Primary central nervous system lymphoma (PCNSL) is a form of extranodal, high-grade non-Hodgkin B-cell lymphoma that originates in the brain, spinal cord, or eyes. It is typically confined to the central nervous system. The standard treatment involves methotrexate-based chemotherapy with or without whole brain radiation therapy. While initial tumor responses are good with chemotherapy alone, recurrence rates are high without consolidation radiation therapy. However, long-term cognitive side effects are common with whole brain radiation therapy. The optimal treatment regimen has not been established.

2. Medhat Moustafa, MD,
Department of Neurosurgery
Suez Canal University, Ismailia, Egypt

3. Primary CNS Lymphoma

4. Overview
Primary central nervous system lymphoma
(PCNSL) has been known by many other names,
including
reticulum cell sarcoma,
diffuse histiocytic lymphoma,
and microglioma.
The proliferation of names reflects initial
uncertainty about the cell of origin.

5. PCNSL is now known to be a form of extranodal,
high-grade non-Hodgkin B-cell neoplasm,
usually large cell or immunoblastic type.

6. It originates in the brain, cerebrospinal fluid,
spinal cord, or eyes.
It typically remains confined to the central
nervous system (CNS),
but 4%–7% of patients with newly diagnosed
PCNSL and 10% of patients with relapsed PCNSL
may have systemic disease.

7. Although the cells of origin are lymphocytes,
PCNSL should be considered a brain tumor,
because the therapeutic challenges resemble
those of other brain tumors..

8. In particular, drug delivery is impaired by the blood-
brain barrier,
and cerebral toxicity limits the use of treatment
modalities

9. Epidemiology
Incidence
Incidence of primary central nervous system lymphoma
(PCNSL) in immunocompetent patients is approximately
51 cases per 10,000,000 per year.
PCNSL has been reported in 6-20% of patients infected
with HIV, and the incidence is expected to rise as
patients with low CD4+ counts survive longer.
Similar trends toward rising frequency of diagnosis of
PCNSL are reported internationally.

10. Sex predilection
Among immunocompetent patients with PCNSL,
males have a higher incidence of PCNSL than
females.
Patients with HIV-associated PCNSL are more
likely to be male. In one study, 74% or HIV
patients with PCNSL were male

11. Age predilection
The median age of immunocompetent patients
with PCNSL is 55 years.
There is an increased incidence with advancing
age with the highest rate of PCSNL in patients
aged 75 years or older.
The median age of HIV-infected patients with
PCNSL is 35 years.

12. Race predilection
Black males aged younger than 50 years have
greater than twice the incidence of white males,
while white males aged 50+ years have twice
the incidence of black males.
A similar pattern to a lesser magnitude is
present in females.

13. Clinical presentation
Patients with primary central nervous system
lymphoma (PCNSL) develop progressive
neurologic deficits fairly rapidly, over weeks to
months.
These deficits are variable depending on the
affected location within the CNS.

14. About 40%–50% of patients present with
nonspecific neurocognitive symptoms, and
about 50%–70% present with focal neurologic
signs.
Seizures may occur but are less common than in
other mass lesions due to relative cortical
sparing

15. Patients with HIV may be more likely to present
with an encephalopathy than other patients
with PCNSL.
This correlates with the more often multifocal,
diffuse enhancement pattern seen on magnetic
resonance imaging (MRI) scans.

16. In contrast to systemic DLBCL, patients with
PCNSL do not typically present with B symptoms
of weight loss, fever, and/or night sweats.

17. As the presence of immune deficiency guides both
the diagnosis and the treatment of PCNSL, much of
the history taking should be devoted to establishing
whether the patient may be immunocompromised.
A careful sexual and drug abuse history is
necessary.
If the patient is a transplant recipient, the nature
and duration of immune suppression must be
clarified.

18. Although ocular involvement is not infrequent, it
is often asymptomatic; if visual symptoms are
present, patients may describe blurred vision,
decreased acuity, or floaters.
.

19. Relapsing, remitting lesions may disappear for
periods of as long as several months to a year or
more.
Administration of corticosteroids may cause
prolonged remission of clinical and radiographic
signs and symptoms, but remission inevitably
occurs

20. Diagnostic Overview
The predilection of PCNSL for certain cerebral sites gives rise
to its characteristic appearance on neuroimaging
studies.
Seventy-five percent of immunocompetent patients will
present with solitary lesions.
The dense cellularity of the tumor accounts for its isodense or
hyperdense appearance on nonenhanced CT scan
and hypointense appearance on long TR-weighted MRI
imaging.
Restricted diffusion .
Homogenous enhancement.

21. While lesions in immunocompetent patients
tend to be solitary, periventricular, and
homogenously enhancing,
lesions in immunocompromised patients may be
cortical or subcortical with a variable
enhancement pattern, with ring enhancement
most commonly seen

22. Since the clinical and neuroimaging presentation
of PCNSL can be varied and the differential
diagnostic possibilities are therefore large,
no patient should be treated for PCNSL without
definitive cytologic proof of diagnosis, either by
vitrectomy, CSF sampling, or brain biopsy.

23. Corticosteroids should be avoided when
possible
Corticosteroids have a cytotoxic effect on
lymphoma cells and can induce a radiographic
response in up to half of patients, which limits
the sensitivity of diagnostic tools like biopsy or
lumbar puncture.

24. Additionally, a biopsy of lymphoma pre-treated
with corticosteroids may reveal only gliosis or
lymphocytic and histiocytic infiltrates without
identifiable neoplastic cells.
Responses to corticosteroids are not durable
and thus only delay definitive diagnosis and
treatment.

25. Procedures
Bone marrow biopsy
Bone marrow biopsy to evaluate for abnormal
lymphomatous cells should be completed for
staging purposes.

26. Lumbar puncture
Lumbar puncture should be performed to
evaluate CSF profile (glucose, protein, and cell
count) and cylology and flow cytometry for
detection of abnormal lymphomatous cells.
Brain biopsy should not be delayed while
awaiting this procedure.

27. Lumbar puncture is low-yield as the majority
of patients with primary central nervous system
lymphoma (PCNSL) will not have leptomeningeal
or CSF involvement;
however, if lumbar puncture identifies
lymphoma cells, this may obviate the need for
brain biopsy.

28. Brain biopsy
Stereotactic brain biopsy is the most appropriate
method for the diagnosis of PCNSL.
If possible, the procedure should be performed
before corticosteroids have been administered.

29. Treatment
Chemotherapy
Radiotherpay either focal or whole
Surgery

30. Treatment
The optimal treatment regimen has not been
established.
Standard systemic chemotherapy regimens such
as CHOP (ie, cyclophosphamide, doxorubicin,
vincristine, prednisone) are ineffective,
which presumably reflects the difficulty of
penetration of the blood-brain barrier by
chemotherapeutic drugs.

31. Chemotherapy
Methotrexate is the single most effective
chemotherapeutic agent for PCNSL.
For this reason, methotrexate based chemotherapy
regimens are used as first line treatment.
The optimal combination of chemotherapies that
include methotrexate is not known, however,
literature supports the use of ;mulit-agent
chemotherapy over methotrexate monotherapy.

32. Chemotherapy
Initial chemotherapy without radiation therapy
results in excellent initial tumor response rates
and avoids the toxicity associated with whole
brain radiation.

33. Radiation
Focal
Whole brain

34. Radiation
Focal radiation
results in increased relapses outside of the
radiation field, presumably because of
microscopic diffuse infiltrative disease thought
to be present at initial diagnosis

35. Radiation
Whole brain radiation therapy
PCNSL patients have been treated with whole
brain radiation therapy alone.
This has yielded high CR rates, but sustained
responses are rare with a median overall
survival of around a year..

36. Surgery
The role of surgery in treatment of PCNSL is
limited to biopsy for confirmation of diagnosis or
for rapid reduction of intracranial pressure to
prevent imminent herniation.
Small retrospective studies have shown no
benefit in outcomes when comparing surgical
resection to supportive care

37. Treatment of Recurrence and Refractory
Disease
There is no standard approach to treatment of
recurrent or refractory PCNSL.
Survival rates after recurrence and chance of
response to further treatment are much lower
than at initial diagnosis.

38. Treatment complications
Long-term sequelae of radiation therapy and
chemotherapy in PCNSL are significant.
Although median survival duration has been
extended with combined chemotherapy and
radiation therapy, the percentage of survivors
with late cerebral white-matter toxicity resulting
in cognitive dysfunction approaches 50%.

39. Serious leukoencephalopathy also is seen in
patients receiving methotrexate chemotherapy
alone, but the incidence appears to be lower
than that of the cerebral white-matter toxicity
seen with combination therapy.

40. A randomized trial investigated whether the
addition of whole brain radiation therapy to
methotrexate based chemotherapy regimens
affected survival and found no survival benefit.