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Neuroblastoma in the bone marrow

A 4-year-old girl presented to her local hospital with a three-week history of intermittent fevers, right hip pain, and walking with a limp. Blood tests showed: raised inflammatory markers (C-reactive protein 203 mg/l, erythrocyte sedimentation rate 118 mm in 1 h), white cell count 12.1 3 10/l, hemoglobin concentration 98 g/l, mean cell volume 71 fl, platelets 373 3 10/l, neutrophils 6.9 3 10/l and lymphocytes 4.1 3 10/l. Ultrasound of the right hip did not show any effusion. She was commenced on ceftriaxone and clindamycin for possible osteomyelitis and transferred to our center for further investigation. Magnetic resonance imaging of the right hip and pelvis showed a diffuse abnormal bone marrow signal involving all of the bones imaged, suggesting a malignant process involving the bone marrow. The blood count was similar to previously and a blood film showed rouleaux, platelet clumps and 12% large granular lymphocytes. Bone marrow aspiration was difficult and the bone was noted to be abnormally firm. Films of the aspirate showed that normal hemopoietic cells were almost entirely replaced by an infiltrate of neoplastic cells. These were mainly small cells with a high nucleocytoplasmic ratio and agranular, moderately basophilic cytoplasm. There were some cytological similarities to leukemic blast cells but the correct diagnosis was revealed by the presence of abundant neurofibrillary bundles (left image). Other cytological features indicative of the diagnosis of neuroblastoma were the presence of some much larger, multinucleated cells (top of left image), the presence of rosettes of neoplastic cells around fibrillar material, the molding of nuclei by the nuclei of adjacent cells (left image) and the presence of occasional cells from which neurofibrils could be seen to emerge (right image). It is of interest that nuclear molding is also characteristic of small cell carcinoma of the lung, a tumor that is likewise of neuroendocrine origin. Immunophenotyping confirmed involvement by a non-hematological neoplasm (CD45 negative, CD56 positive, CD9 positive, CD99 negative). A bone marrow trephine biopsy and immunohistochemistry confirmed the aspirate diagnosis. Computed tomography of the chest and abdomen revealed a calcified mass anterior to the left kidney with enlarged left para-aortic and right axillary lymph nodes, in keeping with the bone marrow diagnosis of neuroblastoma. A further interesting and potentially significant finding was the fact that the patient was highly sensitive to opiates with apnea and oxygen desaturation with a relatively low dose of oral morphine (180 lg/kg). Congenital hypoventilation syndrome, so called Ondine’s curse, is associated with a mutation in the Paired-like Homeobox 2b (PHOX2B) gene, which is involved in the prenatal development of the autonomic nervous system and is also linked to the development of neuroblastoma. Gene mutational analysis will be performed in our patient to investigate this further. .