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Neuroblastoma

Neuroblastoma

Epidemiology:

Neuroblastoma, a highly heterogeneous pediatric malignancy arising from sympathetic nervous system tissue, represents one of the most common solid tumors in childhood, with approximately 700 new cases diagnosed in the United States each year 1. Notably, spontaneous remission (SR) is a relatively frequent, albeit still extraordinary, occurrence in neuroblastoma, with reported rates of regression reaching as high as 50% in infants with low-risk tumors 2. The mechanisms underlying spontaneous regression remain poorly understood but have been attributed to factors including immune response and tumor biology, complicating the establishment of precise estimates for true SR prevalence 3. Although instances of SR can be life-altering and open new avenues for treatment strategies, the sporadic nature of these regressions often means that many cases may remain unreported or inadequately documented, thus obscuring their overall significance within the epidemiological landscape of neuroblastoma 4.

Clinical Characteristics:

To date, 44 well-documented cases of spontaneous remission involving neuroblastoma have been reported between 1953 and 2020. The ages of affected individuals ranged from newborns to four years, with a peak incidence during infancy, particularly in patients less than one year of age. A modest female predominance was observed, consistent with prior reports suggesting a slightly higher frequency of spontaneous regression among females. Hepatic, pelvic, adrenal, and retroperitoneal primary sites were most frequently involved, with remission commonly occurring in the liver, mediastinum, or regional lymph nodes. Overall, spontaneous remission tended to occur in infants with localized or maturing lesions, often in association with metabolic, immune, or differentiation-related mechanisms. See Table 1 for further details.

Histological Characteristics:

Patients who experienced spontaneous remission of neuroblastoma typically presented in early infancy with abdominal masses or hepatomegaly. Diagnosis was confirmed by imaging and histopathology, most often revealing localized or maturing lesions in the liver, adrenal glands, pelvis, or retroperitoneum. Remission commonly occurred in the liver, mediastinum, or lymph nodes and was attributed to mechanisms such as vitamin B12-induced maturation, immune or viral responses, necrosis, or spontaneous differentiation. Follow-up assessments confirmed tumor regression or maturation, with most cases demonstrating long-term remission extending well beyond expected clinical outcomes.

Proposed Contributing Mechanisms:

Various mechanisms have been proposed to explain spontaneous remission in neuroblastoma. The most frequently reported involve tumor maturation and differentiation, often influenced by metabolic or immune factors. Other suggested contributors include viral oncolysis, ischemic necrosis, and immune activation following infection or treatment. Remission has also been associated with vitamin B12 therapy, steroid withdrawal, and radiation exposure, supporting the view that multiple biological pathways may trigger tumor regression.

Site and Extent of Remission:

The liver and adrenal glands were the most common primary sites associated with spontaneous remission in neuroblastoma, followed by the pelvis and retroperitoneum. In most cases, regression occurred at the primary tumor site, while a few demonstrated multifocal or distant remission involving the mediastinum, lymph nodes, or skin. Reports from later decades also described remission following vitamin B12 therapy, radiation exposure, or immune activation at the original site. The duration of follow-up ranged from several months to over two decades, with most patients maintaining long-term clinical stability or complete remission. Unlike other pediatric malignancies, spontaneous remission in neuroblastoma was typically durable, with minimal evidence of recurrence or disease progression.

Table 1: Neuroblastoma SR Cases and Clinical Characteristics

Author–year

Age/sex

Primary site

Remission site

Proposed mechanisms

Follow-up

Bodian, 19535

Not reported

Pelvic

Not reported

Vitamin B12 effect

3 years

Bodian, 19546

Not reported

Not reported

Not reported

Vitamin B12 effect

Not reported

Bodian, 19546

10 months/F

Legs, extradural fat, para-vertebral

Not reported

Vitamin B12 effect

Not r eported

Bodian, 19546

10 months/F

Retroperitoneal

Not reported

Vitamin B12 effect

Not reported

Bodian, 19546

4 months/F

Spinal cord, abdominal, spinal canal

Not reported

Vitamin B12 effect

1 year

Antoniazzi, 19547

2/F

Head, thoracic region

Lymph node, thoracic mass

Necrosis and hemorrhage

Not reported

Bodian, 19558

Newborn/F

Liver

Liver

Vitamin B12 effect

6 months

Bodian, 19569

3 weeks/M

Pelvic, abdominal

Pelvic region

Vitamin B12-induced maturation

7 months

Bodian, 195710

Not reported

Not reported

Not reported

Vitamin B12 effect

7 months to 6 years

Kincaid et al., 195711

Not reported

Abdominal or thoracic paravertebral

Not reported

Spontaneous maturation

Not reported

Bodian, 195912

Not reported

Not reported

Not reported

Vitamin B12 effect

1–8 years

Gross et al., 195913

6 weeks/F

Pelvis, posterior mediastinum

Abdominal mass, mediastinum

Ischemic necrosis, immune response

20–25 years

Gross et al., 195913

11 months/F

Suprarenal area, regional lymph nodes

Abdominal mass, mediastinum

Ischemic necrosis, immune response

20–25 years

Dargeon, 196014

4 months/F

Subcutaneous nodules, liver

Subcutaneous nodules

Not reported

2.5 years

Hornstein & Mülke, 196015

3 weeks/F

Right suprarenal gland

Skin, subcutaneous tissue

Viral oncolysis

2 years

King et al., 196116

3 days/M

Liver, spleen, skin

Skin, liver, spleen

Viral oncolysis

Not reported

Dargeon, 196217

Not reported

Not reported

Not reported

Not reported

Not reported

Eyre-Brook & Hewer, 196218

3 months/F

Right lumbar region, abdomen, pelvis

Abdominal tumor

Spontaneous maturation

10 years

Bodian, 196319

4 months/M

Chest, liver, thorax

Liver, thorax

Not reported

15 years

Bodian, 196319

7 months/M

Pelvis, rectum

Pelvis

Vitamin B12 effect

12 years

Bodian, 196319

4 months/F

Spinal canal, lumbar region

Not reported

Vitamin B12 effect

2 years

Bodian, 196319

Newborn/F

Liver

Liver

Vitamin B12 effect

7.5 years

Bodian, 196319

Newborn/M

Right loin

Abdominal region

Vitamin B12 effect

6 years 7 months

Bodian, 196319

8 months/F

Liver

Liver

Vitamin B12 effect

3 years

Carvalho, 197320

Newborn/M

Right eye

Multiple metastases

Spontaneous cure

Not reported

Ghazali, 197421

7 months/M

Pelvis

Pelvic region

Vitamin B12 effect

4 months

Ghazali, 197421

Newborn/F

Sacrum

Sacral region

Vitamin B12-induced maturation

17 years

Schwartz et al., 197422

1 week/F

Liver

Liver

Immune response

Several months

Schwartz et al., 197422

2 months/F

Paravertebral sympathetic ganglion

Skin

Immune response

4 months

Evans et al., 197623

Newborn/F

Liver, left adrenal

Liver

Spontaneous maturation

3 years

Evans et al., 197623

4 years/M

Abdomen, superior-posterior mediastinum

Abdomen, mediastinum

Spontaneous maturation

14 years

Eklöf et al., 198324

10 months/M

Right adrenal

Brain, scalp, skeleton

Steroid withdrawal response

4.5 years

Haas et al., 198825

Newborn/M

Left suprarenal

Adrenal gland

Spontaneous maturation

6 years 9 months

Bujanover et al., 199026

5.5 months/M

Liver

Liver

Spontaneous necrosis or maturation

6 months

Matsumura et al., 199127

Matsumura et al., 1991

Right adrenal

Adrenal gland

Natural course

18 months

Komuro & Hoshino, 201328

6 months/Not reported

Left cervicomediastinal

Primary tumor

Not reported

21 months

Komuro & Hoshino, 201328

Newborn/Not reported

Right cervicomediastinal

Cervicomediastinal region

Not reported

2 years

Komuro & Hoshino, 201328

Newborn/Not reported

Left cervicomediastinal

Liver, lymph nodes, skin, bone marrow

Radiation-induced necrosis

320 days

Liu et al., 202029

Liu et al., 2020

Retroperitoneum

Retroperitoneal region

Not reported

2 months

Cole, 197630

Immune response

Birewar & Lokeshwar et al., 199131

Newborn/M

Orbits

Orbits

Neurocristopathies

9 months

Sirtori & Pizzetti et al., 195632

2/M

Ischemic necrosis, cellular differentiation, defensive action of the stroma

Spontaneously regressed for five years

Sirtori & Pizzetti et al., 195632

Few months/M

Ischemic necrosis, cellular differentiation, stroma action

Spontaneously regressed for 4 years

Sirtori & Pizzetti et al., 195632

26/F

Ischemic necrosis, cellular differentiation, stroma action

Regressed for 7 years

Evans & Koop et al., 197133

5M

Abdomen

Liver

3 years

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  18. Eyre-Brook AL, Hewer TF. Spontaneous disappearance of neuroblastoma with maturation to ganglioneuroma. J Bone Joint Surg Br. 1962;44-B(4):886–890.
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  20. Carvalho L. Spontaneous regression of an untreated neuroblastoma. Br J Ophthalmol. 1973;57(11):832–835.
  21. Ghazali S. Pelvic neuroblastoma; a better prognosis. Ann Surg. 1974;179(1):115–118.
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