Clinical History: “Rash”

An Approach to Skin Biopsies Without a

Clinical History
Anne M. Stowman, MD, FCAP

M2040H

© 2021 College of American Pathologists. Materials used with permission of faculty.

Clinical History: “Rash”.
An Approach to Skin Biopsies
Without a Clinical History
Anne M. Stowman, MD
University of Vermont Medical Center
• No conflicts of interest or disclosures.
Objectives
• Identify the histologic categories of eruptions including: spongiotic,
psoriasiform, lichenoid/interface, perivascular, vesiculobullous,
vasculopathic, and granulomatous.
• Formulate a differential diagnosis for each of the categories of eruptions.
• Recognize subtle histologic features to narrow the differential diagnosis for
each of the categories of eruptions.
• Identify “not to be missed” entities that must be recognized in biopsy of a
rash.
• Proficiently work up and sign out biopsies for eruptions without a clinical
history.
Outline
• Step-by-step approach to the “rash” biopsy

• Cases
Part 1: Step-by-step approach to the “rash”
biopsy
Step-by-step approach to the “rash” biopsy
1. Identify the principle pattern and formulate a differential diagnosis.
2. Search for any histologic clues to help to narrow down your
differential diagnosis – and recognize the not-to-be missed features.
3. Review any prior path.
4. Additional work up: histochemical stains, immunohistochemistry,
deeper levels, DIF.
5. Signing out the report.
Step-by-step approach to the “rash” biopsy

1. Identify the principle pattern and formulate

a differential diagnosis.
2. Search for any histologic clues to help to narrow down your differential
diagnosis – and recognize the not-to-be missed features.
3. Review any prior path.
4. Additional work up: histochemical stains, immunohistochemistry, deeper
levels, DIF.
5. Signing out the report.
Identify the principle pattern
• Start at the top and work your way down.
• Stratum corneum
• Epidermis
• Junction
What is the pattern
• Papillary dermis
of eruption?
• Reticular dermis
• Vessels
• Subcutis
Histologic categories of eruptions
• Spongiotic
• Lichenoid/interface
• Psoriasiform
• Perivascular The “pattern”
• Vesiculobullous
• Vasculopathic
• Granulomatous
• Normal skin
Histologic categories of eruptions
• Histologic features of rashes are non-specific.

• Once you have identified the principle pattern, you can list a
differential diagnosis and sign out the report.
Histologic categories of eruptions
• Spongiotic
• Lichenoid/interface
• Psoriasiform Formulate a
short
• Perivascular
differential
• Vesiculobullous diagnosis list
• Vasculopathic
• Granulomatous
• Normal skin
 Spongiotic

Spongiotic Acute Subacute Chronic Psoriasiform

Spongiotic dermatitis ddx
• Allergic/contact
• Irritant contact
• Photoallergic
• Id reaction Many, many more….
• Nummular
• Atopic
• Pityriasis rosea
• Dermatophytosis
Lichenoid/interface
• Lichenoid: Band-like inflammation along the dermal-epidermal
junction with partial obscuring
• Interface: Basal layer vacuolization with necrotic keratinocytes (less
inflammation) and less inflammation

Lichen planus Lichen sclerosis

Lichenoid Interface
Lichenoid/interface dermatitis ddx

Lichenoid Interface
• Lichen planus • Lupus erythematosus
• Lichenoid drug-related eruption • Lichen sclerosus
• Pityriasis lichenoides • Fixed drug eruption
• Erythema multiforme/Steven
Johnson syndrome/Toxic
epidermal necrolysis
• Graft-versus-host disease
• Perniosis
Psoriasiform
• Acanthosis
• Regular or irregular
• Parakeratosis
• +/- neutrophils

Psoriasis vulgaris
Psoriasiform dermatitis ddx
• Psoriasis
• Lichen simplex chronicus
• Pityriasis rubra pilaris
• Seborrheic dermatitis
• Reactive arthritis
• Secondary syphilils
• Drug
Perivascular (no epidermal change)
• No/minimal epidermal change
• Perivascular inflammation

Erythema chronicum migrans

Perivascular (no epidermal change) dermatitis ddx
• Superficial and deep (5 L’s):
• Lupus
• Light reaction (polymorphous light eruption (PMLE))
• Lymphoma/pseudolymphoma
• Lues (syphilis)
• Lyme disease (+ arthropod bite)
• Superficial:
• Eosinophilic: allergic, arthropod, viral, drug
• Mast cell: mastocytosis
Vesiculobullous
• Split within or beneath the epidermis creating a bullous cavity

Subcorneal Intraepidermal Suprabasilar Subepidermal

Vesiculobullous ddx
Subcorneal Intraepidermal Suprabasilar Subepidermal
Impetigo Friction blister Pemphigus vulgaris Bullous pemphigoid
Staph scalded skin Spongiotic blistering Pemphigus vegetans Epidermolysis bullosa
Pemphigus foliaceus Palmoplantar pustulosis Paraneoplastic pemphigus Porphyria cutanea tarda
Subcorneal pustular Hailey-Hailey disease Dermatitis herpetiformis
dermatosis
IgA pemphigus Darier’s disease Drug (bullous)
Acute generalized Grover’s disease Linear IgA bullous
exanthematous pustulosis dermatosis

**Will need to recommend DIF for vesiculobullous

Vasculopathic
• Perivascular inflammation Leukocytoclastic vasculitis
• Red cell extravasation
• +/- endothelial cell damage
• +/- leukocytoclasis
• +/- thrombi
Vasculopathic ddx
• Leukocytoclastic vasculitis
• Urticarial vasculitis
• Lymphocytic vasculitis
• Polyarteritis nodosa
• Vascular occlusive diseases
Granulomatous
• Aggregates of dermal histiocytes

• Necrotizing
• Non-necrotizing
• Foreign body giant cell reaction

Granuloma annulare
Granulomatous dermatitis ddx
• Sarcoidosis
• Infection
• Foreign body
• Granuloma annulare
• Necrobiosis lipoidica
• Rheumatoid nodule
Normal skin
• Minimal epidermal change
• +/- scattered melanophages
• +/- perivascular inflammation

Uriticaria
Normal skin ddx
• Urticaria
• Superficial fungal infection (tinea versicolor, dermatophyte, candida)
• Corynebacterium
• Pigmentary disorders (post-inflammatory hyperpigmentation, vitiligo)
• Amyloidosis
• Telangiectasia macularis eruptiva perstans (TMEP)
Histologic categories: the exception
• Mixed patterns favor a drug-related
eruption (eg. lichenoid and
spongiotic).

• Also showing mixed patterns:

• Viral
• Syphilis

Drug-related dermatitis
Step-by-step approach to the “rash” biopsy
1. Identify the principle pattern and formulate a differential diagnosis.
2. Search for any histologic clues to help to
narrow down your differential diagnosis –
and recognize the not-to-be missed features.
3. Review any prior path.
4. Additional work up: histochemical stains, immunohistochemistry, deeper
levels, DIF.
5. Signing out the report.
Histologic clues
• Stratum corneum
• Epidermis
• Junction Start at the top and work your way down
• Papillary dermis
• Reticular dermis
• Vessels
• Subcutis
Histologic clues: stratum corneum
• Mounded parakeratosis Pityriasis rosea, erythema annulare centrifugum

• Serum Eczema

• Confluent parakeratosis Neuts in the horn ddx: PTICS

Psoriasis • Psoriasis
• Neutrophils • Tinea
• Impetigo
• Candida
• Syphilis, seborrheic dermatitis
Histologic clues: epidermis
• Spongiosis (with Langerhans cells) Eczema

• Mitoses along the junction Psoriasis

• Apoptotic keratinocytes Irritant dermatitis, drug-related

Eosinophilic spongiosis: HAPPPI ddx
• Herpes gestationis
• Intraepidermal inflammation • Allergic contact
• Lymphocytes Eczema (r/o atypia) • Arthropod bite
• Pemphigoid (bullous pemphigoid)
• Neutrophils Psoriasis • Pemphigus vulgaris
• Eosinophils HAPPPI ddx • Parasite (scabies)
• Incontinentia pigmenti
• Also: drug
Histologic clues: dermal-epidermal junction
• Apoptosis
• Vacuolization Lichenoid / Interface
• Inflammation
Histologic clues: dermis
• Inflammation (where, how much, what)
• Perivascular / Interstitial / Peri-adnexal (follicular, eccrine)
• Lymphs / Eos / Mast cells / Plasma cells / Histiocytes

• Pigment incontinence Lichenoid/interface

• Sclerosis Lichen sclerosis

• Edema Diffuse: Urticaria

Papillary: Polymorphous light eruption, Sweet’s, pernio, bug, drug
• Red cell extravasation Drug, pityriasis rosea, PLEVA, pigmented purpuric
dermatosis, vasculitis
• Mucin Connective tissue disorder
Histologic clues: vessels
• Endothelial cell damage and/or fibrinoid necrosis
Leukocytoclastic
• Red cell extravasation
vasculitis
• Leukocytoclasis

• Increased numbers
Venous stasis
• Hemosiderin
Histologic clues: not to be missed
• Cytologic atypia of lymphoid cells Atypical lymphoid infiltrate (MF, CD30+)

• Interface change EM/SJS/TEN, GVHD

• Subcorneal split Staph scalded skin syndrome

• Subcutaneous calcifications Calciphylaxis

• Dense dermal neutrophilic infiltrate Sweet’s syndrome, pyoderma

gangrenosum
• Vasculitis Leukocytoclastic vasculitis (HSP)
Erythema multiforme / Steven Johnson syndrome
/ Toxic epidermal necrolysis
Staph scalded skin syndrome
Calciphylaxis
Sweet’s syndrome
Step-by-step approach to the “rash” biopsy
1. Identify the principle pattern and formulate a differential diagnosis.
2. Search for any histologic clues to help to narrow down your differential
diagnosis – and recognize the not-to-be missed features.
3. Review any prior path.
4. Additional work up: histochemical stains, immunohistochemistry, deeper
levels, DIF.
5. Signing out the report.
Review prior path
• Always compare to prior biopsies and discuss in your report.
• Prior specimens may also have history included.
• Especially important if biopsy is of hematopoietic disorders.
Step-by-step approach to the “rash” biopsy
1. Identify the principle pattern and formulate a differential diagnosis.
2. Search for any histologic clues to help to narrow down your differential
diagnosis – and recognize the not-to-be missed features.
3. Review any prior path.
4. Additional work up: histochemical stains,
immunohistochemistry, deeper levels, DIF.
5. Signing out the report.
Additional work up
• Deeper levels
• Histochemical stains
• PAS, AFB, gram stain, spirochete, Fontana Masson, colloidal iron
• Immunohistochemistry
• Hematopoietic work up
• Direct immunofluorescence
• Vesiculobullous, vasculitis
• Michel’s fixative
• Perilesional skin
• Recommendations for serology, work up and culture
• Lyme and syphilis
• Sarcoid
• Additional biopsy for culture
Step-by-step approach to the “rash” biopsy
1. Identify the principle pattern and formulate a differential diagnosis.
2. Search for any histologic clues to help to narrow down your differential
diagnosis – and recognize the not-to-be missed features.
3. Review any prior path.
4. Additional work up: histochemical stains, immunohistochemistry, deeper
levels, DIF.
5. Signing out the report.
How to sign out the report
• Nearly all histopathology for rashes is “nonspecific” and therefore offering
a differential diagnosis based on histologic features alone is acceptable.
• Review prior biopsies and make comparisons.
• If you identify any “clues” in your histology, best to favor a diagnosis – as
the more specific you can be, the better and happier your clinicians will be.
• Can recommend additional biopsies if clinically indicated (rash persists,
worsens, develops).
• May need to make recommendations for additional work up and/or clinical
correlation.
Part 2: Cases (16)
Cases
• Clinical history: Rash; dermatitis unspecified; R21; L98.9
Case 1
• 25-year-old male with biopsy from the left thigh.
Perivascular (no epidermal change) dermatitis:
Arthropod bite reaction
• Wedge-shaped dermal inflammation with eosinophils.
• +/- Epidermal changes (spongiosis, ulceration).

• One of the “dermal hypersensitivity” reactions

• Bug: arthropod
• Hug: allergic contact
• Drug: drug
Case 2
• 82-year-old male with biopsy from the right lower leg.
Spongiotic dermatitis: Stasis dermatitis
• Mild epidermal spongiosis.
• Increased dermal vessels.
• Hemosiderin-laden macrophages.
• Red cell extravasation.
Case 3
• 17-year-old female with biopsy from the trunk.
Psoriasiform dermatitis: Guttate psoriasis
• Dilated papillary dermal vessels.
• Patchy parakeratosis. Neuts in the horn ddx: PTICS
• Psoriasis
• Neutrophils in the stratum corneum. • Tinea
• Impetigo
• Candida
• Syphilis, seborrheic dermatitis
Case 4
• 60-year-old male with biopsy from the face.
PAS
Spongiotic dermatitis: Seborrheic dermatitis
• Perifollicular parakeratotic mounding.
• Pityrosporum yeast in follicles.
• Neutrophils in epidermis.
Case 5
• 34-year-old female with biopsy from the back.
Spongiotic dermatitis: Pityriasis rosea
• Mild spongiosis. Mounded parakeratosis:
• Pityriasis rosea
• Mounded parakeratosis. • Erythema annulare centrifugum
• RBC extravasation.

Dermal red cell extravasation:

• Drug
• Pityriasis rosea
• PLEVA
• Pigmented purpuric dermatosis
• Vasculitis
Case 6
• 46-year-old male with lower leg punch biopsy.
Perivascular (no epidermal change) dermatitis:
Pigmented purpuric dermatosis
• RBC extravasation without endothelial cell change.
Case 7
• 59-year-old male with biopsy from the axilla.
CD3 CD7

CD4 CD8
Mycosis fungoides
• Epidermotropic lymphocytes with cytologic atypia and “halos”
(without spongiosis).
• Tagging along the junction.
• Pautrier microabcess formation (clusters of atypical lymphs in
epidermis).
• Wiry papillary dermal collagen.

• Other lymphomas can involve the skin (but usually singular/nodular):

• Follicular lymphoma, marginal zone lymphoma
Case 8
• 29-year-old female with biopsy from the chest.
Colloidal iron
Perivascular (no epidermal change) dermatitis:
Connective tissue disease (Lupus erythematosus)
• Interface change with superficial and deep perivascular and peri-
ADNEXAL inflammation.
• Get a colloidal iron stain.

Superficial and deep (5 L’s):

• Lupus
• Light reaction (polymorphous light)
• Lymphoma/pseudolymphoma
• Lues (syphilis)
• Lyme disease (+ arthropod bite)
Case 9
• 31-year-old female with biopsy from the arm.
Granulomatous dermatitis
• Sarcoid vs tattoo-related reaction – can’t tell by histology alone!
• Recommend further work up for sarcoidosis.
Case 10
• 41-year-old male with biopsy from the abdomen.
Plasma cells
Spirochete stain
Syphilis (secondary)
• When you see plasma cells – think syphilis!
• The great mimicker:
• Most commonly psoriasiform with long-slender rete and reactive endothelial
cells.
• Can show interface pattern.

• Recommend serologies when suspicious.

Case 11
• 61-year-old male with biopsy from the arm.
CD3

CD30
CD20
CD30+ atypical lymphoproliferative disorder
• Lymphomatoid papulosis, types A-E
• Multiple, small papules
• Waxing and waning
• Anaplastic large cell lymphoma
• Solitary, large
• Ulcerated

• Transformed mycosis fungoides

Transformed MF
Case 12
• 92-year-old woman with biopsy of the vulva.
Spongiotic dermatitis: Irritant dermatitis
• Mild spongiosis with scattered dyskeratotic keratinocytes.
• Mild perivascular inflammation.

Intraepidermal apoptotic keratinocytes:

• Irritant dermatitis
• Drug-related eruption
Case 13
• 12-year-old boy from the chest.
PAS
Normal skin: Tinea versicolor
• Normal skin biopsy. Normal skin ddx:
• Urticaria
• Fungus
• Corynebacterium
• Get levels and PAS. • Pigmentary disorders
• Amyloidosis
• Telangiectasia macularis eruptive perstans (TMEP)
Case 14
• 80-year-old male with biopsy on the abdomen.
Spongiotic: Bullous pemphigoid, urticarial
phase
• Mild spongiosis with intraepidermal eosinophils.
• Tagging of eosinophils along the junction.
• Dermal eosinophils. DIF: linear IgG and C3

• Requires DIF (linear IgG + C3 along BMZ)

Eosinophilic spongiosis: HAPPPI ddx
• Herpes gestationis
• Allergic contact
• Arthropod bite
• Pemphigoid (bullous pemphigoid)
• Pemphigus vulgaris
• Parasite (scabies)
• Incontinentia pigmenti
• Also: drug
Case 15
• 34-year-old female with biopsy from the upper arm.
CD117 (c-kit)+

Also performed: CD163(-) and SOX10(-)

Perivascular (no epidermal change) dermatitis:
Telangiectasia macularis eruptiva perstans (TMEP)
• Variable histologically – can be “normal skin” ddx.
• Perivascular inflammation.
• Telangiectasias.

CD117

CD117
Case 16
• 56-year-old male with hyperkeratotic areas on his hand and face.
Granulomatous inflammation and
pseudoepitheliomatous hyperplasia:
Blastomycosis infection
• Three key histologic features:
• Pseudoepithelimatous hyperplasia
• Granulomatous dermal inflammation
• Neutrophilic microabcesses
• May come in a rash or rule out neoplasm
• Very common – get a PAS/GMS

Broad based budding yeast, 8-15 microns

Take home points
• Histology of rashes is nonspecific but can be suggestive.
• When you get an inflammatory dermatologic biopsy, your goal is to:
• Identify the pattern of inflammation.
• Form a differential diagnosis.
• Look for clues in the histology to narrow the differential.
• Remember your “not to be missed” short list.
• Be comfortable with listing a differential diagnosis in your report and
punting it back to the clinician to make the clinicopathologic
correlation.
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