Cutaneous melanoacanthoma (MA) is a rare variant of pigmented seborrheic keratosis (1). Mishima and Pinkus (2) were the first to use the term melanoacanthoma to describe a benign skin tumor exhibiting proliferation of both melanocytes and basal and prickle cell keratinocytes. Oral MA is unrelated to seborrheic keratosis. Oral MA is a rare reactive mucosal lesion characterized histologically by a proliferation of benign dendritic melanocytes scattered throughout the thickness of the acanthotic lesional epithelium. There is also an increase in the number of melanocytes in the basal cell layer, spongiosis, and a submucosal chronic inflammatory infiltrate admixed with eosinophils (3). A review of the literature identified 28 reported cases of oral MA (4–17). Oral MA most commonly presents as a rapidly enlarging brown to black macule or plaque on the buccal mucosa of black women. The clinical and histologic differential diagnoses often include malignant melanoma. The purpose of this article is to review the current literature and further characterize MA by reporting the clinical features of 10 additional cases and the results of immunohistochemical analysis for reactivity to HMB-45. The rationale for examining oral MA for HMB-45 immunoreactivity is to determine the marker's usefulness in distinguishing oral MA from malignant melanoma.
MATERIALS AND METHODS
Formalin-fixed and paraffin-embedded tissue from 10 cases diagnosed as MA between the years 1980 and 2001 was retrieved from the archives of the Oral Pathology Laboratory, Flushing, New York. Immunohistochemical staining for HMB-45 was performed using a three-step streptavidin-peroxidase technique. Pretreatment was used for epitope retrieval employing a heat-induced buffer (pH6; Sigma). Monoclonal HMB-45 antibody incubation took place overnight at 4°C. The detection system was peroxidase-labeled streptavidin (Vector Laboratories) with diaminobenzidine (Sigma) chromogen used for visualization. Negative controls consisted of replacing the primary antibody with mouse serum (Biogenex Super Sensitive Negative Control; Biogenex). Positive controls consisted of metastatic malignant melanoma.
The clinical features of the cases in this series are summarized in Table 1. As expected, oral MA presented as a flat to slightly raised brown to black lesion, most often on the buccal mucosa (Fig. 1). The cases occurred over a wide age range (5–77 years), with an average age of presentation of 39.4 years. The oldest patient in the series presented with ill-defined, flat, brown lesions of the buccal mucosa bilaterally. Of the seven patients for whom information regarding race was obtained, five (71.4%) were black. There was a 4:1 female predilection. Three cases presented bilaterally. The patient in one of these cases (Case 10) reported a 2-month duration of bilateral buccal mucosal lesions and a lesion of the right retromolar pad. Only the left buccal lesion was biopsied and proven to be MA, although all were similar in clinical appearance and history. The seven remaining cases manifested as single lesions. Although the buccal mucosa was the most common location (6 of 10 cases), other sites of occurrence included the gingiva, hard palate, lower lip, floor of mouth, and retromolar pad. Presentation on attached mucosa (i.e., mucosa bound to bone such as gingiva and hard palate) occurred in 2 (20%) cases. In 3 of the 10 cases in which symptoms were known, all were reported as asymptomatic. The size of the lesions ranged from 0.2 cm to 2.0 cm for the 5 cases in which size was noted. One case was described as raised, with a corrugated surface (Case 3). Interestingly, this case occurred in a 5-year-old child. Melanoma was cited in the differential diagnosis in 1 case (Case 6). The clinician in this case also reported that the lesion displayed a sudden onset. A single lesion recurred; within 6 months, the 0.2-cm lesion in Case 1 regrew to its original size and then remained stable.
All 10 cases displayed characteristic histologic features of oral MA (3), including spongiosis, acanthosis, and a mild subepithelial chronic inflammatory infiltrate (Fig. 2). Some cases exhibited scattered eosinophils. Most importantly, large benign-appearing dendritic melanocytes characteristic of MA were seen at all levels of the epithelium (Fig. 3). A proliferation of melanocytes in the basal cell layer was also seen in all cases.
Immunohistochemical analysis of the current series of cases revealed strong immunoreactivity to HMB-45 in all 10 cases (Fig. 4). Reactivity could be demonstrated in the cytoplasm of dendritic melanocytes at all levels of the mucosa. All cases also contained dendritic and round cells singly and in clumps in the basal layer that were positive for HMB-45. Dendritic melanocytes at all levels of the mucosa, which were not visible on sections stained with hematoxylin and eosin, were detected using HMB-45.
Analysis of the clinical features of the 28 previously published cases of MA revealed the following. The average age of presentation for oral MA was 27.9 years, with an age range of 9 (5) to 54 years (17). Twenty-five of 28 (89.3%) patients were black. The remaining 3 patients were white. There was a 2.1:1 female predilection. Although the buccal mucosa was the most common location (18 of 28 cases), other sites of occurrence included the labial mucosa, lower lip, palate, gingiva, alveolar mucosa, and oropharynx. The size of the lesions, when noted, varied from 0.3 cm (11) to 5.0 cm (7) in greatest diameter. One case was described as diffuse bilateral pigmentation of the buccal mucosa (14). The patients in 8 cases (8,10,14–17) presented with multiple lesions, including 3 cases (8,10,16) of bilateral lesions of the buccal mucosa. Symptoms were not available in all cases, but of the 13 cases that included relevant information, 11 (84.6%) were asymptomatic. In 2 cases, the lesions were reported to be associated with pain or pruritus (6,15). In cases where follow-up was available, no lesion was documented to progress to a neoplastic melanocytic process. Most often, the lesion was documented to regress within 2 to 6 months of diagnosis. One case was known to recur (10). The report by Wright (10) described a 27-year-old black woman who presented with a small (7 mm) MA of the buccal mucosa, which was excised. Three and a half years later, bilateral buccal mucosal lesions appeared and attained a maximum size of 2.0 cm × 3.0 cm. Local factors, particularly friction, were believed to be related to the etiology in this case. After removal of such factors, the lesions were documented to fully regress within 6 months.
In summary, the following can be stated about the clinical presentation of oral MA. Most commonly, oral MA is seen in adult black women on the buccal mucosa. It may, however, occur over a wide age range from childhood to late adulthood. The current series documents cases in both the youngest (5 years old) and the oldest (77 years old) patients ever reported. Usually, oral MA is asymptomatic; however, pain, burning, and pruritus have been documented.
Oral MA is a benign reactive lesion that needs no further treatment after diagnosis and has been reported to regress spontaneously after biopsy (3,14). Most often, it presents as an enlarging flat or slightly raised area of hyperpigmentation (brown or black) that can rapidly attain a size of several centimeters. Most oral MAs occur on the movable mucosal surfaces that are subject to trauma (e.g., buccal mucosa, labial mucosa) or on the stress-bearing mucosa bound to bone (gingiva and hard palate) (17). Infrequently, oral MA can appear bilaterally. Oral MA may develop rapidly after an episode of acute trauma or at a site of chronic mucosal irritation. Resolution may occur after the source of the trauma is eliminated (17). This phenomenon was well documented by Wright (10) in his report of a recurrent oral MA related to local trauma. Consequently, a search for local mechanical sources of irritation, with the aim of eliminating the identified factors, is recommended as first-line therapy (17). Other disease processes in the differential diagnosis of brown-black localized oral mucosal lesions should also be ruled out, because MA can be indistinguishable clinically from oral junctional nevi, blue nevi, melanotic macules, and melanoma (8). Histologically, oral MA exhibits a proliferation of melanocytes in the basal layer as well as large, cytologically bland, heavily pigmented dendritic melanocytes that are present at all levels of the acanthotic epithelium. The presence of large dendritic melanocytes in the superficial portions of the epithelium results in a histologic resemblance to malignant melanoma, particularly acral lentiginous melanoma (ALM). In ALM, atypical pigmented dendritic melanocytes are present throughout an irregularly acanthotic epithelium. There is also a proliferation of atypical nondendritic melanocytes along the basal layer (lentiginous proliferation). Acral lentiginous melanoma can also display a dense subepithelial lymphocytic infiltrate (18).
As previously stated, all 10 cases in the current series were immunoreactive to HMB-45. The aim of examining oral MA for immunoreactivity to HMB-45 was to determine the utility of this relatively specific marker in distinguishing MA from oral melanoma, particularly ALM. Although it is an uncommon form of melanoma, ALM is the most common type seen in blacks, and it is the most common type of oral melanoma (3,18). HMB-45 is a monoclonal antibody to the melanosomal protein gp 100, which is most often expressed in immature or proliferating cells. HMB-45 was originally developed from metastatic melanoma cells. It reacts with both primary and metastatic melanoma, showing cytoplasmic positivity. Its most useful diagnostic role is to differentiate melanomas from nonmelanoma neoplasms, although desmoplastic melanoma and spindle cell melanomas are often negative (19). HMB-45 positivity has also been reported in normal melanocytes located singly and in clusters along the basal layer in normal oral mucosa (20) and in the melanocytes contained in the oral epithelium overlying intramucosal nevi (21). It also readily reacts with the melanocytes of oral intramucosal nevi, including blue nevi (21).
Our immunohistochemical analysis demonstrates the immunoreactivity to HMB-45 of dendritic and nondendritic (basal) melanocytes in oral MA. Consequently, this marker appears not to be a useful diagnostic tool when attempting to differentiate oral MA from malignant melanoma.
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