Journal of Neuro-Oncology

, Volume 97, Issue 1, pp 137–141 | Cite as

Hepatic Sinusoidal Obstruction Syndrome in a child after chemotherapy for medulloblastoma

  • M. Kashif Ishaqi
  • A. Jamil
  • M. Khanani
  • M. Baroudi
  • Omar Trad
  • M. El-Hayek
  • Eric Bouffet
Case Report


Hepatic Sinusoidal Obstruction Syndrome (HSOS), the new name given to veno-occlusive disease (VOD) of the liver, is a well-known complication of high-dose chemotherapy employed with hematopoietic stem cell transplantation, but it has rarely been observed in children who receive conventional chemotherapy. HSOS following standard chemotherapy has been reported in patients receiving vincristine, actinomycin D, and cyclophosphamide for the treatment of Wilms tumor and more rarely rhabdomyosarcoma. We report a 14-year-old boy with high risk medulloblastoma treated with craniospinal radiation followed by chemotherapy, who experienced severe HSOS after only one course of chemotherapy including carboplatin, vincristine, and cyclophosphamide. To our knowledge, this is the second report of HSOS after standard dose chemotherapy for brain tumor in childhood.


Chemotherapy Hepatic Sinusoidal Obstruction Syndrome Medulloblastoma Veno-occlusive disease 


Hepatic Sinusoidal Obstruction Syndrome (HSOS) is a multi-system disorder that has been associated with high-dose chemotherapy and/or radiotherapy for hematopoietic stem cell transplant (HSCT) [1] and less commonly with antineoplastic agents outside the transplant setting [2]. HSOS is a clinical syndrome characterized by tender hepatomegaly, weight gain caused by fluid retention, and hyperbilirubinemia in the absence of other causes [3, 4]. The diagnostic criteria for HSOS have been standardized by two groups of investigators. The Jones criteria (Baltimore) require hyperbilirubinemia (total bilirubin of 34.2 μmol/l or more) and the presence of at least two of the following symptoms: hepatomegaly, ascites, and weight gain >5% over baseline [3]. The McDonald criteria (modified Seattle) stipulate the presence of at least two of the following symptoms: hyperbilirubinemia (total bilirubin of 34.2 μmol/l or more), hepatomegaly with right upper quadrant pain, and ascites or unexplained weight gain >2% over baseline [5]. It is characterized by the obstruction of small intrahepatic venules and injury to sinusoidal endothelial cells and hepatocytes by high-dose alkylating chemotherapy agents which appear to be the primary event in the pathogenesis [6] (Table 1). A characteristic feature seen in many of these patients is thrombocytopenia refractory to platelet transfusions, although clinically severe bleeding related to thrombocytopenia is uncommon [1]. In brain tumor patients, HSOS has mostly been reported after high dose chemotherapy and stem cell transplant [7]. We report an unusual case of HSOS in an adolescent treated with conventional chemotherapy for medulloblastoma.
Table 1

Diagnostic criteria for HSOS

Jones criteria (Baltimore)

McDonald criteria (Seattle)—modified

Elevated total serum bilirubin (≥34.2 μmol/l) before day 21 after SCT, plus two of the three following criteria:

1. Tender hepatomegaly

2. Weight gain >5% from baseline

3. Ascites

Occurrence of two of the following events within 20 days of SCT:

1. Hyperbilirubinemia (total serum bilirubin ≥34.2 μmol/l)

2. Hepatomegaly or right upper quadrant pain of liver origin

3. Unexplained weight gain (>2% of baseline body weight)

HSOS Hepatic Sinusoidal Obstruction Syndrome, SCT stem cell transplantation

Case report

A 14-year-old boy presented with 2-week history of headache, vomiting, and ataxia. Brain MRI scans showed a posterior fossa tumor. Sub-total excision of cerebellar tumor that involved the vermis was performed at another center. Postoperative imaging showed a residual mass that measured more than 1.5 cm in diameter. Histopathologic evaluation was consistent with medulloblastoma. The patient had a negative spinal MRI for drop metastasis. CSF examination did not show any malignant cells. His postoperative management was given according to the institutional high risk protocol. He received 36 Gy to the craniospinal axis with a 20-Gy boost to the posterior fossa with 3D conformal technique with Photon. In addition, he received six doses of vincristine (1.5 mg/m2 per dose) weekly during his radiation treatment. Six weeks later, a pre-Cisplatin audiometric evaluation revealed severe hearing loss equivalent to grade III toxicity Brock criteria [8]. For this reason, Cisplatin was replaced with carboplatin. His first chemotherapy cycle included vincristine 1.5 mg/m2 and carboplatin 560 mg/m2 on day 1 followed by cyclophosphamide 1,000 mg/m2/day on days 2 and 3 along with Mesna. G-CSF was initiated 1 day after completion of chemotherapy. Four days after his discharge, he presented to the emergency room oozing gums and excess bruising. He was afebrile and his general and systemic physical examination was otherwise unremarkable. Laboratory workup indicated Hb: 9.1 g/dl, absolute neutrophil count (ANC): 0.01 × 109/l, platelets: 20 × 109/l, creatinine 53 μmol/l, AST: 224 IU/l, ALT: 165 IU/l, LDH 254 IU/l, total bilirubin: 34 μmol/l, direct bilirubin: 17 μmol/l, total protein: 5.7 g/dl, albumin: 3.1 g/dl. Empirical treatment was immediately started for febrile neutropenia with ceftazidime and amikacin with a presumptive diagnosis of sepsis or DIC. Over the subsequent 48-h period, he continued to have gum bleeding that was refractory to platelet transfusions, and he developed mild respiratory distress, severe oral mucositis, and watery diarrhea. On the third day of admission, his physical examination revealed jaundice, a weight gain of 14%, tender hepatomegaly, and ascites. His chest X-ray revealed bilateral interstitial infiltration. IV fluconazole and metronidazole were initiated, and his antibiotics were changed to meropenem and vancomycin. At that time, hepatic function tests and coagulation tests were as follows: total bilirubin 102 μmol/l, direct bilirubin 72 μmol/l, AST 1,954 IU/l, ALT 1,339 IU/l, LDH 1,085 IU/l, PT 17.0 s (normal 8.7–14.2), aPTT 42.4 s (normal 22.7–40.3), fibrinogen 4.6 (normal 1.5–3.8). Abdominal ultrasonography (US) revealed enlarged liver with moderate ascites. Serologic tests for viral hepatitis were negative. Clinical and laboratory findings were strongly suggestive of HSOS secondary to conventional chemotherapy. During this acute phase, the patient was hydrated with intravenous saline and 5% dextrose solution and received regular fresh frozen plasma, pack red blood cells and platelet transfusions. As defibrotide was not available, the patient was treated with oral ursodiol at a dose of 10 mg/kg/dose TID for 7 days and IV N-acetylcysteine (NAC) 65 mg/kg/dose q 12 h for 3 days [9]. Over a period of 2 weeks, he showed progressive clinical improvement with gradual normalization of blood counts and liver function tests. He was given one cycle of carboplatin followed by vincristine a week later with the plan to continue these alternating with cyclophosphamide. He tolerated this well.


HSOS was first described in South Africa and was linked to the ingestion of pyrrolizidine alkaloids contained in herbal tea [10]. HSOS occurring after allogeneic HSCT was first described in 1979, and now most cases of HSOS in the Western world are seen with allogeneic HSCT [11, 12]. HSOS has also been reported after autologous bone marrow transplant, particularly in relation to busulfan conditioning regimen [7, 13].

However, HSOS is not a common complication of conventional chemotherapy. Outside the transplant setting, HSOS has been observed in children with Wilm’s tumor following vincristine and actinomycin D administration [14, 15, 16, 17]. However, sporadic cases in children treated for Rhabdomyosarcoma with escalating doses of cyclophosphamide (2.2 g/m2) have been reported [18, 19, 20].

In medulloblastoma patients, HSOS has essentially been reported in the context of high dose chemotherapy regimens. In a series of 23 patients treated with high dose chemotherapy followed by bone marrow transplant for recurrent medulloblastoma, Dunkel et al. [21] reported grade 3-4 hepatic toxicity in 13 patients and one toxic death related to HSOS. In a review paper on 50 recurrent medulloblastoma patients treated with a combination of busulfan and thiotepa, Valteau-Couanet et al. [7] observed symptoms of HSOS in 22 patients. In this experience, previous treatment with craniospinal radiation was associated with a higher risk of hepatic disease. The role of busulfan in the induction of liver toxicity seems to be significant, and in a series of 9 patients with supratentorial PNET treated with sequential high-dose thiotepa alone and stem cell transplant after craniospinal radiation, Massimino et al. [22] did not observe any occurrence of HSOS. Likewise, no case of HSOS has been observed in the St Jude Study SJMB96, which uses craniospinal radiation followed by intensive chemotherapy with cyclophosphamide, cisplatin, and vincristine [23]. However, this may be related to the use of amifostine in this protocol, as this agent has shown hepatoprotective properties in pre-clinical studies [24]. Our case is remarkable, as HSOS occurred in a teenager who received chemotherapy for medulloblastoma in a non-transplant setting. To our knowledge, this is the second case reported in that context [25]. Our patient developed HSOS after one course of post-radiation chemotherapy with vincristine 1.5 mg/m2 and carboplatin 560 mg/m2 on day 1 followed by Cyclophosphamide 1,000 mg/m2/day on days 2 and 3. HSOS has been observed at a younger age with use of vincristine and cyclophosphamide for rhabdomyosarcoma [19]. The use of cyclophosphamide as a conditioning regimen in HSCT setting is a known risk factor for developing HSOS [4].

Our patient did not have any identified risk factor such as young age, pre-existing liver disease, abdominal or total body irradiation, or fungal infection as reported earlier [4, 5, 27]. Aside from previous craniospinal radiation; age may be another risk factor in that context, as previous work has suggested that toxicity of chemotherapy is more pronounced in teenagers and young adults treated for medulloblastoma [28].

The occurrence of severe unexpected hearing and liver toxicity also raises the possibility of an underlying predisposing condition, including chromosomal instability syndromes such as Fanconi anemia or Nijmegen syndrome [26, 27, 28]. Both conditions are associated with hypersensitivity to DNA cross-linking agents and/or radiation. No specific testing has been performed on our patient, and in particular no chromosome breakage analysis. However, our patient did not show any of the dysmorphic features associated with these syndromes. Toxicity in these patients is mostly hematological rather than hepatic. In addition, all reports of medulloblastoma associated with Fanconi anemia concern infants and young children below the age of 6 years [28, 29, 30, 31, 32, 33, 34]. Similarly, the two reports on medulloblastoma associated with Nijmegen syndrome involved young children aged 3 and 7, respectively [26, 27]. The role of craniospinal radiation in the occurrence of HSOS is possible. Even if our patient was treated with a 3D photon technique, there is little doubt that megavoltage photon beams delivered to the spinal axis result in scattered doses to the liver. In a comparative dosimetric study of standard megavoltage photon treatment and proton therapy, Miralbell et al. [35] showed that the former technique delivers at least 50% of the prescribed dose to almost one-third of the liver whereas the proton plan is able to completely avoid both the heart and the liver.

The prognosis of HSOS is variable and depends on the severity of the disease with mortality ranging from 3 to 60%, and death is uniformly inevitable in severe cases [4, 12]. In our case, the course of HSOS was favorable after symptomatic treatment.

This observation suggests that both vincristine and cyclophosphamide may play a role in the development of HSOS outside the transplant setting. HSOS should be considered in children receiving conventional chemotherapy who develop unexplained thrombocytopenia refractory to platelet transfusion, weight gain, tender hepatomegaly, and alteration of liver enzymes. A high index of suspicion is required to identify this complication. Aggressive supportive measures should be instituted and if necessary other options like defibrotide or N-acetylcysteine needs to be considered, as patients surviving the acute phase can expect to make a full recovery. The main issue in such situations concerns further chemotherapeutic management, as the risk of recurrence of symptoms of HSOS is significant, even after chemotherapy dose reduction [14]. In our experience, chemotherapy was successfully resumed after a modification of the protocol.

In summary, HSOS may occur as a consequence of craniospinal radiation and chemotherapy in the management of patients with medulloblastoma. The respective role of hepatic radiation injury and drug related liver toxicity cannot be determined in this context. However, this case report reinforces the potential benefit of advanced techniques of radiotherapy, such as protons that deliver superior target dose coverage and maximize sparing of normal structures [35, 36].


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Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • M. Kashif Ishaqi
    • 1
  • A. Jamil
    • 1
  • M. Khanani
    • 1
  • M. Baroudi
    • 1
  • Omar Trad
    • 1
  • M. El-Hayek
    • 1
  • Eric Bouffet
    • 2
  1. 1.Division of Pediatric Hematology/OncologyTawam Hospital, Johns Hopkins MedicineAl-AinUnited Arab Emirates
  2. 2.Division of Hematology and OncologyHospital for Sick ChildrenTorontoCanada

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