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Melanoma-Astrocytoma Syndrome

Melanoma and Neural System Tumor Syndrome

Melanoma-astrocytoma syndrome (MAS) is a tumor predisposition syndrome linked to the inactivation of tumor suppressor gene CDKN2A and possibly other gene defects. It is a rare entity which is inherited in an autosomal dominant manner. Affected individuals may present with malignant melanoma, astrocytoma, and nerve sheath types of nervous system cancer in childhood or adolescence. Treatment is symptomatic.


Presentation

MAS patients are predisposed to develop cutaneous malignant melanoma and nervous system tumors. Melanoma has initially been described to be the presenting symptom [1], but astrocytoma and other brain tumors may develop at rather young ages: MAS patients have indeed died of cerebral neoplasms in adolescence or early adulthood [2], and a number of patients have been reported in recent years who developed multiple melanomas after receiving radiotherapy for astrocytoma or similar conditions. Individuals prone to melanoma development are often found to carry multiple atypical nevi, and it's these lesions that may eventually transform into skin cancer [3]. Atypical nevi are characterized by mild asymmetry, irregular borders, and diameters > 6mm. Irregularity of color is less pronounced than in melanoma.

Tumors developing in the peripheral nervous system may be clinically recognized as mass lesions. They may restrict mobility, be painful and/or lead to neurological deficits, but they may also be asymptomatic. With regards to cerebral tumors, signs and symptoms presented by affected individuals largely correspond to the clinical picture of other mass lesions of the brain. Most patients suffer from headaches, nausea, and vomiting. Seizures may occur [2]. Neurological deficits are common and may comprise sensory, motor, and cognitive functions. Changes in behavior, disorientation, and confusion may be reported by the patient's family. As a general rule, larger brain tumors tend to trigger more severe symptoms, but even small neoplasms may induce extensive deficits. They may interfere with the drainage of cerebrospinal fluid and thus cause hydrocephalus and increased intracranial pressure. Distant brain regions may then be limited in functionality.

Of note, MAS patients may develop melanoma only, nervous system tumors only, or both. The joint predisposition to both types of tumors may not become evident until obtaining the patient's family history [4].

Type A Personality
  • . * Skin type — Most persons who develop melanoma have blond or red hair, fair skin, and blue eyes; are prone to sunburn; and are of Celtic or Scandinavian ancestry.[checkorphan.org]
Headache
  • Most patients suffer from headaches, nausea, and vomiting. Seizures may occur. Neurological deficits are common and may comprise sensory, motor, and cognitive functions.[symptoma.com]
  • More detailed inform Symptoms - Melanoma astrocytoma syndrome * Unusual mole * Changing mole * Irregular mole * Brain tumor * Increased pressure inside skull * Headache * Changes in vision * Seizures * Vomiting * Personality changes * Dementia * Memory[checkorphan.org]
  • Bradly's astrocytoma diagnosis Bradly had been having headaches on and off, so his primary care doctor prescribed several different headache and sinus medications. When these didn't work, the doctor finally ordered a CT scan of his head.[mdanderson.org]
  • (Left) Contrast-enhanced CT scan shows three separate tumor nodules (arrows) in a 42-year-old woman with breast cancer who developed headaches and confusion.[aafp.org]
  • […] tumor Other names Intracranial neoplasm, brain tumour Brain metastasis in the right cerebral hemisphere from lung cancer, shown on magnetic resonance imaging Specialty Neurosurgery, oncology Symptoms Vary depending on the part of the brain involved, headaches[en.wikipedia.org]
Tonic-Clonic Seizure
  • Case report A 23-year-old Caucasian man initially presented with new-onset generalized tonic-clonic seizures. He was found to have a non-enhancing lesion in the left frontal lobe and underwent resection which demonstrated a low-grade astrocytoma.[ncbi.nlm.nih.gov]

Workup

Patients tend to present early in life, and the treating physician may not consider cancer a likely differential diagnosis - but any delay in the diagnosis may have detrimental consequences. It is thus of utmost importance to evaluate the patient's family history, to recognize their predisposition to melanoma, astrocytoma, and other types of neoplasms. The oncological examination of an MAS patient doesn't differ from the evaluation of a non-syndromic case, and tumor staging and grading are realized in a similar manner:

  • The entire skin should be assessed for suspicious lesions, which may or may not fulfill the conventional ABCD criteria of Asymmetry, Border irregularity, Color variegation, and Diameter >6 mm. Virtual all melanomas evolve. Notwithstandig, a reliable diagnosis of melanoma cannot be made unless biopsy specimens are obtained and microscopically examined.
  • Imaging tools are essential for the diagnosis of nervous system tumors. Magnetic resonance imaging is most commonly used to confirm the presence of cerebral mass lesions, to localize brain tumors and to define their demarcation from the surrounding tissue. It also allows for the identification of cerebral edema and/or hydrocephalus. But even though the tumor's shape and texture may translate into specific findings in neuroimaging [5], the reliable identification of its type and grade calls for the histological analyses of tissue samples.
  • Little is known about the histological features of MAS-related tumors. Distinct types of neoplasms have been identified in MAS patients, and they may develop simultaneously in a single individual [2]. The metastatic potential of MAS-related tumors is associated with its molecular background and growth behavior, rather than the predisposing germline mutation. What's more, it may not always be feasible to distinguish metastatic disease from additional primary tumors.

The workup of the index case and their family history should guide the decisions regarding genetic testing. The diagnosis of MAS requires the identification of a pathogenic variant of CDKN2A, but it should be kept in mind that high-risk gene defects can only be determined in a minor share of families with a strong history of skin cancer. If the patient's predisposition to tumor development cannot be attributed to CDKN2A, genetic studies should be extended to other forms of familial melanoma [6].

In any case, the molecular biological characterization of the individual tumor may be helpful to estimate its susceptibility to specific molecular-targeted therapies.

Mass Lesion of the Brain
  • Magnetic resonance imaging is most commonly used to confirm the presence of cerebral mass lesions, to localize brain tumors and to define their demarcation from the surrounding tissue.[symptoma.com]

Treatment

Cyclin-dependent kinases have been considered promising therapeutic targets for years, but most candidates for drug development have failed rigorous clinical testing. Still, progress has been made, and inhibitors of cyclin-dependent kinases 4 and 6, namely palbociclib and dinaciclib, have recently been demonstrated to possess anti-cancer efficacy and low toxicity [7]. Neither one has yet received approval for MAS, but this type of research may eventually pave the way towards the causative treatment of this syndrome. To date, MAS treatment is symptomatic only.

Specific recommendations regarding the management of MAS have not yet been formulated, and optimal treatment strategies for patients suffering from this disease remain unknown [2]. At present, they are mostly treated according to the guidelines for the therapy of melanoma, astrocytoma, and other tumors of the nervous system.

Surveillance plays a key role in the management of MAS. There are no therapies available to prevent the development of further tumors, and the patient's prognosis largely depends on the early recognition of neoplasms.

Prognosis

Tumors developing in the central nervous system are the main cause of disease-related morbidity and mortality [1] [8]. The life expectancy of MAS patients is largely reduced and may be as low as 20 years in the case of early tumor development [3].

Etiology

MAS is caused by inactivating mutations of the CDKN2A gene, which is located on the short arm of chromosome 9 and encodes for cyclin-dependent kinase inhibitor 2A [9]. There are distinct variants of this protein, which are generated by alternative splicing. They have been shown to function as inhibitors of CDK4 kinase or act as a stabilizer of the tumor suppressor protein p53, both of which are involved in G1-phase cell-cycle regulation. They are also referred to as p16 and p14, respectively, and the MAS-related gene defect may affect either one or both proteins [8].

Mutations of the CDKN2A gene have been related to familial melanoma more than 20 years ago [6]. But while some families harboring such mutations are prone to the development of melanomas only, others are predisposed to melanoma, astrocytoma, and other neoplasms of the nervous system. There is thus reason to presume additional gene defects that may explain the broader clinical spectrum. In this context, it is worth mentioning that mutations of the CDKN2B gene have been associated with the predisposition to melanoma and some types of neural tumors [3] [10].

MAS is inherited in an autosomal dominant manner and affected individuals are heterozygous for germline mutations of CDKN2A. Tumorigenesis, however, may depend on additional gene defects that are acquired throughout life. Environmental factors are likely to be involved in this process, and they may trigger the somatic loss of the wild-type allele of CDKN2A, among others [2]. Ionizing radiation, as is used in radiotherapy, has been speculated to promote the formation of MAS-related tumors. The treatment of MAS may thus contribute to tumorigenesis and induce the development of additional tumors [3].

Epidemiology

According to epidemiological data, about 1% of cases of cutaneous malignant melanoma occurs in individuals with a strong family history of skin cancer. While mutations of CDKN2A have been estimated to account for 20-40% of the families with three or more individuals with melanoma, they may give rise to a variety of syndromes: MAS, pancreatic cancer-melanoma syndrome, and cutaneous malignant melanoma type 2, among others [11].

In a larger case series reported by Azizi and colleagues, 17 of 904 melanoma patients were found to have one or more relatives with tumors of the nervous system [12]. It is, however, not known whether the respective families were harboring MAS-related mutations. Few additional cases have been reported to date, and MAS is currently considered a rare condition affecting a small number of families worldwide [3]. The penetrance of MAS has been estimated to be 67% by 80 years of age [8].

Sex distribution
Age distribution

Pathophysiology

MAS-related tumorigenesis is a multistep process. Cyclin-dependent kinase inhibitor 2A has been classified as a tumor suppressor, but the presence of a single wild-type allele may suffice to prevent the development of neoplasms. This delicate balance may, however, be upset upon the somatic loss of the remaining CDKN2A allele. Further aberrations favoring the proliferation and survival of tumor cells have been identified in MAS-related tumors, such as activating BRAF mutations, which are characteristic of melanoma but not specific to MAS [Chan]. According to current knowledge, there is no one molecular profile of MAS-related neoplasms, and the pathophysiological cascade induced by the driver mutation of CDKN2A remains to be defined.

Prevention

Families affected by MAS will benefit from genetic counseling. Both genealogical and genetic analyses should be performed to identify those family members who are predisposed to melanoma, astrocytoma, and other tumors. They may then be included in surveillance programs: Patients known to carry germline mutations of the CDKN2A gene are recommended to undergo annual dermatological, ophthalmological, and dental examinations to monitor for the development of cutaneous, ocular, and mucosal melanoma, as well as regular surveillance imaging of the brain. There is no consensus as to the optimum starting age for surveillance; yet, 10 years before the age of the youngest tumor diagnosis in the family seems a reasonable time to start [13]. Patients should also be informed about the possible signs and symptoms of nervous system tumors, so they may contribute to the early diagnosis of neoplasms [2].

Precise knowledge regarding the underlying mutation also allows for the prenatal diagnosis of MAS.

Summary

Familial melanoma has first been related to an increased prevalence of astrocytoma in 1993, when Kaufman et al. described a three-generation family case series of MAS [1]. The authors of later publications reported peripheral nerve sheath tumors, neurofibroma, vestibular schwannoma, meningioma, ependymoma, and glioma, but also medulloblastoma and glioblastoma multiforme to hereditary skin cancer [2] [4] [10] [12]. Because the genetic background of the neural component of MAS remains poorly understood, it can only be speculated on whether all these conditions correspond to a single entity like MAS.

Patient Information

Melanoma-astrocytoma syndrome (MAS) is a rare hereditary disorder, affecting a small number of families worldwide. It is caused by mutations of the CDKN2A gene and possibly other gene defects that interfere with the regulation of cell growth, proliferation, and apoptosis. Carriers of the respective mutations have a high risk of developing malignant melanoma - a common type of skin cancer - as well as tumors of the nervous system. With regard to the latter, it has initially been assumed that MAS patients are most likely to develop astrocytoma, a type of tumor originating from astrocytes. More recent studies have shown, however, that MAS may predispose to a wide variety of neoplasms, including peripheral nerve sheath tumors, neurofibroma, vestibular schwannoma, meningioma, ependymoma, and glioma, but also medulloblastoma and glioblastoma multiforme.

MAS-related tumors tend to develop early in life, possibly in childhood or adolescence, and they may induce distinct symptoms:

  • Melanoma typically originates from atypical nevi, i.e., from unusual benign moles which may be characterized by mild asymmetry, irregular borders, and diameters > 6mm.
  • Tumors developing in the peripheral nervous system may be recognized as mass lesions. They may cause pain and neurological deficits.
  • Brain tumors often induce headaches, nausea, and vomiting. Patients may suffer from seizures and present neurological deficits comprising sensory, motor, and cognitive functions.

Tumors developing in the central nervous system are the main cause of disease-related morbidity and mortality. Because there is no therapy to prevent tumor growth in MAS patients, it is of utmost importance they are included in surveillance programs. They should undergo dermatological, ophthalmological, and dental examinations to monitor for the development of cutaneous, ocular, and mucosal melanoma, as well as regular surveillance imaging of the brain. The early diagnosis of MAS-related tumors significantly improves the outcome.

References

Article

  1. Kaufman DK, Kimmel DW, Parisi JE, Michels VV. A familial syndrome with cutaneous malignant melanoma and cerebral astrocytoma. Neurology. 1993; 43(9):1728-1731.
  2. Chan AK, Han SJ, Choy W, et al. Familial melanoma-astrocytoma syndrome: synchronous diffuse astrocytoma and pleomorphic xanthoastrocytoma in a patient with germline CDKN2A/B deletion and a significant family history. Clin Neuropathol. 2017; 36(5):213-221.
  3. Frigerio S, Disciglio V, Manoukian S, et al. A large de novo 9p21.3 deletion in a girl affected by astrocytoma and multiple melanoma. BMC Med Genet. 2014; 15:59.
  4. Bahuau M, Vidaud D, Kujas M, et al. Familial aggregation of malignant melanoma/dysplastic naevi and tumours of the nervous system: an original syndrome of tumour proneness. Ann Genet. 1997; 40(2):78-91.
  5. Zacharaki EI, Wang S, Chawla S, et al. Classification of brain tumor type and grade using MRI texture and shape in a machine learning scheme. Magn Reson Med. 2009; 62(6):1609-1618.
  6. Aoude LG, Wadt KA, Pritchard AL, Hayward NK. Genetics of familial melanoma: 20 years after CDKN2A. Pigment Cell Melanoma Res. 2015; 28(2):148-160.
  7. Law ME, Corsino PE, Narayan S, Law BK. Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics. Mol Pharmacol. 2015; 88(5):846-852.
  8. Randerson-Moor JA, Harland M, Williams S, et al. A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. Hum Mol Genet. 2001; 10(1):55-62.
  9. Bahuau M, Vidaud D, Jenkins RB, et al. Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors. Cancer Res. 1998; 58(11):2298-2303.
  10. Pasmant E, Laurendeau I, Héron D, Vidaud M, Vidaud D, Biéche I. Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. Cancer Res. 2007; 67(8):3963-3969.
  11. Saiyed FK, Hamilton EC, Austin MT. Pediatric melanoma: incidence, treatment, and prognosis. Pediatric Health Med Ther. 2017; 8:39-45.
  12. Azizi E, Friedman J, Pavlotsky F, et al. Familial cutaneous malignant melanoma and tumors of the nervous system. A hereditary cancer syndrome. Cancer. 1995; 76(9):1571-1578.
  13. Baker MJ, Goldstein AM, Gordon PL, et al. An interstitial deletion within 9p21.3 and extending beyond CDKN2A predisposes to melanoma, neural system tumours and possible haematological malignancies. J Med Genet. 2016; 53(11):721-727.

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Last updated: 2019-07-11 20:14