Journal of Neuro-Ophthalmology, September 1995, Volume 15, Issue 3

Angiocentric Tcell Lymphoma Presenting with Multiple Cranial Nerve Palsies and Retrobulbar Otpic Neuropathy

Angiocentric T-cell lymphoma (lymphomatoid granulomatosis) may present with prominent central nervous system (CNS) findings with variable radiographic features. We describe a patient who presented with multiple cranial nerve palsies involving the left optic nerve, left facial nerve, left ocular motor nerves, and bilateral acoustic nerves. Enhancement of the right temporal meninges and a cavernous sinus mass were noted on magnetic resonance (MR) scan. A right temporal craniectomy and meningeal biopsy were performed. Meningeal biopsy revealed atypical angiocentric granulomatous lymphoid infiltrates without associated necrosis, giant cells, or granuloma formation. Morphologic and T-cell, receptor gene rearrangement findings were diagnostic of an angiocentric T-cell lymphoma. Retrobulbar optic neuropathy and multiple cranial nerve palsies may be the presenting features of angiocentric T-cell lymphoma. The neurologic and unique radiographic changes in our case expand the previously reported findings in CNS angiocentric T-cell lymphoma.

journal of Ncuro- Ophthnlmologij 15( 3): 152- 157, 1995. © 1995 Lippiincott- Ravcn Publishers, Philadelphia Angiocentric T- Cell Lymphoma Presenting with Multiple Cranial Nerve Palsies and Retrobulbar Optic Neuropathy Paul W. Brazis, M. D., David M. Menke, M. D., William M. McLeish, M. D., Daniel F. Broderick, M. D., William P. Cheshire, M. D., Robert E. Wharen, Jr., M. D., and Markus Tiemann, M. D. Angiocentric T- cell lymphoma ( lymphoma toid granulo­matosis) may present with prominent central nervous system ( QMS) findings with variable radiographic fea­tures. We describe a patient who presented with multi­ple cranial nerve palsies involving the left optic nerve, left facial nerve, left ocular motor nerves, and bilateral acoustic nerves. Enhancement of the right temporal me­ninges and a cavernous sinus mass were noted on mag­netic resonance ( MR) scan. A right temporal craniec­tomy and meningeal biopsy were performed. Meningeal biopsy revealed atypical angiocentric granulomatous lymphoid infiltrates without associated necrosis, giant cells, or granuloma formation. Morphologic and T- cell receptor gene rearrangement findings were diagnostic of an angiocentric T- cell lymphoma. Retrobulbar optic neu­ropathy and multiple cranial nerve palsies may be the presenting features of angiocentric T- cell lymphoma. The neurologic and unique radiographic changes in our case expand the previously reported findings in CNS angiocentric T- cel) lymphoma. Key Words: Lymphoma- Lymphomatoid granulomato­sis- Retrobulbar optic neuropathy- Multiple cranial nerve palsies. Manuscript received January 25, 1995. From the Departments of Neurology ( P. W. B., W. P. C), Pa­thology ( D. M. M.), Ophthalmology ( P. W. B., W. M. M.), Radiol­ogy ( D. F. B.), and Neurosurgery ( R. E. W.), Mayo Clinic Jackson­ville, Jacksonville, Florida, U. S. A., and the Department of He-ma topathology, Ch r istia n- A lb re chts- University ( M. T.), Kiel, Germany. Address correspondences and reprint requests to Dr. Paul W. Brazis, c/ o Mayo Clinic Jacksonville, 4500 San Pablo Road, Jack­sonville, R 32224, U. S. A. Angiocentric immunoproliferative lesions ( AIL) are angiocentric, destructive lymphoproliferative diseases that are characterized neither by multinu­cleated giant cells nor by true granulomas ( 1,2). Lymphoma to id granulomatosis lies at the higher-grade end of the histologic spectrum of AIL and should probably be considered a malignant angio­centric T- cell lymphoma from onset ( 1- 3). Al­though angiocentric T- cell lymphoma usually af­fects the lungs, other sites, such as the kidney, skin, upper respiratory tract, and peripheral nerve, may be involved ( 4,5). The central nervous system ( CNS) is involved in approximately 30% of cases with varying clinical presentations ( 2,4). Most primary CNS lymphomas are of B- cell origin and present with discrete masses; angiocentric T- cell lymphomas are much less common and of­ten present with a diffuse " vasculitic" CNS pro­cess. We present a case of biopsy- proven angiocen­tric, angiodestructive T- cell lymphoma in a patient who presented with multiple cranial neuropathies, a severe retrobulbar optic neuropathy, enhance­ment of the right temporal meninges, and a cav­ernous sinus mass on magnetic resonance ( MR) scan. CASE REPORT A 71- year- old man was evaluated for visual and hearing loss and facial paresis. In April 1991, he noted progressive bilateral hearing loss, especially on the left. In December 1991, he developed a com­plete, painless visual loss on the left. Ophthalmic examination revealed a left relative afferent pupil- 152 T- CELL LYMPHOMA PRESENTATION 153 lary defect and an acuity of 20/ 200 OS. Fundu-scopic examination was essentially normal, and a diagnosis of " retrobulbar optic neuropathy of un­known cause" was made. In February 1992, he noted difficulty in closing his left eye and was di­agnosed as having a left peripheral cranial nerve VII paresis. At that time, he also noted low- grade fever, occasional night sweats, and arthralgias es­pecially affecting his knees. Work- up at another institution revealed a sedimentation rate of 120 mm but temporal artery biopsies showed athero­sclerosis only. CT scan of the head February 26, 1992, was negative. An enhanced cranial MR scan on April 9, 1992, demonstrated a right cavernous sinus mass with decreased Tl and increased T2 signal intensity with uniform contrast enhance­ment. There was also thickening and contrast en­hancement of the meninges of the right middle cranial fossa ( Fig. 1A). CSF studies showed three white cells, 53 red cells, protein 48 mg/ dl, glucose 58 mg/ dl, with cytology negative for malignant cells. Sinus biopsy on April 14, 1992, showed " chronic inflammatory changes without vasculitis or granuloma" and mycobacterium was suspected, as the patient stated that his mother had tubercu­losis. The patient was started on INH and rifampin and, later, because his clinical status was un­changed, on steroids. The patient was seen at the Mayo Clinic Jack­sonville initially on July 14, 1992. He felt that his neurologic status had been stable since being on the steroids. He denied any eye pain, diplopia, tinnitus, dysphagia, dysarthria, or other neuro­logic complaints except for occasional mild bifron-tal headaches. General neurologic examination revealed a left peripheral incomplete cranial nerve VII palsy and bilateral sensorineural hearing loss ( left greater than right). Acuity was 20/ 60 OD and NLP OS with a 4+ relative afferent pupillary defect on the left. The left eye was mildly exotropic and hypertropic with decreased movement in all planes. Visual fields in the right eye were normal. The right fun-duscopic examination was normal, but the left disc was pale with attenuated vessels. The remainder of the neurologic examination was normal. No gammopathy was detected on serum Immu­noelectrophoresis or protein electrophoresis stud­ies. Sedimentation rate was 41 mm with hemoglo­bin 12.2, hematocrit 36.7, MCV 95.2, and white count 7,000. Chemistries were normal with normal ACE ( 12.5 U/ L); thyroid stimulating hormone, B12, and folate levels; ANCA; and RPR. Spinal tap re­vealed an opening pressure of 195 mm of water with seven white cells ( 91% lymphs, 1% polys, 8% monocytes); five red blood cells; protein, 38.3 mg/ dl; glucose, 62 mg/ dl; cryptococcal antigen, nega­tive; VDRL, negative; fungal, AFB, bacterial stains and cultures, negative; cytology, atypical lympho­cytes ( with multiple small nucleoli) with reactive monocytosis; immunostaining of spinal fluid cells and B- cell stains were negative with T- cell stains weakly positive. Too few cells were present for gene rearrangement studies by Southern methodology. FIG. 1. Axial ( A) and coronal ( B) enhanced magnetic resonance scans showing enhancing right cavernous sinus mass ( arrow) and thickened enhancing meninges of the right middle cranial fossa ( arrowhead). / Neum- Oyhllwlmol, Vul. 15, No. 3, 1995 154 P. W. BRAZ1S ET AL. The enhanced cranial MR scan of June 2, 1992, showed no change in the enhancing cavernous si­nus mass or meningeal enhancement. New en­hancing soft tissue was seen in the left orbital apex with lateral displacement of the left optic nerve; there was also enhancement of the left optic nerve ( Fig. 2A and B). No parenchyma] lesions were present. Four- vessel cerebral angiography was negative. A right temporal craniectomy and meningeal bi­opsy revealed atypical angiocentric granulomatous lymphoid infiltrates without associated necrosis, giant cells, or granuloma formation ( Figs. 3 and 4). Immunostaining of the lymphoid infiltrates showed scattered CD3H lymphocytes. The mor­phologic differential diagnosis was a vasculitis with an atypical lymphoid component versus an­giocentric T- cell lymphoma. As tissues were fixed in formalin and the biopsy fragments were small, PCR- based T- cell receptor ( TCR) gene rearrange­ment analysis was performed on paraffin section ( 6- 8). A TCR gamma rearrangement was detected ( Fig. 5). The combination of morphologic and T- cell receptor gene rearrangement findings was diagnostic of an angiocentric T- cel! lymphoma, pleomorphic medium- sized, and large- cell T- cell lymphoma in the Kiel classification, The patient was continued on steroids; later, cy­clophosphamide was added. Six months after his presentation to Mayo Clinic Jacksonville, his neu­rologic status has remained unchanged. DISCUSSION The patient's clinical picture was that of multiple cranial nerve palsies, involving the left optic nerve, left facial nerve, left ocular motor nerves, and bi­lateral acoustic nerves with systemic symptoms of low- grade fever, night sweats, and arthralgias. The left visual loss, normal initial funduscopie exami­nation, and initial presence of a relative afferent pupillary defect all suggested a retrobulbar optic neuropathy. Although this optic neuropathy may have been caused by optic nerve compression in the orbital apex or optic canal, the rather acute onset of visual loss raised the possibility of a retrobulbar ischemic optic neuropathy. The multiple other cra­nial nerve palsies and MRI features suggested a diffuse, meningeal process. The clinically evident predominance of cranial nerve findings was on the left, while MRI studies revealed significant changes around the right cavernous sinus and right middle cranial fossa meninges. The finding of thickened enhancing meninges is nonspecific. The differen­tial diagnosis in this patient primarily included in­flammation, infection, and neoplasm, both pri­mary and metastatic. Specifically considered were granulomatous etiologies such as tuberculosis, fungus, and sarcoid; bacterial etiologies; syphilis; histiocytosis X; lymphoma; carcinomatous menin­gitis; and idiopathic cranial pachymeningitis, A right temporal craniectomy and meningeal biopsy revealed angiocentric T- cell lymphoma. FIG. 2. Unenhanced ( A) and enhanced ( B) coronal magnetic resonance scans showing enhancing soft tissue mass ( arrowhead) medial and inferior to the enhancing left optic nerve ( arrow). I Neitm- Ophllmltiml, Vol. 15, No. .1, 3995 T- CELL LYMPHOMA PRESENTATION 155 FIG. 3. Granulomatous lym­phoid infiltrate of meninges. H& E, x200. Neurologic manifestations occur in approxi­mately 30% of patients with angiocentric T- cell lymphoma ( lymphoma toid granulomatosis) and are the presenting feature of the disease in up to 21% ( 4). The central nervous system clinical pre­sentations include mass lesions with focal neuro­logic deficits and signs of increased intracranial pressure, multiple cranial nerve palsies, " aseptic meningitis," dementia and obtundation, and even extrapyramidal dysfunction ( 2). Kleinschmidt- DeMasters et al. noted that while pulmonary in­volvement is generally the most prominent finding in cases with CNS involvement, patients may present with early or dramatic CNS disease ( 2). The radiographic presentations of CNS angio­centric T- cell lymphoma ( lymphomatoid granulo­matosis) are also variable ( 9- 12). Most often re­ported are intraparenchymal lesions, which may be unifocal or multifocal, supra- or infratentorial in location, with variable contrast enhancement. These lesions may be solid or necrotic, commonly demonstrate hemorrhage, and may have associ­ated leptomeningeal thickening and/ or enhance­ment. Less often seen are cerebral infarction, ex- FIG. 4. Angiocentric atypi­cal lymphoid infiltrate ( dark convoluted cells, upper ar­row) admixed with endothe­lial cells of blood vessels ( lower arrow). H& E stain, A 400. j Neuro- O)>): thnh> iat, Vol. 15, No. 3, 1995 • 15b P. W. BRAZIS ET AL. neg. pt. pos. • mo)- wt. std. * FIG. 5. PCR- amplified T- gamma receptor gene rear­rangement ( silver stain of TGGE) ( arrow) thermal gra­dient gel electrophoresis; pos = positive control ( T-cell line), neg = negative control ( placental DNA), pt = patient, Molecular weight standard is pBR 322 Haelll digest. tensive nonconfluent regions of white matter ab­normality, and aneurysm ( 9- 12). Our case is unusual as no intraparenchymal lesions were present; rather, enhancing cavernous sinus and isolated leptomeningeal thickening and enhance­ment were seen initially. Follow- up MR scan showed an enhancing lesion in the orbital apex. Although primary T- cell lymphoma confined to the leptomeninges has been documented patho­logically ( 13), the neurologic and radiographic changes in our case expand the previously re­ported findings in CNS angiocentric T- cell lym­phoma. No characteristic ocular manifestations occur with angiocentric T- cell lymphoma ( lymphomatoid granulomatosis), but patients with uveitis, retini­tis, and eyelid involvement have been described ( 4,14- 16). In cases with predominant CNS involve­ment, neuro- ophthalmic symptoms have included blurred vision, diplopia, and oscillopsia ( 2,4,10,17- 21). For example, blurred vision in a case described by Dumont et al. was due to right parietal and left occipital lesions ( 17), and a patient reported by Hogan et al. complained of oscillopsia with bilat­eral internuclear ophthalmoplegia ( 19). Hamilton et al. reported a patient with right head tilt, right beating nystagmus, abnormal smooth pursuit eye movements, and right jaw movements induced by eyelid blinking ( synkenesis) due to an isolated cer­ebellar lesion ( 21). Optic nerve involvement in patients with angio­centric T- cell lymphoma is rarely reported. Pa­tients may develop papilledema secondary to in­creased intracranial pressure induced by a mass lesion ( 22). Kokmen et al. reported a patient who developed right facial pain, right peripheral facial paresis, bilateral hearing loss, and right optic disc swelling ( 20). The disc swelling subsided over sev­eral weeks, but 30 months later the patient devel­oped dysphagia, ataxia, dysarthria, nystagmus, and progressive spastic quadraparesis. Autopsy revealed the cranial nerves to be normal, but the brainstem showed an angiocentric, angiodestruc-tive lymphoma ( 20). The retrobulbar optic neuropathy in our patient could have been secondary to optic nerve com­pression or ischemic retrobulbar optic nerve insult. Progressive visual loss associated with evidence of optic nerve dysfunction may be the presenting symptom in patients with B- cell lymphoma ( 23,24), and in some cases the optic disc on the affected side appears normal and a diagnosis of retrobulbar neuritis is assumed until visual loss progresses or until other neurologic signs and symptoms develop ( 25,26). Thus, in patients with an optic neuropathy and multiple cranial nerve palsies, angiocentric T- cell lymphoma must be considered in the differential diagnosis of a diffuse meningeal process. REFERENCES Jaffe ES. Pathologic and clinical spectrum of post- thymic T- cell malignancies. Cancer Invest 1984; 2: 413- 26. Kleinschmidt- DeMasters BK, Filley CM, Bitter MA. 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