Micropapillary Serous Carcinoma Research Articles

Abstract LB-039: PDX and PDX-derived cell line development from peritoneal metastasis of micropapillary serous carcinoma of the ovary

Abstract Peritoneal spread is an indicator of poor prognosis in patients with micropapillary serous carcinoma of the ovary. In general, these patients are treated by surgical cytoreduction followed by intraperitoneal chemotherapy. Although this strategy has encouraging efficacy, personalized treatment regimens may potentially further improve efficacy of cancer management. To investigate such a personalized approach, patient-derived xenografts (PDX) and PDX-derived cell lines from peritoneal implants from micropapillary serous carcinoma of the ovary are developed and characterized. Freshly resected peritoneal implants from consenting donors were obtained. A cell suspension was made and immediately subperitoneally implanted in female immunocompromised mice and expanded as peritoneal metastasis (PM)-PDX. A transplantable PM-PDX was established from 1/1 donor. Histology confirmed the micropapillary and cribriform growth pattern, which was further characterized by intraluminal tumor budding. PM-PDX dissociated cells were maintained as a plastic-adherent cell culture up to 20 passages. The PM-PDX derived cell line is characterized by an epithelial morphotype with doubling time of 42 hours and shows a colony formation efficiency of 25-40% independent of estrogen signaling. The cell line is sensitive to the microtubule stabilizing agent paclitaxel (IC50 = 1.485 nM) and the allosteric MEK inhibitor trametinib (IC50 = 1.299 nM). Future work will provide insights on the mutational status of RAS and RAF, important indicators of potential MEK-targeted personalized medicine. Citation Format: Elien De Thaye, An Vermeulen, Wim Ceelen, Jan Van Bocxlaer, Olivier De Wever. PDX and PDX-derived cell line development from peritoneal metastasis of micropapillary serous carcinoma of the ovary [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-039.

Is Invasive Micropapillary Serous Carcinoma a Low-grade Carcinoma?

"Invasive micropapillary serous carcinoma" has been proposed as a synonym for low-grade serous carcinoma by some expert pathologists. In contrast, Singer and colleagues reported that some serous carcinomas with conspicuous invasive micropapillary pattern (SC-IMPs) can show high-grade nuclear atypia. However, the molecular features of such tumors have not been well documented. The aim of this study was to demonstrate and emphasize the fact that high-grade serous carcinoma confirmed by immunohistochemistry and molecular analysis can show conspicuous invasive micropapillary pattern. We selected 24 "SC-IMPs" and investigated: (1) their morphologic features; (2) the immunostaining pattern of p53 protein; and (3) KRAS/BRAF/TP53 gene mutations. The 24 SC-IMPs were subdivided into low-grade and high-grade tumors based primarily on the nuclear atypia, with the mitotic rate used as a secondary feature: low grade (n=5) and high grade (n=19). Low-grade SC-IMPs were characterized by low-mitotic activity, absence of abnormal mitosis, presence of serous borderline tumor, occasional BRAF mutation, and infrequent TP53 mutation. High-grade SC-IMPs were characterized by high-mitotic activity, presence of abnormal mitosis, conventional high-grade serous carcinoma, frequent TP53 mutation, and lack of KRAS/BRAF mutation. We demonstrated that high-grade serous carcinoma confirmed by aberrant p53 immunostaining and molecular analysis can show conspicuous invasive micropapillary pattern, validating Singer and colleague's report. Serous carcinoma with conspicuous invasive micropapillary pattern should not be readily regarded as low-grade serous carcinoma. Nuclear grade is the most important diagnostic feature in the SC-IMPs.

Two-tier system on the origin of epithelial ovarian carcinomas and associated molecular biological basis

Ovarian epithelial carcinomas are the most common lethal gynecological malignancies. Ovarian carcinomas are divided into Types I and II based on different morphologies, genetic alterations, and biomarker expression. Low-grade micropapillary serous carcinoma are Type I tumors. Type I tumors are slow growing, generally confined to the ovary at diagnosis, and with better prognosis. These tumors develop from well established precursor lesions that are termed "borderline" tumors. Type 1 tumors are genetically stable and are characterized by mutations in a number of different genes including KRAS, BRAF, PTEN, and beta-catenin. Type II tumors are rapidly growing and highly aggressive neoplasms, for which well defined precursor lesions have not been described. They may arise in the fimbrial epithelium of the oviduct with advanced stage, more aggressive behavior, and worse prognosis. High-grade serous carcinoma belongs to Type II tumors. This group of tumors has a high level of genetic instability and is characterized by TP53 mutation. Hence, ovarian cancer comprises a heterogeneous group of tumors with distinctly different histological characteristics, molecular genetic features, and clinical course.

Unusual Skin Metastasis in a Patient with Recurrent Micropapillary Serous Ovarian Carcinoma – A Case Report and Review of the Literature

The presence of skin metastasis in ovarian cancer patients is uncommon and related with poor prognosis. We report a 49-year-old patient with recurrent ovarian cancer presented with extensive skin metastasis on the anterior chest (including bilateral breast skin), lower abdomen, vulva and the upper part of the lower limbs at 21 months after initial diagnosis of ovarian cancer. The skin biopsy revealed metastasis of adenocarcinoma in the dermis. The patient underwent palliative chemotherapy and she died after 2 months of the diagnosis of the skin metastasis. It is the first case of skin metastasis from a micropapillary serous ovarian carcinoma published in Romania.

Fallopian tube precursors of ovarian low‐ and high‐grade serous neoplasms

Traditionally, it was thought that ovarian high-grade serous carcinoma arises from the ovarian surface epithelium and epithelial inclusion glands and that the pathogenesis is de novo; nonetheless, a convincing precursor in the ovary or peritoneum has not been identified to date. During the last few years, however, there has been a dramatic shift in thinking, and a candidate precursor is now recognized in the fallopian tube, especially within the fimbriated end - serous tubal intra-epithelial carcinoma (STIC). Accordingly, STIC is probably the earliest histologically recognizable lesion in the pathogenesis of high-grade serous carcinoma, but steps in this pathway which precede STIC have also been proposed. With subsequent progression, STIC implants onto the ovary and then develops into an invasive high-grade serous carcinoma with rapid tumour growth. For invasive low-grade serous carcinoma, it is well-established that its pathogenesis begins with serous cystadenoma/adenofibroma, which develops sequentially into atypical proliferative serous tumour (typical serous borderline tumour), non-invasive micropapillary (low-grade) serous carcinoma (micropapillary serous borderline tumour) and then invasive low-grade serous carcinoma in a relatively slow stepwise process. It is presumed that cystadenoma/adenofibroma arises from epithelial inclusion glands in the ovary, but recent evidence suggests that epithelial inclusion glands originate in the fallopian tube. Alternatively, it has been proposed that the other early precursors in the low-grade pathway, including serous borderline tumours, non-invasive implants and endosalpingiosis, may also arise directly from tubal mucosa. Therefore, the precursor of most ovarian high-grade serous carcinomas originates in the fallopian tube, and that for low-grade serous tumours may also be derived from the tube. This review paper provides an overview of the fallopian tube's potential role in the pathogenesis of both types of serous neoplasms of the ovary.

Abstract 363A: PAX2 is an oncogene in type I ovarian cancer

Abstract Ovarian cancer is the second most common gynecologic malignancy, but the most lethal gynecologic cancer. Ovarian cancer is divided into Type I and Type II subgroups. Type I tumors include low-grade micropapillary serous carcinoma, mucinous, endometrioid, and clear cell carcinomas and are characterized by high frequency of KRAS, BRAF, PTEN, or beta-catenin mutations. Type II tumors include high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcomas) and undifferentiated carcinomas and are characterized by high genetic instability and high frequency of TP53 mutation. Using gene expression profiling, we found that Pax2, a transcription factor of the Pax gene family, is highly expressed in type I ovarian tumors but is less expressed in Type II tumors. Pax2 is one of the nine Pax genes which have a conserved DNA sequence motif called the paired box, a 128 amino acid domain in the amino-terminal portion of the protein. Pax2 regulates tissue development and cellular differentiation in embryos and Pax2 expression is attenuated after development. Unattenuated Pax2 expression has been found in several cancer types, but the function of Pax2 in ovarian cancer is not clearly understood. In this study, we further validated the expression of Pax2 in Type I ovarian cancer by immunohistochemistry, western blot analysis and quantitative real-time PCR. Furthermore, the expression of Pax2 in two Type I ovarian cancer cell lines (RMUGL and TOV21G) was knockdown by Pax2 specific shRNA. By comparing to the control non-target shRNA cancer cell lines and the parental cell lines, Pax2 knockdown cell lines have significant reduction in growth rate as measured by WST cell proliferation assay. From the gene expression profiles of three independent Pax2 knockdown cell lines, we identified 196 genes that were significantly affected by the down-regulation of Pax2. Many of these genes are involved in cell cycle control, cellular growth and proliferation, and the TP53 pathway such as BBC3, CHEK1, GADD45A and GADD45B and JUN genes. This suggests that Pax2 may play an oncogenic role in the pathogenesis of ovarian cancer through a TP53-dependent pathway. Since immunotherapy targeting Pax2 is currently being developed, Pax2 could be a therapeutic target for Type I ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 363A.

Low-grade Serous Carcinoma of the Ovary Displaying a Macropapillary Pattern of Invasion

Invasive micropapillary serous carcinoma (MPSC) also designated "low-grade serous carcinoma" (LGSC) of the ovary is characterized by small micropapillae that infiltrate underlying tissue (ovarian stroma). On occasion these tumors in addition to the micropapillae contain large macropapillae lined by bland epithelium. In rare cases, the entire tumor is composed of macropapillae. In these cases, the question of whether this is an invasive carcinoma or an unusual type of adenofibroma has been raised. The goal of this study was to describe this unusual macropapillary pattern of invasion in LGSC. Cases of LGSC containing macropapillae were retrieved from the files of the Johns Hopkins Hospital. In addition to a detailed morphologic analysis, the mutational status of KRAS and BRAF in the macropapillary, noninvasive, and invasive MPSC components was analyzed by nucleotide sequencing. There were 14 cases containing macropapillae (11 cases of LGSC, 2 cases of atypical proliferative serous tumor (APST) with microinvasion, and 1 case of APST with a focus of LGSC with macropapillae in perivaginal soft tissue). In 3 cases, extraovarian metastases contained macropapillae. Molecular analysis of the primary tumor components (macropapillary, noninvasive, and invasive MPSC and/or APST) was performed in 7 cases and of a lymph node metastasis with macropapillae in 1 case. The identical KRAS mutation was detected in all of the analyzed components of the primary ovarian tumors in 4 cases. In one of these cases, macropapillae in the lymph node metastasis contained a KRAS mutation identical to the primary tumor. The BRAF mutation identified in 1 case was identical in all components of the ovarian tumor. The identical mutations in the macropapillae and the other tumor components in each case indicate that they are clonally related. The finding of macropapillae within lymph nodes supports the interpretation that the macropapillary component is another manifestation of invasion in LGSC. The recognition of this pattern is important, especially in cases when a tumor is composed entirely of macropapillae.

Subdividing Ovarian and Peritoneal Serous Carcinoma Into Moderately Differentiated and Poorly Differentiated Does not Have Biologic Validity Based on Molecular Genetic and In Vitro Drug Resistance Data

Serous carcinoma of the ovary has been traditionally graded as well-differentiated, moderately differentiated, and poorly differentiated (ie, a 3-tier system). A new 2-tier system grades serous carcinomas into low or high grade. Recent morphologic and molecular studies have shown that invasive well-differentiated serous carcinoma, referred to by us as "invasive low-grade micropapillary serous carcinoma," is clearly distinct from high-grade serous carcinoma from the standpoint of pathogenesis and clinicopathologic features. As high-grade serous carcinoma is histologically heterogeneous, the goal of this study was to determine, based on molecular and drug resistance data, whether further subclassification of high-grade serous carcinomas into additional grades (moderately and poorly differentiated) has biologic validity. One hundred eleven ovarian and peritoneal high-grade serous carcinomas further subclassified as moderately and poorly differentiated types using the International Federation of Gynecology and Obstetrics (FIGO) grading system were analyzed for TP53 mutations and in vitro extreme drug resistance to 10 chemotherapeutic drugs. Seventy-six and 35 cases were subclassified as moderately and poorly differentiated, respectively. A TP53 mutation was present in 84% of moderately and 70% of poorly differentiated types of high-grade serous carcinomas, respectively (P=0.21), and there were no significant differences in the frequency of extreme drug resistance for each of the 10 drugs tested (P values ranging from 0.14 to >0.99). Although additional investigation is warranted, this study suggests that subclassification of high-grade serous carcinoma into moderately and poorly differentiated is not relevant. Accordingly, they can be simply classified as high-grade serous carcinoma.

Pathogenesis of Ovarian Cancer

The accepted view of ovarian carcinogenesis is that carcinoma begins in the ovary, undergoes progressive "dedifferentiation" from a well to a poorly differentiated tumor, and then spreads to the pelvic and abdominal cavities before metastasizing to distant sites. It has therefore been reasoned that survival for this highly lethal disease could be improved by developing screening methods that detect disease when it is confined to the ovary. To date, however, no prospective randomized trial of any ovarian cancer screening test(s) has demonstrated a decrease in mortality. We believe that one of the main reasons for this is that the dogma underlying ovarian carcinogenesis is flawed. Based on studies performed in our laboratory during the last decade, we have proposed a model of ovarian carcinogenesis that takes into account the diverse nature of ovarian cancer and correlates the clinical, pathological, and molecular features of the disease. In this model, ovarian tumors are divided into 2 groups designated type I and type II. Type I tumors are slow growing, generally confined to the ovary at diagnosis, and develop from well-established precursor lesions that are termed "borderline" tumors. Type I tumors include low-grade micropapillary serous carcinoma, mucinous, endometrioid, and clear cell carcinomas. They are genetically stable and are characterized by mutations in a number of different genes including KRAS, BRAF, PTEN, and beta-catenin. Type II tumors are rapidly growing highly aggressive neoplasms for which well-defined precursor lesions have not been described. Type II tumors include high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinomas. This group of tumors has a high level of genetic instability and is characterized by mutation of TP53. The model helps to explain why current screening techniques, aimed at detecting stage I disease, have not been effective. Tumors that remain confined to the ovary for a long period belong to the type I group, but they account for only 25% of the malignant tumors. Most of what is considered ovarian cancer belongs to the type II category, and these are only rarely confined to the ovary. Although the reasons for this are not entirely clear, possible explanations include rapid spread from the ovary early in carcinogenesis and development of carcinoma in extra ovarian sites, notably, the peritoneum and fallopian tube, with secondary involvement of the ovary. The latter tumors are advanced stage at their inception. Therefore, a more realistic end point for the early detection of ovarian cancer is volume and not stage of disease. The model does not replace the histopathologic classification but, by drawing attention to the molecular genetic events that play a role in tumor progression, sheds light on new approaches to early detection and treatment.

Skin metastases revealing a bilateral ovarian invasive micropapillary serous carcinoma

Skin involvement is a late complication that rarely occurs in ovarian cancer patients. This event invariably carries a bad prognosis in the course of an advanced stage ovarian carcinoma which is usually of the conventional serous type. Micropapillary serous carcinoma (MPSC) was recently recognized as a distinct neoplasm that seems to be less aggressive than conventional serous ovarian carcinoma. Indeed, a few cases of stage IV MPSC have been reported. Herein, we describe an unusual case of ovarian invasive MPSC occurring in a young woman, particularly by its mode of presentation as multiple subcutaneous nodules that were subsequently diagnosed as metastatic lesions. This case demonstrates the potential of MPSC for aggressive clinical behaviour.

Germ line and somatic mutations of BRAF V599E in ovarian carcinoma

It has been shown that ovarian low-grade serous carcinoma evolves out of a stepwise progression from benign serous cystadenoma to serous borderline tumor (SBT) to micropapillary serous carcinoma (MPSC), and that BRAF activation is a very early somatic event in the tumorigenesis. We postulated that BRAF could be a SBT susceptibility gene, and investigated both germ line and somatic mutations of BRAF V599E in 104 ovarian cancer patients. BRAF V599E mutation in histologic samples was found in 5 (24%) of 21 SBTs, 1 (33%) of 3 MPSCs, 1 (17%) of 6 endometrioid carcinomas, but not detected in 42 conventional serous carcinomas, 12 mucinous borderline tumors, 10 mucinous, and 10 clear-cell carcinomas. No V599E mutation could be detected in blood samples from these 104 patients. We also found no BRAF V599E mutation in 101 normal healthy women and 10 well-established ovarian cancer cell lines. Our results suggest that BRAF gene plays a “gatekeeper” role but does not act as a predisposition gene in the development of low-grade serous carcinomas

Micropapillary Serous Carcinoma

Noninvasive micropapillary serous carcinoma of the ovary is also referred to as the micropapillary variant of serous borderline tumor and displays a characteristic pattern of papillary branching but lacks invasion. In contrast, invasive micropapillary serous carcinoma is the usual form of low-grade invasive serous carcinoma. There is a consensus that peritoneal “implants” associated with serous borderline tumors that display invasive features (“invasive implants”) have a poor prognosis with a 7-year survival of 66%, and can also be referred to as invasive carcinoma. Evidence indicates that noninvasive micropapillary serous carcinoma has a strong association with invasive implants as compared with typical serous borderline tumors (49% vs. 7%, respectively, P < 0.0001). After excluding micropapillary serous borderline tumors and those with invasive implants, the remaining patients with serous borderline tumors have a survival of virtually 100%, thereby obviating the need for the serous borderline category.

The Development of High-grade Serous Carcinoma From Atypical Proliferative (Borderline) Serous Tumors and Low-grade Micropapillary Serous Carcinoma

Recently, we have proposed a model for the development of ovarian surface epithelial tumors. In this model, all histologic types of surface epithelial tumors are divided into 2 categories designated type I and type II which correspond to 2 pathways of tumorigenesis. Type I tumors include low-grade serous carcinoma, mucinous carcinoma, endometrioid carcinoma, malignant Brenner tumor, and clear cell carcinoma which develop slowly in a stepwise fashion from well-recognized precursors, namely atypical proliferative (borderline) tumors. Type II tumors are high-grade, rapidly growing tumors that typically have spread beyond the ovaries at presentation. They include high-grade serous carcinoma ("moderately" and "poorly" differentiated), malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinoma. These tumors are rarely associated with morphologically recognizable precursor lesions and it has been proposed that they develop "de novo" from ovarian inclusion cysts. This model implies that the pathogenesis of type I and type II tumors are separate and independent but it is not clear whether some type II tumors develop from type I tumors. In this study, we attempted to address this issue by determining the clonality of 6 cases of high-grade serous carcinomas that were closely associated with atypical proliferative serous (borderline) tumors and invasive low-grade micropapillary serous carcinomas. We reviewed 210 ovarian serous tumors from the surgical pathology files of the Johns Hopkins Hospital and identified 3 high-grade serous carcinoma that were directly associated with atypical proliferative serous (borderline) tumors and 3 that were associated with invasive low-grade micropapillary serous carcinomas. A morphologic continuum between the high-grade carcinoma and the low-grade tumors was observed in 4 cases whereas in the remaining 2 cases the high-grade and low-grade components were separate. Mutational analyses for KRAS, BRAF, and p53 genes were performed on microdissected samples from the high-grade and low-grade tumor areas for each case. All 6 tumors demonstrated wild-type BRAF and p53 genes. Only 2 of the 6 cases were informative from a molecular genetic standpoint. In those 2 cases we found the same mutations of KRAS in both the atypical proliferative serous (borderline) tumor and the high-grade serous carcinoma component of the tumor, indicating a clonal relationship. The above results suggest that the majority of high-grade and low-grade carcinomas develop independently but in rare cases, a high-grade serous carcinoma may arise from an atypical proliferative serous (borderline) tumor.

Germ line and somatic mutations of BRAF V599E in ovarian carcinoma

It has been shown that ovarian low-grade serous carcinoma evolves out of a stepwise progression from benign serous cystadenoma to serous borderline tumor (SBT) to micropapillary serous carcinoma (MPSC), and that BRAF activation is a very early somatic event in the tumorigenesis. We postulated that BRAF could be a SBT susceptibility gene, and investigated both germ line and somatic mutations of BRAF V599E in 104 ovarian cancer patients. BRAF V599E mutation in histologic samples was found in 5 (24%) of 21 SBTs, 1 (33%) of 3 MPSCs, 1 (17%) of 6 endometrioid carcinomas, but not detected in 42 conventional serous carcinomas, 12 mucinous borderline tumors, 10 mucinous, and 10 clear-cell carcinomas. No V599E mutation could be detected in blood samples from these 104 patients. We also found no BRAF V599E mutation in 101 normal healthy women and 10 well-established ovarian cancer cell lines. Our results suggest that BRAF gene plays a "gatekeeper" role but does not act as a predisposition gene in the development of low-grade serous carcinomas.

Bilateral micropapillary serous carcinoma of the ovary: a case report

Micropapillary serous carcinoma (MPSC), a recently described entity in the group of serous borderline tumor, needs to be recognized and separated from serous borderline tumor of usual type (SBT) as MPSC has a worse prognosis. We report the case of a 21-year-old female with gradually increasing lump abdomen for 6 months. Ultrasonography showed bilateral ovarian enlargement with cysts. Laparotomy revealed both ovaries to be enlarged and right ovary showed capsular breach. With a per-operative diagnosis of bilateral malignant ovarian tumor, total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed. Multiple sections from both ovaries showed non-invasive micropapillary serous carcinoma with right ovary showing surface growth but no definite capsular breach. The final histological diagnosis was bilateral micropapillary serous carcinoma. The patient has been asymptomatic in 10-month follow-up. MPSC, classified as serous borderline tumor, needs to be differentiated from APST as well as conventional serous carcinoma. It is diagnosed according to strict criteria laid down. Multiple sections should be studied to exclude invasion. Adequate peritoneal sampling should be performed to look for implants, which is of prognostic significance.

Histopathological challenges in assessing borderline ovarian tumours

The diagnosis of borderline ovarian tumours is problematic. Traditionally, the absence of stromal invasion has distinguished borderline ovarian tumours from their malignant counterparts. The recent recognition of microinvasion associated with borderline neoplasms, the analysis of peritoneal implants (PIs), and issues associated with tumour nomenclature contribute to this diagnositc challenge. Furthermore, a proposed reclassification of serous ovarian tumours abandoning the borderline category in favour of atypical proliferative serous tumour (APST) and micropapillary serous carcinoma (MPSC); the latter being subdivided into invasive (invasive MPSC or low-grade serous carcinoma) and non-invasive (non-invasive MPSC or intraepithelial low-grade serous carcinoma) variants, has resulted in the inconsistent use of tumour nomenclature. To facilitate understanding, both the old and new terminologies of serous tumours will be used in this review. Unfortunately, diagnostic dilemmas are not restricted to serous ovarian tumours, in mucinous ovarian tumours, benign, borderline and malignant epithelium can co-exist in the same lesion and metastatic mucinous carcinoma from the gastrointestinal tract can mimic a primary mucinous ovarian tumour. Pseudomyxoma peritonei, which was originally considered as the peritoneal lesion (or implant) associated with a borderline mucinous ovarian tumour, is now believed to be secondary to a low-grade primary mucinous tumour of the appendix. Finally, accurate and complete histological assessment requires the pathologist to be aware of newly described lesions e.g. the seromucinous tumours. In this article, the difficulties associated with the histological diagnosis of the above tumours will be considered with emphasis on the identification of early invasion.

Sustained response to bevacizumab in refractory well-differentiated ovarian neoplasms

Background. Bevacizumab has demonstrated activity against a variety of solid tumors, including ovarian carcinoma. However, there have not been reproducible prognostic features associated with its activity. Cases. One patient each with recurrent, refractory well-differentiated serous-endometrioid ovarian carcinoma, micropapillary serous carcinoma of the ovary, and primary peritoneal micropapillary serous carcinoma were treated with single agent bevacizumab (15 mg/m 2 intravenously every 3 weeks). All three have had dramatic sustained responses of 15, 15, and 22 months' duration. Conclusion. Bevacizumab may have significant activity against well-differentiated ovarian carcinoma and micropapillary serous carcinomas of the ovary or peritoneum. Since these tumors are generally indolent and not responsive to adjuvant therapy, further investigation is warranted.

Clinical significance of surgical staging and lymphadenectomy in patients with borderline ovarian tumors

Objective : To compare the outcome of patients with borderline ovarian tumors who had been surgically staged with those who were not staged. Methods : Between 1997 and 2004, there were 204 patients who underwent surgery and were diagnosed as borderline ovarian tumors. A retrospective review was performed. Two groups were identified: patients who underwent surgical staging (n=98) versus those who were not staged (n=106). Clinical outcomes were compared between the two groups. Results : Between the two groups, there were no differences of the mean age of the time of diagnosis, parity, BMI, family history, pretreatment CA 125 level, tumor size, and disease recurrence, but were significant differences of FIGO stage (p=0.04), histologic types (p＜0.01), operation time (p＜0.01), length of hospital stay (p＜0.01), and adjuvant chemotherapy (p＜0.01). The lymph node positivity rate were 3.5% and 7.1% in patients with pelvic and para-aortic lymphadenectomy respectively. All patients with postive lymph nodes showed the micropapillary serous carcinoma. The 5 year disease-free survival rate was 90%. The overall disease-free survival was significantly found to be decreased in patients with advanced FIGO stage (p＜0.01). There was no significant difference of overall disease-free survival regard to pretreatment CA 125 level (p=0.72), histologic types (p=0.78), adjuvant chemotherapy (p=0.45), and surgical staging with lymphadenectomy (p=0.79). Conclusion : Disease-free survival was not significantly different between staged and unstaged patients who had surgery with borderline ovarian tumors. It seems that routine pelvic and para-aortic lymphadenectomy is not necessary in the majority of women with borderline ovarian tumors.

Fine Needle Aspiration of Borderline Ovarian Lesions

Borderline ovarian tumors are a low grade form of epithelial ovarian carcinoma with a low rate of growth and a low potential to invade or metastasize. According to the new World Health Organization classification, these tumors are placed between clearly benign and obviously malignant tumors because they exhibit some, but not all, of the morphologic features of malignancy. For a distinction between borderline lesions and cystadenomas or carcinomas, 2 criteria are of the utmost importance: presence of nuclear atypia and absence of stromal invasion. The pathologic subtype ofperitoneal implants is probably one of the main prognosticfactors in patients with serous tumors of low malignant potential, while the prognostic value of micropapillary serous carcinoma in patients with noninvasive implants remains debatable. Although fine needle aspiration (FNA) is the most accurate diagnostic method in cytopathology, its value in the diagnosis of borderline lesions is limited, mainly because of its inability to establish the absence of stromal invasion. The diagnostic accuracy of RNA can be improved by supplementing cytologic examination with such diagnostic techniques as immunocytochemistry and cytometry.

Noninvasive and invasive micropapillary (low-grade) serous carcinoma of the ovary: a clinicopathologic analysis of 135 cases.

Reports describing the behavior of micropapillary serous carcinomas (MPSCs) of the ovary have focused on those that are noninvasive. There are only very limited data on the behavior of those that are invasive. To further characterize the behavior of MPSCs, invasive versus noninvasive primary tumors were distinguished based on the presence or absence of destructive infiltrative growth. To qualify for inclusion, invasive MPSCs, like the noninvasive tumors, were required to display a micropapillary architecture and low-grade nuclei. A total of 135 cases of MPSC were identified: 96 noninvasive and 39 invasive. On follow-up, survival for 10 patients with stage I noninvasive and invasive MPSCs was 100%, and survival for women with stage II and III noninvasive and invasive MPSCs with noninvasive implants was 80%. In contrast, the 5-year and 10-year survival for patients with stage II and III noninvasive MPSCs with invasive implants was 85% and 55%, respectively. The 5-year and 10-year survival for women with invasive MPSCs and invasive implants was 55% and 45%, respectively. The median time from diagnosis to death for women with noninvasive and invasive MPSCs with invasive implants was 60 months (range 33-240 months). The indolent behavior of these low-grade carcinomas distinguishes them from conventional serous carcinomas, which are high-grade aggressive neoplasms. Five of six patients with small (<5 mm) MPSCs in whom follow-up was available presented with high stage disease. Of these five women, three are alive and well and two are alive with disease (one with invasive and one with noninvasive implants). Nearly three fourths of noninvasive MPSCs were associated with atypical proliferative serous tumors, adenofibromas, or both, and 62% of invasive MPSCs were associated with noninvasive MPSCs, atypical proliferative serous tumors, and adenofibromas, alone or in combination. In addition to the frequent mixtures of these tumor components, transitions between them were common. These data in conjunction with recent molecular genetic studies strongly suggest that MPSCs (low-grade carcinomas) arise from atypical proliferative serous tumors unlike conventional serous carcinomas (high-grade carcinomas), which appear to develop de novo. The findings provide further support for the hypothesis that there are distinct pathways of carcinogenesis for low-grade and high-grade serous carcinoma of the ovary.