“Some Like It Hot: A Curious Case of Non Malignant CNS Lymphoma” Terrel Sanders, MD March 23rd, 2018 UCSD HIV & Global Health Rounds

2. AVRC Grand Rounds:
“Some Like It Hot: A Curious Case of Non Malignant CNS
Lymphoma”
Terrel Sanders, MD
LT, MC, USN
23-MAR-2018

3. DoD DISCLAIMER
The views expressed herein and those of the author
and do not purport to reflect the position of the
Department of Defense, United States Navy, nor
Naval Medical Center San Diego.

4. CASE PRESENTATION
HISTORY OF PRESENT ILLNESS:
• 51-year-old white treatment experienced male with HIV/AIDS
and medical noncompliance brought in on 5150
• Roommate called police to report that the patient was
repeating "playing with fire" and leaving the gas stove burning
unattended
• Patient insists he was not playing with fire and that he was
simply using the gas burner at his apartment for warmth

5. HPI (cont)
• Prior admission apprx 1.5yrs ago: May 2016 due PJP required
intubation improving clinically according to his outpatient
follow up appt 16May2016 and scheduled to return to clinic in
3-4 weeks, however he was lost to follow up
• At time of current admission, he states that he has not taken
his ARVs for at least the past few months, but cannot specify
exactly when he stopped
• Last documented medication refill 16Oct2017 was for Septra,
Fluconazole, Levofloxacin and Nystatin
– last filled ARV meds on 07May2016

6. HPI (cont)
REVIEW OF SYSTEMS:
• He denies any recent or current illness, prolonged fevers,
chills, night sweats, rigors, chest pain, dyspnea, cough,
pharyngitis, dysphagia/odynophagia, abdominal pain,
nausea/vomiting, diarrhea, or dysuria or difficulty voiding.
• Overall the patient states he is at his baseline health but
weight loss; he denies pain or discomfort but does endorse
difficulty falling asleep, and decreased appetite/thirst for
approximately 6 months
• Denies feelings of confusion, difficulty performing ADLs,
memory/concentration impairment, but he reports recently
feeling “listless”

7. PAST MEDICAL HISTORY
• HIV [NOV1988]; multiple resistances on prior genotype testing
• AIDS:
– Viral Load 731993, CD4+ 27 [16May2016]
– Viral Load 356873, CD4+ 384 [04Apr2012]
– PJP pneumonia, required intubation [May2016]
– Oral candidiasis/thrush [May2016]
• Late Latent Syphilis s/p Bicillin 2.4Million Units per wk x 3 doses
[May 2004]
• H/o Herpes Zoster
• Substance Abuse Disorder (alcohol, opiates, benzodiazapines)

8. PMH (CONT)
• PAST SURGICAL HISTORY:
– None
• SOCIAL HISTORY:
– Denies rec drug use. Per chart review, has had (+)UDS for codeine and
morphine. Smoking quit 1988, 15PYH;
– UDS positive for morphine and codeine, denies use.
– Denies all other drugs;
– Not currently working. Spends most of his time at home where he
"doesn't do much of anything."
• FAMILY HISTORY:
– Noncontributory
• ALLERGIES:
– NKDA
• MEDICATIONS:
– Denies

9. PHYSICAL EXAM (cont)
• VS: BP 103/68| HR 81 | RR 16| SpO2 95%RA | T 97.8F
• GEN: Ill-appearing cachectic male, laying in bed in NAD.
Disheveled,
• HEENT: NCAT, EMOI; temporal wasting, extensive oral
thrush (entire tongue surface, bilateral buccal mucosa)
• PULM: CTAB, no wheezes; coarse breath sounds
bilateral lung bases, right worse than left
• CV: RRR, no m/r/g.
• ABD: Flat, soft, NT, ND, NABS
• EXT: Trace edema b/l, no calf tenderness
• VASC: 2+ pulses throughout, cap refill <2s

10. PHYSICAL EXAM (cont)
• NEURO: AOx3, CN 2-12 intact; responding appropriately
to questions. Strength 5/5 throughout, sensation to light
touch intact. Finger to nose intact. Gait pattern normal,
but slowed beyond expected for age.
• PSYCH: Guarded on exam, but no psychomotor agitation,
evidence of SI/HI/AVH. Psychiatry performed MOCA
(15/30), and recommended continued 5150.
• DERM: Multiple red crusted lesions on LE b/l, 3-5mm.
Right temporal scalp lesion c/w kerion 3x4cm

11. DIAGNOSTIC STUDIES (on admission)
• CBC
– WBC 3.1 Hb 12.6 Hct 35.9 PLT 177
• CHEM PANEL:
– Na 127 |K 3.3 | Cl 86 | HCO3- 27
– BUN 15 |Cr 0.7
– AG: 14 | Ca 8.9 | Mg 2.4 | Ph 3.0
• TSH: WNL
• ETOH, APAP levels: NEG

12. IMAGING
PA/LAT CXR 11/21/17:
Nodular density within the
left upper and left lower
lobes which are
superimposed on a
background of diffuse
reticular interstitial
markings.

13. 11/21/17 CT CHEST W/O CONTRAST
No segmental or subsegmental
pulmonary embolus; however, the
pulmonary artery is enlarged to a
diameter of 3.4 cm and the
interventricular septum is
straightened.
Consolidation within the superior
segment left lower lobe with
surrounding ground-glass
attenuation.
Ground-glass attenuation is
present diffusely within the
posterior lungs. This may be seen
in PCP pneumonia

14. HIV/AIDS – ALTERED MENTAL STATUS
MASS LESION OTHER
INFECTIONS
OTHER
CNS TOXOPLASMOSIS
PRIMARY CNS
LYMPHOMA
BRAIN ABSCESS
CRYPTOCOCCOMA
METASTATIC TUMORS
BACTERIAL MENINGITIS
CRYPTO MENIGITIS
TB MENINGITIS
NEUROSYPHILIS
HSV ENCEPHALITIS
HAND/AIDS DEMENTIA
PML
STROKES
SEIZURE D/O
METABOLIC
-HYPONATREMIA
-HYPOXIA
-HYPOGLYCEMIA
-UREMIA
-HEPATIC
ENCEPHALOPATHY

15. 11/21/17 CT HEAD W/O CONTRAST

16. No acute intracranial hemorrhage.
Subtle hypodensities within the left cerebellum,
splenium of the corpus callosum and subcortical
white matter of the left occipital lobe. This is a
nonspecific finding and may represent age-
indeterminate infarcts.
Soft tissue defects/irregularity about the frontal
convexity of the right scalp. Correlate with clinical
exam findings.
11/21/17 CT HEAD W/O CONTRAST

17. 11/22/17
• HIV RNA PCR VL - 408,785 copies
• CRYPTO SP AG NEG (serum)
• GC/C PROBE NEG
• UCX: 25K CFU/ML MIXED GP GROWTH Staph epi >100K (S/Vanc,
Macrobid)
• QUANT GOLD NEG
• TOXOPLASMA DNA PCR NEG
• BRONCH BAL (RML/LINGULA)–
– Candida albicans ... Quantity: 200 CFU/Ml
– Haemophilus influenzae, Beta-lactamase Positive ... Quantity: 10,000
CFU/mL
– A Galactomanan NEG
– NONGYN CYTO – No malignant cells; Candidal elements and PJP
(RML/LINGULA BAL)

18. 11/23/17 CT CHEST W/O CONTRAST

19. Multifocal nodular consolidation throughout the lungs in a
bronchovascular distribution. There is additional multifocal
bilateral ground-glass opacity. This is favored to represent
infection. However, given the patient's reported clinical history,
other entities to include Kaposi sarcoma or lymphoma could
have this appearance.
Pneumomediastinum with small amount of pneumopericardium,
which extends from the diaphragmatic hiatus to the thoracic
inlet.
Coronary artery disease, moderate to severe, greater than
expected for age.

20. 11/23/17
• EBV PANEL: EBV VCA IGG +/VCA IGM -/EBV DNA -/EBV EA +/HETERO AB -
• C. IMMITIS IGG/IGM NEG
• HISTOPLAMSA Ag NEG
• SYPHILIS SCREEN: T. PALLIDUM IGG + (HIGH)/T. PALLIDUM AB
REACTIVE/RPR NON-REACTIVE
11/24:
• RESP ASPIRATE MTB PCR: Negative
• AFB Smear: Negative, Culture pending
• CSF PROTEIN 65.4
• WBC 13 (PMNS-14%; L-70%, M-14% Macro-2%)
• RBC 581
• JCV DNA PCR: Negative
11/25:
• -Induced Sputum AFB Smear: Negative, Culture pending

21. 11/24/17 MRI BRAIN W/ W/O CONTRAST

23. Constellation of findings strongly favored to represent neoplastic
etiology, namely CNS lymphoma given periventricular (ependymal
/ subependymal) location with enhancement and restricted
diffusion as well as increased attenuation on the comparison
noncontrast head cm 11/21/2017 (implies hypercellularity) …
Primary neuroepithelial CNS neoplasm not excluded but given the
clinical history, and overall appearance, lymphoproliferative
process is the lead differential consideration. PML would generally
not be favored as this entity typically does not enhance and is not
hyperdense on CT as demonstrated in this case…
Right external capsule/putamen lesion with restricted diffusion
without enhancement. Additional punctate focus of restricted
diffusions without enhancement within the right occipital lobe. It
is unclear whether these could be cytotoxic due to sequela of
cerebral ischemia, versus separate foci of lymphoproliferative
deposits.

24. BRAIN MASS IN HIV/AIDS
DIFFERENTIAL DIAGNOSES
• CNS TOXOPLASMOSIS
• PRIMARY CNS LYMPHOMA
• PRIMARY/METASTATIC TUMORS
• BACTERIAL BRAIN ABSCESS
• NOCARDIA BRAIN ABSCESS
• FUNGAL BRAIN ABSCESS
• CRYPTOCOCCOMA
• TUBERCULOMA

25. 11/27:
• CSF (IR-guided):
– WBC 54, RBC 87500, Prot 270, GLC 56,
– CSF Cx: NEG
– India Ink: negative
– Biofire Meningitis/Encephalitis – Negative (includes H. influenza,
CMV, HSV1/2, HHS6, VZV, Crypto)
– AFB smear+Cx: QNS
– MTB PCR: negative
– Cocci complement fixation: Quantity not-sufficient; negative by
immunodiffusion
– Fungal Cx: pending
– Toxoplasma gondii DNA PCR QN: negative
– EBV DNA PCR QL: Positive
– TGONDI PCR Negative
• CSF Cytology - CEREBROSPINAL FLUID: SATISFACTORY FOR
INTERPRETATION. NEGATIVE FOR MALIGNANCY.

26. • EPIDEMIOLOGY
– INCIDENCE/PREVALENCE
• PATHOGENESIS
• DIAGNOSTICS
• MANAGEMENT
– ROLE OF ANTIRETROVIRAL THERAPY
– ROLE FOR CHEMOTHERAPY
• PROGNOSIS

27. WHO CLASSIFICATION: MORPHOLOGIC CATEGORIES
OF HIV-ASSOCIATED LYMPHOMAS
• Lymphomas also occurring in immunocompetent patients
– Burkitt's lymphoma (BL)
– Diffuse large B-cell lymphoma (DLBCL)
• Centroblastic (CB)
• Immunoblastic (IB)
• Rare - Extranodal marginal zone B-cell lymphoma of MALT-type
• Lymphomas occurring primarily in HIV-positive patients
– Primary effusion lymphoma (PEL) - rare
– Plasmablastic lymphoma of the oral cavity - very rare
– KSHV-associated extracavity lymphoma (not in WHO classification) - not defined
• Lymphomas occurring in other immunodeficiency states
– Polymorphic B-cell lymphoma (PT-LPD-like)
WHO 2016 Classification on CNS Tumors

28. AIDS-RELATED LYMPHOMAS (ARL)
• HIV-related Burkitt lymphoma
• Diffuse Large B cell lymphoma
• Hodgkin’s lymphoma (HL)
• Primary effusion lymphoma (PEL)
• Plasmablastic lymphoma (PBL)
• Lymphoma arising in KSHV-associated multicentric Castleman’s disease
(MCD)
• Polymorphic B-cell lymphoma (PTLD-LIKE)
– Extremely rare; morphologically similar to solid organ transplant post
transplant lymphoproliferative disorder
Ceserman, Cancer Letter 2011
Chadburn et al 2013.

29. • EPIDEMIOLOGY
– INCIDENCE/PREVALENCE
• PATHOGENESIS
• DIAGNOSTICS
• MANAGEMENT
– ROLE OF ANTIRETROVIRAL THERAPY
– ROLE FOR CHEMOTHERAPY
• PROGNOSIS

30. Cancer Lett. 2011 Jun 28; 305(2): 163–174.

31. Cancer Lett. 2011 Jun 28; 305(2): 163–174.

32. • EPIDEMIOLOGY
– INCIDENCE/PREVALENCE
• PATHOGENESIS
• DIAGNOSTICS
• MANAGEMENT
– ROLE OF ANTIRETROVIRAL THERAPY
– ROLE FOR CHEMOTHERAPY
• PROGNOSIS

33. 12/1/17 MRI STEALTH

34. 12/1/17 MRI STEALTH

35. 12/1/17 MRI STEALTH

36. 12/5/17 Brain Biopsy Results
• The findings in aggregate are compatible with the diagnosis … Aids-related
polymorphic lymphoproliferative disorder is similar to polymorphic post-
transplant lymphoproliferative disorder; however, is much less common
accounting for <5% of HIV-associated lymphomas (WHO 2016). “
• Immunohistochemical stains highlight the malignant lymphoid proliferation
which is CD20+, PAX5+, kappa+(ish), CD30+, BCL2+, CD5-, CD10-, BCL6-, cyclin
D1-, and CD138-
• CD3 and CD5 highlight a sizeable subset of interspersed T-cells.
• HHV-8 and CMV immunostains are NEGATIVE.
• EBER(ish) is POSITIVE and highlights numerous cells. Ki-67 is positive in 30% of
cells.

37. • EPIDEMIOLOGY
– INCIDENCE/PREVALENCE
• DIAGNOSTICS
• PATHOGENESIS
• MANAGEMENT
– ROLE OF ANTIRETROVIRAL THERAPY
– ROLE FOR CHEMOTHERAPY
• PROGNOSIS

38. ECOG PERFORMANCE STATUS
GRADE
• 0- Fully active, able to carry on all pre-disease performance
without restriction
• 1- Restricted in physically strenuous activity but ambulatory
and able to carry out work of a light or sedentary nature,
e.g., light house work, office work
• 2- Ambulatory and capable of all selfcare but unable to carry
out any work activities; up and about more than 50% of
waking hours
• 3- Capable of only limited selfcare; confined to bed
or chair more than 50% of waking hours
• 4- Completely disabled; cannot carry on any selfcare; totally
confined to bed or chair
• 5- Dead

39. HAART and CHOP improve survival in AIDS-related
lymphoma
• AIM: Can you safely administer ART and chemotherapy simultaneously
• 72 patients with aggressive ARL from centres in Germany were stratified
into two groups according to the following criteria:
– CD4 cells <50/mL at diagnosis;
– WHO performance status ≥3
– previous AIDS-defining opportunistic infection.
• 48 patients were classified as standard risk
• 24 patients were classified as high-risk
• All patients continued to receive HAART during 3-weekly chemotherapy
with CHOP
Burton et al. 2006

40. • Standard Risk group: 79% achieved complete
remission
• Median survival: 47 months at f/u
• High Risk Group: 29% achieved complete
remission
• Median survival: 7.2 months
• **3 high risk pts did survive up to 3 yrs

41. 1/24/18 MRI BRAIN

43. Adverse trend of disease with large infiltrative mass right basal
ganglia and right parietal lobe… These lesions demonstrate
imaging characteristics similar to the initial lesions within the
posterior horn of the left lateral ventricle and splenium of
corpus callosum.
Given the clinical scenario, as well as interval improved
appearance of the lesions about the posterior horn of the left
lateral ventricle and splenium of the corpus in the face of
improving CD4 counts a superimposed element of immune
reconstitution inflammatory syndrome (IRIS) must be
considered.
Interval enlargement of the left lateral ventricle in the face of
mass effect causing mild leftward midline shift. Findings
worrisome for early trapping of left lateral ventricle.

44. Neurologic immune reconstitution
inflammatory syndrome
• NeuroIRIS is a recognized complication of combination
antiretroviral therapy1
• In a recent retrospective study of 461 patients started on
combination antiretroviral therapy2
– 7 patients (0.7%) developed NeuroIRIS
• Risk of IRIS appears to be high in patients whose CD4+ count
is below 50 cells/mL at the start of antiretroviral therapy3
1. Venkatraman et al. Neurology 2006
2. McCombe et al Neurology 2009
3. Muller et al Lancet Infect Dis 2010

45. • EPIDEMIOLOGY
– INCIDENCE/PREVALENCE
• DIAGNOSTICS
• PATHOGENESIS
• MANAGEMENT
– ROLE OF ANTIRETROVIRAL THERAPY
– ROLE FOR CHEMOTHERAPY
• PROGNOSIS

46. Prognostic significance of MYC, BCL2, and BCL6 rearrangements
in patients with diffuse large B-cell lymphoma treated with
cyclophosphamide, doxorubicin, vincristine, and prednisone
plus rituximab.
• AIM: The aim of this study was to investigate the frequency and prognostic
impact of BCL2, BCL6, and MYC rearrangements in (R-CHOP)-treated DLBCL
cases.
• DESIGN: Tissue microarrays were constructed from 239 cases of DLBCL, and
the expressions of CD10, BCL6, MUM1/IRF4, and BCL2 were evaluated by
immunohistochemistry.
• MYC, BCL2, and BCL6 rearrangements were investigated by interphase
fluorescence in situ hybridization on tissue microarrays.
• Survival analysis was constructed from 145 R-CHOP-treated patients.
Akvurek et al. Cancer 2012

47. • MYC, BCL2, and BCL6 rearrangements were detected in 14
(6%), 36 (15%), and 69 (29%) of 239 DLBCL patients
• Double or triple rearrangements were detected in 7 (3%) of
239 DLBCL cases.
– Of these, 4 had BCL2 and MYC, 2 had BCL6 and MYC, and
1 had BCL2, BCL6, and MYC rearrangements.
• BCL6 rearrangement also predicted significantly shorter
overall survival (P = .04), especially for the non-GC
phenotype (P = .03).
• BCL2 rearrangement had no prognostic impact on outcome.
Akvurek et al. Cancer 2012

48. BCL-6 Gene Mutations in Posttransplantation
Lymphoproliferative Disorders Predict Response to Therapy and
Clinical Outcome
• 57 PT-LPD lesions obtained from 36 solid organ transplant recipients for
the presence of mutations in the BCL-6 proto-oncogene
• BCL-6 gene mutations were identified in 44% of the specimens and in 44%
of the patients
– mutations were present in 43% of the polymorphic lesions
– mutations were present in 90% of the PT-LPDs diagnosed as non-Hodgkin's lymphoma
or multiple myeloma
• RESULTS: suggest BCL-6 gene structure is a reliable indicator for the
division of PT-LPDs into the biological categories
– hyperplasia – regress on immune reconstitution
– malignant lymphoma – requires aggressive chemotherapy
Ceserman et al. Blood 1998.

49. 1/29/18 INTERVAL MRI BRAIN

50. 1. Mild overall decreased size of the bilateral multifocal enhancing mass-
like lesions with surrounding vasogenic edema suggesting a positive
treatment response since 01/29/2018. Given the mass like appearance,
restricted diffusion, increased density on CT, abnormal choline elevation
and prominent surrounding vasogenic edema/capillary leakage these
findings are strongly suspected to represent a lymphoproliferative process,
in the spectrum of that recently biopsy proven.
2. However, given the worsening findings after initiation of highly active
anti-retroviral therapy (HAART) there may well be a component of
paradoxical CNS immune reconstitution inflammatory syndrome (IRIS)
associated with the probable CNS lymphoproliferative disease…
3. Intrinsic T1 hyperintense signal seen in the distribution of the multifocal
enhancing lesions are most consistent with laminar necrosis suggesting an
element of late subacute ischemia. In comparing with the abnormal MRA
these findings are raise concern for angiocentric lymphoproliferative
involvement.

51. BACK TO OUR PATIENT
• DISCHARGED 09FEB2018
– (ADMIT: 21NOV2017)
– LOS: 81 DAYS
• GROUP HOME
• RE-ADMITTED OSH LATE FEB2018,
– THEN TRANSFERRED TO NMCSD
• DISCHARGED TO SNF, ID FOLLOW UP PENDING

52. References
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2012 Jun 17. PubMed PMID:22706705.
• Cesarman E. Gammaherpesvirus and lymphoproliferative disorders inimmunocompromised patients. Cancer
Lett. 2011 Jun 28;305(2):163-74. doi:10.1016/j.canlet.2011.03.003. Epub 2011 Apr 13. Review. PubMed
PMID: 21493001;PubMed Central PMCID: PMC3742547.
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