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Authors: Dr. Pankaj Agarwal(Senior Lecturer), Dr. Umesh Chandra Prasad (Professor), Dr. Ramballabh (Senior Lecturer), Dr. Juhi (Senior Lecturer),

Abstract
Intraoral pigmentation is quite common and has numerous etiologies, ranging from exogenous to physiological to neoplastic. Many pigmented lesions of the oral cavity are associated with melanin pigment. The differential diagnosis of mucosal pigmented lesions includes hematomas, varices, and petechiae which may appear to be pigmented. Unlike cutaneous melanomas, oral melanomas are diagnosed late and have a poor prognosis regardless of depth of invasion. As such, the clinical presentation and treatment of intraoral melanoma will be discussed. Developing a differential diagnosis is imperative for a clinician faced with these lesions in order to appropriately treat the patient. This article will focus on the most common oral melanocytic lesions, along with mimics.

KEYWORDS: melanin, melanotic macule, oral melanoma

Introduction

Oral pigmentation is quite common, and its differential diagnosis is broad. The pigmentation can be the result of exogenous factors such as embedded foreign material including tattoo pigment, amalgam from dental restorations, or pencil lead. Endogenous pigmentation can be associated with numerous physiological conditions and syndromes, including Addison’s disease, Peutz-Jeghers syndrome, Laugier–Hunziker syndrome, and rarely neurofibromatosis type 1.1,3 Other endogenous sources of pigmentation can include hemoglobin, hemosiderin, and bilirubin. Post- inflammatory pigmentation can result from chronic trauma (e.g., cheek biting) or inflammation (e.g., erosive oral lichen planus). Tobacco use can cause smoker’s melanosis.4 A variety of systemic medications including antimalarials such as chloroquine, estrogen, and zidovudine have also been associated with oral pigmentation.1,5 Minocycline pigmentation in almost all cases involves the bone and teeth rather than the mucosa.6,8 Although uncommon, acquired melanocytic nevi, including junctional, compound, intramucosal, and blue nevi, can present in the oral cavity..9, 10
Melanocytes present in the basal cell layer of the oral mucosa are similar to those found in the skin. The melanocytes synthesize melanin that is then transferred to the epithelial cells, as well as to macrophages (melanophages). Incontinent melanin pigment can often be noted, particularly in the superficial lamina propria. The color of mucosal pigmentation can vary from brown to blue to black depending on the depth of the pigment within the mucosa (Tyndall effect).
Because of the varied appearance of oral pigmented lesions, diagnosis cannot always be reliably made by clinical examination alone. Clinicians should therefore have a low threshold to biopsy these important lesions. This review will focus on developing a differential diagnosis for the most common melanin-pigmented lesions of the oral mucosa.
Physiological pigmentation
Physiological pigmentation is common and results not from an increase in melanocyte number, but rather greater melanocytic activity. 1. Darker- skinned individuals are more commonly affected.
The color of physiological pigmentation can range from light brown to almost black. Physiological pigmentation increases with age, and color intensity can be influenced by smoking, hormones, and systemic medications.2The attached gingiva is the most common location, but physiological pigmentation can be noted anywhere in the oral cavity, including the tips of the fungiform papillae on the dorsal tongue.

The diagnosis of physiological pigmentation can be made clinically, and no treatment is necessary unless for cosmetic concerns. The use of lasers such as erbium-YAG laser has been reported to effectively remove oral pigmentation, including physiological pigmentation.
A biopsy of physiological pigmentation will show no increase in the number or upward migration of melanocytes. It will demonstrate increased melanin pigmentation of the basal layer, as well as occasional incontinent melanin and/or melanophages in the superficial lamina propria (connective tissue just beneath the epithelium). These microscopic features are similar to those seen in oral melanotic macule. The clinical differential is based on diffuse versus focal pigmentation.

Amalgam tattoo

Inadvertent implantation of dental amalgam is one of the most common etiologies of intraoral pigmentation and may be mistaken for a melanocytic lesion. 1,9,14 Amalgam tattoos are painless; gray- blue macules that range in size from a few millimeters to greater than 1 cm. The tattoo can be single or multiple. Most amalgam tattoos are located on the gingiva and edentulous mucosa, but can also be seen on the hard palate, buccal mucosa, and floor of the mouth. Radiographic evaluation may be positive. When mucosal pigment exhibits a blue-gray color in a patient that reports a history of dental amalgam restorations of either primary deciduous or permanent dentition, a biopsy may be unnecessary. However, if either of these criteria is not met, a biopsy is indicated. On histological examination, fine black granular or fibrillar material embedded in the connective tissue or in a perivascular location with little or no inflammatory response is seen. Foreign body giant cell reactions are uncommon.

The differential diagnosis of amalgam tattoo includes graphite/lead tattoo, implantation of other foreign material, and post-inflammatory pigmentation.

Smoker’s melanosis

Smoker’s melanosis is a phenomenon of increased melanin pigmentation seen in heavy smokers, most commonly cigarette smokers4Smoker’s melanosis is more common in women, suggesting that estrogen may play a role. This pigmentation is thought to be caused by increased melanin production in response to heat or exposure to tobacco smoke. The increased melanin is postulated to have a protective effect against the harmful components of tobacco smoke.1 The most common location of smoker’s melanosis is the labial gingiva, although any oral site can be affected.
Smoker’s melanosis seen in pipe smokers most often is noted on the buccal mucosa or the commissure of the lip along the vermilion border. Diagnosis is made by correlating the clinical findings with the patient’s smoking history. Other diagnostic considerations include physiological pigmentation; systemic causes of oral melanosis such as Addison’s disease, Peutz–Jeghers syndrome, and hemochromatosis; or drug. The microscopic features are similar to those described for physiological pigmentation.

Oral melanotic macule

The oral melanotic macule, also known as focal melanosis, is a benign, mucosal macule uniformly tan to dark brown in color less than 1 cm in size.15 Although generally solitary, multiple lesions have been reported. The color is typically a result of increased melanin deposition, although there may also be an increase in the number of melanocytes. The melanotic macule is not dependent on solar exposure. Although the lower lip is the most common site of occurrence (33%), other intraoral sites include the buccal mucosa, gingiva, and palate. Oral melanotic macules occur in a wide age range with a 2: 1 female predominance. They can occur in Caucasians, as well as darker-skinned patients. Buccal mucosa lesions may occur more frequently in blacks.1

The diagnosis rests on both the clinical presentation of a solitary lesion along with the microscopic features, because the pathology is not specific. On microscopic examination, increased melanin deposition predominantly in the basal cell layer is demonstrated. The epithelium otherwise is of normal stratified squamous epithelium without atypia or elongated rete pegs. Incontinent melanin pigment and melanophages may be noted in the superficial lamina propria.
Generally, oral melanotic macules do not require treatment unless for aesthetic concerns. There are no reports of malignant transformation to melanoma. A biopsy should be performed on melanotic macules that exhibit recent onset, increased size, or irregular pigmentation. Because the palate is the most common site for intraoral melanoma, complete removal of all palatal pigmented lesions is recommended.11,12

Oral melanoacanthoma
Oral melanoacanthoma is an uncommon benign pigmented tumor of the oral mucosa most commonly seen in black women in the third to fourth decades. The buccal mucosa is the most common location, but involvement of the lips, palate, and gingiva has also been reported. The color can range from brown to almost black. Most lesions are solitary and asymptomatic; however, burning and pain have been reported. This lesion is remarkable for rapid increase in size to several centimeters. The etiology of oral melanoacanthoma is not understood; however, trauma has been reported to be a factor in some cases.12,16,17Despite the large size, many cases resolve without treatment or after biopsy. A biopsy to rule out melanoma is indicated because of the worrisome appearance of a rapidly growing, darkly pigmented lesion.

Oral melanoacanthoma microscopically exhibits acanthosis and spongiosis of the epithelium.Dendritic melanocytes that are normally confined to the basal layer are instead dispersed throughout the epithelium and can be highlighted with S100 immunohistochemistry.16 A mild inflammatory cell infiltrate can be seen in the superficial lamina propria.

Melanocytic nevi
Intraoral melanocytic nevi are uncommon and present on the hard palate, gingiva, buccal mucosa, and lip as painless, pigmented macules or papules that range in color from brown to black or blue.12 Most intraoral melanocytic nevi are thought to be acquired rather than congenital.12,18,19 Unlike mature cutaneous nevi which often have a  papillary surface, oral nevi are smooth. In a series of 130 cases of oral nevi from California, the average age at diagnosis was 35 years (range 3–85) with a 1.5: 1 female: male ratio.19In one series from The Netherlands, the annual incidence was 4.35 cases per 10 million persons.18 The differential diagnosis of intraoral nevi includes melanotic macule, physiological pigmentation, amalgam tattoo, and melanoma.19 Approximately 15% of intraoral nevi are amelanotic and present as a solitary sessile mucosal-colored lesion that can be mistaken for a fibroma.12,18
Intraoral nevi have similar histological classification schemes as their cutaneous counterparts: junctional, compound, and intramucosal. In junctional nevi, there is a proliferation of benign melanocytes along the basal cell layer. In compound nevi, benign neoplastic melanocytes are found in the basal cell layer and in the superficial lamina propria. In intramucosal nevi, the nevo melanocytes are located in the lamina propria without a junctional component. The most common oral nevi are intramucosal nevi, which may reflect the age of the patient at the time of biopsy. Intraoral dysplastic nevi have not been reported.1
There are no reports of malignant transformation of intraoral nevi even in patients who have had mutiple nevi or congenital nevi. Biopsy is advisable for any new oral pigmentation because an early melanoma may be mistaken for a melanocytic nevus.
The blue nevus is the second most common type of intraoral nevus, present as a small, less than 1 cm, blue-black macule or dome-shaped papule most commonly on the palate.19Blue nevi are more common in women and are noted usually in the second to fourth decades, although congenital blue nevi have been reported. Malignant transformation of an oral blue nevus to melanoma has not been documented.
On microscopic examination, spindled-shaped melanocytes with abundant melanin pigment are seen deep in the lamina propria, arranged in a parallel fashion to the overlying epithelium. A combined nevus showing histological features of both a blue nevus and a melanocytic nevus can also be seen.20

Intraoral melanoma
Primary mucosal melanoma of the oral cavity is extremely rare accounting for less than 1% of all melanomas.21 The incidence of oral mucosal melanoma is relatively stable. In the head and neck areas, the most common sites for mucosal malignant melanoma are the sinonasal and oral mucosae. Within the oral cavity, the palate is the most common site.12 In a 20-year review of the surgical pathology files in the Department of Pathology at our institution, only eight cases of primary oral melanoma were diagnosed compared to 22 cases of sinonasal melanoma.11 The palate and maxillary alveolus accounted for all these cases.11 To date, no precursor lesion is known for intraoral melanoma, although a prior history of pigmentation in the area of the tumor has been noted in about one-third of patients.12

Biopsies of these pigmented areas often show atypical melanocytic hyperplasia.1,22 Oral Malignant melanoma is seen in the sixth to seventh decades, and a male: female ratio of 2.5,3: 1 is noted.12 Patients often present at an advanced stage with pain, mobile teeth, and bone involvement. Nodal metastases at the time of diagnosis have been reported in more than 50% of cases.23

The most common growth patterns noted are acral lentiginous and/or nodular patterns.22 Rarely, amelanotic melanoma can be seen intraorally presenting as a mass that has ill-defined borders and may appear erythematous.12 Histologically,amelanotic melanomas may demonstrate pigmentation.

Microscopically, intraoral melanoma can demonstrate areas of radial growth phase typical of a superficial spreading melanoma similar to acral lentiginous melanoma. Pagetoid spread with large melanoma cells either singly or in nests may be seen in the superficial epithelium. Nodular melanoma is the other most common pattern of intraoral melanoma and is often noted early in tumor development. When intraoral melanoma is diagnosed at an advanced stage, the associated radial growth phase is often absent. In nodular malignant melanoma, the malignant melanocytes typically will have an epithelioid or spindle-shaped appearance containing fine melanin granules. Bone and/or cartilage invasion can be seen in 35% of cases, whereas vascular invasion is not a common finding. 11 When intraoral melanoma presents with an acral lentiginous or nodular growth pattern with abundant melanin pigment, the diagnosis is usually not difficult. Independent of histological suspicion, immunohistochemistry studies such as HMB45, S100, melanA, or MitF are necessary for definitive diagnosis.

Once a diagnosis of oral melanoma is made, appropriate imaging of patients may include a positron emission tomography (PET) for the evaluation of metastatic disease along with computed tomography (CT) to evaluate the primary tumor and cervical lymph nodes. In patients with extensive metal dental restorations, magnetic resonance imaging may be preferable to CT because of artifactual streaking.

The mainstay of treatment for oral melanoma is surgical excision. Clear margins are not always possible because of the anatomical and functional considerations of this region.11,23With regard to the management of the clinically and radiographically negative neck, some centers advocate prophylactic cervical lymph node dissection because of the high rate of metastases.23 Both radiation and immunotherapy have been used in the treatment of oral melanoma particularly in patients with a strong likelihood of local or regional recurrence. The use of adjuvant chemotherapy and/or immunotherapy in oral melanoma has been extrapolated from cutaneous melanoma data.

These are not advocated as monotherapy because they do not improve overall survival. Despite all available treatments, oral melanoma has a poor prognosis with a 10–20% 5-year survival rate.11,19,23 This poor survival rate is a result of the difficulty in obtaining wide surgical margins of excision as mentioned above, as well as early hematogenous spread. Many intraoral melanoma patients develop widespread metastases to lung, liver, brain, as well as lymph nodes.

The parotid gland is also a site of cutaneous melanoma metastasis because of its numerous intra- and periparotid lymph nodes which are primary sites of lymphatic drainage from auricle, cheek, parietal scalp, and forehead skin. Parotid swelling in a patient with a cutaneous malignancy of the head and neck should be investigated for metastases. Often, these lesions are amenable to fine-needle aspiration to obtain a tissue diagnosis.CT scans are also helpful in the evaluation.

Conclusion

When a patient presents with intraoral pigmentation, a thorough medical and dental history, along with extraoral and intraoral examinations, should be undertaken. Important information includes size, color, onset, and duration of the lesion(s) in addition to any localized or systemic symptoms. Smoking history and medication history should be included. Many pigmented lesions can be clinically diagnosed based on size, shape, or color, along with the clinical information. However, pigmented lesions that have increased in size or that cannot be explained by local factors, such as an amalgam tattoo, require biopsy to establish a diagnosis.

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