Acute pancreatitis is recognized with increasing
frequency in the pediatric population as a result of trauma, biliary
tract disease, viral illness, states of intracranial hypertension and
steroids(1). Children with acute lymphoblastic leukemia(ALL) treated
with L-asparaginase represent an additional group at risk to develop
pancreatitis(1,2). L-asparaginase induced pancreatitis is a relatively
benign disease with few complications in 80-90% of cases. Several
cases of L-asparaginase related pancreatitis have been reported in
literature, but there are only seven reports of L-asparaginase related
pancreatic pseudocyts(3-7). L-asparaginase induced pancreatitis has a
mortality as high as 12%(7). The principal toxicites of the drug,
besides pancreatitis, include: hypersensitivity reactions, central
nervous system and liver dysfunction, coagulopathy and hyper-glycemia.
The incidence of pancreatitis has been reported to range between
2-16%(2). We report a case of pancreatic pseudocyst developing in a
child undergoing treatment for ALL.
Case Report
A 12-year-old female child was diagnosed as acute
lymphoblastic leukemia based on an initial complete blood count (CBC),
which demonstrated hemoglobin 7 g/dL, WBC 2,68,000/mm3 with 95%
lymphoblasts (L2 morphology), and platelet count 32,000/mm3. The child
was put on the Indo-US multi-centric protocol 841 for ALL, which
included a 4-drug induction (prednisolone, vincristine, L-asparaginase
and daunorubicin) followed by consolidation and 6 maintenance cycles
of 90 days each subsequently. Each maintenance cycle consisted of an
initial 7-day period of prednisolone with vincristine and 4 injections
of L-asparaginase on alternate days, followed by weekly oral
methotrexate and daily 6-mercaptopurine. With the above treatment
protocol, the child was in state of hemato-logical remission and had
reached the 5th maintenance cycle.
Soon after receiving four injections of L-asparaginase
in the initial week of the 5th maintenance cycle, she was admitted in
hospital with severe epigastric pain and bilious vomiting. Pain was
radiating to the back, aggravated by food intake and relieved by
sitting or leaning forward. On examination, she was febrile and
tachypneic and abdominal guarding and reduced bowel sounds. Her serum
amylase was 450 somogyi units (normal 60-200 SU). Based on the
clinical presentation and high serum amylase, a diagnosis of L-asparaginase
induced acute pancreatitis was made. She inproved on conservative
treatment with intravenous fluids, nasogastric decompression and broad
spectrum antibiotics, and was discharged after 7 days. She returned
three weeks later with fever and abdominal lump of 2 days duration. On
physical examination, her abdomen was diffusely tender with absent
bowel sounds. CBC revealed: Hb 5g/dL, WBC 5,300/mm3, platelets
65,000/mm3. Serum amylase was 106 somogyi units and serum calcium was
normal. Chest X-ray was normal. Ultrasound examination of the
abdomen showed a bulky hypoechoic pancreas with ill defined outline
and a large pseudocyst in left hypochondrium anterior to the left
kidney measuring 13.4 × 10.7 cm in size consistent with a
pseudo-pancreatic cyst.
The pseudopancreatic cyst was managed
conservatively with continuous nasogastric suction, intravenous fluids
and antibiotics. Her temperature returned to normal, oral feedings
were resumed and was discharged after 1 week. Subsequent ultrasound
studies showed disappearance of the pseudocyst. Maintenance
chemotherapy without L-asparaginase was started again. The child is
presently in complete remission since the past 2 years following
completion of therapy.
Discussion
L-asparaginase, an enzyme extracted from
Escherichia coli, is one of the most imporant drugs in the current
multiagent protocols used for treating ALL. Among a total of 1,403
patients, studied for L-asparaginase induced toxicities in several
series, only 34 cases (2.5%) were reported to have developed
clinically apparent pancreatitis(2). Pancreatitis, which is usually
mild and self limited, may begin any time during treatment or even
upto 16 weeks after discontinuation of treatment with
L-asparaginase(6). Serum amylase and lipase levels may remain normal
during clinically apparent pancreatitis since L-asparaginase is known
to interfere with the synthesis of these enzymes(8). Of the seven
previously reported pseudocyst cases(3-7), 4 cases occurred within two
weeks of administration of L-asparaginase; 2 cases occurred 7 and 16
weeks after administration respectively and 1 case occurred after 3
days of L-asparaginase administration. In our patient, the interval
between the last dose of L-asparaginase and development of the
pseudocyst was 24 days.
Corticosteroids are capable of inducing acute
pancreatitis in children and the incidence of clinical pancreatitis
seems much higher in patients receiving combination chemotherapy
comprising L-asparaginase, corticosteroids and other agents(2,3).
Since our patient had received corticostroids, she was at increased
risk of developing acute pancreatitis and pseudocyst formation.
Pancreatic pseudocyst is known to resolve spontaneously and thus an
initial period of observation is indicated in a stable patient(9).
However, in cases of progressive enlargement of pseudocyst, signs of
gastric outlet obstruction or rupture/hemorrhage of the cyst, prompt
surgical intervention is indicated. Internal drainage of the
pseudocyst by cystogastrostomy or roux-en-Y-cystojejuno-stomy is the
procedure of choice(9). External drainage has been less satisfactory
and is often complicated by formation of a persistent pancreatic
cutaneous fistula. Recently octreotide, a synthetic somatostatin
analogue in the dose of 5 microgram/kg/day in divided doses has been
suggested for use in the management of pancreatitis(7). Samatostatin
is a naturally occurring oligopeptide produced primarily in the
gastrointestinal tract. The rationale for use of octreotide is that by
inhibiting pancreatic exocrine function, autodigestion of the pancreas
along with damage to the surrounding tissue will be prevented(7). It
has seen found to have few side effects with soreness at the injection
site being the most common.
In summary, acute pancreatitis is an uncommon but
potentially lethal complication of L-asparaginase therapy. A high
index of suspicion and careful periodic physical examination are
crucial to the diagnosis. Serum amylase determination must not be
relied upon to rule out evolving acute pancreatitis(8). Abdominal
sonography at regular intervals has been suggested as a noninvasive
and accurate means of detecting early pancreatitis(10). Skillful
management of pancreatitis as well as alertness in identifying its
attendant complications such as necrosis, abscess and pseudocyst
formation can minimize morbidity and death in children undergoing
multiagent chemotherapy for ALL.
Contributors: LSA conceptualized the report and
will act the guarantor of the paper. ST was the resident involved in
the management of the patient and helped in drafting of the
manuscript. SN and SB drafted the final manuscript. SKK helped to
co-ordinate the study as well as helped in drafting of the manuscript.
Funding: None.
Competing interests: None stated.
