Adenomyosis: is the present classificaons adequate for ... · Adenomyosis: definions • As adenomyosis is defined the presence of heterotopic endometrial glands and stroma in

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


No nuclear atypia or significant mitoses are observed in higher magnifica4on


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

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

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


P

0

10

20

30

40

50

Implanta4on Clinical pregnancies Ongoing pregnancies

31,6 31,1

26,1 28,3

35,1

29,7


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



Pa4ents

(n)

PJZ

(mm±SD)

p

Without Endometriosis 160 8.3±2.6

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




Prevalence of adenomyosis in pa'ents with DIE: 59/121 (48.7%) Dyspareunia (P




A`er surgery, remained significantly higher (P

• 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


•  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 adenomyomas

Special categories

1.   Adenomyomas of endocervical type

2. Retroperitoneal adenomyosis

or rectovaginal endometriosis

Surgical/histological classifica'on of adenomyosis


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



Subtype II

Extrinsic

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?




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%)


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?

Ø  How this sub-‐classifica4on of adenomyosis could be implemented in the

currently available surgical/histologic classifica4on



Current and poten4al characteris4cs to be used for

categoriza4on

•  Anatomical characteris4cs

–  Uterine zone: outer myometrium, inner myometrium

(junc4onal zone myometrium), endometrium

–  Loca4on: anterior wall, posterior wall, fundus, lateral wall

–  Infiltra4on: depth of disease

•  Histological characteris4cs

–  Variant: cys4c, predominantly grandular/muscular, atypical

•  PaQern

–  Diffuse, localized

•  Others?

–  Extra-‐uterine lesions (endometriosis, adhesions etc)

Conclusions

•  Adenomyosis represents a clinical challenge due to its various histological forms and to the fact that it infiltrates myometrium

•  MRI and TVS are extremely useful tools with high diagnos4c accuracy and

•  MRI has the addi4onal advantage of the excellent correla4on of findings with histology

•  Current classifica4on should be based on anatomical and histological characteris4cs of the disease (as they expressed in MRI) and should be fiQed to the needs of the treatment

•  Further work is needed for finding the best correla4on with disease’s impact on reproduc4ve poten4al

Documents

Adenomyosis: is the present classificaons adequate for ... · Adenomyosis: definions • As adenomyosis is defined the presence of heterotopic endometrial glands and stroma in