1 Departments of Gynaecology, 2 Pathology and 3 Digestive Surgery, Hospital Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium
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Abstract |
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Key words: adenomyosis/hypogastric nerve plexus/pelvic pain/perineurial invasion/rectovaginal endometriosis
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Introduction |
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The rectovaginal septum and posterior cul-de-sac locations represent the most common pelvic locations of endometriosis after the pelvic peritoneum and ovaries. Deep infiltrating endometriosisdefined as the presence of endometriotic glands and stroma >5 mm under the peritoneumrepresents a distinct entity of the disease and, as stated above, is strongly associated with pelvic pain (Cornillie et al., 1990). Rectovaginal endometriotic nodules represent a certain form of deeply infiltrating endometriosis. Three types of deep infiltrating endometriosis have been defined: the infiltrating form (type 1); the retractile form (type 2); and the rectovaginal septum nodule (type 3) (Koninckx and Martin, 1992
).
According to this classification, rectovaginal endometriotic nodulesas investigated in the present studyrepresent the deepest and most severe lesions. They are spherical in shape, located deep in the rectovaginal septum, and are often only visible as small typical peritoneal lesions at laparoscopy. According to other authors, this type of lesion should not be considered as endometriosis, but rather represents adenomyosis or an adenomyoma, a circumscribed nodule composed of endometrial-like glands, scanty stroma and abundant smooth muscle (Donnez et al., 1995). These lesions are often more palpable than visible. In gynaecological terms, there may exist dysmenorrhoea which appears progressively, dyspareunia, menometrorrhagia and lower pelvic pains that may radiate posteriorly to the sacrococcygial region. These symptoms are initially cyclical, but tend to become continuous as the lesion increases. Clinical examination reveals a nodule in the posterior fornix or in the pouch of Douglas, which can become completely filled in certain cases, creating the sensation of a tumour. In the digestive tract, a rectal syndrome may occur with rectalgia and proctalgia radiating to the perineum, pain during defaecation, tenesmus, a feeling of rectal or anal heaviness, and problems with bowel movements. Finally, dyscheziaan occlusive syndrome with malignant neoplastic similaritiesmay be noted, together with cyclic proctorrhagia (Coronado et al., 1990
).
Hormone manipulations are most often only palliative because the symptoms tend to reappear as soon as the treatment ceases. Surgical resection of such lesions has been shown to be effective in the relief of deep dyspareunia and dysmenorrhoea. Nevertheless, the exact mechanism by which endometriotic nodules produce chronic pelvic pain and an exacerbation of the pain at palpation remains unclear. In order to clarify this issue, we have analysed the relationship between nerve invasion by endometriotic foci, its concomitant fibrosis, and the intensity of pelvic pain.
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Materials and methods |
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According to the revised classification of endometriosis of the American Fertility Society (AFS), and not including one patient who was lost to follow-up (see below), 10 patients had endometriosis stage 1, 13 had stage 3 and five had stage 4. With regard to the revised AFS scores, 10 patients had a score of <15, and 18 patients had a score >15.
The patients with stage 1 endometriosis were those who presented a partial posterior cul-de-sac obliteration, while those with stage 3 and stage 4 had a complete posterior cul-de-sac obliteration.
All 29 operated patients had stopped taking any hormonal medication for at least 3 months before surgery.
In order to rule out involvement of the digestive mucosa and/or a stricture of the rectum, all patients underwent a rectosigmoidoscopy and a barium enema. In 17 patients (59%), the barium enema showed the presence of a retractile perivisceritis on the anterior rectal wall. None of the 29 patients presented either rectum calibre reduction at barium enema, nor red or dark-blue mucosal or submucosal areas at rectosigmoidoscopy. Therefore, neither discoid anterior rectal wall resection nor anterior rectal resection with end-to-end or lateroterminal anastomosis were performed. It must be stressed that rectal endoscopic ultrasonography (EUS) was not performed preoperatively in these patients. The use of preoperative rectal EUS was recently proposed (Chapron et al., 1998) in order to select patients with deep digestive wall endometriotic infiltration. Those patients are probably better candidates for bowel resection than conservative digestive surgery (Chapron et al., 1998
). Therefore, we cannot totally exclude that some of our patients had deep endometriotic infiltration of the bowel muscularis or submucosa.
All patients provided their informed consent for this study.
Pain evaluation
In total, 28 patients (97%) answered mailed questionnaires, one in the preoperative and one in the postoperative phase after a mean (± SD) follow-up of 21.0 ± 2.3 months. One patient had moved abroad and was lost to follow-up.
The designer and corresponding author (F.B.) of the questionnaires was unknown to the patients, and had not participated at either the pre- or postoperative consultation, or at the operations.
The questionnaires were designed to obtain information about the intensity of pre- and postoperative pain, using visual analogue pain scales for pelvic pain, dysmenorrhoea and deep dyspareunia. The pain scales were ungraduated lines of 10 cm length. `No pain' was indicated at the left side of the scale, and `the maximal pain you could imagine' at the right side of the scale.
Comparison of pre- and postoperative pain scores was made using the non-parametric Wilcoxon signed-rank test. Patients were allocated arbitrarily to two groups according to the intensity of their preoperative pain (group 1, pain score >7; group 2, pain score 7).
Preoperative data
Five patients (17%) had undergone diagnostic laparoscopy for pelvic pain during the past 5 years. A review of the charts and operative protocols mentioned the presence of a pouch of Douglas obliteration in four cases, though the underlying lesion had not been removed. Twelve patients (41%) had previously received different regimens of hormonal therapies composed of gonadotrophin-releasing hormone (GnRH) agonists, danazol or progestagens, and of those patients, seven (58%) were improved under medical therapy, although symptoms recurred rapidly after treatment interruption. Before undergoing laparoscopic resection of the rectovaginal nodule, the mean duration of symptoms was 40.4 (range 3052) months for chronic pelvic pain, 42 (range 3659) months for cyclical dysmenorrhoea, 36 (range 2448) months for deep dyspareunia, and 28 (range 2142) months for cyclical rectal pain. Neither GnRH agonists, danazol nor progestagens were prescribed after the intervention, and such medications had been stopped for at least 3 months before surgery.
Surgical technique for the resection of the rectovaginal endometriotic nodule
All 29 patients underwent the same surgical procedure for excision of the rectovaginal endometriotic nodule, performed by the same two surgeons (V.A. and Ph.S.). The surgical technique used was described previously (Donnez et al., 1995). In brief, the patients were placed in the dorsal decubitus position, and three suprapubic trocars (one in the midline and two laterally) each of 5 mm diameter were inserted. The CO2 laser was connected to the laparoscope. A cannula was inserted in the uterus, a sponge on a forceps applied against the nodule, and a probe (Hegar 18) placed in the rectum. When the nodule was clearly identified by palpation, the plane between the posterior aspect of the nodule and the anterior rectal wall was dissected with help from the CO2 laser until the healthy vagina was reached under the inferior edge of the lesion. The vagina was then incised with the CO2 laser, and the nodule circumscribed and removed transvaginally. No systematic laser uterine nerve ablation (LUNA) procedure was performed, but any residual induration in the surrounding tissues was removed transvaginally. The colpotomy was then closed sagitally using a Catgut 1 (Ethicon, Neuilly, France) running suture. The patients were discharged from hospital on day 2 or 3 postoperatively, and advised to avoid sexual intercourse during the subsequent 3-week period. All patients had their first sexual intercourse within 2 months postoperatively.
Histological and immunohistological study
After CO2 laser laparoscopic excision, the greatest diameter of each excised specimen was measured in groups 1 and 2, using a graduated scale. The rectovaginal nodules were fixed immediately in 10% phosphate-buffered formaldehyde for 12 h and then embedded in paraffin. For each specimen, four serial sections each of 4 µm were prepared. The first and second sections were stained with haematoxylin and Masson's trichrome respectively, as described previously (Masson, 1929). Masson's trichrome staining is a specific staining for the detection of collagen fibres. The third section was used as a negative control. The final section was coated on silanated glass for S100 immunohistochemistry. Briefly, the sections were deparaffinized and the endogenous peroxidase blocked with 0.6% hydrogen peroxidemethanol for 30 min. Tissues were then incubated overnight at 4°C with the primary antibody S100 (clone 15E2E2; dilution 1/100; Biogenex, San Ramon, CA, USA). The Elite ABC kit (Vector Laboratories, Burlingame, CA, USA) was used for the subsequent steps according to the manufacturer's instructions. Chromogenic development was accomplished using diaminobenzidinehydrogen peroxide. Slides were then slightly counterstained with haematoxylin, dehydrated and coverslips applied.
S100 protein is a highly sensitive marker for myelinated nerves which are normally present in the rectovaginal septum. S100 monoclonal antibody is directed against an acidic, dimeric calcium-binding protein (mol. wt 21 000 Da) composed of different combinations of and ß subunits, and is present in the nucleus and cytoplasm of Schwann cells. S100 protein is structurally similar in terms of its calcium-binding domains to calmodulin, an important transducer of calcium-mediated signals.
To control for non-specific binding of the primary antibody, non-immune mouse serum at the same concentration as the primary antibody preparation was substituted as the first layer of the serial sections for S100 immunohistochemistry.
Positive controls for S100 staining were large biopsies of the upper third of the unaffected rectovaginal septum in non-menopausal patients (n = 6) [mean age 32 (range 2439) years] with (n = 3) and without (n = 3) laparoscopically proven endometriosis. A nerve was considered as `encapsulated' in fibrotic tissue when it was totally surrounded by Masson's trichrome-positive tissue. The number of nerve structures encapsulated in fibrotic tissue was determined in groups 1 and 2 by calculating the mean number of S100-positive nerve structures located within Masson's trichrome-positive areas in at least 10 randomly selected non-overlapping (x40) high-power fields (hpf). Similarly, in each group the total number of S100-positive nerve structures was calculated, and the respective percentages of nerves situated within endometriotic glands and/or stroma. Results were expressed as the mean (± SD) number of nerves per x40 hpf and mean (± SD) percentages of nerves located in fibrosis and within endometriotic lesions. In each studied field of lesions from groups 1 and 2, each nerve structure was then examined histologically at x400 in order to detect the presence of perineurial or endoneurial invasion by stromal and/or glandular endometriotic cells.
Perineurial invasion was defined as the presence of stromal cells that have penetrated the perineurium which is composed of concentric flattened cells separated by layers of collagen at the periphery of the myelinated neural cells (Sternberg, 1992). Endoneurial or intrafascicular invasion was defined as the presence of stromal and/or glandular cells within the nerve fascicle (Sternberg, 1992
). The results for endoneurial and intraneurial invasion were expressed as mean (± SD) percentages of intra-endometriotic nerves showing perineurial or endoneurial invasion. The comparison between the mean number of nerve structures per x40 hpf, the mean (± SD) percentages of nerves encapsulated in fibrosis or located within endometriotic glands and/or stroma, and the mean (± SD) percentages of intra-endometriotic nerves showing perineurial or endoneurial invasion in groups 1 and 2 was performed using Student's two-tailed t-test.
The same histological and immunohistological data were compared between the different revised AFS stages and scores.
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Results |
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Discussion |
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The exact mechanism by which this lesion causes pain is still unknown, but numerous theories have been proposed to explain pain mediation by endometriotic tissue, including production and release of prostaglandins; inflammatory mediators such as kinins, histamine, interleukins, etc., fibrosis and cyclical haemorrhage. An early theory of pain production suggested that both fibrotic reaction and functional glands were required for pain mediation (Sturgis and Call, 1954). In the particular case of rectovaginal septum endometriotic nodule, the fixed position of the posterior pelvic structures (upper vagina, cervix and rectum) could also represent a cause of pain occurring during intercourse or at defaecation. All 29 patients presented with an important exacerbation of pain when pressure was exerted on the nodule at physical examination. This lesion appeared to be a `pain-triggering zone' at vaginal palpation, suggesting a close relationship between the endometriotic lesion and nerve structures. However, the relationship between nerves and rectovaginal endometriotic nodules has, until now, not been studied.
S100 immunohistochemical staining performed on the clinically unaffected rectovaginal septum and the rectovaginal endometriotic nodules showed the presence of numerous nerve structures. Pain impulses from that region, the uterus and cervix are transmitted through afferent sympathetic nerve fibres that course through the uterosacral ligaments and the posterolateral pelvis, and come together in the midline as the superior hypogastric plexus, en route to the dorsal horn of the spinal cord (Frankenhauser, 1864). Painful stimuli are then processed, modulated, and centrally transmitted to higher levels.
In both groups 1 and 2, a major proportion of the nerves were totally surrounded by fibrosis (Table II). Fibrous tissue, which is absent in the unaffected rectovaginal septum, possibly results from an inflammatory process that follows cyclical bleedings in the rectovaginal endometriotic nodule. It is of course difficult to demonstrate that the fibrosis surrounding the nerves exerts pressure on the nerve fascicles rather than being apposed to them. However, the rigid aspect of the lesion at palpation and the retractile perivisceritis that was often visible at barium enema strongly suggested that a `compression phenomenon' may occur in this type of lesion. Neurophysiological and electron microscopy studies have demonstrated that induced perineural fibrosis results in morphological changes as well as functional nerve changes (compound action potentials and motor nerve conduction velocity decrease, fast axonal transport decrease). Such nerve morphological and functional changes are generally present in `compression neuropathy' and associated with hyperaesthesia (Ando, 1990
; Sommer et al., 1995
; Bai et al., 1999
). There are a number of examples of pain caused by the compression of peripheral somatic (discal hernia) or autonomic nerves (chronic pancreatitis), and the frequent entrapment of nerve structures within the fibrotic tissue of the nodule may represent one of the aetiopathogenic mechanisms of pain.
Carcinomas arising in various organs exhibit a capacity, and in some instances a proclivity, to invade around (perineurial invasion) and into (endoneurial or intrafascicular invasion) nerves (Sternberg, 1992). This phenomenon is frequently observed in pancreatic carcinomas, but less frequently in invasive mammary carcinomas, where it is estimated at about 10% of invasive duct carcinomas (Rosen, 1998
). Adenoid cystic carcinomas of the Bartholin's gland are also characterized by the frequent presence of perineurial and endoneurial invasion, and this may explain why such lesions are often painful before they become palpable (Rosai, 1996
; Anaf et al., 1999
). The finding of epithelial invasion of the perineurial and endoneurial space was at one time considered evidence of malignant disease. The theoretical basis for the viewpoint that perineurial invasion was evidence for malignancy was weakened when it was concluded that the perineurial space is not a lymphatic space, and that involvement may represent extension into the tissue plane of least resistance (Rodin et al., 1967
). Descriptions of perineurial invasion by benign lesions such as endometriosis are much less frequent. In 1956, a case of breast chronic cystic disease was described in which normal mammary ducts were found within the perineurial space (Ackerman, 1957
), while others (Taylor and Norris, 1967
) later demonstrated perineurial invasion in 2% of breast biopsies, essentially in patients with sclerosing adenosis. Interestingly, as in rectovaginal septum endometriotic nodules, the pain produced by sclerosing adenosis of the breast is also characterized by an exacerbation when pressure is applied to the lesion (Preece et al., 1979
). Perineurial and endoneurial invasion have also been described in chronic pancreatitis, another very painful benign disease (Bartow et al., 1981
). The involvement of somatic pelvic nerves by endometriosis is a rare, but well-described, clinical and pathological entity (Head et al., 1962
; Baker et al., 1966
; Forrest and Brooks, 1972
). Cyclical sciatica caused by biopsy-proven endometriosis was first described in 1955 (Denton and Sherrill, 1955
). Symptomatic deposits of endometrial tissue involving the sciatic nerve may be identified radiographically and surgically. Catamenial pain, weakness and sensory loss represent the most frequent symptoms of endometriotic involvement of the sciatic, femoral or lumbosacral nerve roots (Zager et al., 1998
). In the available literature, perineurial invasion of the autonomic nervous system by endometriosis has been described in only one case of uterosacral painful nodule discovered after total hysterectomy with bilateral adnexectomy for endometrial cancer (Roth, 1973
). Such observations associated with the frequent presence of perineurial and endoneurial involvement in rectovaginal endometriotic or adenomyotic lesions (Figure 3
) suggest a certain `neurotropism' of deep infiltrating endometriosis.
In conclusion, we have demonstrated that in rectovaginal septum endometriotic nodules, a high proportion of the nerves are encapsulated in the nodular fibrosis of the nodule and that there is a close morphological relationship between nerves and endometriotic foci by means of perineurial and endoneurial invasion. In addition, patients with the highest preoperative pain scores display higher proportions of nerve encapsulation in fibrosis and endometriotic lesions and more frequent peri- and endoneurial invasion than patients with lower preoperative pain scores (Table II). Similar histological results were found when stage 1 endometriosis patients were compared with stage 3 and 4 patients, as well as when patients with a pain score <15 were compared with those with a score >15 (Tables III and IV
). From a methodological point of view, we recognize that we were unable to provide adequate controls. Theoretically, the most adequate controls should be rectovaginal endometriotic nodules from women with no history of pelvic pain, dysmenorrhoea or deep dyspareunia. However, in our experienceas well as in the available literaturethe presence of a rectovaginal endometriotic nodule is always associated with pelvic pain, dysmenorrhoea and/or deep dyspareunia (Cornillie et al., 1990
; Koninckx and Martin, 1992
; Nezhat et al., 1992
; Donnez et al., 1995
; Clayton et al., 1999
; Porpora et al., 1999
). In addition, it would be unethical to remove a rectovaginal septum endometriotic nodule in an asymptomatic patient. We postulate that the topographical relationship between nerves and endometriotic foci and between nerves and fibrosis could at least partly explain the strong association between rectovaginal endometriotic nodules and pain.
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Notes |
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References |
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Anaf, V., Buxant, F., Rodesch, F. et al. (1999) Adenoid cystic carcinoma of the Bartholin's gland: what is the optimal approach? Eur. J. Surg. Oncol., 26, 406409.
Ando, Y. (1990) Experimental study on chronic entrapment neuropathy. Nippon Seikeigeka Gakkai Zasshi, 64, 633647.[Medline]
Bai, Y.H., Takemitsu, M., Atsuta, Y. and Matsuno, T. (1999) Peripheral mononeuropathy induced by loose ligation of the sciatic nerve in the rat: behavioral, electrophysiological and histopathological studies. Exp. Anim., 48, 8794.[ISI][Medline]
Baker, G.S., Parsons, W.R. and Welch, J.S. (1966) Endometriosis within the sheath of the sciatic nerve. Report of two patients with progressive paralysis. J. Neurosurg., 25, 652655.[ISI][Medline]
Bartow, S., Mukai, K. and Rosai, J. (1981) Pseudoneoplastic proliferation of endocrine cells in pancreatic fibrosis. Cancer, 47, 26272633.[ISI][Medline]
Chapron, C., Dumontier, I., Dousset, B. et al. (1998) Results and role of rectal endoscopic ultrasonography for patients with deep pelvic endometriosis. Hum. Reprod., 13, 22662270.[Abstract]
Clayton, R.D., Hawe., J.A., Lowe, J.C. et al. (1999) Recurrent pain after hysterectomy and bilateral salpingo-oophorectomy for endometriosis: evaluation of laparoscopic excision of residual excision. Br. J. Obstet. Gynaecol., 106, 740744.[ISI][Medline]
Cornillie, F.J., Oosterlynck, J., Lauweryns, M. and Koninckx, P.R. (1990) Suggestive evidence that endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain. Fertil. Steril., 55, 759765.[ISI]
Coronado, C., Franklin, R.R., Lotze, E.C. et al. (1990) Surgical treatment of symptomatic colorectal endometriosis. Fertil. Steril., 53, 411416.[ISI][Medline]
Denton, R.O. and Sherrill, J.D. (1955) Sciatic syndrome due to endometriosis of sciatic nerve. South. Med. J., 48, 10271031.
Donnez, J., Nisolle, M., Casanas-Roux, F. et al. (1995) Rectovaginal septum endometriosis or adenomyosis: laparoscopic management in a series of 231 patients. Hum. Reprod., 10, 630635.[Abstract]
Forrest, J.S. and Brooks, D.L. (1972) Cyclical sciatica of endometriosis. JAMA, 222, 11771178.[Medline]
Frankenhauser, G. (1864) Die Bewegungenerven der Gebarmutter. Z. Med. Nat. Wiss., 1, 35.
Head, H.B., Welch, J.S., Mussey, E. et al. (1962) Cyclical sciatica: report of case with introduction of a new surgical sign. JAMA, 180, 521524.[ISI][Medline]
Koninckx, P.R. and Martin, D.C. (1992) Deep endometriosis: a consequence of infiltration or retraction or possibly adenomyosis externa? Fertil. Steril., 58, 924928.[ISI][Medline]
Masson, P. (1929) Some histological methods. Trichrome stainings and their preliminary technique. J. Tech. Meth., 12, 7590.
Nezhat, C., Nezhat, F. and Pennington, E. (1992) Laparoscopic treatment of infiltrative rectosigmoid colon and rectovaginal septum endometriosis by the technique of videolaparoscopy and the CO2 laser. Br. J. Obstet. Gynaecol., 99, 664667.[ISI][Medline]
Porpora, M.G., Koninckx, P.R., Piazze, J. et al. (1999) Correlation between endometriosis and pelvic pain. J. Am. Assoc. Gynecol. Laparosc., 6, 429434.[ISI][Medline]
Preece, P.E., Fortt, R.W., Gravelle, I.H. et al. (1979) Some clinical aspects of sclerosing adenosis. Clin. Oncol., 2, 192.
Rodin, A.E., Larson, D.R. and Roberts, D.K. (1967) Nature of the perineural space invaded by prostatic carcinoma. Cancer, 20, 17721779.[ISI][Medline]
Rosai, J. (ed.) (1996) Ackerman's Surgical Pathology, Vol. 1, 8th edn. Mosby, St Louis, pp. 837838.
Rosen, P.P. (1998) Invasive mammary carcinoma. In Harris, J.R., Lippman, M.E., Morrow, M. and Hellman, S. (eds), Diseases of the Breast. Lippincott-Raven, Philadelphia, New York, pp. 393444.
Roth, L.M. (1973) Endometriosis with perineural involvement. Am. J. Clin. Pathol., 59, 807809.[ISI][Medline]
Sommer, C., Galbraith, J.A. and Heckman, H.M. (1995) Pathology of experimental compression neuropathy producing hyperesthesia. J. Neuropath. Exp. Neurol., 52, 223233.
Sternberg, S. (ed.) (1992) Histology for Pathologists. Raven Press, New York, pp. 169193.
Sturgis, S.H. and Call, B.J. (1954) Endometriosis peritonei relationship of pain to functional activity. Am. J. Obstet. Gynecol., 68, 1421.[ISI][Medline]
Taylor, H.B. and Norris, H.J. (1967) Epithelial invasion of nerves in benign diseases of the breast. Cancer, 20, 22452249.[ISI][Medline]
Zager, E.L., Pfeifer, S.M., Brown, M.J. et al. (1998) Catamenial mononeuropathy and radiculopathy: a treatable neuropathic disorder. J. Neurosurg., 88, 827830.[ISI][Medline]
Submitted on January 31, 2000; accepted on May 11, 2000.