Semin Reprod Med 2020; 38(02/03): 108-118
DOI: 10.1055/s-0040-1718922
Review Article

Pathology and Pathogenesis of Adenomyosis

Maria Facadio Antero
1   Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
,
Ayse Ayhan
2   Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
,
James Segars
1   Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
,
Ie-Ming Shih
1   Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
2   Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
› Author Affiliations
Funding This study is supported by an NIH grant RO1HD096147 and by the Richard W. TeLinde Endowment, Department of Gynecology and Obstetrics, Johns Hopkins University.

Abstract

Adenomyosis represents a unique pathophysiological condition in which normal-appearing endometrial mucosa resides within myometrium and is thus protected from menstrual shedding. The resulting ectopic presence of endometrial tissue composed of glands and stroma is thought to affect normal contractile function and peristalsis of uterine smooth muscle, causing menometrorrhagia, infertility, and adverse obstetric outcomes. Since the first description of adenomyosis more than 150 years ago, pathologists have studied this lesion by examining tissue specimens, and have proposed multiple explanations to account for its pathogenesis. However, as compared with endometriosis, progress of adenomyosis research has been, at best, incremental mainly due to the lack of standardized protocols in sampling tissue and a lack of consensus diagnostic criteria in pathology practice. Despite these limitations, recent advances in revealing the detailed anatomy and biology of eutopic endometrium offer an unprecedented opportunity to study this common but relatively understudied disorder. Here, we briefly summarize the pathological aspects of adenomyosis from an historical background, and discuss conventional morphology and recent tissue-based molecular studies with a special emphasis on elucidating its tissue of origin from a pathologist's perspective. We also discuss unmet needs in pathology studies that would be important for advancing adenomyosis research.



Publication History

Article published online:
20 October 2020

© 2020. Thieme. All rights reserved.

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  • References

  • 1 Wang Y, Nicholes K, Shih IM. The origin and pathogenesis of endometriosis. Annu Rev Pathol 2020; 15: 71-95
  • 2 Bruun MR, Arendt LH, Forman A, Ramlau-Hansen CH. Endometriosis and adenomyosis are associated with increased risk of preterm delivery and a small-for-gestational-age child: a systematic review and meta-analysis. Acta Obstet Gynecol Scand 2018; 97 (09) 1073-1090
  • 3 Harada T, Taniguchi F, Amano H. et al. Japan Environment and Children's Study Group. Adverse obstetrical outcomes for women with endometriosis and adenomyosis: a large cohort of the Japan Environment and Children's Study. PLoS One 2019; 14 (08) e0220256
  • 4 Orazov M, Nosenko EN, Radzinsky VE, Khamoshina MB, Lebedeva MG, Sounov MA. Proangiogenic features in chronic pelvic pain caused by adenomyosis. Gynecol Endocrinol 2016; 32 (Suppl. 02) 7-10
  • 5 Seidman JD, Kjerulff KH. Pathologic findings from the Maryland Women's Health Study: practice patterns in the diagnosis of adenomyosis. Int J Gynecol Pathol 1996; 15 (03) 217-221
  • 6 Nnoaham KE, Hummelshoj L, Webster P. et al. World Endometriosis Research Foundation Global Study of Women's Health Consortium. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril 2011; 96 (02) 366-373.e8
  • 7 Struble J, Reid S, Bedaiwy MA. Adenomyosis: a clinical review of a challenging gynecologic condition. J Minim Invasive Gynecol 2016; 23 (02) 164-185
  • 8 Rokitansky C. Ueber Uterusdrusen-neubildung in Uterus and Ovariul Sarcomen. Z Gesellschaft Aerzte Wien 1860; 16: 577
  • 9 Chiari H. Zur pathologischen anatomie des eileitercatarrhs. Z Heilkunde 1887; 8: 457-464
  • 10 Meyer R. Uber eine adenomatose Wucherung der Serosa in einer Bauchnarbe. Z Geburtshilfe Gynakol 1903; 49: 32-41
  • 11 Kelly HA, Cullen TS. Myomata of the Uterus. Saunders; 1909
  • 12 Cullen T. Adenomyoma of the Uterus. Philadelphia, PA: W. B. Saunders Company; 1908
  • 13 Von Recklinghausen F. Die Adenomyome und Cystadenome der Uterus-und Tubenwandung: ihre Abkunft von Resten des Wolff'schen Körpers. Hirschwald: 1896
  • 14 Diesterweg A. Ein Fall von Cystofibroma uteri verum. Z. Geburtshilfe 1883; 9: 191-195
  • 15 Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 1927; 14 (04) 422-469
  • 16 Frankl O. Adenomyosis uteri. Am J Obstet Gynecol 1925; 10 (05) 680-684
  • 17 Bird CC, McElin TW, Manalo-Estrella P. The elusive adenomyosis of the uterus. Am J Obstet Gynaecol 1972; 112: 583-593
  • 18 Shutter J. Uterus-like ovarian mass presenting near menarche. Int J Gynecol Pathol 2005; 24 (04) 382-384
  • 19 Bell CD, Ostrezega E. The significance of secretory features and coincident hyperplastic changes in endometrial biopsy specimens. Hum Pathol 1987; 18 (08) 830-838
  • 20 Ferenczy A. Pathophysiology of adenomyosis. Hum Reprod Update 1998; 4 (04) 312-322
  • 21 Molitor JJ. Adenomyosis: a clinical and pathological appraisal. Am J Obstet Gynecol 1971; 110 (02) 275-284
  • 22 Langlois PL. The size of the normal uterus. J Reprod Med 1970; 4 (06) 220-228
  • 23 Azziz R. Adenomyosis: current perspectives. Obstet Gynecol Clin North Am 1989; 16 (01) 221-235
  • 24 Brosens I, Gordts S, Habiba M, Benagiano G. Uterine cystic adenomyosis: a disease of younger women. J Pediatr Adolesc Gynecol 2015; 28 (06) 420-426
  • 25 Tempest N, Jansen M, Baker AM. et al. Histological 3D reconstruction and in vivo lineage tracing of the human endometrium. J Pathol 2020; 251 (04) 440-451
  • 26 Goldblum JR, Clement PB, Hart WR. Adenomyosis with sparse glands. A potential mimic of low-grade endometrial stromal sarcoma. Am J Clin Pathol 1995; 103 (02) 218-223
  • 27 Haber G, Ferenczy A. Electrosurgical solutions to gynecological problems. Contemp Obstet Gynecol 1993; 1: 25-36
  • 28 Pistofidis G, Makrakis E, Koukoura O, Bardis N, Balinakos P, Anaf V. Distinct types of uterine adenomyosis based on laparoscopic and histopathologic criteria. Clin Exp Obstet Gynecol 2014; 41 (02) 113-118
  • 29 Qu H, Li L, Wang TL, Seckin T, Segars J, Shih IM. Epithelial cells in endometriosis and adenomyosis upregulate STING expression. Reprod Sci 2020; 27 (06) 1276-1284
  • 30 Birnholz JC. Ultrasonic visualization of endometrial movements. Fertil Steril 1984; 41 (01) 157-158
  • 31 Exacoustos C, Brienza L, Di Giovanni A. et al. Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology. Ultrasound Obstet Gynecol 2011; 37 (04) 471-479
  • 32 Quinn M. Uterine innervation in adenomyosis. J Obstet Gynaecol 2007; 27 (03) 287-291
  • 33 Mehasseb MK, Bell SC, Pringle JH, Habiba MA. Uterine adenomyosis is associated with ultrastructural features of altered contractility in the inner myometrium. Fertil Steril 2010; 93 (07) 2130-2136
  • 34 Guo S-W, Mao X, Ma Q, Liu X. Dysmenorrhea and its severity are associated with increased uterine contractility and overexpression of oxytocin receptor (OTR) in women with symptomatic adenomyosis. Fertil Steril 2013; 99 (01) 231-240
  • 35 Leyendecker G, Bilgicyildirim A, Inacker M. et al. Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI study. Arch Gynecol Obstet 2015; 291 (04) 917-932
  • 36 Goteri G, Lucarini G, Montik N. et al. Expression of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1α (HIF-1α), and microvessel density in endometrial tissue in women with adenomyosis. Int J Gynecol Pathol 2009; 28 (02) 157-163
  • 37 Schindl M, Birner P, Obermair A, Kiesel L, Wenzl R. Increased microvessel density in adenomyosis uteri. Fertil Steril 2001; 75 (01) 131-135
  • 38 Mori M, Furusawa A, Kino N, Uno M, Ozaki Y, Yasugi T. Rare case of endometrioid adenocarcinoma arising from cystic adenomyosis. J Obstet Gynaecol Res 2015; 41 (02) 324-328
  • 39 Kazandi M, Zeybek B, Terek MC, Zekioglu O, Ozdemir N, Oztekin K. Grade 2 endometrioid adenocarcinoma arising from adenomyosis of the uterus: report of a case. Eur J Gynaecol Oncol 2010; 31 (06) 719-721
  • 40 Baba A, Yamazoe S, Dogru M, Ogawa M, Takamatsu K, Miyauchi J. Clear cell adenocarcinoma arising from adenomyotic cyst: a case report and literature review. J Obstet Gynaecol Res 2016; 42 (02) 217-223
  • 41 Koike N, Tsunemi T, Uekuri C. et al. Pathogenesis and malignant transformation of adenomyosis (review). Oncol Rep 2013; 29 (03) 861-867
  • 42 Longacre TA, Chung MH, Rouse RV, Hendrickson MR. Atypical polypoid adenomyofibromas (atypical polypoid adenomyomas) of the uterus. A clinicopathologic study of 55 cases. Am J Surg Pathol 1996; 20 (01) 1-20
  • 43 Young RH, Treger T, Scully RE. Atypical polypoid adenomyoma of the uterus. A report of 27 cases. Am J Clin Pathol 1986; 86 (02) 139-145
  • 44 Singh N, Hirschowitz L, Zaino R. et al. Pathologic prognostic factors in endometrial carcinoma (other than tumor type and grade). Int J Gynecol Pathol 2019; 38 (Suppl. 01) S93-s113
  • 45 FIGO Committee on Gynecologic Oncology. FIGO staging for carcinoma of the vulva, cervix, and corpus uteri. Int J Gynaecol Obstet 2014; 125 (02) 97-98
  • 46 Levgur M, Abadi MA, Tucker A. Adenomyosis: symptoms, histology, and pregnancy terminations. Obstet Gynecol 2000; 95 (05) 688-691
  • 47 Hulka CA, Hall DA, McCarthy K, Simeone J. Sonographic findings in patients with adenomyosis: can sonography assist in predicting extent of disease?. AJR Am J Roentgenol 2002; 179 (02) 379-383
  • 48 Nishida M. Relationship between the onset of dysmenorrhea and histologic findings in adenomyosis. Am J Obstet Gynecol 1991; 165 (01) 229-231
  • 49 Sammour A, Pirwany I, Usubutun A, Arseneau J, Tulandi T. Correlations between extent and spread of adenomyosis and clinical symptoms. Gynecol Obstet Invest 2002; 54 (04) 213-216
  • 50 Grimbizis GF, Mikos T, Tarlatzis B. Uterus-sparing operative treatment for adenomyosis. Fertil Steril 2014; 101 (02) 472-487
  • 51 Exacoustos C, Morosetti G, Conway F. et al. New sonographic classification of adenomyosis: Do type and degree of adenomyosis correlate to severity of symptoms?. J Minim Invasive Gynecol 2020; 27 (06) 1308-1315
  • 52 Signorile PG, Baldi F, Bussani R. et al. Embryologic origin of endometriosis: analysis of 101 human female fetuses. J Cell Physiol 2012; 227 (04) 1653-1656
  • 53 Signorile PG, Baldi A. Endometriosis: new concepts in the pathogenesis. Int J Biochem Cell Biol 2010; 42 (06) 778-780
  • 54 Benagiano G, Brosens I, Habiba M. Adenomyosis: a life-cycle approach. Reprod Biomed Online 2015; 30 (03) 220-232
  • 55 Yang J-H, Wu MY, Chen CD, Chen MJ, Yang YS, Ho HN. Altered apoptosis and proliferation in endometrial stromal cells of women with adenomyosis. Hum Reprod 2007; 22 (04) 945-952
  • 56 Jones RK, Searle RF, Bulmer JN. Apoptosis and bcl-2 expression in normal human endometrium, endometriosis and adenomyosis. Hum Reprod 1998; 13 (12) 3496-3502
  • 57 Wang F, Li H, Yang Z, Du X, Cui M, Wen Z. Expression of interleukin-10 in patients with adenomyosis. Fertil Steril 2009; 91 (05) 1681-1685
  • 58 Wang F, Wen Z, Li H, Yang Z, Zhao X, Yao X. Human leukocyte antigen-G is expressed by the eutopic and ectopic endometrium of adenomyosis. Fertil Steril 2008; 90 (05) 1599-1604
  • 59 Yang JH, Wu MY, Chang DY, Chang CH, Yang YS, Ho HN. Increased interleukin-6 messenger RNA expression in macrophage-cocultured endometrial stromal cells in adenomyosis. Am J Reprod Immunol 2006; 55 (03) 181-187
  • 60 Yang J-H, Chen MJ, Chen HF, Lee TH, Ho HN, Yang YS. Decreased expression of killer cell inhibitory receptors on natural killer cells in eutopic endometrium in women with adenomyosis. Hum Reprod 2004; 19 (09) 1974-1978
  • 61 Sotnikova N, Antsiferova I, Malyshkina A. Cytokine network of eutopic and ectopic endometrium in women with adenomyosis. Am J Reprod Immunol 2002; 47 (04) 251-255
  • 62 Mehasseb MK, Panchal R, Taylor AH, Brown L, Bell SC, Habiba M. Estrogen and progesterone receptor isoform distribution through the menstrual cycle in uteri with and without adenomyosis. Fertil Steril 2011; 95 (07) 2228-2235 , 2235.e1
  • 63 Nie J, Lu Y, Liu X, Guo SW. Immunoreactivity of progesterone receptor isoform B, nuclear factor kappaB, and IkappaBalpha in adenomyosis. Fertil Steril 2009; 92 (03) 886-889
  • 64 Inoue S, Hirota Y, Ueno T. et al. Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations. Nat Commun 2019; 10 (01) 5785
  • 65 Noë M, Ayhan A, Wang TL, Shih IM. Independent development of endometrial epithelium and stroma within the same endometriosis. J Pathol 2018; 245 (03) 265-269
  • 66 Suda K, Nakaoka H, Yoshihara K. et al. Clonal expansion and diversification of cancer-associated mutations in endometriosis and normal endometrium. Cell Rep 2018; 24 (07) 1777-1789
  • 67 Anglesio MS, Papadopoulos N, Ayhan A. et al. Cancer-associated mutations in endometriosis without cancer. N Engl J Med 2017; 376 (19) 1835-1848
  • 68 Di Donato N, Montanari G, Benfenati A. et al. Prevalence of adenomyosis in women undergoing surgery for endometriosis. Eur J Obstet Gynecol Reprod Biol 2014; 181: 289-293
  • 69 Chapron C, Tosti C, Marcellin L. et al. Relationship between the magnetic resonance imaging appearance of adenomyosis and endometriosis phenotypes. Hum Reprod 2017; 32 (07) 1393-1401
  • 70 Eisenberg VH, Arbib N, Schiff E, Goldenberg M, Seidman DS, Soriano D. Sonographic signs of adenomyosis are prevalent in women undergoing surgery for endometriosis and may suggest a higher risk of infertility. Biomed Res Int, :8967803 2017
  • 71 Donnez J, Dolmans M-M, Fellah L. What if deep endometriotic nodules and uterine adenomyosis were actually two forms of the same disease?. Fertil Steril 2019; 111 (03) 454-456
  • 72 Khan KN, Fujishita A, Koshiba A. et al. Biological differences between intrinsic and extrinsic adenomyosis with coexisting deep infiltrating endometriosis. Reprod Biomed Online 2019; 39 (02) 343-353
  • 73 Dior UP, Nisbet D, Fung JN. et al. The association of sonographic evidence of adenomyosis with severe endometriosis and gene expression in eutopic endometrium. J Minim Invasive Gynecol 2019; 26 (05) 941-948
  • 74 Suda K, Nakaoka H, Yoshihara K. et al. Different mutation profiles between epithelium and stroma in endometriosis and normal endometrium. Hum Reprod 2019; 34 (10) 1899-1905
  • 75 Moore L, Leongamornlert D, Coorens THH. et al. The mutational landscape of normal human endometrial epithelium. Nature 2020; 580 (7805): 640-646
  • 76 Zannoni L, Del Forno S, Raimondo D. et al. Adenomyosis and endometriosis in adolescents and young women with pelvic pain: prevalence and risk factors. Minerva Pediatr 2020
  • 77 Arnold LL, Ascher SM, Simon JA. Familial adenomyosis: a case report. Fertil Steril 1994; 61 (06) 1165-1167
  • 78 Xiang Y, Sun Y, Yang B. et al. Transcriptome sequencing of adenomyosis eutopic endometrium: A new insight into its pathophysiology. J Cell Mol Med 2019; 23 (12) 8381-8391
  • 79 Wang W, Taylor RN, Bagchi IC, Bagchi MK. Regulation of human endometrial stromal proliferation and differentiation by C/EBPβ involves cyclin E-cdk2 and STAT3. Mol Endocrinol 2012; 26 (12) 2016-2030
  • 80 Zahnow CA. CCAAT/enhancer-binding protein β: its role in breast cancer and associations with receptor tyrosine kinases. Expert Rev Mol Med 2009; 11: e12
  • 81 Streuli I, Santulli P, Chouzenoux S, Chapron C, Batteux F. Activation of the MAPK/ERK cell-signaling pathway in uterine smooth muscle cells of women with adenomyosis. Reprod Sci 2015; 22 (12) 1549-1560
  • 82 Hufnagel D, Li F, Cosar E, Krikun G, Taylor HS. The role of stem cells in the etiology and pathophysiology of endometriosis. Semi Reprod Med 2015; 33 (05) 333-340
  • 83 Vannuccini S, Tosti C, Carmona F. et al. Pathogenesis of adenomyosis: an update on molecular mechanisms. Reprod Biomed Online 2017; 35 (05) 592-601
  • 84 Gargett CE. Uterine stem cells: What is the evidence?. Hum Reprod Update 2007; 13 (01) 87-101