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Department of Haematology, Concord Repatriation General Hospital, NSW, AustraliaThe University of Sydney, Faculty of Medicine and Health, NSW, Australia
The University of Sydney, Faculty of Medicine and Health, NSW, AustraliaDepartment of Anatomical Pathology, Concord Repatriation General Hospital, NSW, Australia
Department of Haematology, Concord Repatriation General Hospital, NSW, AustraliaThe University of Sydney, Faculty of Medicine and Health, NSW, Australia
The University of Sydney, Faculty of Medicine and Health, NSW, AustraliaDepartment of Neurology, Concord Repatriation General Hospital, University of Sydney, NSW, Australia
Primary angiitis of the central nervous system (PACNS) occurring as a paraneoplastic phenomenon has been described in association with several different types of lymphoma but an association with Hodgkin lymphoma (HL) is rare (up to 26 cases in the literature, with the first report in 1950).
Most of these cases are seen in the setting of classical HL. We present a case associated with nodular lymphocyte predominant Hodgkin lymphoma (NLPHL),
recently renamed nodular lymphocyte predominant B-cell lymphoma (NLPBL) in the 2022 International Consensus Classification of Mature Lymphoid Neoplasms.
A 44-year-old right-handed male smoker presented with a 6-month history of bilateral headaches, cognitive decline, hypersomnolence, and constitutional symptoms including fevers and 20 kg of weight loss. Neurological examination was notable for right horizontal gaze-evoked nystagmus and brisk upper and lower limb reflexes. Formal neuropsychometric testing identified impairments in executive function, working memory, and verbal and non-verbal cognition, and he scored 73/100 on Addenbrooke's Cognitive Examination-III.
Magnetic resonance imaging (MRI) of the brain with gadolinium revealed extensive T2 signal change in the cerebral white matter bilaterally with punctate foci of perivascular enhancement associated with vascular congestion (Fig. 1A–F). There was no restricted diffusion or haemorrhage. Mild leptomeningeal enhancement was seen involving the cerebellar vermis, bifrontal meninges and bilateral vestibulocochlear-facial nerve complexes.
Fig. 1(A–F) MRI of the brain at the time of diagnosis. (A) T2 FLAIR image showing patchy abnormal parenchymal hyperintensities predominantly in the white matter as well as the basal ganglia. (B,C) Post-gadolinium T1 images showing nodular enhancement along the surface of cortical vessels (B white arrows) and extensive perivascular enchancement in the parenchymal (C white arrows). (D) SWI image showing congested intraparenchymal vessels which were tortuous but without haemorrhage. (E) Sagittal FLAIR showing radial periventricular white matter hyperintensities. (F) DWI sequence demonstrating absence of diffusion restriction in the same axial plane as (A). (G) Whole body PET showing increased metabolism in right axillary, infraclavicular, supraclavicular lymph nodes and left inguinal lymph nodes (red arrows).
Full blood count, serum lactate dehydrogenase, C-reactive protein and erythrocyte sedimentation rate were all within normal limits. A serum vasculitis screen (ANCA, ANA, ENA) and anti-neuronal antibodies (to PCA-1, ANNA-1/2, Amphiphysin, PNMA2, CV-2, Recoverin, SOX-1, Titin, Zic4, GAD65, Tr) were negative. Cerebrospinal fluid (CSF) analysis revealed markedly raised protein 2.68 g/L [normal range (NR) 0.15–0.45 g/L], low glucose 1.9 mmol/L (NR 2.5–4.5 mmol) and a mononuclear pleocytosis of 80×106/L (NR<5 ×106/L). CSF cytology and flow cytometry were normal. Oligoclonal bands were negative. CSF bacterial culture, infective polymerase chain reaction panel including mycobacteria, herpes zoster virus, varicella virus, and John Cunningham (JC) virus were negative.
Brain positron emission tomography (PET) was normal. Whole body PET revealed glucose avidity in right axillary, infraclavicular, supraclavicular and a single inguinal lymph node (Fig. 1G). Biopsy of a right axillary lymph node was consistent with NLPHL/NLPBL (Fig. 2A,B).
Fig. 2(A,B) Histopathology of axillary lymph node biopsy. (A) H&E section shows a lymph node with large binucleated and mononucleated cells which display prominent large nucleoli, scattered on a background of small lymphocytes. (B) MEF2B immunohistochemistry highlighting large cells which also positively stained for CD20, PAX5, J-chain, Oct2 and Mum1 (not shown). (C–F) Histopathology of brain biopsy. (C) Leptomeningeal medium-sized vessel with non-necrotising granulomatous inflammation and adjacent secondary necrosis (H&E). (D) Parenchymal vessels within the cortex showing predominantly lymphocytic inflammation with small non-necrotising granulomata (H&E). (E) CD3 immunohistochemistry showing predominance of small reactive T-cells within vessel wall. (F) CD20 immunohistochemistry showing rarity of small reactive B-cells within a vessel wall.
Given the rarity of NLPHL/NLPBL directly involving the brain, a left frontal brain biopsy of dura, leptomeninges and underlying parenchyma was performed. Histopathology showed florid non-necrotising granulomatous vasculitis involving leptomeningeal small and medium-sized vessels as well as small parenchymal muscularised vessels most consistent with arterioles (Fig. 2C–F). There were areas of tissue necrosis in the intervening areas between the vessels, as a secondary change, but fibrinoid necrosis of the vessels was not seen. A Congo red special stain was negative for amyloid. In the absence of infection, or other underlying disease, the features were consistent with PACNS.
The patient was treated with methylprednisolone 1 g daily for 3 days followed by tapering oral prednisolone, and then chemoimmunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R–CHOP) for six 21-day cycles. He achieved complete metabolic remission on interim and end of treatment PET scans. He subsequently underwent consolidative radiotherapy to the right axilla (30 Gy in 15 fractions). Repeat neuropsychiatric assessment at 3 months showed almost complete resolution of cognitive deficits except for a disproportionate weakness in phonemic fluency suggestive of residual frontal system compromise. Progress brain MRI at 3 months showed significantly reduced abnormal white matter enhancement with no new abnormalities.
PACNS is an uncommon condition that can present rarely as a paraneoplastic neurological syndrome. It is characterised by small-to-medium vessel vasculitis that exclusively involves the blood vessels of the CNS, in the absence of systemic vasculitis.
Clinical presentations of PACNS are diverse and can include headache, confusion, cognitive and personality changes, depressed consciousness, seizures, focal neurological deficits, ischaemic and haemorrhagic stroke.
CSF findings are non-specific and frequently show elevated CSF protein and lymphocytic pleocytosis. Brain MRI may show widespread leukoencephalopathy, perivascular gadolinium-enhancing lesions, and less frequently, ischaemic, or haemorrhagic lesions.
PACNS poses a diagnostic challenge as both clinical and radiological features are diverse and lack a pathognomonic signature. Thus, histological confirmation remains essential for the diagnosis of PACNS, as proposed in the diagnostic criteria outlined by Birnbaum and Hellman.
A biopsy is useful in excluding differential diagnoses such as infection, direct involvement with lymphoma or other malignancy, and complications of treatment (e.g., radiation necrosis). Caution is required as false negative biopsies may occur when the distribution of disease is patchy.
A granulomatous pattern of PACNS is the most common, although some cases may show a predominantly lymphocytic pattern or a necrotising vasculitis. Granulomatous inflammation is characterised by vasculocentric destructive mononuclear inflammation, with well-formed granulomas and/or multinucleated giant cells; this may be associated with vascular or parenchymal necrosis.
The histopathological features of cases of PACNS associated with HL are summarised in Table 1. It is important to exclude β-amyloid deposition, as this condition can also present as a granulomatous vasculitis.
In addition, autoimmune disorders (e.g., sarcoidosis, immune complex mediated vasculitides and infection (particularly tuberculosis) can show overlapping patterns of granulomatous inflammation involving vessels.
Table 1Summary of cases of primary angiitis of the central nervous system associated with Hodgkin lymphoma with supportive histopathology
Case report
Diagnosis
Clinical history
Histopathology report
Treatment
Outcome
Rottino et al. J Neuropath Exp Neurol 1950; 9: 103–8.
HL (not specified)
37M with convulsions, aphasia, choreiform movements and aphasia associated with progression of HL despite radiation therapy
Rewcastle et al. Neurol Neurosurg Psychiatry 1962; 25: 51–8.
HL (not specified)
31F with 21 months of untreated HL. Experienced generalised convulsions and short period of unconsciousness
Small leptomeningeal and perforating vessels exhibited focal severe stenosis or occlusion of lamina. There was proliferation of histiocyte-like cells some coalesced to form multinucleated giant cells
Brain RTx only
Died
Rosenblum et al. Neurology 1972; 22: 348–54.
HL (not specified)
32F with 3 years of HL progressing despite treatment. Complicated by herpes zoster during terminal admission
Small arteries with thickened walls infiltrated by lymphocytes and mononuclear cells. Some included multi-nucleated giant cells. Occasional vessels demonstrate organised thrombus. Brain tissue infarction noted
Leptomeningeal vessel obliteration by non-caseating granulomatous containing giant cells
RTx and corticosteroids then MOPP
Full neurological recovery
Linnemann et al. Arch Neurol 1980; 37: 239–40.
HL (not specified)
20M HL in remission for three years presenting with disseminated VZV, progressing to confusion, hallucination and coarse tremor
Infarcts in pons, medulla oblongata, upper cervical cord, with basilar artery involved by granulomatous inflammatory process characterised by subintimal infiltration by histiocytes and mononuclear cells. Vascular necrosis present. Intranuclear viral particles seen by electron microscopy
RTx, chemotherapy (not specified)
Died
Younger et al. Arch Neurol 1988; 45: 514–8.
HL (not specified)
43M with left hemiparesis, ataxia, dysarthria
Compact mass of epithelioid cells, multinucleate giant cells and lymphocytes engulf small blood vessels of the leptomeninges
Corticosteroids alone
Died
Johnson et al. Surg Neurol 1989; 31: 49–53.
NLPHL
49F with headache, left lower limb spastic paraparesis
Lymphocyte, histiocytes and occasional epithelioid giant cells affecting small and larger arterioles and venules
BCVPP, whole brain radiation
Limited residual spasticity
Inwards et al. Cancer 1991; 68: 1318–22.
NS HL
28M with headache, confusion, speech disturbance, left facial and limb weakness and numbness. MRI brain normal, but spine demonstrated increased signal at T7-8 level of spinal cord
Spinal cord biopsy showed small vessel granulomatous and non-granulomatous vasculitis. No viral particles on electron microscopy
RTx, corticosteroid
Persistent but unchanged neurology
Yuen et al. Arch Pathol Lab Med 1996; 120: 573–6.
NS HL
55M with 10 months history of urinary retention, weakness of right lower limb and impaired co-ordination
Widespread focal and segmental vasculitis involving leptomeningeal and intracerebral small and medium arterioles and venules. There were lymphocytes, histiocytes and multinucleated giant cells. Multiple foci of acute haemorrhage. Patchy areas of myelin and axon loss seen
Chemotherapy (not specified)
Died from brainstem haemorrhage a week after first cycle of chemotherapy
Rosen et al. Neurosurgery 2000; 46: 1504–7.
NS HL
27F with headache, nausea and vomiting
Angiocentric and angiodestructive granulomas with epithelioid histocytes, sparse lymphocytes and occasional giant cells. Focal non-caseating necrosis and microvascular thrombus present
ABVD, corticosteroid taper to headache
Returned to work after chemotherapy Substantial improvement on MRI at 6 months
Sheehy et al. J Neurol 2003; 250: 112–3.
NS HL
52M with months of personality changes followed by generalised tonic-clonic convulsion. Additional episodes of absence and lip smacking
The pathogenesis of PACNS remains mostly unknown with limited data on proposed mechanisms of disease. In one case, a predominance of CD45R0+ T cells suggested involvement of memory T-cells,
Outcomes of PACNS associated with HL are generally excellent if diagnosed and treated promptly, although poor outcomes have occurred in the context of haemorrhagic transformation, herpes zoster co-infection and refractory HL.
Initial management with high-dose corticosteroids with or without intravenous cyclophosphamide, followed by multi-agent chemotherapy leads to complete neurological recovery in most cases. An extended period of tapered corticosteroid regimen over months is favoured. Long term neurologic monitoring is required as late neurologic relapse without recurrence of lymphoma has been reported.
The immunochemotherapy regimen R–CHOP was chosen in this case owing to the advanced stage of the haematological disease requiring more aggressive therapy, for the action of rituximab to ameliorate the immune-mediated paraneoplastic process, and for the efficacy of cyclophosphamide against PACNS.
In conclusion, this case highlights the granulomatous vasculitic pattern of PACNS as a rare neurological paraneoplastic phenomenon that should be considered in the differential diagnosis for CNS neurological symptoms occurring in patients with HL. PACNS in the context of HL is highly treatable and requires histological confirmation for diagnosis and optimal management.
Conflicts of interest and sources of funding
The authors state that there are no conflicts of interest to disclose.
References
Rottino A.
Hoffman G.
A sarcoid form of encephalitis in a patient with HL.
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