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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
Introduction and aim of the study
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
Introduction and aim of the study
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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
Oral pigmented lesions
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
Oral pigmented lesions
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
Oral pigmented lesions
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
Oral pigmented lesions
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
Oral pigmented lesions
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
Oral pigmented lesions
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
Oral pigmented lesions
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
Oral pigmented lesions
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
Oral pigmented lesions
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
Oral pigmented lesions
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
Oral pigmented lesions
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Oral pigmented lesions 87. Krutchik AN, Buzdar AU. Pigmentation of the toungue and mucous membranes
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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
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
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
Oral malignant melanoma: a review
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
Oral malignant melanoma: a review
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
Oral malignant melanoma: a review
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
Oral malignant melanoma: a review
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
64
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
Oral malignant melanoma: a review
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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-
74
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
Oral malignant melanoma : the Amsterdam experience
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
Oral malignant melanoma : the Amsterdam experience
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
Oral malignant melanoma : the Amsterdam experience
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.
80
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
Oral malignant melanoma : the Amsterdam experience
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
82
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
Oral malignant melanoma : the Amsterdam experience
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..
Current management of mucosal melanoma of the head and neck. J Surg Oncol 2003;83:116-122.
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.
16. Chaudhry AP, Hampel A, Gorlin RJ. Primary malignant melanoma of the oral
cavity: a review of 105 cases. Cancer 1958;11:923-928.
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.
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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
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
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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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
pseudoepitheliomatous hyperplasia. Report of three cases of a pseudomalignant condition. Am J Surg Pathol 2002;26:774-777.
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
3 Department of Pathology, VU medical center, 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
Melanotic pigmentation of minor salivary gland
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).
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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
Melanotic pigmentation of minor salivary gland
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
Melanotic pigmentation of minor salivary gland
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
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 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–
112
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,
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Oral melanocytic naevi
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.
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Oral melanocytic naevi
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–
116
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
Oral melanocytic naevi
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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Oral melanocytic naevi
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
120
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
Oral melanocytic naevi
References
1. Grichnik JM, Rodhes AR, Sober AJ. Benign hyperplasias and neoplasias of melanocytes. In: Lever’s hystopathology of the skin. 7th ed., 2005. p. 889 [chapter 91].
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.
122
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.
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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.
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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
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
Submitted
126
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
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Head and neck mucosal melanoma
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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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
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Head and neck mucosal melanoma
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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Head and neck mucosal melanoma
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)
134
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).
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Head and neck mucosal melanoma
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).
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Head and neck mucosal melanoma
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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Chapter 8
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
Head and neck mucosal melanoma
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
Head and neck mucosal melanoma
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.
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Head and neck mucosal melanoma
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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Chapter 8
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Chapter 9.
Summary and conclusions
148
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
Summary and conclusions
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
Summary and conclusions
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
Samenvatting en conclusies
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
Samenvatting en conclusies
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.
161
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
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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.
Finito di stampare nel mese di Dicembre 2007 da Copy & Press S.r.l. - Pr
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