Abstract
Dear Editor,
We read with great interest the study by Sauter et al, which addresses the diagnostic challenge of distinguishing benign lateral neck cysts (LNCs) from cervical cancer of unknown primary (CUP) using patient-specific factors. 1 While this study presents important observations, several critical methodological and conceptual gaps deserve attention.
First, the study’s reliance on age as a diagnostic discriminator—proposing a 50- to 59-year threshold with a ~50% probability of CUP—is statistically appealing but lacks validation through multivariate modeling. The analysis does not control for confounding variables such as prior malignancy history, imaging modality differences, or human papillomavirus (HPV) status, which may independently influence the likelihood of a CUP diagnosis. 2 The absence of regression-based risk stratification weakens the robustness of the proposed age cutoff, potentially leading to oversimplified clinical heuristics.
Second, while the authors emphasize the diagnostic utility of positron emission tomography-computed tomography (PET-CT) scan, they do not quantify its true predictive value across subgroups. Despite reporting multiple false positives and false negatives, particularly in tonsillar and tongue base lesions, no sensitivity, specificity, or likelihood ratios were presented for PET-CT in detecting primaries. This limits the interpretive power of their recommendation that PET-CT should not replace panendoscopy. A stratified diagnostic performance analysis (eg, PET-CT in cystic vs solid masses) would have clarified its limitations and contextual strengths.
Third, the decision to exclude fine-needle aspiration cytology (FNAC) entirely due to concerns over tumor cell seeding, while citing a 14.6% malignancy rate among initially suspected LNCs, is debatable. Current evidence supports FNAC combined with HPV DNA testing and p16 immunostaining as effective triage tools to expedite diagnosis while avoiding unnecessary surgery.3,4 The study’s wholesale avoidance of FNAC may have led to overtreatment in patients ultimately confirmed to have benign cysts. This approach limits the generalizability of their algorithm, especially in centers lacking immediate surgical access.
Fourth, despite the study’s 10-year timeframe, it remains monocentric and retrospective, subject to referral biases and variations in surgeon-dependent decisions such as whether to perform bilateral tonsillectomy. Importantly, no standardized preoperative diagnostic workflow was employed. For instance, only about half of CUP patients underwent PET-CT, and the timing of panendoscopy (simultaneous vs sequential) was highly variable. Without a uniform diagnostic algorithm, the comparative evaluation of diagnostic pathways lacks internal consistency.
Lastly, the reported survival data for CUP patients—5-year overall survival of 77%—is surprisingly high, conflicting with existing literature.5,6 However, the study fails to differentiate outcomes based on HPV status, treatment modality (surgical vs chemoradiation), or tumor burden. Given the known prognostic disparity between HPV-positive and HPV-negative CUP, 6 this omission critically hampers interpretation of the survival results.
In summary, while Sauter et al contribute valuable real-world data, the lack of multivariate diagnostics, omission of FNAC-based protocols, variable imaging implementation, and incomplete prognostic stratification limit the clinical applicability of their findings. Future research should validate the age threshold in a prospective, multicentric cohort using structured diagnostic algorithms incorporating cytopathology, molecular testing, and uniform imaging criteria.
Footnotes
Author Contributions
Renu Sah: validation, supervision, project administration, conceptualization, methodology, writing—original draft, writing—review and editing. Ankita Mathur: writing—original draft, writing—review and editing.
Generative AI Use Statement
Generative AI tools, including Paperpal and ChatGPT-4o, were utilized solely for language, grammar, and stylistic refinement. These tools had no role in the conceptualization, data analysis, interpretation of results, or substantive content development of this manuscript. All intellectual contributions, data analysis, and scientific interpretations remain the sole work of the authors. The final content was critically reviewed and edited to ensure accuracy and originality. The authors take full responsibility for the accuracy, originality, and integrity of the work presented.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.