ORIGINAL ARTICLE
Distant metastases in head and neck cancer
Frederic Duprez, MD, PhD,1* Dieter Berwouts, MD,2 Wilfried De Neve, MD, PhD,1 Katrien Bonte, MD,3 Tom Boterberg, MD, PhD,1
Philippe Deron, MD, PhD,3 Wouter Huvenne, MD, PhD,3 Sylvie Rottey, MD, PhD,4 Marc Mareel, MD, PhD1
1
Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium, 2Department of Nuclear Medicine, Ghent University Hospital, Ghent, Belgium, 3Department of
Head and Neck Surgery, Ghent University Hospital, Ghent, Belgium, 4Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium.
Accepted 18 November 2016
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.24687
ABSTRACT: Background. Most trials in head and neck cancer empha-
size locoregional control, as this is the main pattern of therapy failure.
However, up to 15% of patients develop distant metastases. The pur-
pose of this study was to present the investigated factors associated
with distant metastasis in a single-center patient cohort.
Methods. A retrospective analysis of a single-center patient cohort over an
18-year period has been performed. We report on prevalence and incidence
of distant metastasis, timing in relation to locoregional failure, Kaplan–Meier
analysis for actuarial distant control rates, and univariate analysis taking into
account histological, etiologic, surgical, site-dependent, stage-dependent
characteristics, modality of primary therapy, and locoregional control.
Results. Of 1022 patients, 141 (13.8%) were diagnosed with distant
metastases involving 283 sites. Actuarial rates of distant control were
INTRODUCTION
In locally advanced head and neck squamous cell carcinoma
(HNSCC), locoregional control at 5 years is limited to 50%,
whereas distant control, also called freedom from distant metas-
tasis, is about 85%.1 Therefore, most HNSCC studies empha-
size locoregional control and survival. Frequently, prevalence
or incidence of distant metastasis is just briefly reported without
uniform methodology and as part of secondary endpoints.
There are several reasons why distant metastasis from
HNSCC deserves detailed attention. Distant metastases
have a dismal prognosis: with the best systemic therapy, the
median overall survival (OS) is 10 months for metastatic
squamous cell carcinoma.2 The proportion of patients with
HNSCC dying from distant metastasis is around 15% to
20%. Observations from autopsy series point to an inci-
dence of distant metastasis that is 3 to 4 times higher than
reported in clinical series.3,4 Therefore, it might be expected
that better locoregional control and longer survival could
lead to an increased incidence of distant metastasis. Most
investigational protocols in HNSCC aim at improving
locoregional control, leaving open the question how
improved locoregional control leading to a longer OS
would affect the rate of distant metastasis.
*Corresponding author: F. Duprez, Department of Radiation Oncology, Ghent
University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
E-mail: frederic.duprez@UZGent.be
88%, 84%, 80%, and 79% at 1, 2, 5, and 10 years, respectively. Factors
associated with distant metastasis are stage grouping and regional node
positivity, extranodal extension, locoregional residual disease, and
human papillomavirus (HPV) negative status in oropharyngeal squamous
cell carcinoma.
Conclusion. Distant metastases in head and neck cancer led to dismal
prognosis. Factors associated with distant metastasis are related to
characteristics of the primary tumor. V
C 2017 Wiley Periodicals, Inc. Head
Neck 00: 000–000, 2017
KEY WORDS: metastasis, head and neck cancer, survival, outcome,
prognostic factors
We performed a single-center retrospective analysis of a
cohort of 1022 patients treated with primary or adjuvant
intensity-modulated radiotherapy (IMRT) with or without che-
motherapy for non-metastatic HNSCC. We emphasized fac-
tors determining distant metastasis and their characteristics.
MATERIALS AND METHODS
This retrospective study has been approved by the Ethical
Committee of Ghent University Hospital on September 24,
2014 (Belgian registration number B670201422031). Where-
ever possible, patients signed an informed consent form.
Acquisition of clinical data
All medical files of patients who were treated with
IMRT between September 1996 and February 2015 for a
histologically proven squamous cell carcinoma of the oral
cavity, larynx, oropharynx, or hypopharynx, either prima-
ry or recurrent, were retrieved. Patients with squamous
cell carcinoma of unknown primary (CUP) with lymph
nodes in the neck were taken into consideration (Table 1).
None of the patients had clinically detectable distant
metastasis at the time of primary diagnosis.
Treatment
All treatments were discussed in a weekly multidisciplinary
meeting with head and neck surgeons, medical oncologists,
radiation oncologists, radiologists, and pathologists. Primary
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DUPREZ ET AL.

TABLE 1. Patient and tumor characteristics. IMRT treatments were scheduled at 5 fractions per week. The
median dose prescription was 35 3 2.0 Gy until 2003 and
Characteristics No. of patients (n 5 1022) % 32 3 2.16 Gy thereafter to tumor regions and pathological
Age, y lymph nodes and 32 3 1.75 Gy to the elective neck and
Range (median) 31–95 (61) 33 3 2.0 Gy in adjuvant setting if section margins were free.
Sex From 2005, concomitant cisplatin-based chemotherapy was
Male:female 919:168 given at 100 mg/m2 on days 1, 22, and 43 until mid-2013 and
Site thereafter weekly at 40 mg/m2 for patients with extracapsular
Oropharynx 342 33.5 extension (ECE) in pathological lymph nodes, positive section
Larynx 286 28.0 margins, and primary IMRT for classification T3 to T4. In
Oral cavity 182 17.8 only a small minority of cases, cetuximab has been used
Hypopharynx 146 14.3 (Table 1).
CUP 66 6.5
HPV status
After completion of IMRT, all patients were clinically
Oropharynx 342 100 followed at least every 3 months during the first year,
Positive 41 12.0 every 4 months during the second year, biannually in the
Negative 143 41.8 subsequent 3 years, and thereafter annually by a head
Unknown 158 46.1 and neck surgeon together with a radiation oncologist.
Other sites 680 100 Toxicity as well as locoregional control were assessed by
Positive 10 1.7 clinical examination and endoscopy. MRI, CT, and/or 18F-
Negative 96 14.1 fluoro-2-deoxy-D-glucose positron emission tomography/
Unknown 574 84.4
Stage
CT were performed in case of clinical suspicion of distant
I 83 8.1 metastasis or as part of staging when locoregional failure
II 100 9.8 was diagnosed. Histological confirmation was performed
III 179 17.5 whenever possible.
IVA 528 51.7
IVB 118 11.5
Unknown 14 1.4 Analysis
T classification Patient and tumor characteristics suspected to
T0 107 10.5
influence metastasis development are summarized in
T1 138 13.5
T2 293 28.7 Table 2.
T3 194 19.0 Time-to-event was calculated from the first day of IMRT.
T4a 216 21.1 An event is defined as the initial diagnosis of distant metas-
T4b 72 7.0 tasis. Cases were censored in the absence of distant metasta-
Unknown 2 0.2 sis, at last follow-up, or death.
N classification Prevalence as well as incidence-rates were calculated.
N0 342 33.5 Prevalence is defined as an absolute number or percentage
N1 680 66.5
of patients with distant metastasis at the time of analysis,
Grade
Well differentiated 99 9.7 incidence as the number or percentage of patients in whom
Moderately differentiated 507 49.6 distant metastasis occurred within a certain period of their
Poorly differentiated 211 20.6 individual follow-up. The actuarial rates of distant control
Unknown 205 20.1 (also called freedom from distant metastasis) and distant
Previous HNSCC metastasis-free survival were calculated using Kaplan–
Yes 188 18.4 Meier statistics. Univariate analysis using log-rank test was
Recurrent 104 10.2 performed for the factors described in Table 2. SPSS ver-
Second primary 84 8.2
sion 23 (IBM, Chicago, IL) was used for statistical analysis.
No 834 81.6
Surgery of primary tumor
Yes 227 22.2 RESULTS
No 795 77.8
Neck dissection Scores of distant metastases
Yes 361 35.3
No 661 64.7
Of 1022 patients, 141 (13.8%) developed distant metas-
Chemotherapy tasis involving 283 metastatic sites found in 12 different
Yes 318 31.1 metastatic organs (Table 3).
Platinum-based 296 29.0 Actuarial rates of distant control and distant metastasis-
Cetuximab 22 2.2 free survival are shown in Figure 1A and 1B. Of all patients
No 704 68.9 with distant metastases, 70% were diagnosed within 1 year
after treatment and 89% within 2 years. Actuarial distant
Abbreviations: CUP, cancer unknown primary; HPV, human papillomavirus; HNSCC, head and control was 88%, 84%, 80%, and 79% at 1, 2, 5, and 10
neck squamous cell carcinoma.
years, respectively. Actuarial distant metastasis-free surviv-
surgery was generally performed in patients with operable oral al was 67%, 55%, 41%, and 29% at 1, 2, 5, and 10 years,
cavity tumors and bulky laryngeal-hypopharyngeal tumors respectively. The steepest increase in distant metastasis is
in which organ preservation was estimated as unlikely. All observed during the first 12 months.

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 DISTANT METASTASES IN HEAD AND NECK CANCER

TABLE 2. Selected factors. plateau comes later. Presence or absence of perineural inva-
sion after primary surgery was mentioned in 125 patients,
Factors of whom 43 (34%) were positive. There was no significant
Sex difference in the actuarial rate of distant control between
Differentiation grade the presence or absence of perineural invasion: 89% and
HPV status
84% at 1 year, 77% and 78% at 2 years, and 77% and 75%
HPV status in oropharyngeal SCC
HPV status in SCC in other sites at 5 years, respectively (p 5 .8). Data on lymphovascular
Surgical features invasion were found for 117 patients: 30 (26%) were posi-
Presence of capsular rupture in node-positive patients after tive. There was no significant difference in the actuarial
neck dissection for HNSCC rate of distant control between presence versus absence of
Section margins lymphovascular invasion: 84% and 85% at 1 year, 77% and
Lymphovascular invasion 75% at 2 years, and 77% and 73% at 5 years, respectively
Perineural invasion (p 5 .5). Of 209 operated patients, section margins were
Site of the primary tumor
free of tumor (R0) in 125 patients (60%), microscopically
Stage
Stage grouping invaded (R1) in 78 patients (37%), and macroscopically
T classification invaded (R2) in 6 patients (3%). There was no significant
Node-positivity vs node-negativity difference in prevalence of distant metastasis between R0
In case of node-positivity: N1 vs N2 vs N3 and R1-2: 17.6% and 13.1%, respectively. Also, the actuari-
Pathological neck node levels al rate of distant control in patients with R0 vs R1-2 disease
Reirradiation for recurrent carcinoma did not differ: 86% and 91% at 1 year, 82% and 85% at 2
Locoregional failure/persistent disease after (chemo)radiation years, and 78% and 80% at 5 years, respectively (p 5 .6).
For squamous cell carcinoma of the oropharynx, human
Abbreviations: HPV, human papillomavirus; SCC, squamous cell carcinoma; HNSCC, head papillomavirus (HPV) status was determined by chromo-
and neck squamous cell carcinoma.
genic in situ hybridization in 184 patients and in 106
patients with a tumor in other sites (oral cavity, n 5 53;
Causes of death and time from distant metastases larynx, n 5 24; hypopharynx, n 5 17; and CUP, n 5 12).
to death There was a clearly higher actuarial rate of distant control
During follow-up, 514 patients (50.3%) died. Causes of in the HPV-positive oropharyngeal group as well as in
death are summarized in Table 4. the whole HPV-positive patient group: actuarial 1-year, 2-
The median time from distant metastasis to death was year, and 5-year distant control rates were 98%, 95%, and
only 3.3 months (range, 0.0–64.2 months). Actuarial surviv- 91% versus 81%, 76%, and 70% for HPV positivity ver-
al rates at 6 months and 1 year, calculated from the date of sus negativity, respectively (p 5 .005). Figure 2B shows
distant metastasis, were 40% and 22%, respectively. the curves for HPV positivity versus negativity in oropha-
OS at 6, 12, and 24 months after diagnosis of distant ryngeal versus non-oropharyngeal carcinoma. The distant
metastasis was 42%, 25%, and 15% in patients with pre- control rate between HPV positivity versus negativity
vious radiotherapy only versus 37%, 17%, and 11% with remained significant in the oropharyngeal group
concurrent chemoradiation as primary treatment (p 5 .44). (p 5 .011) but not in the non-oropharyngeal group
OS at 6, 12, and 24 months after diagnosis of distant (p 5 .28).
metastasis was 50%, 34%, and 22% in patients with a sin-
gle site of metastasis versus 30%, 9%, and 4% with mul- TABLE 3. Organ distribution in 181 patients with distant metastases.
tiple metastatic sites involved (p 5 .03).
% of all % of all distant
Histological features Site of metastases Number patients metastases

Prevalence of distant metastasis was 9.1%, 14.1%, and Lungs 110 10.8 78.0
15.6% in patients with well (World Health Organization Bones 42 4.1 29.7
[WHO] grade 1), moderately (WHO grade 2), and poorly Liver 24 2.3 17.0
differentiated (WHO grade 3) HNSCC, respectively Lymph nodes outside neck 28 2.7 19.8
All 11 1.1 7.8
(p 5 .30). One-year, 2-year, and 5-year actuarial distant
Mediastinal 11 1.1 7.8
control was 93%, 86%, and 86%, respectively, in well Axillar 2 0.2 1.4
differentiated and 88%, 83%, and 79%, respectively, in Other
moderately and poorly differentiated HNSCC (p 5 .27). Skin
Pre-IMRT neck dissection in 360 patients was pathologi- skin 16 1.6 11.3
cally negative (“pN0”) in 45 and positive (“pN1-3”) in 315 Head and neck 12 1.2 8.5
patients. From the latter, presence or absence of ECE was Thorax 5 0.5 3.5
mentioned in 237 patients: 153 (65%) had ECE and 84 Pleura 13 1.2 9.2
(35%) did not. Prevalence of distant metastasis was 11.9% Adrenal gland 2 0.2 1.4
and 32.0% in the absence and presence of ECE, respective- Soft tissues 2 0.2 1.4
Pancreas 2 0.2 1.4
ly (p 5 .001). Actuarial rates of distant control in ECE- Brain 1 0.1 0.7
positive patients were significantly (p < .001) lower than in Omentum 1 0.1 0.7
ECE-negative patients (Figure 2A). In ECE-positive Spleen 1 0.1 0.7
patients, the initial slope of the curve is steeper and the

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DUPREZ ET AL.

FIGURE 1. Distant control (A) and distant metastases-free survival (B) in all patients (%). For distant control, distant metastasis is considered as an
event; patients are censored in case of death or dropout from follow-up. For distant metastasis-free survival, distant metastasis and death are con-
sidered as events; patients are censored in case of being alive in the absence of distant metastasis at last follow-up.

Epidemiology of distant metastases Stage

The prevalence of patients with distant metastases was
equal for men and women (both 14%; p 5 1.0). The
median age of death in patients with and without distant
metastasis did not differ: 59 years (range, 40–87 years)
versus 61 years (range, 31–95 years).
Site
Prevalence of distant metastasis was 20.5%, 19.7%,
15.4%, 12.9%, and 9.1% in patients with hypopharyngeal,
CUP, oral cavity, oropharyngeal, and laryngeal SCC,
respectively (p 5 .008). The actuarial rate of distant con-
trol was the lowest in hypopharyngeal HNSCC (74% at 2
years), the highest in patients with laryngeal HNSCC
(90% at 2 years), and in-between for CUP, oral cavity,
and oropharyngeal HNSCC (79%, 80%, and 85% at 2
years, respectively).
Stage grouping at diagnosis was correlated with preva-
lence of distant metastasis: 1 of 83 (1.2%), 6 of 100
(6.0%), 15 of 179 (8.4%), and 117 of 646 (18.0%), in
stages I, II, III, and IV, respectively (p < .001). In addi-
tion, the actuarial distant control rate was lower in higher
stages (Figure 3A).
There was a trend toward lower prevalence of distant
metastasis in lower T classifications: 11 of 138 (8.0%),
38 of 293 (13.0%), 31 of 194 (16.0%), and 44 of 288
(15.3%) in classifications T1, T2, T3, and T4, respective-
ly (p < .13). The actuarial distant control rate at 1, 2, and
5 years was 76%, 69%, and 63% for classification T4b
and ranged from 84% to 93%, 82% to 91%, and 78% to
90% at 1, 2, and 5 years for classifications T1 to T4a,
respectively.
Prevalence of distant metastasis was significantly lower
in lower N classifications: 17 of 333 (5.1%), 18 of 160
(11.3%), 91 of 476 (19.1%), and 13 of 45 (28.9%) in

TABLE 4. Causes of death.

All patients Patients with distant metastasis

Cause of death Number (total 514) % Number (total 122) %

Cancer progression 240 47 101 83

Locoregional progression 140 27 12 10
Distant metastasis 66 13 64 52
Locoregional progression 1 distant metastasis 16 3 13 11
Unknown locoregional progression vs distant metastasis 18 4 12 10
Toxicity 23 4 0 0
Disease-related* 52 10 8 7
Second primary tumor 63 12 2 2
Intercurrent (noncancer) death 45 9 2 2
Unknown 91 18 9 7

* Unclear whether cancer progression or toxicity.

4 HEAD & NECK—DOI 10.1002/HED MONTH 2017


FIGURE 2. Distant control in subgroups with different histologic features. All Y-axes start at 50% for clarity reasons. Curves for differentiation grade
(A), node-positive patients with and without extracapsular extension (B) and human papilloma virus (HPV)-positivity versus negativity (C).
classifications N0, N1, N2, and N3, respectively
(p < .001). Node-positive patients had lower actuarial dis-
tant control than node-negative patients: the actuarial dis-
tant control rate at 1, 2, and 5 years was 96%, 93%, and
92% versus 84%, 78%, and 74% for patients with node-
negative versus node-positive disease, respectively
(p < .001).
Of 680 patients with positive lymph nodes, the exact N
classification was known in 679 patients: N1 in 154
patients (23%), N2a in 43 patients (6%), N2b in 226
patients (33%), N2c in 211 patients (31%), and N3 in 45
patients (6%). Figure 3B demonstrates the curves of dis-
tant control for different N classifications: there is signifi-
cantly lower actuarial distant control in patients with
more advanced N classifications. Positive lymph nodes in
regions III, IV, and V were correlated with a lower actu-
arial distant control rate (Table 5).
Reirradiation
Reirradiation was performed in 111 patients (locore-
gional recurrent disease in 64 patients [58%] and second
primary HNSCC in 47 patients [32%]). In this cohort,
actuarial distant control at 1 and 2 years was 89% and
86%, respectively (Figure 4A). In both groups, locore-
gional failure outweighed by far distant metastasis (Figure
4B) after reirradiation.
Distant metastases and locoregional failure
Venn diagrams show the prevalence of patients diag-
nosed with all local and/or regional recurrences and/or
distant metastasis during the entire follow-up period
(Figure 5A) as well as first occurrence only (Figure 5B).
In 64 patients, distant metastasis was combined with local
and/or regional recurrence at any time of follow-up; when
only the first site of recurrence was considered, only 37
patients were diagnosed with distant metastasis and
locoregional recurrence.
In the cohort of 141 patients who were diagnosed with
distant metastasis during follow-up, locoregional failure
DISTANT METASTASES IN HEAD AND NECK CANCER
was seen in 64 patients (45%). In 37 of these 64 patients
(58%), distant metastasis and locoregional failure were
diagnosed synchronously, whereas, in 27 patients (42%),
they were diagnosed metachronously; locoregional failure
was diagnosed >1 month before distant metastasis in 31
patients and in 6 patients > 1 month thereafter. The time
interval between diagnosis of distant metastasis and
locoregional failure in patients with metachronous distant
metastasis and locoregional failure had a median of 7
months (range, 1–42 months). Figure 6 shows a timeline
for all 64 patients with locoregional failure and distant
metastasis.
The presence of locoregional failure, including locore-
gional persistent disease after therapy, was strongly corre-
lated with the prevalence of distant metastasis: 64 of 263
patients (24%) with and 77 of 759 patients (10%) without
locoregional failure (p < .001). Also, locoregional failure
after a period of locoregional control was strongly corre-
lated with distant metastasis: 58 of 203 patients (29%)
with and 83 of 819 patients (10%) without locoregional
failure (p < .001).
DISCUSSION
Once distant metastasis in HNSCC is diagnosed, the
median time to death is 64 months. Despite such dismal
prognosis, recent literature on distant metastasis in the
cohort of patients with HNSCC is limited. In our cohort,
all patients were treated with IMRT and, since 2005, with
concomitant cisplatin-based chemotherapy for locally
advanced HNSCC.
Distant metastasis from HNSCC appeared shortly after
treatment, in line with most previous observations.4–9 Typi-
cal curves of distant metastases as a function of time after
diagnosis show a rapid increase between months 0 and 8, a
slow increase between months 8 and 24, and a plateau
between months 24 and 84,5 indicating the absence of late
metastasis. This is in contrast with other types of tumors in
the head and neck and other regions: incidence of distant
metastasis from adenoid cystic carcinoma of the salivary
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DUPREZ ET AL.

FIGURE 3. Distant control per stage grouping (A) and per N classification (B). The Y-axis begins at 50% for clarity reasons.

glands or mammary cancer, for example, continue to lymphovascular nor perineural invasion affected distant
increase with time, even up to more than 20 years after metastasis.
diagnosis.10,11 Such differences in development of late Table 63,4,6,7,13–24 systematically compares our data with
metastases between HNSCC and adenoid cystic carcinoma literature. For this comparison, we selected large series
or mammary cancer may reflect different capabilities of reporting only distant metastasis in HNSCC. We arbitrarily
metastatic cancer cells to survive periods of dormancy and defined a minimal number of patients of 3/4 of our cohort
to respond to autocrine or paracrine, resident or imported (ie, 766 patients) to include series and systematically com-
awakening signals. Dormancy genes (eg, NR2F1) present in pared all factors studied in our series (Table 2). However, in
disseminated tumor cells from patients with prostate cancer these studies, we did not find data on the relation between
with dormant disease were found to be upregulated also in distant metastasis and perineural or lymphovascular inva-
human HNSCC cell lines, leading to dormancy of distant sion, nor on reirradiation.
metastasis. Inactivation of NR2F1 leads to a rapid switch Prevalence of distant metastasis in our cohort was in
from dormancy to proliferation of distant metastasis.12 line with most other series. It has to be noted, however,
Development of distant metastasis in HNSCC is clearly that our 13.7% prevalence seems somewhat higher than
a multifactorial phenomenon. In our cohort, the following in most other series, except for autopsy series, which fea-
factors significantly increased distant metastasis: ECE, ture clearly higher rates. The exceptionally high preva-
location of the primary tumor in the hypopharynx, higher lence of distant metastasis in autopsy series could reflect
stage grouping, N classification, locoregional failure, an overestimation of the real number of distant metastasis
including relapse and persistent disease. HPV positivity as patients were only autopsied if they died in the hospi-
was associated with less distant metastasis. Neither tal; this might create bias, as patients who were not con-
fronted with symptoms of their disease are less likely to
be hospitalized.3
TABLE 5. Correlation between positive lymph nodes per region and Comparison between series must be performed cau-
distant metastases in patients with pathological regional lymph nodes tiously. Especially the older series can be biased for sev-
at diagnosis. eral reasons. First, the real number of distant metastasis is
probably underestimated in series without autopsy confir-
Lymph node Containing Actuarial distant mation, especially if they date from before the CT era.
region positive nodes control rate at 2 y p value Diagnosis of clinically occult distant metastasis is depen-
I Yes 73% .06 dent on the quality of the diagnostic procedures. Second,
No 79% in older series, with less aggressive locoregional treat-
II Yes 78% 1.0 ment, patients might have been more likely to die early
No 78% from locoregional problems before distant metastasis
III Yes 72% <.001 could become clinically apparent. Third, an important
No 85% bias is introduced by the composition of patient series:
IV Yes 62% <.001 they differ widely in stage and site distribution and HPV-
No 82% positivity, which is often not known in older series. As an
V Yes 66% .003
No 80% example, in our series, 81% of patients can be staged as
Retropharyngeal Yes 68% .10 locoregionally advanced HNSCC (17.5% stage III; 63.2%
No 79% stage IVA–B) and only 22% of the patients with oropha-
ryngeal cancer with known HPV status are HPV positive.

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 DISTANT METASTASES IN HEAD AND NECK CANCER

FIGURE 4. Freedom from distant metastasis in 111 patients after reirradiation (A), and from distant metastasis as compared to locoregional failure
in patients reirradiated for locoregional recurrent (dashed lines) versus second primary cancer (full lines). DM, distant metastasis; LRF, locoregional
failure.

Based on our results and literature comparison (Table
6) incidence of distant metastasis seems to have hardly
changed over the last 50 years.4,25 Also, time sequence of
distant metastasis after treatment is very comparable
between series as well as the time to death after diagnosis
of distant metastasis; the series reporting a median 7-
month survival as compared to the 4-month survival
mostly reported, was limited to patients with only locore-
gional control.16 These observations suggest that advances
in locoregional or systemic anticancer treatment and sup-
portive care had little impact on distant metastasis. Tak-
ing into account both the type of failure and time to
failure shows that locoregional failure and distant metas-
tasis are competing risks, in as much as when one occurs,
it shortens the period of being at risk of failure because
of the other. It is, therefore, crucial to follow closely the
impact of novel locoregional and adjuvant systemic treat-
ment strategies on the development of distant metastasis.
The distant visceral organs in which HNSCC metasta-
ses are diagnosed most frequently are the lungs. Our
result of bone and liver as most frequent sites of distant
metastasis after the lungs (Table 3) is in line with most
other series (Table 6) and literature review.26 However, in
a few studies, bone metastases came out in the third
place, after liver or noncervical lymph nodes (Table 6).
Some studies that are not included in Table 6 address
specific attention to distant metastases from HNSCC in
organs that are not frequently affected (eg, skin and
brain). Skin metastases occur in 1% to 2% of patients
with HNSCC, accounting for less than 10% of distant
metastases.26,27 In our series, skin metastases occurred in
16 patients (1.5%), in line with the above-mentioned

FIGURE 5. Venn diagrams showing types of recurrences at any time during follow-up (regardless of their time sequence) (A) and at first occurrence
(B).

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DUPREZ ET AL.
studies. The majority of these patients had previous neck
dissection and all patients have been irradiated in the
neck. Risk factors described in literature include former
neck surgery that changes normal lymphatic spread, high-
dose neck irradiation, cervical lymph node metastases,
and ECE all causing aberrant lymph node drainage.26,27
Based on these observations, it seems logical that cervical
or thoracic skin metastases represent locoregional spread
through the lymphatic system. This is in contradiction
with the M1 classification of the Union for International
Cancer Control TNM classification, pointing toward a
hematogenous metastatic process. Clinically, however,
skin metastases in the neck and distant visceral metastases
have an equally dismal prognosis.27
Brain metastases are very rare in HNSCC with a rate of
0.4% detected clinically in a cohort of more than 5000
patients.28 This is in line with the 0.7% in our present
series.
In patients with HPV-positive HNSCC, the incidence of
distant metastasis at 2 years was lower than in patients
with HPV-negative HNSCC (8.7% vs 14%, not signifi-
cant); these values were not affected by smoking.29 In
stages III to IV oral SCC, treated by surgery plus radio-
therapy, more distant metastasis (p 5 .035) and lower OS
(p 5 .041) were associated with only HPV16-positive, but
not with only HPV18-positive tumors.30 Our present
results confirm the lower incidence of distant metastasis
in patients with HPV-positive oropharyngeal carcinoma
but not in patients with HPV-positive nonoropharyngeal
carcinoma (Figure 2B). The only large series included in
our literature comparison with data on HPV resulted in
very comparable results.14
In line with all other studies, most distant metastases
are observed in hypopharyngeal HNSCC. For the other
sites, results differ widely between series (Table 6). This
might be explained by large differences in HPV positivity
within the oropharyngeal groups between patients and
presence or absence of T1 to T2 N0 glottic cancer within
the laryngeal cohorts.
8 HEAD & NECK—DOI 10.1002/HED MONTH 2017
FIGURE 6. Time sequences of locoregional
failure and distant metastasis. On the X-
axis, each line represents an individual
patient; the Y-axis represents the time
interval in months between diagnosis of
locoregional failure and distant metastasis
(positive value) or vice versa (negative val-
ue). The patients at the 0-value had syn-
chronous diagnosis of locoregional failure
(LRF) and distant metastasis.
In our series, more advanced cancers with higher N
classification and stage grouping have lower actuarial dis-
tant control rates (see Figure 3) confirming literature data
(Table 6).24,31 The effect of stage on distant metastasis is
less obvious in studies using autopsy data3,32: up to 42%
of distant metastases has been observed in classification
N0, suggesting early escape of metastatic cancer cells
from the primary tumor without establishment of lymph
node metastases. We have no reason to think that under-
estimation of distant metastasis by a factor 2 to 43,4
would not hold for our cohort in which no autopsies were
done. This would mean that more than half of distant
metastases did not appear clinically during the relatively
short course of the disease.
The presence of locoregional failure was strongly corre-
lated with distant metastasis, synchronously, or metachro-
nously, in line with the literature (Table 6 and Figures 5
and 6).23,25,33 Possible interpretations could be that
locoregional failure is a continuous source of distant
metastasis or that locally recurrent tumors stimulate the
growth of micrometastasis.
Sequences of failures (Figures 5 and 6) may be inter-
preted in terms of roads of metastatic cancer cell spread
or in terms of tumor growth. Synchronous distant metas-
tasis and locoregional failure points to remnant cancer
cells at the locoregional site as well as at distant sites
(micrometastasis), developing synchronously into a
clinical lesion. Locoregional failure followed by distant
metastasis (metachronous distant metastasis) suggests
post-therapeutic seeding from the locoregional failure,
which is more likely with longer time intervals. Distant
metastases followed by locoregional failure could indicate
that locoregional failure originates from distant metasta-
sis. Venn diagrams show that distant metastases represent
41% of all failures and half of all distant metastases are
solitary (see Figure 5). Note that isolated distant metasta-
ses (22%) are less frequent than isolated local failure
(43%) but more frequent than isolated nodal failure
(11%). Furthermore, isolated distant metastases (22%) are
 TABLE 6. Comparison with literature.

Literature
Confirmatory Conflicting

Characteristic Current study Score Authors Score Authors

13
Overall prevalence 13.7% 12.0% J€ackel and Rausch Higher
of distant metastasis 11.6% Kjems et al14 46.8% Kotwall et al3
11.4% Probert et al6 Lower:
11.0% Al-Othman et al24 6% Bernier and Bataini21
10.9% Merino et al4 4.8% Carvalho et al22
10.9% van der Schroeff et al15 3.5% Kowalski et al23
9.5% Leon et al7
9.4% Lim et al16*
9.2% Garavello et al17
8.9% Fortin et al18
8.5% Spector et al19
8.0% Bourhis et al20
Time to develop 70% to 89% at 1 to 2 y 55% to 89% Probert et al6 None
distant metastasis 61% to 80% Merino et al4
n.g./84% Leon et al7
n.g./94% J€ackel and Rausch13
Median survival after 3.3 mo, Worse if > 1 4.1 mo Kowalski et al23 7 mo Lim et al16*
diagnosis of distant site involved 4.0 mo J€ackel and Rausch13
metastasis
Site of distant metastasis Lung ! bone ! liver Kowalski et al23 Lung fi liver ! bone J€ackel and Rausch13
and lymph nodes Merino et al4 Lung ! lymph nodes ! Kotwall et al3
Garavello et al17 liver 5 bone
Probert et al6
Kowalski et al23
Lim et al16
Differentiation grade: % distant 9.1%/14.0%/15.6% (n.s.) 8.3/10.9/24.4% J€ackel and Rausch13 None
metastasis in primary HNSCC 1.0%/8.5%/17.8% Garavello et al17
with grades 1/2/3 3.2%/6.2%/23.6% Lim et al16*
ECE: % distant metastasis 11.9%/32.0% (significant) 14%/29% Leon et al7 None
DISTANT

without/with 14.4%/36.6% Garavello et al17

7.5%/14.3% Lim et al16*
Resection margin: % distant 17.6%/13.1% (n.s.) None 6.0%/13.1% Lim et al16*
metastasis in R0/R1–2
Oropharynx HPV 1 vs HPV- 92% vs 77% 3-y 3-y distant control Kjems et al14 None
distant control 92% vs 87%

HEAD & NECK—DOI 10.1002/HED

(significant) (trend, n.s.)
% distant metastasis 14%/14% (n.s.) 9.1%/10.3% Garavello et al17
in men/women
Site of primary tumor: % 20.5%/15.4%/12.9%/9.1% 22.9%/13.3%/12.2%/6.9% J€ackel and Rausch13 23.6%/7.5%/11.6%/7.3% Merino et al4
distant metastasis in (significant) 14.6%/13.8%/11.1%/1.4% Probert et al6 16.7%/3.0%/10.4%/9.2% Garavello et al6

MONTH 2017
hypopharynx/oral cavity/ 16.9%/n.g./n.g./4.4% Spector et al19 60.2%/41.3%/48.6%/43.8% Kotwall et al3†
oropharynx/larynx 23.6%/3.2%/9.4%/5.6% Lim et al16*

9
METASTASES IN HEAD AND NECK CANCER
10
DUPREZ ET AL.

TABLE 6. Continued

HEAD & NECK—DOI 10.1002/HED

Literature
Confirmatory Conflicting

Characteristic Current study Score Authors Score Authors

MONTH 2017
4
Stage grouping: I/II/III/IV 1.2%/6.0%/8.4%/18.0% 2.0%/5.7%/8.5%/19.5% Merino et al 11.6%/7.3%/ J€ackel and Rausch13
(significant) 1.9%/6.3%/12.2%/17.6% Spector et al19 14.2%/19.9%
42%/35%/43%/55% Kotwall et al3†
4
T classification: 8.0%/13.0%/16.0%/15.3% (n.s.) 5.2%/9.6%/12.7%/16.1% Merino et al None
T1/T2/T3/T4 5.6%/9.8%/16.8%/16.4% J€ackel and Rausch13
0.3%/7.8%/12.7%/21.0% Garavello et al17
N classification: 5.1%/11.3%/19.1%/28.9% 4.9%/11.8%/21.8%/27.1% Merino et al4 3%/7%/8%/8% Bernier and Bataini21
N0/N1/N2/N3 (significant) 5.3%/15.8%/19.7%/30.6% J€ackel and Rausch13
2.5%/22.0%/23.7%/29.5% Garavello et al17
Incidence of distant 10%/24% (significant) 16.7%/7.9% Merino et al4 None
metastasis in 23.2%/14.8% J€ackel and Rausch13
presence/absence 18%/5% Leon et al7
of locoregional failure 17.3%/5.4% Garavello et al17

Abbreviations: n.g., not given; HNSCC, head and neck squamous cell carcinoma; n.s., not significant; ECE, extracapsular extension; HPV, human papillomavirus.
Comparison with literature selected on basis of HNSCC in >767 patients: Al-Othman et al24 (873), Bernier and Bataini21 (1.646), Garavello et al17 (1.979), J€ackel and Rausch13 (1.087), Kjems et al14 (942), Kotwall et al3 (775), Kowalski et al23 (2.327), Lim et al16*
(795), Merino et al4 (5.019), Probert et al6 (779), Spector et al19 (2.550), and van der Schroeff et al15 (2.927). Differences in literature are shown in bold italics.
* Study included patients with locoregional control only.
†
Fifty-seven patients with nasopharyngeal and paranasal sinus were excluded from this table.

more frequent than distant metastasis in combination with
regional failure (6%), local failure (9%), or both (3%).
The observation that a substantial number of patients
develop distant metastases without locoregional failure
indicates that micrometastases are present at the moment
of complete locoregional clinical response.
In conclusion, unlike the introduction of radiochemo-
therapy for locally advanced HNSCC and conformal tech-
niques, such as IMRT, that enable adequate dose
deposition to tumoral regions, the appearance of distant
metastasis did not change compared with decades ago.
Advanced stage grouping and increasing N classification,
node positivity, extranodal extension, and HPV-negativity
are factors associated with the development of distant
metastases and are present independently of any change
in treatment paradigm. Because some of these factors are
associated with advanced HNSCC, it can be assumed that
the most efficient way to lower incidence of distant
metastases is to diagnose HNSCC in earlier stages.
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