Lymphoma and plasma cell neoplasms
T / NK cell disorders
Anaplastic large cell lymphoma, ALK positive

Author: Dragos Luca, M.D. (see Authors page)

Revised: 23 March 2017, last major update September 2011

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PubMed search: anaplastic large cell lymphoma [title] ALK positive

Cite this page: Anaplastic large cell lymphoma, ALK positive. PathologyOutlines.com website. http://pathologyoutlines.com/topic/lymphomanonBanaplastic.html. Accessed March 30th, 2017.
Definition / General
  • 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
  • Also called Ki-1 (CD30+) lymphoma, ALCL
Epidemiology
  • 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
  • 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
  • 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)
Diagrams / Tables

Images hosted on other servers:

Translocation diagram

Clinical Features
  • 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
Prognostic Factors
  • 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
Case Reports
Treatment
Postulated normal counterpart
  • Activated mature cytotoxic T cell
Micro Description
  • 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
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
Sarcomatoid:
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
  • Deeply basophilic cytoplasm, prominent vacuoles, round or lobate nuclei, prominent nucleoli, clumped chromatin, multinucleation
Cytology Images

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Various images

Positive Stains
  • ALK expression varies by translocation; use monoclonal antibodies (note: all postnatal 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
Electron Microscopy Description
  • 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)
Molecular / Cytogenetics Description
  • 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 nonmuscular 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 / Cytogenetics Images

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FISH for NPM / ALK fusion product

Differential Diagnosis
  • 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+
  • Nonneoplastic 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