Pure Endometrial Clear Cell Carcinoma Research Articles

Survival outcomes and the prognostic significance of clinicopathological features in patients with endometrial clear cell carcinoma: a 35-year single-center retrospective study

BackgroundTo evaluate the oncological outcomes and the impact of clinicopathological factors on endometrial clear cell carcinoma (ECCC) outcomes.MethodsMedical records of patients with primary ECCC treated at our center between 1985 and December 2020 were reviewed. Overall survival (OS) and progression-free survival (PFS) were the endpoints. The Kaplan–Meier method and Cox regression analysis were used.ResultsIn total, 156 patients were included, of whom 59% and 41% had early- and advanced-stage ECCC, respectively. The median age of onset was 61 years, and 80.8% of the patients were postmenopausal. Ninety-two (59%) and 64 (41%) patients had pure ECCC and mixed endometrial carcinoma with clear cell carcinoma (CCC) components, respectively. Mixed pathological components, elevated cancer antigen 125 levels, positive lymphovascular space invasion, deep myometrial invasion, and malignant peritoneal washing cytology (PWC) were more frequently observed in the advanced stage. Thirty-nine patients (25%) experienced relapse and 32 patients (20.5%) died. The 5-year PFS and OS rates for the entire cohort were 72.6% and 79%, respectively. Multivariate analysis showed that advanced-stage disease and positive PWC significantly decreased PFS, while advanced-stage disease and older age (> 61 years) significantly decreased OS.ConclusionsECCC is a rare and aggressive type II endometrial carcinoma that is common in older women and patients with advanced-stage disease. Positive PWC was associated with decreased PFS, although its presence did not influence the stage. Positive PWC, and advanced stage and older age were independent negative prognostic factors.

Clear cell carcinoma of the endometrium: an immunohistochemical and molecular analysis of 45 cases

The aim of the present paper is to study a cohort of pure selected endometrial clear cell carcinomas (ECCCs) from an immunohistochemical and molecular perspective to provide new data about the molecular profile of this disease. In detail, 45 consecutive patients with a proven diagnosis of pure ECCC, according to World Health Organization criteria, were included into the study. We determined the incidence of KRAS, BRAF, and PIK3CA mutations as well as the immunohistochemical expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, PMS2), estrogen, progesterone receptors, p16, and p53. Immunohistochemical analyses for α-methylacyl-coenzyme-A racemase and Napsin A were performed to support the diagnosis of ECC. All cases were positive for at least 1 of the 2 markers. In detail, 34 of 45 (75.5%) cases were positive for α-methylacyl-coenzyme-A racemase, and 40 of 45 (88.8%) cases showed positive staining for Napsin A. All selected cases exhibited negative immunostain for estrogen receptor and progesterone receptor, a "patchy" immunostain for p16, and a "wild-type" staining pattern for p53. Fifteen patients (15/45; 33.3%) showed loss of 1 or more MMR proteins by immunohistochemistry. Seven patients showed dual loss of MSH2 and MSH6, 4 patients (8.8%) showed isolated loss of MSH6, and the remaining 4 patients showed isolated loss of PMS2, respectively. Pyrosequencing analysis revealed the presence of 5 of 45 mutations (11%) at codon 12 in exon 2 of KRAS (3/5 p.G12D, 60%; 2/5 p. G12V, 40%) and 5 of 45 (11%) mutations in PIK3CA gene, of which 3 of 5 (60%) were in exon 9 of PIK3CA (2 p.E542K and 1 p.Q546K) and 2 of 5 (40%) were in exon 20 (p.H1047R). Two synchronous mutations affecting exon 9 of PIK3CA (p.Q546K) and exon 2, codon 12 of KRAS (p.G12D) were found. No mutations were detected in the hot spot region of BRAF. In conclusion, we provided detailed immunohistochemical and molecular data in a series of ECC, demonstrating a high incidence (33%) of MMR deficiencies detected by immunohistochemistry as well as a synchronous mutation affecting PIK3CA and KRAS genes. A more extensive interrogation of the genomic features of a much larger series of clear cell carcinomas will be required to define the genomic landscape of this subtype and to determine whether there are molecular alterations that are unique to, or significantly enriched in, clear cell tumors compared to other subtypes.

Targeted Molecular and Immunohistochemical Analyses of Endometrial Clear Cell Carcinoma Show that POLE Mutations and DNA Mismatch Repair Protein Deficiencies Are Uncommon.

Endometrial clear cell carcinoma (ECCC) is an uncommon histotype without unique identified molecular alterations. Recently, The Cancer Genome Atlas molecular subtypes have been reported in ECCC. ECCC cases were collected from 11 institutions with diagnoses confirmed by morphologic review and immunohistochemistry. DNA mismatch repair (MMR) proteins, p53 expression, and ARID1A expression was assessed by immunohistochemistry on tissue microarrays. Targeted next-generation sequencing was completed for POLE, TP53, KRAS, and PIK3CA. Pathogenicity of mutations was determined using MutationTaster and PolyPhen databases. For p53, immunohistochemistry and sequencing were complimentarily used to assess the p53 status. Of 57 cases, 46 were considered prototypical ECCC by morphology and immunohistochemical profile (Napsin A-positive and ER-negative). Three cases were excluded because of insufficient sample for complete immunohistochemical analysis, and 6 had failed sequencing, resulting in 37 cases. Of the 37 remaining cases, 6/37 (16%) had predicted pathogenic mutations in the exonuclease domain of POLE with an allelic frequency >10%; however, no hot-spot mutations were identified. No cases were MMR-deficient. The gene most commonly affected was TP53 (59%, 22/37), followed by KRAS (13%, 2/15) and PIK3CA (13%, 2/15). The current study is the largest molecular analysis of pure ECCC reported to date. When strict classification criteria are applied, MMR-deficient and POLE mutated subtypes are not represented. Further consensus on what represents a deleterious POLE mutations is needed. The findings support separately studying histologically/immunohistochemically defined ECCC to identify characteristic molecular alterations in future studies.

Frequent Mismatch Repair Protein Deficiency in Mixed Endometrioid and Clear Cell Carcinoma of the Endometrium.

Mixed endometrioid and clear cell carcinoma of the endometrium refers to a scenario in which the tumor exhibits histologic features of both endometrioid and clear cell carcinoma. We observed a tendency for these tumors to occur in a mismatch repair (MMR) protein-deficient molecular background in a prior study that examined a small cohort of mixed-type endometrial carcinomas. The aim of this study was to determine the rate of MMR protein deficiency in a larger series of endometrial mixed endometrioid and clear cell carcinomas, through a retrospective survey of MLH1, PMS2, MSH2, and MSH6 expression in such tumors at 5 tertiary centers. A total of 41 cases were identified and 27 (66%) tumors demonstrated MMR protein deficiency with a comparable frequency across the contributing centers (ranging from 56% to 83%). Among the MMR protein-deficient cases, 59% showed concurrent MLH1 and PMS2 loss, 33% showed concurrent MSH2 and MSH6 loss, and 4% showed isolated PMS2 or MSH6 loss. Compared with a previously published series of 15 pure endometrial clear cell carcinomas, mixed endometrioid and clear cell carcinomas are associated with significantly better disease-specific survival (P=0.02). In summary, endometrial carcinomas with mixed endometrioid and clear cell histology are frequently MMR protein deficient. This finding has implications both for our understanding of its tumor biology and for the identification of patients with potential Lynch syndrome.

Prognostic factors in endometrial clear cell carcinoma

To document the experience regarding patients treated for endometrial clear cell carcinoma (ECCC), with reference to clinical, biochemical, histopathologic, and prognostic features. Twenty-six ECCC patients, diagnosed and treated between 2008 and 2014, were reviewed retrospectively. From the hospital records, all data related to patients' demographic, clinical, biochemical, and histopathologic assessments and adjuvant therapy adjustments were evaluated. Disease-free survival (DFS), overall survival (OS), and 5-year cumulative survival rates (CSR) were estimated as well as prognostic factors associated with OS. The median follow-up time was 22.7months, and the mean age at diagnosis was 64.0years. Fourteen (53.8%) women had early stage and 12 (46.2%) women had advanced-stage disease. There were 17 (65.3%) patients with pure clear cell carcinoma and 8 (30.7%) patients with mixed histology on the hysterectomy specimen. Extra-uterine disease occurred more frequently in patients with pure ECCC and elevated CA-125 concentrations. Seventeen (65.3%) patients received adjuvant platinum and taxane chemotherapy with (n: 13/17, 76.4%) or without radiotherapy in the form of external beam radiotherapy (ERT) and/or vaginal brachytherapy (BRT). The rest of the patients (n: 9/26, 34.6%), who had tumor with no or limited myometrial invasion without LVSI, impaired general health status, and non-compliance-to-post-operative treatment proposal received no adjuvant therapy. The mean DFS and OS were 49.54 and 50.01months, respectively, with the 5-year CSR of 46.4%. The mean OS was significantly shorter in patients with higher pre-operative CA-125 values, >2cm tumor diameter, myometrial invasion ≥1/2, cervical involvement, uterine serosal and/or adnexal invasion, lymph node metastasis, and, thus, with advanced-stage disease. Uterine serosal invasion was the only significant prognostic factor associated with OS in the multivariate analysis. Increased pre-operative serum CA-125 levels are associated with advanced-stage disease, and uterine serosal involvement is a significant prognostic factor associated with OS in women with ECCC.

Diagnostic Impacts of Serum CA-125 Levels, Pap Smear Evaluation, and Endometrial Sampling in Women with Endometrial Clear Cell Carcinoma

Background: Endometrial clear cell carcinoma (ECCC) is a rare variant of endometrial cancer with an unfavorable prognosis. The aim of this study was to determine the relationships, if any, between preoperative serum cancer antigen 125 (CA-125) levels, the last Papanicolaou (Pap) smear, the results of endometrial biopsy and tumor histology, and disease-stage according to permanent histopathology. Materials and Methods: The data of 26 women with ECCC were collected from their medical records to compare demographics, preoperative serum CA-125 levels, Pap test results, histological diagnosis of the endometrial biopsy, and tumor histology, as well as the disease stage according to permanent histopathology. Results: The mean age at diagnosis was 64.0 years. There were 17 (65.3%) women with pure ECCC and 8 (30.7%) women with a mixed histology. Stage III-IV disease was diagnosed in 12 (46.2%) women and occurred more frequently in pure ECCC (n = 11, 91.7%). CA-125 values were significantly higher in advanced stage disease. Cytological evaluation indicated the presence of 71.4% (10/14) cytological abnormalities in pure ECCC. The overall sensitivity of endometrial sampling for the detection of malignancy was 92.3% (24/26), whereas the accurate diagnosis of ECCC was only 34.7% (8/23) with the Pipelle sampler. Conclusion: Pap test abnormalities are frequent in ECCC. Although it is less accurate in the diagnosis of ECCC than in the detection of malignancy, endometrial sampling is still the main procedure for the diagnosis of ECCC. Higher preoperative CA-125 concentrations imply the presence of advanced stage ECCC.

Immunohistochemical characterization of prototypical endometrial clear cell carcinoma—diagnostic utility of HNF‐1β and oestrogen receptor

The great majority of ovarian clear cell carcinomas have a hepatocyte nuclear factor 1 homeobox B (HNF-1β)-positive and oestrogen receptor (ER)-negative immunoprofile. However, the pattern of HNF-1β and ER immunostaining in clear cell carcinomas of the endometrium and the usefulness of this panel in distinguishing clear cell carcinoma from other histological types of endometrial carcinoma have yet to be well defined. We examined the immunostaining patterns of HNF-1β, ER and p53 in 15 morphologically classic pure endometrial clear cell carcinomas, and compared these patterns with 15 endometrioid and 15 serous carcinomas of the endometrium. We observed the presence of diffuse (>70%) moderate to strong nuclear HNF-1β staining and negative ER staining in 14 of 15 clear cell carcinomas, with the remaining case showing both diffuse strong nuclear HNF-1β staining and focal ER staining. In comparison, only one of 15 serous carcinomas and none of 15 endometrioid carcinomas showed a combination of diffuse moderate to strong HNF-1β nuclear staining and negative ER staining. Aberrant p53 immunostaining was observed in five of 15 (33%) clear cell carcinomas. Overall, our findings demonstrate that, similarly to the situation for the ovary, a diagnostic panel of HNF-1β and ER may be considered for separating clear cell carcinoma from endometrioid and serous carcinoma of the endometrium.

Precursors of Endometrial Clear Cell Carcinoma

The recognition of morphologically identifiable lesions which may confer an increased risk for subsequent development of an invasive malignancy offers an opportunity to investigate and better understand the molecular-genetic etiopathogenesis of the well-developed tumor, and potentially, to administer a therapeutic intervention before its development. In contrast to uterine endometrioid and serous carcinomas, very little is known about the potential precursor lesions of endometrial clear cell carcinoma (ECCC). In our routine practice, we have noted the presence of a spectrum of atypical glandular changes in the endometria adjacent to ECCC or endometrial carcinomas with a clear cell component, which on the basis of current criteria, would not qualify for any specific designation. We hypothesize that these lesions represent the earliest morphologically recognizable precursor lesions of ECCC and systematically characterize their clinicopathologic features herein. Thirty archived cases of pure ECCC (n=14) or mixed endometrial carcinomas with a >10% clear cell component (n=16) were retrieved and the "normal" endometria adjacent to the malignancies were evaluated in detail. Thirty-eight benign uteri and 30 uteri with classic endometrial endometrioid carcinoma (EEC) served as controls. All cases were reviewed in a blinded fashion. Putative precursor lesions (PPL) were searched for and identified microscopically. The lesions were typically isolated glands or surface epithelium (within an otherwise normal endometrial region) that displayed cytoplasmic clarity and/or eosinophilia with varying degrees of nuclear atypia. Twenty-seven (90%) of the 30 cases had at least 1 PPL. In contrast, PPL were identified neither in the benign uteri nor in endometrioid carcinoma control groups (P<0.001). A total of 67 foci of PPL were identified in the 27 cases with an average of 2.5 foci per case. The immunohistochemical expression of p53, mib-1, estrogen receptor (ERs), and progesterone receptor in the benign endometria, ECCC, and the PPL were evaluated on all 27 cases. The mean p53 scores for the benign endometria, PPL, and ECCC were 0, 4.5, and 6.2, respectively. Parallel values for mib-1 were 15%, 45%, and 63%. ER/progesterone receptor indices for benign endometria, PPL, and carcinoma were 90/80, 21.52/4.61, and 11/4, respectively. The PPL described herein have a morphologic and immunophenotypic profile which seems to be distinct from both the benign endometria in which they reside and the adjacent areas of ECCC. The high frequency of association of these lesions with ECCC, their frequent occurrence as isolated lesions within otherwise "benign-appearing" endometria, and their continuous spectrum of nuclear atypia from minimum (grade 1, cytologic atypia falls short of ECCC cells) to maximum (grade 3, cytologically identical to ECCC cells), argues in favor of our hypothesis that these may represent precursor lesions of ECCC. Further studies are required to conclusively define the nature of these lesions. However, such studies can only be performed if diagnostic surgical pathologists recognize, highlight, and segregate these lesions for further analysis.