- Email: [email protected]
Prognostic factors in maxillary sinus and nasal cavity carcinoma
EJSO (2005) 31, 1206–1212
www.ejso.com
Prognostic factors in maxillary sinus and nasal cavity carcinoma ˜ate-Ocan ˜ac ¨emesa, M.C. Ramı´rez-Ortegab, L.F. On J.F. Carrilloa,*, A. Gu a
´n de Cirugı´a, Instituto Nacional de Cancerologı´a, Mexico City, Head and Neck Department, Subdireccio Mexico b ´n de Investigacio ´n, Instituto Nacional de Cardiologı´a Ignacio Cha ´vez, Pharmacology Department, Direccio ´xico City, Mexico Me c ´n de Investigacio ´n Clı´nica, Instituto Nacional de Cancerologı´a, Mexico City, Mexico Subdireccio Accepted for publication 1 April 2005 Available online 31 May 2005
KEYWORDS Paranasal sinuses; Surgery; Prognostic factors; Orbit invasion; Maxillectomy; Maxillary sinus cancer
Abstract Aims: The aim of the present study is to define prognostic factors, particularly the impact of treatment on paranasal sinus and nasal cavity malignancies. Material and methods: Retrospective study of patients with maxillary antrum and nasal fossae malignancies. A maxillectomy classification as performed to treat malignancies in our institution is described. Multivariate analysis of prognostic factors was done using the Cox’s model. Results: One hundred and nine patients were evaluated. Squamous cell carcinoma was found in 62 cases and in 95 patients the epicentre of the tumour was located in the maxillary antrum. Ten patients were treated with surgery only, 39 patients with surgery and adjuvant radiation therapy, 37 cases received only radiotherapy, and 18 received radiotherapy followed by surgery; in five cases a combination of chemoradiotherapy was used. Multivariate analysis identified T classification, orbit invasion, N classification, site of origin of tumour in nasal fossae, and no surgical resection as independent prognostic factors (pZ0.0001). Conclusion: T4 tumours with orbit invasion present bad prognosis as compared to other T4 tumours. Surgical resection should be included in the treatment strategy. Because of the high frequency of lymph-node metastasis, neck treatment should be considered in T4 tumours. Q 2005 Elsevier Ltd. All rights reserved.
Introduction
* Corresponding author. Address: Selva 45, apt 401, Colonia Insurgentes Cuicuilco, CP 04530, Me ´xico City, Me ´xico. Tel.: C52 55 55287235; fax: C52 55 56066947. E-mail address: [email protected] (J.F. Carrillo).
Paranasal and nasal cavity malignancies have a poor prognosis. Most patients present with advanced disease with direct extension to critical areas of the skull base or with rapidly recurrent loco-regional disease after treatment.1
0748-7983/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2005.04.001
Maxillary sinus and nasal cavity carcinoma Several regional characteristics contribute to the complexity in treating maxillary antrum carcinoma such as anatomy, which makes invasion of critical structures swift and planning of treatment difficult, even when computerized tomography (CT) or magnetic resonance imaging (MRI) of the area are performed. The presence of air filled spaces permits silent growth of these tumours, which produce few symptoms and signs until a considerable volume has been reached. Recently, the TNM classification system of the American Joint Committee on Cancer (AJCC), was reviewed and important changes according to location of the tumour were established, specifically related to infratemporal fossa and pterygoid plates invasion as well as to orbit involvement.2 The epicentre of the tumour, lymph node metastasis (LNM), modality and sequence of treatment are prognostic factors which have been found significant, while others such as age, gender, clinical presentation and histology have not been confirmed as relevant.3,4 Another subject of debate is a classification system for the surgical procedures performed to treat malignancies of the paranasal sinuses. The reporting of surgery is not uniform.5,6 The aim of the present study was to report a series of 109 tumours to define prognostic factors, especially the role of surgery and radiation therapy and the sequence or extension of treatments. A classification of surgical procedures of these areas is suggested from our experience.
1207 were determined with clinical information from case notes, which included in all patients results of nasopharyngoscopy, rhinoscopy and CT. When patients had invasion of orbit contents documented by CT scan, an MRI was employed to assess extent of invasion. Consequently, in our study, patients with T4 category were also divided in two subcategories: T4 without orbit cavity invasion and T4 with orbit cavity invasion. Operative notes completed these evaluations when present. Neck assessment was performed with clinical data, fine needle aspiration biopsy and completed with CT scan performed in all cases. No elective neck dissections were performed. TNM classification was performed according to the 2002 edition of the AJCC staging system.2
Treatment design The sequence of treatment with radiotherapy and/or surgery, surgical procedures, radiotherapy doses and protraction were recorded. Treatment options were: surgery alone, surgeryCadjuvant radiotherapy, radiotherapy alone, radiotherapyCsalvage surgery and chemo-radiotherapy. Patients with advanced age or stage (T4 stages) and debilitating conditions tended to receive radiation therapy as primary treatment. In Fig. 1 we describe the anatomy of the maxillary sinus, as a triangular prism. Surgical procedures are thus classified in four types as described in Table 1, where medial maxillectomy does not differ essentially from what has already been described in the literature.7
Material and methods Clinical charts of patients who attended the head and neck department at the Instituto Nacional de Cancerologı´a, who had diagnosis of paranasal sinuses and nasal cavity malignant neoplasms during the period from January 1981 to December 2001 were retrospectively reviewed. Inclusion criteria were any age and sex as well as treatment given at the Instituto with curative attempt, with a minimum follow-up of 12 months. Diagnosis of plasmocytoma, sarcoma and lymphoma were considered exclusion criteria. The following data were obtained: age, sex, basal hemoglobin, basal lymphocyte counts, tumour epicentre, histopathology type, differentiation grade, invasion to neighboring structures such as orbit, infratemporal fossae, anterior cranial base, nasopharynx, pterygoid plates, middle fossae and skin. The epicentre and staging of the tumour
Statistics Univariate analysis of prognostic factors was performed using the Kaplan and Meier method and differences were analysed with the log-rank test.8 Disease-specific survival times were calculated from admittance date to the hospital to the last visit recorded in charts or death. Death of other causes than cancer, lost to follow-up and last date of follow-up without or with recurrence were censored observations. Those prognostic factors with a probability value of 0.2 or less in the univariate analysis were tested for multivariate analysis. Multivariate analysis of prognostic factors was performed using the Cox’s proportional hazards method.9 The final model was selected by the maximum likelihood criteria.9 SPSS, version 10
1208
J.F. Carrillo et al.
Figure 1 Diagram showing anterior (a), posterolateral (b) and medial walls (c) of the maxillary antrum in an axial view. Letters (d) and (e) correspond to the pterygoid plates and the nasopharynx, respectively. The small drawing shows a tridimensional view of the maxillary antrum, where points 1–2–3 and points 4–5–6 demonstrate schematically the floor of the orbit and palate, respectively. The shadowed wall in the small drawing corresponds to wall (a) in the large drawing.
(1999), software (SPSS, Inc., Chicago, IL) was used for computations.
mean of 52.9. Follow-up period ranged from 12 to 197.3 months with a median of 29 months. Squamous cell carcinoma was found in 78 cases, adenoid cystic carcinoma in 14, undifferentiated carcinoma in seven, mucoepidermoid carcinoma in six, and adenocarcinoma in four. The epicentre of the tumour was located in 96 cases in the maxillary antrum body and in 13 cases in the nasal cavity (medial wall of the maxillary antrum). Tumours with a clear epicentre in the ethmoid, frontal or sphenoid sinuses were not found, but extension to these sinuses occurred in 40, 14 and 8 cases, respectively. There were nine cases with invasion to floor or medial wall of the orbit. Extension to pterygomaxillary fissure, infratemporal fossae, anterior floor of skull base, middle floor of skull base and nasopharynx occurred in 21, 37, 14, 6 and 19 cases, respectively. Presenting symptoms were: facial asymmetry (84 patients), palate tumour (68), pain (67), nasal fossa tumour (46), diplopia (29), epistaxis (11) and trismus (1 case). Tumours presented in T1–T2 stage in 10 cases, T3 stage in 29 cases, in T4 without orbit invasion in 35 cases, and 35 cases were T4 tumours with orbit invasion. Lymph-node metastasis (LNM) were present in 16 patients and the nodal disease was staged N1 in eight patients, N2a in four patients, and N2b in four patients. A correlation between T classification and LNM was found, with 0/10, 4/29, 5/35 and 7/35 patients with LNM for T1–T2, T3, T4 without orbital invasion and T4 with orbit cavity invasion, respectively. The correlation coefficient was 0.128 (pZ 0.118). In addition to this incidence, during followup, 20 patients with T3–T4 tumours recurred with lymph node metastasis, and from these 16 have died.
Results Treatment One hundred and nine patients attended our institution in his period and constitute the database of this study. There were 66 men and 43 women (a ratio of 1.2:1). The age range was 14–87 years with a Table 1
The characteristics of patients and modality of treatment received in our series are described in Table 2.
Surgical classification of maxillectomy for treatment of malignancy of the paranasal sinus and nasal cavity Details
Type I: total maxillectomy Type IIa: subtotal superior maxillectomy Type IIb: subtotal inferior maxillectomy Type III: medial maxillectomy
Resection of the five walls of the maxillary antrum trying to preserve as much as possible of the floor of the orbit Resection of four walls of the antrum with preservation of palate Resection of four walls of the antrum preserving the floor of the orbit Resection of the medial wall of the antrum with varying extensions of floor of the orbit as well as the ethmoid cells. May be combined with resection of the palate
Maxillary sinus and nasal cavity carcinoma
1209
Of note is that 67 patients had surgery included in their treatment strategy, while radiation therapy was administered to 99 cases. Regarding radiotherapy the median tumour dose was 63.8 Gy (range, 46.4–72.1 Gy); the median fraction size was 2 Gy (range 1.5–3) and the median overall times were 55 days, range (35–60).
Recurrences and survival Sixty-nine patients had recurrences. Recurrences occurred locally in 46 cases, locally and regionally in three cases and only regionally in 17 cases. Metastasis occurred in three cases. Salvage treatment was successful in three patients with local recurrences, and in four patients with only regional recurrences. The rest of patients are dead because of progression of recurrent disease. At the time of the analysis of this study 72 patients have died, 62 were cancer-related mortality and 10 were due to other causes. The median overall cancer-specific survival for the entire cohort was 2.36 years (95% CI 1.16–3.56). The overall survival was 39.6% at 5 years. When survival according to histologic diagnosis was analysed no statistical difference was found when comparing squamous cell carcinoma, salivary gland malignancies, and undifferentiated lesions (pZ0.5). Survival curves by T classification and lymph node status are depicted in Fig. 2(A) and (B), where we can see that T4 tumours and positive lymph nodes were associated with lower survival (p! 0.05). Orbit invasion was analysed as well as a specific prognostic factor and worse prognosis was found for patients who had extension of the tumour to the orbit, as is shown in Fig. 2(A) (pZ0.0006). Disease specific survival of patients treated with surgery as primary treatment was 56% at 5 years, and of those treated with radiotherapy 19.5% at 5 years, as depicted in the Kaplan–Meier curves shown in Fig. 2(C) (pZ0.0011). The corresponding curves Table 2
for patients who had surgical resection included in the design of treatment (50% survival at 5 years) and of those who did not (20% survival at 5 years) are shown in Fig. 2(D), with statistical significance (pZ 0.0003). Other prognostic factors which reached statistical significance in the univariate analysis were: age, hemoglobin level, nasal cavity epicentre, and anterior skull base invasion. Invasion to nasopharynx, infratemporal fossae, pterygoid plates, floor or medial wall of the orbit, invasion to anterior versus posterior half of orbit, histology and surgical margins did not reach statistical significance. By multivariate analysis, T classification, invasion to the orbit, presence of positive lymph nodes, nasal cavity epicentre, and the inclusion of surgical resection in treatment design were independent prognostic factors predicting survival (Table 3).
Discussion Paranasal sinus malignancies have been difficult to diagnose in early stages,10 because of the air filled nature and deep position of structures involved. Besides, adequate diagnostic tools have been unavailable until recently.3 Consequently, strategies for treatment have not been devised uniformly, and modalities of therapy are still in stage of development.
Staging and orbit invasion In 1977, the AJCC established the first staging system for paranasal sinus carcinoma, and invasion to the pterygoid muscles, infratemporal fossa and orbit indicated T3 tumours. Attempts to demonstrate prognostic significance with this staging system failed, and major modifications were done in the AJCC staging system of 1997. However, infratemporal fossa and pterygoid plates invasion remained in the T3 category.11 In the 2002 staging
Age and TNM of patients according to modality of treatment
Patients characteristics No. of patients Mean age T1 T2 T3 T4 NC
Sx 10 42 1 0 6 3 1
SxCRT 39 52 1 8 12 18 1
RT 37 59 0 0 5 32 9
RTCSx 18 49 0 0 4 14 4
ChtCRT 5 51 0 0 2 3 1
Sx, surgery; RT, radiotherapy; Cht, chemotherapy; SxCRT, surgeryCadjuvant radiotherapy; RTCSx, radiotherapyCsalvage surgery; ChtCRt, chemo-radiotherapy.
1210
J.F. Carrillo et al.
Figure 2 Kaplan–Meier disease specific survival curves. (A) According to T stage and orbital invasion, log-rank pZ 0.0006. (B) According to lymph node metastasis, log-rank pZ0.00001. (C) According to primary treatment used, logrank pZ0.0011. (D) According to surgical resection inclusion in design of treatment, log-rank pZ0.0003.
system,3 a division of orbit invasion as well as of dural involvement was established and infratemporal fossa and pterygoid plates invasion were considered T4 lesions. Table 3 Results of multivariate analysis: Cox proportional hazards model Prognostic factor
R.R.
p
95% CI
T classification T1–T2 T3 T4 without orbit invasion T4 with orbit invasion NC No nasal epicentre No surgical resection
–
0.0001
–
1 1.98 2.97
– 0.38 0.152
0.44–8.99 0.67–13.18
6.88
0.01
1.59–29.8
4.13 1.8
0.0001 0.029
2.14–7.94 1.06–3.07
1.59
0.1
0.92–2.76
In the multivariate analysis, T classification was the most significant prognostic factor (pZ0.0001), particularly with the difference established in our work between T4 tumours without orbit invasion and T4 tumours with orbit invasion. High prognostic significance (pZ0.01) was found for T4 tumours with orbit invasion in multivariate analysis, which has been confirmed in few reports.11,12 However, we could not find any difference in survival when dividing anterior half invasion versus posterior half invasion to the orbit. Recently, studies which consider orbital preservation in cases with maxillary antrum carcinoma with invasion to the orbit have appeared.13 Our findings apparently support this conservative approach, since bad prognosis is already established with orbit invasion, and preservation procedures do not compromize survival nor increase recurrence rates as described by Imola.14 Moreover, primary treatment with radiotherapy or chemoradiation would probably give similar results in these cases in terms of loco-regional control and survival with better quality of life than orbit exenteration.15 Invasion to floor or medial wall of the orbit
Maxillary sinus and nasal cavity carcinoma compared with frank invasion did not reach significance, probably because of the small number of patients in the first category. Invasion to infratemporal fossa or pterygoid plates were not significant prognostic factors, (probably because we had a significant number of cases with involvement of the orbit and anterior skull base as well). However, the oncologic results for cases with invasion to these areas are not better than results in cases of orbital or anterior skull base involvement, even with recent developments in skull base surgery.16,17 These considerations support recent changes in the T classification by the AJCC2 which has moved tumours with invasion to infratemporal fossa and pterygoid plates to the T4 category.
Histology and lymph node metastasis Histology had no major impact on prognosis, as reported in other studies.11,18 This may be explained because most of these studies, like ours, refer to T3–T4 tumours, and such lesions probably already have a median to bad prognosis because of the extensive nature of the disease making the comparison of histologies non-significant. This could also be explained by the small numbers of salivary gland malignancies. Some studies point out the adverse prognostic impact of positive lymph nodes on local control, overall survival19,20 and possibility of development of distant metastasis; we also found the presence of positive lymph nodes to have and adverse prognostic effect on survival in the multivariate analyses. Although the overall frequency of clinical LNM was low in our study (14%), these presented in up to 20.6% of cases with T4 tumours with orbit invasion. Moreover, it has been reported in other works11 the presence of lymph node metastasis in up to 22% of cases with advanced stages of epithelial malignancies, with prognostic impact in multivariate analysis as well. Considering these results, and the fact that at follow-up in our study 20% of patients developed lymph node metastasis with 80% mortality, we believe that although the need to treat the neck in T3–T4 lesions has not been studied in depth in previous trials, this should be done in future works. Consideration should be given to treat lymph nodes in T4 tumours19 especially in those with orbit invasion, probably with radiotherapy, since in these malignancies the first echelon of lymph nodes affected are the retro and parapharyngeal nodes.21
1211
Treatment and surgical procedures At present, many of the reports point out the importance of surgery as primary treatment particularly in resectable cases.3 Although our series is biased in patient selection and the group of patients who received radiation therapy as primary treatment has a greater number of T4 cases, the absence of a surgical procedure in the treatment design had an adverse prognostic impact in multivariate analysis. Accordingly, no definitive conclusions can be drawn on the primary treatment to be administered to these patients, although in advanced cases, a combined treatment, which includes surgery, could be the best therapeutic approach. Probably, in patients with non-resectable tumours (lesions with massive invasion to brain parenchyma, infratemporal fossa, unilateral or bilateral orbit involvement, cavernous sinus or carotid artery extension) where free resection margins will not be obtainable upfront, the best modality of treatment would be primary radiotherapy followed by salvage or complementary surgery. Patients with resectable tumours where negative margins could be obtained with surgery and in whom no major aesthetic or functional loss would ensue with the procedure are candidates to surgical treatment followed by adjuvant radiotherapy. In our study, status of surgical margins was not a significant prognostic factor, as has been reported.22 However, others find11 significantly better loco-regional control for patients with negative margins. Resection margins are extremely difficult to evaluate in paranasal sinus carcinomas, since very frequently resection is not in one piece and important aesthetic and functional structures preclude wide limits for excision. It could be that because of the low probability of achieving negative margins in patients with advanced stages of maxillary sinus carcinoma, surgery is more a debulking procedure from the biological standpoint with the objective of leaving the least amount of viable tumour. In Fig. 1 an axial view is shown of the maxillary antrum where three walls are demonstrated, and in the small draw, the floor and roof of the antrum are depicted constituting a five walls triangular prism. Studies like the present, and on osteoplastic maxillotomy where orderly dissection and mobilization is performed of the maxilla,23 as well as analysis of axial views of CT validate these concepts. In this respect, to treat malignancies in our institution the surgical procedures were divided in total maxillectomy, subtotal maxillectomy: superior or inferior, and medial maxillectomy
1212 (Table 1), considering that in a substantial number of patients no other approaches were suitable to treat malignancies, and combination of these procedures with skull base procedures is feasible. When we perform inferior and total maxillectomy for malignancy, pterygoid plates resection is included in an attempt to obtain negative margins.14,15 We try to preserve the malar eminence for better aesthetic results. In conclusion, our study refers to a group of maxillary sinus and nasal fossa cancer cases in advanced stages. We identified T staging, orbit invasion, positive lymph nodes, and absence of surgery in the treatment strategy as adverse prognostic factors. Despite the selection bias in our series, we propose a combined treatment for these lesions where surgery should be included in the treatment strategy. Lymph node treatment should be considered in T3–T4 tumours specially in those with orbit invasion.
References 1. Schantz SP, Harrison LB, Forastiere AA. Tumors of the nasal cavity and paranasal sinuses, nasopharynx, oral cavity, and oropharynx. In: DeVita Jr VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 6th ed. Philadelphia, PA: Lippincott; 2001. p. 797–860. 2. Greene FL, Page DL, Fleming ID, Fritz AG, Balch Ch, Haller DG, et al. Nasal cavity and paranasal sinuses. In: Greene FL, Page DL, Fleming ID, Fritz AG, Balch Ch, Haller DG, Morrow M, editors. American Joint Committee on Cancer: AJCC cancer staging handbook. 6th ed. New York, NY: Springer-Verlag New York, Inc.; 2002. p. 73–80. 3. Dulguerov P, Jacobson MS, Allal AS, Lehmann W, Calcaterra T. Nasal and paranasal sinus carcinoma: are we making progress? Cancer 2001;92:3012–29. 4. Myers LL, Nussenbaum B, Bradford CR, Teknos TN, Esclamado RM, Wolf GT. Paranasal sinus malignancies: an 18-year single institution experience. Laryngoscope 2002; 112:1964–9. 5. Spiro RH, Strong EW, Shah JP. Maxillectomy and its classification. Head Neck 1997;19:309–14. 6. Cordeiro PG, Santamaria E. A classification system and algorithm for maxillectomy and reconstruction of midfacial defects. Plast Reconstr Surg 2000;105:2331–46. 7. Close LG. Medial maxillectomy. In: Bailey B, Calhoun KH, Coffey AR, Neely JG, editors. Atlas of head and neck surgery—otolaryngology. 1st ed. Philadelphia, PA: Lippincott-Raven Publishers; 1996. p. 24–5. 8. Kaplan EL, Meier PM. Nonparametric estimation from incomplete observations. J Am Stat Soc 1958;53:457–81.
J.F. Carrillo et al. 9. Feinstein AR. Proportional hazards analysis (Cox regression). Multivariable analysis: an introduction. New Haven, CT: Yale University Press; 1996. p. 370–97. 10. Yoshimura R, Shibuya H, Ogura I, Miura M, Amagasa T, Enomoto S, et al. Trimodal combination therapy for maxillary sinus carcinoma. Int J Radiat Oncol Biol Phys 2002;53:656–63. 11. Le QT, Fu KK, Kaplan M, Terris DJ, Fee WE, Goffinet DR. Treatment of maxillary sinus carcinoma. Cancer 1999;86: 1700–11. 12. Cantu G, Soleero Cl, Mariani L, Mattavelli F, Pizzi N, Licitra L. A new classification for malignant tumors involving the anterior skull base. Arch Otolaryngol Head Neck Surg 1999;125:1252–7. 13. Nishino H, Ichimura K, Tanaka H, Ishikawa K, Abe K, Fujisawa Y, et al. Results of orbital preservation for advanced malignant maxillary sinus tumors. Laryngoscope 2003;113:1064–9. 14. Imola MJ, Schramm VL. Orbital preservation in surgical management of sinonasal malignancy. Laryngoscope 2002; 112:1357–65. 15. Papadimitrakopoulou VA, Ginsberg LE, Garden AS, Garden AS, Kies MS, Glisson BS, Diaz Jr EM, et al. Intraarterial cisplatin with intravenous paclitaxel and ifosfamide as an organ-preservation approach in patients with paranasal sinus carcinoma. Cancer 2003;98:2214–23. 16. Carrillo JF, Rivas-Leon B, Celis M, Ponce-De-Leon S, OchoaCarrillo FJ. Anterolateral and lateral skull-base approaches for treatment of neoplastic diseases. Am J Otolaryngol 2004; 25:58–67. 17. Bigelow DC, Smith PG, Leonetti JP. Treatment of malignant neoplasms of the cranial base with the combined frontotemporal-anterolateral approach: five year follow-up. Otolaryngol Head Neck Surg 1999;120:17–24. 18. Myers LL, Nussenbaum B, Bradford CR, Teknos TN, Esclamado RM, Wolf GT. Paranasal sinus malignancies: an 18 year single institution experience. Laryngoscope 2002; 112:1964–9. 19. Jeremic B, Shibamoto Y, Milicic B, Nikolic N, Dagovic A, Aleksandrovic J, et al. Elective ipsilateral neck irradiation of patients with locally advanced maxillary sinus carcinoma. Cancer 2000;88:2246–51. 20. Paulino AC, Fisher SG, Marks JE. Is prophylactic neck irradiation indicated in patients with squamous cell carcinoma of the maxillary sinus? Int J Radiat Oncol Biol Phys 1997;39:283–9. 21. Hanna EYN, Westfall ChT. Cancer of the nasal cavity, paranasal sinuses and orbit. In: Myers EN, Suen JY, Myers JN, Hanna EYN, editors. Cancer of the head and neck. 4th ed. Saunders: Philadelphia, PA; 2003. p. 155–205. 22. Sua ´rez C, Llorente JL, Ferna ´ndez de Leo ´n R, Maseda E, Lo ´pez A. Prognostic factors in sinonasal tumors involving the anterior skull base. Head Neck 2004;26:136–44. 23. Carrillo JF, Celis MA, Ramı´rez MC, Rivas-Leo ´n B, OchoaCarrillo FJ. Osteoplastic maxillotomy for the treatment of neoplasms of the nasopharynx and infratemporal fossa. Ann Otol Rhinol Laryngol 2005;104:58–64.
www.ejso.com
Prognostic factors in maxillary sinus and nasal cavity carcinoma ˜ate-Ocan ˜ac ¨emesa, M.C. Ramı´rez-Ortegab, L.F. On J.F. Carrilloa,*, A. Gu a
´n de Cirugı´a, Instituto Nacional de Cancerologı´a, Mexico City, Head and Neck Department, Subdireccio Mexico b ´n de Investigacio ´n, Instituto Nacional de Cardiologı´a Ignacio Cha ´vez, Pharmacology Department, Direccio ´xico City, Mexico Me c ´n de Investigacio ´n Clı´nica, Instituto Nacional de Cancerologı´a, Mexico City, Mexico Subdireccio Accepted for publication 1 April 2005 Available online 31 May 2005
KEYWORDS Paranasal sinuses; Surgery; Prognostic factors; Orbit invasion; Maxillectomy; Maxillary sinus cancer
Abstract Aims: The aim of the present study is to define prognostic factors, particularly the impact of treatment on paranasal sinus and nasal cavity malignancies. Material and methods: Retrospective study of patients with maxillary antrum and nasal fossae malignancies. A maxillectomy classification as performed to treat malignancies in our institution is described. Multivariate analysis of prognostic factors was done using the Cox’s model. Results: One hundred and nine patients were evaluated. Squamous cell carcinoma was found in 62 cases and in 95 patients the epicentre of the tumour was located in the maxillary antrum. Ten patients were treated with surgery only, 39 patients with surgery and adjuvant radiation therapy, 37 cases received only radiotherapy, and 18 received radiotherapy followed by surgery; in five cases a combination of chemoradiotherapy was used. Multivariate analysis identified T classification, orbit invasion, N classification, site of origin of tumour in nasal fossae, and no surgical resection as independent prognostic factors (pZ0.0001). Conclusion: T4 tumours with orbit invasion present bad prognosis as compared to other T4 tumours. Surgical resection should be included in the treatment strategy. Because of the high frequency of lymph-node metastasis, neck treatment should be considered in T4 tumours. Q 2005 Elsevier Ltd. All rights reserved.
Introduction
* Corresponding author. Address: Selva 45, apt 401, Colonia Insurgentes Cuicuilco, CP 04530, Me ´xico City, Me ´xico. Tel.: C52 55 55287235; fax: C52 55 56066947. E-mail address: [email protected] (J.F. Carrillo).
Paranasal and nasal cavity malignancies have a poor prognosis. Most patients present with advanced disease with direct extension to critical areas of the skull base or with rapidly recurrent loco-regional disease after treatment.1
0748-7983/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2005.04.001
Maxillary sinus and nasal cavity carcinoma Several regional characteristics contribute to the complexity in treating maxillary antrum carcinoma such as anatomy, which makes invasion of critical structures swift and planning of treatment difficult, even when computerized tomography (CT) or magnetic resonance imaging (MRI) of the area are performed. The presence of air filled spaces permits silent growth of these tumours, which produce few symptoms and signs until a considerable volume has been reached. Recently, the TNM classification system of the American Joint Committee on Cancer (AJCC), was reviewed and important changes according to location of the tumour were established, specifically related to infratemporal fossa and pterygoid plates invasion as well as to orbit involvement.2 The epicentre of the tumour, lymph node metastasis (LNM), modality and sequence of treatment are prognostic factors which have been found significant, while others such as age, gender, clinical presentation and histology have not been confirmed as relevant.3,4 Another subject of debate is a classification system for the surgical procedures performed to treat malignancies of the paranasal sinuses. The reporting of surgery is not uniform.5,6 The aim of the present study was to report a series of 109 tumours to define prognostic factors, especially the role of surgery and radiation therapy and the sequence or extension of treatments. A classification of surgical procedures of these areas is suggested from our experience.
1207 were determined with clinical information from case notes, which included in all patients results of nasopharyngoscopy, rhinoscopy and CT. When patients had invasion of orbit contents documented by CT scan, an MRI was employed to assess extent of invasion. Consequently, in our study, patients with T4 category were also divided in two subcategories: T4 without orbit cavity invasion and T4 with orbit cavity invasion. Operative notes completed these evaluations when present. Neck assessment was performed with clinical data, fine needle aspiration biopsy and completed with CT scan performed in all cases. No elective neck dissections were performed. TNM classification was performed according to the 2002 edition of the AJCC staging system.2
Treatment design The sequence of treatment with radiotherapy and/or surgery, surgical procedures, radiotherapy doses and protraction were recorded. Treatment options were: surgery alone, surgeryCadjuvant radiotherapy, radiotherapy alone, radiotherapyCsalvage surgery and chemo-radiotherapy. Patients with advanced age or stage (T4 stages) and debilitating conditions tended to receive radiation therapy as primary treatment. In Fig. 1 we describe the anatomy of the maxillary sinus, as a triangular prism. Surgical procedures are thus classified in four types as described in Table 1, where medial maxillectomy does not differ essentially from what has already been described in the literature.7
Material and methods Clinical charts of patients who attended the head and neck department at the Instituto Nacional de Cancerologı´a, who had diagnosis of paranasal sinuses and nasal cavity malignant neoplasms during the period from January 1981 to December 2001 were retrospectively reviewed. Inclusion criteria were any age and sex as well as treatment given at the Instituto with curative attempt, with a minimum follow-up of 12 months. Diagnosis of plasmocytoma, sarcoma and lymphoma were considered exclusion criteria. The following data were obtained: age, sex, basal hemoglobin, basal lymphocyte counts, tumour epicentre, histopathology type, differentiation grade, invasion to neighboring structures such as orbit, infratemporal fossae, anterior cranial base, nasopharynx, pterygoid plates, middle fossae and skin. The epicentre and staging of the tumour
Statistics Univariate analysis of prognostic factors was performed using the Kaplan and Meier method and differences were analysed with the log-rank test.8 Disease-specific survival times were calculated from admittance date to the hospital to the last visit recorded in charts or death. Death of other causes than cancer, lost to follow-up and last date of follow-up without or with recurrence were censored observations. Those prognostic factors with a probability value of 0.2 or less in the univariate analysis were tested for multivariate analysis. Multivariate analysis of prognostic factors was performed using the Cox’s proportional hazards method.9 The final model was selected by the maximum likelihood criteria.9 SPSS, version 10
1208
J.F. Carrillo et al.
Figure 1 Diagram showing anterior (a), posterolateral (b) and medial walls (c) of the maxillary antrum in an axial view. Letters (d) and (e) correspond to the pterygoid plates and the nasopharynx, respectively. The small drawing shows a tridimensional view of the maxillary antrum, where points 1–2–3 and points 4–5–6 demonstrate schematically the floor of the orbit and palate, respectively. The shadowed wall in the small drawing corresponds to wall (a) in the large drawing.
(1999), software (SPSS, Inc., Chicago, IL) was used for computations.
mean of 52.9. Follow-up period ranged from 12 to 197.3 months with a median of 29 months. Squamous cell carcinoma was found in 78 cases, adenoid cystic carcinoma in 14, undifferentiated carcinoma in seven, mucoepidermoid carcinoma in six, and adenocarcinoma in four. The epicentre of the tumour was located in 96 cases in the maxillary antrum body and in 13 cases in the nasal cavity (medial wall of the maxillary antrum). Tumours with a clear epicentre in the ethmoid, frontal or sphenoid sinuses were not found, but extension to these sinuses occurred in 40, 14 and 8 cases, respectively. There were nine cases with invasion to floor or medial wall of the orbit. Extension to pterygomaxillary fissure, infratemporal fossae, anterior floor of skull base, middle floor of skull base and nasopharynx occurred in 21, 37, 14, 6 and 19 cases, respectively. Presenting symptoms were: facial asymmetry (84 patients), palate tumour (68), pain (67), nasal fossa tumour (46), diplopia (29), epistaxis (11) and trismus (1 case). Tumours presented in T1–T2 stage in 10 cases, T3 stage in 29 cases, in T4 without orbit invasion in 35 cases, and 35 cases were T4 tumours with orbit invasion. Lymph-node metastasis (LNM) were present in 16 patients and the nodal disease was staged N1 in eight patients, N2a in four patients, and N2b in four patients. A correlation between T classification and LNM was found, with 0/10, 4/29, 5/35 and 7/35 patients with LNM for T1–T2, T3, T4 without orbital invasion and T4 with orbit cavity invasion, respectively. The correlation coefficient was 0.128 (pZ 0.118). In addition to this incidence, during followup, 20 patients with T3–T4 tumours recurred with lymph node metastasis, and from these 16 have died.
Results Treatment One hundred and nine patients attended our institution in his period and constitute the database of this study. There were 66 men and 43 women (a ratio of 1.2:1). The age range was 14–87 years with a Table 1
The characteristics of patients and modality of treatment received in our series are described in Table 2.
Surgical classification of maxillectomy for treatment of malignancy of the paranasal sinus and nasal cavity Details
Type I: total maxillectomy Type IIa: subtotal superior maxillectomy Type IIb: subtotal inferior maxillectomy Type III: medial maxillectomy
Resection of the five walls of the maxillary antrum trying to preserve as much as possible of the floor of the orbit Resection of four walls of the antrum with preservation of palate Resection of four walls of the antrum preserving the floor of the orbit Resection of the medial wall of the antrum with varying extensions of floor of the orbit as well as the ethmoid cells. May be combined with resection of the palate
Maxillary sinus and nasal cavity carcinoma
1209
Of note is that 67 patients had surgery included in their treatment strategy, while radiation therapy was administered to 99 cases. Regarding radiotherapy the median tumour dose was 63.8 Gy (range, 46.4–72.1 Gy); the median fraction size was 2 Gy (range 1.5–3) and the median overall times were 55 days, range (35–60).
Recurrences and survival Sixty-nine patients had recurrences. Recurrences occurred locally in 46 cases, locally and regionally in three cases and only regionally in 17 cases. Metastasis occurred in three cases. Salvage treatment was successful in three patients with local recurrences, and in four patients with only regional recurrences. The rest of patients are dead because of progression of recurrent disease. At the time of the analysis of this study 72 patients have died, 62 were cancer-related mortality and 10 were due to other causes. The median overall cancer-specific survival for the entire cohort was 2.36 years (95% CI 1.16–3.56). The overall survival was 39.6% at 5 years. When survival according to histologic diagnosis was analysed no statistical difference was found when comparing squamous cell carcinoma, salivary gland malignancies, and undifferentiated lesions (pZ0.5). Survival curves by T classification and lymph node status are depicted in Fig. 2(A) and (B), where we can see that T4 tumours and positive lymph nodes were associated with lower survival (p! 0.05). Orbit invasion was analysed as well as a specific prognostic factor and worse prognosis was found for patients who had extension of the tumour to the orbit, as is shown in Fig. 2(A) (pZ0.0006). Disease specific survival of patients treated with surgery as primary treatment was 56% at 5 years, and of those treated with radiotherapy 19.5% at 5 years, as depicted in the Kaplan–Meier curves shown in Fig. 2(C) (pZ0.0011). The corresponding curves Table 2
for patients who had surgical resection included in the design of treatment (50% survival at 5 years) and of those who did not (20% survival at 5 years) are shown in Fig. 2(D), with statistical significance (pZ 0.0003). Other prognostic factors which reached statistical significance in the univariate analysis were: age, hemoglobin level, nasal cavity epicentre, and anterior skull base invasion. Invasion to nasopharynx, infratemporal fossae, pterygoid plates, floor or medial wall of the orbit, invasion to anterior versus posterior half of orbit, histology and surgical margins did not reach statistical significance. By multivariate analysis, T classification, invasion to the orbit, presence of positive lymph nodes, nasal cavity epicentre, and the inclusion of surgical resection in treatment design were independent prognostic factors predicting survival (Table 3).
Discussion Paranasal sinus malignancies have been difficult to diagnose in early stages,10 because of the air filled nature and deep position of structures involved. Besides, adequate diagnostic tools have been unavailable until recently.3 Consequently, strategies for treatment have not been devised uniformly, and modalities of therapy are still in stage of development.
Staging and orbit invasion In 1977, the AJCC established the first staging system for paranasal sinus carcinoma, and invasion to the pterygoid muscles, infratemporal fossa and orbit indicated T3 tumours. Attempts to demonstrate prognostic significance with this staging system failed, and major modifications were done in the AJCC staging system of 1997. However, infratemporal fossa and pterygoid plates invasion remained in the T3 category.11 In the 2002 staging
Age and TNM of patients according to modality of treatment
Patients characteristics No. of patients Mean age T1 T2 T3 T4 NC
Sx 10 42 1 0 6 3 1
SxCRT 39 52 1 8 12 18 1
RT 37 59 0 0 5 32 9
RTCSx 18 49 0 0 4 14 4
ChtCRT 5 51 0 0 2 3 1
Sx, surgery; RT, radiotherapy; Cht, chemotherapy; SxCRT, surgeryCadjuvant radiotherapy; RTCSx, radiotherapyCsalvage surgery; ChtCRt, chemo-radiotherapy.
1210
J.F. Carrillo et al.
Figure 2 Kaplan–Meier disease specific survival curves. (A) According to T stage and orbital invasion, log-rank pZ 0.0006. (B) According to lymph node metastasis, log-rank pZ0.00001. (C) According to primary treatment used, logrank pZ0.0011. (D) According to surgical resection inclusion in design of treatment, log-rank pZ0.0003.
system,3 a division of orbit invasion as well as of dural involvement was established and infratemporal fossa and pterygoid plates invasion were considered T4 lesions. Table 3 Results of multivariate analysis: Cox proportional hazards model Prognostic factor
R.R.
p
95% CI
T classification T1–T2 T3 T4 without orbit invasion T4 with orbit invasion NC No nasal epicentre No surgical resection
–
0.0001
–
1 1.98 2.97
– 0.38 0.152
0.44–8.99 0.67–13.18
6.88
0.01
1.59–29.8
4.13 1.8
0.0001 0.029
2.14–7.94 1.06–3.07
1.59
0.1
0.92–2.76
In the multivariate analysis, T classification was the most significant prognostic factor (pZ0.0001), particularly with the difference established in our work between T4 tumours without orbit invasion and T4 tumours with orbit invasion. High prognostic significance (pZ0.01) was found for T4 tumours with orbit invasion in multivariate analysis, which has been confirmed in few reports.11,12 However, we could not find any difference in survival when dividing anterior half invasion versus posterior half invasion to the orbit. Recently, studies which consider orbital preservation in cases with maxillary antrum carcinoma with invasion to the orbit have appeared.13 Our findings apparently support this conservative approach, since bad prognosis is already established with orbit invasion, and preservation procedures do not compromize survival nor increase recurrence rates as described by Imola.14 Moreover, primary treatment with radiotherapy or chemoradiation would probably give similar results in these cases in terms of loco-regional control and survival with better quality of life than orbit exenteration.15 Invasion to floor or medial wall of the orbit
Maxillary sinus and nasal cavity carcinoma compared with frank invasion did not reach significance, probably because of the small number of patients in the first category. Invasion to infratemporal fossa or pterygoid plates were not significant prognostic factors, (probably because we had a significant number of cases with involvement of the orbit and anterior skull base as well). However, the oncologic results for cases with invasion to these areas are not better than results in cases of orbital or anterior skull base involvement, even with recent developments in skull base surgery.16,17 These considerations support recent changes in the T classification by the AJCC2 which has moved tumours with invasion to infratemporal fossa and pterygoid plates to the T4 category.
Histology and lymph node metastasis Histology had no major impact on prognosis, as reported in other studies.11,18 This may be explained because most of these studies, like ours, refer to T3–T4 tumours, and such lesions probably already have a median to bad prognosis because of the extensive nature of the disease making the comparison of histologies non-significant. This could also be explained by the small numbers of salivary gland malignancies. Some studies point out the adverse prognostic impact of positive lymph nodes on local control, overall survival19,20 and possibility of development of distant metastasis; we also found the presence of positive lymph nodes to have and adverse prognostic effect on survival in the multivariate analyses. Although the overall frequency of clinical LNM was low in our study (14%), these presented in up to 20.6% of cases with T4 tumours with orbit invasion. Moreover, it has been reported in other works11 the presence of lymph node metastasis in up to 22% of cases with advanced stages of epithelial malignancies, with prognostic impact in multivariate analysis as well. Considering these results, and the fact that at follow-up in our study 20% of patients developed lymph node metastasis with 80% mortality, we believe that although the need to treat the neck in T3–T4 lesions has not been studied in depth in previous trials, this should be done in future works. Consideration should be given to treat lymph nodes in T4 tumours19 especially in those with orbit invasion, probably with radiotherapy, since in these malignancies the first echelon of lymph nodes affected are the retro and parapharyngeal nodes.21
1211
Treatment and surgical procedures At present, many of the reports point out the importance of surgery as primary treatment particularly in resectable cases.3 Although our series is biased in patient selection and the group of patients who received radiation therapy as primary treatment has a greater number of T4 cases, the absence of a surgical procedure in the treatment design had an adverse prognostic impact in multivariate analysis. Accordingly, no definitive conclusions can be drawn on the primary treatment to be administered to these patients, although in advanced cases, a combined treatment, which includes surgery, could be the best therapeutic approach. Probably, in patients with non-resectable tumours (lesions with massive invasion to brain parenchyma, infratemporal fossa, unilateral or bilateral orbit involvement, cavernous sinus or carotid artery extension) where free resection margins will not be obtainable upfront, the best modality of treatment would be primary radiotherapy followed by salvage or complementary surgery. Patients with resectable tumours where negative margins could be obtained with surgery and in whom no major aesthetic or functional loss would ensue with the procedure are candidates to surgical treatment followed by adjuvant radiotherapy. In our study, status of surgical margins was not a significant prognostic factor, as has been reported.22 However, others find11 significantly better loco-regional control for patients with negative margins. Resection margins are extremely difficult to evaluate in paranasal sinus carcinomas, since very frequently resection is not in one piece and important aesthetic and functional structures preclude wide limits for excision. It could be that because of the low probability of achieving negative margins in patients with advanced stages of maxillary sinus carcinoma, surgery is more a debulking procedure from the biological standpoint with the objective of leaving the least amount of viable tumour. In Fig. 1 an axial view is shown of the maxillary antrum where three walls are demonstrated, and in the small draw, the floor and roof of the antrum are depicted constituting a five walls triangular prism. Studies like the present, and on osteoplastic maxillotomy where orderly dissection and mobilization is performed of the maxilla,23 as well as analysis of axial views of CT validate these concepts. In this respect, to treat malignancies in our institution the surgical procedures were divided in total maxillectomy, subtotal maxillectomy: superior or inferior, and medial maxillectomy
1212 (Table 1), considering that in a substantial number of patients no other approaches were suitable to treat malignancies, and combination of these procedures with skull base procedures is feasible. When we perform inferior and total maxillectomy for malignancy, pterygoid plates resection is included in an attempt to obtain negative margins.14,15 We try to preserve the malar eminence for better aesthetic results. In conclusion, our study refers to a group of maxillary sinus and nasal fossa cancer cases in advanced stages. We identified T staging, orbit invasion, positive lymph nodes, and absence of surgery in the treatment strategy as adverse prognostic factors. Despite the selection bias in our series, we propose a combined treatment for these lesions where surgery should be included in the treatment strategy. Lymph node treatment should be considered in T3–T4 tumours specially in those with orbit invasion.
References 1. Schantz SP, Harrison LB, Forastiere AA. Tumors of the nasal cavity and paranasal sinuses, nasopharynx, oral cavity, and oropharynx. In: DeVita Jr VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 6th ed. Philadelphia, PA: Lippincott; 2001. p. 797–860. 2. Greene FL, Page DL, Fleming ID, Fritz AG, Balch Ch, Haller DG, et al. Nasal cavity and paranasal sinuses. In: Greene FL, Page DL, Fleming ID, Fritz AG, Balch Ch, Haller DG, Morrow M, editors. American Joint Committee on Cancer: AJCC cancer staging handbook. 6th ed. New York, NY: Springer-Verlag New York, Inc.; 2002. p. 73–80. 3. Dulguerov P, Jacobson MS, Allal AS, Lehmann W, Calcaterra T. Nasal and paranasal sinus carcinoma: are we making progress? Cancer 2001;92:3012–29. 4. Myers LL, Nussenbaum B, Bradford CR, Teknos TN, Esclamado RM, Wolf GT. Paranasal sinus malignancies: an 18-year single institution experience. Laryngoscope 2002; 112:1964–9. 5. Spiro RH, Strong EW, Shah JP. Maxillectomy and its classification. Head Neck 1997;19:309–14. 6. Cordeiro PG, Santamaria E. A classification system and algorithm for maxillectomy and reconstruction of midfacial defects. Plast Reconstr Surg 2000;105:2331–46. 7. Close LG. Medial maxillectomy. In: Bailey B, Calhoun KH, Coffey AR, Neely JG, editors. Atlas of head and neck surgery—otolaryngology. 1st ed. Philadelphia, PA: Lippincott-Raven Publishers; 1996. p. 24–5. 8. Kaplan EL, Meier PM. Nonparametric estimation from incomplete observations. J Am Stat Soc 1958;53:457–81.
J.F. Carrillo et al. 9. Feinstein AR. Proportional hazards analysis (Cox regression). Multivariable analysis: an introduction. New Haven, CT: Yale University Press; 1996. p. 370–97. 10. Yoshimura R, Shibuya H, Ogura I, Miura M, Amagasa T, Enomoto S, et al. Trimodal combination therapy for maxillary sinus carcinoma. Int J Radiat Oncol Biol Phys 2002;53:656–63. 11. Le QT, Fu KK, Kaplan M, Terris DJ, Fee WE, Goffinet DR. Treatment of maxillary sinus carcinoma. Cancer 1999;86: 1700–11. 12. Cantu G, Soleero Cl, Mariani L, Mattavelli F, Pizzi N, Licitra L. A new classification for malignant tumors involving the anterior skull base. Arch Otolaryngol Head Neck Surg 1999;125:1252–7. 13. Nishino H, Ichimura K, Tanaka H, Ishikawa K, Abe K, Fujisawa Y, et al. Results of orbital preservation for advanced malignant maxillary sinus tumors. Laryngoscope 2003;113:1064–9. 14. Imola MJ, Schramm VL. Orbital preservation in surgical management of sinonasal malignancy. Laryngoscope 2002; 112:1357–65. 15. Papadimitrakopoulou VA, Ginsberg LE, Garden AS, Garden AS, Kies MS, Glisson BS, Diaz Jr EM, et al. Intraarterial cisplatin with intravenous paclitaxel and ifosfamide as an organ-preservation approach in patients with paranasal sinus carcinoma. Cancer 2003;98:2214–23. 16. Carrillo JF, Rivas-Leon B, Celis M, Ponce-De-Leon S, OchoaCarrillo FJ. Anterolateral and lateral skull-base approaches for treatment of neoplastic diseases. Am J Otolaryngol 2004; 25:58–67. 17. Bigelow DC, Smith PG, Leonetti JP. Treatment of malignant neoplasms of the cranial base with the combined frontotemporal-anterolateral approach: five year follow-up. Otolaryngol Head Neck Surg 1999;120:17–24. 18. Myers LL, Nussenbaum B, Bradford CR, Teknos TN, Esclamado RM, Wolf GT. Paranasal sinus malignancies: an 18 year single institution experience. Laryngoscope 2002; 112:1964–9. 19. Jeremic B, Shibamoto Y, Milicic B, Nikolic N, Dagovic A, Aleksandrovic J, et al. Elective ipsilateral neck irradiation of patients with locally advanced maxillary sinus carcinoma. Cancer 2000;88:2246–51. 20. Paulino AC, Fisher SG, Marks JE. Is prophylactic neck irradiation indicated in patients with squamous cell carcinoma of the maxillary sinus? Int J Radiat Oncol Biol Phys 1997;39:283–9. 21. Hanna EYN, Westfall ChT. Cancer of the nasal cavity, paranasal sinuses and orbit. In: Myers EN, Suen JY, Myers JN, Hanna EYN, editors. Cancer of the head and neck. 4th ed. Saunders: Philadelphia, PA; 2003. p. 155–205. 22. Sua ´rez C, Llorente JL, Ferna ´ndez de Leo ´n R, Maseda E, Lo ´pez A. Prognostic factors in sinonasal tumors involving the anterior skull base. Head Neck 2004;26:136–44. 23. Carrillo JF, Celis MA, Ramı´rez MC, Rivas-Leo ´n B, OchoaCarrillo FJ. Osteoplastic maxillotomy for the treatment of neoplasms of the nasopharynx and infratemporal fossa. Ann Otol Rhinol Laryngol 2005;104:58–64.