We thank Prof. Guntinas-Lichius for his comments. In the rare cases of cervical lymph node metastases where in spite of all interdisciplinary methods (including panendoscopy and imaging) no primary tumor can be found, measuring the p16 protein level and testing for HPV (human papillomaviruses) as well as EBV (Epstein-Barr virus) in the tumor cells may be helpful and confirm a nasopharyngeal carcinoma. The TNM classification recommends applying the classification for nasopharyngeal cancers in cases where it is definitely not possible to identify a primary tumor and where the patient has tested positive for EBV. However, the subject here is only classification/staging, not the clinically relevant situation of the question of what should guide treatment.

For reasons of space, in our review article we did not explain nasopharyngeal cancers, which are rare in our latitudes (annual incidence 0.3–0.7/100 000 population) (1). In contrast to EBV positivity of the nasopharyngeal cancers in endemic areas, the virus is almost always absent from the (keratinized) nasopharyngeal cancers in our own regions, which are not among the relevant endemic areas. Classic histology of a nasopharyngeal carcinoma—also in lymph node metastases—therefore in most cases allows an indication of this tumor entity. Furthermore, the 2017 article by Cheol Park et al. cited by Prof. Guntinas-Lichius mentions a total of 54 patients, of whom only two tested positive for EBV, and only one patient had a nasopharyngeal cancer, whereas no tumor was found in the second patient. Ultimately, this article too ascribes the greatest sensitivity for the detection of the primary tumor in squamous cell carcinomas of the head and neck not to an individual examination but to a combination of the biomarkers HPV, EBV, and p16, as well as 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography/computed tomography (FDG-PET/CT).

We can only agree with Dr. Thöns regarding the importance of palliative medical care in disseminated CUP syndrome. However, this applies to all cases of advanced tumor disease (and many other non-malignant disorders), and not only to CUP syndrome. However, in our opinion, this important cornerstone of the therapy of tumor patients—whether as palliative treatment in addition to radiotherapy or medication or as mere “best supportive care” treatment—does not have any place in a review article of the current therapeutic options for CUP syndrome, but only in a separate, detailed article on palliative medicine.

It goes without saying that in patients with advanced tumor disease—and thus also in advanced CUP syndrome—general palliative medical measures should always be considered. And of course, in very advanced CUP syndrome, purely palliative treatment measures in the sense of “best supportive care” need to be discussed with the patient if no treatment options of greater usefulness are available—but only if that is the case.

DOI: 10.3238/arztebl.2018.0354c

On behalf of the authors

Dr. med. Gregor Zaun

Innere Klinik (Tumorforschung), Universitätsklinikum Essen

gregor.zaun@uk-essen.de

Conflict of interest statement

All authors declare that no conflict of interest exists.

1.
WHO: WHO classification of head and neck tumours. El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ (eds.): 4th edition, Lyon: IARC 2017; 65.
2.
Zaun G, Schuler M, Herrmann K, Tannapfel A: CUP syndrome—metastatic malignancy with unknown primary tumor. Dtsch Arztebl Int 2018; 115: 157–62 VOLLTEXT
1.WHO: WHO classification of head and neck tumours. El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ (eds.): 4th edition, Lyon: IARC 2017; 65.
2.Zaun G, Schuler M, Herrmann K, Tannapfel A: CUP syndrome—metastatic malignancy with unknown primary tumor. Dtsch Arztebl Int 2018; 115: 157–62 VOLLTEXT

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