Primary leptomeningeal melanoma: the prognostic significance of its genetic signature and embryological origin

Abstract

Primary leptomeningeal melanomas are rare, comprising less than one percent of all brain tumours. They are aggressive and radioresistant tumours, with a poor prognosis. The mainstay of treatment is complete surgical resection and chemotherapy with limited success. Distinguishing a primary leptomeningeal melanoma from the more common metastatic disease can be difficult, and often requires the use of ancillary molecular testing. Primary central nervous system melanomas, including uveal melanomas, frequently exhibit mutations in GNAQ and GNA11, rare in the cutaneous and mucosal counterparts.

A case of a primary leptomeningeal melanoma of the cerebellopontine angle is described. Molecular studies identified a GNA11 p.Q209L and a KIT p.M541L missense variant, with losses of chromosomes 1p and 3p demonstrated with cytogenetic studies. Complete surgical resection was not possible and leptomeningeal metastatic disease rapidly ensued despite immunotherapy. Further understanding of the molecular signature may translate to improved diagnosis, prognostication and development of targeted therapies.

Background

Melanocytes of the central nervous system (CNS) are derived from ventral neural crest tissue that differs from cutaneous melanocytes which arise from the dorsal neural crest.¹ Melanocytes are found in the pia layer of the meninges throughout the neural axis with maximal numbers in the cervical cord and anterolateral medulla.¹ Their function is to protect the vital brainstem centres and cranial nerves from oxidative damage.¹ Melanocytes in the cochlear and uveal tract have a similar embryological origin.¹

Cerebellopontine angle tumours usually present with unilateral hearing loss, tinnitus, facial hyperesthesia, speech impediment or cerebellar symptoms. The differential diagnosis of these tumours includes schwannoma, meningioma, metastases or an epidermoid cyst. Vestibular schwannoma is the most common (70%–80%), followed by meningioma (10%–15%), epidermoid cyst (3%) and a wide variety of other lesions. MRI sequences (FLAIR DWI, gadolinium enhancement) have been used successfully on occasions to discriminate between these tumours.²

Primary leptomeningeal melanoma and secondary melanoma have distinctive features on MRI. Owing to the paramagnetic properties of melanin there is hyperintensity on T1WI sequences and hypointensity or isointensity on T2WI.³ In contrast, both melanocytoma and meningioma are typically isointense on T1WI with homogeneous enhancement.³

Histopathology discriminates melanocytoma from melanoma, but cannot reliably differentiate primary from secondary disease. The diagnosis of primary melanoma requires clinical exclusion of cutaneous, mucosal and uveal melanomas. The divergent molecular signatures of uveal and cutaneous melanomas provide diagnostic support.⁴ In primary leptomeningeal melanoma, the incidence and significance of associated mutations is evolving. Its molecular signature and implications may be similar to uveal melanoma, with mutations of the GNAQ and GNA11 genes, chromosome 3 monosomy and immunohitochemical loss of BAP1 expression are reported.⁴ Typically, they lack the BRAF, NRAS and HRAS mutations, which typically define cutaneous melanomas.⁴

Unresectable primary leptomeningeal melanomas are typically aggressive, radioresistant and with no effective medical treatment. The median survival time is 10 weeks following established leptomeningeal spread.³ Refined understanding of the molecular genetic profile may offer diagnostic, prognostic and therapeutic potential.

Case presentation

A 34-year-old woman presented to hospital with a 2-day history of a left facial weakness and headache, accompanied by nausea and vomiting. There was no preceding anorexia or weight loss. The headache was a generalised throbbing headache and did not change with position or valsalva. Examination revealed left lower motor neuron facial palsy with accompanying partial ptosis and mild slurring dysarthria. There was mild dysmetria and dysdiadochokinesis of the left upper limb with intact strength, reflexes and sensation to pin prick and position. Romberg’s sign was negative. She did not have hearing loss, and therefore, hearing was not formally tested. The remainder of the neurological examination was unremarkable including normal funduscopy.

Investigations

CT revealed a left extra-axial cerebellopontine angle mass, measuring 26.5× 28mm, with associated partial effacement of the fourth ventricle. The mass demonstrated low T2 signal and T1 hyperintensity on MR brain imaging (figure 1) with gadolinium enhancement (figure 2). There was no evidence of metastatic disease clinically or on whole body positron emission tomography.

Figure 1.

Preoperative MRI demonstrated a 26.5 x 28 mm lesion at the left cerebellopontine angle.

Figure 2.

Preoperative MRI with gadolinium demonstrating the contrast enhancement.

A left retro sigmoid craniotomy was performed at 1-week postpresentation. The operative finding was a highly vascular tan coloured tumour encasing the facial nerve, the lower cranial nerves IX and X) and blood vessels. Resection was not possible due to the tumour location and vascularity. The sampled lesion was macroscopically tan with areas of haemorrhage. On microscopy, the lesion was biphasic, with epithelioid and spindled morphology exhibiting a range of cytologic atypia, ranging from monotonous areas to foci of pleomorphic cells with bizarre nuclear forms. The melanoma cells had round to spindle nuclei with prominent nucleoli, surrounded by eccentric eosinophilic cytoplasm, some with finely granular melanin pigment (figure 3). There was scant mitotic activity (figure 4) and no necrosis but overt cytological atypia. There was an associated inflammatory stromal component, comprising macrophages and small lymphocytes, predominantly T-cells. Electron microscopy revealed neoplastic cells arranged in nests without cell junctions and with cytoplasmic melanosomes, confirming melanocytic differentiation.

Figure 3.

×400 magnification imaging demonstrating sheets of biphasic malignant melanocytes, with finely granular melanin pigment.

Figure 4.

×400 magnification image of areas of melanoma with overt cytological atypia and stromal lymphocytes.

On immunohistochemistry, the tumour cells demonstrated nuclear staining with Sox10 and cytoplasmic staining with Melan-A and antimelanoma antibody (HMB-45), in keeping with melanocytic origin. The tumour cells demonstrated aberrant loss of BAP-1 staining (figure 5). Subsequent multiplex ligation-dependent probe amplification confirmed a loss of both chromosome 1p and 3p. There was no BRAF, NRAS, SF3B1 or EIFAX variants detected by molecular studies. A missense GNA11 p.Q209L (guanine nucleotide-binding protein subunit alpha-11 (Gq class) variant was identified using the Illumina TruSight Oncology 500 targeted hybrid capture-based next generation sequencing assay. Additionally, BRCA1 p.R1347G and KIT p.M541L.missense variants of uncertain clinical significance were detected.

Figure 5.

BAP-1 immunohistochemistry, demonstrating aberrant nuclear loss of expression.

Differential diagnosis

The clinical history and examination were atypical for a vestibular schwannoma with no reported hearing loss or tinnitus. The short history suggested an aggressive process most likely a malignancy. The headache in this setting was worrying as the lesion was close to the fourth ventricle with the potential for obstructive hydrocephalus.

The histological and radiological features were consistent with malignant melanoma. Melanocytoma was excluded due to the degree of atypia. Secondary uveal melanoma was excluded by normal funduscopy and normal imaging of globes together with lack of hepatic involvement. A careful skin examination revealed no abnormal melanotic lesions or areas of hyper pigmentation or hypo pigmentation. This rendered cutaneous metastasis unlikely. The enhancement of the internal auditory meatus raised the possibility of primary cochlear melanoma but hearing loss was not detected on initial presentation. Melanotic schwannoma was excluded histologically.

Treatment

Postoperative deficits included left abducens palsy, sensorineural hearing loss, oropharyngeal dysphagia and left lower limb weakness. At 1-month postsurgery, staging MRI confirmed leptomeningeal metastatic disease. Combination check point inhibitor therapy was commenced, with ipilimumab and nivolumab induction. Four cycles were planned followed by maintenance nivolumab monotherapy.

Outcome and follow-up

Within 10 days of ipilimumab induction, the patient presented with severe vomiting and diarrhoea consistent with immune related proctocolitis. There was rapid systemic decline despite treatment with intravenous hydration, steroids and antibiotics. The patient died in hospital, 10 weeks following her initial presentation.

Discussion

Melanocytes are present in normal leptomeningeal tissue and may have a central immunological and bioregulatory role additional to melanin synthesis.¹

Primary leptomeningeal melanomas are rare tumours, representing 0.07% of all brain tumours.⁵ They are typically diagnosed in the fourth decade.⁶ The cerebellopontine angle location is unusual for primary melanoma; reported in less than 10% of published cases.^{6 7}

Primary leptomeningeal melanomas occur with mutations causing the hereditary loss of BAP1 (BVERCA-1 associated protein 1), together with uveal melanoma, renal cell carcinoma and mesothelioma. The BAP1 gene is found on chromosome 3 and has a role in maintaining cell differentiation and in apoptosis.⁴ Chromosome 3 monosomy has been reported in both melanoma and melanocytoma.⁴ In this tumour, there was loss of BAP-1 staining by immunohistochemistry. On Multiplex ligation-dependent probe amplification panel, there was a corresponding dual chromosomal loss of 3p and 1p. The consequence of BAP-1 mutation is cell specific. In cutaneous melanoma it constitutes a good prognostic marker associated with reduced cellularity and is linked to benign lesions.^{8 9} In contrast, in uveal melanoma, a BAP1 mutation is a poor prognostic marker associated with dedifferentiation and upregulated growth capacity.¹⁰ In primary leptomeningeal melanoma, the prognostic significance is unclear though appears to be poor, similar to uveal melanoma.⁴

The GNAQ or the GNA11 mutations can be used to determine the origin of the melanocytes as they are rare in cutaneous melanomas. They are detected in blue naevi both malignant and benign and the naevi of Ota but not naevi of Ito.¹¹ Interestingly naevi of Ota which are most commonly found in the ophthalmic and maxillary divisions of the trigeminal nerve have been associated with intracranial melanocytomas of Meckel’s cave and of the cerebellopontine angle.¹² It is thought that this represents primitive melanocytes that these have failed to migrate appropriately. In uveal melanoma, mutations in GNA11 and GNAQ are common and BRAF mutation is extremely rare.⁴ The inverse is true in cutaneous melanoma where BRAF mutation predominates with its linked eligibility for BRAF inhibitor therapy.

Somatic mutations of GNAQ and GNA11 have both been reported in primary meningeal melanoma, although GNAQ mutations predominate.⁴ GNA11 is a homologue of GNAQ. GNA11 mutations have been reported in 10% of meningeal melanoma cases.⁴ In this tumour, there was a missense mutation at GNA11 p.Q209L but no GNAQ variant. This oncogenic, hotspot variant is most common in uveal melanoma, particularly when metastatic, and indeed predicts spontaneous tumour metastasis.¹¹ The substitution of glutamine (Q) at codon 209 causes reduced intrinsic guanosine triphosphatase activity, preventing guanosine triphosphate hydrolysis.⁴ In a mouse model of uveal melanoma, this induces constitutive activation of the Gq protein with persistent mitogen activated protein kinase pathway signalling and oncogenesis.⁴

A KIT p.M541L missense variant was identified in this tumour and was of uncertain significance. KIT is expressed in melanocytes and when activated, stimulates melanocyte proliferation. Deranged KIT expression affects melanoblast differentiation and migration, as seen in piebaldism. This may be relevant to tumourigenesis, aligned with the neurogenic theory of erroneous migration of neural crest cells.³ This particular variant has been reported in several cases of meningioma and in cutaneous melanoma.¹³ It also been demonstrated in one family study with hereditary piebaldism.¹⁴ Diverse KIT mutations occur in head and neck melanoma, which may be relevant given the shared embryological origin with meningeal melanocytes. A recent review of head and neck mucosal melanomas reported one quarter of their 28 cases had KIT activating mutations, although none listed this p.M541L variant.¹⁵ Further understanding of KIT expression in primary melanoma could potentially lead to personalised targeted therapy.

The prognosis for primary leptomeningeal melanoma directly relates to the success of the excision. Once there is leptomeningeal metastasis, the average survival is 10 weeks, similar to this presentation.⁵ Therapy has been tried with radiotherapy, temozolomide and dacarbazine with minimal success.⁶ There is a paucity of data on use of combination check point inhibitors. It is hoped that that increased understanding of the molecular signature will underpin the development of novel targeted therapies.

Patient’s perspective.

As the patient’s partner this ordeal has had a devastating impact on our lives, seeing a loved one leave so young and endure the symptoms associated with this illness has been horrific. The patient’s three year old son now faces a life without his mother, while family and friends have been left in shock with the reality of this ordeal.

It is the patient’s wishes that further knowledge can be gained and shared from this ordeal in order to benefit others in such an unfortunate situation.

Learning points.

• Primary leptomeningeal melanoma is a rare cause of a cerebellopontine tumour.

• The molecular signature appears to be similar to uveal melanoma.

• There are currently no known targeted treatments available.

• Improved understanding its molecular signature may support diagnosis, prognostication and ultimately, direct therapy.