Molecular pathways of all important CNS tumors have been explained

1. Molecular pathogenesis
of CNS tumors
Imtiaz Ahmed

2. Present Scenario
• Morphological diagnosis assisted by radiological
findings
• Tumor grade (WHO grade)
• Treatment according to tumor grade (Surgery,
Chemotherapy, Radiotherapy)
• Targeted therapy

3. Today’s lecture
• Epidemiology
• Gliomas
• Medulloblastoma
• Ependymomas
• Meningiomas
• Primary CNS lymphomas
• WHO 2007 classification
• WHO 2016 classification

4. Hallmarks of cancer. (Adapted from Hanahan D, Weinberg RA.Hallmarks of cancer: the next generation. Cell 2011; 144:646.)

5. Epidemiology of CNS tumors
• Primary cerebral malignancy* -
• 4 to 10/lac general population
• 1.6% of all primary tumors
• 2.3% of all cancer related deaths
• 2nd most common cancer in children
• 20% of all cancers in children <15 yrs
• Therapeutic X-irradiation has been unequivocally linked
with brain tumors (7–9 years)
*Francis Ali-Osman, Brain tumors, 2005

6. Distribution of Primary Brain and CNS Tumors by Behavior (N = 356,858), CBTRUS Statistical Report:
NPCR and SEER, 2008-2012

7. Distributiona in Children (Age 0-14 years) of Primary Brain and CNS Tumors by CBTRUS Histology Groupings
and Histology (N = 16,366), CBTRUS Statistical Report: NPCR and SEER, 2008-2012

8. Cell of Origin
• Glial cells
• Neural stem cells (NSC): proposed that carcinogenesis is
dependent on a small population of cells termed ‘‘cancer stem
cells*’’ (CSCs)
• Genes that are expressed in NSC are Nestin, EGFR, PTEN,
Hedgehog etc : Neurogenesis and Gliogenesis
• Aberrant activation of developmental genetic programs in NSCs
gives rise to CNS tumors
*Ignatova et al. 2002; Shen et al. 2004

9. Gliomas

11. Gliomas
• Gliomas (a primary tumor of glial cell origin) are the
most common intracranial neoplasm
• Astrocytomas, glioblastomas, and oligodendrogliomas
accounting for more than 80%
• Grade I to Grade IV tumors
• GBMs: most aggressive and deadly of these tumors, are
the most common of the gliomas (55%)

12. Distributiona of Primary Brain and CNS Gliomasb by Histology Subtypes (N = 97,910), CBTRUS Statistical
Report: NPCR and SEER, 2008-2012

13. Gliomas
• 1985 : Epidermal growth factor receptor (EGFR) gene
amplification in glioblastoma
• Subsequent discoveries :
• Phosphatase and tensin homolog (PTEN) gene
• Mutations in the TP53 gene
• BRAF fusion
• MGMT gene
• IDH mutations

14. Molecular markers: Glioma
• 1p/19q co-deletion in oligodendroglial tumors
• Mutations in the IDH1/2 genes in diffuse gliomas
• Hypermethylation of the MGMT gene promoter in
glioblastomas
• Alterations in the EGFR and PTEN genes, and 10q deletions
in GBMs
• BRAF alterations in pilocytic astrocytomas
MGMT: O6-methylguanine DNA methyltransferase ;, BRAF :v-raf murine sarcoma viral oncogene
homologe B1, IDH: isocitrate dehydrogenase; PTEN: Phosphatase and tensin homolog

15. BRAF, v-raf murine sarcoma viral oncogene homolog B1 gene; CDKN2A/B, cyclin-dependent kinase inhibitors 2A and 2B genes; EGFR, epidermal
growth factor receptor gene; GBM, glioblastoma multiforme; IDH, isocitrate dehydrogenase gene; mut., mutation; PTEN, phosphatase and tensin
homolog gene; TP53, tumor protein p53 gene
Molecular Diagnostics of Gliomas—Nikiforova & Hamilton; Arch Pathol Lab Med—Vol 135, May 2011

16. Gliomas
1. 1p/19q CODELETION:
• Loss of the short arm of chromosome 1 (1p), along with the long
arm of chromosome 19 (19q); "genetic signature" of
oligodendrogliomas
• Early genetic event in oligodendroglial tumorigenesis
• 80% to 90% in oligodendrogliomas (WHO grade II)
• 60% in anaplastic oligodendrogliomas (WHO grade III)
• 30% to 50% in oligoastrocytomas
• Partial loss of chromosome 1p in oligodendrogliomas has an
opposite prognostic significance when compared with tumors
that have a complete 1p/19q loss
• Almost all oligodendrogliomas with a 1p/19q codeletion are also
positive for IDH1 or IDH2 mutations

17. Gliomas
• The first allele is lost (1st Hit) due to an imbalanced reciprocal translocation between
chromosomes 1 and 19
• The second allele is disrupted (2nd Hit) by a somatic mutation capable of inhibiting protein
function

18. Gliomas
1. 1p/19q CODELETION:
• The CIC gene is a tumor suppressor gene present in the Chr 19
• Encodes for protein capicua homolog
• Member of the high mobility group (HMG)-box superfamily of
transcriptional repressors
• Loss of CIC gene results in loss of transcription repressor function

19. Gliomas
1. 1p/19q CODELETION:
• The status of the 1p/19q loci detected by:
• FISH
• PCR
• Loss of heterozygosity (LOH) analysis or virtual karyotyping
• Comparative genomic hybridization array
• Single nucleotide polymorphism array
• Cairncross et al.: (1998) : better response to procarbazine-
lomustine-vincristine chemotherapy and a longer survival in
patients with anaplastic oligodendroglioma
• Co-deletions (ie, 9p or 10q loss) may lead to poor outcome
independent of the 1p/19q status

20. Gliomas
2. IDH1 AND IDH2 MUTATIONS
• Mutations in the IDH1 gene were discovered in 2008 during a
genome-wide analysis of 22 glioblastomas as a part of the Cancer
Genome Atlas Project
• Presence of the mutation is associated with young age, a
secondary-type GBM, and increased overall survival
• 60% to 90% of secondary glioblastomas that developed from
lower-grade tumors
• IDH1 mutations are rare in primary GBMs and are completely
absent in pilocytic astrocytomas
• Mutations in IDH2 gene were detected in a smaller proportion of
gliomas (5%), mostly in oligodendroglial tumors

21. Gliomas
HIF1: hypoxia inducible factor 1; NADP: nicotinamide adenine dinucleotide phosphate; NADPH: reduced nicotinamide adenine
dinucleotide phosphate; wt, wild type

22. Gliomas
2. IDH1 AND IDH2 MUTATIONS
• Sanger sequencing analysis: most commonly used method for
detection of IDH1 and IDH2 mutations. It allows for detection of
all mutational variants
• Pyrosequencing : better sensitivity than Sanger sequencing
• Real-time PCR amplification: fast, less laborious, and more
sensitive; allows detection of as little as 10% mutant alleles or
20% of cells with mutations in a background of normal DNA
• Immunohistochemistry: monoclonal antibodies for detection of
IDH1 R132H mutation. Convenient detection of mutations in
tissue sections. IHC will miss approximately 10% of gliomas
carrying less-common mutations of IDH1 and all of the IDH2
mutations

23. Gliomas
Primary glioblastoma (A-C);
Secondary glioblastoma (D-F)
EGFR (A, D); p53 (B, E); IDH-1 (C, F)

24. Gliomas
3. MGMT METHYLATION :
• The MGMT gene is located at chromosome 10q26 and encodes
for a DNA repair protein
• Epigenetic silencing of this gene by promoter hypermethylation
leads to reduced expression of the MGMT protein
• MGMT gene silencing improves survival in patients with
glioblastoma who are treated concurrently with alkylating drug
temozolomide and radiation therapy
• Prognostic and predictive marker
• Hegi and colleagues (2005): reported that 49% of patients with
glioblastoma and methylated MGMT were alive at 2 years after
treatment with temozolomide and radiotherapy, as compared
with 15% of patients with unmethylated MGMT
MGMT: Methylguanine-DNA-methyltransferase

25. Gliomas
3. MGMT METHYLATION :
• Most of the methods for MGMT analysis are based on evaluation
of the methylation status of the ‘CG island’ of the MGMT gene
• Methylation-specific PCR (MSP) : methylation status at 6 to 9
CpGs
• Real-time PCR
• Methylation-specific Pyrosequencing
• IHC: assessment of MGMT methylation by IHC has failed to
correlate with disease outcome
CG : Cytosine/Guanine

26. Gliomas
4. BRAF/KIAA1549 FUSION :
• Part of the mitogen-activated protein kinase (MAPK) pathway
• Serine/threonine kinase, modulates cell proliferation and survival
• First BRAF mutation reported in papillary thyroid carcinomas
• In gliomas: BRAF activation is by gene duplication or point
mutation
• Fusion between the KIAA1549 and BRAF genes
• Identified in 60% to 80% of pilocytic astrocytomas
• Rare in diffuse astrocytic gliomas
• Prognostic significance is still under investigation
• RAF inhibitors (vemurafenib and dabrafenib)
• Interphase FISH: currently the best method for testing for this
fusion
• IHC : anti-BRAF V600E (VE1) antibody

27. Gliomas
5. EGFR AND PTEN ALTERATIONS:
• Cell surface receptors for Endothelial growth factors
• EGFR affects cell proliferation and growth through the activation
of downstream effector molecules in the MAPK and PI3K-AKT
pathways
• EGFR gene : located on chromosome 7p12
• Activation of EGFR signaling through gene amplification or
mutations is found in about 30% to 40% of primary glioblastomas
• Mutant EGFR: characterized by a deletion of 267 amino acids in
the extracellular domain of the EGFR protein
• Truncated protein: EGFRvIII receptor : lacks an extracellular
domain but remains constitutively activated
• Detection of either EGFR amplification or EGFRvIII is indicative of
high-grade glioma and can be used diagnostically

28. Gliomas
5. EGFR AND PTEN ALTERATIONS:
• Attractive target for new therapies in gliomas
• anti-EGFR tyrosine kinase inhibitors
• anti-EGFRvIII vaccine: addition of vaccine to radiation and
chemotherapy resulted in increased overall survival*
• EGFR amplification: FISH
• EGFRvIII analysis: performed by RT-PCR amplification
• Phosphatase and tensin homolog (PTEN) : tumor suppressor
gene located on the long arm of chromosome 10
• Counteracts one of the most critical cancer-promoting pathways,
the PI3K-AKT signaling pathway
• Genetic alterations: LOH at 10q frequently found in high-grade
gliomas (15-40%)
• Poor prognostic marker for anaplastic astrocytomas and
glioblastoma
• Detected in FFPE tissue by LOH analysis or FISH
*Heimberger AB, Sampson JH. The PEPvIII-KLH (CDX-110) vaccine in glioblastoma multiforme patients. Expert Opin Biol Ther. 2009;9(8):1087–1098. 84. Yoshimoto K, Dang J, Zhu S, et al.
Development of a real-time RT-PCR assay for detecting EGFRvIII in glioblastoma samples. Clin Cancer Res. 2008; 14(2):488–493

29. Medulloblastoma

30. Medulloblastomas
• Second most frequent BT in children after pilocytic astrocytoma
• First decade of life, second peak in the early 20s
• Genetic tumor syndrome: Turcot syndrome, Gorlin syndrome
• Embryonal tumor of the brain, analogous to Wilms tumor of the
kidney
• Origin: stem cells located in the subependymal matrix and the
external granular layer (EGL) of the cerebellum
• Medulloblastomas are tumors of the cerebellum, arising more
frequently in the midline, especially in the posterior vermis,
adjacent to the roof of the fourth ventricle
Medulloblastoma: molecular pathways and histopathological classifcation ; Anna Borowska, Jarosław Jóźwiak ; Arch Med Sci 2016; 12, 3: 659–666

31. Medulloblastomas
• Molecular pathogenesis:
• Previously, thought to represent a subset of primitive
neuroectodermal tumor (PNET) of the posterior fossa
• Gene expression profiling: distinct molecular profile and are distinct
from other PNET tumors
• Five histological subtypes:
1. Classical type (CMB)
2. Desmoplastic/nodular type (DN),
3. Medulloblastoma with extensive nodularity (MBEN),
4. Anaplastic type
5. Large cell Medulloblastoma (LC)
• Four molecular subgroups:
1. Wnt subgroup
2. Sonic hedgehog subgroup
3. Group 3
4. Group 4

32. Medulloblastomas
1. WNT subgroup:
• The Wnt/β-catenin pathway participates in the control of
vertebrate development
• Rarest subgroup of medulloblastoma, accounting for 11%
• Patients with Turcot syndrome: predisposition to Wnt MB
• Germline mutation of Apc gene
• Thought to arise from ‘mossy-fiber neuron precursors’, involved
in the formation of synapses in the developing cerebellum

33. Medulloblastomas
1. WNT subgroup:
*DSV: Disheveled
LRP: Low density lipoprotein receptor-related protein 1

34. Medulloblastomas
1. WNT subgroup:
• Includes mainly classic MB
• Large cell/anaplastic MB (good prognosis)
• Monosomy of chromosome 6 is present in about 100% of
Wnt tumors
• Overall excellent long term prognosis (90% 5 year survival
rate)

35. Medulloblastomas
1. WNT subgroup:
• IHC: monoclonal antibodies against the C-terminal domain of β-
catenin
• CTNNB1 (β-catenin encoding gene) mutation analysis by direct
gene sequencing
• Cantharidin and norcantharidin: drugs on trial against Wnt
associated medulloblastoma

36. (A) Classic MB with nuclear
β-catenin immunostaining
(B) Nodular MB with cytoplasmic β-
catenin immunostaining
(C) Anaplastic MB with cytoplasmic
β-catenin immunostaining

37. Medulloblastomas
2. Shh Medulloblastomas
• Account for 28% of all medulloblastomas
• Intermediate prognosis
• Dichotomous age distribution: common in both children
(<4 years) and adults (>16 years)
• Gorlin syndrome : germline mutations in PTCH gene*
• Sonic hedgehog (Shh) pathway: plays a key role in normal
cerebellar development, induces proliferation of neuronal
precursor cells in the developing cerebellum and other
tissues
• Normal conditions: The Shh ligand is secreted by Purkinje
neurons and promotes formation of the external germinal
layer in the cerebellum
PTCH: patched 1

38. Medulloblastomas
2. Shh Medulloblastomas
GLI: glioblastoma family protein

39. Medulloblastomas
2. Shh Medulloblastomas
• Molecular analysis of sporadic medulloblastomas commonly
shows Patched-1 (PTCH1) mutations
• Desmoplastic/nodular and MBEN are almost exclusively
associated with Shh pathway activation
• IHC: GLI1, and GAB1 have been proposed
• Hh pathway inhibitor: Cyclopamine, Vismodegib, Saridegib
• SMO inhibitors: SANT1–SANT4
• Arsenic compounds: targets GLI1
SFRP1: secreted frizzled related protein 1; GLI1: glioblastoma family protein; GAB1: GRB2-associated-binding protein 1

40. Medulloblastomas
3. Group 3 Medulloblastomas
• 28% of all medulloblastomas
• Associated with the worst prognosis of all the subgroups and
are frequently metastatic
• Predominantly found in infants/children
• Relatively little is known about the molecular pathogenesis
• Associated with MYC amplification
• Further categorized in to 3α and 3β, depending on MYC
expression
• 3α – tumors: increased MYC expression and worse prognosis
• 3β – tumors: normal MYC expression and better prognosis
• Mostly associated with classic or large cell/anaplastic
morphology
• Detected by transcriptional profiling, although IHC for NPR3*
has been proposed
*NPR3: Natriuretic peptide receptor

41. Medulloblastomas
4. Group 4 Medulloblastomas
• Most common “typical” subgroup of medulloblastoma,
accounting for around 34%
• Rarely affect infants (0–3 years) and mainly affect children,
with a peak age of 10 years
• Intermediate prognosis
• Classic histology
• Associated with isochromosome 17q (2/3rd cases)
• Associated with CDK6 and MYCN amplification but minimal
MYC over-expression
• Chromosome X loss is seen in 80% of females

42. Medulloblastomas
4. Group 4 Medulloblastomas
• Currently detected by gene expression profiling
• Immunohistochemistry for KCNA* has been proposed
*Potassium Voltage-Gated Channel Subfamily A

43. Ctnnb: catenin b1; APC: adenomatous polyposis coli; LC: Large cell; A: anaplastic; DN: diffuse nodular

44. Ependymoma

45. Ependymal Tumors
 Third most common pediatric brain tumors
 50% of cases arising in children under 5 years of age
 Ependymal neuroepithelium of the ventricles and spinal
canal
 Occur in three distinct locations:
 Supratentorial brain comprising the cerebral hemispheres
 Brain stem and cerebellum
 Spinal cord
 Pediatric: Intracranial, cerebellum and brain stem
 Adult: Spinal cord

46. Ependymal Tumors
1. Myxopapillary ependymoma Grade I
2. Subependymoma Grade I
3. Ependymoma Grade II
1. Cellular
2. Papillary
3. Clear cell
4. Tanycytic
4. Anaplastic ependymoma Grade III

47. Ependymal Tumors
1. Cytogenetic abnormalities
2. Molecular genetic abberations
3. Epigenetic modifications
4. Gene expression profiling studies

48. *Taylor MD, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of ependymoma [J]. Cancer Cell, 2005,8 (4):323-335
CDKN2A: cyclin-dependent kinase Inhibitor 2A

49. Ependymal Tumors
2. Molecular Genetic Aberrations
 Taylor et al*, aCGH profiles of 103 ependymomas, three
molecularly distinct subtypes of ependymomas depending on
tumor location:
1. Supratentorial ependymomas : CDKN2A deletion in >90%
cases, poor prognosis
2. Spinal tumors: Deletion of chromosome 22q12,
3. Posterior fossa ependymomas : chromosome 1q gain, good
prognosis
*Taylor MD, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of ependymoma [J]. Cancer Cell, 2005,8
(4):323-335

50. Ependymal Tumors
2. Molecular Genetic Aberrations
 RELA fusion positive ependymomas:
 Subset of supratentorial ependymomas
 Fusion between C11orf95, a gene with unknown function, and
RELA gene on Chr 11q13
 RELA encodes RelA (p65), protein which interacts with IκB and
p50 in the central signaling complex in the NF-κB pathway
 Amenable to targeted therapy
Supratentorial ependymomas of childhood carry C11orf95–RELA fusions leading to pathological activation of the NF-κB signaling pathway: Acta
Neuropathol (2014) 127:609–611
RELA: v-rel avian reticuloendotheliosis viral oncogene homolog A

51. Ependymal Tumors
2. Molecular Genetic Aberrations
 RELA fusion positive ependymomas:
*NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) ; IKK: IĸB kinase
RELA Fusion gene protein

52. Ependymal Tumors
3. Epigenetics:
 Methylation status of the hypermethylated in cancer 1 (HIC-1)
putative tumor suppressor gene: downregulation in 81% of
cases, correlated with non-spinal localization and pediatric age
 The RAS association domain family 1 isoform A (RASSF1A) gene:
silenced by methylation in 86% of ependymoma, results in loss
of cell cycle control, enhanced genetic instability and cell
motility, and resistance to K-Ras and TNF-α induced apoptosis

53. Ependymal Tumors
4. Gene expression profiling:
 112 abnormally expressed genes* in ependymoma
 WNT5A, TP53 homologue, TP63, ZIC1, VEGF and
Fibronectin1
 Cell cycle, proliferation, adhesion, and extracellular matrix
regualtion
*Suarez Merino B, Hubank M, Revesz T, et al. Microarray analysis of pediatric ependymoma identifies a cluster of 112 candidate genes including four
transcripts at 22q12.1 -q13.3 [J]. Neuro Oncol, 2005,7(1):20-31
**Taylor MD, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of ependymoma [J]. Cancer Cell, 2005,8 (4):323-335

54. Meningioma

55. Meningioma
• Meningiomas are mostly benign, slow-growing tumors of the
CNS
• Most common CNS tumor in adults
• Originate from Arachnoidal cap cells
• Annual incidence of meningiomas is 2.3 per 100,000
• Peaks in the 7th decade of life
• Associated risk factors:
• Deletions of the neurofbromatosis Type 2 (NF2) gene
• Ionizing radiation

58. Meningioma
• Benign meningiomas are slow growing and have a 5-
year recurrence rate of 5% following gross-total
resection
• Atypical meningiomas have 5-year recurrence rate of
40%
• Anaplastic meningiomas have recurrence rates of up to
80%
• Surgical resection and radiotherapy, mainstay
treatment

59. Meningioma
• Cytogenetic abnormality:
• Monosomy 22 is the most frequent genetic abnormality
• Association between the long arm of chromosome 22 (22q)
and meningiomas was first studied in patients with NF2
• Bilateral vestibular schwannomas, multiple meningiomas,
and other CNS tumors
• Allelic losses in 22q12.2: Nearly all NF2-associated
meningiomas, and 70% of sporadic meningiomas
• NF2 gene encodes the tumor suppressor merlin, critical role
in controlling cell growth and motility
NF2: Neurofibromatosis 2

60. Schematic diagram of merlin's role in tumourigenesis.
C. O. Hanemann Brain 2008;131:606-615

61. Meningioma
• Cytogenetic abnormality:
NDGR2: N-myc downregulated gene family

62. Meningioma
• Cytogenetic abnormality:
• Chr 1p deletions comprise the second most common
chromosomal abnormality
• Found in:
• 13%–26% of Grade I
• 40%–76% of Grade II
• 70%–100% of Grade III
• Loss of 1p is also associated with a 30% recurrence rate

63. Meningioma
• Sex steroids:
• The incidence of meningiomas is more than 2-fold
greater in women than in men
• Increased growth during pregnancy and the luteal phase
of the menstrual cycle
• Expression of the progesterone receptor is most
frequently observed
• Progesterone receptor is expressed in 81% of women
and 40% of men with meningiomas
• Expression is highest in benign meningiomas (50%–80%)
• PR status can help to describe the biological behavior of
meningiomas

65. CNS
Lymphomas

66. Primary CNS lymphoma
• Accounts for less than 5% of all primary brain tumors
• Lymphoma occurring in the brain, leptomeninges, spinal cord, or
eyes without evidence of lymphoma outside the CNS
• Majority are high-grade B-cell lymphomas
• 95%-98% diagnosed as high-grade DLBCL
• 05% of cases include Burkitt, Burkitt-like, and lymphoblastic B-cell
lymphomas as well as T-cell lymphomas
• Patients with AIDS develop PCNSL at a rate 3600-fold
higher than the general population and have a lifetime risk of CNS
lymphoma that approaches 20%

67. Primary CNS lymphoma
• Age group: 60 yrs
• Intracranial mass lesion, 70% cases are supratentorial
• Basal ganglia, the corpus callosum, and/or the periventricular
subependymal tissues
• Periventricular location, facilitating leptomeningeal seeding
• Extend across the corpus callosum and involve both cerebral
hemispheres

68. Primary CNS lymphoma
• Pathogenesis :
• Gain on chromosome 12
• EBV
• Chemokines
• Protooncogene mutation
• Ectopic expression of Interleukin-4
• Promoter hypermethylation of the CDKN2A gene
• STAT6 overexpression
• Unfolded protein response pathway
• Somatic mutations in Ig variable region genes
• Allelic deletions of the long arm of chromosome 6

69. Primary CNS lymphoma
• Gain on chromosome 12 :
• Comparative genomic hybridization
• Most frequent alteration
• Gain in a region of 12q
• MDM2, CDK4, and GLI1 overexpression

70. Primary CNS lymphoma
• EBV:
• Immunocompromised individuals
• Proliferation of EBV infected B-cells is usually suppressed by
normal T-cell immunity
• EBV infected clone may progress to malignant lymphoma
• EBV extracted from the CSF via PCR

71. Primary CNS lymphoma
• Chemokines:
• Class of molecules that regulate the trafficking of leukocytes as
well as their proliferation and adhesion
• BCA1 (CXCL13) : expressed at significant levels in PCNSL tumors
• Promotes B-cell homing to secondary lymphoid organs
• Helicobacter pylori–induced MALTomas as well as in gastric
lymphoma
BCA1: B-cell attracting chemokine1

72. Primary CNS lymphoma
• Protooncogene mutation:
• Somatic mutation of PIM1 and MYC oncogene
• High level of expression of PIM1 and MYC proteins
• Ectopic expression of Interleukin-4:
• Interleukin4 is not expressed in the vasculature of normal brain
• Expression by tumor associated endothelia in PCNSL
• May contribute to the angiotropic growth pattern of lymphoma
cells within the CNS

73. Primary CNS lymphoma
• Hypermethylation of the CDKN2A gene:
• Established molecular event
• Produces p14ARF
CDKN2A: cyclin-dependent kinase Inhibitor 2A
HDM2: human double minute 2 (HDM2)

74. WHO 2007

75. WHO 2007

76. WHO 2016

77. WHO 2016

78. Summary
• First impression is not the last impression
• Not only a morphological diagnosis, but also molecular
data
• Prognosis and response to treatment
• 1p/19q assessment, IHC for IDH1 and β-catenin*
The Molecular Pathology of Primary Brain Tumors; David S. Hersh et al, Pathol Case Rev 2013;18: 210-220

79. Thank You