CASE REPORT

Sinonasal Non-Hodgkin's Lymphomawith Skull Base InvolvementAmos 0. Dare, M.D.,1 Rajiv V. Datta, M.D.,2 Thom R. Loree, M.D.,2Wesley L. Hicks, Jr., M.D.,2 and Walter Grand, M.D.'

ABSTRACT

Non-Hodgkin's lymphoma (NHL) is a rare tumor of the skull base. Asthe incidence ofprimary central nervous system (CNS) lymphoma has increased,atypical presentations involving the skull or cranial base exclusively have been re-ported. In immunocompetent patients with no previous history or predisposingfactors, the diagnosis of primary NHL of the skull base may be delayed. Wepresent four cases of nasal and paranasal sinus NHL with both skull base and in-tracranial involvement in immunocompetent patients. Clinicopathologic correla-tion suggests that cranial base and intracranial involvement with NHL representsadvanced-stage primary sinonasal disease. Surgical biopsy before definitive treat-ment is recommended. Radiation therapy provides local control; adjuvantchemotherapy after primary radiation therapy may be required for recurrentdisease.

KEYWORDS: Lymphoma, skull base, paranasal

Non-Hodgkin's lymphoma (NHL) repre-sents 5% of head and neck malignancies, and itmay involve almost any location in this region.1'2As the reported incidence of primary central ner-vous system (CNS) lymphoma has increased,3'4several atypical presentations of head and neckNHL involving the cranial base exclusively havebeen reported.5 In immunocompetent patientswith no predisposing history, the disease may be

least suspected. The diagnosis may be ftirther de-layed by a differential diagnosis that includesmore common malignancies of the head and neckregion such as squamous cell carcinoma.6'7 We re-port four cases of nasal and paranasal sinus NHLwith invasion of the skull base and intracranialspace in immunocompetent patients. Clinical,histologic, and initial treatment outcomes arepresented.

Skull Base, volume 11, number 2, 2001. Reprint requests: Amos 0. Dare, M.D. Department of Neurosurgery, SUNYAB, 3 Gates Circle,Buffalo, NY 14209-1194. E-mail: aodare@yahoo.com. 'Department of Neurosurgery, University at Buffalo, State University of New York,Buffalo, New York; 2Head and Neck Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York. Copyright 3 2001 by ThiemeMedical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. 1531-5010,p;2001,11,02,129,136,ftx,en;sbsOO216x.

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130 SKULL BASE: AN INTERDISCIPLINARY APPROACH/VOLUME 11, NUMBER 2 2001

CASE STUDIES

Case 1

A 64-year-old woman presented with a 3-monthhistory of left-sided headaches and progressive lossof vision. Neurologic examination showed ptosis,homonymous hemianopsia, and faint light percep-tion in the left eye. Loss of sensation in the oph-thalmic and maxillary distributions of the trigemi-nal nerve on the left was also appreciated. Theremainder of her neurologic examination wasotherwise remarkable. Magnetic resonance imaging(MRI) confirmed abnormal soft tissue in the leftethmoid and sphenoid sinuses with extension intothe left orbital apex and the floor of the left middlecranial fossa (Fig. 1A). Tumor could be visualized toa lesser extent in the anterior cavernous sinus (Fig.1B). Computed tomography (CT) showed destruc-tion of the ethmoid and sphenoid bones (Fig. 1C).Biopsy of this mass demonstrated a diffuse largecell malignant NHL, B-cell type (Fig. 2). Furtherevaluation (including CT of the skull base, chest,abdomen, and pelvis; cerebrospinal fluid (CSF)analysis; gallium scan; and bone marrow biopsy)

showed no evidence of immunosuppression, sys-temic disease, or other tumors. The patient wastreated with intravenous steroids and focused radia-tion therapy (3600 centigray [cGy]) to the skullbase. Intrathecal chemotherapy (methotrexate, cy-tarabine, and hydrocortisone) was administered forprophylaxis. Three months after therapy, the pa-tient's disease remained unchanged on MRI. Sys-temic chemotherapy consisting of cyclophospha-mide, vincristine, and adriamycin was thereforeinstituted. At a follow-up examination 12 monthsafter the patient's initial presentation, MRI showedstable disease with partial regression of the middlefossa lesion.

Case 2

A 71-year-old man presented with visual distur-bance, epistaxis, and difficulty breathing. Neuro-logical examination revealed decreased right visualacuity. A right nasal mass was appreciated on phys-ical examination. Plain radiographs of the skullshowed a large, right-sided intranasal mass extend-ing posteriorly to the nasopharynx and sphenoid

A-CFigure 1 Case 1. (A) Gadolinium-enhanced axial T1-weighted MRI shows abnormal soft tissue in the left ethmoid andsphenoid sinuses with involvement of the left orbital apex and the floor of the left middle cranial fossa. (B) Minimal in-volvement of anterior cavernous sinus. (C) CT shows bone destruction in the ethmoid and sphenoid sinuses.

SINONASALAND SKULL BASE LYMPHOMA/DARE ET AL 131

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A _v } : 7 _ BFigure 2 Case 1. Hematoxylin and eosin (H&E) staining method. (A) 10x magnification. (B) 10x magnification, prolif-erating, large lymphoid cells of non-Hodgkin's lymphoma.

sinuses bilaterally. The mass also invaded the eth-moid sinuses and the right frontal sinus superiorly.Intranasal biopsy of this lesion demonstrated lym-phosarcoma, reticulum cell type, retrospectivelyclassified as malignant NHL. Further evaluationincluding a bone marrow biopsy showed no evi-dence of immunosuppression, systemic disease, orother tumors. The patient received focused radia-tion therapy (2900 cGy), with complete response.

Case 3

A 73-year-old man presented with left retro-orbital pain and diplopia. Physical examinationshowed decreased left visual acuity and ptosis onthat side. CT showed a left frontal sinus mass withextension into the anterior ethmoid sinuses and or-bital apex. MRI confirmed these findings anddemonstrated minimal invasion of the frontalfossa. Biopsy demonstrated large-cell malignantNHL, positive for common leukocyte antigen.There was no evidence of distant or systemic dis-ease, other malignancies, or immunosuppression.The patient received focused radiation therapy(4500 cGy) with complete response at a 3-month

follow-up examination. The patient remained dis-ease free until his death at 20 months from unre-lated medical treatment complications.

Case 4

An 83-year-old man presented with left-sidedheadache and diplopia. Neurologic examinationwas significant for decreased left visual acuity, limi-tation in left extraocular movement, and decreasedsensation in the ophthalmic distribution of the lefttrigeminal nerve. MRI revealed an ill-defined, hy-perintense mass centered within the frontal sinuswith extension superiorly into the epidural space,inferiorly into the left frontonasal duct, and medi-ally into the left ethmoid sinus (Fig. 3A). The leftoptic nerve was diplaced inferiorly (Fig. 3B).A supraorbital craniotomy was performed, and abiopsy demonstrated malignant NHL, large cell,B-cell phenotype (positive for markers CD20,HLADR, and CD19). Further evaluation revealedno evidence of immunosuppression, systemic dis-ease, or other tumors. The patient received focusedradiation therapy (3900 cGy) with complete re-sponse on follow up MRI at 3 months.

132 SKULL BASE: AN INTERDISCIPLINARY APPROACH/VOLUME 11, NUMBER 2 2001

Figure 3 Case 4. Gadolinium-enhancedT,-weighted MRI. (A) Coronal image reveals a hyperintense mass in the frontalsinus with epidural extension. (B) Sagittal view shows displacement of the left optic nerve inferiorly.

DISCUSSION

Lymphoma is characterized by abnormal prolifera-tion of lymphoreticular tissue occurring nodally as

Hodgkin's lymphoma or extranodally as NHL. Inthe head and neck region, extracranial NHL may

occur as primary disease-primary head and neckNHL-or as part of disseminated disease.2'8'9 Thehead and neck region, especially Waldeyer's lym-phatic ring, is the second most common site for in-volvement of extranodal NHL, the most common

site being the gastrointestinal tract.1 Primary sino-

nasal manifestation is less common, occurring in6 to 13% ofhead and neck NHL.7'0

Until recently, only a handful of cases ofNHL involving the skull base had been reported inthe literature.1014 The disease was reported partic-ularly in immunosuppressed patients,'2"4 patientswith known systemic disease,14 and Asians.1""13The increasing incidence of NHL in the UnitedStates3'4 has been accompanied by several reportsof atypical presentations ofNHL in immunocom-

petent patients. Roman-Goldstein et al.5 reportedtwo patients with disease involving primarily thecavernous sinus and one patient with disease lim-ited to the internal auditory canal. Erlich et al.15reported diffuse infiltration oflymphoma involvingthe calvarium and bone of the cranial base in a pa-tient who presented with multiple cranial nervepalsies.

Secondary involvement of the skull base byNHL arising from adjacent head and neck struc-tures has been recognized previously, albeit sporad-ically,16 in the setting of immunosuppression ordisseminated disease,'4 as well as in Asia.'7 Skullbase involvement associated with sinonasal lym-phoma is rare. In several large series ofNHL ofthenasal cavity and paranasal sinuses, disease involvingthe cranial base has not been reported.610"18-20 Thefour cases described here represent more extensivedisease involving the skull base and intracranialspace than has previously been reported in im-munocompetent patients with primary sinonasalNHL. Of particular significance is that three of

SINONASALAND SKULL BASE LYMPHOMA/DAREET AL 133

these four patients were diagnosed during the lastdecade, consistent with a nationally reported in-crease in the incidence ofNHL.34

The clinical presentation, disease stage, andAnn Arbor classification of our patients are sum-

marized in Table 1. Presentation with progressiveophthalmoplegia in NHL involving the cranialbase has previously been reported and reflects cra-

nial base involvement, especially of the cavernous

sinus.16'17 The male-to-female ratio of 3:1 and theaverage age of 72.7 years (range, 64 to 83 years)are consistent with data on the epidemiology ofsinonasal NHL as a disease of the "elderlymale."18-20

In immunocompetent individuals presentingwith ophthalmoplegia and symptoms referable to

the sinonasal region and cavernous sinus, the diag-nosis of NHL of the skull base is not readilymade."6 This difficulty partly reflects that the clin-ical presentation and initial radiological featuresare similar to those associated with squamous cellcarcinoma, a more common tumor of this region.6Table 2 summarizes the sinonasal, intracranial, andbony involvement by disease in our cases. Theimaging characteristics of NHL that involve thecranial base have previously been described.11 As inour patients, lesions often appear isointense to gray

matter on T1-weighted images and slightly hypo-,iso-, or hyperintense on T2-weighted or proton-

density images. Skull base NHL often showsheterogeneous enhancement with gadolinium. Le-sions in the intracranial epidural space may en-

hance en plaque (dural tail) or homogeneously;both features are reminiscent of meningioma.

Table 1 Demographics and Clinical Presentation

Age (yr)/ AnnCase Sex CN Deficits Arbor TNM

1 64/F 11, Ill,V1j,V2 1E T4NOMO2 71/M II 1 E T4NOMO3 73/M 11,111 1 E T4NOMO4 83/M 11, III, V 1E T4NOMO

Ann Arbor, Ann Arbor classification; CN, cranial nerve; TNM,tumor-node-metastasis classification.

Table 2 Sinonasal, Intracranial, and BonyInvolvement by Disease

BoneCase Fron Ethm Sph Max CS IC Dest

1 + ++ + + Mid +

2 + ++ + + Ant +

3 ++ + - Ant +4 ++ + - - - Ant +

Ant, anterior fossa; Bone Dest, bone destruction; CS, cavernoussinus; Ethm, ethmoid sinus; Fron, frontal sinus; IC, intracranialcompartment; Max, maxillary sinus; Mid, middle fossa; Sph,sphenoid sinus; ++, primary focus; +, secondary involvement.

However, unlike meningioma, NHL does not in-duce hyperostosis of the adjacent bone. Instead, itmay present variably with sclerotic or osteoblasticchanges,' a permeative type of bone involvementthat leaves the cortical outlines intact.9 Less fre-quently, a destructive, lytic pattern ofbone involve-ment more characteristic of squamous cell carci-noma is present.6 In one patient (case 1) and in fivepatients reported by Han et al.,11 cavernous sinusinvolvement byNHL was without luminal narrow-ing ofthe carotid arteries. This feature may serve asan additional criterion for differentiating betweenNHL and meningioma involving the skull base.Nonetheless, NHL involving the skull base is a"great mimic" of other pathologies in the region.The differential diagnosis is best resolved by surgi-cal biopsy, as was performed in our patients.

The pathologically confirmed diagnosis ofdiffuse large cell lymphoma of B-cell origin in ourpatients is consistent with the predominant histo-logic grade reported in several series of nasal andparanasal NHL.10,181922 For example, in a reviewof 16 patients presenting with NHL of theparanasal sinuses, Hausdorff et al.18 reported a pre-dominance (81%) of diffuse large cell lymphomasof B-lineage (63%). Among 70 patients reportedby Logsdon et al.,19 60 (86%) were of a diffuselarge cell histologic type. These observations sug-gest that extensive disease involvement of the skullbase and cranial fossa may represent a clinically ad-vanced stage of sinonasal NHL. Indeed, several in-vestigators have noted that disease stage may be a

134 SKULL BASE: AN INTERDISCIPLINARY APPROACH/VOLUME 11, NUMBER 2 2001

more important prognosticator for survival thanhistologic grade.10'21'22 The clinical significance ofskull base and intracranial involvement on survivalremains to be determined, however.

Traditionally, treatment of extranodal NHLhas been dictated by the site of primary involve-ment, the histology, and the stage of disease. Forstage I or II patients who have low-grade histology,primary radiation therapy has been considered ad-equate.23 However, prognosis with radiation ther-apy alone is often poor even in early-stage disease.In one report, the 5-year survival rate did notexceed 12%.7 Consequently, combined-modalitytreatment with radiation and chemotherapy has re-cently been used with improved outcome.19 Con-current with this evolution in the medical manage-ment of NHL, we have been able to obtain acomplete response with radiation therapy alone inthree of four patients with Ann Arbor stage 1E dis-ease. In one patient (case 1), radiation therapy aloneresulted in a partial response; chemotherapy wastherefore instituted and the disease stabilized at12 months. The reason for initial treatment failurein this patient is unclear. Recurrence of extranodalNHL in the head and neck region after radiationtherapy is usually in the form of distant spread.Local or regional recurrence, or both, is rarely re-ported, especially in stage 1E disease.7,19 Further-more, previous studies have not identified any spe-cific histologic features associated with recurrencein B-lineage extranodal NHL.1821 A poorer prog-nosis, however, has consistently been associatedwith T-lineage extranodal NHL.10 Technical con-siderations cannot be excluded, including the po-tential for a marginal miss at radiotherapy. Irrespec-tive of disease stage, this factor may becomeincreasingly important to the outcome of large tu-mors. Consequently, first-line combined modalitytherapy has been suggested for more advanced dis-ease, including stages 1E (T4), II, and IV.

In immunocompetent older patients pre-senting with a visual disturbance, partial or com-plete ophthalmoplegia, and imaging evidence ofsinonasal disease with cranial base and/or intracra-

nial involvement, the possibility ofNHL should beraised along with other more common lesions suchas squamous cell carcinoma. The differential diag-nosis is resolved by surgical biopsy. In our experi-ence, local control may be achieved with primaryradiation therapy, reserving combined modalitytreatment with appropriate chemotherapeuticagents and radiation for disease unresponsive tosingle therapy.

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