Precursors To Melanoma And The Problematic Nevomelanocytic Proliferation
Section 8 -
Neil Crowson, MD
Cynthia M. Magro, MD
Martin C. Mihm, Jr., MD
An Introduction to the Essential Subtypes of Melanoma
Melanoma was for many years considered a single neoplasm with a uniformly bad prognosis. In 1969
Clark and McGovern described new classifications based on clinicopathologic features that led to a new
understanding of the pathogenesis and developmental biology of the tumor and to increased awareness of
early diagnostic features. This in turn led to a more complete understanding of histologic factors
important in diagnosis. Another impetus is the increasing incidence that has been described as 'a
melanoma epidemic'. The original subtypes were superficial spreading
melanoma, lentigo maligna melanoma, and nodular melanoma (Clark et al, 1969; Barnhill, 1995;
Crowson et al, 2001), supplemented by Richard Reed to include acral lentiginous melanoma. Other less
common but clinicopathologically distinctive forms of melanoma have since been described. These include
minimal deviation melanoma, malignant cellular blue nevus, desmoplastic melanoma, nevoid melanoma,
mucosal and paramucosal melanoma, and a form of melanoma with prominent melanin synthesis termed
pigment-synthesizing or animal-type melanoma. It behooves the pathologist to recognize cytological
variants of melanoma so that appropriate immuohistochemical evaluation can be performed to ensure
Three clinically and histologically distinctive steps in melanoma progression (Guerry et
al, 1993) are describe and included: melanoma in situ, or that confined to the epidermis designated
radial growth phase melanoma in situ; melanoma that invades the papillary dermis, termed radial growth
phase microinvasive melanoma and melanoma that has invades the papillary anad reticular dermis to form a
tumorigenic nodule, termed vertical growth phase melanoma. (Taran and Heenan 2001; Clark et al, 1984).
These three phases are not present in all forms and lesions, but their identification in any given
neoplasm is essential to its accurate subclassification and also to a critical analysis of its potential
to metastasize (Barnhill, 1995; Crowson et al, 2001). Recognition of the aforementioned
phases in any given neoplasm is essential to the assessment of prognosis and to the selection of
appropriate treatment. Melanoma in the radial growth phase is virtually curable by surgery as shown in
one landmark study of 161 patients whose pure radial growth phase-confined melanomas showed no histologic
evidence of regression in the primary excision specimen. They had a metastasis-free survival at a median
follow-up of 13.7 years (Guerry et al, 1993). In the absence of regression in the primary
tumor, radial growth phase melanoma is usually incapable of metastasis, although the number of
metastasizing radial growth phase lesions continues to accumulate (Guitart et al, 2002).
Patients with radial growth phase-confined melaomas tend to be younger than those with vertical growth
phase melanoma (Guerry et al, 1993).
Later in its evolution the above-described lesion may form expansile nodules and aggressively invade
the reticular dermis and/or subcutaneous fat. The appearance of an expansile nodule either de novo or in
a preexisting radial growth phase signals that the lesion has acquired the capacity to metastasize and is
said to be in vertical growth phase. The patient's prognosis is then directly related to the measured
depth of invasion (Breslow, 1970). and to other histologic parameters (Day et al,
1981; Day et al, 1982; Harrist et al, 1984; Leon et al, 1991; Balch et al, 2000; Balch et al, 2000:
Crowson et al, 2001) Nodular melanoma, in contrast, has no identifiable preexisting radial growth phase
and is presumed to be in vertical growth phase from its inception.
Specific Subtypes of Melanoma
Superficial Spreading Melanoma
Superficial spreading melanoma represents the most common form of the radial growth phase and
comprises some 70–75% of all melanomas (Barnhill, 1995; Crowson et al, 2001; Elder et al,
1984). Lesions occur most often on the trunk and the sun-exposed areas of the upper arms and the lower
legs but may arise anywhere (Holman and Armstrong, 1984). Melanoma arising in a preexisting
dysplastic nevus is usually of superficial spreading type. Clinically, these lesions are plaques in the
radial growth phase average 2.5 cm in diameter although both smaller and much larger lesions may be
observed. They exhibit a palpable border that is sharply demarcated. They have striking variations in
coloration including shades of brown, black red, blue and white. When the vertical growth phase
supervenes the lesion exhibits a nodule of blue black, grey, reddish brown or even of pale grey or
amelanotic coloration (Clark et al, 1969).
Histopathology of Radial Growth Phase-Confined Malignant Melanoma of Superficial Spreading Type
Superficial spreading melanoma by definition must have a radial growth phase (Clark et
al, 1969, Crowson et al., 2001) confined to the epidermis. Although different patterns of
intraepidermal growth may be observed, the lesion most commonly is composed of epithelioid cells that
have large round or oval nuclei with obvious nucleoli and a cytoplasm filled with melanin granules of
varying sizes and shapes. Mitotic figures are often easily visible in the malignant populace. At least
occasional cells extend to the granular cell layer. The epidermis is frequently hyperplastic. Other
patterns include a continuous proliferation of singly disposed cells along the dermoepidermal junction
replacing the basal cells in an epidermis with effaced rete ridges. The atypical melanocytes comprising
this lentiginous pattern have angulated hyperchromatic nuclei that lack internal detail and exceed the
size of adjacent keratinocyte nuclei. The cytoplasm of each cell contains finely dispersed melanin
granules. A third pattern exhibits confluent oblong nests of hyperchromatic spindle-shaped cells with
distinct nuclear grooves, large nucleoli, and variable melanization. A fourth pattern comprises a hybrid
array of the aforementioned intraepidermal melanocytic proliferations. The radial growth phase may
rarely comprise spindled melanocytes. When radial growth phase-confined malignant melanoma arises in the
background of a dysplastic nevus the foci of residual dysplastic nevus are present at the periphery or,
rarely, are interposed as small foci between areas of melanoma (Crowson et al, 2001; Barnhill, 1995).
Lymphocytic infiltration of the subjacent papillary dermis may herald the onset of incipient
microinvasive malignant melanoma. Although delicate fibroplasia is common, the organized periretal
fibrosis of the dysplastic nevus is not observed in such areas, except in the context of a residual
precursor dysplastic nevus.
The radial growth phase melanoma expresses itself as microinvasive tumor in the papillary dermis and
comprises nested and dispersed cells with a cytomorphology similar to the intraepidermal cells, albeit
often with more abundant cytoplasm having an eosinophilic hue. The nests should not exceed the size of
those along the dermo-epidermal junction and dermal-based mitoses should not be identified; either of
these features is a clue to vertical growth phase melanoma. Extension of the intraepidermal component
for more than three rete ridges past the confines of the dermal component has been used to define the
superficial spreading subtype of melanoma (Clark et al, 1969). The presence of regression that may
herald the capacity to metastasize as discussed above consists of the zone of absent melanoma in the
epidermis and dermis (Ronan et al, 1987). The dermis exhibits delicate fibroplasia forming a band of
fibres parallel to the epidermal surface, vertically oriented ectatic vessels within the collagenized
zone, admixed with lymphocytes and melanophages. These zones are flanked on one or both sides by tumor
in the epidermis and or dermis (Clark et al, 1989).
Other malignant intraepidermal lesions exhibiting pagetoid spread may mimick melanoma-in-situ. These
include epidermotropic neuroendocrine carcinoma (Gillham et al, 1991) which can be easily
excluded by immunohistochemistry, Paget's disease, pigmented extramammary Paget's disease, pigmented
Bowen's disease, and sebaceous carcinoma. Appropriate histochemical and immunochemical techniques can
allow for the correct interpretation (Crowson et al, 2001).
Case # 8: Lentigo Maligna
Lentigo maligna (LM, Hutchinson's melanotic freckle) occurs on sun-exposed skin of Caucasians and
predominantly affects the face, the head and neck and, less often, other sun-exposed areas of the body
(Clark and Mihm,1969; Cox et al, 1998). Extrafacial lentigo maligna melanoma (LMM) constitutes 18% of
all cases and preferentially involves the trunk in men and lower legs in women, and presents at a thinner
depth relative to LMM of the head and neck. A debate exists as to whether LM is an in situ melanoma or a
precursor. A distinction between a precursor and an in situ phase has been offered (Tannous et al 2000).
The term lentigo maligna melanoma (LMM) is used when the tumor assumes invasive properties, the lifetime
risk of which has been estimated to be 5% (Winstock, and Sober 1987). Long-term exposure to UV
irradiation is the greatest risk factor; diagnosis of LM or LMM is not made if the lesion is on
sun-protected skin or in the absence of solar elastosis. Other risk factors include rearrangement of
chromosome 10 at the 10q24–26 region (Grammatico et al, 1992) and use of estrogen, progesterone, and hair
dyes. Some 15% of all melanomas and 10–26% of all head and neck melanomas represent LMM (Crowson et al.,
Clinically, LM presents as a macule that exhibits variations in the colors of tan to brown. It
commonly presents in the 4 to 5th decade of life, although presentation in the early 20's has
been rarely documented. Initially presenting as a tan lesion a few millimeters in size, it gradually
enlarges and changes in color and shape. There are varying shades of tan and brown; as the lesion grows
partial regression often occurs with areas of blue grey or white appearing in the midst of the darker
large lesion. The appearance of a palpable area usually signals invastion. The invasive component
appears when the lesions are several centimeters in size and may be multifocal. There is a slight female
predominance. There is no apparent difference in survival versus other subtypes of melanoma, when
controlled for level of invasion and thickness (Koh et al, 1984).
The histology of LM is one of polygonal melanocytes with hyperchromatic, angulated nuclei dispersed
as individual units, initially confined to the basal layer of an atrophic epidermis in a discontiguous
fashion and extending along the eccrine ducts and the outer root sheath epithelium of hair follicles.
Also, characteristic is the multinucleated giant melanocyte set along the basal layer of the epidermis;
termed "star-burst giant cells", these may contain more than 30 fully-malignant nuclei and have been
identified in up to 85% of cases (Cohen,1995). Sun-damaged skin of the head and neck of the elderly may
show multinucleation of melanocytes as a sequel of photoactivation, in which case nuclei of the
multinucleated giant cells show only mild hyperchromasia with regular nuclear contours. The epidermis in
LM is characteristically manifests marked thinning and loss of the retiform pattern overlying elastotic
dermal collagen; telangiectasia and melanophages complete the picture (Tannous et al,2000). As the
lesion progresses, continuity of single-cell basilar melanocytic proliferation is observed, followed by
variably sized dyshesive junctional thèques along the dermo-epidermal junction which assume a parallel
disposition to the long axis of the epidermis and are referred to as "the swallow's nest sign". Nesting,
confluence of melanocytes along the basal layer and pagetoid spread of neoplastic melanocytes, which we
designate as melanoma in situ (Tannous et al, 2000), are the harbingers of the next phase of lesional
evolution, namely, dermal invasion that is accompanied by a lichenoid infiltrate with admixed
melanophages. The invasive cells are typically epithelioid with abundant pigmented cytoplasms. For a
discussion of vertical growth phase of LMM, see the section on subtypes of melanoma
Problematic is deciding whether a low-density proliferation of singly disposed atypical melanocytes
in sun-damaged skin represents LM or photoactivation. Critical in this determination are the clinical
circumstances. When in doubt, additional biopsies or complete removal of the lesion may be necessary.
Novel application of topical biological response modifiers such as Imiquimod may make this distinction
less crucial in the near future.
- Crowson AN, Magro CM, Mihm MC, Jr. The nevomelanocytic proliferations : a comprehensive textbook of
pigmented lesions. New York : Wiley-Liss, 2001: 550pp.
- Clark WH, Mihm MC.Lentigo maligna and lentigo maligna melanoma. Am J Pathol 1969;55:39.
- Tannous ZS, Lerner LH, Duncan LM, Mihm MC Jr, Flotte TJ. Progression to invasive melanoma from
malignant melanoma in situ, lentigo maligna type. Hum Pathol 2000;31:705-708.
- Weinstock MA, Sober AJ. The risk of progression of lentigo maligna to lentigo maligna melanoma. Br
J Dermatol 1987;116:303-310.
- Grammatico P, Modesti A, Steindl K, et al. Lentigo maligna: cytogenetic, ultrastructural, and
phenotypic characterization of a primary cell culture. Cancer Genet Cytogenet 1992;60:141–146.
- Koh HK, Michalik E, Sober et al. Lentigo maligna melanoma has no better prognosis than other types
of melanoma. J Clin Oncol 1984;2:994–1001.
- Cohen LM. Lentigo maligna and lentigo maligna melanoma. J Am Acad Dermatol 1995;33:923.
Assessment of Depth and Level of Invasion in Lentigo Maligna Melanoma
Assessment of level of invasion in lentigo maligna melanoma can be difficult as the dermis is often
thin with abundant elastotic material making the demarcation between papillary and reticular dermis ill
defined. Invasion of the adventitia of a follicle situated in the reticular dermis may be misinterpreted
as level IV melanoma if the follicular epithelium is not apparent in the plane of section examined.
Depth of invasion should not be based on the depth of adventitial dermal involvement unless that is the
only invasion discernible, and under that circumstance the measured depth is the distance from the point
of infiltration of the adventitial dermis to the innermost layer of the outer root sheath epithelium.
(Cox et al, 1998; Crowson et al, 2001)
Neurotropism in Lentigo Maligna Melanoma
Desmoplastic lentigo maligna melanoma may be associated with neurotropism which can extend into
subcutaneous fat. We give a separate measurement for the depth and level of the neurotropic component;
the Breslow depth is still determined by the depth of invasive melanoma from the granular cell layer of
the interfollicular epidermis. Although there is some controversy, most authorities would agree that
neurotropism portends more aggressive local recurrence (Baer et al, 1995).