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,2R. 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

Background: New criteria for classifying nasopharyngeal car-cinoma were defined in the 5th edition of the American JointCommittee on Cancer (AJCC) staging manual. We investigatedthe clinical implications of the new system by comparing itwith the 4th edition in a cohort of pediatnc undifferentiatednasopharyngeal carcinoma (UNPC).

Patients and methods: We retrospectively restaged 54 patientsyounger than 17 years who had biopsy-proven UNPC, treatedbetween 1965 and 1999 in a single institution.

Results: Using the 5th edition an overall downstaging of thepopulation according to T status, N status, and stage groupingwas evident along with a better correlation with likelihood of

survival. The comparison between local and advanced diseaseaccording to T stage (T1+T2 vs. T3+T4) became highly signifi-cant in the new system (P = 0.0011 vs. P = 0.067 in the 4thedition).

Conclusions: As far as prognostic categories are concerned,the 5th edition of the AJCC staging manual appears to be animprovement over the previous classification, even though forpediatric patients a uniform distribution among stages cannotbe observed because most children present with advanceddisease. The overall downstaging should be taken into consid-eration for the stratification of patients in future trials.

Key words: childhood head and neck cancer, comparison,nasopharyngeal carcinoma, prognosis, tumor staging

Introduction

Nasopharyngeal carcinoma is a common tumor of thehead and neck in adults, but it is very rare in children.The incidence varies widely depending on geographicaland racial factors. In the US and Europe nasopharyngealcarcinoma represents less than 1% of all pediatric malig-nancies and approximately one third of primary malig-nant tumors occurring in the nasopharynx (the inci-dence of nasopharyngeal lymphomas or sarcomas ishigher in the young) [1]. Children with nasopharyngealcarcinoma differ from their adult counterparts in thatthey have a close association with Epstein-Barr virusinfections [2]. As far as histopathologic classification isconcerned, the World Health Organization has simplifiedand clarified typing of nasopharyngeal epithelial tumorswith three different groups: 1) keratinizing squamouscell carcinoma, 2) non-keratinizing carcinoma, and 3)undifferentiated nasopharyngeal carcinoma (UNPC)[3]. Children and adolescents almost always have theUNPC variant, which is closely related to a higher rateof advanced locoregional disease and distant metastases[4-11]. Several classifications for nasopharyngeal carci-noma have been formulated, however the most popularin Western countries is the American Joint Committeeof Cancer (AJCC) staging system. The 5th edition ofthis classification was designed to merge the best pre-

dictive factors of the 4th edition and the Ho stagingsystem which is the most frequently applied to Asianpopulations [12]. To assess the value of this new classi-fication in pediatric age we applied it to a series ofpatients treated in a single institution. There is no studycomparing the 5th edition of the AJCC staging systemwith the previous one in this cohort of patients, the onlypublished experience in adult squamous cell carcinomaof the nasopharynx [13].

Patients and methods

Over a period of 34 years, from July 1965 lo September 1999. 54patients with a diagnosis of UNPC were treated at the Pediatric andRadiotherapy 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 takenfrom the nasopharyngeal mass in 37% of cases, from the metastaticadenopathy in 39%, and from both sites in 24%. In all patients anasopharyngeal mass was clinically delectable, cervical adenopathieswere observed in 53 patients and distant metaslases in 5. For thepurpose of this analysis all tumors were restaged according to thecriteria of both the 4th and 5th edition [14. 15] of the AJCC stagingsystem (Tables 1 and 2). All base-line clinical and radiographic datawere available at our institution. All patients had complete clinicalexaminations including indirect mirror examination of nasopharynxand direct nasopharyngoscopy up until 1989. and direct flexible orrigid fibreoptic nasopharyngoscopy thereafter. Plain films of the naso-

by guest on April 10, 2015

http://annonc.oxfordjournals.org/D

ownloaded from

1158

Table I The 4th edition of the AJCC staging system.

Tl Tumor limited to one subsite of nasopharynx.T2 Tumor invades more than one subsite of nasopharynxT3 Tumor invades oropharynx and/or nasal cavity.T4 Tumor invades skull and/or cranial nerves.

NO No regional lymph node metastasisN1 Single ipsilateral lymph node measuring < 3 cm in greatest

dimensionN2 Single ipsilateral lymph node measuring > 3 cm but not

> 6 cm in greatest dimension; or multiple lpsilateral lymphnodes, none measuring > 6 cm, or in bilateral or contro-lateral lymph nodes, none measuring > 6 cm in greatestdimensionN2a: Metastasis in single ipsilateral lymph node measur-

ing 3-6 cm in greatest dimensionN2b: Metastases in multiple ipsilateral lymph nodes,

none measuring > 6 cm.N2c Metastases in bilateral or controlateral lymph nodes.

none measuring > 6 cm in greatest dimension.N3 Massive ipsilateral lymph node(s), bilateral or controlateral

lymph node(s)MO No distant metastases.Ml Distant metastases.

Stage I TINOMO.Stage II T2N0M0.Stage 111 T3NOMOorTl-3NlMO.Stage IV T4(any N ) o r N2-3 (anyT) or Ml (anyT, any N)

Table 2 The 5th edition of the AJCC staging system

TlT2

T3

T4

NO

Nl

N2

N3

MOMl

Stage IStage MAStage 11B

Stage 111

Stage IVAStage 1VBStage 1VC

Tumor confined to the nasopharynx.Tumor extends to soft tissue of nasopharynx and/ornasal fossa.T2a: without parapharyngeal extension.T2b. wilh parapharyngeal extentionTumor invades bony structures and/or paranasalsinuses.Tumor with intracranial extension and/or involvementof cranial nerves, infratemporal fossa, hypopharynx, ororbit.

No regional lymph node metastasisUnilateral metastasis lymph node(s) measuring < 6 cmin greatest dimension above the supraclavicular fossa.Bilateral metastases in lymph node(s) measuring < 6 cmin greatest dimension above the supraclavicular fossaMetastasis in a lymph node(s):(a) > 6 cm in greatest dimension:(b) extention to the supraclavicular fossa.No distant metastasesDistant metastases

TlT2aTlT2aT2bTlT2T3T4AnyTAnyT

NONONlNlNO-1N2N2NO-2NO-2N3Any N

MOMOMOMOMOMOMOMOMOMOMl

pharynx with tomograms of the base of skull were performed until1978. Computer tomography became available in 1979 and magneticresonance imaging in 1985. Size, position, laterality, and multiplicity ofthe cervical node metastases were recorded for each patient. Cervicalnerve palsy was assessed clinically. Routine systemic investigationincluded chest radiography, liver ultrasonograms, skeletal survey and/or bone scans. Unfortunately climco-radiographic data in each patientwere not complete enough to identify the extent of the parapharyngealtumor, so we could not subdivide the T2 stage into T2a and T2b, assuggested in the 5th edition of the AJCC staging system. All patientsreceived conventional fractionation radiotherapy for the primarytumor and cervical adenopathies with a median dose of 60 Gy (range55-70 Gy), as well as for uninvolved cervical areas with a median doseof 45 Gy (range 40-55 Gy). From 1970 onwards, patients withadvanced disease also received chemotherapy with different schedulesthrough the years [5-6]. Once off therapy, patients were regularlyexamined in the outpatient clinic every two months for the first year,every three months in year 2, and bi-annually to annually thereafterThe median follow-up was 126 months (range 9-396); no patient waslost at follow-up. The survival curves were actuarial measurementsfrom the date of diagnosis till the date of death or last follow-up inJanuary 2000 as calculated by the Kaplan-Meier method [16]. Thedifferences between the curves were compared by log-rank test, withP-values less than 0.05 being considered to be significant [17].

Results

Distribution of all the 54 patients according to theextent of primary tumor and nodal involvement by the4th edition of the AJCC staging manual is shown inTable 3, and by the 5th edition in Table 4. By the 5thedition, an overall downstaging according to T and Nstatus is evident: by the 4th edition, T3+T4 patients were81.5% 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 groupingaccording to the two classifications. Even if a migrationin lower categories was confirmed (stage IV 98% in 4thedition and 58% in the 5th), the new system was not ableto assign patients to the more uniformly sized stagegrouping observed in adults because a great proportionof patients presented advanced disease. However thenew system does correlate stage and likelihood of sur-vival 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. Thedifferences between these percentages was not statisti-cally significant (P = 0.0825). No comparison can bemade according to the 4th edition as 53 of 54 patientswere in stage IVand only one in stage III.

Considering the T status separately, the new systemseparated patients into cohorts of more equal size andwell-separated from a prognostic point of view. Thedifference between local and advanced disease (Tl +T2vs. T3+T4) became highly significant in the last edition:P = 0.0011 in the 5th edition vs. P = 0.067 in the 4thedition. In Figures 2 and 3 actuarial survival ratesaccording to T status are shown. For disease staged bythe 4th edition of the AJCC staging system, a problem isevident: the survival rates at 5 and 10 years for T1+T2patients (calculated together because only one patientwas classified as Tl) and T3 patients are not clearlyseparated. On the contrary, the 5th edition highlights

by guest on April 10, 2015

http://annonc.oxfordjournals.org/D

ownloaded from

1159

Table 3 T and N distribution according to the 4th edition of the AJCC staging manual.

Primary tumorTlT2T3T4All T (%)

Nodal involvement

NO

1(1.8)

Nl1-

-

45(9.3)

N2a-

-

144(7.4)

N2b-

355

13(24.1)

N2c-

173

11 (20.4)

N3-

587

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 tumorTlT2T3T4All T (%)

NO-

_

11(1.8)

Nl3393

18(33 3)

N2126-

9(16.7)

N3a3442

13(24 1)

N3b1363

13(24.1)

All N (%)8(14.8)

12(22.2)25 (46.3)9(16.7)

54(100)

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

4th edition of theAJCC (%)

5th edition of theAJCC (%)

Stage IStage IIStage IIIStage IV

001(2)

53(98)

06(11)

16(30)32(59)

the differences between advanced and local disease evenif the curves of Tl and T2 patients are essentially thesame.

Irrespective of the T stage classification, survivalcorrelates poorly with N stage both in the 4th and 5theditions of the AJCC staging manual. The five-yearsurvival rates inappropriately increase from Nl to N2stage in the 4th edition (Figure 4); in the 4th edition Nlpatients have the worst prognosis (even worse than N3patients), while in the 5th edition (Figure 5) Nl and N3patients have a similar outcome (44.4% vs. 48.8% at fiveyears). A partial explanation for this observation is that80% of Nl patients in the 4th edition and 66.6% in the5th edition are associated with advanced T stage.

The subclassification in N3a (lymphnodal metastasisgreater than 6 cm in greatest dimension) and N3b(extention to the supraclavicolar fossa) of the 5th editionseems to have minor prognostic significance in ourexperience (five-year survival 50.7% vs. 48.3%). Con-versely, the subdivision of N2 patients in the 4th editionidentifies three different populations with survival ratesthat surprisingly increase from N2a to N2c stage. Allthe four patients classified as N2a died with a mediansurvival of 23 months; the five-year survival was 72.7%for the 13 N2b patients and 90.1% for the 11 N2cpatients (P = 0.003).

Discussion

Among different classifications formulated for naso-pharyngeal cancer, the most popular in Western coun-tries is the AJCC staging system, while in Easterncountries the most utilized is the Ho classification [12].

Between 1977 and 1992, four different editions of theAJCC system were proposed with relatively few changes.While in the 1st edition of 1977 the T category wasdefined according to maximum primary tumor diame-ter, in the following editions of 1983, 1988 and 1992 itwas assigned according to anatomic extent. In the 1stand 2nd edition the bilateral nodal involvement wasdesignated as N3b, whereas it became N2c in the 3rdand 4th version [14].

There are two major differences between the Hostaging system and the 4th edition of the AJCC. Firstly,the Ho system classifies all nasopharyngeal tumors con-fined within the nasopharynx in the Tl status, whereasin the AJCC systems tumors that involve more thanone subsite of the nasopharynx are designated as T2.Secondly, the Ho system categorizes lymph node diseaseby its anatomic position (Nl = upper cervical region,N2 = lower cervical region, and N3 = supraclavicularregion) whereas in the AJCC system lymph node cate-gories are based on the size of the largest lymph node,the number of involved lymph nodes, and the presenceor absence of controlateral disease [13]. Recent inter-national discussions have lead to the creation of the 5thedition of the AJCC staging system, that seeks to mergethe most predictive factors of previous classifications [15].

Due to the rare occurrence of UNPC in childhood,few institutions have acquired substantial experience inits treatment, and published clinical studies consist ofsmall series accrued over long periods (4-8). Conse-quently, refinement of the AJCC system in pediatricpopulation has been hindered by relatively infrequent

by guest on April 10, 2015

http://annonc.oxfordjournals.org/D

ownloaded from

1160

I>Ou.O>

CD 1 -

M , 8 -

Oo

t5m

Sa.

,6 -

,4 -

,2 -

o -

O 5 O 2OO 25O1OO 15OMONTHS

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

by guest on April 10, 2015

http://annonc.oxfordjournals.org/D

ownloaded from

1162

of early distant metastases, and the possibility of micro-metastases present at the time of diagnosis [4-11]. De-spite this bias, which should reduce the distance betweenthe curves of local and advanced disease, the compar-ison between T1+T2 vs. T3+T4 patients identifies twosignificantly different groups. This confirms the effective-ness of T status in predicting the outcome and groupingpatients with comparable prognosis. The power of Tstage explains why patients with low N categories, thatin our experience are often associated with a high-T,faired worse than those with advanced N. Regardingthe peculiar results we obtained in the analysis of sub-groups of N stage, we have to remember that such smallnumbers hinder any reasonable comments.

The overall downstaging observed in the 5th editionof the AJCC staging system will be critical for thestratification of patients in future trials. In the lastdecade in our center as well as in others, chemotherapywas administered only to pediatric patients with ad-vanced disease (i.e., T3-T4 or stage IIIIV). If thistreatment policy would be maintained, the wide clinicaladoption of the 5th edition will possibly lead to adecrease in the number of patients receiving chemo-therapy.

References

1 Ingersoll L. Woo SY. Donaldson S et al Nasopharyngeal carci-noma in the young. A combined M.D. Anderson and Stanfordexperience. Int J Radiat Oncol Biol Phys 1990; 19: 881-7.

2. Hawkins EP, Krischer JP, Smith BE et al. Nasopharyngeal carci-noma in children - a retrospective review and demonstration ofEpstein- Barr viral genomes in tumor cell cytoplasm. A report ofthe Pediatnc Oncology Group. Human Pathol 1990: 21: 805-10.

3. Shanmugaratnam K. Chan SH, de-The G et al. Histopathologyof nasopharyngeal carcinoma. Correlation with epidemiology,survival rates and other biological characteristics. Cancer 1979,44: 1029-44.

4 Lombardi F. Gaspanni M. Gianni C et al. Nasopharyngealcarcinoma in childhood. Med Pediatr Oncol 1982; 10: 243-50.

5. Gaspanni M. Lombardi F. Rottoli L et al. Combined radio-therapy and chemotherapy in stage T3 and T4 nasopharyngealcarcinoma in children. J Clin Oncol 1988; 6: 4914.

6. Ayan I. Altun M Nasopharyngeal carcinoma in children: Retro-

spective review of 50 patients. Int J Radiat Oncol Biol Phys 1996;35: 485-92.

7. Strojan P, Benedik MD, Kragelj B, Jereb B. Combined radiationand chemotherapy for advanced undifferentiated nasopharyngealcarcinoma in children. Med Pediatr Oncol 1997; 28: 366-9.

8. Ghim TT, Briones M, Mason P et al Effective adjuvant chemo-therapy for advanced nasopharyngeal carcinoma in children: Afinal update of a long-term prospective study in a single institu-tion. J Pediatr Hematol Oncol 1998; 20: 131-5.

9. Sahraoui S, Acharki A, Benider A et al. Nasopharyngeal carcino-ma in children under 15 years of age: A retrospective review of 65patients. Ann Oncol 1999, 10: 1499-502.

10. Wolden SL, Steinherz PG, Kraus DH el al. Improved long-term survival with combined modality therapy for pedialricnesopharynx cancer. Int J Radiat Oncol Biol Phys 2000: 46:859-64.

11 Zubizarreta PA, D'Antonio G, Raslawski E et al Nasopharyngealcarcinoma in childhood and adolescence- A single-institutionexperience with combined therapy. Cancer 2000; 89: 690-5.

12. Ho JHC. Stage classification of nasopharyngeal carcinoma: Areview. In De-The G, Eto Y (eds): Nasopharyngeal Carcinoma:Etiology and Control. IARC Scientific Publications No. 20. Lyon:International Agency for Research on Cancer 1978; 99-113.

13. Cooper JS, Cohen R, Stevens RE. A comparison of stagingsystem for nasopharyngeal carcinoma Cancer 1998; 83: 213-9.

14. Fleming ID, Cooper JS, Henson DE et al. (eds). AJCC CancerStaging Manual, 5th edition. Philadelphia. Lippincott-Raven 1997;31-9.

15. Beahrs OH. Henson DE, Hutter RVP, Kennedy BJ (eds). Manualfor Staging of Cancer, 4th edition. Philadelphia: J.B. Lippincott1992, 33-8.

16 Kaplan E, Meier P. Nonparametric estimation from incompleteobservations. J Am Stat Assoc 1958; 53- 457-81.

17. Mantel N. Evaluation of survival data and two rank order statis-tics arising in its consideration. Cancer Chemother Rep 1974; 50:163-70.

18. Al-Sarraf, LeBlanc M, Giri PGS et al. Chemoradiotherapy vs.radiotherapy in patients with advanced nasopharyngeal cancer'Phase 111 randomized intergroup study 0099 J Clin Oncol 1998:16. 1310-7.

Received 23 January 2001; accepted 20 March 2001.

Correspondence toM. Casanova, MDPediatric Oncology UnitIstituto NazionaleTumoriVia G.Venezian. 120133 MilanoItalyE-mail: casanova@istitutotumon.mi.it

by guest on April 10, 2015

http://annonc.oxfordjournals.org/D

ownloaded from