Skin -Normal Skin -Normal Stratified Squamous epithelial

1
Skin -Normal
2
Skin -Normal

• Stratified Squamous epithelial cells
  (keratinocytes) production of keratin protein,
• Melanocytes production of a brown pigment
  (melanin)
• Langerhans cells take up and process antigens
• Neural end-organs and axonal processes
• Merkel cells
• within the basal cell layer
• mechanoreceptors or neuroendocrine function

3
Skin -Normal

• Sweat glands - temperature control
• Specialized dermal cells (dendrocytes) - for
  antigen presentation as well as for production of
  molecules (e.g., factor XIIIa)
• Hair follicle- harbor protected repositories of
  epithelial stem cells

4
Skin - Pathology

• DEFINITIONS OF MACROSCOPIC TERMS
• Macule
• Circumscribed lesion of up to 5 mm in diameter
  characterized by flatness and usually
  distinguished from surrounding skin by its
  coloration.
• Patch
• Circumscribed lesion of gt 5 mm in diameter
  characterized by flatness and usually
  distinguished from surrounding skin by its
  coloration.
• Papule
• Elevated dome-shaped or flat-topped lesion 5 mm
  or less across.
• Nodule
• Elevated lesion with spherical contour gt 5 mm
  across.

5
Skin - Pathology

• Plaque
• Elevated flat-topped lesion, usually gt 5 mm
  across (may be caused by coalescent papules).
• Vesicle
• Fluid-filled raised lesion 5 mm or less across.
• Bulla
• Fluid-filled raised lesion gt 5 mm across.
• Blister
• Common term used for vesicle or bulla.
• Pustule
• Discrete, pus-filled, raised lesion.
• Wheal
• Itchy, transient, elevated lesion with variable
  blanching and erythema formed as the result of
  dermal edema.

6
Skin - Pathology

• Scale
• Dry, horny, plaque like excrescence usually the
  result of imperfect cornification.
• Lichenification
• Thickened and rough skin characterized by
  prominent skin markings usually the result of
  repeated rubbing in susceptible persons.
• Excoriation
• Traumatic lesion characterized by breakage of the
  epidermis, causing a raw linear area (i.e., a
  deep scratch) often self-induced.
• Onycholysis
• Separation of nail plate from nail bed.

7
Skin - Pathology

• Hyperkeratosis
• Thickening of the stratum corneum, often
  qualitative abnormality of the keratin.
• Parakeratosis
• Modes of keratinization characterized by the
  retention of the nuclei in the stratum corneum.
• Hypergranulosis
• Hyperplasia of the stratum granulosum, often due
  to intense rubbing.
• Acanthosis
• Diffuse epidermal hyperplasia.
• Papillomatosis
• Surface elevation caused by hyperplasia and
  enlargement of contiguous dermal papillae.

8
Skin - Pathology

• Dyskeratosis
• Abnormal keratinization
• Acantholysis
• Loss of intercellular connections resulting in
  loss of cohesion between keratinocytes.
• Spongiosis
• Intercellular edema of the epidermis.
• Hydropic swelling (ballooning)
• Intracellular edema of keratinocytes, often seen
  in viral infections.
• Exocytosis
• Infiltration of the epidermis by inflammatory or
  circulating blood cells.
• Erosion
• Discontinuity of the skin exhibiting incomplete
  loss of the epidermis

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Skin - Pathology

• Ulceration
• Discontinuity of the skin exhibiting complete
  loss of the epidermis and often of portions of
  the dermis and even subcutaneous fat.
• Vacuolization
• Formation of vacuoles within or adjacent to
  cells often refers to basal cell-basement
  membrane zone area.
• Lentiginous
• Referring to a linear pattern of melanocyte
  proliferation within the epidermal basal cell
  layer. occur as a reactive change or as part of a
  neoplasm of melanocytes.

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Disorders of Pigmentation and Melanocytes

• 1.VITILIGO
• loss of pigment-producing melanocytes within the
  epidermis
• All ages and races, noticeable in darkly
  pigmented individuals
• Clinical lesions
• macules and patches of pigment loss
• Hands and wrists, axillae and perioral,
  periorbital, and ano-genital skin (Muco-cutaneous
  Jxns)
• Koebnerization (as in Lichen planus)- lesions at
  sites of repeated trauma
• Morphology.
• Loss of melanocytes revealed by electron
  microscopy
• IHC for melanocyte-associated proteins (e.g.,
  tyrosinase or Melan-A, or S-100

11
Disorders of Pigmentation and Melanocytes -
VITILIGO

• Pathogenesis.
• Theories
• 1) autoimmunity,
• 2) neurohumoral factors
• 3) self-destruction of melanocytes by toxic
  intermediates of melanin synthesis
• interesting facet of vitiligo -therapy with UVA
  with use of the photosensitizing drug, psoralen
  (known as PUVA)
• Regain pigment initially at the ostia of hair
  follicles,
• Other causes of Hypopigmentation
• 1.Postinflammatory hypopigmentation
• 2.Albinism
• melanocytes are present but melanin pigment is
  not produced
• lack or defect in Tyrosinase

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Disorders of Pigmentation and Melanocytes

• 2. FRECKLE (EPHELIS)
• MC pigmented lesions of childhood in lightly
  pigmented individuals
• after sun exposure
• Small (1 to several mm in diameter), tan-red or
  light brown macules cyclic fashion with winter
  and summer
• DD from a Lentigo, which maintains stable
  coloration independent of sun exposure.
• Clinically
• hyperpigmentation -result of increased amounts
  of melanin pigment within basal keratinocytes
• melanocytes are normal in slightly enlarged
• café au lait spots are histologically
  indistinguishable from freckles (evolve
  independent from sun exposure)

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Disorders of Pigmentation and Melanocytes

• 3.MELASMA
• mask-like zone of facial hyperpigmentation
• association with
• pregnancy "mask of pregnancy."
• oral contraceptives
• administration of Hydantoins,
• Idiopathic, resolves spontaneously
• poorly defined, blotchy, tan-brown macules and
  patches involving the cheeks, temples, and
  forehead bilaterally
• Sunlight -accentuate

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Disorders of Pigmentation and Melanocytes

• 4. LENTIGO (plural-lentigines)
• Hyperplasia of melanocytes often in infancy and
  childhood
• no sex or racial predilection
• Cause and pathogenesis - unknown.
• mucous membranes as well as the skin
• No change on exposure to sunlight.
• Essential histologic feature- hyperpigmented
  basal cell layer
• Elongation and thinning of the rete ridges
• variant - solar or actinic lentigo
• alteration in keratinocyte maturation in
  sun-damaged skin of older pts.
• Lentiginous -proliferation within the basal cell
  layer in melanocytic tumor
• Lentiginous nevi and melanomas (Acral lentiginous
  melanomas).

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Disorders of Pigmentation and Melanocytes

• 5.MELANOCYTIC NEVUS (PIGMENTED NEVUS, MOLE)
• (NEVI/ NEVUS benign lesion of the skin may be
  pigmented or nonpigmented, flat or raised, smooth
  or warty. May become malignant).
• tan to brown, uniformly pigmented, small (usually
  lt6 mm across), solid regions of relatively flat
  (macules) to elevated skin (papules) with
  well-defined, rounded borders
• Morphology.
• formed by melanocytes grow in aggregates, or
  "nests," along the dermoepidermal junction called
  junctional nevi ? grow into the underlying dermis
  as nests or cords of cells (compound nevi) ?older
  lesions - intradermal
• Maturation- correlates with enzymatic changes
  (progressive loss of tyrosinase activity and
  acquisition of cholinesterase activity
• sequence of maturation - diagnostic importance in
  distinguishing benign nevi from melanomas, which
  usually show little or no maturation
• Clinically, compound and dermal nevi are often
  more elevated than junctional nevi

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Disorders of Pigmentation and Melanocytes

• 6. DYSPLASTIC NEVI
• BK moles (initial two families studied)
• Clinically
• larger than most acquired nevi (often gt5 mm
  across)
• hundreds of lesions on the body surface
• flat macules, slightly raised plaques
• variability in pigmentation (variegation)
• borders that are irregular in contour
• occur on non-sun-exposed as well as on
  sun-exposed body surfaces
• in multiple members of families prone to the
  development of malignant melanoma (the heritable
  melanoma syndrome).
• autosomal dominant
• peculiar linear fibrosis surrounding the
  epidermal rete ridges

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Disorders of Pigmentation and Melanocytes

• DYSPLASTIC NEVI
• Cytologic atypia ,irregular, often angulated,
  nuclear contours and hyperchromasia
• sparse lymphocytic infiltrate, loss of melanin
  or melanin pigment incontinence
• single nevus cells replace the normal basal cell
  layer dermoepidermal junction, - lentiginous
  hyperplasia
• Precursors of malignant melanoma
• gt 5 of family members - melanoma
• probability of developing melanoma is 56 at age
  59 years
• Clark and associates
• steps? benign nevi ? aberrant differentiation ?
  dysplastic ? metastasizing malignant tumors

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7. MALIGNANT MELANOMA

• Skin, other sites (oral and anogenital mucosal
  surfaces, esophagus, meninges eye)
• Skin Mc site
• Non cutaneous UVEA of the eye
• Sunlight - important role
• Men - on upper back
• Women -both the back and legs
• Higher risk
• Carcinogens
• dysplastic nevus
• ( pre malignant ) gt 5 lt10mm
• hereditary factors
• Lightly pigmented individuals
• Clinical Features
• early feature itching ( itching moles bad)
• greater than 10 mm in diameter
• most important clinical sign -change in color,
  size, or shape in a pigmented lesion
• variations in pigmentation
• Borders not smooth, round, and uniform,
• If the size is more than 5mm follow

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MALIGNANT MELANOMA

• Clinical warning signs
• 1) enlargement of a pre-existing mole,
• 2) itching or pain in a pre-existing mole,
• 3) development of a new pigmented lesion during
  adult life,
• 4) irregularity of the borders of a pigmented
  lesion, and
• 5) variegation of color within a pigmented lesion
• Growth Patterns and Morphology
• radial and vertical growth (longitudinal growth
  into the epidermis, into blood vessels if more
  than 1.7mm thick. Radial or horizontal not
  important still limited to the dermis)
• vertical component of growth
• clinically
• nodule in the relatively flat radial growth phase
• emergence of a clone of cells with true
  metastatic potential ( moves from monoclonal to
  multiclonal )
• probability of metastasis predicted by simply
  measuring in millimeters the depth of invasion
  below the granular cell layer

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MALIGNANT MELANOMA

• Melanoma cells -
• larger than nevus cells
• large nuclei with irregular contours
• chromatin clumped at the periphery of the nuclear
  membrane
• large prominent red (eosinophilic) nucleoli
• nature and extent of the vertical growth phase
  determine the biologic behavior of malignant
  melanoma
• Diagnostic Criteria and Prognostic Attributes
• assessment of prognosis based on
• 1) measurement of tumor depth in millimeters
• 2) number of tumor cell mitoses per square
  millimeter in the microscope
• 3) evidence of an immune response to the
  superficial (radial) growth component (termed
  regression)
• 4) presence and degree of tumor infiltrating
  lymphocytes (TILs)
• 5) gender FEMALES GOOD
• (6) location

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MALIGNANT MELANOMA

• More favorable prognosis
• tumor depth of less than 1.7 mm, (more than 1.7mm
  bad prog.)
• absence or low numbers of mitoses,
• presence of a brisk TIL tumor infultrating
  lymphocytes response,
• absence of regression,
• female gender, and
• location on extremity skin
• Gray zone - melanocytic tumors of uncertain
  malignant potential (MELTUMP)

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Benign Epithelial Tumors

• Derived from
• keratinizing stratified squamous epithelium of
  the epidermis
• hair follicles (keratinocytes)
• ductular epithelium of cutaneous glands
• confused with malignancy,
• Biopsy required
• 1. SEBORRHEIC KERATOSES
• arise spontaneously, on the trunk
• Face- Dermatosis papulosa nigra
• Clinically - round, flat, coin like waxy plaques
• uniformly tan to dark brown
• "stuck on" appearance easily peeled off.
• small, round, pore like ostia impacted with
  keratin seen with a hand lens. (Differentiating
  between malignant melanomas)
• Part of paraneoplastic syndrome (Leser-Trélat
  sign)
• whorling" squamous cells resembling eddy currents
  in a stream

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2. ACANTHOSIS NIGRICANS

• Acanthosis proliferation hyperplasia of the
  stratum spinosum of the epidermis
• Hyperpigmented zones and "velvet-like" texture
• flexural areas
• cutaneous marker for associated benign and
  malignant conditions
• Benign type
• childhood or during puberty
• autosomal dominant
• with obesity or endocrine abnormalities (excess
  cortico steroids)
• pituitary and pineal tumors and with diabetes
• congenital syndromes
• Malignant type
• underlying GI adenocarcinoma.

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3. FIBROEPITHELIAL POLYP

• squamous papilloma, skin tag
• Most common cutaneous lesions, during pregnancy
• part of a syndrome called Birt-Hogg-Dubé syndrome.

4. EPITHELIAL CYST (WEN)

• Invagination and cystic expansion of epidermis or
  of the epithelium forming the hair follicle
• filled with keratin and lipid-containing debris
• Histologic types
• Epidermal inclusion cyst
• Pilar or trichilemmal cysts
• Dermoid cyst (air follicles) budding outward from
  its wall.
• steatocystoma multiplex -resembling the sebaceous
  gland duct

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ADNEXAL (APPENDAGE) TUMORS

• Mendelian patterns of inheritance multiple
  disfiguring
• Eccrine poroma on the palms and soles derived
  from eccrine sweat glands
• Cylindroma on the forehead and scalp
• hat like growth turban tumor
• Syringomas, lesions of eccrine differentiation
• multiple, small lower eyelids
• Trichoepitheliomas, - follicular differentiation
• Markers for internal malignancy (trichilemmomas
  and breast carcinoma of Cowden syndrome, also
  seen in familial polyposis coli) cells try to
  differentiate into hair follicles

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KERATOACANTHOMA

• sun-exposed skin of whites older than age 50
  years, facial skin
• mimic squamous cell carcinoma (mutations in the
  p53 gene)
• heal spontaneously, without treatment
• flesh-colored, dome-shaped nodules
• central, keratin-filled plug, imparting a
  crater-like topography
• NB squamous cell carcinomas usually develop at a
  site of chronic irritation

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Premalignant and Malignant Epidermal Tumors

• ACTINIC KERATOSIS chronic exposure to sunlight
  UVB ( sun light causes MCC in skin basal cell
  carcinoma, best prognosis ,squamous cell
  carcinoma, second best prognosis and malignant
  melanomas, worse prognosis chronic exposure to
  sunlight
• excess keratin in lightly pigmented individuals.
• ionizing radiation, hydrocarbons, and arsenicals
• less than 1 cm in diameter are tan-brown, red,
  or skin-colored
• sandpaper-like consistency
• dyskeratosis with pink or reddish cytoplasm
• Dermis shows thickened, blue-gray elastic fibers
  (elastosis),
• nuclei in stratum corneum (parakeratosis)
• intercellular bridges are present

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SQUAMOUS CELL CARCINOMA

• 2nd MC tumor arising on sun-exposed sites in
  older people,
• men gt women (Except for lesions on the lower
  legs)
• predisposing factors
• sunlight
• industrial carcinogens (tars and oils),
• chronic ulcers and
• draining osteomyelitis,
• old burn scars,
• ingestion of arsenicals,
• ionizing radiation,
• tobacco and betel nut chewing (in the oral
  cavity).

Basal cell Carcinoma pallisding peripheral
cell Perpendicular to rest
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SQUAMOUS CELL CARCINOMA

• exposure to UV light with subsequent DNA damage
• Immunosuppressed Drugs
• chemotherapy
• organ transplantation
• Xeroderma pigmentosum
• Sunlight has transient immunosuppressive effect
  on
• antigen-presenting Langerhans cells in the
  epidermis
• chemical agents- direct mutagenic effects by
  producing DNA adducts
• Morphology.
• less than 5 have metastases to regional nodes

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BASAL CELL CARCINOMA

• Common, slow-growing ,rarely metastasize
• sites subject to chronic sun exposure
• in lightly pigmented people
• Immunosuppression
• defects in DNA repair (e.g., Xeroderma
  pigmentosum
• pearly papules often containing prominent,
  dilated sub epidermal blood vessels
  (telangiectasias)
• unusually aggressive tumors- rodent ulcers
• resemble normal basal cell layer of the epidermis
• Two patterns
• multifocal growths originating from the epidermis
  
• nodular lesions growing downward deeply into the
  dermis
• islands of variably basophilic cells with
  hyperchromatic nuclei surrounded by many
  fibroblasts and lymphocytes
• cells forming the periphery arranged radially
  (pallisading)

31
Basal Cell Nevus Syndrome

• dominantly inherited
• numerous basal cell carcinomas in early life
• abnormalities of bone, nervous system, eyes, and
  reproductive organs

32
MERKEL CELL CARCINOMA

• Merkel cell of the epidermis (neural
  crest-derived cell)
• for tactile sensation in lower animals
• clinically
• ulcerated nodules
• cytokeratin 20 positive
• capable of metastasis and are potentially lethal
• Fast metastasizing bad prognosis but rare

33
MOLECULAR GENETICS OF SKIN CANCERS

• organ constantly exposed to environmental hazards
  most commonly affected by neoplasms
• Basal cell carcinoma is the most common invasive
  cancer in humans,
• 1 million estimated cases per year in the United
  States
• incidence of malignant melanoma risen almost
  exponentially
• hereditary cancer syndromes provided important
  insights of molecular pathogenesis of sporadic
  nonmelanoma skin tumors and melanomas
• basal cell nevus syndrome or Gorlin syndrome
• autosomal dominant
• multiple basal cell carcinomas - lt age 20
• other conditions
• tumors (especially Medulloblastoma a rapidly
  growing tumor usually of the vermis of the
  cerebellum, composed of preneurogliar cells and
  ovarian Fibroma),

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MOLECULAR GENETICS OF SKIN CANCERS

• pits of the palms and soles
• odontogenic keratocysts
• generalized overgrowth
• systemic manifestations
• intracranial calcification, cleft lip and palate,
  abnormal segmentation of the vertebra, and rib
  anomalies (bifid, fused, missing, splayed ribs)
• Gene for NBCCS chromosome 9 (PTCH) (nevoid basal
  cell carcinoma syndrome)
• "two-hit" hypothesis
• born with a germ-line mutation
• second mutation either by environmental mutagens
  or random genetic rearrangement
• PTCH mutations in 30 of sporadic basal cell
  carcinomas
• Link- sun exposure and defects in PTCH and p53
• one-third have mutations (C to T transitions)
• Mutations in p53 occur in 40 to 60-60 of these
  have UV signature
• mutations in PTCH and p53 in Xeroderma
  pigmentosum (90 and 40, bear the UV signature).

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MOLECULAR GENETICS OF SKIN CANCERS

• Squamous Cell Carcinoma
• no inherited single gene defect associated with
  squamous cell carcinomas
• mutations in p53 in Caucasian patients with
  actinic keratoses is high
• Sunlight-alterations at the early stages of
  carcinogenesis
• pyrimidine dimers
• Unlike basal cell carcinomas, aneuploidy (
  abnormal of chromosomes) is very common in
  squamous cell carcinomas, loss of heterozygosity
  of chromosomes 3, 9, and 17 occurs in
  approximately 30 of cases
• in severely immunosuppressed
• HPV types 5 and 8,
• pathogenesis of epidermodysplasia verruciformis
• formation of numerous cutaneous squamous cell
  carcinomas

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MOLECULAR GENETICS OF SKIN CANCERS

• Melanomas
• 10 to 15 arise in a familial setting
• familial melanoma syndrome (FMS)
• the familial BK mole syndrome
• have large numbers of dysplastic nevi
• is frequently deleted in melanomas
• main locus chromosome on 9p21and it encodes
  p16INK4A
• p16INK4A is the most commonly mutated gene in
  familial melanoma
• other genes CDK4 and BRAF

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Tumors of the Dermis

• BENIGN FIBROUS HISTIOCYTOMA (DERMATOFIBROMA)
• family of benign dermal neoplasms of fibroblasts
  and histiocytes.
• adults and
• legs of young to middle-aged women
• Morphology
• Most common form -dermatofibroma
• benign, spindle-shaped fibroblasts arranged in a
  well-defined, nonencapsulated mass within the
  mid-dermis
• overlying epidermal hyperplasia forms downward
  elongation of hyperpigmented rete ridges ("dirty
  fingers" pattern)
• express coagulation factor XIIIa

38
Tumors of the Dermis

• DERMATOFIBROSARCOMA PROTUBERANS
• primary Fibrosarcoma of the skin.
• slow growing, locally aggressive, rarely
  metastasize.
• Clinically firm, solid nodules ,most frequently
  on the trunk
• Morphology
• In contrast to dermatofibroma, the overlying
  epidermis is generally thinned
• extension from the dermis into subcutaneous fat
  (honeycomb" pattern)
• composed of fibroblasts arranged radially,
  reminiscent of blades of a pinwheel, a pattern
  referred to as storiform
• Mitoses not as numerous good prognosis

39
Tumors of the Dermis

• XANTHOMAS
• collections of foamy histiocytes within the
  dermis lipid filled
• Familial or acquired resulting in hyperlipidemia
• five types.
• Eruptive wax and wane according to variations in
  plasma triglyceride and lipid contents
• Tuberous and tendinous Achilles tendon extensor
  tendons of the fingers
• Plane with primary biliary cirrhosis
• Xanthelasma (without lipid abnormality) -eyelids.
  

40
Tumors of the Dermis

• DERMAL VASCULAR TUMORS
• Benign (capillary and cavernous hemangiomas),
• malformations (nevus flammeus or port-wine
  stain), gone with age 14 to15
• malignant vascular tumors (Angiosarcomas) bad
  prognosis seen in liver patients exposed to
  plastics
• angioproliferative lesions (Kaposi sarcoma HIV
  (tumor like- bacillary angiomatosis)

41
Tumors of Cellular Immigrants to the Skin

• Primary cutaneous disorders
• Epidermal Langerhans cells- Langerhans cell
  histiocytosis
• T lymphocytes -cutaneous T-cell lymphoma (CTCL),
  sezary syndrome
• Dermal mast cells Mastocytosis
• See table in WBC review

42
Tumors of Cellular Immigrants to the Skin

• LANGERHANS CELL HISTIOCYTOSIS
• Histiocytosis X, multiple forms
• histologic patterns
• First-dermal infiltrate of large, round to ovoid
  cells
• second pattern -that resemble granulomas
• Third-xanthoma-like cytoplasm
• IHC methods -CD1a antigen
• ultrastructural identification of specific
  organelles (Birbeck granules),

43
Tumors of Cellular Immigrants to the Skin

• MYCOSIS FUNGOIDES
• (CUTANEOUS T-CELL LYMPHOMA) ( seen in celiac
  sprue and HTLV)
• lymphoproliferative disorders affecting the skin
• Two different clinical types
• Mycosis fungoides, a chronic proliferative
  process
• Nodular eruptive variant, mycosis fungoides
  d'emblée
• Mycosis fungoides
• primarily in the skin and that may evolve into
  generalized lymphoma
• most commonly persons older than age 40.

44
Tumors of Cellular Immigrants to the Skin

• MYCOSIS FUNGOIDES
• (CUTANEOUS T-CELL LYMPHOMA)
• Clinically
• scaly, red-brown patches raised, scaling plaques
  that may even be confused with psoriasis
• Fungating nodules- Development of multiple
  red-brown nodules correlates with systemic
  spreading
• seeding of the blood by malignant T cells is
  accompanied by diffuse erythema and scaling of
  the entire body surface (erythroderma), a
  condition known as Sézary syndrome

45
Tumors of Cellular Immigrants to the Skin

• MYCOSIS FUNGOIDES
• (CUTANEOUS T-CELL LYMPHOMA)
• Morphology
• histological hallmark -Sézary-Lutzner cells they
  have cerebriform nuclei ie looks like brain
  (T-helper cells (CD4 positive) that
  characteristically form band like aggregates
  within the superficial dermis
• infolded nuclear membranes -hyperconvoluted or
  cerebriform contour
• (epidermotropism) and form clusters Pautrier
  microabscesses.

46
Tumors of Cellular Immigrants to the Skin

• MASTOCYTOSIS -? mast cells in the skin other
  organs
• Localized cutaneous form
• children and accounts for more than 50 of all
  cases is termed urticaria pigmentosa
• shortly after birth
• Systemic mastocytosis- 10
• adults
• prognosis may be poor
• Darier sign -localized area of dermal edema and
  erythema (wheal) that occurs when lesion skin is
  rubbed.
• Dermatographism -area of dermal edema resembling
  a hive that occurs in normal skin as a result of
  localized stroking with a pointed instrument
• Pathogenesis.-point mutation of the c-KIT
  proto-oncogene

47
Disorders of Epidermal Maturation

• ICHTHYOSIS
• Hyperkeratosis-fishlike scales
• around the time of birth
• ichthyosis vulgaris (autosomal dominant or
  acquired)
• congenital ichthyosiform erythroderma (autosomal
  recessive),
• lamellar ichthyosis (autosomal recessive),
• X-linked ichthyosis.
• Acquired (noninherited) -in adults
• Associated with lymphoid and visceral malignant
  neoplasms

48
ICHTHYOSIS

• Morphology
• compacted stratum corneum
• loss of the normal basket-weave pattern
• Pathogenesis
• primary abnormality -defective mechanisms of
  desquamation
• retention of abnormally formed scale
• adhesive organelles called Odland bodies, or
  membrane-coating granules

49
Acute Inflammatory Dermatoses

• 1. URTICARIA
• characterized by
• localized mast cell degranulation
• dermal microvascular hyperpermeability
• pruritic edematous plaques called wheals
• Angioedema-deeper edema of both the dermis and
  the subcutaneous fat
• develop and fade within hours (usually lt24 hours)
  or last for days or persist for months
• superficial perivenular infiltrate of
  mononuclear cells Eosinophils

50
URTICARIA

• Pathogenesis
• IgE-dependent degranulation can follow exposure
  to a number of antigens
• IgE-independent urticaria from substances
  directly incite the degranulation of mast cells
  (opiates, curare, and radiographic contrast
  media)
• Hereditary Angioneurotic edema- production of
  vasoactive mediators (complement-mediated
  urticaria). Deficiency complement 1 inhibitor

51

• 2. ACUTE ECZEMATOUS DERMATITIS
• Eczema
• Early lesion - red, papulovesicular less than
  5mm, oozing, and crusted
• Later - raised, scaling plaques
• acute spongiotic dermatitis
• chronic form - epidermal hyperplasia and
  excessive scale
• Clinical classification -allergic contact,
  atopic, drug-related, primary irritant
  photo-eczematous

52
. ACUTE ECZEMATOUS DERMATITIS

• Poison ivy- most obvious example is an acute
  contact reaction
• Edema
• in urticaria - localized to the perivascular
  spaces of the superficial dermis
• in spongiotic dermatitis - seeps into the
  intercellular spaces of the epidermis,
• Spongy like epidermis is due to prominent
  Intercellular bridges
• Intraepidermal vesicles are due to shearing of
  intercellular attachment sites (desmosomes) and
  cell membranes

53
ACUTE ECZEMATOUS DERMATITIS

• The pattern and composition of infiltrate give
  clues to the underlying cause
• systemic antigens (drugs) -lymphocytic
  infiltrate, eosinophils, and extending deep as
  well as superficial dermal vessels
• surface contact with antigens -affects the more
  superficial dermal layer

54

• 3. ERYTHEMA MULTIFORME
• hypersensitivity reaction to certain infections
  and drugs
• Infections-typhoid, and leprosy, herpes simplex,
  mycoplasmal infections, histoplasmosis
• drugs (sulfonamides, penicillin, barbiturates
• collagen vascular diseases (SLE, PAN,
  dermatomyositis,).
• malignant disease (carcinomas and lymphomas

55
3. ERYTHEMA MULTIFORME

• "multiform" lesions, including macules, papules,
  vesicles, and bullae
• symmetric involvement of the extremities
• extensive and
• toxic epidermal necrolysis -clinical situation
  analogous to an extensive burn like a 3rd degree
  burn
• Stevens-Johnson syndrome seen in children
• symptomatic febrile form of the disease, result
  in life-threatening sepsis ( sulfonamide use kids
  causes) derm. Emergency
• The target lesion exhibits central necrosis
  surrounded by a rim of perivenular inflammation.
• immunologic similarities
• fixed drug eruptions
• GVHD
• skin allograft rejection

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Chronic Inflammatory Dermatoses

• 1. PSORIASIS
• 1 to 2 of people in the United States
• associated with arthritis, myopathy, enteropathy,
  spondylitic joint disease, or the acquired
  immunodeficiency syndrome
• Clinically
• skin of the elbows, knees, scalp, lumbosacral
  areas, intergluteal cleft, and glans penis.
• Most typical lesion - salmon-colored plaque
  covered by adherent scales (silver-white in color
  )
• Erythroderma-total body erythema
• Nail changes- separation of the nail plate from
  the underlying bed (onycholysis), thickening, and
  crumbling
• pustular psoriasis-rare variant most dangerous
• generalized and life-threatening

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2. SEBORRHEIC DERMATITIS

• More common than psoriasis
• Regions with a high density of sebaceous glands,
  (scalp, forehead (especially the glabella),
  external auditory canal, retroauricular area,
  nasolabial folds)
• Not a disease of the sebaceous glands
• Macules and papules with extensive scaling and
  crusting
• Fissures- behind the ears
• Dandruff is the common
• Infants-presents as cradle cap
• also be part of Leiner disease (with diarrhea and
  failure to thrive)
• severe and refeactory in HIV patients

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2. SEBORRHEIC DERMATITIS

• Features
• both spongiotic dermatitis and psoriasis
• parakeratosis containing neutrophils and serum
  are present at the ostia of hair follicles
  (so-called follicular lipping)
• HIV-apoptotic keratinocytes and plasma cells
• Etiology is unknown
• yeast Malassezia furfur with tinea versicolor
  play a pivotal role (Rx.ketoconazole)
• sebum is also involved
• patients with Parkinsonism show increased sebum
  production increased incidence of seborrheic
  dermatitis

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3.LICHEN PLANUS

• "Pruritic, purple, polygonal papules"
• of the skin and mucous membranes
• self-limiting resolves spontaneously 1 to 2
  years after onset
• in chronic mucosal and para -mucosal
  lesions-Malignant degeneration
• zones of postinflammatory hyperpigmentation
• Wickham striae -papules are highlighted by white
  dots or lines
• zones of hypergranulosis
• loss of melanin pigmentation into the dermis as
  the basal cell layer is destroyed

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3.LICHEN PLANUS

• Multiple, symmetrically distributed on wrists and
  elbows glans
• 70 of cases, oral lesions are white, or netlike
  areas
• Koebner phenomenon
• infiltrate of lymphocytes along the
  dermoepidermal junction - angulated zigzag
  contour (saw- toothing) ,
• basal keratinocytes resemble of the stratum
  spinosum (squamatization) also seen in vetaligo
• Anucleate, necrotic basal cells inflamed
  papillary dermis
• colloid or Civatte bodies (also in any chronic
  dermatitis)
• epithelium of hair follicles is referred to as
  lichen planopilaris.
• pathogenesis -not known
• cell-mediated immune reactions

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4. LUPUS ERYTHEMATOSUS

• SLE
• systemic manifestations,
• localized, cutaneous form -discoid lupus
  erythematosus (DLE).
• discoid lupus erythematosus (DLE).
• poorly defined malar erythema or erythematous
  scaling plaques
• develop or worsen with sun exposure
• keratotic plugs in follicular ostia
• lateral compression often produces wrinkling, a
  sign of epidermal atrophy
• lymphocytes along the dermoepidermal or the
  dermal-follicular epithelial junction
• Deep perivascular and periappendageal (e.g.,
  around sweat glands) infiltrates

Band test
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4. LUPUS ERYTHEMATOSUS

• infiltration of subcutaneous fat is called lupus
  profundus.
• basal cell layer -diffuse vacuolization
• epidermal layer -atrophied, with loss of the
  normal rete ridge pattern
• Involved hair follicles -epithelial atrophy,
  dilated and plugged with keratin
• Periodic acid-Schiff (PAS) -marked thickening of
  the epidermal basement membrane zone
• direct immunofluorescence - characteristic
  granular band of immunoglobulin and complement
  along the dermoepidermal and dermal-follicular
  junctions ( lupus band test)
• both lesional and normal skin in many cases of
  SLE
• seen in lesional skin but not normal skin in DLE
• Both formation and deposition of immune complexes
  and complement components C5b to C9 -humoral
  mechanisms of injury
• In DLE band test positive only in affected skin
  SLE both affected and normal skin

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Blistering (Bullous) Diseases

• 1.PEMPHIGUS
• autoimmune blistering disorder resulting from
  loss of the integrity of normal intercellular
  attachments within the epidermis and mucosal
  epithelium
• life-threatening
• fourth to sixth decades of life
• 1) Pemphigus vulgaris -MC type (more than 80)
• mucosa and skin, especially on the scalp, face,
  axilla, groin, trunk,
• (2) Pemphigus vegetans -rare (groin, axillae, and
  flexural surfaces)
• presents not with blisters but with large, moist,
  verrucous (wartlike), vegetating plaques,
• (3) Pemphigus foliaceus -more benign form,
  epidemic form in South America
• (4) Pemphigus erythematosus rare, groin,
  axillae, and flexural surfaces
• face in a lupus erythematosus-like fashion.
• localized, less severe form of pemphigus foliaceus

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1.PEMPHIGUS

• In all forms
• Acantholysis-dissolution, or lysis, of the
  intercellular adhesion sites within a squamous
  epithelial surface
• Blister
• P. vulgaris - suprabasal acantholytic bliste
• P. foliaceus -selectively involves the
  superficial epidermis at the level of the stratum
  granulosum
• Sera-antibodies (IgG) to intercellular cement
  substance of skin and mucous membranes
• Basis for direct and indirect diagnostic
  immunofluorescence testing of skin and serum,
  respectively
• P. vulgaris antibody reacts with desmoglein 3
• P.foliaceus antibody reacts with desmoglein 1

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2. BULLOUS PEMPHIGOID

• common autoimmune, vesiculobullous disease
• elderly
• less often
• involvement of mucosal surfaces
• bullae do not rupture as easily
• inner aspects of the thighs, flexor surfaces of
  the forearms, axillae, groin, and lower abdomen
• heal without scarring
• subepidermal, nonacantholytic blister
• Eosinophils showing degranulation
• beneath the epidermal basal cell layer.
• vacuolated basal cell layer

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2. BULLOUS PEMPHIGOID

• subepidermal, nonacantholytic blister
• Eosinophils showing degranulation
• beneath the epidermal basal cell layer.
• vacuolated basal cell layer
• antibodies directed against proteins at the
  dermal-epidermal junction.
• linear zone deposition of immunoglobulin and
  complement
• lupus erythematosus is similar, but granular
• circulating antibody reacts with antigen
• (hemidesmosomes)
• Degranulating eosinophils are often associated
  with necrosis of basal keratinocytes

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3.DERMATITIS HERPETIFORMIS

• papules, vesicles, and occasional bullae on an
  erythematous, often urticarial base
• Malesgt Females
• third and fourth decades
• with celiac disease (both enteropathy respond to
  a diet free of gluten)
• plaques and vesicles are extremely pruritic
• bilaterally and symmetrically
• extensor surfaces, elbows, knees, upper back, and
  buttocks grouped, name herpetiformis
• early lesions
• Fibrin and neutrophils
• tips of dermal papillae, forming small
  microabscesses subepidermal blister
• Eosinophils of older lesions (creating confusion
  with bullous pemphigoid)

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3.DERMATITIS HERPETIFORMIS

• immunofluorescence
• granular deposits of IgA selectively localized in
  the tips of dermal papillae
• antibodies against gliadin, reticulin (IgA and
  IgG )
• HLA-B8 and HLA-DRw3- prone

69
Immunofluorescence
pemphigus vulgaris
Bullous pemphigoid
Dermatitis herpetiformis
lupus band test
70
4. NONINFLAMMATORY BLISTERING DISEASES
EPIDERMOLYSIS BULLOSA, PORPHYRIA

• vesicles and bullae are not mediated by
  inflammatory mechanisms.
• Epidermolysis bullosa
• group of disorders with blisters at sites of
  pressure, rubbing, or trauma, at or soon after
  birth
• Simplex type
• degeneration of the basal cell layer of the
  epidermis
• mutations in the genes encoding keratins 14 and 5
• Junctional type
• blisters in normal skin at lamina lucida
• scarring dystrophic types, blisters
• beneath the lamina densa,
• inherited disease
• mutations in the COL 7A1 gene that encodes type
  VII collagen

71
NONINFLAMMATORY BLISTERING DISEASES
EPIDERMOLYSIS BULLOSA, PORPHYRIA

• Porphyria
• inborn or acquired disturbances of porphyrin
  metabolism
• Classification based on clinical and biochemical
  features
• five major types
• Cutaneous
• urticaria and vesicles that heal with scarring
• exacerbated by exposure to sunlight
• subepidermal vesicle
• marked thickening of the walls of superficial
  dermal vessels

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Disorders of Epidermal Appendages

• ACNE VULGARIS
• middle to years late teenage males have more
  severe disease
• milder in Asian descent
• in adolescents result of physiologic hormonal
  variations and alterations in hair follicle
  maturation
• induced or exacerbated by drugs
• occupational contactants
• Some families
• heavy clothing and tropical climates
• noninflammatory and inflammatory types
• without a visible central plug
• Open comedones
• central black keratin plug
• oxidation of melanin pigment (not dirt)
• Closed comedones
• open and closed comedones

73
ACNE VULGARIS

• Four key components
• changes in keratinization of follicular
  infundibulum
• increase in size of sebaceous glands with puberty
  or increased activity
• lipase-synthesizing bacteria (Propionibacterium
  acnes)
• induction of inflammation in the follicle
• Dermal abscesses with scarring
• Pathogenesis is incompletely understood
• Endocrine (especially androgens)
• bacterial lipases of Propionibacterium acnes
• resulting in the earliest inflammatory phases
• clinical improvement with synthetic vitamin A
  derivative 13-cis-retinoic acid (isotretinoin)

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Panniculitis

• ERYTHEMA NODOSUM MCC ERYTHEMA
• INDURATUM
• Panniculitis
• inflammatory reaction in the subcutaneous fat
• Erythema nodosum
• the most common form of panniculitis
• acute presentation in infections (beta-hemolytic
  streptococcal infection, tuberculosis and, less
  commonly, coccidioidomycosis, histoplasmosis, and
  leprosy
• drug (sulfonamides, oral contraceptives),
  sarcoidosis, inflammatory bowel disease)
• malignant neoplasms
• lower legs
• erythematous plaques and nodules
• better felt than seen
• Biopsy usually required

75
Panniculitis

• Erythema induratum
• uncommon type of panniculitis
• adolescents and menopausal women
• cause is not known
• primary vasculitis affecting deep vessels
• most commonly occurs without an associated
  underlying disease.
• Erythema nodosum
• Vasculitis is not present
• erythema induratum,
• necrotizing vasculitis
• granulomatous inflammation and zones of caseous
  necrosis
• Weber-Christian disease (relapsing febrile
  nodular panniculitis) is a rare form of lobular,
  nonvasculitic panniculitis seen in children and
  adults
• Factitial panniculitis caused by self-inflicted
  trauma or injection of foreign or toxic substances

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Infection and Infestation

• 1. VERRUCAE (WARTS)
• common lesions of children and adolescents
• caused by HPV, self-limited, regressing
  spontaneously
• Classification
• Verruca vulgaris is the most common type of wart
• hands, dorsal surfaces and periungual areas
• Verruca plana, or flat wart- face or the dorsal
• hands
• Verruca plantaris and verruca palmaris -soles and
  palms
• Condyloma acuminatum (venereal wart) occurs on
  the penis, female genitalia, urethra, perianal
  areas, and rectum
• cytoplasmic vacuolization (koilocytosis)
• verrucous or papillomatous epidermal hyperplasia

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2. MOLLUSCUM CONTAGIOSUM

• common, self-limited viral disease of the skin
  caused by a poxvirus
• brick shaped,
• largest pathogenic poxvirus in humans
• largest viruses in nature
• children and young adults
• trunk and anogenital areas
• Firm, pruritic, pink to skin-colored umbilicated
  papules
• curd-like material on staining with Giemsa show
  diagnostic molluscum bodies
• cytoplasmic inclusion in cells of the stratum
  granulosum and the stratum corneum
• virions are present within molluscum bodies.

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3. IMPETIGO

• Common superficial bacterial infection of the
  skin
• Highly contagious - healthy children, adults in
  poor health
• impetigo contagiosa and impetigo bullosa (differ
  in size of the pustules)
• Staphylococcus aureus
• Face and hands
• Honey-colored crust.
• characteristic microscopic features
• accumulation of neutrophils beneath the stratum
  corneum
• Sub-corneal pustule
• Blister formation - due to bacterial production
  of a toxin specifically cleaves the desmoglein 1
  cell-to-cell adhesion within the uppermost
  epidermis

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4. SUPERFICIAL FUNGAL INFECTIONS

• confined to the stratum corneum
• caused primarily by dermatophytes
• organisms grow in the soil and on animals
• Tinea capitis usually occurs in children
• Scalp-asymptomatic, often hairless patches of
  skin
• erythema, crust formation, and scale
• Tinea barbae - uncommon disorder beard area of
  adult men
• Tinea corporis - common superficial fungal
  infection of children affecting body surface

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4. SUPERFICIAL FUNGAL INFECTIONS

• Tinea cruris - inguinal areas of obese men during
  warm weather
• Tinea pedis (athlete's foot) affects 30 to 40
  of the population
• diffuse erythema and scaling of web spaces
• Spread to nails- onychomycosis.
• Tinea versicolor - upper trunk
• Caused by Malassezia furfur, a yeast
• present in cornified layer of lesional skin,
  hair, or nails
• scraping - produce colonies
• Fungal cell walls, rich in MPS, stain bright pink
  to red with PAS stain

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5 . ARTHROPOD BITES, STINGS, AND INFESTATIONS

• Arachnida (spiders, scorpions, ticks, and mites),
  Insecta (lice, bedbugs, bees, wasps, fleas,
  flies, and mosquitoes), and Chilopoda
  (centipedes)
• Vectors for secondary invaders, such as viruses,
  bacteria, rickettsiae, and parasites
• Black widow spider venom -severe cramps and
  excruciating pain
• Brown recluse spider venom - enzymes that produce
  tissue necrosis