Keywords
Crigler–Najjar syndrome - DeAngelis protocol - hyperbilirubinemia - primary CNS lymphoma
Introduction
A rare form of non-Hodgkin lymphoma, primary central nervous system lymphoma (PCNSL)
is confined to the CNS. Around 90% of PCNSLs consist of B-cell lymphomas that account
for 2 to 3% of all brain tumors and less than 1% of all non-Hodgkin lymphomas.[1] PCNSL is a curable malignancy with a 5-year survival rate of 30%, and standard chemotherapy
regimens consisting of high-dose methotrexate and high-dose cytarabine are used for
its treatment.[2] Hepatic dysfunction in such patients could be detrimental, as high-dose methotrexate
has been associated with a range of liver-related adverse effects that may lead to
progressive fibrosis and cirrhosis.[3] Crigler–Najjar is a syndrome wherein indirect bilirubin is high with no liver dysfunction.
Our present report elucidates a case of PCNSL in a known case of Crigler–Najjar syndrome
with a baseline bilirubin of 13.5 mg/dL, and we highlight modifications in the treatment
protocol of this curable malignancy.
Case Report
A 26-year-old man with a history of the consanguineous marriage of parents presented
with somnolence, ataxia, and forgetfulness for a duration of 4 weeks, which was progressing.
His medical history included a diagnosis of Crigler–Najjar syndrome, type II, and
on examination icterus was present with vital signs being in the normal range. Magnetic
resonance imaging (MRI) scan of the brain demonstrated a lesion in the bilateral medial
thalami extending along the posterior wall of the third ventricle and proximal aqueduct
of Sylvius measuring 2.7 × 1.8 × 2.5 cm with mild perilesional edema ([Fig. 1]). This was followed by an endoscopic third ventriculostomy and a biopsy of the space-occupying
lesion, which was suggestive of diffuse B-cell lymphoma of the CNS. No atypical or
malignant cells were detected on cerebrospinal fluid cytology. Whole-body positron
emission tomography–computed tomography (PET-CT) scan was done to exclude systemic
diffuse large B-cell lymphoma.
Fig. 1 Pretreatment MRI shows mass lesion in the region of the third ventricle with involvement
of bilateral thalami, with perilesional edema in the thalami showing restricted diffusion
with diffuse T2, fluid-attenuated inversion recovery (FLAIR) hyperintensity, and postcontrast
enhancement and dilatation of the lateral ventricles with periventricular hyperintensity.
Given his present history of Crigler–Najjar syndrome and a raised indirect bilirubin,
magnetic resonance elastography was done to evaluate the status of the liver before
starting the treatment for PCNSL. It demonstrated hepatomegaly with diffuse hepatic
steatosis with a fat fraction of 12 to 17% (normal range: <5%) and a mean shear stiffness
value of 2.4 kPa (reference range: 2.6–6.1 kPa). Blood work-up was normal, except
for the liver function test where hyperbilirubinemia was observed with total bilirubin
levels of 13.5 mg/dL and normal direct bilirubin, serum glutamic-oxaloacetic transaminase
(SGOT; 21 U/L), serum glutamic-pyruvic transaminase (SGPT; 47 U/L), serum albumin
(5.6 g/dL), and international normalized ratio (1.0), and the patient was categorized
as Child–Pugh status B. After consultation with the hepatology team, considering PCNSL
is a rare tumor with aggressive biology in conjunction with Crigler–Najjar syndrome,
all the available treatment options including high-dose methotrexate as a part of
the DeAngelis protocol was discussed. In view of hyperbilirubinemia, the DeAngelis
protocol was modified and he was treated with high-dose cytarabine (3 g/m2) at weeks 1 and 3 to begin with. After the first cycle of cytarabine, the patient's
bilirubin increased to 20 mg/dL with normal direct bilirubin, SGOT, and SGPT. The
bilirubin levels over the period of 2 weeks dropped to 11.5 mg/dL, and the second
cycle of high-dose cytarabine was given. The patient had responded very well clinically,
and further decision of continuing with high-dose methotrexate (3,500 mg/m2 at weeks 7, 9, 11, 16, 18), vincristine, and procarbazine was taken. The patient's
creatinine and estimated glomerular filtration rate values before high-dose methotrexate
administration were 1.09 and 147, respectively; he tolerated high-dose methotrexate
well with no clinically significant deterioration of the liver function and also no
added hematological toxicity was seen. Whole-brain radiotherapy (36 Gy/20 fractions)
was later given as a consolidation therapy. He remains asymptomatic 6 months after
the onset of the symptoms with a clinically well-responding disease and improving
functional status with MRI scan suggestive of signal intensity in the right middle
cerebellar peduncle without postcontrast enhancement with a new area of gliosis ([Fig. 2]).
Fig. 2 Posttreatment MRI shows complete resolution of the mass lesion in the region of the
third ventricle and bilateral thalami.
Discussion
PCNSLs are unusual tumors and are recorded as 0.7 to 0.9% of all lymphomas, with only
0.3 to 1.5% of all intracranial tumors. These are diagnosed in immunocompromised as
well as immunocompetent individuals, with a more common occurrence in men than women,
in a ratio of 3:2.[4] Intracranial lesions in the brain parenchyma are the most observed imaging of PCNSL,
with the common presentation of neuropsychiatric and behavior changes in 43% of patients,[5] corroborating with the clinical presentation in the present case. The present-day
treatment of PCNSL includes two phases: induction and consolidation; however, age
and performance status are important prognostic factors and other details, such as
comorbidity, frailty, organ function, and risk of neurotoxicity, should be considered
in the selection of the better treatment.
The present case had a baseline diagnosis of Crigler–Najjar syndrome, type II, which
is a rare genetic disorder, and an inborn error of bilirubin metabolism noticeable
by persistent rising of unconjugated bilirubin. It is an autosomal recessive disorder,
where the fundamental pathogenesis of partial mutation in the UGTA1 gene, which contains instructions for encoding liver enzyme, if characterized by
type II is less severe and has good prognosis.[6] Crigler–Najjar syndrome presents with persistent jaundice and is exacerbated by
intercurrent illness, stress, or drug use and the bilirubin level could go as high
as 40 mg/dL.[7] Similarly, our patient presented with a bilirubin of 13.5 mg/dL and a normal direct
bilirubin with subsequent rise to 20 mg/dL following the first cycle of chemotherapy;
however, there was no derangement of the functional status of the liver. High-dose
cytarabine has negligible hepatotoxicity and hence was chosen to begin the therapy.[8] Drugs that displace bilirubin from albumin such as penicillin,, salicylates, furosemide,
sulfonamides, and ceftriaxone were avoided as they can affect bilirubin levels.[7]
High-dose methotrexate or long-term use of methotrexate leads to hepatotoxicity and
hence there is significant restriction on its use in the doses desired and as a consequence
is avoided in patients with hepatotoxicity[3]; however, in the present case, after hepatology consult and MRI elastography report
and in view of the curable nature of the disease in a young patient, we started with
high-dose methotrexate following two cycles of cytarabine as per the DeAngelis protocol
(intravenous methotrexate, leucovorin, vincristine, procarbazine, dexamethasone, intrathecal
methotrexate), and the patient tolerated chemotherapy well and was able to complete
the whole course of treatment with significant clinical and radiological improvement
and without any significant hepatotoxicity or hematological toxicity. The patient
was later consolidated with whole-brain radiotherapy and now continues to stay in
complete remission. There is paucity of data for the use of high-dose methotrexate
in patients with Crigler–Najjar syndrome and hence this experience can help in taking
the treatment decisions in such challenging clinical scenarios. However, the limitation
of this study is that it is a single case–based report and not a case series. The
major outcome is we could give all the drugs safely. Furthermore case series and research
would help in future to establish the benefit of using high-dose methotrexate in patients
with Crigler–Najjar syndrome.
Conclusion
PCNSL is a curable malignancy and hence completing treatment especially in younger
patients is imperative. Comorbidities such as Crigler–Najjar syndrome with hyperbilirubinemia
can affect the treatment decisions in view of dearth of data on the use of high-dose
chemotherapy in such patients. Based on the current case, we suggest the use of standard
chemotherapeutic drugs for PCNSL in Crigler–Najjar syndrome is safe; however, it requires
close observation on liver function and involvement of a multidisciplinary team.
