The endometriosis syndromes: a clinical classification in the presence of aetiological confusion and therapeutic anarchy

Ray Garry

School of Women’s and Infants’ Health, University of Western Australia, King Edward Memorial Hospital, 374 Bagot Road, Subiaco, Western Australia 6008 e-mail: rgarry{at}obsgyn.uwa.edu.au


    Abstract
 Top
 Abstract
 Background
 Clinical confusion
 ‘Two types of...
 Classification
 Classification based on symptom...
 Classification based on analysis...
 Confusion about names
 The need for syndromes
 Conclusions
 References
 
Clinical confusion and inappropriate management continues to surround endometriosis. It is poorly recognized that the disorder can exist in two different morphological forms that have different symptoms, signs and prognosis. Earlier classification systems have been useful for research but are of limited value in aiding day-to-day management. In the clinic, two discrete phenotypes can be defined by the presence or absence of palpable nodules in the deep pelvis. Patients with such nodules with or without associated ovarian endometrioma usually have severe symptoms with significant risks of bowel and urinary tract involvement. The predominant histological feature of these lesions is extensive fibromuscular hyperplasia (adenomyoma). These patients will often need extensive surgical intervention. Patients without such palpable lesions usually have the classic superficial subperitoneal lesions with endometrial-like glands and stroma on histological examination. This group often has less severe symptoms and has little risk of developing serious associated problems. These lesions may be helped by medications and/or simple ablative surgery. It is suggested that these collections of symptoms and signs or syndromes be named after the pioneers who first described the lesions. Cullen’s syndrome can be used to describe those patients with severe symptoms of endometriosis associated with palpable pelvic nodules. Sampson’s syndrome can describe those with similar symptoms associated with a structurally normal pelvis.

Key words: adenomyoma/classification/Cullen/endometriosis/Sampson


    Background
 Top
 Abstract
 Background
 Clinical confusion
 ‘Two types of...
 Classification
 Classification based on symptom...
 Classification based on analysis...
 Confusion about names
 The need for syndromes
 Conclusions
 References
 
Endometriosis is as enigmatic today as it ever has been. Its fundamental cause continues to elude us and its protean manifestations continue to surprise us. The disorder we call endometriosis can be a condition that presents as an incidental finding in aysmptomatic women or as a disorder of such severity that the sufferer’s quality of life is destroyed. Diagnosis of the extent and location may be simple and self-evident or complex in the extreme. Treatments may be cheap or extraordinarily expensive. Mild analgesic agents and/or simple hormone therapy may be appropriate in many cases, whereas for others nothing less than major extirpative surgery will suffice. Therapeutic operations may take a few minutes or many hours. In this confused situation, the wrong therapeutic option is often chosen.

Much recent research work has concentrated on the earliest stages of the genesis of endometriosis and much of the most informed opinion about this disease has concentrated on the investigation of superficial lesions. ‘Red’ and ‘black’ implants scattered over the peritoneum represent the iconic image of endometriosis to most gynaecologists. Everyone concerned with the management of endometriosis recognizes this type of presentation. A hard, nodular lesion invading the deep pelvic structures is another clearly documented but clinically less well recognized manifestation of endometriosis. Classification confusion, with both phenotypes being collected under one all-inclusive name, can lead to misunderstanding when trying to compare results and outcomes. Without careful definition of the type of disease, almost any therapeutic option can be chosen and justified, and so in effect therapeutic anarchy exists. In these increasingly closely managed times in health care, this confusion may also lead managers and health care funding agencies to question why some surgeons are able to ‘adequately’ treat endometriosis with drugs or simple operations, while others insist on extensive and radical surgery for apparently the same condition registered in the same diagnostic category. From a clinical, if not also an aetiological point of view, ‘endometriosis’ seems to be two different types of disease processes collected together under a single generic name. This paper seeks to present evidence to suggest the reality of this ‘two forms of endometriosis’ concept, and the possibility of developing a simple clinically useful method of differentiating them.


    Clinical confusion
 Top
 Abstract
 Background
 Clinical confusion
 ‘Two types of...
 Classification
 Classification based on symptom...
 Classification based on analysis...
 Confusion about names
 The need for syndromes
 Conclusions
 References
 
The American College of Obstetrics and Gynaecology (2000Go) has recently recommended that it is efficacious to give empirical treatment with GnRH agonists to patients with chronic pelvic pain consistent with endometriosis without preliminary laparoscopic diagnosis. This recommendation is based on the results of a randomized controlled trial (Ling, 1999Go) that demonstrated a significant improvement in pain in those treated with GnRH agonist compared to placebo. An expert consensus group subsequently endorsed these conclusions (Gambone et al., 2002Go). It should be noted that almost 20% of the group thought to have endometriosis had no evidence of the disease at subsequent laparoscopy. The key message from this group of papers is that accurate diagnosis of endometriosis is not necessary before commencing treatment. They also suggested that pragmatic treatment of patients without definite diagnosis is preferable to exposing large numbers of patients to the risks and potential complications of diagnostic laparoscopy.

This conclusion appears to conflict with the well-recognized problems associated with our collective inability to make an early accurate diagnosis of endometriosis. The observed mean delay between onset of symptoms and diagnosis of endometriosis is 12 years in the USA and 8 years in the UK (Hadfield et al., 1996Go). More recently, further studies from Norway (Husby et al., 2003Go) and Brazil (Arruda et al., 2003Go) confirm these findings and indicate delays in diagnosis of 6.7 and 7.0 years. In contrast to the Ling (1999Go) study, these reports suggest that a more rapid and accurate diagnosis of endometriosis may be helpful to patients.

The evidence as to whether to treat or not treat in the absence of a firm diagnosis remains confused. The dilemma is whether to withhold early diagnostic laparoscopy with the risks of delaying accurate diagnosis when this may be disadvantageous and of giving inappropriate medications to patients without an indication or to sanction the widespread use of early laparoscopy that is not without risks and significant cost implications. Together these apparently conflicting studies surely indicate the need to ensure that patients are correctly assigned to the appropriate level of investigation, but how can this be achieved?


    ‘Two types of endometriosis’
 Top
 Abstract
 Background
 Clinical confusion
 ‘Two types of...
 Classification
 Classification based on symptom...
 Classification based on analysis...
 Confusion about names
 The need for syndromes
 Conclusions
 References
 
The majority of patients with endometriosis have only minor degrees of the disease associated with mild or moderately severe symptomatology. The absolute prevalence is unknown and is dependent on the clinical source of the patients. The presence of superficial endometriosis in asymptomatic infertile patients varies between 20 and 50% (American College of Obstetricians and Gynecologists, 2000Go), and even among women unexposed to sperm, deposits were found in 32% of cases (Matorras et al., 1996Go). Similar lesions were found in 2–5% of patients having sterilization procedures (Strathy et al., 1982Go). Multiple superficial deposits scattered widely across the pelvis, broad ligaments, ovaries and abdominal cavity are features of this type of lesion (Sampson, 1927aGo). The classic illustrations of Sampson (Figure 1) show small blood-filled lesions on the peritoneum, the ovary (Figure 2) and the surface of the bowel. Subsequently laparoscopic studies have revealed several variations in the gross morphology of such peritoneal endometriosis (Jansen and Russel, 1986Go; Redwine, 1987Go; Stripling et al., 1988Go; Martin et al., 1989Go; Nisolle et al., 1990Go). The characteristic histology is of deposits of endometrial-like glands and stroma (Figure 3) sometimes with evidence of menstrual shedding (Sampson, 1924aGo). Even these peritoneal lesions have recently been shown also to contain smooth muscle cells, but in this situation this element is usually not clinically apparent (Anaf et al., 2000Go). These superficial lesions may be symptomatic and associated with both infertility and pain. Various medical treatments including progestogens (Prentice et al., 2000Go), Danazol (Selak et al., 2001Go), oral contraceptives (Moore et al., 2003Go) and GnRH agonists (Prentice, 2003Go) have been shown to be effective with none being more efficacious than the others. CO2 Laser ablation is effective in the relieving pain associated with minimal, mild and moderate endometriosis (Sutton et al., 1994Go). Laparoscopic surgery (Marcoux et al., 1997Go) but not medical therapy (Hughes et al., 2000Go) has also been shown to be of benefit in treating infertility associated with superficial disease. A proportion of superficial lesions is, however, asymptomatic and the clinical importance of this group has been questioned. A study from Norway demonstrated that there appears to be little risk that asymptomatic minimal endometriotic lesions will become symptomatic (Moen, 2002Go) and a study from the UK showed that minimal endometriosis was not significantly associated with pelvic pain (Thorton et al., 1997Go).



View larger version (146K):
[in this window]
[in a new window]
 
Figure 1. John A.Sampson.

 


View larger version (78K):
[in this window]
[in a new window]
 
Figure 2. Sampson’s illustration of a superficial implant (imp) on the surface of an ovary.

 


View larger version (84K):
[in this window]
[in a new window]
 
Figure 3. Sampson’s illustration of the histology of a superficial implant.

 
The second clinical manifestation of endometriosis is that associated with more severe symptoms and signs. Thomas Cullen (Figure 4) described a condition that he called adenomyoma of the rectovaginal septum (Cullen, 1920Go). He characterized these lesions as tumours of non-striped muscle with islands of uterine mucosa scattered throughout them, that arise from behind the cervix and that spread laterally to blend with the anterior wall of the rectum and the uterosacral ligaments. He noted that the disease might also invade the broad ligaments, encircle the ureter and break through into the vagina (Figure 5). He commented that ‘many will have undoubtedly seen these lesions, but may not have recognized them. They are of unusual importance, and if overlooked will, in time, cause the patient to become a chronic invalid’. He ventured the view that ‘In less than 10 years, I feel sure that the surgeon will recognize and operate on these ‘adenomyomas of the rectovaginal septum’ long before the wall of the rectum or the broad ligament have been involved’. Sadly, 83 years later these views seem rather optimistic, for this type of lesion is frequently missed and/or subjected to multiple ineffective therapies. These adenomyoma require surgical removal that has been shown to be effective in a number of large series (Redwine, 1991Go; Donnez et al., 1997Go; Redwine and Wright, 2001Go; Abbott et al., 2003Go) and most recently in a placebo-controlled randomized controlled trial (Abbott J, Hawe J, Hunter D, Holmes M, Finn P and Garry R, unpublished data).



View larger version (130K):
[in this window]
[in a new window]
 
Figure 4. Thomas Cullen.

 


View larger version (43K):
[in this window]
[in a new window]
 
Figure 5. Cullen’s diagram illustrating the distribution of adenomyomata.

 
Cullen’s term of ‘adenomyoma’ is purely descriptive and gives no hint as to the possible source or cause of the lesion. These lesions show marked fibrosis in almost every case and associated smooth muscle metaplasia in 88% of cases in addition to the classical combination of endometrial glands and stroma (Itoga et al., 2003Go). These tumours have a substantial mass that can usually be palpated on careful vaginal examination. Such deeply located endometriosis is found only in the cul de sac (55%), the uterosacral ligaments (34%) and the uterovesical fold (11%) (Cornillie et al., 1990Go). This group found no deep lesions of endometriosis in the ovarian fossa or scattered across the peritoneum. The intensity of the patient’s pain is strongly correlated with the depth of the lesion (Cornillie et al., 1990Go; Koninckx et al., 1991Go; Chapron et al., 2003aGo). This type of lesion produces not only intense dysmenorrhoea, but also severe non-menstrual pain, dysparunia and dyskesia (Redwine, 1991Go; Garry, 2000Go). The location of the lesion is correlated with the nature of the symptoms, for example dysparunia is associated with uterosacral involvement and non-cyclical pelvic pain and dyskesia with bowel involvement (Fauconnier et al., 2002Go). In addition to various types of pain, patients with deep endometriosis have profound disturbance in quality of life and sexual activity as assessed by a number of validated instruments (Garry et al., 2000Go; Redwine and Wright, 2001Go; Abbott et al., 2003Go). In a series of patients with this type of deeply infiltrating endometriosis 58% of patients had disease principally in the uterosacral ligaments, 18% in the cul de sac, 16% involving the bowel and 8% the bladder (Chapron et al., 2003bGo). The histology of this type of lesion has been described repeatedly over the years (Cullen, 1920Go; Sampson, 1921Go and 1927bGo; Reich et al., 1991Go; Koninckx and Martin, 1992Go; Donnez et al., 1997Go; Brosens and Brosens, 2000Go; Itoga et al., 2003Go). The nodules have three histological components characterized by endometrial-like glands and stroma surrounded by much fibrosis and smooth-muscle hyperplasia (Anaf et al., 2000Go). This type of histological lesion can be best described as an adenomyoma.

It is well recognized that endometriosis is associated with infertility. Reduced chances of conception appear to be associated with both superficial and deep phenotypes of endometriosis. Despite the clinical importance of this symptom its presence or absence does not seem to help in the clinical classification of endometriosis and so more detailed review of this major area has not been performed in this study.

Although deep cul de sac endometriosis or adenomyoma can cause severe pain and distress such lesions alone seldom threaten survival. However, some aggressive forms of adenomyoma may be potentially life threatening. This occurs when it involves the bowel, ureter and bladder or when the lesions undergo malignant transformation (Garry, 2001Go).

The intestines are involved in between 5–15% of patients with symptomatic endometriosis (Jubanyik and Comite, 1997Go). Usually only the serosal surface of the bowel is involved for example in only 5.4% of 3037 cases of endometriosis requiring laparotomy in one series (Weed et al., 1987Go). Such lesions produce anatomical distortion and associated bowel dysfunction that may be improved by correction of the anatomy without the need for excisional bowel surgery (Reich, 1991Go; Donnez et al., 1997Go). Deeper colo-rectal endometriosis may, however, produce an obstructive syndrome and/or cyclical rectal bleeding. Formal bowel resection is then required (Weed and Ray, 1987Go; Possover et al., 2000Go; Kavallaris, 2003Go). This is required in about 1.2% and 16% of those with adenomyoma (Donnez et al., 2001Go; Redwine and Wright, 2001Go; Chapron et al., 2003bGo). It was noted in Donnez’s series that no case of bowel involvement was found without associated adenomyoma. The histology of this type of lesion had been clearly described previously (Cullen, 1920Go; Sampson, 1921Go). ‘Cullen described a case who had a recto-vaginal growth of typical adenomyatous tissue and a separate tumour that projected into the sigmoid consisted of normal rectal mucosa but with greatly thickened muscular tissue. Scattered throughout the muscular tissue were uterine glands surrounded by the characteristic stroma.’ The rectovaginal lesion and the lesion within the bowel had identical histological features predominated by muscular hyperplasia that both authorities termed adenomyoma. It is clear that bowel endometriosis is usually multifocal and effective therapy will need to remove all deposits (Chapron et al., 2003bGo; Kavallaris et al., 2003Go). Malignant change in colonic endometriosis has been documented. The rate of progression is unknown but is uncommon. In a recent series, 17 cases were reviewed of whom nine developed in patients taking unopposed oestrogens (Jones et al., 2002Go). A similar lesion has been described after using long-term tamoxifen therapy (Bese et al., 2003Go) and a clear cell carcinoma of the rectum has also been described in a 40 year woman with severe endometriosis treated on a long-term basis with medroxyprogesterone acetate (Pokieser et al., 2002Go)

The urinary tract is involved in 1–4% of women with endometriosis of which around 90% involve the bladder (Jubanyik and Comite, 1997Go). Full thickness bladder lesions are less common and were found in only 17 of 9200 (0.2%) women with symptomatic endometriosis (Donnez et al., 2000Go). The histological features are consistent and are similar to uterine adenomyosis with foci of endometrial-like glands surrounded by thin rims of endometrial-type stroma surrounded by muscular tissue (Fedele et al., 1992Go; Donnez et al., 2000Go). Both these groups suggested that these lesions should be considered as bladder adenomyosis. This condition was not, however, associated with uterine adenomyosis (Donnez et al., 2000Go; Vercellini et al., 2002Go). Malignant transformation of bladder endometriosis although rare has been described repeatedly (Al-Izzi et al., 1989Go; Vara et al., 1990Go; Balat et al., 1996Go; Nezhat et al., 2002Go) and must represent a risk if bladder lesions remain untreated.

Ureteral endometriosis is even less common, with an incidence of <0.1% of all cases of endometriosis (Donnez and Brosens, 1997Go). However, this group, in a later prospective study confined to cases of rectovaginal endometriosis reported that 4.4% of all cases (18 of 405) had associated ureteral endometriosis (Donnez et al., 2002Go). Each case of ureteral endometriosis was associated with extensive rectovaginal disease and all but one arose from large nodules of >3 cm in diameter. The histology of these lesions is again mainly composed of hyperplasia of smooth muscle with some glands and scanty stroma (Ferenczy, 1998Go; Donnez et al., 2002Go). Obstructive uropathy that may lead to renal cortical atrophy and severe loss of renal function can occur with this type of lesion. The author has observed two young women with totally non-functioning kidneys that developed as a consequence of prolonged undiagnosed endometriosis. Ureteral endometriosis therefore appears to be due to direct lateral extension of rectovaginal nodules and like the ‘parent’ lesion the predominant feature is myohyperplasia (Donnez et al., 2002Go).


    Classification
 Top
 Abstract
 Background
 Clinical confusion
 ‘Two types of...
 Classification
 Classification based on symptom...
 Classification based on analysis...
 Confusion about names
 The need for syndromes
 Conclusions
 References
 
Thus we appear to have one phenotype of endometriosis that is superficial in location, is associated with relatively minor symptoms and is amenable to simple treatments and a second phenotype associated with deep lesions, more severe symptoms and potentially serious complications that may require extensive surgery to relieve. How did we come to use the single term ‘endometriosis’ to cover this apparently disparate group of conditions? It would appear that John Sampson laid the seeds that others then developed. In his early writings Sampson used the term adenomyoma to describe deep lesions. In one of his earliest works he observes that ‘if (adenomas) are invasive they may cause adenomyoma of the uterus by invasion of the uterine wall from without or adenomyoma of the uterosacral ligament, round ligament, rectovaginal septum, rectum, sigmoid etc’ (Sampson, 1921Go). Thereafter he used the term less and less frequently preferring the term endometriosis. He felt that this was a better term for displaced endometrial tissue. His view was that the term endometriosis was the most appropriate to describe the presumed source of the ectopic endometrium (Sampson 1925Go). Thus Sampson’s term was chosen because it indicated what Sampson believed, but what is still not yet proven, to be the origin of the condition.

The correct classification of ovarian endometriotic cysts greatly preoccupied Sampson. The histology of the lesions has been clarified with most believing they are usually superficial lesions of endometrial glands and stroma on the surface of an invaginated cortex (Sampson, 1921Go; Hughesdon, 1957Go; Brosens et al., 1994Go). About 16% of patients with endometriosis have an associated endometrioma (Donnez, 2001Go). Malignant change in ovarian endometriosis has long been recognized (Sampson, 1924bGo, 1925). Sampson ventured the opinion that ‘I do not believe that all carcinomas of the ovary are of endometrial origin. Some are however, and possibly the percentage is large’. The prevalence of ovarian cancers associated with endometriosis was between 7.7 and 24% in three large individual unit series of ovarian cancers although it should be noted that these studies might reflect particularly high-risk areas (Fukunagama et al., 1997Go; Jimbo et al., 1997Go; Garry, 2001Go; Oral et al., 2003Go). In the USA the most common histological types of endometriosis-associated cancers were clear cell 23% and endometrioid carcinoma 23% (Modesitt et al., 2002Go). In a Japanese study where the incidence of clear cell carcinoma of the ovary is substantially higher in general than in the west, the prevalence of clear cell ovarian cancer was 54% of the total and 42% of the remainder were endometriod in type (Fukunaga et al., 1997Go). The standardized risk of developing ovarian cancer in patients with long-standing ovarian endometriosis in Sweden is >400% higher than the normal population (standardized incidence ratio 4.2, 95% confidence interval 2.0–7.7) (Brinton et al., 1997Go).

GnRH agonists reduce the size of endometrial ovarian cysts but there is no evidence to confirm the efficacy of medical treatment in the reduction of pain associated with such lesions (American College of Obstetricians and Gynecologists, 2000Go). There is a consensus that ovarian endometriosis requires surgical treatment that may be either excision or ablation of the cyst capsule (Canis et al., 1992Go; Donnez et al., 1994Go). Because of this and the facts the ovarian cysts are usually associated with endometriosis in other sites with a high incidence of associated intestinal involvement (Redwine, 1999Go) and a substantial risk of malignant change it is suggested that ovarian endometriomata are classified along with the deeply invasive lesions despite much work linking their formation with superficial peritoneal endometriosis

How then we can we correctly but conveniently define these two clinically different groups? All readers of this paper will be familiar with the rAFS classification system. Devised as a guide for the management of patients with infertility associated with endometriosis it remains the most widely used system. In 1991 a comprehensive review of this and 12 other classification systems for endometriosis was produced (Groff, 1991Go).

Since this time a number of alternative systems have been suggested. Martin et al., (1989Go) and later Cornillie et al. (1990Go) suggested that endometriosis should be classified according to the depth of invasion into superficial (<1 mm), intermediate (2–4 mm), deep (>5 mm) and very deep (>10 mm). This classification showed correlations between the depth of invasion and severity of pain. Although this system has been helpful in aiding understanding of the disease process, it is based on histological measurements and is therefore not relevant to the clinic situation. David Redwine introduced the term Mülleriosis because he believed the term endometriosis is too limiting and that the retrograde menstruation theory is unproven (Redwine, 1987Go). His theory is an expansion of the theory of Russell who suggested that endometriotic lesions arise from embryonic rests of the Müllerian system (Redwine, 1998Go). This terminology, like endometriosis before it, is based on a presumed, but still controversial theory of the aetiology of the condition. Nisolle et al. (1997Go) suggested that rectovaginal, ovarian and peritoneal endometriosis should be considered three different diseases with three discrete aetiologies. This group suggest that peritoneal lesions are derived from implantation of shed endometrium, ovarian lesions result from a combination of invagination and metaplastic changes on the ovarian cortex and rectovaginal lesions represent retroperitoneal adenomyomas derived from metaplasia of Müllerian remnants This is another classification system based on presumed, but as yet, unproven aetiological mechanisms (Donnez et al., 2001Go). Brosens and Brosens (2000Go) suggest that the classification of endometriosis should not be based on depth but on the expression of a specific endometrial activity: either sex steroid hormone dependant bleeding or smooth muscle metaplasia. This theory can be extended to suggest that there are two types of ‘endometriosis’ one of which behaves like superficial endometrium and the other that resembles basal endometrium in phenotype and function. This latter type is in-fact phenotypically identical with adenomyosis. Most recently a classification system for deep endometriosis based on the anatomical location of the lesion with a recommended preferred surgical treatment for each location has been developed (Chapron et al., 2003bGo).

We therefore have multiple classification systems based on several different criteria. Some are based on anatomical location, some on functional behavior and some to reflect presumed aetiology. There is, as yet, no agreement about the aetiological antecedents of endometriosis and therefore there can, at this time, be no universally acceptable classification system based on aetiology. Until a definitive aetiological classification can be agreed I suggest that the most useful subdivision will be made on the basis of clinical findings. This could be on the basis of symptoms, signs or a combination of both.


    Classification based on symptom analysis
 Top
 Abstract
 Background
 Clinical confusion
 ‘Two types of...
 Classification
 Classification based on symptom...
 Classification based on analysis...
 Confusion about names
 The need for syndromes
 Conclusions
 References
 
The relevance of symptom analysis in predicting the severity of endometriosis is confusing. Dysmenorrhoea, pelvic pain, dysparunia and dyskesia are non-specific symptoms and may be found in patients without endometriosis (Ling et al., 1999Go), and in association with both mild (Sutton et al., 1994Go; Ling et al., 1999Go) and severe endometriosis (Abbott et al., 2003Go). Moreover endometriosis may be asymptomatic (Moen et al., 2002Go) or mild and not associated with pain (Fedele et al., 1992Go; Thorton et al., 1997Go). Severe dysmenorrhoea, however, does appear to predict the presence of endometriosis with a positive predictive value (PPV) of 63% and 95% (negative predictive value) NPV (Foreman et al., 1993Go; Naish et al., 1993Go). Some authors believe the severity of the painful dysmenorrhoea also correlates with the severity of the AFS score (Muzii et al., 1997Go; Eskenazi et al., 2001Go) while others have found no such correlation (Grupo Italiano, 2001Go; Abbott, 2003Go). Vaginal endometriosis is significantly associated with deep dysparunia (Vercellini et al., 1996Go). and the presence of rectal or vaginal lesions are significantly related to the severity of dysmenorrhoea (Chapron et al., 2003aGo). The type of pelvic pain is related to the anatomical location (Fauconnier et al., 2002Go). This group has demonstrated that the frequency of dysparunia increases with the presence of uterosacral invasion, painful defaecation with bowel and vaginal lesions and severe dysmenorrhoea with increased obliteration of the pouch of Douglas. In summary, the severity and nature of the symptoms of endometriosis are associated with the location and depth of the lesions but probably not with the rAFS score.


    Classification based on analysis of findings
 Top
 Abstract
 Background
 Clinical confusion
 ‘Two types of...
 Classification
 Classification based on symptom...
 Classification based on analysis...
 Confusion about names
 The need for syndromes
 Conclusions
 References
 
The value of pelvic examination as a screening test in asymptomatic pelvic disease has been questioned (Dragisic et al., 2003Go). Analysis of the findings on vaginal examination in symptomatic patients with presumed endometriosis however suggests that palpable induration or nodules in the posterior vaginal fornix and/or along the uterosacral ligaments appears to be pathognomonic signs of deep endometriosis (Matorras et al., 1996Go). These lesions are tender and pressure reproduces symptoms. The PPV of such tenderness predicting endometriosis is between 76 and 79% and this rises to 83% with a specificity of 92% if focal tenderness is located only in the uterosacral ligaments and cul de sac (Ripps and Martin, 1992Go; Koninckx et al., 1996Go; Eskenazi, 2001Go). The accuracy of these findings is further increased if the examination is performed during menstruation (Koninckx et al., 1996Go). Deep invasive endometriosis is frequently associated with ovarian endometriosis (Redwine, 1999Go). The co-existence of these two conditions further improves the reliability of the clinical diagnosis. It is possible that it is not the size of ovarian endometriomata but the associated lesions that cause pelvic pain (Porpora et al., 1999Go).

In summary, the presence or absence of palpable nodular or infiltrative lesions is related to the location and depth of the lesions and reflects the severity of the pain and the risks of severe complications.


    Confusion about names
 Top
 Abstract
 Background
 Clinical confusion
 ‘Two types of...
 Classification
 Classification based on symptom...
 Classification based on analysis...
 Confusion about names
 The need for syndromes
 Conclusions
 References
 
Cullen’s original name for deep pelvic disease was adenomyoma of the rectovaginal septum (Cullen, 1920Go). It is now recognized that endometriosis only rarely involves the true rectovaginal septum (Martin and Batt, 2001Go; Vercellini et al., 2000Go) and much more frequently involves the overlying rectovaginal pouch (Martin and Batt, 2001Go). A variety of other descriptions has been used to describe the anatomical location of these lesions and includes cul-de sac endometriosis (Martin et al., 1989Go), obliteration of the cul-de-sac (Redwine, 1991Go) and rectocervical endometriosis (Adamyan et al., 1993Go; Perry et al., 1995Go), These three terms were combined to produce an anatomically precise but hardly concise cul-de-sac obliteration secondary to retrocervical deep fibrotic endometriosis (Reich et al., 1991Go). Other terms that have also been used include pelvic wall-infiltrating endometriosis (Khare et al., 1996Go), rectovaginal septum adenomyotic nodules (Donnez et al., 1997Go), retroperitoneal adenomyosis (Donnez, 2001Go) and rectovaginal endometriosis (Kavallaris et al., 2003Go). From this review it is not immediately obvious what these lesions should be called or how we should describe their locations.


    The need for syndromes
 Top
 Abstract
 Background
 Clinical confusion
 ‘Two types of...
 Classification
 Classification based on symptom...
 Classification based on analysis...
 Confusion about names
 The need for syndromes
 Conclusions
 References
 
What then can we conveniently and accurately call these two types of endometriosis? In the absence of an agreed aetiological mechanism or unambiguous symptomatology or even a concise agreed anatomical description, it is perhaps pragmatic at this stage to classify the disease according to the sum of the anatomical location, clinical findings and associated histological appearances. Such a collection of symptoms, signs and findings is a syndrome. Endometriosis appears to be two different syndromes currently collected under the single ‘endometriosis’ terminology.

The first syndrome may be defined as the combination of symptoms suggestive of endometriosis together with a tender palpable nodular or indurative lesion in the deep pelvis. Such nodules are associated with the histological finding of marked fibromuscular hyperplasia containing islands of endometrium-like glands. This collection of findings is precisely that described by Cullen in 1920. I would therefore suggest that this collection of signs and symptoms be called Cullen’s syndrome. The incidence of this syndrome is not known, but probably represents a fairly small proportion of all cases of endometriosis with estimates of between 1/170 and 1/3800 women (Martin and Batt, 2001Go). Cullen’s syndrome, although relatively infrequent, will include many of those with the more severe symptoms, almost all those at risk of developing malignancy, and all those at risk of lower bowel and urinary tract involvement.

The other syndrome also consists of the symptoms of infertility and/or chronic pelvic pain with dysmenorrhoea, and dyspareunia. This syndrome is, however, associated with the absence of deep pelvic local tenderness, induration or nodule formation. This condition is usually associated with the laparoscopic appearances of multiple classical superficial clear, red, black or white lesions. The histology of such lesions is characteristic by the findings of superficial deposits containing endometrial-like glands and stroma. These lesions have little or no associated myohyperplasia and are those described by Sampson. This syndrome of pelvic pain without focal nodular lesions could therefore be known as Sampson’s syndrome. This syndrome is associated with more minor symptoms, less structural change in the pelvis and substantially less risk of major complications.

These suggestions are made in an attempt to familiarize doctors without a special interest in endometriosis with the important realities of differing clinical degrees of endometriosis. Of course from an expert’s view this clinical classification is inherently inaccurate and will only produce a fairly crude subdivision. Severe cases may be missed and there will be inaccuracies in assignment and some overlap with both ‘syndromes’ co-existing. Many cases will have evidence of both superficial and deep disease, and it is quite probable that some lesions will evolve from one syndrome to the other over time. In such circumstances the presence of the clinically most severe group (Cullen’s syndrome) would take precedent. This classification makes no attempt to determine the origin of the lesions. They may represent different aspects of a single disease continuum or two (or three) completely different disease processes.


    Conclusions
 Top
 Abstract
 Background
 Clinical confusion
 ‘Two types of...
 Classification
 Classification based on symptom...
 Classification based on analysis...
 Confusion about names
 The need for syndromes
 Conclusions
 References
 
The proposals are presented as a pragmatic attempt to help the clinicians of all levels of experience in this confused area. The goal is to differentiate ‘endometriosis’ into clinically important categories to ensure that many patients with mild disease are not over-investigated or over-treated while patients with potentially serious disease are not subject to prolonged delays and the use of multiple ineffective therapies. In general, patients with Sampson’s syndrome will be managed with medications and/or with superficial ablation type laparoscopic surgery of the kind provided by many gynaecologists. Patients with Cullen’s syndrome on the other hand are unlikely to respond to medical therapy and may require extensive and at times potentially dangerous surgery. For these high-risk patients, delay in accurate diagnosis could be associated with serious adverse outcomes. These patients should be referred to units with particular expertise in this field as early in the disease process as possible. The universal recognition of the clinical imperatives associated with this syndrome may facilitate the widespread establishment of specialized endometriosis treatment centres.


    References
 Top
 Abstract
 Background
 Clinical confusion
 ‘Two types of...
 Classification
 Classification based on symptom...
 Classification based on analysis...
 Confusion about names
 The need for syndromes
 Conclusions
 References
 
Abbott JA, Hawe J, Clayton RD and Garry R (2003) The effects and effectiveness of laparoscopic excision of endometriosis: a prospective study with 2–5 year follow-up. Hum Reprod 18,1992–1927.[Abstract/Free Full Text]

Abeshouse BS and Abeshouse G (1960) Endometriosis of the urinary tract: a review of the literature and a report of four cases of vesical endometriosis. J Int Coll Surg 34,33–37.

American College of Obstetricians and Gynecologists (2000) Medical management of endometriosis. Practice Bulletin Number 11, December 1999. Int J Gynecol Obstet 71,183–196.[CrossRef][ISI][Medline]

Adamyan L (1993) Additional international perspectives. In Nichols DH (ed) Gynecologic and Obstetrics Surgery. Mosby–Year Book, 1993, St Louis, pp 1167–1182.

Al-Izzi MS, Horton LW, Keleher J and Fawcett D (1989) Malignant transformation in endometriosis of the urinary bladder. Histopathology 14,191–198.[ISI][Medline]

Anaf V, Simon PL, Layt I and Noel JC (2000) Smooth muscles are frequent components of endometriotic lesions. Hum Reprod 15,767–771.[Abstract/Free Full Text]

Arruda MS, Petta CA, Abrao MS and Benitti-Pinto CL (2003) Time elapsed from onset of symptoms to diagnosis of endometriosis in a cohort study of Brazilian women. Hum Reprod 18,756–759.[Abstract/Free Full Text]

Balat O, Kudelka AP, Edwards CL, Silva E and Kavanagh JJ (1996) Malignant transformation in endometriosis in the urinary bladder; case report of clear cell adenocarinoma. Eur J Gynaecol Oncol 17,13–16.[Medline]

Bese T, Simseh Y, Bese N, Ivan S and Arvas M (2003) Extensive endometriosis with malignant change in tamoxifen treated postmenopausal women. J Gynecol Cancer 13,376–381.[CrossRef]

Brinton LA, Gridley g, Persson I, Baron J and Berquist A (1997) Cancer risk after a hospital discharge diagnosis of endometriosis. Am J Obstet Gynecol 176,572–579.[ISI][Medline]

Brosens IA and Brosens J (2000) Redefining endometriosis: a progressive disease. Hum Reprod 15,1–7.[Free Full Text]

Brosens IA, Puttemans PJ and Deprest J (1994) The endoscopic localization of endometrial implants in the ovarian chocolate cyst. Fertil Steril 61,1034–1038.[ISI][Medline]

Canis M, Mage G, Wattiez A and Bruhat M (1992) Second look laparoscopy after cystectomy of large ovarian endometriomas. Fertil Steril 62,63–66.

Chapron C, Fauconnier A, Dubuisson JB, Barakat H, Viers M and Breart G (2003a) Deeply infiltrating endometriosis: relation between severity of dysmenorrhoea and extent of disease. Hum Reprod 18,760–766.[Abstract/Free Full Text]

Chapron C, Fauconnier A, Vieira M, Barakath H, Dousset D, Pansini V, Vacher-Lavenn MC and Dubuisson JB (2003b) Anatomical distribution of deeply infiltrating endometriosis: surgical implications and proposition for a classification. Hum Reprod 18,157–161.[Abstract/Free Full Text]

Cornillie FJ, Oosterlynck D, Lauweryns JM and Koninckx P (1990) Deeply infiltrating pelvic endometriosis: histology and clinical significance. Fertil Steril 53,411–416.[ISI][Medline]

Cullen TS (1920) The distribution of adenomyomas containing uterine mucosa. Arch Surg 1,215–283.

Donnez J and Brosens I (1997) Definition of ureteral endometriosis? Fertil Steril 68,178–179.[ISI][Medline]

Donnez J, Nisolle M and Gillerto S (1994) Ovarian endometrial cysts: the role of gonadotrophin-releasing hormone agonists and/or drainage. Fertil Steril 62,63–66.[ISI][Medline]

Donnez J, Nisolle M, Gillerot S, Smets M, Bassil S and Casanas-Roux F (1997) Rectovaginal septum adenomyotic nodules: a series of 500 cases. Br J Obstet Gynecol 104,1014–1018.[ISI][Medline]

Donnez J, Spada F, Suiffllet J and Nisolle M (2000) Bladder endometriosis must be considered as bladder adenomyosis. Fertil Steril 74,1175–1181.[CrossRef][ISI][Medline]

Donnez J, Donnez O, Squiffet J and Nisolle M (2001) The concept of retroperitoneal adenomyotic disease is born. In Donnez J and Nisolle M (eds) An Atlas of Operative Laparoscopy and Hysteroscopy. Parthenon, New York.

Donnez J, Nisolle M and Squifflet J (2002) Ureteral endometriosis: a complication of rectovaginal endometriotic (adenomyotic) nodule. Fertil Steril 77,32–37.[ISI][Medline]

Dragisic KG, Padilla LA and Milad MP (2003) The accuracy of the rectovaginal examination in detecting cul-de-sac disease in patients under general anaesthesia. Hum Reprod 18,1712–1715.[Abstract/Free Full Text]

Eskenazi B, Warner M, Bonsignore L, Olive D, Samuel S and Vercellini P (2001) Validation study of non-surgical diagnosis of endometriosis. Fertil Steril 76,929–935.[CrossRef][ISI][Medline]

Fauconnier A, Chappron C, Dubuisson JB, Vieria M, Doussett B and Breart G (2002) Relationship between pain symptoms and the anatomic location of deeply infiltrating endometriosis. Fertil Steril 78,719–726.[CrossRef][ISI][Medline]

Fedele L, Bianchi S, Bocciolone L, Di Nola G and Parazzini F (1992) pain symptoms associated with endometriosis. Obstet Gynecol 79,767–769.[Abstract]

Ferenczy A (1998) Pathophysiology of adenomyosis. Hum Reprod Update 4,312–322.[Abstract/Free Full Text]

Foreman RG, Robinson JN, Metha Z and Barlow DH (1993) Patient history as a simple predictor of pelvic pathology in subfertile women. Hum Reprod 8,53–55.[Abstract]

Fukunaga M, Nomura k, Ishikawa E and Ushigome S (1997) Ovarian atypical endometriosis; its close association with malignant epithelial tumours. Histopathology 30,249–255.[CrossRef][ISI][Medline]

Gambone JC, Mitthan BS, Munro MG, Scialli AR and Winkel CA (2002) Consensus statement for the management of chronic pelvic pain and endometriosis: proceedings of an expert-panel consensus process. Fertil Steril 78,961–972.[CrossRef][ISI][Medline]

Garry R (2001) Endometriosis: an invasive disease. Gynaecol Endosc 10,79–82.[CrossRef][ISI]

Garry R, Clayton R and Hawe J (2000) The effects of endometriosis and its radical excsion on quality of life indicators. Br J Obstet Gynecol 107,44–54.[ISI]

Groff TR (1991) The classification of endometriosis. In Thomas E and Rock J (eds) Modern Approaches to Endometriosis. Kluwer, Dordrecht, pp 131–150.

Gruppo Italiano per lo studio dell’Endometriosi (2001) Relationship between stage, site and morphological characteristics of pelvic endometriosis and pain. Hum Reprod 16,2668–2671.[Abstract/Free Full Text]

Hadfield R, Mardon H, Barlow D and Kennedy S (1996) Delay in the diagnosis of endometriosis: asurvey of women from the USA and the UK. Hum Reprod 11,878–880.[Abstract]

Hughes E, Fedorkaw D, Collins J and Vanderkerchkove P (2000) Ovulation suppression for endometriosis. Cochrane Database System. Rev. CD 0001555.

Husby GK, Haugen RS and Moen MH (2003) Diagnostic delay in women with pain and endometriosis. Acta Obstet Gynecol Scand 82,649–653.[CrossRef][ISI][Medline]

Hughesdon PE (1957) The structure of the endometrial cysts of the ovary. J Obstet Gynaecol Br Emp 44,481–487.

Itoga T, Matsumoto T, Takeuchi H, Yamasaki S, Sasahara N, Hoshi T and Kinoshita K (2003) Fibrosis and smooth muscle metaplasia in rectovaginal endometriosis. Pathol Int 53,371–375.[CrossRef][ISI][Medline]

Jansen RPS and Russel P (1986) Non-pigmented endometriosis: clinical, laparoscopic and pathologic definition. Am J Obstet Gynecol 15,1154–1161.

Jimbo H, Yoshikawa H, Onda T, Yasugi T, Sakamoto A and Taketani Y (1997) Prevelance of ovarian endometriosis in epithelial ovarian cancer. Int J Gynecol Obstet 59,245–250.[CrossRef][ISI][Medline]

Jones KD, Owen E, Berresford A and Sutton C (2002) Endometrial adenocarinoma arising from endometriosis of rectosigmoid colon. Gynecol Oncol 86,220–222.[CrossRef][ISI][Medline]

Kavallaris A, Kohler C, Kune-Heid R and Schneider A (2003) Histolopathological extent of rectal invasion by rectovaginal endometriosis. Hum Reprod 18,1323–1327.[Abstract/Free Full Text]

Khare VK, Martin DC and Eltorky E (1996) A comparative study of ovarian and pelvic wall-infiltrating endometriosis. J Am Assoc Gynecol Laparosc 3,235–239.[Medline]

Koninckx PR and Martin DC (1992) Deep endometriosis: a consequence of infiltration or retraction or possibly adenomyosis externa? Fertil Steril 58,924–928.[ISI][Medline]

Koninckx PR, Meuleman C, Demeyere S, Lesaffre E and Cornille FJ (1991) Suggestive evidence that pelvic endometriosis is a prospective disease whereas deeply infiltrating endometriosis is associated with pelvic pain. Fertil Steril 55,759–765.[ISI][Medline]

Koninckx PR, Meuleman C, Oosterlynck D and Cornillie FJ (1996) Diagnosis of deep endometriosis by clinical examination during menstruation and plasma CA-125 concentration. Fertil Steril 65,280–287.[ISI][Medline]

Ling FW (1999) Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspect endometriosis. Obstet Gynecol 93,51–58.[Abstract/Free Full Text]

Jubanyik KJ and Comite F (1997) Extra-pelvic endometriosis. Obstet Gynaecol Clin North Am 24,411–440

Marcoux S, Maheux R and Berabe S (1997) Laparoscopic surgery in infertility with minimal or mild endometriosis. Canadian Collaborative group on endometriosis. N Engl J Med 337,217–222.[Abstract/Free Full Text]

Martin DC and Batt RE (2001) Rectocervical, rectovaginal pouch, and rectovaginal septum endometriosis. J Am Assoc Gynecol Laposc 8,12–17.[ISI][Medline]

Martin DC, Hubert GD, Van der Zwaay R and el-Zeky FA (1989) Laparoscopic appearances of peritoneal endometriosis. Fertil Steril 51,63–67.[ISI][Medline]

Matorras R, Rodriguez F, Pijoan JI, Soto E, Perez C, Ramo O and Rodrigueez-Escudero F (1996) Are there any clinical signs and symptoms that are related to endometriosis in infertile women? Am J Obstet Gynecol 174,620–623.[ISI][Medline]

Modesitt SC, Tortolero-luna G, Robinson JB, Gershenson DM and Wolf JK (2002) Ovarian and extra-ovarian endometriosis-associated cancers. Obstet Gynecol 100,788–795.[Abstract/Free Full Text]

Moen MH and Stokstad (2002) A long term follow-up study of asymptomatic endometriosis diagnosed incidentally at sterilisation. Fertil Steril 78,773–776.[CrossRef][ISI][Medline]

Moore J, Kennedy S and Prentice A. (2003) Modern combined oral contraceptives for pain associated with endometriosis (Cochrane review). Cochrane Library Issue 2, 2003. Update Software, Oxford.

Muzii L, Catalano GF, Marana R, Mancuso S and Pedulla S (1997) Correlation between endometriosis-associated dysmenorrhoea and the presence of typical or atypical lesion. Fertil Steril 68,19–22.[CrossRef][ISI][Medline]

Naish CE, Kennedy BH and Barlow DH (1993) Correlation between pain symptoms and laparoscopic findings. In Brosens IA and Donnez J (eds), Abstracts of Third World Congress of Endometriosis 1993, Brussels.

Nezhat Ch, Malik S, Osias J, Nezhat F and Nezhat C (2002) The laparoscopic management of 15 patients with infiltrating endometriosis of the bladder and a case of primary intravesical endometriod adennosarcoma. Fertil Steril 78,872–875.[CrossRef][ISI][Medline]

Nisolle M and Donnez J (1997) Peritoneal endometriosis, ovarian endometriosis and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril 68,585–596.[CrossRef][ISI][Medline]

Nisolle M, Paindaveine B, Bourdon A et al. (1990) Histologic study of peritoneal endometriosis in infertile women. Fertil Steril 53,984–988.[ISI][Medline]

Oral E, Ilvan S, Tustas E, Korbeyli B, Beste T, Demirkiran F, Arvas M and Kosebay D (2003) Prevalence of endometriosis in malignant epithelial ovary tumours. Eur. J Obstet Gynecol Reprod Biol 109,97–101.[CrossRef][ISI][Medline]

Perry CP and Victoria MM (1995) Occult retrocervical endometriosis. J Reprod Med. 40,652–659.[ISI][Medline]

Pokieser W, Schmerker R, Kisser M, Peter-Engl C, Muhlbauer H and Ulrich W (2002) Pathol Res Pract 198,121–124.[ISI][Medline]

Porpora MG, Koninckx PR, Paizzw J, Natili M and Colagrande S (1999) Correlation between endometriosis and pain. J Am Assoc Gynecol Laparosc 6,429–434.[ISI][Medline]

Possover M, Diebolder H, Plaul K and Schneider A (2000) Laparoscopic assisted vaginal resection of rectovaginal endometriosis. Obstet Gynecol 96,304–307.[Abstract/Free Full Text]

Prentice A, Deary AJ and Bland E (2000) Prostagens and anti-prostagens for pain associated with endometriosis. Cochrane Database Syst. Rev. CD 002122.

Prentice A, Deary AJ, Goldbeck-Wood S, Farquhar C and Smith SK (2003) Gonadotrophin-releasing hormone analogues for pain associated with endometriosis (Cochrane review). Cochrane Library, Issue 2, 2003. Update Software, Oxford.

Redwine DB (1987) The distribution of endometriosis in the pelvis by age group and fertility. Fertil Steril 47,173–175[ISI][Medline]

Redwine DB (1991) Conservative laparoscopic excision of endometriosis by sharp dissection: life table analysis of re-operation and persistent or recurrent disease. Fertil Steril 56,628–634.[ISI][Medline]

Redwine DB (1987) Mulleriosis instead of endometriosis. Am J Obstet Gynecol 156,761.

Redwine DB (1999) Ovarian endometriosis: a marker for more extensive pelvic and intestinal disease. Fertil Steril 72,310–315.[CrossRef][ISI][Medline]

Redwine DB and Sharp DR (1991) Laparoscopic segmental resection of sigmoid colon. J Laparoendosc 1,217–220.

Redwine DB and Wright JT (2001) Laparoscopic treatment of complete obliteration of the cul de sac associated with endometriosis: long-term follow-up of en bloc resection. Fertil Steril 76,358–365.[CrossRef][ISI][Medline]

Reich H, McGlynn F and Salvat J (1991) Laparoscopic treatment of cul de sac obliteration secondary to retrocervical deep fibrotic endometriosis. J Reprod Med 36,516–522.[ISI][Medline]

Ripps BA and Martin DC (1992) Correlation of focal pelvic tenderness with implant dimension and stage of endometriosis. J Reprod Med 37,620–624.[ISI][Medline]

Sampson JA (1921) Perforating hemorrhagic (chocolate) cysts of the ovary. Their importance and especially their relation to pelvic adenomas of endometriotic type ("adenomyoma" of the uterus, rectovaginal septum, sigmoid etc.). Arch Surg 3,245–322.

Sampson JA (1924a) Benign and malignant endometrial implants in the peritoneal cavity and their relation to certain ovarian tumors. Surg Gynecol Obstet 38,287–311.

Sampson JA (1924b) Endometrial carcinoma of the ovary arising in endometrial tissue in that organ. Arch Surg 10,1–72.

Sampson JA (1925) Heterotopic or misplaced endometrial tissue. Am J Obstet Gynecol 10,649–664.

Sampson JA (1927a) Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 14,422–469.

Sampson JA (1927b) Metastatic or embolic endometrisosis due to menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol 3,93–151.

Selak V, Farquahar C, Prentice A and Single A (2001) Danazol for pelvic pain associated with endometriosis. Cochrane Database Syst. Rev. CD 000068.

Strathy JH, Molgaard CA and Coulman CB (1982) Endometriosis and infertility: a laparoscopic study of endometriosis among fertile and infertile women. Fertil Steril 39,667–672.

Stripling MC, Martin DC and Chatman DL (1988) Subtle appearance of pelvic endometriosis. Fertil Steril 49,427–438.[ISI][Medline]

Sutton CJG, Ewens SP, Whitelaw N and Haines P (1994) Propsective, randomized, double-blind, controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild and modearate endometriosis. Fertil Steril 62,696–700.[ISI][Medline]

Thorton JG, Morley S, Lilleyman J, Onwude J Currie I and Crompton AC (1997) The relationship between laparoscopic disease, pelvic pain and infertility: an unbiased assessment. Eur J Obstet Gynecol Reprod Biol 74,57–62.[CrossRef][ISI][Medline]

Vara AR, Ruzics EP, Moussabeck O and Martin DC (1990) Endometrial adenosarcoma of the bladder arising from endometriosis. J Urol 143,813–815.[ISI][Medline]

Vercellini P, Trespidi L, De Giorgi O, Cortesi I, Parazzini F and Crosig PR (1996) Endometriosis and pelvic pain: relation to disease stage and localization. Fertil Steril 65,299–304[ISI][Medline]

Vercellini P, Aimi G, Panazza S, Vincenti S, Piacreta A and Crosignani PG (2000) Deep endometriosis conundrum: evidence in favor of a peritoneal origin. Fertil Steril 73,1043–1046.[CrossRef][ISI][Medline]

Vercellini P, Frontino G, Pisacreta A, De Giorgi O, Cattaneo M and Crosignani PG (2002) The pathogenesis of bladder detrusor endometriosis. Am J Obstet Gynecol 187,538–542.[CrossRef][ISI][Medline]

Weed J and Ray JE (1987) Endometriosis of the bowel. Obstet Gynecol 69,727–730.[Abstract]

Submitted on August 13, 2003; resubmitted on October 3, 2003; accepted on December 4, 2003.