To the Editor
Neuroblastoma is a well-recognized tumor in children but is sometimes
highly aggressive. Morgenstern et al. reported an “ultra-high-risk”
(UHR) subpopulation with inferior outcomes 1. Several
clinical factors, such as serum lactate dehydrogenase (LDH), are
predictors of a poor prognosis 2 34. However, despite clinical experience, few studies
have assessed the association between clinical factors and the disease
status during treatment or the treatment response. We report a case of
UHR neuroblastoma in which serum LDH concentrations were correlated best
with the disease activity.
A 20-month-old Japanese girl
presented to our hospital with poor vitality,
tiredness, hematuria, and
abdominal distension. There was no medical history. An examination
showed the following: blood pressure, 139/59 mmHg; temperature, 38.0℃;
pulse, 138/min; respiratory rate, 36/min; and oxygen saturation, 90% on
ambient air. She was irritable and had a distended abdomen and an
elastic mass. Laboratory studies showed the following: hemoglobin, 8.3
g/dL, LDH, 3117 IU/L, and ferritin, 117 ng/mL. She had no electrolyte
abnormalities. An abdominal computed tomography (CT) scan showed
an 11.1 × 8.6 ×
10.3-cm3 heterogeneous mass at the upper left kidney
and thoracic ascites. Urine catecholamines were increased, with a
homovanillic acid (HVA) concentration of 452 µg/mg creatinine and
vanillylmandelic acid (VMA) concentration of 201 µg/mg creatinine.
123I-metaiodobenzylguanidine (MIBG) scintigraphy showed accumulation at
the tumor site but no metastasis. A tumor biopsy showed an
undifferentiated neuroblastoma with MYCN amplification and the diploid
karyotype of chromosomes, and a bone marrow biopsy showed tumor
invasion. We diagnosed high-risk neuroblastoma using the International
Neuroblastoma Risk Group system. Previous reports suggested that this
tumor was UHR 1.
We planned multiagent
chemotherapy with five cycles of remission induction chemotherapy,
tandem high-dose chemotherapy (HDC), surgery, and radiation therapy5 6. After remission induction therapy, LDH
concentrations increased from 262 IU/L to 1118 IU/L just before HDC.
Contrast CT and MIBG scintigraphy showed that the tumor was reduced, and
a bone marrow biopsy showed disappearance of the tumor. Urinary VMA and
HVA concentrations were decreased. We administered HDC as planned
because these results suggested that the chemotherapy was adequate. The
maximum LDH concentration during the first HDC was 3264 IU/L, which was
assumed to be the result of tumor disruption. By day 28 after the first
HDC, the LDH concentration was decreased to 285 IU/L. Before the second
HDC, urine VMA and HVA concentrations were decreased, but the LDH
concentration was increased to 1155 IU/L. Enhanced CT did not show
progressive disease. Therefore, we performed a second HDC course. The
LDH concentration was decreased, and VMA and HVA concentrations remained
decreased. On the day of surgery,
40 days after the second HDC, the LDH concentration spiked to 1558 U/L,
but the tumor was small on CT, and we attempted tumor resection.
Intraoperative findings showed that the tumor invaded the omentum,
mesentery, pancreas, spleen, and left kidney. Ascitic fluid cytology was
positive. Pediatric surgeons resected the tumor and left kidney, and the
mesentery was resected to the extent that intestinal blood flow was
unaffected. They also preserved the pancreas and spleen. Pathologically,
the margins were positive. Therefore, we started radiotherapy
immediately. Radiotherapy was started 10 days after surgery, and the LDH
concentration was decreased to 525 U/L. During radiotherapy, we noticed
abdominal distention and a high LDH concentration (1303 U/L). CT showed
that the tumor was disseminated in the thoracic and abdominal cavities.
The patient had treatment-resistant neuroblastoma. We decided to perform
palliative treatment at the request of the patient’s parents. The
patient required continuous abdominal drainage owing to considerable
abdominal distention caused by ascites effusion. Palliative chemotherapy
was challenging to control the tumor, and bone marrow suppression made
continuation difficult. The patient was discharged home and died 2 weeks
later.
We describe an aggressive case of UHR neuroblastoma with serum LDH
concentrations closely associated with disease activity. Several
clinical research groups have advocated risk stratification of high-risk
neuroblastoma. They also attempted to recognize an UHR status to improve
the prognosis and offer appropriate therapy for these patients. In
addition to the initial status, treatment responsiveness is essential,
but there are no established indicators. Tumor markers and imaging tests
may be adequate to assess the response to therapy. At our facility,
tumor marker results take longer than a week to obtain.
Contrast-enhanced CT is invasive owing to radiation exposure and
contrast agents, and MIBG scintigraphy is not available in some
facilities. These imaging tests are often subjective and may require
more work for accurate assessment. However,
LDH is simple to measure and
results are prompt. LDH is useful
for reassessment because it reflects the disease activity and treatment
responsiveness sensitively and accurately. LDH measurement is also
helpful in areas with limited medical resources. In our case, elevated
LDH concentrations may have triggered the addition of conventional
chemotherapy to control the tumor before further HDC, contributing to
the improved prognosis. We were not able to assess genomic factors;
therefore, whether 1p loss, 11q loss, or 17q gain is relevant is
unknown. However, elevated LDH
concentrations after advanced treatment likely due to enlargement of the
tumor may help rapid reconsideration of treatment strategies.