ALK+ Anaplastic Large Cell Lymphoma



ALK+ Anaplastic Large Cell Lymphoma


Francisco Vega, MD, PhD





Key Facts


Terminology



  • CD30(+) lymphoma of T- or null cell lineage having chromosomal abnormalities involving 2p23 (ALK locus)


Clinical Issues



  • Children and adults


  • Most patients present with clinical stage III/IV


  • Extranodal involvement common (60%)


  • 5-year survival: 80-90%


Microscopic Pathology



  • Cytological spectrum of neoplastic cells from small to large


  • “Hallmark cells” characteristic


Ancillary Tests



  • Immunophenotypic studies needed to confirm diagnosis



    • ALK positive


    • CD30 strongly and uniformly positive


  • Lymphoma characterized by chromosomal translocations involving ALK gene


  • Most frequent is t(2;5)(p23;q35), detected in 75%


Top Differential Diagnoses



  • Classical Hodgkin lymphoma (CHL)


  • ALK(−) ALCL


  • Peripheral T-cell lymphoma, NOS


  • DLBCL expressing CD30


  • Cutaneous ALCL







ALK(+) ALCL, classical variant, involving lymph node. The neoplastic cells grow cohesively and preferentially involve sinuses. (Courtesy M. Lim, MD, PhD.)






Necrosis is frequently seen, particularly in those ALK(+) ALCL cases with extensive involvement.


TERMINOLOGY


Abbreviations



  • Anaplastic lymphoma kinase (ALK) positive, anaplastic large cell lymphoma (ALCL)


Definitions



  • CD30-positive systemic lymphoma of T- or null cell lineage with chromosomal abnormalities involving 2p23 and ALK


  • Current WHO classification distinguishes 2 types of systemic ALCL



    • ALK(+) and ALK(−)


CLINICAL ISSUES


Presentation



  • Children and young adults


  • Male predominance


  • B symptoms, especially fever


  • Most patients present with clinical stage III/IV disease


  • Extranodal involvement common (60%)



    • Particularly skin, soft tissue, and lungs


    • Bone marrow (5-30%)


    • Involvement of central nervous system is rare


Treatment



  • Intensive chemotherapy, doxorubicin-based regimens


Prognosis



  • 5-year survival 90%


MICROSCOPIC PATHOLOGY


Histologic Features



  • Neoplastic cells: Large, irregular, and bizarre



    • Often with polylobated nuclei


  • Cytological spectrum of neoplastic cells from small to large



    • Cell size variability helpful in distinguishing ALCL from classical Hodgkin lymphoma


  • “Hallmark” cells characteristic



    • Large cells with eccentric horseshoe- or kidney-shaped nuclei


    • Prominent paranuclear eosinophilic Golgi region


  • Histologic variants



    • Common or classical (80%)


    • Lymphohistiocytic (5-10%)


    • Small cell (5-10%)


    • Sarcomatoid (1%)


ANCILLARY TESTS


Immunohistochemistry



  • Strongly and uniformly positive for CD30 and ALK


  • ALCL can be of T- or null cell lineage



    • In cases of T-cell lineage, aberrant T-cell immunophenotype is common



      • Most tumors do not express CD3, CD5, or T-cell receptors (suggests defective T-cell signaling)


  • Cytotoxic molecules(+)


  • Clusterin(+)


  • EMA(+/−), CD45/LCA(+/−)


  • Bcl-2(−), EBV(−)


  • B-cell antigens(−)


  • Type of ALK staining correlates with type of underlying genetic abnormality



    • Cytoplasmic and nuclear: t(2;5)


    • Cytoplasmic, not coarsely granular: Variant translocations



      • Except t(2;X) and t(2;17)


    • Cytoplasmic, coarsely granular: t(2;17)


    • Membranous: t(2;X)


Cytogenetics



  • ALK(+) ALCL characterized by chromosomal translocations involving ALK gene at 2p23


  • Methods used for demonstrating ALK abnormalities




    • Conventional cytogenetics


    • Fluorescence in situ hybridization (FISH)


    • Reverse-transcriptase (RT) PCR


    • Long-range PCR


    • Immunohistochemistry


  • Chromosomal translocations



    • 75-80% of cases t(2;5)(p23;q35)



      • t(2;5) juxtaposes nucleophosmin (NPM) gene at 5q35 with ALK gene at 2p23


      • t(2;5) drives expression of novel fusion protein NPM-ALK


    • Variant chromosomal abnormalities (25% of cases)



      • ALK gene rearranged with other genes


      • Tropomyosin 3 (TPM3), t(1;2)(p25;p23)


      • TRK-fused gene (TFG), t(2;3)(p23;q21)


      • ATIC, inv(2)(p23;q35)


      • Moesin (MSN), t(2;X)(p23; q11-12)


      • Clathrin heavy chain (CLTCL), t(2;17)(p23;q23)


      • Tropomyosin 4 (TPM4), t(2;19)(p23;q13.1)


      • ALO17, t(2;17)(p23;q25)


      • MYH9, t(2;22)(p23;q11.2)


    • Additional translocations involving ALK will be recognized in future


DIFFERENTIAL DIAGNOSIS


Classical Hodgkin Lymphoma (CHL)



  • Immunophenotype very helpful to confirm diagnosis of CHL


  • HRS cells are positive for



    • pax-5 (nuclear and characteristically weak)


    • CD20 or CD79a in 20% of cases; variable


  • Negative for



    • EMA


    • CD45/LCA


    • ALK


  • In contrast, ALK(+) ALCL tumor cells are ALK(+) and pax-5(−)

Tags:
Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on ALK+ Anaplastic Large Cell Lymphoma

Full access? Get Clinical Tree
Get Clinical Tree app for offline access