Pigmented lesions of the oral and head and neck mucosa ... · Pigmented lesions of the oral and head and neck mucosa, including malignant melanoma A clinicopathological study ACADEMISCH

Pigmented lesions of the oral and head and neck mucosa, including malignant

melanoma

A clinicopathological study

The studies presented in this thesis were performed at the Department

of Oral and Maxillofacial Surgery/Oral Pathology of the VU University

medical center/ Academic Center for Dentistry Amsterdam (ACTA). The

printing of this thesis has been financially supported by:

• The Academic Center for Dentistry Amsterdam (ACTA) Research Institute

• The VU University medical center in Amsterdam

© M. Meleti, Parma, 2007

VRIJE UNIVERSITEIT

Pigmented lesions of the oral and head and neck mucosa, including malignant melanoma

A clinicopathological study

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam,

op gezag van de rector magnificus prof.dr. L.M. Bouter,

in het openbaar te verdedigen ten overstaan van de promotiecommissie

van de faculteit der Tandheelkunde op vrijdag 25 januari 2008 om 10.45 uur

in de aula van de universiteit, De Boelelaan 1105

door

Marco Meleti

geboren te Nardo’ (Lecce), Italië

promotoren: prof.dr. I. van der Waal

prof.dr. P. Vescovi

5

Contents: Chapter 1: Introduction and aim of the study. 7 Chapter 2: Pigmented lesions of the oral mucosa and perioral 21

tissues: A flow-chart for the diagnosis and some recommendations for the management.

Chapter 3: Oral malignant melanoma: A review of the literature. 53 Chapter 4: Oral malignant melanoma. Report of 14 cases: 71

The Amsterdam experience. Chapter 5: Oral malignant melanoma associated with 89

pseudoepitheliomatous hyperplasia. Report of a case. Chapter 6: Melanotic pigmentation of palatal salivary glands; 99

Report of an unusual case. Chapter 7: Melanocytic nevi of the oral mucosa – No evidence 109

of increased risk of oral malignant melanoma: An analysis of 119 cases.

Chapter 8: Head and neck mucosal melanoma. Experience 125

with 42 patients with emphasis on the role of postoperative radiotherapy.

Chapter 9: Summary and conclusions 147 Chapter 10: Samenvatting en conclusies 153 Curriculum Vitae 159 Acknowledgments 161

7

Chapter 1.

Introduction and aim of the study.

8

Chapter 1

Introduction

Pigmented lesions of the oral mucosa Human oral and head and neck mucosa is not uniformly coloured and several

degrees of chromatic variegation may be observed in physiological and

pathological conditions 1-6. The term “pigmentations of the oral and head and

neck mucosa” may be applied to a wide range of entities caused by the

accumulation of one or more pigments and featuring a change in colour of

tissues 1-5, 7. Pigments associated with mucosal discoloration can be

subclassified into endogenous (e.g melanin and blood-related pigments) and

exogenous (e.g. metals and drug-related pigments). Melanin-associated lesions

represent the most common pigmentations and include benign entities as well

as mucosal melanoma, an extremely aggressive neoplasm 1-7.

With the exception of several studies on sinonasal, pharyngeal and conjunctival

melanomas 8-36, most of the analyses on pigmented lesions of the head and

neck mucosa reported in the literature are focused on the oral cavity 1-6, 37-71.

Benign melanin-associated pigmentations of the oral mucosa include racial

pigmentations, melanotic macules, oral melanocytic naevi (OMNs),

melanoacanthoma, post-inflammatory pigmentations and so-called “smoker’s

melanosis” 1-6, 37-71. Several systemic diseases such as Peutz-Jeghers and

Laugier-Hunziker syndromes as well as the Addison’s disease are also

characterized by the presence of benign melanin-associated lesions of the oral

and perioral tissues 72-77.

Non-melanin associated pigmentations may be caused by blood-related

(bilirubin and biliverdin), iron-containing (ferritin and hemosiderin) and metal

pigments 1-6, 78-82. Among these, amalgam pigmentation (“amalgam tattoo”)

represent the most frequently described 78-82. Several drugs have been reported

to induce mucosal discoloration through direct deposition on oral surfaces, local

accumulation after systemic absorption, stimulation of melanin-related pathways

and bacterial metabolism 1-6.

9

Introduction and aim of the study

Clinical and histopathological diagnosis of pigmented lesions of the oral and

head and neck mucosa may be challenging. No reliable criteria exist for the

clinical differentiation between mucosal melanoma and a number of other

pigmented lesions such as melanotic macules, OMNs or amalgam tattoos 1-6.

With the exception of oral malignant melanoma (OMM), all pigmented primary

lesions in the oral cavity are benign and treatment usually is required only when

discomfort is present 1-6.

Head and neck mucosal melanoma Head and neck mucosal melanomas (HNMMs) are rated among the most

malignant tumours of the human body with a 5-year survival rate for nasal,

pharyngeal, oral and sinus melanomas of respectively 30.9, 13.3, 12.3 and less

than 5.0 percent 8-36.

The incidence of HNMM is approximately four per 10 million population per year

in the United States and this malignancy accounts for 8-15% of all head and

neck neoplasms, including cutaneous melanoma 6, 8-10, 83, 84 .

With regard to the subgroup of OMM, it has been reported that it accounts for

0.5% of all oral malignancies and that its incidence is slightly higher among the

Japanese population 83-86.

Etiology and pathogenesis of HNMM are essentially unknown 8-36, 83-86. On the

base of epidemiological data some authors hypothesized a possible influence of

formaldehyde exposure 27. The close anatomic proximity of the commonly

affected head and neck mucosal sites (nasal cavity and paranasal sinuses and

the palate) may lead to the hypothesis that the pathogenesis of these tumours

is related to some abnormality during the embryogenesis of this region 29. It has been reported that almost one third of OMMs are preceded for months or

years by pigmented lesions but the nature of such precursors has never been

clarified 83, 86. Since OMNs and OMM share similar epidemiologic features such

as the frequent localization on the hard palate, it may be hypothesized that a

particular histotype of OMN represents a potentially malignant precursor 46.

10

Chapter 1

However, no data on the potential malignant transformation rate of OMNs are

available as they are for the melanocytic nevi of the skin 54, 57.

The clinical manifestations of HNMM are extremely heterogeneous. Painful

black or brown nodules in the oral cavity and dark polypoid masses in the nasal

and paranasal sinus cavities are the most commonly clinical features reported.

Other unspecific signs consist of ulceration and bleeding. Few HNMM are non-

pigmented (amelanotic melanomas) 8-36, 83-86.

From the histopathologic point of view, malignant melanoma cells show a wide

range of shapes including spindle, clear cell and epithelioid ones. A distinction

between “in situ” melanomas, melanomas with an invasive pattern and

melanoma with a combined pattern has been proposed for OMMs 87. Useful

immunohistochemical markers include S-100 protein and HMB-45 8-36, 83-86.

The TNM clinical staging system for HNMM recognizes three stages: Stage I,

primary tumor present only (T any N0 M0); Stage II, tumor metastatic to

regional lymph nodes (T any N1 M0); Stage III, tumor metastatic to distant sites

(T any N any M1) 21, 23.

Therapy of HNMM is commonly based on surgical excision of the primary

tumour, supplemented by radiotherapy, with chemotherapy and immunotherapy

serving as adjuncts 8-36, 83-86.

Recurrent melanoma may manifest itself up to 10-15 years after primary

therapy and distant metastases to the lungs, brain, liver, or bones are frequently

observed 8-36, 83-86.

11


Aim of the study The aim of the present thesis is to report the clinical and pathological features of

a number of pigmented lesions of the oral mucosa particularly with regard to

malignant melanoma.

A clinicopathological review of the recent literature on oral pigmented lesions,

with emphasis on the main diagnostic features, including the use of

immunohistochemical markers is presented in chapter 2. After an overview on

embryology and histology of oral mucosal melanocytes, we analyze the oral

pigmented lesions describing the epidemiological, clinical, histopathological and

therapeutical aspects of a number of oral pigmented lesions. A flow-chart for

diagnosis and some recommendations for the management are included.

The current knowledge on OMM is critically reviewed in chapter 3. Etiology,

clinical and histological features, diagnostic aspects, terminology and

classification, staging systems, prognostic factors and survival are extensively

discussed. A section of the paper is dedicated to the analysis of the differences

between excisional and incisional biopsies in terms of spreading of malignant

cells. The role of surgery, including the policy with regard to the neck and the

role or primary and postoperative radiotherapy are also reviewed.

The experience with 14 patients with a histopathological diagnosis of OMM and

treated at the Department of Oral and Maxillofacial Surgery/Oral Pathology of

the VU University medical center (VUmc) in Amsterdam between 1978 and

2005 is presented in chapter 4.

The exceptional finding of pseudoepitheliomatous hyperplasia (PEH) in

malignant melanoma of the palate in a 46-year-old female patient is reported in

detail in chapter 5. A discussion on the possible histogenesis of PEH is also

included.

A case of melanotic pigmentation of the palatal minor salivary glands is reported

in detail in chapter 6. Four years later the patient developed a malignant

melanoma at the junction of the hard and the soft palate. A discussion on the

12

Chapter 1

presumptive potentially malignant nature of the salivary glands pigmented

lesion is included.

The role of oral melanocytic naevi as markers for oral malignant melanoma

development is discussed in chapter 7. The paper reports an epidemiological

and pathological evaluation on 119 cases of OMNs registered in the nationwide

Registry of Pathology (PALGA) in the Netherlands in the period 1980-2005.

The experience with a group of 42 patients with a primary HNMM referred to the

VU University medical center (VUmc) in Amsterdam, the Netherlands, and to

the Academic Hospital of Parma University, Italy, in the last 30 years, is

reported in chapter 8. The emphasis of the study was on the role of surgery and

post-operative radiotherapy.

13


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18

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19

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21

Chapter 2.

Pigmented lesions of the oral mucosa and perioral tissues: A flow-chart for the diagnosis and some

recommendations for the management.

Marco Meleti 1,2

Paolo Vescovi 1

Wolter J. Mooi 3

Isaäc van der Waal 2

1 Department of ENT/Dental/Ophthalmological and Cervico-Facial Sciences, University of Parma, Italy

2 Department of Oral and Maxillofacial Surgery/Oral Pathology, VU medical center/ACTA, Amsterdam, The Netherlands

3 Department of Pathology, VU medical center, Amsterdam, The Netherlands

Accepted for publication in Oral Surgery, Oral Medicine,

Oral Pathology, Oral Radiology and Endodontics.

22

Chapter 2

Abstract The term “pigmentation of the oral mucosa” is applied to a wide range of lesions

or conditions featuring a change of colour of oral tissues. Lesions not

associated with an accumulation of pigment (e.g. Fordyce’s spots) are usually

not classified as pigmented lesions.

Two groups of pigmented lesions of the oral mucosa are recognized :1)

melanin-associated lesions, including racial pigmentations, melanotic macules,

melanocytic naevi and malignant melanoma; 2) non-melanin-associated (e.g.

blood-related pigmentations, metallic pigmentations) lesions.

This paper presents a clinicopathological review of the recent literature with

emphasis on the main diagnostic features, including the use of

immunohistochemical markers. A flow-chart is added that may help the clinician

in the diagnosis and management of these lesions.

23

Oral pigmented lesions

1. Introduction Human oral mucosa is not uniformly colored and several degrees of chromatic

variegation may be observed in physiologic and pathologic conditions 1-5. Oral

subsites are characterised by different structural colors, depending on degree of

keratinization, numbers and melanogenic activity of melanocytes,

vascularization and type of submucosal tissue (muscle, bone, cartilage). The

physiologic color of the oral mucosa thus ranges from white to red-purple in

white-skinned people, while an evenly black to brown color of gingiva and

buccal mucosa and the lips, are characteristic of black-skinned people 1-5.

In this review, two groups of pigmented lesions are discussed: melanotic

lesions, and lesions caused by other pigments. After an overview of oral

histology and physiology of melanocytes, a flow-chart will be presented that

may help the clinician in the diagnostic process (Figure 1).

24

Chapter 2

Figure 1. Diagnosis and management of pigmented lesions. * Palate and gingiva are considered subsite at risk for OMM development. ** In case of multiple or diffuse pigmentation(s) further examination for underlying diseases or syndromes (e.g. Addison’s, Peutz-Jeghers syndrome, etc.) may be considered.

25


2. Melanin-associated pigmented lesions of the oral cavity 2.1. Oral mucosal melanocytes : histology and physiology Melanocytes were first identified in the oral epithelium by Becker in 1927; a few

years later they were isolated from samples of gingival tissue by Laidlaw and

Cahn 6, 7. During early intrauterine life, precursors of melanocytes,

melanoblasts, migrate from the neural crest to the epidermis and the hair

follicles, becoming differentiated dendritic cells 8-10. The head and neck region

represents the first part of the body where melanocytes appear after

approximately 10 weeks of gestation 10.

Melanocytes are located in the basal epithelial layer of squamous mucous

membranes and do not contact each other. They are regularly interspersed

between the basal keratinocytes. Melanocytic dendrites reach a number of

keratinocytes in the close vicinity, and through these dendrites, melanin is

transported and transmitted to these epithelial cells 4, 11-13. An age related

increase of oral melanocytes has been observed 14.

The normal melanocytes of the oral mucosa have a small, round nucleus and a

small amount of a clear cytoplasm, with slender dendrites extending between

adjacent keratinocytes. Melanocytes are devoid of desmosomes or attachment

plates 15. Melanin-containing electron-dense vesicles, so called melanosomes,

are formed within the cytoplasm and transported along the dendrites 13.

The use of 3, 4 dihydroxyphenylalanine (DOPA), a substrate for tyrosinase,

represents the most specific histochemical method for labeling melanocytes 11.

Other methods include argentaffinic melanin-labeling techniques such as the

Masson-Fontana staining. Inactive oral mucosal melanocytes, lacking melanin

and melanin precursors, may not stain with this method 11.

Immunohistochemically, the S100 antigen is by far the most common marker

used. S100 staining appears to be stronger in melanocytes lacking pigment.

Another commonly used marker is HMB-45, a monoclonal antibody directed

against a melanosomal glycoprotein 1, 14. HMB-45 is not expressed by

melanocytes that lack all melanogenic activity 11.

26

Chapter 2

The main biochemical function of the mature melanocyte is a process called

melanogenesis through which the cell produces and delivers melanin pigment 9.

Eumelanin (brown-black melanin) causes a brown-black color of the skin, hair

and eye, while pheomelanin has a reddish color. Neuromelanin, found in some

nerve cells, is an unrelated substance 16.

Various stimuli such as trauma, hormonal changes, medication and radiation

may result in an increased production of melanin 17. Melanin functions include

absorption of ultraviolet light and scavenging of some cytotoxic compounds 13.

2.2 Racial Pigmentation (physiologic pigmentation) No agreement exists in the literature on the definition of “race”, “racial group”,

“ethnic group” and “ethnicity” 18. Furthermore, it has been demonstrated that the

strength of the relationship between skin color and ancestry is quite variable. As

a matter of fact, the melanin content of the skin does not seem to be strictly

related to ancestry, genetically defined by the so-called “ancestry-informative

markers” (AIMs) 18. On the basis of a multivariate evaluation, three categories of

humans have been defined: whites, blacks and intermediates. Factors

considered include skin color in the medial part of the arm, color and texture of

the hair, and shape of nose and lips 19.

Oral “racial” pigmentations (ORPs) are usually observed in dark-skinned

populations 1-5. In a study on 1300 children, ORPs were identified in 13.5% 17.

Pigmentations are usually diffuse and bilateral even though a variety of patterns

have been observed 1, 3. Color ranges from light dark to brown. Gingiva, with the

exclusion of the marginal border, and buccal mucosa are the most commonly

involved sites (Figure 2). Other sites include lips, palate and tongue 1-5 (Figure

3). Racial pigmentations are innocuous and treatment is only for aesthetic reasons.

27


2.3 Melanotic macules Melanotic macules of the oral cavity are relatively common lesions, caused by

an increased production and deposition of melanin within the basal cell layer,

the lamina propria, or both 1-3.

In the largest series from one source, Buchner et al. reported that melanotic

macules of the lips and oral cavity represented 86.1% (665 cases) in a group of

773 cases of solitary melanocytic lesions and the 0.7% in a group of nearly

90,000 biopsies from oral cavity and perioral tissues 20. Of these, 207 where

located on the lips and 458 involved various subsites of the oral mucosa. The

vermillion border and the gingiva were the most commonly affected subsites

(60%). In another review, Kaugars et al. reported a prevalence of 0.4% among

86,202 biopsies from the oral cavity. Labial lesions almost exclusively affect the

lower lip, while gingival melanotic macules are more frequently localized in the

anterior part of the maxilla. Black patients are more likely to have involvement of

the buccal mucosa 21. The female to male ratio is almost 2:1 and the highest

incidence is reported during the fifth decade 20, 21. Controversy exists on the pathogenetic mechanism that leads to the

development of melanotic macules and it is not clear if they represent a

physiologic or a reactive process 1. Some authors reported a positive family

history and a genetic predisposition has been hypothesized 22.

Figure 2. Racial pigmentation. Gingival involvement.

Figure 3. Physiologic pigmentation on the tips of the fungiform papillae.

28

Chapter 2

Melanotic macules are usually single, well-circumscribed blue or brown-to-black

lesions homogeneously colored, and less than 1 cm in diameter 1, 3. Intraoral

lesions tend to be larger than those located on the lips 1. Unlike ephelides,

melanotic macules do not darken after exposure to sun radiation 23.

Dermatoscopy may show a structureless pattern, characterized by a diffuse

brown black pigmentation, seldom irregularly distributed, without pigment

network or globules and/or streaks 24.

The diagnosis is usually made on clinical grounds alone 1.

From the histopathologic point of view there is absence of rete ridge elongation

and lack of prominent melanocytic activity 1-3. Pigmentation is usually most

marked at the tips of the rete ridges and melanophages can also be observed in

the upper part of lamina propria. 2, 22. There is lack of atypia of melanocytes and

HMB-45 immunoreactyivity is typically lacking 1, 3, 20, 21, 25. When melanin

pigment is observed in the epithelium of a clinically non-pigmented lesion, the

term “focal melanosis” has been used by some 26.

2.4 Lentigines and ephelides The term lentigo (plural : lentigines) indicates a well-defined hyperpigmented

lesion of the skin with an increased number of melanocytes arranged as solitary

units along the epithelial-mesenchymal junction, without formation of nests 27.

Lentigines are subdivided in simple lentigines and solar lentigines, the latter

being associated with epithelial hyperplasia, which generally takes the form of

rete ridge elongation. Melanocytic hyperplasia is minimal in solar lentigines.

Lentigo simplex is a lesion histologically characterized by more obvious

melanocytic hyperplasia, together with increased melanin formation 27. No clear

data on epidemiology are available in white skinned population while lentigo

simplex has been reported to be the most frequent pigmented lesion in acral

sites of darkly pigmented races. Pathogenesis is most likely related to

developmental or intrinsic defects in melanocytes homeostasis. Clinical features

of lentigo simplex include light to dark brown pigmentation, usually sharply

29


circumscribed. Lesions can be single or multiple, the latter situation being

associated with a number of rare syndromes 27. Different from lentigo simplex, solar lentigines (synonyms sun-induced freckles,

lentigo senilis) are ultraviolet (UV)-induced pigmented lesions. Epidemiology

shows an increased incidence among the general population over 60 years of

age 1, 3.

Ephelides (freckles) are small (less than 1 cm) red or light-to dark-brown

macules localized on sunexposed areas of the body 2, 28. They typically affect

white-skinned individuals, are multiple, and uniform in color and regular in

outline, although confluence leads to irregularly shaped larger patches 2.

Ephelides may appear at any age but most frequently occur in childhood 2, 28.

They wax and wane with the degree of solar exposure, being most conspicuous

in the summer months.

No data exist on the prevalence of intraoral lentigines and ephelides; they

mainly affect the vermillion border of the lips or the perioral tissues 2.

2.5 Melanocytic Naevi Oral melanocytic naevi (OMNs) are benign tumors of melanocytes 27.

Approximately 500 cases have been reported in the English literature; no

systematically assembled data on their frequency are available 20, 29. A recent

report from the Netherlands revealed an annual incidence of excised OMNs of

4.35 cases per 10 million population per year 29.

The etiology and pathogenesis of OMNs are poorly understood even though, as

for their cutaneous counterpart, oncogenic mutations of genes coding for

components of the RAS signaling pathways may play a role 30.

Regarding morphogenesis, the melanocytic proliferation can be divided into

three phases: 1) proliferation of benign neoplastic melanocytes along the

epithelial-mesenchymal junction (junctional naevus); 2) migration of these cells

into the mesenchymal compartment (compound naevi); and 3) loss of the

junctional component of the naevus, so that all remaining nevomelanocytes are

30

Chapter 2

located within the subepithelial compartment (subepithelial naevi) 12, 27, 31

(Figure 4). These steps correspond to the histologic variants of OMNs 29. Less

common naevus subtypes include blue naevus (Figures 5 and 6), combined

naevus and Spitz naevus 32-36.

Figure 4. Histopathological features of subepithelial naevus. All nevomelanocytes are confined within the subepithelial compartment (H&E stain; orig. magn. x50).

In the histopathological evaluation, the additional use of immunohistochemical

stains may be required, such as the melanocytic markers Melan A, HMB45 and

Figure 5. Blue naevus of the palate. Figure 6. Histopathological features of a blue naevus. Spindle- shaped nevomelanocytes (Schmorl stain: orig. magn x 150).

31


microphthalmia transcription factor (mitf). In melanin pigment laden cells, additional markers, e.g. CD68, a marker for macrophages, may be helpful in identifying the nature of such cells. Such a procedure may be particularly helpful

in arriving at a correct diagnosis of a blue naevus. Congenital melanocytic naevi are present at birth, while those developing after

birth are referred to as acquired naevi 37-39. Probably, most melanocytic naevi of

the oral mucosa are acquired, 37 even though some cases of congenital naevi

have been reported 38. Sizes range from 0.1 to, rarely, 3.0 cm 37, 40. OMNs

typically are well circumscribed round or oval macules or papules, but polypoid

larger lesions have been reported as well 27, 37, 40. OMNs have been reported to

occur in a multiple fashion 41. Elevated acquired naevi are usually lightly

pigmented, while flatter lesions tend to be more darkly pigmented 27. Colors

vary from brown to blue, bluish-gray, or black; generally an individual lesion has

a similar color throughout 27, 37, 40, 42. Rare non-pigmented naevi are on record 43.

The hard palate, buccal mucosa and gingiva are most commonly affected 37, 40,

42, 44, 45.

Despite a strong epidemiological correlation between OMNs and OMMs with

regard to age, gender predisposition and oral subsites, there is no proof that

naevi of the oral mucosa are markers of the development of malignant

melanoma 29.

2.6 Melanoacanthoma The term melanoacanthoma has been used to describe a rare, benign mixed

lesion of keratinocytes and pigmented-laden dendritic melanocytes 46-48. Oral

melanoacanthoma is thought to have a reactive nature and usually regresses

spontaneously or after incomplete removal, such as incisional biopsy 46-48.

Approximately 40 cases of oral melanoacanthoma have been reported 46.

Differently from its cutaneous counterpart, oral lesions occur almost exclusively

in Blacks, affect a much younger population, develop rapidly and generally have

a flat surface. The buccal mucosa is the most frequently affected subsite.

32

Chapter 2

2.7 Tobacco-associated melanin pigmentation (smoker’s melanosis) Smoking has been found to cause diffuse oral melanin pigmentation in

European and Asian population 49-52. It has been reported in 21.5% of smokers

and the intensity of the pigmentation is related to the number of cigarettes

consumed 51. Some authors noticed a significant increase in gingival melanosis

of children with parents who smoke 53. Smoker’s melanosis seems to be directly

related to a stimulant effect of substances in smoke on melanocytes. In parallel

to a model accepted for the skin, some authors hypothesized that melanin may

play a role in detoxification of polycyclic amines nicotine and benzopyrene 49, 50.

Subsites involved are mainly gingiva, hard palate, buccal and commissural

mucosa, inferior surface of the tongue and lip mucosa (Figure 7). Smoker’s

melanosis is usually black-brown 49-52 .

From a histologic point of view, increased melanin is found in the basal layer of

the epithelium, and there may be melanophages in the subjacent connective

tissue. No melanin is detected in the upper part of the epithelium 54. Smoker’s

melanosis does not require treatment and disappearance has been reported

after cessation of the smoking habit 1, 49.

Figure 7. Smoker’s melanosis of the lower lip.

33


2.8 Malignant Melanoma Oral malignant melanoma (OMM) is an aggressive tumor of melanocytes,

accounting for 0.5% of all oral malignancies 55, 56. The neoplasm is more

common in Japan and Africa than in Western countries 57-59. The etiology of

OMM is unknown. Tobacco use and chronic mechanical irritation resulting from

ill-fitting dentures have been mentioned as possible risk factors 57, 60. Most

OMMs arise de novo, from apparently normal mucosa, but about 30% are

preceded by oral pigmentations for several months or even years 57, 61.

The initial symptom and sign of OMM is the emergence of a mass lesion, which

is usually pigmented. OMM may be uniformly brown or black, or may show

variation of color, with black, brown, grey, purple and red shades, or

depigmentations 62. Satellite foci occasionally surround the primary tumor. In

amelanotic melanomas, pigmentation is absent 55, 56 (Figure 8). The most

frequently affected oral sites are the palate and the maxillary gingiva 12, 62.

Figure 8. Amelanotic melanoma of the palate.

OMMs probably originate from junctional melanocytes; in its first phase of

development, the cells are restricted to the epithelial compartment: in situ

melanoma. Subsequently, melanoma cells invade the underlying tissues 62.

34

Chapter 2

Melanoma cells show a wide range of shapes, including spindle, plasmacytoid,

and epithelioid ones. Clear cell change is occasionally seen 56, 62, 63.OMM is not

subdivided into the classical cutaneous melanoma categories, which include

superficial spreading melanoma (SSM), nodular melanoma (NM) and acral

lentiginous melanoma (ALM). There is, however, often some similarity to ALM

and NM 12, 59, 62, 64. The histological microstaging system of Clark, used in

cutaneous melanoma, can not be applied to oral mucosa because of the lack of

histologic landmarks analogous to papillary and reticular dermis 12, 62. Tumor

thickness does not appear to be associated with prognosis 63. The TNM clinical

staging system for OMM recognizes three stages: Stage I, primary tumor

present only (T any N0 M0) ; Stage II, tumor metastatic to regional lymph nodes

(T any N1 M0); Stage III, tumor metastatic to distant sites (T any N any M1) 56.

In different series, the actuarial-5 year overall survival rate for head and neck

mucosal melanoma ranges from 21% to 40% and for OMM it is 15%, with a

median survival of 25 months 12, 58. Gingival melanoma has a better 5-year

survival rate than the palatal one, with a longer median survival period (46

months vs. 22 months) 12. Recurrent melanoma may manifest itself up to 10-15

years after primary therapy 65. Distant metastases often affect the lungs, brain,

liver, or bones 66.

3. Systemic disorders associated with the presence of oral pigmented melanocytic lesions 3.1 Peutz-Jeghers and other familial hamartoma syndromes The Peutz-Jeghers syndrome (PJS) consists of mucocutaneous macules,

intestinal hamartomatous polyposis and increased risk of carcinomas of the

gastro-intestinal tract, pancreas, breast and thyroid 67-68. The disease is

associated with germline mutations in the LKB1/STK11 gene, located on the

short arm of chromosome 19, 68-69.

35


Black-to-brown spots of less than 1 mm in size are typically localized on the

lower lip and in the perioral area (Figure 9). Intraoral, intranasal, conjunctival

and rectal pigmented lesions as well as spots localized on the acral surfaces

may also be present 1-3, 68.

The oral lesions are benign and histologically characterized by an increase in

melanin in the basal layer, without an obviously increased number of

melanocytes 1, 2. A fading or a disappearance of the spots is usually observed in

older age 70. Interestingly, perioral lesions tend to persist 1.

So-called “PTEN hamartoma tumor syndromes” (PHTS), characterized by

mutations in the tumor suppressor gene PTEN (phosphatase and tensin

homologue deleted on chromosome 10) include several rare diseases such as

the Ruvalcaba-Myhre-Smith and the Cowden syndrome 68. Perioral lentigines

have occasionally been reported in these 2.

Figure 9. Perioral involvement in Peutz-Jegher’s syndrome.

3 .2 Addison’s disease and other endocrine disorders Primary hypoadrenalism caused by autoimmune disease, infection or

malignancy, also referred to as Addison’s disease, is characterized by deficient

production of hormones of the adrenal cortex, leading to increased production

36

Chapter 2

of adrenocorticotropic hormone (ACTH) 71. This may result in a diffuse dark

pigmentation of the skin and the oral mucosa 2, 72. Other signs and symptoms of

Addison’s disease include anorexia, nausea and postural hypotension.

Lips, gingival, buccal mucosa, hard palate and tongue are usually involved

(Figure 10). Pigmented lesions may be diffuse or localised and usually precede

skin manifestations 2, 3.

Diffuse or discrete pigmentations of the lips and oral mucosa are sometimes

observed in monostotic and polyostotic fibrous dysplasia (McCune-Albright

syndrome), hyperthyroidism and Nelson’s syndrome 2.

Treatment of pigmented lesions of the oral mucosa associated with a systemic

disorder is usually not required unless discomfort is present. The disappearance

of oral lesions may follow the treatment of the underlying condition.

Figure 10. Oral Manifestation of Addison’s disease (Courtesy of dr. J.van Hooff, The Netherlands).

3.3 Other conditions Oral melanocytic pigmentations have been reported in patients with Laugier-

Hunziker syndrome (idiopathic lenticular mucocutaneous pigmentations) and

37


with Carney complex (spotty skin pigmentations, myxomas and endocrine

overactivity) 2, 73-77. HIV infection has been associated with multiple, usually well-circumscribed

melanotic macules localized on the buccal and palatal mucosa, gingiva and lips 5. However, the association may be only coincidental. The histolopathological

appearance is similar to classical melanotic macules. It remains unclear

whether such pigmentations are caused by the virus, by therapy, or other

factors 1, 2, 78.

Chronic inflammatory conditions such as oral lichen planus, pemphigus,

pemphigoid or chronic periodontal disease are sometimes associated with

deposition of melanin within the connective tissue resulting in a darkening of the

mucosal area 1, 4. These phenomenon is mostly observed in dark-skinned

individuals 3. Fixed drug reaction after administration with cotrymazole,

tetracycline, colchicine, ketoconazole has also been associated with post-

inflammatory hyperpigmantation 3, 79. It is debatable if these reactions only

depend on melanin.

The presence of lesions resembling melanotic macules of the palate in patients

with lung diseases, including cancer, has also been reported, but there is lack of

evidence on a true association 80. Melanin production and stimulation may sometimes also follow surgical

procedures 4.

4. Non-melanin-associated pigmented lesions of the oral cavity 4.1 Lesions caused by endogenous pigments (blood-related pigmentations) Extravasations of blood in hematomas, petechiae, purpurae and ecchymoses

may cause pigmentation 3, 81 as a result of accumulation and degradation of

38

Chapter 2

haemoglobin to bilirubin and biliverdin 3. Color of the lesions depend on length

of time from trauma and may range from red to black. Typical traumatic events

in the oral cavity possible associated with blood extravasations and hyperpigmentation include biting, traumas with eating and iatrogenic

procedures.

Patients with haemochromatosis (“bronze diabetes”) frequently display bluish-

grey pigmentation of the hard palate, gingival and buccal mucosa 2, 4 (Figure

11). The pigmentation is caused by deposition of iron containing pigments

(ferritin and hemosiderin) within the skin and mucous membranes 4. Similarly, a

diffuse black-brown pigmentation, most commonly in the junction between the

hard and soft palate, may be observed in patients with beta-thalassemia 1.

Figure 11. Palatal pigmentation in a patient with hemochromatosis. (Courtesy of dr. J.G.N. Swart, The Netherlands).

4.2 Lesions caused by exogenous pigments (metallic pigmentations) 4.2.1 Amalgam pigmentation (amalgam tattoo) Accidental displacement of metal particles in oral soft tissues during restorative

dental procedures using amalgam may result in amalgam pigmentation, the

39


so-called “amalgam tattoo” 1-5. Terms such as focal argyrosis or oral localized

argyria should be avoided, since not only silver, but also mercury and tin are

contained in the amalgam alloy.

Despite the high prevalence of these lesions among the general population,

little information is available in the dental literature. Buchner and Hansen

identified 268 (1.3 %) amalgam tattoos among 20.731 specimens from the oral

cavity 82. The etiology of amalgam tattoos can be iatrogenic or traumatic. Metal

particles may over time leach in the soft oral tissues, resulting in the

discoloration. Buchner and Hansen and Owens et al. listed several iatrogenic

and traumatic modalities through which amalgam may be introduced in the oral

tissues: condensation of the material in abraded mucosa during routine

amalgam restorative work; introduction of the material within the lacerated

mucosa during removal of amalgam fillings or crowns and bridges; introduction

of broken pieces into a socket or the periosteoum during extraction of teeth;

introduction of metal particles in a surgical wound during root canal treatment

with a retrograde amalgam filling 82, 83.

Amalgam tattoos usually range from 0.1 up to (rarely) 2 cm in size and can be

solitary or multiple. Colors reported are blue, grey or black with a spectrum of

variegation depending on the depth of metal within tissues. Gingiva and alveolar

mucosa are the subsites most frequently involved. In alveolar edentulous

ridges, amalgam tattoos can also be associated with restored antagonistic teeth

(Figure 12). The diagnosis is based on clinical findings and the relationship with

present or removed amalgam restorations.

40

Chapter 2

Figure 12. Amalgam tattoo.

Radiographic features may show localized radiopacities 1. Biopsy is indicated

only when suspicion of OMM can not be ruled out on clinical grounds alone.

Histopathologic investigation reveals amalgam particles dispersed in the

connective tissue and sometimes in the walls of vessels. These particles may

also line the basement membrane of the surface epithelium. Brownish granules

within phagocytic cells and fibroblasts cytoplasm can also be observed 82, 84, 85.

A spreading of these pigmented lesions mediated by local migration of

phagocytic cells containing metal has also been described 1-3 , 82-84.

Histopathologic examination of an amalgam tattoo is usually diagnostic because

of the size and shape of the metal particles and the way they are spread in the

tissue. However, in rare cases, one may need additional stains. The common

melanin and iron stains are often not sufficient for differentiating between metal

particles and melanin pigment. Instead, immunohistochemical markers such as

HMB-45 and Melan A are more suitable for this purpose.

When dealing with metal pigmentation, one may be able to identify the type of

metal(s) by using electron-probe micro-analysis. There is no indication for complete removal of an amalgam tattoo.

41


Accidentally or voluntary introduction of other foreign particles include graphite

from pencil tips, tattoo inks and chronic contact with charcoal toothpaste and

vegetables, such as Juglans regia, Cola Nitida and Catha Edulis 1, 2, 86.

4.2.2 Heavy metals Systemically absorbed metals may induce discoloration of the oral mucosa,

caused by peripheral metal accumulation. These conditions were frequent in the

past as result of occupational exposures to certain drugs. Arsenic, lead,

bismuth, mercury, silver and gold are the metals most frequently involved 1-5.

Bismuth was typically used for the treatment of syphilis and its administration

was associated with diffuse oral pigmentation and formation of a blue-black line

at the marginal gingival 1. A characteristic feature of plumbism (lead poisoning)

is the so-called “Burtonian line”, a grey linear area of discoloration below the

gingival margin 1, 3, 4 (Figure 13). Silver (argyria) and gold (chrysiasis) may

produce slate-grey oral pigmentation and purple gingival discoloration,

respectively 2.

Heavy metal intoxication can be associated with a wide range of systemic signs

and symptoms 1, 3.

Figure 13. Oral manifestation of lead poisoning (“Burtonian line”).

42

Chapter 2

5. Drugs associated with pigmented lesions of the oral cavity (excluding heavy metal containing drugs) Many non-heavy metal containing drugs can induce discoloration of oral tissues 1-5, 87 . Direct deposition on oral surfaces, local accumulation after systemic

absorption, stimulation of melaninrelated pathways, bacterial metabolism, alone

or in combination, may result in oral pigmentations.

The most commonly reported drugs are listed in table 1. Table 1. Drugs potentially associated with oral pigmentations. (Ref. 2 and 3)

43


6. Discussion and proposal of a flow-chart Diagnosis of pigmented lesions of the oral cavity and perioral tissues is

challenging 1-5. Even though epidemiology may be of some help in orientating

the clinician and even though some lesions may confidently be diagnosed on

clinical grounds alone, such a diagnosis remains “provisional”. Definitive

diagnosis usually requires histopathological evaluation. Occasionally,

immunohistochemical stains such as melanocyte marker HMB-45 and

marcophage marker CD68 may be required to arrive at a correct diagnosis.

With the exception of OMM, all pigmented primary lesions in the oral cavity are

benign and treatment usually is required only when discomfort is present. No

reliable criteria exist for the clinical differentiation between OMM and a number

of other pigmented lesions such as melanotic macules, oral melanocytic naevi

or amalgam tattoos 1-5.

The so-called ABCD checklist (“Asymmetry”, “Border” irregularities, “Color”

variegation and “Diameter” > 6mm) that is commonly used to aid in the

identification of cutaneous melanoma may be of some help in the clinical

diagnosis of oral melanoma 88, 89. Rapidly growing pigmented lesions should

always be biopsied 1.

Location on the palate increases the rate of suspicion of melanoma and usually

requires a biopsy or long-term follow-up. When located on the gingiva, the main

differential diagnosis is between amalgam tattoo and melanoma. In case of the

slightest doubt a biopsy should be taken.

In figure 1 a flow-chart is depicted that may help the clinician in the diagnostic

pathway of pigmented lesions of the oral cavity. When history allows to classify

a lesion as melanocytic, a subclassification should be made, according to the

clinical suspicion of malignancy (ABCD checklist, recent history, age and

subsite involved). Lesions presenting “no or low suspicion of malignancy” may

be confidently diagnosed on clinical grounds alone (e.g. oral manifestations of

systemic diseases, physiologic pigmentations, smoker’s melanosis) or may

require histopathological evaluation.

44

Chapter 2

Some non-melanocytic lesions such as ethnic tattoos or pigmentations

associated with heavy metal poisoning are easily recognized on clinical grounds

(e.g. Burtonian line). In other cases such as an bluish discolorations not clearly

related to amalgam restorations and/or not showing radiological signs for the

presence of metal particles, histopathological evaluation is needed to reach a

firm diagnosis.

A biopsy or referral to a specialist for further evaluation is indicated if the history

does not allow to distinguish between melanocytic and non-melanocytic lesion.

45


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49. Hedin CA, Pindborg JJ, Axell T. Disappearance of smoker’s melanosis after reducing smoking. J Oral Pathol Med 1993;22:228-230.

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55. van der Waal RI, Snow GB, Karim AB, van der Waal I. Primary malignant melanoma of the oral cavity: a review of eight cases. Br Dent J 1994;176:185-188.

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Oral pigmented lesions 58. Lengyel E, Gilde K, Remenar E, Esik O. Malignant mucosal melanoma of the

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67. Amos CI, Keitheri-Cheteri MB, Sabripour M, Wei C, McGarrity TJ et al. Genotypephenotype correlations in Peutz-Jeghers sindrome. J Med Genet 2004;41:327-333.

68. Bauer AJ, Stratakis CA. The lentiginoses: cutaneous markers of systemic

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69. Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A and

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71. Kim HW. Generalized oral and cutaneous hyperpigmentation in Addison’s disease. Odontostomatol Trop 1988;11:87-90.

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Chapter 2 72. McKenxie AD, McIntosh HW. Hyperpigmentation and pituitary tumour as

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73. Laugier P, Hunziker N. Pigmentation melaniques lenticulare, essentielle de la

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75. Mignogna MD, Lo Muzio L, Ruoppo E, Errico M, Amato M, Satriano RA. Oral

Manifestation of idiopathic lenticular mucocutaneous pigmentation (LaugierHunziker syndrome) : a clinical, histopathological and ultrastructural review of 12 cases. Oral Dis 1999;5:80-86.

76. Makhoul EN, Ayoub NM, Helou JF, Abadjian GA, Familial Laugier-Hunziker

sindrome. J Am Acad Dermatol 2003;49(2 Suppl Case Reports): S143-145.

77. Bain F. “Carney Complex” Mayo Clin Proc 1986;61:508.

78. Ficarra G, Shillitoe EJ, Adler-Storhz K et al. Oral melanotic macules in patients infected with human immunodeficiency virus. Oral Surg Oral Med Oral Pathol 1990;70:748-755.

79. Sharma VK, Dhar S, Gill AN. Drug related involvement of specific sites in fixed

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80. Merchant HW, Hayes LE, Ellison LT. Soft palate pigmentation in lung disease, including cancer. Oral Surg Oral Med Oral Pathol 1976;41:726-733.

81. Carpenter, WM, Rudd M. Focal, flat pigmentation of the mucosa: a clinical

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82. Buchner A, Hansen LS. Amalgam pigmentation (amalgam tattoo) of the oral mucosa. A clinicopathologic study of 268 cases. Oral Surg 1980;49:139-147.

83. Owens BM, Johnson WW, Schuman NJ. Oral amalgam pigmentations (tattoos):

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84. Daley TD, Don Gibson CET. Practical applications of energy dispersive X-ray microanalysis in diagnostic oral pathology. Oral Surg Oral Med Oral Pathol 1990;69:339-344.

85. Harrison JD, Rowley PSA, Peters PD. Amalgam tattoos: light and electron

microscopy and electron-probe micro analysis. J Path 1977;121:83-92.

86. More UA, Ashiri N, Gasi M. Unusual pigmentation of the gengiva. Oral Surg Oral Med Oral Pathol 1990;70:445-449.

51

Oral pigmented lesions 87. Krutchik AN, Buzdar AU. Pigmentation of the toungue and mucous membranes

associated with cancer chemotherapy. South Med J 1979;72:1615-1616.

88. Giard RW, Neumann HA. [Diagnosis of pigmented skin lesions: how to recognize a malignant melanoma]. Ned Tijdschr Geneeskd 2004;148:2261-2267.

89. Younes MN, Myers JN. Melanoma of the head and neck: current concepts in

staging, diagnosis, and management. Surg Oncol Clin N Am 2004;13:201-229.

53

Chapter 3. Oral malignant melanoma: A review of the literature.

Marco Meleti 1,2

René C. Leemans 3

Wolter J. Mooi 4

Paolo Vescovi 1




3 Department of Otolaryngology/ Head and Neck Surgery, VU medical center, Amsterdam, The Netherlands


Oral Oncology 2007; 43:116-121

54

Chapter 3

Abstract Primary oral malignant melanoma (OMM) is a rare neoplasm, accounting for

0.5% of all oral malignancies. The etiology is unknown; tobacco use and chronic

irritation may play some role. Clinically, OMM may mimick other pigmented

lesions. A biopsy is required in order to establish the diagnosis. The reported

risk of malignant cells spreading during invasive procedures and factors such as

size of the lesion or anatomical limitations, may influence the diagnostic surgical

procedure. Therapy of OMM is commonly based on surgical excision of the

primary tumour, supplemented by radiotherapy, with chemotherapy and

immunotherapy serving as adjuncts. Prognosis is poor, with a 5-year survival

rate of approximately 15%.

55

Oral malignant melanoma: a review

1. Introduction Malignant melanoma is a potentially aggressive tumour of melanocytic origin 1.

The incidence of head and neck mucosal melanomas (HNMM) is approximately

four per 10 million population per year in the USA 2. Only about 1% of all

melanomas arise in the oral mucosa and these account for 0.5% of all oral

malignancies 2-4. The most frequently affected oral sites are the palate and the

maxillary gingival 2, 5. Oral metastasis of melanoma, derived from a primary

elsewhere in the body, is extremely rare and will not be discussed here.

The age of reported patients ranges from 20 to 80 years; some authors have

reported a male preponderance 4, 5. The neoplasm is more common in Japan

and Africa than in Western countries 4, 6-9. Therapy is commonly based on

combinations of surgery, radiotherapy and chemotherapy 5, 6, 10. The prognosis

of OMM is poor, with a 5-year survival of about 15% 2.

The present review is based on a critical analysis of the relevant literature of the

past decades.

2. Etiology The etiology of OMM is essentially unknown. Tobacco use and chronic irritation

from ill-fitting dentures have been mentioned as possible risk factors 3,4, but the

evidence is weak. Ingested and inhaled environmental carcinogens at high

internal body temperature may play some role 11. Most OMMs arise de novo,

from apparently normal mucosa, but about 30% are preceded by oral

pigmentations for several months or even years 4, 12. Some of these flat

precursor lesions consist of cytologically atypical melanocytes and may in fact

constitute the preinvasive macular phase of melanoma. However, in other

lesions a preexistent, histologically benign melanocytic proliferation accounts for

the pigmentation.

The histological spectrum of benign melanocytic lesions of the oral mucosa is

varied, and includes so-called mucosal melanosis, i.e., a junctional proliferation

of melanocytes with or without cytological atypia, resulting in a macular

56

Chapter 3

hyperpigmentation, and a variety of melanocytic naevi. The latter comprise

junctional, compound and subepithelial naevi as well as a variety of blue and

combined naevi, which are proportionally more common than in the skin. Some

melanoma-associated antigens become expressed during the transformation

process from a benign melanocytic nevus to melanoma; most of these are

related to the melanin production process and most are HLA-restricted 2. p53

protein alterations have been identified in about two-thirds of OMM 13. A recent

study demonstrates that loss of heterozygosity at 12p13 and loss of p27KIP1

protein expression contribute to melanoma progression 14. Cytogenetic analysis

and evaluation of melanocyte-specific gene-1 (MSG-1) appears to be very

helpful for understanding the pathogenesis of OMM 15, 16.

3. Clinical features The initial symptom and sign of OMM is often swelling, which is usually

pigmented. OMM may be uniformly brown or black, or may show variation of

colour, with black, brown, grey, purple and red shades, or depigmentations 5.

Satellite foci may surround the primary. In amelanotic melanomas, pigmentation

is absent 17. The tumour surface may be smooth, with an intact overlying

mucosa, or may be ulcerated. Other presenting signs and symptoms include

bleeding, ill-fitting dentures, pain, increased mobility of teeth and delayed

healing of extraction sockets. Regional lymphadenopathy may be present and

connotes a poor prognosis 1, 18.

Tanaka et al. identified five types of OMM on the basis of the clinical

appearance: pigmented nodular type, nonpigmented nodular type, pigmented

macular type, pigmented mixed type and nonpigmented mixed type 17, 19 , 20.

4. Diagnostic aspects Oral melanocytic pigmentations can be observed in dark skinned persons

(“racial pigmentations”), in Peutz–Jeghers syndrome 21, in Addison’s disease 22,

and in some patients with pulmonary disease, including lung cancer 23. The so-

57


called ABCD checklist (“Asymmetry”, “Border” irregularities, “Colour” variegation

and “Diameter” > 6 mm) that is commonly used in the identification process of

cutaneous melanoma 24 could also be of some help in the diagnosis of oral

melanoma 25. When an oral pigmentation cannot be confidently diagnosed as

benign on clinical grounds, a biopsy is mandatory in order to exclude OMM 1, 25,

26.

Greene et al. proposed three criteria for the diagnosis of primary OMM:

demonstration of malignant melanoma in the oral mucosa; presence of so-

called ‘junctional activity’ (i.e., melanocytes arranged along the basal layer of

the surface epithelium) in the lesion; inability to show malignant melanoma at

any other primary site 27. However, the presence of ‘junctional activity’ is now

known to be an unreliable indicator that the lesion is a primary one, since

melanoma metastases may similarly involve the epithelial junction. Delgado et

al. proposed a simple clinical method (“rubbing a gauze”) for the diagnosis of

OMM but the value of such procedure seems somewhat questionable.28, 29 In a

report by Garzino-Demo et al. cytological examination and brushed samples

were negative in all their cases with a proven histological diagnosis of OMM 30.

It should be borne in mind that in cutaneous melanoma, fine needle aspiration

or exfoliative cyotology of primary pigmented lesions is contraindicated.

Radiological examination through computed tomography, magnetic resonance

imaging or positron emission tomography (PET) could be useful for evaluation

of primary tumour and regional or distant metastases. In a study on 10 patients,

Goerres et al. found that PET may be suitable for the staging of patients with

HNMM 31.

4.1 Excisional versus incisional biopsy The current guidelines for the surgical management of primary cutaneous

melanoma recommend a diagnostic excisional biopsy of the lesion followed by

a wide local excision where the diagnosis is proven 32-34. However, in the oral

cavity, the size of the lesion or anatomical limitations, particularly the presence

58

Chapter 3

of teeth, may preclude the taking of an excisional biopsy. Younes et al.

proposed to take an excisional biopsy with a 1- to 2-mm margin for small

lesions in amenable locations, but incisional biopsy, through the thickest or the

most suspicious part of the tumour, in case of a large lesion or a location in

sites where an excisional procedure would involve extensive and mutilating

surgery 25 ,35.

It has often been suggested that cutting into a malignant neoplasm during an

incisional biopsy or other invasive procedure, could result in accidental

dissemination of malignant cells within the adjacent tissues (“seeding”) or even

in the blood or lymphatic stream, with the subsequent risk of local recurrence, or

regional or distant metastasis 36-38. However, in a retrospective study of 265

patients who had an incisional biopsy of cutaneous melanoma and 496 control

cases of excisional biopsy, no such correlation was found 26. These findings are

in agreement with similar studies by Lederman and Sober 39 and by Lees and

Briggs 40. On the other hand, Rampen et al.41 and Austin et al.35 did find a

somewhat reduced survival rate in patients with melanoma who had incisional

biopsies.

Some authors have postulated that a stimulation of tumour outgrowth through

release of fibroblast growth factor (FGF) during wound healing could result from

the surgical procedures, but this hypothesis has not been supported by results

from other studies 42.

5. Histologic features The 1995 WESTOP (Western Society of Teachers of Oral Pathology) Banff

Workshop on OMM drew attention to the fact that most OMMs are discovered

and biopsied in an advanced stage, which probably contributes to the

heterogeneity of microscopic patterns 5.

Like cutaneous melanoma, OMM probably has in many cases an initial phase

characterized by radial growth followed by a phase of invasion of the underlying

tissues (the so-called ‘vertical growth phase’).

59


OMMs can be histologically subclassified into: (1) in situ melanoma, which is

limited to the epithelium and the epithelial–connective tissue interface; (2)

melanomas with an invasive pattern, in which the neoplasm extends into the

connective tissue; (3) melanomas with a combined pattern of invasive

melanoma with in situ component 5. Malignant cells of OMM show a wide range

of shapes, including spindle, plasmocytoid, clear cell and epithelioid ones 5, 43.

The surface epithelium may be flattened and there may be ulceration;

conversely, some OMMs induce pseudoepitheliomatous hyperplasia of the

mucosal epithelium 44, 45. Shivas and Maclennan46 described the presence of

melanin pigment in the ductal epithelial cells of the underlying salivary glands,

using the term“melanogenic metaplasia”.

Usually, OMM can be diagnosed with confidence on H&E-stained sections. If

pigment is completely absent immunohistochemical stains are of significant

help. Useful markers include S-100 protein, gp100 (HMB-45), Mart-1 (Melan-

A).6, 47, 48

OMM does not fit well into any of the classical cutaneous melanoma categories

like superficial spreading melanoma (SSM), nodular melanoma (NM) and acral

lentiginous melanoma (ALM). There is, however, often some similarity to ALM

and NM.2, 5, 9, 49

The pathology report should include all information necessary for further

treatment planning, such as the extent of tumour, tumour spread in relation to

underlying and surrounding tissues, and a statement on the completeness of

resection. In many centers, some additional information of established or

possible prognostic significance will be added: tumor thickness, presence of

ulceration and necrosis, tumor mitotic rate (TMR), vascular invasion 47. Finally, it

is advisable to specify cell morphology and tumour tissue architecture 47, 50, 51.

6. Terminology and classification The term atypical melanocytic proliferation has been used in case of oral

melanocytic lesions in which microscopic evaluation does not result in an

60

Chapter 3

unequivocal diagnosis. Atypical melanocytes have been defined as

melanocytes with hyperchromatic and angular nuclei, but with infrequent mitotic

figures 2, 5. In some studies this histologic pattern has been called “atypical

melanocytic hyperplasia” 2. However, since the word “hyperplasia” suggests a

reactive rather than a neoplastic origin, the term “proliferation” seems to be

preferred here.

Lentigines are small, round to oval, brown or black macules. In the skin several

types of lentigo such as lentigo simplex (LS), and lentigo maligna (LM) 52 are

recognized. The term “lentigo” alone has sometimes been used to refer to

lentigo simplex.21, 52 LS is histologically characterized by heavy pigmentation of

the basal layer, with increased numbers of basal melanocytes, typically, but not

always, associated with elongation of the rete ridges.21, 52

LM is a cutaneous lesion occurring in sun-damaged skin, usually in elderly

persons, most frequently on the face. Histologically, it consists of a proliferation

of atypical melanocytes, in lentiginous patterns, within a flat and atrophic

epidermis, and often extending into cutaneous adnexae. LM is generally

regarded as the pre-invasive phase of lentigo maligna melanoma (LMM) 21, but

it should be realized that only a very few percent of cases, if untreated, will

progress to invasive melanoma.52 LM has also been referred to as morbus

Dubreuilh, or Hutchinson’s freckle.9, 52, 53 The term LM should not be applied to

lesions of the oral mucosa, because of absence of sun damage at that site 52. The term melanoacanthoma has been used to describe a benign mixed tumor

of keratinocytes and pigmented-laden dendritic melanocytes. In contrast to

cutaneous melanoacanthoma, oral lesions occur almost exclusively in Blacks,

affect a much younger population, develop rapidly and generally have a flat

surface. Oral melanoacanthoma is thought to be reactive in nature, and

regression is usually observed after elimination of traumatic factors 52, 54, 55.

61


7. Staging system The histological microstaging system of Clark, used in cutaneous melanoma,

cannot be applied to oral mucosa because of the lack of histologic landmarks

analogous to papillary and reticular dermis.50, 56, 57

The 2002 (revised) TNM Melanoma Staging System of the American Joint

Committee on Cancer, applying the T-symbol for the thickness and the

ulceration status of the tumour, the symbol N for the regional lymph nodes, the

symbol M for distant metastases and the serum lactic dehydrogenase (LDH)

level,58 does not provide specific guidelines for OMM.

A simple TNM clinical staging system for HNMM (including OMM), shown in

Table 1, recognizing three stages, has shown to be of prognostic value.10, 50, 51,

59 A recent histopathological microstaging for Stage I subclassifies three levels

(Table 1) 50. Table 1. Clinical Staging System for OMM with histopathological microstaging for Stage I

Stage I: Primary tumour present only (Tany N0M0)

Level I: Pure in situ melanoma without evidence of invasion or in situ melanoma with “microinvasion”

Level II: Invasion up to the lamina propria

Level III: Deep skeletal tissue invasion into skeletal muscle, bone or cartilage

Stage II: Tumour metastatic to regional lymph nodes (Tany N1M0)

Stage III: Tumour metastatic to distant sites (Tany Nany M1)

62

Chapter 3

8. Treatment

Treatment of OMM is still controversial and there is no consensus regarding the

best therapeutical approach 6, 10, 60. Data from several studies indicate radical

resection of the primary as the treatment of choice 5, 6, 10, 51, 61, 62. Surgery could

be combined with radiotherapy, chemotherapy or immunotherapy even though

the effectiveness of such therapies both as primary or in association with the

surgical treatment is mostly unknown.

8.1 The role of surgery, including the policy with regard to the neck Unlike cutaneous melanoma, where randomized clinical trials have been carried

out to establish the optimal width of the tumour-free margins, no guidelines are

available for the surgical treatment of OMM. A protocol adopted by Umeda and

Shimada 63 refers to the extent of the margins:

1. excision of the primary lesion, preferably using an intraoral approach and

involving at least 1.5 cm of healthy tissue.

2. Excision of any lymph node metastases (Stage II).

3. Consider chemotherapy.

Unfortunately, local control is not a strong predictor for survival 10. Many

patients with a presumptive radical excision of tumours develop a recurrence 5,

which may be explained by the presence of atypical melanocytes in the surgical

margins and/or the presence of satellites 6.

Controversy still remains on the issue of prophylactic neck dissection 3, 64.

Patients with primary OMM present lymph node metastasis in 25% of cases and

this incidence is higher than HNMM at other sites 51. According to Tanaka et

al.,60 neck dissection should be reserved for cases with preoperatively

confirmed lymph node metastases and the choice of the neck dissection

modality should be guided by the extent and the level of the nodes. There is no

proof that elective nodal dissection improves survival. To our knowledge, no

data are available on the issue of the sentinel node biopsy or on the use of PET

scanning in OMM except from the study of Goerres et al 31.

63


8.2 The role of primary and postoperative radiotherapy Most of the studies on the effects of primary radiotherapy have been performed

on the entire group of HNMM and specific data on OMM are scarce 51, 65. In a

study on 35 patients with OMM, Tanaka et al. observed a 5-year cumulative

survival rate of 35.5% in the group of patients treated with irradiation alone,

while it was 15.4% for patients treated with surgery 60. Postoperative

radiotherapy is generally recommended if poor prognostic pathologic features

are present, such as multiple positive nodes, or extranodal spread of

metastastic melanoma, even though OMMs are regarded as poorly

radiosensitive 5, 10. Apparently, postoperative radiotherapy does not seem to

improve the survival rate, even though on this point, no agreement exists in the

literature 6, 10, 51. Temam et al. recently found that in a group of 69 patients

affected by HNMM, including 19 with primary OMM, postoperative radiotherapy

was useful for increasing local control 66. Current postoperative radiotherapy for

cutaneous melanoma delivers 30 Gy or 24 Gy, e.g., in five fractions of 6 Gy

spread over 2.5 weeks or 3 weeks 67, 68. Other irradiation modalities such as

intraoral mould (60Co, 192Ir, or 198Au), intraoral electron beam or interstitial

brachytherapy have also been used 69.

8.3 Other therapies Adjuvant chemotherapy with decarbazine, platinum analogs, nitrosureas, and

microtubular toxins have been used for palliative purposes or for therapy of

metastatic melanoma, but does not seem to influence survival 6. Umeda and

Shimada 63, suggested dimethyl triazeno imidazole carboxamide (DTIC),

nimustine hydrocloride (ACNU) or vincristine (VNC) as drugs of choice for

postoperative chemotherapy.

Anticancer therapy using IFN-γ and anti-Fas antibody has shown positive

results against OMM cells in an experimental model 70.

Systemic immunotherapy has been used as adjuvant or for palliation in the

treatment of disseminated disease. Immunotherapy with IL-2 and other

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Chapter 3

cytokines is not associated with an enhanced survival rate 6. The definition of

the so-called cancer testis antigens (CTAs) expression profile in OMM could

lead to the development of a new vaccine-based therapy 11. Gene therapy is still

in an experimental phase 71.

9. Prognostic factors and survival From a prognostic point of view, clinical stage at presentation is probably the

most important factor in determining outcome 51. In a study on 230 patients

surgically treated for OMM, Liu et al. found that thickness of the tumour, cervical

lymph node metastasis, presence or absence of ulceration and the anatomic

sites were all independent risk factors 72. It has been calculated that nodal

involvement in OMM reduces the median survival time from 46 to 18 months 2.

Furthermore, a tumour thickness greater than 5 mm, presence of vascular

invasion, necrosis, polymorphous tumour cell morphology and the inability to

properly resect the lesions with negative margins have been associated with

poor survival in patients with primary HNMM 2, 10, 51, 57, 73.

Despite the improvement of surgical techniques and the introduction of new

chemotherapeutic agents, prognosis of this malignancy remains poor. The

generally advanced stage of the tumour at initial diagnosis leads to a poorer

survival of patients with mucosal melanoma as compared to patients with

cutaneous melanoma. and the presence of a vertical growth phase are

associated with a reduced median survival rate 2.

In different series, the actuarial 5-year overall survival rate for HNMM ranges

from 21% to 40% 6 and for OMM it is 15% with a median survival of 25 months 2. Gingival melanoma has a better 5-year survival rate than palatal melanoma,

with a longer median survival period (46 months versus 22 months).2

Recurrences may occur even 10–15 years after primary therapy. Distant

metastases to the lungs, brain, liver and bones are frequently observed 74.

65


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71

Chapter 4.

Oral malignant melanoma. Report of 14 cases: The Amsterdam experience.

Marco Meleti 1,2

René C. Leemans 3

Wolter J. Mooi 4

Isaäc van der Waal 2 1 Department of ENT/Dental/Ophthalmological and Cervico-Facial Sciences,

University of Parma, Italy 2 Department of Oral and Maxillofacial Surgery/Oral Pathology, VU medical

center/ACTA, Amsterdam, The Netherlands 3 Department of Otolaryngology/ Head and Neck Surgery, VU medical center,

Amsterdam, The Netherlands 4 Department of Pathology, VU medical center, Amsterdam, The Netherlands

Journal for Oral and Maxillofacial Surgery 2007; 65: 2181-2186

72

Chapter 4

Abstract Purpose. To report the clinical, pathological and therapeutical experience with

a group of patients with primary oral malignant melanoma (OMM).

Patients. 14 patients (5 males, 9 females, mean age 57.9 years) with

histopathological diagnosis of OMM were treated at the Department of Oral and

Maxillofacial Surgery/Oral Pathology of the Vrije Universiteit Medical Centrum

(VUmc) in Amsterdam between 1978 and 2005. A pigmented, flat or swollen,

irregularly bordered lesion of oral mucosa was detected in most patients during

the first clinical examination. Pain was the most commonly referred symptom.

The palate was the most frequently affected subsite. Following the mucosal

melanoma microstaging system all patients staged as stage I (TanyN0M0)

could be subclassified as microstage II (invasion up to the lamina propria),

except one who was microstaged as III (deep skeletal tissue invasion into

skeletal muscle, bone or cartilage). Where possible, surgery has been the

treatment of choice. Postoperative radiotherapy, using fractions of 6 Gy twice a

week for a total dose of 3 30 Gy, was given to 3 patients. Three patients were

primarily treated with radiotherapy alone.

Results. Five patients developed a local recurrence within a period of 4 to 72

months and 10 patients developed distant metastases within a period of 6 to 78

months. Ten patients died of their disease within an average interval of 40

months, with a range of 12 to 80 months. Of the

ten patients who qualified for evaluation of the five-year-survival rate, one was

alive with disease and two were alive without evidence of disease, which results

in a five-year survival rate of 30%. However, all patients have died of their

disease before the end of the ten-year follow-up period.

Conclusions. Our study confirms that OMM is a rare and aggressive

malignancy with a low five-year-survival rate. No evidence-based protocol is

available for the best therapeutical approach.

73

Oral malignant melanoma : the Amsterdam experience

1. Introduction The incidence of head and neck mucosal melanomas (HNMMs) is

approximately four per 10 million population per year in the USA 1. Oral

malignant melanomas (OMMs) represent about 1% of all melanomas and

approximately the 0.5% of all oral malignancies. 2, 3. The neoplasm is more

common in Japan and in some african regions (e.g. Uganda) than in Western

countries 4, 5. The age of reported patients affected by OMM ranges from 20 to

80 years and a male predilection has been observed 2, 3. OMM mostly affects

the palate and the maxillary gingiva 1,3. The possible role of chronic trauma (e.g.

ill-fitting dentures), tobacco habits or environmental pollution as “promoter”

factors has not been established. It is largely unknown if UV light can have

some effects on the oral mucosa biology (especially for mouth-breather

patients) as it happens for the sun-exposed skin. Combinations of surgery,

radiotherapy and chemotherapy for the management of OMM have variously

been reported 3, 6, 7. The prognosis of this malignancy is extremely poor, with a

five year survival ranging between 15% and 20% 1. Metastasis to the oral cavity

derived from a primary melanoma elsewhere in the body, is extremely rare.

In 1994 we have reported 8 cases of primary OMM treated at the Vrije

Universiteit Medical Center (VUmc) in Amsterdam between 1978 and 1993 8.

The present review is based on our experience with six additional patients

referred to our institution between 1994 and 2005.

2. Patients and Methods Clinical and histopathological data from 14 patients with a diagnosis of OMM,

referred to the Department of Oral and Maxillofacial Surgery of VUmc in

Amsterdam between 1978 and 2005, were included in this study. There were

five males and nine females (table 1). The age of the patients ranged from 31 to

91 years (average 57.9 years).

At first clinical evaluation, presence of a pigmented, flat or swollen, irregularly

bordered lesion of oral mucosa was noticed in 12 out of 14 patients while a non-

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Chapter 4

pigmented swelling was recorded in two cases (amelanotic melanoma). In three

cases, lesions were superficially ulcerated. Colours observed were brown, black

or purple. The size ranged from 0.3 to 1.8 cm in diameter. Pain was the most

common referred symptom. The palate was the affected subsite in 9 out of 14

patients (64%); in three cases the lesions were localized in the edentulous

maxilla; one patient presented involvement of the buccal mucosa and one of the

tongue. No reliable information was available about the presence or absence of

pre-existing melanotic pigmentations in the oral subsite where OMM developed,

except for one patient in whom a benign melanotic pigmented lesions was

removed four years previously (patient 12) and another patient who had been

irradiated six years before because of a malignant melanoma of the left cheek

mucosa (patient 7).

In all patients an incisional biopsy was performed. Immunohistochemical

markers such as S-100 protein, gp100 (HMB- 45) and Mart-1 (Melan A) were

used in case of doubt. Applying the histopatological system used in the

WESTOP Banff workshop proceedings on OMMs 3 all but two lesions could be

subclassified as in situ lesions with neoplastic activity limited to epithelium or to

epithelial-connective tissue interface. Cases 6 and 14 were characterized by

tumour extending within the underlying connective tissue. According to the

clinical staging system 7, 9 (table 2), patients without regional lymph node

metastases were subclassified as stage I (TanyN0M0) (13 patients), while one

patient with clinical positive regional lymph nodes was staged as II (TanyN1M0).

Following the mucosal melanoma microstaging system after Prasad et al. 10

(table 2) all patients staged as I (TanyN0M0) could be subclassified as

microstage II (invasion up to the lamina propria) except patient 6 who was

microstaged as III (deep skeletal tissue invasion into skeletal muscle, bone or

cartilage).

Ten out of 14 patients received radical surgery without neck dissection as

primary treatment. Simultaneous neck dissection was performed in one patient with preoperatively confirmed lymph node involvement. Postoperative

75


radiotherapy, using fractions of 6 Gy twice a week for a total dose of 30 Gy, was

given to three patients. Three patients were primarily treated with radiotherapy

alone.

Disease specific survival rates were recorded after five and ten years,

respectively. Table 1. Relevant clinical features of fourteen patients treated between 1978 and 2005.

76

Chapter 4 Table 2. Clinical staging system for OMM with histopathological microstaging for Stage I 10.

3. Results Complete resection of the primary was achieved in 7 out the 11 patients that

received surgery as first treatment (table 3).

Five patients developed a local recurrence within periods of 4 to 72 months.

None of these recurrent tumours could successfully be treated.

Regional metastases were present in one patient at initial admission, while six

patients developed such metastases within periods of 2 to 21 months.

Treatment of such regional metastases consisted in most patients of radical

neck dissection followed by radiotherapy.

Distant metastatic spread occurred in 10 patients within periods of 6 to 78

months. The most commonly involved sites were the lung, the mediastium, and

the liver with rare metastatic spread to the adrenal glands, thyroid glands,

pancreas, atrium and the skin. Some of these distant metastases were only

disclosed at autopsy. In one patient a lobectomy was performed,

unsuccessfully. In one other patient with lung metastases, treatment with

dimethyl-triazeno imidazole carboxamide (DTIC) once every four weeks in a

dose of 800 mg/m2 was administered. Although there was a good response of

the lung lesions, the patient developed a metastasis in one of the adrenal

glands and finally died of the disease. Yet two patients were unsuccessfully

77


treated for distant metastases in the lung and the liver with gammainterferon

and interleukin 2. Of the 11 patients who had at least a follow-up of 12 months and of whom

complete follow-up information was available, ten died of their disease within an

average interval of 40 months, with a range of 12 to 73 months. Of the ten

patients who qualified for the five-year-survival rate, seven had died of their

disease, one was alive with disease and two were alive without evidence of

disease. The latter 3 patients died of their disease within the ten-years follow-up

period.

The follow-up data are summarized in table 3.

78

Chapter 4 Table 3. Follow-up data of 14 patients.

4. Discussion Most of the epidemiologic, histopathologic and clinical features of our patients

were in accordance with those reported in the literature. The incidence in

females was almost twice as high as in males, which is in contrast with the

finding in a few other papers where a higher prevalence was reported in males 2, 9. The palate was the most commonly oral subsite involved.

79


Our experience confirms that the spectrum of clinical manifestations of these

rare tumours is extremely heterogeneous. The lesions can be solitary or

multiple, flat and/or elevated (fig. 1), usually dark pigmented even though

pigmentation can be completely absent (amelanotic melanoma) 3, 11. Borders of

lesions are usually irregular and no clear demarcation exists between the tumor

and the adjacent tissues. A melanocytic activity, clinically corresponding to a

light brown-black pigmentation gradually fading in the surrounding mucosa, can

be observed in most patients.

Satellite foci around the primary may be present as well (fig. 2) giving some

support to the theory of “field cancerization” already proposed for other

histological types of malignancy 12.

Figure 2. Malignant melanoma of the palate in a 33-year-old woman. Notice the separate pigmented area caudally.

Figure 1. Malignant melanoma of the palate witha mixed flat/elevated clinical appearance.

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Chapter 4

Pain, superficial ulceration and bleeding were additional signs and symptoms

recorded in our patients. One out of 14 (7%) of the patients in this series had

regional lymph node involvement at the time of diagnosis. Data form the

National Cancer Data Base (NCDB) USA, show that 27% of patients with

malignant mucosal melanoma of the head and neck develop regional lymphatic

metastases during the course of the disease 6,13.

The existence of an “oral potentially malignant melanocytic lesion” has not

clearly been defined and little is known about the pathobiological mechanism

that leads to the development of OMM 14, 15. According to some authors about

30% of OMMs are preceded by oral pigmentations for several months or even

years 2, 16. It is interesting to notice that among pigmented lesions of oral cavity,

oral nevomelanocytic nevi (OMNs) and OMMs are mostly localized in the palate 17 and this finding may lead to the hypothesis that subtypes of OMNs could

represent precursor lesions in the pathogenesis of OMM. Documentation on the

presence of a pre-existing melanotic pigmentation in the same subsite where

OMM developed was available only for one patient of our series.

From the diagnostic point of view several procedures have been cited in the

literature including cytological examination of brushed samples and clinical

methods such as “rubbing a gauze” 18, 19.

Histopathological examination of an incisional or excisional biopsy still

represents the most accurate diagnostic tool. In the guidelines provided for the

surgical management of cutaneous melanoma a diagnostic excisional biopsy of

the suspected lesion is recommended followed by a wide local excision when

the diagnosis is proven. 20-22. In the head and neck region, however, an

excisional biopsy with a 1- to 2-mm margin for small lesions in amenable

locations, or an incisional biopsy in case of a large lesion or a location in sites

where an excisional procedure would involve extensive and mutilating surgery

seem to be preferred because of the presence of anatomical limitations 23. In all

the cases we faced, an incisional biopsy has been performed since the large

81


dimensions of the tumor and/or the close relationship to teeth or vital structures,

precluded an excisional biopsy. It should be borne in mind that surgical diagnostic or therapeutical procedures

performed on malignant neoplasms could hypotetically increase the risk of

malignant cells spreading in the adjacent tissues (so-called “seeding”) or in

other parts of the body through the blood or lymphatic stream 24,25. Such an

iatrogenic dissemination might play a part in the pathogenesis of recurrences or

distant metastases. Results from studies by Rampen et al. and Austin et al. 26,27

show a somewhat reduced survival rate in patients with melanoma who had

incisional biopsies. Conversely, results from a retrospective study on 265

patients who had an incisional biopsy of cutaneous melanoma and 496 control

cases of excisional biopsy, did not show such correlation 28; other authors seem

to support these findings 29, 30. Five , 6 and 10 patients out of the 14 described

in the present series respectively developed recurrences, regional and distant

metastases. We are not able to quantify which role the incisional biopsy may

have played in the development of metastases since such evaluation would

require the measurement of the level of specific OMM markers in the blood

stream before and after the biopsy.

The value of the sentinel node biopsy for OMM has not been established.

Adjunctive radiological diagnostic methods such as computed tomography,

magnetic resonance imaging and positron emission tomography (PET) are

sometimes useful. In a study on the all group of head and neck mucosal

melanomas (HNMMs) Goerres et al. recently reported that PET scanning may

have some value for staging purposes 31.

From the histopathological point of view our experience confirms the usefulness

of the WESTOP subclassification for uniform reporting and staging 3. The

pathology report should also indicate the OMM cellular subtype as well as the

presence of atypical findings. Our cases showed a wide range of cellular

morphological features such as spindle, plasmacytoid, epithelioid and clear

cells. In one of our patients we also observed and recently reported in detail the

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Chapter 4

extremely rare histological association between OMM and

pseudoepitheliomatous hyperplasia 32. Presence of melanin pigment in the ductal epithelial cells of the underlying salivary glands was described in another

case. This feature has rarely been reported and has previously been named

“melanogenic metaplasia” 33.

Complete excision of the primary tumour, with radiotherapy, chemotherapy or

immunotherapy as adjuncts, has been the treatment of choice, although the

value of adjuvant treatment has not been established. A 1-2 cm tumour-free

margin, generally required and accepted for cutaneous melanoma, can rarely

be applied in the oral cavity 23. Nevertheless, local control does not seem to be

a strong predictor for survival and even after a presumptive radical excision of

tumours many patients develop a recurrence 3, 7. Some factors potentially

implied in the pathogenesis of recurrence may be related to the stimulation of

tissues by growth factors after surgery and to the difficulty of obtaining a

complete excision 6, 34. Thus, despite a presumptive radical surgery of the

primary, the microscopic evaluation of the specimen may reveal the presence of

atypical melanocytes in the margins. In the present evaluation, a radical

excision of the primary was achieved in 7 of the 11 patients treated with

surgery. Nevertheless all of them experienced recurrence and/or metastases

(table 3). The question as whether the usual poor outcome of this disease

should condition the surgical approach remains unanswered.

The policy with regard to the treatment of the neck is still controversial. There is

no evidence that prophylactic neck dissection enhances survival rate of patients

with OMM 35, 36. According to Tanaka et al. 37, neck dissection should be

reserved for cases with preoperatively confirmed lymph node metastases and

the choice of the neck dissection modality should be guided by the extent and

the level of the nodes 38. Six out of fourteen patients (43%) developed regional

metastases during the follow-up.

83


Malignant melanoma has been generally regarded as a poorly radiosensitive

malignancy 3,7. Data on the possible role of primary and postoperative

radiotherapy in the management of OMM are scarce and mostly refer to the

entire group of HNMM 9, 39. In a study on 35 patients affected by OMM primary

radiotherapy appeared to be more effective than surgical treatment when the 5-

years cumulative survival rates were compared 37. Postoperative radiotherapy

could be of some usefulness especially when prognostic pathologic features are

poor (e.g. histopathological evidence of no radical excision or regional lymph

node involvement). Teman et al. recently found that postoperative radiotherapy

did improve local control in a group of 69

patients affected by HNMM, including 19 patients with primary OMM 40. In the

present report, 3 patients received primary radiotherapy and 3 had

postoperative radiotherapy. This small number of patients does not allow to

draw statistical conclusions on the effectiveness of radiation in the treatment of

OMM. Adjuvant chemotherapy does not seem to influence survival 6.

Prognosis of this malignancy remains extremely poor. In different series, the

actuarial-5 year overall survival rate for HNMM ranges from 21% to 40% 6 and

for OMM approximately 15% with a median survival of 25 months 1. Gingival

melanoma seems to have a better 5-year survival rate than palatal melanoma,

(46 months vs. 22 months of median survival period) 1. In the present report

recurrences developed within a period of 4 to 72 months even though lesions

occurring on the same subsite of the primary have been reported after 10-15

years 38, 41.

The relatively small number of included cases does not allow us to make

significant statements about a possible relationship between staging, treatment

and prognosis. Early diagnosis might be essential for successful treatment

and is perhaps the key factor for improving the prognosis of OMM, but this still

has to be proven.

84

Chapter 4

References 1. Hicks MJ, Flaitz CM. Oral mucosal melanoma: epidemiology and pathobiology.

Oral Oncol 2000;36:152-169.

2. Rapini RP, Golitz LE, Greer RO, Jr, Krekorian EA, Poulson T. Primary malignant melanoma of the oral cavity. A review of 177 cases. Cancer 1985;55:1543-1551.

3. Barker BF, Carpenter WM, Daniels TE, Kahn MA, Leider AS, Lozada-Nur F, et

al.. Oral mucosal melanomas: the WESTOP Banff workshop proceedings. Western Society of Teachers of Oral Pathology. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83: 672-679.

4. Takagi M, Ishikawa G, Mori W. Primary malignant melanoma of the oral cavity

in Japan. With special reference to mucosal melanosis. Cancer 1974;34:358-370.

5. Broomhall C, Lewis MG. Malignant melanoma of the oral cavity in Ugandan

Africans. Br J Surg 1967;54:581-584.

6. Lengyel E, Gilde K, Remenar E, Esik O. Malignant mucosal melanoma of the head and neck. Pathol Oncol Res 2003;9:7-12,

7. Medina JE, Ferlito A, Pellitteri PK, Shaha AR, Khafif A, Devaney KO, et al..


8. van der Waal RI, Snow GB, Karim AB, van der Waal I. Primary malignant

melanoma of the oral cavity: a review of eight cases. Br Dent J 1994;176:185-188.

9. Patel SG, Prasad ML, Escrig M, Singh B, Shaha AR, Kraus DH, et al.. Primary

mucosal malignant melanoma of the head and neck. Head Neck 2002;24:247-57.

10. Prasad ML, Patel SG, Huvos AG, Shah JP, Busam KJ: Primary mucosal

melanoma of the head and neck: a proposal for microstaging localized, Stage I (lymph node-negative) tumors. Cancer 2004;100:1657-1664.

11. Notani K, Shindoh M, Yamazaki Y, Nakamura H, Watanabe M, Kogoh T et al..

Amelanotic malignant melanomas of the oral mucosa. Br J Or Maxillofac Surg 2002;40:195-200.

12. Braakhuis BJ, Tabor MP, Leemans CR, van der Waal I, Snow GB, Brakenhoff

RH. Second primary tumors and field cancerization in oral and oropharyngeal cancer: molecular techniques provide new insights and definitions. Head Neck 24 2002:198-206.

85

Oral malignant melanoma : the Amsterdam experience 13. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on

cutaneous and noncutaneous melanoma. Cancer 1998;83:1664-1678.

14. Kahn MA, Weathers DR, Hoffman JG. Tranformation of a benign oral pigmentation to primaty oral melanoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100:454-459.

15. Umeda M, Komatsubara H, Shibuya Y, Yokoo Satoshi, Komori T. Premalignant

melanocytic dysplasia and malignant melanoma of the oral mucosa. Oral Oncol 2002;38:714-722.



17. Buchner A, Merrel PW, Carpenter WM. Relative frequency of solitary melanocytic lesions of the oral mucosa. J Oral Pathol Med 2004;33:550-557.

18. Garzino-Demo P, Fasolis M, Maggiore GM, Pagano M, Burrone S. Oral

mucosal melanoma: a series of case reports. J Craniomaxillofac Surg 2004;32:251-257.

19. Delgado Azañero WA, Mosqueda Taylor A. A practical method for clinical

diagnosis of oral mucosal melanomas. Med Oral 2003;8:348-52.

20. Roberts DL, Anstey AV, Barlow RJ, Cox NH, Newton Bishop JA, Corrie PG, et al.. U.K. guidelines for the management of cutaneous melanoma. Br J Dermatol 2002;146:7-17.

21. Sober AJ, Chuang TY, Duvic M, Farmer EM, Grichnik JM, Halpern AC, et al..

Guidelines of care for primary cutaneous melanoma. J Am Acad Dermatol 2001;45:579-586.

22. McKenna DB, Lee RJ, Prescott RJ, Doherty VR. A retrospective observational

study of primary cutaneous malignant melanoma patients treated with excision only compared with excision biopsy followed by wider local excision. Br J Dermatol 2004;150:523-530.

23. Younes MN, Myers JN. Melanoma of the head and neck: current concepts in

staging, diagnosis, and management. Surg Oncol Clin N Am 2004;13:201-229.

24. Harter LP, Curtis JS, Ponto G, Craig PH. Malignant seeding of the needle track during stereotaxic core needle breast biopsy. Radiology 1992;185:713-714.

25. Kusukawa J, Suefuji Y, Ryu F, Noguchi R, Iwamoto O, Kameyama T.

Dissemination of cancer cells into circulation occurs by incisional biopsy of oral squamous cell carcinoma. J Oral Pathol Med 2000; 29:303-307.

26. Rampen FH, van der Esch EP. Biopsy and survival of malignant melanoma. J

Am Acad Dermatol 1985;12:385-388.

86

Chapter 4 27. Austin JR, Byers RM, Brown WD, Wolf P. Influence of biopsy on the prognosis

of cutaneous melanoma of the head and neck. Head Neck 1996;18:107-117.

28. Bong JL, Herd RM, Hunter JA. Incisional biopsy and melanoma prognosis. J Am Acad Dermatol 2002;46:690-694.

29. Lederman JS, Sober AJ. Does biopsy type influence survival in clinical stage I

cutaneous melanoma? J Am Acad Dermatol 1985;13:983-987.

30. Lees VC, Briggs JC. Effect of initial biopsy procedure on prognosis in Stage 1 invasive cutaneous malignant melanoma: review of 1086 patients. Br J Surg 1991;78:1108-1110.

31. Goerres GW, Stoeckli SJ, von Schulthess, Gustav K, Steinert HC. FDG PET for

mucosal malignant melanoma of the head and neck. Laryngoscope 2002;112:381-385.

32. Meleti M, Mooi WJ, van der Waal I. Oral malignant melanoma associated with

pseudoepitheliomatous hyperplasia. Report of a case. J Cutan Pathol 2006;33:331-333.

33. Maclennan WD, Shivas AA. "Melanogenic Metaplasia" Of Mucous Glands. Br J

Oral Surg 1963; 35: 50-54.

34. Hofer SO, Shrayer D, Reichner JS, Hoekstra HJ, Wanebo HJ. Wound-induced tumor progression: a probable role in recurrence after tumor resection. Arch Surg 1998;133: 383-389.

35. Gu GM, Epstein JB, Morton TH, Jr.. Intraoral melanoma: longterm follow-up and

implication for dental clinicians. A case report and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;96: 404-413.

36. Rigel DS. Malignant melanoma: incidence issues and their effect on diagnosis

and treatment in the 1990s. Mayo Clin Proc 1997;72:367-371.

37. Tanaka N, Mimura M, Ogi K, Amagasa T. Primary malignant melanoma of the oral cavity: assessment of outcome from the clinical records of 35 patients. Int J Oral Maxillofac Surg 2004;33:761-765.

38. Meleti M, Mooi WJ, Leemans RC, Vescovi P, van der Waal I. Oral malignant

melanoma. Review of literature. Oral Oncol 2007;43:116-121.

39. Ang KK, Byers RM, Peters LJ, Maor MH, Wendt CD, Morrison WH, et al.. Regional radiotherapy as adjuvant treatment for head and neck malignant melanoma. Arch Otolaryngol Head Neck Surg 1990;116:169-172.

40. Temam S, Mamelle G, Marandas P, Wibault P, Avril MF, Janot F et al..

Postperative radiotherapy for primary mucosal melanoma of the head and neck. Cancer 2005;103:313-319.

87

Oral malignant melanoma : the Amsterdam experience 41. Calabrese V, Cifola M, Pareschi M, Parma A, Sonzogni A.. Primary malignant

melanomas of the oral cavity. J Laryngol Otol 1989;103:887-9.

89

Chapter 5.

Oral malignant melanoma associated with

pseudoepitheliomatous hyperplasia. Report of a

case.

Marco Meleti 1,2

Wolter J. Mooi 3





Journal of Cutaneous Pathology 2006;33:331-333

90

Chapter 5

Abstract Background: Pseudoepitheliomatous hyperplasia (PEH), a histological

mimic of squamous cell carcinoma, is an exuberant reactive epithelial

proliferation that may be induced by a variety of infectious, traumatic,

inflammatory and neoplastic conditions of the skin and mucous

membranes. PEH has been described in association with Spitz nevi and

intramucosal nevi but not with oral malignant melanoma.

Methods and results: A case of PEH in malignant melanoma of the

palate in a 46 year old female patient has been described. A search of

the English literature did not disclose any previously reported case of

such event.

Conclusions: PEH associated with oral malignant melanoma is

apparently very rare and most likely originates from the surface

epithelium. This is in contrast with PEH in cutaneous melanoma where

follicular or eccrine units have been suggested to be the origin.

91

Oral malignant melanoma and PEH

1. Introduction Pseudoepitheliomatous hyperplasia (PEH) or pseudocarcinomatous hyperplasia

is a reactive proliferation of surface epithelium, occasionally occurring in a

variety of infectious, traumatic, inflammatory, and neoplastic conditions of the

skin or mucous membranes 1, 2. Diseases of the skin commonly associated with

PEH include mycobacterial, fungal, and parasitic infections as well as chronic

irritations and neoplasms1, 3. PEH has also been reported at the edges of

chronic ulcers after burns or in stasis dermatitis1, 4. As stated by Hanly et al.,

Mott et al., and by Filho, association of PEH with melanoma of the skin has not

been documented in detail 2, 3, 5.

In the oral mucosa, PEH has been described in association with granular cell

tumor and pleomorphic adenoma 6, 7. Dorji et al.8 and Suzuki et al.9 described

Spitz nevi and intramucosal nevi of the oral cavity associated with PEH but, to

the best of our knowledge, no case of oral malignant melanoma (OMM) with

PEH has thus far been described.

PEH of the skin is thought to represent a proliferation of squamous epithelium of

follicular and eccrine units or the epidermis itself 3, 5, 6, 10, 11. Considering the

absence of the follicular apparatus in the oral cavity, some authors have

hypothesized a histogenic origin from minor salivary glands or ectopic

sebaceous glands for PEH at this site 3, 12, 13.

We report a patient with malignant melanoma of the oral cavity with associated

PEH.

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Chapter 5

2. Case report A 46-year-old woman was referred to the Department of Oral and Maxillofacial

Surgery for multiple areas of brown-black flat pigmentation involving the

edentulous maxilla, partly located on the palate and partly on the adjacent

alveolar ridge (Fig. 1). The patient was otherwise healthy.

A biopsy of the most suspicious area on the anterior part of the palate showed

malignant melanoma associated with PEH of the surface epithelium (Figs 2 and

3).

Figure 1. Malignant melanoma involving the palate and the maxillary gingiva.

Figure 2. Histologic features of oral malignant melanoma in association with pseudoepitheliomatous hyperplasia of the overlying epithelium, more or less masking the malignant melanoma cells (H&E _50; microstage level II).

Figure 3. Pseudoepitheliomatous hyperplasia. Higher magnification (H&E 100).

93

Oral malignant melanoma and PEH Clinically, there were no signs of regional or distant metastases. CT scanning of

the maxilla did not show destruction of the underlying bone. Further work-up,

including CT of the thorax, did not show the presence of metastases. According

to the TNM staging system proposed for mucosal melanoma of the head and

neck (Stage I: localized disease; Stage II: regional metastases; Stage III distant

metastases), 14 the patient was subclassified as Stage I. The histopathological

microstaging of Clark, used in cutaneous melanoma, cannot be applied to oral

mucosa because of the lack of histologic landmarks analogous to papillary and

reticular dermis. A recently proposed microstaging system for Stage I

recognizes three levels:

1. Level I: pure in situ melanoma without evidence of invasion or in situ

melanoma with microinvasion

2. Level II: invasion up to the lamina propria

3. Level III: deep tissue invasion into skeletal muscle, bone, or cartilage 15

The present case has been microstaged level II. Treatment consisted of a

maxillectomy. The defect was temporarily closed with a prosthesis.

Two years later, a second malignant melanoma, most likely a second primary,

was observed on the right cheek mucosa. This lesion was surgically removed

as well. Two months later, a lymph node metastasis developed on the right side

of the neck. Radical neck dissection with post-operative radiotherapy was

performed.

A few months later, local and regional recurrence was noticed. In addition,

metastases were detected in the mediastinum, the lungs, and in the liver. The

patient was treated with dimethyl triazino imidazole carboxamide chemotherapy

once every 4 weeks in a dose of 800 mg/m2. A total of 15 courses of

chemotherapy were administered. Clinically, there was a partial response, but 6

months later a metastasis was diagnosed in one of the adrenal glands, the

patient refused additional treatment, and died 1 year later.

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Chapter 5

3. Discussion The distinction between malignant melanoma with PEH and pigmented

squamous cell carcinoma (SCC) can be difficult on routine hematoxylin–eosin

sections. Histologically, PEH is characterized by irregular cords and nests of

epithelial cells, extending into the underlying connective tissue. The irregular

contour of nests and strands, hyperkeratosis and papillomatosis, and the

presence of occasional squamous pearls and of mitotic activity may lead to an

erroneous diagnosis of SCC 1, 2. The identification of the underlying disorder

(e.g. granular cell tumor) and the absence of nuclear atypia, abnormal mitotic

figures, or individual dyskeratotic keratinocytes are the key features that

characterize PEH 2, 3. In the present case, the presence of both melanocytic and keratinocytic cells

could also lead to the misdiagnosis of a tumor with biphenotypic characteristics

such as OMM associated with SCC or pigmented SCC. However, the atypical

cells of pigmented SCC show strong positivity for cytokeratin and are S-100

negative 16. Our case was characterized by positivity with S-100 but not to

cytokeratin, indicative of malignant melanoma associated with PEH.

The origin of PEH in oral mucosa is unclear. Where for the skin a stimulated

proliferation of squamous epithelium within follicular and eccrine units has been

hypothesized, the same theory cannot be applied to the oral mucosa, because

of the lack on non-hair-bearing squamous-lined mucosae of the follicular

apparatus 3, 6, 10, 11. Even if a role of the so-called Fordyce's spots (ectopic

sebaceous glands) could be postulated, we would stress the fact that some oral

lesions typically associated with PEH (e.g. granular cell tumor) usually develop

within oral sites in which these glands are uncommon (e.g., dorsal surface of

the tongue). Some authors have also suggested a histogenic origin from minor

salivary glands for PEH in this site, but there is no consensus in the literature 3. Several growth factors (EGF, TGF-α, TGF-β, bFGF, and PDF) and interleukins

(IL-1, IL-6, IL-7, IL-8, IL-10, and IL-12) expressed by in vitro melanoma could

provide the proliferative stimulus to the epithelial cells 17. Some authors have

95

Oral malignant melanoma and PEH

emphasized the possible role of the epidermal growth factor receptor in the

molecular pathogenesis of melanoma-associated PEH, but results from different

studies are inconclusive 2, 18, 19.

Although we cannot provide definitive proof of the structure giving rise to the

PEH, we feel that its presence along much of the surface epithelium, in the

absence of underlying salivary gland tissue, and as illustrated in Figs 2 and 3, is

most compatible with an origin from the surface epithelium itself.

In conclusion, although some studies on the rare association between

cutaneous melanoma and PEH have been reported in the English literature, we

were not able to find such as association for OMM 2, 3, 5, 20. The present case

report documents this intriguing feature of PEH in association with OMM.

96

Chapter 5

References 1. Elder DE, Elenitsas R, Jhonson BL Jr, Murphy GF. Pseudocarcinomatous

hyperplasia. In: Lever's histopathology of the skin. 9th edn. Lippincott, Philadelphia PA: Williams & Wilkins, 2005:836.

2. Mott T, Rosemberg A, Livingston S, Morgan MB. Melanoma associated with

pseudoepitheliomatous hyperplasia: a case series and investigation into the role of epidermal growth factor receptor. J Cutan Pathol 2002;29:490-497.

3. Hanly AJ, Jorda M, Elgart GW. Cutaneous malignant melanoma associated

with extensive pseudoepitheliomatous hyperplasia. Report of a case and discussion of the origin of pseudoepitheliomatous hyperplasia. J Cutan Pathol 2000;27:153-156.

4. Winer LH. Pseudoepitheliomatous hyperplasia. Arch Belg Dermatol Syphiligr

1940;42:856.

5. Filho JSR. Pseudoepitheliomatous hyperplasia in cutaneous malignant melanoma: a rare and misleading feature. J Cutan Pathol 2001;28:496-497.

6. Grunwald MH, Lee JY, Ackerman AB. Pseudocarcinomatous hyperplasia. Am J

Dermatopathol 1988;10:95-103.

7. Takeda Y, Sasou S, Obata K. Pleomorphic adenoma of the minor salivary gland with pseudoepitheliomatous hyperplasia of the overlying oral mucosa. Report of two cases. Pathol Int 1998;48:389.

8. Dorji T, Cavazza A, Nappi O, Rosai J. Spitz nevus of the tongue with


9. Suzuki T, Kumamoto H, Nagasaka H, Kawamura H, Ooya K. Intramucosal

naevus with pseudoepitheliomatous hyperplasia in the gingiva: a case report. Int J Oral Maxillofac Surg 2002;31:330-333.

10. Hurwitz RM. Pseudocarcinomatous or infundibular hyperplasia. Am J

Dermatopathol 1989;11:189.

11. Freeman RG. On the pathogenesis of pseudoepitheliomatous hyperplasia. J Cutan Pathol 1974;1:231.

12. Hanley AJ, Elgart GW. Reply to: Pseudoepitheliomatous hyperplasia of follicular

origin and malignant melanoma. J Cutan Pathol 2001;28:326.

13. Sànchez Yus E, Requena L. Pseudoepitheliomatous hyperplasia of follicular origin and malignant melanoma. J Cutan Pathol 2001;28:325.

14. Patel SG, Prasad ML, Escrig M, et al. Primary mucosal malignant melanoma of

the head and neck. Head Neck 2002;24:247-257.

97

Oral malignant melanoma and PEH 15. Prasad ML, Patel SG, Huvos AG. Primary mucosal melanoma of the head and

neck. A proposal for microstaging localized, Stage I (lymph node-negative) tumours. Cancer 2004; 100:1657-1664.

16. Chapman MS, Quitadamo MJ, Perry AE. Pigmented squamous cell carcinoma.

J Cutan Pathol 2000;27:93-95.

17. Mattei S, Colombo MP, Melani C, et al. Expression of cytokine/ growth factors and their receptors in human melanoma and melanocytes. Int J Cancer 1994;56:853.

18. Courville P, Wechsler J, Tomine E, et al. Pseudoepitheliomatous hyperplasia in

cutaneous T-cell lymphoma. A clinical, histopathological and immunohistochemical study with particular interest in epithelial growth factor expression. The French Study Group on Cutaneous Lymphoma. Br J Dermatol 1999;140:421.

19. Horenstein MG, Prieto VG, Burchette JL Jr, Shea CR. Keratoric melanocytic

nevus: a clinicopathologic and immunohistochemical study. J Cutan Pathol 2000;27:334.

20. Kamino H, Tam ST, Alvarez L. Malignant melanoma with pseudocarcinomatous

hyperplasia – an entity that can simulate squamous cell carcinoma. Am J Dermatopathol 1990;12:446-451.

99

Chapter 6.

Melanotic pigmentation of palatal salivary glands; Report of an unusual case.

Marco Meleti1,2

Wolter J. Mooi3

Isaäc van der Waal2 1 Department of ENT/Dental/Ophthalmological and Cervico-Facial Sciences,

University of Parma, Italy 2 Department of Oral and Maxillofacial Surgery/Oral Pathology, VU medical

center/ACTA, Amsterdam, The Netherlands


Submitted

100

Chapter 6

Abstract Presence of melanin pigment within the epithelial cells of minor salivary glands

(“melanotic pigmentation”) is an exceptionally rare finding and to the best of our

knowledge only one documented case, in association with a malignant

melanoma, has been described.

In the present paper, a case of melanotic pigmentation of the palatal minor

salivary glands is reported. Four years later the patient developed a malignant

melanoma at the junction of the hard and the soft palate.

101

Melanotic pigmentation of minor salivary gland

1. Introduction Melanocytes are embryologically derived from the neural crest and are

generally thought not to be constituents of normal salivary tissue 1, 2. However,

Takeda documented the presence of pigmented cells, most likely melanocytes,

in 1.8% of 445 specimens from autopsies and biopsies of human minor salivary

glands 3. Melanin-containing cells have also been observed within salivary gland

tumours as well as in minor salivary glands adjacent to oral malignant

melanoma (OMM) 2, 4, 5. Phagocytosis and transfer of melanin from melanocytes

to other cells types are the two possible explanations for the presence of

melanin pigment within the cytoplasm of non-melanogenic cells.

The present case reports the finding of melanotic pigmentation of the ductal

cells of minor salivary glands of the palate in the presence of melanosis in the

overlying mucosal epithelium and the subsequent development of an OMM, four

years later. A review of the English literature disclosed only one somewhat

similar case 5.

2. Case report A 50-year-old man was referred to the Department of Oral and Maxillofacial

Surgery/Oral Pathology of the Free University Medical Centrum in Amsterdam

because of a pigmented lesion in the oral cavity. Intraoral evaluation showed

the presence of a flat, irregularly-shaped, not uniformly pigmented lesion

localized on the left side of the hard palate. The lesion was predominantly

brown-black, measured approximately 1.5 cm and was surrounded by several

minor brownish pigmentations (Figure 1). Symptoms were absent and no

palpable regional lymph nodes could be detected in the neck. The medical

history was essentially negative. The patient did not use any medication. He did

not smoke and drank approximately one glass of wine per day.

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Chapter 6

Figure 1. “Melanotic macule” of the left side of the palate surrounded by minor satellite pigmentations. Under the tentative clinical diagnosis of melanotic macule an excisional biopsy

was performed, that included the underlying periosteum. The defect was

covered with a skin graft. Histopathological evaluation showed the presence of

melanin pigment in the basal layer of the mucosal epithelium. There were no

distinct signs of melanocytic atypia. In one of the underlying salivary gland

lobules several pigmented epithelial cells were observed in the interlobular and

excretory ductal cells. Morphology and architectural pattern resembled those of

normal epithelial duct cells with the exception for the presence of

intracytoplasmic pigment, staining positive for melanin (Figures 2 and 3).

103


Figure 2. Presence of melanin pigment within the ductal epithelium of a minor salivary gland in the margin of the surgical specimen (H&E stain; x 50).

Figure 3. Presence of melanin pigment within the ductal epithelium of a minor salivary gland.(H&E stain; x 100).

104

Chapter 6

Follow-up visits were scheduled twice a year. After four years, a white-yellowish

soft tissue mass, surrounded by pigmentation, was noticed in the midline at the

junction of the hard and the soft palate (Figure 4). An incisional biopsy was

performed and histopathological evaluation revealed the presence of a truly

invasive malignant melanoma. Further work-up, including a CT -thorax, did not

show the presence of regional or distant metastases, resulting in Stage I,

according to Patel et al. 6. Treatment consisted of a partial maxillectomy. The

surgical margins were free in all directions and there was no bone invasion.

One year later there was a local recurrence and at the same time a pancreatic

metastasis was detected. The patient died one year thereafter.

Figure 4. Oral malignant melanoma developed four years after the diagnosis of possible neoplastic melanocytic proliferation with extension of melanin into the salivary ductal cells.

3. Discussion OMM is a rare and aggressive neoplasm of melanocytic origin, accounting for

about 1% of all oral malignancies 7. Approximately one third of OMMs are

105


preceded for months or years by a melanotic macule but the histopathologic

nature of such entity is still poorly understood 8. Oral melanocytic naevi (OMNs)

and OMM display similar epidemiological features such as age at occurrence

and the frequent involvement of the palate 9. However, in the present case there

has been no evidence of a pre-existing melanocytic nevus.

Presence of melanin pigment within the epithelial cells of minor salivary glands

is an exceptional finding 5. The biological mechanism underlying this

phenomenon is unknown although several hypotheses have been put forward 2

,4, 5. Shivas and Maclennan excluded the concept of a phagocytic property of the

salivary gland cells leading to the ingestion of melanin produced in melanocytes

elsewhere 5. Instead, They interpreted their finding as melanogenic metaplasia

of mucous cells. In the case of a pigmented mucoepidermoid carcinoma of

minor salivary glands of the palate, Sekine et al. speculated about the possible

presence of a “migration factor” from cancer cells to pre-existing melanocytes

acting as a stimulating factor for melanin production, being delivered to the

adjacent cells 2. In another report of a pigmented pleomorphic adenoma and a

pigmented mucoepidermoid carcinoma, Takeda et al. stated that quiescent

melanocytes of salivary glands can be activated under certain conditions such

as the presence of neoplastic changes 4, 11. Azzopardi et al. investigated

melanin pigmentation in breast carcinomas and also mentioned the possible

existence of a cancer cell-related factor stimulating the adjacent melanocytes 12.

Sakaki et al. reported seven cases of “melanotic oncocytic metaplasia” of the

nasopharynx, hypothesizing a neuropeptidergic stimulation of the melanocytes

and a deposition of melanin within the metaplastic oncocytes 13. A possible

stimulating influence of tobacco smoke on melanocytes was also mentioned by

these authors 13. The phenomenon of melanocytic colonization of neoplasms,

reported for malignancies on other sites, may probably occur also in salivary

glands tumours 15.

Takeda et al. identified pigmented cells, most likely melanocytes, in only 1.8%

of 455 specimens from minor salivary glands 3. These cells were located in the

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Chapter 6

periductal and periacinar fibrous tissue close to the epithelial surface. They

displayed a concentric-circular arrangement and were gathered in groups or

presented as single cells not connected to epithelial cells 3. In another series,

pigmented cells were observed in the interlobular duct of the parotid gland of

only one out of 400 cases 14. In the present case, we were not able to

demonstrate the presence of melanocytes around the pigmented duct cells. On

the basis of the present knowledge we have no convincing hypothesis to

explain the presence of melanin pigment within the salivary gland ductal cells.

Most likely there has been a transfer of the melanin produced by epithelial

melanocytes into the ductal cells of the underlying salivary glands. The concept

of “melanogenic metaplasia” as being proposed by Shivas and Mclennan 5 is an

interesting one. However, until now there is no scientific evidence to support

such concept.

107


References 1. Renaut AJ. Melanoma arising within the parotid salivary gland – a case report

and review of management. Eur J Surg Oncol 1996;22:201-202. 2. Sekine J, Anami M, Fujita S, Vieth M, Inokuchi T. A case of mucoepidermoid

carcinoma with melanin pigmentation manifested in the palate. Virchows Arch 2005;446:460-462.

3. Takeda Y. Existence and distribution of melanocytes and HMB-45 positive cells

in the minor salivary glands. Pathol Int 2000;50:15-19. 4. Takeda Y, Satoh M, Nakamura S. Pigmented pleomorphic adenoma, a novel

melanin-pigmented benign salivary gland tumour. Virchows Arch 2004;445:199-202.

5. Shivas AA, Maclennan WD. “Melanogenic metaplasia” of mucous glands. Br J

Canc 1963;17:411-414. 6. Patel SG, Prasad ML, Escrig M. Primary mucosal melanoma of the head and

neck. Head Neck 2002;24:247. 7. Meleti M, Leemans CR, Mooi WJ, Vescovi P, van der Waal I. Oral malignant

melanoma: a review of the literature. Oral Oncol 2007;43: 116-121. 8. Rapini RP, Golitz LE, Greer Jr RO, Krekorian EA, Poulson T. Primary malignant

melanoma of the oral cavity. A review of 177 cases. Cancer 1985;55:1543-1551.

9. Meleti M, Mooi WJ, Casparie MK, van der Waal I. Melanocytic nevi of the oral

mucosa – No evidence for increased risk of oral malignant melanoma: an analysis of 119 cases. Oral Oncol 2007; Epub ahead of print.

10. Hicks MJ, Flaitz CM. Oral mucosal melanoma: epidemiology and pathobiology.

Oral Oncol 2000;36:152-169. 11. Takeda Y, Kurose A. Pigmented mucoepidermoid carcinoma, a case report and

a review of the literature on melanin-pigmented salivary gland tumors. J Oral Sci 2006;48:243-256.

12. Azzopardi JG, Eusebi V. Melanocytic colonization and pigmentation of breast

carcinoma. Histopathology 1977;1:21-30. 13. Sakaki M, Shek TW, Hirokawa M, Kashima K, Daa T, Gamachi A, Sano T.

Melanotic oncocytic metaplasia of the nasopharynx: a report of seven cases and review of the literature. Virchows Arch 2004;444:345-349.

14. Takeda Y. Melanocytes in the human parotid gland. Pathol Int 1997;47:581-583.

108

Chapter 6 15. Wyatt AJ, Agero AL, Delgado R, Busam KJ, Marghoob AA. Cutaneous

metastatic breast carcinoma with melanocyte colonization: a clinical and dermoscopic mimic of malignant melanoma. Dermatol Surg 2006;32:949-954.

109

Chapter 7.

Melanocytic nevi of the oral mucosa – No evidence of increased risk of oral malignant melanoma: An

analysis of 119 cases.

Marco Meleti 1,2

Wolter J. Mooi 3

Mariel K. Casparie 4




3 Department of Pathology, VU medical center, Amsterdam, The Netherlands 4 Foundation PALGA, Utrecht, The Netherlands

Oral Oncology 2007; 43:976-981

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Chapter 7

Abstract Pigmented nevi of the oral mucosa are rare benign melanocytic tumours.

Epidemiological data are scanty, and the etiology and pathogenesis of these

lesions are poorly understood. Reports are mainly based on isolated cases or a

relatively small series of cases. Some reviews have drawn attention to the

frequent localization of these lesions on the hard palate, the site of preference

for oral malignant melanoma (OMM). However, as yet, there is no direct proof

that oral melanocytic nevi (OMNs) constitute precursor lesions of OMM. 119

cases of OMNs, registered at the nationwide Registry of Pathology (PALGA) in

The Netherlands during the period 1980–2005, have been evaluated.

Subepithelial OMNs were the most commonly recorded lesions (96 cases),

followed by blue (10 cases), compound (7 cases) and junctional OMNs (5

cases). Only one case of a combined nevus was recorded. None of the patients

developed OMM during a mean follow-up period of 8.6 years.

We present an analysis of this series of cases, together with a review of the

literature. The findings of the present evaluation do not give support for the

hypothesis of OMN being a marker for an increased risk of future development

of OMM.

111

Oral melanocytic naevi

1. Introduction Oral melanocytic nevi (OMNs) are benign tumours of melanocytes, the pigment

producing cells found in the skin and in juxtacutaneous mucous membranes,

including the oral mucosa 1. While cutaneous melanocytic nevi of young adult

Caucasians number in the dozens, OMNs are rare, and their etiology and

pathogenesis are poorly understood 2, 3. A Medline database search disclosed

approximately 120 articles on OMNs published between 1965 and 2005, most

of these being reports of isolated cases or small series of cases. In a review of

the literature of 2004, Buchner et al. identified a total number of less than 300

reported OMNs, to which they added a further 91 cases 3.

The prevalence and incidence of OMNs have not been studied systematically.

In Buchner’s study from northern California, OMNs represented 0.1% of about

90.000 biopsies accessed at the Oral and Maxillofacial Pathology Laboratory

during a 19-year period 3. The reported female to male ratio was approximately

1.5:1. There was no racial preference. Age at diagnosis ranged from 3 to

85 years 3-5.

Regarding etiology and pathogenesis, most studies have focused on cutaneous

lesions. It is now clear that melanocytic naevi constitute benign neoplasms of

cutaneous melanocytes, which frequently harbour oncogenic BRAF or, less

commonly, NRAS or HRAS mutations 6. Probably, oncogenic mutations drive

the initial hyperproliferation that results in the formation of the naevus, while a

subsequent growth-arrest response with the features of oncogene-induced

cellular senescence accounts for the cessation of further growth 7, 8.

Different from normal melanocytes which are regularly interspersed as single

cells among basal keratinocytes, forming the so-called “epidermal-melanin unit”,

nevomelanocytes tend to cluster in compact so-called theques 1, 9. In view of the many histologic similarities, it seems plausible that the

pathogenesis of OMNs is similar to that of the cutaneous lesions. Regarding

morphogenesis, the melanocytic proliferation can be divided into three phases:

(1) proliferation of benign neoplastic melanocytes along the submucosal–

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Chapter 7

mucosal junction (junctional nevus); (2) migration of these cells to the

underlying mesenchymal tissue (compound nevi); and (3) loss of the junctional

component of the naevus, so that all remaining nevomelanocytes are located

within the subepithelial compartment (subepithelial nevi) 1, 9, 10.

Congenital melanocytic nevi are present at birth, while those developing after

birth are referred to as acquired nevi 5, 11, 12. Probably, most melanocytic nevi of

the oral mucosa are acquired 5. Reported size have ranged from 0.1 to, rarely,

3.0 cm 4, 5. OMNs typically are well circumscribed round or oval macules,

although slightly raised papules, and polypoid larger lesions have been reported

as well 1, 4, 5. OMNs have been reported to occur multiple 13. Elevated acquired

nevi are usually lightly pigmented, while flatter lesions tend to be more darkly

pigmented 1. Colours vary from brown to blue, bluish-gray, or black; generally

an individual lesion has a similar colour throughout 1, 4, 5, 14. Rare non-pigmented

nevi are on record 15. The hard palate, buccal mucosa and gingiva are most

commonly affected 3, 4, 5, 14, 16, 17. No data in the literature are available regarding

presence of symptoms. OMNs are usually discovered during routine dental

examinations. The clinical appearance is not diagnostic, so that a biopsy is

usually required to exclude other pigmented lesions such as melanotic macula,

amalgam tattoo and, most importantly, malignant melanoma 3. Similarly to their cutaneous counterpart, OMNs are classified in five types: (1)

junctional; (2) compound; (3) subepithelial (sometimes referred to as

intramucosal); (4) blue and (5) combined 5. In the junctional OMN, nests of

nevomelanocytes are arranged along the epithelial–subepithelial junction.

Compound and subepithelial nevi are characterized by sheets and cords of

nevomelanocytes spreading into the underlying connective tissue. In the

subepithelial type the nevus cells are entirely located in the connective tissue

compartment, 1, 10 while in the compound nevus, the nevomelanocytes are

partly arranged at the epithelial–subepithelial junction and partly in the

underlying connective tissue. The blue nevus is characterized by subepithelial

proliferation of generally pigmented, elongated, often bipolar, melanocytes,

113


often accompanied by some stromal fibrotic response and the presence of

melanophages 18-20. Large, so-called plaque-type blue nevi have occasionally

been reported 20. Another rare variant is the Spitz nevus, a subtype

characterized mainly by the large size of the lesional cells 21, 22. Combined nevi

show a combination of a blue nevus with another nevus type, usually a

compound nevus 4, 5, 23.

The aim of the present retrospective analysis is to report the epidemiological

and pathologic features as well as the follow-up data of a series of 119 patients

with OMNs from the files of the nationwide network and Registry of histo- and

cytopathology (PALGA) in The Netherlands in the period between 1980 and

2005. Since 1991 all pathologists in The Netherlands automatically report their

diagnoses to that registry. In the period between 1980 and 1991 the

participation rate gradually increased from 8% in 1980 to 45% and 96% in 1985

and 1989, respectively. Permission was obtained to retrieve all registered cases

of OMNs.

2. Material and methods Data analyzed in the present retrospective evaluation were obtained from the

files of the PALGA Registry of The Netherlands. Criteria adopted for the

database search were based on the association of the term “nevus” with “oral

mucosa”, “oral cavity”, “mouth” or “alveolar process”. Information on the age

and gender, oral subsite, histologic diagnosis, and treatment were obtained.

The search disclosed 809 cases recorded between 1st January 1980 and 31st

December 2005 (Fig. 1). Of these, 137 lesions could be classified as intraoral;

the other cases were located on the lips or the perioral tissues and were

excluded from further evaluation. Lesions histologically diagnosed as

“melanocytic hyperplasia”, “focal melanosis” or “melanocytic lesion” as well as

“white sponge nevus” were excluded from the study. Thus, 119 cases remained

for evaluation.

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Chapter 7

Figure 1. Criteria for the inclusion of the OMNs cases (1980–2005).

All histopathologic reports were reviewed and OMNs were classified into five

groups: junctional, compound, subepithelial, blue nevus and combined nevus

according to accepted histologic criteria outlined above 1, 3-5, 10. Oral subsites

were subclassified in seven groups: hard palate, soft palate, gingiva,

mucobuccal fold, buccal mucosa, floor of the mouth and tongue.

Follow-up data of the 119 patients were obtained from the PALGA Registry. The

length of follow-up varied from 0.5 to 24 years the mean being 8.6 years.

Endpoints included the date of 31st December 2005 or a diagnosis of OMM.

115


3. Results According to the present evaluation of the period 1991–2005, the annual

incidence of excised OMNs in The Netherlands, is 4.35 cases per 10 million

population per year.

The relative frequency of the histopathologic types of the 119 OMNs is listed in

Table 1. Ninety-six (80.6%) nevi were of the subepithelial type, while blue,

compound, junctional and combined nevi accounted for 10 (8.3%), 7 (5.9%), 5

(4.2%) and 1 (0.8%), respectively. The hard palate was the most frequently

involved oral subsite (41 cases, 34.4%), followed by the mucobuccal fold (29 cases, 24.3%), the gingiva (27 cases, 22.6%), the buccal mucosa (13 cases,

11%), the soft palate (5 cases, 4.2%), the tongue (2 cases, 1.7%) and the floor

of the mouth (2 cases, 1.7%). All OMNs from the gingiva and the soft palate

were of the subepithelial type. Eight out 10 (80%) of the common blue nevi were

localized in the palate or in the mucobuccal fold, while no such lesions were

found in the gingiva. Table 1. Histopathologic subclassificasion of 119 OMNs

The gender distribution of OMNs according to histopathologic type and oral

subsite involved is presented in Table 2. Age of patients at the time of diagnosis

ranged from 5 to 87 years. The age range of patients with subepithelial,

compound, junctional and common blue nevi was 5–87 years (mean: 38 years),

16–44 years (mean: 28.7 years), 7–52 years (mean: 28.6 years) and 31–

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Chapter 7

74 years (mean: 49.1 years), respectively. The only patient with a combined

nevus was 38 years of age. In the group of patients younger than 30 years, 15

lesions were located on the hard palate while only four affected the gingiva.

Conversely, during the fourth, fifth and sixth decades, the distribution between

these subsites was almost the same (hard palate: 22; gingiva: 21). Results from

the same evaluation by gender are shown in Table 3. Table 2. Gender distribution of OMNs.

Table 3. Age distribution (years) of OMNs according to the histological type.

117


Complete excision of the lesion was performed in 70 cases, while in 49

instances an incisional biopsy was taken. Three out of the 70 excised lesions (4.3%) were reported to have incompletely removed. Presence of melanin

pigment was mentioned in 20 cases. Ballooning of lesional melanocytes

(presence of copious amounts of finely vacuolated cytoplasm), intralesional

calcification, and mucinous degeneration of nearby minor salivary glands, were

observed in three cases each.

In none of the 119 patients concerned, an OMM was registered during the

follow-up period.

4. Discussion The PALGA Registry is rather unique in registering, since 1991, all

histopathologic and cytopathologic diagnoses rendered in The Netherlands. For

reasons of privacy only data on gender, date of birth and date of diagnosis are

made available for research purposes, such as in the present case. The registry

does not contain information on the date of death or the cause of death.

Since the oral epithelial lining is considered part of the oral mucosa, the

adjective subepithelial rather than intramucosal would seem more appropriate

for describing those lesions entirely confined within the connective tissue. At

present, melanotic nevi are considered to represent neoplasms rather than

malformations, as has been previously thought 6.

Subepithelial OMN is the most common histologic type, followed by blue nevus,

compound, junctional and combined nevi. Even though some cases of Spitz

nevi and epithelioid or plaque-type variant of blue nevi of the oral cavity have

been reported,19-22 no such cases were disclosed in the PALGA data base. One

case of balloon cell intramucosal-type nevus was encountered. This subtype of

nevus, rarely described in the oral cavity, is characterized by nevomelanocytes

with copious, finely vacuolated cytoplasm, caused by swelling of abnormal

melanosomes, together with the presence of nevomelanocytes of usual

appearance and melanophages at the lesional periphery 1, 24. When comparing

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Chapter 7

percentages of our study with those from the study of Buchner et al.,

subepithelial nevi are more frequent in the present series (80.6% vs 55%), while

the frequency of blue nevi is lower (8.3% vs 32%) 5.

OMNs were more frequently biopsied in females (F:M = 1.5:1); it is, however,

unclear whether this means that OMNs are really more frequent in females.

Seven out of 10 blue nevi occurred in women; this contrasts with other studies

where a predilection of blue nevi in men has been reported 3, 8.

The hard palate is the most common subsite affected by OMNs, followed by

mucobuccal fold and gingiva. Involvement of the tongue and the floor of the

mouth is exceptional (4 cases out 119, 3.5%). Two out of 4 of lesions at these

oral subsites were blue nevi. Our data confirm a distinct predilection of OMNs

for the upper part of the oral cavity,3-5, 14 a feature that is shared with oral

melanoma and differs from that of epithelial neoplasms of the oral mucosa.

In accordance with the literature, our data indicate that junctional and combined

nevi are mostly found in young individuals; 75% of the lesions (9 out of 12) were

from patients under 40 years of age. Conversely, the peak incidence of

diagnosis of subepithelial nevi is in the fifth decade (Fig. 2).

Figure 2. Distribution of OMNs in relation to age.

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These data support the idea that melanocytic nevi go through a junctional and a

compound phase before they become subepithelial.3-5, 9, 14 All 10 common blue

nevi were found in patients over 30 years of age (Table 4).

Table 4. Age distribution (years) of OMNs according to oral subsite.

The present evaluation shows that location of OMNs seems to be significantly

related to both age and gender. The reason of the differences of topographical

distribution between males and females remains unknown (Fig. 3).

No data on the potential malignant transformation rate of OMNs are available as

they are for the cutaneous counterpart 5, 25, 26. About one third of OMMs are

preceded by oral pigmentations for months or even years, but the histologic

phenotype of such presumed precursor lesions remains to be reported in detail 26-28. The apparently strong correspondence between oral subsites affected

either by OMNs and OMMs (hard palate, mucobuccal fold, gingiva) may

constitute an indirect argument supporting the idea that some OMNs do

progress to OMM. In the present study all oral melanocytic nevi have been

excised. Therefore, the question as whether such nevi, if left untreated, may in

time transform into a malignant melanoma, remains unanswered. None of the

patients developed a malignant melanoma in the oral cavity in an admittedly

short mean follow-up period of 8.6 years. Since the PALGA Registry does not

contain information about the date of death, the figure of the mean follow-up

period may not be completely accurate. Nevertheless, the present evaluation

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Chapter 7

does not provide concrete support for the idea that the presence of an oral

melanocytic nevus indicates a risk of future development of OMM.

121


References

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2. MacKie RM, English J, Aitchinson TC, Fitzsimonos CP and Wilson P. The number and distribution of benign pigmented moles (melanocytic nevi) in healthy British population. Br J Dermatol 1985;113:167–174.

3. Buchner A, Merrel PW and Carpenter WM. Relative frequency of solitary melanocytic lesions of the oral mucosa. J Oral Pathol Med 2004;34:550–557.

4. Buchner A and Hansen LS. Pigmented nevi of the oral mucosa: a clinicopathologic study of 36 new cases and review of 155 cases from the literature. Part I : a clinicopathologic study of 36 new cases. Oral Surg Oral Med Oral Pathol 1987;63:566–572.

5. Buchner A and Hansen LS. Pigmented nevi of the oral mucosa: a clinicopathologic study of 36 new cases and review of 155 cases from the literature. Part II: analysis of 191 cases. Oral Surg Oral Med Oral Pathol 1987;63:676–682.

6. Takata M and Saida T, Genetic alterations in melanocytic tumors. J Dermatol Sci 2006;43:1–10.

7. Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuliman T van der Horst CM et al. BRAFE600-associated senescence-like cell cycle arrest of human nevi. Nature 2005;436:720–724.

8. Gray-Schopfer VC, Cheong SC, Chong H, Chow J, Moss T, Abdel-Malek ZA et al. Cellular senescence in naevi and immortalisation in melanoma: a role for p16? Br J Cancer 2006;95:496–505.

9. Hicks MJ and Flaitz CM. Oral mucosal melanoma: epidemiology and pathobiology Oral Oncol 2000;36:152–169.

10. Mooi WJ and Kraus T. Biopsy pathology of melanocytic disorders. Biopsy pathology series 17, Chapman & Hall Medical 1991:346 [chapter 11.3.2].

11. Rose C, Kaddu S, El-sherif TF and Kerl H. A distinctive type of widespread congenital melanocytic nevus with large nodules. J Am Acad Dermatol 2003;49:732–735.

12. Allen CM and Pellegrini A. Probable congenital melanocytic nevus of the oral mucosa: case report. Pediatr Dermatol 1995;12:145–148.

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13. Biesbrock AR and Aguirre A. Multiple focal pigmented lesions in the maxillary tuberosity and hard palate: a unique display of intraoral junctional nevi. J Periodontol 1992;63:718–721.

14. Buchner A, Leider AS, Merrel PW and Carpenter WM. Melanocytic nevi of the oral mucosa: a clinicopathological study of 130 cases from northern California. J Oral Pathol Med 1990;19:97–201.

15. Laskaris G., Kittas C and Triantafyllou A. Unpigmented nevus of the palate. An unusual clinical presentation. Int J Oral Maxillofac Surg 1994;23:39–40.

16. Esguep A, Solar M, Encina AM and Fuentes G, Primary melanotic alterations in the oral cavity. J Oral Med 1983;4:141–146.

17. Watkins KV, Chaundry AP, Yamane GM, Sharlock SE and Jain R. Benign focal melanotic lesions of the oral mucosa. J Oral Med 1984;39:91–96.

18. Weedon D. Skin pathology. Churchill Livingstone London 2002:811–826.

19. Pinto A, Raghavendra S, Lee R, DeRossi S and Alawi F. Epithelioid blue nevus of the oral mucosa: a rare histologic variant. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;96:429–436.

20. Fistarol SK and Itin HP. Plaque-type blue nevus of the oral cavity. Dermatology 211 2005:224–233.

21. Nikai H, Miyauchi M, Ogawa I, Takata T, Hayashi Y and Okazaki K. Spitz nevus of the palate. Report of a case. Oral Surg Oral Med Oral Pathol 1990;69:603–608.

22. Dorji T, Cavazza A, Nappi O and Rosai J. Spitz nevus of the tongue with pseudoepitheliomatous hyperplasia. Report of three cases of a pseudomalignant condition. Am J Surg Pathol 2002;26:774–777.

23. Leopold JG and Richards DB. The interrelationship of blue and common nevi. J Pathol Bacteriol 1968;95:37–46.

24. Ide F, Obara K, Enatsu K, Mishima K and Saito I. Balloon cell nevus of the soft palate: an immunohistochemical and ultrastructural study, Pathol Int 2004;54:872–876.

25. Hansen LS and Buchner A. Changing concepts of the junctional nevus and melanoma: review of the literature and report of a case. J Oral Surg 1981;39:961–965.

26. Meleti M, Mooi WJ, Leemans RC, Vescovi P and van der Waal I. Oral malignant melanoma. Review of literature. Oral Oncol 2007;43:106–111.

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27. Rapini RP, Golitz LE, Greer RO Jr, Krekorian EA and Poulson T. Primary malignant melanoma of the oral cavity. A review of 177 cases, Cancer 1985;55:1543–1551.

28. Chaudhry AP, Hampel A and Gorlin RJ. Primary malignant melanoma of the oral cavity: a review of 105 cases. Cancer 1958;11:923–928.

125

Chapter 8. Head and neck mucosal melanoma. Experience with

42 patients with emphasis on the role of postoperative radiotherapy.

Marco Meleti 1,2

René C. Leemans 3

Remco de Bree 3

Paolo Vescovi 1

Enrico Sesenna 1




3 Department of Otolaryngology/ Head and Neck Surgery, VU medical center, Amsterdam, The Netherlands

Submitted

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Chapter 8

Abstract Background. Treatment of head and neck mucosal melanoma (HNMM)

remains a challenge. Surgery has traditionally been the main therapeutic

approach. The role of postoperative radiotherapy has never been clearly

established.

Methods. The experience with a group of 42 patients (16 males; 26 females)

with a primary HNMM is reported.

Results. Eleven out of 19 patients (57.9 %) receiving surgery alone developed

a regional lymphatic metastasis. For patients receiving postoperative

radiotherapy (19 cases), regional metastatic spread occurred in 4 cases (21%).

Percentages of local failure were 57.9 % (11/19) and 26.3 % (5/19) for patients

treated with surgery alone and for those treated with surgery and radiotherapy,

respectively.

Distant metastases occurred in 10 out of 19 patients (52.6 %) receiving surgery

alone and in 9 out of 19 patients (47.3 %) receiving both therapies.

Conclusions. The present evaluation confirms a poor prognosis for patients

with HNMM, independent from the treatment modality.

127

Head and neck mucosal melanoma

1. Introduction Head and neck mucosal melanoma (HNMM) is a rare and aggressive neoplasm

of melanocytic origin 1. This malignancy was firstly described by Weber in 1859

and recognized as a distinct clinical entity, named “melanotic sarcoma” in 1869 2. HNMM accounts for 8-15% of all head and neck malignancies, including

cutaneous melanomas, representing 0.2-10% of all melanomas that may arise

in the body 1-4. In the National Cancer Database of the USA, only 1.3% out of

84,836 cases of melanoma were proven to be of mucosal origin and 611 (0.7%)

of these were located in the head and neck region 5. In their review, Manolidis

and Donald, disclosed a total number of nearly 1000 cases reported in the

literature up to 1997 6.

It has been suggested that the incidence of mucosal melanomas is lower in

geographic areas where cutaneous melanomas are more frequently observed 7,

8. Furthermore, HNMM are apparently more common among Japanese and

Ugandan Africans than among Caucasian populations. 7,9,10. There is no distinct

gender predilection 6, 11, although a few authors reported a female

preponderance in their series 12, 13. The etiology and pathogenesis are still

obscure; this also applies to the role of possible precursor lesions 11, 14, 15. The

clinical manifestations are rather heterogeneous and the histopathologic

appearance is sometimes bizarre 6, 11, 16. HNMMs are rated among the most

malignant tumours of the human body with a 5-year survival rate for nasal,

pharyngeal, oral and sinus melanomas of 30.9, 13.3, 12.3 and less than 5.0

percent, respectively 6, 13, 17-20.

Here we report our experience with a group of 42 patients with a primary HNMM

referred to the VU University Medical Center in Amsterdam, the Netherlands,

and to the Academic Hospital of Parma University, Italy, during the past 30

years together with a discussion on the role of postoperative radiotherapy.

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Chapter 8

2. Patients and Methods Clinical and histopathological data from patients affected by HNMM and

referred to the Otolaryngology/Head and Neck Surgery and to the Oral and

Maxillofacial Surgery/Oral Pathology departments of the VU University Medical

Center in Amsterdam, the Netherlands, and to the Oral and Maxillofacial

Surgery department of the Academic Hospital of Parma University, Italy,

between 1976 and 2006 were retrieved and analyzed. Patients with a neck

lymph node metastasis from cutaneous melanoma or from an unknown primary

and patients with a metastasis to the head and neck region from a primary

located elsewhere in the body were not included in the study.

Forty-two patients (16 males and 26 females, m:f = 1:1.6) qualified for the

evaluation. Age at diagnosis ranged from 31 to 91 years (mean age 63.7 years).

The epidemiological data are summarized in table 1.

Table 1. Epidemiological features of 42 patients affected by HNMM.

Gender Age (years)

Site of primary Number of cases m f m

(mean) f

(mean) total

(range and mean)

Sinonasal tract

Nasal cavity Paranasal sinuses

Nasopharynx

25 (59.5%)

18 5 2

10 7 2 1

15

11 3 1

67.4 66.9 37 to 88 mean 67.1

Oral cavity 17 (40.5%) 6 11 64.3 55.8 31 to 91 mean 58.8

Total 42 (100%) 16 26 66.2 62.2 62.7

129


Clinical data included anatomic subsite (nasal cavity and/or paranasal sinuses,

nasopharynx, oral cavity and lymph nodes of the neck), signs and symptoms,

macroscopic appearance and presence of regional lymph nodes and/or distant

metastasis at the time of diagnosis. Twenty-five out of 42 patients (59.5 %)

were affected by a primary sinonasal mucosal melanoma (SNMM), the

remaining 17 cases (40.5 %) being diagnosed within the oral cavity.

Where available, additional information such as smoking habits and alcohol

intake were collected. Tumour size and presence of neck node metastases

were variously evaluated through clinical and radiological examination including

CT-scan, MRI and ultrasound. Possible presence of distant metastasis was

assessed through chest films, total body CT-scan or bone scintigraphy. All

cases were re-staged according to the mucosal melanoma staging system :

Stage I primary tumour present only (T any N0 M0); Stage II, tumour metastatic

to regional lymph nodes (T any N1 M0) and Stage III tumour metastatic to

distant sites (T any N any M1) 21-24.

In all patients an incisional biopsy had been taken and the diagnosis was made

on conventional H&E stained sections and, in case of doubt, with the use of

immunohistochemical markers ( S-100, HMB45, Melan A).

Histopathologic reports from biopsies and surgical specimens as well as

surgical reports were reviewed and data regarding melanoma subtype and

radicality of the surgical excision were recorded. All patients with stage I

disease were microstaged according to the histopathologic staging system for

stage I mucosal melanomas 24.

Three out of 42 patients were primarily treated with radiotherapy alone and one

patient refused treatment. The remaining 38 patients received surgery with or

without post-operative radiotherapy. One patient received pre-operative radiotherapy. Chemotherapy and

immunotherapy were administered in some cases for the treatment of

disseminated disease and for palliative purposes.

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Chapter 8

For 35 patients complete follow-up data were available. The length of follow-up

varied from 2 to 80 months, the mean being 27.8 months. Endpoint of data

collecting was the date of June 30th, 2006.

Kaplan-Meier survival curves were generated and logrank tests were used to

evaluate the differences between the overall and disease-specific survival rates.

Comparisons of incidence of local and distant metastases as well as local

failure were statistically determined through the Fisher’s exact test. A p- value <

0.05 was considered of statistical significance.

2.1 Clinical presentation Clinical signs and symptoms of patients with SNMM included nasal obstruction,

facial swelling, epistaxis and pain. At clinical evaluation, presence of a black-

brown polypoid mass invading the nasal cavity, the paranasal sinuses with

radiological evidence of bone destruction was often reported. In some cases,

the tumour was growing in the nasopharyngeal area and in few cases the

lesions were reported as non-pigmented. For patients with OMM, presence of

pigmented flat or swollen, often ulcerated lesion accompanied by pain and

bleeding were the most frequently reported manifestations. Complete

information on smoking habit and alcohol intake were available for 22 out of 42

patients. Of these, 9 were smokers (at least 20 cigarettes/day). Only in 2

patients a positive history of alcohol abuse was recorded.

2.2 Histopathology and microstaging The differential histopathologic diagnosis based on conventional stained

sections (H&E) included a variety of tumours such as poorly differentiated

squamous cell carcinoma, lymphoma, esthesioneuroblastoma,

rhabdomyosarcoma and unspecific diagnoses like “malignant necrotizing

tumour”, “malignant subepithelial tumour” or “poorly differentiated tumour”. In 22

lesions immunohistochemistry was performed; 17 stained positive for S-100

131


protein and 8 for HMB45. Lesions positively reacting to both markers were 5.

Eight out of 42 lesions (19 %; 6 SNMM, 2 OMM) were amelanotic melanomas. Twenty-seven patients (13 SNMM; 14 OMM) and 11 (10 SNMM; 1 OMM) were

microstaged as level II and level III respectively, according to the microstaging

system for stage I mucosal melanoma (level II : invasion up to the lamina

propria and level III deep skeletal tissue invasion into skeletal muscle, bone or

cartilage) (Table 2) 24.

Table 2. Relationship between histopathologic microstaging* for Stage I, level II and level III patients and local recurrence, regional and distant metastatic spread.

Patients Regional metastasis

Local recurrence Distant metastasis

Patients with microstage level II (27 Patients)

12 (44.4%)

13 (48.1%)

14 (51.8%)

Patients with microstage level III (11 Patients)

2 (18.1%)

4 (36.3%)

4 (36.3%)

P value 0.1596 0.7210 0.4848

* Level I : Pure in situ melanoma without evidence of invasion or in situ melanoma with “microinvasion” ; not such cases included in the present study Level II : Invasion up to the lamina propria Level III : Deep skeletal tissue invasion into skeletal muscle, bone or cartilage No statistically significant differences are observed between microstage levels II and III. However, a decreased incidence of regional and distant metastasis, as well as local failure can be outlined for microstage level III patients.

2.3 Treatment of the primary and radicality Thirty-eight patients underwent surgical excision of the tumour as the treatment

of choice. Simultaneous neck dissection was performed in the two patients with

preoperatively confirmed lymph node involvement. In 19 cases, additional

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postoperative radiotherapy was administered. Three out of 42 patients were

treated by radiotherapy alone. One patient refused treatment.

Depending on the extension of the primary and the subsite involved, the

surgical approach included lateral rhinotomy, nasal septum resection, partial or

total maxillectomy, partial glossectomy or a combination of these. Laser

treatment was used in one case of SNMM with involvement of the maxillary and

sphenoid sinuses in which general conditions of the patient precluded other

treatments. Such a treatment was not curative and the patient had a recurrence

and died 8 months after therapy.

According to the evaluation of the surgical and the histopathological reports,

radicality after excision of the primary was achieved in 23 patients (15 SNMM; 8

OMM). In 11 cases no radicality was obtained (7 SNMM; 4 OMM). For 4

patients the data on radicality were not available.

The most frequently adopted scheme of postoperative radiotherapy consisted of

600 cGy twice a week for a total dose of 3000 cGy.

3. Results 3.1 Local recurrence and metastatic spread Seventeen out of 42 patients (40.4%; 10 SNMM – 40%; 7 OMM – 41.1%)

experienced local failure (development of a recurrence and/or of a second

primary) after a period of time ranging between 1 and 72 months (mean 20.4

months; mean SNMM: 10 months; mean OMM: 35.4 months) from the therapy.

Recurrences were usually treated by surgery, in some cases followed by

radiotherapy.

Fourteen out of 42 patients (33%; 7 SNMM – 28%; 7 OMM – 41.1% ) developed

regional lymph node metastases during follow-up, in a period ranging between

2 and 39 months (mean 14.2 months: mean SNMM: 13.5 months; mean OMM:

15 months). For patients with SNMM, the involvement of the neck was

homolateral in 5 cases, contralateral in one case and bilateral in another. Neck

metastases mainly occurred in the submandibular region (5 cases), the others

being localized in the submental, subdigastric or infraclavicular areas.

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Treatment of these neck metastases mainly consisted of radical neck dissection

followed by radiotherapy. Extranodal spread was reported in 2 cases. Twenty-one out of 42 patients (50%; 11 SNMM – 44%, 10 OMM – 58.8%)

developed single or multiple distant metastases in a mean period of 21.2

months (ranging between 0 to 78 months; mean SNMM: 16.5 months; mean

OMM: 26.4 months ). The most commonly involved sites were the lungs (8

patients) and the bone (6 patients). Other sites of distant metastatic spread

included brain, liver, breast, pancreas and subcutaneous tissues. Therapy

strategies for metastatic disease were mainly based on chemotherapy with

dimethyl-triazeno-imidazole carboxamide (DITC), fluorouracil (5-FU) and

doxorubicin (L-DOX), immunotherapy with gamma-interferon and interleukin 2,

or on a vaccine prepared from the neoplastic cells.

3.2 Follow-up and survival rates; microstaging and prognosis Overall and disease-specific 2-year and 5-year survival rates were evaluated for

patients with SNMM, OMM and for the whole group of patients with HNMM

(Table 3; overall and disease-specific 2-year survival rates for OMM = 62.5%

and 66.6%; overall and disease-specific 2-year survival rates for SNMM =

38.8% and 53.8%; overall and disease-specific survival rates for HNMM = 50%

and 60.7%. Overall and disease-specific 5-year survival survival rates for OMM

= 38.4% and 41.6%; overall and disease-specific 5-year survival rates for

SNMM = 0%; overall and disease-specific 5-year survival rates for HNMM =

17.2 % and 21.7 %). The Kaplan-Meier survival curves show a statistically

higher 5-year survival rate for patients affected by OMM as compared to

SNMM. (Logrank test : P = 0.0227; 95% CI : 0,1610 to 0,8718). (Figures 1 and

2)

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Chapter 8 Table 3. Two-year and 5-year overall and disease-specific survival rate for the patients with SNMM, OMM and for the whole group of patients with HNMM.

2-year survival rate 5-year survival rate Site of the primary

Overall Disease-specific Overall Disease-specific

SNMM 38.8% 53.8% 0% 0% OMM 62.5% 66.6% 38.4% 41.6%

HNMM 50% 60.7% 17.2% 21.7%

Figure 1. Overall 5-year survival rate of patients affected by OMM and SNMM. (Logrank test : P = 0.0227; 95% CI : 0,1610 to 0,8718).

135


Correlations between histopathological microstaging and occurrence of regional

metastasis, local failure and development of distant metastases are shown in

Table 2. Histopathologic microstage levels did not significantly correlate with

any of the parameters evaluated (P value for regional metastases = 0.1596; P

value for local failure = 0.7210; P value for distant metastases = 0.4848), even

though a decreased incidence of negative events can be outlined for patients

with microstage level III.

The Kaplan-Meier survival curves do not show a difference in the overall and

disease-specific 5-year survival rates for patient with microstage level II and III

(Logrank test : P1 = 0.2919; 95% CI : 0,1786 to 1,6784. P2 = 0.2254; 95% CI :

0,1037 to 1,8257) (Figures 3 and 4).

Figure 2. Disease-specific 5-year survival rate of patients affected by OMM and SNMM. (Logrank test : P = 0,0643; 95% CI : 0,1475 to 1,0566).

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Chapter 8

Figure 3. Kaplan-Meier estimator for patients with microstage level II and III (overall 5-year survival rate). (Logrank test : P = 0.2919; 95% CI : 0,1786 to 1,6784).

Figure 4. Kaplan-Meier estimator for patients with microstage level II and III (disease-specific 5-year survival rate). (Logrank test : P = 0.2254; 95% CI : 0,1037 to 1,8257).

137


3.3 Surgery versus surgery + postoperative radiotherapy Data on the comparison between patients treated with surgery alone or in

association with radiotherapy are summarized in Table 4. Eleven out of 19

patients (57.9 %) receiving surgery as only treatment for the primary developed

a regional lymphatic metastasis (mean time of occurrence : 14.5 months). On

the other hand, in the group of patients receiving postoperative radiotherapy (19

cases) metastatic spread to the lymph nodes of the neck occurred in 4 patients

only (21%; mean time of occurrence : 13.75 months) (P = 0.0448).

Table 4. Surgery versus surgery + postoperative radiotherapy.

Treatment of the primary

Regional metastasis Local failure Distant

metastases

Surgery (19 Patients) 11 (57.9 %) 11 (57.9 %) 10 (52.6 %)

Surgery + radiotherapy (19 Patients)

4 (21 %) 5 (26.3 %) 9 (47.3 %)

P value 0.0448 0.0991 1.000

A statistically significant difference is observed between patients receiving surgery and patient receiving surgery and postoperative radiotherapy with regard to regional metastasis. A not-statistically significant decreased incidence of regional and distant metastasis, as well as local failure can be outlined for patients treated with postoperative radiotherapy. Percentages of local failure were 57.9 % (11/19; mean time of occurrence 24.5

months) and 26.3 % (5/19; mean time of occurrence 9.4 months) for patients

treated with surgery alone and for those treated with surgery and radiotherapy,

respectively (P = 0.0991). Distant metastases occurred in 10 out of 19 patients (52.6 %; mean time of

occurrence 26.3 months) receiving surgery alone and in 9 out of 19 (47.3 %;

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mean time of occurrence 15.6 months) patients receiving both therapies (P =

1.000). A lesser incidence of regional and distant metastasis, as well as local failure

was observed for patients treated with surgery and postoperative radiotherapy.

The Kaplan-Meier estimator, however, shows a statistically significant better

prognosis for patients receiving surgery alone (Logrank tests : P = 0.0028; 95%

CI : 0,1162 to 0,6396) (Figures 5 and 6).

Data on stage at diagnosis (including microstage) as well as on radicality of

surgery, separately evaluated for the two groups, are reported in tables 5 and 6.

Figure 5. Overall 5-year survival for patients treated by surgery and surgery + postoperative radiotherapy. “S” = Surgery; “SR” = Surgery + radiotherapy; (Logrank test : P = 0.0028; 95% CI : 0,1162 to 0,6396).

139


Table 5. Relationship between treatment and stage at diagnosis (including microstaging for Stage I *).

Stage at diagnosis Treatment of the

primary I-II* I-III* II III

Surgery (19 Patients) 14 (73.6%) 4 (21%) 1 (5.2%) No patients

Surgery + radiotherapy (19 Patients) 10 (52.63%) 7 (36.8%) 1 (5.2%) 1 (5.2%)

* Level I : Pure in situ melanoma without evidence of invasion or in situ melanoma with “microinvasion” ; not such cases included in the present study; Level II : Invasion up to the lamina propria; Level III : Deep skeletal tissue invasion into skeletal muscle, bone or cartilage

Figure 6. Overall 5-year survival for OMM and SNMM patients treated by surgery and surgery + postoperative radiotherapy. “OS” = OMM treated with surgery; “OSR” = OMM treated with surgery + radiotherapy; “SNS” = SNMM treated with surgery; SNSR = SNMM treated with surgery + radiotherapy; (Logrank test : P = 0,0129)

140

Chapter 8 Table 6. Relationship between treatment and radicality after the surgical excision of the primary.

Radicality after the surgical excision of the primary Treatment of the

primary Radical Not radical No data

Surgery (19 Patients) 14 (73.6%) 3 (15.8%) 1 (5.2%)

Surgery + radiotherapy (19 Patients) 9 (47.3%) 8 (42.1%) 2 (10.5%)

4. Discussion Most of the epidemiological and clinical data analyzed in the present study are

comparable to those reported in the literature 4, 21, 25-27. The peak incidence of

HNMM is between the sixth and the seventh decade. In the present series,

OMM seems to affect patients younger (mean age 58.8 years) than patients

with SNMM (mean age 67.1 years). Women with OMM were significantly

younger than men (mean age of 55.8 and 64.3 years respectively). No distinct

gender predilection was found.

Nasal obstruction, epistaxis and pain are the most frequently reported

symptoms in patients with SNMM 6, 27. A diagnostic delay, probably mainly

related to patients attitudes, ranging between 2 months and 2 years from the

appearance of the first symptoms, was recorded in different series 6. OMM

usually presents as a painful pigmented swelling, even though flat lesions or

non-pigmented masses are sometimes described (amelanotic melanoma). Both

SNMM and OMM are often ulcerated 28, 29.

The role of tobacco habits and formaldehyde exposure as risk factors for

inducing abnormal melanocytic differentiation has been hypothesized by some

authors 6, 30. In the present series, chronic tobacco use was recorded only in a

few patients. In contrast to melanoma of the skin, the pathogenesis of HNMM

141


seems to be based on genetic mechanisms unrelated to ultraviolet light

exposure 31. The close anatomic proximity of the commonly affected head and

neck mucosal sites (nasal cavity and paranasal sinuses and the palate) may

lead to the hypothesis that the pathogenesis of these tumours is related to

some abnormality during the embryogenesis of this region 32.

Approximately one third of OMMs are preceded by localized pigmentation for

months or years 11. The nature of such precursor lesions has not been clearly

established yet. A recent evaluation on 119 patients with oral melanocytic nevi

(OMNs) did not show an increased risk for OMM development 15. The present experience confirms the rather variable histopathological

appearance of HNMM. In many of the cases, a definitive diagnosis could only

be obtained with the use of specific markers such as antivimentin, S-100,

NKI/C-3 and HMB-45. The histopathologic differential diagnosis mainly included

poorly differentiated squamous cell carcinoma, lymphoma and sarcoma. The

use of electronic microscopy may provide some help in the demonstration of

premelanosomes 6. Differently from its cutaneous counterpart, where a radical excision can often be

achieved, the management of HNMM still represents a challenge. The often late

diagnosis, anatomical limitations that preclude the possibility of a radical

excision, and probably a more malignant biologic behaviour, negatively

influence the success of treatment and the prognosis 33, 34.

The limited size of most reported series and the heterogeneity of data do not

enable to assess the effectiveness of the various treatment modalities with

regard to variables such as local control, metastatic spread and survival rates 35. Surgery has traditionally been the main therapeutic approach for the

treatment of this malignancy 35. The role of postoperative radiotherapy in the

management of HNMM has not yet been clearly established and the results of

various studies on this subject remain controversial 1, 25, 35-37. Because of the

rarity of this neoplasm it will be difficult to perform a randomized-controlled trial

for a critical evaluation and comparison of the two treatment modalities. As a

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Chapter 8

matter of fact, most of the studies in the literature are retrospective analyses

performed on small series of patients and these evaluations are biased by the

lack of randomized selection criteria, as is the case in the present series.

In the present evaluation the number of patients who experienced regional

and/or distant metastases as well as a local failure is higher among those who

did not receive postoperative radiotherapy. In particular, the percentage of neck

lymph node metastases seems to be significantly decreased by the

administration of radiotherapy. Surprisingly, the analysis of the overall 5-year

survival rate through the Kaplan-Meier estimator, demonstrates a better

prognosis for patients treated by surgery without postoperative radiotherapy.

This observation holds true when the analysis is separately performed for

patients with SNMM and patient with OMM (Figures 5 and 6). These results

may probably be explained through the evaluation of data on the radicality after

excision of the primary (table 4). In fact, the resection of the tumour was radical

for 14 out 19 (76.3%) patients in the group receiving surgery alone. This

percentage is significantly decreased in the group of patients treated with post-

operative radiotherapy (47.3%; 9 out of 19 patients). Stage at diagnosis

(including microstaging) does not seem to be different in the two groups (table

5). These findings are in accordance with some other previously reported

studies. Lund et al. did not find any statistical difference of the overall survival

rate in a group of 58 patients with SNMM treated with surgery or with surgery

and radiotherapy 36. In a retrospective analysis on 48 patients affected by

HNMM, Owens et al. showed that the addition of radiotherapy to surgical

treatment leads to an improvement of locoregional tumour control 35. Similarly,

Temam et al. reported a significant higher local control rate for patients

additionally treated with postoperative radiation 25. However, in most of the

reported series, local control was not associated with an increased survival rate.

An exception is the study by Kingdom and Kaplan who observed an increased

survival rate among patients treated with surgery and radiotherapy compared to

those treated by surgery alone 38.

143


The low number of stage II and stage III patients (regional disease and distant

metastases, respectively) in the present series does not allow to draw any

statistically significant conclusions about the relationship between stage at

presentation and prognosis. The observation by Prasad et al. that the

histopathological microstage for stage I disease, reflecting tumour progression

within the surrounding tissues, is a predictor of survival 24, is not supported by

the results of the present study.

The results of the present evaluation confirm a poor prognosis for patients

affected by primary HNMM, independent from the treatment modality, being

surgery alone or surgery followed by radiotherapy. In particular, the overall 5-

year survival rate for the whole group of HNMM of 17.2% seems to be slightly

lower compared with those reported in other studies 8, 18, 21, 36, 37, 39-41.

A site specific difference was noticed with regard to survival. Patients with OMM

seem to have an higher disease-specific 5-year survival rate compared to

patients with SNMM (38.4 % and less than 5 percent respectively). It is

debatable if this difference depends on factors such as the histopathological

microstage for stage I tumour (56.5 % of patients with SNMM had a microstage

level III while only 6.6% of patients with OMM had the same microstage level)

since such a microstaging system does not seem to correlate with the survival-

rate in the present evaluation. However, these results are in contrast with

some reports where melanoma arising in the nasal mucosa appears to have a

better prognosis 17.

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malignant mucosal melanoma of the head and neck region: pooled analysis of 60 published cases from India and review of literature. Europ J Canc Prevent 2002;11:3-10.

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17. Moore ES, Martin H. Melanoma of the upper respiratory tract and oral cavity.

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18. Shah JP, Huvos AG, Strong EW. Mucosal melanoma of the head and neck. Am J Surg 1977;134:531-535.

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20. Freedman HM, De Santo LW, Devine KD. Malignant melanoma of the nasal cavity and paranasal sinuses. Arch Otolaryngol 1973;97:322-325.

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Chapter 9.

Summary and conclusions

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Chapter 9

Summary and conclusions The diagnostic procedure of pigmented lesions of the oral cavity and perioral

tissues is a challenging one. Even though epidemiology may be of some help in

orientating the clinician and even though some lesions may confidently be

diagnosed on clinical grounds alone, such a diagnosis remains “provisional”. A

definitive diagnosis usually requires histopathological evaluation. Occasionally,

immunohistochemical stains such as melanocyte marker HMB-45 and

macrophage marker CD68 may be required to arrive at a correct diagnosis. The so-called ABCD checklist (“Asymmetry”, “Border” irregularities, “Color”

variegation and “Diameter” > 6mm) that is commonly used to aid in the

identification of cutaneous melanoma may also be of some help in the clinical

diagnosis of oral malignant melanoma (OMM). Rapidly growing pigmented

lesions should always be biopsied. Location on the palate increases the rate of

suspicion of melanoma and usually requires a biopsy or long-term follow-up.

A critical analysis of the literature on human OMM discloses a lack of thorough

knowledge on the etiology and pathogenesis of this malignancy as well as a

lack of evidence on the best therapeutical approach. The hypothesis that

inhaled environmental carcinogens, including tobacco and formaldehyde, may

have some influence in promoting an abnormal melanocytic proliferation is

based on few epidemiological observations. Most of the reports do not include

data on the presence or absence of exposure to carcinogenetic factors. p53

protein alterations have been identified in about two-thirds of OMM.

Surgical excision is the most frequently reported treatment for OMM. Surgery

could be combined with radiotherapy, chemotherapy or immunotherapy even

though the effectiveness of such therapies either as primary treatment or in

association with surgical treatment is largely unknown.

The Amsterdam experience with 14 patients affected by OMM confirms the

extremely malignant and aggressive behaviour or this neoplasm. Five patients

developed a local recurrence within a period of 4 to 72 months and 10 patients

developed distant metastases within a period of 6 to 78 months. Ten patients

149


died of their disease within an average interval of 40 months, with a range of 12

to 80 months. Of the ten patients who qualified for evaluation of the five-year

survival rate, one was alive with disease and two were alive without evidence of

disease, which results in a 30% five-year survival rate. However, all patients

have died of their disease before the end of the ten-year follow-up period.

From the histopathological point of view it seems remarkable to report a case of

OMM associated with pseudoepitheliomatous hyperplasia (PEH). The presence

of both melanocytic and keratinocytic cells could lead to the misdiagnosis of a

tumour with biphenotypic characteristics such as OMM associated with

squamous cell carcinoma (SCC) or pigmented SCC. The presence of PEH

along much of the surface epithelium, in the absence of underlying salivary

gland tissue, appears to point at an origin of the PEH from the surface

epithelium itself.

In another case, the presence of melanotic pigmentation of the palatal minor

salivary glands was documented four years before a diagnosis of an OMM of

the palate was established. Presence of melanin pigment within the epithelial

cells of minor salivary glands is an exceptional finding and the biological

mechanism underlying this phenomenon is unknown. The concept of

“melanogenic metaplasia” as being proposed by Shivas and Mclennan is an

interesting one. However, until now there is no scientific evidence to support

such concept. It is questionable whether melanotic pigmentation of the palatal

minor salivary glands represents a potentially malignant disease.

Data from the literature show that about 30% of OMM are preceded by mucosal

pigmentation for several months or even years. Some of these flat precursor

lesions consist of cytologically atypical melanocytes and may in fact constitute

the preinvasive macular phase of melanoma.

The apparently strong correspondence between oral subsites affected either by

oral melanocytic naevi (OMNs) and OMMs (hard palate, mucobuccal fold,

gingiva) may constitute an indirect argument supporting the idea that some

OMNs do progress to OMM.

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Chapter 9

However, the results of our own study do not confirm the hypothesis that the

presence of an OMN indicates a risk of future development of OMM. In fact, None of the 119 patients with a diagnosis of OMN developed a malignant

melanoma in the oral cavity in a mean follow-up period of 8.6 years.

With regard to the whole group of patients affected by head and neck mucosal

melanoma (HNMM), oral malignant melanoma seems to affect patients at a

younger age (mean age 58.8 years) than patients with sinonasal mucosal

melanoma (SNMM) (mean age 67.1 years). The number of patients who

experienced regional and/or distant metastases as well as a local failure was

higher among those who did not receive postoperative radiotherapy. In

particular, the percentage of neck lymph node metastases seems to be

significantly decreased by the administration of radiotherapy. Surprisingly, the

analysis of the overall 5-year survival rate through the Kaplan-Meier estimator,

showed a better prognosis for patients treated by surgery without postoperative

radiotherapy. A similar result was shown when the analysis was separately

performed for patients with SNMM and patients with OMM. Because of the

retrospective nature and the incompleteness of the clinical records no clear

guidelines were provided with regard to the indication for postoperative

radiotherapy in the individual patients. A bias of the present evaluation may be

represented by the fact that melanomas with an apparently intrinsic worse

prognosis (e.g. SNMM) are overrepresented in the group of patients receiving a

combined treatment. Unfortunately, the rarity of this neoplasm makes it rather unrealistic to perform a

randomized-controlled trial for a critical evaluation of the role of postoperative

radiotherapy. The observation by Prasad et al. that the histopathological microstage for stage

I disease of OMM, reflecting tumour progression within the surrounding tissues,

is a predictor of survival, is not supported by the results of the present study.

The overall 5-year survival rate for the entire group of HNMM patients of the

present series is 17.2%. A site specific difference was noticed with regard to

151


survival. Patients with OMM seem to have an better disease-specific 5-year

survival rate than patients with SNMM.

153

Chapter 10.

Samenvatting en conclusies

154

Chapter 10

Samenvatting en conclusies De diagnostiek van gepigmenteerde lesies van de mond en omgevende

structuren kan bijzonder lastig zijn. In veel gevallen lijkt het verantwoord om op

grond van bijvoorbeeld de leeftijd, de localisatie, de anamnese en het klinische

aspect op alleen klinische gronden tot een diagnose te komen, maar in

sommige gevallen is toch behoefte aan een meer zekere diagnose met behulp

van weefselonderzoek. Het kan daarbij nodig zijn om immuunhistochemische

kleuringen toe te passen, zoals de melanocytenmerker HMB-45 en de

macrophagenmerker CD68, naast bijvoorbeeld routinematige kleuringen zoals

de ijzerkleuring. De in de Engelse literatuur bekende ABCD checklist, waarbij

de A staat voor asymmetry, de B voor border irregularities, de C voor

verschillen in kleur en de D voor diameter ( > 6 mm) die wordt gebruikt bij de

diagnostiek van melanomen van de huid is ten dele ook toepasbaar bij het

maligne melanoom van het mondslijmvlies. Snel groeiende gepigmenteerde

lesies dienen echter altijd te worden gebiopteerd. Localisatie van de

pigmentatie op het palatum verhoogt de verdenking op de aanwezigheid van

een maligne melanoom of eventueel een voorstadium daarvan en maakt

derhalve een biopsie en/of langdurige controle noodzakelijk.

Een kritische analyse van de bestaande literatuur over het orale maligne

melanoom laat zien, dat er eigenlijk geen goed inzicht is in de etiologie en de

pathogenese van deze kwaadaardige tumor. Bovendien zijn er geen

betrouwbare gegevens beschikbaar over de beste manier van behandelen. Ten

aanzien van de etiologie wordt door sommigen gesuggereerd, dat schadelijke

stoffen uit het milieu carcinogeen kunnen zijn; het gaat daarbij in het bijzonder

om tabakrook en formaldehyde. Er zijn echter maar weinig studies van het

maligne melanoom van het mondslijmvlies die iets over deze factoren

vermelden. Daarnaast wordt in sommige studies melding gemaakt van

veranderingen in het p53 gen.

Chirurgische verwijdering is de meest gangbare behandeling van een maligne

melanoom van het mondslijmvlies. Chirurgische behandeling kan worden

155


gecombineerd met bestraling, chemotherapie of immuuntherapie. De

effectiviteit van dergelijke aanvullende behandelingen in combinatie met

chirurgie of als enkele behandelmodaliteit is nooit met zekerheid aangetoond.

In het onderzoek naar 14 patiënten met maligne melanoom van het

mondslijmvlies, gediagnosticeerd in een periode van ruim 30 jaar op de

afdelingen mondziekten en kaakchirurgie en keel-, neus- en oorheelkunde van

het VU medisch centrum te Amsterdam blijkt duidelijk sprake van het

kwaadaardige agressieve karakter van deze tumor. Vijf patiënten ontwikkelden

een locaal recidief binnen een periode van 4-72 maanden en tien patiënten

ontwikkelden metastasen op afstand, dat wil zeggen buiten het hoofd-

halsgebied, binnen een periode van 6 tot 78 maanden. Tien patiënten zijn aan

hun ziekte overleden binnen een gemiddeld interval van 40 maanden (spreiding

12-80 maanden).

Van de tien patiënten van wie de 5-jaarsoverleving kon worden nagegaan,

bleek er na vijf jaar één in leven te zijn met de ziekte, terwijl twee patiënten in

leven waren zonder aanwijzingen voor aanwezigheid van de ziekte. Hoewel het

bij kleine getallen niet verantwoord is om de gegevens in percentages uit te

drukken, zou het voorgaande betekenen dat er sprake is van een 5-

jaarsoverleving van 30%. Alle patiënten zijn uiteindelijk binnen tien jaar aan hun

ziekte overleden. De bevinding vanuit de literatuur dat de voorgestelde

histopathologische microstadiëring voor stadium I (maligne melanoom van

mondslijmvlies, ongeacht de maximale afmeting, maar zonder aanwijzingen

voor metastasering) voorspellende waarde heeft voor de overleving, werd niet

bevestigd door de resultaten in het huidige onderzoek.

Een ander aspect van het onderzoek betrof onderzoek naar maligne

melanomen van andere slijmvliezen in het hoofd-halsgebied, in het bijzonder

van de neus- en neusbijholten. Er werd daarbij een vergelijking gemaakt tussen

de behandelingsresultaten van patiënten met een maligne melanoom van het

mondslijmvlies en die met een maligne melanoom van de neus- en

neusbijholte. Opvallend genoeg bleek dat patiënten met een maligne

156

Chapter 10

melanoom van het mondslijmvlies gemiddeld ongeveer tien jaar jonger waren

dan de patiënten van de andere groep. De 5-jaarsoverleving was voor patiënten

met een maligne melanoom van het mondslijmvlies beter dan voor patiënten

met een maligne melanoom elders in het hoofd-halsgebied. Daarbij zij echter

opgemerkt, dat het om relatief kleine aantallen patiënten gaat.

Verder bleek dat de kans op locaal recidief en/of regionale en

afstandsmetastasering groter was bij patiënten, die niet werden nabestraald.

Verrassenderwijs bleek echter de 5-jaarsoverleving voor patiënten die alleen

met chirurgie waren behandeld – dus zonder postoperatieve bestraling – beter

te zijn dan voor patiënten die werden nabestraald. Gelet op het retrospectieve

karakter van het onderzoek en het op sommige plaatsen niet volledig zijn van

de patiëntendossiers ten aanzien van de indicatie voor postoperatieve

bestraling, kan geen betrouwbare uitspraak worden gedaan over de mogelijke

waarde van postoperatieve bestraling bij het orale maligne melanoom. Gelet op

de relatieve zeldzaamheid van het maligne melanoom in het hoofd-halsgebied

is het niet zonder meer mogelijk een prospectieve studie op dit gebied uit te

voeren.

In ons onderzoek hebben wij melding gemaakt van een nogal ongewone casus

van een maligne melanoom van het mondslijmvlies waarbij tevens sprake was

van pseudo-epitheliomateuze hyperplasie. Er waren in de betreffende casus

een aantal argumenten, die het inderdaad het meest waarschijnlijk maakten dat

hier sprake was pseudo-epitheliomateuze hyperplasie van het overliggende

plaveiselepitheel en dat het niet ging om een plaveiselcelcarcinoom met

melaninepigmentatie. Een andere bijzondere casus die in ons onderzoek werd opgenomen, betrof

een patiënt met melaninepigmentatie in de kleine speekselklieren van het

gehemelte. Bij deze patiënt werd vier jaar later een maligne melanoom op de

betreffende plaats gediagnosticeerd. Aanwezigheid van melaninepigment in

epitheliale cellen van kleine speekselklieren is uitzonderlijk en er is geen goede

verklaring voor dit fenomeen. In de literatuur wordt wel de term "melanogene

157


metaplasie" genoemd, maar er is weinig wetenschappelijke ondersteuning voor

een dergelijk concept. Verder is de vraag of het aantreffen van

melaninepigment in kleine speekselklieren inderdaad als een potentieel

kwaadaardig fenomeen moet worden beschouwd.

Uit de literatuur blijkt, dat ongeveer 30% van het maligne melanoom van het

mondslijmvlies geassocieerd is of mogelijk jarenlang voorafgegaan is door

pigmentatie van het mondslijmvlies. Er kan daarbij sprake zijn van

aanwezigheid van atypische melanocyten zonder dat op dat moment de

diagnose maligne melanoom kan worden gesteld. De aanwezigheid van

dergelijke atypische melanocyten lijkt als een pre-invasief stadium van een

maligne melanoom te oeten worden beschouwd.

Een naevus naevocellularis, zoals deze op de huid kan voorkomen, komt een

enkele maal ook in de mond voor. De voorkeursplaats van orale naevi komt

sterk overeen met die van een maligne melanoom. Het ligt daarom voor de

hand om te veronderstellen, dat orale naevi wellicht voorloperlesies zijn van een

maligne melanoom van het mondslijmvlies. Uit een landelijk onderzoek, waarbij

dankbaar gebruikgemaakt is van het landelijke geautomatiseerde bestand van

de pathologen (PALGA) werd echter geen ondersteuning voor deze hypothese

gevonden. Geen van de 119 patiënten met een naevus naevocellularis van het

mondslijmvlies heeft in een gemiddelde nacontrole periode van 8.6 jaar een

maligne melanoom ontwikkeld.

159

Curriculum Vitae

Pregraduation - Born in Nardò (Lecce - Italy) 07/12/1977. - Maturità Scientifica at “Leonardo da Vinci” Scientific Lyceum in

Maglie (Lecce) 1996. - Three-month course of English language at Pitzer College

(member of the Claremont Colleges), Los Angeles (CA) in 2001.

- Graduated in dentistry (D.D.S.) at University of Parma (Italy) on 25/02/2002 (after two

years of internship at the Oral Pathology and Medicine Department). Full votation (110/110 cum laude). Thesis title : “Epidemiology and clinical manifestations of gingival overgrowth in a group of 121 renal transplant recipients immunosuppressed with cyclosporine”.

Postgraduation - Postgraduated course of Oral Pathology and Medicine at University of Milan (Prof.

Antonio Carrassi) in 2003. - Postgraduated course of Oral Pathology and Medicine at University of Florence (Prof.

Giuseppe Ficarra) in 2004. - Full-time clinical activity at the Oral Pathology and Medicine Department (Prof. Paolo

Vescovi) of the University of Parma, from 2002 to 2004. - Ph.D. student at the Department of Oral and Maxillofacial Surgery/ Oral Pathology of

the Free University medical center / ACTA (Prof. Dr. Isaäc van der Waal), in Amsterdam from 2004 to 2007.

- Clinical training in Oral Medicine at the Department of Oral Medicine of the University

of San Francisco (Prof. Sol Silverman Jr., Prof. Francina Lozada-Nur). October-November 2006

- Member of SIPMO (Italian Society of Oral Medicine and Pathology) since 2002. - Member of SIOCMF (Italian Society of Oral and Maxillofacial Surgery) since 2002. - Member of the EAOM (European Association of Oral Medicine) since 2004. - Member of the SFOPOM ( Scandinavian Society of Oral Medicine and Pathology)

since 2005 - Currently is “Contract Professor” of “Clinical Stomatology” at the School of

Dentistry of the Medical Faculty of the University of Parma.

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Acknowledgements

“If I have seen further it is by standing on the shoulders of giants” Sir Isaäc Newton

Prof. Dr. Isaäc van der Waal. Dear Professor van der Waal, it is really hard even trying to find some words to express my feelings of gratitude for everything You thaught me. The knowledge, the passion and the devotion for the Oral Pathology, Medicine and Surgery that You transmitted me, are simply the most precious things that I received throughout my whole life. Prof. Paolo Vescovi. Caro Paolo. Eccomi qui, a distanza di pochi anni dalla tesi di laurea, a ringraziarti ancora. Senza il tuo costante appoggio ed il tuo aiuto non sarebbe stato immaginabile realizzare questa esperienza eccezionale. A te devo l’incalcolabile merito di avermi “iniziato” e pazientemente condotto per mano nell’apprendimento e nella pratica della nostra disciplina. Grazie Paolo. Maestro. Amico. Dr. Jacques Baart. Dear Dr. Baart, It has been a pleasure to have the possibility to spend a lot of working and social time with you and your family. Thank you for the beautiful moments and emotions. Prof. Dr. Charles R. Leemans. Dear Professor Leemans, I thank you very much for the support and help during my work. Your contribution has been essential for clarifying a lot of issues related to the head and neck mucosal melanoma. Prof. Dr. Wolter J. Mooi. Dear Professor Mooi, thank you very much for all the scientific imputs, help and collaboration you gave me throughout the preparation of the present thesis.

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Prof. Dr. Mauro Bonanini. Caro Professor Bonanini, La ringrazio di cuore per il supporto e l’incoraggiamento che mi ha fornito durante la permanenza in Olanda e nella fase finale di studio effettuata a Parma. Grazie per avermi dato la possibilità di continuare a formarmi. Grazie per l’affetto e la fiducia costantemente dimostrati nei miei confronti Prof. Dr. Silvia Pizzi. Cara Silvia, ti esprimo la mia gratitudine per essermi stata vicina durante tutta questa lunga esperienza di studio. Grazie per la visita al dipartimento e per i bellissimi giorni trascorsi insieme ad Amsterdam. Prof. Dr. Enrico Sesenna. Chiarissimo Professor Sesenna, desidero ringraziarLa di cuore per l’aiuto e il supporto nella stesura di alcuni capitoli di questa tesi. In particolare, Le esprimo la mia gratitudine per aver reso possibile la collaborazione scientifica tra i dipartimenti di chirurgia maxillo-facciale di Parma e di Amsterdam. The staff and the residents of the Department of Oral and Maxillofacial Surgery/Oral Pathology of the Vrije Universiteit Medisch Centrum at Amsterdam. Dear all, I just wanted to thank everyone of you for constantly making me feeling like home. I am indebted to everybody. I am particularly grateful to Dr. Schulten and Dr. Becking. A special thought goes to my roommates Dr. Carol Saridin and Dr. Marnix Bom and to my friends Dr. Jantien Bremmer, Dr. Roeland Wijs, Dr. Tim Forouzanfar, Dr. Christian Grientschnig, Dr. M. Gilijamse, Dr. Jurgen Bosgra, Dr. Luk Verdonschot. Dr. Ivo ten Hove and Dr. Hakki Karagozoglu. Dear Ivo and Hakki, I am really lucky to have two paranymphs as you. I will always remember all the magnificent working and social time spent together. Dr. Martijn van Steenbergen and Dr. Remi Allard. Dear Martijn and Remi, thank you very much for assisting and helping me throughout all the phases of this experience. You perfectly planned every aspect of my permanence at the Department. Prof. Dr. Elizabeth Bloemena. Dear Professor Bloemena, I would like to thank you for the improvement I have had through your lessons at the Oral pathology Department. A particular thanking goes to Mrs Dini Chevalking and Mr Wilem de Jong at the Oral Pathology Department.

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Prof. Dr. Sol Silverman Jr. and Prof. Dr. Francina Lozada-Nur. Dear Professors, I thank you very much for the enlighting experience in the Deapartment of Oral Medicine of the University of San Francisco. Dr. Maddalena Manfredi. Cara Maddalena, ti ringrazio per il sostegno che mi hai sempre fornito durante questo lungo e complesso periodo. Ti sono grato soprattutto per i consigli preziosi, maturati dall’esperienza durante lo svolgimento del tuo Ph.D. Un ringraziamento particolare va all’equipe di Patologia e Medicina Orale dell’Università di Parma e ai miei colleghi e amici con i quali ogni giorno condivido le gioie e i problemi: Dr. Elisabetta Merigo, Dr. Alessandro Ripasarti, Dr. Rebecca Guidotti, Dr. Carlo Fornaini. Ringrazio inoltre tutto il Personale Medico e Paramedico della Clinica Odontostomatologica dell’Azienda Ospedaliero-Universitaria di Parma. Dr. Luigi Corcione. Caro Gino, queste poche righe sono per testimoniarti il mio affetto e la mia riconoscenza per i lunghi pomeriggi passati davanti al microscopio. Grazie. Dr. Angelo Catellani. Caro Angelo, ci sono molte cose per le quali dovrei ringraziarti e sarebbe impossibile elencarle tutte. Con la tua gentilezza e cortesia hai saputo pazientemente tollerare gli impegni scientifici paralleli alla mia attività lavorativa al tuo fianco. Ti sono debitore. Grazie. Lady Olga van der Waal. Dear Lady van der Waal, I would like to express my gratitude for all the sweetness you always had for me and Diana and for all the pleasant days we spent together in Italy and in Holland. Dimitri van Versendaal. Dear Dimitri, you are the only one who completely shared all my social life in Amsterdam during the past years. It is not possible to forget all the situations and atmospheres we passed through. I will always store in my mind and in my heart the irripetible emotions we lived together. Panagiotis Vodinas. Dear Panos, it hard to forget a guy like you are. Thank you very much for all the happiness you brought in my life. Gabriele Surdo. Gabriele, amico, fratello di sempre. Le parole non sono mai bastate a chiarire la natura del nostro legame. Non basta la musica e non basta il cinema, non basta la poesia e non basta la pittura. Tu solo

164

sai cosa intendo. Grazie per l’incalcolabile e infinito sostegno che hai saputo darmi soprattutto quando eravamo lontani. Un sentito ringraziamento ad Ada Lolli. Gabriele Vizzi. Caro Gabriele, amico, compagno di mille avventure. Anche per te è difficile esprimere un ringraziamento con le parole. Ti voglio bene. Grazie. I miei pensieri di gratitudine vanno inoltre ai miei amici di Parma come Matteo, Anna, Donato, Laura, Luigi ,Marco, Margherita. Sentiti ringraziamenti alla “cupola” : Sandro, Fabio, Teo, Milo, Davide! Compagni eccezionali di studio e divertimento. E’ doveroso ringraziare tutti i miei parenti (elencarli tutti sarebbe impossibile!), il ricordo dei quali mi ha sostenuto nei momenti difficili. Il mio pensiero è particolarmente rivolto a Anna e Tommasa Mangia, donne eccezionali. Un saluto metafisico và anche ai miei nonni, Donato e Maria Meleti e Antonio e Vincenza Mangia. Un affettuoso ringraziamento ai genitori di Diana, Dr. Paolo Cassi e Dr.ssa Donatella Censori. Last but not Least Papà, Mamma, Stefano, Massimo. Ho sempre pensato di aver avuto la fortuna di essere nato e cresciuto nella più bella di tutte le famiglie. Oggi, a 30 anni dalla mia nascita ne ho la conferma. Grazie Papà, grazie Mamma per essere riusciti a creare qualcosa di così meraviglioso. Diana Cassi. Diana, pochi uomini hanno la fortuna di incontrare una donna come te. Io sono uno di loro. Il tuo costante appoggio ha reso possibile tutto questo. Grazie Amore mio.

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