Nevus of Ota with Intraoral Involvement : Case Report and Review of the Literature

Nevus of Ota (ocular dermal melanocytosis, congenital melanosis bulbi, nevus fuscoceruleus, ophthalmomaxillaris, oculodermal melanocytosis, oculomucodermal melanocytosis) [1], is a benign pigmentary dermatosis in which melanocytes are found deep within the dermis and sclera [2] due to proliferation and nesting of fuso cellular melanocytes that follow the first and second branches of the trigeminal nerve [3], resulting in clinical blue pigmentation [4]. It was first described by Hulkein 1860 and later detailed by Ota in 1939 [2,5]. Although its etiology is unknown, it is believed to result from abnormal migration of melanoblastic cells within the primitive neural tube along the trigeminal nerve during embryogenesis. Some studies have revealed that hormonal alterations and exposure to ultraviolet light may have an important role in the pathogenesis of this condition [6].


Introduction
Nevus of Ota (ocular dermal melanocytosis, congenital melanosis bulbi, nevus fuscoceruleus, ophthalmomaxillaris, oculodermal melanocytosis, oculomucodermal melanocytosis) [1], is a benign pigmentary dermatosis in which melanocytes are found deep within the dermis and sclera [2] due to proliferation and nesting of fuso cellular melanocytes that follow the first and second branches of the trigeminal nerve [3], resulting in clinical blue pigmentation [4].It was first described by Hulkein 1860 and later detailed by Ota in 1939 [2,5].Although its etiology is unknown, it is believed to result from abnormal migration of melanoblastic cells within the primitive neural tube along the trigeminal nerve during embryogenesis.Some studies have revealed that hormonal alterations and exposure to ultraviolet light may have an important role in the pathogenesis of this condition [6].
Nevus of Ota is a rare entity and occurs five times more frequently in women than in men [7], although this datum may be a consequence of an inter consultation bias resulting from aesthetic concerns [2].Worldwide, the condition mainly affects patients of Asian and African origin and is uncommon in Caucasians [5,7].Its exact prevalence among the Mexican population is unknown; however, the disorder was present in 0.7% of patients with facial hyperchromic spots in a dermatologic consultation center [8].
Nevus of Ota is generally characterized by confluent greyish-blue unilateral patches with ill-defined margins, involving preferentially the areas innervated by the first and second divisions of the trigeminal nerve [2,5].The color of the lesion depends on the location of melanocytes; deeper lesions appear blue due to the Tyndall effect [4].Lesions may or may not be present at birth and tend to persist through life [9].
According to its distribution, nevus of Ota has been classified as type I or mild, affecting the orbit (I-A), zygomatic (I-B), frontal (I-C) and nasal (I-D) regions; type II ormoderate, involving eyelids, periocular, zygomatic, cheek and temporal regions; type III, affecting scalp, forehead, eyebrows and nose; and type IV orbilateral [4,[10][11][12].It may also be classified according to the ISSN: 2578-7683 pigmentation and extension of the affected area [13] as type I or mild, in which lesions are light brown and affect the zygomatic region, and both upper and lower eyelids; type II or moderate, characterized by deep slate-grey lesions involving zygomatic area, eyelids and base of the nose; and type III or intense, with lesions that range from deep blue to brown in the regions of the first and second branches of the trigeminal nerve [13].
Nevus of Ota is essentially cutaneous, but often affects the mucosa.Pigmentation can affect the sclera, conjunctiva, cornea, iris, choroid, and less frequently the optic nerve, retrobulbar fat or the orbital periosteum [14] Melanocytosis may also affect the oral and nasal mucosa, external auditory canal, tympanic membrane, orbital fissures, meninges and the brain [15,16].
The aim of this manuscript is to present an exceptional case of a bilateral nevus of Ota with oral cavity involvement.Additionally, we review the cases published in the English literature, analyzing documents that at least included an abstract in English.

Case report
A 40 year-old Mexican female presented to an Oral Pathology Clinic due to an asymptomatic facial dermatosis present since birth.On skin examination, the patient presented photoype V and diffuse brownishgray macules on both eyelids and conjunctiva, and left periauricular skin and external ear (Figure 1A), eyelids and conjunctiva (Figure 1B).Intraorally, we observed multiple brown to greyish macules with irregular and diffuse margins affecting the right hemipalate folds and posterior (glandular) zone of hard palate (Figure 1C).No other medical relevant findings were detected.
We made a clinical diagnosis of oculodermal melanocytosis of Ota type IV [10] by location, and type III by intensity.In the differential diagnosis, we considered amalgam tattoo, hypermelanosis associated to systemic diseases, or hyperpigmentation secondary to drugs.Due to the brown-gray discoloration of the oral lesions and the absence of systemic disease or medication intake, we excluded the above diagnoses.The patient did not consent to a biopsy and was later lost to follow-up.

Discussion
The present case was classified as oculodermal melanocytosis of Ota type IV (or bilateral) [10] by location, and type III by intensity; [13,17]only 1-5% of nevi of Ota [18,19] belong to this type.Intraoral pigmentation in nevus of Ota is extremely rare, and only 45 cases including ours have been described in the English literature (Table 1); being the palate the most frequently involved area [20].We present a case with palate manifestations and bilateral facial distribution, it is the ninth case reported in the English literature (Table 1) and the first in our country.Nevus of Ota is a well-established entity essentially diagnosed by clinical characteristics and classic morphology.Main differential diagnoses include nevi of Hori and Ito [10,21], drug eruptions, post-inflammatory hyperpigmentation, lichen planus pigmentosus, Sturge-Weber syndrome, café-au-lait macules, blue nevi, melasma and actinic lentigo [5].Intraorally, the differential diagnoses comprise amalgam/metal tattoo, melanocytic nevi, melanosis of multiple causes (including racial, physiologic, endocrine or tobacco-inducedpostinflammatory hyperpigmentation), and melanoma.Dermal dendritic melanocytic proliferations, including nevus of Ota, are still poorly defined from a dermoscopic point of view.Most of the descriptions are based on the findings of the blue nevi.The most common dermoscopic feature of the latter is a homogeneous bluish to steelblue pigmentation.Dermoscopy is a routine diagnostic technique that may aid in the diagnosis of nevus of Ota.
On histological examination, nevus of Ota is defined by the presence of dendritic melanocytes dispersed among collagen fibers in the papillary dermis in the absence of stromal scleral reaction [3] [22]; in the later, histopathology is essential to rule-out melanoma [23].In our case, it was proposed to confirm the diagnosis histologically, but the patient rejected the procedure.
Nevus of Ota is generally asymptomatic and benign, although clinical appearance is a common complaint [2].Certain conditions have been associated to the presence of nevus of Ota, including Sturge-Weber syndrome, Klippel-Trenaunay syndrome, neurofibromatosis, multiple hemangioma, cerebrospinal degeneration, glaucoma, and ipsilateral deafness and congenital cataracts [5,13,19,24].Furthermore, more than 50 cases of melanoma developing on a nevus of Ota have been described [20,25].Several of these cases occur intracranially, most of them are congenital, and some are accompanied by the presence of hyperpigmented macules in the intraoral mucosa [18,26].
Because of its rarity, epidemiologic studies that describe the malignant transformation of nevi of Ota are lacking.Nevertheless, it seems that malignant transformation is more common in females (male-female ratio 1:7.2); when mucosa is involved (mainly ocular mucosa) [18], and in Caucasians [18,25], amongst who the risk of developing malignant melanoma, although rarely observed [2], is 35 times greater [18] than in other racial groups.Compared with cutaneous and ocular melanoma, oral malignant melanoma is associated with lower rates of 5-year survival and mutations are less common [5]; GNAQ/GNA11 p.Q209L mutation has been found in 77% of primary uveal melanomas, but it is rare in oral mucosal melanoma.Therefore, it is recommended to perform early annual ophthalmologic examination for congenital nevus of Ota with eye involvement, and magnetic resonance imaging screening for all patients beginning at age 25 and in cases with incompletely excised melanocytomas.Interestingly, concurrent development of malignancy has been described in eight subjects (17.8%) with intraoral nevus of Ota (Table 1).In all of them, malignancy was ipsilateral, two cases adjacent to the nevi and one developed from the parotid gland [26].Although cancer rarely develops within nevi of Ota, the percentage of malignant transformation observed when the oral mucosa is involved should be considered when evaluating subjects.This risk should not be underestimated, and histopathological analysis is advised to confirm the diagnosis and rule out melanoma [18,25].In the presence of malignant melanoma, the excision of the entire intraoral lesion (nevi of Ota) is recommended.In our case, the presence of melanosis in the palate, female gender, bilaterality and ocular lesions supported the need to perform a biopsy or completely remove the lesion from the palatine mucosa.
In summary, we describe an unusual clinical presentation of a nevus of Ota.Although the possibility of malignant transformation from a nevus of Ota is low, the risk should be considered [27] and biannual followup is recommended to monitor sudden changes in color, ulceration or paresthesia [13].In the context of nevus of Ota with oral involvement, it is important to consider that 17.8% of the cases can develop malignant tumors; thus, histopathology is essential to confirm the condition and to discard malignancy, notwithstanding its low frequency [23].

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Figure 1 :
Figure 1: Clinical findings in a female patient with nevus of Ota. A. Slate-gray patches affecting the ear lobe, helix, and retroauricular skin B. Macules and patches on the eyelids and conjunctiva, concealed by heavy makeup.C. Multiple macules with irregular and diffuse limits involving the hard palate.

Table 1 :
. It has been classified into five types according to melanocyte distribution: superficial, superficial dominant, diffuse, deep dominant, and deep English literature review of cases with nevus of Ota and intraoral involvement.
*Oral Ota nevus component contiguous to malignant neoplasia; **Oral Ota nevus component not contiguous to malignant neoplasia; ND=No data