eMedicine Specialties > Radiology > Brain/Spine

Ganglioneuroma and Ganglioneuroblastoma

Author: Andrzej R Jedynak, MD, MS, Resident Physician, Department of Radiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, University Hospital
Coauthor(s): Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School; Yaron Lebovitz, MD, Assistant Professor of Radiology, University of Medicine and Dentistry of New Jersey; Consulting Staff, Department of Radiology, Section of Neuroradiology, University Hospital
Contributor Information and Disclosures

Updated: Jun 18, 2009

Introduction

Background

Ganglioneuromas and ganglioneuroblastomas are tumors of the sympathetic nervous system that originate from neural crest sympathogonia, which are completely undifferentiated cells of the sympathetic nervous system. Along with neuroblastomas, ganglioneuromas and ganglioneuroblastomas are collectively known as neuroblastic or neurogenic tumors.^1,2

Most frequently occurring in the abdomen, these tumors can grow wherever sympathetic nervous tissue is found. Common locations for ganglioneuromas and ganglioneuroblastomas include the adrenal gland, paraspinal retroperitoneum (sympathetic ganglia), posterior mediastinum, head, and neck; it is uncommon to find them in the urinary bladder, bowel wall, abdominal wall, and gallbladder.

Pathophysiology

Ganglioneuromas, ganglioneuroblastomas, and neuroblastomas are histologically differentiated by their stage of neuroblast maturation.³ Ganglioneuromas are composed of mature ganglion cells and are considered benign tumors. Ganglioneuroblastomas and neuroblastomas are less mature and are considered more aggressive and dangerous. These tumors have a higher neuroblast content and tend to occur in young children (median age: 2 years).

Composite neuroblastic tumors have been described as well; these tumors may have malignant nerve-sheath or pheochromocytoma tumors growing within them. In rare cases, von Recklinghausen disease, Beckwith-Wiedemann syndrome, Hirschsprung disease, central failure of ventilation, and DiGeorge syndrome have been associated with ganglioneuroma and ganglioneuroblastoma.⁴

In general, neuroblastic or neurogenic tumors appear radiologically as well-circumscribed, smooth or lobulated masses that may contain calcifications. The benign (ganglioneuromas) and malignant (ganglioneuroblastomas) forms of these tumors are virtually identical radiologically. The only differentiating factor is the possibility of distant metastases with malignant ganglioneuroblastomas. In the mid-1980s, the International Neuroblastoma Staging System (INSS) was developed to stage these tumors by using clinical, radiologic, and surgical data (see the eMedicine article Neuroblastoma in the Pediatrics section for more information on the INSS).⁴

Ganglioneuromas

Ganglioneuromas are rare, benign, fully differentiated tumors that contain mature Schwann cells, ganglion cells, fibrous tissue, and nerve fibers. These tumors have no immature elements (such as neuroblasts), atypia, mitotic figures, intermediate cells, or necrosis. The presence of any these tissue characteristics excludes the diagnosis of ganglioneuroma.⁵ Ganglioneuromas can grow almost anywhere along the paravertebral sympathetic ganglia, and they can sometimes grow in the adrenal medulla.⁶

These tumors can arise de novo and result from the maturation of a ganglioneuroblastoma or neuroblastoma into a ganglioneuroma. They may also develop within a neuroblastoma treated with chemotherapy. Metastases from ganglioneuromas are exceedingly rare. Metastasis is thought to be the end result of matured ganglioneuroblastomas or neuroblastoma metastases rather than true ganglioneuroma metastases. Ganglioneuromas secrete catecholamines in as many as 37% of cases.⁷

Overall, patients with ganglioneuroma have a favorable prognosis.

Ganglioneuroblastomas

Ganglioneuroblastomas are a mix of malignant neuroblastoma and benign ganglioneuroma tissues; they are sometimes called transitional tumors. These lesions also originate from sympathetic cells. Histologically, they are considered malignant because they contain primitive neuroblasts along with mature ganglion cells.¹

Ganglioneuroblastomas have a propensity for secreting catecholamines; approximately 90-95% actively secrete vanillylmandelic acid (VMA) and homovanillic acid (HVA). Catecholamine toxicity rarely results.⁴ HVA tends to be secreted by more mature and differentiated tumors, whereas VMA is usually a product of less differentiated tumors. In fact, the ratio of VMA to HVA secreted can be used as a prognostic factor to assess tumor maturity. In addition, more mature tumors may contain vasoactive intestinal peptide (VIP)–producing ganglion cells. Elevated levels of VIP can produce diarrhea, hypokalemia, and acidosis.

Despite these possible comorbidities, the prognosis for patients with ganglioneuroblastomas is relatively good. These tumors may spontaneously regress or mature. Maturation occurs at an unknown rate that eventually stops at the ganglioneuroma stage. In fact, all ganglioneuromas are thought to have once been, at an earlier stage of their development, ganglioneuroblastomas or neuroblastomas.³ Regression occurs in 1-2% of tumors; the cause of ganglioneuroblastoma regression is unknown.

Frequency

United States

The posterior mediastinum is the most frequent site of occurrence (38% of cases), followed by the retroperitoneum.⁸ Roughly 20% of these tumors occur in the adrenal medulla, and cervical lesions account for only 10% of cases. Uncommon locations, such as heart, bone, and intestines, have also been described.⁴ Tumors located in the central nervous system are rare.

Ganglioneuroblastoma tumors are usually found in the adrenal medulla (35%), retroperitoneum (30-35%), posterior mediastinum (20%), neck (1-5%), and pelvis (2-3%). Other locations, such as the thymus, lung, kidney, anterior mediastinum, stomach, and cauda equina, are affected less frequently and are considered unusual. Approximately 1% of these tumors metastasize.^1,6,9,10,11

Mortality/Morbidity

Patients with low-risk or intermediate-risk tumors have a relatively good prognosis. Children with INSS stage 1, 2, and 4S tumors have a 3-year event-free survival rate of 75-90%. Children younger than age 1 year with stage 3 tumors have a 1-year event-free survival rate of 80-90%, and children younger than age 1 year with stage 4 tumors have a 1-year event-free survival rate of 60-75%. Children older than age 1 year with INSS stage 3 tumors have a 3-year event-free survival rate of 50%, and children older than age 1 year with INSS stage 4 tumors have a 3-year event-free survival rate of 15%.¹²

• Ganglioneuromas can metastasize. See Ganglioneuromas in the Clinical Details section below.
• Overall, patients with ganglioneuroma have a favorable prognosis. See Intervention below.

Sex

Ganglioneuromas occur slightly more often in girls than in boys, with a female-to-male ratio of about 1.5:1.⁴ Ganglioneuroblastomas occur with equal frequency in boys and girls.¹

Age

Neuroblastic tumors account for approximately 15% of neoplasms in children younger than age 4 years, and more than 90% of cases are diagnosed before the patient is aged 5 years. These statistics make neuroblastic tumors the most common solid neoplasm in children occurring outside the central nervous system.

• Ganglioneuromas usually occur in adolescents and young adults (40-60%), but individuals of all ages can be affected.¹ The mean age of occurrence is 7 years.
• Ganglioneuroblastomas most commonly occur in infants and in young children; they almost never occur after age 10 years.¹ Ganglioneuroblastomas and neuroblastomas tend to occur in young children (median age: 2 years).

Anatomy

Gross anatomic features

The gross appearance of neurogenic tumors varies greatly as a result of several factors, such as the number of ganglion cells and the degree of differentiation.¹ In general, these neoplasms are rarely larger than 10 cm in diameter, and they can be either well-circumscribed or infiltrative; neoplasms occurring in the adrenal medulla and posterior mediastinum tend to be well-circumscribed. Although neuroblastic tumors are generally not encapsulated, they do appear to have a capsule.

Ganglioneuroma and ganglioneuroblastoma specimens feel firm to the touch, and they can be either smooth or lobulated. The cut surface may be hemorrhagic (neuroblastic tissue), tan (stroma), or necrotic. Areas of calcifications may be observed.⁴

Histologic features

The primary histologic features of these tumors are neuroblasts (immature, undifferentiated sympathetic cells), ganglion cells (mature cells), Schwann cells, and stroma (tissue surrounding the ganglion cells). Secondary histologic features include necrosis, mitosis, hemorrhage, fibrosis, calcification, lymphocytic infiltrate, and karyorrhexis (fragmentation of cellular nuclei that usually symbolizes cell death).

Ganglioneuromas are considered to be mature tumors that do not have immature elements such as neuroblasts and mitotic activity. The presence of neuroblasts automatically makes the tumor a ganglioneuroblastoma or neuroblastoma, thereby excluding the diagnosis of ganglioneuroma. Ganglioneuromas average 8 cm in size and have a pseudocapsule. They are firm to the touch and have a light color, ranging from white to yellow. Internally, the tumor may have a whorled appearance, with trabeculae.

Risk groups

These neoplasms are histologically classified into risk groups by using 2 distinct systems: the Shimada classification (see the eMedicine article Neuroblastoma in the Pediatrics section for a discussion of the Shimada classification system) and the Pediatric Oncology Group (POG) classification.¹³ These systems are not meant for staging the disease; instead, they use histologic features to assess the prognosis of a specific tumor.

The POG classification system uses only the histologic differentiation of the tumor components to assess the prognosis. Ganglioneuroma, for example, has completely mature and differentiated cells and stroma; therefore, patients with ganglioneuroma have a good prognosis.

Ganglioneuroblastoma, on the other hand, is composed of both mature ganglion cells and immature neuroblasts; therefore, it is considered to have an intermediate potential for malignancy.

The Shimada classification considers patient age in addition to the histologic appearance in the stratification of a tumor. Histologic features taken into consideration are stromal components (stroma-rich tumors are more mature than stroma-poor tumors), grade, cellular differentiation, and nuclear morphology.

Each of these categories is further divided into multiple subcategories. The tumors are eventually classified as having either favorable or unfavorable histologic characteristics. Favorable histologic characteristics are usually found in patients younger than age 1.5 years with a low-to-intermediate mitosis-karyorrhexis index (MKI) and a differentiating or partially differentiating tumor, and in patients aged 1.5–5 years with a low MKI and a differentiating tumor.

All remaining combinations are classified as unfavorable histologic characteristics.¹⁴ "The mitosis-karyorrhexis index (MKI) is defined as the number of tumor cells in mitosis and in the process of karyorrhexis. Mitotic figures are characterized by more or less rod-shaped condensations of chromatin, with spiked projections and the absence of a nuclear membrane. Karyorrhectic cells show condensed and fragmented nuclear material usually accompanied by condensed eosinophilic cytoplasm."³

Presentation

Ganglioneuromas

Ganglioneuromas are usually asymptomatic, regardless of their size, and they are typically discovered on a routine radiograph; however, abdominal pain, dyspnea, cough, and palpation of an abdominal mass may be clinical indicators of a ganglioneuroma. These tumors may be hormonally active, and hypertension, diarrhea, flushing, and virilization may occur as a result the secretion of catecholamine, vasoactive intestinal polypeptide, or androgenic hormone. Nonetheless, emergency situations caused by catecholamine secretion are rare.^9,15

Ganglioneuroblastomas

Patients with ganglioneuroblastomas often present with pain caused by either the primary tumor or by metastatic disease and abdominal distention. Patients may also complain of irritability, weight loss, malaise, shortness of breath, peripheral neurologic symptoms (nerve or nerve root compression), and Horner syndrome (ptosis, myosis, and ipsilateral anhydrosis).⁴

When ganglioneuromas and ganglioneuroblastomas metastasize, bone is the most common site of metastatic spread. Up to 60% of ganglioneuroblastoma/neuroblastoma patients have bone metastasis at the time of presentation. Bone metastasis accompanied by limping and irritability is called Hutchinson syndrome. Bone metastases occur in 2 patterns: diffuse (cortical, with a poor prognosis and a poor response to chemotherapy) and nodular (prognostically more favorable disease of the bone marrow). 

Another organ that may harbor metastatic tumors is the liver. Liver metastases can also have diffuse or nodular patterns. Pepper syndrome is the presence of large liver metastases in infants. Intra-abdominal pressure may reach such high values in these patients that abdominal surgery may be required to relieve it.

In children younger than 1 year, skin metastases are common. These metastases occur as darkly pigmented masses resembling blueberries (called "blueberry muffin syndrome").

The lung, dura, and brain are considered unusual locations for metastases.⁴

A case report of nephrotic syndrome (membranous glomerulonephritis) caused by ganglioneuroma antigen–specific antibodies cross-reacting with glomerular podocyte membrane antigen has been reported.⁸

Screening

Screening infants for ganglioneuroblastoma by using vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels in urine has been investigated. The results indicate that screening usually can detect small, low-grade, and histologically favorable tumors. These tumors most likely regress, mature, or remain undiscovered. In addition, infant screening has no affect on the incidence of higher-grade, more malignant tumors in older children. One study showed no effect on the outcomes of aggressive tumors discovered in infants with screening.¹⁶

Preferred Examination

Magnetic resonance imaging (MRI) and computed tomography (CT) scanning are the preferred methods for imaging ganglioneuromas and ganglioneuroblastomas.^17,18,19

MRI is the modality of choice for evaluating the extension of spinal tumors.⁴

CT scanning is the imaging modality that is most commonly used to evaluate neuroblastic tumors. It has proven to be the superior imaging technique when identifying tumor size, organ of origin, tissue invasion, vascular encasement, adenopathy, and calcifications. Newly diagnosed cases are evaluated with standard chest, abdominal, and pelvic CT scans.⁴

Differential Diagnoses

Adrenal Adenoma
Adrenal Carcinoma
Neuroblastoma
Pheochromocytoma

Other Problems to Be Considered

Neurofibroma
Schwannoma

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• Presence of Cancer-associated Fibroblasts Inversely Correlates with Schwannian Stroma in Neuroblastoma Tumors