Accuracy of Sentinel Lymph Node Biopsy for Inguinal

Lymph Node Staging of Penile Squamous Cell Carcinoma:

Systematic Review and Meta-Analysis of the Literature

Ramin Sadeghi,* Hassan Gholami, Seyed Rasoul Zakavi,Vahid Reza Dabbagh Kakhki, Kamyar Tavakkoli Tabasi and Simon HorenblasFrom the Nuclear Medicine Research Center (RS, SRZ, VRDK) and Department of Urology (KTT), Mashhad University of Medical Sciences,and Faculty of Medicine, Imam Reza Hospital, and Evidence Based Medicine Committee (RS, HG), Mashhad University of Medical Sciences,Mashhad, Iran, and Department of Urology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam,The Netherlands (SH)

Purpose: Sentinel lymph node biopsy is emerging as a promising method foringuinal lymph node staging of penile squamous cell carcinoma. In the currentsystematic review we evaluated the accuracy of sentinel lymph node biopsy foringuinal lymph node staging of penile squamous cell carcinoma and studiedpossible influential factors.Materials and Methods: MEDLINE®, Scopus®, ISI®, Ovid SP®, Springer, Science-Direct® and Google™ Scholar were searched by the key words “(penile OR penis)AND sentinel”. No date or language limitation was imposed on the search andmeeting abstracts were not excluded from analysis. A random effects model wasused for statistical pooling.Results: A total of 17 studies suitable for meta-analysis were detected. Threearticles had 2 different subgroups of patients and each subgroup was consideredas a separate study. Overall 18 studies (including the subgroups) were used fordetection rate meta-analysis and 19 for sensitivity meta-analysis. The pooleddetection rate was 88.3% (95% CI 81.9–92.6). Pooled detection rate of 90.1% (95%CI 83.6–94.1) was calculated for the studies using blue dye and radiotracer. Thepooled sensitivity was 88% (95% CI 83–92). The highest pooled sensitivity (92%[95% CI 86–96]) was in the studies using radiotracer and blue dye, and recruitingonly cN0 cases.Conclusions: Sentinel lymph node mapping in penile squamous cell carcinoma isa method with a high detection rate and sensitivity. Using radiotracer and bluedye for sentinel lymph node mapping and including only cN0 disease ensures thehighest detection rate and sensitivity.

Key Words: meta-analysis; penile neoplasms; sentinel lymph node biopsy;

Abbreviations

and Acronyms

FNA � fine needle aspiration

SCC � squamous cell carcinoma

SLN � sentinel lymph node

Submitted for publication March 9, 2011.Supported by the Vice Chancellery of Re-

search of Mashhad University of Medical Sci-ences.

Nothing to disclose.Supplementary material for this article can be

obtained at http://www.mums.ac.ir/shares/nmrc/nmrc/Tables.pdf.

* Correspondence: Nuclear Medicine ResearchCenter, Mashhad University of Medical Sciences,Faculty of Medicine, Imam Reza Hospital, Mashhad,Iran (telephone: �98(511)8022729; FAX: �98(511)8599359; e-mail: sadeghir@mums.ac.ir).

Editor’s Note: This article is the

second of 5 published in this is-

sue for which category 1 CME

credits can be earned. Instruc-

tions for obtaining credits are

given with the questions on

pages 364 and 365.

carcinoma, squamous cell; review

SENTINEL lymph node biopsy is a fairlynew technique in medical practice andis becoming the standard of care forregional lymph node staging of manysolid tumors. This technique is basedon the hypothesis of orderly distribu-tion of malignant cells in the lymphatic

system. It proposes the first lymph

0022-5347/12/1871-0025/0THE JOURNAL OF UROLOGY®

© 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RES

node(s) in the lymphatic drainage of atumor (called SLN) are representativeof the regional lymph node basin(s).1

SLN biopsy is actually the preferredmethod of lymph node staging in breastcancer2 and melanoma.3 This field isalso rapidly extending into other uro-

logical malignancies.4

Vol. 187, 25-31, January 2012Printed in U.S.A.

EARCH, INC. DOI:10.1016/j.juro.2011.09.058www.jurology.com 25

META-ANALYSIS OF SENTINEL NODE BIOPSY FOR PENILE CANCER26

It is worth mentioning that the SLN concept wasapplied to penile cancer for the first time by Ca-banas.5 Since then several groups have reported theaccuracy of SLN biopsy in penile cancer as an alter-native to inguinal lymph node dissection and thisprocedure was included in the 2009 European Asso-ciation of Urology guidelines on penile cancer.6

Inguinal lymph node dissection is used in pa-tients with penile cancer for 2 reasons. 1) Staginghas strong prognostic implications in penile cancer.Node-free patients have excellent survival whilethose with lymph node involvement have a signifi-cantly worse prognosis.7 Although most patientspresenting with penile carcinoma are clinically nodenegative, approximately 20% to 25% have occult re-gional lymph node metastasis, which indicates thesame grave prognosis.8 2) Compared to surgical re-moval when metastases become clinically palpable,regional lymph node dissection improves survivalconsiderably.8–10

However, regional lymph node dissection in pe-nile cancer results in significant morbidity and, asmentioned, is not necessary in approximately 75% to80% of patients.10 The main advantage of SLN bi-opsy in penile cancer is to decrease this morbiditywithout compromising the survival benefit. In 2009results of the largest study on sentinel node biopsyof penile cancer were published.11 Several other re-search groups also reported their experience in thisfield, and systematic review and meta-analysis isuseful, especially given the scarcity of this malig-nancy as well as the small sample size of manypublished studies. Therefore, we performed a com-prehensive search of the literature to evaluate thesensitivity and detection rate of SLN biopsy in in-guinal lymph node staging of penile squamous cellcarcinoma using the meta-analysis of the includedstudies.

MATERIALS AND METHODS

Search Strategy, Selection

Criteria and Data AbstractionSeveral databases were comprehensively searched for rel-evant articles including MEDLINE, Scopus, ISI, OVIDSP, Springer, ScienceDirect and Google Scholar (lastsearch December 2010). The search terms (free text notMeSH [Medical Subject Headings] terms) were “(penileOR penis) AND sentinel”. No date or language limitationwas imposed on the search and meeting abstracts werealso not excluded. Only studies performed on SCC of thepenis were included in the study. The reference lists of theretrieved studies were hand searched for possible missingrelevant articles. For more complete data we contacted thecorresponding authors when necessary.

Studies were included for sensitivity evaluation pro-vided they 1) used inguinal lymph node dissection for all

patients or followup of those SLN negative as the gold

standard, 2) recruited at least 5 patients, 3) reported thenumber of groins with involved inguinal lymph nodes(identified by inguinal lymph node dissection or inguinalrecurrence during followup) as well as the number offalse-negative groins, and 4) used modern techniques ofSLN mapping (blue dyes and/or radiotracers).

Studies were included for detection rate evaluation pro-vided they 1) recruited at least 5 patients, 2) had data onthe total number of groins and number of groins withdetected sentinel nodes during surgery, and 3) used mod-ern techniques of SLN mapping (blue dyes and/or radio-tracers).

Two of the authors reviewed the retrieved articles in-dependently. The third author opinion was used in case ofany controversy. Possible duplicate studies were discussedand the most recent reports were included in the meta-analysis.

Not all studies that were included had the highestquality. The quality of the included studies was evaluatedusing the Oxford Centre for Evidence Based Medicinechecklist for diagnostic studies.12 This checklist has sev-eral sections outlining the best possible quality for each.The best method for patient recruitment would be pro-spective consecutive inclusion (or random inclusion). Thebest reference standard is radical inguinal lymph nodedissection for all patients regardless of SLN biopsy re-sults. Alternatively, followup of the patients with negativeSLN biopsy results would also be acceptable. Followupand/or pathological evaluation of lymph nodes should bedone blindly regarding the SLN biopsy results. The bestspectrum of the patients would be all cN0 (including thosewith palpable inguinal lymph nodes with negative FNAresults). Data abstraction was done by 2 authors indepen-dently, and data on authors, publication year, method,patient characteristics, detection and false-negative rateswere recorded.

Statistical AnalysisConsidering the different methods used in the includedstudies, we applied a random effects model (Der-Simonianand Laird method13) for the meta-analysis of the propor-tions without any transformation. The random effectsmodel is a statistical method in which the between studyvariability is accounted for. This method is used especiallyin pooling data across studies which are different in termsof design, included patients etc. The Cochrane Q test wasused for heterogeneity evaluation and the significancelevel was set at p �0.05. The I2 index was also calculatedto quantify the extent of heterogeneity.14 The I2 indexshows the amount of variability that is caused by realheterogeneity and is not spurious.

Funnel plots, Egger’s regression intercept,15 and Du-val-Tweedie’s trim and fill16 method were used for publi-cation bias evaluation. The Funnel plot is the plot of thestandard errors of the included studies on the y-axis andthe effect size on the x-axis. Asymmetry of this plot may bedue to publication bias. Egger’s regression intercept is themathematical counterpart of this visual assessment. Sta-tistically significant results of this test indicate a largeasymmetry in the funnel plot. Duval-Tweedie’s trim andfill method uses an iterative method to omit the smallest

studies from the funnel plot until a symmetrical plot

META-ANALYSIS OF SENTINEL NODE BIOPSY FOR PENILE CANCER 27

results. The new measured effect size by this methodshows the impact of possible publication bias.

For statistical analyses Comprehensive Meta-Analysis(version 2) and Meta-DiSc (version 1.4) were used.17 Majorindices of interest were detection rate and sensitivity.Specificity was not used because it is always 100% instudies of sentinel node biopsy accuracy. Subgroup anal-ysis or sensitivity analysis was used to evaluate the lym-phatic mapping method (blue dye and/or tracer), numberof recruited patients (more than 30 or less than 30), stud-

Figure 1. Process of study inclusion in meta-analysis

Study name Year of publication Stat

Event Lower rate limit

525.0059.01002la te namudkA

Detection

156.0597.05002la te anodreP986.0028.06002la te dvohnnerB

Gonzaga-Silva et al 2007 0.537 0.405348.0798.07002la te etjieL317.0679.07002la te sseipS116.0267.07002la te sseipS

Hernandez-Toris et al 2007 0944 0693Hernandez Toris et al 2007 0.944 0.693335.0009.08002la te ibuR817.0059.08002la te ibuR146.0318.08002la te arierreF097.0319.08002la te snyeH809.0969.08002la te nesneJ039.0859.09002la te etjieL139.0269.09002la te etjieL557.0688.09002la te kayaniV326.0067.00102la te artsmeL776.0318.00102la te rentsroF nov

0.883 0.819Summary effect

Figure 2. Forrest plot of studies inclu

ies including clinically node positive disease and the effectof inguinal sonography in all patients before SLN biopsy.

RESULTS

Figure 1 shows the diagram of the study searchstrategy. A total of 5,590 studies seemed to be po-tentially relevant in the first search. However, 5,376studies were excluded (irrelevant subjects) by screeningthe titles and/or abstracts. The number of evaluatedcitations was high due to the inclusion of GoogleScholar in the search strategy, which has a lowspecificity in any search. Full text of the remaining214 studies was evaluated in more depth. In addi-tion, 197 studies were excluded as narrative reviewarticles, duplicates, letters to editors, recruiting lessthan 5 patients, or using methods other than bluedye and/or radiotracers. The remaining 17 articleswere included in the meta-analysis.11,18–33 Of theincluded studies 3 were meeting abstracts.19,31,33

Three articles had 2 different subgroups of pa-tients and each subgroup was considered as a sepa-rate study.11,25,27 Overall 18 studies (including thesubgroups mentioned) met the criteria of detectionrate meta-analysis and 19 met the criteria of sensi-tivity meta-analysis.

Detection Rate

Figure 2 shows the forest plot of the detection ratemeta-analysis from the 18 included studies. The

r each study

er it Z-Value p-Value

240.0920.2799

Detection rate and 95% CI

000.0436.3098000.0911.4409

664 0.544 0.587000.0407.8439900.0495.2999100.0112.3768

992 2753 0006992 2.753 0.006730.0480.2689400.0078.2399100.0832.3319000.0494.4769000.0378.5099000.0844.11579

79 9 10.021 0.000000.0423.4259000.0184.3858000.0569.3998

926 7.786 0.000

-1.00 -0.50 0.000.00 0.50 1.00

istics fo

Upplim

.0

.0

.00..0.0.0

00..0.0.0.0.0.0.0.0.0.0

0.

ded for detection rate pooling

META-ANALYSIS OF SENTINEL NODE BIOPSY FOR PENILE CANCER28

pooled detection rate was 88.3% (95% CI 81.9–92.6).The Cochrane Q value was 105.942 (p �0.0001) andI2 � 83.95%. Figure 3 shows the funnel plot of the

0.0

Funnel Plot of Standard Error by Logit event ratedetection rate

0.5

r

1.0

Stan

dard

Err

or

1.5

2 0

S

-4 -3 -2 -1 0 1 2 3 4

2.0

Logit event ratedetection rate

Figure 3. Funnel plot of studies included for detection rate pool-ing. Note asymmetry of plot which indicates possible importantpublication bias.

Figure 4. Forrest plot of studies inc

detection rate meta-analysis. Egger’s regression in-tercept was 1.21 (p � 0.20124), which indicates afairly symmetrical funnel plot. The adjusted pooleddetection rate after trimming 6 studies (using Du-val-Tweedie’s trim and fill method) was 82.6% (95%CI 73.5–89). This shows that the best estimate ofunbiased effect size is 5.7% lower than the calcu-lated pooled detection rate. The subgroup analysis ofstudies using blue dye and radiotracers for SLNmapping vs those using only 1 method demonstratedpooled detection rates of 90.1% (95% CI 83.6–94.1)vs 85.1% (95% CI 71.3–92.9), respectively.

Sensitivity

Figure 4 shows the forest plot of the sensitivitymeta-analysis from 19 included studies. The pooledsensitivity was 88% (95% CI 83–92). The CochraneQ value was 31.04 (p � 0.0285) and I2 � 42%. Figure 5shows the funnel plot of the included studies for thesensitivity meta-analysis. The Egger’s regression in-tercept was -0.65 (p � 0.1743), which indicates asymmetrical funnel plot. Duval-Tweedie’s trim andfill method was unable to find any study for trim-ming and the adjusted pooled sensitivity was the

luded for sensitivity pooling

META-ANALYSIS OF SENTINEL NODE BIOPSY FOR PENILE CANCER 29

same as before trimming. Therefore, the best esti-mate of unbiased effect size was not different fromthe calculated pooled sensitivity. Subgroup analysisof the SLN mapping method (blue dye and/or radio-tracer) showed a pooled sensitivity of 60% (95% CI15–95) for blue dye alone, 84% (95% CI 72–92) forradiotracer alone and 90% (95% CI 85–95) for stud-ies using both methods.

Excluding 2 studies in which patients with palpa-ble inguinal node regardless of FNA results wererecruited21,29 resulted in a pooled sensitivity of 90%(95% CI 85–94). Considering the SLN mappingmethod, the pooled sensitivity of studies using ra-diotracer and blue dye for SLN mapping and recruit-ing only patients with cN0 disease was 92% (95% CI86–96). Only 2 studies (2 subgroups of the study byLeijte et al11) used inguinal ultrasonography to de-tect suspicious inguinal lymph nodes and performedFNA if necessary. Pooling the sensitivity of these 2studies revealed a 93% sensitivity (95% CI 85–97).

DISCUSSION

The condition of regional lymph nodes is an impor-tant factor affecting the survival of patients withseveral solid tumors, and penile cancer is no excep-tion in this regard.34,35 An important aspect of pe-nile SCC in contrast to many other solid tumors isthe therapeutic benefit of regional lymph node dis-section in this tumor.7 Immediate resection of occultlymph node metastases improves the survival ofpatients with penile cancer considerably comparedto the delayed resection of palpable inguinal lymphnode involvement.8–10 The relative ineffectiveness ofchemotherapy and radiotherapy compared to the

0.0

Funnel Plot of Standard Error by Logit event ratesensitivity

0.5

r

1.0

Stan

dard

Err

or

1.5

2 0

S

-4 -3 -2 -1 0 1 2 3 4

2.0

Logit event ratesensitivity

Figure 5. Funnel plot of studies included for sensitivity pooling.Note asymmetry of plot is less than that of funnel plot of detec-tion rate.

surgical approach is also important in this regard.36

However, prophylactic inguinal lymph node dissec-tion for penile cancer is not required in those with-out regional lymph node involvement, which consti-tutes almost 75% to 80% of cN0 disease.7,10 Inaddition to the significant morbidity of inguinallymph node dissection,37 this is the main impetusbehind the search of urologists for an alternative toinguinal lymph node dissection.

Several alternatives to inguinal lymph node dissec-tion are currently under study and several nomogramsfor predicting inguinal lymph node involvement arecurrently in use.6,38 However, their performance is notperfect enough and needs to be externally vali-dated.39,40 Several imaging techniques such as com-puterized tomography or conventional magnetic reso-nance imaging can also be used for inguinal lymphnode staging. However, their accuracy is also subopti-mal, especially for cN0 disease.41–43 Although noveltechniques such as positron emission tomography/computerized tomography44 and nanoparticle enhancedmagnetic resonance imaging45 seem to be promisingin this regard, their sensitivity for detecting micro-metastases is actually low.43,45

SLN biopsy is another technique which is prom-ising for inguinal lymph node staging and our cur-rent meta-analysis determines the accuracy of thisapproach. The overall detection rate (per groin, notper patient) of 88.3% (95% CI 81.9–92.6) was fairlyhigh. However, the I2 value was 83.95%, meaningthat most of the observed variance between the de-tection rates of the included studies was real andcould be attributed to the between study differences(and not only to sampling errors of the includedstudies). To address this high level of heterogeneitywe performed a subgroup analysis of the SLN map-ping method. The pooled detection rate of the stud-ies using radiotracer and blue dye was 5% more thanthe studies using only 1 of the methods (90.1% [95%CI 83.6–94.1] vs 85.1% [95% CI 71.3–92.9]). Thisshows the importance of methodology in SLN map-ping and this issue should be considered carefullywhile performing SLN biopsy for penile cancer.

The sensitivity of SLN mapping for inguinallymph node staging is the more important issue inour meta-analysis. The pooled sensitivity of the in-cluded studies was 88% (95% CI 83–92), which wasalso fairly high. However, the heterogeneity of theincluded studies (I2 � 42%) warranted evaluation inmore depth.

The spectrum of the patients recruited in thestudies seemed to be important. Excluding 2 studieswhich recruited patients with palpable inguinallymph nodes (without performing FNA) increasedthe pooled sensitivity to 90% (95% CI 85–94).21,29

This was also supported by Leijte et al, who reported

rerouting of lymphatic drainage in 76% of the groins

META-ANALYSIS OF SENTINEL NODE BIOPSY FOR PENILE CANCER30

with palpable lymph nodes with resultant false-neg-ative SLN biopsy.46

Another aspect of the included studies was themethod of SLN mapping. The highest sensitivity wasin the studies using blue dye and radiotracer (90%[95% CI 85–95]) and the lowest sensitivity was inthose using only blue dye for SLN mapping (60% [95%CI 15–95]). Excluding the studies that recruited pa-tients with palpable inguinal lymph nodes as well asthose using only blue dye or radiotracers increased thesensitivity to 92% (95% CI 86–96), which is highenough to be considered safe and is comparable torecommendations for patients with breast cancer.47

A method for decreasing the false-negative rateproposed by Leijte et al is performing inguinal ul-trasonography to detect suspicious inguinal nodesrequiring FNA for better evaluation.24 They re-ported a decreased false-negative rate by thismethod. We also performed sensitivity analysis andthe pooled sensitivity of the 2 studies with inguinalultrasonography in all patients was 93%, which is inagreement with the study by Leijte et al.

The sensitivity of SLN mapping, with provensafety and efficacy in many cancers such as breast,2

prostate,4 melanoma48 etc, is not different fromwhat we found for penile cancer in our meta-analy-sis. In fact, SLN mapping is included in the 2009European Association of Urology guidelines on pe-nile cancer (level of evidence 2b).6

Our study did have some limitations. Penile SCCis one of the rare carcinomas in humans, whichresults in a low sample size in many studies evalu-ating this malignancy. This is especially true whenit comes to studies on SLN biopsy for penile SCC.For statistical reasons we excluded studies with asample size of less than 5 patients (10 groins). Infact, pooling all relevant studies improves overallprecision, and the fairly narrow confidence intervalsof our meta-analysis results are also in agreementwith this idea. Another related limitation is the pos-sibility of a learning curve for the performance ofSLN biopsy in penile cancer. This is a major concernsince this malignancy is rare and the urologistwould not have the chance to pass the learning curvesimilar to surgeons treating breast cancer. Leijte etal addressed this issue (by evaluating the first 30cases for false-negative rate and complications) andthey could not demonstrate the presence of this phe-nomenon.11 However, as they mentioned this could

be due to pure chance and should be evaluated more

REFERENCES

reporting. Curr Diagn Pathol 2007; 13: 106. breast cancer. J Surg Res

in future studies. Actually only 3 of all includedstudies in the current meta-analysis recruited morethan 30 patients.11,24,30 Subgroup analysis usingonly these 3 studies demonstrated a pooled detectionrate and sensitivity of 94.9% (95% CI 90.9–97.2) and90.9% (95% CI 84.7–95.2), respectively, which arehigher than overall pooled indices, and show theeffect of a high volume of patients on the success ofthe sentinel node procedure.

In introducing SLN biopsy a main obstacle couldbe the necessity of multidisciplinary teams, espe-cially considering that the geographic areas with thehighest rates of penile cancer have limited resourcesand would have more limitations in this regard.28 Aparticular aspect of many studies evaluating SLNmapping accuracy in penile SCC is the reliance onfollowup to determine the false-negative rate. Mostinguinal recurrence in penile SCC occurs within ap-proximately 2 years after surgery.11,24 However, notall studies included in the current meta-analysisfollowed all patients that long, which is a majorlimitation of our meta-analysis.

An important issue in all meta-analyses is publi-cation bias. We included meeting abstracts as wellas nonEnglish studies in the meta-analysis, whichcan decrease publication bias. Although Egger’stests were not statistically significant in sensitivityor detection rate pooling, this test has low power andvisual assessment of the funnel plots, and showssome asymmetry, especially for the detection ratepooling. This was also supported by Duval-Tweedie’strim and fill method, which showed an almost 6%decrease in the pooled detection rate after trimmingwhile no study could be trimmed for sensitivity pool-ing. Thus, another limitation of our study is thatpublication bias, if present, affects the results of thecurrent meta-analysis (especially for detection rate,not sensitivity).

CONCLUSIONS

The current meta-analysis showed that SLN map-ping in penile SCC is a method with a high detectionrate and sensitivity. However, the technical aspectsof this procedure are important. Using radiotracerand blue dye for SLN mapping and including onlycN0 disease ensures the highest detection rate andsensitivity. However, the possible presence of alearning curve as well as limited resources in manyareas with a high incidence of this malignancy could

reduce the usefulness of this procedure.

1. Purdie CA: Sentinel lymph node biopsy: review of theliterature and guidelines for pathological handling and

2. Miltenburg DM, Miller C, Karamlou TB et al:Meta-analysis of sentinel lymph node biopsy in

1999; 84: 138.

3. Warycha MA, Zakrzewski J, Ni Q et al: Meta-analysis of sentinel lymph node positivity in thin

melanoma (�/�1 mm). Cancer 2009; 115: 869.

META-ANALYSIS OF SENTINEL NODE BIOPSY FOR PENILE CANCER 31

4. Sadeghi R, Tabasi KT, Bazaz SM et al: Sentinelnode mapping in the prostate cancer. Meta-anal-ysis. Nuklearmedizin 2011; 50: 107.

5. Cabanas RM: An approach for the treatment ofpenile carcinoma. Cancer 1977; 39: 456.

6. Pizzocaro G, Algaba F, Horenblas S et al: EAUpenile cancer guidelines 2009. Eur Urol 2010; 57:1002.

7. Wespes E: The management of regional lymphnodes in patients with penile carcinoma andreliability of sentinel node biopsy. Eur Urol 2007;52: 15.

8. Kroon BK, Horenblas S, Lont AP et al: Patientswith penile carcinoma benefit from immediateresection of clinically occult lymph node metas-tases. J Urol 2005; 173: 816.

9. McDougal WS, Kirchner FK Jr, Edwards RH et al:Treatment of carcinoma of the penis: the case forprimary lymphadenectomy. J Urol 1986; 136: 38.

10. Protzel C, Alcaraz A, Horenblas S et al: Lymph-adenectomy in the surgical management of pe-nile cancer. Eur Urol 2009; 55: 1075.

11. Leijte JA, Hughes B, Graafland NM et al: Two-center evaluation of dynamic sentinel node bi-opsy for squamous cell carcinoma of the penis.J Clin Oncol 2009; 27: 3325.

12. Oxford Centre for Evidence-Based Medicine: Lev-els of Evidence. Available at http://www.cebm.net/index.aspx?o�1025. Accessed October 5,2010.

13. DerSimonian R and Laird N: Meta-analysis inclinical trials. Control Clin Trials 1986; 7: 177.

14. Higgins JP and Thompson SG: Quantifying heter-ogeneity in a meta-analysis. Stat Med 2002; 21:1539.

15. Egger M, Davey Smith G, Schneider M et al: Biasin meta-analysis detected by a simple, graphicaltest. BMJ 1997; 315: 629.

16. Duval S and Tweedie R: A nonparametric ‘trimand fill’ method of accounting for publication biasin meta-analysis. J Am Stat Assoc 2000; 95: 89.

17. Zamora J, Abraira V, Muriel A et al: Meta-DiSc:a software for meta-analysis of test accuracydata. BMC Med Res Methodol 2006; 6: 31.

18. Akduman B, Fleshner NE, Ehrlich L et al: Earlyexperience in intermediate-risk penile cancerwith sentinel node identification using thegamma probe. Urology 2001; 58: 65.

19. Lemstra C, de Jong I, Leliveld A et al: Evaluationof lymphoscintigraphy and sentinel node biopsyin patients with penile carcinoma. J Nucl Med2010; 51: 2004.

20. Perdona S, Autorino R, De Sio M et al: Dynamicsentinel node biopsy in clinically node-negativepenile cancer versus radical inguinal lymphade-nectomy: a comparative study. Urology 2005; 66:

1282.

21. Hungerhuber E, Schlenker B, Frimberger D et al:Lymphoscintigraphy in penile cancer: limitedvalue of sentinel node biopsy in patients withclinically suspicious lymph nodes. World J Urol2006; 24: 319.

22. Brennhovd B, Johnsrud K, Berner A et al: Sentinelnode procedure in low-stage/low-grade penilecarcinomas. Scand J Urol Nephrol 2006; 40: 204.

23. Gonzaga-Silva LF, Tavares JM, Freitas FC et al:The isolated gamma probe technique for sentinelnode penile carcinoma detection is unreliable. IntBraz J Urol 2007; 33: 58.

24. Leijte JA, Kroon BK, Valdes Olmos RA et al:Reliability and safety of current dynamic sentinelnode biopsy for penile carcinoma. Eur Urol 2007;52: 170.

25. Spiess PE, Izawa JI, Bassett R et al: Preoperativelymphoscintigraphy and dynamic sentinel nodebiopsy for staging penile cancer: results withpathological correlation. J Urol 2007; 177: 2157.

26. Hernandez-Toris N, Quintero-Becerra J, Gallegos-Hernandez JF et al: Lymphatic mapping and sen-tinel node biopsy in penis cancer. Feasibilitystudy and preliminary report. Cir Cir 2007; 75: 87.

27. Rubi S, Vidal-Sicar S, Ortega M et al: Localizationof sentinel node in squamous cell carcinoma ofthe penis. Initial experience. Rev Esp Med Nucl2008; 27: 3.

28. Ferreira U, Ribeiro MA, Reis LO et al: Sentinellymph node biopsy in penile cancer: a compara-tive study using modified inguinal dissection. IntBraz J Urol 2008; 34: 725.

29. Heyns CF and Theron PD: Evaluation of dynamicsentinel lymph node biopsy in patients with squa-mous cell carcinoma of the penis and palpableinguinal nodes. BJU Int 2008; 102: 305.

30. Jensen JB, Jensen KM, Ulhoi BP et al: Sentinellymph-node biopsy in patients with squamouscell carcinoma of the penis. BJU Int 2009; 103:1199.

31. Pytel A, Damasdi M, Frick A et al: Surgical man-agement of low and medium risk penile cancers,with isotope guided sentinel lymph node biopsytechnique. Urology 2009; 74: S63.

32. Vinayak RS and Rajen TA: Sentinel node biopsy incarcinoma penis using methylene blue dye tech-nique. Urol Ann 2009; 1: 18.

33. von Forstner C, Naumann M, Henze E: Improve-ment of the surgical procedure for penile carci-noma by sentinel lymph node scintigraphy withSPECT and SPECT/CT. Eur J Nucl Med Mol Im-aging 2010; 37: S270.

34. Zini L, Cloutier V, Isbarn H et al: A simple andaccurate model for prediction of cancer-specificmortality in patients treated with surgery forprimary penile squamous cell carcinoma. Clin

Cancer Res 2009; 15: 1013.

35. Dechev J, Banchev A and Georgieva-Mateva N:Overall survival in carcinoma of the penis–a sin-gle institution study. J BUON 2007; 12: 377.

36. Lubke WL and Thompson IM: The case for ingui-nal lymph node dissection in the treatment ofT2-T4, N0 penile cancer. Semin Urol 1993; 11: 80.

37. Tobias-Machado M, Tavares A, Ornellas AA et al:Video endoscopic inguinal lymphadenectomy: anew minimally invasive procedure for radicalmanagement of inguinal nodes in patients withpenile squamous cell carcinoma. J Urol 2007;177: 953.

38. Ficarra V, Zattoni F, Artibani W et al: Nomogrampredictive of pathological inguinal lymph nodeinvolvement in patients with squamous cell car-cinoma of the penis. J Urol 2006; 175: 1700.

39. Ficarra V, Novara G, Boscolo-Berto R et al: Howaccurate are present risk group assignment toolsin penile cancer? World J Urol 2009; 27: 155.

40. Novara G, Artibani W, Cunico SC et al: Howaccurately do Solsona and European Associationof Urology risk groups predict for risk of lymphnode metastases in patients with squamous cellcarcinoma of the penis? Urology 2008; 71: 328.

41. Heyns CF, Fleshner N, Sangar V et al: Manage-ment of the lymph nodes in penile cancer. Urol-ogy 2011; 76: S43.

42. Kochhar R, Taylor B and Sangar V: Imaging inprimary penile cancer: current status and futuredirections. Eur Radiol 2011; 20: 36.

43. Hughes B, Leijte J, Shabbir M et al: Non-invasiveand minimally invasive staging of regional lymphnodes in penile cancer. World J Urol 2009; 27:197.

44. Graafland NM, Leijte JA, Valdes Olmos RA et al:Scanning with 18F-FDG-PET/CT for detection ofpelvic nodal involvement in inguinal node-posi-tive penile carcinoma. Eur Urol 2009; 56: 339.

45. Mueller-Lisse UG, Scher B, Scherr MK et al:Functional imaging in penile cancer: PET/com-puted tomography, MRI, and sentinel lymph nodebiopsy. Curr Opin Urol 2008; 18: 105.

46. Leijte JA, van der Ploeg IM, Valdes Olmos RA etal: Visualization of tumor blockage and reroutingof lymphatic drainage in penile cancer patients byuse of SPECT/CT. J Nucl Med 2009; 50: 364.

47. MacNeill F, Mansel R, Horgan K et al: NEWSTART: the United Kingdom sentinel lymph bi-opsy training programme. A model of how multi-professional training can achieve competent na-tional performance whilst maintaining patientsafety. Breast Cancer Res Treat 2007; 106: S233.

48. Mattsson J, Bergkvist L, Abdiu A et al: Sentinelnode biopsy in malignant melanoma: Swedishexperiences 1997-2005. Acta Oncol 2008; 47:

1519.