Lymphoma & related disorders

• Disease develops from EBV infected T cell lymphocytes (Pediatr Blood Cancer 2019;66:e27798, Diagn Pathol 2021;16:48, Leuk Lymphoma 2017;58:53, Blood 2000;96:443)

• 16 year old girl with fatal disease course (Indian J Pathol Microbiol 2020;63:78)
• 30 year old woman with systemic EBV positive T cell lymphoma of childhood developing following systemic CAEBV disease (Diagn Pathol 2023;18:111)
• 68 year old woman with disease involving bone marrow and soft tissue (Pathol Int 2022;72:376)

Contributed by Yoon Kyung Jeon, M.D.

• CD3+ / CD8+
• CD3+, CD4+ (CD8 negative) in cases following systemic CAEBV disease
• EBER in situ hybridization (ISH)
• TIA1
• CXCR3 (60% of cases)
• CD2
• References: Leuk Lymphoma 2017;58:53, Blood 2000;96:443, Diagn Pathol 2021;16:48, Pediatr Blood Cancer 2019;66:e27798, Indian J Pathol Microbiol 2020;63:78, Diagn Pathol 2023;18:111

• CD20
• Often loss of CD5 or CD7
• References: Leuk Lymphoma 2017;58:53, Blood 2000;96:443, Diagn Pathol 2021;16:48, Pediatr Blood Cancer 2019;66:e27798, Indian J Pathol Microbiol 2020;63:78, Diagn Pathol 2023;18:111

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• Aggressive natural killer cell leukemia (ANKL) (Cancers (Basel) 2020;12:2900, Blood Cancer J 2017;7:660, Blood 2012;119:673):
  • Primarily a leukemic disease by definition, with secondary hepatosplenomegaly and bone marrow involvement
  • Positive expression of CD56, CD16, EBER and cytoplasmic CD3ε with lack of surface CD3 expression
  • Lack of expression of surface T cell receptor and monoclonal TCR gene rearrangements
  • Aggressive clinical course, overall survival is < 1 year after diagnosis
• Chronic active EBV disease of T / NK cell type, systemic form (T / NK sCAEBV) (Blood Adv 2020;4:2918, Blood 2012;119:673, Pathogens 2018;7:28, Semin Diagn Pathol 2020;37:32, Am J Clin Pathol 2024 Feb 12 [Epub ahead of print]):
  • Persistent high EBV titers and infectious mononucleosis symptoms for > 3 months
  • Positive EBV infection of T or NK cells in peripheral blood or involved tissues
  • Most commonly, it involves the spleen, liver and bone marrow
  • By definition, EBV infected T or NK cells lack cytological atypia and do not efface the background tissue architecture
  • T cell type (59% of cases) (CD4 > CD8)
  • NK cell type (CD56 positive of 41% of cases)
  • It often shows monoclonality by TCR gene rearrangement or EBV clonality testing; fewer cases are oligoclonal or polyclonal
  • Can develop following EBV negative HLH; it is proposed that cases of EBV+ HLH that do not respond to initial therapies with persistent high EBV counts may constitute T / NK sCAEBV
• EBV+ hemophagocytic lymphohistiocytosis (EBV+ HLH) (J Clin Invest 1993;92:1444, Int J Clin Exp Pathol 2014;7:5738, Br J Haematol 2022;196:31, Semin Diagn Pathol 2020;37:32, Pediatr Blood Cancer 2007;48:124):
  • Diagnosis requires meeting the HLH 2004 diagnostic criteria, including 5 out of 9 clinical and laboratory findings
  • Hemophagocytosis is detected in the bone marrow, liver or lymph nodes
  • Small numbers of EBV+ T cell lymphocytes are identified
    • Most commonly, EBV infection of CD8+ / CD4- T cells; however, cases with EBV+ CD8- / CD4+ T cells have been reported
  • T cells do not show cytologic atypia or effacement of the background architecture
  • Lack of clonal cytogenetic abnormality
  • EBV+ T cells are CD8+ / CD4-
  • Lack of monoclonal TCR gene rearrangement
• EBV+ nodal T and NK cell lymphoma (Hum Pathol 2015;46:981, Am J Surg Pathol 2015;39:462, Int J Hematol 2016;104:591, Histopathology 2012;61:186, J Clin Exp Hematop 2020;60:30, Pathol Res Pract 2013;209:448, Haematologica 2018;103:278):
  • Primarily, it is a nodal disease with limited extranodal disease, including the bone marrow, spleen or liver
  • Diffuse effacement of the lymph node architecture by lymphocytes with marked cytological atypia; the atypical lymphocytes are most commonly medium to large with pleomorphism
  • Most cases show a CD3+ / CD8+ phenotype (~90%)
  • Positive for EBER (in at least 30% of the tumor cells) and cytotoxic markers (TIA1, granzyme B)
  • Monoclonal TCR gene rearrangement (75 - 85%)

Table 1: Comparison of the clinical and laboratory findings between the entities included in the differential diagnosis of systemic EBV+ T cell lymphoma of childhood (adapted from Am J Clin Pathol 2024 Feb 12 [Epub ahead of print])

	Epstein-Barr virus associated hemolymphohistiocytosis (EBV HLH)	Chronic active EBV disease of T / NK cell type systemic form (T / NK sCAEBV)	Systemic EBV positive T cell lymphoproliferative disorder of childhood	Nodal EBV positive T / NK cell lymphoma	Aggressive NK cell leukemia
Morphological features	Small T cell lymphocytes with no definitive cytological atypia	The infiltrates are predominantly composed by lymphocytes and plasma cells with no effacement or distortion of the background tissue and without morphological atypia; HRS-like cells may be present	Variable expansion of lymphocytic infiltrates composed by small to medium sized T cells with no morphological atypia	Effacement of the nodal architecture by medium to large lymphocytes with marked cytological atypia	Medium sized atypical lymphocytes, frequently with prominent nucleoli
Immunophenotype	A subset of T cells are EBV and CD8 positive; loss of pan T cell markers may be observed	The HRS-like cells are CD30 positive with variable expression of PAX5 and CD20; the EBV positive T cells are predominantly CD4 positive with loss of pan T cell markers (rare EBV+ CD8 T cells have been reported)	Majority of cases are composed by CD8 positive neoplastic T cells (CD4+ cases are rare)	A minimum of 30% EBV positive T cell lymphocytes is required; majority of the cases are composed by CD8 positive neoplastic cells	Cytoplasmic CD3 expression and positive expression of CD2, CD56 and CD16; negative for CD57
Anatomical sites of presentation	Bone marrow and liver	Liver, bone marrow and spleen	Bone marrow, liver, lymph nodes, spleen	Lymph nodes	Peripheral blood and bone marrow
Age at diagnosis	Predominantly pediatric population	Predominantly pediatric population	Predominantly pediatric population	Adult populations	Peak incidence between 21 and 30 year old
Relevant clinical features	Meets diagnostic criteria for HLH; good responses to etoposide based regimens	Persistent mononucleosis-like symptoms and high EBV titers for at least 3 months; good responses to systemic chemotherapy and hematopoietic stem cell transplantation is curative in most of pediatric patients; dismal clinical course in adult populations	Rapid development of multiorgan failure and end organ damage including liver failure, hepatosplenomegaly and pancytopenia, with high mortality rates	Aggressive clinical course and poor responses to current chemotherapeutic agents	Fulminant clinical course with a median overall survival of < 2 months
Relevant clinical features and prognosis	Meets diagnostic criteria for HLH; overall good prognosis with good responses to etoposide based regimens	Persistent mononucleosis-like symptoms and high EBV titers for at least 3 months; pediatric patients display good responses to systemic chemotherapy and hematopoietic stem cell transplantation is curative in most of pediatric patients; adult patients are characterized by dismal clinical course and poor prognosis	Rapid development of multiorgan failure and end organ damage including liver failure, hepatosplenomegaly and pancytopenia, with high mortality rates and poor prognosis	Aggressive clinical course, poor responses to current chemotherapeutic agents and bad prognosis	Fulminant clinical course, median overall survival of < 2 months and dismal prognosis

Which of the following features supports a diagnosis of systemic EBV+ T cell lymphoma of childhood over EBV+ hemophagocytic lymphohistiocytosis (EBV+ HLH)?

1. EBER positivity in CD8+ T cells
2. Lack of cytologic atypia
3. Onset of disease in childhood
4. Presence of a clonal cytogenetic abnormality

D. Presence of a clonal cytogenetic abnormality. Clonal cytogenetic abnormalities are found in systemic EBV+ T cell lymphoma of childhood but not EBV+ HLH. Answer A is incorrect because both systemic EBV+ T cell lymphoma of childhood and EBV+ HLH show EBER positivity in CD8+ T cells in most cases. Answer B is incorrect because systemic EBV+ T cell lymphoma of childhood and EBV+ HLH show no cytologic atypia; however, the presence of cytologic atypia would favor a diagnosis of systemic EBV+ T cell lymphoma of childhood. Answer C is incorrect because systemic EBV+ T cell lymphoma of childhood and EBV+ HLH most commonly occur in children and young adults (Int J Clin Exp Pathol 2014;7:5738).

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Reference: Systemic EBV+ T cell lymphoma of childhood

Which of the following is correct regarding EBV+ T cell lymphoproliferative neoplasms of childhood?

1. An indolent clinical course characterizes EBV+ T cell lymphoproliferative neoplasms
2. Diagnosis can be established only after documentation of T cell receptor clonality studies
3. Distinction between systemic EBV+ T cell lymphoma and chronic active EBV disease of T / NK cell type, systemic form (T / NK sCAEBV) can be established solely on morphological analysis of the lymphocytic infiltrates
4. These groups of diseases constitute a continuum with similar histological features and overlap in clinical and laboratory findings

D. These groups of diseases constitute a continuum with similar histological features and overlap in clinical and laboratory findings. Systemic EBV+ T cell lymphoma, T / NK sCAEBV and HLH EBV overlap in clinical features, are indistinguishable in histological features and can precede one another. Answer A is incorrect because these entities usually have an aggressive clinical course. Answer B is incorrect because T cell receptor clonality studies are not positive in all cases and its presence is not required to establish the diagnosis. Answer C is incorrect because the histological features between systemic EBV+ T cell lymphoma and T / NK sCAEBV are similar (Leuk Lymphoma 2017;58:53, Am J Clin Pathol 2024 Feb 12 [Epub ahead of print]).

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Reference: Systemic EBV+ T cell lymphoma of childhood