Neurocutaneous melanocytosis

Neurocutaneous melanocytosis

Neurocutaneous melanosis (NCM; MIM # 249400; ORPHA: 2481], first reported by the Bohemian pathologist Rokitansky in 1861, and now more precisely defined as neurocutaneous melanocytosis.

Congenital syndrome characterised by the association of (1) congenital melanocytic nevi (CMN) of the skin with overlying hypertrichosis, presenting as (a) large (LCMN) or giant and/or multiple (MCMN) melanocytic lesions (or both; sometimes associated with smaller “satellite” nevi) or (b) as proliferative melanocytic nodules; and (2) melanocytosis (with infiltration) of the brain parenchyma and/or leptomeninges. CMN of the skin and leptomeningeal/nervous system infiltration are usually benign, more rarely may progress to melanoma or non-malignant melanosis of the brain.

Epidemiology

It is a rare phakomatosis.

Approximately 12% of individuals with LCMN will develop NCM: wide extension and/or dorsal axial distribution of large (LCMN) or giant and/or multiple (MCMN) melanocytic lesions increases the risk of neurocutaneous melanocytosis.

Etiology

This syndrome is believed to result from an error in the morphogenesis of embryonal neuroectoderm.

The special association of neurocutaneous melanosis with Dandy-Walker malformation complex may be explained by a common pathogenesis 1).

Pathogenically, single postzygotic mutations in the NRAS (neuroblastoma RAS viral oncogene homologue; MIM # 164790; at 1p13.2) proto-oncogene explain the occurrence of single/multiple CMNs and melanocytic and non-melanocytic nervous system lesions in NCM: these disrupt the RAS/ERK/mTOR/PI3K/akt pathways. Diagnostic/surveillance work-ups require physical examination, ophthalmoscopy, brain/spinal cord magnetic resonance imaging (MRI) and angiography (MRA), positron emission tomography (PET), and video-EEG and IQ testing. Treatment strategies include laser therapy, chemical peeling, dermabrasion, and surgical removal/grafting for CMNs and shunt surgery and surgical removal/chemo/radiotherapy for CNS lesions. Biologically targeted therapies tailored (a) BRAF/MEK in NCM mice (MEK162) and GCMN (trametinib); (b) PI3K/mTOR (omipalisib/GSK2126458) in NMC cells; © RAS/MEK (vemurafenib and trametinib) in LCMNs cells; or created experimental NMC cells (YP-MEL) 2).

Clinical features

The congenital melanocytic nevi (CMN) are recognised at birth and are distributed over the skin according to 6 or more patterns (6B patterns) in line with the archetypical patterns of distribution of mosaic skin disorders. Neurological manifestations can appear acutely in infancy, or more frequently later in childhood or adult life, and include signs/symptoms of intracranial hypertension, seizures/epilepsy, cranial nerve palsies, motor/sensory deficits, cognitive/behavioural abnormalities, sleep cycle anomalies, and eventually neurological deterioration. NMC patients may be symptomatic or asymptomatic, with or without evidence of the typical nervous system changes at MRI. Associated brain and spinal cord malformations include the Dandy Walker malformation (DWM) complex, hemimegalencephaly, cortical dysplasia, arachnoid cysts, Chiari I and II malformations, syringomyelia, meningoceles, occult spinal dysraphism, and CNS lipoma/lipomatosis. There is no systemic involvement, or only rarely.

Diagnosis

Diagnostic/surveillance work-ups require physical examination, ophthalmoscopy, brain/spinal cord magnetic resonance imaging (MRI) and angiography (MRA), positron emission tomography (PET), and video-EEG and IQ testing 3).


Although the MR manifestations of this disease have been reported in a small series of cases, the usefulness of fluid-attenuated inversion recovery (FLAIR) MR findings has not been documented.

Hayashi et al. present a case of NCM that showed diffuse leptomeningeal hyperintensity on FLAIR images. This FLAIR finding may be a clue to the detection of leptomeningeal abnormalities in NCM 4).

Complications

It is often complicated by hydrocephalus due to melanotic deposits interfering with cerebrospinal fluid (CSF) reabsorption in the basal cisterns or causing foraminal or aqueductal obstruction. In 10% of cases, it is associated with Dandy Walker complex.

Treatment

The management of cutaneous manifestations remains controversial; for neurological manifestations, outcome remains poor even with the use of radiotherapy and chemotherapy.


Treatment strategies include laser therapy, chemical peeling, dermabrasion, and surgical removal/grafting for congenital melanocytic nevi (CMN)s and shunt surgery and surgical removal/chemo/radiotherapy for CNS lesions. Biologically targeted therapies tailored (a) BRAF/MEK in NCM mice (MEK162) and GCMN (trametinib); (b) PI3K/mTOR (omipalisib/GSK2126458) in NMC cells; © RAS/MEK (vemurafenib and trametinib) in LCMNs cells; or created experimental NMC cells (YP-MEL) 5).

Outcome

The prognosis of patients with symptomatic neurocutaneous melanosis is extremely poor, even in the absence of malignancy. Chemotherapy has been ineffective in the few patients in whom it has been tried 6).

Review

Ma et al. reviewed 30 adults with NCM (20 males [66.7%] and 10 females [33.3%]), age 19-65 years (average, 27.9 years). These include 24 cases of malignant melanoma (80.0%), 3 cases of melanocytoma (10.0%), 2 cases of diffuse melanocytosis (6.7%), and 1 case of unknown pathology (3.3%). Satellite nevi were reported in 25 cases (83.3%) and in 5 cases their presence was unknown (16.7%). Intracranial lesions were present in 28 cases (93.3%), and intraspinal lesions were present in 2 cases (6.7%). There are 4 cases of combined hydrocephalus (13.3%), and 2 cases of combined Dandy-Walker deformity (6.7%) 7).


Kadonaga and Frieden reviewed 39 reported cases of neurocutaneous melanosis and propose revised criteria for diagnosis. Most patients with neurocutaneous melanosis presented in the first 2 years of life with neurologic manifestations of increased intracranial pressure, mass lesions, or spinal cord compression. Leptomeningeal melanoma was present in 62% of the cases, but even in the absence of melanoma, symptomatic neurocutaneous melanosis had an extremely poor prognosis. Useful diagnostic procedures include cerebrospinal fluid cytology and magnetic resonance imaging with gadolinium contrast. Patients may be aided by palliative measures such as shunt placement to reduce intracranial pressure. Dermatologists in their follow-up of patients with large or multiple congenital melanocytic nevi should be aware of this condition, to aid in prompt diagnosis and because the treatment of cutaneous lesions may be altered in the presence of symptomatic neurocutaneous melanosis 8).

Case series

Of 14 patients (11 males, 3 females) identified, eight were living. Median age of survivors was 31 months (range 12mo-6y 10mo) while median age of death was 81 months (19mo-28y). Of the six patients who died, all had diffuse leptomeningeal melanocytic deposits and four had leptomeningeal melanoma. All patients had neuroimaging: six had findings suggestive of diffuse leptomeningeal melanocytosis; seven had multifocal melanocytic deposits; and one patient had normal neuroimaging but focal seizures. Spinal abnormalities were common: three patients had extensive dorsal spinal arachnoid cysts and one had a benign cervical spindle cell tumor. Seven patients had epilepsy. Three patients had profound developmental delay; the other 11 patients had no or mild delay.

Children with neurocutaneous melanocytosis exhibit a wide range of intracranial and intraspinal abnormalities and variable clinical outcomes 9).

Case reports

Omar AT 2nd et al. present the case of a 6-year-old female with multiple congenital hairy nevi presenting with generalized tonic clonic seizures, headache, and vomiting. Neuroimaging showed communicating hydrocephalus associated with Dandy-Walker variant, melanotic deposits in the amygdalae, thalami, and cortical sulci, and abnormal leptomeningeal enhancement. After undergoing ventriculoperitoneal shunt (VPS) insertion, symptoms of increased intracranial pressure abated. However, she again deteriorated a month post-operatively from progressive leptomeningeal spread suspicious for malignant degeneration.

This case, as well as a review of related literature, suggests that shunt insertion (ventriculoperitoneal or cystoperitoneal) is an effective palliative measure for patients with neurocutaneous melanosis with associated hydrocephalus. Despite treatment, however, the prognosis of these patients remains poor because of malignant progression and leptomeningeal spread of lesions, particularly in cases associated with Dandy-Walker complex 10).


Sharouf et al. describe the case of a 5-month-old boy who presented with giant congenital melanocytic nevus and hydrocephalus. MR imaging and CSF immunohistochemistry confirmed leptomeningeal melanosis. We discuss the diagnosis, treatment and prognosis of this rare disorder in the light of recent published literature.

Patient required placement of right-sided ventriculoperitoneal shunt to control hydrocephalus. The patient tolerated the procedure well and was discharged home with normal neurological function. A presumptive diagnosis of NCM was made based on the MR characteristics, CSF cytology and clinical presentation. He received trametinib, a MAPK/Erk kinase inhibitor for 7 months. At 30 months of age, he developed left-sided weakness and status epilepticus requiring paediatric intensive care unit admission and ventilator support. The patient eventually succumbed to malignant transformation of leptomeningeal disease.

Cutaneous manifestations of NCM are usually congenital, and neurological manifestations develop early in life. Patients with large or multiple congenital nevi should therefore be investigated early to facilitate treatment. MR imaging is the investigation of choice which can further assist in performing biopsy. Symptomatic NCM is refractory to radiotherapy and chemotherapy and has a poor prognosis. A multidisciplinary approach is necessary in the management of NCM patients 11).


Das et al. present an unusual case of NCM accompanied by right frontal intermediate grade melanocytoma with intratumoral bleeding in a 17-year-old boy 12).


Neurocutaneous melanocytosis is a rare neurocutaneous syndrome defined by the presence of large and/or multiple congenital cutaneous nevi and melanocytic deposits in the central nervous system. We sought to define the spectrum of central nervous system abnormalities in children with neurocutaneous melanocytosis.

Method: We retrospectively reviewed cases of neurocutaneous melanocytosis referred to the pediatric neuro-oncology service at our center from 2003 to 2010.

Results: Of 14 patients (11 males, 3 females) identified, eight were living. Median age of survivors was 31 months (range 12mo-6y 10mo) while median age of death was 81 months (19mo-28y). Of the six patients who died, all had diffuse leptomeningeal melanocytic deposits and four had leptomeningeal melanoma. All patients had neuroimaging: six had findings suggestive of diffuse leptomeningeal melanocytosis; seven had multifocal melanocytic deposits; and one patient had normal neuroimaging but focal seizures. Spinal abnormalities were common: three patients had extensive dorsal spinal arachnoid cysts and one had a benign cervical spindle cell tumor. Seven patients had epilepsy. Three patients had profound developmental delay; the other 11 patients had no or mild delay.

Interpretation: Children with neurocutaneous melanocytosis exhibit a wide range of intracranial and intraspinal abnormalities and variable clinical outcomes 13).


Neurocutaneous melanocytosis (NCM) is a poorly understood disease due to its rarity. A study aimed to summarize the characteristics of adult NCM and improve the awareness of this disease.

The clinical data of 13 adult patients with NCM were retrospectively reviewed, including neuroimages, cerebrospinal fluid (CSF), and histological features.

There were 9 males and 4 females. The mean age at symptom onset was 36.5 years. The initial symptoms included intracranial hypertension in 8 patients and seizure in 4 patients. Ten patients had large and/or multiple congenital melanocytic nevi. MRI revealed hydrocephalus and diffuse thickening of the leptomeninges with T1 shortening in all patients. Post-contrast T1-weighted images showed diffuse linear enhancement of the leptomeninges. Lumbar punctures showed increased open pressure, and elevated protein levels and decreased glucose concentrations in CSF. Cells with intracytoplasmic coarse black granules were found in the CSF and were positive for S100, HMB45, and vimentin. Histopathology of the cutaneous lesions and meninges showed melanocytes but no evidence of malignant melanoma.

Adult NCM patients present a diversity of clinical manifestations. Brain MRI showing diffuse thickening of the leptomeninges with T1 shortening is useful in diagnosing NCM. Heterocellular melanin may be of great value for early diagnosis of NCM in challenging cases 14).

Diffuse leptomeningeal melanocytosis

Diffuse leptomeningeal melanocytosis

References

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Flores-Sarnat L. Neurocutaneous melanocytosis. Handb Clin Neurol. 2013;111:369-88. doi: 10.1016/B978-0-444-52891-9.00042-7. Review. PubMed PMID: 23622187.
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Ruggieri M, Polizzi A, Catanzaro S, Bianco ML, Praticò AD, Di Rocco C. Neurocutaneous melanocytosis (melanosis). Childs Nerv Syst. 2020 Oct 13. doi: 10.1007/s00381-020-04770-9. Epub ahead of print. PMID: 33048248.
4) 

Hayashi M, Maeda M, Maji T, Matsubara T, Tsukahara H, Takeda K. Diffuse leptomeningeal hyperintensity on fluid-attenuated inversion recovery MR images in neurocutaneous melanosis. AJNR Am J Neuroradiol. 2004 Jan;25(1):138-41. PubMed PMID: 14729544.
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Di Rocco F, Sabatino G, Koutzoglou M, Battaglia D, Caldarelli M, Tamburrini G. Neurocutaneous melanosis. Childs Nerv Syst. 2004 Jan;20(1):23-8. Epub 2003 Oct 24. PubMed PMID: 14576958.
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Ma M, Ding ZL, Cheng ZQ, Wu G, Tang XY, Deng P, Wu JD. Neurocutaneous Melanosis in an Adult Patient with Intracranial Primary Malignant Melanoma: Case Report and Review of the Literature. World Neurosurg. 2018 Jun;114:76-83. doi: 10.1016/j.wneu.2018.02.007. Epub 2018 Mar 10. Review. PubMed PMID: 29530698.
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Kadonaga JN, Frieden IJ. Neurocutaneous melanosis: definition and review of the literature. J Am Acad Dermatol. 1991 May;24(5 Pt 1):747-55. Review. PubMed PMID: 1869648.
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Ramaswamy V, Delaney H, Haque S, Marghoob A, Khakoo Y. Spectrum of central nervous system abnormalities in neurocutaneous melanocytosis. Dev Med Child Neurol. 2012 Jun;54(6):563-8. doi: 10.1111/j.1469-8749.2012.04275.x. Epub 2012 Apr 2. PubMed PMID: 22469364.
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Omar AT 2nd, Bagnas MAC, Del Rosario-Blasco KAR, Diestro JDB, Khu KJO. Shunt surgery for neurocutaneous melanosis with hydrocephalus: case report and review of the literature. World Neurosurg. 2018 Sep 8. pii: S1878-8750(18)32022-9. doi: 10.1016/j.wneu.2018.09.002. [Epub ahead of print] PubMed PMID: 30205217.
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Sharouf F, Zaben M, Lammie A, Leach P, Bhatti MI. Neurocutaneous melanosis presenting with hydrocephalus and malignant transformation: case-based update. Childs Nerv Syst. 2018 Aug;34(8):1471-1477. doi: 10.1007/s00381-018-3851-5. Epub 2018 Jun 12. PubMed PMID: 29948137; PubMed Central PMCID: PMC6060827.
12) 

Das K, Nair A, Jaiswal S, Sahu R, Srivastava A, Kumar R, Mehrotra A. Supratentorial intermediate grade meningeal melanocytoma with intratumoral bleed in the background of neurocutaneous melanosis: Report of an unusual case and review of literature. Asian J Neurosurg. 2017 Jan-Mar;12(1):98-102. doi: 10.4103/1793-5482.145113. PubMed PMID: 28413547; PubMed Central PMCID: PMC5379819.
13) 

Ramaswamy V, Delaney H, Haque S, Marghoob A, Khakoo Y. Spectrum of central nervous system abnormalities in neurocutaneous melanocytosis. Dev Med Child Neurol. 2012 Jun;54(6):563-8. doi: 10.1111/j.1469-8749.2012.04275.x. Epub 2012 Apr 2. PMID: 22469364.
14) 

Qian M, Ren H, Qu T, Lu Z, Zou Y, He J, Zhao Y, Chen L, Guan H. Spectrum of Clinical, Neuroimaging, and Cerebrospinal Fluid Features of Adult Neurocutaneous Melanocytosis. Eur Neurol. 2018;80(1-2):1-6. doi: 10.1159/000488687. Epub 2018 Jul 13. PMID: 30007971.

Diffuse leptomeningeal melanocytosis

Diffuse leptomeningeal melanocytosis

Primary melanocytic tumors of the central nervous system (CNS) are rare lesions arising from melanocytes of the leptomeninges. They include diffuse leptomeningeal melanocytosis or melanomatosis, melanocytoma and primary malignant melanoma 1).


Diffuse leptomeningeal melanocytosis is a rare tumor of meninges arising from leptomeningeal melanocytes, characterized by diffuse infiltration of the leptomeninges (pia mater and arachnoidea) anywhere in the central nervous system.

Leptomeningeal melanocytes, are derived from neural crest and include diffuse melanocytosis, melanocytomas, and malignant melanomas. Meningeal melanocytomas are extremely rare benign lesions.

Pathology

The aim of a study was to analyze melanocytic proliferation in 2 rare and severe cases of isolated Diffuse leptomeningeal melanocytosis (DLM) and neurocutaneous melanocytosis (NCM) of prenatal onset by neuropathologic and molecular analysis. Uguen et al. performed neuropathologic examination, comparative genomic hybridization arrays, fluorescence in situ hybridization, BRAF and NRAS pyrosequencing in the 2 cases, and next-generation sequencing in the case of isolated DLM. The neuropathologic examination showed diffuse meningeal melanocytic proliferation involving the whole central nervous system with multiple areas of intraneural invasion, associated with large nevi in 1 case. They did not find any chromosomal imbalances. A NRAS(Q61K) mutation was found in the cutaneous and meningeal lesions from the NCM. No mutation was found within a panel of oncogenes including BRAF, NRAS, HRAS, KIT, GNAQ, and GNA11 concerning the isolated DLM. They reported 2 exceptional cases of hydrocephalus of prenatal onset related to DLM and NCM. The molecular mechanisms underlying the case of DLM remain unsolved despite the panel of analysis applied 2).

Clinical features

May include stillbirth, intracranial hypertension and hydrocephalus, seizure, ataxia, syringomyelia, cranial nerve palsy, intracranial hemorrhage, sphincter dysfunction and neuropsychiatric symptoms. Transformation into malignant melanoma of the central nervous system was reported. It may be associated with congenital nevi, as a part of neurocutaneous melanosis.

Diagnosis

Brain MRI showing diffuse thickening of the leptomeninges with T1 shortening is useful in diagnosing Neurocutaneous melanocytosis. Heterocellular melanin may be of great value for early diagnosis of NCM in challenging cases 3).


Over a 5-year period (1989-1994) Byrd et al. evaluated with MR imaging the central nervous system of five children with a confirmed histologic diagnosis of neurocutaneous melanosis. The children ranged in age from 7 to 10 years and consisted of two girls and three boys. They all had multiple pigmented skin lesions (cutaneous nevi) and presented with seizures, signs of raised intracranial pressure, cranial nerve palsies and/or myelopathy. The MR studies were performed with T1-weighted, T2-weighted and T1-weighted post-gadolinium images of the brain in addition to T1-weighted post-gadolinium images of the entire spine. The MR findings in all the children consisted of marked, diffuse enhancement of thickened leptomeninges surrounding the brain and spinal cord which was only demonstrated on the post-gadolinium T1-weighted images and mild to moderate hydrocephalus. We present our MR findings and compare these findings with other imaging findings in the literature. The findings represent part of a spectrum of imaging abnormalities seen in patients with neurocutaneous melanosis 4).

Differential diagnosis

Pigmented lesions of the central nervous system (CNS) are a diverse group of entities that run the gamut from benign to malignant. These lesions may be well circumscribed or diffuse, and their imaging appearances are influenced by the degree of melanin content as well as the presence or absence of hemorrhage. Pigmented lesions include primary melanocytic lesions of the CNS and metastatic melanoma, as well as other CNS neoplasms that may undergo melanization, including schwannoma, medulloblastoma, and some gliomas. Primary melanocytic lesions of the CNS arise from melanocytes located within the leptomeninges, and this group includes diffuse melanocytosis and meningeal melanomatosis (seen in neurocutaneous melanosis), melanocytoma, and malignant melanoma. Primary melanin-containing lesions of the CNS must be differentiated from metastatic melanoma because these lesions require different patient workup and therapy. Absence of a known primary malignant melanoma helps in the differential diagnosis, but an occult primary lesion outside the CNS must be sought and excluded. Pigmented lesions of the CNS are uncommon, and knowledge of their imaging characteristics and pathologic features is essential for their identification 5).


Melanocytoma and meningeal melanocytosis, are similar but different lesions.

Meningeal melanomatosis is an extra-axial well-encapsulated malignant tumour with diffuse meningeal growth and dark coloration (due to high melanin contents), while meningeal melanocytoma is the focalized benign variant. Melanocytic tumors may be secondary to melanoma or be histologically benign, however, their diffuse nature makes them impossible to cure. Melanocytosis is a diffuse tumour that can form solitary extra-axial tumours, which invades the parenchyma and presents signs of malignancy with increased mitosis and Ki67, observed in 1 to 6% of immunopathological exams. Melanoma of the leptomeninges, presents signs of malignancy with anaplastic cells, which cluster in fascicles of melanin in the cytoplasm, with more than 3 atypical mitoses per field and Ki67 presenting in more than 6% of the immunopathological fields analysed 6).

Treatment

The usual treatment of intradural extramedullary melanocytomas involves surgical removal through a posterior approach using a laminectomy or laminotomy.

Outcome

Diffuse leptomeningeal melanocytosis (DLM) is a rare nevomelanocytic proliferation arising in the meninges. Despite their lack of morphological features of malignancy, these clonal nevomelanocytic cells are capable of extensive invasion and of malignant behavior. When associated with congenital melanocytic nevi, the disorder is named neurocutaneous melanocytosis (NCM). When symptomatic, DLM is usually revealed during childhood, but some cases remain clinically silent 7).


Leptomeningeal melanocytosis: a fatal course of a benign tumor 8).

Case reports

A 30-year-old female harboring a C6-T1 ventrally located intradural extramedullary lesion compressing the cord anteriorly. The lesion was totally resected via an anterior approach with oblique corpectomy even if the usual treatment involves surgical removal through a posterior approach using a laminectomy or laminotomy.

There is no evidence of recurrence at 4-year follow-up records of the patient 9).


A 38 years old male with primary diffuse leptomeningeal melanomatosis with presence of a NRASQ61K mutation without features of neurocutaneous melanosis 10).


Two cases of primary leptomeningeal melanomatosis presenting as subacute meningitis. Both cases have pleocytosis and high protein on cerebrospinal fluid analysis, and demonstrated atypical cells on cytology. On magnetic resonance imaging, there is diffuse leptomeningal thickening and avid enhancement of intracranial and intraspinal leptomeninges. One of them demonstrates T1 shortening due to magnetic effects of melanin, the other case is amelanotic and shows hypointensity on precontrast T1-weighted images. Both cases can be diagnosed with biopsy. In conclusion, these cases highlight the importance of the correct interpretation of cytological and magnetic resonance imaging findings in patients with atypical findings 11).


Padilla-Vázquez et al. presented the case of a patient with long-term meningeal melanomatosis, with progressive neurologic deficit and characteristic radiologic features, and another case of meningeal melanocytoma.

Benign melanocytic neoplasms of the central nervous system must be treated aggressively in the early phases with strict follow-up to avoid progression to advanced phases that do not respond to any treatment method. Unfortunately, the prognosis for malignant melanocytic lesions is very poor irrespective of the method of treatment given 12).


Uguen et al. reported 2 exceptional cases of hydrocephalus of prenatal onset related to DLM and NCM. The molecular mechanisms underlying our case of DLM remain unsolved despite the panel of analysis applied 13).


A 30-year-old woman with a giant congenital melanocytic nevus covering nearly the entire right thoracodorsal region and multiple disseminated melanocytic nevi presented with neurological symptoms. Cerebral magnetic resonance imaging revealed a large expansive lesion in the left frontal region. Postsurgically pathological diagnosis revealed characteristics of melanoma. Immunohistochemical examination showed S100(+), HMB45(+), MelanA(+), and MiTF(+). She received radiotherapy with temozolomide followed by two more chemotherapy cycles with temozolomide. She followed a rapidly progressive course, reflecting widespread leptomeningeal infiltration, and she died of multiorgan failure seven months after diagnosis of cerebral melanoma. Discussion. This patient was diagnosed as having a neurocutaneous melanosis with malignant widespread leptomeningeal infiltration. Diffuse spinal involvement is unusual and is described in only another patient 14).


An autopsy case of leptomeningeal melanomatosis associated with neurocutaneous melanosis (NCM) involving a 44-year-old male is reported. The autopsy showed that the leptomeningeal surface of the brain and the spinal cord were covered with a diffuse black lesion. A histological examination detected diffusely distributed, proliferating, melanin-containing cells and demonstrated that the lesion consisted of three different components; i.e. regions of melanomatosis, melanocytosis, and melanocyte hyperplasia. In the leptomeningeal melanomatosis component, tumor cells with pleomorphic nuclei and prominent nucleoli had infiltrated into the cerebral parenchyma via Virchow-Robin spaces. The Ki-67 labeling index and the nuclear accumulation of p53 and p16 protein were immunohistochemically examined in each component. The Ki-67 labeling indices of the melanomatosis, melanocytosis, and melanocyte hyperplasia components were 8.7%, 0.8%, and 0%, respectively. Immunostaining of nuclear p16 produced a negative result in the melanomatosis component, but positive results in the melanocytosis and melanocyte hyperplasia components, whereas nuclear p53 expression was not detected in any of the components. This case suggests that p16(INK4) /CDKN2 may play a significant role in progression of leptomeningeal melanocytic neoplasms. We also reviewed previously reported cases of leptomeningeal neoplasms associated with NCM and discussed the relationship between the biological behavior and proliferative activity of such lesions 15).


A 43-year-old woman presented with a 1-week history of neck pain and dizziness. Computed tomography of brain showed communicating hydrocephalus and subarachnoid hyperintensity suspicious of previous subarachnoid haemorrhage. Investigations revealed no underlying vascular lesion and leptomeningeal biopsy showed diffuse melanocytosis 16).


Dechaphunkul A, Kayasut K, Oearsakul T, Koonlaboon K, Sunpaweravong P. Common presentation in an uncommon disease: case report of a patient with primary diffuse leptomeningeal melanocytosis. J Clin Oncol. 2011 Nov 20;29(33):e816-8. doi: 10.1200/JCO.2011.37.3175. Epub 2011 Oct 24. PMID: 22025160.


A rare and atypical case of a 31-year-old adult male with no evident congenital melanocytic lesions who presented with neurologic symptoms and was found to have leptomeningeal melanocytosis. The brain biopsy demonstrated a conspicuous but benign-appearing melanocytic infiltrate that was discordant with the severity of the patient’s symptoms. Ultimately, the patient was suspected to represent a case of former fruste neurocutaneous melanosis. Herein the relevant clinical and histopathologic features are discussed along with a brief review of the literature 17).


A 75-year-old man, undergoing treatment for metastatic prostate cancer with a novel cancer cell vaccine, presented with a 4 week history of poor balance, gait disturbance and cognitive decline. Blood tests including HIV and onconeuronal and voltage gated potassium channel antibodies were normal. Computed tomography and two magnetic resonance images of the brain showed possible non-specific meningeal or vascular enhancement. Two cerebrospinal fluid analyses, including cytology, were negative, other than six lymphocytes in the former. Despite intravenous aciclovir and dexamethasone the patient deteriorated over 16 days, with worsening confusion and involuntary movements, and died. Postmortem examination showed that the leptomeninges overlying the brain and spinal cord were diffusely infiltrated by a melanocytosis with a focal area of melanomatosis. Moreover, there were two sites of metastases of a highly malignant clone present in the pulmonary parenchyma 18).


A rapidly fatal case in an 18-year-old man presenting with symptoms and imaging features suggestive for subarachnoid hemorrhage or meningitis. The laboratory findings and imaging examination were still confusing and the diagnosis remained unclear during the patient’s life. Autopsy was the cornerstone in disclosing the lesion, confirming its usefulness in the assessment of such unusual cases. The complete profile of the tumor was obtained only by histology and immunohistochemistry. Clinicians and pathologists must be aware of diagnosis difficulties in this rare disease which can represent a serious challenge in clinical practice 19).


1-year-old boy with congenital melanocytic nevi had met normal developmental milestones until the age of 11 months, when he began regressing in ambulation and language function. Intractable vomiting had developed 1 week later. Magnetic resonance (MR) imaging of the brain revealed DWC with hydrocephalus, and spinal MR images demonstrated a proliferative process within the meninges, consistent with NM. The patient underwent right frontal VP shunt placement resulting in immediate symptom relief, but 3 weeks later became irritable, increasingly lethargic, unable to pull to stand, and unable to tolerate solid food without choking. Due to these symptoms and intractable vomiting, the patient presented to the authors’ institution. Brain MR imaging revealed a new-onset diffuse cystic process with anterior and posterior brainstem compression, marked kinking of the cervicomedullary junction, melanocyte pigmentation of the left temporal lobe, diffuse leptomeningeal enhancement, and no evidence of hydrocephalus. Consistent with these imaging findings, the degree of brainstem involvement upon gross visualization predictably deterred resection attempts beyond those necessary for biopsy. Pathological examination revealed diffuse melanocytosis, and the family decided not to pursue aggressive measures postoperatively. This report indicates the potential for rapid intracranial manifestation of diffuse melanocytosis in NM patients. Although the prognosis is poor, early neurosurgical involvement in these patients may provide tissue diagnosis and the potential for decompression if the process is caught early in its course 20).


A 26-year-old man had had a large patch of pigmented nevus over his back and left arm since birth. He had begun to have seizures as well as symptoms and signs of increased intracranial pressure about six months before admission. Serial computed tomography of brain showed hydrocephalus, diffuse leptomeningeal enhancement and multiple well-enhanced, rapid-growing nodules on the surface of the cerebellum and left parietal lobe. Magnetic resonance imaging (MRI) revealed T1 shortening of leptomeninges on precontrast T1 weighted imaging. Skin biopsy was done twice and showed intradermal nevus. Biopsy on one of the intracranial nodules revealed malignant melanoma arising in the melanocytosis. He died one year after the onset of neurologic symptoms. For early diagnosis of neurocutaneous melanocytosis, we suggest 1) MRI, and 2) leptomeningeal biopsy in patients with suspected leptomeningeal malignant melanoma 21).

References

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Qian M, Ren H, Qu T, Lu Z, Zou Y, He J, Zhao Y, Chen L, Guan H. Spectrum of Clinical, Neuroimaging, and Cerebrospinal Fluid Features of Adult Neurocutaneous Melanocytosis. Eur Neurol. 2018;80(1-2):1-6. doi: 10.1159/000488687. Epub 2018 Jul 13. PMID: 30007971.
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