DERMATOPATHOLOGY

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CHAPTER 11 DERMATOPATHOLOGY

Approach to pediatric skin biopsy interpretation
Aplasia cutis congenita

Cutis laxa
Focal dermal hypoplasia (Goltz syndrome)
Ichthyoses

Non-syndromic ichthyoses

Ichthyosis vulgaris
X-linked recessive ichthyosis
Lamellar ichthyosis / congenital ichthyosiform erythroderma (non-bullous ichthyosiform erythroderma)
Bullous ichthyosiform erythroderma / epidermolytic hyperkeratosis
Ichthyosis hystrix of Curth-Macklin
Syndromic ichthyoses

Sjögren-Larsson syndrome
Neutral lipid storage disease
Netherton’s syndrome
Omenn syndrome
KID syndrome (keratitis, ichthyosis and deafness)
Conradi-Hunermann-Happle syndrome
CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects)
Trichothiodystrophy
Hereditary Palmoplantar Keratodermas (PPKs)

Epidermolytic palmoplantar keratoderma (Vorner type)
Pachonychia congenita
Epidermolysis bullosa (EB)

Epidermolysis bullosa simplex (EBS)

Weber-Cockayne EBS
Dowling-Meara EBS
EBS with muscular dystrophy
Plectin mutations
Plakophilin mutations
Junctional epidermolysis bullosa (JEB)

Lethal junctional EB (“Herlitz” JEB)
Non-lethal JEB
JEB with pyloric atresia
Dystrophic Epidermolysis Bullosa

Transient bullous dermolyis of the newborn
Incontinentia Pigmenti
Acrodermatiis enteropathica
Porokeratosis

Porokeratosis of Mibelli
Linear porokeratosis
Acantholytic diseases

Darier’s disease
Hailey-Hailey disease
Pemphigus vulgaris
Pemphigus foliaceus
Other blistering and bullous diseases

Bullous impetigo
Staphylococcal scalded skin syndrome
IgA pemphigus
Infantile acropustulosis
Erythema toxicum neonatorum
Herpes simplex
Erythema multiforme
Fixed drug eruption
Polymorphous light eruption
Bullous pemphigoid
Insect and mite bites
Dermatitis herpetiformis
Bullous dermatosis of childhood (Linear IgA disease)
Bullous lupus erythematosus
Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)
Bullous urticaria pigmentosa and bullous mastocytosis
Atopic dermatitis/eczema
Seborrheic dermatitis
Psoriasis
Pityriasis lichenoides
Pityriasis rubra pilaris
Cutaneous infection-related diseases

Molluscum contagiosum
Varicella zoster virus (VZV) infection
Gianotti-Crosti syndrome
Fish tank granuloma
Cutaneous candidiasis
Scabies
Necrotizing fasciitis (echthyma gangrenosum)
Cutaneous lupus erythematosus (LE)
Morphea
Systemic sclerosis / scleroderma
Lichen sclerosus et atrophicus
Sweet’s syndrome (acute febrile neutrophilic dermatosis)
Pyoderma gangrenosum
Cutaneous graft versus host disease (GVHD)
Granuloma annulare
Rheumatoid nodule
Necrobiosis lipoidica (NL)
Panniculitis

Septal panniculitis

Erythema nodosum
Lobular panniculitis

Idiopathic nodular panniculitis
Alpha 1 antitrypsin deficiency
Lipoatrophy (lipodystrophy)

Familial lipodystrophy

Congenital generalized lipodystrophy
Familial partial lipodystrophy, Dunnigan type
Acquired lipodystrophy

Generalised
Partial
Cytophagic histiocytic panniculitis
Lupus panniculitis (lupus profundus)
Subcutaneous fat necrosis of the newborn
Vasculopathy including vasculitis

Vascular occlusive diseases

Purpura fulminans
Urticaria

Cryopyrinopathies

Familial cold autoinflammatory syndrome
Muckle-Wells syndrome
Neutrophilic (leukocytoclastic) vasculitis

Acute hemorrhagic edema of the skin of the newborn (Finkelstein’s disease)
Henoch-Schonlein purpura
Microscopic polyarteritis
Polyarteritis nodosa (PAN)
Behçet’s disease
Wegener’s granulomatosis
Churg-Strauss syndrome
Vascular malformations and vascular tumors

Vascular malformations

Arteriovenous malformation
Venous malformation
Glomangioma or glomulovenous malformation
Blue rubber bleb nevus syndrome
Lymphatic malformation

Lymphangioma circuscriptum
Cystic hygroma / lymphangioma
Capillary malformation (‘port wine stain’)
Complex combined vascular malformations with limb overgrowth
Angiokeratoma
Vascular tumors

Infantile hemangioma (hemangioma of infancy)
Congenital hemangioma (rapidly involuting and non involuting- ‘RICH’ and ‘NICH’)
Tufted angioma
Pyogenic granuloma
Glomus tumor
Kaposiform hemangioendothelioma
Kaposi sarcoma
Cutaneous infiltrations

Leukemia
Lymphoma
Rhabdomyosarcoma
Neuroblastoma
Langerhans cell histiocytosis
Mastocytosis
Tumors and hamartomas

Pilomatrixoma
Trichoepithelioma
Trichofolliculoma
Follicular poroma
Nevus sebaceus
Syringocystadenoma papilliferum
Epidermal nevus
Connective tissue nevus
Collagenoma
Buschke-Ollendorff syndrome (BOS)
Dermatofibroma
Smooth muscle hamartoma and Becker’s nevus
Juvenile xanthogranuloma
Malignant skin tumors in childhood

Basal cell carcinoma
Squamous cell carcinoma
Dermatofibrosarcoma protuberans (DFSP)
Melanocytic lesions

Congenital melanocytic nevus (CMN)
Acquired melanocytic nevi
Spitz nevus
Spindle cell nevus of Reed
Blue nevus
Malignant melanoma
Hypertrophic scar/keloid
Cutaneous calcification

Subepidermal calcified nodule
Tumoral calcinosis
Cysts

Epidermoid cyst
Dermoid cyst
Mucinous cyst
Median raphe cyst
Lip cleft cyst / lip pits

APPROACH TO PEDIATRIC SKIN BIOPSY INTERPRETATION

• Close clinicopathological correlation and frequent multidisciplinary team meetings with joint discussion of clinical photographs and histopathological material is essential in pathological interpretation of skin biopsies

image similar histological features may require different interpretations according to the circumstances

• Interpretation of vascular lesions is assisted by attendance of the pathologist at meetings where discussion of radiological findings including Doppler flow studies takes place
• Punch biopsies need to be examined at several levels for assessment of subtle findings
• Beware the biopsy which looks ‘normal’ on routine histology

image clinical discussion may direct attention to subtle changes compatible with a particular clinical diagnosis

• Timing of the biopsy in relation to the evolutionary stage of the disease may affect histological features

image eg in vasculitic disease, the stage of infiltration of vessel walls by inflammatory cells may have passed and only perivascular inflammation remains

• Prior consultation with the pathologist is important to ensure optimal handling of tissue
• A good maxim in investigation of a skin condition is ‘If in doubt, biopsy’

image punch biopsy is minimally invasive

• Beware the traumatic biopsy taken with forceps which may induce artefactual separation of the epidermis from the underlying dermis (Fig 11.1)
image

Fig 11.1 Photomicrograph of incisional skin biopsy taken while holding the skin with a forceps demonstrating artefactual separation of the epidermis from the dermis.

SPECIFIC ENTITIES IN PEDIATRIC DERMATOPATHOLOGY

• Almost any pathological process can potentially affect children
• Many conditions common in adult practice almost never occur
• Many conditions are unique to pediatric practice
• This section concentrates on entities common or specific to pediatric practice

image for details on conditions more usually seen in adults see standard dermatopathology texts

• Due to the importance of clinicopathological correlation of clinical, genetic and histopathological findings for correct interpretation of skin biopsies, for many conditions relevant diagnostic clinical and genetic findings are provided in this chapter

APLASIA CUTIS CONGENITA

• Estimated incidence 3 in 10,000 births
• Familial cases reported

image compatible with autosomal dominant transmission

– no gene locus identified

• May be associated with a large number of other anomalies (Frieden 1986)

Clinical features

• 80% located on scalp

image most in midline

– at or in close proximity to parietal hair whorl

• Any skin site may be involved
• Commonly presents at birth with a well-circumscribed ulcer
• Lesions single in 70–75% of cases

image double in 20%
image triple in 8%

• Typically 1–3 cm in diameter, round or oval, sharply marginated and hairless
• Involvement of underlying bone, dura or meninges may occur if lesion large and in one of the cranial suture lines

Histopathological features

• Flattened epidermis
• Total absence of adnexal structures
• Dermal fibrosis
• Variable reduction of elastic fibers

Differential diagnosis and diagnostic pitfalls

• Clinically, iatrogenic injuries caused by forceps or scalp electrodes
• Histopathologically, an ulcer or scar due to trauma cannot be differentiated from aplasia cutis congenita

CUTIS LAXA

• Group of extremely rare disorders of elastic tissue characterized by loose inelastic skin

Genetics

• Congenital or acquired forms

image one autosomal dominant
image two major autosomal recessive (type I and type II)

– AR cutis laxa type I is the most severe form

· associated in some cases with mutations in fibulin-5 (Mégarbané et al 2009)

image X-linked recessive form

• Some forms are caused by mutations in the elastin gene
• Acquired form has an immunological basis

image reported following febrile illness or surgery or as an apparent hypersensitivity reaction to penicillin

• May also occur in a localized or generalized form following an inflammatory skin disorder such as erythema multiforme, dermatitis herpetiformis or Sweet’s syndrome

Clinical features

• Skin hangs in loose folds

image impression of being too large for the body

• Cutis laxa type I

image involves nearly the entire body surface

– worsens over time

image hoarse low-pitched voice (redundant vocal cords)
image associated with emphysema

– may develop in first few months

image diaphragmatic hernia, diverticula of the gastrointestinal tract and bladder

• Cutis laxa type II

image pre- and post-natal growth restriction
image joint laxity
image intellectual and motor development is unpredictable

Histopathological features

• Loss of fine elastic fibers in papillary dermis (Fig 11.2)

image remaining fibers shortened and vary in diameter

– may be fragmented

• In acquired form may be associated inflammatory component

image neutrophils, eosinophils and lymphocytes in superficial and deep dermis

• Electron microscopy shows abnormal elastic fibers

image tangled microfibrils
image reduced elastin
image fragmentation of fibers

image

Fig 11.2 Photomicrograph of skin biopsy from a patient with cutis laxa. Elastic van Gieson stain demonstrates epidermal atrophy and absence of elastic fibers in the superficial dermis.

Differential diagnosis and diagnostic pitfalls

• Histological features may be subtle

image special stain for elastin (Elastic Van Gieson) required
image compare with age-matched control

FOCAL DERMAL HYPOPLASIA (GOLTZ SYNDROME)

• Rare

image minimally affected individuals may remain unrecognized

Genetics

• X-linked dominant

image deletion in Xp11.23P, X-linked PORCN

• History of miscarriages of male fetuses and stillbirths suggests male lethality
• Linear pattern of skin lesions following Blaschko’s lines as well as streaking of long bones indicate X chromosome mosaicism

Clinical features

• Typically linear cutaneous atrophy with telangiectasia and pigmentation

image usually present from birth
image any part of the body

• Lesions may be striate, atrophic, lipomatous and papillomatous
• Hair can be sparse and brittle
• Nail abnormalities also described
• Eye involvement in 20%

image usually coloboma

• Hands and feet involved in 60–70%

image syndactyly, polydactyly, absence or hypoplasia of digits
image lobster claw deformity

• Scoliosis in 15–20%
• Osteopathia striata

image longitudinal linear striations in metaphyses of long bones

– 20% of gene carriers
– characteristic but not diagnostic

• Dental anomalies in 40%

image enamel defects, hypoplastic or dysplastic teeth, delayed eruption, irregular spacing and notched incisors

• 15% have variable mental deficiency
• Abnormalities also described in respiratory, digestive, genitourinary tract and cardiovascular system

Histopathological features (Fig 11.3)

• Depending on timing of biopsy
• Early lesions

image thinning of the dermis
image few collections of fat around dermal blood vessels

• Later lesions

image marked thinning of dermis and fat deposits in the papillary dermis

• Late lesions

image fat nodules separated from the epidermis by only a few collagen fibers

image

Fig 11.3 Photomicrograph of skin biopsy from a patient with focal dermal hypoplasia (Goltz syndrome) demonstrating focal thinning of the dermis and clusters of fat cells in the reticular dermis. Clinically the lesion was linear and striate.

Differential diagnosis and diagnostic pitfalls

• No adipocytes are present in the dermis of young infants with focal dermal hypoplasia

image appear over time

• Biopsies of very early lesions may show only an increase in numbers of small venules and capillaries in the upper dermis

image occasional small cluster of adipocytes in the reticular dermis

RESTRICTIVE DERMOPATHY

Clinical features

• Rare lethal genodermatosis

image lamin A deficiency

– autosomal recessive

• Premature birth
• Fixed facial expression
• Thin, slightly adherent shiny skin
• Significant restriction of limb movements and respiratory effort
• Characteristic dysmorphic facies
• Arthygryposis with limbs in fixed flexion deformity tightly encased by skin
• Death within hours or within a few weeks

Histopathological features (Fig 11.4)

• Marked thinning of dermis compared with age-matched controls
• Decrease or absence of elastin
• Collagen fibers in bundles parallel to skin surface
• Decreased numbers of adnexal structures
• Electron microscopy

image disorganized collagen bundles
image abnormally thin collagen fibrils
image decrease in elastic fibers

image

Fig 11.4 Photomicrograph of skin biopsy from a patient with restrictive dermopathy demonstrating thinning of the epidermis, decreased elastin, and a reduction in numbers of adnexal structures which are poorly differentiated.

POIKILODERMA CONGENITA (ROTHMUND–THOMSON SYNDROME)

Clinical features

• Rare
• Autosomal recessive

image helicase gene mutations

• Poikiloderma affecting cheeks and backs of hands
• Short stature
• Sparse hair
• Cataracts
• Hypogonadism
• Midface hypoplasia
• Increased incidence of squamous carcinoma and osteogenic sarcoma

Histopathological features (Fig 11.5)

• Hyperkeratosis
• Epidermal atrophy
• Vasodilatation
• Pigment incontinence
• Fragmentation of elastic tissue
• Loss of appendages
image

Fig 11.5 Photomicrograph of skin biopsy from a patient with poikiloderma demonstrating epidermal atrophy. The dermis shows numerous small telangiectatic vessels associated with some melanophages and loss of skin appendages.

ICHTHYOSES

Introduction

• Group of mainly hereditary disorders characterized clinically by visible scaling
• Inflammatory scaling disorders, such as psoriasis and eczema, and disorders such as pityriasis rubra pilaris are usually categorized separately
• Pathology may be confined to the skin or part of a generalized syndrome
• Genetic testing is becoming increasingly available

image many genes implicated
image algorithmic approach to direct testing

• Skin biopsy is a screening procedure

image often not diagnostic although there are a few notable exceptions

• Most characterized histologically by thickened stratum corneum
• Epidermal hyperplasia and dermal inflammatory response are variable

image result of disordered epidermal homeostasis and barrier dysfunction

Handling of the specimen

• Prior consultation between dermatologist and pathologist is advised to narrow the differential diagnosis
• Consideration of need for frozen sections

image Oil red O staining in neutral lipid storage disease
image alcohol dehydrogenase staining for Sjögren–Larsson syndrome

• Fixation in glutaraldehyde if electron microscopy is likely to be required

image to confirm ichthyosis vulgaris, Netherton syndrome, epidermolytic hyperkeratosis, harlequin ichthyosis, ichthyosis hystrix of Curth–Macklin

• Hair sample examined if differential diagnosis includes Netherton syndrome or trichothiodystrophy

NON-SYNDROMIC ICHTHYOSES

ICHTHYOSIS VULGARIS

• Most common and often mildest form of generalized ichthyosis
• Prevalence difficult to measure

image clinical overlap with other conditions associated with dry skin
image variable expression in response to temperature and humidity

Genetics

• Likely autosomal dominant with variable expression
• Linkage to 1q21 (Compton et al 2002)

image contains several genes vital to epidermal function including profilaggrin
• Recently described mutations in filaggrin gene (Oji et al 2009, Nomura et al 2009)

Clinical features

• Not present at birth

image manifests within first year of life

• Fine white scales most prominent on the trunk and extensor surfaces of the limbs
• Flexural areas almost always spared
• Improves in warm humid environments
• Keratosis pilaris (keratotic plugging of hair follicles) in 75%
• Hyperlinear palms and soles in 80%
• Increased incidence of atopic dermatitis

Histological features (Fig 11.6)

• Compact hyperkeratosis of stratum corneum
• Reduced or absent granular layer

image useful diagnostic feature

• Epidermis of average thickness
• Hair follicles and sweat ducts may show keratotic plugs
• Electron microscopy

image reduced or absent keratohyaline granules

image

Fig 11.6 Photomicrograph of skin biopsy from a patient with ichthyosis vulgaris demonstrating compact orthokeratosis and reduced granular layer.

X-LINKED RECESSIVE ICHTHYOSIS

• Relatively common
• 1 in 2000–10,000
• Heterozygous females clinically unaffected

image rare reports of affected homozygous females

Genetics

• Steroid sulfatase (STS) gene

image Xp22.3

– > 90% due to complete deletion
– minority due to partial gene deletions or point mutations

Clinical features

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