Additional parameters to improve the prognostic value of the 8th edition of the UICC classification for human papillomavirus-related oropharyngeal tumors.

BACKGROUND: The prognostic reliability of the UICC's TNM classification (8th edition) for human papillomavirus (HPV)-positive tonsillar squamous cell carcinomas (TSCCs) compared to the 7th edition was explored, and its improvement by using additional anatomical and nonanatomical parameters. METHODS: One hundred and ten HPV-positive and 225 HPV-negative TSCCs were retrospectively analyzed. Survival was correlated with patient and tumor characteristics (7th and 8th edition UICC TNM classification). RESULTS: In HPV-positive TSCCs, the 8th edition UICC's TNM classification correlated better with prognosis than the 7th edition. Also, smoking status was a stronger prognosticator of survival than UICC staging. Non- or former smokers had a 5-year overall survival of 95.1% regardless of tumor stage. Furthermore, age (>65 years), cN3, and M1 classification were significant prognostic factors. CONCLUSION: The prognostic value of the 8th edition UICC's TNM classification improved significantly when compared to the 7th edition. Nonetheless, further improvement is possible by adding nonanatomical factors (smoking, age >65 year) and separating N0-N2 from N3.

Tumor control of cervical lymph node metastases of unknown primary origin: the impact of the radiotherapy target volume.

PURPOSE: Debate on the extent of treatment of neck metastasis of cancer of unknown primary tumors (CUPs) is still ongoing. In two Dutch tertiary referral centers, the post-surgical radiation target volume changed from the bilateral neck including the pharyngeal axis to the unilateral neck only, in the course of the last decade. This study aims to investigate the outcome of patients with CUP before and after de-escalation of post-surgical radiotherapy. METHODS: Data of two Dutch tertiary referral centers were merged. Disease-free survival (DFS), overall survival (OS), and regional control rate (RCR) of 80 patients diagnosed with CUP (squamous cell and undifferentiated carcinomas) between 1990 and 2009 were retrospectively analyzed. RESULTS: Thirty patients received bilateral neck and pharyngeal axis radiotherapy and 42 patients ipsilateral radiotherapy only. In another eight patients, the postsurgical radiation target volume was expanded to the contralateral neck or to the pharyngeal axis, due to suspicious lesions on imaging. The 5-year DFS, OS and RCR were 60%, 51.2%, and 80%, respectively, in the total patient population. RCR did not differ in patients treated with ipsilateral as compared to bilateral radiotherapy nor did 5-year OS and DFS. No tumors occurred in the pharyngeal axis. CONCLUSION: In this study, omitting elective treatment of the contralateral neck and pharyngeal axis did not lead to a decrease in locoregional control or survival rates when treating patients with CUP.

P16(INK4A) immunostaining is a strong indicator for high-risk-HPV-associated oropharyngeal carcinomas and dysplasias, but is unreliable to predict low-risk-HPV-infection in head and neck papillomas and laryngeal dysplasias.

Human papillomavirus (HPV) is a risk factor for the development of benign and malignant mucosal head and neck lesions. P16(INK4A) is often used as a surrogate marker for HPV-infection, although there is still controversy with respect its reliability. Our aim was to determine if p16(INK4A) overexpression can accurately predict both high-risk and low-risk-HPV-presence in (pre)malignant and benign head and neck lesions. P16(INK4A) immunohistochemistry was performed on paraffin-embedded tissue sections of 162 oropharyngeal squamous cell carcinomas (OPSCC), 14 tonsillar and 23 laryngeal dysplasias, and 20 tonsillar and 27 laryngeal papillomas. PCR, enzyme-immunoassay and FISH analysis were used to assess HPV-presence and type. Of the 162 OPSCC and 14 tonsillar dysplasias, 51 (31%) and 10 (71%) were HPV16-positive, respectively. All tonsillar papillomas were HPV-negative and four laryngeal dysplasias and 26 laryngeal papillomas were positive for HPV6 or -11. P16(INK4A) immunohistochemistry revealed a strong nuclear and cytoplasmic staining in 50 out of 51 HPV16-positive and 5 out of 111 HPV-negative OPSCC (p < 0.0001) and in all HPV16-positive tonsillar dysplasias, whereas highly variable staining patterns were detected in the papillomas and laryngeal dysplasias, irrespective of the HPV-status. In addition, the latter lesions generally showed a higher nuclear than cytoplasmic p16(INK4A) immunostaining intensity. In conclusion, our data show that strong nuclear and cytoplasmic p16(INK4A) overexpression is a reliable surrogate indicator for HPV16 in OPSCC and (adjacent) dysplasias. For HPV6 or -11-positive and HPV-negative benign and premalignant lesions of the tonsil and larynx, however, p16(INK4A) immunostaining is highly variable and cannot be recommended to predict HPV-presence.

Next-generation treatment strategies for human papillomavirus-related head and neck squamous cell carcinoma: where do we go?

Oncogenic human papillomavirus (HPV) is currently recognised as a major risk factor for the development of head and neck squamous cell carcinomas (HNSCC). HPV is mostly detected in tumours arising from the oropharynx and more specifically from the tonsil. HPV-related tumours display clinical and molecular characteristics that are distinct from HPV-unrelated tumours, which are generally induced by alcohol and tobacco abuse. Detection of biologically active HPV in HNSCC has prognostic relevance, which warrants the separate classification of HPV-induced tumours and is a prerequisite for further optimisation of treatment protocols for this distinct group. Current guidelines for the treatment of oropharyngeal squamous cell carcinoma (OPSCC) have not incorporated specific treatment modalities for HPV-related tumours. The development of such treatment options is still in a preclinical phase or in early clinical trials. Recent data on treatment response of OPSCC have been obtained by retrospectively analysing HPV-status and indicate that patients with HPV-related tumours show a favourable prognosis, independent of the type of treatment. These patients may benefit from de-intensified treatment, which should be assessed in prospective clinical trials. The development and future use of new antiviral and immunomodulatory therapeutics may be instrumental in this approach to improve survival rates and decrease disease-and-treatment-related morbidity. In this review we will focus on present therapeutic HPV-targeting strategies and discuss future directions for de-intensified treatment of HPV-positive HNSCC.

Human papillomavirus reduces the prognostic value of nodal involvement in tonsillar squamous cell carcinomas.

OBJECTIVES/HYPOTHESIS: Assessment of the prognostic value of nodal status in relation to human papillomavirus (HPV) status and the various treatment modalities in tonsillar squamous cell carcinomas (TSCC). STUDY DESIGN: Retrospective 5-year survival analysis. METHODS: A 5-year follow-up of disease-free, disease-specific, and overall survival in a group of 81 patients with TSCC was conducted. The nodal status and integration of HPV-DNA in the genome (detected with fluorescence in situ hybridization) as prognostic indicators were examined while correcting for other clinical parameters (smoking habits, alcohol consumption, treatment modality, differentiation, TNM classification). RESULTS: Of TSCCs, 41% were positive for HPV type 16. In these TSCCs, the primary tumor was significantly smaller when compared to HVP-negative TSCCs (P = .04), whereas the percentage of cases with cervical metastases was identical. In the total population, it was not nodal involvement, but rather HPV manifestation, which was related to patient prognosis. Within the treatment modalities (surgery combined with radiotherapy and radiotherapy alone), neither nodal status nor HPV were prognostic indicators. CONCLUSIONS: Since a substantial percentage of TSCCs are HPV-positive and metastasizes to cervical lymph nodes in less advanced primary tumors, the N status is an unreliable prognostic indicator in TSCCs. HPV is only prognostically relevant in the total tumor population, but loses its value within patient groups receiving a single treatment modality. The value of HPV for prognosis of patients with TSCC requires further study.

Genetic signatures of HPV-related and unrelated oropharyngeal carcinoma and their prognostic implications.

PURPOSE: Patients with human papillomavirus (HPV)-containing oropharyngeal squamous cell carcinomas (OSCC) have a better prognosis than patients with HPV-negative OSCC. This may be attributed to different genetic pathways promoting cancer. EXPERIMENTAL DESIGN: We used comparative genomic hybridization to identify critical genetic changes in 60 selected OSCC, 28 of which were associated with HPV-16 as determined by HPV-specific PCR and fluorescence in situ hybridization analysis and positive p16(INK4A) immunostaining. The results were correlated with HPV status and clinical data from patients. RESULTS: Two thirds of OSCC harbored gain at 3q26.3-qter irrespective of HPV status. In HPV-negative tumors this alteration was associated with advanced tumor stage (P=0.013). In comparison with HPV-related OSCC, the HPV-negative tumors harbored: (a) a higher number of chromosomal alterations and amplifications (P=0.03 and 0.039, respectively); (b) significantly more losses at 3p, 5q, 9p, 15q, and 18q, and gains/amplifications at 11q13 (P=0.002, 0.03; <0.001, 0.02, 0.004, and 0.001, respectively); and (c) less often 16q losses and Xp gains (P=0.02 and 0.03). Survival analysis revealed a significantly better disease-free survival for HPV-related OSCC (P=0.02), whereas chromosome amplification was an unfavorable prognostic indicator for disease-free and overall survival (P=0.01 and 0.05, respectively). Interestingly, 16q loss, predominantly identified in HPV-related OSCC, was a strong indicator of favorable outcome (overall survival, P=0.008; disease-free survival, P=0.01) and none of these patients had a tumor recurrence. CONCLUSIONS: Genetic signatures of HPV-related and HPV-unrelated OSCC are different and most likely underlie differences in tumor development and progression. In addition, distinct chromosomal alterations have prognostic significance.

Erythema nodosum as an early sign of Crohn's disease.

Erythema nodosum is the most common form of septal panniculitis and the most frequent skin manifestation associated with inflammatory bowel disease. Since the development of erythema nodosum is closely related with a variety of disorders and conditions, it can serve as an important early sign of systemic disease. We report on a 25-year-old woman with Crohn's disease following a long history of recurrent erythema nodosum.

Health problems of people with intellectual disabilities: the impact for general practice.

This study aimed to analyse the health problems and prescriptions of people with intellectual disabilities registered with GPs. Within the Second Dutch National Survey of General Practice evidence was gathered on the differences in health problems between people with intellectual disabilities and control persons (without intellectual disabilities). In a 1:5 matched sample, people with intellectual disabilities paid 1.7 times more visits to GPs. They presented a different morbidity pattern, and received four times as many repeat prescriptions. People with intellectual disabilities increase a GP's workload.