ADENOCARCINOMA OF THE NOSE AND PARANASAL SINUSES: A RETROSPECTIVE STUDY OF DIAGNOSIS, HISTOLOGIC CHARACTERISTICS, AND OUTCOMES IN 24 PATIENTS

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1 ADENOCARCINOMA OF THE NOSE AND PARANASAL SINUSES: A RETROSPECTIVE STUDY OF DIAGNOSIS, HISTOLOGIC CHARACTERISTICS, AND OUTCOMES IN 24 PATIENTS Laura J. Orvidas, MD, 1 Jean E. Lewis, MD, 2 Amy L. Weaver, MS, 3 Stephanie M. Bagniewski, BS, 3 Kerry D. Olsen, MD 1 1 Department of Otorhinolaryngology, Mayo Clinic, 200 First Street SW, Rochester, MN orvidas.laura@mayo.edu 2 Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota 3 Division of Biostatistics, Mayo Clinic, Rochester, Minnesota Accepted 5 November 2004 Published online 15 February 2005 in Wiley InterScience ( DOI: /hed Abstract: Background. Adenocarcinomas of the sinonasal cavity are unusual tumors with variable clinical courses. Methods. We conducted a retrospective chart review between 1980 and Results. Twenty-four patients (17 men) with sinonasal adenocarcinoma were identified. Nasal obstruction was the most common presenting symptom (75%), and the nose was the most common site of involvement (83%). Eleven tumors (46%) were high grade (grade 3 or 4). Twenty-three patients (95%) underwent an attempt at surgical excision, with tumor recurrence or residual disease in seven. Age and tumor grade were associated with overall survival, and tumor grade and intracranial extension were associated with death from disease. Conclusions. Presentation and treatment for nasal adenocarcinoma vary widely. Some low-grade variants of nasal adenocarcinomas seem to be associated with a more favorable prognosis and, depending on the extent of the tumor, can be treated with less-aggressive therapy. A 2005 Wiley Periodicals, Inc. Head Neck 27: , 2005 Keywords: adenocarcinoma; malignancy; nose; paranasal sinuses Cancers of the nose and paranasal sinuses are uncommon, representing less than 1% of all malignancies. 1 Adenocarcinoma is the third most common mucosal malignancy found in this area, after squamous cell carcinoma and adenoid cystic carcinoma, 2 and represents approximately 15% of all sinonasal cancers. 3 Because these tumors are rare, few long-term studies outline treatments and outcomes in patients with sinonasal adenocarcinoma. To better define this disease and its treatment, we reviewed the Mayo Clinic experience with adenocarcinoma of the nose and paranasal sinuses. Correspondence to: L. J. Orvidas Presented at the Middle Section of the Triologic Society, Indianapolis, Indiana, January 17, B 2005 Wiley Periodicals, Inc. MATERIALS AND METHODS After obtaining Mayo Foundation Institutional Review Board approval, the Mayo Clinic Surgical Information Recording System was used to identify all patients diagnosed as having sinonasal 370 Nose and Paranasal Sinus Adenocarcinoma HEAD & NECK May 2005

2 adenocarcinoma at our institution between 1980 and Patients were excluded if they did not receive their initial treatment at our institution. Tissue specimens were available from all patients, and tumor histology was reviewed and confirmed by our pathologist (JEL). Perineural or vascular space involvement was not evaluated. All medical records were reviewed for age, sex, presenting symptoms, site of the tumor, side of the tumor, radiographic findings, treatment, and outcomes. Only tumors with glandular differentiation, such as intestinal adenocarcinoma or adenocarcinomas consistent with surface epithelial or minor salivary origin, were included in this study. Tumors that could be classified as a specific salivary type (eg, adenoid cystic or polymorphous low-grade carcinoma) were excluded. Overall survival, cancer-specific survival, and recurrence-free survival were estimated with the Kaplan-Meier method. The duration of follow-up was calculated from the date of treatment to the date of the outcome or last followup. Associations between clinical and pathologic features and each of these outcomes were evaluated univariately by fitting Cox proportional hazards regression models. Relationships with the outcomes were summarized with risk ratios (RRs). All calculated p values were two-sided, and p values less than.05 were considered statistically significant. RESULTS Twenty-four patients with sinonasal adenocarcinoma were identified. Seventeen (71%) were men, and the mean age was 64 F 15 years (range, years). The most common presenting symptom was nasal obstruction, followed by epistaxis (Table 1). Only three patients had a history of wood dust exposure. Diagnosis was Table 1. Symptoms at presentation. No. patients (%) Symptom (N = 24)* Nasal obstruction 18 (75) Epistaxis 9 (38) Rhinitis 5 (21) Face pain 2 (8) Proptosis 2 (8) History of recurrent sinusitis, headache, 1 each (4) history of malignancies, diplopia, serious otitis *Some patients presented with more than one symptom. aided in all patients by radiographic images, with 21 patients (88%) having undergone CT scanning, 11 (46%) having undergone MRI, and two having undergone only plain radiography. All patients who underwent MRI also had a CT scan. The most common site of involvement was the nose (20 patients [83%]), and the most common sinus involved was the ethmoid (12 patients [50%]). Data on demographics, tumor characteristics, treatment, and follow-up are presented for all patients in Table 2. Figure 1 shows an axial MRI scan of a low-grade adenocarcinoma that was resected endoscopically from a patient in this group (patient 21). Of the 24 patients, eight (33%) had intestinaltype adenocarcinomas (three of grade 1, three of grade 2, and two of grade 3); 14 (58%) had adenocarcinomas, not further classified (three of grade 1, two of grade 2, four of grade 3, and five of grade 4); and two had tumors previously diagnosed as low-grade adenocarcinoma that were reclassified on review as probable atypical salivary adenoma. These were included in the review because of their atypical appearance and to increase awareness of the confusion with lowgrade adenocarcinoma. One patient opted for treatment with chemotherapy and radiotherapy alone; 23 patients underwent surgical treatment for their tumor. All but four of these 23 underwent lateral rhinotomy, after which the appropriate resection was performed to ensure negative margins. Resection methods included medial maxillectomy, ethmoidectomy, and craniofacial resection (in 11 patients [48%]) (Table 2). Three of the four patients not undergoing lateral rhinotomy had tumors removed endoscopically (two of grade 1, one of grade 3), and one underwent medial maxillectomy (grade 1). Nine patients (38%) received adjuvant therapy in addition to surgery: two received radiotherapy and chemotherapy preoperatively (one before endoscopic tumor removal), six received radiotherapy postoperatively, and one received radiotherapy and chemotherapy postoperatively. One patient (patient 14) died of postoperative complications 9 days after surgery and was removed from the remainder of the analysis. Another patient (patient 15) had positive margins at the time of surgery. Overall, six patients have experienced at least one recurrence of tumor: two patients (patients 3 and 20) have had one recurrence, three patients (patients 8, 9, and 13) have had two recurrences, and one patient (patient 21) has Nose and Paranasal Sinus Adenocarcinoma HEAD & NECK May

3 Table 2. Summary of patient data. Patient/age, y/sex Location Grade/histologic subtype Treatment Recurrence Length of follow-up Outcome 1/76/F R nose Atypical adenoma LR, MM No 2.8 y NED 2/85/F L nose 2/Adeno LR, MM No 2.3 y DOC 3/56/M L max 1/Adeno MM, Caldwell-Luc 21.3 mo 9.0 y DOC 4/43/M B nose, L NP 1/Adeno LR, MM, ETHM, No 6.5 y NED partial septectomy 5/60/M R nose 2/CI LR, MM No 19.5 y NED 6/78/M L nose, L max, L eth 1/CI LR, MM No 10.7 y DOC 7/77/M R nose, R crib 4/Adeno LR, CFR No 3.9 y DOC 8/55/F L nose, L max, L eth 2/CI LR, MM 15 mo and 19 mo 15.6 y NED 9/60/M L nose, L eth, L front, L crib, 4/Adeno LR, CFR 1.4 mo and 21.1 mo 3.1 y DOD L SK base, L orbit, L int 10/84/F L nose, L eth 1/CI Endo No 0.9 y NED 11/46/M L nose, L max, L eth, L orbit Atypical adenoma LR, MM, ETHM, post rad No 13.3 y NED 12/77/M B nose, L eth, L sphen, L crib 1/CI LR, MM, CFR, post rad No 2.2 y Dead, unknown 13/78/F L nose, L max, L eth, L sphen, L crib, L NP 3/Adeno LR, MM, CFR, post rad 8.1 mo and 14 mo 1.3 y DOD 14/79/M R nose, R max, R SK base, R ET/NP 4/Adeno LR, total max No 9 d DOC 0.7 y DOD 15/52/M R nose, R eth, R crib 3/CI LR, MM, CFR, O, free flap, pre rad, pre chemo No, but positive margins at surgery 16/47/M L nose, L eth, L crib 2/CI LR, MM, CFR, ETH/SPHEN No 8.0 y NED 17/24/M L nose, L crib, L SK base, 4/Adeno LR, MM, CFR, post rad No 8.2 y NED L int, L NP 18/68/M L nose, L max 3/Adeno LR, MM, CFR No 7.7 y NED 19/64/M R max 3/Adeno Endo, pre rad, pre chemo No 6.1 y DOC 20/69/M L eth, L crib, L SK base, L int 3/Adeno LR, MM, CFR, ETH/SPHEN, 8.8 mo 4.0 y DOD post rad 21/66/F R nose 1/Adeno Endo 23.5 mo, 32.9 mo, 2.1 y NED and 35.9 mo 22/59/M L max, L sphen, L SK base, L int 4/Adeno Rad, chemo No 0.6 y DOD 23/61/M R nose, R max, R eth, R crib 3/CI LR, CFR, post rad, post chemo No 2.1 y NED 24/74/M R nose, R eth, R sphen 2/Adeno LR, MM, CFR, post rad No 2.2 y NED Abbreviations: R, right; LR, lateral rhinotomy; MM, medial maxillectomy; NED, alive, no evidence of disease; L, left; Adeno, adenocarcinoma; DOC, dead of other causes; max, maxillary sinus; B, both right and left; NP, nasopharynx; ETHM, ethmoidectomy; CI, colonic or intestinal adenocarcinoma; eth, ethmoid sinus; crib, cribriform; CFR, craniofacial resection; SK base, other skull base; int, intracranial extension; front, frontal sinus; DOD, dead of disease; Endo, endoscopic removal; post rad, postoperation radiotherapy; sphen, sphenoid sinus; ET, eustachian tube; total max, total maxillectomy; O, orbital exenteration; pre rad, preoperative radiotherapy; pre chemo, preoperative chemotherapy; ETH/SPHEN, ethmoidectomy/sphenoidectomy; post chemo, postoperative chemotherapy. 372 Nose and Paranasal Sinus Adenocarcinoma HEAD & NECK May 2005

4 FIGURE 1. Axial MR image showing a left intranasal low-grade adenocarcinoma. had three recurrences. All initial recurrences occurred within 2 years of treatment, and the estimated survival free of recurrence (standard error [SE]; number still at risk) at 1 and 2 years after treatment was 86% (7.4%; 17) and 71% (10%; 14), respectively. Two instances of recurrence were in the four patients not undergoing lateral rhinotomy; one occurred 21 months after medial maxillectomy, and one occurred 23 months after the tumor was removed endoscopically. Two patients (patients 9 and 13) had local metastasis of their tumor to both the parotid gland and neck; both of these patients died of disease. Of the remaining patients with recurrences, one patient died of disease, one died of other causes, and two are currently alive without evidence of disease at 2.1 and 15.6 years after treatment. Two factors, sex and the presence of intracranial tumor, were univariately associated with recurrence. Tumors were 5.8 times more likely to recur in women than men (95% confidence interval [CI], ; p =.04). Patients with intracranial tumor were 5.1 times more likely to have tumor recurrence than those without intracranial tumor, although this association did not attain statistical significance (95% CI, ; p =.07). Age, tumor grade, histologic subtype, adjuvant therapy, and craniofacial resection showed no association with survival free of recurrence. Eleven patients were deceased at last followup, including five who died of disease. Among these 11, the median time from treatment to death was 3.1 years (range, years). The median time from treatment to death from disease was 1.3 years (range, years), compared with the median time from treatment to death from other causes, which was 5.0 years (range, years). The median duration of follow-up for the 12 patients still alive at last follow-up was 7.1 years (range, years). The estimated overall survival rates (SE; number still at risk) at 1, 3, and 5 years were 91% (5.9%; 20), 76% (9.5%; 13), and 58% (11.5%; 10), respectively. Age and tumor grade (low vs high) were univariately associated with overall survival. Each 10-year increase in age was associated with a 75% increase in the risk of death from any cause (RR, 1.8; 95% CI, ; p =.04). Patients with high-grade tumors (grade 3 or 4) were 5.4 times more likely to die of any cause than patients with low-grade tumors (grade 1 or 2) (95% CI, ; p =.04). Sex, histologic subtype, tumor location (with the exception of intracranial extension), adjuvant radiotherapy, and craniofacial resection were not associated with overall survival. The estimated cancer-specific survival rates (SE; number still at risk) at 1, 3, and 5 years were 91% (5.9%; 20), 87% (7.1%; 13), and 73% (10.9%; 10), respectively. Of the five patients who died of disease, three had recurrence of tumor, one was not treated surgically and died within 7 months, and one had positive margins at surgery and died within 8.5 months of initial treatment. Tumor grade (low vs high) determined by pathologic diagnosis and the presence of an intracranial tumor were univariately associated with death from disease. None of the 13 patients with low-grade tumors have died of disease to date, after a median of 6.5 years of follow-up, whereas five of the 10 patients with high-grade tumors have died of disease (p =.008). Of the four patients with an intracranial tumor, three died of disease. The presence of an intracranial tumor was associated with a 7.2-fold increase in the risk of death from disease (95% CI, ; p =.03). In addition, all five deaths from disease occurred among the 13 patients with tumors in more than two locations. Age, sex, histologic subtype, adjuvant radiotherapy, and craniofacial resection showed no association with cancer-specific survival. DISCUSSION Clinical Features. Sinonasal adenocarcinomas can present in a variety of ways. As in the case of most tumors of the nose and paranasal sinuses, however, nasal obstruction and epistaxis are the most common symptoms. Unfortunately, Nose and Paranasal Sinus Adenocarcinoma HEAD & NECK May

5 because of the frequency of these symptoms in many sinonasal diseases and the difficulty in visualizing tumors in this area, adenocarcinomas may be undetected for long periods before diagnosis. This is evidenced by the large number of patients (75% in our series) who have involvement of more than one area of the nose and sinuses at the time of diagnosis. Also in agreement with other studies, 4 7 our study group had a preponderance of men and more frequent involvement of the ethmoid sinus (50% in our series) compared with other sinuses. The association between wood dust exposure and adenocarcinoma of the sinuses is also well established, 8,9 and although only three of our patients (13%) were noted to have wood dust exposure, it is unclear whether the remaining patients were specifically asked about their wood dust exposure. All patients should receive radiographic evaluation to help establish the extent of their tumor, as did all patients in our study. died of disease (Table 2). Although the use of this procedure did not reach statistical significance in our study, further investigation may show this approach to help improve outcomes for patients with sinonasal adenocarcinomas. Perhaps because of its use in patients with extensive disease and high-grade tumors, the addition of radiotherapy to the treatment regimen in our series did not affect survival. Two of our patients were treated for low-grade, localized lesions by endoscopic resection, and although one patient had a late recurrence, it also was managed endoscopically. Although some clinicians advocate endoscopic removal of benign tumors, such as inverting papillomas, 15 removal of malignancy in this fashion is more controversial, because endoscopic visualization of the tumor margins may be more difficult and incomplete resection may be more likely. The best means of ensuring complete removal is by an open approach. Pathologic Considerations. Confusion remains regarding the histologic classification of adenocarcinomas arising in the sinonasal cavity. 10,11 To simplify the comparison and outcomes of these tumors, only intestinal-type tumors and atypical adenomas were differentiated from the general category of adenocarcinomas (believed to be derived from surface epithelium or minor salivary glands) in our patients. Comparison of these subsets of tumors showed no statistically significant difference in survival and agrees with previous studies, 12,13 which found no prognostic advantage to a specific tumor type. An advantage may exist, however, for patients with atypical adenomas. Neither of the two patients in our study reclassified as having atypical adenomas had tumor recurrence or diseaserelated death. Treatment. Surgical excision remains the primary treatment for patients with these tumors. Our only patient who did not undergo resection was treated with radiotherapy and chemotherapy and died 7 months after diagnosis. Also, as would be expected, patients with incomplete resection or intracranial involvement (Table 2) had poor outcomes (four of five died of disease). More recently, studies have shown that patients with resectable disease have benefited from craniofacial resection. 14 Of the 11 patients in our study who underwent craniofacial resection, only four Recurrence. As would be expected, the recurrence rate in our patients was primarily related to the extent of tumor at the time of treatment. Those patients having intracranial extension were 5.1 times more likely to experience tumor recurrence. A more unusual finding was the influence of sex on recurrence. In our series, women were 5.8 times more likely to experience recurrence, yet sex had no influence on overall survival. Survival. Because of the variability in the time of onset of symptoms and the extent of disease at the time of presentation, comparing prognostic indications is difficult. We found no association between cancer-specific survival and age, sex, or histologic subtype. However, higher grade tumors (grade 3 or 4) and the presence of intracranial extension (all were high grade) were associated with death from disease. These factors may influence how aggressively these tumors are treated in the future. The improved 5-year cancer-specific survival rate in our patients (73%) and the rate reported by Dulguerov et al 16 (63%), when compared with earlier studies, 12,13 may be associated with increased use of craniofacial resection in treating this disease, 17 although this variable did not achieve statistical significance in our study. The risk ratios reported here lack precision, as reflected in the widths of the confidence intervals, 374 Nose and Paranasal Sinus Adenocarcinoma HEAD & NECK May 2005

6 but this may be a result of the small sample size. Despite this limitation, this study identified several variables that were significantly associated with tumor recurrence and survival. CONCLUSION Sinonasal adenocarcinomas encompass a variety of histologic variants. Although limited by the small number of patients and the wide range of nose and sinus involvement at the time of presentation, this study demonstrated that the histology of the tumor was not associated with patient survival. Instead, survival was related to grade of tumor and intracranial involvement at the time of diagnosis. Surgical therapy remains the most common treatment, and the use of craniofacial resection may improve outcomes in this area. The addition of radiotherapy to the treatment of these patients does not seem to affect survival, but it may have a role in local or regional control. This was not addressed in our study. The use of endoscopic resection for localized low-grade tumors remains controversial, and further study is needed. REFERENCES 1. Weber AL, Stanton AC. Malignant tumors of the paranasal sinuses: radiologic, clinical, and histopathologic evaluation of 200 cases. Head Neck Surg 1984;6: Batsakis JG. Tumors of the head and neck: clinical and pathologic considerations. 2nd ed. Baltimore, MD: Williams & Wilkins; p Roush GC. Epidemiology of cancer of the nose and paranasal sinuses: current concepts. Head Neck Surg 1979; 2: Harbo G, Grau C, Bundgaard T, et al. Cancer of the nasal cavity and paranasal sinuses: a clinico-pathological study of 277 patients. Acta Oncol 1997;36: Cecchi F, Buiatti E, Kriebel D, Nastasi L, Santucci M. Adenocarcinoma of the nose and paranasal sinuses in shoemakers and woodworkers in the province of Florence, Italy ( ). Br J Ind Med 1980;37: Svane-Knudsen V, Jorgensen KE, Hansen O, Lindgren A, Marker P. Cancer of the nasal cavity and paranasal sinuses: a series of 115 patients. Rhinology 1998;36: Alessi DM, Trapp TK, Fu YS, Calcaterra TC. Nonsalivary sinonasal adenocarcinoma. Arch Otolaryngol Head Neck Surg 1988;114: Luce D, Gerin M, Leclerc A, Morcet JF, Brugere J, Goldberg M. Sinonasal cancer and occupational exposure to formaldehyde and other substances. Int J Cancer 1993;53: Moran CA, Wenig BM, Mullick FG. Primary adenocarcinoma of the nasal cavity and paranasal sinuses. Ear Nose Throat J 1991;70: Batsakis JG, Holtz F, Sueper RH. Adenocarcinoma of nasal and paranasal cavities. Arch Otolaryngol 1963;77: Franchi A, Gallo O, Santucci M. Clinical relevance of the histological classification of sinonasal intestinal-type adenocarcinomas. Hum Pathol 1999;30: Urso C, Ninu MB, Franchi A, Paglierani M, Bondi R. Intestinal-type adenocarcinoma of the sinonasal tract: a clinicopathologic study of 18 cases. Tumori 1993;79: Salassa JR, McDonald TJ, Weiland LH. Colonic type adenocarcinoma of the nasal cavity and paranasal sinuses. Otolaryngol Head Neck Surg 1980;88: Cheesman AD, Lund VJ, Howard DJ. Craniofacial resection for tumors of the nasal cavity and paranasal sinuses. Head Neck Surg 1986;8: Blokmanis A. Endoscopic diagnosis, treatment, and follow-up of tumours of the nose and sinuses. J Otolaryngol 1994;23: Dulguerov P, Jacobsen MS, Allal AS, Lehmann W, Calcaterra T. Nasal and paranasal sinus carcinomas: are we making progress? A series of 220 patients and a systematic review. Cancer 2001;92: Wax MK, Yun KJ, Wetmore SJ, Lu X, Kaufman HH. Adenocarcinoma of the ethmoid sinus. Head Neck 1995;17: Nose and Paranasal Sinus Adenocarcinoma HEAD & NECK May