Adult Patient With Neuroblastoma Presenting as Acute Leukemia

Neuroblastoma (NB) is the most common extra-cranial cancer of early childhood and rarely occurs in adults. The clinical symptoms of NB can be diverse. We discuss a rare case of an adult NB presenting as acute leukemia. A 45-year-old woman presented with persistent hip pain, weight loss, anemia, and incidental fever for several months. Imaging studies showed diffuse bone marrow (BM) uptake and hypermetabolic lesions involving the left adrenal gland, bilateral axillary nodes, and left lateral aspect of the abdomen. Her 24-hour urine catecholamines were within the normal range. On the peripheral blood film, blast-like cells were noted, occupying approximately 2% of leukocytes. The BM imprints showed infiltration of blast-like cells with convoluted nuclei and scant cytoplasm in more than 85% of the total nucleated cells. Acute leukemia was initially suspected based on morphology. Blast-like cells were negative for myeloperoxidase, combined esterase, periodic acid-Schiff, CD45RB, CD68, and CD138. In a further study, these cells were positive for CD56, synaptophysin (SYN), and CD99 with negativity for desmin, myogenin, NKX-2.2, CD31, cytokeratin (AE1/AE3), Melan-A, ERG, S-100, and SALL4. Morphologically similar neoplastic cells in axillary node biopsy were positive for CD56, chromogranin A, SYN, and neurofilament, but negative for GFAP, CD246, and vimentin. Based on laboratory, pathological, and imaging studies, metastatic NB with BM and multifocal involvement was diagnosed. The differential diagnosis of metastatic small blue round cell tumors should be considered for adult patients with circulating blast-like cells, and an accurate diagnosis would enable the patient to receive appropriate and timely treatment.


Introduction
Neuroblastoma (NB) is an embryonal cancer arising from peripheral sympathetic nervous system and the most common extra-cranial cancer of early childhood [1]. NB affects one in 8000 live birth and represents 6-10% of all childhood tumors [2]. It occurs rarely in adults and commonly affects adults with age in the fifth to sixth decades [2]. The incidence rate of NB for patients over 30 years old is 0.2 cases per million inhabitants per year and its incidence becomes increasingly scarce in the elderly population [3].
NB commonly occurs in the adrenal medulla, neck, chest, and pelvis [4]. Metastatic NB commonly involves regional lymph nodes, bone marrow (BM), cortex, and liver [5]. Since NB may develop throughout the sympathetic nervous system, the clinical symptoms can be diverse depending on the location of the tumor [5]. We discuss a rare case of an adult NB involving multiple sites presenting as acute leukemia.

Case Presentation
A 45-year-old woman presented with persistent hip pain, weight loss, anemia, and incidental fever for several months. Imaging studies showed mild splenomegaly, diffuse BM uptake, and hypermetabolic lesions involving the left adrenal gland, bilateral axillary nodes, and left aspect of the lateral abdomen. Her 24-hour urine vanillylmandelic acid and catecholamines, including epinephrine, norepinephrine, and dopamine, were within the normal range. Laboratory tests were notable for elevated serum lactate dehydrogenase (LDH) and elevated serum ferritin. A complete blood count with differential showed microcytic anemia, and a peripheral blood smear revealed a few blast-like cells occupying approximately 2% of leukocytes (Table 1, Figure 1).   BM examination and fine-needle aspiration at the enlarged axillary node were performed. The BM imprints showed infiltration of blast-like cells in more than 85% of the total nucleated cells with markedly decreased normal hematopoietic components ( Figure 2A). Based on morphology only, acute leukemia was initially suspected. However, these blast-like cells were negative for myeloperoxidase (MPO), combined esterase, and periodic acid-Schiff ( Figures 2B-2D). Most of the cells presented as a single cell, whereas the minority of the cells were concentrically arranged with fibrillar extension and formed so-called Homer-Wright rosettes ( Figures 3A, 3B). Morphologically similar neoplastic cells with hyperchromatic nuclei and scant cytoplasm were seen in BM biopsy tissue ( Figure 4A). These cells were negative for hematologic markers (CD45RB, CD68, and CD138), making hematological malignancies less likely. Therefore, small blue round cell tumors (SBRCTs) were considered. On further study, these cells were positive for neural-related markers, including CD56, CD99, and synaptophysin (SYN) ( Figures 4B-4D  Morphologically similar small cells with hyperchromatic nuclei were seen in a biopsy from an enlarged axillary lymph node as well ( Figure 5A). These neoplastic cells were positive for neural-related markers, including CD56, chromogranin A (CGA), SYN, and neurofilament ( Figures 5B-5D, 6) but negative for GFAP, CD246, and Vimentin. These findings were consistent with neuroblasts.    multifocal involvement was diagnosed. The patient received radiation therapy at the left adrenal gland and adjuvant high-dose chemotherapy with autologous peripheral blood stem cell transplantation. She has kept follow-up appointments with the hematologist since then.

Discussion
We presented a rare case of adult NB with the clinical manifestations mimicking acute leukemia. Our case had life-threatening anemia with circulating blast-like cells, and BM imprints revealed infiltration of these neoplastic cells in more than 85% of the total nucleated cells. Since the preliminary immunoprofiles were not compatible with a hematopoietic neoplasm, the diagnosis of SBRCT was taken into account. SBRCTs consist of a heterogeneous group of malignant neoplasms characterized by a monotonous population of poorly differentiated tumor cells with relatively small-sized, hyperchromatic nuclei, and scant cytoplasm [6].
The most common SBRCTs include non-Hodgkin's lymphoma, NB, ES/primitive neuroectodermal tumor (PNET), RMS, and small cell neuroendocrine carcinoma (SNEC) [2]. The similar cytomorphology of SBRCTs makes it essential to rely on immunoprofiles to yield an accurate diagnosis. Immunohistochemical markers and histological features of SBRCTs included in our differential diagnoses are shown in Tables 2, 3.

NHL (unclassified) RMS ES/PNET
The rarity of adult NB makes it a valuable opportunity to appreciate the complexity of the disease. The biological characteristics of NB may be different between young patients and adult counterparts. First of all, elevated urinary catecholamine is known as one of the features of NB. However, our case showed no elevation of catecholamines in her 24-hour urine as reported previously [8]. Furthermore, immune expression of NB might vary from adult cases to pediatric cases. A high level of CD246 or anaplastic lymphoma kinase protein has been detected in fetal neuroblasts [15]. There was an aberrantly negative expression of CD246 in our case. Finally, the prognosis of the disease shows a noticeable difference between adults and infants. For infant patients with NB, five-year survival is near 85%; in contrast, the overall survival rate at five years is 36% for adults. Adult patients, up to one-third, are diagnosed with metastasis [16].
Based on the International Neuroblastoma Staging System (INSS), our case with distant metastatic disease belongs to INSS stage IV, which indicates the worst outcome of all the other stages. Pediatric patients with NB can receive standard treatment with optimal risk stratification, while there are still no standard therapies for adult NB patients [4,16,17]. Though chromosomal and molecular studies, such as MYCN amplification, were not applied for risk assessment in our case, other laboratory findings including serum LDH and ferritin may be indicators of poor prognosis [17,18].
as exempt from review of IRB (Koo Foundation Sun Yat-Sen Cancer Center) by the chairman on July 13th, 2022. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.