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Lymphoma - Non B cell neoplasms

T/NK cell disorders

Anaplastic large cell lymphoma, ALK positive


Reviewer: Dragos Luca, M.D. (see Reviewers page)
Revised: 29 September 2011, last major update September 2011
Copyright: (c) 2001-2011, PathologyOutlines.com, Inc.

Definition
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● T cell lymphoma consisting of large lymphoid cells with abundant cytoplasm, pleomorphic often horseshoe-shaped nuclei, an ALK (anaplastic lymphoma kinase) gene translocation, and expression of ALK protein and CD30 (WHO 2008)
● Anaplastic lymphoma kinase (ALK) is tyrosine kinase receptor, part of the insulin receptor superfamily, normally silent in lymphoid cells

Terminology
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● Also called Ki-1 (CD30+) lymphoma, ALCL

Epidemiology
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● 3% of adult and 10-20% of childhood non-Hodgkin lymphomas
● Most frequent in the first 3 decades of life
● Male predominance (M:F ratio 1.5:1)

Sites
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● Usually nodal; nodal involvement often not contiguous
● Frequent involvement of both lymph nodes and extranodal sites
● Compared to Hodgkin lymphoma, inguinal nodal involvement is more common and mediastinal disease is less common
● Most common extranodal sites are skin, bone, soft tissues, lung and liver
● Rare GI and CNS involvement
● See also Primary cutaneous CD30+ T cell lymphoproliferative disorders
● Marrow involvement detected in 10% of cases without immunostains, rises to 30% with immunostains
● Occasional leukemic presentation in peripheral blood with the small cell variant

Etiology
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● Usually T cell origin and T cell lineage, which can usually be proven by molecular studies, even if no T cell antigen expression
● Null cell types are rare; patients are younger than T cell types (28 vs. 42 years, Hum Pathol 2002;33:146)
● May be primary or a secondary transformation of another lymphoma
● Associated with HIV, mycosis fungoides, pulmonary inflammatory pseudotumors (Hum Pathol 2001;32:428)
● Not EBV related (Hum Pathol 2004;35:455)

Clinical features
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● 70% present with stage III-IV disease
● Peripheral or abdominal lymphadenopathy, extranodal infiltrates, bone marrow involvement, B symptoms (especially high fever)
● Anemia, pancytopenia, high LDH, occasional eosinophilia

Case reports
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● Bone, monomorphic variant (Arch Pathol Lab Med 2000;124:1339)
● Breast, not implant related (J Pediatr Hematol Oncol 2010;32:e75)
● Breast, implant related (Arch Pathol Lab Med 2003;127:e115)
● CNS in 4 year old boy (Pediatr Neurosurg 2007;43:516)
● Endobronchial in 17 year old girl (Arch Pathol Lab Med 2003;127:e430)
● Leukemic presentation (Pathol Int 2009;59:345)
● Pulmonary (Acta Haematol 2007;118:188)
● Skeletal muscle in 14 year old boy (Pediatr Hematol Oncol 2009;26:142)

Treatment and prognosis
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● Moderately aggressive, may be curable; better prognosis than other peripheral T cell lymphomas
● ALK+ tumors have longer 5 year survival then ALK- (80% vs. 48%)
● 5 year failure free survival (FSS) also better than ALK- tumors (60% vs. 36%, Blood 2008;111:5496)
● Young age and ALK+ are favorable prognostic factors in CNS tumors (Am J Surg Pathol 2003;27:487)
● International prognostic index (IPI) has limited prognostic value, compared to other lymphomas
● No prognostic difference between classic and variant translocations
● 30% relapse, often remain sensitive to chemotherapy
● Allogeneic bone marrow transplant is useful in refractory cases (Lancet Oncol 2004;5:127)
● ALK inhibitors currently being explored (Cancer Gene Ther 2010;17:633)

Postulated normal counterpart
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● Activated mature cytotoxic T cell

Micro description
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● Broad morphologic spectrum
● Infiltration of interfollicular T zones and nodal sinuses by anaplastic large cells with abundant cytoplasm, horseshoe (“hallmark”) cells, wreath-like or multiple nuclei, multiple nucleoli, perinuclear eosinophilic region, occasional nuclear pseudoinclusions (“doughnut” cells), brisk mitotic activity
● Cells resemble Reed-Sternberg cells, but prefer lymph node sinuses, may mimic metastatic carcinoma, behave differently than Hodgkin lymphoma (Mod Pathol 2001;14:219)
● Anaplastic cells may mimic megakaryocytes; small cell variant may resemble normal marrow
● Vascular wall invasion is frequently seen in extranodal cases
● Typically NO nodal architecture; monomorphic variant uncommon
● Bone marrow varies from extensive involvement by tumor cells to only scattered cells that may be overlooked

Micro images
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Scalp lesion - A: H&E, B: CD30+, C: ALK1+


Monomorphic variant - A: H&E, B: CD30+, C: ALK1+


Endobronchial mass - A: CT scan, B: H&E, C: CD30+


Associated with breast implant - A: H&E; B: silicone particles; C: CD43+; D: CD30+

Morphologic variants
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Lymphohistiocytic (10%)
● Numerous histiocytes and small lymphocytes, occasional erythrophagocytosis
● Neoplastic cells tend to cluster around blood vessels
● Positive stains: CD30, ALK

Small cell (5-10%)
● 25% transform to classic anaplastic large cell lymphoma, usually associated with death within a year; necrosis may predict transformation (Am J Surg Pathol 1999;23:49)
● Often systemic symptoms, often misdiagnosed as peripheral T cell lymphoma NOS
● High incidence of marrow involvement, but difficult to identify without immunostains
Micro: mainly small cells with irregular nuclei, “hallmark” cells present (tend to be perivascular), occasional “fried egg” cells, rare “signet-ring” cells

Hodgkin-like (3%)
● Mimics nodular sclerosis classical Hodgkin lymphoma

Hypocellular
● Small cell types may have hypocellular, granulation tissue like appearance
● Young patients with lymphadenopathy (Am J Surg Pathol 2000;24:1537)
Micro: lymphoid cells separated by edematous or fibromyxoid stroma with myofibroblast-like neoplastic cells forming short, sweeping fascicles and histiocytes; occasional large cells with atypical nuclei noted; perivascular cuffing of large cells
Positive stains: CD30+, ALK+
DD: inflammatory process

Neutrophil-rich cutaneous T cell
● Associated with HIV
● DD: abscess with atypical CD30+ cells (Am J Surg Pathol 2003;27:912)

Sarcomatoid
● Rare, resembles sarcoma, anaplastic carcinoma, melanoma
● Micro images: -5: H&E; 6-UCHL-1+; 7-CD30+; 8: EMA+

Composite pattern (15%)
● More than one pattern may be seen in a single lymph node
● Relapses may differ morphologically from the original tumor

Cytology description
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● Deeply basophilic cytoplasm, prominent vacuoles, round or lobate nuclei, prominent nucleoli, clumped chromatin, multinucleation

Cytology images
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Various images

Positive stains
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● ALK expression varies by translocation; use monoclonal antibodies (note: all post-natal human tissue is ALK negative except rare cells in brain)
● Note: ALK is name of gene and protein; ALK1 is name of antibody
● CD30 (cytoplasmic and Golgi staining, strongest in large cells), EMA (majority)
● CD2, CD4, CD5 (one is positive in 70% of cases), also TIA1, granzyme B, perforin, CD45, CD45RO, CD61, CD25 (strong), BNH9
● Variable CD3 (<25%), CD43, B cell markers (10%)
● Rare CD8, CD15, clusterin, fascin, factor VIII, CD13 (Arch Pathol Lab Med 2000;124:1804)
● “Small cell” and lymphohistiocytic variants are ALK1 positive, but cells are not large or anaplastic
● ALK+ ALCL (T or null) is considered a single entity since no other differences can be found, and “null cell” phenotypes show genetic evidence for T cell lineage

Negative stains
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● CD15, CD20, CD79a, cytokeratin, BCL2, PAX5/BSAP, PGM1, EBV (EBER & LMP1)

Molecular / genetics
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● T-cell receptor (TCR) gene rearrangement seen in 90% (irrespective of T/null cell phenotype)
● All translocations result in upregulation of ALK protein (Science 1994;263:1281)
● t(2;5)(p23;q35): ALK and NPM (84%); translocation of anaplastic lymphoma kinase on #2 and nucleophosmin gene on #5; gene product present in nucleus and cytoplasm, can also be detected by RT-PCR
● t(1;2)(q25;p23): tropomyosin 3 (TPM3) and ALK (13%), diffuse cytoplasmic staining with peripheral intensification
● inv(2)(p23;q35) ALK and ATIC (1%), diffuse cytoplasmic staining
● t(2;3)(p23;q21): ALK and TRK-fused gene (TFG) (<1%), diffuse cytoplasmic staining
● t(2;17)(p23;q23): ALK and clathrin heavy chain-like (CLTCL) (<1%), granular cytoplasmic staining
● t(2;X)(p23;q11-12): ALK and moesin gene (MSN) (<1%), membrane staining
● t(2;19)(p23;p13.1): ALK and non-muscular tropomyosin gene (TPM4) (<1%), diffuse cytoplasmic staining
● t(2;22)(p23;q11.2): ALK and myosin heavy chain 9 gene (MYH9) (<1%), diffuse cytoplasmic staining
● t(2;17)(p23;q25): ALK and ALK lymphoma oligomerization partner (ALO17) (<1%), diffuse cytoplasmic staining
● Secondary genetic alterations: -4, del11q, del13q, +7, +17p, +17q (different from ALCL, ALK negative, Br J Haematol 2008;140:516)
● ALK immunohistochemistry, FISH and RT-PCR results are comparable (Am J Surg Pathol 1999;23:1386)

Molecular images
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Translocation diagram


FISH for NPM/ALK fusion product

Electron microscopy descriptions
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● Similar to Hodgkin lymphoma
● Nuclear shapes similar to lacunar or Reed-Sternberg cells
● Gold immunolabeling: CD30+ particles in the Golgi complex and cell membranes
● Long, slender, microvillus-like processes (“anemone” cell tumors, Ultrastruct Pathol 1984;7:143); however, most microvillous lymphomas are unusual variants of diffuse large B cell lymphoma (Am J Surg Pathol 1990;14:1047)

Differential diagnosis
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ALK negative anaplastic large cell lymphoma
ALK positive diffuse large B cell lymphoma with immunoblastic / plasmablastic features: B cell markers, CD30-, granular cytoplasmic ALK staining
Pleomorphic carcinoma: keratin positive
Hodgkin lymphoma: lacks cohesive growth pattern, has few neoplastic cells, CD15+, PAX5/BSAP+, ALK-, EMA- (Am J Clin Pathol 2007;127:707)
Lymphomatoid granulomatosis: angiocentric, has a background of reactive lymphocytes and histiocytes, EBV+)
Histiocytic sarcoma: ALK-, histiocytic markers+
Non-neoplastic disorders with atypical CD30+ cells
Rhabdomyosarcoma and inflammatory myofibroblastic tumor: may express ALK but are negative for CD30 and EMA; they also express markers of myoid/myofibroblastic differentiation

End of Lymphoma - Non B cell neoplasms > T/NK cell disorders > Anaplastic large cell lymphoma, ALK positive


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