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Premalignant melanocytic dysplasia and malignant melanoma of the oral mucosa
Oral Oncology 38 (2002) 714–722 www.elsevier.com/locate/oraloncology
Premalignant melanocytic dysplasia and malignant melanoma of the oral mucosa Masahiro Umeda*, Hideki Komatsubara, Yasuyuki Shibuya, Satoshi Yokoo, Takahide Komori Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan Received 8 January 2002; accepted 23 January 2002
Abstract Although malignant melanoma of the oral cavity frequently arises in pre-existing melanosis of the oral mucosa, little is known about oral melanoma precursor lesions. We reviewed three patients with premalignant melanocytic dysplasia and 14 with malignant melanoma of the oral mucosa. Thirteen of the 14 malignant melanoma cases had radial growth phases similar to those of acral lentiginous melanoma (ALM) of the skin. The prognosis of oral melanoma was not poor in contrast to that of cutaneous melanoma. Premalignant melanocytic dysplasia of the oral mucosa showed lentiginous or pagetoid proliferation of atypical melanocytes in the lower epithelium in the central part of the lesion, and lentiginous proliferation of dendritic melanocytes or simple hyperpigmentation in the basal cell layer in the peripheral part. These findings were similar to those of the radial growth phase of ALM of the oral mucosa. # 2002 Elsevier Science Ltd. All rights reserved. Keywords: Malignant melanoma of the oral mucosa; Acral lentiginous melanoma; Premalignant melanocytic displasia
1. Introduction
2. Patients and methods
In contrast to Caucasians, the percentage of oral melanoma among all melanomas is relatively high in the Japanese people. Malignant melanoma of the skin has been divided into four types; lentigo maligna melanoma (LMM), superficial spreading melanoma (SSM), nodular melanoma (NM), and acral lentiginous melanoma (ALM). We previously reported that oral melanoma with a radial growth phase was similar to ALM clinically and histologically [1,2], but the classification of oral melanoma is still controversial. Further, premalignant oral melanocytic lesions have not been well understood. The purpose of this paper is to describe the clinical and histologic characteristics of patients with premalignant and malignant melanocytic lesions of the oral cavity, and to discuss the classification and precursors of oral melanoma.
We experienced three patients with premalignant melanocytic dysplasia and 14 with malignant melanoma of the oral mucosa at the Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine between 1980 and 2000. Clinical and histological features of the patients were examined, retrospectively.
* Corresponding author. Tel.: +81-78-382-5111; fax: +81-78-3826229. E-mail address: [email protected] (M. Umeda).
3. Results 3.1. Premalignant melanocytic dysplasia We experienced three cases of premalignant melanocytic dysplasia of the oral mucosa (Table 1). Case 1 (44year-old male) had noticed pigmentation of the lower lip for about 5 years, but it began to grow larger 2 months before the first visit to our hospital. Close observation of the lesion showed two phases macroscopically; a flat, irregular-shaped, brownish-black pigmented plaque lesion in the centre, and an adjacent light brown macular lesion with no clear borderline (Fig. 1).
1368-8375/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S1368-8375(02)00008-8
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M. Umeda et al. / Oral Oncology 38 (2002) 714–722 Table 1 Patients with premalignant melanocytic dysplasia of the oral mucosa Case
Age
Sex
Site
Diagnosis
Prognosis
1 2 3
44 68 56
Male Female Female
Lower lip Palate Palate
Premalignant melanocytic dysplasia Premalignant melanocytic dysplasia Premalignant melanocytic dysplasia
27 months alive 13 months alive 63 months dead
Fig. 1. Premalignant melanocytic dysplasia of the lip (Case 1).
He underwent resection of the lesions under the clinical diagnosis of premalignant melanocytic lesions. Histological examination of the plaque lesion revealed lentiginous proliferation of atypical melanocytes along the basal cell layer and occasionally nest formation of these melanocytes in the lower epithelial layer. The macular lesion exhibited various histologic features such as an increase in melanocytes, simple hyperpigmentation without an increase in melanocytes, lymphocytes infiltration and phagocytosis of melanin in the submucosa (Fig. 2). He has been free of disease for 27 months after the operation. Case 2 (68-year-old female) was referred to our hospital because of a pigmented lesion on the palate which her dentist noticed accidentally. Clinical examinations revealed a brownish-black plaque lesion in the centre and an adjacent, exudation-like, light brown pigmented macule with no apparent borderline (Fig. 3). She underwent surgical resection of the lesions under the clinical diagnosis of premalignant melanocytic lesions. Histological examination revealed lentiginous or pagetoid proliferation of atypical melanocytes in the epithelial layer in the central part, and proliferation of dendritic melanocytes or simple hyperpigmentation along the basal cell layer in the peripheral region (Fig. 4). She has been free of disease for 13 months after the operation. Case 3 (56-year-old female) had undergone resection of an amelanotic tumour of the palate. Histological diagnosis of the surgical material was an undifferentiated carcinoma. Two years later, a pigmented macule appeared in the vicinity of the resected area
(Fig. 5), and we performed a biospy of this lesion. Histological diagnosis of the biopsy specimen was lentigo simplex, so she was followed up periodically at our hospital. However, 3 years after the biopsy, malignant melanoma occurred in the pigmented area, so the biopsy specimen from 3 years earlier was examined retrospectively. Histological examination revealed lentiginous proliferation of dendritic melanocytes and melanin products. These melanocytes had lost contact inhibition and formed small nests in the tip of rete ridges (Fig. 6). These findings indicated melanocytic dysplasia rather than lentigo simplex. Further, the first surgical material was examined retrospectively, and the diagnosis was changed from undifferentiated melanoma to amelanotic malignant melanoma. She underwent surgery of the recurrent tumour, but died of distant metastasis 27 months after the last operation. 3.2. Malignant melanoma Table 2 shows oral malignant melanoma cases. The patients ranged from 50 to 82 years in age, with an average age of 64 years. There was a slight female predominance (male:female=5:9). The most frequent primary site was the palate or the maxillary gingiva. In 13 of 14 patients, there was mucosal melanosis surrounding the nodular lesion. Detailed examinations revealed that the lesion went through three phases: a nodular phase usually affecting the centre, a flat or slightly elevated, deep brownish-black pigmented plaque phase, and a non-elevated, light-brown macular phase (Fig. 7). Case 7, however, showed only a nodular phase. Histological examination of the nodular phase revealed spindle or epithelioid melanoma cells in the submucosa. These tumour cells contained varying amounts of melanin, but in some cases there was no distinct melanin pigment in the HE-stained specimens. Immunohistochemical analysis using S-100 protein or HMB-45 monoclonal antibodies was useful for diagnosing these amelanotic type melanomas. The tumour thickness was 3–24 mm (average: 9.7 mm), which suggested that oral melanoma was likely to be more locally advanced than is usual for cutaneous melanoma. The pigmented plaque phase consisted of preinvasive, atypical tumour cell nests or individually proliferating tumour cells in the lower epithelial layers (Fig. 8). Some
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Fig. 2. Histologic features of premalignant melanocytic dysplasia (Case 1). A: Proliferation of atypical nested melanocytes in the lower epithelium. B: Lentiginous proliferation of atypical metanocytes. C: Hyperpigmentation of the basal cell layer. HE stain, original magnification 100.
Fig. 3. Premalignant melanocytic dysplasia of the palate (Case 2).
of the plaques were lentiginous and others were pagetoid. The macular phase exhibited lentiginous proliferation of dendritic melanocytes along the basal cell layer without apparent cellular atypia or simple hyperpigmentation in the basal cell layer (Fig. 9). The histologic features of the macular phase were similar to those of lentigo simplex or melanotic macule. These findings of oral malignant melanoma in the radial growth phase
corresponded to those of acral lentiginous melanoma (ALM) of the skin reported by Mishima et al. However, one case (Case 7) showed no radial growth phase and appeared to have a nodular melanoma (NM). The 14 patients with oral malignant melanoma underwent the following therapies: (1) resection of the primary lesion via an intraoral approach in consideration of minimizing cosmetic and functional morbidity, (2) therapeutic radical neck dissection when neck metastasis was detectable clinically, and (3) postoperative immunochemotherapy with dimethyl triazeno imidazole carboxamide (DTIC), nimustine hydrochloride (ACNU), vincristine (VCR) and a biological response modifier, OK-432 (Picibanil1, Chugai Pharmaceutical Co. Ltd. Japan). Biopsy, radiotherapy, and preoperative chemotherapy were not done because they can promote distant metastasis. Local control of the primary lesion was possible in 13 of 14 patients. Control of neck metastasis was possible in all 13 patients in whom local control of the primary lesion was achieved. Three patients died due to tumours; one of local recurrence and two of lung metastasis. The 5-year cumulative survival rate was 76% (Fig. 10).
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Fig. 4. Histologic features of premalignant melanocytic dysplasia (Case 2). A: Proliferation of atypical melanocytes and nest formation. Pagetoid upward migration of individual melanocytes was occasionally observed. B: Proliferation of lentiginous melanocytes along the basal cell layer. C: Hyperpigmentation of the basal cell layer. HE stain, original magnification 100.
Fig. 5. Premalignant melanocytic dysplasia (an arrow) of the palate (Case 3).
4. Discussion The classification of oral melanoma has not yet been determined. Prior to the introduction of the ALM concept in 1977, many authors who attempted to classify oral melanoma pointed out the similarity of the
histologic features of oral melanoma to those of skin LMM. Grinspan et al. [3] reported a case of oral melanoma of the palate originating in Hutchinson’s melanotic freckle in 1969. Takagi et al. [4] reported in 1975 that many cases of oral melanoma had pre-existing melanosis around the tumour and that a certain number of oral melanomas were similar to skin LMM. Robinson and Hukill [5] also reported a malignant melanoma case related to Hutchinson’s melanotic freckle of the gingiva in 1975. After palmar, plantar, and subungual melanoma with a radial growth phase were recognized as another entity from SSM and classified as ALM in 1976 [6], some investigators reported that oral melanoma may be classified as ALM rather than LMM, in consideration of the poor clinical outcome of oral melanoma patients. Regezi et al. [7] reported in 1978 that their two cases of oral melanoma had histologic features similar to those of volar and subungual melanomas. Clark et al. [8] stated in 1979 that the radial growth phase of ALM was clinically and histologically identical to that of oral melanoma, and that ALM and and mucous membrane
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Table 2 Patients with malignant melanoma of the oral mucosa Case
Age
Sex
Site
Diagnosis Treatment
Tumour thickness
Level of LN metastasis
Number of LN metastasis
Prognosis
4 5 6 7 8
66 82 73 50 64
Female Male Female Female Female
ALM Resection, DAVa, OK-432 ALM Resection, DAV, OK-432 ALM Resection, DAV, OK-432 NM Resection+RND, DAV, OK-432 ALM Resection+RND, DAV, OK-432
3 mm 8 6 12 8
– – – II and III I and II
– – – 3 5
155 months alive 52 months alive 94 months alive 188 months alive 79 months alive
9 10
57 56
Female Female
Palate Palate Palate Palate Maxillary gingiva Palate Palate
ALM Resection+RND, DAV, OK-432 ALM Resection+RND, DAV, OK-432
24 23
I and II I and II
2 6
11
62
Male
ALM Resection+RND, DAV, OK-432
10
I and III
3
12 13 14
62 58 79
Female Female Male
ALM Resection, DAV, OK-432 ALM Resection+RND, DAy, OK-432 ALM Resection, DAV, OK-432
5 5 3
– II –
– 1 –
48 months alive 11 months dead (local recurrence) 32 months dead (distant metastasis) 110 months alive 87 months alive 29 months alive
15 16
66 61
Female Male
ALM Resection, DAV, OK-432 ALM Resection+RND, DAV, OK-432
6 8
– –
– –
17
62
Male
ALM Resection+RND, DAV, OK-432
16
I
3
a
Maxillary gingiva Palate Palate Buccal mucosa Palate Maxillary gingiva Maxillary gingiva
83 months alive 30 months dead (distant metasrasis) 5 months alive
DAV:DTIC+ACNU+VCR.
Fig. 6. Histologic features of premalignant melanocytic dysplasia (Case 3). Proliferation of dendritic melanocytes and melanin products were observed. Focal nest formation of melanocytes was also seen. HE stain, original magnification 200.
melanomas ultimately would be regarded as a single kind of melanoma. Coleman et al. [9], and McDonald et al. [10] also described the similarity of oral melanoma to ALM, in 1980 and 1983, respectively. On the other hand, Seiji et al. [11] advocated in 1983 that although mucous membrane melanomas were similar to palmar–planter–subungual melanomas except that the clinical behavior of the lesions on the mucosas was different from that of other acral lesions, and that at that time, acral and mucosal melanomas were recommended to be treated separately until more information could be gathered to allow statistical evaluation
Fig. 7. Macroscopic features of oral malignant melanoma (Case 5). N: nodular phase, P: plaque phase, M: macular phase.
of both their clinical and histologic features, as well as their course. Rapini et al. [12] reviewed 177 cases of oral melanoma including six new cases, and described in 1985 that because the distinction between LMM, ALM, and SSM had not been shown to be valuable prognostically in a prospective study of oral melanomas, and because authors had not been consistent in their terminology in classifying these lesions, it could be preferable to designate oral lesions simply as ‘‘oral malignant melanoma with a radial growth phase’’. McGovern et al. [13] pointed out that mucosal lentiginous melanomas were similar clinically and histologically to melanomas occuring in hairless (glabrous) skin, but they finally classified oral mucosal melanoma separately from ALM
M. Umeda et al. / Oral Oncology 38 (2002) 714–722
Fig. 8. Histologic features of the plaque phase of malignant melanoma exhibiting tumor cell nests or individual proliferation of tumor cells in the lower epithelium (Case 5). HE stain, original magnification 100.
as ‘‘malignant melanoma with an adjacent component of mucosal lentiginous type’’ (1982 Revised Sydney Classification of Melanomas). Kato et al. [14] reported in 1987 that 10 of 13 cases of mucosal melanoma died due to tumours, and that there appeared to be some clinical and histological similarities between mucosal melanomas and melanomas of the volar skin, while the difference in biological behavior warranted that the two be classified separately. Tanaka et al. [15] also felt that oral melanoma should be classified separately from cutaneous melanoma in 1994. In 1997, The WESTOP Banff Workshop on Oral Mucosal Melanomas [16] stated that oral melanomas appeared similar to ALM, and less frequently, to NM when no in situ component was evident. However, the workshop described that the particularly poor prognosis of oral melanomas was unlike most cutaneous lesions, and that until detailed prospective studies were completed it would seem appropriate to classify oral lesions separately from cutaneous lesions. Hicks and Flaitz [17] reviewed oral melanoma cases and reported the 5-year survival rate was 15% for all oral melanomas, and stated that oral melanomas did not fit well into any specific cutaneous melanoma category. As mentioned above, most authors in the recent literature recommended classifying oral melanomas separately from cutaneous melanomas, since their prognosis was poorer than that of skin ALM. We reported in 1988 that most of 43 oral melanomas in Japan had radial growth phases, and that they were interpreted as ALM clinically, histologically and epidemiologically [1]. Further, in 1994, we reported in 14 patients with oral melanoma that most cases were interpreted as ALM and obtained good outcome, which indicated that the prognosis for oral melanoma cases was not poorer than that of cutaneous melanoma cases, when adequate tharapy was given [2]. We agree with Regezi [7], Clark [8], Coleman [9], and McDonald [10] in that oral melanoma with a radial growth phase is
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Fig. 9. The macular phase of malignant melanoma shows lentiginous proliferation of dendritic melanocytes or simple hyperpigmentation along the basal cell layer (Case 5). HE stain, original magnification 100.
Fig. 10. The cumulative survival rate of 14 patients with oral malignant melanoma.
identical to ALM both clinically and histologically. The rationale of those who advocate that oral melanoma should be classified separately from ALM because its prognosi is extremely poor in contrast to that of ALM seems to be unfounded in consideration of the fairly good results with our cases, as described in the current study. We believe the poor prognosis of reported oral melanoma cases was not due to the extremely aggresive biological behavior of oral melanoma, but rather to the advanced stage of oral cases and the inexperience of surgeons, because the frequency of oral melanoma is quite low. When a larger number of oral melanomas are reported, we think that it and ALM will be regarded as a simple entity in the future. There have been various studies on cutaneous melanoma precursor lesions. Wayte and Helwig [18] reported clinicopathologic features of Hutchinson’s melanotic freckle and concluded that it was an obligate precancerous lesion with a possible eventual outcome of malignant melanoma. The lesion has been known by many synonyms, which include lentigo malin des vieillards, melanose circonscrite precancereuse, lentigo
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maligna, premalignant lentigo, malignant freckle, melanosis circumscripta precancerosa (Dubreuilh’s precancerous melanosis), and cancerous melanosis. Hutchinson’s melanotic freckle occurrs frequently in the facial skin of the elderly. The microscopic features consist of irregular proliferation of individual atypical melanocytes without formation of distinctive theques. Malignant melanoma arising in Hutchinson’s melanotic freckle (LMM) has a better prognosis than melanoma of other types. Mishima and Matsunaka [19] analyzed 23 cases of SSM precursor lesions which were distinctive from Hutchinson’s melanotic freckle clinically and histologically, and used the term pagetoid premalignant melanosis for the lesions. The lesion exhibits cellular nests which proliferate laterally in all portions, but predominantly in the lower levels of the epidermis. Individual tumor cells composing these cellular nests are large, ovoid or fusiform, atypical pigment cells containing fine melanin granules to varying degrees. These cells have no conspicuous cytoplasmic dendrites and have vesicular abundant cytoplasm and large nuclei. McGovern [20] reported in 723 cases of SSM, that 39% originated in a precursor lesion, that is, premalignant melanocytic hyperplasia, and the remaining 61% were melanomas from the beginning. Clark et al. [21] also demonstrated in their detailed study of tumour progression that 91 of 150 SSM, and 13 of 31 NM cases had histologic evidence of precursor lesions, and most of them were melanocytic dysplasia with or without associated nevic tissue. There have been some other reports of SSM and NM precursor lesions, such as premalignant dysplasia [22], melanocytic dysplasia [23], and dysplastic nevus [24]. On the other hand, little is known of the precursorz of ALM. Clark et al. [21] reported that in 12 of 13 ALM cases, precursor lesions were not demonstrable histologically, while only one case showed presence of a melanocytic precursor. Mishima and Nakanishi [25] reported four cases of ALM precursors and designated them plantar or palmar premalignant melanosis. They reported that ALM showed three lesion phases; A-, B-, and Cphases clinically and histologically. The A-phase was an invasive, nodular lesion almost indistinguishable from SSM. The B-phase was a deep brownish-black plaque lesion exhibiting pre-invasive tumor cell nests indistinguishable from pagetoid premalignant melanosis or the radial growth phase of SSM. The C-phase was a light brown macular lesion consisting of proliferation of highly dendritic melanocytes without apparent cellular atypia. They reported that plantar or palmar premalignant melanosis showed B- and C-phases, and therefore it was considered to be an ALM precursor lesion. There have been few reports on benign melanocytic lesions of the oral mucosa. Buchner and Hansen [26] reported 32 new, and 75 reviewed, cases of oral
pigmented nevi, but their significance as precancerous lesions was not well determined. Lentigo simplex usually involves small (a few millimeters in diameter), round to oval, brown to black macules. Histologically, lentigo simplex reveals elongation of the rete ridges; the basal cell layer is heavily pigmented, and there is an increase in the number of basal cell layer melanocytes. On the other hand, melanotic macules show no increase in melanocytes, but rather an increase in melanin deposition within the basal cell layer and submucosa/ lamina propria of the oral mucosa. Elongation of the rete ridges does not typically occur. Lentigo simplex is sometimes confused with oral melanotic macules. Trodahl and Sprague [27] reported 11 cases that fulfilled the criteria of lentigo simplex, including hyperpigmentation, downward proliferation of rete ridges, and focal proliferation of melanocytes. Watkins et al. [28] described five oral pigmented lesions that were diagnosed as lentigo simplex, but their photomicrograph shows oral melanotic macules rather than lentigo simplex. Shapiro and Zegarelli [29] used the term labial lentigo for lesions that exhibited only hyperpigmentation of the basal cell layer, but without elongation of the rete ridges and without an increase in the number of melanocytes. Whereas some authors use the terms lentigo and oral melanotic macule interchangeably, we are of the opinion that, as in the skin, these are different entities, especially with regard to melanocyte proliferation. The relationship between lentigo simplex and malignant melanoma has not been well documented. In contrast to various studies on cutaneous melanoma precursor lesions mentioned above, there have been few reports relating to premalignant melanosis of oral melanoma. Liversedge [30] reported that patients with oral melanoma frequently had pigmented areas for a long time before melanoma developed, but detailed data was not shown. Grinspan et al. [3], Takagi et al. [4], and Robinson and Hukill [5] stated that oral melanoma probably arises from Hutchinson’s melanotic freckle, but that is not yet proven, as mentioned above. Hicks and Flaitz [17] described that atypical melanocytic hyperplasia, designated for oral mucosal lesions with equivocal histopathologic features, such as hyperchromatic and angulated nuclei with very infrequent mitotic activity, essentially represented an indeterminant premalignant melanocytic lesion similar to that of atypical moles (dysplastic nevus [24]). Dysplastic nevus may share clinicopathological features with melanoma in situ, but it is uncommon among the Japanese and is usually found on nonacral portions of the skin. No malignant melanoma associated with dysplastic nevus syndrome has been found on the palms or soles, where they frequently occur in the Japanese. These findings indicate that dysplastic nevus is probably not the precursor of ALM, including melanoma of the oral mucosa.
M. Umeda et al. / Oral Oncology 38 (2002) 714–722
We reported here three patients with premalignant melanocytic dysplasia of the oral mucosa. Two of the three lesions showed two phases of deep brownish black plaque and light brown macular lesions, and were diagnosed as premalignant lesions macroscopically. Histological examinations of the plaque lesions of the former two revealed nest formation of atyipical melanocytes or individually proliferating atypical melanocytes in the lower part of the epithelium. Pagetoid upward migration of individually proliferating melanocytes was found in one case. Peripheral, macular lesions exhibited lentiginous proliferation of dendritic melanocytes without apparent cellular typia, and simple hyperpigmentation in the basal cell layer. These macro- and microscopic findings resemble the B- and C-phases of plantar or palmar premalignant melanosis described by Mishima and Nakanishi [25]. On the other hand, one case of premalignant melanocytic displasia was incorrectly diagnosed as lentigo simplex initially, but malignant melanoma later developed in the lesion. Buchner et al. [31] stated that pigmented melanocytic and nevomelanocytic lesions are important primarily because of their close histogenic relationship to melanoma. In recent years, our knowledge has increased in the area of nevomelanocytic lesions of the oral mucosa [26]. Little is known, however, about pigmented oral lesions that exhibit melanocytic hyperplasia, such as lentigo simplex. The relationship among premalignant melanocytic dysplasia and benign melanocytic lesions such as pigmented nevus or lentigo simplex has not been clarified. Some cases of oral malignant melanomas showed pigmented nevus-like structures in the radial growth phase. However, most oral melanomas seem to arise from lentiginous rather than nevoid lesions. In fact, the histologic features of the peripheral part of premalignant melanocytic dysplasia were similar to those of lentigo simplex or melanotic macules. We could not find any relationsip between benign melanocytic lesions and precursors of oral melanoma because of too small a number of patients. We think that any pigmented lesions which show proliferation of melanocytes should be resected until detailed clinicopathological data is obtained as to the precursors of oral melanoma. We think that oral lesions exhibiting melanocytid hyperplasia represent an interesting, challenging, and confusing range of diagnostic problems and treatment for oral surgeons and pathologists.
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Premalignant melanocytic dysplasia and malignant melanoma of the oral mucosa Masahiro Umeda*, Hideki Komatsubara, Yasuyuki Shibuya, Satoshi Yokoo, Takahide Komori Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan Received 8 January 2002; accepted 23 January 2002
Abstract Although malignant melanoma of the oral cavity frequently arises in pre-existing melanosis of the oral mucosa, little is known about oral melanoma precursor lesions. We reviewed three patients with premalignant melanocytic dysplasia and 14 with malignant melanoma of the oral mucosa. Thirteen of the 14 malignant melanoma cases had radial growth phases similar to those of acral lentiginous melanoma (ALM) of the skin. The prognosis of oral melanoma was not poor in contrast to that of cutaneous melanoma. Premalignant melanocytic dysplasia of the oral mucosa showed lentiginous or pagetoid proliferation of atypical melanocytes in the lower epithelium in the central part of the lesion, and lentiginous proliferation of dendritic melanocytes or simple hyperpigmentation in the basal cell layer in the peripheral part. These findings were similar to those of the radial growth phase of ALM of the oral mucosa. # 2002 Elsevier Science Ltd. All rights reserved. Keywords: Malignant melanoma of the oral mucosa; Acral lentiginous melanoma; Premalignant melanocytic displasia
1. Introduction
2. Patients and methods
In contrast to Caucasians, the percentage of oral melanoma among all melanomas is relatively high in the Japanese people. Malignant melanoma of the skin has been divided into four types; lentigo maligna melanoma (LMM), superficial spreading melanoma (SSM), nodular melanoma (NM), and acral lentiginous melanoma (ALM). We previously reported that oral melanoma with a radial growth phase was similar to ALM clinically and histologically [1,2], but the classification of oral melanoma is still controversial. Further, premalignant oral melanocytic lesions have not been well understood. The purpose of this paper is to describe the clinical and histologic characteristics of patients with premalignant and malignant melanocytic lesions of the oral cavity, and to discuss the classification and precursors of oral melanoma.
We experienced three patients with premalignant melanocytic dysplasia and 14 with malignant melanoma of the oral mucosa at the Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine between 1980 and 2000. Clinical and histological features of the patients were examined, retrospectively.
* Corresponding author. Tel.: +81-78-382-5111; fax: +81-78-3826229. E-mail address: [email protected] (M. Umeda).
3. Results 3.1. Premalignant melanocytic dysplasia We experienced three cases of premalignant melanocytic dysplasia of the oral mucosa (Table 1). Case 1 (44year-old male) had noticed pigmentation of the lower lip for about 5 years, but it began to grow larger 2 months before the first visit to our hospital. Close observation of the lesion showed two phases macroscopically; a flat, irregular-shaped, brownish-black pigmented plaque lesion in the centre, and an adjacent light brown macular lesion with no clear borderline (Fig. 1).
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M. Umeda et al. / Oral Oncology 38 (2002) 714–722 Table 1 Patients with premalignant melanocytic dysplasia of the oral mucosa Case
Age
Sex
Site
Diagnosis
Prognosis
1 2 3
44 68 56
Male Female Female
Lower lip Palate Palate
Premalignant melanocytic dysplasia Premalignant melanocytic dysplasia Premalignant melanocytic dysplasia
27 months alive 13 months alive 63 months dead
Fig. 1. Premalignant melanocytic dysplasia of the lip (Case 1).
He underwent resection of the lesions under the clinical diagnosis of premalignant melanocytic lesions. Histological examination of the plaque lesion revealed lentiginous proliferation of atypical melanocytes along the basal cell layer and occasionally nest formation of these melanocytes in the lower epithelial layer. The macular lesion exhibited various histologic features such as an increase in melanocytes, simple hyperpigmentation without an increase in melanocytes, lymphocytes infiltration and phagocytosis of melanin in the submucosa (Fig. 2). He has been free of disease for 27 months after the operation. Case 2 (68-year-old female) was referred to our hospital because of a pigmented lesion on the palate which her dentist noticed accidentally. Clinical examinations revealed a brownish-black plaque lesion in the centre and an adjacent, exudation-like, light brown pigmented macule with no apparent borderline (Fig. 3). She underwent surgical resection of the lesions under the clinical diagnosis of premalignant melanocytic lesions. Histological examination revealed lentiginous or pagetoid proliferation of atypical melanocytes in the epithelial layer in the central part, and proliferation of dendritic melanocytes or simple hyperpigmentation along the basal cell layer in the peripheral region (Fig. 4). She has been free of disease for 13 months after the operation. Case 3 (56-year-old female) had undergone resection of an amelanotic tumour of the palate. Histological diagnosis of the surgical material was an undifferentiated carcinoma. Two years later, a pigmented macule appeared in the vicinity of the resected area
(Fig. 5), and we performed a biospy of this lesion. Histological diagnosis of the biopsy specimen was lentigo simplex, so she was followed up periodically at our hospital. However, 3 years after the biopsy, malignant melanoma occurred in the pigmented area, so the biopsy specimen from 3 years earlier was examined retrospectively. Histological examination revealed lentiginous proliferation of dendritic melanocytes and melanin products. These melanocytes had lost contact inhibition and formed small nests in the tip of rete ridges (Fig. 6). These findings indicated melanocytic dysplasia rather than lentigo simplex. Further, the first surgical material was examined retrospectively, and the diagnosis was changed from undifferentiated melanoma to amelanotic malignant melanoma. She underwent surgery of the recurrent tumour, but died of distant metastasis 27 months after the last operation. 3.2. Malignant melanoma Table 2 shows oral malignant melanoma cases. The patients ranged from 50 to 82 years in age, with an average age of 64 years. There was a slight female predominance (male:female=5:9). The most frequent primary site was the palate or the maxillary gingiva. In 13 of 14 patients, there was mucosal melanosis surrounding the nodular lesion. Detailed examinations revealed that the lesion went through three phases: a nodular phase usually affecting the centre, a flat or slightly elevated, deep brownish-black pigmented plaque phase, and a non-elevated, light-brown macular phase (Fig. 7). Case 7, however, showed only a nodular phase. Histological examination of the nodular phase revealed spindle or epithelioid melanoma cells in the submucosa. These tumour cells contained varying amounts of melanin, but in some cases there was no distinct melanin pigment in the HE-stained specimens. Immunohistochemical analysis using S-100 protein or HMB-45 monoclonal antibodies was useful for diagnosing these amelanotic type melanomas. The tumour thickness was 3–24 mm (average: 9.7 mm), which suggested that oral melanoma was likely to be more locally advanced than is usual for cutaneous melanoma. The pigmented plaque phase consisted of preinvasive, atypical tumour cell nests or individually proliferating tumour cells in the lower epithelial layers (Fig. 8). Some
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Fig. 2. Histologic features of premalignant melanocytic dysplasia (Case 1). A: Proliferation of atypical nested melanocytes in the lower epithelium. B: Lentiginous proliferation of atypical metanocytes. C: Hyperpigmentation of the basal cell layer. HE stain, original magnification 100.
Fig. 3. Premalignant melanocytic dysplasia of the palate (Case 2).
of the plaques were lentiginous and others were pagetoid. The macular phase exhibited lentiginous proliferation of dendritic melanocytes along the basal cell layer without apparent cellular atypia or simple hyperpigmentation in the basal cell layer (Fig. 9). The histologic features of the macular phase were similar to those of lentigo simplex or melanotic macule. These findings of oral malignant melanoma in the radial growth phase
corresponded to those of acral lentiginous melanoma (ALM) of the skin reported by Mishima et al. However, one case (Case 7) showed no radial growth phase and appeared to have a nodular melanoma (NM). The 14 patients with oral malignant melanoma underwent the following therapies: (1) resection of the primary lesion via an intraoral approach in consideration of minimizing cosmetic and functional morbidity, (2) therapeutic radical neck dissection when neck metastasis was detectable clinically, and (3) postoperative immunochemotherapy with dimethyl triazeno imidazole carboxamide (DTIC), nimustine hydrochloride (ACNU), vincristine (VCR) and a biological response modifier, OK-432 (Picibanil1, Chugai Pharmaceutical Co. Ltd. Japan). Biopsy, radiotherapy, and preoperative chemotherapy were not done because they can promote distant metastasis. Local control of the primary lesion was possible in 13 of 14 patients. Control of neck metastasis was possible in all 13 patients in whom local control of the primary lesion was achieved. Three patients died due to tumours; one of local recurrence and two of lung metastasis. The 5-year cumulative survival rate was 76% (Fig. 10).
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Fig. 4. Histologic features of premalignant melanocytic dysplasia (Case 2). A: Proliferation of atypical melanocytes and nest formation. Pagetoid upward migration of individual melanocytes was occasionally observed. B: Proliferation of lentiginous melanocytes along the basal cell layer. C: Hyperpigmentation of the basal cell layer. HE stain, original magnification 100.
Fig. 5. Premalignant melanocytic dysplasia (an arrow) of the palate (Case 3).
4. Discussion The classification of oral melanoma has not yet been determined. Prior to the introduction of the ALM concept in 1977, many authors who attempted to classify oral melanoma pointed out the similarity of the
histologic features of oral melanoma to those of skin LMM. Grinspan et al. [3] reported a case of oral melanoma of the palate originating in Hutchinson’s melanotic freckle in 1969. Takagi et al. [4] reported in 1975 that many cases of oral melanoma had pre-existing melanosis around the tumour and that a certain number of oral melanomas were similar to skin LMM. Robinson and Hukill [5] also reported a malignant melanoma case related to Hutchinson’s melanotic freckle of the gingiva in 1975. After palmar, plantar, and subungual melanoma with a radial growth phase were recognized as another entity from SSM and classified as ALM in 1976 [6], some investigators reported that oral melanoma may be classified as ALM rather than LMM, in consideration of the poor clinical outcome of oral melanoma patients. Regezi et al. [7] reported in 1978 that their two cases of oral melanoma had histologic features similar to those of volar and subungual melanomas. Clark et al. [8] stated in 1979 that the radial growth phase of ALM was clinically and histologically identical to that of oral melanoma, and that ALM and and mucous membrane
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Table 2 Patients with malignant melanoma of the oral mucosa Case
Age
Sex
Site
Diagnosis Treatment
Tumour thickness
Level of LN metastasis
Number of LN metastasis
Prognosis
4 5 6 7 8
66 82 73 50 64
Female Male Female Female Female
ALM Resection, DAVa, OK-432 ALM Resection, DAV, OK-432 ALM Resection, DAV, OK-432 NM Resection+RND, DAV, OK-432 ALM Resection+RND, DAV, OK-432
3 mm 8 6 12 8
– – – II and III I and II
– – – 3 5
155 months alive 52 months alive 94 months alive 188 months alive 79 months alive
9 10
57 56
Female Female
Palate Palate Palate Palate Maxillary gingiva Palate Palate
ALM Resection+RND, DAV, OK-432 ALM Resection+RND, DAV, OK-432
24 23
I and II I and II
2 6
11
62
Male
ALM Resection+RND, DAV, OK-432
10
I and III
3
12 13 14
62 58 79
Female Female Male
ALM Resection, DAV, OK-432 ALM Resection+RND, DAy, OK-432 ALM Resection, DAV, OK-432
5 5 3
– II –
– 1 –
48 months alive 11 months dead (local recurrence) 32 months dead (distant metastasis) 110 months alive 87 months alive 29 months alive
15 16
66 61
Female Male
ALM Resection, DAV, OK-432 ALM Resection+RND, DAV, OK-432
6 8
– –
– –
17
62
Male
ALM Resection+RND, DAV, OK-432
16
I
3
a
Maxillary gingiva Palate Palate Buccal mucosa Palate Maxillary gingiva Maxillary gingiva
83 months alive 30 months dead (distant metasrasis) 5 months alive
DAV:DTIC+ACNU+VCR.
Fig. 6. Histologic features of premalignant melanocytic dysplasia (Case 3). Proliferation of dendritic melanocytes and melanin products were observed. Focal nest formation of melanocytes was also seen. HE stain, original magnification 200.
melanomas ultimately would be regarded as a single kind of melanoma. Coleman et al. [9], and McDonald et al. [10] also described the similarity of oral melanoma to ALM, in 1980 and 1983, respectively. On the other hand, Seiji et al. [11] advocated in 1983 that although mucous membrane melanomas were similar to palmar–planter–subungual melanomas except that the clinical behavior of the lesions on the mucosas was different from that of other acral lesions, and that at that time, acral and mucosal melanomas were recommended to be treated separately until more information could be gathered to allow statistical evaluation
Fig. 7. Macroscopic features of oral malignant melanoma (Case 5). N: nodular phase, P: plaque phase, M: macular phase.
of both their clinical and histologic features, as well as their course. Rapini et al. [12] reviewed 177 cases of oral melanoma including six new cases, and described in 1985 that because the distinction between LMM, ALM, and SSM had not been shown to be valuable prognostically in a prospective study of oral melanomas, and because authors had not been consistent in their terminology in classifying these lesions, it could be preferable to designate oral lesions simply as ‘‘oral malignant melanoma with a radial growth phase’’. McGovern et al. [13] pointed out that mucosal lentiginous melanomas were similar clinically and histologically to melanomas occuring in hairless (glabrous) skin, but they finally classified oral mucosal melanoma separately from ALM
M. Umeda et al. / Oral Oncology 38 (2002) 714–722
Fig. 8. Histologic features of the plaque phase of malignant melanoma exhibiting tumor cell nests or individual proliferation of tumor cells in the lower epithelium (Case 5). HE stain, original magnification 100.
as ‘‘malignant melanoma with an adjacent component of mucosal lentiginous type’’ (1982 Revised Sydney Classification of Melanomas). Kato et al. [14] reported in 1987 that 10 of 13 cases of mucosal melanoma died due to tumours, and that there appeared to be some clinical and histological similarities between mucosal melanomas and melanomas of the volar skin, while the difference in biological behavior warranted that the two be classified separately. Tanaka et al. [15] also felt that oral melanoma should be classified separately from cutaneous melanoma in 1994. In 1997, The WESTOP Banff Workshop on Oral Mucosal Melanomas [16] stated that oral melanomas appeared similar to ALM, and less frequently, to NM when no in situ component was evident. However, the workshop described that the particularly poor prognosis of oral melanomas was unlike most cutaneous lesions, and that until detailed prospective studies were completed it would seem appropriate to classify oral lesions separately from cutaneous lesions. Hicks and Flaitz [17] reviewed oral melanoma cases and reported the 5-year survival rate was 15% for all oral melanomas, and stated that oral melanomas did not fit well into any specific cutaneous melanoma category. As mentioned above, most authors in the recent literature recommended classifying oral melanomas separately from cutaneous melanomas, since their prognosis was poorer than that of skin ALM. We reported in 1988 that most of 43 oral melanomas in Japan had radial growth phases, and that they were interpreted as ALM clinically, histologically and epidemiologically [1]. Further, in 1994, we reported in 14 patients with oral melanoma that most cases were interpreted as ALM and obtained good outcome, which indicated that the prognosis for oral melanoma cases was not poorer than that of cutaneous melanoma cases, when adequate tharapy was given [2]. We agree with Regezi [7], Clark [8], Coleman [9], and McDonald [10] in that oral melanoma with a radial growth phase is
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Fig. 9. The macular phase of malignant melanoma shows lentiginous proliferation of dendritic melanocytes or simple hyperpigmentation along the basal cell layer (Case 5). HE stain, original magnification 100.
Fig. 10. The cumulative survival rate of 14 patients with oral malignant melanoma.
identical to ALM both clinically and histologically. The rationale of those who advocate that oral melanoma should be classified separately from ALM because its prognosi is extremely poor in contrast to that of ALM seems to be unfounded in consideration of the fairly good results with our cases, as described in the current study. We believe the poor prognosis of reported oral melanoma cases was not due to the extremely aggresive biological behavior of oral melanoma, but rather to the advanced stage of oral cases and the inexperience of surgeons, because the frequency of oral melanoma is quite low. When a larger number of oral melanomas are reported, we think that it and ALM will be regarded as a simple entity in the future. There have been various studies on cutaneous melanoma precursor lesions. Wayte and Helwig [18] reported clinicopathologic features of Hutchinson’s melanotic freckle and concluded that it was an obligate precancerous lesion with a possible eventual outcome of malignant melanoma. The lesion has been known by many synonyms, which include lentigo malin des vieillards, melanose circonscrite precancereuse, lentigo
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maligna, premalignant lentigo, malignant freckle, melanosis circumscripta precancerosa (Dubreuilh’s precancerous melanosis), and cancerous melanosis. Hutchinson’s melanotic freckle occurrs frequently in the facial skin of the elderly. The microscopic features consist of irregular proliferation of individual atypical melanocytes without formation of distinctive theques. Malignant melanoma arising in Hutchinson’s melanotic freckle (LMM) has a better prognosis than melanoma of other types. Mishima and Matsunaka [19] analyzed 23 cases of SSM precursor lesions which were distinctive from Hutchinson’s melanotic freckle clinically and histologically, and used the term pagetoid premalignant melanosis for the lesions. The lesion exhibits cellular nests which proliferate laterally in all portions, but predominantly in the lower levels of the epidermis. Individual tumor cells composing these cellular nests are large, ovoid or fusiform, atypical pigment cells containing fine melanin granules to varying degrees. These cells have no conspicuous cytoplasmic dendrites and have vesicular abundant cytoplasm and large nuclei. McGovern [20] reported in 723 cases of SSM, that 39% originated in a precursor lesion, that is, premalignant melanocytic hyperplasia, and the remaining 61% were melanomas from the beginning. Clark et al. [21] also demonstrated in their detailed study of tumour progression that 91 of 150 SSM, and 13 of 31 NM cases had histologic evidence of precursor lesions, and most of them were melanocytic dysplasia with or without associated nevic tissue. There have been some other reports of SSM and NM precursor lesions, such as premalignant dysplasia [22], melanocytic dysplasia [23], and dysplastic nevus [24]. On the other hand, little is known of the precursorz of ALM. Clark et al. [21] reported that in 12 of 13 ALM cases, precursor lesions were not demonstrable histologically, while only one case showed presence of a melanocytic precursor. Mishima and Nakanishi [25] reported four cases of ALM precursors and designated them plantar or palmar premalignant melanosis. They reported that ALM showed three lesion phases; A-, B-, and Cphases clinically and histologically. The A-phase was an invasive, nodular lesion almost indistinguishable from SSM. The B-phase was a deep brownish-black plaque lesion exhibiting pre-invasive tumor cell nests indistinguishable from pagetoid premalignant melanosis or the radial growth phase of SSM. The C-phase was a light brown macular lesion consisting of proliferation of highly dendritic melanocytes without apparent cellular atypia. They reported that plantar or palmar premalignant melanosis showed B- and C-phases, and therefore it was considered to be an ALM precursor lesion. There have been few reports on benign melanocytic lesions of the oral mucosa. Buchner and Hansen [26] reported 32 new, and 75 reviewed, cases of oral
pigmented nevi, but their significance as precancerous lesions was not well determined. Lentigo simplex usually involves small (a few millimeters in diameter), round to oval, brown to black macules. Histologically, lentigo simplex reveals elongation of the rete ridges; the basal cell layer is heavily pigmented, and there is an increase in the number of basal cell layer melanocytes. On the other hand, melanotic macules show no increase in melanocytes, but rather an increase in melanin deposition within the basal cell layer and submucosa/ lamina propria of the oral mucosa. Elongation of the rete ridges does not typically occur. Lentigo simplex is sometimes confused with oral melanotic macules. Trodahl and Sprague [27] reported 11 cases that fulfilled the criteria of lentigo simplex, including hyperpigmentation, downward proliferation of rete ridges, and focal proliferation of melanocytes. Watkins et al. [28] described five oral pigmented lesions that were diagnosed as lentigo simplex, but their photomicrograph shows oral melanotic macules rather than lentigo simplex. Shapiro and Zegarelli [29] used the term labial lentigo for lesions that exhibited only hyperpigmentation of the basal cell layer, but without elongation of the rete ridges and without an increase in the number of melanocytes. Whereas some authors use the terms lentigo and oral melanotic macule interchangeably, we are of the opinion that, as in the skin, these are different entities, especially with regard to melanocyte proliferation. The relationship between lentigo simplex and malignant melanoma has not been well documented. In contrast to various studies on cutaneous melanoma precursor lesions mentioned above, there have been few reports relating to premalignant melanosis of oral melanoma. Liversedge [30] reported that patients with oral melanoma frequently had pigmented areas for a long time before melanoma developed, but detailed data was not shown. Grinspan et al. [3], Takagi et al. [4], and Robinson and Hukill [5] stated that oral melanoma probably arises from Hutchinson’s melanotic freckle, but that is not yet proven, as mentioned above. Hicks and Flaitz [17] described that atypical melanocytic hyperplasia, designated for oral mucosal lesions with equivocal histopathologic features, such as hyperchromatic and angulated nuclei with very infrequent mitotic activity, essentially represented an indeterminant premalignant melanocytic lesion similar to that of atypical moles (dysplastic nevus [24]). Dysplastic nevus may share clinicopathological features with melanoma in situ, but it is uncommon among the Japanese and is usually found on nonacral portions of the skin. No malignant melanoma associated with dysplastic nevus syndrome has been found on the palms or soles, where they frequently occur in the Japanese. These findings indicate that dysplastic nevus is probably not the precursor of ALM, including melanoma of the oral mucosa.
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We reported here three patients with premalignant melanocytic dysplasia of the oral mucosa. Two of the three lesions showed two phases of deep brownish black plaque and light brown macular lesions, and were diagnosed as premalignant lesions macroscopically. Histological examinations of the plaque lesions of the former two revealed nest formation of atyipical melanocytes or individually proliferating atypical melanocytes in the lower part of the epithelium. Pagetoid upward migration of individually proliferating melanocytes was found in one case. Peripheral, macular lesions exhibited lentiginous proliferation of dendritic melanocytes without apparent cellular typia, and simple hyperpigmentation in the basal cell layer. These macro- and microscopic findings resemble the B- and C-phases of plantar or palmar premalignant melanosis described by Mishima and Nakanishi [25]. On the other hand, one case of premalignant melanocytic displasia was incorrectly diagnosed as lentigo simplex initially, but malignant melanoma later developed in the lesion. Buchner et al. [31] stated that pigmented melanocytic and nevomelanocytic lesions are important primarily because of their close histogenic relationship to melanoma. In recent years, our knowledge has increased in the area of nevomelanocytic lesions of the oral mucosa [26]. Little is known, however, about pigmented oral lesions that exhibit melanocytic hyperplasia, such as lentigo simplex. The relationship among premalignant melanocytic dysplasia and benign melanocytic lesions such as pigmented nevus or lentigo simplex has not been clarified. Some cases of oral malignant melanomas showed pigmented nevus-like structures in the radial growth phase. However, most oral melanomas seem to arise from lentiginous rather than nevoid lesions. In fact, the histologic features of the peripheral part of premalignant melanocytic dysplasia were similar to those of lentigo simplex or melanotic macules. We could not find any relationsip between benign melanocytic lesions and precursors of oral melanoma because of too small a number of patients. We think that any pigmented lesions which show proliferation of melanocytes should be resected until detailed clinicopathological data is obtained as to the precursors of oral melanoma. We think that oral lesions exhibiting melanocytid hyperplasia represent an interesting, challenging, and confusing range of diagnostic problems and treatment for oral surgeons and pathologists.
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