Zusammenfassung
Die Krebsinzidenz auf dem Boden einer bestehenden Endometriose wird auf rund 0,7 - 1 % geschätzt. Eine ovarielle Endometriose scheint mit 2,5 % noch häufiger zu entarten. Retrospektive Studien verzeichneten ein erhöhtes Risiko bei Frauen mit Endometriose vor allem für Schilddrüsenkarzinome (standardisierte Inzidenzrate SIR 4,65), Ovarialkarzinome (SIR 1,43 - 4,2) und Non-Hodgkin-Lymphome (SIR 1,24 - 3,2). Die Adenomyosis uteri dagegen scheint kein erhöhtes Risiko für Malignome zu haben. Die Assoziation zwischen Endometriose und Ovarialkarzinomen wurde durch klinische Untersuchungen belegt. Nach achtjähriger Krankheitsdauer findet bei 0,7 % der Patientinnen eine maligne Umwandlung der Endometriose statt. Andererseits wurde Endometriose zu 40 - 70 % gleichzeitig mit klarzelligen Adenokarzinomen und zu 21 - 43 % gleichzeitig mit endometrioiden Adenokarzinomen identifiziert. Seltener war Endometriose mit serösen (3 - 9 %) oder muzinösen Adenokarzinomen (0 - 3 %) assoziiert. Da sich Endometriose-assoziierte Ovarialkarzinome (EAOC) von anderen Ovarialkarzinomen unterscheiden, wurde dieser Begriff im Sinne einer neuen Entität eingeführt. Patientinnen mit einem Endometriose-assoziierten Ovarialkarzinom haben im Vergleich zu Patientinnen mit anderen Ovarialkarzinomen ein niedrigeres Tumorstadium, eine unterschiedliche Verteilung der histologischen Unterarten (am häufigsten endometrioide und klarzellige Karzinome) und eine signifikant bessere Überlebensrate (80 - 100 %). Außerdem erkranken Frauen mit Endometriose früher in ihrem Leben an einem Ovarialkarzinom (45,9 ± 8,9 Jahre) als Frauen ohne Endometriose (54,9 ± 16,2 Jahre). Auch eine atypische Endometriose ist häufig mit epithelialen Ovarialkarzinomen assoziiert. Sie tritt bei rund 60 - 80 % der Endometriose-assoziierten Ovarialkarzinome auf, wobei 25 % direkt in ein Ovarialkarzinom übergehen. Die Inflammation scheint ein wichtiger pathogenetischer Faktor sowohl beim Ovarialkarzinom als auch bei der Endometriose zu sein. Mutagene Eigenschaften der Entzündungsreaktion können durch Zellzerstörung, oxidativen Stress und erhöhte Zytokin- und Prostaglandinspiegel verursacht sein. Neben Endometriose und Inflammation zählen zu den weiteren Risikofaktoren eines Ovarialkarzinoms Infertilität, Asbest, Talk und Hyperöstrogenismus bei Adipositas. Protektive Faktoren sind Tubensterilisation, Hysterektomie, Geburten und orale Kontrazeptiva. Bei einer malignen Transformation der Endometriose entfallen 80 % auf das Ovar und 20 % auf extragonadale Manifestationen. Letztere waren im Allgemeinen mit Östrogensubstitutionstherapien verknüpft. Der Verlust von genetischem Material wurde auf mehreren Genloci im Endometriosegewebe entdeckt und ist potenziell mit der Inaktivierung von Tumorsuppressorgenen assoziiert. Die kausale Verbindung zwischen Endometriose und Ovarialkarzinom scheint sowohl durch diese Assoziationen als auch durch die zugrunde liegenden molekularen Mechanismen definiert zu sein.
Abstract
The risk of cancer arising from pre-existing endometriosis is estimated to be around 0.7 - 1 %. With an incidence of 2.5 %, ovarian endometriosis is suggested to transform even more frequently into ovarian cancer. Retrospective studies have shown an increased risk for some types of malignancy for endometriosis patients, especially for thyroid tumours (standardised incidence ratio SIR 4.65), ovarian cancer (SIR 1.43 - 4.2) and Non-Hodgkin's lymphoma (SIR 1.24 - 3.2). Adenomyosis uteri seems not to be related to an increased cancer risk. The association between endometriosis and ovarian cancer was proved by clinical studies. Malignant transformation of endometriosis is reported in 0.7 % of all endometriosis patients after eight years. On the other hand, endometriosis was identified in 40 - 70 % of clear cell carcinomas and in 21 - 43 % of endometrioid carcinomas. Endometriosis was rarely associated with serous (3 - 9 %) or mucinous carcinomas (0 - 3 %). Since endometriosis-associated ovarian cancer (EAOC) differs from other types of ovarian cancers, this concept was introduced as a new entity. Women with endometriosis-associated ovarian cancer most likely represent a different class of patients compared to traditional ovarian cancer patients. The patients with EAOC usually have a lower stage disease, show a completely different distribution of histological subtypes (significant overrepresentation of endometrioid and clear cell carcinomas), have predominantly lower grade lesions, and they have a statistically significant better overall survival (80 - 100 %). Furthermore, among patients with malignant tumours, those with endometriosis were statistically significant younger (45.9 ± 8.9 years) compared to those without endometriosis (54.9 ± 16.2 years). An atypical endometriosis is also frequently associated with epithelial ovarian cancer. It appears in about 60 - 80 % of endometriosis-associated ovarian cancers and 25 % showed a direct transition into ovarian cancer. Inflammation seems to be a pathophysiological contributor for ovarian cancer as well as for endometriosis. Mutagenic qualities of the inflammatory reaction could be caused by cell damage, oxidative stress and elevation of cytokines and prostaglandins. In addition to endometriosis and inflammation, further risk factors for ovarian cancer are infertility, asbestos, talcum and hyperoestrogenism. Protective factors are tubal ligation, hysterectomy, births and oral contraceptives. Malignant transformation of endometriosis occurs in the ovary in 80 % and in extragonadal sites in 20 %. The latter were generally associated with oestrogen substitution therapies. The loss of genetic material was discovered on several gene loci in endometriosis tissue and is potentially associated with inactivation of tumour suppressor genes. The causal link between endometriosis and ovarian cancer remains to be defined both in terms of entity of association and of underlying molecular mechanisms.
Schlüsselwörter
Endometriose - Ovarialkarzinom - maligne Transformation - Inzidenzraten
Key words
Endometriosis - ovarian cancer - malignant transformation - incidence ratios
Literatur
-
1
Nishida M, Watanabe K, Sato N, Ichikawa Y.
Malignant transformation of ovarian endometriosis.
Gynecol Obstet Invest.
2000;
50
18-25
-
2
Erzen M, Kovacic J.
Relationship between endometriosis and ovarian cancer.
Eur J Gynaecol Oncol.
1998;
19
553-535
-
3
Heaps J M, Nieberg R K, Berek J S.
Malignant neoplasms arising in endometriosis.
Obstet Gynecol.
1990;
75
1023-1028
-
4
Van Gorp T, Amant F, Neven P, Vergote I, Moerman P.
Endometriosis and the development of malignant tumours of the pelvis. A review of literature.
Best Pract Res Clin Obstet Gynaecol.
2004;
18
349-371
-
5
Brinton L A, Gridley G, Persson I, Baron J, Bergqvist A.
Cancer risk after a hospital discharge diagnosis of endometriosis.
Am J Obstet Gynecol.
1997;
176
572-579
-
6
Brinton L A, Westhoff C L, Scoccia B, Lamb E J, Althuis M D, Mabie J E, Moghissi K S.
Causes of infertility as predictors of subsequent cancer risk.
Epidemiology.
2005;
16
500-507
-
7
Olson J E, Cerhan J R, Janney C A, Anderson K E, Vachon C M, Sellers T A.
Postmenopausal cancer risk after self-reported endometriosis diagnosis in the Iowa Women's Health Study.
Cancer.
2002;
94
1612-1618
-
8
Melin A, Sparen P, Persson I, Bergqvist A.
Endometriosis and the risk of cancer with special emphasis on ovarian cancer.
Hum Reprod.
2006;
21
1237-1242[Epub ahead of print 2006 Jan 23]
-
9
Ness R B, Grisso J A, Cottreau C, Klapper J, Vergona R, Wheeler J E, Morgan M, Schlesselman J J.
Factors related to inflammation of the ovarian epithelium and risk of ovarian cancer.
Epidemiology.
2000;
11
111-117
-
10
Sainz de la Cuesta R, Izquierdo M, Canamero M, Granizo J J, Manzarbeitia F.
Increased prevalence of p 53 overexpression from typical endometriosis to atypical endometriosis and ovarian cancer associated with endometriosis.
Eur J Obstet Gynecol Reprod Biol.
2004;
113
87-93
-
11
Jimbo H, Yoshikawa H, Onda T, Yasugi T, Sakamoto A, Taketani Y.
Prevalence of ovarian endometriosis in epithelial ovarian cancer.
Int J Gynaecol Obstet.
1997;
59
245-250
-
12
Yoshikawa H, Jimbo H, Okada S, Matsumoto K, Onda T, Yasugi T, Taketani Y.
Prevalence of endometriosis in ovarian cancer.
Gynecol Obstet Invest.
2000;
50
11-17
-
13
Fukunaga M, Nomura K, Ishikawa E, Ushigome S.
Ovarian atypical endometriosis: its close association with malignant epithelial tumours.
Histopathology.
1997;
30
249-255
-
14
Brinton L A, Sakoda L C, Sherman M E, Frederiksen K, Kjaer S K, Graubard B I, Olsen J H, Mellemkjaer L.
Relationship of benign gynecologic diseases to subsequent risk of ovarian and uterine tumors.
Cancer Epidemiol Biomarkers Prev.
2005;
14
2929-2935
-
15
Ogawa S, Kaku T, Amada S, Kobayashi H, Hirakawa T, Ariyoshi K, Kamura T, Nakano H.
Ovarian endometriosis associated with ovarian carcinoma: a clinicopathological and immunohistochemical study.
Gynecol Oncol.
2000;
77
298-304
-
16
Oral E, Ilvan S, Tustas E, Korbeyli B, Bese T, Demirkiran F, Arvas M, Kosebay D.
Prevalence of endometriosis in malignant epithelial ovary tumours.
Eur J Obstet Gynecol Reprod Biol.
2003;
109
97-101
-
17
Benoit L, Arnould L, Cheynel N, Diane B, Causeret S, Machado A, Collin F, Fraisse J, Cuisenier J.
Malignant extraovarian endometriosis: A review.
Eur J Surg Oncol.
2006;
32
6-11[Epub 2005 Nov 11]
-
18
Leiserowitz G S, Gumbs J L, Oi R, Dalrymple J L, Smith L H, Ryu J, Scudder S, Russell A H.
Endometriosis-related malignancies.
Int J Gynecol Cancer.
2003;
13
466-471
-
19
Komiyama S, Aoki D, Tominaga E, Susumu N, Udagawa Y, Nozawa S.
Prognosis of Japanese patients with ovarian clear cell carcinoma associated with pelvic endometriosis: clinicopathologic evaluation.
Gynecol Oncol.
1999;
72
342-346
-
20
Modesitt S C, Tortolero-Luna G, Robinson J B, Gershenson D M, Wolf J K.
Ovarian and extraovarian endometriosis-associated cancer.
Obstet Gynecol.
2002;
100
788-795
-
21
Erzen M, Rakar S, Klancnik B, Syrjanen K.
Endometriosis-associated ovarian carcinoma (EAOC): an entity distinct from other ovarian carcinomas as suggested by a nested case-control study.
Gynecol Oncol.
2001;
83
100-108
-
22
McMeekin D S, Burger R A, Manetta A, DiSaia P, Berman M L.
Endometrioid adenocarcinoma of the ovary and its relationship to endometriosis.
Gynecol Oncol.
1995;
59
81-86
-
23
Takahashi K, Kurioka H, Irikoma M, Ozaki T, Kanasaki H, Miyazaki K.
Benign or malignant ovarian neoplasms and ovarian endometriomas.
J Am Assoc Gynecol Laparosc.
2001;
8
278-284
-
24
Crozier M A, Copeland L J, Silva E G, Gershenson D M, Stringer C A.
Clear cell carcinoma of the ovary: a study of 59 cases.
Gynecol Oncol.
1989;
35
199-203
-
25
Goff B A, Sainz de la Cuesta R, Muntz H G, Fleischhacker D, Ek M, Rice L W, Nikrui N, Tamimi H K, Cain J M, Greer B E, Fuller Jr A F.
Clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy in stage III disease.
Gynecol Oncol.
1996;
60
412-417
-
26
Sampson J A.
Endometrial carcinoma of the ovary arising in endometrial tissue in that organ.
Archives of Surgery.
1925;
10
1-72
-
27
Scott R B.
Malignant changes in endometriosis.
Obstet Gynecol.
1953;
2
283-289
-
28
LaGrenade A, Silverberg S G.
Ovarian tumors associated with atypical endometriosis.
Hum Pathol.
1988;
19
1080-1084
-
29
Seidman J D.
Prognostic importance of hyperplasia and atypia in endometriosis.
Int J Gynecol Pathol.
1996;
15
1-9
-
30
Bayramoglu H, Duzcan E.
Atypical epithelial changes and mutant p 53 gene expression in ovarian endometriosis.
Pathol Oncol Res.
2001;
7
33-38
-
31
Fukunaga M, Ushigome S.
Epithelial metaplastic changes in ovarian endometriosis.
Mod Pathol.
1998;
11
784-788
-
32
Wang X, Wang E, Kavanagh J J, Freedman R S.
Ovarian cancer, the coagulation pathway, and inflammation.
J Transl Med.
2005;
3
25
-
33
Freedman R S, Deavers M, Liu J, Wang E.
Peritoneal inflammation - A microenvironment for Epithelial Ovarian Cancer (EOC).
J Transl Med.
2004;
2
23
-
34
Ness R B, Cottreau C.
Possible role of ovarian epithelial inflammation in ovarian cancer.
J Natl Cancer Inst.
1999;
91
1459-1467
-
35
Oner-Iyidogan Y, Kocak H, Gurdol F, Korkmaz D, Buyru F.
Indices of oxidative stress in eutopic and ectopic endometria of women with endometriosis.
Gynecol Obstet Invest.
2004;
57
214-217[Epub 2004 Feb 11]
-
36
von Georgi R, Münstedt K.
Ein multifaktorielles Modell zur Ätiologie des Ovarialkarzinoms.
Geburtsh Frauenheilk.
2002;
62
1060-1068
-
37
Koninckx P R, Kennedy S H, Barlow D H.
Pathogenesis of endometriosis: the role of peritoneal fluid.
Gynecol Obstet Invest.
1999;
47
23-33
-
38
Hornung D, Bentzien F, Wallwiener D, Kiesel L, Taylor R N.
Chemokine bioactivity of RANTES in endometriotic and normal endometrial stromal cells and peritoneal fluid.
Mol Hum Reprod.
2001;
7
163-168
-
39
Bergqvist A, Bruse C, Carlberg M, Carlstrom K.
Interleukin 1beta, interleukin-6, and tumor necrosis factor-alpha in endometriotic tissue and in endometrium.
Fertil Steril.
2001;
75
489-495
-
40
Wu M Y, Chao K H, Yang J H, Lee T H, Yang Y S, Ho H N.
Nitric oxide synthesis is increased in the endometrial tissue of women with endometriosis.
Hum Reprod.
2003;
18
2668-2671
-
41
Hornung D, Licht P, Wallwiener D.
Endometriose: Bewährte und innovative Therapiestrategien bei Schmerzen und Infertilität.
Geburtsh Frauenheilk.
2004;
64
584-588
-
42
Ness R B, Cramer D W, Goodman M T, Kjaer S K, Mallin K, Mosgaard B J, Purdie D M, Risch H A, Vergona R, Wu A H.
Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies.
Am J Epidemiol.
2002;
155
217-224
-
43
Riman T, Persson I, Nilsson S.
Hormonal aspects of epithelial ovarian cancer: review of epidemiological evidence.
Clin Endocrinol (Oxf).
1998;
49
695-707
-
44
Modugno F, Ness R B, Allen G O, Schildkraut J M, Davis F G, Goodman M T.
Oral contraceptive use, reproductive history, and risk of epithelial ovarian cancer in women with and without endometriosis.
Am J Obstet Gynecol.
2004;
191
733-740
-
45
Green A, Purdie D, Bain C, Siskind V, Russell P, Quinn M, Ward B.
Tubal sterilisation, hysterectomy and decreased risk of ovarian cancer. Survey of Women's Health Study Group.
Int J Cancer.
1997;
71
948-951
-
46
Kjaer S K, Mellemkjaer L, Brinton L A, Johansen C, Gridley G, Olsen J H.
Tubal sterilization and risk of ovarian, endometrial and cervical cancer. A Danish population-based follow-up study of more than 65 000 sterilized women.
Int J Epidemiol.
2004;
33
596-602[Epub 2004 May 26]
-
47
Zanetta G M, Webb M J, Li H, Keeney G L.
Hyperestrogenism: a relevant risk factor for the development of cancer from endometriosis.
Gynecol Oncol.
2000;
79
18-22
-
48
Nelson L R, Bulun S E.
Estrogen production and action.
J Am Acad Dermatol.
2001;
45
S116-S124
-
49
Akahane T, Sekizawa A, Okuda T, Kushima M, Saito H, Okai T.
Disappearance of steroid hormone dependency during malignant transformation of ovarian clear cell cancer.
Int J Gynecol Pathol.
2005;
24
369-376
-
50
Del Carmen M G, Smith Sehdev A E, Fader A N, Zahurak M L, Richardson M, Fruehauf J P, Montz F J, Bristow R E.
Endometriosis-associated ovarian carcinoma: differential expression of vascular endothelial growth factor and estrogen/progesterone receptors.
Cancer.
2003;
98
1658-1663
-
51
Park S W, Hong S M, Wu H G, Ha S W.
Clear cell carcinoma arising in a cesarean section scar endometriosis: a case report.
J Korean Med Sci.
1999;
14
217-219
-
52
Slavin R E, Krum R, Van Dinh T.
Endometriosis-associated intestinal tumors: a clinical and pathological study of 6 cases with a review of the literature.
Hum Pathol.
2000;
31
456-463
-
53
Yantiss R K, Clement P B, Young R H.
Endometriosis of the intestinal tract: a study of 44 cases of a disease that may cause diverse challenges in clinical and pathologic evaluation.
Am J Surg Pathol.
2001;
25
445-454
-
54
Chen K T.
Endometrioid adenocarcinoma arising from colonic endometriosis mimicking primary colonic carcinoma.
Int J Gynecol Pathol.
2002;
21
285-288
-
55
Petersen V C, Underwood J C, Wells M, Shepherd N A.
Primary endometrioid adenocarcinoma of the large intestine arising in colorectal endometriosis.
Histopathology.
2002;
40
171-176
-
56
Slomovitz B M, Soslow R A, Chang R C, Golub R, Kuo D Y.
Serous adenocarcinoma of the inguinal region arising from endometriosis followed by a successful pregnancy.
Gynecol Oncol.
2002;
87
152-154
-
57
Gucer F, Pieber D, Arikan M G.
Malignancy arising in extraovarian endometriosis during estrogen stimulation.
Eur J Gynaecol Oncol.
1998;
19
39-41
-
58
Goumenou A G, Arvanitis D A, Matalliotakis I M, Koumantakis E E, Spandidos D A.
Microsatellite DNA assays reveal an allelic imbalance in p 16(Ink4), GALT, p 53, and APOA2 loci in patients with endometriosis.
Fertil Steril.
2001;
75
160-165
-
59
Jiang X, Hitchcock A, Bryan E J, Watson R H, Englefield P, Thomas E J, Campbell I G.
Microsatellite analysis of endometriosis reveals loss of heterozygosity at candidate ovarian tumor suppressor gene loci.
Cancer Res.
1996;
56
3534-3539
-
60
Jiang X, Morland S J, Hitchcock A, Thomas E J, Campbell I G.
Allelotyping of endometriosis with adjacent ovarian carcinoma reveals evidence of a common lineage.
Cancer Res.
1998;
58
1707-1712
-
61
Martini M, Ciccarone M, Garganese G, Maggiore C, Evangelista A, Rahimi S, Zannoni G, Vittori G, Larocca L M.
Possible involvement of hMLH1, p 16(INK4a) and PTEN in the malignant transformation of endometriosis.
Int J Cancer.
2002;
102
398-406
-
62
Bischoff F Z, Heard M, Simpson J L.
Somatic DNA alterations in endometriosis: high frequency of chromosome 17 and p 53 loss in late-stage endometriosis.
J Reprod Immunol.
2002;
55
49-64
-
63
Nakayama K, Toki T, Nikaido T, Zhai Y L, Konishi I.
Genetic alterations in microsatellite marker sites among tumor suppressor genes in endometriosis.
Gynecol Obstet Invest.
2001;
51
240-242
-
64
Sato N, Tsunoda H, Nishida M, Morishita Y, Takimoto Y, Kubo T, Noguchi M.
Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary.
Cancer Res.
2000;
60
7052-7056
-
65
Obata K, Hoshiai H.
Common genetic changes between endometriosis and ovarian cancer.
Gynecol Obstet Invest.
2000;
50
39-43
-
66
Thomas E J, Campbell I G.
Molecular genetic defects in endometriosis.
Gynecol Obstet Invest.
2000;
50
44-50
-
67
Chang C C, Hsieh Y Y, Tsai F J, Tsai C H, Tsai H D, Lin C C.
The proline form of p 53 codon 72 polymorphism is associated with endometriosis.
Fertil Steril.
2002;
77
43-45
-
68
Okuda T, Otsuka J, Sekizawa A, Saito H, Makino R, Kushima M, Farina A, Kuwano Y, Okai T.
p 53 mutations and overexpression affect prognosis of ovarian endometrioid cancer but not clear cell cancer.
Gynecol Oncol.
2003;
88
318-325
-
69
Gogusev J, Bouquet de Joliniere J, Telvi L, Doussau M, du Manoir S, Stojkoski A, Levardon M.
Detection of DNA copy number changes in human endometriosis by comparative genomic hybridization.
Hum Genet.
1999;
105
444-451
-
70
Gogusev J, Bouquet de Joliniere J, Telvi L, Doussau M, du Manoir S, Stojkoski A, Levardon M.
Genetic abnormalities detected by comparative genomic hybridization in a human endometriosis-derived cell line.
Mol Hum Reprod.
2000;
6
821-827
-
71
Tamura M, Fukaya T, Murakami T, Uehara S, Yajima A.
Analysis of clonality in human endometriotic cysts based on evaluation of X chromosome inactivation in archival formalin-fixed, paraffin-embedded tissue.
Lab Invest.
1998;
78
213-218
-
72
Vigano P, Somigliana E, Chiodo I, Abbiati A, Vercellini P.
Molecular mechanisms and biological plausibility underlying the malignant transformation of endometriosis: a critical analysis.
Hum Reprod Update.
2006;
12
77-89[Epub 2005 Sep 19]
-
73
Sekizawa A, Amemiya S, Otsuka J, Saito H, Farina A, Okai T, Tachikawa T.
Malignant transformation of endometriosis: application of laser microdissection for analysis of genetic alterations according to pathological changes.
Med Electron Microsc.
2004;
37
97-100
-
74
Ueda M, Yamashita Y, Takehara M, Terai Y, Kumagai K, Ueki K, Kanda K, Yamaguchi H, Akise D, Hung Y C, Ueki M.
Survivin gene expression in endometriosis.
J Clin Endocrinol Metab.
2002;
87
3452-3459
-
75
Bell D A.
Origins and molecular pathology of ovarian cancer.
Mod Pathol.
2005;
18
S19-S32
PD Dr. Daniela Hornung
Universitätsfrauenklinik
Ratzeburger Allee 160
23538 Lübeck
eMail: D.Hornung@gmx.de
