- Email: [email protected]
Penile Cancer: Contemporary Lymph Node Management
Author's Accepted Manuscript Penile Cancer: Contemporary Lymph Node Management Jonathan S. O'Brien , Marlon Perera , Todd Manning , Mike Bozin , Sonja Cabarkapa , Emily Chen , Nathan Lawrentschuk
PII: DOI: Reference:
S0022-5347(17)30085-X 10.1016/j.juro.2017.01.059 JURO 14333
To appear in:
The Journal of Urology
Please cite this article as: O'Brien JS, Perera M, Manning T, Bozin M, Cabarkapa S, Chen E, Lawrentschuk N, Penile Cancer: Contemporary Lymph Node Management, The Journal of Urology® (2017), doi: 10.1016/j.juro.2017.01.059. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.
Embargo Policy All article content is under embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date. Questions regarding embargo should be directed to [email protected].
ACCEPTED MANUSCRIPT
Penile Cancer: Contemporary Lymph Node Management
RI PT
Jonathan S O'Brien, B. Arts Sci, MSc, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia
Marlon Perera, MBBS, BMedSci, Austin Health, University of Melbourne, Heidelberg, VIC, Australia
Todd Manning, MBBS, Austin Health, University of Melbourne, Heidelberg, VIC, Australia
Mike Bozin, MBBS, B.AppSci, Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne,
SC
VIC, Australia
M AN U
Sonja Cabarkapa, BPharm (Hons), Austin Health, University of Melbourne, Heidelberg, VIC, Australia
Emily Chen, MBBS, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia
AC C
EP
TE D
Nathan Lawrentschuk, PhD, University of Melbourne and Ludwig Institute for Cancer Research
1
ACCEPTED MANUSCRIPT
Abstract Purpose: In penile cancer, optimal diagnostics and management of metastatic lymph nodes is not clear. Advances in minimally invasive staging, including dynamic sentinel lymph node biopsy (DSLNB) have widened the diagnostic repertoire of the urologist. We aimed to provide an
RI PT
objective update in the recent trends in the management of penile SCC and inguinal and pelvic lymph node metastases.
Methods: We systematically reviewed several medical databases including: Web of Science (including MEDLINE), EMBASE and Cochrane databases according to PRISMA guidelines.
SC
The search terms used were "penile cancer", "lymph node", "sentinel node", "minimally
invasive", "surgery" and "outcomes", alone and in combination. Articles pertaining to the
M AN U
management of lymph nodes in penile cancer were review, including: original research, reviews and clinical guidelines published between 1980 and 2016.
Results: Accurate and minimally invasive lymph-node staging is of utmost importance in the surgical management of penile SCC. In clinically node negative patients, a growing body of evidence supports in the use of sentinel lymph node biopsies. DSLNB exposes the patient to minimal risk and results in superior sensitivity and specificity profiles when compared to
TE D
alternate nodal staging techniques. In the presence of locoregional disease, improvements in inguinal or pelvic lymphadenectomy have reduced morbidity and improved oncological outcomes. A multimodal approach of chemotherapy and surgery has demonstrated a survival benefit for patients with advanced disease.
EP
Conclusions: Recent developments in lymph node management have occurred in penile cancer, such as minimally invasive LN diagnosis and intervention strategies. These advances have been
AC C
met with a degree of controversy in contemporary literature. Current data suggests that DSLNB provides excellent sensitivity and specificity in detecting lymph node metastases. More robust long-term data from multicenter patient cohorts is required to determine the optimal management of lymph nodes in penile cancer.
2
ACCEPTED MANUSCRIPT
INTRODUCTION Primary cancer of the penis is a rare disease, accounting for less than 0.1% of all malignancies in men living in the developed world1. Greater than 95% of penile cancers are caused by squamous cell carcinomas (SCC) and commonly occur in men between 50-70 years
RI PT
old2. Social stigma among patients and insufficient clinician expertise have created an
environment where up to 25% of men present with advanced disease at time of diagnosis3. Accordingly, many patients with penile cancer present with metastatic disease. Metastatic
progression follows a predictable and stepwise pattern of invasion from the primary tumour to
SC
inguinal lymph basin before spreading to pelvic nodes and systemic dissemination4.
Traditionally, surgical intervention with radical inguinal lymph node dissection (ILND) was the
M AN U
standard of care for node positive penile cancer. Despite being potentially curative in half of patients this procedure it is associated with a considerable impact on patients’ physical and psychological wellbeing.
Due to the potential for significant morbidity of nodal dissection, identification of suitable surgical candidates is critical. Over the last decade, significant changes have occurred in penile cancer management as a result of an improved understanding of disease mechanisms,
TE D
increased diagnostic sensitivity, refined surgical techniques and novel minimally invasive lymph node dissection techniques. Furthermore, the focus on multidisciplinary sub-specialist management in tertiary centers has reinforced evidence-based care, reduced morbidity and improved oncological outcomes5.
EP
We aim to provide an objective update in the recent trends in the management of penile
AC C
SCC and inguinal and pelvic lymph node metastases.
3
ACCEPTED MANUSCRIPT
MATERIALS AND METHODS A systematic review of the literature was performed according to the PRISMA guidelines6. Medical databases that were searched include: Web of Science (including MEDLINE), EMBASE and Cochrane databases. Articles assessed were limited to English-
RI PT
language peer-reviewed publications that included original research, reviews and clinical
guidelines published between 1980 and 2016. The search terms used were “penile cancer”,
“lymph node”, “sentinel node”, “minimally invasive”, “surgery” and “outcomes”, alone and in combination. Acceptable articles were searched for further relevant references.
SC
In total, 687 studies were identified from an initial search, and 234 studies were excluded for duplicated reporting (Figure 1). All the 454 studies were screened and 279 studies were
M AN U
excluded by screening of titles and abstracts. The remaining 175 original studies were reviewed by careful screening of the full texts, after which 110 were eliminated due to lack of eligible data. Finally, 50 studies were chosen to be included in this review.
ANATOMY OF THE INGUINAL LYMPHATICS
Penile lymphatic drainage is highly variable and can be grossly divided into: the
TE D
superficial and deep systems. The superficial lymphatics drain the prepuce as well as the skin of the shaft to the inguinal nodes. The glans and deep penile structures are drained by separate lymph vessels to the inguinal nodes in the femoral triangle. Both systems traverse the penis to the base in the ‘Buck’s fascia’ before draining through presymphyseal lymphatics, where
EP
crossover can occur before entering the inguinal region4. It must be carefully considered that metastatic spread of penile cancer may infrequently occur to the contralateral groin through
AC C
lymphatic intercommunication. Although the anatomical nomenclature and specific drainage pathways for this area remains controversial, it is widely accepted that penile lymph traverses inguinal nodes before proceeding into ipsilateral iliac nodes7. The distinction between superficial and deep inguinal nodes is clinically insignificant
because they are difficult to appreciate on physical examination or imaging. Although anatomy in this region can be variable, recent lymphoscintigraphic evidence has demonstrated that sentinel lymph nodes for penile drainage are most commonly located in Dassler’s superomedial segment8.
4
ACCEPTED MANUSCRIPT
CLINICAL PRESENTATION AND EXAMINATION Penile cancer is an insidious condition that carries a significant social stigma, which often leads to patients seeking treatment late in the course of the disease. It has been demonstrated that patients wait an average of six months from the onset of symptoms before presenting to their
RI PT
general practitioner due to embarrassment, a fear of the implications of diagnosis and treatment, and the stigma that it may be related to a sexually transmitted condition3. The most common reason for presentation is a lump (47%), ulcer (35%), or erythematous lesion (17%)9. Many men also reported bleeding, discharge, or dysuria from a lesion concealed by a phimotic foreskin as
SC
their initial concern.
At the time of presentation, approximately 20% of patients will have locally advanced
M AN U
disease manifested by clinically palpable groin abnormalities10. Although physical examination of inguinal nodes is important for providing an overall clinical picture of tumour burden in the setting of advanced disease, it is of limited value for accurately guiding management. In a study of 102 patients with penile cancer, Horenblas and colleagues demonstrated that clinically assessing the inguinal region had a sensitivity and specificity 82% and 79%, respectively11. The study further established that physical examination incorrectly staged lymph node disease in 26%
TE D
of cases, with understaging in 10% and overstaging in 16% of cases. The importance of diagnostic imaging in lymph node management is highlighted in a study lead by Hegarty, which proposed that 20% of patients with impalpable inguinal nodes harbored occult metastases12. Of patients with at least one clinically palpable node (cN+), approximately 70% will be the result
EP
of metastatic lymphadenopathy13. In the remaining cases, lymph node enlargement is caused by inflammation, often secondary to infection of the primary tumour. Historically, all patients with
AC C
palpable lymphadenopathy were all treated with prophylactic antibiotics. However, concerns over delayed intervention adversely impacting survival have prompted guidelines to recommend lymphadenectomy in all men diagnosed with lymph node involvement14.
IMAGING
The ability to accurately investigate the presence or absence of inguinal and pelvic metastases in patients with node negative penile cancer remains problematic. Historically, all patients with non-palpable inguinal nodes were managed with observation, regardless of the characteristics of the primary tumour. Surveillance remains the current practice for patients with
5
ACCEPTED MANUSCRIPT
low risk disease such as pTis, pTa, and pT1a. More advanced penile tumours demonstrate a higher risk of metastatic disease and more sophisticated lymph node assessment has been shown to confer a survival benefit15. The discussed staging modalities are summarized in Table 1.
RI PT
Ultrasound (US)
Ultrasonography (US) can be used to identify inguinal lymph node metastases via their distortion of the normal lymphatic architecture. US combined with fine needle aspiration
cytology (FNAC) is indicated for staging in patients with palpable inguinal lymph nodes, but
SC
remains unreliable in patients with non-palpable (cN0) disease. For cN+ patients, FNAC showed a sensitivity of 93% and a specificity of 91%, with a false negative rate of 20-30%16. However,
M AN U
in study of 43 patients with clinically negative groins, US-guided FNAC had a sensitivity and specificity of 39% and 100%, respectively17.
In the context of clinically suspicious lymphadenopathy, guidelines recommend that in order to mitigate the risk of metastatic, spread there should be no unnecessary delay to treatment. US-guided FNAC is a reliable option for confirming the aetiology of clinically palpable lymph nodes in uncertain cases15. If a positive node is detected, radical inguinal lymph node dissection
TE D
(ILND) with excision of the overlying skin and biopsy needle should be performed to prevent seeding malignant cells into healthy tissue18.
EP
Computed Tomography (CT)
The role of conventional CT in staging the inguinal lymph nodes remains limited because of inaccurate detection and paucity of follow up studies. A group led by Horenblas investigated a
AC C
series of 14 patients and found that CT possessed a sensitivity and specificity of 36% and 100%, respectively, but was unable to detect occult metastases in the cN0 groins11. The advent of multislice high-resolution scanners have improved the sensitivity of CT in staging other cancers. However, few follow up studies have been conducted and CT imaging is not recommended as the initial staging modality in patients with cN0 disease. Under the current guidelines, conventional CT is recommended for assessing the inguinal region in obese patients or in those who have had prior inguinal surgery, in whom the physical examination may be unreliable and for determining the extent of disease in patients with clinically palpable nodes15.
6
ACCEPTED MANUSCRIPT
Recently, single photon emission computed tomography–computed tomography (SPECTCT) imaging has been used to investigate clinically node negative penile cancer patients. Nuclear tracer (99m technetium nanocolloid) is injected into the primary penile tumour and allowed to drain into inguinal lymph nodes where single emission photons are detected by a gamma camera.
RI PT
This modality provides functional information by identifying first draining lymph nodes.
Overlaying SPECT with conventional CT, provides 3-dimensional functional anatomy of the inguinal lymphatics (Figure 3). SPECT-CT has been gaining traction as a useful modality to
Positron Emission Tomography (PET)/CT
SC
identify sentinel lymph nodes inform surgical approach.
M AN U
PET is a sophisticated imaging technique capable of detecting sub-nanomolar concentrations of radioactive tracer in vivo. Penile SCCs are known to have a high glucose metabolism, and have a greater uptake of a radiolabelled glucose analog 18F-fluorodeoxyglucose (18F-FDG) than non-transformed surrounding cells19. When PET is overlaid with low dose CT (PET/CT), the combined imaging modality allows clinicians to investigate the functional
TE D
anatomy of the tissues.
Studies involving a small number of patients have demonstrated sensitivity and specificity of up to 90% and 100% respectively20. The data currently available establishes that it is difficult to distinguish metastatic deposits of <10mm and that discerning between
EP
inflammatory and metastatic 18F-FDG uptake will remain an ongoing challenge. The limitations of PET/CT are characterized by its poor diagnostic accuracy in patients presenting with impalpable groins. This was highlighted by a 2012 meta-analysis, which
AC C
established a pooled sensitivity of 96% for cN+ patients and 57% for those with cN0 disease21. A more recent study has established that combining PET/CT with advancements in sentinel node biopsy has achieved a sensitivity of 94% and false negative rate of 6% in a cohort of 68 node native patients22.
As such, the current body evidence does not support a role for PET/CT as a standalone diagnostic procedure in patients with minimal disease. Until larger trials with more reliable data emerge, the greatest role of PET/CT will be restricted to quantifying the burden of disease and assessing treatment response in lymph node–positive patients15.
7
ACCEPTED MANUSCRIPT
Magnetic Resonance Imaging (MRI) Lymphotrophic nanoparticle–enhanced MRI (LNMRI) characterizes the functional anatomy of inguinal lymph nodes and has demonstrated highly accurate staging potential in
RI PT
prostate and bladder malignancies 23. This technique uses a composite of superparamagenetic iron oxide nanoparticles called Ferumoxtran-10. In normal lymph nodes, macrophages will engulf these particles and they will show up homogeneously dark on T2-weighted MRI.
However, uninfected malignant nodes lack phagocytes and the free Ferumoxtran-10 appears bright on MRI. Because the image interpretation involves both nodal function and structure it is
SC
possible to detect metastases <10mm.
In a small series of 7 patients, LNMRI has shown a sensitivity of 100% and a specificity
M AN U
of 97% in detecting occult lymph node metastases24.Furthermore, in four patients metastases less than 1cm in size were detected. Despite the promise of LNMRI its application remains limited because no follow up studies have been performed and Ferumoxtran-10 not has not been approved for diagnostic use. Furthermore, future utility of LNMRI for detecting micrometastatic disease in cN0 groins remains limited by the spatial resolution of MRI technology which has a
TE D
current threshold of 1-2mm25.
MANAGEMENT OF NODE NEGATIVE DISEASE The crux of penile cancer management is balancing the limitations of physical examination and imaging techniques with the curative potential of radical lymphadenectomy. In intermediate to
EP
high risk tumours (pT1b, T2- T4), the presence of lymph node invasion can be upwards of 49%26. Historically, prophylactic inguinal lymph node dissection (ILND) has demonstrated a
AC C
survival advantage in this population of patients and failed detection of micrometastatic disease can have a significant impact on survival. However, contemporary philosophy dictates that subjecting all patients with intermediate risk disease to radical ILND carries an unacceptable risk of complications and long-term morbidity. Sentinel lymph node biopsy is increasingly becoming the diagnostic standard of care because of its ability to identify patients with micrometastatic disease with a high sensitivity with minimal risk to patients. The sentinel node concept is based on the relatively consistent physiology of penile lymphatic drainage that passes first into a sentinel node or group of nodes before disseminating
8
ACCEPTED MANUSCRIPT
into other ilioinguinal lymphatics. A negative sentinel node suggests the absence of further lymphatic spread, and therefore subsequent lymphadenectomy is contraindicated. Over the past decade, dynamic sentinel lymph node biopsy (DSLNB) combined with US FNAC of first draining lymph nodes has emerged as the gold standard for investigating cN0
RI PT
penile cancer27. This minimally invasive technique employs a combination of strategies to locate and assess sentinel lymph nodes. Prior to surgery, a radiolabelled tracer is injected into the
primary tumour, which is taken up by the lymphatic system. Sentinel lymph nodes are identified and marked on the groin using lymphosintographic SPECT-CT. In the operating theatre,
SC
methylene blue dye is injected into the lesion and allowed to drain into the lymphatics. All radiopositive and blue-stained lymph nodes are excised and sent for histopathological examination.
node dissection.
M AN U
Confirmed node positive malignancy is a sufficient indication for an ipsilateral radical lymph
The most comprehensive meta-analysis on the accuracy of DSLNB to date pooled 19 studies to establish sensitivity of 88% and specificity of 90%. The team furthermore concluded that using radiotracer and blue dye for sentinel lymph node mapping confers the highest sensitivity and detection rate28.
TE D
Modifications to DSLNB have been reported to aid intraoperative visualization of sentinel nodes using hybrid radioactive and fluorescent tracer indocyanine green (ICG)-(99m) technetium-nanocolloid. Near-infrared fluorescence penetrates tissue more effectively, generating a greater contrast under excitation light and superior visualization of small lymphatic
EP
channels29. In an investigation that included 183 lymph basins, 95% of sentinel lymph nodes were detected using the hybrid tracer compared 54% being seen with the standard blue dye30.
AC C
Although the applications of this study are currently experimental, it demonstrates future sensitivity improvements are emerging from refining DSLNB techniques. Furthermore, long term data have established the benefit of reduced morbidity and improved fiver year cancerspecific survival, it is emerging that DSLNB has been a breakthrough for patients with cN0 penile cancer.
MANAGEMENT OF NODE POSITIVE DISEASE Lymph node involvement is the single greatest prognostic factor for penile cancer survival31. For patients with metastatic disease in the groin, lymph node dissection remains the
9
ACCEPTED MANUSCRIPT
cornerstone of treatment. In men with disease limited to 1-2 metastatic inguinal nodes, radical ILND is curative in approximately 80% of cases which is reflected in a 5-year disease specific survival (DSS) of 75%32. Current guidelines define pN3 disease as greater than two positive inguinal lymph nodes,
RI PT
or extracapsular spread. It is recommended that ipsilateral pelvic LND be performed in these patients because there is a 56% probability of positive pelvic nodes33. In men with confirmed pelvic nodal metastasis, prognosis was worse than disease limited to the inguinal region with 5year DSS of 33%31. Although these men may have a higher risk for surgical complications,
SC
delaying surgery has been shown to adversely affect survival34.
Historically patients presenting pN2/pN3 disease characterised by bulky, fixed or greater
M AN U
than 4 positive nodes were considered inoperable. However, recent evidence has demonstrated that neoadjuvant chemotherapy shrink tumours to an acceptable size for resection, leading to improved survival35. In a phase II trial involving 30 pN2/pN3 penile cancer patients, Pagliaro and colleagues were able to achieve an objective response in 50% of men using neoadjuvant TIP (paclitaxel/ifosfamide/cisplatin)36. A follow up study of 61 patients lead by Dickstein demonstrated that if the 50% TIP responders underwent consolidative lymphadenectomy a 5-
TE D
year DSS of 50% could be achieved37. Despite the optimistic results, interpretation of these studies is limited by small patient cohorts and the lack of chemotherapeutic regime standardization and dose optimization. Current management guidelines have accommodated these limitations and recommend that radical ILND can deliver robust oncological control and
AC C
Radical ILND
EP
should is offered to patients who respond to neoadjuvant chemotherapy15.
Briefly, an oblique incision is made 2-3cm below and parallel to the inguinal ligament
extending laterally from the anterior superior iliac spine (ASIS) to the pubic tubercle (Figure 2). A vertical ‘lazy-S’ incision made starting approximately 10 cm above and 15cm below the inguinal ligament. Alternatively, an incision can be made a few centimeters below and parallel to the inguinal ligament and curved medially down in the femoral triangle. Superior and inferior skin flaps are raised below the Scarpas fascia and fat and areolar tissue is removed to expose the external oblique, external inguinal ring, spermatic cord, and the inferior border of the inguinal ligament. The long saphenous vein is exposed at the apex of the femoral triangle and divided. In 10
ACCEPTED MANUSCRIPT
patients with minimal metastatic disease, it is beneficial to spare the saphenous vein. The dissection continues through the fascia lata overlaying the sartorius muscle, allowing for excision of the deep inguinal nodes. After the complete femoral triangle dissection, the sartorius muscle is mobilized from the ASIS, transposed over the femoral vessels as a myocutaneous flap and
RI PT
sutured to the inguinal ligament superiorly. Primary closure of the dissection is usually possible with minimal mobilization of the excision margins and a closed suction drain is placed under the subcutaneous tissue minimize dead space and prevent seroma or lymphocele formation38.
Despite the curative potential of ILND, a significant number of penile cancer patients
SC
with high risk disease have not been offered the procedure because of the high incidence of
morbidity following open surgery39. In the most comprehensive assessment to date, a team led
M AN U
by Gopman established that 55% of patients experienced a postoperative complication. Although most of these complaints were minor and resolved without prolonged morbidity, one third met Clavien–Dindo II classification and required intervention. The most common issues reported were infection, lymphocele, skin flap necrosis, lyphpoedema and wound dehiscence40. Refinement to open INLD technique has occurred at a rapid pace since 2008. Plastic surgical consultation for myocutaneous flap coverage and preservation of the dermis, Scarpa
TE D
fascia, and saphenous vein, as well as limiting of the extent of the dissection have been successful at decreasing the overall complication rate of ILND to 25%41. More recently, a phase I study lead by Martin described that robotic assisted video endoscopic inguinal lymphandenectomy achieved an adequate dissection in 18/19 procedures42. Validation and long
EP
term follow up of complications remains critical. However, minimally invasive ILND has demonstrated promise for further reducing the morbidity associated with open surgery while
AC C
delivering comparable oncological outcomes43. In a time where the application of ILND routinely falls below half of all indicated cases, wider adoption of these techniques may make clinicians more comfortable recommending surgery.
Pelvic Lymph Node Dissection (PLND) Pelvic lymph nodes are the final site of locoregional metastasis from the penis before widespread disease becomes a paramount concern. Historically pN3 penile SCC carried a poor prognosis with a 5-year DSS of between 9-42%44. Current guidelines have recognized this risk
11
ACCEPTED MANUSCRIPT
and have recommended that men with two or more metastatic inguinal nodes or extranodal extension should undergo an ipsilateral PLND15,45. Unlike the inguinal lymphatic architecture, pelvic nodes metastases always arise from positive ipsilateral inguinal nodes with no established incidence of contralateral
RI PT
communication46. Unilateral PLND is undertaken either through a lower abdominal midline incision or a unilateral muscle splitting incision and may be undertaken at the same time as ILND or as a separate procedure. For bilateral PLND a midline suprapubic extraperitoneal excision is recommended. The boundaries of PLND are delineated by the iliac bifurcation
SC
proximally, ilioinguinal nerve laterally, and the obturator nerve medially. The procedure involves excision of the obturator, internal iliac, and external iliac nodes as well as any clinically positive
M AN U
nodes in the region. Carefully occluding the lymphatic channels with surgical clips or ligation and the insertion of a suction drain are recommended to manage postoperative lymphocele47. In addition to its potential for diagnostic staging, PLND can improve survival in patients with high-risk disease, but is of limited benefit those with low risk disease. Long-term retrospective data on the outcome of patients who have undergone PLND for penile SCC is hindered by a small patient population with advanced disease. The few reports that have
TE D
examined these patients indicate that PLND carries a considerable complication and morbidity profile to radical ILND. The most comprehensive study to date included 40 patients and recorded an overall complication rate of 45%, with the most common indications lymphocele, lymphedema, infection, wound dehiscence and flap necrosis48.
EP
Although guidelines have reached a consensus indication for PLND, significant debate centers on candidate selection for the procedure, appropriate boundaries of dissection, optimal
AC C
surgical approach, and absolute survival benefit15,45. A recent meta-analysis has weighed in on this debate, by pooling data from 51 men over a mean follow up period of 13 months. The researchers proposed that PLND when combined with recent chemotherapeutic advances may produce a modest survival benefit but statistical significance was not achieved49. Furthermore, recent advances in PLND the field of prostate cancer have established that robotic assisted PLND has the possibility to lower complication rates to 16% while maintaining equivalent oncological control to the open procedure50. These efforts have pushed the boundaries of penile cancer management and prolonged survival in patients who were historically treated with palliation. By virtue of their advanced
12
ACCEPTED MANUSCRIPT
disease, these patients are rare and difficult to study and more data is required to optimise standard of care. It is clear from the data, that these patients will benefit from multidisciplinary management informed by uro-oncologists, medical oncology, palliative care to best align
RI PT
survival benefit with patient expectations.
CONCLUSION
Because of its location, traditional surgical intervention for penile cancer has exacted a devastating impact on the anatomic, functional and psychosocial domains of a patient’s quality
SC
of life. With the advent of new approaches such as DSLNB, minimally invasive LN
management, patients have better oncological and psychosocial outcomes. These advances have
M AN U
been met with a degree of controversy in contemporary literature. Further, more robust long-term
AC C
EP
TE D
data is required to determine the optimal management of lymph nodes in penile cancer.
13
ACCEPTED MANUSCRIPT
REFERENCES Breen KJ, O'Connor KM, Power DG et al: Penile cancer—guideline adherence produces optimum results. Surgeon 2015; 13: 200–206.
2.
Christodoulidou M, Sahdev V, Houssein S et al: Epidemiology of penile cancer. Curr Probl. Cancer 2015; 39: 126–136.
3.
Skeppner E, Andersson S-O, Johansson J-E et al: Initial symptoms and delay in patients with penile carcinoma. Scand. J. Urol. Nephrol. 2012; 46: 319–325.
4.
Dewire D and Lepor H: Anatomic considerations of the penis and its lymphatic drainage. Urol Clin North Am 1992; 19: 211–219.
5.
Veeratterapillay R, Teo L, Asterling S et al: Oncologic outcomes of penile cancer treatment at a UK supraregional center. Urology 2015; 85: 1097–1103.
6.
Moher D, Shamseer L, Clarke M et al: Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Systematic Reviews 2015; 4: 1.
7.
Riveros M, Garcia R and Cabañas R: Lymphadenography of the dorsal lymphatics of the penis. Technique and results. Cancer 1967; 20: 2026–2031.
8.
Leijte JA, Valdés Olmos RA, Nieweg OE et al: Anatomical mapping of lymphatic drainage in penile carcinoma with SPECT-CT: implications for the extent of inguinal lymph node dissection. Eur. Urol. 2008; 54: 885–892.
9.
Hernandez BY, Barnholtz-Sloan J, German RR et al: Burden of invasive squamous cell carcinoma of the penis in the United States, 1998-2003. Cancer 2008; 113: 2883–2891.
10.
Persson B, Sjödin J-G, Holmberg L et al: The National Penile Cancer Register in Sweden 2000-2003. Scand. J. Urol. Nephrol. 2007; 41: 278–282.
11.
Horenblas S, van Tinteren H, Delemarre JF et al: Squamous cell carcinoma of the penis: accuracy of tumor, nodes and metastasis classification system, and role of lymphangiography, computerized tomography scan and fine needle aspiration cytology. J. Urol. 1991; 146: 1279–1283.
SC
M AN U
TE D
EP
AC C
12.
RI PT
1.
Hegarty PK, Kayes O, Freeman A et al: A prospective study of 100 cases of penile cancer managed according to European Association of Urology guidelines. BJU Int. 2006; 98: 526–531.
13.
Lont AP, Kroon BK, Gallee MPW et al: Pelvic lymph node dissection for penile carcinoma: extent of inguinal lymph node involvement as an indicator for pelvic lymph node involvement and survival. J. Urol. 2007; 177: 947–952.
14.
Kroon BK, Horenblas S, Lont AP et al: Patients with penile carcinoma benefit from
14
ACCEPTED MANUSCRIPT
immediate resection of clinically occult lymph node metastases. J. Urol. 2005; 173: 816– 819. Hakenberg OW, Compérat EM, Minhas S et al: EAU guidelines on penile cancer: 2014 update. Eur. Urol. 2015; 67: 142–150.
16.
Saisorn I, Lawrentschuk N, Leewansangtong S et al: Fine‐needle aspiration cytology predicts inguinal lymph node metastasis without antibiotic pretreatment in penile carcinoma. BJU Int. 2006; 97: 1225–1228.
17.
Kroon BK, Horenblas S, Deurloo EE et al: Ultrasonography-guided fine-needle aspiration cytology before sentinel node biopsy in patients with penile carcinoma. BJU Int. 2005; 95: 517–520.
18.
Goldberg BB, Merton DA, Liu J-B et al: Contrast-enhanced sonographic imaging of lymphatic channels and sentinel lymph nodes. J Ultrasound Med 2005; 24: 953–965.
19.
Protzel C and Spiess PE: Molecular research in penile cancer—lessons learned from the past and bright horizons of the future? Int J Mol Sci 2013; 14: 19494–19505.
20.
Schlenker B, Scher B, Tiling R et al: Detection of inguinal lymph node involvement in penile squamous cell carcinoma by 18F-fluorodeoxyglucose PET/CT: A prospective single-center study. Urol Oncol 2012; 30: 55–59.
21.
Sadeghi R, Gholami H, Zakavi SR et al: 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; 37: 436–441.
22.
Jakobsen JK, Alslev L, Ipsen P et al: DaPeCa-3: promising results of sentinel node biopsy combined with (18) F-fluorodeoxyglucose positron emission tomography/computed tomography in clinically lymph node-negative patients with penile cancer - a national study from Denmark. BJU Int. 2016; 118: 102–111.
23.
Thoeny HC, Triantafyllou M, Birkhaeuser FD et al: Combined ultrasmall superparamagnetic particles of iron oxide-enhanced and diffusion-weighted magnetic resonance imaging reliably detect pelvic lymph node metastases in normal-sized nodes of bladder and prostate cancer patients. Eur. Urol. 2009; 55: 761–769.
SC
M AN U
TE D
EP
AC C
24.
RI PT
15.
Tabatabaei S, Harisinghani M and McDougal WS: Regional lymph node staging using lymphotropic nanoparticle enhanced magnetic resonance imaging with ferumoxtran-10 in patients with penile cancer. J. Urol. 2005; 174: 923–928.
25.
Yeung LL and Brandes SB: Dynamic sentinel lymph node biopsy as the new paradigm for the management of penile cancer. Urol. Oncol. 2013; 31: 693–696.
26.
Graafland NM, Lam W, Leijte JAP et al: Prognostic factors for occult inguinal lymph node involvement in penile carcinoma and assessment of the high-risk EAU subgroup: a two-institution analysis of 342 clinically node-negative patients. Eur. Urol. 2010; 58: 742–
15
ACCEPTED MANUSCRIPT
747. Pizzocaro G, Algaba F, Horenblas S et al: EAU penile cancer guidelines 2009. Eur. Urol. 2010; 57: 1002–1012.
28.
Sadeghi R, Gholami H, Zakavi SR et al: Accuracy of sentinel lymph node biopsy for inguinal lymph node staging of penile squamous cell carcinoma: systematic review and meta-analysis of the literature. J. Urol. 2012; 187: 25–31.
29.
Namikawa T, Sato T and Hanazaki K: Recent advances in near-infrared fluorescenceguided imaging surgery using indocyanine green. Surg Today 2015; 45: 1467–1474.
30.
Brouwer OR, van den Berg NS, Mathéron HM et al: A hybrid radioactive and fluorescent tracer for sentinel node biopsy in penile carcinoma as a potential replacement for blue dye. Eur. Urol. 2014; 65: 600–609.
31.
Marconnet L, Rigaud J and Bouchot O: Long-term followup of penile carcinoma with high risk for lymph node invasion treated with inguinal lymphadenectomy. J. Urol. 2010; 183: 2227–2232.
32.
Pandey D, Mahajan V and Kannan RR: Prognostic factors in node‐positive carcinoma of the penis. J Surg Oncol 2006; 93: 133–138.
33.
Lughezzani G, Catanzaro M, Torelli T et al: Relationship between lymph node ratio and cancer-specific survival in a contemporary series of patients with penile cancer and lymph node metastases. BJU Int. 2015; 116: 727–733.
34.
Graafland NM, Lam W, Leijte JAP et al: Prognostic factors for occult inguinal lymph node involvement in penile carcinoma and assessment of the high-risk EAU subgroup: A two-institution analysis of 342 clinically node-negative patients. Eur. Urol. 2010; 58: 742– 747.
35.
Leijte JAP, Kerst JM, Bais E et al: Neoadjuvant Chemotherapy in Advanced Penile Carcinoma. Eur. Urol. 2007; 52: 488–494.
36.
Pagliaro LC, Williams DL, Daliani D et al: Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase II study. J. Clin. Oncol. 2010; 28: 3851–3857.
SC
M AN U
TE D
EP
AC C
37.
RI PT
27.
Dickstein RJ, Munsell MF, Pagliaro LC et al: Prognostic factors influencing survival from regionally advanced squamous cell carcinoma of the penis after preoperative chemotherapy. BJU Int. 2016; 117: 118–125.
38.
Ercole CE, Pow-Sang JM and Spiess PE: Update in the surgical principles and therapeutic outcomes of inguinal lymph node dissection for penile cancer. Urol. Oncol. 2013; 31: 505–516.
39.
Johnson TV, Hsiao W, Delman KA et al: Extensive inguinal lymphadenectomy improves
16
ACCEPTED MANUSCRIPT
overall 5‐year survival in penile cancer patients: results from the Surveillance, Epidemiology, and End Results program. Cancer 2010; 116: 2960–2966. Gopman JM, Djajadiningrat RS, Baumgarten AS et al: Predicting postoperative complications of inguinal lymph node dissection for penile cancer in an international multicentre cohort. BJU Int. 2015; 116: 196–201.
41.
Yao K, Tu H, Li Y-H et al: Modified technique of radical inguinal lymphadenectomy for penile carcinoma: morbidity and outcome. J. Urol. 2010; 184: 546–552.
42.
Matin SF, Cormier JN, Ward JF et al: Phase 1 prospective evaluation of the oncological adequacy of robotic assisted video-endoscopic inguinal lymphadenectomy in patients with penile carcinoma. BJU Int. 2013; 111: 1068–1074.
43.
Kharadjian TB, Matin SF and Pettaway CA: Early experience of robotic-assisted inguinal lymphadenectomy: review of surgical outcomes relative to alternative approaches. Curr Urol Rep 2014; 15: 412.
44.
Graafland NM, van Boven HH, van Werkhoven E et al: Prognostic significance of extranodal extension in patients with pathological node positive penile carcinoma. J. Urol. 2010; 184: 1347–1353.
45.
Clark PE, Spiess PE, Agarwal N et al: Penile cancer: Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2013; 11: 594–615.
46.
Cabanas RM: Anatomy and biopsy of sentinel lymph nodes. Urol Clin North Am 1992; 19: 267–276.
47.
Sharma P, Zargar-Shoshtari K and Spiess PE: Current surgical management of penile cancer. Curr Probl Cancer 2015; 39: 147–157.
48.
Nelson BA, Cookson MS, Smith JA Jr et al: Complications of inguinal and pelvic lymphadenectomy for squamous cell carcinoma of the penis: a contemporary series. J. Urol. 2004; 172: 494–497.
49.
Zargar-Shoshtari K, Sharma P, Djajadiningrat R et al: Extent of pelvic lymph node dissection in penile cancer may impact survival. World J Urol 2016; 34: 353–359.
SC
M AN U
TE D
EP
AC C
50.
RI PT
40.
Ledezma RA, Negron E, Razmaria AA et al: Robotic-assisted pelvic lymph node dissection for prostate cancer: frequency of nodal metastases and oncological outcomes. World J Urol 2015; 33: 1689–1694.
17
ACCEPTED MANUSCRIPT
TABLE 1 – Summary of Accuracy of Lymph Node Staging Modalities Specificity (%) 79
Comments •
Requires experienced clinician
Ultrasound + FNAC16
93
91
•
First line investigation for palpable nodes
CT11
36
100
•
Adjunct for difficult clinical exam
PET/CT20
88
98
•
Cannot discern inflammation from metastasis Difficult to resolve <2mm
• 100
97
•
• •
DSLNB28
90-95
•
First line investigation for cN0 disease
AC C
EP
TE D
88
Experimental and not widely available Few patients studied Resolution limited by power of magnet available
M AN U
MRI24
RI PT
Clinical Examination11
Sensitivity (%) 82
SC
Staging Modality
1
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
FIGURE 1 – PRISMA analysis.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
FIGURE 2 – Mapping out anatomical landmarks for a right radical inguinal dissection. The femoral triangle is demarked in dotted lines and is bordered by the anterior superior iliac spine and pubic tubercle superiorly. The medial boarder of sartorius forms the lateral boarder. The medial line follows the lateral boarder of adductor longus. A vertical ‘lazy-S’ incision demarked by the solid line is made starting approximately 10 cm above and 15cm below the inguinal ligament.
ACCEPTED MANUSCRIPT
Transverse
Coronal
Sagittal
RI PT
A.
M AN U
SC
B.
TE D
C.
AC C
EP
FIGURE 3 - Sentinel lymph node SPECT-CT images demonstrating bilateral positive inguinal lymphadenopathy prior to DSLNB. A. Conventional scintigraphy demonstrating nuclear tracer present in sentinel lymph nodes. B. Conventional CT imaging providing anatomical context for the inguinal region. C. Fused SPECT-CT images establishes 3-dimensional functional anatomy of the penile sentinel lymph nodes. Computer generated tracer bars are used to further increase the utility of SPECT-CT.
ACCEPTED MANUSCRIPT
DEFINITIONS AND ABBREVIATIONS
AC C
EP
TE D
M AN U
SC
RI PT
18-FDG - 18-Fluorodeoxyglucose ASIS - Anterior Superior Iliac Spine CT – Computed Tomography DSLNB - Dynamic Sentinel Lymph Node Biopsy DSS – Disease Specific Survival FNAC – Fine Needle Aspirate Cytology ICG - Indocyanine Green ILND – Inguinal Lymph Node Dissection LN – Lymph Node LNMRI - Lymphotrophic Nanoparticle–enhanced Magnetic Resonance Imaging MRI – Magnetic Resonance Imaging PET - Positron Emission Tomography PLND - Pelvic Lymph Node Dissection SCC – Squamous Cell Carcinoma SPECT – Single-Photon Emission Computed Tomography US – Ultrasound
PII: DOI: Reference:
S0022-5347(17)30085-X 10.1016/j.juro.2017.01.059 JURO 14333
To appear in:
The Journal of Urology
Please cite this article as: O'Brien JS, Perera M, Manning T, Bozin M, Cabarkapa S, Chen E, Lawrentschuk N, Penile Cancer: Contemporary Lymph Node Management, The Journal of Urology® (2017), doi: 10.1016/j.juro.2017.01.059. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.
Embargo Policy All article content is under embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date. Questions regarding embargo should be directed to [email protected].
ACCEPTED MANUSCRIPT
Penile Cancer: Contemporary Lymph Node Management
RI PT
Jonathan S O'Brien, B. Arts Sci, MSc, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia
Marlon Perera, MBBS, BMedSci, Austin Health, University of Melbourne, Heidelberg, VIC, Australia
Todd Manning, MBBS, Austin Health, University of Melbourne, Heidelberg, VIC, Australia
Mike Bozin, MBBS, B.AppSci, Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne,
SC
VIC, Australia
M AN U
Sonja Cabarkapa, BPharm (Hons), Austin Health, University of Melbourne, Heidelberg, VIC, Australia
Emily Chen, MBBS, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia
AC C
EP
TE D
Nathan Lawrentschuk, PhD, University of Melbourne and Ludwig Institute for Cancer Research
1
ACCEPTED MANUSCRIPT
Abstract Purpose: In penile cancer, optimal diagnostics and management of metastatic lymph nodes is not clear. Advances in minimally invasive staging, including dynamic sentinel lymph node biopsy (DSLNB) have widened the diagnostic repertoire of the urologist. We aimed to provide an
RI PT
objective update in the recent trends in the management of penile SCC and inguinal and pelvic lymph node metastases.
Methods: We systematically reviewed several medical databases including: Web of Science (including MEDLINE), EMBASE and Cochrane databases according to PRISMA guidelines.
SC
The search terms used were "penile cancer", "lymph node", "sentinel node", "minimally
invasive", "surgery" and "outcomes", alone and in combination. Articles pertaining to the
M AN U
management of lymph nodes in penile cancer were review, including: original research, reviews and clinical guidelines published between 1980 and 2016.
Results: Accurate and minimally invasive lymph-node staging is of utmost importance in the surgical management of penile SCC. In clinically node negative patients, a growing body of evidence supports in the use of sentinel lymph node biopsies. DSLNB exposes the patient to minimal risk and results in superior sensitivity and specificity profiles when compared to
TE D
alternate nodal staging techniques. In the presence of locoregional disease, improvements in inguinal or pelvic lymphadenectomy have reduced morbidity and improved oncological outcomes. A multimodal approach of chemotherapy and surgery has demonstrated a survival benefit for patients with advanced disease.
EP
Conclusions: Recent developments in lymph node management have occurred in penile cancer, such as minimally invasive LN diagnosis and intervention strategies. These advances have been
AC C
met with a degree of controversy in contemporary literature. Current data suggests that DSLNB provides excellent sensitivity and specificity in detecting lymph node metastases. More robust long-term data from multicenter patient cohorts is required to determine the optimal management of lymph nodes in penile cancer.
2
ACCEPTED MANUSCRIPT
INTRODUCTION Primary cancer of the penis is a rare disease, accounting for less than 0.1% of all malignancies in men living in the developed world1. Greater than 95% of penile cancers are caused by squamous cell carcinomas (SCC) and commonly occur in men between 50-70 years
RI PT
old2. Social stigma among patients and insufficient clinician expertise have created an
environment where up to 25% of men present with advanced disease at time of diagnosis3. Accordingly, many patients with penile cancer present with metastatic disease. Metastatic
progression follows a predictable and stepwise pattern of invasion from the primary tumour to
SC
inguinal lymph basin before spreading to pelvic nodes and systemic dissemination4.
Traditionally, surgical intervention with radical inguinal lymph node dissection (ILND) was the
M AN U
standard of care for node positive penile cancer. Despite being potentially curative in half of patients this procedure it is associated with a considerable impact on patients’ physical and psychological wellbeing.
Due to the potential for significant morbidity of nodal dissection, identification of suitable surgical candidates is critical. Over the last decade, significant changes have occurred in penile cancer management as a result of an improved understanding of disease mechanisms,
TE D
increased diagnostic sensitivity, refined surgical techniques and novel minimally invasive lymph node dissection techniques. Furthermore, the focus on multidisciplinary sub-specialist management in tertiary centers has reinforced evidence-based care, reduced morbidity and improved oncological outcomes5.
EP
We aim to provide an objective update in the recent trends in the management of penile
AC C
SCC and inguinal and pelvic lymph node metastases.
3
ACCEPTED MANUSCRIPT
MATERIALS AND METHODS A systematic review of the literature was performed according to the PRISMA guidelines6. Medical databases that were searched include: Web of Science (including MEDLINE), EMBASE and Cochrane databases. Articles assessed were limited to English-
RI PT
language peer-reviewed publications that included original research, reviews and clinical
guidelines published between 1980 and 2016. The search terms used were “penile cancer”,
“lymph node”, “sentinel node”, “minimally invasive”, “surgery” and “outcomes”, alone and in combination. Acceptable articles were searched for further relevant references.
SC
In total, 687 studies were identified from an initial search, and 234 studies were excluded for duplicated reporting (Figure 1). All the 454 studies were screened and 279 studies were
M AN U
excluded by screening of titles and abstracts. The remaining 175 original studies were reviewed by careful screening of the full texts, after which 110 were eliminated due to lack of eligible data. Finally, 50 studies were chosen to be included in this review.
ANATOMY OF THE INGUINAL LYMPHATICS
Penile lymphatic drainage is highly variable and can be grossly divided into: the
TE D
superficial and deep systems. The superficial lymphatics drain the prepuce as well as the skin of the shaft to the inguinal nodes. The glans and deep penile structures are drained by separate lymph vessels to the inguinal nodes in the femoral triangle. Both systems traverse the penis to the base in the ‘Buck’s fascia’ before draining through presymphyseal lymphatics, where
EP
crossover can occur before entering the inguinal region4. It must be carefully considered that metastatic spread of penile cancer may infrequently occur to the contralateral groin through
AC C
lymphatic intercommunication. Although the anatomical nomenclature and specific drainage pathways for this area remains controversial, it is widely accepted that penile lymph traverses inguinal nodes before proceeding into ipsilateral iliac nodes7. The distinction between superficial and deep inguinal nodes is clinically insignificant
because they are difficult to appreciate on physical examination or imaging. Although anatomy in this region can be variable, recent lymphoscintigraphic evidence has demonstrated that sentinel lymph nodes for penile drainage are most commonly located in Dassler’s superomedial segment8.
4
ACCEPTED MANUSCRIPT
CLINICAL PRESENTATION AND EXAMINATION Penile cancer is an insidious condition that carries a significant social stigma, which often leads to patients seeking treatment late in the course of the disease. It has been demonstrated that patients wait an average of six months from the onset of symptoms before presenting to their
RI PT
general practitioner due to embarrassment, a fear of the implications of diagnosis and treatment, and the stigma that it may be related to a sexually transmitted condition3. The most common reason for presentation is a lump (47%), ulcer (35%), or erythematous lesion (17%)9. Many men also reported bleeding, discharge, or dysuria from a lesion concealed by a phimotic foreskin as
SC
their initial concern.
At the time of presentation, approximately 20% of patients will have locally advanced
M AN U
disease manifested by clinically palpable groin abnormalities10. Although physical examination of inguinal nodes is important for providing an overall clinical picture of tumour burden in the setting of advanced disease, it is of limited value for accurately guiding management. In a study of 102 patients with penile cancer, Horenblas and colleagues demonstrated that clinically assessing the inguinal region had a sensitivity and specificity 82% and 79%, respectively11. The study further established that physical examination incorrectly staged lymph node disease in 26%
TE D
of cases, with understaging in 10% and overstaging in 16% of cases. The importance of diagnostic imaging in lymph node management is highlighted in a study lead by Hegarty, which proposed that 20% of patients with impalpable inguinal nodes harbored occult metastases12. Of patients with at least one clinically palpable node (cN+), approximately 70% will be the result
EP
of metastatic lymphadenopathy13. In the remaining cases, lymph node enlargement is caused by inflammation, often secondary to infection of the primary tumour. Historically, all patients with
AC C
palpable lymphadenopathy were all treated with prophylactic antibiotics. However, concerns over delayed intervention adversely impacting survival have prompted guidelines to recommend lymphadenectomy in all men diagnosed with lymph node involvement14.
IMAGING
The ability to accurately investigate the presence or absence of inguinal and pelvic metastases in patients with node negative penile cancer remains problematic. Historically, all patients with non-palpable inguinal nodes were managed with observation, regardless of the characteristics of the primary tumour. Surveillance remains the current practice for patients with
5
ACCEPTED MANUSCRIPT
low risk disease such as pTis, pTa, and pT1a. More advanced penile tumours demonstrate a higher risk of metastatic disease and more sophisticated lymph node assessment has been shown to confer a survival benefit15. The discussed staging modalities are summarized in Table 1.
RI PT
Ultrasound (US)
Ultrasonography (US) can be used to identify inguinal lymph node metastases via their distortion of the normal lymphatic architecture. US combined with fine needle aspiration
cytology (FNAC) is indicated for staging in patients with palpable inguinal lymph nodes, but
SC
remains unreliable in patients with non-palpable (cN0) disease. For cN+ patients, FNAC showed a sensitivity of 93% and a specificity of 91%, with a false negative rate of 20-30%16. However,
M AN U
in study of 43 patients with clinically negative groins, US-guided FNAC had a sensitivity and specificity of 39% and 100%, respectively17.
In the context of clinically suspicious lymphadenopathy, guidelines recommend that in order to mitigate the risk of metastatic, spread there should be no unnecessary delay to treatment. US-guided FNAC is a reliable option for confirming the aetiology of clinically palpable lymph nodes in uncertain cases15. If a positive node is detected, radical inguinal lymph node dissection
TE D
(ILND) with excision of the overlying skin and biopsy needle should be performed to prevent seeding malignant cells into healthy tissue18.
EP
Computed Tomography (CT)
The role of conventional CT in staging the inguinal lymph nodes remains limited because of inaccurate detection and paucity of follow up studies. A group led by Horenblas investigated a
AC C
series of 14 patients and found that CT possessed a sensitivity and specificity of 36% and 100%, respectively, but was unable to detect occult metastases in the cN0 groins11. The advent of multislice high-resolution scanners have improved the sensitivity of CT in staging other cancers. However, few follow up studies have been conducted and CT imaging is not recommended as the initial staging modality in patients with cN0 disease. Under the current guidelines, conventional CT is recommended for assessing the inguinal region in obese patients or in those who have had prior inguinal surgery, in whom the physical examination may be unreliable and for determining the extent of disease in patients with clinically palpable nodes15.
6
ACCEPTED MANUSCRIPT
Recently, single photon emission computed tomography–computed tomography (SPECTCT) imaging has been used to investigate clinically node negative penile cancer patients. Nuclear tracer (99m technetium nanocolloid) is injected into the primary penile tumour and allowed to drain into inguinal lymph nodes where single emission photons are detected by a gamma camera.
RI PT
This modality provides functional information by identifying first draining lymph nodes.
Overlaying SPECT with conventional CT, provides 3-dimensional functional anatomy of the inguinal lymphatics (Figure 3). SPECT-CT has been gaining traction as a useful modality to
Positron Emission Tomography (PET)/CT
SC
identify sentinel lymph nodes inform surgical approach.
M AN U
PET is a sophisticated imaging technique capable of detecting sub-nanomolar concentrations of radioactive tracer in vivo. Penile SCCs are known to have a high glucose metabolism, and have a greater uptake of a radiolabelled glucose analog 18F-fluorodeoxyglucose (18F-FDG) than non-transformed surrounding cells19. When PET is overlaid with low dose CT (PET/CT), the combined imaging modality allows clinicians to investigate the functional
TE D
anatomy of the tissues.
Studies involving a small number of patients have demonstrated sensitivity and specificity of up to 90% and 100% respectively20. The data currently available establishes that it is difficult to distinguish metastatic deposits of <10mm and that discerning between
EP
inflammatory and metastatic 18F-FDG uptake will remain an ongoing challenge. The limitations of PET/CT are characterized by its poor diagnostic accuracy in patients presenting with impalpable groins. This was highlighted by a 2012 meta-analysis, which
AC C
established a pooled sensitivity of 96% for cN+ patients and 57% for those with cN0 disease21. A more recent study has established that combining PET/CT with advancements in sentinel node biopsy has achieved a sensitivity of 94% and false negative rate of 6% in a cohort of 68 node native patients22.
As such, the current body evidence does not support a role for PET/CT as a standalone diagnostic procedure in patients with minimal disease. Until larger trials with more reliable data emerge, the greatest role of PET/CT will be restricted to quantifying the burden of disease and assessing treatment response in lymph node–positive patients15.
7
ACCEPTED MANUSCRIPT
Magnetic Resonance Imaging (MRI) Lymphotrophic nanoparticle–enhanced MRI (LNMRI) characterizes the functional anatomy of inguinal lymph nodes and has demonstrated highly accurate staging potential in
RI PT
prostate and bladder malignancies 23. This technique uses a composite of superparamagenetic iron oxide nanoparticles called Ferumoxtran-10. In normal lymph nodes, macrophages will engulf these particles and they will show up homogeneously dark on T2-weighted MRI.
However, uninfected malignant nodes lack phagocytes and the free Ferumoxtran-10 appears bright on MRI. Because the image interpretation involves both nodal function and structure it is
SC
possible to detect metastases <10mm.
In a small series of 7 patients, LNMRI has shown a sensitivity of 100% and a specificity
M AN U
of 97% in detecting occult lymph node metastases24.Furthermore, in four patients metastases less than 1cm in size were detected. Despite the promise of LNMRI its application remains limited because no follow up studies have been performed and Ferumoxtran-10 not has not been approved for diagnostic use. Furthermore, future utility of LNMRI for detecting micrometastatic disease in cN0 groins remains limited by the spatial resolution of MRI technology which has a
TE D
current threshold of 1-2mm25.
MANAGEMENT OF NODE NEGATIVE DISEASE The crux of penile cancer management is balancing the limitations of physical examination and imaging techniques with the curative potential of radical lymphadenectomy. In intermediate to
EP
high risk tumours (pT1b, T2- T4), the presence of lymph node invasion can be upwards of 49%26. Historically, prophylactic inguinal lymph node dissection (ILND) has demonstrated a
AC C
survival advantage in this population of patients and failed detection of micrometastatic disease can have a significant impact on survival. However, contemporary philosophy dictates that subjecting all patients with intermediate risk disease to radical ILND carries an unacceptable risk of complications and long-term morbidity. Sentinel lymph node biopsy is increasingly becoming the diagnostic standard of care because of its ability to identify patients with micrometastatic disease with a high sensitivity with minimal risk to patients. The sentinel node concept is based on the relatively consistent physiology of penile lymphatic drainage that passes first into a sentinel node or group of nodes before disseminating
8
ACCEPTED MANUSCRIPT
into other ilioinguinal lymphatics. A negative sentinel node suggests the absence of further lymphatic spread, and therefore subsequent lymphadenectomy is contraindicated. Over the past decade, dynamic sentinel lymph node biopsy (DSLNB) combined with US FNAC of first draining lymph nodes has emerged as the gold standard for investigating cN0
RI PT
penile cancer27. This minimally invasive technique employs a combination of strategies to locate and assess sentinel lymph nodes. Prior to surgery, a radiolabelled tracer is injected into the
primary tumour, which is taken up by the lymphatic system. Sentinel lymph nodes are identified and marked on the groin using lymphosintographic SPECT-CT. In the operating theatre,
SC
methylene blue dye is injected into the lesion and allowed to drain into the lymphatics. All radiopositive and blue-stained lymph nodes are excised and sent for histopathological examination.
node dissection.
M AN U
Confirmed node positive malignancy is a sufficient indication for an ipsilateral radical lymph
The most comprehensive meta-analysis on the accuracy of DSLNB to date pooled 19 studies to establish sensitivity of 88% and specificity of 90%. The team furthermore concluded that using radiotracer and blue dye for sentinel lymph node mapping confers the highest sensitivity and detection rate28.
TE D
Modifications to DSLNB have been reported to aid intraoperative visualization of sentinel nodes using hybrid radioactive and fluorescent tracer indocyanine green (ICG)-(99m) technetium-nanocolloid. Near-infrared fluorescence penetrates tissue more effectively, generating a greater contrast under excitation light and superior visualization of small lymphatic
EP
channels29. In an investigation that included 183 lymph basins, 95% of sentinel lymph nodes were detected using the hybrid tracer compared 54% being seen with the standard blue dye30.
AC C
Although the applications of this study are currently experimental, it demonstrates future sensitivity improvements are emerging from refining DSLNB techniques. Furthermore, long term data have established the benefit of reduced morbidity and improved fiver year cancerspecific survival, it is emerging that DSLNB has been a breakthrough for patients with cN0 penile cancer.
MANAGEMENT OF NODE POSITIVE DISEASE Lymph node involvement is the single greatest prognostic factor for penile cancer survival31. For patients with metastatic disease in the groin, lymph node dissection remains the
9
ACCEPTED MANUSCRIPT
cornerstone of treatment. In men with disease limited to 1-2 metastatic inguinal nodes, radical ILND is curative in approximately 80% of cases which is reflected in a 5-year disease specific survival (DSS) of 75%32. Current guidelines define pN3 disease as greater than two positive inguinal lymph nodes,
RI PT
or extracapsular spread. It is recommended that ipsilateral pelvic LND be performed in these patients because there is a 56% probability of positive pelvic nodes33. In men with confirmed pelvic nodal metastasis, prognosis was worse than disease limited to the inguinal region with 5year DSS of 33%31. Although these men may have a higher risk for surgical complications,
SC
delaying surgery has been shown to adversely affect survival34.
Historically patients presenting pN2/pN3 disease characterised by bulky, fixed or greater
M AN U
than 4 positive nodes were considered inoperable. However, recent evidence has demonstrated that neoadjuvant chemotherapy shrink tumours to an acceptable size for resection, leading to improved survival35. In a phase II trial involving 30 pN2/pN3 penile cancer patients, Pagliaro and colleagues were able to achieve an objective response in 50% of men using neoadjuvant TIP (paclitaxel/ifosfamide/cisplatin)36. A follow up study of 61 patients lead by Dickstein demonstrated that if the 50% TIP responders underwent consolidative lymphadenectomy a 5-
TE D
year DSS of 50% could be achieved37. Despite the optimistic results, interpretation of these studies is limited by small patient cohorts and the lack of chemotherapeutic regime standardization and dose optimization. Current management guidelines have accommodated these limitations and recommend that radical ILND can deliver robust oncological control and
AC C
Radical ILND
EP
should is offered to patients who respond to neoadjuvant chemotherapy15.
Briefly, an oblique incision is made 2-3cm below and parallel to the inguinal ligament
extending laterally from the anterior superior iliac spine (ASIS) to the pubic tubercle (Figure 2). A vertical ‘lazy-S’ incision made starting approximately 10 cm above and 15cm below the inguinal ligament. Alternatively, an incision can be made a few centimeters below and parallel to the inguinal ligament and curved medially down in the femoral triangle. Superior and inferior skin flaps are raised below the Scarpas fascia and fat and areolar tissue is removed to expose the external oblique, external inguinal ring, spermatic cord, and the inferior border of the inguinal ligament. The long saphenous vein is exposed at the apex of the femoral triangle and divided. In 10
ACCEPTED MANUSCRIPT
patients with minimal metastatic disease, it is beneficial to spare the saphenous vein. The dissection continues through the fascia lata overlaying the sartorius muscle, allowing for excision of the deep inguinal nodes. After the complete femoral triangle dissection, the sartorius muscle is mobilized from the ASIS, transposed over the femoral vessels as a myocutaneous flap and
RI PT
sutured to the inguinal ligament superiorly. Primary closure of the dissection is usually possible with minimal mobilization of the excision margins and a closed suction drain is placed under the subcutaneous tissue minimize dead space and prevent seroma or lymphocele formation38.
Despite the curative potential of ILND, a significant number of penile cancer patients
SC
with high risk disease have not been offered the procedure because of the high incidence of
morbidity following open surgery39. In the most comprehensive assessment to date, a team led
M AN U
by Gopman established that 55% of patients experienced a postoperative complication. Although most of these complaints were minor and resolved without prolonged morbidity, one third met Clavien–Dindo II classification and required intervention. The most common issues reported were infection, lymphocele, skin flap necrosis, lyphpoedema and wound dehiscence40. Refinement to open INLD technique has occurred at a rapid pace since 2008. Plastic surgical consultation for myocutaneous flap coverage and preservation of the dermis, Scarpa
TE D
fascia, and saphenous vein, as well as limiting of the extent of the dissection have been successful at decreasing the overall complication rate of ILND to 25%41. More recently, a phase I study lead by Martin described that robotic assisted video endoscopic inguinal lymphandenectomy achieved an adequate dissection in 18/19 procedures42. Validation and long
EP
term follow up of complications remains critical. However, minimally invasive ILND has demonstrated promise for further reducing the morbidity associated with open surgery while
AC C
delivering comparable oncological outcomes43. In a time where the application of ILND routinely falls below half of all indicated cases, wider adoption of these techniques may make clinicians more comfortable recommending surgery.
Pelvic Lymph Node Dissection (PLND) Pelvic lymph nodes are the final site of locoregional metastasis from the penis before widespread disease becomes a paramount concern. Historically pN3 penile SCC carried a poor prognosis with a 5-year DSS of between 9-42%44. Current guidelines have recognized this risk
11
ACCEPTED MANUSCRIPT
and have recommended that men with two or more metastatic inguinal nodes or extranodal extension should undergo an ipsilateral PLND15,45. Unlike the inguinal lymphatic architecture, pelvic nodes metastases always arise from positive ipsilateral inguinal nodes with no established incidence of contralateral
RI PT
communication46. Unilateral PLND is undertaken either through a lower abdominal midline incision or a unilateral muscle splitting incision and may be undertaken at the same time as ILND or as a separate procedure. For bilateral PLND a midline suprapubic extraperitoneal excision is recommended. The boundaries of PLND are delineated by the iliac bifurcation
SC
proximally, ilioinguinal nerve laterally, and the obturator nerve medially. The procedure involves excision of the obturator, internal iliac, and external iliac nodes as well as any clinically positive
M AN U
nodes in the region. Carefully occluding the lymphatic channels with surgical clips or ligation and the insertion of a suction drain are recommended to manage postoperative lymphocele47. In addition to its potential for diagnostic staging, PLND can improve survival in patients with high-risk disease, but is of limited benefit those with low risk disease. Long-term retrospective data on the outcome of patients who have undergone PLND for penile SCC is hindered by a small patient population with advanced disease. The few reports that have
TE D
examined these patients indicate that PLND carries a considerable complication and morbidity profile to radical ILND. The most comprehensive study to date included 40 patients and recorded an overall complication rate of 45%, with the most common indications lymphocele, lymphedema, infection, wound dehiscence and flap necrosis48.
EP
Although guidelines have reached a consensus indication for PLND, significant debate centers on candidate selection for the procedure, appropriate boundaries of dissection, optimal
AC C
surgical approach, and absolute survival benefit15,45. A recent meta-analysis has weighed in on this debate, by pooling data from 51 men over a mean follow up period of 13 months. The researchers proposed that PLND when combined with recent chemotherapeutic advances may produce a modest survival benefit but statistical significance was not achieved49. Furthermore, recent advances in PLND the field of prostate cancer have established that robotic assisted PLND has the possibility to lower complication rates to 16% while maintaining equivalent oncological control to the open procedure50. These efforts have pushed the boundaries of penile cancer management and prolonged survival in patients who were historically treated with palliation. By virtue of their advanced
12
ACCEPTED MANUSCRIPT
disease, these patients are rare and difficult to study and more data is required to optimise standard of care. It is clear from the data, that these patients will benefit from multidisciplinary management informed by uro-oncologists, medical oncology, palliative care to best align
RI PT
survival benefit with patient expectations.
CONCLUSION
Because of its location, traditional surgical intervention for penile cancer has exacted a devastating impact on the anatomic, functional and psychosocial domains of a patient’s quality
SC
of life. With the advent of new approaches such as DSLNB, minimally invasive LN
management, patients have better oncological and psychosocial outcomes. These advances have
M AN U
been met with a degree of controversy in contemporary literature. Further, more robust long-term
AC C
EP
TE D
data is required to determine the optimal management of lymph nodes in penile cancer.
13
ACCEPTED MANUSCRIPT
REFERENCES Breen KJ, O'Connor KM, Power DG et al: Penile cancer—guideline adherence produces optimum results. Surgeon 2015; 13: 200–206.
2.
Christodoulidou M, Sahdev V, Houssein S et al: Epidemiology of penile cancer. Curr Probl. Cancer 2015; 39: 126–136.
3.
Skeppner E, Andersson S-O, Johansson J-E et al: Initial symptoms and delay in patients with penile carcinoma. Scand. J. Urol. Nephrol. 2012; 46: 319–325.
4.
Dewire D and Lepor H: Anatomic considerations of the penis and its lymphatic drainage. Urol Clin North Am 1992; 19: 211–219.
5.
Veeratterapillay R, Teo L, Asterling S et al: Oncologic outcomes of penile cancer treatment at a UK supraregional center. Urology 2015; 85: 1097–1103.
6.
Moher D, Shamseer L, Clarke M et al: Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Systematic Reviews 2015; 4: 1.
7.
Riveros M, Garcia R and Cabañas R: Lymphadenography of the dorsal lymphatics of the penis. Technique and results. Cancer 1967; 20: 2026–2031.
8.
Leijte JA, Valdés Olmos RA, Nieweg OE et al: Anatomical mapping of lymphatic drainage in penile carcinoma with SPECT-CT: implications for the extent of inguinal lymph node dissection. Eur. Urol. 2008; 54: 885–892.
9.
Hernandez BY, Barnholtz-Sloan J, German RR et al: Burden of invasive squamous cell carcinoma of the penis in the United States, 1998-2003. Cancer 2008; 113: 2883–2891.
10.
Persson B, Sjödin J-G, Holmberg L et al: The National Penile Cancer Register in Sweden 2000-2003. Scand. J. Urol. Nephrol. 2007; 41: 278–282.
11.
Horenblas S, van Tinteren H, Delemarre JF et al: Squamous cell carcinoma of the penis: accuracy of tumor, nodes and metastasis classification system, and role of lymphangiography, computerized tomography scan and fine needle aspiration cytology. J. Urol. 1991; 146: 1279–1283.
SC
M AN U
TE D
EP
AC C
12.
RI PT
1.
Hegarty PK, Kayes O, Freeman A et al: A prospective study of 100 cases of penile cancer managed according to European Association of Urology guidelines. BJU Int. 2006; 98: 526–531.
13.
Lont AP, Kroon BK, Gallee MPW et al: Pelvic lymph node dissection for penile carcinoma: extent of inguinal lymph node involvement as an indicator for pelvic lymph node involvement and survival. J. Urol. 2007; 177: 947–952.
14.
Kroon BK, Horenblas S, Lont AP et al: Patients with penile carcinoma benefit from
14
ACCEPTED MANUSCRIPT
immediate resection of clinically occult lymph node metastases. J. Urol. 2005; 173: 816– 819. Hakenberg OW, Compérat EM, Minhas S et al: EAU guidelines on penile cancer: 2014 update. Eur. Urol. 2015; 67: 142–150.
16.
Saisorn I, Lawrentschuk N, Leewansangtong S et al: Fine‐needle aspiration cytology predicts inguinal lymph node metastasis without antibiotic pretreatment in penile carcinoma. BJU Int. 2006; 97: 1225–1228.
17.
Kroon BK, Horenblas S, Deurloo EE et al: Ultrasonography-guided fine-needle aspiration cytology before sentinel node biopsy in patients with penile carcinoma. BJU Int. 2005; 95: 517–520.
18.
Goldberg BB, Merton DA, Liu J-B et al: Contrast-enhanced sonographic imaging of lymphatic channels and sentinel lymph nodes. J Ultrasound Med 2005; 24: 953–965.
19.
Protzel C and Spiess PE: Molecular research in penile cancer—lessons learned from the past and bright horizons of the future? Int J Mol Sci 2013; 14: 19494–19505.
20.
Schlenker B, Scher B, Tiling R et al: Detection of inguinal lymph node involvement in penile squamous cell carcinoma by 18F-fluorodeoxyglucose PET/CT: A prospective single-center study. Urol Oncol 2012; 30: 55–59.
21.
Sadeghi R, Gholami H, Zakavi SR et al: 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; 37: 436–441.
22.
Jakobsen JK, Alslev L, Ipsen P et al: DaPeCa-3: promising results of sentinel node biopsy combined with (18) F-fluorodeoxyglucose positron emission tomography/computed tomography in clinically lymph node-negative patients with penile cancer - a national study from Denmark. BJU Int. 2016; 118: 102–111.
23.
Thoeny HC, Triantafyllou M, Birkhaeuser FD et al: Combined ultrasmall superparamagnetic particles of iron oxide-enhanced and diffusion-weighted magnetic resonance imaging reliably detect pelvic lymph node metastases in normal-sized nodes of bladder and prostate cancer patients. Eur. Urol. 2009; 55: 761–769.
SC
M AN U
TE D
EP
AC C
24.
RI PT
15.
Tabatabaei S, Harisinghani M and McDougal WS: Regional lymph node staging using lymphotropic nanoparticle enhanced magnetic resonance imaging with ferumoxtran-10 in patients with penile cancer. J. Urol. 2005; 174: 923–928.
25.
Yeung LL and Brandes SB: Dynamic sentinel lymph node biopsy as the new paradigm for the management of penile cancer. Urol. Oncol. 2013; 31: 693–696.
26.
Graafland NM, Lam W, Leijte JAP et al: Prognostic factors for occult inguinal lymph node involvement in penile carcinoma and assessment of the high-risk EAU subgroup: a two-institution analysis of 342 clinically node-negative patients. Eur. Urol. 2010; 58: 742–
15
ACCEPTED MANUSCRIPT
747. Pizzocaro G, Algaba F, Horenblas S et al: EAU penile cancer guidelines 2009. Eur. Urol. 2010; 57: 1002–1012.
28.
Sadeghi R, Gholami H, Zakavi SR et al: Accuracy of sentinel lymph node biopsy for inguinal lymph node staging of penile squamous cell carcinoma: systematic review and meta-analysis of the literature. J. Urol. 2012; 187: 25–31.
29.
Namikawa T, Sato T and Hanazaki K: Recent advances in near-infrared fluorescenceguided imaging surgery using indocyanine green. Surg Today 2015; 45: 1467–1474.
30.
Brouwer OR, van den Berg NS, Mathéron HM et al: A hybrid radioactive and fluorescent tracer for sentinel node biopsy in penile carcinoma as a potential replacement for blue dye. Eur. Urol. 2014; 65: 600–609.
31.
Marconnet L, Rigaud J and Bouchot O: Long-term followup of penile carcinoma with high risk for lymph node invasion treated with inguinal lymphadenectomy. J. Urol. 2010; 183: 2227–2232.
32.
Pandey D, Mahajan V and Kannan RR: Prognostic factors in node‐positive carcinoma of the penis. J Surg Oncol 2006; 93: 133–138.
33.
Lughezzani G, Catanzaro M, Torelli T et al: Relationship between lymph node ratio and cancer-specific survival in a contemporary series of patients with penile cancer and lymph node metastases. BJU Int. 2015; 116: 727–733.
34.
Graafland NM, Lam W, Leijte JAP et al: Prognostic factors for occult inguinal lymph node involvement in penile carcinoma and assessment of the high-risk EAU subgroup: A two-institution analysis of 342 clinically node-negative patients. Eur. Urol. 2010; 58: 742– 747.
35.
Leijte JAP, Kerst JM, Bais E et al: Neoadjuvant Chemotherapy in Advanced Penile Carcinoma. Eur. Urol. 2007; 52: 488–494.
36.
Pagliaro LC, Williams DL, Daliani D et al: Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase II study. J. Clin. Oncol. 2010; 28: 3851–3857.
SC
M AN U
TE D
EP
AC C
37.
RI PT
27.
Dickstein RJ, Munsell MF, Pagliaro LC et al: Prognostic factors influencing survival from regionally advanced squamous cell carcinoma of the penis after preoperative chemotherapy. BJU Int. 2016; 117: 118–125.
38.
Ercole CE, Pow-Sang JM and Spiess PE: Update in the surgical principles and therapeutic outcomes of inguinal lymph node dissection for penile cancer. Urol. Oncol. 2013; 31: 505–516.
39.
Johnson TV, Hsiao W, Delman KA et al: Extensive inguinal lymphadenectomy improves
16
ACCEPTED MANUSCRIPT
overall 5‐year survival in penile cancer patients: results from the Surveillance, Epidemiology, and End Results program. Cancer 2010; 116: 2960–2966. Gopman JM, Djajadiningrat RS, Baumgarten AS et al: Predicting postoperative complications of inguinal lymph node dissection for penile cancer in an international multicentre cohort. BJU Int. 2015; 116: 196–201.
41.
Yao K, Tu H, Li Y-H et al: Modified technique of radical inguinal lymphadenectomy for penile carcinoma: morbidity and outcome. J. Urol. 2010; 184: 546–552.
42.
Matin SF, Cormier JN, Ward JF et al: Phase 1 prospective evaluation of the oncological adequacy of robotic assisted video-endoscopic inguinal lymphadenectomy in patients with penile carcinoma. BJU Int. 2013; 111: 1068–1074.
43.
Kharadjian TB, Matin SF and Pettaway CA: Early experience of robotic-assisted inguinal lymphadenectomy: review of surgical outcomes relative to alternative approaches. Curr Urol Rep 2014; 15: 412.
44.
Graafland NM, van Boven HH, van Werkhoven E et al: Prognostic significance of extranodal extension in patients with pathological node positive penile carcinoma. J. Urol. 2010; 184: 1347–1353.
45.
Clark PE, Spiess PE, Agarwal N et al: Penile cancer: Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2013; 11: 594–615.
46.
Cabanas RM: Anatomy and biopsy of sentinel lymph nodes. Urol Clin North Am 1992; 19: 267–276.
47.
Sharma P, Zargar-Shoshtari K and Spiess PE: Current surgical management of penile cancer. Curr Probl Cancer 2015; 39: 147–157.
48.
Nelson BA, Cookson MS, Smith JA Jr et al: Complications of inguinal and pelvic lymphadenectomy for squamous cell carcinoma of the penis: a contemporary series. J. Urol. 2004; 172: 494–497.
49.
Zargar-Shoshtari K, Sharma P, Djajadiningrat R et al: Extent of pelvic lymph node dissection in penile cancer may impact survival. World J Urol 2016; 34: 353–359.
SC
M AN U
TE D
EP
AC C
50.
RI PT
40.
Ledezma RA, Negron E, Razmaria AA et al: Robotic-assisted pelvic lymph node dissection for prostate cancer: frequency of nodal metastases and oncological outcomes. World J Urol 2015; 33: 1689–1694.
17
ACCEPTED MANUSCRIPT
TABLE 1 – Summary of Accuracy of Lymph Node Staging Modalities Specificity (%) 79
Comments •
Requires experienced clinician
Ultrasound + FNAC16
93
91
•
First line investigation for palpable nodes
CT11
36
100
•
Adjunct for difficult clinical exam
PET/CT20
88
98
•
Cannot discern inflammation from metastasis Difficult to resolve <2mm
• 100
97
•
• •
DSLNB28
90-95
•
First line investigation for cN0 disease
AC C
EP
TE D
88
Experimental and not widely available Few patients studied Resolution limited by power of magnet available
M AN U
MRI24
RI PT
Clinical Examination11
Sensitivity (%) 82
SC
Staging Modality
1
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
FIGURE 1 – PRISMA analysis.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
FIGURE 2 – Mapping out anatomical landmarks for a right radical inguinal dissection. The femoral triangle is demarked in dotted lines and is bordered by the anterior superior iliac spine and pubic tubercle superiorly. The medial boarder of sartorius forms the lateral boarder. The medial line follows the lateral boarder of adductor longus. A vertical ‘lazy-S’ incision demarked by the solid line is made starting approximately 10 cm above and 15cm below the inguinal ligament.
ACCEPTED MANUSCRIPT
Transverse
Coronal
Sagittal
RI PT
A.
M AN U
SC
B.
TE D
C.
AC C
EP
FIGURE 3 - Sentinel lymph node SPECT-CT images demonstrating bilateral positive inguinal lymphadenopathy prior to DSLNB. A. Conventional scintigraphy demonstrating nuclear tracer present in sentinel lymph nodes. B. Conventional CT imaging providing anatomical context for the inguinal region. C. Fused SPECT-CT images establishes 3-dimensional functional anatomy of the penile sentinel lymph nodes. Computer generated tracer bars are used to further increase the utility of SPECT-CT.
ACCEPTED MANUSCRIPT
DEFINITIONS AND ABBREVIATIONS
AC C
EP
TE D
M AN U
SC
RI PT
18-FDG - 18-Fluorodeoxyglucose ASIS - Anterior Superior Iliac Spine CT – Computed Tomography DSLNB - Dynamic Sentinel Lymph Node Biopsy DSS – Disease Specific Survival FNAC – Fine Needle Aspirate Cytology ICG - Indocyanine Green ILND – Inguinal Lymph Node Dissection LN – Lymph Node LNMRI - Lymphotrophic Nanoparticle–enhanced Magnetic Resonance Imaging MRI – Magnetic Resonance Imaging PET - Positron Emission Tomography PLND - Pelvic Lymph Node Dissection SCC – Squamous Cell Carcinoma SPECT – Single-Photon Emission Computed Tomography US – Ultrasound