Serous Otitis Media An
Opportunity for Early Recognition of Nasopharyngeal Carcinoma
Jonathan S.
T.
Sham, MBBS, DMRT, FRCR; William
I. Wei, MBBS, DLO, FRCS; S. K. Lau, MBBS, C. C. Yau, MBBS, MRCP, FRCR; D. Choy, MBBS, DMRT, FRCR
In a prospective study of 271 new patients with nasopharyngeal carcinoma, 36 (13.3%) were found to have cranial
\s=b\
nerve involvement. Serous otitis media (SOM) was found in 98 (41.4%) of 237 patients who had undergone complete otologic assessment. The local control of tumor and actuarial survival of three subgroups of patients, namely, 80 patients with SOM only, 11 patients with cranial nerve palsy only, and 18 patients with both SOM and cranial nerve palsy, were analyzed. The local control of tumor was better in patients with SOM alone than in those with cranial nerve palsy alone; those patients with both SOM and cranial nerve involvement had worse local control as well as survival. As SOM is not uncommon in the diagnosis of nasopharyngeal carcinoma, and adult-onset SOM is otherwise distinctly uncommon, this provides a good opportunity for early recog-
nition and, cinoma.
perhaps,
better control of
nasopharyngeal
car-
(Arch Otolaryngol Head Neck Surg. 1992;118:794-797) the malignant tumors of the head and neck re¬ gion, those in the nasopharynx often escape early detection. The nasal symptoms of nasopharyngeal carci¬ noma (NPC) are often nonspecific. The nasopharynx is difficult to examine, and cancers in this region are not un¬ commonly involved submucosally.1"3 Both cranial nerve palsy4"9 and symptoms referable to the ear have been asso¬ ciated with NPC. It has been an established teaching that NPC is associated with ear symptoms and conduction deafness,10"15 and NPC should be considered in the differ¬ ential diagnosis of an adult presenting with serous otitis media (SOM).1619 Although as early as 1938 Furstenberg20 had advocated that ear symptoms should be one of the things to consider in the early diagnosis of NPC, little information has been reported subsequently on the prognostic value of SOM in NPC, and its role in the early recognition of this tumor has not been stressed. More recently, a report was published that challenged the practice of exclusion of NPC for patients with adult-onset SOM.21
Among
Accepted for publication
October 17, 1991.
Departments of Radiotherapy and Oncology (Drs Sham, Yau, and Choy) and Surgery (Drs Wei and Lau), University of Hong Kong and Queen Mary Hospital, Hong Kong. Reprints not available. From the
DLO, FRCS;
In the 1960s, authors had written specifically on the neurologic manifestations of NPC and hoped that recog¬ nition of the association may result in earlier diagnosis and, hence, better control of the disease.6-7 Unfortunately, the improvement in treatment results in such patients has been modest despite recognition of such association and ad¬ vancement of
In this
radiotherapy.22-23
article,
we
review
our
experience with an ongo¬
ing prospective study on SOM and cranial nerve palsy in patients with NPC and explore the relationship between the two and the prognostic value of each. Between
PATIENTS AND METHODS January 1987 and December 1988, 271
new cases
of
histologically proven nasopharyngeal carcinoma were diagnosed in the Department of Radiotherapy and Oncology and the Department of Surgery, University of Hong Kong and Queen Mary Hospital, Hong Kong. In addition to other staging proce¬ dures, these patients were assessed for cranial nerve palsy and
SOM. The assessment for cranial nerve palsy was by clinical exami¬ nation. Otologie assessments to document SOM included otoscopy for evidence of effusion, pure-tone audiometry, and tympanometry. Serous otitis media is considered present when effusion is detected behind the tympanic membrane and there is an air-bone gap of 10 dB or more on a pure-tone audiogram. The tympanometry test result supplements the above findings. One hundred nine of these 271 patients who had documented cranial nerve palsy or SOM at diagnosis formed the basis of the present study. Seven patients with cranial nerve palsy but who had not completed the otologie assessment were excluded from the analysis on local control and survival, as the reason for not completing the otologie assessment in some patients was poor performance status at diagnosis, which may bias the result of the survival analysis. This group of patients was treated primarily with external ra¬ diotherapy as described by Ho.24 Thirty-one of them were treated using the split-field technique, which employed two lateral opposing facial fields and one anterior facial field for the primary tumor, while the neck was treated concurrently with a matching anterior cervical field. For 19 of these patients, a central tumor dose of 3.5 Gy per fraction was given three times per week up to 59.5 Gy. For the other 12 patients, the central tumor dose of 2.0 Gy per fraction was given daily to a total dose between 62 and 68 Gy. Sixty-two patients were treated using lateral opposing faciocervical fields for the initial phase of treatment and a midplane tumor dose of 2.5 Gy per fraction was given four times per week
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Table 1.—Breakdown of 271 Patients According to Presence of Serous Otitis Media (SOM) and Cranial Nerve Palsy* Cranial Nerve
Table 2.—Local Tumor Control by the Extent of Cranial Nerve Involvement*
Palsy
-1
Without
With
128
11
80
18
No SOM
With SOM
Incomplete otologie
assessment
for SOM *P=.0266.
27
7
or
No Local
Relapse
Relapsed Locally
One
6
6
Two
6
4
Three
3
4
More than three
7
*/-=.1085.
Table 3.—Sex and
Age Distribution of 109 Patients With
Serous Otitis Media (SOM)
-1
Male
Female
61
19
9
2
15
3
only
Cranial nerve palsy only Both SOM and cranial nerve palsy
or
Cranial Nerve
Palsy
Age Group, yt
Sex*
SOM
Persistent Local Disease
No. of Cranial Nerves Involved
10-19
20-29
-1 30-39 40-49 50-59 70-79 60-69
1
14
19
24
18
4
2
4
2
2
6
3
6
1
...
...
1
...
1
1
...
*P=.7656. +P=.2398.
Gy, while the neck was treated concurrently with a matching lower anterior cervical field. Phase two treatment was given using the split-field technique that employed two lateral opposing facial fields and one anterior facial field; a central tumor dose of 3.5 Gy per fraction was given three times per week for another 21 Gy. Another 13 patients were treated by the same technique but were given 2 Gy per fraction daily throughout, up to between 60 and 70 Gy. Three patients died before the course of radiotherapy was completed. Response to therapy was documented by endoscopy and serial up to 40
Table
4.—T-Stage Distribution of
Serous Otitis Media (SOM)
or
109 Patients With Cranial Nerve Palsy* T1
SOM
only
Cranial nerve palsy only Both SOM and cranial nerve *P=.0001.
T3
T4
63
4
13
...
...
...
...
or
T2
11
palsy
18
biopsy.25 Patients with a disease-free interval of 3 months or less
considered as having persistent disease. Patients with doc¬ umented complete remission were followed up every 6 weeks for the first year, every 2 months for the second year, and every 3 months for the third year. Endoscopy was used when examina¬ tion of the nasopharynx was inadequate in the follow-up. One hundred seven of 109 patients had complete follow-up; the follow-up duration ranged from 16 to 39 months, the median follow-up being 25 months. The correlation between cranial nerve palsy and SOM and their prognostic significance on local control of tumor as well as sur¬ vival were studied. The actuarial disease-free survival and actu¬ arial survival were computed by the Kaplan-Meier method, and the difference between curves were tested by the Mantel-Cox
were
test.26-27
RESULTS In the whole group of 271 patients, otologie assessment for SOM was not completed in 34 because of preexisting ear disease or poor performance status. Ninety-eight (41.4%) of the remaining 237 patients had SOM at sis (Table 1), the involvement being bilateral in seven pa¬ tients. One hundred thirty-nine patients had no evidence of SOM. For the 98 patients with SOM, 77 had related symptoms such as tinnitus and deafness, lasting 1 to 15 months; the mean duration of symptoms was 3.5 months. Among the same group of 271 patients, 36 suffered from
diagno¬
cranial nerve palsies at diagnosis. Three of patients had isolated 12th-nerve palsy, and these patients had no symptoms attributable to the 12thnerve palsy. For the remaining 33 patients, the duration of one or more
these three
symptoms ranged from duration
was
1 week to 12 3.3 months.
months; the
mean
The sixth cranial nerve was the most commonly in¬ volved (26 [72.2%] of 36), followed by fifth (16 [44.4%] of 36), fourth (13 [36.1%] of 36), third (10 [27.8%] of 36), and then the last four cranial nerves (10 [27.8%] of 36). The trend was toward associating more extensive cranial nerve involvement with worse local control. Local control failed in all patients who had more than three cranial nerves in¬ volved (Table 2). The occurrence of SOM and cranial nerve palsy were correlated (P=.0266). There were 80 patients with SOM only, 11 patients with cranial nerve palsy only, 18 patients with both SOM and cranial nerve palsy, and seven patients with cranial nerve palsy but incomplete otologie assess¬ ment (Table 1). Only the former three subgroups of patients were analyzed for tumor control and actuarial survival. The sex and age distribution among the three subgroups of patients with SOM only, cranial nerve palsy only, or both, were comparable (Table 3). Patients with cranial nerve palsy alone or in association with SOM had signif¬ icantly more advanced disease compared with the sub¬ group with SOM only (P=.0001) (Table 4); this is not un¬ expected as patients with cranial nerve palsy will automatically be staged as T4 in the American Joint Com¬ mittee for Cancer Staging system,28 while SOM has no bearing on the staging. The local control and survival of the three subgroups of patients are shown in Figs 1 and 2 and summarized in Ta¬ ble 5. The local control of tumor was better in patients with SOM alone than in those with cranial nerve palsy alone.
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Fig 1.—Local tumor control of patients with serous otitis media (SOM), cranial
nerve
2.—Actuarial survival of patients with serous otitis media (SOM), cranial nerve palsy (CNP), and both SOM and CNP (Both); P=.0001.
Fig
palsy (CNP), and both SOM and CNP (Both); P=.0001.
Table 5.—Local Tumor Control and Survival of 109 Patients With Serous Otitis Media (SOM)
Relapse
Alive With No Evidence of Disease or With Disease
Died of Disease
63
17
61
16
6
5
8
3
5
13
4
14
Persistent Local Disease or
SOM
Relapsed Locally
only
Cranial nerve palsy only Both SOM and cranial nerve
palsy
or
No Local
Cranial Nerve
Palsy*
Unavailable for Follow-up or Died of Intercurrent Disease
*P=.0001.
Those ment
patients with both SOM and cranial nerve involve¬
had
worse
local control
as
well
as
survival.
COMMENT manifestations of nasopharyngeal carci¬ Neurologic Its occur¬ noma at diagnosis has been well rence is the result of the infiltrative nature of this tumor, its proximity to the base of the skull, and the proximity of the parapharyngeal nodes to the cranial nerves leaving the
recognized.4"9
skull.7-29
Interestingly, the majority of cases of neurologic manifestations were the result of tumor involvement of the intracranial or extracranial portion of cranial nerves; few were the result of direct involvement of the brain. In fact, Ho8 has not seen one well-documented case of brain me¬ tastasis in his long practice treating NPC, and cases strongly suspicious of brain metastasis from NPC have been proven wrong by subsequent studies.30 The findings of our study agree with those of Thomas and Waltz7 that, despite proximity of the tumor to the cra¬ nial nerves, isolated involvement of the cranial nerves does occur and may lead to a wrong diagnosis, if it is presumed that cranial nerve involvement by NPC is invariably mul¬ tiple. The results of our study also confirmed that patients with isolated involvement of the cranial nerves fared bet¬ ter than those with more extensive involvement (Table 2).2 In many patients, the nonspecific nature of the early symptoms such as nasal obstruction and bleeding and the inaccessibility of the nasopharynx to examination had re¬ sulted in a delay in diagnosis, sometimes not until the manifestation of neurologic signs and symptoms. The re¬ ported frequency of cranial nerve palsy at diagnosis ranged from 25% to 50%. The rate of 13.3% in the present series and the comparable low rate in another series reported from Hong Kong31 seems to indicate that our pa¬ tients were diagnosed at an earlier stage. This is not unex-
as NPC is a common cancer in this part of the world; our medical professionals and the public are more
pected, aware
of this disease.
However, early diagnosis has only been achieved inso¬
far
as the percentage of patients with cranial nerve palsy diagnosis is smaller. Those patients with cranial nerve palsy are, nevertheless, suffering from advanced disease; their prognosis is no better than it was for those with cra¬ nial nerve palsy decades ago. Expectations that treatment result may improve with advancement in radiotherapy treatment machines and perhaps earlier diagnosis6"7 have not been realized. The poor treatment result of patients with cranial nerve palsy in the present series was despite
at
technical refinements: use of a simulator for localization, head casts for beam direction as well as immobilization, and radiotherapy with linear accelerators. It had also been recognized for a long time that NPC is associated with SOM.16"19 The present study confirmed the association; SOM is present in 41.4% of our patients at di¬ agnosis. The treatment of SOM in patients with NPC is simple32 but is not without complications.33 The optimal treatment of such patients has not been determined. The significance of SOM, other than as a source of morbidity, is its impact on prognosis and its role in early recognition of the disease. Sham et al34 had shown the adverse prog¬ nostic effect of ear symptoms in patients with Tl and T2 tumors. Serous otits media in patients with NPC is asso¬ ciated with the parapharyngeal extension of tumor,35-36 and parapharyngeal extension of tumor has been shown to be an important adverse prognostic factor.37 It would not be surprising to find SOM associated with adverse prognosis. Serous otitis media and cranial nerve palsy is associated (Table 1). The worst prognosis of those patients with both SOM and cranial nerve palsy among the three subgroups seems to indicate that SOM and cranial nerve palsy are, at
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least, partly independent prognostic factors
on local con¬ trol. The adverse prognostic effect of SOM was less grave compared with that of cranial nerve palsy, as evident from the significantly better local control for patients with SOM than for those with cranial nerve palsy. However, we have shown that the mean duration of symptoms relating to cranial nerve palsy was no longer than the mean duration of auditory symptoms relating to SOM, indicating that tu¬ mors associated with SOM may not be at an earlier stage of development than tumors associated with cranial nerve palsy. The basis for the deleterious effect of cranial nerve involvement on the local control of NPC needs further in¬ vestigation. The fluctuation in absorbed dose in the neigh¬ borhood of an interface between different materials, such as between the brain and the skull base and between the bony wall and air content of the sinuses, may be an impor¬ tant factor.38 As SOM is not uncommon at the diagnosis of NPC, and adult-onset SOM is otherwise distinctly uncommon,39 this provides a good opportunity for early recognition of NPC. Furthermore, the treatment result for NPC patients with SOM is better than that for NPC patients with cranial nerve palsy, if clinicians are more alert to the association between NPC and SOM.40 Early recognition of the disease may re¬ sult in improvement in survival. Although NPC is so rare in the white patient that investigations to exclude or con¬ firm NPC in a white adult presenting with SOM may not be warranted,21 the converse will be true for individuals of southern Chinese or northern African origin. With the in¬ crease in migration and integration of people of different ethnic origin, the importance of NPC in the practice of cli¬ nicians in the western countries will increase.
This study was supported by grants from the Asian Oceanian Clin¬ ical Oncology Association Hong Kong, the Hong Kong Jockey Club (Charity) Ltd, and Croucher Foundation, Hong Kong. References 1. Simmons MW, Ariel IM. Carcinoma of the
nasopharynx: report of 150 Surg Gynecol Obstet. 1949;88:763-775. 2. Vaeth JM. Nasopharyngeal malignant tumors: 82 consecutive patients treated in a period of twenty-two years. Radiology. 1960;74:364-372. cases.
3. Sham JST, Wei WI, Kwan WH, Chan CW, Choi PHK, Choy D. Fibreoptic endoscopic examination and biopsy in determining the extent of
nasopharyngeal
carcinoma. Cancer. 1989;64:1838-1842. 4. Woltman HW. Malignant tumors of nasopharynx with involvement of
system. Arch Neurol
Psychiatry. 1922;8:421-429. Ophthalmologic and neurologic symptoms at malignant nasopharyngeal tumors: clinical study comprising 454 cases with special reference to histopathology and possibilities of earlier recognition. Acta Otolaryngol (Stockh). 1944;59:319-323. 6. Godtfredsen E, Lederman M. Diagnostic and prognostic roles of ophthalmoneurologic signs and symptoms in malignant nasopharyngeal tumors. Am J Ophthalmol. 1965;59:1063-1069. 7. Thomas JE, Waltz AG. Neurological manifestations of nasopharyngeal malignant tumors. JAMA. 1965;192:103-106. 8. Ho JHC. An epidemiologic and clinical study of nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 1978;4:183-198. 9. Huang SC. Nasopharyngeal cancer: a review of 1605 patients treated radically with cobalt 60. Int J Radiat Oncol Biol Phys. 1980;6:401-407. 10. New GB. Syndrome of malignant tumors of the nasopharynx. JAMA. nervous
5. Godtfredsen E.
1922;79:10-14.
11. Simmons MW, Ariel IM. Carcinoma of the cases.
Surg Gynecol Obstet. 1949;88:763-775.
nasopharynx: report of 150
12. McConnell EM. Nasopharyngeal carcinoma in children and young adults. Br J Cancer. 1958;12:195-201. 13. Crowe SJ, Baylor JW. Benign and malignant growths of the nasopharynx and their treatment with radium. Arch Surg. 1923;6:429-488. 14. Christianson O, MacArthur SW. Nasopharyngeal carcinoma. Arch
Surg. 1933;27:1109-1119.
15. Choa G. Nasopharyngeal carcinoma. J Laryngol Otol. 1974;8:145\x=req-\ 148. 16. Trotter W. On certain clinically obscure malignant tumours of the na-
sopharyngeal wall. BMJ. 1911;2:1057-1059. 17. Neel HB. Nasopharyngeal carcinoma: clinical presentation, diagnosis, treatment and prognosis. Otolaryngol Clin North Am. 1985;18:479-490. 18. Booth JB: Otitis media with effusion. In: Booth JB. Otology. Stoneham, Mass: Butterworths; 62-87. 19. Wei WI, Lund VJ, Howard DJ. Serous otitis media in
malignancies of nasopharynx and maxilla. J Laryngol Otol. 1988;102:129-132. 20. Furstenberg AC. Malignant neoplasms of the nasopharynx. Surg Gy-
the
ncol Obstet. 1938;66:400-404. 21. Dempster JH, Simpson DC. Nasopharyngeal neoplasms and their association with adult onset otitis media with effusion. Clin Otolaryngol.
1988;13:363-365. 22. Stillwagon GB, Lee DJ, Moses H, Kashima H, Harris A, Johns M. Response of cranial nerve abnormalities in nasopharyngeal carcinoma to radiation therapy. Cancer. 1986;57:2272-2274. 23. Chen MS, Lin FJ, Tang SG, Leung WM, Leung W. Clinical significance of cranial nerve deficit in the therapy of nasopharyngeal carcinoma. Br J Radiol. 1989;62:739-743. 24. Ho JHC. Nasopharynx. In: Halnan KE: Treatment of Cancer. London, England: Chapman and Hall Ltd; 1982:249-267. 25. Sham JST, Wei WI, Kwan WH, Chan CW, Kwong WK, Choy D. Nasopharyngeal carcinoma: pattern of tumor regression after radiotherapy.
Cancer. 1990;65:216-220. 26. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481. 27. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719-748. 28. American Joint Committee for Cancer Staging and End Result Reporting. Manual for Staging of Cancer. Chicago, Ill: American Joint Committee for Cancer Staging; 1978. 29. Del Regato JA. The neurological manifestations of cancers of the nasopharynx. Bull St Louis Med Soc. 1946;40:331-332. 30. Annis JA, Phelps PD, Croft CB. A revealing CT examination in nasopharyngeal carcinoma. J Laryngol Otol. 1989;103:801-802. 31. Leung SF, Tsao SY, Teo P, Foo W. Cranial nerve involvement by nasopharyngeal carcinoma: response to treatment and clinical significance. Clin Oncol. 1990;2:138-141. 32. Chowdhury CR, Ho HC, Wright A, Tsao SY, Au GK, Tung Y. Prospective study of the effects of ventilation tubes on hearing after radiotherapy for carcinoma of nasopharynx. Ann Otol Rhinol Laryngol. 1988;97:142-145. 33. Wei WI, Engzell UCG, Lam KH, Lau SK. The efficacy of myringotomy and ventilation tube insertion in middle-ear effusion in patients with nasopharyngeal carcinoma. Laryngoscope. 1987;97:1295-1298. 34. Sham JST, Choy D. Prognostic factors of nasopharyngeal carcinoma: a review of 759 patients. Br J Radiol. 1990;63:51-58. 35. Sato H, Kurata K, Yen YH, Honjo I, Young YH, Hsieh T. Extension of nasopharyngeal carcinoma and otitis media with effusion. Arch Otolaryngol Head Neck Surg. 1988;114:866-867. 36. Sham JST, Wei WI, Lau SK, Yau CC, Choy D. Serous otitis media and paranasopharyngeal extension of nasopharyngeal carcinoma. Head Neck. In press. 37. Sham JST, Choy D. Prognostic value of paranasopharyngeal extension of nasopharyngeal carcinoma on local control and short term survival. Head Neck. In press. 38. Johns H, Cunningham J. Measurement of radiation: dosimetry. In: lohns H, Cunningham J, eds. The Physics of Radiology. 4th ed. Springfield, III: Charles C Thomas Publisher; 1977:217-269. 39. Dempster JH, Swan IRC. The management of otitis media with effusion in adults. Clin Otolaryngol. 1988;13:197-199. 40. Robinson PM. Secretory otitis media in the adult. Clin Otolaryngol.
1987;12:297-302.
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Opportunity for Early Recognition of Nasopharyngeal Carcinoma
Jonathan S.
T.
Sham, MBBS, DMRT, FRCR; William
I. Wei, MBBS, DLO, FRCS; S. K. Lau, MBBS, C. C. Yau, MBBS, MRCP, FRCR; D. Choy, MBBS, DMRT, FRCR
In a prospective study of 271 new patients with nasopharyngeal carcinoma, 36 (13.3%) were found to have cranial
\s=b\
nerve involvement. Serous otitis media (SOM) was found in 98 (41.4%) of 237 patients who had undergone complete otologic assessment. The local control of tumor and actuarial survival of three subgroups of patients, namely, 80 patients with SOM only, 11 patients with cranial nerve palsy only, and 18 patients with both SOM and cranial nerve palsy, were analyzed. The local control of tumor was better in patients with SOM alone than in those with cranial nerve palsy alone; those patients with both SOM and cranial nerve involvement had worse local control as well as survival. As SOM is not uncommon in the diagnosis of nasopharyngeal carcinoma, and adult-onset SOM is otherwise distinctly uncommon, this provides a good opportunity for early recog-
nition and, cinoma.
perhaps,
better control of
nasopharyngeal
car-
(Arch Otolaryngol Head Neck Surg. 1992;118:794-797) the malignant tumors of the head and neck re¬ gion, those in the nasopharynx often escape early detection. The nasal symptoms of nasopharyngeal carci¬ noma (NPC) are often nonspecific. The nasopharynx is difficult to examine, and cancers in this region are not un¬ commonly involved submucosally.1"3 Both cranial nerve palsy4"9 and symptoms referable to the ear have been asso¬ ciated with NPC. It has been an established teaching that NPC is associated with ear symptoms and conduction deafness,10"15 and NPC should be considered in the differ¬ ential diagnosis of an adult presenting with serous otitis media (SOM).1619 Although as early as 1938 Furstenberg20 had advocated that ear symptoms should be one of the things to consider in the early diagnosis of NPC, little information has been reported subsequently on the prognostic value of SOM in NPC, and its role in the early recognition of this tumor has not been stressed. More recently, a report was published that challenged the practice of exclusion of NPC for patients with adult-onset SOM.21
Among
Accepted for publication
October 17, 1991.
Departments of Radiotherapy and Oncology (Drs Sham, Yau, and Choy) and Surgery (Drs Wei and Lau), University of Hong Kong and Queen Mary Hospital, Hong Kong. Reprints not available. From the
DLO, FRCS;
In the 1960s, authors had written specifically on the neurologic manifestations of NPC and hoped that recog¬ nition of the association may result in earlier diagnosis and, hence, better control of the disease.6-7 Unfortunately, the improvement in treatment results in such patients has been modest despite recognition of such association and ad¬ vancement of
In this
radiotherapy.22-23
article,
we
review
our
experience with an ongo¬
ing prospective study on SOM and cranial nerve palsy in patients with NPC and explore the relationship between the two and the prognostic value of each. Between
PATIENTS AND METHODS January 1987 and December 1988, 271
new cases
of
histologically proven nasopharyngeal carcinoma were diagnosed in the Department of Radiotherapy and Oncology and the Department of Surgery, University of Hong Kong and Queen Mary Hospital, Hong Kong. In addition to other staging proce¬ dures, these patients were assessed for cranial nerve palsy and
SOM. The assessment for cranial nerve palsy was by clinical exami¬ nation. Otologie assessments to document SOM included otoscopy for evidence of effusion, pure-tone audiometry, and tympanometry. Serous otitis media is considered present when effusion is detected behind the tympanic membrane and there is an air-bone gap of 10 dB or more on a pure-tone audiogram. The tympanometry test result supplements the above findings. One hundred nine of these 271 patients who had documented cranial nerve palsy or SOM at diagnosis formed the basis of the present study. Seven patients with cranial nerve palsy but who had not completed the otologie assessment were excluded from the analysis on local control and survival, as the reason for not completing the otologie assessment in some patients was poor performance status at diagnosis, which may bias the result of the survival analysis. This group of patients was treated primarily with external ra¬ diotherapy as described by Ho.24 Thirty-one of them were treated using the split-field technique, which employed two lateral opposing facial fields and one anterior facial field for the primary tumor, while the neck was treated concurrently with a matching anterior cervical field. For 19 of these patients, a central tumor dose of 3.5 Gy per fraction was given three times per week up to 59.5 Gy. For the other 12 patients, the central tumor dose of 2.0 Gy per fraction was given daily to a total dose between 62 and 68 Gy. Sixty-two patients were treated using lateral opposing faciocervical fields for the initial phase of treatment and a midplane tumor dose of 2.5 Gy per fraction was given four times per week
Downloaded From: http://archotol.jamanetwork.com/ by a University of Michigan User on 06/14/2015
Table 1.—Breakdown of 271 Patients According to Presence of Serous Otitis Media (SOM) and Cranial Nerve Palsy* Cranial Nerve
Table 2.—Local Tumor Control by the Extent of Cranial Nerve Involvement*
Palsy
-1
Without
With
128
11
80
18
No SOM
With SOM
Incomplete otologie
assessment
for SOM *P=.0266.
27
7
or
No Local
Relapse
Relapsed Locally
One
6
6
Two
6
4
Three
3
4
More than three
7
*/-=.1085.
Table 3.—Sex and
Age Distribution of 109 Patients With
Serous Otitis Media (SOM)
-1
Male
Female
61
19
9
2
15
3
only
Cranial nerve palsy only Both SOM and cranial nerve palsy
or
Cranial Nerve
Palsy
Age Group, yt
Sex*
SOM
Persistent Local Disease
No. of Cranial Nerves Involved
10-19
20-29
-1 30-39 40-49 50-59 70-79 60-69
1
14
19
24
18
4
2
4
2
2
6
3
6
1
...
...
1
...
1
1
...
*P=.7656. +P=.2398.
Gy, while the neck was treated concurrently with a matching lower anterior cervical field. Phase two treatment was given using the split-field technique that employed two lateral opposing facial fields and one anterior facial field; a central tumor dose of 3.5 Gy per fraction was given three times per week for another 21 Gy. Another 13 patients were treated by the same technique but were given 2 Gy per fraction daily throughout, up to between 60 and 70 Gy. Three patients died before the course of radiotherapy was completed. Response to therapy was documented by endoscopy and serial up to 40
Table
4.—T-Stage Distribution of
Serous Otitis Media (SOM)
or
109 Patients With Cranial Nerve Palsy* T1
SOM
only
Cranial nerve palsy only Both SOM and cranial nerve *P=.0001.
T3
T4
63
4
13
...
...
...
...
or
T2
11
palsy
18
biopsy.25 Patients with a disease-free interval of 3 months or less
considered as having persistent disease. Patients with doc¬ umented complete remission were followed up every 6 weeks for the first year, every 2 months for the second year, and every 3 months for the third year. Endoscopy was used when examina¬ tion of the nasopharynx was inadequate in the follow-up. One hundred seven of 109 patients had complete follow-up; the follow-up duration ranged from 16 to 39 months, the median follow-up being 25 months. The correlation between cranial nerve palsy and SOM and their prognostic significance on local control of tumor as well as sur¬ vival were studied. The actuarial disease-free survival and actu¬ arial survival were computed by the Kaplan-Meier method, and the difference between curves were tested by the Mantel-Cox
were
test.26-27
RESULTS In the whole group of 271 patients, otologie assessment for SOM was not completed in 34 because of preexisting ear disease or poor performance status. Ninety-eight (41.4%) of the remaining 237 patients had SOM at sis (Table 1), the involvement being bilateral in seven pa¬ tients. One hundred thirty-nine patients had no evidence of SOM. For the 98 patients with SOM, 77 had related symptoms such as tinnitus and deafness, lasting 1 to 15 months; the mean duration of symptoms was 3.5 months. Among the same group of 271 patients, 36 suffered from
diagno¬
cranial nerve palsies at diagnosis. Three of patients had isolated 12th-nerve palsy, and these patients had no symptoms attributable to the 12thnerve palsy. For the remaining 33 patients, the duration of one or more
these three
symptoms ranged from duration
was
1 week to 12 3.3 months.
months; the
mean
The sixth cranial nerve was the most commonly in¬ volved (26 [72.2%] of 36), followed by fifth (16 [44.4%] of 36), fourth (13 [36.1%] of 36), third (10 [27.8%] of 36), and then the last four cranial nerves (10 [27.8%] of 36). The trend was toward associating more extensive cranial nerve involvement with worse local control. Local control failed in all patients who had more than three cranial nerves in¬ volved (Table 2). The occurrence of SOM and cranial nerve palsy were correlated (P=.0266). There were 80 patients with SOM only, 11 patients with cranial nerve palsy only, 18 patients with both SOM and cranial nerve palsy, and seven patients with cranial nerve palsy but incomplete otologie assess¬ ment (Table 1). Only the former three subgroups of patients were analyzed for tumor control and actuarial survival. The sex and age distribution among the three subgroups of patients with SOM only, cranial nerve palsy only, or both, were comparable (Table 3). Patients with cranial nerve palsy alone or in association with SOM had signif¬ icantly more advanced disease compared with the sub¬ group with SOM only (P=.0001) (Table 4); this is not un¬ expected as patients with cranial nerve palsy will automatically be staged as T4 in the American Joint Com¬ mittee for Cancer Staging system,28 while SOM has no bearing on the staging. The local control and survival of the three subgroups of patients are shown in Figs 1 and 2 and summarized in Ta¬ ble 5. The local control of tumor was better in patients with SOM alone than in those with cranial nerve palsy alone.
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Fig 1.—Local tumor control of patients with serous otitis media (SOM), cranial
nerve
2.—Actuarial survival of patients with serous otitis media (SOM), cranial nerve palsy (CNP), and both SOM and CNP (Both); P=.0001.
Fig
palsy (CNP), and both SOM and CNP (Both); P=.0001.
Table 5.—Local Tumor Control and Survival of 109 Patients With Serous Otitis Media (SOM)
Relapse
Alive With No Evidence of Disease or With Disease
Died of Disease
63
17
61
16
6
5
8
3
5
13
4
14
Persistent Local Disease or
SOM
Relapsed Locally
only
Cranial nerve palsy only Both SOM and cranial nerve
palsy
or
No Local
Cranial Nerve
Palsy*
Unavailable for Follow-up or Died of Intercurrent Disease
*P=.0001.
Those ment
patients with both SOM and cranial nerve involve¬
had
worse
local control
as
well
as
survival.
COMMENT manifestations of nasopharyngeal carci¬ Neurologic Its occur¬ noma at diagnosis has been well rence is the result of the infiltrative nature of this tumor, its proximity to the base of the skull, and the proximity of the parapharyngeal nodes to the cranial nerves leaving the
recognized.4"9
skull.7-29
Interestingly, the majority of cases of neurologic manifestations were the result of tumor involvement of the intracranial or extracranial portion of cranial nerves; few were the result of direct involvement of the brain. In fact, Ho8 has not seen one well-documented case of brain me¬ tastasis in his long practice treating NPC, and cases strongly suspicious of brain metastasis from NPC have been proven wrong by subsequent studies.30 The findings of our study agree with those of Thomas and Waltz7 that, despite proximity of the tumor to the cra¬ nial nerves, isolated involvement of the cranial nerves does occur and may lead to a wrong diagnosis, if it is presumed that cranial nerve involvement by NPC is invariably mul¬ tiple. The results of our study also confirmed that patients with isolated involvement of the cranial nerves fared bet¬ ter than those with more extensive involvement (Table 2).2 In many patients, the nonspecific nature of the early symptoms such as nasal obstruction and bleeding and the inaccessibility of the nasopharynx to examination had re¬ sulted in a delay in diagnosis, sometimes not until the manifestation of neurologic signs and symptoms. The re¬ ported frequency of cranial nerve palsy at diagnosis ranged from 25% to 50%. The rate of 13.3% in the present series and the comparable low rate in another series reported from Hong Kong31 seems to indicate that our pa¬ tients were diagnosed at an earlier stage. This is not unex-
as NPC is a common cancer in this part of the world; our medical professionals and the public are more
pected, aware
of this disease.
However, early diagnosis has only been achieved inso¬
far
as the percentage of patients with cranial nerve palsy diagnosis is smaller. Those patients with cranial nerve palsy are, nevertheless, suffering from advanced disease; their prognosis is no better than it was for those with cra¬ nial nerve palsy decades ago. Expectations that treatment result may improve with advancement in radiotherapy treatment machines and perhaps earlier diagnosis6"7 have not been realized. The poor treatment result of patients with cranial nerve palsy in the present series was despite
at
technical refinements: use of a simulator for localization, head casts for beam direction as well as immobilization, and radiotherapy with linear accelerators. It had also been recognized for a long time that NPC is associated with SOM.16"19 The present study confirmed the association; SOM is present in 41.4% of our patients at di¬ agnosis. The treatment of SOM in patients with NPC is simple32 but is not without complications.33 The optimal treatment of such patients has not been determined. The significance of SOM, other than as a source of morbidity, is its impact on prognosis and its role in early recognition of the disease. Sham et al34 had shown the adverse prog¬ nostic effect of ear symptoms in patients with Tl and T2 tumors. Serous otits media in patients with NPC is asso¬ ciated with the parapharyngeal extension of tumor,35-36 and parapharyngeal extension of tumor has been shown to be an important adverse prognostic factor.37 It would not be surprising to find SOM associated with adverse prognosis. Serous otitis media and cranial nerve palsy is associated (Table 1). The worst prognosis of those patients with both SOM and cranial nerve palsy among the three subgroups seems to indicate that SOM and cranial nerve palsy are, at
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least, partly independent prognostic factors
on local con¬ trol. The adverse prognostic effect of SOM was less grave compared with that of cranial nerve palsy, as evident from the significantly better local control for patients with SOM than for those with cranial nerve palsy. However, we have shown that the mean duration of symptoms relating to cranial nerve palsy was no longer than the mean duration of auditory symptoms relating to SOM, indicating that tu¬ mors associated with SOM may not be at an earlier stage of development than tumors associated with cranial nerve palsy. The basis for the deleterious effect of cranial nerve involvement on the local control of NPC needs further in¬ vestigation. The fluctuation in absorbed dose in the neigh¬ borhood of an interface between different materials, such as between the brain and the skull base and between the bony wall and air content of the sinuses, may be an impor¬ tant factor.38 As SOM is not uncommon at the diagnosis of NPC, and adult-onset SOM is otherwise distinctly uncommon,39 this provides a good opportunity for early recognition of NPC. Furthermore, the treatment result for NPC patients with SOM is better than that for NPC patients with cranial nerve palsy, if clinicians are more alert to the association between NPC and SOM.40 Early recognition of the disease may re¬ sult in improvement in survival. Although NPC is so rare in the white patient that investigations to exclude or con¬ firm NPC in a white adult presenting with SOM may not be warranted,21 the converse will be true for individuals of southern Chinese or northern African origin. With the in¬ crease in migration and integration of people of different ethnic origin, the importance of NPC in the practice of cli¬ nicians in the western countries will increase.
This study was supported by grants from the Asian Oceanian Clin¬ ical Oncology Association Hong Kong, the Hong Kong Jockey Club (Charity) Ltd, and Croucher Foundation, Hong Kong. References 1. Simmons MW, Ariel IM. Carcinoma of the
nasopharynx: report of 150 Surg Gynecol Obstet. 1949;88:763-775. 2. Vaeth JM. Nasopharyngeal malignant tumors: 82 consecutive patients treated in a period of twenty-two years. Radiology. 1960;74:364-372. cases.
3. Sham JST, Wei WI, Kwan WH, Chan CW, Choi PHK, Choy D. Fibreoptic endoscopic examination and biopsy in determining the extent of
nasopharyngeal
carcinoma. Cancer. 1989;64:1838-1842. 4. Woltman HW. Malignant tumors of nasopharynx with involvement of
system. Arch Neurol
Psychiatry. 1922;8:421-429. Ophthalmologic and neurologic symptoms at malignant nasopharyngeal tumors: clinical study comprising 454 cases with special reference to histopathology and possibilities of earlier recognition. Acta Otolaryngol (Stockh). 1944;59:319-323. 6. Godtfredsen E, Lederman M. Diagnostic and prognostic roles of ophthalmoneurologic signs and symptoms in malignant nasopharyngeal tumors. Am J Ophthalmol. 1965;59:1063-1069. 7. Thomas JE, Waltz AG. Neurological manifestations of nasopharyngeal malignant tumors. JAMA. 1965;192:103-106. 8. Ho JHC. An epidemiologic and clinical study of nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 1978;4:183-198. 9. Huang SC. Nasopharyngeal cancer: a review of 1605 patients treated radically with cobalt 60. Int J Radiat Oncol Biol Phys. 1980;6:401-407. 10. New GB. Syndrome of malignant tumors of the nasopharynx. JAMA. nervous
5. Godtfredsen E.
1922;79:10-14.
11. Simmons MW, Ariel IM. Carcinoma of the cases.
Surg Gynecol Obstet. 1949;88:763-775.
nasopharynx: report of 150
12. McConnell EM. Nasopharyngeal carcinoma in children and young adults. Br J Cancer. 1958;12:195-201. 13. Crowe SJ, Baylor JW. Benign and malignant growths of the nasopharynx and their treatment with radium. Arch Surg. 1923;6:429-488. 14. Christianson O, MacArthur SW. Nasopharyngeal carcinoma. Arch
Surg. 1933;27:1109-1119.
15. Choa G. Nasopharyngeal carcinoma. J Laryngol Otol. 1974;8:145\x=req-\ 148. 16. Trotter W. On certain clinically obscure malignant tumours of the na-
sopharyngeal wall. BMJ. 1911;2:1057-1059. 17. Neel HB. Nasopharyngeal carcinoma: clinical presentation, diagnosis, treatment and prognosis. Otolaryngol Clin North Am. 1985;18:479-490. 18. Booth JB: Otitis media with effusion. In: Booth JB. Otology. Stoneham, Mass: Butterworths; 62-87. 19. Wei WI, Lund VJ, Howard DJ. Serous otitis media in
malignancies of nasopharynx and maxilla. J Laryngol Otol. 1988;102:129-132. 20. Furstenberg AC. Malignant neoplasms of the nasopharynx. Surg Gy-
the
ncol Obstet. 1938;66:400-404. 21. Dempster JH, Simpson DC. Nasopharyngeal neoplasms and their association with adult onset otitis media with effusion. Clin Otolaryngol.
1988;13:363-365. 22. Stillwagon GB, Lee DJ, Moses H, Kashima H, Harris A, Johns M. Response of cranial nerve abnormalities in nasopharyngeal carcinoma to radiation therapy. Cancer. 1986;57:2272-2274. 23. Chen MS, Lin FJ, Tang SG, Leung WM, Leung W. Clinical significance of cranial nerve deficit in the therapy of nasopharyngeal carcinoma. Br J Radiol. 1989;62:739-743. 24. Ho JHC. Nasopharynx. In: Halnan KE: Treatment of Cancer. London, England: Chapman and Hall Ltd; 1982:249-267. 25. Sham JST, Wei WI, Kwan WH, Chan CW, Kwong WK, Choy D. Nasopharyngeal carcinoma: pattern of tumor regression after radiotherapy.
Cancer. 1990;65:216-220. 26. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481. 27. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719-748. 28. American Joint Committee for Cancer Staging and End Result Reporting. Manual for Staging of Cancer. Chicago, Ill: American Joint Committee for Cancer Staging; 1978. 29. Del Regato JA. The neurological manifestations of cancers of the nasopharynx. Bull St Louis Med Soc. 1946;40:331-332. 30. Annis JA, Phelps PD, Croft CB. A revealing CT examination in nasopharyngeal carcinoma. J Laryngol Otol. 1989;103:801-802. 31. Leung SF, Tsao SY, Teo P, Foo W. Cranial nerve involvement by nasopharyngeal carcinoma: response to treatment and clinical significance. Clin Oncol. 1990;2:138-141. 32. Chowdhury CR, Ho HC, Wright A, Tsao SY, Au GK, Tung Y. Prospective study of the effects of ventilation tubes on hearing after radiotherapy for carcinoma of nasopharynx. Ann Otol Rhinol Laryngol. 1988;97:142-145. 33. Wei WI, Engzell UCG, Lam KH, Lau SK. The efficacy of myringotomy and ventilation tube insertion in middle-ear effusion in patients with nasopharyngeal carcinoma. Laryngoscope. 1987;97:1295-1298. 34. Sham JST, Choy D. Prognostic factors of nasopharyngeal carcinoma: a review of 759 patients. Br J Radiol. 1990;63:51-58. 35. Sato H, Kurata K, Yen YH, Honjo I, Young YH, Hsieh T. Extension of nasopharyngeal carcinoma and otitis media with effusion. Arch Otolaryngol Head Neck Surg. 1988;114:866-867. 36. Sham JST, Wei WI, Lau SK, Yau CC, Choy D. Serous otitis media and paranasopharyngeal extension of nasopharyngeal carcinoma. Head Neck. In press. 37. Sham JST, Choy D. Prognostic value of paranasopharyngeal extension of nasopharyngeal carcinoma on local control and short term survival. Head Neck. In press. 38. Johns H, Cunningham J. Measurement of radiation: dosimetry. In: lohns H, Cunningham J, eds. The Physics of Radiology. 4th ed. Springfield, III: Charles C Thomas Publisher; 1977:217-269. 39. Dempster JH, Swan IRC. The management of otitis media with effusion in adults. Clin Otolaryngol. 1988;13:197-199. 40. Robinson PM. Secretory otitis media in the adult. Clin Otolaryngol.
1987;12:297-302.
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