Key-words:
Immunotherapy - melanoma - meningeal melanocytoma - nerve root - spine
Introduction
Melanocytomas comprise <0.1% of all brain tumors.[[1]] The primitive neural crest cells give origin to melanocytes present in the leptomeningeal
tissues. These melanocytes on acquiring melanoblastic activity give rise to the benign
entity known as melanocytoma. Limas and Tio first coined this term in 1972 to describe
a pigmented tumor around the foramen magnum on autopsy.[[2]] The majority of spinal melanocytomas remain benign and are intradural extramedullary
in location with a predilection for the cervical spine due to the increased concentration
of melanocytic cells.[[3]] This case stands distinct in highlighting the rare occurrence of a lumbar spinal
nerve root extradural melanocytoma, emphasizing the remote possibility of its histological
progression into malignant melanoma, tackled with the help of adjuvant radiotherapy
(RT) and immunotherapy.
Case Report
A 36-year-old female, professional dancer, presented to us with complaints of low
back pain for 6 months with acute exacerbation in the last 20 days. The pain was sharp,
radiating along the anterior aspect of the thigh up to the knee, and aggravated on
walking for a few seconds or on trying to get up from sitting position. Her straight
leg raising was severely restricted to 20° on the left side without any sensory or
motor deficit. Magnetic resonance imaging (MRI) showed a dumbbell-shaped mass in the
left L3–L4 intervertebral foramen with a large extraforaminal component and a minimal
intraspinal component. The lesion was well-defined, hyperintense on T1-weighted images
(T1WIs) [[Figure 1]]a, hypointense on T2WI [[Figure 1]]b, and showed homogeneous contrast enhancement [[Figure 1]]c. A provisional diagnosis of a nerve sheath tumor with bleed was made. A left paramedian
Wiltse's muscle-splitting approach was taken using tubular retractors. On splitting
the intertransverse ligament between the left L3 and L4 transverse process, a swollen
L3 nerve root was identified. No tumor was visualized on the surface of the nerve.
The epineurium of the nerve was split in the direction of the nerve fibers, and the
lesion was visualized within the nerve splaying the nerve fibers. No definite attachment
to the nerve fascicles was noted. It was extremely vascular and pigmented [[Figure 1]]d. Left L3–L4 lateral foraminotomy was performed, and the foraminal component was
curetted out. There was no intradural extension or cerebrospinal fluid leak during
the procedure. A gross resection of the lesion with preservation of nerve root [[Figure 1]]e was achieved.
Figure 1: (a) Magnetic resonance imaging lumbar spine (T1 axial) showing a dumbbell-shaped
hyperintense mass in the left L3‒L4 intervertebral foramen with extraforaminal component,
(b) T2 axial magnetic resonance imaging showing the hypointense lesion, (c) Postcontrast
coronal magnetic resonance imaging showing homogeneous enhancement, (d) Intraoperative
image of the dark brown pigmented tumor (yellow arrow) seen on incising the epineurium
of the L3 nerve root (*). S = Superior, I = Inferior, M = Medial, L = Lateral. (e)
Intraoperative image of the preserved nerve root (*) following complete excision of
the melanocytoma. S = Superior, I = Inferior, M = Medial, L = Lateral
Postoperatively, there was a marked improvement in her pain and mobility. Histopathology
showed a nonencapsulated lesion with round-to-oval cell nests, eosinophilic nucleoli,
and dense melanin-pigmented tumor cells [[Figure 2]]. Differential diagnosis of a melanocytic meningioma, intermediate-grade melanocytoma,
or a melanocytic paraganglioma was considered. Immunohistochemistry was positive for
S100 and homatropine methylbromide-45 (HMB-45) and negative for epithelial membrane
antigen (EMA). The MIB-1 score was 3%–4%. Mitosis and pleomorphism were absent. These
features were consistent with an intermediate-grade melanocytoma. Retrospectively,
a detailed general examination did not reveal any cutaneous melanotic lesion. The
patient was discharged without any new deficit.
Figure 2: Histopathology image with hematoxylin and eosin stain (magnification, ͯ100) showing
round-to-oval cell nests with eosinophilic nucleoli and interspersed dense melanin-pigmented
tumor cells (yellow arrow)
On follow-up after 6 months, she had complaints of left lower-limb pain and sensory
loss over the left anterior thigh. Imaging showed a recurrence at the local site [[Figure 3]]a and [[Figure 3]]b infiltrating into the iliopsoas muscle [[Figure 3]]c with minimal foraminal and intraspinal extension. Positron emission tomography–computed
tomography did not reveal any other systemic uptake. Oncology opinion was sought,
and it was decided to do a left L3–L4 laminectomy, complete facetectomy, and a radical
excision of her tumor with the affected muscle and left L3 root. She also underwent
a right-sided L2–L4 pedicle screw and rod fixation [[Figure 3]]d, [[Figure 3]]e, [[Figure 3]]f. Histopathology revealed a high-grade melanocytic tumor consistent with melanoma
suggestive of histological progression. Adjuvant treatment in the form of spinal intensity-modulated
radiation therapy (50 Gy in 25 fractions) and immunotherapy (240 mg nivolumab) was
started. Her previous histopathology findings were revisited by a different pathologist,
given the relatively short duration of recurrence, and reconfirmed to be intermediate-grade
melanocytoma.
Figure 3: (a) Magnetic resonance imaging spine axial view (T1-weighted image) showing the local
recurrence (orange arrow), (b) Magnetic resonance imaging spine axial view (T2-weighted
image) showing the local recurrence (orange arrow), (c) Magnetic resonance imaging
spine axial view (postcontrast image) showing the iliopsoas deposits (blue arrow),
(d) Postoperative X-ray lateral view showing the L2‒L4 pedicle screw and rod fixation,
(e) Postoperative CT scan axial view showing the resected local cavity, (f) Postoperative
positron emission tomography-computed tomography showing the resected local cavity
Over the next year, she developed multiple metastases in the lung, pleura, and iliopsoas
muscle. The resultant pleural effusion was symptomatically managed. Lung nodule biopsy
was suggestive of metastasis from the melanocytic neoplasm. Hence, ipilimumab was
added (1 mg/kg), and oral targeted therapy with pazopanib (800 mg twice a day) was
started. Nivolumab was temporarily put on hold. She was found to be intolerant to
pazopanib, the medication was stopped after 7 days, and combination immunotherapy
of nivolumab plus ipilimumab was restarted. She completed her immunotherapy cycles
a few months ago (48 doses of nivolumab and 4 doses of ipilimumab). Clinically, till
recently, she had a mild weakness 4+ out of 5 of the left quadriceps and subtle hypoesthesia
in the anterior thigh. She was able to resume her passion for dance in a limited manner
by avoiding squatting maneuvers and extreme lumbar movements. Unfortunately, she expired
after 4 years of regular follow-up.
Discussion
The WHO classification of central nervous system (CNS) tumors lists melanocytic tumors
as meningeal melanocytosis (Grade 0), meningeal melanocytoma (Grade I), meningeal
melanoma (Grade III), and meningeal melanomatosis (Grade III).
Melanocytoma arising from within the nerve root is an extremely rare occurrence and
so is its progression to malignant melanoma with only four such cases published to
date [[Table 1]].[[4]],[[5]],[[6]],[[7]] A series of 16 cases of meningeal melanocytomas followed up for close to 5 years
showed no evidence of pathological progression.[[8]]
Table 1: Published cases of melanocytoma showing malignant transformation (including the present
case)
Schwannoma and neurofibroma are the most common cause of a dumbbell-shaped lesion
in the intervertebral foramen with associated scalloping. Other rare causes include
malignant melanomas, pigmented meningiomas, and melanocytomas. Hemorrhage within a
schwannoma and a malignant melanoma share similar clinical and radiological features
with a benign melanocytoma. Melanocytomas are usually isointense to hyperintense on
T1WI and isointense to hypointense on T2WI with homogeneous contrast enhancement,
whereas spinal schwannomas are predominantly hypointense on T1WI and hyperintense
on T2WI.[[9]] Retrospectively, the presence of T1 hyperintense signal should have alerted us
regarding the possible diagnosis of melanocytoma, however, we considered the diagnosis
of a tumor with bleed due to the relatively acute onset of pain. Immunohistochemistry
is diagnostic in characterizing these lesions. Melanocytomas are specifically positive
for HMB-45 and S-100 and negative for EMA with a low MIB-1 index score.
The treatment goals for an intraneural melanocytoma are unknown, but complete surgical
excision is generally recommended except in cases which are extremely vascular or
excessively bulky. The role of adjuvant RT is still unclear. In a review of CNS melanocytomas,
by Chow et al.,[[10]] it was suggested that the long-term survival of cases, where subtotal resection
was done, was not influenced by the administration of adjuvant RT. Conversely, Rades
et al.[[11]] have suggested that the survival rate reduced significantly in patients who underwent
a subtotal resection without adjuvant radiation. RT in doses of 45–55 Gy has been
recommended for optimal benefit. Stereotactic radiosurgery (SRS) and dacarbazine-based
chemotherapy have also been attempted in the past with limited results.[[12]]
Recently, an immunotherapy combination of anti-cytotoxic T-lymphocyte-associated protein
drug ipilimumab and anti-programmed cell death protein-1 drug nivolumab has been found
to have better progression-free survival and overall survival in cases with metastatic
melanoma.[[13]] Pazopanib, a tyrosine kinase inhibitor, has been tried for advanced melanoma treatment.
However, it has been found to have very poor tolerability with limited patient adherence.[[14]] To the best of our knowledge, the current case is the only extradurally occurring
melanocytoma to undergo malignant transformation with the previous four cases consisting
of melanocytomas present in the frontal lobe, petroclival region, thoracic intramedullary
spine, and lumbar intradural extramedullary location [[Table 1]]. This is also the first instance where immunotherapy has been employed for malignant
transformation of a CNS melanocytoma. All the previous reported cases received either
RT or SRS, with one case receiving chemotherapy in addition to RT and SRS [[Table 1]]. The survival in the literature has been extremely variable ranging from 17 months
to 13 years [[Table 1]].
Ideal management of a spinal nerve root melanocytoma is still debatable with no single
modality proven to be completely effective. Close and prolonged follow-up seems prudent,
given the risk of recurrence which can be as high as 50%.[[15]] Patients with melanocytoma must be counseled regarding the risk of malignant progression
of the disease. Radical resection of locally invasive melanocytoma may be considered
in the absence of systemic disease after thorough oncology and pathology review.
Conclusion
Benign melanocytoma originating from the nerve root is a rare phenomenon. MRI features
of a dumbbell-shaped lesion with T1 hyperintensity, T2 hypointensity, and homogeneous
contrast enhancement should raise a suspicion of this rare entity. Definite diagnosis
is based on histological and immunohistochemistry evaluation. Surgical resection followed
by RT and immunotherapy should be the preferred modality of treatment in cases of
malignant transformation.
Patient consent
The patient has consented to the submission of the case report for submission to the
journal.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form, the patient has given her consent for her images and other clinical information
to be reported in the journal. The patient understands that her name and initials
will not be published and due efforts will be made to conceal identity, but anonymity
cannot be guaranteed.
