Non-malignant skin disease

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Non-malignant skin disease is relatively common. The pathology may or may not be specific. Some diseases require clinical information to diagnose.

An introduction to dermatopathology is in the dermatopathology article. Nevi (moles) and other melanocytic lesions are dealt with in the article melanocytic lesions. Inflammatory skin conditions are dealt with in inflammatory skin disorders.

Other

Lichen simplex chronicus

  • Abbreviated LSC.
  • AKA squamous cell hyperplasia.[1]

General

Etiology:[4]

  • Pruritus (itchness) -> mechanical trauma -> lichenification (thickened/leathery[5].

Microscopic

Features:[6]

  • Acanthosis (epithelial thickening) - irregular.
  • Hyperkeratosis.

Other features:[7]

  • Spongiosis (epidermal intercellular edema -- cells appear to have a clear halo around 'em).
  • Parakeratosis = retention of nuclei in the stratum corneum.

DDx:

Images:

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SKIN, PUNCH BIOPSY:
- LICHEN SIMPLEX CHRONICUS.
- NEGATIVE FOR MALIGNANCY.

Prurigo nodularis

  • Abbreviated PN.
  • AKA chronic prurigo and picker nodule.[3]

General

Gross

  • Dome-shaped/raised - papular (<1 cm) or nodular (>1 cm).[8]

Microscopic

DDx:

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SKIN LESION, LEFT CHIN, BIOPSY: 
- PRURIGO NODULARIS.

Micro

The sections show a raised lesion with compact hyperkeratosis and irregular acanthosis. Spongiosis is seen focally. There is minimal hypergranulosis.

There is no thinning of the suprapapillary plate and no dilated superficial blood vessels. There is no interface activity.

Very common

Dermatomycosis

General

Note:

  • Dermatophytosis (ring worm) is a type of dermatomycosis.

Microscopic

Features:

  • Microorganisms - key feature.
    • Often hyphae (candida) - like twigs of a tree... branching.
      • May be very fragmented in section ~ size of a neutrophil.
  • Perivascular inflammation, esp. neutrophils.
  • Exocytosis - blood cell infiltrate the epidermis.

Images:

Stains

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SKIN, BIOPSY:
- SKIN WITH SUPERFICIAL FUNGAL ORGANISMS CONSISTENT WITH CANDIDA.
- REACTIVE CHANGES OF THE EPITHELIUM.

Micro

The sections show skin with a neutrophilic infiltrate in the superficial epidermis. PAS-D staining demonstrates fungal organisms with a morphology suggestive of candida.

The epithelium has parakeratosis, acanthosis and spongiosis. No mitotic activity is appreciated. The keratinocytes are moderately enlarged and have evident nucleoli.

Cicatrix

  • AKA scar, dermal scar.

General

  • Previous surgery, biopsy, trauma.

Microscopic

Features:

  • Loss of dermal papilla.
  • Dense collagen - fibers run parallel to the dermal-epidermal (DE) junction[9] - key feature.
  • Loss of adnexal structures.

Other feature:

  • Thin-walled blood vessels.
    • Described as running perpendicular to the surface[9] - this may not be apparent.

DDx:

Image:

IHC

  • S100 focal/scattered +ve.
    • Desmoplastic melanoma strong +ve.
  • HMB-45 -ve.
    • Sclerosing blue nevus +ve.

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SKIN, LOWER MID BACK, RE-EXCISION:
- DERMAL SCAR.
- SOLAR ELASTOSIS.

Micro

The sections show skin with a dermis with dense collagen fibres that run parallel to the skin surface without adnexal structures. The overlying dermal-epidermis interface lacks the typical undulation.

Fibroepithelial polyp

  • AKA acrochordon, skin tag.

General

Gross

  • Raised skin-coloured lesion.

Image:

Microscopic

Features:

  • On a stalk / epithelium on three sides.
  • Benign epidermis.

DDx:

Image:

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SKIN ("SKIN TAG"), THIGH, EXCISION:
- FIBROEPITHELIAL POLYP.

Micro

The sections show a fragment of skin with epithelium on three sides. The epithelium matures and is not hypertrophic. Orthokeratosis is present. The core of the lesion has fibrofatty tissue. There is no inflammation.

Actinic keratosis

Bowenoid actinic keratosis redirects to here.

General

Risk factors:[13]

  • Sun exposure.
  • Immune suppression (e.g. organ transplant recipients).

Gross

Features:

  • Yellow-brown scaly, patches.
  • Sandpaper sensation - on touching.

Note:

  • May be pigmented.[14]

Microscopic

Features:[15]

  • Epidermal nuclear atypia:
    • Variation is size, shape and staining - must involve basilar layer.
      • Nuclear enlargement - key feature.
      • Hyperchromasia.
  • Abnormal epidermal architecture:
  • +/-Parakeratosis - may alternate with orthokeratosis, esp. early lesions.[16]
  • +/-Irregular acanthosis.

Note:

  • May be full thickness - known as bowenoid actinic keratosis.[17]

DDx:

Images:

Histologic subtypes

Like most common things, there are several variants:[16]

  • Hypertrophic actinic keratosis.
  • Acantholytic actinic keratosis.
  • Proliferative actinic keratosis - downward finger-like projections of the epidermis.
  • Pigmented actinic keratosis - DDx lentigo maligna.
  • Lichenoid actinic keratosis.

Seborrheic keratosis

  • Abbreviated SK.

General

  • Benign.
  • Most common tumour in older people.[18]
  • "Large number" of SKs = paraneoplastic syndrome (Leser–Trélat sign).[19]

Epidemiology:

  • Old people.
  • Usually in sun exposed area.[20]

Gross

  • "Stuck-on" appearance - raised lesion.

Image(s):

Microscopic

Features:[19]

  • Raised above skin surface.
  • Border sharply demarcated.
  • Hyperkeratosis - stratum corneum extra thick.
  • Horn cysts - intraepidermal collections of keratin - key feature.
    • Actually invaginations - not true cysts; thus, they may more accurately be called pseudohorn cysts.[21]
  • Clusters of cells with brown granular material in the superficial dermis/dermoepidermal junction - pigmented melanocytes.

DDx:[22]

Images:

Histologic subtypes

Like very common lesion, there are subtypes:[22]

  • Acanthotic seborrheic keratosis - thickened stratum spinosum; thick epidermis.
  • Reticulated seborrheic keratosis - vaguely resembles fibroepithelioma of Pinkus (BCC, fibroepitheliomatous pattern).
  • Irritated seborrheic keratosis - spongiosis (epidermal intercellular edema) and inflammation.
  • Digitated seborrheic keratosis - papillomatous projections.

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SKIN, MID BACK, SHAVE BIOPSY:
- SEBORRHEIC KERATOSIS.

Micro

The sections show skin with acanthosis, pseudohorn cysts, parakeratosis, hyperkeratosis and focal basal epidermal pigmentation. There is no basal nuclear atypia, no mitoses and no melanocytic nests. There is minimal dermal inflammation. There is no solar elastosis.

Pilomatricoma

  • AKA calcifying epithelioma of Malherbe[23], AKA pilomatrixoma.

General

  • Benign skin tumour.
  • Most common solid skin tumour of children.[24]
  • CTNNB1 gene mutation important in pathogenesis.[25]

Clinical:

  • Hard nodule - calcification.
  • +/-Painful.

Treatment:

  • Surgical excision.[24]

Microscopic

Features:[26]

  • Nodular circumscribed lower dermis/subcutaneous adipose lesion; thus, usu. surrounded by connective tissue.
    • Sharpy demarcated island of cells.
    • Calcification in 75%.
  • Cells:[27]
    • Basaloid epithelial cells - have prominent nucleoli.
    • Anucleate squamous cells ("ghost cells").
    • Giant cell foreign body type granulomas (form in reaction to keratin).

Notes:

  • Keratin a prominent feature on cytology - lots of orange stuff.
  • May ossify.

Images:

DDx:

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SKIN LESION, RIGHT ARM, EXCISION:
- PILOMATRICOMA.

Dermatofibroma

  • Abbreviated DF.

General

  • AKA fibrous histiocytoma.
  • Reactive process -- it is not a neoplasm.
  • Usually associated with previous trauma.
    • In women... usually legs.

Microscopic

Features:[29]

  • Prominent fibrous bundles, especially at the edge of the lesion.
    • Surrounded by spindle cells (fibroblasts).
      • Usually thought of as fibroblasts surrounded by fibrous material ("collagen-trapping").
  • Lack of adnexal structures, i.e. no sweat glands, no hair.
  • +/-Epidermal changes - known as "dirty fingers":[30]
    • Acanthosis (thickened epithelial layer - specifically thickened stratum spinosum).
    • Basal keratinocyte hyperpigmentation.

DDx:

Images:

Subtypes

Like all common things... there are subtypes:[31]

  • Cellular.
  • Deep penetrating.
  • Lipidized - with foamy macrophages, hemorrhage and Touton-like giant cells.
  • Epithelioid cell histiocytoma.
  • Fibrotic.
  • Aneurysmal - large blood filled + features of lipidized.
  • Granular cell dermatofibroma.
  • Dermatofibroma with monster cells.
Cellular dermatofibroma

Features:

  • High cell density in the dermis - "blue" at low power.
  • Collagen bundles - key feature.

Images:

IHC

Features:[33][34]

  • Factor XIIIa +ve.
    • Usually negative in DFSP.
  • CD34 -ve.
    • Usually positive in DFSP.
  • D2-40 +ve.[35]
    • Usually negative in DFSP.

Ezcema

General

  • A nebulous thingy.
  • Very common.

DDx:

Microscopic

Features:[36]

  • Spongiosis (epidermal edema); keratinocytes spacing increased - key feature.
  • +/-Interdermal vesicles.
  • +/-Eosinophils (may suggest Rx reaction).
  • Perivascular lymphocytes.

Acne vulgaris

General

  • Extremely common - esp. among adolescents.
  • Very rarely seen by pathologists.

Treatments:

  • Antibiotic (minocycline).
  • Isotretinoin AKA all-trans retinoic acid (ATRA).

Gross

  • Papules, pustules, nodules or cysts.
    • White, black or erythematous.

Images:

Microscopic

Features:[37]

  • Folliculitis:[38]
    • Neutrophils around hair follicle and infiltrate into it - including the follicular canal.
  • Epidermal invagination or cyst at site of a hair follicle - contains:
    • Sebum.
    • +/-Bacteria (Propionibacterium acnes) and inflammatory cells - typically neurophils.

Subtyped into:

  1. Open comedones ("blackheads") - no extension to epidermal surface.
  2. Closed comedones ("whiteheads") - to epidermal surface have wide opening.

DDx - acneiform disorder:[38]

  • Rosacea.
  • Infective folliculitis.
  • Perioral dermatitis.
  • Acne vulgaris.

Image:

Very common - viral

Verruca vulgaris

  • AKA common wart.

General

  • Etiology - HPV.

Notes:

Microscopic

Features:[39]

  • Hyperkeratosis (more keratin - thick stratum corneum).
  • Hypergranulosis (thicker stratum granulosum).
  • Acanthosis (thickening of the stratum spinosum).
  • Rete ridges lengthened (~7-10x normal).
  • Large blood vessels at the dermal-epidermal junction.

Memory device: there is more of everything - more s. corneum, s. granulosum, s. spinosum, longer rete ridges, more (larger) blood vessels.

Images:

Verruca plana

General

  • Common.
  • Usu. hands and face.[40]

Microscopic

Features:[40]

  • Orthokeratosis with basketweave pattern.
  • Hypergranulosis.
  • Viral keratohyaline.
  • Koilocytes.
  • Acanthosis - yet flat surface and base.

Notes:

  • It differs from verruca vulgaris... (1) orthokeratosis, (2) flat surface and base.

Less common

Clear cell acanthoma

General

  • Benign.
  • Elderly.
  • Classically on the leg.[41]
  • Rare.
  • Clinically not distinct.
    • Suspected clinically in only ~3% of cases.[42]

Microscopic

Features:[43]

  • Psoriasiform pattern - epidermal thickening (acanthosis).
  • Keratinocytes:
    • Pale or light pink cytoplasm (when compared to surrounding non-lesional keratinocytes).
    • Separated from one another (spongiosis).
  • +/-Stratum corneum neutrophils.

DDx:

Images:

Chondrodermatitis nodularis chronica helicis

  • AKA chondrodermatitis nodularis helicis.
  • Abbreviated CNCH.

General

  • Tender/painful - key clinical feature.
  • Typically right ear - people more often sleep on this one.[44]
  • Usually >40 years old.

Etiology:

  • Trauma/mechanical.

Clinical DDx:[44]

Microscopic

Features:[44]

  • Dermal inflammation.
  • Epithelial hyperlasia.
  • Fibrosis.
  • Cartilaginous pathology:
    • Perichondrial inflammation - key feature.
    • Perichondrial disruption.
    • +/-Necrosis.
    • +/-Hemorrhage.

Images:

Cutaneous calcinosis

  • AKA calcinosis cutis.

General

  • Benign in itself; underlying cause may not be benign.
  • May be a scrotal lesion - known as scrotal calcinosis.[45]

Subtypes:[46]

  1. Dystrophic - due to death of cells; may be related to a tumour.
  2. Metastatic - due to chronic renal failure; hyperkalemia; paraneoplastic phenomenon.
  3. Iatrogenic - post surgical.
  4. Idiopathic.

Microscopic

Features:

  • Dermal calcification:
    • Acellular purple blobs on H&E.
      • +/-Artefactual tearing of surrounding tissue due to processing (cutting).
      • +/-Small artefactual lines ~1-2 micrometers due to processing (cutting).
    • Usu. well-circumscribed.

Images:

Dilated pore of Winer

General

  • Benign.
  • Looks like zit.

Microscopic

Features:[47]

  • Dilated hair follicle with keratin.
  • Acanthosis.
  • Budding of epidermis (into dermis).

Lichenoid keratosis

  • AKA lichen planus-like keratosis.

General

Clinical DDx:[48]

Microscopic

Features:[49]

  • Hyperkeratosis.
  • Parakeratosis.
  • Band of inflammatory cells at DE junction (lichenoid inflammation).
  • Dead keratinocytes (Civatte bodies).
  • Dermal melanophages.

DDx:

Images:

Granuloma annulare

General

  • Benign and self-limited condition.
  • Etiology unknown - may be assoc. with trauma.[50]

Gross

  • Typically extremities - usu. arms and hands.[50]

Microscopic

Features:[51]

  • Dermal palisading granuloma - typically superficial-to-mid dermis - surrounds:
    • Necrotic collagen - key feature.
      • Nuclei "missing" - have undergone karyolysis.
    • Mucin - important.
      • Loose/pale, paucicellular, eosinophilic.
  • Chronic inflammatory cells.

Notes:

  1. There may be multiple small foci with intervening normal dermis.[50]
  2. Granuloma annulare can be subclassified into subcutaneous and interstitial.
  3. Histomorphologically similar to Rheumatoid nodule.

DDx:

Images:

Stains

  • Alcian blue (pH 2.5) +ve (for mucin).[54][50]

Image:

Necrobiosis lipoidica

General

Associated with:

Microscopic

Features:[50]

  • Dermal palisading granuloma around:
    • Necrotic collagen - key feature.
      • Nuclei "missing" - have undergone karyolysis.
  • Little mucin, no normal dermis between foci.
  • Plasma cells - common.[52]
  • May involve adipose tissue.

DDx:

Images:

Keloid

  • Hypertrophic scar redirects to this section.

General

  • Sites of previous trauma/surgery, esp. in dark skinned individuals.[29]

Microscopic

Features:[29]

  • Thick collagen bundles - surrounded by paler staining fibroblasts - key feature.
  • Lesion replaces adnexal structures, e.g. hair, sweat glands.

DDx:

  • Hypertrophic scar.

NB:

  • Reported as "keloidal-type collagen"; the clinician decides between hypertrophic scar and keloid.

Images:

Angiofibroma

See also: nasopharyngeal angiofibroma.
Should not be confused with angiokeratoma.
Fibrous papule redirects here.

General

  • May be seen in the context of tuberous sclerosis - especially "butterfly area of the face".[29]
  • Solitary lesions in adults are known as fibrous papules and classically arise on the nose.[55]

Clinical:

  • Firm, dome-shaped, flesh coloured.

Microscopic

Features:[29]

  • Dome-shaped.
  • Fibrotic dermis.
    • Enlarged fibroblasts.
  • Dilated small vessels.

Image:

Molluscum contagiosum

General

  • Etiology: caused by molluscum contagiosum virus.

Microscopic

Features:

  • A suprabasilar epidermal lesion consisting of "molluscum bodies", i.e. molluscum bodies are found above the stratum basale.[57]
  • Molluscum bodies - key feature:
    • Large cells with abundant granular eosinophilic cytoplasm.
    • Small peripheral nucleus.

Image(s):

Notes:

  • Molluscum bodies very vaguely resemble signet ring cells -- but:
    • Cytoplasm eosinophilic and granular.
    • Nucleus usually smaller than in signet ring cell.
    • Molluscum bodies are only the epidermis - an uncommon place to find SRCs without finding them elsewhere.
  • The granular eosinophilic cytoplasm represents accumulated virons.

Superficial dermal infiltrates

Discussed in detail by Alsaad and Ghazarian.[58]

Dermal perivascular lymphoeosinophilic infiltration

  • Abbreviated DPLI.

Microscopic appearance is just what it is called:

  • Lymphocytes and eosinophils around the vessels in the superficial dermis.

DDx:[58]

Notes:

  • May superficially resemble cutaneous lymphoma.[59]

Images:

Congenital dermal melanocytosis

  • AKA Mongolian spots.
  • Classically seen in asian children.

Gross:

  • Brown or blue-grey patch in the lumbosacral area.

Mastocytosis

General

Classification:[60]

  1. Cutaneous (only) - usually children.
    • Urticaria pigmentosa.
    • Others.
  2. Systemic - usually adults.
    • Indolent subvariant.
    • Aggressive subvariant.
    • Leukemic subvariant.

Microscopic

Features:[61]

  • Cells in the superficial/mid dermis that are:
    • Lymphocyte-like with more cytoplasm that is granular.
      • Cells may have spindled or stellate morphology.
      • Tend to be more abundant around vessels.
  • +/-Eosinophils (common).
  • +/-Edema - often prominent; gives cells a white halo.

Notes:

  • Lymphocyte vs. mast cell:
    • Lymphocytes = round; mast cells = ovoid.

Images:

Stains

IHC

  • CD117 +ve.
  • Tryptase +ve.[62]

Ichthyosis

General

  • Comes in different flavours.
  • Usu. inherited... thus a pediatric condition.

Gross

  • Fish scale-like appearance.

Image:

Microscopic

Features:[61]

  • Thick stratum corneum without basket-weave pattern.

Palmar fibromatosis

General

  • AKA Dupuytren's contracture.

Clinical:[63]

  • Usually older 60-70s.
  • Male > female.
  • Associated with:
    • Alcohol abuse.
  • May be familial.

Microscopic

Features:[64]

  • Bland spindle cells in dense collagen.
    • No nuclear atypia.
  • Giant cells.
  • +/-Mitotic figures.

Images:

Angiomyoma

General

  • Benign.
  • Female > male.[66]

Microscopic

Features:

  • Well-circumscribed lesion with fascicular architecture.
  • Spindle cells/epithelioid cell with moderate eosinophilic (pink) cytoplasm.
  • Thick-walled blood vessels. (???)

Images:

Angiokeratoma

General

Notes:

Microscopic

Features:[67]

  • Ectatic superficial dermal vessels.
  • Overlying hyperkeratosis (thick stratum corneum).

Others features:[citation needed]

  • Irregular acanthosis.
  • Longer rete ridges.

DDx:

Images:

Inverted follicular keratosis

General

  • Benign skin lesion.
  • Central face - middle age.[68]
  • Uncommon.
  • May be considered a variant of seborrheic keratosis that is predominantly endophytic.[69]

Clinical DDx:[68][70]

Microscopic

Features:[68]

  • Keratinocyte of cytologically benign proliferation.
  • "Squamous eddies" (whorls of keratin).
  • Coarse keratohyaline granules.

DDx:

Images:

Sign out

SKIN LESION, FACE, BIOPSY:
- INVERTED FOLLICULAR KERATOSIS.

Focal cutaneous mucinosis

General

  • Benign.
  • May be associated with systemic disease.[71]

Microscopic

Features:

  • Light blue whispy material in the dermis - key feature.

DDx:

Panniculitis

This is dealt with in the panniculitis article.

DDx for panniculitis:

Rare

Necrotizing fasciitis

Not to be confused with nodular fasciitis.
  • AKA flesh-eating disease.

General

  • High mortality.
  • May be diagnosed at frozen section.[72]
  • Classically associated with Group A streptococcus.

Treatment:

  • Operative debridement.

Microscopic

Features:

  • Necrosis of fascia - key feature.[73]
    • PMNs and necrotic debris (amorphous grey or pink material).

Note:

  • Fat lobules between septae may be normal.

DDx:

Images:

Porokeratosis

General

  • Genetic.
  • Several subtypes.

Notes:

  • Not the same as punctate porokeratotic keratoderma.[74]

Microscopic

Features:

  • Cornoid lamella (pathognomonic) - key feature:
    • Compact keratosis over a hair follicle.
  • +/-Rete ridge loss.

Images:

Nevus sebaceous

  • AKA nevus sebaceous of Jadassohn.

General

  • Congenital.
  • Face or scalp.

Microscopic

Features:

  • Abundant sebaceous glands.

Nevus lipomatosus superficialis

  • Abbreviated NLS.

General

  • Rare.
  • Congenital.
  • Usually lower trunk or gluteal region.[75]

Microscopic

Features:[76]

  • Benign adipose tissue in the superficial dermis.

DDx:

Image:

Bullous disease

Cysts

See also

References

  1. Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 1011. ISBN 978-1416031215.
  2. Tadrous, Paul.J. Diagnostic Criteria Handbook in Histopathology: A Surgical Pathology Vade Mecum (1st ed.). Wiley. pp. 296. ISBN 978-0470519035.
  3. 3.0 3.1 Busam, Klaus J. (2009). Dermatopathology: A Volume in the Foundations in Diagnostic Pathology Series (1st ed.). Saunders. pp. 26. ISBN 978-0443066542.
  4. URL: http://emedicine.medscape.com/article/1123423-overview. Accessed on: 20 August 2010.
  5. URL: http://www.medterms.com/script/main/art.asp?articlekey=10131. Accessed on: 20 August 2010.
  6. Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 1065-6. ISBN 0-7216-0187-1.
  7. URL: http://emedicine.medscape.com/article/1123423-diagnosis. Accessed on: 20 August 2010.
  8. URL: http://www.pediatrics.wisc.edu/education/derm/text.html. Accessed on: 23 August 2012.
  9. 9.0 9.1 Busam, Klaus J. (2009). Dermatopathology: A Volume in the Foundations in Diagnostic Pathology Series (1st ed.). Saunders. pp. 499. ISBN 978-0443066542.
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  11. Busam, Klaus J. (2009). Dermatopathology: A Volume in the Foundations in Diagnostic Pathology Series (1st ed.). Saunders. pp. 342. ISBN 978-0443066542.
  12. URL: http://dermatlas.med.jhmi.edu/derm/result.cfm?Diagnosis=1196583692. Accessed on: 1 September 2011.
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  14. URL: http://www.dermoscopy-ids.org/index.php/newest-case/79-lentigo-maligna-vs-pigmented-actinic-keratosis. Accessed on: 23 August 2012.
  15. URL: http://emedicine.medscape.com/article/1099775-workup#a0723. Accessed on: 1 September 2011.
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  17. 17.0 17.1 Bagazgoitia, L.; Cuevas, J.; Juarranz, A. (Feb 2010). "Expression of p53 and p16 in actinic keratosis, bowenoid actinic keratosis and Bowen's disease.". J Eur Acad Dermatol Venereol 24 (2): 228-30. doi:10.1111/j.1468-3083.2009.03337.x. PMID 19515076.
  18. URL: http://emedicine.medscape.com/article/1059477-overview#a0199. Accessed on: 26 August 2011.
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  20. URL: http://emedicine.medscape.com/article/1059477-overview. Accessed on: 26 August 2011.
  21. URL: http://www.healthcare.uiowa.edu/dermatology/dpt/HornCyst.htm. Accessed on: 13 September 2012.
  22. 22.0 22.1 Busam, Klaus J. (2009). Dermatopathology: A Volume in the Foundations in Diagnostic Pathology Series (1st ed.). Saunders. pp. 338-9. ISBN 978-0443066542.
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  24. 24.0 24.1 URL: http://emedicine.medscape.com/article/1058965-overview. Accessed on: 10 September 2011. Cite error: Invalid <ref> tag; name "emed1058965" defined multiple times with different content
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  26. URL: http://emedicine.medscape.com/article/1058965-diagnosis. Accessed on: 10 September 2011.
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