A Review of the Aetiopathogenesis and Clinical and

Review ArticleA Review of the Aetiopathogenesis and Clinical andHistopathological Features of Oral Mucosal Melanoma

Liviu Feller Razia A G Khammissa and Johan Lemmer

Department of Periodontology and OralMedicine SefakoMakgatho Health Sciences University Medunsa Pretoria 0204 South Africa

Correspondence should be addressed to Liviu Feller liviufellersmuacza

Received 6 January 2017 Accepted 20 April 2017 Published 30 May 2017

Academic Editor Stefania Staibano

Copyright copy 2017 Liviu Feller et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Oral mucosal melanoma is an uncommon usually heavily melanin-pigmented but occasionally amelanotic aggressive tumourwith a poor prognosis Despite radical surgery radiotherapy or chemotherapy local recurrence and distant metastasis arefrequent Microscopical examination is essential for diagnosis and routine histological staining must be supplemented byimmunohistochemical studies The aetiology is unknown the pathogenesis is poorly understood and the 5-year survival raterarely exceeds 30 In most cases oral mucosal melanoma arises from epithelial melanocytes in the basal layer of the epitheliumand less frequently from immature melanocytes arrested in the lamina propria In both cases the melanocytes undergo malignanttransformation invade deeper tissues andmetastasize to regional lymph nodes and to distant sites Very rarelymetastasis from skinmelanomamay give rise to oral mucosal melanoma that may bemistaken for primary oral mucosal melanomaThe pathogenesis oforal mucosal melanoma is complex involving multiple interactions between cytogenetic factors including dysregulation of the cKitsignalling pathways cell cycle apoptosis and cell-to-cell interactions on the one hand and melanin itself melanin intermediatesand local microenvironmental agents regulating melanogenesis on the other hand The detailed mechanisms that initiate themalignant transformation of oral melanocytes and thereafter sustain and promote the process of melanomagenesis are unknown

1 Introduction

Oral mucosal melanoma is a rare and ultimately fatal canceroriginating frommalignant transformation and clonal expan-sion of neural crest-derivedmelanocytes residing either in thebasal cell layer of the oral epithelium or in the lamina propriaof the oral mucosaThe five-year survival rate seldom exceeds32 [1ndash3]

Oral mucosal melanoma constitutes about 25 of allmucosal melanomas of the head and neck [4 5] about 2 ofall mucocutaneous melanomas [6] and about 05 of all oralmalignancies [1 7] It is more prevalent in Japanese Africanand American indigenous populations than in Whites [3 78]

According to various publications between 2 and 40of all oral mucosal melanomas are amelanotic Although theclinical and epidemiological features of melanotic and ame-lanotic melanoma are similar the prognosis of subjects withamelanoticmucosalmelanoma seems to be poorer than those

with melanotic melanomas probably because owing to theabsence of pigment the diagnosis of the former is moredifficult thus delaying the commencement of treatment [9]

The aetiology of oral mucosal melanoma is unknownthere is no evidence that repetitive trauma chronic inflam-mation human papilloma virus (HPV) infection or tobaccosmoking plays any role in its pathogenesis The only knownrisk factor is the preexistence of a mucosal field of melaninhyperpigmentation [7]

Although the prognosis for oral mucosal melanoma isnever good indicators of a dire prognosis for establishedmelanoma include a tumour thickness of greater than 6mmmetastatic involvement of cervical lymph nodes presence ofdistant metastases and the presence of exophytic ulceratedlesions and a high tumour cell mitotic rate [1 7]

As oral mucosal melanoma is a complex and relativelyrare malignancy and as most data are derived mainly fromretrospective studies and from series of reports of small num-bers of cases each using different clinical staging systems

Hindawie Scientific World JournalVolume 2017 Article ID 9189812 7 pageshttpsdoiorg10115520179189812

2 The Scientific World Journal

the evidence-based information about risk and aetiologicalfactors genetic factors associated with the initiation and pro-gression of the disease and prognostic factors and outcomesof different treatment modalities is scarce Hopefully thispaper may shed light on various aspects of oral mucosalmelanoma

2 Oral Mucosal Melanoma Precursor Cells

Most primary oral mucosal melanomas arise from melano-cytes in the basal cell layer of the oral epithelium but somefrom immature melanocytes residing in the lamina propriaof the oral mucosa

Oralmelanocytes are derived fromneural crest stempro-genitor cells most of which during embryogenesis migrate totheir final destination in the basal cell layer of the oral epi-thelium The migration of precursor melanocytes and theirdifferentiation into mature melanin-producing or amelan-otic melanocytes are mediated by a number of biologicalagents and intracellular signalling pathways including stemcell factor (SCF) and its tyrosine kinase receptor cKit sig-nalling pathway endothelins 1 and 3 hepatocyte growthfactor and basic fibroblast growth factor [10] However forreasons unknown in their pathway of migration towardsthe oral epithelium some immature melanocytes becomearrested in the lamina propria [11]

The functions of oral melanocytes are not well under-stood they produce melanin which contributes to the colourof the oralmucosa provides protection from stressors such asreactive oxygen species and free radicals and has the capacityto sequester metal ions and bind organic molecules [10]Apart from their role in melanin biosynthesis melanocytescan act as immunocytes producing cytokines thus having thecapacity to modulate immunoinflammatory responses andas neuroendocrine cells secreting melanocortins opioidscatecholamines and acetylcholine into the local microenvi-ronment These functions of oral melanocytes all contributeto the homeostasis of the oral tissues [10 12]

Signals from neighbouring keratinocytes biologicalagents released from intramucosal nerve sensory endingsmesenchymal-epithelial interactions and autocrine signalsall together play a role in regulating the functional activity oforal melanocytes [11]

Although the population of oral melanocytes appears toremainmore or less constant throughout life themechanismsfor their replacement in the basal cell layer of the epitheliumafter loss to physiological processes of apoptosis or tomechanical thermal or chemical injury are not well under-stoodThis replacementmay be either the result of division ofldquomaturerdquomelanocytes in the basal cell layer of the oral epithe-lium which still retain the capacity to replicate or the resultof migration of melanocyte stemprogenitor cells from localmicroenvironmental niche reservoirs However niche reser-voirs of tissue-specific stemprogenitor cells containing thegenetic information and the regenerative capacity of oralmelanocytes have not as yet been identified [13]

The origin of the melanoma precursor cell is open todebate but it is most probably a tissue-specific stemprogeni-tor melanocyte that over time has acquired cytogenetic and

epigenetic alterations and has ultimately undergone malig-nant transformation Melanoma stemprogenitor cells likenormal melanocyte progenitor cells maintain their undif-ferentiated phenotypes and their capacity for self-renewalAlternatively it is also possible that melanoma precursorcells either in the basal cell layer of the epithelium or in thelamina propria of the oral mucosa are derived from mel-anocytes having undergone a process of dedifferentiationsubsequently to cytogenetic alterations acquiring a mela-noma stemprogenitor cell phenotype These melanomastemprogenitor cells are the driving force behind the ongo-ing growth of the primary tumour and behind the establish-ment of distant metastases Their replication provides newmelanoma transient-amplifying cells that have a high prolif-erative rate and promote tumour growth [14 15]

3 The Pathogenesis of OralMucosal Melanoma

Oral mucosal melanomagenesis is not associated with anyknown carcinogenic agents [16] Only some of the intracellu-lar molecular signalling pathways that drive the complex pro-cess of mucosal melanomagenesis have been identified How-ever it is probable that dysregulation of cell cycle progressionapoptosis cell-to-cell interactions cKit signalling pathwaysmelanocortin receptor 1 (MC1R) polymorphism melaninitself and products ofmelanin biosynthesis are all risk factors(Figure 1) Biological agents in the microenvironment whichunder physiological conditions regulate the proliferationdifferentiation and function of local melanocytes also appearto play a role in the process of oral melanomagenesis [14]

The activation of the receptor tyrosine kinase (RTK) cKitby its ligand the stem cell factor (SCF) induces intracellularsignalling pathways which are critical tomelanocyte develop-ment andmigration during embryogenesis and later postde-velopmentally to the regulation of melanocyte proliferationdifferentiation and survival as well as for mediation of mela-nin biosynthesis [16ndash18] cKit is a product ofKIT protoonco-genes is a transmembrane glycoprotein and is expressed bya variety of cells including melanocyte precursors haemato-poietic progenitor cells and mast cells [19 20] The RTKcKit downstream intracellular signalling pathways includethe PI3K (phosphoinositide 31015840-kinase) pathway the JanusKinases (JAKs)Signal Transduction and Activator of Tran-scription (STAT) pathway and theRas-Raf-MAPK (p38 ERK12 JNK) pathways [21]

Up to 40 of mucosal melanoma cells either overexpressthe cKit protein or express gain-of-functionmutations inKITprotooncogenes or both These molecular alterations maysubsequently activate the Ras-Raf-MAPK transduction path-way resulting in increased proliferation and survival of mela-noma cells [19 22 23] (Figure 1) Oral mucosal melanomacells however show only infrequent mutations in either theNRAS or the BRAF molecular pathways that are common inmelanoma of sun-exposed skin [14 23]

In oral mucosal melanoma the dysregulated increasedactivation of cKit signalling pathways is not owing to upregu-lation of autocrine secretion of the cKit ligand SCF but ratherto ligand-independent constitutive activation of cKit receptor

The Scientific World Journal 3

Melanomagenesis

MC1R polymorphism

(i) Compromised DNA repair mechanisms(ii) Promotion of biosynthesis of toxic

melanin particles(iii) Increased proliferation and survival

of melanocytes

Gain-of-function mutations inKIT protooncogene

Dysregulated cKit intracellular signallingpathways

(i) PI3K pathway(ii) JAKSTAT pathway(iii) Ras-Raf-MAPK pathway

Increased melanocyte proliferation andsurvival

Altered expression of cell adhesion molecules

(i) Downregulation of E-cadherin(ii) Upregulation of N-cadherin

Loss of integrity of melanosomalmembrane with leakage of toxicmelanin particles

Products of melanin biosynthesis

(i) Reactive oxygen species(ii) Intermediates of melanin biosynthesis

such as quinones and semiquinones

Melanin itself(i) Fields of benign melanin hyperpigmentation(ii) Toxic melanin particles

Figure 1 Mechanisms of melanomagenesis of oral mucosal melanoma

tyrosine kinase secondary to gain-of-function mutations ofthe KIT protooncogene [17] This results in receptor auto-phosphorylation with the activation of the downstream Ras-Raf-MAPK signalling pathways [20]

Many mucosal melanoma cells overexpress the cKit pro-tein but only in some of these cells does activatingmutation ofthe KIT oncogene occur and some oral mucosal melanomasthat express KIT mutations do not in fact overexpress theencoded protein This is probably because overexpression ofcKit protein can also be induced by autocrineparacrine stim-ulation increased copy number of the KIT gene and epige-netic factors [17 24] Some of the activatingmutations encodenonfunctional rather than functional proteins and thesenonfunctional proteins account for the overexpression of cKitreceptor and not all gain-of-functionmutations result in dys-regulated increased melanocyte proliferation and survivalThus the biopathological significance of cKit overexpressionor of activating mutations of the KIT oncogene in oral muco-sal melanomagenesis has not been fully determined [17 18]and it is very likely that other factors must interact with thedysregulated cKit-induced signalling pathways for the cKit toexert an oncogenic effect [21 24]

Melanocortin 1 receptor (MC1R) plays a role in melaninbiosynthesis Its activation by proopiomelanocortin (POMC)and its derivates particularly 120572-melanocyte stimulating hor-mone (120572MSH)mediates the production of both brownblackeumelanin and yellowred pheomelanin MC1R inducedintracellular signalling pathways in melanocytes can alsomediate immunoinflammatory responses in the microenvi-ronment regulate proliferation and survival of melanocytesand promote DNA repair of damaged DNA caused byoxidative stresses [10]

TheMC1R gene is highly polymorphic with some geneticvariants associated with reduced capacity for DNA repair orfor apoptosis and with the generation of oxidative stress sec-ondary to dysregulated melanin production Thus melano-cytes with certain MC1R variants may be at increased risk ofmalignant transformation [25]

Altered expression of the cadherin cell adhesion mole-cules has also been implicated in the pathogenesis of oralmucosal melanoma In melanoma cells there is abnormaldownregulation of expression of E-cadherin molecules andupregulation of expression of N-cadherin molecules thatprobably contribute to the increased proliferation migrationand invasive potential of melanoma cells [26]

As outlined above melanin itself provides protectionagainst reactive oxygen species and toxic free radicals buton the other hand the process of melanin biosynthesis itselfparticularly that of pheomelanin has the capacity to generatereactive oxygen species that may cause DNA damage andintermediates of melanin biosynthesis such as quinones andsemiquinones are potentially mutagenic and as such can pro-mote cytogenetic instability Therefore loss of the integrityof melanosome membranes with leakage of toxic melaninparticles intermediates ofmelanogenesis and reactive oxygenspecies into the cytoplasm and nucleoplasm of melanocytesmay render these melanocytes prone to an increased risk ofDNA damage and consequently to malignant transformation(Figure 1) [10]

As about 30 of all cases of oral mucosal melanoma arisewithin fields of benign or physiological melanin hyperpig-mentation it is reasonable to assume that the dysregulationof melanin biosynthesis by hyperactive melanocytes and theincreased cytoplasmic and nucleoplastic content of melanin


and byproducts of melanin synthesis may play roles in theinitial transformation of epithelial melanocytes [14 27ndash29]

With regard to oral mucosal melanomas which arise denovo most of them are densely to very densely melanin-pigmented but it is not knownwhether the increased produc-tion of melanin is an early biopathological event in melano-magenesis or whether it is a late biopathological event asso-ciated with acquisition of a malignant phenotype by the pro-liferating atypical initially transformed melanocytes In anycase melanin itself seems to be a risk factor for melanomage-nesis

4 Clinical Features

Clinically the lesions of early oral mucosal melanoma areusually painless irregularly shaped brown to black maculesor papules which may progressively enlarge growing intonodules or exophytic masses and gradually becoming moredeeply pigmented Advanced lesions may be painful ulcer-ated and fragile and may bleed readily The pigmentation isusually nonuniform with mottled shades of grey dark bluedark brown or black [6 30] Sometimes multiple indepen-dent melanomas may arise within a limited field of restrictedoral epithelium harbouring atypical melanocytes that haveundergone malignant transformation [14 30] It appears thatthere is a higher risk of regional metastasis from exophyticulcerated than frommaculopapular oral mucosal melanomas[9]

Oral mucosal melanoma usually develops de novo inclinically normal-looking mucosa but it has been reportedthat in up to one-third of cases it arises from within areas ofbenign oral melanotic hyperpigmentation of the oral mucosa[6] It most commonly (about 80) affects the palate and themaxillary gingiva followed by the retromolar region and thebuccal mucosa It affects males and females in their 5th to7th decades of life equally though some studies have shown aslightly highermale prevalence [1 2 8 9] A list of differentialdiagnoses of oral mucosal melanoma is given in Table 1

About 25 of subjects with oral mucosal melanomaalready have regional lymph node metastases at the time ofdiagnosis and about 10 have distant haematogenous dis-semination to the lung liver bone or brain [9 14]

5 Histopathological Features

Oral mucosal melanoma can be classified into three micro-scopic patterns in situ invasive and combined The tumourusually starts with radial proliferation of atypicalmelanocytesin the basal cell layer of the epithelium This is followed bya phase of vertical growth of invasive nodular aggregates ofatypical melanocytes in the lamina propria In a combinedlesion the radial in situ and the vertical invasive nodularpatterns of malignant proliferation can be observed ab initio[1] However if a melanoma arises from an atypical immaturemelanocyte or melanocytes residing in the lamina propriait will initially proliferate forming nodular aggregates in thelamina propriasubmucosa before invading more widely andmetastasizing [1 7 14]

Table 1 Differential diagnoses of mucosal melanoma [1 6 8]

(1) Oral mucosal melanin hyperpigmentation(i) Physiological (racial)(ii) Melanotic maculae(iii) Melanoacanthoma(iv) Melanotic nevus(v) Tobacco-induced(vi) Drug-induced(vii) Inflammation related(viii) Associated with syndromes or systemic disease

(Peutz-Jegher syndrome McCune-Albright syndromeLaugier-Hunziker syndrome Addison diseaseneurofibromatosis)

(2) Angioproliferative disorders(i) Haemangioma(ii) Vascular malformations(iii) Kaposi sarcoma

(3) Extrinsic pigment(i) Amalgam tattoo(ii) Recreational tattoo

(4) Benign inflammatory reactive neoplastic growths that shouldbe differentiated from amelanotic melanoma

(i) Pyogenic granuloma(ii) Fibrous hyperplasia(iii) Peripheral giant cell granuloma

Melanoma cells may be polyhedral round fusiformepithelioid spindle-shaped or pleomorphicTheir size variesand their nuclei contain one or more eosinophilic nucleolimitotic activity is a prominent feature Proliferating mela-noma cells form either solid loosely cohesive pseudoalve-olar or organoid patterns [9] In about two-thirds of casesvariable amounts of melanin can be detected either in thetumour cells in macrophages or as free extracellular parti-cles In some cases the amount and density of the pigment areenough to obscure the morphology of the tumour cells [14]Those melanoma cells without melanin are referred to asbeing amelanotic

Oral mucosal melanoma cells express the melanocyticmarkers MART-1Melan-A HMB-45 MITF tyrosinase andS-100 protein to varying degrees These markers can bedetected immunohistochemically However as their sensitiv-ity and specificity are not absolute no single marker shouldbe relied upon but a battery of tests should be undertaken inattempting to confirm a diagnosis of a suspected oralmucosalmelanoma [9]

6 Staging and Principles of Treatment

Once a diagnosis of oral mucosal melanoma has been madecomprehensive clinical and special investigations must bedone to determine whether the oral melanoma is primary ormetastatic and if primary the extent of local invasion and


Table 2 American Joint Committee on Cancer (AJCC) TNM staging of mucosal melanoma [1ndash3 35]

T primary tumour N regional lymph node M distant metastasis

T3 mucosal disease NX regional lymph nodesthat cannot be assessed MO no distant metastasis

T4a moderately advanced disease involvingdeep soft tissues bone and overlying skin

NO no regional lymphnode metastasis

M1 distant metastasispresent

T4b very advanced disease involving braindura skull base lower cranial nerves (IX XXI and XII) masticator space paravertebralspace or mediastinal structures

N1 regional lymph nodemetastasis present

Different clinical stages of oral mucosal melanoma

Stage T N M

Stage III T3 NO MO

Stage IVa T4a NO MOor T3-T4a N1 MO

Stage IVb T4 Any N MO

Stage IVc Any T Any N M1

whether or not there is spread to regional lymph nodes or todistant sites [1 9]

The most commonly used system of classification forstaging of mucosal melanoma of the head and neck is themelanoma staging system of the American Joint Committeeon Cancer (AJCC) (Table 2) In this TNM (tumourlymphnodemetastases) staging system owing to the aggressivehistopathological behaviour of oral mucosal melanoma thelowest T (tumour) category is T3 which is associated withclinical stage III (Table 2) Oral mucosal melanoma in situ isregarded as being already a T3 and should thus be treated asan invasive melanoma [1 2 9]

It appears that the tumour clinical stages according tothe AJCC correlate well with observed prognosis and providepredictive information about survival rates [1 9 31] Forstages IIIIVa complete surgical resection with tumour-freemargins of 1-2 cm is the mainstay of treatment Unfortu-nately more than 50 of surgically treated subjects eventhough their resectionmarginswere apparently clear developdistant metastases relatively soon after surgery and dieRealistically however although surgical intervention does notsubstantially increase the overall survival rate it remainsthe first line of treatment and even in cases of postsurgicalrecurrent local disease without distant metastases furtherresection is the best option [1 9]

Although melanoma cells have long been considered tobe resistant to radiotherapy new modalities of radiotherapyappear to be more effective so that postsurgery adjuvantradiotherapy improves control of local disease Unfortu-nately this does not translate into improvement of overallsurvival rates [2 3 9] probably because distant spread ofprimary oral melanoma cells with a metastatic genotypeoccurs early in the course of the disease

Radiotherapy alone should be reserved for palliation ofprimary and recurrent oral mucosal melanomas that arebeyond surgical treatment [9] No evidence-based data show

that any cytotoxic agents andor biological immunomodu-latory agents are effective in the treatment of oral mucosalmelanoma However for lack of any better treatment theseagents have been used in the management of subjects withdisseminated (stage IVb) or with advance recurrent diseaseas a palliative measure [1ndash3 9]

In addition for those oral mucosal melanoma cells withKIT activating mutations treatment with cKit inhibitorswhich target the cKit intracellular signalling pathway may bebeneficial [32] However as in mucosal melanoma activatingmutations of theKIT oncogene can occur at each of the genersquosseveral exons [20 33] target therapy may be successful onlyif the targeted molecules of the molecularly altered receptorprotein are expressed by tumour cells Furthermore thegene mutations that bring about the molecular amino-acidsequences cannot always be targeted by the drug [34] Infact subjects with oral mucosal melanoma with tumour cellswhich stained positively for cKit protein but without KITgain-of-functionmutations do not respond to treatment withcKit inhibitors [19]

The lack of a significant response of oral mucosal mela-noma to targeted molecular therapy is probably because thepathogenesis of the disease involves concurrent interactionsbetween several molecular pathways and that several onco-genic events are required for the development of occultdisease Therefore targeting a single molecule of one specificdysregulated oncogenic pathway is not sufficient to bringabout beneficial effects [23]

Neck dissection is necessary in any case of lymph nodeinvolvement by metastatic oral melanoma and as about 50of cases where there were no regional metastasis at the timeof diagnosis eventually develop nodal disease initial electivedissection of the neck is recommended in most cases [1 9]Although there are no evidence-based guidelines availableand despite the fact that radiotherapy is not effective in thetreatment of oral mucosal melanoma subjects with extensive


nodal metastasis are not infrequently given radiotherapy inthe hope of reducing distant dissemination [9]

7 Distant Metastasis of Oral MucosalMelanoma and Melanoma Metastasis tothe Mouth

In general the genetic profile that imparts to certain cancercells in a primary tumour the capacity to metastasize may beexpressed early in the process of cancerization or may beacquired only later in the course of growth of the primary can-cer secondary to evolution of multiple subclones of cells thathave undergone many additional episodes of cytogenetic andepigenetic alterations [36] Regardless of whether they leavethe primary tumour at an early or at a late stage of its growthoralmucosalmelanoma cells almost invariablymetastasize todistant sites by haematogenous spread [36]

Primary cancer cells with a metastatic genotype whichdisseminate early often remain dormant in their new loca-tion for variable periods The dormant metastatic cells willbecome active only if a favourable local microenvironmentalniche develops [36] The development of such a favourablemetastatic niche is mediated by biological agents secreted bythe primary cancer-associated stroma cells that accompanythe metastatic cells by haematopoietic progenitor cells byendothelial progenitor cells and by fibronectin [37]

Very rarely oral mucosal melanoma is not a primarymelanoma but is metastatic from a distant site Clinically itis impossible to distinguish between primary and metastaticoral mucosal melanoma but it has been reported thatmetastatic oral melanoma if it occurs affects the floor of themouth and the tongue which are seldom affected by primaryoral mucosal melanoma [38 39]

It has been suggested that in metastatic melanoma therewill be proliferation of metastatic melanoma cells in the lam-ina propriasubmucosa without any epitheliallamina pro-prial junctional activity or invasion of the epithelium whileprimary melanoma will always show junctional activity [38]However this is not true as metastatic melanoma cells canshow junctional activity [6] and primary melanoma cellsoriginating from immature melanocytes residing in the lam-ina propria may proliferate and invade deeply without any-thing resembling intraepithelial or junctional activity [14] Tofurther complicate matters if in a subject with cutaneousmelanoma oral mucosal melanoma was subsequently todevelop it might be assumed that this must be metastaticfrom the cutaneous melanoma but it may well be an inde-pendent second primary tumour Only genetic molecularinvestigation can solve this uncertainty but the issue isacademic rather than practical

8 Conclusion

Owing to the rarity of oral mucosal melanoma there islittle evidence-based information about its pathogenesis andits treatment though there is overwhelming evidence thatdespite any treatment the outcome is invariably fatal

It is clear that susceptibility to oral mucosal melanomais a polygenetic trait with genetic variants of MC1R geneand gain-of-function mutations of the KIT receptor tyro-sine kinase playing important roles and melanin itself andbyproducts ofmelanin biosynthesis all contribute to the over-all carcinogenic effect It seems that the extrinsic risk factorswidely known to be associated with carcinogenesis have littlecapacity to modify the process of melanomagenesis

Abbreviations

SCF Stem cell factorMC1R Melanocortin receptor 1JAK Janus Kinase120572MSH 120572-Melanocyte stimulating hormoneSTAT Signal Transduction and Activator of

TranscriptionTNM Tumourlymph nodemetastasesRTK Receptor tyrosine kinasePI3K Phosphoinositide 31015840-kinasePOMC ProopiomelanocortinAJCC American Joint Committee on Cancer

Disclosure

This research did not receive any specific grant from fundingagencies in the public commercial or nonprofit sectors

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

References

[1] I Chatzistefanou A Kolokythas K Vahtsevanos and K Anto-niades ldquoPrimary mucosal melanoma of the oral cavity currenttherapy and future directionsrdquoOral Surgery OralMedicine OralPathology and Oral Radiology vol 122 no 1 pp 17ndash27 2016

[2] O Breik F Sim T Wong A Nastri T A Iseli and D Wiesen-feld ldquoSurvival outcomes of mucosal melanoma in the head andneck case series and review of current treatment guidelinesrdquoJournal ofOral andMaxillofacial Surgery vol 74 no 9 pp 1859ndash1871 2016

[3] F K Bakkal A Basman Y Kizil et al ldquoMucosal melanomaof the head and neck recurrence characteristics and survivaloutcomesrdquo Oral Surgery Oral Medicine Oral Pathology andOral Radiology vol 120 no 5 pp 575ndash580 2015

[4] D G Pfister K Ang D M Brizel et al ldquoMucosal Melanomaof the Head and Neckrdquo Journal of the National ComprehensiveCancer Network vol 10 no 3 pp 320ndash338 2012

[5] L A Kottschade T E Grotz and R S Dronca ldquoRare presenta-tions of primary melanoma and special populations a system-atic reviewrdquo American Journal of Clinical Oncology vol 37 no6 pp 635ndash641 2014

[6] F Femiano A Lanza C Buonaiuto F Gombos F D Spiritoand N Cirillo ldquoOral malignant melanoma a review of the liter-aturerdquo Journal of Oral Pathology and Medicine vol 37 no 7 pp383ndash388 2008


[7] M Mohan V Y Sukhadia D Pai and S Bhat ldquoOral malignantmelanoma systematic review of literature and report of twocasesrdquo Oral Surgery Oral Medicine Oral Pathology and OralRadiology vol 116 no 4 pp e247ndashe254 2013

[8] M H Smith I Bhattacharyya D M Cohen et al ldquoMelanomaof the oral cavity an analysis of 46 new cases with emphasison clinical and histopathologic characteristicsrdquo Head and NeckPathology vol 10 no 3 pp 298ndash305 2016

[9] F Lopez J P Rodrigo A Cardesa et al ldquoUpdate on primaryhead and neck mucosal melanomardquoHead and Neck vol 38 no1 pp 147ndash155 2016

[10] L Feller A Masilana R A G Khammissa M Altini Y Jadwatand J Lemmer ldquoMelanin the biophysiology of oralmelanocytesand physiological oral pigmentationrdquo Head and Face Medicinevol 10 no 1 p 8 2014

[11] L Feller R Chandran B Kramer R A G Khammissa MAltini and J Lemmer ldquoMelanocyte biology and function withreference to oral melanin hyperpigmentation in HIV-seroposi-tive subjectsrdquo AIDS Research and Human Retroviruses vol 30no 9 pp 837ndash843 2014

[12] R Chandran R A G Khammissa J Lemmer and L FellerldquoHIV-associated oral melanin hyperpigmentationrdquo Journal ofthe South African Dental Association vol 69 no 8 pp 370-3712014

[13] A Masilana R A G Khammissa J Lemmer and L FellerldquoOral medicine case book 66 Physiologicalracial oral melaninhyperpigmentationrdquo Journal of the South African Dental Associ-ation vol 70 no 1 pp 28ndash31 2015

[14] M M Tlholoe R A G Khammissa M Bouckaert M AltiniJ Lemmer and L Feller ldquoOral mucosal melanoma somepathobiological considerations and an illustrative report of acaserdquo Head and Neck Pathology vol 9 no 1 pp 127ndash134 2015

[15] L Feller M Bouckaert U M Chikte et al ldquoA short accountof cancermdashspecifically in relation to squamous cell carcinomardquoJournal of the South AfricanDental Association vol 65 no 7 pp322ndash324 2010

[16] J M Grichnik A R Rhodes and A J Sober ldquoBeign neoplasiasand hyperplasias of melanocytesrdquo in in Fitzpatrickrsquos Dermatol-ogy in General Medicine A M Sydor and R Pancotti Eds vol2 pp 1377ndash1416 The McGraw-Hill Companies Inc 2016

[17] C A Torres-Cabala W-L Wang J Trent et al ldquoCorrelationbetween KIT expression and KIT mutation in melanoma astudy of 173 cases with emphasis on the acral-lentiginousmucosal typerdquoModern Pathology vol 22 no 11 pp 1446ndash14562009

[18] R M White and L I Zon ldquoMelanocytes in developmentregeneration and cancerrdquo Cell Stem Cell vol 3 no 3 pp 242ndash252 2008

[19] G Papaspyrou C Garbe D Schadendorf J A Werner AHauschild and F Egberts ldquoMucosalmelanomas of the head andneck New aspects of the clinical outcomemolecular pathologyand treatmentwith c-kit inhibitorsrdquoMelanomaResearch vol 21no 6 pp 475ndash482 2011

[20] M C Heinrich C D Blanke B J Druker and C L CorlessldquoInhibition of KIT tyrosine kinase activity a novel molecularapproach to the treatment of KIT-positive malignanciesrdquo Jour-nal of Clinical Oncology vol 20 no 6 pp 1692ndash1703 2002

[21] J A Curtin K Busam D Pinkel and B C Bastian ldquoSomaticactivation of KIT in distinct subtypes of melanomardquo Journal ofClinical Oncology vol 24 no 26 pp 4340ndash4346 2006

[22] N Seetharamu P A Ott and A C Pavlick ldquoMucosal melano-mas a case-based review of the literaturerdquo Oncologist vol 15no 7 pp 772ndash781 2010

[23] R R Buery C H Siar N Katase et al ldquoNRAS and BRAFmuta-tion frequency in primary oral mucosal melanomardquo OncologyReports vol 26 no 4 pp 783ndash787 2011

[24] R S Rivera H Nagatsuka M Gunduz et al ldquoC-kit proteinexpression correlated with activating mutations in KIT gene inoral mucosal melanomardquo Virchows Archiv vol 452 no 1 pp27ndash32 2008

[25] L Feller R A G Khammissa B Kramer M Altini and J Lem-mer ldquoBasal cell carcinoma squamous cell carcinoma andmela-noma of the head and facerdquoHead and FaceMedicine vol 12 no1 p 11 2016

[26] B Bandarchi CA Jabbari AVedadi andRNavab ldquoMolecularbiology of normal melanocytes and melanoma cellsrdquo Journal ofClinical Pathology vol 66 no 8 pp 644ndash648 2013

[27] P Garzino-Demo M Fasolis G M L T Maggiore M Paganoand S Berrone ldquoOral mucosal melanoma a series of casereportsrdquo Journal of Cranio-Maxillofacial Surgery vol 32 no 4pp 251ndash257 2004

[28] M A Kahn D R Weathers and J G Hoffman ldquoTransforma-tion of a benign oral pigmentation to primary oral melanomardquoOral Surgery OralMedicine Oral Pathology Oral Radiology andEndodontology vol 100 no 4 pp 454ndash459 2005

[29] Z-Y Shen W Liu Z-X Bao Z-T Zhou and L-Z WangldquoOralmelanoticmacule and primary oralmalignantmelanomaepidemiology location involved and clinical implicationsrdquoOralSurgery Oral Medicine Oral Pathology Oral Radiology andEndodontology vol 112 no 1 pp e21ndashe25 2011

[30] L Feller J NMasipa N HWood R A Khamissa RMeyerovand J Lemmer ldquoPrimary oral melanoma associated with HIVinfectionrdquo Journal of the South African Dental Association vol63 no 1 pp 016-017 2008

[31] K Luna-Ortiz M Aguilar-Romero V Villavicencio-Valencia etal ldquoComparative study between two different staging systems(AJCC TNM VS BALLANTYNErsquoS) for mucosal melanomas oftheHeadampNeckrdquoMedicinaOral PatologiaOral y Cirugia Bucalvol 21 no 4 pp e425ndashe430 2016

[32] K Tomic GMihajlovic S Jankovic NDjonovic N Jovanovic-Mihajlovic and V Diligenski ldquoPrimary mucosal melanomasa comprehensive reviewrdquo International Journal of Clinical andExperimental Pathology vol 5 no 8 pp 739ndash753 2012

[33] C-Y Kim D W Kim K Kim J Curry C Torres-Cabala andS Patel ldquoGNAQmutation in a patient with metastatic mucosalmelanomardquo BMC Cancer vol 14 no 1 p 516 2014

[34] S Ugurel R Hildenbrand A Zimpfer et al ldquoLack of clinicalefficacy of imatinib in metastatic melanomardquo British Journal ofCancer vol 92 no 8 pp 1398ndash1405 2005

[35] X Wang H-M Wu G-X Ren J Tang and W Guo ldquoPrimaryoral mucosal melanoma advocate a wait-and-see policy in theclinically no patientrdquo Journal of Oral and Maxillofacial Surgeryvol 70 no 5 pp 1192ndash1198 2012

[36] L Feller and J Lemmer ldquoCancer metastasis a short accountrdquoJournal of the South African Dental Association vol 66 no 4pp 180ndash183 2011

[37] L Feller and J Lemmer ldquorsquosecond primaryrsquo cancersrdquo Journal ofthe South African Dental Association vol 67 no 4 pp 175ndash1782012

[38] R S Leandro Santos M F Andrade F de Abreu Alves L PKowalski and D E da Cruz Perez ldquoMetastases of melanomato head and neck mucosa a report of short seriesrdquo Clinical andExperimental Otorhinolaryngology vol 9 no 1 pp 80ndash84 2016

[39] F Tas and S Keskin ldquoMucosal melanoma in the head and neckregion different clinical features and same outcome to cuta-neous melanomardquo ISRN Dermatology vol 2013 pp 1ndash5 2013

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the evidence-based information about risk and aetiologicalfactors genetic factors associated with the initiation and pro-gression of the disease and prognostic factors and outcomesof different treatment modalities is scarce Hopefully thispaper may shed light on various aspects of oral mucosalmelanoma

2 Oral Mucosal Melanoma Precursor Cells

Most primary oral mucosal melanomas arise from melano-cytes in the basal cell layer of the oral epithelium but somefrom immature melanocytes residing in the lamina propriaof the oral mucosa

Oralmelanocytes are derived fromneural crest stempro-genitor cells most of which during embryogenesis migrate totheir final destination in the basal cell layer of the oral epi-thelium The migration of precursor melanocytes and theirdifferentiation into mature melanin-producing or amelan-otic melanocytes are mediated by a number of biologicalagents and intracellular signalling pathways including stemcell factor (SCF) and its tyrosine kinase receptor cKit sig-nalling pathway endothelins 1 and 3 hepatocyte growthfactor and basic fibroblast growth factor [10] However forreasons unknown in their pathway of migration towardsthe oral epithelium some immature melanocytes becomearrested in the lamina propria [11]

The functions of oral melanocytes are not well under-stood they produce melanin which contributes to the colourof the oralmucosa provides protection from stressors such asreactive oxygen species and free radicals and has the capacityto sequester metal ions and bind organic molecules [10]Apart from their role in melanin biosynthesis melanocytescan act as immunocytes producing cytokines thus having thecapacity to modulate immunoinflammatory responses andas neuroendocrine cells secreting melanocortins opioidscatecholamines and acetylcholine into the local microenvi-ronment These functions of oral melanocytes all contributeto the homeostasis of the oral tissues [10 12]

Signals from neighbouring keratinocytes biologicalagents released from intramucosal nerve sensory endingsmesenchymal-epithelial interactions and autocrine signalsall together play a role in regulating the functional activity oforal melanocytes [11]

Although the population of oral melanocytes appears toremainmore or less constant throughout life themechanismsfor their replacement in the basal cell layer of the epitheliumafter loss to physiological processes of apoptosis or tomechanical thermal or chemical injury are not well under-stoodThis replacementmay be either the result of division ofldquomaturerdquomelanocytes in the basal cell layer of the oral epithe-lium which still retain the capacity to replicate or the resultof migration of melanocyte stemprogenitor cells from localmicroenvironmental niche reservoirs However niche reser-voirs of tissue-specific stemprogenitor cells containing thegenetic information and the regenerative capacity of oralmelanocytes have not as yet been identified [13]

The origin of the melanoma precursor cell is open todebate but it is most probably a tissue-specific stemprogeni-tor melanocyte that over time has acquired cytogenetic and

epigenetic alterations and has ultimately undergone malig-nant transformation Melanoma stemprogenitor cells likenormal melanocyte progenitor cells maintain their undif-ferentiated phenotypes and their capacity for self-renewalAlternatively it is also possible that melanoma precursorcells either in the basal cell layer of the epithelium or in thelamina propria of the oral mucosa are derived from mel-anocytes having undergone a process of dedifferentiationsubsequently to cytogenetic alterations acquiring a mela-noma stemprogenitor cell phenotype These melanomastemprogenitor cells are the driving force behind the ongo-ing growth of the primary tumour and behind the establish-ment of distant metastases Their replication provides newmelanoma transient-amplifying cells that have a high prolif-erative rate and promote tumour growth [14 15]

3 The Pathogenesis of OralMucosal Melanoma

Oral mucosal melanomagenesis is not associated with anyknown carcinogenic agents [16] Only some of the intracellu-lar molecular signalling pathways that drive the complex pro-cess of mucosal melanomagenesis have been identified How-ever it is probable that dysregulation of cell cycle progressionapoptosis cell-to-cell interactions cKit signalling pathwaysmelanocortin receptor 1 (MC1R) polymorphism melaninitself and products ofmelanin biosynthesis are all risk factors(Figure 1) Biological agents in the microenvironment whichunder physiological conditions regulate the proliferationdifferentiation and function of local melanocytes also appearto play a role in the process of oral melanomagenesis [14]

The activation of the receptor tyrosine kinase (RTK) cKitby its ligand the stem cell factor (SCF) induces intracellularsignalling pathways which are critical tomelanocyte develop-ment andmigration during embryogenesis and later postde-velopmentally to the regulation of melanocyte proliferationdifferentiation and survival as well as for mediation of mela-nin biosynthesis [16ndash18] cKit is a product ofKIT protoonco-genes is a transmembrane glycoprotein and is expressed bya variety of cells including melanocyte precursors haemato-poietic progenitor cells and mast cells [19 20] The RTKcKit downstream intracellular signalling pathways includethe PI3K (phosphoinositide 31015840-kinase) pathway the JanusKinases (JAKs)Signal Transduction and Activator of Tran-scription (STAT) pathway and theRas-Raf-MAPK (p38 ERK12 JNK) pathways [21]

Up to 40 of mucosal melanoma cells either overexpressthe cKit protein or express gain-of-functionmutations inKITprotooncogenes or both These molecular alterations maysubsequently activate the Ras-Raf-MAPK transduction path-way resulting in increased proliferation and survival of mela-noma cells [19 22 23] (Figure 1) Oral mucosal melanomacells however show only infrequent mutations in either theNRAS or the BRAF molecular pathways that are common inmelanoma of sun-exposed skin [14 23]

In oral mucosal melanoma the dysregulated increasedactivation of cKit signalling pathways is not owing to upregu-lation of autocrine secretion of the cKit ligand SCF but ratherto ligand-independent constitutive activation of cKit receptor


Melanomagenesis

MC1R polymorphism



of melanocytes























4 Clinical Features



























Stage T N M

Stage III T3 NO MO




















8 Conclusion



Abbreviations



Disclosure




References
















































Biomaterials












Journal of




















Melanomagenesis

MC1R polymorphism



of melanocytes























4 Clinical Features



























Stage T N M

Stage III T3 NO MO




















8 Conclusion



Abbreviations



Disclosure




References
















































Biomaterials












Journal of






















4 Clinical Features



























Stage T N M

Stage III T3 NO MO




















8 Conclusion



Abbreviations



Disclosure




References
















































Biomaterials












Journal of





























Stage T N M

Stage III T3 NO MO




















8 Conclusion



Abbreviations



Disclosure




References
















































Biomaterials












Journal of


























8 Conclusion



Abbreviations



Disclosure




References
















































Biomaterials












Journal of




























































Biomaterials












Journal of


























Biomaterials












Journal of



















Documents

A Review of the Aetiopathogenesis and Clinical and