Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma: Real-life Data on Liver Disease, Treatment and Prognosis.

Background and Aims: Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) have common features and differences. This real-life study investigated their characteristics, treatment modalities, and prognoses. Methods: This retrospective comparative study was performed in 1,075 patients seen at one tertiary center between January 2008 and December 2020. Overall survival (OS) was estimated by the Kaplan-Meier method. Subclassification of iCCAs after histological and radiological review, and molecular profiling was performed. Results: HCCs patients were more likely to have early-stage disease than iCCA patients. iCCA patients were more likely to be female, especially those patients without cirrhosis (43% vs. 17%). Cirrhosis was prominent among HCC patients (89% vs. 34%), but no difference in underlying liver disease among cirrhotic patients was found. OS of HCC patients was 18.4 (95% CI: 6.4, 48.3) months, that of iCCA patients was 7.0 (95% CI: 3.4, 20.1) months. OS of Barcelona Clinic Liver Cancer C HCC patients was 7.8 (95% CI: 4.3, 14.2) months, that of advanced/metastatic iCCA patients was 8.5 (95% CI: 5.7, 12.3) months. In patients treated with sorafenib, OS was longer in HCC patients who received subsequent tyrosine kinase inhibitor therapies. No significant OS difference was found between iCCA patients with and without cirrhosis or according to histological subtype. A targetable molecular alteration was detected in 50% of the iCCA patients. Conclusions: In this French series, cirrhosis was common in iCCA, which showed etiological factors comparable to those of HCC, implying a distinct oncogenic pathway. Both entities had a dismal prognosis at advanced stages. However, systemic therapies sequencing in HCC and molecular profiling in iCCA offer new insights.

FGFR3 Mutational Activation Can Induce Luminal-like Papillary Bladder Tumor Formation and Favors a Male Sex Bias.

BACKGROUND: Bladder cancer (BCa) is more common in men and presents differences in molecular subtypes based on sex. Fibroblast growth factor receptor 3 (FGFR3) mutations are enriched in the luminal papillary muscle-invasive BCa (MIBC) and non-MIBC subtypes. OBJECTIVE: To determine whether FGFR3 mutations initiate BCa and impact BCa male sex bias. DESIGN, SETTING, AND PARTICIPANTS: We developed a transgenic mouse model expressing the most frequent FGFR3 mutation, FGFR3-S249C, in urothelial cells. Bladder tumorigenesis was monitored in transgenic mice, with and without carcinogen exposure. Mouse and human BCa transcriptomic data were compared. INTERVENTION: Mutant FGFR3 overexpression in mouse urothelium and siRNA knockdown in cell lines, and N-butyl-N(4-hydroxybutyl)-nitrosamine (BBN) exposure. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Impact of transgene dosage on tumor frequency, synergy with BBN treatment, and FGFR3 pathway activation were analyzed. The sex-specific incidence of FGFR3-mutated tumors was evaluated in mice and humans. FGFR3 expression in FGFR3-S249C mouse urothelium and in various human epithelia was measured. Mutant FGFR3 regulation of androgen (AR) and estrogen (ESR1) receptor activity was evaluated, through target gene expression (regulon) and reporter assays. RESULTS AND LIMITATIONS: FGFR3-S249C expression in mice induced low-grade papillary BCa resembling human luminal counterpart at histological, genomic, and transcriptomic levels, and promoted BBN-induced basal BCa formation. Mutant FGFR3 expression levels impacted tumor incidence in mice, and mutant FGFR3-driven human tumors were restricted to epithelia presenting high normal FGFR3 expression levels. BCa male sex bias, also found in our model, was even higher in human FGFR3-mutated tumors compared with wild-type tumors and was associated with higher AR and lower ESR1 regulon activity. Mutant FGFR3 expression inhibited both ESR1 and AR activity in mouse tumors and human cell lines, demonstrating causation only between FGFR3 activation and low ESR1 activity in tumors. CONCLUSIONS: Mutant FGFR3 initiates luminal papillary BCa formation and favors BCa male sex bias, potentially through FGFR3-dependent ESR1 downregulation. Patients with premalignant lesions or early-stage BCa could thus potentially benefit from FGFR3 targeting. FGFR3 expression level in epithelia could account for FGFR3-driven carcinoma tissue specificity. PATIENT SUMMARY: By developing a transgenic mouse model, we showed that gain-of-function mutations of FGFR3 receptor, among the most frequent genetic alterations in bladder cancer (BCa), initiate BCa formation. Our results could support noninvasive detection of FGFR3 mutations and FGFR3 targeting in early-stage bladder lesions.

Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans.

Specific germline activating point mutations in the gene encoding the tyrosine kinase receptor FGFR3 (fibroblast growth factor receptor 3) result in autosomal dominant human skeletal dysplasias. The identification in multiple myeloma and in two epithelial cancers-bladder and cervical carcinomas-of somatic FGFR3 mutations identical to the germinal activating mutations found in skeletal dysplasias, together with functional studies, have suggested an oncogenic role for this receptor. Although acanthosis nigricans, a benign skin tumor, has been found in some syndromes associated with germinal activating mutations of FGFR3, the role of activated FGFR3 in the epidermis has never been investigated. Here, we targeted an activated receptor mutant (S249C FGFR3) to the basal cells of the epidermis of transgenic mice. Mice expressing the transgene developed benign epidermal tumors with no sign of malignancy. These skin lesions had features in common with acanthosis nigricans and other benign human skin tumors, including seborrheic keratosis, one of the most common benign epidermal tumors in humans. We therefore screened a series of 62 cases of seborrheic keratosis for FGFR3 mutations. A large proportion of these tumors (39%) harbored somatic activating FGFR3 mutations, identical to those associated with skeletal dysplasia syndromes and bladder and cervical neoplasms. Our findings directly implicate FGFR3 activation as a major cause of benign epidermal tumors in humans.

Absence of FGFR3 mutations in urinary bladder tumours of rats and mice treated with N-butyl-N-(-4-hydroxybutyl)nitrosamine.

Frequent activating mutations of FGFR3 (fibroblast growth factor receptor 3) are found in human urothelial cell carcinomas, particularly in superficial papillary tumours (in 74%-84% of pTaG1-G2), but not in carcinomas in situ (CIS) and at a low rate in invasive tumours (in 16%-21% of pT1-4). In mice and rats, BBN (N-butyl-N-(4-hydroxybutyl)nitrosamine) specifically induces bladder tumours. In rats, superficial papillary tumours are mostly observed. In mice, tumour progression follows the CIS pathway: CIS are first observed, followed by tumours that invade surrounding muscle. Therefore, we looked for FGFR3 mutations in these two animal models of bladder cancer. Only the FGFR3b isoform is expressed in human urothelium and derived tumours. We identified the FGFR3b isoform in rats for the first time and showed that this is the main isoform expressed in the bladder urothelium and derived carcinomas in mice and rats, as in humans. SSCP and sequence analysis of FGFR3b showed sequence changes (polymorphisms or silent mutations) in four BBN-induced rat and mouse bladder tumours. The absence of activating mutations of FGFR3 in the mouse model was in agreement with the fact that mouse BBN-induced bladder tumour progression mimics the CIS pathway. The absence of FGFR3 mutations in the rat bladder tumours suggests that, at least at the genetic level, rat superficial papillary tumours differ from their human counterparts.

Introducing a prognostic score for pretherapeutic assessment of seminal vesicle invasion in patients with clinically localized prostate cancer.

PURPOSE: To identify prostate cancer patients who will have the most likely benefit from sparing the seminal vesicles during 3D conformal radiation therapy. METHODS AND MATERIALS: From 1988 to 2001, 532 patients underwent radical prostatectomy for clinically localized prostate cancer. Primary endpoint was the pathological evidence of seminal vesicle invasion. Variables for univariate and multivariate analyses were age, prostate weight, clinical stage, PSA level, Gleason score, number and site of positive prostate sextant biopsies. Multivariate logistic regression with backward stepwise variable selection was used to identify a set of independent predictors of seminal vesicle invasion, and the variable selection procedure was validated by non-parametric bootstrap. RESULTS: Seminal vesicle invasion was reported in 14% of the cases. In univariate analysis, all variables except age and prostate weight were predictors of seminal vesicle invasion. In multivariate analysis, only the number of positive biopsies (P<0.0001), Gleason score (P<0.007) and PSA (P<0.0001) were predictors for seminal vesicles invasion. Based on the multivariate model, we were able to develop a prognostic score for seminal vesicle invasion, which allowed us to discriminate two patient groups: A group with low risk of seminal vesicles invasion (5.7%), and the second with a higher risk of seminal vesicles invasion (32.7%). CONCLUSIONS: Using the number of positive biopsies, Gleason score and PSA, it is possible to identify patients with low risk of seminal vesicles invasion. In this population, seminal vesicles might be excluded as a target volume in radiation therapy of prostate cancer.

Prognostic consequences of the location of positive surgical margins in organ-confined prostate cancer.

INTRODUCTION: The purpose of the present study was to evaluate and compare the risk of progression in organ-confined prostate cancers (stage pT2), according to the location of positive surgical margins. MATERIALS AND METHODS: Between 1988 and 2001, 538 consecutive men underwent radical prostatectomy for localized prostate cancer. All patients had preoperative physical examinations, serum PSA assays (Hybritech assay, N.l. <4 ng/ml) and ultrasound-guided sextant biopsies to confirm diagnosis. Radical prostatectomy specimens were analyzed according to the Stanford protocol. Positive margins were classified as single or multiple and main locations (apex, bladder neck and posterolateral) were noted. Postoperative follow-up data were obtained through routine serum PSA assays. Biochemical recurrence was defined as a single postoperative PSA level >0.2 ng/ml. Biochemical progression was studied in patients with organ-confined tumors (stage pT2) according to the location of the single positive margin. Kaplan-Meier analysis was performed to determine the actuarial biochemical recurrence-free likelihood and the log-rank test was used for statistical analysis. Differences were considered significant when the p value was <0.05. RESULTS: 371 patients had organ-confined tumors, and 60 patients (16.1%) had solitary positive margins (apex 26, bladder neck 14, posterolaterally 20). Eleven patients (18.3%) had biochemical progression. 5-year biochemical free progression was 54.5, 76.9 and 87.9% for apex, bladder and the posterolateral location, respectively (p < 0.05). CONCLUSIONS: In the present study, a positive surgical margin at the apex was associated with worse clinical prognosis compared to the bladder neck and posterolateral locations.

Location of positive surgical margins after retropubic, perineal, and laparoscopic radical prostatectomy for organ-confined prostate cancer.

OBJECTIVES: To evaluate and compare the location of positive surgical margins after retropubic, perineal, and laparoscopic radical prostatectomy for organ-confined prostate cancer (pT2). METHODS: From 1988 to 2001, 538 patients underwent radical prostatectomy for clinically localized prostate cancer. Patient age at surgery, clinical stage, preoperative prostate-specific antigen, and Gleason score of positive biopsies were noted. Postoperatively, specimen weight, final Gleason score, and capsular, seminal vesicle, and lymph node status, as well as tumor volume, were studied. The incidence and location of positive margins and the pathologic stage were noted according to the surgical approach. RESULTS: A total of 371 patients (69.5%) had organ-confined tumors. Of the 371 patients, 116 underwent the retropubic, 86 the perineal, and 169 the laparoscopic approach, and positive surgical margins were noted in 22 (18.9%), 12 (13.9%), and 32 (18.9%) patients, respectively. Positive surgical margins were reported in 72 specimen locations, 32 (44.4%) at the apex, 17 (23.6%) at the bladder neck, and 29 (31.9%) posterolaterally. The distribution for the retropubic, perineal, and laparoscopic approaches was apex in 50%, 33.3%, and 44.4%, bladder neck in 29.1%, 41.7%, and 13.9%, and posterolaterally in 20.8%, 25%, and 41.6%, respectively. CONCLUSIONS: In our series, each approach had a specific high-risk location of positive margins: the apex for the retropubic, the bladder neck for the perineal, and posterolaterally for the laparoscopic approach. Improvements in the surgical techniques should take these specific locations under consideration to decrease the incidence of positive surgical margins.

Prognostic significance of tumor volume after radical prostatectomy: a multivariate analysis of pathological prognostic factors.

OBJECTIVES: To analyze the association between Gleason score, stage and status of surgical margins with tumor volume in prostate cancer progression after radical prostatectomy. METHODS: 200 consecutive radical prostatectomy specimens were analyzed. Preoperative clinical stage, PSA, results of prostate biopsies as well as pathological results were noted. A biochemical recurrence was defined as a single, postoperative detectable PSA level (>0.2 ng/ml). Tumor volume was compared to postoperative staging, Gleason score, and surgical margin status to predict tumor progression. Univariate and multivariate analysis using stepwise logistic regression were used to identify parameters with additional prognostic value. RESULTS: Pathological results of the prostatectomy specimens showed 149 (74.5%) pT2a-b, 29 (14.5%) pT3a and 22 (11%) pT3b tumors. Tumor volume was 0.57 cc for pT2a, 1.2cc for pT2b, 1.7cc for pT3a and 2.9cc for pT3b, respectively (p<0.05). Taken together, mean volume for pT2 and pT3 were 1.06 and 2.2 cc, respectively (p<0.0001). Five-year progression-free actuarial survival was 69.7%. Using univariate analysis, tumor progression correlated with final Gleason score (p<0.0007), positive surgical margins (p=0.02), tumor volume (p=0.009) and stage (p<0.0001). In a multivariate analysis, tumor progression correlated only with the final Gleason score (p=0.04) and stage (p=0.0002). CONCLUSION: Gleason score and pathological stage are independent factors to predict prostate cancer progression after radical prostatectomy. When these parameters are known, tumor volume does not provide additional information.

[Seminal vesicle invasion afer radical prostatectomy: study of risk factors for progression]. / Envahissement des vésicules séminales après prostatectomie radicale: étude des facteurs de risque de progression.

OBJECTIVE: Seminal vesicle invasion (pT3b) is a known factor of poor prognosis after radical prostatectomy. The authors retrospectively studied the course of stage pT3b tumours, and the clinical, laboratory and histological factors that could influence this course. METHODS: From 1988 to 2001, out of a total of 538 radical prostatectomies, 62 (11.5%) cases with isolated seminal vesicle invasion were analysed according to the Stanford technique. Half-yearly postoperative surveillance was based on physical examination and PSA assay. Progression was defined as PSA greater than 0.2 ng/ml or when complementary treatment was performed. Actuarial progression-free survival was studied according to the Kaplan-Meier method. Actuarial survivals were compared by the Log-rank method, and a difference was considered to be significant for p < 0.05. Multivariate analysis using the Cox model was performed. RESULTS: The mean Gleason score of the radical prostatectomy specimen was 6.9, and the mean tumour volume was 2.7 cm3. Forty eight (77.4%) specimens showed capsular effraction and 33 (53.2%) had positive surgical margins. The 5-year laboratory progression-free survival was 16%. A low preoperative PSA, a radical prostatectomy specimen Gleason score less than 7 and capsular effraction were factors of good prognosis on multivariate analysis. CONCLUSION: Prostatic tumours with seminal vesicle invasion have a high risk of progression after radical prostatectomy. A preoperative PSA level less than 10 ng/ml, a Gleason score of the operative specimen less than 7 and effraction of the prostatic capsule can be used to identify a subpopulation of patients with a better prognosis.

[Localization of positive surgical margins after retropubic, perineal and laparoscopic radical prostatectomy]. / Localisation des marges d'exérèse positives après prostatectomie radicale par voie rétropubienne, périnéale et laparoscopique.

OBJECTIVE: To study the sites of positive surgical margins after radical prostatectomy according to the technique used: retropubic, perineal or laparoscopic. MATERIAL AND METHODS: 538 radical prostatectomies were performed between 1988 and 2001: 184 via a retropubic approach, 119 via a perineal approach and 235 by laparoscopy. Clinical examination, PSA assay (Hybritech, Normal < 4 ng/ml) and transrectal biopsies were performed in all patients. The radical prostatectomy specimen was examined by the same pathologist according to the Stanford protocol. The frequency and site of positive surgical margins were studied as a function of pathological stage. RESULTS: The positive surgical margins rate was 32%, 18.5% and 26.4% for the retropubic, perineal and laparoscopic techniques, respectively. The most frequent site of positive surgical margins was the apex for retropubic (41.1%) and perineal (41.6%) prostatectomy and the posterolateral part of the prostate for laparoscopic prostatectomy (41.9%). The most frequent site of positive surgical margins in pT2 tumours was the apex for the retropubic approach (50%), the base of the prostate (bladder neck) for the perineal approach (41.6%) and the apex and posterolateral part of the prostate for the laparoscopic approach (44.4% and 41.6%). CONCLUSION: Each radical prostatectomy technique corresponds to a preferential site of positive surgical margins: the apex for the retropubic approach, the bladder neck for the perineal approach and the posterolateral part of the prostate for the laparoscopic approach.

Radical prostatectomy by the retropubic, perineal and laparoscopic approach: 12 years of experience in one center.

OBJECTIVES: We retrospectively evaluated the oncological outcome of radical prostatectomy performed by the retropubic, perineal and laparoscopic approaches. METHODS: From 1988 to 2000, 401 patients underwent radical prostatectomy for localized prostate cancer by the retropubic, perineal or laparoscopic approach. Age, clinical stage, preoperative PSA and Gleason score of positive biopsies were noted. Operating time, complication rate, transfusion rate, length of hospital stay, catheterization time and pathological results were reviewed. Kaplan-Meier analysis was used to evaluate the likelihood of biochemical recurrence (PSA > or =0.2 ng/ml). RESULTS: There were no significant differences between the three groups regarding preoperative characteristics, except for PSA (21.4 ng/ml, 13.2 ng/ml, and 11.6 ng/ml for the retropubic, perineal, and laparoscopic approach, p<0.05) and the frequency of stage T1c tumors (31.7%, 47.1% and 63.5%, respectively, p<0.05). The operating time was significantly longer in the laparoscopic approach (285 min) compared to the retropubic and perineal techniques (197 min and 178 min, respectively). The retropubic approach was associated with a higher transfusion rate (26.2% versus 15.9% and 2.9% with the perineal and laparoscopic approaches), longer bladder catheterization time (15.9 days versus 11.7 days and 6.8 days, respectively), and longer hospital stay (15.2 days versus 8.5 days and 7.4 days, respectively) (p<0.05 for each). With the retropubic, perineal and laparoscopic approaches, medical complication rates were 8.3%, 4.2% and 5.1%, and surgical complication rates were 16.5%, 12.7% and 13.1%, respectively. The rates of pathological stage pT2 tumors were 62.1%, 72.2% and 75.9%, in the retropubic, perineal and laparoscopic groups, respectively. Positive surgical margins in pT2 tumors were noted in 19%, 14% and 22%, respectively. The actuarial 3-year recurrence-free survival rates were not significantly different between the three techniques (75%, 85.2% and 84.1%, respectively; 91.7%, 95.8% and 90.4% among patients with organ-confined tumors). CONCLUSION: Despite changes in patient selection criteria over time, and the relatively short follow-up, this study showed no significant difference in oncologic outcome between the retropubic, perineal and laparoscopic approaches to radical prostatectomy.

[Protocol for examination of orchidectomy specimen: proposal for a standardized reporting form]. / Prise en charge des pièces d'orchidectomie et fiche de réponse anatomo-pathologique.

We present practical guidelines for the examination of orchidectomy specimens and propose a standardized worksheet for the pathology report of germinal tumors.