he 4th Edition WHO Classication
of Skin Tumours and the 8th Edition
AJCC Cancer Staging Manual have
introduced changes to our practices.
Highlights are described below.
y Keratoacanthoma is reclassied as a
subtype of squamous cell carcinoma.
y 80% of Merkel cell carcinomas
have clonal integration of Merkel
cell polyomavirus (MCPyV). The
remaining 20% have mutations in
TP53 and a UV radiation signature
mutation prole. MCPyV is a
surrogate immunohistochemical
marker for viral genomic integration,
and limited data suggest that it
could distinguish primary cutaneous
tumors from extracutaneous
metastases with 98% specicity
(PMID 21453956).
Melanocytic Tumors
y There have been extensive updates
to melanoma staging:
Breslow depth is rounded to the
nearest tenth of a millimeter (e.g.
0.76 mm = 0.8 mm).
Mitoses no longer distinguish
pT1a vs. pT1b.
Changes to Breslow depth cut-os:
pT1a: < 0.8 mm thickness
without ulceration.
pT1b: < 0.8 mm thickness
with ulceration or 0.8 - 1.0
mm thickness with or without
Regional lymph node pN categories:
pN1a: 1 nodal metastasis,
clinically occult (no in transit,
satellite or microsatellite
pN1b: 1 nodal metastasis,
clinically detected (no in
transit, satellite or microsatellite
pN1c: negative for nodal
metastasis (positive in transit,
satellite or microsatellite
pN2a: 2 to 3 nodal metastases,
clinically occult (no in transit,
satellite or microsatellite
pN2b: 2 to 3 nodal metastases,
clinically detected (no in
transit, satellite or microsatellite
pN2c: 1 nodal metastasis,
clinically occult or detected
(positive for in transit, satellite or
microsatellite metastasis).
pN3a: 4 or more nodal
metastases, clinically occult (no in
transit, satellite or microsatellite
pN3b: 4 or more nodal
metastases, clinically detected
(no in transit, satellite or
microsatellite metastasis).
pN3c: 2 or more nodal metastases
(positive for in transit, satellite or
microsatellite metastasis).
y BAP1 tumor predisposition
Germinal BAP1 mutations
(autosomal dominant inheritance)
are associated with an increased
risk of renal cell carcinoma,
mesothelioma, basal cell carcinoma,
and uveal and cutaneous
In their second decades, patients
can develop multiple BAP1-
inactivated nevi which are
dome-shaped papules that show
morphologic overlap with Spitzoid
tumors and a loss of nuclear BAP1
immunohistochemical expression.
y BAP1-inactivated nevi:
These recently classied neoplasms
can arise in individuals with or
without an undelrying BAP1
syndrome, and often as a portion of
a combined nevus (Figure 1).
They generally have either a BRAF
or NRAS activating mutation
(present in the precursor common
nevus), in addition to inactivation of
both BAP1 alleles.
This is analogous to deep
penetrating nevi which have an
activating mutation (e.g. involving
BRAF) in addition to secondary
Wnt pathway activation by gain-
of-function mutations in CTNNB1
(β-catenin) or loss of APC.
y BAP1-inactivated nevi with features
overlapping melanoma:
Features include asymmetry,
expansive nests compressing the
nevoid component, necrosis, non-
traumatic epidermal ulceration,
nuclear pleomorphism or more than
a rare mitotic gure.
It is appropriate to call these BAP1-
inactivated melanocytomas.
Ancillary testing (e.g. single
nucleotide polymorphism
chromosomal microarray) can
help predict the behavior of these
ambiguous lesions.
Issue 13 || August 2020
By Robert E. LeBlanc, M.D.
Figure 1: BAP1-inactivated nevi are
comprised of epithelioid melanocytes with
abundant cytoplasm and large nuclei.
Sponsored by an unrestricted grant from Bio-Techne.com
y Spitz nevi, atypical Spitz tumor
(AST) and malignant Spitz tumor
Now recognized as a spectrum
of tumors characterized by
enlarged, epithelioid or spindled
melanocytes mimicking those of
melanoma; however, genetically
distinct from melanomas, blue nevi,
deep penetrating nevi and BAP1-
inactivated nevi.
Spitz nevi are generally < 6 mm,
symmetric, circumscribed, wedge-
shaped, exhibit dermal maturation
and have little or no mitotic activity.
MST shows non-traumatic
ulceration, conuent nesting, >
6 dermal mitoses/mm
, atypical
mitoses and necrosis.
AST is a term reserved for
biologically indeterminate lesions
that exceed criteria for Spitz nevus
but fall short of MST.
Without ancillary testing, it can
be dicult to distinguish between
AST, MST and rare conventional
melanomas with Spitzoid features.
In contrast with conventional
melanomas with Spitzoid features,
both MST and AST generally
lack BRAF and NRAS activating
mutations and possess mutually
exclusive kinase fusions involving
MET and RET.
FISH or single nucleotide
polymorphism chromosomal
microarray can help predict the
behavior of ambiguous lesions.
Tumors Of Hematopoietic
And Lymphoid Origin
y Primary cutaneous marginal
zone lymphoma (PCMZL) is now
recognized as having two distinct
The IgM+/CXCR3+ non-class-
switched subset resembles
extracutaneous MALT lymphomas
with sheets of monomorphous
A class-switched CXCR3- subset
shows signicant overlap with
cutaneous lymphoid hyperplasia
including a predominance of T-cells.
Demonstration of a
light chain restriction by
immunohistochemistry can aid in
the distinction.
There is discussion as to whether
class-switched PCMZL should be
reclassied as a lymphoproliferative
disorder in lieu of lymphoma
given its appearance and indolent
y Primary cutaneous CD4+ small/
medium T-cell lymphoproliferative
disorder is no longer classied as a
lymphoma in light of its indolent
behavior. Clinicopathologic
correlation is required in order to
establish this diagnosis.
y New lymphomatoid papulosis (LyP)
subtypes have been added. Clinical
correlation is required to distinguish
them from the lymphomas they
histologically resemble.
Type D resembles primary
cutaneous CD8+ aggressive
epidermotropic cytotoxic T-cell
Type E resembles an
angiodestructive lymphoma.
LyP with DUSP22-IRF4
rearrangement resembles
transformed mycosis fungoides
and has small, epidermotropic cells
and larger intradermal cells with
cerebriform nuclei. This variant is
often CD4-/CD8+ or CD4-/CD8-.
Soft Tissue Tumors
y Atypical smooth muscle tumor:
the preferred nomenclature for an
intradermal smooth muscle neoplasm
with mitoses, nucleomegaly or nuclear
hyperchromasia. These tumors have
essentially no risk of metastasis when
conned to the dermis.
y Lesions extending into the subcutis
have low metastatic potential
and should be designated as
y The distinction between atypical
broxanthoma (AFX) and
pleomorphic dermal sarcoma (PDS),
which has a low metastatic potential,
similarly requires examination of the
entire lesion. In contrast to PDS, AFX
should not involve the subcutis, and
should not show perineural invasion,
lymphovascular invasion, or necrosis
(Figure 2).
y Radiation-induced angiosarcomas
show MYC amplication by FISH
while atypical vascular lesions do not.
y A majority of epithelioid brous
histiocytomas have an ALK
rearrangement and stain with ALK
by immunohistochemistry, which
can help distinguish them from other
brohistiocytic neoplasms, cellular
neurothekeoma and myoepithelioma.
y A majority of supercial acral
bromyxomas show loss of RB1
expression and combined with the
CD34+/S100- immunophenotype
can help distinguish them from other
cutaneous tumors with myxoid
stroma including neurobroma,
supercial angiomyxoma and myxoid
Meet the Author
ur dermatopathol-
ogy section editor,
Robert E. LeBlanc, M.D.
directs the dermato-
pathology fellowship
program at Dartmouth-
Hitchcock Medical Center, where
he serves as an Assistant Professor
and residency committee member
in the Department of Pathology
and Laboratory Medicine. He is
passionate about patient safety and
medical education. Robert is also
a member of the American Society
for Dermatopathology ethics
committee as well as the fellowship
program director committee. He
has mentored dozens of medical
students and trainees in pathology
and dermatology, referees agship
dermatology and dermatopathol-
ogy journals, and has lectured
extensively on cutaneous lym-
phomas, melanoma and high risk
non-melanoma skin cancers.
Figure 2: This PDS with extension
into the fat was histologically
indistinguishable from AFX in the initial