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7.1 Essential Concepts in Dermatopathology
Table 7.3 Most Commonly Used Special Stains
Stain Target Color(s) Comments
Collagen/elastic bers
Verhoeff-van Gieson (VVG) Elastic bers
Smooth muscle
Masson trichrome Collagen bers
Movat’s pentachrome Elastic bers
Phosphotungstic acid
hematoxylin
Lipids (all stains must be performed on frozen tissue only! → not commonly used); may be helpful in conrming that clear cell changes attributable
to sebum in sebaceous neoplasms
Oil-red-O Lipids Red
Sudan black B Lipids Black –
Scarlet red Lipids Red-brown –
Iron/hemosiderin
Perls/Prussian blue Hemosiderin/iron Blue Most commonly used in conjunction with Fontana-Masson stain to
Calcium
von Kossa Calcium (salts) Brown-black Most commonly used “calcium stain,” but actually stains the anions
Alizarin red Calcium Red-orange More specific for calcium than von Kossa
Mucin
Alcian blue pH 0.5 Sulfated acid MPS (heparin,
Alcian blue pH 2.5 Nonsulfated acid MPS
Colloidal iron Acid MPS (sulfated and
Mucicarmine Epithelial mucin (primarily
Periodic acid–Schiff (PAS) Neutral MPS (basement
Toluidine blue Acid MPS Red-purple
Collagen
Rest of connective tissue
Smooth muscle
Collagen
Smooth muscle, brin
Collagen
Smooth muscle, brin
chondroitin, and dermatan
sulfates)
(hyaluronic acid)
nonsulfated)
sialomucin)
membrane), fungi, and
glycogen
Black
Red
Yellow
Blue or green
Red
Black
Yellow
Red
Red
Blue
Blue In normal skin, most mucin is sulfated acid MPS
Blue
Blue Hyaluronidase may be added to distinguish between hyaluronic acid
Pink-red Used primarily for adenocarcinoma, Paget disease, and Crypto-
Pink Highlights BMZ material, fungal organisms, and glycogen
(“metachromatic
staining”: stains tissue
a different color than
blue color of stain)
Most commonly used collagen/elastin stain
Distinguishes between various perforating diseases, can show areas
of loss (morphea) or clumping (PXE)
Stains the inclusions (red) in infantile digital fibromatosis ;
shows dense collagen in collagenoma
Stains the inclusions (red) in infantile digital fibromatosis
Stains the inclusions (blue) in infantile digital fibromatosis
distinguish between melanin (black w/ Fontana-Masson) and hemosiderin pigment
Does not stain iron in intact RBCs → does not work well for talon noir
Hemosiderin also a common nding in stasis dermatitis, pigmented
purpuric dermatosis, and Kaposi sarcoma
rather than calcium itself → less calcium-specific than Alizarin red
Hyaluronic acid (nonsulfated acid MPS) does not stain with Alcian
blue at pH 0.5
In diseases w/ ↑ mucin (lupus, GA, and follicular mucinosis), most
mucin is hyaluronic acid
Mnemonic: “HIGH-luronic acid stains with Alcian blue at HIGH
pH (pH 2.5) only!”
Sulfated acid MPS stain with Alcian blue at both pH 2.5 and pH 0.5
and other mucin types
coccus (capsule)
Not a good stain for dermal mucins
Does not stain acid MPS (hyaluronic acid and other mucins)
Rarely used as a mucin stain → more commonly used as mast cell
stain
Continued
395
CHAPTER 7 • Dermatopathology
Table 7.3 Most Commonly Used Special Stains—cont'd
Stain Target Color(s) Comments
Amyloid (Note: Mass spectrometry can be used to subtype amyloid [AA vs. AL])
Congo red Amyloid Pink-red; apple green
Thioflavin T Amyloid (fluorescence
Cresyl violet Amyloid Red Of note, cotton dyes (e.g., Pagoda red or Dylon) also stain amyloid
Melanin
Fontana-Masson (silver
stain)
Silver nitrate Melanin Black May represent artifact from prior treatment with silver nitrate sticks
Mast cell stains (all except Leder stain and c-KIT are unreliable in degranulated skin → use lidocaine without epinephrine to avoid mast cell
degranulation and improve staining)
Leder (chloroacetate
esterase)
cKit (CD117) (immunostain,
but is discussed here for
convenience)
Tryptase (immunostain,
but is discussed here for
convenience)
Giemsa Mast cell granules Purple-blue
Toluidine blue Mast cell granules Purple (metachromatic) Dependent on presence of mast cell granules
Microbial stains
Periodic acid–Schiff (PAS) Fungi, neutral MPS
Periodic acid–Schiff w/
diastase (PAS-D)
Gomori methenamine silver
(GMS; a silver stain)
Gram stain (Brown-Hopps
and Brown-Brenn)
Fite Mycobacterium leprae,
Ziehl-Neelsen Acid-fast bacteria (AFB) Red Most commonly used AFB stain
Auramine-rhodamine Acid-fast bacteria Yellow fluorescence Requires fluorescence microscopy
Warthin-Starry (silver stain) Spirochetes (syphilis,
Steiner (silver stain) Spirochetes (syphilis,
Giemsa Leishmania, Histoplasma,
Other stains
Bodian Nerve axons (filaments) Black Positive in neurofibromas, traumatic neuromas, and PEN; negative
Methyl green pyronin RNA
Feulgen DNA Red-purple —
microscopy)
Melanin Black Most commonly used in conjunction with an iron stain (e.g., Perls) to
Mast cell cytoplasm and
granules
Mast cell cytoplasm Brown or red (color
Mast cell granules Brown or red (color
(basement membrane),
and glycogen
Fungi, neutral MPS
(basement membrane)
Fungi Black (stains fungal
Gram-positive bacteria
Gram-negative bacteria
Nocardia, and atypical
mycobacteria
Borrelia)
Borrelia)
and Rickettsia
DNA
birefringence when
polarized
Yellow-green Requires fluorescence microscopy
Red Unlike most other mast cell stains, it is NOT dependent on presence
depends on type of
peroxidase used)
depends on type of
peroxidase used)
(metachromatic)
Pink Positive in clear cell acanthoma and trichilemmoma, as a result
Pink Helpful for demonstrating BMZ thickening (lupus, DM) and thickened
wall)
Blue
Red
Red Stain of choice for “partially acid-fast” organisms ( M. leprae
Black Also stains organisms in bacillary angiomatosis, granuloma inguinale
Black Same staining pattern as Warthin-Starry
Purple-blue —
Pink
Blue-green
Most commonly used amyloid stain
In real world, not always reliable for macular/lichen amyloid
distinguish melanin from hemosiderin.
Vitiligo has complete loss of epidermal staining
of mast cell granules → effective even in degranulated skin
Only Leder and c-KIT (CD117) are reliable in degranulated skin
NOT dependent on presence of mast cell granules
Also stains melanocytes and myeloid cells
Dependent on presence of mast cell granules
Dependent on presence of mast cell granules
of ↑ glycogen → becomes negative if add diastase (PAS-D)
Does not stain acid MPS (hyaluronic acid and other mucins)
vessel walls of porphyria
Green background (counterstain)
Gram-negative bacteria not well-visualized in skin biopsies
Nocardia), and atypical mycobacteria because these are
over-decolorized by Ziehl-Neelsen
Peanut oil and gentle decolorization process allows for better color
preservation than in Ziehl-Neelsen
Less effective for M. leprae and atypical AFB → use Fite instead
(Donovan bodies), and rhinoscleroma
Disadvantage: nonspecic (“dirty”) staining pattern → has been
largely replaced by spirochete immunostain
in schwannoma (lacks axons)
Requires frozen tissue
396
7.1 Essential Concepts in Dermatopathology
Table 7.4 Characteristic Immunostains by Cell Type
Cell Type Immunostain
B lymphocytes CD20 (most commonly used B-cell marker; absent in plasma cells; target for rituximab), PAX-5 (more sensitive and specific than CD20, can
Dermal dendritic
cells
Endothelial cells
Fibroblasts Vimentin, procollagen I (also expressed in DFSP, AFX, NSF, and scleromyxedema)
Histiocytes/
macrophages
Keratinocytes Cytokeratin, p63, and p40
Langerhans cells
Lymphatics D2-40 (podoplanin), LYVE-1 (negative in blood vessel endothelium), PROX1 (nuclear) and vimentin
Mast cells c-KIT (CD117) and tryptase (conventional/non-immunostains: Giemsa, Leder, toluidine blue)
Melanocytes S100, HMB-45 (gp100; less sensitive but more specific than S100; typically negative in desmoplastic melanoma), MART-1/Melan-A
Merkel cells CK20 (paranuclear-dot pattern), synaptophysin, chromogranin, neurofilament (extremely useful and under-utilized stain; esp. helpful for
Myofibroblasts SMA (“tram-track” pattern); myofibroblasts do not express desmin (vs. true smooth muscle cells)
Natural killer cells CD56 (most commonly used), granzyme A/B, and TIA-1 (latter two stains are also positive in cytotoxic T cells)
Nerves Axons: neurofilament and NSE
Neutrophils MPO (myeloperoxidase; esp. useful stain in histiocytoid Sweet’s)
Plasma cells CD138, CD79a, and CD45
Plasmacytoid
dendritic cells
Sebaceous glands EMA, adipophilin, androgen receptor , and cytokeratin
Smooth muscle SMA (diffuse pattern), desmin
Sweat glands
T lymphocytes CD2, CD3 (most specific), CD4, CD5, CD7, CD8, CD45 (LCA), CD45Ra (naïve T-cells), CD45Ro (memory T cells; positive in MF), and
be negative in plasma cells), CD19 (target for CAR-T-cell therapy; useful in monitoring response to rituximab therapy, because CD20-negative
B cells may arise following therapy), CD79a (B cells and plasma cells), CD45 (LCA; expressed on all hematopoietic cells except platelets and
RBCs), and IgG light chains (k and l). When patient has received rituximab, use marker other than CD20 to detect B lymphocytes.
Two distinct populations:
Type I: factor XIIIa1; reside in papillary dermis; involved in phagocytosis, antigen presentation, and wound healing; abundant in
dermatobroma
Type II: CD341; reside in reticular dermis; CD34 expression is lost in scleroderma/morphea , and ↑ in NSF and scleromyxedema
*Notable CD341 tumors in dermpath: DFSP, spindle cell lipoma/pleomorphic lipoma, Kaposi sarcoma (endothelial cells), neuro-
broma (diffuse NF can be misdiagnosed as DFSP!), brofolliculoma/trichodiscoma (spindled stromal cells), trichilemmoma/DTL
(epithelial cells), solitary brous tumor (STAT61), leukemia cutis (less sensitive than CD43, c-KIT, CD68, lysozyme, MPO), Kapo-
siform hemangioendothelioma (endothelial cells), epithelioid hemangioendothelioma (endothelial cells), sclerotic broma, pleomorphic
broma, supercial angiomyxoma, supercial acral bromyxoma (and cellular digital broma), cellular angiobroma of vulva/genital
region, and ischemic fasciitis
CD31 (previous gold standard for endothelial cells → superseded by ERG and FLI-1), CD34 (less specific than CD31), ERG (excellent
stain; very sensitive and specific), FLI-1 (nuclear stain; improvement over CD31 and CD34 but not as good as ERG), Ulex europaeus
agglutinin 1, factor VIII ag
CD68, CD163 (more specific than CD68), lysozyme, a-1 antitrypsin, HAM-561 (esp. JXG and related xanthogranulomas), CD11b,
CD14b, factor XIIIa, MAC-387 (true macrophages), and vimentin
S100, CD1a, Langerin (CD207; stains Birbeck granules→ extremely specific), BRAF (in certain malignant Langerhans cell processes
such as LCH and Erdheim-Chester disease), peanut agglutinin, and vimentin
(less sensitive but more specific than S100; typically negative in desmoplastic melanoma), MITF (nuclear stain; positive in only 30% of
desmoplastic melanomas and macrophages), p16 (positive in Spitz nevi; often lost or diminished in spitzoid melanoma and ASTs), p75/
NGFR (useful in desmoplastic melanoma, esp. when S100 is negative), Sox10 (nuclear stain; helpful in distinguishing desmoplastic
melanoma from scar tissue), tyrosinase, vimentin, and c-Kit
CK20-negative Merkel cell carcinomas), and NSE. TTF-1 negative
Schwann cells: S100, GFAP, and MBP
CD123, with coexpression of CD4 (but not other T-cell markers)
↑ Plasmacytoid dendritic cells are present in perivascular clusters in lupus (but not in dermatomyositis) and ↑ in GA (» NLD, rheumatoid
nodules). When present in sheets and with blastoid morphology, may represent blastic plasmacytoid dendritic cell neoplasm
CEA,EMA, GCDFP-15 (apocrine . eccrine), and cytokeratin
FOX-P3 (T-regulatory cells); T-cell markers often diminished/lost in MF (CD7 most commonly lost) and other neoplastic T-cell processes
397
CHAPTER 7 • Dermatopathology
Table 7.5 Most Commonly Used Epithelial Immunostains
Immunostain Description/Staining Pattern Comments
AE1/AE3 Cocktail of low- (AE1) and high- (AE3) MW keratin
MNF116 Newer pankeratin immunostain w/ better sensitivity
CK5/6 High-MW keratin immunostain; stains lower level of
CAM5.2 Low-MW keratin immunostain directed against
CK7 Stains glandular epithelium Positive in Paget’s and EMPD
EMA (epithelial
membrane antigen)
CEA Stains normal sweat glands (eccrine and apocrine);
Ber-EP4 Stains non-keratinizing epithelial cells Differentiates between BCC (positive), SCC (always negative), and sebaceous
p63 Homologue of p53 that is positive in normal epidermis
antibodies; typically positive in all epithelial tumors
than AE1/AE3; stains all epithelial tissue
epidermis
CK8/18; stains glandular epithelium (mnemonic:
“CAM5.2 = Gland5.2”); negative in squamous
epithelium (including epidermis)
Stains normal skin adnexae Positive in Paget’s and EMPD, adnexal neoplasms (including sebaceous
positive in sweat gland neoplasms
and adnexal epithelium
Helps conrm diagnosis of SCC and adnexal carcinomas
Often fails to stain sarcomatoid SCC → need additional cytokeratin stains
(MNF116, CK903, or CK5/6), p63 or p40 to diagnose high-grade/
sarcomatoid SCC
Helps differentiate high-grade/sarcomatoid SCC (positive) versus AFX (negative)
Positive in primary cutaneous SCCs and adnexal carcinomas, but negative
in metastatic adenocarcinomas → distinguishes primary cutaneous
adnexal carcinoma (positive) versus metastatic adenocarcinomas from internal organs (negative), particularly when used in combination with p63
and/or D2-40 (same staining prole)
Helps differentiate high-grade/sarcomatoid SCC (positive) versus AFX (negative)
Positive in Paget’s and EMPD, and eccrine glands/neoplasms
Also used in conjunction with CK20 to determine origin of metastatic
adenocarcinoma
• CK715 malignancy above the diaphragm (breast, lung)
• CK2015 malignancy below diaphragm (stomach, colon)
carcinoma), most SCCs, and epithelioid sarcoma (INI-1 loss and EMA
positivity are the two classic stains!)
Positive in Paget’s and EMPD
carcinoma (usually negative)
Stains . 90% of adnexal neoplasms (benign and malignant; Notable excep-
tion 5 primary apocrine carcinoma)
Differentiates between primary cutaneous adnexal carcinomas (positive)
and metastatic adenocarcinomas involving the skin (negative)
Also stains high-grade/sarcomatoid SCC (distinguishes from AFX)
Table 7.6 Artifacts and Effects of Exogenous Materials
Inciting Cause Histopathologic Features
Cryotherapy/freezing
artifact
Electrocautery artifact Vertically oriented parallel keratinocytes (Fig. 7.2)
Knife/“chatter” artifact Long parallel cuts in tissue, can be seen near
Gelfoam Purple, angulated foreign material with surrounding
Suture granuloma Foreign body granuloma surrounding suture
Intralesional
corticosteroids
Fillers Features depend on specific filler (see Figs. 7.5–7.8
Keratinocyte vacuolization, subepidermal blister
foreign body (Fig. 7.3)
granulomatous inflammation (Fig. 7.4)
material (polarized light may show birefringence)
Amorphous, homogenous white to pink material
1/– surrounding fibrous capsule
and corresponding captions for details)
Fig. 7.2 Electrocautery. (From Ferringer T: External agents and artifacts. In:
Elston DM, Ferringer T, eds. Dermatopathology, ed 3. Philadelphia: Elsevier,
2019:509-516.)
398
Fig. 7.3 Knife (“chatter”) artifact from calcinosis cutis.
7.1 Essential Concepts in Dermatopathology
Fig. 7.4 Gelfoam (purple, angled deposits with surrounding host foreign-body
response.
Fig. 7.5 Histopathologic features of granulomatous reaction to New-Fill (L-polylactic
acid). Most of the particles show fusiform or oval shape. (From Requena L,
Requena C, Christensen L, Zimmermann US, Kutzner H, Cerroni L. Adverse
reactions to injectable soft tissue llers. J Am Acad Dermatol 2011;64[1]:1-34).
Fig. 7.6 Silicone granuoma, showing variably sized tissue vacuoles with an associated host granulomatous response.
Fig. 7.7 Regularly sized mauve-to-gray or beige spherules of calcium hydroxylapatite in skeletal muscle surrounded by histiocytes and within foreign body giant
cells (hematoxylin-eosin, original magnication x100).
399
CHAPTER 7 • Dermatopathology
Fig. 7.8 Granulomatous reaction to hyaluronic acid. Basophilic material resembling mucin is surrounded by histiocytes and multinucleated giant cells.
Table 7.7 Spindle Cell Neoplasms
CK Vimentin S100 SMA
SCC
Leiomyosarcoma –
AFX –
Melanoma –
Modied from Ferringer T, Ko CJ. The basics: diagnostic terms, skin
anatomy, and stains. In: Elston DM, Ferringer T, eds. Dermatopathology
3rd ed. Philadelphia: Elsevier; 2019:1–35.
Table 7.8 Neoplasms With Pagetoid Scatter
Bowen disease
Paget’s/EMPD
MF – – –
Melanoma – –
Sebaceous
carcinoma
Modied from Ferringer T, Ko CJ. The basics: diagnostic terms, skin
anatomy, and stains. In: Elston DM, Ferringer T, eds. Dermatopathology
3rd ed. Philadelphia: Elsevier; 2019:1–35.
Table 7.9 Epithelial Carcinomas
SCC –
BCC
Sebaceous
carcinoma
1
CK CEA S100 LCA
1
1 1
1 1
Ber-EP4 EMA Androgen Receptor Adipophilin
1 1/–
– – –
1 1 (also desmin1)
1
1 1
– – –
1
1 1 1
– –
– –
1
– –
– –
1
Immunouorescence and related studies
Immunodermatology is its own subspecialty within dermatopathology and key details are as follows (summarized in
Table 7.10).
• Direct immunouorescence (DIF)
■
Performed on sections obtained from a biopsy of intact,
inamed perilesional skin
Exception: if dermatitis herpetiformis (DH) is
suspected, the DIF should be 1 cm away from active
lesions
■
Requires Michel’s/Zeus transport media or fresh frozen
tissue
■
DIF patterns:
Linear (Fig. 7.9)
♦ C3 only: pemphigoid gestationis
♦ IgG and C3: bullous pemphigoid (BP), lichen
planus pemphigoides, epidermolysis bullosa
acquisita (EBA), cicatricial pemphigoid,
anti-p200, anti-p105, anti-laminin-332, and
bullous systemic lupus erythematosus (SLE)
NEED further studies to distinguish!
♦ IgA: linear IgA bullous dermatosis (LABD)
♦ IgM: rarely reported in Waldenström
macroglobulinemia; usually spurious
Granular
♦ IgM, C3, IgG, IgA (in descending order of
frequency) along the basement membrane
zone (BMZ) 5 lupus band (Fig. 7.10)
♦ IgA in dermal papillae 1/– along BMZ: DH
(Fig. 7.11)
Intercellular
♦ IgG and C3 (“pemphigus pattern”; [Fig 7.12]):
pemphigus vulgaris, pemphigus vegetans,
pemphigus foliaceus, pemphigus erythematosus,
fogo selvagem, and paraneoplastic pemphigus
(paraneoplastic autoimmune multiorgan syndrome)
Need clinical correlation and further studies to
differentiate
♦ IgA: IgA pemphigus
Linear to granular BMZ and intercellular: pemphigus
erythematosus (Senear-Usher)
Linear BMZ and intercellular: paraneoplastic
pemphigus (PNP)
♦ May also see lichenoid tissue reaction
Lichenoid tissue reaction
♦ Shaggy BMZ deposition with brinogen 1/–
cytoid bodies with various conjugates
♦ Nonspecic nding; may be seen in any
lichenoid process (lichen planus, lichenoid drug
reaction, erythema multiforme, xed drug
eruption, connective tissue diseases, PNP, etc.)
and also following excoriation
Vessel wall staining
♦ Stippled, not thickened: leukocytoclastic
vasculitis (LCV), including IgA vasculitis/
Henoch-Schonlein purpura (HSP) (Fig. 7.13)
♦ Thickened and smooth: porphyrias with
cutaneous involvement and pseudoporphyria;
may also see thick linear BMZ staining in these
entities!
n-serrated/u-serrated pattern of linear deposition
evaluated on DIF and may be used as a substitute
for salt-split skin analysis (Fig. 7.14)
• Indirect immunouorescence (IIF): serologic study
where patient serum is incubated with a biologic substrate
(salt-split skin; monkey esophagus; rat bladder
400
7.1 Essential Concepts in Dermatopathology
Table 7.10 Staining Characteristics of Subepidermal Blistering Diseases
Parameter BP EBA BSLE LAD DH
DIF Linear IgG, C3 Linear IgG
IIF (monkey esophagus substrate) Linear IgG
IIF (human salt-split skin substrate) Roof Floor Floor Roof, or floor, or both N/A
Type IV collagen (immunostain on
fixed tissue)
EM: site of split LL Sub-LD Sub-LD LL, sub-LD, or both Papillary dermis
Western blot BP180 kD
BMZ, Basement membrane zone; BP, bullous pemphigoid; BSLE, bullous systemic lupus erythematosus; DH, dermatitis herpetiformis; DIF, direct immunouo-
rescence; EBA, epidermolysis bullosa acquisita; EM, electron microscopy; IIF, indirect immunouorescence; LAD, linear IgA disease; LL, lamina lucida; sub-LD,
sub-lamina densa; N/A, not applicable.
Modied from Luzar B, McGrath JA. Inherited and autoimmune subepidermal blistering diseases. In: Calonje E, Brenn T, Lazar AJ, Billings SD, eds. McKee’s
Pathology of the Skin With Clinical Correlations . 5th ed. Philadelphia: Elsevier; 2020:118–170.
75%–80%
Floor Roof Roof Roof or floor N/A
BP230 kD
. C3
Linear IgG
25%–50%
290kD
(type VII
collagen)
Linear IgG, C3, 1/ lupus band
(granular IgM . IgA . C3 . IgG;
along BMZ)
Linear IgG 60% Linear IgA 30% Antiendomysial
290kD (type VII collagen) BP180 kD
Linear IgA Granular IgA (BMZ and in
dermal papillae)
antibodies (IgA .. IgG)
Antigen uncertain
BP230 kD
200/280kD
285kD
250kD
290kD
Fig. 7.9 Direct immunouorescence showing linear IgG along the dermoepidermal junction, as may be seen in pemphigoid, epidermolysis bullosa acquisita,
and bullous lupus erythematosus.
Fig. 7.10 Direct immunouorescence showing granular IgM deposition along the
basement membrane zone, as may be seen as part of a lupus band. (From Brinster
NK, Liu V, Diwan AH, McKee PH. Dermatopathology: A Volume in the High Yield
Pathology Series. Philadelphia: Elsevier; 2011.)
Fig. 7.11 Direct immunouorescence showing granular deposition of IgA along
the basement membrane zone and in the dermal papillae, as is characteristic of
dermatitis herpetiformis.
Fig. 7.12 Intercellular deposition of IgG in pemphigus.
401
CHAPTER 7 • Dermatopathology
Fig. 7.13 Perivascular granular deposition of IgA within walls of multiple supercial dermal blood vessels in IgA vasculitis.
epithelium); staining patterns same as for DIF; generally
less sensitive than DIF (Table 7.11).
• Salt-split skin studies (IIF): incubation of normal human
skin in 1M NaCl → separation of the skin at the
dermoepidermal junction (DEJ; at lamina lucida) →
visualization of where the immunoreactants are depositing
→ allows differentiation amongst various subepidermal
blistering diseases (see Table 7.11 and Fig. 7.15).
• Collagen IV immunostaining (lamina densa) of xed
patient tissue
■
Performed on parafn-embedded sections to localize
the level of the dermal-epidermal separation to above
or below the lamina densa
■
An alternative to salt-split skin immunouorescence (but
is not well-validated; mostly used for research purposes)
■
Staining of collagen IV along the oor of a blister: BP
■
Staining of collagen IV along the roof of a blister:
diseases targeting collagen VII (EBA and bullous SLE)
■
BE CAREFUL! Collagen IV immunostaining patterns
are OPPOSITE of salt-split skin DIF and IIF patterns!
Text continued on p. 415
Fig. 7.14 Overview n- and u-serrated pattern and different forms of subepidermal autoimmune blistering diseases (sAIBD). BMZ, Basement membrane zone; BP, bullous
pemphigoid; bSLE, bullous systemic lupus erythematosus; CP, cicatricial pemphigoid; DIF, direct immunouorescence; EBA, epidermolysis bullosa acquisita; IIF, indirect
immunouorescence; LAD, linear IgA disease; MMP;
deposition pattern differentiates type VII collagen targeting bullous diseases from other subepidermal bullous autoimmune diseases. Brit J Dermatol. 2004;151[1]:112–118.)
Table 7.11 High-Yield Dermatopathology Diagnoses at a Glance
Dx Buzzwords/Essential Features Mimics in DDx
Acanthosis nigricans Epidermal papillomatosis Microscopically identical to CARP, acrokeratosis verruciformis
Accessory digit Pedunculated papule, numerous nerve bundles Acquired digital fibrokeratoma (lacks nerves, more fibrotic), and
Accessory nipple
Accessory tragus
Acne keloidalis nuchae Suppurative folliculitis with mixed inflammation
Acquired digital fibrokeratoma Polypoid, massive orthohyperkeratosis, and vertically
Actinomycosis Light-colored grains of filamentous bacteria,
Atypical fibroxanthoma Dense dermal proliferation of spindled cells, histiocyte-
Domed papule, papillomatous surface 1/– central
invagination, ↑ smooth muscle, sebaceous glands
opening directly onto skin surface, and mammary
ducts/glands
Polypoid, multiple vellus hairs, 1/– cartilage
(neutrophils, plasma cells, and lymphocytes),
hypertrophic scar, and naked hair shafts
oriented collagen
surrounded by Splendore-Hoeppli phenomenon (pink)
like cells, foam cells, and bizarre multinucleated
cells; numerous atypical mitoses; 1/– ulceration
mucous membrane pemphigoid. (From Vodegel RM, Jonkman MF, Pas HH, De Jong MCJM. U-serrated immuno-
of Hopf, and SK
accessory tragus (vellus hairs, cartilage, and lacks nerve bundles)
Becker’s nevus (lacks mammary glands and sebaceous glands
opening directly onto skin surface), and normal nipple (need
clinical Hx)
Accessory digit (nerve bundles; lacks vellus hairs)
Folliculitis decalvans (similar, but lacks hypertrophic scar),
infection, LPP (lymphocytic inflammation; usually lacks free hair
shafts)
Wart (koilocytes), accessory digit (nerves)
Eumycetoma, botryomycosis
Undifferentiated pleomorphic sarcoma (UPS) and pleomorphic
dermal sarcoma (PDS): cells appear identical but tumor
extends into fat or deeper soft tissue; more aggressive
SLAM DDx
402
7.1 Essential Concepts in Dermatopathology
Table 7.11 High-Yield Dermatopathology Diagnoses at a Glance—cont'd
Dx Buzzwords/Essential Features Mimics in DDx
Alopecia areata “Swarm of bees” lymphocytic infiltrate near hair
Amalgam tattoo Oral mucosa, dark colored specks along BMZ and
Amyloid (macular and lichen) Waxy pink globules in papillary dermis, pigment
Amyloid (nodular) Large fissured pale pink material in superficial and
Angiofibroma (fibrous papule,
Koenen tumor, and adenoma
sebaceum)
Angiolipoma
Angiosarcoma Poorly-circumscribed dermal proliferation of anastomos-
Arteriovenous malformation
(AV hemangioma)
Balloon cell nevus Melanocytes w/ abundant vacuolated clear
Blastomycosis PEH w/ intraepidermal pustules, dermal
Bowen’s disease “ Wind-blown” architecture, full-thickness atypia, and
Branchial cleft cyst Epidermoid or ciliated pseudostratified cyst lining;
Bronchogenic cyst Ciliated columnar/pseudostratified epithelium, goblet
Bullous impetigo Superficial acantholysis (PF-like), subcorneal
Bullous pemphigoid/herpes
gestationis
Bullous SLE Sub-epidermal blister w/ neuts, dermal PV/PA lym-
Calcinosis cutis Large purple deposits;
Calciphylaxis Concentric calcication of small to medium sized
bulb in fat; profound shift to catagen/telogen;
lymphocytes, eosinophils, and melanin in
fibrous tracts, 1/ pigment casts
scattered throughout dermis (in macrophages or
along elastic fibers)
incontinence; amyloid is keratin-derived (AK) and
stains with Congo red (weak) and keratin stains
deep dermis, prominent inflammation w/ plasma
cells, and amyloid is light chain-derived (AL)
Papule, proliferation of normal and stellate fibroblasts
w/ concentric perivascular fibrosis
Lipoma w/ lobular capillary proliferations 1/–
intravascular thrombosis
ing vessels; atypical, plump, hyperchromatic endo-
thelial cells with multi-layering, mitoses;
Often arises in irradiated skin, severely sun-dam-
aged sites (head/neck) or chronic lymphedema
Mix of thick (centrally located) and thin (peripherally
located) walled vessels in mid-upper dermis
cytoplasm arranged in nests that decrease in size
with descent into the dermis, dermal melanophages,
and scattered conventional nevus nests (critical
clue to diagnosis!)
granulomatous inflammation, large 8–15mm round
yeast w/ broad-based budding
dyskeratotic keratinocytes
prominent lymphoid aggregates with germinal
centers surrounding cyst
cells, smooth muscle and cartilage around cyst
neutrophilic microabscesses 1/– bacteria
Sub-epidermal blister w/ eos , eosinophilic spongio-
sis, and DIF1 (linear IgG and C3 along BMZ)
For pemphigoid gestationis, often only C3 is positive
on DIF
phocytic inammation, ↑ mucin, and DIF1 (granular
to linear IgG (1/– IgA and IgM) along BMZ);
Dermal deposition on human salt-split skin indirect IF
Knife artifact often present, due to dragging of calcium
across tissue during tissue processing
vessels w/ thrombosis, extra-vascular calcication
(esp. peri-eccrine), 1/– ulceration
Trichotillomania (has pigment casts but inside follicle, also has
trichomalacia; lacks eosinophils and lymphocytes in brous
streamer tracts), LPP (inammation much more supercial
[infundibulum]), syphilitic alopecia (can show swarm of bees
but also contains plasma cells and epidermal/dermal changes
of syphilis)
Normal skin DDx
Normal skin DDx, colloid milium (extends deeper into dermis;
adult form has prominent solar elastosis); nodular amyloid
(deeper, ↑ inflammation w/ plasma cells, and amyloid is light-
chain derived 5 AL)
Macular/lichen amyloid (more superficial, keratin-derived, and
lacks inflammation), colloid milium (lacks inflammation)
DF (collagen trapping, epidermal hyperplasia)
Lipoma (lacks proliferative collections of capillaries), spindle cell
lipoma (myxoid stroma w/ small spindle cells, “ropey” bright pink
collagen, lacks capillary proliferations)
Kaposi (cells are spindled and not nearly as hyperchromatic
nor as mitotically active; slit-like vessels, hemorrhage, plasma
cells, promontory sign); aneurysmal DF (peripheral collagen
trapping; giant cells containing hemosiderin)
Lobular capillary hemangioma (small thin-walled capillaries and
endothelial cells), angioleiomyoma (located much deeper in SQ;
concentric pink smooth muscle compresses large vessels to
form slit-like vessels)
Renal cell carcinoma (very vascular w/ hemorrhage; lacks
dermal melanophages and conventional nevus nests), clear cell
hidradenoma (sweat ducts; foci of keratinizing dermal nests,
lacks conventional nevus nests), xanthoma (lacks pigment and
conventional nevus nests)
Coccidioidomycosis (much larger spherules with endosporulation;
lacks broad-based budding), PEH with pus DDx
Paget’s/EMPD (mucin, nests compress basal keratinocytes),
melanoma (pigment, lacks dyskeratotic keratinocytes), MF
(lacks dyskeratotic keratinocytes, less cytologic atypia)
Bronchogenic cyst (smooth muscle and cartilage around cyst;
abundant goblet cells), thyroglossal cyst (pink hyaline thyroid
follicles)
Branchial cleft cyst (prominent lymphoid nodules/germinal
centers), thyroglossal cyst (pink thyroid follicles), and cutaneous
ciliated cyst (lacks smooth muscle and cartilage)
Pemphigus foliaceus (lacks bacteria and subcorneal neutrophilic
microabscesses; positive DIF); IgA pemphigus (can have subcorneal
neutrophilic microabscesses and superficial acantholysis but has
1DIF)
PCT (pauci-inflammatory, sun-damaged skin), EBA (pauci-
inflammatory 1/– scattered neuts), bullous EM (apoptotic
keratinocytes, lymphocytic, eos uncommon), LABD/DH
(neutrophils)
PCT (pauci-inflammatory, sun-damaged skin), EBA (more pauci-
inflammatory), bullous EM (apoptotic keratinocytes, lymphocytic,
eos uncommon), LABD/DH (neutrophilic papillitis)
PXE (small, wavy calcified fibers), calcified pilomatricoma or
epidermoid cyst (epithelium surrounds calcified material)
Thrombotic vasculopathies (lack intra- and extravascular
calcification)
Continued
403
CHAPTER 7 • Dermatopathology
Table 7.11 High-Yield Dermatopathology Diagnoses at a Glance—cont'd
Dx Buzzwords/Essential Features Mimics in DDx
Cellular blue nevus Highly cellular, purely dermal proliferation of plump or
Cellular neurothekeoma Fibrohistiocytic neoplasm (despite name); comprised
Chondrodermatitis nodularis
helicis (CNH)
Chromoblastomycosis
Clear cell acanthoma Psoriasiform hyperplasia with clear (glycogenated)
Clonal SK Whorled intraepidermal nests of keratinocytes within SKHidroacanthoma simplex (sweat ducts w/ eosinophilic cuticle;
Coccidioidomycosis
Coma/barbiturate blister Paucicellular/noninflammatory subepidermal bulla,
Congenital nevus Usually compound nevus with extension down
Cryoglobulinemia type 1 Noninflammatory intravascular occlusion w/
Cryptococcus
Cylindroma See Chapter 6, Neoplastic Dermatology See Chapter 6, Neoplastic Dermatology
Darier disease Acantholytic dyskeratosis, corps ronds, corps
Deep penetrating nevus Typically compound w/ small junctional component,
Dermal melanocytosis (nevus of
Ito/Ota/Mongolian spot)
Dermatitis herpetiformis Abscess-like neutrophil aggregates in dermal
Dermatofibroma Interstitial “fibrohistiocytic” infiltrate in mid-deep
Dermatofibroma (aneurysmal
variant)
fusiform pale gray melanocytes containing mini-
mal pigment 1 admixed dendritic melanocytes
resembling common blue nevus cells; bulges into
subcutis (“dumbbell conguration ”)
Often located on the buttock, head, or low back
of dermal nests and fascicles of spitzoid to
histiocytoid appearing cells, S100–, S100A61,
NKI-C31, and PGP9.51
Central ulceration w/ adjacent epidermal hyperplasia,
subjacent healing skin changes, and degenerating
(eosinophilic) cartilage
PEH 1 clusters of pigmented round yeast (“copper
pennies/Medlar bodies”) within granulomatous
dermal infiltrate
cells, intracorneal neutrophils, sharp demarcation
from surrounding normal skin
Large spherules (up to 80mm) containing smaller
endospores
diffuse epidermal necrosis, and sweat gland necrosis
adnexae; melanocytes become singly distributed
between collagen in deep dermis
homogeneous light pink PAS1 material in lumen
Clear gelatinous capsule (mucicarmine1)
surrounding yeast clusters; entire dermis may be
gelatinous appearing (“gelatinous Cryptococcus”)
grains
superficial dermal nests resembling ordinary
nevus nests, and dense wedge-shaped dermal
component of plump epithelioid pigmented
melanocytes with abundant melanophages
extending into deep dermis/subcutis, tracks along
adnexal and neurovascular structures; may have
“dumbbell configuration” like cellular blue nevus.
b-catenin1 (nuclear) in heavily pigmented cells
Paucicellular, spindled dendritic melanocytes scattered
randomly throughout dermis; lacks dermal
sclerosis
papillae, small subepidermal bullae, and DIF1
(granular IgA in dermal papillae)
dermis, collagen trapping (best seen at periphery),
follicular and epidermal induction, and Touton giant
cells containing hemosiderin (ringed sideroblasts);
Factor XIIIa1 stromelysin 31, CD34
DF w/ abundant hemorrhage and hemosiderin within
giant cells; collagen trapping seen at periphery
Deep penetrating nevus (usually has junctional component and
superficial dermal nests resembling ordinary nevus nests n
CBN always lacks both these features!)
“Neurothekeoma”/nerve sheath myxoma (nodules are much less
cellular and much more myxoid, cells are S1001 and spindled/
fibroblast-like rather than epithelioid/spitzoid)
SCC and AK (atypia), relapsing polychondritis (lichenoid
lymphocytic inltrate adjacent to degenerating cartilage)
Blastomycosis (also has PEH, but has broad-based budding;
lacks brown pigmentation), phaeohyphomycosis (pigmented
hyphae rather than round yeast)
Trichilemmoma (large endophytic lobules rather than psoriasiform,
peripheral palisading, and thickened pink BMZ), psoriasis (lacks
clear cells and is not as sharply demarcated)
smaller monotonous poroid cells), SCCIS (atypical cytology w/
mitoses, dyskeratotic keratinocytes, and “windblown” pattern)
Rhinosporidiosis (gigantic sporangia with central dot-like nuclei
and many endospores), blastomycosis (PEH more common;
smaller organisms without endospores)
SJS/TEN (scattered eos; sweat gland necrosis less common and
less pronounced when present)
Acquired nevi (do not extend as deeply and do not involve
adnexal structures as much)
LCV (vessels destroyed, fibrin in vessel walls rather than
occluding lumens), thrombotic vasculopathies (very difficult to
distinguish, except calciphylaxis which has calcium deposits)
Histoplasmosis (much smaller organism, intracellular within
histiocytes, and has a pseudocapsule rather than a true
capsule), lepromatous leprosy (clear cell changes but also has
pink globi 1/–perineural granulomatous inflammation)
Pemphigus (lacks dyskeratosis, corps ronds/grains), warty
dyskeratoma (more endophytic, more circumscribed lesion),
herpetic infection (viral cytopathic change and neutrophils)
Cellular blue nevus (never has junctional component, never
has superficial dermal nests resembling ordinary nevus nests;
melanocytes are smaller and much less pigmented), nodular
melanoma (severe cytologic atypia w/ mitoses)
Blue nevus (more cellular, more circumscribed, has dermal
sclerosis); drug-induced hyperpigmentation
BP (eosinophils predominate, bigger bullae), bullous SLE
(lymphocytic and neutrophilic inflammation along DEJ and around
adnexae, increased mucin), and LABD (neutrophilic infiltrate and
blisters are more diffuse along DEJ; DIF easily distinguishes)
DFSP (infiltrates fat deeply [honeycombing pattern], lacks follicular
and epidermal induction, lacks giant cells with hemosiderin;
stains: CD341, factor XIIIa–, and stromelysin 3–)
Angiosarcoma (lacks multinucleate giant cells and collagen
trapping), Kaposi sarcoma (lacks multinucleate giant cells)
404