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Sinonasal Adenoid Cystic Carcinoma The M. D. Anderson Cancer Center Experience
Allison D. Lupinetti, MD1 Dianna B. Roberts, PhD1 Michelle D. Williams, MD2 Michael E. Kupferman, MD1 David I. Rosenthal, MD3 Franco Demonte, MD4 Adel El-Naggar, MD2 Randal S. Weber, MD1 Ehab Y. Hanna, MD1
BACKGROUND. Adenoid cystic carcinoma of the sinonasal tract is a rare cancer that accounts for 10% of all malignancies at this site. The objective of the current study was to evaluate prognostic factors, treatment outcomes, recurrence patterns, and survival rates for sinonasal adenoid cystic carcinoma.
METHODS. A retrospective chart review was performed at an academic tertiary referral center. Between 1990 and 2004, 105 patients were evaluated for adenoid cystic carcinoma of the sinonasal tract at a single institution. Demographics, presentation, anatomic site, Tumor, Lymph Node, Metastasis (TNM) classification, pathology, treatment, recurrences, and survival were evaluated.
RESULTS. One hundred five patients with adenoid cystic carcinoma were evalu1
Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 2
Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
ated, including 58 women and 47 men. Their median age was 50 years, and the mean follow-up was 47 months. The maxillary sinus (47%) and the nasal cavity (30%) were the most common primary tumor sites. The majority of patients presented with T3/T4 (76.7%), N0 (98%), M0 (97%) disease. Eighty-four percent of patients underwent surgery and received postoperative radiation as treatment for their primary disease. The local recurrence rate was 30%, and the distant metas-
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
tases rate was 38%. The 5-year overall survival and disease specific survival rates
4
ease, and the ideal treatment paradigm has yet to be defined. The current data
3
Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
were 62.9% and 70.9%, respectively.
CONCLUSIONS. Adenoid cystic carcinoma of the paranasal sinuses is a rare dissuggested that surgical resection with postoperative radiation therapy offers durable local control and compares favorably with historic data. Although local recurrences develop in a significant percentage of patients, survival from this disease exceeds that of other sinonasal malignancies. Cancer 2007;110:2726–31. 2007 American Cancer Society.
KEYWORDS: sinonasal carcinoma, paranasal sinus, nasal cavity, prognostic indicators, surgery, survival.
M Supported in part by the RNR Cross Family Foundation and the Patricia L. Knebel Memorial Fund of the Pittsburgh Foundation. Address for reprints: Ehab Y. Hanna, MD, Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Unit 441, 1515 Holcombe Boulevard, Houston, TX 77030-4095; Fax: (713) 794-4662; E-mail:
[email protected] Received June 28, 2007; accepted July 6, 2007.
ª 2007 American Cancer Society
alignant sinonasal tumors are relatively rare, accounting for 3% of all upper respiratory tract cancers. Adenoid cystic carcinoma (ACC) is of salivary gland origin and is the second most common tumor of the nasal cavity and paranasal sinuses. Sinonasal ACC accounts for 10% to 25% of all head and neck ACC.1 Sinonasal tumors often are asymptomatic or mimic inflammatory diseases, leading to a delay in diagnosis. Many patients present with advanced-stage disease and extensive involvement of surrounding structures, including the dura, brain, orbits, carotids, and cranial nerves. In addition, ACC has a propensity for perineural spread and bony invasion, which can lead to significant skull base involvement and intracranial extension. These findings make treating sinonasal ACC challenging and potentially morbid.
DOI 10.1002/cncr.23096 Published online 24 October 2007 in Wiley InterScience (www.interscience.wiley.com).
Sinonasal ACC at MDACC/Lupinetti et al.
Because sinonasal tumors are uncommon, it has been difficult to define the characteristics and treatment options for the different histologies that are observed in this area. The objective of this study was to evaluate prognostic factors, treatment outcomes, recurrence patterns, and survival rates for patients with sinonasal ACC at a single institution.
MATERIALS AND METHODS A retrospective chart review was conducted of patients who were treated for ACC of the sinonasal tract between 1990 and 2004 at the University of Texas M. D. Anderson Cancer Center (MDACC). Patients who were included in the study had biopsyproven ACC of 1 of the following sites: nasal cavity; maxillary sinus, ethmoid sinus, sphenoid sinus, or frontal sinus. Computed tomography scans and magnetic resonance studies were used to determine the epicenter of the tumor. In patients with advancedstage disease, the site of origin was assigned to the location with the greatest tumor volume. Radiographic imaging also was used to evaluate tumor extension into surrounding structures, including the palate, orbit, infratemporal fossa, cranial nerves, carotid artery, skull base, dura, brain, and cavernous sinus. Tumors were staged according to the 2002 American Joint Committee on Cancer staging system for nasal cavity and paranasal sinus tumors. Primary tumors of the sphenoid and frontal sinus were uncommon and, thus, were analyzed with tumors of the ethmoid sinuses. Pathology was reviewed by 1 pathologist at the MDACC. Surgical resection specimens were analyzed for growth pattern (tubular, cribriform, or solid), for margins, and for perineural, bony, dural, brain, and orbital invasion. Tumors were classified into predominately tubular, cribriform, or solid if the tubular or cribriform pattern exceeded 80%, and they were classified as solid when 30% of this growth pattern was present. Medical records concerning patient risk factors, presenting symptoms, surgical interventions, adjuvant therapy, and recurrences were reviewed. Tobacco and alcohol use were evaluated as patient risk factors. Presenting symptoms, including sinonasal, orbital, and oral complaints and sensory changes, were analyzed. The surgical treatments that were reviewed included craniofacial resection, endoscopic or endoscopic-assisted resection, maxillectomy, septectomy, and rhinectomy. Adjuvant therapies were analyzed and included radiation and chemotherapy. Recurrences were determined by clinical ex-
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TABLE 1 Demographic Data Parameter
No. of patients (%)
All patients Sex Women Men Age, y Mean Range Ethnicity White Black Latin American Asian Tobacco use Never Former/current Alcohol use Never Former/current
105 (100) 58 (55.2) 47 (44.8) 50.8 18–81 76 (72.4) 14 (13.3) 12 (11.4) 2 (1.9) 46 (48.4) 49 (51.6) 67 (74.4) 23 (25.6)
amination, laboratory work, chest x-rays, and computed tomography scans. The outcomes that were measured included disease-specific survival, disease-free survival, and overall survival. Curves describing these outcomes were generated by using the Kaplan-Meier product-limit method. The statistical significance between the actuarial curves was tested with the log-rank test. Follow-up was calculated as the time from the first appointment at MDACC for the primary tumor of concern until the date of either last contact or death. Disease-free survival was measured from the date patients completed treatment to the date of documented disease recurrence.
RESULTS From 1990 to 2004, 105 patients with sinonasal ACC were seen at MDACC. The mean patient age at presentation was 50.8 years (range, 18–81 years). Most patients were Caucasians (72.4%), nonsmokers (48.4), and nondrinkers (74.4%) (Table 1). Common presenting symptoms included nasal obstruction, facial pain, epistaxis, nasal drainage, and facial numbness in the distribution of the second division of the trigeminal nerve (Table 2). Forty-eight percent of patients presented to MDACC after initial diagnosis of their disease, whereas 19% presented with residual disease after prior treatment, and 33% presented with recurrent disease. The site of origin of the tumor was the maxillary sinus in 46.7% of patients, the nasal cavity in 29.5%, the ethmoid sinus in 11.4%, and the sphenoid
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TABLE 2 Presenting Symptoms of Sinonasal Adenoid Cystic Carcinoma
TABLE 3 Disease Characteristics
Symptom
Percentage of patients
Parameter
Nasal obstruction Facial pain Epistaxis Nasal drainage V2 numbness Oral swelling Facial swelling Loss of visual acuity Loss of smell Epiphora Oral ulcers
45.7 32.4 26.7 14.3 14.3 14.3 12.4 7.6 4.8 3.8 2.9
Disease presentation at MDACC Initial Persistent Recurrent Tumor epicenter Maxillary sinus Nasal cavity Ethmoid sinus Sphenoid sinus Other Tumor extends to skull base Tumor invades skull base TNM classification T1 T2 T3 T4 N0 N1 M0 M1 Clinical stage I–III IV
V2 indicates the second division of the trigeminal nerve.
sinus in 4.8%. At the time of initial diagnosis, 27.6% of tumors extended to the skull base, and 23.8% invaded the skull base (Table 3). Most patients presented with tumors that were classified as T4 (65%), followed by T2 (20.4%), T3 (11.7%), and T1 (2.9%). Lymph node and distant metastatic disease was uncommon at presentation. Sixty-four percent of patients had stage IV disease, and 35.8% of patients had stage I, II, or III disease (Table 3). Reevaluation of tumor tissues confirmed the ACC diagnosis in all cases. On the basis of the extent of the histologic phenotype the cribriform histopathology type of ACC was most common Surgical margins were evaluated and a majority of resection specimens contained microscopically positive disease (60.6%). Other characteristics were also evaluated on the surgical specimens including bone invasion (41%), perineural invasion (40%) and angioinvasion (3.8%) (Table 4). Seventy-one patients underwent surgery (67.6%). Surgical intervention included total maxillectomy (19%), medial maxillectomy (18.1%), craniofacial resection (16.2%), infrastructure maxillectomy (13.3%), and orbital exenteration (7.6%). Only 5 patients (7.1%) underwent neck dissection. Most surgical patients received postoperative radiation therapy (84.5%). Only 14 patients received radiation therapy as their sole modality of treatment. Radiation also was used as palliative treatment in 2 patients. The mean dose of radiation therapy was 60 grays (Gy) (range, 25–77 Gy). Chemotherapy most commonly was reserved for palliative treatment (14.5%). The agents used included 5-fluorouracil, cisplatin, and carboplatin. The overall treatment complication rate was 15.2%, and the surgical complication rate was 6.7%.
No. of patients (%)
48 (48) 19 (19) 33 (33) 49 (46.7) 31 (29.5) 12 (11.4) 5 (4.8) 8 (7.6) 29 (27.6) 25 (23.8) 3 (2.9) 21 (20.4) 12 (11.7) 67 (65) 101 (98) 2 (2) 98 (97) 3 (3) 34 (35.8) 61 (64.2)
MDACC indicates M. D. Anderson Cancer Center; TNM, Tumor, Lymph Node, Metastasis classification.
TABLE 4 Histopathology of Sinonasal Adenoid Cystic Carcinoma Parameter Histologic type Tubular Cribriform Solid Margins Negative Microscopically positive Grossly positive Bone invasion Perineural invasion Angioinvasion
No. of patients (%)
11 (19.6) 29 (51.8) 16 (28.6) 12 (36.4) 20 (60.6) 1 (3) 43 (41) 42 (40) 4 (3.8)
Complications included fistula, cranial nerve 7 paralysis, epiphora, ectropion, dystopia, trismus, intracranial hematoma, cerebrospinal fluid leak, pneumocephalus, and osteoradionecrosis. The mean follow-up after presentation at MDACC was 47.2 months. The mean follow-up after the end of original treatment to the date of last contact was 76.6 months. The overall recurrence rate was 56.2%. Of these recurrences, 30.5% were local, 18.1% were regional, and 38.1% were distant. The lung was the most common site of distant metastatic
Sinonasal ACC at MDACC/Lupinetti et al.
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TABLE 5 Recurrence Patterns for Sinonasal Adenoid Cystic Carcinoma Parameter
No. of patients (%)
Mean follow-up, mo Type of recurrence Local Regional Distant Sites of distant metastasis Lung Liver Bone Adrenal Spleen
76.6 32 (30.5) 19 (18.1) 40 (38.1) 31 7 6 1 1
FIGURE 2. Overall survival by tumor site. NasalCav indicates nasal cavity; MaxSinus, maxillary sinus; MDACC, M. D. Anderson Cancer Center.
FIGURE 1. Overall and disease-specific survival for all patients with sinonasal adenoid cystic carcinoma. MDACC indicates M. D. Anderson Cancer Center.
FIGURE 3. Overall survival by tumor stage. MDACC indicates the M. D. disease followed by liver, bone, adrenal, and spleen (Table 5). The overall survival and disease-specific survival rates at 5 years for patients with sinonasal ACC were 62.9% and 70.9%, respectively (Fig. 1). When the overall survival and disease-specific survival of patients was compared according to the epicenter of the original tumor, patients with nasal cavity tumors had the best survival, and patients with sphenoid tumors had the worst survival (P 5 .003 and P 5 .031, respectively) (Fig. 2). Skull base invasion also was identified as a significant factor for overall and disease-specific survival compared with no skull base invasion (P 5 .029 and P 5 .031, respectively). Orbital and infratemporal fossa invasion were not identified as significant factors that affected overall or diseasespecific survival. Patients with stage IV disease had worse overall survival than patients with stage I, II, and III disease (P 5 .018) (Fig. 3). In addition, when
Anderson Cancer Center.
patients were grouped according to T classification, patients who had T4 disease had a worse overall survival compared with patients who had T1, T2, or T3 disease (P 5 .013) When the histopathologic types of ACC were compared, there was a significant difference in overall and disease-specific survival: Patients with cribriform tumors had the best survival, and patients with solid tumors had the worst outcome (P 5 .002 and P 5 .019, respectively) (Fig. 4). Surgery with postoperative radiation provided the best overall and disease-specific survival compared with other treatment modalities (P 5 .018 and P 5 .05, respectively) (Fig. 5). In addition, treating the original disease with surgery as opposed to radiation or chemotherapy significantly improved survival (P < .001).
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FIGURE 4. Overall survival by histopathologic subtype of adenoid cystic
FIGURE 5. Overall survival by treatment modality. XRT indicates external-
carcinoma. Path type indicates pathologic type; MDACC, M. D. Anderson
beam radiotherapy; Chemo, chemotherapy; Surg/Srg, surgery; MDACC, M. D.
Cancer Center.
Anderson Center.
There was no significant difference in overall or disease-specific survival for sex, age, ethnicity, tobacco, or alcohol use. Recurrences of any type, treatment of recurrence, or response to treatment of recurrence did not affect overall survival. There was no significant difference in the time to first recurrence for T classification, overall stage, histopathologic type, or pathologic grade.
DISCUSSION Malignancies of the sinonasal tract account for only 3% to 5% of all head and neck cancers.1,2 ACC is one of several minor salivary gland tumors that can arise in the nasal cavity and paranasal sinuses, and it is the second most common malignancy in this region after squamous cell carcinoma.2 Common presenting symptoms of sinonasal ACC include nasal obstruction, facial pain, epistaxis, nasal drainage, and loss of smell—the same symptoms observed in patients with sinusitis and inflammatory nasal conditions.1 This can lead to a delay in diagnosis and treatment. In the current study, the majority of patients presented with advanced-stage disease (64.2%), which illustrates this point. In this study, we observed that patients who had stage IV disease had a worse overall and disease-specific survival than patients who had earlier stage disease. The maxillary sinus is the most common site of these tumors followed by the nasal cavity, as reported previously.1,3,4 This was confirmed in our study. In addition, when we examined survival based on the epicenter of the tumor, patients who had tumors of the nasal cavity had the best overall and
disease-specific survival, whereas patients who had sphenoid tumors had the worst survival. The sphenoid sinus is a rare site (4.8%); however, its proximity to the skull base allows for early involvement. In the current study, we observed that skull base invasion had a negative study impact on overall and diseasespecific survival. This would account for why patients with sphenoid tumors had such poor survival. ACC can be composed of 1 histopathologic subtype(s), including tubular, cribriform, and solid. Cribriform is known as the most common type,1 which also was demonstrated in the current study. When we examined overall and disease-specific survival for the histopathologic subtypes of ACC, patients who had the cribriform type had significantly better outcomes than patients who had solid tumors. Prior studies5,6 have indicated that surgery with postoperative radiation therapy is the most common treatment for patients with sinonasal ACC; however, those studies failed to identify a significant association with survival. In our study, we examined treatment types, including surgery, radiation, and chemotherapy as well as combinations of these therapies. We observed that patients who were treated with surgery and postoperative radiation had significantly improved overall and disease-specific survival compared with patients who underwent other treatment options, including surgery alone and radiation alone. ACC is considered a radiosensitive disease; however, in most patients, it cannot be cured by radiation alone.6,7 The major advantage of using postoperative radiation therapy may be to clear positive margins
Sinonasal ACC at MDACC/Lupinetti et al.
that are left after surgery.8 Despite radiation, patients who were treated with surgery and postoperative radiation had a high recurrence rate (65%). This may be because of the tendency of ACC to spread perineurally. Some authors have postulated that postoperative radiation likely delays rather than prevents recurrences.5,9 The treatment of a patient’s original disease also had an impact on survival. In the current study, patients who underwent surgery as part of their primary treatment had significantly improved overall survival compared with patients who did not undergo surgery. In contrast, the type of treatment for recurrent disease did not affect survival. This observation suggests that, to make a difference in a patient’s overall survival, aggressive initial surgical intervention is warranted. Overall 5-year survival rates for patients with sinonasal ACC from 50% to 86% have been reported.1,4,9 In our study, the overall and disease-specific 5-year survival rates were 62.9% and 70.9%, respectively. Our overall recurrence rate was 56.2%: This demonstrates that these tumors have a high tendency to recur, which impacts long-term survival. In conclusion, sinonasal ACC is a rare tumor that usually presents as late-stage disease. Poor prognostic factors that affect survival include tumor site, skull base invasion, stage, histopathologic type, and pathologic grade. Surgery combined with postoperative radiation provides the best overall survival in patients with sinonasal ACC. Chemotherapy still has not been proven effective in the treatment of this disease. Although local recurrences develop in a sig-
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nificant percentage of patients, survival from this disease exceeds that of other sinonasal malignancies. Further studies will help define the therapeutic modalities that would maximize outcome and minimize treatment-related morbidity.
REFERENCES 1. Rhee CS, Won TB, Lee CH, et al. Adenoid cystic carcinoma of the sinonasal tract: treatment results. Laryngoscope. 2006; 116:982–986. 2. Cruz Perez DE, Pires FR, Lopes MA, de Almeida OP, Kowalski LP. Adenoid cystic carcinoma and mucoepidermoid carcinoma of the maxillary sinus: report of a 44-year experience of 25 cases from a single institution. J Oral Maxillofac Surg. 2006;64:1592–1597. 3. Dulguerov P, Jacobsen MS, Allal AS, Lehmann W, Calcaterra T. Nasal and paranasal sinus carcinoma: are we making progress? A series of 220 patients and a systematic review. Cancer. 2001;92:3012–3029. 4. Myers LL, Nussenbaum B, Bradford CR, Teknos TN, Esclamado RM, Wolf GT. Paranasal sinus malignancies: an 18year single institution experience. Laryngoscope. 2002;112: 1964–1969. 5. Katz TS, Mendenhall WM, Morris CG, Amdur RJ, Hinerman RW, Villaret DB. Malignant tumors of the nasal cavity and paranasal sinuses. Head Neck. 2002;24:821–829. 6. Wiseman SM, Popat SR, Rigual NR, et al. Adenoid cystic carcinoma of the paranasal sinuses or nasal cavity: a 40-year review of 35 cases. Ear Nose Throat J. 2002;81:510–517. 7. Leafstedt SW, Gaeta JF, Sako K, Marchetta FC, Shedd DP. Adenoid cystic carcinoma of major and minor salivary glands. Am J Surg. 1971;122:756–762. 8. Garden AS, Weber RS, Morrison WH, Ang KK, Peters LJ. The influence of positive margins and nerve invasion in adenoid cystic carcinoma of the head and neck treated with surgery and radiation. Int J Radiat Oncol Biol Phys. 1995;32:619–626. 9. Spiro RH. Distant metastasis in adenoid cystic carcinoma of salivary origin. Am J Surg.. 1997;174:495–498.
