DaPeCa-1: Diagnostic accuracy of sentinel node biopsy in 222 penile cancer patients at four tertiary referral centres - a national study from Denmark - Beyond the Abstract

Lymph node involvement is crucial for penile cancer prognosis and sentinel node biopsy (SNB) has proven a reliable staging procedure. With this abstract, we provide the first national multicentre data on the subject.

Apart from the very rare distant metastasis, regional lymph node involvement is the strongest known prognosticator in penile squamous cell carcinoma (pSCC). Number of inguinal lymph nodes involved, extranodal extension of metastatic growth, and pelvic node disease are independent prognostic factors for cancer specific survival (1,2). Accordingly, inguinal lymph node examination and relevant handling strategies are crucial in pSCC patients. The sentinel node procedure introduced by Cabanas in 1977 and modified and revitalized for penile cancer by Horenblas et al. in 1994 with low complication rates and a high sensitivity is a reasonable lymph staging procedure for this group of patients (3-6). Most publications on the subject rely on single institution data and often a small number of patients with limited follow-up. We provide data from 409 sentinel lymph node biopsy (SNB) procedures in 222 Danish pSCC patients and long term follow-up from four centres.

Patients considered for SNB had a median age of 64.3 yr. (IQR 58 – 71 yr.) and at least one clinically node negative (cN0) groin. Groins with non-palpable lymph nodes and groins with palpable lymph nodes and subsequent negative fine needle aspiration cytology were considered cN0. Routine ultrasound scan of non-palpable inguinal lymph nodes was not conducted. Clinically node-positive groins and patients not examined by SNB at primary diagnosis were excluded from the study. We defined a false negative SNB as the occurrence of inguinal or pelvic nodal metastasis after a negative SNB, without evidence of a de novo or recurrent pSCC that predated nodal metastasis. Penile tumour and lymph node histology reports were reviewed and recorded according to TNM 2009 criteria.
At all four centres sentinel lymph nodes (SLN) were located with aid of the lymphoscintigraphy, the preoperative skin markings and a handheld gamma probe. In three centres an additional intradermal injection of 1mL patent blue dye was used pre-operatively. Nodes were harvested through small inguinal incisions and thorough intraoperative palpation of the exposed wound was used to identify potential suspicious nodes not detected by the probe. The exploration of an inguinal basin ceased when the radioactivity counts reached background levels and no further blue or palpable lymph nodes were identified in the field. Sentinel nodes were all nodes harvested by SNB whether radioactive, blue and/or per-operatively suspicious. Primary penile surgery was local resection with or without reconstruction, partial penectomy or total penectomy as appropriate.

Excised SLNs were bisected longitudinally and paraffin embedded. One slide was stained with haematoxylin and eosin (H&E). If no metastases were detected, the whole paraffin-embedded block was step-sectioned at 250 μm intervals. At each level two sections were stained with H&E and the immunohistochemical marker cytokeratin A1/A3 (a mixture of the cytokines CK10, CK13-16 and CK19)(7). The SLNs were recorded positive if metastases were detected by H&E, cytokeratin positivity or both.

Patients with positive SLN were referred to ipsilateral inguinal lymph node dissection (ILND) within four weeks of SNB. Follow-up of node positive patients was a standardised surveillance program which included four-monthly computed tomography (CT) scan and inguinal palpation in the first two years and CT scan and inguinal palpation every six months hereafter. The surveillance program for node negative patients consisted of two-monthly clinical examinations in the first two years and six-monthly hereafter. Patients found to be recurrence free for five consecutive years were meticulously instructed in self-examination and had their surveillance program terminated.

A total of 1004 lymph nodes were removed of which 93 nodes (9.3 %) harboured metastatic tissue at histopathological examination. All groins with a positive SNB underwent complementary ipsilateral inguinal lymph node dissection (ILND). Sixteen groins with positive SNB (24 %) contained further positive lymph nodes at complementary ILND, while 50 groins (76 %) had no further metastases on histopathological examination of ILND specimen.

Twenty-eight of 222 (13%) patients experienced 39 postoperative complications to SNB during a median follow-up period of 73 (IQR 53-102) months. No patient was lost to follow-up. Complications were encountered after 30 of 409 (7%) procedures. One patient was readmitted because of severe wound infection, the remaining complications were handled as a part of primary hospitalization, or in the outpatient clinic. Eight patients experienced more than one SNB-related complication. No patient needed to return to the operating room because of SNB related complications. No patient died from complications. The SNB-related morbidity is summarised in table 5. (8)

The prognostic significance of lymph node metastases and the crucial role of early surgical removal of metastatic nodes in pSCC patients is well established (1,2,10,11). On the other hand ILND is associated with frequent and heavy morbidity and minimally invasive lymph node staging is important to prevent over-treatment of lymph node negative groins (12-14).
No non-invasive staging tool has proven competitive to invasive techniques and the EAU guidelines recommend invasive staging with either modified inguinal lymphadenectomy or SNB of clinically node negative (cN0) patients at intermediate- or high risk of lymphatic spread (≥T1G2)(11).

Considering the occasional very aggressive nature of the disease and the fact that two of the false negative patients died from penile cancer despite further surgical and oncological treatment a false negative rate at 10.8 % still leaves room for improvement. Initiatives to improve conditions for penile cancer patients have been implemented after the end of the study period of the current study. In 2009 SNB in Denmark was centralised to 2 of the four centres participating in this study. A prospective database has been established and further improvement by introduction of routine ultrasonography of non-palpable nodes is considered. We are also aware of the fact that technological development may standardise more modern approaches.

References:
1. Protzel C, Alcaraz A, Horenblas S, Pizzocaro G, Zlotta A, Hakenberg OW. Lymphadenectomy in the surgical management of penile cancer. Eur Urol 2009 May;55(5):1075-1088.
2. Lont AP, Kroon BK, Gallee MP, van Tinteren H, Moonen LM, Horenblas S. 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 Mar;177(3):947-52; discussion 952.
3. Jensen JB, Jensen KM, Ulhoi BP, Nielsen SS, Lundbeck F. Sentinel lymph-node biopsy in patients with squamous cell carcinoma of the penis. BJU Int 2009 May;103(9):1199-1203.
4. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 1977 Feb;39(2):456-466.
5. Kroon BK, Horenblas S, Estourgie SH, Lont AP, Valdes Olmos RA, Nieweg OE. How to avoid false-negative dynamic sentinel node procedures in penile carcinoma. J Urol 2004 Jun;171(6 Pt 1):2191-2194.
6. Horenblas S, Jansen L, Meinhardt W, Hoefnagel CA, de Jong D, Nieweg OE. Detection of occult metastasis in squamous cell carcinoma of the penis using a dynamic sentinel node procedure. J Urol 2000 Jan;163(1):100-104.
7. Miller RT. Cytokeratin AE1/AE3. Pro Path Immunohistochemistry 2003.
8. Clavien PA, Barkun J, de Oliveira ML, Vauthey JN, Dindo D, Schulick RD, et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg 2009 Aug;250(2):187-196.
9. Kroon BK, Horenblas S, Lont AP, Tanis PJ, Gallee MP, Nieweg OE. Patients with penile carcinoma benefit from immediate resection of clinically occult lymph node metastases. J Urol 2005 Mar;173(3):816-819.
10. Hakenberg OW, Comperat E, Minhas S, Necchi A, Protzel C, Watkin N. EAU guidelines on Penile Cancer. 2014; Available at: http://www.uroweb.org/gls/pdf/12%20Penile%20Cancer_LR.pdf. Accessed 09/09, 2014.
11. Bevan-Thomas R, Slaton JW, Pettaway CA. Contemporary morbidity from lymphadenectomy for penile squamous cell carcinoma: the M.D. Anderson Cancer Center Experience. J Urol 2002 Apr;167(4):1638-1642.
12. Bouchot O, Rigaud J, Maillet F, Hetet JF, Karam G. Morbidity of inguinal lymphadenectomy for invasive penile carcinoma. Eur Urol 2004 Jun;45(6):761-5; discussion 765-6.
13. Nelson BA, Cookson MS, Smith JA,Jr, Chang SS. Complications of inguinal and pelvic lymphadenectomy for squamous cell carcinoma of the penis: a contemporary series. J Urol 2004 Aug;172(2):494-497.

Written by:
Jakob Kristian Jakobsen(1), Kim Predbjørn Krarup(2), Peter Sommer(2), Henrik Nerstrøm(2), Vivi Bakholdt(3), Jens Ahm Sørensen(3), Kasper Ørding Olsen(1), Bjarne Kromann-Andersen(4), Birgitte Grønkær Toft(5), Søren Høyer(6), Kirsten Bouchelouche(7) and Jørgen Bjerggaard Jensen(1)
(1)Aarhus University Hospital, Department of Urology, (2)Copenhagen University Hospital, Department of Urology, (3)Odense University Hospital, Department of Plastic Surgery, (4)Herlev University Hospital, Department of Urology, (5)Copenhagen University Hospital, Department of Pathology, (6)Aarhus University Hospital, Department of Pathology, (7)Aarhus University Hospital, Department of Nuclear Medicine & PET-Centre

Abstract: DaPeCa-1: Diagnostic Accuracy of Sentinel Node Biopsy in 222 Penile Cancer Patients at four Tertiary Referral Centres -- a National Study from Denmark

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