Peripheral neuroblastic tumors (pNTs) are malignant neoplasms originating from multipotential sympathetic neuroblasts, which themselves differentiate from embryonic primitive neural crest cells. These tumors are predominantly located along the sympathetic nervous tract. Classification of pNTs, based on the ratio of Schwann cells to neuroblasts and the extent of cellular maturation and differentiation, includes neuroblastoma (NB), ganglioneuroblastoma (GNB) and ganglioneuroma (GN) (1). GNB is comprised of elements of both malignant NBs and benign GNs, meaning that it has intermediate malignant potential (2). GNB features intermediate cell types with varying degrees of maturation, reflecting the biological heterogeneity of pNTs and their differentiation and maturation capabilities. The pathogenesis of GNB is commonly attributed to the abnormal development, maturation or regression of primitive neural crest cells or neuroblasts (3). GNBs are very rare, with an incidence of ~0.5 cases per 100,000 individuals in the pediatric population. In the adult population, the incidence of GNB is even rarer, with <0.01 cases per 100,000 individuals (4). The clinical symptoms are non-specific, complicating the preoperative diagnosis, and the definitive diagnosis relies on the postoperative pathological examination (5).

The present study reports the case of an adult female diagnosed with left adrenal GNB, accompanied by metastasis near the renal hilum. To enhance comprehension of this rare tumor, a comprehensive literature review was also conducted, focusing on the clinical manifestations and pathological features of GNB, and summarizing the current knowledge on its diagnosis, treatment and prognosis. The study aims to offer valuable insights for the effective understanding and management of this uncommon condition.

A 20-year-old woman, with no prior history of disease, presented with the incidental discovery of a left adrenal mass during a routine physical examination in September 2022 at The First People's Hospital of Yunnan Province (Kunming, China). A computed tomography (CT) scan revealed an oval, soft-tissue density shadow in the left splenorenal space, ~5.7×4.1 cm in size. The mass exhibited mild arterial phase enhancement and persistent venous phase enhancement, with heterogeneous contrast (Fig. 1A). Initially, the radiologist diagnosed it as a left adrenal gland adenoma. The patient's overall health was satisfactory, and a comprehensive physical examination was otherwise normal. Laboratory tests indicated plasma catecholamines levels as follows: 3-methoxytyramine, <0.08 nmol/l (normal reference, <0.18 nmol/l); methoxyadrenaline, 0.12 nmol/l (normal reference, ≤0.5 nmol/l); and methoxynorepinephrine, 0.3 nmol/l (normal reference, ≤0.9 nmol/l). A 24-h urine specimen revealed the following: Methoxyadrenaline, 118 nmol/24 h (normal reference, <216 nmol/l/24 h); methoxynorepinephrine, 179 nmol/24 h (normal reference, <312 nmol/l/24 h); 3-methoxytyramine, 413 nmol/24 h (normal reference, <382 nmol/l/24 h); and urinary cortisol, 32.9 µg/24 h (normal reference, 3.5–45 µg/24 h). In a standing and supine position, whole-body blood analysis showed renin at 99.8 (normal reference, 4.0–38.0) and 15.0 pg/ml (normal reference, 4.0–24.0 pg/ml), respectively, adrenocorticotropic hormone at 15.052 and 31.276 pg/ml (normal reference, 7.200–63.400 pg/ml), respectively, cortisol at 15.008 and 18.108 µg/dl (normal reference, 4.260–24.850 µg/dl), respectively, and aldosterone at 275.173 pg/ml (normal reference, 40.000–310.000 pg/ml) and 114.743 pg/ml (normal reference, 10.000–160.000 pg/ml), respectively. The adrenal function tests were within normal limits, except for an elevated 24-h urinary 3-methoxytyramine level and standing plasma renin concentration. Liver and kidney function tests showed total protein at 60.9 g/l (normal reference, 65–85 g/l) and globulin at 19.9 g/l (normal reference, 20–40 g/l), both slightly below normal, and uric acid at 420 µmol/l (normal reference, 178–416 µmol/l), slightly above normal. Among the tumor markers, the carbohydrate antigen 72-4 level was 8.93 U/ml (normal reference, 0.0–6.9 U/ml). The urinary routine indicator urinary biliogen was measured at 34 µmol/l, which was marginally elevated. Other parameters such as blood routine, electrolyte level and coagulation function were within the normal ranges. For enhanced preoperative planning, a three-dimensional reconstruction of the preoperative mass area was performed. This process unexpectedly revealed a small-diameter mass near the renal hilum and adjacent to the left renal artery (Fig. 2A and B), suggesting a potential metastasis from the primary tumor. However, the proximity of the two masses did not eliminate the possibility of multiple separate tumors, thereby challenging the initial adenoma diagnosis.

Following meticulous preoperative planning and preparation, a laparoscopic resection of the left adrenal tumor was executed. Intraoperative observations corroborated the prior assessment of tumor metastasis. Leveraging the insights from the preoperative three-dimensional reconstruction, both the primary adrenal mass and the adjacent renal hilum mass were successfully excised. The perioperative period was uneventful with no complications. Postoperative pathological evaluation confirmed the renal hilum mass as a metastatic lesion originating from the adrenal GNB. The excised tumor was bifurcated for analysis. The adrenal mass presented as an oval, solid entity with an intact capsule, measuring ~7 cm in diameter. The tumor adjacent to the renal hilum was a round mass, ~1.5 cm in diameter. Neither section exhibited nodules or bleeding, displaying a grayish-yellow hue, with a slightly lobulated appearance (Fig. 2C and D). Histopathology and immunohistochemistry affirmed the diagnosis as intermixed GNB (Fig. 3). For histopathology, the specimens were fixed in 10% formalin solution for 14 h at room temperature (22–30°C). Embedding was performed in paraffin, and sections were cut to a thickness of 4 µm. Hematoxylin (10–30 min) and eosin (1–3 min) were used as stains, at room temperature. Observations were made using a light microscope (CX43; Olympus Corporation), with a magnification of ×40. For immunohistochemical analysis, paraffin-embedded tissue sections were fixed in 10% formalin solution at room temperature for 14–18 h and sectioned at a 4-µm thickness. Synapsin (Syn) and glial fibrillary acidic protein (GFAP) were highlighted as representative in immunohistochemistry. The polymer method was employed to block endogenous HRP activity, with a 3% hydrogen peroxide solution applied for 10 min prior to primary antibody application to eliminate endogenous activity. The primary antibody for Syn (cat. no. MAB-0742; Fuzhou Maixin Biotech Co., Ltd.) was used as supplied and incubated at 25°C for 60 min. DAB staining revealed the cytoplasmic localization of the target antigen as brown, with nuclei counterstained blue with hematoxylin. GFAP (cat. no. MAB-0769; Fuzhou Maixin Biotech Co., Ltd.) and Syn antibodies were also used for cytoplasmic staining. Observations were made using a light microscope (CX43), with a magnification of ×100. The gross tumor specimen exhibited a partial capsule with a gray-white to gray-yellow, slightly firm texture, without visible tumor nodules. Immunohistochemical and hematoxylin and eosin (H&E) staining revealed neuroblastic components positive for neurofilament proteins and Nestin, with varying expression levels of Syn, CgA, CD56 and S-100, while GFAP was negative. The presence of Nestin-positive ganglion cells and Schwannian stroma expressing S-100 was noted. Under H&E staining, neuroblastic components did not form nodular structures, displaying a diffuse and small nested distribution. Ganglion cells and Schwannian stroma (>50%) were interspersed within. These findings led to the diagnosis of GNB intermixed type.

At 3 months post-discharge, the patient returned for a follow-up and a residual oval soft-tissue density shadow, ~3.5×2.0 cm, was detected by CT in the area of the initial surgery (Fig. 1B). This finding raised the possibility of recurrence. Consequently, a follow-up positron emission tomography/CT scan was conducted, which indicated that recurrence of the aforementioned mass could not be discounted, although there was no evidence of systemic metastasis (Fig. 1C). Following internal discussions, it was deduced that while tumor recurrence could not be entirely excluded, the likelihood of scar encapsulation within the surgical area was plausible. To refine this assessment, the opinion of an external expert in pediatric tumors was sought through a national multicenter consultation. The expert's opinion leaned towards postoperative changes and advised close monitoring. The patient underwent further follow-ups at 7 and 12 months post-surgery, during which the mass progressively diminished in size (Fig. 1D and E), corroborating the initial assessment. Consequently, no recurrence or metastasis of the mass was observed during the 1-year postoperative period. In the second year post-surgery, it was recommended that the patient undergo follow-up examinations every 3 months, and subsequently, every 6 months. The patient's most recent follow-up revealed no discomfort, indicating a good recovery.

Previous reviews of the literature (6,7) reported ~50 cases of adult GNB. However, a search in the PubMed database (www.pubmed.ncbi.nlm.nih.gov/?db=PubMed) using the terms ‘ganglioneuroblastoma’ or ‘GNB’ combined with ‘adult’ yielded data inconsistent with these reports, particularly regarding basic information and case numbers. Data were modified and reorganized, excluding cases where patients were younger than 18 years at the onset of the disease, had significant missing clinical information or had mixed-type tumors, resulting in the identification of 104 cases of adult GNB (4,6–78) (Table I). The demographic breakdown included 54 males and 50 females, yielding a male-to-female ratio of 1.08:1. The mean age of the patients was 37.8 years (range, 19–88 years), with a median age of 34 years. The tumors appeared in various anatomical locations, with abdominal and pelvic involvement in 50 cases (48%), for which the adrenal glands were the most common site (29/50; 58%). This distribution, with a nearly equal male-to-female ratio (15:14), aligns with recent findings by Stevens et al (79), but contrasts with those in the studies by Bolzacchini et al (66) and Vassallo et al (77), which reported a male predominance in adult adrenal GNB. Following the adrenal glands, other common sites included the retroperitoneum, abdomen, kidneys, pelvis, small intestine and ovaries. The intrathoracic cavity was another frequent location for adult GNB (23/104; 22%), predominantly the mediastinum. GNB in the central nervous system accounted for 19% of cases (20/104), most commonly affecting the brain and spinal cord. Additional rare sites included the neck (3/104; 3%), bones (3/104; 3%), parotid glands (2/104; 2%) and nose (2/104; 2%). Distant metastases were noted in 27 cases (26%), with localized infiltration in 15 cases (14%), indicating that ~40% (42/104) of patients experienced metastasis or dissemination. This finding corresponds with the research of LaBrosse et al (80). However, Schipper et al (7) reported a slightly higher incidence of metastasis or localized infiltration (56%) and purely localized infiltration (20%) in a study of 50 GNB cases.

Data analysis in the present study was performed using the R language (R Core Team), with a threshold of P<0.05 set for statistical significance. The analysis focused on the association between seven clinicopathological factors and OS in patients, and concentrating on those with complete follow-up data. Survival analysis was conducted using the Kaplan-Meier method, with differences between categories within same groups assessed using the log-rank test. The results indicated that factors such as patient sex, age, tumor size, primary tumor location, tumor pathology type and treatment regimen did not exhibit a statistically significant impact on OS (Fig. 4). However, the presence of local infiltration or distant metastasis was identified as a critical factor influencing OS rates (P=0.017) (Fig. 5). While traditional classification systems and several studies have categorized GNBn as having a poor prognosis and GNBi as having a favorable prognosis (81–83), the present analysis revealed that the effect of different tumor pathology types on OS in adult patients was not significant. Given the importance of tumor infiltration and distant metastasis in determining patient OS, further analysis was conducted using χ² tests and Fisher's exact probability tests. This analysis assessed the relationship between these outcomes and five clinicopathological characteristics (Table II). The findings showed that tumor infiltration and metastasis were not associated with the patient's sex, age, tumor size or tumor pathological type, but were significantly associated with the anatomical location of the tumor (P=0.017) (Table II). The highest incidence of infiltration and metastasis was found in tumors situated in the abdominal cavity and pelvis, excluding the adrenal gland (12/16; 75%). By contrast, the infiltration and metastasis rates for adrenal and intrathoracic tumors were both at 50% (11/22; 8/16), with the lowest incidence observed in central nervous system tumors (2/13; 15%).

pNTs represent the most prevalent category of extracranial neoplasms in children, originating from the primitive neural crest. The International Neuroblastoma Pathology Committee revised the International Neuroblastoma Pathology Classification in 1999, delineating pNTs into four histopathological types: NB, GNB intermixed type (GNBi), GN mature type and GNB nodular type (GNBn). Based on factors such as patient age, mitosis-karyorrhexis index and cell differentiation, these tumors are further classified into either a favorable histology group or an unfavorable histology group, with implications for prognosis (1,84). The present case was assigned to the favorable histology category according to this classification. Additionally, NB prognosis can be predicted using the International Neuroblastoma Staging System (INSS) and the International Neuroblastoma Risk Group (INRG) staging system (85,86). This case was classified as stage 1 in the INSS and stage L1 in the INRG staging, falling into the very low-risk group (risk grouping of A). Consequently, in accordance with pediatric guidelines (1), close follow-up was recommended without the administration of radiotherapy or chemotherapy.

When diagnosing GNB, its clinical presentations are generally non-specific. Among the 104 reported cases, symptoms predominantly arose from compression by the primary or metastatic lesions (8,35,47,60,62,65). Some GNB cases with endocrine activity presented with endocrine-related symptoms such as diarrhea and malaise (4,15,36,49,77). GNBs occurring in the central nervous system more frequently manifested neurological symptoms (7,20,22,23,31,44,48,67). While laboratory tests and imaging studies provide valuable preoperative references, they are not definitive for diagnosis. Pathological examination remains essential for a conclusive diagnosis. In the present case, a mass in the left adrenal gland was identified during a routine physical examination. The CT findings and laboratory tests, including adrenal function, were non-specific. The diagnosis was ultimately established based on the results of a postoperative pathological examination.

The treatment approach for GNB in adults largely mirrors pediatric guidelines, encompassing surgery, radiation therapy and chemotherapy (84). However, specific standardized guidelines or treatment protocols for adults are not established. Previous treatment strategies for adult GNB suggested that adult patients with distant metastases should continue radiotherapy and chemotherapy based on surgical resection (77). However, the present analysis of 24 patients with preoperative metastases and complete follow-up indicated that the choice of treatment in metastatic patients did not influence outcomes significantly (Fig. 6). By contrast, radiotherapy and chemotherapy might adversely impact the quality of life due to more severe side effects. Recent reports (66,68,71–73) have documented complete tumor resection in six cases, with metastases developing in two of them. Follow-up outcomes showed that all six patients achieved disease-free survival. Although the literature suggests that residual tumor does not adversely affect the prognosis in pediatric patients with GNB (87,88), reports in adults imply that complete resection of both primary and metastatic lesions is advisable, irrespective of the presence of metastatic lesions. For patients who cannot undergo a complete resection or who develop postoperative metastases, individualized comprehensive treatment is recommended to optimize survival rates. In the present case, complete surgical resection of the adrenal mass and metastasis was performed. The postoperative pathology and immunohistochemistry classified the case into a histologically favorable prognosis group. Consequently, despite the presence of metastases, and in line with pediatric guidelines and the literature analysis of previous case reports, the patient was advised to undergo close follow-up without further radiotherapy and chemotherapy.

Regarding prognosis and follow-up, the present analysis suggested that abdominal and pelvic lesions, excluding those of the adrenal gland, necessitate thorough preoperative examination and vigilant postoperative monitoring. Despite a lower incidence of metastasis in central nervous system tumors (2/13; 15%), adrenal or intrathoracic tumors may portend a more favorable outcome, often due to their association with more severe clinical symptoms. The interval for recurrence post-surgery varies widely, ranging from 3 months to as long as 192 months (57,59). Notably, a significant number of patients experience recurrence beyond the 2-year postoperative mark. Consequently, we advocate for a rigorous follow-up schedule: Examinations every 3 months for the first 2 years, followed by biannual check-ups for long-term monitoring.

Although the existing treatment approaches and prognostic assessments for adults with GNB are predominantly derived from pediatric guidelines and associated studies, their effects in managing GNB in adults have shown limitations. There is a pressing need for more comprehensive research specifically focused on adult GNB. The present case report and literature review is vital to enrich our understanding of the disease, increase awareness among physicians and adult patients, alleviate patients' apprehension about the disease, and ultimately, enhance the cure rate.