paywalled: Long-term survival in patients with clear cell adenocarcinoma of ovary treated with irinotecan hydrochloride plus cisplatin therapy as first-line

Long-term survival in patients with clear cell adenocarcinoma of ovary treated with irinotecan hydrochloride plus cisplatin therapy as first-line chemotherapy

Article first published online: 28 MAY 2012

DOI: 10.1111/j.1447-0756.2012.01884.x

© 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology

Issue

Journal of Obstetrics and Gynaecology Research

Early View (Online Version of Record published before inclusion in an issue)

Abstract

Aim:  Several previous reports showed that irinotecan hydrochloride plus cisplatin (CPT-P) was a candidate first-line chemotherapy regimen for clear cell adenocarcinoma of the ovary (CCC). However, long-term survival in CCC patients treated with CPT-P as first-line chemotherapy remains to be determined. The aim of the present study was to evaluate the long-term results of CPT-P as first-line chemotherapy for CCC.

Material and Methods:  We performed a retrospective review of 31 patients with CCC who were treated with CPT-P between 1996 and 2004.

Results:  The median follow-up period was 91 months.........

Conclusion:  The long-term results suggest CPT-P as a candidate in first-line chemotherapy for CCC in not only stage I, but also in optimally debulked stage II-IV patients with pT1/pT2 disease.

abstract: Endometriosis does not confer improved prognosis in ovarian carcinoma of uniform cell type.

Endometriosis does not confer improved prognosis in ovarian carcinoma of uniform cell type [Am J Surg Pathol. 2012]

Abstract

The role of endometriosis in ovarian cancer, disease progression, and survival is a subject of active investigation. A series of 144 ovarian cancers with clear cell or endometrioid histology or associated endometriosis, all classified on the basis of strict histologic criteria, was evaluated to further explore the relationship between endometriosis-associated ovarian cancer and age at presentation, FIGO stage, histology, presence of synchronous primary disease elsewhere in the mullerian tract, and survival.

Patients with endometrioid carcinomas were significantly younger (mean, 52 y) in comparison with patients with either clear cell carcinoma (mean, 55 y) or mixed tumors (mean, 59 y; P=0.002).

Clear cell carcinoma presented as low-stage disease (FIGO I) in 33% of cases compared with endometrioid carcinomas in 97% of cases and mixed carcinomas in 27% of cases. Endometriosis was associated with 53% of clear cell carcinomas, 33% of endometrioid carcinomas, and 45% of mixed tumors (P<0.001). Synchronous primary tumors, observed in 31% of endometrioid tumors, 5% of mixed tumors, and in 2% of clear cell tumors (P<0.001), were unlikely to be associated with endometriosis (P=0.04). Univariate analysis of the aggregate cohort demonstrated that the single best overall predictor of disease-free survival was FIGO stage at presentation (P<0.001), followed by histologic subtype (P=0.003).

Endometriosis did not have a significant relationship with disease-free survival (P=0.7). We conclude that the link between endometriosis and ovarian cancer is much stronger for clear cell carcinoma than for other histologic subtypes (P<0.001). Furthermore, when uniform histologic criteria are applied, true mixed endometrioid and clear cell carcinomas are uncommon; most endometriosis-associated mixed tumors are heterogenous mixtures of endometrioid, mucinous, and serous histology with areas of clear cell cytoplasm. Endometriosis per se does not appear to predict prognosis in clear cell and endometrioid tumors, with the possible exception of tumors with mixed histology. Until more data are collected, pathologists should classify ovarian tumors with mixed histology as a separate and potentially unique biological and prognostic group.

(Apr 2012) Commentary: Link between endometriosis and ovarian-cancer subtypes : The Lancet Oncology

Link between endometriosis and ovarian-cancer subtypes : The Lancet Oncology

"Previous large epidemiological studies have attempted to identify benign gynaecological disorders that predispose to the development of epithelial ovarian cancer. The only disorder that has been repeatedly1—4 (although not universally5) associated with this cancer is endometriosis. Results of some of these studies have suggested a specific link with endometrioid and clear-cell ovarian cancers, but until now none had the power to allow definitive subgroup analysis based on a contemporary definition of histological subtype.

 

In a study reported in the Lancet Oncology, Celeste Leigh Pearce and colleagues6 assessed self-reported endometriosis data from 13 pooled case—control studies in the Ovarian Cancer Association Consortium (OCAC). They confirm that a history of endometriosis is significantly associated with an increased risk of clear-cell (odds ratio 3·05, 95% CI 2·43—3·84) and endometrioid (2·04, CI 1·67—2·48) ovarian cancers, and for the first time show an association with low-grade serous ovarian cancer (2·11, 1·39—3·20). No association was noted between endometriosis and high-grade serous, mucinous, serous borderline, or mucinous borderline ovarian cancers.

 

With more than 23 000 participants (7911 with a diagnosis of ovarian cancer), the main strengths of this study are its statistical power and its robust methods. Incidences of reported endometriosis differ substantially between the pooled studies. Although clinicopathological and genetic differences between the populations could reasonably be expected, importantly there was no significant heterogeneity of the association with histological subtype in the different studies.

The main truly novel finding is an association between a history of endometriosis and low-grade serous ovarian cancer. Perhaps surprisingly, serous borderline tumours (from which invasive low-grade serous ovarian cancers are believed to arise7) are not also associated with a history of endometriosis.

Pathol. 2012 - abstract (Japan) "Piling up" clear cells in müllerian-type mucinous and mixed cell-type borderline tumor do not represent concomitant clear cell neoplasms (mucinous/mixed/clear cell/borderline/ER....)

Hum Pathol. 2012 Mar 19. [Epub ahead of print]

"Piling up" clear cells in müllerian-type mucinous and mixed cell-type borderline tumor do not represent concomitant clear cell neoplasms.

Abstract

The nature of "piling up" proliferation of clear cells in müllerian mucinous/mixed borderline tumor has not been well characterized. The purpose of this study was to clarify whether or not such clear cells represent concomitant clear cell neoplasms.

First, we carefully reviewed hematoxylin and eosin slides taken from 139 ovarian tumors diagnosed as clear cell carcinoma (112 cases) and müllerian mucinous/mixed borderline tumor (27 cases) to clarify (1) the frequency of piling-up clear cells in müllerian mucinous/mixed borderline tumor and (2) the frequency of the coexistence of typical clear cell carcinoma and müllerian mucinous/mixed borderline tumor.

Second, we investigated the immunohistochemical expression of estrogen receptor, hepatocyte nuclear factor-1β, and glypican-3 in proliferating clear cells in both tumors.

We identified piling-up clear cells in 56% of müllerian mucinous/mixed borderline tumors. Such clear cells lacked the severe nuclear atypia, complex branching, and dense hyalinized cores of typical clear cell carcinoma. We did not find coexistence of typical clear cell carcinoma and müllerian mucinous/mixed borderline tumor in any tumors.

Piling-up clear cells and endocervical-like mucinous cells were positive for estrogen receptor but negative for hepatocyte nuclear factor-1β and glypican-3. Most clear cell carcinomas showed a hepatocyte nuclear factor-1β-positive/estrogen receptor-negative immunophenotype, and about half of them were glypican-3 positive.

In conclusion, piling-up clear cells in müllerian mucinous/mixed borderline tumor do not represent concomitant clear cell neoplasms because clear cell carcinoma and müllerian mucinous/mixed borderline tumor hardly ever coexist and because such clear cells in both tumors are immunophenotypically distinct.

open access: Does the Loss of ARID1A (BAF-250a) Expression in Endometrial Clear Cell Carcinomas Have Any Clinicopathologic Significance? A Pilot Assessment (note comments re: clear cell ovarian)

"....Accordingly, their loss of function has been associated with malignant transformation. ARID1A (the expression of whose product, BAF250a, a key complex component, is lost when mutated) has recently been identified as a tumor suppressor gene that is mutated in 46-57% of ovarian clear cell carcinoma (CCC). The purposes of this study are to assess the frequency of loss of BAF250a expression in endometrial CCC and whether this loss has any discernable clinicopathologic implications....."

"....The fact that BAF250a expression is lost in only a small percentage of endometrial CCC may suggest that ARID1A mutations plays a significant role in only a small proportion of CCC, or that these mutations represent only a small component of the genesis of this specific tumor type. It may also bolster the argument that endometrial CCC represents a phenotype that arises via a multitude of different pathways (3,7), with no one pathway being notably dominant. However, it is unclear if those clear cell carcinomas whose pathogenesis does involve ARID1A mutations, represents a clinicopathologically distinct group with definable characteristics."

abstract: Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case–control studies : The Lancet Oncology

Background

Endometriosis is a risk factor for epithelial ovarian cancer; however, whether this risk extends to all invasive histological subtypes or borderline tumours is not clear. We undertook an international collaborative study to assess the association between endometriosis and histological subtypes of ovarian cancer.

 Interpretation

Clinicians should be aware of the increased risk of specific subtypes of ovarian cancer (clear cell, endometrioid) in women with endometriosis. Future efforts should focus on understanding the mechanisms that might lead to malignant transformation of endometriosis so as to help identify subsets of women at increased risk of ovarian cancer.

abstract: Biological significance of plasminogen activator inhibitor-1 expression in ovarian clear cell adenocarcinoma.

Wiki:   Plasminogen activator inhibitor-1 (PAI-1) also known as endothelial plasminogen activator inhibitor or serpin E1 is a protein that in humans is encoded by the SERPINE1 gene.

Abstract


PURPOSE: Ovarian clear cell adenocarcinoma (OCCA) has been reported to display different characteristics from other histological types of epithelial ovarian cancer, and especially differs from serous adenocarcinoma. We investigated plasminogen activator inhibitor-1 (PAI-1) expression in patients with OCCA and attempted to assess its biological significance.

METHODS: Fifty-seven patients with OCCA were enrolled. We used formalin-fixed, paraffin-embedded sections of the primary tumor obtained at the first operation to investigate the immunohistochemical expression of PAI-1 and the association of PAI-1 expression with various clinicopathologic factors.

RESULTS: The 57 patients were classified into a high PAI-1 expression group and a low expression group. Comparison between the two groups revealed that the percentage of patients with concomitant endometriosis was significantly larger in the high expression group, while the percentage of Stage I patients with positive peritoneal cytology was significantly larger in the low expression group. Comparison of cumulative 5-year survival rates showed that the high expression group had a better prognosis than the low expression group.

CONCLUSION: These data suggest an association between concomitant endometriosis and increased expression of PAI-1 in OCCA. The data also suggest that PAI-1 expression influences both peritoneal dissemination of early OCCA and the prognosis.

abstract: A rare case of the coexistence of ovarian clear cell carcinoma, mucinous cystadenoma, and endometriosis in the same ovary (Taiwan)

Abstract

Clear cell carcinomas and endometrioid carcinomas are associated with endometriosis. The association of clear cell carcinomas with mucinous lesions has only been reported infrequently, and with mucinous cystadenoma has been rarely reported.

This is the second reported case of the coexistence of ovarian clear cell carcinoma, mucinous cystadenoma, and endometriosis in the same ovary.

A 57-year-old woman presented with lower abdominal pain for three weeks. Ultrasonography revealed a 16 x 14 x 10 cm mass in the left ovary with solid and cystic components. Hysterectomy and bilateral salpingo-oophorectomy were performed. Histopathological examination of the left ovary revealed the presence of clear cell carcinoma, mucinous cystadenoma, and endometriosis. Continuity between the areas of mucinous epithelium and clear cell carcinoma were noted; this may suggest that clear cell carcinoma may arise from endometriosis or mucinous cystic tumors.

updated - link to full free paper: Review: Therapeutic strategies in epithelial ovarian cancer (references clear cell ovarian)

 Blogger's Note: numerous references to clear cell ovarian cancer as per Japanese historical ovarian cancer research



direct link to pdf file 

 "In summary, it appears that the vast majority of what seem to be primary epithelial ovarian and primary peritoneal carcinomas are, in fact, secondary.

Previous data support the view that serous tumors develop from the fimbria, the most distal part of the fallopian tube, endometrioid and clear cell tumors from endometrial tissue passing through the fallopian tube resulting in endometriosis and mucinous and Brenner tumors from transitional-type epithelium located at the tubal-mesothelial junction where the fimbria makes contact to the peritoneum.

Although the data suggesting that epithelial ovarian carcinoma arises in extra-ovarian sites and involves the ovaries secondarily are compelling, low- and high-grade serous carcinomas involve the ovaries and other pelvic and abdominal organs, such as the omentum and mesentery, much more extensively than the fallopian tubes. Similarly, although endometrioid carcinomas develop from endometriosis, which frequently involves multiple sites in the pelvis, these tumors are usually confined to the ovaries.

It is likely that the predisposition for
growth in the ovary is multifactorial but the precise reasons for this are unknown."

Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features.

Abstract

Malignant epithelial tumors (carcinomas) are the most common ovarian cancers and also the most lethal gynecological malignancies.
Based on histopathology and molecular genetic alterations, ovarian carcinomas are divided into five main types (high-grade serous (70%), endometrioid (10%), clear cell (10%), mucinous (3%), and low-grade serous carcinomas (5%)) that account for over 95% of cases.

These types are essentially distinct diseases, as indicated by differences in epidemiological and genetic risk factors, precursor lesions, patterns of spread, and molecular events during oncogenesis, response to chemotherapy, and prognosis. For a successful specific treatment, reproducible histopathological diagnosis of the tumor cell type is critical.

The five tumor types are morphologically diverse and resemble carcinomas of the uterus. Actually, recent investigations have demonstrated that a significant number of cancers, traditionally thought to be primary ovarian tumors (particularly serous, endometrioid, and clear cell carcinomas), originate in the fallopian tube and the endometrium and involve the ovary secondarily. This review summarizes recent advances in the molecular pathology which have greatly improved our understanding of the biology of ovarian carcinoma and are also relevant to patient management.

abstract: A Systematic Review of Papers Examining the Use of Intraoperative Frozen Section in Predicting the Final Diagnosis of Ovarian Lesions Intl Jnl Gyn Pathology (clear cell, mucinous, borderline, invasive...)

Abstract

"This systematic review assesses the accuracy of the frozen section classification of benign and borderline lesions or invasive carcinoma when compared with the final diagnosis on paraffin section. A Pubmed database search identified 18 retrospective cohort studies, published since 2005 that satisfied the criteria, on the critical appraisal sheet of the center for evidence-based medicine, The University of Oxford.

The sensitivity, specificity, and negative and positive predictive values suggest that frozen section is more accurate at discriminating between benign lesions and invasive carcinoma than between benign and borderline or borderline lesions and invasive carcinoma and indicate a tendency to overcall benign tumors as borderline and borderline tumors as invasive malignancies.
A narrative review of individual papers and abstracts suggests that this particular difficulty is encountered when dealing with clear cell carcinoma and mucinous lesions of all sorts.
This may have greater importance in the future with the introduction of targeted chemotherapy requiring accurate typing to guide the use of genetic analysis. It would be beneficial if future researchers comparing the results of frozen section and paraffin sections presented their results in the context of preoperative assessment of the clinical and radiological findings or the intraoperative appearances of the tumor and abdominal cavity, which would allow the identification of those cases in which the frozen section allowed a refinement of the diagnoses made using these modalities."

Correspondence: Authors' response: 'Focusing on HER2 as a potential therapeutic target in primary ovarian mucinous carcinomas' (includes stats on serous/endometrioid/clear cell/mucinous)

Blogger's Note: without a subscription ($$$), the following is available for viewing:

Authors' response: 'Focusing on HER2 as a potential therapeutic target in primary ovarian mucinous carcinomas':
In a study involving a large series of epithelial ovarian carcinomas (EOCs), McCaughan et al1 reported human epidermal growth factor receptor 2 (HER2) protein overexpression and amplification in all major histological subtypes, an observation consistent with the literature.2 3 Specifically, they document HER2 gene amplification in 3.0% (7/259) of serous papillary carcinomas, 2.1% (2/92) of endometrioid carcinomas, 25.0% (3/12) of mucinous carcinomas, 4.0% (1/25) of clear cell carcinomas and 11.9% (7/60) of mixed type carcinomas. Although their number of mucinous carcinomas was low (n=12), the higher prevalence of HER2 gene amplification relative to the other histological subtypes is also consistent with the literature.4 5
We had previously reported similar findings of primary ovarian mucinous carcinomas having the highest prevalence of HER2 genomic amplification and protein overexpression among the various EOC histological subtypes and had proposed that ovarian mucinous carcinomas represent a...

abstract: Am J Clin Pathology - Value of PAX8 and WT1 Immunostaining in Confirming the Ovarian Origin of Metastatic Carcinoma in Serous Effusion Specimens.(note reference to clear cell ovarian/malignant effusion)

Am J Clin Pathol. 2012 Feb;137(2):304-9.

Value of PAX8 and WT1 Immunostaining in Confirming the Ovarian Origin of Metastatic Carcinoma in Serous Effusion Specimens.

Abstract

We evaluated the detection rates of PAX8 and WT1 immunostaining in 68 (45 as cell blocks, 23 as smears) serous effusion specimens that had a cytologic diagnosis of metastatic carcinoma of ovarian origin. Of the cases, 58 (85%) were positive for PAX8, 56 (82%) were positive for WT1, and 64 (94%) were immunoreactive with either or both markers.

Detection rates of PAX8 and WT1 were 85% (44/52) and 92% (48/52), respectively, for metastatic serous carcinoma and 100% (5/5) and 20% (1/5), respectively, for metastatic clear cell carcinoma (Blogger's note: small sample size in clear cell).

Detection rates using cell blocks and smears were 91% and 78%, respectively, with PAX8 and 82% and 83%, respectively, with WT1.

We concluded that PAX8 and WT1 had comparable overall detection rates in confirming ovarian origin of malignant effusion. The combination of both markers substantially improved the detection rate. Cell blocks and smears can be used for staining, but a cell block is preferred for PAX8 staining.

Pathology of Breast and Ovarian Cancers among BRCA1 and BRCA2 Mutation Carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

Background: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. 

Methods: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers. 

There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%). 

Loss of ARID1A-Associated Protein Expression is a Frequent Event in Clear Cell and Endometrioid Ovarian Cancers

Abstract

Background: Inactivating somatic mutations in the ARID1A gene are described in a significant fraction of clear cell and endometrioid ovarian cancers leading to loss of the corresponding protein (BAF250a).

Conclusions:

These data confirm that loss of the ARID1A-encoded protein BAF250a is a frequent event in the genesis of clear cell and endometrioid ovarian cancers. Loss of BAF250a was not associated with clinical or epidemiologic characteristics. One explanation for these findings is that inactivation of the chromatin remodeling pathway may be a requisite event in the development of these cancers.

Loss of ARID1A protein expression occurs as an early event in ovarian clear-cell carcinoma development and frequently coexists with PIK3CA mutations : Modern Pathology

ARID1A is a recently identified tumor suppressor gene that is mutated in ~50% of ovarian clear-cell carcinomas. This mutation is associated with loss of ARID1A protein expression as assessed by immunohistochemistry. The present study aimed at determining the timing of the loss of ARID1A protein expression during the development of ovarian clear-cell carcinoma and assessing its relevance in correlation to PIK3CA gene mutations......

Clear Cell Adenocarcinoma With a Component of Poorly Differentiated Histology: A Poor Prognostic Subgroup of Ovarian Clear Cell Adenocarcinoma

Preneoplasias of ovarian carcinoma : Biological and clinical aspects of different pathways of tumorigenesis

abstract: The association between endometriosis and gynecological cancers and breast cancer: A review of epidemiological data

CONCLUSIONS:

Endometriosis seems to be a precursor of epithelial ovarian cancer, especially clear cell and endometrioid adenocarcinomas. However, current evidence is insufficient to draw any definitive conclusions whether this association represents causality or the sharing of similar risk factors and/or antecedent mechanisms

repost (abstract) - Gynecologic Oncology : Ovarian cancer linked to lynch syndrome typically presents as early-onset, non-serous epithelial tumors

Research highlights

► Lynch syndrome-associated ovarian cancer develops at early age (mean 48 years) with half of the tumors diagnosed at early stage and an overrepresentation of endometrioid (35%) and clear cell (17%) histologies.
► MMR gene mutations affect MSH2 in 49%, MSH6 in 33% and MLH1 in 17% with immunohistochemical loss of MMR protein staining in 92%