Association between etiopathogenesis of morbidly adherent placenta and adenomyosis

doi:10.4236/ojog.2012.23067

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Open Journal of Obstetrics and Gynecology, 2012, 2, 321-324 OJOG

http://dx.doi.org/10.4236/ojog.2012.23067 Published Online September 2012 (http://www.SciRP.org/journal/ojog/)

Association between etiopathogenesis of morbidly

adherent placenta and adenomyosis

Christopher A. Enakpene1,2, Ozgul Muneyyirci-Delale1,2*

1Department of O bstetrics and Gynecology, SUNY Downstate Medical Center, New York, USA

2Department of O bstetrics and Gynecology, Kings County Hospital Center, New York, USA

Email: *[email protected]

Received 25 March 2012; revised 30 April 2012; accepted 11 May 2012

ABSTRACT

The association between etio-pathogenesis of mor-

bidly adherent placenta (MAP) or placenta cretas and

adenomyosis has never been described in medical

literature. Contrary to the believe that MAP is due to

direct invasion of trophoblastic tissues into the adja-

cent normal myometrium due to prior uterine sur-

geries, this article describes how pre-existence of

adenomyosis acts as a precursor for the develop-

ment of placenta cretas. It elucidates how prior

uterine traumas such as surgeries, repeated child-

births and endometritis cause endometrial tissues to

invade the myometrium as a result of disruption of

decidua basalis. The invaded endometrial tissues

cause hyperplasia and hypertrophy of surrounding

myometrium to form the clinical entity called ade-

nomyosis. The over-expression of bcl-2 oncogene in

the endometrium causes inhibition of apoptosis of

endometrial cells removing the barrier of trophoblas-

tic tissues to invade the myometrium to form MAP.

This hypothesis is based on the similarity of their

clinical perspectives, similar pathological description

of the two disease entities and their common molecu-

lar components. Both diseases increase with age; more

in women older than 35 years and also in those with

history of previous endometrial traumas such as sur-

geries, childbirth and endometritis. Both diseases also

share common pathological factors and molecular

components due to absence of deciduas basalis and

over-expression of bcl-2 oncoprotein gene, inhibition

of cell apoptosis and failure to find genetic abnor-

malities such as mutations of K-ras, P53 or LOH. An

on-going study looking at uterine specimens from

cesarean hysterectomies and pelvic MRI evaluation of

patients with retained placentas to prove that pre-

existing adenomyosis may be a precursor to the de-

velopment of morbidly adherent placenta is near to

conclusion.

Keywords: Morbidly Adherent Placenta (Placenta

Accretes); Adenomyosis, Association; Epidemiology;

Etio-Pathogenesis and Clinical Persp ective

1. INTRODUCTION

Adenomyosis is a disorder characterized by the presence

of islets within the myometrium that consist of both

epithelial and stroma elements of endometrial tissues. It

was first descri bed by Rokitansky i n 1860 and then clearly

defined by Von Reckinghausen in 1896 [1,2]. In 1991,

Sathganarayana divided adenomyosis into 3 categories

depending on the location of the lesion; basal, deep and

surface layers. The minimum myometrial invasion re-

quired for diagnosis has been debated, but a depth of 2.5

mm or half a low-power field (LPF) from the endomyo-

metrial border has been universally accepted in most

assessments [3-6]. Any site may be involved, but the

posterior wall is affected the most [7,8].

Morbidly adherent placenta is globally referred to as

placenta cretas and it is define d as the abnormal adherence

either in whole or in part of the place nta to the underlying

uterine wall. It occurs when a defect of the d ecidua basalis

results in abnormally invasive placenta implantation. Risk

factors inclu de placenta pr evia, previous cesarean section,

advanced maternal age, multiparity and previous uterine

curettage. It is classified into 2 broad categories according

to depth of myometrial invasion and amount of placenta

involvement. A partial or total absence of the deciduas

basalis and imperfect development of the fibrinoid layer

(Nitabuch layer) results in chorionic villi adherent to

superficial myometrium—placenta accreta, or chorionic

villi involving myometrium—placenta increta and chori-

onic villi penetrating full thickness myometrium and

involving the serosa—placenta percreta. Classification

based on the amount of placental involvement are: focal

adherence—when part of the cotyledon is involved, par-

tial adherence—when more than one of the cotyledon is

involved and total adherence when whole placenta is in-

volved.

*Corresponding author.

OPEN ACCESS

C. A. Enakpene, O. Muneyyirci-Delale / Open Journal of Obstetrics and Gynecology 2 (2012) 321-324

322

2. EPIDEMIOLOGY

2.1. Epidemiology of Adenomyosis

Accurate determination of the prevalence of adenomyosis

is difficult because the diagnosis can reliably be made

with certainty by microscopic examination of extirpated

uterus. It has been estimated to affect 20% of women,

however, it was fo und in appr oximat ely 65% of w omen in

one study of meticulous histopathological analysis of

multiple myometrial sections [9]. Adenomyosis most

often co-exi st s w i t h other organi c pel vi c pathologie s such

as leiomyoma, endometriosis and pelvic inflammatory

disease. The co-existence of adenomyosis and leiom yoma

has been reported in up to 60% of cases studied. Black

women have been reported to have a higher incidence of

leiomyomas than Adenomyosis [10]. Adenomyosis is

usually found in women 35 - 50 years of age who are

multiparous and present with abnormal uterine bleeding,

usually hypermnorrhea and secondary dysmenorrheal

[11].

2.2. Epidemiology of Morbidly Adherent

Placenta

Morbidly adherent placenta (MAP) was first reported by

Plater in a case of a noble woman; Galla who was deli-

vered on March 25 in the year 88 AD [12]. The placenta

was retained and she die d. Upon autopsy, the placenta was

found to be firmly adherent to the uterine wall above the

internal Os. The incidence ranges between 1:2500 to

1:110 [13-15]. The increasing incidence of morbidly ad-

herent placenta is link to the rising cesarean section rate.

This is suggested to result from the consequences of

failure of reconstitution of the endometrium/decidua ba-

salis after repair of a cesarean incision. Histopathology of

the placental bed usually shows that the trophoblasts in-

vade the myometrium without interv ening deciduas [16].

3. ETIO-PATHOGENESIS

Adenomyosis has been variously described by different

experts as “ elusiv e dis ease” or “dé jà vu” d is ease base d on

the little knowledge of its pathogenesis. However, the

universal agreement is that it is associated with accentua-

tion of the myometrial muscle pattern, multiparity, and

endometrial hyperplasia. Common proposed etiologies

are hereditary, hormonal influences, trauma, viral trans-

mission, and chronic postpartum endometritis. Some

authors suggest that the myometrium is vulnerable to

invasion by endometrial hyperplasia. Other authors pos-

tulate that the myometrium is vulnerable to invasion by

endometrial glands because of the absence of a basal

membrane—decidua basalis [17]. A retrospective study

by Panganamamula et al. found a link between prior

uterine surgery and adenomyosis. The hypothesis is that

there is a disruption of the junction of the endometrium

and myometrium by any surgical intervention. This re-

sults in the endometrial glands growing into the uterine

muscle leading to the developmen t of Adenomyosis [18].

However, there is a strong suggestion that adenomyosis

does not originate from the basal endometrium based on

the variation of cell death repressor activity, bcl-2 gene

expression and proliferative marker, ki-67 expression as

compared with eutopic Endometrium [19]. Other theories

proposed are: invasive tissue growth, developmental ori-

gins and uterine inflammation related to childbirth. Risk

factors incl ude uterine surgeri es such as previous cesar ean

section, dilatation and curettage, myomectomy , and child-

birth.

The ectopic endometrial tissue appears to induce hy-

pertrophy and hyperplasia of the surrounding myome-

trium, which results in a diffusely enlarged uterus called

“globular enlar gement”. A focal occurrence of a denomyo-

sis can result to nodules; called “adenomyoma” which

clinically resemble leiomyoma. The uterus generally does

not exceed the size of a pregnant uterus at 12 weeks of

gestation.

4. THE LINK BETWEEN THE

ETIOLOGY OF MORBIDLY

ADHERENT PLACENTA AND

ADENOMYOSIS

The hypothesis of an association between adenomyosis

and future de vel opm ent of se con d or t hird trim est er ret ain

placenta and morbidly adherent placenta such as placenta

accretas can be viewed at three different levels: Clinical,

pathological and molecular perspective.

4.1. Clinical Perspective

Age and prior uterine surgeries such as cesarean section

are inde pend ent r isk fac tors for placenta prev ia—placenta

accreta as well as Adenomyosis [11,20]. T he incide nce of

both disease entities are increased in women older than 35

years and history of previous uterine surgeries. Disruption

of endomyometrial junction by any surgical intervention

allows in-growth of endometrial tissue into the myo-

metrium and this creates a pathway for trophoblasts to

invade the myom et r i um during pl a centation . The ass oci a -

tion between etiology of morbidly adherent placenta and

adenomyosis is based on the hypothesis that pre-existing

adenomyosis heralds the development of placenta cretas.

Our hypothesis is proposing that patients with suspected

adenomyosis based upon its clinical, radiological and

hysteroscopy features are more likely to develop placenta

cretas. The clinical symptom s of a denomy osis include but

not limited to dysmenorrhea, menorrhagia, metrorrhagia,

dyspareunia and/or dyschezia. Global shape uterus, hy-

poechoic or slightly heterogeneous appearance on trans-

C. A. Enakpene, O. Muneyyirci-Delale / Open Journal of Obstetrics and Gynecology 2 (2012) 321-324 323

vaginal sonogram and MRI features of widening of the

junctional zone of 12 mm or greater increase the risk of

future de velopment of placenta accretas in pregnancy. The

presence of irregular endometrium, endometrial defects,

hypervascularization, strawberry pattern or cystic hem-

orrhagic lesions which are hysteroscopic characteristics of

possible adenomyosis are also proposed in this hypothesis

as risk factors for the development of placenta cretas.

Adenomyosis and placenta cretas share common other

risk factors such as multiparity, endometritis and previous

uterine surgeries such as dilatation and curettage, myo-

mectomy and cesarean section. Any condition that leads

to disruption of the endometrium can alter decidualization

and placentation during pregnancy which can lead to

invagination of placenta tissues.

4.2. Pathological and Molecular Perspectives

The apparent similarity between the etio-pathogenesis of

morbidly adherent placenta and adenomyosis is based on

the common pathological factors such as absence of de-

ciduas basalis and over expression of bcl -2 in both disease

entities. There is a possibility that the invading endo-

metrial tissues leaves the decidua basalis devoid of nor-

mal endometrium covering leading to invasion of corre-

sponding myometrium by immortal endometrial tissues

due to over-expression of the bcl-2 oncoprotein gene, an

inhibitor of cell apoptosis. The pathogenesis of placenta

cretas is multi-dimensional involving increased but in-

complete trophoblast invasion in a background of absent

decidua. Placenta cretas result from prim ary deficie ncy of

decidua, abnormal maternal vascular remodeling and

excessive trophoblastic invasion of the myometrium [21].

4.3. The Role of Bcl-2 Oncoprotein Gene in the

Etiology of Morbidly Adherent Placenta

and Adenomyosis

Morbidly adherent placenta is associated wit h retention of

a piece or the whole placenta tissue resulting in uterine

sub-involution and delayed secondary postpartum hem-

orrhage. Increase bcl-2 oncoprotein is associated with

inhibition of apoptosis and prolonged cell survival. It is

seen mostly in sub-involuted placenta bed as compared

with involuted bed. The expression of bcl-2 gene is asso-

ciated with sub-involution of the utero-placental arteries

which inhibit complete resolution of pregnancy induced

changes [22]. There is also a decrease cellular apoptosis

in adenomyosis and ectopic endometrium due to high

bcl-2 gene e xpression in ectopi c endometrium tissues. In a

study by Ueki et al, occurrence of adenomyosis was cor-

related to bcl-2 expression regulated by estrogen and

estrogen receptor rather than genetic mutation [23]. Con-

stant expression of bcl-2 with estrogen receptor (ER) and

hyper-estrogenic metabolic states promote invagination

and spreading of a denomyosis into the myomet rium. This

hypothesis is also an chored on the failure to find genetic

abnormalities such as mutations of K-ras, P53 or LOH

[23].

5. CONCLUSION

Any patient with retained placental tissues following

delivery should be evaluated for prior history of sym-

ptoms, ra di ol o gi c or hyster oscopic feat ures of adenomy o-

sis. Till date, transvaginal sonogram and magnetic reso-

nance im aging are the m ainstay of pre-operative diagnosis

of adenomyosis with sensitivity of 68% and 70% and

specificity of 65% and 86% respectively [24]. When

available, they should be utilized without hesitation.

Other diagnostic approaches are pre-operative biopsy,

hysterosalpingography and hysteroscopy. The definitive

treatment and diagnosis of adenomyosis is hysterectomy

and pathological examination of extirpated uterus. How-

ever, conservative management such as norethindrone

acetate, levonorgestrol impregnated IUD (mirena), est-

rogen, danazol, GnRH agonists, resection of lesions, hys-

teroscopic endometrial ablation, uterine artery emboli-

zation (UAE) and magnetic resonance guided focused

ultrasound surgery (MRgFUS) can be employed [24,25].

Our hypothesis suggesting an association between etiopa-

thogenesis of placenta cretas and pre-existing adeno-

myosis may be factual rather than a mere proposition.

Fertility preserving management of adenomyosis may

play a great role in reducing the incidence of placenta

cretas. More research study to explore temporal associa-

tion between the etiology of MAP and adenomyosis is

under way. The result of our on-going study on this topic

will finalize whether this association is true or not.

REFERENCES

[1] Rokitansky, K. (1860) Ueber uterus-neubildung. Aerzte

zu Wien Ztsc hr K Gesellsch, 16, 577.

[2] Von Recklinghausen, F. (1896) Die adenomyoma die

uterus und tuberwandung ihne abkunft von resten des

wolffschen korpeus. August Hirschwald, Berlin.

[3] Atzori, E., Tronci, C. and Sionis, L. (1996) Transvaginal

ultrasound in the diagnosis of diffuse adenomyosis. Gy-

necologic and Obstetric Investigation, 42, 39-41.

doi,10.1159/000291887

[4] Vercellini, P., Cortesi, I., De Giorgi, O., et al. (1998)

Transvaginal ultrasound versus uterine needle biopsy in

the diagnosis of diffuse adenomyosis. Human Reproduc-

tion, 13, 2884-2887. doi,10.1093/humrep/13.10.2884

[5] Ascher, S.M., Arnold, L.L., Patt, R.H., et al. (1994) Ade-

nomyosis, prospective comparison of MRI and trans-

vaginalsonography. Radiology, 190, 803-806.

[6] Bazot, M., Darai, E., Rouger, J., et al. (2002) Limitations

of transvaginalsonography for diagnsosis of adenomyosis

C. A. Enakpene, O. Muneyyirci-Delale / Open Journal of Obstetrics and Gynecology 2 (2012) 321-324

324

OPEN ACCESS

with histopathological correlation. Ultrasound in Obstet-

rics & Gynecology, 20, 605-611.

doi,10.1046/j.1469-0705.2002.00852.x

[7] Benson, R.C. and Sneeded, V.D. (1958) Adenomyosis, a

reappraisal of symptomatology. American Journal of Ob-

stetrics & Gynecology, 76, 1044-1061.

[8] Vercellini, P., Ragni, G., Trespidi, L., et al. (1993) Ade-

nomyosis, a déjà vu? Obstetrical & Gynecological Survey,

48, 789-794. doi,10.1097/00006254-199312000-00004

[9] MCelin, T.W. and Bird, C.C. (1974) Adenomyosis of the

uterus. Obstetrics and Gynecology Annual, 3, 425.

[10] Owolabi, T.O. and Strickler, R.C. (1977) Adenomyosis a

neglected diagnosis. Obstetrics & Gynecology, 50, 424-

427.

[11] Pavlik, R.M. (1995) Adenomyosis, an ignored uterine

disease. Nursing Practitioner, 20, 32-43.

[12] Plater, F. (1937) Quoted in Surgery. Obstetrics & Gyne-

cology, 64, 178.

[13] Gielchinsky, Y., Rojansky, N., Faouliotis, S.T. and Ezra, Y.

(2002) Placenta accrete-summary of 10 years, a survey of

310 cases. Placenta, 23, 210-214.

doi,10.1053/plac.2001.0764

[14] ACOG committee on obstetric practice (2002) ACOG

committee opinion number 266 January 2002, placenta

accrete. Obstetrics & Gynecology, 99, 169-170.

[15] Morken, N.H. and Henriksen, H. (2001) Placenta percreta

two cases and review of the literature. European Journal

of Obstetrics & Gynecology and Reproductive Biology,

100, 112-115. doi,10.1016/S0301-2115(01)00422-5

[16] Benirschke, K. and Kaufmann, P. (2000) Pathology of the

human placenta. 4th Edition, Springer, New York.

[17] Thompson, J.R. and Davion, R.J. (1986) Adenomyosis of

the uterus, an enigma. Journal of the American Medical

Association, 78, 305-307.

[18] Panganamamula, U.R., Harmanli, O.H., Isik-Akbay, E.F.,

et al. (2004) Is prior uterine surgery a risk factor for ade-

nomyosis? Obstetrics & Gynecology, 104, 1034-1038.

doi,10.1097/01.AOG.0000143264.59822.73

[19] Matsumoto, Y., Iwasaka, T., Yamasaki, F. and Sugimori,

H. (1999) Apoptosis and ki-67 expression in adenomyotic

lesions and the corresponding eutopic endometriosis. Ob-

stetrics & Gynecology, 94, 71-77.

doi,10.1016/S0029-7844(99)00279-3

[20] Miller, D.A., Chollet, J.A. and Goodwin, T.M. (1997)

Clinical risk factors for placenta previa-placenta accreta.

American Journal of Obstetrics & Gynecology, 177, 210-

214. doi,10.1016/S0002-9378(97)70463-0

[21] Tantbirojn, P., Crum, C.P. and Parast, M.M. (2008) Patho-

physiology of placenta creta, the role of decidua and ex-

travilloustrophoblast. Placenta, 29, 639-645.

doi,10.1016/j.placenta.2008.04.008

[22] Kong, T.Y. and Abdul Rahman, H. (1997) Bcl-2 expres-

sion delays postpartum involution of pregnancy-induced

vascular changes in the human placenta bed. Interna-

tional Journal of Gynecological Pathology, 16, 138-142.

doi,10.1097/00004347-199704000-00009

[23] Ueki, K., Kumagai, K., et al. (2004) Expression of apop-

tosis related protein in adenomyotic uteri treated with

danazol and GnRh agonists. International Journal of Gy-

necological Pathology, 23, 248-258.

doi,10.1097/01.pgp.0000130109.80359.57

[24] Rabinovici, J. and Stewart, E.A. (2006) New intervene-

tional techniques for adenomyosis. Best Practice and Re-

search Clinical Obstetrics and Gynecology, 20, 617-636.

doi,10.1016/j.bpobgyn.2006.02.002

[25] Muneyyirci-Delale, O., Chandrareddy, A., Battala, N., et

al. (2008) Norethindrone acetate in the medical manage-

ment of adenomyosis. Obstetrics and Gynecology, 111 ,

29S.