Gynecological Malignancies

In close collaboration with excellent gynecologic oncologists and pathologist, we are performing research on archival material from patients with different gynecological malignancies.

Background

The three most common forms of gynecological cancer are cervical cancer, uterine cancer, and ovarian cancer. Cancer of the clitoris and labia also occur, but only in rare cases.
Ovarian cancer is the most common form of gynecological cancer. The disease is the sixth most common cancer form among women ñ around 450 new cases and 270 deaths per year in Norway. The incidence increases with age. The average age at the time of diagnosis is 59 years.

The term “uterine cancer” is use of all cancer that occurs in the uterus:

• Endometrial cancer
• Carcinosarcoma
• Adenosarcoma
• Leiomyosarcoma
• Endometrial stromal sarcoma

Endometrial cancer is cancer originating from the lining of the uterine cavity, and is the 4th most common form of cancer for women in Norway. Carcinosarcoma and adenosarcoma are mixed epithelial and mesenchymal tumors. These tumors consist of an epithelial part and a sarcomatous part. In carcinosarcomas both components are malignant, while in adenosarcomas the epithelial component is benign. Leiomyosarcomas and edometrial stromal sarcomas are the most common types of uterine sarcomas, but all soft tissue sarcomas can occur in the uterus. Adenosarcomas behave biologically similar to sarcomas. Sarcomas have a biology which is different from carcinomas. The most drastic differences being that sarcomas almost never metastasize to the lymph nodes, but metastasize hematogenically. They have a great tendency for implantation in the peritoneum by contamination. It is extremely important to be aware of this during surgery. 500 cases of uterine cancer diagnoses are made each year. 14 new cases per 100,000 each year. In recent years this frequency has increased. The disease in more common in older women, and the average age at the time of diagnosis is 65 years.

Ovarian malignancies

Stages of ovarian cancer types I & II

(All figures from www.oncolex.no)

Ovarian cancer is the most common gynecological cancer and the 6th most common cancer in Norwegian women. The incidence increases by age and the average age at diagnosis is 59 years.

Ovarian carcinomas

Develops from the epithelium.

90% of all ovarian malignancies

Sixty percent of patients with ovarian cancer already have spread of disease at the time of diagnosis.
Prognosis is dependent on stage of disease.

5 year survival

• Stage I: 80 %
• Stage II: 60 %
• Stage III: 25 %
• Stage IV: 15 %
• Overall 5 year survival: 40 %

Non-epithelial ovarian tumors

Develops from germ cells or sex cord cells.

Germ cell tumors of the ovary

- Approximately 3% of ovarian malignancies are germ cell tumors. These tumors affect women at younger age than epithelial carcinomas (often below the age of 30).

Tumortypes

• dysgerminoma
• immatura teratoma
• endodermal sinus tumor
• choriocarcinoma
• embryonal carcinoma

Most of them respond to chemotherapy and the prognosis is good (over 95% overall 5-year survival).

Sex cord tumors

58 % of all ovarian cancers
Granulosa-stroma cell-tumors: Includes granulosa cell tumores and thecomas. Develops from stromal tissue. Granulosa cell tumors affects women in all age groups. Adult and juvenil form. The tumors produce estrogens, which can give rise to hyperplasia and endometrial cancer.
Approximately 90% 5-year survival.

Cervical cancer

Stages of cervical cancer

About 270 women are diagnosed with cervical cancer in Norway each year (2004), and of these around 100 will die from the disease. The average age at the time of diagnosis is 52 years. The disease is the 9th most common form of cancer in women. The incidence has gradually fallen since the 70ís. With systematic screening of all women between 25 and 69 every third year with cytology examinations, cell changes are discovered and treated before cancer develops. Cervical cancer usually originates from flat or cylinder epithelial cells. Carcinomas often starts with pre-stages, or intraepithelial neoplasia (CIN) grade 1, 2, or 3. About 85 % of the tumors are flat epithelial carcinomas, about 10 % adenocarcinomas and other types around 5%.

Research Materials

• L23 – Ovarian carcinomas Stage I. The material consists of paraffin blocks from surgical specimens from 300 patients with ovarian cancer in Stage 1 (tumor limited to the ovaries). The patients were followed up at the Radium Hospital for at least 10 years or until death. In addition to clinical data, histopathology data and DNA ploidy data exists (Kristensen et al. Ann Oncol 2003, 14:1494-1500). DNA ploidy is known to be a significant prognostic marker for relapse of the disease after treatment. We will continue with Nucleotyping analyses.

• M05 – Uterine sarcomas. This is a population based material containing uterine sarcomas in Norway from 1970-2000. The material consists of paraffin blocks from about 500 patients, and vital status and cause of death is cross-checked with the Cancer Registry/Cause of death registry, up until October 2007.

• M40/M84 – Endometrial carcinomas. The material consists of paraffin blocks with endometrial carcinomas from curettage and hysterectomy specimens from 51 patients treated at the Radium Hospital. Karyotyping and CGH was previously carried out on fresh material from the same tumors.

• M74 – Endometrial carcinomas. This is a different material from 80 patients consisting of paraffin blocks from both curettage and operation specimens exists. The purpose is to compare whether the two specimen types give different test results from, among others, DNA ploidy analyses.

Tubal carcinoma

A rare tumor rising from the tube (Below 1% of gynecological malignancies). Median age at diagnosis is 60 years. Hard to separate from ovarian cancers, and has the same symtoms, treatment and prognosis. The tumors tend to spread to lymph nodes. The tumor has often disseminated at time of diagnosis.

5 year survival

• Stage I 69 %
• Stage II 58 %
• Stage III 20 %
• Stage IV 22 %
• Overall 5 year survival is 45 %

Uterine malignancies

• Develops from the uterine corpus
• The 4th most common cancer in women in Norway

Figure x. Overall survival of uterine malignancies is dependent on stage of disease.
(From The Cancer Registry of Norway)

Endometrial carcinomas

• Develops from the endometrial mucosa
• Most common uterine malignancy ñ account for 90% of the cases
• Approximately 500 cases in Norway each year.
• Average age at diagnosis is 65 years.

Stages of Uterine sarcomas

Uterine sarcomas

Rare tumors developing from uterine stroma.
The most common histological types are leiomyosarcomas (LMS) and endometrial stromal sarcomas (ESS). In contrast to for carcinomas, the sarcomas spread haematogenously. The prognosis is poor and stage dependent for LMS. The prognosis is better for patients with ESS.

Research

The main goal has been to examine the prognostic value of chromosomal instability as determined by DNA ploidy measurement in the different tumor types and correlate the findings with other methods for the determination of chromosomal instability. In addition we have prepared tissue micro arrays for future studies of molecular markers implicated in gynecological carcinogenesis. Images from these analyses are stored for future nucleotyping analyses on some of these materials.

Two PhD theses:

• Genomic instability in gynecological malignancies, Project by M.Sc. Wanja Kildal
• Image cytometric DNA ploidy analysis of endometrial carcinoma, Project by Cand. Med. Manohar Pradhan

Publications

Thigpen T, Dubois A, McAlpine J, Disaia P, Fujiwara K, Hoskins W, Kristensen G, Mannel R, Markman M, Pfisterer J, Quinn M, Reed N, Swart AM, Berek J, Colombo N, Freyer G, Gallardo D, Plante M, Poveda A, Rubinstein L, Bacon M, Kitchener H, Stuart GC; on behalf of the Gynecologic Cancer InterGroup.
First-Line Therapy in Ovarian Cancer Trials
Int J Gynecol Cancer, 21 (4), 756-762.
PMID: 21543937

Bock AJ, Dong HP, Tropé CG, Staff AC, Risberg B, Davidson B.
Nucleoside transporters are widely expressed in ovarian carcinoma effusions.
Cancer Chemother Pharmacol. 2011 Aug 6.
PMID: 21822668

Rustin GJ, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, du Bois A, Kristensen G, Jakobsen A, Sagae S, Greven K, Parmar M, Friedlander M, Cervantes A, Vermorken J
Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG)
Int J Gynecol Cancer. 2011 Feb;21(2):419-23.
PMID: 21270624

Verleye L, Ottevanger PB, Kristensen GB, Ehlen T, Johnson N, van der Burg ME, Reed NS, Verheijen RH, Gaarenstroom KN, Mosgaard B, Seoane JM, van der Velden J, Lotocki R, van der Graaf W, Penninckx B, Coens C, Stuart G, Vergote I.
Quality of pathology reports for advanced ovarian cancer: Are we missing essential information? An audit of 479 pathology reports from the EORTC-GCG 55971/NCIC-CTG OV13 neoadjuvant trial
European Journal of Cancer, Volume 47, Issue 1 , Pages 57-64, January 2011
PMID:20850296

Pradhan M, Abeler VM, Davidson B, Kildal W, Nybøen A, Tropé CG, Risberg B, Danielsen HE
DNA ploidy heterogeneity in endometrial carcinoma: comparison between curettage and hysterectomy specimens
Int J Gynecol Pathol, 29 (6), 572-8
PMID: 20881853

Rustin GJ, van der Burg ME, Griffin CL, Guthrie D, Lamont A, Jayson GC, Kristensen G, Mediola C, Coens C, Qian W, Parmar MK, Swart AM; MRC OV05; EORTC 55955 investigators.
Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial.
Lancet. 2010 Oct 2;376(9747):1155-63.
PMID: 20888993

du Bois A, Herrstedt J, Hardy-Bessard AC, Müller HH, Harter P, Kristensen G, Joly F, Huober J, Avall-Lundqvist E, Weber B, Kurzeder C, Jelic S, Pujade-Lauraine E, Burges A, Pfisterer J, Gropp M, Staehle A, Wimberger P, Jackisch C, Sehouli J.
Phase III Trial of Carboplatin Plus Paclitaxel With or Without Gemcitabine in First-Line Treatment of Epithelial Ovarian Cancer
J Clin Oncol. 2010 Sep 20;28(27):4162-9. Epub 2010 Aug 23.
PMID: 20733132

Pradhan M, Risberg BA, Tropé CG, van de Rijn M, Gilks CB, Lee CH (2010)
Gross genomic alterations and gene expression profiles of high- grade serous carcinoma of the ovary with and without BRCA1 inactivation
BMC Cancer, 10, 493
PMID: 20843305

Vergote I, Tropé CG, Amant F, Kristensen GB, Ehlen T, Johnson N, Verheijen RH, van der Burg ME, Lacave AJ, Panici PB, Kenter GG, Casado A, Mendiola C, Coens C, Verleye L, Stuart GC, Pecorelli S, Reed NS; European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group; NCIC Clinical Trials Group.
Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer
N Engl J Med. 2010 Sep 2;363(10):943-53.
PMID: 20818904

Micci F, Skotheim RI, Haugom L, Weimer J, Eibak AM, Abeler VM, Trope CG, Arnold N, Lothe RA, Heim S
Array-CGH analysis of microdissected chromosome 19 markers in ovarian carcinoma identifies candidate target genes
Genes Chromosomes Cancer, 49 (11), 1046-53
PMID: 20725991

Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, Gebski V, Heywood M, Vasey PA, Volgger B, Vergote I, Pignata S, Ferrero A, Sehouli J, Lortholary A, Kristensen G, Jackisch C, Joly F, Brown C, Le Fur N, du Bois A
Pegylated liposomal Doxorubicin and Carboplatin compared with Paclitaxel and Carboplatin for patients with platinum-sensitive ovarian cancer in late relapse
J Clin Oncol. 2010 Jul 10;28(20):3323-9. Epub 2010 May 24.
PMID: 20498395

Micci F, Haugom L, Ahlquist T, Andersen HK, Abeler VM, Davidson B, Trope CG, Lothe RA, Heim S
Genomic aberrations in borderline ovarian tumors
J Transl Med, 8, 21
PMID: 20184781

Abeler VM, Røyne O, Thoresen S, Danielsen HE, Nesland JM, Kristensen GB.
Uterine sarcomas in Norway. A histopathological and prognostic survey of a total population from 1970 to 2000 including 419 patients.
Histopathology. 2009 Feb;54(3):355-64.
PMID: 19236512

Kildal W, Abeler VM, Kristensen GB, Jenstad M, Thoresen SO, Danielsen HE.
The prognostic value of DNA ploidy in a total population of uterine sarcomas.
Ann Oncol. 2009 Feb 6.
PMID: 19201782

Micci F, Haugom L, Abeler VM, Tropé CG, Danielsen HE, Heim S.
Consistent numerical chromosome aberrations in the cofibromas of the ovary.
Virchows Arch. 2008 Mar;452(3):269-76.
PMID: 18188592

Pradhan M, Abeler VM, Danielsen HE, Risberg B.
A distinct pattern in the DNA ploidy histograms of hydatidiform moles and nonmolar abortuses is caused by accumulation of trophoblasts in the late s-phase.
Int J Gynecol Pathol. 2007 Oct;26(4):432-6.
PMID: 17885494

Nielsen B, Danielsen HE.
Prognostic value of adaptive textural features—the effect of standardizing nuclear first-order gray level statistics and mixing information from nuclei having different area.
Cell Oncol. 2006;28(3):85-95.
PMID: 16823177

Pradhan M, Abeler VM, Danielsen HE, Tropé CG, Risberg BA.
Image cytometry DNA ploidy correlates with histological subtypes in endometrial carcinomas.
Mod Pathol. 2006 Sep;19(9):1227-35. Epub 2006 May 26.
PMID: 16729014

Kaern J, Aghmesheh M, Nesland JM, Danielsen HE, Sandstad B, Friedlander M, Tropé C.
Prognostic factors in ovarian carcinoma stage III patients. Can biomarkers improve the prediction of short- and long-term survivors?
Int J Gynecol Cancer. 2005 Nov-Dec;15(6):1014-22.
PMID: 16343177

Brandal P, Bjerkehagen B, Danielsen H, Heim S.
Chromosome 7 abnormalities are common in chordomas.
Cancer Genet Cytogenet. 2005 Jul 1;160(1):15-21.
PMID: 15949565

Kildal W, Risberg B, Abeler VM, Kristensen GB, Sudbø J, Nesland JM, Danielsen HE.
beta-catenin expression, DNA ploidy and clinicopathological features in ovarian cancer: a study in 253 patients.
Eur J Cancer. 2005 May;41(8):1127-34. Epub 2005 Apr 14.
PMID: 15911235

Kildal W, Kaern J, Kraggerud SM, Abeler VM, Sudbø J, Tropè CG, Lothe RA, Danielsen HE.
Evaluation of genomic changes in a large series of malignant ovarian germ cell tumors—relation to clinicopathologic variables.
Cancer Genet Cytogenet. 2004 Nov;155(1):25-32.
PMID: 15527899

Wang Y, Helland A, Holm R, Skomedal H, Abeler VM, Danielsen HE, Tropé CG, Børresen-Dale AL, Kristensen GB.
TP53 mutations in early-stage ovarian carcinoma, relation to long-term survival.
Br J Cancer. 2004 Feb 9;90(3):678-85.
PMID: 14760384

Kildal W, Kraggerud SM, Abeler VM, Heim S, Tropé CG, Kristensen GB, Risberg B, Lothe RA, Danielsen HE.
ÆGenome profiles of bilateral dysgerminomas, a unilateral gonadoblastoma, and a metastasis from a 46, XY phenotypic female.Æ
Hum Pathol. 2003 Sep;34(9):946-9.
PMID: 14562293

Kristensen GB, Kildal W, Abeler VM, Kaern J, Vergote I, Tropé CG, Danielsen HE.
Large-scale genomic instability predicts long-term outcome for women with invasive stage I ovarian cancer.
Ann Oncol. 2003 Oct;14(10):1494-500.
PMID: 14504048

Nielsen B, Albregtsen F, Kildal W, Danielsen HE.
Prognostic classification of early ovarian cancer based on very low dimensionality adaptive texture feature vectors from cell nuclei from monolayers and histological sections.
Anal Cell Pathol. 2001;23(2):75-88.
PMID: 11904463

Nielsen B, Albregtsen F, Danielsen HE.
The use of fractal features from the periphery of cell nuclei as a classification tool.
Anal Cell Pathol. 1999;19(1):21-37.
PMID: 10661622

Schulerud H, Kristensen GB, Liestøl K, Vlatkovic L, Reith A, Albregtsen F, Danielsen HE.
A review of caveats in statistical nuclear image analysis.
Anal Cell Pathol. 1998;16(2):63-82. Review.
PMID: 9692681

Kaern J, Wetteland J, Tropé CG, Farrants GW, Juhng SW, Pettersen EO, Reith A,Danielsen HE.
Comparison between flow cytometry and image cytometry in ploidy distribution assessments in gynecologic cancer.
Cytometry. 1992;13(3):314-21.
PMID: 1576895

Contact Information

If you have questions regarding the project, please contact us for more information.

Responsible Clinician
Gunnar B. Kristensen

Post doc
Birgitte Nielsen
Wanja Kildal

Collaborators
Vera M Abeler
Bjørn Risberg
Manohar Pradhan
Ben Davidson
Jahn M. Nesland
Claes Trope
Steinar Thoresen