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Endometriosis and the neoplastic process

¹ Section of Medical and Molecular Genetics, ² Academic Department of Obstetrics and Gynaecology and ³ Department of Histopathology, Birmingham Women’s Hospital, Birmingham B15 2TG, UK

Correspondence should be addressed to R Varma; Email r.varma{at}bham.ac.uk

	Abstract

Top Abstract What is endometriosis? Endometriosis and the neoplastic... Clinicopathological similarities... Molecular similarities of... Implications of the... Molecular re-classification of... Conclusion Acknowledgements References

 
Endometriosis is a frequent disorder that commonly presents with infertility and pelvic pain. Although the precise aetiology of endometriosis is unclear, it is generally considered to involve multiple genetic, environmental, immunological, angiogenic and endocrine processes. Genetic factors have been implicated in endometriosis but the susceptibility genes remain largely unknown. Although endometriosis is a benign disorder, recent studies of endometriosis suggest endometriosis could be viewed as a neoplastic process. Evidence to support this hypothesis includes the increased susceptibility to develop ovarian clear-cell and endometrioid cancers in the presence of endometriosis, and molecular similarities between endometriosis and cancer. In this article we discuss (i) the evidence suggesting that endometriosis might be viewed as a neoplastic process, and (ii) the implications of this hypothesis for elucidating the pathogenesis of endometriosis and developing novel methods of diagnostic classification and individualised treatments.

	What is endometriosis?

Top Abstract What is endometriosis? Endometriosis and the neoplastic... Clinicopathological similarities... Molecular similarities of... Implications of the... Molecular re-classification of... Conclusion Acknowledgements References

 
Endometriosis is defined as the implantation of endometrium-like glandular and stromal cells outside their normal location in the uterus. Endometriotic lesions are usually identified at laparoscopy localised to ovaries and the pouch of Douglas (Fig. 1). Endometriosis is diagnosed in 30% of cases referred for infertility investigations (Lapp 2000) and in 10–70% of women with pelvic pain (Lapp 2000). Overall, studies estimate that endometriosis may affect around 7–15% of women of reproductive age, thus making this a common condition.

View larger version (85K): [in this window] [in a new window]   Figure 1 Typical uterosacral/pouch of Douglas endometriosis lesion.

These disparities suggest that endometriosis may not be a true ‘disease’ but a heterogeneous entity with differing subtypes. One subtype may be capable of causing symptomatic disease directly consequent to endometriotic pathology (e.g. ovarian endometriomas, pelvic adhesions). While another subtype may be associated with symptoms without an obvious endometriotic-lesion basis. Another subtype may be clinically asymptomatic and its presence be considered a normal ‘non-pathogenic’ phenomena. Consequently the current focus on treating the endometriotic lesion should be reconsidered, and efforts to understand the pathogenesis of endometriosis, and its temporo–spatial relationship with symptomology, should be increased.

	Endometriosis and the neoplastic process

Top Abstract What is endometriosis? Endometriosis and the neoplastic... Clinicopathological similarities... Molecular similarities of... Implications of the... Molecular re-classification of... Conclusion Acknowledgements References

 
For some time, endometriosis research has focused on comparisons of various physiological processes in the endometrium (ectopic vs eutopic) of women affected by endometriosis, against unaffected women (Sharpe-Timms 2001). This has identified multiple anomalies in genetic, environment, angiogenic, endocrine, metabolic and immunological mechanisms. Some of these correlate with the severity of endometriosis and/or associated clinical sequelae implying a causative rather than simply associative role. However, the major obstacle has been the difficulty in discriminating between processes fundamental to endometriosis aetiopathogenesis and epiphenomena. Importantly, these physiological differences are multi-compartmental (endometrium, peritoneal fluid, follicular fluid and blood) and not just localised to the site of the endometriotic lesion, implying a fundamental widespread alteration in reproductive tract function. This multifactorial multi-compartmental pathogenesis, coupled with the clinical heterogeneity, has created a confusion of data, with little consensus on a unifying mechanism.

Since Sampson first reported in 1925 (Sampson 1925) that endometriosis may give rise to malignant change, and proposed criteria for diagnosis of malignancy arising in endometriosis, extensive evidence for an association between endometriosis and cancer (especially ovarian) has accumulated. A recent landmark publication, ‘Hallmarks of cancer’ (Hanahan & Weinberg 2000), defined seven critical features of the cancer phenotype (Table 1). To evaluate the hypothesis that endometriosis may be viewed as a neoplastic process, we review the (i) clinicopathological and (ii) molecular and genetic features of endometriosis in relation to the framework suggested by Hanahan. In addition, we outline how the hypothesis provides a basis for elucidating the pathogenesis of endometriosis and the prospect of using ‘molecular signatures’ for the classification and treatment of endometriosis.

	Clinicopathological similarities of endometriosis and cancer

Top Abstract What is endometriosis? Endometriosis and the neoplastic... Clinicopathological similarities... Molecular similarities of... Implications of the... Molecular re-classification of... Conclusion Acknowledgements References

Histopathology
Like malignancy, endometriosis displays features of atypia, adherence, invasion and metastases. Atypical endometriosis is characterised histologically by endometrial glands with cytological or architectural atypia (LaGrenade & Silverberg 1988), and has been observed in 12–35% of ovarian endometriosis (Seidman 1996, Nishida et al. 2000, Bayramoglu & Duzcan 2001). Around 60–80% of cases of endometriosis-associated ovarian cancer (EAOC) occur in the presence of atypical ovarian endometriosis (Fukunaga et al. 1997, Ogawa et al. 2000, Oral et al. 2003). Of these cases, 25% show direct continuity of the atypical ovarian endometriosis with ovarian cancer (Fukunaga et al. 1997), underlying a potential ‘premalignant’ transition spectrum of non-atypical to atypical and malignant variants.

Morphometry
Morphometric analysis of cancer, used for assessing mitotic activity and grading, has been shown to correlate with clinical prognosis (Kronqvist et al. 2002). Although morphometric analysis of non-atypical endometriosis showed no difference between active (red) and inactive (black or white) lesions, it has yet to be studied in atypical endometriosis (Regidor et al. 2002). Nonetheless, mild cytological atypia in the glandular epithelium of endometriotic cysts has been associated with normal DNA diploid patterns, whereas severe atypia may be associated with aneuploidy (Ballouk et al. 1994).

Ovarian malignancy may arise directly from ovarian endometriosis
Around 60% of EAOCs occur with the cancer adjacent to endometriosis or arising directly from ovarian endometriosis, with the remaining 40% occurring with distant endometriotic disease (Erzen & Kovacic 1998, Modesitt et al. 2002). Clear-cell and endometrioid carcinomas are the commonest EAOCs with ovarian endometriosis, while clear-cell adenocarcinoma and adenosarcoma are the commonest EAOCs in extra-ovarian endometriosis (Erzen & Kovacic 1998, Stern et al. 2001, Zaino et al. 2001). The risk of direct malignant transformation of ovarian endometriosis has been estimated as 0.7–1.6% over an average of 8 years (Seidman 1996, Nishida et al. 2000). Interestingly, there is a common unexplained left-sided predominance for endometriotic cysts, and ovarian endometrioid and clear-cell cancers (Vercellini et al. 2000, Al Fozan & Tulandi 2003).

Increased risk of ovarian cancer in women with endometriosis, irrespective of whether endometriosis is distant or adjacent to ovarian tumour
The age-standardised incidence of ovarian cancer in women in the UK is 21.9 per 100 000 (0.02%), with around 75% of cases diagnosed in postmenopausal women (National Statistics 2003). If there were no association between cancer and endometriosis then the incidence of endometriosis in women with ovarian cancer would be similar to that in the general population. However, the incidence of endometriosis in women with ovarian cancer is 8–30% (Fukunaga et al. 1997, Ogawa et al. 2000, Oral et al. 2003). This compares with a background incidence of endometriosis of 7–15% in women of reproductive age, and less than 2% in postmenopausal women (Lapp 2000). These data correlate with the finding from a Swedish population study, where the risk of ovarian cancer was increased 4.2-fold (95% confidence interval 2.0–7.7) in the presence of endometriosis (Brinton et al. 1997).

Furthermore, the histology of EAOC (40–55% clear-cell, 20–40% endometrioid and < 10% serous and mucinous subtypes) (Fukunaga et al. 1997, Yoshikawa et al. 2000, Modesitt et al. 2002) differs considerably from that seen in all ovarian cancers (FIGO 1998 annual report 55% serous, 13% mucinous, 14% endometrioid, 6% clear-cell) (Pecorelli et al. 1998).

Increased risk of synchronous endometrial and ovarian cancers, especially endometrioid type, in the presence of endometriosis
Simultaneously detected endometrial and ovarian carcinomas are most often associated with endometrioid subtypes, and ovarian endometriosis was identified in around 30% of these cases (Erzen & Kovacic 1998, Stern et al. 2001, Zaino et al. 2001).

Clinical behaviour and prognosis of EAOC differs from matched ovarian cancer subtypes not associated with endometriosis
EAOC compared with ovarian cancer without endometriosis, presents at a less-advanced stage, lower grade, predominantly endometrioid and clear-cell type, and has a better overall survival (Erzen et al. 2001, Modesitt et al. 2002).

Increased risk of extra-ovarian cancers
Around 80% of intraperitoneal cancers associated with endometriosis relate to ovarian cancer, with the remainder extra-ovarian (Modesitt et al. 2002). A separate study showed an increased risk of extra-pelvic cancers (breast and non-Hodgkin’s lymphoma) in women with endometriosis (Brinton et al. 1997).

	Molecular similarities of endometriosis and cancer

Top Abstract What is endometriosis? Endometriosis and the neoplastic... Clinicopathological similarities... Molecular similarities of... Implications of the... Molecular re-classification of... Conclusion Acknowledgements References

 
In the following subsections we review the molecular and genetic features of endometriosis in relation to the characteristics of cancer suggested by Hanahan & Weinberg (2000) (see Table 1).

Self-sufficiency in growth signals
Like uterine and breast cancer, endometriosis behaves as an oestrogen-dependent neoplasm. Endometriosis has specifically adapted to oestrogen-induced signalling by:

1. Increased local production of oestrogen through increased expression of aromatase cytochrome P450 expression but deficient 17ß-hydroxysteroid dehydrogenase type 2 expression (which impairs inactivation of potent oestradiol to less-potent oestrone (Bulun et al. 2000b)).
   
2. Increased responsiveness to oestrogen. There is increased oestrogen receptor (ER-) expression in active (red lesions) compared with inactive (black lesions) endometriosis (Matsuzaki et al. 2001b).
   
3. Inherited genetic polymorphisms in oestrogen and progesterone receptors (PRs), which predispose to endometriosis (Kitawaki et al. 2001, Wieser et al. 2002).
   
4. Inherited genetic polymorphisms in drug-metabolising enzymes (CYP1A1, CYP19 and GSTM1) which predispose to endometriosis (Baranova et al. 1999, Hadfield et al. 2001, Nakago et al. 2001, Arvanitis et al. 2003) and ovarian endometrioid and clear-cell cancers (Baxter et al. 2001). These alterations may induce endometriosis or cancer by altering a dioxin-induced oestrogen growth signal. Dioxins are environmental contaminants, and have been shown to induce endometriosis-like and oestrogen-dependent tumours in animal models (Birnbaum & Cummings 2002). Of importance, there is a doubled risk of developing endometriosis amongst women with high serum dioxin levels (Eskenazi et al. 2002). Activation of ERs in endometriosis may occur indirectly through up-regulated CYP1A1 activity, which causes increased aromatase P450 and oestrogen production (Bulun et al. 2000a), or directly by dioxin-activated aryl hydrocarbon receptor (Ohtake et al. 2003).
   

Other growth factors, such as transforming growth factor- and insulin-like growth factor-I (IGF-I) have also been implicated in endometriosis and cancer development (Lebovic et al. 2001). IGF-I signalling is required for cell-cycle progression and appears to be a pre-requisite for malignant transformation and implantation. A higher risk for cervical, ovarian and endometrial cancer is related to high IGF-I levels in post- and premenopausal women. Plasma IGF-I levels are higher in cases of severe endometriosis; however, in endometriosis IGF-I levels locally in the endometrium are reduced (Druckmann & Rohr 2002).

Insensitivity to anti-proliferative signals
Cell division relies on the activation of cyclins (e.g. cyclin D1), which bind to cyclin-dependent kinases (cdk) to induce cell-cycle progression towards S phase and later to initiate mitosis. Since uncontrolled cdk activity is often the cause of human cancer, their function is tightly regulated by cdk inhibitors (e.g. p21 and p27 Cip/Kip proteins). For example, increased expression of cyclin D1 and cdk occurs in breast cancer and is associated with poor outcome.

At the cellular level, differences in expression of p27Kip1 protein (cdk inhibitor) in active and inactive endometriotic lesions (Matsuzaki et al. 2001a), coupled with increased p21 expression in endometriomas compared with benign and malignant ovarian tumours (Fauvet et al. 2003), suggest a role for increased cdk activity through reduced cell-cycle inhibitor activity, which is an imbalance frequently seen in cancer.

At the tissue level, endometriosis may resist the anti-proliferative effect of progesterone by the predominant expression of the inhibitory PR-A isoform instead of the stimulatory PR-B isoform (Attia et al. 2000).

Resistance to apoptosis
Malignancy commonly displays overexpression of anti-apoptotic (Bcl-2), under-expression of pro-apoptotic (BAX) factors, and inactivation of p53 gene (p53 is a tumour suppressor gene (TSG) whose protein (TP53) is pro-apoptotic) through mutation. Similarly, endometriotic lesions have also evolved strategies to evade apoptosis by: (i) increased Bcl-2, and decreased BAX (Meresman et al. 2000); (ii) up-regulation of survivin and matrix metalloproteinases (MMPs) (Ria et al. 2002, Ueda et al. 2002a); (iii) elevated soluble Fas ligand (FasL) and interleukin (IL)-8 in endometriotic peritoneal fluid (the increased FasL expression by IL-8 may induce apoptosis of T lymphocytes and thus enable endometriosis to evade immune-mediated cell death (Garcia-Velasco et al. 2002)); and (iv) germline (Chang et al. 2002) and somatically acquired (Bischoff et al. 2002) inactivating mutations of p53 gene.

Limitless replicative potential
With each replicative cycle, telomeres (repetitive DNA sequences capping each chromosome) become progressively shorter, eventually resulting in cell senescence and cell death. Tumours commonly express the enzyme telomerase, which protects the telomeres from shortening and thus preventing ‘cell ageing’. Oestrogen and progesterone stimulate, while tamoxifen and wild-type (normal variant) p53 inhibit, telomerase activity in breast and endometrial cancer cells (Vidal et al. 2002, Wang et al. 2002). Although there are no published studies examining telomerase function in endometriosis, it is notable that estrogen-dependent neoplasms are potentially susceptible to telomerase control.

Sustained angiogenesis
Pathological angiogenesis, immune cell suppression and immune cell activation co-exist in endometriosis and cancer processes (Folkman 2002, Gazvani & Templeton 2002). Genetically transmitted or environmentally induced (e.g. exposure to dioxins) alterations in the angiogenic and/or immune response may predispose women to the ectopic implantation of endometrial cells, transported into the peritoneal cavity by retrograde menstruation, which thereby leads to endometriosis. Significantly, both cancer and endometriosis share some of the mediators implicated in this ‘inflammatory angiogenesis’ model. Furthermore, the genes of these mediators exhibit genetic polymorphisms that predispose either to endometriosis (e.g. intercellular adhesion molecule-1, IL-6 and IL-10 gene promoters) (Kitawaki et al. 2002, Vigano et al. 2003, Wieser et al. 2003) or to cancer (e.g. IL-6, IL-8, tumour necrosis factor (TNF)-, NFB-1, and peroxisome proliferator-activated receptor- genes) (Landi et al. 2003).

Anti-angiogenic therapy involves the inhibition of pro-angiogenic factors (e.g. anti-vascular endothelial growth factor (VEGF) monoclonal antibodies) or activation of endogenous inhibitors of angiogenesis (e.g. endostatin and angiostatin). Pre-clinical studies have shown that endostatin effectively inhibits tumour growth and shrinks existing tumour blood vessels. Phase 1 clinical cancer trials of endostatin and angiostatin are ongoing, and preliminary results show minimal toxicities. Similarly, anti-angiogenic strategies for treating endometriosis exist, but are still at the experimental phase (Hull et al. 2003). Soluble truncated receptor (Flt-1) and an affinity-purified antibody to human VEGF-A, significantly inhibited the growth of endometrial explants in a mouse in vivo model of endo-metriosis by disrupting the vascular supply. Gene transfection (using a replication-deficient adenovirus vector AdAngiostatin) of the endogenous angiogenesis inhibitor angiostatin to the peritoneum of a mouse was successful in treating a mouse in vivo model of endometriosis (Dabrosin et al. 2002).

Tissue invasion and metastasis
The ability to invade through the basement membranes characterises the transition from non-invasive to invasive cancer. Tumours secret proteases (e.g. MMPs) to degrade the basement membrane and surrounding stroma. Expression of MMP-2 and MMP-9 is correlated with grade and stage of many cancers. Likewise, MMP activity is up-regulated in endometriotic lesions (Mizumoto et al. 2002).

De-regulation of cell adherence signalling involving integrins, ß-catenin, E-cadherin and P-cadherin has been demonstrated in the genesis of a number of malignancies (Morin 1999), and has also been implicated in endometriosis aetiopathogenesis (Scotti et al. 2000, Witz et al. 2000, GT Chen et al. 2002, Ueda et al. 2002b). ß-Catenin mutations have been identified in endometrial and ovarian endometrioid cancers (Palacios & Gamallo 1998, Moreno-Bueno et al. 2001) but have not been looked for in endometriosis. Cytokeratin-positive and E-cadherin-negative endometriotic cells have an invasive phenotype in an in vitro collagen invasion assay similar to metastatic carcinoma cells (Starzinski-Powitz et al. 1999).

Genomic instability
The classic model of malignant transformation of the cell involves the stepwise acquisition of multiple genetic alterations, which confers a clonal selective advantage at each step, predisposing to the next step (Lengauer et al. 1998). This is often accompanied by activation of protooncogenes to oncogenes (transformation of normal cellular growth, proliferation and differentiation genes) and inactivation of TSGs (genes that encode for proteins which inhibit excess cellular proliferation and malignant transformation). The genetic alterations can occur at different levels and include single nucleotides, small stretches of DNA (microsatellites), whole genes, chromosomal components or whole chromosomes. The genetic alterations can be intragene or epigenetic (e.g. gene silencing by promoter hypermethylation). Six principal genetic mechanisms have been identified to contribute to genomic instability in cancer, but only the first three have been looked for in endometriosis:

1. Gain in oncogenic activity
   
2. Inactivation of TSG (loss of both gene copies of allele confers functional loss), or inactivation of haploinsufficient TSG (loss of only a single gene copy of allele confers functional loss)
   
3. Anomalies in DNA mismatch repair enzymes, identified by microsatellite instability (MSI)
   
4. Inactivation of genes that monitor genomic instability at cell cycling (e.g. mitotic spindle assembly checkpoint genes)
   
5. Telomere dysfunction (provokes chromosomal aberrations initiating carcinogenesis) and telomerase-mediated telomere maintenance (enables cells to achieve a fully malignant endpoint and metastasis)
   
6. Hypermethylation
   

These mechanisms often act in synergy to promote genomic instability and tumour cell proliferation. For example, deficiency of the TSG p53 alters the cellular response to DNA damage, in that it leaves cells with attenuated DNA damage checkpoint controls and a reduced propensity for apoptotic cell death. Thus, although the DNA repair capacity of these cells is reduced, survival is increased. This promotes genomic instability and contributes to the resistance of p53-deficient cells to cytotoxic agents.

Importantly, pre-malignant lesions display similar genetic aberrations to established cancer. Loss of mismatch repair enzyme activity, and loss of PTEN (phosphatase and tensin homologue gene) and p53 TSGs frequently occurs in premalignant and malignant stages of breast, endometrial and ovarian carcinomas (Obata et al. 1998, Codegoni et al. 1999, Saito et al. 2000, Lalloo & Evans 2001, Mills et al. 2001). Furthermore, epithelial–stromal interactions are important in the tumour microenvironment and tumour development. Mutually exclusive germline mutations in PTEN and TP53 have been reported in epithelial and stromal cells of breast cancer underlying the co-dependence of these two cell types in tumourigenesis (Kurose et al. 2002).

In a similar manner, endometriosis demonstrates somatically acquired genetic alterations analogous to those found in cancer, resulting in the clonal expansion of genetically abnormal cells. The genetic evidence supporting the ‘preneoplastic’ state of endometriosis involves the following:

Monoclonality
Most neoplasms are monoclonal in origin and evidence for monoclonality of endometriosis has been demonstrated in several studies (Jimbo et al. 1997, Tamura et al. 1998, Wu et al. 2003), although these findings have been challenged recently (Mayr et al. 2003).

Comparative genomic hybridisation (CGH)
CGH has shown over-representation (increased copy-number) of chromosomes 1, 2, 3, 5, 6p, 7, 16, 17q, 20, 21q and 22q in an endometriosis cell culture line FbEM-1, while chromosomes 5p, 6q, 9q, 11p, 12, 13q, 18 and X were under-represented. CGH repeated in endometriotic tissue revealed loss of DNA copy number on 1p, 22q and chromosome X, while gain on 6p and 17q. Fluorescent in situ hybridisation (FISH) analysis confirmed that the gain at 17q includes amplification of the proto-oncogene HER-2/neu (Gogusev et al. 1999, 2000).

FISH
FISH analysis of late-stage endometriotic lesions showed monosomy of chromosome 17, and loss of TP53 (17p13.1) locus. Because not all endometriotic cells displayed this genetic alteration it was suggested that this was a somatically acquired mutation, perhaps occurring in mainly advanced endometriosis states (Kosugi et al. 1999, Bischoff et al. 2002).

Loss of heterozygosity (LOH)
LOH commonly indicates regions of TSG inactivation, and has been identified in endometriosis and endometriosis-derived cell lines at 5q, 6q, 9p, 10q, 11q, 22q, p16 (Ink4), galactose-1-phosphate uridy ltransferase, p53 and apolipoprotein All (Jiang et al. 1996, Obata & Hoshiai 2000, Thomas & Campbell 2000, Goumenou et al. 2001). Importantly, cases with ovarian cancer adjacent to endometriosis or arising from endometriosis showed common genetic LOH alterations in the endometriosis and cancer, indicating a possible malignant genetic transition spectrum between endometriosis and cancer (Jiang et al. 1998, Campbell & Thomas 2001).

MSI
Hypermethylation of hMLH1 (whose gene product is a component of the DNA mismatch repair pathway), with concurrent absence of hMLH1 protein expression, is noted in 8.6% of endometriotic lesions (Martini et al. 2002).

Somatic mutations in TSGs
Mutations of PTEN, a TSG, were identified in 20% of ovarian endometrioid carcinomas (EAOC and sporadic) and 20% of solitary endometrial cysts, suggesting that inactivation of the PTEN is an early event in the malignant transformation of endometriotic implants (Sato et al. 2000). A separate study identified reduced PTEN protein expression in 15% of endometriosis cases (Martini et al. 2002).

Germline mutations in TSGs
As stated earlier, there are germline (Chang et al. 2002) and somatically acquired (Bischoff et al. 2002) inactivating mutations of the p53 gene.

Evidence from EAOCs arising from endometriosis
Endometrioid EAOCs arising from endometriosis show higher expression of p53 and c-erB-2 oncoproteins than similar ovarian endometrioid cancers without endometriosis (Prefumo et al. 2003). The different pattern of expression in the two groups suggests different molecular pathways and could explain variations in cancer subtype and prognosis between the two groups (Erzen et al. 2001, Modesitt et al. 2002).

	Implications of the ‘endometriosis is a neoplastic process’ hypothesis

Top Abstract What is endometriosis? Endometriosis and the neoplastic... Clinicopathological similarities... Molecular similarities of... Implications of the... Molecular re-classification of... Conclusion Acknowledgements References

 
In summary, there is extensive clinicopathological, molecular and genetic evidence supporting the hypothesis that endometriosis is a neoplastic process with a potential for malignant transformation. Like sporadic cancer (Balmain et al. 2003), endometriosis may be considered to arise by complex interactions between inherited germline polygenic low-penetrance alleles (polymorphisms) (Hadfield et al. 2001, Zondervan et al. 2001), somatically acquired genetic alterations (Campbell & Thomas 2001), environmental factors (Birnbaum & Cummings 2002), and the processes of the hallmarks of cancer described earlier. A visual summary of the main pathways of this hypothesis is shown in Fig. 2. Acceptance of this hypothesis permits the use of investigative strategies that have proved successful in defining the molecular processes that underlie cancer: genomic, transcriptomic and proteomic profiling. Thus the analysis of genetic changes associated with normal endometrium, non-atypical, atypical and EAOC lesions could define the sequential changes involved in the initiation, proliferation and malignant transformation of endometriosis.

View larger version (44K): [in this window] [in a new window]   Figure 2 Proposed model for endometriosis pathogenesis based on cancer framework.

Transcriptomic profiling of endometriosis
Gene expression microarray analysis has been demonstrated to provide better subclassification and prognostic predictions than conventional histopathology in many cancers (van de Vijver et al. 2002, Liu 2003). Notably, DNA microarrays have been recently undertaken in endometriosis (Eyster et al. 2002, Kao et al. 2003), endometrial cancer (Mutter et al. 2001, Risinger et al. 2003), normal endometrium (Borthwick et al. 2003), and endometrium of women with endometriosis (H-W Chen et al. 2002). Indeed, the combination of CGH and expression microarrays (Bayani et al. 2002, Tay et al. 2003), or SNP microarrays could be valuable for prioritising the analysis of candidate TSGs and proto-oncogenes (Dobrin & Stephan 2003).

Proteomic profiling of endometriosis
This is a complementary approach to genomic profiling. Immunohistochemistry can be used to provide a limited proteomic profile, but recently developed high throughput proteomic technology (e.g. mass spectrometry, matrix-assisted laser desorption and ionisation time-of-flight, surface enhanced laser desorption and time-of-flight, and protein microarrays) promise the capacity to define a wide-ranging proteomic profile (Dobrin & Stephan 2003).

	Molecular re-classification of endometriosis

Top Abstract What is endometriosis? Endometriosis and the neoplastic... Clinicopathological similarities... Molecular similarities of... Implications of the... Molecular re-classification of... Conclusion Acknowledgements References

 
Genomic and proteomic profiling should provide new insights into the pathogenesis of endometriosis and malignant transformation. A better understanding of reproductive tract molecular pathology, and the temporo–spatial relationship of endometriosis with clinical sequelae, allows the development of novel therapies targeted to the aberrant process at the molecular level, rather than focussing solely on endometriotic lesion eradication. Examples of agents under investigation for endometriosis and cancer using the cancer hallmark model are listed in Table 2. However, it should be noted there is considerable overlap in the endocrine, metabolic, angiogenic, immunological roles of the mediators implicated in endometriosis and cancer. Thus great care should be taken in delivering the agent and selecting the mechanism to be targeted, in order to avoid systemic compromise, or impairing other critical aspects of reproductive tract function (e.g. fertility).

	Conclusion

Top Abstract What is endometriosis? Endometriosis and the neoplastic... Clinicopathological similarities... Molecular similarities of... Implications of the... Molecular re-classification of... Conclusion Acknowledgements References

 
Endometriosis possesses many features of a benign neoplastic process with the potential for malignant transformation. Application of strategies used in the investigation of cancer should provide new insights into the classification and molecular pathogenesis and of endometriosis.

	Acknowledgements

Top Abstract What is endometriosis? Endometriosis and the neoplastic... Clinicopathological similarities... Molecular similarities of... Implications of the... Molecular re-classification of... Conclusion Acknowledgements References

 
This work, and R V, are supported by grants from the Royal College of Obstetricians and Gynaecologists Endometriosis Millennium Fund 2003, and a Springboard Fellowship funded jointly by Birmingham Women’s Hospital and the University of Birmingham.

	Footnotes

 
Received 26 September 2003
First decision 13 November 2003
Accepted 18 December 2003

	References

Top Abstract What is endometriosis? Endometriosis and the neoplastic... Clinicopathological similarities... Molecular similarities of... Implications of the... Molecular re-classification of... Conclusion Acknowledgements References

 

Al Fozan H & Tulandi T 2003 Left lateral predisposition of endometriosis and endometrioma. Obstetrics and Gynecology 101 164–166.[Abstract/Free Full Text]

Arvanitis DA, Koumantakis GE, Goumenou AG, Matalliotakis IM, Koumantakis EE & Spandidos DA 2003 CYP1A1, CYP19, and GSTM1 polymorphisms increase the risk of endometriosis. Fertility and Sterility 79 (Suppl 1) 702–709.[CrossRef][ISI][Medline]

Attia GR, Zeitoun K, Edwards D, Johns A, Carr BR & Bulun SE 2000 Progesterone receptor isoform A but not B is expressed in endometriosis. Journal of Clinical Endocrinology and Metabolism 85 2897–2902.[Abstract/Free Full Text]

Ballouk F, Ross JS & Wolf BC 1994 Ovarian endometriotic cysts. An analysis of cytologic atypia and DNA ploidy patterns. American Journal of Clinical Pathology 102 415–419.[ISI][Medline]

Balmain A, Gray J & Ponder B 2003 The genetics and genomics of cancer. Nature Genetics 33 (Suppl) 238–244.[CrossRef][ISI][Medline]

Baranova H, Canis M, Ivaschenko T, Albuisson E, Bothorishvilli R, Baranov V, Malet P & Bruhat MA 1999 Possible involvement of arylamine N-acetyltransferase 2, glutathione S-transferases M1 and T1 genes in the development of endometriosis. Molecular Human Reproduction 5 636–641.[Abstract/Free Full Text]

Baxter SW, Thomas EJ & Campbell IG 2001 GSTM1 null polymorphism and susceptibility to endometriosis and ovarian cancer. Carcinogenesis 22 63–65.[Abstract/Free Full Text]

Bayani J, Brenton JD, Macgregor PF, Beheshti B, Albert M, Nallainathan D, Karaskova J, Rosen B, Murphy J, Laframboise S, Zanke B & Squire JA 2002 Parallel analysis of sporadic primary ovarian carcinomas by spectral karyotyping, comparative genomic hybridization, and expression microarrays. Cancer Research 62 3466–3476.[Abstract/Free Full Text]

Bayramoglu H & Duzcan E 2001 Atypical epithelial changes and mutant p53 gene expression in ovarian endometriosis. Pathology Oncology Research 7 33–38.[Medline]

Birnbaum LS & Cummings AM 2002 Dioxins and endometriosis: a plausible hypothesis. Environmental Health Perspectives 110 15–21.[ISI][Medline]

Bischoff FZ, Heard M & Simpson JL 2002 Somatic DNA alterations in endometriosis: high frequency of chromosome 17 and p53 loss in late-stage endometriosis. Journal of Reproductive Immunology 55 49–64.[CrossRef][ISI][Medline]

Borthwick JM, Charnock-Jones DS, Tom BD, Hull ML, Teirney R, Phillips SC & Smith SK 2003 Determination of the transcript profile of human endometrium. Molecular Human Reproduction 9 19–33.[Abstract/Free Full Text]

Brinton LA, Gridley G, Persson I, Baron J & Bergqvist A 1997 Cancer risk after a hospital discharge diagnosis of endometriosis [Comment]. American Journal of Obstetrics and Gynecology 176 572–579.[CrossRef][ISI][Medline]

Bulun SE, Zeitoun KM & Kilic G 2000a Expression of dioxin-related transactivating factors and target genes in human eutopic endometrial and endometriotic tissues. American Journal of Obstetrics and Gynecology 182 767–775.[CrossRef][ISI][Medline]

Bulun SE, Zeitoun KM, Takayama K & Sasano H 2000b Estrogen biosynthesis in endometriosis: molecular basis and clinical relevance. Journal of Molecular Endocrinology 25 35–42.[Abstract]

Campbell IG & Thomas EJ 2001 Endometriosis: candidate genes. Human Reproduction Update 7 15–20.[Abstract/Free Full Text]

Chang CC, Hsieh YY, Tsai FJ, Tsai CH, Tsai HD & Lin CC 2002 The proline form of p53 codon 72 polymorphism is associated with endometriosis. Fertility and Sterility 77 43–45.[CrossRef][ISI][Medline]

Chen GT, Tai CT, Yeh LS, Yang TC & Tsai HD 2002 Identification of the cadherin subtypes present in the human peritoneum and endometriotic lesions: potential role for P-cadherin in the development of endometriosis. Molecular Reproduction and Development 62 289–294.[CrossRef][ISI][Medline]

Chen H-W, Li H-N, Lee Y-T, Yang P-C, Chen JJW & Tzeng C-R 2002 Global analysis of differentially expressed genes in endometrium with or without endometriosis using human cDNA microarray. Fertility and Sterility 77 S16.

Codegoni AM, Bertoni F, Colella G, Caspani G, Grassi L, D’Incalci M & Broggini M 1999 Microsatellite instability and frameshift mutations in genes involved in cell cycle progression or apoptosis in ovarian cancer. Oncology Research 11 297–301.[ISI][Medline]

Dabrosin C, Gyorffy S, Margetts P, Ross C & Gauldie J 2002 Therapeutic effect of angiostatin gene transfer in a murine model of endometriosis. American Journal of Pathology 161 909–918.[Abstract/Free Full Text]

Dobrin SE & Stephan DA 2003 Integrating microarrays into disease-gene identification strategies. Expert Review of Molecular Diagnostics 3 375–385.[CrossRef][ISI][Medline]

Donnez J, Squifflet J, Pirard C, Jadoul P, Wyns C & Smets M 2002 The efficacy of medical and surgical treatment of endometriosis-associated infertility and pelvic pain. Gynecologic and Obstetric Investigation 54 (Suppl 1) 2–7.[ISI][Medline]

Druckmann R & Rohr UD 2002 IGF-I in gynaecology and obstetrics: update 2002. Maturitas 41 (Suppl 1) S65–S83.[CrossRef][ISI][Medline]

Erzen M & Kovacic J 1998 Relationship between endometriosis and ovarian cancer. European Journal of Gynaecological Oncology 19 553–555.[ISI][Medline]

Erzen M, Rakar S, Klancar B & Syrjanen K 2001 Endometriosis-associated ovarian carcinoma (EAOC): an entity distinct from other ovarian carcinomas as suggested by a nested case-control study. Gynecologic Oncology 83 100–108.[CrossRef][ISI][Medline]

Eskenazi B, Mocarelli P, Warner M, Samuels S, Vercellini P, Olive D, Needham LL, Patterson DG Jr, Brambilla P, Gavoni N, Casalini S, Panazza S, Turner W & Gerthoux PM 2002 Serum dioxin concentrations and endometriosis: a cohort study in Seveso, Italy. Environmental Health Perspectives 110 629–634.[ISI][Medline]

Eyster KM, Boles AL, Brannian JD & Hansen KA 2002 DNA microarray analysis of gene expression markers of endometriosis. Fertility and Sterility 77 38–42.[CrossRef][ISI][Medline]

Fauvet R, Poncelet C, Hugol D, Lavaur A, Feldmann G & Darai E 2003 Expression of apoptosis-related proteins in endometriomas and benign and malignant ovarian tumours. Virchows Archiv 443 38–43.[CrossRef][ISI][Medline]

Folkman J 2002 Role of angiogenesis in tumor growth and metastasis. Seminars in Oncology 29 (Suppl 16) 15–18.[ISI][Medline]

Fukunaga M, Nomura K, Ishikawa E & Ushigome S 1997 Ovarian atypical endometriosis: its close association with malignant epithelial tumours. Histopathology 30 249–255.[CrossRef][ISI][Medline]

Garcia-Velasco JA, Mulayim N, Kayisli UA & Arici A 2002 Elevated soluble Fas ligand levels may suggest a role for apoptosis in women with endometriosis. Fertility and Sterility 78 855–859.[CrossRef][ISI][Medline]

Gazvani R & Templeton A 2002 Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosis. Reproduction 123 217–226.[Abstract]

Gogusev J, Bouquet DJ, Telvi L, Doussau M, du Manoir S, Stojkoski A & Levardon M 1999 Detection of DNA copy number changes in human endometriosis by comparative genomic hybridization. Human Genetics 105 444–451.[CrossRef][ISI][Medline]

Gogusev J, Bouquet DJ, Telvi L, Doussau M, du Manoir S, Stojkoski A & Levardon M 2000 Genetic abnormalities detected by comparative genomic hybridization in a human endometriosis-derived cell line. Molecular Human Reproduction 6 821–827.[Abstract/Free Full Text]

Goumenou AG, Arvanitis DA, Matalliotakis IM, Koumantakis EE & Spandidos DA 2001 Microsatellite DNA assays reveal an allelic imbalance in p16(Ink4), GALT, p53, and APOA2 loci in patients with endometriosis. Fertility and Sterility 75 160–165.[CrossRef][ISI][Medline]

Hadfield RM, Manek S, Weeks DE, Mardon HJ, Barlow DH & Kennedy SH 2001 Linkage and association studies of the relationship between endometriosis and genes encoding the detoxification enzymes GSTM1, GSTT1 and CYP1A1. Molecular Human Reproduction 7 1073–1078.[Abstract/Free Full Text]

Hanahan D & Weinberg RA 2000 The hallmarks of cancer. Cell 100 57–70.[CrossRef][ISI][Medline]

Hoque MO, Lee CC, Cairns P, Schoenberg M & Sidransky D 2003 Genome-wide genetic characterization of bladder cancer: a comparison of high-density single-nucleotide polymorphism arrays and PCR-based microsatellite analysis. Cancer Research 63 2216–2222.[Abstract/Free Full Text]

Hull ML, Charnock-Jones DS, Chan CL, Bruner-Tran KL, Osteen KG, Tom BD, Fan TP & Smith SK 2003 Antiangiogenic agents are effective inhibitors of endometriosis. Journal of Clinical Endocrinology and Metabolism 88 2889–2899.[Abstract/Free Full Text]

Jiang X, Hitchcock A, Bryan EJ, Watson RH, Englefield P, Thomas EJ & Campbell IG 1996 Microsatellite analysis of endometriosis reveals loss of heterozygosity at candidate ovarian tumor suppressor gene loci. Cancer Research 56 3534–3539.[Abstract/Free Full Text]

Jiang X, Morland SJ, Hitchcock A, Thomas EJ & Campbell IG 1998 Allelotyping of endometriosis with adjacent ovarian carcinoma reveals evidence of a common lineage. Cancer Research 58 1707–1712.[Abstract/Free Full Text]

Jimbo H, Hitomi Y, Yoshikawa H, Yano T, Momoeda M, Sakamoto A, Tsutsumi O, Taketani Y & Esumi H 1997 Evidence for monoclonal expansion of epithelial cells in ovarian endometrial cysts. American Journal of Pathology 150 1173–1178.[Abstract]

Kao LC, Germeyer A, Tulac S, Lobo S, Yang JP, Taylor RN, Osteen K, Lessey BA & Giudice LC 2003 Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology 144 2870–2881.[Abstract/Free Full Text]

Kitawaki J, Obayashi H, Ishihara H, Koshiba H, Kusuki I, Kado N, Tsukamoto K, Hasegawa G, Nakamura N & Honjo H 2001 Oestrogen receptor-alpha gene polymorphism is associated with endometriosis, adenomyosis and leiomyomata. Human Reproduction 16 51–55.[Abstract/Free Full Text]

Kitawaki J, Obayashi H, Ohta M, Kado N, Ishihara H, Koshiba H, Kusuki I, Tsukamoto K, Hasegawa G, Nakamura N, Yoshikawa T & Honjo H 2002 Genetic contribution of the interleukin-10 promoter polymorphism in endometriosis susceptibility. American Journal of Reproductive Immunology 47 12–18.[CrossRef]

Kosugi Y, Elias S, Malinak LR, Nagata J, Isaka K, Takayama M, Simpson JL & Bischoff FZ 1999 Increased heterogeneity of chromosome 17 aneuploidy in endometriosis. American Journal of Obstetrics and Gynecology 180 792–797.[CrossRef][ISI][Medline]

Kronqvist P, Kuopio T, Jalava P & Collan Y 2002 Morphometrical malignancy grading is a valuable prognostic factor in invasive ductal breast cancer. British Journal of Cancer 87 1275–1280.[CrossRef][ISI][Medline]

Kurose K, Gilley K, Matsumoto S, Watson PH, Zhou XP & Eng C 2002 Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nature Genetics 32 355–357.[CrossRef][ISI][Medline]

LaGrenade A & Silverberg SG 1988 Ovarian tumors associated with atypical endometriosis. Human Pathology 19 1080–1084.[ISI][Medline]

Lalloo F & Evans G 2001 Molecular genetics and endometrial cancer. Best Practice and Research in Clinical Obstetrics and Gynaecology 15 355–363.[CrossRef]

Landi S, Moreno V, Gioia-Patricola L, Guino E, Navarro M, de Oca J, Capella G & Canzian F 2003 Association of common polymorphisms in inflammatory genes interleukin (IL)6, IL8, tumor necrosis factor alpha, NFKB1, and peroxisome proliferator-activated receptor gamma with colorectal cancer. Cancer Research 63 3560–3566.[Abstract/Free Full Text]

Lapp T 2000 ACOG issues recommendations for the management of endometriosis. American College of Obstetricians and Gynecologists. American Family Physician 62 1431, 1434.[ISI][Medline]

Lebovic DI, Mueller MD & Taylor RN 2001 Immunobiology of endometriosis. Fertility and Sterility 75 1–10.[CrossRef][ISI][Medline]

Lengauer C, Kinzler KW & Vogelstein B 1998 Genetic instabilities in human cancers. Nature 396 643–649.[CrossRef][Medline]

Liu ET 2003 Classification of cancers by expression profiling. Current Opinion in Genetics and Development 13 97–103.[CrossRef][ISI][Medline]

Marnellos G 2003 High-throughput SNP analysis for genetic association studies. Current Opinion in Drug Discovery and Development 6 317–321.

Martini M, Ciccarone M, Garganese G, Maggiore C, Evangelista A, Rahimi S, Zannoni G, Vittori G & Larocca LM 2002 Possible involvement of hMLH1, p16(INK4a) and PTEN in the malignant transformation of endometriosis. International Journal of Cancer 102 398–406.[CrossRef][ISI][Medline]

Matsuzaki S, Canis M, Murakami T, Dechelotte P, Bruhat MA & Okamura K 2001a Expression of the cyclin-dependent kinase inhibitor p27Kip1 in eutopic endometrium and peritoneal endometriosis. Fertility and Sterility 75 956–960.[CrossRef][ISI][Medline]

Matsuzaki S, Murakami T, Uehara S, Canis M, Sasano H & Okamura K 2001b Expression of estrogen receptor alpha and beta in peritoneal and ovarian endometriosis. Fertility and Sterility 75 1198–1205.[CrossRef][ISI][Medline]

Mayr D, Amann G, Siefert C, Diebold J & Anderegg B 2003 Does endometriosis really have premalignant potential? A clonal analysis of laser-microdissected tissue. FASEB Journal 17 693–695.[Abstract/Free Full Text]

Meresman GF, Vighi S, Buquet RA, Contreras-Ortiz O, Tesone M & Rumi LS 2000 Apoptosis and expression of Bcl-2 and Bax in eutopic endometrium from women with endometriosis. Fertility and Sterility 74 760–766.[CrossRef][ISI][Medline]

Mills GB, Lu Y, Fang X, Wang H, Eder A, Mao M, Swaby R, Cheng KW, Stokoe D, Siminovitch K, Jaffe R & Gray J 2001 The role of genetic abnormalities of PTEN and the phosphatidylinositol 3-kinase pathway in breast and ovarian tumorigenesis, prognosis, and therapy. Seminars in Oncology 28 125–141.[CrossRef][ISI][Medline]

Mizumoto H, Saito T, Ashihara K, Nishimura M, Takehara M, Tanaka R, Ito E & Kudo R 2002 Expression of matrix metalloproteinases in ovarian endometriomas: immunohistochemical study and enzyme immunoassay. Life Sciences 71 259–273.[CrossRef][ISI][Medline]

Modesitt SC, Tortolero-Luna G, Robinson JB, Gershenson DM & Wolf JK 2002 Ovarian and extraovarian endometriosis-associated cancer. Obstetrics and Gynecology 100 788–795.[Abstract/Free Full Text]

Moreno-Bueno G, Gamallo C, Perez-Gallego L, de Mora JC, Suarez A & Palacios J 2001 beta-Catenin expression pattern, beta-catenin gene mutations, and microsatellite instability in endometrioid ovarian carcinomas and synchronous endometrial carcinomas. Diagnostic Molecular Pathology 10 116–122.[CrossRef][ISI][Medline]

Morin PJ 1999 beta-Catenin signaling and cancer. Bioessays 21 1021–1030.[CrossRef][ISI][Medline]

Mutter GL, Baak JP, Fitzgerald JT, Gray R, Neuberg D, Kust GA, Gentleman R, Gullans SR, Wei LJ & Wilcox M 2001 Global expression changes of constitutive and hormonally regulated genes during endometrial neoplastic transformation. Gynecologic Oncology 83 177–185.[CrossRef][ISI][Medline]

Nakago S, Hadfield RM, Zondervan KT, Mardon H, Manek S, Weeks DE, Barlow D & Kennedy S 2001 Association between endometriosis and N-acetyl transferase 2 polymorphisms in a UK population. Molecular Human Reproduction 7 1079–1083.[Abstract/Free Full Text]

National Statistics 2003 Cancer trends in England and Wales 1950–1999. (UK Government) http://www.statistics.gov.uk

Nishida M, Watanabe K, Sato N & Ichikawa Y 2000 Malignant transformation of ovarian endometriosis. Gynecologic and Obstetric Investigation 50 (Suppl 1) 18–25.[CrossRef][ISI][Medline]

Obata K & Hoshiai H 2000 Common genetic changes between endometriosis and ovarian cancer. Gynecologic and Obstetric Investigation 50 (Suppl 1) 39–43.[Medline]

Obata K, Morland SJ, Watson RH, Hitchcock A, Chenevix-Trench G, Thomas EJ & Campbell IG 1998 Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors. Cancer Research 58 2095–2097.[Abstract/Free Full Text]

Ogawa S, Kaku T, Amada S, Kobayashi H, Hirakawa T, Ariyoshi K, Kamura T & Nakano H 2000 Ovarian endometriosis associated with ovarian carcinoma: a clinicopathological and immunohisto-chemical study. Gynecologic Oncology 77 298–304.[CrossRef][ISI][Medline]

Ohtake F, Takeyama K, Matsumoto T, Kitagawa H, Yamamoto Y, Nohara K, Tohyama C, Krust A, Mimura J, Chambon P, Yanagisawa J, Fujii-Kuriyama Y & Kato S 2003 Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature 423 545–550.[CrossRef][Medline]

Oral E, Ilvan S, Tustas E, Korbeyli B, Bese T, Demirkiran F, Arvas M & Kosebay D 2003 Prevalence of endometriosis in malignant epithelial ovary tumours. European Journal of Obstetrics and Gynecology and Reproductive Biology 109 97–101.[CrossRef]

Palacios J & Gamallo C 1998 Mutations in the beta-catenin gene (CTNNB1) in endometrioid ovarian carcinomas. Cancer Research 58 1344–1347.[Abstract/Free Full Text]

Pecorelli S, Odicino F, Maisonneuve P, Creasman W, Shepherd J, Sideri M & Benedet J 1998 Carcinoma of the ovary. Annual report on the results of treatment in gynaecological cancer. Journal of Epidemiology and Biostatistics 3 75–102.

Prefumo F, Venturini PL & Fulcheri E 2003 Analysis of p53 and c-erbB-2 expression in ovarian endometrioid carcinomas arising in endometriosis. International Journal of Gynecological Pathology 22 83–88.[CrossRef][ISI][Medline]

Regidor PA, Wagner I, Ruwe M, Regidor M & Schindler AE 2002 Morphometric analyses of endometriotic tissues to determine their grade of activity. Gynecological Endocrinology 16 235–243.[CrossRef][ISI][Medline]

Ria R, Loverro G, Vacca A, Ribatti D, Cormio G, Roccaro AM & Selvaggi L 2002 Angiogenesis extent and expression of matrix metalloproteinase-2 and -9 agree with progression of ovarian endometriomas. European Journal of Clinical Investigation 32 199–206.[CrossRef][ISI][Medline]

Risinger JI, Maxwell GL, Chandramouli GV, Jazaeri A, Aprelikova O, Patterson T, Berchuck A & Barrett JC 2003 Microarray analysis reveals distinct gene expression profiles among different histologic types of endometrial cancer. Cancer Research 63 6–11.[Abstract/Free Full Text]

Roberts CP & Rock JA 2003 The current staging system for endometriosis: does it help? Obstetrics and Gynecology Clinics of North America 30 115–132.[CrossRef][ISI][Medline]

Saito M, Okamoto A, Kohno T, Takakura S, Shinozaki H, Isonishi S, Yasuhara T, Yoshimura T, Ohtake Y, Ochiai K, Yokota J & Tanaka T 2000 Allelic imbalance and mutations of the PTEN gene in ovarian cancer. International Journal of Cancer 85 160–165.[ISI][Medline]

Sampson JA 1925 Endometrial carcinoma of the ovary arising in endometrial tissue in that organ. Archives of Surgery 10 1–72.[CrossRef][ISI]

Sato N, Tsunoda H, Nishida M, Morishita Y, Takimoto Y<