Introduction
The paranasal cavity is anatomically situated in proximity to the esthetically important
organs, such as visual organs and the face. Malignant tumors that develop in the paranasal
cavity are often difficult to treat; it is also challenging to ensure an adequate
safety margin while performing surgery. Other factors complicating treatment include
the facts that (1) subjective symptoms are negligible in the early stage, (2) the
disease highly advances in several patients even before a diagnosis is made, and (3)
various histopathological types are presented. Generally, multimodal treatment combines
surgery, radiotherapy, and (intra-arterial) chemotherapy. Moreover, newly developed
chemotherapies, including molecular-targeting drugs and advancements in radiotherapy
such as proton beam, baryon beam, and intensity-modulated radiotherapy (IMRT), have
recently been reported. However, compared with oral, pharyngeal, and laryngeal cancers,
few patients present with paranasal cavity cancer, and it is difficult to say that
the treatment method is established. Here, we examined and reported the clinical characteristics
and treatment outcomes of maxillary sinus squamous cell carcinoma observed in inpatients
at our hospital.
Materials and Methods
The study included 22 (males, 19; females, 3; age, 45–83 years [mean age, 64.2 years])
patients diagnosed with and treated for maxillary sinus squamous cell carcinoma at
the Department of Otorhinolaryngology and Head and Neck Surgery, University of Occupational
and Environmental Health School of Medicine during the 11-year period between January
2005 and 2016. Patients with recurrence and a treatment history at any other institution
were excluded. The mean observation period was 34.3 months.
Disease stage was determined based on the Union for International Cancer Control tumor
node metastasis (UICC TNM) classification (7th ed.), and treatment outcomes were evaluated
according to overall and disease-specific survival. The Kaplan–Meier method was used
to analyze the survival rate, and significant differences in survival rate were verified
using log-rank test. p < 0.05 was considered statistically significant, and p < 0.1 was considered a trend.
The basic policy for treating primary lesions followed by our department during the
study period is presented in [Fig. 1 ]. First, preoperative superselective intra-arterial chemotherapy (radiotherapy and
concomitant intra-arterial cisplatin [RADPLAT]) was administered. Intra-arterial infusion
was administered in accordance with the Seldinger method, whereby a catheter was inserted
via the right femoral artery and tumor-feeding vessels, such as the maxillary and
facial arteries, were identified. Thereafter, cisplatin (CDDP) was administered via
a microtube inserted into these blood vessels at a dose of 100 to 120 mg/body surface
area (m2 ) per week, total two to four times (mean doses, three). Radiation was given via the
simple fractionated irradiation technique (2.0 Gy/fraction, 1 fraction/day), and when
doses of 30 to 40 Gy were received, the primary lesion was evaluated according to
the response evaluation criteria in solid tumors. In patients exhibiting good response
in this interim evaluation (complete response [CR]: disappearance or good partial
response [good PR]: cicatrization) and in those unable to or refusing to undergo surgery,
treatment was continued by either RADPLAT, chemoradiotherapy (CRT), or radiotherapy
alone (RT) until 72 Gy. Among patients exhibiting other responses (PR:tumor reduction/stable
disease [SD]:unchanged/progressive disease [PD]:exacerbation) and those who were able
to undergo surgery, radical surgery by partial maxillectomy, total maxillectomy, or
extended maxillectomy (± extensive skull base tumorectomy and reconstruction) was
selected in accordance with the extent of progression of the primary lesion. Following
surgery, based on the histopathology of the surgical specimen, CRT or RT was administered
until a total dose of 72 Gy was reached.
Fig. 1 Basic treatment policy for primary lesions of maxillary sinus squamous cell carcinoma
followed at our department. RADPLAT, radiotherapy and concomitant intra-arterial cisplatin;
RT, radiotherapy alone; CRT, chemoradiotherapy; Surgery, partial maxillectomy, total
maxillectomy, and extended maxillectomy (± extensive skull base tumorectomy and reconstruction);
CR, complete response and disappearance; good PR, good partial response and cicatrization.
Results
Patients' Clinical Characteristics and Treatment Outcomes
Clinical Staging
The number of patients chosen for each T and N classification is listed in [Table 1 ]. No patients exhibited T1 or T2 disease, 6 (21.4%) exhibited T3 disease, and 16
(72.7%) exhibited T4 disease. The staging classification was stage III in 4 patients
and stage IV in 18 (IVA, 15 patients; IVB, 2 patients; and IVC, 1 patient), thus indicating
that all patients were in the advanced disease stage.
Table 1
Number of patients according to each TN stage
T/N
N0
N1
N2
N3
Total
T1
0
0
0
0
0
T2
0
0
0
0
0
T3
4
0
2
0
6
T4
11 (1[a ])
3
2
0
16
Total
15
3
4
0
22
a Patients with distal metastasis are shown in parentheses.
First-Line Treatment
As the first-line treatment, RADPLAT was performed in 20 patients (90.9%), CRT in
one patient who received concurrent treatment for hypopharyngeal cancer, and partial
maxillectomy in one patient considering the general condition.
Among the 20 patients who received RADPLAT, radical surgery was performed in 15 (T3,
4 patients; T4, 11 patients; 70%). Surgery included total maxillectomy in 13 patients
(65.0%), partial maxillectomy in 1 (5.0%), and extended total maxillectomy + extensive
skull base tumorectomy and reconstruction in 1 (5.0%). Nonsurgery patients included
two patients with CR/good PR on the interim evaluation, one (5.0%) who refused surgery,
and two (10.0%) with highly advanced disease who were judged unable to undergo surgery
(one patient with clivus invasion and another with invasion into the orbital apex).
Treatment Outcomes
Overall survival and disease-specific survival curves of maxillary sinus squamous
cell carcinoma are presented in [Fig. 2 ]. For all patients, the 5-year overall survival rate was 47.8%, whereas the 5-year
disease-specific survival rate was 56.9%. The overall survival and disease-specific
survival curves according to T classification are presented in [Figs. 3 ] and [4 ]. The 5-year overall survival rate was 80.0% in T3 patients; however, this rate was
significantly lower in T4 patients (29.9%; p = 0.077). The 5-year disease-specific survival rate was 80.0% in T3 patients and
was lower at 42.3% in T4 patients; however, the difference observed was not significant
(p = 0.133).
Fig. 2 Overall survival and disease-specific survival for maxillary sinus squamous cell
carcinoma. The 5-year overall survival was 47.8%, whereas the 5-year disease-specific
survival was 56.9%.
Fig. 3 Overall survival rate according to T-staging of maxillary sinus squamous cell carcinoma.
The 5-year overall survival was 80.0% in T3 patients and 29.9% in T4 patients (p = 0.077).
Fig. 4 Disease-specific survival rate according to T-staging of maxillary sinus squamous
cell carcinoma. The 5-year overall survival was 80.0% in T3 patients and 42.3% in
T4 patients (p = 0.133).
In the 20 patients who received RADPLAT, the 5-year overall survival rate was 47.9%,
whereas the 5-year disease-specific survival rate was 59.8%. Among the 15 patients
who received RADPLAT and radical surgery, the 5-year overall survival rate was 59.4%,
whereas the 5-year disease-specific survival rate was 71.8%.
During initial examination, seven patients had N+ disease. In the N− group, the 5-year
overall survival rate was 53.2% and the 5-year disease-specific survival rate was
63.3%. In the N+ group, the 5-year overall survival rate and disease-specific survival
rate were lower at 33.3%; however, the difference observed was not significant (overall
survival rate, p = 0.472; disease-specific survival rate, p = 0.397).
Outcomes
Of the 22 patients, 9 patients died (7 cancer-specific deaths and 2 due to other causes).
The cancer-specific deaths included T-related death in two patients, N-related death
in one, and M-related death in four.
Discussion
The incidence of primary malignancy of the nasal and paranasal cavity is relatively
rare, affecting 0.5 to 1.0 per 100,000 individuals; further, primary malignancy of
the nasal and paranasal cavity is said to account for approximately 0.5% of all malignancies
and 3% of head and neck cancers.[1 ] The incidence of maxillary sinus carcinoma is also low. Furthermore, while there
is no clearly established evidence owing to very few prospective clinical treatment
trials conducted worldwide, surgery-based treatment is recognized as the standard
treatment in Europe and the United States. Surgery (total maxillectomy and extended
total maxillectomy) is considered the standard treatment when resection is possible,
and many patients receive postoperative radiotherapy. For overseas, patients in whom
resection and surgery are not possible, CRT is generally administered.[2 ]
At our department, the 5-year overall survival rate was 47.8% and the disease-specific
survival rate was 56.9% for all patients with maxillary sinus squamous cell carcinoma.
Several Japanese studies reported the 5-year survival rate to be 44.0 to 57.0%,[3 ]
[4 ]
[5 ] and our results corroborated with those reported in these studies.
The histopathological types of nasal and paranasal cavity malignancies are more varied
compared with those of laryngeal and pharyngeal malignancies; however, most instances
are of squamous cell carcinoma. This is attributable to the fact that the mucosa of
the nasal and paranasal cavities consists of ciliated pseudostratified columnar epithelium,
which develops into squamous epithelium where cancer develops.[6 ] Squamous cell carcinoma responds relatively well to CRT; therefore, multimodal treatment
is administered.
Regarding the degree of progression of the primary lesion in maxillary sinus carcinoma,
several studies reported to date indicate that T3 disease or greater is common.[7 ]
[8 ]
[9 ] In our reports also, all patients had T3 disease or greater. T-staging has the greatest
impact as a prognosticator of maxillary sinus carcinoma,[10 ] and reportedly, prognosis is significantly worse in patients with T4 disease than
with T3 or lesser.[4 ]
[5 ]
[6 ]
[8 ]
[9 ] In the present study, the 5-year overall survival rate in T3 patients was 80.0%;
however, the rate reduced to 29.9% in patients with T4 disease. Maxillary sinus carcinoma
with the tumor limited to within the sinus (T1/T2) presents no symptoms or symptoms
that barely differ from those of sinusitis; further, it is difficult to detect T1/T2
early-stage maxillary sinus carcinoma. By the time specific symptoms, such as foul-smelling
nasal discharge, buccal pain, dental pain, and buccal redness and swelling, are observed,
many patients would have had already developed T3/T4 disease. It is common for patients
to observe and ignore symptoms such as nasal congestion and nasal flow; further, when
buccal pain and swelling appears, many patients consult a dentist thinking it is a
tooth-related problem. From a physician's perspective, general nasal symptoms should
not be neglected; particularly, when the symptoms are unilateral, image examination
such as computed tomography should be proactively performed. To detect maxillary sinus
carcinoma well in advance, we believe it is important to educate the society in general
and provide information to not only departments of otorhinolaryngology but also to
medical departments of adjacent areas, such as the department of dentistry and ophthalmology.
The incidence of N+ disease at the initial examination is reported to be 6 to 22%
in maxillary sinus carcinoma, and our result of seven patients (31.8%) is somewhat
higher than the usual. In the process of evaluating prognosis according to the presence
or absence of cervical lymph node metastasis, Maeda et al[8 ] reported that the 5-year disease-specific survival rate is 63% in N− patients and
18% in N + patients, thereby indicating poorer prognosis in N+ patients. By contrast,
Asakura et al[11 ] reported that the survival rate does not depend on cervical lymph node metastasis
and that control of the primary lesion is more important. Our results indicated that
the 5-year overall survival rate was lower in N+ patients; however, this difference
was not statistically significant. In the future, an ongoing follow-up survey should
be conducted with a larger number of samples.
The basic treatment method for maxillary sinus squamous cell carcinoma at our department,
as shown in [Fig. 1 ], is preoperative RADPLAT combined with surgery. A comparative study conducted in
Holland[12 ] revealed that RADPLAT is not superior to CRT; therefore, administration of RADPLAT
has recently ceased in the West.[13 ] On the contrary, RADPLAT is generally used to treat maxillary sinus carcinoma in
Japan. Similar to that performed at our institution, Koike et al administered preoperative
RADPLAT using the Seldinger method combined with surgery and reported a 5-year disease-specific
survival rate of 100% in T3 patients and 84.7% in T4 patients, indicating good outcomes.[14 ] Shiga et al administered RADPLAT via superselective intra-arterial chemotherapy
for maxillary sinus squamous cell carcinoma and reported no difference in survival
in the group with surgery compared with in the group without surgery and radiation
therapy up to the curative dose; further, they reported good outcomes in both groups
and improved prognosis in stage IV patients.[7 ]
[15 ] Based on these reports, we can adequately infer that RADPLAT has a certain effectiveness.
Among the patients at our department, long-term survival was achieved in two patients
with ongoing RADPLAT without surgery. In the interim evaluation, good PR was observed
in one patient with T3 disease and one with T4b disease who was unable to undergo
surgery. Currently, both these patients are alive and recurrence free. While it is
hard to draw a conclusion owing to the small sample size, we believe that continuing
using RADPLAT for patients who responded well to RADPLAT based on the interim evaluation
might be sufficient to preserve the maxilla and achieve long-term survival. Particularly,
it should be noted that CR was achieved in a patient with T4b disease, which corroborates
with the finding reported by Shiga,[7 ] thus indicating that RADPLAT monotherapy should be considered in the treatment of
advanced maxillary sinus carcinoma.
The dose/CDDP infusion using the original method reported by Robbins et al is 150
mg/m;[2 ]
[16 ] however, CDDP is often administered at a dose of 100 mg/m2 in Japan. Yoshizaki et al compared the outcomes achieved with CDDP doses of 100 and
150 mg/body surface area and observed that the outcomes were better with the latter
dose; furthermore, they discussed the need for high-dose CDDP administration because
maxillary sinus carcinoma has a greater tumor volume compared with that of laryngeal
or hypopharyngeal cancer.[17 ] Moreover, the Japan Clinical Oncology Group conducted a multicenter, prospective
clinical trial of maxillary sinus carcinoma in Japan and reported that RADPLAT was
effective for localized advanced maxillary sinus squamous cell carcinoma and that
cisplatin administered at a dose of 100 mg/m2 for seven cycles is safe and stable.[18 ] To date, at our department, we have mainly administered CDDP arterial infusion at
a dose of 100 mg/body surface area; however, for localized, highly advanced patients,
we believe that increasing the CDDP dosage will ease further examination. On the contrary,
a certain incidence of severe adverse events of RADPLAT including cerebrovascular
accidents, central nervous system disorder, and respiratory stenosis, as well as late
adverse events including osteonecrosis, brain necrosis, and severe visual impairment,
which are irreversible adverse events that decrease quality of life, has been reported.[19 ] Among all the patients at our department, one patient had temporary visual impairment
and another had facial nerve paralysis; however, there was no occurrence of the abovementioned
severe adverse events. Both these patients recovered; we believe that in the future,
the possibility of the onset of late adverse events should be recognized and careful
follow-up observation should continue over a long period.
The outcomes observed via the current treatment, which combined RADPLAT with surgery,
used at our department were generally good for maxillary sinus carcinoma up to the
T3 disease. However, in highly advanced patients (T4), the disease is often difficult
to control, and more treatment methods need to be developed. Upon examining fatal
cases, the most common cause of death was found to be M-related, followed by T-related
deaths. As presented in [Table 1 ], patients with distal metastasis (+) at the time of initial examination were in
the T4 stage; in advanced patients, appropriate intervention via systemic chemotherapy
might be needed from the time of initial treatment. Therefore, a more effective chemotherapy
regimen needs to be established in the future. Noronha et al[20 ] achieved certain outcomes by treating patients with localized advanced cancer with
systemic chemotherapy followed by surgery and radiotherapy. Furthermore, the first-line
treatment is important for improving the primary lesion control rate. Because the
center of the face is adjacent to the orbit and the cranium, and particularly in advanced
maxillary sinus carcinoma, performing surgery while ensuring an adequate safety margin
is often functionally and esthetically difficult, which we believe leads to T-related
death. To improve the localized control rate, we believe it might be useful to examine
the use of surgery-assisting tools, such as endoscopy and navigation systems, which
have made remarkable advancements recently, as well as the concomitant use of advanced
radiotherapies, such as IMRT and particle beam radiotherapy.
Conclusion
We examined 22 patients with maxillary sinus squamous cell carcinoma who underwent
first-line treatment at our department. The 5-year overall survival and disease-specific
survival rates were 47.8 and 56.9%, respectively. The survival rate was good up to
the T3 disease stage and then declined in the T4 disease stage. In fatal cases, the
most common cause of death was M-related, followed by T-related death. We believe
that improving the survival rate in the future involves early detection and treatment,
establishing improved treatment methods for advanced cancer, and, in particular, controlling
the metastatic lesions and the primary lesion.
