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  Table of Contents    
Year : 2022  |  Volume : 65  |  Issue : 3  |  Page : 657-667
Beyond central nervous system tuberculosis: A clinico-radio-pathological correlation of an unusual cause of death

1 Department of Pathology, Command Hospital (Southern Command), Pune, Maharashtra, India
2 Department of Radiodiagnosis, Command Hospital (Southern Command), Pune, Maharashtra, India
3 Department of Neurology, Command Hospital (Southern Command), Pune, Maharashtra, India

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Date of Submission30-Apr-2021
Date of Decision28-Aug-2021
Date of Acceptance29-Aug-2021
Date of Web Publication21-Jul-2022

How to cite this article:
Majumder A, Sen D, Nanda SK. Beyond central nervous system tuberculosis: A clinico-radio-pathological correlation of an unusual cause of death. Indian J Pathol Microbiol 2022;65:657-67

How to cite this URL:
Majumder A, Sen D, Nanda SK. Beyond central nervous system tuberculosis: A clinico-radio-pathological correlation of an unusual cause of death. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 Aug 15];65:657-67. Available from: https://www.ijpmonline.org/text.asp?2022/65/3/657/351591

   Clinical Presentation Top

A 32-year-old male patient with no known comorbidities initially presented in May 2012 with focal motor seizures involving the right upper limb without any secondary generalization. The magnetic resonance imaging (MRI) of the brain revealed an inflammatory granuloma in the left parietal lobe. His cerebrospinal fluid (CSF) examination revealed features of central nervous system (CNS) tuberculosis (TB) [Table 1]. He received anti-tubercular treatment (ATT) for 1 year along with anti-epileptic drugs (AED) and his follow-up imaging showed resolution of the granuloma. Thereafter, the patient was asymptomatic on regular follow-up. His AEDs were stopped in 2017 and he was seizure-free.
Table 1: Table depicting the results of CSF studies over the course of the patient's illness

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In the first week of February 2020, he presented with complaints of recurrent headaches for the past month. There was no history of associated nausea, vomiting, neurological deficit or fever, or other systemic manifestations. A contrast-enhanced (CE) MRI study of the patient's brain revealed multiple tiny conglomerated ring-enhancing lesions with perifocal edema in the left medial temporal lobe and were reported as tuberculomas [Figure 1]. Areas of leptomeningeal enhancement were noted along the involved neuroparenchyma. Lacunar infarcts were also reported in both frontal lobes and the posterior aspect of the right thalamus. A CSF study revealed pleocytosis with lymphocyte predominance, increased protein, and normal glucose levels. The CSF adenosine deaminase (ADA) levels were normal. The CSF polymerase chain reaction (PCR) for TB and herpes simplex virus (HSV) 1 and 2 were negative [Table 1]. Mantoux test, tests for cryptococca antigen, and toxoplasma serology were also negative. A presumptive diagnosis of recurrent CNS TB was made and he was restarted on ATT (Isoniazid Rifampicin Pyrazinamide Ethambutol; HRZE regime) with steroids. To exclude any other etiology such as a neoplasm, a positron emission tomography (PET) scan of the brain was also performed and reported as normal. Computerized Tomography (CT) of the chest and abdomen done to evaluate for extracranial tuberculosis was reported as normal. The patient tolerated the ATT well. Two weeks after the initiation of ATT, he was discharged with advice to continue ATT, and report for review after 6 weeks.

However, by the end of March 2020, his condition began to deteriorate with alteration of the sensorium, instability of gait, double vision, and slurring of speech, and he was admitted to a peripheral hospital. A CE MRI was performed on April 01, 2020, and a large tuberculoma was reported in the right thalamus and gangliocapsular region. There was extensive perilesional edema with a significant mass effect. The previously detected lesions in the left medial temporal lobe had near-completely resolved [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d. A CSF study showed features of chronic aseptic meningitis [Table 1]. The patient's steroid dosage was escalated and he was also started on injection streptomycin. His condition somewhat improved and after 2 weeks of hospitalization, and he was transferred to our center on April 18, 2020.
Figure 1: MRI scan performed on 01 February 2020. Axial fluid attenuation inversion recovery (FLAIR) (a) and T2-weighted (b) images showing multiple granulomata in the left medial temporal lobe with surrounding edema (arrows). Subacute infarcts are seen in the right thalamus (forked arrow) and splenium (asterisks) of the corpus callosum on the FLAIR, T2-weighted and diffusion-weighted images (DWI) (a, b, c). Post-contrast T1-weighted sagittal images showing ring-enhancement of the lesions in the right medial temporal lobe (arrows) (d)

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Figure 2: MRI scan performed on 01 April 2020. Axial T2-weighted (a) and fluid attenuation inversion recovery (FLAIR) images (b) show a large lesion with thick hypointense walls and central hyperintensity (forked arrows). Another nodular hypointense lesion is also seen (arrows). Marked edema is seen around these lesions. On apparent diffusion coefficient (ADC) images, these lesions are markedly hypointense suggestive of low ADC values (c). On coronal post-contrast T1-weighted images, the large thalamic lesion (forked arrow) and the smaller nodule (arrow) show solid and avid contrast-enhancement (d). NCCT head performed on 19 April 2020 (panel of caudo-cranial axial images (e) shows a large irregularly marginated hyperdense lesion with central hypodensity in the right thalamus and gangliocapsular region (arrows). There is marked perifocal edema causing significant mass effect. A VP-shunt tube is seen in the left lateral ventricle

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   Clinical Examination on Admission and Investigations Top

The patient was confused and his speech was slurred. He was afebrile and his vital parameters were normal. The CNS examination revealed a Glasgow Coma Scale (GCS) score of E3V5M6. The pupils were symmetric and equally reacting to light. There was palsy of the left VIth cranial nerve. The tone was increased on the left side with grade 3/5 power at the joints of the left upper and lower limbs. Deep tendon jerks were exaggerated on the left side with knee and ankle clonus. The plantar reflex was extensor on the left side. Neck rigidity was present. There was also generalized sensory loss over the left side of the body. The respiratory system, cardiovascular system, and per abdominal examination did not reveal any abnormality.

An urgent non-contrast computerized tomography (NCCT) of the head was performed, which revealed diffuse cerebral edema. A lobulated iso/hyperdense rounded lesion with central hypodensity was noted in the right thalamus with marked perifocal edema. This was associated with a significant mass effect in the form of dilatation of the left ventricle (with features of transependymal CSF transudation) and descending transtentorial herniation.

His blood investigations revealed normocytic normochromic anemia, normal total and differential leukocyte count, and platelet count. The biochemical studies including the renal function test, liver function test, and serum electrolytes were normal. The urine examination was normal. The serum procalcitonin level was normal (0.05 ng/mL, reference range [RR] <0.5 ng/mL). The PCR test for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was negative. Immunochromatography for malarial parasite and dengue serology was negative. He was found to be negative for hepatitis B/hepatitis C/human immunodeficiency virus (HIV), and non-reactor for the Venereal Disease Research Laboratory (VDRL) test. The blood culture showed no growth after 7 days. In view of the recurrent CNS TB in a young, immune-competent male with no known comorbidities, an undiagnosed primary immune-deficiency state was also suspected. However, quantitative immunoglobulin estimations yielded normal results.

   Course in the Hospital Top

Given his deteriorating neurological status and the presence of hydrocephalus on neuroimaging, the patient underwent ventriculoperitoneal (VP) shunting on day 2 of admission [Figure 2]e. The CSF was sent for detailed investigations, however, all yielded negative results [Table 1]. He was managed with ATT, broad-spectrum intravenous antibiotics, intravenous steroids, and AEDs; however, his condition progressively deteriorated with the worsening of sensorium and development of fever and he had to be put on ventilatory support. A repeat CT scan of the brain showed an increase in cerebral edema and midline displacement, and consequently, a decompressive right hemicraniectomy was performed on day 10 of admission; however, there was no neurological improvement. The development of ATT-induced liver injury further aggravated his condition and he was put on liver-sparing ATT. On a subsequent CE MRI of the brain performed on May 02, 2020 (day 15), tuberculomas in the right thalamus, right gangliocapsular, and right periventricular regions with possible ischemic infarcts in both occipital lobes were reported [Figure 3]. With aggressive management, his condition somewhat improved. However, on day 24 of admission, he developed hypotension, tachycardia, and desaturation with recurrence of fever. The possibility of hospital-acquired infection with septic shock was considered. Despite aggressive management, the patient's condition kept worsening and he succumbed to his illness on day 30 of admission. The cause of death was documented as CNS tuberculosis (operated) with tubercular arteritis.
Figure 3: MRI scan performed on 02 May 2020. Axial FLAIR (a) and T1-weighted (b) images show a right craniectomy defect associated with a large extradural collection. The focal lesions that were seen in the right gangliocapsular region in Figure 2 now appear ill-defined. Extensive edema is seen in the entire gangliocapsular region, right thalamus, and the brainstem on the right side, and both occipital poles. Patchy areas of hypointensity are seen on the ADC images (c) in the right posteromedial thalamus and the brainstem. On post-contrast T1-weighted axial images (d), patchy contrast-enhancement is seen in the posteromedial thalamus and brainstem on the right side and the medial aspect of both occipital lobes

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An autopsy was carried out the next day to ascertain the cause of death. The relevant clinical investigations during treatment at our center are listed in [Table 2].
Table 2: Table depicting the results of the laboratory investigations at our center

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   Clinical Diagnosis Top

CNS TB (operated) with tubercular arteritis.

   Discussion on Clinical Course by the Neuro physician Top

The deceased was a 32-year-old male, with a history of treated and resolved CNS TB in 2012. He was seizure-free since 2012 and off AEDs since 2017.

During evaluation in Feb 2020, a CE MRI brain revealed multiple small conglomerated ring-enhancing lesions in the left temporal lobe associated with leptomeningitis and multiple chronic lacunar infarcts. The CSF cytology showed lymphocytic pleocytosis with increased proteins; however, CSF ADA and TB-PCR were negative. The various differentials of ring-enhancing cerebral lesions were considered [Table 3] and he was extensively investigated for various infectious and non-infectious pathologies that yielded negative results [Table 1]. Given the typical MRI findings, a diagnosis of recurrent CNS TB was made. The points against this diagnosis were the absence of fever, negative CSF TB-PCR and ADA, and lack of evidence of TB elsewhere in the body. However, the sensitivity of TB-PCR is reported to be only around 56% and that of ADA ranging from 44 to 100%.[1],[2] The PET scan of his brain was also done in this stage to exclude any neoplastic pathology.
Table 3: Main differential diagnoses of primary central nervous system lymphoma (PCNSL) and their typical imaging features

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After about 6 weeks of therapy, the patient again presented with complaints of headache, giddiness, diplopia, and left-sided weakness. A repeat CE MRI on Apr 01, 2020, reported a large tuberculoma in the right thalamus and gangliocapsular region with significant perifocal edema and mass effect. The thalamic and gangliocapsular lesion corroborated with the patient's symptomatology. A partial resolution of the tuberculomas in the left temporal lobe was also reported. This unusual sequence of events (occurrence of a new tubercular lesion in the right thalamus while on ATT) prompted consideration of a 'paradoxical reaction.' A paradoxical reaction is the enlargement or the appearance of new intracranial or spinal tuberculous lesions in patients receiving effective anti-TB therapy.[3] The points favoring this diagnosis were an initial response to ATT followed by clinical and radiological deterioration after 3 weeks. However, the absence of contributory CSF findings (increasing lymphocytic pleocytosis, increasing protein, and a shift toward neutrophilic predominance) and an increase in blood absolute lymphocyte count were against this diagnosis [Table 1] and [Table 2]. Based on the inputs from imaging, his steroids were escalated and he was also started on injection streptomycin. A VP shunt was placed followed by a decompressive craniectomy to alleviate the hydrocephalus and increase in mass effect. Given the unusual location and large size of the right thalamic-basal ganglia tuberculoma, a CSF study for toxoplasma was carried out as it has a greater predilection for the basal ganglia region. However, the CSF serology for toxoplasma was negative.

A subsequent CE MRI performed on May 02, 2020, reported multiple tuberculomas in the thalamus and gangliocapsular region, periventricular region, and parieto-occipital lobes on the right side. The possibility of ischemic infarcts in both the occipital lobes was also raised. Infarcts secondary to tubercular arteritis in CNS TB are a common and known entity, and their presence did not detract from the clinico-radiological diagnosis.

The patient was continued on ATT, steroids, and supportive therapy. Despite the initial improvement, his condition progressively deteriorated and the patient eventually succumbed to his illness. The patient's rapid downhill course was unusual.

The cause of death was attributed to CNS TB (operated) with tubercular arteritis.

   Discussion on Neuroimaging by the Radiologist Top

The deceased, a known patient of treated CNS TB, was referred for CE MRI on Feb 01, 2020, during a routine follow-up. Multiple small conglomerated solid and thick-walled ring-enhancing lesions were seen in the left medial temporal lobe. These lesions were isointense on T1-weighted images and hypointense on T2-weighted images, with central hyperintensity on T2-weighted images in some of them. Perifocal edema was present. Areas of leptomeningeal enhancement were also noted along the left medial temporal lobe. There was no restriction of diffusion. Though a magnetic resonance spectroscopy (MRS) would have strengthened the diagnosis, these findings were typical of tuberculomas and leptomeningitis [Figure 1], and in developing countries like India, should always merit the first diagnosis. The nodular lesions that were seen in the splenium of the corpus callosum and posterior right thalamus showed characteristics of early subacute infarcts (hyperintense on T2-weighted images, isointense on T1-weighted images with restriction of diffusion, and absence of contrast-enhancement). While infarcts are a known phenomenon in CNS TB secondary to basal meningitis and arteritis, they usually involve the lenticulostriate and thalamoperforating arterial vascular territories.[4],[5] However, as foci of gliosis were also seen in the right parietal lobe (suggestive of chronic infarcts) no other diagnosis was considered.

The second CE MRI that was performed at a different institute on April 01, 2020, revealed a large (2.7 cm × 2.5 cm) well-defined rounded lesion in the right thalamus and gangliocapsular region and was reported as a tuberculoma [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d. This was followed by an urgent NCCT of the head at the time of admission in our institute which showed an iso/hyperdense rounded lesion with central hypodensity in the same location associated with marked perifocal edema causing significant mass effect [Figure 2]e. On review of the MRI images, the thalamic-gangliocapsular lesion was hypointense on T2-weighted, fluid attenuation inversion recovery (FLAIR), and T1-weighted images with some central hyperintensity on the T2-weighted images. A smaller lesion with similar signal characteristics (without central hyperintensity) was seen posterolateral and cranial to the larger lesion. The larger lesion demonstrated marked restriction of diffusion peripherally. The smaller lesion showed uniform restriction of diffusion. Both these lesions demonstrated solid and avid contrast enhancement [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d. Extensive perilesional edema causing significant mass effect was present. There was near-resolution of the left medial temporal lobe lesions. Based on the imaging findings of the thalamic/periventricular nodular lesions that were hypointense (on all MRI sequences), demonstrated marked restriction of diffusion with avid contrast-enhancement on MRI and hyperattenuating on CT, a diagnosis of primary CNS lymphoma (PCNSL) should have been considered.[6] However, it should be noted that tuberculomas have a wide spectrum of appearances on MRI, often confounding accurate diagnosis. Caseating tuberculomas with central liquefaction may show a hypointense rim with central hyperintensities on T2-weighted images and variable restriction of diffusion, similar to the lesion in this case. However, they exhibit ring enhancement on post-contrast images, unlike the solid and avid contrast enhancement pattern as seen in this case.[7],[8],[9],[10]

PCNSL in immune-competent individuals is considered to be a disease of the elderly with a peak incidence in the fifth to seventh decades of life and a median age of occurrence of 56 years. Very few isolated case reports of PCNSL in young adults exist in literature with most of these patients exhibiting some form of underlying congenital or acquired immunodeficiency. Also, necrosis (the central hyperintensity on T2-weighted images in the thalamic lesion) is more commonly found in PCNSL in immunocompromised individuals.[6] Our patient was a young immunocompetent male. Therefore, in the background of recurrent CNS TB on ATT, a diagnosis of a tuberculoma and a possible paradoxical reaction were considered. However, a careful analysis of the imaging features of the nodular lesion cranial and posterolateral to the thalamic lesion could have been a hint to the true diagnosis as non-caseating granulomas never show any restriction of diffusion unlike the lesion in question.

By the time the third CE MRI was performed on May 02, 2020, the patient had already been exposed to 2 weeks of high-dose steroids. The lesions in the right thalamus and gangliocapsular regions were no longer well-defined and showed a heterogeneous pattern of contrast-enhancement. Also, a few infarct-like lesions were noted in the gray and white matter of both occipital lobes and splenium of the corpus callosum which were attributed to tubercular arteritis. Steroids can significantly alter and confound the imaging appearances in PCNSL, and expectedly, the imaging appearances in our patient had changed.[11]

It is possible that the small 'subacute infarct'-like lesions detected in the right thalamus and splenium of the corpus callosum on the MRI performed in February 2020 were early PCNSL lesions. The PET scan did not show any hypermetabolic focus as the lesions were small and the scan got delayed due to the non-availability of radiopharmaceutical and by then the patient had been placed on steroids. Also, PCNSL is known to spread in an angiocentric fashion and also involves vessels, producing infarcts; such infarcts can mimic the infarcts produced by tubercular arteritis and further confound the diagnosis.[6]

   Pathology Protocol by the Pathologist Top

At autopsy, the deceased was found to be an averagely built and nourished individual. A tracheostomy insertion site was noted.

There was evidence of right-sided hemicraniectomy with a small extradural collection and VP shunt in situ. The dura appeared congested. The dural sinuses were normal. The leptomeninges adjoining the left temporal lobe showed a few discrete scattered white areas of possible inflammation. There were no basal exudates and 20 mL of clear CSF was aspirated. The brain weighed 1402 g (RR: 1100–1700 g). Subfalcine herniation was noted toward the left side. On serial sectioning, a well-circumscribed whitish firm lesion measuring 3.5 cm × 3 cm was noted in the region of the right thalamus and right basal ganglia [Figure 4]a. Some areas of necrosis were seen within the lesion; no hemorrhagic foci were noted. A few small ill-defined grayish-tan-colored lesions were also noted on the right side of the midbrain and pons, the largest measuring 1.2 cm × 0.8 cm. The spinal cord was not opened. The post-mortem CSF examination revealed white blood cell (WBC): 20/mm3 (predominantly lymphocytes), red blood cell (RBC): 12/mm3. No atypical cells were seen. The PCR for Mycobacterium tuberculosis (MTB) was negative.
Figure 4: Gross photographs of organ specimens showing: (a) a large mass in the region of the right thalamus and basal ganglia (red arrow); (b) heavy, congested lungs; (c) enlarged liver; (d) cut section of the right kidney

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The right and left lungs weighed 625 g (RR: 360–570 g) and 580 g (RR: 325–480 g), respectively [Figure 4]b. Both lungs were heavy and congested, and frothy hemorrhagic fluid exuded on sectioning them. No cavitation, consolidation, or mass lesion was seen. A 100 mL of hemorrhagic pleural effusion was drained bilaterally.

The liver weighed 1730 g (RR: 1500–1800 g) [Figure 4]c. The cut surface was unremarkable. The spleen appeared enlarged and weighed 250 g (RR: 150–200 g); its external surface was smooth and the cut surface appeared congested.

Both kidneys appeared grossly normal [Figure 4]d.

The cardiovascular system, gastrointestinal tract, endocrine system, and testes were unremarkable on gross examination. No lymphadenopathy was noted.

All relevant viscera were preserved for histopathological examination.

   Microscopic Findings Top

Hematoxylin and Eosin (H and E)-stained sections from the right basal ganglia, right thalamus, right occipital lobe, and right side of midbrain showed a highly cellular, diffusely growing, pattern-less tumor with interspersed areas of necrosis. The tumor was composed of atypical lymphoid cells arranged in a perivascular distribution and also infiltrating into the surrounding brain parenchyma. The individual tumor cells were large with scant cytoplasm, high nuclear: cytoplasmic (N: C) ratio, irregular round nuclei with open chromatin, and prominent nucleoli. Large areas of necrosis were noted. Brisk mitosis was present (6–8/high-power field) along with frequent apoptotic figures. Numerous reactive astrocytic and glial cells were seen in the periphery admixed with mononuclear inflammatory infiltrate. The tumor cells were positive for CD45, CD20, CD19, CD79a and negative for CD10, BCL2, BCL6, MUM1, Tdt, CD38, CD138, CD15, CD30, Pan-CK, EMA, GFAP, EBV. Scattered CD3 positivity was seen in the reactive T-cells and CD68 positivity in the background histiocytes. The Ki-67 proliferation index was 70–80% in hotspots [Figure 5]a, [Figure 5]b, [Figure 5]c, [Figure 5]d, [Figure 5]e, [Figure 5]f, [Figure 5]g, [Figure 5]h. These features were consistent with the primary diffuse large B-cell lymphoma of the CNS. No granulomata or Langhan's giant cells were seen. A few scattered foci of gliosis were noted. No acid-fast bacilli (AFB) were detected on the Ziehl–Neelsen stain (ZN) stain. The uninvolved brain parenchyma showed extensive liquefactive necrosis and cerebral edema. Sections from the meninges showed a lymphomononuclear inflammatory infiltrate with a few congested vessels. No atypical cells, granulomata, necrosis, or Langhan's giant cells were seen.
Figure 5: Photomicrographs of the brain showing: (a) highly cellular, diffusely infiltrating tumor involving the right basal ganglia and thalamus of brain (H and E, 40X magnification); (b) Perivascular distribution of tumour cells (black arrows) (H and E, 40X magnification); (c) Tumour cells showing strong diffuse cytoplasmic positivity for CK 20 (40X magnification); (d) High Ki-67 proliferation index in the hotspots (40X magnification); (e) Background reactive T cells showing scattered CD3 positivity (black arrows) (40X magnification); (f-h) Tumor cells were negative for CD10, BCL-6 and MUM-1, respectively (40X magnification). Photomicrographs showing: (i) interstitial and intra-alveolar accumulation of mixed inflammatory infiltrate and waxy, hyaline membrane (black arrows) (H and E, 40X magnification); (j) portal and peri-portal inflammatory infiltrate with dilated hepatic sinusoids and spotty necrosis (black arrow) (H and E, 40X magnification); and (k) tubular necrosis of the kidneys (black arrow) (H and E, 40X magnification)

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The sections from both lungs showed features of diffuse alveolar damage. There was congestion along with an interstitial and intra-alveolar accumulation of edema fluid, fibrin deposition, and the presence of mixed inflammatory infiltrate. The alveolar walls were lined with waxy, hyaline membranes. A variable number of hemosiderin-laden alveolar macrophages (heart failure cells) were noted [Figure 5i]. No granulomata, giant cells, or atypical cells were seen. No organisms were noted.

The sections from the liver showed spotty necrosis along with portal and periportal lymphomononuclear inflammatory infiltrate. There was no pericellular fibrosis. Ground-glass hepatocytes were not seen. There was no evidence of cirrhosis. No portal fibrosis or piecemeal necrosis were noted [Figure 5j].

The sections from the spleen showed congestion with an expansion of the red pulp. No atypical cells were seen.

The sections from the kidneys showed normal glomeruli. Features of acute tubular necrosis were seen in the form of variable flattening of tubular epithelial cells, loss of the brush border, and intratubular sloughed epithelial cells [Figure 5k]. The interstitium and blood vessels appeared unremarkable.

The other organs were normal on microscopy.

   Final Diagnosis Top

Primary diffuse large B-cell lymphoma (DLBCL) of the CNS with bilateral diffuse alveolar damage, drug-induced liver injury (DILI), and bilateral acute tubular necrosis.

   Clinicopathological Correlation Top

The deceased was a 32-year-old male, with a history of treated and resolved CNS TB in 2012. During routine evaluation in February 2020, the CE MRI brain revealed small conglomerated tuberculomas in the left temporal lobe associated with leptomeningitis and multiple chronic lacunar infarcts. However, CSF ADA and TB-PCR studies were negative. A presumptive diagnosis of CNS TB was made and the patient was restarted on ATT with steroids. After about 1 month of therapy, the patient again presented with complaints of headache, giddiness, diplopia, and left-sided weakness. A repeat CE MRI reported a large tuberculoma in the right gangliocapsular region and thalamus with significant perifocal edema and mass effect. His steroids were escalated and he was also started on injection streptomycin. A VP shunt was placed followed by a decompressive craniectomy. Despite the initial improvement, his condition progressively and rapidly deteriorated and he eventually died.

The post-mortem findings were consistent with the features of DLBCL of the CNS, diffuse alveolar damage to both lungs, ATT-induced liver injury, and acute tubular necrosis of the kidneys.

All CNS symptoms of the patient can be attributed to the extensive involvement of the brain parenchyma by DLBCL. The headache can be attributed to the raised intracranial tension caused by perifocal edema and mass effect. His giddiness, gait instability, left-sided hemiparesis, and left-sided sensory loss can also be attributed to the involvement of the gangliocapsular region, thalamus, and midbrain on the right side. While the left temporal lobe tuberculomas responded to ATT, the lesions (PCNSL) on the right side of the brain were not responsive to therapy. The tapering dosage of steroids administered in CNS TB is much lower than that administered in CNS lymphoma (along with methotrexate-based polychemotherapy and radiation), however, the steroids did affect the symptomatology, and more importantly, the morphology of the right-sided lesions on imaging.

The patient's young age, absence of any known immunodeficiency state, history of treated CNS TB, recurrence of typical tuberculous lesions in the left temporal lobe that responded to ATT, multiple chronic and subacute infarcts, and the administration of steroids probably confounded the diagnosis of the lesions in the gangliocapsular region, thalamus, and midbrain on the right side. However, the detection of a spherical lesion in the right gangliocapsular region and thalamus that appeared iso-hyperdense in the CT scan, and showed marked restriction of diffusion and avid contrast-enhancement on MRI should have prompted the consideration of PCNSL.

The deep location of the lesions and the deteriorating clinical status of the patient precluded a stereotactic biopsy which would have helped establish the correct diagnosis in this very unusual case with so many confounding factors.

The terminal events of sudden-onset desaturation and bradycardia were probably due to the diffuse alveolar damage to the lungs and brainstem involvement by PCNSL and resulted in the patient's death.

   Brief Comments on PCNSL Top

As per the 2016 World Health Organization (WHO) classification of the tumors of the CNS, PCNSLs are subdivided into DLBCLs (> 95% of lesions), immunodeficiency-associated CNS lymphomas, intravascular large B-cell lymphomas, a group of miscellaneous subtypes, and mucosa-associated lymphoid tissue (MALT) lymphoma of the dura.[12] The immunodeficiency-associated PCNSLs comprise ¥ AIDS-related DLBCL, Epstein-Barr virus-positive diffuse large B-cell lymphoma-NOS, lymphomatoid granulomatosis, and post-transplant lymphoproliferative disorder. The miscellaneous group comprises low-grade B-cell lymphoma, T- and natural killer (NK)/T-cell lymphomas, and anaplastic large cell lymphoma.

PCNSL is an aggressive form of extranodal non-Hodgkin lymphoma that is confined to the brain, spinal cord, leptomeninges, or eyes at presentation without any systemic spread. It accounts for 4% of all intracranial neoplasms and 4–6% of all extranodal lymphomas. Historically, an AIDS-defining illness, the incidence of PCNSL has been steadily increasing in recent years particularly in the elderly immune-competent population over the age of 60 years. The overall incidence is around 0.5 per 100,000 per year with a male predominance.[13] PCNSL has a varied clinical presentation that is mostly defined by the anatomic location of the tumor. The most common presenting features are focal neurological deficits, cognitive and behavioral changes, seizures, and those attributable to increased intracranial pressure like headache, nausea, vomiting, and papilledema. Seizures are less common than other primary brain tumors. Though concurrent ocular and lepto-meningeal involvement may be seen in a significant percentage of these patients, many of these patients do not display specific ocular symptoms or meningeal signs. Leptomeningeal involvement may be noted in 7–42% of the cases. Spinal cord involvement is rare.[14]

The lymphoma cells exhibit a distinct, highly selective neurotropism for the CNS microenvironment and its vasculature, and intra- and perivascular tumor spread is common. Up to 75% of all PCNSLs contact a CSF surface, either the ventricular ependyma or pia. PCNSL lesions are deep-seated having a predilection for the periventricular white matter, especially the corpus callosum. The basal ganglia and thalami are the next most common locations. The uncommon sites are the hypothalamus, infundibulum, and pituitary gland. Primary DLBCL may also develop in the leptomeninges, calvarium, and the skull base, however, these locations are more commonly involved by secondary spread from extracranial sites.[15]

The DLBCL lesion size varies from microscopic to large bulky masses. Up to two-thirds are solitary lesions and the lesions are relatively well-demarcated rather than diffusely infiltrating. Frank necrosis and gross intratumoral hemorrhage are more common in AIDS-related PCNSL. Rarely, DLBCL may diffusely infiltrate the brain and this anatomic pattern is called 'lymphomatosis cerebri.'[15]

On microscopy, PCNSLs are highly cellular tumors. Large atypical cells that are CD20(+) and CD45(+) are commonly seen. MIB-1 is high, often exceeding 50% (significantly higher than with glioblastoma). PCNSLs are not assigned a grade by WHO.[12]

Contrast-enhanced MRI of the brain is the imaging modality of choice for evaluating patients with suspected PCNSL. As occult extracranial lymphomas are present in 5–8% of the patients suspected of PCNSL, contrast-enhanced computerized tomography (CECT) of the chest, abdomen, and pelvis or PET/CT is generally recommended in patients with suspected PCNSL.[13] As these tumors are hypercellular, most lesions appear hyperdense compared to the normal brain on NCCT scans. Marked peritumoral edema is common, however, necrosis, hemorrhage, and calcification are rarely seen in immunocompetent patients. These tumors exhibit mild to moderate, relatively homogeneous enhancement on CECT in immunocompetent patients. Necrosis, hemorrhage, and irregular ring enhancement are commonly seen in immunocompetent patients. On MRI, the majority of PCNSLs are iso- or slightly hypointense on T1-weighted imaging (T1WI) and isointense on T2-weighted imaging (T2WI) with respect to the gray matter. The signal intensity on FLAIR images is variable but is usually iso- or hyperintense. Gross hemorrhage is rare in immunocompromised patients, though microhemorrhages showing 'blooming' on T2* images are present in 5–8% of the cases. Most PCNSLs show solid homogeneous or mildly heterogeneous enhancement; ring enhancement is seen in the immunocompromised. MRS typically demonstrates elevated choline and high lipids. Because of their high cellularity, over 95% of the PCNSLs show mild to moderate diffusion restriction. Despite its highly malignant nature, PCNSL lacks abundant neovascularization; therefore, the relative cerebral blood volume (rCBV) is low, and permeability is not increased on perfusion MRI. The administration of steroids significantly alters the imaging findings of PCNSLs. Owing to cell lysis and normalization of the blood-brain barrier, tumors typically diminish in size with reduced or absent contrast enhancement ('ghost tumor'), although some signal abnormalities may persist on T2-weighted and FLAIR images.[15] The major differential diagnoses and their imaging features are listed in [Table 3].

CNS DLBCL is an aggressive tumor with short a median survival of a few months in untreated patients. Immunocompetent patients younger than 60 years have a better prognosis than older patients and patients with acquired immunodeficiency syndromes. A stereotactic biopsy helps in the conformation of the diagnosis and histologic tumor typing. The treatment options include corticosteroids, high-dose methotrexate-based polychemotherapy, and radiation.[15]

   Lessons Learned Top

This case highlights the variable presentation and often overlapping and confounding imaging features of CNS TB and PCNSL. The fact that the administration of steroids markedly alters the imaging findings in CNS lymphoma is reiterated. The importance of carefully and holistically reviewing each patient's temporal clinical profile and pharmacotherapy and sequentially evaluating the previous and different imaging studies while interpreting the current imaging study is also brought to the fore. While there have been major advances in imaging and laboratory-based diagnostic tests, this case underlines the importance of an autopsy to resolve the diagnostic conundrums.

Ethics statement

The study was performed in a manner to conform to the Helsinki Declaration of 1975, and as revised in 2013 concerning Human and Animal Rights and the authors followed the policy concerning Informed Consent.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

Anusree Majumder, Debraj Sen, Subrat Kumar Nanda declare that they do not have any conflict of interest to report.

   References Top

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Hsieh EY, Chia LG, Shen WC. Locations of cerebral infarctions in tuberculous meningitis. Neuroradiology 1992;34:197-9.  Back to cited text no. 4
Tai MS, Viswanathan S, Rahmat K, Nor HM, Kadir KAA, Goh KJ, et al. Cerebral infarction pattern in tuberculous meningitis. Sci Rep 2016;6:38802.  Back to cited text no. 5
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Correspondence Address:
Anusree Majumder
Department of Pathology, Command Hospital (Southern Command), Pune - 411 040, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_106_21

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1], [Table 2], [Table 3]


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