European Annals of Otorhinolaryngology, Head and Neck diseases 131 (2014) 305–308

Available online at

ScienceDirec t
www.sciencedirect.com

Original article

The role of tonsillectomy in the initial diagnostic work-up of head and neck
squamous cell carcinoma of unknown primary
a,∗ a,b,c a,b a a,b a,b,c
E. Berta , I. Atallah , E. Reyt , E. Boyer , A. Karkas , C.-A. Righini
a
Pôle TCCR, clinique universitaire d’ORL, CHU de Grenoble, 1, avenue des Maquis-du-Grésivaudan, 38330 Grenoble cedex 09, France
c
b Faculté de médecine, université Joseph-Fourier – Grenoble-I, domaine de la Merci, place du Commandant-Nal, 38706 La Tronche, France Centre de
recherche Inserm-UJF U823, institut Albert-Bonniot, UJF site santé, BP 170, 38042 Grenoble-La Tronche cedex 9, France

article info abstract

Keywords: Objective: The aim of the present study was to determine the value of tonsillectomy in the initial diag-nostic work-up of head
Head and neck squamous cell carcinoma of and neck squamous cell carcinoma of unknown primary (HNSCCUP).
unknown primary Material and methods: A single-center retrospective study (1999–2012) included 45 patients. All cases underwent physical
Cystic adenopathy examination, panendoscopy and contrast-enhanced neck and chest CT scan; 27 (60%) also underwent 18-FDG PET scan.
18-FDG PET scan
Imaging was systematically performed before panendoscopy. In 34 cases (75%), histologic tonsil samples ipsilateral to the
Palatine tonsil
HNSCCUP were collected (28 tonsillectomies and 6 biopsies) during panendoscopy. Categoric variables were compared on
Squamous cell carcinoma
Chi-square test.
Results: Clinical examination and CT did not identify any primary tumor. In 13 cases (38%), invasive squamous cell
carcinoma (SCC) was diagnosed on histological samples (12 tonsillectomies, 1 biopsy). For these 13 cases, lymph nodes were
located in the upper or middle jugular group, and in 3 cases lymph nodes were cystic on CT scan. In 7 cases (26%), there was
an abnormal tonsillar 18-FDG uptake ipsilateral to the cervical lymphadenopathy; tonsillectomy was performed, and SCC was
found in 5 of these cases: i.e., 18-FDG PET showed sensitivity and specificity of respectively 55.5 and 88.8%.

Conclusion: Tonsillectomy has a role in the initial diagnostic work-up of HNSCCUP. It is especially useful when lymph nodes
are located in the upper and/or middle jugular group with a cystic aspect on CT.
© 2014 Elsevier Masson SAS. All rights reserved.

1. Introduction
Exploration for the primary tumor is fundamental to the man-agement of
head and neck squamous cell carcinoma of unknown primary (HNSCCUP),
enabling targeted therapy, thus reducing the morbidity incurred by systematic
irradiation of 2 or even 3 levels of the pharynx, while also minimizing the risk
of subsequent manifestation of the primary, which is a factor of poor
prognosis [1–3]. Initial diagnostic work-up, however, is a matter of debate,
especially as regards the contribution of associating systematic palatine tonsil
biopsy and/or tonsillectomy ipsilateral to the HNSC-CUP to panendoscopy to
explore the primary tumor. Most reports find primary tonsillar tumor in 18 to
39% of histologic specimens collected ipsilaterally to the HNSCCUP as part
of the diagnostic work-up [4–6]. Two types of sampling are involved:
tonsillectomy or multiple non-targeted tonsillar biopsies. 18-FDG PET scan
allows sampling to be targeted, revealing primary cancer in 25% of HNSC-
CUP work-ups, with sensitivity and specificity of respectively 88
∗ the HNSCCUP. Two patients showed
Corresponding author.
E-mail address: eberta@chu-grenoble.fr (E. Berta).
and 75% [7]. The present study sought to determine the percentage of palatine
tonsil squamous cell carcinoma (SCC) found in tonsil samples from initial
HNSCCUP work-up, and to compare the rela-tive contributiveness of
tonsillectomy versus 18-FDG PET.
2. Material and method
A single-center retrospective study included 45 HNSCCUP patients
between January 1999 and December 2012. All under-went complete head and
neck examination including fiberoptic nasopharyngoscopy, which was
systematically normal. Palpation of the palatine tonsils and the tongue base
was systematically nor-mal. All underwent contrast-enhanced morphologic
neck and chest CT scan. Twenty-seven (60%) underwent 18-FDG PET scan,
per-formed prior to panendoscopy. In 34 cases (75%), a tonsillar biopsy was
performed ipsilaterally to the HNSCCUP during panendoscopy (28
tonsillectomies, 6 multiple palatine tonsil biopsies), since endo-scopic
exploration failed to find any suspicious mucosal lesion. One patient
underwent multiple biopsies during initial endoscopy followed by a
tonsillectomy during cervicotomy, which was per-formed for the treatment of

http://dx.doi.org/10.1016/j.anorl.2014.03.005
1879-7296/© 2014 Elsevier Masson SAS. All rights reserved.
306 E. Berta et al. / European Annals of Otorhinolaryngology, Head and Neck diseases 131 (2014) 305–308

Table 1 (12 tonsillectomy specimens and 1 from multiple biopsies). In the patient in
Characteristics of patients presenting with apparently primary malignant adenopa-thy between
whom biopsy was followed by tonsillectomy, biopsy samples were normal
January 1999 and December 2012.
whereas SCC was found in the tonsillectomy specimen. There was no
Number of patients 45 significant difference between the rates of palatine tonsil cancer detected on
Male 37
Female 8
biopsy versus tonsillectomy (P = 0.23). Tonsillar tumor size was
Mean age (years) [range] 60 [49–85] systematically ≤8 mm.
Alcoholism (%) / mean consumption (g/days, in 42% / 44 Seven of the 27 patients with 18-FDG PET scan showed palatine tonsil
6 patients for whom data were available) uptake despite normal CT scan. All underwent tonsillectomy; pathological
Smoking (%) / (pack year) in 31 patients for 77% / 38
examination found SCC in 5 cases and healthy pala-tine tonsil in 2 cases: i.e.,
whom data were available
18-FDG PET sensitivity and specificity of respectively 55.5 and 88.8%. Two
patients showed pulmonary uptake, corresponding to small non-specific
nodules, on contrast-enhanced neck and chest CT scan; pulmonary metastasis
bilateral cervical adenopathies; multiple bilateral tonsillar biopsies were
was confirmed by transparietal fine-needle aspiration of a nodule in 1 case and
performed in 1, with no tonsillar sampling in the other.
by pulmonary segmentectomy with mini-thoracotomy in the other case. Two
Categoric variables were compared on Chi-square test.
patients showed suspicious mediastinal lymph node with no pulmonary
parenchymatous lesion on the chest CT scan. A multidisciplinary team
3. Results meeting decided against further investigation, so as not to delay initiation of
treatment; 1 of the patients died from metastasis with mediastinal lymph node
Tables 1 and 2 present patient data, work-up, and cTNM (UICC 2002) progression associated with bilateral pulmonary cannon ball metastasis during
staging following clinical and imaging work-up and before 18-FDG PET. the first year of follow-up. Finally, 1 patient showed bone and adrenal gland
There were no complications related to sampling. In 13 cases (38%), invasive involvement. In the 2 patients with isolated mediastinal lymph node
SCC was detected in the tonsillar sample involvement, work-up was incomplete; otherwise, diagnostic 18-FDG PET
showed metastasis in 3 cases, whereas neck and chest CT scan alone failed to
Table 2 detect any lesion or was inconclusive. Table 2 shows cTNM (UICC 2002)
Work-up and results in patients presenting with apparently primary malignant lymphadenopathy stag-ing following clinical and radiological work-up including 18-FDG PET
between January 1999 and December 2012. and following panendoscopy with tonsillar sampling.
Morphologic CT scan imaging (%) 100%
18-FDG PET (n/%) 27 (60%)
Tonsillar uptake (n) 7
Tonsillar SCC (n) 5 In the 13 cases of tonsillar SCC, cervical lymphadenopathy was located in
No tonsillar SCC (n) 2
No tonsillar uptake (n) 20
the upper (n = 9) or middle (n = 4) jugular groups patients. In 3 cases, CT
Tonsillar SCC (n) 4 morphology suggested second branchial arch cyst, with a lesion of liquid-like
No tonsillar SCC (n) 16 density surrounded by a thin regular wall without peripheral contrast uptake, 2
Sensitivity 55.5% in the upper and 1 in the middle jugular group. These patients underwent
Specificity 88.8%
ipsilateral tonsil-lectomy, and all 3 specimens revealed infraclinical tonsillar
Head and neck panendoscopy (%) 100%
cTNM (UICC 2002) after clinical/radiological work-up and before 18-FDG PET SCC. No cystic adenopathies were found in the sub-population with HNSC-
(n) CUP without a tonsillar primary. There was a significant correlation (P =
TxM0 45 0.005) between malignant cystic adenopathy and ipsilateral tonsillar primary.
N1 7 Partially necrotic adenopathies were not counted as cystic.
N2a 18
N2b 9
N2c 2
N3 9
cTNM (UICC 2002) after clinical/radiological work-up, panendoscopy with
4. Discussion
ipsilateral tonsillar sampling and 18-FDG PET (n)
Tonsillar primary detected
T1 13 In the present series, 7 patients (26%) showed tonsillar uptake on 18-FDG
N1 3 PET. All underwent tonsillectomy, revealing invasive SCC in 5 cases. Four
N2a 7 patients (44% of those with tonsillar SCC who under-went 18-FDG PET) had
N2b 1 tonsillar SCC without palatine tonsil uptake (Table 2). The sensitivity and
N2c 0
specificity of 18-FDG PET were thus respectively 55 and 88%. In a meta-
N3 2
M0 13 analysis of 16 studies, Rusthoven et al. [7] found that 18-FDG PET detected
No primary detected (HNSCCUP) primary pharyngeal locations in 25% of HNSCCUPs, with sensitivity and
Tx 32 specificity of respectively 88 and 75%. The sensitivity and specificity of 18-
N1 4 FDG PET thus seem insufficient for an isolated means of detecting infra-
N2a 11
N2b 8
clinical tumors in initial HNSCCUP work-up [1,7]. Sensitivity in the present
N2c 2 series was poorer than in Rusthoven et al. ’s,
probably due to the small
N3 7
M0 29 size of the present cohort. Even so, 18-FDG PET seems to be
M1 3 essential in initial HNSCCUP work-up: leaving aside 2 cases of
Tonsillar sampling (n) 34 P = 0.23
Biopsies (n) 6 isolated mediastinal lymph node involvement in which work-
Tonsillectomy (n) 28
Carcinoma site in samples (n) 13 (1 biopsy)
up was incomplete, it was able to confirm 2 cases of
Lymphadenopathy location in tonsillar primaries pulmonary metastasis and 1 of diffuse metastatic extension
Area II (n) 9
Area III (n) 4 which neck and chest CT alone failed to diagnose. It also
Number of cystic adenopathies 3 P = 0.005 enables targeted sampling, especially when contrast uptake is
Tonsillar SCC sub-population 3
HNSCCUP sub-population 0 extra-oropharyngeal. 18-FDG PET should precede
panendoscopy, to target lesions for endoscopic biopsy and
avoid artifactual uptake caused by mucosal trauma, especially
at the biopsy site.
 E. Berta et al. / European Annals of Otorhinolaryngology, Head and Neck diseases 131 (2014) 305–308
Fig. 1. HNSCCUP management algorithm.
Lymph node metastasis in the form of cystic adenopathy has been widely
reported since the 1970s [2,8–10]. Gourin and John-son [11], in a series of
121 patients with cervical cystic adenopathy, found a 23.5% rate of metastatic
adenopathy in over-40-year-olds. Cystic adenopathy without known primary
used wrongly to be con-sidered to be of branchial origin [12–14]. Thompson
and Heffner [12], in a retrospective study performed between 1971 and 1991,
found 136 HNSCCUP patients with cervical cystic metastasis; initial work-up
or clinical follow-up found 87 lingual or palatine tonsillar primaries (64%)
and 11 nasopharyngeal primaries (8%), suggest-ing that most primary tumors
in HNSCCUP are oropharyngeal and, more particularly, located in the
palatine tonsils; the authors strongly recommended panendoscopy with biopsy
of any suspect pharyngeal mucosal region, with ipsilateral tonsillectomy if no
mucosal lesions are found, regardless of smoking or alcohol sta-tus, as part of
initial work-up for any cervical cystic mass found in over-40-year-olds
[11,14]. In this particular context, any metastatic adenopathy with primary
located in the palatine tonsils should be considered suspect by default.
In our own experience, the rate of tonsillar SCC diagnosed dur-ing initial
HNSCCUP work-up is independent of the type of sampling (tonsillectomy or
multiple biopsies), although this finding is to be taken with caution due to the
small size of the present series. According to the literature, tonsillectomy is
more effective than untargeted biopsy in diagnosing infraclinical cancer: e.g.,
Randall et al. [15] and McQuone et al. [16]. In the present study, 39% of ton-
sillar SCCs were diagnosed on tonsillectomy, compared to 13% on multiple
biopsies. Untargeted tonsillar biopsy may miss and over-look an invasive
SCC site. Tonsillectomy is therefore to be preferred in HNSCCUP work-up.
Some teams [4,17–19] recommend systematic bilateral tonsil-lectomy in
HNSCCUP work-up. In a series of 22 patients, Kothari et al. [18] reported 5
cases (23%) of bilateral tonsillar SCC, although cTNM stage was not reported
and, in particular, the rate of bilat-eral cervical lymphadenopathy (cN2c) was
not specified. Most cases in the literature are either isolated [19] or from very
small retrospective series [17,18]. The contribution of systematic bilateral
tonsillectomy in HNSCCUP work-up thus remains to be
307
demonstrated, as the level of evidence of the published studies allows no
definitive conclusion to be drawn. The attitude seems worthwhile to us only in
work-up for apparently primary malignant adenopathy with bilateral lymph
node involvement (cN2c). Only a prospective study with systematic bilateral
tonsillectomy as part of HNSCCUP work-up, regardless of cN staging, could
determine its diagnostic contribution.
An interesting new means of exploring for primary tumor in ini-tial
HNSCCUP work-up has emerged since the turn of the century with the
demonstration that HPV-16 is often associated with SCC of the oropharynx,
and in particular of the palatine tonsils and, less frequently, of the base of the
tongue. Epidemiology differs from that of head and neck cancer in general:
patients are often young, with only slight if any implication of smoking or
alcohol abuse [20]. HPV-16 is rarely (<10%) found in fragments of
macroscopi-cally healthy mucosa sampled outside tumors overexpressing p16
protein [21,22]. It is confirmed by PCR detection of viral DNA or indirectly
by immunohistochemical findings of overexpression of p16 protein. p16
overexpression in healthy tissue, however, should not, taken in isolation, be
interpreted as indicating presence of HPV, as other poorly understood factors
may also induce overexpress-ion; it is, however, a reliable marker of HPV
within head and neck SCC [22]. Weiss et al. [23], in a retrospective study of
131 patients, reported significant correlation between HPV-16+ viral DNA
find-ings (P < 0.00001) and/or p16 overexpression (P = 0.001), on the one
hand, and histologic findings of malignant cervical lymphadeno-pathy in neck
dissection fragments and of oropharyngeal (tongue base or palatine tonsil)
SCC, on the other hand. They therefore recommend systematic exploration for
HPV-16 in lymph node frag-ments as part of etiological analysis in
HNSCCUP, with multiple oropharyngeal biopsy or tonsillectomy ipsilateral to
the lymph node involvement in case of HPV-16+ adenopathy. This attitude,
however, entails a second general anesthesia, for oropharyngeal sampling in
case of one or more HPV-16+ adenopathies. In current practice, in case of
HNSCCUP, fine-needle aspiration is frequently included in the initial work-up
to determine the malignancy of lymphadenopathies. There are reports of
screening for HPV-16 by in situ hybridization and for p16 by
immunohistochemistry on
308 E. Berta et al. / European Annals of Otorhinolaryngology, Head and Neck diseases 131 (2014) 305–308
fine-needle aspiration lymph node samples [24,25]; the tech-niques are
experimental and not recommended for routine clinical practice, but early
results have been encouraging and fine-needle aspiration may yet be included
in initial work-up in HNSCCUP to select patients for multiple oropharyngeal
(tongue base or palatine tonsil) histology sampling during panendoscopy.
In the light of our own experience and an analysis of the liter-ature, Fig. 1
presents a diagnostic algorithm for initial HNSCCUP work-up.
5. Conclusion
In the present state of knowledge, we suggest that initial work-up in
HNSCCUP should, after classical contrast-enhanced neck and chest CT scan
imaging, include systematic 18-FDG PET scan ahead of panendoscopy, to
explore for the primary tumor and remote metastases. Taken alone, however,
diagnostic imaging cannot rule out pharyngeal, and notably tonsillar
primaries, due to the lack of sensitivity and specificity. We therefore
recommend, given the low associated morbidity, systematic tonsillar
sampling, preferably by tonsillectomy ipsilateral to the suspicious
lymphadenopathy. This exploration is particularly effective when the
adenopathy lies in the upper or middle jugular groups or when it shows a
cystic aspect.
Disclosure of interest
The authors declare that they have no conflicts of interest con-cerning this
article.
References
[1] Jereczek-Fossa BA, Jassem J, Orecchia R. Cervical lymph node metastases of squamous
cell carcinoma from an unknown primary. Cancer Treat Rev 2004;30:153–64.
[2] Micheau C, Klijanienko J, Luboinski B, et al. So-called branchiogenic carcinoma is
actually cystic metastases in the neck from a tonsillar primary. Laryngoscope
1990;100:878–83.
[3] Cizmarevic B, Lanisnik B, Dinevski D. Cervical lymph node metastasis of squamous cell
carcinoma from unknown primary tumor. Coll Antropol 2012;36:27–32.
[4] Kazak I, Haisch A, Jovanovic S. Bilateral synchronous tonsillar carcinoma in cervical
cancer of unknown primary site (CUPS). Eur Arch Otorhinolaryngol 2003;260:490–3.
[5] Lapeyre M, Malissard L, Peiffert D, et al. Cervical lymph node metastasis from an
unknown primary: is a tonsillectomy necessary? Int J Radiat Oncol Biol Phys
1997;39:291–6.
[6] Reiter ER, Randolph GW, Pilch BZ. Microscopic detection of occult malignancy in the
adult tonsil. Otolaryngol Head Neck Surg 1999;120:190–4.
[7] Rusthoven KE, Koshy M, Paulino AC. The role of fluorodeoxyglucose positron emission
tomography in cervical lymph node metastases from an unknown primary tumor. Cancer
2004;101:2641–9.
[8] Micheau C, Cachin Y, Caillou B. Cystic metastases in the neck revealing occult carcinoma
of the tonsil. A report of six cases. Cancer 1974;33:228–33.
[9] Flanagan PM, Roland NJ, Jones AS. Cervical node metastases presenting with features of
branchial cysts. J Laryngol Otol 1994;108:1068–71.
[10] Verma K, Mandal S, Kapila K. Cystic change in lymph nodes with metastatic squamous
cell carcinoma. Acta Cytol 1995;39:478–80.
[11] Gourin CG, Johnson JT. Incidence of unsuspected metastases in lateral cervical cysts.
Laryngoscope 2000;110:1637–41.
[12] Thompson LD, Heffner DK. The clinical importance of cystic squamous cell carcinomas
in the neck: a study of 136 cases. Cancer 1998;82:944–56.
[13] Maturo SC, Michaelson PG, Faulkner JA. Primary branchiogenic carcinoma: the
confusion continues. Am J Otolaryngol 2007;28:25–7 [Erratum in: Am J Otolaryngol
2007;28:143].
[14] Devaney KO, Rinaldo A, Ferlito A, et al. Squamous carcinoma arising in a branchial cleft
cyst: have you ever treated one? Will you? J Laryngol Otol 2008;122:547–50.
[15] Randall DA, Johnstone PA, Foss RD, et al. Tonsillectomy in diagnosis of the unknown
primary tumor of the head and neck. Otolaryngol Head Neck Surg 2000;122:52–5.
[16] McQuone SJ, Eisele DW, Lee DJ, et al. Occult tonsillar carcinoma in the unknown
primary. Laryngoscope 1998;108:1605–10.
[17] Koch WM, Bhatti N, Williams MF, et al. Oncologic rationale for bilateral ton-sillectomy
in head and neck squamous cell carcinoma of unknown primary source. Otolaryngol Head
Neck Surg 2001;124:331–3.
[18] Kothari P, Randhawa PS, Farrell R. Role of tonsillectomy in the search for a squamous cell
carcinoma from an unknown primary in the head and neck. Br J Oral Maxillofac Surg
2008;46:283–7.
[19] Rajenderkumar D, Chan KK, Hayward KA, et al. Bilateral synchronous tonsillar
carcinoma. J Laryngol Otol 1999;113:255–7.
[20] Vent J, Haidle B, Wedemeyer I, et al. p16 expression in carcinoma of unknown primary:
diagnostic indicator and prognostic marker. Head Neck 2013;35:1521–6.
[21] Klussmann JP, Weissenborn SJ, Wieland U, et al. Prevalence, distribution, and viral load
of human papillomavirus 16 DNA in tonsillar carcinomas. Cancer 2001;92:2875–84.
[22] Klingenberg B, Hafkamp HC, Haesevoets A, et al. p16 INK4A overexpression is
frequently detected in tumour-free tonsil tissue without association with HPV.
Histopathology 2010;56:957–67.
[23] Weiss D, Koopmann M, Rudack C. Prevalence and impact on clinicopatholog- ical
characteristics of human papillomavirus-16 DNA in cervical lymph node metastases of
head and neck squamous cell carcinoma. Head Neck 2011;33: 856–62.
[24] Bishop JA, Maleki Z, Valsamakis A, et al. Application of the hybrid capture 2 assay to
squamous cell carcinomas of the head and neck: a convenient liquid- phase approach for
the reliable determination of human papillomavirus status. Cancer Cytopathol
2012;120:18–25.
[25] Mehrotra R, Sharma N, Umudum H, et al. The role of cytopathology in diagnosing HPV
induced oropharyngeal lesions. Diagn Cytopathol 2012;40: 839–43.