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Lymphoma - Non B cell neoplasms

T/NK cell disorders

Adult T cell leukemia/lymphoma (HTLV-1 positive)


Reviewer: Dragos Luca, M.D. (see Reviewers page)
Revised: 31 January 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
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● A peripheral T cell neoplasm usually composed of highly pleomorphic lymphoid cells
● Disease is usually widely disseminated and is caused by the human retrovirus known as human T cell leukemia virus type I (HTLV-I) (WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue, IARC 2008)

Terminology
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● Also called HTLV-I associated T cell lymphoma; T cell lymphoma-small cell type or pleomorphic medium and large cell type HTLV-I+; T cell immunoblastic sarcoma

Epidemiology
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● Most common where HTLV-I is endemic (southwestern Japan, Caribbean basin, parts of Central and West Africa, South America)
● Sporadic cases also described but patients often lived in an endemic region
● Acquired vertically from mother at birth (most common), human milk, blood products or sexually transmitted; usually several decades before clinical features appear
● Almost only adults, age 20 to 80s, average 58 years; very rarely in children (Brazil)
● M:F ratio 1.5:1
● Patients have defects of cell-mediated immunity, are at risk for multiple opportunistic infections (Arch Pathol Lab Med 2000;124:1241)
● Occurs in 1-5% of HTLV-I+ patients
● Cumulative incidence among HTLV-I carriers in Japan is 2.5%
● Long latency, virus exposure usually occurs very early in life

Etiology / Pathogenesis
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● HTLV-I identified in a cell line from a patient with T cell lymphoma involving the skin (1979) – first oncogenic human virus discovered
● Type C virus belongs to retrovirus family and delta retrovirus genus
● Infection occurs and is transmitted via cell to cell contact
● HTLV-I is causally linked to adult T cell leukemia/lymphoma (ATLL) but is insufficient for neoplastic transformation (molecular models suggest 6 or 7 “hits” required)
● HTLV-I p40 tax viral protein: non structural protein that causes transcriptional activation of many genes in infected lymphocytes; has central role in leukemogenesis
● Enhancement of c-AMP response element binding transcription factor (CREB) phosphorylation by HTLV-I – also important in leukemogenesis
● HTLV-I basic leucine zipper factor (HBZ): causes T cell proliferation and oncogenesis
● JAK/STAT pathway constitutively activated in HTLV-I infected cells
● HTLV-I can also infect immature thymocytes

Postulated normal counterpart
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● Peripheral CD4+ cells, probably the CD4+ CD25+ FOXP3+ regulatory T cells (also correlates with the immunodeficiency characteristic of the disease)

Sites
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● Most patients present with widespread lymph node and peripheral blood involvement
● Degree of peripheral blood involvement does not correspond with degree of bone marrow involvement (circulating cells probably recruited from other organs like skin)
● Most common extralymphatic site is skin (>50%)
● Usually systemic, affecting skin, spleen, lung, liver, GI tract and CNS; usually spares the mediastinum
● Epidemiological differences exist: peripheral blood involvement is much more common in Japan than in the Caribbean basin

Clinical features
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● Hypercalcemia in 50% during course of disease (28% at diagnosis); associated with increased osteoclastic activity (J Clin Oncol 2009;27:453)

● Note: HTLV-I also causes HTLV-I associated myelopathy/tropical spastic paraparesis

Acute subtype:
● Most common; has leukemic phase, constitutional symptoms, elevated LDH; also hepatosplenomegaly, generalized lymphadenopathy, bone marrow infiltration, skin lesions, high WBC count and lymphocytosis/eosinophilia, hypercalcemia, variable lytic bone lesions
● Associated T cell immunodeficiency with frequent opportunistic infections (P. jirovecii pneumonia and Strongyloidiasis)
● Median survival of less than 1 year despite aggressive chemotherapy

Lymphomatous subtype:
● Prominent lymphadenopathy without significant peripheral blood involvement
● Most patients present with advanced stage similar to the acute form
● Hypercalcemia less common, cutaneous lesions as common

Chronic subtype:
● Increased WBC count, slight lymphadenopathy or hepatosplenomegaly
● Frequently associated with an exfoliative skin rash
● May have lymphocytosis but only a few atypical lymphocytes
● No hypercalcemia

Smoldering subtype:
● Few malignant cells in peripheral blood, may have slight lymphadenopathy, hepatosplenomegaly or marrow infiltrates
● WBC usually normal with <5% circulating neoplastic cells
● Frequent skin or lung lesions but no hypercalcemia
Note: chronic and smoldering subtypes may evolve into acute form in 25% of cases but usually after a long duration

● A fifth variant has been proposed: cutaneous ATLL (no leukemic phase, no lymphadenopathy, no hepatosplenomegaly or hypercalcemia)

Case reports
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● 15 year old boy from Brazil (Rev Inst Med Trop Sao Paulo 2001;43:283)
● 32 year old man from West Africa (Arch Pathol Lab Med 2003;127:636)
● 43 year old Caribbean man with CD4+/CD8+ disease (Case Rep Oncol 2010;3:489)
● 47 year old woman with CLL-like morphology (Korean J Hematol 2011;46:9)
● 48 year old woman presenting with intracranial mass (Neurol Med Chir (Tokyo) 2010;50:492)
● 66 year old man with GI lymphomatous polyposis (World J Gastroenterol 2008;14:6584)

Treatment and prognosis
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● Major prognostic factors: clinical subtype, age, performance status, serum calcium and LDH levels
● Acute and lymphomatous variants: survival ranges from 2 weeks to >1 year
● Chronic and smoldering forms: more protracted clinical course and better survival but can progress
● Death usually from infectious complications (P. jirovecii pneumonia, Cryptococcus meningitis, disseminated herpes zoster) and hypercalcemia

Clinical images
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Papules (last row)


Nodules

Micro description
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● Diffuse infiltrate of medium to large cells with agranular basophilic cytoplasm, multilobated nuclei (cloverleaf/flower cells), thick nuclear membranes and coarse chromatin, distinct/prominent nucleoli
● Reed-Sternberg like cells (in Hodgkin lymphoma like cases with expansion of EBV+ B cells), blast-like cells, giant cells may also be present
● Cutaneous infiltrates are dermal (mainly perivascular but larger nodules extending into the subcutaneous fat also possible) or epidermotropic with Pautrier’s microabscesses (resembling mycosis fungoides)
● Rare cases have predominantly small lymphocytes with irregular nuclei (cell size not correlated with clinical course except chronic and smoldering forms where lymphocytes appear more normal)
Bone marrow: usually patchy infiltrates; may have increased osteoclastic activity without marrow involvement by lymphoma; broad morphologic spectrum of pleomorphic small, medium and large cell types, anaplastic, and rarely angioimmunoblastic T cell lymphoma-like
Lymph node: Paracortical T cell zones initially, may have leukemic pattern of infiltration with preservation or dilation of sinuses containing malignant cells and sparse inflammatory background, variable eosinophilia

Micro images
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Left: cloverleaf-type cell; right: flower cells


Lymph node


Skin


47 year old woman with CLL-like morphology

   
66 year old man with GI lymphomatous polyposis

Positive stains
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● CD2, CD3, CD4, CD5, CD25, TCR α/β, CD45RO; rarely CD30+
● A few cases are CD4-/CD8+ or CD4+/CD8+; occasional CD56 expression may be seen
● Frequent expression of CCR4, FOXP3, HLA-DR, L-selectin (CD62), MUM-1

Negative stains
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● CD7, CD8, ALK, cytotoxic molecules, CD10, CXCL13, TCL-1

Flow cytometry images
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CD3+/CD4+/CD25+/CD7-/CD8-

Electron microscopy images
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Genetics & molecular
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● HTLV-I provirus present in tumor cells; clonal T cell receptor gene rearrangement
● Monoclonal integration of HTLV-I in neoplastic cells (no clonal integration in healthy carriers)
● Clonal chromosome abnormalities but none is specific

Differential diagnosis
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● Peripheral T cell lymphoma, NOS
● Angioimmunoblastic T cell Lymphoma
● Anaplastic large cell lymphoma
● Mycosis fungoides/Sézary syndrome
● HTLV-I-positive reactive lymphadenitis


Clinical and morphological spectrum of HTLV-I-related diseases

General
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Neoplastic disorders:
● Peripheral blood (leukemia)
     ● Smoldering type
     ● Chronic type
     ● Acute type

● Lymph node (lymphoma)
     ● Hodgkin-like type
     ● Pleomorphic small cell type
     ● Pleomorphic (medium and large cell) type
     ● Anaplastic large cell type

● Skin
     ● Erythema
     ● Papule
     ● Nodule

● Gastrointestinal tract
     ● Erosion
     ● Ulceration
     ● Tumor

● Liver
     ● Portal or sinus infiltration

● Bone marrow
     ● Infiltration with or without fibrosis

Reactive disorders:
● Confirmed
     ● HTLV-I-associated myelopathy (HAM)
     ● HTLV-I-associated uveitis
     ● HTLV-I-associated lymphadenitis

● Not confirmed
     ● HTLV-I-associated bronchopneumopathy (HAB)
     ● HTLV-I-associated arthropathy (HAAP)
     ● HTLV-I-associated nephropathy

Diagnostic criteria for clinical subtypes of ATLL:



Additional references
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● Diagnostic Pathology: Lymph Nodes and Spleen with Extranodal Lymphomas, L. Jeffrey Medeiros, Amirsys 2011
● Review articles: J Clin Pathol 2007;60:1373, Am J Clin Pathol 2007;127:496, Cancer 2002;96:110

End of Lymphoma - Non B cell neoplasms > T/NK cell disorders > Adult T cell leukemia/lymphoma (HTLV-1 positive)


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