Significantly Greater Expression of ER, PR, and ECAD in Advanced-Stage Low-Grade Ovarian Serous Carcinoma as Revealed by Immunohistochemical Analysis
Kwong‐Kwok WongKaren H. LuAnaís MalpicaDiane C. BodurkaHyun S. ShvartsmanRosemarie SchmandtAngela ThorntonMichael T. DeaversElvio G. SilvaDavid M. Gershenson
135
Citation
27
Reference
10
Related Paper
Citation Trend
Abstract:
Summary: A 2-tier system that classifies ovarian serous carcinoma (OSC) as low grade or high grade is gaining acceptance. Women with low-grade OSC generally have higher 5-year survival rates than do women with high-grade OSC. We examined the expression of various markers to further understand the molecular differences between low-grade and high-grade OSCs: the potential therapeutic targets or prognostic markers Her-2/neu, estrogen receptor, and progesterone receptor (PR); the metastasis-associated markers cyclin D1 (BCL1), E-cadherin, matrix metalloproteinase (MMP) 2, and MMP-9; and the cell proliferation-associated markers BCL1, Ki-67 antigen (Ki-67), and p53. For this immunohistochemical analysis, we used paraffin-embedded specimens from 47 patients with advanced-stage low-grade OSC and from 49 patients with advanced-stage high-grade OSC. Our results showed that low-grade tumors expressed significantly higher levels of estrogen receptor, PR, and E-cadherin than did high-grade tumors, suggesting the involvement of gonadal steroid hormones, especially in the pathogenesis of low-grade OSC; the PR positivity was also observed in the stromal component of these low-grade tumors. On the other hand, high-grade tumors trended toward increased expression of MMP-9, BCL1, p53, and Ki-67, and robust MMP-9 positivity was observed in the stromal component of these high-grade tumors. These differences may lead to the development of different therapeutic strategies for women with either the low-grade or the high-grade form of OSC.Keywords:
Progesterone receptor
Serous carcinoma
The pathogenesis of serous ovarian tumors has been extensively investigated, with a dualistic model dividing these cancers into 2 groups. Type I tumors, including low-grade serous carcinoma, is characteristic for concurrent presence of borderline tumors, less atypical cytology, relatively indolent biologic behavior, and molecular aberrations related to the MAPK pathway with chromosomal stability. Meanwhile, type II tumors, such as high-grade serous carcinoma, are notable for no significant association with borderline tumors, higher grade cytology, more aggressive biologic behavior, and TP53 mutations along with chromosomal instability. We describe a case of morphologic low-grade serous carcinoma with focally increased cytologic atypia arising in serous borderline tumors involving both ovaries, which demonstrated highly aggressive behavior despite several years of surgical and chemotherapeutic management. Each recurrent specimen contained more uniform higher grade morphology than what was seen in the original specimen. Immunohistochemical and molecular studies in both the original tumor and the most recent recurrence demonstrate identical mutations in the MAPK genes, but with additional mutations in the latter, notably an acquisition of a variant of possible clinical significance in the SMARCA4 gene, which is associated with dedifferentiation and aggressive biologic behavior. This case challenges our current and still evolving understanding of the pathogenesis, biologic behavior, and expected clinical outcome of low-grade serous ovarian carcinomas. It also underscores the need for further investigation into this complicated tumor.
Serous carcinoma
Atypia
Hematopathology
Cite
Citations (2)
A review of the pathology and cytopathology of 295 endometrial adenocarcinomas treated surgically at King Edward Memorial Hospital for Women, with full 5-year follow-up, revealed 16 cases of pure serous carcinoma (USC), 10 cases of mixed serous and endometrioid carcinoma with a predominant serous component (mixed USC-EAC) and six cases of mixed serous and endometrioid carcinoma with a predominant endometrioid component (mixed EAC-USC). The mixed carcinomas may be characterized microscopically by classical serous features side by side with classical endometrioid features, or additionally by features intermediate between the two. Many of these features are reproduced in preoperative cervicovaginal smears. USC and mixed USC-EAC were found to be indistinguishable clinically and prognostically, with an identical corrected 5-year survival of 40%, although numbers are small. Mixed EAC-USC (which contained 10-25% serous differentiation in this series), however, were similar in many respects to a control population of 95 EAC of Grade 2 and 3. The corrected 5-year survival in these two groups was 67% and 79%, respectively, which is not statistically significant in this small series. This study suggests that the behavior of a mixed tumor containing 50% or more serous differentiation is similar to that of pure serous carcinoma, and that the behavior of a mixed tumor containing less than 25% serous differentiation is similar to that of the other component. Given the poor correlation between pathologic findings in curettage and subsequent hysterectomy specimens, however, identification of any significant serous element in curettage material may prove vital in optimizing surgical and adjuvant therapy.
Serous carcinoma
Curettage
Cite
Citations (29)
Serous carcinoma
Cite
Citations (40)
[Purpose] To investigate the relationship of preoperative serous CA125 with clinicopathological features and prognosis in patients with epithelial ovarian carcinoma.[Methods] The relationship of preoperative serous CA125 with histologic type,grade,FIGO stage,ascites and survival in 279 cases with epithelial ovarian carcinoma were analyzed retrospectively.[Results] The median CA125 value for all 279 patients was 339.2 U/ml(range 3.6～20 220.0U/ml).Preoperative serous CA125 in serous carcinoma was significantly higher than that in non-serous carcinoma(P0.05).For non-serous carcinoma with different histologic types,preoperative serous CA125 in mucinous /clear cell carcinoma was significantly lower than that in serous carcinoma(P0.01),and no significant difference was found between other types of non-serous carcinoma.Preoperative serous CA125 in early stage(stage Ⅰ) patient was significantly lower than that in advanced stage(stage Ⅱ～Ⅳ) patient(P=0.000).For non-mucinous/clear cell carcinoma patient,lower serous CA125 was usually associated with early disease and fairly good prognosis.As compared,higher serous CA125 was usually connected with advanced diseases,among which those with highest CA125 level displayed better survival than those with intermediate CA125 level.[Conclusion] Preoperative serous CA125 might reflect the tumor load for serous and other non-mucinous/clear cell carcinoma in epithelial ovarian carcinoma.
Serous carcinoma
Clear cell carcinoma
Cystadenocarcinoma
Serous membrane
Cite
Citations (0)
Serous carcinoma
Fallopian tube
Cystadenocarcinoma
Serous Cystadenoma
Cite
Citations (0)
Serous carcinoma
Cite
Citations (38)
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.
Serous carcinoma
Serous membrane
Cite
Citations (3)
Although risk factors have been established for the development of serous carcinoma after a diagnosis of serous borderline tumor (SBT), comprising atypical proliferative serous tumor (APST) (ie, conventional SBT) and noninvasive low-grade serous carcinoma (niLGSC) (ie, micropapillary SBT), subsequent invasive carcinoma still occurs in a subset of women who are not at increased risk. Whether subsequent serous carcinoma in women with a prior SBT represents malignant progression/recurrence or an independent primary tumor is unclear, and the combined clinicopathologic and molecular features of SBTs and their subsequent carcinomas have not been fully characterized. In this study, we analyzed a cohort of 42 women initially diagnosed with SBT who subsequently developed serous carcinoma of a total of 1025 cases of ovarian SBT from a nationwide population-based cohort. Review of the diagnostic slides was performed from this subset of SBTs and matched metachronous invasive serous carcinomas (39 low grade, 3 high grade). DNA was extracted from tissue blocks available for 41 cases (both SBT and carcinoma, n=36; SBT only, n=3; carcinoma only, n=2). Samples were subjected to digital droplet PCR to analyze mutation hotspots in KRAS (codon 12) and BRAF (V600E), which are frequently found in low-grade serous tumors. Eighty-one percent of SBTs (34/42) were APST, and 19% (8/42) were niLGSC. Forty percent of cases (17/42) were FIGO stage I, the majority of which were APST (14/17; 82%). The median time to development of carcinoma was 9 years (range, 0.6 to 25 y). Mutations in SBTs were distributed as follows: 5/39 (13%) BRAF mutant, 22/39 (56%) KRAS mutant, and 12/39 (31%) wild-type for both genes. There was a significant relationship between SBT gene mutation and histologic type, with BRAF mutations occurring exclusively in APST and a higher frequency of niLGSC among SBTs wild-type for BRAF and KRAS ( P =0.01). The diffuse presence of tumor cells with abundant eosinophilic cytoplasm was significantly associated with the BRAF mutation ( P =0.001). Mutational analyses of matched SBT/carcinoma pairs revealed concordant profiles in 33/36 (92%) cases, of which 19 (53%) were KRAS mutant, 4 (11%) were BRAF mutant, and 10 (28%) were wild type for both genes. The 3 discordant cases consisted of a wild-type niLGSC with a subsequent BRAF -mutant invasive LGSC, a KRAS G12V -mutant APST with a KRAS G12C -mutant LGSC, and a BRAF -mutant APST with subsequent development of a KRAS G12D -mutant high-grade serous carcinoma. In conclusion, some women with SBTs can subsequently develop serous carcinoma, occasionally over 10 years later. Most subsequent carcinomas are low grade, but a small subset can be high grade. The type of gene mutation in SBT correlates with various histologic features. While most cases of serous carcinoma developing after a diagnosis of SBT probably represent tumor progression, a minority are independent primary tumors, presumably arising from endosalpingiosis.
Serous carcinoma
Cystadenocarcinoma
Serous membrane
Cite
Citations (39)
Serous carcinoma
Cite
Citations (50)
Low-grade serous ovarian carcinoma and its high-grade serous ovarian carcinoma counterpart differ in their precursor lesions, molecular profile, natural history, and response to therapies. As such, low-grade serous ovarian carcinoma needs to be studied separately from high-grade serous ovarian carcinoma, despite challenges stemming from its rarity. A deeper understanding of the pathogenesis of low-grade serous ovarian carcinoma and the most common molecular defects and pathways involved in the carcinogenesis of the ovarian epithelium from normal to serous borderline ovarian tumors to low-grade serous ovarian carcinoma will help develop better therapies. By adopting targeted approaches there may be an opportunity to integrate novel therapies without the need for robust numbers in clinical trials. This manuscript will discuss low-grade serous ovarian carcinoma and focus on the arising treatments being developed with an improved understanding of the pathogenesis of this disease.
Serous carcinoma
Cystadenocarcinoma
Targeted Therapy
Cite
Citations (11)