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6.3 Melanocytic Neoplasms
• More common in blonde or red-haired individuals;
absent at birth, but appear in rst 3 years of life
• ↑ Melanogenesis and ↑ melanin transfer to keratinocytes
• Histology: ↑ basilar keratinocyte pigmentation 1/–
enlarged melanocytes without increased melanocyte
density
• No propensity for malignant transformation, however are
a marker of UV damage
CALM (café au lait macule)
• Discrete uniform tan to brown macules or patches; may
be seen in infants, children, and young adults; isolated
nding in 10%–20% of normal population
• Multiple CALMs may be a/w numerous genodermatoses:
■
Neurobromatosis type 1 (NF1) . type 2 (NF2)
■
McCune-Albright syndrome
■
Russell-Silver
■
Noonan syndrome
■
Bloom syndrome
■
Tuberous sclerosis
■
MEN-I
■
Fanconi anemia
■
Ataxia-telangiectasias
• Histology: ↑ melanin deposition in basilar
keratinocytes
Solar lentigo
• Multiple pigmented macules on sun-exposed areas; most
common in Caucasians (essentially ubiquitous after
60 years of age) . light-skinned Asians
• Histology: elongated bulbous rete ridges with
hyperpigmentation (“dirty socks”); 1/– mild increase in
melanocyte density; solar elastosis in dermis
Dermal melanocytosis
• Congenital (Mongolian/cerulean spot): present at birth in
most Asians and Blacks; lumbosacral region; p/w grayblue patch (as a result of the Tyndall effect where shorter
light wavelengths are reected by melanocytes); often
resolves during childhood
■
Histology: sparsely distributed elongated dendritic
melanocytes in lower 2/3 of dermis, lying parallel to
epidermis
• Nevus of Ota: presents in rst year of life or around
puberty; ↑ incidence in pigmented individuals (Asians
and Blacks); p/w coalescing gray-blue macules in V1/V2
distribution and frequent scleral involvement (60%);
unilateral (90%) . bilateral; persists for life; may enlarge
under hormonal inuences; 10% develop glaucoma;
rare malignant degeneration to uveal melanoma (perhaps
higher risk in nevus of Ota lesions with activating
mutations in GNAQ)
■
Histology: elongated dendritic melanocytes more
numerous than in congenital dermal melanocytosis;
involves upper dermis
• Other clinical variants:
■
Nevus of Ito: located on the shoulder, supraclavicular,
and scapular regions; essentially no risk of progression
to melanoma
■
Hori’s nevus: acquired nevus of Ota-like macules of
the bilateral zygomatic region; East Asian females
■
Sun’s nevus: acquired, unilateral variant of Hori’s
nevus
Mnemonic: “There is only 1 Sun, but the (w)HOle
face is affected in HOri’s”
• Histologically, dermal melanocytoses are distinguished
from blue nevi by their ↓ cellularity, poor
circumscription, and lack of dermal sclerosis
Lentigo simplex
• Well-demarcated, evenly pigmented brown to black
macule; any age and any anatomic site
• Histology: basal layer hyperpigmentation; elongated rete
ridges with mild ↑ melanocyte density
• Conditions a/w multiple lentigines:
■
LEOPARD (most heavily “spotted” appearance)
■
Carney complex (LAMB/NAME)
■
Peutz-Jeghers (especially oral/perioral)
■
Laugier-Hunziker
■
Cowden syndrome
■
Bannayan-Riley-Ruvalcaba (penile)
■
Xeroderma pigmentosum
■
Cronkhite-Canada
Mucosal melanotic macule
• Compared with lentigo simplex can be more irregular and
mottled
• Oral lesions usually occur in adults . 40 years old on
vermilion lip . gingiva, buccal mucosa, or palate; genital
lesions most common on labia minora
• Histology: acanthosis; mild basilar hyperpigmentation
1/– subtle increase in melanocyte density
Blue nevus
• Onset in childhood/adolescence, but can also occur in
older patients; 25% of cellular blue nevi (CBN) are
congenital
• Most common sites: scalp, sacral area, and distal
extensor extremities
• Derived from dermal melanocytes (persist during
embryogenesis rather than populating epidermis)
• Activating mutations in GNAQ and GNA11 seen in 83%;
results in downstream MAPK pathway activation
■
Same mutations are the most common mutations in
uveal melanoma (46%; concomitant BAP-1 loss in
uveal melanoma leads to increased risk of metastasis
and death)
• Multiple blue nevi and epithelioid blue nevi (much more
specic) a/w Carney complex
• Variants:
■
Common blue nevus:
Blue/gray macules or papules usually less than
1 cm
Elongated, dendritic melanocytes containing
melanin pigment usually in the upper 2/3rd of
dermis with associated sclerotic collagen; no
junctional component
345
CHAPTER 6 • Neoplastic Dermatology
■
Cellular blue nevus:
Blue/gray/black plaques or nodules; often larger
(1–3 cm); favor buttocks or scalp
Dense proliferation of plump/fusiform pale gray
melanocytes containing little pigment 1 admixed
dendritic melanocytes resembling common blue
nevus cells; characteristically bulges into subcutis
(“dumbbell conguration”)
■
Epithelioid blue nevus:
Heavily pigmented; strongly a/w Carney complex
Demonstrates PRKAR1A and PRKCA mutations
(inherited or somatic)
Sometimes called pigmented epithelioid
melanocytoma
If signicant atypia/cellularity/mitoses → “animal-
type melanoma”
■
Malignant blue nevus (5 melanoma): often arises
within CBN; scalp (#1); commonly see benign
precursor within specimen; deep tumor extension 1
necrosis 1 mitoses; frequently have concomitant
GNAQ/GNA11 mutations 1 BAP-1 loss (a/w more
aggressive behavior; tumorigenesis similar to uveal
melanoma)
Recurrent melanocytic nevus
• Repigmentation conned to the scar (vs. pigment
extending beyond biopsy site 5 melanoma); usually
arises within 6 months of initial biopsy
• Histology (3 key features)
■
Dermal scar
■
Atypical junctional melanocytic proliferation (resembles
melanoma in situ) conned to area above dermal scar
■
Bland dermal nevus remnants below/adjacent to scar
(#1 Boards clue)
Spitz nevus
• Clinical
■
Acquired, usually solitary lesions in rst two decades
(use caution in diagnosing a patient in the fourth
decade and older); most common on head/neck .
extremities
■
Rapidly growing pink-red papulonodule; usually
, 1 cm
• Pathogenesis
■
HRAS mutations/11p gain
Most Spitz nevi lack BRAF mutations (vs.
conventional nevi and melanomas)
■
Gene fusions: ALK, NTRK1, NTRK3, MET, ROS
■
“BAPoma:” distinctive subset of atypical epithelioid
spitzoid nevi with loss of BAP-1 tumor suppressor
gene; have unique histology, and unlike most Spitz
nevi, have activating BRAF mutations
Two cell populations: conventional nevus cells 1
epithelioid cells (large, rounded, melanocytic
population w/ nuclear inclusions)
Big cells are negative for BAP-1 on
immunohistochemistry (IHC)
• Histology (Fig. 6.5):
■
Symmetric and circumscribed; most often compound
■
Epidermal hyperplasia (vs. consumption of epidermis
in melanoma)
Balloon cell nevus
• Clinically indistinguishable from ordinary nevi
• Histology: .50% dermal melanocytes are “balloon
cells” (large, pale, and polygonal melanocytes with
foamy/vacuolated cytoplasm and variable pigmentation);
balloon cell change is a result of melanosome
degeneration
■
Boards tip: can always identify conventional nevus
somewhere within lesion
Halo nevus (Sutton nevus)
• Pigmented nevus with surrounding hypopigmented zone;
most commonly second decade; most commonly on the
back; most commonly benign
■
May be a/w vitiligo or melanoma (rarely) at another
site (perform full skin exam if seen)
• Multiple lesions can occur idiopathically or w/ various
monoconal antibodies (e.g., iniximab, tocilizumab,
pembrolizumab)
• Histology: bland nevus w/ lymphocytes intertwined
(“mingling”) with melanocytes
■
In contrast, lymphocytes form a lichenoid band
(“riot police barrier”) under and around melanoma
346
A
B
Fig. 6.5 (A) and (B) Spitz nevus histology. Note the pseudoepitheliomatous hyperplasia of the epidermis with vertically oriented spindled and epithelioid nests
(“bananas on the tree”) and clefts around the nests. (From Elston DM. Melanocytic neoplasms. In: Elston DM, Ferringer T, eds. Dermatopathology. 3rd ed.
Philadelphia: Elsevier, 2019:101–131.)
6.3 Melanocytic Neoplasms
■
Large junctional nests with clefting around entire nest
(vs. discohesion of nests in melanoma, where the nest
itself becomes fragmented)
■
Parallel “raining-down” orientation of nests and cells
■
Kamino bodies: pink clumps of basement membrane
zone (BMZ) material (collagen IV) within epidermis
■
“Spitzoid” cytology: large epithelioid and spindled cells
w/ abundant pink-purple (amphophilic) cytoplasm
and prominent lilac-colored nucleoli (vs. cherry red
nucleoli in melanoma); usually not pigmented
■
Dermal component “matures” with depth (reduction
in density and cell size)
■
Supercial mitoses allowable, especially in young
patients → if numerous (.2–3), deep or atypical
mitoses are present, raises concern for melanoma
• Immunostains: S100A61, S1001, Melan-A1, and p161
■
p16 is frequently lost/diminished in atypical Spitz
tumors and spitzoid melanoma
• Treatment: controversial, but complete excision often
recommended, especially if biopsy transected
• Boards fodder: uorescence in situ hybridization
(FISH) analysis and comparative genomic hybridization
(CGH) very helpful in risk stratication of atypical
Spitzoid lesions
■
Homozygous loss of 9p21 (most predictive gene locus;
corresponds to p16/CDKN2a gene) → ↑ risk of
metastasis and death
■
Multiple gains and losses on CGH 5 melanoma
■
On sequencing, TERT promoter mutations →
predictive of poor outcomes
• Histology: compound melanocytic proliferation with
small but nearly-ubiquitous junctional component,
supercial dermal nests resembling ordinary nevus nests
(very helpful clue in distinguishing from CBN), and
prominent wedge-shaped dermal component, which
extends deep into the dermis or subcutis, tracks along
adnexal structures or neurovascular bundles; epithelioid
pigmented melanocytes in loose nests with a lot of
melanophages (Fig. 6.6A and B); b-catenin nuclear
positivity in epithelioid pigmented melanocytes on IHC
■
Versus CBN: DPN has junctional component (always
absent in CBN), supercial dermal nests resembling
ordinary nevus nests (not seen in CBN), more
pigment within melanocytes (CBN melanocytes are
amelanotic → pigment is predominantly in
surrounding melanophages), melanocytes are larger
and have more cytoplasm; nuclear b-catenin1 on IHC
Congenital melanocytic nevus
• NRAS mutations in majority of cases (.BRAF mutations)
• Divided into small (,1.5 cm), medium (1.5–19.9 cm),
and large ($20 cm)
■
Small congenital nevi have same low risk of developing
melanoma as conventional nevi
■
Large congenital nevi (.20 cm) have ↑ melanoma risk
(2%–3%; majority develop in rst decade)
Pigmented spindle cell nevus of Reed
• Heavily pigmented variant of Spitz nevus comprised
exclusively of spindled spitzoid melanocytes
• Young F . M; thigh most commonly (. other extremities
and trunk)
• Darkly pigmented macule/papule, usually , 6 mm
• Histology: junctional or supercial compound,
symmetric, circumscribed proliferation of spindled
melanocytes arranged in vertically oriented fascicles 1
numerous melanophages (much more than in
conventional Spitz nevi) in supercial dermis 1/–
pigmented parakeratosis
■
Architecture: similar to Spitz nevus but almost always
conned to junction (or very supercial dermis)
■
Cytology: spindled melanocytes are same as in Spitz
nevi, but PSCN lacks the epithelioid cells seen in
conventional Spitz nevi
Deep penetrating nevus (DPN)
• Most commonly is a component of combined nevus
(overlaps w/ clonal nevus, and inverted type A nevus)
• Activating b-catenin mutations in a pre-existing nevus →
increased nuclear cyclin D1
• Distinct from blue nevus family based on lack of GNAQ/
GNA11 mutations
• Face, upper trunk and extremities; usually second and
third decades
• Well-circumscribed blue to black papule; ,1 cm in size
A
B
Fig. 6.6 Deep penetrating nevus. (A) A pigmented melanocytic nevus with a
wedge-shaped silhouette is seen. (B) Pigmented spindle and epithelioid melanocytes are present, as well as melanophages. (From Busam KJ. Melanocytic
proliferations. In: Dermatopathology: A Volume in the Series: Foundations in
Diagnostic Pathology. 2nd ed. Philadelphia: Elsevier; 2016:447–512.)
347
CHAPTER 6 • Neoplastic Dermatology
• Initially raised tan lesions that may darken over the rst
year of life; 1/– hypertrichosis
• Often develop “proliferative nodules” → mimic
melanoma clinically and histologically
• Neurocutaneous melanosis/melanocytosis 5 large
congenital nevus in association with melanocytic
proliferation (benign or malignant) within leptomeninges
and brain parenchyma
■
Affects various sites in CNS → variable clinical
presentation; high mortality in symptomatic patients
due to mass effect
• Histology: compound or intradermal melanocytic
proliferation; dermal component extends deeper than
common acquired nevi; dermal component displays
single cell dispersion in deeper dermis, surrounds/
inltrates vessels, adnexal structures, muscle, and nerve
(not concerning)
• Treatment (large congenital nevi):
■
Surgical resection should be attempted when possible
after 6 months of age; if not possible or only partial
resection → serial examinations, early biopsies of
nodular areas
■
If large posterior axial congenital nevi or multiple
satellites (.4, particularly if at least one is at least a
medium congenital nevus) → recommend MRI
screening for neurocutaneous melanosis
Nevus spilus/speckled lentiginous
nevus
• Presents within the rst year of life
• Homogeneous tan patch within which develops small
pigmented macules and papules
• Trunk and extremities most commonly affected sites
• May be a/w phakomatosis pigmentovascularis and
phakomatosis pigmentokeratotica
• Risk of melanoma is low
• Confused w/ agminated nevus, but the latter occurs in
teenage years and with a cluster of nevi over a skincolored (rather than tan) background; signicant subset of
lesions due to activating HRAS mutation
Common acquired melanocytic
nevus
component shows “maturation” with depth (melanocytes
become smaller and less nested)
Atypical (dysplastic) melanocytic
nevus
• Occur sporadically or in the setting of familial atypical
multiple mole melanoma syndrome (FAMMM)
■
FAMMM: AD inheritance; characterized by multiple
melanocytic nevi (501), family history of melanoma,
and mutations in CDKN2A gene (encodes p16 and
ARF
p14
)
• Any site (trunk and scalp most common); wide age
range
■
Potential pitfall: new “atypical/dysplastic nevi” on sundamaged sites of elderly are most likely well-nested
lentigo maligna!
• Solitary or multiple; asymmetric, irregularly bordered,
and variably pigmented nevi ranging in size (often
. 6 mm)
■
When multiple, patients tend to have clinically (and
histologically) similar “signature nevi” → melanomas
in these patients often appear as “ugly duckling”
lesions (different appearance than their signature
nevi)
• Histology: classic features of dysplastic (Clark) nevus:
■
Asymmetry, lack of circumscription
■
Junctional “shoulder” (extends three or rete ridges
beyond dermal component)
■
Irregular size and placement of junctional nests with
bridging or lentiginous pattern (single-cell junctional
growth)
■
Papillary dermal concentric and/or lamellar brosis
■
Cytologic atypia: nuclei enlarged (1/– prominent
nucleoli), “dirty” gray cytoplasm
■
Signicant interobserver variability in grading degree of
atypia!
• Treatment: controversial; recent studies support clinical
observation of mild and moderately atypical nevi;
severely atypical nevi should be re-excised
• Prognosis: risk of melanoma directly related to the
number of atypical/dysplastic nevi; however, individual
dysplastic nevi have extremely low rate of malignant
degeneration
• Most prevalent in Caucasians; may see eruptive acquired
nevi at affected sites in EB (“EB nevi”; benign, but often
confused for melanoma because of atypical clinical and
histologic features) and LS&A
• Any site; increase in number over rst three decades, then
decrease
• “Abtropfung hypothesis”: nevus cells start as junctional
proliferation → subsequently migrate into dermis
(compound nevus) → later become entirely intradermal
→ may involute
• UV exposure, immunosuppression, hormonal inuences
implicated; BRAF mutations in up to 80% (.NRAS
mutations)
• Clinically well-circumscribed, symmetric, small (,6 mm),
and evenly pigmented
• Histology: symmetrically junctional, compound or dermal
proliferations w/ small regular nests, and dermal
348
Becker melanosis (NOT a true
melanocytic disorder)
• 0.5% prevalence, more common in adolescent and young
adult males
• May be as a result of androgen-mediated hyperplasia
• Onset around puberty
• Hyperpigmented plaque with thickening, irregularity, and/
or hypertrichosis on upper torso most commonly
• Ipsilateral breast hypoplasia seen in some patients
(Poland syndrome), rarely a/w skeletal defects and/or
limb asymmetry
• Histology: increased basal melanocytes, epidermal
thickening, elongation of the rete ridges, and dermal
smooth muscle hamartoma-like changes (very difcult to
histologically distinguish from smooth muscle
hamartoma)
6.3 Melanocytic Neoplasms
Melanoma
Epidemiology
• Most cases in Caucasians; rare cases in dark-skinned
individuals (typically acral lentiginous)
• Incidence is increasing; currently the most rapidly rising
cancer in Caucasians; trend toward early detection and
therefore thinner melanomas (vs. over-diagnosis)
• Wide age range, but mostly fourth decade onward
Risk factors
• Genetic:
■
Inherited CDKN2A mutations (FAMMM syndrome;
dysplastic nevus syndrome):
Protein products p14
progression via p53 and retinoblastoma (Rb)
pathways, respectively
Detectable mutations in 25% of familial melanomas
■
Other familial mutations: POT, TERT, TP53, BAP-1
• Other: lightly pigmented skin, UV exposure (cumulative
and short intermittent bursts), organ transplant recipient;
large number of acquired common and atypical
melanocytic nevi, ephelides, and solar lentigines
Pathogenesis (Boards favorite!)
• BRAF (V600E is most common mutation): non–chronic sun-
damaged (non-CSD) sites, supercial spreading melanomas
• NRAS: Chronic sun-damaged (CSD) skin sites, nodular
melanomas
• C-KIT: CSD sites, acral and mucosal melanomas
• CCND1/CDK4: amplications common on CSD sites,
acral and mucosal melanomas
• GNAQ/GNA11: uveal melanoma, blue nevi, and nevus of Ota
• BAP-1 (BRCA1-associated protein 1, a histone
deubiquitinase): germline loss-of-function mutations in
this tumor suppressor gene lead to increased risk of
cutaneous melanoma, uveal melanoma and malignant
CBN (both have concomitant GNAQ/GNA11 mutations; in
this context, BAP-1 loss is strongly a/w worse
prognosis), epithelioid spitzoid nevi (“BAPomas”;
benign, possess concomitant activating BRAF . NRAS
mutations), and internal malignancies (mesothelioma,
renal cell carcinoma [RCC], and others)
Subtypes
• Supercial spreading: most common subtype; may arise
de novo or in association with a nevus; peak onset 40 to
60 years old; predilection for trunk (men) and legs
(women); irregularly shaped/variably pigmented macule
during radial growth phase → becomes papulonodular
during vertical growth phase
• Nodular: onset around sixth decade; most commonly on
head/neck and back; M . F; rapidly growing blue-black
nodule; often ulcerated; lacks horizontal growth phase;
tends to present at a more advanced stage
• Lentigo maligna: onset seventh decade and older; CSD
sites particularly head and neck; presents as an irregularly
pigmented brown macule; long horizontal growth phase
precedes invasion
• Acral lentiginous: less common variant; onset around the
seventh decade; most common type seen in darkly
pigmented races; overall incidence is equal across
ARF
and p16 modulate cell cycle
Caucasians and darkly pigmented races; nail matrix
lesions appear as longitudinal melanonychia w/
Hutchinson sign; usually presents at an advanced stage
because of delayed clinical detection
• Other less common subtypes:
■
Desmoplastic melanoma (Melan-A and HMB-45
negative, S1001 and SOX101); often amelanotic on
head and neck
■
Mucosal melanoma: most common oral site is hard
palate; most important prognostic factor 5 early
diagnosis; metastasis in up to 50%
■
Spitzoid melanoma (homozygous loss of 9p21
detected by FISH → poor outcome)
■
Uveal melanomas (GNAQ/GNA11 mutations 5 most
important driver mutations; very high risk of metastasis
if also have concomitant BAP-1 loss)
■
Malignant blue nevus (GNAQ/GNA11 mutations 5
most important driver mutations; often have
concomitant BAP-1 loss)
Histologic features
• General features: asymmetry, poor circumscription, and
irregularly sized and shaped junctional nests with
discohesion (nest fragments into individual cells);
lentiginous/conuent growth along dermoepidermal
junction (DEJ) predominates over nests; pagetoid scatter;
“epidermal consumption” (melanoma effaces epidermis
→ epidermal thinning, ulceration); extension down
adnexal epithelium; lack of maturation of dermal
component (sheets of melanocytes and large nests at the
base); dermal mitoses; cytologic atypia (irregular, large
nuclei w/ prominent red nucleoli)
• Staging parameters:
■
Most important: Breslow thickness, ulceration
■
Others: mitoses, subtype, regression, lymphovascular
invasion, host response, microsatellites, and associated
nevus (Tables 6.4 and 6.5)
Prognosis
• Variable, depending on stage: .95% 10-year survival for
stage IA disease, versus ,50% for stage IIIC; algorithm
using the 31-gene expression prole (31-GEP) may help
to identify risk of sentinel node positiviey, recurrence,
metastasis, and survival
• Factors a/w poor prognosis: Breslow . 1 mm,
ulceration, ↑ mitotic rate, ↑ age, male sex, palpable LN
metastases, head/neck/trunk location, and visceral
metastases; treatment delays
NCCN treatment guidelines
• Localized melanoma
■
Treatment
Stage 0 in situ → wide excision with 0.5 to 1 cm
margins
Stage IA (T1a) (,0.8 mm thick, no ulceration) →
wide excision with 1 cm margins
Stage IB (T1b) (,0.8 mm thick with ulceration or
0.8–1.0 mm thick 1/– ulceration) → discuss and
consider sentinel lymph node biopsy (SLNB) →
wide excision with 1 cm margins 1/– SLNB
Stage IB (T2a) and stage II (T2b or higher) →
discuss and offer SLNB 1 wide excision (1–2 cm
349
CHAPTER 6 • Neoplastic Dermatology
Table 6.4 Melanoma TNM Classication (AJCC 8th Edition)
Tis NA N/A
T1
T2
T3
T4
N Classification Number of involved nodes In-transit or satellite metastases
N0 0 nodes N/A
N1 N1a: 1 node (clinically occult)
N2 N2a: 2–3 nodes (clinically occult)
N3
M Classification Site Serum Lactate Dehydrogenase
M0 No distant metastases N/A
M1a Distant skin, soft tissue or non-regional node M1a(0): Normal
M1b Lung metastases M1b(0): Normal
M1c All other non-CNS visceral metastases M1c(0): Normal
M1d CNS metastasis M1d(0): Normal
a
In-transit metastases are . 2 cm from the primary tumor, but not beyond the regional lymph nodes; satellite lesions are within 2 cm of the primary.
Adapted from Amin MB, ed. AJCC Cancer Staging Manual . 8th ed. Chicago: American College of Surgeons; 2018.
#1.0 mm a: ,0.8 mm without ulceration
b: ,0.8 mm with ulceration, 0.8–1.0 mm with or without ulceration
.1.0–2.0 mm
a: without ulceration
b: with ulceration
.2.0–4.0 mm
a: without ulceration
b: with ulceration
.4.0 mm
a: without ulceration
b: with ulceration
No
N1b: 1 node (clinically detected)
N1c: 0 nodes
No
Yes
No
N2b: 2–3 nodes (1 1 clinically detected)
N2c:1 node (clinically occult or detected)
N3a:41 nodes (clinically occult)
N3b: 41 nodes (clinically detected)/matted nodes
N3c: 21 nodes (occult or detected) and/or matted nodes
No
Yes
No
No
Yes
M1a(1): Elevated
M1b(1): Elevated
M1c(1): Elevated
M1d(1): Elevated
a
Table 6.5 Stage Groupings for Cutaneous Melanoma
Clinical Staging
a
Pathologic Staging
b
T N M T N M
0 Tis N0 M0 Tis N0 M0
IA T1a N0 M0 Tla/1b N0 M0
IB T1b
N0 M0 T2a
T2a
IIA T2b
T3a
IIB T3b
T4a
N0 M0 T2b
T3a
N0 M0 T3b
T4a
N0 M0
N0 M0
IIC T4b N0 M0 T4b N0 M0
c
III
Any T N1 N2 N3 M0
IIIA T1a/1b-T2a N1a/2a M0
IIIB T1a/b-T2a
T2b/3a
T3b/4a
T4b
N1b/c/2b
N1a-N2b
N2c or N3
N1-3
N1a-2c
M0
M0
IIID T4b N3
IV Any T Any N Any M1 Any T Any N Any M1
a
Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastases. By convention, it should be used after
complete excision of the primary melanoma with clinical assessment for regional and distant metastases.
b
Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial or complete
lymphadenectomy. Pathologic stage 0 or stage IA patients are the exception.
c
There are no stage III subgroups for clinical staging.
Adapted from Amin MB, Ed. AJCC Cancer Staging Manual . 8th ed. Chicago: American College of Surgeons; 2018.
350
6.4 Adnexal Neoplasms and Hamartomas
margin if 1.0–2.0 mm thick or 2 cm margin if
. 2.0 mm thick)
■
Note: Microscopic satellites on biopsy or excision
specimen are beyond the scope of this chapter. Please
refer to detailed NCCN owcharts for further
information.
• Sentinel node positive
■
Workup
Imaging for baseline staging (consider in IIIA,
recommended for IIIB and above) and to evaluate
specic signs or symptoms
BRAF mutation testing (consider in IIIA,
recommended for IIIB and above)
■
Primary treatment
Nodal basin ultrasound surveillance (generally
preferred) or completion LN dissection
■
Adjuvant treatment
Systemic therapy
♦ Preferred systemic options: nivolumab,
pembrolizumab, dabrafenib/trametinib (for
BRAF V600-activating mutation)
Observation based on risk of recurrence
• Clinically node positive
■
Workup
Core biopsy (preferred) or FNA
♦ If needle biopsy not possible, excision LN biopsy
acceptable
Imaging for baseline staging and to evaluate specic
signs or symptoms
BRAF mutation testing
■
Primary treatment
If resectable → wide excision of primary tumor and
therapeutic lymph node dissection
♦ Consider neoadjuvant therapy (preferably in the
context of clinical trial)
■
Adjuvant treatment
Systemic therapy and/or locoregional therapy with
RT to nodal basin in selected high-risk patients
versus observation based on risk of recurrence
♦ Preferred systemic options: nivolumab,
pembrolizumab, dabrafenib/trametinib (for
BRAF V600-activating mutation)
■
Note: Clinical satellites or in-transit disease is beyond
the scope of this chapter. Please refer to detailed NCCN
owcharts for further information.
• Stage IV metastatic disease
■
Workup
Imaging for baseline staging and to evaluate specic
signs or symptoms
LDH
BRAF mutation testing
■
Treatment
Oligometastatic → systemic therapy 1/– metastasis-
directed therapy (resection or stereotactic ablative
therapy)
Widely disseminated → systemic therapy 1/–
palliative resection or RT or intralesional t-vec
Preferred systemic options: nivolumab or
pembrolizumab
♦ Other recommended regimens: nivolumab 1
ipilimumab or BRAF1MEK inhibitors (for BRAF
V600-activating mutation)
♦ Useful in certain circumstances: ipilimumab if
prior exposure to anti-PD-1 agents
6.4 ADNEXAL NEOPLASMS
AND HAMARTOMAS
• High-yield subject area for dermatology examinations,
because of classic histopathologic features
Poroma
• Benign sweat gland neoplasm that presents as a solitary,
vascular-appearing papule/nodule 1/– ulceration and
bleeding; classically surrounded by a thin moat; most
common sites 5 palms/soles (because of ↑ density of
eccrine glands) . head/neck/scalp; may be a/w nevus
sebaceus
■
Poromatosis: widespread or acral eruption of poromas
• Histology: circumscribed endophytic proliferation with
broad, multifocal epidermal connections (Fig. 6.7);
composed of monomorphous “poroid cells” (small
cuboidal cells with intercellular desmosomal bridges;
mnemonic: “poroid cells look like a cute, miniature
version of a keratinocyte”); variably sized sweat ducts
containing a pink cuticle encircling luminal aspect of
duct; highly vascularized stroma resembling granulation
tissue
• Immunostains: CEA, EMA, and PAS highlight ducts and
intracytoplasmic lumina
• Poroma variants:
■
Wholly intraepidermal poroma (hidroacanthoma
simplex): clinically mistaken for SK or squamous cell
carcinoma in situ (SCCIS); most common on distal
extremities; histology: multiple well-demarcated nests
of small poroid cells within the epidermis; ducts may
not be easily visualized
■
Juxtaepidermal poroma (“classic poroma”): described
previously
■
Wholly dermal poroma (dermal duct tumor): wellcircumscribed, “blue balls/nodules within dermis”
composed of poroid cells w/ ducts; lacks epidermal
connection
• Malignant counterpart: porocarcinoma
■
Most common sweat gland malignancy; elderly (avg.
70 years old); most commonly on lower extremity;
arises within longstanding poroma (11%), de novo, or
within nevus sebaceus; frequent metastasis (20% to
regional LN and up to 10% widespread); 10%
mortality
Histology: resembles classic poroma, but has
cytologic atypia, ↑ mitoses, atypical mitoses, and
inltrative growth pattern at tumor base
Hidradenoma
• Benign sweat gland (apocrine . eccrine) neoplasm that
presents as a solitary nodule (often multilobulated) with
a deep red-purplish hue and cystic quality
• Histology: circumscribed, large tumor nodules 1/– large
areas of cystic degeneration; occupies entire dermis;
scattered sweat ducts within the tumor nodules;
351
CHAPTER 6 • Neoplastic Dermatology
Broad-base connection
to epidermis
Poroid cells
Sweat duct
"Poroid cells"
Sweat duct
A
B
Fig. 6.7 (A) Eccrine poroma (low mag). (B) Eccrine poroma (high mag). (From Rapini RP. Sweat gland neoplasms. In: Practical Dermatopathology. 2nd ed. Philadelphia:
Elsevier; 2012:321–330.)
prominent dermal sclerosis with keloidal collagen
(most useful clue!); very focal epidermal connection
(never has broad epidermal connections)
■
Tumor nodules are composed of three main cell types
(Fig. 6.8): (1) squamoid cells, (2) poroid cells, and
(3) clear cells
Any of these three cell types may predominate in a
given tumor, but all three are present to some degree
Variants: clear cell hidradenoma (clear cells
predominate), poroid hidradenoma (poroid cells
predominate), and solid-cystic hidradenoma
(prominent cystic degeneration)
• Malignant counterpart: hidradenocarcinoma
■
Aggressive tumor w/ signicant metastatic and death
risk; head/neck (#1 site); histology: similar to
hidradenoma, but has atypia, numerous mitoses,
atypical mitoses, comedo-like necrosis, and
lymphovascular invasion; treatment: Mohs (study from
Mayo Clinic reported 0% recurrence and 0% metastatic
rate), or wide local excision (WLE; up to 75% local
recurrence rate and 20%–50% metastatic rate)
Syringoma
• Benign tumor consisting of translucent-skin colored
papules; periorbital region (eyelids #1), cheek .
352
Fig. 6.8 Hidradenoma. Supercial dermal nodulocystic tumor with connections
to the epidermis, clear cell features, and squamous metaplasia. (From Prieto VG,
Shea CR, Celebi JT, Busam KJ. Adnexal tumors. In: Busam KJ, ed. Dermatopa-
thology: A Volume in the Series: Foundations in Diagnostic Pathology . 2nd ed.
Philadelphia: Elsevier; 2016:388–446.)
6.4 Adnexal Neoplasms and Hamartomas
anterior trunk, genitals; ↑ incidence in females, Asians,
and in Down syndrome
■
Eruptive syringomas (clinical variant): p/w 100s of
hyperpigmented small papules on anterior trunk/neck;
most commonly in Africans/Asians and in Down syndrome
■
Clear cell syringoma (histologic variant): a/w diabetes
mellitus
• Histology: circumscribed proliferation of small tadpole or
comma-shaped sweat ducts lined by a thin two cell layer
of cuboidal cells; eosinophilic cuticle within sweat ducts
1 amorphous sweat within lumen; surrounding sclerotic
stroma; conned to upper half of dermis
• Malignant counterpart 5 syringomatous carcinoma
(eccrine ductal carcinoma and syringoid carcinoma); rare
sweat gland malignancy w/ inltrative growth and
minimal cytologic atypia; always arises de novo
Mixed tumor (MT; chondroid syringoma)
• Nonspecic, slow-growing, solitary nodule seen on head/
neck (nose, cheek, and upper lip . other facial sites);
middle-aged adults; M . F; clinically mistaken as cyst
• PLAG1 rearrangements in signicant subset of cases
(present in 90% of apocrine MT; rare in eccrine MT);
PLAG1 rearrangements also seen in pleomorphic
adenoma (a salivary gland tumor)
• Probably arise from the myoepithelial cells lining the sweat
glands, which can differentiate toward epithelial or stromal cells
• Composed of 50/50 mixture of epithelial (ectodermal)
and stromal (mesodermal) components → hence the name,
“mixed tumor”; appearance of each component is variable:
■
Epithelial component: usually eccrine or apocrine (.
follicular, sebaceous, or plasmacytoid)
■
Stromal component: myxoid or chondroid (.
collagenous . osteoid or lipoid)
• Histology: circumscribed dermal/SQ tumor consisting of
glandular structures, ducts, and epithelial strands with
myxoid/chondroid stroma (Fig. 6.9)
■
IHC: 1 for keratins in epithelial cells; SMA1, S1001,
SOX101 in myoepithelial cells
• Pleomorphic adenoma: salivary tumor w/ similar PLAG1
rearrangements and histology as cutaneous MT; may
undergo malignant degeneration with subsequent metastasis
• Treatment: benign; excision is curative
• Malignant counterpart 5 malignant MT: extremely rare;
very aggressive (50% metastatic rate and 25% mortality);
usually arises de novo on distal extremities/foot
(uncommon sites for benign MT); histology: epithelial
and/or stromal component appears malignant, w/
inltrative growth, ↑ mitoses, and atypical mitoses
Spiradenoma (“eccrine spiradenoma”)
• Benign sweat gland neoplasm; controversial cell of origin,
likely apocrine (despite historical name of “eccrine
spiradenoma”)
• Solitary, painful dermal or subcutaneous nodule with
blue-purple hue; favors upper half of body
• Histology: well-circumscribed proliferation of “blue balls
in the dermis” w/ ductal formation (including cystically
dilated ducts); tumor nodules are composed of biphasic
epithelial cell population: (1) peripheral small blue cells
with hyperchromatic nuclei and minimal cytoplasm, and
(2) larger, pale-staining inner cells w/ ↑ cytoplasm;
intratumoral lymphocytes (“lymphocytes peppered in
the tumor” 5 classic nding!); PAS1 eosinophilic
hyaline droplets composed of BMZ material (type IV
collagen) found within tumor (same material is found in
cylindromas, but typically encircles the tumor to form
separate jigsaw pieces); very vascular appearance because
of the widely ectatic vessels around periphery of tumor
and cystically dilated ducts w/ hemorrhage (Fig. 6.10)
• Brooke-Spiegler syndrome: AD inherited condition cause
by CYLD mutation; p/w multiple spiradenomas,
cylindromas, trichoblastomas, and trichoepitheliomas
■
CYLD (tumor suppressor): normally binds NEMO
component of I-kappa-B kinase (IKK) complex →
inhibits NF-B–mediated resistance to apoptosis
■
In absence of CYLD, get ↑ NF-B signaling → resistance
to apoptosis
Fig. 6.9 Benign mixed tumor. A combination of ducts, keratocysts, myoepithelial
cells, and myxoid stroma changes are present. (From Prieto VG, Shea CR,
Celebi JT, Busam KJ. Adnexal tumors. In: Busam KJ, ed. Dermatopathology: A
Volume in the Series: Foundations in Diagnostic Pathology. 2nd ed. Philadelphia:
Elsevier; 2016:388–446.)
Fig. 6.10 Eccrine spiradenoma: in this example, there are three discrete tumor
lobules. The largest appears encapsulated. (From Calonje E, Brenn T, Lazar AJ,
Billings SD. Tumors of the sweat glands. In: McKee’s Pathology of the Skin. 5th ed.
Philadelphia: Elsevier; 2020:1611–1679.)
353
CHAPTER 6 • Neoplastic Dermatology
• Malignant counterpart 5 spiradenocarcinoma: very rare,
poorly differentiated tumor with aggressive behavior (30%
metastatic rate and 20% mortality); arises within benign
spiradenoma; more common in patients with BrookeSpiegler syndrome; histology: resembles spiradenoma,
but loses its biphasic nature, lacks the characteristic
intratumoral lymphocytes; has ↑ mitotic rate; atypical
mitoses
Cylindroma
• Benign sweat gland neoplasm (apocrine) existing on a
spectrum w/ spiradenoma; solitary erythematous-purple
nodule with telangiectasias; 90% occur on head/neck
(scalp #1)
• Multiple cylindromas may coalesce to form multinodular
plaques on scalp (“turban tumor”) in Brooke-Spiegler
syndrome
• Histology: well-circumscribed basaloid proliferation
composed of multiple smaller tumor lobules encircled by
thick hyaline BMZ material (type IV collagen) →
multiple small lobules t together like a “jigsaw puzzle”;
biphasic cell population (same as spiradenoma) with
small ducts (Fig. 6.11)
• Malignant counterpart 5 cylindrocarcinoma: very rare,
poorly differentiated tumor with aggressive behavior
(45% metastatic rate); usually seen in Brooke-Spiegler
syndrome; arises within a benign cylindroma; scalp (#1);
histology: resembles cylindroma, but loses biphasic
nature, has ↑ mitotic rate, atypical mitoses, inltrative
growth pattern, and neurovascular invasion
Hidradenoma papilliferum (HPAP)
• Benign, painless 1- to 2-cm skin colored nodule; almost
exclusively on vulva (labia majora #1) of young adult
women
• Histology: well-circumscribed cystic proliferation in
dermis with numerous papillary projections with
apocrine differentiation invaginating into central cyst-like
Fig. 6.12 Hidradenoma papilliferum: low-power view of an exophytic ulcerated
nodule. The epidermal collarette is seen in the lower left of the eld. (From
Calonje E, Brenn T, Lazar AJ, Billings SD. Tumors of the sweat glands.
In: McKee’s Pathology of the Skin . 5th ed. Philadelphia: Elsevier; 2020:
1611–1679.)
spaces → “maze-like” appearance (Fig. 6.12); lacks
epidermal connection (major distinguishing feature from
syringocystadenoma papilliferum (SPAP) → “HPAP Hides
in the dermis whereas SPAP Slides in from the
epidermis”)
Syringocystadenoma papilliferum
(SPAP, SCAP)
• Benign apocrine neoplasm; presents at birth or early
childhood with a solitary, warty papule/plaque on scalp
(. other sites on head/neck . trunk and extremities);
usually a/w nevus sebaceus
• Histology: exo-endophytic papillary glandular
proliferation w/ apocrine differentiation; opens onto skin
surface; abundant plasma cells in peritumoral stroma
(Fig. 6.13)
• Malignant transformation is exceptionally rare
Fig. 6.11 Cylindroma. The jigsaw pattern is well developed in this example. Note
also the hyaline droplets within the tumor lobules. (From Brinster NK, Liu V,
Diwan H, McKee PH. Cylindroma. In: Dermatopathology: A Volume in the High
Yield Pathology Series. Philadelphia: Elsevier; 2011:423.)
354
Papillary eccrine adenoma (PEA)
• Benign; legs (#1); favors Black women
• Histology: well-circumscribed proliferation of small- to
medium-sized sweat ducts w/ papillary projections
(Fig. 6.14) that are often elongated (vs. syringoma)
Tubular apocrine adenoma (TAA)
• Benign; most commonly on scalp a/w nevus sebaceus
• Histology: often indistinguishable from PEA except for
decapitation secretion and ↓ papillary projections