Borderline ovarian tumour: pathological diagnostic dilemma and risk factors for invasive or lethal recurrence

By comparison with ovarian carcinomas, borderline ovarian tumours are characterised clinically by superior overall survival, even in women with peritoneal spread. In this Review, we aimed to clarify the histological and clinical factors potentially defining a high-risk group in whom disease is likely to evolve to invasive disease. Invasive peritoneal implants (in serous borderline ovarian tumours) and residual disease after surgery were the two factors clearly identified. Other factors are controversial owing to increased risk of invasive recurrence: micropapillary patterns in serous borderline ovarian tumour, intraepithelial carcinoma in mucinous lesions, stromal microinvasion in serous lesions, and use of cystectomy in mucinous borderline ovarian tumours. The pathologist has a pivotal role in assessment of the borderline nature of ovarian tumours and in identification of high-risk criteria, most of which are histological. But, reproducibility of the histological interpretation of some of these potential criteria--eg, classification of peritoneal implants (particularly in desmoplastic subtype), stromal microinvasion, micropapillary patterns, and intraepithelial carcinoma in mucinous borderline ovarian tumours--remains unclear, and should be investigated.     

Research Developments on the Histopathology and Prognostic Predictors of Serous Borderline Tumor of Ovary

Serous borderline tumor of ovary (SBT) includes two subtypes of typical serous borderline tumor and micropapillary variant, which have different histopathology features. Although SBTs behave in either way of the benign counterparts or malignant serous carcinomas, microinvasion,peritoneal implants, and nodal involvement are all very common in both subtypes of typical SBT and the micropapillary variant.The prognosis of the patients with serous borderline tumor of ovary and the mechanism of the microinvasion, peritoneal implantation and nodal involvement are still being debated, nor is there universal agreement about the management of SBT. To identify the histopathologic features, prognostic predictors of the SBT, and its association with ovarian serous carcinomas, we reviewed the majority of the relevant papers published in recent literature.     

Research developments on the histopathology and prognostic predictors of serous borderline tumor of ovary

Serous borderline tumor of ovary （SBT） includes two subtypes of typical serous borderline tumor and micropapillary variant, which have different histopathology features. Although SBTs behave in either way of the benign counterparts or malignant serous carcinomas, microinvasion, peritoneal implants, and nodal involvement are all very common in both subtypes of typical SBT and the micropapillary variant. The prognosis of the patients with serous borderline tumor of ovary and the mechanism of the microinvasion, peritoneal implantation and nodal involvement are still being debated, nor is there universal agreement about the management of SBT. To identify the histopathologic features, prognostic predictors of the SBT, and its association with ovarian serous carcinomas, we reviewed the majority of the relevant papers published in recent literature.     

Immunohistochemical staining of GLUT1 in benign, borderline, and malignant ovarian epithelia

BACKGROUND: Aberrant expression of the facilitative glucose transporter GLUT1 is found in a wide spectrum of epithelial malignancies. The authors describe an immunohistochemical study of GLUT1 expression in benign, borderline, and malignant ovarian epithelia. METHODS: One hundred forty one formalin-fixed, paraffin-embedded sections were immunostained with rabbit anti-GLUT1 using the streptavidin-biotin method. The samples were as follows: 3 endometriotic cysts, 9 serous cystadenomas, 15 mucinous cystadenomas, 17 noninvasive borderline implants, 3 invasive borderline implants, and 3 endosalpingiosis. In addition, 35 borderline tumors (26 serous, 7 mucinous, 2 seromucinous) and 56 adenocarcinomas (50 serous, 4 endometrioid, 2 mucinous) were stained. RESULTS: Benign serous and mucinous cystadenomas and endosalpingiosis were non-staining with GLUT1 antiserum. Twenty-eight of 35 borderline tumors (80%) stained positively, with weak to moderate (1-2+ out of 3) staining intensity and focal or patchy distribution. Seventeen noninvasive serous borderline implants were negatively stained; however, three invasive serous borderline implants were positively stained with GLUT1 antiserum. Fifty four of 56 ovarian carcinomas (96%) stained positively, with moderate to strong (2-3+ out of 3) intensity and multifocal distribution. CONCLUSIONS: GLUT1 is a consistent marker of ovarian epithelial malignancy. GLUT1 staining is absent in benign ovarian epithelial tumors, and shows progressively more staining in invasive tumors as compared to borderline tumors. Anti-GLUT1 antibody may be useful in distinguishing invasive from noninvasive serous borderline implants.     

Pathology of ovarian carcinoma

Serous carcinoma is the most common type of ovarian cancer and usually is associated with peritoneal metastases and poor survival except for meticulously staged patients with tumors confined to the ovaries. Endometrioid and clear cell carcinomas account for most nonserous carcinomas and more often present with low-stage disease; survival for the various cell types is similar when stratified by stage. Borderline ovarian tumors can be subdivided into benign and malignant neoplasms, and in the view of some experts, this renders the borderline category obsolete. Women with typical serous borderline tumors (atypical proliferative serous tumors) constitute most of these patients and have virtually 100% survival, unless invasive peritoneal implants are present. Micropapillary serous carcinomas (a less common variant, also called serous borderline tumor with a micropapillary pattern) and tumors with invasive implants behave similar to low-grade invasive carcinomas.     

Body size and risk of epithelial ovarian and related cancers: a population-based case-control study

Different subtypes of ovarian cancer appear to have different causes; however, the association between body mass index (BMI) and the different subtypes is unclear. We examined the associations between body-mass index (BMI) and weight gain and risk of the different histological subtypes of epithelial ovarian cancer in a case-control study in Australia. Cases aged 18-79 with a new diagnosis of invasive epithelial ovarian cancer (n = 1,269) or borderline tumor (n = 311) were identified through a network of clinics and cancer registries throughout Australia. Controls (n = 1,509) were selected from the Electoral Roll. Height and weight (1 year previously, at age 20 and maximum weight) and other risk factor information were ascertained via a self-administered questionnaire. Obesity was positively associated with clear cell tumors (Odds Ratio 2.3; 95% confidence interval 1.2-4.2) but not invasive endometrioid or mucinous tumors. Although there was no association with invasive serous tumors overall (0.9; 0.7-1.2), we did see an increased risk of serous peritoneal tumors (2.9; 1.7-4.9), but not of serous tumors of the ovary and fallopian tube. Of the borderline subtypes, obesity was positively associated with serous (1.8; 1.1-2.8) but not mucinous tumors (1.1; 0.7-1.7). Overweight was not associated with any subtype overall. There was no association with BMI at age 20, or weight gain for any of the histological subtypes. These results add to the current evidence that obesity increases a woman's risk of developing distinct histological subtypes of ovarian cancer.     

Molecular Characterization of 103 Ovarian Serous and Mucinous Tumors

The pathogenesis of ovarian carcinomas is heterogeneous, with even the same entities showing great variance. In our study we investigated the mutations of the BRAF, KRAS, and p53 genes in serous and mucinous borderline tumors and in low grade and high grade serous and mucinous tumors. The mutations of BRAF and KRAS genes have been shown in 60% of borderline and low grade (well differentiated) serous and mucinous tumors, but very rarely in high grade (moderately and poorly differentiated) carcinomas. However mutations of p53 are very common in high grade tumors and this indicates a "dualistic" model of ovarian tumorigenesis. A total of 80 serous tumors, including serous borderline, low grade and high grade tumors, and 23 mucinous tumors, including borderline and invasive tumors were analysed for BRAF and KRAS mutations using real time PCR method followed by melting point analysis. P53 mutation was investigated by immunohistochemistry. We assumed mutation of the p53 gene when 100% of tumor cells showed strong nuclear positivity. We observed differences in genetic alterations in the development of the low grade tumors and between low and high grade tumors too. In some bilateral or stage II-III cases we observed differences between the mutation status of the left and right ovarian tumors and between the primary tumor and its implants. In one case in a tumor with micropapillary pattern showing high grade nuclear atypia we could detect mutations in both KRAS and p53 genes. The majority of our mucinous ovarian tumor cases showed a KRAS mutation. We have not found mutations of the BRAF and p53 genes in these cases. We have found as have others, that there is a dualistic pathway of ovarian carcinogenesis. In the majority of cases, low grade epithelial tumors develop in a stepwise manner due to genetic alterations of the members of MAP-kinase pathway; however mutation of the p53 gene is the key event in the development of high grade tumors.     

Borderline epithelial tumours of the ovary--a retrospective analysis of 31 cases

Thirty one cases of epithelial borderline tumours of the ovary recorded over a period of six years were reviewed. The incidence of borderline tumours was 6% in relation to ovarian epithelial malignancies, with serous and mucinous types comprising three fourth of the lesions. The serous tumours were bilateral in 39%, revealed surface growth in 17% and had peritoneal implants in 11% of cases. The mucinous tumours were bilateral in 11% and had associated pseudomyxoma peritonei in 22% of cases. Nuclear grade appeared to correlate with extraovarian spread and surface growth in the serous borderline tumours, but not in the mucinous borderline tumours. The endometrioid borderline tumours and mixed epithelial borderline tumours were rare lesions. Twenty one patients (68%) presented in Stage-la. Surface growth correlated with recurrences. The prognosis remained good in serous borderline tumours even in the presence of implants as these were non-invasive. The mean disease free survival was 43.03 months. There was no statistical difference in disease free survival of patients with and without implants.     

Peritoneal washing cytologic analysis of ovarian serous tumors of low malignant potential to detect peritoneal implants and predict clinical outcome

BACKGROUND:

Patients with ovarian serous tumors of low malignant potential (OSLMP) who have peritoneal implants, especially invasive implants, are at an increased risk of developing tumor recurrence. To the best of the authors' knowledge, the ability of peritoneal washing (PW) cytology to detect the presence and type of peritoneal implants has not been adequately investigated, and its prognostic significance is unknown.

METHODS:

Records and PW specimens of 101 patients diagnosed with and treated for OSLMP between 1996 and 2010 at The University of Texas MD Anderson Cancer Center were retrospectively reviewed. Patients' staging biopsy findings were compared with the results of the authors' review of the PWs. Follow‐up data were also analyzed.

RESULTS:

Of the 96 patients for whom staging biopsy results were available, 26 (27%) had peritoneal implants (17 noninvasive and 9 invasive), 19 (20%) had endosalpingiosis, and 51 (53%) had negative findings. The PW specimens of 18 of the 26 patients (69%) with peritoneal implants were positive for serous neoplasm, and a correlation was found between cytologic and histologic findings (P < .0001). The sensitivity, specificity, positive predictive value, and negative predictive value were 69%, 84%, 62%, and 88%, respectively. Four of 101 patients had disease recurrence; 3 of these patients had invasive implants and 1 patient had noninvasive implants. None of the patients who had negative staging biopsy findings or endosalpingiosis but did have PW specimens that were positive for serous neoplasm developed disease recurrence.

CONCLUSIONS:

PW cytology detects the presence of peritoneal implants with moderate accuracy. However, long‐term studies are needed to determine whether positive PW cytologic findings are an independent predictor of tumor recurrence. Cancer (Cancer Cytopathol) 2012;. © 2012 American Cancer Society.     

卵巢交界性浆液、粘液性肿瘤病理诊断新概念

本文总结近年有关卵巢交界性浆液、小数点 液性肿瘤文献论述病理诊断的新概念。分别为：（1）卵巢交界性肿瘤基本诊断标准;（2）卵巢交界性浆液性肿瘤概括Piura(1992),Russel(1994)、Silva(1996),Eichhorn(1999),Scully(1999)病理诊断标准;（3）卵巢交界性粘液肿瘤概括Piura(1992),Kuman(1996),Riopel(1999),Scully(1999)病理诊断标准。（4）腹膜假粘液瘤;（5）上皮内癌;（6）微浸润;（7）种植;（8）淋巴结转移;（9）多中心性;（10）命名;（11）预后。     

WT1与P53在卵巢浆液性癌中的表达及意义

目的 检测WT1和P53在卵巢浆液性肿瘤中的表达,探讨其临床病理学意义及二者的关系.方法 采用免疫组化Envision二步法检测在卵巢良性浆液性肿瘤、交界性浆液性肿瘤和浆液性癌各40例中的WT1和P65表达情况,分析其表达水平与卵巢浆液性癌中临床病理特征的关系.结果 WT1在卵巢良性浆液性肿瘤、交界性肿瘤和浆液性癌中阳...     

Ovarian tumors of low malignant potential (borderline tumors): immune morphology and current status

CA 125, CA 19-9 and CEA were demonstrated in tissue samples of 30 ovarian borderline tumors by immunohistochemistry. Of the 21 serous and 9 mucinous borderline tumors, 23 were in stage I and 7 stage III. None of the patients died of disease. All mucinous borderline tumors were CA 125 negative, 89% CA 19-9 positive and 44% CEA positive. 62% of the serous borderline tumors were CA 125 positive, 52% CA 19-9 and 19% CEA positive. Tumors of low malignant potential responded to CA 19-9 like invasive carcinomas. The incidence of positive responses to CA 125 ands CEA fell between that of benign and malignant tumors. The marker pattern did not correlate with tumor stage and cytological grading. The biological behavior of ovarian borderline tumors ranges between that of benign tumors and invasive carcinomas and cannot be classified as definitely belonging to either group. It is plausible that they are primarily of the borderline type, and not benign tumors that undergo malignant degeneration.     

Risk of specific types of ovarian cancer after borderline ovarian tumors in Denmark: A nationwide study

Population-based evidence regarding risk of ovarian cancer after a borderline ovarian tumor (BOT) is sparse. We aimed to examine the incidence of specific types of ovarian cancer in women with serous or mucinous BOTs in a nationwide cohort study with up to 36 years of follow-up. Using the nationwide Danish Pathology Data Bank, we identified 4,281 women with a BOT (2,058 serous BOTs and 2,223 mucinous BOTs) in Denmark during 1978–2012. We computed standardized incidence ratios (SIRs) to compare the incidence of ovarian cancer among women with BOTs compared to general population rates. We found that a serous BOT was especially and strongly associated with subsequent serous ovarian cancer (SIR = 9.2; 95% CI: 6.8–12.2), and that a mucinous BOT was strongly related to mucinous ovarian cancer (SIR = 18.6; 95% CI: 10.8–29.8). The SIRs remained elevated ≥10 years after a serous BOT and up to 5–9 years after a mucinous BOT. The increased incidence of serous ovarian cancer in women with a serous BOT was mostly pronounced in women <50 years at the serous BOT diagnosis. In conclusion, women with a serous BOT experience long-term increased incidence of serous ovarian cancer, and women with a mucinous BOT have long-term elevated incidence of mucinous ovarian cancer compared to the general population. This is the first population-based study to show compelling evidence of the histo-specific increased risk of ovarian cancer following specific types of BOTs. Thus, these results are supportive of the hypothesis that BOTs may be precursor lesions to carcinomas of the corresponding histologic type.     

Tumor protein D52 (TPD52) is overexpressed and a gene amplification target in ovarian cancer

Recurrent chromosome 8q gain in ovarian carcinoma is likely to reflect the existence of multiple target loci, as the separate gain of chromosome bands 8q21 and 8q24 has been reported in independent studies. Since tumor protein D52 (TPD52) has been identified as a chromosome 8q21 amplification target in breast and prostate carcinoma, we compared TPD52 expression in normal ovarian epithelium (n = 9), benign serous adenomas (n = 11), serous borderline tumors (n = 6) and invasive carcinomas of the major histologic subtypes (n = 57) using immunohistochemistry. These analyses revealed that all normal ovarian epithelium samples and benign serous tumors were predominantly TPD52-negative, whereas TPD52 was overexpressed in most (44/57; 77%) ovarian carcinomas regardless of histologic subtype. TPD52 subcellular localization was predominantly cytoplasmic, although nuclear localization was also frequently observed in mucinous and clear cell carcinomas. In an independent cohort of stage III serous carcinomas (n = 18), we also directly compared in situ TPD52 expression using immunohistochemistry and TPD52 copy number using interphase FISH analyses. This revealed that TPD52 dosage and TPD52 expression were significantly positively correlated. TPD52 therefore represents a novel molecular marker in ovarian cancer, which is broadly expressed across the different histologic subtypes and whose upregulation frequently reflects increased TPD52 copy number.     

Invasive and noninvasive implants in ovarian serous tumors of low malignant potential

Ovarian serous tumors of low malignant potential ("borderline" serous tumors) are classified according to the histologic features of the primary ovarian tumor, without regard to any coexisting extraovarian disease. The peritoneal implants display a range of histologic appearances, ranging from benign glands (endosalpingiosis), to noninvasive papillary glandular proliferations resembling the ovarian neoplasms, to irregular glands associated with a desmoplastic stroma and having features of invasive disease. This review of 16 patients with histologically documented extraovarian tumor implants seen at Indiana University Medical Center, Indianapolis, and 13 patients whose tumor implants have been previously described in the literature indicates that the clinical stage of disease has much greater prognostic significance than does the implant histologic features. There is a tendency for patients with more advanced disease to have invasive implants. However, within a given clinical stage, disease progression or recurrence was not influenced by the presence or absence of invasive histologic characteristics in the tumor implants.     

Ⅰ期卵巢交界性肿瘤剥除术后复发危险因素分析

目的：探讨年轻卵巢交界性肿瘤患者行肿物剥除术后复发的危险因素。方法回顾性分析49例行卵巢肿瘤剥除术,年龄﹤35岁,术后病理为Ⅰ期的卵巢交界性肿瘤（BOT）患者的临床及随访资料,分析术后复发的危险因素。结果随访患者中共7例复发,5年生存率为100%,无复发生存率为91.8%,不同年龄、分期、是否存在间质浸润患者术后复发情况比较,差异无统计学意义（P﹥0.05）;黏液性肿瘤及微乳头型卵巢交界性肿瘤患者复发比例高于浆液性肿瘤及非微乳头型肿瘤患者,差异有统计学意义（P﹤0.05）。结论Ⅰ期BOT单侧病变患者,若术中冰冻结果为黏液性或微乳头型肿瘤,宜行患侧附件切除术;双侧病变患者,若无上述危险因素可行双侧卵巢肿物剥除术,若存在上述危险因素可行单侧附件切除术+对侧卵巢肿物剥除术。     

Behavior of borderline tumors with particular interest to persistence, recurrence, and progression to invasive carcinoma: a prospective study.

PURPOSE: Borderline tumors account for 10% to 20% of epithelial ovarian tumors, and their prognosis is outstanding; nevertheless, a mortality of up to 20% has been reported, particularly in earlier reports. There is a lack of information about the actual mortality and the rate of progression into invasive carcinoma in large and prospectively accrued populations. PATIENTS AND METHODS: All women with borderline ovarian tumors undergoing primary surgery in our department or referred within 3 months from surgery performed elsewhere from 1982 to 1997 were prospectively accrued and observed. RESULTS: We studied 339 women (83.4% stage I, 7.9% stage II, and 8.5% stage III). The median age at diagnosis was 39 years. A total of 150 women underwent radical surgery, and 189 underwent fertility-sparing surgery. After surgery, 13 women had macroscopic residual disease. With a median follow-up of 70 months, 317 women are alive with no clinical disease (eight with documented subclinical persistence of implants), three are alive with clinical disease, two died of disease, 10 died of other reasons, and seven women have been lost to follow-up. The recurrence of disease was higher after fertility-sparing surgery (35 of 189 cases) than after radical surgery (seven of 150 cases); nevertheless, all but one woman with recurrence of borderline tumor or progression to carcinoma after conservative surgery were salvaged. We observed seven progressions (2.0%) into invasive carcinoma, five in serous tumors (2.4%), and two in mucinous tumors (1.6%). The disease-free survival is 99.6% in stage I patients, 95.8% in stage II, and 89% in stage III. CONCLUSION: The survival of patients with borderline tumors is higher than previously described in some retrospective studies. Conservative surgery is safe and may be proposed to several patients with early and disseminated disease after thorough discussion of all therapeutic options. Progression to carcinoma is approximately 2% and may be observed in both mucinous and serous tumors.     

Common epithelial tumors of borderline malignancy (carcinomas of low malignant potential)

The creation of the category of ovarian borderline tumors has been a step forward in classification because it has segregated from the general group of common epithelial cancers a subgroup with an unusually good prognosis. Of all borderline tumors, the serous variety is the least difficult for the pathologist to diagnose. The mucinous borderline tumor is not as easy to recognize when an absence of invasion is used as the sole diagnostic criterion, but evaluation of other architectural as well as cytological features is helpful in making the diagnosis. Although the treatment of the majority of serous and mucinous borderline tumors is well standardized, therapy of residual serous borderline tumor is highly controversial and the treatment for pseudomyxoma peritonei, unsatisfactory. Borderline tumors exist in the endometrioid, clear cell, Brenner, and mixed common epithelial categories, but these tumors have been too rare to date in order to clearly characterize their clinical and pathological features. It is hoped that more can be learned about this general group of tumors by a more widespread recognition of their distinctive clinico-pathologic features and by their acceptance as a special subgroup of ovarian cancer. Their behavior differs strikingly from that of other types of malignant ovarian tumors and it is clear that their management should differ accordingly.     

Quantitative analysis of follicle-stimulating hormone receptor in ovarian epithelial tumors: a novel approach to explain the field effect of ovarian cancer development in secondary mullerian systems

The role of FSHR expression in ovarian cancer development is not clear. We examined quantitative expression of FSHR in different types of OET, presumed precursor lesions and peritoneal implants and further discussed FSH as a key growth-promotion factor for the process of ovarian epithelial tumorigenesis. Thirty-five primary OET specimens, including 5 serous cystadenomas, 4 papillary serous cystadenomas, 9 SBTs and 17 serous carcinomas, were examined for quantitative FSHR expression. Ten paired samples (3 benign cystadenomas, 5 SBTs and 2 carcinomas) were obtained from several morphologically different areas, including benign-looking, borderline and cancerous areas in the same OETs, and from the remaining ovarian tissue and contralateral ovaries. Competitive RT-PCR was performed to measure the quantitative expression of FSHR in each tissue sample. FSHR expression levels were compared among nonpaired samples and within paired samples. We found that OSE had the lowest FSHR expression, whereas antral follicles had the highest level. Within benign OETs, papillary serous cystadenomas have 4.9-fold higher FSHR levels than nonpapillary serous cystadenomas. SBTs had the highest level of FSHR expression, which was 12.8-fold, 2.7-fold and 2.4-fold higher than that of serous cystadenomas, papillary serous cystadenomas and grade 1 carcinomas, respectively. A similarly high level of FSHR mRNA was found in peritoneal implants, which were associated with SBTs. FSHR levels among serous carcinomas decreased with an increase in carcinoma grade. Grade 3 carcinomas had the lowest FSHR level, which was similar to that of serous cystadenomas, while grade 1 carcinomas had 6.5-fold higher FSHR levels than those in serous cystadenomas. Our results suggest that not only serum FSH but also FSHR in ovarian epithelium may play important roles in ovarian OET development. Both the receptor and ligand may act in a synergistic way to promote tumor growth. The observation that high FSHR levels are present in peritoneal implants suggests that FSH may also play a similar role in the development of peritoneal serous tumors. From this perspective, circulating FSH may be considered a driving force in the field effect theory for the development of both ovarian neoplasms and their associated peritoneal implants. However, the exact role of FSH and/or FSHR in the development of epithelial tumors arising in both the ovary and peritoneum needs further investigation.     

Lewis y抗原及整合素α_5、β_1在卵巢浆液性肿瘤中的表达及意义

目的：研究Lewis y抗原及整合素α5、β1在卵巢浆液性肿瘤中的表达及其意义。方法：应用免疫组织化学方法检测30例卵巢浆液性囊腺癌、11例交界性卵巢浆液性囊腺瘤、13例卵巢浆液性囊腺瘤、11例正常卵巢组织中Lewis y抗原及整合素α5、β1的表达情况。结果：Lewis y抗原在卵巢浆液性囊腺癌中的阳性表达率为90.0%,明显高于交界性（63.6%）、良性卵巢浆液性囊腺瘤（38.5%）及正常卵巢组织（0）中的表达（P均〈0.05）。整合素α5、β1在卵巢浆液性囊腺癌中的阳性表达率分别为86.7%和83.3%,高于两者在交界性（72.7%,72.7%）、良性卵巢浆液性囊腺瘤（69.2%,53.8%）及正常卵巢组织（36.4%,36.4%）中的表达（P均〈0.05）。Lewis y抗原及整合素α5、β1在卵巢浆液性囊腺癌中的表达呈显著正相关（P均〈0.01）。结论：Lewis y抗原及整合素α5、β1在卵巢浆液性囊腺癌中的阳性表达率普遍增高,且两者的表达呈显著性正相关。提示Lewis y抗原及整合素α5、β1在卵巢浆液性囊腺癌的发生、发展中起着重要作用。