Robbins: Chapter 25 Review Flashcards
Melanocytes are derived from ____ and migrate during embryogenesis to selected ______ sites (skin/CNS), but also eyes and ears.
NC cells
Ectodermal sites (skin/CNS) + eyes + ears
Freckles histology
Hyperpigmentation: ↑↑↑ production of melanin by basal keratinocytes
Disorders of pigmentation and melanocytes
- Freckles
- Lentigo (Lentigines)
- Nevi
- Melanoma
Benign Epithelial Tumors
- Seborrheic keratoses
- Acanthosis nigricans
- Fibroepithelial polyp
- Epithelial Inclusion Cyst
Adnexal Appendage Tumors
- Eccrine poroma
- Cylindroma
- Syringoma
- Sebaceous adenoma
- Pilomatricoma
Premalignant and malignant epidermal tumors
- Actinic keratoses
- Squamous cell carcinoma
- Basal cell carcinoma
Tumors of dermis
- Dermatofibroma (Benign fibrous histiocytoma)
2. DFSP (dermatofibrosarcoma protuberans)
Tumors of cellular migrants of skin (proliferative disorders of cells that arise everywhere, but home to skin)
- Mycosis Fungoides (Cutaneous T-cell lymphoma)
2. Mastocytosis (Uticaria pigmentosa)
Disorders of epidermal maturation
Ichythosis
Acute Inflammatory Dermatitis:
- Uticaria (Hives)/Wheals
- Acute eczematous dermatitis
- Erythema multiforme
- Psoriasis
- Seborrheic Dermatitis
- Lichen planus
Linear (non-nested) hyperplasia of hyperpigmented melanocytes in the basal layer of the epidermis
Lentigo (lentigines): hyperpigmentation is NOT due to sunlight
Melanocytic/ pigmented nevi aka “Mole” are more often acquired or congenital?
Acquired.
Mutations in acquired melanocytic nevi
- RAS signaling (most are due to activating mutations in RAS signaling): BRAF or NRAS
- Loss of CDKN2A (encodes p16/INK4a) => CDK4 activation
Types of acquired melanocytic nevi (moles)
- Junctional nevi (flat macule)
- Compound nevi (elevated papule)
- Intradermal nevi (elevated papule)
Specific histological findings in compound nevi
- Pseudohorn cyst
2. No inflammatory response
Spitz nevus
aka spindle/epitheloid nevus
Red-pink nodule, often confused hemangioma
Large, plump fusiform cells with pink-blue cytoplasm that undergo fasicular growth.
Blue Nevus
Painful black-blue nodules, often confused with melanoma
Non-nests in dermis
Highly dendritic
Very pigmented
Undergo fibrosis
What is a potential marker/ precursor of melanoma
Dysplastic nevus
Also: congenital nevus
What do dysplastic nevus look like
- Flat macules/ slightly raised plaques with variable pigmentation and irregular borders
- Larger than acquired and can be hundreds
Dysplastic nevus mutations
Same as melanocytic nevus
+ TERT
Do all melanomas begin as dysplastic nevus and vise verse
If multiple => ↑↑↑ risk of melanoma. However, majority do NOT become melanomas and not all melanomas are first dystplastic nevi.
Dysplastic nevus syndrome?
Dysplastic nevus syndrome: AD => multiple dysplastic nevi and melanoma at many sites: >50% of getting melanoma by 60 YO
Histology of Dysplastic nevus
- Large and coalesced (fused) intraepidermal nests of melanocytes
- Cytologic atypia = irregularly shaped, dark staining nuclei.
- Lentiginous melanocyte hyperplasia: replacement of basal layer along DE junction
- Underlying dermis undergoes lamellar fibrosis.
Most deadly of all skin cancers
Melanoma
Marker and stain for melanoma
S100
HMB-45 (+)
Are most melanomas acquired or sporadic
sporadic due to UV damage
MC mutated gene in melanoma
TERT => activates telomerase
Driver mutations for melanoma
- Mutations that cause cell cycle to lose control:
CDKN2A mutation encodes CDK-I
(p16/ INK4a) and decreases Rb - Mutations that ↑↑↑ [RAS & PI3K/AKT] proliferation pathway:
- BRAF activating mutation (40-50%
melanomas);
- NRAS activating mutation (15-
20%) - TERT activating mutation: activates telomerase = seen in 70% of
tumors (most
common mutated
gene!!)
How do melanomas grow and which phase can metastatis occur?
Radial: spread along epidermis; do NOT metastasize
Vertical: Melanocytes lacking maturation (no neurotinzation) invade dermis => nodular melanoma (WORST type) that can metastasize
Types of Radial growing melanoma. Which has the best prognosis?
1) Superficial spreading = MC subtype (75% of melanomas) due to sunlight.
2) Lentigo maligna = Hutchinsons freckle (small, flat, dark spots) confined to epidermis that continue to grow slowlyyy. MC on face of older men. BEST prognosis
3) Acral/ mucosal lentiginous = MC type in dark-skinned patients (AZNs & AA) that grow on genitals*, palms, soles and under nails. C-kit mutation
Melanoma is associated with what disorder?
Xeroderma pigmentosum
RF for melanoma
- Sun exposure
- Dysplastic nevi (1/3 of melanomas arise from dysplastic nevi)
- Light skin, hair and eyes
- Hx of blistering, proximity to equator, indoor occupation, outdoor hobby
- FH of melanoma
Where are melanomas MC located?
Sun-exposed areas:
- BANL: Back, arms, neck and legs
- Females = back and legs
- Males = upper back
What determines the risk of a melanoma metastasizing?
↑↑↑ depth of thickness = ↑↑↑ risk of metastasis (Breslow thickness) =
distance from granular epidermis to the
deepest intradermal layer.
______ are inherently immunogenic, eliciting a T-cell response
Melanomas.
Melanomas metastasize to…
Regional LN (sentinel LN)
Favorable prognosis of melanoma
- Thinner depth of tumor (Breslow
thickness) , - No mitosis (<1 mm),
- Brisk response of lymphocytes that infiltrate tumor
- NO tumor
- Regression
- NO ulceration
- No metastasis to sentinel LN
Poor prognosis of melanoma
- Sore that doesn’t heal
- Spread of pigment from border into surrounding skin
- Redn/ swelling @ border
- Itchiness/pain/ oozing
Histology of melanoma
- Nests and single atypical melanocytes at the dermal-epidermal junction.
- Run on feet nests: nests merge
- Large cells with expanded, irregular nuclei + peripherally clumped chromatin + prominent eosinophilic nucleoli
- Mononuclear inflammatory infiltrate: because inherently immunogenic
- Stain with HMB-45
Seborrheic Keratoses
Proliferation of immature keratinocytes that arise spontaneously on the trunk
MC in older people >50
Seborrheic Keratoses can arise as a paraneoplastic syndrome due to..
Leser- Trelat sign (HY): paraneoplastic syndrome associated with gastric adenocarcinoma, causing “explosive” onset of multiple itchy seborrheic keratoses lesions
Seborrheic Keratoses gross morphology
waxy, tan-brown flat plaques (raise, but flat) that “stuck on lk a coin” and itchy.
can scrape off
Seborrheic Keratoses histology
- Dark cells, similar to basal skin cells
- Horn cysts =keratin-filled cysts
- Invagination cysts = invaginations of keratin into the main mass
- NL dermis
What is Acanthosis Nigricans
Diffuse epidermal hyperplasia due to stratum spinosum
Is AN benign or malignant?
can be BOTH
Benign = childhood or puberty
Malignant = middle-age or older
Can be benign or malignant:
80% = Benign
• Acquired or inherited
20% = AN is a paraneoplastic syndrome associated with with malignancy (GI carcinoma)
how can you acquire a benign AN?
(obesity, DB, pineal/pituitary tumor) or inherited (AD)
AN histology
- Epidermal and dermal papillae undulate sharply to form many peaks and valleys
- Hyperkeratosis with prominent rete ridges and basal hyperpigmentation (W/O melanocyte hyperplasia)
Fibroepitelial polyp is also called what?
skin tag, acrochrodon, squamous papilla
Epithelial inclusion cyst is also called what?
What is it?
Complication
wen” or “sebaceous cyst”
Invagination and cystic expansion of epidermis or a hair follicle
Traumatic rupture can spill keratin into dermis, leading to painful granulomatous inflammation
Syringoma
MC where
What are they?
Histology?
- MC = lower eyelid
- Multiple, small tan papule near lower eyelid
- BAsaloid epithelium with eccrine differentiation
Actinic Keratosis
Proliferation of atypical keratinocytes in the epidermis due to UV radiation => premalignant skin lesion
RF for actinic keratosis
- Light skin
- Ionizing radiation
- Hydrocarbons
- Arsenic
Gross morphology of actinic keratosis
- <1cm tan/brown/red skin colored papule or plaques that feel like sand paper
- Cutaneous horns
Histology of actinic keratosis
- Hyperkeratosis
- Parakaratosis: keratin with retained nuclei in stratum corneum
- Dyskeratosis (ABNL premature keratinization in cells below stratum granulosum) => pink cytoplasm
- Cytologic atypia of keratinocytes in basal layer: enlarged and hyperchromatic nuclei
- Intracellular bridges
- INTACT BM
Dermis
- Thick dermis
- Solar elastosis = blue-gray elastic fibers (collagen) in superficial dermis due to sun damage
Squamous cell carcinoma
MC in and genetics
> 75YO M (rare before 45 YO)
- TP53 mutations * (especially in actinic keratosis in whites) DNA damaged caused by UV is NOT repaired
- Xeroderma pigmentosum = AR inherited mutation of nucleotide excision repair pathway, needed to repair pyrimidine dimers => ↑↑↑ risk of cutaneous SCC and BCC
- Epidermodysplasia verruciformis: AD disorder assx with ↑↑↑ susceptibility to HPV and cutaneous SCC
Epidermodysplasia verruciformis: AD disorder assx with ↑↑↑ susceptibility to
HPV
cutaneous SCC
Xeroderma pigmentosum = AR inherited mutation of nucleotide excision repair pathway, needed to repair pyrimidine dimers => ↑↑↑ risk of
SCC and BCC
Melanoma
RF for SCC
- BIGGEST = Lifetime exposure to sun ***
- Chronic immunosuppression (chemo or organ transplant): increase risk of infection by HPV 5/8
- Chronic skin inflammation (burns, chronic ulcers, draining sinus tracts)
- Arsenic exposure
Do SCC metastasize/invade often?
5% metastasize to regional N; RARELY metastasize beyond LN.
If invasive, they are usually found when small and resectable :)
Gross morphology of SCC
In-situ (no post dermoepidermoid junction): Red, scaly plaques with sharp borders
Invasive (more advanced): Nodular, hyperkeratotic and may ulcerate/undergo necrosis
Histology of SCC
In-situ lesion:
• Keratinocytes in ALL of epidermis has cytologic atypia (enlarged and hyperchromic nuclei)
Invasive lesion • Diff amounts of hyperkeratosis • Dyskeratosis (single-cell keratinization) • Infiltrate BM • Highly anaplastic
How do SCC differ from actinic keratosis?
Cytologic atypia (enlarged and hyperchromic nuclei) is seen in ALL levels of epidermis
MC skin cancer BUT LOWEST potential for recurrence or metastasis
Basal Cell carcinoma: Slow growing, locally aggressive skin cancer that RARELY metastasizes, often in sun-exposed areas.
Basal cell carcinoma
Genetics
- LOF PTCH mutation on Chr 9q22.3: PTCH associates with SMO transmembrane protein forming a receptor for SHH. W/o PTCH, SMO (+) without SHH binding constitutive (+) of GLI1 uncontrolled SHH signaling
BCC is associated with what disorders?
- Xeroderma pigmentosum
2. NBCCS (Nevoid BCC syndrome) /Gorlin syndrome / Basal Cell Nevus Syndrome: AD LOF mutation of PTCH on Chr 9q22 => A. many BCC in pts < 20YO + B. Medulloblastomas C. + ovarian fibromas D. + odontogenic keratocysts E. + pits of palms and soles
Clinical presentation of BCC
How do they present if aggressive?
- Pearly papules with telangiectasias (dilated BV in dermis)
2 If aggressive => Rodent Ulcer= may ulcerate and extend into bone or facial sinuses
Histology of BCC
- Nests of basaloid dark cells that extend into dermis surrounded by clear halo (artifact)
- Hyperchromatic nuclei
- Palisading nuclei: cells at periphery of nests whose nuclei line up in parallel.
What is a Dermatofibroma (Benign fibrous histiocytoma)
Benign tumor of fibroblasts + histiocytes (Factor 13a -positive dendritic cells) in dermis that most commonly occurs after trauma, suggesting ABNL injury and inflammation response.
Dermatofibroma (Benign fibrous histiocytoma) is MC in who
young/middle aged F
Dermatofibroma presentation
Tender, asymptomatic firm, tan brown papule MC on LEGS
Dimple sign: lateral pressure causes dimpling
Dermatofibroma histology
- Well-defined non encapsulated mass made up of benign spindle-shaped fibroblasts in mid-dermis
- Overlying epidermal hyperplasia
- Pseudoepthielium hyperplasia: hyper pigmented elongated rete ridges
DFSP mutation
Translocation of collagen 1A1 (COL1A1) and PDGFB ↑↑↑ secretion of PDGF-B tumor grows via autocrine loop
DFSP presenation
trunk
Firm (indurated) plaque that can ulcerate
slow growing
locally aggressive
RARELY metastasizes
DFSP histology
- Storiform pattern of fibroblasts = fibroblasts arranged in pinwheel
- Honeycomb appearance: = extends into SUBQ fat
Osteoporosis in a pre-menopausal W or M is a clue of dx of what?
Mastocytosis (urticaria pigmentosa)
Signs of Uticaria pigmentosa1
- Darrier Sign => when rub=> produces area of dermal edema and erythema (wheal)
- Dermatographism
- If systemic = purititis and flushing triggered by food, temp changed and alcohol
What is ichythosis
Inherited defect in epidermal maturation (defective desquamation => inc cell-cell adhesion) => hyperkeratosis and kids are born with fish-like scales
Ichythosis could be a paraneoplastic syndrome d/t
lymphoid or visceral malignancy
Histology of ichythosis
- Buildup and compaction of statum corneum
2. No inflammation
Acute inflammatory dermatitis disorders
- Uticaria (hives)/wheals
- Acute eczematous dermatitis
- Erythema Multiforme
Charactersitsics of Acute inflammatory dermatitis disorders
- Days - weeks
- Inflammatory infiltrates (usually lymphocytes and MO, rather than neutrophils
- Edema
- Different degrees of epidermal, vascular or subQ injury
Histology of Uticaria/hives
- Superficial perivenular infiltration of mononuclear cells and MO sparsely infiltrate superficial perivenular
- Collagen bundles are more widely spaced apart due to edema
- Dermal edema (angioedema)
Lasts only a few hours
what type of HS reaction is Acute eczematous dermatitis
Type 4 hypersensitivity reaction that is T-cell mediated
Morphology of rash in Acute eczematous dermatitis
red, papulovesicular rash (blistering) that oozes and crusts
If persists => reactive acanthises and hyperkeratosis => red, scaly plaque
Histology of Acute eczematous dermatitis
- Spongiosis => intracellular edema in epidermis, particular in stratum spinosum
- Intracellular bridges = desmosomes that are pulled apart due to edema (spongiosis)
- If spongiosis is severe enough acantholysis
Erythema Multiforme histology
- Interface dermatitis = lymphocytes along DE junction
2. Degenerating and necrotic keratinocytes
Psoriasis histology
- Acanthosis = epidermal thickening Elongation of rete ridges (test-tubes in rack)
- Papillomatosis
- Parakeratotic scaling
- Stratum spinosum = inc size
- Stratum granulosum = thin/absent
- Neutrophils superficial dermis. If go to the stratum corner => Munro microabscesses
Psoriasis is MC in who
HLA-C; (HLA Cw*0602)
Seborrheic Dermatitis
histology
- Spongiotic dermatitis = edema
- Acanthosis
- Mounds of parakeratosis + acute inflammatory cells at ostia hair follicles.
Lichen Planus
associated with =
histology =
- HepC
- Acanthosis = saw-tooth pattern of rete ridges
- Hyperkeratosis
- Hypergranulosis
- Lymphocytes at D-E junction
Lichen planus in oral mucosa can evolve into what
SCC
Lichen planus is MC where
MC= ankle and wrists
*Self-limited: goes away 1-2 years after onset, but leaves a post-inflammatory hyperpigmentation. Oral lesions, however can persist for years
Wickham straie = white dots/lines caused by Hypergranulosis that is best seen on oral lesions is MC in what
lichen planus
