Cancer of unknown primary in the neck—challenging in diagnosis and treatment

Neck squamous cell carcinoma of unknown primary (NSCCUP) is a rare disease. The detection of the occult primary increased over the last decades due to improvements in diagnostic procedures such as positron-emission tomography-computed tomography (PET-CT) and a standardized surgical approach allowing for histopathologic detection of occult primaries in the base of tongue or tonsils, as these are the most common primary sites and source of squamous cell carcinoma cells forming metastases in the draining neck nodes. The National Comprehensive Cancer Network (NCCN) treatment guidelines (1) strongly recommend to include neck dissection and risk-factor-adapted radiation therapy or chemoradiation. However, reliable scientific evidence from randomized controlled trials for the treatment of NSCCUP is missing as the diagnostic and therapeutic approaches vary between institutions and the number of patients with “true” NSCCUP after diagnostic workup and absence of a detectable primary tumor is small. According to register data, a standardized diagnostic work-up including case discussion in the multidisciplinary tumor board improves survival of NSCCUP patients (2,3).

In their recently published paper, Barrett et al. (4) compared retrospectively collected survival data of 53 patients with human papilloma virus-positive (HPV+) NSCCUP receiving standard of care (including imaging, transoral surgery and neck dissection followed by risk-factor-adapted radiation therapy or chemoradiation) to 13 patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) treated within two trials aiming on treatment deintensification. The authors describe their diagnostic work-up for NSCCUP patients in detail including PET-CT scan and their surgical approach for detecting occult primaries located in the tonsils, base of tongue or glossotonsillar sulcus. They report a detection rate of 86.4% for the primary lesion, leading to only seven remaining “true” NSCCUP among initially 66 patients escaping conventional diagnostic procedures. They report very good 5-year survival data for both groups, the NSCCUPs treated with SOC and the HPV+ OPSCCs with de-intensified treatment in two clinical trials.

At this point, the vague definition of “cancer of unknown primary” limits the study’s informative value and comparability to other papers as in most cases an occult primary could be detected after a standardized diagnostic workup including surgery of the palatine and lingual tonsils, and according to their report this was indeed the case by using their approach. The most common origin of their HPV+ NSCCUPs at the time of first diagnosis seems to be the oropharynx, as reported by Barrett and colleagues. The authors’ intention to treat HPV+ NSCCUP according to standards utilized for rather small HPV+ OPSCC is in accordance with the NCCN guidelines for head and neck cancers (5). This may also include treatment deintensification in the future, provided reliable evidence from randomized controlled de-escalation trials supporting successful de-escalation leading to preserved organ function, reduced late toxicities and noninferiority regarding survival will become available. In the past, de-escalation trials for HPV+ OPSCC were negative and demonstrated that de-intensified treatment puts patients at risk because the factors relevant for reliable risk stratification were unknown but turned out to be important (6,7). Only selected p16+ OPSCC with small tumors (T1-T3) and limited metastasis into the neck nodes (N1) may benefit from de-escalation, and the same might be true for clinical T0 or initial p16+ NSCCUP diagnosed with small pT1 or pT2 finally becoming p16+ OPSCC stage I (pT1-2 pN1 according to the 8^th edition). It is remarkable that the mentioned HPV+ NSCCUPs patients show a non-inferior survival compared to HPV+ OPSCC patients after surgery followed by deintensified adjuvant treatment in the mentioned retrospective assessment. The patients with upfront surgery and post-op treated with either 42 Gy alone or 42 Gy with a single dose cisplatin (100 mg/m²) demonstrated favorable outcome despite significantly reduced irradiation doses. Unfortunately, no information about improved organ function and quality of life are provided but these are to be expected based on a multitude of clinical reports.

The authors try to provide data of feasibility and safety for treatment deintensification in a cohort of HPV+ OPSCC and transfer these to the increasing number of HPV+ NSCCUP patients. However, there are limitations regarding transferability of their findings. First, the authors report about a mixture of few true NSCCUP among very small (pT1 and pT2) p16+ OPSCC with limited nodal involvement not hindering resection in curative intent. Second, the analyses provided are retrospective and therefore, the well-known biases associated with this type of study apply. The joint analysis of outcome data of various treatment modalities in a mixed cohort does not help to draw clear conclusions. Third, and unfortunately, the prevalence of HPV-driven OPSCC among p16+ OPSCC and the reliability of the surrogate biomarker p16^INK4a expression for diagnosing HPV-driven cancer depends on the prevalence of HPV-driven cases among OPSCC (8). Consequently, the accuracy in the U.S. is high but strongly reduced in regions with lowered frequencies. For instance, we found in Germany about 23% false positive OPSCC (p16+ without detection of high-risk HPV DNA and/or RNA E6*I transcripts) (9) that is in line with the findings of the BROADEN study (10). However, HPV-seropositivity is linked to improved overall survival and progression-free survival in NSCCUP patients (11). As no information is provided specifying results from molecular analyses, the report may have luckily had not suffered from higher prevalence of false positives that could deteriorate outcome achievable in p16+ OPSCC initially presenting as NSCCUP in other populations. However, the influence of the administered treatment is difficult to interpret with treatment varying considerably between the retrospective and the arms among both prospective trials and the multitude of potentially unconsidered factors between the two entities (NSCCUP vs. OPSCC) essentially reducing the case numbers in the various subgroups compared. Many lessons were learned through failure of sufficiently powered de-escalation trials (12). Moreover, the eagerly awaited outcome data of both de-escalation trials are not published hindering transferability. Considering this, the authors’ findings point in the right direction but essentially need to be confirmed in larger, prospective studies. Indeed, we expect a clarification regarding the probability of successful de-escalation in p16+ HPV+ OPSCC from the sufficiently powered Post-operative Adjuvant Treatment for HPV-positive Tumours (PATHOS) phase-III trial (ClinicalTrials.gov ID NCT02215265) (13) that has the main objective (primary endpoint) to demonstrate noninferiority of reducing the intensity of adjuvant treatment protocols in terms of overall survival in the reduced intensity treatment arms.

Acknowledgments

None.

Footnote

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