Neuroblastoma

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Classification according to ICD-10
C74 Malignant neoplasm of the adrenal gland
C74.1 Adrenal medulla
C48 Malignant neoplasm of the retroperitoneum and peritoneum
C48.0 Retroperitoneum
C47 Malignant neoplasm of the peripheral nerves and the autonomic nervous system
ICD-10 online (WHO version 2019)

The neuroblastoma is seven to eight percent of all cancers in children, the third most common malignant neoplasm in children. Starting from the autonomic nerve tissue - the embryonic neural crest - it is a tumor whose cells (so-called neuroblasts ) have remained in an immature stage. It is mainly found in the adrenal glands, along the spine, in the head, neck and neck area, as well as in the chest, abdomen and pelvis along the cervical, thoracic and abdominal trunk and in the paraganglia . About 70 percent lie outside the abdominal cavity in the retroperitoneal space and about 20 percent between the lungs in the mediastinum .

frequency

Neuroblastoma affects around one in 100,000 children, in Germany around 150 children annually. A third of these children fall ill in their first year of life, 90 percent of tumors appear before school starts, and the mean age at onset is two years. The risk of illness decreases with age, but in rare cases adults can also be affected. In half of the cases, metastases are already present at the time of diagnosis , especially in the regional and distant lymph nodes , in bone marrow , bones , liver , skin , and rarely in the central nervous system .

Symptoms

The symptoms of neuroblastoma are determined by the location of the primary tumor or metastases . In tumors located in the trunk, neurological symptoms up to cross-sectional symptoms can be found through ingrowth into the spinal canal; if they occur in the neck area, Horner's syndrome occurs in 15 to 20 percent ; If it occurs in the chest area, it may cause shortness of breath, with tumors located in the abdominal area or retroperitoneally, stomach and back pain, urinary tract and intestinal problems. Metastases cause a reduced general condition, pain , paleness, fever and weight loss. High blood pressure or diarrhea can occur due to the hormonal activity of the tumor. Eyeglass hematomas are an indication of a retrobulbar neuroblastoma.

Diagnosis

Computed tomography of a neuroblastoma with lymph node metastases and walling of the aorta

The diagnosis is carried out in the early stages usually randomly using ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI), which were made for other reasons. As a result, the MIBG scintigraphy leads to the localization of the primary tumor and any metastases that may already be present. The skeletal scintigraphy using technetium phosphonates is used to distinguish between bone marrow and bone metastases used. With regard to laboratory tests, it should be mentioned that the tumor markers vanillin-mandelic acid , homovanillic acid , dopamine and neuron-specific enolase (NSE) , which were used until recently for tumor screening, are still important for monitoring therapy and progress (see below). Another tumor marker is ferritin. Both NSE and ferritin are primarily used to monitor the progress.

A bone marrow puncture is essential if a neuroblastoma is suspected. It is used to detect (stage IV) or to exclude an involvement of the bone marrow by the neuroblastoma. Typically, in contrast to the standard procedure for bone marrow puncture, a puncture is made at four points of the iliac crest (two puncture points in the anterior pelvis, two puncture points in the rear pelvis). An infestation is present if neuroblastoma cells can be detected in one of the four puncture sites cytologically , immunohistochemically or molecularly. A bone marrow puncture can only be dispensed with in exceptional cases.

Neuroblastoma histology

When examined under a microscope, tumor tissue often consists of cells with dense nuclei that contain only a small amount of cytoplasm . The development of a pseudo rosette pattern is characteristic. Individual ganglion cells are found here and there . If there are numerous ganglion cells, the tumor may already have differentiated into a ganglioneuroblastoma .

Staging, therapy, prognosis

The International Neuroblastoma Staging System (INSS) differentiates between the following disease stages :

  • 1: Localized tumor limited to site of origin,
  • 2a: Localized tumor infiltrates the area without crossing the midline, no lymph node involvement,
  • 2b: Localized tumor infiltrates the area without crossing the midline, homolateral lymph node involvement,
  • 3: Localized tumor crosses the midline, regional lymph nodes can be affected on both sides,
  • 4: Hematogenous distant metastases,
  • 4-S: like 1 or 2, but with distant metastases in the liver, skin; may only minimally encroach on the bone marrow; occurs only in infancy and can resolve spontaneously, so one can wait for clinically stable infants and careful monitoring.

The histological classification (" grading ") is carried out according to Hughes, and molecular genetic analysis of the tumor material is also carried out.

Therapy: In stages 1 and 2, the sole surgical removal of the tumor is sought; in the higher stages, the operation is preceded by chemotherapy . In stage 4, radiation therapy can also be used for selected tumor locations . This is followed by an autologous stem cell transplant with prior conditioning through high-dose chemotherapy. This is often combined with MIBG therapy (radioreceptor therapy). In the event of a relapse, haploident stem cell transplantation , antibody therapy and, if necessary, repeated MIBG therapy are possible. Retinoids and arsenic trioxide are available for maintenance therapy .
Prognosis: The 5-year survival rate for all stages together is approx. 55% and depends very much on the stage itself: in stages 1 to 2 mostly over 90%, in stage 3 approx. 75%, in stage 4 less than 20 %. The oncogene n-myc is a key tumor marker . Strong amplification is synonymous with an unfavorable course and a high likelihood of recurrence .

If MYCN amplification was not found, the 5-year survival rate is approx. 72%, if so, only approx. 31%.

In contrast to other types of cancer, the chance of spontaneous healing is very high. In stage 2a, spontaneous healing can be expected in 50%, in the rare stage 4S even in 80% of the cases.

Neuroblastoma screening

Because of this stage-dependent deterioration in the survival rate , there was an intensive search for reliable early detection methods. Neuroblastoma screening was finally developed at the children's clinic in Graz and introduced in 1991. Between 1991 and 1995 there was only one false negative result from 125,201 initial analyzes ; in 16 cases a disease was diagnosed and treated in good time.

The test was simple and cheap: tumor markers detectable in the urine - vanillin-mandelic acid (VMS) and homovanillic acid (HVS) - as breakdown products of hormones produced by the tumor itself, were tested in a combined method by using a test strip between the ages of 7 and 12 months Parents in the diaper. The costs for an Austria-wide screening would have been extremely cheap at around € 350,000 and the same as the intensive medical treatment of two advanced tumor diseases.

This screening did not meet expectations, as two independent and much larger studies published in the NEJM in April 2002 showed. Neither in Québec, Canada nor in six German federal states could the screening result in a reduction in mortality compared to the comparison groups.

For the German study, around 1.5 million children were examined with the aforementioned urine test in order to detect neuroblastoma at an early stage. About 150 neuroblastomas were diagnosed in this group and about 100 of these children were treated with surgery or chemotherapy. A control group comprised around 2.1 million children who were not actively screened for neuroblastoma and consequently were not treated unless neuroblastoma was diagnosed conventionally.

The overall mortality could not be reduced in the group that had participated in the screening compared to the control group. The reason for this is that the treatment success of those neuroblastomas that would have led to death without treatment were no greater than the risks associated with treatment - sometimes leading to the death of the patient - of those neuroblastomas that would have resolved on their own without treatment. The doctors who carried out this study therefore advise against screening for neuroblastomas given the current status of treatment options.

Special aspects

Correct interpretation of survival data from clinical cancer studies can be difficult, and pitfalls related to the nature of Kaplan-Meier analyzes can lead to incorrect conclusions. While evaluating a randomized controlled trial for the treatment of high-risk patients with neuroblastoma, the authors of a methodological study encountered some statistical problems that were apparently difficult to identify and possibly associated with a misinterpretation of survival functions. These topics included the assumed crossing of survival curves, the change in the statistical approach in the follow-up examination, the different pretreatment between the groups and event-free survival as the primary outcome.

literature

Guidelines

Technical article

  • Thorsten Simon, Catherina Annika Niemann, Barbara Hero, Günther Henze, Meinolf Suttorp, Freimuth H. Schilling, Frank Berthold: "Short- and long-term outcome of patients with spinal cord compression by neuroblastoma" In: "Developmental Medicine & Child Neurology." Number 54, February 2012, pp. 347-352

Web links

Commons : Neuroblastoma  - Collection of Images, Videos, and Audio Files

Individual evidence

  1. ^ JL Weinstein, HM Katzenstein, SL Cohn: Advances in the diagnosis and treatment of neuroblastoma. In: Oncologist . Volume 8, Number 3, 2003, pp. 278-292, ISSN  1083-7159 . PMID 12773750 . (Review).
  2. ^ WG Woods, RN Gao, JJ Shuster, LL Robison, M. Bernstein, S. Weitzman, G. Bunin, I. Levy, J. Brossard, G. Dougherty, M. Tuchman, B. Lemieux: Screening of infants and mortality due to neuroblastoma. In: The New England Journal of Medicine . Volume 346, Number 14, April 2002, pp. 1041-1046, ISSN  1533-4406 . doi : 10.1056 / NEJMoa012387 . PMID 11932470 .
  3. ^ FH Schilling, C. Spix, F. Berthold, R. Erttmann, N. Fehse, B. Hero, G. Klein, J. Sander, K. Schwarz, J. Treuner, U. Zorn, J. Michaelis: Neuroblastoma screening at one year of age. In: The New England Journal of Medicine . Volume 346, Number 14, April 2002, pp. 1047-1053, ISSN  1533-4406 . doi : 10.1056 / NEJMoa012277 . PMID 11932471 .
  4. ↑ Peinemann F: Issues possibly associated with misinterpreting survival data: a method study . In: Journal of Evidence-Based Medicine . 11, No. 3, June 2018, pp. 208–215. doi : 10.1111 / jebm.12301 . PMID 29877035 .