LGCmain
Indian Journal of Pathology and Microbiology
Home About us Instructions Submission Subscribe Advertise Contact e-Alerts Ahead Of Print Login 
Users Online: 575
Print this page  Email this page Bookmark this page Small font sizeDefault font sizeIncrease font size


 
  Table of Contents    
CLINICO-PATHOLOGY CONFERENCE  
Year : 2020  |  Volume : 63  |  Issue : 1  |  Page : 78-82
EBV-positive T/NK-associated lymphoproliferative disorders of childhood: A complete autopsy report


1 Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada, N6A 5C1; Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, Ontario, Canada, N6A 5A5, Canada
2 Department of Pathology and Laboratory Medicine, Joseph Brant Hospital, Burlington, Ontario Canada, L7S 1W7, Canada

Click here for correspondence address and email

Date of Web Publication31-Jan-2020
 

   Abstract 


Introduction: Epstein-Barr Virus (EBV)-associated systemic T-cell lymphoproliferative disorder of childhood is a rare but severe manifestation of chronic EBV infection. Despite several case reports characterizing this rare hematological neoplasm, the literature describes extensive heterogeneity in the presentation of this disease. Case presentation: Here we present a complete autopsy of a 16-year-old girl who ultimately succumbed to EBV-associated systemic T-cell lymphoproliferative disorder of childhood. Her clinical presentation demonstrated a non-specific pharyngitis with positive mono spot test, evolving into fulminant multi-organ failure, disseminated intravascular coagulopathy, sepsis, and ultimately death. Conclusions: Post-mortem findings included extensive hemorrhage, and infiltration of the liver, spleen, lymph nodes and bone marrow with neoplastic T-cells. There was extensive hemophagocytic lymphohistiocytosis (HLH) within these organs, suggesting overlap between the EBV-associated systemic T-cell lymphoproliferative disorder of childhood and EBV-associated HLH. We hope these findings provide a more comprehensive overview of several possible manifestations of EBV-associated systemic T-cell lymphoproliferative disorder of childhood.

Keywords: Epstein-Barr virus infection, hemophagocytic lymphohistiocytosis, T-cell lymphoma

How to cite this article:
Keow JY, Stecho WM, Haig AR, Sangle NA. EBV-positive T/NK-associated lymphoproliferative disorders of childhood: A complete autopsy report. Indian J Pathol Microbiol 2020;63:78-82

How to cite this URL:
Keow JY, Stecho WM, Haig AR, Sangle NA. EBV-positive T/NK-associated lymphoproliferative disorders of childhood: A complete autopsy report. Indian J Pathol Microbiol [serial online] 2020 [cited 2020 Feb 17];63:78-82. Available from: http://www.ijpmonline.org/text.asp?2020/63/1/78/277389





   Introduction Top


Epstein-Barr Virus (EBV) is a member of the human herpesvirus family. Also known as human herpesvirus 4, EBV infection is exceptionally common with over 90% of humans demonstrating a serological response to EBV exposure. The primary infection is generally mild or completely asymptomatic, though it can manifest as infectious mononucleosis in approximately 50% of infected young adults. Lymphoproliferative complications of primary EBV infection are unusual but devastating[1] and are classified within the larger family of EBV-positive lymphoproliferative disorders.[2]

Primary EBV infection typically results in infectious mononucleosis or is cleared by the body with no sequelae of infection. However, in a small minority of cases, the primary exposure to EBV leads to infection of T-cells, leading to a fulminant clinical course and a generally poorer outcome.[3] EBV-positive T/NK-associated lymphoproliferative disorders of childhood are a rare but aggressive manifestation of primary EBV infection. EBV-positive hemophagocytic lymphohistiocytosis (EBV-HLH) and systemic EBV-positive T-cell lymphoma of childhood are two direct sequelae of T-cell infection by EBV, resulting in a clonal proliferation of CD8(+) cytotoxic T-cells.[4] These two entities appear to exist along the same spectrum,[5] sharing many characteristics of primary EBV infection, such as the absence of EBV IgG, but they carry very different prognoses.

In EBV-HLH, infected CD8(+) cytotoxic T-cells release a series of pro-inflammatory cytokines that leads to the activation of macrophages and histiocytes, causing immune dysregulation and a hyperinflammatory state.[6] Liver biopsies will show subtle infiltration of small T-cells in the sinusoids and portal areas, Kupffer-cell hyperplasia, and sinusoidal infiltration of these hemophagocytic histiocytes. Bone marrow aspirates from patients with EBV-HLH will show hemophagocytic histiocytes, myeloid, and erythroid hypoplasia. EBV-encoded small RNAs (EBER)-positive cells are found throughout the liver and bone marrow. EBV-HLH is the most common cause of secondary HLH, with approximately 40% of all cases of HLH due to EBV-HLH.[7] There is no overt neoplastic process in EBV-HLH, thus distinguishing it from systemic EBV-positive T-cell lymphoma of childhood.

Systemic EBV-positive T-cell lymphoma of childhood manifests as a clonal proliferation of EBV-infected cytotoxic T-cells, with a rapid progression leading to multi-organ failure, sepsis, and death, usually in the setting of a concomitant HLH syndrome. This clinical course usually presents days to weeks after an acute EBV infection. Systemic EBV-positive T-cell lymphoma of childhood is almost uniformly fatal. The presence of circulating EBV DNA is an extremely poor prognostic sign, correlating with a 100% mortality rate in all reported cases of systemic EBV-positive T-cell lymphoma of childhood.[8]

Little is known about the complete systemic effects of EBV-positive T-cell lymphoma of childhood. There have been several case reports of the natural history of this disease, but the complete histological characterization of this rare disease has not been rigorously documented. In this study, we present the first complete autopsy report of a patient who developed systemic EBV-positive T-cell lymphoma of childhood.


   Case Description Top


A previously healthy 16-year-old girl with no past medical history presented with a 3-week history of vague upper respiratory tract symptoms, fatigue, and pallor. Upon her initial presentation, she was diagnosed with infectious mononucleosis following a positive mono spot test, and her symptoms subsequently resolved. She then re-presented to the emergency department following a 2-day history of abdominal pain with associated pharyngitis.

Upon presentation, she was hypotensive, bicytopenic (hemoglobin concentration 90 g/L and platelet concentration 19 × 109/L), hypertriglyceridemia (2.31 mmol/L), hypofibrinogenemic (0.99 g/L), hyperferritinemic (48 440.0 mcg/L), suffering from acute hepatitis (alanine aminotransferase concentration 265 units/L and aspartate aminotransferase concentration 1240 units/L), and significant coagulopathy (international normalized ratio 1.7). She was hemodynamically resuscitated with IV fluids, followed by empiric initiation of intravenous immunoglobulins and broad-spectrum antibiotics. Unfortunately, she remained hypotensive and required intensive care for vasopressor and inotropic support to maintain adequate perfusion. A bone marrow aspirate revealed a population of mature T-lymphocytes representing approximately 30% of total leukocytes [Figure 1], and a bone marrow biopsy showing an interstitial infiltrate of atypical lymphocytes [Figure 2]a, positive for CD3 [Figure 2]b and EBER [Figure 2]c, consistent with HLH, and systemic EBV-positive T-cell lymphoproliferative disorder of childhood. This population was positive for CD2, CD3, CD7, CD8, HLA-DR, and alpha/beta chain, and negative for CD1a, CD4, CD5, CD34, Tdt, and gamma/delta chain. A semiquantitative PCR for serum EBV DNA also revealed EBV at a concentration of 5.68 × 105 copies/mL.
Figure 1: A population of lymphocytes representing approximately 30% of total leukocytes is positive for CD2, CD3, CD7, CD8, HLA-DR, and alpha/beta chain. They are negative for CD34, CD1a, TDT, CD4, CD5, and gamma/delta chain. This is consistent with an atypical mature T-lymphocyte population

Click here to view
Figure 2: Hematoxylin and eosin (H/E) stained section of the bone marrow (a) showing interstitial infiltrate of atypical lymphocytes, which are better highlighted by CD3 (b) and positive for EBER (c). A section of the liver (H/E) showing a dense periportal lymphoid infiltrate (d). Higher magnification shows the atypical lymphocytes (e) that are CD3 positive (f) with hemophago lymphohistiocytosis (g). A dilated sinusoidal space in a lymph node (h) showing hemophagocytosis and nuclear positivity for EBER (i)

Click here to view


She was started on etoposide and high dose dexamethasone. In spite aggressive supportive therapy, her clinical condition continued to decline, and she required intubation following an episode of acute respiratory distress. Multi-organ failure quickly manifested, and she developed renal failure requiring dialysis and hypoxic-ischemic encephalopathy. After several discussions about prognosis, the decision was made to withdraw life support and she passed away peacefully while surrounded by her family.

A complete post-mortem examination was requested by her family. Her post-mortem diagnosis was concordant with her pre-mortem diagnosis, demonstrating systemic EBV-positive T-cell lymphoproliferative disorder of childhood, with associated HLH. In addition to the previously mentioned EBV detected by EBV semiquantitative viral PCR, a monoclonal population of EBV-positive CD8(+) cytotoxic T-lymphocytes was seen within the liver, spleen, lungs, lymph nodes, and bone marrow. These organs demonstrated an infiltrating population of cytologically atypical EBER-positive T-cells, immunohistochemically positive for CD3 and CD8. There was a dense lymphohistiocytic infiltrate within the portal tracts of the liver [Figure 2]d, without evidence of hepatonecrosis or cirrhosis. These highly atypical T-cells [Figure 2]e were positive for CD3 [Figure 2]f, demonstrated diffuse EBER reactivity with hemophagic lymphohistiocytosis [Figure 2]g. There was hepatomegaly (2172 g) and significantly associated splenomegaly (574 g), ascites (800 mL), jaundice, and scleral icterus. Examined lymph nodes demonstrated dilated sinusoidal spaces showing hemophagocytosis [Figure 2]h and diffuse positivity for EBER [Figure 2]i. T-cell clonality testing revealed a diffuse monoclonal T-cell population within submitted liver and spleen samples, each showing identical monoclonal TCRβ and TCRγ rearrangements.

The kidneys demonstrated bilateral acute tubular necrosis with hemogranular cast formation, consistent with acute kidney injury. There was extensive hemorrhage observed throughout the post-mortem examination. There were small hemorrhages within the renal parenchyma bilaterally, and an area of small hemorrhage within the right adrenal gland. There was also bilateral conjunctival hemorrhage and 100 mL of coffee-ground emesis within the stomach. There was diffuse intra-alveolar hemorrhage with associated acute and chronic inflammation extending from the alveoli into the bronchioles and bronchi bilaterally. Although this extensive hemorrhage was seen throughout all five lobes of the lungs, they were most prominent on the right side, with an associated right hemothorax (3000 mL). There was also a left pleural effusion, and her lungs had a combined postmortem weight of 1412 g.


   Discussion Top


There were several poor prognostic features in this case to explain its rapid and aggressive course, such as the marked atypia of the neoplastic CD8(+) T-cells, and the presence of circulating EBV DNA.[8] Ultimately, the terminal physiological events manifest into multi-organ failure or HLH, or a combination of both,[6],[7] and these observations were consistent with our case. The post-mortem examination revealed a monomorphic and monoclonal population of EBV-positive CD8(+) cytotoxic T-lymphocytes that had been infected with EBV. These atypical cells were found within multiple organs, with extensive infiltration of the liver, spleen, lymph nodes, and bone marrow. There was also extensive evidence of hemophagocytosis within these organs, suggestive of associated hemophagocytic lymphohistiocytosis. These findings are diagnostic of systemic EBV-positive T-cell lymphoproliferative disorder of childhood with associated hemophagocytic lymphohistiocytosis.

This patient presented with jaundice and an elevated international normalized ratio (INR), which may be consistent with synthetic impairment due to terminal hepatic dysfunction from the extensive infiltration of these neoplastic lymphocytes into her liver. Her elevated serum transaminases, serum ferritin, ascites, and jaundice are certainly consistent with fulminant hepatitis causing a decompensated hepatopathy. However, in the context of her markedly decreased fibrinogen, her jaundice and coagulopathy strongly point toward the presence of consumptive coagulopathy. Disseminated intravascular coagulopathy (DIC) is a consumptive microfibrinous fibrinolytic state that may manifest as a terminal presentation of multi-organ failure, though it may be commonly seen in association with many hematologic malignancies. In addition, this patient demonstrated extensive areas of focal hemorrhage within the thorax, lungs, adrenals, kidneys, conjunctiva, and upper aerodigestive tract, consistent with her coagulopathic state. Although DIC has been documented in the context of advanced HLH,[9],[10],[11] these findings corroborate the observation that an element of overlap exists between the various forms of EBV-associated lymphoproliferative disorder.[6],[12],[13]

Unfortunately, little else is known about this rare disease because the wealth of our knowledge comes from systematic reviews of various case reports detailing the course of this disease.[8] The consensus among observed cases is that this disease carries a dismal prognosis, with poor response to therapy, and an extremely aggressive clinical course resulting in death within days to weeks. We hope these findings provide a more comprehensive overview of several possible manifestations of EBV-associated systemic T-cell lymphoproliferative disorder of childhood.

Declarations

Ethical approval and consent to participate.

Not applicable.

Availability of data and material

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declaration of patient consent

Written informed consent was provided by the next of kin for the use of this case for research purposes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Kim HJ, KoYH, Kim JE, Lee SS, Lee H, Park G, et al. Epstein-barrvirus-associated lymphoproliferative disorders: Review and update on 2016 WHO classification. J PatholTransl Med 2017;51:352-8.  Back to cited text no. 1
    
2.
Carbone A, Gloghini A, Dotti G. EBV-associated lymphoproliferative disorders: Classification and treatment. Oncologist 2008;13:577-85.  Back to cited text no. 2
    
3.
Cohen JI, Kimura H, Nakamura S, KoYH, Jaffe ES. Epstein-barrvirus-associated lymphoproliferative disease in non-immunocompromised hosts: A status report and summary of an international meeting. Ann Oncol 2009;20:1472-82.  Back to cited text no. 3
    
4.
Ohga S, Ishimura M, Yoshimoto G, Miyamoto T, Takada, H, Tanaka T, et al. Clonal origin of Epstein-barrvirus (EBV)-infected T/NK-cell subpopulations in EBV-positive T/NK-cell lymphoproliferative disorders of childhood. J Clin Virol 2011;51:31-7.  Back to cited text no. 4
    
5.
Hong M, KoYH, YooKH, Koo HH, Kim, SJ, Kim, WS, et al. EBV-positive T/NK-cell lymphoproliferative disease of childhood. Korean J Pathol 2013;47:137-47.  Back to cited text no. 5
    
6.
Chen G, Chen L, Qin X, Huang Z, Xie X, Li G, et al. Systemic epstein-barrvirus positive T-cell lymphoproliferative disease of childhood with hemophagocytic syndrome. Int J Clin ExpPathol 2014;7:7110-3.  Back to cited text no. 6
    
7.
Su IJ, Chen RL, Lin DT, Lin KS, Chen CC. Epstein-barrvirus (EBV) infects T lymphocytes in childhood EBV-associated hemophagocytic syndrome in Taiwan. Am J Pathol 1994;144:1219-25.  Back to cited text no. 7
    
8.
Yoshii M, Ishida M, Hodohara K, Okuno H, Nakanishi R, Yoshida T, et al. Systemic epstein-barrvirus-positive T-cell lymphoproliferative disease of childhood: Report of a case with review of the literature. OncolLett 2012;4:381-4.  Back to cited text no. 8
    
9.
Li J, Wang Q, Zheng W, Ma J, Zhang W, Wang W, et al. Hemophagocytic lymphohistiocytosis: Clinical analysis of 103 adult patients. Medicine 2014;93:100-5.  Back to cited text no. 9
    
10.
Valade S, Azoulay E, Galicier L, Boutboul D, Zafrani L, Stepanian A, et al. Coagulation disorders and bleedings in critically ill patients with hemophagocytic lymphohistiocytosis. Medicine 2015;94:e1692.  Back to cited text no. 10
    
11.
George MR. Hemophagocytic lymphohistiocytosis: Review of etiologies and management. J Blood Med 2014;5:69-86.  Back to cited text no. 11
    
12.
Smith MC, Cohen DN, Greig B, Yenamandra A, Vnencak-Jones C, Thompson MA, et al. The ambiguous boundary between EBV-related hemophagocytic lymphohistiocytosis and systemic EBV-driven T cell lymphoproliferative disorder. Int J Clin ExpPathol 2014;7:5738-49.  Back to cited text no. 12
    
13.
Coffey AM, Lewis A, Marcogliese AN, Elghetany MT, PuniaJN, Chang CC, et al. A clinicopathologic study of the spectrum of systemic forms of EBV-associated T-cell lymphoproliferative disorders of childhood: A single tertiary care pediatric institution experience in North America. Pediatr Blood Cancer 2019;16:e27798.  Back to cited text no. 13
    

Top
Correspondence Address:
Jonathan Y Keow
Department of Pathology and Laboratory Medicine, London Health Sciences Centre, Western University, 339 Windermere Rd, London, Ontario N6A 5A5
Canada
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_510_19

Rights and Permissions


    Figures

  [Figure 1], [Figure 2]



 

Top
 
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  


    Abstract
   Introduction
   Case Description
   Discussion
    References
    Article Figures

 Article Access Statistics
    Viewed147    
    Printed1    
    Emailed0    
    PDF Downloaded7    
    Comments [Add]    

Recommend this journal