Anaplastic lymphoma kinase positive cancers in a short note with recent update on treatment

2. ALK Positive
Lymphoma
Dr. Sudip Roy
JR, IPGME&R, KOLKATA

3. OVERVIEW:-
• Introduction
• History
• Physiology of ALK Tyrosine Kinase Receptors
• Health Conditions Related to Genetic Changes
• Pathogenesis of ALK In Malignancy
• Prognosis
• Treatment
• Take Home Message

4. INTRODUCTION:-
• ALK gene produce ALK protein(Anaplastic
Lymphoma Kinase)
• Tyrosine kinase receptor
• Development of nerve cells
• Sequence similarity to LTK
• Also known as:-
• anaplastic lymphoma receptor tyrosine kinase
• CD246 antigen
• NBLST3

5. HISTORY:-
• previously unrecognized
lymphoid tumor
• Ki-1(CD30) +ve
• ALCL discovered in 1985
– t(ch. 2;5)(p23;q35)
– Malignant histiocytosis
• Then, in 1994, Morris et al –
– chimeric NPM-ALK protein
– 60% of all ALCL have this mutation

6. CHROMOSOMAL LOCATION:-
–Cytogenetic Location:
• 2p23, which is the short (p) arm of ch. 2 between
positions 23.2 and 23.1
–Molecular Location:
• base pairs 29,190,992 to 29,921,611 on ch. 2

7. Specific growth factor attached to extracellular
domain
Activated by phosphorylation
Induce a rapid change in receptor
Active dimer state formed
Auto-phosphorylate tyrosine residues of own
intracellular tail
these modified residues serve as sites for
recruitment of a number of signaling molecules,
including RAS and PI3K
Mechanismof action of ALKTyrosine kinase receptors

8. HEALTH CONDITIONS RELATED TO GENETIC
CHANGES:-
Neuroblastoma- both Somatic mutations and
inherited mutation
Anaplastic Large Cell Lymphoma (ALCL)- t(2;5)
produce a fusion protein NPM-ALK
Inflammatory Myofibroblastic Tumor (IMT)-
translocation involving the ALK gene
Non-small Cell Lung Cancer- inv(2) produce
EML4-ALK fusion protein,mostly adeno
carcinoma

9. Other tumours involved:-
Adult and pediatric renal cell carcinomas
Esophageal squamous cell carcinoma
Breast cancer, notably the inflammatory subtype
Colonic adenocarcinoma
Glioblastoma multiforme
Anaplastic thyroid cancer

10. fusion proteins retain functions of both partner protein
abnormally increase the proliferation of immature -
cancer formation
tyrosine kinase are always activated
attached protein allows phosphorylation of ALK
receptor tyrosine kinase without dimerization
Pathogenesis of ALK in malignancy

11. Pathogenesis:-
Anaplastic large-cell lymphoma
fusion gene –ALK gene and the
nucleophosmin (NPM) gene
t(2;5) in 60% ALCLs
The 3' half of ALK(ch.2) is fused to the 5' portion of
NPM(ch. 5).
NPM-ALK fusion gene product is oncogenic.

12. In a smaller fraction of ALCL patients, the 3' half of
ALK is fused to the 5' sequence of TPM3 gene,
encoding for tropomyosin 3.
In rare cases, ALK is fused to other 5' fusion
partners, such as TFG, ATIC, CLTC1, TPM4, MSN,
ALO17, MYH9.
Chromosomal imbalances have been detected in
58% of ALK+ ALCL

13. ALK Expression
hypoxia-induced factor 1a
(HIF1a)
downregulation of miR-16
increased VEGF levels
angiogenesis and tumor growth
+
Pathogenesis of Tumor formation

14. ALK +ve ALCL:-
• Previously known as large cell immunoblastic
polymorphous type
• 20% to 50% of the large cell lymphomas in children
• Virtually all ALCLs seen in children ALCL are ALK-
positive.
• 2% to 8% of NHLs in adults.

15. • systemic symptoms (most often fever)
• extranodal disease- skin, bone, soft tissue, and lung.
• T-cell lineage
• expression of CD30 (Ki-1) and ALK.

16. Morphology:-
–large, pleomorphic (anaplastic) tumor cells with
an eccentric kidney-shaped nucleus
–an eosinophilic para-nuclear region due to
prominent Golgi apparatus
–small lymphoma cells and reactive inflammatory
cells admixed in variable proportions
–perivascular pattern of neoplastic cell infiltration

17. ALCL, ALK+ve

18. Morphological variants of ALCL(ALK+ve):-
–Small cell
–Lymphohistiocytic, others
–Giant cell, sarcomatiod, signet ring cell,
eosinophil rich
morphology is often neither anaplastic nor large cell
But similar clinical behavior
ALK lymphoma1 or ALKoma2
1. Falini B, Bigerna B, Fizzotti M, et al. ALK expression defines a distinct group of T/null lymphomas (“ALK lymphomas”) with a wide
morphological spectrum. Am J Pathol. 1998;153:875-885.
2. Benharroch D, Meguerian-Bedoyan Z, Lamant L, et al. ALK- positive lymphoma: a single disease with a broad spectrum of
morphology. Blood. 1998;91:2076-2084.

19. ALK +ve IHC:-
– CD30 +ve
– Epithelial Membrane Antigen +ve
– CD15 –ve
– the majority of cases (84%), malignant cells showed both
a cytoplasmic and nuclear staining for ALK1
– in a few cases only cytoplasm stains as translocations
other than t(2;5); like t(1;2)(q25;p23)

20. (A)Perivascular pattern of tumor cells infiltration.
(B, C, D) The perivascular pattern is highlighted by staining for CD30
(D)double labeling for vessels, with anti-CD31 (brown) and for ALK protein
(red).
(E) CD30 is strongly expressed by large cells surrounding the vessel, whereas
the small cell population is only weakly positive.

21. Doubts:-
• Only <15% individuals develop the disease.
• presence in a minority of DLBCL and pleomorphic T-
cell neoplasms
-NOT specific for ALCL

22. Hodgkin’s-like pattern
Reed-Sternberg–like malignant cells
–CD15 -ve
–EBER RNA not found

23. ALK +ve DLBCL:-
–rare subtype of B-cell NHL
–All cases are pediatric lymphomas
–translocation t(2;17)(p23;q23) fusing ALK to CLTC
–a granular cytoplasmic staining by ALK1

24. DLBCL, ALK+ve

25. ALK +ve DLBCL IHC:-
–Immunoglobulin light chain kappa or lambda +ve
–VS38c +ve
–CD138 +ve
–Epithelial Membrane Antigen (EMA) +ve
–pan-B cell antigens(CD20 and CD79a) –ve
–pan-T cell antigen (CD3) –ve
–CD30 –ve

26. A. neoplastic cells with immunoblastic
and plasmablastic features
B. fine granular cytoplasmic staining by
the ALK protein

27. Prognosis:-
• the prognosis is remarkably better
• 5 year survival is 71%,
• Independent predictor of survival in ALCL
• anthracycline-based chemotherapy –response in
90%, relapse free at 5 years in 60%
• After relapse, can be cured with intensive salvage
therapy -autologous stem cell transplantation

28. Treatment:-
• doxorubicin-containing poly chemotherapy
• CHOP(cyclophosphamide, doxorubicin, vincristine,
prednisone), an overall response rate of∼90%
• pediatric cases higher cure rate

29. • first remission achieved by high-dose chemotherapy
with autologous stem cell transplantation
• anti-CD30 antibodies:- G1k antibody MDX-06 and
humanantibody5F11
• Brentuximab vedotin

30. Newer horizon:-
• induction of resistance to small molecule inhibitors
• Co-development of small molecules and
monoclonal antibody inhibitors can avoid emerging
resistance

31. Vaccination therapies:-
• DNA-vaccination with plasmids that encode specific
interferon-gamma response
• CD8+ mediated cytotoxicity causes growth arrest

32. Take Home Message:-
• ALK is a cell membrane tyrosine kinase receptor
• Needed for normal cellular growth
• Mutations can cause ALCL or DLBCL
• Distinct morphological entity
• Respond well to treatment
• Newer targeted therapy with complete remission
available

33. THANK YOU