Maarten P.W. Gallee

Risk and prognosis of endometrial cancer after tamoxifen for breast cancer

BACKGROUND Tamoxifen increases the risk of endometrial cancer. However, few studies have produced reliable risk estimates by duration, dose, and recency of use, or addressed the prognosis of endometrial cancers in tamoxifen-treated women. METHODS We did a nationwide case-control study on the risk and prognosis of endometrial cancer after tamoxifen use for breast cancer. Information on tamoxifen use and other risk factors for endometrial cancer was obtained from 309 women with endometrial cancer after breast cancer (cases), and 860 matched controls with breast cancer but without endometrial cancer. For 276 cases, we obtained tissue blocks of endometrial cancer to review the diagnosis, and used immunohistochemistry to examine hormone-receptor status and overexpression of p53. FINDINGS Tamoxifen had been used by 108 (36.1%) of 299 cases and 245 (28.5%) controls (relative risk 1.5 [95% CI 1.1-2.0]). Risk of endometrial cancer increased with longer duration of tamoxifen use (p < 0.001), with relative risks of 2.0 (1.2-3.2) for 2-5 years and 6.9 (2.4-19.4) for at least 5 years compared with non-users. Endometrial cancers of stage III and IV occurred more frequently in long-term tamoxifen users (> or = 2 years) than in non-users (17.4% vs 5.4%, p=0.006). Long-term users were more likely than non-users to have had malignant mixed mesodermal tumours or sarcomas of the endometrium (15.4% vs 2.9%, p < or = 0.02), p53-positive tumours (31.4% vs 18.2%, p=0.05), and negative oestrogen-receptor concentrations (60.8% vs 26.2%, p < or = 0.001). 3-year endometrial-cancer-specific survival was significantly worse for long-term tamoxifen users than for non-users (76% for > or = 5 years, 85% for 2-5 years vs 94% for non-users, p=0.02). INTERPRETATION Long-term tamoxifen users have a worse prognosis of endometrial cancers, which seems to be due to less favourable histology and higher stage. However, the benefit of tamoxifen on breast-cancer survival far outweighs the increased mortality from endometrial cancer. Nevertheless, we seriously question widespread use of tamoxifen as a preventive agent against breast cancer in healthy women.

Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival.

There is evidence that a subset of penile carcinomas is caused by infection with high‐risk human papillomavirus (HPV). However, extensive studies on the possible influence of HPV infection on clinical outcome of penile cancer are lacking. This investigation is aimed to examine the prevalence of high‐risk HPV in a large series of penile squamous‐cell carcinomas (SCCs) and to determine the relationship between HPV and survival. Formalin‐fixed, paraffin‐embedded tumor specimens of 171 patients with penile carcinoma were tested for high‐risk HPV DNA presence by GP5+/6+‐PCR. The clinical course of the patients and the histopathological characteristics of the primary tumors were reviewed. High‐risk HPV DNA was detected in 29% of the tumors, with HPV 16 being the predominant type, accounting for 76% of high‐risk HPV containing SCCs. Disease‐specific 5‐year survival in the high‐risk HPV‐negative group and high‐risk HPV‐positive group was 78% and 93%, respectively (log rank test p = 0.03). In multivariate analysis, the HPV status was an independent predictor for disease‐specific mortality (p = 0.01) with a hazard ratio of 0.14 (95% CI: 0.03–0.63). Our results indicate that the presence of high‐risk HPV (29%) confers a survival advantage in patients with penile carcinoma.

Differences in MHC and TAP-1 expression in cervical cancer lymph node metastases as compared with the primary tumours.

In previous studies we have shown down-regulation of class I major histocompatibility complex (MHC) expression in a significant proportion of primary cervical carcinomas, which was found to be strongly correlated with loss of expression of the transporter associated with antigen presentation (TAP). By contrast, class II MHC expression was frequently up-regulated on neoplastic keratinocytes in these malignancies. In order to investigate whether these changes are associated with biological behaviour of the tumours, 20 cervical carcinomas were analyzed for MHC (HLA-A, HLA-B/C, HLA-DR) and TAP-1 expression in the primary tumours and in lymph node metastases by immunohistochemistry. The results showed a significant increase in the prevalence of HLA-A and HLA-B/C down-regulation in metastasised neoplastic cells as compared with the primary tumour (P = 0.01). In all cases this was accompanied by loss of TAP-1 expression. Up-regulated HLA-DR expression was found exclusively in primary tumours and was absent in the corresponding metastases (P = 0.002). These data are consistent with the hypothesis that loss of TAP-1 and the consequent down-regulation of class I MHC expression provides a selective advantage for neoplastic cervical cells during metastasis. Furthermore, the lack of class II MHC expression in metastasised cells either reflects a different local lymphokine production or indicates that these cells may have escaped CD4+ cytotoxic T-lymphocyte (CTL)-mediated killing.

Evidence for at least three alternative mechanisms targeting the p16INK4A/cyclin D/Rb pathway in penile carcinoma, one of which is mediated by high‐risk human papillomavirus

A comprehensive analysis of 53 penile carcinomas was performed to determine which mechanisms might be involved in the disruption of the p16INK4A/cyclin D/Rb pathway. To that end, human papillomavirus (HPV) presence, p16INK4A expression and promoter methylation, and expression of the BMI‐1 polycomb gene product were studied. Sixteen (30%) of the carcinomas were found to harbour high‐risk HPV DNA, 15 of which contained HPV 16. HPV 16 E6/E7 oncogene transcripts were detected in 13 (87%) of the carcinomas that contained HPV 16. Strong immunostaining for p16INK4A was significantly more frequent in carcinomas that contained high‐risk HPV DNA (p < 0.001) and amongst those with HPV 16 DNA, it was more frequent in lesions in which E6/E7 transcripts were detectable (p = 0.029). This supports an active role for HPV E7 in interfering with the p16INK4A/cyclin D/Rb pathway. Methylation of the p16INK4A promoter or overexpression of the BMI‐1 polycomb gene product may provide alternative modes of interference with this pathway. These phenomena were mutually exclusive and found in the absence of HPV in 15% and 10% of the penile carcinomas, respectively. These data indicate that there are at least three plausible mechanisms by which the p16INK4A/cyclin D/Rb pathway can become disrupted during penile carcinogenesis. Copyright

A comparison of physical examination and imaging in determining the extent of primary penile carcinoma.

To determine the accuracy of physical examination and imaging in assessing the extent of the primary tumour in squamous cell carcinoma of the penis.

Resectable retroperitoneal soft tissue sarcomas : the effect of extent of resection and postoperative radiation therapy on local tumor control

Background. Soft tissue malignancies of the retro‐peritoneum are rare. Surgery is commonly considered the first choice of treatment. There is still no consensus concerning the precise value of the extent of surgery and the value of additional treatment modalities.

Immunogenicity, Including Vitiligo, and Feasibility of Vaccination With Autologous GM-CSF–Transduced Tumor Cells in Metastatic Melanoma Patients

PURPOSE To determine the feasibility, toxicity, and immunologic effects of vaccination with autologous tumor cells retrovirally transduced with the GM-CSF gene, we performed a phase I/II vaccination study in stage IV metastatic melanoma patients. PATIENTS AND METHODS Sixty-four patients were randomly assigned to receive three vaccinations of high-dose or low-dose tumor cells at 3-week intervals. Tumor cell vaccine preparation succeeded for 56 patients (88%), but because of progressive disease, the well-tolerated vaccination was completed in only 28 patients. We analyzed the priming of T cells against melanoma antigens, MART-1, tyrosinase, gp100, MAGE-A1, and MAGE-A3 using human leukocyte antigen/peptide tetramers and functional assays. RESULTS The high-dose vaccination induced the infiltration of T cells into the tumor tissue. Three of 14 patients receiving the high-dose vaccine showed an increase in MART-1- or gp100-specific T cells in the peripheral blood during vaccination. Six patients experienced disease-free survival for more than 5 years, and two of these patients developed vitiligo at multiple sites after vaccination. MART-1- and gp100-specific T cells were found infiltrating in vitiligo skin. Upon vaccination, the T cells acquired an effector phenotype and produced interferon-gamma on specific antigenic stimulation. CONCLUSION We conclude that vaccination with GM-CSF-transduced autologous tumor cells has limited toxicity and can enhance T-cell activation against melanocyte differentiation antigens, which can lead to vitiligo. Whether the induction of autoimmune vitiligo may prolong disease-free survival of metastatic melanoma patients who are surgically rendered as having no evidence of disease before vaccination is worthy of further investigation.

Evaluation of current TNM classification of penile carcinoma.

PURPOSE The TNM classification is the most common tool for staging malignancies. The current classification for penile carcinoma has been unchanged since 1987. There are several shortcomings to this classification. Accurate clinical staging can be troublesome because several categories are defined by anatomical structures that cannot readily be identified by physical examination or imaging. A second drawback is substantial variability with respect to survival in certain T and N categories. We analyzed the prognostic value of the TNM classification in patients with penile carcinoma treated at our institute. We propose modifications to improve prognostic stratification and facilitate clinical staging. MATERIALS AND METHODS The records of 513 patients treated between 1956 and 2006 were analyzed. All tumors were staged according to the most recent classification. We calculated disease specific survival in the different T and N categories. Survival in the different categories was compared using Kaplan-Meier analysis and the log rank test. RESULTS Five-year disease specific survival in the entire group was 80.5% at a median followup of 58.7 months. There was no significant difference in survival between T2 and T3 tumors (p = 0.57). Furthermore, no significant survival difference was found between N1 and N2 categories (p = 0.18). Using a modified classification a significant difference in survival was found among all T and N categories. CONCLUSIONS The current TNM classification for penile carcinoma does not adequately differentiate in terms of survival among several T and N categories. With some modifications prognostic stratification improves and clinical staging is facilitated.

Prognostic Factors for Occult Inguinal Lymph Node Involvement in Penile Carcinoma and Assessment of the High-Risk EAU Subgroup: A Two-Institution Analysis of 342 Clinically Node-Negative Patients

BACKGROUND The European Association of Urology (EAU) guidelines advise an elective bilateral lymphadenectomy in clinically node-negative (cN0) patients with high-risk penile carcinoma (≥pT2, G3, or lymphovascular invasion [LVI]). OBJECTIVE Our aim was to assess prognostic factors for occult metastasis and to determine whether current EAU guidelines accurately stratify patients at high risk. DESIGN, SETTING, AND PARTICIPANTS Data of 342 cN0 patients with histologically proven invasive penile squamous cell carcinoma who had undergone the current dynamic sentinel node biopsy (DSNB) protocol were analysed. A complete ipsilateral inguinal lymphadenectomy was only done if the sentinel node was tumour positive. MEASUREMENTS The presence of occult metastasis was established by preoperative ultrasound and tumour-positive fine-needle aspiration cytology, tumour-positive sentinel nodes, and groin metastases during follow-up after a negative DSNB procedure. Median follow-up was 31 mo. RESULTS AND LIMITATIONS Sixty-eight of 342 patients (20%) and 87 of 684 groins (13%) had occult nodal involvement including 6 patients (2%) with a groin metastasis after negative DSNB. Corpus spongiosum invasion, corpus cavernosum invasion, histologic grade, and LVI were each significant prognosticators for occult metastasis on univariate analysis. On multivariate analysis, grade (odds ratio [OR]: 3.3 for intermediate and 4.9 for poor, respectively) and LVI (OR: 2.2) remained predictive factors. In total, 245 patients (72%) were classified high risk according to EAU guidelines. Among them, the incidence of occult metastasis was 23% (57 of 245). A potential limitation of this study is the lack of external review. CONCLUSIONS Histologic grade and LVI are independent prognostic factors for occult metastasis in penile carcinoma. Although both predictors are incorporated into the current EAU guidelines, the stratification of patients needing a lymph node dissection is inaccurate. Approximately 77% of high-risk patients (188 of 245) would have had a negative bilateral inguinal lymphadenectomy. For the time being, DSNB is considered a more suitable staging method than EAU risk stratification for an accurate determination of patients who require lymph node dissection.

Prognostic factors in transitional cell cancer of the bladder: an emerging role for Bcl-2 and p53

BACKGROUND AND PURPOSE In a recent study on patients with transitional cell cancer of the bladder treated with curative radiotherapy following TUR-T, we demonstrated that a low apoptotic index and p53 positivity were associated with poor local control. The purpose of this study was to assess the prognostic significance of additional markers implicated in regulation of cell cycle and apoptosis. PATIENTS AND METHODS Bcl-2, Bax and p21 positivity were detected immunohistochemically on paraffin-embedded pre-treatment biopsies from 83 patients with invasive transitional cell cancer (TCC) of the bladder, treated with radiotherapy. In addition, markers determined in an earlier analysis, i.e.: p53, apoptotic index, cyclin D1, retinoblastoma protein and Ki-67 were included in the multivariate analysis. A stepwise proportional hazard analysis was performed, adjusting for classic prognostic factors (T-stage, grade, multifocality and macroscopic completeness of the TUR). Positivity was defined as >10% of tumor cells staining positive for Bcl-2, Bax and p21, and >20% for p53. RESULTS Bcl-2 positivity was found in 63%, Bax was positive in 52% and p21 in 55% of cases. In the PH analysis Bcl-2 positivity was found to be related to poor local control (36 vs. 72% at 3 years; P=0.003), as well as to shorter disease-specific survival (74 vs. 94% at 3 years; P=0.017). Evidence for an adverse effect of p53 positivity was also found (local control: 32 vs. 69% at 3 years;P=0.037, disease-specific survival: 76 vs. 92% at 3 years; P=0.043). In an additional PH analysis, we found poor local control rates for bladder cancers with combined Bcl-2 and p53 positivity (17 vs. 65% at 3 years; P=0.0017), and lower disease specific survival (60 vs. 92%; P=0.0024), disease-free survival (7 vs.35%, P=0.0023) and overall survival (39 vs. 80%; P=0.0018). CONCLUSION This study provides evidence for a poor outcome in patients treated with radiotherapy for TCC of the bladder expressing both Bcl-2 and p53. This relationship was found for local control and disease-free, disease-specific and overall survival.