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CLINICO-PATHOLOGY CONFERENCE  
Year : 2018  |  Volume : 61  |  Issue : 2  |  Page : 219-224
A 37-year-old male with extensive cerebral venous thrombosis: Clinicopathological correlation of a rare case


1 Department of Pathology, Command Hospital Air Force, Bengaluru, Karnataka, India
2 Department of Medicine, Command Hospital Air Force, Bengaluru, Karnataka, India

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Date of Web Publication20-Apr-2018
 

   Abstract 


We present the autopsy findings and differential diagnosis of a 37-year-old immunocompetent male patient who presented primarily with extensive cerebral vein thrombosis and was found to have a rare association with JAK2V617F mutation positivity.

Keywords: Autopsy, Burkitt lymphoma, extensive cerebral vein thrombosis

How to cite this article:
Mutreja D, Saxena R, K. Tilak T V, Tewari V, Moorchung N, Nandi B. A 37-year-old male with extensive cerebral venous thrombosis: Clinicopathological correlation of a rare case. Indian J Pathol Microbiol 2018;61:219-24

How to cite this URL:
Mutreja D, Saxena R, K. Tilak T V, Tewari V, Moorchung N, Nandi B. A 37-year-old male with extensive cerebral venous thrombosis: Clinicopathological correlation of a rare case. Indian J Pathol Microbiol [serial online] 2018 [cited 2020 Jul 4];61:219-24. Available from: http://www.ijpmonline.org/text.asp?2018/61/2/219/230542





   Clinical Protocol Top


A 37-year-old previously healthy male, nonsmoker, with no known comorbidities was admitted to our hospital with a history of severe throbbing headache, facial pain, diplopia on the left gaze, and associated diminution of vision for 8 days. There was a history of being treated at another hospital as a case of sinusitis 10 days back. Imaging of the brain done 7 days ago had shown superior sagittal sinus thrombosis. At admission, he was on cerebral decongestants, antiepileptics, low-molecular-weight heparin, and antibiotics.


   Clinical Examination and Investigations Top


Physical examination revealed a well built and well nourished individual who was conscious, alert and oriented in time and place, with normal vital signs. Central nervous system (CNS) examination revealed left-sided 3rd, 4th, 5th, and 6th cranial nerve palsies. Power was grade 4/5 in all muscle groups. Plantars were dorsiflexor and cerebellar signs were positive. Other systemic examination was unremarkable. Investigations showed mild normocytic normochromic anemia, prolonged activated partial thromboplastin time (APTT), and mild elevated lactate dehydrogenase (LDH) [Table 1]. Fundus and cerebrospinal fluid examination were normal.
Table 1: Laboratory investigations*

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The patient was managed with injection enoxaparin 60 mg subcutaneously twice, intravenous mannitol 100 ml and tramadol 50 mg thrice, tablet Diamox 250 mg thrice, tablet oxcarbazepine 150 mg twice, broad-spectrum antibiotics, and supportive care.


   Course in the Hospital Top


On day 2, magnetic resonance (MR) imaging of the brain with MR venogram revealed extensive cerebral venous thrombosis (CVT) involving superior sagittal sinus, torcula, and bilateral cavernous sinuses [Figure 1]a and [Figure 1]b. Mucosal thickening of the right sphenoid sinus was seen. Investigations were sent for tumor marker studies and to rule out primary procoagulant state.
Figure 1: (a and b) MRI brain showing extensive cerebral venous thrombosis involving superior sagittal sinus, torcula, and bilateral cavernous sinuses; (c) bone marrow imprint smears showing predominant population of immature cells with cytoplasmic vacuoles; (d) ascitic fluid showing numerous atypical cells; (e and f) parietal pleura and manubriosternal joint showing fleshy haemorrhagic tumor nodules; (g and h) fleshy tumor nodularities seen on the omentum and appendices epiploicae of large intestines

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During the 1st week, the patient complained of headache, left lower limb pain, and constipation. The cranial nerve palsies showed a fluctuating course with the appearance of palsies on the right side and reduction on the left side. Chest roentgenogram showed mild bibasilar atelectasis. Color Doppler studies of the lower limbs and renal vessels were normal.

On day 7, he developed continued severe headache. Fundoscopy revealed mild papilledema. Noncontrast computed tomography (NCCT) of the brain showed no evidence of venous hemorrhage, but extensive CVT was present. Oral anticoagulants were added. Procoagulant workup revealed moderate homocysteinemia (26 umol/L (N: 5–15umol/L) and positive antiphospholipid antibodies (APLAs) by ELISA in low titers. Folic acid and Vitamin B12 were added to treatment. Peripheral smear showed normocytic normochromic anemia. Liver enzymes were deranged. Workup for sickling, paroxysmal nocturnal hemoglobinuria (PNH), protein C, S, antithrombin levels, and tumor marker studies were normal.

On day 10, he developed right-sided lid edema with chemosis and left-sided hemiparesis. Repeat urgent NCCT of the brain showed diffuse cerebral edema with an iso/hyperdense lesion right supraorbital region, suggestive of possible hematoma or abscess. JAK2V617F mutation by amplification refractory mutation system-polymerase chain reaction was reported positive. Genetic thrombophilia screen including Factor V Leiden mutation, methylenetetrahydrofolate reductase, and prothrombin gene mutation was negative. Vasculitis screening and serum angiotensin-converting enzyme levels were normal.

On day 11, intrasinus thrombolysis was done and urokinase was started, which resulted in only partial recanalization. As optimal international normalized ratio was not achieved using warfarin, newer oral anticoagulants (dabigatran) were added.

On day 12, derangement in renal function was seen with rise in serum creatinine. On day 14, he had an episode of acute urinary retention, and postcatheterization, hematuria was noted. Ryle's tube aspiration brought out coffee ground gastric contents. Anticoagulant-associated coagulopathy was suspected. Heparin and oral anticoagulants were withheld. The patient was shifted to intensive care and administered 6 units of fresh frozen plasma and injection Vitamin K. Chest roentgenogram showed bilateral basal pleural effusion.

On day 15, gum hyperplasia was documented. Review by dental surgeon opined retained tooth stump. A biopsy was taken which later showed only necrotic tissue. His neurological state deteriorated further with the development of bilateral hemiparesis. Pedal edema was noted. Imaging of the chest and abdomen revealed bilateral pleural effusions with ascites. Repeat MRI of the brain showed extensive CVT with minimal recanalization. APTT became markedly prolonged and LDH showed marked increase [Table 1]. Arterial blood gas analysis showed partly compensated metabolic acidosis. Antibiotics were upgraded.

On day 17, consultation with a nephrologist opined rapidly progressive renal failure. A differential diagnosis of (i) membranous glomerulonephritis/IgA nephropathy, (ii) catastrophic antiphospholipid syndrome (APS), (iii) disseminated malignancy, and (iv) sepsis syndrome were thought of. Specific anticardiolipin and anti-β2 glycoprotein-I IgG and IgM were negative. The patient could not be taken up for positron emission tomography (PET) computed tomography (CT) in view of deteriorating renal function. Intravenous methylprednisolone and immunoglobulin infusion resulted in dramatic improvement in clinical condition.

On day 18, renal biopsy and bone marrow aspiration and biopsy were performed. Oral anticoagulants and heparin were restarted.

Bone marrow aspiration showed dry tap; however, imprint smears showed predominant population of immature cells with cytoplasmic vacuoles (80%) [Figure 1]c. Sample could not be processed for flow cytometry immunophenotyping in view of dry tap. Peripheral smear showed leukoerythroblastic blood picture.

On day 19, repeat imaging of the chest and abdomen revealed bilateral pleural effusions and ascites. A guided diagnostic ascitic tap showed exudative fluid with predominance of atypical lymphoid cells fluid (total cells – 156,160/μL, white blood cells – 122,880/μL, protein – 2.7 g/dL, Alb – 1.6/dL, LDH >5000 IU/L) with 90% atypical cells [Figure 1]d. Sample was processed for flow cytometry. Renal biopsy showed nonrepresentative tissue only. The same day, the patient became toxic with high fever, serositis, altered sensorium, tachycardia, and tachypnea. He continued to deteriorate further with drowsiness, dysarthria, rapidly progressive clinical ascites, and pleural effusion.

On day 21, the patient succumbed to his illness. A postmortem was performed.


   Unit's Final Diagnosis Top


Unit's final diagnosis was extensive cerebral vein thrombosis with JAK2V617F mutation-positive hematolymphoid malignancy.


   Discussion on Clinical Protocol Top


A young male, nonsmoker, with no known comorbidities, presented with extensive CVT with cranial nerve, cortical, and cerebellar signs. Primary procoagulant workup revealed positive APLA in low titers and moderate homocysteinemia. Extensive CVT in a young male is multifactorial and main causes are genetic prothrombotic risk factors, and secondary causes namely APS, hyperhomocysteinemia, malignancies, paraproteinemia, PNH, polycythemia vera, and certain drugs, e.g., L-asparaginase.[1],[2]

In this patient, moderate homocysteinemia and APLA positivity were initially implicated in causation of stroke. However, specific anticardiolipin and anti-β2 glycoprotein-I IgG and IgM and genetic coagulation screen results were negative.

The patient had prolonged APTT since admission. This was attributed to LMW heparin and possible lupus anticoagulants. JAK2V617F mutation is present in 95%–98% of polycythemia vera, 50%–60% of primary myelofibrosis, and essential thrombocythemia. It is also described infrequently in other myeloid neoplasms, including chronic myelomonocytic leukemia and myelodysplastic syndrome.[3] In the absence of any hematologic finding, suggestive of a chronic myeloproliferative disorder, this positive result did not contribute to diagnosis.

Was it probable to explicate multisystem involvement on the basis of a single ailment? An acute thrombotic event may trigger the appearance of transient APLAs.[4],[5] Severe thrombosis and a dramatic improvement in clinical condition following steroids can be explained with an underlying malignancy as well. The learning lesson in this case was that PET-CT should have been performed earlier in the disease course.

The bone marrow study finally helped to clinch the diagnosis of acute leukemia. JAK2V617F mutation-positive acute leukemias are myeloid leukemias, are extremely rare, and reportedly comprise <5% of cases in data from many large studies, and more than half of these had a preceding MPD.[6],[7] The terminal event in the deceased was sepsis and multiorgan failure secondary to untreated acute leukemia.


   Final Clinical Diagnosis Top


Extensive CVT with etiological diagnosis of (b) paraneoplastic process due to JAK2V617F mutation-positive leukemia. Terminal event: Sepsis with multiorgan failure.


   Pathology Protocol by Associate Professor Pathology Top


An autopsy revealed bilateral hemorrhagic pleural and peritoneal effusions. The chest wall, the parietal pleura, and the manubriosternal joint showed fleshy hemorrhagic tumor nodules [Figure 1]e and [Figure 1]f. Thymus was enlarged and the right lung showed tumor-associated dense adhesions with the diaphragm. Nodularities were seen on the omentum [Figure 1]g, abdominal wall, peritoneum, mesentery, appendices epiploicae [Figure 1]h, mucosal surface of the stomach [Figure 2]a, and cecum [Figure 2]b. The liver and spleen were enlarged weighing 2.1 kg and 320 g, respectively; cut surfaces were congested; however, no focal or nodular lesions were seen [Figure 2]c and [Figure 2]d. Kidneys were enlarged with a left-sided perirenal hemorrhage (at the site of biopsy) [Figure 2]e and [Figure 2]f. The bladder wall was markedly thickened with dense adhesions of the bladder to perivesical tissue.
Figure 2: (a and b) Mucosal surface of the stomach and cecum showing tumor nodularities; (c and d) enlarged liver and spleen with congested cut surfaces, without any focal or nodular lesions; (e and f) enlarged kidneys with a left-sided perirenal hemorrhage at the site of biopsy; (g) falx cerebri showing cord-like thickening involving superior sagittal sinus; (h) cut surface of the falx showing fleshy haemorrhagic thrombi seen occluding the cerebral sinuses

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Falx cerebri showed cord-like thickening involving superior sagittal sinus, extending to inferior sagittal and transverse sinuses [Figure 2]g. Fleshy hemorrhagic thrombi were seen occluding the cerebral sinuses [Figure 2]h. Cut sections of the brain parenchyma, pericardium, heart, and great vessels were normal.

Histopathologic examination revealed malignant hematolymphoid cells infiltrating all visceral organs [Figure 3]a [Figure 3]b, [Figure 3]c, [Figure 3]d, [Figure 3]e, [Figure 3]f, cerebral sinuses with proximal tubular necrosis of kidneys, and congestive changes in liver, lungs, and spleen.
Figure 3: (a) Section of bone marrow biopsy showing sheets of malignant lymphoid cells infiltrating the marrow spaces (H and E, ×400); (b) section of small intestine showing sheets of malignant lymphoid cells in serosa with normal overlying mucosa (H and E, ×100); (c) malignant lymphoid cells infiltrating the pericardium (H and E, ×100); (d) infiltration of renal capsule by lymphoid cells (H and E, ×100); (e) section of chest wall showing malignant lymphoid cells splitting skeletal muscle fibres (H and E, ×400); (f) medium-sized malignant lymphoid cells with markedly increased mitotic and apoptotic activity (H and E, ×400)

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Diagnosis of Burkitt lymphoma was confirmed by immunohistochemical expression of CD20, CD43, and CD10 with >95% Ki67 expression. Flow cytometry immunophenotyping of ascitic fluid revealed tumor cells positive for CD45, CD19, CD22, and CD79a with a monoclonal light chain expression of kappa. CD10, CD38, CD43, CD71, and bcl-6 were also expressed. The blast markers CD34 and TdT, myeloid, and T-cell markers were negative.


   Final Diagnosis Top


Final diagnosis was Burkitt Lymphoma with JAK2V617F mutation positivity.


   Clinicopathological Correlation Top


Extensive cerebral venous sinus thrombosis in this patient was caused primarily by lymphomatous infiltration of cerebral sinuses. Although rare, this has been described in literature.[8],[9],[10],[11],[12] As the deceased had had no peripheral blood or lymph node involvement and a CNS dominant presentation, a sino-orbital disease with subsequent spread is more likely. Antemortem thrombectomy if submitted for histopathologic evaluation may have provided a clue.

APLA positivity in low to moderate titers may occur in malignancies.[13],[14],[15] Further tumor-associated weakly positive LAs have also been described. This may also prolong APTT. Moderate homocysteinemia may be explained by depletion of folate and B12 due to tumor proliferation.

JAK2V617F mutation positivity in non-Hodgkin's lymphoma has been reported in literature in sporadic case reports.[16],[17],[18],[19] To the best of our knowledge, this is the first report of this association in Burkitt lymphoma. It is possible that this coexistence portends a poorer prognosis.

Burkitt lymphoma has a very high doubling time of <24 h. Poor prognostic factors include primary CNS and marrow involvement at presentation and large disease burden which were present in this patient.[20]


   Conclusion Top


Presentation of Burkitt lymphoma primarily with CNS involvement in the form of CVT is rare. This is the first report of JAK2V617F mutation positivity in Burkitt lymphoma. This case emphasizes the importance of early tumor workup a case of extensive cerebral sinus thrombosis. In a given patient, an exhaustive search for added etiologies should be done even when a specific risk factor is identified.

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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F, ISCVT Investigators. Prognosis of cerebral vein and dural sinus thrombosis: Results of the international study on cerebral vein and dural sinus thrombosis (ISCVT). Stroke 2004;35:664-70.  Back to cited text no. 1
    
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Saposnik G, Barinagarrementeria F, Brown RD Jr., Bushnell CD, Cucchiara B, Cushman M, et al. Diagnosis and management of cerebral venous thrombosis: A statement for healthcare professionals from the American heart association/American stroke association. Stroke 2011;42:1158-92.  Back to cited text no. 2
    
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Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms: Order out of chaos. Cancer 2009;115:3842-7.  Back to cited text no. 3
    
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Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295-306.  Back to cited text no. 4
    
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Out HJ, de Groot PG, Hasselaar P, dan Vliet M, Derksen RH. Fluctuations of anticardiolipin antibody levels in patients with systemic lupus erythematosus: A prospective study. Ann Rheum Dis 1989;48:1023-8.  Back to cited text no. 5
    
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Vicente C, Vázquez I, Marcotegui N, Conchillo A, Carranza C, Rivell G, et al. JAK2-V617F activating mutation in acute myeloid leukemia: Prognostic impact and association with other molecular markers. Leukemia 2007;21:2386-90.  Back to cited text no. 6
    
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Levine RL, Loriaux M, Huntly BJ, Loh ML, Beran M, Stoffregen E, et al. The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood 2005;106:3377-9.  Back to cited text no. 7
    
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Vaphiades MS, Lee AG. Burkitt lymphoma presenting with gingival pain and a cavernous sinus syndrome in an adult. J Neuroophthalmol 2005;25:249-50.  Back to cited text no. 8
    
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Delgado López F, Franco Macias E, Villalobos Chabes F. Cavernous sinus syndrome as the presentation of Burkitt's lymphoma (acute L3 lymphoblastic leukaemia. Rev Neurol 2002;34:299.  Back to cited text no. 9
    
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Chennupati SK, Govindaraj S, Setzen G, Chiu AG. Adult Burkitt lymphoma originating in the sphenoid sinus: Case report and review of the literature. Ear Nose Throat J 2009;88:E07.  Back to cited text no. 10
    
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Landolsi A, Ben Fatma L, Ben Ammou S, Kallel L, Aloulou S, Gharbi O, et al. Non-metastatic thrombosis of the superior sagittal sinus complicating Burkitt's lymphoma. A case report. Ann Med Interne (Paris) 2003;154:67-9.  Back to cited text no. 11
    
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Chen DT, Chen PR, Hsu LP, Chiu TJ, Hsu YH. Burkitt's lymphoma in paranasal sinuses. Otolaryngol Head Neck Surg 2006;135:991-3.  Back to cited text no. 12
    
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Pusterla S, Previtali S, Marziali S, Cortelazzo S, Rossi A, Barbui T, et al. Antiphospholipid antibodies in lymphoma: Prevalence and clinical significance. Hematol J 2004;5:341-6.  Back to cited text no. 13
    
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Tincani A, Taraborelli M, Cattaneo R. Antiphospholipid antibodies and malignancies. Autoimmun Rev 2010;9:200-2.  Back to cited text no. 14
    
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Gómez-Puerta JA, Cervera R, Espinosa G, Aguiló S, Bucciarelli S, Ramos-Casals M, et al. Antiphospholipid antibodies associated with malignancies: Clinical and pathological characteristics of 120 patients. Semin Arthritis Rheum 2006;35:322-32.  Back to cited text no. 15
    
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Papageorgiou MV, Alexopoulou A, Kontopidou F, Filiotou A, Koskinas J, Pectasides D, et al. Concomitant diagnosis of myeloproliferative neoplasm and non-Hodgkin's lymphoma in a patient with portal vein thrombosis. Anticancer Res 2011;31:1467-9.  Back to cited text no. 16
    
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Palandri F, Derenzini E, Ottaviani E, Polverelli N, Catani L, Salmi F, et al. Association of essential thrombocythemia and non-Hodgkin lymphoma: A single-centre experience. Leuk Lymphoma 2009;50:481-4.  Back to cited text no. 17
    
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Tirefort Y, Pham XC, Ibrahim YL, Lecompte TP, Matthes T, Prins C, et al. A rare case of primary cutaneous follicle centre lymphoma presenting as a giant tumour of the scalp and combined with JAK2V617F positive essential thrombocythaemia. Biomark Res 2014;2:7.  Back to cited text no. 18
    
19.
Popov VM, Dobrea CM, Popescu M, Pleşea IE, Grigorean VT, Sinescu RD, et al. Diffuse large B-cell lymphoma and polycythemia vera discovered at the onset - A rare association and its possible importance in lymphoma prognosis. Rom J Morphol Embryol 2016;57:313-8.  Back to cited text no. 19
    
20.
Leoncini L, Raphael M, Stein H, Harris NL, Jaffe ES, Kluin PM. Burkitt lymphoma. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon: IARC; 2008. p. 262-4.  Back to cited text no. 20
    

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Correspondence Address:
Deepti Mutreja
Department of Pathology, Command Hospital Air Force, Bengaluru - 560 007, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_232_17

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