Primary cerebello-pontine angle melanoma: a case report

Intra-cranial melanomas are commonly metastatic from primary melanoma elsewhere in the body. The primary occurrence of a melanoma in the brain parenchyma is rare. We report a case of 38 year aged woman who presented with deviation of left eye and headache. On imaging, a space occupying lesion was found in the left Cerebello-pontine angle and a preoperative diagnosis of meningioma was made. She underwent left retro-mastoid sub-occipital craniectomy and excision of a black vascular tumor. Histopathological examination revealed a melanoma which was confirmed with Immunohistochemical assay. Search for dermal, mucous and ocular lesions were negative. She received adjuvant radiation to the postoperative tumor bed to 5400cGy in 30 fractions using Intensity Modulated Radiation Therapy technique along with concurrent Temozolomide. She tolerated the treatment well and is symptom free 12 months after treatment. Primary Melanomas are rare lesions of the Cerebello-pontine angle and its radiological features, evaluation and management have been discussed.


Introduction
Primary melanocytic lesions are rare tumors of Central Nervous System (CNS) with an incidence of 0.9 per 10 million. 1,2 Though these tumors are seen anywhere along the leptomeningeal axis, they specifically cluster around the Brain stem and high cervical spinal cord because of high aggregation of melanocytes in the leptomeninges at these locations. [3][4][5] The melanotic cells originate either from embryonic neuroectodermal cell rests or from the pial sheaths of the vasculature in the CNS. 6 Focal tumors range from benign melanocytomas to malignant melanomas. Primary focal malignant melanomas are even rarer and account for 1% of all melanoma cases in the CNS. 6 The diagnosis is essentially by exclusion of melanomas in the skin, mucosal membranes and eyes. 4 Total excision, if achieved, results in longer sur-vival. Adjuvant Radiation has a role in cases of incomplete or near-total excision. 4 Temozolomide is an oral alkylating agent which crosses the Blood Brain Barrier (BBB) and is known to be effective in brain metastasis from malignant melanomas. 7,8 We reported a case of rare primary CNS malignant melanoma at Cerebello-pontine (CP) angle, managed successfully with gross total resection (GTR) and adjuvant radiotherapy along with concomitant Temozolomide. To the best of our knowledge this is the first case of primary CNS melanoma managed with concurrent Temozolomide.

Case Report
A thirty-eight-year woman presented to us with a history of medial deviation of the left eye (Figure 1) and double vision of two and a half years duration. She also complained of intermittent head ache of one year duration. Left eye showed hypertropia along with esotropia with IV and VI nerve palsy. Left pupil was mid-dilated, 5 mm in diameter and was reactive. Right pupil was normal. Corneal sensations were normal. Left Superior Oblique showed no intorsion on depression in adducted position. Plain and contrast magnetic resonance imaging (MRI) of the brain revealed an extra-axial, dural based lesion in the posterior part of the left CP angle adjacent to the petrous with a broad base. The lesion was compressing left Cerebellar Hemisphere. It was uniformly isointense on T1W images with a peripheral rim of hyper intensity, isointense on T2W images with a focal area of hyper intensity in the adjacent Cerebellum and showed homogeneous contrast enhancement. Peripheral rim of the lesion was well defined on susceptibility weighted image (SWI). VII-VIII nerve complex and the internal auditory canal were free from invasion. The rest of the brain was normal. With these features, a preoperative diagnosis of left CP angle Meningioma was made. (Figure 2A -E).
She underwent left retro mastoid sub-occipital craniectomy and gross total resection of the tumor. The tumor was jet black in colour (Figure 3), attached to the overlying meninges, soft and friable. Pial breach of the adjacent cerebellar folia was noted. Dural attachment of the tumor was coagulated after resection. Post-operative recovery was uneventful. Histopathological examination revealed a cellular tumor composed of relatively monotonous tumor cells in lobules separated by broad trabeculae. Areas of hemorrhage ( Figure  4A) were noted in between. Tumor cells had enlarged round nuclei with single prominent nucleolus ( Figure 4B). It was richly vascular and contained perivascular siderophages and melanophages. Focal areas within tumor showed fine melanin pigment in the cytoplasm. Extensive brain parenchymal infiltration by numerous tumor cell lobules was noted.
Immunohistochemistry was strongly positive for HMB-45 ( Figure 4C) in all tumor cells suggesting melanocytic origin. S-100 and Vimentin were also positive. Possibility of a meningioma was ruled out as tumor was negative for an Epithelial Membrane Antigen (EMA). The MIB index of 8% at certain foci and 3 -4% in other areas made us to consider this particular tumor a malignant one. The histopathological diagnosis was that of a CP angle malignant melanoma. Post-operative contrast MRI showed complete tumor excision and normal posterior fossa ( Figure 5). She received adjuvant radiation in conventional fractionation to a total dose of 5400 cGy in 30 fractions, 180cGy per fraction, five days per week to the tumor bed on 6MV Linear Accelerator using Intensity Modulated Radiation Therapy (IMRT- Figure 6A, B) technique. She also received concurrent oral Temozolomide. The Dose Volume Histogram (DVH) showed adequate isodose coverage to the Planning Target Volume (PTV) while sparing the adjacent normal tissues (Figure 7). The daily dose of Temozolomide was 75mg/metre square body surface area (BSA) to a dose of 100mg during Radiation for a period of six weeks. She tolerated the treatment well. Now at one year after diagnosis and surgery, she is asymptomatic, on a regular follow-up and is back to work with persistent (L) VI nerve palsy. One year follow-up MRI of the brain showed no recurrent mass (Figure 8).  12,13 Whole body FDG PET CT is highly accurate (91%) in diagnosing loco regional involvement and staging of melanoma. 12 Based on MIB-1 staining, focal lesions can be further classified as benign melanocytomas (0% -2%), intermediate grade melanocytic neoplasms (1% -4%) and malignant melanomas (2% -15%). 14 Benign melanocytomas typically have variably pigmented melanocytic cells arranged in tight nests, sheets, or fascicles. In contrast, malignant melanomas have larger, cytologically atypical, pigmented tumor cells growing in loose nests or sheets, often with CNS invasion or necrosis. 14 HMB-45 is an antimelanosomal antibody, which is specific for melanocytic tumors. It was found positive in 86% -97% of melanocytic tumors. S-100 is a sensitive marker for cells of Neural crest origin and lacks specificity. 13,14 Both HMB-45 and S-100 were positive in our patient. There are no treatment guidelines as these tumors are rare. Surgery remains the key modality of treatment. Subarachnoid spread of melanomas following surgery is known. 2,3 Sometimes total excision becomes difficult in CP angle tumors due to brain infiltration. 2 In a review, 80% of the cases with subtotal resection of CP angle melanocytomas died within 12 months of diagnosis. 10 There are no effective adjuvant therapy guidelines. We treated our patient with post-operative radiation therapy as the literature suggests better recurrence free period. 3 Wadasadawala et al. used adjuvant radiation up to 5400 cGy in conventional fractionation. 4 As the histopathology showed rich infiltration of the cerebellar foliae and high MIB-1 labelling index (8%) suggesting high mitosis, this tumor was considered to be highly malignant and hence we considered adjuvant Radiation. Although Melanomas are known to be chemo-resistant, there are recent reports on the use of chemotherapeutic agents. Temozolomide and Dacarbazine (DTIC) have been used in malignant melanoma with brain metastasis. 2,7 Temozolomide was safe and with the ability to cross BBB, demonstrated activity in melanomatous brain metastasis. 7 In a randomized trial comparing Temozolomide and Dacarbazine in patients with metastatic melanoma brain, the Temozolomide group showed comparable survival benefits with improved quality of life. 7 A retrospective study done by Paul MJ et al. compared Temozolomide and DTIC in patients with advanced malignant melanoma. Results showed significant reduction in CNS relapse in the Temozolomide group compared to DTIC at 19 months follow-up. 8 As Temozolomide has already been used in metastatic malignant melanoma of CNS with positive results and as the Primary CNS melanomas have similar cell lineage, Temozolomide was chosen as the chemotherapeutic agent. 7,8 The patient tolerated the therapy satisfactorily. The role of concurrent Temozolomide in the adjuvant setting needs further evaluation both in primary and metastatic CNS melanomas. She is planned for a close long term follow up as it is still early in the disease.

Conclusion
Primary CNS melanoma is difficult to diagnose preoperatively. Typically the MRI picture, gross features of the tumor, MIB-1 proliferative index, immunohistochemistry and 18 F-FDG PET CT plays a major role in the diagnosis of primary CNS malignant melanoma. Radical excision is the main modality of treatment. Concurrent chemoradiation in adjuvant setting for primary CNS malignant melanoma is beneficial.