DAY 1:

Clinical manifestations of ALL 

Acute lymphocytic leukemia (ALL) aka acute lymphoblastic leukemia is the most common type of malignancy in children, making up 25% of childhood cancers. The incidence of ALL is about 1:25,000 children per year, including 3,000 children per year in the United States. The peak is 2-5 years of age, and is seen more in males than females. Children with Down syndrome have a 14 fold increase in the overall rate of leukemia. 

ALL is a malignancy arising from immature lymphoid stem cells in the bone marrow. There is an overpopulation of immature WBCs (blasts) that overtake normal hematopoiesis, resulting in pancytopenia. Its cause is unknown, and genetic factors may play a role. 

Most patients with ALL have only been feeling sick for a few days or weeks. These patients may also seek medical attention because of bone and joint pain, especially in the pelvis, vertebral bodies and legs. Manifestations of ALL include nonspecific symptoms associated with pancytopenia. Intermittent fevers are common, as a result of either cytokines induced by the leukemia itself or infections secondary to leukopenia. 

Physical examination at diagnosis ranges from normal to highly abnormal. 

• Signs related to bone marrow infiltration by leukemia include pallor, petechiae, and purpura. 
• Hepatomegaly and/or splenomegaly occur in over 60% of patients. It may manifest as anorexia, weight loss, abdominal pain or abdominal distention. 

• Lymphadenopathy is common, either localized or generalized to cervical, axillary, and inguinal regions. 
• The testes may occasionally be unilaterally or bilaterally enlarged secondary to leukemic infiltration. 
• Superior vena cava syndrome is caused by mediastinal adenopathy compressing the superior vena cava. A prominent venous pattern develops over the upper chest from collateral vein enlargement. The neck may feel full from venous engorgement. 
• Periorbital area may be edematous. 
• A mediastinal mass can cause tachypnea, orthopnea, and respiratory distress. 
• CNS involvement may cause cranial nerve palsies with mild nuchal rigidity. 
• The optic fundi may show exudates of leukemic infiltration and hemorrhage from thrombocytopenia. 
• Anemia can cause a flow murmur, tachycardia, and, rarely, congestive heart failure.

Diagnosis is made with CBC and peripheral smear. A CBC checks the number of RBCs and platelets, the number and type of WBCs, the amount of hemoglobin in the RBCs, and the portion of the blood sample made up of RBCs. A peripheral smear is a procedure in which a sample of blood is checked for blast cells, the number and types of WBCs, the amount of platelets, and chances in the shape of blood cells. 95% of patients with ALL have a decrease in at least one cell type: neutropenia, thrombocytopenia, or anemia with most patients having a decrease in at least two blood cell lines. The WBC count is low to normal in 50% of patients, but the differential shows neutropenia along with a small percentage of blasts. In 30% of patients the WBC count is between 10k-50k, and 20% have WBCs over 50k. Blasts are usually seen on peripheral blood smears from patients with elevated WBC counts. Most patients with ALL have decreased platelet counts (< 150,000/μL) and decreased hemoglobin (< 11 g/dL) at diagnosis. In approximately 1% of patients diagnosed with ALL, CBCs and peripheral blood smears are entirely normal, but patients have bone pain that leads to bone marrow examination. Serum chemistries, such as uric acid and lactate dehydrogenase (LDH), are often elevated at diagnosis as a result of cell breakdown.

Next, a bone marrow aspiration and biopsy will be done. This test involves the removal of bone marrow, blood, and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. When these are viewed under a microscope, abnormal cells will be seen – they will be hypercellular with >20% blasts. This gives a definitive diagnosis. 

Immunophenotyping of ALL blasts by flow cytometry helps distinguish precursor B-cell ALL from T-cell ALL or AML. Histochemical stains specific for myeloblastic and monoblastic leukemias (myeloperoxidase and nonspecific esterase) distinguish ALL from AML. About 5% of patients present with CNS leukemia, which is defined as a cerebrospinal fluid (CSF) WBC count greater than 5/μL with blasts present on cytocentrifuged specimen.

Imaging

• Chest x ray may show mediastinal widening or an anterior mediastinal mass and tracheal compression secondary to lymphadenopathy, especially in T cell ALL.
• Abdominal US may show enlarged kidneys from leukemic infiltration or uric acid nephropathy 
• Plain radiographs of the long bones and spine may show demineralization, periosteal elevation, growth arrest lines or compression of vertebral bodies 

DAY 2:

Treatment of esophageal varices and portal hypertension in children – definitive modalities

Treatment of portal hypertension is primarily directed at the management of variceal hemorrhage. Variceal bleeding is a life threatening medical emergency, and these patients should seek immediate care for any signs or symptoms of bleeding. The management is divided into pre primary prophylaxis, prophylaxis of the first episode of bleeding, emergency therapy, and prophylaxis of subsequent bleeding episodes. 

• Preprimary prophylaxis – early treatment of portal hypertension can potentially delay or prevent the development of esophageal varices 
  • The administration of propranolol reduces the development of portal hypertension, portosystemic shunting, and portal venous inflow
• Primary prophylaxis – Surveillance endoscopy in children with liver disease and portal hypertension is recommended if the clinician plans on a prophylactic regimen
  • Beta blocker use in children has reduced the frequency of bleeding episodes and can improve long term survival in patients with esophageal varices 
• Emergency therapy of variceal bleeding
  • The initial management of variceal bleeding in children is stabilization of the patient 
  • Vital signs, fluid resuscitation with crystalloids, and blood transfusion – these need to be administered carefully to avoid overfilling the intravascular space and increasing portal pressure 
  • NG tube placement may be important in these patients because it documents the rate of ongoing bleeding and removal of blood 
  • Platelets could be administered and coagulopathy should be corrected with vitamin K and FFP
  • IV abx should be considered for all patients with variceal bleeding due to the high risk of infectious complications 
  • Once stabilized, an endoscopy is performed 
  • Pharmacotherapy should not be delayed, and at the time of endoscopy, sclerotherapy or band ligation can be done
  • In cases where bleeding may not be controlled, a TIPS procedure can be done – it has the advantage of avoiding a laparotomy
  • Liver transplantation is considered for children with more advanced disease
• Pharmacological therapy usually consists of vasopressin or somatostatin infusions
• The most common secondary approach is endoscopic band ligation – a variety of chemical agents are used (sclerosants) – that are injected either intra or para variceal until bleeding is stopped 
• The major advantage of variceal ligation is avoidance of needle injection of varices, which appears to reduce the rate of complications. It also appears to lead to obliteration in fewer sessions and is associated with a lower rate of rebleeding.

In cases where hemorrhagic episodes are refractory to other treatments, surgery becomes the only option:

• Shunt procedures: 
  • Total portosystemic shunts: control of hemorrhages and ascitis, but at the high cost of encephalopathy, and are rarely used in children. 
  • Partial shunts: comprises portocaval or mesocaval anastomoses of 8 mm in diameter or less, allowing part of the portal flow to reach the liver sinusoids, and thus reducing the risk of systemic complications without losing efficacy for the prevention of further bleeding. This type of shunts has been widely used in children.
  • Selective shunts: constructed by the anastomoses of the splenic vein to the left renal vein, thereby decompressing gastroesophageal varices through the short gastric veins (distal splenorenal shunt), and maintaining portal perfusion to the liver. 
  • Spleno-renal shunts: good hemorrhagic control and reduce systemic complications.