FINAL DIAGNOSIS: Metastatic neuroblastoma, poorly differentiated.
Neuroblastoma is the third most common childhood malignancy after acute leukemias and primary brain tumors, and is the most common pediatric extracranial malignant solid tumor. It comprises 6% to 10% of all childhood cancers, and causes 15% of all pediatric cancer deaths. Seventy-five percent of cases are diagnosed in children 4 years of age or younger, and less than 10% of cases are diagnosed in patients older than 10 years (1). Neuroblastomas are considered to be part of the family of "neuroblastic tumors" of the autonomic nervous system that also includes ganglioneuroblastoma and ganglioneuroma. They may arise in the paravertebral region and posterior mediastinum, but more commonly arise in the adrenal medulla or the extraadrenal retroperitoneum. These tumors usually present as an apparent abdominal mass, with radiologic studies revealing a suprarenal or retroperitoneal mass.
Microscopically, neuroblastoma usually shows a lobular or nested growth pattern, but may show a more solid growth pattern. The amount of pale, neurofibrillary matrix may be more abundant, forming the center of Homer Wright rosettes surrounded by a ring of cells, or it may be absent in poorly differentiated tumors. Cytologically, neuroblastomas are an example of a "small, round, blue cell" tumor, with finely dispersed ("salt and pepper") nuclear chromatin and inconspicuous nucleoli.
Staging of neuroblastoma involves full body scans as well as bone marrow studies. An unfortunately common feature of neuroblastoma is the presence of metastatic disease in 50% to 65% of children at presentation. The most common sites are lymph nodes, bone, and liver (1). In fact, neuroblastoma is the second most common cause of childhood bone marrow infiltration after acute lymphoblastic leukemia (2). Marrow involvement by metastatic tumor often results in cytopenias and a myelophthisic pattern, which is a form of bone marrow failure resulting from the destruction of marrow precursor cells and their stroma (3). The CBC may show a normochromic, normocytic anemia, while the peripheral blood smear may show anisopoikilocytosis with red cell fragments and teardrop cells. A leukoerythroblastic reaction may also be present, with circulating nucleated red blood cells and immature myeloid cells.
Neuroblastoma in the bone marrow may present a diagnostic challenge, particularly if it is the first diagnostic specimen, and the primary tumor is as yet undiscovered as it was in this patient. Also, the amount of tumor may be small, necessitating a search for just a few malignant cells. In both cases, morphology and immunohistochemistry are helpful in the diagnosis. The differential diagnosis of an infiltrate of atypical cells in the bone marrow of a child includes acute leukemia, lymphoma, and sarcoma. On the aspirate smears, hematopoietic cells usually show a dispersed, discohesive pattern, while solid tumors will often show increased cohesiveness, with clumping or molding (4). The biopsy is often helpful in revealing marrow involvement, as in this patient with extensive necrosis and large areas of cohesive atypical cells. The biopsy is also convenient for immunohistochemical studies. Tumor cells from sarcomas will be negative for hematopoietic markers, such as CD45 / LCA. Synaptophysin, PGP 9.5, and neuron specific enolase (NSE) are useful markers that are generally positive in neuroblastoma.
Other ancillary studies include flow cytometry, cytogenetics (including FISH), and molecular studies. Flow cytometry is very important in hematopoietic malignancies, but will be non-specific in metastatic sarcomas. Cytogenetic studies are important in cases of neuroblastoma. N-myc amplification (chromosome 2p), detectable by FISH, is a fairly specific feature of neuroblastoma, and is considered a poor prognostic factor. Other chromosomal abnormalities have been found in these tumors, with gain of material in the long arm of chromosome 17 (17q) and loss of material in the short arm of chromosome 1 (del 1p) being the most common (5).
Neuroblastomas show remarkable clinical heterogeneity, with the prognosis varying widely with age and stage of disease at diagnosis. More recently, molecular methods such as microarray analysis are being developed in an attempt to more precisely stratify patients into different prognostic groups (6). Currently, however, patients are stratified according to the Children's Oncology Group neuroblastoma risk stratification system, which considers age at diagnosis, International Neuroblastoma Staging System (INSS) stage, N-myc gene amplification status, tumor histology, and tumor cell ploidy (7). (Table 1) Tumor histology is based on the Shimada classification, which itself stratifies patients based on favorable or unfavorable histological characteristics (8).
Following diagnosis of neuroblastoma by bone marrow biopsy, the patient underwent full staging for her disease. Radiological studies uncovered a 6.5 cm heterogeneously enhancing mass in her left suprarenal fossa with adjacent lymphadenopathy along the left renal hilum. Additionally, extensive osseous metastases were found, including the skull base, spine, and pelvis. Cytogenetic studies showed a normal chromosome analysis with no numerical or structural abnormalities. FISH was negative for N-myc gene rearrangement, which was somewhat surprising given her advanced disease. In spite of her normal cytogenetic studies, she was still given a poor prognosis due to her age (> 1 year) and advanced disease.
Contributed by Andrew Walls, MD and Lisa Robinson, MD