MELANOMA MALIGNA

DEFINISI
The third most common type of skin cancer, sometimes called malignant melanoma (a
redundant term that emphasizes its danger, but all melanomas are malignant by definition).

 Most commonly (not always) presents with the so-called ABCDE criteria: Asymmetric macule,
papule, plaque, or nodule, with notched or irregular Borders, Colors variegated with red
(inflammation), dark brown–black (1.13, melanin), blue (1.14, deep melanin) white (scarring),
Diameter more than 6 mm in most cases. Since diameter more than 6 mm is relatively lame,
since certainly many lesions more than 6 mm are not melanoma, and this criterion could result
in missing really early small melanomas, it might be better to let the D stand for Darkness.
Lesion is often Evolving (growing or changing).
Melanoma occurs in any location, but is most common in sun-covered areas (especially
shoulders, thighs), despite all the hoopla over the fact that other more common skin cancers
(basal cell and squamous cell carcinomas (BCC and SCC)) are most common in sun-exposed
areas

• Growth phases

: 1. Radial growth ¼ typically precedes vertical growth 2. Vertical growth: • dermal mitosis • dermal
nests > junctional nests •

Risk factors include:

• Two or more sunburns before age 15 • Intermittent intense sun exposure • Large congenital or
atypical nevi • Genetic factors (see below) • Nevi >6 mm • Fair skin or hair color • Tendency to burn
easily • Xeroderma pigmentosum

• Genetic factors: • CDKN2A (cyclin-dependent kinase inhibitor), encodes tumor suppressor proteins
p16 (part of Rb pathway) and p14ARF (part of p53 pathway) • B-RAF gene (60–70%) and NRAS gene,
part of cell signaling and growth • PTEN (50%), tumor suppressor gen
Depth of invasion into the dermis is the most important prognostic indicator.

Depth of invasion is often measured by antiquated Clark levels: � Level I: in situ within the epidermis �
Level II: invades papillary dermis � Level III: fills papillary dermis and reaches reticular dermis � Level
IV: invades reticular dermis � Level V: invades subcutaneous fat

Breslow’s thickness.

Measure the thickness of invasion in millimeters with a micrometer from the top of the granular layer to
the deepest point of invasion. Cure rate 99% if Breslow thickness is less than 0.76 mm. Extension of
melanoma down the adnexal structures does not count for the measurement. Some authors prefer to
define thin melanomas as those less than 0.85 mm or 1.0 mm. Those more than 4 mm are usually
considered deep, and have a high chance of metastasis

� Staging. Do not confuse Clark levels with stages. The American Joint Committee on Cancer staging
system for cutaneous melanoma was updated in 2009, adding consideration of mitoses per square mm
in the dermis, immunostaining of nodal metastases, and deleting Clark levels:112 � Stage 0: melanoma
in situ (no invasion) � Stage Ia: localized. Breslow less than or equal to 1 mm with no ulceration or
dermal mitoses � Stage Ib: localized. Breslow less than or equal to 1 mm with ulceration or one mitosis
or more per square mm, or tumor 1.01 to 2 mm without ulceration � Stage IIa: localized. Breslow 1.01
to 2 mm with ulceration, or 2.01 to 4 mm without ulceration � Stage IIb: localized. Breslow 2.01 to 4
mm with ulceration, or greater than 4 mm without ulceration � Stage III: regional metastasis. Satellite
skin metastasis (defined as within 2 cm of main tumor, or “in transit metastasis” in skin (defined as
beyond 2 cm of the main tumor but still within nodal basin), or any regional node metastasis (even any
size micrometastasis detected with immunostaining by HMB-45 or MART-1/ Melan-A. Stage III is further
subcategorized based upon the number of nodes and whether a node has macrometastasis (clinically
detected), or whether metastasis was satellite or in transit without nodal involvement � Stage IV:
distant metastasis. Any distant skin, distant subcutaneous, distant node, or visceral metastasis. Stage IV
can be further subcategorized depending upon the site of metastasis (distant skin, lung versus other
visceral) and elevation of the serum lactate dehydrogenase
LOW CSD MELANOMA
HIGH CSD MELANOMA
DESMOPLASTIC MELANOMA
Differential diagnosis

1. Other melanocytic neoplasms (this chapter). 2. Melanocytic nevus (20.5): less likely to have
cytologic atypia, mitoses, inflammation, and pagetoid cells. More likely to have symmetry, well-
circumscribed nests of melanocytes in the junction region, nest size uniformity, maturation of
melanocytes deeper in the dermis, and sharp lateral circumscription. Lymphocytes can be a
valuable clue for melanoma because they can be considered smart bombs that can see
melanoma antigens that we cannot see with H&E. Lymphocytes are uncommon in benign nevus,
with noteworthy exceptions being irritated nevus, halo nevus, dysplastic nevus and Spitz nevus.
Lymphocytes are more common in a band deep to a melanoma in the dermis, whereas in halo
nevus the lymphocytes mingle more freely with the melanocytes. To help distinguish melanoma
from nevus, some authorities have relied upon immunostaining, while others feel this is not so
helpful. HMB-45 stain in benign nevus tends to stain the superficial portion, but not the deeper
dermal component, whereas in melanoma it stains patchy or diffuse in the dermis
(“stratification” of staining, analogous to the “maturation” described above with H&E stain). Ki-
67 (MIB-1) staining of less than 5% of the dermal melanocytes suggests nevus, whereas staining
more than 10% of the cells favors melanoma. S-100 and Melan-A usually stain both nevus and
melanoma, except that desmoplastic melanoma tends to be negative for Melan-A as opposed to
desmoplastic nevus. In some cases, it may not be possible to distinguish melanoma from benign
nevus, and disclaimers, euphemisms, or hedging terms are used, such as borderline melanocytic
tumor, AMP (atypical melanocytic proliferation), MELTUMP (melanocytic tumor of uncertain
malignant potential), or SAMPUS (superficial atypical melanocytic proliferation of uncertain
significance). 3. Spitz nevus (20.6). 4. Dysplastic nevus (20.7). 5. Other neoplasms with pagetoid
cells (1.37), or pagetoid melanocytes (1.37). 6. Especially if melanin is lacking, consider other
epithelioid neoplasms (1.38) or spindle cell malignancies (1.131). Melanoma is usually S-100+,
Sox10+, HMB45+, MART-1+, pankeratin negative, desmin negative. CD68 sometimes can be
positive, causing confusion with fibrohistiocytic proliferations.
 PILOMATRICOMA

Clinical manifestasion

Solitary, hard, multilobular papule covered with normal skin; skin-color to bluish color; “tent sign”
(stretching of skin shows multiple facets and angles); may discharge calcium through eroded areas •
Multiple lesions associated with myotonic dystrophy, sarcoidosis, Turner’s, Gardner’s and Rubinstein–
Taybi syndrome • Mutation ¼ activated beta-catenin (75%), CTNNB-1 gene (catenin, beta1); role in hair
follicle development

Histopathology

• Circumscribed, lower dermis nodule similar to a cyst; two cell types present (basophilic cells at
periphery and eosinophilic shadow/ghost cells with a pale, empty space instead of nucleus); keratinous
debris; calcifications (two-thirds of cases); stroma ossification (13%); foreign body giant cells; mixed
inflammatory infiltrate
 Differential diagnosis

1. Shadow cells are rarely present in small numbers in epidermal inclusion cysts (19.1), pilar cysts
(19.2), or other adnexal neoplasms. 2. Completely calcified or ossified lesions may resemble
other diseases with calcification (1.19) or osteoma cutis (29.8). 3. Pilomatrix carcinoma: rare
malignant counterpart of pilomatrixoma, larger, more infiltrating, more atypia, might just be a
squamous cell carcinoma (SCC) with shadow cells. 4. Other basaloid neoplasms (1.11) rarely
cause difficulty once shadow cells are identified.

STEATOCYSTOMA

Definitions

 Small cyst with lining similar to corrugated cuticle of sebaceous duct, associated with
sebaceous glands

Clinical feature

Uncommon, usually on the trunk (1.141), head, neck (1.86), or earlobes (1.28), contains yellowish oily
lipid material and keratin, the only “true” sebaceous cyst.

� Cyst may contain sparse keratin or hair shafts, but frequently appears empty because the oily
sebaceous fluid dissolves during processing � Cyst wall consists of ruggated squamous epithelium with
a wrinkled crenulated eosinophilic refractile cuticle of keratin instead of a granular layer � Sebaceous
glands within or adjacent to the cyst wall, opening into the cyst

Histopathology

� Cyst may contain sparse keratin or hair shafts, but frequently appears empty because the oily
sebaceous fluid dissolves during processing � Cyst wall consists of ruggated squamous epithelium with
a wrinkled crenulated eosinophilic refractile cuticle of keratin instead of a granular layer � Sebaceous
glands within or adjacent to the cyst wall, opening into the cyst

Differential diagnosis

 Cystic sebaceous hyperplasia
 Dermoid cyst
 Pigmented follicular cyst
 Vellus hair cyst
 SEBACEOUS CARCINOMA

• Slight female preponderance

• Two variants:

1. Periocular (75% of cases): • upper eyelid > lower eyelid • arises from meibomian gland of tarsal
plate or gland of Zeiss of the eyelashes • chalazion-like in appearance 2. Extraocular (25%): •
head, neck, trunk • pink to yellow–red nodule • Possible lymph node metastasis (one-third) •
May rarely be associated with Muir–Torre syndrome (see p. 582), nevus sebaceous or a
rhinophyma
Histopatholgy
� Pagetoid cells sometimes in the epidermis or conjunctiva � Disordered invasion of dermis by
poorly defined lobules of basaloid or squamoid cells and poorly developed sebaceous cells �
Moderate to severe atypia

Lobules or sheets of cells separated by a fibrovascular stroma; extends deep possibly to muscle;
variable sebaceous differentiation with foamy or vacuolated clear cells; periocular lesions have
pagetoid sebocytes

HIDRADENOMA PAPILIFERUM

Variant of apocrine adenoma

• Women; middle age • Vulva, perianal area • Solitary, asymmetric papule or nodule (
TUBULAR ADENOMA

Histopathology
Epidermis sometimes hyperplastic (1.61) � Circumscribed tumor in dermis or subcutaneous
tissue consisting of many glandular spaces � Apocrine decapitation secretion usually present �
Papillary projections without stroma extend into the lumina of the tubules � No connection to
the surface epithelium

ORGANOID NEVUS/NEVUS SEBACEOUS

 Definition

 Often incorrectly spelled “nevus sebaceous”

 Congenital, organoid epidermal nevus on scalp and face
 Malformed adnexal structures, increased risk of trichoblastomas, basal cell carcinoma,
squamous cell carcinoma
 Sex hormone responsive: need prophylactic excision before puberty

Somewhat common congenital, yellowish, verrucous, linear plaque, usually on the head or neck,
especially on or near the scalp (1.124), usually with alopecia (1.4) in the area. Often is more
macular at birth, but the papillomatosis increases and sebaceous glands enlarge at puberty,
bringing the patient into the office with a changing birthmark. Nevus sebaceus syndrome
(Schimmelpenning–Feuerstein–Mims syndrome), analogous to epidermal nevus syndrome, is
the sporadic association of nevus sebaceus with ocular, CNS, and skeletal abnormalities.
Phacomatosis pigmentokeratotica is a variant of nevus sebaceus syndrome, in which a nevus
sebaceus is combined with a speckled lentiginous nevus (20.5) in a checkerboard pattern,
sometimes with segmental hyperhidrosis

Clnical feature
Epidermal hyperplasia (1.61) and papillomatosis � Many normal or enlarged sebaceous glands,
usually unassociated with mature hair shafts. Early in childhood, the entire pilosebaceous unit is
poorly developed and appears as small buds � Many apocrine glands � Basaloid hyperplasia,
true basal cell carcinoma (BCC, less than 5% incidence, some authors call them trichoblastoma
instead, 22.7), syringocystadenoma papilliferum (23.3), trichilemmoma, or other adnexal tumors
commonly develop within a nevus sebaceus after puberty

Histopathology
Epidermal hyperplasia (1.61) and papillomatosis � Many normal or enlarged sebaceous glands,
usually unassociated with mature hair shafts. Early in childhood, the entire pilosebaceous unit is
poorly developed and appears as small buds � Many apocrine glands � Basaloid hyperplasia,
true basal cell carcinoma (BCC, less than 5% incidence, some authors call them trichoblastoma
instead, 22.7), syringocystadenoma papilliferum (23.3), trichilemmoma, or other adnexal tumors
commonly develop within a nevus sebaceus after puberty

Diffrential diagnosis
Epidermal hyperplasia (1.61) and papillomatosis � Many normal or enlarged sebaceous glands,
usually unassociated with mature hair shafts. Early in childhood, the entire pilosebaceous unit is
poorly developed and appears as small buds � Many apocrine glands � Basaloid hyperplasia,
true basal cell carcinoma (BCC, less than 5% incidence, some authors call them trichoblastoma
instead, 22.7), syringocystadenoma papilliferum (23.3), trichilemmoma, or other adnexal tumors
commonly develop within a nevus sebaceus after puberty
SKIN TAG
 Deinition

 Benign nonepithelial tumors arising from mesodermal tissue

Very common, often pedunculated (1.106), skin-colored (1.129) to brown, papules of eyelids
(1.43), neck (1.86), axilla (1.10), or groin (1.55). Increased incidence with aging and obesity,
controversial association with intestinal polyps.

• Most common fibrous tumor of the skin • Obese females • Axilla, neck, groin, eyelids • Clinical
variants: • Furrowed papule • Filiform lesion • Large bag-like protuberance • May be associated
with diabetes, abnormal lipids, colonic polyps • Associated with Birt–Hogg–Dube´ syndrome
(see p. 576)

Histopathology

• Varies histologically on clinical type • Polypoid with loose fibrous stroma, lacks adnexal
structures • Fibrovascular core may be replaced by adipose tissue
� Pedunculated papule (1.106), epidermis often extends almost completely around the
specimen when it is sectioned � Papillomatosis and acanthosis common, sometimes epidermal
atrophy (1.9) � Dermis consists of loose connective tissue that is often pale � Dilated blood
vessels often
Variations 1. Dermatosis papulosa nigra (18.2). 2. Birt–Hogg–Dube syndrome (22.6). 3.
Lipofibroma (“fibroma molle”): larger tag with adipose in the stroma, not to be confused with
nevus lipomatosus
Variations 1. Dermatosis papulosa nigra (18.2). 2. Birt–Hogg–Dube syndrome (22.6). 3.
Lipofibroma (“fibroma molle”): larger tag with adipose in the stroma, not to be confused with
nevus lipomatosus

Differential diagnosis
Variations 1. Dermatosis papulosa nigra (18.2). 2. Birt–Hogg–Dube syndrome (22.6). 3.
Lipofibroma (“fibroma molle”): larger tag with adipose in the stroma, not to be confused with
nevus lipomatosus

Dermatofibroma
(see Fig. 27.1A–I) Brownish (1.18) nodules most common on the legs (1.67), also seen on upper
extremities and trunk, rarely on the head or neck, probably originating from folliculitis,
arthropod bites, or some other initial inflammatory condition. Some authors prefer to think of a
dermatofibroma as fibrosing dermatitis rather than a neoplasm. Often mistaken for “nevi” (20.5)
by the non-dermatologist, but they are more indurated than nevi. DFs often have the dimple
sign when inwardly compressed.

Clinical manifestasion
“Benign fibrous histiocytoma” • Young adults • Lower extremities • Round, ovoid, firm dermal
nodules; often central white scar; “dimple sign” • Multiple eruptive DF variant associated with
autoimmune disorders (i.e., SLE), leukemia, atopic dermatitis; immunosuppression (HIV) ;
initiation of HAART medications • Classically, dermoscopy shows central white, scar-like area
and delicate pigment network at periphery (picture above)

Histology
� Epidermal hyperplasia (1.61) often, sometimes with flattened “tabled” rete ridges or basaloid
proliferation simulating a basal cell carcinoma � Hyperpigmented basal layer often � Poorly
circumscribed proliferation of boomerang-shaped spindled fibroblasts or histiocytes in the
dermis, often whorling about, blending into the surrounding dermis like a bomb was dropped in
the dermis, sometimes extending into the subcutaneous fat � Multinucleated giant cells (1.84),
Touton giant cells, or foamy histiocytes (1.46) sometimes � Hemosiderin often (1.58) � Large
bundles of collagen (“keloidal collagen”) often present at periphery of lesion, with fibroblasts
around the bundles (“collagen trapping”

• Poorly demarcated; centered on dermis; grenz zone; epidermal hyperplasia (“dirty fingers”);
spindled, heterogeneous fibroblasts (“boomerang”); giant cells; hemosiderin • Numerous
variants histologically • Myofibroblasts parallel epidermis; “collagen trapping” at edges May be
pigmented (below left) or cause basaloid induction (below right) • Factor XIIIa stain (below)

Differential diagnosis
Differential diagnosis
Scar (27.2): epidermal atrophy, fibroblasts tend to be oriented more parallel to the
epidermis instead of whorling, with blood vessels more perpendicular. 2.
Dermatofibrosarcoma protuberans (27.10): large size, location usually on the trunk,
infiltrating bands of spindle cells extend into adipose, more prominent storiform pattern,
mild cytologic atypia, no epidermal hyperplasia, usually no multinucleated giant cells or
foam cells. DFSP is typically CD34+, factor XIIIaneg, stromelysin-3neg, D2-40neg (all four
stains are the opposite in DF). Intermediate lesions with worrisome histology and equivocal
immunostaining are not rare and might be called fibrous neoplasm of uncertain malignant
potential (FRUMP). 3. Leiomyoma (29.6). 4. Neurofibroma (26.1). 5. Desmoplastic nevus
(20.5). 6. Other spindle cell neoplasms (1.131), epithelioid cell neoplasms (1.38), or
granulomas (1.51).

NEVUS LIPOMATOSUS
Rare connective tissue nevus • Present at birth to 20s • Pelvic girdle and trunk, usually unilateral •
Plaque-type flesh-colored or yellow papules; may have linear or zosteriform arrangement • Usually
solitary lesions, but may be generalize

Histopathology
• “Fatty-skin tag” • Mature fat cells in dermis that extend to epidermal undersurface; thickening of the
collagen bundles; increased vessels in the papillary dermis • May be difficult to distinguish histologically
from focal dermal hypoplasia, but it has attenuated collagen and differs clinically

Differential diagnosis

Differential diagnosis 1. Lipofibroma variant of acrochordon (27.4): much more common, adult onset,
usually solitary, pedunculated nodule with a narrower base. Many doctors misname these large tags
“nevus lipomatosus” by mistake. 2. Goltz syndrome (11.8): nearly no dermis, clinical features much
different. 3. Piezogenic pedal papules (29.1): papules on the heels, occasionally painful (1.96), thought
to be pressureinduced herniations of adipose through an atrophic or secondarily thickened dermis. 4.
Adipose may also be found superficially in the dermis in Proteus syndrome, Michelin tire baby,
lipedematous alopecia (10.13), some lipomas (29.2), some melanocytic nevi (20.5), and healed old
wounds.

LEIMYOMA
Uncommon benign solitary or multiple red nodules, often painful (1.96), most common on the shoulder
(1.140) or upper arm (1.6).

• Pilar leiomyoma • Lesion derived from arrector pili muscle • Age ¼ 20s–30s • Trunk and extensor
surface of extremities • Solitary or multiple, firm, painful (especially in cold weather), reddish-brown
papulonodular lesions • Multiple leiomyomas area associated with: • CLL • HIV • Reed syndrome (see
below

Circumscribed non-encapsulated tumor centered on dermis; uninvolved epidermis separated by “grenz

zone”; whorled pattern; elongated nuclei with blunt ends (“cigar-shaped” nuclei); perinuclear vacuoles •
Trichrome stain (above)

Variations

1. Piloleiomyoma and genital leiomyoma: poorly circumscribed smooth muscle bundles in the
dermis. These originate from arrector pili muscles or sexual smooth muscle. 2. Angioleiomyoma:
well-demarcated deep dermal or subcutaneous nodule (1.135) that “shells out” when excised,
most common on lower leg, with smooth muscle proliferation originating from the smooth
muscle in the walls of dilated blood vessels, sometimes with mucinous areas (1.83). 3. Smooth
muscle hamartoma: congenital plaque that may be large, sometimes with gooseflesh papules
within it, usually on trunk or extremities, sometimes with prominent hairs, may occur with
Becker’s nevus (20.3). 4. Angiomyolipoma and myolipoma (29.2): more adipose tissue present in
subcutaneous nodule. 5. Pleomorphic leiomyoma: some benign leiomyomas can have atypical
nuclei, but lack the features of leiomyosarcoma below. Also known as atypical leiomyoma,
bizarre leiomyoma, symplastic leiomyoma (meaning “lacking cellular structure”, referring to
degenerative changes), or apoplectic leiomyoma (referring to degenerative areas “like a
stroke”). 6. Reed syndrome (leiomyomatosis cutis et uteri): hereditary cutaneous leiomyomas
(autosomal dominant with incomplete penetrance), uterine fibroids (leiomyomas), fumarate
hydratase mutation, renal cell carcinoma (10%). 7. Dermatomyofibroma (myoid fibroma): see
27.1.

Differential diagnosis
Dermatofibroma (27.1): epidermal hyperplasia, nuclei less blunt-ended, different staining with
trichrome, desmin, and actin-neg. 2. Neurofibroma (26.1): nuclei less blunt-ended, wavy
appearance, S-100+, desmin and actin negative. 3. Accessory nipple (29.12) and normal nipple:
has increased smooth muscle, but breast tissue sometimes present. 4. Normal scrotum and
vulva: normally has increased smooth muscle. 5. Leiomyosarcoma (26.7): solitary, larger, more
cellular, more atypical, more infiltrating pattern, more than one or two atypical mitosis per ten
high-power fields, necrosis sometimes. 6. Other spindle cell tumors (1.131): rarely cause
difficulty
ANGIOLEIMYOMA
Clinical manifestasions
• Middle age • Lower leg • Solitary, slow-growing, asymptomatic, firm gray– white round/oval
nodul

Histopathology
• Well circumscribed, round, deep nodule with a fibrous capsule; smooth muscle > vascular
vessels • Three variants: 1. Solid type 2. Cavernous type 3. Venous type • Perinuclear vacuoles
and cigar-shaped nucleus (deep dermis)