10.14639/0392-100X-N2222
As in some other sites of the head and neck, a broad range of tumours can arise in the nasopharynx: epithelial, mesenchymal, lymphoid, and neuro-ectodermal. However, nasopharyngeal carcinoma (NPC) is the most interesting and intriguing type, because it is a “peculiar” malignancy, and “different” from almost all other head and neck tumours according to several points of view. In fact, NPC is a unique disease whose aetiology, clinical behaviour, epidemiology, and histopathology are different from those of all other squamous cell carcinomas of the head and neck. The most distinguishing characteristics of this malignancy are the consistent association with Epstein-Barr virus and the striking geographical differences in its incidence. The aim of this narrative review is to analyse the very large number of studies (sometimes contradictory) on NPC. In this first part, the histopathology, aetiology, epidemiology, clinical behaviour, natural history, diagnostic work up, and staging will be examined.
text/xml
1827-675X
2222
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Giulio Cantù
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staging
Nasopharyngeal carcinoma. A “different” head and neck tumour. Part A: from histology to staging
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1
Giulio Cantù
2023/04/26
10.14639/0392-100X-N2222
85
Former Director of Otorhinolaryngology and Cranio-Maxillo-Facial Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
1827-675X
staging
en
98
Nasopharyngeal carcinoma. A “different” head and neck tumour. Part A: from histology to staging
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ACTA OTORHINOLARYNGOLOGICA ITALICA 2023;43:85-98; doi: 10.14639/0392-100X-N2222




Review


Nasopharyngeal carcinoma. A “different” head
and neck tumour. Part A: from histology to staging
Carcinoma rinofaringeo. Un tumore della testa e collo “diverso”.
Parte A: dalla istologia allo staging
Giulio Cantù
Former Director of Otorhinolaryngology and Cranio-Maxillo-Facial Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy


SUMMARY
As in some other sites of the head and neck, a broad range of tumours can arise in the
nasopharynx: epithelial, mesenchymal, lymphoid, and neuro-ectodermal. However, naso-
pharyngeal carcinoma (NPC) is the most interesting and intriguing type, because it is a
“peculiar” malignancy, and “different” from almost all other head and neck tumours ac-
cording to several points of view. In fact, NPC is a unique disease whose aetiology, clinical
behaviour, epidemiology, and histopathology are different from those of all other squamous
cell carcinomas of the head and neck. The most distinguishing characteristics of this malig-
nancy are the consistent association with Epstein-Barr virus and the striking geographical
differences in its incidence. The aim of this narrative review is to analyse the very large
number of studies (sometimes contradictory) on NPC. In this first part, the histopathology,
aetiology, epidemiology, clinical behaviour, natural history, diagnostic work up, and staging
will be examined.
KEY WORDS: nasopharyngeal carcinoma, aetiology, epidemiology, diagnosis, staging

RIASSUNTO
Come in altre sedi della testa e collo anche nel rinofaringe possono insorgere una notevole
varietà di tumori: epiteliali, mesenchimali, linfoidi e neuro-ectodermici. Comunque, è il
carcinoma rinofaringeo (NPC) il tumore più interessante, perché si tratta di una neoplasia
“peculiare” e “diversa” da quasi tutti gli altri tumori della testa e collo sotto molti punti
di vista. Infatti, esso è un tumore la cui eziologia, storia naturale, epidemiologia e istopa-
                                                                                                  Received: July 13, 2022
tologia sono diverse da quelle di tutti gli altri tumori epiteliali della testa e collo. Le sue
                                                                                                  Accepted: October 18, 2022
caratteristiche più peculiari sono la frequente associazione con il virus di Epstein-Barr e
la grande differenza geografica della sua incidenza. Lo scopo di questa review narrativa
                                                                                                  Correspondence
è quello di analizzare il grandissimo numero di studi (talvolta contradditori) su questa          Giulio Cantù
neoplasia. In questa prima parte saranno esaminati l’istopatologia, l’eziologia, l’epide-         via Milano 36, 20846 Macherio (MB), Italy
miologia, la storia naturale, i mezzi diagnostici e lo staging.                                   E-mail: gcantu43@gmail.com
PAROLE CHIAVE: carcinoma rinofaringeo, eziologia, epidemiologia, storia naturale,
diagnosi, staging                                                                                   How to cite this article: Cantù G. Nasopharyn-
                                                                                                    geal carcinoma. A “different” head and neck
                                                                                                    tumour. Part A: from histology to staging.Acta
                                                                                                    Otorhinolaryngol Ital 2023;43:85-98. https://
                                                                                                    doi.org/10.14639/0392-100X-N2222
Introduction
                                                                                                  © Società Italiana di Otorinolaringoiatria
It is well-known that nasopharyngeal carcinoma (NPC) is rare in most parts                        e Chirurgia Cervico-Facciale
of the world, but is endemic in North Africa and Southeastern Asia, and most
notably in South China. This epidemiologic characteristic may be enough to                                       OPEN ACCESS
define NPC as a peculiar malignancy among head and neck tumours. Further-                         This is an open access article distributed in accordance with
                                                                                                  the CC-BY-NC-ND (Creative Commons Attribution-Non-
more, NPC has several other characteristics that have fascinated generations                      Commercial-NoDerivatives 4.0 International) license. The
of oncologists, pathologists, scientists, and epidemiologists 1. In this review, I                article can be used by giving appropriate credit and mentio-
                                                                                                  ning the license, but only for non-commercial purposes and
will discuss the various, and sometimes not yet solved, problems concerning                       only in the original version. For further information: https://
NPC.                                                                                              creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                            85
G. Cantù




Histopathology                                                                   Table II. Histopathology.
                                                                                  NPC was first described as a separate entity by Regaud and Schmincke in
In 1921 Regaud 2 and Schmincke 3, independently, used                             1921.
the term “lymphoepithelioma” to designate a highly radio-                         Many names have been coined for the various histological subtypes of
sensitive neoplasm of the nasopharynx showing nests of                            NPC.
non-keratinising squamous cells embedded in a lymphoid                            WHO 1978 classification of NPC: squamous cell carcinoma (WHO type 1),
stroma. The unusual histological features of NPC have gen-                        non-keratinising carcinoma (WHO type 2), and undifferentiated carcinoma
                                                                                  (WHO type 3).
erated controversies over the nature of the tumour. There
                                                                                  WHO 1991 classification: keratinising squamous cell carcinoma (K-NPC)
have been more names coined for the various histological                          and non-keratinising carcinoma (NK-NPC); the latter was subsequently
subtypes of NPC than any other tumour type. The World                             distinguished in “differentiated” (DNK-NPC) and “undifferentiated” (UNK-
Health Organization (WHO) Classification of Tumours                               NPC).
Pathology and Genetics of 2005 1 reports as many as 12
synonyms (Tab. I). The correct histologic setting of this
tumour remained a controversial question for many years,                         sification, with the addition of the category basaloid squa-
as one can see in a study published by Scanlon et al. in                         mous cell carcinoma (Tab. II). However, the difficulties in
1967 where the author stated “There is probably no other                         making an undisputable histological diagnosis have been
single group of cancers of the respiratory system about                          clearly stated in the 2005 WHO classification 1: “The wide
which there is less agreement in the world literature with                       ranging reported figures on the frequencies of various sub-
regards to the correct and proper pathological classifica-                       types indicate that the boundaries between the categories
tion” 4. The 1978 World Health Organization (WHO) clas-                          are not always clear, sampling error is a significant prob-
sification 5,6 recognised three histological subtypes of NPC:                    lem due to the small size of the biopsies, and intra- and
squamous cell carcinoma (WHO type 1), non-keratinising                           inter-observer reproducibility of the classification is sub-
carcinoma (WHO type 2), and undifferentiated carcinoma                           optimal”. However, beyond the aforementioned diagnostic
(WHO type 3). The 1991 WHO classification 7 retained the                         difficulties, the 2005 WHO classification reported that the
squamous cell carcinoma subtype (keratinising squamous                           proportion of K-NPC among all NPC was higher in low-
cell carcinoma, K-NPC), while the last two subtypes were                         incidence areas compared with high-incidence areas (1%
combined under a single category of “non-keratinising car-                       in Hong Kong, 17% in Singapore, 8% in Tunisia, 13% in
cinoma” (NK-NPC), which was further subdivided in “dif-                          Japan, and 25% in USA) 1. The rate of K-NPC was 18% in
ferentiated” (DNK-NPC) and “undifferentiated” (UNK-                              a series of 171 NPC treated at a single Italian institution
NPC); lymphoepithelioma-like carcinoma was considered                            between 1990 and 1999 9. The proportion of K-NPC ap-
a morphologic variant of undifferentiated carcinoma. The                         pears to be increasing in non-endemic areas. In fact, a 2013
use of numerical designation of WHO types 1, 2, and 3                            study done using the Surveillance, Epidemiology, and End
was eliminated, although many authors continue to use it.                        Results (SEER) data base, provided a comprehensive de-
The 2005 1 and 2017 8 WHO classifications of head and                            scription of racial differences among 5,868 NPC patients in
neck tumours maintained the terminology of the 1991 clas-                        the USA and reported 2,456 cases of K-NPC (42.2%). The
                                                                                 distributions of K-NPC were also significantly different
                                                                                 across races: non-Hispanic white 1520 (52.4%), Hispanic
Table I. Names coined for NPC in the past (from Barnes et al., 2005, mod. ) 1.   white 89 (42.0%), black 226 (42.9%), Asian 549 (28.2%),
 Lymphoepithelioma                                                               other 72 (31.0%) 10. In a more recent study 11, the authors
 Lymphoepithelioma-like carcinoma                                                conducted a retrospective cohort study of 9,995 patients
 Lymphoepithelial carcinoma                                                      with NPC from the National Cancer Database (NCDB).
 Schminke type lymphoepithelioma                                                 The proportion of each histological subtype varied substan-
 Regaud type lymphoepithelioma                                                   tially between ethnicities. Asian patients had nearly equal
 Transitional cell carcinoma                                                     distributions across the three subtypes. This varied signifi-
 Intermediate cell carcinoma                                                     cantly from black and white patients, among whom K-NPC
 Anaplastic carcinoma                                                            comprised most cases (60 and 68%, respectively), while
 Undifferentiated carcinoma with lymphoid stroma                                 UNK-NPC comprised the minority of cases (18 and 12%,
 Vescicular nucleus cell carcinoma
                                                                                 respectively). Hispanic patients fell in between, with 51%
                                                                                 of cases comprised of the K-NPC type and 19% of cases
 Squamous cell carcinoma
                                                                                 being of UNK-NPC subtype 11. With regards to NK-NPC,
 Non-keratinising carcinoma
                                                                                 in the 2017 WHO classification there is the following state-



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                                                                                                            Nasopharyngeal carcinoma. Part A




ment: “Subclassification into undifferentiated and differen-    Table III. Aetiology and epidemiology.
tiated subtypes has no clinical and prognostic value” 8. This    Tobacco smoking and alcohol consumption are contributing factors only for
categorical statement was refuted by the study of Stepan         K-NPC.
et al. 11 which showed that 5-year overall survival (OS) for     NK-NPC has a complex and unique aetiology that is not yet completely
                                                                 understood (racial predisposition, environmental and dietary factors, and
UNK-NPC was 69%, while that for DNK-NPC was 62%                  infection by Epstein-Barr virus).
(the adjusted hazard ratio in comparison with keratinising       NPC is rare in most parts of the world, but it is endemic in Northern Africa
histology was 0.67 for non-keratinising differentiated and       and Southeastern Asia, and most notably in Southern China.
0.55 for non-keratinising undifferentiated NPC).                 The incidence of NPC is declining in all countries and it is mainly attributed
In another study, Wu et al. 12 analysed non-metastatic NPC       to changing environmental risk factors.
patients between 2004 and 2014 using the SEER data base.         The incidence of NPC is 2-to 3-fold higher in men than in women.
These authors collected information on 2,845 patients, in-
cluding 1,218 (42.8%), 849 (29.8%), and 778 (27.3%) with
K-NPC, DNK-NPC and UNK-NPC, respectively. Within                cies, and its possible oncogenic potential. These authors
the follow-up period of over 5 years, patients with DNK-        found that the incidence of EBV positivity was high in two
NPC had poorer NPC-specific survival (NPC-SS) com-              groups of patients: those with Burkitt’s lymphoma (56% of
pared to UNK-NPC, and had comparable NPC-SS between             55 African cases) and those with “epidermoid carcinoma of
the two subtypes after more than 5 years of follow-up.          the postnasal space” (85% of 39 African and American cas-
                                                                es) 13. Later, other pioneering studies investigated the close
Aetiology and epidemiology                                      association between NPC and EBV 18-21. Today, querying
                                                                PubMed using the keywords “nasopharyngeal carcinoma”
Unlike almost all other head and neck carcinomas (HNCs),        and “Epstein-Barr virus”, you can find as many as 3,810 re-
tobacco smoking and alcohol consumption are contributing        sults. The oncogenic role of the virus in the genesis of NPC,
factors only for K-NPC. On the contrary, NK-NPC has a           especially in endemic regions, is universally recognised.
complex and unique aetiology that is not yet completely         The International Agency for Research on Cancer (IARC)
understood. NPC is uncommon in most countries but it is         classified EBV as carcinogenic in 1997. The association of
endemic in a few well-defined populations, including na-        EBV with NPC is very different between NK-NPC and K-
tives of southern China, Southeast Asia, the Arctic, and the    NPC. In fact, while there is a near constant association of
Middle East/North Africa. Batsakis stated in this regard that   EBV with NK-NPC, EBV is generally absent in K-NPV,
“The racial predisposition for NPC is present among these       especially in non-endemic regions. However, Chang stated
populations whether they are in their native country or have    that “EBV alone is not a sufficient cause of NPC, because
been “transplanted” to other lands” 13. Buell, in 1965, car-    virtually all adults worldwide are infected with the virus,
ried out a noteworthy epidemiologic study in the Chinese        yet only a small proportion of individuals develop NPC” 16.
population of California 14. He found that immigrants from      In fact, Kangro et al. found that over 90% of children in
China have 30 to 40 times mortality from NPC than the           Hong Kong were infected with EBV by 8 years of age 22.
Caucasian population of California, and that Chinese who        “Therefore, it is apparent that environmental and/or genetic
were born in the United States have about 20-fold greater       cofactors also contribute to NPC risk” 16.
mortality. In 1981, Dickson presented a series of 209 pa-       Few studies have investigated the association of human
tients with NPC and found that “Chinese born in China had       papillomavirus (HPV) in NPC and its possible aetiologic
a 117.9 times greater incidence of the disease, while North     role. The results are contradictory. Dogan et al. 23 reported
American born Chinese showed only a 7.3 times greater           on 9/67 patients with HPV-positive NPC. However, 3 cases
incidence than Caucasians” 15.                                  were shown to be of non-nasopharyngeal origin and were
This characteristic ethnic and geographic distribution of       excluded from further analysis because the bulk of the dis-
NPC worldwide suggests a multifactorial aetiology, includ-      ease was in the oropharynx. Furthermore, the K-NPC/NK-
ing genetic traits, environmental and dietary factors, and      NPC ratio was not reported in the article. Nevertheless, the
infection by Epstein-Barr virus (EBV). Hundreds of studies      authors concluded that “The aetiologic role of HPV in NPC
have tried to elucidate how these aetiologic factors inter-     is confirmed. The favourable prognostic significance of
act in the development of the disease. A thorough study         HPV positivity is similar to that of EBV positivity”. Verma
by Chang and Adami defined the epidemiology of NPC as           et al. 24 queried the NCDB for NPC with known HPV status.
“enigmatic” 16 (Tab. III).                                      In all, 956 patients met the study criteria; this included 308
Regarding EBV infection, a 1966 study by Old et al. 17 dem-     patients (32%) with HPV-positive disease and 648 patients
onstrated the association of EBV and two human malignan-        (68%) who were HPV-negative. In both the overall and



                                                                                                                                            87
G. Cantù




matched cohorts, there were no differences in OS between         major susceptibility gene, most likely explain the observed
HPV-positive and HPV-negative patients, and HPV status           pattern of inheritance 16.
did not independently predict for OS. Wu et al., analysing a     Regarding sex and age distributions, the incidence of NPC
mono-institutional series of 78 NPC patients, reported the       is 2-to 3-fold higher in men than in women in almost all
same results: “OS was not significantly different between        populations 1. In low-risk populations, NPC incidence in-
the EBV+ group and the HPV+ group, and double-negative           creases progressively with increasing age in both genders,
EBV-/HPV- tumours had worse OS on univariate analysis            and the peak incidence occurs in the 65-69 year age group.
compared to EBV+ or HPV+ tumours: however, there was             In contrast, in endemic countries the incidence peaks
no difference in OS on multivariate analysis after adjusting     around 50 to 59 years and declines thereafter, suggesting
for covariates of age and baseline health” 25.                   the involvement of exposure to carcinogenic agents early
Regarding environmental and dietary factors, the most            in life.
studied non-viral factor involved in NPC aetiology is con-       NPC is a very rare disease in childhood. Its incidence varies
sumption of salt-preserved fish, a traditional staple food in    widely in different regions, reflecting the aforementioned
several NPC-endemic areas. According to Chang et al. “In         interactions between genetic and environmental factors.
southern China, intake of salted fish and other preserved        Italy is a low-incidence area. The annual incidence of NPC
foods is particularly high among boat-dwelling fishermen         has been estimated at 0.73 per million children (ages 10-
and their families. Furthermore, salted fish is a tradition-     14 years) and at 1.08 per million adolescents (ages 15-17
al weaning food, resulting in early and frequent feeding         years), with an incidence of nil among children aged < 10
of infants, especially in the Cantonese population and in        years 31. Similar data emerged from the SEER database.
families of lower socioeconomic status. Childhood expo-          From 1988 to 2006, 129 children/adolescents (ages 0-19
sure, especially at weaning, seems more strongly related to      years) were registered, for an incidence of 0.5 per million
NPC risk than adulthood exposure” 16. Furthermore, Chang         person-years. In contrast, 6,000 adult cases were collected
wrote “The process of salt preservation is inefficient, al-      in the SEER database during the same period 32.
lowing fish and other foods to become partially putrefied.       The incidence of NPC is declining in all countries, “in
As a result, these foods accumulate significant levels of ni-    Hong Kong since the 1970s, in Taiwan since the 1980s,
trosamines, which are known carcinogens in animals” 16.          and in Singapore Chinese since the late 1990s” 16. Females
In fact, the carcinogenic potential of salt-preserved fish has   had a significantly lower age-standardised incidence (male/
been demonstrated by experiments in rats, which develop          female ratio 2.5-2.6, p < 0.01) and mortality (male/female
malignant nasal and nasopharyngeal tumours after salted          ratio 3.0-3.5, p < 0.01) throughout the period 1980-1999 33.
fish consumption 26,27. Zou et al. analysed 145 samples of       This lag in trend may be attributable to economic devel-
cooked salted fish collected from various areas in China 28.     opment. Especially in Hong Kong, the lifestyle for most
The samples from areas with higher NPC risk showed a             citizens changed progressively from a traditional Southern
higher average level of total volatile N-nitrosamines than       Chinese style to a more western style, particularly in terms
those from areas of lower NPC risk. In contrast with salted      of diets. Preserved salted fish was no longer a common
fish, the frequent consumption of fresh fruits and/or vegeta-    food for most citizens. Although it remains difficult to sin-
bles has been associated with a lower risk of NPC 29.            gle out the exact aetiological factor(s), one can at least con-
Regarding genetic traits, a large number of studies have         fidently postulate that the declining incidence of NPC in
analysed the role of various genetic factors associated with     Hong Kong is mainly attributed to changing environmental
NPC, and in particular polymorphisms in the histocompat-         risk factors 33.
ibility locus antigens (HLA), cytochrome P450 2E1 (CYP2
E1) and alteration of p53 codon 72 Arg > Pro. Those who
wish to investigate thoroughly this item may read the para-
                                                                 Clinical behaviour and natural history
mount paper by Chattopadhyay et al. 30. The importance of        The nasopharynx is a roughly cubical space. It is bound su-
genetic predisposition is demonstrated by an indisputable        periorly and posteriorly by bone walls (basi-sphenoid, basi-
familial aggregation of NPC. Many epidemiologic studies          occiput, and atlas). These structures may be infiltrated and
have demonstrated that the excess risk was generally 4- to       eroded by the NPC, but this is a late occurrence. The naso-
10-fold among individuals with a first-degree relative with      pharynx tapers inferiorly because it is bound by the upper
NPC, compared with those without a family history. How-          surface of the soft palate. Anteriorly, it communicates with
ever, such clustering can result from shared genetic suscep-     the nasal cavity. The lateral wall (clinically the most im-
tibility, shared environmental risk factors, or both. Multi-     portant as regards NPC) is mostly occupied by the opening
ple genetic and environmental factors, rather than a single      of the Eustachian tube with a cartilaginous elevation (torus



88
                                                                                                                  Nasopharyngeal carcinoma. Part A




tubarius). Below this opening, the mucosa bulges because                        various areas of the nasopharynx were primarily involved
of the underlying levator veli palatini muscle. Above and                       by the tumour 38. The lateral wall was the most common
behind this cartilage there is the pharyngeal recess, called                    site, followed by the superior wall. These findings are co-
the fossa of Rosenmüller. A recently published editorial                        herent with the rates of early presenting symptoms. In a
commentary showed the original wonderful images and the                         Californian series of 101 patients presented by Wang et
text of Rosenmüller’s description in 1805 34. This recess is                    al. 39, the most common symptoms were ear-related, and
of paramount importance in the local spread of NPC, be-                         neck masses were the second. Lee et al. 37 studied a very
cause it is closely related with the upper parapharyngeal                       large series of 4,768 patients with NPC treated at the Queen
space and the skull base (anterior foramen lacerum and fo-                      Elizabeth Hospital, Hong Kong. In this endemic area, the
ramen ovale). Chong et al. 35 studied 114 patients with NPC                     most common symptoms presented by patients were the
and demonstrated that these foramina are the most common                        painless enlargement of the upper cervical LN(s) (74.5%),
route of early spread to the cavernous sinus and middle cra-                    nasal symptoms (discharge, bleeding, and/or obstruction,
nial fossa, even without macroscopic skull base erosion. In                     73.4%) and otological symptoms (62.4%). These “tubal
this case, the sixth cranial nerve is the most commonly in-                     occlusive” symptoms 13 are often followed by otitis media
volved with resulting diplopia.                                                 with effusion (OME) (62.4%) 32. While OME is a common
Carcinoma in situ of the nasopharynx (NPCIS) has rarely                         condition in the paediatric population, it is less prevalent in
been reported. The revision of a large series of specimens                      adults. Some authors emphasised that a lasting OME caus-
of nasopharyngeal biopsies performed in 10 years in Hong                        ing deafness is a recognised indicator of nasopharyngeal
Kong identified three cases of NPCIS 36. Two of the three                       obstruction and the possibility of a nasopharyngeal malig-
cases subsequently developed into invasive NPC after initial                    nancy must be considered in all adults, especially in non-
presentation. The interval of transformation varied from 40                     endemic countries. Glynn et al. 40 found a nasopharyngeal
to 48 months. In all three cases, the specimens showed ab-                      mass in 55/85 patients (69%) who presented with unilat-
normal findings on light microscopy and positive staining                       eral or bilateral OME. All patients underwent an exami-
for EBV-encoded RNA (EBER) with in situ hybridisation                           nation under anaesthesia of the ears and a nasopharyngeal
(ISH). Elevated anti-viral capsid antigen (anti-VCA) titres                     biopsy. The four patients with suspicious-looking masses
were present in two of the pre-invasive lesions. No cell-free                   were all found to have malignancies (two squamous cell
EBV DNA was detected in the sera of these patients during                       carcinomas, one B-cell non-Hodgkin lymphoma and one
the pre-invasive phase of the disease (Tab. IV).                                adenocarcinoma). All other patients with masses were
In the nasopharynx there is a rich lymphatic network, mak-                      found to have benign lymphoid hyperplasia. Finkelstein
ing cervical lymph node (LN) involvement from NPC early                         et al. 41, in another non-endemic country, found head and
and frequent. A painless enlargement of the upper cervi-                        neck tumours, mainly NPC, in 8/167 patients with OME
cal LNs was the most common first symptom in several                            (4.8%). The authors concluded that nasopharyngeal and
series (75-80%) 37. Patients with NPC often present with                        parapharyngeal space-occupying lesions should be ruled
locally advanced disease, hence it is sometimes impossible                      out in all cases.
to ascertain the precise area of origin of the tumour. How-                     In spite of these “alarm-bells”, the diagnosis of NPC is too
ever, Lederman analysed 346 cases of NPC and reported                           often very delayed, mainly in Western countries. Also in
significant differences in the frequency with which the                         Hong Kong, Lee et al. found a mean symptom duration be-
                                                                                fore diagnosis of 7.4 months 37. This delay was partially
                                                                                justifiable in the pre-flexible fibrescope era, when the visu-
Table IV. Clinical behaviour and natural history.
                                                                                alisation of the nasopharynx with transoral small mirrors
 Due to the rich lymphatic network of the nasopharynx, cervical lymph node
 (LN) involvement from NPC is early and frequent. A painless enlargement        was a difficult enterprise in some patients; nowadays, it
 of the upper cervical LNs was the most common first symptom in several         is not understandable. Lee et al. 37 wrote: “This disease is
 series, followed by “otological” symptoms for tubal occlusion and otitis       often managed solely by radiotherapists and information
 media with effusion.
                                                                                about the disease from general textbooks is scant due to its
 In spite of these “alarm-bells”, diagnosis of NPC is often very delayed. The   rarity in the West. Consequently, doctors from other spe-
 mean symptom duration before diagnosis was 7.4 months in a study from
 Hong Kong.                                                                     cialties (except otolaryngologists) are often unfamiliar with
 The levels of cervical metastases from NPC are often peculiar (upper and       the natural course of NPC. It is not surprising therefore that
 posterior cervical LN).                                                        very few patients present with Stage I disease”. Unfortu-
 Distant metastasis at presentation has been reported in approximately 5%       nately, in my long experience at the Istituto Nazionale Tu-
 of patients. After loco-regional treatment, distant metastases are the major   mori of Milan, I have seen several patients, although exam-
 cause of mortality.                                                            ined by otolaryngologists for persistent OME and cervical



                                                                                                                                              89
G. Cantù




LN enlargement, who had been treated for a long time with
antibiotics without examination of the nasopharynx. Lee et
al. confirms that “the association of otological symptoms
with NPC is inadequately recognised” 37.
This incorrect interpretation of these symptoms is even less
understandable because the levels of cervical metastases
from NPC are often peculiar. Unfortunately, while many
studies stressed the frequency of neck LN metastases, few
analysed the topographical distribution in each level. Lee et
al. 37 used the generic term “upper cervical lymph node(s)”.
Lindberg 42, in a paramount study published in 1972, re-
viewed the records of 2,044 patients with squamous cell
carcinoma of the head and neck seen from 1948 to 1965
at the University of Texas in Houston, in order to define
the preferred areas of spread for each site of the primary
tumour. He divided each side of the neck into 9 nodal re-
gions (submental, submaxillary, subdigastric, midjugular,
low jugular, upper posterior cervical, mid posterior cervi-
cal, low posterior cervical, and supraclavicular). Overall,
1,155/2,044 patients (57%) presented with clinical evi-
dence of cervical lymph node (CLN) metastasis, but the
                                                                 Figure 1. Levels of the lymph nodes of the neck according to Molinari et
N+ patients with NPC were 147/169 (87%). Moreover, the           al. 1. Submental region; 2. Submandibular region; 3. Subdigastric region; 4.
rates of metastasis in the posterior chain (LN along the spi-    Middle jugular region; 5. Low jugular region; 6. Upper spinal region; 7. Mid-
nal accessory nerve) were very low for all other sites of        dle spinal region; 8. Low spinal region; 9. Lateral supraclavicular region (from
                                                                 Molinari et al., 1977, mod.) 43.
the primary tumour. On the contrary, according to Lind-
berg “nasopharynx lesions have the highest incidence of
bilateral metastases and posterior cervical chain involve-
                                                                 ness. In this case, the symptom was adenopathy and the
ment”; the uppermost nodes, which are “beneath the ster-
                                                                 illness was a tumour localised in a particular site. Each oval
nocleidomastoid muscle at the tip of the mastoid process”,
                                                                 in each cervical level is proportional to probability that it
are the most involved ones 42. Lindberg underlined another
                                                                 is involved by metastasis of a given tumour, and it is wider
peculiarity of NPC. While “the incidence of cervical node
                                                                 when it is frequently involved by a rare tumour (e.g. NPC).
metastasis on admission increases sharply as the size of the
                                                                 NPC was the most probable primary when there were me-
primary increases” in almost all sites of the head and neck,
                                                                 tastases in the spinal chain, either in case of an isolated
“in nasopharyngeal lesions the percentage of patients with
nodal metastasis is really the same for all stages, reflecting   adenopathy or in case of multiple adenopathies (Figs. 2,3).
the aggressiveness of small primaries” 42.                       It should be noted that if the distribution of the node metas-
Another very large study on this topic was made by Moli-         tases represented in Figure 2 is bilateral, the probabilities
nari et al. 43 These authors started from the opposite point     of nasopharyngeal primary tumour are 76% and lymphoma
of view and analysed the records of 3,100 patients with cer-     22%.
vical metastasis seen at the Istituto Nazionale Tumori of        The peculiarity of the NPC to metastasise in the more
Milan in 7 consecutive years in order to discover the prob-      posterior lymph nodes of the neck, demonstrated by Lind-
able site of the primary tumour for each involved cervical       berg and Molinari, has apparently been questioned by a
level(s). They divided the neck in levels similar to those of    long series of more recent studies. Ho et al. 45 performed
Lindberg’s 42 and Robbins’ 44; it should be noted that Rob-      a systematic review of original articles and abstracts ana-
bins’ levels were published 14 years later (Fig. 1). The au-     lysing the cervical nodal metastasis status of patients with
thors made a series of maps in which they calculated the         NPC by searching electronic databases PUBMED (Janu-
rates of involvement of each level(s) of the cervical lym-       ary 1990 to December 2009), CANCERLIT (January 1990
phatic area by a tumour of a given site. They used Bayes’        to December 2009), and the Cochrane Library (January
formula. In biomedical statistics, it allows to establish how    1980 to July 2007). Studies were eligible if the cervical
many probabilities there are that a particular symptom or        (CLN) and/or retropharyngeal node (RLN) positivity rate
combination of symptoms are caused by a particular ill-          in NPC was reported. Search strategy included the key



90
                                                                                                                        Nasopharyngeal carcinoma. Part A




                                                                                     words “nasopharyngeal cancer”, “lymph nodes”, “naso-
                                                                                     pharyngeal carcinoma”, “lymphatic metastasis”, “cervical
                                                                                     nodes”, and “retropharyngeal nodes”. The initial literature
                                                                                     search resulted in 411 studies, but after excluding those
                                                                                     who did not report the incidence of lymph node metasta-
                                                                                     ses, 13 original research reports and a total of 2920 NPC
                                                                                     cases evaluated with MRI were included in the analysis.
                                                                                     Collectively, 84.9% of NPC cases presented with regional
                                                                                     lymphadenopathy. Metastases to neck nodes follow an or-
                                                                                     derly pattern and the probability of “skip” metastasis be-
                                                                                     tween regional nodes vary from 0.5% to 7.9%. The two
                                                                                     most commonly involved regions at staging were the RLN
                                                                                     (69.4%) and level II (70.4%). However, it must be empha-
                                                                                     sised that, with regards to level II, none of the studies re-
                                                                                     viewed made a separation between levels IIa and IIb. The
                                                                                     importance of this distinction has recently been underlined
                                                                                     by a long series of studies on thousands of cases. These
                                                                                     studies have shown that in carcinomas of the oral cavity,
                                                                                     larynx, hypopharynx, etc. the incidence of metastases at
                                                                                     level IIb are very unlikely when there are no involved LN
                                                                                     at level IIa 46-48. For oral carcinoma, Chinn et al. 46 wrote:
Figure 2. Probability of NPC with this type of multiple lymph node metasta-
ses. Monolateral: nasopharynx 59%; lymphoma 22%; tonsil 16%; other 3%.               “Recently, the extent of nodal dissection to include level IIb
Bilateral: nasopharynx 76%; lymphoma 22%; other 2%. Each oval in each                has been questioned. Results of several prospective stud-
cervical level is proportional to probability that it is involved by metastases of   ies support the exclusion of level IIb because of a 3.9%
a given tumour, and it is wider when it is frequently involved by a rare tumour
(e.g. NPC) (from Molinari et al., 1977, mod.) 43.
                                                                                     incidence of positive nodes in oral cavity carcinoma”. The
                                                                                     conclusions of Jia et al. 47 for supraglottic carcinoma were:
                                                                                     “The distribution of pathologically positive lymph nodes
                                                                                     by levels was 35 in ipsilateral level IIa; 4 in ipsilateral level
                                                                                     III, and 8 in contralateral level IIa. There was no positive
                                                                                     lymph node at level IIb pathologically. When selective
                                                                                     neck dissection was carried out for patients with SCC of
                                                                                     the supraglottic larynx with N0 neck, superselective neck
                                                                                     dissection removing lymph nodes in levels IIa and III was
                                                                                     adequate. Level IIb lymph node pads may be left undissect-
                                                                                     ed so that spinal accessory nerve dysfunction is decreased
                                                                                     and operative time reduced”. For hypopharyngeal cancer,
                                                                                     Sakai et al. 48 wrote: “The results suggest that preservation
                                                                                     of level IIb during neck dissection was possible in N0 cases
                                                                                     of hypopharyngeal cancer”.
                                                                                     As for the level IIb, Grégoire et al. 49, in their worldwide
                                                                                     consensus guideline on classification and delineation of the
                                                                                     node groups of the head and neck region, reflecting “in-
                                                                                     depth discussions of a panel of European, Asian, Austral-
                                                                                     ian/New Zealander and North American experts from vari-
                                                                                     ous disciplines, i.e. radiation oncologists, head and neck
                                                                                     surgeons, and anatomists, representing the major relevant
                                                                                     cooperative groups in radiation oncology (DAHANCA,
                                                                                     EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG)”
Figure 3. Probability of NPC with this type of isolated adenopathy. Nasophar-
ynx 58%; tonsil 9.6%; oropharynx 8.5%; base of tongue 7.7 %; hypopharynx
                                                                                     wrote: “Level IIb is more likely associated with primary
7.7%; larynx 4.6%; retromolar trigone 2.9%; other 1% (from Molinari et al.,          tumours of the oropharynx or nasopharynx, and less fre-
1977, mod.) 43.                                                                      quently with tumours of the oral cavity, larynx or hy-



                                                                                                                                                    91
G. Cantù




popharynx”, and, regarding level V, “Level V lymph nodes         tion are even more suitable for NPC because the diagnosis
are at high risk for harbouring metastases from cancers          of this tumour is late in most cases, either for the heedless-
of the nasopharynx, oropharynx and thyroid gland”, and:          ness by the patient or for the scant awareness of physicians,
“Level Vc (supraclavicular nodes) receives efferent lym-         who misinterpret the related symptoms. In the 1970s, when
phatics from the posterior triangle nodes (level Va and Vb)      I was a trainee at the Istituto Nazionale Tumori of Milan,
and is more commonly associated with nasopharyngeal              most patients presented after a cervical LN biopsy with the
tumours” 49. Wang et al. 50 analysed the levels involved by      diagnosis of metastasis from undifferentiated carcinoma
metastases in their series of 3,100 cases of newly diagnosed     of unknown primary origin, without any examination of
NPC between January 2010 and January 2013. A total of            the nasopharynx. As mentioned above, it is worth noting
2,679 (86.4%) cases had involved lymph nodes. The de-            that in the pre-fibrescope era the visualisation of the naso-
tailed distribution was: level IIa 1,798 (67.1%), level IIb      pharynx was a difficult enterprise in some patients. Fortu-
2,341 (87.4%)”. Jiang et al. 51 analysed the records of 960      nately, nowadays the flexible fibrescopes have changed the
NPCs in their institution and found that the top four levels     scenario, making possible both thorough examination of
with the highest rates of lymph node metastasis were: RLN,       the nasopharynx and a biopsy. Nevertheless, even in more
(86.35%), IIb (84.06%), IIa (62.29%), and III (47.29%).          recent years, too many patients presenting with symptoms
Regarding level V, they demonstrated that LN metastasis in       revealing a possible NPC underwent a cervical node biop-
the cervical region posterior to level V can occur in patients   sy before careful inspection of the nasopharynx. When the
with NPC, and that 4.95% of patients with LN metastases          primary tumour has already been histologically diagnosed,
had involvement of that region.                                  a lymph node biopsy is nearly always unnecessary. How-
Both the studies by Lindberg 42 and Molinari et al. 43 were      ever, a lymphadenectomy may rarely be requested by the
carried out before the era of CT and MRI. Hence, they were       pathologist to clarify possible diagnostic doubts between
unable to report the rates of RLN involvement. Since then,       NPC and lymphoma.
several studies demonstrated that RLNs represent the first-      According to the European Society for Medical Oncology
echelon lymph nodes typically involved in NPC 52,53.             (ESMO) guidelines “In terms of imaging, a contrast en-
Distant metastasis at presentation has been reported in ap-      hanced CT and/or MRI from the skull base to the clavicles
proximately 5% of patients 8. After loco-regional treatment,     is recommended” 56. CT has long been used for staging
distant metastases are the major cause of mortality. In the      NPC, especially for the detection of skull base involvement
series by Huang et al. 54, 125 of 629 (19.8%) cases of NPC       with lytic or sclerotic lesions, but it has been now largely
were found to have distant metastasis. The frequency of          replaced by MRI for primary and nodal staging 57. MRI has
metastases in the various sites was as follows: bone (75%        been shown to be superior to CT in the delineation of ex-
of total metastatic patients), lung (46%), liver (38%), retro-   tent of perineural spread along the skull base foramina, in-
peritoneal lymph nodes (10%). Multiple organ involvement         tracranial involvement, retropharyngeal nodal disease, and
was common (57%). Most of the distant metastases (95%)           invasion of adjacent deep neck spaces 56,58.
occurred within 3 years after completion of radiotherapy;        Moreover, two studies from the same centre demonstrated
in the first year (52%), in the second year (23%), and in        that MRI imaging depicts subclinical cancers missed at en-
the third year (20%). QU et al. stated that “Tumours are         doscopy and endoscopic biopsy, and helps identify the ma-
highly likely to metastasize if they have a larger volume,       jority of patients who do not have NPC and therefore do not
the regional LNs are relatively large, or the regional LNs       need to undergo invasive sampling biopsies 59,60. However,
are biopsied but not removed” 55.                                CT is still used for radiotherapy planning and, in some cen-
                                                                 tres, together with positron emission tomography (PET).
Diagnostic workup                                                18F-fluorodeoxyglucose PET/CT has been shown to have a

According to the recent ESMO-EUROCAN guidelines for
the NPC, routine staging procedures include a medical his-       Table V. Diagnostic workup.
tory, physical examination (including cranial nerve exami-        Medical history, with particular attention to “alarm-bells”
nation), complete blood count (CBC), serum biochemistry           Physical examination
[including liver and renal function tests and lactate dehy-       Nasopharyngoscopy (with possible aid of bioendoscopic techniques such
drogenase (LDH)], nasopharyngoscopy, CT scan or MRI               as narrow band imaging)
of the nasopharynx and base of the skull and neck (up to          Tumour biopsy
the clavicle) and 18F-fluorodeoxy-glucose (FDG)-PET/CT            CT scan or MRI of the nasopharynx, skull base, and neck; 18F-FDG-PET/
imaging 56 (Tab. V). Medical history and physical examina-        CT imaging can be useful




92
                                                                                                  Nasopharyngeal carcinoma. Part A




high diagnostic accuracy for detection of distant metastases     response, and disease surveillance, Chan et al. stated that
and is superior to CT alone 61. It is also used to monitor       “there is much less information on the use of analysis of
patients after therapy and to detect NPC recurrence. A thor-     circulating DNA to screen for early cancers. A fundamen-
ough synthesis have been made by a study from Taiwan 62.         tal question is whether a small tumour would release suffi-
These authors demonstrated that “MRI appears to be supe-         cient amounts of tumour DNA into the circulation to allow
rior to PET/CT for the assessment of locoregional invasion       sensitive detection of the cancer-associated changes” 68. A
and RLNs. PET/CT is more accurate than MRI for deter-            paramount prospective study published in the New Eng-
mining cervical nodal metastasis and should be the better        land Journal of Medicine investigated this topic in an en-
reference for the neck status. PET/CT has an acceptable          demic country (Hong Kong). Chan et al. 68 analysed EBV
diagnostic yield and a low false-positive rate for the de-       DNA in plasma specimens of 20,174 men between the ages
tection of distant malignancy and can replace conventional       of 40 and 62 years who did not have symptoms of NPC.
work-up to this aim”.                                            Participants with initially positive results were retested
The NCCN guidelines 63 also suggest performing EBV               approximately 4 weeks later, and those with persistently
DNA testing. “For non-keratinising or undifferentiated           positive EBV DNA in plasma underwent nasal endoscopic
histology, consider testing of EBV in tumour and blood.          examination and MRI. EBV DNA was detectable in plasma
Common means for detecting EBV in pathologic speci-              samples obtained from 1,112 participants (5.5%), and 309
mens include in situ hybridisation for EBER or immuno-           (1.5% of all participants and 27.8% of those who initially
histochemical staining for latent membrane protein (LMP).        tested positive) had persistently positive results on the re-
The EBV DNA load within the serum or plasma may be               peated sample. Among these 309 participants, 300 under-
quantified using polymerase chain reaction (PCR) target-         went endoscopic examination, and 275 underwent both
ing genomic sequences of the EBV DNA such as BamHI-              endoscopic examination and MRI; of these participants, 34
W, Epstein-Barr nuclear antigen (EBNA), or LMP; these            had NPC. The proportion of participants with NPC identi-
tests vary in their sensitivity. The EBV DNA load may            fied by screening with stage I or II disease was significantly
reflect prognosis and change in response to therapy”. The        higher than in a historical cohort (71% vs 20%, p < 0.001 by
possibility to detect the presence of EBV genomes in fine        the chi-square test). Moreover, these patients had superior
needle aspirate (FNA) from neck lymph node metastases            3-year progression-free survival (97% vs 70%). Nine par-
was tested in non-endemic and endemic countries 64,65. Both      ticipants declined to undergo further testing, and one pre-
these studies demonstrated the utility of EBV gene ampli-        sented with advanced NPC at 32 months after enrolment.
fication in FNA samples of neck metastases and suggested         NPC developed in only one participant with negative EBV
that the presence of the EBV genome in FNA samples of            DNA in plasma samples within one year after testing. The
neck nodes is predictive of the presence of NPC.                 sensitivity and specificity of EBV DNA in plasma samples
Circulating EBV DNA analysis has been shown to be valu-          in screening for NPC were 97.1% and 98.6%, respectively.
able in the detection, prognostication and monitoring of         The costs for each EBV DNA analysis, endoscopic exami-
NPC patients. Lo et al. 66 studied the kinetics of circulating   nation, and MRI were $30, $80, and $1,000 (U.S. dollars),
EBV DNA in the plasma of NPC patients undergoing ra-             respectively. The authors concluded: “Considering the po-
diation therapy and demonstrated a rapid decline in plasma       tential decrease in mortality and morbidity, as well as treat-
EBV DNA concentration after treatment with a median              ment cost savings associated with the shift in stage distribu-
half-life of 3.8 days. They concluded that kinetic analysis      tion, screening for NPC appears to be a feasible practice in
of circulating tumour-derived DNA during treatment may           regions with a high incidence of this disease” 68. A subse-
be a powerful tool to evaluate the in vivo response of NPC       quent study examined the cost-effectiveness of screening
to antineoplastic treatment. To et al. 67 analysed plasma        for NPC with plasma EBV DNA among 50-year-old Asian
EBV DNA concentrations in 21 patients with either local          American men in the United States, and concluded that, al-
recurrent NPC (17 cases) or disease persistence (4 cases).       though screening for NPC with EBV DNA for 50-year-old
All patients underwent salvage surgery. The in vivo elimi-       Asian American men may result in earlier detection, it was
nation of EBV DNA was very rapid after surgical resection.       unlikely to be cost-effective 69.
The median half-life of plasma EBV DNA was 139 min.
The failure of complete and rapid elimination of EBV DNA
from circulation predicted disease recurrence.
                                                                 Narrow-band imaging
While circulating cancer-derived EBV DNA in plasma has           To my knowledge, the first reports of a new endoscopic im-
been well established as a tumour marker in patients with        aging technique, the narrow-band imaging (NBI), appeared
diagnosed NPC for prognostication, predicting treatment          about 20 years ago 70. NBI is a diagnostic tool that enhances



                                                                                                                              93
G. Cantù




the endoscopic view of the upper aero-digestive tract (UADT)      surpass the diagnostic accuracy of white light endoscopy in
to reveal small mucosal lesions that would otherwise escape       this regard”. Another study from the same centre demon-
diagnosis even by experienced endoscopists 71. This tech-         strated that: “Intraobserver and interobserver agreement for
nique, which has previously been used for the detection of        nasopharyngeal malignancy was strong on WL endoscopy
adenomas in the gastrointestinal tract, has the potential to      but only moderate on NBI endoscopy. Agreement may be
reduce the false negative rates associated with conventional      improved by adopting a standard set of assessment guide-
white light endoscopy. NBI is an imaging technique that uses      lines, including an objective detailed morphological analy-
two specific wavelengths of light that are strongly absorbed      sis under WL and vasculature analysis under NBI” 76.
by haemoglobin, allowing improved visualisation and de-
lineation of mucosal microvascular patterns 72. “Thus, su-        Radiomics
perficial mucosal lesions that would previously have been
missed by regular white light during endoscopy would be           The most recent tool for the diagnosis and staging of NPC
identified by the blue light of NBI, based on the increased       is the so-called ‘radiomics’. Radiomics, which was first
vascularity and neoangiogenesis of the tumour” 71. In 2008,       proposed by Lambin 77 in 2012, is a relatively ‘young’
the literature on the use of NBI in head and neck oncology        concept and is considered a natural extension of computer-
was very sparse 71. Today, hundreds of studies have been          aided diagnosis and detection systems. It converts imaging
published on this topic in the diagnostic work-up of head         data into a high-dimensional mineable feature space using
and neck cancers, especially those at oropharyngeal and hy-       a large number of automatically extracted data-characteri-
popharyngeal sites. As for the nasopharynx, the number of         sation algorithms to reveal tumour features that may not be
studies is smaller but some studies are very indicative for the   recognised by the naked eye and to quantitatively describe
high number of patients examined. Most of the studies were        the tumour phenotype. These extracted features are called
done in endemic areas where NBI was used as screening.            radiomic features and include first-order statistics fea-
For example, Wen et al. 73 compared the diagnostic accuracy       tures, intensity histograms, shape- and size-based features,
of conventional white-light (WL) imaging endoscopy with           texture-based features and wavelet features. Conceptually
that of NBI endoscopy in patients at high risk for NPC and        speaking, radiomics belongs to the field of machine learn-
found that the sensitivity and negative predictive values of      ing, although human participation is needed. The basic
NBI in NPC screening were significantly higher than those         hypothesis of radiomics is that the constructed descriptive
of WL (93.9% vs 71.2%, p = 0.001; and 98.1% vs 91.7%,             model (based on medical imaging data, sometimes sup-
p = 0.003; respectively). Yang et al. 74 examined a total of      plemented by biological and/or medical data) can provide
1,854 patients by means of an electronic nasopharyngolaryn-       predictions of prognosis or diagnosis 78.
goscope equipped with conventional WL and NBI system.             A complete and in-depth review of the characteristics and
Of these, 62 cases (3.34%) were pathologically confirmed          possibilities of radiomics can be found in the article by
as NPC. The sensitivity, specificity, positive predictive value   Scapicchio et al. 79: “Diagnostic imaging is going through
and negative predictive value for detecting NPC significantly     an epoch-making moment of profound transformation, to
increased from 90.3%, 75.4%, 11.3% and 99.6% with WL              which radiologists must adapt. This is a transformation
up to 100%, 99.2%, 81.6% and 100% with NBI, respective-           from a discipline based on the visual interpretation of the
ly. The authors concluded that these findings suggested that      images toward a new type of radiology, which must inte-
NBI endoscopy might serve as an ideal tool in the detection       grate the quantitative data (biomarkers) coming from the
of NPC. In this regard, it should be emphasised that NBI can      images with the interpretative modality. In fact, since are
be useful to locate the primary tumour in the case of cervical    formed by the interaction of radiation or ultrasounds with
metastases from an unknown primary.                               tissues or organs, medical images are not simple images,
However, it should be noted that, among most of the con-          but they reflect various physical properties of the body.
clusions in favour of NBI, there are also some that are           Medical images can be converted into meaningful and
against it. In the study by Vlantis et al. 75 “The nasophar-      mineable data through a quantification process. The ex-
ynx of 156 patients who failed serological screening for          tracted quantitative features can be analysed to reflect the
or presented with symptoms of nasopharyngeal carcinoma            underlying pathophysiology. However, quantitative data
was graded under WL and NBI endoscopy and a biopsy                are not easily interpretable by the human mind, they can
taken”. The authors concluded that “Narrow band imaging           only be extracted from a computer and analysed through
endoscopy of vasculature alone for suspected nasopharyn-          complex algorithms. Despite promising results in research,
geal carcinoma is not more useful than white light endos-         such applications of radiomics still necessitate a deep ex-
copy of nasopharyngeal morphology, nor does it add to or          ploration, refinement, standardisation and validation to



94
                                                                                                             Nasopharyngeal carcinoma. Part A




achieve routine clinical adoption, but they may be of great       of the American Joint Committee on Cancer-International
help in the clinical management of specific diseases in the       Union Against Cancer (AJCC-UICC) staging system and
near future. Radiomics is a piece in the puzzle of precision      the Chinese one (Tab. VI). China developed independent
medicine, its final goal being to build models able to clas-      criteria for clinical staging of NPC since 1959 and the
sify the disease and/or to predict its outcome or the answer      first TNM staging system was established in Shanghai
to a therapy” 79. A meta-analysis carried out by Park et al. 80   in 1965. It was revised in 1979, 1981, 1992 and 2008 84.
found that 91% of radiomics studies concern oncological           Since 1979, the Chinese classification used levels and fix-
applications, and that for the most part (81%) radiomics is       ity of LN metastases for staging, and divided the lower
studied for diagnostic purposes. They stated that “To date,       LNs from those in the supraclavicular fossa (SCF). N2
radiomics has been applied in various oncology research           stage was: “Upper cervical LNs, mobile or fixed 3-8 cm in
(mainly brain, prostate, breast and lung tumours) for pre-        greatest dimension, lower cervical LNs, mobile, > 8 cm in
cise clinical decision, treatment response and prognosis          greatest dimension”. N3 stage was: “Lower cervical LNs,
predication.” “The evolving branch of radiomics linking           fixed, > 8 cm in greatest dimension, or extension to the
imaging features to gene expression is today known as ra-         SCF, or supraclavicular skin nodule” 84. In 1990, from the
diogenomics. By combining quantitative imaging features           analysis of a series of 410 cases treated at the Istituto Na-
with clinical, genomic and other information in a multi-          zionale Tumori of Milan the authors found that: “With re-
omics study, it is possible to mine these data to detect and      gards to nodal extent, only the level of the involved nodes
validate radiomics biomarkers and better understand their         was a significant variable. Both AJCC and UICC clas-
function and biological significance” 80.                         sifications, when applied to the entire series of patients,
For NPC, Gao et al. wrote: “In current clinical practice, the     appeared to be unsatisfactory” 85. It is important to note
TNM staging system is the most used prognostic tool based         that this study used the AJCC and UICC classifications
on tumour size, nodes, and distant metastasis. However, pa-       in force in those years (4th edition) for staging, both of
tients with the same clinical stage display totally different     which did not provide for the subdivision of lymph node
therapeutic response and clinical outcome. Hence, accu-           metastases into levels. In 1991, a study from Hong Kong
mulated omic-studies including genomics, proteomics, and          analysed 564 patients with NPC and compared the 1979
immunomics have been applied to deepen our understand-            Chinese classification, the UICC, and the AJCC classi-
ing on tumour heterogeneity and malignant progression             fications, for their efficacy in predicting prognosis. Teo
of NPC, seeking for potential prognostic biomarkers and           et al. stated that the Chinese classification was superior
therapeutic molecular targets” 81. Li et al. wrote: “Although     to the other two “because its overall stages differed from
radiomics has been applied to medical imaging since 2012          one another more significantly in the actuarial survival,
and DL (deep learning) has started to be applied to medical       disease-free survival (DFS), and freedom from distant
imaging around 2015, their application in NPC has only            metastasis (FDM) rates, and its N staging was more ac-
gradually begun in 2017. Many attempts have been made to          curate in predicting FDM” 86.
apply AI (artificial intelligence) tools for NPC imaging in       The AJCC and UICC classifications for NPC were different
clinical settings. However, there are still some limitations      from each other in the first four editions, both for T and N.
in this field” 78. Spadarella et al. performed a systematic       Moreover, the definition of N categories was the same for
search in PubMed, Web of Science and Scopus using “MRI,           all head and neck sites in both classifications. The TNM
magnetic resonance imaging, radiomic, texture analysis,           Staging System 5th edition, jointly adopted by the AJCC
nasopharyngeal carcinoma, nasopharyngeal cancer” in all           and the UICC in 1997, was a milestone. Regarding N clas-
possible combinations. They found 24 studies and evalu-
ated them according to the Radiomic quality score. They
concluded that: “Radiomic articles in NPC are mostly of           Table VI. Staging.
low methodological quality. The greatest limitations are the       As many as 18 different classifications of NPC have been developed since
lack of external validation, biological correlates, prospec-       the first in 1952.
tive design and open science” 82.                                  However, only two have been widely used, that of the AJCC-UICC and the
                                                                   Chinese one.
                                                                   Since 1979, the Chinese classification used levels and fixity of LN
Staging                                                            metastases for staging.
As many as 18 different classifications of NPC have been           The definition of N categories was the same for all head and neck sites in
developed since the first proposed by Geist and Portman            the first four AJCC-UICC classifications.
(1952) 83. However, only two have been widely used, that           In the fifth edition, a different N classification scheme was adopted for NPC.




                                                                                                                                              95
G. Cantù




sification, both systems reported the following statement:      References
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