Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 6-4

Five-Day-Old Boy

KAMILLAH N. WOOD

HISTORY OF PRESENT ILLNESS

A 5-day-old Asian male was brought to his pediatrician for poor feeding. Compared to his siblings, his parents felt that he had been a poor feeder since birth. He was taking only 0.5 oz. every 2-3 hours. The mother had initially been breast feeding the baby but began to supplement with formula because of jaundice. In the clinic, the child was noted to have respiratory distress, and was felt to have a cardiac murmur. He was referred to the emergency department for further evaluation. In the review of symptoms there were no fevers or vomiting. The urine and stool patterns were normal. There was decreased activity but no diaphoresis with feeds, cyanosis, or abnormal movements. There was no rash. The infant had been in contact with a 2-year-old sibling with emesis and gastroenteritis.

MEDICAL HISTORY

There was good prenatal care and a prenatal ultrasound was normal. The infant was born by spontaneous vaginal delivery at 39 weeks gestation with a birth weight of 3100 g. The mother was positive for group B Streptococcus and received intrapartum penicillin. The infant received antibiotics empirically for the first 48 hours of life due to tachypnea but was discharged home with clinical improvement after cultures were negative. Family history was remarkable for leukemia in the maternal grandmother. The infant lived with her mother, father, and a 2-year-old sibling. The maternal grandfather died unexpectedly 2 days prior to admission.

PHYSICAL EXAMINATION

T 36.1°C; HR 168 bpm; RR 44/min; BP in the right arm 74/44 mmHg; left arm 85/53 mmHg; right leg 77/57 mmHg; left leg 77/53 mmHg; SpO2 98% room air

Weight 2.9 kg

In general, the infant was awake, crying, and vigorous. The anterior fontanel was open and flat. There were no dysmorphic facial features. There were ecchymoses surrounding both eyes. The tympanic membranes were normal in appearance and mobility. There was no rhinorrhea. The mucosa was pink and moist and the oropharynx was clear. There were mild intercostals retractions but the lungs were clear to auscultation. An IV/VI systolic murmur was noted at the sternal border and radiated to the back. S1 and S2 were normal; however, an S3 gallop was also noted. The point of maximal impulse was displaced slightly to the left. The abdomen was soft and the liver edge was palpable 5 cm below the right costal margin. The spleen was not palpable. There were no palpable abdominal masses. The skin was jaundiced to the waist. Distal pulses were normal and symmetric. The neurologic examination was normal.

DIAGNOSTIC STUDIES

The chest radiograph revealed cardiomegaly and increased interstitial edema but no discrete infiltrates. The complete blood count demonstrated the following: 15 500 white blood cells/mm3 (73% segmented neutrophils, 3% eosinophils, 13% lymphocytes, and 11% monocytes); hemoglobin, 21.5 g/dL; and 140 000 platelets/mm3. Serum electrolytes were as follows: sodium, 140 mEq/L; potassium, 3.9 mEq/L; chloride, 105 mEq/L; and bicarbonate, 15 mEq/L. Tests of liver function were also abnormal: albumin, 3.0 mg/dL; total bilirubin, 17.5 mg/dL; alanine aminotransferase (ALT), 54 IU/L; aspartate aminotransferase, 163 IU/L; and gamma-glutamyl transferase (GGT), 700. The partial thromboplastin time was 28 seconds.

ECG showed diffuse T wave abnormalities but normal voltage. Echocardiography showed a diffusely dilated heart with a particularly large left ventricle. The shortening fraction was 22%. The heart was otherwise structurally normal. Lumbar puncture revealed the following: 17 white blood cells and 39 red blood cells per cubic millimeter. The protein and glucose were normal. No bacteria were seen on Gram stain of the cerebrospinal fluid (CSF). A herpes simplex virus polymerase chain reaction study from the CSF was negative.

COURSE OF ILLNESS

On admission, he was felt to have congestive heart failure and was treated with digoxin and furosemide. Initially, cardiomyopathy and myocarditis were considered most likely. Viral infections (coxsackie, enteroviruses, TORCH infections), bacterial infections, and metabolic storage diseases were all considered.

The infant was initially treated with ampicillin, cefotaxime, and acyclovir until those studies returned negative. A head ultrasound was normal; specifically, no cerebral arteriovenous malformation was visualized. He continued to have mild elevation in his liver function tests. A CT of the abdomen suggested the diagnosis (Figure 6-3).

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FIGURE 6-3. Abdominal CT revealing an enlarged liver with an ill-defined, lobulated, hypodense mass measuring approximately 13 cm × 9 cm × 7 cm.

DISCUSSION CASE 6-4

DIFFERENTIAL DIAGNOSIS

The child presented with heart failure as the cause of his growth failure. The cause of heart failure may be cardiac or noncardiac (Table 6-8). The differential diagnosis of a liver mass in a child is also broad (Table 6-9). Although liver masses are uncommon solid tumors in children, it is important to understand the various types of masses that can present in children based on age and presentation. The most common liver neoplasm is from metastatic disease as it is in adults, with most primary liver masses being malignant. However, up to one-third of these masses are benign with the infantile hemangioendothelioma being the most common type.

TABLE 6-8. Heart failure in the newborn.

A. Structural Heart Defects

1. At birth—Hypoplastic Left Heart Syndrome (HLHS)

  - severe tricuspid regurgitation

  - large systemic arteriovenous fistula

2. First week—Transposition of Great Arteries (TGA)

  - premature infant with large patent ductus arterious

  - total anomalous pulmonary venous return

3. 1-4 weeks

  - critical aortic stenosis or pulmonic stenosis

  - coarctation of the arteries

B. Noncardiac Causes

1. Birth asphyxia resulting in transient myocardial ischemia

2. Metabolic (acidosis, hypoglycemia, hypocalcemia)

3. Severe anemia (hydrops)

4. Overtransfusion or overhydration

5. Neonatal sepsis

6. Endocardial fibroelastosis (rare primary myocardial disease) causes congestive heart failure in infancy. Ninety percent of cases occur in the first 8 months of life

TABLE 6-9. Differential diagnosis of a liver mass in a child.

Malignant Masses

Metastatic disease

Hepatoblastoma carcinoma

Hepatocellular carcinoma

Embyronal sarcoma

Angiosarcoma

Rhaboid tumor

Benign Masses

Hemangioendothelioma

Mesenchymal hamartoma

Focal nodular hyperplasia

Nodular regenerative hyperplasia

Hepatocellular adenoma

DIAGNOSIS

Computed tomography of the abdomen revealed an enlarged liver with an ill-defined, lobulated, hypodense mass (Figure 6-3). The hepatic artery was slightly dilated, which may have been the cause of the significant shunting into the lesion. Magnetic resonance imaging (MRI) of the liver was then performed for better detail of the liver process. On MRI, the patient was felt to have a mass lesion rather than an AVM. The patient underwent open biopsy of the liver mass which revealed a hemangioendothelioma. The findings in this case were due to a large hemangioendothelioma or cavernous hemangioma.These lesions can cause congestive heart failure of the high output type.

INCIDENCE AND EPIDEMIOLOGY OF HEMANGIOENDOTHELIOMA

Liver tumors are rare in children and approximately 30% are benign (nonmalignant) (Table 6-10). Benign liver tumors may be classified into five groups: (1) tumor-like epithelial lesions (e.g., focal nodular hyperplasia); (2) epithelial tumors; (3) cysts and mesenchymal lesions (e.g., cystic mesenchymal hamartomas); (4) benign teratomas; and (5) mesenchymal tumors (e.g., hemangiomas, hemangioendotheliomas). Of these benign lesions, hemangioendothelioma is the most common. Hemangioendotheliomas are soft tissue tumors that demonstrate endothelial proliferation. Similar to cutaneous hemangiomas, these hepatic tumors increase in size during the first year of life and then undergo involution over a period of several months to years.

TABLE 6-10. Classification of liver tumors.

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CLINICAL PRESENTATION

Most (90%) children present in the first 6 months of life, and are rarely discovered after 1 year of age. There is a slight female predominance, but no racial predilection. Before tumor involution, findings may include a palpable liver mass, jaundice, weight loss, anorexia, and fever. Life-threatening complications include rupture with hemorrhage, anemia, obstructive jaundice, or, as in this case, congestive heart failure. Many children have associated cutaneous hemangiomas, particularly if there are multiple hepatic lesions. Similar lesions may be found in the trachea, lungs, gastrointestinal tract, spleen, and pancreas. Although these lesions are benign, several serious complications can occur including high-output congestive heart failure due to large arteriovenous shunts. In addition, Kasabach-Merritt syndrome may be seen due to intratumoral platelet sequestration. Hypothyroidism may also be present secondary to high levels of type 3 iodothyronine deiodinase activity produced by the tumor.

DIAGNOSTIC APPROACH

Diagnostic approach is first based on ultrasound examination followed by CT or MRI with contrast. Measurement of alpha-fetoproteins (AFP) and liver enzymes will be helpful, and laboratory tests also frequently show anemia. A young child with multiple lesions and normal AFP most likely has hemangioendothelioma. An older child with elevated AFP most likely has hepatocellular carcinoma.

Complete blood count. Anemia is noted in 50% of patients. Thrombocytopenia, when present, may range from mild to severe.

Liver function tests. AST is frequently elevated. High bilirubin levels are usually due to obstructive jaundice.

Abdominal ultrasound. Hemangioendotheliomas are usually hypoechoic with well-defined margins. Doppler flow studies reveal high-flow velocity. Differentiation from arteriovenous malformations may be difficult by ultrasonography.

Abdominal CT. On CT, a low-attenuation mass with calcification is seen in approximately 40% of cases. Multifocal lesions are less likely to demonstrate calcification. These lesions usually have peripheral enhancement with central hypoattenuation due to central infarction or hemorrhage in larger lesions.

Abdominal MRI. On MRI, large lesions are heterogeneous with occasional high signal on T1-weighted imaging suggesting central hemorrhage.

Other studies. Biopsy is often required to distinguish these tumors from other hepatic masses.

TREATMENT

A hemangioendothelioma may be resected if singular and uncomplicated by thrombocytopenia. Nonoperative treatment with prednisone and/or interferon α is the treatment of choice. Cyclophosphamide has also been used for therapy, as has radiotherapy. Liver transplantation may be needed.

SUGGESTED READINGS

1. Reis-Filho JS, Paiva ME, Lopes JM. Congenital composite hemangioendothelioma: case report and reappraisal of the hemangioendothelioma spectrum. J Cutaneous Pathol. 2002;29:226-231.

2. Lu CC, Ko SF, Liang CD, et al. Infantile hepatic hemangioendothelioma presenting as early heart failure: report of two cases. Chang Gun Med J. 2002;25:405-410.

3. Zenge JP, Fenton L, Lovell MA, et al. Case report: infantile hemangioendothelioma. Curr Opin Pediatr. 2002; 14:99-102.

4. Ayling RM, Davenport M, Hadzic N, et al. Hepatic hemangioendothelioma associated with production of humoral thyrotropin-like factor. J Pediatr. 2001;138: 932-935.

5. Davenport M, Hansen L, Heaton ND, et al. Hemangioendothelioma of the liver in infants. J Pediatr Surg. 1995;30:44-48.

6. d’Annibale, Piovanello P, Carlini P, et al. Epithelioid hemangioendothelioma of the liver: case report and review of the literature. Transplantation Proc. 2002;34: 1248-1251.

7. Chung E, Cube R, Lewis R, Conran R. Pediatric live masses: radiologic-pathologic correlation, Part 1. Benign tumors. Radiographics. 2010;30:801-826.

8. Litten J, Tomilson G. Liver tumors in children. The Oncologist. 2008;13(7):812-820.