Primary intramedullary malignant melanoma: can imaging lead to the correct diagnosis?

Introduction

Melanoma is a malignant neoplasm of melanin-producing cells. Melanoma usually occurs in the skin, but can also arise in any anatomical site that contains melanocytes, such as mucous membranes, the eyes, and the central nervous system (CNS). ¹ However, primary CNS melanomas accounts for only 1% of all melanomas, and the incidence of primary spinal cord lesions is even more rare. ² The diagnosis of primary CNS melanoma requires histological confirmation and exclusion of a melanoma outside the CNS. ³ We present a case of a rare primary, intradural, intramedullary melanoma of the thoracic spinal cord and discuss the diagnostic utility of imaging studies.

Case report

A 78-year-old man presented with insidious onset of progressive weakness in both lower extremities over 6 months, followed by thoracic spinal pain that impaired ambulation. A neurological examination showed bilateral and symmetrical reduction of lower extremity strength to 3/5 grade bilaterally. Patellar tendon reflexes were brisk and bilateral extensor plantar reflexes were observed. Gross sensation was impaired distally to approximately the T10 level bilaterally. Spinal cord magnetic resonance imaging (MRI) showed an intradural, intramedullary, expansive lesion at the T9–T10 level. There was also a hyperintense signal on pre-contrast T1-weighted imaging and a predominantly hypointense signal on T2-weighted imaging, associated with discrete perilesional edema (Figure 1a–c). Because of the hyperintensity on T1-weighted imaging, a differential diagnosis of hemorrhagic neoplasms (e.g., ependymoma, astrocytoma, or hemangioblastoma) or pigmented lesions (e.g., metastatic or primary melanoma) was considered.

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Figure 1.

Primary intramedullary malignant melanoma of the thoracic spinal cord. Spinal magnetic resonance imaging shows an intradural and intramedullary expansive lesion at the T9–T10 level. There is a hyperintense signal on T1-weighted imaging without (arrow in a) and with fat saturation (arrow in b), and a hypointense signal on T2-weighted imaging (arrow in c), which is associated with discrete perilesional edema. (d) Positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography shows considerable uptake by the spinal cord lesion (arrow). There were no other suspected lesions.

Further diagnostic investigations that included a thorough whole-body skin examination, ophthalmological and otolaryngological evaluations, and endoscopies of the pharyngolarynx, upper gastrointestinal tract, colon, and rectum did not show additional lesions. Positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography (18F-FDG PET-CT) was performed to diagnose disease outside the CNS. This examination showed intense 18F-FDG uptake by the spinal tumor, but did not show any other suspected lesions (Figure 1d).

The patient underwent T8–T10 laminectomy. After opening of the dura, a solid, dark, and hypervascular tumor was visualized. There were no clear margins between the lesion and the spinal cord. Myelotomy and gross total resection of the tumor were performed. Histological analysis showed a hyperplastic lesion composed of large atypical spindle cells arranged in sheets. There was an eosinophilic cytoplasm and a moderate grade of cellular and nuclear pleomorphism. Furthermore, prominent nucleoli and mitoses, with intra- and extracellular melanin deposition were observed. These findings suggested melanoma. Immunohistochemical assays for S-100 protein, Melan-A, and human melanoma black-45 confirmed the diagnosis of malignant melanoma. In histopathological analysis, there was no hemorrhagic component in the lesion.

Postoperatively, the patient had paraparesis, which impaired ambulation. Lower extremity strength was still 3/5 grade bilaterally and gross sensation continued to be impaired distal to the T10 level bilaterally. The patient received local postoperative adjuvant radiotherapy (50 gray, >30 fractions). A follow-up MRI showed only post-treatment changes (Figure 2). However, 6 months later, MRI showed recurrence in the tumor bed and leptomeningeal dissemination (Figure 3). Consequently, immunotherapy (imatinib) was initiated. One year later, the patient presented with severe headache and exacerbation of back pain. MRI showed major progression of the leptomeningeal spread, including intracranial metastasis (Figure 4). Currently, the patient is receiving palliative care.

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Figure 2.

Post-treatment magnetic resonance images. Thoracic spinal magnetic resonance imaging, which was performed in the immediate post-treatment period, shows postoperative changes without suspected lesions on T1-weighted imaging with fat suppression before (a) and after intravenous gadolinium injection (b), and short tau inversion recovery (c).

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Figure 3.

Recurrent melanoma in the surgical bed. Magnetic resonance imaging performed 6 months after completion of radiotherapy shows an expansive lesion with a hyperintense signal on T1-weighted imaging with fat suppression (arrow in a). This is associated with contrast enhancement and minimal leptomeningeal enhancement (arrow in b), which suggest recurrent melanoma.

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Figure 4.

Recurrent melanoma and leptomeningeal spread. Magnetic resonance imaging performed 1 year after recurrence of the tumor and immunotherapy shows multiple leptomeningeal lesions. There is a hyperintense T1 signal in the interpeduncular cistern (arrow in a) and cervical (arrows in b) and thoracic (arrows in c) spinal cord segments, with contrast enhancement (arrows in d–f). These findings suggest advanced disease with progressive leptomeningeal dissemination.

Discussion

Primary CNS malignant melanoma usually develops in the leptomeninges, reflecting the common origin of melanocytes and meningothelial cells in the neural crest. ⁴ Neural crest cells are highly migratory and generate diverse structures that include the peripheral nervous system, skin melanocytes, adrenal neurosecretory chromaffin cells, and the pia mater and arachnoid of the spinal cord. ⁵ Melanocytic cells arise in the neural crest by the sixth week of embryonic development and migrate to their destinations, reaching the skin by the tenth week and the meninges by the twentieth week. A hypothesis for development of primary intramedullary malignant melanoma suggests that a few neural crest cells fail to migrate during embryogenesis and they reside within the neural tube. ⁶ These cells are unable to establish normal signaling pathways with adjacent cells to mediate differentiation and maturation. Oncogenesis could be dependent on cellular migration-related anomalies. ⁶ Additionally, primary CNS melanoma in atypical sites may originate from melanoblasts accompanying the pial sheaths of vascular bundles or from neuroectodermal cells with arrested migration during embryogenesis.^2,7

Primary CNS malignant melanomas are rare neoplasms, with an estimated incidence of 0.005 cases per 100,000 people. ⁸ Most of these melanomas are solitary, intradural, extramedullary tumors of the cervical and thoracic spinal cord segments. ⁹ The lesion found in our case is especially rare because of its intramedullary location. A review of 60 cases of spinal cord melanomas showed that 37.7% were intramedullary and 62.4% were extramedullary. The thoracic spinal cord segment is the most affected by these melanomas, followed by the cervical cord, and finally, by the lumbar segment. ⁴ This lesion occurs most frequently in adults (mean age: approximately 50 years, ranging from 15–80 years), with a slight predominance in men. ¹⁰ Symptoms of spinal cord melanomas depend on the location of the tumor, and a subacute or insidious onset is typical. However, acute onset or deterioration is possible owing to hemorrhage. ¹¹ The most common presenting symptoms of spinal cord melanomas are the gradual onset of lower extremity weakness and paresthesia, but abnormal reflexes, sphincter incontinence, and pain can also occur.^4,8,10 Hydrocephalus and/or signs of increased intracranial pressure, secondary to impaired cerebrospinal fluid circulation and absorption, may indicate leptomeningeal dissemination. ¹²

Radiological features of primary CNS melanoma depend on the degree of melanocytic content and the presence or absence of hemorrhage. ⁷ On computed tomography, the tumor appears as a hyperdense lesion enhanced by intravenous contrast. ¹³ PET-CT is useful for evaluating local and distant disease because malignant melanomas have increased function and metabolic activity of glucose transporter proteins and the glucose phosphorylating enzyme hexokinase.^4,14 MRI of primary CNS melanoma shows hyperintense signals on T1-weighted imaging and hypointense signals on T2- and T2*-weighted imaging. This depends on the degree of pigment content, as well as homogenous enhancement on gadolinium postcontrast images. Enhancement patterns may also be inhomogeneous, peripheral, or nodular.^7,15,16 Lesions secondary to leptomeningeal dissemination also display hyperintense signals on T1-weighted imaging, with gadolinium enhancement and hypointense signals on T2-weighted imaging.^7,12 Similarly, in the present case, the primary lesion and leptomeningeal spread presented with a hyperintense signal on T1-weighted images and a hypointense signal on T2-weighted images owing to intratumoral pigment.

MRI is the imaging method of choice for diagnosing spinal cord tumors, including melanoma. However, unfortunately, there are no imaging characteristics that accurately distinguish primary malignant melanoma from other melanocytic lesions of the CNS, such as metastatic melanoma, and hemorrhagic neoplasms, such as ependymoma and astrocytoma.^2,7

Histopathology of malignant melanoma features hyperplastic sheets or nests of spindled or epithelioid cells, which may have considerable pleomorphism and prominent eosinophilic nucleoli. Cells may display variable amounts of cytoplasmic melanin. Atypical mitoses, invasion of adjacent structures, or necrosis may be observed.^7,17 Human melanoma black-45 is a useful marker for melanocytic differentiation because it indicates active melanosome formation. Cells with melanocytic differentiation also express S-100. Melan-A is a melanocyte lineage-specific marker.^17,18 In our patient, the neoplasm was composed of large atypical spindle cells arranged in sheets, with an eosinophilic cytoplasm and a moderate grade of pleomorphism, with intra- and extracellular melanin deposition. Furthermore, immunohistochemical assays for S-100 protein, Melan-A, and human melanoma black-45 indicated the diagnosis of malignant melanoma.

Because the MRI and histopathological characteristics of intramedullary primary and metastatic melanomas are indistinguishable, thorough examinations of the skin, squamous mucosa, and the eyes must always be performed.^2,19 According to the Hayward criteria for the diagnosis of primary CNS melanoma, histological confirmation and exclusion of melanoma outside the CNS are required. ³ Distinction between primary CNS and metastatic melanoma is essential. The median survival for metastatic CNS melanoma ranges from 3 to 6 months, in contrast to primary CNS melanoma, which may have a better prognosis. This difference may be related to the absence of a CNS lymphatic system, obviating distant metastasis.^9,20

Surgical resection is the primary treatment option for intramedullary melanoma. However, gross total resection is difficult, and most patients will require postoperative adjuvant treatment, such as radiotherapy. Additionally, the rarity of this tumor hinders evaluation of therapeutic options. ²¹ Although the extent of resection is not related to mortality until 60 months after surgery, the overall survival after gross total resection is better than that after partial resection. ⁴ However, the efficacy of radiotherapy and chemotherapy for primary spinal cord malignant melanoma is still controversial. ⁴ Some studies have reported that postoperative adjuvant radiotherapy and chemotherapy confer clinical benefits.^4,22 However, other authors have reported favorable outcomes without adjuvant therapy, ²⁰ and have even concluded that primary CNS malignant melanoma is not radiosensitive. ⁶

In conclusion, awareness of primary intramedullary malignant melanoma is important and this neoplasm needs to be included in the differential diagnosis of spinal cord tumors when appropriate. While imaging plays a major role in the evaluation of this tumor, MRI alone cannot determine the final diagnosis. Therefore, histopathological analysis is fundamental for primary intramedullary malignant melanoma.