Serous Tumors Of Low Malignant Potential Research Articles

Endocrine biomarkers in low-grade serous ovarian cancers (LGSC) and serous ovarian tumors of low malignant potential (LMP).

e18045 Background: LGSC and serous ovarian LMP tumors are rare entities along a disease continuum. Because they are relatively chemotherapy resistant, there is interest in targeted treatment, including endocrine therapy. In studies of endocrine agents for treatment of recurrent ovarian cancer, tumor estrogen receptor (ER) status alone does not effectively predict outcomes. The objective of this study is to utilize protein and gene expression from ER and downstream targets to identify signaling components that will act as prognostic and predictive biomarkers. Methods: A single institution tumor registry was queried for patients with LGSC or serous LMP tumors between 1993-2016. Formalin-fixed, paraffin embedded (FFPE) tissue was obtained. Clinicopathologic data was collected. Immunohistochemistry (IHC) was performed and scored as dichotomous (+/-) and continuous (H-score). NanoString nCounter platform was used for gene expression of a predesigned endocrine biomarker panel. Wilcoxon Rank Sum was used to compare mRNA and protein expression. Survival analyses were performed using Cox proportional hazard (PH) method with elastic net to fit the prediction model for the gene panel. Results: Tissue was analyzed from 23 LGSC, 71 serous LMP tumors, and 2 recurrences. At diagnosis, 86% of patients with LMP tumors had stage I disease vs 78% of patients with LGSC had stage III/IV disease. There were 7 (10%) LMP and 13 (56.5%) LGSC recurrences. Median initial PFS was 76 and 37 months and median OS was 88 and 82 months for LMP and LGSC, respectively. Fourteen received endocrine therapy; nine for treatment of recurrent LGSC. Median therapy was 21 months, with 3 complete responses, 2 partial responses and 1 stable disease. All tumors were ER+ (median H-score 210) and 89% were PR+ (median H-score 130). ER H-scores and ESR1 expression levels were not significantly different between LGSC and LMP tumors (p = 0.1942, p = 0.0893). PR H-scores were higher in LMP tumors (p < 0.00001) but PGR expression was not significantly different (p = 0.6581). In the Cox PH analysis, ER H-score was a significant predictor of both PFS and OS (p < 0.001, p = 0.004). The Cox model identified independent sets of gene expression associated with PFS and OS in both the LGSC and LMP cohorts (c-indices 0.679, 0.570, 0.626, 0.689). Conclusions: Endocrine therapy is an active area of interest in the treatment of ovarian neoplasms. ER H-score and gene expression of downstream ER targets could improve upon the use of hormone receptors to determine risk of recurrence and guide use of adjuvant endocrine therapy.

Abstract B25: Hormone receptor expression and response in ovarian tumors of low malignant potential

Abstract Objective: Primary treatment for ovarian low malignant potential (LMP) tumors is surgical resection with little proven effect of cytotoxic chemotherapy. New therapeutic strategies are needed to prevent and treat recurrence. The objective of this study is to investigate the role of hormone receptors in ovarian low malignant potential tumors. Methods: We obtained formalin-fixed, paraffin embedded (FFPE) tissue samples from patients with ovarian LMP tumors. Clinicopathologic data were collected for all available specimens. Immunohistochemistry (IHC) was performed to determine protein expression. Gene expression was measured using the NanoString nCounter platform. Differences in expression between histologic subtypes were by t-test, followed by a Bonferroni adjustment for multiple comparisons (p<0.01). Results: Thirty-eight patients were included in this study. The histologic subtypes were divided between 20 serous and 18 mucinous tumors. All serous tumors were ERα and PR positive by IHC and 6 of 20 (30%) were ERβ positive. Only one of the 18 mucinous tumors (5.6%) was positive for both ERα and PR, and all the samples were negative for ERβ. ERβ mRNA levels were elevated in the mucinous LMP tumors and ERα mRNA was higher in the serous samples. ERα and PR protein expression correlated with mRNA expression of ESR1 (r2=0.5606) and PR (r2=0.42), respectively. ERβ expression did not correlate with mRNA expression of ESR2 (r2=0.038). Measurement of estrogen-regulated genes and genes involved in ER signaling (n=236) revealed a clear separation of serous from mucinous subtypes, with 44 genes showing a statistically significant difference (p<0.01) between the serous and mucinous subtypes. Conclusion: High levels of ERα, PR, and downstream ERα targets in serous LMP tumors suggest hormone responsiveness and that these tumors are potentially treatable with endocrine therapy. Mucinous tumors largely did not express hormone receptors. In light of this, differences in gene expression observed are more likely attributable to underlying lineage differences than differences in estrogen signaling. Additional large-scale analyses are warranted to better understand the differences between subtypes and to identify avenues for targeted therapy in mucinous LMPs. Citation Format: Sarah E. Taylor, Courtney L. Andersen, Rohit Bhargava, George Tseng, Steffi Oesterreich, Robert P. Edwards, Adrian V. Lee. Hormone receptor expression and response in ovarian tumors of low malignant potential. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B25.

Ovarian Serous Tumors of Low Malignant Potential With Nodal Low-grade Serous Carcinoma

Serous tumor of low malignant potential (SLMP) and low-grade serous carcinoma (LGSC) are part of one biological continuum, whereby SLMP can transform into LGSC. It has been suggested that some nodal SLMPs arise from nodal endosalpingiosis and evolve independently in lymph nodes (rather than being related to the ovarian primary). In this article, we present the clinicopathologic features of 5 cases of nodal LGSC presenting in association with ovarian SLMP. Clinical information was obtained from the patients' charts. Pathologic features of the nodal LGSC, including lymph node location, size of and extent of involvement of tumor, architectural pattern, degree of cytologic atypia, mitotic index, and presence of psammoma bodies, were recorded. Ovarian SLMPs were noted for laterality, size, presence of surface excrescences, microinvasion, and micropapillary/cribriform pattern and for presence of autoimplants, invasive, and noninvasive implants. The distribution of any lymph nodes with nodal endosalpingiosis or SLMPs was also recorded. Patients ranged in age from 28 to 68 years (median, 32 y). In 4 cases, the diagnosis of nodal LGSC occurred at a different time from that of the ovarian SLMPs, ranging from 7 months before to 5 months after the ovarian tumor diagnosis. Nodal LGSC was detected in supraclavicular (2 cases), cervical, intramammary, and periaortic lymph nodes (1 case each). The gross lymph node size ranged from 0.9 to 2.5 cm (median, 1.3 cm). The tumors either replaced the entire lymph node or were found diffusely involving subcapsular and medullary sinuses or lymph node cortices. Tumor cells showed typical cytologic features of LGSC and no mitotic activity. In 2 cases, however, focal pleomorphic cells and 1 mitosis per 10 HPF were noted. Psammoma bodies were identified in all cases. When immunohistochemical analysis was performed, all tumors exhibited a profile in keeping with Müllerian origin. All ovarian tumors were well sampled and ranged in size from 0.1 to 13 cm (median, 2.5 cm). No ovarian SLMP tumors showed the micropapillary/cribriform pattern, whereas only focal microinvasion was detected in 3 cases. Four tumors had surface excrescences. All cases had noninvasive implants, and a single case also had invasive implants. Lymph node dissection was performed in 2 cases, revealing extensive endosalpingiosis in pelvic and periaortic lymph nodes and SLMP in pelvic lymph nodes. In 1 additional case, a single lymph node was sampled, revealing a nodal SLMP. Clinical follow-up ranged from 2 to 14 years (median, 9 y). All patients received postoperative chemotherapy. None of the patients experienced recurrence in pelvic or abdominal soft tissue. Two patients are free of disease. However, 2 patients, one with cervical and another with supraclavicular nodal LGSC, had recurrences at these sites and subsequently succumbed to metastatic disease. Both of these patients had pelvic and periaortic nodal SLMP and extensive nodal endosalpingiosis. Another patient, originally with supraclavicular LGSC, developed pelvic and abdominal lymphadenopathy, and is currently alive with disease. For the first time, we present a case series of patients with ovarian SLMP who, despite any evidence of LGSC in the pelvis or any pelvic recurrences, developed extrapelvic/extra-abdominal nodal LGSC. These patients also had endosalpingiosis and SLMP in pelvic and periaortic lymph nodes, suggesting that SLMP/LGSC tumors in lymph nodes may arise independently of the ovarian primary, progress along their own timeline, and undergo metastatic spread. Therefore, in patients with ovarian SLMP and extensive pelvic/periaortic nodal endosalpingiosis and/or SLMP, examination and follow-up of extrapelvic lymph nodes are warranted, even if the ovarian tumor lacks high-risk features of recurrence.

Prognostic value of elevated preoperative serum CA125 in ovarian tumors of low malignant potential: A multinational collaborative study (ANZGOG0801)

ObjectivePrevious studies on prognostic factors in ovarian tumors of low malignant potential (LMP) were too small for robust conclusions. We examined the prognostic impact of preoperative serum CA125≥50U/ml levels in patients diagnosed with ovarian LMP tumors in a large multinational cohort. MethodsThis retrospective study included 940 patients with ovarian LMP tumors diagnosed between 1985 and 2008 at six gynecologic cancer centers. Patients either had radical treatment (bilateral salpingo-oophorectomy with or without hysterectomy) or conservative, fertility-sparing treatment. Multivariate Cox proportional hazard models were used to determine independent prognostic factors for disease-free (DFS) and overall survival (OS). Based on receiver operating characteristic curve (ROC), a preoperative serum CA125 level≥50U/ml was considered “elevated”. ResultsCA125 was more often elevated in serous than in mucinous tumors and in advanced FIGO stages (2 to 4) compared to stage1. DFS at 5years was 89% and 95% in patients with elevated and normal CA125 levels (p<0.05). Similarly, the 5-year OS was 90% among patients with elevated CA125 compared to 95% among patients with normal levels (p<0.05). For both DFS and OS elevated CA125 levels and advanced stages of the disease were independent prognostic factors. Analysis of subgroups revealed that CA125 was only prognostic in serous LMP tumors. ConclusionsIn the context of serous ovarian LMP tumors, elevated preoperative serum CA125 represents a biomarker independently associated with impaired disease-free and overall survival. CA125 is available in most centers and could inform surgeons about the risk of treatment failure.

Significance of Peritoneal Washing Cytopathology in Ovarian Carcinomas and Tumors of Low Malignant Potential: A Quality Control Study with Literature Review

Objective: The author evaluated a consecutive group of peritoneal washings (PWs) performed in the evaluation of adnexal masses to determine whether the conventional histopathologic prognostic parameters significantly affect the tumor detection rate using this procedure. Study Design: Cytopathologic reports from all PWs performed over a 13-year (1996–2008) period in the evaluation of malignant and borderline ovarian tumors were reviewed and correlated with those of the synchronously obtained histopathologic specimens. Tumors of low malignant potential (LMP) were separated for analysis. Statistical significance was determined using the χ² test. Results: In the study, a total of 134 PWs were associated with primary epithelial malignant tumors (n = 114) or tumors of LMP (n = 20) involving the ovary. The positive PW cytopathology rates for clear cell (83.3%), undifferentiated (80.0%), and serous carcinomas (65.7%) were higher than the overall average positive rate (62.3%) for all histopathologic subtypes. In contrast, endometrioid (41.2%) and mucinous (45.5%) carcinomas had markedly lower cytopathology-positive rates than the overall average positive rate (p = 0.118). As expected, PWs were found to be significantly more likely to yield malignant cells in higher-grade (grades II + III, 71.1%, p = 0.002) and higher-stage (stages III + IV) tumors (76.6%, p = 0.000) than in lower-grade (grade I, 38.7%) and lower-stage (stages I + II) tumors (32.4%) and also in tumors with lymph node involvement (72.7%, p = 0.021) than in tumors without lymph node involvement (46.7%) and in bilateral tumors (74.6%, p = 0.004) than in unilateral tumors (42.9%). The positive cytopathology rates for the PWs of the corresponding primary ovarian carcinomas with prominent pleomorphism (81.0%, p = 0.007), with high mitotic score (80.0%, p = 0.006) and solid architecture (72.9%, p = 0.122) were also higher than the overall average positive rate. The overall sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and efficiency for the ovarian carcinoma (n = 114) cases were 72.3, 85, 95.8, 39.5 and 74.6%, respectively. The positive cytopathology rate for the PWs of the serous tumors of LMP (7.1%) was higher than that of the mucinous tumors of LMP (0.0%) and the overall average positive cytopathology rate (5.0%) for the ovarian tumors with LMP. The calculated sensitivity, specificity, PPV, NPV, and efficiency for tumors of LMP were 33.3, 100, 100, 89.5, and 90%, respectively. Conclusion: PW cytopathology results correlate significantly with almost all of the conventional histopathologic prognostic parameters and the cyto-histomorphologic parameters of the corresponding primary ovarian carcinomas. The positive cytopathology rates also differ according to the histopathologic subtypes. False negativity and ‘false positivity?’ was significantly correlated with tumor grade.

Serous borderline tumor of the fallopian tube presented as an adnexal mass

Serous tumors of low malignant potential (STLMP) of the fallopian tube are uncommon and their clinical behavior is poorly understood. The authors report a case of a 25-year-old patient that presented an adnexal mass following prolonged pelvic pain. She underwent an exploratory laparotomy and a solid tumor in the left fallopian tube was detected. Left adnexectomy was performed and the pathologic examination revealed a serous borderline tumor of the fallopian tube. Subsequently, the patient underwent a surgical staging procedure that included infracolic omentectomy, and multiple pelvic and abdominal peritoneal biopsies. The pathologic evaluation of all specimens revealed no malignancy. During a follow-up period of 3 years, no evidence of disease was detected. Serous borderline tumors of the fallopian tube are diagnosed in the third-fourth decade and are usually discovered incidentally during routine gynecologic examination or during an elective surgery. To date, there are no reports in the literature regarding recurrence or metastatic disease of STLMP of the fallopian tube. Conservative fertility-sparing surgery proved to be a safe and equally effective treatment for patients who wished to preserve their childbearing potential.

Immunohistochemical profiling of benign, low malignant potential and low grade serous epithelial ovarian tumors

BackgroundSerous epithelial ovarian tumors can be subdivided into benign (BOV), low malignant potential (LMP) or borderline and invasive (TOV) tumors. Although the molecular characteristics of serous BOV, LMP and low grade (LG) TOV tumors has been initiated, definitive immunohistochemical markers to distinguish between these tumor types have not been defined.MethodsIn the present study, we used a tissue array composed of 27 BOVs, 78 LMPs and 23 LG TOVs to evaluate the protein expression of a subset of selected candidates identified in our previous studies (Ape1, Set, Ran, Ccne1 and Trail) or known to be implicated in epithelial ovarian cancer disease (p21, Ccnb1, Ckd1).ResultsStatistically significant difference in protein expression was observed for Ccnb1 when BOV tumors were compared to LMP tumors (p = 0.003). When BOV were compared to LG TOV tumors, Trail was significantly expressed at a higher level in malignant tumors (p = 0.01). Expression of p21 was significantly lower in LG tumors when compared with either BOVs (p = 0.03) or LMPs (p = 0.001). We also observed that expression of p21 was higher in LMP tumors with no (p = 0.02) or non-invasive (p = 0.01) implants compared to the LMP associated with invasive implants.ConclusionThis study represents an extensive analyse of the benign and highly differentiated ovarian disease from an immunohistochemical perspective.

Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

Approximately, 10% to 15% of serous ovarian tumors fall into the category designated as tumors of low malignant potential (LMP). Like their invasive counterparts, LMP tumors may be associated with extraovarian disease, for example, in the peritoneal cavity and regional lymph nodes. However, unlike typical invasive carcinomas, patients generally have a favorable prognosis. The mutational profile also differs markedly from that seen in most serous carcinomas. Typically, LMP tumors are associated with KRAS and BRAF mutations. Interrogation of expression profiles in serous LMP tumors suggested overall redundancy of RAS-MAPK pathway mutations and a distinct mechanism of oncogenesis compared with high-grade ovarian carcinomas. Our findings indicate that activating mutation of the RAS-MAPK pathway in serous LMP may be present in >70% of cases compared with approximately 12.5% in serous ovarian carcinomas. In addition to mutations of KRAS (18%) and BRAF (48%) mutations, ERBB2 mutations (6%), but not EGFR, are prevalent among serous LMP tumors. Based on the expression profile signature observed throughout our serous LMP cohort, we propose that RAS-MAPK pathway activation is a requirement of serous LMP tumor development and that other activators of this pathway are yet to be defined. Importantly, as few nonsurgical options exist for treatment of recurrent LMP tumors, therapeutic targeting of this pathway may prove beneficial, especially in younger patients where maintaining fertility is important.

Lymphatic Vascular Invasion in Ovarian Serous Tumors of Low Malignant Potential With Stromal Microinvasion

Stromal microinvasion in ovarian serous tumors of low malignant potential (S-LMP) stratifies patients at long-term risk for disease progression independent of stage and primary ovarian histology. Despite the histologic impression and often-quoted incidence of lymphatic vascular invasion (LVI) in S-LMP with stromal microinvasion, there has been no formal evaluation in a case control series of S-LMP. The presence and extent of (LVI) was assessed in 20 S-LMP with stromal microinvasion and 20 S-LMP case controls without stromal microinvasion and compared with a series of low-grade and high-grade serous carcinomas using D2-40 monoclonal antibody recognizing podoplanin, a novel lymphatic endothelial marker. S-LMP case controls were matched for primary ovarian histology (usual vs. micropapillary), International Federation of Gynecology and Obstetrics (FIGO) stage, and age (best possible match). The patterns of stromal microinvasion included individual eosinophilic cells and cell clusters, cribriform, simple and noncomplex branching papillae, and inverted macropapillae. Immunohistologic staining with D2-40 monoclonal antibody clearly identified intratumoral LVI in 12/20 (60%) S-LMP with stromal microinvasion and 0/20 S-LMP without stromal microinvasion. Although only 4/13 (31%) low-grade serous carcinomas and 7/20 (35%) high-grade serous carcinomas had intratumoral LVI, hilar LVI was more common in the carcinomas (15% low-grade; 69% high-grade). Intratumoral LVI in S-LMP ranged from focal (6 cases) to multifocal (6 cases, maximum of 5 discrete foci) in any 1 section and included isolated single cells, simple papillae, and in 1 case, cribriform glands. Multifocal LVI was identified in 1 study patient who was pregnant. One of the 12 S-LMP patients with LVI had an intra-abdominal recurrence with high-grade disease at 16 months; whereas all other patients with follow-up were free of disease. LVI in ovarian S-LMP was significantly associated with the presence of stromal microinvasion (P<0.0001) and is independent of age, stage, primary ovarian histology, and pattern or extent of microinvasion. The presence of LVI in microinvasive S-LMP corroborates the view that microinvasion represents an early, but very low risk, invasive process that morphologically links S-LMP and low-grade serous carcinoma.

Ovarian Clear Cell Carcinoma With Papillary Features: A Potential Mimic of Serous Tumor of Low Malignant Potential

The differential diagnostic problems usually associated with clear cell carcinoma (CCC) of the ovary have been well characterized and include primitive germ cell tumor, sex cord stromal tumor, and metastasis. Distinction from other types of surface epithelial carcinoma may also pose a diagnostic challenge, but the potential for misdiagnosis of serous tumor of low malignant potential (S-LMP) is not well recognized. We report 13 cases of ovarian CCC with prominent papillary architecture that were initially misdiagnosed as S-LMP or low-grade serous carcinoma either on frozen section or at final diagnosis. The ages of the patients ranged from 39 to 65 years (mean, 52.2 y). All patients presented with a pelvic mass; 1 was undergoing evaluation for infertility. Macroscopically, most were described as unilateral, multilocular cysts with internal papillary structures. On microscopic examination, each tumor had a papillary architecture that accounted for 30% to 95% of the tumor; in 6 cases, the cores of the papillae were hyalinized. The neoplastic cells covering the papillae had clear to granular and eosinophilic cytoplasm. Hobnail cells were focal and often subtle. Most had a low mitotic index (9/13) and/or deceptively bland cytology (8/13); only careful attention to the cytologic features and/or mitotic index allowed correct identification of the tumor type in 5 cases. Six were associated with pelvic/ovarian endometriosis. Ten were Federation of Gynecology and Obstetrics stage I (8 IA, 2 IC), 2 were stage II (1 IIB, 1 IIC), and 1 stage IIIC. CCC with prominent papillary architecture is uncommon, but may pose a challenging differential diagnosis with S-LMP, resulting in inadequate staging and delayed treatment. Features most helpful in distinguishing papillary CCC are unilaterality, nonhierarchical branching, monomorphous cell population, and the presence of more typical CCC patterns elsewhere in the tumor. The presence of endometriosis, although not specific, should also prompt consideration for papillary CCC. Increased numbers of mitotic figures may not be present and high-grade cytologic atypia may be focal, requiring careful examination of multiple tumor sections for detection. As CCC and S-LMP exhibit significantly different immunoreactivity for Wilms' Tumor 1 and estrogen receptor, these markers may also be useful adjunctive tests in problematic cases.

Molecular Genetic Evidence of an Independent Origin of Serous Low Malignant Potential Implants and Lymph Node Inclusions

Patients with ovarian serous tumors of low malignant potential (LMP) are commonly found to have peritoneal implants. Less commonly, similar lesions are seen in lymph nodes, sometimes in association with endosalpingiosis. We compared these lesions to the coexisting ovarian LMP tumors to determine whether they are clonally related to the ovarian neoplasm. Seventeen patients with serous LMP tumors present at 2 or more sites were identified. Tissue samples were microdissected from formalin-fixed paraffin-embedded tissue blocks. Samples of normal tissue, the ovarian LMP tumors, peritoneal LMP implants, and LMP inclusions within lymph nodes were obtained. Genomic DNA was extracted from the samples, and polymerase chain reaction and X-chromosome inactivation (human androgen receptor assay) analysis were performed. The pattern of X-chromosome inactivation could be determined in 15 of the 17 cases, and nonrandom X-chromosome inactivation was observed in 13 of these cases. Twelve of these cases included both ovarian and extraovarian LMP tumors. In 9 of these 12 cases, the extraovarian LMP tumor shared a similar pattern of nonrandom X-chromosome inactivation with the ovarian tumor. In these cases, the shared inactivation pattern was seen at 1 extraovarian site (3 cases), 2 extraovarian sites (4 cases), 5 extraovarian sites (1 case), and 7 of 8 extraovarian sites (1 case). In the remaining 3 cases, opposite patterns of nonrandom X-chromosome inactivation were seen. These data suggest that, in most cases, serous LMP tumor implants and lymph node inclusions share a common clonal origin with the associated ovarian tumors. However, in at least some cases, the implants and inclusions seem to arise independently from the associated ovarian serous LMP tumors.

The Continuum of Serous Tumors of Low Malignant Potential and Low‐Grade Serous Carcinomas of the Ovary

The role of serous tumors of low malignant potential (LMP) in the development of invasive epithelial cancer of the ovary is debatable. This review summarizes the current clinical, genetic, and genomic evidence for the existence of a continuum comprising both LMP serous tumors and low-grade serous ovarian carcinomas.

Patterns of Stromal Invasion in Ovarian Serous Tumors of Low Malignant Potential (Borderline Tumors): A Reevaluation of the Concept of Stromal Microinvasion

Stromal-epithelial patterns of invasion in serous tumors of the ovary have been subclassified as destructive and nondestructive. By definition, well-differentiated serous tumors featuring destructive stromal invasion are classified as low-grade serous carcinomas whereas those with either no stromal invasion or stromal microinvasion are classified as serous tumors of low malignant potential (S-LMP). The histologic features of stromal microinvasion in ovarian S-LMP have been addressed in a variety of studies, but controversy persists regarding diagnostic criteria and prognostic significance, particularly in patients with high-stage disease. In addition, a subset of otherwise typical S-LMP has patterns of invasion that are not classic destructive invasion and do not meet the current diagnostic criteria for stromal microinvasion because of either qualitative features or size restrictions. To further evaluate the full histologic spectrum of stromal-epithelial patterns of invasion in otherwise typical S-LMP, we examined a series of 60 ovarian S-LMP (34 FIGO stage I; 26 FIGO stages II, III, and IV) with stromal-epithelial alterations not meeting criteria for classic destructive invasion. This group of cases included those meeting the definition of microinvasion and a subset that would be excluded based on size measurements or unusual qualitative features, but did not exhibit significant stromal reaction. Five patterns of invasion were identified: individual eosinophilic cells and cell clusters, cribriform, simple and noncomplex branching papillae, inverted macropapillae, and micropapillae. Individual, discrete aggregates of invasive epithelium ranged from 1 to 12 mm (mean, 1.4 mm) in greatest linear dimension as measured by conventional methods. The number of discrete foci ranged from 1 to greater than 10; in 7 tumors (12%), the invasive foci were diffusely scattered throughout the stroma without discrete aggregates. These stromal-epithelial alterations were associated with disease progression and/or death due to disease in 9 of 50 (18%) patients with follow-up (mean, 92.5 mo) and were covariant with other adverse prognostic features (invasive implants, nodular lymph node aggregates, high stage, and unresectable disease). Disease progression was most strongly linked to the presence of micropapillae, but the majority of patients with adverse outcome had the more common, classic stromal-epithelial patterns associated with microinvasion (ie, individual cells, cell clusters, and simple papillae). Neither size of the largest contiguous aggregate nor extent of stromal involvement correlated with outcome. Classic microinvasion disproportionately occurred in patients presenting during pregnancy (P<0.0001), and was not associated with adverse outcome in that setting, but follow-up was limited. Based on the cumulative outcome data, the presence of stromal-epithelial patterns of invasion distinct from classic destructive invasion in otherwise typical S-LMP stratifies patients at long-term risk for disease progression, but does not warrant a diagnosis of carcinoma or a change in current management schemes. Maintaining classification as a serous tumor of low malignant potential (serous borderline tumor) with stromal invasion seems appropriate even in the presence of diffuse stromal involvement or discrete aggregates measuring greater than 3 (or 5) mm. As the stromal-epithelial alteration featuring micropapillae may represent a comparatively higher-risk lesion with a clinical course analogous to that of low-grade serous carcinoma, pathologists should identify this specific stromal-epithelial pattern in the diagnostic report until sufficient data is acquired to form more definitive conclusions regarding its prognosis.

Lymph Node Involvement in Ovarian Serous Tumors of Low Malignant Potential (Borderline Tumors)

The occurrence of regional lymph node involvement (LNI) in patients with primary ovarian serous tumors of low malignant potential (S-LMP), although well described in the literature, continues to be problematic. Most studies indicate that LNI is not associated with an adverse prognosis, but there has not been a comprehensive study addressing the histologic patterns of LNI, the importance, if any, of classifying the type of LNI (ie, as either noninvasive or invasive in analogy to peritoneal implant classification), or the presence and significance of associated endosalpingiosis. To further evaluate LNI in S-LMP, 74 patients with ovarian S-LMP and a lymph node biopsy or sampling were studied. Thirty-one of 74 patients had LNI in pelvic (18; 58%), mesenteric/omental (9; 29%), paraaortic (8; 26%), or supradiaphragmatic (2; 6%) lymph nodes. The number of involved nodes ranged from 1 to 20 (mean, 11.1). Four patterns of LNI were identified: individual cells, clusters of cells, and simple, nonbranching papillae (28 of 31; 90%); intraglandular (21 of 31; 68%); cells with prominent cytoplasmic eosinophilia ("eosinophilic cell" pattern) (16 of 31; 52%); and micropapillary pattern (5 of 31; 16%). LNI was diffuse in at least one lymph node in 13 patients (42%) and formed nodular aggregates greater than 1 mm in 6 patients (19%). Nodal endosalpingiosis was present in 58% of cases with LNI compared with 35% without LNI (P=0.06). There was no significant difference in survival for patients with LNI compared with patients without LNI. However, the presence of discrete nodular aggregates of epithelium greater than 1 mm in linear dimension without intervening lymphoid tissue was associated with a statistically significant decreased disease-free survival when compared with other patterns of LNI (P=0.02). Nodular aggregates were strongly associated with desmoplastic fibrous stromal reaction (P=0.001) and micropapillary architecture (0.02). There was also a trend for decreased survival among patients with LNI without associated endosalpingiosis (56%) compared with patients with LNI associated with endosalpingiosis (85%) and those with endosalpingiosis only (93%). This study suggests that patients with ovarian S-LMP may be further substratified into risk categories by the presence of nodular aggregates of S-LMP in lymph nodes, a feature that is more common in cases with micropapillary architecture and associated stromal reaction in the intranodal tumor. This high risk pattern of LNI may have a predictive value similar to invasive peritoneal implants and deserves independent evaluation in future studies of S-LMP.

Expression Profiling of Mucinous Tumors of the Ovary Identifies Genes of Clinicopathologic Importance

To elucidate the molecular mechanisms contributing to the unique clinicopathologic characteristics of mucinous ovarian carcinoma, global gene expression profiling of mucinous ovarian tumors was carried out. Gene expression profiling was completed for 25 microdissected mucinous tumors [6 cystadenomas, 10 low malignant potential (LMP) tumors, and 9 adenocarcinomas] using Affymetrix U133 Plus 2.0 oligonucleotide microarrays. Hierarchical clustering and binary tree prediction analysis were used to determine the relationships among mucinous specimens and a series of previously profiled microdissected serous tumors and normal ovarian surface epithelium. PathwayAssist software was used to identify putative signaling pathways involved in the development of mucinous LMP tumors and adenocarcinomas. Comparison of the gene profiles between mucinous tumors and normal ovarian epithelial cells identified 1,599, 2,916, and 1,765 differentially expressed in genes in the cystadenomas, LMP tumors, and adenocarcinomas, respectively. Hierarchical clustering showed that mucinous and serous LMP tumors are distinct. In addition, there was a close association of mucinous LMP tumors and adenocarcinomas with serous adenocarcinomas. Binary tree prediction revealed increased heterogeneity among mucinous tumors compared with their serous counterparts. Furthermore, the cystadenomas coexpressed a subset of genes that were differentially regulated in LMP and adenocarcinoma specimens compared with normal ovarian surface epithelium. PathwayAssist highlighted pathways with expression of genes involved in drug resistance in both LMP and adenocarcinoma samples. In addition, genes involved in cytoskeletal regulation were specifically up-regulated in the mucinous adenocarcinomas. These data provide a useful basis for understanding the molecular events leading to the development and progression of mucinous ovarian cancer.

Fertility-Sparing Surgery for Ovarian Low Malignant Potential Tumors

Ovarian tumors with low malignancy potential can be treated with simple surgical excision without removing the uterus and remaining ovary. For this study, the outcomes of women with low-malignant-potential (LMP) ovarian tumors who underwent fertility-sparing surgery were compared with those of women who had more extensive surgery. A review of medical charts at the authors' institution from January 1984 to June 2003 identified 249 women with ovarian LMP tumors, 38 (15%) of whom were treated with fertility-sparing surgery. The remaining 211 patients served as controls for this study. Women who had fertility-sparing surgery were a mean age of 26 years compared to 48 years for women who had complete resection and had lower mean gravidity (0.5 vs 2) and parity (0 vs 2) compared with controls (P <.001 for all). More Hispanic and Asian women were younger than age 40 compared with black and white women (P <.01), and they more commonly underwent fertility-sparing surgery (P =.002). Total estimated blood loss was less among patients who were treated with fertility- sparing procedures than controls (125 mL vs 300 mL; P < 0.001), and surgical staging was less common in the women treated with unilateral oophorectomy than in women who had complete resection (65 vs 184; P =.04). Among patients who were staged, those with stage I disease (34 of 196, 17%) were more likely to receive fertility-sparing treatment than stage II or III patients (4 of 53, 8%). Among the 38 patients who had fertility-sparing surgery, 33 underwent unilateral salpingo-oophorectomy. No evidence of disease was seen in 6 women who had concomitant contralateral ovarian cystectomy or in 3 of 4 women who underwent biopsy of the contralateral ovary with no visible indication of disease. The fourth woman was found to have a serous LMP tumor that mirrored the primary tumor. Five women were treated with ovarian cystectomy (5 of 38; 13%). Four were bilateral procedures and one was unilateral. There were 6 recurrences among the 38 patients treated with fertility-sparing surgery, including 5 serous tumors and one mucinous tumor. Five recurrent lesions were in the contralateral ovary. One woman was diagnosed with positive peritoneal cytology for pelvic pain 5 months after ovarian cystectomy for a serous LMP tumor. She had no other treatment and has not recurred. The remaining 4 patients were disease-free for 62, 122, 117, and 18 months from initial treatment. These 4 patients were treated with surgery alone and all are alive and well.

Expression Profiling of Serous Low Malignant Potential, Low-Grade, and High-Grade Tumors of the Ovary

Papillary serous low malignant potential (LMP) tumors are characterized by malignant features and metastatic potential yet display a benign clinical course. The role of LMP tumors in the development of invasive epithelial cancer of the ovary is not clearly defined. The aim of this study is to determine the relationships among LMP tumors and invasive ovarian cancers and identify genes contributing to their phenotypes. Affymetrix U133 Plus 2.0 microarrays (Santa Clara, CA) were used to interrogate 80 microdissected serous LMP tumors and invasive ovarian malignancies along with 10 ovarian surface epithelium (OSE) brushings. Gene expression profiles for each tumor class were used to complete unsupervised hierarchical clustering analyses and identify differentially expressed genes contributing to these associations. Unsupervised hierarchical clustering analysis revealed a distinct separation between clusters containing borderline and high-grade lesions. The majority of low-grade tumors clustered with LMP tumors. Comparing OSE with high-grade and LMP expression profiles revealed enhanced expression of genes linked to cell proliferation, chromosomal instability, and epigenetic silencing in high-grade cancers, whereas LMP tumors displayed activated p53 signaling. The expression profiles of LMP, low-grade, and high-grade papillary serous ovarian carcinomas suggest that LMP tumors are distinct from high-grade cancers; however, they are remarkably similar to low-grade cancers. Prominent expression of p53 pathway members may play an important role in the LMP tumor phenotype.

Recurrent ovarian carcinoma of low malignant potential: The role of secondary surgical cytoreduction and the prognosis in Chinese patients

The study of pathology and prognosis for patients with ovarian tumors of low malignant potential (LMP) has been well documented. The treatment, particularly the secondary surgery, for recurrent disease is less documented. This study was conducted to investigate the role of secondary surgical cytoreduction for recurrent ovarian carcinoma of LMP. Patients with ovarian carcinoma of LMP at advanced stages experiencing disease recurrence and treated by secondary surgical cytoreduction at Fudan University Cancer Hospital were retrospectively reviewed. Sixteen patients with recurrent serous and mucinous ovarian LMP tumors who underwent secondary surgical cytoreduction were entered in this study. The median age was 46.5 years. The 5-year survival in those with residual disease < or =1 cm after secondary surgical cytoreduction was 83%, compared to 26% in those with residual disease >1 cm (P = 0.01). Multivariate analysis suggested that extent of recurrent disease (solitary vs. multiple, relative risk [RR] =2.69, P < 0.01), and residual disease after secondary surgical cytoreduction (< or =1 cm vs. >1 cm, RR = 2.56, P < 0.01) were determinants of survival. For recurrent ovarian carcinomas of low malignant potential, prolonged survival was observed in patients with solitary recurrent disease and optimal secondary surgical outcome.

Ovarian Serous Tumors of Low Malignant Potential (Borderline Tumors)

The natural history, classification, and nomenclature of ovarian serous tumors of low malignant potential (S-LMP) (serous tumors of borderline malignancy, atypical proliferating tumors) are controversial. To determine long-term outcome for patients with S-LMP and further evaluate whether S-LMP can be stratified into clinically benign and malignant groups, the clinicopathologic features of 276 patients with S-LMP and > or =5 year follow-up were studied. The histology of the ovarian primary, extraovarian implants, and recurrent tumor(s) were characterized using World Health Organization criteria and correlated with FIGO stage and clinical follow-up. After censoring nontumor deaths, overall survival and disease-free survival for the 276 patients was 95% (98% FIGO stage I; 91% FIGO II-IV) and 78% (87% FIGO stage I; 65% FIGO stage II-IV), respectively. Unresectable disease (P < 0.001) and invasive implants (P < 0.001) were associated with decreased survival. When compared with typical S-LMP, S-LMP with micropapillary features were more strongly associated with invasive implants (P < 0.008) and decreased overall survival (P = 0.004), but patient outcome with micropapillary S-LMP was not independent of implant type. Stromal microinvasion in the primary tumor was also correlated with adverse outcome, independent of stage of disease, micropapillary architecture, and implant type (P = 0.03). There was no association between outcome and lymph node status. Transformation to low-grade serous carcinoma occurred in 6.8% of patients at intervals of 7 to 288 months (58% > or = 60 months) and was strongly associated with increased tempo of disease and decreased survival (P < 0.001). S-LMP forms a heterogeneous group, morphologically and clinically distinct from benign serous tumors and serous carcinoma. The majority of S-LMP are clinically benign, but recurrences are not uncommon, and persistent disease as well as deaths occur. Progression to low-grade serous carcinoma is highly predictive of more aggressive disease. Other features associated with recurrent and/or progressive disease include FIGO stage, invasive implants, microinvasion in the primary tumor, and micropapillary architecture. These predictors tend to co-occur, and no single clinical or pathologic feature or combination of features identify all adverse outcomes. The small, but significant risk of progression over time to low-grade serous carcinoma emphasizes the need for prolonged follow-up in patients with S-LMP.

Distinction between serous tumors of low malignant potential and serous carcinomas based on global mRNA expression profiling

Objectives The molecular pathogenesis of ovarian serous tumors of low malignant potential (S-LMP) is not well understood, although the collective data suggest that they arise through molecular mechanisms distinct from those leading to conventional serous carcinomas (S-Ca). To further examine the molecular differences between these two diseases, we studied the gene expression pattern of ovarian S-LMP and S-Ca using high-density spotted cDNA and tissue microarrays. Methods Total RNA from 23 ovarian S-LMP and S-Ca was analyzed on 43,200 spot cDNA microarrays and the differential expression of proteins encoded by differentially expressed genes was validated using tissue microarrays. Results Unsupervised hierarchical clustering analysis of filtered data showed a complete separation between S-LMP and S-Ca, based predominantly on a small set of genes expressed at higher levels in S-LMP than in S-Ca. Many genes previously identified as up-regulated in ovarian carcinoma relative to normal ovarian tissue were expressed at even higher levels in S-LMP. These genes included mucin-1, mesothelin, HE4, PAX 8, and apolipoprotein J/clusterin. Immunohistochemical staining of tissue microarrays confirmed higher expression of selected proteins encoded by these genes in the S-LMP. Few genes were expressed at a higher level in S-Ca; these included E2F1, topoisomerase IIα, and cyclin E, with higher levels of cyclin E protein confirmed by immunohistochemistry. Conclusions S-LMP and S-Ca are distinguished at the molecular level by a relatively small gene set, suggesting the pathogenesis of S-LMP as well as S-Ca may involve molecular pathways that escape detection by global gene expression profiling. In order to obtain biologically and clinically relevant information about the mechanisms involved in ovarian carcinogenesis, future studies based on molecular profiles of ovarian cancer should include analyses of low malignant potential tumors. Inclusion of such tumors is also critical to the evaluation of the efficacy of potential new diagnostic and/or therapeutic biomarkers.