IUHS Student-2-Student USMLE Step 1 Recall

                                                    Dermatology

Nevocellular Nevus (Pigmented Nevus, Mole)

most of us have at least a few moles and probably regard them as mundane and uninteresting...it may be surprising to learn, then, that moles or nevi represent one of the most diverse, dynamic, and biologically interesting tumors of the skin!...

strictly speaking, the term nevus denotes any congenital lesion of the skin...nevocellular nevus, however, refers to any congenital or acquired neoplasm of melanocytes...

in clinical appearance, common acquried nevocellular nevi are tan to brown, uniformly pigmented, small (usually less than 6mm across), solid regions of relatively flat (macules) to elevated skin (papules) with well defined, rounded borders...

there are numerous clinical and histologic types of nevocellular nevi, and the clinical appearance may be variable...

nevocellular nevi are initially formed by melanocytes that have been transformed by melanocyts from highly dendritic single cells normally interspersed among basal keratinocytes to round to oval cells that grow in aggregates, or "nests", along the dermal epidermal junction...

nuclei of nevus cells are unifrom and rounded in contour, contain inconspicuous nucleoli, and show little or no mitotic activity...such lesions are believed to represent an early developmental stage in nevocellular nevi and are called junctional nevi...

eventually, most junctional nevi grow into the underlying nevi as nests or cors of cells (compound nevi), and in older lesions, the epidermal nests may be lost entirely to form pure dermal nevi...clinically, compound and dermal nevi are often more elevated than junctional nevi...

although nevocellular nevi are common, their clincial and histologic diversity necessitates thorough knowledge of their appearance and natural evolution, lest they become confused with other skin conditions, notably malignant melanoma...

the biologic importance of some nevi, however, resides in their recogntion as an important model of tumor progression (dysplastic nevi and the heritable melanoma syndrome)...

Dysplastic Nevi

clinically, BK moles - or dysplastic nevi, as they are frequently called - are larger than those acquired nevi (often greater than 5mm across) and may occur as hundreds of lesions on the body surface...they are flat macules, slightly raised plaques with "peebly" surface, or target like lesions with a darker raised center and irregular flat periphery...

they usually show variability in pigmentation (variegation) and borders that are irregular in contour...unlike ordinary moles, dysplastic nevi have a tendency to occur on non-sun exposed as well as on sunexposed body surfaces...

dysplatic nevi have been documented in multple members of families prone to the development of malignant melanoma (the heritable melanoma syndrome)...

in these cases, genetic analyses have demonstraed the trait to be inherited as an autosomal dominant, possibly involving genes located on 1p36, 9p21, 12g14, and others...

transition from these lesions to early melanoma have actually been documented clinically and histologically within a period as short as several weeks..

on histologic examination, dysplastic nevi consist of compound nevi with both architectural and cytologic evidence of abnormal growth...nevus cell nests within the epidermis maybe enlarged and exhibit abnormal fusion or coalescence with adjacent nests...

as part of this process, single nevus cells begin to replace the normal basal layer along the dermoepidermal junction, producing so-called lentiginous hyperplasia...

several lines of evidence support the concept that some dysplastic nevi are precursors of malignant melanoma...in one study, it was shown that in a large number of families prone to the development of melanoms, more than 5% of family members developed melanoma during an 8-year follow-up period, and new melanomas occurred only in individuals with dysplastic nevi...

Malignant Melanoma

malignant melanoma is a relatively common neoplasm that not long ago was considered almost uniformly deadly...although the great proponderance of melanomas arise in the skin, other sites of origin include the oral and anogenital mucosal surfaces, esophagus, meninges, and notably the eye...

atypical melanocytes scattered singly and in irregular nests, presence of mitoses, inflammatory reaction, and the absence of dermal stroma...

malignant melanoma has increased the most in the U.S. in the last five years...

1 in 72 americans will get melanoma...

the following comments apply to cutaneous melanomas...

today as a result of increased public awareness of the earliest signs of skin melanomas, most are cured surgically...nonetheless, the incidence of these leisons is on the rise, necessitating vigoruous surveillance for their development...

as with epithelial malignant neoplasms of the skin, sunlight appears to play a role in the development of skin malignant melanoma...

for example, men commonly develop this tumor on the upper back, whereas women have a relatively high incidence on both the back and the legs...lightly pigmented individuals are at higher risk for the development of melanoma than are darkly pigmented individuals...

sunlight, however, does not seem to be the only predisposing factor, and the presence of a preexisting

nevus (dysplastic nevus), hereditary factors, or even exposure to certain carcinogens (as in the case of experimental melanomas in rodent models) may play a role in lesion development and evolution...

these melanomas are often (but not invariably) associate with multiple dysplastic nevi...some of the suspected melanoma-associated genes in this setting include:

(1) the CMM1 gene, on chromosome 1p36;

(2) the tumor suppressor gene p16, mapped to chromosome 9p21 (genetic analyses have revealed germline mutations in this gene in certain melanoma patients and their family members...it may be recalled that this tumor suppressor gene is an inhibitor of cyclin dependent kinase 4 (CDK4) and as such negatively regulates the cell cycle; and

(3) the cyclin dependent kinase gene CDK4, on chromosome 12q14...

The depth (as measured in millimeters) of invasion by a melanoma correlates well with prognosis. 98% percent of patients with lesions less than 0.75 mm in thickness are disease free after 5 years.

change in the size or color of a 'mole' should suggest the possibility of a melanoma....

APUD tumor...neurosecretory tumor...

malignant melanoma of the skin is usually asymptomatic, although itching may be an early manifestation...

the most important clincial sign of the disease is change in color in a pigmented lesion...unlike benign (nondysplastic) nevi, melanomas exhibit striking variations in pigmentation, appearing in shades of black, brown, red, dark blue, and gray...

on occasion, zone of white or flesh-colored hypopigmentation are also present...

the borders of melanoma are not smooth, round , and uniform, as in nevocellular nevi, but irregular and often "notched"...

in summary, the clinical warning signs of melanoma are

(1) enlargement of a preexisting mole,

(2) itching or pain in a preexisiting mole,

(3) development of a new pigmented leison during adult life,

(4) irregularity of the borders of a pigmented lesion, and

(5) variegation of color within a pigmented lesion...

the most common subtype of melanoma is superficial spreading melanoma, which occurs in approximately 70% of patients and is most commonly found in the trunks and legs...

Seborrheic Keratoses

these common epidermal tumors occur most frequently in middle age or older individuals...they arise spontaneously and may become particularly numerous on the trunk, although the extremities, head, and neck may also be involved...

in people of color, multiple small lesions on the face are termed dermatosis papulosa nigra...

seborrheic keratoses have characteristic clinical features...they appear as round, flat, coinlike plaques that vary in diameter from millimeters to several centimeters...

they are uniformly tan to dark brown and usually show a velvety to granular surface...

lesions may give the impression that they are "stuck on" and may be easily peeled off...

inspection with a hand lens wlll usually reveal small, round, porelike ostia impacted with keratin, a feature helpful in differentiating these pigmented lesions from melanomas...

on histologic examination, these neoplasms are exophytic and demarcated sharply from the adjacent epidermis...they are composed of sheets of small cells that most resemble basal cells of the normal epidermis...

variable melanin pigmentation is present within these basaloid cells, accounting for the brown coloration clinically...

exuberant keratin production (hyperkeratosis) occurs at the surface of seborrheic keratoses, and small keratin filled cysts (horn cysts) and downgrowths of keratin into the main tumor mass (pseudo-horn cysts) are characteristic features...

Acanthosis Nigricans

acanthosis nigricans is used to describe thickened (acanthosis = hyperplasia of the stratum spinsum of the epidermis), hyperpigmented zone of skin involving most commonly the flexural areas (axillae, skin folds of the neck, groin, and anogenital regions)...

it is an important cutaneous marker for associated benign and malignant conditions and, accordingly, is divided into two types...

the benign type, which constitutes about 80% of all cases, develops gradually and usually occurs in childhood or during puberty...

it may occur (1) as an autosomal dominant trait with variable penetrance, (2) in association with obesity or endocrine abnormalities (particularly with pituitary and pineal tumors and with diabetes), and (3) as part of a number of rare congenital syndromes...

as with seborrheric keratoses, acanthosis nigricans may result from abnormal production of epidermal growth promoting factors by a variety of tumors...this occurrence may account from many instances of the malignant type, in which lesions arise in middle ages and older individuals, often in association with an underlying adenocarcinoma...

all forms of acanthosis nigricans have similar histologic features...the epidermis undulates sharply to form numerous repeating peaks and valleys...

variable hyperplasia may be seen, along with hyperkeratosis and slight basal cell layer hyperpigmentation (but no melanocytic hyperplasia)...

Keratoacanthomas

keratocanthoma is a rapidly developing neoplasm that clinically and histologically may mimic well differentiated squamous cell carcinoma, but it may heal spontaneously, without treatment!

men are more often affected than women are, and lesions most frequently affect sun-exposed skin of whites older than 50 years...

keratocanthomas appear clincially as flesh colored, dome shaped nodules with a central, keratin filled plug, imparting a crater like topography...

lesions range in size form 1cm to several centimeters across and have a predilection for facial skin including the cheeks, nose, and ears and the dorsa of the hands...

keratoacanthomas are characterized histologically by a central, keratin-filled crater surrounded by proliferating epithelial cells that extend upward in a liplike fashion over the sides of the crater and downward into the dermis as irregular tongues... 

this epithelium is composed of enlarged cells showing evidence of reactive cytologic atypia...these cells have a characteristically "glassy" eosinophilic cytoplasm and produce keratin abruptly (without the development of an intervening granular cell layer)...

there is growing belief that keratoacanthomas may represent a form of squamous cell carcinoma that regresses as a consequence of interactions with host tissue that fail to support inexorable growth...

the majority of keratoacanthomas have detectable p53 oncoprotein, and occasional tumors show a point mutation in the p53 gene...

Actinic Keratosis (Solar Keratosis)

before the develeopment of overt malignancy of the epidermis, a series of progressively dysplastic changes occur, a phenomenon analogous to the atypia that precedes carcinoma of the squamous mucosa of the uterine cervix..

b/c this dysplasia is usually the result of chronic exposure to sunlight and is associated with buildup of excess keratin, these lesions are called actinic keratoses...as would be expected, they occur in a particularly high incidence in lightly pigmented individuals...

exposure to ionizing radiation, hydrocarbons, and arsenicals may induce similar lesions....

actinic keratoses are usually less than 1cm in diameter; are tan-brown, red, or skin colored; and have a rough, sandpaper like consistency...some lesions may produce so much keratin that a "cutaneous horn" develops...

such horns may become so prominent that they actually resemble the horns of animals...skin sites commonly involved by sun exposure (face, arms, dorsum of hands) are most frequently affected...

the lips may also develop similar lesions (actinic cheilitis)...

cytologic atypica is seen in the lower most layers of the epidermis and may be associated with hyperplasia of basal cells or, alternatively, with early atrophy that results in diffuse thinning of the epidermal surface of the lesion...

the atypical cells usually have evidence of dyskeratosis with pink or reddish cytoplasm...

also, intercellular bridges are present, in contrast to basal cell carcinoma, in which the cytoplasm is usually basophilic and the cell lack intercellular bridges identifiable by light microscopy...

the dermis contains thickened, blue-gray elastic fibers (elastosis), a probable result of abnormal dermal elastic fiber synthesis by sun-damaged fibroblasts within the superfical dermis... 

the stratum corneum is thickened, and unlike in normal skin, nuclei in the cells in this layer are often retained (a pattern termed parakeratosis)...

actinic (solar) keratoses, found on sun-damaged skin, microscopically show hyperkeratosis, parakeratosis, atypia of the epidermal keratinocytes, and degeneration of the elastic fibers in the dermis (referred to as solar elastosis)...

whether all actinic keratoses would eventuate in skin cancer

(usually squamous cell carcinoma), if given enough time, is conjectural...

Squamous Cell Carcinoma

squamous cell carcinoma is the most common tumor arising on sun-exposed sites in older people...except for lesions on the lower legs, these tumors have a higher incidence in men than in women...implicated as predisposing factors, in addition to sunlight, are industrial carcinogens (tars and oils), chronic ulcers and draining osteomyelitis, old burn scars, ingestion of arsenicals, ionizing radiation, and (in the oral cavity) tobacco and betel nut chewing...

the most commonly accepted exogenous cause of squamous cell carcinoma is exposure to ultraviolet light with subsequent DNA damage and associated mutagenicity...in dividuals who are immunosuppressed as a result to chemotherapy or organ transplantation, or who have xeroderma pigmentosum are at increased risk for developing neoplasms...

a considerable proporiton of these are squamous cell carcinomas, implicating aberrations in local immune networks in the skin in the production of an atmosphere permissive to neoplasia...sunlight, in addition to its effect on DNA, also seems to have a direct and atleast a transient immunosuppressive effect on skin by affecting the normal surveillance function of anitgen presenting langerhans cells in the epidermis...

in experimental animals, it now appears that although langerhans cells responsible for T-lymphocyte activation are injured by ultraviolet light, similar cells responsible for the selectivce induction of suppressor lymphocyte pathways are resistent to ultraviolet damage...such a phenomenon could result in local imbalance in T-cell function that would favor tumorigenesis and progression...

DNA sequnces of certain viruses (HPV type 36) have been detected in DNA extracted from potential precursors of squamous cell carcinoma, suggesting a role for these agents in the evolution of certain cutaneous epithelial neoplasms...

finally, certain chemical agents appear to have direct mutagenic effects by producing DNA adducts with subsequent oncogene activation...

squamous cell carcinomas that have not invaded through the basement membrane of the dermoepidermal jucntion (in situ carcionma) appear as sharply defined, red scaling plaques...more advanced, invasive lesion are nodular, show variable keratin production appreciated clinicaly as hyperkeratosis, and may ulcerate...

well differentiated lesions may be indistinguishable from keratocanthoma...when the oral mucosa is involved, a zone of white thickening is seen, an appearance caused by a variety of disorders and referred to clinically as leukoplakia...

unlike actinic keratoses, squamous cell carcinoma in situ is characterized by cells with atypical (enlarged and hyperchromatic) nuclei at all levels of the epidermis...when these cells break through the basement membrane, the process has become invasive...invasive squamous cell carcinoma exhibits variable differentiation, ranging from tumors formed by polygonal squamous cell, arranged in orderly lobules and exhibiting numerous large zones of keratinization, to neoplasms formed by highly anaplastic, rounded cells with foci of necrosis and only abortive, single-cell keratinization (dyskeratosis)...

these latter tumors may be so poorly differentiated that electron microscopy for the detection of keratinocyte intercellular attachment sites (desmosomes) or reaction of tissue with antibodies to keratin or epithelial membrane associated antigens may be necessary to definitively establish cell lineage...

invasive squamous cell carcinomas are usually discovered while they are small and resectable; less than 5% have metastases to regional nodes...

actinic keratosis is a precursor for squamous cell carcinoma...

often associated with third degree burns...

2nd most common skin cancer...

arsenic leads to squamous cell carcinoma...

Basal Cell Carcinoma

These neoplasms are relentless in their local spread. They should be excised as early as possible.

basal cell carciomas are common, slow growing tumors that rarely metastasize...they have a tendency to occur at sites subject to chronic sun exposure and in lightly pigmented people...as with squamous cell carcinoma, the incidence of basal cell carcinoma rises sharply with immunosuppression and in patients with inherited defects in DNA replication or repair (xeroderma pigmentosum)...

basal cell carcinoma is the most common skin cancer...

these tumors present clinically as pearly papules often containing prominent, dilated subepidermal blood vessels (telangiectasias)...some tumors contain melamin pigment and, thus, appear similar to nevocellular nevi or melanomas...

classic clinical appearance is pearly papule with raised margins and a central ulcer...

advanced lesions may ulcerate, and extensive local invasion of bone or facial sinues may occur after many years of neglect or in unusually aggressive tumors, justifying the past designation "rodunt ulcers"...

The lesion is slow growing...

Metastasis is highly unlikely...

He may also have actinic keratoses...

If left alone, it is likely to affect vision...

The lesion may be pigmented...

infiltrating groups of basaloid cells with peritumoral clefting...

on histologic examination, tumor cells resemble those in the normal basal cell layer of the epidermis...they arise from the epidermis or follicular epithelium and do not occur on mucosal surfaces....

two patterns are seen: multifocal growths originating from the epidermis and extending over several square centimeters or more of skin surface (multifocal superfical type); and nodular lesions growing downward deeply into the dermis as cords and islands of variably basophilic cells with hyperchromatic neuclei, embedded in a mucinous matix, and often surrounded by many fibroblasts and lymphocytes...

the cells forming the periphery of the tumor cell islands tend to be arranged radialy with their long axes in approximately parallel allignment (palisading)...

Merkel Cell Carcinoma

this rare neoplasm is derived from the infrequent and functionally obscure Merkel cell of the epidermis, a neural crest derived cell putatively important for tactile sensation in lower animals...

these potentially lethal tumors are composed of small, round malignant cells containing neurosecretory type cytoplasmic granules...

pathologists must be aware of this rare primary skin tumor since it may closely resemble metastatic small cell carcinoma from lung or certain lymphomas that spread to the dermis...

associated with old burn scars...

secretes calcitonin and serotonin...

"Merk's Children are Cal & Sara!"

Benign Fibrous Histiocytoma

benign fibrous histiocytomas refers to a heterogenous family of morphologically and histogenetically related benign dermal neoplasms of fibroblasts and histiocytes...

these tumors are usually seen in adults and often occur on the legs of young to middle age women...their biologic behavior is indolent, and they should not be confused with the unrelated malignant fibrous histiocytoma, which arise de novo in skin and in extracutaneous sites and often have an aggressive clinical course...

on gross inspection, these neoplasms are tan to brown, firm papules...lesions are asymptomatic to slightly tender, and their size may increase and decrease slightly over time...

actively growing lesions may reach several centimeters in diameter, and with time, they often become flattened...the tendency for fibrous histiocytomas to dimple inward on lateral compression is helpful in distinguishing them from nodular melanomas, which proturde when they are similarly manipulated...

benign fibrous histiocytomas are composed of a mixture of fibroblasts, histiocytes (some of which are lipid laden), mesenchymal cells, and capillaries...

the most common form of fibrous histiocytomas is refered to as a dermatofibroma...

these tumors are formed by benign, spindle shaped fibroblasts arranged in a well defined, nonencapsulated mass within the mid-dermis...

extension of these cells into the subcutaneous fat is frequently observed...the majority of cases demonstrate a peculiar form of overlying epidermal hyperplasia, characterized by downward elongation of hyperpigmented rete ridges ("dirty fingers" pattern)...

although foamy histiocytes may be seen in dermatofibromas, they are generally not conspicuous...

certain variants are composed predominantly of these foamy histiocytes admixed with a paucity of fibroblasts..

dermatofibromas - mainly fibroblasts...

fibroxanthomas - mainly histiocytes...

slcerosing hemangiomas - mainly blood vessels...

finally, variants containing numerous blood vessels and deposits of hemosiderin may be encountered (sclerosing hemangiomas)...

the histogenesis of fibrous histiocytomas remains a mystery....many cases have a history of antecedent trauma, suggesting an abnormal response to injury, perhaps analogous to the deposition of increased amounts of altered collagen in a hypertrophic scar or keloid...

Xanthomas

xanthomas are tumor-like collections of foamy histiocyts within the dermis...they may be associated with familial or acquired disorders resulting in hyperlipidemia, with lymphoproliferative malignant neoplasms, or with no underlying disorder...

on the basis of clinical apppearance, xanthomas are divided into five types...b/c identificaiton of these types may provide important clinical markers of the underlying hyperlipoproteinemia, the classes of lipid abnormality (types I to V) are specified for each kind of clinical lesion...

eruptive xanthomas (types I, IIB, III, IV, V) occur as sudden showers of yellow papules that wax and wane according to variation in plasma triglyceride and lipid content...they occur on the buttocks, posterior thighs, knees, and elbows...

tuberous (types IIA, III; rarely IIB, IV) and tendinous (types IIA, III; rarely IIIB) xanthomas occur as yellow nodules; the latter frequently are found on the achilles tendon and the extensor tendons of the fingers... 

plane xanthomas (type III; IIA associated with primary biliary cirrhosis) are linear yellow lesions in the skinfolds, especially the palmar creases...

Xanthelasma (types IIA, III; also without lipid abnormality) refers to soft yellow plaques on the eyelids...

all types are characterized histologically by dermal accumulation of benign appearing hitiocytes with abundant, finely vacuolated (foamy) cytoplasm...

cholesterol (free and esterified), phospholipids, and triglycerides are present within cells...

Histiocytosis X

in the skin, this condition presents in multiple forms, including solitary or multiple lesions ranging from papules to nodules to scaling erythematous plaques that in infants may resemble seborrheic dermatitis...

histiocytosis X involving the skin has several histologic patterns, all of which may show marked infiltration of the skin...

the first is that of a diffuse dermal infiltrate of large, round to ovoid cells with pale pink cytoplasm containing indented, often bland nuclei...a second pattern consists of a clustering of similar cells into small aggregates that resemble granulomas...the third is characterized by a dermal infiltrate of cells with foamy, xanthoma-like cytoplasm...

variable numbers of eosinophils may also be observed, particularly with the first pattern...b/c these patterns are not specific, special immunohistiochemical methods to identify cell surface markers common to langerhans cells and histiocytosis X cells (CD1a antigen) may be necessary to establish a definitive histologic diagnosis...

in addition, ultrastructural identification of specific organelles (birbeck granules) characteristic of the epidermal langerhans cells from which histiocytosis X cells are believed to originate is also helpful...

Mycosis Fungoides (Cutaneous T-cell Lymphoma, CTCL)

CTCL represents a spectrum of lymphoproliferative disorders affecting the skin...two types of malignant T cell disorders were originally recognized: mycosis fungoides, a chronic proliferative process; and a nodular eruptive variant, mycosis fungoides d'emblee...

it is now known that a variety of presentations of T-cell lymphoma occur, including mycosis fungoides, the eruptive nodular type, and an adult T-cell leukemia or lymphoma type...the latter disorder may have a rapid progressive dowhill course...

mycosis fungoides is the T-cell lymphoproliferative disorder that arises primarily in the skin and that may evolve into generalized lymphomas...most affected individuals have disease that remains localized to the skin for many years; a minority have rapid systemic dissemination...this condition may occur at any age, but most commonly it afflicts persons older than 40 years...

clinically, lesions of the mycosis fungoides type of CTCL include sclay, red-brown patches; raised, scaling plaques that may even be confused with psoriasis; and fungating nodules...

eczema like lesions typify early stages of disease when obvious visceral or nodal spread has not occurred...raised, indurated, irregularly outlined, erythematous plaques may then supervene...

development of multiple, large (up to 10cm or more in diameter), red-brown nodules correlates with systemic spreading...sometimes plaques and nodules ulcerate...lesions may affect numerous body surfaces, including the trunk, extremities, face, and scalp...in some individuals, seeding of the blood by malignant T cells is accompanied by diffuse erythema and scaling of the entire body surface (erythroderma), a condition known as Sezary syndrome...

the hallmark of CTCL of the mycosis fungoides type histologically is the identificaiton of the Sezary-Lutzner cells...

there are T-helper cells (CD4 antigen positive) that characteristically form bandlike aggregates within the superfical dermis and invade the epidermis as single cells and small clusters (Pautrier microabscesses)...

these cells have markedly infolded nuclear membranes, imparting a "hyperconvoluted" or "cerebriform" contour...

HTVL-1 has been implicated in certain forms of T-cell lymphoma, and CTCL may also have an infectious causation...the proliferating cells in CTCL are clonal populations of lymphocytes of the CD4 subset...

these cells often express aberrant cell surface antigens as well as clonal T-cell receptor gene rearrangements, and detection of these features maybe of diagnostic assistance in difficult cases...

topical therapy with steroids or ultraviolet light is often emplyed for early lesion of CTCL, whereas more aggressie systemic chemotherapy is indicated for advanced disease...

Urticaria

urticaria (hives) is a common disorder of the skin characterized by localized mast cell degranulation and resultant dermal microvascular hyperpermeability, culminating in pruritic edematous plaques called wheals...

the histologic features of urticaria may be so subtle that many biopsy specimens at first resemble normal skin...

there is usually a sparse superficial perivenular infiltrate consisting of mononuclear cells and rare neutrophils...

in most cases, urticaria results from antigen induced release of vasoactive mediators from mast cell granules through sensitizaiton with specific immunoglobulin E (IgE) antibodies...

Erythema Multiforme

erythema multiforme is an uncommon self-limited disorder that appears to be a hypersensitivity response to certain infections and drugs...erythema multifomre is a prototype of a cytotoxic reaction pattern (one typified by extensive epithelial cell degeneration and death)...

this disorder affects individuals of any age and is associated with the following conditions: (1) infections such as herpes simplex, mycoplasmal infections, histoplasmosis, coccidioidomycosis, typhoid, and leprosy, among others; (2) administration of certain drugs (sulfonamides, penicillin, barbiturates, salicylates, hydantoins, and antimalarials); (3) malignant disease (carcinomas and lymphomas); and (4) collagen vascular diseases (lupus erythematosus, dermatomyositis, and perarteritis nodosa)...

patients present clinically with an array of "multiform" lesions including macules, papules, vesicles, and bullae as well as the characteristic target lesion consisting of a red macule or papule with a pale, vesicular, or eroded center...

although lesions may be widely distributed, symmetric involvement of the extremities frequently occur...an extensive and symptomatic febrile form of the disesase, which is more common in children, is called the Steven-Johnson syndrome...

typically, erosions and hemorrhagic crusts involve the lips and oral mucosa, although the conjunctiva, urethra, and genital and perinal areas may also be affected...infection of involved areas may result in life-threatening sepsis...another variant, termed toxic epidermal necrolysis, results in diffuse necrosis and sloughing of cutaneous and mucosal epithelial surfaces, producing a clinical situation analogous to an extensice burn...

on histologic examination, early lesions show a superficial perivascular, lymphocytic infiltrate associated with dermal edema and margination of lymphocytes along the dermoepidermal junction, where they are intimately associated with degenerating and necrotic keratinocytes...

Psoriasis

psoriasis is a chronic skin disease characterized by large, sharply defined silver-white scaly erythematous palques...

HLA-B13...

psoriasis is a common chronic inflammatory dermatosis affecting as many as 1-2% of people in the United States...persons of all  ages may develop the disease...psoriasis is sometimes associated with arthritis, myopathy, enteropathy, spondylitis heart disease, or the acquried immunodeficiency syndrome...

psoriatic arthritis may be mild or may produce severe deformities resembling the joint changes seen in RA...

clinically, psoriassis most frequently affects the skin of the elbows, knees, scalp, lumbosacral areas, intergluteal cleft, and glans penis...the most typical lesion is a well demarcated, pink to salmon colored palque covered by loosely adherent scales that are characteristically silver white in color..

variations exist, with some lesions occurring in annular, linear, gyrate, or serpinginous configurations...

psoriasis can be one cause of total body erythema and scaling known as erythroderma...nail changes occur in 30% of cases of psoriasis and consist of yellow-brown discoloration (often likened to tan oil slick), with pitting , dimpling, separation og the nail plate from the underlying bed (onycholysis), thickening, and crumbling...

increased rate of keratinocyte proliferation...

increased epidermal cell turnover results in marked epidermal thickening (acanthosis), with regular downward elognation of the rete ridges...

positive Auspitz Sign (scale of psoriasis is lifted and starts to bleed)...

mitotic figures are easily identified well above the basal cell layer, where mitotic activity is confined in normal skin...

neutrophils form small aggregates within slightly spongiotic foci of the superficial epidermis (spongiform pustules) and within the parakeratotis stratum corneum (munro microabscesses)... 

determination of the pathogenesis of psoriasis is one of the most important challenges in dermatopathologic research...an increased incidence of disease in association with certain HLA types suggest that genetic factors participate in the predispositon for disease development...

the genesis of new lesions at sites of trauma (the Koebner phenomenon) provides certain clues...numerous theories exist, including those that suggest that lesions may result from unmasking of stratum corneum antigens with related antibody and complement depostion, or that lesions evolve at sites containing abnormally reactive endothelial cells...

recent data suggest that lymphocytes from patients with psoriasis are capable of inducing abnormal growth of keratinocytes and dermal blood vessels...

if these results hold, then psoriasis is a systemic disorder of the immune system capable of provoking activation and disordered growth of certain skin cells...

psoriasis is associated with RA in 5% of cases...

HLA-B13...

has a great tendency to recur b/c it is very persistent in the pathological process...

Lupus Erythematosus

however, a localized, cutaneous form of lupus erythematosus, with no associated systemic manifestations, occurs and is called discoid lupus erythematosus (DLE)...

patients who present with DLE usually do not go on to develop systemic disease...however, more than one third of patients with SLE may exhibit, during their course, lesions that are clinicaly and histologically indistinguishable from those of the discoid type...thus, it is often impossible to distinguish patients with SLE from those with DLE on the basis of clinical and histologic inspection of skin lesions alone...

cutaneous lesions usually consist of either poorly defined malar erythema (usuallly seen in systemic disease) or large, sharply demarcated erythematous scaling palques...

these "discoid" plaques may occur in either pure cutaneous lupus erythematosus or SLE...cutaneous manifestations of lupus erythematosus may develop or worsen with sun exposure...

the epidermal surface of lesions is shiny or scaly, and lateral compression often produces wrinkling, a sign of epidermal atrophy...through this thinned epidermis, dilated and tortuous blood vessels (telangiectasia) and small zones of hypopigmentation and hyperpigmentation may be seen...small, keratotic plugs in follicular ostia may be appreciated with a hand lens...

lesions of DLE are characterized histologically by an infiltrate of lymphocytes along the dermoepidermal or the dermal-follicular epithelial junction, or both...

in the skin, it is believed that both humoral and cell mediated mechanism collaborate to result in destruction of pigment-containing basal cells...

humoral mechanisms of injury may involve both formation and depostion of immune complexes and components C5b to C9 ("membrane attack complex") at the dermoepithelial junction...

SLE

Immunofluorescence staining performed on a biopsy of skin reveals band-like deposition of IgG and C3 at the dermal-epidermal junction... 

Pemphigus

pemphigus is an atuoimmune blistering disorder resulting from loss of the intergrity of normal intercellular atttachments within the epidermis and mucosal epithelium...

caused by a disruption of desmosomes linking keratinocytes...

although rare, its clinical consequences without treatment may be life threatening, and its pathobiology provides important insight into molecular mechanisms of keratinocyte adhesion...

the majority of individuals who develop pemphigus are in the fourth to sixth decades of life, and men and women are affected equally...

there are four clinical and pathologic variants: (1) pemphigus vulgaris, (2) pemphigus vegetans, (3) pemphigus foliaceus, and (4) pemphigus erythematosus...

pemphigus vulgaris, by far the most comon type (accouting for more than 80% of cases worldwide), involves mucosa and skin, especially on the scalp, face, axilla, groin, trunk, and portions of pressure...

it may present as oral ulcers that persist sometimes for months before skin involvement appears...

primary lesions are superfical vesicles and bullae that rupture easily, leaving shallow erosions covered with dried serum and crust...

autoantibodies are found at the intercellular junctions of epidermal cells...

positive Nikolsky sign as a result of lack of adhesion in the epidermis, so the upper layers can be made to slip laterally by slight pressure or rubbing...

the common denominator, histologically, in all forms of pemphigus is acantholysis...

this term implies dissolution, or lysis, of the intercellular adhesion sites within a squamous epithelial surface...acantholytic cells that are no longer attached to other epithelial cells lose their polyhedral shape and characteristically become rounded...

in pemphigus vulgaris and pemphigus vegetans, acantholysis selectively involves the layer of cells immediately above the basal cell layer...

the vegetans variant has considerable overlying epidermal hyperplasia...

the suprabasal acantholytic blister that forms is characteristic of pemphigus vulagaris...

sera from patients with pemphigus contain antibodies (IgG) to intercellular cement substance of skin and mucous membranes...this phenomenon is the basis for direct and indirect diagnostic immunofluorescence testing of skin and serum, respectively...

lesional sites show a characteristic netlike pattern of intercellular IgG deposits localized to sites of developed or incipient acantholysis...

Stedmans Definition of Acantholysis - Separation of individual epidermal keratinocytes from their neighbor, as in conditions such as pemphigus vulgaris and Darier disease.

Bullous Pemphigoid

originally considered to be a form of pemphigus, bullous pemphiogoid has been recognized for almost the last four decades as a distinct and relatively common autoimmune, vesiculobullous disease...

generally affecting elderly individuals, bullous pemphogoid shows a wide range of clinical presentations, with localized to generalized cutaneous lesions and involvement of mucosal surfaces...

clinically, lesions are tense bullae, filled with clear fluid, on normal or erythematous skin...the size may reach 4-8cm in diameter...the bullae do not rupture as easily as do the blisters seen in pemphigus and, if uncomplicated by infeciton, heal withoug scarring...

sites of occurrence include the inner aspects of the thighs, flexor surfaces of the forearms, axillae, groin, and lower abdomen...oral involvement is present in up to one third of patients, usually after the development of cutaneous lesions...

some patients may present with urticarial plaques, with extreme associated pruritus...

the separation of bulous pemphigoid from pemphigus, establising the former as a distinctive entity, was based on the seminal observation that pemphigoid resulted from a  subepidermal, nonacantholytic blister...

in bullous pemphogoid there is linear basement membrane zone depositon of immunoglobulin and complement (recall that the pattern for lupus erythematosus is similar, but granular in character)...

the presence of IgG is directed against an antigen in the lamina lucida...

ultrastructural studies have shown that circulating antibody reacts with antigen present in the basal celll - basement membrane attachment plaques (hemidesmosomes)...the actual blister develops at the level of a narrow clear zone (lamina lucida) of the epidermal basement membrane that separates the underlying lamina dense from the plasma membrane of the basal cells..

the antigens present at these sits have been named bullous pemphigoid antigens 1 and 2, and they are now recognized as normal constituents of the hemidesmosomes that bind basal cells at the dermoepidermal junction...

in bullous pemphigoid, it is likely that the generation of autoantibodies to these basement membrane conponents results in the fixation of complement and subsequent tissue injury at this site through locally recruited neutrophils and eosinophils...

Dermatitis Herpetiformis

dermatitis herpetiformis is a rare and fascinating entity characterized by urticaria and vesicles...males tend to be affected more frequently than are females, and the age at onset is often in the third and fourth decades, although disease has been known to develop at any age after weaning...

a major association is with celiac disease; both the vesicular dermatosis and the enteropathy respond to a diet free of gluten...

the urticarial palques and vesicles of dermatitis herpetiformis are extremely pruritic...

they characteristically occur bilaterally and symmetrically, involving preferentially the extensor surfaces, elbows, knees, upper back and buttocks...

vesicles are frequently grouped, as are those of true herpesvirus, and hence the name herpetiform...

the early lesions of dermatitis herpetiformis are histologically characteristic...fibrin and neutrophils accumulate selectively at the tips of dermal papillae, formign small "microabscesses"...

the basal cells overlying these microabscesses show vacuolization, and minute zones of dermoepidermal separation (microscopic blisters) may occur at the tips of involved papillae...

gluten is the protein moiety that persists subsequent to the removal of water and starch from defatted four...gliadin is a class of protein found in the gluten fraction of flour...

patients with dermatitis herpetiformis may develop antibodies of the IgA and IgG classes to gliadin and reticulin, a component of the anchoring fibrils that tether the epidermal basement membrane to the superfical dermis...

in addition, individuals with certain histocompatibility types (HLA-B8 and HLA-DRw3) are particularly prone to this disease...

Impetigo

impetigo is frequently seen in normal children as well as in adults in poor health...cultures most frequently grow coagulase-positive staphylococci or group A beta-hemolytic streptococci, or both...

nephritogenic strains of streptococcus cause impetigo, particularly in tropica areas and in the southern united states...

the condition usually involves exposed skin, particularly that of the face and hands...initially it is an erythematous macule, but multiple small pustules rapidly supervene...

as pustules break, shallow erosions form, covered with drying serum, giving the characteristic clinical appearance of honey-colored crust...

if the crust is not removed, new lesiosn form about the periphery and extensive epidermal damage may ensue...

a bullous form of impetigo occurs in children...

the characteristic microscopic features of impetigo is accumulation of neutrophils beneath the stratum corneum, often with the formation of a subcorneal pustule...

special stains reveal the presence of bacteria in these foci...nonspecific, reactive epidermal alterations and superfical dermal inflammation accompany these findings...

rupture of pustules results in superficial layering of serum, neutrophils, and cellular debris to form the characteristic crust...