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|Year : 2019 | Volume
| Issue : 6 | Page : 1504-1508
“Slow and Steady” Infiltrates the Brain: An Autopsy Report of Lymphomatosis Cerebri
Kirti Gupta1, Vivek Gupta2, Bishan D Radotra1, Manoj K Tewari3
1 Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Radiodiagnosis, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||20-Dec-2019|
Dr. Bishan D Radotra
Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
Primary central nervous system lymphomas (PCNSL) usually present as single or multiple lesions with mass effect involving the cerebral hemispheres or basal ganglia. An extremely rare pattern of involvement termed “Lymphomatosis cerebri” (LC) presents as diffuse, non-enhancing infiltrative lesions without mass effect. We describe the clinical, radiological, and autopsy findings of one such rare example with a patient presenting with a short history of fever, memory loss, and progressive cognitive decline. Because of subtle yet rapidly progressive clinical symptoms and overlapping neuroimaging features, the diagnosis of LC is challenging with wide ranging differential diagnoses. The dilemma in diagnosing such lesions can lead to delay in diagnosis and institution of appropriate management. Thus, knowledge about its imaging and morphological features is very critical for correct categorization and to avoid potential misdiagnosis of this often-missed disease.
Keywords: Autopsy, lymphomatosis cerebri, primary CNS lymphoma
Key Message: Lymphomatosis cerebri is a rare form of primary CNS lymphoma characterized by neoplastic cells which diffusely percolate through the white matter instead of forming cohesive masses. Such a pattern of infiltration is seen with Gliomatosis cerebri, the term which has been deleted from the recent WHO classification.
|How to cite this article:|
Gupta K, Gupta V, Radotra BD, Tewari MK. “Slow and Steady” Infiltrates the Brain: An Autopsy Report of Lymphomatosis Cerebri. Neurol India 2019;67:1504-8
Lymphomatosis cerebri (LC), analogous to the much familiar term”gliomatosis cerebri,” is a rare form of PCNSL characterized by cells diffusely percolating through the white matter instead of forming bulky, cohesive periventricular deposits.,, The clinical symptoms and imaging findings pose considerable diagnostic challenge as it closely mimics commoner white matter etiologies. In this case, we illustrate the clinical and imaging findings of an elderly man presenting with gradually progressive dementia and memory loss and discuss the differentials. The autopsy findings are also described in detail and it is particularly interesting as the imaging features are corroborated with histology.
| » Clinical Summary|| |
A 69-year-old gentleman presented with history of fever of one-week duration followed by gradually progressive memory loss of one and half month duration. He also had a history of tremulousness of his legs followed by his hands and smearing of his face for the same duration. Subsequently, he was bed-ridden with loss of control of bowel and bladder. There was no history of increased intracranial pressure, focal seizures, cranial nerve involvement, or truncal ataxia. There was no past history of diabetes, hypertension, or chronic cough. On examination, he was found to have pallor; no peripheral lymphadenopathy was noted. On examination of central nervous system, he was apathetic with Glasgow Coma Scale of E4V1M5, with equal movements in all four limbs. Cranial nerves and fundus were normal. Motor tone was increased in all four limbs. Sensations could not be assessed in all four limbs. Meningeal signs were positive. Investigations revealed a normal hemogram with raised urea and creatinine. Liver function tests were normal (however, these were deranged slightly towards the latter part of his illness). Fasting blood sugar levels were raised (210 mg/dl). Blood culture grew E. coli. Cerebrospinal fluid (CSF) analysis revealed mildly raised proteins (61 mg/dL) and normal sugar levels (75 mg/dL). No malignant cells were detected. A test performed for human immunodeficiency virus (HIV) was non-reactive. Antinuclear antibody and anti-neutrophilic cytoplasmic antibody performed were negative. Chest X-ray and electrocardiogram was within normal limits.
Contrast enhanced MRI of the brain was done which revealed extensive changes involving the cerebrum, brainstem, and upper cord. There was preferential involvement of the frontal lobar white matter along with deeper involvement of corpus callosum and deep gray nuclei. Also, the involvement extended in contiguous fashion inferiorly to involve thalamus, midbrain, pons, medulla, and the upper-most cervical cord. The lesions were bilateral asymmetric, bright on T2WI, dark on T2WI with mild edema, minimal mass effect, and showed patchy heterogenous enhancement in some of the lesions [Figure 1]. In the following three days, his neurological status deteriorated and he succumbed to his illness before any appropriate treatment could be instituted or antemortem diagnosis could be established. The clinically possibilities considered included acute disseminated encephalitis, viral encephalitis, and PCNSL. An autopsy restricted to brain was performed.
|Figure 1: Axial T2-weighted images (a-d) showing extensive bilateral hyperintensities involving the pons (arrow, a), midbrain (arrow, b), thalamus (short arrow, (c) and basal ganglia (long arrow, (c) Multifocal confluent hyperintensities also seen involving deep and subcortical white matter in bilateral frontal lobes (d). Note is made of lack of mass effect as the adjacent sulci are not effaced. Axial T1-weightd images pre (e) and post contrast (f) showing minimal patchy enhancement. Sagittal post contrast T1-weighed images showing linear enhancement in the upper cervical cord (white arrow, g) and centrum semiovale (arrow in h). Corresponding FLAIR coronal image (i) showing minimal edema and normal looking ventricles and sulci|
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| » Pathology Findings|| |
The brain examined at autopsy weighed 1234 g. No meningeal exudates were detected on convexities or base of the brain. There was no herniation of uncus (indicative of cerebral edema). On coronal slicing, apart from mild congestion of intra parenchymal vessels within central white matter, no mass lesions, necrosis, or haemorrhage was detected [Figure 2]a and [Figure 2]b. Likewise, axial cuts of brainstem and cerebellum did not show any focal lesions [Figure 2]c and [Figure 2]d. Ventricular system including its lining was within normal limits. Histological examination highlighted a diffuse proliferation of neoplastic cells with a variable cell density from different regions of the brain [Figure 3]a and [Figure 3]b. There was relative sparing of gray matter. The frontal lobes bilaterally demonstrated prominent cortical involvement with near total effacement of the neuronal population. The neuronal lamination was disrupted at places with the neoplastic cells permeating through the subcortical white matter and percolating along the white matter tracts [Figure 3]b. The tumor cells were large with folded nuclear membranes, prominent nucleoli, and scant cytoplasm [Figure 3]c and [Figure 3]d. Frequent mitoses and many apoptotic bodies were evident. No necrosis was identified. The infiltrate was particularly prominent in corpus callosum, internal capsule, thalamus, cerebral peduncles, basal ganglia, amygdala, hippocampus and basis pontis, medulla and upper cervical cord. The neoplastic cells exhibited a peculiar tendency tomigrate and cluster along white matter bundles rather than diffusely permeate and destroy them. Perivascular collections were also observed [Figure 4]a, [Figure 4]b, [Figure 4]c, [Figure 4]d. The frontal cortex, nucleus basalis of Meynert, substantia nigra and tectum of midbrain [Figure 5]a, [Figure 5]b, [Figure 5]c, [Figure 5]d demonstrated few larger collections of such cells. Similar to the PCNSL there was slight proclivity to involve the periventricular areas [Figure 4]a with greater cell densities but bulky tumor deposits were not evident anywhere. While subpial aggregates were seen, no leptomeningeal infiltrate was noticed. Demyelination was not observed although some frontal white matter pallor attributable to mild tumor edema was evident. Luxol fast blue-periodic acid Schiff's (LFB-PAS) stain did not reveal any myelin-laden macrophages to suggest demyelination. The neoplastic cells revealed strong and diffuse immunoreactivity for B-cell markers including CD20 [Figure 6]a, [Figure 6]b, [Figure 6]c, CD79a, and CD10 (focally), bcl6 while were negative for CD3 [Figure 6]d, CD5, CD15, CD30, CD138, MUM1, and for Epstein Barr virus antigens. A diagnosis of lymphomatosis cerebri-primary central nervous B cell lymphoma (diffuse large, germinal centerphenotype) was rendered.
|Figure 2: (a and b) Gross of coronal cuts showing mild prominence of intraparenchymal vessels. (c and d) Horizontal cuts of brain stem and cerebellum do not reveal any focal lesions|
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|Figure 3: (a) Scanner image of section of the cortex, higher magnification of box in b; (b) Round to oval cells percolating through the cortex disrupting the lamination of neurons (H and E × 200); (c) Atypical cells diffusely infiltrating the brain parenchyma (H and E × 200); (d): Cells with vesicular chromatin and conspicuous nucleoli seen against a neurofibrillary background (H and E × 400)|
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|Figure 4: (a) Neoplastic cells aggregating around peri-ventricular region, (b) and diffusely permeating along the basal ganglia (b), thalamus (c), and collection around the vessels (d) (a-d, H and E × 200)|
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|Figure 5: (a) Scanner image of the midbrain section demonstrating bulky deposits along the substantia nigra; (b) Scanner image of the corresponding myelin stain of the midbrain section (Luxol fast blue-periodic acid Schiff's (LFB-PAS) ×40; (c) Low magnification showing neoplastic cells within the tectum (H and E × 40); (d) Corresponding section in myelin stain (LFB-PAS × 40)|
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|Figure 6: (a) Neoplastic cells with hyperchromatic nuclei and scant cytoplasm (H and E x1000); (b and c) Neoplastic cells diffusely positive for CD20 (immunoperoxidase ×200 (b), ×1000 (c); (d) Few scattered T cells highlighted by CD3 (immunoperoxidase ×200)|
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| » Discussion|| |
PCNSL usually presents as solitary, isolated lesions located adjacent to the ventricular systemin immunocompetent individuals. LC is a rare form of PCNSL wherein the atypical lymphocytes instead of forming cohesive masses diffusely infiltrate and permeate the white matter , Patients with this form of disease generally present with progressive cognitive decline. The term “lymphomatosis cerebri” was first proposed by Bakshi et al. for this pattern of spread as it was akin to “gliomatosis cerebri”. Although the current 2016 WHO update of CNS tumors no longer recognizes the term “gliomatosis cerebri,”LC continues to hold well. This form of infiltrate is particularly challenging as the imaging findings closely mimics the commoner white matter lesions such as infections, inflammatory, vascular, toxic, or degenerative disorders., In the present case, provisional clinical possibilities considered were acute disseminated encephalitis, viral encephalitis, and PCNSL before a brain biopsy was planned. His deteriorating clinical condition and early demise did not give an opportunity to establish a definitive diagnosis.
In immunocompetent patients, PCNSL typically present with isolated, solitary, enhancing lesions usually located to frontal or parietal lobes, while in immunocompromised individuals, it manifests as multiple, ring-enhancing foci frequently involving basal ganglia or frontal lobes.,, A third, rare interesting pattern is LC which is often missed and is seen as a diffuse hyper intensity of cerebral white matter, without contrast enhancement or mass effect. LC has been described in the literature as short series and isolated case reports, each case emphasizing the importance of imaging in making an early diagnosis.,,,,,,, Unfortunately, as the imaging features are not pathognomic,, and most of them are diagnosed on post mortem or with brain biopsy, which again reflects the fact that identifying this lesion on imaging is challenging. On conventional MRI, the lesions are typically bilateral and asymmetric. The hallmark of the lesions is extensive signal abnormalities on MRI in the lobar white matter and deep nuclei without corresponding mass effect or enhancement. In our case, these typical findings were seen with preferential involvement of frontal lobes along with brain stem. Though the imaging findings were extensive, there was minimal edema and no mass effect as the adjacent sulci and ventricles were not effaced.
On imaging the close differentials include infections such as viral encephalitis, inflammatory diseases like acute disseminated encephalomyelitis, metabolic encephalopathies, and neoplastic conditions like gliomatosis cerebri., Lack of edema/mass effect and minimal enhancement differentiates it from other conditions. The use of magnetic resonance spectroscopy (MRS) increases the diagnostic accuracy at imaging as increased choline/creatinine (Cho/Cr) levels and decreased N-acetylaspartate/creatinine (NAA/Cr) levels are suggestive of a neoplastic process like LC in comparison to other infective/inflammatory and metabolic pathologies. Literature also documents a few cases with the absence of these typical MRS findings thus making differentiation of this from other mimickers even more challenging. Lack of diffusion restriction in LC has also been reported.
From a pathologist's perspective, the tendency of the cells to percolate along the white matter without forming typical cohesive masses is a distinguishing feature on histology. This “encephalitic” pattern is best appreciated at low magnification. In addition, there is no associated significant myelin pallor which is reflected on and LFB-PAS stain as subtle myelin loss. Unlike the usual PCNSL, lymphocytic cuffing, and admixture with reactive CD3 positive mature lymphocytes is very modest, as seen in this case. No bulky periventricular deposits are observed. While B cell lymphoma constitutes the vast majority of LC variant, few rare examples of T-cell lymphoma and a single case of anaplastic large cell lymphoma as LC pattern of spread are also on record.,
Histologically, this pattern of lymphomatous spread closely mimics viral encephalitis. In contrast to latter, perivascular lymphocytic cuffing and microglial nodules are minimal in LC. Progressive multifocal leukoencephalopathy (PML) also enters the list of differentials both on imaging and histology. The presence of of inclusions within the oligodendrocytes and immuno-positivity for JC virus are features in favor PML. Gliomatosis cerebri is the closest mimic amongst the neoplastic lesions. It is characterized by glial fibrillary acidic protein expressing neoplastic astrocytes diffusely infiltrating the brain parenchyma in a similar manner. Brain biopsy examination is essential to confirm the diagnosis of LC. Unfortunately, this was not possible in the index case due to rapid clinical deterioration and early demise and the diagnosis was achieved only at autopsy. In contrast to glioma and other primary brain tumors, PCNSL demonstrates a dramatic resolution of mass lesions with both clinical and radiological improvement following steroids intake. This response is however short-lived and the lesions recur.
The molecular basis for this tendency of cells to permeate through the brain parenchyma instead of forming cohesive masses is attributed to the reduced expression of adhesion molecules namely LFA-1 (CD11a, α1β2) on lymphoma cells as seen in experimental models. Poor prognosis observed in cases of LC patients in comparison to conventional PCNSL underscores the importance of early diagnosis., There is an anecdotal evidence of successful treatment of LC following early biopsy, in which steroids and radiotherapy led to significant improvement and patient was discharged with no deficits. An aggressive early institution of therapy with high-dose methotrexate-based chemotherapy is warranted in cases of LC.
In conclusion, the case highlights the importance of considering LC in the differential diagnosis of an extensive white matter disease. Brain biopsy is vital for clinching the diagnosis and for institution of prompt therapy.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
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