Alk-Related Neuroblastic Tumor Susceptibility
Summary
Clinical characteristics.
ALK-related neuroblastic tumor susceptibility is characterized by increased risk for neuroblastic tumors including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Neuroblastoma is a more malignant tumor and ganglioneuroma a more benign tumor. Depending on the histologic findings, ganglioneuroblastoma can behave in a more aggressive fashion, like neuroblastoma, or in a benign fashion, like ganglioneuroma. Preliminary data from the ten reported families with ALK-related neuroblastic tumor susceptibility suggest an overall penetrance of approximately 57% with the risk for neuroblastic tumor development highest in infancy and decreasing by late childhood.
Diagnosis/testing.
ALK-related neuroblastic tumor susceptibility is established by identification of a heterozygous germline ALK activating pathogenic variant in the tyrosine kinase domain that is known or suspected to cause altered kinase function.
Management.
Treatment of manifestations: Children who develop neuroblastic tumors should be evaluated and treated by a pediatric oncologist at a pediatric cancer center. Treatment for individuals with neuroblastoma and ganglioneuroblastoma who have a germline ALK activating pathogenic variant is the same standard risk-stratified therapy used to treat all neuroblastoma. Ganglioneuromas are typically removed by surgical resection and require no further therapy.
Surveillance:
- Asymptomatic children. Physical examination, abdominal ultrasound examination, chest x-ray, and measurement of urine catecholamine metabolite levels (homovanillic acid and vanillylmandelic acid) every three months between birth and age six years. Physical examination, abdominal ultrasound examination, chest x-ray, and measurement of urine catecholamine metabolite levels (homovanillic acid and vanillylmandelic acid) every six months between age six years and ten years. Screening beyond age ten years is not indicated.
- After successful treatment of a neuroblastic tumor. Screening for neuroblastoma should continue since children with ALK-related neuroblastoma are at risk of developing multiple primary tumors. Screening should continue as described above until age ten years.
Evaluation of relatives at risk: It is appropriate to test relatives at risk (i.e., sibs age <10 years at the time of diagnosis of the proband, as well as sibs born subsequently) for the ALK pathogenic variant found in the proband to identify those for whom early detection of neuroblastoma and initiation of therapy would likely improve quality of life and possibly affect outcome (if therapy is started prior to end organ damage).
Genetic counseling.
ALK-related neuroblastic tumor susceptibility is inherited in an autosomal dominant manner, with reduced penetrance. Some individuals diagnosed with ALK-related neuroblastic susceptibility have an affected parent who may have had any one of the three neuroblastic tumor types. De novo germline pathogenic variants have been reported; the proportion of individuals with a de novo pathogenic variant is unknown. Each child of an individual with ALK-related neuroblastic tumor susceptibility has a 50% chance of inheriting the ALK pathogenic variant; however, the likelihood that a child who inherits the ALK pathogenic variant will develop a neuroblastic tumor is unknown. Prenatal testing is possible for pregnancies at increased risk in families in which the pathogenic variant has been identified.
Diagnosis
Suggestive Findings
ALK-related neuroblastic tumor susceptibility should be suspected in individuals with:
- A neuroblastic tumor including neuroblastoma, ganglioneuroblastoma, or ganglioneuroma;
- Multiple primary neuroblastic tumors that arise either synchronously or metachronously;
- A family history of one or more relatives with one of these three neuroblastic tumors. Note: Both benign and malignant tumors can occur in the same family.
Written guidelines for selection of individuals with a neuroblastic tumor to be tested for germline ALK pathogenic variants are under development, and no consensus opinion currently exists.
Considerations for testing for germline ALK pathogenic variants include the following strong and moderate recommendations [Bourdeaut et al 2012, Brodeur et al 2017].
Recommendations Regarding Testing for Germline ALK Pathogenic Variants
Strong recommendation
- All children with documented somatic ALK pathogenic variants within a neuroblastic tumor
- An individual with a neuroblastic tumor* who has at least one first-degree relative with a neuroblastic tumor* Germline ALK pathogenic variants are equally likely to be identified in individuals with any of the three neuroblastic tumor types and with any stage of malignant neuroblastoma [Liu & Thiele 2012].
- An individual with a neuroblastic tumor and a family history of neuroblastic tumors that are not a manifestation of a neural crest disorder such as Hirschsprung disease or central hypoventilation syndrome, which may suggest pathogenic variants in PHOX2B (See Differential Diagnosis.)
Moderate recommendation. A simplex case (i.e., a single occurrence in a family) with bilateral neuroblastoma or multifocal primary neuroblastic tumors [Bourdeaut et al 2012]
No recommendation. An individual with a neuroblastic tumor and distant relatives (≥2nd degree) with a history of neuroblastic tumors, as such an individual is unlikely to have a germline ALK pathogenic variant [Mossé et al 2008]
Considerations for Testing for Somatic ALK Pathogenic Variants
Some institutions are currently screening tumors of all children with neuroblastoma, and others are screening tumors at the time of recurrence or progression, primarily for potential for ALK-directed therapy (see Molecular Genetics, Cancer and Benign Tumors) rather than identifying those at increased risk of having a germline ALK pathogenic variant.
Establishing the Diagnosis
ALK-related neuroblastic tumor susceptibility is established in a proband by identification of a heterozygous germline ALK activating pathogenic variant in the tyrosine kinase domain that is known or suspected to cause altered kinase function (see Table 1).
Molecular genetic testing approaches can include single-gene testing and use of a multigene panel:
- Single-gene testing. Sequence analysis of ALK may detect heterozygous germline activating pathogenic variants in the tyrosine kinase domain that are known or suspected to cause altered kinase function.Note: ALK-related neuroblastic tumor susceptibility is postulated to occur through a gain-of-function mechanism. Large intragenic deletion or duplication has not been reported; testing for intragenic deletions or duplication is not indicated.
- A multigene panel that includes ALK and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Table 1.
Molecular Genetic Testing Used in ALK-Related Neuroblastic Tumor Susceptibility
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| ALK | Sequence analysis 3 | 100% 4, 5 |
| Gene-targeted deletion/duplication analysis 6 | None reported |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
In families with two or more first-degree relatives with neuroblastoma, the incidence of germline ALK pathogenic variants is 80%. In families in which two second-degree or more distant relatives have neuroblastoma, the incidence of germline ALK pathogenic variants is much lower [Mossé et al 2008].
- 5.
Somatic ALK activating pathogenic variants, which may be found in 7%-8% of sporadic neuroblastoma tumors, are rarely associated with germline ALK pathogenic variants [Liu & Thiele 2012]. In 167 tumors tested from simplex cases with high-risk neuroblastomas, Mossé et al [2008] found that 14 had somatic ALK missense variants that were predicted to be activating. Of these 14 individuals with somatic ALK missense variants, germline DNA was available on nine. In one of those nine individuals the ALK pathogenic variant, p.Ile1250Thr, was identified in both germline and tumor DNA.
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
Clinical Description
Individuals with ALK-related neuroblastic tumor susceptibility are at risk of developing a spectrum of neuroblastic tumors that include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Within this spectrum, neuroblastoma represents a more malignant tumor and ganglioneuroma a more benign tumor. The three neuroblastic tumor types are defined histologically. Depending on the histologic findings, ganglioneuroblastoma can behave in a benign fashion, like ganglioneuroma, or in a more aggressive fashion, like neuroblastoma.
Data from the ten reported families with ALK-related neuroblastic tumor susceptibility suggest that the overall penetrance of this cancer predisposition syndrome is around 57% [Eng 2008]. A recent study showed that 45%-50% of individuals with a germline ALK pathogenic variant will develop a neuroblastic tumor in their lifetime [Brodeur et al 2017].
Risk for neuroblastic tumor development is highest in infancy and decreases by late childhood, with 98% of neuroblastic tumors occurring by age ten years [Brodeur et al 2017]. Individuals with familial neuroblastoma tend to develop tumors at a younger age (average 9 months) than those without familial predisposition (age 2-3 years) [Park et al 2008].
Multiple primary tumors. Individuals with familial neuroblastoma also have a higher-than-average incidence of multiple primary tumors [Mossé et al 2008, Park et al 2008]. The multiple primary tumors may be bilateral adrenal tumors or multiple primary extra-adrenal tumors arising at sites of sympathetic ganglions. The tumors can occur either synchronously or metachronously [Bourdeaut et al 2012].
Outcome. Given the rarity of familial neuroblastic tumors, statistically significant long-term outcome data are not yet available for individuals with ALK-related neuroblastic tumor susceptibility. Although long-term survivors of neuroblastoma who are heterozygous for an inherited germline ALK pathogenic variant have been reported [Carén et al 2008], no prospective studies have evaluated the survival of persons with a germline ALK pathogenic variant compared to those with neuroblastoma not associated with a germline ALK pathogenic variant.
Since neuroblastomic tumor outcome is heavily dependent on biologic characteristics and stage of the tumor, it is likely that survival from a neuroblastic tumor depends more on tumor type (neuroblastoma having the poorest outcome), tumor stage, and appropriate medical intervention than on the presence or absence of a germline ALK activating pathogenic variant [Park et al 2008].
Genotype-Phenotype Correlations
Aside from the following pathogenic variants, no associations between specific germline ALK pathogenic variants and risk of developing neuroblastoma or outcome of neuroblastoma have been established [Azarova et al 2011].
- p.Arg1275Gln, found in approximately 45% of individuals with a germline ALK pathogenic variant [Wood et al 2009], may be associated with somewhat decreased penetrance (40%).
- p.Gly1128Ala, reported as a germline ALK pathogenic variant in one large family, appeared to have lower penetrance: 40% of heterozygotes developed a neuroblastoma during childhood [Mossé et al 2008]. Adult heterozygotes were healthy; no tumor types other than neuroblastoma were reported.
Penetrance
The overall penetrance of a germline ALK pathogenic variant is approximately 50% [Brodeur et al 2017]. Several obligate heterozygous asymptomatic adults have been identified [Mossé et al 2008, Bourdeaut et al 2012]. In at least one family, a child with neuroblastoma inherited the p.Arg1275Gln pathogenic variant from an unaffected father [Mossé et al 2008].
See also Genotype-Phenotype Correlations for information on penetrance.
Prevalence
Familial neuroblastoma occurs in approximately 1%-2% of all individuals with neuroblastoma [Weiss et al 2016]. Of those familial cases, gain-of-function pathogenic variants in ALK account for 75% [Ritenour et al 2018].
Differential Diagnosis
Germline pathogenic variants in ALK and PHOX2B are the etiologic agents for familial neuroblastoma susceptibility.
- Heterozygous germline ALK pathogenic variants are the main cause of familial susceptibility to neuroblastoma in otherwise healthy individuals.
- Heterozygous germline PHOX2B pathogenic variants account for the remainder of families, most of whom also have disorders of neural crest development [Mossé et al 2008, Azarova et al 2011].
PHOX2B-related neuroblastoma susceptibility and other disorders to consider in the differential diagnosis of ALK-related neuroblastic tumor susceptibility are summarized in Table 2.
Table 2.
Disorders to Consider in the Differential Diagnosis of ALK-Related Neuroblastic Tumor Susceptibility (ALK-NTS)
| Disorder | Gene(s) | MOI | Clinical Features of This Disorder | |
|---|---|---|---|---|
| Overlapping w/ALK-NTS | Distinguishing from ALK-NTS | |||
| PHOX2B-related familial neuroblastoma susceptibility (OMIM 613013) | PHOX2B | AD | Familial neuroblastoma |
|
| ROHHAD syndrome 1 | Unknown | Ganglioneuroblastoma, ganglioneuroma |
| |
| KIF1B-neuroblastoma susceptibility (OMIM 256700) | KIF1B | AD | Neuroblastoma, ganglioneuroma | Pheochromocytomas, leiomyosarcoma |
| Neurofibromatosis 1 | NF1 | AD | Neuroblastoma |
|
| Costello syndrome | HRAS | AD | Neuroblastoma |
|
| Noonan syndrome | ≥8 genes | AD | Neuroblastoma |
|
| Li-Fraumeni syndrome | TP53 | AD | Neuroblastoma | Soft-tissue sarcomas, osteosarcoma, breast cancer, brain tumors, adrenocortical carcinoma, leukemias |
| Beckwith-Weidemann syndrome | CDKN1C 2 | Simplex or AD | Neuroblastoma |
|
AD = autosomal dominant; MOI = mode of inheritance; XL = X-linked
- 1.
Ize-Ludlow et al [2007]
- 2.
Beckwith-Wiedemann syndrome is associated with abnormal regulation of gene transcription in the imprinted domain on chromosome 11p15.5, which can be caused by different genetic mechanisms: abnormal methylation of one of two differently methylated regions (DMRs), paternal uniparental disomy, or pathogenic variants in CDKN1C.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with ALK-related neuroblastic tumor susceptibility, the evaluations summarized in this section are recommended:
- Physical examination to assess for clinical manifestations of neuroblastic tumors such as an abdominal mass, Horner syndrome, and/or cutaneous lesions
- Radiograph of the chest and ultrasound examination of the abdomen, the most common sites for neuroblastic tumor development
- Measurement of urine catecholamines, as homovanillic acid and vanillylmandelic acid may be elevated in the presence of a neuroblastic tumor
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Children who develop neuroblastic tumors (neuroblastomas, ganglioneuroblastoma, or ganglioneuroma) should be evaluated and treated by a pediatric oncologist at a pediatric cancer center.
Neuroblastoma and ganglioneuroblastoma. The treatment for individuals with a neuroblastic tumor who have a germline ALK activating pathogenic variant is the same standard risk-stratified therapy used to treat all neuroblastic tumors. Clinical trials are ongoing to study the efficacy of ALK-targeted therapy in the setting of relapsed and refractory neuroblastoma and ganglioneuroblastoma (see Therapies Under Investigation).
The management guidelines for neuroblastoma or ganglioneuroblastoma are complex [Irwin & Park 2015]:
- Depending on the age of the affected individual, stage of the tumor, and biologic characteristics of the tumor, treatment may involve observation or surgical resection.
- Tumors with risk for metastatic spread or those that have already metastasized require chemotherapy and sometimes radiation therapy, stem cell transplantation, and immunotherapy.
Ganglioneuromas are typically removed by surgical resection and require no further therapy.
Surveillance
Asymptomatic children at risk. Guidelines for the screening of individuals with familial neuroblastoma – including those with germline ALK activating pathogenic variants – were published in 2017 [Brodeur et al 2017]. These surveillance recommendations include physical examination, abdominal ultrasound examination, chest x-ray, and measurement of urine catecholamine metabolite levels (homovanillic acid and vanillylmandelic acid) at the following frequency:
- Birth to age 6 years. Every three months
- Age 6-10 years. Every six months
Screening beyond age ten years is not indicated.
After successful treatment of a neuroblastic tumor, screening for neuroblastic tumors should continue since children with ALK-related neuroblastic tumor susceptibility are at risk of developing multiple primary tumors. Screening should continue as described above until ten years of age.
Agents/Circumstances to Avoid
There is currently no evidence that individuals with ALK-related neuroblastoma tumor susceptibility have increased sensitivity to chemotherapeutic agents or radiation therapy; thus, medical and surgical management of tumors should be the same as for the general population.
Evaluation of Relatives at Risk
It is appropriate to test sibs younger than age ten years at the time of the proband's diagnosis as well as sibs born subsequently for the ALK pathogenic variant found in the proband. Genetic testing identifies sibs at high risk for neuroblastoma, for whom early detection of neuroblastoma and initiation of therapy would likely improve quality of life and may affect outcome (if therapy is started prior to end organ damage).
Note: Sibs of all probands with neuroblastoma have an increased chance of developing neuroblastoma themselves, with a standardized incidence ratio of 9.7 compared to the general population [Mossé et al 2008]. This increased risk is likely due in part to the possibility of inherited germline ALK pathogenic variants in some children with neuroblastoma.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Several early-phase clinical trials of small-molecule inhibitors targeting the ALK tyrosine kinase domain have been completed in individuals with ALK-aberrant neuroblastoma. In addition, several trials are ongoing. The role of these agents for the treatment of ALK-aberrant neuroblastoma is yet to be elucidated. Currently, the Children's Oncology Group Phase III trial for children with high-risk neuroblastoma is incorporating the ALK inhibitor crizotinib into the frontline treatment for individuals whose tumors harbor an ALK aberration.
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.