Cytokeratin 5/6 expression, prognosis, and association with estrogen receptor α in high-grade serous ovarian carcinoma
Eliane T. TaubeCarsten DenkertJalid SehouliU UngerCatarina Alisa KunzeJan BudcziesManfred DietelElena Ioana BraicuSilvia Darb‐Esfahani
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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
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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
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Low-grade (LG) serous ovarian carcinoma is believed to arise from serous borderline ovarian tumors; yet the progression from serous borderline tumors to LG serous ovarian carcinoma remains poorly understood. The purpose of this study was to identify differentially expressed genes between the 2 groups. Expression profiles were generated from 6 human ovarian surface epithelia, 8 serous borderline ovarian tumors (SBOTs), 13 LG serous ovarian carcinomas, and 24 high-grade (HG) serous ovarian carcinomas. The anterior gradient homolog 3 (AGR3) gene was found to be highly upregulated in serous borderline ovarian tumors. This finding was validated by real-time quantitative reverse-transcription polymerase chain reaction, Western blotting, and immunohistochemistry. Anti-AGR3 immunohistochemistry was performed on an additional 56 LG and 103 HG tissues, and the results were correlated with clinical data. Expression profiling determined that 1254 genes were differentially expressed (P<0.005) among SBOT, LG, and HG tumors. SBOTs exhibited robust positive staining for AGR3, with a lower percentage of tumor cells stained in LG and HG. Immunofluorescence staining indicated that AGR3 expression was limited to ciliated cells. Tumor samples with a high percentage (>10%) of AGR3 positively stained tumor cells were associated with improved longer median survival in both the LG (P=0.013) and HG (P=0.008) serous ovarian carcinoma groups. The progression of SBOT to LG serous ovarian carcinoma may involve the dedifferentiation of ciliated cells. AGR3 could serve as a prognostic marker for survival in patients with LG and HG serous ovarian carcinomas.
Serous carcinoma
Ovarian tumor
Cystadenocarcinoma
Tumor progression
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[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
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Serous carcinoma
Fallopian tube
Cystadenocarcinoma
Serous Cystadenoma
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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
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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.
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Cystadenocarcinoma
Serous membrane
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The increasingly popular immunohistochemical techniques for assay of the estrogen receptor (ER) allow localization of receptor positivity to specific cell populations. Heterogeneity of the ER in tumor cell populations may have important implications for analytic cell selection and for prognosis in ER-positive carcinomas. We studied 84 tissue blocks for level-to-level and geographic heterogeneity within level of the ER and cytokeratin by staining alternate serial sections for ER and cytokeratin. Distribution of ER and cytokeratin positivity was manually assessed. Homogenous positive staining was seen in 63 of 84 cases for ER and 71 of 84 cases for cytokeratin. Distinct geographic variability constant from level to level was seen in 7 cases for ER. In each of these cases, the cell populations stained uniformly for cytokeratin. Artifactual heterogeneity seemed to be uncommon for ER. Automated image analysis and manual ER estimation resulted in more positive cases than did the dextran-coated charcoal (DCC) technique. Interobserver correlation for the manual method seemed high, as did correlation between the manual method and image analysis. Because a majority of the immunohistochemical staining heterogeneity for ER seemed to be biologic, we believe it may mark carcinomas that are less responsive to tamoxifen and more likely to progress than would be predicted by more traditional methods of ER analysis.
Progesterone receptor
Keratin 8
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Aims: A dualistic pathway of ovarian serous carcinogenesis is now well established whereby high‐grade serous carcinoma and low‐grade serous carcinoma represent two distinct tumour types with a different underlying pathogenesis. The aim of this study was to compare expression of p16 INK4A (p16) in these two tumour types. We also included cases of serous borderline tumour, since these are considered to represent a precursor lesion of low‐grade serous carcinoma. Methods and results : Cases of serous borderline tumour ( n = 18), low‐grade ovarian serous carcinoma ( n = 22) and high‐grade ovarian serous carcinoma ( n = 24) were stained with a monoclonal antibody against p16. Cases were scored both with respect to intensity of immunoreactivity (weak, 1+; moderate, 2+; or strong, 3+) and distribution (0, negative or occasional positive cells; 1+, < 10% cells positive; 2+, 10–25% cells positive; 3+, 26–50% cells positive; 4+, 51–75% cells positive; or 5+, 76–100% cells positive). An immunohistochemical composite score was also calculated (0–15) by multiplying the intensity and distribution scores. There was a statistically significant difference in p16 immunoreactivity with respect to intensity, distribution and composite score between high‐grade serous carcinoma and each of the other two groups, with the high‐grade neoplasms exhibiting stronger and more diffuse positivity. Most high‐grade serous carcinomas exhibited positivity of close to 100% of tumour cells. There was no significant difference in p16 expression between the borderline tumours and low‐grade serous carcinomas. Conclusions: The increased expression of p16 in high‐grade serous carcinoma compared with low‐grade serous carcinoma and serous borderline tumour is in keeping with a different underlying pathogenesis. p16 may be implicated in the development of high‐grade serous neoplasia within the ovary and elsewhere within the female genital tract.
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Cystadenocarcinoma
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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
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