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Lymphoma - Non B cell neoplasms

T/NK cell disorders

T lymphoblastic leukemia/lymphoma


Reviewer: Dragos Luca, M.D. (see Reviewers page)
Revised: 30 October 2011, last major update August 2011
Copyright: (c) 2001-2011, PathologyOutlines.com, Inc.

Definition
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● A neoplasm of lymphoblasts committed to the T cell lineage, typically composed of small to medium-sized blasts with scant cytoplasm, moderately condensed to dispersed chromatin and inconspicuous nucleoli, involving bone marrow and blood (T-ALL) or presenting with primary involvement of thymus, nodal or extranodal sites (T-LBL) (WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, Lyon 2008)

Terminology
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● T-LBL (lymphoblastic lymphoma): mass lesion with no or minimal peripheral blood involvement
● T-ALL (acute lymphoblastic leukemia): extensive bone marrow or peripheral blood involvement
● Defined as T-ALL if >25% lymphoblasts in marrow (in cases presenting with mass lesions and lymphoblasts in bone marrow)
● No definitive agreement on the minimal blast percentage required to diagnose ALL (in contrast to AML); however, diagnosis of ALL should be avoided if <20% blasts

Epidemiology
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● Teens and young men; 40% of childhood lymphomas and 15% of acute lymphoblastic leukemias
● T-ALL represents 25% of adult ALL
● T-LBL represents 85-90% of all LBL’s
● More common in whites than African Americans or Asians
● Males more often affected (M:F among whites is 2.4:1)
● In elderly (>60 years of age), patients usually present as T-ALL, uncommonly with a mediastinal mass

Sites
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● T-ALL: bone marrow in all cases; aleukemic presentations uncommon (in contrast to B-ALL)
● T-LBL: frequent mediastinal (thymic) involvement, also lymph node or extranodal sites (skin, tonsils, liver, spleen, CNS, testis)

Etiology
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● Report of T-ALL in monozygotic twins with same TCR gene rearrangement suggests in utero origin of earliest genetic lesions (Blood 1997;89:281)

Clinical features
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● T-LBL usually presents as anterior mediastinal (thymic) mass with supradiaphragmatic lymphadenopathy and variable splenic, hepatic and bone marrow involvement (with leukemic phase); CNS involvement if untreated
● T-ALL cases often present with mediastinal mass in young adult males, with early blood and diffuse marrow involvement, high leukocyte count
● For a given leukocyte count and tumor burden, T-ALL often shows relative sparing of normal hematopoiesis compared with B-ALL
● In T-LBL rapid growth with respiratory impairment and pleural effusion is common
● Ataxia-telangiectasia is associated with an increased risk of T-ALL

Case reports
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● 26 year old woman with coexisting Langerhans cell histiocytosis (Arch Pathol Lab Med 2001;125:958)
● 45 year old woman with bilateral retinal detachment (Korean J Ophthalmol 2010;24:245)
● 57 year old woman With t(12;17) translocation (Korean J Lab Med 2010;30:239)
● 60 year old woman with disease post-breast cancer treatment (Korean J Lab Med 2010;30:255)
● Elderly woman with coexisting papillary thyroid carcinoma (Indian J Pathol Microbiol 2010;53:125)

Treatment and prognosis
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● Aggressive disease, with 5 year survival of 26%, but chemotherapy cures 60%
● Considered higher risk than B-ALL in childhood (higher risk of induction failure, early relapse and isolated CNS relapse)
● White count does not appear to be an adverse prognostic factor (in contrast to B-ALL)
● Minimal residual disease after therapy is a strong adverse prognostic indicator
● Prognosis for T-LBL depends on age, stage and LDH level
● Rare cases of indolent T lymphoblastic proliferations (upper aerodigestive tract, multiple local recurrences, no systemic dissemination) are morphologically and immunophenotypically indistinguishable from T-LBL, but no clonal TCR gene rearrangements

Postulated normal counterpart
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● T cell progenitor (T-ALL) or thymic lymphocyte (T-LBL)

Micro description
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● T-ALL (similar to B-ALL): diffuse infiltrate of immature small/intermediate cells with scant cytoplasm, delicate chromatin, convoluted nuclear membrane, indistinct nucleoli; frequent mitotic figures, may have cytoplasmic vacuoles
● T-LBL: complete architectural effacement, starry sky pattern produced by interspersed benign macrophages; often extensive pericapsular and soft tissue infiltrates; occasional multinodular pattern of T-LBL may mimic follicular lymphoma; may also see larger blasts with finely dispersed chromatin, conspicuous nucleoli and round-to-irregular-to convoluted nuclei
Bone marrow: varies from scattered blasts to diffuse involvement; prominent mitotic activity (reportedly higher than B-ALL)

Micro images
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Lymphoblastic lymphoma

   
Various images

   
Coexisting Langerhans cell histiocytosis

   
Peripheral blood

Positive stains
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● CD3, CD99, TdT
● Also CD7, variable expression of other T cell markers (CD1a, CD2, CD4, CD5, CD8), CD34, CD10 (63%, Arch Pathol Lab Med 2000;124:704), many tumors coexpress CD4+ and CD8+
● Occasional CD16, CD56, CD57 (NK markers)
● CD52 (virtually all), also CD38 and CD71 in a substantial subset
● CD7 and cytoplasmic CD3 are most often expressed but only the latter is considered lineage-specific
● TAL-1 nuclear staining in 29-48% of cases (not necessarily correlated with TAL-1 gene alterations)
● May also express CD79a (10%), CD13 or CD33 (19-32%), CD117 (occasionally, associated with FLT3 mutations)
● The presence of myeloid markers does not exclude the diagnosis of T-ALL/LBL, nor does it indicate mixed phenotype T/myeloid leukemia (WHO)

Stages of intrathymic differentiation according to immunophenotype:
● Pro-T: cCD3+, CD7+, CD2-, CD1a-, CD34+/-, double negative CD4/CD8
● Pre-T: cCD3+, CD7+, CD2+, CD1a-, CD34+/-, double negative CD4/CD8
● Cortical T: cCD3+, CD7+, CD2+, CD1a+, CD34-, double positive CD4/CD8
● Medullary T: cCD3+, CD7+, CD2+, CD1a-, CD34-, surface CD3+, either CD4+ or CD8+

Negative stains
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● CD19, CD20, HLA-DR, surface immunoglobulin, CD22, CD25

Cytochemistry
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● Periodic acid–Schiff (PAS) shows a discrete, block-like pattern
● Dot-like acid phosphatase reaction, fluoride-resistant non-specific esterase reaction in the paranuclear Golgi zone
● T-lymphoblasts are negative for myeloperoxidase and Sudan black B

Genetics and molecular
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● Almost always clonal TCR gene rearrangements
● Simultaneous IGH@ gene rearrangements in 20% of cases
● Abnormal karyotypes in 50-70% of cases, most commonly involving 14q11.2 (α/δ TCR loci), 7q35 (β) and 7p14-15 (γ)
● t(1;14)(p32;q11): SCL (TAL1) and T cell receptor delta/alpha (15-30%)
● t(10;14)(q24;q11): HOX11 (TLX1) and T cell receptor delta/alpha (7% of childhood and 30% of adult cases)
HOX11L2 (TLX3)(5q35): 20% of childhood and 10-15% of adult cases
● Other genes involved: MYC (8q24.1), RBTN1 (LMO1) (11p15), RBTN2 (LMO2) (11p13), LYL1 (19p13), LCK (1p34.3-35)
● Other translocations: PICALM-MLLT10 [CALM-AF10; t(10;11)(p13;q14)] – 10%, MLL (8%) – most often with ENL (19p13)
● Deletions: del(9p) – loss of CDKN2A (~30%)
NOTCH1 mutations (50%) – shorter survival in adult but not pediatric patients
● Gene expression profiling of childhood T-ALL showed four major molecular types associated with distinct stages of arrested T cell maturation and correlated with cytogenetic abnormalities
● T-LBL + eosinophilia + myeloid hyperplasia = 8p11.2 (FGFR1) cytogenetic abnormality

EM description
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● Lymphoblasts are of medium size, with smooth surfaces and no cytoplasmic processes
● Irregularly shaped nuclei with frequent fissures and convolutions, evenly dispersed chromatin with peripheral condensation, dense nucleoli adjacent to the nuclear membrane
● Scarce cytoplasm with few mitochondria, strands of endoplasmic reticulum, free ribosomes, and perinuclear filaments and microtubules
● Cells with filament bundles are common in blood but rare in lymph nodes

Differential diagnosis
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● Burkitt lymphoma, granulocytic sarcoma, lymphoblastoid mantle cell lymphoma, CML blast crisis (Hum Pathol 2002;33:770)

Additional references
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● Review articles: Pediatr Blood Cancer 2008;51:489

End of Lymphoma - Non B cell neoplasms > T/NK cell disorders > T lymphoblastic leukemia/lymphoma


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