Adenomyosis: is the present classifica4ons adequate for diagnosis and treatment?
Grigoris F. Grimbizis Professor in Obstetrics and Gynecology 1st Department of Obstetrics & Gynecology Medical School, Aristotle University of Thessaloniki
Declara'on of Interests
• None (commercial)
• Member of the Execu4ve CommiQee of ESHRE
• Member of the Execu4ve CommiQee of ESGE
• Vice-‐President of the Execu4ve CommiQee of the Hellenic
Society of Gynecological Endoscopy
Classifica4on of adenomyosis
Defini4ons & diagnosis
Spectrum of clinical presenta4ons: a challenge for grouping
Treatment op4ons: a challenge for selec4ng pa4ents
Current proposals for classifica4on and open issues
Adenomyosis: first descrip'on 1860
The first detailed pathologic descrip'on of endometriosis and adenomyosis, published in Vienna in 1860 by Karl Freiherr von Rokitansky (1804–1878)
Title page of the ar4cle, ‘‘Uterusdrusen-‐Neubildungen in Uterus und Ovarial-‐Sarcomen’’ ‘‘On neoplasias of the uterine glands in uterine and ovarian sarcomas’’
‘‘Some fibrous tumors of the uterus contain gland-‐like structures that resemble endometrial glands. These can be regarded as sarcoma carcinoides uterinum. Cys4c degenera4on of these
glands then leads to the appearance of a cystosar-‐
coma adenoides uterinum.’’
Adenomyosis: defini'ons
• As adenomyosis is defined the presence of heterotopic endometrial glands and stroma in the myometrium with adjacent smooth muscle hyperplasia
• Adenomyosis can be either diffuse or focal, taking the form of adenomyoma or adenomyo4c cyst
• Ademomyomas are grossly circumscribed nodules of hypertrophic and distorted endometrium and myometrium usually embedded within the myometrium
• Histologically, it could range from mostly solid to mostly cys4c
• Adenomyosis could be present in polyps of endometrial cavity
• It it characterized by the presence of endometrial glands between
smooth muscle bundles
Endometrial glands of varying shapes embedded in abundant endometrial stroma are surrounded by smooth muscle bundles
(hematoxylin & eosin, X 50)
Histological characteris'cs of adenomyosis
Macroscopic appearance in a hysterectomy specimen
Mul4ple endometrial glands are found between smooth muscle bundles / Most glands are tubular, while some of them are haphazardly shaped / They somehow give an impression of an infiltra4ve growth paQern
(hematoxylin & eosin, X 50)
No nuclear atypia or significant mitoses are observed in higher magnifica4on
(hematoxylin & eosin, X 100)
Atypical polypoid adenomyosis: Histological characteris4cs
TVS findings in adenomyosis
Na`alin et al, Hum Reprod, 27: 3432–3439, 2012
8 cm
Diagnos'c accuracy of US for adenomyosis
Champaneria et al, AOGS, 89:1374-1384, 2010
Ø Sensi'vity: 0.72 (0.65-‐0.79) Ø Specificity: 0.81 (0.77-‐0.850
Ø Area Under the Curve: 0.85
MRI imaging of myometrium: new insights
The clinical significance of myometrial architecture
Outer myometrium
Thick external hypo-‐dense zone Inner myometrium (junc'onal zone) Thin central zone of increased density
Two different structural and func'onal en''es
• Smooth muscle hyperplasia associated with ectopic endometrium (hyperplasia of myometrium ? / normal variant)
Diffuse or focal thickening of the junc4onal zone / low T2 intensity
• Ectopic endometrial glands cys4cally dilated
Punctuate high T2 intensity foci within low intensity lesions
• Adenomyomas Ill defined low T2 intensity myo-‐
metrial nodule into myometrium
• Benign invasion of basal endome-‐
trium within adjacent myometrium High T2 intensity linear stria'ons
into myometrium
• Adenomyo4c cyst High T2 intensity cys'c lesion
within myometrium
Spectrum of MRI findings and correla'on with histology
MRI imaging in adenomyosis
An excellent correla4on between MRI finding and histology
Increase of junc'onal zone density and thickness
Smooth muscle prolifera4on of the inner myometrium
Foci of increased density
Ectopic endometrial glands
Poten'al changes of overlying endometrium
Due to underlying myometrial pathology
Extend of myometrial pathology / mapping of the disease
Differen4al diagnosis of diffuse and focal adenomyosis
Correla'on of MRI findings with histology
Classifica4on of adenomyosis
Defini4ons & diagnosis
Spectrum of clinical presenta4ons: a challenge for grouping
Treatment op4ons: a challenge for selec4ng pa4ents
Current proposals for classifica4on and open issues
Taran et al, Fer4l Steril, 94: 1223–8, 2010
Women with adenomyosis were more likely to have a history of infer4lity, endometriosis and pelvic pain compared to women with leiomyoma
Understanding adenomyosis: a case control study
Spectrum of adenomyosis’ clinical presenta'on
Pelvic pain
Abnormal uterine bleeding
Impaired reproduc4ve outcome
Mass effects
★
Co-‐existence and rela4on with endometriosis
Vercellini et al, Hum Reprod, 29: 964-‐977, 2014
Uterine adenomyosis and IVF outcome: a systema'c review and meta-‐analysis
Adenomyosis is associated with 30% decrease of the likelihood for pregnancy
0 10 20 30 40 50 60
Implanta'on Clinical pregnancies
Miscarriages Ongoing pregnancies
29,4
47,2
2,8
45,9
18,8 22,2
50
11,1
Normal (n=256) Adenomyosis (n=19) P<0.001
Salim et al, RBM Online 25, 273–277, 2012
Adenomyosis reduces pregnancy rates in infer'le women
undergoing IVF
Thalluri and Tremellen, Hum Reprod, 27: 3487–3492, 2012
Design: Retrospec4ve / Diagnos4c method: Ultrasound
Ultrasound diagnosed adenomyosis has a nega've impact on successful implanta'on
(following GnRH antagonist IVF treatment)
0 10 20 30 40 50 60
Implanta4on Clinical pregnancies
Miscarriages Ongoing pregnancies
30,8
44,4
7,2
37,1 29,6
40
13,1
26,8
Normal (n=147) Adenomyosis (n=152)
P<0.05
P<0.05
Marmnez-‐Conejero et al, Fer4l Steril, 96: 943–50, 2011
Adenomyosis does not affect implanta'on, but is associated
with miscarriage in pa'ents undergoing oocyte dona'on
0 10 20 30 40 50
Implanta4on Clinical pregnancies Ongoing pregnancies
31,6 31,1
26,1 28,3
35,1
29,7
Normal (n=164) Adenomyosis (n=37)
P = NS
Costello et al, Eur J Obstet & Gynecol Reprod Biol 158: 229–234, 2011
The effect of adenomyosis on in vitro fer'liza'on and intra-‐
cytoplasmic sperm injec'on treatment outcome
Vercellini et al, Hum Reprod, 29: 964-‐977, 2014
Uterine adenomyosis and IVF outcome: a systema'c review and meta-‐analysis
Adenomyosis is associated with a 2 fold increase of the likelihood for miscarriage
0 5 10 15 20
Term Delivery Controls (N=208)
Spontaneous Preterm Delivery (N=73)
PRROM (N=21) Preterm Delivery Cases (N=104)
Juang et al, BJOG, 114:165–169, 2007
OR: 1.83 (1.27-‐3.93) OR: 1.84
(1.32-‐4.31)
OR: 1.98 (1.39-‐3.15)
Adenomyosis (%)
Design: Retrospec4ve / Diagnos4c method: MRI
Adenomyosis and pregnancy outcome
The risk of preterm delivery
Is adenomyosis associated with menorrhagia?
Naftalin et al, Hum Reprod, Advance Access, 2014
Menstrual loss is associated only with
1. gravidity 2. fibroids and
3. polyps
Not with adenomyosis
(mul4variable analysis)
Is adenomyosis associated with menorrhagia?
Naftalin et al, Hum Reprod, Advance Access 2014 A significant 22% increase in menstrual loss for each addi'onal
feature of adenomyosis [OR 1.21 (95% CI: 1.04–1.40)]
Menstrual loss is probably associated with the severity and/
or the extend of adenomyosis
Adenomyosis in endometriosis
Prevalence and impact on fer4lity: evidence from MRI
Kunz et al, Hum Reprod, 20: 2309–2316, 2005
0 20 40 60 80
Endometriosis (N=160) Total Controls (N=67) Healthy Controls (N=23)
Study Groups
Endometriosis: Laparoscopically proven endometriosis Total Controls: Laparoscopically normal pa4ents
Healthy Controls: Laparoscopically normal / Male factor
Adenomyosis in endometriosis
Prevalence and impact on fer4lity: evidence from MRI
Kunz et al, Hum Reprod, 20: 2309–2316, 2005
Adenomyosis in endometriosis
Prevalence and impact on fer4lity: evidence from MRI
Kunz et al, Hum Reprod, 20: 2309–2316, 2005 Pa4ents
(n)
PJZ (mm±SD)
p
Without Endometriosis 160 8.3±2.6
<0.001
With Endometriosis 67 11.5±5.3
Minimal and mild endometriosis 81 10.5±4.0
<0.02 Moderate and severe endometriosis 79 12.5±6.4
Deep infiltra'ng endometriosis 11 13.1±5.4
Table: Diameter of the posterior
junc4onal zone (PJZ) in specific
sub-‐groups
The uterine junc'onal zone: a 3-‐dimensional ultrasound study of pa'ents with endometriosis
Exacoustos et al, Am J Obstet Gynecol 2013;209:248.e1-7
Three-‐dimensional TVS features of the JZ in pa4ents with and without endometriosis
Pre-‐ and Post-‐opera've clinical and TVS findings of adenomyosis in pa'ents with Deep Infiltra'ng Endometriosis
Prevalence of adenomyosis in pa'ents with DIE: 59/121 (48.7%)
Dysmenorrhea (P =0.0019) is sta4s4cally higher in the group with DIE and adenomyosis
A`er surgery, painful symptoms improved in the whole group but remained significantly higher (P < .001) in the group with adenomyosis
Lazzeri et al, Reprod Sci, 21: 1027–1033, 2014
Pre-‐ and Post-‐opera've clinical and TVS findings of adenomyosis in pa'ents with Deep Infiltra'ng Endometriosis
Lazzeri et al, Reprod Sci, 21: 1027–1033, 2014
Prevalence of adenomyosis in pa'ents with DIE: 59/121 (48.7%)
Dyspareunia (P<0.001) is sta4s4cally higher in the group with DIE and adenomyosis
A`er surgery, painful symptoms improved in the whole group but remained
significantly higher (P < .001) in the group with adenomyosis
Pre-‐ and Post-‐opera've clinical and TVS findings of adenomyosis in pa'ents with Deep Infiltra'ng Endometriosis
Lazzeri et al, Reprod Sci, 21: 1027–1033, 2014
A`er surgery, remained significantly higher (P <0 .001) in DIE & adenomyosis Heavy Uterine Bleeding is sta4s4cally higher (P<0.001) in the group with DIE
and adenomyosis
Classifica4on of adenomyosis
Defini4ons & diagnosis
Spectrum of clinical presenta4ons: a challenge for grouping
Treatment op4ons: a challenge for selec4ng pa4ents
Current proposals for classifica4on and open issues
• Hormonal treatment: GnRH-‐a / LNG-‐IUS
• Uterine artery emboliza4on
• Magne4c Resonance guided Focused Ultrasound Surgery (MRgFUS)
Non-‐surgical medical and/or interven4onal
• Adenomyomectomy (laparoscopic or hysteroscopic)
• Thermal abla4on of myometrium
Uterus sparing surgical treatment
Treatment op'ons in pa'ents with adenomyosis
Adenomyosis is an estrogen dependent disease developed during reproduc4ve life period and suppressed with menopause
Medical treatment is based on the disease’s hormonal dependency
The effect of medical treatment is transient regressing disease process only during therapy
Recognized approaches are
Systemic hormonal treatment: GnRH-‐a / dienogest (?) Local hormonal treatment: LNG-‐IUS or Dan-‐IUS
Fedele et al, Best Pract Res Clin Obstet Gynecol, 22: 333-‐339, 2008 Petraglia et al, Best Pract Res Clin Obstet Gynecol, 22: 235-‐249, 2008
Hormonal treatment adenomyosis: Ra'onale
Excision or destruc4on of the diseased 4ssue with
concomitant maintenance of the healthy myometriun is the goal of any surgical conserva4ve treatment
Fedele et al, Best Pract Res Clin Obstet Gynecol, 22: 333-‐339, 2008 Petraglia et al, Best Pract Res Clin Obstet Gynecol, 22: 235-‐249, 2008
Adenomyosis/adenomyomas infiltrates myometrium
Adenomyomectomy is always associated with concomitant removal of some amount of myometrial 4ssue
Surgical treatment adenomyosis: Ra'onale
1. Complete excision of adenomyosis
complete removal of all the clinically recognizable, non-‐microscopic lesions with maintenance of uterine wall integrity
2. Par'al excision of adenomyosis / cytoreduc've surgery
par4al removal of the clinically recognizable non-‐microscopic lesions.
complete removal would lead to “func4onal” hysterectomy due to the concomitant excision of a cri4cal amount of healthy myometrium
3. Non-‐excisional techniques
interven4ons where removal of adenomyo4c 4ssue is not included
Classifica'on of Surgical Techniques
Grimbizis et al, Fer4l Steril, 101: 472-‐487, 2014
Classifica'on of uterus sparing techniques and their variants
Excisional techniques
Grimbizis et al, Fer4l Steril, 101: 472-‐487, 2014
Classifica4on of adenomyosis
Defini4ons & diagnosis
Spectrum of clinical presenta4ons: a challenge for grouping
Treatment op4ons: a challenge for selec4ng pa4ents
Current proposals for classifica4on and open issues
• Classifica4on of adenomyosis should ideally be related with:
– the clinical presenta4on and severity of the symptoms (abnormal bleeding, pelvic pain, effect on reproduc4ve poten4al)
– the disease aggressiveness and prognosis
– the selec4on of pa4ents for the various treatment op4ons
• It should also be as much as possible:
– clear in defini4ons, comprehensive and user’s friendly
– related, if clinically important, to the disease’s pathogenesis
Classifica'on of Adenomyosis: Characteris'cs
Gordts et al, RBM Online, 17: 244-‐248, 2008
The first systema'c approach based on the advances provided by MRI
Diffuse adenomyosis
1. Smooth muscle hyperplasia with ectopic endometrium (ñ junc4onal zone)
2. Micro-‐dilated ectopic endometrial glands throughout hyperplas4c myometrium
Focal adenomyosis
1. Adenomyomas
2. Cys4c adult adenomyosis
2a. Juvenile cys4c adenomyosis
Polypoid adenomyosis
1. Typical polypoid adenomyomas 2. Atypical polypoid adenomyomasSpecial categories
1. Adenomyomas of endocervical type 2. Retroperitoneal adenomyosis
or rectovaginal endometriosis
Surgical/histological classifica'on of adenomyosis
Grimbizis et al, Fer4l Steril, 101: 472-‐487, 2014
Four subtypes of adenomyosis assessed by magne'c resonance imaging and their specifica'on
Kishi et al, Am J Obstet Gynecol, 207:114.e1-‐7, 2012
Type Characteris'cs
Subtype I (n=59)
Intrinsic
Adenomyosis occurring in the inner uterine layer (in direct connec'on with the thickened junc'onal zone) without affec'ng the outer structures
Subtype II (n=51)
Extrinsic
Adenomyosis occurring in the outer uterine layer without affec'ng the inner structures (healthy junc'onal zone)
Subtype III (n=22)
Intramural
Adenomyosis occurring solitarily without any
geographic rela'onship to the junc'onal zone or the serosa
Subtype IV (n=20)
Indeterminate
Adenomyosis without any of the categoriza'on criteria men'oned earlier (MRI geography obscure and
indeterminate)
Subtype I Intrinsic
Kishi et al, Am J Obstet Gynecol, 207:114.e1-7, 2012
Four subtypes of adenomyosis assessed by magne'c resonance
imaging and their specifica'on
Subtype II Extrinsic
Kishi et al, Am J Obstet Gynecol, 207:114.e1-‐7, 2012
Four subtypes of adenomyosis assessed by magne'c resonance
imaging and their specifica'on
Four subtypes of adenomyosis assessed by magne'c resonance imaging and their specifica'on
Kishi et al, Am J Obstet Gynecol, 207:114.e1-‐7, 2012
Ø Subtype I: Direct endometrial invasion
Ø Disrup'on of the endometrial-‐myometrial barrier
Ø Trauma4c damage of the barrier (cureQage)
Ø Disrup4on of the barrier during normal pregnancy by the trophoblas4c invasion
Ø In nulliparous women other mechanisms could underlie to this disrup4on that could consequently affect implanta4on?
Ø Subtype II: Endometrio'c invasion from the outside Ø Pelvic endometriosis is the progenitor
Ø In the absence of inner junc4onal zone invasion is there any addi4onal impact on implanta4on and fer4lity poten4al by adenomyosis or this is the result of endometriosis?
Four subtypes of adenomyosis assessed by magne'c resonance imaging and their specifica'on
Kishi et al, Am J Obstet Gynecol, 207:114.e1-‐7, 2012
Characteris'c Subtype I
Intrinsic
Subtype II Extrinsic
CureQage é (32,2%) ê (7,8%)
Anterior wall involvement é (57,6%) ê (5,9%) Teardrop deformity of the rectum ê (8,5%) é (72,5%)
Ovarian endometriomas ê (13,6%) é (66,7%)
Posterior cul-‐de-‐sac endometriosis ê (25,4%) é (92,3%)
Posterior cul-‐de-‐sac oblitera4on ê (6,8%) é (96,1%)
Kishi et al, Am J Obstet Gynecol, 207:114.e1-‐7, 2012
Ø Subtype III: De novo metaplasia?
Ø What is the exact impact on fer4lity poten4al?
Ø Is there a correla4on with size like myomas?
Ø Subtype IV: heterogeneous mixture of advanced stages of previous subtypes
Ø What is the impact on fer4lity poten4al?
