Aktuelle Urol 2019; 50(05): 491-501
DOI: 10.1055/a-0664-0316
Originalarbeit
© Georg Thieme Verlag KG Stuttgart · New York

Bedeutung von p16(INK4A) hinsichtlich des Nachweises von HPV-DNA und in der Stratifizierung der tumorspezifischen Mortalität bei 34 Patienten mit invasivem Peniskarzinom in Langzeit-Nachbeobachtung

Role of p16(INK4A) in detection of human papillomavirus DNA and stratification of cancer-specific mortality on the basis of long term follow-up data of 34 patients with invasive penile cancer
Johannes Bründl
1   Urologische Klinik des Caritas-Krankenhauses St. Josef, Universität Regensburg, Regensburg
,
Christina Neppl
2   Universität Regensburg, Institut für Pathologie, Regensburg
3   Universität Bern, Pathologisches Institut, Bern, Schweiz
,
Thomas Hommer
1   Urologische Klinik des Caritas-Krankenhauses St. Josef, Universität Regensburg, Regensburg
,
Wolfgang Otto
1   Urologische Klinik des Caritas-Krankenhauses St. Josef, Universität Regensburg, Regensburg
,
Johannes Breyer
1   Urologische Klinik des Caritas-Krankenhauses St. Josef, Universität Regensburg, Regensburg
,
Sabine Brookman-May
4   St. Elisabeth Klinikum Straubing, Klinik für Urologie, Straubing
,
Florian Weber
2   Universität Regensburg, Institut für Pathologie, Regensburg
,
Maximilian Burger
1   Urologische Klinik des Caritas-Krankenhauses St. Josef, Universität Regensburg, Regensburg
,
Matthias May*
4   St. Elisabeth Klinikum Straubing, Klinik für Urologie, Straubing
,
Christian Eichelberg*
1   Urologische Klinik des Caritas-Krankenhauses St. Josef, Universität Regensburg, Regensburg
› Author Affiliations
Further Information

Publication History

Publication Date:
18 September 2018 (online)

Zusammenfassung

Hintergrund Bei etwa jedem dritten Patienten mit einem penilen Plattenepithelkarzinom (PSCC) gilt die Infektion mit Humanen Papillomaviren (HPV) als entscheidender Faktor der Karzinogenese. Erste Daten zur optimierten Risikostratifizierung und Therapie anhand des HPV-Status existieren; somit hat der Nachweis einer HPV-Genese möglicherweise mehr als lediglich eine epidemiologische Dimension. Referenz zur Detektion von HPV ist die aufwendige Polymerase-Kettenreaktion (PCR). Unklar ist, ob Alternativen wie die In-situ-Hybridisierung (ISH) oder verschiedene Surrogatmarker (immunhistochemischer Nachweis einer p16INK4a-Expression, histologischer Subtyp, Tumorinvasionsfront, Koilozytose), zur Bestimmung des HPV-Status ausreichend sind.

Methoden In dieser unizentrischen Studie an 34 Patienten mit PSCC wurden eine Multiplex nested-PCR zur Festlegung des HPV-Status und Genotypisierung der HPV-DNA sowie eine ISH durchgeführt. Diverse histologische Kriterien und p16INK4a wurden durch zentralen Review bestimmt. Der Einfluss verschiedener Kriterien auf die karzinomspezifische Mortalität (CSM) wurde mit Cox-Regressionsmodellen geprüft (FU: 92 Mon.). Ferner erfolgte der Vergleich der diskriminativen Qualitäten verschiedener Tumorinvasionsmuster (u. a. TNM-Klassifikation 7. vs. 8. Auflage) hinsichtlich der CSM-Prädiktion.

Ergebnisse Gemäß PCR-Analyse wiesen 26 % der Patienten HR-HPV auf (n = 9). ISH und die untersuchten histologischen Kriterien zeigten eine unzureichende Vorhersagegenauigkeit des HPV-Status (p > 0,3). p16INK4a erreichte in den Testkriterien Sensitivität, Spezifität, positiv-prädiktiver und negativ-prädiktiver Wert sowie Gesamtübereinstimmung 66,7 %, 84 %, 60 %, 87,5 % bzw. 79,4 % (AUC: 0,753; p = 0,026).

Keines der Untersuchungskriterien (inkl. PCR) korrelierte signifikant mit der CSM. Im Vergleich zur 7. wies die 8. Auflage der pT-Klassifikation eine bessere CSM-Prädiktion auf (C-Indizes 70,2 % vs. 72,9 %). In Addition zur Schwellkörper-Invasion besaß die Urethra-Infiltration keinen eigenständigen prädiktiven Wert. Eine durch uns vorgeschlagene Neu-Gruppierung der Schwellkörper-Invasionsmuster erzielte eine Diskriminationssteigerung bzgl. der CSM (C-Index 77,9 %).

Schlussfolgerung p16INK4a erlaubt – im Gegensatz zur ISH und den untersuchten histologischen Kriterien – eine akzeptable Vorhersage des HPV-Status. Der Nachweis von HPV-DNA inkl. seiner Surrogatmarker hatte keinen Einfluss auf die CSM. Die 8. Auflage der pT-Klassifikation scheint prognostisch sinnvoll, da die urethrale Tumorinvasion keinen eigenständigen Einfluss auf die CSM aufweist.

Abstract

Background Human papillomavirus (HPV) infection plays an important role in the pathogenesis of penile squamous cell carcinoma (PSCC) in about one third of the affected patients. Initial data indicate that HPV status could facilitate optimised risk stratification and individualised targeted therapy. The polymerase chain reaction (PCR) assay is the reference method for detection of HPV DNA. It is unclear if alternatives such as in situ hybridisation (ISH) or various surrogate markers (defined as immunohistochemical detection of p16INK4a, histological subtype, tumour invasion front, koilocytosis) are sufficient to determine HPV status

Methods In this single centre study on 34 patients with PSCC, multiplex nested PCR and ISH were conducted for HPV detection and identification of HPV DNA genotypes. Various histological criteria and p16INK4a were determined by central review. The influence of different criteria on cancer-specific mortality (CSM) was investigated with the Cox proportional hazards models (FU: 92 mo.). Furthermore, the discriminative qualities of various tumour invasion patterns (i. e., pT-classification 7th vs. 8th ed.) for CSM prediction were compared.

Results Pursuant to PCR assay, HPV DNA was detected in 26 % of patients (n = 9). ISH and the examined histological criteria were of inadequate quality in the prediction of HPV status (p > ;0.3). Test parameters of p16INK4a were calculated as follows: sensitivity 66.7 %, specificity 84 %, positive predictive value 60 %, negative predictive value 87.5 %, overall agreement 79.4 % (Area-Under-Curve: 0.753, p = 0.026). None of the examined HPV criteria significantly influenced CSM. In comparison to the 7th pT-edition, the 8th version was superior in CSM prediction (c-indices 70.2 % vs. 72.9 %). In addition to penile corpora invasion, infiltration of the urethra had no independent predictive value. Regrouping of the corpora invasion patterns, as proposed by us, resulted in an increase in discriminative quality (c-index 77.9 %).

Conclusions In contrast to ISH and the examined histological criteria, p16INK4a allows a reasonable prediction of HPV status. Neither HPV DNA nor its surrogate markers independently impacted CSM. As urethral tumour invasion does not independently influence CSM, the recent pT classification can be considered useful for prognosis.

* Geteilte Seniorautorenschaft


 
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