Elsevier

Oral Oncology

Volume 48, Issue 11, November 2012, Pages 1178-1184
Oral Oncology

HPV status in patients with head and neck of carcinoma of unknown primary site: HPV, tobacco smoking, and outcome

https://doi.org/10.1016/j.oraloncology.2012.05.022Get rights and content

Summary

Objectives

Infection with human papillomavirus (HPV) is linked to oropharyngeal cancer. This analysis investigated possible associations between HPV status, smoking history and survival outcome in patients with neck metastasis and carcinoma of unknown primary (CUP).

Materials and methods

Registries at the Universities of Hamburg and Kiel were searched for patients with CUP diagnosed from 2002 to 2011 who had formalin-fixed and paraffin-embedded metastatic lymph node samples available. All patients underwent routine diagnostic procedures to establish the primary site and received radiotherapy (60 Gy using conventional fractionation) with or without concurrent cisplatin-based chemotherapy depending on disease extent. Genotyping was performed using polymerase chain reaction; p16[INK4a] expression was assessed using immunohistochemistry.

Results

Sixty-three patients were included; 23 (37%) had HPV DNA/p16+ samples and 40 (63%) were negative for either/both markers. A high proportion of patients had a history of tobacco smoking; significantly fewer patients with HPV+/p16+ samples were smokers than those who were negative for either/both markers (61% vs. 90%, respectively; p = 0.0067). There were no statistically significant differences between overall or recurrence-free survival in HPV+/p16+ patients vs. those negative for either/both markers. Overall survival appeared to be superior in patients with <10 pack-years smoking history and HPV+/p16+ disease.

Conclusions

This study, the largest to date investigating HPV status in head and neck CUP, identified HPV and p16 overexpression in over one-third of patients. Tobacco smoking history appeared to affect survival in HPV+/p16+ patients. Smoking status should be considered as a prognostic factor in patients with CUP, along with HPV DNA status.

Introduction

A diagnosis of carcinoma of unknown primary (CUP) is given when a patient presents with metastatic disease but subsequent evaluation fails to identify the primary tumor. CUP presenting as neck metastasis is rare, accounting for only 2% of head and neck cancers.1 Between 70% and 90% of patients with CUP are diagnosed with squamous cell carcinoma after pathologic examination.2

According to treatment guidelines, such as those from the National Comprehensive Cancer Network,3 patients presenting with neck metastases typically undergo diagnostic procedures including histologic analysis of fine-needle aspirates of the node, followed by tonsillectomy, and random biopsies of mucosal sites, where appropriate. In Germany, standard of care also includes resection of the base of the tongue. If these procedures fail to establish the location of the primary tumor, a diagnosis of CUP syndrome is made followed by a neck dissection of levels I to V.

Lack of information about the location of primary tumors presents the physician with challenges regarding subsequent therapy. Standard radiotherapy for CUP involves treatment of the nasopharynx, oropharynx, and neck; if malignant adenopathy is centered in level III/IV, the hypopharynx and larynx should be irradiated, but the oral cavity is not generally irradiated unless submandibular lymphadenopathy is present.4 Some institutions irradiate the neck only.3 Complications associated with extensive irradiation include acute and chronic mucositis and xerostomia; skin reaction; subcutaneous fibrosis; and lymphedema of the neck or laryngeal edema. Chemotherapy may be used with radiotherapy, in particular when extracapsular spread is evident.[4], [5] Widespread irradiation can, however, result in excessive long-term toxicities.6

A link has been established between human papillomavirus (HPV) infection and various cancers, in particular cervical and oropharyngeal cancers, where 70% and 38%, respectively, of cases are estimated to be linked to HPV infection.[7], [8] Studies suggest that the presence of HPV in cervical lymph nodes is strongly associated with tumors originating in the oropharynx, although none of these studies have been conducted in a true CUP population. Begum et al. analyzed 77 aspirates from neck metastases of patients with squamous cell carcinoma of the head and neck (SCCHN), the primary site of which was known in 67 cases.9 HPV16 was detected in 13 aspirates including aspirates from 10 of 19 oropharyngeal metastases and 3 of 10 cases where the primary site was never diagnosed. HPV was not observed in any metastases from non-oropharyngeal sites. El-Mofty et al. demonstrated the reliability of using HPV status to predict the primary site in patients with cervical lymph node metastases, although this was known in the majority of patients.10 In contrast, however, Desai et al. reported a broad distribution of primary locations for HPV DNA-positive metastases including the oral cavity, skin, oropharynx, and tonsils, among others, in their study of 43 patient samples.11 Although the site of the primary tumor was known for the majority of the samples, the researchers were blinded to this information.

This retrospective analysis was initiated to assess the incidence of HPV involvement and survival outcomes in a large population of patients presenting with neck metastases with true CUP syndrome. The HPV DNA status of a lymph node metastasis is likely to be representative of the tumor, as demonstrated by Hoffmann et al.,12 therefore establishing whether a metastasis is HPV DNA-positive or -negative provides useful information regarding the primary tumor site, even if the latter cannot be identified.

Section snippets

Patients and methods

A search of the multidisciplinary cancer center registry at the Department of Otorhinolaryngology, Head and Neck Surgery, at the University Medical Center Hamburg-Eppendorf (UKE), Germany, and the Department of Otorhinolaryngology, Head and Neck Surgery of the Christian-Albrechts-University of Kiel, Germany, identified patients who presented with squamous cell carcinoma metastases and CUP syndrome between 2002 and 2011. All patients underwent diagnostic procedures starting with examination

Patients

Sixty-three patients fulfilled the study inclusion criteria: 28 were treated at the UKE and 35 at the University of Kiel. The median follow-up was 23.0 months for all patients, 15 months (range 1–105 months) for UKE patients and 32.0 months (range 1–103 months) for those recruited in Kiel. Patient characteristics are summarized in Table 1. Men outnumbered women by a factor of 3:1, which is similar to the 3.5:1 ratio observed for patients with oropharyngeal cancer in Germany.23 The majority of

Discussion

Treatment for patients with CUP of the head and neck is an unaddressed challenge for physicians. A primary squamous cell carcinoma in the head and neck was identified subsequently in only 6% of patients in this study. Therefore with the inability to identify the primary tumor, and in the absence of guidelines for radiotherapy planning on the basis of nodal metastases, treatment usually targets all mucosal sites from the nasopharynx to the larynx and therefore many patients are overtreated and

Conflict of interest statement

None declared.

References (48)

  • R. Feinmesser et al.

    Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissue obtained by fine-needle aspiration

    N Engl J Med

    (1992)
  • National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Occult primary (cancer of unknown...
  • T. Kaprealian et al.

    Management of the neck and unknown primary of the head and neck

  • J.S. Smith et al.

    Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update

    Int J Cancer

    (2007)
  • S. Begum et al.

    Detection of human papillomavirus-16 in fine-needle aspirates to determine tumor origin in patients with metastatic squamous cell carcinoma of the head and neck

    Clin Cancer Res

    (2007)
  • S.K. El-Mofty et al.

    Histologic identification of human papillomavirus (HPV)-related squamous cell carcinoma in cervical lymph nodes: a reliable predictor of the site of an occult head and neck primary carcinoma

    Head Neck Pathol

    (2008)
  • M. Hoffmann et al.

    HPV16 DNA in histologically confirmed tumour-free neck lymph nodes of head and neck cancers

    Anticancer Res

    (2006)
  • J. Johansen et al.

    Prospective study of 18FDG-PET in the detection and management of patients with lymph node metastases to the neck from an unknown primary tumor. Results from the DAHANCA-13 study

    Head Neck

    (2008)
  • M. Hu et al.

    Clinical applications of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in carcinoma of unknown primary

    Chin Med J (Engl)

    (2011)
  • L. Rudmik et al.

    Clinical utility of PET/CT in the evaluation of head and neck squamous cell carcinoma with an unknown primary: a prospective clinical trial

    Head Neck

    (2011)
  • P.B. Deron et al.

    Lymph node metastasis of squamous cell carcinoma from an unknown primary in the upper and middle neck: impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography

    Cancer Biother Rad

    (2011)
  • R.K. Saiki et al.

    Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for the diagnosis of sickle cell anemia

    Science

    (1985)
  • J.J. van Dongen et al.

    Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936

    Leukemia

    (2003)
  • GenBank Basic Local Alignment Search Tool (BLAST) server....
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