Clinical characteristics.

ALK-related neuroblastic tumor susceptibility is characterized by increased risk for neuroblastic tumors including neuroblastomas, ganglioneuroblastomas, and ganglioneuromas. Neuroblastomas are a more malignant tumor and ganglioneuromas a more benign tumor. Depending on the histologic findings, ganglioneuroblastomas can behave in a more aggressive fashion, like neuroblastomas, or in a benign fashion, like ganglioneuromas. The overall penetrance of a germline ALK pathogenic variant is approximately 50%, 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 by molecular genetic testing.

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 neuroblastomas and ganglioneuroblastomas 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: In asymptomatic children and after successful treatment of neuroblastic tumors: abdominal ultrasound and urine catecholamine metabolite levels (homovanillic acid and vanillylmandelic acid) every three months and physical examination and chest radiograph every six months between birth and age six years; physical examination, abdominal ultrasound, and measurement of urine catecholamine metabolite levels every six months and chest radiograph every six to 12 months between ages six and ten years. Screening beyond age ten years is not indicated.

Evaluation of relatives at risk: It is appropriate to test relatives at risk (e.g., 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 neuroblastomas 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. Some individuals diagnosed with ALK-related neuroblastic susceptibility inherited a pathogenic variant from a heterozygous parent. Because of reduced penetrance, a parent may have a germline ALK activating pathogenic variant without having developed a neuroblastic tumor. Some individuals diagnosed with ALK-related neuroblastic tumor susceptibility have the disorder as the result of a de novo germline activating pathogenic variant; the proportion of probands who have 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. The likelihood that a child who inherits the pathogenic variant will develop a neuroblastic tumor is unknown, though the penetrance is estimated to be around 50%. Once the germline ALK activating pathogenic variant has been identified in an affected family member, genetic testing of at-risk asymptomatic relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

ALK-related neuroblastic tumor susceptibility should be suspected in probands 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.

As neuroblastoma most often occurs sporadically and is rarely attributed to germline variants in cancer-predisposing genes (1%-2% of individuals), routine germline testing for ALK pathogenic variants is not standard. However, considerations for testing for germline ALK pathogenic variants include the following strong and moderate recommendations [Bourdeaut et al 2012; Brodeur et al 2017; Kamihara et al, unpublished data].

Establishing the Diagnosis

The diagnosis of ALK-related neuroblastic tumor susceptibility is established in a proband by identification of a heterozygous germline ALK activating pathogenic (or likely pathogenic) variant in the tyrosine kinase domain that is known or suspected to cause altered kinase function by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous ALK variant of uncertain significance does not establish or rule out the diagnosis.

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) may be considered to identify the genetic cause of the condition 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.

Clinical Description

Individuals with ALK-related neuroblastic tumor susceptibility are at risk of developing a spectrum of neuroblastic tumors that include neuroblastomas, ganglioneuroblastomas, and ganglioneuromas. These individuals also have a higher-than-average incidence of other primary tumors (e.g., bilateral adrenal tumors, extra-adrenal tumors arising at sites of sympathetic ganglions).

Neuroblastic tumors. 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 age nine months) than those without familial predisposition (age two to three years) [Park et al 2008]. One 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].

Within this spectrum, neuroblastomas represent a more malignant tumor and ganglioneuromas a more benign tumor. The three neuroblastic tumor types are defined histologically. Depending on the histologic findings, ganglioneuroblastomas can behave in a benign fashion, like ganglioneuromas, or in a more aggressive fashion, like neuroblastomas.

Multiple primary tumors. Individuals with familial neuroblastomas 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].

Non-neuroblastic tumors. There have been rare case reports of germline ALK variants identified in individuals with tumors outside of the neuroblastic family. Twelve individuals with glioma had a germline ALK variant [Bu et al 2021]. Only one of these variants occurred in the tyrosine kinase domain and was a nonsense variant. All other variants were missense. There were no recurrent germline variants, and somatic mutation of the second allele was not investigated, so causality of germline ALK variants in glioma has not been established. ALK germline variants have also been identified, rarely, in individuals with medulloblastoma [Jovanović et al 2023]. There is currently not enough evidence to say that individuals with germline ALK variants are at increased risk for primary central nervous system tumors.

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 neuroblastomas 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 neuroblastomas not associated with a germline ALK pathogenic variant.

Since neuroblastomic tumor outcome is heavily dependent on biological characteristics and stage of the tumor, it is likely that survival from a neuroblastic tumor depends more on tumor type (neuroblastomas 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 neuroblastomas or outcome of neuroblastomas have been established [Azarova et al 2011].

The pathogenic variant 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%).

The pathogenic variant 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].

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 Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

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. Children who develop neuroblastic tumors (neuroblastomas, ganglioneuroblastomas, or ganglioneuromas) should be evaluated and treated by a pediatric oncologist at a pediatric cancer center.

Surveillance

Guidelines for the screening of asymptomatic children with familial neuroblastoma – including those with germline ALK activating pathogenic variants – were published in 2017 and are being updated [Brodeur et al 2017; Kamihara et al, unpublished data]. Surveillance is also recommended for children with a germline ALK activating pathogenic variant who were successfully treated for a neuroblastoma due to risk of developing multiple primary tumors.

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).

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 receptor have been completed in individuals with ALK-aberrant neuroblastomas. In addition, several trials are ongoing. The role of these agents for the treatment of ALK-aberrant neuroblastomas is yet to be elucidated.

• NCT03107988. Phase I study of lorlatinib (an ALK tyrosine kinase inhibitor) as a single agent or in combination with chemotherapy for individuals with relapsed/recurrent neuroblastoma (NANT2015-02)
• NCT05489887. Phase II trial of naxitamab added to induction therapy for individuals with newly diagnosed high-risk neuroblastoma, in which ceritinib will be added to treatment regimens for individuals with an ALK pathogenic variant or amplification
• NCT03126916. Phase III trial for children with high-risk neuroblastoma, incorporating lorlatinib into the frontline treatment for individuals whose tumors contain 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.

Mode of Inheritance

ALK-related neuroblastic tumor susceptibility is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed with ALK-related neuroblastic susceptibility inherited an ALK pathogenic variant from a heterozygous parent.
  • Because of reduced penetrance, a parent may have a germline ALK activating pathogenic variant without having developed a neuroblastic tumor (neuroblastoma, ganglioneuroma, or ganglioneuroblastoma) [Janoueix-Lerosey et al 2008, Mossé et al 2008].
  • As yet, no tumor types other than neuroblastoma, ganglioneuroma, or ganglioneuroblastoma have been reported to be associated with germline ALK activating pathogenic variants, and no data regarding the cancer risk for heterozygous adult parents of a child with ALK-related neuroblastic susceptibility have been published.
• Some individuals diagnosed with ALK-related neuroblastic tumor susceptibility have the disorder as the result of a de novo germline ALK activating pathogenic variant. De novo germline pathogenic variants have been reported; the proportion of probands who have a de novo pathogenic variant is unknown.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo germline ALK activating pathogenic variant to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with ALK-related neuroblastic tumor susceptibility may appear to be negative because of reduced penetrance or failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the germline ALK pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected or has a germline ALK activating pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. The likelihood that a sib who inherits the ALK pathogenic variant will develop a neuroblastic tumor is not yet definitively known, but penetrance is estimated to be around 50%.
• If the proband has a known ALK pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism [Rahbari et al 2016].
• The sibs of a proband with clinically unaffected parents whose ALK variant status is unknown are still at increased risk (for the disorder) because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.

Offspring of a proband

• Each child of an individual with ALK-related neuroblastic tumor susceptibility has a 50% chance of inheriting the ALK pathogenic variant.
• The likelihood that a child who inherits the ALK pathogenic variant will develop a neuroblastic tumor is unknown, though the penetrance is estimated to be around 50% (significantly higher than in a child in the general population, in which neuroblastomas are rare).

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected or has a germline ALK activating pathogenic variant, members of the parent's family may be at risk for neuroblastomas or related tumors.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Testing of at-risk asymptomatic relatives of individuals with ALK-related neuroblastic tumor susceptibility is possible after molecular genetic testing has identified the specific germline ALK pathogenic variant in the family. Although molecular genetic testing can identify the presence of a germline ALK pathogenic variant and thereby identify family members at high risk for neuroblastomas, it cannot predict whether neuroblastomas, ganglioneuromas, or ganglioneuroblastomas will develop.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, have a germline ALK activating pathogenic variant, or are at risk of having a germline ALK activating pathogenic variant.

Prenatal Testing and Preimplantation Genetic Testing

Once the germline ALK activating pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Note: Although molecular genetic testing can identify the presence of a germline ALK activating pathogenic variant, it cannot predict whether neuroblastomas will develop.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

ALK encodes a single chain receptor tyrosine kinase, the ALK tyrosine kinase receptor; its normal function is not known [Mossé et al 2008]. Expression is restricted to the developing central and peripheral nervous system, with a postulated role in regulation of neuronal differentiation.

ALK is predicted to function as an oncogene in the pathogenesis of neuroblastomas [Chen et al 2008, George et al 2008, Janoueix-Lerosey et al 2008, Mossé et al 2008]. In ALK-related neuroblastomas, both germline and somatic pathogenic variants are found exclusively within the ALK tyrosine kinase domain. Pathogenic variants in the ALK tyrosine kinase domain result in constitutive phosphorylation and activation of the ALK tyrosine kinase receptor [Mossé et al 2008], and are predicted with high probability to drive oncogenesis [Mossé et al 2008]. Both ALK pathogenic variants and amplification have been shown to have direct oncogenic effects, as evidenced by autophosphorylation of mutated strains and activation of downstream targets in neuroblastoma cell lines containing ALK pathogenic variants and amplification [Janoueix-Lerosey et al 2008, Mossé et al 2008]. Tumors with aberrant ALK signaling display transforming potential in vivo, inducing soft agar colony formation in mutated cell lines, rapid tumor growth in nude mice, and increased apoptosis in response to small-interfering RNA or small-hairpin RNA targeted against ALK [Chen et al 2008, George et al 2008, Park et al 2008].

Mechanism of disease causation. Gain of function

Cancer and Benign Tumors

Somatic ALK pathogenic variants. The frequency of somatic ALK pathogenic variants involving neuroblastoma tumor tissue is 8%-10% and enriched in high-risk neuroblastomas, where aberrations are identified in 14% of neoblastic tumors [Pugh et al 2013, Bresler et al 2014]. Disruption of normal ALK signaling likely plays a critical role in neuroblastic tumor pathogenesis. Furthermore, it appears that individuals whose tumor contains a somatic ALK activating pathogenic variant have a poorer prognosis than individuals with otherwise similar tumor stage and biology [Chen et al 2008, Mossé et al 2008, Mossé et al 2013, Pugh et al 2013, Bresler et al 2014].

Preclinical data suggest that responsiveness to crizotinib may depend on the presence or absence and specific type of somatic ALK pathogenic variant (i.e., in the tumor). Specifically, tumors with the somatic ALK pathogenic variants p.Phe1174Leu, p.Gly1128Ala, p.Met1166Arg, p.Phe1245Cys, p.Phe1245Val, and p.Tyr1278Ser are relatively crizotinib resistant, whereas the p.Ile1170Asn, p.Ile1170Ser, p.Ile1171Asn, p.Leu1196Met, and p.Arg1275Gln variants are sensitive to crizotinib. The p.Arg1192Pro variant is intermediate in sensitivity [Mossé et al 2013]. Subsequent Phase II and III clinical trials for neuroblastomas will incorporate ALK molecular genetic testing for the tumors of all individuals enrolled in the trial.

Several recent clinical trials have incorporated ALK tyrosine kinase inhibitors into therapy. These trials are not specific to individuals with ALK germline pathogenic variants but have included small numbers of individuals with neuroblastoma and an ALK germline pathogenic variant with good response. One (of one) individual with a germline ALK pathogenic variant responded to lorlatinib, and 2/2 and 3/3 individuals with a germline ALK pathogenic variant responded to crizotinib in separate studies [Mossé et al 2013, Fischer et al 2021, Goldsmith et al 2023].

These data have been confirmed in other studies as well. For example, human neuroblastoma-derived cell lines containing mutated proteins with the p.Arg1275Gln substitution, the most common abnormal protein described in ALK-related neuroblastoma [Azarova et al 2011], were more sensitive to the small-molecule ALK inhibitor PF-02341066 than cell lines containing proteins with the p.Phe1174Leu substitution or those without ALK aberrations [Wood et al 2009]. The cell line most sensitive to pharmacologic inhibition contains high-level amplification of ALK (wild type sequence). Clinical correlation in individuals with neuroblastoma has yet to be determined [Wood et al 2009].

The variant p.Phe1174Leu, associated with amplification of the oncogene MYCN, is found as a somatic pathogenic variant in 30% of sporadic neuroblastoma tumors that contain an ALK pathogenic variant [Carpenter & Mossé 2012]. Individuals with this pathogenic variant have a poorer prognosis than individuals with MYCN amplification alone [Azarova et al 2011].

Somatic amplification of ALK on chromosome 2p23 has also been identified in a subset of sporadic neuroblastomas with unfavorable biologic characteristics and aggressive clinical course. Individuals whose tumor contains an ALK amplification (i.e., >10 copies of ALK) have a poorer prognosis than individuals with otherwise similar tumor stage and biology.

Somatic translocations involving ALK resulting in fusion proteins have been identified in anaplastic large-cell lymphomas, non-small-cell lung cancer, inflammatory myofibroblastic tumors, diffuse large B-cell lymphomas, and squamous cell carcinomas of the esophagus. In all these tumors, aberrant ALK tyrosine kinase receptor signaling occurs as a result of a chromosome translocation involving the ALK locus at 2p23.

Author Notes

Melissa R Perrino, MD: www.stjude.org/directory/p/melissa-perrino

Author History

Emily G Greengard, MD (2015-present)
Rebecca H Johnson, MD; Seattle Children's Hospital (2009-2015)
Julie R Park, MD (2009-present)
Melissa R Perrino, MD (2024-present)

Revision History

• 23 May 2024 (sw) Comprehensive update posted live
• 17 January 2019 (sw) Comprehensive update posted live
• 9 April 2015 (me) Comprehensive update posted live
• 27 September 2012 (me) Comprehensive update posted live
• 5 January 2010 (me) Review posted live
• 14 August 2009 (rhj) Original submission

Published Guidelines / Consensus Statements

• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2010. Accessed 5-14-24.

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