HPV-negative tumors of the uterine cervix Nicolás, Inmaculada; Marimon, Lorena; Barnadas, Esther ...
Modern pathology,
08/2019, Letnik:
32, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Human papillomaviruses (HPV) are the causative agents of virtually all cervical carcinomas. Nevertheless, a small proportion of cervical cancer are negative for HPV, although the significance of this ...finding remains unclear. We aimed to provide insight into the differential clinico-pathological characteristics of this unusual subset of HPV-negative cervical cancer. We performed HPV-DNA detection using a highly sensitive PCR test (SPF10) and p16 immunostaining in 214 cervical carcinomas specimens from women treated at the Gynecological Oncology Unit of the Hospital Clinic (Barcelona, Spain) from 2012 to 2015. The clinical and pathological characteristics, including disease-free survival and overall survival, of HPV-negative and -positive cervical carcinomas were compared. Twenty-one out of 214 tumors (10%) were negative for HPV DNA. HPV-negative tumors were more frequently of the non-squamous type (9/21, 43% vs. 37/193, 19%; p < 0.01) and showed negative p16 staining (9/21; 43% vs. 7/193; 4%; p < 0.01). HPV-negative tumors were more frequently diagnosed at advanced FIGO stage (19/21, 91% vs. 110/193, 57%; p < 0.01) and more frequently had lymph node metastases (14/21, 67% vs. 69/193, 36%; p < 0.01). Patients with HPV-negative cervical cancer had a significantly worse disease-free survival (59.8 months, 95% confidence interval 32.0-87.6 vs. 132.2 months, 95% confidence interval 118.6-145.8; p < 0.01) and overall survival (77.0 months, 95% confidence interval 47.2-106.8 vs. 153.8 months, 95% confidence interval 142.0-165.6; p = 0.01) than women with HPV-positive tumors. However, only advanced FIGO stage and lymph node metastases remained associated with a poor disease-free survival and overall survival on multivariate analysis. In conclusion, our results suggest that a low percentage of cervical cancer arise via an HPV-independent pathway. These HPV-negative tumors are diagnosed at advanced stages, show higher prevalence of lymph nodes metastases and have an impaired prognosis.
Objective The objective of this study was to evaluate the usefulness of p16INK4a staining to classify cervical intraepithelial neoplasia grade 1 according to its progression/regression risk. Study ...Design Patients with a histologic diagnosis of cervical intraepithelial neoplasia grade 1 were prospectively recruited (n = 138). Simultaneous detection of high-risk human papillomaviruses and p16INK4a evaluation were performed. Follow-up was conducted every 6 months by cytology and colposcopy and annually by high-risk human papillomavirus testing, for at least 12 months (mean, 29.0). Progression was defined as a histologic diagnosis of cervical intraepithelial neoplasia grades 2-3, regression as a negative cytology and high-risk human papillomaviruses, and persistence as a cytologic result of low-grade squamous intraepithelial lesions and/or a positive test for high-risk human papillomaviruses. Results Progression was observed in 14 women (10.1%), 66 (47.6%) regressed, and 58 (42.0%) had a persistent disease. p16INK4a was positive in 77 (55.8%) initial biopsy specimens. Progression to cervical intraepithelial neoplasia grades 2-3 was identified in 14 of 77 (18.2%) women with positive and none of 61 (0.00%) women with negative p16INK4a immunostaining ( P < .001). Conclusion p16INK4a negative cervical intraepithelial neoplasia grade 1 lesions rarely progress and may benefit from a less intensive follow-up.
Objectives
Accurate assessment of disease extent is required to select the best primary treatment for advanced epithelial ovarian cancer patients. Estimation of tumour burden is challenging and it is ...usually performed by means of a surgical procedure. Imaging techniques and tumour markers can help to estimate tumour burden non-invasively. 2-
18
FFDG PET/CT allows the evaluation of the whole-body disease. This study aimed to correlate HE4 and CA125 serum concentrations with tumour burden evaluated by volumetric 2-
18
FFDG PET/CT parameters in advanced high-grade epithelial ovarian cancer.
Methods
We included 66 patients who underwent 2-
18
FFDG PET/CT and serum tumour markers determination before primary treatment. Volumes of interest were delimited in every pathological uptake. Whole-body metabolic tumour volume (wb_MTV) and total lesion glycolysis (wb_TLG) were calculated summing up every VOI’s MTV value. SUVmax thresholds were set at 40% (MTV40 and TLG40) and 50% (MTV50 and TLG50). In addition, four VOI subgroups were defined: peritoneal carcinomatosis, retroperitoneal nodes, supradiaphragmatic nodes, and distant metastases. MTV and TLG were calculated for each group by adding up the corresponding MTV values. TLG was calculated likewise.
Results
wb_MTV and wb_TLG were found to be significantly correlated with serum CA125 and HE4 concentrations. The strongest correlation was observed between HE4 and wb_MTV40 (
r
= 0.62,
p
< 0.001). Pearson’s correlation coefficients between peritoneal carcinomatosis MTV40 and tumour markers were 0.61 (
p
< 0.0001) and 0.29 (
p
= 0.02) for HE4 and CA125 respectively. None of these tumour markers showed a positive correlation with tumour load outside the abdominal cavity assessed by volumetric parameters.
Conclusion
HE4 performs better than CA125 to predict metabolic tumour burden in high-grade epithelial ovarian cancer before primary treatment. 2-18FFDG PET/CT volumetric parameters arise as feasible tools for the objective assessment of tumour load and its anatomical distribution. These results support the usefulness of HE4 and PET/CT to improve the stratification of these patients in clinical practice.
Key Points
• In patients with high-grade advanced ovarian epithelial carcinoma, both CA125 and HE4 correlate to whole-body tumour burden assessed by PET/CT before primary treatment.
• HE4 estimates peritoneal disease much better than CA125.
• PET/CT volumetric parameters arise as feasible tools for the objective assessment of tumour load and its anatomical distribution.
Objective
To analyze the utility of carbohydrate antigen (CA)125 and human epididymis protein 4 (HE4) to detect malignancy in women with ovarian endometriosis, when ovarian cancer is suspected and ...ultrasonography results are inconclusive.
Methods
Women who underwent surgery between 2015 and 2019 for ovarian endometriosis or for adnexal masses, with a final diagnosis of ovarian carcinoma (clear cell and endometrioid) were included in this retrospective study. The women were divided into three groups: ovarian endometriosis (OE), ovarian carcinoma without endometriosis (OC), and ovarian carcinoma with endometriosis (OC + E). Adnexal masses were assessed preoperatively by transvaginal ultrasonography according to the International Ovarian Tumor Analysis (IOTA) simple rules, and CA125 and HE4 blood levels were obtained.
Results
Of 208 women, 45 had malignancy, 16 in the OC + E group and 29 in the OC group. According to transvaginal ultrasonography, 13 were classified as undetermined risk of malignancy: OC group: 3, OE group: 3, and OC + E group: 7. When we compared the tumor biomarkers, significant differences in HE4 but not in CA125 levels were found between the groups.
Conclusions
When ovarian malignancy is suspected in patients with ovarian endometriosis, HE4 is a more useful tumor biomarker to diagnose OC when ultrasonography results are inconclusive.
Abstract Background Two independent pathways in the development of vulvar squamous cell carcinoma (VSCC) have been described, one related to and the other independent of high-risk human ...papillomavirus (HR-HPV). The aim of our study was to evaluate whether the HPV status has a prognostic significance or can predict response to radiotherapy. Methods All VSCC diagnosed from 1995 to 2009 were retrospectively evaluated ( n = 98). HPV infection was detected by amplification of HPV DNA by PCR using SPF-10 primers and typed by the INNO-LIPA HPV research assay. p16INK4a expression was determined by immunohistochemistry. Disease-free and overall survival (DFS and OS) were estimated by Kaplan–Meier analysis with the log-rank test and a multivariate Cox proportional hazard's model. Results HR-HPV DNA was detected in 19.4% of patients. HPV16 was the most prevalent genotype (73.7% of cases). p16INK4a stained 100% HPV-positive and 1.3% HPV-negative tumors ( p < .001). No differences were found between HPV-positive and -negative tumors in terms of either DFS (39.8% vs. 49.8% at 5 years; p = .831), or OS (67.2% vs. 71.4% at 5 years; p = .791). No differences in survival were observed between HPV-positive and -negative patients requiring radiotherapy (hazard ratio HR 1.04, 95% confidence interval CI .45 to 2.41). FIGO stages III–IV ( p = .002), lymph node metastasis ( p = .030), size ≥ 20 mm ( p = .023), invasion depth ( p = .020) and ulceration ( p = .032) were associated with increased mortality but in multivariated only lymph node metastasis retained the association (HR 13.28, 95% CI 1.19 to 148.61). Conclusions HPV-positive and -negative VSCCs have a similar prognosis. Radiotherapy does not increase survival in HPV-positive women.
Objectives
To evaluate the efficacy of the O-RADS MRI criteria in the stratification of risk of malignancy of solid or sonographically indeterminate ovarian masses and assess the interobserver ...agreement of this classification between experienced and inexperienced radiologists.
Methods
This single-centre retrospective study included patients from 2019 to 2022 with sonographically indeterminate or solid ovarian masses who underwent MRI with a specific protocol for characterisation according to O-RADS MRI specifications. Each study was evaluated using O-RADS lexicon by two radiologists, one with 17 years of experience in gynaecological radiology and another with 4 years of experience in general radiology. Findings were classified as benign, borderline, or malignant according to histology or stability over time. Diagnostic performance and interobserver agreement were assessed.
Results
A total of 183 patients with US indeterminate or solid adnexal masses were included. Fifty-seven (31%) did not have ovarian masses, classified as O-RADS 1. The diagnostic performance for scores 2–5 was excellent with a sensitivity, specificity, PPV, and NPV of 97.4%, 100%, 96.2%, and 100%, respectively by the experienced radiologist and 96.1%, 92.0%, 93.9%, and 94.8% by the inexperienced radiologist. Interobserver concordance was very high (Kappa index 0.92). Almost all the misclassified cases were due to misinterpretation of the classification similar to reports in the literature.
Conclusion
The diagnostic performance of O-RADS MRI determined by either experienced or inexperienced radiologists is excellent, facilitating decision-making with high diagnostic accuracy and high reproducibility. Knowledge of this classification and use of assessment tools could avoid frequent errors due to misinterpretation.
Critical relevance statement
Up to 31% of ovarian masses are considered indeterminate by transvaginal US and 32% of solid lesions considered malignant by transvaginal US are benign. The O-RADs MRI accurately classifies these masses, even when used by inexperienced radiologists, thereby avoiding incorrect surgical approaches.
Key points
• O-RADS MRI accurately classifies indeterminate and solid ovarian masses by ultrasound.
• There is excellent interobserver agreement between experienced and non-experienced radiologists.
• O-RADS MRI is a helpful tool to assess clinical decision-making in ovarian tumours.
Graphical Abstract
Introduction
Based on their etiological relationship with human papillomavirus (HPV), the 2020 WHO classification has divided vulvar squamous cell carcinomas (VSCC) into two distinct types, ...HPV‐associated and HPV‐independent, and HPV‐independent tumours have recently been divided according to p53 status. Nevertheless, the clinical and prognostic significance of this classification has not been clearly established. We analysed the differential clinical, pathological, and behavioural characteristics of these three types of VSCC in a large series of patients.
Methods and results
VSCC samples from patients who underwent primary surgery at the Hospital Clinic of Barcelona, Spain, during a 47‐year period (January 1975 to January 2022) were analysed (n = 190). HPV detection, p16, and p53 immunohistochemical staining were evaluated. We also analysed recurrence‐free survival (RFS) and disease‐specific survival (DSS). Thirty‐three tumours (17.4%) were HPV‐associated and 157 (82.6%) HPV‐independent. Of these, 20 showed normal and 137 abnormal p53 expression. The two types of HPV‐independent tumours showed worse RFS in the multivariate analysis (hazard ratio HR = 3.63; P = 0.023 for the HPV‐independent p53 normal VSCC and HR = 2.78; P = 0.028 for the HPV‐independent p53 abnormal VSCC). Although the differences were not significant, HPV‐independent VSCC had worse DSS than HPV‐associated VSCC. Although patients with HPV‐independent p53 normal tumours had worse RFS than patients with HPV‐independent p53 abnormal tumours, the DSS was better for the former group. Only advanced FIGO stage was associated with worse DSS in multivariate analysis (HR = 2.83; P = 0.010).
Conclusion
The association of HPV and p53 status have prognostic implications, reinforcing a three‐tier molecular classification of VSCC (HPV‐associated VSCC, HPV‐independent VSCC with normal p53, HPV‐independent VSCC with abnormal p53).
Currently, all VSCC are treated similarly, irrespective of HPV and p53 status. Our findings suggest that in the future, the treatment of VSCC might be tailored in accordance with these molecular subgroups (HPV‐associated VSCC, HPV‐independent VSCC with wildtype p53, HPV‐independent VSCC with mutated p53), given their different prognosis and behaviour.
Human papillomaviruses (HPVs) are the causative agents of carcinoma of the uterine cervix. A number of HPV genotypes have been associated with cervical cancer and almost all tumors associated with ...HPV show strong p16 expression. However, there is little information on the possible impact of the HPV genotype and p16 immunostaining on the clinicopathological features or their prognostic value in cervical carcinoma. We evaluated a series of 194 patients with HPV-positive cervical cancers treated at our institution, focusing on the clinicopathological features and the relationship of the HPV genotypes and p16 immunostaining with the prognosis. A single HPV type was identified in 149 (77%) tumors, multiple HPV infection was detected in 30 cases (15%), and undetermined HPV type/s were identified in 15 (8%) carcinomas. HPV 16 and/or 18 were detected in 156 (80%) tumors. p16 was positive in 186 (96%) carcinomas, but eight tumors (4%) were negative for p16 (seven squamous cell carcinomas, one adenocarcinoma); 5/8 caused by HPV 16 and/or 18. Patients with HPV 16 and/or 18 were younger (49 ± 15 vs. 57 ± 17 years, p < 0.01) and more frequently had nonsquamous tumors than patients with other HPV types (24% 37/156 vs. 0% 0/38; p = 0.01). Neither the HPV type nor multiple infection showed any prognostic impact. Patients with p16-negative tumors showed a significantly worse overall survival than women with p16-positive carcinomas (45 vs. 156 months, p = 0.03), although no significant differences in disease-free survival were observed. In the multivariate analysis, negative p16 immunostaining was associated with a worse overall survival together with advanced FIGO stage and lymph node metastases. In conclusion, the HPV genotype has limited clinical utility and does not seem to have prognostic value in cervical cancer. In contrast, a negative p16 result in patients with HPV-positive tumors is a prognostic marker associated with a poor overall survival.
Sistematic pelvic and para-aortic lymphadenectomy is part of the staging surgery for early-stage epithelial ovarian cancer, with no therapeutic value. The Mapping Sentinel Lymph Nodes In Early-Stage ...Ovarian Cancer (MELISA) trial prospectively assessed the SLN detection rate and the diagnostic accuracy of the SLN mapping technique in patients with early-stage epithelial ovarian cancer.
This prospective, single-arm study included patients diagnosed with early-stage epithelial ovarian cancer (FIGO stages I and II), via either primary surgery or re-staging surgery. SLN mapping was performed by injecting 0.2 mL of 37-mBq
Tc-nanocoloid albumin and 2 mL of 2.5 mg/mL indocyanine green into the infundibulopelvic and utero-ovarian ligaments. After removal of SLNs, a complete systematic pelvic and para-aortic lymphadenectomy was performed. SLN Ultrastaging analysis was applied. The primary outcome was the overall SLN detection rate, either with one or both tracers. Secondary outcomes were the diagnostic accuracy of detecting lymph node metastases and factors that may influence SLN detection.
Thirty patients were included. SLNs were identified in 27 patients (90%). Detection rates in primary and re-staging surgery were 89% and 92%, respectively. Para-aortic drainage was the predominant lymphatic spread, observed in 26 of 27 patients. Ultrastaging pathologic reports listed 1 SLN with macrometastasis, 1 with micrometastasis, and 5 with isolated tumor cells; the sensitivity of SLN mapping was 100%, with a false-negative rate of 0%. Univariate analysis showed a nonsignificant higher proportion of patients with uterine fibroids, adenomyosis, and endometriosis (100%, 67%, 67%, respectively) in patients in whom SLNs were not detected.
SLN mapping has a high detection rate (90%) and is an accurate technique for detecting lymph node involvement in early-stage epithelial ovarian cancer. SLN mapping is a potential alternative to systematic lymphadenectomy to reduce associated morbidity, but further research is needed to evaluate the impact of SLN mapping on oncologic outcomes and its cost-effectiveness.
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