Annals of Oncology 12: 1157-1162.2001.

2001 Kluwer Academic Publishers. Primed in the Netherlands.

Original article
Undifferentiated nasopharyngeal carcinoma in children and adolescents:
Comparison between staging systems
M. Casanova,1 A. Ferrari,1 L. Gandola,2 E. Orlandi,1 F. Spreafico,1 M. Terenziani,1 P. Navarria,2
R. Luksch,1 M. Massimino,1 G. Cefalo,1 F. Lombardi2 & F. Fossati-Bellani'
'Pedialnc Oncology Unit, 2Radiotherapy B Unit, Istituto Nazionale Tumon. Milano, Italy

Summary

Introduction
Nasopharyngeal carcinoma is a common tumor of the
head and neck in adults, but it is very rare in children.
The incidence varies widely depending on geographical
and racial factors. In the US and Europe nasopharyngeal
carcinoma represents less than 1% of all pediatric malignancies and approximately one third of primary malignant tumors occurring in the nasopharynx (the incidence of nasopharyngeal lymphomas or sarcomas is
higher in the young) [1]. Children with nasopharyngeal
carcinoma differ from their adult counterparts in that
they have a close association with Epstein-Barr virus
infections [2]. As far as histopathologic classification is
concerned, the World Health Organization has simplified
and clarified typing of nasopharyngeal epithelial tumors
with three different groups: 1) keratinizing squamous
cell carcinoma, 2) non-keratinizing carcinoma, and 3)
undifferentiated nasopharyngeal carcinoma (UNPC)
[3]. Children and adolescents almost always have the
UNPC variant, which is closely related to a higher rate
of advanced locoregional disease and distant metastases
[4-11]. Several classifications for nasopharyngeal carcinoma have been formulated, however the most popular
in Western countries is the American Joint Committee
of Cancer (AJCC) staging system. The 5th edition of
this classification was designed to merge the best pre-

Key words: childhood head and neck cancer, comparison,

nasopharyngeal carcinoma, prognosis, tumor staging

dictive factors of the 4th edition and the Ho staging

system which is the most frequently applied to Asian
populations [12]. To assess the value of this new classification in pediatric age we applied it to a series of
patients treated in a single institution. There is no study
comparing the 5th edition of the AJCC staging system
with the previous one in this cohort of patients, the only
published experience in adult squamous cell carcinoma
of the nasopharynx [13].

Patients and methods

Over a period of 34 years, from July 1965 lo September 1999. 54
patients with a diagnosis of UNPC were treated at the Pediatric and
Radiotherapy Departments of the Istituto Nazionale Tumori of Milan.
Italy. Ages ranged from 3 to 17 years with a median age of 13 years.
There were 20 females and 34 males. Tissue samples were taken
from the nasopharyngeal mass in 37% of cases, from the metastatic
adenopathy in 39%, and from both sites in 24%. In all patients a
nasopharyngeal mass was clinically delectable, cervical adenopathies
were observed in 53 patients and distant metaslases in 5. For the
purpose of this analysis all tumors were restaged according to the
criteria of both the 4th and 5th edition [14. 15] of the AJCC staging
system (Tables 1 and 2). All base-line clinical and radiographic data
were available at our institution. All patients had complete clinical
examinations including indirect mirror examination of nasopharynx
and direct nasopharyngoscopy up until 1989. and direct flexible or
rigid fibreoptic nasopharyngoscopy thereafter. Plain films of the naso-

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Background: New criteria for classifying nasopharyngeal carcinoma were defined in the 5th edition of the American Joint
Committee on Cancer (AJCC) staging manual. We investigated
the clinical implications of the new system by comparing it
with the 4th edition in a cohort of pediatnc undifferentiated
nasopharyngeal carcinoma (UNPC).
Patients and methods: We retrospectively restaged 54 patients
younger than 17 years who had biopsy-proven UNPC, treated
between 1965 and 1999 in a single institution.
Results: Using the 5th edition an overall downstaging of the
population according to T status, N status, and stage grouping
was evident along with a better correlation with likelihood of

survival. The comparison between local and advanced disease

according to T stage (T1+T2 vs. T3+T4) became highly significant in the new system (P = 0.0011 vs. P = 0.067 in the 4th
edition).
Conclusions: As far as prognostic categories are concerned,
the 5th edition of the AJCC staging manual appears to be an
improvement over the previous classification, even though for
pediatric patients a uniform distribution among stages cannot
be observed because most children present with advanced
disease. The overall downstaging should be taken into consideration for the stratification of patients in future trials.

1158
Table I The 4th edition of the AJCC staging system.
Tl
T2
T3
T4

Tumor
Tumor
Tumor
Tumor

NO
N1

No regional lymph node metastasis

Single ipsilateral lymph node measuring < 3 cm in greatest
dimension
Single ipsilateral lymph node measuring > 3 cm but not
> 6 cm in greatest dimension; or multiple lpsilateral lymph
nodes, none measuring > 6 cm, or in bilateral or controlateral lymph nodes, none measuring > 6 cm in greatest
dimension
N2a: Metastasis in single ipsilateral lymph node measuring 3-6 cm in greatest dimension
N2b: Metastases in multiple ipsilateral lymph nodes,
none measuring > 6 cm.
N 2 c Metastases in bilateral or controlateral lymph nodes.
none measuring > 6 cm in greatest dimension.
Massive ipsilateral lymph node(s), bilateral or controlateral
lymph node(s)

N2

N3

Stage
Stage
Stage
Stage

No distant metastases.
Distant metastases.
I
II
111
IV

TINOMO.
T2N0M0.
T3NOMOorTl-3NlMO.
T4(any N ) o r N2-3 (anyT) or Ml (anyT, any N)

Results

Table 2 The 5th edition of the AJCC staging system

Tl
T2

T3
T4

NO

Nl
N2
N3

Tumor confined to the nasopharynx.

Tumor extends to soft tissue of nasopharynx and/or
nasal fossa.
T2a: without parapharyngeal extension.
T2b. wilh parapharyngeal extention
Tumor invades bony structures and/or paranasal
sinuses.
Tumor with intracranial extension and/or involvement
of cranial nerves, infratemporal fossa, hypopharynx, or
orbit.
No regional lymph node metastasis
Unilateral metastasis lymph node(s) measuring
in greatest dimension above the supraclavicular
Bilateral metastases in lymph node(s) measuring
in greatest dimension above the supraclavicular
Metastasis in a lymph node(s):
(a) > 6 cm in greatest dimension:
(b) extention to the supraclavicular fossa.

MO
Ml

No distant metastases
Distant metastases

Stage I
Stage MA
Stage 11B

Tl
T2a
Tl
T2a

T2b
Stage 111

Stage IVA
Stage 1VB
Stage 1VC

Tl
T2
T3
T4
AnyT
AnyT

NO
NO
Nl
Nl
NO-1
N2
N2
NO-2
NO-2
N3
Any N

MO
MO
MO
MO
MO
MO
MO
MO
MO
MO
Ml

< 6 cm
fossa.
< 6 cm
fossa

Distribution of all the 54 patients according to the

extent of primary tumor and nodal involvement by the
4th edition of the AJCC staging manual is shown in
Table 3, and by the 5th edition in Table 4. By the 5th
edition, an overall downstaging according to T and N
status is evident: by the 4th edition, T3+T4 patients were
81.5% and N2+N3 88.9%; conversely by the 5th edition,
T3+T4 patients represented 63% and N2+N3 64.9%.
Table 5 shows the comparison between stage grouping
according to the two classifications. Even if a migration
in lower categories was confirmed (stage IV 98% in 4th
edition and 58% in the 5th), the new system was not able
to assign patients to the more uniformly sized stage
grouping observed in adults because a great proportion
of patients presented advanced disease. However the
new system does correlate stage and likelihood of survival well (Figure 1). At five years the figures were 82.2%
in stage II, 60.3% in stage III, and 39.2% in stage IV. The
differences between these percentages was not statistically significant (P = 0.0825). No comparison can be
made according to the 4th edition as 53 of 54 patients
were in stage IVand only one in stage III.
Considering the T status separately, the new system
separated patients into cohorts of more equal size and
well-separated from a prognostic point of view. The
difference between local and advanced disease (Tl +T2
vs. T3+T4) became highly significant in the last edition:
P = 0.0011 in the 5th edition vs. P = 0.067 in the 4th
edition. In Figures 2 and 3 actuarial survival rates
according to T status are shown. For disease staged by
the 4th edition of the AJCC staging system, a problem is
evident: the survival rates at 5 and 10 years for T1+T2
patients (calculated together because only one patient
was classified as Tl) and T3 patients are not clearly
separated. On the contrary, the 5th edition highlights

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MO
Ml

limited to one subsite of nasopharynx.

invades more than one subsite of nasopharynx
invades oropharynx and/or nasal cavity.
invades skull and/or cranial nerves.

pharynx with tomograms of the base of skull were performed until

1978. Computer tomography became available in 1979 and magnetic
resonance imaging in 1985. Size, position, laterality, and multiplicity of
the cervical node metastases were recorded for each patient. Cervical
nerve palsy was assessed clinically. Routine systemic investigation
included chest radiography, liver ultrasonograms, skeletal survey and/
or bone scans. Unfortunately climco-radiographic data in each patient
were not complete enough to identify the extent of the parapharyngeal
tumor, so we could not subdivide the T2 stage into T2a and T2b, as
suggested in the 5th edition of the AJCC staging system. All patients
received conventional fractionation radiotherapy for the primary
tumor and cervical adenopathies with a median dose of 60 Gy (range
55-70 Gy), as well as for uninvolved cervical areas with a median dose
of 45 Gy (range 40-55 Gy). From 1970 onwards, patients with
advanced disease also received chemotherapy with different schedules
through the years [5-6]. Once off therapy, patients were regularly
examined in the outpatient clinic every two months for the first year,
every three months in year 2, and bi-annually to annually thereafter
The median follow-up was 126 months (range 9-396); no patient was
lost at follow-up. The survival curves were actuarial measurements
from the date of diagnosis till the date of death or last follow-up in
January 2000 as calculated by the Kaplan-Meier method [16]. The
differences between the curves were compared by log-rank test, with
P-values less than 0.05 being considered to be significant [17].

1159
Table 3 T and N distribution according to the 4th edition of the AJCC staging manual.
Nodal involvement
Primary tumor
Tl
T2
T3
T4
All T (%)

NO

1(1.8)

Nl
1
4
5(9.3)

N2a
1
4
4(7.4)

N2b
3
5
5
13(24.1)

N2c
1
7
3
11 (20.4)

N3
5
8
7
20(37)

All N (%)
1(1.8)
9(16.7)
21 (38.9)
23 (42.6)
54(100)

Table 4. Tand N distribution according to the 5th edition of the AJCC staging manual.
Nodal involvement
Primary tumor
Tl
T2
T3
T4
All T (%)

NO
_
1
1(1.8)

Nl
3
3
9
3
18(33 3)

N2
1
2
6
9(16.7)

Stage I
Stage II
Stage III
Stage IV

4th edition of the

AJCC (%)

5th edition of the

AJCC (%)

0
0
1(2)
53(98)

0
6(11)
16(30)
32(59)

the differences between advanced and local disease even

if the curves of Tl and T2 patients are essentially the
same.
Irrespective of the T stage classification, survival
correlates poorly with N stage both in the 4th and 5th
editions of the AJCC staging manual. The five-year
survival rates inappropriately increase from Nl to N2
stage in the 4th edition (Figure 4); in the 4th edition Nl
patients have the worst prognosis (even worse than N3
patients), while in the 5th edition (Figure 5) Nl and N3
patients have a similar outcome (44.4% vs. 48.8% at five
years). A partial explanation for this observation is that
80% of Nl patients in the 4th edition and 66.6% in the
5th edition are associated with advanced T stage.
The subclassification in N3a (lymphnodal metastasis
greater than 6 cm in greatest dimension) and N3b
(extention to the supraclavicolar fossa) of the 5th edition
seems to have minor prognostic significance in our
experience (five-year survival 50.7% vs. 48.3%). Conversely, the subdivision of N2 patients in the 4th edition
identifies three different populations with survival rates
that surprisingly increase from N2a to N2c stage. All
the four patients classified as N2a died with a median
survival of 23 months; the five-year survival was 72.7%
for the 13 N2b patients and 90.1% for the 11 N2c
patients (P = 0.003).

2
13(24 1)

N3b
1
3
6
3
13(24.1)

All N (%)
8(14.8)
12(22.2)
25 (46.3)
9(16.7)
54(100)

Discussion
Among different classifications formulated for nasopharyngeal cancer, the most popular in Western countries is the AJCC staging system, while in Eastern
countries the most utilized is the Ho classification [12].
Between 1977 and 1992, four different editions of the
AJCC system were proposed with relatively few changes.
While in the 1st edition of 1977 the T category was
defined according to maximum primary tumor diameter, in the following editions of 1983, 1988 and 1992 it
was assigned according to anatomic extent. In the 1st
and 2nd edition the bilateral nodal involvement was
designated as N3b, whereas it became N2c in the 3rd
and 4th version [14].
There are two major differences between the Ho
staging system and the 4th edition of the AJCC. Firstly,
the Ho system classifies all nasopharyngeal tumors confined within the nasopharynx in the Tl status, whereas
in the AJCC systems tumors that involve more than
one subsite of the nasopharynx are designated as T2.
Secondly, the Ho system categorizes lymph node disease
by its anatomic position (Nl = upper cervical region,
N2 = lower cervical region, and N3 = supraclavicular
region) whereas in the AJCC system lymph node categories are based on the size of the largest lymph node,
the number of involved lymph nodes, and the presence
or absence of controlateral disease [13]. Recent international discussions have lead to the creation of the 5th
edition of the AJCC staging system, that seeks to merge
the most predictive factors of previous classifications [15].
Due to the rare occurrence of UNPC in childhood,
few institutions have acquired substantial experience in
its treatment, and published clinical studies consist of
small series accrued over long periods (4-8). Consequently, refinement of the AJCC system in pediatric
population has been hindered by relatively infrequent

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Table 5. Stage grouping according to the 4th and 5th AJCC staging
manual.

N3a
3
4
4

1160

Stage II
Stage DI
Stage IV

1 "

I
,6

"

,2

>

O
u.
O
>

CD
<
CO

O "

a.

5O

1OO

15O

2OO

25O

Figure I Overall survival according to stage grouping calculated by the 5th edition of the AJCC Staging system

1 ,8

S .4 1
03

o -\

OH

5O

1OO

15O

2OO

25O

MONTHS
Figure 2 Overall survival according toT-stage calculated by the 4th edition of the AJCC Staging system.

testing of its rules and by limited data sets. Our series of

54 patients appear comparable to those reported in the
literature as far as histology and overall survival are
concerned (50.5% at five years), and confirms the data
of the high rate of advanced disease at the time of
diagnosis both in the 4th and 5th editions of the AJCC
staging manual. This could be explained with a delay in
the clinical diagnosis that could be attributed to the
difficulty in performing an easy and thorough examination of the nasopharynx in children. Furthermore, the
rarity of UN PC could lead the physician to misinterpret
persisting pain in the throat, ears, and neck areas as well
as nasal bleeding and small cervical adenopathies. From
this point of view in the 5th edition, despite a better

distribution among stage II to IV, still no patient was

assigned to stage I. Therefore our results suggest that the
new system is more useful prognostically than the previous one with regard to stage grouping and particularly
in separating local and advanced disease according to
T stage. A bias in this analysis should be the fact that
treatment was not uniform in our series. In fact, it has
today been shown that the combination of chemotherapy and radiotherapy can improve disease-free survival
as well as overall survival in adult patients with advanced nasopharyngeal cancers [18]. No randomized
trial has been conducted in children so far, but most
authors agree that advanced UNPC in pediatric age
demands chemotherapy because of the high incidence

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MONTHS

1161

1H

co

1
u.
O

00

Si

OH

50

1OO

15O

200

250

MONTHS

"

,6

S ,4 H

d
5

H
1

.2

ffi

o
2s

o -

SO

1OO

ISO

2OO

2SO

MONTHS
Figure 4 Overall survival according to N-stage calculated by the 4th edition of the AJCC Staging system

>

,8

,6

,4

,2

t
5m
S
a.

o O

5O

1OO

15O

2OO

25O

MONTHS
Figure 5 Overall survival according to N-stage calculated by the 5th edition of the AJCC Staging system.

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Figure 3. Overall survival according toT-stage calculated by the 5th edition of the AJCC Staging system.

1162

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Received 23 January 2001; accepted 20 March 2001.

Correspondence to
M. Casanova, MD
Pediatric Oncology Unit
Istituto NazionaleTumori
Via G.Venezian. 1
20133 Milano
Italy
E-mail: casanova@istitutotumon.mi.it

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of early distant metastases, and the possibility of micrometastases present at the time of diagnosis [4-11]. Despite this bias, which should reduce the distance between
the curves of local and advanced disease, the comparison between T1+T2 vs. T3+T4 patients identifies two
significantly different groups. This confirms the effectiveness of T status in predicting the outcome and grouping
patients with comparable prognosis. The power of T
stage explains why patients with low N categories, that
in our experience are often associated with a high-T,
faired worse than those with advanced N. Regarding
the peculiar results we obtained in the analysis of subgroups of N stage, we have to remember that such small
numbers hinder any reasonable comments.
The overall downstaging observed in the 5th edition
of the AJCC staging system will be critical for the
stratification of patients in future trials. In the last
decade in our center as well as in others, chemotherapy
was administered only to pediatric patients with advanced disease (i.e., T3-T4 or stage IIIIV). If this
treatment policy would be maintained, the wide clinical
adoption of the 5th edition will possibly lead to a
decrease in the number of patients receiving chemotherapy.