The Histopathology and Molecular Pathology of Endometriosis
University of Sheffield
In 1921 John Sampson gave the first of three presentations on endometriosis he was to make to the
American Gynaecological Society. In the first of these he graphically described the clinicopathological
findings of ovarian endometriosis. He developed the histogenic theory of retrograde menstruation as a
causative factor . His opponents, including Emil Novak, favoured
the theory of coelomic metaplasia propounded by Robert Meyer of Germany.
Sampson died before subsequent definitive studies supported his theory, showing that endometrial cells in
menstrual blood were capable of growth. Sampson also first described the
relationship of endometriosis to ovarian malignancy .
John Albertson Sampson (1873-1946) was born at Troy, New York. He graduated MD from Johns Hopkins in
1899 and completed his residency in obstetrics and gynaecology at the same institution. In 1905 he went
to Albany, New York, where he was to spend the rest of his life. He became Professor of Gynaecology at
the Albany Medical College .
Richard Wesley Te Linde (1894-1985) was appointed Professor and Chairman of Gynaecology, at Johns
Hopkins in 1939 and retired in 1960. In his early years Te Linde carried out
basic research with rhesus monkeys which gave support to Sampson's theories of
histogenesis in endometriosis . However, the two theories are not necessarily mutually
exclusive and the "coelomic metaplastic theory" has won recent support from other experimental
studies . The rare occurrence of endometriotic foci in extra-abdominal sites such as the lung
is probably due to haematogenous spread .
The pathology of endometriosis has recently been extensively reviewed . The recognition of
endometrial epithelium and stroma outside the uterine corpus usually presents no diagnostic difficulty
for the histopathologist. Nevertheless, there are many unusual aspects of its pathology that merit
special attention and there have been several recent developments in our understanding of its molecular
pathogenesis and its relationship to endometrioid neoplasia.
There are numerous websites devoted to the subject e.g. http://www.endometriosis.org and http://www.nlm.nih.gov/medlineplus/endometriosis.html
and endometriosis remains the most important cause of pelvic pain in women and an important cause
of female infertility. There is a huge literature on the subject; a recent "PubMed" search on
endometriosis yielded 11772 articles.
The following aspects can be considered:
It is likely that there are multiple mechanisms (see above) by which endometriosis might occur and
recently it has been divided into three entities :
|cell adhesion and angiogenic factors|
There is increasing evidence that endometriosis is inherited as a complex genetic trait in which
multiple genes conferring disease susceptibility interact with each other and the environment to produce
the phenotype .
Immunological factors may affect a woman's susceptibility to implantation of shed endometrial cells.
Immune responses include increased number and activation of peritoneal macrophages, decreased T cell
reactivity and natural killer cell cytotoxicity, increased circulating antibodies and changes in the
cytokine network .
Matrix metalloproteinases (MMPs) that mediate normal tissue turnover, including endometrial breakdown
at menstruation, appear to be involved in the establishment of endometriosis. In addition, several MMPs
appear to be inappropriately expressed in the endometrium of women with this disease in association with
a reduced sensitivity to progesterone . Altered regulation of endometrial MMP expression in
response to steroids may represent a mechanism linking the invasive potential of refluxed endometrium to
the establishment of the disease in certain women .
Oestrogen is an extremely potent mitogen for endometrium and endometriosis. Progesterone, on the
other hand, inhibits the mitogenic action of oestrogen on endometrium and enhances differentiation.
These antiproliferative and differentiative effects of progesterone are less pronounced on endometriotic
tissue compared with endometrium. Thus, endometriosis is, at least in part, resistant to progesterone
action . Aromatase synthesizes oestrogen. Oestradiol is metabolized and thus inactivated by
17beta-hydroxysteroid dehydrogenase (HSD) type 2 that is normally induced by progesterone in endometrium.
Progesterone action is mediated by its receptor subtypes progesterone receptor (PR)-A and PR-B. A number
of abnormalities in the expression of aromatase, 17beta-HSD type 2, and the PR-B/PR-A ratio can be
identified in endometriotic tissue .
The following features have been shown:
|endometriotic cysts are monoclonal
(though apparently not peritoneal endometriosis )|
|there is loss of heterozygosity in 75% of cases associated with adenocarcinoma but, more interestingly, in 28% of cases without associated carcinoma. The most frequently affected chromosomes are 9p, 11q, 22q |
Relationship to endometrioid neoplasia
Endometriosis and ovarian cancer; shared risk factors:
|more regular periods|
|shorter cycle lengths|
|tubal ligation-protective for clear cell and endometrioid but not for serous or mucinous carcinoma|
|relative risk of ovarian cancer 4.2 with a long history of endometriosis|
Atypia (intraepithelial neoplasia) in endometriosis
|2% of cases without a neoplasm|
|60% of endometriosis associated with tumours|
|frequent association with endometrioid and clear cell carcinoma|
|endometriosis and adjacent/contiguous ovarian carcinoma show identical genetic lesions |
Ovarian and extra-ovarian neoplasia associated with endometriosis
|clear cell carcinoma|
|mucinous borderline tumour of Mullerian type|
|mixed Mullerian tumour (uncommon)|
|endometrioid stromal sarcomas (uncommon)|
|squamous cell carcinoma (rare)|
Other aspects for discussion
Metaplastic changes in endometriosis as a source of diagnostic confusion
pre-malignant neoplastic atypia (endometriotic intraepithelial neoplasia)
Endometriotic epithelium may exhibit the full range of metaplastic changes seen in the eutopic
endometrium and such changes should not be confused with true neoplastic atypia (intraepithelial
Endometrioid adenocarcinoma of the colon associated with endometriosis
Endometrioid adenocarcinoma is a rare complication of colorectal endometriosis with a total of 25
cases in the literature. In approximately a quarter of patients there is a history of prolonged
unopposed oestrogen therapy
Endocervicosis associated with endometriosis
The failure to recognise endocervical type epithelium as part of the spectrum of mullerianosis, that
can be associated with endometriosis, could lead to inappropriate surgery, particularly if erroneously
diagnosed as adenocarcinoma on bladder biopsy.
Necrotising granuloma formation in endometriosis
Rarely granulomatous nodules, characterised by a central zone of necrosis surrounded by pseudoxanthoma
cells, often in a palisaded arrangement, referred to as "necrotic pseudoxanthomatous nodules" have been
observed in endometriosis
. The author has recently seen such findings in the ovary of a
patient with endometriosis treated by Zoladex (goserelin acetate), a potent synthetic decapeptide
analogue of luteinizing hormone-releasing hormone used in the treatment of endometriosis (personal
The effects of hormone replacement therapy and tamoxifen on
In women with endometriosis treated by hysterectomy and bilateral oophorectomy, there is an increased
risk of recurrent disease with hormone replacement therapy in the presence of peritoneal
lesions . Hyperoestrogenism, either endogenous or exogenous, appears to be a significant
risk factor for the development of cancer from endometriosis  and there continue to be
isolated case reports in the literature of endometrioid adenocarcinoma arising in women on long term
unopposed oestrogen therapy .
The occurrence of endometriosis in postmenopausal women with tamoxifen suggests a causal link between
the drug and endometriosis in this age group . A range of neoplastic changes have now also
been reported in endometriosis in women on tamoxifen mirroring those changes seen in the eutopic
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