Uterine Sarcoma With EML4::NTRK3 Fusion: A Spectrum of Mesenchymal Neoplasms Harboring Actionable Gene Fusions.

NTRK gene fusions are part of a paradigm shift in oncology, arising as one of the main genomic alterations with actionability in the so-called "agnostic setting." In gynecologic pathology, the recent description of uterine sarcoma resembling fibrosarcoma and with NTRK rearrangements ( NTRK -rearranged uterine sarcoma) highlights the importance of recognizing clinicopathological cues that can lead to genomic profiling. Herein, we report the case of a 43-year-old woman presenting with vaginal bleeding and pelvic mass. Histopathology of the tumor showed moderately atypical spindle cells arranged in long fascicles reminiscent of fibrosarcoma, along with immunohistochemical positivity for S100, CD34, and pan-tropomyosin receptor kinase. This prompted RNA-sequencing and the finding of a rare EML4::NTRK3 fusion. Clinical, histologic, and molecular findings are described, in addition to discussions regarding differential diagnoses and possible implications of the findings in clinical practice.

Genomic landscapes of ovarian clear cell carcinoma from latin countries reveal aberrations linked to survival and progression.

BACKGROUND: Ovarian clear cell carcinomas (OCCCs) are rare, aggressive and chemoresistant tumors. Geographical and ethnic differences in the incidence of OCCC have been reported with a higher incidence in Asiatic countries. There is a paucity of information regarding OCCC in Latin America (LA) and other countries. METHODS: Here, we characterized two cohorts of 33 patients with OCCC from LA (24 from Brazil and 9 from Costa Rica) and a cohort of 27 patients from Spain. Genomic analysis was performed for 26 OCCC using the OncoScan platform. Tumors were classified according to their genomic landscapes into subgroups. Clinical parameters were related to the frequency of genomic aberrations. RESULTS: The median overall survival (OS) was not significantly different between the cohorts. Genomic landscapes were characterized by different homologous recombination deficiency (HRD) levels. No difference in the distribution of genomic landscapes profiles was detected between patients from the different cohorts. OCCCs with MYC-amplified tumors harboring a concomitant loss of a region in chromosome 13q12-q13 that includes the BRCA2 gene had the longest OS. In contrast, patients carrying a high number (> 30) of total copy number (CN) aberrations with no concomitant alterations in MYC and BRCA2 genes presented the shortest OS. Furthermore, amplification of the ASH1L gene was also associated with a shorter OS. Initial-stage OCCCs with early progression were characterized by gains in the JNK1 and MKL1 genes. CONCLUSIONS: Our results provide new data from understudied OCCC populations and reveal new potential markers for OCCCs.

Can mismatch repair status be added to sentinel lymph node mapping algorithm in endometrioid endometrial cancer?

OBJECTIVE: To evaluate the relation between mismatch repair (MMR) status and the risk of lymph node metastasis in endometrial cancer, and whether this additional data can be incorporated to current SLN (sentinel lymph node) algorithm. METHODS: We included a series of 332 women that underwent SLN mapping ± systematic lymphadenectomy from January 2013 to December 2021. Protein expressions of MLH1, MSH2, MSH6, PMS2 were examined by immuno-histochemistry and considered MMRd (deficient) when at least one protein was not expressed. RESULTS: MMRd was noted in 20.8% of cases and correlated to grade 3 (p = 0.018) and presence of lymphovascular space invasion (p = 0.032). Moreover, MMRd was an independent risk factor for lymph node metastasis (OR 2.76, 95% CI 1.36-5.62). Notably, 21.7% (15/69) cases with MMRd had lymph node metastasis compared to 9.5% (25/263) of cases with MMRp (proficient) (p = 0.005). The overall and bilateral SLN detection rates were 91.9% and 75.9%, respectively. Of the 80 (24%) cases of non-bilateral SLN detection, 66.2% had low-grade tumors (G1/G2) and myometrial invasion <50%. Considering MMR status an independent prognostic factor for lymph node metastasis, a systematic lymphadenectomy (side specific or bilateral) would forgo in 53.7% (43/80) of cases with non-bilateral detection, representing 13% (43/332) of all endometroid tumors. CONCLUSION: MMR status was independently related to lymph node metastasis in endometrioid EC. Moreover, MMR status may help to select patients that can forgo systematic lymphadenectomy in case of undetected SLN.

Amplicon-based NGS test for assessing MLH1 promoter methylation and its correlation with BRAF mutation in colorectal cancer patients.

Detecting MLH1 promoter methylation is highly relevant to differentiate between possible Lynch syndrome patients or patients with sporadic causes of MLH1/PMS2 deficiency in colorectal (CRC) and endometrial cancers. Here, we aimed to develop a test for assessing MLH1 promoter methylation based in next generation sequencing (NGS), and to evaluate the concordance of MLH1 methylation and BRAF-V600 mutation status in CRC. For that, we performed a series of experiments with DNA from tumor, saliva and commercial control samples and our in house developed amplicon-based NGS test. In patients' samples, MLH1 methylation above 10% was only observed in tumors with MLH1/PMS2 loss. We confirmed the reproducibility and accuracy of MLH1 promoter analysis performing a serial dilution experiment with completely methylated and unmethylated control DNAs and a comparison between two NGS platforms (Ion Proton and Illumina). In MLH1/PMS2 deficient tumors, the MLH1 methylation status was concordant with the BRAF mutation status in 90% (18/20) of the cases. Our amplicon-based NGS test showed a great sensitivity and specificity for detecting MLH1 methylation in CRC samples, with a high agreement with the evaluation of BRAF mutation. This simple and affordable test could be used as a reflex test to identify patients with sporadic causes of MLH1/PMS2 deficiency in CRC, aiding to genetic test referral and identification of Lynch syndrome patients.

Does sentinel node mapping impact morbidity and quality of life in endometrial cancer?

OBJECTIVES: To evaluate the prevalence of post-operative complications and quality of life (QoL) related to sentinel lymph node (SLN) biopsy vs systematic lymphadenectomy in endometrial cancer. METHODS: A prospective cohort included women with early-stage endometrial carcinoma who underwent lymph node staging, grouped as follows: SLN group (sentinel lymph node only) and SLN+LND group (sentinel lymph node biopsy with addition of systematic lymphadenectomy). The patients had at least 12 months of follow-up, and QoL was assessed by European Organization for Research and Treatment of Cervical Cancer Quality of Life Questionnaire 30 (EORTC-QLQ-C30) and EORTC-QLQ-Cx24. Lymphedema was also assessed by clinical evaluation and perimetry. RESULTS: 152 patients were included: 113 (74.3%) in the SLN group and 39 (25.7%) in the SLN+LND group. Intra-operative surgical complications occurred in 2 (1.3%) cases, and all belonged to SLN+LND group. Patients undergoing SLN+LND had higher overall complication rates than those undergoing SLN alone (33.3% vs 14.2%; p=0.011), even after adjusting for confound factors (OR=3.45, 95% CI 1.40 to 8.47; p=0.007). The SLN+LND group had longer surgical time (p=0.001) and need for admission to the intensive care unit (p=0.001). Moreover, the incidence of lymphocele was found in eight cases in the SLN+LND group (0 vs 20.5%; p<0.001). There were no differences in lymphedema rate after clinical evaluation and perimetry. However, the lymphedema score was highest when lymphedema was reported by clinical examination at 6 months (30.1 vs 7.8; p<0.001) and at 12 months (36.3 vs 6.0; p<0.001). Regarding the overall assessment of QoL, there was no difference between groups at 12 months of follow-up. CONCLUSIONS: There was a higher overall rate of complications for the group undergoing systematic lymphadenectomy, as well as higher rates of lymphocele and lymphedema according to the symptom score. No difference was found in overall QoL between SLN and SLN+LND groups.

Prognostic value of isolated tumor cells in sentinel lymph nodes in low risk endometrial cancer: results from an international multi-institutional study.

OBJECTIVE: The prognostic significance of isolated tumor cells (≤0.2 mm) in sentinel lymph nodes (SLNs) of endometrial cancer patients is still unclear. Our aim was to assess the prognostic value of isolated tumor cells in patients with low risk endometrial cancer who underwent SLN biopsy and did not receive adjuvant therapy. Outcomes were compared with node negative patients. METHODS: Patients with SLNs-isolated tumor cells between 2013 and 2019 were identified from 15 centers worldwide, while SLN negative patients were identified from Mayo Clinic, Rochester, between 2013 and 2018. Only low risk patients (stage IA, endometrioid histology, grade 1 or 2) who did not receive any adjuvant therapy were included. Primary outcomes were recurrence free, non-vaginal recurrence free, and overall survival, evaluated with Kaplan-Meier methods. RESULTS: 494 patients (42 isolated tumor cells and 452 node negative) were included. There were 21 (4.3%) recurrences (5 SLNs-isolated tumor cells, 16 node negative); recurrence was vaginal in six patients (1 isolated tumor cells, 5 node negative), and non-vaginal in 15 (4 isolated tumor cells, 11 node negative). Median follow-up among those without recurrence was 2.3 years (interquartile range (IQR) 1.1-3.0) and 2.6 years (IQR 0.6-4.2) in the SLN-isolated tumor cell and node negative patients, respectively. The presence of SLNs-isolated tumor cells, lymphovascular space invasion, and International Federation of Obstetrics and Gynecology (FIGO) grade 2 were significant risk factors for recurrence on univariate analysis. SLN-isolated tumor cell patients had worse recurrence free survival (p<0.01) and non-vaginal recurrence free survival (p<0.01) compared with node negative patients. Similar results were observed in the subgroup of patients without lymphovascular space invasion (n=480). There was no difference in overall survival between the two cohorts in the full sample and the subset excluding patients with lymphovascular space invasion. CONCLUSIONS: Patients with SLNs-isolated tumor cells and low risk profile, without adjuvant therapy, had a significantly worse recurrence free survival compared with node negative patients with similar risk factors, after adjusting for grade and excluding patients with lymphovascular space invasion. However, the presence of SLNs-isolated tumor cells was not associated with worse overall survival.

Prognostic factors in locally advanced cervical cancer with pelvic lymph node metastasis.

OBJECTIVE: To evaluate the prognostic impact of clinical and pathological variables and patterns of recurrence in patients with locally advanced cervical cancer with pelvic lymph node involvement (stage IIIC1 according to the 2018 FIGO Staging System). METHODS: We retrospectively analyzed 62 patients with locally advanced cervical cancer treated with curative intent with radiotherapy associated with chemotherapy in AC Camargo Cancer Center from January 2007 to December 2018. RESULTS: Lymph node involvement was assessed by CT, MRI and positron emission tomography (PET)/CT in 28 (45.2%), 20 (32.3%) and 14 (22.6%) patients, respectively. The median tumor size was 5.0 cm and 72.6% of cases were squamous cell carcinomas. The median number of positive pelvic lymph nodes was three, and the median size of lymph nodes was 24 mm. Twenty-two (35.5%) patients had recurrence and 50% had only one site of recurrence. The sites of recurrence were pelvic, para-aortic and distant in 12 (19.4%), 6 (9.7%) and 16 (25.8%) patients, respectively. The 3 year overall and disease-free survival were 70.8% and 64.6%, respectively. Patients with adenocarcinoma had worse disease-free survival (HR 2.38; 95% CI 1.01 to 5.60; p=0.047) and overall survival (HR 2.99; 95% CI 1.14 to 7.75; p=0.025) compared with squamous cell carcinoma. In multivariate analysis, metastatic pelvic lymph node size of >2.5 cm (HR 4.38; 95% CI 1.65 to 11.6; p=0.003) and incomplete response to radiotherapy (HR 5.14; 95% CI 1.60 to 16.4; p=0.006) maintained the negative impact for overall survival. CONCLUSIONS: We found that pelvic lymph node size and incomplete response to radiotherapy negatively impact overall survival in patients with advanced cervical cancer with pelvic lymph node involvement. This finding may help to stratify risk in this group of patients.

Sentinel lymph node mapping versus sentinel lymph node mapping with systematic lymphadenectomy in endometrial cancer: an open-label, non-inferiority, randomized trial (ALICE trial).

BACKGROUND: Growing evidence suggest that sentinel lymph node (SLN) biopsy in endometrial cancer accurately detects lymph node metastasis. However, prospective randomized trials addressing the oncological outcomes of SLN biopsy in endometrial cancer without lymphadenectomy are lacking. PRIMARY OBJECTIVES: The present study aims to confirm that SLN biopsy without systematic node dissection does not negatively impact oncological outcomes. STUDY HYPOTHESIS: We hypothesized that there is no survival benefit in adding systematic lymphadenectomy to sentinel node mapping for endometrial cancer staging. Additionally, we aim to evaluate morbidity and impact in quality of life (QoL) after forgoing systematic lymphadenectomy. TRIAL DESIGN: This is a collaborative, multicenter, open-label, non-inferiority, randomized trial. After total hysterectomy, bilateral salpingo-oophorectomy and SLN biopsy, patients will be randomized (1:1) into: (a) no further lymph node dissection or (b) systematic pelvic and para-aortic lymphadenectomy. MAJOR INCLUSION AND EXCLUSION CRITERIA: Inclusion criteria are patients with high-grade histologies (endometrioid G3, serous, clear cell, and carcinosarcoma), endometrioid G1 or G2 with imaging concerning for myometrial invasion of ≥50% or cervical invasion, clinically suitable to undergo systematic lymphadenectomy. PRIMARY ENDPOINTS: The primary objective is to compare 3-year disease-free survival and the secondary objectives are 5-year overall survival, morbidity, incidence of lower limb lymphedema, and QoL after SLN mapping ± systematic lymphadenectomy in high-intermediate and high-risk endometrial cancer. SAMPLE SIZE: 178 participants will be randomized in this study with an estimated date for completing accrual of December 2024 and presenting results in 2027. TRIAL REGISTRATION NUMBER: NCT03366051.

Predictive Factors for Residual Disease After Conization in Cervical Cancer.

OBJECTIVE: The aim of this study was to evaluate predictive factors for the presence of residual disease after conization followed by definitive surgery in cervical cancer, and suggest a margin distance threshold that could predict residual disease. METHODS: We retrospectively analyzed a series of 42 patients with early-stage cervical cancer who underwent primary conization before definitive surgical treatment from March 2009 to May 2020. All conization specimens were reviewed for endocervical, ectocervical, and radial margins. Cases with residual disease in magnetic resonance imaging before definitive surgery were excluded. RESULTS: Thirty-three (78.6%) patients underwent hysterectomies and 9 (21.4%) trachelectomies ± lymph node staging. Twelve (28.6%) cases were stage IA1, 5 (11.8%) cases were stage IA2, 13 (31%) cases were stage IB1, 11 (26.2%) cases were stage IB2, and 1 (2.4%) case was stage IIIC1 [International Federation of Gynecology and Obstetrics (FIGO) 2019]. We found residual disease in 17 (40.4%) surgical specimens. Of the 20 patients with negative margins, there were still 3 (15%) cases with residual disease. Conversely, residual disease was identified in 14 (63.6%) of the 22 patients with positive cone margins (p = 0.001). Tumor size [odds ratio (OR) 1.71, 95% confidence interval (CI) 1.02-1.33] and positive endocervical margin status (OR 33.6, 95% CI 3.85-293.3) were related to a higher risk of residual disease in multivariate analysis. Notably, all patients with tumors larger than 2 cm had residual disease, in contrast to 29.4% in lesions up to 2 cm (p = 0.002). CONCLUSION: We found that tumor size and positive margin were predictive factors for residual disease. We could not suggest a reliable minimum margin distance threshold that could predict residual disease.

Oncologic outcomes of endometrial cancer in patients with low-volume metastasis in the sentinel lymph nodes: An international multi-institutional study.

OBJECTIVE: To assess oncologic outcomes in endometrial cancer patients with low-volume metastasis (LVM) in the sentinel lymph nodes (SLNs). METHODS: Patients with endometrial cancer and SLN-LVM (≤2 mm) from December 3, 2009, to December 31, 2018, were retrospectively identified from 22 centers worldwide. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IV, adnexal involvement, or unknown adjuvant therapy (ATx) were excluded. RESULTS: Of 247 patients included, 132 had isolated tumor cell (ITC) and 115 had micrometastasis (MM). Overall 4-year recurrence-free survival (RFS) was 77.6% (95% CI, 70.2%-85.9%); median follow-up for patients without recurrence was 29.6 (interquartile range, 19.2-41.5) months. At multivariate analysis, Non-endometrioid (NE) (HR, 5.00; 95% CI, 2.50-9.99; P < .001), lymphovascular space invasion (LVSI) (HR, 3.26; 95% CI, 1.45-7.31; P = .004), and uterine serosal invasion (USI) (HR, 3.70; 95% CI, 1.44-9.54; P = .007) were independent predictors of recurrence. Among 47 endometrioid ITC patients without ATx, 4-year RFS was 82.6% (95% CI, 70.1%-97.2). Considering 18 ITC patients with endometrioid grade 1 disease, without LVSI, USI, or ATx, only 1 had recurrence (median follow-up, 24.8 months). CONCLUSIONS: In patients with SLN-LVM, NE, LVSI, and USI were independent risk factors for recurrence. Patients with any risk factor had poor prognosis, even when receiving ATx. Patients with ITC and grade 1 endometrioid disease (no LVSI/USI) had favorable prognosis, even without ATx. Further analysis (with more patients and longer follow-up) is needed to assess whether ATx can be withheld in this low-risk subgroup.

Pathological factors associated with non-sentinel lymph node metastasis in early stage cervical cancer.

OBJECTIVE: To analyze the predictive factors for non-sentinel lymph node (non-SLN) metastasis in early-stage cervical cancer. METHODS: We analyzed a series of 113 patients who underwent sentinel lymph node (SLN) mapping for cervical cancer. The SLNs were examined by immunohistochemistry (IHC) when the hematoxylin-eosin stain was negative. RESULTS: The overall bilateral detection rate was 81.5%, with a median of two SLNs resected. The study ultimately included 92 patients with SLNs that were mapped who had also undergone systematic pelvic lymph node dissection. Thirteen (14.1%) patients had positive SLNs, with a median of one positive SLN. Regarding the size of SLN metastasis, one (1.1%) had isolated tumor cells (ITC), seven (7.6%) had micrometastases, and five (5.4%) had macrometastases. Notably, 46.1% (6/13) had lymph node metastases detected only after IHC. Five (38.5%) cases had positive non-SLNs, with a median count of one positive lymph node. Parametrial invasion was the only risk factor for positive non-SLN (p = .045). Regarding the size of SLN metastasis, non-SLN involvement was present in the only case with ITC (1/1), 42.9% (3/7) of cases with micrometastases, and in 20% (1/5) with macrometastases. CONCLUSIONS: Our data suggest that parametrial invasion correlates with the risk of non-SLN metastasis in cervical cancer.

FIGO 2018 stage IB endocervical adenocarcinomas: an international study of outcomes informed by prognostic biomarkers.

OBJECTIVE: Prognostic factors for endocervical adernocarcinomas are well known, but little is known about prognostic biomarkers influencing outcome for the newly defined International Federation of Gynecology and Obstetrics (FIGO) 2018 IB sub-stages. The aim of this study was to identify prognostic biomarkers influencing recurrence-free and overall survival for FIGO 2018 stage IB cervical adenocarcinoma sub-types. We sought to identify these factors using a large international multi-institutional series of cases. METHODS: Stage IB endocervical adenocarcinomas were retrospectively collected from nine international institutions; full slide sets (n=464) were used to assign prognostic biomarkers. Inclusion criteria were the following: FIGO stage IB endocervical adenocarcinomas with follow-up in which all paraffin blocks/glass slides were available for review and/or additional studies and the patient was surgically treated from 1985 to 2019. The types of specimens included in the study were conizations, trachelectomies, and simple/radical hysterectomies with or without lymph node samples. We excluded in situ carcinomas, squamous cell carcinomas, adenosquamous carcinomas, tumors with a neuroendocrine component, carcinosarcomas, and any tumor showing clinical, macroscopic, or microscopic features suggesting a lower uterine segment, uterine corpus, or an adnexal primary origin. Tumors treated with neoadjuvant chemotherapy and/or radiation therapy were also excluded, as well as biopsies and loop electrosurgical excision procedures. RESULTS: Of 464 cases, 225 (48%) were stage IB1, 177 (38%) were stage IB2, and 62 (13%) were stage IB3. Five-year and 10-year recurrence-free survivals were statistically different among stage IB sub-types (p=0.005). Silva pattern of invasion was significant for recurrence-free survival at 5 and 10 years (p=0.04); overall survival and recurrence-free survival were higher in human papillomavirus (HPV)-associated cases (p=0.007 and p=0.001, respectively) and in cases without lymphovascular invasion (p=0.004 and p=0.00001, respectively). Factors that significantly influenced recurrence-free survival were HPV-independent status (p=0.05; HR 2.31; 95% CI 1.02 to 5.46), presence of lymphovascular invasion (p=0.011; HR 3.50; 95% CI 1.33 to 9.19), and presence of lymph node metastasis (p=0.016; HR 2.66; 95% CI 1.20 to 5.90). CONCLUSION: HPV status and the presence of lymphovascular invasion are prognosticators in stage IB endocervical adenocarcinoma sub-types. These parameters should be included in future sub-staging modifications of FIGO stage IB endocervical adenocarcinomas and in treatment strategies.

Adnexal Involvement in Endometrial Cancer: Prognostic Factors and Implications for Ovarian Preservation.

PURPOSE: To determine the risk factors related to adnexal involvement in endometrial cancer (EC) and its implications for ovarian preservation in young women. METHODS: We analyzed a series of 802 patients who were treated at AC Camargo Cancer Center from July 1991 to July 2017. Patients who had peritoneal or systemic dissemination (stage IV) were excluded. Chi square and Fisher's exact tests were used to analyze the correlations between categories and clinicopathological variables. Multivariate analysis was performed by logistic regression. RESULTS: Forty-nine (6.2%) patients had adnexal involvement-43 (5.4%) ovarian and 24 (2.9%) tubal. After excluding the 14 (28%) cases with suspicious findings, 788 subjects were analyzed and adnexal involvement found in 35 (4.4%) cases. Adnexal involvement was statistically related to non-endometrioid histologies (12.6% vs. 3.1%; p < 0.001), lymph node metastasis (17% vs. 2.6%; p < 0.001), histological grade 3 tumors (9.4% vs. 2.1%; p < 0.001), presence of LVSI (14.2% vs. 2.4%; p < 0.001), and deep myometrial invasion (≥ 50%) (10.8% vs. 3.5%; p < 0.001). Although age younger than 45 years had higher risk of adnexal involvement, it was not statistically significant (8.9% vs. 4.2%; p = 0.13). Seven (14.2%) patients with adnexal involvement were aged < 45 years, 3 of whom (42.8%) had suspicious adnexal masses that were detected before surgery. Notably, all patients aged < 45 years and with adnexal involvement had at least 1 risk factor, such as presence of LVSI, grade 3 disease, node metastasis, or deep myometrial invasion. No patient with clinically normal ovaries and aged under 45 years, with endometrioid grades 1 and 2, superficial myometrial invasion, or node negativity had adnexal involvement. CONCLUSIONS: Ovarian preservation may be considered for patients younger than 45 years old with low-risk EC (grades 1 and 2 tumors, absence of LVSI, and myometrial invasion < 50%).

Size of Sentinel Node Metastasis Predicts Non-sentinel Node Involvement in Endometrial Cancer.

PURPOSE: To analyze the relationship between the size of metastatic sentinel lymph nodes (SLNs) and the risk of non-sentinel lymph node (non-SLN) metastasis in endometrial cancer. PATIENTS AND METHODS: From a total of 328 patients with endometrial cancer who underwent SLN mapping from January 2013 to April 2019, 142 patients also underwent systematic completion pelvic ± paraaortic node dissections, and they form the basis of this study. The SLNs were examined by immunohistochemistry (IHC) when the hematoxylin-eosin stain was negative. RESULTS: The median age was 60 years. The overall detection rate for SLNs was 87.5%, and bilateral SLNs were observed in 66.2%, with a median of 2 SLNs resected (range 1-8). Twenty-nine (20.4%) cases had positive SLNs, with a median of one positive SLN. Regarding the size of SLN metastasis, 5 (3.5%) cases had isolated tumor cells (ITCs), 13 (9.2%) had micrometastases, and 11 (7.7%) had macrometastases. Notably, 14/29 (48.3%) had node metastases that were detected after IHC. Eight (27.6%) patients had positive non-SLNs, with a median count of 7 positive nodes (range 2-23). Regarding the size of SLN metastasis, non-SLN involvement was not present in cases with ITC (0/5) but was present in 15.4% (2/13) of cases with micrometastases and 54.5% (6/11) of cases with macrometastases. The only risk factor for positive non-SLNs was the size of SLN metastasis. CONCLUSIONS: Our data suggest that size of SLN metastasis is associated with the risk of non-SLN metastasis. No patients with ITCs in SLNs had another metastatic lymph node in this study.

Should we wait 3 months for a repeat aspiration in non-diagnostic/indeterminate thyroid nodules? A cancer centre experience.

INTRODUCTION: The Bethesda System recommends repeat fine needle aspiration (rFNA) as a management option for nodules classified under the non-diagnostic (ND) and atypia of undetermined significance (AUS/FLUS) categories. We evaluated the impact of an rFNA in diagnostic resolution and the role of early (≤3 months) vs delayed (more than 3 months) rFNA of nodules initially diagnosed as ND and AUS/FLUS. METHODS: We retrospectively collected all thyroid FNA performed in a 4-year period with repeat aspiration. For cases initially signed out as ND or AUS/FLUS, diagnostic resolution was defined as a change to a Bethesda System category other than these two on rFNA. Comparison and regression models were fitted to identify the impact of time of rFNA on diagnostic resolution. RESULTS: In total, 184 cases were initially assigned as ND and 143 as AUS/FLUS, with overall diagnostic resolution rates for the reassessment of these nodules calculated at 70.1% and 62.9%, respectively. For ND cases, time of rFNA was not significantly associated with diagnostic resolution (P > .05). For AUS/FLUS nodules, however, repeat aspiration performed in more than 3 months after the initial diagnosis was 2.5 times more likely to achieve a resolution in diagnosis than early rFNA (P = .024). CONCLUSIONS: Repeat aspiration of ND and AUS/FLUS nodules helped define diagnosis for the majority of cases, being highly effective in determining correct patient management. For AUS/FLUS nodules, repeat aspiration performed more than 3 months after the initial diagnosis was associated with a higher diagnostic resolution.

Two-year study on the application of the Paris system for urinary cytology in a cancer centre.

INTRODUCTION: The Paris system for reporting urinary cytology (TPS) was published in order to provide clear cytomorphological criteria for urine cytology specimens, focusing on high-grade urothelial lesions. The aim of this study was to evaluate the impact of implementing TPS and to correlate with available concomitant histological samples, accessing overall sensitivity and specificity. METHODS: A retrospective analysis of urine cytology reports from 2017 to 2018 using TPS was carried out, with histological correlation to concomitant samples (up to 3 months). Statistical analysis was performed with calculation of sensitivity and specificity, positive and negative predictive values and risk of malignancy (ROM) for all TPS categories. RESULTS: A total of 1660 specimens were evaluated. Histological specimens were available for 611 (36.8%) cases. Urine cytology categorised by TPS had 2.4% non-diagnostic cases, 87.1% negative for high-grade urothelial carcinoma (HGUC), 4.6% atypical urothelial cells, 2.7% suspicious for HGUC, 2.7% HGUC and 0.5% cases of other malignancies. Sensitivity, specificity, negative predictive value and positive predictive value were 40.0%, 99.3%, 88.2% and 92.3%, respectively. ROM of each category was 0% for non-diagnostic, 11.1% for negative for HGUC, 32.4% for atypical, 64.9% for suspicious for HGUC and 87.9% for HGUC and other malignancies. CONCLUSION: Our findings indicated that implementation of TPS provided a high specificity and predictive positive value for the detection of high-grade urothelial lesions, with proportionally increasing ROMs as categories progress from negative to positive.

Genomic profiling in ovarian cancer retreated with platinum based chemotherapy presented homologous recombination deficiency and copy number imbalances of CCNE1 and RB1 genes.

BACKGROUND: Ovarian carcinomas presenting homologous recombination deficiency (HRD), which is observed in about 50% of cases, are more sensitive to platinum and PARP inhibitor therapies. Although platinum resistant disease has a low chance to be responsive to platinum-based chemotherapy, a set of patients is retreated with platinum and some of them are responsive. In this study, we evaluated copy number alterations, HR gene mutations and HR deficiency scores in ovarian cancer patients with prolonged platinum sensitivity. METHODS: In this retrospective study (2005 to 2014), we selected 31 patients with platinum resistant ovarian cancer retreated with platinum therapy. Copy number alterations and HR scores were evaluated using the OncoScan® FFPE platform in 15 cases. The mutational profile of 24 genes was investigated by targeted-NGS. RESULTS: The median values of the four HRD scores were higher in responders (LOH = 15, LST = 28, tAI = 33, CS = 84) compared with non-responders (LOH = 7.5, LST = 17.5, tAI = 23, CS = 47). Patients with high LOH, LST, tAI and CS scores had better response rates, although these differences were not statistically significant. Response rate to platinum retreatment was 22% in patients with CCNE1 gains and 83.5% in patients with no CCNE1 gains (p = 0.041). Furthermore, response rate was 54.5% in patients with RB1 loss and 25% in patients without RB1 loss (p = 0.569). Patients with CCNE1 gains showed a worse progression free survival (PFS = 11.1 months vs 3.7 months; p = 0.008) and a shorter overall survival (OS = 39.3 months vs 7.1 months; p = 0.007) in comparison with patients with no CCNE1 gains. Patients with RB1 loss had better PFS (9.0 months vs 2.6 months; p = 0.093) and OS (27.4 months vs 3.6 months; p = 0.025) compared with cases with no RB1 loss. Four tumor samples were BRCA mutated and tumor mutations were not associated with response to treatment. CONCLUSIONS: HR deficiency was found in 60% of our cases and HRD medium values were higher in responders than in non-responders. Despite the small number of patients tested, CCNE1 gain and RB1 loss discriminate patients with tumors extremely sensitive to platinum retreatment.

Prevalence of BRCA1 and BRCA2 pathogenic and likely pathogenic variants in non-selected ovarian carcinoma patients in Brazil.

BACKGROUND: BRCA1/2 pathogenic (P) and likely pathogenic (LP) germline variants are frequent among patients with ovarian carcinoma. However, these variants have not been extensively characterized in patients with ovarian cancer in Brazil. METHODS: In this retrospective study we evaluated clinical characteristics and BRCA1/2 genetic test results from patients with ovarian carcinoma who underwent genetic counseling at A.C.Camargo Cancer Center (Brazil) between 2015 and 2017 and had performed germline genetic testing of BRCA1/2 genes. RESULTS: Among 158 patients, 33 P and LP variants and were found (20.8%), 27 in BRCA1 and six in BRCA2, and six variants of unknown clinical significance (VUS). Thirteen percent of the patients did not have Multiplex Ligation-dependent Probe Amplification (MLPA) results. Three P variants in BRCA1 were found in more than one patient: c.5266dupC (p.Gln1756Profs*74), c.3331_3334delCAAG (p.Gln1111Asnfs5*), and c.211A > G (p.Arg71Gly). One LP variant in BRCA1 had not been previously described, c.4153_4154delCT (p.Leu1385Ilefs*5). Patients with previous diagnosis of breast cancer were carriers of P or LP variant in 8 of 12 cases (66.7%), and patients with a family history of ovarian or breast cancer in first- or second-degree relatives were carriers of P or LP variant in 26.7% of cases compared to 16.9% for patients without family history (p = 0.166). CONCLUSION: Prevalence of BRCA1/2 germline P and LP variants is slightly higher than previously described by the largest occidental studies, with a high prevalence of variant c.5266dupC (p.Gln1756Profs*74) in BRCA1 observed. Moreover, we identified a new LP variant.

Prognostic impact of platinum sensitivity in ovarian carcinoma patients with brain metastasis.

BACKGROUND: Brain metastasis (BM) is a rare event in ovarian cancer patients. The current prognostic scores that have been used for other tumors do not account for specific characteristics of ovarian cancer, such as platinum sensitivity. METHODS: This retrospective cohort study examined patients with ovarian carcinoma and BM who were treated at a single institution from January 2007 to December 2017. Clinical data on the diagnosis of BM and follow-up were collected. Cox regression was used to evaluate prognostic factors for overall survival (OS). RESULTS: Of 560 patients, 26 presented with BM. Eight patients were treated with surgery, 15 with whole-brain radiotherapy (RT), and 5 with stereotactic RT, and 4 patients received systemic treatment at the diagnosis of BM. The median OS was 10.8 months. The following factors were associated with OS: platinum-sensitive recurrence (HR 0.34, 95% CI 0.12-0.99; p = 0.049), higher number of previous treatment lines (HR 1.57, 95% CI 1.12-2.19; p = 0.008), ECOG performance status (HR 2.52, 95% CI 1.24-5.09; p = 0.010), and longer interval from initial diagnosis to BM (p = 0.025). Notably, the number of brain metastasis, the largest tumor size, and progression outside of the CNS were not related to survival. Platinum sensitivity was not associated with any of the classic prognostic factors in brain metastasis patients such as number or size of brain metastasis or disease progression outside the CNS strengthening the hypothesis of the importance of platinum sensitivity to the prognosis of ovarian cancer patients with BM. CONCLUSIONS: The factors related to the biological behavior of the ovarian cancer such as platinum sensitivity at the time of BM diagnosis, fewer number of previous treatment lines and interval from initial diagnosis were associated with survival in ovarian cancer patients with BM, while factors that are usually related to survival in BM in other cancers were not associated with survival in this cohort of ovarian cancer patients. The small number of patients did not allow us to exclude the prognostic role of these former factors that were not associated with survival in the present cohort.

A 2-year retrospective study on pleural effusions: A cancer centre experience.

BACKGROUND: Cytopathological examination of pleural effusions is a fast and minimally invasive method for verification of the presence of neoplastic cells. We report our 2-year experience using a categorised diagnostic system and reporting risks of malignancy (ROMs) for each defined category. METHODS: Cytological reports of patients between November 2016 and October 2018 were collected, with results primarily classified into a five-tiered classification scheme. Immunohistochemistry markers used in cytology and their results were also recorded. Final agreement to histology and overall test performance was calculated for cases with available concomitant (up to 3 months) pleural biopsies. RESULTS: A total of 519 samples from 385 patients were collected, being 29 (5.6%) classified as non-diagnostic, 291 (56%) as negative, 28 (5.4%) as atypical, 30 (5.8%) as suspicious and 141 (27.2%) as positive. Most requested markers were calretinin, TTF1, Ber-EP4 and Gata-3, being conclusive in 45 (76.3%) cases. Total cyto-histological agreement was achieved in 49 (80.3%) specimens, with an overall sensitivity and specificity of 69.4% and 93.3%, respectively. Positive predictive value was 96.2% and negative predictive value was of 56%. ROM for each diagnostic category was 50% for non-diagnostic, 44% for negative, 50% for atypical, 83.3% for suspicious and 96.2% for positive. CONCLUSIONS: Our 2-year retrospective study has shown a high specificity and positive predictive value for pleural cytology. The use of a five-tiered system has also shown to be highly effective, with a concordantly progressive higher ROM for the assigned diagnostic categories.