Wayne Lam

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.

Dynamic sentinel lymph node biopsy in patients with invasive squamous cell carcinoma of the penis: a prospective study of the long-term outcome of 500 inguinal basins assessed at a single institution.

BACKGROUND Dynamic sentinel node biopsy (DSNB) in combination with ultrasound scan (USS) has been the technique of choice at our centre since 2004 for the assessment of nonpalpable inguinal lymph nodes (cN0) in patients with squamous cell carcinoma of the penis (SCCp). Sensitivity and false-negative rates may vary depending on whether results are reported per patient or per node basin, and with or without USS. OBJECTIVE To determine the long-term outcome of patients undergoing DSNB and USS-guided fine-needle aspiration cytology (FNAC) in our cohort of newly diagnosed cN0 SCCp patients, as well as to analyse any variation in sensitivity of the procedure. DESIGN, SETTING, AND PARTICIPANTS A series of consecutive patients with newly diagnosed SCCp, over a 6-yr period (2004-2010), were analysed prospectively with a minimum follow-up period of 21 mo. All patients had definitive histology of ≥ T1G2 and nonpalpable nodes in one or both inguinal basins. Patients with persistent or untreated local disease were excluded from the study. INTERVENTION All eligible patients had DSNB and USS with or without FNAC of cN0 groins. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was no nodal disease recurrence on follow-up. The secondary end point was complications after DSNB. Sensitivity of the procedure was calculated per node basin, per patient, with DSNB alone, and with USS with DSNB combined. RESULTS AND LIMITATIONS Five hundred inguinal basins in 264 patients underwent USS with or without FNAC and DSNB. Seventy-three positive inguinal basins (14.6%) in 59 patients (22.3%) were identified. Four inguinal basins in four patients were confirmed false negative at 5, 8, 12, and 18 mo. Two inguinal basins had positive USS and FNAC and negative DSNB results. Sensitivity of DSNB with USS, with and without FNAC, per inguinal basin was 95% and per patient was 94%. Sensitivity of DSNB alone per inguinal basin and per patient was 92% and 91%, respectively. The DSNB morbidity rate was 7.6%. CONCLUSIONS DSNB in combination with USS has excellent performance characteristics to stage patients with cN0 SCCp, with a 5% false-negative rate per node basin and a 6% false-negative rate per patient.

Treatment of Carcinoma In Situ of the Glans Penis with Topical Chemotherapy Agents

BACKGROUND The use of topical agents in the treatment of carcinoma in situ (CIS) of the penis has been well described in the literature. Previous studies have been limited by small sample size and imprecise end points. OBJECTIVE Establish the response rate of 5-fluorouracil (5-FU) and imiquimod (IQ) in the treatment of penile CIS in a large contemporary series in a supranetwork centre. DESIGN, SETTING, AND PARTICIPANTS Retrospective review of all primary and recurrent cases of penile CIS treated with 5-FU and IQ identified from a prospective database over a 10-yr period. Therapy was standardised in all cases with application to the lesion for 12h every 48 h for 28 d. INTERVENTION 5-FU was the first-line therapy, and IQ was the second-line topical agent. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was defined as complete response (CR; i.e., resolution of lesion), partial response (PR; i.e., lesion reduced in size and or visibility), or no response (NR; ie, no improvement in lesion size and or visibility). The secondary end points included local toxicity and adverse events. No statistical analysis or software was used. RESULTS AND LIMITATIONS A total of 86 patients were diagnosed with CIS of the penis over the 10-yr period. Forty-four (51%) received topical chemotherapy. The mean follow-up was 34 mo. CR to topical chemotherapy was seen in 25 (57%), PR was seen in 6 (13.6%), and NR was seen in the remaining 13 (29.5%) patients. Local toxicity was experienced by 10% of patients, and 12% had an adverse event following application of 5-FU. The retrospective design and short follow-up were the major limitations of this study. CONCLUSIONS Topical chemotherapy agents are moderately effective first-line therapy in the treatment of penile CIS. Toxicity and adverse events were few with our treatment protocol. The issues of long-term surveillance and assessment of partial responders remain a challenge. Topical chemotherapy should remain a first-line treatment option for penile CIS.

Alternative HER/PTEN/Akt pathway activation in HPV positive and negative penile carcinomas

Background The pathogenesis of penile squamous cell carcinoma (PSCC) is not well understood, though risk factors include human papillomavirus (HPV). Disruption of HER/PTEN/Akt pathway is present in many cancers; however there is little information on its function in PSCC. We investigated HER family receptors and phosphatase and tension homolog (PTEN) in HPV-positive and negative PSCC and its impact on Akt activation using immunohistochemistry and fluorescent in situ hybridisation (FISH). Methodology/Principal Findings 148 PSCCs were microarrayed and immunostained for phosphorylated EGFR (pEGFR), HER2, HER3, HER4, phosphorylated Akt (pAkt), Akt1 and PTEN proteins. EGFR and PTEN gene status were also evaluated using FISH. HPV presence was assessed by PCR. pEGFR expression was detected significantly less frequently in HPV-positive than HPV-negative tumours (p = 0.0143). Conversely, HER3 expression was significantly more common in HPV-positive cases (p = 0.0128). HER4, pAkt, Akt and PTEN protein expression were not related to HPV. HER3 (p = 0.0054) and HER4 (p = 0.0002) receptors significantly correlated with cytoplasmic Akt1 immunostaining. All three proteins positively correlated with tumour grade (HER3, p = 0.0029; HER4, p = 0.0118; Akt1, p = 0.0001). pEGFR expression correlated with pAkt but not with tumour grade or stage. There was no EGFR gene amplification. HER2 was not detected. PTEN protein expression was reduced or absent in 62% of tumours but PTEN gene copy loss was present only in 4% of PSCCs. Conclusions/Significance EGFR, HER3 and HER4 but not HER2 are associated with penile carcinogenesis. HPV-negative tumours tend to express significantly more pEGFR than HPV-positive cancers and this expression correlates with pAkt protein, indicating EGFR as an upstream regulator of Akt signalling in PSCC. Conversely, HER3 expression is significantly more common in HPV-positive cases and positively correlates with cytoplasmic Akt1 expression. HER4 and PTEN protein expression are not related to HPV infection. Our results suggest that PSCC patients could benefit from therapies developed to target HER receptors.

Nicorandil-induced penile ulcerations: a case series.

Study Type – Harm (case series)
Level of Evidence 4

The prognostic value of Ki-67 expression in penile squamous cell carcinoma

Aims To determine whether Ki-67 immunoexpression in penile squamous cell carcinoma (PSCC) has a prognostic value and correlates with lymph node metastasis, human papillomavirus (HPV) infection and patient survival. Methods 148 formalin-fixed paraffin-embedded PSCC samples were tissue-microarrayed, including 97 usual-type SCCs, 17 basaloid, 15 pure verrucous carcinomas, 2 warty and 17 mixed-type tumours. All samples were immunostained for Ki-67 protein. HPV DNA was detected with INNO-LiPA assay. Follow-up data were available for 134 patients. Results Ki-67 was strongly expressed in 57/148 (38.5%) of PSCCs. Different cancer subtypes showed significant difference in Ki-67 expression (p<0.0001) with highest positivity in basaloid, 16/17 (94%), followed by usual type, 38/97 (39%) and lack of Ki-67 positive cases within verrucous tumours, 0/15. Ki-67 positively correlated with high-risk HPV (p<0.0001) and showed good specificity (84%) but low sensitivity (61%) for high-risk HPV detection. Ki-67 protein strongly positively correlated with tumour grade (p<0.0001) but not with stage (p=0.2193), or lymph node status (p=0.7366). Ki-67 showed no prognostic value for cancer-specific survival (HR=1.00, 95%, CI 0.99 to 1.02, p=0.54) or overall survival (HR=1.00, 95%, CI 0.99 to 1.02, p=0.45). High tumour stage, lymph node metastasis, high tumour grade and age at diagnosis were all independent prognostic factors for cancer-specific survival and overall survival. Conclusions Ki-67 is only a moderate surrogate marker for HPV infection in PSCC. It does not show prognostic value for cancer-specific survival and overall survival in PSCC.

Is Routine Postoperative Diuresis Renography Indicated in All Adult Patients After Pyeloplasty for Ureteropelvic Junction Obstruction

OBJECTIVE To determine if routine follow-up diuresis renography is indicated in all adult patients after pyeloplasty for ureteropelvic junction obstruction (UPJO). METHODS A multicenter retrospective analysis was conducted in adults who underwent pyeloplasty for symptomatic UPJO between January 2002 and August 2012. Patients with unilateral UPJO demonstrated on diuresis renography, treated with pyeloplasty, and aged >18 years at time of surgery were included in the study. Patients with contralateral renal abnormalities, genitourinary anomalies, and those who declined renography during follow-up were excluded. All eligible patients underwent diuresis renography approximately 3 months postoperatively. Minimal follow-up was 12 months. Patients were divided into 2 groups: patients with persistent pain at 3 months after pyeloplasty and patients who became asymptomatic. Treatment failures in each cohort were identified. Comparisons were performed using the Fisher exact test. RESULTS A total of 100 pyeloplasties were performed. Of them, 90 were eligible for the study. Mean age was 40 years. Mean follow-up was 21 months. Seventy-three patients (81.1%) became pain free after pyeloplasty. One patient (1.4%) had worsening of differential renal function despite unobstructed drainage on diuresis renogram. None of the patients in the asymptomatic cohort was identified to have unequivocal drainage obstruction on postoperative renogram. Seventeen patients (18.9%) remained symptomatic with pain at 3 months after pyeloplasty; 3 (17.6%) of those patients with loin pain after pyeloplasty were confirmed to have persistent obstructed drainage postoperatively on diuresis renogram (P <.001). All 3 patients required insertion of ureteric stents and/or revision surgery (P <.007). CONCLUSION In our series, adult patients who became pain free after unilateral pyeloplasty for UPJO did not have persistent obstruction of renal drainage on renography. Routine diuresis renogram to assess drainage and differential renal function in patients who become pain free after pyeloplasty for UPJO may not be necessary. If objective evidence of postoperative outcome is required, then a single renogram at 3 months is recommended.

Penile lesion in end-stage renal failure — cancer or otherwise?: Calcific uremic arteriolopathy presenting with a penile lesion

Calcific uremic arteriolopathy or calciphylaxis is a rare condition that can present with clinical features similar to penile cancer. It is a diagnosis to consider in patients with end-stage renal failure (ESRF) presenting with a penile lesion. We describe one such case, where a patient with ESRF presented with a solid, tender penile mass and underwent surgery for presumed penile cancer. Histopathological analysis however confirmed a diagnosis of calcific uremic arteriolopathy, without evidence of malignancy. The clinical diagnosis of calcific uremic arteriolopathy relies on a high index of suspicion, and lesion biopsy is controversial due to a high risk of poor wound healing and sepsis. New treatment options are encouraging, and have been reported, albeit in small numbers. Delayed diagnosis can adversely affect both quality of life and prognosis in a condition with an extremely high mortality rate.