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Sarcoma of the female genital tract: Histopathology, DNA cytometry, p53 and mdm-2 analysis related to prognosis
Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
1999 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Sarcomas of the female genital tract are rare tumors and account for less than 5% of gynecologic malignancies. Traditionally, gynecologic sarcomas have been divided into different tumor types according to their histopathological features. The most common are leiomyosarcoma (LMS), malignant mixed Müllerian tumors (MMMT), endometrial stromal sarcoma (ESS) and (Müllerian) adenosarcoma. The different tumor types are highly aggressive with early lymphatic and/or hematogenous spread. Treatment is difficult and it is believed that sarcomas have a low radio-and chemosensitivity, and the mainstay in treatment is surgical removal of the tumor. The most important prognostic feature has been tumor stage. Nevertheless, there are some early-stage tumors that run a biological course different from that expected and additional prognostic factors indicating high-risk tumors are desirable.

The study cohort consists of 49 uterine LMS, 44 uterine MMMTs, 17 uterine ESS, 11 uterine adenosarcomas and 26 ovarian MMMTs. The tumors were analyzed in a retrospective manner for DNA ploidy, S-phase fraction (SPF), p53 and mdm-2 expression, as well as traditional clinical and pathological prognostic factors, such as tumor stage. grade, atypia and mitotic index.

Of the 49 LMS, 36 (86%) were non-diploid and 13 (27%) were p53-positive. Among the 44 uterine MMMTs, 30 (68%) were non-diploid and 27 (61%) had an SPF>10%. Twenty-seven (61%) overexpressed p53 and 11 (25%) were mdm-2 positive. Furthermore, 40 (91%) of the uterine MMMTs had a high mitotic count and 42 (95%) had high grade cytologic atypia. All low-grade ESS were DNA diploid and had a low SPF. Among the four high-grade ESS, three (75%) were DNA aneuploid and three (75%) were p53-positive. Among 1 1 adenosarcomas, eight (73%) were non-diploid. All ovarian MMMTs were non-diploid and all but two had an SPF>10%. 19 (73%) ovarian MMMTs were p53positive.

The 5-year survival rate was 33% for LMS, 38% for uterine MMMT, 57% for ESS, 69% for adenosarcoma and 30% for ovarian MMMT.

Thirty-five (71%) patients with LMS died of disease and two of intercurrent disease. Stage was found to be the most important factor for survival (p=0.007); in addition DNA ploidy (p=0.045) and SPF (p=0.041) had prognostic significance.

Twenty-seven (61%) patients with uterine MMMT died of disease and six (14%) died of intercurrent disease. Stage was the only prognostic factor for survival.

Nine (53%) patients with ESS died of disease. There was a significant correlation of survival to tumor grade (p=0.007), DNA ploidy (p=0.026), SPF (p=0.048) and stage (p=0.026).

Of the 11 patients with adenosarcoma, four (36%) patients died of disease and three (27%) patients died of intercurrent disease. There were no variables that correlated with survival.

Eighteen (69%) patients with ovarian MMMT died of disease and two (8%) patients died of intercurrent disease. In a multivariate analysis, only stage reached independent prognostic significance for survival (p=0.023).

In summary, stage represents the most important prognostic factor for survival for uterine and ovarian sarcomas. DNA flow cytometry is useful in gaining additional prognostic information for LMS and ESS. P53-and mdm-2 overexpression had no prognostic value for survival rate. Most of the MMMT overexpressed p53 and were non-diploid. Treatment of sarcomatous neoplasms is difficult and the mainstay remains surgical removal of the tumor. For patients with early stage sarcoma there was a high recurrence rate, which suggests that a large proportion of patients may have systemic micrometastasic disease at the time of diagnosis. Recurrent and metastatic uterine sarcoma remains an incurable disease, and treatment must be considered palliative.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 1999. , 60 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 583
Keyword [en]
Sarcoma, female genital tract, tumors, MMMT
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-4990ISBN: 91-7219-325-5 (print)OAI: oai:DiVA.org:liu-4990DiVA: diva2:20887
Public defence
1999-02-19, Onkologens föreläsningssal, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Note
On the day of the public defence the status of the articles III and IV was: Accepted for publication. ; Bild/Image 1=p53/mdm-2 interaction ; Bild/Image 2=Leiomysarcoma stage I ; Bild/Image 3=Survival in uterine sarcoma.Available from: 1999-02-26 Created: 1999-02-26 Last updated: 2012-01-24Bibliographically approved
List of papers
1. Leiomyosarcoma of the uterus: A clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 49 cases
Open this publication in new window or tab >>Leiomyosarcoma of the uterus: A clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 49 cases
Show others...
1998 (English)In: Gynecologic Oncology, ISSN 0090-8258, Vol. 68, no 1, 54-61 p.Article in journal (Refereed) Published
Abstract [en]

AIM: The authors analyzed in a retrospective manner the prognostic significance of p53 and mdm-2 expression, DNA ploidy, S-phase fraction (SPF), and traditional clinical and pathological prognostic factors in patients with uterine leiomyosarcomas. MATERIAL: Forty-nine patients were diagnosed with uterine leiomyosarcoma (25 stage I, 4 stage II, 8 stage III, and 12 stage IV). DNA flow cytometric analysis and immunohistochemical staining for p53 and mdm-2 were performed on paraffin-embedded archival tissue from the uterine tumors. RESULTS: Of the 49 patients, 35 (71%) died of disease and 2 died of intercurrent disease. The 5-year survival rate was 33%. FIGO surgical stage, DNA ploidy, SPF, mitotic index, cellular atypia, and tumor grade obtained significance (P < 0.05) in a univariate survival analysis of the leiomyosarcomas. In a multivariate analysis with survival as the end point, stage was found to be the most important factor (P = 0.007); DNA ploidy (P = 0. 045) and SPF (P = 0.041) also had independent prognostic significance. For FIGO stage I tumors, DNA ploidy (P = 0.04) and tumor grade (P = 0.01) were statistically significant in a univariate analysis, while only grade had independent prognostic significance (P = 0.01) in a multivariate analysis. In a univariate analysis including only FIGO stage I and II tumors with disease-free survival as the end point, p53 overexpression (P = 0.0016), DNA ploidy (P = 0.042), and tumor grade (P = 0.008) obtained significance. In a multivariate analysis, only p53 had independent statistical significance (P = 0.01). All p53 immunopositive stage I-II tumors recurred within 28 months from diagnosis. CONCLUSION: This study found that stage represents the most important prognostic factor for uterine leiomyosarcomas. DNA ploidy and SPF had independent prognostic value. DNA flow cytometry is useful in gaining additional prognostic information. In stage I patients, tumor grade gives significant information regarding clinical outcome. In addition, p53 overexpression may predict a higher risk of recurrence in early stage leiomyosarcomas.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13510 (URN)
Available from: 1999-02-26 Created: 1999-02-26 Last updated: 2009-02-09
2. Malignant mixed Mullerian tumors of the uterus: a clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 44 cases
Open this publication in new window or tab >>Malignant mixed Mullerian tumors of the uterus: a clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 44 cases
Show others...
1998 (English)In: Gynecologic Oncology, ISSN 0090-8258, Vol. 68, no 1, 18-24 p.Article in journal (Refereed) Published
Abstract [en]

AIM: The authors retrospectively analyzed the prognostic significance of p53, mdm-2, DNA ploidy, S-phase fraction (SPF), and traditional clinical and pathologic factors in patients with malignant mixed Müllerian tumors (MMMT) of the uterus. METHODS: Between 1970 and 1995, 44 uterine tumors were diagnosed as MMMT (21 stage I, 2 stage II, 10 stage III, and 11 stage IV). Thirty-two were homologous type and 12 were heterologous type. DNA flow cytometry and immunohistochemical analysis for p53 and mdm-2 overexpression were performed on paraffin-embedded archival tissue. RESULTS: 68% of the tumors were nondiploid and 61% had an SPF greater than 10%. Sixty-one percent overexpressed p53 and 25% were mdm-2-positive. Furthermore, 91% of the tumors had a mitotic count greater than 10/10 hpf and 95% had high-grade cytologic atypia. Twenty-seven (61%) patients died of tumor and 6 (14%) died of intercurrent disease. Eleven (25%) patients are alive with no evidence of disease. The median follow-up for patients still alive was 59 months (range, 28-178 months). The overall 5-year survival rate was 38%. In a univariate analysis that included stage, histologic type, DNA ploidy, SPF, p53, mdm-2, mitotic index, and age, and with survival as the end point, only stage reached statistically prognostic significance. CONCLUSION: The majority of the tumors had obvious signs of aggressiveness such as high grade, high mitotic count, nondiploid pattern, high SPF, and overexpression of p53. This study found that stage is the most important prognostic factor for survival in MMMTs of the uterus.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13511 (URN)
Available from: 1999-02-26 Created: 1999-02-26 Last updated: 2009-02-09
3. Endometrial stromal sarcoma of the uterus: a clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 17 cases
Open this publication in new window or tab >>Endometrial stromal sarcoma of the uterus: a clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 17 cases
1999 (English)In: International Journal of Gynecological Cancer, ISSN 1048-891X, Vol. 9, no 2, 98-104 p.Article in journal (Refereed) Published
Abstract [en]

Seventeen patients with endometrial stromal sarcoma (ESS) diagnosed between 1970 and 1996 were evaluated according to DNA ploidy, S-phase fraction (SPF), p53, and mdm-2 expression, as well as traditional clinical and pathologic prognostic factors, such as tumor stage, grade, and mitotic index. DNA flow cytometric analysis and immunohistochemical staining for p53 and mdm-2 were performed on paraffin-embedded archival tissue from the uterine tumors. Flow cytometric DNA histograms were obtained from 16 patients.

The patients ranged in age from 41 to 78 years (median, 57 years). Seven (41%) patients were premenopausal. Thirteen low-grade ESS were DNA diploid and had a low SPF. Of these, two overexpressed p53, while only one was mdm-2 positive. Among the four high-grade ESS we found one (25%) DNA diploid tumor and three (75%) DNA aneuploid tumors. Two (50%) had an SPF greater than 10%, three (75%) were p53-positive, and two (50%) overexpressed mdm-2. During the observation period, nine (53%) patients (five with low-grade and four with high-grade tumors) died of disease. The 5-year survival rate for patients with low-grade ESS was 74%, while all four patients with high-grade ESS died of disease within 14 months of diagnosis. Using the log-rank test, we found a significant correlation between survival and tumor grade (P = 0.007), DNA ploidy (P = 0.026), SPF (P = 0.048), and FIGO surgical stage (P = 0.026).

In conclusion, we found that tumor grade was a strong predictor of clinical outcome in ESS. In addition, a worse prognosis was found for those ESS patients with advanced disease, DNA aneuploidy, and a high SPF. There was no difference between the recurrent and nonrecurrent group of early stage (surgical stage I), low-grade ESS with regard to clinicopathological features, DNA ploidy, SPF, p53, and mdm-2 expression. All patients with high-grade ESS died of disease within 14 months of diagnosis. In contrast, only three of the 11 patients with early stage, low-grade ESS died of disease.

Keyword
DNA ploidy, endometrial stromal sarcoma, mdm-2, p53
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13512 (URN)10.1046/j.1525-1438.1999.09870.x (DOI)
Available from: 1999-02-26 Created: 1999-02-26 Last updated: 2009-04-28
4. Adenosarcoma of the uterus: a clinicopathologic, DNA flow cytometric, p53 and mdm-2 analysis of 11 cases
Open this publication in new window or tab >>Adenosarcoma of the uterus: a clinicopathologic, DNA flow cytometric, p53 and mdm-2 analysis of 11 cases
1999 (English)In: International Journal of Gynecological Cancer, ISSN 1048-891X, Vol. 9, no 1, 37-43 p.Article in journal (Refereed) Published
Abstract [en]

Eleven patients with uterine adenosarcoma diagnosed between 1970 and 1995 were evaluated according to DNA ploidy, S-phase fraction, p53 and mdm-2 expression, and traditional clinical and pathological prognostic factors, such as tumor stage, grade and mitotic index. DNA flow cytometric analysis and immunohistochemical staining for p53 and mdm-2 were performed on paraffin-embedded archival tissue from the uterine tumors. The patients ranged in age from 41 to 90 years (median, 76 years). Only one patient was premenopausal at the time of diagnosis and five (45%) were nulliparous. One patient had received previous pelvic irradiation for anal squamous carcinoma. Six of the tumors (55%) were pure adenosarcoma and five (45%) were adenosarcoma with sarcomatous overgrowth. Nine patients had a stage I tumor and two had a stage II tumor. Among the six adenosarcomas we found three DNA diploid tumors, two DNA aneuploid tumors, and one DNA multiploid tumor. All adenosarcomas had an S-phase fraction less than 10%, except one that was not assessable. None was p53 positive and only one overexpressed mdm-2. All five adenosarcomas with sarcomatous overgrowth were DNA aneuploid, three (60%) had an S-phase fraction > 10%, two (40%) were p53 positive, and one (20%) overexpressed mdm-2. Five of the eleven patients suffered recurrences, and three (60%) of these developed lung metastases. During the observation period four (36%) patients (2 adenosarcomas and 2 adenosarcoma with sarcomatous overgrowth) died of disease, three patients died of intercurrent disease without recurrence, and the remaining four are alive with no evidence of disease. The overall five-year survival rate for all stages was 69%; for patients with AS it was 80%, while for those with adenosarcoma with sarcomatous overgrowth it was 50%. There were no variables which correlated with survival. In conclusion, we found hat the typical adenosarcoma had a tendency to be of low stage, have a lower mitotic rate and an S-phase fraction <10%. On the other hand, adenosarcomas with sarcomatous overgrowth were of high grade, had a high mitotic rate, and were DNA aneuploid with an S-phase fraction >10%. None of the variables studied correlated with survival. Tumors that were p53-positive or overexpressed mdm-2 did not behave worse than their negative counterpart. All patients who recurred with distant metastases died of disease.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13513 (URN)
Available from: 1999-02-26 Created: 1999-02-26 Last updated: 2009-02-09
5. Malignant mixed Müllerian tumors of the ovary: A clinicopathologic, DNA ploidy and p53 study of 26 cases
Open this publication in new window or tab >>Malignant mixed Müllerian tumors of the ovary: A clinicopathologic, DNA ploidy and p53 study of 26 cases
1999 (English)Article in journal (Refereed) Submitted
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13514 (URN)
Available from: 1999-02-26 Created: 1999-02-26

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