Primary CNS Lymphoma

1
Primary CNS Lymphoma

• Hematology Grand Rounds
• February 17, 2006
• Tom Fong, MD

2
Case Presentation

• HPI 61 yo female with h/o HTN presents with new
  onset seizure, with shaking in both hands,
  confusion, and post-ictal combativeness. No
  focal weakness or numbness. In ED, found on
  brain MRI to have mass lesion in left
  parietooccipital region.

3
Case Presentation

• PMH HTN, asthma, depression
• PSH S/p TAH, CCK, appy
• Meds Nadolol, advair, zoloft
• Family Hx CAD, no malignancies
• Social Hx Married, works in factory, former
  smoker, social EtOH
• ROS Otherwise negative

4
Case Presentation

• Vitals afebrile, BP 140/80, HR 80
• Neuro exam Cranial nerves intact. Mental status
  exam with mild memory impairment and difficulty
  with spelling backwards. Speech normal. No
  focal motor or sensory deficits. Coordination
  and gait intact.
• Physical exam otherwise unremarkable.
• Labs CBC, CMP, LDH within normal limits.

5
Case Presentation

• Brain MRI 3.5 x 3.1 x 3.5 cm mass at left
  parietooccipital juncture and a second satellite
  lesion just lateral and inferior measuring 1.4 x
  1.2 x 1.3 cm
• Course After MRI findings, pt underwent biopsy
  of brain mass
• Path Diffuse large B cell lymphoma
• Staging PET - no distant disease, BM bx
  -negative, LP - cytology positive for lymphoma

6
Case Presentation

• Diagnosis Primary CNS lymphoma
• Course Treatment begun with high dose
  methotrexate-based regimen. Ommaya reservoir
  also placed for intrathecal chemotherapy.

7
Primary CNS Lymphoma (PCNSL) Epidemiology

• Once rare (1 of brain tumors in immunocompetent
  individuals), now becoming increasingly more
  common
• Incidence has risen dramatically in past few
  decades, as PCNSL now accounts for 4-7 of all
  newly diagnosed primary brain tumors
• Incidence has risen in the HIV/immunocompromised
  and also immunocompetent population
• Median age of onset 55 years in immunocompetent,
  incidence rises with age
• Greatest rise has occurred among the elderly

8
Sites of Disease Involvement

• Brain parenchyma is usual location (gt90)
• Usually solitary lesion (75), can be multifocal
• Mainly occur in supratentorial sites (75), but
  may also be infratentorial
• Tend to be periventricular in location
• Leptomeningeal disease may occur, but usually not
  without brain involvement
• Ocular only involvement in 10
• Primary spinal disease is rare (lt1 PCNSL)

9
Diagnosis

• History
• Focal neurologic deficit (i.e. hemiparesis,
  aphasia) present in gt50 of all patients with
  PCNSL
• Altered mental status (memory loss, confusion,
  etc.) found in 33 - may be insidious onset
• Headache, nausea (from increased ICP) in 33
• May present with new-onset seizure in lt10
• Blurred vision if ocular lymphoma is present
• Radiologic imaging
• Head CT detects most lesions (90)
• Brain MRI may detect lesions missed on CT

10
Radiologic Imaging Head CT

• Usually solitary, non-hemorrhagic lesion in deep
  white matter, near ventricles
• Lesion is isodense to hyperdense
• Surrounding edema is typically less profound than
  in metastatic brain lesions or gliomas

11
Radiologic Imaging Brain MRI

• Isointense to hypointense on T2-weighted images
• Enhances densely and homogenously with gadolinium
  contrast
• May also reveal leptomeningeal disease

12
Imaging Other considerations

• Features of mass lesion in brain that are
  suggestive of CNS lymphoma
• Periventricular distribution
• Ring enhancement
• Multiple lesions
• Less edema than expected for brain met or glioma
• Steroids can significantly alter appearance on
  imaging by decreasing tumor size, edema, and
  enhancement and preferably should be held prior
  to Dx if CNS lymphoma suspected

13
PCNSL Tissue diagnosis

• Can be made with LP cytology alone, though biopsy
  is often required for Dx
• Stereotactic biopsy is usually preferred
• Goal of surgery is to obtain a tissue diagnosis
  with minimal morbidity, without formal attempt at
  surgical resection
• Steroids can cause false negative biopsy results
  due to cytolytic effects, and should be held if
  suspected PCNSL on imaging

14
PCNSL Pathology

• Vasocentric neoplasm composed of dense,
  monoclonal proliferation of lymphocytes
• Infiltrative, usually extends beyond primary
  lesion
• Majority are diffuse large B cell or
  immunoblastic
• Immunohistochemistry can help establish clonality
  with kappa or lambda light chains, molecular
  markers (i.e. bcl-6, bcl-2)

15
PCNSL Staging

• Slit-lamp eye exam recommended if positive,
  consider XRT to orbit
• LP is recommended if positive, IT chemo
• CBC, LFTs, CXR, HIV test
• Extensive staging studies such as PET, CT of
  chest/abdomen/pelvis, BM biopsy are not routinely
  required, but may be considered if clinically
  indicated (i.e. B symptoms, etc.)

16
PCNSL Treatment

• No treatment median survival 1.5 mos
• Surgery alone median survival lt4 mos
• Radiation therapy (XRT) with steroids was
  historical mainstay of treatment median survival
  12 mos
• Tumors are highly radiosensitive, but responses
  brief, recurrence within months
• This is still reasonable treatment option in
  patients with poor performance status WBXRT (45
  Gy) /- RT to orbit/spine

17
PCNSL Treatment

• Chemotherapy /- XRT median survival of 30-41
  months
• High-dose methotrexate (gt3gm/m2) is most active
  drug against PCNSL
• CHOP regimens less effective mainly due to
  limited CNS penetration of cyclophosphamide,
  doxorubicin

18
RTOG 93-10 (DeAngelis et al.)

• 98 patients, median age 56.5 yrs
• Methotrexate 2.5 gm/m2, vincristine,
  procarbazine, IT MTX x 5 cycles, then WBXRT (45
  Gy), then high dose Ara-C
• 58 CR, 36 PR --gt 94 overall RR
• Median PFS 24.0 mos, OS 36.9 mos

19
RTOG 93-10 (DeAngelis et al.)
PFS Age-stratified
OS Age-stratified
Overall Survival
20
EORTC Lymphoma Group 20962 (Poortmans et al.)

• 52 patients, median age 51 yrs
• MTX 3 gm/m2, teniposide, carmustine, solumedrol,
  IT MTX/Ara-C/HC, then WBXRT (40 Gy)
• Overall response rate 81
• Median OS 46 months

21
EORTC Lymphoma Group 20962 (Poortmans et al.)
Overall Survival
22
MSKCC (Abrey et al.) JCO 2000, 18 3144-3150

• 52 patients, median age 65 yrs
• HD MTX 3.5 gm/m2, vincristine, procarbazine, IT
  MTX x 5 cycles, then 45 Gy WBXRT, then HD Ara-C
• CR 56, PR 33 to chemo (RR 90)
• Overall RR 94 by end of all therapy
• Median OS 60 mos

23
MSKCC (Abrey et al.) JCO 2000, 18 3144-3150
Overall survival and DFS
24
MSKCC (Abrey et al.) JCO 2000, 18 3144-3150
Patients gt age 60
Patients lt age 60
25
PCNSL Treatment Issues

• Some controversy over role of XRT used as
  up-front therapy after chemo or reserved until
  time of relapse
• Most do recommend XRT after chemo
• Older patients (gt60) probably should not get
  WBXRT with HD MTX
• Salvage options include WBXRT, chemotherapy,
  rituxan, temozolomide

26
References

• Abrey et al. Treatment for Primary CNS Lymphoma
  The Next Step. J Clin Oncol 2000 18 3144-3150.
• DeAngelis LM et al. Combination chemotherapy and
  radiotherapy for primary central nervous system
  lymphoma Radiation Therapy Oncology Group Study
  93-10. J Clin Oncol 2002 204643-4648.
• Hochberg et al. Clinical and pathologic features
  of primary central nervous system lymphoma.
  UpToDate 2005.
• Hochberg et al. Treatment and prognosis of
  primary central nervous system lymphoma. UpToDate
  2005.
• NCCN Practice Guidelines in Oncology 2005
  Central Nervous System Cancers
• Poortmans et al. High-dose Methotrexate-based
  Chemotherapy followed by Consolidating
  Radiotherapy in Non-AIDS-Related Primary Central
  Nervous System Lymphoma European Organization
  for Research and Treatment of Cancer Lymphoma
  Study Group Phase II Trial 20962. J Clin Oncol
  2003 21 4483-4488.