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Review article
A. W. Barrett and C. Scully
Human oral mucosal Centre for Ihe Study of Oral Disease.
Department of Oral Medicine. Pathology and
Microbiology. Bristol Dental Hospital and

melanocytes: a review School. Bristol. England

B;irictt AW. Scully C: Human oral mucosal melanocytes: a review. J Oral Pathol
Med 1994; 23: 97' 103. c Munksgaard, 1994.
Key words: melanocytes; oral mucosa.
Despite the eomplex role of melanoeytes in skin physiology, the function of oral
mueosal melanocytes has attracted little research interest and remains largely A. W. Barrett. Department of Oral Pathology.
Institute of Dental Surgery, 256. Grays Inn
unclear. This artielercvievvswhat is known about oral mueosal melanocytes and Road. London WC1X 8LD, England
identifies areas of research that may shed further light on their role in oral
biology. Accepted for publication September 17. 1993

Melatioeytes are highly differentiated tnelanoeytes (5 9). They contain a well- of white skinned individuals, the size
cells situated in the basal stratum of developed rough endoplastnie reticu- and melanisation of tnelatiosotnes re-
surface epithelia. They are of neural lum, mitoehondria and Golgi appara- flects the degree of clitiieal pigmenta-
crest origin and are the only cells that tus, suggesting active protein synthesis. tion. Where this is mote pronounced,
synthesise the pigment melanin, which but lack tonofilatnents and destnosomal the tiielanosomes tnay aggregate into
is paekaged in specialised orgaiielles: eotinectiotis to adjacent keratinocytes. large eotnplexes 1-3 |.mi in diameter (8).
melanosomes. The presence of centrioles suggests that Melanosotnes are transferred, via den-
Kpidetmal tnelanoeytes have a eom- OMMC are self-replicating (5). Cellular dritic proeesses of the tnelanocyte, to
plex biology and may be involved in outgrowths spread, but do not break, some of the adjacent keratinocytes. The
many aspects of epithelial physiology; the desmosomes between whieh they precise mechanistn is unknown, but has
for example, they have been shown to permeate. Using histoehemistty. it has been described as "cytoerine secretion"
be responsive to many imtnunologieal been teported that OMMC are ptesent (14).
mediators and are also protective in utiipolar, bipolar or multiple-dendrit-
against tiltraviolet irradiation. ic forms, with tiiarked variation in cell
Histochemistry and distribution of
Tlic role of the tnelanoeytes ptesent size and complexity of dendritie systems
OMMC
within tnticosal epithelia is less clear. (10). Work on epidermal melanoeytes
Oral nnicosal melanocytes [OMMC] has suggested that actin microfilaments The nature of the preeursor cell of mela-
were identified early this ecntury. but ate needed for dendrite extension, and nocytes betweeti the neural erest and
have altradcd .stirprisingly little re- niierotubtiles are needed lor mainte- skin is unknown (15). Melanocytes eati
search interest, presumably because nance of extension. Faetors produced be dcteeted in oral tissues by the third
their role in health and disease has beeti by keratitioeytes may dictate tuelano- month in uienr. then, dendritic cells eon-
unclear. cyte morphology to sotne degree taining melanin are present within the
This paper reviews OMMC and spec- (il 13). buccal tnucosa atid at the base of the
ulates on their possible tole in otal phys- Melanin is present within OMMC. dental latnina (16). Although epidertnal
iology and pathology, mainly extrapo- An ultrastructural study of labial mela- melanoeytes ate tnote nutnerous above
lating from the tesiilts of investigatiotis nocytes in Caucasians suggested that the dertiial papillae than in the rete
on epidertnal melanocytes. they contain only ptetnelanin granules ridges (17). the converse is the case with
(3). whereas iti Caucasian buccal tnela- OMMC (10). BARKHR (18) foutid gingi-
noeytes formed melanin is present (4). val tnelanoeytes to be regularly distrib-
Cytological features of OMMC uted and ptesent at about every 15 basal
Melanin granules are more nutnetous
B l i t K l R iti 1 9 2 7 ( 1 ) r e p o r t e d t h e p t e s - and better melanised in gingiva frotn keratinoeytes. There are anatotmieal
ence of dendritic cells in the basal stra- negroid than from white-skinned indi- variations in distribution of epidermal
tum of oral epithelium, and OMMC viduals, where tnost melanoeytes eoti- tnelanoeytes (19). atid tnacroscopic
were identilleil in gingiva by LAIDI.AW & tain striated, incompletely melanised studies have reported anatotnical varia-
CAHN in 1932 (2). The ultrasttucturc granules 0.3 xO. I ^ttn in size (5). It has tions in oral pigmentation in tiegroes
of OMMC has since been described in beeti postulated that buds from Golgi (20, 21). orientals (22) and Europeans
labial (3). buccal (4) and gingival epithe- vesicles ate responsible for providing (21, 23) (Table I). However, it is un-
lium, whete they are histologically and the framework on whieh the tiielanin known whether thete are consistent
uhiastructuially similar to epidermal granule is built. In gitigival melanoeytes variations in melanocyte distribution
98 BARRETT & SCULLY
Table 1. Analomic distribution of OMMC and melanin in relation to clinical pigmentation and melanocytic lesions of oral mucosa

BM MxG MnG HP SP LM VB KoM Ref

Prevalence of DOPA+ OMMC (%) 74 (1)

62 - - - (28)
Numbers of DOPA + OMMC (/mm-) 562 476 530 _ (10)
_ _ _ _ 1940 - (38)
.- 1/15* - - - - - - (18)
Histological prevalence of melanin (whites) (Vt.) 31
31 _ _ _ (28)
45 21 28 46 25 52 _ - (30)
26 - - - - - - (31)
Prevalence of clinical pigmentation (whites) 5 0 0 0 0 0 0 _ _ (21)
2 4 7 - - - - 1 - (23)
Prevalence of clinical pigmentation (blacks) 40 89' _ 38 26 33 30 _ (20)
38 23" - 8" - 5 53 ~ - (21)
Prevalence of oral nevi 10 9" _ 15" _ 0 65' 0 (40 + )
20 12" 41 3 1 12 13 (41)
Prevalence of oral melanotic macules 16 13 10 7 6 3 9 31 2 (42)
31 36" 14 9 1 - - - (43)
Prevalence of smoker's melanosis 3 II 17 - - - 1 - (23)
Prevalence of oral malignant melanoma 10 33" 26" 10 _ \1- 2 (40)
22" 41 5 _ _ (44)
5 68" 12 _ 8 8'- (45)
10 26 5 47" 2 _ 6' (46)
0 49 11 37 3 () 0 (47)
BM= buccal mucosa; MxG = maxillary gingiva; MnG = mandibular gingiva; HP = hard palate; SP = soft palate; T = tongue; LM = labial
mucosa; VB = vermilion border; KoM = noor of mouth.
• OMMC per basal keratinocyte.
+ also includes non-nevoid macules.
' combined value for maxillary and mandibular gingivae.
" combined value for hard and soft palate.
' not specified whether vermilion border or labial mucosa affected.
" combined value for maxillary gingival and palatal lesions.

within the oral cavity because the meth- OMMC), though most are not specific. samples are positive using both DOPA
ods used in past histological studies of Argentaffinic techniques, for example and Masson-Fontana histochemistry
OMMC have been varied. It is therefore the Masson-Fontana method, rely on (1). Thus, in white-skinned individuals,
necessary to consider the means used to the reducing properties of substrates even when melanin is produced by
identify OMMC when discussing their such as melanin and melanin precursors OMMC, it is insufficient to produce
anatomical distribution. (25). Therefore, inactive OMMC may clinical pigmentation since it has been
The most specific histochemical not stain. In contrast, keratinocytes found that less than IO%i of such indi-
method for labelling melanocytes uti- containing melanosomes will be viduals have clinically apparent buccal
lises 3, 4 dihydroxyphenylalanine detected by these methods. Thus, reduc- pigmentation (21, 23, 24).
(DOPA). a substrate for tyrosinase. tion methods are of no use for specific Melanin is present in 28%) of mandib-
This enzyme is present in all cells which OMMC identification, though they ular (.30) and between 21-26% of maxil-
have the potential to synthesise melanin, have the advantage of working in fixed, lary (30, 31) gingival samples from
though some authors regard only active processed and wax-embedded tissue. white-skinned individuals. These values
OMMC as being DOPA + (10.24). This HANKKI; (28) adopted a different ap- are very different from those found in
view is supported by SCHR()[;DI;R (6), proach by using formaldehyde vapori- gingiva using the DOPA method, where
since DOPA reactivity is weak in sam- sation and fluorescence microscopy a 100%) incidence has been reported (2,
ples of clinically non-pigmented gingi- with which to visualise OMMC. Tri- 10). The latter study found that the
va. In contrast, some melanoeytes ehrome stains have been used to label number of OMMC per mm* ranges
packed with melanin may lack tyrosi- melanin within oral mucosa (26), and from 195 1200 in labial and palatal gin-
nase (25. 26) and hence may be DOPA- gold impregnation and osrnium iodide giva.
negative. A further potential problem have been used in some studies (16). OMMC are only rarely seen in nor-
with DOPA staining lies in the fact that The latter, however, are unpredictable mal gingival crevicular epithelium (18),
Langerhans cells may also bind DOPA methods which may also label Langer- though they appear in regenerating gin-
(27). Only cysteinyl DOPA is specific hans cells and even some keratinocytes gival sulcular epitheliutn (32). Some au-
for melanocytes (28). but fresh or frozen (18, 29). thorities have stated that OMMC are
tissue is necessary for this method of In buccal mucosa, 31 45% of subjects not present in lingual epithelium
staining. are positive for melanin using a Mas- (33-35), but melanin has been detected
Melanin is seen in routinely stained son-Fontana method (28, 30) (Table 1); in 25'M) of samples from the lateral bor-
sections and may be bleached by oxidis- 62% of samples contain fluorescent mel- der of the tongue (30) and extensive,
ing agents (25); other histochemical anocytes if the section is exposed to physiological pigmentation of the dor-
methods label melanin (rather than formaldehyde vapor (28). Some 74'/o of sum of the tongue has been well de-
 Oiitl mucosal melanocytes 99
.scribed (36). In addition, melanotic pig- are also positive immunohistochemical- lor a and p SlOO subunits, but malig-
mentation of the dorsum of the tongue ly for SI00 protein. nant OMMC from primary tumors are
has been reported in response to amino- Melanocytes occasionally cause pig- negative for the P chain, in contrast to
pyrine medication (37). mentation of odontogenic cysts and tu- cutaneous melanomas (63). Metastatic
Despite the fact that only premelanin mors (50, 51). The means by which mel- deposits of oral melanotna had SlOO
granules were observed in labial mela- anocytes become entrapped is un- profiles oftheir own. and dendritic cells
nocytes at the ultrastructural level, mel- known, but tnay be as a result of within sotne malignant melanomas -
anin was detected in 52% of a large incotnplete migration from the neural which were positive for the P subunit
sample of labial mucosal specimens crest. It has been shown, however, that only - lacked melanin granules and mi-
from white-skinned individuals when melanocytes are resident within the totic activity, and were assumed to be
stained with the Masson-Fontana meth- primitive oral epithelium whieh gives Langerhans cells intermingling with tu-
od (30). DOPAH- melanocytes num- rise to the dental latnina (52). Racial mor cells. One study on lingual epitheli-
bered 1700 2100/mtn- in tissue from factors may also be involved, since there um found no dilTerence between num-
the vermilion border, which compared is a predilection for these tumors to af- bers of SI00+ dendritic cells labelled
with a maximum of 950/mm' in skin fect coloured individuals. with either poly- or monoclonal (epitope
from the trunk and 2500/mm- in skin Oral hyperpigmentation secondary to unspecified) antisera, but concluded
from the cheek (19, 38). systetnic endocrine changes, such as that all SI00+ cells were Langerhans
those occurring in pregnancy, Addison's cells on the grounds that DOPA histo-
The histochemical findings appear to
hypoadrenalism and lung disease are chemistry was negative. This may. how-
support conclusions, based on ultra-
presumably due to increased sensitivity ever, have been due to the use of forma-
structural studies, that OMMC arc ind-
of OMMC to circulating horrnones (53, lin-fixed, wax-embedded tissue (35).
eed present in oral mucosa, but that
only a proportion are actively engaged 54). An alternative explanation, that Some antigens present on malignant
melanocyte numbers are increased as a melanomas also label normal melano-
in tnclanin synthesis. This is possibly
result of systetnic hortmonal variations, cytes. For example, K-I-2 antigen
explained by the fact that tyrosinase is
was not conclusively supported by the detected melanocytes in normal skin in
more active at the cooler tetnperaturcs
results of a histochetnical study on epi- some individuals (64). The gp75 anti-
found at the skin surface (39). dermis (55). gen, which is specific for human mela-
Melanocytic lesions of the oral nosomes, was discovered in a patient
mucosa are rare, but it is of interest with malignant melanoma and is also
that the anatomical differences in the Immunohistochemistry of OMMC present in normal, pigmented epidermal
distribution of active OMMC have re- melanocytes (65. 66). An antibody
Although several markers of epidermal
fiected the location of benign melano- termed K^. which is directed against a
tiielanocytes have now been identified,
cytic lesions in some reports (Table 1). ganglioside moiety of hutnan melano-
none of the antigens detected on nortnal
In reviewing all oral melanocytic hyper- mas, also labels normal adult melano-
adult melanocytes are totally specific or
pigmentation, it was found that, exclud- regularly found. The SI00 antigen is by cytes (67). Antibodies to these epitopes
ing the vermilion border, most lesions far the most common marker used. SI00 arc not currently commercially avail-
were located in the keratinised tnucosa protein is a dimer of cither two a subun- able. Antigens specific for the human
of the gingiva and the palate (40). 41% its, two p subunits or one a and one P melanosomes derived from malignant
of oral pigmented iicvi affect the hard subunit (56). Studies on epidermis have melanocytes, but which are not found
palate, and 2()%i are situated in buccal reported variable staining of tnelano- on normal epidermal melanocytes. have
mucosa (41). Excluding the vermilion cytes with anti-SlOO antibodies (57. 58). also been reported (68).
border, the most conimon sites of non- Monoclonal antibodies to the subunits HMB-45. a monoclonal antibody di-
nevoid melanotic macules are the gingi- have shown that some, but not all. epi- rected against a melanocytic cytoplasm-
va and bticcal mucosa (42). In a separate dermal melanocyles are positive for the ic glycoprotein (69). is not expressed by
study, ['AUI; ct at. (43) also reported gin- a and p subunits (59. 60). SI00 staining melanocytes which arc metabolieally in-
giva, buccal mucosa and palate to be is stronger in melanocytes lacking active (70-72). Normal OMMC that
the commonest sites of non-nevoid mac- formed pigment (58). stain positively with HMB-45 have been
ules. Smoking may cause increased mel- In view of the latter observation, it identified in oral squamous cell carcino-
anotic pigmentation of all oral mucosal might be expected that OMMC would ma (73). where it was postulated that
regions (22, 23). be SlOO-t-, since most are inactive. the tumor had released factors chetno-
The pattern of OMMC activity does However, using polyclonal anti-SlOO tactic for OMMC. Anti-HMB-45 anti-
not mirror the incidence of pritiiary otal antisera. lingual and buccal epithelia bodies stain effectively in routinely pro-
malignant melanocytic tumors (Table have been reported as containing no cessed and wax-embedded tissue (71).
I): between 67 8^^ of such malignan- SI00+ cells (61). though SIOO-^ den- MS-44B antigen, also raised against a
cies affect the maxillary gingiva or the dritic cells were identified in gingival melanoma cell line, is present on basally
palate (44-47). This contrasts with skin, epithelium (61). Basal and suprabasal situated dendritic cells in healthy skin
where distribution of epidermal mela- SI00+ cells were also seen, because po- and oral epithelium, which arc also pos-
nocytes does resemble that of melanoma lyclonal antisera also reacted with itive for HMB-45 and K-1-2 (74). Some
Langerhans cells. Monoclonal antibod- MS-44B-positive cells, however, are sit-
DOPA+ melanocytes have also been ies to a and P subunits of SI00 may uated suprabasally. and strong MS-44B
found within the parotid glatid (48) and eliminate this cross-reactivity, since epi- staining, is associated with weak tyrosi-
there arc a few reports of primary mela- dermal Langerhans cells express only nase activity.
nocytic tumors at this site (49). In these the p subunit of SUM) protein (59, 60). Major histocompatibility complex
neoplasms, the cells containing melanin Oral pigmented nevus cells are positive (MHC) class 1 antigens are expressed
100 BARRKTT & Sc ULLY

by normal epidermal melanocytes (75). antigen, as well as staining dendritic is evidence that melanosis attributable to
MHC class I antigens are also expressed cells co-expressing melanoeyte pheno- smoking regresses after cessation of the
on cells in the basal half of gingival types, is also expressed by lymphoid de- habit (97). However, it has been shown
epithelium, but only weakly so on basal ndritic cells which lack Langerhans cell that some carcinogens ean bind melanin,
cells m buccal mucosa (76). MHC class determinants, and by endothelial cells causing speculation that melanomas de-
H antigens, however, are not expressed (74). Such phenotypic diversity raises veloping at anatomical sites not exposed
hy normal adult melanocytes (77), and intriguing questions about the relation- to ultraviolet light might result from the
dendritic cells positive for MS-44B anti- ship of melanocytes with immune cells accumulation of carcinogens in melanin-
gen do not stain with anti-HLADR an- of dendritic morphology. Studies on containing cells (98). Cultured human
tibody (74). MHC class II antigen ex- cultured melanocytes show that melanocytes can catabolisc polycyclic
pression is increased within the basal HLADR is inducible by infiammatory aromatic hydrocarbons to the principal
layer of the epithelium in the presence of mediators such as interferon-y (89), a carcinogenic agents (99). Free radicals
infiammation, but whether expression is cytokine known to modulate other mel- associated with the superoxide anion,
induced on OMMC is not clear (76. 78). anocyte phenotypes (90). Interleukins which is generated as a result of the "re-
Intcgrins function as receptors for ex- (IL)-1 -f. and -6 and tumor necrosis fac- spiratory burst" of phagocytes during
tracellular components such as fibro- tor-ot downregulate melanocyte metabo- bacterial killing, arc scavenged by mcla-
nectin, thus regulating melanocyte at- lism in culture (91), but 1L-1 -a increases nins. Conversely, melanins also continu-
tachment and migration (79). Each re- the number of melanocyte-stimulating ally generate their own free radicals, es-
ceptor consists of two subunits, a and hormone (MSH) receptors, so increas- pecially when they absorb the superoxide
p. Integrins have been identified on cul- ing epidermal pigmentation (92). Sever- ion (100. 101). Potentially lethal, muta-
tured melanocytes, but results in vitro al cytokines released by keratinocytes in gcnic and even carcinogenic hydroxyl
have been inconsistent with those in inflammatory situations upregulate the radicals are produced by melanins when
vivo. Most studies agree that epidermal expression on cultured melanocytes of the scavenging ability of the melanin is
melanocytes express 'z, and P|, but intercellular adhesion molecules exceeded (39). This raises the question of
whereas ZAMBRUNO et al. (80) reported (ICAM) (93), particularly ICAM-1. The whether OMMC have a role in the pro-
that melanocytes are positive for ot,, effects of cytokines on OMMC pheno- tection of the oral mucosa from noxious
using immunohistochemistry, cultured types are unknown. substances potentially involved in oral
melanocytes are not positive (79, 81). mucosal tumors. It remains to be seen
One case of inflammatory oral hyper-
Intraepithelial dendritic cells expressing whether the role of melanin in scaveng-
pigmentation has been investigated with
0(4. 7.,, and PI subunits in normal oral ing free radicals in oral mucosa is limited
a battery of antibodies (94). Pigment
epithelium have been identified, but are by the apparent metabolic inactivity of
containing cells were situated on either
thought to be Langerhans cells (82). OMMC, or whether OMMC adapt to
side of the basement membrane and
environmental changes as they occur.
were positive for HLADR and other
markers which suggested they were
Possible functions of OMMC bone marrow-derived melanophages,
Prospects for the future
There has been little speculation on the rather than OMMC. DOPA histochem-
possible function of OMMC or melanin, istry was not. however, performed, and Human OMMC remain to be definitive-
but oral melanotic macules may develop so the relationship between these anti- ly mapped and this is now possible using
in several situations where there is gen presenting cells and local OMMC conventional histochemistry or using
chronic local stimulation of the oral could not be assessed. immunohistochemistry either with
mucosa. for example in cheek biting It is unclear why abnormal oral mela- monoclonal antibodies to SlOO a subun-
(42), oral lichen planus (83, 84), tobacco notic pigmentation can develop where its, or possibly with HMB-45 antibody.
smoking (22, 23, 85) and non-amalgam levels of circulating MSH remain un- //) .stftt hybridisation using recombinant
dental restorations (86). as well as in changed. However, one plausible expla- DNA fragments of human tyrosinase is
some leukoplakias (42). Hyperpigmen- nation lies in the finding of MSH pep- also now possible (102).
tation has also been observed in patients tides in oral mucosa. Using monoclonal OMMC have not yet been cultured,
with human immunodeficiency virus in- antibodies in clinically healthy attached but epidermal melanocytes can be cul-
fection (87, 88), due to the presence of gingiva, it has been shown that y-MSH tured since EISINGHR ct al. (103) devised
melanosomes in superficial keratino- is present not only in isolated neutrophil a technique using media containing
cytes and higher numbers of subepith- granulocytcs in the lamina propria adja- phorbol esters, which favour melano-
elial melanophages (9). It has been sug- cent to oral epithelium, but also in nerve cyte growth at the expense of keratino-
gested that the term "melanotic maculc" fibres (95). At sites of inflammation, cytes. Melanocyte culture has subse-
be used when the etiology is unclear and clusters of MSH+ granulocytes can be quently been refined using other selec-
be reserved for lesions where there is seen (96). Hence, OMMC may be stim- tive media (13, 104). There appears to
evident clinical pigmentation. The term ulated by local MSH in infiammatory be no reason why OMMC should not
"focal melanosis" is applied where ex- situations where there is infiltration of now be cultured.
cessive melanin production is an inci- MSH + neutrophils.
dental histopathological finding in elini- It is also feasible that OMMC have a
cally non-pigmented lesions (42). It is role in oral carcinogenesis. It has been References
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