Primary versus Secondary Central Nervous System Melanoma : a Diagnostic Dilemma and Report of a Case

1 Department of Neurology, Colentina Clinical Hospital, Bucharest, Romania 2 Research Department, Colentina Clinical Hospital, Bucharest, Romania 3 „Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 4 Department of Neurosurgery, Colentina Clinical Hospital, Bucharest, Romania 5 Department of Anatomic Pathology, Colentina Clinical Hospital, Bucharest, Romania 6 Division of Clinical Neuroscience, Academic Clinical Neurology, University of Nottingham, Queen`s Medical Centre, Nottingham, United Kingdom 7 Laboratory of Molecular Biology, „Victor Babes” Institute of Pathology, Bucharest, Romania Corresponding author: Bogdan Ovidiu Popescu Department of Neurology, Colentina Clinical Hospital, Bucharest, Romania. E-mail: bogdan_ovidiu_popescu@yahoo.com Abstract


CASE REPORT
A 65-year old Caucasian male, hypertensive, diabetic, with long-term anticoagulant and antiplatelet therapy, and a history of myocardial infarction initially presented with a hemorrhagic venous infarction of the left temporal lobe responsible for sudden motor aphasia and right-sided hemiparesis, which he recovered completely over the next year.A follow-up brain magnetic resonance imaging (MRI) performed six months later revealed an asymptomatic hemorrhagic venous infarction in the territory of the left vein of Labbe, as well as peculiar intra-axial and meningeal lesions of the right hemisphere (Figure 1, left).At the time he was referred to our Department and underwent a comprehensi-

INTRODUCTION
Melanoma is the third most frequent cause of brain metastases, after lung and breast cancer, accounting for approximately 6-11% of all metastatic brain lesions 1, 2 .Apart from cutaneous melanoma, which is the commonest subtype, melanoma may also arise from other sites containing melanocytes such as the glabrous skin of the palms, soles and nail beds (i.e.acral melanoma), the mucosal epithelium lining the respiratory, alimentary and genitourinary tracts, the conjunctival epithelium, the uveal tract and the leptomeninges 3 .Primary central nervous system (CNS) melanoma is rare, comprising 1% of all cases of melanoma and 0.07% of brain tumours 4 .Herein we report the case of a patient with melanoma of uncertain origin, cutaneous in all likelihood, and brain metastases, with a view to raising awareness of the matter and delineating the particularities vârstă de 65 de ani cu infarct venos hemoragic la nivelul lobului temporal stâng responsabil de afazie motorie şi hemipareză dreaptă.Rezonanţa magnetică cerebrală a evidenţiat de asemenea leziuni supratentoriale cerebrale şi meningeale suspecte, cu posibil substrat neoplazic sau vasculitic.Bilanţul investigaţional nu a fost concludent, s-a propus biopsia cerebrală, însă pacientul a refuzat.După 1,5 ani de la simptomatologia iniţială, simptomele au reapărut, iar imageria cerebrală a relevat progresia leziunilor, cu necroză şi edem vasogenic înconjurător.În cele din urmă, pacientul a consimţit la efectuarea biopsiei cerebrale pentru diagnostic de certitudine.Rezultate: Evaluarea histopatologică şi imunohistochimică a fost compatibilă cu melanom malign pigmentat.Nu s-au depistat leziuni primare suspecte, însă pacientul şi-a amintit faptul că în urmă cu câţiva ani i s-a excizat o formaţiune toracică, aparent benignă, însă indisponibilă pentru second opinion.Concluzii: În cazul prezentărilor suspecte ale sistemului nervos central, reevaluarea histopatologică a leziunilor cutanate excizate anterior este recomandabilă, mai ales atunci când nu se poate practica biopsia cerebrală.Melanomul primar al sistemului nervos central, deşi este rar, reprezintă un diagnostic de avut în vedere.Cuvinte-cheie: melanom, metastaze cerebrale, second opinion.ve workup covering a potential neoplastic or vasculitic ground, comprising extensive blood testing, lumbar puncture with cerebrospinal fl uid analysis, including oligoclonal bands, immunoglobulin G index and lymphocyte immunophenotyping, all of which were unremarkable.A brain biopsy was discussed, but the patient declined.He was readmitted after fi ve months for left-sided hemiparesis 3/5 BMRC and motor aphasia.Brain MRI showed progression of lesions with expansion of a right parietal mass of probable meningeal origin described on previous examination (Figure 1, right) and a novel right temporal lesion with an inner necrotic area and surrounding vasogenic oedema (Figure 2).Th ere was complete neurological remission upon treatment with dexamethasone.Th e patient fi nally agreed to undergo neurosurgical treatment and one month later tumour debulking and brain biopsy were performed for histological and immunohistochemical assessment, which were consistent with cerebral metastasis from malignant pigmented melanoma (Figure 3).Th ere were no clinically suspicious primary lesions, however the patient recalled having had a thoracic lump excised some years prior, allegedly benign, but unavailable for second opinion.

DISCUSSION
Th is case is a starting point for revising general important aspects concerning melanoma, a major health issue whose overall prognosis is grounded on timely diagnosis and treatment.Although there are no randomized trials to establish the effi cacy of screening for melanoma on mortality reduction, screening is sensible for persons considered at high risk of developing melanoma, i.e., fair-skinned, carrying a history of sun exposure, a family or personal history of skin cancer, an increased number of nevi and atypical nevi, an immunocompromising condition 5 .Screening involves a full-body examination performed yearly by a trained specialist, education about risk factors and monthly self-examination.Th e US Preventive Services Task Force (USPSTF) hold that there is insuffi cient evidence to assess the benefi ts and harms of counseling adults about skin self-examination, but recommend that counseling be provided for children, parents of children and adults with fair skin about minimizing exposure to ultraviolet radiation5.Th e ABCDE criteria for the assessment of pigmented cutaneous lesions are instrumental in early detection of cutaneous melanoma.Th e acronym stands for asymmetry, border irregularities, colour variegation, diameter equal to and over 6 mm and evolution 6 .All suspicious pigmented lesions should be further examined dermoscopically 7 .Th e definitive diagnosis of melanoma is histopathologic, with supporting immunohistochemical testing.Aside from cutaneous melanoma, which is the most common type, there are also other unusual types of melanoma such as acral, mucosal, conjunctival, uveal and leptomeningeal melanoma 3 , that tend to be diagnosed at a more advanced stage and therefore bear a worse prognosis 8 .Melanoma has a strong propensity for brain metastases 2 .Cerebral haemorrhagic masses should prompt considering the existence of a melanoma with subsequent thorough clinical screening.In the setting of melanoma and cerebral lesions, the latter are more likely brain metastases, yet a primary CNS melanoma, albeit less frequent, should also be entertained.As regards the therapeutic management of melanoma patients with and BRAF V600 respectively were concerned 15 .Th ere is still concern about devising proper protocols combining systemic therapy agents and immunotherapy with local surgery and radiosurgery, but the outlook is encouragingly promising.Nevertheless, a prompt diagnostic is a key-element for a benefi cial outcome.In our patient there are no follow-up data over 2.5 years from the initial neurological manifestations, yet the prolonged survival surpassing the reported overall average of four months [16][17][18] is particular.

CONCLUSION
 Unusual sites of origin for melanoma are the mucosal epithelium lining the respiratory, digestive and genitourinary tracts, the conjunctival epithelium, the uveal tract and the leptomeninges  Prompt histopatologic reevaluation of previously excised skin lesions should be considered in people with suspicious CNS presentations, especially if CNS biopsy cannot be performed.brain metastases, a multidisciplinary approach is warranted.Important factors to consider in treatment selection are tumour-related, such as number, size, location of brain metastases, B-Raf (BRAF) mutation status of the melanoma, as well as patient-related, including age, overall performance status, other comorbidities and the extent of systemic metastatic disease.Surgical resection is generally preferred in patients with a good performance status (i.e.Karnofsky performance status over 70%), with solitary or few brain metastases located in noneloquent areas or to relieve symptoms from larger lesions (greater than 3 cm), and potentially life-threatening ones 9 .Stereotactic radiosurgery (SRS) is employed for multiple small lesions (under 3 cm in diameter) 10 or lesions that are not surgically accessible.Th e total tumour volume appears to be a better prognostic of outcome, including overall survival, than the number of metastases 11 .Th e advent of systemic therapy comprising immunotherapy and targeted therapy has signifi cantly advanced the treatment of metastatic melanoma.Th e combination of ipilimumab and nivolumab has proven more eff ective in improving overall survival than either agent in monotherapy as regards advanced melanoma 12 and brain metastases in melanoma specifi cally 13 .Furthermore, associating immunotherapy with surgical treatment or radiosurgery resulted in longer median overall survival 14 .Targeted agents are inhibitors of protein kinases involved in the mitogenactivated protein kinase (MAPK) pathway, which is pivotal in the pathogenesis of melanoma.Th erefore, BRAF inhibitors such as dabrafenib, vemurafenib or MEK inhibitors such as trametinib have shown benefi t in overall survival were mutations in BRAF V600E

Figure 1 .
Figure 1.Brain MRI.Axial fluid attenuation inversion recovery (FLAIR)-weighted image showing a right parietal mass of pro bable meningeal origin (left) and axial T1-weighted image showing the same mass of larger size, with surrounding vasogenic oedema, seven months later (right).

Figure 2 .
Figure 2. Brain MRI.Axial FLAIR-weighted image (left) and T1-weighted image (right) showing a right temporal contrastenhancing lesion with an inner necrotic area and surrounding vasogenic oedema.

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Th is case report was fi rst presented as ePoster at the 4 th Congress of the European Academy of Neurology in June 2018.