tumorous and could form abscesses that were susceptible to haemorrhaging. After describing the womb, Schrn gives a definition of ulcus, as
solutio continui ... cum corruptione lenta et deperditione
substantiae ipsius uteri, a materia acri, salina erodente ibi
collecta dependens (a solution of continuity with slow
corruption and loss of uterine substance, caused by salty
and sour eroding matter, collected into it; p. 5). Uterus,
Benagiano /Brosens /Lippi

orificia and vagina can be affected for different causes:

the causa immediata is the erosion (erosio; p. 9) with
loss of matter; the causa mediata proximior is pus, which
can originate from or be only collected in the womb (p.
10).
Among the causes of ulcers, Schrn (pp. 1215) also
takes into consideration sex res non naturales (6 nonnatural things), an expression commonly used in the
Middle Ages to indicate 6 agents that determine health
and disease and to which the human body is exposed in
the course of daily life. The age of the woman is important
as aetas mulierum ad coniugium matura his potissimum
vexatur ulceribus (sexually mature women are more susceptible to these ulcers; p. 12).
According to Schrn, there are at least 4 kinds of uterine ulcerae and chirurgi oculorum acies penetrare non
valeat ... (the surgeon cannot see them; p. 15). Because
they can be compared to external ulcerae, Schrn deduces that they too can be different in shape and qualities,
in position, in causes and according to their symptoms.
Heat, pain and the loss of materia peccans (blood and/
or pus) may indicate the presence of an ulcus, which
causes a prickling pain (pungitivus; p. 17). Sometimes
men who have sexual intercourse with suffering women
can have their penis eroded. The loss of blood is different
from the one in menstruation: women who suffer from
this disease may have miscarriage and painful deliveries.
Prognosis depends on the seriousness of the problem;
treatment includes surgery, drugs, lifestyle change. Sexual intercourse may have to be interrupted till complete
recovery.
In fact, Knapp examined many dissertations, the titles
of which range from ulcers [912] to inflammations of
the uterus [1318], concluding that already in 1739 Crell
described ovarian endometriotic cysts with the words:
Tumorem fundo uteri externe adherentem describit
[19].
It seems that Knapp has been quoted over and over,
without any attempt to confirm his statements; unfortunately his untimely death prevented any critical discussion of his findings. As far as we could evaluate the texts
he quoted, they simply do not show the macroscopic features of endometriosis. In addition, without a microscope, these early authors had no way to even predict the
presence of endometrial (or even epithelial) tissue in the
lesions they described. Therefore, it becomes a physical
impossibility for the specific features of endometriosis to
have been described during the 17th and 18th centuries.
In the case of Nezhat et al. [1], they provide a reconstruction of gynaecological troubles in the past and detail

the work of a long series of classic authors, starting with

Hippocrates, who described symptoms that we know are
associated with adenomyosis or endometriosis, concluding that they described the conditions.
In historical terms, the contamination of different
texts by Hippocrates (pp. 5354; menstrual disorders are
described in the Aphorisms; uterine ulcers in the book On
the Nature of Women) and odd interpretations of iconography (p. 519, fig.25 and 26) seem to weaken their case.
Indeed, it is now accepted that paintings entitled lovesickness show cases of unwanted pregnancy [20]. At any
rate, they fail to mention any reference to objective findings (description of lesions) and therefore to any cause of
the reported symptoms. In addition, the suggestion by
Schrn not to have sexual intercourse in the presence of
ulcerae seems to contradict a supposed relationship with
hysteria (pp. 519, 535536) and lovesickness. Even the
statement by Soranus of Ephesus that women menstruating with difficulty and suffering uterine pressure have
been freed of their troubles after pregnancy [21] cannot
be taken as evidence that they had endometriosis.
In conclusion, in reconstructing the path leading to the
identification of a disease or condition, we must avoid
precisely what Nezhat et al. [1] did: filtering all histories
and ancient reports through the lens of modern understandings. By doing it, we presume in ancient physicians
a knowledge that they simply could not have.

The History of Endometriosis

Gynecol Obstet Invest 2014;78:19

DOI: 10.1159/000358919

The Discovery of Ovarian Endometriosis

The Work of Carl Rokitansky

When, in 1991, we first became interested in the history of endometriosis [22], we omitted altogether to mention Carl Rokitansky. The reason was simple: Rokitansky
labelled his cases sarcomas and this, in our view, ipso
facto excluded the possibility that he may have described
endometriosis. Then, we became aware of the fact that, as
reported by Batt [23], Rokitansky utilized a personal definition of tumours. In his opus magnum (A Manual of
Pathological Anatomy) [24], he wrote:
Sarcoma and carcinoma ... Kindred new growths, important
from their frequency no less than from the question arising, in every concrete case, as to their innocence or malignancy. We have
selected the term sarcoma to designate the benign growths, not
because of any especial analogy with muscle flesh, but in order to
fix and define a name familiarized by long usage, and also by no
little abuse. The malignant we shall leave in possession of their ancient characteristic appellation cancer-carcinoma.

This prompted us to give Rokitansky credit for being

the first to describe adenomyosis [25].
In order to attempt to resolve, once and forever, the
ongoing controversy over the nature of descriptions
made by Rokitansky in 1860 [26], we requested Dr. J.D.
Umpleby, member of the Swiss Association of Translators, Terminologists and Interpreters, to carry out a full
translation of his article On the neoplasm of uterus
glands on uterine and ovarian sarcomas with the description of an ovarian cystosarcoma. It has been claimed
that this represented the first description of an endometrioma; Rokitansky wrote:
The autopsy carried out on a 66-year-old marasmic female on
2 March 1859 showed the following ... Uterus small, and retroflexed, wherein its fundus, wedged between the cervix and the
tumour (to be described in more detail) of the left ovary, stretched
out in the recto-vaginal cavity towards the left. The left ovary degenerated to an approximately fist-sized tumour, whose right
half consisted of a compact fibrous mass, whereas the left half was
formed from an aggregate of serous cysts, of which the largest
partly sat in a cup of the fibrous mass. In the remaining extent the
other smaller cysts adhered to it. The whole tumour was turned
around in its aforesaid position such that the cyst part itself faced
to the right. The tuba ran over the tumour, somewhat stretched
and fixed to it up to the stretched fringed end. The right ovary,
compact, shrunken, penetrated by an externally protruding
bean-sized cyst. In a closer examination of the tumour, namely
of the fibrous matter, it showed, particularly near to the cysts, on
average a glandular appearance, in that it was interspersed by
delicate vesicles and granules. Alongside, several millet-sized to
hemp seed-sized mucous-containing cysts were present therein.
With the microscope one could perceive in a compact connective
tissue layer numerous tube-like structures coated by an epithelium and their sections, additionally several crack-like sinuous
openings, in which papilla-like excrescences of the layer mass
protruded.

Whereas there is no doubt that Rokitansky identified

epithelial structures in this tumour and considered them
as endometrial in nature, the description can hardly be
considered that of an ovarian endometrioma. Indeed,
there is no mention of the presence of degenerated blood;
on the contrary, the cysts were serous or mucous and
(presumably in these cysts) there were protruding excrescences. Rokitanskys conclusion was: A sarcoma with
uterine gland tubules is also found in the ovary and these
cystic structures of the ovaries immediately signify a cystosarcoma adenoides uterinum.
Clearly, Rokitansky had a great intuition: that endometrial glands and stroma could be present in ovarian
and uterine neoplasias. He wrote: Among the connective
tissue tumours of the diseased uterus, there are some in
whose composition glandular tubes form that accord
with the uterine glands [26]. Yet, among early research4

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ers of this type of pathology, only the British surgeon J.

Bland Sutton [27] cited Rokitansky, although he considered his work interesting for describing organ torsion.
We found no reference to the work of the already famous
Rokitansky in any of the articles published around the
turn of the 19th century and dealing with the presence of
haemorrhagic cysts of the ovary [2837]. It was only recently that the discovery of endometriosis was attributed
to Rokitansky [23, 38]. A possible explanation may rest in
a simple reality: on the one hand, the nature of the mucosal invasions of the peritoneal cavity (as they were
called in the early days) was debated for more than 50
years following Rokitanskys publication and they were
usually not considered endometrial in nature. On the
other hand, the features he described in the case he labelled cystosarcoma adenoides uterinum of the ovary,
irrespective of the unusual name, were too different from
ovarian haematomas or from chocolate cysts to be taken into consideration.
In conclusion, we believe that taken together, the
findings by Rokitansky in both ovaries cannot be considered the description of an endometrioma. Several observations support this contention: Emge [39] in analysing Rokitanskys work gained the impression that his
usage of the word sarcoma was meant to indicate an
abnormally active proliferation of stroma rather than a
truly malignant process. Clearly, for pathologists the description of abnormally active proliferation of a glandular tissue in the ovary of a 66-year-old lady could hardly
be suggestive of endometriosis. Thirdly, there are few
descriptions of ovarian endometriomas in non-treated
postmenopausal women. In 1996, Toki et al. [40] studied histological features of 21 cases of postmenopausal
endometriosis comparing them to the corresponding
eutopic endometrium. They concluded that endometriotic lesions seem to have remained biologically active
even in the low-oestrogen milieu of the postmenopausal
age. Addressing the issue of ovarian endometriomas, in
all 26 cases the foci of endometriosis were recognized in
the ovary ... both epithelial and stromal components
were identified in all cases. The glands were in a proliferative phase and they could not identify either the presence of atrophic or secretory epithelium, although in
some cases hyperplastic and atypical changes were present. In 2009, Manero et al. [41] described one case of
postmenopausal endometrioma in an untreated woman
and provided a microphotograph of the cystic wall. Even
though we have no drawing of the case described by
Rokitansky, it is easy to conclude that it bears no similarity.
Benagiano /Brosens /Lippi

The Central Role of the Chocolate Cyst in the

Discovery of Endometriosis
The first unequivocal description (with a clear illustration) of the presence of endometrial tissue within an ovary is contained in a little-known paper published in 1899
by Russel [28]. During a meeting he described the case of
a premenopausal woman who underwent surgery for a
cystic adenocarcinoma of the left ovary and found the
right ovary enveloped in adhesion of the posterior face of
the broad ligament. Russel explained that at gross inspection nothing unusual was noticed about the ovary, it
being of normal size. However, under the microscope, he
found a number of areas, which were an exact prototype
of the uterine glands and interglandular connective tissue. These glands were arranged as in normal uterine
mucous membrane and opened into spaces, their epithelium being continuous with its lining membrane. In addition, both the glands and interglandular connective tissue were occasionally surrounded by bundles of smooth
muscle. More than half a century later, Hughesdon [42],
studying intact endometriotic cysts, confirmed the presence of smooth muscle fibres surrounding the cysts. Because of the prevailing climate of his time, Russel believed
that the tumour was due to the presence of aberrant
portions of the mllerian duct in the ovary.
Russels presentation was followed by a discussion
during which Dr. Barker, an anatomist, stated that the
case is an extremely rare one, indeed I believe it is the only
one on record. However, Russel had commented that
gland-like spaces within normal ovaries had already
been described. We do not know to whom Russel was referring.
A few additional cases were published within a few
years: in 1905, Semmelink and De Josselin de Jong [29]
reported an ovarian cyst the structure of which was similar to endometrial stroma and believed to be of wolffian
origin; the same year Pick published 4 more cases [30],
and in 1909, Sitzenfrei [31] described 2 cases with rectouterine adenomyome. In the first case, he found the
presence of two cystic cavities as big as a walnut full of
blood but did not describe the nature of the lining; in the
second case, he described glandular formations and
blood-containing cytogenic tissues in the adherent part
of the ovary, clearly an ovarian endometrioma. Several
descriptions of haematoma of the ovary were also published: in 1906, Savage [32] presented 7 cases, failing to
identify the lining of the cysts as being made by endometrial tissue, although he believed that these haematomas
were associated with the presence of fibroids. Indeed, the
coexistence of uterine myomas and haematoma of ovary

had been reported by several authors [3335], although

considered very rare. Intriguingly, in spite of fairly precise
descriptions, no mention of a possible endometrial origin
of these cysts was made. In 1920, Smith [36] also described several cases of ovarian haematomas; one in particular had all the characteristics of ovarian endometriosis; the patient suffered of severe dysmenorrhoea, and
there was a marked pain relief after she had been operated. At surgery, the ovary was enveloped in adhesions
and during the adhesiolysis a chocolate-coloured fluid
leaked from the soft, fixed mass in the left cul-de-sac. Finally, in dissecting the ovary, numerous small cysts in the
ovary containing dark material were found.
During a meeting held in 1919, Casler [35] described
the case of a woman who after hysterectomy consistently maintained that, at regular monthly intervals, she
menstruated for a part of one day each month. The author
specified that the entire cyst, or uterine cavity as it really
is, is lined throughout by a single layer of tall columnar
epithelium of the uterine type, and in places cilia can be
made out. It is noteworthy that Casler also found interlacing bundles or columns of smooth muscle tissue. It is
possible that the repeated presence of muscular tissue
convinced researchers that this was a variety of adenomyoma. Here again, in the already-mentioned discussion, Dr Norris, described the case of a woman in whom,
at surgery, one ovary was enveloped in numerous adhesions. Inside the ovary a small cyst (less than 1 cm in diameter) lined by endometrium was found, containing a
little free blood. Dr. Norris specified that the endometrium of the ovary was similar to that removed from the uterus by curettage and was of the same periodicity [37]. In
1920, Cullen [4] published 2 additional cases: the first consisted of a cyst with a brownish membrane and an inner
lining of cylindrical epithelium; in the second, the right
ovary looked like a miniature uterine cavity. In this case,
the ovarian cyst was associated with a widespread adenomyoma of the rectovaginal septum, suggesting that the
uterine mucosa on the surface of the ovary was due to an
overflow of the adenomyoma of the rectovaginal septum.
In his paper, Cullen also reported a third case sent to him
from St. Louis. It consisted of an ovary in which several
cavities were found, filled with partially coagulated blood.

The History of Endometriosis

Gynecol Obstet Invest 2014;78:19

DOI: 10.1159/000358919

The Chocolate Cyst of the Ovary as Endometrial

Incubator
In the well-known 1921 publication Perforating hemorrhagic (chocolate) cysts of the ovary [43], Sampson described 23 cases of ovarian haematomas of endometrial
type as follows:
5

The hematomas varied in size from 1 to 9 cm in diameter, most

of them being from 2 to 4 cm. They were bilateral in eight of the
23 cases. A perforation had occurred in all the 23 cases and was
found on the lateral, or on the free surface of the ovary. At operation the cyst or ovary was found to be adherent, and in freeing it
the chocolate-like content escaped because a previous perforation, which had become sealed by whatever structure of the ovary
had become adherent, was reopened, or the wall of the cyst was
torn. Adhesions were present in all cases and these varied greatly
in location and extent.

Initially, Sampson based his implantation theory on

the assumption that the tubules found in the ovary arise
from epithelium (possibly both tubal and uterine) escaping from and through the tube. In his specimens, the epithelium is found on the surface of the ovaries and invades
the underlying tissue in the form of tubules. The epithelium lining these tubules is often ciliated; sometimes the
tubules suggest a tubal origin and at other times a uterine
one. He felt that the adjective mllerian would be more
inclusive and therefore preferable to that of endometrial,
since in some instances the epithelium lining the ovarian
haematomas may possibly derive from the tubal epithelium.
In 1922, Sampson [44] described a series of 37 cases of
superficial and deep chocolate cysts (22% of his abdominal operations for pelvic disease from May 1, 1921, till
May 1, 1922) in a study entitled The life history of ovarian hematomas (hemorrhagic cysts) of endometrial (mllerian) type. At this stage Sampson considered the ovary
as an incubator, hot bed, or intermediary host in the development of pelvic implantation of adenomas of endometrial type, which in some instances may possibly impart greater virulence to the epithelium developing in it;
but it is not an essential intermediary host in the origin of
all implantation adenomas of endometrial (mllerian)
type. The reactions of the lining of ovarian hematomas
of endometrial type were similar to those of the uterine
mucosa mimicking menstruation in terms of bleeding,
pregnancy in terms of decidualization, and the ageing
process by undergoing atrophy. After discarding the term
perforating haemorrhagic cyst and referring to them as
haematomas or haemorrhagic cysts of endometrial (mllerian) type, the road was open to call them ovarian endometriomas.
Sampson [45] assumed that rupture of the endometrial cyst was the cause of peritoneal endometriosis,
whereas several authors proposed the opposite mechanism, namely that endometriotic lesions on the cortex invaded the ovary, or that endometrial cells arrived inside
the ovary via lymphatics [46]. Schwarz and Crossen [47]
remarked that small cysts notched on the surface pushed
6

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the cortex of the ovary ahead of them. Finally, in 1957,

Hughesdon [42] demonstrated histologically on a series
of 27 ovaries with chocolate cyst in situ that in 90% of the
cases the wall of the cyst was formed by ovarian cortex.
Moreover, he observed that invagination of the inner cortex was followed by a more or less abortive attempt at a
muscular wall, concluding that the ectopic endometrium
does not simply erode its way into the ovary. It is actively
invaginated and, producing a pseudo-uterus, followed by
a more or less abortive attempt at a muscular wall. The
presence of an inner cortex shows that the relation to the
surface is primary and not secondary, such as would be
implied by the title of Sampsons original paper Perforating hemorrhagic cysts of the ovary [43], or by Halbans
[46] exposition of the lymphatic theory. In 1994, using
laparoscopy and ovarioscopy, Brosens et al. [48] demonstrated that indeed the inner lining was cortex, at least
partially covered by a thin lining of endometrial surface
epithelium and stroma. Both the invagination of the ovarian cortex and the extensive smooth muscle metaplasia
are of immense importance for understanding the pathophysiology and proper management of the ovarian endometrioma in young women.

The Identification of Adenomyoma

In his 1860 paper, Rokitansky [26] described 3 cases of

fibrous polyps of the uterus and stated that among them
there are some, in which glandular tubes are found. In
theory, this description has nothing to do with either adenomyosis or endometriosis; however, in the general description of his autopsy findings Rokitansky mentions
that in some rare cases the extension of the uterine glands
occurred in both directions, i.e. both into the uterus cavity, as well as into the uterus parenchyma, such that the
sloped bulge represents a plug of longitudinal fibrous appearance driven into, as it were, the uterine mass. We
believe that by describing polyps Rokitansky misled later readers, since a structure protruding inside the uterus
has been considered almost by definition not an adenomyoma.
To clarify the situation, we searched the modern literature for adenomyomatous polyp with surprising results: In 2008, Fitzhugh et al. [49] described 1 case and
stated that only another case had been reported; in 2012,
Raghavendra Babu et al. [50] found 5 publications on the
subject; whereas our search of the literature identified 13
reports of adenomyomatous polyp (mostly by Japanese
authors), structures that in addition to the usual features
Benagiano /Brosens /Lippi

of endometrial polyps, also contain a smooth muscle

component. Histologically they are composed of endometrial glands intimately mixed with smooth muscle and
thick-walled blood vessels [50]. Although adenomatous
polyps were mentioned in gynaecological pathology
books already 50 years ago [51], the first detailed report
seems to be that of Nasu et al. [52] who, in 1995, described
9 cases, concluding that all of the polypoid lesions were
composed of endometrial glands admixed with smooth
muscle cells. Neither the glandular epithelium nor the
stromal cells exhibited atypia. Three of the cases described were found in older patients treated with tamoxifen [5355]. Their description is strikingly similar to that
made by Rokitansky; in addition, an imaging review of
adenomyosis features by Tamai et al. [56] considered adenomatous polyps a variant of adenomyosis: Less commonly, adenomyosis can present as a well-circumscribed
form known as adenomyoma, adenomyotic cyst characterized by the presence of haemorrhagic cyst, or adenomyomatous polyp protruding into the uterine cavity. De
Brux [57] also mentioned this type of polyps and debated
whether they are a variant of adenomyosis or endometriosis, or are truly neoplastic. Finally, in their 1974 textbook, Novak and Woodruff [58] state that 3 types of endometrial polyp can be distinguished, the third type,
much less common than those already described, is composed not only of endometrial, but shows in addition a
variable, at times considerable amount of involuntary
muscle tissue. This variety is properly called adenomyomatous polyp, and, as might be expected, is often associated with adenomyosis of the uterus.
At any rate, for the first of the 3 cases Rokitansky specifies:
The thick-walled uterus of an aged female showed this inter
alia. On the left hand side under the mouth of the tuba was a swollen, about 1 to 2 long smoothly coated polyp of 11/2 diameter in
the pedunculus, from 45 on the free end. A similar bisecting
perpendicular section continuing into the uterine mass shows that
the pedunculus penetrates to a depth of 4 into the uterine mass
and stores a wedge driven right into the uterine tissue; on its section along its length it has a fibrous appearance and can be torn
into fibres in this direction; the arrangement of the fibres is determined by numerous extremely long glandular tubes held together
by means of a core-rich connective tissue.

This can indeed be first the description of a case of adenomyosis. Once again, however, early researchers of adenomyoma failed to mention Rokitanskys cases.
The name adenomyoma was coined around the end of
the 19th century. In 1896, both Cullen and Von Recklinghausen described the condition [59, 60], followed by Pick
[61] and Rolly [62, 63] in 1897.
The History of Endometriosis

Twenty years later, Lockyer provided a comprehensive

definition [64]: The term adenomyoma implies a new
formation composed of gland-elements, hyperplastic cellular connective tissue, and smooth muscle. He added:
So far as the adenomatous elements are concerned, the
same type of tumour-formation can be found also in the
digestive tract (bowel and stomach), and some observers
claim that analogous conditions can exist in the gall-bladder, in the kidney, and elsewhere.
During the early days of the 20th century, attention
focused on the origin of adenomyomas, and ignoring
Rokitanskys conclusions pathologists of the fame of
Von Recklinghausen [60] argued that adenomyomas
were the result of displacement of wolffian or mesonephric vestiges. In fact, the majority of pathologists
and gynaecologists rejected the hypothesis that the
glands they observed were endometrial. As late as
1918, Lockyer, in detailing the various theories on the
origin of epithelial glands and stroma found in the pelvis outside the uterine cavity, was unable to resolve the
question of their origin. He wrote: Nothing but the topography of the tumour, nothing but laborious research
entailing the cutting of serial sections in great numbers,
can settle the question as to the starting point of the
glandular inclusions for many of the cases of adenomyoma [64].
In our reconstruction of the history of endometriosis
[2, 22, 25], we have argued that the first clear description
of the morphological and clinical picture of adenomyoma
was made by the American Surgeon Thomas Cullen. In
his book Adenomyoma of the Uterus [65] he describes an
observation made during October 1882:
I found a uniformly enlarged uterus about four time(s) the natural size. On opening it I found that the increase in size was due to
a diffuse thickening of the anterior wall ... Examination of the(se)
sections showed that the increase in thickness was due to the presence of a diffuse myomatous tumor occupying the inner portion
of the uterine wall, and that the uterine mucosa was at many points
flowing into the diffuse myomatous tissue.

To our knowledge, after the controversial description

of fibrous polyps of the uterus made by Rokitansky, this
was the first time that the endometrial nature of the mucosal nests found in adenomyomas was affirmed.
Cullen collected 90 uteri with adenomyomas and described their various presentations; his specimens were
from the myometrial wall (where he appreciated the continuity between eutopic endometrial glands and the nests
in the myometrium), uterine horns, the subserosa, uterine ligaments, ovaries and even the umbilicus [4].

Gynecol Obstet Invest 2014;78:19

DOI: 10.1159/000358919

There is no doubt that Cullen considered uterine adenomyoma, ovarian endometriosis and deep endometriosis as one disease characterized by the presence of endometrial tissue outside the uterine mucosa.

Separating Adenomyosis from Endometriosis

In 1925, Sampson [66] affirmed that in menstruating

women, endometrium sloughing into uterine veins could
cause adenomyosis and disease beyond the pelvis. In the
same year, in another paper, he first introduced the term
endometriosis, although he was not quite sure about the
newly coined word and also utilized the term implantation adenomyoma. He provided pictures of lesions of
various colours, including white, together with photomicrographs of superficial endometriosis of the uterus and
ovarian cortex [67].
Still, in 1927, Sampson stated: The histologic study of
the ectopic endometrial tissue in a direct or primary endometriosis (so-called adenomyoma of mucosal origin)
shows that this tissue contains venous capillaries similar
to those of the mucosa lining the uterine cavity [45]. He
felt the necessity to explain the term, as he was not yet
comfortable in using it [68].
While Sampson struggled with the best term to define
his findings, Frankl [5] had carefully described the anatomical picture for the mucosal invasion of the myometrium; he called it adenomyosis uteri and explained:
I have chosen the name of adenomyosis, which does not suggest
any inflammatory origin as do terms like adenometritis, adeno-

myositis, adenomyometritis, still employed. ... We were never able

to find any trace of an inflammatory infiltration, either in the musculature or in the mucosa of this region. In the history of these
patients, we did not find a single symptom suggesting a preceding
puerperal or gonorrheal infection.

In his thorough evaluation of adenomyosis, Frankl

also provided the criteria for a differential diagnosis with
endometriosis (although, obviously, he still called it adenomyoma): In an adenomyoma the glands originate
independently within the myoma as an autochthonous
growth, while in adenomyosis, even when localized, the
direct connection of the endometrium with the islands of
mucosa located in the musculature can be established in
serial sections. In the majority of cases of genuine adenomyoma, which are extremely rare, the glands are not accompanied by stroma. Having done this, he could point
out similarities between his observations and those of
Sampson:
An observation made only once should be mentioned, namely,
the presence of blood in the glands within the myometrium. This
finding was made in a woman of fifty years, who still was menstruating regularly. The last menstruation had occurred three weeks
previous to operation. In a few glands, which were dilated cystically, we found only slightly changed blood. This observation reminds one of menstruating uterine mucosa on the surface of the
ovary, first described by Sampson. By the courtesy of Sampson I
had an opportunity of studying the original slides and I confirm
that both in his and in my case, misplaced uterine glands were seen
filled with blood, undoubtedly menstrual blood.

At this point, adenomyoma was subdivided into endometriosis and adenomyosis: two separate entities.

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