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Review Article

Intradural Intramedullary Primary Spinal Melanoma: A Case Report and Review of the Literature?

Kashif Majeed1, Ibrahim Hussain1, David J. Pisapia2, Wei Song2, Rajiv Magge3, Ali A. Baaj1 and Philip E. Stieg1*

1Department of Neurological Surgery, Weill Cornell Brain and Spine Center, New York Presbyterian Hospital, New York
2Department of Pathology and Laboratory Medicine; Weill Cornell Medicine, New York Presbyterian Hospital, New York
3Department of Neurology; Weill Cornell Medicine, New York Presbyterian Hospital, New York

*Address for Correspondence: Philip E. Stieg, Department of Neurological Surgery, 525 E 68th St. Starr 651-Box 99, New York, Tel: +212-746-9883; Fax: +212-746-6607; E-mail: pes2008@med.cornell.edu

Submitted: 17 December 2019; Approved: 26 December 2019; Published: 27 December 2019

Citation this article: Majeed K, Hussain I, Pisapia DJ, Song W, Magge R, et al. Intradural Intramedullary Primary Spinal Melanoma: A Case Report and Review of the Literature. Sci J Neurol Neurosurg. 2019;5(1): 012-018.

Copyright: © 2019 Majeed K, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Keywords: Primary melanoma; Spinal cord; Thoracic; Cervical; Gross total resection; Radiotherapy; Chemotherapy

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Background & Importance: Primary CNS melanoma of the spinal cord are rare neoplasms. They represent a spectrum of benign melanocytomas to malignant melanomas.

Clinical Presentation: A 53-year-old female had presented with several months of right thigh pain and paresthesia’s. There was also midthoracic pain. MRI revealed a 1.5 cm contrast enhancing mass at T10-T11 level. It was exophytic, intradural and intramedullary. Patient underwent laminectomy, gross total excision and received radiotherapy post-operatively. Histopathology analysis showed features of malignant melanoma and molecular study revealed a GNAQ mutation. Full body exam and scanning did not reveal any other primary malignancy. Literature was reviewed and correlated to the current case with regards to symptoms, surgical management, adjuvant therapy, follow up and outcomes.

Conclusion: Most cases do remarkably well with gross total resection only. Post-op adjuvant therapy and long term follow up is advised in cases where gross total resection is not possible.

Background and Importance

Melanomas can arise wherever melanocytes exist [1]. Primary melanocytic tumors of the Central Nervous System (CNS) present along a spectrum from benign melanocytomas to malignant melanoma [2]. Primary Central Nervous System Melanoma (PCNSM) arise from leptomeningeal melanocytes [3,4]. PCNSM are rare, representing only 1% of total body melanomas and 0.07% of all brain neoplasms [1,3,5,6]. Hayward proposed the first diagnostic criteria to differentiate PCNSM from metastatic tumors [7,8].

Technological advances since then have enhanced our understanding of the genetic and molecular aberrations driving their development. PCNSM frequently harbor one of the two mutually exclusive mutations, GNAQ or GNA11 affecting codon 183 on exon 4 or codon 209 of exon 5, respectively, impairing enzymatic function that constitutively activates GTP-signaling cascades promoting oncogenesis [9,10].

Within PCNSM, Primary Spinal Melanoma (PSM) are even rarer with only 64 reported cases [11-16] (Supplementary Table 1). Here a unique case of a thoracic Intradural Intramedullary (IDIM) PSM, its histopathologic and genetic analyses and review of literature is presented. Whereas previous cases have reported GNAQ mutations in PCNSM, this is the first case to demonstrate this mutation in a solitary IDIM PSM.

Table 1: Adjuvant therapies patients received in relation to the extent of surgical resection for PSM.
EOR No Therapy IT CT RT RT & CT/IT AT NOS Total
GTR 17 1 8 3 3 0 32
STR 6 0 10 1 1 1 19
Surgery NOS 5 0 1 2 1 4 13
Total 28 1 19 6 5 5 64
EOR: Extent of Resection; NOS: Not Otherwise Specified; GTR: Gross Total Resection; STR: Subtotal Resection; IT: Immunotherapy; CT: Chemotherapy; RT: Radiotherapy; AT NOS: Adjuvant Therapy, Not Otherwise Specified.

Clinical Presentation

A 53-year-old female with no known family history presented with 6 months of progressive numbness, and right anterior thigh and mid-thoracic pain. There were no other symptoms including bowel or bladder incontinence. On examination her only deficit was in thigh sensation and no upper motor neuron signs elsewhere.

Preoperative imaging

An MRI of the thoracic spine demonstrated a 14mm x 6mm gadolinium enhancing mass at the T10-T11 level (Figure 1A). There was mild cord effacement without intramedullary T2 hyperintensity (Figure 1B). There was a questionable pial enhancement versus an engorged vasculature extending superoinferior to the lesion (Figure 1A). MRI of the brain and cervical spine and preoperative angiography for tumor blush were negative. Considering an ependymoma, an astrocytoma or a hemangioblastoma surgery was recommended for decompression and definitive diagnosis.

Figure 1: Sagittal and axial MRI scans of IDIM PSM taken pre-operatively (1A & 1B) and post-operatively (1C & 1D). A questionable pial enhancement vs an engorged blood vessel is seen (1A & 1C) extending above and below the lesion. Residual contrast enhancing tumor is demarcated by yellow arrows (1D).

Intraoperative findings

She underwent a T10-T11 laminectomy for tumor resection (Figure 1C). Intraoperative Somatosensory Evoked Potentials (SSEP) and Motor Evoked Potentials (MEP) were monitored. The tumor extent was determined using an intraoperative ultrasound. The mass lacked clear planes, appeared intramedullary, exophytic and invading the adjacent peripheral nerves. Laterally, the capsule was cauterized, incised, and tumor was debulked significantly but not completely due to over 50% drop in MEPs bilaterally. SSEPs remained stable though. Frozen section revealed a highly-cellular spindle cell neoplasm. A small capsule adherent to the cord was left behind (Figure 1D), hemostasis was secured and the dura, closed (Figure 2).

Figure 2: Intraoperative images of the IDIM PSM tumor showing before and after subtotal resection.

Postoperative course

On her immediate post-op exam, there was anterior thigh sensory loss and decreased right foot proprioception. Motor exam remained normal. In ICU she was on high dose steroids. On the floor on postoperative day 2, she had difficulty ambulating requiring assistance. She was discharged to an acute rehabilitation center. On one-month follow-up, her only deficit was sensory. Final pathology confirmed a PCNSM. A full body workup and an FDG-PET ruled out another primary, a cutaneous or a uveal melanoma. 

Histopathology and genetic analysis

Histopathologically, the tumor cells were predominantly spindled demonstrating a fascicular growth pattern (Figure 3A). A nodular area of epithelioid features, increased nuclear atypia and prominent nucleoli (Figure 3B) revealed mitotic activity (2 mitotic figures in a single 600X field) and increased MIB-1 (Ki67) index of about 10 to 15% (Figure 3C). The neoplasm involved peripheral nerve axons splaying them apart as apparent on neurofilament staining (Figure 3D). Melanin containing cells were rare. Immunostaining was diffusely and strongly positive for SOX10 and A103 along with strong GFAP, S-100, and CK labelling, and diffuse yet weak labeling for S-100 and HMB45 in some foci (Figure 3E). Stains for EMA, PR, ERG, and CD45 were only focally weak or negative, and H3K27-me3 expression was preserved. PLD1 levels were 0%.

Figure 3: Histopathological and molecular analysis. A. Hematoxylin and Eosin (H&E) stained section demonstrating a highly cellular spindle cell neoplasm with a fascicular growth pattern. B. H&E stained nodular focus with increased cytological atypia including prominent nucleoli. C. Immunohistochemical staining (IHC) for MIB-1 (Ki67) shows increased labeling in the focus shown in panel B. D. Neurofilament staining (in brown) shows native peripheral nerve axonal elements splayed apart by tumor cells (counterstained with hematoxylin to show nuclei). E. A subset of cells demonstrates positive labeling for HMB-45. F. Next generation sequencing showed a GNAQ, c.616 A > T p.Q209L mutation is shown (using the Integrative Genomics Viewer). Scale bars: 200µm (A,D); 100µm (C); 50µm (B,E).

Therefore, melanotic schwannoma with focal atypical features, metastatic melanoma and PMM of the CNS were considered. Only upon 143 gene targeted next generation sequencing assay, Oncomine v2 (ThermoFisher) [17], a GNAQ Q209L mutation was confirmed (Figure 3F) without any other variants. GNAQ-Q209L is characteristic of PCNSM as well as uveal melanomas thereby ruling out metastatic cutaneous melanoma or a melanotic schwannoma.

Treatment

At 2-month follow-up, MRI revealed stable residual disease and no postoperative complication. With negative PDL1, a GNAQ mutation, and elevated MIB index, ipilimumab plus nivolumab combination toxicity appeared to outweigh benefits, like uveal melanomas where immunotherapy fails [18]. Therefore, only radiotherapy, of 5400 cGY over 30 fractions was given without any adverse sequalae. One-month post-radiation MRI failed to discern radiation effects from persistent tumor. Her surveillance MRIs every 3 months are pending. On her last 6 months follow-up, she remained clinically stable.

Literature review

Methods: Literature was searched for “primary CNS melanoma”, “primary melanoma of the spinal cord” and “primary malignant melanomas of the spinal cord.”

Results: The search yielded 201 articles in total. After removing 20 duplicates, metastatic and non-spinal cord melanomas, 65 articles remained. Fifty-five of these were case reports, 7, case series and 3, retrospective reviews. Four non-English articles were further excluded. Forty-five articles were available for final review (Figure 4).

Figure 4: Flow diagram showing literature search and PSM cases selection.

Discussion

Melanoma represents the 3rd most common metastatic tumor to the CNS, behind breast and lung [6]. In contrast, the incidence of PCNSM is only 0.005 cases per 100,000 [7]. PSM is even rarer, with only 64 reported cases (Supplementary table 1). While many studies have reported solitary IDEM tumors in the cervical or thoracic spine [5,19,20], the incidence of IDIM PSM is far rarer [21], as seen in this case.

The peak incidence of PSM is in the fifth decade of life (52.4 15.5) with ages ranging from 15 to 80 years (Supplementary table 1) [5,20,22]. Motor weakness along with dysesthesias, abnormal reflexes, loss of bowel and bladder function, or pain are the most common presenting signs and symptoms [19,23,24]. MRI is the imaging modality for visualization [3,8,25], with tumors appearing hyperintense on T1 weighted imaging and hypo- to isointense on T2 weighted imaging with uniform contrast enhancement [1,5,8,25,26]. Confirmatory diagnosis with histology is required with genetic features aiding in ambiguous situations. Immunostaining characteristically demonstrates S-100 and HMB-45 immunoreactivity, markers of melanogenesis [8]. Additionally, GNAQ Q209L mutation is characteristic of PCNSM as well as uveal melanoma [9,10,27].

PSM must be differentiated from the metastatic cutaneous melanoma [1,19]. The 5-year survival rate for local melanoma is 98%, however it drops to 23% with widespread metastases [28]. The preferred treatment for PSM is complete surgical resection whenever possible followed by radiotherapy [1,5,20]. In cases where Gross Total Resection (GTR) was achieved, survival reached around 88%, compared to 78% in cases of Subtotal Resection (STR). Adjuvant radiation with 4700 cGy in subtotal resections has been reported, however, given the relatively small number of these cases, its effectiveness remains unclear [5,25]. The efficacy of adjuvant chemotherapeutic agents, used for PSM, like dacarbazine, vincristine, bleomycin, and cisplatin also needs to be ascertained [15,21,22,26,29,30] (Table 1).

Supplementary Table 1: Characteristics of PSM cases reported in literature (Adopted and modified [15,16]).
Sr.No Author, Year Age & Sex Location Onset, Duration S & S Treatment & Extent Follow up, outcome
1 De Blasi [15,16], 1930 71, F Thoracic 6 months NR Surgery 6 months, alive
2 Schnitke [15,16],1938 49, F T8-10 30 months Lower back paresthesia’s & numbness and stiffness of BL LE GTR + RT 6 months, succumbed
3 Forbes [15,16], 1950 57, M Thoracic NR Right buttock and leg severe pain, left leg weakness Surgery 2 months, died
4 Gibson [15,16], 1957 51, F T10 NR Left leg and right-hand numbness and paresthesia, and left leg stiffness Adjuvant therapy 23 months, died
5 Zimmerman [15,16], 1958 42, M T9-10 8 months NR Surgery 4 months, died
6 Hirano A [15,16], 1959 42, M T10 4 months Sudden onset of constant pain in left flank Surgery, STR 6.5 months, died
7 Kiel FW [15,16], 1961 33, F C4-5 15 years Left shoulder and base of the neck pain Surgery, GTR 19 months, died
8 Clifford JH [15,16], 1968 64, M C5-6 4 months Left shoulder arm and neck pain Surgery, GTR 24 months, died
9 Faillace WJ [15,16], 1984 F C-L 24 months Hydrocephalus, no mass lesion Radio + Chemo 4 months, died
10 Ozden [15,16], 1984 30, F T7-10 NR NR Surgery + adjuvant 16 months, alive
11 Schneider SJ [15,16], 1987 68, F L3-4 NR Lower back pain radiating into left thigh and knee Surgery, GTR + RT 10 months, alive
12 Larson TC [15,16,24], 1987 73, M T6-8 6 months LE weakness, numbness, dysesthesias, bowel and bladder incontinence Surgery, STR, RT 84 months, alive
13 Larson TC [15,16,24], 1987 63, M T9 96 months Spastic paraparesis, decreased sensation, bowel & bladder incontinence, impotence Surgery, STR + RT 13 months, died
14 Larson TC [15,16,24], 1987 67, F T9-11 18 months LE weakness, dysesthesias, low back pain Surgery, STR, RT alive
15 Larson TC [15,16,24], 1987 57, F C1-3 3 months Dysesthesias, triparaparesis, weight loss, incontinent bladder, neck pain Surgery, STR, RT 30 months, alive
16 Larson TC [15,16,24], 1987 69, F T9-10 24 months LE weakness, decreased sensation, back, abdominal, thigh and calf pain Surgery, STR 45 months, alive
17 Yamasaki T [15,16], 1989 31, M T6-8 NR NR Chemotherapy, Partial resection 12 months, alive
18 Rastogi N [15,16],1996 57, M L1 60 months Choroidal melanoma of right eye, intracerebral metastasis in right fronto-parietal region Radiotherapy 8 months, died
19 Magni [15,16], 1996 64, M Thoracic 24 months NS Surgery, adjuvant 18 months, alive
20 Francois [15,16], 1998 62, M T7-9 18 months Progressive BL LE weakness and sensory loss and urinary dysfunction Surgery, GTR 28 months, alive
21 Salpietro FM [15,16], 1998 62, M C3 1 months Neck pain, gradual weakness of left arm and leg, pins and needle sensation in left hand Surgery, partial,radiotherapy 15 months, died
22 Salame [15,16], 1999 76, F T9-10 6 months Progressive LE weakness Surgery, partial, adjuvant `15 months, alive
23 Brat [15,16], 1999 71, F T10 NR NR Surgery 14 months, alive
24 Bidzinski [15,16], 2000 36, M C6-7 8 months Legs and hands numbness, sometimes painful Surgery, GTR, RT 48 months, alive
25 Farrokh D [15,16], 2001 80, F T12-L1 A few days Back pain, weakness in Les, bowel and bladder incontinence Surgery, STR 9 months, alive
26 Tosaka M [15,16], 2001 20, M CPA&T 7 months Headache, appetite loss, progressive nausea and vomiting Chemotherapy 5 months, died
26 Schneider [15,16], 2002 65, M L2-4 10yr Lumbar pain, acute sensorimotor radiculopathy Surgery 1 months, died
28 Sanz-Trelles [15,16], 2003 26, M L3 3 months NR Surgery GTR, 24 months, alive
29 Freudenstein [15,16], 2004 54, F T10-12 8 years NR Surgery STR, RT, Chemo 72 months, died
30 Kwon [15,16], 2004 45, F C6-7 4 years NR Surgery GTR, RT 8 months, alive
31 Montinaro [15,16], 2004 57, F L1-2 NR NR Surgery GTR 3 months, alive
32 Mlaiki [15,16], 2004 51, M C5-7 NR NR Surgery GTR 4.75 months, alive
33 Kounin GK [15,16], 2005 41, F C2-4 9 months Headache, intermittent nausea and vomiting Surgery GTR 3 months, alive
34 Denaro L [15,16], 2007 68, M T8-9 6 years Disorders of LEs and gait disturbances Surgery, GTR, RT 12 months, alive
35 Kanatas AN [15,16], 2007 76, F C6-7 8 months Neck pain, parasthesias, weakness in right arm with progressive myelopathy Surgery STR, RT 6 months, alive
36 Mekni [15,16], 2007 34, M T6-8 NR NR Surgery, STR 3 months, alive
37 Unal [15,16], 2007 37, F T7 4 months NR Surgery, GTR, Chemo 6 months, alive
38 Kwang [15,16], 2010 68, F T7-8 NR NR Surgery + adjuvant 6 months, alive
39 Jo KW [15,16], 2010 68, F T7-8 5 days Progressive paresis and altered sensation Surgery GTR, RT, chemotherapy 6 months, died
40 Kolasa M [15,16], 2010 57, F T10 2 months Spinal pain and LE pain and progressive paresis Surgery GTR, Chemo 12 months, alive
41 Kim MS [15,16], 2010 34, F T4 12 months Right leg numbness Surgery GTR 36 months, alive
42 Lee CH [15,16], 2010 39, M C1-6 11 months NR Surgery GTR, RT, Chemo 17 months, alive
43 Vij M [15,16], 2010 40, M C2-3 6 months Pain in right shoulder and neck Surgery GTR 12 months alive
44 Fuld AD [15,16], 2011 62, M C2-3 Several months Progessive right sided weakness with ataxia and gait disturbance Surgery GTR, RT 11 months, alive
45 Jaiswal [15,16], 2011 16, M C1-5 NR NR Surgery GTR 4 months, alive
46   40, M C1-2 NR NR Surgery GTR 4 months, alive
47 YU [15,16], 2012 48, M C2-6 6 months UE & LE numbness Surgery STR 2 months, alive
48 Cicuendes [15,16], 2012 82, F L2 1 months NS Surgery STR, Radiotherapy 2 months, Died
49 Ganiusmen O [15,16], 2012 49, F L3 2 years Low back and leg pain Surgery GTR, RT, chemotherapy 48 months, alive
50 Marx S [15,16], 2014 54, F C2-3 6 months Intermittent dizziness, slight weakness of LEs and foot parasthesias Surgery GTR, Chemo 24 months alive
51 Jeong DH [15,16], 2013 42, M T2 8 months A seizure attack, hydrocephalus Surgery, STR 22 months, alive
52 Sinha H [15,16], 2013 55, M L4   Back pain, weakness of LEs, bowel and bladder incontinence Surgery GTR 38 months, alive
53 Cetinalp NE [15,16], 2014 47, F T9-L1 6 months Progressive back pain, weakness in LEs Surgery GTR, 6 months, alive
54 Chance A [15,16], 2015 46, M T12 and L5` 1 year LE parasthesias, urinary retention Surgery, partial, RT 10 months, alive
55 Liu QY [15,16], 2015 39, M T9 2 months BL LE weakness from hip and numbness, 10 day of ataxia Surgery GTR, 7 months, alive
56 Liu QY [15,16], 2015 47, M C4-5 11 months Right finger numbness Surgery GTR 76 months, alive
57 Liu QY [15,16], 2015 76, M L 3 weeks LE weakness Surgery GTR 67 months, alive
58 Mallick S [22], 2015 28, M NR NR NR Surgery, chemotherapy 24 months, alive
59 Hering K [12], 2016 57, F T12 2 months Progressive LE paresis and paresthesia’s Surgery, STR, RT 26 months, alive
60 Wu L [14], 2016 51, M C2-7 1 year BL UE & LE numbness, progressive weakness in right limbs and cough while drinking Surgery, GTR 10 months, alive
61 Wuerderman [21], 2018 39, M C2, C4-5 1 year Numbness of UEs and back Surgery GTR + antiPD-1 chemo 24 months, alive
62 Takahito [13], 2018 64, F T9-10 NR Dysesthesia and weak of RLE followed by RUE & LLE Surgery STR, RT 8 years, alive
63 Zhang M [15], 2018 52, F T10-11 3 years Numbness in LEs & urinary incontinence Surgery GTR + Chemotherapy 3 months, alive
64 Chatterjee [11], 2019 78, M C3-T3 2 months R UE & LE weakness, paresthesia and urinary incontinence Surgery, GTR 18 months, alive
65 Current case 53, F T10-11 6 months Midthoracic and Right thigh pain and numbness Surgery STR + RT 2 months, alive
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