Parkin DM, Bray F.
Chapter 2: The burden of HPV-related cancers.
Vaccine. 2006 Aug 31;24 Suppl 3:S3/11-25. doi: 10.1016/j.vaccine.2006.05.111.
Abstract/Text
On the basis of current evidence regarding human papillomavirus (HPV) and cancer, this chapter provides estimates of the global burden of HPV-related cancers, and the proportion that are actually "caused" by infection with HPV types, and therefore potentially preventable. We also present trends in incidence and mortality of these cancers in the past, and consider their likely future evolution.
Marugame T, Katanoda K, Matsuda T, Hirabayashi Y, Kamo K, Ajiki W, Sobue T; Japan Cancer Surveillance Research Group.
The Japan cancer surveillance report: incidence of childhood, bone, penis and testis cancers.
Jpn J Clin Oncol. 2007 Apr;37(4):319-23. doi: 10.1093/jjco/hym020.
Abstract/Text
Daling JR, Madeleine MM, Johnson LG, Schwartz SM, Shera KA, Wurscher MA, Carter JJ, Porter PL, Galloway DA, McDougall JK, Krieger JN.
Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease.
Int J Cancer. 2005 Sep 10;116(4):606-16. doi: 10.1002/ijc.21009.
Abstract/Text
Few population-based case-control studies have assessed etiologic factors for penile cancer. Past infection with high-risk human papillomavirus (HPV) is a known risk factor for penile cancer; however, few previous studies have related the HPV DNA status of the tumor to potential demographic and behavioral risk factors for the disease or evaluated whether in situ and invasive penile cancer share risk factors. Little information is available on the role and timing of circumcision in the etiology of penile cancer. We conducted a population-based case-control study in western Washington state that included 137 men diagnosed with in situ (n = 75) or invasive (n = 62) penile cancer between January 1, 1979, and December 31, 1998, and 671 control men identified through random digit dialing. Cases and controls were interviewed in person and provided peripheral blood samples. Case and control blood samples were tested for antibodies to HPV16 and HSV-2, and tumor specimens from cases were tested for HPV DNA. Men not circumcised during childhood were at increased risk of invasive (OR = 2.3, 95% CI 1.3-4.1) but not in situ (OR = 1.1, 95% CI 0.6-1.8) penile cancer. Approximately 35% of men with penile cancer who had not been circumcised in childhood reported a history of phimosis compared to 7.6% of controls (OR = 7.4, 95% CI 3.7-15.0). Penile conditions such as tear, rash and injury were associated with increased risk of disease. Among men not circumcised in childhood, phimosis was strongly associated with development of invasive penile cancer (OR = 11.4, 95% CI 5.0-25.9). When we restricted our analysis to men who did not have phimosis, the risk of invasive penile cancer associated with not having been circumcised in childhood was not elevated (OR = 0.5, 95% CI 0.1-2.5). Cigarette smoking was associated with a 4.5-fold risk (95% CI 2.0-10.1) of invasive penile cancer. HPV DNA was detected in 79.8% of tumor specimens, and 69.1% of tumors were HPV16-positive. The proportion of HPV DNA-positive tumors did not vary by any risk factors evaluated. Many risk factors were common for both in situ and invasive disease. However, 3 factors that did not increase the risk for in situ cancer proved significant risk factors for invasive penile cancer: lack of circumcision during childhood, phimosis and cigarette smoking. The high percentage of HPV DNA-positive tumors in our study is consistent with a strong association between HPV infection and the development of penile cancer regardless of circumcision status. Circumcision in early childhood may help prevent penile cancer by eliminating phimosis, a significant risk factor for the disease.
(c) 2005 Wiley-Liss, Inc.
Dillner J, von Krogh G, Horenblas S, Meijer CJ.
Etiology of squamous cell carcinoma of the penis.
Scand J Urol Nephrol Suppl. 2000;(205):189-93. doi: 10.1080/00365590050509913.
Abstract/Text
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 photochemotheraphy (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.
American Cancer Society: Cancer Facts and Figures 2022. American Cancer Society, October 7, 2022.
Larke NL, Thomas SL, dos Santos Silva I, Weiss HA.
Male circumcision and penile cancer: a systematic review and meta-analysis.
Cancer Causes Control. 2011 Aug;22(8):1097-110. doi: 10.1007/s10552-011-9785-9. Epub 2011 Jun 22.
Abstract/Text
OBJECTIVE: We systematically reviewed the evidence of an association between male circumcision and penile cancer.
METHODS: Databases were searched using keywords and text terms for the epidemiology of penile cancer. Random effects meta-analyses were used to calculate summary odds ratios (ORs) and 95% confidence intervals (CI).
RESULTS: We identified eight papers which evaluated the association of circumcision with penile cancer, of which seven were case-control studies. There was a strong protective effect of childhood/adolescent circumcision on invasive penile cancer (OR = 0.33; 95% CI 0.13-0.83; 3 studies). In two studies, the protective effect of childhood/adolescent circumcision on invasive cancer no longer persisted when analyses were restricted to boys with no history of phimosis. In contrast, there was some evidence that circumcision in adulthood was associated with an increased risk of invasive penile cancer (summary OR = 2.71; 95% CI 0.93-7.94; 3 studies). There was little evidence for an association of penile intra-epithelial neoplasia and in situ penile cancer with circumcision performed at any age.
CONCLUSIONS: Men circumcised in childhood/adolescence are at substantially reduced risk of invasive penile cancer, and this effect could be mediated partly through an effect on phimosis. Expansion of circumcision services in sub-Saharan Africa as an HIV prevention strategy may additionally reduce penile cancer risk.
Sonpavde G, Pagliaro LC, Buonerba C, Dorff TB, Lee RJ, Di Lorenzo G.
Penile cancer: current therapy and future directions.
Ann Oncol. 2013 May;24(5):1179-89. doi: 10.1093/annonc/mds635. Epub 2013 Jan 4.
Abstract/Text
Background Penile cancer (PC) is a rare cancer in western countries, but is more common in parts of the developing world. Due to its rarity and the consequent lack of randomized trials, current therapy is based on retrospective studies and small prospective trials. Design Studies of PC therapy were searched in PubMed and abstracts at major conferences. Results PC is generally an aggressive malignancy characterized by early locoregional lymph node (LN) spread and later metastases in distant sites. Given the strong predictive value of LN involvement for overall survival, evaluating regional LNs is critical. Advanced LN involvement is increasingly being treated with multimodality therapy incorporating chemotherapy and/or radiation. A single superior cisplatin-based regimen has not been defined. Further advances may occur with a better collaboration on an international scale and comprehensive understanding of tumor biology. To this end, the preventive role of circumcision and understanding of the oncogenic roles of Human Papilloma Virus-16, and smoking may yield advances. Preliminary data suggest a role for agents targeting epidermal growth factor receptor and angiogenesis. Conclusion Advances in therapy for PC will require efficient trial designs, synergistic collaboration, incentives to industry and the efforts of patient advocacy groups and venture philanthropists.
Touloupidis S, Zisimopoulos A, Giannakopoulos S, Papatsoris AG, Kalaitzis C, Thanos A.
Clinical usage of the squamous cell carcinoma antigen in patients with penile cancer.
Int J Urol. 2007 Feb;14(2):174-6. doi: 10.1111/j.1442-2042.2007.01694.x.
Abstract/Text
BACKGROUND: We present our initial experience with the use of the squamous cell carcinoma (SCC) antigen (SCCAg) in 16 men with penile SCC (SCC group), in four men with condyloma acuminatum (benign group), and in 32 blood donors (control group).
METHODS: The SCCAg levels were measured at presentation and every 6 months (upper limit was 2 ng/mL). The mean follow-up time was 4 years.
RESULTS: All non-SCC patients had normal SSCAg serum levels in contrast with the SCC patients. The presence of nodal and/or distant metastases resulted in statistically significant higher SCCAg levels, both at presentation and during the follow-up. In patients undergoing lymph node dissection with elevated SCCAg levels prior to the procedure, there was a statistically significant decrease of the SCCAg levels after the operation.
CONCLUSION: The SCCAg level could be a serum marker that holds promise for clinical use in penile SCC. Sequential monitoring of SCCAg level might indicate developing of nodal and/or distant metastases and could be useful in following the response to treatment.
Hungerhuber E, Schlenker B, Schneede P, Stief CG, Karl A.
Squamous cell carcinoma antigen correlates with tumor burden but lacks prognostic potential for occult lymph node metastases in penile cancer.
Urology. 2007 Nov;70(5):975-9. doi: 10.1016/j.urology.2007.07.013.
Abstract/Text
OBJECTIVES: In penile cancer, radical groin dissection is the reference standard for lymph node staging, but it is associated with high morbidity. Prognostic markers for lymphatic spread would be helpful to select patients for a surveillance program. Squamous cell carcinoma (SCC) antigen is a well-known marker for various carcinomas. Our aim was to evaluate the value of the SCC antigen in terms of lymph node staging and treatment control.
METHODS: From 1994 to 2004, the serum levels of SCC antigen were analyzed in 54 men with penile carcinoma at different disease stages. The SCC antigen values were compared in patients without evidence of tumor, with a primary tumor only, with nodal metastases, and with progressive metastatic disease. In 13 patients, repeated SCC antigen measurements correlated with the treatment effects.
RESULTS: Once lymph node metastases occurred, a trend was found toward increased SCC antigen levels and at the stage of organ metastases, the SCC antigen levels had risen significantly (P <0.01). In cases of repeated measurements, a correlation was found between SCC antigen values and treatment effect. A response to treatment occurred, even if the values were within normal limits.
CONCLUSIONS: The SCC antigen levels seemed to correlate with tumor burden in patients with penile carcinoma. However, it is of limited value in the primary prediction of occult lymph node metastases because the SCC antigen levels increased significantly only after massive lymph node involvement or metastatic disease has occurred. However, the SCC antigen could be used as a marker for treatment control in penile carcinoma.
Horenblas S, Kröger R, Gallee MP, Newling DW, van Tinteren H.
Ultrasound in squamous cell carcinoma of the penis; a useful addition to clinical staging? A comparison of ultrasound with histopathology.
Urology. 1994 May;43(5):702-7. doi: 10.1016/0090-4295(94)90189-9.
Abstract/Text
OBJECTIVE: As part of the staging procedure in squamous cell carcinoma of the penis, we assessed the role of ultrasound examination, in particular its role in assessing the extent and the invasion into the corpora.
METHODS: From 1988 until 1992, all patients referred for primary treatment underwent ultrasound assessment with a 7.5 MHz linear array small parts transducer as part of the clinical workup. All ultrasound images were reviewed by one radiologist, without knowledge of the clinical outcome and were compared with the results obtained at histopathologic examination.
RESULTS: In 16 patients the primary tumor and in 1 patient a recurrent cancer after primary therapy were examined. All tumors were identified as hypoechoic lesions. Ultrasound examination in the region of the glans was not able to differentiate between invasion of the subepithelial tissue and invasion into the corpus spongiosum, but absence or presence of invasion into the tunica albuginea of the corpus cavernosum was clearly demonstrated. Accurate measurement by ultrasound of maximum tumor thickness was seen in seven of sixteen examinations.
CONCLUSIONS: While ultrasound examination is inexpensive and easily done, it is not accurate enough for staging small penile cancers located at the glans penis. However, for larger tumors ultrasound can be a useful addition to physical examination by delineating reliably the anatomic relations of the tumor to structures such as the tunica albuginea, corpus cavernosum, and urethra.
Agrawal A, Pai D, Ananthakrishnan N, Smile SR, Ratnakar C.
Clinical and sonographic findings in carcinoma of the penis.
J Clin Ultrasound. 2000 Oct;28(8):399-406. doi: 10.1002/1097-0096(200010)28:8<399::aid-jcu4>3.0.co;2-j.
Abstract/Text
PURPOSE: This study was performed to assess the accuracy of high-resolution sonography in measuring penile carcinoma.
METHODS: Sonography was performed using a 7.5-MHz linear-array transducer in 59 patients with penile carcinoma. The sonographic measurement of tumor extent was compared with clinical and pathologic measurements. The tumor extent measured by gross pathologic evaluation on cut sections of the fresh penectomy specimen was used as the definitive standard. The echogenicity of the tumor was compared with that of the surrounding normal penile tissue to classify the tumor as hyperechoic, hypoechoic, or of mixed echogenicity (containing both hyperechoic and hypoechoic elements). We evaluated the relationship between the echogenicity of the tumor and both tumor morphology (exophytic or infiltrative) and tumor grade as determined on pathologic examination.
RESULTS: The overall mean difference +/- standard deviation in the tumor extent between clinical and gross pathologic evaluation was 3.9 +/- 5.3 mm (range, 1-9 mm), whereas the overall mean difference between sonographic and gross pathologic evaluation was 1.2 +/- 1.7 mm (range, 1-7 mm). As determined with reference to the gross pathologic extent, the error in measuring the extent on clinical examination was significantly greater than the error on sonography (p < 0.001). Lesions involving the glans alone were more often underestimated by clinical examination than were lesions involving the shaft (with or without glanular involvement). The error in measuring the extent of tumor by sonography was not related to the site of the tumor. The tumor was hyperechoic in 21 cases (36%), hypoechoic in 28 cases (47%), and of mixed echogenicity in 10 cases (17%). There was no significant association between echogenicity and tumor morphology or grade.
CONCLUSIONS: Sonography gives a more accurate estimate of penile tumor extent than does physical examination. Routine use of sonography for such measurements should enable preservation of more of the penis.
Copyright 2000 John Wiley & Sons, Inc.
Lont AP, Besnard AP, Gallee MP, van Tinteren H, Horenblas S.
A comparison of physical examination and imaging in determining the extent of primary penile carcinoma.
BJU Int. 2003 Apr;91(6):493-5. doi: 10.1046/j.1464-410x.2003.04119.x.
Abstract/Text
OBJECTIVE: To determine the accuracy of physical examination and imaging in assessing the extent of the primary tumour in squamous cell carcinoma of the penis.
PATIENTS AND METHODS: A physical examination, ultrasonography and magnetic resonance imaging (MRI) were used before surgery in 33 patients with penile carcinoma. The tumour size, infiltration of the penile structures and infiltration depth were assessed. The results were compared with the histopathological examination of the resected specimen.
RESULTS: Tumour size was determined with the highest precision by the physical examination (residual sd of 8.1 mm); ultrasonography and MRI were less precise (residual sd 8.9 mm and 9.3 mm). In assessing infiltration depth, ultrasonography and MRI had comparable precision (residual sd 3.7 mm and 3.8 mm). The positive predictive value of corpus cavernosum infiltration was 6/6 for physical examination, 4/6 for ultrasonography and 6/8 for MRI; the sensitivity was 6/7, 4/7 and 6/6, respectively.
CONCLUSION: Physical examination is a reliable method for estimating penile tumour size and predicts corpus cavernosum infiltration with a high positive predictive value. Tumours for which the infiltration of the corpora cannot be determined properly by physical palpation only should be examined by imaging.
Kayes O, Minhas S, Allen C, Hare C, Freeman A, Ralph D.
The role of magnetic resonance imaging in the local staging of penile cancer.
Eur Urol. 2007 May;51(5):1313-8; discussion 1318-9. doi: 10.1016/j.eururo.2006.11.014. Epub 2006 Nov 13.
Abstract/Text
OBJECTIVES: To assess the accuracy of magnetic resonance imaging (MRI) as a local staging technique in penile cancer and its role in selecting patients for conservative surgical management.
METHODS: Fifty-five men diagnosed with invasive penile carcinoma on biopsy were locally staged with the use of MRI. Prostaglandin E1 (alprostadil) was injected into the corpora to induce an artificial erection. Radiologic staging was compared against final histopathologic stage of the tumour. Sensitivity, specificity, and kappa agreement values were calculated for each tumour stage. Additionally, corpora cavernosa involvement was reviewed in 20 consecutive cases and suitability for conservative surgery assessed.
RESULTS: A good correlation between radiologic and histologic staging was achieved with an overall kappa value of 0.75 (p<0.001). Stage-specific sensitivities and specificities were calculated: T1 (85%; 83%), T2 (75%; 89%), and T3 (88%; 98%). MRI accurately predicted corpora cavernosa invasion in all cases of pathologically proven disease. These patients were selected to undergo partial penectomy. There were no complications using this imaging technique.
CONCLUSIONS: This study demonstrates that penile MRI is highly accurate in the local staging of penile cancer. Associated improvements in surgical planning allow the provision of conservative surgical treatments over more radical procedures.
Kirkham A.
MRI of the penis.
Br J Radiol. 2012 Nov;85 Spec No 1(Spec Iss 1):S86-93. doi: 10.1259/bjr/63301362.
Abstract/Text
MRI of the penis is an expensive test that is not always superior to clinical examination or ultrasound. However, it shows many of the important structures, and in particular the combination of tumescence from intracavernosal alprostadil, and high-resolution T(2) sequences show the glans, corpora and the tunica albuginea well. In this paper we summarise the radiological anatomy and discuss the indications for MRI. For penile cancer, it may be useful in cases where the local stage is not apparent clinically. In priapism, it is an emerging technique for assessing corporal viability, and in fracture it can in most cases make the diagnosis and locate the injury. In some cases of penile fibrosis and Peyronie's disease, it may aid surgical planning, and in complex pelvic fracture may replace or augment conventional urethrography. It is an excellent investigation for the malfunctioning penile prosthesis.
Graafland NM, Leijte JA, Valdés Olmos RA, Hoefnagel CA, Teertstra HJ, Horenblas S.
Scanning with 18F-FDG-PET/CT for detection of pelvic nodal involvement in inguinal node-positive penile carcinoma.
Eur Urol. 2009 Aug;56(2):339-45. doi: 10.1016/j.eururo.2009.05.016. Epub 2009 May 19.
Abstract/Text
BACKGROUND: Penile carcinoma patients with inguinal lymph node involvement (LNI) have an increased risk for pelvic nodal involvement with or without distant metastases.
OBJECTIVE: To evaluate the diagnostic accuracy of fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) with computed tomography (CT; 18F-FDG PET/CT) scanning in determining further metastatic spread in patients with tumour-positive inguinal nodes.
DESIGN, SETTING, AND PARTICIPANTS: Eighteen patients with penile squamous cell carcinoma with unilateral or bilateral cytologically tumour-positive inguinal disease underwent whole-body 18F-FDG-PET/CT scanning for tumour staging.
MEASUREMENTS: Images were blindly assessed by two nuclear medicine physicians. All scans were evaluated for pelvic nodal involvement per basin and for distant metastases. Histopathology (when available), radiologic imaging, and clinical follow-up (with a minimum of 1 yr) served as a reference standard. The diagnostic value of PET/CT scanning for predicting pelvic nodal involvement was evaluated using standard statistical methods.
RESULTS AND LIMITATIONS: The reference was available in 28 of the 36 pelvic basins. Of the 11 tumour-positive pelvic basins, 10 were correctly predicted by PET/CT scan, as were all 17 tumour-negative pelvic basins. PET/CT scan showed a sensitivity of 91%, a specificity of 100%, a diagnostic accuracy of 96%, a positive predictive value of 100%, and a negative predictive value of 94% in detecting pelvic nodal involvement. Additionally, PET/CT scans showed distant metastases in five patients. In four patients, the presence of distant metastases could be confirmed, while in one patient, no radiologic confirmation was found for that particular lesion. A potential limitation is that the diagnostic accuracy of PET/CT scanning was calculated on 28 pelvic basins only. Furthermore, no comparison was made with conventional CT scans, as not all patients had undergone contrast-enhanced CT scans.
CONCLUSIONS: PET/CT scanning appears promising for detecting pelvic lymph node metastases with great accuracy, and it identifies distant metastases in penile carcinoma patients with inguinal LNI. In our practice, PET/CT scanning has become part of routine staging in such patients.
Souillac I, Rigaud J, Ansquer C, Marconnet L, Bouchot O.
Prospective evaluation of (18)F-fluorodeoxyglucose positron emission tomography-computerized tomography to assess inguinal lymph node status in invasive squamous cell carcinoma of the penis.
J Urol. 2012 Feb;187(2):493-7. doi: 10.1016/j.juro.2011.10.033. Epub 2011 Dec 15.
Abstract/Text
PURPOSE: We prospectively evaluated (18)F-fluorodeoxyglucose positron emission tomography-computerized tomography to assess inguinal lymph node status, the main prognostic factor in invasive squamous cell carcinoma of the penis.
MATERIALS AND METHODS: From March 2005 to January 2010, 30 patients with invasive squamous cell carcinoma of the penis from the department of urology at our institution were prospectively included in this study. Lymph node status was assessed preoperatively by positron emission tomography-computerized tomography to detect subclinical metastasis in 22 patients with initially cN0 disease and quantify inguinal lymph node invasion in 8 with cN+.
RESULTS: In the 22 cN0 cases (total of 44 inguinal lymph node basins analyzed) positron emission tomography-computerized tomography had 75% sensitivity and 87.5% specificity. Positive and negative predictive values were 37.5% and 97.2%, respectively. In the 8 cN+ cases (total of 16 inguinal lymph node basins analyzed) this type of imaging had 100% sensitivity, specificity and positive predictive value. In 3 cases staged clinically as cN1 positron emission tomography-computerized tomography revealed several metabolically active lesions on the same side, which was confirmed by histological examination, up-staging these cases to pN2.
CONCLUSIONS: (18)F-fluorodeoxyglucose positron emission tomography-computerized tomography is a useful staging examination for invasive penile cancer. It confirms inguinal lymph node invasion and can detect subclinical inguinal lymph node invasion.
Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
Leijte JA, Graafland NM, Valdés Olmos RA, van Boven HH, Hoefnagel CA, Horenblas S.
Prospective evaluation of hybrid 18F-fluorodeoxyglucose positron emission tomography/computed tomography in staging clinically node-negative patients with penile carcinoma.
BJU Int. 2009 Sep;104(5):640-4. doi: 10.1111/j.1464-410X.2009.08450.x. Epub 2009 Mar 5.
Abstract/Text
OBJECTIVE: To prospectively evaluate the performance of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to detect occult metastasis in patients with clinically node-negative (cN0) penile carcinoma, as there is little information on the use of (18)F-FDG-PET/CT in penile carcinoma.
PATIENTS AND METHODS: In 24 patients, scheduled to undergo dynamic sentinel-node biopsy, hybrid PET/CT was used before surgery to assess the nodal status of the cN0-groins. Six of the 24 patients were unilaterally cN0. Thus, 42 cN0-groins were evaluated for occult metastasis using PET/CT. All scans were assessed by two experienced nuclear physicians. The histopathological tumour status of the removed sentinel node was used as the standard of care to evaluate the PET/CT-results.
RESULTS: Histopathology was tumour-positive in five of the 42 (12%) evaluated cN0-groins, two of which contained only micrometastases (<2 mm). One of the five tumour-positive cN0-groins was correctly predicted on the PET/CT-images. All false-negative PET/CT scans contained metastasis of CONCLUSION: The role of PET/CT in evaluating the groins of patients with cN0 penile cancer appears to be limited, due to its low sensitivity. In this series, only one of the five tumour-positive groins was identified. Surgical staging methods remain necessary at present.
Sadeghi R, Gholami H, Zakavi SR, Kakhki VR, Horenblas S.
Accuracy of 18F-FDG PET/CT for diagnosing inguinal lymph node involvement in penile squamous cell carcinoma: systematic review and meta-analysis of the literature.
Clin Nucl Med. 2012 May;37(5):436-41. doi: 10.1097/RLU.0b013e318238f6ea.
Abstract/Text
PURPOSE: Metastatic involvement of the inguinal lymph nodes is associated with decreased survival and is a strong prognostic factor in penile squamous cell carcinoma. The aim of the current systematic review was to evaluate the accuracy of (18)F-FDG PET/CT for inguinal lymph node staging in penile squamous cell carcinoma and possible influential factors.
MATERIALS AND METHODS: Medline, SCOPUS, Springer, Science Direct, and Google Scholar were searched using the key words "(penile or penis) and PET," with no date or language limitation. The meeting abstracts were not excluded either. Statistical pooling was performed using the random-effects model.
RESULTS: Seven studies were included in the meta-analysis. One article had 2 different subgroups of patients, and each subgroup was considered as a separate study. Pooled sensitivity and specificity were 80.9% (95% confidence interval [CI]: 69.5%-89.4%) and 92.4% (95% CI: 86.8%-96.2%), respectively. Pooled sensitivity was 96.4% (95% CI: 81.7%-99.9%) for cN+ and 56.5% (95% CI: 34.5%-76.8%) for cN0 patients.
CONCLUSIONS: (18)F-FDG PET/CT imaging has relatively low sensitivity (especially in cN0 patients) for detection of inguinal lymph node involvement in penile cancer patients, which does not justify its routine use. However, patients with clinically palpable lymph nodes may benefit from (18)F-FDG PET/CT because the sensitivity in this subgroup of patients is high.
Role of Human Papillomavirus in Penile Carcinomas Worldwide. European Urology. Volume 69, Issue 5, May 2016, Pages 953-961.
Heyns CF, Mendoza-Valdés A, Pompeo AC.
Diagnosis and staging of penile cancer.
Urology. 2010 Aug;76(2 Suppl 1):S15-23. doi: 10.1016/j.urology.2010.03.002.
Abstract/Text
A comprehensive literature study was conducted to evaluate the levels of evidence (LEs) in publications on the diagnosis and staging of penile cancer. Recommendations from the available evidence were formulated and discussed by the full panel of the International Consultation on Penile Cancer in November 2008. The final grades of recommendation (GRs) were assigned according to the LEs of the relevant publications. The following consensus recommendations were accepted: physical examination of the primary penile lesion is mandatory, evaluating the morphologic and physical characteristics of the lesion (GR A). Evaluation of the primary lesion with ultrasonography is of limited value for local tumor staging (GR C); however, evaluation of the primary tumor with magnetic resonance (MRI) imaging during artificial erection induced by intracavernosal injection of prostaglandin might be more useful (GR B). Histologic or cytologic diagnosis of the primary lesion is mandatory (GR A). For accurate histologic grading and staging, a resected specimen is preferable to a biopsy specimen alone (GR B). Penile cancer should be staged according to the TNM system; however, the 1987/2002 TNM staging system requires revision using data from larger patient cohorts to validate the recently proposed modifications (GR B). The histopathology report should provide information on all prognostic parameters, including the tumor size, histologic type, grade, growth pattern, depth of invasion, tumor thickness, resection margins, and lymphovascular and perineural invasion (GR B). Physical examination of the inguinal and pelvic areas to assess the lymph nodes is mandatory (GR B). Ultrasound-guided fine needle aspiration cytology is indicated for both palpable and nonpalpable inguinal nodes. If the findings confirm lymph node metastasis (LNM), complete inguinal lymph node dissection is indicated (GR B). In patients with nonpalpable inguinal nodes, if the ultrasound-guided fine needle aspiration cytology findings are negative for tumor, dynamic sentinel node biopsy can be performed if the equipment and technical expertise are available (GR C). In patients at high risk of inguinal LNM according to the available guidelines and nomograms, surgical staging can be performed by complete, bilateral inguinal lymph node dissection, which might also be curative (GR B). In patients at intermediate risk of LNM, sentinel node biopsy or modified (limited) inguinal lymph node dissection might be performed (GR B). In patients with nonpalpable inguinal nodes, imaging with computed tomography (CT) or MRI is not indicated, because they are not useful in detecting small-volume LNM. Also, it is very unlikely that large-volume LNM (detectable by CT/MRI) would be present in the pelvic nodes (GR B). In patients with confirmed inguinal LNM, CT of the pelvis is indicated to detect iliac LNMs (GR B). Abdominal CT and chest radiography are advisable if the pelvic CT findings are positive (GR B).
Copyright (c) 2010 Elsevier Inc. All rights reserved.
Hakenberg OW, Compérat EM, Minhas S, Necchi A, Protzel C, Watkin N.
EAU guidelines on penile cancer: 2014 update.
Eur Urol. 2015 Jan;67(1):142-150. doi: 10.1016/j.eururo.2014.10.017. Epub 2014 Nov 1.
Abstract/Text
CONTEXT: Penile cancer has high mortality once metastatic spread has occurred. Local treatment can be mutilating and devastating for the patient. Progress has been made in organ-preserving local treatment, lymph node management, and multimodal treatment of lymphatic metastases, requiring an update of the European Association of Urology guidelines.
OBJECTIVE: To provide an evidence-based update of treatment recommendations based on the literature published since 2008.
EVIDENCE ACQUISITION: A PubMed search covering the period from August 2008 to November 2013 was performed, and 352 full-text papers were reviewed. Levels of evidence were assessed and recommendations graded. Because there is a lack of controlled trials or large series, the levels of evidence and grades of recommendation are low compared with those for more common diseases.
EVIDENCE SYNTHESIS: Penile squamous cell carcinoma occurs in distinct histologic variants, some of which are related to human papilloma virus infection; others are not. Primary local treatment should be organ preserving, if possible. There are no outcome differences between local treatment modes in superficial and T1 disease. Management of inguinal lymph nodes is crucial for prognosis. In impalpable nodes, invasive staging should be done depending on the risk factors of the primary tumour. Lymph node metastases should be treated by surgery and adjuvant chemotherapy in N2/N3 disease.
CONCLUSIONS: Organ preservation has become the standard approach to low-stage penile cancer, whereas in lymphatic disease, it is recognised that multimodal treatment with radical inguinal node surgery and adjuvant chemotherapy improves outcome.
PATIENT SUMMARY: Approximately 80% of penile cancer patients of all stages can be cured. With increasing experience in the management of penile cancer, it is recognized that organ-preserving treatment allows for better quality of life and sexual function and should be offered to all patients whenever feasible. Referral to centres with experience is recommended.
Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Diorio GJ, Leone AR, Spiess PE.
Management of Penile Cancer.
Urology. 2016 Oct;96:15-21. doi: 10.1016/j.urology.2015.12.041. Epub 2016 Jan 20.
Abstract/Text
Although rare, penile cancer carries high morbidity and mortality particularly when pertaining to the management of locally advanced or metastatic disease. The current scientific literature lacks level 1 evidence and current guidelines are based largely on retrospective studies and small single center studies. Despite these limitations, there has been paradigm shifts in the management of both local and systemic disease. Current guidelines emphasize penile sparing strategies, minimizing morbidity from surgical management of loco-regional metastasis and multimodal management of bulky inguinal lymph node metastases. The present review highlights the current state of knowledge and recommended treatment strategies of penile carcinoma.
Copyright © 2016 Elsevier Inc. All rights reserved.
Sharp DS, Angermeier KW. Surgery of penile and urethral carcinoma. In: Wein AJ, Kavoussi L, Novick AC, et al., eds. Campbell-ed9 2007.
Videtic GM, Ago CT, Winquist EW.
Hypercalcemia and carcinoma of the penis.
Med Pediatr Oncol. 1997 Dec;29(6):576-7. doi: 10.1002/(sici)1096-911x(199712)29:6<576::aid-mpo11>3.0.co;2-4.
Abstract/Text
Hypercalcemia is the most common metabolic disorder associated with malignancies. Squamous cell carcinoma of the penis is a tumor for which this abnormality has rarely been described. This report presents a case of hypercalcemia seen in a patient with advanced penile cancer. A chemotherapy regimen of intravenous cisplatin and fluorouracil caused regression of the primary tumor and normalization of the serum calcium. A literature review supported an association between squamous cell carcinoma of the penis and hypercalcemia.
Dorfinger K, Maier U, Base W.
Parathyroid hormone related protein and carcinoma of the penis: paraneoplastic hypercalcemia.
J Urol. 1999 May;161(5):1570.
Abstract/Text
Kroon BK, Horenblas S, Nieweg OE.
Contemporary management of penile squamous cell carcinoma.
J Surg Oncol. 2005 Jan 1;89(1):43-50. doi: 10.1002/jso.20170.
Abstract/Text
Squamous cell carcinoma (SCC) is the most common tumor of the penis. The natural history and its proclivity to spread via regional lymphatics has been well defined. Laser ablation of the primary tumor has a prominent role in patients with a superficial tumor as a penis-conserving approach. Patients with deeper infiltrating tumors, should undergo (partial) penile amputation. For patients presenting with proven metastatic nodes complete (ilio-) inguinal lymphadenectomy should be performed. During the last two decades, the management of penile carcinoma patients with impalpable regional lymph nodes has improved due to better knowledge of risks for metastases, the introduction of modified lymphadenectomy, and sentinel node biopsy. Future perspectives in penile cancer comprises continuing research to reduce mutilation without jeopardizing clinical outcome.
Slaton JW, Morgenstern N, Levy DA, Santos MW Jr, Tamboli P, Ro JY, Ayala AG, Pettaway CA.
Tumor stage, vascular invasion and the percentage of poorly differentiated cancer: independent prognosticators for inguinal lymph node metastasis in penile squamous cancer.
J Urol. 2001 Apr;165(4):1138-42.
Abstract/Text
PURPOSE: We determine if histopathological factors of the primary penile tumor can stratify the risk of the development of inguinal lymph node metastases.
MATERIALS AND METHODS: Clinical records of 48 consecutive patients with squamous cell carcinoma of the penis who underwent resection of the primary lesion and either inguinal lymph node dissection or were observed for signs of recurrence (median followup 59 months) were reviewed. Parameters examined included pathological tumor stage, quantified depth of invasion and tumor thickness, histological and nuclear grade, percentage of poorly differentiated cancer in the primary tumor, number of mitoses and presence or absence of vascular invasion. Variables were compared in 18 lymph node positive and 30 lymph node negative cases.
RESULTS: Pathological tumor stage, vascular invasion and presence of greater than 50% poorly differentiated cancer were the strongest predictors of nodal metastasis on univariate and multivariate regression analyses. None of 15 pT1 tumors exhibited vascular invasion or lymph node metastases. Of 33 patients with pT2 or greater tumors 21 (64%) had vascular invasion and 18 (55%) had metastases. Only 4 of 25 patients (15%) with 50% or less poorly differentiated cancer in the penile tumor had metastases compared with 14 of 23 patients (61%) with greater than 50% poorly differentiated cancer (p = 0.001). No other variables tested were significantly different among the patient cohorts.
CONCLUSIONS: Pathological stage of the penile tumor, vascular invasion and greater than 50% poorly differentiated cancer were independent prognostic factors for inguinal lymph node metastasis. Prophylactic lymphadenectomy in compliant patients with pT1 lesions without vascular invasion and 50% or less poorly differentiated cancer does not appear warranted.
Hegarty PK, Kayes O, Freeman A, Christopher N, Ralph DJ, Minhas S.
A prospective study of 100 cases of penile cancer managed according to European Association of Urology guidelines.
BJU Int. 2006 Sep;98(3):526-31. doi: 10.1111/j.1464-410X.2006.06296.x.
Abstract/Text
OBJECTIVE: To prospectively assess the outcome of patients treated according to the European Association of Urology (EAU) guidelines on the management of penile cancer, a system originally based on retrospective series.
PATIENTS AND METHODS: Between 2002 and 2005, 100 consecutive patients (median age 62 years) with penile cancer were treated at one institution; all were categorized and treated according to EAU guidelines. Data were analysed using the z-test, with significance defined as P < 0.05.
RESULTS: Survival curves were limited to those with >12 months of follow-up (mean 29); the survival of the whole group was 92%. Of men with palpable nodes, 72% had lymph node involvement, whereas 18% of those with impalpable nodes who had lymphadenectomy according to the guidelines had lymph node disease. The grade of the primary tumour was more predictive than T stage for lymph node involvement and survival. The 3-year disease-specific survival for N0, N1 and N2 disease was 100%, 100% and 73%, respectively, and survival at 12 months for N3 disease was 67%. The median survival for those with metastases was 3 months.
CONCLUSION: The overall survival of men with penile cancer is high, with a clear benefit for early lymphadenectomy in men with positive nodal disease. However, the current EAU guidelines are limited in predicting those patients with micrometastatic disease, with the result that 82% of patients undergo unnecessary prophylactic lymphadenectomy. There is a need to identify more accurate molecular markers for predicting lymph node disease, or the role of novel staging techniques must be assessed.
Leijte JA, Kroon BK, Valdés Olmos RA, Nieweg OE, Horenblas S.
Reliability and safety of current dynamic sentinel node biopsy for penile carcinoma.
Eur Urol. 2007 Jul;52(1):170-7. doi: 10.1016/j.eururo.2007.01.107. Epub 2007 Feb 7.
Abstract/Text
OBJECTIVES: Dynamic sentinel node biopsy (DSNB) has been performed at our department since 1994 to assess status of inguinal lymph nodes of clinically node-negative (cN0) patients with penile carcinoma. Over time, several modifications were made to reduce the false-negative rate and thus increase sensitivity. We compared the false-negative and complication rates of the current procedure, as performed at our institute since 2001, with the prior procedures.
MATERIALS AND METHODS: The patients who underwent DSNB for penile carcinoma in the period from 1994 until July 2004 were divided into two cohorts: cohort A: patients treated from 1994 until 2001; cohort B: patients treated from 2001 until 2004. Cohort A consisted of 92 patients, in whom 157 groins were explored. Cohort B consisted of 58 patients, with a total of 105 explored groins. Medians for follow-up in cohorts A and B were 83 (range: 24-130) and 30 (range: 24-49) mo, respectively. The false-negative and complication rates were determined in both cohorts.
RESULTS: In cohort A, 21 of 157 explored groins contained tumour-positive sentinel nodes, and five false-negative procedures were encountered, resulting in a false-negative rate of 19.2%. In cohort B, 20 of 105 explored groins contained tumour-positive sentinel nodes, and one procedure was false-negative. The false-negative rate was 4.8%. The rate of complications dropped from 10.2% in cohort A to 5.7% in cohort B. All complications were minor and transient.
CONCLUSIONS: The false-negative and complication rates of DSNB have decreased since the procedure was modified. The current procedure has false-negative and complication rates of 4.8% and 5.7%, respectively. DSNB has matured into a reliable and safe method for assessing status of lymph nodes in cN0 penile carcinoma patients.
Pizzocaro G, Algaba F, Horenblas S, Solsona E, Tana S, Van Der Poel H, Watkin NA; European Association of Urology (EAU) Guidelines Group on Penile Cancer.
EAU penile cancer guidelines 2009.
Eur Urol. 2010 Jun;57(6):1002-12. doi: 10.1016/j.eururo.2010.01.039. Epub 2010 Feb 4.
Abstract/Text
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.
Copyright © 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Kroon BK, Horenblas S, Estourgie SH, Lont AP, Valdés Olmos RA, Nieweg OE.
How to avoid false-negative dynamic sentinel node procedures in penile carcinoma.
J Urol. 2004 Jun;171(6 Pt 1):2191-4. doi: 10.1097/01.ju.0000124485.34430.15.
Abstract/Text
PURPOSE: Evaluation of the false-negative dynamic sentinel node procedures in penile carcinoma at our institute.
MATERIALS AND METHODS: Between January 1994 and February 2003, 123 patients with penile squamous cell carcinoma underwent dynamic sentinel node biopsy.
RESULTS: The sentinel node revealed metastasis in 28 (23%) of 123 patients. Regional recurrence after excision of a tumor-negative sentinel node or after nonvisualization was seen in 6 patients resulting in a false-negative rate of 18% (6 of 34). We assume that 1 false-negative case was due to tumor blockage, 3 to tumor blockage and rerouting, 1 to a pathological sampling error and 1 to a low radioactivity level in the sentinel node during surgery.
CONCLUSIONS: Based on the false-negative results, important adaptations have been made in the dynamic sentinel node biopsy procedure for penile carcinoma at our institute. Pathological analysis was extended by serial sectioning and immunohistochemical staining, and preoperative ultrasonography with fine needle aspiration cytology has been added. Furthermore, exploration of groin without visualized sentinel nodes and intraoperative palpation of the wound have been introduced.
Lopes A, Hidalgo GS, Kowalski LP, Torloni H, Rossi BM, Fonseca FP.
Prognostic factors in carcinoma of the penis: multivariate analysis of 145 patients treated with amputation and lymphadenectomy.
J Urol. 1996 Nov;156(5):1637-42. doi: 10.1016/s0022-5347(01)65471-5.
Abstract/Text
PURPOSE: The major issue in penile cancer is deciding who should or should not undergo lymph node dissection. Clinical and invasive methods are not reliable for staging. Clinical and pathological factors involved in lymph node metastases and prognosis were evaluated in 145 patients with penile carcinoma staged according to the 1978 TNM system, and treated with amputation and lymphadenectomy.
MATERIALS AND METHODS: Clinical factors studied were patient age, race, disease evolution time, symptoms, and clinical T and N stages. Pathological factors of the primary tumor considered were tumor thickness, histological grade, lymphatic and venous embolization, infiltration of the corpora cavernosa, corpus spongiosum and urethra, mononuclear and eosinophilic infiltrates, and cell alterations suggestive of human papillomavirus. All slides were reviewed by 1 pathologist. The Cox regression hazards method for multifactorial analysis was used.
RESULTS: Followup ranged from 0.7 to 453.2 months (mean 85.8, median 32.7). The 5-year disease-free and overall survival rates were 45.3 and 54.3%, respectively. Venous and lymphatic embolizations were the main factors affecting significantly the incidence of lymph node metastasis, which were the main risks factors for recurrence and death. Pathologically proved infiltration of the corpora cavernosa, urethra and adjacent structures, which corresponded to stages T2, T3 and T4 disease, respectively, of the current TNM classification, were not significant predictors for incidence of lymph node metastasis, disease-free and overall survival or risk factors for recurrence and death.
CONCLUSIONS: Because venous and lymphatic embolizations were related to greatest risk of lymph node metastasis, we propose their evaluation in staging and therapeutic planning of patients with infiltrative tumors of the penis.
Cubilla AL.
The role of pathologic prognostic factors in squamous cell carcinoma of the penis.
World J Urol. 2009 Apr;27(2):169-77. doi: 10.1007/s00345-008-0315-7. Epub 2008 Sep 3.
Abstract/Text
PURPOSE: The aim of this review was to identify prognostic pathologic factors which are independent from other clinical or molecular variables.
METHODS: We reviewed the literature on morphological prognostic factors emphasizing our personal experience.
RESULTS: We found that for a proper evaluation of prognostic factors a familiarity with penile complex anatomy is required. A biopsy of the primary tumor is not useful for a complete evaluation of prognostic factors other than malignancy and a resected specimen should be utilized. Penile carcinomas have a fairly predictable pattern of local, regional and systemic spread. Pathologic factors affecting patients outcome are multiple but it is difficult from the available studies using heterogeneous pathologic methodologies, different therapeutic approaches and ecologically variable patient populations to ascertain the independent validity of these factors. Invasion of perineural spaces by tumor, lymphatic-venous embolization and histological grade appear to be the most important pathologic predictors of nodal spread and cancer mortality. Other commonly cited factors influencing prognosis are tumor depth or thickness, anatomical site and size of the primary tumor, patterns of growth, irregular front of invasion, pathologic subtypes of the SCC, positive margins of resection and urethral invasion. A combination of two factors, histological grade and depth has been reported as significant predictor of cancer regional spread. After a preselection of significant factors, nomograms have been constructed to collectively evaluate the predictive power of various clinical and pathological indicators.
CONCLUSIONS: Among various factors perineurial invasion, vascular invasion and high histological grade appear to be the most important adverse pathological prognostic factors.
Horenblas S.
Lymphadenectomy for squamous cell carcinoma of the penis. Part 2: the role and technique of lymph node dissection.
BJU Int. 2001 Sep;88(5):473-83. doi: 10.1046/j.1464-410x.2001.00379.x.
Abstract/Text
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Penile Cancer. Version 2.2019 http://www.nccn.org/professionals/physician_gls/pdf/penile.pdf.
Lindegaard JC, Nielsen OS, Lundbeck FA, Mamsen A, Studstrup HN, von der Maase H.
A retrospective analysis of 82 cases of cancer of the penis.
Br J Urol. 1996 Jun;77(6):883-90. doi: 10.1046/j.1464-410x.1996.02221.x.
Abstract/Text
OBJECTIVE: To identify prognostic factors for penile cancer and to evaluate the treatment strategy for early-stage disease, proposed recently by the European Board of Urology (EBU).
PATIENT AND METHODS: The records of 82 patients consecutively referred to the uro-oncological centre at Aarhus University Hospital between 1965 and 1993 were reviewed. The importance of tumour stage, differentiation, patient age, local control and regional lymph node control were assessed using univariate and multivariate analyses.
RESULTS: Cox multivariate analysis identified differentiation (odds ratio [OR] = 6.04), UJCC-1978 T-stage (OR = 1.88) and age (OR = 1.04) as independent prognostic variables for survival. Penile amputation in tumours < 4 cm in diameter improved local control but not survival. Regional control and survival were not significantly improved by prophylactic adenectomy.
CONCLUSION: Differentiation, T-stage and age were prognostic factors for survival. The results support the EBU treatment strategy involving penis-conserving therapy and watchful waiting for early-stage disease.
Ornellas AA, Seixas AL, Marota A, Wisnescky A, Campos F, de Moraes JR.
Surgical treatment of invasive squamous cell carcinoma of the penis: retrospective analysis of 350 cases.
J Urol. 1994 May;151(5):1244-9. doi: 10.1016/s0022-5347(17)35222-9.
Abstract/Text
Between 1960 and 1987, 414 patients with invasive squamous cell carcinoma of the penis were referred to the Brazilian National Cancer Institute. Inguinal metastases were demonstrated by lymphadenectomy in 39% of the 23 patients with stage N0, 49% of 92 with stages N1 and N2, and 100% of 18 with stage N3 disease. We analyzed the followup of 350 patients who underwent surgical treatment. In 224 patients (64%) amputation or some form of penile surgery was done initially, while 102 (29%) underwent amputation and lymphadenectomy, and 24 (7%) underwent palliative surgery for advanced squamous cell carcinoma. The statistics revealed a better 5-year survival rate for the patients who underwent lymphadenectomy concomitantly with penile surgery compared to those who underwent delayed lymphadenectomy (p < 0.001). Patients in whom systematic lymphadenectomy was negative had a better prognosis than those with positive systematic lymphadenectomy results (p < 0.001). The latter patients had a better prognosis compared with those in whom delayed lymphadenectomy was positive (p = 0.0103). Patients with well and moderately differentiated carcinoma had a higher survival rate at 5 years than did those with poorly differentiated carcinoma (p < 0.001 and p = 0.003, respectively). All deaths from metastatic disease occurred within 24 months among the patients who underwent systematic lymphadenectomy and within 5 years after simple penile surgery. In the short term, surgical debulking combined with reconstruction techniques allowed for improved quality of life in patients with advanced local-regional disease.
Kroon BK, Valdés Olmos RA, van Tinteren H, Nieweg OE, Horenblas S.
Reproducibility of lymphoscintigraphy for lymphatic mapping in patients with penile carcinoma.
J Urol. 2005 Dec;174(6):2214-7. doi: 10.1097/01.ju.0000181813.43631.e5.
Abstract/Text
PURPOSE: We evaluated the reproducibility of lymphoscintigraphy in the assessment of the location and number of sentinel nodes in patients with penile carcinoma.
MATERIALS AND METHODS: A total of 20 patients were prospectively included in analysis. Lymphoscintigraphy was performed after intradermal injection of technetium nanocolloid around the tumor or excision scar. We performed 10-minute anterior dynamic imaging, and static anterior and lateral images were obtained at 30 minutes and 2 hours. The following day scintigraphy was repeated after a second injection of the radiolabeled colloid given in an identical fashion, preceded by acquisition of a starting image. An observer evaluated the paired images and count rates were calculated from the images.
RESULTS: At least 1 sentinel node was visualized in all patients on the first lymphoscintigram. A total of 56 sentinel nodes were seen in 38 basins. Drainage to both groins was seen in 18 patients. In 1 of these patients drainage to the prepubic area was also observed. There were 2 patients with drainage to 1 groin. The second lymphoscintigram revealed the same drainage pattern in all patients- the same number of nodal basins and number of sentinel nodes were visualized at identical locations. All hotspots that were visualized during the first lymphoscintigram showed an unequivocal increase in radioactivity after repeat injection. Thus, the reproducibility of penile lymphoscintigraphy was 100% (95% CI 85%-100%). The Pearson correlation coefficient of the paired count rates was 0.69 (p <0.0001).
CONCLUSIONS: Results of lymphoscintigraphy in patients with penile carcinoma are highly reproducible for assessment of the number and location of sentinel nodes.
Heyns CF, Fleshner N, Sangar V, Schlenker B, Yuvaraja TB, van Poppel H.
Management of the lymph nodes in penile cancer.
Urology. 2010 Aug;76(2 Suppl 1):S43-57. doi: 10.1016/j.urology.2010.03.001.
Abstract/Text
A comprehensive literature study was conducted to evaluate the levels of evidence (LEs) in publications on the diagnosis and staging of penile cancer. Recommendations from the available evidence were formulated and discussed by the full panel of the International Consultation on Penile Cancer in November 2008. The final grades of recommendation (GRs) were assigned according to the LE of the relevant publications. The following consensus recommendations were accepted. Fine needle aspiration cytology should be performed in all patients (with ultrasound guidance in those with nonpalpable nodes). If the findings are positive, therapeutic, rather than diagnostic, inguinal lymph node dissection (ILND) can be performed (GR B). Antibiotic treatment for 3-6 weeks before ILND in patients with palpable inguinal nodes is not recommended (GR B). Abdominopelvic computed tomography (CT) and magnetic resonance imaging (MRI) are not useful in patients with nonpalpable nodes. However, they can be used in those with large, palpable inguinal nodes (GR B). The statistical probability of inguinal micrometastases can be estimated using risk group stratification or a risk calculation nomogram (GR B). Surveillance is recommended if the nomogram probability of positive nodes is <0.1 (10%). Surveillance is also recommended if the primary lesion is grade 1, pTis, pTa (verrucous carcinoma), or pT1, with no lymphovascular invasion, and clinically nonpalpable inguinal nodes, but only provided the patient is willing to comply with regular follow-up (GR B). In the presence of factors that impede reliable surveillance (obesity, previous inguinal surgery, or radiotherapy) prophylactic ILND might be a preferable option (GR C). In the intermediate-risk group (nomogram probability .1-.5 [10%-50%] or primary tumor grade 1-2, T1-T2, cN0, no lymphovascular invasion), surveillance is acceptable, provided the patient is informed of the risks and is willing and able to comply. If not, sentinel node biopsy (SNB) or limited (modified) ILND should be performed (GR B). In the high-risk group (nomogram probability >.5 [50%] or primary tumor grade 2-3 or T2-T4 or cN1-N2, or with lymphovascular invasion), bilateral ILND should be performed (GR B). ILND can be performed at the same time as penectomy, instead of 2-6 weeks later (GR C). SNB based on the anatomic position can be performed, provided the patient is willing to accept the potential false-negative rate of /=2 nodes on one side, contralateral limited ILND with frozen section analysis can be performed, with complete ILND if the frozen section analysis findings are positive (GR B). If clinically suspicious inguinal metastases develop during surveillance, complete ILND should be performed on that side only (GR B), and SNB or limited ILND with frozen section analysis on the contralateral side can be considered (GR C). Endoscopic ILND requires additional study to determine the complication and long-term survival rates (GR C). Pelvic lymph node dissection is recommended if >/=2 proven inguinal metastases, grade 3 tumor in the lymph nodes, extranodal extension (ENE), or large (2-4 cm) inguinal nodes are present, or if the femoral (Cloquet's) node is involved (GR C). Performing ILND before pelvic lymph node dissection is preferable, because pelvic lymph node dissection can be avoided in patients with minimal inguinal metastases, thus avoiding the greater risk of chronic lymphedema (GR B). In patients with numerous or large inguinal metastases, CT or MRI should be performed. If grossly enlarged iliac nodes are present, neoadjuvant chemotherapy should be given and the response assessed before proceeding with pelvic lymph node dissection (GR C). Antibiotic treatment should be started before surgery to minimize the risk of wound infection (GR C). Perioperative low-dose heparin to prevent thromboembolic complications can be used, although it might increase lymph leakage (GR C). The skin incision for ILND should be parallel to the inguinal ligament, and sufficient subcutaneous tissue should be preserved to minimize the risk of skin flap necrosis (GR B). Sartorius muscle transposition to cover the femoral vessels can be used in radical ILND (GR C). Closed suction drainage can be used after ILND to prevent fluid accumulation and wound breakdown (GR B). Early mobilization after ILND is recommended, unless a myocutaneous flap has been used (GR B). Elastic stockings or sequential compression devices are advisable to minimize the risk of lymphedema and thromboembolism (GR C). Radiotherapy to the inguinal areas is not recommended in patients without cytologically or histologically proven metastases nor in those with micrometastases, but it can be considered for bulky metastases as neoadjuvant therapy to surgery (GR B). Adjuvant radiotherapy after complete ILND can be considered in patients with multiple or large inguinal metastases or ENE (GR C). Adjuvant chemotherapy after complete ILND can be used instead of radiotherapy in patients with >/=2 inguinal metastases, large nodes, ENE, or pelvic metastases (GR C). Follow-up should be individualized according to the histopathologic features and the management chosen for the primary tumor and inguinal nodes (GR B).
Copyright (c) 2010 Elsevier Inc. All rights reserved.
Hughes B, Leijte J, Shabbir M, Watkin N, Horenblas S.
Non-invasive and minimally invasive staging of regional lymph nodes in penile cancer.
World J Urol. 2009 Apr;27(2):197-203. doi: 10.1007/s00345-008-0288-6. Epub 2008 Jul 2.
Abstract/Text
INTRODUCTION: The management of the regional lymph nodes in penile cancer patients, particularly when these lymph nodes are impalpable, remains controversial. Prophylactic bilateral inguinal lymphadenectomy is associated with high morbidity and is often unnecessary. However, there is no non-invasive or minimally invasive staging technique that can determine the lymph node status of penile cancer patients with 100% accuracy.
METHODS: We reviewed the current literature to examine the role of non-invasive and minimally invasive techniques for staging regional lymph nodes in penile cancer with particular reference to clinically impalpable disease.
RESULTS: Cross-sectional imaging (un-enhanced CT and MRI) modalities have a role in the assessment of patients with palpable inguinal basins and in locating distant metastases, but are unreliable in staging impalpable regional lymph nodes. The spatial resolution of lymphotropic nanoparticle enhanced MRI (LNMRI) and positron emission tomography (PET)/CT are limited to several millimetres and so these modalities cannot reliably detect micro-metastases (<2 mm). Ultrasound (US) and fine-needle aspiration cytology (FNAC) are indicated in staging palpable inguinal basins but are unreliable in isolation in the assessment of impalpable lymph nodes. They are, however, useful as an adjunct to dynamic sentinel lymph node biopsy (DSLNB) in lowering false-negative rates.
CONCLUSIONS: While we await staging modalities that can equal the results of DSLNB with fewer disadvantages, histological staging in the form of DSLNB remains the best minimally invasive staging modality we can offer at risk patients presenting with clinically node negative groins.
Saisorn I, Lawrentschuk N, Leewansangtong S, Bolton DM.
Fine-needle aspiration cytology predicts inguinal lymph node metastasis without antibiotic pretreatment in penile carcinoma.
BJU Int. 2006 Jun;97(6):1225-8. doi: 10.1111/j.1464-410X.2006.06159.x.
Abstract/Text
OBJECTIVE: To evaluate the accuracy of fine-needle aspiration (FNA) cytology of palpable inguinal lymphadenopathy before definitive management of the primary tumour, in predicting inguinal lymph node (LN) metastasis in men with primary squamous cell carcinoma (SCC) of the penis.
PATIENTS AND METHODS: Sixteen men with primary SCC of the penis and palpable inguinal lymphadenopathy (unilateral or bilateral) were treated by primary resection and bilateral inguinal LN dissection. FNA cytology was analysed for 25 palpable inguinal LNs at the time of penile biopsy. The sensitivity, specificity and accuracy of FNA cytology was compared with the histological findings from surgical LN clearance.
RESULTS: The 25 FNAs were without complication and without evidence of implantation of metastasis in the needle tracts; 14 FNA samples were positive for metastasis, 10 were negative, and one was inconclusive. From the histological assessment of the surgical inguinal LN specimens, FNA cytology had a sensitivity of 93%, and specificity of 91% in predicting metastatic disease.
CONCLUSION: FNA cytology of palpable inguinal lymphadenopathy before surgery for the primary tumour has a high sensitivity and specificity for metastatic penile cancer. This procedure permits early inguinal lymphadenectomy where appropriate without need for prolonged initial antibiotic treatment.
Schlenker B, Scher B, Tiling R, Siegert S, Hungerhuber E, Gratzke C, Tilki D, Reich O, Schneede P, Bartenstein P, Stief CG, Seitz M.
Detection of inguinal lymph node involvement in penile squamous cell carcinoma by 18F-fluorodeoxyglucose PET/CT: a prospective single-center study.
Urol Oncol. 2012 Jan-Feb;30(1):55-9. doi: 10.1016/j.urolonc.2009.10.012. Epub 2009 Dec 21.
Abstract/Text
BACKGROUND: The extent of lymph node involvement is the most relevant prognostic factor in patients with penile cancer.
OBJECTIVE: To prospectively analyze the diagnostic accuracy of 18F-FDG-PET/CT-scan in the assessment of inguinal lymph node involvement in patients with invasive penile carcinoma.
PATIENTS AND METHODS: Thirty-five patients with invasive penile carcinoma were staged prospectively by 18F-FDG-PET/CT-scan, and blindly evaluated by 2 nuclear medicine physicians. In total, lymph node involvement was assessed in 70 inguinal groins. Reference standard was either histology or clinical follow-up with a minimum of 31 months (mean: 48.4 months; range: 31-68 months).
RESULTS: 18-FDG-PET/CT showed a sensitivity of 88.2% and a specificity of 98.1%. Positive predictive value (PPV) was 93.8%, while negative predictive value (NPV) was 96.3%. In two groins, metastasis of 5 and 7 mm were missed by PET/CT scan.
CONCLUSION: 18F-FDG-PET/CT is a promising staging tool in assessing the inguinal lymph node involvement of patients with penile carcinoma. Integration of PET/CT scanning into preoperative staging algorithms may avoid surgical staging in selected patients.
Copyright © 2012 Elsevier Inc. All rights reserved.
Mueller-Lisse UG, Scher B, Scherr MK, Seitz M.
Functional imaging in penile cancer: PET/computed tomography, MRI, and sentinel lymph node biopsy.
Curr Opin Urol. 2008 Jan;18(1):105-10. doi: 10.1097/MOU.0b013e3282f151fd.
Abstract/Text
PURPOSE OF REVIEW: The presence and extent of lymph node metastasis and primary tumor are among the most important prognostic factors in penile cancer. While inguinal lymphadenectomy is currently the most accurate means of staging, it is associated with severe morbidity and even mortality. Recent literature was reviewed for alternative means of staging.
RECENT FINDINGS: Functional imaging modalities distinguish between inguinal lymph nodes with and without metastasis. The false-negative rate of dynamic sentinel lymph node biopsy has recently improved from approximately 20 to 5% in one study. In 13 patients with penile cancer, (18)F-fluorodeoxyglucose-PET/computed tomography was 80% sensitive and 100% specific for lymph node metastasis, but missed micro-metastasis. In seven patients with penile cancer, MRI with lymphotrophic nanoparticles was 100% sensitive and 97% specific for lymph node metastasis.
SUMMARY: Combined PET/computed tomography and sentinel lymph node biopsy may help to detect both inguinal micrometastasis and pelvic and abdominal metastasis. Since MRI is highly accurate for staging of both primary penile cancer and its lymph node metastasis, however, it may turn out to be a powerful tool for a one-stop modality in the staging of penile cancer.
Scher B, Seitz M, Albinger W, Reiser M, Schlenker B, Stief C, Mueller-Lisse U, Dresel S.
Value of PET and PET/CT in the diagnostics of prostate and penile cancer.
Recent Results Cancer Res. 2008;170:159-79. doi: 10.1007/978-3-540-31203-1_13.
Abstract/Text
Scher B, Seitz M, Reiser M, Hungerhuber E, Hahn K, Tiling R, Herzog P, Reiser M, Schneede P, Dresel S.
18F-FDG PET/CT for staging of penile cancer.
J Nucl Med. 2005 Sep;46(9):1460-5.
Abstract/Text
UNLABELLED: The value of PET or PET/CT with (18)F-FDG for the staging of penile cancer has yet to be determined. The objective of this study was to investigate the pattern of (18)F-FDG uptake in the primary malignancy and its metastases and to determine the diagnostic value of (18)F-FDG PET/CT in the staging and restaging of penile cancer.
METHODS: Thirteen patients (mean +/- SD age, 64 +/- 14.0 y) with suspected penile cancer or suspected recurrent disease were examined with a Gemini PET/CT system (200 MBq of (18)F-FDG). The reference standard was based on histopathologic findings obtained at biopsy or during surgery.
RESULTS: Both the primary tumor and regional lymph node metastases exhibited a pattern of (18)F-FDG uptake typical for malignancy. Sensitivity in the detection of primary lesions was 75% (6/8), and specificity was 75% (3/4). On a per-patient basis, sensitivity in the detection of lymph node metastases was 80% (4/5), and specificity was 100% (8/8). On a nodal-group basis, PET/CT showed a sensitivity of 89% (8/9) in the detection of metastases in the superficial inguinal lymph node basins and a sensitivity of 100% (7/7) in the deep inguinal and obturator lymph node basins. The mean +/- SD maximum standardized uptake value for the 8 primary lesions was 5.3 +/- 3.7, and that for the 16 lymph node metastases was 4.6 +/- 2.0.
CONCLUSION: According to our results, the main indication for (18)F-FDG PET in the primary staging or follow-up of penile cancer patients may be the prognostically crucial search for lymph node metastases. With the use of a PET/CT unit, the additional information provided by CT may be especially useful for planning surgery. Implementing (18)F-FDG PET and PET/CT in future staging algorithms may lead to a more precise and stage-appropriate therapeutic strategy. Furthermore, invasive procedures with a high morbidity rate, such as general bilateral lymphadenectomy, may be avoided.
Tabatabaei S, Harisinghani M, McDougal WS.
Regional lymph node staging using lymphotropic nanoparticle enhanced magnetic resonance imaging with ferumoxtran-10 in patients with penile cancer.
J Urol. 2005 Sep;174(3):923-7; discussion 927. doi: 10.1097/01.ju.0000170234.14519.19.
Abstract/Text
PURPOSE: We evaluated lymphotropic nanoparticle enhanced magnetic resonance imaging (LNMRI) with ferumoxtran-10 in determining the presence of regional lymph node metastases in patients with penile cancer.
MATERIALS AND METHODS: Seven patients with squamous cell carcinoma of the penis underwent LNMRI. All patients subsequently underwent groin dissection and the nodal images were correlated with histology.
RESULTS: We found that LNMRI had sensitivity, specificity, and positive and negative predictive values of 100%, 97%, 81.2% and 100%, respectively, in predicting the presence of regional lymph node metastases in patients with penile cancer.
CONCLUSIONS: Lymph node scanning using LNMRI accurately predicts the pathological status of regional lymph nodes in patients with cancer of the penis. LNMRI may accurately triage patients for regional lymphadenectomy.
Zhang S, Li W, Liang F.
Clinical value of fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in penile cancer.
Oncotarget. 2016 Jul 26;7(30):48600-48606. doi: 10.18632/oncotarget.9375.
Abstract/Text
PurposeThis study investigated the value of Fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) imaging in the management of patients with advanced penile cancer.Patients and MethodsBetween January 2009 and August 2012, 48 patients with penile cancer at our center underwent FDG-PET/CT after CT (n=39) or magnetic resonance imaging (MRI; n=9). The accuracy of FDG-PET/CT was assessed with both organ-based and patient-based analyses. FDG-PET/CT findings were validated by either biopsy or serial CT/MRI. Clinician questionnaires performed before and after FDG-PET/CT evaluated whether the scan results affected management.ResultsOne hundred fifteen individual lesions were evaluable in 42 patients for the organ-based analysis. Overall sensitivity was 85% and specificity was 86%. In the patient-based analysis, overall sensitivity and specificity were 82% and 93%, respectively. Pre- and post-PET surveys showed that FDG-PET/CT detected more malignant diseases than CT/MRI in 33% patients. Planned treatments were changed in 57% patients after FDG-PET/CT scan.ConclusionFDG-PET/CT has good sensitivity and specificity in the detection of metastatic penile cancer. It provides more diagnostic information to enhance clinical management than CT/MRI.
Solsona E, Algaba F, Horenblas S, Pizzocaro G, Windahl T; European Association of Urology.
EAU Guidelines on Penile Cancer.
Eur Urol. 2004 Jul;46(1):1-8. doi: 10.1016/j.eururo.2004.03.007.
Abstract/Text
OBJECTIVES: The European Association of Urology (EAU) consensus group on penile cancer has prepared these guidelines to help urologists assess the scientific evidence for the management of penile cancer and to incorporate recommendations into their clinical practice.
METHOD: References used in the text have been assessed according to the level of scientific evidence involved and guideline recommendations have also been evaluated according to the Agency for Health Care Policy and Research [Clinical Practice Guidelines Development: Methodological Perspectives. Washington DC: US Department of Health and Human Services, Public Health Service; 1992, pp. 115-127].
RESULTS: The diagnosis, treatment and follow-up of patients suspected of, or diagnosed with, penile cancer is listed as an easy reference text.
CONCLUSION: A guidelines text is presented which aims at aiding medical specialists in determining the most optimal diagnostic and treatment options for this pathology.
Copyright 2004 Elsevier B.V.
Pagliaro LC, Williams DL, Daliani D, Williams MB, Osai W, Kincaid M, Wen S, Thall PF, Pettaway CA.
Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase II study.
J Clin Oncol. 2010 Aug 20;28(24):3851-7. doi: 10.1200/JCO.2010.29.5477. Epub 2010 Jul 12.
Abstract/Text
PURPOSE: Men with penile squamous cell carcinoma and regional lymph node involvement have a low probability of survival with lymphadenectomy alone. A multimodal approach to treatment is desirable for such patients. We performed a phase II study of neoadjuvant chemotherapy with the objective of determining the response rate, time to progression (TTP), and overall survival (OS) among patients with bulky adenopathy.
PATIENTS AND METHODS: Eligible patients had stage N2 or N3 (stage III or stage IV) penile cancer without distant metastases. Neoadjuvant treatment (four courses every 3-4 weeks) consisted of paclitaxel 175 mg/m(2) administered over 3 hours on day 1; ifosfamide 1,200 mg/m(2) on days 1 to 3; and cisplatin 25 mg/m(2) on days 1 to 3. Clinical and pathologic responses were assessed, and patient groups were compared for TTP and OS.
RESULTS: Thirty men received chemotherapy of whom 15 (50.0%) had an objective response and 22 (73.3%) subsequently underwent surgery. Three patients had no remaining tumor on histopathology. Nine patients (30.0%) remained alive and free of recurrence (median follow-up, 34 months; range, 14-59 months), and two patients died of other causes without recurrence. Improved TTP and OS were significantly associated with a response to chemotherapy (P < .001 and P = .001, respectively), absence of bilateral residual tumor (P = .002 and P = .017, respectively), and absence of extranodal extension (P = .001 and P = .004, respectively) or skin involvement (P = .009 and P = .012, respectively).
CONCLUSION: The neoadjuvant regimen of paclitaxel, ifosfamide, and cisplatin induced clinically meaningful responses in patients with bulky regional lymph node metastases from penile cancer.
Guidelines on penile cancer (European Association of Urology 2018) https://uroweb.org/guidelines/penile-cancer.
Zargar-Shoshtari K, Djajadiningrat R, Sharma P, Catanzaro M, Zhu Y, Nicolai N, Horenblas S, Spiess PE.
Establishing Criteria for Bilateral Pelvic Lymph Node Dissection in the Management of Penile Cancer: Lessons Learned from an International Multicenter Collaboration.
J Urol. 2015 Sep;194(3):696-701. doi: 10.1016/j.juro.2015.03.090. Epub 2015 Mar 20.
Abstract/Text
PURPOSE: Penile carcinoma with bilateral pelvic lymph node metastasis is a relatively rare condition with poor outcomes. There are little data available on optimal strategies for staging and treating this group of patients. We assessed factors predicting bilateral pelvic lymph node metastasis in patients with penile cancer and confirmed inguinal lymph node metastasis.
MATERIALS AND METHODS: Multi-institutional data from a total of 4 centers in Europe, the People's Republic of China and the United States were retrospectively analyzed. Patients with penile carcinoma and inguinal lymph node metastasis who underwent bilateral pelvic lymphadenectomy were included in analysis. The Kaplan-Meier and log rank tests were used to express overall survival. Logistic regression was used for multivariate analysis of factors predicting bilateral pelvic lymph node metastasis. Cox regression was done in the multivariable analysis of overall survival.
RESULTS: We identified 140 patients with penile carcinoma who had confirmed pelvic lymph node metastasis. Of the patients 83 had bilateral inguinal lymph node metastasis and 64 underwent bilateral pelvic lymphadenectomy. Bilateral pelvic lymph node metastasis was observed in 16 patients (25%). The ROC of the total number of inguinal lymph node metastases and the detection of bilateral pelvic lymph node metastasis had an AUC of 0.76 (p = 0.002) with 95% sensitivity for the cutoff point of 4 inguinal nodes. On logistic regression analysis the detection of 4 or more positive inguinal nodes was the only independent predictor of bilateral pelvic lymph node metastasis (OR 14.0, CI 1.71-115). On Cox regression analysis 4 or more inguinal lymph node metastases, adjuvant chemotherapy, inguinal extraprostatic extension and bilateral procedures were associated with overall survival.
CONCLUSIONS: Patients with bilateral inguinal lymph node metastasis who are treated with unilateral pelvic lymphadenectomy should be considered for bilateral pelvic lymphadenectomy in the presence of 4 or more metastatic inguinal nodes.
Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
Leijte JA, Valdés Olmos RA, Nieweg OE, Horenblas S.
Anatomical mapping of lymphatic drainage in penile carcinoma with SPECT-CT: implications for the extent of inguinal lymph node dissection.
Eur Urol. 2008 Oct;54(4):885-90. doi: 10.1016/j.eururo.2008.04.094. Epub 2008 May 19.
Abstract/Text
BACKGROUND: Knowledge regarding the lymphatic drainage pattern of penile cancer is the basis for the extent of inguinal lymph node dissection for this disease.
OBJECTIVE: To prospectively analyze the lymphatic drainage pattern of penile carcinoma using SPECT-CT and evaluate the implications for the extent of inguinal lymph node dissection.
DESIGN, SETTING, AND PARTICIPANTS: The lymphatic drainage patterns of 50 patients scheduled for dynamic sentinel node biopsy were analyzed using a hybrid SPECT-CT scanner.
MEASUREMENTS: A total of 86 clinically node-negative (cN0) inguinal and pelvic regions was evaluated. The sentinel and higher-tier nodes on SPECT-CT were divided into different zones in the groin and pelvic region. The groin was divided according to Daseler's five zones, four zones obtained by drawing a vertical and horizontal line over the saphenofemoral junction and one zone directly overlying this junction. The nodes in the pelvic region were classified into three zones: the external iliac/obturator zone, the common iliac zone, and the paraaortal zone.
RESULTS AND LIMITATIONS: Lymphatic drainage was visualised in 82 of the 86 cN0 groins (95.3%). A total of 115 sentinel nodes and 182 higher-tier nodes was found. All sentinel nodes were located in superior and central inguinal zones. The higher-tier nodes were located in the groin and pelvic region. No lymphatic drainage was seen to the inferior two regions of the groin. A potential limitation of the study is that the unilateral lymphatic drainage seen in some patients could be normal, but it could also be caused by blockage of lymphatic drainage due to a grossly involved metastatic lymph node. Another possible limitation is that this study relies on the quality and accuracy of lymphoscintigraphy and the subsequent sentinel node procedure.
CONCLUSIONS: All sentinel and higher-tier nodes were located in the superior and central inguinal zones and the pelvic region. No lymphatic drainage to the inferior inguinal zones was seen. This suggests that the extent of inguinal node dissection in cN0 patients could be reduced to removal of the superior and central inguinal zones. This may decrease the extensive morbidity associated with this procedure.
Leijte JA, van der Ploeg IM, Valdés Olmos RA, Nieweg OE, Horenblas S.
Visualization of tumor blockage and rerouting of lymphatic drainage in penile cancer patients by use of SPECT/CT.
J Nucl Med. 2009 Mar;50(3):364-7. doi: 10.2967/jnumed.108.059733. Epub 2009 Feb 17.
Abstract/Text
UNLABELLED: The reliability of sentinel node biopsy is dependent on the accurate visualization and identification of the sentinel node(s). It has been suggested that extensive metastatic involvement of a sentinel node can lead to blocked inflow and rerouting of lymph fluid to a "neo-sentinel node" that may not yet contain tumor cells, causing a false-negative result. However, there is little evidence to support this hypothesis. Recently introduced hybrid SPECT/CT scanners provide both tomographic lymphoscintigraphy and anatomic detail. Such a scanner enabled the present study of the concept of tumor blockage and rerouting of lymphatic drainage in patients with palpable groin metastases.
METHODS: Seventeen patients with unilateral palpable and cytologically proven metastases in the groin underwent bilateral conventional lymphoscintigraphy and SPECT/CT before sentinel node biopsy of the contralateral groin. The pattern of lymphatic drainage in the 17 palpable groin metastases was evaluated for signs of tumor blockage or rerouting.
RESULTS: On the CT images, the palpable node metastases could be identified in all 17 groins. Four of the 17 palpable node metastases (24%) showed uptake of radioactivity on the SPECT/CT images. In 10 groins, rerouting of lymphatic drainage to a neo-sentinel node was seen; one neo-sentinel node was located in the contralateral groin. A complete absence of lymphatic drainage was seen in the remaining 3 groins.
CONCLUSION: The concept of tumor blockage and rerouting was visualized in 76% of the groins with palpable metastases. Precise physical examination and preoperative ultrasound with fine-needle aspiration cytology may identify nodes with considerable tumor invasion at an earlier stage and thereby reduce the incidence of false-negative results.
Protzel C, Alcaraz A, Horenblas S, Pizzocaro G, Zlotta A, Hakenberg OW.
Lymphadenectomy in the surgical management of penile cancer.
Eur Urol. 2009 May;55(5):1075-88. doi: 10.1016/j.eururo.2009.02.021. Epub 2009 Feb 23.
Abstract/Text
CONTEXT: Uncertainty remains about the extent and indications for inguinal lymphadenectomy in penile cancer, a procedure known for relatively high morbidity. Several attempts have been made to develop strategies which can improve the diagnostic quality and reduce the morbidity of the management of inguinal lymph nodes in penile cancer.
OBJECTIVE: To analyse the existing published data on the surgical management of inguinal nodes in penile cancer regarding morbidity and survival.
EVIDENCE ACQUISITION: A Medline search was performed of the English-language literature (1966-September 2008) using the MeSH terms penile carcinoma, lymph node dissection, lymphadenectomy, and complications.
EVIDENCE SYNTHESIS: Lymph node metastases are frequent in penile cancer, even in early pT1G2 stages. Since the results of systemic treatment of advanced penile cancer are disappointing, complete dissection of all involved lymph nodes is highly recommended. The extent of lymph node dissection should be adapted to clinical stage, as this corresponds to metastatic spread. For low-risk patients (pTis, pTa, and pT1G1) without palpable lymph nodes and with good compliance, a surveillance strategy may be chosen. For all other patients without palpable lymph nodes (including intermediate risk pT1G2 disease), a modified bilateral lymphadenectomy is recommended. An alternative to this is a dynamic sentinel lymph node biopsy in specialised centres. All patients with histologically proven lymph node metastases should undergo radical inguinal lymphadenectomy. Pelvic lymph node dissection should be done in all patients with more than two metastatic inguinal lymph nodes. In case of fixed inguinal lymph nodes, neoadjuvant chemotherapy is recommended, followed by node resection.
CONCLUSIONS: Lymphadenectomy is an integral part of the management of penile cancer, since early dissection of involved lymph nodes improves survival.
Cabanas RM.
The concept of the sentinel lymph node.
Recent Results Cancer Res. 2000;157:109-20. doi: 10.1007/978-3-642-57151-0_9.
Abstract/Text
Lymphangiograms performed via direct cannulation of lymphatic ducts demonstrate drainage of the lymph into a specific lymph node center, the so-called SLN. Contrast materials such as lipiodol, injected directly into the tissue (e.g., tongue) can demonstrate the SLN. As the neoplastic cells can be carried through the lymphatic ducts, the SLN is the first filter in the lymphatic pathway, and the SLN is indeed the most likely regional node to harbor metastatic carcinoma. The results of these efforts challenged the surgical community worldwide to recognize the importance of the concept of SLN. This concept needs to be inexpensive and easily applied in daily practice. Recently, brilliant investigators have found that using "blue dye" and or radioactive tracers are a resourceful way in identifying SLN and have applied the benefits in their daily practice. Morton [15] using the "blue dye" and Krag [1] using radioactive tracers are pioneers in the application of these concepts in other malignant diseases. The SLN concept today is feasible to apply in the investigation, diagnosis, staging and treatment of almost all solid tumors in human pathology. Numerous elegant reports have proved the validation of the concept [2, 7-9, 11, 12, 16, 17, 20, 21, 26-28].
Pettaway CA, Pisters LL, Dinney CP, Jularbal F, Swanson DA, von Eschenbach AC, Ayala A.
Sentinel lymph node dissection for penile carcinoma: the M. D. Anderson Cancer Center experience.
J Urol. 1995 Dec;154(6):1999-2003.
Abstract/Text
PURPOSE: We determined whether an extended sentinel lymph node dissection is effective for staging penile squamous carcinoma associated with clinically negative inguinal lymph nodes.
MATERIALS AND METHODS: A retrospective review was done of 20 consecutive patients who underwent extended sentinel lymph node dissection between 1985 and 1994.
RESULTS: Of the patients 14 underwent bilateral extended sentinel lymph node dissection, and 6 underwent ipsilateral extended sentinel lymph node dissection plus contralateral inguinal or ilioinguinal lymphadenectomy. All lymph nodes included in the extended sentinel node dissection were negative for metastases. Five patients had inguinal metastases at a median of 10 months (range 3 to 21) after negative extended sentinel lymph node dissection.
CONCLUSIONS: Although it is a more extensive procedure than sentinel lymph node biopsy, extended sentinel lymph node dissection is still associated with a significant false-negative rate (25%). Thus, its routine use can no longer be recommended.
Shammas FV, Ous S, Fossa SD.
Cisplatin and 5-fluorouracil in advanced cancer of the penis.
J Urol. 1992 Mar;147(3):630-2. doi: 10.1016/s0022-5347(17)37327-5.
Abstract/Text
A total of 8 patients with advanced squamous cell carcinoma of the penis (Jackson stages III and IV) received chemotherapy with 100 mg./m2. cisplatin intravenously on day 1 and a 24-hour infusion of 1,000 mg./m.2 5-fluorouracil on days 1 to 5. Of the patients 2 (25%) achieved a partial response: 1 required a further operation and 1 required surgery with radiotherapy to achieve a complete response. These 2 patients were disease-free at 32+ and 57+ months. Nonresponders had a survival range of 2+ to 28 months after chemotherapy. Nausea and vomiting were the most frequent side effects of chemotherapy. Chemotherapy-related increase in serum creatinine occurred in 3 patients. Two patients had septicemia and 1 complained of tinnitus. Poor tolerability especially in the elderly was the main reason for discontinuing chemotherapy. The combination of cisplatin and 5-fluorouracil may have a role in the management of advanced penile cancer together with surgery and radiotherapy.
Theodore C, Skoneczna I, Bodrogi I, Leahy M, Kerst JM, Collette L, Ven K, Marréaud S, Oliver RDT; EORTC Genito-Urinary Tract Cancer Group.
A phase II multicentre study of irinotecan (CPT 11) in combination with cisplatin (CDDP) in metastatic or locally advanced penile carcinoma (EORTC PROTOCOL 30992).
Ann Oncol. 2008 Jul;19(7):1304-1307. doi: 10.1093/annonc/mdn149. Epub 2008 Apr 15.
Abstract/Text
BACKGROUND: The aim of this study is to determine efficacy and feasibility of the combination regimen irinotecan and cisplatin in patients with cisplatin advanced penile cancer.
PATIENTS AND METHODS: Patients with T3, T4, N1, N2, N3 or M1 cisplatin advanced penile cancer were treated with a combination of irinotecan (60 mg/m(2)) on days 1, 8 and 15 and cisplatin (80 mg/m(2)) administered every 28 days. Patients were treated either in the neo-adjuvant setting for T3 or N1-N2 disease with a maximum of four cycles before surgery or up to eight cycles for T4 or N3 or M1 disease. The study was designed with the aim to exclude a response rate (complete response + partial response) <30% (alpha = 10%, power = 95%).
RESULTS: Twenty-eight patients were included and evaluated for toxicity, and 26 eligible patients were evaluated for response. Toxicity was acceptable with three cases of grade 3 diarrhoea and two cases of grade 4 neutropenic fever. There were eight responses (two complete response and six partial response) (30.8%, 80% confidence interval 18.8% to 45.1%): three patients undergoing histological verification after chemotherapy had no evidence of malignancy.
CONCLUSION: The study fails to demonstrate a response rate significantly >30%. The observation regarding M0 patients suggests to repeat this study in the neo-adjuvant setting.
Giannatempo P., et al. Survival analyses of adjuvant or neoadjuvant combination of a taxane plus cisplatin and 5-fluorouracil (T-PF) in patients with bulky nodal metastases from squamous cell carcinoma of the penis (PSCC): Results of a single high-volume .
Leijte JA, Kirrander P, Antonini N, Windahl T, Horenblas S.
Recurrence patterns of squamous cell carcinoma of the penis: recommendations for follow-up based on a two-centre analysis of 700 patients.
Eur Urol. 2008 Jul;54(1):161-8. doi: 10.1016/j.eururo.2008.04.016. Epub 2008 Apr 15.
Abstract/Text
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.
Kroon BK, Horenblas S, Lont AP, Tanis PJ, Gallee MP, Nieweg OE.
Patients with penile carcinoma benefit from immediate resection of clinically occult lymph node metastases.
J Urol. 2005 Mar;173(3):816-9. doi: 10.1097/01.ju.0000154565.37397.4d.
Abstract/Text
PURPOSE: In this retrospective study we compared the clinical outcome of early vs delayed excision of lymph node metastases in patients with penile squamous cell carcinoma.
MATERIALS AND METHODS: A total of 40 patients with a T2-3 penile carcinoma with lymph node metastases were included in this study. All patients initially presented with bilateral impalpable lymph nodes. In 20 patients (50%) metastases were removed when they became clinically apparent during meticulous followup (median interval 6 months, range 1 to 24). There were 20 patients (50%) who underwent resection of inguinal metastases detected on dynamic sentinel node biopsy before they became palpable. The histopathological characteristics of the tumors and lymph nodes were reevaluated.
RESULTS: The 2 populations were similar in terms of patient age, T-stage, pathological tumor grade, vascular invasion and infiltration depth. Disease specific 3-year survival of patients with positive lymph nodes detected during surveillance was 35% and in those who underwent early resection, 84% (log rank p = 0.0017). In multivariate analysis early resection of occult inguinal metastases detected on dynamic sentinel node biopsy was an independent prognostic factor for disease specific survival (p = 0.006).
CONCLUSIONS: Early resection of lymph node metastases in patients with penile carcinoma improves survival.
Pettaway CA, Pagliaro L, Theodore C, Haas G.
Treatment of visceral, unresectable, or bulky/unresectable regional metastases of penile cancer.
Urology. 2010 Aug;76(2 Suppl 1):S58-65. doi: 10.1016/j.urology.2010.03.082.
Abstract/Text
OBJECTIVES: To review the treatment strategies among patients with Stage IV penile cancer to describe potentially curative or palliative therapy.
METHODS: The International Consultation on Urologic Disease for Penile Cancer subcommittee on the treatment of Stage IV penile cancer reviewed reports related to the topics of advanced penile cancer and metastatic penile cancer alone and combined with chemotherapy, radiotherapy, and inguinal lymphadenectomy. The reports were rated as to their level of evidence using the criteria of the Oxford Centre for evidence-based medicine. Treatment recommendations were made by consensus, with the appropriate grades determined from the level of evidence.
RESULTS: The incidence of Stage IV disease using the current or modified TNM or Jackson descriptions was 0%-14%. Cisplatin-containing regimens were the most active, with patients exhibiting an average response and survival rate of 26% (range 15%-32%) and 5.5 months (range 4.7-7), respectively. Bleomycin-containing regimens were associated with significant pulmonary toxicity. The role of radiotherapy for advanced penile cancer has been largely palliative. Data have suggested that surgical consolidation among patients exhibiting an objective response to chemotherapy could be associated with durable survival.
CONCLUSIONS: Treatment with a cisplatin-containing regimen in Stage IV penile cancer should be considered and might facilitate curative resection. The use of bleomycin was associated with a high level of toxicity and should be discouraged as first-line therapy. Surgical consolidation to achieve disease-free status or palliation should be considered in fit patients with an objective response to systemic chemotherapy. Palliative radiotherapy to inguinal or skeletal metastases might be of benefit.
Copyright (c) 2010 Elsevier Inc. All rights reserved.
Mahesan T, Hegarty PK, Watkin NA.
Advances in Penile-Preserving Surgical Approaches in the Management of Penile Tumors.
Urol Clin North Am. 2016 Nov;43(4):427-434. doi: 10.1016/j.ucl.2016.06.004. Epub 2016 Aug 11.
Abstract/Text
Penile-preserving surgery offers a revolutionary alternative to more traditional radical surgery. It offers better sexual, functional, and psychological results and evidence suggests it achieves this without sacrificing oncological outcomes. We examined the evolving nature of such surgeries, addressing controversies such as safe margins and survival outcomes and discussing more conventional techniques, including laser. At our UK center, we treat a high volume of penile cancer and here, based on such experience, we describe our glans resurfacing, glansectomy, and partial penectomy techniques; their application by disease stage; and the limitations of such surgeries.
Copyright © 2016 Elsevier Inc. All rights reserved.
Philippou P, Shabbir M, Malone P, Nigam R, Muneer A, Ralph DJ, Minhas S.
Conservative surgery for squamous cell carcinoma of the penis: resection margins and long-term oncological control.
J Urol. 2012 Sep;188(3):803-8. doi: 10.1016/j.juro.2012.05.012. Epub 2012 Jul 19.
Abstract/Text
PURPOSE: We assessed the oncological outcome of penile conserving surgery and identified parameters predicting local recurrence, including resection margins.
MATERIALS AND METHODS: A total of 179 patients with invasive penile cancer treated with organ sparing surgery at a tertiary center between 2002 and 2010 fulfilled our study criteria. Demographic, histopathological, management and followup data were recorded in a prospective database. Local, regional and distant recurrence rates, time to recurrence and survival rates were calculated. Survival analysis was performed by the Kaplan-Meier method. Multivariate analysis was used to identify predictors of local recurrence.
RESULTS: Mean followup was 42.8 months (range 4 to 107). Local, regional and distant metastatic recurrence developed in 16 (8.9%), 19 (10.6%) and 9 patients (5.0%) at a mean of 26.1, 26.8 and 11.7 months, respectively. The 5-year disease specific survival rate after recurrence was 54.7% (95% CI 46.1-63.3). For patients with isolated local recurrence the 5-year disease specific survival rate was 91.7% compared to 38.4% for those with regional recurrence. The overall 5-year local recurrence-free rate was 86.3% (95% CI 82.6-90.4). Tumor grade (p = 0.003), stage (p = 0.021) and lymphovascular invasion (p = 0.014) were identified as predictors of local recurrence on multivariate analysis.
CONCLUSIONS: Penile conserving surgery is oncologically safe and a surgical excision margin of less than 5 mm is adequate. Higher local recurrence rates are associated with lymphovascular invasion, and higher tumor stage and grade. Local recurrence has no negative impact on long-term survival.
Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
Ornellas AA, Kinchin EW, Nóbrega BL, Wisnescky A, Koifman N, Quirino R.
Surgical treatment of invasive squamous cell carcinoma of the penis: Brazilian National Cancer Institute long-term experience.
J Surg Oncol. 2008 May 1;97(6):487-95. doi: 10.1002/jso.20980.
Abstract/Text
BACKGROUND AND OBJECTIVES: We reviewed our long-term experience with surgical treatment of patients with penile carcinoma.
METHODS: From 1960 to 2006, 688 patients with penile carcinoma underwent surgical treatment at our Institute. Several forms of surgical treatment were compared and follow-up data analyzed.
RESULTS: Stage stratification demonstrated a better survival rate for patients with stages T1N0 and T1N1,T2N0-1. Patients with well differentiated carcinoma had a higher survival rate than those with moderately and poorly differentiated carcinoma (P < 0.0001 and P = 0.006). Risk stratification showed a better survival rate for patients in the low-risk group (T1G1,T1G2) (P = 0.013 and P < 0.00001). Patients in the intermediate group (T2G1,T2G2,T3G1,T3G2) presented a higher survival rate than patients in the high-risk group (T1-3G3,T4G1-3) (P < 0.00001). Patients who underwent immediate lymphadenectomy had a better survival rate than those who underwent delayed lymphadenectomy (P = 0.002).
CONCLUSIONS: Stage and tumor grade affected the prognosis of the disease. The presence and the extent of metastasis to the inguinal region were the most important prognostic factors for survival in our patients. Immediate lymphadenectomy is indicated in all patients. Since recurrences were noted within 8, 10, and 25 years after primary treatment, a frequent and lasting follow-up is essential for all patients.
(c) 2008 Wiley-Liss, Inc.
Agrawal A, Pai D, Ananthakrishnan N, Smile SR, Ratnakar C.
The histological extent of the local spread of carcinoma of the penis and its therapeutic implications.
BJU Int. 2000 Feb;85(3):299-301. doi: 10.1046/j.1464-410x.2000.00413.x.
Abstract/Text
OBJECTIVE: To explore the possibility of reducing the margin of clearance at surgery for carcinoma of the penis without causing an increase in the incidence of local tumour recurrence, so that the functional and cosmetic compromise associated with penectomy might be minimized.
PATIENTS AND METHODS: Sixty-four patients underwent partial or total penectomy based on the extent of tumour. The specimens were evaluated histologically for grade and for proximal microscopic extensions beyond the grossly visible tumour margin, by examining serial proximal 5 mm sections. The histological grade of the lesion was correlated with its clinical site, morphology and proximal microscopic spread. Differences were assessed using the chi-squared test.
RESULTS: Of 64 tumours, 31% were grade 1, 50% grade 2 and the remaining 19% grade 3. Higher grade lesions were more likely to involve the penile shaft. The maximum proximal histological extent was 5 mm for grades 1 and 2, and 10 mm for grade 3 tumours; there was no discontinuous spread.
CONCLUSIONS: Histological grading is mandatory in the management of carcinoma of the penis. A 10-mm clearance is adequate for grade 1 and 2 lesions, and 15 mm for grade 3 tumours. This approach would qualify more patients for partial rather than total amputation; the residual length of the penis would then be cosmetically and functionally more acceptable.
