Nevi of Ota and Ito 

Updated: Mar 26, 2019
Author: Omobola Onikoyi, DO, MSc; Chief Editor: Dirk M Elston, MD 

Overview

Background

Nevus of Ota is a dermal melanocytosis originally described by Ota and Tanino in 1939. Clinically, nevus of Ota is distributed along the ophthalmic and maxillary divisions of the trigeminal nerve and presents as a blue or gray patch on the face.[1] Around 50% of cases occur at birth, while the remaining occur during puberty and adulthood. Initial hyperpigmentation may present as light in color with continued hyperpigmentation as the individual ages. In addition to the pigmented macule observed on the skin, there have also been rare cases involving ocular and oral mucosal surfaces.[2, 3] See the images below.

Nevus of Ota. Courtesy of DermNet New Zealand (htt Nevus of Ota. Courtesy of DermNet New Zealand (http://www.dermnetnz.org/assets/Uploads/lesions/ota2.jpg).
Nevus of Ota. Courtesy of DermNet New Zealand (htt Nevus of Ota. Courtesy of DermNet New Zealand (http://www.dermnetnz.org/assets/Uploads/lesions/ota.jpg).

Nevus of Ito, initially described by Minor Ito in 1954,[2, 3, 4] is a similar dermal melanocytic condition like nevus of Ota, differing in distribution. Nevus of Ito is usually found distributed along the posterior supraclavicular and lateral cutaneous brachial nerves of the shoulder. Nevus of Ito often occurs in association with nevus of Ota in the same patient but is much less common, although the true incidence is unknown. From a pathophysiological standpoint, both nevus of Ota and Ito result from failed migration of melanocytes from the neural crest to basal layer of the epidermis. See the image below.

Nevus of Ito. Courtesy of DermNet New Zealand (htt Nevus of Ito. Courtesy of DermNet New Zealand (http://www.dermnetnz.org/assets/Uploads/lesions/melanocytosis-ito.jpg).

Additionally, the Medscape article Melanocytic Nevi may be of interest.

Pathophysiology

The etiology and pathogenesis of nevi of Ota and Ito are not known. Although unconfirmed, nevus of Ota and other dermal melanocytic disorders, such as nevus of Ito, blue nevus, and Mongolian spots, may represent melanocytes that have not migrated completely from the neural crest to the epidermis during the embryonic stage.[5] The variable prevalence among different populations suggests genetic influences, although familial cases of nevus of Ota are exceedingly rare. The two peak ages of onset in early infancy and in early adolescence suggest that hormones are a factor in the development of these conditions. Schwann cell precursors have been shown to be a source of melanocytes in skin.[6] The observation of dermal melanocytes in close proximity with peripheral nerve bundles in nevus of Ito suggests that the nervous system is a factor in the development of nevus of Ito, although the true pathogenesis remains unknown.

One theory regarding the pathogenesis of nevi of Ota and Ito. It has been demonstrated that most nevi and melanomas are associated with mutations in the BRAF and NRAS genes of the MAP kinase pathway.[7, 8] However, blue nevi and nevi of Ota and Ito do not possess these mutations. Instead, it has been discovered that the melanocytes present in these lesions often contain a mutation in a G-coupled protein gene, GNAQ. This mutation causes the G-coupled protein to be constitutively turned on, resulting in increases in the melanoblast pool. These melanoblasts then migrate during embryogenesis to the skin, the uvea, and/or the meninges, creating the various manifestations of Nevus of Ota.[9, 10, 11] This would explain the association between nevus of Ota and uveal and leptomeningeal melanocytosies. GNAQ mutations have also been shown to underlie other cutaneous disorders, including phakomatosis pigmentovascularis (of which melanocytosis may be a feature),[12] nevus flammeus,[13] and Sturge-Weber syndrome.

It has also been shown that the risk of developing cutaneous, uveal, or leptomeningeal melanomas in the setting of lesions such as nevus of Ota is related to monosomy of chromosome 3. The tumor suppressor gene BAP1 (BRCA-associated protein 1) is located on this chromosome. Loss of one the BAP1 allele is linked with an adverse prognosis. Monosomy 3, coupled with loss of 1q or gain of 8q, is associated with a worse outcome. Evaluation for this abnormality in melanomas associated with nevus of Ota could aid in prognosis, treatment, and follow-up.[14]

Epidemiology

Race

Nevi of Ota and Ito occur most frequently in individuals of Asian descent, with an estimated prevalence of 0.2-0.6% for nevus of Ota in the Japanese population. Nevus of Ito is less common than nevus of Ota, although the true incidence is unknown.

Studies have shown prevalence in other ethnic groups including Africans, African Americans, and East Indians.

Nevi of Ota and Ito are uncommon in whites.

Sex

Females are shown to be affected five times more than males, with the male-to-female ratio is 1:5 for nevus of Ota.[15] The ratio for nevus of Ito is unknown.

Age

The initial presentation of both nevus of Ota and Ito occurs in infancy, with as many as 50% of nevus of Ota cases present at birth.

Nevus of Ota may also present itself during adolescence.

Additionally, there have been rare cases of delayed-onset nevi of Ota that first appear in adults, including in older patients.[16, 17]

Prognosis

Lesions may display progressive hyperpigmentation with age, and, without treatment, lesions remain permanent.

It is important to note the psychosocial impact that Nevus of Ota can have on those affected, as disease progression can cause facial disfigurement.[18] In rare cases, melanoma, which can be life threatening, has been reported to arise from nevus of Ota.[19] Glaucoma also has been associated with nevus of Ota. Recurrence may also occur with incomplete removal of lesions.

Nevus of Ito usually does not have symptoms and causes little cosmetic concern to patients; sensory changes occasionally are present in the lesion. Rarely, nevus of Ito has progressed to cutaneous melanoma.[19, 20]

Patient Education

It is important that patients be made aware of the risk associated with the development of glaucoma as this may progress to vision loss. Periodic follow-up visits with an ophthalmologist should be encouraged.

Despite there being a rare risk of transformation into malignant melanoma, patients should be encouraged to report any changes in size and/or color to the lesional areas.

 

Presentation

History

After onset, nevus of Ota may slowly and progressively enlarge and darken in color, and its appearance usually remains stable once adulthood is reached. The color or perception of the color of nevus of Ota may fluctuate according to personal and environmental conditions, such as fatigue, menstruation, insomnia, and cloudy, cold, or hot weather conditions. Nevus of Ota can be associated with other cutaneous disorders and ocular disease. Nevus of Ito can be associated with sensory changes in the involved skin.

Benign cutaneous and leptomeningeal conditions associated with nevus of Ota are as follows[21] :

  • Nevus of Ito

  • Phakomatosis pigmentovascularis

  • Nevus flammeus

  • Sturge-Weber syndrome

  • Klippel-Trenaunay syndrome

  • Takayasu disease

  • Neurofibromatosis and leptomeningeal melanosis

Malignant degeneration of nevus of Ota is rare. More than 100 cases of malignant melanoma in association with nevus of Ota have been described in the literature as follows[22] :

  • Ocular tissues - 79 cases[23, 24, 25, 26, 27, 28, 29, 30, 31, 32]

  • Meninges - 14 cases[14]

  • Skin - 10 cases[19]

To date, 13 cases of malignant degeneration of nevus of Ito have been described.[19]

Ocular abnormalities (ocular acuity normal) are as follows:

  • Pigmentation of the sclera, cornea, iris, retina, and optic disc[33]

  • Cavernous hemangiomas of the optic disc

  • Elevated intraocular pressure

  • Glaucoma (10.3%)[34]

  • Ocular melanoma

Physical Examination

Table. Clinical and Histologic Features for Differential Diagnoses of Nevi of Ota and Ito (Open Table in a new window)

Condition

Onset

Appearance

Location

Histology

Nevi of Ota and Ito

Birth or early adolescence

Blue or gray speckled coalescing macules or patches

Nevus of Ota: Unilateral, rarely bilateral, on forehead, temple, zygomatic, or periorbital areas

Nevus of Ito: Shoulder and upper arm areas

Increased dermal melanocytes, with surrounding fibrosis and melanophages

Mongolian spot

Birth

Poorly demarcated large blue-to-gray patches that tend to spontaneously resolve by age 3-6 y

Most frequently on lumbosacral areas, buttocks, and rarely, other areas

Increased dermal melanocytes; no surrounding fibrosis

Blue nevus

Congenital or acquired

Blue papules or plaques

Anywhere on skin

Dermal nodular proliferation of heavily pigmented spindle cells

Acquired nevus of Ota-like macules (Hori nevus)

Acquired, presenting in adulthood

Gray macules or patches

Usually bilateral and symmetrical; over the cheeks, temples, root of the nose, alae nasi, eyelids, and forehead

Diffuse upper-dermal melanocytosis

Melasma

Acquired; may be associated with pregnancy and other estrogen excess stages

Well-to-poorly demarcated and irregularly outlined brown-to-gray brown patches

Maxillary and zygomatic areas on face

No increase in dermal melanocytes; presence of melanophages

Lentigo maligna

Acquired; presenting usually after fifth decade of life

Brown patches, usually with pigmentary variegation

Photodistribution, particularly within zygomaticomaxillary areas

Atypical melanocytes in nests at dermal-epidermal junction, with pagetoid spread

Actinic lentigo

Acquired; usually after fifth decade of life

Well-demarcated brown papules or plaques

Photodistribution, especially on face

Elongation of rete ridges; basal layer hyperpigmentation; slight increase of melanocyte number along basal layer

Phytophotodermatitis

Acquired; exposure to certain plants or cosmetics

Gray-to-brown macules and patches

Photodistribution, according to sites of contact with photosensitizer

Dermal melanophages

Drug-induced hyperpigmentation

Acquired; following drug exposure (eg, minocycline, amiodarone, gold)

Variable according to offending drugs

Variable according to specific offending drugs

Variable but may involve presence of dermal melanophages; pigmentation of basal keratinocytes

Exogenous ochronosis (rare)

Adulthood; following topical application of hydroquinone

Irregularly shaped blue-to-gray patches or macules

Areas corresponding to exposure to hydroquinone

Yellow banana-shaped spindle cells in papillary dermis

Ochronosis (alkaptonuria, rare)

First decade of life

Blue-gray discoloration of ear cartilage, tip of nose, and sclera

Symmetrical distribution over cartilage, nose, cheeks, and extensor tendons of hands, as well as flexural areas

Yellow-to-brown pigmentary granules within dermal macrophages

Nevus of Ota most frequently presents as blue-to-gray speckled or mottled coalescing macules or patches affecting the forehead, temple, malar area, or periorbital skin.[35] Nevus of Ito presents as a patch on the shoulder or upper arms with blue, gray, or brown pigmentation. Most cases of nevus of Ota are unilateral (90%), although pigmentation is present bilaterally in 5-10%.[36] Nevus of Ito usually is unilateral. In addition to skin, pigmentation of nevus of Ota may involve oral mucosa and ocular structures such as the sclera, retrobulbar fat, cornea, and retina.

Clinically, nevus of Ito is similar to nevus of Ota, except that it typically presents over the shoulder girdle region.

Specific variants of nevus of Ota have been described in the literature under the names of nevus fuscoceruleus zygomaticus, plaque-type variant of blue nevus. Differential features of these conditions are related to the following:

  • Location of patch or macules

  • Extent of involvement

  • Age of onset

  • Tendency to occur as familial cases

  • Presence of a papular component

Pathology and response to therapy appear similar for all forms of nevus of Ota. The pathology of nevus of Ito is similar to that of nevus of Ota.

Tanino created the following four classifications of nevus of Ota based on the extent of disease and localization of distribution:

  • Type I (mild): Type A has an orbital distribution, is periocular, and is localized to the upper/lower eyelid or temporal region. Type B is localized to the zygomatic region. Type C is localized only to the forehead. Type D is localized only to the nasal ala.
  • Type II (moderate): Lesions may be distributed as those seen in type I, but to a more extensive degree.
  • Type III (intensive): Lesions have forehead, eyebrow, nose, and scalp involvement.
  • Type IV: Lesions have a bilateral distribution.

Complications

Studies have shown that patients with dermal melanocytosis subsequently went on to develop uveal melanoma had an increased risk for metastasis double that of patients without melanocytosis.[37]

Skin biopsies are warranted if clinical changes are suspected of malignant transformation (eg, ulceration, new papular lesions, variegations in color) within the involved skin, ocular tissues, or mucosal tissues.

Ophthalmologic follow-up care is necessary for patients with increased intraocular pressure. Biannual follow up is recommended.

 

DDx

 

Workup

Other Tests

Consider ophthalmologic examination and follow-up care for nevus of Ota because of a reported 10% association of nevus of Ota with increased intraocular pressure. Iris mammillations, sometimes occurring with nevus of Ota, should not be confused with other nodular alterations of the iris, such as the Lisch nodules of neurofibromatosis, as they are associated with a higher risk of malignant transformation.[33]

Lesions should be closely observed for any changes in size or color, as there is a mild risk for melanoma.

Histologic Findings

Histologic findings for nevi of Ota and Ito have some similarities. Overlying epidermis is normal. In the papillary and upper reticular dermis, dendritic melanocytes are present and surrounded by fibrous sheaths (which are not present in other dermal melanocytosis, such as blue nevus or Mongolian spots). Dermal melanophages may be present.

Nevi of Ota have been classified histologically into 5 types based on the locations of the dermal melanocytes, which are (1) superficial, (2) superficial dominant, (3) diffuse, (4) deep dominant, and (5) deep.[38]

This histologic classification correlates clinically with the observation that the more superficial lesions tend to be located on the cheeks, while deeper lesions occur on periorbital areas, the temple, and forehead.

 

Treatment

Approach Considerations

It is important to note that some treatment methods may result in scarring, and recurrence is a possibility.

Medical Care

Cosmetic camouflage makeup can minimize the disfiguring facial pigmentation resulting from nevus of Ota.[39] Nonsurgical methods include chemical peeling, dermabrasion, and topical hydroquinone-based bleaching products.

Surgical Care

Laser surgery is the first-line treatment.[40] Pulsed Q-switched laser surgery is the treatment of choice for nevi of Ota and Ito, and it works via selective photothermal and photomechanical destruction of dermal melanocytes and melanophages. High success rates and minimal adverse effects have been reported with the Q-switched ruby,[41] Q-switched alexandrite,[42, 43, 44] and Q-switched Nd:YAG lasers.[42, 45] After 4-8 treatments, skin pigmentation is reduced dramatically or removed in 90-100% of cases, with a less than 1% risk of scarring.

In 2016, it has been shown that similar results may be achieved using a 755-nm Q-switched picosecond laser compared with Q-switched nanosecond lasers. In a 2016 study of patients with nevus of Ota, there was no statistically significant difference in visual analog scores for six patients treated with the picosecond laser and ten patients treated with nanosecond laser. Notably, no picosecond laser‒treated patients experienced any permanent dyspigmentation, compared with 16% in the nanosecond laser group.[46]

Other surgical methods currently have been superseded by laser surgery but include the following:

  • Cryotherapy [47]
  • Microsurgery
  • Dermabrasion (alone or combined with other modalities, such as carbon dioxide snow, autologous epithelial grafting)
  • Sequential dry ice epidermal peeling

Consultations

Secondary to the increased risk of ocular melanoma in patients with nevus of Ota, it is important for patients to receive consultation with ophthalmologists with biannual follow up.

Complications

Complications of surgical treatment include a risk of scarring.