Early-stage Borderline Ovarian Tumors Research Articles

Fertility and Pregnancy Outcomes after Fertility-Sparing Surgery for Early-Stage Borderline Ovarian Tumors and Epithelial Ovarian Cancer: A Single-Center Study.

This study examined treatment outcomes, including preserved fertility, menstrual regularity, and pregnancy outcomes, in patients with stage I epithelial ovarian cancer (EOC) or borderline ovarian tumors (BOTs) who underwent fertility-sparing surgery (FSS). Patients with stage I EOC and BOTs who were aged 18-45 years and underwent FSS between 2007 and 2022 were retrospectively reviewed. Significant differences between various subgroups in terms of disease recurrence, menstrual irregularity due to the disease, and pregnancy outcomes were analyzed. A total of 71 patients with BOTs and 33 patients with EOC were included. In the BOT group, the median age was 30 (range, 19-44) years. Recurrence occurred in eight patients, with one case exhibiting a malignant transformation into mucinous EOC. Among the 35 married patients with BOTs, 20 successfully conceived, resulting in 23 live births and 3 spontaneous abortions. A higher pregnancy rate was observed in those without prior childbirth (82.4%) than in those who had prior childbirth (33.3%). In the EOC group, the median age was 34 (range, 22-42) years. Recurrence occurred in one patient. Menstrual regularity was maintained in 69.7% of the patients. Among the 14 married patients in this group, 12 achieved a total of 15 pregnancies (including 2 twin pregnancies), 16 live births, and 1 spontaneous abortion. The results of the study confirmed that FSS is a favorable surgical option for young women with early-stage BOTs or EOC who wish to preserve their fertility. However, additional investigations are needed to validate these findings.

Is There Re-staging Surgery Necessity for Borderline Ovarian Tumors.

This study assessed the necessity of surgical re-staging in women with borderline ovarian tumors (BOTs) and evaluated the impact of complete surgical staging, lymphadenectomy, and omentectomy on disease recurrence and survival. We retrospectively reviewed the medical records of patients with BOTs. A total of 901 patients were eligible for inclusion in the study, and we evaluated some of the variables and clinical/surgical characteristics of the cases. The effects of the type of surgical procedure, surgical staging, and complete or incomplete staging on recurrence were calculated. The rates of disease-free survival, overall survival, and recurrence were compared according to complete surgical staging. A Cox regression analysis was performed to identify potential prognostic factors, and survival curves were constructed using the Kaplan-Meier method. The overall recurrence rate was 13.9%, and recurrence was comparable between the complete surgical staging group and the incomplete groups (P>0.05). The performance of complete surgical staging did not show an effect on long-term survival, and complete surgical staging, omentectomy, and lymphadenectomy had no effect on recurrence. In multivariate analyses, only radical surgery and adjuvant chemotherapy were risk factors for the recurrence of BOTs. Furthermore, we found that omentectomy led to a relatively low recurrence rate in patients with International Federation of Gynecology and Obstetrics (FIGO) stage > I (P=0.022). Our results suggest that complete surgical staging should be considered a standard treatment for patients with advanced stage BOTs but not for those at FIGO stage I. It might be safe to reduce the scope of surgical procedures in patients with early-stage BOTs. However, it is not necessary to perform re-staging operations for BOTs with a macroscopically normal extra-ovarian appearance.

Is cystectomy an option as conservative surgery for young patients with borderline ovarian tumor? A multi-institutional retrospective study.

To investigate the impact of cystectomy for borderline ovarian tumor (BOT) on tumor recurrence compared with salpingo-oophorectomy using inverse probability of treatment weighting (IPTW). A central pathologic review and a search of the medical records from 14 collaborating institutions from 1986 to 2017 identified 4708 women with a malignant ovarian neoplasm. Data for young women with Stage I BOT were extracted. To compare recurrence-free survival between the surgery groups, Cox regression analyses and the IPTW-adjusted Kaplan-Meier method were employed. During a median follow-up of 62.0 (1.2-270.4) months, 10 of the 285 patients identified (3.5%) developed recurrence. In multivariate analysis, the practice of cystectomy was not a significant prognostic indicator of recurrence-free survival (hazard ratio [95% confidence interval] 1.276 [0.150-10.864]; P=0.823). In the IPTW-adjusted cohort, the 5-year recurrence-free survival rates were 95.8% and 96.0% in patients receiving cystectomy and salpingo-oophorectomy, respectively (P=0.378). If patients are selected appropriately, cystectomy in itself may not increase tumor recurrence in young women with early-stage BOT. A large-scale prospective clinical study is necessary to validate this finding.

Malignant Ovarian Tumors During Pregnancy: A Multicenter Retrospective Analysis.

PurposeThe aim of this study was to investigate the clinical characteristics and management of malignant ovarian tumors during pregnancy, as well as the feto-maternal outcomes and analyze the influential factors on the pregnancy outcomes.Patients and MethodsEighty-five patients with ovarian malignancies during pregnancy treated at 12 tertiary hospitals between 2009 and 2019 were analyzed in this study. The clinical features, histopathological characteristics, clinical management, and maternal and perinatal outcomes were retrospectively analyzed. The clinical features and managements were compared between abortion group and live birth group.ResultsThe following diagnoses were made: 41 (48.24%) patients with borderline ovarian tumors, 18 (21.18%) patients with epithelial ovarian cancers, 17 (20.00%) patients with non-epithelial ovarian malignancies and 9 (10.59%) patients with metastatic ovarian tumors. Thirty-six (42.45%) patients underwent conservative surgical treatment. Thirty-four (40.00%) patients opted for fertility-sparing surgery, and fifteen (17.56%) patients received radical surgery. Chemotherapy was administered to 32.94% of the patients. The proportion of ovarian malignancies diagnosed in the first trimester in the abortion group was higher than that in the live birth group (P<0.05). However, tumor diameter, reproductive history, stage and surgical indications showed no significant differences between groups. A total of 67 live babies were recorded in this study, including 19 premature babies and 1 full-term newborn who died of respiratory distress. All of the BOTs were diagnosed with stage I, among whom 38 (92.68%) patients exhibited disease-free survival. Twenty-eight ovarian cancers were in stage I–II and 26 of them had disease-free survival with the longest follow-up time of 10 years. Five of the sixteen patients in advanced stage (stage III–IV) died, four of whom had metastatic tumors.ConclusionPregnant women with early-stage malignant ovarian tumors appear to have favorable outcomes. Conservative surgery is acceptable for early-stage borderline ovarian tumors during pregnancy. The gestational age of ovarian malignancy detection is key for pregnancy outcomes.

Utero-ovarian preservation and overall survival of young women with early-stage borderline ovarian tumors.

To examine survival of women who had uterine and ovarian preservation during surgical treatment for early-stage borderline ovarian tumors (BOTs). The Surveillance, Epidemiology, and End Results Program was used to identify women aged < 50years with stage I BOTs who underwent ovarian conservation at surgical treatment between 1988 and 2003. Survival outcomes were examined based on the use of concurrent hysterectomy at surgery. Among 6379 cases of BOT, there were 1065 women who had utero-ovarian preservation at surgery, and there were 52 women who had hysterectomy with ovarian preservation alone. Women who had uterine preservation were more likely to be single and diagnosed in recent years (both, P < 0.05). On univariable analysis, women who had utero-ovarian preservation had cause-specific survival similar to those who had ovarian preservation alone without uterine preservation (10-year rates: 99.2% versus 98.1%, P = 0.42); however, overall survival was higher in the utero-ovarian preservation group compared to the hysterectomy group (95.8% versus 87.6%, P < 0.001). On multivariable analysis, utero-ovarian preservation remained an independent prognostic factor for improved overall survival (adjusted hazard ratio 0.35, 95% confidence interval 0.15-0.79, P = 0.012). Cardiovascular disease mortality was lower in the utero-ovarian preservation group compared to the hysterectomy group, but it did not reach statistical significance (20-year cumulative rate, 0.8% versus 3.0%, P = 0.29). Our study suggests that utero-ovarian preservation for young women with early-stage BOTs may be associated with improved overall survival compared to ovarian preservation alone without affecting BOT-related survival outcome.

Borderline Ovarian Tumors: Fifteen Years' Experience at a Scottish Tertiary Cancer Center.

Since the recognition of borderline ovarian tumors (BOTs) in the 1970s, the management of this subset of epithelial ovarian tumors has presented a challenge to clinicians. The majority present at an early stage, but their diagnosis is often only made following surgery, hence the heterogeneity of surgical management. Borderline ovarian tumors are morphologically diverse, and their behavior is subsequently also heterogeneous. We aimed to assess recurrence rates and the rate of malignant transformation in patients diagnosed with BOT. Secondary objectives included a review of current management and assessment of tumor markers, stage, cyst dimensions, and the presence of micropapillary features as prognostic indicators of recurrence. This retrospective cohort study included all patients treated with BOT between 2000 and 2015 in the southeast region of Scotland. Clinical, surgicopathological, and follow-up data were collated. Data were analyzed with reference to recurrence and malignant transformation. Two hundred seventy-five patients underwent treatment for BOT in the study period. Surgical management was highly variable. A diagnosis of recurrent/persistent BOT or ovarian malignancy following initial treatment of BOT was rare, with only 12 (4%) of 275 cases. There were 7 cases (3%) of ovarian malignancy. Advanced International Federation of Gynecology and Obstetrics stage was the most prominent prognostic factor. Elevated preoperative serum CA-125 and the presence of micropapillary features correlated with advanced stage at presentation. With a lack of clear guidance, follow-up was highly variable with a median of 43 months (0-136 months). To our knowledge, this study is the largest BOT cohort in the United Kingdom. Recurrent disease is rare in optimally staged, completely resected, early-stage BOT, without high-risk features. Caution is needed in women electing not to undergo completion staging after diagnosis and in those opting for a fertility-preserving approach. Thorough informed consent and clear plans for surveillance and follow-up are needed with consideration of delayed completion surgery as appropriate.

Utero-ovarian preservation and overall survival of young women with early-stage borderline ovarian tumors

Utero-ovarian preservation and overall survival of young women with early-stage borderline ovarian tumors

Borderline-Tumoren am Ovar: Begrenztes chirurgisches Vorgehen ist vertretbar

Matsuo K et al. Role of hysterectomy and lymphadenectomy in the management of early-stage borderline ovarian tumors. Gynecol Oncol 2017; 144: 496 – 502

Role of hysterectomy and lymphadenectomy in the management of early-stage borderline ovarian tumors

ObjectiveTo examine survival of women with stage T1 borderline ovarian tumors (BOTs) stratified by hysterectomy and lymphadenectomy status at surgery. MethodsThis is a retrospective study examining The Surveillance, Epidemiology, and End Results Program to identify surgically-treated stage T1 BOTs between 1988 and 2003 (n=4943). Association of surgery patterns and cause-specific survival (CSS) was examined in multivariable analysis. ResultsMean age was 48.7. The majority had stage T1a disease (75.3%). Median follow-up was 15.6years and 159 (3.2%) women died of BOTs. Hysterectomy and lymphadenectomy were performed in 1909 (38.6%) and 1295 (26.2%) cases, respectively. Most commonly, neither procedure was performed (46.5%), followed by hysterectomy alone (27.3%), lymphadenectomy alone (14.9%), and both procedures (11.3%). Surgery patterns for hysterectomy and lymphadenectomy significantly differed across age, ethnicity, marital status, registry area, year at diagnosis, histology type, sub-stage, and tumor size (all, P<0.001). On multivariable analysis, surgery patterns for hysterectomy and lymphadenectomy were not associated with CSS: 20-year rates for neither hysterectomy and lymphadenectomy 96.7%, hysterectomy alone 94.5%, lymphadenectomy alone 95.7%, and both procedures 95.2% (adjusted-P>0.05). Age≥50, T1b-c stages, and mucinous histology remained independent prognostic factors for decreased CSS (all, P<0.05). Among 3723 women with stage T1a disease, hysterectomy and lymphadenectomy patterns were not associated with CSS in 2115 women aged <50 (P=0.14) and 1608 women aged ≥50 (P=0.48). ConclusionOur study suggests that both hysterectomy and lymphadenectomy may be omitted in the surgical management of women with stage T1 BOTs, especially for those with T1a disease regardless of age.

New Pointers for Surgical Staging of Borderline Ovarian Tumors.

Surgical management of borderline ovarian tumors (BOTs) is similar to that of ovarian cancer apart from lymphadenectomy. However, the complete procedure including peritoneal washing, infracolic omentectomy and random peritoneal biopsies remains a subject of controversy especially in presumed early stage BOTs. To evaluate the prognostic value of complete surgical staging on recurrence rates, recurrence free (RFS) and overall survival (OS) in a multicentre cohort of BOTs. This retrospective multicentre study included 428 patients with BOTs diagnosed from January 1980 to December 2008. Survival estimates were based on Kaplan-Meier calculations and RFS defined as the time from the date of surgery to the date of recurrence. The median time of follow-up was 94.9 months (range: 60.00-207.3). The overall recurrence rate was 23.8 %. There was no difference in 5-year RFS between patients with and without complete surgical staging 78.1 % (95 % CI 68.9-88.6) and 70.9 % (95 % CI 64.6-77.8), (p = 0.0806). In the whole cohort, 5-year OS was higher for patients with complete surgical staging 98.4 % (95 % CI 96.8-1.0) and 93.8 % (95 % CI 88.1-1), (p = 0.0182) but this difference was not significant for patients with FIGO stage I 98.6 % (95 % CI 96.7-1) and 92.7 % (95 % CI 83.4-1.0), p = 0.1275, respectively. Complete staging surgery should be considered as a cornerstone treatment for patients with advanced stage BOT but not for those with stage I disease.

Fertility and borderline ovarian tumor: a systematic review of conservative management, risk of recurrence and alternative options

The aim of this systematic review was to evaluate the fertility outcome after borderline ovarian tumor (BOT) management and the results of conservative management, risk of recurrence and alternative options. The search strategy was based on relevant terms concerning BOT using Medline and the Central Cochrane Library. Both early and advanced stages of serous and mucinous BOT were included, but not rare entities such as endometrioid, Brenner or clear-cell BOT because of their low incidence. We considered all articles-case reports, original studies, meta-analyses and reviews-in English and French. Overall, 230 articles were screened of which 120 were retained for review. Most pregnancies were spontaneous but some data were obtained from studies analyzing the contribution of assisted reproductive technology (ART). However, not all studies differentiated spontaneous pregnancy from those obtained after fertility treatment including ovulation induction, intrauterine insemination and IVF. Conservative management of early stage BOT resulted in a pooled estimate for spontaneous pregnancy rate of 54% with a low risk of lethal recurrence (pooled estimate: 0.5%). In patients with advanced stage BOT, the spontaneous pregnancy rates was lower (34% in the single series reporting pregnancy rate in this context) and the risk of lethal recurrence increased (pooled estimate: 2%). This systematic review underlines that fertility subsequent to treatment of BOT depends mainly on histology and initial staging to distinguish early from advanced stages. In patients with advanced stage BOT, several alternative options to conservative management are available to allow patients to conceive without compromising their prognosis.

Outcomes of Controlled Ovarian Hyperstimulation/In Vitro Fertilization for Infertile Patients with Borderline Ovarian Tumor after Conservative Treatment

To evaluate the outcomes of controlled ovarian hyperstimulation (COH)-in vitro fertilization (IVF) such as clinical pregnancy rate (CPR), implantation rate (IR) and live birth rate (LBR) for infertile patients with borderline ovarian tumor (BOT) after conservative treatment, 10 IVF cycles in five patients from January 1999 to July 2005 were analyzed. At the time of diagnosis with BOT, the mean age of patients was 30.0 yr (range, 22-40). For 8 cycles out of 10 attempted IVF cycles, except for 2 cancellation cycles, the mean number of oocytes retrieved was 5.6 (range, 2-16) with a mean fertilization rate of 74.4%. The CPR, IR, and LBR were 50.0% (4/8 cycles), 31.6% (6/19) and 50.0% (4/8 cycles) respectively. The mean follow-up period after COH-IVF initiation was 29.6 (range, 14-61) months. A gynecological oncologist followed all patients every 3 months during the first year and every 6 months thereafter. There was no recurrence during the follow-up period. Our results suggest that COH-IVF may be acceptable for infertile patients with BOT, especially in patients with early-stage BOT after conservative treatment.

Impact of infertility treatment in patients with previous history of borderline ovarian tumors: Results of a multicenter study

5055 Background: The use of infertility drugs (ID) in infertile patients treated conservatively for ovarian malignancies remains theoretically contraindicated. Few recent case reports seem to suggest that ID could be used in patients treated for a borderline ovarian tumors (BOT). The aim of this multicenter retrospective study was to report the outcomes of the largest series of patients with a previous history of a BOT who underwent the use of ID. Methods: A multicenter retrospective study was conducted among centers which participate in the French National Register on In Vitro Fertilization registry to evaluate the outcomes of patients with a previous history of a BOT treated with ID. Four criteria were defined to select cases: 1. Histologic confirmation of BOT, 2. The use of a conservative surgery, 3. The use of ID and 4. A follow-up ≥ 12 months after the end of infertility treatment. Results: Thirty cases fulfilled inclusion criteria. Infertility therapy began in November 1989. Disease stages were: I (n = 20), II /III with noninvasive implants (n = 8) and unknown in 2 cases. The mean number of cycles of ovarian induction per patient was 2.6 (range,1–10). After a median follow-up of 42 months after infertility treatment, 4 recurrences were observed (all of them were borderline tumors on a remaining ovary treated by surgery alone). All patients are currently disease-free. Thirteen patients have since become pregnant. The median interval between treatment of the BOT and the use of ID is shorter in patients who relapsed compared to patients who did not (5 versus 29 months; p=.07). Conclusions: These results suggest that infertility drugs could be safely used in patients who experience infertility after conservative management of an early-stage BOT. A minimal interval should be respected between treatment of the ovarian tumor and the use of infertility drugs in order to decrease the risk of recurrence. No significant financial relationships to disclose.

Impact of surgical approach on the management of macroscopic early ovarian borderline tumors

Objective. The aim of this study was to evaluate the impact of the surgical approach on the management and outcomes of patients with early borderline ovarian tumors (BOTs). Material and methods. We retrospectively reviewed the medical charts of patients with stage Ia to Ic BOT treated surgically between January 1, 1985, and December 31, 2001. We compared patients initially managed by laparoscopy vs. laparotomy in terms of potentially harmful procedures and quality of staging. Results. Of the 118 included patients, 48 (41%) had laparoscopy for initial surgery, 54 (45%) had laparotomy, and 16 (14%) had conversion from laparoscopy to laparotomy. Conservative treatment (57% of patients) was more common with laparoscopy (vs. laparotomy, P < 0.05) and in women older than 44 years (vs. younger than 44 years, P < 0.001). Intraoperative tumor rupture occurred in 9% of patients and was not associated with the surgical approach ( P = 0.1). Bag extraction was used in 19 (40%) of the 48 laparoscopy patients. Staging was incomplete in 73% of patients overall. By univariate analysis, better quality of staging was associated with bilateral adnexectomy, age >44 years, laparotomy, hysterectomy, and treatment after 1995. By multivariate analysis, bilateral adnexectomy or hysterectomy was associated with better staging. Mean follow-up was 40 months, during which recurrence and survival rates were similar in the laparoscopy and laparotomy groups. Conclusion. Staging of macroscopic early stage BOTs was better in patients requiring radical surgery. After adjustment on disease severity, type of surgical access was not related to staging quality.

Traitement cœlioscopique des tumeurs frontières (borderline) de l'ovaire : analyse d'une série de 54 patientes et implications thérapeutiques

The aim of this study is to assess the clinical outcomes of laparoscopic treatment of borderline ovarian tumor (BOT). Retrospective analysis of 54 patients treated using a laparoscopic approach for a BOT between January 1984 and January 2002. A conservative management was initially performed in 45 patients (83%). Twenty-six patients underwent a reassessment surgery and 7 (27%) of them were upstaged following this procedure. Seven (13%) patients recurred in a remaining ovary following conservative surgery (5 patients) or on the peritoneum (2 patients). Three port-site localizations were observed. None of the patients treated with conservative management had recurrent disease under the form of ovarian carcinoma. Nine spontaneous pregnancies were observed in 6 patients from a group of 19 patients desiring pregnancy. All patients are today alive and disease-free. Our study suggests that laparoscopic treatment could be safely performed in young patients with early stage BOT. Such procedure should be further evaluated in patients with BOT and peritoneal implants.

Clinical outcome after laparoscopic pure management of borderline ovarian tumors: results of a series of 34 patients

BackgroundThe aim of this study was to assess clinical outcome after laparoscopic treatment of borderline ovarian tumor (BOT). Patients and methodsThirty-four patients treated initially and/or for recurrent disease using a laparoscopic approach for BOT from 1984 to January 2002. ResultsThirty-four patients underwent laparoscopic pure treatment (without conversion by laparotomy and/or reassessment surgery by laparotomy) for BOT. Conservative treatment was performed in 31 (91%) patients. Median follow-up time was 45 months (range 6–228). Six (17%) patients recurred (in the remaining ovary following conservative surgery in five patients and in the peritoneum in one patient). Two port-site metastases were observed. None of the patients had recurrent disease in the form of ovarian carcinoma. Nine spontaneous pregnancies were observed in six patients from a group of 15 patients desiring pregnancy. All patients are alive today and disease-free. ConclusionThese results seem to demonstrate that laparoscopic treatment can be safely performed in young patients with early stage BOT. Such a procedure is then feasible, but should be evaluated in patients with BOT and peritoneal implants.

Fertility and tumor recurrence rate after conservative laparoscopic management of young women with early-stage borderline ovarian tumors

Objective: To evaluate the efficacy of laparoscopic conservative surgery in young women with borderline ovarian tumors who want to preserve their childbearing potential, and to assess whether pregnancy influences the recurrence rate during the follow-up evaluation period. Design: Retrospective study. Setting: Center for Reconstructive Pelvic Endosurgery, Reproductive Medicine Unit, S. Orsola Hospital, University of Bologna, Italy. Patient(s): Nineteen women (mean age 27.4 ± 4.7) with borderline ovarian tumors who underwent laparoscopy between January 1995 and January 1998. All of the women wanted to preserve their fertility. Intervention(s): A standardized conservative laparoscopic approach and a strict follow-up schedule. Main Outcome Measure(s): A complete preoperative examination. Result(s): Follow-up evaluations (mean 42 ± 19 months) were made available to all patients. Among 19 patients, 10 attempted pregnancy and 6 conceived spontaneously. All six pregnancies went to term and the disease did not affect the gestation or the follow-up period after the pregnancy (24.5 ± 15.7 months). Conclusion(s): Conservative laparoscopic management of borderline ovarian tumors is a potentially safe alternative in young women who want to retain their childbearing potential. Fertility and pregnancy outcome remain excellent in these women. Our preliminary data seem to indicate that the recurrence rate after pregnancy is not influenced by this approach.

A trend toward more conservative surgery in gynecologic oncology.

A trend toward more conservative surgical intervention is evident in the current management of many gynecologic malignancies. The trend to manage vulvar carcinoma has moved away from the standard en bloc radical vulvectomy and bilateral lymphadenectomy and now consists of more limited excision of the primary tumor as well as of the regional lymph nodes. In preinvasive cervical carcinoma, conization is preferred instead of hysterectomy. The possibility for a more conservative surgical approach is also being explored for the treatment of selected early stage and advanced or recurrent cervical carcinomas. Although the primary surgical treatment of endometrial carcinoma remains unchanged, the necessity to perform (in all cases) the more extensive procedure required for staging purposes is being challenged. In early stage borderline ovarian tumors, not only adnexectomy but cystectomy alone is considered acceptable and reexploration for staging purposes may be unwarranted. In stage IA invasive carcinoma, adnexectomy of the involved side only is probably also sufficient. In advanced ovarian carcinoma, the more aggressive cytoreduction involving multiple organ resection is being restrained. Secondary debulking is performed only on a selective basis and the routine performance of second-look laparotomy has been given up.

Overexpression of p53 is not a feature of benign and early-stage borderline epithelial ovarian tumors.

Since overexpression of mutant p53 protein is a common feature of invasive epithelial ovarian cancers, we investigated whether overexpression of the p53 tumor suppressor gene product occurs in benign and borderline epithelial ovarian tumors. Immunohistochemical staining for p53 was performed in frozen samples of 17 benign tumors and in 49 borderline tumors (4 frozen, 45 paraffin embedded). Overexpression of p53 was observed in 0/17 (0%) benign ovarian tumors and 2/49 (4%) borderline tumors. Overexpression of p53 in borderline tumors was only seen in advanced stage cases; overexpression was seen in 2/8 (25%) stage III cases, but not in any of 41 stage I/II cases. In conclusion, overexpression of p53 is not a feature of benign epithelial ovarian tumors or early-stage borderline ovarian tumors. Similar to invasive epithelial ovarian cancers, however, a fraction of metastatic borderline tumors also overexpress p53.