ESTHESIONEUROBLASTOMA: IS THERE A ROLE FOR ELECTIVE NECK TREATMENT? Jonathan J. Beitler, MD, Daniel E. Fass, MD, Harry A. Brenner, MD, Andrew HUVOS,MD, Louis B. Harrison, MD, Steven A. Leibel, MD, and Zvi Fuks, MD
A retrospective review of the Memorial Sloan Kettering Cancer Center experience (MSKCC) with esthesioneuroblastoma was performed. From 1975 to 1985 14 cases were identified.Overall 5- and 10-year survival was 86% and 70%, respectively. Four local failures were observed and 4 neck failures were observed. A review of the literature since 1966 revealed an unexpectedly high incidence of neck failure, and of the 21 of 110 patients with neck failures that were identified through the literature, there were 6 subsequent deaths. HEAD 81NECK 1991;13:321-326
Esthesioneuroblastoma is an uncommon disease with a long natural history. Five-year survival after recurrence is common. In addition to defining a staging system (group A: tumor confined to the nasal cavity; group B: tumor involving nasal cavity and paranasal sinuses; group C: tumor beyond the nasal cavity and paranasal sinuses), From the Departments of Radiation Oncology (all doctors but one) and Pathology (Dr. Huvos), Memorial Sloan-Kettering Cancer Center, New York, New York. Acknowledgments: The authors thank Dr. James T. Parsons for reviewing the article, Mr. Christopher Lofreddo for statistical support, Dr. William Sweeney for follow-up information, and Ms. Sarah Greene for expert secretarial assistance. Presented at the 30th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, New Orleans, Louisiana, October 12, 1988. Address reprint requests to Dr. Beitler at the Department of Radiation Oncology, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467. Accepted for publication December 26, 1990.
CCC 0148-6403/91/040321-06 $04.00 B 1991 John Wiley &Sons, Inc.
Kadish et al.' recommended preoperative radiotherapy to the primary site for groups A and B and unresectable group C patients. Controversies regarding treatment abound. MATERIALS AND METHODS
From 1975 to 1985, 14 patients with esthesioneuroblastoma were identified by the MSKCC tumor registry. The MSKCC experience from 1949 to 1975 was previously published.' Of the 14 patients, 8 were men (57%). The age at the time of first symptom ranged from 22 to 66 years with an average age at the time of first symptom of 45 years. The time from first symptom until medical attention was sought ranged from immediately to 4 years with a mean value of 5.7 months. The period of time from when the patient first sought medical attention until the diagnosis was made varied from on presentation (3 cases) to 39.5 months with a mean delay from presentation until definitive diagnosis of 8.5 months. Median follow-up from time of diagnosis was 7.66 years with a 5-year follow-up for 11of 14 patients and a 10-year follow-up for 3 of 14 patients. None of the 14 patients were lost to follow-up. Prior to treatment, all histologies were reviewed by a pathologist. Eleven of the 14 patients in this series were evaluable and have been re-reviewed histologically by one of us (AH). Microscopically, the lesion was characterized by a diffusely infiltrating round and small
HEAD & NECK
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cell tumor, which varied somewhat in its cellular differentiation. The most well-differentiated tumors exhibited occasional rosettes of the HomerWright type, exhibiting a central tangle of eosinophilic fibrillary material. No rosettes of the Flexner- Wintersteiner type were recognized. These rosettes display a central lumen with an internal limiting membrane. A focally prominent fibrillary matrix, the so-called neuropil, was focally present in the more differentiated neuroblastomas. On ultrastructural examination this neurofibrillary matrix contained multiple unmyelinated cellular processes. The individual tumor cells had rounded or oval nuclei which appeared to be irregular and hyperchromatic. These cells did not contain any intracellular stainable glycogen as demonstrable by periodic acid-Schiff (PAS) preparation with diastase digestion. At the time of definitive therapy, 2 of 14 patients were Kadish group A, 4 of 14 patients were group B, and 8 of 14 patients were group C. Two patients had documented computed tomography (CT) at the time of their original diagnosis. Statistical analyses were performed using the SPSS-X computer program (Release 2.2). Survival was calculated from date of pathologic diagnosis rather than date of definitive treatment. Treatment methods are presented in Table 1. Not all treatment was performed at MSKCC and not all patients were diagnosed during the period from 1975 to 1985. RESULTS
Overall 5- and 10-year survival was 86% and 70%, respectively, with 11 and 3 patients at risk (Figure 1A). Disease-free survival at 5 and 10
0
A
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24
30
u
w
72
MONTHS SURVIVAL
M
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loo
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years, respectively, was 57% and 41% (Figure 1B). Median disease-free survival was 6.5 years. One patient (patient 8), who was treated palliatively with radiotherapy alone because of anterior cranial fossa invasion, was not included in any analyses of patients treated for cure. There were 4 local failures. One stage B patient (patient 6) had a curative resection and no adjuvant therapy. A second stage B patient (patient 4) had postoperative external radiotherapy (6,200 cGy), but prior to local recurrence had neck failure. A third patient (patient 10) had no radiotherapy until 14 years after cribiform plate recurrence and then was treated with a palliative dose (4,200 cGy). A fourth patient (patient 9) was stage B and showed minimal response to 6,645 cGy by CT scan. Follow-up CT scan 6 months later revealed progression of disease. Patient 9 underwent left nasal exenteration and remains without evidence of disease 7 years, 4 months after resection. There were 4 neck failuers in our series of 14 patients. Their clinical courses are as follows: Patient 11, Kadish stage C, failed in her neck within a year of definitive surgery and local radiotherapy (6,400 cGy) which did not include the patient’s neck. After excisional biopsy confirmed the diagnosis of cervical disease, the patient was treated with 5,000 cGy to the right neck. There was complete response of the right cervical adenopathy, and the patient did well until 2 years later when she failed in her left neck. The patient received 5,000 cGy to her left neck using 14 MeV electrons and received 3,000 cGy via lg21r after-loading catheters for persistent disease. She died 4 years later with widely metastatic disease.
0
o
12
24
56
u
w
72
m
w
IM
,
110
B
MONTHS MSEASE-FREE SURVIVAL
FIGURE 1. Overall survival (A) and disease-free survival (B), Memorial Sloan Kettering Cancer Center patients (1975-1985).
322
Esthesioneuroblastoma
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Table 1. Treatment methods. No.
Age (yr)
Sex
Stage
1
58
M
C
2
20
M
C
3
70
M
C
4
37
F
B
5
37
F
A
6
37
M
B
7
47
M
B
8
22
M
C
9
65
F
B
10
39
M
C
11
49
F
C
12
29
M
C
13
70
F
C
14
63
F
A
Initial treatment
Site of 1st failure
S- bifrontal craniotomy right maxillectomy, ethmoidectomy, exenteration of nasal cavity RT-4, 750 CGY S- biopsy RT-5,000 CGY S- unknown RT-5,600 CGy S-partial right maxillectomy, ethmoidectomy excision of tumor from right nasal cavity and cribiform plate RT-6,200 CGY S-right medial maxillectomy RT-none S-ethmoidectomy, frontal sinus RT- none
Treatment of failure
Current status NED 108 months
NED 87 months
Right neck at 79 months
NED 54 months, blind left eye AWD 139 months
Right radical neck dissection
NED 92 months
S- partial maxillectomy, ethmoidectomy, nasal exenteration, bifrontal craniotomy RT-4,000 cGy preoperatively (approx.) S- biopsy only RT-palliative whole brain RT
S-Biopsy only RT-6,645 CGY S-left total maxillectomy orbital exenteration and curettage of ethmoids RT- none S-right frontal craniotomy inc. partial exc. of sphenoid RT-6,409 cGy to primary postoperatively S-right partial maxillectomy, right radical neck dissection RT-6,900 cGy to primary, 6,000 cGy to upper neck S- biopsy RT-6,000 cGy to primary S- bilateral partial maxillectomies RT-6,000 CGY
Local recurrence at 78 months Right neck at 52 months
6,000 cGy to primary
AWD 116 months
Right radical neck dissection
NED 141 months
1. Persistent disease at primary 2. Lung metastases at 32 months Local failure at 6 months Cribiform plate at 13% years
Lung metastases treated with chemotherapy
DOD 64 months
Left nasal exenteration RT 4,200 cGy 241h years after presentation 5,000 cGy external
NED 97 months
Submandibular node 9 months after surgery Bone metastases at 12 months Right neck at 2 months
AWD at 30 years DOD 85 months
Vincristine, Adriamycin, Cytoxan
DOD 85 months
3,900 cGy to neck
DOD 10 months NED 92 months
S. surgery; RT. radiotherapy; NED, no evidence of disease; DOD. dead of disease.
Patient 4, Kadish stage B, did receive postoperative radiotherapy to the area of her primary disease but did not receive cervical radiotherapy and failed in her neck. She has subsequently had 2 operations for neck failure and local recurrence
Esthesioneuroblastoma
and is alive with presumed disease at 139 months. Patient 7, Kadish stage B, after receiving 20 fractions of preoperative irradiation to what was described as a very local field that did not in-
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323
clude his neck (records not available), failed in his neck 4 years after undergoing a radical ethmoidectomy, partial maxillectomy, nasal cavity exenteration, and exploration of the left frontal lobe. After neck failure (submandibular node), the patient underwent a unilateral radical neck dissection and 1 of 52 sampled nodes was consistent with esthesioneuroblastoma. It is now 7 years since his radical neck dissection, and he has no evidence of disease. Patient 13, Kadish stage C, developed a right neck mass while undergoing definitive radiotherapy to her primary disease. The patient was treated palliatively with 3,900 cGy to the right neck and during treatment of her right neck developed disease of her left neck. The left neck was not treated and the patient died with widely metastatic disease 10 months after she was diagnosed. As the first of failure there were 3 local failures, 4 neck failures, 1 distant metastases, and a patient with regional extension to the anterior cranial fossa who was treated with biopsy and whole brain irradiation only. Median survival after recurrence (Figure 2) was 6 years, 7 months in our series, including the patient treated palliatively with whole brain irradiation. There was one radiotherapy-induced cataract that caused unilateral blindness (no light perception) in 1 patient. One patient developed a persistent cerebrospinal fluid leak and recurrent episodes of meningitis. DISCUSSION
In 1976, Kadish et a1.l reported on a 17-case Massachusetts General Hospital and Massachusetts Eye and Ear Infirmary experience with
I 10
1
OO
12
24
36
u)
60
72
u
ma
100
120
UONm SURVIVAL
FIGURE 2. Survival after recurrence, Memorial Sloan Kettering Cancer Center patients (1975- 1985).
324
Esthesioneuroblastoma
“primary intranasal neuroblastoma” from 1941
to 1971. Besides devising the classical staging system that bears his name, Dr. Kadish concluded from his review that following surgical resection the incidence of local recurrence was unacceptably high and that the optimal treatment for groups A and B was 5,000 rad over 5 to 6 weeks followed by surgical resection. Unresectable group C patients were advised to undergo a preoperative course of 6,000 to 6,500 rad for 7 weeks followed by surgical resection, if possible. With a median follow-up of approximately 3.5 years, Dr. Kadish found the incidence of cervical lymph node metastases to be 3 of 17, or less than 20%, and argued against elective neck dissection or irradiation. In 1979, Dr. Elkon et al.3 reviewed 97 patients reported in the world literature since 1966. Dr. Elkon concluded that for groups A and B single modality therapy (either surgery or radiotherapy) had results similar to combined modality therapy. For group C patients, combined modality therapy was thought to offer the best chance of cure. In 1986 Levine et al.4 reviewed the University of Virginia experience from 1960 to 1985. In their review they contrasted results from the precraniofacial period (1960- 1975) to results from the craniofacial period (1976- 1985). In the craniofacial era, which parallels the period of the current review, there were 9 eligible group C patients. These patients were treated with preoperative radiotherapy (5,000 cGy) to the area of primary disease and postoperative chemotherapy. Spaulding et al.5 questioned whether the aggressive initial treatment of the patients had resulted in improved treatment results. Because of the incidence of neck failure (4 of 13) in those patients treated for cure, a review of the English literature since 1966 was performed in an attempt to corroborate our results (see Table 2). The review attempted to examine all patients treated for cure who did not have cervical disease or metastatic disease at presentation. Two patients had elective neck treatment.7 One hundred and ten patients from 16 institutions were identified who fulfilled the criteria outlined above. The median follow-up estimated from time of pathologic diagnosis, when possible, was 42 months. Twenty-one patients (19%) suffered delayed neck failure. Six of the 21 neck failure patients died of their disease, and 6 of the 21 patients failing in the neck eventually developed bilateral neck failure.
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July/August 1991
Table 2. Neck node failure of patients treated for cure without evidence of neck or metastatic disease at presentation, English language literature, 1966- 1989.
No. of patients
No. of neck failures
No. of neck failures with primary site continuously controlled disease
Manelfe' and Daly'
10
4
3
1
L e ~ i n eO'Connor,B ,~ Contrell,' Newbill,' O and Wade"
22
3
2
1
Kadish'
16
2
1
0
Ahmad," Appelblatt,'3 and Obermani4
24
3
1
2
1
0 1 0 0 0 1
0 1 1 0 0 0
1
0 0
0 0 0 0 0
0
0
First author
Ijaduolai5 Bidstrup" Tyler" Castroi8 Chaudhry" Franklin" and Bailey' Mackaf' MohantiZ3 DjalilianZ4 CantyZ5 Tamadax Withersz7
1 8 3 6 1 4
1 1 9 2 1 1
2 1 0 0 1 1 0 2 1 0 0
0 0
Neck node faiIures who died
From English language literature. 1966- 7989.
Ten of the 21 patients suffering neck failures had continuous control of their disease at the primary site when they failed in the neck. For 2 cases reported by Appelblatt and McClatchey,13 it was not discernable whether the neck or primary site had failed first, and these cases were not included in the 10 patients with continuous control of their disease in the primary site. In 2 other case^,^^*^' clinical examination at failure revealed no disease at the primary site, but later events revealed that the patients may well have had disease at the time of neck failure. Once again, these unclear cases were not included as having had continuous control of the primary site at the time of neck failure. Only 10 of the 21 neck failure occurred within 24 months of pathologic diagnosis. Eighteen neck failures occurred within 60 months of the pathologic diagnosis. It should be noted that the data from some relatively large s e r i e could ~ ~ ~not ~ be ~ ~used. A series from Olsen and DeSanto" reported on 21 patients seen at the Mayo Clinic from 1960 to 1980.Metastatic disease occurred in 13 patients
Esthesioneuroblastoma
with the most common site of metastases being the cervical lymph node (10cases). Two of the 13 presented with metastases, so the incidence of delayed neck failure apparently ranged from 38%(8 of 21)to 48% (10of 21)with only 4 of 21 patients having a greater than 5-year follow-up. CONCLUSIONS
In a rare and unpredictable tumor with only retrospective data to analyze, bias is easily introduced and conclusions are tenuous. It is recognized that those patients who did develop neck failure were more likely to have been in longterm contact with their physicians, and those who remained disease-free may be underrepresented in the literature. Alternatively, less than 50% of the neck failures occurred within 2 years, so it can be presumed that many of the reported patients had inadequate follow-up. According to our experience, the rate of neck recurrence is 28%. Review of the literature since 1966 demonstrated a 19% neck failure rate and confirms that such failure is a poor prognostic sign. It can be logically argued that by using the
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conservative figure of 10 neck recurrences with the primary continuously controlled, 9% of the esthesioneuroblastoma patients will potentially be cured with elective neck treatment. As only 2 patients in the literature have had elective neck treatment, it is unknown whether elective neck irradiation could affect either the rate of distant metastases or the rate of local control. Our recommendation is to consider elective neck therapy for those patients approached radically. It is recognized that if local failure occurs,
initial elective neck treatment will not prevent late reseeding of the neck. At this time we cannot offer specific recommendations for unilateral versus bilateral elective neck treatment, nor can we recommend surgery or radiotherapy on the basis of any published experience. We confirm from this analysis that the 5-year survival following recurrence is quite good at 78% with a median value of 6 years, 7 months and recommend that local or regional recurrences be treated aggressively.
REFERENCES
1. Kadish S, Goodman M, Wang CC. Olfactory neuroblastoma. Cancer 1976;37:1571- 1576. 2. Shah JP, Feghali J. Esthesioneuroblastoma. CA 1983;33:154- 159. 3. Elkon D, Hightower S, Lim ML, Cantrell RW, Constable WC. Esthesioneuroblastomas. Cancer 1979;44:10871094. 4. Levine PA, McClean C, Cantrell RW. Esthesioneuroblastoma: The University of Virginia Experience 1960- 1985. L ~ I Y ~ ~ O S1986;96:742-746. COJE 5. Spaulding CA, Kranyak MS, Constable WC, Stewart FM. Esthesioneuroblastoma: a comparison of two treatment eras. Znt J Radiat Oncol BWl Phys 1988;15:581590. 6. Manelfe C, Bonaf6 A, Fabre P, Pessey JJ. Computed tomography in olfactory neuroblastoma: one case of esthesioneuroepithelioma and four cases of esthesioneuroblastoma. J Comp Assist Tomogr 1978;2:412-420. 7. Daly NJ, Voigt J J , Combes PF. Diagnosis and treatment of olfactory neuroblastomas in seven patients. Znt J Rad i d Onc01 BWl Phys 1980;6:1735-1738. 8. O'Conor GT, Drake CR, Johns ME, Cail WS, Winn HR, Niskanen E. Treatment of advanced esthesioneuroblastoma with high-dose chemotherapy and autologous bone marrow transplantation. Cancer 1985;55:347-349. 9. Cantrell RW, Ghorayeb, Fitzhugh GS. Esthesioneuroblastoma: diagnosis and treatment. Ann Otol 1977;86760-765. 10. Newbill RT, Johns ME, Cantrell RW. Esthesioneuroblastoma: diagnosis and management. South Med J 1985;78:275-282. 11. Wade PM, Smith RE, Johns ME.Response of esthesioneuroblastoma to chemotherapy. Report of 5 cases and review of the literature. Cancer 1984,53:1036- 1041. 12. Ahmad H, Fayos JV. Role of radiation therapy in the treatment of olfactory neuroblastoma. Znt J Radiat Oncol BWl Phys 1980;6:349-352. 13. Appelblatt NH, McClatchey KD. Olfactory meduloblastoma: a retrospective clinicopathologic study. Head Neck Surg 1980;5108-113. 14. Oberman HA, Rice DH. Olfactory neuroblastomas. Cancer 1976382494-2502.
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15. Ijaduola GTA, Olude 10, Okeowo PA. Olfactory neuroblastoma in a 5 and 112 month old Nigerian baby. Clin Oncol1982;8:159- 162. 16. Bidstrup RJ, Wilkins SA. Olfactory esthesioneuroblastoma. South Med J 1970;63:1426- 1430. 17. Tyler TC, Chandler JR, Wetli C, Moffitt BM. Olfactory neuroblastoma. South Med J 1974;67:640-643. 18. Castm L, DeLaPava S, Webster JH. Esthesioneuroblastomas. AJR 1969105:7-13. 19. Chaudhry AP, Haar JG, Koul A, Nickerson PA. Olfactory neuroblastoma. Cancer 1979;44564-579. 20. Franklin D, Miller RH, Bloom MGK, Easley J , Stiernberg CM. Esthesioneuroblastoma metastatic to the trachea. Head Neck Surg 1987;10:102-106. 21. Bailey BJ, Barton S. Olfactory neuroblastoma. Arch Otolaryngol 1975;lOl:l-5. 22. Mackay B, Luna MA, Butler JJ. Adult neuroblastoma. Cancer 1976;37:1334- 1351. 23. Mohanti BK, Rath GK, Baser B, Bahadur S, Mathur M. Recurrent olfactory neuroblastoma treated by radiation, surgery, and chemotherapy: a case report. J Surg Oncol 1987;34:22-26. 24. Djalilian M, Zujto RD, Weiland LH, Devine HD. Olfactory neuroblastoma. Surg Clin North Am 1977;57:751762. 25. Canty P. Olfactory neuroblastoma: long-term survival. J Luryngol Otol1979;93:285-292. 26. Tamada A, Makimoto K, Okawa M, Hirono Y, Yamabe H. Olfactory neuroblastoma: presentation of a case and review of the Japanese literature. Laryngoscope 198*94:252 -256. 27. Withers EH, Lynch JB, Rosenfeld L. Esthesioneuroblastoma. Plast Recomtr Surg 1977;59:760-762. 28. Olsen KD, DeSanto LW. Olfactory neuroblastoma: biologic and clinical behavior. Arch Otolaryngol 1983;109797- 802. 29. Schenck NL, Ogura JH. Esthesioneuroblastoma: an enigma in diagnosis, a dilemma in treatment. Arch Otolaryng01 1972;96:322-324. 30. Mills SE, Frierson HF. Olfactory neuroblastoma-a clinicopathologic study of cases. Am J Surg Pathol 1985;9:317-327.
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July/August 1991
A retrospective review of the Memorial Sloan Kettering Cancer Center experience (MSKCC) with esthesioneuroblastoma was performed. From 1975 to 1985 14 cases were identified.Overall 5- and 10-year survival was 86% and 70%, respectively. Four local failures were observed and 4 neck failures were observed. A review of the literature since 1966 revealed an unexpectedly high incidence of neck failure, and of the 21 of 110 patients with neck failures that were identified through the literature, there were 6 subsequent deaths. HEAD 81NECK 1991;13:321-326
Esthesioneuroblastoma is an uncommon disease with a long natural history. Five-year survival after recurrence is common. In addition to defining a staging system (group A: tumor confined to the nasal cavity; group B: tumor involving nasal cavity and paranasal sinuses; group C: tumor beyond the nasal cavity and paranasal sinuses), From the Departments of Radiation Oncology (all doctors but one) and Pathology (Dr. Huvos), Memorial Sloan-Kettering Cancer Center, New York, New York. Acknowledgments: The authors thank Dr. James T. Parsons for reviewing the article, Mr. Christopher Lofreddo for statistical support, Dr. William Sweeney for follow-up information, and Ms. Sarah Greene for expert secretarial assistance. Presented at the 30th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, New Orleans, Louisiana, October 12, 1988. Address reprint requests to Dr. Beitler at the Department of Radiation Oncology, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467. Accepted for publication December 26, 1990.
CCC 0148-6403/91/040321-06 $04.00 B 1991 John Wiley &Sons, Inc.
Kadish et al.' recommended preoperative radiotherapy to the primary site for groups A and B and unresectable group C patients. Controversies regarding treatment abound. MATERIALS AND METHODS
From 1975 to 1985, 14 patients with esthesioneuroblastoma were identified by the MSKCC tumor registry. The MSKCC experience from 1949 to 1975 was previously published.' Of the 14 patients, 8 were men (57%). The age at the time of first symptom ranged from 22 to 66 years with an average age at the time of first symptom of 45 years. The time from first symptom until medical attention was sought ranged from immediately to 4 years with a mean value of 5.7 months. The period of time from when the patient first sought medical attention until the diagnosis was made varied from on presentation (3 cases) to 39.5 months with a mean delay from presentation until definitive diagnosis of 8.5 months. Median follow-up from time of diagnosis was 7.66 years with a 5-year follow-up for 11of 14 patients and a 10-year follow-up for 3 of 14 patients. None of the 14 patients were lost to follow-up. Prior to treatment, all histologies were reviewed by a pathologist. Eleven of the 14 patients in this series were evaluable and have been re-reviewed histologically by one of us (AH). Microscopically, the lesion was characterized by a diffusely infiltrating round and small
HEAD & NECK
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cell tumor, which varied somewhat in its cellular differentiation. The most well-differentiated tumors exhibited occasional rosettes of the HomerWright type, exhibiting a central tangle of eosinophilic fibrillary material. No rosettes of the Flexner- Wintersteiner type were recognized. These rosettes display a central lumen with an internal limiting membrane. A focally prominent fibrillary matrix, the so-called neuropil, was focally present in the more differentiated neuroblastomas. On ultrastructural examination this neurofibrillary matrix contained multiple unmyelinated cellular processes. The individual tumor cells had rounded or oval nuclei which appeared to be irregular and hyperchromatic. These cells did not contain any intracellular stainable glycogen as demonstrable by periodic acid-Schiff (PAS) preparation with diastase digestion. At the time of definitive therapy, 2 of 14 patients were Kadish group A, 4 of 14 patients were group B, and 8 of 14 patients were group C. Two patients had documented computed tomography (CT) at the time of their original diagnosis. Statistical analyses were performed using the SPSS-X computer program (Release 2.2). Survival was calculated from date of pathologic diagnosis rather than date of definitive treatment. Treatment methods are presented in Table 1. Not all treatment was performed at MSKCC and not all patients were diagnosed during the period from 1975 to 1985. RESULTS
Overall 5- and 10-year survival was 86% and 70%, respectively, with 11 and 3 patients at risk (Figure 1A). Disease-free survival at 5 and 10
0
A
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12
24
30
u
w
72
MONTHS SURVIVAL
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loo
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years, respectively, was 57% and 41% (Figure 1B). Median disease-free survival was 6.5 years. One patient (patient 8), who was treated palliatively with radiotherapy alone because of anterior cranial fossa invasion, was not included in any analyses of patients treated for cure. There were 4 local failures. One stage B patient (patient 6) had a curative resection and no adjuvant therapy. A second stage B patient (patient 4) had postoperative external radiotherapy (6,200 cGy), but prior to local recurrence had neck failure. A third patient (patient 10) had no radiotherapy until 14 years after cribiform plate recurrence and then was treated with a palliative dose (4,200 cGy). A fourth patient (patient 9) was stage B and showed minimal response to 6,645 cGy by CT scan. Follow-up CT scan 6 months later revealed progression of disease. Patient 9 underwent left nasal exenteration and remains without evidence of disease 7 years, 4 months after resection. There were 4 neck failuers in our series of 14 patients. Their clinical courses are as follows: Patient 11, Kadish stage C, failed in her neck within a year of definitive surgery and local radiotherapy (6,400 cGy) which did not include the patient’s neck. After excisional biopsy confirmed the diagnosis of cervical disease, the patient was treated with 5,000 cGy to the right neck. There was complete response of the right cervical adenopathy, and the patient did well until 2 years later when she failed in her left neck. The patient received 5,000 cGy to her left neck using 14 MeV electrons and received 3,000 cGy via lg21r after-loading catheters for persistent disease. She died 4 years later with widely metastatic disease.
0
o
12
24
56
u
w
72
m
w
IM
,
110
B
MONTHS MSEASE-FREE SURVIVAL
FIGURE 1. Overall survival (A) and disease-free survival (B), Memorial Sloan Kettering Cancer Center patients (1975-1985).
322
Esthesioneuroblastoma
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July/August 1991
Table 1. Treatment methods. No.
Age (yr)
Sex
Stage
1
58
M
C
2
20
M
C
3
70
M
C
4
37
F
B
5
37
F
A
6
37
M
B
7
47
M
B
8
22
M
C
9
65
F
B
10
39
M
C
11
49
F
C
12
29
M
C
13
70
F
C
14
63
F
A
Initial treatment
Site of 1st failure
S- bifrontal craniotomy right maxillectomy, ethmoidectomy, exenteration of nasal cavity RT-4, 750 CGY S- biopsy RT-5,000 CGY S- unknown RT-5,600 CGy S-partial right maxillectomy, ethmoidectomy excision of tumor from right nasal cavity and cribiform plate RT-6,200 CGY S-right medial maxillectomy RT-none S-ethmoidectomy, frontal sinus RT- none
Treatment of failure
Current status NED 108 months
NED 87 months
Right neck at 79 months
NED 54 months, blind left eye AWD 139 months
Right radical neck dissection
NED 92 months
S- partial maxillectomy, ethmoidectomy, nasal exenteration, bifrontal craniotomy RT-4,000 cGy preoperatively (approx.) S- biopsy only RT-palliative whole brain RT
S-Biopsy only RT-6,645 CGY S-left total maxillectomy orbital exenteration and curettage of ethmoids RT- none S-right frontal craniotomy inc. partial exc. of sphenoid RT-6,409 cGy to primary postoperatively S-right partial maxillectomy, right radical neck dissection RT-6,900 cGy to primary, 6,000 cGy to upper neck S- biopsy RT-6,000 cGy to primary S- bilateral partial maxillectomies RT-6,000 CGY
Local recurrence at 78 months Right neck at 52 months
6,000 cGy to primary
AWD 116 months
Right radical neck dissection
NED 141 months
1. Persistent disease at primary 2. Lung metastases at 32 months Local failure at 6 months Cribiform plate at 13% years
Lung metastases treated with chemotherapy
DOD 64 months
Left nasal exenteration RT 4,200 cGy 241h years after presentation 5,000 cGy external
NED 97 months
Submandibular node 9 months after surgery Bone metastases at 12 months Right neck at 2 months
AWD at 30 years DOD 85 months
Vincristine, Adriamycin, Cytoxan
DOD 85 months
3,900 cGy to neck
DOD 10 months NED 92 months
S. surgery; RT. radiotherapy; NED, no evidence of disease; DOD. dead of disease.
Patient 4, Kadish stage B, did receive postoperative radiotherapy to the area of her primary disease but did not receive cervical radiotherapy and failed in her neck. She has subsequently had 2 operations for neck failure and local recurrence
Esthesioneuroblastoma
and is alive with presumed disease at 139 months. Patient 7, Kadish stage B, after receiving 20 fractions of preoperative irradiation to what was described as a very local field that did not in-
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clude his neck (records not available), failed in his neck 4 years after undergoing a radical ethmoidectomy, partial maxillectomy, nasal cavity exenteration, and exploration of the left frontal lobe. After neck failure (submandibular node), the patient underwent a unilateral radical neck dissection and 1 of 52 sampled nodes was consistent with esthesioneuroblastoma. It is now 7 years since his radical neck dissection, and he has no evidence of disease. Patient 13, Kadish stage C, developed a right neck mass while undergoing definitive radiotherapy to her primary disease. The patient was treated palliatively with 3,900 cGy to the right neck and during treatment of her right neck developed disease of her left neck. The left neck was not treated and the patient died with widely metastatic disease 10 months after she was diagnosed. As the first of failure there were 3 local failures, 4 neck failures, 1 distant metastases, and a patient with regional extension to the anterior cranial fossa who was treated with biopsy and whole brain irradiation only. Median survival after recurrence (Figure 2) was 6 years, 7 months in our series, including the patient treated palliatively with whole brain irradiation. There was one radiotherapy-induced cataract that caused unilateral blindness (no light perception) in 1 patient. One patient developed a persistent cerebrospinal fluid leak and recurrent episodes of meningitis. DISCUSSION
In 1976, Kadish et a1.l reported on a 17-case Massachusetts General Hospital and Massachusetts Eye and Ear Infirmary experience with
I 10
1
OO
12
24
36
u)
60
72
u
ma
100
120
UONm SURVIVAL
FIGURE 2. Survival after recurrence, Memorial Sloan Kettering Cancer Center patients (1975- 1985).
324
Esthesioneuroblastoma
“primary intranasal neuroblastoma” from 1941
to 1971. Besides devising the classical staging system that bears his name, Dr. Kadish concluded from his review that following surgical resection the incidence of local recurrence was unacceptably high and that the optimal treatment for groups A and B was 5,000 rad over 5 to 6 weeks followed by surgical resection. Unresectable group C patients were advised to undergo a preoperative course of 6,000 to 6,500 rad for 7 weeks followed by surgical resection, if possible. With a median follow-up of approximately 3.5 years, Dr. Kadish found the incidence of cervical lymph node metastases to be 3 of 17, or less than 20%, and argued against elective neck dissection or irradiation. In 1979, Dr. Elkon et al.3 reviewed 97 patients reported in the world literature since 1966. Dr. Elkon concluded that for groups A and B single modality therapy (either surgery or radiotherapy) had results similar to combined modality therapy. For group C patients, combined modality therapy was thought to offer the best chance of cure. In 1986 Levine et al.4 reviewed the University of Virginia experience from 1960 to 1985. In their review they contrasted results from the precraniofacial period (1960- 1975) to results from the craniofacial period (1976- 1985). In the craniofacial era, which parallels the period of the current review, there were 9 eligible group C patients. These patients were treated with preoperative radiotherapy (5,000 cGy) to the area of primary disease and postoperative chemotherapy. Spaulding et al.5 questioned whether the aggressive initial treatment of the patients had resulted in improved treatment results. Because of the incidence of neck failure (4 of 13) in those patients treated for cure, a review of the English literature since 1966 was performed in an attempt to corroborate our results (see Table 2). The review attempted to examine all patients treated for cure who did not have cervical disease or metastatic disease at presentation. Two patients had elective neck treatment.7 One hundred and ten patients from 16 institutions were identified who fulfilled the criteria outlined above. The median follow-up estimated from time of pathologic diagnosis, when possible, was 42 months. Twenty-one patients (19%) suffered delayed neck failure. Six of the 21 neck failure patients died of their disease, and 6 of the 21 patients failing in the neck eventually developed bilateral neck failure.
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July/August 1991
Table 2. Neck node failure of patients treated for cure without evidence of neck or metastatic disease at presentation, English language literature, 1966- 1989.
No. of patients
No. of neck failures
No. of neck failures with primary site continuously controlled disease
Manelfe' and Daly'
10
4
3
1
L e ~ i n eO'Connor,B ,~ Contrell,' Newbill,' O and Wade"
22
3
2
1
Kadish'
16
2
1
0
Ahmad," Appelblatt,'3 and Obermani4
24
3
1
2
1
0 1 0 0 0 1
0 1 1 0 0 0
1
0 0
0 0 0 0 0
0
0
First author
Ijaduolai5 Bidstrup" Tyler" Castroi8 Chaudhry" Franklin" and Bailey' Mackaf' MohantiZ3 DjalilianZ4 CantyZ5 Tamadax Withersz7
1 8 3 6 1 4
1 1 9 2 1 1
2 1 0 0 1 1 0 2 1 0 0
0 0
Neck node faiIures who died
From English language literature. 1966- 7989.
Ten of the 21 patients suffering neck failures had continuous control of their disease at the primary site when they failed in the neck. For 2 cases reported by Appelblatt and McClatchey,13 it was not discernable whether the neck or primary site had failed first, and these cases were not included in the 10 patients with continuous control of their disease in the primary site. In 2 other case^,^^*^' clinical examination at failure revealed no disease at the primary site, but later events revealed that the patients may well have had disease at the time of neck failure. Once again, these unclear cases were not included as having had continuous control of the primary site at the time of neck failure. Only 10 of the 21 neck failure occurred within 24 months of pathologic diagnosis. Eighteen neck failures occurred within 60 months of the pathologic diagnosis. It should be noted that the data from some relatively large s e r i e could ~ ~ ~not ~ be ~ ~used. A series from Olsen and DeSanto" reported on 21 patients seen at the Mayo Clinic from 1960 to 1980.Metastatic disease occurred in 13 patients
Esthesioneuroblastoma
with the most common site of metastases being the cervical lymph node (10cases). Two of the 13 presented with metastases, so the incidence of delayed neck failure apparently ranged from 38%(8 of 21)to 48% (10of 21)with only 4 of 21 patients having a greater than 5-year follow-up. CONCLUSIONS
In a rare and unpredictable tumor with only retrospective data to analyze, bias is easily introduced and conclusions are tenuous. It is recognized that those patients who did develop neck failure were more likely to have been in longterm contact with their physicians, and those who remained disease-free may be underrepresented in the literature. Alternatively, less than 50% of the neck failures occurred within 2 years, so it can be presumed that many of the reported patients had inadequate follow-up. According to our experience, the rate of neck recurrence is 28%. Review of the literature since 1966 demonstrated a 19% neck failure rate and confirms that such failure is a poor prognostic sign. It can be logically argued that by using the
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conservative figure of 10 neck recurrences with the primary continuously controlled, 9% of the esthesioneuroblastoma patients will potentially be cured with elective neck treatment. As only 2 patients in the literature have had elective neck treatment, it is unknown whether elective neck irradiation could affect either the rate of distant metastases or the rate of local control. Our recommendation is to consider elective neck therapy for those patients approached radically. It is recognized that if local failure occurs,
initial elective neck treatment will not prevent late reseeding of the neck. At this time we cannot offer specific recommendations for unilateral versus bilateral elective neck treatment, nor can we recommend surgery or radiotherapy on the basis of any published experience. We confirm from this analysis that the 5-year survival following recurrence is quite good at 78% with a median value of 6 years, 7 months and recommend that local or regional recurrences be treated aggressively.
REFERENCES
1. Kadish S, Goodman M, Wang CC. Olfactory neuroblastoma. Cancer 1976;37:1571- 1576. 2. Shah JP, Feghali J. Esthesioneuroblastoma. CA 1983;33:154- 159. 3. Elkon D, Hightower S, Lim ML, Cantrell RW, Constable WC. Esthesioneuroblastomas. Cancer 1979;44:10871094. 4. Levine PA, McClean C, Cantrell RW. Esthesioneuroblastoma: The University of Virginia Experience 1960- 1985. L ~ I Y ~ ~ O S1986;96:742-746. COJE 5. Spaulding CA, Kranyak MS, Constable WC, Stewart FM. Esthesioneuroblastoma: a comparison of two treatment eras. Znt J Radiat Oncol BWl Phys 1988;15:581590. 6. Manelfe C, Bonaf6 A, Fabre P, Pessey JJ. Computed tomography in olfactory neuroblastoma: one case of esthesioneuroepithelioma and four cases of esthesioneuroblastoma. J Comp Assist Tomogr 1978;2:412-420. 7. Daly NJ, Voigt J J , Combes PF. Diagnosis and treatment of olfactory neuroblastomas in seven patients. Znt J Rad i d Onc01 BWl Phys 1980;6:1735-1738. 8. O'Conor GT, Drake CR, Johns ME, Cail WS, Winn HR, Niskanen E. Treatment of advanced esthesioneuroblastoma with high-dose chemotherapy and autologous bone marrow transplantation. Cancer 1985;55:347-349. 9. Cantrell RW, Ghorayeb, Fitzhugh GS. Esthesioneuroblastoma: diagnosis and treatment. Ann Otol 1977;86760-765. 10. Newbill RT, Johns ME, Cantrell RW. Esthesioneuroblastoma: diagnosis and management. South Med J 1985;78:275-282. 11. Wade PM, Smith RE, Johns ME.Response of esthesioneuroblastoma to chemotherapy. Report of 5 cases and review of the literature. Cancer 1984,53:1036- 1041. 12. Ahmad H, Fayos JV. Role of radiation therapy in the treatment of olfactory neuroblastoma. Znt J Radiat Oncol BWl Phys 1980;6:349-352. 13. Appelblatt NH, McClatchey KD. Olfactory meduloblastoma: a retrospective clinicopathologic study. Head Neck Surg 1980;5108-113. 14. Oberman HA, Rice DH. Olfactory neuroblastomas. Cancer 1976382494-2502.
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15. Ijaduola GTA, Olude 10, Okeowo PA. Olfactory neuroblastoma in a 5 and 112 month old Nigerian baby. Clin Oncol1982;8:159- 162. 16. Bidstrup RJ, Wilkins SA. Olfactory esthesioneuroblastoma. South Med J 1970;63:1426- 1430. 17. Tyler TC, Chandler JR, Wetli C, Moffitt BM. Olfactory neuroblastoma. South Med J 1974;67:640-643. 18. Castm L, DeLaPava S, Webster JH. Esthesioneuroblastomas. AJR 1969105:7-13. 19. Chaudhry AP, Haar JG, Koul A, Nickerson PA. Olfactory neuroblastoma. Cancer 1979;44564-579. 20. Franklin D, Miller RH, Bloom MGK, Easley J , Stiernberg CM. Esthesioneuroblastoma metastatic to the trachea. Head Neck Surg 1987;10:102-106. 21. Bailey BJ, Barton S. Olfactory neuroblastoma. Arch Otolaryngol 1975;lOl:l-5. 22. Mackay B, Luna MA, Butler JJ. Adult neuroblastoma. Cancer 1976;37:1334- 1351. 23. Mohanti BK, Rath GK, Baser B, Bahadur S, Mathur M. Recurrent olfactory neuroblastoma treated by radiation, surgery, and chemotherapy: a case report. J Surg Oncol 1987;34:22-26. 24. Djalilian M, Zujto RD, Weiland LH, Devine HD. Olfactory neuroblastoma. Surg Clin North Am 1977;57:751762. 25. Canty P. Olfactory neuroblastoma: long-term survival. J Luryngol Otol1979;93:285-292. 26. Tamada A, Makimoto K, Okawa M, Hirono Y, Yamabe H. Olfactory neuroblastoma: presentation of a case and review of the Japanese literature. Laryngoscope 198*94:252 -256. 27. Withers EH, Lynch JB, Rosenfeld L. Esthesioneuroblastoma. Plast Recomtr Surg 1977;59:760-762. 28. Olsen KD, DeSanto LW. Olfactory neuroblastoma: biologic and clinical behavior. Arch Otolaryngol 1983;109797- 802. 29. Schenck NL, Ogura JH. Esthesioneuroblastoma: an enigma in diagnosis, a dilemma in treatment. Arch Otolaryng01 1972;96:322-324. 30. Mills SE, Frierson HF. Olfactory neuroblastoma-a clinicopathologic study of cases. Am J Surg Pathol 1985;9:317-327.
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