International Journal of Rheumatic Diseases 2014; 17: 803–807


Paraneoplastic polyarteritis nodosa with cerebral masses: case report and literature review David VEITCH,1 Ted TSAI,1 Shaun WATSON2 and Fredrick JOSHUA1 1 Department of Rheumatology, and 2Institute of Neurological Sciences, Prince of Wales Hospital, Sydney, New South Wales, Australia

Abstract Polyarteritis nodosa (PAN) as a paraneoplastic vasculitis is rarely described, especially in association with squamous cell carcinoma (SCC). Furthermore, only 5% of all PAN patients have central nervous system (CNS) involvement, almost exclusively in the form of cerebral infarction or intracerebral haemorrhage. We report the first case of PAN with multiple immunosuppressant-responsive, cerebral vasculitic lesions in association with metastatic SCC. Key words: cerebral lesions, paraneoplastic polyarteritis nodosa, paraneoplastic vasculitis, squamous cell carcinoma.

CASE REPORT A 65-year-old Caucasian man presented with rightsided dull chest pain, followed by progressive symptoms of erectile dysfunction, memory loss, labile mood, headaches and left hand paraesthesia. These symptoms evolved over 10 weeks, accompanied by an 8 kg weight loss. He had no fevers or night sweats. His medical background included a prosthetic aortic root and aortic valve replacement for a biopsy-proven, degenerative ascending aortic aneurysm and aortic regurgitation. He additionally had gout, prostatic hyperplasia, gastro-esophageal reflux disease, lumbar spine fusion and recurrent herpes simplex oris infections. His medications included warfarin, allopurinol, tamsulosin and pantoprazole. He had a 60 pack a year smoking history, drank minimal alcohol and previously worked in the coal mines. Family history was unremarkable. Salient examination findings included diminished left hand sensation to pinprick and light touch, and a reduced left triceps jerk. His cranial nerve and limb

Correspondence: Dr Fredrick Joshua, Combined Rheumatology Practice, 19 Kensington St, Kogarah, Sydney, New South Wales 2217, Australia. Email: [email protected]

neurological examinations were otherwise unremarkable. Cardiovascular examination revealed an ejection systolic murmur with prosthetic heart sounds and normal peripheral pulses. Chest examination showed quiet breath sounds in hyperexpanded lungs consistent with mild emphysema. There was no lymphadenopathy. Abdominal examination was normal. His urine analysis was bland. Initial investigations including full blood count, renal and liver function tests were normal. His erythrocyte sedimentation rate was 2 mm/h (0–14) and C-reactive protein was 10 mg/L (< 3). Blood cultures were negative. There were no serum or urine paraproteins. Given his smoking history, persistent chest pain and weight loss, computed tomography (CT) scan of the chest was performed. This showed multiple pulmonary nodules and a 2.6 9 4.4 cm right-sided paravertebral mass extending into the pleural space. A fine needle aspiration (FNA) biopsy showed scant macrophages and cell debris only, with no evidence of inflammation or malignancy. CT scan of the brain, neck, abdomen and pelvis revealed an ill-defined, hypodense lesion in the left temporal lobe and a mesenteric soft tissue mass. With the presumption of metastatic malignancy, a positron emission tomography (PET) scan was performed. This demonstrated four glucose avid lesions in the left temporal lobe, right lateral frontal lobe, right

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anterolateral temporal cortex and the fusiform gyrus of the left temporal lobe. In addition, there were glucose avid lesions in the right maxilla, cervical lymph nodes, base of tongue, lungs, mediastinum, mesentery, neck and soft tissues (Fig. 1), suggestive of high-grade lymphoma or metastatic melanoma. However, skin examination was normal and multiple FNA and core biopsies of the pulmonary lesions were not diagnostic, revealing

only bland epithelioid cells. A bone marrow trephine excluded hematological malignancy. During this time, the patient noticed progressive right facial and leg numbness and bilateral lower leg weakness. Examination showed reduced pinprick and light touch in the right cranial nerve V2 and V3 distributions, and reduced pin-prick over the whole right leg, with patchy sensory loss on the left leg. Magnetic resonance imaging (MRI) of the brain with contrast confirmed the multiple enhancing lesions as shown on the PET scan. These had surrounding edema, adjacent dural enhancement and mass effect with a 5mm midline shift. The largest lesion was in the left temporal lobe (Fig. 2). MR angiography was unremarkable. Dexamethasone 24 mg daily was commenced. Prior to brain biopsy, a repeat PET scan showed complete resolution of the cerebral lesions after 2 months of high-dose dexamethasone therapy. A repeat MRI brain confirmed almost complete resolution of the multiple cerebral lesions (Fig. 3), and the biopsy was cancelled. Dexamethasone was tapered over the next 3 months. A progress PET scan 2 months after steroid cessation showed no recurrence of the cerebral lesions and resolution of the pulmonary lesions. However, there were

Figure 1 A maximum intensity projection image from the first positron emission tomography scan demonstrating the widespread glucose-avid lesions involving the right maxilla, cervical lymph nodes, base of tongue, lungs, mediastinum, mesentery, neck and soft tissues.

Figure 2 Coronal fluid-attenuated inversion recovery magnetic resonance imaging: left temporal lobe enhancing mass with associated swelling and white matter edema. There were also masses in the right anterior frontal lobe not seen on this image.


International Journal of Rheumatic Diseases 2014; 17: 803–807

Paraneoplastic PAN with cerebral masses

Figure 3 Coronal post-gadolinium T1 weighted magnetic resonance imaging: there is no longer enhancement in the left temporal lobe.

new glucose avid lesions in various limbs and paraspinal muscles and the left kidney, with persisting uptake at the base of the tongue. A specialist ear, nose and throat review with nasoendoscopy was unremarkable, with multiple random oropharynx and tongue biopsies showing normal mucosa. There was no clinical lymphadenopathy. CT abdomen performed to assess the new renal lesion showed three small aneurysms in branches of the superior mesenteric artery on angiographic reconstruction with contrast. Post-weaning of his dexamethasone 1 year after his initial presentation, the patient developed inflammatory arthritis affecting the wrists, metacarpophalangeal joints, metatarsophalangeal joints and ankles. He also had increased fatigue, generalized weakness and myalgia with severe functional impairment such that he was unable to rise unaided. His headaches worsened. Multiple investigations were performed for these new symptoms. Nerve conduction study demonstrated a diffuse axonal sensorimotor neuropathy suggestive of mononeuritis multiplex. Vasculitis was confirmed on sural nerve biopsy. Muscle biopsy of vastus lateralis was consistent with an autoimmune inflammatory myopathy. Anti-nuclear antibody was speckled with a titre of 1 : 320. Double-stranded DNA antibodies, complement levels, extractable nuclear antigen (ENA) screen, anti-neutrophil cytoplasmic antibodies (ANCA),

International Journal of Rheumatic Diseases 2014; 17: 803–807

anti-neuronal antibodies, angiotensin-converting enzyme (ACE), rheumatoid factor, anti-cyclic-citrullinated peptide (CCP) antibodies and immunoglobulin levels were unremarkable. Syphilis, hepatitis B, hepatitis C and human immunovirus serologies were negative. A diagnosis of polyarteritis nodosa (PAN) was made, fulfilling at least three out of the 10 1990 American College of Rheumatology (ACR) classification criteria:1 weight loss ≥ 4 kg, clinical and biopsy-proven myositis and polyneuropathy, multiple mesenteric aneurysms and presence of mixed leukocyte infiltrate in an artery consistent with vasculitis on sural nerve biopsy. Additionally, he had widespread, immunosuppressantresponsive cerebral, pulmonary and mesenteric lesions. The patient was commenced on prednisolone 50 mg daily with immediate clinical improvement. One month later the prednislone was weaned and oral cyclophosphamide was then commenced with up-titration to 100 mg daily. A progress PET scan showed complete resolution of the cerebral and pulmonary lesions 6 months after immunosuppression. He remained clinically well throughout 12 months of follow-up on cyclophosphamide. After 1 year, cyclophosphamide was then changed to methotrexate. A 1-year follow-up MRI brain revealed a new trilobed aneurysm in the left sylvian fissure. A digital subtraction angiography confirmed three new fusiform type aneurysms in the left middle cerebral artery distribution, adjacent to the resolved, presumed inflammatory lesions. The patient was investigated for a new, gradually enlarging right-sided submandibular mass 15 months after treatment commencement for PAN and while still on methotrexate. CT scan revealed a 30 9 17 mm lesion anterior to the sternomastoid, and a 17 9 15 mm lesion above the level of the hyoid bone. Cytology on FNA was consistent with a metastatic squamous cell carcinoma (SCC). He underwent chemoradiotherapy, with subsequent surgical management of his middle cerebral artery aneurysms. A final diagnosis of paraneoplastic polyarteritis nodosa with cerebral lesions secondary to metastatic squamous cell carcinoma was made.

DISCUSSION Our patient’s initial presentation of subacute chest pain, headache, hand paresthesia and profound weight loss was concerning for metastatic malignancy, especially given his smoking history. Imaging revealed multiple masses in his brain, lungs and mesentery which were highly glucose-avid on PET scan, but biopsy negative


D. Veitch et al.

for malignancy or atypical infection. Surprisingly, these lesions appeared to be inflammatory as they resolved promptly with dexamethasone alone before a cerebral biopsy could be performed. No paraneoplastic source was found despite progress PET scan guidance and multiple blind biopsies in the oropharyngeal tract. As the dexamethasone was weaned 10 months after his initial presentation, our patient declared ANCA-negative vasculitis with progression of biopsy-proven mononeuritis multiplex affecting his cranial and limb nerves, biopsy-proven autoimmune myositis, as well as new mesenteric artery aneurysms, and inflammatory arthritis. He also had widesspread mass lesions which resolved with immunosuppression. This pattern is most consistent with, and fulfilled the 1990 ACR vasculitis classification criteria for PAN, a rare, systemic, necrotizing vasculitis affecting small and medium-sized arteries with peak incidence in the sixth decade of life, affecting predominately males.2 The other possible differential diagnoses for his widespread steroid-responsive lesions include lymphoma or paraneoplastic inflammatory lesions due to other malignancies, such as melanoma. Only after 2 years from his presentation did the submandibular metastatic SCC become apparent; despite targeted and thorough evaluation of the oropharygneal tract due to the persistent PET scan uptake 1 year earlier. The timing and course of his illness strongly suggest that the PAN was most likely paraneoplastic. PAN as a paraneoplastic vasculitis is uncommon, although its clinical presentation is similar to that of classical PAN.3 Although the pathogenesis is unclear, immunological cross-reactivity between antigens of the primary malignancy and antigens on the vascular endothelial cells has been proposed.4 Paraneoplastic PAN is most commonly associated with hairy cell leukemia, with over 50 cases in the literature. It has also been described with myelodysplastic syndrome and chronic myelomonocytic leukemia. Various solid tumor associations include bladder, colorectal, gastric, lung and liver tumors.3 With the exception of our case, Okada et al.5 is the only other case report of PAN in association with a SCC, in which the PAN and hypopharyngeal SCC were diagnosed simultaneously. In that case, there was complete resolution of symptoms at 6 months follow-up post-treatment with oral methylprednisolone and intravenous cyclophosphamide, and radiation therapy to the SCC. The patient had no central nervous system (CNS) complications.


Only 5% of all PAN patients have CNS involvement, almost exclusively in the form of cerebral infarction or intracerebral hemorrhage.6 Reichart et al.7 retrospectively reviewed all cases of PAN-related stroke from 1966 to 1998 using the 1990 ACR classification criteria for PAN, thus excluding microscopic polyangiitis, which has a much higher 20–40% CNS complication rate.2 Fifteen cases were found, 11 with lacunar infarcts, two with large cerebral infarcts and two with hemorrhagic strokes. These occurred within 8 months after the onset of vasculitis. Since then, 13 cases of PAN associated with cerebral infarction or hemorrhage have been reported.8–19 Few cases describe post-inflammatory cerebral aneurysms identified on angiography and biopsy11,12,18, but none described inflammatory cerebral mass lesions. To conclude, we report the first case of paraneoplastic polyarteritis nodosa with multiple immunosuppressant-responsive, cerebral vasculitic lesions.

ACKNOWLEDGEMENTS With thanks to Dr Eva Wegner, Department of Nuclear Medicine, Prince of Wales Hospital, Sydney and Dr Ron Shnier, Southern Radiology, Sydney for their radiological expertise.

REFERENCES 1 Lightfoot RW Jr, Michel BA, Bloch DA et al. (1990) The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum 33 (8), 1088–93. 2 Watts RA, Scott DGI (1997) Classification and epidemiology of vasculitis. Baillieres Clin Rheumatol 11, 191–217. 3 Park HJ, Ranganathan P (2011) Neoplastic and paraneoplastic vasculitis, vasculopathy, and hypercoagulability. Rheum Dis Clin North Am 37 (4), 593–606. 4 Vankalakunti M, Joshi K, Jain S, Nada R, Radotra BD, Varma S (2007) Polyarteritis nodosa in hairy cell leukaemia: an autopsy report. J Clin Pathol 60 (10), 1181–2. 5 Okada M, Suzuki K, Hidaka T et al. (2002) Polyarteritis associated with hypopharyngeal carcinoma. Intern Med 41 (10), 892–5. 6 Minagar A, Fowler M, Harris MK, Jaffe SL (2010) Neurologic presentations of systemic vasculitides. Neurol Clin 28 (1), 171–84. 7 Reichart MD, Bogousslavsky J, Janzer RC (2000) Early lacunar strokes complicating polyarteritis nodosa: thrombotic microangiopathy. Neurology 54 (4), 883–9. 8 Marignier R, Derex L, Philippeau F, Streichenberger N, Nighoghossian N, Trouillas P (2002) Anterior choroidal

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artery infarction revealing polyarteritis nodosa. Rev Neurol 158 (2), 221–4. Kostina-O’Neil Y, Jirawuthiworavong GV, Podell DN, Lesser RL (2007) Choroidal and optic nerve infarction in hepatitis C-associated polyarteritis nodosa. J Neuroophthalmol 27 (3), 184–8. Morfın-Maciel B, Medina A, Espinosa Rosales F, Berr on R, Huerta L opez J (2002) Central nervous system involvement in a child with polyarteritis nodosa and severe atopic dermatitis. Rev Alerg Mex 49 (6), 189–95. Sharma S, Kumar S, Mishra NK, Gaikwad SB (2010) Cerebral miliary micro aneurysms in polyarteritis nodosa: report of two cases. Neurol India 58 (3), 457– 9. Bouvard B, Lavigne C, Marc G, Menei P, Debray JM, Dubas F (2007) Two consecutive episodes of intracerebral hemorrhage as the presenting feature of polyarteritis nodosa. Rev Med Intern 28 (9), 651–4. Shimizu M, Honma M, Endo K et al. (2002) Recurrent multiple cerebral hemorrhages complicated with polyarteritis nodosa. Clin Neurol 42 (7), 603–7.

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14 De Reuck J (2003) Dorsal thalamic haemorrhage complicating polyarteritis nodosa: a clinico-pathologic case report. Acta Neurol Belg 103 (1), 40–2. 15 Laconetta G, Benvenuti D, Lamaida E, Gallicchio B, Signorelli F, Maiuri F (1994) Cerebral hemorrhagic complication in polyarteritis nodosa. Case report and review of the literature. Acta Neurol 16 (1–2), 64–9. 16 Oomura M, Yamawaki T, Naritomi H, Terai T, Shigeno K (2006) Polyarteritis nodosa in association with subarachnoid hemorrhage. Intern Med 45 (9), 655–8. 17 Topaloglu R, Kazik M, Saatci I, Kalyoncu M, Cil BE, Akalan N (2005) An unusual presentation of classic polyarteritis nodosa in a child. Pediatr Nephrol 20 (7), 1011–5. 18 Takahashi JC, Sakai N, Iihara K et al. (2002) Subarachnoid hemorrhage from a ruptured anterior cerebral artery aneurysm caused by polyarteritis nodosa. Case report. J Neurosurg 96 (1), 132–4. 19 Taieb G, Renard D, Briere M (2011) Polyarteritis nodosa associated with essential mixed cryglobulinemia revealed by subarachnoid hemorrhage. Intern Med 50 (23), 2905– 9.


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Paraneoplastic polyarteritis nodosa with cerebral masses: case report and literature review.

Polyarteritis nodosa (PAN) as a paraneoplastic vasculitis is rarely described, especially in association with squamous cell carcinoma (SCC). Furthermo...
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