Antonella Cingolani, MD

1
Changing pattern of primary cerebral lymphomas in
the HAART era

• Antonella Cingolani, MD
• Institute of Infectious Diseases, Catholic
  University
• Roma, Italy

2
Main challenges of PCNSL in the HAART era

• Epidemiologic trends

• Histologic and molecular pathogenesis

• Not invasive diagnosis
• Role of brain biopsy

• Response to therapy and survival

3
Sustained decline of HIV-death rate in the late
HAART era
Mocroft, Lancet 2003
4
Changing incidence of AIDS events in pts
receiving HAART
The Antiretroviral Therapy Cohort Collaboration
dArminio Monforte, Arch Intern Med 2005
5
Incidence of AIDS-lymphoma during HAART. EuroSIDA
Study Group
Kirk, Blood 2001
PBL from 0.83 (lt1995) to 0.04 cases/100PYF
(gt1999), plt0.001
6
Incidence rates of HIV-related NHL by period of
impact of HAART
International Collaboration on HIV and Cancer,
JNCI, 2000
7
Incidence rates of AIDS-related neurologic
disorders. (MACS data - Years 1990-1998)
Sacktor, Neurology, 2001
8
Incidence of individual CNS-D during
follow-up(dArminio Monforte, Ann Neurol, 2004)
10
Toxo
ADC
Crypto
PML
PBL
FBL
1
Incidence per 100 PYFU
0,1
0,01
1994
1995
1996
1997
1998
1999
2000
2001
Decline of incidence/year PBL 48, 95CI 39-59
9
Prevalence of main neurological disorders
stratified by ARV exposure, CD4 and viral load
Prevalence of HIV-associated neurological
disorders (2000-2004). Italian Registry
Investigative NeuroAIDS.
Prevalence of main neurological disorders ()
(1233 pts notified between January 2000 and
December 2004)
Larussa D et al., poster session, n 64
10
Main challenges of PCNSL in the HAART era

• Epidemiologic trends

• Histologic and molecular pathogenesis

• Not invasive diagnosis
• Role of brain biopsy

• Response to therapy and survival

11
Histogenesis and molecular pathogenesis of
AIDS-PBL
GC B-CELLS BCL-6 CD138-
PLASMACELLS BCL-6 CD138
pre-GC B-CELLS BCL-6
HOMING in the BRAIN
Carbone, Blood 2001, mod
PCNSL/IBPL
PCNSL/LNCCL
BCL-6 LMP-1 BCL-2
BCL-6 LMP-1 BCL-2
Molecular lesions of AIDS-NHL EBV BCL-6 Inf
ect. LMP-1 hhv-8 c-myc rearr. mut BL 30 - - 10
0 - 70 DLCL LNCCL 40 - - - 20 70
IBPL 90 - - - 70 PCNSL LNCCL 100 - - - -
70 IBPL 100 - - - 70 PEL 90 - 100 - - 7
0
Gaidano, Semin Oncol 2000, mod
Larocca, Blood 1998
12
No differences in pathologic spectrum of PBL
after early years of HAART
Levine, Blood 2000
13
Main challenges of PCNSL in the HAART era

• Epidemiologic trends

• Histologic and molecular pathogenesis

• Not invasive diagnosis
• Role of brain biopsy

• Response to therapy and survival

14
Poor survival and high morbility for brain biopsy
in AIDS-FBL
Survival probability according with baseline
factors
Antinori, Neurology, 2000
15
High diagnostic value of combinedTl-201-SPECT
and CSF EBV-DNA
Antinori, J Clin Oncol, 1999
16
1988-1995 Prevalence 16 Estimated PPV
90 1998-2002 Prevalence 4 Estimated PPV 67
1998-2002 Specificity 79 PPV 29
17
Reduced value of Tl-201-SPECT for PCNSL diagnosis
Giancola, AIDS Res Hum Retrovir, 2004
18
Main challenges of PCNSL in the HAART era

• Epidemiologic trends

• Histologic and molecular pathogenesis

• Not invasive diagnosis
• Role of brain biopsy

• Response to therapy and survival

19
GCVHD-AZTIL-2HAART for AIDS-PCNSL
Aboulafia, Clin Infect Dis 2002
20
Survival of AIDS PBL according with HAART
exposure.
21
Role of immune recovery on survival


Still alive after 6 and 4 years, respectively
(Hoffman, personal data).
Hoffmann, AIDS 2001
22
Role of specific PCNSL treatment
Newell, Cancer 2004
Hoffmann, AIDS 2001
Proportion of surviving
HAARTCT and/or RT
Cingolani, 12th CROI 2005
Only CT and/or RT
Only HAART
No tx
Days
Skiest, AIDS 2003
23
Is there a real impact of HAART on survival ?
P at log rank0.01
Cingolani, 12th CROI 2005
HAART post PCNSL
Newell, Cancer 2004
HAART pre PCNSL
never
Skiest, AIDS 2003
Hoffmann, AIDS 2001
24
Reasons of not significant improved survival a
still unfinished puzzle
Variable CNS penetration of HAART
Low efficacy of PCNSL tx
Persistent EBV burden
Cronic B cells stimulation
RT/CT toxicities
Increased EBV-infected cells during immune
reconstitution
Impaired EBV-specific immunologic control
Delayed diagnosis
25
Van Baarle, 2001
Van Baarle, 2002
26
2001
Increase of EBV-DNA by 1 log more HR 2.9 (95CI
1.7-4.8, plt0.001) for EBV-LPD
27
Van Baarle, 2002
28
EBV DNA load in CSF of patients with HIV-related
lymphoma and controls
P0.007
7
P0.006
6
5
EBV DNA log copies/mL
4
3
2
1
PCNSL n20
NHL n22
CNS-NHL n12
Controls n16
Bossolasco S et al., J Neurovirol 2002
29
P0.022
P0.004
P0.60
Epstein-Barr virus in monitoring the response to
therapy of AIDS- PCNSL.
Antinori, Ann Neurol 1999
Case WF EBERs BCL-6 LMP-1
EBV-DNA Response

(log10 copies/ml) baseline cha
nge CT CTRT after CT _________________
_________________________________________________
1 LNCCL - 5.0 -1.3 PR CR 2 LNCCL - 4
.7 -1.4 PR PR 3 LNCCL/IBPL 5.3 0.0 SD
PR 4 IBPL - 3.3 1.4 SD PR 5 IBPL - 3
.7 -0.4 SD PR 6 IBPL - 3.0 1.3 PD PD 7
IBPL - 3.3 0.7 PD SD 8 IBPL - 4.0 1.
3 PD ne 9 IBPL - 4.7 1.0 PD ne
30
2003
31
EBV-associated leiomyosarcoma in a HAART
responder HIV-infected patient previously
affected by EBV-associated primary central
nervous system lymphoma molecularly identical
tumour-associated EBV infection
Figure 1. The microphotograph shows that the
tumor is relatively monomorphous and
predominantly consist of large tumor cells
displaying a large non cleaved and
immunoblastic-plasmocitoid morphology (A). Tumor
cells show cytoplasmic membrane positivity for
CD20 (B). LMP-1 positivity is evident as
cytoplasmic staining in some large tumor cells
(C). All tumor cells display ISH nuclear
staining for EBERs (D).
Figure 2. The microphotograph shows that the
tumor is moderately cellular and composed of
elongate cells with eosinophilic cytoplasm and
elongate nuclei with several mitotic figures (A).
Neoplastic cells are Vimentine-positive (B) and
display LMP-1 cytoplasmic staining (C). The vast
majority of tumor cells display ISH nuclear
staining for EBERs (D).
Cingolani, 2005
32
Rationale low dose hydroxyurea eradicates
extrachromosomal DNA elements (drug resistance
genes, amplified c-myc, EBV-episome-4)
The Lancet, 2001
33
Conclusions

• A strong decline of incidence and prevalence of
  AIDS-PCNSL has been observed after the
  introduction of HAART

• No significant changes of the pathologic
  spectrum of the disease has been reported, even
  though on a limited number of studies

• A probable reduction of positive predictive value
  of criteria for non invasive diagnosis has been
  reported, opening the debate on new and probably
  stronger indication for brain biopsy

• Despite positive results in limited case reports,
  no substantial improvement of survival has been
  observed in larger and cohort studies.

• The reasons for that could probably be searched
  in the complex interaction between EBV infection
  of the tumor clone, specific EBV and HIV
  immunologic control and other variables not well
  controlled by the HAART itself, which are still
  unknown

34
Aknowledgments
Department of Infectious Diseases Catholic
University, Roma Andrea De Luca Adriana
Ammassari Giancarlo Scoppettuolo Roberto
Cauda Department of Pathology Luigi Maria
Larocca SR- San Raffaele Scientific
Institute Università Vita e Salute, Milan Paola
Cinque Simona Bossolasco Adriano Lazzarin
INMI L. Spallanzani, IRCCS, Roma Clinical
Department Lucia Alba Lucia Fratino Maria L
Giancola Dora Larussa Patrizia Lorenzini Andrea
Antinori Department of Epidemiology Diego
Serraino