abstract: Calculator for ovarian carcinoma subtype prediction : Modern Pathology

Abstract:

With the emerging evidence that the five major ovarian carcinoma subtypes (high-grade serous, clear cell, endometrioid, mucinous, and low-grade serous) are distinct disease entities, management of ovarian carcinoma will become subtype specific in the future.

In an effort to improve diagnostic accuracy, we set out to determine if an immunohistochemical panel of molecular markers could reproduce consensus subtype assignment.

Immunohistochemical expression of 22 biomarkers were examined on tissue microarrays constructed from 322 archival ovarian carcinoma samples from the British Columbia Cancer Agency archives, for the period between 1984 and 2000, and an independent set of 242 cases of ovarian carcinoma from the Gynaecologic Tissue Bank at Vancouver General Hospital from 2001 to 2008. Nominal logistic regression was used to produce a subtype prediction model for each of these sets of cases. These models were then cross-validated against the other cohort, and then both models were further validated in an independent cohort of 81 ovarian carcinoma samples from five different centers.

Starting with data for 22 markers, full model fit, backwards, nominal logistic regression identified the same nine markers (CDKN2A, DKK1, HNF1B, MDM2, PGR, TFF3, TP53, VIM, WT1) as being most predictive of ovarian carcinoma subtype in both the archival and tumor bank cohorts. These models were able to predict subtype in the respective cohort in which they were developed with a high degree of sensitivity and specificity (κ statistics of 0.88±0.02 and 0.86±0.04, respectively).

When the models were cross-validated (ie using the model developed in one case series to predict subtype in the other series), the prediction equation's performances were reduced (κ statistics of 0.70±0.04 and 0.61±0.04, respectively) due to differences in frequency of expression of some biomarkers in the two case series. Both models were then validated on the independent series of 81 cases, with very good to excellent ability to predict subtype (κ=0.85±0.06 and 0.78±0.07, respectively).

A nine-marker immunohistochemical maker panel can be used to objectively support classification into one of the five major subtypes of ovarian carcinoma.

open access journal: Journal of Ovarian Research Differential hRad17 expression by histologic subtype of ovarian cancer

Background
In the search for unique ovarian cancer biomarkers, ovarian specific cDNA microarray analysis identified hRad17, a cell cycle checkpoint protein, as over-expressed in ovarian cancer. The aim of this study was to validate this expression.

Methods
Immunohistochemistry was performed on 72 serous, 19 endometrioid, 10 clear cell, and 6 mucinous ovarian cancers, 9 benign ovarian tumors, and 6 normal ovarian tissue sections using an anti-hRad17 antibody. Western blot analysis and quantitative PCR were performed using cell lysates and total RNA prepared from 17 ovarian cancer cell lines and 6 normal ovarian epithelial cell cultures (HOSE).


Results
Antibody staining confirmed upregulation of hRad17 in 49.5% of ovarian cancer cases. Immunohistochemistry demonstrated that only 42% of serous and 47% of endometrioid subtypes showed overexpression compared to 80% of clear cell and 100% of mucinous cancers.

Conclusions
hRad17 is over-expressed in ovarian cancer. This over-expression varies by subtype suggesting a role in the pathogenesis of these types. Functional studies are needed to determine the potential role of this protein in ovarian cancer.

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abstract: Indication for oophorectomy during cytoreduction for intraperitoneal metastatic spread of colorectal or appendiceal origin(cytoreductive surgery/HIPEC)

BACKGROUND: The incidence of ovarian metastases at the time of peritoneal carcinomatosis, and the influence of such metastases on survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), are unknown.
METHODS: This retrospective analysis included 194 women subjected to CRS and HIPEC since 2001. The incidence of ovarian metastases, disease-free survival and disease-specific survival were analysed.
RESULTS: The histological diagnosis was colorectal cancer carcinomatosis in 108 patients, peritoneal mucinous carcinomatosis (PMCA) in 23 and disseminated peritoneal adenomucinosis (DPAM) in 63. Ninety-nine patients underwent oophorectomy during the HIPEC procedure. Ovarian metastases were confirmed in at least 52 per cent of the patients. There was a significant difference in disease-free survival between women with or without ovarian metastases in both PMCA and DPAM groups (P = 0·044 and P = 0·010 respectively). No significant differences in survival were found in the group with colorectal cancer carcinomatosis.
CONCLUSION: When peritoneal carcinomatosis of colorectal or appendiceal origin is confirmed, at least 52 per cent of ovaries will have synchronous metastases. Disease-free survival after a HIPEC procedure for PMCA or DPAM is significantly lower in women with ovarian metastases. Oophorectomy during CRS for peritoneal carcinomatosis should be strongly considered.

abstract: Tubal ligation and the risk of ovarian cancer: review and meta-analysis — Hum Reprod Update (serous/mucinous/endometrioid)

BACKGROUND The reduction of ovarian cancer (OC) risk in women with a history of tubal ligation (TL) has been reported repeatedly, mostly on small populations. We have aimed to provide a critical overview of the studies available to date and to conduct a meta-analysis.

METHODS There were 40 relevant studies identified. The studies were divided into two groups for strict and extended meta-analysis, respectively. Subgroup analysis was performed for age, time dependency since TL, histological types of OC and BReast CAncer (BRCA) mutation.

RESULTS Meta-analysis of 13 strictly selected studies showed a reduced risk of epithelial OC by 34%. The protective effect of TL was confirmed even in a subgroup of women 10–14 years after the procedure. The risk reduction was confirmed for the endometrioid (RR = 0.40) and serous (RR = 0.73) cancers but not for mucinous.

CONCLUSIONS The review of relevant articles, as well as the meta-analysis of selected studies, yields consistent data on a significant reduction of OC risk in women who had undergone TL. The results of this meta-analysis should provide an impulse for further research on the etiology of ovarian epithelial cancers, focusing particularly on the importance of retrograde transport of endometrial cells.

Ovarian Metastases of Pancreaticobiliary Tract Adenocarcinomas: Analysis of 35 Cases, With Emphasis on the Ability of Metastases to Simulate Primary Ovarian Mucinous Tumors

Serous and mucinous borderline ovarian tumors (LMP): are there real differences between these two entities?

Objective
To evaluate the clinical outcome and pathological features of patients with borderline ovarian tumors (BOT) with special emphasis on serous and mucinous histology.


Conclusions
Serous tumors present more unfavorable anatomopathological characteristics but are associated with better prognosis than mucinous tumors. If mucinous BOT diagnosis is retained physicians should be aware that their aggressive potential is not negligible.

Abstract: Cervical manifestation of a borderline type ovarian cancer with pseudomyxoma peritonei - a case report

Note: mucinous cell type is a cell type found in numerous organs including colon/rectum Abstract: Borderline tumours of the ovary (BOTs) are rare tumour entities that do not show any destructive or invasive growth in the majority of cases, even though they can display characteristics of malignant tumours The mucinous subtype can also originate from the appendix, and ovarian metastases can mimic primary ovarian BOTs, often accompanied by peritoneal manifestation in terms of pseudomyxoma peritonei. In cases where a concomitant appendiceal tumour is present, it may prove difficult to determine the primary tumour. This report describes a special case of BOT with a specific example of the complexity of the differential diagnosis of pseudomyxoma peritonei. Especially the case was simultaneously linked to appendiceal and ovarian cancer. Moreover, this case was exceptional for its unusual manifestation of BOT in the cervix.

abstract: (Aug 6, 2010) Histotype predicts the curative potential of radiotherapy: the example of ovarian cancers

Blogger's Note: 

1) assumption - WAR (whole abdominal radiation - low dose/dosage; 2) ratio of cell types/RT; 3) study time period; 'apparent' stage 1/11; 4) surgical intervention by ?; 5) primary and/or secondary surgical debulking; 6) 'enhanced' as a %..... many questions in the absence of the full paper

 

Background: To explore the influence of ovarian cancer histotype on the effectiveness of adjuvant radiotherapy (RT).

Methods: A review of a population-based experience included all referred women with no reported macroscopic residuum following primary surgery who underwent adjuvant platin-based chemotherapy (CT), with or without sequential RT, and for whom it was possible to assign histotype according to the contemporary criteria.

Results: Seven hundred and three subjects were eligible, of these 351 received RT. For those with apparent stage I and II tumors, the cohort with clear cell (C), endometrioid (E), and mucinous (M) disease who additionally received RT exhibited a 40% reduction in disease-specific mortality and a 43% reduction in overall mortality.

Conclusions: The curability of those with stage I and II C-, E-, and M-type ovarian carcinomas was enhanced by RT-containing adjuvant therapy. This benefit did not extend to those with stage III or serous tumors. These findings necessitate reassessments of the role of RT and of the nonselective surgical and CT approaches that have characterized ovarian cancer care.

Prognostic Relevance of Uncommon Ovarian Histology (abstract) multinational study

 Note:   and stage 1/11??;  see abstract for authors

Prognostic Relevance of Uncommon Ovarian Histology in Women With Stage III/IV Epithelial Ovarian Cancer.

BACKGROUND::
The prognostic relevance of uncommon epithelial ovarian cancer (EOC) histological subtypes remains controversial. The Gynecologic Cancer InterGroup (GCIG) initiated this meta-analysis to assess the relative prognosis of women with a diagnosis of rare EOC histologies from completed, prospectively randomized studies performed by cooperative GCIG study groups.

METHODS::
Studies eligible for analysis included first-line treatment of at least 150 patients with stage III/IV EOC treated with a platinum/taxane-based regimen. Collaborating groups were to provide patient-level data. Serous acted as the reference histology, and a proportional hazards model was used to estimate the relative rate of progression or death.

RESULTS::
Data on 8704 women with stage III/IV EOC from 7 randomized trials were included in these analyses. Two hundred twenty-one patients (2.5%) had clear cell carcinoma; 264 (3.0%), mucinous; and 36 (0.4%), transitional cell. The mean age of patients with serous histology was greater than those with mucinous (4.1 years) and clear cell (2.6 years, P < 0.001). Mucinous, clear cell, and transitional cell tumors were more likely to be completely resected than serous (P < 0.05). When controlling for age and residual disease, mucinous and clear cell tumors had shorter times to progression (hazards ratio [HR], 2.1; 95% confidence interval [CI], 1.8-2.4 and HR, 1.6; 95% CI, 1.4-1.9, respectively) and death (HR, 2.7; 95% CI, 2.3-3.1 and HR, 2.2; 95% CI, 1.8-2.6, respectively) compared with serous. The median overall survival for serous, clear cell, mucinous, and endometrioid histologies were 40.8, 21.3, 14.6, and 50.9 months.

CONCLUSIONS:: Mucinous and clear cell carcinomas are independent predictors of poor prognosis in stage III/IV EOC. Studies targeting these rare histological subtypes are warranted and will require significant intergroup collaboration.

abstract: (repost) Differences in tumor type in low-stage versus high-stage ovarian carcinomas

Int J Gynecol Pathol. 2010
Köbel M, Kalloger SE, Huntsman DG, Santos JL, Swenerton KD, Seidman JD, Gilks CB; Cheryl Brown (ovarian cancer survivour/deceased) Ovarian Cancer Outcomes Unit of the British Columbia Cancer Agency, Vancouver BC.
Department of Pathology, University of Calgary, Calgary AB, Canada T2N 2T9. martin.kobel@cls.ab.ca


Abstract

Although there are recognized differences in the type of ovarian carcinomas between those tumors diagnosed at low versus high stage, there is a lack of data on stage distribution of ovarian carcinomas diagnosed according to the current histopathologic criteria from large population-based cohorts. We reviewed full slide sets of 1009 cases of 2555 patients diagnosed with ovarian carcinoma that were referred to the British Columbia Cancer Agency over a 16-year period (1984 to 2000).
On the basis of the reviewed cases we extrapolated the distribution of tumor type in low-stage (I/II) and high-stage (III/IV) tumors. We then compared the frequencies with those seen in a large hospital practice.
The overall frequency of tumor types was as follows: high-grade serous-68.1%, clear-cell-12.2%, endometrioid-11.3%, mucinous-3.4%, low-grade serous-3.4%, rare types-1.6%. High-grade serous carcinomas accounted for 35.5% of stage I/II tumors and 87.7% of stage III/IV tumors.
In contrast, clear-cell (26.2% vs. 4.5%), endometrioid (26.6% vs. 2.5%), and mucinous (7.5% vs. 1.2%) carcinomas were relatively more common among the low-stage versus high-stage tumors.
This distribution was found to be very similar in 410 consecutive cases from the Washington Hospital Center. The distribution of ovarian carcinoma types differs significantly in patients with low-stage versus high-stage ovarian carcinoma when contemporary diagnostic criteria are used, with consistent results seen in 2 independent case series. These findings reflect important biological differences in the behavior of the major tumor types, with important clinical implications.

Ovarian metastasis following gallbladder carcinoma: a case report (mucinous cell type)

Abstract

"BACKGROUND: Mucinous ovarian cancer raises problems of differential diagnoses because it is often difficult to distinguish the primary from the metastatic form. Most metastatic ovarian tumors originate from the gastrointestinal tract, mainly colorectal, gastric, pancreatic; the gallbladder is a very rare source of ovarian metastases.
CASE: We report a case of ovarian metastases from a gallbladder cancer, incidentally diagnosed more than 2.5 years earlier during a laparoscopic intervention for biliary lithiasis.
CONCLUSION: The interest of this case lies in the long progression-free survival, the venous thromboembolism syndrome that preceded by a few months the diagnosis of the ovarian mass and the discrepancy between the radiologic and the laparoscopic stage assessment."

Ovarian metastasis following gallbladder carcinoma

Abstract

BACKGROUND: Mucinous ovarian cancer raises problems of differential diagnoses because it is often difficult to distinguish the primary from the metastatic form. Most metastatic ovarian tumors originate from the gastrointestinal tract, mainly colorectal, gastric, pancreatic; the gallbladder is a very rare source of ovarian metastases.
CASE: We report a case of ovarian metastases from a gallbladder cancer, incidentally diagnosed more than 2.5 years earlier during a laparoscopic intervention for biliary lithiasis.
CONCLUSION: The interest of this case lies in the long progression-free survival, the venous thromboembolism syndrome that preceded by a few months the diagnosis of the ovarian mass and the discrepancy between the radiologic and the laparoscopic stage assessment.

The pathology of and controversial aspects of ovarian borderline tumours

Abstract
PURPOSE OF REVIEW: Ovarian borderline tumours are relatively uncommon, but not rare, neoplasms. Pathologists and oncologists often struggle with various aspects of borderline tumours which are sometimes controversial and poorly understood.

Appendiceal mucinous neoplasms: controversial issues - pathology

Abstract:

"...reviewed is the largely resolved controversy about whether ovarian mucinous tumors in this setting are separate primaries or are metastases from the appendiceal tumor."

abstract/free full pdf access:P redictive and Prognostic Protein Biomarkers in Epithelial Ovarian Cancer: Recommendation for Future Studies Cancers

"Abstract: Epithelial ovarian cancer is the most lethal gynecological malignancy. Due to its lack of symptoms, this disease is diagnosed at an advanced stage when the cancer has already spread to secondary sites. While initial rates of response to first treatment is >80%, the overall survival rate of patients is extremely low, mainly due to development of drug resistance. To date, there are no reliable clinical factors that can properly stratify patients for suitable chemotherapy strategies. Clinical parameters such as disease stage, tumor grade and residual disease, although helpful in the management of patients after their initial surgery to establish the first line of treatment, are not efficient enough. Accordingly, reliable markers that are independent and complementary to clinical parameters are needed for a better management of these patients. For several years, efforts to identify prognostic factors have focused on molecular markers, with a large number having been investigated. This review aims to present a summary of the recent advances in the identification of molecular biomarkers in ovarian cancer patient tissues, as well as an overview of the need and importance of molecular markers for personalized medicine in ovarian cancer."
 ..........
"High grade serous tumors show particular differences in terms of their development, genetic alterations and prognosis. This has led to the classification of ovarian cancer into two types: type 1 tumors, which are low grade and slowly developing (endometrioid, mucinous and low grade serous tumors), and type 2 tumors, which rapidly progress (high grade serous). In addition, the association of biomarker expression with survival varies substantially between subtypes, and can easily be overlooked in whole cohort analyses. Although these data suggest substantial differences between subtypes, until recently ovarian carcinomas were typically approached as a monolithic entity by researchers and clinicians. This practice impeded progress in understanding the biology or improving the management of the less common ovarian carcinoma subtypes. To avoid this effect, each subtype within a cohort should be analyzed individually. Therefore, molecular classifiers of ovarian cancer are of high clinical relevance in the management of these cancer patients...." cont'd

Review Unmasking the complexities of mucinous ovarian carcinoma

Note: mucinous/KRAS is also prevalant in colorectal cancers

Conclusions

Primary mucinous ovarian cancer should be considered separate from the other epithelial ovarian cancers. Ongoing clinical trials in this disease will likely offer improvements in chemotherapeutic agents used to treat women with primary and recurrent mucinous ovarian cancer.

Ovarian intestinal type mucinous borderline tumors: are we ready for a nomenclature change?

Note: mucinous is not specific to ovarian cancer but found in other tumour sites and without expert pathology can be confused with mucinous gastrointestinal tumours

"At a National Cancer Institute-sponsored workshop it was proposed that the borderline category of ovarian intestinal-type mucinous tumors (OInMTs) could be eliminated if the apparent benign behavior of these tumors could be confirmed..."

Full access: HER2 overexpression and amplification is present in a subset of ovarian mucinous carcinomas and can be targeted with trastuzumab therapy

Serum CA19.9 levels are commonly elevated in primary ovarian mucinous tumours but cannot be used to predict the histological subtype -- Journal of Clinical Pathology

Conclusion: Preoperative CA19.9 levels cannot be used to predict whether a suspected ovarian mucinous tumour is benign, borderline or malignant. Markedly elevated serum levels (>1000 U/ml) may be found in benign mucinous neoplasms as well as in borderline and malignant tumours.

Journal of Chemotherapy 2009 full access: What is the Benefit of 'Avastin' Combined with Chemotherapy in Patients - recurrent Ovarian, Primary ....

Journal of Chemotherapy 2009 full access: What is the Benefit of 'Avastin' Combined with Chemotherapy in Patients - recurrent Ovarian, Primary Peritoneal, Fallopian Tube Cancers.
Note: 64 patients in study; descriptive (stage 1C+); stage 1/11=4 pts; clear cell (2);endometrioid (3); mucinous (2);platinum resistant; side effects....(paper takes time to download)