A 58-year-old lady with progressive neurological syndrome: Presence of an intravascular lymphoma
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.156288
Source of Support: None, Conflict of Interest: None
A 58-year-old lady presented to the emergency department (ED) in an altered sensorium. Approximately 2 months ago, she had developed five to six transient episodes of right hemiparesis lasting for 5-10 min over a period of 1 month. She also had an episode of focal seizures for which she was evaluated in a hospital. A brain imaging was performed and she received antiepileptics and injectable steroids and was discharged after 2 weeks on the same medications. She showed an initial marked improvement and became independent for daily activities for 15 days. The current admission followed an episode of focal seizure with secondary generalization and altered sensorium. There was no history of fever, headache, rash, joint pains and vomiting or any chronic illness like diabetes, hypertension or heart disease.
At admission, her pulse rate was 88/min and regular and all peripheral pulses were well palpable. Her blood pressure was normal. Her general physical examination, and respiratory, cardiovascular and gastrointestinal system examination were normal. On central nervous system (CNS) examination, she was drowsy and responsive to deep painful stimuli. She was not vocalizing but localizing with both upper limbs to pain. There were no signs of meningeal irritation. Cranial nerves and fundi could not be examined due to the presence of bilateral cataract. Her pupils were 3 mm, and equal and reacting to light equally on both sides. Her extraocular movements were preserved both in horizontal and vertical directions. The other cranial nerves were normal. On motor system examination, the bulk was normal and there was hypertonia in all four limbs. She was moving all the limbs equally and there was no paucity of any movement. Her deep tendon jerks were symmetrically brisk and plantar reflexes were bilaterally extensor.
Blood: Hemogram: - Hemoglobin 11.5 gm%; TLC 5900/cmm; DLC - N70, L24, M06; platelets 1,39,000/cmm; ESR 8 mm/h; Peripheral blood smear: microcytic, hypochromic RBCs, leukocytes normal and platelets adequate. Biochemistry: Fasting sugar 204 mg/dL; urea 16 mg/dL; creatinine 0.6 mg/dL; total bilirubin 0.9 mg/dL; alkaline phosphatase 77 U/L; SGOT 53 U/L; SGPT 19 U/L; Na 130 meq/L; K 4.0 meq/L. HIV status negative. Urine: Routine examination normal. Cerebrospinal fluid: Nil cells; glucose 91 mg/dL; protein 72 mg/dL; India ink stain negative; cerebrospinal fluid (CSF) VDRL non-reactive; antibody for tuberculosis and cysticercus negative. CSF cytology showed occasional lymphocytes with no abnormal cells. Bleeding time 1 min and clotting time 3 min. Chest X-ray: Normal. Serological tests: ANA/RF negative; Autoantibody profile - negative; vasculitis profile (immunoline and ANCA) negative. VDRL non-reactive. Electroencephalogram (EEG): Background was slow (theta). Periodic bilateral symmetrical frontal dominant slow waves spreading to the temporal leads were seen. Triphasic waves were predominantly seen on both frontal regions. There were no definite seizure discharges. Computed tomography (CT) brain: See [Figure 1]a; magnetic resonance imaging (MRI) brain See [Figure 1]b-e. DSA of the cerebral vessels was normal.
Course in hospital
The patient was started on injectable anticonvulsants (phenytoin and levetiracetam), anti-edema (Inj mannitol) and other supportive measures (intravenous [IV] fluids, Inj ranitidine, Inj insulin, Ryle's tube feeding). Seven days after admission, a stereotactic biopsy from the left frontal lesion was performed and the patient was started on IV methyl prednisolone (1 g). There was an initial mild improvement in her sensorium in the form of spontaneous eye opening but she developed right hemiparesis 1 day later, which did not improve in the following days. Injectable methyl prednisolone was continued for 5 days and later switched over to oral steroids (Tab prednisolone 50 mg per day). There was a gradual deterioration in her general condition and level of sensorium. She had a cardiorespiratory arrest and died on the 14 th day of admission.
The clinical impression was that of a progressive neurological syndrome with partial seizures and focal deficits.
Hematoxylin and eosin stained sections of the formalin-fixed lesional biopsy tissue contained fragmented bits of grey and white matter. Several parenchymal blood vessels were plugged with large atypical lymphoid cells with a high nuclear: cytoplasmic ratio and occasional mitoses. A few vessels showed perivascular spillage of abnormal cells infiltrating focally into the brain parenchyma. Reactive mature lymphocytic infiltrates were also seen. Around the vessels or in the vicinity were small microbleeds and infarcts containing foamy macrophages [Figure 2].
On staining for immunohistochemical (IHC) markers, the atypical cells were positive for LCA, CD20 (B cell), CD5 and MUM1 and negative for CD3 (T cell), CD10, CD30, CD138, CD68, CD31 and cytokeratin, indicating a clonal population of B cell lymphoma cells [Figure 3]. The CD10-negative and MUM1-positive profile indicates a non-germinal center B cell-like subgroup (non-GCB). The reactive lymphocytes were highlighted by CD3 (T cell), while foam cells were stained by CD68, a marker for macrophages. Ki-67 labeling was high in the atypical lymphoid cells [Figure 3]. Glial fibrillary acidic protein (GFAP) highlighted the reactive astrocytosis surrounding the infarcted region.
Diagnosis: Intravascular large B cell lymphoma (IVLBCL; non-GCB).
The defining feature of an intravascular lymphoma (IVL) is the localization of neoplastic lymphoma cells within the vessel lumen with minimal parenchymal extravasation. It is a rare and unique variant of extranodal diffuse large B cell lymphoma (DLBCL) involving small and medium sized vessels and excluding large arteries and veins.  The incidence is less than one per million;  however, it may be under-diagnosed due to the lack of specific clinical features, its protean manifestations mimicking other conditions, and the necessity of a tissue diagnosis as a gold standard. Although any organ may be involved, the CNS and skin manifestations are often the presenting features, and the lymphoreticular system and peripheral blood tend to be spared.  It affects older individuals (median 70 years, range 34-90 years) and involves men and women equally. ,
Most cases arise de novo; however, rare instances of conventional diffuse large B-cell lymphoma (DLBCL; nodal, uretral) recurring as an intravascular lymphoma [IVL] (diffuse multiorgan, cutaneous) years after therapy suggest that the intravascular clone may have been selected by chemotherapy survival. , The presence of an initial inconspicuous intravascular component raises the possibility that this histological feature may be predictive of a later recurrence as IVL.
Despite their extensive intravascular presence, lymphoma cells are generally absent in the peripheral blood and there is no parenchymal mass lesion. This may be due to (1) specific interaction between the lymphoma and the endothelial cells, favoring intravascular localization and proliferation; and, (2) lack of homing receptors on the lymphoma cells that normally mediate the transvascular migration of lymphocytes into the organs.  Supporting these hypotheses is the aberrant expression of adhesion molecules CD11a and CD49d (VLA-4) on lymphoma cells and the absence of CD29 and CD54 (ICAM-1) markers, both of which are regarded as essential for lymphocyte homing and transvascular migration. ,
Classically, IVL is of B cell type (88%),  with B cell-associated antigen-positive CD19+CD20+CD22+CD79a+. The Han's algorithm classifies DLBCL into germinal centre B type [GCB] (CD10+) and non-GCB subtypes (CD10-BCL6- or CD10-BCL6+MUM1+).  Accordingly, most cases of IVL (87.5%) belong to the non-GCB type.  Similarly, the present case is CD10-MUM+, i.e., the non-GCB phenotype. DLBCL with the non-GCB phenotype and IVL have a poorer prognosis than DLBCL of the GCB subtype. Expression of CD5, a B cell subgroup marker, has also been used to subtype IVLBCL. CD5 positivity is associated more frequently with bone marrow/peripheral blood involvement. CNS features, although less frequently seen in CD5-positive IVL, are seen in 13% of the cases,  as occurred in this instance. Rarely, IVL with T-cell (6%) and NK (2%) cell phenotypes have also been identified. 
The potentially widespread intravascular involvement of nearly every organ results in a multitude of clinical presentations. The absence of lymphadenopathy, hepatosplenomegaly or circulating cells in the peripheral blood makes accurate and timely diagnosis difficult.  The following patterns of clinical presentation are the most common: (1) Central nervous system (CNS) manifestations, (2) cutaneous involvement, (3) fever of unknown origin, and (4) hemophagocytic syndrome. 
The presentation of IVL differs according to the geographic area. The Asian/Eastern variant is characterized by predominant bone marrow involvement in the form of hemophagocytosis syndrome, while the European/Classical/Western variant is characterized more by the involvement of CNS and skin. Few cases show only skin involvement (cutaneous variant). ,, The most frequent sites of disease in the Western-IVL series, i.e. CNS (42%) and skin (38%) are involved in a significantly lower proportion of Eastern-IVL cases (21% and 3%, respectively).  The geographic variation is possibly caused by genetic and epigenetic differences in the production of inflammatory cytokines. ,
Majority of the reported cases are single cases or short series with very few large cohorts, making it difficult to draw conclusions regarding its natural history, prognostic factors and best treatment options. A large meta-analysis of IVL involving 740 cases from 431 publications addresses this issue systematically.  IVL was initially diagnosed in the CNS (41%), skin (20%), bone marrow and spleen (17%) and lungs (7%) and occasionally in the other organs. The in vivo diagnosis was often delayed and was established only at the post-mortem studies in as high as 34% of the cases. This was more so in CNS-IVL (cIVL), where the post-mortem assessment established the diagnosis in 60% of the cases. 
Patients with neurologic disease usually have one or more of the following presentations: (1) Progressive, multifocal cerebrovascular events, (2) spinal cord and nerve root vascular syndromes, (3) subacute encephalopathy, or (4) peripheral or cranial neuropathies.  Other manifestations include dementia, seizures, conus syndrome, myopathy and ocular difficulties. ,,
Skin lesions may be single or multiple, maculopapular eruptions, nodules, plaques, hyperpigmented patches, purpura, ulcers and infiltrative "peau d'orange." They tend to favor the proximal extremities, lower abdomen and submammary areas. Non-specific general symptoms like fever, fatigue and loss of appetite are the only symptoms in some patients contributing to the difficulty in accurate and prompt diagnosis. Hemophagocytic syndrome presents with fever, hepatosplenomegaly, liver dysfunction, coagulopathy and a multisystem involvement. The marrow biopsy reveals sinusoidal involvement and hemophagocytosis. 
MRI may show multiple areas of increased signal intensity in bilateral gray and white matter. Infarct-like lesions, non-specific white matter lesions, meningeal enhancement, mass-like lesions and hyperintense pontine lesions have been described.  IVL tends to favor the subcortical and periventricular white matter, whereas CNS vasculitis usually favors the deep white matter. Cerebral angiography reveals patterns consistent with CNS vasculitis in only 45% of IVL, underscoring the need for a definitive biopsy in patients with apparent CNS vasculitis with normal angiographic findings. The features may mimic ADEM, while acute hemorrhagic leukoencephalitis (AHLE) and intracerebral hemorrhage have also been reported. , The utility of fluorodeoxyglucose positron emission tomography in its early detection remains controversial. ,
An organ biopsy is mandatory for the diagnosis of IVLBCL. In Eastern cohorts, the most appropriate site seems to be the bone marrow. Reports on random skin biopsies (RSBs) are very promising for a prompt diagnosis. The tumor cells have been identified not only in the Western cohort where the cutaneous variant is more common but also in the Eastern series where the cutaneous variant is rare. The benefit of biopsy of senile hemangiomas is recognized in several reports. 
In patients with neurological features, the presence of hemocytopenia, elevated lactate dehydrogenase and soluble serum interleukin-2 receptor (sIL-2R), and no lymph node enlargement, the possibility of a cryptic lymphomatous process should be suspected and a random skin biopsy may be useful.  A brain biopsy should contain meninges, cortex and white matter in sufficient quantities to facilitate definitive IHC studies. Liver, kidney and adrenal biopsies can also be taken. 
Treatment and prognosis
IVL is considered as a Stage IV-B disease due to its widespread involvement. The cutaneous variant of IVL with a single skin lesion is considered as a Stage I disease. The treatment of IVL has evolved over the years, and studies have shown that a rituximab-CHOP-(cyclophosphamide, adriamycin, vincristine and prednisolone) containing regime provides a good chance of prolonged survival. A high-dose chemotherapy followed by autologous stem cell transplantation, and a high-dose methotrexate-based polychemotherapy according to the Bonn protocol plus rituximab have resulted in partial or complete remissions. ,,
IVL is a rare disease with non-specific and heterogeneous clinical manifestations necessitating an increased awareness and a high index of suspicion to enable an early tissue diagnosis, which will play a role in initiating a prompt and suitable therapy.
[Figure 1], [Figure 2], [Figure 3]