Primary (extranodal) lymphoma arising in the paranasal sinus (e.g. the maxilla) is quite rare and there is a minimal amount of information available. The survival statistics vary widely as noted below. In general these patients are treated with combine modality therapy (CMT) generally chemotherapy (e.g. R-CHOP) followed by involved field irradiation

From Cancer. 1997 Aug 1;80(3):477-88. below:   In Western populations, lymphomas of the nasal cavity and paranasal sinuses rank among the uncommon extranodal lymphomas, accounting for 0.17% of all lymphomas in the Kiel Lymph Node Registry  The limited clinical experience with these lesions has resulted in controversies regarding pathologic classification, natural history, and optimal management.Historically, an ambiguous nomenclature has been applied to lesions in this region. Terms have included polymorphic reticulosis, pseudolymphoma, midline granuloma syndrome, lethal midline granuloma, nonhealing midline granuloma, necrosis with atypical cellular exudate, midline destructive granuloma, and idiopathic midline destructive disease. Over the past decade, it has become appreciated that these lesions are lymphomas of the sinonasal tract, rendering this previously used nomenclature obsolete.

Geographic differences in the frequency and histologic subtype of these tumors have become more apparent. In Asian populations and in Peru, nasal lymphomas are more common and are predominantly T-cell lymphomas with angiocentric features, whereas B-cell subtypes are typically more common among the sinonasal lymphomas observed in Western populations. Although pathologic classification of these lesions has become more clear, controversies regarding clinical behavior remain. This retrospective review of 70 cases of lymphoma of the nasal cavity and paranasal sinuses in a Western population was undertaken to further define the natural history of these lesions and to evaluate the treatment results and prognostic factors for two sequentially treated groups of patients.

In this update of the authors' experience with sinonasal lymphomas, the clinical presentation was similar to that previously reported from MDACC as well as others in Western countries. Patients tend to be elderly males with locally advanced tumors. Maxillary sinus tumors are more common than nasal cavity primaries. Cervical lymph node metastases are present in approximately 25% of patients with localized disease, and the histology of > 90% of the lesions is intermediate grade. Reports concerning the immunophenotype of sinonasal lymphomas in Western populations have been mixed, with some finding B-cell lesions to be much more common,whereas others note a greater frequency of T-cell lesions. In this series, immunophenotype was available for 19 tumors. In agreement with a large series recently reported by Abbondanzo a slight predominance of B-cell lesions was observed.

The above clinical picture is in contrast to that observed in Asian populations. Asian patients tend to be male but younger than those observed in Western populations, with a median age near 50 years. The nasal cavity, the second most frequent site of extranodal lymphomas after the gastrointestinal tract, is more common as a primary site than the maxillary sinus in Asia. Although most lesions are classified as intermediate grade in the Working Formulation, they are predominantly T-cell lymphomas with angiocentric features, also termed angiocentric immunoproliferative lesions (AILs)

The use of chemotherapy in patients with sinonasal lymphoma has been standard treatment at many institutions for years. This practice has been based on the high rates of distant recurrence after XRT in all but those patients with small Stage IE disease and on the general efficacy of chemotherapy in treating intermediate grade lymphomas. The report by Liang et al. from China of 100 primary nasal T-cell lymphomas found no improvement in outcome with the addition of chemotherapy.In contrast, the results of the current study demonstrate a statistically significant improvement in FFP with CMT for patients with paranasal sinus and nasal cavity lymphomas. The explanation for the discrepancy between the two series is unclear, but the high percentage of AILs in the Hong Kong experience is one possible explanation. When compared with B-cell lymphomas, T-cell lymphomas have been reported to have a significantly worse recurrence free survival and OS when treated with combination chemotherapy. In addition, Aviles et al. reported that the presence of angiocentric features in sinonasal lymphomas predict for lower recurrence free survival when treated by XRT alone as well as an inferior salvage rate with combination chemotherapy.

Variable patterns of failure after treatment have been reported. In this report, only 4 patients (6%) experienced local failure. However, local failure appears to be more common in nasal T-cell lymphoma. In the series by Liang et al., local failure occurred in 15% of patients and accounted for 71% of all recurrences after complete response.Again, the high proportion of angiocentric lesions may explain this discrepancy, but technical XRT considerations cannot be excluded.

Several institutions have reported a high incidence of CNS relapse for patients with sinonasal lymphoma. Along with others, the authors have not observed this predilection for CNS spread. The reasons for this difference are not known. Cooper et al. have suggested that as in other lymphomas, the development of CNS disease may be a reflection of systemic lymphoma progression. The authors of the current study have observed cases that support this explanation. One of the 12 patients who presented with Stage IV disease had widespread lymphoma with CNS involvement, and another patient had CNS failure after salvage chemotherapy as one manifestation of widely disseminated lymphoma. However, the authors have also found CNS failure to be associated with local failure, again suggesting technical explanations for failure pattern. The single CNS failure after initial therapy that they observed was secondary to a radiotherapy marginal miss. In addition, two of the five patients excluded from the study because they received XRT outside MDACC developed local recurrence, and one presented with CNS failure at the time of an otherwise isolated local failure. Local failure at the base of the skull can remain unrecognized clinically and can provide access to the CNS. This issue of CNS failure is reminiscent of a similar one involving parameningeal rhabdomyosarcoma. Early reports of high rates of CNS failure led to children with parameningeal primaries receiving whole brain or craniospinal irradiation. With improvement in diagnostic imaging allowing better tumor definition and increased recognition of the need for generous base of skull coverage, CNS failures have become less common. Based on more recent treatment results, XRT to the CNS is currently recommended only for patients with documented CNS disease at diagnosis. Consistent with the parameningeal rhabdomyosarcoma experience, each of the series reporting high CNS failure rates in paranasal sinus lymphomas included patients treated prior to the development of high quality CT imaging and MRI. In addition, in one of these series, all primary lymphomas in the anatomic vicinity of the maxillary sinus (including the orbit, palate, and nasopharynx) were associated with high CNS recurrence rates. Local failure may be a more common cause of CNS failure than previously believed for these lymphomas. Lumbar puncture and MRI of the brain appear to be indicated for patients with base of skull involvement.

Significant treatment-related morbidity occurred in this series of patients. This reflects the long period of time that the study spans. Fewer complications have occurred in patients treated more recently. With improved dental prophylaxis, treatment of all radiotherapy fields daily, and lower radiation doses, osteonecrosis has become very rare in this patient group. Radiation-induced visual complications have been carefully analyzed in two recent reports. At the authors' currently recommended dose of 39.6 Gy in 22 fractions, damage to the optic nerve is not observed. Corneal damage and resultant loss of vision are a function of the structures being irradiated and the dose they receive. If the cornea and lacrimal gland can both be spared, damage is not observed. If only one of these structures can be blocked, the complication rate historically has been 15-25%. Newer methylcellulose and/or polyvinyl alcohol-based eye lubricants may decrease complications in this group of patients, but data are not yet available. If neither the cornea nor the lacrimal gland can be blocked, loss of vision approaches 100%. Unfortunately, patients with lesions large enough to warrant such extensive radiation fields are the ones who are at greatest risk for local recurrence with its attendant morbidity and mortality. Omitting XRT to spare morbidity can be considered, but in the only data available for treatment of these lesions with chemotherapy alone, local recurrence occurred in 4 of 16 patients. Furthermore, the local recurrence rate in the report by Liang et al. supports the need for local treatment in addition to chemotherapy for patients with AILs.

Reported 5-year survival rates for sinonasal lymphomas have ranged from 12-86%.  The combination of a broad distribution of survival rates and variable patterns of recurrence has resulted in diverse therapy recommendations. These have included whole brain XRT, intrathecal chemotherapy, or both. It has also been suggested that these patients should be considered for experimental consolidation therapy such as autologous bone marrow transplantation. The authors' results with CMT (and no CNS treatment) in a Western population yielded 5-year FFP rates of 87% and 70% for patients with Stage IE and IIE lymphoma, respectively. Two recent randomized studies also favor CMT over chemotherapy alone for patients with early stage intermediate and high grade non-Hodgkin's lymphoma. Therefore, the authors continue to recommend combination chemotherapy with involved field XRT for these patients. Currently, their preference for chemotherapy is a doxorubicin-containing regimen such as CHOP. Although the median number of cycles of chemotherapy in this series was eight, there are now data indicating that three cycles of CHOP may be sufficient when compared with XRT. Currently, different numbers of chemotherapy cycles are being tested in a prospective trial at MDACC. When chemotherapy is medically contraindicated, XRT is a reasonable alternative for patients with Stage IE(T1-3) disease but is insufficient for patients with more advanced disease (Stage IE(T4), II-IV).
Sinonasal lymphoma: a clinicopathologic analysis of 58 cases from the Massachusetts General Hospital.

Cuadra-Garcia I, .Am J Surg Pathol. 1999 Nov;23(11):1356-69.

Departamento de Patologia, Hospital de Oncologia, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Segura Social, Mexico City.

Few large series compare lymphomas of the nasal cavity with those of the paranasal sinuses. We studied the cases of 58 patients, 34 males and 24 females, aged 7 to 92 years (mean, 57 years), who had lymphoma involving the nasal cavity or paranasal sinuses. Thirty-three patients had diffuse large B-cell lymphoma (DLBCL). Twenty-three were male and 10 were female, with an age range of 7 to 91 years (mean, 63 years); two were HIV-positive. Only 2 of 11 cases tested (one in an HIV-positive patient and one of lymphomatoid granulomatosis type) were Epstein-Barr virus (EBV)-positive. Thirty (91%) involved paranasal sinuses, 10 with nasal involvement, whereas three cases had nasal, but not sinus, involvement. At last follow-up, 16 (67%) were free of disease 7 to 169 months later (mean, 65 months), and 8 (33%) had died of disease 2 to 166 months later (mean, 45 months). Seventeen patients had nasal-type natural killer (NK)/T-cell lymphoma. There were 10 women and 7 men, aged 27 to 78 years (mean, 48 years). Thirteen of 14 were EBV-positive. Sixteen patients had nasal involvement, eight with sinus involvement. Eleven (73%) of 15 were alive and well 6 to 321 months later (mean, 139 months), three (20%) died of lymphoma 1, 11, and 12 months later, and one (7%) is alive with disease. There was one case each of marginal zone B-cell lymphoma, Burkitt's lymphoma, Burkitt-like lymphoma, peripheral T-cell lymphoma of unspecified type, and adult T-cell lymphoma/leukemia. In an additional three cases, the lymphomas were composed predominantly of large cells, but no immunophenotyping could be performed for subclassification. In 19 cases (17 DLBCLs, 1 Burkitt-like lymphoma, and 1 lymphoma of uncertain lineage), presenting symptoms included complaints related to the eyes. In 16 cases (13 DLBCLs, 1 Burkitt-like lymphoma, 1 nasal NK/T-cell lymphoma, and 1 lymphoma of uncertain lineage), the orbit was invaded by lymphoma. In our series, the most common lymphoma to arise in the sinonasal area is DLBCL, followed by nasal NK/T-cell lymphoma. Comparison of these two types of lymphoma showed that lymphomas involving sinuses without nasal involvement were predominantly DLBCLs (20 of 21), whereas nasal cavity lymphomas without sinus involvement were usually NK/T-cell type (8 of 11) (p = 0.000125). Compared with patients with DLBCL, patients with nasal NK/T-cell lymphoma were overall younger, with a lower male-to-female ratio. Lymphomas of B-cell lineage were more likely to be associated with symptoms related to the eyes (p < 0.0005) and to have extension to the orbit (p < 0.01) than were lymphomas of T- or NK-cell lineage. In contrast to results of Asian studies in which nasal NK/T-cell lymphoma has a very poor prognosis, our nasal NK/T-cell lymphomas had an outcome similar to that of DLBCL.

Non-Hodgkin's malignant lymphoma of the sinonasal tract--treatment outcome for 53 patients according to REAL classification.

Hatta C, Auris Nasus Larynx. 2001 Jan;28(1):55-60.

Department of Otolaryngology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, 663-8501, Hyogo, Japan. chatta@hyo-med.ac.jp

OBJECTIVE: Although the Working Formulation is commonly used to classify NHL in Japan, it has been recognized as imperfect for primary extranodal lymphoma, especially for patients with sinonasal disease because of their histological characteristics. The present study investigated the clinical characteristics and the prognosis of sinonasal lymphomas according to REAL classification. METHODS: Fifty-three patients with non-Hodgkin's malignant lymphoma (NHL) of the sinonasal tract were treated between 1981 and 1997. The age at clinical presentation was from 10 to 84 years (mean, 52.4 years). According to the Ann Arbor system, there were 30 patients with Stage IE, 13 with Stage IIE, 4 with Stage IIIE, and 6 with Stage IVE lymphomas. Twenty-two patients (41.5%) had B symptoms. The primary sites were the nasal cavity (67.8%), maxillary sinus (20.8%), ethmoidal sinus (9.4%), and frontal sinus (1.9%). The survival data was calculated by Kaplan-Meier method. Statistical analysis was performed with a generalized Wilcoxon method. RESULTS: All of the lymphomas showed a diffuse growth pattern. Based on the origin of the tumor cells, the authors classified NHL of the sinonasal tract into five groups with the REAL classification of Japan: diffuse large B-cell lymphoma (22.6%), peripheral T-cell lymphomas (15.1%), angiocentric lymphoma (35.9%), other lymphomas and unclassified types. Of 53 patients, 39 (73.6%) received chemotherapy and radiotherapy, eight patients received chemotherapy alone, and four patients received radiotherapy alone. The cumulative 5-year survival rates were 28.5% for all of the types, 55.0% for diffuse large B-cell lymphoma, 33.3% for peripheral T-cell lymphoma, and 19.7% for angiocentric lymphoma. Results suggest that conventional combined treatment (CHOP chemotherapy+radiotherapy) is ineffective for NHL of the sinonasal tract, and especially so for NHL in the nasal cavity, NHL with tumor cells with positive T-cell markers, NHL further than Stage IIE and NHL with B symptoms. CONCLUSION: (1) In light of this ineffectiveness, new therapies must be developed to improve patient outcome instead of the conventional combined treatment; (2) REAL classification is clear and useful for sinonasal lymphomas in Japan.

Non-Hodgkin's lymphoma of the paranasal sinuses: clinical and pathological features, and response to combined-modality therapy.

Hausdorff J, Davis Cancer J Sci Am. 1997 Sep-Oct;3(5):303-11.

Department of Medicine, Stanford University, California, USA.

PURPOSE: Lymphomas of the paranasal sinuses may have poorer prognoses compared with other extranodal lymphomas of the head and neck, and are not well defined as a particular clinicopathologic entity. The outcome of combined-modality therapy and central nervous system (CNS) prophylaxis has not been fully determined. PATIENTS AND METHODS: We retrospectively reviewed our experience with 16 consecutive, carefully defined patients, all treated with both chemotherapy and radiotherapy. RESULTS: There were 11 men and five women, mean age 52. All presented with local symptoms; 13 had stage I or II disease. Thirteen had diffuse large cell lymphoma, two diffuse mixed, and one small noncleaved. Phenotyping revealed 10 B-cell, four T-cell, and two T or natural killer (NK). Most received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy; the order of chemotherapy and radiotherapy varied. Twelve received CNS prophylaxis. Of 12 complete responses, six relapsed, all at distant sites, and two died during initial therapy. Five-year survival was 29%, and median survival 18 months. Four of 10 B-lineage patients were relapse-free at 4 years; all six T- or T/NK-lineage patients relapsed or were dead within 6 months. Tumors of T or NK lineage often expressed CD56 and showed evidence of Epstein-Barr viral infection; otherwise, pathological features were not predictive of lineage or outcome. Neither age nor lactate dehydrogenase predicted prognosis. No complete responder recurred in the CNS as site of first relapse. CONCLUSION: Despite localized stage at presentation, sinus lymphoma is an aggressive disease, characterized by distant relapse and early mortality. Combined-modality therapy with CNS prophylaxis improves outcome compared with radiotherapy alone; however, prognosis remains poor. Patients with T-lineage disease appear to have a particularly bad outcome. Autologous bone marrow transplantation should be evaluated as first-line therapy for those at high risk of relapse.

Lymphoma of the nasal cavity and paranasal sinuses: improved outcome and altered prognostic factors with combined modality therapy.

Logsdon MD Cancer. 1997 Aug 1;80(3):477-88.

Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.

BACKGROUND: Lymphoma of the nasal cavity and paranasal sinuses is a rare presentation of extranodal lymphoma with a natural history that is not well characterized in this era of combination chemotherapy. The goals of this retrospective study were 1) to define the natural history of sinonasal lymphomas; 2) to compare the results of radiation therapy (XRT) alone with those of combined modality therapy (CMT) in the treatment of patients with lymphoma of the nasal cavity and paranasal sinuses; and 3) to define prognostic factors for each treatment. METHODS: Between 1947 and 1993, 70 patients with newly diagnosed lymphoma of the nasal cavity and paranasal sinuses were treated. The Ann Arbor stages were: Stage IE: 42 patients; Stage IIE: 14 patients; Stage IIIE: 2 patients; and Stage IV: 12 patients. The distribution of T classifications of the primary tumors was as follows: T1: 2 patients; T2: 16; T3: 18; and T4: 34. Greater than 90% of the patients had intermediate grade lymphoma (Working Formulation), and none had follicular lymphoma. Twenty-eight patients received XRT alone, and 42 received CMT. RESULTS: The actuarial 5-year freedom from progression (FFP) and overall survival (OS) rates for the entire group were 57% and 52%, respectively. For patients with localized disease (Stages IE and IIE) receiving CMT, the actuarial 5-year FFP and OS were 83% and 67%, respectively. In multivariate analysis, treatment with CMT (P = 0.0005) and stage (IE vs. IIIE-IV) (P = 0.0001) were associated with improved FFP. In the group of patients receiving XRT, extent of disease (Stage IE, T1-3 vs. Stage IE, T4 vs. Stage IIE-IV) (P = 0.0001) was the only clinical characteristic associated with improved FFP in multivariate analysis. For patients receiving CMT, International Index (0 vs. 1-3 vs. 4, 5) (P = 0.0001) was the only significant factor predictive of improved FFP in multivariate analysis. One patient failed in the central nervous system (CNS) after initial therapy as a result of a radiation therapy marginal miss. CONCLUSIONS: In a Western population, patients with localized lymphoma of the nasal cavity and paranasal sinuses have a favorable prognosis when treated with CMT. FFP is significantly improved by treatment with CMT. For patients treated with XRT, extent of disease is the strongest predictor of outcome. International Index is the most significant prognostic factor for patients receiving CMT. Failure in the CNS is rare after initial therapy and is associated with local failure.

Lymphoma of the nasal cavity and paranasal sinuses: treatment and outcome of early-stage disease.

Proulx GM, Am J Clin Oncol. 2003 Feb;26(1):6-11.

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

The records of 23 patients diagnosed and treated at the Massachusetts General Hospital for extranodal non-Hodgkin's lymphoma of the paranasal sinus and nasal cavity were reviewed. The majority of patients were Ann Arbor stage I and approximately evenly divided in T1 or T2 (n = 10) and T3 or T4 (n = 13). Eight patients had nasal-type NK/T cell and 15 patients had diffuse large B-cell lymphoma (DLBCL). The patients with nasal-type NK/T cell lymphoma predominately involved the nasal cavity (5/8), whereas the DLBCL more often had the paranasal sinuses as the primary site (12/15). All patients received radiation as part of their treatment. Only three patients received chemotherapy as part of their initial treatment for three cycles using a cyclophosphamide, doxorubicin, vincristine, and prednisone-based regimen. By coincidence, the estimated overall survival (OS) and disease-free survival rates for both 5 and 10 years were all the same for all analyses. The OS for the entire group at 10 years was 78%. Significant prognostic factors were Ann Arbor stage IEA versus IIEA ( p = 0.0001) and T stage with (T1 or T2) versus (T3 or T4) (p = 0.0243). Combining Ann Arbor stage and T stage created a highly significant prognostic variable (IEA & [T1 or T2], IEA & [T3 or T4], IIEA & [T1 or T2], IIEA & [T3 or T4]) at p = 0.0001, regardless of site or histology. Patients with local-regional disease appear to be well controlled with radiation alone, but distant failure remains a problem. A combined-modality approach with local-regional radiation and systemic chemotherapy is recommended for these patients.

Non-Hodgkin's lymphoma of the sinonasal tract.

Quraishi MS,    Laryngoscope. 2000 Sep;110(9):1489-92.

University Hospital, Nottingham, UK.

OBJECTIVES: A review of the presenting features, management, and outcome of extranodal non-Hodgkin's lymphoma (NHL) of the sinonasal tract during a 10-year period in Nottingham, UK. STUDY DESIGN: Twenty-four patients received a diagnosis of extranodal NHL of the nasal cavity, paranasal sinuses, or both, from 1987 to 1996. The patients' data were collected prospectively in the Nottinghamshire Lymphoma Registry. METHODS: All patients' records and their histology were reviewed along with data entered into the Nottinghamshire Lymphoma Registry, noting the patient's age, sex, presenting symptoms and signs, staging, computed tomography findings, histology, treatment, complications, and outcome. RESULTS: The 24 patients with extranodal NHL of the sinonasal tract represent 1.63% of the 1,457 patients with NHL seen in the 10-year period of this study in Nottinghamshire. The median age was 72 years (range, 42-96 y), with a male dominance (male-to-female ratio: 15:9). Most patients presented with nonspecific nasal symptoms such as nasal obstruction and epistaxis. Only one patient had a relapse involving the central nervous system after treatment. All the histology was reviewed and showed a predominance of large B-cell subtype (21 patients). The overall 5-year survival was 40% (95% CI, 19%-61%) and 33% for 10-year (95% CI, 12%-54%). The cause-specific survival at 5 years and 10 years was 62% (95% CI, 39%-86%). CONCLUSIONS: A high degree of suspicion and appropriate use of computed tomography scans and surgical biopsy are the keys to the management of NHL.

Primary non-Hodgkin's lymphomas of the paranasal sinuses and nasal cavity. A report of 18 cases with stage IE disease.

Tran LM, Am J Clin Oncol. 1992 Jun;15(3):222-5.

Radiation Therapy Service, V.A. Medical Center, West Los Angeles, California 90073.

During a 26-year period (1961-1987), a total of 18 patients with primary non-Hodgkin's lymphoma (NHL) of the paranasal sinuses and nasal cavity received radiation therapy at (University of California at Los Angeles) UCLA Medical Center. At the time of diagnosis and using the available diagnostic methods, none of these patients had clinically detectable disease beyond the paranasal sinuses. All 18 patients were staged IE by the Ann-Arbor system. When the patients were staged according to the AJC staging system from epithelial tumors, half presented with advanced T3-4 disease. Diffuse histiocytic lymphoma was the most common histology (eight cases) and maxillary sinus, the most common site of origin (11 cases). All nine T1-2 tumors received radiation therapy alone, while radiation and chemotherapy was used in seven of nine advanced T3-4 staged tumors. The mean follow-up was 71 months. At last follow-up, eight of nine T1-2 patients were rendered disease-free. In contrast, only four of nine T3-4 patients had long-term disease-free survival. Seventy-five percent of the failure occurred within 2 years. Radiation therapy alone achieves high local control in small tumors (T1-2), while large tumors (T3-4) require aggressive combined treatment, i.e., radiation and chemotherapy.