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Combined p16 and p53 expression in cervical cancer of unknown primary and other prognostic parameters

A single-center analysis

Kombinierte p16- und p53-Expression beim Zervixkarzinom mit unbekanntem Primarius und andere prognostische Parameter

Eine unizentrische Analyse

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An Erratum to this article was published on 24 May 2017

Abstract

Background and purpose

Cervical cancer of unknown primary (CUP) represents an uncommon and heterogeneous subentity of head and neck cancer. However, both optimal diagnostics and therapy remain unclear. An improved understanding of the underlying pathology is essential to enable future tailored therapies and optimized outcomes.

Materials and methods

We retrospectively analyzed 53 patients with head and neck CUP and 48 available cervical lymph node specimens. All patients have received radiotherapy between 2007 and 2015. Preradiotherapy involved lymph node specimens were analyzed for p16 and p53 immunoreactivity. The prognostic relevance of the combined p16 and p53 status and other clinical parameters were examined by univariate and multivariate analyses.

Results

Median patient age was 61.5 years and median irradiation dose to the involved nodal levels was 66 Gy. Of the 48 evaluated specimens, 13 (27%) were p16-positive and 31 (64.6%) p53-positive. After a median follow up of 32.9 months, patients with p16-negative and simultaneously p53-positive tumors showed a significantly inferior tumor-specific survival (TSS) compared to those with either p16+/p53−, p16+/p53+, or p16−/p53− (univariate: p = 0.055, multivariate: p = 0.038). Other factors with an adverse impact on TSS in the univariate analysis were smoking history (p = 0.032) and nodal stage (p = 0.038).

Conclusions

The combined p16- and p53-expression status in cervical metastases of CUP may represent a simple method for risk stratification. Further validation of these biomarkers in large prospective trials is essential to design rational trials for CUP treatment optimization.

Zusammenfassung

Hintergrund

Zervikale Lymphknotenmetastasen eines unbekannten Primarius (CUP) sind eine seltene und heterogene Entität innerhalb der Kopf-Hals-Tumoren. Sowohl die optimale Diagnostik als auch die Behandlung dieser Erkrankung bleiben unklar. Ein besseres Verständnis der zugrundeliegenden Pathologie ist für künftige individualisierte Therapien und verbesserte Behandlungsergebnisse essentiell.

Materialien und Methoden

Wir analysierten retrospektiv 53 Patienten mit zervikalem CUP und 48 verfügbare Paraffinblöcke von tumorbefallenen Lymphknoten. Alle Patienten wurden zwischen 2007 und 2015 radiotherapeutisch behandelt. Die prätherapeutischen Lymphknotenschnitte wurden auf p16- und p53-Immunreaktivität untersucht. Die prognostische Relevanz des kombinierten p16- und p53-Status und andere klinische Parameter wurden mittels univariater und multivariater Analysen untersucht.

Ergebnisse

Das mediane Patientenalter war 61,5 Jahre und die mediane Bestrahlungsdosis für die befallenen Lymphknotenregionen war 66 Gy. Von den 48 ausgewerteten Proben waren 13 (27%) p16- und 31 (64,6%) p53-positiv. Nach einem medianen Follow-up von 32,9 Monaten zeigten Patienten mit p16-negativen und gleichzeitig p53-positiven Tumoren ein signifikant unterlegenes tumorspezifisches Überleben (TSS) im Vergleich zu Patienten mit p16+/p53−, p16+/p53+ oder p16−/p53− (univariat: p = 0,055, multivariat: p = 0,038). Andere Faktoren mit signifikanter negativer Korrelation mit dem TSS in der univariaten Analyse waren Raucheranamnese (p = 0,032) und Lymphknotenstadium (p = 0,038).

Schlussfolgerung

Die kombinierte p16- und p53-Expression in zervikalen Metastasen eines CUP könnte eine einfache Methode zur Risikostratifizierung darstellen. Weitere Validierung dieser Biomarker in großen prospektiven Studien ist notwendig, um rationale Studien zur Optimierung der CUP-Therapie zu entwerfen.

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Authors and Affiliations

  1. Department of Radiation Oncology, University Hospital, Johann Wolfgang Goethe University, Theodor Stern Kai 7, 60590, Frankfurt, Germany

    Müjdat Yildirim MD, Jens Müller von der Grün, Emmanouil Fokas MD, PhD, Franz Rödel PhD, Claus Rödel MD & Panagiotis Balermpas MD

  2. Senckenberg Institute of Pathology, University Hospital, Johann Wolfgang Goethe University, Frankfurt, Germany

    Ria Winkelmann MD

  3. German Cancer Research Center (DKFZ), Heidelberg, Germany

    Emmanouil Fokas MD, PhD, Claus Rödel MD & Panagiotis Balermpas MD

  4. German Cancer Consortium (DKTK), partner site: Frankfurt a. M., Germany

    Emmanouil Fokas MD, PhD, Claus Rödel MD & Panagiotis Balermpas MD

  5. Department of Biomedical Statistics, Johann Wolfgang Goethe University, Frankfurt, Germany

    Hanns Ackermann PhD

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  1. Müjdat Yildirim MD
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Correspondence to Panagiotis Balermpas MD.

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Conflict of interest

M. Yildirim, J. Müller von der Grün, R. Winkelmann, E. Fokas, F. Rödel, H. Ackermann, C. Rödel, and P. Balermpas declare that they have no competing interests.

Ethical standards

All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies.

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/s00066-017-1155-4.

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Yildirim, M., Müller von der Grün, J., Winkelmann, R. et al. Combined p16 and p53 expression in cervical cancer of unknown primary and other prognostic parameters. Strahlenther Onkol 193, 305–314 (2017). https://doi.org/10.1007/s00066-017-1102-4

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