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The Histopathology and Molecular Pathology of Endometriosis


Michael Wells
University of Sheffield
Sheffield, UK


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 [1]. 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 [2].

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 [3].

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 [4]. However, the two theories are not necessarily mutually exclusive and the "coelomic metaplastic theory" has won recent support from other experimental studies [5]. The rare occurrence of endometriotic foci in extra-abdominal sites such as the lung is probably due to haematogenous spread [6].

The pathology of endometriosis has recently been extensively reviewed [7]. 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:

Pathogenesis
It is likely that there are multiple mechanisms (see above) by which endometriosis might occur and recently it has been divided into three entities [8]:

peritoneal
ovarian
recto-vaginal-septal

Pathogenetic factors [7, 9]

These include:

familial predisposition
immunological factors
cell adhesion and angiogenic factors
hormonal 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 [10].

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 [11].

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 [12]. 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 [12].

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 [13]. 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 [13].

Molecular pathology

The following features have been shown:

endometriotic cysts are monoclonal [14, 15, 16, 17] (though apparently not peritoneal endometriosis [18])
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 [19]

Relationship to endometrioid neoplasia [7, 20]

Endometriosis and ovarian cancer; shared risk factors:

early menarche
more regular periods
shorter cycle lengths
lower parity
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 [21, 22]

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 [23]

Ovarian and extra-ovarian neoplasia associated with endometriosis [7, 24]

endometrioid adenocarcinoma
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
with 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 neoplasia) [25].

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 [26, 27] .

Endocervicosis associated with endometriosis [28, 29]
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 [30, 31] . 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 observation).

The effects of hormone replacement therapy and tamoxifen on endometriosis
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 [32]. Hyperoestrogenism, either endogenous or exogenous, appears to be a significant risk factor for the development of cancer from endometriosis [33] and there continue to be isolated case reports in the literature of endometrioid adenocarcinoma arising in women on long term unopposed oestrogen therapy [34].

The occurrence of endometriosis in postmenopausal women with tamoxifen suggests a causal link between the drug and endometriosis in this age group [35]. A range of neoplastic changes have now also been reported in endometriosis in women on tamoxifen mirroring those changes seen in the eutopic endometrium [36, 37] .

References

  1. Sampson JA Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 1927; 14: 422-469.
  2. Sampson JA. Endometrial carcinoma of the ovary, arising in endometrial tissue in that organ. Arch Surg 1925; 10: 1-72.
  3. Baskett TF. On the Shoulders of Giants; Eponyms and names in Obstetrics and Gynaecology, RCOG Press, 1996; 193-194.
  4. Te Linde RW, Scott RB Experimental endometriosis. Am J Obstet Gynecol 1950; 60: 1147-1173.
  5. Matsuura K, Ohtake H, Katabuchi H, Okamura H. Coelomic metaplasia theory of endometriosis: evidence from in vivo studies and an in vitro experimental model. Gynecol Obstet Invest 1999; 47 (Suppl): 118-120.
  6. Flieder DB, Moran CA, Travis W, Koss MN, Mark EJ. Pleuro-pulmonary endometriosis and pulmonary ectopic deciduosis; a clinicopathologic and immunohistochemical study of 10 cases with emphasis on diagnostic pitfalls. Hum Pathol 1998; 29: 1495-1503.
  7. Czernobilsky B, Fox H. Endometriosis In: Haines & Taylor Obstetrical and Gynaecological Pathology, Editors H Fox and M Wells, Churchill Livingstone, 2003; 963-987.
  8. Nisolle M, Donnez J Peritoneal endometriosis, ovarian endometriosis and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril 1997; 68: 585-596.
  9. Donnez J, Van Langendonckt A, Casanas-Roux F et al. Current thinking on the pathogenesis of endometriosis. Gynecol Obstet Invest 2002; 54 (Suppl 1): 52-58
  10. Kennedy S. genetics of endometriosis: a review of the possible positional cloning approaches. Semin Reprod Med 2003; 21: 111-118.
  11. Berkkanoglu M, Arici A. Immunology and endometriosis. Am J Reprod Immunol 2003; 50: 48-59.
  12. Osteen KG, Yeaman GR, Bruner-Tran KL. Matrix metalloproteinases and endometriosis. Semi Reprod Med 2003; 21: 155-164.
  13. Gurates B, Bulun SE. Endometriosis: the ultimate hormonal disease. Semin Reprod Med 2003; 21: 125-134.
  14. Nilbert M, Pejovic T, Mandahl N et al. Monoclonal origin of endometriotic cysts. Int J Gynecol Cancer 1995; 5: 61-63.
  15. Jimbo H, Hitomi Y, Yoshikawa H et al. Evidence for monoclonal expansion of epithelial cells in ovarian endometrial (sic) cysts. Am J Pathol 1997; 150: 1173-1178.
  16. Tamura M, Fukaya T, Murakami T, Uehara S, Yajima A. Analysis of clonality in human endometriotic cysts based on evaluation of X chromosome inactivation in archival formalin-fixed, paraffin embedded tissue. Lab Invest 1998; 78: 213-218.
  17. Yano T, Jimbo H, Yoshikawa H, Tsutsumi O, Taketani Y. Molecular analysis of clonality in ovarian endometrial (sic) cysts. Gynecol Obstet Invest 1999; 47 (Suppl): 141-145.
  18. Nabeshima H, Murakami T, Yoshinaga K, Sato K, Terada Y, Okamura K. Analysis of the clonality of ectopic glands in peritoneal endometriosis using laser microdissection. Fertil Steril 2003; 80: 1144-1150.
  19. Jiang X, Hitchcock A, Bryan EJ et al. Microsatellite analysis of endometriosis reveals loss of heterozygosity at candidate ovarian tumour suppressor gene loci. Cancer Res; 56: 3534-3539.
  20. Feeley KM, Wells M. Precursor lesions of ovarian epithelial malignancy. Histopathology 2001; 38: 87-95.
  21. Fukazawa M, Nomura K, Ishikawa E, Ushigome S. Ovarian atypical endometriosis: its close association with malignant epithelial tumours. Histopathology 1997; 30: 249-255.
  22. Ogawa S, Kaku T, Amada S et al. Ovarian endometriosis associated with ovarian carcinoma: a clinicopathological and immunohistochemical study. Gynecol Oncol 2000; 77: 298-304.
  23. Jiang X, Morland SJ, Hitschcock A, Thomas EJ, Campbell IG. Allelotyping of endometriosis with adjacent ovarian carcinoma reveals evidence of a common lineage. Cancer Res 1998; 58: 1707-1712.
  24. Stern RC, Dash R, Bentley RC, Snyder MJ, Haney AF, Robboy SJ. Malignancy arising in endometriosis: frequency and comparison of ovarian and extraovarian types. Int J Gynecol Pathol 2001; 20: 133-139.
  25. Fukunaga M, Ushigome S. Epithelial metaplastic changes in ovarian endometriosis. Mod Pathol 1998; 11: 784-788.
  26. Slavin RE, Krum R, Van Dinh T. Endometriosis-associated intestinal tumors: a clinical and pathological study of 6 cases with a review of the literature. Hum Pathol 2000; 31: 456-463.
  27. Petersen VC, Underwood JC, Wells M, Shepherd NA. Primary endometrioid adenocarcinoma of the large intestine arising in colorectal endometriosis. Histopathology 2002; 40: 171-176.
  28. Clement PB, Young RH. Endocervicosis of the urinary bladder. A report of six cases of a benign mullerian lesion that may mimic adenocarcinoma. Am J Surg Pathol 1992; 16: 533-542.
  29. Young RH, Clement PB. Endocervicosis involving the uterine cervix: a report of four cases of a benign process that may be confused with deeply invasive endocervical adenocarcinoma. Int J Gynecol Pathol 2000; 19: 322-328.
  30. Clement PV, Young RH, Scully RE. Necrotic pseudoxanthomatous nodules of ovary and peritoneum in endometriosis. Am J Surg Pathol 1988; 12: 390-397
  31. McCluggage WG. Ovarian granulomas: a report of 32 cases. J Clin Pathol 1997; 50:324-327.
  32. Matorras R, Elorriaga MA, Pijoan JI, Ramon O, Rodriguez-Escuder FJ. Recurrence of endometriosis in women with bilateral adnexectomy (with or without total hysterectomy) who receive hormone replacement therapy. Fertil Steril 2002; 77: 303-308.
  33. Zanetta GM, Webb MJ, Li H Keeney GL. Hyperestrogenism: a relevant risk factor for the development of cancer from endometriosis. Gynecol Oncol 2000; 79: 18-22.
  34. Lavery S, Gillmer M. Malignant transformation of residual endometriosis in women on unopposed oestrogen hormone replacement therapy. Br J Obstet Gynaecol 2001; 108: 1106-1107.
  35. Buckley CH, Ismail SM. Pathology of contraception and hormonal therapy. In: In: Haines & Taylor Obstetrical and Gynaecological Pathology, Editors H Fox and M Wells, Churchill Livingstone, 2003; 1071-1132.
  36. McCluggage WG, Bryson C, Lamki H, Boyle DD. Benign, borderline and malignant endometrioid neoplasia arising in endometriosis in association with tamoxifen therapy. Int J Gynecol Pathol 2000; 19: 276-279.
  37. Bese T, Simsek Y, Bese N, Ilvan S, Arvas M. Extensive pelvic endometriosis with malignant change in tamoxifen-treated postmenopausal women. Int J Gynecol Cancer 2003; 13: 376-380.