Suat W. Loo and Tom Roques
Case history
A 73-year-old white man presented with a 3-month history of right neck swelling. He had no other associated symptoms. He had never smoked and consumed alcohol only occasionally. His past medical history included hypertension and diet-controlled diabetes mellitus. His Eastern Cooperative Oncology Group (ECOG) performance status was 0. On clinical examination, there was a palpable right-sided level II lymph node. Flexible nasoendoscopy failed to identify a primary mucosal lesion. An ultrasound-guided core biopsy of the right neck node revealed poorly differentiated squamous cell carcinoma showing strong immunohistochemical staining for p16. Magnetic resonance imaging (MRI) demonstrated two necrotic lymph nodes in the right level II neck measuring 2.5 and 1.5cm in maximum dimension, respectively. Again, no definite primary site could be seen.
Questions
1. What investigation should be performed next?
2. What is the clinical and prognostic significance of p16 expression in tumour cells?
Answers
1. What investigation should be performed next?
Approximately 3% of patients with squamous cell carcinoma of the head and neck present with cervical lymph node metastasis from an unknown primary site. The most commonly affected nodal region is level II, and the majority present with N2a/b disease with unilateral lymph node involvement. Initial evaluation should include a detailed history, complete physical examination of the head and neck, flexible nasoendoscopy, imaging studies such as MRI of the head and neck, and needle biopsy of the cervical lymph node. If the primary tumour remains unidentified, a fluorine-18 fluorodeoxyglucose positron emission tomography–computed tomography (18FDG PET-CT) scan should be performed next. This permits detection of occult primary tumours in up to 40% of patients. Lesions of the tonsil and base of the tongue are the primary tumours most commonly identified. It also allows identification of unsuspected metastases in the neck and distant sites.
2. What is the clinical and prognostic significance of p16 expression in tumour cells?
In 2007, the International Agency for Research on Cancer (IARC) convened a panel of experts to review data on the relationship between human papillomavirus (HPV) and squamous cell carcinoma of the head and neck. They concluded that HPV is a causative agent in oropharyngeal cancer. HPV-associated cancers most commonly arise from the tonsils of patients without the traditional risk factors of smoking and alcohol consumption. They usually present with early T stage and advanced N stage disease. Thus, HPV-associated oropharyngeal cancers are more likely to present as occult primary tumours. p16 positivity is commonly used as a surrogate marker of HPV status and is thus useful in the evaluation of patients presenting with squamous cell carcinoma with unknown head and neck primary site. The primary cancer is more likely to be located within the oropharynx if immunohistochemical analysis of tumour cells from the cervical nodes shows strong p16 expression. Similarly, the presence of Epstein–Barr virus in the cervical nodes suggests a nasopharyngeal primary tumour. p16-positive oropharyngeal cancers have a better prognosis than their p16-negative counterparts, with an estimated 50% reduction in the risk of death regardless of treatment modality.
The patient underwent PET-CT scanning. The scan results showed focal increased uptake of FDG in the right level II neck node with a maximum standardized uptake value of 8.3, corresponding to the two necrotic enlarged cervical nodes. No other lesions were seen.
Question
3. What further investigation should be performed?
Answer
3. What further investigation should be performed?
An evaluation under general anaesthesia (EUA) is the next step in the diagnostic workup of this patient. Obtaining PET-CT images prior to EUA has several advantages. It facilitates the evaluation and biopsy of suspicious areas of increased 18FDG uptake and minimizes false positive results at biopsy sites which can be a problem if EUA preceded PET-CT. At EUA, all suspicious-looking lesions should be biopsied. Tonsillectomy and blind biopsies from the base of tongue, nasopharynx, and pyriform sinus should also be performed. This permits the detection of primary tumours that are too small to be visualized on PET-CT in up to 15% of cases. Approximately 80% of these lesions are located in the tonsil and tongue base.
An EUA was performed in this patient. Careful evaluation of the mucosal sites did not reveal any abnormalities. Bilateral tonsillectomy was carried out and blind biopsies were taken from the tongue base, post-nasal space, and pyriform sinus on both sides. No malignancy was found on histology.
Question
4. What is the optimal management of this patient?
Answer
4. What is the optimal management of this patient?
Due to a lack of randomized clinical studies, the optimal management of patients presenting with squamous cell carcinoma from an unknown head and neck primary site remains undefined. Treatment depends largely on the nodal stage at presentation. The priority is to achieve long-term loco-regional disease control. The risk of subsequent distant failure is considered low. Patients with N1 disease can be managed with single-modality treatment—either neck dissection or radiotherapy. Both options are equally effective and result in comparable nodal control rates. Post-operative radiotherapy is only indicated in those with extracapsular nodal extension and pathological N2 disease. Those with inoperable neck disease should be managed with radiotherapy and concurrent chemotherapy. In patients with N2 or N3 disease, irradiation of the bilateral neck and putative mucosal sites results in a reduction in the risk of subsequent loco-regional recurrence of tumour. As the majority of squamous cell carcinomas of unknown head and neck primaries are likely to have originated from the oropharynx, the base of the tongue and ipsilateral tonsil should be included within the clinical target volume (CTV). It is reasonable not to include the supraglottic or glottic larynx in the radiotherapy treatment volume. This is because damage to these structures, as well as the nearby pharyngeal constrictor muscles, by radiotherapy can result in long-term dysphagia and the risk of aspiration, with an adverse impact on the patient’s quality of life. Nonetheless, it remains unclear whether irradiation of the bilateral neck and putative mucosal sites improves survival compared with the more limited approach of surgery and ipsilateral radiotherapy. Published results from single-centre series show excellent loco-regional control rates with acceptable long-term treatment-related complications with either approach. The primary mucosal tumour will subsequently emerge in approximately 25% of patients managed with neck dissection and adjuvant ipsilateral radiotherapy. Regular clinical follow-up after completion of treatment is therefore needed to look for recurrence of tumour or development of a second primary head and neck malignancy and to manage treatment-related complications.
The patient underwent irradiation of the bilateral neck and putative mucosal sites using intensity-modulated radiotherapy to a dose of 65Gy in 30 fractions over 6 weeks with concurrent weekly cisplatin. There was complete regression of the right level II cervical nodes and clinical evaluation 6 weeks post-treatment showed no residual disease.
Question
5. Does the patient require a post-treatment neck dissection?
Answer
5. Does the patient require a post-treatment neck dissection?
There has been debate over the role of planned neck dissection following chemoradiotherapy in patients with N2 head and neck squamous cell carcinoma. Some clinicians recommend adjuvant neck dissection for all patients with N2 tumours regardless of treatment response, while others advocate its use only in those with residual nodal disease following chemoradiotherapy. There is now strong evidence to support the use of PET-CT in the evaluation of treatment response after chemoradiotherapy. Patients with a negative PET-CT 3 months after completion of treatment can avoid neck dissection without the risk of regional recurrence. The negative predictive value of post-treatment PET-CT in this setting is greater than 95%.
Follow-up details of the case
PET-CT performed 3 months following chemoradiotherapy showed a complete metabolic and radiological response. The patient was observed. He was last reviewed at 32 months following treatment with no evidence of tumour recurrence and no late sequelae of treatment.
Further reading
Jereczek-Fossa BA, Jassem J, Orecchia R. Cervical lymph node metastases of squamous cell carcinoma from an unknown primary. Cancer Treatment Reviews 2004; 30: 153–164.
Loo SW, Geropantas K, Beadsmoore C, et al. Neck dissection can be avoided after sequential chemoradiotherapy and negative post-treatment positron emission tomography-computed tomography in N2 head and neck squamous cell carcinoma. Clinical Oncology (Royal College of Radiologists) 2011; 23: 512–517.
Lu H, Yao M, Tan H. Unknown primary head and neck cancer treated with intensity-modulated radiation therapy: to what extent the volume should be irradiated. Oral Oncology 2009; 45: 474–479.
Waltonen JD, Ozer E, Hall NC, Schuller DE, Agrawal A. Metastatic carcinoma of the neck of unknown primary origin: evolution and efficacy of the modern workup. Archives of Otolaryngology–Head and Neck Surgery 2009; 135: 1024–1029.