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Adenocarcinoma of the Ethmoidal Sinus Complex
Surgical Debulking and Topical Fluorouracil May Be the Optimal Treatment
Paul P. Knegt, MD, PhD;
Kim W. Ah-See, MB ChB, FRCS, FRCS(ORL), MD;
Lilly-Ann vd Velden, MD, PhD;
Jeroen Kerrebijn, MD, PhD
Arch Otolaryngol Head Neck Surg. 2001;127:141-146.
ABSTRACT
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Objectives To report our experience with the management of adenocarcinoma of the
ethmoidal sinuses using a regimen of surgical debulking and topical chemotherapy,
to report long-term survival, and to compare our results with recently published
series of patients undergoing craniofacial resection.
Design Review of prospectively collected data.
Setting Tertiary cancer center.
Patients Seventy consecutive patients with ethmoidal adenocarcinoma referred
to the Department of Head and Neck Surgery, University Hospital of Rotterdam,
Rotterdam, the Netherlands, between January 1976 and December 1997. Sixty-two
patients were eligible for primary treatment.
Interventions Surgical debulking via an extended anterior maxillary antrostomy followed
by a combination of repeated topical chemotherapy (fluorouracil) and necrotomy.
Additionally 8 patients (13%) required radiotherapy for local recurrence;
1 patient required surgery for regional lymph node metastases.
Main Outcome Measures Survival measured by the Kaplan-Meier method. Clinical complications
related to the therapy.
Results There were no perioperative deaths. Complications did occur, such as
temporary periorbital swelling (25 patients [40%]) and temporary cerebrospinal
fluid leakage (5 patients [8%]). One patient (1.6%) developed meningitis.
Adjusted disease-free survival at 2, 5, and 10 years is 96%, 87%, and 74%,
respectively.
Conclusion Our 23-year experience with a combination of surgical debulking and
repeated topical chemotherapy for patients with adenocarcinoma of the ethmoidal
sinuses leads us to believe that it represents the current treatment of choice
for these patients for long-term disease-free survival.
INTRODUCTION
PARANASAL SINUS tumors are rare forms of head and neck malignant neoplasms
accounting for only 3% of head and neck cancers. Within this group exist various
histological forms including squamous cell carcinoma, adenocarcinoma, and
undifferentiated carcinoma. Epidemiologically adenocarcinoma has been associated
with workers exposed to hardwood dust, with this association being first reported
in 1965 by MacBeth.1 With improvements in surgical
and anesthetic techniques, more radical surgical approaches have been developed,
with the current choice being a 2-pronged approach from above and below the
tumor, namely, the craniofacial resection (CFR).
Craniofacial resection has been adopted worldwide as the standard therapy
for tumors of the paranasal sinuses involving the anterior skull base.2, 3, 4 Since its publication
by Ketcham et al5 in 1963, the technique has
been refined and consequently morbidity and mortality have been reduced.
For some types of histopathology like esthesioneuroblastoma, CFR offers
a better prognosis than other forms of treatment.6
Unfortunately, for adenocarcinoma of the ethmoidal sinus, CFR has not rendered
significantly improved survival rates.2, 3, 4, 7
Lateral rhinotomy followed by radiotherapy has recently been shown to produce
comparable survival results8 while primary
radiation therapy alone remains an alternative for patients unfit for surgery.9, 10
As regards the clinical outcome and survival data for these patients,
therefore, the question still remains as to whether CFR is the best approach
to these tumors. The aim of this article is to present our 23-year experience
in the management of the patients with adenocarcinoma of the ethmoidal sinus
complex treated in our department using a technique modified from that originally
described by Sato et al11 in 1970.
MATERIALS AND METHODS
In Rotterdam since 1976 we have treated all patients with adenocarcinoma
of the ethmoid in a standard fashion. This consists of surgical debulking
followed by topical chemotherapy combined with frequent necrotomy.12 In the period January 1976 through December 1988,
these patients also received low-dose radiotherapy (ie, 2 x 2 Gy preoperatively
and 5 x 2 Gy postoperatively). However, in consultation with our radiotherapy
colleagues it was believed that this low-dose radiotherapy was insufficient
to have any influence on the results. Therefore, in 1988, this practice was
stopped and patients thereafter received only surgical debulking and topical
chemotherapy with regular necrotomy.
Preoperative assessment included computer tomographic scanning to assess
the extent of the tumor with particular attention given to the orbit and anterior
cranial floor. Gross invasion through the dura to brain tissue or through
the periorbital lining is a contraindication to this approach and consideration
is then given to possible CFR. All pathologic sections were reviewed by our
own pathologist to confirm the diagnosis of adenocarcinoma. It can often be
difficult to ascertain whether the tumor has originated from the ethmoidal
sinus or the maxillary sinus. All of our patients, however, had biopsy-proved
evidence of ethmoidal sinus disease, while tumor in the maxillary sinus may
or may not also have been present.
The surgical approach to the paranasal sinuses is via the anterior wall
of the maxillary sinus as in a Caldwell-Luc procedure. The anterior wall,
however, is more extensively opened up to within 2 mm of the inferior oribital
rim, while taking care to preserve the infraorbital nerve. The lateral nasal
wall, including the frontal process, medial wall of the maxilla, and the turbinates
are removed. All sinuses including the maxillary, ethmoids, and sphenoid are
meticulously cleaned. In essence a complete medial maxillectomy plus sphenoethmoidectomy
according to Denker13 and as described by us14 is done. As much tumor as possible is removed, taking
care to try to preserve important structures such as the dura and periorbit.
In our experience these 2 structures have proved to be robust at resisting
tumor invasion.
At the end of the procedure, areas in which tumor may have remained
are liberally covered with a 5% fluorouracil emulsion (Efudix; Hoffmann-LaRoche,
Basel, Switzerland). The cavity is then packed with 10 x 10-cm gauze
swabs impregnated with 3% tetracycline hydrochloride in a petroleum jelly
ointment.
Postoperative treatment consists of twice-weekly changes of the tetracycline
packs and meticulous removal of necrotic material, followed by further fluorouracil
application. This is performed in the outpatient clinic. The first postoperative
change is performed after the patient has received intramuscular morphine.
Subsequent visits require only acetaminophen (in Europe, paracetamol) (1 g,
orally) 1 hour prior to the appointment. The dead tissue slough is easily
identified as a painless gray tissue layer that can be removed with brisk
suction.
Endoscopic surgery and subsequent endoscopic treatment has not been
been adopted in this series. In our experience the open surgical technique
provides an unhampered view of the sinuses, especially of the orbital floor
and the zygomatic and alveolar recesses. The postoperative treatment can be
performed with minimal burden for the patient via the large anterior antrostoma.
Routine inspection of the cavity after treatment can, however, be performed
endoscopically.
A total of 8 dressing changes and meticulous necrotectomies are performed.
Further packing of the cavity is continued, however, for a further 4 weeks
during the healing phase to prevent closure of the anterior maxillary sinus
wall defect, thus providing a permanent portal for treatment and, importantly,
for regular inspection. From the first postoperative day patients eat a normal
diet. The tetracycline-impregnated gauzes protect the cavity during the early
stages, while regular nasal douching keeps the cavity clean thereafter. Patients
are advised to regularly rinse both the oral and nasal cavities after meals
with an isotonic (0.9%) saline solution. Nasal douching can easily be performed
using a 10-mL syringe filled with warm saline solution. Our patients tolerate
this method of aftercare very well.
Between 12 and 16 weeks after the start of therapy an endoscopic inspection
of the cavity is performed under general anesthetic and multiple biopsy specimens
are obtained. If no tumor is detected, the frequency of follow-up visits is
reduced.
If tumor should be detected either macroscopically or histologically,
then further treatment of the residual tumor consisting of surgical removal,
continued fluorouracil application, and necrotomy plus additional radical
radiotherapy (70 Gy) is performed. Postoperative radiotherapy is also indicated
in cases of regional metastases or when the tumor extends beyond the reach
of the local chemotherapy, such as the cheek or infratemporal fossa. Likewise
treatment of later local tumor recurrence following initial treatment success
consists of surgical removal, frequent fluorouracil application, necrotomy,
and radiotherapy.
Patients initially seen with regional lymph node metastases are treated
additionally with a neck dissection and locoregional radiotherapy. Treatment
of patients developing metastatic lymph nodes during follow-up depends on
the situation with the local primary site: presence of local recurrence indicates
standard treatment with neck dissection and full-dose radiotherapy; if there
is no evidence of local recurrence, the patient undergoes a neck dissection
followed by radiotherapy as indicated by the histological findings (ie, extranodal
spread, >1 involved node or angioinvasion). Treatment of patients with distant
metastases is tailored individually.
RESULTS
Between January 1976 and December 1997 seventy patients with adenocarcinoma
of the ethmoid were referred for treatment to our department. Sixty-two of
these patients were eligible for primary therapy according to the aforementioned
regimen and form the basis of the following analysis (Table 1). Six patients (10%) were female; all others were male.
Twenty-eight patients (45%) had a history of working with wood.
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Table 1. Details of Patients Treated
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Eight patients were excluded for a variety reasons: 2 received no treatment
(1 died before treatment was started and 1 remained untreated owing to severe
Alzheimer disease from which the patient died). Six patients were treated
by alternative methods: 2 patients received preoperative radiotherapy followed
by debulking surgery alone, 2 patients had extensive intracranial extension
requiring CFR (3%), and 2 patients received palliative therapy in the presence
of metastatic disease.
According to the American Joint Committee on Cancer–International
Union Aganst Cancer Classification,15 the tumors
of 3 patients were classified as T1, 10 as T2, 24 as T3, and 25 as T4. Involvement
of the anterior skull base was found in 40% (25 of 62 patients) and of the
medial orbital wall and/or periorbital lining in 60% (37 of 62 patients) of
patients. The orbit was preserved in all patients.
The minimum follow-up to date is 2 years (mean follow-up, 8.2 years).
Overall survival and disease-free survival rates are shown in Figure 1. Disease-free survival was 96%, 87%, and 74% at 2, 5, and
10 years, respectively (Kaplan-Meier). Local and distant relapse-free survival
are shown in Figure 2.
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Figure 1. Kaplan-Meier analysis of survival.
Analysis is adjusted for disease-free survival.
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Figure 2. Local relapse-free and distance
relapse-free survival.
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Thirty-two patients received preoperative low-dose radiotherapy during
the pre-1988 phase of this study, while after 1988 thirty patients did not.
There was no difference between the pre-1988 and post-1988 groups, 5-year
disease-free survival being 84% and 89%, respectively, while 10-year survival
was 74% and 74%, respectively.
None of these patients had residual tumor at inspection under anesthetic
approximately 3 months after therapy. Eight patients (13%) developed a local
tumor recurrence: 4 of them are alive and free of disease after 1 round of
additional treatment with debulking surgery, local chemotherapy combined with
a second necrotomy and radiotherapy, 1 is alive with disease after repeated
local treatment, and 3 died of their tumor. One patient developed a regional
metastasis and was salvaged with a radical neck dissection and survived for
a further 7 years after surgery but then died of a second primary carcinoma
of the lung. Five patients (8%) developed distant metastases; they all died
of their disease.
The complications are listed in Table
2. Most complications were not serious. There were no postoperative
deaths. Despite involvement of the anterior skull base in 25 patients, there
was only 1 episode of postoperative meningitis that responded rapidly to antibiotic
therapy. Five patients (8%) developed temporary postoperative cerebrospinal
fluid leaks that were successfully managed with bed rest and local nasal tamponade
with tetracycline-saturated gauze. None of these patients required further
surgery for persistent leakage. Periorbital bruising and swelling was the
most common postoperative complication occuring to varying degrees in many
patients who had involvement of the lamina papyracea (25 patients [40%]).
This was of minor concern to the patients and generally resolved spontaneously
within 1 week of surgery. There were no episodes of visual disturbance or
of intraorbital bleeding. At the conclusion of this study, 42 patients were
alive and free of disease; 9 have died of their disease, 2 are alive with
disease, and 10 died of other causes without signs of locoregional or distant
disease.
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Table 2. Types of Complication
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COMMENT
This treatment regimen seems to improve the prognosis of patients with
adenocarcinoma of the ethmoidal sinuses. In animal experiments it has been
demonstrated that local chemotherapy causes not only necrosis of tumor cells
but also initiates a strong potentiation of the immune system.16, 17, 18, 19
This is one possible explanation for the apparent success of this form of
treatment. It clearly goes against the concept of radical excisional surgery
for these tumors20 but is perhaps more in line
with a philosophy of organ preservation surgery.
In 1985 we published our results of this form of treatment for all histological
types of paranasal sinus carcinoma.12 Our results
then were similarly good not only for adenocarcinoma (100% 5-year survival,
N = 20) but also were very encouraging for squamous cell carcinoma and undifferentiated
carcinoma (50% 5-year survival). It remains unclear to us why in the past
15 years this form of treatment has not been more widely accepted for its
simplicity but more importantly for its higher success rates when compared
with other forms of conventional therapy.
In 3 recent reviews3, 4, 7
the long-term results of CFR for adenocarcinoma of the ethmoids have been
published (Table 3). The 5-year
survival rates vary from 39% to 57%. Comparing CFR with debulking surgery
and topical chemotherapy, the results of CFR seem inferior.
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Table 3. Comparison of the Treatment of Adenocarcinoma of the Ethmoidal
Sinus Complex Using a Craniofacial Approach
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If the validity of a treatment regimen is based on the clinical outcome,
eg, survival data, then our current form of therapy would seem to be the treatment
of choice for these tumors. We acknowledge that this hypothesis has not been
tested in a clinical controlled trial. We suggest, however, that such a trial
would be difficult to administer in view of the rarity of these tumors and
the differences that exist between the forms of treatment. We believe that
our experience in a large tertiary referral center with a population base
of about 3 million is likely to be representative of other published series.
We accept that CFR remains the treatment of choice for esthesioneuroblastoma
as it provides to-date results that are superior to other forms of treatment.6 Adenocarcinoma of the ethmoids, however, is a different
disease and, despite improvements in surgical and anesthetic techniques that
have allowed CFR to be performed with minimal morbidity and mortality, survival
data to date with this treatment remain disappointing. Our current choice
of treatment, therefore, is surgical debulking followed by repeated topical
fluorouracil therapy and necrotomy.
CONCLUSIONS
We have reported our 23-year experience with a surgical debulking and
topical chemotherapy technique for the treatment of adenocarcinoma of the
ethmoidal sinuses. To date our survival figures have been encouraging and
seem superior to those of the more conventional form of treatment, namely,
CFR. We would suggest that our form of treatment (surgical debulking plus
repeated topical fluorouracil therapy and necrotectomy) should be more widely
adopted as we believe it provides patients with a better chance of survival
from this malignancy.
AUTHOR INFORMATION
Accepted for publication November 10, 2000.
From the Department of Head and Neck Surgery, University Hospital Rotterdam,
Rotterdam, the Netherlands.
Corresponding author: Paul P. Knegt, MD, PhD, Department of Head
and Neck Surgery, University Hospital Rotterdam Dijkzigt, 3000 CA Rotterdam,
the Netherlands (e-mail: knegt{at}knod.azr.nl).
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