To The Editor
The overlap between alkaline phosphatase (ALP) elevation related to malignancy and that related to viral illness can present a diagnostic dilemma for the pediatric oncologist. We present two cases of transient hyperphosphatasemia following cancer therapy and review the differential diagnosis and work-up.
First we present an 18-month old female who presented six months following therapy with carboplatin, etoposide, cyclophosphamide and doxorubicin for stage 4, intermediate-risk neuroblastoma with an ALP of 5527 U/L. The history of neuroblastoma raised concern for bone or liver metastases. Imaging, bone marrow aspiration, and urine VMA, HVA showed no evidence of malignancy; workup did not suggest nephropathy, endocrinopathy, hepatopathy or biliary tract obstruction. Six weeks previously, she experienced a febrile illness with upper respiratory infection (URI) symptoms and diarrhea. ALP was followed serially and 3 months later normalized to 208 U/L She remains free of neuroblastoma greater than 5 years off therapy.
The second case is a 16-month-old male who presented 6 months following therapy with cisplatin/carboplatin, etoposide and bleomycin for abdominal yolk sac tumor with ALP of 2,290 U/L. Two months prior, he had experienced a URI. Evaluation for malignancy was negative. There was no evidence of nephropathy or hepatopathy. Parathyroid hormone was slightly elevated; evaluation for rickets and decreased bone mineral density (BMD) revealed only a minimal decrease in BMD for age. Four weeks later he remained clinically well with a normal ALP of 240 U/L. He remains free of disease with normal AFP 12 months after therapy.
ALP originates predominantly from bone and liver but also from kidney, intestine, leukocytes and placenta. The normal values for ALP vary with hormonal and bone growth status, with higher values in growing children than adults. Hyperphosphatasemia prompts concern for several pathologic conditions [1-4] (Table I). Isoenzyme fractionation of ALP can help determine the tissue of origin, refine the differential diagnosis, and direct the work-up [2, 5, 6]. Decreased BMD may manifest as elevated ALP and hyperparathyroidism and has been a well-documented late effect of childhood acute lymphoblastic leukemia and intracranial tumors; changes may also occur with solid tumors and may begin to occur early in therapy [7-13]. Benign transient hyperphosphatasemia, with ALP as high as 10,000 U/L, has been reported in children several weeks after febrile/viral illnesses [3, 4, 14-16]. Diagnostic criteria for this condition are given in Table I. The bone fraction typically exceeds the liver fraction. Specific associations have been observed with echovirus 22, enterovirus 71 and coxsackie virus B4 [3, 14, 15].
Table I.
Differntial Diagnosis and Work-Up of Elevated Alkaline Phosphatase Following Therapy For Pediatric Malignancy
| Condition | Elevated ALP Profile | Other Work-up (as clinically indicated) |
|||
|---|---|---|---|---|---|
| Bone | Liver | Kidney | Leukocyte | ||
| Medications | + | + | +/− | − | Review med list |
| Sepsis | + | + | +/− | +/−* | Metabolic panel LAP* |
| Osseus Malignancy | +++ | +/− | +/− | − | Tumor markers Bone Scan Imaging |
| Bony Injury | +++ | +/− | +/− | − | Plain radiography |
| Rickets | +++ | +/− | +/− | − | Elevated PTH TSH/FT4 may be elevated 1,25 and 25-OH Vitamin D levels |
|
Osteopenia/
Osteomalacia |
+++ | +/− | +/− | − | QCT DXA |
|
Hepatic disease
Or malignancy |
+ | +++ | +/− | − | Liver/gallblader US/imgaing Hepatic Enzymes Hepatitis Serologies Tumor Markers |
| Biliary Obstruction | + | +++ | +/− | − | Liver/gallbladder US Hepatic Enzymes GGT markedly elevated |
| Germ Cell Tumors | + | + | +/− | − | Rule out pregnancy AFP HCG Imaging as indicated |
|
Benign Transient
Hyperphosphatasemia |
++ | + | +/− | − | Recent viral illness Age<5 years ALP 3-50 × ULN for age |
Leukocyte alkaline phosphatase may help differentiate leukemoid reaction from CML
Legend: +++ Markedly elevated, ++ Moderately elevated, + Mildly elevated, +/− May be elevated or normal, −Not elevated; Abbreviations (in order of appearance):LAP=Leukocyte Alkaline Phosphatase, PTH=Parathyroid Hormone, TSH=Thyroid Stimulating Hormone, FT4=Free T4, QCT=Quantitative Computed Tomograpy, DXA=Dual Energy X-ray Absorptiometry,GGT=Gamma-glutamyltransferase, AFP=Alpha-fetoprotein, HCG=Human Chorionic Gonadotropin, ALP=Alkaline Phosphatase, ULN=Upper Limit of Normal.
ALP elevations can be a sign of several processes concerning to the pediatric oncologist, including cancer recurrence, osseous or hepatic metastases, hepatic dysfunction and bone demineralization. However, young children may develop dramatic but benign and transient ALP elevations in the weeks to months following acute illness. For oncology patients in remission who are younger than five years (particularly with a history of recent illness) with hyperphosphatasemia but without evidence of malignancy recurrence or hepatic dysfunction, observation and close follow-up may be a reasonable initial management approach.
Acknowledgments
This work was supported in part by grant CA-21765 from the National Cancer Institute, and by the American Lebanese and Syrian Associated Charities (ALSAC).
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