Large neck metastasis with unknown primary tumor - a case report

Introduction. Metastatic head and neck carcinoma from an unknown primary
 tumor is defined as a metastatic disease in the neck?s lymph nodes without
 evidence of a primary tumor after appropriate investigation. Multiple
 national guidelines recommend that essential steps in diagnostic protocols
 involve a detailed clinical exam with radiological imaging, fine-needle
 aspiration (FNA) biopsy of the cervical tumor, panendoscopy with palatine
 and lingual tonsillectomy, immunohistochemical staining, and human
 papillomavirus (HPV) detection. Treatment of head and neck carcinomas of
 unknown primary (CUPs) origin involves surgery (neck dissection) with
 radiotherapy, while some authors recommend chemo-radiotherapy in cases of
 the advanced regional disease. Case report. A 44-year old male was referred
 to the tertiary medical center because of a large ulcero-infiltrative
 cervical mass on the right side. Examination of the head and neck and
 flexible nasopharyngolaryngeal endoscopy was conducted, followed by computed
 tomography (CT) of the head, neck, and thorax with intravenous contrast. The
 primary localization of the tumor was not confirmed by these diagnostic
 methods. Open biopsy of the neck mass confirmed histopathology diagnosis of
 metastatic squamous cell carcinoma. Results of panendoscopy with biopsies
 and bilateral tonsillectomy were negative for malignancy. Treatment included
 extended radical neck dissection with reconstruction and postoperative
 ipsilateral radiotherapy. Five years after the first surgery, the patient
 presented with an extensive pharyngolaryngeal tumor. Biopsy with
 histopathology examination confirmed the diagnosis of squamous cell
 carcinoma. Conclusion. A structured step-by-step diagnostic approach in
 identifying the primary site of the metastatic head and neck carcinoma is
 mandatory. Substantial advances in diagnostics and operative techniques have
 increased the likelihood of primary tumor identification, as well as
 detection of regional and systemic spread of the disease. Purpose of
 adherence to guidelines results in higher overall-survival and longer
 regional disease-free survival in these patients.

Treatment of head and neck SCCUPs prioritizes loco-regional control. Initial recommendations involve surgery (neck dissection) with radiotherapy. 1,2,9 The importance of chemo-radiotherapy is stressed for N2, N3, and metastases with extracapsular extension. 1,10 Treatment remains heterogeneous and still based on retrospective studies, clinical experience, and institutional policies.
We present a case of squamous cell carcinoma neck metastasis with an unknown primary tumor to illustrate the importance of a structured diagnostic protocol and appropriate treatment choice in achieving better overall and disease-free survival.

Case report
A 44-year old male patient was referred to our clinic with a painless large ulcerousinfiltrative cervical mass on the right side. The neck mass appeared four months prior referral. On admission, he did not report any other relevant symptoms in the head and neck region or any comorbidities or allergies. He was a heavy smoker (up to 60 cigarettes a day for 20 years) and frequently consumed alcohol (over 500ml of spirits a day for over 15 years). 6 We conducted a complete and careful clinical otorhinolaryngology examination, followed by flexible nasopharyngolaryngeal endoscopy. Clinical findings appeared normal. Prior to hospitalization, computed tomography (CT) of the head, neck, and thorax with intravenous contrast was done. Imaging findings indicated nodal metastatic disease in the right neck, with central necrosis, infiltration of adjacent muscles, internal jugular vein, and skin. All parts of the pharynx and larynx were without pathological findings. (Figure 1)

Discussion
The failure to detect the primary tumor location in a patient with metastatic head and neck cancer poses a clinical challenge that can affect the course of treatment and disease prognosis. New recommendations were made in recent guidelines, but weren't applied in the case presented above, which further illustrates their importance in the diagnostic protocol, choice of treatment, and better overall and disease-free survival.
After clinical examination and diagnostic imaging, fine-needle aspiration (FNA) biopsy is a crucial step in assessing neck nodal mass in SCCUP. The American Joint Committee on Cancer (AJCC) 3 recommended adding HPV staining to the diagnostic work-up. HPV specific marker p16 positive immunohistochemical staining would indicate a potential oropharyngeal primary tumor (palatine tonsil and base of the tongue). Lymph nodes metastases in SCCUP were positive for HVP in 7.8 to 30%. 6,9 In Serbia, oropharyngeal carcinoma were positive for p16 HPV in 45%. 10,11 A positive p16 result should at least be followed by HPV specific testing (in situ hybridization or PCR), especially in cases where no non-keratinizing histology or lymph nodes are not found in II or/and III region.
PET/CT is recommended in all patients where conventional imaging failed to identify the tumor's primary site. PET/CT has high sensitivity (up to 88.3%) and negative predictive value (from 68.9% to 93%), which makes it an excellent complementary diagnostic tool. 7,12,13 Diagnostic protocols that use preoperative PET/CT preceding panendoscopy with directed biopsies resulted in detection of the primary lesion in over 90% of the patients. 12 to deep tonsil biopsies where the identification rate was only 3%. 15 Bilateral tonsillectomy is preferred to unilateral due to a possible bilateral and contralateral tumor location in 15% of the cases with tonsillar malignancies. 16 Recommendation on lingual tonsillectomy is still not firmly established. With advances in operative techniques that include transoral laser microsurgery and transoral robotic surgery, lingual tonsillectomy provided a tumor detection rate of 56% in patients with SCCUP. 8 Bilateral tonsillectomy should always be performed in cases of SSCUP, while in the presented case, only blind biopsies were done in the absence of the evident tumor site. In this case, the pharyngolaryngeal tumor was considered a secondary primary, but we cannot exclude the possibility of the contralateral recurrent disease if the tonsils were positive for occult carcinoma.
Further treatment in patients with unknown primary carcinoma with neck metastases involves neck dissection followed by postoperative radiotherapy (RT) or consideration of chemo-radiotherapy. 1,15 Multiple retrospective studies had inconsistent results regarding radiotherapy field size. Some reports reported that patients who underwent bilateral RT did not have significantly better overall survival and regional recurrence compared to patients treated with unilateral radiotherapy to the neck and mucosal surfaces. On the other hand, some studies favor bilateral nodal and mucosal irradiation. 17,18 The NCCN recommends chemo-radiotherapy in N2/N3 disease cases with the extracapsular extension (ECE) 14 , although it should be noted that no randomized trials are demonstrating the superiority of this treatment over radiotherapy alone. Due to the low incidence of the disease and the lack of high-quality evidence, clear clinical management protocols are not available.

Conclusion
Substantial advances in diagnostics and operative techniques have increased the likelihood of primary tumor identification, regional and systemic spread of the disease. If a CT or MRI does not identify a primary site, the PET-CT scans should be performed before surgical endoscopy and biopsies. In cases of SCCUP, bilateral tonsillectomy with lingual tonsillectomy is indicated during panendoscopy. Although high-quality evidence of treatment protocols is lacking, patients with more advanced stages of the regional disease