Dermatopathology

Dermatopathology is the pathology of skin.

Pathology is a significant part of dermatology and dermatologists spend five years in residency. So, it is a huge area.

Specimens

• Shave biopsy = done for what is presumed to be benign disease - classically exophytic lesions, e.g. seborrheic keratosis.
• Saucerization = scooped shave biopsy.
• Punch biopsy = cylindrical piece of skin, usu. epidermis and dermis - suspicious lesions/malignant lesions, e.g. basal cell carcinoma.
• Incisional biopsy = a piece of the lesion for pathologic assessment; lesion not completely removed.
• Excision = lesion cut-out with intent for complete removal - usual has a generous margin, e.g. malignant melanoma excision.
• Re-excision = done to get a wider margin or remove part of a lesion that was incompletely removed in a prior excision.
  • Conservative re-excision = cut-out more with a minimal rim of normal tissue.
• Sentinel lymph node removal = a special type of lymphadenectomy usu. done for staging, esp. malignant melanoma.

Histology

Layers of the skin

Schematic showing the layers and structures of skin. (WC/cancer.gov)

• Epidermis - outer most layer, avascular, separated from dermis by a basement membrane, epithelial tissue.
• Dermis - below the epidermis, vascular, separated from the epidermis by a basement membrane, connective tissue.

Note:

• The layer below the skin is the subdermis (AKA hypodermis, AKA subcutaneous tissue).
  • It is below the dermis and consists of adipose tissue.

Image:

• Dermis and hypodermis (stevegallik.org).

Epidermis

Layers of the epidermis

Layers of the epidermis. (WC/Wbensmith)

Epidermis layers - from the surface to epidermal-dermal junction:

• Stratum corneum.
• Stratum lucidum.
  • Present only in "thick" skin.
• Stratum granulosum.
• Stratum spinosum (aka prickle layer).
• Stratum basale (germinativum).

Mnemonic: Corn Lovers Grow Several Bales.

Cells of the epidermis

• Keratinocytes.
  • Usually eosinophilic cytoplasm - important feature.
  • May have clear perinuclear halo (glycogenated keratinocytes).
  • Intercellular bridges (high power) - key feature.
• Melanocytes.
  • Usuallly basal location.
  • Epithelioid or dendritic morphology.
  • Pericellular clearing - key feature.
  • Clear cytoplasm.
  • +/-Pigmentation.
• Other:
  • Toker cell.
  • Neutrophils.
    • Trilobated nuclei - 2-3 little dots - key feature.
  • Lymphocytes.
    • Small (round) nucleus.
    • Scant/indistinct cytoplasm.
  • Other foreign cells:
    • Paget disease: large cells with clear cytoplasm, may cluster, above basal layer.

Normal histology

Features:

• Keratinocytes:
  • Basal ~ 2x RBC.
    • May palisade focally ~ 1:2 = width: height.
• Melanocytes < 25 melanocytes / 0.5 mm of basal layer.
• Basket weave stratum corneum (non-acral skin).

Dermis

Subdivided into layers:

1. Papillary dermis.
   • Location: superficial - opposed to the deep aspect of the epidermis.
   • Appearance: dense, thick collagen bundles.
2. Reticular dermis.
   • Location: deep - between papillary dermis and subdermis.
   • Appearance: loose connective tissue.

Images:

• Layers of the dermis - labelled (biology-online.org).
• Layers of the skin (melanoma.blogsome.com).

Adnexal structures

The top five structures of the skin:

Structure / Attribute	Histomorphology	Function	IHC	Other	Image
Eccrine gland	clusters of tubular structures, pale cytoplasm	thermoregulation (cooling) - produce sweat	CK7+, CEA+, CAM5.2+, EMA+	?	?
Apocrine gland	apical snouts, tubular structures	ear wax, body odor	?	?	?
Sebaceous gland	clusters of cells side-by-side, pale fluffy cytoplasm	grease hair, sexual lubrication	?	assoc. with hair follicle	?
Hair follicle	linear structure	keep individual warm	?	assoc. with sebaceous glands	?
Nail	epidermal structure	weapon (claw-like), look pretty?	?	?	(osumc.edu), (ctrgenpath.net)

Ducts vs. glands:

• Eccrine glands - spindle-shaped myoepithelial cells surround luminal cells.
• Eccrine ducts - cuboidal type subepithelial cells.

Common terms

Clinical descriptors

There are multitude of clinical descriptors - common ones are:

Name	Size †	Description	Other	Image
Macule	<= 10 mm	flat + change of colour	if > 10 mm --> patch	Macule (WC)
Patch	> 10 mm	flat + change of colour	if <= 10 mm --> macule	Patch (WC)
Papule	<= 10 mm	raised	if > 10 mm --> nodule	Papule (WC)
Nodule	> 10 mm	raised	if <= 10 mm --> papule	Nodule (WC)
Plaque	> 10 mm	raised, flat-top	plateau-like	Plaque (WC)
Vesicle	<= 10 mm	raised, fluid filled	if > 10 mm --> bulla	Vesicle (WC)
Bulla	> 10 mm	raised, fluid filled	if <= 10 mm --> vesicle	Bulla (WC)

Note:

• † Definitions vary -- some authors use a 5 mm cut-off.

Histologic descriptors

Dermatopathology doesn't have intuitive terms, e.g. thickening of the stratum spinosum isn't spinosum hyperplasia. The terms have to committed to memory.

Common terms in a table

Term	Meaning	Reference
Acanthosis	thickening of the prickle layer (stratum spinosum) of epidermis
Acantholysis	loss of intercellular connections in the epidermis
Dyskeratosis	abnormal keratinization, often refers to keratinization below the stratum granulosum; keratinization above may be abnormal (dependent on body site)
Parakeratosis	retention of nuclei in the stratum corneum, normal in mucous membranes
Spongiosis	epidermal intercellular edema; cells appear to have a clear halo around 'em
Basketweave stratum corneum	appearance of the normal stratum corneum; presence in the context of pathology suggests an acute process
Compact hyperkeratosis	stratum corneum layer is dense and thickened; this suggests a chronic process
Hyperkeratosis	thickened stratum corneum - also see compact hyperkeratosis and basketweave stratum corneum
Epidermotropism †	intraepithelial lymphocytes in CTCL; how to remember: epidermotropism = malignant
Exocytosis †	intraepithelial lymphocytes in benign conditions
Orthokeratosis	anuclear keratin layer is present (stratum corneum) - seen in normal skin; ortho- means correct

Note:

• † These definitions are not universally accepted. Epidermotropism is sometimes used in the context of benign disease.

Image:

• Spongiosis (WC).

Others terms

• Crust = epithelial elements, blood.

Image:

• Crust (eplasty.com).

Skin diseases

Neoplasms

Main article: Dermatologic neoplasms

Malignant

Skin cancer is very common. The basic DDx of a malignant skin lesion is:

• Squamous cell carcinoma (SCC).
• Basal cell carcinoma (BCC).
• Malignant melanoma.
• Metastases.

Non-malignant disease

Main article: Non-malignant skin disease

Non-malignant skin disease is common. It is the domain of dermatologists. It can be scary for general anatomical pathologists because the differential diagnosis is often broad, and, it's generally not something the general anatomical pathologist sees a lot of.

Subarticles

• Dermal cysts, e.g. epidermal cyst, pilar cyst.
• Epidermal necrosis, e.g. erythema multiforme, toxic epidermal necrolysis.
• Inflammatory skin diseases.
  • Bullous diseases, e.g. pemphigus vulgaris.
  • Panniculitis.

Common entities in tables

Non-malignant non-cystic - very common

Entity	Key histologic feature	Other features	Clinical	Stains/IHC	DDx	Other	Image
Seborrheic keratosis (SK)	horn cysts (intraepidermal collections of keratin)	hyperkeratosis, brown granular material at the DE junction, sharply demarcated	stuck on appearance	none	fibroepithelial polyp	Leser–Trélat sign = many SKs in malignancy	SK (WC)
Dermatofibroma	fibrous bundles esp. at edge of lesion	"dirty fingers" = acanthosis + basal keratinocyte hyperpigmentation	+/-trauma Hx	CD34-, Factor XIIIa+	DFSP	very common	DF (WC)
Fibroepithelial polyp (skin tag)	on a stalk (epithelium on 3+ sides)	no horn nests, no hyperkeratosis	raised lesion	none	seborrheic keratosis	very common	Skin tag (WC)
Lipoma	mature adipocytes - uniform size	var. of size may be seen, should prompt search for lipoblasts	mobile subcutaneous mass	S100 (???)	liposarcoma	variants: angiolipoma (blood vessels), myolipoma (muscle)	Lipoma (WC)
Cicatrix (dermal scar)	dense collagen bundles running parallel to DE junction, loss of dermal papillae	loss of adnexal structures, +/-giant cells, +/-foreign material, +/-inflammatory cells	site of previous trauma/surgery	usu. none; S-100 (to exclude melanoma)	residual disease, hypertrophic scar, (desmoplastic) melanoma		Scar (WC)

Non-malignant non-cystic - common

Entity	Key histologic feature	Other features	Clinical	Stains/IHC	DDx	Other	Image
Neurofibroma	bland spindle cells	mast cells, mixed with collagen, assoc. with a nerve	may be associated with neurofibromatosis, esp. plexiform type	S100+, GFAP+	neurotized melanocytic nevus	may develop into MPNST	Neurofibroma (WC)
Keratoacanthoma	keratin plug, glassy pink cytoplasm, pushing downward growth	minimal/no nuclear atypia	grow rapidly then involute	none	squamous cell carcinoma	some don't believe in the entity	Keratoacathoma (WC)
Molluscum contagiosum	suprabasilar cells with abundant granular eosinophilic cytoplasm	small peripheral nucleus	polypoid lesion; mushroom-like (?)	none (?)	DDx (?)	favourite exam case	Molluscum contagiosum (WC)
Verruca vulgaris	hypergranulosis (thick granular layer) + keratohyaline granules	hyperkeratosis (thick s. corneum), acanthosis (thick s. spinosum), rete ridges lengthened (~7-10x normal), large vessels at DE junction, koilocytic change (???)	raised lesions, classically on hand	none (p16+?)	squamous cell carcinoma	caused by HPV	Verruca vulgaris (WC)
Condyloma acuminatum	koilocytes	parakeratosis, long folded rete ridges (papillomatosis) - pseudopapillary look	genital lesion	none (p16+)	fibroepithelial polyp	caused by HPV	Condyloma acuminatum (WC)
Granuloma annulare	dermal palisading granuloma around necrotic collagen	mucin in centre of lesion, (peripheral) lymphocytes, usu. more superficial than necrobiosis lipoidica	benign, self-limited	none (CD68?)	necrobiosis lipoidica, rheumatoid nodule, epithelioid sarcoma	Other ?	GA (WC)
Necrobiosis lipoidica	dermal palisading granuloma around necrotic collagen, plasma cells	mucin in centre of lesion, (peripheral) chronic inflammatory cells	may be assoc. diabetes mellitus	none (CD68?)	granuloma annulare, rheumatoid nodule	histology identical to necrobiosis lipoidica diabeticorum	(drmihm.com)
Angiofibroma	fibrotic dermis, dilated capillaries	enlarged (stellate fibroblasts)	dome-shaped - face, boys & nosebleeds (nasopharyngeal angiofibroma)	Stains/IHC	DDx	may be associated with tuberous sclerosis	Angiofibroma (WC)
Keloid	thick collagen bundles - surrounded by paler staining fibroblasts	replaces adnexal structures	site of previous trauma, esp. in blacks	none	dermatofibroma (???)	hypertrophic scar	Keloid (WC)
Eccrine poroma	abundant basaloid cells with (small) ductal structures	incloses islands of sclerotic stroma with edema	erythematous lesions	Stains/IHC ?	DDx ?	Other ?	EP (WC)
Syringoma	bilayered ducts, occasionally tadpole like shape		usu. close to eyelid	Stains/IHC ?	DDx ?	Other ?	(cdlib.org)
Chondroid syringoma (mixed tumour of skin)	chondromyxoid stroma, epithelial component	epithelial component in nests with eosinophilic cytoplasm, round/ovoid nuclei with nucleoli	Clinical ?	Stains/IHC ?	DDx ?	related to pleomorphic adenoma (???)	Image ?
Angiokeratoma	ectatic superficial dermal vessels + overlying hyperkeratosis	-	may be seen in Fabry disease	Stains/IHC ?	venous lake	Other ?	Angiokeratoma (WC)

Non-malignant non-cystic - children

Entity	Key histologic feature	Other features	Clinical	Stains/IHC	DDx	Other	Image
Pilomatricoma	anucleate squamous cells (ghost cells), giant cells	bland basaloid cells	common in children	none	squamous cell carcinoma	mutations of CTNNB1 gene	Pilomatrixcoma (WC)
Juvenile xanthogranuloma (JXG)	Touton giant cells - multi-nucleated cells where nuclei are distributed around the cell periphery forming a ring	abundant cytoplasm	children	CD68+, CD1a-, CD207-	Langerhans cell histiocytosis	may be seen in adults, known as adult xanthogranuloma	JXG (WC)

Non-malignant cystic

Entity	Key histologic feature	Other features	Clinical	Stains/IHC	DDx	Other	Image
Epidermal cyst	cyst lined by squamous epithelium with a granular layer	keratinous debris, no skin adnexal structures	cyst	none	pilar cyst, dermoid cyst	Other?	Epidermal inclusion cyst (WC)
Pilar cyst (trichilemmal cyst)	cyst lined by squamous epithelium without a granular layer	keratinous debris	cyst	none	epidermal cyst	Other?	Pilar cyst (WC)
Steatocystoma	cyst lined by squamous epithelium with a corrugated eosinophilic lining	epidermis has no granular layer	cyst	none	dermoid cyst, follicular cyst	Other?	Steatocystoma (WC)
Dermoid cyst	cyst lined by keratinizing squamous epithelium with adnexal structures	adnexal structure = hair, sebaceous gland, sweat glands	cyst	none	epidermal cyst	may be seen in the ovary	(uiowa.edu)

Pre-malignant

Entity	Key histologic feature	Other features	Clinical	Stains/IHC	DDx	Other	Image
Actinic keratosis	epidermal atypia, esp. (basal) nuclear enlargement	var. of nuclear size, shape and staining, parakeratosis (important in early lesions); does not involves adnexal epithelium and follicular epithelium	yellow-brown scaly	none	squamous carcinoma, Bowen disease	seen with solar elastosis	AK (WC)
Bowen disease (squamous cell carcinoma in situ)	epidermal atypia, esp. suprabasal nuclear enlargement	var. of nuclear size, shape and staining; usually full thickness involvement; involve adnexal epithelium and follicular epithelium		none	squamous carcinoma, actinic keratosis	typically seen with solar elastosis	Bowen's disease (WC)

Common malignant

Entity	Key histologic feature	Other features	Clinical	Stains/IHC	DDx	Other	Image
Basal cell carcinoma (BCC)	basaloid cells with peripheral palisading, artificial cleft	myxoid stroma	raised, pearly, telangiectasia	usu. none req., CK5/6+	trichoepithelioma, basaloid squamous cell carcinoma	assoc. nevoid basal cell carcinoma syndrome, Bazex syndrome	BCC (WC)
Squamous cell carcinoma (SCC)	nuclear enlargement, eosinophilic cytoplasm, central nucleus	small nucleolus, intercellular bridges	flaky appearance	usu. none req., p63+, HMWK+	keratoacanthoma, Paget disease (EMPD & PDB), malignant melanoma, Toker cell hyperplasia	Other	SCC (WC)
Malignant melanoma	spindle and/or epithelioid morphology +/-nuclear atypia (esp. nucleoli)	mitoses (esp. deep), +/-pigment, +/-nested arch., asymmetry, upward spread (into epidermis), epithelioid m. deep, +/-single cells, +/-sheets of cells	ABCD = Asymmetry, Borders poor demarc., Colour dark, Diameter large	S100+, Melan A+, HMB-45+, microphthalmia+, tyrosinase+	melanocytic lesions esp. Spitz nevus, Bowen's disease	may be familial, dysplastic nevus	Melanoma (WC)

Less common malignant

Entity	Key histologic feature	Other features	Clinical	Stains/IHC	DDx	Other	Image
Kaposi sarcoma	vascular spindle cell lesion	hyaline globules (intracytoplasmic)	often HIV/AIDS	HHV-8	Masson's hemangioma, angiosarcoma, Kaposiform hemangioendothelioma	stages: patch stage, plaque stage, nodular stage, exophytic, infiltrative, lymphadenopathic	Kaposi sarcoma (WC)
Cutaneous T-cell lymphoma (includes mycosis fungoides)	single lymphocytes in epidermis ("lymphocyte exocytosis")	lymphocyte nests in the epidermis ("Pautrier microabscesses"), short arrays of lymphocytes along the basal layer of the epidermis ("epidermotropism")	Clinical	CD45, CD4	B cell lymphoma (?)	Other	CTCL (WC)
Atypical fibroxanthoma	dermal lesion with marked nuclear atypia	multinucleated cells, mitoses, vacuolated cytoplasm	old men, head and neck	p63-, 34betaE12-, S100-, desmin-	sarcomatoid squamous carcinoma, melanoma, leiomyosarcoma	some classify this as benign; thought to be related to undifferentiated pleomorphic sarcoma	AFX (WC)
Merkel cell carcinoma	neuroendocrine nuclear features (stippled chromatin, no nucleolus), scant cytoplasm	+/-nuclear moulding, usu. intermediate cell size	Merkel cell polyomavirus associated, usu. head & neck or extremities	CK20+, EMA+	cutaneous Ewing sarcoma, basal cell carcinoma, (dermal) lymphoma, metastatic small cell carcinoma (e.g. lung)	rare, aggressive	MCC (WC)
Dermatofibrosarcoma protuberans (DFSP)	spindle cell tumour with storiform pattern, tumour often contains adipocytes	dermal tumour with preserved adnexal structures	locally aggressive	CD34+, factor XIIIa-	dermatofibroma, solitary fibrous tumour (usu. deeper)	rarely metastases, characteristic translocation: t(17;22)(q22;q15) COLA1/PDGFB; may transform to fibrosarcoma	DFSP (WC)

Presentations

Leukoplakia

Main article: Leukoplakia

DDx:

• Vitiligo (loss of pigment).
• Inflammation.
  • Chronic dermatitis.
  • Psoriasis.
• Neoplasia.
  • Vulvar intraepithelial neoplasia.
  • Paget disease.
  • Invasive carcinoma.
• Other.
  • Lichen sclerosus.
  • Lichen simplex chronicus.

Skin disease and systemic conditions

Tabular list

Entity	Disease/syndrome	Key histologic feature	Image
Acanthosis nigricans	diabetes mellitus, malignancy	basal cell hyperpigmentation, hyperkeratosis, prominent rete ridges	(cdlib.org)
Trichilemmoma	Cowden disease	"hyperkeratosis"	(cancer.gov)
Angiokeratoma	Fabry disease	hyperkeratosis + vessels in superficial dermis	(WC)
Dermatitis herpetiformis	Celiac disease	subepidermal bullous disease, papillary abscesses	(lampyris101.com)
Angiofibroma	tuberous sclerosis	fibrotic dermis + dilated blood vessels	(drdittmar.lu)
Sebaceous adenoma	Muir-Torre syndrome	abundant sebaceous glands with abn. arch.	(WC)
Seborrheic keratosis, multiple with explosive onset	Leser–Trélat sign (malignancy)	horn cysts, hyperkeratosis	gross (WC), micro. (WC)

Acanthosis nigricans

General

Associated with:

• Diabetes mellitus.
• Malignancy.

Microscopic

Features (memory device BPH):

• Basal cell hyperpigmentation.
• Prominent rete ridges.
• Hyperkeratosis.

DDx:

• Seborrheic keratosis - typically has more hyperkeratosis, pseudohorn cysts.

Images:

• AN (cdlib.org).

Others

• Dermatitis herpetiformis: gluten enteropathy (celiac disease), thyroid disease, intestinal lymphoma.
• Pemphigus vulgaris: thymoma, myasthenia gravis, malignancy.

Lipoid proteinosis

• 

  Lipoid proteinosis (A)

• 

  Lipoid proteinosis (B)

A. Inner labial biopsy shows subepithelial hyalinized pink/red material, about blood vessels and in general. B. The particularly glassy appearance of the material in areas is evident at high power.

Xanthogranuloma in scrotal skin.

• 

  Xanthogranuloma in scrotal skin. (A)

• 

  Xanthogranuloma in scrotal skin. (B)

• 

  Xanthogranuloma in scrotal skin. (C)

• 

  Xanthogranuloma in scrotal skin. (D)

A. Pseudoepitheliomatous hyperplasia seemingly forms a dermal mass. B. Parakeratosis tops epidermis. C. Neutrophils lie in the center of the apparent mass. D. Diagnostic xanthoma cells lie in dermal papillae.

Silicone granuloma

• 

  Silicone granuloma (A)

• 

  Silicone granuloma (B)

• 

  Silicone granuloma (C)

• 

  Silicone granuloma (D)

A. The dermis resembles Swiss cheese. B. Macrophages, some with more than one nucleus, accompany empty ovoid spaces. C. Some macrophages resemble Teuton body giant cells. D. An admixture of lymphocytes is not at all unusual.

Histoplasmosis in skin

• 

  Dermal histoplasmosis (A)

• 

  Dermal histoplasmosis (B)

• 

  Dermal histoplasmosis (C)

• 

  Dermal histoplasmosis (D)

A. Extending from papillary dermis into dermis is a chronic, blue inflammatory infiltrate. B. The infiltrate comprises lymphocytes, plasma cells, and macrophages. C. At the edge of the biopsy pink strews inflammatory cells; this pink invasion of inflammation, so to speak, is a good place to look for organisms.   D. High power reveals sometimes budding yeast forms in clear spaces.

Herpes Zoster

• 

  Changes of herpes zoster (A)

• 

  Changes of herpes zoster (B)

• 

  Changes of herpes zoster (C)

• 

  Changes of herpes zoster (D)

Changes of herpes zoster in lower right abdominal skin of a 48 yo Hispanic man. A. Note the edema at the dermoepidermal junction along with a focal separation at the left as well as the inflamed superficial and deep blood vessels. B,C. Careful examination along the junction uncovers smudged chromatin diagnostic of viral infection. D. Vasculitis associated changes include extravasated neutrophils with nuclear dust, as well as pervascular macrophages, lymphocytes and occasional eosinophils.