Adult-onset neuroblastic tumor: An extremely rare entity in the adult population

Abstract

The neuroblastic tumor spectrum (NTS) encompasses a group of extracranial neoplasms arising from neural crest derived cells of the sympathetic nervous system. Although neuroblastoma, the most undifferentiated subtype, is one of the most common solid tumors in the pediatric population, NTs of any subtype are exceedingly rare in adults. Ganglioneuroblastoma represents an intermediate entity within the NT spectrum, characterized by immature neuroblasts and maturing ganglion cells, and demonstrates heterogeneous clinical behavior. Radiologically, NTs present as a large, multilobulated, heterogeneously enhancing and solid masses. Imaging must be supplemented with laboratory and pathological study to achieve a definitive diagnosis. We report the case of a 33-year-old male with adult-onset lumbosacral ganglioneuroblastoma. This case highlights the importance of correlating imaging with histopathological and laboratory study to diagnose this entity that is exceedingly rare in adults.

Introduction

Neuroblastic tumors (NTs) arise from neural crest–derived progenitor cells of the sympathetic nervous system. NTs exist along a histopathologic spectrum, described in the International Neuroblastoma Pathology Classification, that reflects the degree of cellular differentiation and clinical behavior. At one end of this spectrum lies neuroblastoma (NBL), the most primitive and aggressive form, composed predominantly of undifferentiated neuroblasts. In the intermediate category is ganglioneuroblastoma (GNB), which demonstrates a mixture of immature neuroblasts and maturing ganglion cells. At the most differentiated end is ganglioneuroma (GN), a benign neoplasm composed of mature ganglion cells and Schwannian stroma [1].

Neuroblastoma is the most common extracranial solid tumor in children, accounting for approximately 8% of pediatric malignancies and 15% of childhood cancer-related mortality [2]. In contrast, adult-onset neuroblastic tumors, whether neuroblastoma or more differentiated variants, are exceptionally rare, with an estimated incidence of 0.01 cases per million people annually [3]. Adult-onset NTs often demonstrate distinct tumor biology and significantly poorer clinical outcomes compared with pediatric disease [4]. Diagnosis requires integration of multimodal imaging and histopathologic evaluation, and presenting symptoms are frequently nonspecific, including back, leg, or abdominal pain.

We present the rare case of a 33-year-old male with an adult-onset NT within the lumbosacral region, demonstrating variable percentages of the neuroblastic component along the NT spectrum, comparing the primary to the metastases. This case highlights the importance of recognizing the potential for NTs to manifest outside the pediatric population and underscores the critical role of coordinated imaging, histopathologic correlation, and laboratory evaluation in establishing an accurate diagnosis and guiding management in this exceptionally uncommon presentation.

Case report

A 33-year-old male was referred to our institution for further evaluation of a large retroperitoneal paraspinal mass. The patient initially presented at a different institution with a 6-month history of nonspecific lower back pain intermittently radiating to the left lower extremity with associated stiffness and limited range of motion. CT evaluation at the time revealed a multilobulated and heterogeneously enhancing mass with involvement of the psoas muscle and lumbosacral spine. Fine-needle aspiration biopsy of the mass revealed the presence of ganglion and neuroglial differentiation strongly positive for synaptophysin and chromogranin, but was nondiagnostic due to limited tissue sampling. Based on these preliminary findings, a teratoma with neuroglial differentiation was favored as the initial working diagnosis.

The patient presented to our institution with lower back and left leg pain and associated low back and left hip stiffness that limited ambulation. On examination, decreased sensation in the left fifth digit of the foot and the left lateral heel was noted. The patient showed no other signs of neurological or motor deficit. Computed tomography (CT) performed at our institution (Fig. 1) redemonstrated a heterogeneously enhancing, multilobulated paraspinal mass measuring 8.2 × 6.5 × 13.7 cm in the left retroperitoneum, located anterior to the L3-S1 vertebral levels. The mass showed no clear plane of separation from the left psoas muscle. Sclerotic changes with cortical disruption were noted along the left anterolateral aspects of the L4 and L5 vertebral bodies. Invasion of the L4 and L5 vertebral bodies was noted. Vertebral body heights and intervertebral disc spaces were otherwise well maintained, with no evidence of neuroforaminal narrowing. Minimal spinal canal stenosis was appreciated at the L5-S1 level. Minor levoscoliosis in the lumbar spine was also noted, most likely owing to the mass effect. Enhancing soft tissue within the epidural space was also observed, suggesting epidural extension of the mass.

Fig. 1.

A 33-year-old male with a history of nonspecific back pain and associated paraspinal mass, now presenting with lower back and lower left extremity pain with stiffness. Initial contrast-enhanced CT scan in the axial (A–C) and coronal (D–E) views with three-dimensional volume rendering (F) demonstrated the known retroperitoneal mass measuring 8.2 × 6.5 × 13.7 cm (arrows–B, D, F). involvement of the left psoas muscle was observed with no clear plane of separation (arrow – A). Sclerotic changes with cortical disruption were visualized along the left anterolateral aspects of L4 and L5 (arrow–C, E).

A CT-guided biopsy of the paraspinal lesion confirmed osseous invasion with reactive sclerosis of the left anterior aspects of the L4 and L5 vertebral bodies. Histologic sections of the paraspinal lesion demonstrated a neoplasm comprised predominantly of small cells with scant eosinophilic cytoplasm and a neuropil background (Figs. 2A and B). A component of maturing and differentiating ganglion cells was noted, consistent with intermediate features along the NT spectrum. Immunohistochemical stains were positive for synaptophysin, chromogranin, and S100 but negative for keratin AE1/3 with a Ki67 index of 30-40%. Isochromosome 12p was tested by FISH and the results were negative, which ruled out the possibility of teratoma. Catecholamine urinalysis was performed and the patient’s homovanillic acid (HVA) and vanillylmandelic (VMA) acid levels were 16.0 mg/g creatinine (Reference Range (RR): 1.4-5.3 mg/g creatinine) and 12.2 mg/g creatinine (RR: 1.1-4.1 mg/g creatinine), respectively. Urinary creatinine level was 16.4 mg/dL. A biopsy was performed on the left iliac crest to assess metastasis and revealed no malignancy. A meta-[¹²³I]iodobenzylguanidine (MIBG) SPECT-CT was performed (Fig. 3) and demonstrated the large mass with avid radiotracer uptake. Mass extension into the pelvis, lumbar and sacral vertebrae, and the left psoas muscle was observed. Collectively, these findings along with the degree of cell differentiation supported the diagnosis of ganglioneuroblastoma.

Fig. 2.

(A–B) CT-guided biopsy of the paraspinal lesion. H&E demonstrated small cells with scant eosinophilic cytoplasm and a fibrillary background with developing ganglion cells (A). Immunohistochemical stain was positive for synaptophysin (B); (C–D) Radical en bloc resection of the mass. H&E demonstrated both primitive neuroblastic (C) and mature ganglion components (D); (E–F) Peritoneal metastases. H&E demonstrated predominantly primitive neuroblastic component (E), which was positive for PHOX2B (F). Bar = 100 um.

Fig. 3.

A 33-year-old male with a history of nonspecific back pain and associated paraspinal mass, now presenting with lower back and lower left extremity pain with stiffness. Positron emission tomography demonstrated the known lumbosacral paraspinal mass with intense metabolic activity (arrow–A). Anterior (left) and posterior (right) projections of a meta-[¹²³I]-iodobenzylguanidine (MIBG) SPECT-CT demonstrate the large mass with avid MIBG uptake (arrow–B).

Two cycles of carboplatin, etoposide, cyclophosphamide, and doxorubicin were administered prior to surgery. The patient underwent a radical en bloc resection of the mass with discectomies at L3-L4 and L5-S1 and neurolysis of the L3-L5 nerve roots. Histologic sections demonstrated both primitive neuroblastic and mature ganglion components (Figs. 2C and D), and the final diagnosis of ganglioneuroblastoma, nodular type, was confirmed. The patient’s postoperative period was complicated by a pulmonary embolism which was managed with heparin therapy. Imaging on the 3-month follow-up showed no signs of recurrence at the site of resection. Six cycles of all-trans retinoic acid were begun as adjuvant therapy. Localized radiation therapy was employed to further manage his recovery. The patient is currently alive with metastatic recurrence to the spine and supraclavicular region and peritoneum 7 years after initial operation. Recent biopsy of the peritoneal metastasis demonstrated predominantly primitive neuroblastic component, which is positive for PHOX2B (Figs. 2E and F).

Discussion

Etiology and genetics

This article reviews a rare case of an adult-onset NT. Over 90% of documented NT cases are discovered before the age of 10, with the median age of diagnosis being 18 months [5]. Hence, there is a paucity of literature describing these entities in adolescent and adult populations. NBLs and other NTs arise from neural crest cells in the peripheral sympathetic nervous system (SNS), accounting for over 97% of SNS-derived tumors [6]. NBLs most commonly originate from the adrenal medulla or paravertebral sympathetic ganglia [7,8]. NTs are often heterogeneous in nature due to the variety of progenitor cells that may give rise to them, including pericytes, mesenchymal cells, immune cells, stem cells, and extracellular matrix components [9]. Neuroblastoma is a notoriously aggressive cancer, known to have a high propensity for metastasis. It has been reported that at the time of diagnosis, 75% of adult NBL patients have metastatic disease [10]. NBLs are characterized by several hallmark genetic mutations, the most common of which among adults include ATRX (58%) and ALK (42%) mutations [10]. Although MYCN amplification is frequently found in pediatric NBL tumor cells, this has not been demonstrated in adult populations. Deletions in chromosomes 1p, 11q, 14q, and insertions in chromosome 17q have also been documented in NBL patients [5]. The presence of these genetic mutations and hypermethylation of RASSF1A and CASP8 have been strongly correlated with poorer clinical outcomes [11]. Other etiologies of NTs include exposure to environmental carcinogens, radiation exposure, or sporadic mutations. Given that this patient had no known family history of cancer, it was favored that this tumor was sporadic in origin.

Imaging

The most common first-line screening modality for NTs is ultrasound (US) due to its wide availability and noninvasive nature [12]. However, this recommendation may be biased towards pediatric populations, and its efficacy in adults is not described. NTs typically present on US as heterogeneous solid masses with internal calcifications. Other features on US indicative of NTs include encasement of local vessels and bulky lymphadenopathy [13]. In addition to US, cross-sectional imaging to assess disease extension remains a necessary step in the diagnosis and staging of NTs [14]. CT and magnetic resonance imaging (MRI) are effective cross-sectional modalities, but MRI may be more advantageous due to its intrinsic high contrast and radiation-free procedure. Furthermore, diffusion weighted imaging (DWI) is particularly useful in assessing distant metastasis of NBL as these tumors exhibit strong diffusion restriction [13]. NTs typically present on CT and MRI as large, multilobulated, heterogeneous and solid masses [15]. Stippled calcifications are a strong indicator of NBL, and they are known to be present in over 85% of NBL cases [16]. Bone metastasis is a central concern in NBL, and ¹²³I -MIBG scintigraphy is used to assess malignancy in bone. Over 90% of primary NBLs exhibit avid uptake of the ¹²³I -MIBG radiotracer [17]. The large, heterogeneously enhancing and multilobulated paraspinal mass found on this patient’s CT imaging was consistent with the NT spectrum. Furthermore, this patient’s MIBG imaging demonstrated marked radiotracer uptake by the retroperitoneal mass.

Imaging features of NTs are key components in risk stratification for the disease. The International Neuroblastoma Risk Group Staging System (INGRSS) is a preoperative staging system that accounts for 20 image-defined risk factors (IDRFs) to classify NBL and other NTs. These IDRFs include but are not limited to encapsulation of neurovascular elements, intraspinal tumor extension, and compression of local structures [15]. The INGRSS classifies NBL in one of 4 stages: locoregional tumor without IDRFs (L1), locoregional tumor with one or more IDRFs (L2), tumor with distant metastatic disease (M), and tumor with metastatic disease confined to the skin, liver, or bone marrow (MS) [18]. This patient’s NT was classified in the L2 group given the presence of several IDRFs and absence of metastases at the skin, liver, bone marrow, or distant sites. As treatment strategies differ between NT stages, accurately characterizing a patient’s NT is a key component of effective management for this entity.

Pathology and laboratory study

Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma are all neuroblastic tumors that share many radiological features, but they can be distinguished with histopathological analysis. Neuroblastomas are composed primarily of neuroblasts with less than 50% Schwannian cells present [19]. Morphologically, these tumors are composed of small and uniformly sized cells with hyperchromatic nuclei and scant cytoplasm [20]. The immunohistochemistry of neuroblastomas is consistent with neural crest origin, positive for neuron-specific enolase (NSE), synaptophysin, chromogranin, Phox2b, and S100 stains surrounding Schwann cells. [21]. Neuroblastomas can be categorized as one of 3 subtypes: undifferentiated, poorly differentiated (<5% of cells showing ganglionic differentiation), and differentiating (>5% of cells showing ganglionic differentiation) [1]. Generally, undifferentiated neuroblastomas result in the least favorable prognoses. Ganglioneuroblastomas have a dominant proportion of Schwannian cells (>50%) and have either small nests of neuroblasts (intermixed ganglioneuroblastoma) or nodules of neuroblasts (nodular ganglioneuroblastoma). Ganglioneuromas are composed predominantly of Schwannian cells with scattered mature ganglion cells, and they are benign. Neuroblastomas can also be analyzed via catecholamine urinalysis, as these tumors are characteristically known to produce and secrete homovanillic acid (HVA) and vanillylmandelic acid (VMA) [22]. Elevated levels of HVA and MVA in a urinalysis may confirm catecholamine-secreting activity of a suspected neuroblastoma, further supporting diagnosis. In our patient’s case, the suspected NT demonstrated reactivity for synaptophysin, chromogranin, and S100. Furthermore, catecholamine urinalysis revealed abnormally high levels of HVA and VMA. This patient’s histology revealed components of maturing and differentiating ganglion cells, consistent with intermediate features along the NT spectrum. Along with prior imaging studies, these histopathological and laboratory results supported a diagnosis of GNB.

Presentation, diagnosis, and management

NTs often present clinically with nonspecific pain associated with tumor mass effects on locoregional structures. Diagnosis is facilitated by various imaging modalities and laboratory studies but ultimately requires confirmation by surgical biopsy and histopathological analysis [20].

There is no putatively established therapy for adult-onset NTs, but they are typically treated in the same manner as pediatric cases [10]. Standard treatment for malignant NTs entails chemotherapy, surgical resection, and radiotherapy. Patients with locoregional NBLs generally have excellent response to surgery alone, with chemotherapy administered only in cases of relapse [20]. However, in cases of metastasis, surgery may not be a viable option, in which case high-dose chemotherapy is chosen as a management strategy. Commonly employed chemotherapeutic agents include cyclophosphamide, doxorubicin, vincristine, cisplatin, and etoposide [23]. In many cases, external beam radiotherapy may be administered to the primary tumor site following surgical resection. The patient reported in the case above was managed with 2 cycles of carboplatin, etoposide, doxorubicin, and cyclophosphamide, followed by radical en bloc resection of the mass. Adjuvant chemotherapy and radiotherapy were employed for postoperative management.

The complex tumor microenvironment of NTs often makes them challenging etiologies to treat, as molecular and genetic variations in the disease may render certain treatments ineffective. Various mechanisms underlying the pathogenesis of NBL, such as VEGF dysregulation, MHC class I antigen dysregulation, and various genetic mutations and aberrations respond to different treatments [2]. In the event of relapse or chemorefractory NBL, anti-GD2 immunotherapy serves as a viable treatment option [24]. Inhibitor therapies for molecular targets such as ALK2, histone deacetylases, PI3K, and mTOR also show therapeutic promise in cases of high-risk NBL [25]. Genetic testing and/or laboratory analysis prior to chemotherapy selection for NTs can be advantageous in both adult and pediatric populations. More options for targeted treatment are emerging as our understanding of NT etiologies continues to grow.

Conclusion

In conclusion, NTs are predominantly pediatric tumors, most commonly manifesting as NBL. Despite their profound rarity, NTs can still occur in adult populations. Imaging remains a crucial diagnostic modality in the evaluation of paraspinal masses, but histopathological analysis and laboratory study are essential to make a final diagnosis. Although age is commonly used as a predictor of NTs in children, it is important to consider NTs in the differential of retroperitoneal masses in adults. As NTs have a high propensity for metastasis, it is important to employ cross-sectional imaging and radiotracer scintigraphy to assess disease extension and therefore select the optimal treatment regimen.

Data availability

Data sharing is not applicable to this article as no new data was created or analyzed in this study.

Patient consent

Written informed consent for publication of this case report and associated images was obtained from the patient.