Human Reproduction Update 1998, Vol. 4, No. 4 pp. 312322 European Society for Human Reproduction and Embryology

Pathophysiology of adenomyosis

Alex Ferenczy

Department of Pathology, The Sir Mortimer B.Davis Jewish General Hospital, 3755 Cte Ste-Catherine Road, Montreal,Quebec, Canada H3T 1E2

TABLE OF CONTENTS

Historical background and definition 312Pathogenesis 313Incidence/predisposing factors 316Clinical features 316Associated pathology 317Adenomyosis and pregnancy 317Diagnosis 317Pathology 318Treatment 320References 321

Adenomyosis refers to endometrial glands and stromalocated haphazardly deep within the myometrium.Similar histological alterations may be found in extra-uterine locations such as the rectovaginal septum. Theaetiology and pathogenic mechanism(s) responsiblefor adenomyosis are poorly understood. Both humanand experimental studies favour the theory of endo-myometrial invagination of the endometrium, al-though the de-novo development of adenomyosis fromMllerian rests in an extrauterine location is a possi-bility. The prerequisite for adenomyosis may be trig-gered or facilitated by either a weakness of thesmooth muscle tissue or an increased intrauterinepressure or both. Relatively high oestrogen concentra-tions and impaired immune-related growth control inectopic endometrium may be necessary for the main-tenance of adenomyosis. Smooth muscle cell hyperpla-sia and hypertrophy are a reflection of reactive changesecondary to ectopic endometrial proliferation.Further studies are needed for insight into the preciseaetiology and pathogenesis of adenomyosis. Adeno-myosis is a relatively frequent endomyometrial pa-thology discovered in multiparous women between 40and 50 years of age. About 2/3 of women are sympto-matic with menorrhagia and dysmenorrhoea; 80% ofadenomyotic cases are associated with leiomyomata

uteri; and in women with endometrial adenocarcino-ma, adenomyosis is relatively often seen. Definite diag-nosis is made on hysterectomy specimens, althoughattempts are made at securing preoperative diagnosisby magnetic resonance imaging and myometrialbiopsies. Definite treatment of symptomatic women ishysterectomy.

Key words: adenomyosis/pathogenesis

Historical background and definitionIt was Rokitansky (1860) who first alluded to the presenceof endometrial glands in the myometrium as cystosarco-ma adenoides uterinum. In 1896, Von Recklinghausendescribed the same phenomenon under the term adeno-myomata and cystadenomata of the uterus and tubal wall.Cullen (1908) distinguished between adenomyoma, an in-tramyometrial tumour-like condition made of endometrialglands and stroma, and diffuse adenomyoma, in whichboth elements were distributed throughout the myome-trium. The term adenomyosis uteri was first used byFrankl (1925). In 1972, Bird et al. defined adenomyosis asthe benign invasion of endometrium into the myome-trium, producing a diffusely enlarged uterus which micro-scopically exhibits ectopic, non-neoplastic, endometrialglands and stroma surrounded by the hypertrophic andhyperplastic myometrium. This definition still prevailstoday; however, we like to qualify it further as to the pres-ence of endometrial glands and stroma located haphazardlyand deep within the myometrium. The issue of depth isimportant because the normal endomyometrial junction isoften irregular, and adenomyosis must be distinguishedfrom minimally invaginated basalis surrounded bymyometrium (Figure 1). There are two ways to circumvenethis problem. The first is to determine whether there ismyometrial hypertrophy (collar) around foci of adeno-myosis. Such alteration is not seen at the endomyometrialjunction (Figure 2). The second is to measure the distancebetween the endomyometrial junction and the closest ade-

1To whom correspondence should be addressed. Tel: (514) 340-7526; Fax: (514) 340-7542; E-mail: mdfe@musica.mcgill.ca

Uterine and extra uterine adenomyosis 313

Figure 1. Endomyometrial junction featuring basalis endometriuminvaginating into superficial myometrium. There is no evidence ofhypertrophy of the surrounding myometrium. Such findings shouldnot be considered as adenomyosis. Original magnification 100.

nomyotic foci. This should be ~25% of the total thicknessof the myometrium. The latter approach is particularly rel-evant in the postmenopausal and gravid uterus becauseperiadenomyotic muscular hypertrophy in these uteri isgenerally absent (Hendrickson and Kempson, 1980). Al-though many consider adenomyosis a variant of endome-triosis, so-called internal endometriosis (Emge, 1956;Israel and Woutersz, 1959), we like to define endometriosisas endometrial glands and stroma located outside of themyometrium, e.g. uterine serosa, posterior subperitonealsurface of the corpus, etc.

Pathogenesis

The precise aetiology and the developmental events lead-ing to adenomyosis are unknown. A number of theorieshave been proposed in the past 50 years and these havebeen reviewed in detail by Ridley (1968). Currently, themost widely held opinion is that adenomyosis develops as aresult of down-growth and invagination of the basalis en-dometrium into the myometrium. Indeed, one can often seedirect continuity between the basalis endometrium and theunderlying adenomyosis in the myometrium. In extrauter-ine regions such as the rectovaginal septum, adenomyosis

Figure 2. Deeply located endometrial glands and stroma surroundedby hypertrophic myometrium. This is a focus of adenomyosis.Original magnification 100.

may develop de novo from embryologically misplacedMllerian remains.

The triggering mechanism of endometrial invasion ofthe myometrium in humans remains to be determined. Pro-liferative changes such as mitotic activity, increased nu-clear DNA synthesis and ciliogenesis are significantlymore pronounced in the functionalis than the basalis layerof the endometrium (Ferenczy and Bergeron, 1991). Thebiological rationale for the geographic variation in prolife-rative indices may lie in the difference in physiologicalfunctions of the functionalis compared to the basalis layer.The former is the seat of blastocyst implantation, whereasthe latter provides the origin for the regenerative endome-trium following menstrual degeneration of the functionalis(Ferenczy, 1980). During periods of regeneration, epithe-lial cells from the stump of basalis glands are in directcontact with the spindle-shaped cells of the endometrialstroma, and ultrastructurally contain intracellular microfi-lamentous/trabecular systems and pseudopodial cyto-plasmic projections. These features are consistent withmigration by amoeboid contraction and expansion (Fer-enczy, 1980). Such morphological alterations have as yetnot been described in adenomyotic endometrial glandularepithelium. Nevertheless, in-vitro studies showed that en-dometriotic cells have invasive potential and their invasionindex is similar to that of metastatic bladder cell lines

314 A.Ferenczy

(Gaetje et al., 1995). Such invasive potential may facilitateextension of the basalis endometrium into the myome-trium. In MCF-7 breast cancer cells, production of tenascinis stimulated by the hormonally regulated epidermalgrowth factors (EGF) (Chiquet-Ehrismann et al., 1989).The fact that endometrial stromal fibroblasts produce ten-ascin, a fibronectin inhibitor which in turn facilitates epi-thelial migration suggests a complex physico-chemicalinterrelationship during the process of endometrialugrowth processes. Tenascin has been immunolocalizedaround proliferative phase endometrial glands but not inpost-ovulatory phase endometrial glands (Vollmer et al.,1990). It is possible that tenascin mediates epithelialme-senchymal interactions by inhibiting cell attachment to fi-bronectin in adenomyotic type endometrium as it does inits endometrial counterpart.

A recent study using in-situ hybridization and immuno-histochemistry demonstrated that endometrial glands inadenomyosis selectively express more human chorionicgonadotrophin (HCG)/luteinizing hormone (LH) receptormRNA and immunoreactive receptor protein than the non-invaginating glandular epithelium (Lei et al., 1993). Innormal endometrium, the glands fail to demonstrate geo-graphic variation (as a function of their depth) in HCG/LHreceptor expression. It is thus possible although not proventhat the increased receptor expression of invaginating en-dometrial epithelium may be related to the potential toinvaginate into the myometrium and form adenomyoticfoci. It is of interest that increased HCG/LH receptor ex-pression was found in endometrial carcinomas comparedto normal endometrial glands (Lei et al., 1992) as well as ininvasive versus non-invasive trophoblasts in choriocarci-nomas (Lin et al., 1994).

Earlier steroid receptor studies using cytosol prepara-tions yielded inconsistent results; some found no proges-terone receptors in 40% of the adenomyotic cases studied

(Tamaya et al., 1979), whereas others found higher proges-terone than oestrogen receptor concentrations (van derWalt et al., 1986). Using immunohistochemical tracingtechniques the author found relatively high concentrationsof both oestrogen and progesterone receptors in both thebasalis and adenomyotic endometrium (unpublished ob-servations) (Table I). Oestrogen receptors are prerequisitesfor oestrogen-mediated endometrial growth. Althoughthere is no clear-cut evidence of impaired hormonal envi-ronment in most women with adenomyosis, hyperoes-trogenaemia may play a role in the invagination processsince high frequency of endometrial hyperplasia is found inwomen with adenomyosis. According to some researchers,a relatively high oestrogen concentration is necessary forthe development and maintenance of adenomyosis as wellas endometriosis (Yamamoto et al., 1993). Supporting thiscontention is the clinical observation that suppression ofoestrogenic environment by danazol induces involution ofthe ectopic endometrium as well as the associated symp-toms such as menorrhagia and dysmenorrhoea (Yamamotoet al., 1993). Akin to uterine leiomyomata, oestrogen issynthesized and secreted in adenomyotic tissues (Yama-moto et al., 1993). These investigators demonstrated botharomatase and oestrogen sulphatase activities by steroido-biochemical analysis in the supernatant faction of myome-trium containing foci of adenomyosis. Oestrogensulphatase and particularly aromatase activity was higher(1 mg protein of tissue) than that observed in the normaladjacent myometrium and leiomyomata and overlying en-dometrium (P < 0.010.001). Moreover, endometrialenzymatic activity was suppressed in vitro by up to 50%after addition of 106 M danazol (Yamamoto et al., 1993).Aromatase was also demonstrated by immunohistoche-mistry in the cytoplasmic substance of gland lining cellsbut not stromal cells in foci of adenomyosis in human uteri.

Table I. Immunohistochemical characteristics of uterine adenomyosis, endometriosis, basalis endometrium and leiomyoma

Antibodies AdenomyosisDiffuse Focal Endometriosis Basalis Leiomyoma

(adenomyoma) endometriumG S M G S M SE S G S

AE1/AE3 4+ 1+ 2+ 2+ 1+ 4+ 4+ 1+Vimentin 1+ 1+ 1+ 1+ 1+ 2+ 1+ 1+ ER 4+ 4+ 4+ 2+ 2+ 1+ 4+ 4+ 4+ 4+ 2+PR 3+ 4+ 4+ 3+ 3+ 3+ 4+ 4+ 1 to 3+ 1 to 3+ 4+

(focal) (focal) (focal) (focal) (focal)Actin 3+ 3+ 4+Desmin 3+ 3+ 4+

AE1/AE3 = low and high molecular weight cytokeratin; ER/PR = oestrogen/progesterone receptor; G = glandular epithelium; S =stromal cells; M = myometrium surrounding ectopic endometrium; SE = surface epithelium.

Uterine and extra uterine adenomyosis 315

Oestrogen production by adenomyotic tissue is also sup-ported by finding more women with high oestradiol con-centration (30 pg/ml) in the menstrual blood in those withadenomyosis than in those without adenomyosis and nor-mal ovulatory cycles (Takahashi et al., 1989). The secre-tory response of adenomyotic tissue to hormonalstimulation is consistent with effective progestogenic in-fluence on the ectopic endometrium. Progestogens en-hance aromatase activity both in eutopic and adenomyotictissues (Urabe et al., 1989) contributing thereby tooestrogen biosynthesis in adenomyotic foci.

It may be that bioavailability of sex steroids is not suffi-cient alone to produce adenomyosis. It is possible that themyometrium in cases of adenomyosis is either predisposedto be invaded by the basalis endometrium, and that benigninvasion of the endometrium occurs secondary to weak-ness of the myometrium, or that myometrial weakness iscaused by trauma, such as curettage, myomectomy andCaesarean section. In this regard, adenomyosis can be pro-duced in pregnant rabbits by curetting one horn and tube,while retaining pregnancy in the opposite horn (Lewinski,1931). It is possible, although not proven, that myometrialinvasion by the endometrial basalis is enhanced by in-creased intrauterine pressure which, according to Cullen(1908), could be produced by elevated concentrations ofcirculating progesterone.

Increased expression of the major histocompatibilitycomplex class II antigen (HLA-DR) in the gland cells ofnormal (eutopic) and ectopic endometrium (18 patients)and adenomyosis (50 patients) was observed by immuno-histochemistry (Ota and Igarashi, 1993). In addition, ma-crophages in the myometrium of adenomyosis appear to beincreased; these may activate helper T cells and B cells toproduce antibodies. Autoantibodies against phospholipidsin endometriosis and adenomyosis as well as marked de-position of immunoglobulin (Ig)S or complement compo-nents have been observed (Weed and Arquembourg, 1980;Kreiner et al., 1986). The precise significance of theseaberrant immune phenomena in adenomyosis or endome-triosis is not understood at present.

Experiments in vitro showed that activated CD3+ T cellsin the endometrium and their secretory productinterferon- induce expression of HLA-DR immunoreac-tivity in endometrial gland cells and inhibition of theirproliferation (Tabibzadeh et al., 1993). The closer the en-dometrial cells are to activated T cells, the greater is theirgrowth-inhibition. It appears that lymphoid follicle-likestructures, mostly located in the endomyometrial junction,are rich in activated T helper cells. Their location coincideswith maximal inhibition of endometrial growth observedboth morphologically (Ferenczy et al., 1979) and by prolif-

eration marker studies (Tabibzadeh et al., 1993). Con-versely, endometrial proliferation is at its maximum nearthe endometrial surface far away from basalis-containinglymphoid aggregates (Ferenczy et al., 1979; Tabibzadeh etal., 1993). It is plausible, although not proven, that adeno-myotic uteri are poor in activated T cells, thus the basalisendometrium may have growth advantage over non-ade-nomyotic, lymphoid-rich basalis endometria. Whethersuch anomaly is necessarily associated with acquiredmyometrial weakness or whether it is an independent pre-requisite for the development of adenomyosis remains tobe determined.

The precise reason for myometrial hyperplasia/hyper-trophy located around deep foci of endometrium is notknown but may indicate either an attempt at controllingendometrial invagination of the myometrium or may sim-ply represent smooth muscle bundles pushed aside by theingrowing endometrium. By immunohistochemistry, themyometrium surrounding the ectopic endometrium,whether diffuse (adenomyosis) or focal (adenomyoma),contains no abnormalities. Indeed, smooth muscle cells inadenomyotic foci, normal myometrium and leiomyomata(coexistent or not with adenomyosis) are all rich in actinand desmin (Table I).

There are several animal models for the study of pa-thogenesis of adenomyosis. In one, intrauterine isografts ofanterior pituitary mice lead to the development of adeno-myosis (Jeffcoate and Potter, 1934). Prolactin may amplifythis event, for the isograft-free horn contained compara-tively less developed adenomyosis. Whereas ovariectomyprevented, oestradiol benzoate stimulated, the develop-ment of adenomyosis in this animal model. In anothermodel, mice treated prenatally with high doses of diethyls-tilboestrol (DES) developed adenomyosis. It appears thatcertain strains of mice are prone to develop adenomyosis inresponse to high concentrations of prolactin, oestrogensand progestogens. More recently, Ficicioglu et al. (1995)induced adenomyosis in non-castrated rats with hyperpro-lactinaemia. The authors suggested that high prolactin con-centrations cause myometrial degeneration in the presenceof ovarian steroids which may result in myometrial weak-ness and subsequent myometrial invasion by the endome-trial basalis. Of interest were the observations of Mori andNagasawa (1983) in mice in which myometrial invasion bystromal fibroblasts along the branches of blood vesselspreceded invagination of endometrial glands. In anotherstudy, Sakamoto et al. (1992) induced a high rate of uterineadenomyosis in mice by ectopic pituitary isografts. DNA-synthesizing activities and related enzymes, i.e. thymidi-late synthetase and thymidine kinase, were markedlyincreased in adenomyosis compared to control uteri.

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In the same experimental animal model, the finding ofthe small molecular weight matrix metalloproteinase wassuggested to play a role in the development of adenomyosisat the level of gene transcription, activation and inhibition(Mori et al., 1996). Certain experimental observations sug-gested that some hereditary factors may be involved in thepathogenesis of adenomyosis. For example, the uteri ofrecombinant inbred SMXA mice develop spontaneouslyhistological changes similar to adenomyosis and containtenascin around adenomyotic glands (Kida, 1994). Theseobservations together with the biological property of tenas-cin detailed earlier in this article are consistent with theendometrial origin of adenomyosis and the intramyome-trial invagination concept of a genetically predisposedmyometrium. Also, compared to SMXA mice, the uteri ofF1 mice, a strain between SMXA and NJL strains, containeven more prominent spontaneous changes resemblinghuman adenomyosis. Whether heredity is an important fac-tor in adenomyosis in the human remains to be determined.

The de-novo origin of adenomyosis from Mllerian re-mains in extrauterine sites seems to be supported by theobservation of adenomyosis in the rectovaginal septum.Endometrial glands and stroma associated with smoothmuscle cell hypertrophy may be found in this locationforming adenomyotic nodules (Nisolle and Donnez, 1997).Although these nodules may develop as a result of invagi-nating peritoneal endometriosis, the Mllerian remains ori-gin is favoured by some. According to Nisolle and Donnez(1997), in most cases adenomyotic nodules are locateddeep in the septum and occasionally in the muscularis pro-pria of the rectum far from the pelvic peritoneum. Coex-pression of vimentin and cytokeratin in endometriumwhether lining the endometrial cavity or located withinadenomyotic foci is typical of Mllerian-derived tissue.Morphologically and receptor content-wise, rectovaginaladenomyosis is identical to its intramyometrial counter-part, including poor or no response to postovulatory pro-gestational stimuli. Despite large doses of exogenousprogestational agents given to women with rectovaginaladenomyosis to produce secretory transformation, hor-monal therapy is poor. Obtaining definite cure of recto-vaginal lesion by surgery is suggestive also of a metaplasticde-novo process from Mllerian remains in that locationrather than implantation/invagination of peritoneal en-dometriosis.

Admittedly, there are many more questions than answerswith respect to the precise origin and pathogenic mechan-ism(s) of adenomyosis. Experimental and human studiesare needed to shed light onto the pathophysiology of thischallenging condition of the female genital tract.

Incidence/predisposing factors

The frequency of adenomyosis reported in the literatureranges from 5 to 70% (Azziz, 1989), and is largely depend-ent on how thoroughly the uterus is sampled, the histologi-cal criteria for making the diagnosis of adenomyosis andthe selection of specimens to be evaluated. The more sec-tions taken from a given specimen, the higher the fre-quency. For example, when three routine sections aretaken, 31% of hysterectomy specimens contained adeno-myosis and at six sections the rate increased to 61% (Bird etal., 1972). Using stringent diagnostic criteria, e.g. deeperthan 25% of myometrial thickness, yields lower adeno-myotic rates than if more superficially located glands areconsidered. Uteri removed because of symptoms containhigher rates of adenomyosis than those without symptoms.Even in the latter cases, the rates vary from 19% (Lee et al.,1984) in hysterectomy specimens to 57% in uteri examinedat autopsy (Emge, 1962).

The vast majority of cases (80%) are reported in womenaged 40 and 50 years old (Bird et al., 1972) and are asso-ciated with the most severe symptoms. The remainder ofcases are observed in women younger than 39 years withrelatively mild or no symptoms and in women older than 60years of age (Benson and Sneeden, 1958).

Nearly all cases (90%) of adenomyotic uteri occur inmultiparous women (Lee et al., 1984); it is not clearwhether the condition is more prevalent in white than inblack women (Israel and Woutersz, 1959; Mathur et al.,1962). Prior Caesarean section and obesity are not predis-posing factors (Benson and Sneeden, 1958; Bird et al.,1972; Harris et al., 1985).

Tamoxifen in treated postmenopausal women seems toreactivate pre-existing adenomyosis, which leads to an in-crease in myometrial volume and uterine size (Ugwumaduet al., 1993; Cohen et al., 1995). Adenomyosis has beenreported in 60% of 14 postmenopausal women on chronictamoxifen therapy who eventually received hysterectomyfor unrelated indications (Cohen et al., 1995).

Clinical features

About 35% of adenomyotic cases are asymptomatic (Bensonand Sneeden, 1958); in the remaining cases, the most frequentsymptoms are menorrhagia (50%), dysmenorrhoea (30%)and metrorrhagia (20%). Occasionally, dyspareunia may bean additional complaint. The frequency and severity ofsymptoms correlate with the extent (Benson and Sneeden,1958) and depth (Nishida, 1991) of adenomyosis. The pre-cise cause of menorrhagia in these patients is not known. It

Uterine and extra uterine adenomyosis 317

may be due to poor contractibility of the adenomyoticuterus and compression of the endometrium by submucousadenomyomata or leiomyomata. Mefenamic acid adminis-tration can reduce blood loss suggesting that prostaglan-dins (F2) may also play a role in the greater degree ofblood loss in women with adenomyosis (Azziz, 1989).Other factors may be anovulation, hyperplasia and rarelyadenocarcinoma. Dysmenorrhoea is due to uterine irrita-bility which in turn is secondary to increased amounts ofblood loss. Not all investigators have demonstrated adeno-myosis-related symptoms. For example, in one study of136 patients with histologically verified adenomyosis,symptoms were variable, non-specific and according to theinvestigators were related to the associated pathologiessuch as leiomyomata, endometriosis, polyps, etc. ratherthan adenomyosis (Nikkanen and Punnonen, 1980). Inanother study carried out prospectively, there were no dif-ferences in either the frequency or severity of dysmenorr-hoea and pelvic pain between 28 women with adenomyosisand 157 controls (Kilkku et al., 1984). A study of 23women with uterine adenomyosis found no qualitative dif-ferences in the spontaneous mobility of isolated myome-trial tissue throughout the menstrual cycle from normalregenerative and leiomyomatous uteri (Martinez-Mir etal., 1990). The mobility pattern was of low amplitude andhigh frequency of spontaneous contractions during the pro-liferative phase; both changes were amplified in the secre-tory phase. Histamine-produced myometrial contractionswere similar in all myometrial tissues investigated(Martinez-Mir et al., 1990)

Associated pathologyUp to 80% of adenomyotic uteri contain associatedpathology. The most frequent one is leiomyomata (Azziz,1989). Endometrial polyps (2.3%), hyperplasia without andwith atypia as well as adenocarcinoma appear more frequentin patients with adenomyosis than in the general population(Table II). In one study, 60% of uteri with endometrialcarcinoma contained coexistent adenomyosis compared to39% in control uteri (Marcus, 1961). However, the presenceof adenomyosis has no adverse (negative) influence on theprognosis of endometrial carcinoma (Marcus, 1961; Hall etal., 1984). Pelvic endometriosis is observed only in 620%of women with adenomyosis and in all likelihood the formeris unrelated to the latter.

Adenomyosis and pregnancyAlthough adenomyosis occurs relatively frequently inpregnancy [27 of 151 (17%) of Caesarean hysterectomy

specimens] it is not a major cause of obstetric or surgicalcomplications. A review of 80 years of literature yieldedonly 29 reports of complications, mainly uterine ruptureand perforation associated with adenomyosis (Azziz,1986).

Table II. Associated pathology and adenomyosis

Disease %Leiomyoma 3555Pelvic endometriosis 620Salpingitis isthmica nodosa 1.419.8Endometrial polyps 2.3Endometrial hyperplasia 7.0

(types not specified)Endometrial hyperplasia with atypia 3.5Adenocarcinoma 1.4

DiagnosisThe clinical diagnosis of adenomyosis is only suggestive atbest (50%) (Hayata and Kawashima, 1987) and most oftenis either not made (75%) (Owalabi and Strickler, 1977;Azziz, 1989) or overdiagnosed (35%) (Lee et al., 1984).Menorrhagia and dysmenorrhoea in a multiparous womanin her late 40s/early 50s are suggestive but not diagnostic ofadenomyosis. The uterus may be diffusely enlarged (12weeks of gestational size), soft and tender on palpation.

Hysterosalpingography for diagnosing adenomyosis isnot recommended because it misses 75% of the cases(Marshak and Eliasoph, 1955) and is expensive. Similarly,ultrasonography is of questionable diagnostic value. Ex-perience with endovaginal ultrasonography seems to indi-cate a better diagnostic accuracy than grey-scaleultrasound with a sensitivity of 87%, a specificity of 98%, apositive predictive value of 74% and a negative predictivevalue of 99% (Fedele et al., 1992). Adenomyosis in tamox-ifen-treated women appears as irregularly distributedmicrocysts beneath the endometrium and in the myome-trium masquerading as increased endometrial thickness ontransvaginal ultrasonography (Goldstein, 1994; Perrotet al., 1994) and leads to undue anxiety and unnecessaryendometrial biopsies. The best radiological means so far ismagnetic resonance imaging (MRI) although experience islimited. Low signal intensity myometrium surrounds nor-mal, high-signal intensity endometrium. In other cases,irregular cystic spaces in the myometrium give a honey-comb-type appearance of adenomyosis. Blood CA125 de-terminations have provided inconsistent results so far(Takahashi et al., 1985; Halila et al., 1987) have little, if

318 A.Ferenczy

Figure 3. Diffuse adenomyosis of anterior wall of uterus. Note coarselytrabeculated, diffusely hypertrophied myometrium stippled with foci ofectopic endometrium. Original magnification 4.

any, diagnostic value. More recently, myometrial biopsiesof the posterior uterine wall were performed using biopsyneedle (Bohlman et al., 1987) or resectoscope (McCaus-land, 1992). The upper third posterior myometrial wallbiopsy without important bleeding revealed adenomyosisin five of 45 women (11%) aged 40 years or younger whowere undergoing laparoscopy or laparotomy for miscel-laneous reasons (Pasquinucci et al., 1991). Alternatively,hysteroscopy-aided biopsy of the posterior uterine wallwith a 5 mm loop electrode in 50 women with normaluterine cavity demonstrated adenomyosis in 66% of thecases (McCausland, 1992). Others found very low sensi-tivity of myometrial needle biopsy performed in 68 surgi-cally removed uteri. The rates ranged between 8 and18.7%; however, specificity was 100% (Popp et al., 1993).In two studies, MRI predicted adenomyosis in eight ofeight patients (Mark et al., 1987) and in eight of 16 patients(Marshak and Eliasoph, 1955) whose disease was con-firmed by histology. The principal diagnostic means foradenomyosis is histology of hysterectomy specimens.

PathologyThe characteristic gross appearance of adenomyosis is dueto myometrial hypertrophy surrounding endometrial mu-

Figure 4. Adenomyoma (focal adenomyosis) made of cystically di-lated endometrial glands and hypertrophied smooth muscle. Typicalof adenomyoma, its margin is indistinct from the surrounding nor-mal myometrium. Original magnification 40.

cosa. When the whole myometrium or one of the myome-trial walls is diffusely involved, the uterus is enlarged andglobular. On cross-section, the haphazardly distributedhypertrophied muscular trabeculae surrounding foci ofadenomyosis are apparent (Figure 3). The latter may onoccasion contain brown-staining old blood correspon-ding to hemolysed blood and haemosiderin pigment de-posits (Azziz, 1989). The focally involved uterus withadenomyosis resembles a leiomyoma; the term adenomyo-ma is applied to this rather frequent presentation of adeno-myosis (Figure 4). Since the process is not neoplastic, theterm focal adenomyosis is preferred by Hendrickson andKempson (1980). Since adenomyoma is often confusedclinically with leiomyoma, a benign but neoplastic condi-tion, we believe that the use of the term adenomyoma isacceptable. Typically, adenomyoma has poorly definedmargins because they merge with the surrounding normalmyometrium (Figure 5). In contrast, leiomyomata com-press the surrounding myometrium and have clear-cut,well-circumscribed margins (Figures 6 and 7). The lattercan be enucleated, whereas the former cannot.

Over the years, the author accumulated experience witha relatively large number of cases of adenomyosis (n = 50),endometriosis (n = 50) (unpublished data) and normal en-dometrium (n = 200) (Bergeron et al., 1988a,b; Ferenczy

Uterine and extra uterine adenomyosis 319

Figure 5. Detail of poorly defined margin of adenomyoma. Unlikeordinary leiomyomata, such a lesion cannot be enucleated. Magnifi-cation: 400.

Figure 6. Leiomyomata uteri with well-circumscribed margins contrastwith adenomyoma shown in Figure 5. Original magnification 4.

and Bergeron, 1991; Ferenczy, 1994) in both ovulating andpostmenopausal women.

Histologically and by immunohistochemistry, both theendometrial glands and stroma in foci of adenomyosis re-semble the basalis endometrium (Figures 8 and 9 and TableI). It seldom responds to hormonal stimuli, a phenomenonwhich explains at least partly why one sees only oc-casionally haemorrhagic or reparative morphological ev-ents in foci of adenomyosis. The reason for an increasedtendency for focal haemorrhage in deeply located adeno-myotic foci is not understood (Sandberg and Cohn, 1962).In contrast, ectopic endometrium in foci of endometriosisoften undergo cyclic changes including degeneration,bleeding and regeneration in all respects similar to thefunctionalis layer of the endometrium. The different fre-quency in menstrual-type changes between the two en-dometria are likely due to the relatively poorvascularization of the basalis-type adenomyotic endome-trium compared to the richly vascularized functionalis-type endometrium in endometriosis. However,adenomyotic endometrium seems to retain its proliferativepotential, to be the seat of endometrial growth and to beresponsible for failure of providing amenorrhoea or hy-pomenorrhoea following endometrial ablation (Haber andFerenczy, 1993). Secretory transformation including stro-mal decidualization in foci of adenomyosis is seen mainly

Figure 7. Histology of sharply defined margin of ordinary leiomyo-ma. Original magnification 100.

320 A.Ferenczy

during gestation and exogenous progestational therapy, thechanges being mediated by oestrogen and progesteronereceptors (Table I). Progestational effect in non-graviduterus occurs between 30 and 50% of adenomyotic foci(Mathur et al., 1962; Molitor, 1971). During intrauterinepregnancy, 57% of the articles reviewed by Azziz (1986)described decidualization. Others observed decidualiz-ation during pregnancy only in deeply located foci (atdepth of two low power fields), whereas decidualizationwas absent or inconspicuous in foci located less than twolow power fields from the basalismyometrium junction(Sandberg and Cohn, 1962). Also, it is not unusual to findhyperplastic changes with or without atypia in adenomyo-sis associated with similar conditions in the overlying en-dometrium. Hyperplasia in adenomyotic foci may containmetaplastic changes of the glandular epithelium such astubal metaplasia, squamous metaplasia (squamous mo-rules) and mucinous metaplasia. Adenocarcinoma mayalso involve foci of adenomyosis. When carcinoma islimited to adenomyotic foci, it should be consideredintramucosal since it does not make the prognosis worsethan the carcinoma for which the patient has had surgery.Whether adenocarcinomas located in both the overlyingendometrium and foci of adenomyosis represent simulta-neous primaries or extension of the former in adenomyoticfoci is not possible to determine by histology. The latterhypothesis is preferable because adenocarcinoma in foci ofadenomyosis without surface component is an extremelyrare event (Colman and Rosenthal, 1959; Winkelman andRobinson, 1966).

Treatment

Suppressive hormonal therapies using oral contraceptivesand progestational agents are of no value. GnRH agonist isgiven for 6 months to relieve symptoms (dysmenorrhoeaand menorrhagia) and decreases uterine volume; however,the symptoms reappear after discontinuation of leuprolideacetate therapy (Grow and Filer, 1991). Some women withsuperficial adenomyosis (

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References

Azziz, R. (1986) Adenomyosis in pregnancy. A review. J. Reprod. Med.,31, 224227.

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Received on January 27, 1998; accepted on June 30, 1998