ORIGINAL ARTICLE
Sinonasal lymphoma: case series and review of the literature Kevin A. Peng, MD1 , Ashley E. Kita, BS1 , Jeffrey D. Suh, MD1 , Sunita M. Bhuta, MD2 and Marilene B. Wang, MD1
Background: Sinonasal lymphoma is a rare rhinologic entity. We present a case series and review the literature surrounding the diagnosis and management of this disease.
5-year overall survival rates were 75% and 53%, respectively, whereas disease-free 2-year and 5-year survival rates were 70% and 49%, respectively.
Methods: A pathology database spanning 22 years at a tertiary care center was searched for a diagnosis of lymphoma in the paranasal sinuses or the nasal cavity. Seventeen cases were identified, and retrospective chart review was performed.
Conclusion: Lymphoma of the nasal cavity and paranasal sinuses is extremely rare, may mimic benign processes, and may manifest either in an isolated fashion or in conjunction with systemic disease. B-cell lymphomas, a more favorable diagnosis, account for a majority of cases, whereas ENKL is associated with rapid disease progression and death. Chemotherapy and radiation are the main therapies. Histologic diagnosis is of paramount importance, and clinicians must remain cognizant of this entity to differentiate it from C 2014 ARS-AAOA, LLC. other sinonasal malignancies.
Results: Maxillary and ethmoid sinuses were affected more frequently (n = 8 patients each) than sphenoid and frontal sinuses (n = 5 patients each). Histologically, the most common type was diffuse large B-cell lymphoma (53%, 9 patients), followed by extranodal natural killer/T-cell lymphoma (ENKL, 21%, 3 patients). Presenting symptoms included nasal obstruction and rhinorrhea (53%, 9 patients) and diplopia (18%, 3 patients); and radiographic imaging demonstrated a discrete mass (59%, 10 patients), sinus opacification (53%, 9 patients), and/or bony erosion (35%, 6 patients). Treatment included chemotherapy alone (71%, 12 patients), chemotherapy and radiation (6%, 1 patient), and radiation alone (6%, 1 patient). The 2-year and
L
ymphomas, which are solid cancers of the lymphoreticular system, are subclassified as Hodgkin’s lymphoma, comprising approximately 10% of all cases, and nonHodgkin’s lymphoma, comprising approximately 90% of all cases.1 Lymphomas account for 4% to 5% of all new cancers diagnosed annually.2 Sinonasal lymphoma is rare,
1 Department
of Head and Neck Surgery, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA; 2 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA Correspondence to: Kevin A. Peng, MD, Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, CHS 62–132, Los Angeles, CA 90095; e-mail: [email protected] Potential conflict of interest: None provided. Presented at the Combined Sections Meeting of the Triological Society, Inc., January 24–26, 2013, Scottsdale, AZ. Received: 21 January 2014; Revised: 6 March 2014; Accepted: 23 March 2014 DOI: 10.1002/alr.21337 View this article online at wileyonlinelibrary.com.
Key Words: chronic rhinosinusitis; endoscopic sinus surgery; radiology; paranasal sinus diseases How to Cite this Article: Peng KA, Kita AE, Suh JD, Bhuta SM, Wang MB. Sinonasal lymphoma: case series and review of the literature. Int Forum Allergy Rhinol. 2014;4:670–674.
representing only 1.5% of all lymphomas.3, 4 Subtypes of non-Hodgkin’s lymphoma presenting in the sinonasal tract include B-cell lymphomas, extranodal natural killer (NK)/T-cell lymphoma (ENKL), nasal type, and other rarer entities. Lymphomas may involve the soft tissues of the external nose, the nasal mucosa, and the paranasal sinuses.4 Previous work has demonstrated an increased incidence of Epstein-Barr virus (EBV)-positive sinonasal lymphoma in Asian countries as compared to the United States and Europe.5 The diagnosis of sinonasal lymphoma is included under the broader entity of midline destructive lesions, alternatively termed lethal midline granulomas and idiopathic midline destructive disease, although this disease entity also includes, most notably, Wegener’s granulomatosis.6, 7 Over the past 2 decades, advances in lymphoma therapy have more recently included the development of rituximab, a chimeric monoclonal antibody against CD-20, which is expressed on over 90% of B-cell lymphomas.6 Therapy for sinonasal lymphoma remains nonsurgical, with most International Forum of Allergy & Rhinology, Vol. 4, No. 8, August 2014
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patients treated with chemotherapy. More aggressive, localized disease may warrant radiation therapy. The goal of the present study was to characterize our institution’s experience with sinonasal lymphoma. Patients with nasal masses, including lymphomas, often present with similar sinonasal symptoms mimicking benign inflammatory sinonasal disease. The objective of this study was to outline the incidence and management of sinonasal lymphoma to allow optimal treatment of the disease.
TABLE 1. Patient characteristics Characteristic
Age, years, median (range)
65 (42–93)
Gender, n (%) Male
8 (47)
Female
9 (53)
Race, n (%)
Materials and methods
White
9 (53)
Institutional Review Board approval was obtained for this study. All pathology records at the University of California, Los Angeles, spanning a 22-year period, 1990 to 2012, were searched using the definition for sinonasal lymphoma as histologically-proven lymphoma specimens isolated from the external nose, nasal mucosa, and paranasal sinuses. Following retrieval of records, a retrospective chart review was performed, and presenting symptomatology, imaging, treatment, and outcomes were reviewed where possible.
Asian
3 (18)
Hispanic
3 (18)
Black
1 (6)
Other
1 (6)
Results Seventeen patients with lymphoma of the nasal cavity and/or paranasal sinuses were identified, of which 8 were male and 9 were female. Patient demographic information is found in Table 1. Median age at diagnosis was 65 (range, 42 to 93) years. Presenting symptoms included nasal obstruction and rhinorrhea (53%, 9 patients) as well as diplopia (18%, 3 patients). Two patients presented with expansile soft tissue masses involving the external nose, whereas 1 patient presented simply with unilateral serous otitis media. All patients underwent imaging, including computed tomography (CT) imaging and magnetic resonance (MRI) prior to any surgical attempts for histologic diagnosis. Initial radiographic findings included a discrete sinonasal mass (59%, 10 patients), opacification of sinuses (53%, 9 patients), and/or bony erosion (35%, 6 patients) (Fig. 1). In 1 patient, a sinonasal mass extended to the orbit, but spared the intraconal space (Fig. 2). Of the paranasal sites, the maxillary sinuses were affected in 8 patients (47%), ethmoid sinuses in 8 patients (47%), frontal sinuses in 5 patients (29%), and sphenoid sinuses in 5 patients (29%). Five patients (29%) had involvement of more than 1 paranasal sinus. One patient had histologically-confirmed involvement of the soft tissues of the external nose, whereas another patient had extension of disease into bilateral cavernous sinuses. Histologically, the most common type of lymphoma was diffuse large B-cell lymphoma (DLBCL, 53%, 9 patients), followed by ENKL (24%, 4 patients), with follicular lymphoma, small lymphocytic lymphoma (SLL), mucosaassociated lymphoid tissue (MALT) lymphoma, and mantle lymphoma less common (6%, 1 patient each) (Figs. 3, 4, and 5).
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Presenting symptoms, n (%) Nasal obstruction, rhinorrhea
9 (53)
Diplopia
3 (18)
External nasal mass
2 (12)
Serous otitis media
1 (6)
Radiographic findings, n (%) Sinonasal mass
10 (59)
Sinus opacification
9 (53)
Bony erosion
6 (35)
Paranasal sinuses involved, n (%) Maxillary
8 (47)
Ethmoid
8 (47)
Sphenoid
5 (29)
Frontal
5 (29)
Pathological diagnosis, n (%) Diffuse large B-cell lymphoma
9 (53)
Extranodal NK/T-cell lymphoma, nasal type
4 (24)
Follicular lymphoma
1 (6)
Mantle cell lymphoma
1 (6)
MALT lymphoma
1 (6)
Small lymphocytic lymphoma
1 (6)
Treatment received, n (%) Chemotherapy alone
11 (65)
Chemotherapy and radiation
2 (12)
Radiation alone
1 (6)
No treatment
1 (6)
Unknown
2 (12) (Continued)
Peng et al.
TABLE 1. Continued Characteristic
Outcome, n (%) Deceased
6 (35)
Alive
8 (47)
Unknown
3 (18)
Overall survival, % 2-year
75
5-year
53
Disease-free survival, % 2-year
70
5-year
49
*All values are n (%) except where indicated. MALT = mucosa-associated lymphoid tissue; NK = natural.
FIGURE 2. Coronal T1-weighted MRI, postcontrast, in a patient presenting with diplopia and left nasal congestion. An expansile ethmoid mass invading the left extraconal space is seen. MRI = magnetic resonance imaging.
FIGURE 1. Noncontrast coronal CT in a patient presenting with symptoms of chronic rhinosinusitis who underwent functional endoscopic sinus surgery. Pathologic diagnosis (see Figs. 3–5) was consistent with low-grade B-cell lymphoma. In this patient, positive histology was obtained from bilateral nasal cavities. CT = computed tomography.
Three patients (12%) carried a prior diagnosis of lymphoma at a separate anatomic location (specifically, 1 case each of SLL, follicular lymphoma, and DLBCL) prior to the diagnosis of sinonasal lymphoma. One patient (6%) harbored a diagnosis of Waldenstrom’s macroglobuline¨ mia for 2 years prior to the diagnosis of B-cell lymphoma. In the remaining 13 patients who were newly diagnosed with lymphoma from sinonasal histology, initial staging via whole-body positron emission tomography (PET) was performed in 11 patients. Other initial staging modalities included CT of the chest, abdomen, and pelvis. Of the 13
patients newly diagnosed with lymphoma from sinonasal histology, metastatic workup revealed 7 patients with disease outside of the nose and paranasal sinuses. Among metastatic manifestations, the most common was cervical lymphadenopathy (4 patients). Treatment included chemotherapy alone (65%, 11 patients), chemotherapy and radiation (12%, 2 patients), and radiation alone (6%, 1 patient). Observation was recommended for 1 patient secondary to lowgrade histopathology, and treatment for 2 patients was unknown. Chemotherapeutic regimens included cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R) as well as rituximab, ifosfamide, carboplatin, and etoposide (R-ICE). Two patients underwent autologous stem-cell transplantation, and 1 patient underwent autologous bone marrow transplantation. Median length to follow-up was 2.1 years (range, 1 month to 17 years). Six patients (3 ENKL, 3 DLBCL) died (mean time from diagnosis of sinonasal lymphoma to death, 2.3 years; range, 11 months to 19 years), all of whom succumbed to local and/or distant lymphoma burden. Eight patients were alive, and long-term follow-up for 3 patients was unavailable. Actuarial 2-year and 5-year overall survival rates were 75% and 53%, respectively, whereas disease-free 2-year and 5-year survival rates were 70% and 49%, respectively.
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FIGURE 3. Low-power magnification of H&E stain of sinonasal mucosa obtained from the patient whose imaging is seen in Figure 1, demonstrating a submucosal plasmacytoid infiltrate, consistent with low-grade B cell lymphoma. H&E = hematoxylin and eosin.
FIGURE 4. High-power magnification of H&E stain of tissue in Figure 3; green arrow denotes plasmacytoid B cell. H&E = hematoxylin and eosin.
Discussion Lymphomas are uncommon malignancies of the sinonasal tract. Mass effect and progressive mucociliary dysfunction often lead to symptoms consistent with chronic inflammatory sinus disease, including nasal obstruction and rhinorrhea. Presenting symptoms can also result from direct extension of tumor to the orbit and cavernous sinus.8, 9 Age of presentation has been variably reported as the 4th or 5th decades of life.10, 11 In our series, average presentation was in the 7th decade, similar to a study by Cuadra-Garcia et al.8 Radiographic studies may demonstrate opacification of the sinuses with or without a sinonasal mass. Importantly, imaging suggestive only of chronic rhinosinusitis with mu-
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FIGURE 5. Immunohistochemistry reveals positivity for CD 138, a B-cell marker.
cosal thickening with or without frank opacification of the sinuses does not exclude a diagnosis of sinonasal lymphoma. Histologic diagnosis is, of course, of paramount importance whenever sinonasal malignancy is suspected. In order to obtain tissue for analysis, each patient in the current series underwent endoscopic sinus surgery. However, as sinonasal lymphoma and other sinonasal malignancies can mimic benign disease, any viable tissue obtained during endoscopic sinus surgery must be sent for pathological analysis. Indeed, 1 patient in this study underwent functional endoscopic sinus surgery for symptoms of chronic rhinosinusitis refractory to medical management, and was only thereafter diagnosed with lymphoma. Non-Hodgkin’s lymphoma encompasses a broad range of histopathologies, and in our series, DLBCL accounted for a majority of cases, with ENKL second. In our series, other pathologies included follicular, small lymphocytic, mantle cell, and even a single case of MALT lymphoma. This distribution is largely in accordance with other series in the United States.8 Yet other series, particularly in Asia, report a higher incidence of T-cell lymphomas, including ENKL.12, 13 Treatment included chemotherapy for nearly all patients in our series. Oncologic treatment for 1 patient with lowgrade B-cell lymphoma in our series was deferred, as the risks of chemotherapy were thought to outweigh the benefits. Combined-modality therapy for B-cell lymphomas, including both chemotherapy and radiation, has been shown to increase freedom from progression as well as overall survival.14 The majority of patients with B-cell lymphoma underwent chemotherapy alone. Chemotherapeutic regimens included CHOP-R and R-ICE; specific choice of chemotherapy was performed on a case-by-case basis by oncologic specialists.
Peng et al.
In our series, external beam radiation therapy was administered to 2 patients with ENKL (dose not available). There is increasing evidence to suggest that radiation therapy is a cornerstone of therapy for ENKL.15 It has been reported that ENKL is associated with high failure rates despite combination therapy, as chemotherapy is often insufficient to address systemic disease and radiation alone is insufficient to address locoregional disease.4 In our series, actuarial 2-year and 5-year survival was 75% and 53%, whereas disease-free 2-year and 5-year survival was 70% and 49%, respectively. This is in accordance with studies by Abbondanzo et al.16 and Kim et al.,13 the latter reporting a 5-year actuarial and disease-free survival of 57% and 51%, respectively, and slightly better than a report by Hatta et al.,17 who reported an overall 5-year survival of 28.5%. When considering prognosis based on histological classification, both ENKL as well as DLBCL have the potential to exhibit aggressive behavior. Indeed, the patient with the shortest time from diagnosis to death (11 months) had DLBCL, whereas the patient with longest follow-up (17 years) had ENKL with multiple recurrences. Although the latter patient is a clear outlier, our data are
in accordance with Cuadra-Garcia,8 who suggest similar outcomes for DLBCL and ENKL. Others have suggested a more favorable prognosis for DLBCL but an unfavorable prognosis for ENKL.18 The rarity and heterogeneity of ENKL,19 in addition to varying therapies, both accepted and experimental, likely contribute to the disparate outcomes reported among different series.15
Conclusion Sinonasal lymphoma is a rare disease, and presentation may mimic chronic rhinosinusitis. Histologic diagnosis is essential, as specific histopathologies confer differing prognoses and require different therapeutic regimens. Following diagnosis, therapy is nonsurgical. Further research will include immunophenotyping of lymphoma specimens and associations with EBV. By further stratifying these patients, treatment paradigms segregated by disease phenotype may be developed, ideally leading to increased survival of this often-deadly disease. It is critical that otolaryngologists remain cognizant of this entity, and maintain diligence in sending tissue from sinus surgery for pathologic analysis.
References 1. 2.
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7.
Shankland KR, Armitage JO, Hancock BW. NonHodgkin lymphoma. Lancet. 2012;380:848–857. Hennessy BT, Hanrahan EO, Daly PA. Non-Hodgkin lymphoma: an update. Lancet Oncol. 2004;5:341– 353. Cleary KR, Batsakis JG. Sinonasal lymphomas. Ann Otol Rhinol Laryngol. 1994;103:911–914. Li CC, Tien HF, Tang JL, et al. Treatment outcome and pattern of failure in 77 patients with sinonasal natural killer/T-cell or T-cell lymphoma. Cancer. 2004;100:366–375. Liang GZ, Zhuang HG, Li WC, Guo RZ. T-cell lymphoma: a morphological, histochemical and immunological study of nine Chinese cases. Histopathology. 1986;10:1035–1046. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16:2825–2833. Borges A, Fink J, Villablanca P, Eversole R, Lufkin R. Midline destructive lesions of the sinonasal tract: simplified terminology based on histopathologic criteria. AJNR Am J Neuroradiol. 2000;21: 331–336.
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Cuadra-Garcia I, Proulx GM, Wu CL, et al. Sinonasal lymphoma: a clinicopathologic analysis of 58 cases from the Massachusetts General Hospital. Am J Surg Pathol. 1999;23:1356–1369. Shohat I, Berkowicz M, Dori S, et al. Primary nonHodgkin’s lymphoma of the sinonasal tract. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;97:328–331. Duncavage JA, Campbell BH, Hanson GA, et al. Diagnosis of malignant lymphomas of the nasal cavity, paranasal sinuses and nasopharynx. Laryngoscope. 1983;93:1276–1280. Fajardo-dolci G, Magana RC, Bautista EL, Huerta D. Sinonasal lymphoma. Otolaryngol Head Neck Surg. 1999;121:323–326. Yen TT, Wang RC, Jiang RS, Chen SC, Wu SH, Liang KL. The diagnosis of sinonasal lymphoma: a challenge for rhinologists. Eur Arch Otorhinolaryngol. 2012;269:1463–1469. Kim GE, Koom WS, Yang WI, et al. Clinical relevance of three subtypes of primary sinonasal lymphoma characterized by immunophenotypic analysis. Head Neck. 2004;26:584–593. Logsdon MD, Ha CS, Kavadi VS, Cabanillas F, Hess MA, Cox JD. Lymphoma of the nasal cavity
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and paranasal sinuses: improved outcome and altered prognostic factors with combined modality therapy. Cancer. 1997;80:477–488. Kohrt H, Advani R. Extranodal natural killer/T-cell lymphoma: current concepts in biology and treatment. Leuk Lymphoma. 2009;50:1773–1784. Abbondanzo SL, Wenig BM. Non-Hodgkin’s lymphoma of the sinonasal tract. A clinicopathologic and immunophenotypic study of 120 cases. Cancer. 1995;75:1281–1291. Hatta C, Ogasawara H, Okita J, Kubota A, Ishida M, Sakagami M. Non-Hodgkin’s malignant lymphoma of the sinonasal tract–treatment outcome for 53 patients according to REAL classification. Auris Nasus Larynx. 2001;28:55–60. Seki D, Ueno K, Kurono Y, Eizuru Y. Clinicopathological features of Epstein-Barr virus-associated nasal T/NK cell lymphomas in southern Japan. Auris Nasus Larynx. 2001;28:61–70. Kanemitsu N, Isobe Y, Masuda A, et al. Expression of Epstein-Barr virus-encoded proteins in extranodal NK/T-cell Lymphoma, nasal type (ENKL): differences in biologic and clinical behaviors of LMP1-positive and -negative ENKL. Clin Cancer Res. 2012;18:2164– 2172.
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Sinonasal lymphoma: case series and review of the literature Kevin A. Peng, MD1 , Ashley E. Kita, BS1 , Jeffrey D. Suh, MD1 , Sunita M. Bhuta, MD2 and Marilene B. Wang, MD1
Background: Sinonasal lymphoma is a rare rhinologic entity. We present a case series and review the literature surrounding the diagnosis and management of this disease.
5-year overall survival rates were 75% and 53%, respectively, whereas disease-free 2-year and 5-year survival rates were 70% and 49%, respectively.
Methods: A pathology database spanning 22 years at a tertiary care center was searched for a diagnosis of lymphoma in the paranasal sinuses or the nasal cavity. Seventeen cases were identified, and retrospective chart review was performed.
Conclusion: Lymphoma of the nasal cavity and paranasal sinuses is extremely rare, may mimic benign processes, and may manifest either in an isolated fashion or in conjunction with systemic disease. B-cell lymphomas, a more favorable diagnosis, account for a majority of cases, whereas ENKL is associated with rapid disease progression and death. Chemotherapy and radiation are the main therapies. Histologic diagnosis is of paramount importance, and clinicians must remain cognizant of this entity to differentiate it from C 2014 ARS-AAOA, LLC. other sinonasal malignancies.
Results: Maxillary and ethmoid sinuses were affected more frequently (n = 8 patients each) than sphenoid and frontal sinuses (n = 5 patients each). Histologically, the most common type was diffuse large B-cell lymphoma (53%, 9 patients), followed by extranodal natural killer/T-cell lymphoma (ENKL, 21%, 3 patients). Presenting symptoms included nasal obstruction and rhinorrhea (53%, 9 patients) and diplopia (18%, 3 patients); and radiographic imaging demonstrated a discrete mass (59%, 10 patients), sinus opacification (53%, 9 patients), and/or bony erosion (35%, 6 patients). Treatment included chemotherapy alone (71%, 12 patients), chemotherapy and radiation (6%, 1 patient), and radiation alone (6%, 1 patient). The 2-year and
L
ymphomas, which are solid cancers of the lymphoreticular system, are subclassified as Hodgkin’s lymphoma, comprising approximately 10% of all cases, and nonHodgkin’s lymphoma, comprising approximately 90% of all cases.1 Lymphomas account for 4% to 5% of all new cancers diagnosed annually.2 Sinonasal lymphoma is rare,
1 Department
of Head and Neck Surgery, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA; 2 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA Correspondence to: Kevin A. Peng, MD, Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, CHS 62–132, Los Angeles, CA 90095; e-mail: [email protected] Potential conflict of interest: None provided. Presented at the Combined Sections Meeting of the Triological Society, Inc., January 24–26, 2013, Scottsdale, AZ. Received: 21 January 2014; Revised: 6 March 2014; Accepted: 23 March 2014 DOI: 10.1002/alr.21337 View this article online at wileyonlinelibrary.com.
Key Words: chronic rhinosinusitis; endoscopic sinus surgery; radiology; paranasal sinus diseases How to Cite this Article: Peng KA, Kita AE, Suh JD, Bhuta SM, Wang MB. Sinonasal lymphoma: case series and review of the literature. Int Forum Allergy Rhinol. 2014;4:670–674.
representing only 1.5% of all lymphomas.3, 4 Subtypes of non-Hodgkin’s lymphoma presenting in the sinonasal tract include B-cell lymphomas, extranodal natural killer (NK)/T-cell lymphoma (ENKL), nasal type, and other rarer entities. Lymphomas may involve the soft tissues of the external nose, the nasal mucosa, and the paranasal sinuses.4 Previous work has demonstrated an increased incidence of Epstein-Barr virus (EBV)-positive sinonasal lymphoma in Asian countries as compared to the United States and Europe.5 The diagnosis of sinonasal lymphoma is included under the broader entity of midline destructive lesions, alternatively termed lethal midline granulomas and idiopathic midline destructive disease, although this disease entity also includes, most notably, Wegener’s granulomatosis.6, 7 Over the past 2 decades, advances in lymphoma therapy have more recently included the development of rituximab, a chimeric monoclonal antibody against CD-20, which is expressed on over 90% of B-cell lymphomas.6 Therapy for sinonasal lymphoma remains nonsurgical, with most International Forum of Allergy & Rhinology, Vol. 4, No. 8, August 2014
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patients treated with chemotherapy. More aggressive, localized disease may warrant radiation therapy. The goal of the present study was to characterize our institution’s experience with sinonasal lymphoma. Patients with nasal masses, including lymphomas, often present with similar sinonasal symptoms mimicking benign inflammatory sinonasal disease. The objective of this study was to outline the incidence and management of sinonasal lymphoma to allow optimal treatment of the disease.
TABLE 1. Patient characteristics Characteristic
Age, years, median (range)
65 (42–93)
Gender, n (%) Male
8 (47)
Female
9 (53)
Race, n (%)
Materials and methods
White
9 (53)
Institutional Review Board approval was obtained for this study. All pathology records at the University of California, Los Angeles, spanning a 22-year period, 1990 to 2012, were searched using the definition for sinonasal lymphoma as histologically-proven lymphoma specimens isolated from the external nose, nasal mucosa, and paranasal sinuses. Following retrieval of records, a retrospective chart review was performed, and presenting symptomatology, imaging, treatment, and outcomes were reviewed where possible.
Asian
3 (18)
Hispanic
3 (18)
Black
1 (6)
Other
1 (6)
Results Seventeen patients with lymphoma of the nasal cavity and/or paranasal sinuses were identified, of which 8 were male and 9 were female. Patient demographic information is found in Table 1. Median age at diagnosis was 65 (range, 42 to 93) years. Presenting symptoms included nasal obstruction and rhinorrhea (53%, 9 patients) as well as diplopia (18%, 3 patients). Two patients presented with expansile soft tissue masses involving the external nose, whereas 1 patient presented simply with unilateral serous otitis media. All patients underwent imaging, including computed tomography (CT) imaging and magnetic resonance (MRI) prior to any surgical attempts for histologic diagnosis. Initial radiographic findings included a discrete sinonasal mass (59%, 10 patients), opacification of sinuses (53%, 9 patients), and/or bony erosion (35%, 6 patients) (Fig. 1). In 1 patient, a sinonasal mass extended to the orbit, but spared the intraconal space (Fig. 2). Of the paranasal sites, the maxillary sinuses were affected in 8 patients (47%), ethmoid sinuses in 8 patients (47%), frontal sinuses in 5 patients (29%), and sphenoid sinuses in 5 patients (29%). Five patients (29%) had involvement of more than 1 paranasal sinus. One patient had histologically-confirmed involvement of the soft tissues of the external nose, whereas another patient had extension of disease into bilateral cavernous sinuses. Histologically, the most common type of lymphoma was diffuse large B-cell lymphoma (DLBCL, 53%, 9 patients), followed by ENKL (24%, 4 patients), with follicular lymphoma, small lymphocytic lymphoma (SLL), mucosaassociated lymphoid tissue (MALT) lymphoma, and mantle lymphoma less common (6%, 1 patient each) (Figs. 3, 4, and 5).
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Presenting symptoms, n (%) Nasal obstruction, rhinorrhea
9 (53)
Diplopia
3 (18)
External nasal mass
2 (12)
Serous otitis media
1 (6)
Radiographic findings, n (%) Sinonasal mass
10 (59)
Sinus opacification
9 (53)
Bony erosion
6 (35)
Paranasal sinuses involved, n (%) Maxillary
8 (47)
Ethmoid
8 (47)
Sphenoid
5 (29)
Frontal
5 (29)
Pathological diagnosis, n (%) Diffuse large B-cell lymphoma
9 (53)
Extranodal NK/T-cell lymphoma, nasal type
4 (24)
Follicular lymphoma
1 (6)
Mantle cell lymphoma
1 (6)
MALT lymphoma
1 (6)
Small lymphocytic lymphoma
1 (6)
Treatment received, n (%) Chemotherapy alone
11 (65)
Chemotherapy and radiation
2 (12)
Radiation alone
1 (6)
No treatment
1 (6)
Unknown
2 (12) (Continued)
Peng et al.
TABLE 1. Continued Characteristic
Outcome, n (%) Deceased
6 (35)
Alive
8 (47)
Unknown
3 (18)
Overall survival, % 2-year
75
5-year
53
Disease-free survival, % 2-year
70
5-year
49
*All values are n (%) except where indicated. MALT = mucosa-associated lymphoid tissue; NK = natural.
FIGURE 2. Coronal T1-weighted MRI, postcontrast, in a patient presenting with diplopia and left nasal congestion. An expansile ethmoid mass invading the left extraconal space is seen. MRI = magnetic resonance imaging.
FIGURE 1. Noncontrast coronal CT in a patient presenting with symptoms of chronic rhinosinusitis who underwent functional endoscopic sinus surgery. Pathologic diagnosis (see Figs. 3–5) was consistent with low-grade B-cell lymphoma. In this patient, positive histology was obtained from bilateral nasal cavities. CT = computed tomography.
Three patients (12%) carried a prior diagnosis of lymphoma at a separate anatomic location (specifically, 1 case each of SLL, follicular lymphoma, and DLBCL) prior to the diagnosis of sinonasal lymphoma. One patient (6%) harbored a diagnosis of Waldenstrom’s macroglobuline¨ mia for 2 years prior to the diagnosis of B-cell lymphoma. In the remaining 13 patients who were newly diagnosed with lymphoma from sinonasal histology, initial staging via whole-body positron emission tomography (PET) was performed in 11 patients. Other initial staging modalities included CT of the chest, abdomen, and pelvis. Of the 13
patients newly diagnosed with lymphoma from sinonasal histology, metastatic workup revealed 7 patients with disease outside of the nose and paranasal sinuses. Among metastatic manifestations, the most common was cervical lymphadenopathy (4 patients). Treatment included chemotherapy alone (65%, 11 patients), chemotherapy and radiation (12%, 2 patients), and radiation alone (6%, 1 patient). Observation was recommended for 1 patient secondary to lowgrade histopathology, and treatment for 2 patients was unknown. Chemotherapeutic regimens included cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R) as well as rituximab, ifosfamide, carboplatin, and etoposide (R-ICE). Two patients underwent autologous stem-cell transplantation, and 1 patient underwent autologous bone marrow transplantation. Median length to follow-up was 2.1 years (range, 1 month to 17 years). Six patients (3 ENKL, 3 DLBCL) died (mean time from diagnosis of sinonasal lymphoma to death, 2.3 years; range, 11 months to 19 years), all of whom succumbed to local and/or distant lymphoma burden. Eight patients were alive, and long-term follow-up for 3 patients was unavailable. Actuarial 2-year and 5-year overall survival rates were 75% and 53%, respectively, whereas disease-free 2-year and 5-year survival rates were 70% and 49%, respectively.
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FIGURE 3. Low-power magnification of H&E stain of sinonasal mucosa obtained from the patient whose imaging is seen in Figure 1, demonstrating a submucosal plasmacytoid infiltrate, consistent with low-grade B cell lymphoma. H&E = hematoxylin and eosin.
FIGURE 4. High-power magnification of H&E stain of tissue in Figure 3; green arrow denotes plasmacytoid B cell. H&E = hematoxylin and eosin.
Discussion Lymphomas are uncommon malignancies of the sinonasal tract. Mass effect and progressive mucociliary dysfunction often lead to symptoms consistent with chronic inflammatory sinus disease, including nasal obstruction and rhinorrhea. Presenting symptoms can also result from direct extension of tumor to the orbit and cavernous sinus.8, 9 Age of presentation has been variably reported as the 4th or 5th decades of life.10, 11 In our series, average presentation was in the 7th decade, similar to a study by Cuadra-Garcia et al.8 Radiographic studies may demonstrate opacification of the sinuses with or without a sinonasal mass. Importantly, imaging suggestive only of chronic rhinosinusitis with mu-
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FIGURE 5. Immunohistochemistry reveals positivity for CD 138, a B-cell marker.
cosal thickening with or without frank opacification of the sinuses does not exclude a diagnosis of sinonasal lymphoma. Histologic diagnosis is, of course, of paramount importance whenever sinonasal malignancy is suspected. In order to obtain tissue for analysis, each patient in the current series underwent endoscopic sinus surgery. However, as sinonasal lymphoma and other sinonasal malignancies can mimic benign disease, any viable tissue obtained during endoscopic sinus surgery must be sent for pathological analysis. Indeed, 1 patient in this study underwent functional endoscopic sinus surgery for symptoms of chronic rhinosinusitis refractory to medical management, and was only thereafter diagnosed with lymphoma. Non-Hodgkin’s lymphoma encompasses a broad range of histopathologies, and in our series, DLBCL accounted for a majority of cases, with ENKL second. In our series, other pathologies included follicular, small lymphocytic, mantle cell, and even a single case of MALT lymphoma. This distribution is largely in accordance with other series in the United States.8 Yet other series, particularly in Asia, report a higher incidence of T-cell lymphomas, including ENKL.12, 13 Treatment included chemotherapy for nearly all patients in our series. Oncologic treatment for 1 patient with lowgrade B-cell lymphoma in our series was deferred, as the risks of chemotherapy were thought to outweigh the benefits. Combined-modality therapy for B-cell lymphomas, including both chemotherapy and radiation, has been shown to increase freedom from progression as well as overall survival.14 The majority of patients with B-cell lymphoma underwent chemotherapy alone. Chemotherapeutic regimens included CHOP-R and R-ICE; specific choice of chemotherapy was performed on a case-by-case basis by oncologic specialists.
Peng et al.
In our series, external beam radiation therapy was administered to 2 patients with ENKL (dose not available). There is increasing evidence to suggest that radiation therapy is a cornerstone of therapy for ENKL.15 It has been reported that ENKL is associated with high failure rates despite combination therapy, as chemotherapy is often insufficient to address systemic disease and radiation alone is insufficient to address locoregional disease.4 In our series, actuarial 2-year and 5-year survival was 75% and 53%, whereas disease-free 2-year and 5-year survival was 70% and 49%, respectively. This is in accordance with studies by Abbondanzo et al.16 and Kim et al.,13 the latter reporting a 5-year actuarial and disease-free survival of 57% and 51%, respectively, and slightly better than a report by Hatta et al.,17 who reported an overall 5-year survival of 28.5%. When considering prognosis based on histological classification, both ENKL as well as DLBCL have the potential to exhibit aggressive behavior. Indeed, the patient with the shortest time from diagnosis to death (11 months) had DLBCL, whereas the patient with longest follow-up (17 years) had ENKL with multiple recurrences. Although the latter patient is a clear outlier, our data are
in accordance with Cuadra-Garcia,8 who suggest similar outcomes for DLBCL and ENKL. Others have suggested a more favorable prognosis for DLBCL but an unfavorable prognosis for ENKL.18 The rarity and heterogeneity of ENKL,19 in addition to varying therapies, both accepted and experimental, likely contribute to the disparate outcomes reported among different series.15
Conclusion Sinonasal lymphoma is a rare disease, and presentation may mimic chronic rhinosinusitis. Histologic diagnosis is essential, as specific histopathologies confer differing prognoses and require different therapeutic regimens. Following diagnosis, therapy is nonsurgical. Further research will include immunophenotyping of lymphoma specimens and associations with EBV. By further stratifying these patients, treatment paradigms segregated by disease phenotype may be developed, ideally leading to increased survival of this often-deadly disease. It is critical that otolaryngologists remain cognizant of this entity, and maintain diligence in sending tissue from sinus surgery for pathologic analysis.
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