4. Epidemiologie, Ätiologie und Pathologie – Peniskarzinom
4.1 Definition von Peniskarzinomen
Das Peniskarzinom ist ein maligner Tumor, der von der epithelialen Oberfläche der Glans penis, des Sulcus coronarius oder des inneren Blattes des Präputiums ausgeht. Peniskarzinome der Schafthaut sind extrem selten. Karzinome der penilen Harnröhre, Sarkome, Melanome, hämatologische Tumoren und primäre Hauttumoren sind nicht Gegenstand dieser Leitlinie.
4.2 Epidemiologie
Das Peniskarzinom ist weltweit ein seltener Tumor, zeigt jedoch regional Unterschiede in den Inzidenzraten. In Teilen Südamerikas, Asiens und Afrikas ist er häufiger und macht dort bis zu 10% der malignen Neoplasien bei Männern aus [43]; [44]. In den nordafrikanischen und den arabischen Ländern sowie in Israel ist das Peniskarzinom dagegen extrem selten (<1 Erkrankungsfall auf 1 Million Männer) [44]. In Deutschland wurden im Jahr 2014 insgesamt 950 Neuerkrankungen diagnostiziert [45], das jährliche Erkrankungsrisiko liegt somit bei zwei auf 100.000 Männern (rohe Inzidenzrate) [44]. Die Neuerkrankungsraten nehmen kontinuierlich mit dem Alter zu. Bei den über 85-Jährigen erkranken etwa 12/100.000 Männer. Im Mittel erkranken die Männer mit 70 Jahren [46]. Die altersstandardisierte Neuerkrankungsrate liegt bei 1,3 auf 100.000 Männer (alte Europastandardbevölkerung) [46]. Die Überlebensaussichten sind, gemessen an anderen Krebserkrankungen des Mannes, überdurchschnittlich gut, allerdings niedriger als beim Hoden- oder Prostatakarzinom. Das relative 5-Jahres-Überleben liegt bei 71%. In 2014 verstarben insgesamt 197 Männer am Peniskarzinom [45].
Entsprechend der verschiedenen pathogenetischen Mechanismen bei der Entstehung des Peniskarzinoms werden die Plattenepithelkarzinome des Penis anhand der aktuellen WHO-Klassifikation in HPV- und nicht-HPV-assoziierte Tumoren klassifiziert [47]. Etwa die Hälfte der Peniskarzinome sind vermutlich mit HPV der Hochrisikogruppe assoziiert [48].
Penile Vorläuferläsionen werden in den deutschen Krebsregisterdaten seltener registriert als die invasiven Krebserkrankungen (zuletzt jährlich etwa 180 Fälle), wobei eine Untererfassung möglich erscheint. Männer mit penilen Vorläuferläsionen waren im Durchschnitt drei Jahre jünger bei Diagnosestellung als Männer mit einem invasiven Karzinom [46].
4.3 Risikofaktoren und Prävention
Zirkumzision im Kindesalter und Genitalhygiene senken das individuelle Risiko, an einem Peniskarzinom zu erkranken.
Hintergrundinformationen: Zu Statement 4.1
Nach derzeitiger Auffassung existieren mindestens zwei pathogenetische Wege, auf denen ein Peniskarzinom entstehen kann [51], [52]. Ein Teil der Karzinome ist statistisch gehäuft mit einer chronischen Balanoposthitis oder eines Lichen sclerosus assoziiert [53], [54], sodass diese Erkrankungen als präkanzeröse Läsionen diskutiert werden. Risikofaktoren sind weiterhin eine Phimose, eine lange Vorhaut und eine mangelhafte Genitalhygiene [55]. Der zweite Pathogeneseweg ist auf eine Infektion mit HPV der Hochrisikogruppe, besonders HPV-Typ 16 und 18, zurückzuführen (siehe auch Kapitel 4.4.3 Peniskarzinome und HPV [56].
Eine Zirkumzision im Kindesalter reduziert das Risiko der Karzinomentstehung, wobei als Faktoren die reduzierte Oberfläche des penilen Epithels, die verbesserten Hygienebedingungen und eine reduzierte Suszeptibilität gegenüber HPV durch eine vermehrte Keratinisierung des Epithels diskutiert werden [57].
Hintergrundinformationen: Zu Statement 4.2
Von initialen Zellschäden bis zur Entwicklung von prämalignen Epithelläsionen, Präkanzerosen und schließlich Peniskarzinomen werden Pathogenese-Intervalle von 20 bis 30 Jahren angenommen. Seit Einführung der HPV-Impfstoffe 2006 und ersten Empfehlungen zur HPV-Impfung bei Jungen 2012/13 können deshalb noch keine Studien darüber vorliegen, ob und in welchem Maße eine systematische HPV-Impfung von Jungen das Risiko für ein späteres Peniskarzinom senken wird. In Analogie zur Wirksamkeit der HPV-Impfstoffe bei der Verhinderung von Präkanzerosen weiblicher Anogenitalkarzinome wird aber ein protektiver Effekt auch für das Peniskarzinom wissenschaftlich begründet unterstellt [50], [58], [59].
Im Gegensatz zu der offiziellen deutschen HPV-Impfempfehlung für Jungen [50] wurden beispielsweise in England und Griechenland gezielte HPV-Impfprogramme auch für Männer in Risikogruppen beschlossen [60]. In der deutschen S3-Leitlinie zur Impfprävention HPV-assoziierter Neoplasien von 2013 wurde ebenfalls das erhöhte Risiko für Männer, die Sex mit Männern haben (MSM), an HPV-assoziierten Tumoren zu erkranken, bereits beschrieben und die Präventivimpfung empfohlen [49]. In den Leitlinien der Europäischen AIDS-Gesellschaft wird für alle Menschen, die mit einer HIV-Infektion leben, bis zum 26. Lebensjahr-, und für alle HIV-positiven MSM bis zum 40. Lebensjahr empfohlen, eine Impfung mit drei Impfdosen des 9-valenten HPV-Vakzine durchzuführen [61].
In der deutsch-österreichischen Leitlinie „Anale Dysplasien und Analkarzinome bei HIV-Infizierten“ werden jährliche Screenings auf Analkarzinome und deren Vorstufen für HIV-Infizierte empfohlen, welche die Inspektion der Genitalien mit einschließt [62].
4.4 Pathologie
Der pathologische Befundbericht soll eine Klassifikation der histologischen Subtypen des Peniskarzinoms entsprechend der aktuellen WHO-Klassifikation enthalten.
Vorläuferläsionen und entzündliche Begleiterkrankungen sollen im pathologischen Befund berichtet werden.
Hintergrundinformationen: Zu Empfehlung 4.3
Die Klassifikation des Peniskarzinoms in histologische Subtypen gibt nicht nur Hinweise auf die Pathogenese im individuellen Fall, sondern liefert darüber hinaus wichtige prognostische Informationen [63]. Am häufigsten ist das Plattenepithelkarzinom vom gewöhnlichen Typ. Das pseudohyperplastische Karzinom entsteht typischerweise auf dem Boden eines Lichen sclerosus und ist durch eine gute Prognose gekennzeichnet [64]. Die Diagnose eines verrukösen Karzinoms sollte ausschließlich unter Berücksichtigung der typischen histologischen Kriterien einschließlich des p16-Status gestellt werden [65]. Im Gegensatz zu den anderen exophytischen Karzinomen (papilläres Karzinom NOS, papillär-basaloides Karzinom, warziges Karzinom) wird dem typischen verrukösen Karzinom die Fähigkeit zur Metastasierung abgesprochen. Das Lymphoepitheliom- ähnliche Karzinom ist im Gegensatz zum lymphoepithelialen Karzinom des Kopf-Hals- Bereiches nicht mit einer Epstein-Barr-Virusinfektion, sondern mit einer HPV-Infektion assoziiert [66].
Hintergrundinformationen: Zu Empfehlung 4.4
Die aktuelle WHO-Klassifikation unterscheidet folgende, nicht-invasive, histologische Vorläuferläsionen [47]:
- Nicht-HPV-assoziierte Penile intraepitheliale Neoplasie (differenzierte PeIN)
- HPV-assoziierte Penile intraepitheliale Neoplasie (basaloide PeIN, warzige PeIN, warzig-basaloide PeIN)
- Seltene Muster der Penilen intraepithelialen Neoplasie (pleomorphe PeIN, spindelzellige PeIN, klarzellige PeIN, pagetoide PeIN)
- Extramammärer Morbus Paget
Das parallele Vorhandensein von Vorläuferläsionen gibt Hinweise auf die Pathogenese und die histologische Subtypisierung des invasiven Karzinomanteils [67]; [68]; [69]; [54]. Bei organerhaltenden Operationsverfahren können Vorläuferläsionen abseits des Primärtumors das Risiko für ein Lokalrezidiv erhöhen.
Tabelle 1: WHO-Klassifikation der histologischen Subtypen des Peniskarzinoms (Moch et al. 2016) (Übersetzung durch die Autoren der Leitliniengruppe)
|
1. Nicht-HPV-assoziierte Plattenepithelkarzinome |
|
Plattenepithelkarzinom, gewöhnlicher Typ |
|
Pseudohyperplastisches Karzinom |
|
Verruköses Karzinom · Reines verruköses Karzinom · Carcinoma cuniculatum |
|
Papilläres Karzinom NOS (not otherwise specified) |
|
Adenosquamöses Karzinom |
|
Sarkomatoides Plattenepithelkarzinom |
|
Mischdifferenziertes Karzinom |
|
2. HPV-assoziierte Plattenepithelkarzinome |
|
Basaloides Karzinom · Papillär-basaloides Karzinom |
|
Warziges (kondylomatöses) Karzinom · Warzig-basaloides Karzinom |
|
Klarzelliges Karzinom |
|
Lymphoepitheliom-ähnliches Karzinom |
|
3. Andere, seltene Karzinome |
4.4.1 Grading
Der pathologische Befundbericht soll ein Grading des Peniskarzinoms enthalten.
Hintergrundinformationen: Zu Empfehlung 4.5
Das histopathologische Grading wurde in mehreren, vorwiegend retrospektiven Studien als signifikanter prognostischer Parameter identifiziert [70]; [71]; [72]; [73]; [74]. Als Besonderheit des Peniskarzinoms ist das Grading darüber hinaus Teil der T- Kategorie bei der TNM-Klassifikation, indem der Grad beim pT1-Tumor zwischen einer pT1a- und einer pT1b-Kategorie differenziert dargestellt wird. Allerdings wurde bislang kein einheitliches Grading-System verbindlich festgelegt und eine Studie zeigte eine relativ hohe Interobserver-Variabilität beim Peniskarzinom (mittlerer Kappa-Koeffizient: 0,34) [75].
4.4.2 Prognostische Faktoren
Zusätzlich zum histologischen Tumortyp und Grading des Peniskarzinoms soll der pathologische Befundbericht zum Primärtumor Aussagen zu folgenden prognostischen Faktoren enthalten:
- anatomische Lokalisation,
- perineurale Invasion,
- Infiltrationstiefe,
- Lymphgefäßinvasion,
- venöse Gefäßinvasion,
- Wachstumsmuster an der Invasionsfront.
Der pathologische Befundbericht der Lymphknoten soll die Zahl und Lokalisation der präparierten Lymphknoten, die Zahl der befallenen Lymphknoten und die maximale Metastasengröße enthalten sowie Aussagen darüber, ob die Metastase auf den Lymphknoten beschränkt bleibt oder die Lymphknotenkapsel überschreitet.
Hintergrundinformationen: Zu Empfehlung 4.6
Es existieren einige retrospektive Studien zu prognostischen morphologischen Faktoren beim Peniskarzinom, die allerdings meistens durch eine geringe Fallzahl limitiert sind [76]. Als Besonderheit des Peniskarzinoms ist die Lymphgefäßinvasion (L1) darüber hinaus Teil der T-Kategorie bei der TNM-Klassifikation, indem ein L1-Status beim pT1-Tumor zwischen einer pT1a- und einer pT1b-Kategorie differenziert. Es gibt mehrere retrospektive Studien, die eine prognostische Relevanz einer perineuralen Tumorinvasion im Primärtumor zeigen [51]; [74].
Hintergrundinformationen: Zu Empfehlung 4.7
Die Studienlage zeigt, dass der inguinale Lymphknotenstatus den wichtigsten prognostischen Faktor des Peniskarzinoms darstellt [76]. In einer prospektiven Studie konnte darüber hinaus eine prognostische Signifikanz einer extranodalen Tumorausdehnung bei Lymphknotenmetastasierung gezeigt werden [77]. Eine sorgfältige histopathologische Aufarbeitung der Präparate inguinaler Lymphknoten ist deshalb erforderlich.
4.4.3 Peniskarzinome und HPV
Der pathologische Befundbericht soll eine Aussage darüber enthalten, ob das Peniskarzinom mit einer HPV-Infektion assoziiert ist.
- Empfehlungsgrad
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Evidenzlevel
- 3
- Literatur
- [78]
Evidenztabellen (1)
4.4.3 EvT 4.8Hintergrundinformationen: Zu Empfehlung 4.8
Nach derzeitiger Studienlage sind ca. 50% der Peniskarzinome in Europa und weltweit mit einer HPV-Infektion assoziiert [48]. Zur Beantwortung der Frage, ob Patienten mit einer HPV-Infektion eine bessere Prognose haben, wurde eine systematische Literatursuche durchgeführt. In einem systematischen Review mit Metaanalyse konnte gezeigt werden, dass Peniskarzinom-Patienten mit Nachweis von HPV bzw. des Markers p16 ein besseres krankheitsspezifisches Überleben aufweisen [78].
Allerdings muss berücksichtigt werden, dass die aktuelle histologische Subklassifikation der WHO-Klassifikation bereits Aussagen zur HPV-Assoziation des Tumors liefert (siehe Empfehlung 4.3). Nach WHO-Klassifizierung sind sowohl bei HPV-abhängigen als auch HPV-unabhängigen Peniskarzinomen histologische Subtypen besserer und schlechterer Prognose nebeneinander enthalten. Damit kann die HPV-Assoziation schwerlich entscheidend der einzige Prognosefaktor sein.
4.4.4 Molekularbiologie
Es existieren bislang keine molekularbiologischen Marker, die für die Routinediagnostik des Peniskarzinoms empfohlen werden können.
Hintergrundinformationen: Zu Statement 4.9
Die Studienlage zu molekularbiologischen Markern beim Peniskarzinom ist sehr dürftig und basiert auf retrospektiven Untersuchungen mit geringen Fallzahlen, die darüber hinaus auch mit sehr unterschiedlichen Methoden durchgeführt wurden. Ein aneuploider Chromosomenstatus, Allel-Imbalancen an verschiedenen Chromosomenloci, MYC- Amplifikationen und epigenetische Alterationen waren in kleinen Studien mit dem Auftreten von Lymphknotenmetastasen und/oder dem Gesamtüberleben korreliert [80]; [81]; [82]; [83].
Die Studienlage zur immunhistologischen Expression von p16INK4a zeigt ein besseres Gesamtüberleben und/oder rezidivfreies Überleben bei p16-Positivität [84]; [78]; [79]. Eine abnormale immunhistologische Expression von p53 war in mehreren Studien mit einem schlechteren Gesamtüberleben, Tumorrezidiven und/oder dem Auftreten von Lymphknotenmetastasen assoziiert [84]; [85]; [86]; [87]; [88]; [89]; [90]; [91]; [92].
Die Studienlage zum Proliferationsmarker Ki-67 zeigt überwiegend eine Assoziation mit dem Lymphknotenstatus und dem Gesamtüberleben [93]; [94]. Die Datenlage zu Markern der Immuncheckpoint-Inhibition sind noch im Anfangsstadium [95]; [96].
4.4.5 Penisbiopsie
Die Biopsietechnik für die initiale Diagnosestellung soll eine hinreichend große Gewebemenge aus repräsentativen Tumorarealen liefern, um eine sichere histopathologische Diagnosestellung zu garantieren.
Hintergrundinformationen: Zu Empfehlung 4.10
Die Diagnose eines Peniskarzinoms kann üblicherweise in fortgeschrittenen Stadien schon durch die klinische Untersuchung und die Inspektion vermutet werden. Dennoch erfordert die sichere Abgrenzung von entzündlichen Erkrankungen und anderen, nicht- epithelialen Neoplasien eine histologische Diagnosesicherung vor Einleitung der definitiven Therapie.
Die Art der Biopsietechnik (Punch-Biopsie, Inzisions-Biopsie, Exzisions-Biopsie) und die Zahl der entnommenen Gewebeproben muss an die Tumorlokalisation und an den makroskopischen Tumoraspekt angepasst werden. In der Regel sind mindestens zwei getrennte Biopsie-Entnahmen aus Tumorrand und Zentrum sinnvoll. Die Größe und die Entnahmetiefe der Biopsieproben sollen sicherstellen, dass die invasive Front des Tumors erfasst ist. Nach einer Studie kam es in 30% der Fälle zu Diskrepanzen zwischen Biopsie und Penektomiepräparat bezüglich der histologischen Subklassifikation und des Gradings. In 91% war keine definitive Aussage zur Invasionstiefe möglich [97].
Bei kleinen oder ausschließlich auf das Präputium eindeutig begrenzten Peniskarzinomen kann eine sanierende Exzisionsresektion (beispielsweise durch radikale Zirkumzision) auch ohne vorausgehende histologische Diagnosesicherung erfolgen, wenn dadurch kosmetisch und funktionell keine Nachteile für den Patienten entstehen.
Eine Untersuchung der primären Biopsien oder Resektate als Schnellschnittproben ist nur in Ausnahmefällen sinnvoll, da durch die Gefrierschnitt-Technik die Aussagen zur Dignität erschwert sein können (insbesondere bei hochdifferenzierten Tumoren), und Aussagen zur histologischen Subtypisierung und zum Grading nur eingeschränkt möglich sind.
4.4.6 Intraoperative Schnellschnitte und chirurgische Absetzungsränder
Ziel der chirurgischen Therapie des Peniskarzinoms ist die vollständige Tumorentfernung mit negativen Schnitträndern. Letztere können durch die pathohistologische Schnellschnittuntersuchung bereits intraoperativ gesichert werden [98]. Die anatomische Lokalisation der Schnellschnitte und das Ausmaß des tumorfreien Sicherheitsabstandes werden prinzipiell durch das individuelle Risiko und das Ausmaß der Resektion vorgegeben. Da bevorzugte Ausbreitungsformen des Peniskarzinoms entlang von Perineuralspalten der penilen Faszie und intramukosal entlang der penilen Harnröhre beschrieben sind, verdienen diese Regionen besondere Beachtung [99].
Evidenztabellen
4.4.3 EvT 4.8
|
Referenz |
Studiendesign |
Studiencharakterisitika |
Studienziel |
Patientenmerkmale |
Intervention |
Kontrolle |
Ergebnisse |
Schlussfolgerungen |
Bemerkungen |
LoE |
|
Sand, 2018, Cancer Epidemiology, Biomarkers & Prevention |
Systematic review with meta-analysis |
n= 20 studies 1992-2017 Europe, USA, Brazil, Canada |
To examine the association between HPV DNA and p16 status with survival in men diagnosed with penile cancer. |
n= 1107 men tested for HPV G1-4 Stages I-IV Tis or Ta
Median age ranging from 52-70.9 y |
HPV+ n= 437
|
HPV- n= 670
|
DSS HR 0.61 (95% CI 0.38-0.98)
OS HR 1.04 (95% CI 0.69-1.57)
DFS (n= 3 studies, pooled analysis not available)
First study: p= 0.552
Second study: HR 0.8 (95% CI 0.1-4.2, p= 0.825)
Third study: p= 0.779 |
This systematic review and meta-analysis suggests that men with HPV DNA or p16-positive penile cancer have a significantly more favorable DSS compared with HPV/ p16-negative. Neither HPV nor p16 status were predictive markers for OS. |
Detailed results of quality assessment and detailed search strategy are not reported. |
LoE 3
ROBIS: Low |
Inwiefern hat die Bestimmung von p53, p16, Ki-67 im Präparat eine prognostische Aussagekraft?
|
Referenz |
Studien-design |
Studien-charak-terisitika |
Studienziel |
Patienten- merkmale |
Testverfahren/ Schwellenwert/ Anzahl der Testevaluatoren |
Ergebnisse |
Schluss- folgerung |
Bemer-kungen |
LoE/ RoB |
|
|
p16 |
||||||||||
|
Bethune, 2012, Oncology |
Retrospective cohort study |
n= 43 patients Canada 1997-2009
Mean follow-up 3.9 y ± 3.3 y |
To analyze, in a clinicopathologic correlation study, a small population of primarily white men with invasive squamous cell carcinoma of the penis for potential prognostic predictors. |
G1-3 T1-3 N0-2
Mean age 63y ± 12.5 y |
Immunohistochemistry
· positive, strong cytoplasmic and nuclear staining in >30% of tumor cells · equivocal, strong staining in <30% of tumor cells or weak to moderate staining in >30% of tumor cells · negative, weak to moderate staining in <5% of tumor cells or no staining
2 investigators |
Lack of p16INK4a OS HR 0.54 (95% CI 0.31-0.93) p= 0.026
CSS HR 0.53 (95% CI 0.26-1.06) p= 0.073
|
Our results have shown that 53% of the invasive penile squamous cell carcinoma cases in this population were associated with human papillomavirus, using p16INK4a as a surrogate marker of human papillomavirus infection. These patients had a statistically significant survival advantage, independent of other prognostic factors. |
|
LoE 3
QUIPS: moderate |
|
|
Bezerra, 2015, Human Pathology |
Retrospective cohort study |
n= 53 patients USA 1985-2013 |
To evaluate the correlation of p16INK4a expression and high-risk human papillomavirus with clinicopathological features and outcome in a cohort of patients with penile squamous cell carcinomas. |
pTa-4 pN0-3 Stage 0-IV
Median age 65 y (38-93 y) |
Immunohistochemistry
· Negative p16INK4a expression: Complete absence of p16INK4a staining or only focal positivity · Positive p16INK4a expression: Strong and diffuse nuclear and cytoplasmic p16INK4a positivity in most tumor cells
2 uropathologists
|
p16INK4a overexpression Tumor recurrence OR 1.43 (95% CI 0.15-13.02) p= 0.99
Tumor progression OR 1.54 (95% CI 0.46-5.20) p= 0.47
Overall mortality OR 0.80 (95% CI 0.25-2.48) p= 0.85
Cancer-specific mortality OR 0.61 (95% CI 0.11-2.66) p= 0.57
Overexpression of p16INK4a was found in 23 cases (44%) showing a significant association with histologic subtype (p= 0.01) and lymphovascular invasion (p= 0.015). |
p16INK4a overexpression was significantly associated with histologic subtype and presence of lymphovascular invasion. |
|
LoE 3
QUIPS: moderate
|
|
|
Cubilla, 2012, American Journal of Surgical Pathology |
Case serie |
n= 12 Spain, Paraguay, Mexico, USA
Median follow-up (n= 11) 48 mo |
To characterizing their clinical, morphologic, differential, and outcome features in detail, as well as their association with specific HPV genotypes. |
n= 5 noninvasive tumors
11/12 HPV 9/12 HPV-16 12/12 overexpression of p16ink4a
Median age 79 y ( 35-90 y) |
Immunochemistry |
7/12 alive with no evidence of metastatic disease 3/12 died from other causes 1/12 died postoperatively 1/12 recurrence |
The overall prognosis was excellent. Deeply invasive tumors were associated with regional nodal metastasis indicating a potential for tumor-related death. |
|
LoE 4
QUIPS: high |
|
|
Ferrandiz-Pulido, 2013, JAAD
|
Retrospective cohort study |
n= 82 patients Spain 1987-2010 |
We sought to provide novel data about the prevalence of HPV in a large series of penile intraepithelial neoplasia and invasive penile squamous cell carcinoma, correlating the results with the histologic subtype, p16INK4a immunostaining, and prognosis. |
n= 69 invasive penile squamous cell carcinoma n= 13 penile intraepithelial neoplasia
Median age 69 y (35-96 y) |
Immunohistochemical expression
Cut-off point H-Score for positive cases: 50
2 independent observers |
Tumor stage (p> 0.05) Tumor stage I p16 positive: 29% p16 negative: 71%
Tumor stage >1 p16 positive: 36% p16 negative: 64%
Lymph node metastases (p> 0.05) Lymph node metastases p16 positive: 26% p16 negative: 74%
No lymph node metastases p16 positive: 37.5% p16 negative: 62.5%
Died of disease (p> 0.05) Died p16 positive: 18% p16 negative: 82%
Alive p16 positive: 37.5% p16 negative: 62.5% |
p16INK4a overexpression had a trend toward higher tumoral stages, development of lymph node metastases, disease-related death, or a combination of these, without reaching statistical significance. |
|
LoE 3
QUIPS: moderate |
|
|
Gunia, 2012, Journal of Urology
|
Retrospective cohort study |
n= 92 patients Germany 1993-2010
Median follow-up 32 mo (6-66 mo) |
To assess the prognostic role of p16INK4a expression in penile cancer with respect to cancer specific survival. |
pT1a-pT3 pN0-N+ G1-G3
n= 38 P16INKa negative n= 54 P16INKa positive
Mean age 67.2 ± 12.1 y |
Immunohistochemistry
Negative: · 0: absent p16INK4a expression in all epithelial cells, pattern
Positive: · 1: spotty, patchy and discontinuous immunostaining in suprabasal epithelial cells, pattern · 2: comparatively more extensive but discontinuous suprabasal expression and pattern · 3: full-thickness, continuous immunostaining in all epithelial cells except in the parakeratotic layer
two pathologist |
2 y-CSS Negative P16INKa: 73% Positive P16INKa: 95%
5 y-CSS Negative P16INKa: 57% Positive P16INKa: 85% p= 0.011
Prognostic parameter (multivariate analysis) Model 2 incorporating dichotomized p16INK4a: HR 0.25 (95% CI 0.08-0.079) p= 0.018 Model 3 incorporating nondichotomized p16INK4a: HR 0.44 (95% CI 0.23–0.84) p= 0.013 |
Results show that p16INK4a seems to be a prognostic parameter for primary invasive penile cancer with excellent interobserver reproducibility. |
|
LoE 3
QUIPS: moderate
|
|
|
McDaniel, 2015, Cancer Res |
Retrospective cohort study |
n= 43 patients USA 2005-2013 |
We performed comprehensive, targeted next-generation sequencing to identify relevant somatic genomic alterations. |
n= 60 fixed tumor samples |
Immunohistochemistry
two pathologist |
p16 expression Event-free survival log-rank test p= 0.03 |
Positive p16 expression was significantly associated with longer event-free survival. |
Only result of p16 are extracted here. |
LoE 3
QUIPS: high |
|
|
Sand, 2018, Cancer Epi-demioloy, Biomarkers & Prevention |
Systematic review with meta-analysis |
n= 20 studies Europe, United States, Brazil, Canada 1992-2017
|
To examine the association between HPV DNA and p16 status with survival in men diagnosed with penile cancer. |
n= 646 men tested for p16 expression
G1-4 Stages I-IV Tis or Ta
Median age ranging from 52-70.9 y |
s. Bemerkungen |
DSS p16-positive vs. p16-negative HR 0.45 (95% CI 0.30-0.69)
OS p16-positive vs. p16-negative HR 0.88 (95% CI 0.49-1.59)
|
This systematic review and meta-analysis suggests that men with HPV DNA or p16-positive penile cancer have a significantly more favorable DSS compared with HPV/ p16-negative. Neither HPV nor p16 status were predictive markers for OS. |
Many different definitions of p16 over-expression were applied in the studies included, which we were unable to take into account in the analysis. |
LoE 3
ROBIS: Low
|
|
|
Steinestel, 2015, BMC Cancer |
Retrospective cohort study |
n= 58 patient tissues Germany 1995-2012
Follow-up up to 204 mo |
We analysed penile squamous cell carcinoma tissue samples for expression of p16INK4a and presence of HPV DNA and correlated the results with tumour- and patient-specific characteristics as well as CSS. |
pTis-pT4 N0-N+ M0-M+
HPV+ 29.3%
Positive immunostaining for p16INK4a: 58.6% (wide variety in p16INK4a expression patterns)
Mean age 64.5 y (31-93 y)
|
Immunohistochemistry
one pathologist |
p16INK4a positivity and histologic differentiation grade (G1-2 vs. G3-4) were not significantly associated with CSS (p= 0.49 and p= 0.15).
Histopathologic tumour grade was not significantly associated with presence of HPV DNA.
Expression of p16INK4a and presence of HR-HPV DNA, but not histologic grade, were inversely associated with penile squamous cell carcinoma tumour invasion (p= 0.01, p= 0.03, and p= 0.71).
For verified nodal involvement or distant metastasis, there was no significant association with HPV status, p16INK4a positivity or grade of differentiation of the primary tumour (p = 0.22, p = 0.25, and p = 0.41).
Test statistics for basaloid histologic subtype and p16INK4a immunostaining to predict HR-HPV positivity Basaloid histologic subtype ppV: 40% Sensitivity: 11% Specificity: 95%
Any positivity for p16INK4a ppV: 53% Sensitivity: 100% Specificity: 60%
Intense nuclear p16INK4a staining ppV: 75% Sensitivity: 100% Specificity: 85% |
Our results confirm intense nuclear positivity for p16INK4a, rather than histologic subtype, as a good predictor for presence of HR-HPV DNA in penile squamous cell carcinoma. HR-HPV / p16INK4a positivity, independent of histological tumour grade, indicates a less aggressive local behaviour; however, its value as an independent prognostic indicator remains to be determined. Since local invasion can be judged without p16INK4a/HPV-detection on microscopic evaluation, our study argues against routine testing in the setting of penile squamous cell carcinoma. |
|
LoE 3
QUIPS: high |
|
|
Tang, 2015, Journal of Urology
|
Retrospective cohort study |
n= 119 patients USA 1998-2013
Median follow-up 30 mo |
We evaluated high risk human papillomavirus status with respect to various clinical features, including recurrence and OS, among others. |
Tis-T2+ N1-3
P16ink4a over expression: 49.5%
Median age 64 y (33-88 y) |
Immunohistochemistry
Over expression: Diffuse, continuous and strong nuclear and cytoplasmic staining of the neoplastic cells on both tissue cores
Negative for P16ink4a over expression: Discontinuous, focal and weak staining as well as the absence of staining
one genitourinary pathologist |
Recurrence after primary resection and positive lymph node dissection (multivariate analysis) P16 negative: OR 1.0 (reference) P16 positive: OR 0.066 (95% CI 0.007-0.556) p= 0.012
P16ink4a expression vs. · Overall recurrence (p= 0.0383) · Recurrence after positive lymph nodes at diagnosis (p= 0.0018) · Tumor stage (p= 0.518) · Histological grade (p= 0.225) · Lymphovascular invasion (p= 0.388) · OS (p= 0.156) · Lymph node metastasis (p= 0.748) · DSS (p= 0.605) |
These data suggest that P16ink4a/high risk human papillomavirus status is associated with recurrence, especially in patients with positive lymph nodes at diagnosis. Patients with P16ink4a negative penile cancer, particularly those with lymph node metastases, may warrant closer observation after surgery. |
|
LoE 3
QUIPS: low |
|
|
Zargar-Shoshtari, 2016, Clinical Geni-tourinary Cancer |
Retrospective cohort study |
n= 57 patient tissues USA 1999-2013
Median follow-up 22 mo |
To assess clinical utility of p16ink4a and p53 staining in a contemporary cohort of patients treated for penile cancer. |
T1-4 N0-N3
Median age 60 y (53-73 y) |
Immunohistochemistry
Overexpression of p16ink4a: continuous strong nuclear and cytoplasmic staining of the entire carcinoma
one specialized genitourinary pathologist |
p16 positive vs. negative OS HR 0.33 (95% CI 0.13-0.85) p= 0.02
CSS HR 0.36 (95% CI 0.13-0.99) p= 0.05 |
p53 and p16 status showed clinical utility in predicting nodal disease as well as survival.
|
|
LoE 3
QUIPS: moderate |
|
|
Zhang, 2018, BioMed Research Inter-national |
Systematic review with meta-analysis |
n= 5 studies Canada, Germany, Spain, USA
Mean or median follow-up 1.8-3.9 y
|
We performed this meta-analysis to clarify the prognostic value of P16INK4a for penile squamous cell carcinoma. |
n= 323 cases
Mean or median age 60-69 y
|
Immunohistochemistry
different cut-off values for P16INK4a expression |
Pooled outcome of five eligible studies on the association between P16INK4a positive expression and penile cancer prognosis HR: 0.45 (95% CI 0.3-0.67) p< 0.001 |
P16INK4a positive expression is independently associated with improved CSS for patients with penile squamous cell carcinoma. |
|
LoE 3
ROBIS: low |
|
|
p53 |
||||||||||
|
Bethune, 2012, Oncology |
Retrospective cohort study |
n= 43 patients Canada 1997-2009
Mean follow-up 3.9 y ± 3.3 y |
To analyze, in a clinicopathologic correlation study, a small population of primarily white men with invasive squamous cell carcinoma of the penis for potential prognostic predictors. |
G1-3 T1-3 N0-2
Mean age 63y ± 12.5 y |
Immunohistochemistry
Positive: >5% of the tumor cells showed nuclear staining
Negative: Nuclear staining of <5%
2 investigators |
p53-positive staining 9/17 have distant metastasis 5/17 died of disease
Without p53-positive staining 5/26 have distant metastasis 4/26 died of disease
p53 status did not show significant differences in survival in our analysis. |
p53 and Ki-67, were not independent predictors of outcome in our analysis |
|
LoE 3
QUIPS: moderate |
|
|
Ferrandiz-Pulido, 2013, Journal of Urology
|
Retrospective cohort study |
n= 67 patients Spanish Mediterranean population 1987-2010
Median follow-up 27 mo (1-247 mo)
|
To assess a possible role for mTOR signaling pathway activation as a potential predictive biomarker of outcome and a therapeutic target for penile cancer. |
pT1-3 G1-4
Median age 70 y (40-96 y)
|
Immunohistochemical staining
Over expression was considered when the H-score of each marker was greater than the median H-score of that marker for all invasive penile squamous cell cancer.
2 investigators |
p53 over expression was associated with disease related death on Kaplan-Meier plots (p <0.001).
Over expression of p53 was significantly associated with lymph node disease.
p53 correlated with a poor outcome, including recurrence, metastasis or disease specific death. |
Over expression of p53 is a prognostic factor of poor survival in penile squamous cell carcinoma cases. |
|
LoE 3
QUIPS: moderate |
|
|
Gunia, 2012, Journal of Clinical Pathology
|
Retrospective cohort study |
n= 110 patients 1993-2010
Median follow-up 32 mo (6-66 mo) |
To evaluate the role of p53, p21 and cyclin D1 expression in patients with penile cancer. |
pT1a-pT3 pN0-N+ G1-G3
n= 62 p53 negative n= 30 p53 positive
Mean age 67.2 ± 12.1 y |
Immunostaining
Negative absent or weak nuclear expression restricted to basal cells
Positive at least moderately strong nuclear expression in basal and suprabasal cells
two independent pathologists |
5 y-CSS Negative p53: 84% Positive p53: 51% p= 0.003
p53 expression vs. no p53 expression (univariate analysis) HR 4.22 (1.50-11.91) p= 0.007 |
In patients with penile cancer, the expression of p53 in the primary tumour specimen can be reproducibly assessed and is negatively associated with cancer specific survival. |
|
LoE 3
QUIPS: low |
|
|
Liu, 2013, World Journal of Urology |
Retrospective cohort study
|
n= 146 patients China 1998-2011
Follow-up 42 mo (13-108 mo) |
To evaluate factors in penile squamous cell carcinoma predictive of pelvic lymph node metastasis and survival.
|
Grade I-III T1-4
Mean age 51 y (24-82 y) |
The immunoreactivity of p53 staining was graded as positive when at least 20% of cells were stained in the nucleus.
reviewed by pathologists |
Prognostic factors for pelvic lymph node metastasis Immunoreactivity of p53 (weak vs. strong) OR/HR: 22.431 (95% CI 3.928–128.111) p<0.001
Multivariate Cox regression analysis of prognostic factors for overall survival Immunoreactivity of p53 (weak vs. strong) OR: 5.997 (95% CI 1.615–22.275) p= 0.007 |
Strong p53 expression, vascular or lymphatic invasion of the primary tumor, involvement of more than two inguinal lymph nodes and 30 % or greater lymph node density were independent prognostic factors for pelvic lymph node metastasis. |
|
LoE 3
QUIPS: low |
|
|
Lopes, 2002, Journal of Urology
|
Retrospective cohort study |
n= 82 tisusses Brazil 1953-1992
Mean follow-up 88.7 mo (0.1-453 mo) |
To evaluate the prognostic value of immunohistochemical p53 staining in the primary tumor. |
T2-4 N0-3 Grade I-II
n= 57 HPV positive
n= 34 p53 positive
Mean age 52 y (27-77 y)
|
Immunohistochemical testing
p53 staining was graded as positive when at least 20% of cells were stained in the nucleus.
1 pathologist |
OS 5 y- OS Positive p53: 30.2% Negative p53: 65.2%
10 y- OS Positive p53: 26.4% Negative p53: 54.6% (p= 0.009)
HPV and p53 neg 5 y-survival: 65.3% 10 y-surival: 54.5% p= 0.017
HPV and p53 pos 5 y-survival: 12.5% 10 y-survival: 12.5% (p= 0.017) |
Immunoreactivity of p53 is an independent factor for lymph node metastasis. The association of positive p53 with positive HPV DNA was related to a worse prognosis. |
|
LoE 3
QUIPS: moderate |
|
|
Martins, 2002, Journal of Urology |
Retrospective cohort study |
n= 50 tissues Brazil 1978-1995
Median follow-up 9 y (5-22 y) |
To examine p53 protein and proliferating cell nuclear antigen immunoexpression as prognostic factors to the outcome of squamous cell carcinoma of the penis in 50 patients. |
pT1-4 G1-2 N0-N+
Median age 59 y (35-88 y)
|
Immunohistochemistry
two investigators |
Cause-specific death Overall p53 labeling index <10% vs. p53 labeling index >10% p< 0.0001 (95% CI 3.7778-2.220)
N0 p53 labeling index <10% vs. p53 labeling index >10% p= 0.003 (95% CI 2.174-51.01)
Multivariate analysis of p53 in relation to nodal metastasis Overall p= 0.002 (95% CI 3.820-493.9)
N0 p= 0.02 (95% CI 1.600-2.66.436) |
Over expression of p53 was associated with regional lymphatic spread, recurrence and cause specific death. |
|
LoE 3
QUIPS: moderate |
|
|
McDaniel, 2015, Cancer Res |
Retrospective cohort study |
n= 43 patients USA 2005-2013 |
We performed comprehensive, targeted next-generation sequencing to identify relevant somatic genomic alterations. |
n= 60 fixed tumor samples |
Immunohistochemistry
two pathologist |
Event-free survival TP53 expression p= 0.01 |
TP53 expression (p= 0.01) was significantly associated with shorter event-free survival. |
|
LoE 3
QUIPS: high |
|
|
Necci, 2016, Clinical Geni-tourinary Cancer |
Retrospective cohort study |
n= 21 patients 2004-2012
Follow-up 52 mo (47.6-100.4 mo) |
To identify whether some prognostic factors might be found to guide further research in the field of adjuvant therapy for penile squamous cell carcinoma. |
N1-3 pN0, N2, N3
n= 11 p53 positive n= 8 p53 negative
Median age 63 y (55-69 y)
all patients received TPF chemotherapy |
Immunohistochemistry
Positive percentage of positive nuclei ≥90%
Negative percentage of positive nuclei <90%
two pathologist |
p53 positive vs. negative (multivariate analysis) DFS: 3.76 (95% CI 0.79-17.96 p= 0.096)
OS: HR 4.29 (95% CI 0.89-20.57) p=0.068
Median DFS for p53-expressing patients 8.9 mo (5.9-22.7 mo)
Median OS for p53-expressing patients 17.2 mo (12.8-22.7 mo)
Kaplan-Meier curves for DFS and OS according to the immunohistochemistry expression of was statistically significant for OS (DFS: p= 051, OS: p= 0.037) |
In patients who had received adjuvant TPF for node-positive penile squamous cell carcinoma, p53 immunohistochemistry expression seemed to be associated with a poorer outcome, and further study is warranted in larger data sets to confirm these findings. |
|
LoE 3
QUIPS: moderate |
|
|
Rocha, 2012, Human Pathology |
Cohort study |
n= 297 patients Brazil 1980-2009 |
To examine the immunohistochemical expression of p53 and murine double minute 2 in 297 cases of penile carcinoma, to determine whether protein alterations were associated to gene and chromosomal numeric alterations or to gene mutations. |
G1-3
Average age 55 y
|
Immunohistochemistry
two evaluator |
Survival analysis positive p53 (multivariate analysis) HR 1.83 (95% CI 1.11-3.04) p= 0.024
OS p53 negative vs. p53 positive p= 0.0013
Patients who died of disease expressed higher levels of p53 compared with patients with no evidence of disease (p= 0.0030). |
We demonstrated the prognostic value of evaluating p53 in penile cancer because survival declined in patients with p53-positive tumors.
|
|
LoE 3
QUIPS: moderate
|
|
|
Zargar-Shoshtari, 2016, Clinical Geni-tourinary Cancer |
Retrospective cohort study |
n= 57 patients USA 1999-2013
Median follow-up 22 mo |
To assess clinical utility of p16ink4a and p53 staining in a contemporary cohort of patients treated for penile cancer. |
T1-4 N0-N3
n= 31 p53 negative
Median age 60 y (53-73 y) |
Immunohistochemistry
Negative p53 expression no staining or weak staining of ≤5% (ie, H score ≤5)
Significant p53 expression expression of moderate intensity at 50% or greater or any strong p53 expression (H score of ≥150)
one specialized genitourinary pathologist |
p16 status had a more pronounced protective influence on CSS in p53-negative (H < 5) patients (p16 positive vs. p16 negative; median, not reached; p= 0.07), than in p53-positive patients. (median, not reached; p= 0.89). |
p53 and p16 status showed clinical utility in predicting nodal disease as well as survival. |
|
LoE 3
QUIPS: moderate |
|
|
Zhu, 2007, BJUI |
Cohort study |
n= 73 patients China 1990-2005 |
To evaluate the prognostic significance of p53, Ki-67, epithelial cadherin and matrix metalloproteinase-9 in primary penile cancer. |
T1 - ≥T2 G1- ≥ 2
33% high expression of p53
45% high expression of KI-67
Median age 55 y (27-75 y) |
Immunohistochemical staining
p53 expression was categorized as high when >20% of the tumour nuclei were stained
two observers |
Multivariate analysis showed that the expression of p53 (RR 5.31, 95% CI 1.477–19.086) was the only independent predictor of CSS.
CSS (multivariate analysis) p53 low vs. high: p= 0.016
3 y-CSS (multivariate analysis) p53 low vs. high: p= 0.011 |
The expression of p53 is an independent predictor of CSS in Chinese patients with penile cancer. In stage T1 tumours, p53 staining is an important variable determining the prognosis and treatment outcome. |
|
LoE 3
QUIPS: moderate |
|
|
Zhu, 2010, Journal of Urology
|
Retrospective cohort study |
n= 110 patients China 1990-2008
|
To develop and evaluate a nomogram to stratify patients who are suitable candidates for further treatment. |
T1-3 G1-3 N0-3
n= 78 weak p53 expression n= 32 strong p53 expression |
Immunohistochemical staining
Cutoff: strong p53 expression was 20% |
Multivariate analysis of clinicopathological factors to predict inguinal lymph node metastasis p53 expression strong (reference p53 weak): OR 3.22 (95% CI 0.96-10.86) p= 0.058 |
Lymphovascular invasion was the only independent lymph node metastasis prognostic factor in clinically lymph node negative cases of penile cancer. p53 expression failed to achieve statistical significance. |
|
LoE 3
QUIPS: moderate |
|
|
Ki-67 |
||||||||||
|
Berdjis, 2005, BJU Int |
Retrospective case serie |
n= 44 patients Germany 1992-2003
Mean follow-up 25.6 mo |
To investigated the relationship of Ki-67 labelling in primary penile carcinoma with relevant clinicopathological variables and survival of the patients. |
G1-3 T1-2 N0-1
Mean age 61.4 y (35-89 y) |
Immunohistochemistry
The mean Ki-67 labelling index was defined as the percentage of total tumour cell nuclei that were Ki-67- positive.
two observer |
Mean Ki-67 labelling index: 40.5 (6.4-93%)
High mean Ki-67 LI was significantly inversely correlated with tumour differentiation (p< 0.005).
There was a tendency for high Ki-67 expression with advanced local tumour stage (p= 0.07), nodal metastasis (p= 0.07) and disease progression (p= 0.06). |
The Ki-67 labelling index is correlated with tumour grade in penile cancer, and may indicate a greater risk of nodal metastasis. |
|
LoE 4
QUIPS: high |
|
|
Bethune, 2012, Oncology |
Retrospective cohort study |
n= 43 patients Canada 1997-2009
Mean follow-up 3.9 y ± 3.3 y |
To analyze, in a clinicopathologic correlation study, a small population of primarily white men with invasive squamous cell carcinoma of the penis for potential prognostic predictors. |
G1-3 T1-3 N0-2
Mean age 63y ± 12.5 y |
Immunohistochemistry
Positive: >10% of the tumor cells showed nuclear staining
Negative: Nuclear staining of <10%
2 investigators |
No significant differences or trends were identified with respect to outcome and Ki-67 status, most likely because of the overwhelming percentage of Ki-67 positive cases (36 [86%] of 43). |
p53 and Ki-67, were not independent predictors of outcome in our analysis. |
|
LoE 3
QUIPS: moderate |
|
|
Kayes, 2009, Clinical Cancer Research
|
Retrospective cohort study |
n= 141 patients United Kingdom 1988-2007
Survival follow-up 20.1 mo (1-160 mo)
|
We have analyzed replication licensing factors, together with DNA ploidy status, to investigate their role in progression of penile squamous cell carcinoma and to assess their utility as novel prognostic tools. |
G1-3 T1-4 N0-3 M0-1
Mean age 62.7 y (27-86) |
Immunohistochemistry
one uro-oncology pathologist |
Univariate analysis showed that Mcm2 (p= 0.02) and Ki67 (p= 0.04) expression and Ki67-geminin score (p= 0.03) were all significantly associated with overall survival. |
Mcm2 and Ki67 LIs, Ki67-geminin score, age, tumor stage, depth of invasion, tumor extent, vascular invasion, and nodal and ploidy status were all identified as predictors of overall survival, with lymph node status, tumor extent, and ploidy status identified as independent predictors of overall survival. |
|
LoE 3
QUIPS: moderate |
|
|
Li, 2013, Medical Oncology |
Retrospective cohort study |
n= 54 patients China 2004-2011 |
The expressions of HDGF, VEGFA, and Ki-67 proteins were detected by immunohistochemistry to investigate their correlations with both clinicopathologic factors and clinical prognosis. |
Median age 61 y (22-86 y)
|
Immunohistochemistry |
Overall survival Ki-67 Positive: 57.7% Negative: 53.6% Risk: 1.182 (95% CI 0.403-3.465), p= 0.761
|
Age, tumor size, grade, lymphatic involvement, cell subtype, smoking status, and VEGF-A and Ki-67 expressions, were insignificantly related with survival rate of penile squamous cell carcinoma patients. |
|
LoE 3
QUIPS: moderate |
|
|
May, 2013, BJUI |
Retrospective cohort study |
n= 158 tissues Germany 1992-2010
Median follow-up 33 mo (3-63 mo) |
To assess the role of cell proliferation-associated biomarkers to predict CSS in patients with surgically treated squamous cell carcinoma of the penis. |
pTa/CIS-pT3 pN0-N+ G1-3 M0
Median age 67y (57-74.3 y) |
Immunohistochemistry
Score 1+ marker expression predominantly in basal cell nuclei with no more than occasional extension to suprabasal cell nuclei
Score 2+ nuclear expression in basal and many suprabasal cell nuclei, but no full-thickness marker expression
Score 3+ nuclear marker expression throughout the entire neoplastic epithelium corresponding to full-thickness marker expression
two independent study pathologists |
KI-67 expression CSS (univariate analysis) HR 1.47 (95% CI 1.01–1.82) p= 0.047
Multivariate analysis: not statistically significant
|
Ki-67, MCM2 and geminin do not represent independent prognostic parameters but reflect a more aggressive behaviour in surgically treated squamous cell carcinoma of the penis. |
|
LoE 3
QUIPS: moderate |
|
|
Protzel, 2007, Histology & Histo-pathology
|
Case serie |
n= 28 patients 1993-2003
Median follow-up 46.1 mo (2-105 mo) |
To gain insight into the role of Ki67 and HPV infection in PSCC, Ki67 expression was assessed immunohistochemically in the present study in penile squamous cell carcinoma primary tumors. |
pT1-4 N1-3 M0-1
10,5% HPV+
|
Immunohistochemistry
Weak less than 15% of the nuclei positive
Intermediate 15-60% of nuclei positive
Strong more than 60% of the nuclei positive
two independent observers |
Ki67 expression and presence of HPV DNA in relation to nodal metastasis N0 <15% 4/4 patients 15-60% 8/17 patients >60% 0/7 patients
N+ <15% 0/4 patients 15-60% 9/17 patients >60% 7/7 patients p= 0.005
Ki67 expression and presence of HPV DNA in relation to nodal metastasis M0 <15% 4/4 patients 15-60% 8/17 patients >60% 3/7 patients
M+ <15% 0/4 patients 15-60% 2/17 patients >60% 4/7 patients p= 0.026
Chi-Square test showed a significant association between HPV status and Ki67 expression (p=0.009). |
Our study demonstrated a strong Ki67 labeling index significantly associated to positive lymph nodes, we suggest Ki67 expression as a prognostic marker for lymph node metastasis in penile squamous carcinoma. |
|
LoE 4
QUIPS: moderate |
|
|
Stankiewicz2012, Journal of Clinical Pathology |
Retrospective cohort study |
n= 148 samples United Kingdom 2001-2007
|
To determine whether Ki-67 immunoexpression in penile squamous cell carcinoma has a prognostic value and correlates with lymph node metastasis, HPV infection and patient survival. |
G1-3 N0-3 |
Immunohistochemistry
Cut-off point for antibody positivity: >40%
one genitourinary pathologist |
Positive vs. negative Ki-67 expression CSS: HR= 1.00 (95% CI 0.99-1.02) p= 0.54 OS: HR= 1.00 (95% CI 0.99-1.02) p= 0.45
There was no significant difference in OS (p= 0.5538) and CSS (p= 0.6221) for patients with positive and negative Ki-67 expression. |
Ki-67 is only a moderate surrogate marker for HPV infection in penile squamous cell carcinoma. It does not show prognostic value for cancer-specific survival and overall survival in penile squamous cell carcinoma. |
|
LoE 3
QUIPS: moderate |
|
|
Zhu, 2007, BJUI |
Cohort study |
n= 73 China 1990-2005 |
To evaluate the prognostic significance of p53, Ki-67, epithelial cadherin and matrix metalloproteinase-9 in primary penile cancer. |
T1 - ≥T2 G1- ≥ 2
33% high expression of p53
45% high expression of KI-67
Median age 55 y (27-75 y) |
Immunohistochemical staining
Overall mean expression score (20%) was used as the threshold.
two observers |
CSS (multivariate analysis) Ki-67 low vs. high: p= 0.861
3 y-CSS (multivariate analysis) Ki-67 low vs. high: p= 0.323
|
The expression of p53 is an independent predictor of CSS in Chinese patients with penile cancer. |
Ergebnisse zur Ki-67 wurden nicht in die Schluss-folgerungen aufge-nommen, da diese nicht signifikant waren. |
LoE 3
QUIPS: moderate |
|
Literaturhinweise
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[52] Rubin, M. A., Kleter, B., Zhou, M., Ayala, G., Cubilla, A. L., Quint, W. G., et.al. Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis, Am J Pathol, 2001. 159(4): p. 1211-8., https://www.ncbi.nlm.nih.gov/pubmed/11583947
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