Malignant Melanoma - Text from Schafer and images from both Neville & Schafer

1. MALIGNANT TUMORS OF THE
EPITHELIAL
TISSUE ORIGIN
MALIGNANT MELANOMA

2. Introduction
 neoplasm of epidermal melanocytes
 more biologically unpredictable and deadly of
all human neoplasms
 third most common cancer of the skin (basal
and squamous cell carcinomas are more
prevalent)
 3%
 Results in over 83% of all deaths due to skin
cancer in the United States
 increasing in incidence
 The frequency of its occurrence is closely
associated with the constitutive color of the
skin, and depends on the geographical zone.

3. Introduction
 among dark skinned ethnic groups is 1
per 100,000 per year or less
 affecting mainly the palms, soles, and
mucous membranes
 light-skinned Caucasians up to 50 and
higher in some areas of the world
 Cutaneous malignant melanoma is the
most rapidly increasing cancer in whites
 sunlight is an important etiologic factor in
cutaneous melanoma

4.  Melanomas may develop in or near a
previously existing precursor lesion or in
healthy-appearing skin
 A malignant melanoma developing in
healthy skin is said to arise de novo,
without evidence of a precursor lesion
 Certain lesions are considered to be
precursor lesions of melanoma, including
the common acquired nevus, dysplastic
nevus, congenital nevus, and cellular
blue nevus

5. Etiology
Environmental
1. Sun exposure
2. Artificial UV sources
3. Socioeconomic status
4. Fair skin, freckles, red hair
5. Number of melanocytic nevi
ETIOLOGY
Genetic
1. Familial melanoma
2. Xeroderma pigmentosum

6. Environmental Factors
Sun exposure
 The highest incidence of melanoma -
areas with long hours of sunlight
throughout most of the year
 lower risk for melanoma among people
who resided in a low ultraviolet
environment in childhood compared with
those who resided in a high UV
environment
 Recreational activity leading to sunburns
in adulthood, such as sailing, has also
been incriminated as an etiological factor

7. Environmental Factors
Artificial UV sources
 melanoma risk and tanning lamp use
have demonstrated a
 positive relation
 longer wave artificial UVA may play a
part in the etiology of melanoma in
addition to exposure to natural sunlight
 The association of melanoma with PUVA
(combination of psoralen (P) and long
wave ultraviolet radiation (UVA)) therapy
has also been reported

8. Environmental Factors
Socioeconomic status
 melanoma is more prevalent in those
of high socioeconomic status
 An explanation - better afford holidays
in areas of high UV intensity, as well
as expensive outdoor hobbies like
sailing

9. Environmental Factors
Fair skin, freckles, red hair
 increase the risk of melanoma
Number of melanocytic nevi.
 The total number of melanocytic nevi,
dysplastic or bland, has been reported
by several groups as a strong risk
factor

10. Genetic Factors
Familial melanoma
 2-5% of melanoma patients - positive
family history of melanoma in at least
one first degree relative
 In approximately 30% of melanoma
patients abnormalities on
chromosome 9p21 are seen

11. Genetic Factors
Xeroderma pigmentosum
 In this genetically determined disorder,
defective DNA repair mechanisms
lead to excessive chronic UV damage
and subsequent development of
different sun-related skin tumors,
including melanoma, in sun-exposed
areas

12. Risk Factors for oral mucosal
melanomas
 unknown
 no apparent relationship to chemical, thermal,
or physical events (e.g. smoking, alcohol
intake, poor oral hygiene, irritation from teeth,
dentures, or other oral appliances) to which
the oral mucosa is constantly exposed
 Although benign, intraoral melanocytic
proliferations (nevi) occur and are potential
sources of some oral melanomas; the
sequence of events is poorly understood in
the oral cavity
 Currently, most oral melanomas are thought
to arise de novo

13. Growth of melanoma
 In 1975, Clark and his coworkers –
interesting concept - developmental
biology of cutaneous melanoma
 They documented two phases in the
growth of melanoma:
1. the radial-growth phase and
2. the vertical-growth phase

14. Radial-growth phase
 initial phase of growth
 may last many years
 confined to the epidermis
 Neoplastic cells are shed with
normally maturing epithelial cells
 some neoplastic cells may actually
penetrate the basement membrane,
they are destroyed by a host-cell
immunologic response

15. Vertical-growth phase
 begins when neoplastic cells populate
the underlying dermis.
 Because of increased virulence of the
neoplastic cells, a decreased host-cell
response, or a combination of both
 Metastasis is possible
 not all melanomas have both radial- and
vertical-growth phases
 Nodular melanoma (q.v.) exists only in
the vertical-growth phase.

16. Vertical-growth phase

17. H/P

18. Classification
 Cutaneous melanoma has been
classified into a number of types
1. superficial
2. spreading melanoma
3. nodular melanoma
4. lentigo maligna
5. melanoma (Hutchinson’s freckle)
6. acral lentiginous melanoma

19. Clinical Features
Superficial spreading melanoma
 most common
 65% of cutaneous melanomas
 exists in a radial-growth phase (called
premalignant melanosis or pagetoid melanoma in
situ)
 tan, brown, black or admixed lesion on sun-
exposed skin, especially the back
 occurs on the skin of the head and neck, chest
and abdomen and the extremities
 The radial-growth phase may last for several
months to several years
 The vertical-growth phase - an increase in size,
change in color, nodularity and, at times,
ulceration

21. Clinical Features
Nodular melanoma
 approximately 13%
 no clinically recognizable radial-growth
phase, existing solely in a vertical growth
phase
 sharply delineated nodule with varying
degrees of pigmentation
 Pink (amelanotic melanoma) or black
 Predilection for occurrence on the skin of the
back and head and neck skin of men
 In other cutaneous sites, there is an even
gender distribution

22. Clinical Features
Lentigo maligna melanoma
 approximately 10%
 radial-growth phase which is known as lentigo
maligna or melanotic freckle of Hutchinson
 macular lesion on the malar skin of middle-aged
and elderly Caucasians
 more often in women than in men
 An average age of 58 years in men and 55 in
women
 median age was 70 years
 lesion can remain in the radial-growth phase for
years
 not only on the skin but also in the eye and on
mucous membranes

24. Clinical Features
Acral lentiginous melanomas
 palms and soles, as well as on toes and
fingers
 10% of cases in whites
 50% of all melanomas on Black and Asian
skin
 macular, lentiginous pigmented area around
a nodule
 Mechanical stress - erosion and ulceration
 Subungual melanomas - pigmentations of the
nail bed
 extremely aggressive, with rapid progression
from the radial to vertical growth phase

25. Clinical Features
Mucosal lentiginous melanomas
 develop from the mucosal epithelium that
lines the respiratory, gastrointestinal, and
genitourinary systems
 Approximately 3% of the melanomas
 may occur on any mucosal surface,
including the conjunctiva, oral cavity,
esophagus, vagina, female urethra,
penis, and anus
 Noncutaneous melanomas - advanced
age
 aggressive course

26. Clinical Features
Amelanotic melanoma
 erythematous or pink, sometimes
eroded, nodule
 often confused for other tumors
 only the histological examination
provides the right diagnosis

27. ABCDE-rule
The following criteria aid clinical diagnosis of
melanoma (ABCDE-rule):
 Asymmetry—in which one half does not
match the other half
 Border irregularity—with blurred, notched, or
ragged edges
 Color irregularity—pigmentation is not
uniform. Brown black, tan, red, white, and
blue—can all appear in a melanoma
 Diameter—greater than 6 mm. Growth in
itself is also a sign
 Elevation—a raised surface can also be a
sign

28. Tumor-node-metastasis (TNM) Classification System and
Stage Groupings for Cutaneous Melanoma

29. Tumor-node-metastasis (TNM) Classification System and
Stage Groupings for Cutaneous Melanoma (contd)

30. Oral Manifestation
 Uncommon neoplasm of the oral
mucosa
 0.2–8%
 melanoma of the oral mucosa - one of
the most common sites for the
neoplasm in Japanese
 Melanomas in Blacks are seldom
found in the skin yet occur on mucous
membranes and on the plantar skin

35. Oral Manifestation
 Primary oral melanoma is nearly twice as
common in men as in women
 55 years (40 and 70 years)
 definite predilection for the palate and maxillary
gingiva/alveolar ridge
 also recorded on the buccal mucosa, mandibular
gingiva, tongue, lips and floor of the mouth
 deeply pigmented area
 At times ulcerated and hemorrhagic
 tends to increase progressively in size
 Amelanotic melanoma accounts for 5–35% of
oral melanomas which appear as a white,
mucosa-colored, or red mass

36. Oral Manifestation
 focal pigmentation precedes before
the development of the actual
neoplasm
 the appearance of melanin
pigmentation in the mouth and its
increase in size and in depth of color
should be viewed seriously
 melanomas of the oral mucosa - can
exist in radial- and vertical-growth
phases

37. Oral Manifestation
types of oral melanomas are
1. superficialspreading
2. acral-lentiginous and
3. nodular

38. Tumor-node-metastasis (TNM) Classification System and
Stage Groupings for Mucosal Melanoma
of the Head and Neck

39. H/P
 malignant cells - nest or cluster in groups in
an organoid fashion
 however, single cells can predominate
 Cells are round or polygonal
 melanoma cells have large nuclei, often with
prominent nucleoli, and show nuclear
pseudoinclusions due to nuclear membrane
irregularity
 The abundant cytoplasm may be uniformly
eosinophilic or optically clear
 Occasionally, the cells become spindled or
neurotized in areas (interpreted as a more
aggressive feature)

40. H/P
SUPERFICIAL
SPREADING
MELANOMA
 The intraepithelial
component (radial-
growth phase) is
characterized by the
presence of large,
epithelioid melanocytes
distributed in a so-called
‘pagetoid’ manner
(‘buckshot scatter’)

41. H/P
SUPERFICIAL SPREADING MELANOMA
 Malignant cells - confined to the epithelium - no
host cell response in the underlying connective
tissue
 If Melanocytes penetrate basement membrane, a
florid host cell response of lymphocytes develops
 Macrophages and melanophages may be
present
 The tumor cells are often destroyed by this
cellular response
 The vertical-growth phase is characterized by the
proliferation of malignant epithelioid melanocytes
in the underlying connective tissues
 The cells may be arranged singly or in clusters
 Melanin pigment is usually scanty

44. H/P
 Nodular melanoma also is characterized
by large, epithelioid
 melanocytes within the connective
tissue. However, small
 ovoid and spindle-shaped cells may be
present. Melanin
 pigment is usually but not invariably
present. The tumor
 cells may invade and ulcerate the
overlying epithelium and
 penetrate the deep soft tissues

46. H/P
Lentigo maligna (melanotic freckle of Hutchinson)
 Well defined histologic features
 increased numbers of atypical melanocytes within the
basal epithelial layer
 Epithelium - generally atrophic
 dermal collagen shows the effects of sun-damage
(basophilic degeneration)
 If skin appendages are present, they are often involved
with atypical melanocytes as well.
 In time, cords and nests of atypical melanocytes may
be evident
 characterized by invasive spindle-shaped cells into the
underlying dermis
 A lympho-histiocytic infiltrate is usually present

47. H/P
Acral-lentiginous Melanoma
 histologically similar to lentigo maligna
melanoma
 salient histologic features are:
 A lentiginous radial-growth phase
 A deep vertical-growth phase composed
predominantly of spindle-shaped cells
 Psoriasiform epidermal hyperplasia
 An intense host-cell response
 A prominent desmoplasia associated
with the vertical growth phase

49. H/P
 Less common histologic variants of
melanoma
1. Desmoplastic
2. Neurotropic
3. spindle cell and
4. balloon cell melanomas

50. Investigation
 The lymph node metastasis is
identified – lympho-scintigraphy and a
radioactive tracer (technetium labeled
sulfur colloid or human serum
albumin)

51. Investigation
 immunohistochemical stains – not necessary for
diagnosis
 performed for confirmation
 Both S-100 and homatropine methylbromide (HMB45)
stains are positive in melanoma
 The S-100 is highly sensitive, although not specific, for
melanoma
 HMB45 is highly specific and moderately sensitive for
melanoma.
 Both stains, in concert, can be useful in diagnosing
poorly differentiated melanomas
 Vimentin is positive in most cases
 Recently, microphthalmic transcription factor,
tyrosinase, and melano A immunostains have been
used to highlight melanocytes

52. Differential Diagnosis

53. Treatment and Prognosis
 The treatment of cutaneous malignant
melanoma is surgical excision
 regional lymph node dissection is indicated
when nodes are involved
 tumors greater than 0.75 millimeters in
thickness and located in the so-called BANS
(back, arm, neck and scalp) sites have a
greater tendency to metastasize
 On the other hand, melanomas of the skin of
the face have a much more favorable
prognosis
 Chemotherapy, immunotherapy and radiation
therapy have been used in the treatment of
cutaneous melanoma

54. Treatment and Prognosis
 The treatment of oral melanoma –
surgical excision
 Jaw resection and lymph node
dissection - in cases involving bone
and regional lymph nodes

55. Treatment and Prognosis
 both clinical and histologic factors which
are of great prognostic significance in
cutaneous melanomas
 According to McGovern, clinical features
with prognostic significance are the
gender and age of the patient and the
site of the lesion
 Women have a much better survival rate
up to the age of 50 years and then the
rate declines

56. Treatment and Prognosis
 Histologic features -of prognostic
significance - histologic type and
depth of invasion
 Nodular melanoma and superficial
spreading melanoma have much
poorer prognosis than lentigo maligna
melanoma
 tumors less than 0.75 mm in thickness
rarely metastasize or cause death,
regardless of the location on skin

57. Treatment and Prognosis
 Unfortunately, oral mucosal
melanomas have a far worse
prognosis than cutaneous melanomas
 the five-year survival rate for such
tumors is approximately 7%

58. Treatment and Prognosis
 The level of tumor invasion is another
important indicator of the prognosis of
MM
 The Clark system is generally used
to grade tumor invasion based on the
deepest histologic cutaneous structure
the tumor infiltrates

59. Treatment and Prognosis

60. Treatment and Prognosis