Simon Horenblas

Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer

PURPOSE To compare radiotherapy and chemotherapy effects on long-term risks of second malignant neoplasms (SMNs) and cardiovascular diseases (CVDs) in testicular cancer (TC) survivors. PATIENTS AND METHODS In our nationwide cohort comprising 2,707 5-year TC survivors, incidences of SMNs and CVDs were compared with general-population rates by calculating standardized incidence ratios (SIRs) and absolute excess risks (AERs). Treatment effects on risks of SMN and CVD were quantified in multivariable Cox regression and competing risks analyses. RESULTS After a median follow-up time of 17.6 years, 270 TC survivors developed SMNs. The SIR of SMN overall was 1.7 (95% CI, 1.5 to 1.9), with an AER of 32.3 excess occurrences per 10,000 person-years. SMN risk was 2.6-fold (95% CI, 1.7- to 4.0-fold) increased after subdiaphragmatic radiotherapy and 2.1-fold (95% CI, 1.4- to 3.1-fold) increased after chemotherapy, compared with surgery only. Subdiaphragmatic radiotherapy increased the risk of a major late complication (SMN or CVD) 1.8-fold (95% CI, 1.3- to 2.4-fold), chemotherapy increased the risk of a major late complication 1.9-fold (95% CI, 1.4- to 2.5-fold), and smoking increased the risk of a major late complication 1.7-fold (95% CI, 1.4- to 2.1-fold), compared with surgery only. The median survival time was 1.4 years after SMN and 4.7 years after CVD. CONCLUSION Radiotherapy and chemotherapy increased the risk of developing SMN or CVD to a similar extent as smoking. Subdiaphragmatic radiotherapy strongly increases the risk of SMNs but not of CVD, whereas chemotherapy increases the risks of both SMNs and CVDs. Prolonged follow-up after chemotherapy is needed to reliably compare the late complications of radiotherapy and chemotherapy after 20 years.

EAU Penile Cancer Guidelines 2009

CONTEXT Squamous cell carcinoma (SCC) of the penis is a relatively rare but ominous disease. OBJECTIVE To present a condensed version of the updated 2009 European Association of Urology (EAU) guidelines on penile SCC. EVIDENCE ACQUISITION We performed a literature search of new data available up to December 2009. No randomized study was found; consequently, level of evidence (LE) and grade of recommendations (GR) are low. EVIDENCE SYNTHESIS More insight was gained into the etiology of SCC of the penis, together with improved staging and treatment: Human papillomavirus 16 plays an etiologic role in approximately 40-50% of cases. Similarities in etiology with SCC of the head and neck, the female genitalia, and the anal canal have been found. Improved diagnostics allowed earlier diagnosis, leading to more conservative treatments. Adjuvant and neoadjuvant chemotherapy showed promising results in patients with advanced or recurrent disease. Centralization of the disease contributed to standardization and rapid diffusion of new treatments with improved results and increased organ preservation. CONCLUSIONS Improvements in the management of SCC of the penis are reflected in changes in the guidelines, but the rarity of the disease precluded randomized studies, leading to low level of evidence and grade of recommendation.

Etiology of squamous cell carcinoma of the penis.

Objective: To review the epidemiology of invasive cancer of the penis based on scientific publications identified by a Medline search from 1966-2000 for the keywords penis/penile, cancer/carcinoma and risk as well as the cited references in the identified papers. Results: Strong risk factors (OR >10) identified by case-control studies included phimosis, chronic inflammatory conditions such as balanopostitis and lichen sclerosus et atrophicus and treatment with psoralen and ultraviolet A photo\chemotheraphy (PUVA). A consistent association was found between penile cancer and smoking that was dose-dependent and not explained by investigated confounding factors such as sexual history. Sexual history and self-reported history of condyloma were associated with a 3-5-fold increased penile cancer risk. Cervical cancer in the wife was not consistently associated with cancer of the penis in the husband. Circumcision was associated with penile cancer risk in ecological studies. In a case-control study, circumcision neonatally, but not after the neonatal period, was associated with a 3-fold decreased risk, albeit 20% of penile cancer patients had been circumcised neonatally. In a large number of case series, human papillomavirus (HPV) DNA was identified in penile neoplastic tissue. In penile intraepithelial neoplasia, between 70 and 100% of lesions were HPV DNA positive, whereas invasive penile cancer was positive in only 40-50% of cases. A few serological case-control studies and one prospective study also identified an association between HPV type 16 and penile cancer risk. An association between penile cancer risk and HPV prevalence in the population was also suggested by ecological studies. Conclusion: The evidence on risk factors for penile cancer suggests that preventive measures that could be considered include prevention of phimosis, treatment of chronic inflammatory conditions, limiting PUVA treatment, smoking cessation and prophylactic prevention of HPV infection.

Penile cancer: epidemiology, pathogenesis and prevention

ObjectivesPenile cancer is a disease with a high morbidity and mortality. Its prevalence is relatively rare, but the highest in some developing countries. Insight into its precursor lesions, pathogenesis and risk factors offers options to prevent this potentially mutilating disease. This review presents an overview of the different histologically and clinically identified precursor lesions of penile cancer and discusses the molecular pathogenesis, including the role of HPV in penile cancer development.MethodsA systematic review of the literature evaluating penile carcinogenesis, risk factors and molecular mechanisms involved.ResultsCareful monitoring of men with lichen sclerosis, genital Bowen’s disease, erythroplasia of Queyrat and bowenoid papulosis seems useful, thereby offering early recognition of penile cancer and, subsequently, conservative therapeutic options. Special attention is given to flat penile lesions, which contain high numbers of HPV. Their role in HPV transmission to sexual partners is highlighted, but their potential to transform as a precursor lesion into penile cancer has been unsatisfactorily explored.ConclusionsFurther research should not only focus on HPV mediated pathogenic pathways but also on the non-HPV related molecular and genetic factors that play a role in penile cancer development. Options for prevention of penile cancer include (neonatal) circumcision, limitation of penile HPV infections (either by prophylactic vaccination or condom use), prevention of phimosis, treatment of chronic inflammatory conditions, limiting PUVA treatment, smoking cessation and hygienic measures.

Detection of occult metastasis in squamous cell carcinoma of the penis using a dynamic sentinel node procedure.

PURPOSE We evaluated the so-called dynamic sentinel node procedure in patients with penile cancer. This new staging technique consists of excisional biopsy of the first lymph node onto which a tumor drains the so-called sentinel node, based on individual mapping of lymphatic drainage. MATERIALS AND METHODS From 1994 to 1998, 55 consecutive patients with stage T2 or greater bilateral or unilateral node negative squamous cell carcinoma of the penis were prospectively entered in this study. Tumor stage was T2N0 in 42, T2N1 in 4 and T3N0 in 9 cases. To locate the sentinel node each patient underwent lymphoscintigraphy with 99mtechnetium nanocolloid injected intradermally around the tumor. The following day the sentinel node was identified intraoperatively using patent blue dye injected intradermally around the tumor and a gamma detection probe. Regional lymph node dissection was restricted to patients with a tumor positive sentinel node only. RESULTS Scintigraphy revealed 125 sentinel nodes in 107 inguinal regions, including no sentinel node in 2 patients, 1 or more unilateral nodes in 10 and bilateral drainage in 43. At surgery 108 sentinel nodes were removed. In 8 patients with 2 or more sentinel nodes on lymphoscintigraphy only 1 was noted intraoperatively and in 9 an additional sentinel node was removed, which was not identified by scintigraphy. All nodes were identified with the gamma detection probe. In 1 patient a wound abscess developed. Regional lymph node dissection was performed in 11 patients with sentinel node metastasis. Median followup was 22 months (range 4.1 to 61). In 1 patient lymph node metastasis was noted at followup despite prior excision of a tumor-free sentinel node. CONCLUSIONS The dynamic sentinel node procedure is a promising staging technique to detect early metastatic dissemination of penile cancer based on individual mapping of lymphatic drainage, and enables identification of patients with clinically node negative disease requiring regional lymph node dissection.

Squamous Cell Carcinoma of the Penis. IV. Prognostic Factors of Survival: Analysis of Tumor, Nodes and Metastasis Classification System

Various prognostic factors of survival were assessed in 118 patients with squamous cell carcinoma of the penis treated at The Netherlands Cancer Institute between 1956 and 1989. Using the clinical parameters of the tumor, nodes and metastasis classification system of the International Union Against Cancer (1978 version) and a differentiation system consisting of 3 grades the prognostic relevance for survival was analyzed. T category, N category and grade of differentiation showed statistical significance in the univariate analysis. Patients with small tumors, clinically negative nodes and well differentiated tumors showed a favorable prognosis. Only N category and grade were independent prognostic factors of survival using the Cox proportional hazards model. On the basis of the survival analysis a stage grouping consisting of 3 stages is proposed with 5-year survival probabilities for stages 1, 2 and 3 of 93%, 55% and 30%, respectively. A revised version of the tumor, nodes and metastasis system was introduced in 1987. This latest version was analyzed with the previous method, which was used in this report, and prognostically important and clinically useful parameters, such as the size of the primary tumor and evidence of fixation of the regional lymph nodes, have been discarded. The changes in the revised version seem to have little relevance to clinical staging. The revised version should be considered a histopathological classification only.

Recurrence Patterns of Squamous Cell Carcinoma of the Penis: Recommendations for Follow-Up Based on a Two-Centre Analysis of 700 Patients

BACKGROUND Current follow-up recommendations for patients with penile carcinoma are based on small numbers of patients. OBJECTIVES To give further insight into the recurrence patterns of penile carcinoma in different treatment settings and provide recommendations for follow up. DESIGNS, SETTING, AND PARTICIPANTS: In this retrospective study, we analysed 700 patients from two referral centres for penile carcinoma for recurrences. MEASUREMENTS Recurrences were categorized as local, regional, or distant. The rate of local recurrences was compared between patients undergoing penile-preserving treatments and partial/total amputation. Regional recurrences were compared between patients surgically staged as pN0 or pN+ and clinically node-negative (cN0) patients subjected to a wait-and-see policy. The total recurrence rate, type of recurrence, time to recurrence, and survival were calculated. RESULTS AND LIMITATIONS 205 out of 700 patients (29.3%) had a recurrence, consisting of 18.6% local, 9.3% regional, and 1.4% distant recurrences. Of the recurrences, 92.2% occurred within 5 yr after primary treatment. All regional and distant recurrences occurred within 50 and 16 mo, respectively. The local recurrence rate was 27.7% after penile-preserving therapy and 5.3% after amputation. The regional recurrence rate was 2.3% in patients staged as pN0, 19.1% in patients staged as pN+, and 9.1% in patients undergoing a wait-and-see policy. The 5-yr disease-specific survival was 92% after a local recurrence and 32.7% after a regional recurrence. All patients with a distant recurrence died within 22 mo. Although the number of analysed patients is substantial, the results do not necessarily reflect those of other centres using different techniques for the management of penile carcinoma. CONCLUSIONS Patients undergoing penile-preserving therapy, patients surgically staged as pN+, and those undergoing a wait-and-see policy for the nodal status are at high risk of developing a recurrence. Follow-up recommendations are provided based on the risk and impact on survival of a recurrence.

Squamous Cell Carcinoma of the Penis. III. Treatment of Regional Lymph Nodes

We analyzed the management of regional lymph nodes in 110 patients with squamous cell carcinoma of the penis treated at the Netherlands Cancer Institute between 1956 and 1989 with curative intent. Of 66 patients who presented with unsuspected nodes 57 were placed on a surveillance program, while lymph node dissection was performed in 5 (with adjuvant external radiation therapy in 1) and 4 were treated with external radiation therapy only. The management of 40 patients with clinically suspected nodes included surveillance in 5, lymph node dissection in 27 (with adjuvant radiotherapy in 11), biopsy in 4 and external radiation therapy in 4. Postoperative radiotherapy had been given if more than 2 nodes were involved or when extracapsular growth was observed. Overall, 25 patients had a regional recurrence, 5 of whom could be cured subsequently. All regional recurrences developed within 2 years after primary treatment. Analysis showed 100% survival in histologically proved node negative patients (stage pN0). The success of lymph node dissection was related to the extent of the metastatic spread and to the number of involved nodes. Patients with 1 positive node and unilateral inguinal involvement showed a statistically significant survival advantage compared to patients with more extensive spread. Considering the indications for node dissection we found a clear relationship among T category, grade and the probability of lymph node invasion. Patients with stage T1 tumors and stage T2, grades 1 and 2 tumors presented significantly less often with lymphatic invasion than those with other categories of disease and were less likely to have a regional recurrence after treatment of the primary tumor only. In these categories we recommend surveillance of the regional lymph nodes in patients who present with unsuspected nodes. However, patients with stage T2 grade 3, stage T3 and operable stage T4 tumors should undergo an immediate inguinal node dissection because of the high probability of clinically occult lymph node invasion (in our material more than 50%). With respect to the extent of the node dissection, we found that the likelihood of spread to the contralateral and/or pelvic regions was related to the number of invaded nodes in the inguinal region. We recommend contralateral node dissection and unilateral pelvic node dissection when 2 or more positive nodes are found in the dissected groin specimen. Primary pelvic node dissection should be performed in patients who present initially with cytologically or biopsy proved positive inguinal nodes.(ABSTRACT TRUNCATED AT 400 WORDS)

Dynamic sentinel node biopsy for penile cancer: reliability of a staging technique

PURPOSE We determine the value of dynamic sentinel node biopsy for staging squamous cell carcinoma of the penis. MATERIALS AND METHODS A total of 90 patients with clinically node negative penile cancer were prospectively entered in this study. Preoperative lymphoscintigraphy was performed after intradermal injection of 99mtechnetium nanocolloid around the primary tumor. The sentinel node was intraoperatively identified with the aid of intradermal administered patent blue dye and a gamma ray detection probe. Histopathological examination of sentinel nodes included serial sectioning and immunohistochemical staining. Regional lymph node dissection was performed only if metastasis was found in a sentinel node. Median followup was 36 months (range 5 to 95). RESULTS Lymphoscintigraphy visualized 217 sentinel nodes in 159 inguinal regions of 88 patients. A total of 208 sentinel nodes were intraoperatively identified in 149 inguinal regions of 88 patients. Sentinel node metastasis was found in 19 inguinal regions of 18 patients. Four of 8 patients with unilateral clinical stage N1 disease had a tumor positive sentinel node on the opposite site. Regional recurrence after excision of a tumor negative sentinel node or after nonvisualization was seen in 5 patients, resulting in a false-negative rate of 22% (5 of 23). The 3-year disease specific survival was 98% and 71% for patients with a tumor negative or tumor positive sentinel node, respectively (p = 0.0018). CONCLUSIONS Occult lymph node metastases in penile cancer can be detected with a sensitivity of about 80% by dynamic sentinel node biopsy, including preoperative lymphoscintigraphy, vital dye and a gamma ray detection probe.

Metastasectomy in Renal Cell Carcinoma: A Multicenter Retrospective Analysis

Objective: In 60–70% of patients with renal cell carcinoma (RCC), metastases develop in the course of the disease. In the present analysis, the surgical management of metastases is described, and survival data are presented. This retrospective analysis may help in the management of future cases. Due to the retrospective nature of the data, no comparison between surgical and nonsurgical management is possible. Methods: Between 1985 and 1995, 152 resections of RCC metastases were performed in 101 patients at four Dutch Hospitals. Thirty-five and 6 patients had metastases resected 2 and 3 times, respectively. In most patients, the primary tumor was resected (n = 95). Resections were performed for metastases at different locations: lung n = 54, bone n = 42, lymph nodes n = 18, cerebrum n = 12 and locations in the spinal canal, thyroid, bowel, and testis. Skin excisions were excluded from the analysis. Solitary metastases were resected in 40 patients. Results: Median survival after the initial metastasectomy was 28 months. Initial tumor stage, grade, or size were not related to metastasis location or survival. The number of initially resected pulmonary metastases was of no influence on survival, however, multiple consecutive resections were related with longer survival. Patients with solitary metastases (n = 40) did not show longer survival after the first metastasectomy compared to no solitary lesions. Better survival was found for lung metastases compared to other tumor locations (p = 0.0006, log rank test) and for patients that were clinically tumor free after metastasectomy (p = 0.0230, log rank test). Additional immuno- or radiotherapy did not independently influence survival. Time interval between primary tumor resection and metastasectomy correlated positively with survival: a tumor-free interval of more than 2 years between primary tumor and metastasis was accompanied by a longer disease-specific survival after metastasectomy. Eleven patients were free of disease after metastasectomy with a median time of 47 (14–65) months. The median time of hospital admittance for metastasectomy was 9 days (4–64). Lethal complications were found in 2 patients. Long-term (>5 years) disease-free survival was achieved in 7% of patients whereas 14% of patients were free of disease with a minimal follow-up of 45 months. Conclusions: (1) Surgical management of metastases could be performed with short hospital stay, and low complication rates were found. (2) Disease-free survival was found in 14 and 7%, with follow-ups of at least 45 and 60 months, respectively. (3) The longest survival was found after surgery for pulmonary lesions. (4) Resection of solitary metastases did not result in longer survival compared to resection of nonsolitary lesions. (5) An interval shorter than 2 years between primary tumor and metastases was correlated with a shorter disease-specific survival.