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What are the RF for actinic keratosis?
- Sun exposure (more in white)
- ionizing radiation, industrial hydrocarbons and arsenicals
What are the clinical features of actinic keratosis?
- Actinic keratoses are usually less than 1 cm in diameter; are tan-brown, red, or skin-colored; and have a rough, sandpaper-like consistency.
- Some lesions may produce so much keratin that a “cutaneous horn” develops
- Sun-exposed sites (face, arms, dorsum of hands)
What are the histologic characteristics of actinic keratosis?
- Cytologic atypia in the lowermost layers of the epidermis and may be associated with hyperplasia of basal cells or, with atrophy that results in thinning of the epidermis.
- The atypical basal cells usually have pink or reddish cytoplasm due to dyskeratosis.
- Intercellular bridges are present, in contrast to BCC.
- The superficial dermis contains thickened, blue-gray elastic fibers (elastosis), a probable result of abnormal elastic fiber synthesis by sun-damaged fibroblasts.
- The stratum corneum is thickened, and unlike normal skin, the cells in this layer often retain their nuclei (parakeratosis).
What is the mechanism of imiquimod in treatment of actinic keratosis?
It activates the innate immune system through stimulation of Toll-like receptors (TLRs)
What is the epidemiological features of SCC?
- sun-exposed sites in older people
- M>F expect for lower legs
What are the histological features of SCC?
- Those not invaded through the basement membrane of the dermoepidermal junction (CIS) appear as sharply defined, red, scaling plaques. More advanced, invasive lesions are nodular, show variable keratin production (hyperkeratotic scale), and may ulcerate
- Unlike actinic keratoses, in squamous cell carcinoma in situ, cells with atypical (enlarged and hyperchromatic) nuclei involve all levels of the epidermis.
- IHC for keratin
What are the features of keratoacanthoma?
- After a period of rapid growth, it usually regresses spontaneously.
- Grossly, it is a symmetric cup-shaped tumor with a central depression filled with keratin debris.
- Histologically, the tumor is composed of lobules of squamous cells with glassy cytoplasm that undergo kertinization without an intervening granular layer.
- Once established, keratoacanthomas elicit a brisk lymphocytic and eosinophilic host response.
The most important cause of cutaneous squamous cell carcinoma is ........................................
DNA damage induced by exposure to UV light
SCC incidence is proportional to ..............
the degree of lifetime sun exposure.
What is the second most important RF for skin SCC?
How can chronic immunosuppression cause SCC of the skin?
reducing host surveillance and increasing the susceptibility of keratinocytes to infection and transformation by oncogenic viruses, particularly human papilloma virus (HPV) subtypes 5 and 8
Which HPV infection is related to skin SCC?
How does sunlight cause SCC?
- DNA damage
- Decreased function of Langerhans cells
What are other RF for SCC of skin?
- industrial carcinogens (tars and oils),
- chronic ulcers and draining osteomyelitis,
- old burn scars,
- ingestion of arsenicals,
- ionizing radiation,
- and (in the oral cavity) tobacco and betel nut chewing
What is the earliest genetic defect in SCC and AK?
P53 (mainly pyrimidine dimer)
Why are patients with xeroderma pigmentosum more susceptible to squamous cell carcinoma?
This disorder is caused by inherited mutations in genes in the nucleotide excision repair pathway, which is required for accurate repair of pyrimidine dimers; when this pathway is defective, error-prone repair pathways take over, leading to the rapid accumulation of mutations and eventual carcinogenesis
What is the mc invasive cancer in human?
What is the epidemiology of BCC?
- Upper part of face (SCC lower lip)
- These are slow-growing tumors that rarely metastasize. They have a tendency to occur at sun-exposed sites and in lightly pigmented people. As with squamous cell carcinoma, the incidence of basal cell carcinoma rises sharply with immunosuppression and in people with inherited defects in DNA repair such as xeroderma pigmentosum
What is the major clinical presentation of BCC?
- Pearly papules often containing prominent, dilated subepidermal blood vessels (telangiectasias) Advanced lesions may ulcerate, and extensive local invasion of bone or facial sinuses may occur after many years of neglect or in unusually aggressive tumors, ( rodent ulcers)
What is the variant of BCC that resemble melanoma?
The superficial basal cell carcinoma, presents as an erythematous, occasionally pigmented plaque that may resemble early forms of melanoma
What is the histology of BCC?
- Tumor cells resemble those in the normal basal cell layer of the epidermis.
- They arise from the epidermis or follicular epithelium and do not occur on mucosal surfaces.
- Two patterns are seen: multifocal growths originating from the epidermis and sometimes extending over several square centimeters or more of skin surface (multifocal superficial type) and nodular lesions growing downward deeply into the dermis as cords and islands of variably basophilic cells with hyperchromatic nuclei, embedded in a mucinous matrix, and often surrounded by many fibroblasts and lymphocytes.
- The cells at the periphery of the tumor cell islands tend to be arranged radially with their long axes in parallel alignment (palisading).
- In sections, the stroma retracts away from the carcinoma, creating clefts or separation artifacts that assist in differentiating basal cell carcinomas from certain appendage tumors that are also characterized by proliferation of basaloid cells, such as trichoepithelioma.
What are the features of nevoid BCC syndrome?
- AD, 9q, PTCH
- Multiple BCC
- <20 years
- medulloblastomas and ovarian fibromas), odontogenic keratocysts, and pits of the palms and soles
- intracranial calcification, cleft lip and palate, rib and vertebra abnormality
- germline mutation in one of the PTCH alleles (second hit)
What are some familial disorders associated with skin involvement?
- Ataxia-telangiectasia: AR,11q, DNA repair after radiation injury/neurologic and vascular lesions
- Nevoid basal cell carcinoma syndrome ,AD, 9q PTCH, Developmental patterning gene/multiple basal cell carcinomas; jaw cysts, etc.
- Cowden syndrome: AD 10q, PTEN, Lipid phosphatase/benign follicular appendage tumors (trichilemmomas); internal adenocarcinoma (often breast)
- Familial melanoma syndrome: AD, 9p, CDKN2/p16/INK4Inhibits CDK phosphorylation of RB, promoting cell cycle arrest/melanoma; pancreatic carcinoma| CDKN2/p14/ARFBinds MDM2, promoting p53 function/melanoma; pancreatic carcinoma
- Muir-Torre syndrome: AD, 2p, MSH2/MLH1 Involved in DNA mismatch repair/sebaceous neoplasia; internal malignancy (colon and others)
- Neurofibromatosis I: AD, 17q, NF1/neurofibromin, Negatively regulates RAS signaling/neurofibromas
- Neurofibromatosis II: AD, 22q NF2/merlin, Integrates cytoskeletal signaling/ neurofibromas and acoustic neuromas
- Tuberous sclerosis: AD 9q, TSC1/hamartin, 16p TSC2/tuberin, Work together in a complex that negatively regulates mTOR/angiofibromas/mental retardation
- Xeroderma pigmentosum: AR, 9q, Nucleotide excision repair/melanoma and nonmelanoma skin cancers
How does PTCH mutation cause BCC?
- The PTCH gene encodes a receptor for the protein product of the sonic hedgehog gene (SHH), a member of the hedgehog (HH) family of genes that determine polarity during embryonic development.
- The pathway is also involved in hair follicle formation and the hair cycle in skin.
- The PTCH protein forms a receptor complex with another transmembrane protein, known as SMO.
- In the absence of its ligand, SHH, PTCH inactivates SMO and sequesters it from transducing a down-stream signal.
- Binding of SHH to PTCH (or inactivating mutation of PTCH) releases the suppression of SMO, causing the up-regulation of hedgehog target genes through a signal cascade that involves the GLI1 transcription factor.
What are the genetic defects in BCC?
(C➙T transitions) that are considered hallmarks of UV damage in P53, PTCH
What are the features of BENIGN FIBROUS HISTIOCYTOMA (DERMATOFIBROMA)?
- Papules on Legs
- Dimple inward on lateral compression (Nodular melanoma protrude)
- benign, spindle-shaped cells arranged in a well-defined, nonencapsulated mass within the mid-dermis
- overlying epidermal hyperplasia, characterized by downward elongation of hyperpigmented rete ridges (a pseudo-epitheliomatous pattern).
- Tendency of fibroblasts to surround individual collagen bundles
What are the features of DERMATOFIBROSARCOMA PROTUBERANS?
- well-differentiated, primary fibrosarcoma of the skin
- locally aggressive
- Nodules on trunk
- fibroblasts arranged radially, reminiscent of blades of a pinwheel, a pattern referred to as storiformoverlying epidermis in thinned
- Balanced translocation of COL1A1 promoter sequences and the coding region of PDGFβ Treat with surgery or imatinib
What are the clinical features of mycosis fungoides?
- Scaly, red-brown patches; raised, scaling plaques and fungating nodules.
- Prognosis is related to the percentage of body surface involved and progression from patch to plaque to nodular forms.
- Eczema-like lesions typify early stages of disease when obvious visceral or nodal spread has not occurred. Development of multiple, large nodules correlates with systemic spread.
- 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
What are the molecular features of T cells in mycosis fungoides?
The neoplastic cells are targeted to the skin by expression of CLA and often express aberrant cell surface antigens as well as clonal T-cell receptor gene rearrangements
What is the histology of MF?
- The histologic hallmark of CTCL of the mycosis fungoides type is the presence of the Sézary-Lutzner cells. These are T-helper cells (CD4+) that characteristically form band-like aggregates within the superficial dermis and invade the epidermis as single cells and small clusters (Pautrier microabscesses). These cells have markedly infolded nuclear membranes, imparting a hyperconvoluted or cerebriform contour.
- More advanced lesions (nodular) show less epidermotropism
What are the three types of mastocytosis?
- 1)urticaria pigmentosa--> mc , children, multiple nonscaling papules and plaques
- 2) mastocytoma--> nodule, after birth
- 3)systemtic--> adult, poor prognosis, like UP+LN, liver, spleen, BM involvement
What are the clinical features of mastocytosis?
- Darier sign refers to a localized area of dermal edema and erythema (wheal) that occurs when lesion skin is rubbed.
- Dermatographism refers to an area of dermal edema resembling a hive that occurs in normal skin as a result of localized stroking with a pointed instrument.
- In systemic disease, all of the following may be seen: pruritus and flushing triggered by certain foods, temperature changes, alcohol, and certain drugs (morphine, codeine, aspirin); watery nasal discharge (rhinorrhea); rarely, gastrointestinal or nasal bleeding, possibly due to the anticoagulant effects of heparin; and bone pain as a result of osteoblastic and osteoclastic involvement.
How is mastocytosis histologically diagnosed?
- metachromatic stains (toluidine blue or Giemsa)
- IHC for tryptase
What is the pathogenesis of mastocytosis?
activating point mutations in the c-KIT receptor tyrosine kinase
What is the role of AT?
DNA repair after radiation injury
Which inherited syndromes with cutaneous manifestations are inherited AR?
Which inherited syndromes with cutaneous manifestations are inherited AD?
TS, NF, Nevoid BCC (PTCH), Cowden, Familial melanoma (P14, P16), Muir-Torre (MSH2/MLH1)
What is the involved gene in Cowden syndrome?
- PTEN Lipid phosphatase
- Involved in trichilemmoma and breast adenocarcinoma
What is the genetic of Familial melanoma syndrome?
- Pancreatic cancer and melanoma
- CDKN2/p16/INK4: Inhibits CDK phosphorylation of RB, promoting cell cycle arrest
- CDKN2/p14/ARF: Binds MDM2, promoting p53 function
What is the genetic of NF?
- I: 17q: NF1: neurofibromin: Negatively regulates RAS signaling
- II: 22q: NF2: merlin: Integrates cytoskeletal signaling
What are the features of ichthyosis?
- If congenital appear at birth
- If acquired may be associated with malignancy
- MC vulgaris (AD)
- Due to fillagrin abnormality
- compacted stratum corneum that is associated with loss of the normal basket-weave pattern
What is the problem in XL ichthyosis?
X-linked ichthyosis, affected individuals have a deficiency of steroid sulfatase, an enzyme important for the removal of proadhesive cholesterol sulfate secreted into the intercellular spaces. Accumulation of cholesterol sulfate results in persistent cell-to-cell adhesion within the stratum corneum, hindering the desquamation process.