REVIEW

CURRENT
OPINION Unknown primary of the head and neck: a new
entry in the TNM staging system with old
dilemmas for everyday practice
Cesare Piazza a, Fabiola Incandela a, and Lorenzo Giannini a,b

Purpose of review
To summarize the most recent nuances in diagnosis, management, and prognostic stratification of
carcinoma of unknown primary of the head and neck (CUPHN), in light of its recent re-assessment in the
eighth edition of the TNM Classification Manual.
Recent findings
At least in Western Countries, most CUPHN are expected to be Human Papilloma Virus (HPV)-positive with an
oropharyngeal origin. Their appropriate diagnosis starts with fine needle aspiration cytology and/or core
biopsy of pathologic lymph node(s) with staining for p16 by immunohistochemistry and subsequent HPV
detection by PCR. If these exams are negative (especially in Eastern Countries), in-situ hybridization for
Epstein–Barr virus detection should be added. Thorough clinical examination should encompass white light
videoendoscopy with the adjunction of bioendoscopic techniques (such as narrow band imaging). Radiologic
workup (by CT, MR and/or PET) should be limited to cases that are persistently negative after comprehensive
endoscopic evaluation. Invasive diagnostic procedures, such as unilateral or bilateral palatine tonsillectomy
and base of tongue mucosectomy, may play a staging as well as a therapeutic role in CUPHN management.
Summary
Every effort should be made to identify and remove the primary site of a CUPHN: in doing so, possible
subsequent de-intensification protocols by irradiation of the neck alone (with or without previous neck
dissection according to the cN category, patient’s risk profile, and general status) can be taken into
consideration on a case-by-case basis.
Keywords
carcinoma, diagnosis, endoscopy, head and neck, imaging, irradiation, unknown primary

INTRODUCTION applied and to the point along the treatment algo-

Carcinoma of unknown primary of the head and
neck (CUPHN) is defined as the clinical scenario in
which an overt cervical lymphadenopathy (most
frequently staged ab initio as cN2a or cN2b) takes
origin from a primary that cannot be identified in
spite of thorough medical history, clinical examina-
tion, and noninvasive as well invasive state-of-the-
art diagnostic workup [1]. The reasons why this
happens may range from inability to detect the
primary site because of suboptimal diagnostics,
small tumor volume, hidden location (especially
within the reticulated tonsillar crypt epithelium
deep to the surface, with little stromal reaction),
slow growth rate, or even primary involution as a
consequence of unrecognized tumor-metastasis
immunologic interactions [2,3].
The reported relative incidence of CUPHN vary
according to the accuracy of the diagnostic workup
rithm in which such a definition is tagged. Gener-
ally, the most accredited incidence of such a
phenomenon is around 1–5% of all head and neck
cancers [4–6], even though it is actually increasing
as a result of a described mounting incidence of
HPV-related oropharyngeal tumors (in the last
a
Department of Otorhinolaryngology, Maxillofacial, and Thyroid Surgery,
Fondazione IRCCS National Cancer Institute of Milan and bDepartment
of Otorhinolaryngology – Head and Neck Surgery, ASST Santi Paolo e
Carlo, University of Milan, Milan, Italy
Correspondence to Cesare Piazza, MD, Department of Otorhinolaryn-
gology, Maxillofacial, and Thyroid Surgery, Fondazione IRCCS National
Cancer Institute of Milan, University of Milan, Via Giacomo Venezian 1,
20133 Milan, Italy.
E-mail: cesare.piazza@istitutotumori.mi.it, ceceplaza@libero.it
Curr Opin Otolaryngol Head Neck Surg 2019, 27:73–79
DOI:10.1097/MOO.0000000000000528

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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Head and neck oncology
KEY POINTS
 Most carcinomas of unknown primary of the head and
neck (CUPHN) in the Western Countries are human
papilloma virus (HPV)-related oropharyngeal tumors
and must be accordingly classified whenever p16 and/
or HPV have been identified within
the lymphadenopathies.
 In the Eastern Countries, a significant proportion of
these tumors may be Epstein–Barr virus-related and, in
this case, should be staged as for
nasopharyngeal cancers.
 Whenever, after adequate immunohistochemistry, in-situ
hybridization, and PCR, no virus-related origin of the
CUPHN can be identified, these tumors must be staged
according to the rules used for nonvirus-related lesions
(with extranodal extension playing a pivotal role in
upstaging of the neck).
 The diagnostic pathway for CUPHN identification
should follow the shortest and most effective strategy,
starting from state-of-the-art endoscopic evaluation
(always including some forms of bioendoscopy),
followed by imaging and invasive diagnostic/
therapeutic maneuvers, such as targeted biopsy,
tonsillectomy, and/or lingual mucosectomy.
 Finding and removing the CUPHN may allow sparing
the visceral axis from irradiation in selected cases.
decades at an alarming 5% per year rate in the
United States and other Western countries) [7], with
a reported ‘epidemic’ prevalence between 20 and
90% [8,9].
CUPHN is by definition a diagnosis of exclusion,
and what constitutes the ideal sequence of inves-
tigations to consolidate (or rule out) such a noso-
logical definition has still to be unanimously
codified by the international scientific community.
However, in a time of general constrains for health
care systems, it is impossible to overemphasize the
need to get a quick and proper CUPHN diagnosis by
using the shortest and the least invasive pathway
available, simultaneously aiming to the optimal
therapeutic choice with the least morbidity and
the highest cost-effectiveness ratio [10].
The great interest of the scientific community
towards CUPHN has been demonstrated (and some-
what reinforced) by the recent introduction in the
American Joint Cancer Commission (AJCC) and
Union for International Cancer Control (UICC)
eighth edition of the TNM Staging Manual [11,12]
of substantial changes related to the CUPHN itself.
In fact, although these lesions were previously cate-
gorized as T0 but not assigned to a specific anatomic
subsite, nowadays identification in lymph nodes of
74 www.co-otolaryngology.com
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
p16 by immunohistochemistry (IHC) or EBV-
encoded RNA by in-situ hybridization (ISH) auto-
matically carries to their staging as for oropharyn-
geal (currently more than 90% of CUPHN) [13,14]
and nasopharyngeal cancers, respectively. Other-
wise, clinical and pathological node definitions fol-
low the rules so far defined for non-HPV-related
tumors of the upper aerodigestive tract (UADT)
mucosal lining. Of note, whereas in the latter, the
presence of extranodal extension (ENE) has been
recognized as a dismal prognosticator and, per se,
sufficient to upstage the neck to pN2 even when the
lymphadenopathy is less than 3 cm, and to pN3
even when constituted between 3 and 6 cm, ENE
does not play such a negative role in HPV-related T0
(taken over by the number of lymph nodes). For the
nasopharynx, apart from nodal size, location below
a plane passing through the caudal border of the
cricoid cartilage is maintained as an adverse prog-
nosticator [11,12].
DIAGNOSTIC TECHNIQUES FOR FINDING
THE PRIMARY
Apart from the obvious detailed clinical history
aimed at obtaining possible (and often under-
reported) meaningful details (such as removal of
tiny skin lesions from the head and neck region,
especially when done in the office and without
appropriate histopathologic examination), the long
and sometimes unfruitful search for the CUPHN
may often resemble the endless quest for the Holy
Grail. However, given the clinical presentation of
such a disease, the first-line approach to a CUPHN
remains unquestionably fine needle aspiration
cytology (FNAC) of the lymphadenopathy with
ultrasound-guidance (reported to substantially
increase the maneuver sensitivity) [15]. Takes
et al. [16] compared HPV-PCR analysis in FNAC from
cervical lymph node metastases with the gold stan-
dard represented by HPV-PCR on formalin-fixed
paraffin-embedded histological material from the
same patients, finding a sensitivity, specificity, pos-
itive, and negative predictive values of 96, 100, 92,
and 100%, respectively. Of note, specific features,
such as cystic or necrotic metastases (highly repre-
sented in the HPV-related scenario), may reduce
FNAC diagnostic performance, thus leading to a
higher false negative rate (42%) and a sensitivity
around 33–50% [17,18] because of the issue of
differential diagnosis with branchial cleft cysts
and nonneoplastic lymphadenopathies, such as
those observed in tuberculosis.
An algorithm including both staining for p16 by
IHC as a first diagnostic step followed by subsequent
detection of HPV by PCR is often used to evaluate
Volume 27  Number 2  April 2019

HPV-status in oropharyngeal cancers. In this clinical
scenario, Smeets et al. [19] and Schache et al. [20]
have shown that such an approach has a strong
accuracy, with 97–100% sensitivity and 94–100%
specificity. Takes et al. [16] noted that a similar
algorithm could be feasible in analysis of cytological
samples obtained from cervical neck nodes of
CUPHN, first doing p16 IHC on histologically proc-
essed cytological material and, thereafter, in case of
p16 expression, undertaking further evaluation by
PCR. To by-pass the potential IHC-related problems
derived by the reduced amount of tissue available
from FNAC, some authors have advocated the sys-
tematic use of US-guided core biopsy both after [21]
&
or in substitution of FNAC [22 ]. Novoa et al. [21], in
a meta-analysis and review on 1267 core biopsies
applied in the evaluation of head and neck lesions,
showed that such a maneuver was successful in
retrieving adequate material for histologic diagnosis
in 95% of cases. On the other hand, there is no need
to underline in this context how an open-neck inci-
sional/excisional biopsy of a metastatic lymph node
without a simultaneous comprehensive neck dissec-
tion should be always considered an unacceptable
procedure, hampered by an unjustified morbidity,
let alone the risk of complications, mainly related
to untreatable local recurrences spreading beyond
physiological fascial planes [23].
Before any attempt of imaging and expensive
radiologic workup, the first opportunity to get an
optimal evaluation of the UADT of a patient bearing
a possible CUPHN is obviously represented by
detailed endoscopic evaluation. In this sense, every
type of bioendoscopic visual aid able to add a clue or
even a subtle diagnostic gain to standard white light
evaluation should be enforced. In fact, a number
&&
of authors [24–29,30 ] have recently described
encouraging results when applying, among the var-
ious bioendoscopic tools available [31], the narrow
band imaging (NBI) technique, both as an office-
based exam, as well as during panendoscopy under
general anesthesia to better target biopsies. In a
recent review, Cosway et al. [32] found a remarkable
sensitivity (74%) and specificity (86%) of NBI in the
CUPHN scenario, underlining its potential in iden-
tifying patients even with tiny, superficial mucosal
lesions. What is more striking, moreover, is that NBI
demonstrated a high negative predictive value, pro-
viding good evidence that patients with negative
evaluation have a very low probability of harboring
UADT primary lesions [32]. Nonetheless, it should
be clear that the heterogeneous accuracy data
related to the application of NBI across different
studies reported in the literature may be heavily
influenced by various selection strategies applied
beforehand in the inclusion criteria of CUPHN
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Unknown primary of the head and neck Piazza et al.
patients. If NBI is used straightforward after white
light endoscopy, and before any kind of imaging (as
strongly warranted by the authors of the present
review), the diagnostic gain will be quite high and,
consequently, the number of ‘missed’ primaries
found only after expensive imaging and/or more
risky maneuvers under general anesthesia (such as
unilateral or bilateral palatine and/or lingual tonsil-
lectomies) will inevitably decline. With this caveat
in mind, none should be surprised by the findings of
Sakai et al. [25] of significantly higher detection of
CUPHN by NBI (71%) compared with white light
(40%), or by those from Shinozaki et al. [27] who, in
a series of patients with negative white light endos-
copy, identified the primary in 11% using NBI and
in 7% by PET-computed tomography (CT) evalua-
tion. Similarly, in a carefully selected cohort of
patients with CUPHN already evaluated by white
light endoscopy and complete radiologic workup
including both CT and/or MR, and PET-CT (entirely
&&
negative), Filauro et al. [30 ] recently obtained, by
office-based use of NBI, a detection rate of 34.5%,
with an overall sensitivity and specificity of 91 and
95%, respectively. Interestingly, in that study, the
authors underlined how office NBI evaluation is not
inferior to intraoperative exam as all the true posi-
tive lesions in their study had been identified in the
preoperative setting, with no adjunctive role of
&&
panendoscopy under general anesthesia [30 ].
If the state-of-the-art videoendoscopic examina-
tion (including NBI) in the hands of the most expe-
rienced clinician is not successful in detecting the
primary, neck CT with contrast enhancement or MR
(both with equivalent CUPHN detection rates
reported to be between 9 and 23%) [33–35] and
chest CT should be performed to find possible
submucosal lesions. Others would prefer PET-CT
instead of conventional imaging, even though the
cost-effectiveness ratio may be an issue and diagnos-
tic gain questionable if not performed after negative
&
CT/MR [22 ,36]. However, every clinical and endo-
scopic effort should be made before embracing any
imaging approach.
TREATMENT MODALITIES OF THE
PRIMARY
The current state of the art about the optimal treat-
ment strategies for CUPHN remains controversial
because of a lack of randomized prospective clinical
trials. Moreover, patient age, performance status,
local extension, site of lymph node metastases,
and histology are the essential parameters heavily
impacting choice of the ensuing therapeutic option.
The treatment of the potential primary tumor
site (PPTS) should be based on a number of different
www.co-otolaryngology.com 75
Head and neck oncology
clinical variables. The first aspect to be taken into
account is the possibility to convert the diagnostic
procedures aimed at identifying the CUPHN in
therapeutic maneuvers, as in case of unilateral or
bilateral palatine and/or lingual tonsillectomies.
With the addition of both maneuvers, Karni et al.
[37] reached a primary site detection rate of 94%, and
a 5-year disease-free survival of 100%. Similarly, Patel
et al. [38] and Durmus et al. [39] showed that palatine
and lingual tonsillectomies using transoral robotic
surgery together resulted in a tumor identification
rate ranging from 72 to 77%. In a recent meta-analysis
&
on 14 studies (673 patients), Di Maio et al. [40 ]
analyzed the CUPHN catch rate of palatine tonsillec-
tomy (through a classical or robotic approach) and
found it to be a nonnegligible 0.34. Nagel et al. [41],
instead, reported that only 57% of CUPHN primary
sites were detected with lingual tonsillectomy alone
by transoral laser microsurgery.
Even the need of a unilateral or bilateral palatine
tonsillectomy is debated. Some authors sustain that
a bilateral approach has the advantage of discover-
ing unknown primary synchronous tumors (10% in
&
the meta-analysis from Di Maio et al. [40 ]) and
create an oropharyngeal symmetric anatomy, in
order to simplify radiological and clinical follow-
up [42]. Moreover, the presence of possible contra-
lateral nodal spread from a tonsillar primary in 1–
10% of cases is well-known from the literature
&
[40 ,43].
Identifying and treating the PPTS in a single step
would also allow clinicians to avoid or de-intensify
chemoradiotherapy [(C)RT], limiting related toxic-
ities and side effects. In fact, the identification and
radical excision of the primary mucosal site could be
followed by radiotherapy on the neck only (where
large and multiple lymph nodes, possibly with ENE,
are frequently found), excluding the pharynx from
the irradiation field, thus avoiding xerostomia and
dysphagia related to the constrictor muscles fibrosis.
Furthermore, successfully identifying the PPTS in
the diagnostic and therapeutic phases allows to
focus on a restricted area during the follow-up
instead of investigating all head and neck structures.
When the tumor remains undiagnosed in spite
of a comprehensive diagnostic workup, one must
consider irradiation of the entire pharyngeal
mucosa. Nevertheless, there is open debate about
the craniocaudal extension of the field to irradiate
and the dose intensity, as well as the need for
ipsilateral or bilateral mucosal irradiation. In fact,
it has been shown that radiotherapy of the PPTS,
compared with surgery alone, gives better outcomes
in terms of local relapse [44] but, while Nieder et al.
[45] showed a significant reduction of local recur-
rence in case of total mucosal irradiation, a recent
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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
large meta-analysis [46] found no differences in
terms of 5-year overall survival (OS) between ipsilat-
eral and bilateral treatments. Moreover, the viral
status itself (HPV-positivity versus EBV-positivity)
is becoming a major indicator of the target volume
to be irradiated. For example, in CUPHN associated
with HPV-positivity (up to 70% of the CUPHNs of
the Caucasian population) [47], palatine and/or lin-
gual tonsils are found to be the primary sites in 80–
90% of cases [48]. Thus, if the PPTS has not been
found after bilateral palatine and lingual tonsillec-
tomies, one can consider performing selective oro-
pharyngeal bilateral irradiation (even though, at
this point, the ensuing burden of the two associated
therapeutic weapons would not be negligible).
Treatment of the nasopharynx, however, is not
mandatory if patients are non-Asian, and HPV-posi-
tive, EBV-negative neck nodes have been diagnosed.
In fact, Mourad et al. [49] demonstrated that the
exclusion of nasopharynx from the irradiation
fields, in such a case, does not change the risk of
mucosal relapse. On the other hand, radiotherapy of
the nasopharynx should be always performed in
presence of retropharyngeal nodes, considered to
be of nasopharyngeal origin in 64–94% of cases
[50]. In such a clinical scenario, Du et al. [50] showed
rates of 5-year OS, progression free survival (PFS),
regional relapse-free, and distant metastasis-free sur-
vivals of 79.6, 61.1, 83.4, and 73.8%, respectively, in
patients treated by radical radiotherapy of the naso-
pharyngeal mucosal and bilateral neck dissection.
Considering the downward inclusion of the lar-
ynx and hypopharynx in the irradiation field, it has
been proposed to spare the organ when the main
nodal disease is located in level II, whereas in case of
level III localization laryngeal radiotherapy should
be always performed [51,52]. By contrast, the radio-
therapy dose is still under discussion. Total dose
usually ranges from 50 to 64 Gy: lower doses are
usually given in case of adjuvant treatment follow-
ing neck dissection, whereas for definitive radiother-
apy the dose rises up to 60 Gy [53]. Others [41]
increased the dose (up to 60–64 Gy) on the ipsilat-
eral oropharyngeal mucosa, as this is the most
frequent PPTS.
TREATMENT MODALITIES OF THE NECK
The first clinical decision to be taken for the appro-
priate management of the neck concerns the choice
of a unimodal treatment (surgery alone versus radio-
therapy alone) instead of a multimodal treatment
(surgery and adjuvant radiotherapy/CRT versus CRT
from the beginning).
The choice of surgery alone requires accurate
identification of a patient at low-risk for mucosal
Volume 27  Number 2  April 2019

emergence and regional recurrence, even though
data in the literature are conflicting [54]. Liu et al.
[46] identified 18 studies in their meta-analysis,
totaling 1582 patients, and compared radiotherapy
alone and the combination of surgery and radio-
therapy for treatment of CUPHN, finding a signifi-
cant difference in terms of 5-year OS, complete
response, and neck recurrence in favor of a multi-
modal approach, but similar DFS.
The main indicator that should guide the choice
of a given therapeutic strategy is the nodal stage,
whereas other factors can be used to identify high-
risk patients (viral and performance status, and alco-
hol-smoking habits). Galloway and Ridge [54]
recently proposed a ‘guideline’ for neck treatment
in CUPHN, assuming that a lesion was not found
after an appropriate diagnostic pathway (T0). In
particular, early N categories like cN1 can be ade-
quately controlled by performing radiotherapy or
surgery alone, thus avoiding mucosal irradiation
[52]. By contrast, in case of cN2a disease, there are
many scenarios, which may condition the therapeu-
tic program: radiotherapy alone can be considered
in low-risk patients (HPV-associated disease in non-
smokers), whereas a multimodal approach with
surgery and radiotherapy is preferable in high-risk
individuals (HPV-negative disease or HPV-positivity
associated with smoking history). Moreover, radio-
graphic evidence of ENE should lead clinicians to
perform primary CRT.
Stage cT0N2b represents the most frequent clin-
ical manifestation of the CUPHN, and can be man-
aged by either neck dissection followed by adjuvant
radiotherapy or with primary CRT (with the latter
being mandatory when there is strong clinical-
radiological evidence for ENE). On the other hand,
in case of cN2c and cN3 diseases, CRT should be
considered as the first-line therapeutic approach
[54].
The dose of neck irradiation is fairly standard-
ized: 66–70 Gy for gross disease, 60–66 Gy for adju-
vant therapy to high-risk areas, and 45–54 Gy for
elective zones of the neck [52]. Finally, the issue of
unilateral or bilateral radiotherapy on the neck is
still debated. This is largely because of the fact that
many studies gave contrasting results: Ligey et al.
[55] and Straetmans et al. [56], for example, did not
find any difference between bilateral and ipsilateral
treatment, whereas Liu et al. [46] showed a trend
towards increased OS and DFS in patients with
bilateral neck radiotherapy.
PROGNOSIS AND PROGNOSTIC FACTORS
Considering survival rates and prognostic factors in
patients affected by CUPHN, the literature presents
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Unknown primary of the head and neck Piazza et al.
variable data. For example, Huang et al. [57] in a
retrospective study observed patients treated for
CUPHN between 1980 and 2000, finding a median
survival time (MST) of 44 months, 3-year and 5-year
OS of 60.4 and 39.6%, respectively, whereas Axels-
son et al. [58] analyzed 68 patients observed from
1993 to 2009 and reported 2-year, 5-year, and 10-
year OS of 87, 82, and 72%, and a DFS of 81, 74, and
68%, respectively. Such a wide range of variation
could be explained on the base of several variables,
such as patient’s performance status (depending on
comorbidities, personal habits, and social environ-
ment), stage of disease, different therapeutic strate-
gies adopted, and presence of virus-related
carcinogenesis versus nonvirus (with field cancer-
ization phenomenon) oncogenesis.
Nodal status and ENE are known to heavily
impact prognosis: N1 and N2 categories are charac-
terized by significantly better survival than N3 (85–
90 versus 50%) [58–60]. On the other hand, the role
of age is still controversial as it has been associated
with decreased survival by some authors [58], even
though others did not find a significant correlation
[60,61]. The association of unhealthy habits, such as
smoking, betel nut chewing, and excessive alcohol
intake seem to strongly correlate with worse prog-
nosis in Asian people with CUPHN as well as with all
the other types of head and neck tumors [61].
As already said, the prevalence of HPV positivity
in the western population affected by CUPHN has
steeply increased in the last decades: in this context,
many authors have focused their attention on its
prognostic value in the unknown primary clinical
scenario [47,58,62,63]. Most studies agreed in find-
ing better survival rates in patients with HPV-related
disease compared with those who had no viral infec-
tion: Cheraghlou et al. [63] recently found a 3-year
OS in N1, N2, and N3 HPV-positive CUPHN of 98.5,
94.4, and 84.2%, respectively, whereas in HPV-
negative disease, survival rates were 82.5, 87.1,
and 56.8%, respectively. The same authors did not
find a significant association with survival and treat-
ment modality for advanced nodal categories in
HPV-positive patients, whereas in the HPV-negative
population, radiotherapy alone was related to a
significantly lower survival [63]. These data support
the previous study conducted by Kharytaniuk et al.
[64] in 2016, in which ENE, according to HPV-
positivity, was not correlated with an adverse prog-
nosis as commonly observed in HPV-negative head
and neck cancers. In such a scenario, clinicians may
consider HPV-related CUPHN in the panorama of
treatment de-intensification in order to reduce iat-
rogenic toxicities. In this regard, Yoo et al. [65] in
2018 analyzed unfavorable prognostic variables in
HPV-positive patients, finding HPV genotype 18
www.co-otolaryngology.com 77
Head and neck oncology
and low performance status as significant indicators
of reduced survival, thus suggesting to not include
these subjects in treatment de-intensification trials.
CONCLUSION
Recognizing that the vast majority of CUPHN are
nowadays virus-related definitely played an essen-
tial role in the evolution of their diagnostic and
therapeutic management. With the modern (bio)-
endoscopic tools and sophisticated radiologic imag-
ing techniques available, as well as more aggressive
(but still minimally invasive) maneuvers like tar-
geted biopsy, tonsillectomy, and base of tongue
mucosectomy, finding the actual primary of a
CUPHN when concentrating purely on the naso-
pharynx and oropharynx should be the rule more
than the exception. In the same way, especially for
HPV-related CUPHN, by definition of small size, in
case of successful identification and complete
transoral removal of the primary, a de-intensifica-
tion approach to the neck may be considered, at
least in presence of favorable cN-pN categories, tiny
mucosal lesions, and a profile of low-risk.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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