Midterm Flashcards
(612 cards)
1
Q
Where are melanocytes found
A
Epidermis
2
Q
T cells expressing what home back to the dermis?
A
CCR and CCR10
3
Q
What do the efferent nerve fibers do on the skin
A
Sweating, control erector pili mm
4
Q
What is excoriation
A
Traumatic lesions breaking epidermis an causing a raw linear area (often self induced like a scratch)
5
Q
What is lichenification
A
Thickened, rough skin; usually resulting from chronic Rubbing
6
Q
What is a macule or patch
A
Circumscribed, flat lesion distinguished from skin by color; maccules are 5 mm or less; patches >5mm
7
Q
What is onycholysis
A
Separation of nail plate from nail bed
8
Q
What are papules or nodules
A
Elevated dome shaped or flat topped lesion; papules <5mm nodules >5mm
9
Q
What are plaques
A
Elevated flat topped lesion
10
Q
What are pustules
A
Discrete pus filled raised lesion
11
Q
What are scales
A
Dry horny platelike excrescences
12
Q
What are vesicles, bulla, blisters
A
Fluid filled raised lesion 5mm or less (vesicle) or greater than 5mm (bulla); blister is common term for either
13
Q
What is a wheal
A
Itchy transient elevated lesion with variable blanching and erythema formed s result fo dermal edema
14
Q
What is acanthosis
A
Diffuse epidermal hyperplasia
15
Q
What is dyskeratosis
A
Abnormal premature keritnization within cells below stratum granulosum
16
Q
What are erosions
A
Discontinuity of the skin showing incomplete loss of epidermis
17
Q
What is exocytosis
A
Infiltration of epidermis by inflammatory cells
18
Q
What is hydropic swelling (ballooning)
A
Intracellular edema of keratinocytes; often seen in viral infections
19
Q
What is hypergranulosis
A
Hyperplasia of stratum granulosum; often due to intense rubbing
20
Q
What is hyperkeratosis
A
Thickening of stratum cornermen
21
Q
What is lentiginous
A
Linear pattern of melanocytes proflieration within epidermal basal cell layer
22
Q
What is papillomatosis
A
Surface elevation caused by hyperplasia and enlargement of contiguous dermal papillae
23
Q
What is parakeratosis
A
Keratinization with retained nuclei in stratum Corneum; normal on mucous membranes
24
Q
What is spongiosis
A
Intracellular edema of epidermis
25
What is ulceration
Discontinuity of skin showing complete loss of piper is revealing debris or subcutis
26
What is vacuolization
Formation of vacuoles within or adjacent to cells
27
What is ephelis
Freckle; most common pigmented lesions of childhood in light individuals
28
How do cafe au lait spots differ from freckles
Larger, arise independently of sun exposure and contain aggregated melanosomes (macromlanosomes)
29
What is lentigo
Benign hyperplasia of melanocytes often in infancy and childhood; no sex or racial predilection; do not darken when exposed to light; histo* linear melanocytic hyperplasia, elongation and thinning of rete ridges
30
What is melanocytic nevi
Moles; acquired activating mutations in RAS pathway;
31
What are the different forms of melanocytic nevi
- congenital: deep dermal growth around adnexa, NV bundles, and bv walls; present at birth; large variants have increased melanoma risk
- blue: non-nested dermal infiltration with assoc fibrosis; highly dendritic; black-blue nodule often confused with melanoma
- spindle (spitz): fascicular gwoth; pink-blue cytoplasm and fusiform cells; common in children; red-pink nodule often confused with hemangioma
- halo: lymphocytic infiltration surround nevus;
- dysplastic: coalescing intraepidermal nests; potential marker or precursor of melanoma
32
What is the progression of morphological changes of melanocytic nevi
-earliest lesions are junctional nevi (aggregates or nests of round cells that grow along dermoepidermal junction)
-then grow into underlying dermis to form compound nevi
-in older lesions, epidermal nests are lost to form pure i trader always nevi
At deepest extent, grow in fascicles and resemble neural tissue (neurotinization) important to distinguish from melanoma
33
What are dysplastic nevus syndromes
AD; tendency to develop multiple dysplastic nevi and melanoma
34
What mutations do people with dysplastic nevi syndromes have
RAS/BRAF in addition to CDKN2A
35
What is the morphology of dysplastic nevi
Larger than most acquired nevi; pebbly surface or target like lesions with darker aided center and irregular flat periphery; variability in pigmentation (variegation); occur in both supposed and protected body surfaces (unlike moles); involve dermis and epidermis; nevus nest cells can fuse with adjacent nests; produces lentiginous hyperplasia; release of melanin from dead nevus cells (melanin incontinence)
36
What are the most frequent diver mutations in melanoma
- CDKN2A: encodes for p15/INK4b, p16/INK4a, p14/ARF; inhibit CDK4 and 6 (p16), p14 enhances p53 activity by inhibiting MDM2
- RAS and PI3K/AKT; melanomas in non-sun expose areas rarely have mutations in BRAF or NRAS and more likely to have KIT mutations and PTEN
- reactivation of telomerase; TERT*most commonly mutate gene
37
What is the morphology of melanoma
Variations in color (can sometimes have white areas - where tumor is regressing), bores are irregular and notched; radial growth - horizontal within epidermis and superficial dermis (can’t met here); then vertical growth - appearance of nodule; ability to met measured by Breslow thickness
38
What are the types of melanoma in radial growth phase
- lentigo maligna: presents as indolent lesion on face of older men that can remain in those phase for decades
- superficial spreading: most common type of melanoma* usually involving sun exposed skin
- acral/mucosal lentiginous melanoma: unrelated to sun exposure*
39
What is a melanoma marker
HMB-45
40
What are the prognostic factors of melanoma
Breslow thickness, number of mitosis, evidence of tumor regression, ulceration or skin, presence and number of infiltrating lymphocytes, gender, location
Favorable: thinner, no mitosis, brisk tumor infiltrating response, absence of regression, lack of ulceration
41
What are the ABCDEs of melanoma
Asymmetry, irregular borders, variegated color, increasing diameter, evolution or change over time
42
What skin manifestation does cowden have
Trichilemmonomas
43
What skin manifestation does Muir-torre have
Multiple sebaceous neoplasms
44
What are sebeorrheic keratoses
Epidermal tumors;; middle to older age; mostly on trunk; in people of color - lesions on face are termed dermatosis papulosa Nigra
45
What is the pathogenesis of seborrheic keratoses
Activation mutations in FGFR3; can appear is part of paraneoplastic syndrome - Leser-trelat sign (most commonly from GI carcinomas)
46
What is the morphology of seborrheic keratoses
Coinlike, waxy plaques; velvety to granular surface; pore-like Ostia impacted with keratin; keratin production at the surface and small keratin filled cysts and invaginations of keratin into main mass are characteristic
47
What are the 2 types of acanthosis Nigricans
- in most cases, assoc with benign conditions and develops gradually during childhood; can occur as AD trait, assoc with obesity or endocrine ab, or part of congenital syndromes
- in remaining cases, arises in assoc with cancers, mostly GI adenocarcinomas in middle aged and older adults; paraneoplastic
48
What is the pathogensis of acanthosis nigricans
Disturbance that leads to increased GF signaling; familial form assoc with FGFR3 mutation; can be seen in combo with achondroplasia and thanatophhoric dysplasia
49
Does acanthosis nigricans have melanocytic hyperplasia
No
50
What is a fibroepithelial polyp
Aka acochordon, squamous papilloma, skin tag; middle aged individuals on neck, trunk, face, and intertriginous areas; can be seen with birt-Hogg-dube syndrome; soft, flesh colored, attached by stalk - can undergo ischemic necrosis; can become more numerous during pregnancy
51
What is an epithelial or follicular inclusion cyst (wen)
Formed by invagination and cystic expansion of epidermis or a hair follicle; can rupture which can spill keratin into dermis and lead to painful granulomatous response
52
What are adenxal (appendage) tumors
Fresh colored, solitary or multiple
53
What are eccrine poromas
Adnexal tumor that occurs predominately on palms and solves where swat glands are numerous
54
What are cylindromas
Appendage tumor with ductal differentiation; occurs on forehead and scalp; *turban tumor; can be AD inherited (mutation in CYLD); mutations in CYLD also assoc with familial trichoepithelioma and Brooke Spielberg syndrome
55
What are syringomas
Adnexal tumors with eccrine differentiation; usually on lower eyelids
56
What are sebaceous adenomas
Can be assoc with internal malignancy in Muir-torre syndrome (HNPCC subset); DNA mismatch mutation
57
What are pilomatricomas
Adnexal tumor showing follicular differentiation; assoc with CTNNB1 mutations (encodes B catenin); regulates hair growth
58
What is the morphology of the adnexal tumors
- cylindroma: islands that. Fit together like jigsaw puzzle within fibrous matrix
- trichoepithelioma: forms primitive structures resembling hair follicles
- sebaceous adenoma: lobular proliferation; frothy or bubble cytoplasm
- pilomatrixomas: trichilemmal or hairlike differentation; Ghost cells
59
What are actinic. Keratoses
Occur in sundamaged skin and exhibit hyperkeratosis; exposure to UV light, hydrocarbons and arsenic; may show progressively worsening dysplastic changes that end in SCC; sandpaper consistency - can produce cutaneous horn from overproduction of keratin; face, arms dorsum of hands most affected; lips can develop similar lesions (cheilitis)
60
What is the morphology of actinic keratoses
Atypia seen in lowermost layers of epidermis; pink or reddish cytoplasm; intercellular bridges NOT present; superficial dermis contains thickened blue gray elastic fibers (elastosis); stratum corneum is thickened and often retain their nuclei (parakeratosis)
61
How are actinic keratoses treated
Cut off, frozen off, topical application of imiquimod (activates TLRs)
62
Is SCC of the skin more common in men or women
Men; except for those on the legs
63
What is the pathogenesis of SCC of the skin
Lifetime sun exposure; immunosuppression - susceptible to HPV 5 and 8 (also seen in people with epidermodysplasia verruciformis); exposure to tars and oils, chronic ulcers and draining osteomyelitis, old burns, ingestion of aresenicals
64
What kind of skin cancer are people with xeroderma pigmentosum at risk for
SCC
65
What is the morphology of SCC of the skin
Involves all levels of epidermis
66
What is basal cel carcinoma
Locally aggressive tumor assoc with mutations that activate the hedgehog pathway; *most common invasive cancer in humans; occur at sun exposed sights
67
What syndrome leads to an increased risk of basal cell carcinoma
Nevoid basal cell carcinoma syndrome (NBCCS) aka gorlin syndrome; AD; development of BCC before age 20 accompanied by ot her tumors - medulloblastomas and ovarian fibromas, odontognic keratocytes, pits of palms and soles and developmental abnormalities; mutation is PTCH - leads to excessive GLI1 activation
68
What is the morphology of basal cell carcinoma
Pearly papules containing prominent dilated subepidermal bv (telangiectasias); “rodent ulcers”; do NOT occur on mucosal surfaces; two patterns: multifocal - originates from epidermis; nodular: goes deeply into dermis; cells at periphery of tumor arranged radially (palisading)
69
What is benign fibrous histiocytoma (dermatofibroma)
Heterogeneous family of morph and histo related benign dermal neoplasms; sen in adults; occur on legs of young Nd middle aged women; asymptomatic or tender; indolent; composed of factor XIIIa-positive dermal dendritic cells; spindle shaped cells arranged in nonncapsulated mass within mid dermis; some contain pseudoepitheliomatous hyperplasia - downward elongation of hyperpigmented rete ridges
70
What is dermatofibrosarcoma protuberant
Dermis tumor primary fibrosarcoma; slow growing; rarely met; translocation* involving collagen 1A1 (COL1A1) and platelet deriveed growth factor beta (PDGFB) - overexpression of PDGFB; treat with local excision or those than cant be excised - PDGFB inhibitors (imatinib mesylate) - lifelong use
71
What is the morphology of dermatofibrosarcoma protuberans
Protuberant nodule most often on t runs firm plaque; composed of fibroblasts, reminiscent of blades of a pinwheel (storiform pattern); rare mitosis; overlying epidermis is thinned (in contrast to dermatofibroma); honeycomb pattern frequently seen; need wide excision; “Swiss cheese” infiltration of subcutis
72
What are the features of mycosis fungoides
Most involve turn; scaly, red brown patches; can be confused with psoriasis; prognosis related to percentage of body surface involved and progression from patch to plaque to nodular forms; nodules correlates with systemic spread; if diffuse erythema and scarring of entire body surface - Sezary syndrome
73
What is the morphology of mycosis fungoides
Sezary-lutzner cells - form bandlike aggregates within superficial dermis; invade dermis as singl cells sand small clusters (pautrier microabscesses)
74
What is mastocytosis
Increased number of mast cells in skin; childhood form called urticaria pigmentosa; prognosis can be poor
75
What are the signs and sx of mastoytosis
Due to histamine and heparin; Darier sign - localized area of dermal edema and erythema (wheal) that occurs when lesional skin is rubbed; dermatogaphism - area of dermal edema resembling a hive that occurs as a result of localized stroking of normal skin; can cause osteoporosis by excessive histamine release
76
What is the pathogenesis of mastocytosis
Acquired mutations in KIT
77
What is ichthyosis
Chronic excessive keratin buildup (hyperkeratosis) that results in fishlike scales
78
What are the types of ichthyosis
- ichthyosis vulgaris: AD or acquired
- congenital ichthyosiform erythroderma: AR
- lamellar ichthyosis: AR
- x-linked ichthyosis
79
What is the pathogensis of ichthyosis
Defective deesquamation leading to retention of abnormally formed scale - X linked caused by def of steroid sulfatase (removes proadhesive cholesterol sulfate from intercellular spaces; results in persistent cell to cell adhesion within stratum corneum
80
What is the morphology of ichthyosis
Buildup of compacted stratum corneum assoc with loss of normal basket-weave pattern
81
What is angioedema
Edema of deeper dermis and subcutaneous fat
82
What are the major sites of hives
Areas exposed to pressure - trunk, distal extremities, ears
83
What is the pathogenesis of urticaria
Antigen induced release of vasoactive mediators is main cause
Other causes:
-mast cell dependent, IgE dependent: follows exposure to antigens; type I reaction
-mast cell dependent, IgE independent: results from substances that directly incidence degranulation of mast cells such as opiates, abx, curare, and contrast
-mast cell independent, IgE independent: triggered by local factors that increase permeability; aspirin; hereditary angioneurotic edema
84
What is the morphology of urticaria
Collagen bundles more widely spaced than in normal. Skin as a result of superficial dermal edema; no changes in epidermis
85
What are the categories of acute eczematous dermatitis
- allergic contact dermatitis
- atopic
- drug related
- photoeczematous
- primary irritant
86
What is the pathogeneis of acute eczematous dermatitis
Results from type IV hypersensitivity; chemicals act as happens and become antigens which are taken up by langerhans cells -> migrate to draining LN -> CD4 cells; on reexposure response within 24 hours
87
What is the morphology of acute eczematous dermatitis
Red, papulovsicular oozing and crusted lesions; if persist can develop reactive acanthosis and hyperkeratosis; ex: Rhus toxiodendron (poison ivy) - can have superimposed bacterial infection with yellow crust (impetiginization); spongiosis; unlike urticaria, edema seeps into epidermis - shearing of desmosomes can lead to vesicles
88
What are the stages of morphology of eczema
- superficial perivascular infiltrate with dermal edema and mast cell degranulation
- epidermal spongiosis and microvesicle formation
- abnormal scale, including parakeratosis and acanthosis I
- hyperkeratosis
89
What is erythema multiforme
Uncommon self limited hypersensitivity reaction; assoc with herpes simplex, mycoplasma infections, histoplasmosis, coccidioidomycosis, typhoid, leprosy, sulfonamides, penicillin, barbiturates, salicylates, hydantoins, antimalarials, cancer, collagen vascular dz
90
What is the pathogenesis of erythema multiforme
Keratinocytes injury mediated by skin homing CD8 T cells - more prominent in center of lesion; CD4 and langerhans in periphery
91
What is the morphology of erythema multiforme
Diverse array of lesions - macules, papules, vesicles, Bullae, and characteristic taretoid lesions; *febrile form - Stevens Johnson syndrome - involves skin, lips, oral mucosa, conjunctiva, urethra, and genital and perianal areas; another variant - toxic epidermal necrosis - diffuse necrosis and sloughing
92
What is the histo of erythema multiforme
Targetoid lesions show infiltrate along dermodepidermal junction here they are assoc with necrotic keratinocytes (interface dermatitis)
93
What is psoriasis
Chronic inflammatory dermatosis that appears to have autoimmune basis; strong assoc its HLA-Cw*0602; dominated by Th1 and 17 hype cytokines; treat with TNF blockers; can be induced in susceptible individuals by local trauma (koebner phenomennon)
94
What is the morphology of psoriasis
Most commonly affects skin of elbows, knees, scalp, lumbo-sacral area, intergluteal cleft and glans penis; pink to salmon colored plaque covered by silver-white scales that are loosely adherent; nail changes - yellow-brown discoloration with pitting, dimpling, or separation of nail plate (onycholysis); epidermal thickening with downward elongation of rete ridges (test tubes in a rack) *stratum granulosum thinned or absent and extensive parakeratotic scale seen; thinning of layer that lines dermal papillae* neutrophils form spongiform pustules and parakeratotic stratum corneum (Munro microabscess)
95
What is auspitz sign
Pulling back scales of psoriasis results in pinpoint bleeds
96
What is seborrheic dermatitis
Chronic inflammatory dermatosis; involves regions with high density of sebaceous glands (scalp, forehead especially labella, external auditory canal, retroauricular area, nasolabial olds, presternal area); inflammation of epidermis
97
What is the pathogenesis of seborrheic dermatitis
Increased sebum production n response to androgens *parkinsons patients have increased likelihood; colonization of skin with fungus - malassezia; severe form seen in AIDs individuals
98
What is the morphology of seborrheic dermatitis
Individual lesions are macules or papules on erythematous yellow, greasy base assoc with scaling and crusting; fissures can be present, esp behind ears; dandruff is common; parakeratosis containing neutrophils found at Ostia of hair follicles (follicular lipping)
99
What is lichen planus
Pruritic purple, polygonal, planar, papules, plaques *six Ps; self limited usually (1-2 years); resolution leaves hyperpigmented residue
100
What is the morphology of lichen planus
Itchy papules tat coalesce; highlighted. By white dots or lines called wick ham striae created by hypergranulosis; interface dermatitis; sawtooth* pattern; anucleate necrotic basal cells may become incorporated into inflamed papillary dermis referred to as colloid or civatte bodies
101
What is pemphigus
Blistering disorder caused by autoabs that result in dissolution of intercellular attachments within epidermis and mucosal epithelium; most are in 4-6th decade of life; men=women; multiple variants: vulgaris, vegetable, foliaceus, erythematosus, paraneoplastic; usually benign but can become fatal
102
What is a subcorneal blister
Stratum corneum forms the roof of the bulla (as in pemphigus foliaceus)
103
What is a suprabasilar blister
Portion of the epidermis including the stratum corneum forms the roof (as in pemphigus vulgaris)
104
What is a subepidermal blister
Entire epidermis separates from dermis (as in bullous pemphigoid)
105
What is pemphigus vulgaris
Most common type* involves mucosa and skin, esp scalp, face, axilla, groin, trunk and points of pressure; vesicles and bullae that rupture easily
106
What is pemphigus vegetans
Rare; presents with large moist verrucous (wart like) vegetating plaques studded wit pustules on groin, axilla and flexural surfaces
107
What is pemphigus foliaceus
More benign form; endemic in Brazil (fogo selvagem); scalp, face, chest and back; bullae very superficial and present as areas of erythema and crusting
108
What is pemphigus erytematosus
Localized less severe form of pemphigus foliaceus; may selectively involve malar area of face in lupus erythematosus like fashion
109
What autoabs are seen in pemphigus vulgaris
Dsg1 and Dsg3 - causes blisters in deep suprabasal epidermis
110
What abs are seen in pemphigus foliaceus
Dsg1; leads to superficial blisters
111
What abs are seen in bullous pemphigoid
BPAG2 (component of hemidesmosome) leads to blister formation at level of lamina Lucida of BM
112
What does paraneoplastic pemphigus occur in assoc with
Non-Hodgkin lymphoma mostly
113
What is the pathogenesis of all pemphigus dz
Autoimmune IgG abs against desmogleins; net-like partner of IgG deposits
114
What is the morphology of pemphigus
Acanthosis (dissolution or lysis of intercellular bridges); in vulgaris and vegetans, selectively involves cells immediately above basal layer; in vegetans, their is overlying epidermal hyperplasia; an immediately suprabasal acantholytic blister is characteristic of vulgaris*
115
What is bullous pemphigoid
Affects elderly; sites of involvement inner thighs, flexor surfaces of forearms, axillae, groin, lower abdomen; oral lesions appear after cutaneous
116
What is the pathogensis of bullous pemphigoid
Autoabs to proteins that are required for adherence of basal keratinocytes to BM; deposition in continuous linear pattern at dermoepidermal junction
117
What is the morphology of bullous pemphigoid
Tense bullae filled with clear fluid involving erythematosus or normal appearing skin; do not rupture easily *unlike in pemphigus; heal without scarring; separation of bullous from pemphigus is identification of supepidermal nonacantholytic blisters
118
What are the characteristics of dermatitis herpetaformis
Mostly males in 3rd-4th decade; very itchy
119
What is the pathogenesis of dermatitis herpetiformis
IgA abs cross react with reticulum (component of anchoring fibrils that tether epidermal BM to superficial dermis); produces subepidermal blister
120
What is the morphology of dermatitis herpetiformis
B/l symmetric and grouped involving extensor surfaces, elbow,s knees, upper back and butt; fibrin and neutrophils accumulate selectively at tips of dermal papillae* forming microabscesses; discontinuous granular deposits of IgA that selectively localize to tips of dermal papillae
121
What are the noninflammatory blistering disorders
Epidermolysis bullosa and porphyria
122
What is epidermolysis bullosa
Grou pf disorders caused by inherited defects in structural proteins that land mechanical stability to the skin; common feature is proclivity to form blisters at sites of pressure, rubbing or trauma at or soon after birth
123
What are the types of epidermolysis bullosa
- simplex: defects of basal cell layer of epidermis resulting from mutations in genes encoding keratin 14 or 5; normally pair with one antlers to make keratin fiber; dominant negative activity; AD; most common type
- junctional: blisters occur in otherwise histo normal skin at level of lamina Luisa; AR defect in subunit of lamina (binds hemidsmosomes and anchoring filaments)
- dystrophic: blisters beneath lamina densa in assoc with rudimentary to defective anchoring I rails; mutations in COL7A1 (type VII collagen); AD or AR
- mixed.
124
What is porphyria
Group of uncommon or acquired disturbances of porphyria metabolism (pigments that are normally present in Hb, myoglobin and cytochromes)
125
What are the types of porphyria
Congenital erythropoietin porphyria, erythrohepatic protoporphyai, acute intermittent porphyria, porphyria cutanea Garda, mixed
126
What are the manifestations of porphyria
Urticaria, subepidermal vesicles assoc with scarring exacerbated by sunlight; adjacent dermis contains vessels with walls thickened by glassy depsotis of serum proteins (Igs)
127
What is acne vulgaris
Males have more severe dz; milder in Asians; inflammatory and noninflammatory type; noninflammatory broken down into
- open comedones: follicular papules containing central black keratin plug; result of oxidation of melanin pigment
- closed comedones:follicular papaules without visible central plug; keratin plug trapped beneath epidermal surface - potential sources of follicular rupture and inflammation
128
What is the pathogensis of acne
- keratinization of lower portion of follicular infundibulum and development of keratin plug that blocks outflow of sebum to skin surface
- hypertrophy of sebaceous glands during puberty under influence of androgens
- lipase-synthesizing bacteria (propionibaterium acnes) colonizing upper and midportion of hair follicle converting lipids to proinflammatory FA
- secondary inflammation of involved follicle
129
How doe acutane work
Antisebaceous action
130
What is the morphology of acne
Erythematous papules, nodules and pustules; severe variants (acne conglobata) result in sinus tract formation and dermal scarring
131
What is rosacea
Predilection for females; 4 stages
- flushing episodes (prerosacea)
- persistent erythema and telangiectasia
- pustules and papules
- rhinophyma (permanent thickening of nasal skin by confluent erythematous papules and prominent follicles)
132
What is the pathogenesis of rosacea
High cutaneous levels of antimicrobial peptide cathelicidin;; diff from peptides in individuals without rosacea as a result of alternative processing by kallikrein 5; TLR2 involve
133
What is panniculitis
Inflammatory reaction in subcutaneous adipose tissue that affects lobules of fat or connective tissue that separates fat into lobules; often involves lower legs; erythema nodosum most common form* erythema induration another form
134
What is erythema nodosum
Poorly defined, exquisitely tender erythematosus plaques and nodules that may be more palpated rather than seen; assoc with infections (beta hemolytic strep, TB, coccidiomycosis, histo, leprosy), drugs (sulfonamides, OCP), sarcoidosis, IBD; delayed hypersensitivity; over weeks, lesions flatten and become bruiselike leaving no scars while new lesions develop; need deep wedge of tissue bx
135
What is erythema induratum
Affects adolescents and menopausal women; primary vasculitits of deep vessels supplying the fat lobules of subcutis; leads to fat necrosis and inflammation; presents as erythematous slightly tender nodule that usually ulcerates
136
What is the morphology of erythema nodosum
In early lesions, connective tissue septae are widened by edema, fibrin exudate, and neutrophils; later infiltration by lymphocytes, histiocytes and giant cells assoc with septal fibrosis; no vasculitis
137
What is the morphology of erythema induratum
Granulomatous inflammation and zones of caseous necrosis involve fat lobule; early lesions show necrotizing vasculitis affecting small to medium sized arteries and veins in deep dermis and subcutis
138
What is Weber-Christian dz
Relapsing febrile nodular panniculitis; rare form of lobular nonvasculitits panniculitis seen in kids and adults; crops of erythematous plaque or nodules on the LE created by deep-seated foci of inflammation containing aggregates of foamy macrophages
139
What is factorial panniculitis
Secondary panniculitis caused by self-inflicted traum or injection of foreign substance
140
What are verrucae
Squamoproflierative disorders caused by HPV; self limited regress within 6 months to 2 year s
141
What HPV is assoc with bowenoid papulosis
HPV 16
142
What is the morphology of verrucae
- verruca vulgaris: most common; occur anywhere but mostly on hands (dorsal surfaces); flat to convex; rough, pebble like surface
- verruca plana: flat wart common on face or dorsal hand; elevated, flat smooth; smaller
- verruca plantaris and palmaris: occur on soles and palms; rough scaly lesions coalesce ; look like calluses
- condyloma acuminatum: penis, female genitalia, urethra, perianal areas and rectum; cauliflower like mass
143
What are the histo features of verrucae
Epidermal hyperplasia termed verrucous or papillomatous epidermal hyperplasia; halos of pallor surrounding nuclei
144
What are the characteristics of Molluscum contagiosum
Virus is brick shaped, dumbbell shaped DNA core
145
What causes impetigo
Staph aureus
146
What is the pathogensis of impetigo
Bacteria in epidermis evoke innate immune response that causes epidermal injury leading to exudate and formation of a scale crust; bacterial toxin cleaves desmoglein 1 -forms blister; heals without scarring
147
What is the morphology of impetigo
Starts ad macule, but pustules supervenes; as pustules break, erosions form covered with drying serum giving honey colored crust appearance; need to remove crust or new lesions will form and can damage epidermis; accumulation of neutrophils beneath stratum corneum
148
What are superficial fungal infections
Confined to stratum corneum and caused primarily by dermatophytes
149
What is tinea capitis
Occurs in kids; dermatophytosis of scalp - asymptomatic hairless patches of skin assoc with mild erythema, crust formation and scaling
150
What is tinea Barbae
Dermatophyte infection of beard that affects adult men
151
What is tinea corporis
Common superficial fungal infection; all ages,but mostly kids; predisposing factors include excessive heat, exposure to infected animals, and chronic dermatophytosis of feet or nails; most common type is expanding round erythematous plaque with scaling border
152
What is tinea cruris
Inguinal ares of obese men during warm weather
153
What is tinea pedis
Athletes foot; diffuse erythema and scaling; initially localized to web spaces; most of inflammatory reaction is result of bacterial superinfection and not directly related to primary dermatophytosis; can spread to nail (onychomycosis) - produces discoloration, thickening and deformity of nail plate
154
What is tinea versicolor
Usually on upper trunk; caused by malassezia furfur (yeast; not dermatophyte); macules of varied size and color with fine peripheral scale
155
What makes up the bone matrix
Osteoid (mostly type I collagen) and a mineral component
156
What is a measure of osteoblast activity
Serum osteopontin (osteocalcin)
157
What makes the bone matrix hard
Hydroxyapatite
158
What is the cellular component of mature bone
Osteoblasts, osteocytes and bone resorbing osteoclasts
- osteoblast: surface of matrix; synthesize, transport and assemble matrix and regulate mineralization
- osteocytes:interconnected by network of dendritic processes through tunnels known as canaliculi; control calcium nad phosphate levels and detect mechanical forces and translate them into biological activity (mechanotransduction)
- osteoclasts: multinucleated macrophages derived from monocytes that are responsible for bone resorption; attach to bone matrix and create extracellular trench
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What is intramembraneous ossification use for
Formation of flat bones; no cartilage anlagen
160
What is the development of bone controlled by
- growth hormone: acts on resting chondrocyts to induce proliferation
- T3: acting on proliferating chondrocytes to induce hypertrophy
- Indian hedgehog: locally secreted; coordinates chondrocyte proliferation and osteoblast proliferation
- PTHrP: local; expressed by stromal cells
- Wnt: bind to Frizzld and LRP5/6 to activate Bcatenin
- SOX9: TF produced by proliferating chondrocytes essential for differentation into chondrocytes
- RUNX2: chondrycote and osteoblast differentiation; expressed in hypertrophic chondrocytes
- FGFs
- BMPs
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Where does bone remodeling take place
Bone multicellular unit BMU
162
Describe the RANK-RANKl pathway
RANK expressed on osteoclasts precursors; RANKL expressed on osteoblasts; OPG secreted decoy receptor made by osteoblasts (prevents RANKL interaction with RANK); when stimulated by RANKL, RANK activates NFkB -> generation of osteoclasts
163
What factors promote bone turnover
PTH, IL-1, glucocorticoids
164
When is peak bone mass achieved
Early adulthood after cessation of skeletal growth
165
What are dysostosis
Problems in migration and condensation of mesenchyme; most common forms: complete absence of bone or entire digit (aplasia), extra bones or digits (supernumerary digit), and abnormal fusion of bones (syndactyly, craniosynostosis); homeobox mutations most common
166
What are dysplasias of bone
Caused by global disorganization of bone or cartilage; arise from mutations in genes that control development or remodeling of entire skeleton
167
What defects in transcription factors can cause diseases of skeleton
- HOXD13: brachydactyly types D and E; short broad terminal phalanges of first digit
- SOX9: camptomelic dysplasia; sex reversal; ab skeleton
- RUNX2: cleidocranial dysplasia; abnormal clavicles, Wormian bones, supernumerary tenth
- TBX5: holt-oral syndrome; congenital ab; forelimb anomalies
- LMX1B: nail-patella syndrome; hypoplastic nails, patellar, dislocated radial head, progressive nephropathy
- PAX3: waardenburg syndrome; hearing loss, abnormal pigmentation, craniofacial abnormalities
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What defects in signal transduction proteins can lead to skeletal defects
- FGFR3: achondroplasia; short stature, frontal bossing, midface def
- FGFR3: hypochondroplasia; disproportionately short stature, Micromelia, relative microcephalic
- LRP5: osteopetrosis AD; increased bone density, hearing loss, skeletal fragility
- RANKL: osteopetrosis infantile; increased bone density
- LRP5: osteporosis pseudoglioma syndrome; congenital or infant-onset loss of vision, skeletal fragility
- FGFR3: thanatophoric dysplasia; severe limb shortening and bowing, frontal bossing, depressed nasal bridge
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What defects in extracellular structural proteins can cause diseases of skeleton
- COL2A1: achondrogenesis type 2; short trunk
- COL10A1: type x collagen; metaphyseal dysplasia, Schmidt type; mildly short stature
- COL1A1 COL1A2: osteogenesis imperfects; bone fragility
170
What defects in metabolic enzymes and transporters can cause skeletal disease
- CA2: osteopetrosis with renal tubular acidosis; affects carbonic anhydrase; increased bone density, fragility
- CLCN7: osteopetrosis, late onset type 2; affects chloride channel; increased bone density, fragility
171
What is cleidocranial dysplasia
AD; patent fontanelles, delayed closure of cranial sutures, Wormian bones (extra bones that occur within cranial suture), delayed eruption of secondary teeth, primitive clavicles, short height
172
What is the most common skeletal dysplasia
Achondroplasia; AD; retarded cartilage growth; shortened prox extremities; normal trunk; big head with depression of root of nose; GOF in FGFR3
173
What is thanatophoric dysplasia
Most common lethal for of dwarfism; shortening of limbs, frontal bossing, microcephalic; small chest cavity; bell-shaped abdomen; GOF in FGFR3
174
What is the most common inherited disorder of connective tissue
OI
175
What are the features of OI
Blue sclera, hearing loss (sensorineural and conduction), dental imperfections (small misshapen and blue-yellow)
176
Which type of OI is fatal in utero or during perinatal period
Type 2
177
What are the features of OI type 1
Decreased synthesis of pro-alpha1chain; AD; postnatal features, blue sclera, normal stature, fragility, dentinogenesis imperecta, hearing impairment, joint laxity, compatible with survival
178
What are the features of OI type 2
Abnormally short pro-alpha 1 chain, unstable triple helix, abnormal or insufficiency pro-alpha 2 chain; most AR, some AD; death in utero or within days of birth; blue sclera
179
What are the features of OI type 3
Altered structure of propeptides of pro-alpha2; impaired formation of triple helix; AD or AR; compatible with survival; growth retardation, multiple fractures, progressive kyphoscoliosis, blue sclera at birth that becomes white, hearing impairment, dentinogenesis imperfecta; progressive deforming
180
What are the features of OI type IV
Short pro-alpha2 chain; unstable triple helix; AD; postnatal fractures; NORMAL sclera; moderate skeletal fragility; short stature; sometimes denitogenesis imperfecta; compatible with survival
181
What collagens are important in hyaline cartilage
II, IX, X, XI
182
What is osteopetrosis
Marble bone disease aka albers-schonberg dz; genetic; reduced bone resorption and diffuse symmetric skeletal sclerosis due to impaired function or formation of osteoclasts; stone like quality of bones but they are abnormally brittle and fracture like chalk
183
What is the pathogenesis of osteopetrosis
Most mutations interfere with process of acidification of osteoclasts resorption pit which is required for dissolution of calcium hydroxyapatite within matrix; ex: AR defect in CA2 (carbonic anhydrase) - also affects ability to acidify urine; another form has mutation in CLCN7 (encodes proton pump located on surface of osteoclasts)
184
What is the morphology of osteopetrosis
Lack medullary canal; ends of long bones are bulbous (erlenmeyer flask deformity); neural foramina are small and compress exiting nerves; primary spongiosa persists Nd fills medullary cavity leaving not room for hematopoietic marrow; bone is woven
185
What are the clinical features of osteopetrosis
Severe infantile is AR and becomes evident in utero or soon afte birth; fracture, anemia and hydrocephaly are seen resulting in postpartum mortality; those who survive have CN defects (optic atrophy, deafness, facial paralysis) and repeated infections b/c of leukopenia; HSM; mild AD form may not be detected until adolescence - repeat fractures; mild CN defect and anemia; treat with hematopoietic SC transplant
186
What are the mucopolysaccharidoses
Lysosomal storage disease caused by def in enzymes that degrade derrmatan sulfate, heparin sulfate and keratin sulfate; accumulate in chondrocytes causing death o cells resulting in defects in cartilage; short stature, chest wall abnormalities, malformed bones
187
What is the dif between osteopenia and osteoporosis
Osteopenia: decreased bone mass
Osteoporosis: osteopenia severe enough to increase risk of fracture
188
Other than bone mass 2.5 SD below the mean, what signifies osteoporosis
Presence of atraumatic fracture or vertebral compression fracture
189
What are the most common forms of osteoporosis
Senile and postmenopausal type
190
What are the age related changes in bone
Osteoblasts have reduced proliferation and lower response to GF; senile osteoporosis categorized as low-turnover variant
191
What effect does reduced physical activity have on bone
Increased rate of bone loss (mechanical forces stimulation bone remodeling); lose bone when immobilized or paralyzed extremity, astronauts; higher bone density in athletes; weight training most effective rather than repetitive endurance (ie bicycling)
192
What genes have been assoc with osteoporosis
RANKL, OPG, PANK
193
What effect does calcium nutritional state have on bone
Influences peak bone mass
194
What kind of osteoporosis is postmenopausal
High-turnover; lack of estrogen stimulates both bone resorption and formation but latter cant keep up with the order; lack of estrogen stimulates cytokines which increase RANKL and stimulate osteoclasts recruitment
195
What is the morphology of osteoporosis
Histological normal bone that is decreased in quantity; loss of horizontal trabecular and thickened vertical trabecular
196
What are the clinical features of osteoporosis
-fractures of vertebrae causes deformities- lumbar lordosis and kyphosclosiosis
-fractures of femoral neck, pelvis or spine can cause PE and pneumonia
Cannot be detects on plain radio graph until 30% of bone mass lost
197
What is denosumab
Anti-RANKL ab used for some orbs of postmenopausal osteoporosis
198
What is paget dz
Aka osteitis deformans; disorder of increased, but disordered and structurally unsound bone mass
199
What are the stages of paget dz
- initial osteocytes stage
- mixed osteoclastic-osteoblasts stage which ends with predominance of osteoblasts activity and evolves into
- a final burned out quiescent osteosclerotic stage
200
What are the features of paget dz
Usually begins in late adulthood (average 70 years); common in whites in England, France, Austria, Germany, Australia, and US; most are asymptomatic
201
What is the pathogenesis of paget dz
Uncertain; familial and some sporadic cases show mutations in SQSTMI - increases activity of NFkB; activating RANk and inactivating OPG mutations account from some juvenile cases; modulation of vit D sensitivity and IL-6 secretion by virally infected osteoclasts - can play a role
202
What is the morphology of paget dz
Hallmark is mosaic pattern of lamellar bone seen in sclerotic phase; jigsaw puzzle like appearance produced by prominent cement lines
203
What is the clinical course of paget
Depend on extent and site of dz; most are asymptomatic; mostly polyostotic; axial skeleton or proximal femur involved in most cases; enlargement of craniofacial skeleton can produce leontiasis ossea (lion face) and cranium too heavy to hold head erect; can lead to invagination of skull base (platybasia) and compression of posterior fossa; anterior bowing of femurs and tibia - secondary osteoarthritis; chalk stick fractures; hypervascularitiy warms overlying skin -> can lead to high output heart failure
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What tumor and tumor-like conditions develop in pagetic bone
Giant cell tumor, extra osseous massses of hematopoietic tissue; most dreaded complication is sarcoma - usually osteo or fibrosarcoma
205
How can diagnosis of paget dz be made
Radiograph; bone is enlarged with thick coarsened vortices and cancellous bone; active dz has wedge shaped lyric leading edge; many of elevated serum alk phosphatase but normal calcium and phosphorus
206
How do you treat paget
Calcitonin and bisphosphonates
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What other aspects does renal failure contribute to bone disease besides just secondary hyperPTH
Decreased vit D synth; hyperphosphatemia further inhibits alpha1 hydroxylase; metabolic acidosis and aluminum deposition in bone
208
What is the morphology of bone in primary hyperPTH
-osteoporosis (most severe in phalanges, vertebrae and prox femur - can produce dissecting osteitis - railroad tracks), brown tumors (reactive mass) and osteitis fibrosa cystica
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What is renal osteodystrophy
Seen in chronic renal dz; osteopenia/porosis; osteomalacia; secondary hyperPTH growth retardation
210
What are the types of bone changes in ESRD
- high turnover osteodystrophy: increased bone resorption and bone formation with the former predominating
- low-turnover or aplastic dz: a dynamic bone (little osteoclasts and osteoblasts activity)
- mixed pattern of dz: areas of high turnover and low turnover
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What is the pathogenesis of renal osteodystrophy
- tubular dysfunction: ie renal tubular acidosis; low pH dissolves hydroxyapatite resulting in demineralization of matrix and osteomalacia
- generalized renal failure: reduced phosphate excretion, secondary hyper PTH
- decreased production of secreted factors: decreased BMP-7 (induces osteoblast differentiation)
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What are the types of fractures
Simple: overlying skin intact
Compound: bone communicates with skin surface
Comminuted: bone is fragmented
Displaced: ends of bone at fracture site are not aligned
Stress: slowing developing fracture
Green stick: extends only partially through bone; common in infants
Pathological: involving bone weakened by underlying disease
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What is involved in the healing of fractures
Immediately after fractures, hematoma forms filling fracture gap; clotted blood provides fibrin mesh and creates framework for influx. Of inflammatory cells; platelets release factors that activate osteoprogenitor cells in periosteum, medullary cavity; en of first week - matrix production and remodeling of fractured ends; soft tissue callus or procallus
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What happens after 2 weeks of fracture
Soft tissue callus transformed into bony callus; deposit subperiosteal trabecular of woven bone oriented perpendicular to cortical axis; stabilizes site; undergoes endochonral ossification
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How can the healing of a fracture be messed up
Improper immobilization can cause non union, which if persists the callus undergoes cystic degeneration and luminal surface can become lined by synovial like cells creating a false joint (pseudoarthrosis)
216
What do most cases of bone necrosis stem from
Fractures or corticosteroid administration
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What are the sx of avascular necrosis
- subbchondral: pain withactivity that becomes constant as secondary changes supervenes; often collapse and lead to secondary osteoarthritis
- medullary: clinically silent except in gaucher dz, sickle cell, dysbarism
218
What is osteomyelitis
Inflammation of bone and marrow
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What are the features of pyogenic osteomyelitis
In kids, most common hematogenous in origin and develops in long bones
In adults, most commonly from open fractures, surgery or diabetic infections
Staph aureus most common cause
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What are the most common causes of osteomyelitis in individuals with UTIs or IV drug users
Klebsiella, E. coli, pseudomonas
221
What are frequent causes of osteomyelitis in neonatal period
Haemophilus and group B strep
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What are the different sites of osteomyelitis in kids vs adults
- neonate: metaphysic, epiphysis or both
- children: meteaphysis
- adults: emphyses and subchondral regions
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What is the dead bone in osteomyelitis known as
Sequestrum
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What can occur after the first week of osteomyelitis
Chronic inflammatory cells release cytokines that stimulate osteoclastic bone resporption newly deposited bone can form shell of living tissue known as involucrum around segment of devitalized infected bone; Brodie abscess (small intraosseous abscess that involves cortex and walled off by reactive bone); sclerosing osteomyelitis of garre develops in jaw
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What is the clincial course of hematogenous osteomyelitis
Unexplained fever in kids; localized bone pain in adults; diagnosis strongly suggested by radiographic findings of lyric focus of bone destruction surrounded by zone of sclerosis
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What are the features of chronic osteomyelitis
Can cause flare puts years after initial infection; complications include fracture, secondly amyloidosis, endocarditis, sepsis; development of SCC of draining sinus tract and sarcoma in infected bone
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What are complications of tuberculous arthritis
Destruction of discs and vertbrae, sinus tract formation, psoas abscess, amyloidosis
228
What is skeletal syphilis
Syphilis and yaws (treponema pertenue) can involve bone; in congenital syphilis, bone lesions appear about 5th month of gestation; localize in areas of active endochondral ossification (osteochondritis) and periosteum (periostitis); saber shin produced by massive reactive periosteum bone deposition in medial and anterior surfaces of tibia
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What is the morphology of skeletal syphilis
Edematous granulation tissue containing numerous plasma cells and necrotic bone
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What age does osteosarcoma incidence peak
Adolescence; most commonly involves the knee
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What age does chondrosarcoma incidence peak
Older adults; mostly involves pelvis and proximal extremities
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What is the most common primary cancer of bone
Osteosarcoma
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What increases the risk of bone neoplasia
Chronic injury: bone infarcts, chronic osteomyelitis, paget dz, radiation, metal prostheses
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What are the common locations of hematopoietic bone tumors
Vertebrae, pelvis; age 50-60
235
What are the cartilage forming tumors in bone and where are they commonly located
Benign:
-osteochondroma: metaphysic of long bones; age 10-30
-chondroma: small bones of hands and feet; 30-50
-chondroblastoma: epiphysis of long bones; 10-20
-chondromyxoid fibroma: tibia, pelvis; 20-30
Malignant:
-chondrosarcoma: pelvis, shoulder; 40-60
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What are the bone forming tumors of bone
Benign
-osteoid osteoma: metaphysic of long bones; 10-20
-osteoblastoma: vertebral column 10-20
Malignant:
-osteosarcoma: metaphysic of distal femur, prox tibia; 10-20
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Where do notochodral tumors of bone form
Chordoma - malignant; Clivus and sacrum; age 30-60; foamy cells in myxoid matrix
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What do bone forming tumors all produce
Unmineralized osteoid or mineralized woven bone
239
What are osteoid osteomas
By definition, less than 2cm in diameter occur in young men in teens and 20s; predilection for appendicular Skeleton; femur or tibia; arise in cortex, less frequent in medullary cavity; thick rind of reactive cortical bone on XR; severe nocturnal pain relieved by aspirin* - pain caused by PGE2 released by osteoblasts; treated with radiofrequency ablation
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What are osteoblastomas
Larger than 2 cm; involves posterior spine (laminate and Pedicles); pain is unresponsive to aspirin* tumor does not induce bony reaction; excised
241
What is the morphology of osteoid osteoma and osteoblastoma
Both are masses of hemorrhagic gritty tan tissue;composed of interconnecting trabecular of woven bone rimmed by single layer of osteoblasts
242
What is osteosarcoma
Malignant tumor that produces osteoid matrix or mineralized bone; bimodal age distribution: <20 and older adults who have paget, bone infarcts or prior radiation; more common in men; arise in metaphyseal region of long bones and most occur around the knee; breaks through cortex and lifts periosteum resulting in reactive periosteal bone formation; triangular shadow btw Corte and raised periosteum known as codman triangle and is indicative of aggressive tumor (but not diagnostic of osteosarcoma)
243
What is the pathogenesis of osteosarcoma
- RB
- TP53
- INK4a
- MDM2 and CDK4
244
How are the subtypes of osteosarcoma grouped
- site of origin (intramedullary, intracortical, or surface)
- histo grade
- primary (underlying bone is unremarkable) or secondary to preexisting disorders
- histo features (osteoblasts, chondroblastic, fibroblastic, telangiectatic, small cell, giant cell)
245
What is the most common subtype of osteosarcoma
Arises in metaphysic of long bones; primary intramedullary osteoblasts high grade
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What is the morphology of osteosarcoma
Bulky tumors; hemorrhage and cystic degeneration; destroy cortex and produce soft tissue masses; spread in medullary canal, can invade joint and grow along tendoligamentous structures; formation of bone by tumor cells is diagnostic*; neoplastic bone has lace like architecture
247
How is osteosarcoma treated
Neodjuvant chemo followed by surgery; spread hematogenously to lungs
248
What is osteohondroma
Aka exostosis; benign cartilage capped tumor attached to underlying skeleton by bony stalk; most are solitary; remainder seen as part of multiple hereditary exostosis syndrome (AD); men>women; most near the knee
249
What is the pathogenesis of exostoses (osteochondroma)
Hereditary assoc with LOF in EXT1/2; encodes enzymes that synthesize heparin sulfate - reduced amounts of these prevent Normal diffusion of factor Indian hedgehog disrupting chondrocytes differentation
250
What is the morphology of osteochondroma
Sessile or pedunculated cap composed of hyaline cartilage and covered by perichondrium; cortex of stalk merges with cortex of host bone so that medullary cavity of osteochondroma is continuous with bone
251
What is the clinical course of osteochondroma
Stop growing at time of growth plate closure sx tumors cured by excision; in multiple hereditary exostosis, can progress to chondrosarcoma
252
What are chondromas
Benign tumors of hyaline cartilage that occur in bones of enchondral origin; can arise in medullary cavity where they are known as enchondromas or on surface of bone where they are called juxtacortical chondromas; most common intraosseous cartilage tumor; appear in hands and feet most commonly; XR - shows circumscribed lucency with central irregular calcifications, sclerotic rim and intact cortex
253
What are Ollier dz and maffucci syndrome
Nonhereditary disorders characterized by multiple enchondromas; maffucci syndrome is distinguished by presence of spindle cell hemangiomas
254
What is the pathogenesis of chondromas
Heterozygous mutations in IDH1/2 - encodes isocitrate DH; synthesizes 2-hydroxyglutarate which interfered with regulation of DNA methylation
255
What is the morphology of enchondromas
Gray-blue and translucent; composed of hyaline cartilage center can calcify
256
What are people with maffucci syndrome at risk for
Ovarian carcinomas and brain gliomas
257
What are chondrosarcomas
Malignant tumors that produce cartilage; subclassified as congenital (hyaline), clear cell, dedifferentiated and mesenchymal
258
What are conventional tumors subdivided into
By site: central (intramedullary) and peripheral (juxtacortical)
*central tumors constitute 90% of chondrosarcomas
259
What kind of chondrosarcoma occurs in younger patients
Clear cell and mesenchymal
260
What are the features of chondrosarcoma
Men>women; axial skeleton, esp pelvic, shoulder and ribs; on XR, calcified matrix appears as foci of flocculent densities; clear cell is unique in that it originates in emphysema of long tubular bones; mutations in EXT, IDH1/, and CDKN2A mutations
261
What is the morphology of chondrosarcoma
Large bulky tumors; glistening gray-white; translucent but matrix is gelatinous; spreads through cortex into m or fat
- dedifferentiation: low grade with second high grade component that does not produce cartilage
- clear cell: sheets of large, malignant chondrocytes that have clear cytoplasm, numerous osteoclasts giant cells and intralesional reactive bone formation
- mesenchymal: islands of well-difff hyaline cartilage surrounded by sheets of small round cells which can mimic Ewing sarcoma
262
How do chondrosarcomas spread
Hematogenously to lungs
263
How do you treat chondrosarcoma
Excision; mesenchymal and dedifferentiated excised and treated with chemo bc more aggressive
264
What is Ewing sarcoma.
Malignant bone tumor characterized by round cells without obvious differentiation; in same category as primitive neuroectodermal tumor (PNET); arises in diaphysis of long. Tubular bones especially femur and flat bones of pelvis; affected side is typically tender, warm and swollen; *onion skin reactive bone
265
What is the pathogenesis of Ewing sarcoma
11;22 (EWS-FLI1)
266
What is the morphology of Ewing sarcoma
Arise in medullary cavity; invades cortex, periosteum and soft tissue; tumors contains areas of hemorrhage and necrosis; homer-wright rosettes (round groupings of cells with central fibrillary core)indicate greater degree of neuroectodermal differentiation
267
What is the clinical course of Ewing sarcoma
Aggressive; treated with neoadjuvant chemo followed by local excision with or without radiation
268
What is a giant cell tumor
Multiucleated osteoclast type giant cells; aka osteoblastoma; uncommon, benign but locally aggressive
269
What is the pathogenesis of giant cell tumor
Neoplastic cells are primitive osteoblast precurosurs but most of tumor consist of non-neoplastic osteoclasts; neoplastic cells express high levels of RANKL - results in localized destruction of bone matrix by osteoclasts; arise in epiphysis but may extend into metaphysis; most around knee; causes arthritis like sx
270
What is the treatment for giant cell tumors
Curettage but high percentage recur; some can met to lungs but these sometimes spontaneously regress and are seldom fatal; denosumab has shown promise as adjuvant therapy
271
What are aneurysms bone cysts
Multiloculated blood-filled cyst spaces; radiographic and histo findings typical of these can b seen as secondary reaction to other primary bone tumors; mostly in metaphysic of long bones and posterior elements of vertebral bodies; *most common sx are pain and swelling
272
What do aneurysmal bone cysts (ABC) look like on XR
Eccentric, expansive lesion with well defined margins; ost are lyric and contain thin shell of reactive bone at periphery; CT and MRI may show characteristic fluid-fluid levels
273
What is the pathogenesis of aneurysmal bone cysts
Spindle cells of ABC frequently show rearrangements of chrom 17p13 resulting in fusion of USP6 (increases NFkB) which increases MMPs that lead to cystic resorption of bone; secondary ABCs do not have USP6 rearrangements
274
What is the morphology of ABC
Blood filed cystic spaces separated by thin tan-white septa; some contain densely calcified matrix called blue bone; necrosis uncommon
275
What is the treatment for ABC
Surgical; recurrence rate is low
276
What are fibrous cortical defects
Aka metaphyseal fibrous defects; very common; present in children; most arise in metphaysis of distal femur and prox tibia; most are b/l; if grow >6 cm classified as nonossifying fibromas
277
What is the morphology of fibrous cortical defects
Sharply demarcated radiolucencies with a long axis of bone parallel to cortex; gray lesions; fibroblasts arranged in st oriform (pinwheel) pattern; hemosiderin commonly present
278
What is the clinical course of fibrous cortical defects
Asymptomatic; most regress spontaneously and are replaced by normal cortical bone; the few that progress to nonossifying fibroma present with fracture or require bx
279
What is fibrous dysplasia
Benign tumor; all of the components of normal bone at present but they do not differentiate into mature structures; lesions arise during skeletal development and appear in several overlapping patterns:
- monostotic: involvement of single bone
- pollyostotic: multiple bones
- mazabraud syndrome: fibrous dysplasia and soft tissue myxomas
- McCune Albright: polyostotic dz, cafe au lait pigmentations, endocrine abnormalities (precocious puberty)
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What is the pathogenesis of fibrous dysplasia
Somatic GOF mutation in GNAS1; extent of phenotype depends on stage of embryogenesis when mutation is acquired and the fate of the cell harboring the mutation; ie: mutation during embryogenesis -> mccune albright; mutation in osteoblast precursor during or after formation of skeleton -> monostotic fibrous dysplasia
281
What is the morphology of fibrous dysplasia
Well circumscribed, intramedullary; vary in size; tissue is gritty and composed of curvilinear trabecular of woven bone surrounded by cellular fibroblastic proliferation; mimics chinese characters* and bone lacks prominent osteoblastic rimming
282
What is the clinical course of monostotic fibrous dysplasia
Occurs equally in boys and girls usually in adolescence; stops enlarging at time of growth plate closure; femur, tibia, ribs, jawbones, calvarium and humerus most common;asymptomatic but can cause discrepancies in limb length; lesions on XR - *ground glass appearance; cured by curettage
283
What is the clincial course of polyostotic fibrous dysplasia
Early age than monostotic type; can cause problems into adulthood; most common are femur, skull, tibi, humerus, ribs, fibula, radius, ulna, mandible and vertebrae; craniofacial involvement common; propensity to involve shoulder and pelvic girdles resulting in severe crippling deformities; bisphosphonates used to reduce pain; can rarely transform to sarcoma
284
What is mazabraud syndrome
Presents with skeletal fractures of polyostotic fibrous dysplasia with multiple skeletal deformities identified in childhood; intramuscular myxomas often in same anatomic region; benign but can cause local compression sx; cured by local excision
285
What is mccune albright syndrome
Most common presentation is precocious puberty in girls; can lose have hyperthyroidism, pituitary adenomas, and primary adrenal hyperplasia; bone lesions are unilateral and skin pigmentation on same side of lesion
286
How can tumors spread to bone
Hematogenous, direct extension, or intraspinal seeding (via batson plexus of veins)
287
What are the most common cancers to met to bone
Prostate, breast, kidney, lung
288
What part of the skeleton do most mets involve
Axial skeleton
289
What radiographic appearance can bone mets have
Lytic, blastic, or mixed
| *prostate has blastic; kidney, lungs, GI and melanoma are lytic
290
What are the types of joints
Solid (nonsynovial aka synarthroses) and cavitated (synovial)
-ex: fibrous synarthroses - sutures; teeth to jawbone; cartilaginous synarthroses (synchondroses) - symphyses
291
What cells line synovial membranes
Type A synoviocytes: specialized macrophages with phagocytic activity
Type B: similar to fibroblasts and synthesize hyaluronic acid
Synovial lining lacks and BM
292
What makes up hyaline cartilage
Water (resistance to compression), type II collagen (resiste tensile stresses and transmits vertical load), proteoglycans and chondrocytes
293
What is osteoarthritis
Degenerative joint dz; degeneration o cartilage resulting in structural and functional failure of synovial joints; most common joint dz; mostly primary arthritis (no initiating cause; in these cases mostly oligoarticular - affecting few joints)
294
What effect does gender have on distribution of osteoarthritis
Usually in knees and hands in women and hips in men
295
What is the pathogenesis of OA
Phases:
- chondrocyte injury
- early OA, in which chondrocytes proliferate an secrete inflammatory mediators, collagen, proteoglycans and proteases to remodel cartilaginous matrix
- late OA in which repetitive injury and chronic inflammation lead to chondrocyte drop out, loss of cartilage and subchondral bone changes
296
What is the morphology of OA
Joint mice (dislodged pieces of cartilage and subchondral bone); exposed bone plate becomes new articulate surface and friction with opposite surface polishes it (ivory looking - bone eburnation)
297
What are the characteristic symptoms of OA
Deep achy pain worsens with use; morning stiffness, crepitus, limitation of ROM; impingement on spinal foramina by osteophytes results in cervical and lumbar n root compression and radical are pain, muscle spasms and atrophy
298
What are heberden nodes
Prominent osteophytes at DIPs - common in women
299
Can joint deformity occur in OA
Yes, but unlike in RA, fusion does not occur
300
What is RA
Chronic inflammatory AI disorder that attacks joints producing a nonsupurative proliferative and inflammatory synovitis; destruction of articulate cartilage and ankylosis of joints; extraarticular lesions involve skin, heart, blood vessels and lungs; peaks in 2nd-4th decade and more common in women
301
What is the the pathogenesis of RA
CD4 cells initiate AI response by reacting with arthritogenic agent; important cytokines
- IFNy from TH1 cells activate macrophages and resident synovial cells
- IL-17: recruits neutrophils and monocytes
- TNF and IL-1: stimulate resident synovial cells to secrete protease and destroy hyaline cartilage
- RANKL stimulates bone resorption
302
What does the synovium of RA look like
Contains germinal centers within secondary follicles and plasmas cells that produce abs - most specific for citrullinated peptides (CCPs); antigen-ab complexes containing citrullinated fibrinogen type II collagen, alpha enolase and vimentin deposit in joints; diagnostic markers;
303
What is rheumatoid factor
Serum IgM or IgA auto abs that bind to Fc portion of their own IgG
304
What HLA is related to RA
HLA-DRB1; also implicated PTPN22 - encodes protein tyrosine phosphatase
305
What are the comparisons btw RA and OA
- RA: inflammation, pannus, eroding cartilage, fibrous ankylosis, bony ankylosis
- OA: bony spur, no ankylosis, subchondral cyst, subchondral sclerosis, osteophytes, thinned and fibrillated cartilage
306
What is the joint morphology of RA
Symmetric arthritis principally affected small joints of hands and feet; synovium becomes edematous, thickened and hyperplastic transformation it to bulbous villi; characteristic histo features: synovial cell hyperplasia, dense inflammatory infiltrates, increased vascularity, fibrinopurulent exudate, osteoclastic activity in underlying bone - produces a pannus (mass of edematous synovium Inflam cells, granulation tissue and fibroblasts); after cartilage destroyed, pannus bridges bones to form fibrous ankylosis which ossifies Nd forms bony ankylosis
307
What is the skin morphology of RA
Rheumatoid subcutaneous nodules; arise in regions of skin subjected to pressure (ulnar aspect of forearms, elbows, occiput and lumbosacral area); can less commonly form in lungs, spleen, pericardium, myocardium, heart valves, aorta; firm nontender round in SQ tissue; resemble necrotizing granulomas with central zone of fibrinoid necrosis surrounded by prominent rim of macrophages
308
What is the bv morphology of RA
Ppl with severe dz, rheumatoid nodules and high titers of RF at risk; acute necrotizing vasculitis involves small and large aa; can involve pleura, pericardium or lung evolving into chronic fibrosing process; vas nervorum and digital aa obstructed by obliterating end arteritis resulting in peripheral neuropathy, ulcers and gangrene; leukocytolastic vsculitis produces purpura, cutaneous ulcers and nail bed infarction; ocular changes such as uveitis and keratoconjunctivitis can be seen
309
What is the clinical course of RA
Can begin with malaise’s, generalized MSK pain mediated by IL-1 and TNF; after several weeks-months joints become involved; involved joints are warm, painful and stiff in the morning; can go into remission but comes back and affects new joints; *radial deviation of wrist, ulnar deviation of fingers, flexion-hyperextension of fingers (swan-neck or boutonnière deformity) caused by mm inflammation; can develop baker cyst
310
What are the radiographic hallmarks of RA
Joint effusions and juxta-articulate osteopenia with erosions and narrowing of joint space and loss of articulate cartilage
311
What is the diagnosis of RA supported by
Characteristic XR findings, sterile, turbid synovial fluid with decreased viscosity, poor mucin clot formation and inclusion-bearing neutrophils, Nd the combination of RF and anti-CCP abs
312
What are the treatments for RA
Corticosteroids, methotrexate and TNF inhibitors
313
What are long term complications of RA
Systemic amyloidosis; infection with opportunistic organisms
314
What is juvenile idiopathic arthritis
Group of disorders of unknown cause that present with arthritis before age 16 and persists for at least 6 weeks
315
What are the differences between juvenile idiopathic arthritis and RA
JIA - oligoarthritis is more common, systemic dz is more frequent, larger joints are affected more often than small joints, rheumatoid nodules and RF absent, ANA is positive
316
What causes the damage in JIA
Th1 and 17
317
What are the features of seronegative spondyloarthropathies
- path changes in ligamentous attachments rather than synovium
- involvement of SI joint with or without other joints
- absence of RF
- asssociation with HLA-B27
Immune mediated
318
What is ankylosing spondylitis
Spondyloarthropathy that causes destruction of articular cartilage and bony ankylosis especially of SI and apophyseal joints (btw tuberosities and processes); aka rheumatoid spondylitis and Marie-strumpell dz
319
What is reactive arthritis
Spondyloarthropathy; arthritis, nongonococcal urethritis or cervicitis and conjunctivitis; most are men in 20s-30s; HLA-B27 positivity; affects HIV individuals; caused by AI reaction initiated by prior infection with chlamydia, shigella, salmonella, yersinia, or campylobacter; ankles, knees feet most common in asymmetric pattern; synovitis of digital tendon sheath produces sausage finger
320
What is the extraarticular manifestation of reactive arthritis
Inflammatory balanitis, conjunctivitis, cardiac conduction abnormalities, aortic regurgitation
321
What is enteritis associated arthritis
Caused by yersinia, salmonella, shigella and campylobacter; outer cell membranes have lipopolysaccharides Nd st insulate immuno responses; arthritis appears abruptly and involves knees and ankles; it lasts for about a year then clears and is only rarely accompanied by ankylosing spondylitis
322
What is psoriatic arthritis
Chronic inflammatory arthropathy assoc with psoriasis that affects peripheral and axial joints and entheses (ligaments and tendons); related to HLA-B27 and HLA-Cw6 (spondyloarthorpathy); predominately peripheral arthritis of hands and feet; DIP first affected in asymmetric pattern *pencil in cup deformity (unlike RA which affects PIP)
323
What is suppurative arthritis
Bacterial infections usually enter joints from hematogenous spread; in neonates increased incidence of spread from epiphyseal osteomyelitis
324
What causative organisms are responsible for suppurative arthritis at diff ages
- haemphilus in children <2
- staph aureus in older children and adults
- gonococcus in late adolescence and young adults (seen more in women) and those with deficiencies in MAC
Sickle cell: salmonella
325
What is the presentation of suppurative arthritis
Sudden development of acutely painful and swollen joint that has restricted ROM; systemic findings: fever, leukocytosis, elevated ESR; in most nongonococcal infection, involves one joint (mostly knee); *axial joints more common in drug users s
326
What is mycobacterial arthritis
Chronic progressive monoarticular infection; complication of adjoining osteomyelititis; seeding of joint causes confluent. Granulomas; affected synovium can grow as pannus over articular cartilage and erode bone; chronic dz results in fibrous ankylosis and obliteration of joint space; weight bearing joints affected (mostly hips)
327
What is Lyme arthritis
Primarily involves large joints (knees shoulders), one or 2 joints affected at once; attacks last for few weeks-months migrating to new sites; confirm with serologic testing for anti-borrelia abs; infected synovium exhibits chronic synovitis with synoviocyte hyperplasia, fibrin deposition, mononuclear infiltrates and onion skin thickening of arterial walls
328
What is viral arthritis
Caused by alphavirus, parvovirus B19, rubella, EBV, hep B and C;
329
What are the types of endogenous crystals
- monosodium urate: gout
- calcium pyrophosphate dehydrate: pseudogout
- basic calcium phosphate
330
What are the exogenous. Crystals
Corticosteroid ester talcum, polyethylene and methyl methacrylate; silicone polylethylene and methyl methacrylate used in prostethetic joint - debris can cause local arthritis
331
What is the diff in uric acid excretion btw primary and secondary gout
In primary it is normal; in secondary it is either increased (leukemia, congenital - lesch-nyhan) or decreased (chronic renal dz)
332
What is the pathogenesis of gout
Hyperuricemia (urate >6.8) is necessary but not sufficient for. Gout; inflammation in gout triggered by precipitation of monosodium urate which results in production of cytokines that recruit leukocytes; inflammasome activated; remits spontaneously in days to weeks
333
What factors contribute to confusion of asymptomatic hyperuricemia to primary gout
- age and duration of hyperuricemia: usually appears 20–30 years after hyperuricemia
- genetic predisposition: x-linked abnormalities of HGPRT; polymorphism in URAT1 and GLUT9
- heavy alcohol consumption
- obesity
- drugs (thiazides) that reduce excretion of urate
- leads toxicity
334
What does repeated attacks of gouty arthritis lead to
Chronic topheceous arthritis and formation of topi in inflamed synovial membranes and periarticular tissue; damage to cartilage and function of the joint compromised
335
What are the stages of gout
Acute arthritis -> chronic tophaceous arthritis -> tophi in various sites -> gouty nephropathy
336
What makes up tophi
Aggregates of urate crystals surrounded by intense inflammatory reaction of foreign body giant cells
337
Who is at increased risk for gout
Men >30; obesity, metabolic syndrome, excess alcohol intake, renal failure
338
What are the clinical stages of gout
- asymptomatic: puberty in males, menopause in females
- acute arthritis
- asymptomatic intercritical period: resolution of acute arthritis leads to symptom free interval
- chronic tophaceous gout: develops about 12 years after initial acute attack XR shows juxta-articular bone erosion
339
What is pseudogout
Aka chondrocalcinosisis; calcium pyrophosphate crystal deposition disease; usually >50 yo; sexes equally affected; diff forms: sporadic, hereditary and secondary; caused by mutations in pyrophosphate transport channel; secondary form assoc with previous joint damage, hyperPTH, hemochromatosis, hypomagnesemia, hypothyroidism, ochronosis and diabetes
340
What is the morphology of pseudogout
Crystals dvelop in articular cartilage, meniscus, and intervertebral disc; can rupture and send joint; form chalky, white friable deposits seen in stained prep as oval blue-purple aggregates; crystals are rhomboid and positively birefringent*
341
What is a ganglion cyst
Small; always located near joint capsule or tendon sheath; firm, fluctunt pea sized translucent* nodule; arises as a result of cystic or myxoid degeneration of connective tissue; lacks a cell lining
342
What is a synovial cyst
Produced by herniation of synovium through joint capsule or massive enlargement of brush; ex: baker cyst; synovial lining may be hyperplastic and contain inflammatory cells and fibrin
343
What is a tenosynovial giant cell tumor
Term for several closely related benign neoplasms that develop in synovial lining of joints, tendon sheaths and bursae; variants include diffuse type involving large joints(pigmented villonodular synovitis) and localized type (giant cell tumor of tendon sheath) presents as iscrete nodule attached to tendon sheath mostly in hand
344
What is the pathogenesis of tenosynovial giant cell tumor
Reciprocal somatic chrom translocation t(1;2)(p13;q37) resulting in fusion of type VI collagen alpha-3 promoted upstream of coding sequences of M-CSF gene; overexpress M-CSF which stimulates proliferation of macrophages
345
What is the morphology of tenosynovial isn’t cell tumors
Red-brown to orange-yellow; in diffuse, synovium is tangled mat itch fingerlike projections and nodules; in localized tumors, well circumscribed; in diffuse, spread along surface and infiltrate subsynovial tissue; in nodular, cells grow in solid aggregate and attach by Pericles
346
What are the clinical features of diffuse tenosynovial giant cell tumors
Present mostly in knee; pain, locking Nd recurrent swelling; aggressive tumors erode into adjacent bones
347
What are the clincial features of localized tenosynovial giant cell tumors
Slow growing painless mass; wrist and fingers; most common mesenchymal neoplasm of the hand
Both types surgical excision but recurrence is common
348
Where do most soft tissues tumors arise
Thigh
349
What is the pathogenesis of soft tissue tumors
Most are sporadic; small minority’s assoc with germline mutations in tumor suppressor genes (NF-1, Gardner, li-fraumeni, Osler-weber-rendu)
350
What generalizations can be made about karyotypic complexity of sarcomas
- simple karyotype: often euploid with single number of chrom changes; mostly in younger patients and have monomorphic appearance; ex: Ewing, synovial sarcoma
- complex: most common; usually aneuploidy or polyploid and demonstrate multi chrom gains and losses; ex: leiomyosarcomas and undifferentiated sarcomas more common in adults
351
What are the chrom abnormalities seen in liposarcoma
12;16; FUS-DDIT3
352
What is the translocation seen in synovial sarcoma
X;18; SS18-SSX1
353
What is the chrom ab in rhabdomyosarcoma alveolar type
2;13 (PAX3-FOX01)
354
What is the chrom ab in dermatofibrosarcoma protuberans
17;22 (COLA1-PDGFB)
355
What is the chrom ab in infantile fibrosarcoma
12;15 ETV6-NTRK3
356
Where are the common locations of adipose tumors
- benign: superficial extremity, trunk
| - malignant: well diff - deep extremity, retroperitoneum; myxoid: thigh/leg *chicken wire vessels
357
Where do fibrous ST tumors present
All benign: nodular fasciitis - arm; forearm
| Deep fibromatosis: ab wall
358
Where do skeletal m tumors present
Benign: rhabdomyoma - head and neck *spider cells
Malignant: alveolar - extremity and sinuses
Embryonal - GU tract; strap cells
359
Where do smooth m tumors present
Benign: leiomyoma - extremity
Malignant: leiomyosarcoma - thigh, retroperitoneum
360
Where do vascular ST tumors present
Benign: hemangioma - head and neck
Malignant: angiosarcoma - skin, deep lower extremity
361
Where do nerve sheath tumors present
Benign: schwannoma - head and neck *palisading; neurofibromas - wide cutaneous subcutis (myxoid, ropy collagen, mast cells)
Malignant: malignant peripheral nerve sheath tumor - extremities, shoulder girdle
362
What is the most common soft tissue tumor of adulthood
Lipoma; most common is conventional lipoma (mature adipocytes); soft, mobile, painless (except angiolipoma) and cured by simple excision
363
What is liposarcoma
Occurs in 50-60; in proximal extremity and retroperitonem; amplification of 12q13 and 12;16 characteristic of well diff and myxoid respectively; MDM2 amplified
364
What are the histo types of liposarcoma
- well diff: adipocytes with scattered atypical spindle cells
- myxoid: abundant basophilic extracccellular matrix arborizing cap and primitive cells reminiscent of fetal fat
- pleomorphic: sheets of anaplastic cells, bizarre nuclei and lipoblasts
365
What are important clinical features of liposarcoma
All types recur locally unless adequately excised; well diff is indolent, myxoid is i ntemediate; pleomorphic is aggressive and frequently mets
366
What is nodular fasciitis
Self limited fibroblastic and myofibroblastic proliferation that typically occurs in young adults in UE; hx of trauma sometimes present; grow rapidly; 17;22 (MYH9-USP6)
367
What is the morphology of nodular fasciitis
Arises in deep dermis, subcutis or m; <5cm; contains fibroblasts and myofibroblasts in short fascicles; gradient of maturation (zonation) is typical
368
What is superficial fibromatosis
Infiltrative fibroblastic proliferation that can cause local deformity but has innocuous clinical course; all forms affect M>F; nodular or poorly defined broad fascicles of fibroblasts in sweeping fascicles surrounded by dense collagen
369
What are the subtypes of superficial fibromatosis
- palmar (dupuytren contracture): nodular thickening of palmar fascia either u/l or b/l; over years, attachment to overlying skin causes puckering and dimpling; contracture affects 4-5th digits
- plantar: common in young patients; u/l and without contracture
- penile (peyronie): palpable induration or mass on dorsolteral aspect of penis; can cause curvature of shaft or constriction of urethra
370
What is deep fibromatosis (Desmoid tumors)
Large, infiltrative masses that frequently recur but do not met teens-30s; mostly women; abdominal arises in musculoponeurotic structures of anterior ab wall; deep fibromatoses contain mutations in APC or bcatenin; most are sporadic; but ppl with Gardner syndrome (FAP) at increased risk
371
What is the treatment for deep fibromatosis
Excision often difficult; COX 2 inhibitors, RTK inhibitors or tamoxifen
372
What is rhabdomyoma frequent in
People with tuberous sclerosis
373
What are the types of rhabdomyosarcoma
Alveolar, embryonal (most common), pleomorphic; most common soft tissue sarcoma of childhood; appears <20 except pleomorphic which is seen in adults
374
Where does the pediatric form of rhabdomyosarcoma present
Sinuses, head and neck, GU tract
375
What mutations does alveolar rhabdomyosarcoma contain
Fusions of FOX01 to PAX3 or 7; 2;13 or 1;13
376
What is the morphology of embryonal rhabdomyosarcoma
Soft gray infiltrative mass; round and spindle cells in myxoid stroma; *sarcoma botryoides is variant that develops in walls of hollow, mucosal-lined structures (nasopharyngeal, common bile duct, bladder, and vagina); form submucosal zone of hyper cellularity called cambium layer
377
What is the morphology of alveolar rhabdomyosarcoma
Network of fibrous septae that divide cells into clusters; center are discohesivve; no cross strait ions
378
What is the morphology of pleomorphic rhabdomyosarcoma
Large bizarre eosinophilic tumors cells
379
How is rhabdomyosarcoma treated
Surgery and chemo with or without radiation; botryoid has best prognosis; pleomorphic is often fatal
380
What are Pilar leiomyomas
Leiomyomas arise from erector pili m in the skin, nipples, scrotum and labia; can be painful; multiple assoc with AD hereditary leiomyomatosis and renal cell cancer syndrome (multiple leiomyomas and RCC) LOF in mutation in fumarate hydratase gene
381
What is the morphology of soft tissue leiomyomas
Fascicles of eosinophilic spindle cells that intersect each other at right angles; tumors cells have blunt-ended elongated nuclei
382
What are the features of leiomyosarcoma
Adults; women; most in deep soft tissue of extremities and retroperitoneum; deadly form arises from great vessels, esp IVC; present as painless firm masses; stain with Desmin
383
What is synovial sarcoma
Can present in areas that lack synovium; 20s-40s; present with deep-seated mass present for several years; most show x;18 producing SS18-SSX1/2/4; contain spindle and gland like structures; *positive for keratin; treated aggressively with limb sparing surgery and chemo; met to lung and LN
384
What is undifferentiated pleomorphic sarcoma
Includes malignant mesenchymal tumors with high-grade, pleomorphic cells that cannot be classified into another category; most aris in deep tissue of extremity, esp thigh; malignant fibrous histiocytoma used interchangeably; coagulative necrosis common ; prognosis poor
385
What do thin unmyelinated fibers mediate
Autonomic functions as wel as pain and temp; slowest conduction
386
What do large diameter axons with thick myelin transmit
Light touch and motor signals
387
How are unmyelinated axons assoc with Schwann cells
One cell surrounds segments of multiple axons
388
What are the connective tissue components of an axon
Epineurium: encloses entire nerve
Perineurium: multilayered concentric connective tissue sheath that groups axons into fascicles
Endometrium: surrounds individual nerve fibers
389
What is wallerian degeneration
Cutting a peripheral n can cause this pattern; portions of axons distal to point of transaction are disconcnnected from central neuron and degeneration; within a day of injury, distal axons begin to fragment and myelin sheaths unravel and disintegrate into spherical structures (myelin ovoids); macrophages remove debris; regeneration starts at site of transsection with formation of growth cone and new branches from stump of prox axon; new myelin is thinner and shorter
390
What is a traumatic neuroma
If there is a failure of outgrowing axons to. Find their distal target; nonneoplastic haphazard whirled proliferation of axonal processes and associated Schwann cells that results in painful nodule
391
What happens in demyelinating neuropathies
Schwann cells are targets of damage and axons are persevered; discontinuous damage of myelin segments Schwann cells proliferate in response - thinner and shorter myelin produced; *slowed nerve conduction velocity
392
What are neuronopathies
Destruction of neurons leading to secondary degeneration of axonal processes; infections like herpes zoster and toxins like platinum can lead to his; equally likely to affect proximal and distal parts of body
393
What are the patterns of peripheral neuropathy.
- mononeuropathies: affect single nerve; result in deficits in a restructured distribution dictated by normal anatomy; trauma, entrapment and infection are causes
- polyneuropathies: involvement of multiple nerves usually symmetric; most cases leads to deficits starting in feed and ascend “stocking and glove”
- mononeuritis multiple: damages several nerves in haphazard fashion ie: might have right wrist drop and let food drop; vasculitis is common cause
- polyradiculoneuropathies: affect nerve roots as well as peripheral nerves leading to diffuse symmetric symptoms in prox and distal parts of body
394
What illnesses are linked to Guillain-barre
Campylobacter, CMV, EBV, mycoplasma pneumoniae
395
What is the morphology of Guillain barre
Inflammation of peripheral nerves; perivnular and endometrial infiltration by lymphocytes, macrophages and plasma cells; segmental demyelination is most prominent, damage to axons also seen; macrophages penetrate BM of Schwann cells and strip myelin sheath from axons and remnants engulfed ; close to nerve roots
396
What are the clinical features of Guillain barre
Ascending paralysis and Areflexia; sensory loss; CSF protein fluid elevated; treat with plasmapheresis and IV Ig
397
What is chronic inflammatory demyelinating polyradiculoneuropathy
Most common chronic acquired inflammatory peripheral neuropathy; symmetrical mixed sensorimotor polyneuropathy that persists for 2 months or more*; relapse and remits; treat with glucocorticoids, IV Ig, plasmapheresis and biologically agents against T or B cells; the time course and response to steroids distinguish it from Guillain barre
398
What is the pathogenesis of chronic inflammatory demyelinating polyradiculoneuropathy
T cells attack Schwann cell-axon junction; complement fixing IgG and IgM can be found on myelin sheath; recurrent demyelination and remyelination ; when excessive this leads to formation of onion-bulbs
399
What neuropathy does vasculitis present with
Mononeuritis multiplex; show patchy axonal degeneration and loss it’s some fascicles being more severely affected than others
400
What is Hansen dz
Leprosy; 2 types
- lepromatous: Schwann cells invaded by m. Leprae; segmental demyelination and remyelination; loss of both myelinated and unmyelinated axons; as infxn advances, endometrial fibrosis and multilayered thickening of perineurial sheath occurs; symmetric polyneuropathy most severe in distal extremities and face; loss of sensation leads to injury
- tuberculoid: active cell mediated immune response to m leprae; manifests as dermal nodules containing granulomatous inflammation; injures cutaneous nerves axons, Schwann cells and myelin lost; fibrosis of perineurium and endometrium; more localized n involvement
401
When does Lyme dz affect nerves
2nd and 3rd stage; polyradiculoneurropathy and u/l or b/l facial n palsies
402
What neuropathies are assoc with HIV
Early infection assoc with mononeuritis multiplex and demyelinated disorders; later stages show distal sensory neuropathy that is often painful
403
What neuropathy does diphtheria cause
Caused by diphtheria exotoxins; produces acute peripheral neuropathy assoc with prominent bulbar and resp m dysfunction which can lead to death or long term disability
404
What does varicella zoster infect to cause the rash of shingles
Keratinocytes; most commonly in thoracic or trigeminal dermatomes; affected ganglia show neuronal death with mononuclear infiltrates; peripheral ns show degeneration of axons that belong to dead sensory neurons; focal destruction of large motor neurons of anterior horns or cranial n motor nuclei may be seen; intranuclear inclusions not found in PNS
405
What is the most common cause of peripheral neuropathy
DM
406
What is the most common pattern of diabetic peripheral neuropathy
Ascending distal symmetric sensoimotor polyneuropathy
407
What is the morphology of diabetic neuropathy
Individual with distal symmetric sensorimotor neuropathy: axonal neuropathy reduced numbers of axons; endoneurial arterioles show thickening hyalinization and PAS positivity
408
What are the clinical features of distal symmetric diabetic polyneuropathy
Sensory sx (numbness, loss of pain, difficulty with balance); paresthesias or dysesthesias called positive sx (painful sensations result from abnormal discharges of damaged nerves); leds to considerable morbidity
409
What can dysfunction of autonomic seen in diabetes lead to
Seen in assoc with distal sensorimotor neuropathy; postural hypotension, incomplete emptying of bladder resulting in recurrent UTIs, sexual dysfunction; mononeuropathy, cranial neuropathy and radiculoplexus neuropathy
410
What is uremic neuropathy
Distal symmetric neuropathy that can be asymptomatic or assoc with m cramps, distal dysesthesias and diminished DTRs; axon degeneration is primary event; regeneration common after dialysis
411
What is the neuropathy assoc it thyroid dysfunction
Hypothyroidism can lead to compression mononeuropathies such as carpal tunnel or abuse distal symmetric sensory polyneuropathy; rarely hyperthyroidism is assoc with neuropathy resembling Guillain barre
412
What is the neuropathy assoc with vit B12
Subacute combined degeneration with damage to long tracts of the spinal cord and peripheral nerves
413
What are causes of toxic peripheral nerve damage
Alcohol, heavy metals (lead, mercury, arsenic and thallium) and organic solvents; chemo
414
What cancers can cause neuropathies from direct infiltration or compression
Apex lung cancer-> brachial plexopathy
Pelvic neoplasms -> obtrator palsy
Intracranial tumors -> CN palsies; polyradiculopathy of LE can develop when cauda quinoa is involved by meninges carcinomatosis
415
What is the most common form of paraneoplastic neuropathy
Sensorimotor neuronopathy: commonly assoc with small cell lung cancer - anti-Hu abs present; mediated by CD8 cell on dorsal root ganglion; sensory s start dismally in asymmetric and multifocal pattern; other parties with anti-CV2 abs (recognize CRMP5) present with mixed axonal Nd demyelinating sensorimotor neuropathy
416
What are the neuropathies assoc with monoclonal gammopathies
Neoplastic B cells secrete Ig fragments that damage nerves; IgM assoc with demyelinating peripheral neuropathy - binds to myelin associated antigen (MAG) *POEMS - polyneuropathy organomegaly, endocrinopathy, monoclonal gammopathy and skin changes
417
What can carpal tunnel be seen in association with
Pregnancy, edema inflammatory arthritis hypothyroidism, amyloidosis (esp those on renal dialysis), acromegaly, DM, and excessive repetitive motion of wrist
418
What is Saturday night palsy
Radial n palsy caused by laying with the arm in awkward position
419
What is a Morton neuroma
Perineural fibrosis which can cause metatarsalgia (foot pain)
420
What are the inherited peripheral neuropathies
- motor and sensory: Charcot-Marie-tooth
- hereditary sensory with or without autonomic
- familial amyloidosis and metabolic diseases
421
What is Charcot-Marie-tooth
Distal muscle atrophy, sensory loss and foot deformities; characterized by mode of inheritance and pattern of injury
422
What are the variations of Charcot-Marie-tooth
- CMT1: AD; most common; caused by duplication of region on chrom 17 that includes PMP22; presents in 2nd decade as slowly progressive distal demyelinating motor and sensory neuropathy
- CMTX: X linked; mutations in GJB1 which encodes connexin32 (gap junction component in Schwann cells)
- CMT2: AD assoc with axonal rather than demyelinating injury; mutations in MFN2 - required for normal mitochondrial fusion; severe* onset in childhood
423
What is hereditary neuropathy with pressure palsy
Caused by deletion of gene encoding PMP22; transient motor and sensory mononeuropathies triggered by compression of individual nerves at sites prone to entrapment; resolve within days to weeks but can progress to chronic neuropathy; *swollen bulbous myelin sheaths at end of internodes (tomaculi) are characteristic finding
424
What are familial amyloid polyneuropathies
Caused by mutations in transthyretin gene
425
What inherited metabolic disorders are associated with peripheral neuropathies
Adrenoleukodystrophy, porphyria, refsum (def of peroxisomal enzyme)
426
What do disorders that impair the function of NMJ lead to
Painless weakness
427
What is myasthenia gravis
AI dz with abs against ACh receptors; bimodal age distribution; more in females in young adults but in older adults, males more common
428
What is the pathogenesis of myasthenia gravis
Autoabs against postsynaptic ACh receptors (most) - fixes complement
some have abs against sarcolemmal protein muscle-specific RTK - exhibit more focal muscle involvement
429
What will electrophysiologic studies show on someone with myasthenia gravis
Decrement in muscle response with repeated stimulation
430
What is the treatment for myasthenia gravis
AChE inhibitors; thymectomy effective in patients with thymoma but not thyroid hyperplasia
431
What is lambert-Eaton myasthenic syndrome
AI disorder caused by abs that block ACh release by inhibiting presynpatic calcium channel; rapid repetitive stimulation increases muscle response; present with weakness of extremities; in half of cases, there is an underlying malignancy mostly neuroendocrine carcinoma of the lung; patients without cancer have vitiligo or thyroid dz
432
What are congenital myasthenic syndromes
AR; varying degrees of m weakness; LOF in SU of ACh receptor; present in perinatal period with poor m tone, external eye m weaknesss, and breathing difficulties
433
How does Botox work
Blocks ACh release from presynpatic neurons
434
How does curare works
Muscle relaxant that blocks ACH receptors resulting in flaccid paralysis
435
What patterns of atrophy are seen with diff etiologies
- clusters or. Groups of atrophic fibers seen in neurogenic dz
- perifascicular atrophy seen in dermatomyositis
- type II fiber atrophy with sparing of type I fibers seen with prolonged corticosteroid therapy or disuse
436
What are the features of type I muscle fibers
Used for sustained force, aerobic exercise, low power, high resistance to fatigue, high lipid content, low glycogen content, low glycolysis capacity, high oxidative capacity, high mitochondrial density, MYH7 expressed; red (high myoglobin)
437
What are the features of type II muscle fibers
Fast movement; anaerobic exercise, high power, low resistance to fatigue, low lipid content, highglycogn, low mithondral density, pale,
438
What do neurogenic injuries lead to
Fiber type groping and grouped atrophy; fibers assume flattened angulated shape; reinnervation restores fiber size and shap but may make denervated myofibrer part of a diff motor unit that may lead to a switch in fiber type
439
What is segmental myofiber degeneration and regeneration
Seen when only part of a myofiber undergoes necrosis; also with release of cytoplasmic enzymes into blood such as CK (marker for damage); removed by myophagocytosis; fusion of activated satellite cells impt for regeneration; regenerating myofibers rich in RNA (will stain basophilic); large nuclei with randomly distributed nucleoli; if chronic, will sho endomysial fibrosis (collagen deposition), and fatty replacement
440
What are the inflammatory Myopathies
Dermatomyositis and poliomyositis
441
What is dermatomyositis
AI dz that presents with proximal m weakness and skin changes
442
What is the pathogenesis of dermatomyositis
Damage to small bv contributes to muscle injury; can be telangiectasia (dilated cap loops) in nail folds, eyelids and gums and dropout of cap vessels in skeletal m; biopsies can show deposition of MAC within cap beds
443
What autoabs are assoc with specific clin features of dermatomyositis
- anti-Mi2: directed against helicase implicated in nucleoside remodeling; shows a strong assoc with prominent gottron papules and heliotrope rash
- anti-Jo1: directed against histidyl t-RNA synthetase; assoc with interstitial lung dz, nonerosive arthritis, and skin rash described as mechanic’s hands
- anti-P155/P140: directed against transpcriptional regulators; assoc with paraneoplastic and juvenile cases of dermatomyositis
444
What is the morphology of dermatomyositis
Perifascicular atrophy; infilatration of CD4 cells and deposition of MAC in cap; EM shows tubuloreticular endothelial cell inclusions (feature of IFN response)
445
What are the clinical features of dermatomyositis
Muscle weakness slow in onset, symmetric and accompanied by myalgia; affects prox m first; *getting up from a chair or climbing steps difficult; elevated CK; lilac colored discoloration of upper eyelid (heliotrope rash) assoc with periorbital edema and scaling erythematous eruption or dusky red patches over knuckles, elbows and knees (gottron papules) dysphasia from involvement of esophageal mm; interstitial lung dz; cardiac involvement common but rarely causes issues
446
What is the most common inflammatory myopathy in children
Dermatomyositis *compared to adult dz, childhood dz is more likely to be assoc with calcinosis and lipodystrophy and less likely to be assoc with myositis specific abs, cardiac involvement, interstitial lung dz, or underlying malignancy; prognosis better in kids
447
What is polymyositis
Adults onset inflammatory myopathy that has myalgia and weakness but ones not have cutaneous features; symmetric prox muscle weakness
448
Where is the inflammatory infiltrate found in polymyositis
Endomysial
449
What is inclusion body myositis
Disease of late adulthood; most common inflammatory myopathy in patients >65 slow progressive m weakness that tends to be most severe in quads and distal UE ; dysphagia; ab to cN1A but no myositis bs
450
What are the features of inclusion body myositis that are similar to polymyositis
Patchy endomysial nonnuclear inflamatory infiltrates rich in CD8 cells, increased sarcolemmal expression of MHC I, focal invasion of normal appearing myofibers, admixed degenerating and regenerating myofibers
451
What morph changes are specific for inclusion body myositis
Abnormal cytoplasmic inclusions (Rimmed vascuoles), tubolofilamentous inclusions even in myofibers, cytoplasmic inclusions containing proteins assoc with neurodegernative dz (beta amyloid, TDP-43 and ubiquitin), endomysial fibrosis and fatty replacement
452
What is the treatment for inflammatory Myopathies
Corticosteroids but inclusion body usually responds poorly
453
What can chloroquine and hydroxychloroquine have an efffet on
Interfere with normal lysosomal function and can cause drug-induced lysosomal storage myopathy; presents with slowly progressive muscle weaknesss; predominantly affects type I fibers; *aggegates of whirled, lamellar membraneous structures including curvilinear bodies
454
What is ICU myopathy aka myosin deficient myopathy
NM disorder seen in patients during course of critical illness; selective degradation of sarcomeric myosin thick filaments producing profound weakness that can c implicate course *ie: trouble weaning off respirator
455
What is thyrotoxic myopathy
Presents as acute or chronic prox m weakness
456
What m problems can hypothyroidism cause
Cramping or aching of mm and decreased movement; reflexes may be slowed; fiber atrophy and increased numb of abnormally localized nuclei, glycogen aggregates
457
How do congenital Myopathies present
In infancy and tend to improve over time
458
What are examples of conditions with defects in ECM surrounding myofibers
- ullrich congenital muscular dystrophy: mutation in collagen VI; hypotonia, proximal contracture and distal hyperextensibility; mismatched expression of Perlecan and collagen VI
- merosin def
459
What is central-core dz
AD; mutation in ryanodine receptor (RYR1); early onset hypotonia and weakness, “floppy infant” assoc skeletal ab (scoliosis, hip dislocation, foot deformities); path findings: cytoplasmic cores represent demarcated central zones in which normal arrangement of sarcomeres is disrupted and mitochondria decreased
460
What is nemaline myopathy
Mutations in tropomyosin, nebulae, actin, troponin or coffilin; childhood weakness; hypotonia at birth “floppy baby”; path findings: aggreagates of spindle shaped particles (nemaline) rods in type I fibers; seen with gomori stain
461
What is centronuclear myopathy
Severe congenital hypotonia; floppy infant; poor prognosis in x linked for
462
What are examples of conditions with abnormalities in receptors for ECM
Diseases that disrupt posttranslational modification of alpha-dystroglycan; congenital muscular dystrophy, seizures, blindness
463
What is the function of dystrophin
Links cytoskeleton inside myofiber and BM outside of the cell
464
What is the morphology of duchenne and Becker MD
Young children: Segmental myofiber degeneration and regeneration asoc with admixture of atrophic myofibers; fasciular architecture preserved at this stage and no inflammation
-as progresses, muscle tissue replaced by collagen and fat; myofibers show variation in size; distorts fascicular architecture
465
What are the clincial features of duchenne MD
First indications usually clumsiness; weakness begins in pelvic girdle m and then extends to shoulder girdle; pseudohypetrophy of lower leg; develop joint contracture, scoliosis, worsening resp reserve and sleep hypoventilation; cardiomyopathies and arrhythmias; cognitive impairment can produce mental retardation
466
Does Becker MD have a reduced life expectancy
No
467
What are the CK values in MD
Increased initially then decreases as m mass is lost
468
What is myotonic dystrophy
AD multisystem disorder with skeletal m weakness, cataracts, endocrinopathy and cardiomyopathy; sustained involuntary contraction
469
What is the pathogenesis of myotonic dystrophy
CTG trinucleotide repeats in DMPK gene
470
What is emery-Dreifuss MD
Caused by mutation in genes that encode nuclear lamina proteins; *Triad: slowly progressive humeroperoneal weakness, cardiomyopathy assoc with conduction defects and early contracture of Achilles’ tendon, spine and elbows; x linked form (EMD1) and autosomal form (EMD2) caused by mutations in emerging and lamin A/C respectively
471
What is fascioscpulohumeral dystrophy
Assoc. with characteristic pattern of m involvement that includes prominent weakness of facial mm and mm of shoulder girdle; AD
472
What is the pathogenesis of fascioscapulohumeral dystrophy
Overexpresion of DUX4; also need to inherit certain single nucleotide polymorophysms in DUX4 coding sequence
473
What is limb-girdle MD
Group of AD and AR disorders; muscle weakness that involves proximal m groups
474
What is carnitine palmitoyltransferase II de
Most common disorder of lipid metabolism to cause episodic m damage with exercise or fasting; impairs transport of FFA into mitochondria
475
What is myophosphorylase deficiency
Mcardle disease: glycogen storage dz; episodic m damage with exercise
476
What is acid Maltase def
Impaired lysosomal conversion of glycogen to glucose causing glycogen to accumulate in lysosomes; Pompey’s disease; milder dz can cause adult onset myopathy that involves respiratory and truncates mm
477
Involvement of what mm is common in mitochondrial Myopathies
Extraocular *chronic progressive eternal opthlaoplegia is common
478
What is the morphology of mitochondrial Myopathies
Ragged red fibers (abnormal aggegates of mitochondrial in subsarcolemmal area)
479
What is Kearns-Sayre syndrome
Opthalmoplegia, pigmentary degeneration of retina, complete heart block
480
What is spinal muscular atrophy
Loss of motor neurons leads to muscle weakenss and atrophy ; infants can present with floppy baby; AR; LOF in SMN1 (survival of motor neuron)
481
What are channelopathies
Inherited diseases caused by mutations affecting the function of ion channel proteins; most are AD
482
What are examples of channelopathies
- mutation in KCNJ2: potassium channel; leads to andersen-twail syndrome; AD periodic paralysis, heart arrhythmias and skeletal abnormalities
- mutation in SCN4A: sodium channel; myotonia or periodic paralysis
- mutation in CACNA1S: missense mutation; calcium channel; most common cause of hypokalemic paralysis
- CLC1: chloride; causes myotonia congenital
- RYR1: central core and malignant hyperthermia - hypermetabolic state
483
What are the peripheral n sheath tumors
Most. Show Schwann cell diff - schwannoma, neurofibromas and malignant peripheral n sheath tumor
484
What are MPNSTs thought to arise fro m
Malignant transformation of preexisting plexiform neurofibromas in NF1
485
What are schwannomas a component of
NF2 (Merlin) LOF
486
What is the morphology of schwannomas
Well circumscribed, encapsulated, abut assoc n without invading it; simple surgical excision; comprised of antoni A and B; palisading nuclei and area between termed verocay bodies ; stain S-100
487
What kind of tumor is an acoustic neuroma
Schwannoma
488
What are neurofibromas
Neoplastic Schwann cells admixed with perineurial like cells, fibroblasts, mast cells and CD34+ spindle cells; can be sporadic or assoc with NF1
489
What are the diff types of neurofibromas
- superficial cutaneous: pedunculated nodules (NF1)
- diffuse neurofibromas: large plaqulike elevated of skin (NF1)
- plexiform neurofibromas: deep or superficial locations in assoc with n roots or large nerves (NF1)
490
What is the pathogenesis of neurofibromas
Only Schwann cells in neurofibromas show loss of NF1 (neurofibromin) - inhibits RAS
491
What is the morphology of localized cutaneous neurofibromas
Unencapsulated; arise in dermis and SQ fat; low cellularity
492
What is the morphology of diffuse neurofibromas
Diffusely infiltrates dermis and SQ CT entrapping fat and producing plaquelike apperance; mimick appearance of Meissen corpuscles (tactile like bodies)
493
What is the morphology of plexiform neurofibromas
Grow within and expand nerve fascicles entrapping axons; perineural layer is preserved giving it encapsulated appearance; *bag of worms* b thickening of multiple nerve fascicles; collagen looks like shredded carrot
494
What are the features of MPNST
Most assoc with larger nerves in chest, abdomen, pelvis, neck or Limb girdle; tumor appears marbelized; divergent differentiation - presence of focal areas that exhibit other lines of differentiation; if exhibits rhabdomyoblastic morph termed triton tumor
495
What are the features of NF1
AD; neurofibromas, MPNST, gliomas of optic nerve, other glial and harmartomatous lesions, pheochromocytomas; mental retardation or seizures, skeletal defects, pigmented nodules of iris (lich nodules), cafe au lait spots
496
What is NF2
AD; b/l acoustic neuromas, multiple meningiomas; gliomas typically ependymomas of SC; schwannosis (ingrowth of schwann cells into SC), meningioangiomatosis, and glial hamartia (glial cells at weird locations)
497
What are the non-biological disease modifying antirheumatoid drugs (DMARDs)
Methotrexate, hydroxychloroquine, sulfasalazine, leflunomide
498
What are the biological DMARDs
- TNF alpha blocker: etanercept, adalimumab, infliximab
- B cell depleter: rituximab
- T cell activation inhibitor: abatacept
- IL-6 receptor mab: tocilizumab
- JAK3 inhibitor: tofacitinib
- recombinant IL-1 antagonist: anakinra
499
What is the drug of choice for analgesia in RA
NSAIDs; either aspirin or naproxen (COX-1 and 2) or celecoxib (COX-2)
500
What is the main use of prednisone in RA
Relieves pain and inflammation while waiting for DMARD effects; treats flares
501
What is mild RA
<5 inflamed joints; no extra articular dz; no evidence of erosion or cartilage loss; most will lack RF or abs to citrullinated peptides
502
What is the treatment for early RA
DMARD monotherapy if low dz activity
| If moderate or high dz activity - DMARDs with TNF inhibitor +/- MTX or non-TNF biologic +/- MTX
503
What is moderate RA
>5 inflamed joints; increased ESR and CRP; + RF and/or anticyclic citrullinated peptide abs; evidence of inflammation on radiograph
504
What is the established RA treatment
If low dz activity - DMARD monotherapy
| If moderate or high: DMARD with TNF +/- MTX or non-TNF biologic +/- MTX or tofacitinib +/- MTX
505
How does MTX work in RA
Undergoes polyglutamation which accumulates in cells over multiple weeks and blocks thymidylate synthase and AICAR transformylase leading to accumulation of AICAR -> adenosine efflux which binds to purinergic GPCRs on cell surface to exert anti-inflamatory effects
506
What are the features of MTX
Non-biologic DMARD; Acts faster than all other DMARDs - effects in 3-6 weeks; low cost; often used in combo with other traditional DMARDs; often continued when patient switched to biologic DMARD
507
How is MTX administered
Once per week either orally or injected (best absorption)
Cleared by kidneys; effects persists for several weeks after d/c
508
What are the side effects of MTX
BM suppression, hepatic fibrosis, GI ulceration, pneumonitis; fetal death; lower life expectancy
509
What is hydroxychloroquine
Nonbiologic DMARD; lipophilic weak base that accumulates in lysosomes; increases pH to 6 which limits association of peptides on APCs with class II MHC; onset in 3-6 months; antimalarial; *can be first choice for mild RA with lack of poor prognostic features; often combined with MTX and sulfasalazine in more severe RA; ***SAFE IN PREGNANCY
510
What are the side effects of hydroxychloroquine
Retinal damage
511
What is sulfasalazine
Nonbiologic DMARD; Sulfapyridine is active form in RA (in IBD, active form is 5-ASA); onset 1 month; used alone or in combo with hydroxychloroquine and/or MTX (triple therapy); ok in pregnancy
512
What are the side effects of sulfasalazine
GI side effects; sulfa allergy
513
What is leflunomide
Nonbiologic DMARD; inhibition of dihydroorate DH blocks synthesis if rUMP; inhibits T cell proliferation; alternative nonbiologic to MTX; second choice drug; can be used in combo with MTX, sulfa, and hydrox; *Need loading dose b/c long half life
514
What are the adverse effects of leflunomide
Diarrhea, resp infection, reversible alopecia, rash, nausea; heptatotoxic; pancytopenia, Stevens Johnson syndrome, severe HTN
515
What are the “other DMARDS’
Penicillamine (serious affects), gold salts (purplish gray skin discoloration), azathioprine, cyclosporine, protein A column
516
What are the monitoring you have to do for each of the nonbiologic drugs for RA
- NSAIDS: CBC yearly, LFTs, Cr testing
- glucocorticoids: BP at each visit; urinalysis for glucose yearly, bone density scan
- MTX: CBC, LFTs and CR q 2-4 weeks for first 3 months; q8-12 weeks for 3-6 months and then q 12 weeks
- hydroxychloroquine: fundoscopic exam
- sulfasalazine: same as MTX
- leflunomide: same as MTX
517
Can you ever combine biologic DMARDs with each other
NO
518
What are the features of biologic DMARDs
Faster onset, high rate or response; more expensive and increased risk for adverse effects
519
What do the suffixes of biologic DMARDs tell you
- cept: fusion of receptor to Fc portion of human IgG
- mab: monoclonal ab
- ximab: chimeric mAb
- Zumab: humanized mAb
- umab: human mAb
520
What are the features of TNF antagonists
Biologic DMARD indicated or moderate to severe RA generally after traditional DMARDs have been ineffective; combo with MTX
Risk for infections (TB), can have severe allergic rxn
521
What are the TNF inhibitors and their properties
- etanercept: 2 TNF receptors bound to Fc portion of IgG; administered once or twice weekly by SQ injection
- infliximab: chimeric mAb against TNF;administered by IV q 6 weeks
- adalimumab: recombinant fully human anti-TNF mAb administered SQ q 2 weeks
522
What are the features of rituximab
Biological DMARD Because plasma cells are resistant, autoabs persist for months following single course; indicated in combo with MTX for RA that has not responded to TNF antagonists; *positive testing or RF and anti-cyclic citrullinated peptide abs predicts greater likelihood of responsiveness; administer IV q 6 months
523
What are the toxicities of rituximab
Infusion related hypersensitivity; Stevens Johnson; reactivation of hep b
524
What is abatacept
Biologic DMARD; prevents CD28 from binding to CD80/86; CTLA4-Ig; approved for use in moderate to severe RA but not used until after TNF antagonists have failed; well tolerated; can increase risk of infection; SQ q 1 week or IV q 4 weeks
525
What is tocilizumab
IL-6 receptor antagonist (both membrane bound and soluble form); limits hepatic acute phase response and activation of T cells, B cells, macrophages, and osteoclasts; use if other DMARDs and TNF alpha blockers ineffective; can be used with or without MTX; IV monthly
526
What are the side effects of IL-6 receptor antagonist
URIs; life threatening infections
527
What is tofacitinib
Biologic DMARD; JAK3 antagonist; suppresses production of IL-17 and IFNy and proliferation of CD4 cells resulting in decreased IL-6 and IL-8 production; give to those who are intolerant to MTX; used with or without MTX; administered orally*; very expensive
528
What are the side effects of tofacitinib
Serious and sometimes fatal infections; increased malignancies
529
What is anakinra
IL-1 antagonist; use in those that don’t respond to non-biologic DMARDs; less efficacious so late choice; SQ; increases risk of infection and hypersensitivity reaction
530
What NSAIDs are used for gout
Naproxen, indomethacin, celecoxib
531
What glucocorticoids are used for gout
Betamethasone, methylprednisone, triamcinolone
532
What microtubule formation disrupted is used for gout
Colchicine
533
What are the xanthine oxidase inhibitors
Allopurinol and febuxostat
534
What is the recombinant uricase used for gout
Pegloticase
535
What are the uricosurics used for gout
Probenecid, sulfinpyrazone
536
What foods should people with gout avoid
Gravies, sardines, mussels, meat, internal organs, yeast, nuts, avocado, sweet beans, tuna fish
537
What is uricase
Converts uric acid to allantoin
538
How are purines salvaged
APRT converts adenine to AMP
| HGPRT converts hypoxanthine to AMP and guanine to GMP - def results in leach-Nyhan
539
What do you give for recurrences of gout
Uricosuric drugs (increase uric acid renal excretion)
And/or: diet, xanthine oxidase inhibitors, recomibinant uricase
540
What is the treatment of acute gout
- If NSAID therapy not contraindicated, use NSAIDs (do not use in renal, heart failure, PUD)
- if NSAIDs cannot be used, use oral colchicine
- if you cant use colchicine and >2 joints are involved use oral, IV, or IM glucocorticoids; if <2 joints sects use intraarticular, oral, IV or IM glucocorticoids
541
What are each of the NSAIDs used for gout specific for
Naproxen is nonselective
Indomethacin: COX-
Celecoxib: COX-2 *use if others not tolerated
542
How does colchicine work in gout
Prevent migration of leukocytes; used in patients with contraindications to NSAIDs; effective within 12-24 hrs; given orally; met by CYP3A4 and excreted in kidney so contraindicated in advanced renal or hepatic impairment
543
How do you manage someone with interval gout
If frequent and diet cant change outcome, allopurinol *drug of choice when tophi present, low GFR, history of urolithiasis, hyper excretion of uric acid
Otherwise, can use any urate lowering therpapy: allopurinol, febuxostat, uricosuric agent
If intolerance to allopurinol, use febuxostat; biological last resort (pegloticase)
544
What are the indications for allopurinol
Recurrent gout, cancer induced hyperuricemia; need to lower doses or purine chemo such as azathioprine; side effect: skin rash, gout, increased liver enzymes; Stevens Johnson syndrome *risk of HLAB*5801 (chineses)
545
What is febuxostat
Non purine inhibitor of xanthine oxidase; well tolerated in those who cannot tolerate allopurinol; recommended that NSAID or colchicine also administered every 6 months to prevent flares; Need to lower dose of purine chemo;
546
What is pegloticase
Recombinant mammalian uricase; attached to methoxy polytheylene glycol; converts uric acid to allantoin; treatment of chronic gout in those refractory to conventional therapy; given IV q 2 weeks; side effects infusion reactions - need to premeditates with glucocorticoids and antihistamines
547
What is rasburicase
Nonpegylated recombinant uricase; prevents acute uric acid nephropathy due to tumor lysis syndrome inpatient with high risk lymphoma or leukemia
548
What is probenecid
Organic acid that acts as anionic transport sites of renal tubule to block urate reabsoprtion (aspirin promotes urate reabsoprtion so dont use in gout); increases fractional excretion of urate; can be used in *underexcreters with GFR >60 and no stones; oral; increases risk of kidney stones (keep hydrated); sulfa drug; sulfinpyrazone is similar
549
What NSAIDs are used for pain
Aspirin, ketorolac, indomethacin, ibuprofen, naproxen, diclofenac, celecoxib
550
What antidepressants are used for pain
Amitriptyline (TCA), duloxetine (SNRI), tramadol and tapentadol (antidepressant + weak mu activity)
551
What NMDA antagonists are used for pain
Ketamine, methadone
552
What alpha 2 agonist are used for pain
Dexmedetomidine, clonidine
553
What antiepileptic drugs are used for pain
Pregabalin and gabapentin
554
What are the N-type calcium antagonists used for pain
Ziconotide
555
What are the topical analgesics
Capsaicin, camphor, methol, lidocaine
556
What are the antimigraine agents used for pain
Ergotamine, dihydroergotamine, sumatriptan
557
What drugs alter the perception of pain
Opioids, alpha 2 agonists, General anesthetics, TCAs, SSRIs, SNRIs
558
What is the nociceptive pain algorithm
If mild - topical agents, actominophen/paracetamol, NSAIDs + PPI or COX2 inhibitors
If severe: NSAIDs if no risk; if risk factors, acetominophen
For both, if those dont work, TCAs or duloxetine -> opioids -> baclofen or tizanidine if spasmodic
559
What are the functions of PGE2
Increased permeability, mucosal protection, sodium and water excretion, m contraction, temp, pain sensitization, bone remodeling
560
What are the indications for NSAIDs
OA, bursitis, gout flare, ankylosing spondylitis
561
What are the benefits of aspirin
Suppression of inflammation, relief of pain, reduction of fever (COX 2 inhibition), prevention of MI and stroke (due to COX-1 inhibition) ; inhibits COX-1 and 2 irreversibly; risks: ulcer, renal impairment, bleeding
562
How long does the antiplatelet effect of aspirin last
8 days
563
How do you minimize the risks for ulcers with aspirin therapy
Test for and eliminate h pylori; give PPI
564
What are the affects of ibuprofen and naproxen on the antiplatelet effects of aspirin
Reverses it
565
When should high dose aspirin be discontinued before surgery
1 week; low dose can be continued
566
When does aspirin usually impair renal function
In setting of advanced age, preexisting renal dysfunction, hypovolemia, HTN ,hepatic cirrhosis, heart failure
567
What kind of renal injury can be caused by long term aspirin use
Papillary renal necrosis
568
Who is at risk for reye syndrome
Children with chicken pox or influenza; dont use aspirin
569
What is the progression of apsirin/salicylate toxicity
- uncouples mitochondria oxphos in CNS
- resp center registers decreased ATP as hypoxemia and responds with hyperventilation
- blows of CO2 -> resp alkalosis; kidney depletes bicarbonate
- met acidosis
570
What are the differences btw nonaspirin NSAIDs an aspirin
Unlike aspirin, they are reversible, suppresses platelet aggregation but use increases risk of MI and stroke; so use lowest effective dose for shortest possible time
571
What are the actions of celecoxib
Suppresses inflation, pain and fever; may cause less ulcers; does not inhibit platelet aggregtion so does not have risk of bleeding; increases risk of MI and stroke
572
How is ketorolac given
IV/IM
573
How is diclofenac given
Topical
574
What NSAID is recommended for patients at risk of CV complications
Naproxen
575
What are the actions of acetominophen
Suppresses pain and fever but not inflammation
576
How is acetominophen overdose treated
Acetylcysteine - substitutes for depleted glutathione
577
What should you not give acetominophen with
Warfarin - inhibits its metabolism so risk of bleeding
578
What are the first line agents for neuropathic pain
Calcium channel alpha 2 delta ligands (pregabalin, gabapentin), SNRIs (duloxetine, venlafaxine), TCAs (amitriptyline, notriptyline)
Use with topical agents
579
What are the features of TCAs as analgesics
Can take up to 6-8 weeks to work; adverse effects: dry mouth, constipation, tachycardia, N/V, sedation, mental clouding
580
What are the adverse effects of SNRIs
N, dizziness, sexual dysfunction, insomnia, diaphoresis, agitation, increase in BP; not as effective as TCAs for pain
581
What are the approved indications for pregabalin
Neuropathic pain assoc with diabetic neuropathy, postherpetic neuralgia, adjunctive therapy for partial seizures, fibromyalgia
582
What is gabapentin used for
Partial seizures, postherpetic neuralgia, diabetic neuropathy, migraine, fibromyalgia, restless leg syndrome
583
What are the second line agents for neuropathic pain
Opioids, tramadol, antiepileptics (valproic acid)
584
What is tramadol
Codeine analog, weak mu agonist; works by blocking NE and 5-HT reuptake; activates spinal inhibition of pain; causes sedation, dizziness, HA, dry mouth, consitpation
Serious side effects: seizures in epileptics, HTN crisis if combined with MAO, serotonin syndrome if combined with SSRI, TCA, triptans, MAO
585
What is tapentadol used for
Patients not managed by non-opioids or other opioids
586
What are the third line agents for neuropathic pain
NMDA antagonists (dextromethorpan), tizanidine, baclofen
587
What are the last line meds for neuropathic pain
Botox, intrathecal ziconotide
588
What are the side effects of ketamine
Hallucinations, increased BP
589
What is dexmedetomidine
Alpha2 agonist used for analgesia and sedation; administered IV; causes hypotension, bradycardia, nausea, dry mouth, HTN, agitation, constipation, resp depression
590
How does clonidine reduce pain
Blocks transmission of pain signals from periphery to brain; administered by cutaneous infusion through epidural catheter; approved for severe cancer pain; causes hypotension, confusion, dry mouth
591
What is ziconotide
Selective antagonist at N-the voltage sensitive calcium channels on nociceptive afferent neurons in dorsal horn - prevents transmission of pain signals from periphery; indicated only for chronic severe pain in those whom intrathecal administration is warranted and refractory to other treatment
592
What are the side effects of ziconotide
Cognitive impairment; psych sx, m injury - elevated CK
593
What is the MOA of the topical pain meds
- capsaicin: heat from red peppers stimulation of TRPV1 receptors -> desensitizes or depletes substance P; nociceptive and neuropathic pain
- camphor: heat desensitizes TRPV1 receptors
- menthol: stimulates TRPM8 cold receptors
- topical NSAIDs; topical sodium Channel blockers
594
What are the risk factors for osteoporosis
Female; low levels of testosterone in men; Caucasian or Asian, poor nutrition, physical inactivity, smoking, low body weight
595
What drugs increase osteoporosis risk
Heparin, anticonvulsants (phenobarbital, phenytoin, carbamazepine), aromatase inhibitors (anastrazole, exemestane), cyclosporine, tacrolimus, chemo, glucocorticoid, GRH agonists, lithium, MTX, PPIs, SSRIs, thyroxine
596
What are calcium salts used for
Treat mild hypocalcemia, dietary supplements in adolescents, elderly and postmenopausal women; parenteral calcium salts given to rapidly increase calcium in severe hypocalcemia
Taking too much can cause constipation, CNS effects and renal dysfunction
597
What foods have vitamin D
Shiitake mushrooms and oily fish
598
What is calcitonin-salmon
Similar to human calcitonin but has longer half life and potency; decreases bone resorption by inhibiting osteoclast activity; inhibits renal tubular resorption of calcium; used to treat established osteporosis but doesn’t prevent it; also used in paget dz; intravascular spray, parenteral for SC or IM
599
What is alendronate
Bisphosphonate; analog of pyrophosphate; incorporates into bone and inhibits bone resorption by decreases number and activity of osteoclasts
*drug of first choice for - postmenopausal osteoporosis, osteoporosis in men, glucocorticoid induced osteoporosis, paget dz, hypercalcemia of malignancy
600
What are the side effects of bisphosphonates
Esophagitis and ulceration (minimized by taking meds with 8 oz of water an waiting 30 min before any other liquid or food), ocular inflammation, osteopetrosis of jaw, atypical femur fractures, a fib
601
What are the other bisphosphonates
Risedronate (PO), ibandronate (PO, IV), tiludronate (PO), zolendronic acid (IV, typically once per year - most commonly assoc its osteonecrosis of jaw)
602
What is raloxifene
SERM; blocks estrogen in breast in uterus, agonist in bone; used to prevent and treat postmenopausal osteoporosis; orally; increased risk of DVT, PE, stroke - d/c 72 hours before planned immobilization; NOT in pregnancy
603
What is teriparatide
Truncated version of PTH; *only drug for osteoporosis that increases bone formation; increases bone resorption by osteoclasts and increases bone deposition by osteoblasts; when given continuously, bone resorption predominates *when given as daily pulsed therapy, osteoblast response predominates; used for postmenopausal osteoporosis, osteoporosis in men, glucocorticoid induced osteoporosis; injected
604
What are the side effects of teriparatide
Levels of calcium, magnesium and uric acid rise transiently but return to normal
605
What is denosumab
RANKL inhibitor; decreases function of osteoclasts; used for postmenopausal osteoporosis, prevention of skeletal related events in patients with bone mets (higher dose at shorter intervals; SQ q 4 weeks), take with calcium and vit D to prevent hypocalcemia
606
What are the adverse effects of denosumab
- in women with osteoporosis: back pain, MSK pain, hypercholesterolemia, UTI
- in bone mets: fatigue, hypophosphatemia, nausea
- in all patients: delayed fracture healing, risk of new fractures and osteonecrosis of jaw
607
What should be involved in the treatment of osteoporosis in men
Major risk factor is hypogonadism so testosterone replacement
608
What are the drugs for hypercalcemia
- Furosemide
- glucocorticoids: reduce intestinal absorption of calcium
- gallium nitrate: prevents bone resorption - used for hypercalcium of malignancy; *highly nephrotoxic
- bisphophonates
- inorganic phosphates: *IV use is lifethreatening and limited to severe hypercalcemia;
- edetate disodium: calcium chelating agent - can lead to profound hypocalcemia
609
What is cinacalcet
Calcimimetic drug; binds to CASR on PT gland and increases sensitivity to calcium which decreases PTH; treatment for primary hyperPTH and secondary hyperPTH
Oral - increased absorption with food
610
What are some OA OTC remedies
- dietary supplements: glucosamine, chondroitin, dimethyl sulfoxide (DMSO), S-adenosyl-L-methionine (SAMe) - failed to provide benefits in OA
- herbal remedies: devils claw, stinging nettle, rose hips, avocado soybean unsaponifiables; lack evidence of benefit
611
What are the treatments for pain in OA
- acetominophen for noninflammatory OA
- NSAIDs
- Topical NSAIDs or capsaicin (1% diclofenac gel)
Resistant pain therapy: opioids, intraarticular hyaluronans
612
What is the treatment of osteomyelitis
Clindamycin, rifampin, TMP-SMX, fluroquinolones
4-6 weeks
