Pathology (skin pigmented, benign epi)
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What are the most common pigmented lesions of childhood in lightly pigmented individuals
What are the clinical features of freckles?
- Small , tan-red or light brown macules that appear after sun exposure.
- Fade and darken in a cyclic fashion during winter and summer, respectively.
- This is not because of changes in the number of melanocytes, but in the degree of pigmentation.
What are the histological features of freckles?
- 1) Hyperpigmentation of freckles results from increased amounts of melanin pigment within basal keratinocytes2) Melanocytes may be slightly enlarged but are normal in density.
- 3) The freckle represents: (1) a focal abnormality in pigment production by a discrete field of melanocytes, (2) enhanced pigment donation to adjacent basal keratinocytes, or (3) both.
What is the difference between freckles and Cafe au Lait spot?
The café au lait spots seen in neurofibromatosis are histologically indistinguishable from freckles, but the former evolve independently from sun exposure and can contain aggregated melanosomes (macromelanosomes) within the cytoplasm of melanocytes
What is lentigo?
benign localized hyperplasia of melanocytes
What are the clinical features of lentigo?
- may involve mucous membranes as well as the skin, and consist of small (5–10 mm across), oval, tan-brown macules or patches.
- Unlike freckles, lentigines do not darken when exposed to sunlight
What is the histological hallmarks of lentigo?
- linear (non-nested) melanocytic hyperplasia restricted to the cell layer immediately above the basement membrane that produces a hyperpigmented basal cell layer
- Elongation and thinning of the rete ridges
What are the clinical features of ordinary melanocytic nevus?
acquired melanocytic nevi are tan to brown, uniformly pigmented, small (usually <6 mm across), solid regions of relatively flat (macules) to elevated skin (papules) with well-defined, rounded borders
What are the five types of nevi in addition to ordinary nevus?
- Congenital nevus (cytology like ordinary)
- Blue nevus
- Spindle and epithelioid cell nevus (Spitz nevus)
- Halo nevus (cytology like ordinary)
- Dysplastic nevus
What are the features of congenital nevus?
- Deep dermal and sometimes subcutaneous growth around adnexa, neurovascular bundles, and blood vessel walls
- Identical to ordinary acquired nevi
- Present at birth; large variants have increased melanoma risk
What are the features of blue nevus?
- Non-nested dermal infiltration, often with associated fibrosis
- Highly dendritic, heavily pigmented nevus cells
- Black-blue nodule; often confused with melanoma clinically
What are the features of spitz nevus?
- Fascicular growth
- Large, plump cells with pink-blue cytoplasm; fusiform cells
- Common in children; red-pink nodule; often confused with hemangioma clinically
What are the features of halo nevus?
- Lymphocytic infiltration surrounding nevus cells
- Identical to ordinary acquired nevi
- Host immune response against nevus cells and surrounding normal melanocytes
What are the features of dysplastic nevus?
- Coalescent intraepidermal nests
- Cytologic atypia
- Potential marker or precursor of melanoma
What are the three stages of nevus growth?
- The earliest lesions are believed to be junctional nevi, which consist of aggregates or nests of round cells that grow along the DEJ. Eventually, most junctional nevi grow into the underlying dermis as nests or cords of cells to form compound nevi. In older lesions the epidermal nests may be lost entirely to form pure intradermal nevi. Clinically, compound and dermal nevi are often more elevated than junctional nevi.
What is nevus maturation?
- Whereas superficial nevus cells are larger, tend to produce melanin, and grow in nests, deeper nevus cells are smaller, produce little or no pigment, and appear as cords and single cells.
- The most “mature” nevus cells may be found at the deepest extent of lesions, where they often acquire fusiform contours and grow in fascicles resembling neural tissue (neurotization ). This striking metamorphosis correlates with enzymatic changes (progressive loss of tyrosinase activity and acquisition of cholinesterase activity in deeper, nonpigmented, nervelike nevus cells).
What is the importance of nevus maturation?
This sequence of maturation of individual nevus cells is of diagnostic importance in distinguishing some benign nevi from melanomas, which usually show little or no maturation
Why nevi are considered neoplasms?
They have acquired mutations in either BRAF or NRAS (both involved in RAS/BRAF pathway)
What does BRAF encode?
a serine/threonine kinase that is a positive mediator of RAS signals
Given that RAS lies in a potent transforming signaling pathway, then why nevi only rarely give rise to malignant melanomas?
- Oncogene-induced senescence.
- Expression of either activated RAS or BRAF in normal human melanocytes causes only a limited period of proliferation that is followed by a permanent growth arrest mediated by the accumulation of p16/INK4a, a potent inhibitor of several cyclin-dependent kinases, including CDK4 and CDK6
What is the relation of dysplastic nevus to melanoma?
Both marker and less commonly a precursor particularly in familial cases
What are the clinical features of dysplastic nevus?
- 1) Dysplastic nevi are larger than most acquired nevi (often >5 mm across) and may number in the hundreds in those with the dysplastic nevus syndorme .
- 2) They are flat macules, slightly raised plaques with a “pebbly” surface, or target-like lesions with a darker raised center and irregular flat periphery.
- 3) They can be recognized by their size, variability in pigmentation (variegation) and irregular borders. 4) Unlike ordinary moles, dysplastic nevi occur on both sun-exposed and protected body surfaces.
What are the histological features of dysplastic nevus?
- Usually compoundArchitectural and cytologic atypia.
- Nevus cell nests within the epidermis may be enlarged and often fuse or coalescence with adjacent nests.
- As part of this process, single nevus cells begin to replace the normal basal cell layer along the dermoepidermal junction, producing lentiginous hyperplasia.
- Associated alterations in the superficial dermis include lymphocytic infiltrates (usually sparse); release of melanin from dead nevus cells into the dermis (melanin incontinence), where it is phagocytosed by dermal macrophages; and a peculiar linear fibrosis surrounding the epidermal rete ridges that are involved by the nevus.
What is the first potential step in progression from dysplastic nevus to melanoma?
Lentiginous melanocytic hyperplasia
What is the genetic of dysplastic nevus?
- AD--> CDKN2A and CDK4
- Also like mole-->BRAF, NRAS
What are the clinical features of melanoma?
1) Usually asymptomatic, although itching or pain may be early manifestations.
4) (1) asymmetry; (2) irregular borders; and (3) variegatedcolor. Other features of pigmented lesions that should raise concern are a diameter greater than 6 mm, any change in appearance, and new onset of itching or pain.
- 2) The majority of lesions are greater than 10 mm in diameter at diagnosis. The most consistent clinical signs are changes in the color, size, or shape of a pigmented lesion.
- 3) The borders of melanomas are irregular and often notched, not smooth, round, and uniform as in melanocytic nevi.
- FIGURE 25-8 Melanoma. A, Typically, lesions are irregular in contour and pigmentation. Macular areas correlate with the radial growth phase, while raised areas usually correspond to nodular aggregates of malignant cells in the vertical phase of growth. B, Radial growth phase, showing irregular nested and single-cell growth of melanoma cells within the epidermis and an underlying inflammatory response within the dermis. C, Vertical growth phase, demonstrating nodular aggregates of infiltrating cells. D, High-power view of melanoma cells. The inset shows a sentinel lymph node with a tiny cluster of melanoma cells (arrow) staining for the melanocytic marker HMB-45. Even small numbers of malignant cells in a draining lymph node may confer a worse prognosis.
What is radial growth phase in melanoma?
- Radial growth describes the horizontal spread of melanoma within the epidermis and superficial dermis.
- During this initial stage the tumor cells seem to lack the capacity to metastasize.
- Tumors in radial growth phase fall into several clinicopathologic classes, including: lentigo maligna, usually presenting as an indolent lesion on the face of older men that may remain in the radial growth phase for several decades; superficial spreading, the most common type of melanoma, usually involving sun-exposed skin; and acral/mucosal lentiginous melanoma that is unrelated to sun exposure.
What is vertical growth phase in melanoma?
- After a variable (and unpredictable) period of time, melanoma shifts from the radial phase to a vertical growth phase, during which the tumor cells invade downward into the deeper dermal layers as an expansile mass .
- The vertical growth phase is often heralded by the appearance of a nodule and correlates with the emergence of a clone of cells with metastatic potential.
- Unlike melanocytic nevi, maturation is absent from the deep invasive portion of melanoma.
The probability of metastasis in melanoma correlates with what feature?
the depth of invasion, which by convention is the distance from the superficial epidermal granular cell layer to the deepest intradermal tumor cells; this measurement is known as the Breslow thickness
What are the features of neoplastic cells in melanoma?
- Individual melanoma cells are usually considerably larger than normal melanocytes or cells found in melanocytic nevi.
- They contain large nuclei with irregular contours, chromatin that is characteristically clumped at the periphery of the nuclear membrane, and prominent red (eosinophilic) nucleoli
What are the prognostic factors for melanoma?
- (1) tumor depth (the Breslow thickness); (2) number of mitoses; (3) evidence of tumor regression (presumably due to the host immune response); (4) the presence and number of tumor infiltrating lymphocytes (TILs); (5) gender; and (6) location (central body or extremity).
- Determinants of a more favorable prognosis in this model include tumor depth of less than 1.7 mm, no or very few mitoses, a brisk TIL response, absence of regression, female gender, and location on an extremity
- Tumor thickness and presence or absence of ulceration had prognostic significance independent of clinical stage.
- Also LN involvement even micrometastasis
What are the two most important risk factors for melanoma?
inherited genes and sun exposure
What is the mc location for melanoma?
- sun-exposed surfaces, particularly the upper back in men and the back and legs in women
- More common in white
What kind of sun exposure is the most important RF for melanoma?
severe sunburns early in life are the most important risk factor
What are the two genetic pathways associated with melanoma?
- 1) Mutations that diminish the activity of the retinoblastoma (RB) tumor suppressor
- 2) aberrant increases in RAS and PI-3K/AKT signaling
What is the major mutation that affect RB pathway in melanoma?
- CDKN2A is a complex locus that encodes three different tumor suppressors, p15/INK4b, p16/INK4a, and p14/ARF. Of these, loss of p16/INK4a is clearly implicated in human melanoma, and experimental evidence also strongly supports a role for loss of p14/ARF.
- p16/INK4a enhances the activity of tumor suppressor proteins of the RB family by inhibiting cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6)
- p14/ARF enhances the activity of the p53 tumor suppressor by inhibiting the activity of the MDM2 oncoprotein.
- P16/INK4a is involved in up to 70% of melanoma
What are the mutations that involve RAS and PI-3K/AKT signaling in melanoma?
- Activating mutations in BRAF, which encodes a serine/threonine kinase that is downstream of RAS, are seen in 60% to 70% of melanomas, while activating mutations in NRAS (which is upstream of BRAF) occur in additional 10% to 15% of tumors.
- Melanomas arising in non-sun exposed sites are much more likely to have activating mutations in the c-KIT receptor tyrosine kinase, which sits upstream of both RAS and PI-3K/AKT, than in NRAS or BRAF.
- PTEN, a tumor suppressor that acts by downregulating PI-3K/AKT signaling, is epigenetically silenced in another 20% of melanomas
Where do we see multiple trichilemmomas?
Cowden syndrome (PTEN mutation)
What are the clinical features of seborrheic keratosis?
- Middle-aged or older individuals.
- Particularly numerous on the trunk
- In people of color, multiple small lesions on the face are termed dermatosis papulosa nigra.
- Seborrheic keratoses characteristically appear as round, flat, coin-like, waxy plaques that vary in diameter. They are uniformly tan to dark brown and usually have a velvety to granular surface.
- Inspection with a hand lens usually reveals small, round, porelike ostia impacted with keratin, a feature helpful in differentiating these pigmented lesions from melanomas.
How can one differentiate between SK and melanoma?
Inspection with a hand lens usually reveals small, round, porelike ostia impacted with keratin, a feature helpful in differentiating these pigmented lesions from melanomas.
What is the histological feature of SK?
- Exophytic and sharply demarcated from the adjacent epidermis.
- They are composed of sheets of small cells that most resemble basal cells of the normal epidermis.
- Variable melanin pigmentation is present within these basaloid cells, accounting for the brown coloration.
- Exuberant keratin production (hyperkeratosis) occurs at the surface, and small keratin-filled cysts (horn cysts) and invaginations of keratin into the main mass (invagination cysts) are characteristic features.
- Interestingly, when seborrheic keratoses become irritated and inflamed, they develop whirling foci of squamous differentiation resembling eddy currents in a stream.
What is the genetic change in SK?
Activating mutations in FGFR3
When are rapid eruption of multiple SK seen?
GI adenocarcinoma (TGF-alpha)
What is acanthosis nigricans?
thickened, hyperpigmented skin with a “velvet-like” texture
What are the types of AN?
- The benign type, which constitutes about 80% of all cases, develops gradually and usually occurs in childhood or during puberty. It may occur (1) as an autosomal dominant trait with variable penetrance (FGFR3), (2) in association with obesity or endocrine abnormalities (particularly with pituitary or pineal tumors and diabetes), and (3) as part of several rare congenital syndromes.
- As with seborrheic keratoses, acanthosis nigricans sometimes occurs as a paraneoplastic process resulting from the production of growth factors by a variety of tumors. The malignant type refers to lesions arising in middle-aged and older individuals in association with underlying cancers, most commonly gastrointestinal adenocarcinomas.
What are the two paraneoplastic lesion in the skin associated with GI adenocarcinoma?
AN and SK
What is the histology of AN?
- The epidermis and underlying enlarged dermal papillae undulate sharply to form numerous repeating peaks and valleys.
- Variable hyperplasia may be seen, along with hyperkeratosis and slight basal cell layer hyperpigmentation (but no melanocytic hyperplasia).
What are the three skin lesions that increase with pregnancy and hence are hormone sensitive?
Fibroepithelial polyps (skin tag), melanocytic nevi and hemangioma
What are the clinical characteristics of fibroepithelial polyps?
The fibroepithelial polyp (acrochordon, squamous papilloma, skin tag) seen in middle-aged and older individuals on the neck, trunk, face, and intertriginous areas as a soft, flesh-colored, bag-like tumor often attached to the surrounding skin by a slender stalk.
What is the histology of fibroepithelial polyp?
- fibrovascular cores covered by benign squamous epithelium
- May undergo torsion and necrosis
What are the clinical features of epidermal cysts?
- Formed by the invagination and cystic expansion of the epidermis or a hair follicle.
- Filled with keratin and lipid-containing debris derived from sebaceous secretions.
- Dermal or subcutaneous, well-circumscribed, firm, and often moveable nodules.
What are the types of epidermal cysts?
- 1) The epidermal inclusion cyst has a wall resembling normal epidermis and is filled with laminated strands of keratin.
- 2) Pilar or trichilemmal cysts have a wall that resembles follicular epithelium, without a granular cell layer and filled by a more homogeneous mixture of keratin and lipid.
- 3)Dermoid cyst is similar to the epidermal inclusion cyst, but also contains multiple appendages (such as small hair follicles) budding outward from its wall.
simplex is a cyst with a wall resembling the sebaceous gland duct, and from which numerous compressed sebaceous lobules originate. Has heritable nature (steatocystoma multiplex), which can be caused by missense mutations in the gene encoding keratin 17
What are cylindroma?
- Cylindroma, an appendage tumor with ductal (apocrine or eccrine) differentiation, usually occurs on the forehead and scalp where coalescence of nodules with time may produce a hat-like growth, hence the name turban tumor.
- If AD--> tumor suppressor gene CYLD, which encodes a deubiquitinating enzyme that regulates NF-κB and the cell cycle
- Islands of cells resembling those of the normal epidermal or adnexal basal cell layer (basaloid cells). These islands fit together like pieces of a jigsaw puzzle within a fibrous dermal matrix
What are syringoma?
Syringomas, lesions with eccrine differentiation, usually occur as multiple, small, tan papules in the vicinity of the lower eyelids
What is sebaceous adenoma?
- Sebaceous adenomas can be associated with internal malignancy in the Muir-Torre syndrome, a subset of the hereditary nonpolyposis colorectal carcinoma syndrome associated with germline deficits in DNA mismatch repair proteins
- Lobular proliferation of sebocytes with increased peripheral basaloid cells and more mature sebocytes in the central portion, characterized by frothy or bubbly cytoplasm due to lipid vesicle content
What is the major genetic defect in Pilomatricomas?
- Follicular differentiation, are associated with activating mutations in CTNNB1, the gene encoding β-catenin.
- WNT signaling through β-catenin is critical for early hair development and regulates the hair cycle
............is a proliferation of basaloid cells that forms primitive structures resembling hair follicles
...................are composed of basaloid cells that show trichilemmal or hairlike differentiation similar to that seen in the germinal portion of the normal hair bulb in the anagen growth
What is the distinguishing feature of apocrine carcinoma?
- Apocrine carcinoma shows ductal differentiation with prominent decapitation secretion similar to that seen in the normal apocrine gland.
- The infiltrative growth pattern is a hint of malignancy in this otherwise well-differentiated tumor.
- More common than benign counterpart
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