J Oral Maxillofac Surg66:547-550, 2008

Neurotropic Melanoma of the TrigeminalNerve: A Case of Atypical Facial Pain

Hugh Walters, MD,* Emma Lewis, MD, BDS,†

Regina Wolper, BSc,‡ Anthony T. Yachnis, MD, MS,§

Jim Green, MD, DDS,¶ and Stephen Lewis, MD�

Desmoplastic melanoma is a distinct form of mela-noma characterized by Conley et al as consisting ofdeeply infiltrating nodules that are amelanotic andhave a spindle pattern.1 Reed and Leonard reported avariant of desmoplastic melanoma in 1979 with 22cases of a deeply infiltrating tumor with neuroma-likepathological features that had a predilection for neu-ral invasion. They termed this variant neurotropicmelanoma.2 A major component of this tumor is aspindle cell downgrowth that appears to representSchwann cell differentiation of a precursor epidermalmelanocytic dysplasia. This characteristic is believedto account for the neurotropism and resultant diffi-culty in clinical management of the tumor due to thetracking of the neoplastic cells along the peripheralnerves.3 The tumor is of a biphasic growth patterninitially presenting as a mildly abnormal growth ofmelanocytes; the tumor eventually recurs as a more

obviously malignant lesion with a change in cell mor-phology and tissue behavior.4 During this latterphase, the tumor takes on the property of neurotro-pism, resulting in direct neural invasion and clinicallyevident cranial neuropathies.

Report of a Case

HISTORYThe patient is a 41-year-old white woman with a history

of malignant melanoma diagnosed in 1995 from a lesion onher lower lip. The patient underwent several excisions ofthe lesion but with problems obtaining tumor-free margins.She eventually underwent plastic surgery and reconstruc-tion of her lower lip, after which she remained lesion freefor a period of approximately 4 years. After this period, arecurrence was noted on the inner aspect of the left lowerlip, and the lesion was subsequently removed. Pathologicanalysis of the lesion showed histology consistent withdesmoplastic neurotropic malignant melanoma. The patientreceived a melanoma vaccination in combination with in-terferon as part of her postoperative management and re-mained tumor free for 2 years.

In November 2001, the patient developed a pain in herneck that was described as a constant ache in an occipito-frontal distribution. She was seen by a chiropractor, withminimal improvement. In January 2002, she noted the onsetof a new pain, which was described as a constant, radiatingache originating around the lower temporal region approx-imating the position of the left temporomandibular joint(TMJ). A bone scan was performed at another institution,which was interpreted as osteomyelitis of the left mandible.The patient was subsequently put on vancomycin for 6weeks, during which time there was no change in thequality or character of the pain. She was referred to a localneurologist, who believed the pain was consistent withtrigeminal neuralgia despite a proven bone scan abnormal-ity. The patient underwent 2 radiofrequency lesioning pro-cedures with no relief from the pain apart from somenumbness in the V-1 and V-2 distributions of the trigeminalnerve. She was finally referred to our institution for consul-tation with a maxillofacial surgeon. An orthopantomo-graphic image (Panorex) was performed. This studyshowed an abnormally widened inferior alveolar nerve ca-nal. A subsequent magnetic resonance imaging (MRI) scanconfirmed abnormal pathology of the V-3 branch of thetrigeminal nerve.

*Fellow, General Surgery, University of Florida College of Medi-

cine, Gainesville, FL.

†Assistant Professor, Department of Oral and Maxillofacial Sur-

gery and Diagnostic Sciences, University of Florida College of Den-

tistry, Gainesville, FL.

‡Laboratory Technician, Department of Neurological Surgery,

University of Florida College of Medicine, Gainesville, FL.

§Associate Professor, Department of Pathology, Immunology and

Laboratory Medicine, University of Florida College of Medicine,

Gainesville, FL.

¶Clinical Associate Professor, Department of Oral and Maxillofa-

cial Surgery and Diagnostic Sciences, University of Florida College

of Dentistry, Gainesville, FL.

�Assistant Professor, Department of Neurological Surgery, Uni-

versity of Florida College of Medicine, Gainesville, FL.

Address correspondence and reprint requests to Dr Lewis: De-

partment of Neurological Surgery, McKnight Brain Institute at the

University of Florida, 100 S Newell Drive, PO Box 100265, Gaines-

ville, FL 32610; e-mail: lewis@neurosurgery.ufl.edu

© 2008 American Association of Oral and Maxillofacial Surgeons

0278-2391/08/6603-0021$34.00/0

doi:10.1016/j.joms.2006.11.033

WALTERS ET AL 547

EXAMINATIONThe patient was referred to the oral and maxillofacial

surgery department of our institution, and a neurosurgeryconsultation was made. The patient presented in consider-able discomfort, with constant and aching pain predomi-nantly involving the area around the TMJ on the left side andradiating into the left mandible. She also complained of newonset discomfort in her left eye.

Physical examination of the patient showed decreased pin-prick sensation in all 3 distributions of the trigeminal nerve onthe left. There was also evidence of decreased corneal sensa-tion involving the left eye. Lymph node examination withinthe neck showed small nodes present in the left submandib-ular region. An orthopantomographic image (Panorex)showed a significantly widened inferior alveolar nerve canalalong its entire length on the left-hand side with loss of thecortical outline of the canal superiorly (Fig 1). A review of the

MRI studies showed a contrast-enhancing lesion associatedwith the V-3 branch of the trigeminal nerve emanating fromthe trigeminal ganglion descending and expanding the fora-men ovale, extending all the way to the inferior alveolarbranch (Fig 2). Given the previous history of cutaneous neu-rotropic malignant melanoma of the lip and the radiologicalfindings previously described, there was a strong suspicionthat a neoplastic process was the cause of the continuing facialpain. Surgical intervention consisting of surgical excision ofthe V-3 division of the trigeminal nerve was undertaken. Acombined procedure consisting of a left anterior temporalextradural approach to the trigeminal ganglion by neurosur-gery and an inferior approach to the tumor by oral-maxillofa-cial surgery was proposed.

A combined supra- and infratemporal fossa approach withexcision of the tumor was undertaken. A large mass involvingthe trigeminal nerve ganglion and extending through foramenovale was found. The tumor extended posteriorly to the originof the fifth cranial nerve. Excision included the trigeminalnerve from its origin at the level of the pons and included thethird division and part of the second division.

After the neurosurgical excision, the distal end of thethird division of the trigeminal nerve was approached via asubmandibular skin incision. Dissection was performed toexpose the mental foramen and nerve, which was found tobe markedly enlarged. The inferior alveolar nerve canal wasthen decorticated back to the region of the posterior man-dible as well as anteriorly to locate the incisive branch. Themandible was sectioned in the angle region so as to gainlingual access and release the nerve from the mandibularforamen. This was then dissected superiorly to the previ-ously excised end from the cranial approach. The thirddivision of the trigeminal nerve, including the incisive, men-tal, and inferior alveolar branches were excised and sent forhistopathological evaluation.

FIGURE 1. The orthopantomographic image (Panorex) shows a sig-nificantly widened inferior alveolar nerve canal along the entire lengthon the left-hand side with loss of the cortical outline of the canalsuperiorly.

Walters et al. Neurotropic Melanoma of the Trigeminal Nerve.J Oral Maxillofac Surg 2008.

FIGURE 2. MRI showing a contrast-enhancing lesion associated with the V-3 branch of the trigeminal nerve emanating from the trigeminal gangliondescending and expanding the foramen ovale, extending to the inferior alveolar branch.

Walters et al. Neurotropic Melanoma of the Trigeminal Nerve. J Oral Maxillofac Surg 2008.

548 NEUROTROPIC MELANOMA OF THE TRIGEMINAL NERVE

Histological Examination

Tissue sections were processed and stained with he-matoxylin and eosin (H & E). Immunohistochemical stud-ies for S-100, neurofilament protein, and Melan A wereaccomplished using a standard automated protocol (Ven-tana, Tuscon, AZ). The S-100 antibody (polyclonal) waspurchased from DAKO (Carpinteria, CA), and the neuro-filament antibody was from BioGenex (San Ramon, CA;clone NE14). Immunoperoxidase staining was performedusing diaminobenzidine (DAB) as the chromogen. TheMelan A antibody is from Ventana (clone A103), and thestain was performed using fast red (alkaline phosphatase)as the red chromogen.

Histologic study showed diffuse invasion of peripheralnerves by a malignant spindle cell neoplasm (Fig 3A).Tumor cells showed significant cellular pleomorphismand contained hyperchromatic elongated nuclei withprominent nucleoli (Fig 3B). A desmoplastic reaction wasevident in areas (Fig 3C). Tumor cells were strongly anddiffusely immunoreactive for S-100 protein, and scatteredindividual cells were positive for Melan A (Fig 3D). Thetumor was negative for cytokeratin and HMB-45. These

findings were consistent with a desmoplastic (neuro-tropic) melanoma.

POSTOPERATIVE CAREThe patient recovered well from her preoperative condi-

tion, with complete resolution of her facial pain. Postoper-atively, she received a course of fractionated radiation ther-apy to the affected area. She remains free from facial pain.

Discussion

Neurotropic melanoma is a rare malignant variantof desmoplastic melanoma. It represents a neuroidcutaneous lesion that may be preceded by lentigomaligna melanoma or minimal deviation melanoma.Reed has more recently considered neurotropic mel-anoma to be a separate clinicopathological entity dueto its greater propensity of local invasion and recur-rences when compared with other variants. Addition-ally, Reed has emphasized cranial neuropathies and

FIGURE 3. A, H & E stained cross-section (right) and longitudinal section(left) of 2 peripheral nerves diffusely in-vaded by the tumor. Original magnifica-tion: 50�. B, Tumor cells invading pe-ripheral nerve. Immunohistochemicalstain for neurofilament protein showingaxons (positively stained) of a peripheralnerve invaded by tumor (arrows). Origi-nal magnification: 500�. C, High mag-nification view of an H & E–stained sec-tion showing a desmoplastic reaction inthe stroma (arrows) and a resident gan-glion cell (*). Original magnification:500�. D, Immunohistochemistry—Left:S-IOU is strongly immunoreactive in spin-dle-shaped tumor cells (brown chromo-gen). Right: Melan A was immunoreac-tive in a few scattered individual tumorcells (red chromogen). Original magnifi-cation: 500�.

Walters et al. Neurotropic Melanomaof the Trigeminal Nerve. J Oral Max-illofac Surg 2008.

WALTERS ET AL 549

brain involvement by direct extension along thenerves.2

According to published reports, males are morecommonly diagnosed with neurotropic melanomathan females, at a rate of nearly 70%. Compared withother melanomas, it occurs at a higher age, with themean age of onset at approximately 60 years. Sun-exposed surfaces in fair-skinned individuals also havea higher penchant for developing neurotropic anddesmoplastic neurotropic melanomas.4 They are mostcommon in the head and neck region, which is con-sistent with the high number of cutaneous nerves inthe face and the location of the trigeminal nerve,which is often affected.3-5

Neurotropic melanomas are generally at an ad-vanced stage of development when they are firstdetected.6 The most common initial presentation is aflesh-colored nodule that has been present for a fewmonths to several years. The lesions are often mis-taken for other conditions on both clinical and histo-logical levels, therefore delaying proper diagnosis andtreatment. It was found that incorrect pathologicalinterpretation, insufficient surgical margins (�1 cm)used to achieve a better cosmetic result, the primarylocation of the head and neck, and the advanced leveland thickness staging are associated with local recur-rence.7

Neurotropic melanoma possesses a characteristicpattern of amelanotic spindle or Schwann cells thatblend with the perineum of peripheral nerves to pro-duce a hypercellularity of the nerves due to infiltra-tion of these structures due to atypical tumor cells. Ithas been proposed that axons regenerating from pre-vious trauma may influence the aggregation and ori-entation of tumor cells and may contribute to theSchwann cell metaplasia of the neoplastic melano-cytes in a precursor epidermal lesion.1-3,5,6 Conse-quently, it is important to identify epidermal melano-cytic dysplasia in the diagnosis of neurotropicmelanoma.

Schwann cells and melanocytes are considered toarise from the neural crest. Based on this, it is pro-posed that the epidermal melanocyte in a precursormelanocytic dysplasia is the progenitor to neuro-tropic melanoma, and the following Schwann cellmetaplasia of the melanocytic component accountsfor the characteristic spindle cell pattern and neuro-tropism.8

The characteristics of the tumor presented fol-lowed a course that could be predicted from a reviewof the literature. The final diagnosis, desmoplasticneurotropic melanoma, arose from a precursor lesion,most possibly acral lentiginous melanoma of the

lower lip. The future development of neurotropicmelanoma has to be considered by the physician, andappropriate steps with regard to treatment need to betaken when such a clinical finding is made.

Neurotropic melanoma and its precursor lesionsare notorious for getting insufficient surgical marginson initial excision, which leads to local recurrence.Once detected, neurotropic melanoma should betreated with a wide local excision. Use of S-100 stain-ing should be considered in evaluating margins. Thepresence of S-100 protein immunoreactivity shouldsuggest the diagnosis of neurotropic melanoma evenin the absence of staining for the melanocyte-relatedantigens HMB-45 and Melan A, as the latter may benegative in the desmoplastic variant.8,9 The use ofsurgical resection in combination with radiation andchemotherapy should also be considered. Careful fol-low-up is essential.

Although neurotropic melanoma is rare and oftenoverlooked, early diagnosis is crucial to improvedprognosis and to prevent threatening outcomes fromeventual neural invasion. A thorough examination ofthe skin, including scalp and mucous membranes ofthe head and neck, should be undertaken in patientssuspected of melanocytic abnormalities. In patientswith head and neck pain and a previous history ofmelanoma in that area, evaluation for persistent orrecurrent melanoma as an explanation for their symp-toms is mandatory. Given the frequent location andpotential for local invasion, neurotropic melanomashould always be a consideration in the differentialdiagnosis of atypical facial pain.

References1. Conley J, Lattes R, Orr W: Desmoplastic malignant melanoma (a

rare variant of spindle cell melanoma). Cancer 28:914, 19712. Reed RJ, Leonard DD: Neurotropic melanoma: A variant of

desmoplastic melanoma. Am J Surg Pathol 3:301, 19793. McGinnis JP, Greer JL, Wolfe NL: Neurotropic melanoma of the

lower lip. J Oral Pathol 15:445, 19864. Quinn MJ, Crotty KA, Thompson JF, et al: Desmoplastic and

desmoplastic neurotropic melanoma: Experience with 280 pa-tients. Cancer 83:1128, 1998

5. Mack EE, Gomez EC: Neurotropic melanoma—A case report andreview of the literature. J Neurooncol 13:165, 1992

6. Hui JI, Linden KG, Barr RJ: Desmoplastic malignant melanoma ofthe lip: A report of 6 cases and review of the literature. J AmAcad Dermatol 47:863, 2002

7. Smithers BM, McLeod GR, Little JH: Desmoplastic, neural trans-forming and neurotropic melanoma: A review of 45 cases. AustN Z J Surg 60:967, 1990

8. Kossard S, Doherty E, Murray E: Neurotropic melanoma: Avariant of desmoplastic melanoma. Arch Dermatol 123:907,1987

9. Madrigal B, Fresno MF, Junquera L, et al: De novo desmoplasticneurotropic melanoma of the lower lip: A neoplasm with om-nious behavior. Oral Surg Oral Med Oral Pathol Oral RadiolEndod 86:452, 1998

550 NEUROTROPIC MELANOMA OF THE TRIGEMINAL NERVE