10.14639/0392-100X-N0879
The incidence of distant metastasis (DM) in head and neck squamous cell cancer (HNSCC) is relatively low. Multiple risk factors have been described for development of DM at baseline and after treatment. However, to date, there is no meta-analysis or systematic review investigating the relationships between clinical and histopathological factors and the appearance of DM in HNSCC patients. Among 1,272 eligible articles, 23 met inclusion criteria for qualitative analysis, and 6 for quantitative analysis. The meta-analysis on 5,353 patients showed that hypopharyngeal site, T3-T4 categories, extranodal extension, positive lymph node size &gt; 6 cm, locoregional failure after previous treatment(s) and poor differentiation all significantly increase the risk of DM. According to our results, patients with the above-mentioned clinical and histopathological risk factors should be considered at high risk for DM and therefore submitted to strict pre-treatment assessment and undergo careful post-therapeutic follow-up.
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1827-675X
879
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Cesare Piazza
https://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
distant metastasis, head and neck, cancer, risk factors
Clinical and histopathological risk factors for distant metastasis in head and neck cancer patients.
Text.Serial.Journal
https://www.actaitalica.it/
41
Reviews
2021-03-19
2020-05-23
2021-03-19
2021-03-24
6-17
1
Cesare Piazza
2021/03/19
10.14639/0392-100X-N0879
6
Department of Otorhinolaryngology, Maxillofacial and Thyroid Surgery, Fondazione IRCCS, National Cancer Institute of Milan, University of Milan, Milan, Italy
1827-675X
distant metastasis, head and neck, cancer, risk factors
17
Clinical and histopathological risk factors for distant metastasis in head and neck cancer patients.
https://www.actaitalica.it/article/download/879/519
41
ACTA OTORHINOLARYNGOLOGICA ITALICA 2021;41:6-17; doi: 10.14639/0392-100X-N0879




Review


Clinical and histopathological risk factors for distant
metastasis in head and neck cancer patients
Fattori di rischio clinici e istopatologici per metastasi a distanza in pazienti
con carcinoma della testa e del collo
Carlos Miguel Chiesa-Estomba1,2, Jerome R. Lechien2,3, Tareck Ayad2,4, Christian Calvo-Henriquez2,5,
José Ángel González-García1, Jon Alexander Sistiaga-Suarez1, Didier Dequanter6, Nicolas Fakhry2,7,
Gebeyehu Melesse8, Cesare Piazza9
1
  Department of Otorhinolaryngology - Head and Neck Surgery, Hospital Universitario Donostia, San Sebastian, Spain; 2 Head &
Neck Study Group of Young-Otolaryngologists of the International Federations of Oto-rhino-laryngological Societies (YO-IFOS);
3
  Department of Human Anatomy and Experimental Oncology, University of Mons, Mons, Belgium; 4 Division of Otolaryngology -
Head and Neck Surgery, Centre Hospitalier de l’Université de Montréal, Montreal, Canada; 5 Department of Otolaryngology,
Hospital Complex of Santiago de Compostela, Santiago de Compostela, Spain; 6 Department of Otolaryngology - Head and Neck
Surgery, Centre Hospitalier Universitaire Saint-Pierre, Brussels, Belgium; 7 Department of Otolaryngology - Head and Neck Surgery,
Universitary Hospital of la Conception, Marseille, France; 8 Department of Otolaryngology - Head and Neck Surgery, Bahir Dar
University, Tibebe Ghion Specialised Hospital, Bahir Dar, Ethiopia; 9 Department of Otorhinolaryngology, Maxillofacial and Thyroid
Surgery, Fondazione IRCCS, National Cancer Institute of Milan, University of Milan, Milan, Italy


SUMMARY
The incidence of distant metastasis (DM) in head and neck squamous cell cancer (HN-                  Received: May 23, 2020
SCC) is relatively low. Multiple risk factors have been described for development of DM              Accepted: June 6, 2020
at baseline and after treatment. However, to date, there is no meta-analysis or systematic
review investigating the relationships between clinical and histopathological factors and            Correspondence
the appearance of DM in HNSCC patients. Among 1,272 eligible articles, 23 met inclusion              Carlos Miguel Chiesa-Estomba
criteria for qualitative analysis, and 6 for quantitative analysis. The meta-analysis on 5,353       Department of Otorhinolaryngology - Head and
patients showed that hypopharyngeal site, T3-T4 categories, extranodal extension, positive           Neck Surgery, Hospital Universitario Donostia, Cal-
                                                                                                     le Doctor Begiristain #1. CP. 20014, San Sebastian -
lymph node size > 6 cm, locoregional failure after previous treatment(s) and poor differen-
                                                                                                     Donosti, Spain
tiation all significantly increase the risk of DM. According to our results, patients with the       Tel. +34 635 793 435
above-mentioned clinical and histopathological risk factors should be considered at high             E-mail: chiesaestomba86@gmail.com
risk for DM and therefore submitted to strict pre-treatment assessment and undergo careful
post-therapeutic follow-up.                                                                          Funding
KEY WORDS: distant metastasis, head and neck, cancer, risk factors                                   None.

                                                                                                     Conflict of interest
RIASSUNTO                                                                                            The Authors declare no conflict of interest.
L’incidenza di metastasi a distanza nel carcinoma squamocellulare della testa e del collo è
relativamente bassa. Sono stati descritti molteplici fattori di rischio per lo sviluppo di me-
                                                                                                       How to cite this article: Chiesa-Estomba CM,
tastasi sistemiche, sia al momento della diagnosi che dopo il trattamento. In ogni caso, ad
                                                                                                       Lechien JR, Ayad T, et al. Clinical and histo-
oggi, non esiste una meta-analisi o una revisione sistematica che indaghi i rapporti tra fat-
                                                                                                       pathological risk factors for distant metastasis
tori clinico-istopatologici e la comparsa di metastasi a distanza nei pazienti con carcinoma           in head and neck cancer patients. Acta Otorhi-
squamocellulare della testa e del collo. Tra i 1,272 articoli utili, 23 presentavano i criteri di      nolaryngol Ital 2021;41:6-17. https://doi.
inclusione per un’analisi qualitativa e 6 erano adatti ad un’analisi di tipo quantitativo. La          org/10.14639/0392-100X-N0879
meta-analisi, condotta su un totale di 5,353 pazienti, ha mostrato come la sede ipofaringea,
le categorie T3-T4, l’estensione extra-nodale, linfonodi metastatici di diametro > 6 cm, il          © Società Italiana di Otorinolaringoiatria
fallimento loco-regionale dopo pregressi trattamenti e la scarsa differenziazione aumentino          e Chirurgia Cervico-Facciale
tutti in modo significativo il rischio di metastasi a distanza. In base ai nostri risultati, quin-
di, i pazienti con i fattori di rischio clinici e istopatologici sopra citati dovrebbero essere                     OPEN ACCESS
considerati ad alta probabilità di sviluppare metastasi a distanza e, pertanto, sottoposti ad        This is an open access article distributed in accordance with
una rigorosa valutazione pre-trattamento, così come ad un attento follow-up.                         the CC-BY-NC-ND (Creative Commons Attribution-Non-
                                                                                                     Commercial-NoDerivatives 4.0 International) license. The
PAROLE CHIAVE: metastasi a distanza, testa e collo, cancro, fattori di rischio                       article can be used by giving appropriate credit and mentio-
                                                                                                     ning the license, but only for non-commercial purposes and
                                                                                                     only in the original version. For further information: https://
                                                                                                     creativecommons.org/licenses/by-nc-nd/4.0/deed.en




6
                                                                                                Distant metastasis in head and neck cancer




Introduction                                                         guidelines proposed by the Preferred Reporting Items for
                                                                     Systematic reviews and Meta-Analyses (PRISMA) state-
In head and neck squamous cell carcinoma (HNSCC), the
                                                                     ment.
main sites of distant metastases (DM) are the lung, bone
and liver, accounting for approximately 70-85%, 15-39%
                                                                     Population and inclusion/exclusion criteria
and 10-30% of events, respectively 1. The incidence of DM
                                                                     Inclusion criteria consisted of clinical series comprehen-
in HNSCC is, however, relatively low, with a reported prev-
                                                                     sively reporting clinical (age, pharyngeal site, T and N cat-
alence of clinically identified distant localisations at diag-
nosis ranging from 3% to 50% 2-18.                                   egories, neck lymph nodes status, local and regional con-
HNSCC patients with DM are generally candidates for pallia-          trol or failure) and histopathological data (ENE, p16 status,
tive treatment since no systemic therapy has curative potential in   lymph node size > 6 cm, and number of lymph nodes) of
such a clinical scenario 18. As a consequence, the reported medi-    HNSCC patients without DM at presentation to evaluate
an overall survival (OS) in the literature is around 10 months 19,   the appearance of DM during follow-up after treatment.
and extensive locoregional treatments are universally believed       Studies that evaluated the association between relevant
to be futile for their modest (if any) improvement in OS.            clinical or histological factors with the appearance of DM
Multiple studies have evaluated the main risk factors for de-        through univariate and multivariate analysis were consid-
velopment of DM at baseline and/or after treatment of HN-            ered. Case reports, case series and expert opinion papers
SCC 14,17,21-24. These generally include the presence of ≥ 3         were excluded, as well as articles focusing on non-HNSCC
neck lymph nodes metastases 7,25, radiological or histologi-         patients, with different or multiple histology, and absence
cal extranodal extension (ENE) 22,25,27-29, low jugular posi-        of detailed clinical and/or histopathological information.
tive lymph nodes 25,30, nodal metastases ≥ 6 cm in size 7,25,31,
bilateral lymph nodes metastases 7,25, presence of a second          Intervention and comparison
primary HNSCC 5, regional recurrence 25, primary tumour              Intervention and comparison groups were defined accord-
of the pharynx 4,7,22,30,31 and advanced T categories 4,31.          ing to risk factors: T1-T2 versus T3-T4, tobacco use, p16
Using the Surveillance, Epidemiology, and End Results                status, ENE, positive versus negative lymph nodes, N cat-
(SEER) database, Kuperman et al. 11 conducted a cohort               egory, age < 60 versus > 60 years, lymph node size < 6 cm
study on 27,877 patients aimed at identification of risk fac-        versus > 6 cm, presence of < 3 versus ≥ 3 positive lymph
tors for DM at the time of HNSCC diagnosis. The authors              nodes, and locoregional control versus locoregional failure.
identified hypopharyngeal cancer, N3 category and size of            The degrees of histological differentiation (well, moderate,
the primary tumour > 4 cm as the most important risk fac-            and poor) were also compared.
tors for DM. In the same way, Liu et al. 18 used the National
Cancer Database (NCDB) data on 151,730 patients to iden-             Outcomes
tify patterns of DM in HNSCC at the time of diagnosis. In            The primary outcome evaluated in this study was risk of
that study, the authors identified age at diagnosis, ethnicity,      developing DM in HNSCC patients according to the above-
HPV status, tumour grade, T4 and N3 categories as the most           mentioned clinical and histopathological factors.
predictive variables for DM. Interestingly, high-risk HPV
status was associated with a lower proportion of DM 18. The          Search strategy
design in these two studies was population-based and the             A systematic search of electronic databases was conducted
findings help in partially understanding the behaviour of
                                                                     on MEDLINE/PUBMED, Google Scholar, Ovid Med-
DM in HNSCC. However, to date, no systematic review
                                                                     line, Embase, Scopus, Cochrane Database of Systematic
or meta-analysis has been carried out to investigate the re-
                                                                     Reviews, Cochrane Central Register of Controlled Trials,
lationships between clinical-histopathological risk factors
                                                                     and the Database of Abstracts of Reviews of Effects. Pa-
and DM in HNSCC patients. The objective of this work is,
                                                                     pers in English language from January 1960 to July 2019
therefore, to better understand the available evidence in the
                                                                     were included. The following keywords were used: ([“dis-
contemporary literature about the clinical and histopatho-
logical risk factors for DM in HNSCC patients after treat-           tant metastasis” OR “head and neck cancer” OR “distant
ment with curative intention.                                        metastasis workup” OR “follow-up”]). Titles and abstracts
                                                                     were screened by two investigators (CMCE and JASS) to
                                                                     discard irrelevant publications. For each study, the follow-
Materials and methods                                                ing information were extracted: author, year of publication,
This systematic review used Population Intervention Com-             number of patients evaluated, and clinical and histopatho-
parison and Outcome (PICO) modeling and followed the                 logical characteristics.



                                                                                                                                        7
C.M. Chiesa-Estomba et al.




Assessment of quality                                            mented in the Discussion section, while 6 (accounting for
Methodological quality of identified studies was appraised       5,353 patients) were included in the meta-analysis (Fig. 1).
using the Oxford Centre for Evidence-Based Medicine              According to the OCEBM grading system, all the studies
(OCEBM) Levels of Evidence. According to this, prospec-          were rated as Level B (2c) and the overall bias according
tive or retrospective studies (Grading A-B) were included.       to ROBIN-I was considered to be at low to moderate risk
Concerning assessment of risk of bias in individual cohort       in all studies. Demographic data of the studies included are
studies, the risk of bias in non-randomised studies of inter-    summarised in Table I. A total of 4,814 (89.9%) patients
ventions tool (ROBIN-I) was used.                                were males and 535 (10.1%) females. DM were present
                                                                 in 516 (9.6%) patients and were more common in men
Statistical analysis                                             (Tab. I). Variables between each group were only partially
An inverse variance meta-analysis of selected studies with       comparable, which made challenging every comparison
an odds ratio (OR) comparing information about tumour            between cohorts due to the heterogeneity of data reported
location, T and N categories, number of positive lymph           in each study (Tab. II). Concerning the primary site, the
nodes, age, histological differentiation, site of DM, ENE,       hypopharynx was related to a higher risk of DM develop-
locoregional control and recurrence rate was performed.          ment (18.7%) (Tab. II). DM were more common in T4 tu-
The comparison was made using Cochrane Review Manag-             mors (17.1%), N3 category (17.1%), and in tumours with
er 5.3 (Nordic Cochrane Centre, Cochrane Collaboration,          poorly differentiated histology (29.3%). The lung was the
2014, Copenhagen, Denmark). Heterogeneity was checked            most commonly affected organ (61.8%). Additional data
using the Q-test and I2 test. The I2 value was > 50%, and        on T and N categories, histological differentiation and the
the random-effects model was more appropriate, in which          organs affected by DM are reported in Tables III-V. For-
both random variation within studies and variations among        est plots related to T and N categories, age, ENE, size and
the different studies were incorporated.                         number of positive lymph node(s) and locoregional control
Cochrane Review Manager uses the Mantel-Haenszel meth-           (LRC) versus recurrence or treatment failure (R-F) are re-
od for calculating the heterogeneity and statistic is incor-     ported in Figures 2 and 3.
porated to calculate the summary of adjusted OR under the
random-effects model. The pooled OR with 95% confidence          Subgroups analysis
interval (CI95%) is given for the random-effects model.          a) T category
In addition, a chi-square test with Yates correction for con-       When stratifying patients according to T category (T1-
tinuity was applied with a 2-tailed p value for comparison          T2 versus T3-T4), the incidence of DM was 4.85%
of proportions according to gender and histological differ-         (CI95% 4.05-5.65%) versus 14% (CI95% 12.6-15.3%)
entiation from independent samples. A p < 0.05 was con-             (p = 0.0001). These differences were significantly in fa-
sidered statistically significant.                                  vour of T3-T4 categories as a risk factor for DM (OR
                                                                    0.39; CI95% 0.32-0.47; p = 0.001) (Tab. III and Fig. 2A).
Overview of clinical and epidemiological characteristics         b) Age
In addition to the meta-analysis, we extended our research          When stratifying patients according to age (< 60 ver-
to all trials carried out during the past six decades with the      sus > 60-year-old), the incidence of DM was 9.4%
aim to assess the clinical significance of HPV, impact of           (CI95% 8.06-10.7%) versus 8.2% (CI95% 7.05-9.35%)
radiological development and type of organs affected by             (p = 0.173). These differences were not significant (OR
DM in HNSCC patients. Thus, in a second step, the two               1.14; CI95% 0.92-1.43%; p = 0.213) (Tab. I and Fig. 2B).
main investigators (CMCE and JASS) performed the same            c) Locoregional control
extraction and analysis of data for all controlled or uncon-        When stratifying patients according to LRC versus R-F,
trolled, prospective, or retrospective studies conducted.           the incidence of DM was 5.9% (CI95% 4.7%-7.07%) in pa-
The intent of this analysis was to allow robust overview of         tients with favorable disease control versus 16.5% (CI95%
the characteristics of DM in HNSCC patients, which may              13.9%-19.07%) in those with recurrence or treatment fail-
allow elaboration of recommendations and perspectives.              ure (p = 0.0001). These differences were significant with
                                                                    the absence of locoregional control as a risk factor for DM
                                                                    (OR 0.35; CI95% 0.26-0.47; p = 0.0001) (Fig. 2C).
Results                                                          d) N category
The literature search retrieved a total of 1,272 manuscripts,       When stratifying patients according to N category (N0
72 of which met eligibility for full text review. Only 23           versus N+), the incidence of DM was 3.27% (CI95% 2.62-
papers were included in the systematic review and com-              3.92%) versus 19.4% (CI95% 17.7-21.05%) (p = 0.0001).



8
                                                                                                                  Distant metastasis in head and neck cancer




Figure 1. Algorithm for selection of studies.


Table I. Demographics, overall, and gender-related distant metastasis rates in the 6 studies included in the meta-analysis.
 Authors                  Type of         Period          Mean         Patients         Male       Females       Overall DM     DM rate        DM rate
                           study                           age         included                                     rate        in men        in women
 Leemans (1993) 28                  R           1973-1986       62       281         77.5%         22.5%          9.2%             NA             NA
 León (2000) 4                      R           1984-1996       NA      1244         88.1%         11.9%          5.1%            5.5%          3.5%
 Garavello (2006) 5                 R           1981-1998       62      1972          94%            6%           9.1%            9.1%          10.2%
 Li (2009) 6                        R           1990-2000       NA       391          80%           20%          11.2%           12.4%          7.6%
 Coca-Pelaz (2011) 7                R           1999-2006      60.2      443         97.2%          2.8%         13.9%           13.2%           25%
 Duprez (2017) 22                   R           1996-2015       61      1022         89.9%         10.1%         13.7%             NA             NA
 Total                                                          62      5353         89.9%         10.1%         9.6%            8.8%           8.2%
R: retrospective; NA: not available; DM: distant metastasis.


   These differences were significantly in favour of a N+                           tive versus positive), the incidence of DM was 13.6%
   neck as a risk factor for DM (OR 0.16; CI95% 0.13-0.21;                          (CI95% 11.2%-15.9%) versus 26% (CI95% 22.9%-29.06%)
   p = 0.0001) (Tab. III and Fig. 3A).                                              (p = 0.0001). These differences were significantly in fa-
e) Extranodal extension                                                             vour of the presence of ENE as a risk factor for DM (OR
   When stratifying N+ patients according to ENE (nega-                             0.52; CI95% 0.40-0.67; p = 0.0001) (Fig. 3B).



                                                                                                                                                          9
C.M. Chiesa-Estomba et al.




Table II. Distant metastasis rates according to primary sites.
 Authors                 Oral        Oropharynyx Hypopharynx                         Larynx       Glottis        Supraglottis     Oropharynx           CUP     Nasopharynx
                        cavity                                                                                                    HPV-positive
 León (2000) 4               0.8%             7.3%               18.7%                4%          1.2%             8.4%                -                 -           11.9%
 Garavello (2006) 5          2.9%            10.4%               16.7%               9.2%         8.7%             10.1%               -                 -             -
 Coca-Pelaz (2011) 7        14.7%            16.6%               20.4%               7.6%          NA               NA                 -                 -             -
 Duprez (2017) 22           15.3%            12.6%a              20.5%                9%           NA               NA              22.2%b             19.6%           -
 Total                      6.3%             11.1%               18.7%               7.2%          NA               NA                 -                 -             -
CUP: carcinoma of unknow primary; NA, not available; a These patients correspond to those without HPV testing; b These patients correspond to those with known HPV-positive
status.


Table III. Relationship between T, N categories and degree of histological differentiation with the rate of distant metastasis.
 Authors                                 T0                        T1                          T2                         T3                                     T4
 León (2000)   4
                                              0                           0.2%                           4.9%                        7.8%                      13.7%
 Garavello (2006) 5                           0                           0.3%                           7.8%                        12.6%                     20.9%
 LI (2009) 6                                  0                            6%                             8%                         11.7%                     14.9%
 Coca-Pelaz (2011) 7                          0                           5.7%                           11.6%                        14%                      17.6%
 Duprez (2017) 22                           15.8%                          8%                            12.9%                       15.9%                     15.2%
 Total                                      15.8%                         1.7%                           8.5%                         12%                      17.1%
 Authors                                      N0                          N1                                N2                           N3
 León (2000) 4                              1.7%                          1.5%                           16.4%                       24.1%
 Garavello (2006) 5                         2.5%                         21.9%                           23.7%                       29.4%
 Coca-Pelaz (2011) 7                        4.7%                           9%                             23%                         33%
 Duprez (2017) 22                            5%                          11.2%                            8.5%                       28.8%
 Total                                      2.7%                         16.6%                           20.6%                       29.3%
 Authors                                   Well (G1)              Moderately (G2)                        Poorly
                                                                                                          (G3)
 León (2000) 4                              2.5%                          4.7%                           13.1%
 Garavello (2006) 5                          1%                           8.4%                           17.7%
 LI (2009) 6                                7.6%                         13.6%                           13.6%
 Coca-Pelaz (2011) 7                         5%                           17%                             25%
 Duprez (2017) 22                            9%                           14%                            15.6%
 Total                                      4.2%                         9.2%                            16.9%


Table IV. Organs affected by HNSCC distant metastases.
 Authors           Lung   Liver     Bone       Skin     Multi- Parotid Exter-    Soft                Brain       Pleura     LN    LN me-      LN ax-   Omen-   Spleen Adrenal
                                                        ple DM         nal au- tissues                                    outside diasti-      illa     tum            gland
                                                                        ditory                                             neck    num
                                                                        canal
 Leemans       44.9%       4%        16%        4%       22%      0        0      0                   4%           0        0       4%          0        0       0            0
 (1993) 28
 León              51%    4.6%      12.5%        0      31.2%        0           0            0        0           0        0        0          0        0       0            0
 (2000) 4
 Garavello     55.8%      3.8%      9.9%         0      30.3%        0           0            0        0           0        0        0          0        0       0            0
 (2006) 5
 Li (2009) 6   48.7%      7.3%      2.4%       2.4%     26.8%      2.4%      2.4%         2.4%         0          2.4%     2.4%      0          0        0       0            0
 Coca-Pelaz    52.3%      1.6%      3.1%       1.6%      38%         0           0        1.6%       1.6%          0        0        0          0        0       0            0
 (2011) 7
 Duprez            40%    8.9%      15.6%     12.2%        0         0           0        0.7%       0.3%         4.8%    10.4%     4%        0.7%      0.3%   0.3%      0.7%
 (2017) 22
 Total         61.8%      7.7%      15.3%      7.1%     23.4%      0.2%      0.2%         0.8%       1.1%         2.7%     5.6%     2.5%      0.4%      0.2%   0.2%      0.4%




10
                                                                                                                    Distant metastasis in head and neck cancer




Table V. Risk of bias in individual cohort studies ((ROBIN-I).
 Author                          Bias due to            Bias in         Bias in         Bias due to      Bias due to         Bias in              Bias in
                                 confunding          selection of   classification      deviations       missing data      measurement          selection
                                                    participants          of               from                                 of           of the reported
                                                       into the     interventions        intended                           outcomes              results
                                                        study                          intervention
 Coca-Pelaz (2011) 7           No information         Low risk         Low risk          Low risk        Moderate risk      Moderate risk       Low risk
 Duprez (2017) 22              No information         Low risk         Low risk          Low risk        Moderate risk      Moderate risk       Low risk
 León (2000) 4                 No information         Low risk         Low risk          Low risk        Moderate risk      Moderate risk     Moderate risk
 Garavello (2006) 5            No information         Low risk         Low risk          Low risk        Moderate risk      Moderate risk       Low risk
 Li (2009) 6                   No information         Low risk         Low risk          Low risk        Moderate risk      Moderate risk       Low risk
 Leemans (1993) 28             No information         Low risk         Low risk          Low risk        Moderate risk      Moderate risk     Moderate risk




Figure 2. Forest plots showing the relationships between: (A) T-category; (B) Age; (C) Locoregional control and the appearance of DM. The experimental cohort
was represented by patients with T1-T2 tumours and locoregional control, aiming to demonstrate the protective effect of these factors against the appearance of
DM.



                                                                                                                                                           11
C.M. Chiesa-Estomba et al.




Figure 3. Forest plots showing the relationships between: (A) N-category; (B) Extranodal extension; (C) Lymph node size; (D) Number of lymph nodes and ap-
pearance of DM. The experimental cohort was represented by patients with negative lymph nodes, absence of ENE, lymph node < 6 cm in size, and less than 3
positive lymph nodes, aiming to demonstrate the protective effect of these factors on the development of DM.



12
                                                                                               Distant metastasis in head and neck cancer




f) Lymph node size                                                 ated with the highest risk for development of DM. Duprez
   After stratifying N0 and N+ patients, comparing DM ap-          et al. 22 reported that advanced N category, advanced stages,
   pearance according to lymph node size (N0 or N+ < 6cm           presence of ENE, tumour location in the hypopharynx and
   versus > 6 cm), the incidence of DM was 9.5% (CI95%             oropharynx with HPV-negative status, and locoregional
   8.6%-10.3%) versus 29.3% (CI95% 22.85%-35.7%)                   persistent/recurrent disease were risk factors for DM. León
   (p = 0.0001). These differences were significant with           et al. 4 analysed the development of DM in 1,244 patients
   lymph node size > 6 cm as a risk factor for DM (OR              with oral cavity, pharyngeal and laryngeal SCC with appar-
   0.32; CI95% 0.23-0.44; p = 0.00001) (Fig. 3C).                  ently complete locoregional control, and found that 86%
g) Number of lymph nodes                                           of DM appeared within the first 2 years after diagnosis of
   When stratifying N+ patients according to the number            the primary tumour, and tumour location in the hypophar-
   of lymph nodes (< 3 or ≥ 3), the incidence of DM was            ynx and supraglottis were independently associated with
   15.9% (CI95% 12%-19.8%) versus 19.3% (CI95% 14.1%-              increased risk of DM. Li et al. 6 in a study including 391
   24.4%) (p = 0.361). These differences were not signifi-         patients reported that the number of neck levels involved,
   cant (OR 0.82; CI95% 0.53-1.27; p = 0.39) (Fig. 3D).            level of tumour invasion and site of primary tumour were
h) Histological differentiation                                    decisive risk factors in determining the development of
   When stratifying patients according to histological dif-        DM. Finally, Garavello et al. 5 in a study on 1,972 patients
   ferentiation (well versus moderate versus poorly differ-        reported that the risk of DM was influenced by age, site of
   entiated), the incidence of DM was 4.2% (CI95% 2.9%-            primary tumour, local and/or regional extension, grading
   5.5%) versus 9.2% (CI95% 8.1%-10.2%) versus 16.9%               and achievement of locoregional control.
   (CI95% 14.4%-19.4%) (p = 0.0001). These differences
   were significant, with DM being more common in pa-              Rate of DM in HNSCC patients
   tients with poorly differentiated tumours (Tab. IV).            The rate of DM varies substantially in the literature de-
                                                                   pending on the type of study. As mentioned above, in pop-
                                                                   ulation-based studies, Kuperman et al. 11 and Liu et al. 18
Discussion
                                                                   reported that the rates of DM in patients with HNSCC were
To the best of our knowledge, this study is the first systematic   2.8% and 3.1%, respectively. On the other hand, in clinical
review and meta-analysis to investigate the clinical and histo-    studies, DM rates vary from 4.2 to 23.8% 4,12-14,21,32-38, while
pathological factors related to the appearance of DM in HN-        in autopsy studies the frequency is usually higher, rang-
SCC patients. In the diagnostic workup of primary HNSCC,           ing between 37%7 and 57% 15-17,39-50. Such figures might be
DM screening may have two main but distinct objectives:            also influenced by the site of tumours considered: in fact,
detection of occult DM in patients without curative options,       DM are significantly higher in patients affected by naso-
and counseling on prognosis and how to optimise quality of         pharyngeal carcinomas, with incidences varying from 36%
life in patients who are already symptomatic. Moreover, the        to 51% in autopsy studies 51. These higher rates have been
presence of DM at baseline evaluation influences survival,         also clinically confirmed in two studies published by Palaz-
treatment selection and management of locoregionally recur-        zi et al. analysing the outcomes of patients with regionally
rent disease. However, it is important to understand that, in      and non-regionally advanced nasopharyngeal carcinomas,
selected cases, depending on histology and natural history         where the authors reported DM in 21% and 18% of pa-
of the disease, appropriate treatment schedules for palliative     tients, respectively 52,53.
(when not potentially curative) trials may be available.           As previously highlighted by León et al. 4, a higher fre-
Studies which fulfilled criteria to be included in our meta-       quency of DM in autopsies could be explained by the
analysis are in line with the comprehensive results of our         greater sensitivity in finding DM in this type of study. Risk
study. In particular, Leemans et al. 28 reported on the devel-     of bias from autopsy data is mainly related to the fact that
opment of DM in 281 patients who underwent neck dissec-            most patients with unfavourable oncologic evolution die
tion and had locoregional control during follow up. Fac-           in hospitals, and these patients have a greater tendency
tors such as histologically proven lymph node metastasis,          of harbouring DM. Moreover, autopsy studies are more
more than 3 positive lymph nodes, and the presence of ENE          prone to detect small and incidental DM whose real oc-
were associated with the highest risk for DM. Coca-Pelaz           currence can be higher than that reported in clinical and
et al. 7 analysed risk factors for development of DM in 443        population-based studies. However, the DM rate found in
patients with surgically treated primary HNSCC. Patients           our meta-analysis (9.6%) is similar to what has been re-
with poorly differentiated tumours, 3 or more positive             ported in previous clinical papers, and higher than those in
lymph nodes and bilateral nodal metastases were associ-            population-based studies.



                                                                                                                                     13
C.M. Chiesa-Estomba et al.




Clinical and histopathological factors related to DM               (68.5%), liver (23.8%) and bones (20%) were the most com-
According to our results and the previous studies men-             mon sites of DM. Concerning the incidence of intracranial
tioned above, poorly differentiated tumours, hypopharyn-           metastases, the rates reported are around 0.4%. Moreover,
geal location, T3-T4 categories, presence of metastatic            brain metastases are detected much more frequently (2-8%
lymph nodes larger than 6 cm or with evidence of ENE               of patients) if another DM is already present 54.
and locoregional persistence or failure after treatment sig-       The incidence of skin metastasis in HNSCC is reported to
nificantly increase the risk of developing DM. However, we         be between 1% and 2% and accounts for 10-15% of the
were not able to find a significant impact of the presence         overall DM burden. Pitman and Johnson 55 reported that
of more than 3 positive lymph nodes and age on the risk            rate of skin DM was 0.76%, an incidence consistent with
of DM. Finally, we judged the overall quality of the evi-          the results of other studies 14, accounting for 10% of the
dence to be moderate, since the OCEBM graded all studies           DM load. It could be argued that regional skin metastases
as Level B (2c) and the ensuing findings related to some           are, in fact, caused by changed lymphatic drainage pat-
factors remain uncertain, which should be addressed more           terns following locoregional treatment. However, skin of
carefully in future research.                                      the head, neck, and chest are also common locations for
                                                                   metastasis from primary tumours arising outside the head
Radiological implications in HNSCC and DM                          and neck 56. Finally, there is some debate about DM in the
Histopathological risk factors were based on postoperative         mediastinum, because these could also be lower extensions
specimen examination and were thus not available for pre-          of regional metastases, as in the case of hypopharyngeal
treatment decision making. This can be a drawback in se-           cancer, since the boundaries between VI and VII levels are
lection of patients for DM pretreatment screening, in which        notoriously ill-defined and wandering. In addition, occult
clinical risk factors would be much more valuable. However,        second primary lung cancers may be responsible for this,
modern radiological advances allow even more detailed in-          especially if suboptimal diagnostic workup is performed.
vestigation during preoperative diagnostic workup. In fact,        Regarding DM treatment, the evidence for metastasectomy
as recently highlighted by de Bree et al. 2, some validated        in HNSCC is still controversial, and large prospective stud-
clinical-radiological high-risk factors are bilateral as well as   ies are needed. A systematic review reported Level 2a evi-
more than 3 lymph node metastases, lymph node metastases           dence of the effectiveness of pulmonary metastasectomy
of 6 cm or larger, low jugular lymph node metastases, re-          for metachronous DM in HNSCC 57. However, evidence
gional recurrence and second primary tumours 25. Other re-         for liver metastasectomy in HNSCC is scarce 58. In a retro-
ported factors of increased risk for DM development like T4        spective analysis recently published by Schultz et al. 59, the
category and/or N2-N3 status, oropharyngeal, hypopharyn-           authors demonstrated a significant survival benefit for HN-
geal, and supraglottic sites, levels IV and VB lymph nodes         SCC patients who received specific treatments (surgery or
involvement and radiologic signs suspicious for ENE are all        RT) for DM regardless of their origin. They also described
within the detection capability of modern imaging 29-31.           significantly worse outcomes in patients with metastases
                                                                   to multiple organs, underlying the importance of treating
Organs affected by DM                                              mainly oligometastatic and/or single metastatic clinical
The results from our meta-analysis are consistent with             scenarios. Other approaches to disease eradication, such
those described in the literature, being the lung, bone, liver     as stereotactic body RT, have also been used to treat one
and skin (61.8%, 15.3%, 7.7%, and 7.1%, respectively) the          or a limited number of pulmonary metastases 60. However,
most common sites for DM in our study population. This             long-term follow-up data are even more limited than that
represents the rationale for routine PET/CT or neck and            available for surgical resection.
chest CT in HNSCC patients with the abovementioned risk
factors. The main argument in favour of chest CT instead           Oropharyngeal HPV-related carcinoma
of PET/CT, apart from a more favourable cost-effective-            Among the studies included in this meta-analysis, only
ness ratio and widespread geographic availability, is that         Duprez et al.22 reported the incidence of HPV in HNSCC.
the former would likely capture DM in the chest, cervical          Therefore, at the moment, we were not able to extract any
or thoracic spine, and in part of the liver. Combining these       new conclusions about the relationships between HPV sta-
advantages, it is probable that chest CT should be viewed in       tus and the risk of DM. From our systematic review, the
terms of its overall superiority over PET/CT for detection         evidence from the current literature is too heterogeneous to
of DM in the HNSCC population 18.                                  draw any meaningful assumptions about this aspect.
In a study by Jäckel et al. 13 on 1,087 patients with newly        Regarding the identification of risk factors associated with
diagnosed SCC of the upper aerodigestive tract, the lung           a higher incidence of DM in HPV-positive oropharyngeal



14
                                                                                                    Distant metastasis in head and neck cancer




SCC, Weller et al.61 found that, among these patients, those      three decades. Moreover, as different authors have hypoth-
with T4 tumours and/or active smokers had substantial             esised 22, in previous times a less aggressive locoregional
rates of DM. They further reported an increased rate of DM        treatment might have been used for patients who were more
in patients treated with cetuximab compared with those            likely to die from locoregional recurrence before DM could
managed by cisplatin.                                             even become clinically apparent. Finally, we need to high-
More recently, in a systematic review and meta-analysis by        light as another potential study limitation, the lack of ad-
Tiedemann et al. 62, time to DM following primary treat-          equate information about nasopharyngeal cancer in almost
ment of patients with HPV-positive SCC appeared to be             all the studies included.
longer, with metastases more likely to disseminate to more
than two organs compared to patients with HPV-negative            Conclusions
oropharyngeal tumours.
                                                                  According to the results of the present meta-analysis, hy-
Perspectives                                                      popharyngeal site, advanced T and N categories, ENE,
One of the most intriguing issue related to the DM topic in       lymph node size > 6 cm, locoregional failure and poorly
HNSCC comes from the question of a real need for routine          differentiated histology significantly increase the risk of
screening of asymptomatic patients during follow-up. The          developing DM in patients with HNSCC. Imaging can play
evidence to date has a limited clinical value since DM from       a relevant role in the diagnostic work-up of these patients
HNSCC usually cannot be treated with curative intent, and         as it evaluates clinical and radiological factors related to
asymptomatic DM may not require immediate palliative              DM and, possibly, can help modulate palliative/curative
treatment 4,9,34,35,63. Importantly, DM usually appear shortly    management. Larger studies comparing the risk of DM in
after treatment, with typical curves during follow-up show-       HPV-positive and negative oropharyngeal SCC are needed.
ing a rapid increase between months 0 and 8 after treat-
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