Toward understanding the natural history of ovarian carcinoma development: a clinicopathological approach

Horiuchi, Akiko; Itoh, Kazuko; Shimizu, Morihito; Nakai, Ikuko; Yamazaki, Teruyuki; Kimura, Koutarou D.; Suzuki, Akihiko; Shiozawa, I; Ueda, Noritane; Konishi, Ikuo

doi:10.1016/s0090-8258(02)00104-x

Cited by 82 publications

(72 citation statements)

References 22 publications

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“…Benign ovarian neoplasms are almost always removed as soon as they are detected, and therefore their natural history is largely unknown. Evidence of a benign to malignant transformation is largely circumstantial and includes: (1) a generally observed older-age incidence of carcinomas than benign tumors of the same cell type; in that most investigators have reported progressively higher mean ages for benign, borderline, and invasive tumors in both the serous and mucinous categories, with average ages for the combined categories 44, 48 and 56 years, respectively; 51 (2) a reported five-fold increase in the frequency of benign epithelial tumors in first-and second-degree relatives of women with ovarian carcinoma; 52 (3) the presence of enlarging ovarian cysts on ultrasound prior to the development of carcinoma, 53 and (4) the frequent observation of various combinations of benign, borderline, and invasive neoplasia within the same specimen; 54,55 Morphologic Data…”

Section: Benign and Borderline Serous Tumors As Precursor Lesionsmentioning

confidence: 99%

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Origins and molecular pathology of ovarian cancer

2005

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Epithelial ovarian cancer comprises the majority of malignant ovarian tumors in adult women. These neoplasms are classified into distinct morphologic categories based on the appearance of the epithelium into tumors of serous, mucinous, endometrioid, clear cell, transitional, squamous, mixed and undifferentiated type. Current data indicate that each of these histologic subtypes is associated with distinct morphologic and molecular genetic alterations: high-grade serous and possibly endometrioid carcinomas most probably arise from surface epithelial inclusion glands with TP53 mutations and dysfunction of BRCA1 and/or BRCA2; low-grade serous carcinomas probably arise in a stepwise fashion in an adenoma-borderline tumor-carcinoma sequence from typical to micropapillary borderline tumors to low-grade invasive serous carcinoma via activation of the RAS-RAF signaling pathway secondary to mutations in KRAS and BRAF; mucinous carcinomas arise via an adenoma-borderline tumor-carcinoma sequence with mutations in KRAS; low-grade endometrioid carcinomas arise from endometriosis via mutations in CTNNB1 (the gene encoding b-catenin) and PTEN. Although the morphologic data strongly support an origin of clear cell carcinoma from endometriosis, there is limited data on the genetic alterations in these uncommon tumors. Thus it is likely that most low-grade, relatively indolent ovarian carcinomas of serous, mucinous and endometrioid type arise from pre-existing cystadenomas or endometriosis whereas most high-grade serous carcinomas arise without an easily identifiable precursor lesion. Modern Pathology (2005) 18, S19-S32. doi:10.1038/modpathol.3800306Keywords: ovarian cancer; ovarian borderline tumors; histogenesis; molecular pathology Epithelial ovarian cancer comprises the majority of malignant ovarian tumors in adult women. These neoplasms are classified into distinct morphologic categories based on the appearance of the epithelium into tumors of serous, mucinous, endometrioid, clear cell, transitional, squamous, mixed and undifferentiated type. 1,2 Two types of ovarian surface epithelial lesions have been described as possible precursors of these carcinomas: lesions that appear in situ in surface epithelium or surface epithelial inclusion glands (SEIG); and preexisting benign epithelial ovarian tumors and endometriosis. The morphologic and genetic data implicating each as a precursor lesion of the major histologic subtypes of ovarian carcinoma are discussed. Surface epithelium and surface epithelial inclusion glands as precursor lesions Morphologic DataTwo types of morphologic data are available regarding the malignant potential of ovarian surface epithelium and inclusion glands, alterations in these structures and studies on microscopic ovarian carcinoma.Surface epithelium and surface epithelial inclusion glands Despite the widespread acceptance of the origin of surface epithelial cancers from the ovarian surface epithelium and its inclusion glands, only rarely have putative precursor lesions been described at these sites. Two...

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Section: Benign and Borderline Serous Tumors As Precursor Lesionsmentioning

confidence: 99%

“…90 It has also been noted in one clinical study that 20% of endometrioid and 88% of clear cell carcinomas were preceeded by an ultrasonographically detected endometriotic cyst. 53 …”

Section: Endometriosis As a Precursor Lesionmentioning

confidence: 99%

Origins and molecular pathology of ovarian cancer

2005

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“…Type I tumours are thought to develop in a stepwise fashion from benign/borderline ovarian neoplasms,19, 20 whereas accumulating evidence suggests that Type II cancers arise from precursor lesions in the fallopian tubes 18. While type‐specific classification is likely to be an oversimplification of non high‐grade serous histotypes,21, 22 it broadly represents two groups of interest; aggressive, rapidly advancing tumours and slow‐growing tumours.…”

Section: Introductionmentioning

confidence: 99%

Time to diagnosis of Type I or II invasive epithelial ovarian cancers: a multicentre observational study using patient questionnaire and primary care records

Lim

Mesher

Gentry‐Maharaj

et al. 2015

BJOG

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ObjectiveTo compare time to diagnosis of the typically slow‐growing Type I (low‐grade serous, low‐grade endometrioid, mucinous, clear cell) and the more aggressive Type II (high‐grade serous, high‐grade endometrioid, undifferentiated, carcinosarcoma) invasive epithelial ovarian cancer (iEOC).DesignMulticentre observational study.SettingTen UK gynaecological oncology centres.PopulationWomen diagnosed with primary EOC between 2006 and 2008.MethodsSymptom data were collected before diagnosis using patient questionnaire and primary‐care records. We estimated patient interval (first symptom to presentation) using questionnaire data and diagnostic interval (presentation to diagnosis) using primary‐care records. We considered the impact of first symptom, referral and stage on intervals for Type I and Type II iEOC.Main outcome measuresPatient and diagnostic intervals.ResultsIn all, 78% of 60 Type I and 21% of 134 Type II iEOC were early‐stage. Intervals were comparable and independent of stage [e.g. median patient interval for Type I: early‐stage 0.3 months (interquartile range 0.3–3.0) versus late‐stage 0.3 months (interquartile range 0.3–4.5), P = 0.8]. Twenty‐seven percent of women with Type I and Type II had diagnostic intervals of at least 9 months. First symptom (questionnaire) was also similar, except for the infrequent abnormal bleeding (Type I 15% versus Type II 4%, P = 0.01). More women with Type I disease (57% versus 41%, P = 0.04) had been referred for suspected gynaecological cancer. Median time from referral to diagnosis was 1.4 months for women with iEOC referred via a 2‐week cancer referral to any specialty compared with 2.6 months (interquartile range 2.0–3.7) for women who were referred routinely to gynaecology.ConclusionOverall, shorter diagnostic delays were seen when a cancer was suspected, even if the primary tumour site was not recognised to be ovarian. Despite differences in carcinogenesis and stage for Type I and Type II iEOC, time to diagnosis and symptoms were similar. Referral patterns were different, implying subtle symptom differences. If symptom‐based interventions are to impact on ovarian cancer survival, it is likely to be through reduced volume rather than stage‐shift. Further research on histological subtypes is needed.Tweetable abstractNo difference in time to diagnosis for Type I versus Type II invasive epithelial ovarian cancers.

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“…In a recent study using a serial transvaginal ultrasonography approach, approximately fifty percent of ovarian carcinomas were shown to develop from pre-existing benign-appearing cysts or endometriotic cysts, while no pre-existing lesions had been evident in the remaining cases 12 months prior to diagnosis (Horiuchi et al, 2003). Strikingly, upon histopathological analysis, the majority of tumors that arose from pre-existing lesions were mucinous, endometrioid or clear cell carcinomas with adjacent benign-or borderline-like lesions in the vicinity of the carcinoma.…”

Section: Disease Etiologymentioning

confidence: 99%

Role of p53 and Rb in Ovarian Cancer

Corney

Flesken‐Nikitin

Choi

et al.

Advances in Experimental Medicine and Biology

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Ovarian cancer remains a major health concern worldwide, primarily in postmenopausal women. Among the most common genetic alterations in human sporadic epithelial ovarian cancer (EOC) are p53 mutations, defective retinoblastoma (RB) pathway (p16 INK4a /RB) and activation of oncogenes such as c-myc, K-ras and Akt. Although these alterations are frequently associated with poor clinical prognosis, their specific contributions to EOC formation remain unclear. In order to gain a better understanding of the roles of these proteins in vivo, a number of mouse models have been generated, largely based upon inducing specific genetic lesions in the ovarian surface epithelium from which the majority of carcinomas are thought to arise in humans. Here, we review the role of tumor suppressor p53 and the Rb pathway in EOC with particular attention to association of p53 to high grade serous carcinomas as opposed to low grade and benign tumors. We also provide an overview of the utility and application of genetically engineered mouse models, in particular towards rational drug design and development of improved imaging techniques in ovarian cancer.

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Toward understanding the natural history of ovarian carcinoma development: a clinicopathological approach

Cited by 82 publications

References 22 publications

Origins and molecular pathology of ovarian cancer

Origins and molecular pathology of ovarian cancer

Time to diagnosis of Type I or II invasive epithelial ovarian cancers: a multicentre observational study using patient questionnaire and primary care records

Role of p53 and Rb in Ovarian Cancer

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