MELANOMA (ROSAI)

General Features

-large majority of melanomas are associated with sunlight exposure and thought to be due to ultraviolet radiation

-most are found in the head and neck area and on the lower extremities, the latter location being particularly more common in
women

-Rare but well-known locations of cutaneous melanomas are the subungual region (“melanotic whitlow”)807–809 and the palms
and soles.

-The presence of a large number of melanocytic nevi represents a risk factor for melanoma, even if these nevi are not of the
dysplastic type

-The genetically determined disease xeroderma pigmentosum predisposes to the development of melanoma

-Cases of melanoma have been reported in association with type I Recklinghausen disease

-Malignant melanomas can present as multiple primary tumors

-A proportion of cases of hereditary melanoma are caused by germline inactivating mutation in CDKN2A on chromosome
9p21 (encoding two tumor suppressor gene products, p16INK4a and p14ARF) or less commonly, activating mutation in
CDK4.830–835 Germline muta- tions in the tumor suppressor gene BAP1 have been associated with an increased risk for
developing cutaneous and uveal melanoma, as well as malignant mesothelioma

-The fact that malignant melanomas can develop from nevi can be no longer denied, but the exact percentage is not clear.

-only an infinitesimal portion of acquired nevi become malignant.

-The percentage is higher for congenital nevi and for dysplastic nevi, but the exact figures are again unknown.
Clinical Appearance and Major Clinicopathologic Types

(1) Lentigo Maligna Melanoma

Lentigo maligna (Hutchinson freckle)

-typically occurs in the sun- exposed areas of elderly white persons, most commonly on the cheek

-It is a flat, slowly growing lesion, its color varying from tan to black

-Microscopically, it is characterized by a proliferation of atypical melanocytes in the basal layer, distributed individually as well
as in nests

-Retraction of the cytoplasm is common and pleomorphism may be prominent.

-Upward migration is less prominent than in other types of melanoma.

-The proliferation of atypical basal melanocytes in the deep portion of the rete ridges can simulate invasion, especially in a
tangential section. It is advisable to be very conservative in the evaluation of this lesion, just as one should be in actinic keratosis.

-When confined to the epidermis, it is considered lentigo maligna, a form of melanoma in situ.

-When a dermal component is present, the term lentigo maligna melanoma is used.

-Another type of invasive melanoma that can develop within lentigo maligna is desmoplastic melanoma . This tumor tends to
recur locally, as well as to metastasize distantly.854 It can also be seen in connection with other pigmented lesions.

Figure 3.68 So-Called Lentigo Maligna. The atypical melanocytes are present along the basal layer individually and in theques.

(2) Superficial Spreading Melanoma

-previously called premalignant melanosis and pagetoid melanoma

-it can occur anywhere on the body surface.

-It has a variegated appearance, the colors including hues of tan, brown, black, blue, pink, and white. The telltale color of early
superficially spreading melanoma is most frequently a shade of blue admixed with tan, brown, or dark brown

-The surface is slightly elevated, and the margins are barely palpable

-The white areas correspond to areas of spontaneous regression; they are related to tumor size but not to the level of invasion or
prognosis

-Pink and blue areas also correspond to areas of tumor regression, associated with dermal fibrosis and accumulation of melanin-
laden macrophages.

-The borders of the lesion are irregular and usually include a prominent indentation or notch.

-Deep invasion generally is accompanied by the appearance of an elevated nodule on the surface.

-Microscopically, the noninvasive areas are composed of uniform atypical melanocytes with nest formation and pagetoid
appearance

Figure 3.69 Clinical appearance of melanoma of superficially spreading type. The nodular light area corresponds to a focus of amelanotic
malignant melanoma featuring deep dermal invasion.
Figure 3.70 A, Pagetoid appearance of melanocytes in superficially spreading malignant melanoma. B, Malignant melanoma showing
transepidermal migration. There is also individual necrosis of neoplastic melanocytes. Some of the melanin has reached the horny layer (so-called
pigmented parakeratosis).

(3) Nodular Melanoma

-can present as a smooth nodule covered by normal epidermis, as an elevated blue–black plaque, or as a polypoid, frequently
ulcerated mass

-A lateral flat component is not seen clinically or microscopically

-This type of melanoma affects all body surfaces, is usually of short duration

-occurs in a younger age group than either of the foregoing two categories.

(4) Acral Lentiginous Melanoma

-has an intraepidermal component of lentiginous type, which is similar in many respects to that seen in lentigo maligna

-In contrast to the latter, however, the intraepidermal melanocytes tend to be dendritic and bizarre, the involved epidermis is
markedly hyperplastic rather than atrophic, and the papillary dermis in this region is widened and inflamed.
-Tumors with these features have been seen on the palms, soles, subungual areas, mucocutaneous junction of the oral and
nasal cavities, and anus

-This type of melanoma is more common in blacks and Asian people

The clinical differential diagnosis of malignant melanoma includes a wide variety of lesions, particularly those containing
melanin or hemosiderin pigment: benign nevi of various types, benign fibrous histiocytoma, inflamed or thrombosed
hemangioma, pigmented seborrheic keratosis, and pigmented basal cell carcinoma.862 Conversely, malignant melanomas that
are amelanotic or covered by a thick layer of keratin can simulate a pyogenic granuloma or a callus, respectively.

Microscopic Features and Other Melanoma Types

-The typical example of malignant melanoma is easily identified microscopically because of its

junctional activity;
prominent melanin pigmentation;
invasion of the surrounding tissue;
marked cytologic atypia;
nuclear grooves, folds, and pseudoinclusions;
large eosinophilic nucleoli;
and abundant mitotic figures, some of them atypical

BUT NOT ALWAYS THE CASE!

-malignant melanoma is notorious for the great microscopic variability that it may exhibit

>The cells can be epithelioid, spindle shaped, or extremely bizarre (“monster cells”)

Figure 3.71 Malignant melanoma in the region of the Achilles tendon showing prominent spindling. This is a common finding in tumors at this
site.
>Their size can range from small (lymphocyte-like) to spindled to giant multinucleated forms (Figs. 3.71 and 3.72). The
cytoplasm can be eosinophilic, basophilic, foamy, of signet ring type,869,870 rhabdoid,871–873 oncocytic874 or completely clear (balloon
cell melanoma).875 Melanin can be abundant, scanty, or absent (amelanotic melanoma).

Figure 3.72 Melanoma containing highly anaplastic tumor cells.

-Sometimes the amount of melanin production is so massive as to obscure the cellular details; such cases have been
inelegantly called animal-type melanoma on the grounds that they resemble melanocytic neoplasms in horses and other
mammals

>behavior is low-grade neoplasms, with the potential for local recurrence, nodal metastases, and very exceptionally
distant metas- tases.

-The pattern of growth of melanoma may be pseudoglandular, pseudopapillary, peritheliomatous, hemangiopericytoma-like,

Figure 3.73 Prominent trabecular pattern of growth in melanoma.

The tumor can be accompanied by marked fibroblastic response, myxoid changes (Fig. 3.75),885,886 osteoclast-like giant cells,887–889
Touton-like giant cells,890 pseudoepitheliomatous hyperplasia of the overlying epidermis,131 and a variety of divergent
differentiations, including osteocartilaginous, rhabdomyoblastic, and neuroendocrine.891–894 Occasionally, formations suggesting
differentia- tion toward Schwann cells, tactile corpuscles, ganglion cells, and other neuroid structures are observed. 895–897
Sometimes the lymph node and other metastases of a melanoma acquire an appearance that is practically indistinguishable from
that of an MPNST.898 The knowledge that MPNSTs rarely metastasize to lymph nodes is helpful in the distinction.
DESMOPLASTIC MELANOMA

-represents a distinct subtype of spindle cell melanoma

-The head and neck is the most commonly affected region.

-This is an important subtype of melanoma because of the fact that it can be easily misdiagnosed, sometimes with serious
consequences.

-An overlying junctional component consisting of melanocytic hyperplasia to lentigo maligna is frequently, but not invariably,
present.

-The dermal component is formed of spindle cells arranged in short fascicles surrounded by a heavy desmoplastic stroma. The
tumor cells can be very scanty and not overly atypical.

-The difficulty is compounded by the fact that these cells are positive for S-100 protein but usually not for HMB-45, Melan-A,

or any of the other more specific melanoma markers, while sometimes acquiring mesenchymal markers, such as actin

-can be “pure” or represent a portion of an otherwise conventional melanoma

-More cellular examples with less collagenous stroma are better regarded as spindle cell melanoma rather than desmoplastic
melanoma.

-The differential diagnosis of desmoplastic melanoma includes hypertrophic scar (which may contain S-100 protein–positive
cells),904 atypical fibroxanthoma, spindle squamous cell carcinoma, and peripheral nerve sheath tumors.

-Clues to the diagnosis at the H&E level are focal fascicular pattern of growth, deep invasion, infiltration of nerves, and
lymphoid aggregates at the tumor periphery (sometimes so prominent as to resemble cutaneous lymphoid
hyperplasia/pseudolymphoma), and the presence of a lesion with the features lentigo maligna in the overlying epidermis

Figure 3.76 Desmoplastic Malignant Melanoma. The spindle cells have a deceptively bland appearance. The collections of lymphocytes are a
characteristic feature.

NEUROTROPIC MELANOMA

-a variant of desmoplastic/spindle cell melanoma growing in a peripheral nerve sheath pattern, either because the tumors invade
preexisting nerves or because they differentiate along peripheral nerve structures.
-Along these lines, it is interesting that spindle cell melanomas have often been found to express the p75 neurotrophin receptor
and nerve growth factor receptor (NGFR) (a marker of schwannian differentiation), two features further supporting a dif-
ferentiation along neural lines

BORDERLINE OR MINIMAL DEVIATION MELANOMA

-another proposed subtype of melanoma, a controversial concept that includes the previously cited verrucous and spitzoid
melanoma, as well as a halo nevus–like type

-Nearly all primary melanomas exhibit an intraepidermal component (“junctional activity”) during their initial phase.

-Therefore a melanoma lying entirely within the dermis should be suspected of being metastatic.

-However, many well-documented cases of primary intradermal melanoma exist, the possible explanations for their
occurrence being total regression of the intraepidermal component or origin from an intradermal nevus. When
encountering a purely intradermal primary melanoma, it should be distinguished from cutaneous clear cell sarcoma.

-At a practical level, there are two major diagnostic challenges in this field.

The first is how to identify as melanoma an obviously malignant tumor when melanin formation is not apparent in routine
sections.

>Features suggestive of melanoma in H&E sections are: cells with abundant acidophilic, finely granular cytoplasm;
pseudonuclear inclusions; a combination of epithelial and spindle cell patterns of growth; a fascicular arrangement of
tumor cells; and pseudoalveolar arrangemen

>Special stains, immunohistochemical stains, and ultrastructural examination are of great utility in establishing the
diagnosis in difficult cases

The other important diagnostic problem is the determination of whether a skin lesion of obvious melanocytic nature is
benign or malignant.

>Benign lesions most commonly overdiagnosed as melanomas are Spitz nevi (especially the desmoplastic type of
pure epithelioid nevus), halo nevi, activated and dysplastic nevi, vulvar (genital-type) nevi, and nevi that have
recurred following incomplete excision. Conversely, the type of melanoma that is more likely to be underdiagnosed as
benign is a level I or II superficially spreading type, especially if occurring in sites such as the plantar and the
subungual regions.

We have found the criteri, a listed here to be the most useful for the identification of early malignant
[Link], none of them is pathognomonic. The diagnosis of melanoma can be made only on the basis of a
combination of features.

1. Poor circumscription (lack of cohesiveness) of the intraepidermal melanocytic component. The nests are not as sharply
defined as those of benign lesions, and the individual cells within the nests are separated from each other. A related
phenomenon of similar diagnostic significance is subepidermal cleft formation, i.e., the presence of clefting of at least 0.3 mm in
length between the epidermal layer and the underlying melanocytic proliferation
2. Lateral extension of individual melanocytes. Benign lesions usually exhibit a sharp cutoff, whereas in most malignant
lesions there is a trailing off of atypical melanocytes spreading from the center of the lesion.

3. Extension of melanocytes, individually and in nests, throughout the malpighian layer and within adnexal epithelium.
This phenomenon of transepidermal migration results in a pagetoid appearance of the lesion, hence the term “pagetoid
melanoma” that is sometimes used. The melanin pigment can reach the horny layer, a process known as pigmented parakeratosis;
this is rare in benign nevi, but appears with some frequency in some variants of benign lentigo and in “activated” benign lesions.

4. Size variation, shape variation, and confluence of melanocytic nests.

5. Asymmetry. This pertains to many of the items described in this list, such as lateral extension, the extent of the dermal
component, architectural features of the nests, cell type, the distribution and appearance of the melanin, and the degree of
inflammation and fibrosis.

6. Lack of maturation of dermal melanocytes. In benign nevi, the nests and individual melanocytes become smaller with
descent into the dermis, whereas this is usually absent in melanoma.

7. Melanocytic atypia, evidenced by the prominence of nuclei and nucleoli and an increase of the nucleocytoplasmic ratio.

8. Mitotic activity. Most benign nevi have a very small number of mitotic figures, although some spindle and epithelioid cell
nevi may contain many. The presence of atypical mitoses and dermal mitoses (especially deeply located) are strong
indicators that the lesion is malignant. The same is true for the presence of mitoses in the dermal component of melanocytic
lesions other than Spitz nevi. Some benign and malignant melanocytic lesions are associated with marked hyperplasia of the
epidermis: in these cases, one should be careful to distinguish mitoses in keratinocytes from mitoses in melanocytes.

9. Melanocytes with an abundant clear cytoplasm having a finely dispersed (“dusty”) chromatin. This has been interpreted
as a sign of degeneration and is a particularly useful sign.

10. Necrosis of individual melanocytes. This phenomenon should be distinguished from the eosinophilic hyaline bodies
(Kamino bodies) seen most often in Spitz nevi.

11. Dermal infiltrate of chronic inflammatory cells, mainly lymphocytes. This is particularly prominent in early lesions and
tends to have a bandlike distribution instead of the patchy appearance usually seen in irritated nevi.

-So far, no completely reliable ultrastructural, immunohistochemical, or molecular genetic features distinguishing between
benign and malignant melanocytic lesions have been described

Histochemical and Immunohistochemical Features

-but none of them is of great utility in the separation between benign and malignant melanocytic neoplasms.

-Melanin stains are silver based and rely on the reducing properties of melanin granules. These argentaffin stains (of which
the Fontana– Masson is the most widely used) are particularly useful in two situations: detecting finely dispersed granules that
are not immediately apparent in H&E sections or demonstrating (when used in conjunction with a negative iron stain) that the
brown pigment seen in the routine sections is melanin rather than hemosiderin.
-
Immunohistochemically, the typical melanoma is reactive for S-100 protein, HMB-45, Melan-A, tyrosinase, MiTF, and
SOX10.599,924–926

-
Positivity for S-100 protein, although nonspecific, is of greater practical importance because it is negative in many of the
tumors that enter in the differential diagnosis (Fig. 3.77).927,928 This reactivity is both nuclear and cytoplasmic and is present in
more than 90% of the cases.929 However, it should be noted that melanomas (particularly in their metastases) can lose their
immunoreactivity for S-100 protein (and most of the markers discussed next) as a consequence of phenotypic
dedifferentiation.930–932

HMB-45 is a much more specific marker than S-100 protein (Fig. 3.78).603 It is particularly useful when the differential
diagnosis includes a nonmelanocytic tumor that can also be S-100 protein positive, such as breast carcinoma.933 It may be
detected in S-100 protein–negative melanomas, but on the whole it is less sensitive than the latter. It recognizes a
premelanosomal glycoprotein (gp100) related to the tyrosinase system, which explains why it may be negative in
undifferentiated amelanotic neoplasms

Melan-A (Mart-1; A103) is a melanocyte differentiation antigen originally identified as a target for cytotoxic T cells, which is
detected with the monoclonal antibody A103. It is positive in approximately 80% of melanomas and has become a widely used
marker for this tumor; however, it also stains steroid-producing cells from adrenal cortex, ovary, and testis and the tumors
originating from them

Tyrosinase is a key enzyme for the production of melanin from tyrosine; it can be detected with conventional enzyme
histochemical methods (which require fresh tissue) but now also with immuno- histochemistry or reverse transcription-
polymerase chain reaction (RT-PCR) in paraffin-embedded material.596,938,939 At the immuno- histochemical level, the positivity is
in the range of 80%–90%.

MiTF is a nuclear protein needed for the development and postnatal viability of melanocytes, through its function as a master
regulator of extracellular signals. It stains nearly all melanomas of conventional type,598 but—like most other markers—it fails to
stain most spindle cell/desmoplastic melanomas,940 despite early statements to the contrary; furthermore, it can also be positive in
a variety of nonmelanocytic spindle cell tumors, including dermatofibroma and smooth muscle tumors.940

SOX10 is a nuclear transcription factor that is widely expressed in melanocytic and nerve sheath tumors. It stains nearly all
mela- nocytic tumors, including desmoplastic melanomas, but will also stain myoepithelial cell

SM5-1 and PNL2 are two relatively new antibodies said to offer significant advantages in terms of sensitivity, a claim that needs
independent confirmation

MAGE-1 (melanoma antigen-encoding gene) has also been introduced as a sensitive marker for melanoma, but its diagnostic
utility seems very limited.943,944 NK1/C3 has also been advocated for the identification of melanoma but suffers from considerable
cross-reactivity with many other neoplasms.

NSE also stains melanoma cells, in keeping with the neuroecto- dermal nature of these cells, but the stain is of little practical
utility. WT1 is negative in most nevi and positive in most melanomas (including the desmoplastic variety), but its potential utility
is diminished by the fact that most Spitz nevi and a third of dysplastic nevi are also positive.

Molecular Genetic Features