Journal of Neuro-Ophthalmology, March 2008, Volume 28, Issue 1

Third Cranial Nerve Palsy Caused by Intracranial Extension of a Sino-Orbital Natural Killer T-Cell Lymphoma

Natural killer/T-cell lymphomas (NKTLs) are rare destructive lesions that usually involve the nasal cavity or paranasal sinuses. Orbital and intracranial involvement is rare. A 53-year-old man with systemic lupus erythematosus who was receiving chronic low-dose prednisone treatment developed proptosis of the right eye. Biopsy of a sino-orbital lesion suggested nonspecific inflammation. Clinical and imaging manifestations resolved with a higher dose of prednisone, but when the prednisone dose was tapered, the patient developed a complete right third cranial nerve palsy. Imaging showed return of the original lesion, now with intracranial extension and enhancement of the right third cranial nerve. Repeat biopsy showed features consistent with NKTL. Biopsy of this lesion in its early stage may misleadingly suggest a primary inflammatory disorder because of a paucity of neoplastic cells, a large number of inflammatory cells recruited by the innate natural killer (NK) cell immune response, and extensive necrosis caused by angiodestructive tumor cells.

ORIGINAL CONTRIBUTION Third Cranial Nerve Palsy Caused by Intracranial Extension of a Sino- Orbital Natural Killer T- Cell Lymphoma Celia S. Chen, MBBS, MPH, FRANZCO, Neil R. Miller, MD, FACS, Andrew Lane, MD, and Charles Eberhart, MD, PhD Abstract: Natural killer/ T- cell lymphomas ( NKTLs) are rare destructive lesions that usually involve the nasal cavity or paranasal sinuses. Orbital and intra­cranial involvement is rare. A 53- year- old man with systemic lupus erythematosus who was receiving chronic low- dose prednisone treatment developed proptosis of the right eye. Biopsy of a sino- orbital lesion suggested nonspecific inflammation. Clinical and imaging manifestations resolved with a higher dose of prednisone, but when the prednisone dose was tapered, the patient developed a complete right third cranial nerve palsy. Imaging showed return of the original lesion, now with intracranial extension and enhancement of the right third cranial nerve. Repeat biopsy showed features consistent with NKTL. Biopsy of this lesion in its early stage may misleadingly suggest a primary inflammatory disorder because of a paucity of neoplastic cells, a large number of inflammatory cells recruited by the innate natural killer ( NK) cell immune response, and extensive necrosis caused by angiodestructive tumor cells. (/ Neuro- Ophthalmol 2008; 28: 31- 35) Natural killer T- cell lymphoma ( NKTL) is an uncommon lymphoproliferative disorder account­ing for less than 1% of all lymphomas in North America and Europe ( 1). The pathologic characteristics of NKTLs are distinct from those of other extranodal T- and B- cell lymphomas. Immunohistochemical analysis generally shows CD56 ( N- CAM) positivity ( 2). However, the current World Health Organization classification mandates that the Departments of Ophthalmology ( CSC, NRM, CE), Otolaryngology ( AL), and Pathology ( CE), The Johns Hopkins Hospital, Baltimore, Maryland. Address correspondence to Neil R. Miller, MD, Maumenee 127, Wilmer Eye Institute, Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21287; E- mail: nrmiller@ jhmi. edu diagnosis of NKTL should not be made in the absence of Epstein- Barr virus ( EBV) or cytotoxic granule proteins in tumor cells ( 2). The sinuses and nasal cavity are the most common sites of involvement of NKTL. Orbital involvement is infrequent and intracranial spread is rare ( 3). We describe a case of NKTL that presented as a mass involving the paranasal sinuses and orbit. Initial biopsy of the lesion showed mixed inflammatory cells. The lesion regressed during treatment with systemic corticosteroids but recurred upon tapering of the prednisone dose and subsequently extended intracranially and produced a complete third cranial nerve palsy, at which time repeat biopsy with specialized immunostaining led to a diagnosis of NKTL. CASE REPORT A 53- year- old man with systemic lupus erythemato­sus for which he was being treated with 1 mg/ day prednisone for 20 years presented with a 1- month history of right eye swelling. His primary care physician initially treated him for sinusitis, but his condition worsened and he developed double vision. CT showed a right ethmoid, sphenoid, and frontal sinus mass that extended into the medial aspect of the right orbit. He was referred to an otolaryngologist who performed a transnasal endoscopic biopsy. Before the biopsy, the patient had been evaluated in the Neuro- Ophthalmology/ Orbital Division of the Wilmer Eye Institute, The Johns Hopkins Hospital, at which time he had a best- corrected visual acuity of 20/ 20 in both eyes, normal color vision, and normal visual fields in both eyes. The pupils were isocoric, and the pupillary responses were normal. The right eye showed mild limitation of supra-duction. The left eye had full ductions. The patient was orthophoric in primary gaze but developed a 4 prism diopter ( PD) left hypertropia in upgaze and an esotropia of 5 PD on downgaze. There was 2 mm of proptosis of the right eye. The patient was given 20 mg/ day prednisone with improvement in right eye swelling and diplopia. J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 31 J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 Chen et al At biopsy, the sinuses were filled with mucus, and there was no evidence of infection. The orbit was therefore entered, at which time a firm mass was encountered. Biopsy of the lesion showed chronic inflammation; immunophe-notyping showed a mixed process including both B and T cells ( Fig. 1). No cellular atypia was present. A diagnosis of idiopathic sino- orbital inflammation was made, and the prednisone dose was increased to 40 mg/ day Within 4 weeks, the patient's symptoms and signs had resolved completely, and CT showed complete resolution of the sino- orbital lesion. A slow taper of his prednisone dose was initiated whereupon his symptoms and signs recurred, and CT showed recurrence of the lesion. Accordingly, low- dose fractionated radiation therapy was recommended. The patient elected to delay radiation treatment, and his pred­nisone dose was increased to 20 mg/ day. Despite this treatment, during the next 2 months he developed right upper eyelid swelling, right ptosis, and a severe headache. CT now showed intracranial extension of the mass, and MRI showed a right orbital lesion that measured 2.2 X 0.9 X 3.0 cm extending intracranially through a dehiscent cribriform plate with intraparenchymal involvement of the right frontal lobe and surrounding edema with focal areas suggestive of either necrosis or abscess formation ( Fig. 2). Leptomenin-geal enhancement of the subarachnoid portion of the right third cranial nerve was also visible. A neuro- ophthalmological examination now revealed a best- conected visual acuity of 20/ 60 in the right eye and 20/ 20 in the left eye. The right pupil was 2 mm larger than the left and unreactive to direct light. There was no relative afferent pupillary defect. The patient had a com­plete right ptosis. The right eye showed absent supra-duction, infraduction, and adduction but intact abduction and intorsion on attempted downgaze. There was a right exotropia of 60 PD and a small left hypertropia in primary gaze position, findings all consistent with a complete third cranial nerve palsy ( Fig. 3). A firm, nontender mass was palpable in the superomedial orbit. Slit- lamp biomicro-scopic examination and ophthalmoscopy revealed no abnormalities. A transcutaneous trans- septal orbital biopsy showed friable fibrous tissue containing an inflammatory infiltrate with numerous large, irregular cells featuring vacuolated cytoplasm and heterochromatic nuclei. The Ki67 pro­liferation index was more than 25%. Results of immu-nostaining were positive for CD56 as well as for cytoplasmic CD3, CD4, CD7, CD43, and the cytotoxic granule protein T- cell intracellular antigen- 1 ( TIA- 1) ( Fig. 4). Results of immunostains for CD5 and CD8 and Epstein- Barr virus ( EBV) latent membrane protein ( LMP)- l were negative. In situ hybridization also failed to detect EBV Systemic evaluation revealed two pulmonary masses in the right upper lobe. Lumbar puncture showed a mixed pleocytosis with polymorphonuclear leukocytes and mono­cytes and protein of 87 mg/ dL ( normal 15- 45 mg/ dL). No tumor cells were detected in the cerebrospinal fluid, but Wm „ A"" • • s\ FIG. 1. Histopathology and immu­nologic staining of initial transnasal biopsy of the right orbital lesion. A. Hematoxylin and eosin ( H& E) stain­ing shows abundant lymphocytes ( original magnification: X64). B. the cells stain positively for cyto­plasmic CD3 an epitope found in T cells and natural killer cells ( original magnification: X100). C. The cells are positive for CD20, a B- cell marker ( original magnification: X100). D. the cells are positive for CD68, a histiocytic marker. The positive staining for CD3, CD20, and CD68 in various subsets of cells would appear to indicate an inflammatory process. W$ M I-.- 32 © 2008 Lippincott Williams & Wilkins Third Cranial Nerve Palsy from NKTL J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 FIG. 2. Postcontrast T1 coronal MRI ( A and B) shows a right orbital mass that extends intracranially with fron­tal lobe edema and a focal area of hypointensity surrounded by zones of increasing hyperintensity and enhancement, suggesting necrosis or abscess. Postcontrast T1 axial MRI ( C) shows enhancement and en­largement of the subarachnoid por­tion of the right third cranial nerve as it exits the midbrain ( arrow). The precavernous portion of the right third cranial nerve is enlarged and enhances ( D, arrowhead). flow cytometry of the fluid showed mainly T cells. Spine The patient was treated with intrathecal cytarabine, MRI was normal. Bone marrow biopsy was negative for intravenous doxorubicin, vincristine, and cyclophospha-tumor, but positron emission tomographic scanning showed mide, and oral allopurinol as well as whole- brain irra-intense activity in the chest. A diagnosis of metastatic NKTL diation. His condition improved initially, but he died 13 was made. months after the onset of symptoms and signs. FIG. 3. Complete right third cranial nerve palsy with pupil involvement. Note right ptosis and a right exotropia of 60 PD. There is also a small left hypertropia. The right eye shows no supraduction, infraduction, or adduction, but there is full abduction; intorsion is present on attempted infraduction. 33 J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 Chen et al ;•>&*'*&:# E ' * • * CD3 . " ' •' F \ » : f* row CD56 FIG. 4. Histopathology and immu-nostaining of repeat right orbital biopsy. A. Hematoxylin and eosin ( H& E) staining shows large basophilic cells with vacuolated cytoplasm and pleomorphic, het-erochromatic nuclei. B. Ki67 stain­ing shows a high proliferation index. C. Cells stain positive for the cytotoxic granule protein T- cell intracellular antigen- 1 ( TIA- 1). D. Cells stain positively for CD43. E. Cells stain positively for CD3. F. Cells stain positively for CD56 ( Original magnification for all im­ages: X400). DISCUSSION NKTL is a predominantly extranodal malignancy most commonly positive for EBV and CD56, reflecting a natural killer ( NK) cell phenotype, with occasional patients lacking CD56 expression ( cytotoxic T- cell phenotype) ( 2). This tumor is thought to derive from the malignant transformation of mature NK cells or post- thymic T cells ( 4). It comprises 1% of all lymphomas in patients of Euro­pean descent, although the incidence is higher in Asian, South American, and Hispanic peoples ( 5). NKTL usually is located in the nasal cavity or paranasal sinuses, in which it was previously called idiopathic midline destructive lesion, angiocentric lym­phoma, or, in cases in which the angiocentrically oriented cells appeared to form granulomas, malignant midline granuloma or lethal midline granuloma- NKTL ( 6,7). Oph­thalmic involvement is reported infrequently. For example, Davison et al ( 8). reported 30 cases of nasal NKTL without orbital involvement, and Cuadra- Garcia et al ( 9) found only one case of orbital involvement among 17 cases of NKTL. Because of the location of most NKTLs, the ophthalmic manifestations usually arise from direct in­filtration of orbital structures or associated orbital in­flammation and include proptosis, conjunctival chemosis, and restriction of eye movements ( 10). Other ophthalmic manifestations of NKTL include vision loss from optic nerve dysfunction, rhegmatogenous retinal detachment, and uveitis ( 11,12). Neurologic deficits are rare in patients with NKTL. Luther et al ( 3) reported that fewer than 3% of cases of nasal NKTL were associated with intracranial involvement. When intracranial extension does occur, the process usually is characterized by an abscess- like appearance on neuro-imaging as seen in our patient. This appearance is caused 34 © 2008 Lippincott Williams & Wilkins Third Cranial Nerve Palsy from NKTL J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 by the angiocentric growth pattern and surrounding destruc­tion, resulting in zonal necrosis. Neuro- ophthalmologic manifestations of NKTL are also rare. Hon et al ( 12) reported a case of NKTL that produced unilateral ophthalmoplegia from combined third fourth, and sixth cranial nerve palsies. We believe our patient is the first in whom an isolated third cranial nerve palsy was caused by intracranial extension of an NKTL. In our patient, the subarachnoid and cavernous portions of the nerve showed enhancement on MRI, suggesting either infiltration by the tumor or a local inflammatory response. The diagnosis of NKTL is difficult in its early stages for several reasons. First, NKTL has a broad cytologic spectrum. The atypical cells may be small or medium- sized large and hyperchromatic, or a mixture of these cell types. If small and medium- sized cells predominate, the disease may be difficult to distinguish from an inflammatory or infectious process ( 13) as occurred in our patient. Second NK cells may produce a variety of cytokines such as interferon- a and tumor necrosis factor- a that modulate the adaptive portion of the immune response and recruit a prominent mixture of inflammatory cells, causing further difficulty in differentiating NKTL from admixed or adjacent nonspecific chronic inflammation ( 11). Third, in the early stages of the disease, relatively few neoplastic cells are present, and the NK cells that are present are usually located angiocentrically with areas of surrounding necrosis ( 14). Thus, biopsy of these lesions may not include the neoplastic cells. Because of these issues, multiple or extensive biopsies are often required to obtain sufficient viable tissue ( 14). Evidence of EBV infection is detected in 80% of cases of NKTL and is associated with a shorter survival and a more advanced clinical stage than is NKTL without EBV infection ( 15). In addition, NKTLs commonly express cytotoxic granule proteins such as TIA- 1, perforin, and Fas ligand, all of which are important mediators of tissue damage ( 16). The marker CD56 almost always is present in NK cells as well as in some T cells, and CD3 is found in the cytoplasm of both NK cells and T cells ( 2,5). In our case, neither EBV nuclei acid nor EBV LMP was detected in the second biopsy specimen; however, the cells expressed both CD56 and TIA- 1. An unusual feature of this case was the expression of CD4, which is present in 10% or fewer NKTLs ( 17). Because of the rarity of NKTL, treatment recom­mendations are based primarily on the results of pro­spective cohort reports. Localized nasal NKTL is usually sensitive to radiation therapy ( 11), but failure to achieve a complete response and early relapse are common problems ( 4). Once dissemination to the orbit or intracranial space occurs, as in this patient, long- term remission, even with aggressive chemotherapy, is rare. 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