2 - PATHOLOGY OF SKIN LESIONS Flashcards
Different tissue compartments interconnect anatomically and interact functionally. These are the _______________
reactive units of the skin
The superficial reaction unit comprises the _______
epidermis, the junctional zone, and the papillary body with its vascular system
the second reactive unit
The reticular dermis with the deeper dermal vascular plexus
The third reactive unit
subcutaneous tissue with its septal and lobular compartments.
fourth reactive unit embedded into these three units
Hair follicles and glands
Type of biosy which is best for cases where most of the pathology is in the epidermis or superficial dermis
shave biopsies
Examples include nonmelanoma skin cancer (basal cell carcinoma, squamous cell carcinoma), seborrheic keratosis, actinic keratosis, verruca vulgaris, and some melanocytic nevi. For most inflammatory dermatoses, a punch biopsy produces the best results.
Type of biopsy used for complete removal of a cutaneous neoplasm as well as in cases of panniculitis or fasciitis where substantial deep tissue is needed
Excisional biopsies
Type of biopsy restricted to lesions with a known diagnosis, such as a seborrheic keratosis, verruca, or basal cell carcinoma, where histopathologic examination is less important, and mostly performed for confirmation.
Curettage
Curettage results in fragmented and distorted tissue making evaluation by the pathologist extremely difficult.
Where is the best site for biopsy?
It is best to choose lesions that have not been treated, excoriated, or secondarily infected. In general, it is better to choose fully evolved lesions rather than a brand-new lesion.
The exception is blistering disorders, when a new blister is ideal. In this scenario, it is important to include the edge of the blister as well as the surrounding skin that has not yet blistered.
When a biopsy is performed for alopecia, two 4-mm punch biopsies are optimal:
one for horizontal sections and one for vertical sections.
Identify the Type of Biopsy:
Actinic keratosis
Shave
Identify the Type of Biopsy:
Seborrheic keratosis
Shave
Identify the type of biopsy
Verruca
Shave
Identify the type of biopsy
BCC, SCC
Shave most common; punch/excision
Identify the type of biopsy
blistering disease
Punch or deep shave edge of blister
Identify the type of biopsy
contact dermatitis
punch
Identify the type of biopsy
Connective tissue disease
punch
Identify the type of biopsy
mycosis fungoides
punch
Identify the type of biopsy
Vasculitis
Punch
Identify the type of biopsy
granulomatous process
punch
Identify the type of biopsy
atypical nevi
Deep shave, punch, or excision
Identify the type of biopsy
panniculis
Punch (minimum 6 mm) or ellipse
In cold weather, ________ must be added to the formalin to prevent freezing of the tissue and subsequent freeze artifacts, which can lead to misdiagnosis.
95% ethyl alcohol (10% of the formalin volume)
Pathophysiologically, the skin can be subdivided into 3 reactive units that extend beyond anatomic boundaries (Fig. 2-1); they overlap and can be divided into different subunits that respond to pathologic stimuli according to their inherent reaction capacities in a coordinated pattern:
(a) superficial reactive unit,
(b) reticular dermis, and
(c) subcutaneous fat.
Hair follicles and glands are a separate reactive unit that are predominantly in the reticular dermis.
Figure 2-1 Reactive units of skin. The superficial reactive unit (SRU) comprises the epidermis (E), the junction zone (J), and the papillary body (PB, or papillary dermis) with the superficial microvascular plexus. The dermal reactive unit (DRU) consists of the reticular dermis (RD) and the deep dermal microvascular plexus (DVP). The subcutaneous reactive unit (S) consists of lobules (L) and septae (Sep). A fourth unit is the appendages (A; hair and sebaceous glands are the only appendages shown). HF, hair follicle.
The superficial reactive unit is composed of
epidermis, the junction zone, the subjacent loose, delicate connective tissue of the papillary dermis and its capillary network, and the superficial vascular plexus
Figure 2-1 Reactive units of skin. The superficial reactive unit (SRU) comprises the epidermis (E), the junction zone (J), and the papillary body (PB, or papillary dermis) with the superficial microvascular plexus. The dermal reactive unit (DRU) consists of the reticular dermis (RD) and the deep dermal microvascular plexus (DVP). The subcutaneous reactive unit (S) consists of lobules (L) and septae (Sep). A fourth unit is the appendages (A; hair and sebaceous glands are the only appendages shown). HF, hair follicle.
EPIDERMIS
Keratinocytes represent the bulk of the epidermis. The epidermis, an ectodermal epithelium, also harbors a number of other cell populations such as melanocytes, Langerhans cells, and Merkel cells. The basal cells of the epidermis undergo proliferation cycles that provide for the renewal of the epidermis and, as they move toward the surface of the skin, undergo a differentiation process that results in surface keratinization. Thus, the epidermis is a dynamic tissue in which cells are constantly nonsynchronized replication and differentiation; this precisely coordinated physiologic balance between progressive keratinization as cells approach the epidermal surface to eventually undergo programed cell death and be sloughed, and their continuous replenishment by dividing basal cells, is in contrast to the relatively static minority populations of Langerhans cells, melanocytes, and Merkel cells.
Commonly Used Immunohistochemical Stains
Epithelial Markers
P63
Cutaneous spindle cell squamous carcinoma
Epithelial Markers
CAM5.2, CK7
Paget disease, extramammary Paget disease
Epithelial Markers
CK20
Merkel cell carcinoma
Epithelial Markers
Epithelial membrane antigen (EMA)
Squamous cell carcinoma
Epithelial Markers
Carcinoembryonic antigen (CEA)
Sweat gland neoplasms, Paget disease, extramammary Paget disease
Mesenchymal Markers
Desmin
Skeletal and smooth muscle tumors (leiomyoma)
Mesenchymal Markers
Smooth muscle actin (SMA)
Glomus tumor, leiomyosarcoma
Mesenchymal Markers
CD34
Dermatofibrosarcoma protuberans, trichoepitheliomas
Mesenchymal Markers
Factor XIIIa
Dermatofibroma
Mesenchymal Markers
CD31
Vascular tumors
Mesenchymal Markers
D2-40 (podoplanin)
Lymphatic endothelial marker
Mesenchymal Markers
GLUT1
Infantile hemangiomas
Mesenchymal Markers
Vimentin
Sarcomas
Neuroectodermal Markers
S100
Desmoplastic melanoma, Langerhans cell histiocytosis, granular cell tumor
Neuroectodermal Markers
HMB-45
Desmoplastic melanoma, blue nevus
Neuroectodermal Markers
Melan-A, Mart-1
Desmoplastic melanoma
Hematopoietic Markers
CD45Ra (LCA)
Hematolymphoid proliferations
Hematopoietic Markers
CD20
B-cell lymphomas
CD10 (CALLA)
Atypical fibroxanthomas, clear-cell hidradenoma, sebaceous tumors
CD79a
Plasma cell, B-cell marker
CD138 (syndecan-1)
Plasma cell marker
CD3
T-cell lymphomas
CD4
T-helper lymphocytic marker
CD5
Mantle cell lymphoma, chronic lymphocytic leukemia
CD7
Most commonly lost antigen in T-cell lymphoma
CD8
T-cell cytotoxic/suppressor marker
CD30
Anaplastic large cell lymphoma, lymphomatoid papulosis, chronic arthropod bites (scabies, tick)
CD1a
Langerhans cell histiocytosis
Langerin CD207)
Langerhans cells
BCL2
B-cell lymphoproliferative disorders
HHV8
Kaposi sarcoma
Commonly Used Histochemical Stains
Enhanced cell proliferation accompanied by an enlargement of the germinative cell pool and increased mitotic rates lead to an increase of the epidermal cell population and thus to a thickening of the epidermis
acanthosis
Figure 2-2 Acanthosis. The epidermis on the right side of this photomicrograph is thicker than normal because of a proliferation of keratinocytes.
thinning of epidermis, Fig. 2-3
Figure 2-3 Atrophy. The epidermis is thin and there is flattening of the rete ridge architecture.
Although there are many causes of atrophy, one primary etiology is a decrease in epidermal proliferative capacity, as may be seen with physiological aging or after the prolonged use of potent topical or systemic steroids. With atrophy, the epidermal rete ridges are initially lost, followed by progressive thinning of the epidermal layer.
faulty and accelerated cornification leads to retention of pyknotic nuclei of epidermal cells at the epidermal surface
parakeratosis
Instead of the normal anucleate “basket-weave” pattern, one sees retained nuclei in the stratum corneum. Parakeratosis can be the result of incomplete differentiation (eg, squamous cell carcinoma), or the result of reduced transit time, which does not permit epidermal cells to complete the entire differentiation process (eg, psoriasis).
represents altered, often premature or abnormal, keratinization, of individual keratinocytes, but it also refers to the morphologic presentation of apoptosis of keratinocytes.
Dyskeratosis
Dyskeratotic cells have an eosinophilic cytoplasm and a pyknotic nucleus and are packed with keratin filaments arranged in perinuclear aggregates. It is important to remember that although both premature or abnormal keratinization and apoptosis may produce an end-product referred to as “dyskeratosis,” the early events and mechanisms responsible are different. Whereas cells early in the process of abnormal keratinization often have increased eosinophilic keratin aggregates within their cytoplasm with viable-appearing nuclei, apoptotic cells during early evolutionary stages have shrunken, pyknotic, and sometimes fragmented nuclei in the setting of normal-appearing cytoplasm.
In some diseases, dyskeratosis is the expression of a genetically programed disturbance of keratinization as is the case in Darier disease. Dyskeratosis may occur in actinic keratosis and squamous cell carcinoma. Dyskeratosis may also be caused by direct physical and chemical injuries. In the sunburn reaction, eosinophilic apoptotic cells—so-called sunburn cells—are found within the epidermis within the first 24 hours after irradiation with ultraviolet B (UVB); similar cells may occur after high-dose systemic cytotoxic treatment. Individual cell death within the epidermis is a regular phenomenon in graft-versus-host disease and in erythema multiforme.
result of intercellular attachment devices (desmosomes) and the related intercellular molecular interactions
Epidermal cohesion
Desmosomes dissociate and reform at new sites of intercellular contact as cells migrate through the epidermis and keratinocytes mature toward the epidermal surface. The most common result of disturbed epidermal cohesion is the intraepidermal vesicle, a small cavity filled with fluid. Table 2-4 shows a classification of blistering diseases.
an example of the secondary loss of cohesion between epidermal cells caused by the influx of tissue fluid into the epidermis
spongiosis
Serous exudate may extend from the dermis into the intercellular compartment of the epidermis; as it expands, epidermal cells remain in contact with each other only at the sites of desmosomes, acquiring a stellate appearance and giving the epidermis a sponge-like morphology (spongiosis). As the intercellular edema increases, increased white space is noted between keratinocytes (Fig. 2-4), individual cells rupture and lyse, and microcavities (spongiotic vesicles) result. Confluence of such microcavities leads to larger blisters. Leukocytes then migrate into the epidermis with spongiotic edema, which is best illustrated in acute allergic contact dermatitis. The accumulation of polymorphonuclear leukocytes within the epidermis eventually leads to the formation of a pustule.
Figure 2-4 Spongiosis. Accumulation of fluid in the epidermis is manifested by white space between the keratinocytes.
primary loss of cohesion of epidermal cells
Acantholysis
Figure 2-5 Acantholysis. Epidermal keratinocytes separate from each other and take on a rounded, rather than elongate, appearance.
This is initially characterized by a widening and separation of the interdesmosomal regions of the cell membranes of keratinocytes, followed by splitting and a disappearance of desmosomes. The cells are intact but are no longer attached; they revert to their smallest possible surface and round up (Fig. 2-5). Intercellular gaps result, and the influx of fluid from the dermis leads to a cavity, which may form in a suprabasal, midepidermal, or even subcorneal location. Acantholysis occurs in a number of different pathologic processes that do not have a common etiology and pathogenesis. In the pemphigus group, acantholysis results from the interaction of autoantibodies and antigenic determinants on the keratinocyte membranes and related desmosomal adhesive proteins, and in the staphylococcal scalded-skin syndrome, it is caused by a staphylococcal exotoxin. In familial benign pemphigus, it results from the combination of a genetically determined defect of the keratinocyte cell membrane and exogenous factors.
A similar phenomenon, albeit more confined to the suprabasal epidermis, occurs in Darier disease, where it is combined with dyskeratosis in the upper epidermal layers (Fig. 2-6) and a compensatory proliferation of basal cells. When acantholysis results from viral infection, it is usually combined with other cellular phenomena such as ballooning, giant cells, and nuclear moulding.
Figure 2-6 Acantholysis and dyskeratosis. This combination of features can be seen in Darier disease, warty dyskeratoma, and Grover disease.
Indeed, a loss of epidermal cohesion can also result from a primary dissolution of cells (ie, cytolysis). In the epidermolytic forms of epidermolysis bullosa, genetically defective and thus structurally compromised basal cells rupture as a result of trauma so that the cleft forms through the basal cell layer. Cytolytic phenomena in the stratum granulosum are characteristic for epidermolytic hyperkeratosis, bullous congenital ichthyosiform erythroderma, ichthyosis hystrix, and some forms of hereditary palmoplantar keratoderma.
In bullous pemphigoid (Fig. 2-7), cleft formation runs through the lamina lucida of the basal membrane and is caused by autoantibodies directed against specific antigens on the ______
cytomembrane of basal cells (junctional blistering)
Junctional blistering also occurs in the junctional forms of epidermolysis bullosa, but here it is due to the hereditary impairment or absence of molecules important for dermal–epidermal cohesion.
there is an inflammatory reaction of the papillary dermis and superficial microvascular plexus and spongiosis of the epidermis.
Lymphocytes infiltrate the epidermis early in the process and aggregate around Langerhans cells, and this is followed by spongiotic vesiculation (Fig. 2-8). Parakeratosis develops as a consequence of epidermal injury and proliferative responses, and the inflammation results in acanthosis and hyperkeratosis in chronic lesions.
spongiotic dermatitis such as nummular, contact, and atopic dermatitis
Figure 2-8 Spongiotic dermatitis. Accumulation of fluid in the epidermis leads to formation of an intraepidermal microvesicle.
The initial pathologic events in psoriasis appear to be the ______
perivascular accumulation of lymphocytes within the papillary dermis and focal migration of leukocytes (often neutrophils, although T cells are also integral to pathogenesis) into the epidermis.
Acanthosis caused by increased epidermal proliferation, elongation of rete ridges sometimes accompanied by an undulant epidermal surface (papillomatosis), and edema of the elongated dermal papillae together with vasodilatation of the capillary loops develop almost simultaneously (see Fig. 2-9).
Figure 2-9 Psoriasis. There is uniform thickening of the epidermis with elongate rete ridges and a diminished granular layer.
The disturbed differentiation of the epidermal cells results in parakeratosis, and small aggregates of neutrophils infiltrating the upper epidermis (spongiform pustules), in the parakeratotic stratum corneum (Munro microabscesses). Therefore, the composite picture characteristic of psoriasis results from a combined pathology of the papillary dermis with participation of superficial venules, the epidermis, and circulating cells. Psoriasis is an instructive example of the limited specificity of histopathologic reaction patterns within the skin because psoriasiform histologic features occur in a number of diseases unrelated to psoriasis.
In an ______ reaction, the infiltrate is sparse, and in _______ reactions, the infiltrate is dense and band-like at the dermal–epidermal junction.
In an interface reaction, the infiltrate is sparse, and in lichenoid reactions, the infiltrate is dense and band-like at the dermal–epidermal junction.
Subsequently there is dyskeratosis of keratinocytes, hyperkeratosis, and, occasionally, hypergranulosis (lichen planus, Fig. 2-10). Depending on the disease state, the epidermis may be thickened (lichen planus) or atrophic (lupus erythematosus).
Figure 2-10 Lichen planus. An acanthotic epidermis with a band-like lymphocytic infiltrate that approximates the dermal–epidermal junction.
In addition to lupus erythematosus and lichen planus, interface/lichenoid changes can be seen in dermatomyositis, erythema multiforme, secondary syphilis, fixed drug reaction, graft-versus-host disease, and lichenoid drug reactions. Differentiating these entities depends on the cellular makeup of the infiltrate (lymphocytes, eosinophils, plasma cells) and, importantly, the clinical presentation.
the roof of the blister is composed of full-thickness intact epidermis, and the floor of the blister is dermis without attached keratinocytes
Subepidermal Blistering Processes
In evaluating this group of diseases, one studies the edge of the blister and the character of the inflammatory cells. For example, in bullous pemphigoid, eosinophils align at the dermal–epidermal junction, at the edge of the blister (see Fig. 2-7).
If neutrophils are seen in this area, the differential diagnosis includes dermatitis herpetiformis, linear immunoglobulin A disease, bullous lupus erythematosus, and inflammatory epidermolysis bullosa acquisita. Subepidermal blistering with little to no inflammatory cells generally indicates porphyria cutanea tarda, epidermolysis bullosa acquisita, or the cell-poor variant of pemphigoid. Direct and indirect immunofluorescence testing and/or enzyme-linked immunosorbent assay (ELISA) testing for antibodies to BP180/BP230 are often helpful in distinguishing entities in the subepidermal blister disease group.
In the superficial microvascular system, two reaction patterns occur:
(a) acute inflammatory processes in which the epidermis and junctional zone are often involved together with the vascular system, and (b) more chronic processes that often remain confined to the perivascular compartment.
Figure 2-11 Angiocentric pattern. Inflammatory cells are seen primarily around small vessels in the dermis.
In this context, it should be noted that the cytologic composition of the infiltrate is important: neutrophils, eosinophils, lymphocytes, mast cells. For example, an infiltrate composed mostly of neutrophils associated with fibrin and hemorrhage is typical of small vessel or leukocytoclastic vasculitis that presents clinically as palpable purpura. In contrast, perivascular lymphocytes with hemorrhage is typical of Schamberg’s pigmented purpuric dermatosis.
Follicular units (hair follicle with sebaceous gland), eccrine ducts/glands, and apocrine glands constitute the skin adnexal structures. Inflammatory processes concentrated predominantly around hair follicles raise a differential diagnosis of folliculitis, acneiform processes, and infectious folliculitis by bacteria, fungus, or herpesvirus. Perieccrine inflammation is not specific, but it is often a clue that leads to a diagnosis of lupus erythematosus, neutrophilic eccrine hidradenitis, perniosis, or syringotropic mycosis fungoides. Evaluation of the character of the infiltrate is important in the pattern.
Periadnexal Pattern (Fig. 2-12)
Figure 2-12 Perifollicular pattern. In this example of folliculitis, inflammatory cells surround a follicle.
In this pattern of inflammation, the collections of dermal cells form larger aggregates than what is seen in the angiocentric pattern. Similar to other patterns, one must evaluate the cellular make-up of the infiltrate. Nodular collections of lymphocytes raise a differential diagnosis of cutaneous B-cell lymphoma, cutaneous lymphoid hyperplasia (pseudolymphoma), and angiolymphoid hyperplasia. In these cases, immunohistochemical staining for various T-cell and B-cell antigens is helpful in establishing the diagnosis. If neutrophils predominate in a nodular infiltrate, one considers Sweet syndrome, pyoderma gangrenosum, follicular rupture, or abscess formation associated with infection.
Nodular or Diffuse Pattern (Fig. 2-13)
Figure 2-13 Nodular pattern. Dense aggregates of inflammatory cells are present in the dermis.
recognized by their characteristic bilobed nucleus and eosinophilic granular cytoplasm
Eosinophils
Figure 2-14 Eosinophils. The nuclei are bilobed and the cytoplasm is bright pink and granular. The lymphocytes have small dark nuclei and scant cytoplasm.
The presence of many eosinophils in a dermal infiltrate can be helpful in diagnosing an allergic reaction (insect bite, medication reaction, scabies), but also in the differential diagnosis of Wells syndrome (eosinophilic cellulitis), angiolymphoid hyperplasia with eosinophilia, and the prodromal stage of pemphigoid.
characterized by nodules of epithelioid histiocytic cells, occasional Langerhans giant cells, and only a small number of lymphocytes
Sarcoidal granulomas
In addition to sarcoidosis, silica, zirconium, and beryllium granulomas, and a number of foreign-body granulomas may have such histopathologic features (Fig. 2-15).
Granulomatous reactions of the skin comprise a large spectrum of histopathologic features. Palisading granulomas surround hypocellular areas of the connective tissue with histiocytes in radial alignment (Fig. 2-16).
Figure 2-16 Granuloma annulare. In granuloma annulare, histiocytes and giant cells surround a zone of hypocellular collagen that shows few to no nuclei.
Granuloma annulare, necrobiosis lipoidica, and rheumatoid nodules belong to this group. These reactions may have significance as signs of systemic disease. 6 Rheumatoid nodules can be associated with rheumatoid arthritis, and interstitial granulomatous dermatitis can be associated with arthritis and immune-mediated disorders.
Infectious granulomas with a sarcoidal appearance may occur in tuberculosis, syphilis, leishmaniasis, leprosy, and atypical mycobacterial or fungal infections. Necrosis can also develop within the granuloma proper, as is the case for fibrinoid necrosis in sarcoidosis, caseation in tuberculosis, or the necrosis developing in mycotic granulomas. Many of the infectious granulomas are associated with epidermal hyperplasia, often exhibiting intraepidermal abscesses. In the dermis, there is a mixture of cells, including histiocytes, epithelioid cells, eosinophils, neutrophils, and lymphocytes.
A specific form of granulomatous reaction results when the cellular infiltrate consists almost exclusively of the key granuloma cell, the _______
histiocyte
One property of this cell is its capacity to store phagocytosed material. In xanthomatous reaction patterns, histiocytes take up, store fat, and are thus transformed into foam cells (Fig. 2-17). These cells are characteristic of various types of xanthomatous processes including tuberous and eruptive xanthomas as well as xanthelasma.
Figure 2-17 Xanthoma cells. The cytoplasm is enlarged and shows a vacuolated (bubbly) appearance.
Figure 2-18 Actinic (solar) elastosis. The superficial dermis show many gray-colored elastotic fibers from chronic sun damage. In the lower portion of the photomicrograph, the collagen shows the normal pink color.
Faulty synthesis or crosslinking of collagen results in a number of well-defined diseases or syndromes but leads to relatively few characteristic histopathologic changes. In the different types of the Ehlers-Danlos syndrome, the faulty collagen cannot be recognized histopathologically, and only the relative increase of elastic tissue may indicate that something abnormal has occurred in the dermis. The fragmentation and curled and clumped appearance of elastic fibers are diagnostic in pseudoxanthoma elasticum. On the other hand, in actinic elastosis, a consequence of chronic sun damage, all components of the superficial connective tissue are involved. Except for a narrow grenz zone below the epidermis, the papillary dermis, and the superficial layers of the reticular dermis are filled with clumped and curled fibers that progressively become homogenized and basophilic (Fig. 2-18). They are stained by dyes that have an affinity for elastic tissue and thus histochemically behave similar to elastic fibers.
Alterations in elastic tissue generally cannot be visualized on routine H&E staining except for actinic elastosis, and the use of special stains is necessary. Verhoeff-van Gieson staining is often used to highlight presence, absence, or alteration of elastic fibers in the dermis.
Figure 2-19 Tattoo. Foreign substances can be deposited in the dermis. Tattoo pigment is seen here as course clumps of black pigment in the superficial dermis.
Endogenous and exogenous materials can also alter the dermis. Examples of endogenous materials include the accumulation of mucinous ground substance as one can see in pretibial myxedema, or deposits of proteinaceous amyloid as nodular aggregates in the dermis or surrounding vessels and adnexal structures (systemic amyloidosis). Materials that are not produced by the body can be introduced into the dermis accidentally or in cosmetic procedures (tattoos: Fig. 2-19, filler agents).
Septal panniculitis that follows inflammatory changes of the trabecular vessels is usually accompanied by edema, infiltration of inflammatory cells, and a histiocytic reaction. This is the classic appearance in ________
erythema nodosum (Fig. 2-20)
Figure 2-20 A and B, Erythema nodosum. The subcutaneous septa are thickened by fibrosis and inflammation.
Recurring septal inflammation may lead to a broadening of the interlobular septa, fibrosis, and the accumulation of histiocytes and giant cells.
Verrucae vulgaris demon- strate marked____, ______ and ______
hyperkeratosis, papillomatosis, and acanthosis (Fig. 2-21A)
Figure 2-21 A, Verruca vulgaris showing hyperkeratosis, acanthosis and papillomatosis of the epidermis
Verrucae vulgaris prominently feature _______, cells which have structural changes secondary to human papillomavirus (HPV) infection.
koilocytes
Koilocytes are identified by small round nuclei, perinuclear halos, and clumping of keratohyaline granules (Fig. 2-21B). They tend to be localized in the upper stratum spinosum and stratum granulosum in newer warts, and may be absent in more mature verrucae. Parakeratosis may be seen in the stratum corneum, most often localized to the areas directly overlying koilocytes. The epidermal rete within verrucae are elongated, and the rete at the periphery of the lesions often are oriented toward the center of the warts
Figure 2-21 B, Koilocytes seen in a verruca, showing clumping of keratohyaline granules and perinuclear halos.
Condyloma acuminata display slight _______ and prominent ______ (Fig. 2-22A).
Condyloma acuminata display slight hyperkeratosis and prominent acanthosis (Fig. 2-22A).
Figure 2-22 A, Condyloma acuminatum demonstrating hyperkeratosis and acanthosis. In contrast to verruca vulgaris, there are rounded, rather than pointed, epidermal crests.
While papillomatosis is a common feature, the surface of condyloma acuminata show rounded crests (so-called _______) as compared to verrucae vulgaris, which demonstrate elongated, pointed spires. Compared to other types of viral warts, koilocytes are not as prominently observed in condyloma acuminata (Fig. 2-22B).
knuckling
Figure 2-22 B, Koilocytes in condyloma acuminatum, which are frequently less prominent than those seen in verruca vulgaris.
HPV immunostaining may be employed to help assess for viral change within condyloma acuminata, although in our experience immunostaining is commonly negative when koilocytes are not readily observed on H&E-stained sections.
Seborrheic keratoses show marked _______, ______, and _______ on histology (Fig. 2-23).
Seborrheic keratoses show marked hyperkeratosis, papillomatosis, and acanthosis on histology (Fig. 2-23).
Figure 2-23 Seborrheic keratosis with hyperkeratosis, acanthosis, and multiple pseudo horn cysts.
In some cases, thin strands of anastomosing epithelium are seen within seborrheic keratoses, resulting in a reticulated pattern. Pseudo horn cysts and horn cysts are frequently observed in the acanthotic epidermis. There is often keratinocyte pigmentation. The keratinocytes within seborrheic keratoses are usually small and bland in appearance, although when lesions are irritated or inflamed the nuclei may become enlarged. Squamous eddies, which are composed of whorls of squamous epithelial cells, are more frequently observed in inflamed or irritated seborrheic keratoses.
Inverted follicular keratoses are considered variants of seborrheic keratoses. Inverted follicular keratoses have an endophytic architecture compared to other types of seborrheic keratoses. Squamous eddies are a prominent feature in this variant.
When squamous cell carcinoma (SCC) is restricted only to the epidermis, it is referred to as
SCC in situ
Such lesions show fullthickness atypia of the epidermis with keratinocytes that have enlarged nuclei, nuclear pleomorphism, and increased mitotic activity (Fig. 2-24). Apoptotic or dyskeratotic keratinocytes are also commonly observed in SCC in situ. There is typically parakeratosis in the stratum corneum, with underlying loss of the granular layer. By definition, SCC in situ does not invade the underlying dermis, but may show extension of the atypical keratinocytes along adnexal structures including hair follicles and eccrine ducts. The term “Bowen disease” is often used interchangeably with “SCC in situ,” although in our practice “Bowen disease” is reserved for SCC in situ of sun-protected anatomic sites such as the anogenital region.
Figure 2-24 Squamous cell carcinoma in situ demonstrating full-thickness keratinocyte atypia within the epidermis. Enlarged, hyperchromatic keratinocyte nuclei are easily seen.
Invasive SCC shows ________
acanthosis of the epidermis, composed of atypical keratinocytes, as well as lobules of keratinocytes that have broken away from the epidermis and are embedded within the dermis (Fig. 2-25).
The keratinocytes may be enlarged and glassy in appearance, with associated horn pearls composed of parakeratin. This type of pattern is seen frequently in well to moderately differentiated SCCs. More poorly differentiated tumors lack significant keratinization and often have an infiltrative pattern within the dermis. Solar elastosis is frequently observed in invasive SCCs.
Figure 2-25 Invasive squamous cell carcinoma characterized by a nodule of atypical keratinocytes in the dermis with prominent keratinization consisting of parakeratin.
Histopathologically, basal cell carcinomas (BCCs) are comprised of
lobules of purple or basophilic cells, which most closely resemble the cells found in the basal layer of the epidermis
The lobules display palisading of columnar cells at the periphery (Fig. 2-26A). Within the lobules, mitotic figures and apoptotic cells (often referred to as single-cell necrosis) are observed (Fig. 2-26B). The basaloid lobules typically demonstrate connection to the epidermis, and may also be seen arising from hair follicles. In superficial BCC, the basaloid lobules are small and arise from the epidermis, without deeper involvement. In the nodular type of BCC, larger basaloid lobules with deeper dermal involvement are observed. The stroma surrounding the basaloid lobules is distinctive as it is fibromyxoid in appearance, composed of fibroblasts set within a loose mucinous matrix. Stromal retraction, or spaces between the basaloid lobules and the surrounding fibromucinous connective tissue, is commonly seen.
demonstrate lobules of basaloid cells in embedded in the dermis, which have a cribriform or lace-like appearance (Fig. 2-27)
Trichoepithelioma
Figure 2-27 Trichoepithelioma showing cribriform basaloid lobules with a dense fibrous stroma. Papillary mesenchymal bodies are observed.
Horn cysts are often present within the basaloid lobules. The stroma surrounding the basaloid lobules shows an increased number of fibroblasts, and lacks the mucinous ground substance typically observed in the stroma of BCCs. Papillary mesenchymal bodies are a characteristic feature of trichoepitheliomas. They form invaginations into the basaloid tumor lobules, showing many fibroblasts and strongly resembling the papillae of normal hair follicles.
A variant of a trichoepithelioma is the desmoplastic trichoepithelioma, which classically occurs on the face of young adult women. In contrast to conventional trichoepitheliomas, desmoplastic trichoepitheliomas show elongated thin islands of basaloid cells set within a fibrotic (desmoplastic) stroma. Horn cysts are commonly seen, indicating follicular differentiation of these benign tumors. In addition, areas of calcification are frequently present.
Melanocytic nevi may involve the epidermis only, the dermis only, or both the epidermis and dermis, and accordingly are classified as being junctional, intradermal, or compound. Many nevi evolve over time, progressing from junctional to compound to primarily intradermal nevi. Common nevi are composed of nests of nevic cells, which involve in the tips of the epidermal rete in junctional and compound nevi, and the dermis in intradermal and compound nevi. Within the dermal compartment, the nevus cells show maturation, a term that refers to the distribution of larger nests of melanocytes in the superficial dermis and smaller nests, and/or single nevic cells at the base of the lesion.
Figure 2-28 Dermal nevus. Nests of nevic cells, some showing melanin pigmentation, are present within the dermis.
In common nevi, the melanocytes are typically round, with varying amounts of cytoplasm (Fig. 2-28), although nevic cells that are neurotized (resembling neural cells) are also frequently encountered.
Under the microscope, dysplastic nevi exhibit architectural disorder and random (as opposed to uniform) cytologic atypia. Some of the architectural features used to render a diagnosis of a dysplastic nevus include ______-
the presence of a shoulder, bridging of melanocytic nests between adjacent epidermal rete, lamellar fibroplasia, pagetoid spread, and lentiginous growth of melanocytes along the dermal epidermal junction (Fig. 2-29)
The “shoulder” refers to the junctional component of a nevus that extends at least 3 rete pegs beyond a central area of dermal nevus cells
a phenomenon in which nests of nevic cells from adjacent rete appear to grow toward each other and fuse
Melanocytic bridging
Figure 2-29 A, Dysplastic nevus displaying bridging of nests of melanocytes between adjacent epidermal rete pegs.
commonly observed in dysplastic nevi, and indicates fibrosis in the papillary dermis that runs in parallel to areas of bridging in the epidermis
Figure 2-29 B, Lamellar fibroplasia, a common finding in dysplastic nevi.
Pagetoid spread is seen to some degree in dysplastic nevi, although not as extensively in melanomas, and denotes upward spread of melanocytes in the epidermis away from the basilar epidermis. Finally, dysplastic nevi may exhibit increased growth of single melanocytes (as opposed to merely nested growth) along the dermal–epidermal junction, a finding that is described as a lentiginous growth pattern.
Cytologic atypia is frequently observed within dysplastic nevi, and may be graded as mild, moderate, or severe. In contrast to melanomas, the cytologic atypia of dysplastic nevi is typically isolated to a subset of melanocytes (random atypia), rather than affecting nearly all the lesional melanocytes.
melanocytic nevi that are composed of spindled and/or epithelioid melanocytes
Spitz Nevi
Because of some of their architectural and cytologic features, there can be difficulty in distinguishing these lesions from melanoma. Spitz nevi typically occur in children and young adults, although are sometimes also seen in older adults.
Spitz nevi may be compound, junctional, or intradermal. Compound lesions are most frequently observed, and demonstrate a proliferation of large nested spindled and/or epithelioid melanocytes, sometimes pigmented, along the dermal–epidermal junction, with similar nests in the underlying dermis. The epidermis is usually hyperplastic. There is often clefting around the nests of melanocytes in the epidermis (Fig. 2-30).
Figure 2-30 Spitz nevus with vertically oriented nests of epithelioid and spindled melanocytes. Kamino bodies are also seen.
Pagetoid spread may be seen, predominantly in the center of the lesion. Kamino bodies are a characteristic feature of Spitz nevi. These are acellular, globular eosinophilic inclusions in the epidermis, which are thought to be derived from basement membrane material. Conventional Spitz nevi show symmetry and sharp lateral circumscription. The dermal nevus cells exhibit maturation, a term that indicates the tendency of nevus cells at the base of Spitz nevi to be smaller than those in the more superficial dermis. Although dermal mitoses may be observed in Spitz nevi, the mitotic rate does not usually exceed 2 per mm2 .
Figure 2-31 Malignant melanoma characterized by highly crowded growth of atypical melanocytes along the dermalepidermal junction and extensive pagetoid spread. Atypical melanocytes are also present in the dermis.
While radial growth phase melanomas may be classified into several histologic types (superficial spreading, lentigo maligna, acral lentiginous, and mucosal lentiginous), a disorganized growth pattern with cytologic atypia is common to all of them (Fig. 2-31). Intraepidermal melanomas are commonly found to have confluent or near confluent growth of nested and single melanocytes along the dermal–epidermal junction. Lesions are often markedly asymmetrical. The lesional cells classically harbor uniform severe cytologic atypia. Pagetoid spread is commonly observed, to a greater extent than seen in dysplastic nevi. Solar elastosis is also frequently present, particularly in the superficial spreading and lentigo maligna types.
exhibit fibroblastic differentiation, and are often classified as “fibrohistiocytic” because they may also display histiocytic differentiation in the form of foamy and/or giant cells
Dermatofibroma
Dermatofibromas are benign lesions, which tend to have a hyperplastic epidermis and hyperpigmented, flattened rete, which are described as “dirty feet.” Follicular induction is also commonly observed in the epidermis, which may closely resemble superficial BCCs. In the reticular dermis, bland-appearing spindled cells with tapered ends are observed (Fig. 2-32A), sometimes in association with round cells with foamy cytoplasm and/or giant cells. The degree of cellularity in dermatofibromas vary, as some lesions are relatively paucicellular while others are more densely cellular.
Figure 2-32 A, Dermatofibroma, demonstrating a proliferation of bland-appearing spindled cells in the dermis with associated collagen wrapping.
“Collagen wrapping” is frequently seen, particularly at the periphery of dermatofibromas, in which spindle cells encircle collagen bundles (Fig. 2-32B).
B, Higher power view of collagen wrapping.
a malignant neoplasm that is typically locally aggressive without a high incidence of metastasis
Dermatofibrosarcoma Protuberans
These tumors are characterized by a proliferation of bland-appearing spindle cells in the reticular dermis and subcutaneous fat. The cells intercalate between adipocytes in the subcutaneous fat, resulting in a “honeycomb” appearance (Fig. 2-33A).
Figure 2-33 A, Dermatofibrosarcoma protuberans with elongated spindled cells intercalating between adipose cells in the subcutaneous fat, also known as “honeycombing.”
Dermatofibrosarcoma protuberans
Figure 2-33 B, Storiform pattern of spindled cells in the dermis.
A storiform or whorled pattern of the cells is commonly observed in the dermal compartment (Fig. 2-33B). There is often very little cytologic atypia. The lesional cells are positive for CD34 immunohistochemical stains but negative for Factor XIIIa stains, allowing differentiation from cellular dermatofibromas.
pyogenic granuloma is a benign vascular lesion which is also known as
Lobular capillary hemangioma
Pyogenic granulomas are exophytic clinically, and the polypoid architecture under the microscope reflects this. Typically, there is an epidermal collarette around the dermal vascular proliferation (Fig. 2-34A).
Figure 2-34 A, Pyogenic granuloma characterized by an epidermal collarette and clusters of capillaries in the dermis
In the dermis are clusters of small capillaries lined by bland endothelial cells (Fig. 2-34B). The lobules of capillaries are set within a loose stroma containing fibroblasts.
Figure 2-34 B, Higher power view of lobules of capillaries in the dermis.
malignant vascular tumors
ANGIOSARCOMA
In relatively well-differentiated lesions, irregular vascular channels are seen in the dermis, which are lined by atypical endothelial cells (Fig. 2-35).
Figure 2-35 Angiosarcoma with a proliferation of atypical endothelial cells in the dermis and associated irregular vascular spaces.
The endothelial cells have variably enlarged nuclei and nuclear pleomorphism. The lesional cells are highlighted by endothelial cell markers, including CD31 and CD34. Poorly differentiated angiosarcomas may display increased cellularity, increased nuclear atypia, and increased number of mitoses compared to welldifferentiated lesions.
dermal tumors that consist of small, bland neural cells with wavy, S-shaped nuclei, set within a light pink stroma (Fig. 2-36)
NEUROFIBROMA
Figure 2-36 Neurofibroma showing spindled cells with wavy nuclei and characteristic pink stroma.
Neurofibromas are benign lesions that may occur sporadically or in the context of neurofibromatosis. The stroma may be myxoid. Neurofibromas tend to be well circumscribed within the dermis. Mast cells are commonly observed within neurofibromas.
there is a proliferation of smooth muscle bundles in the reticular dermis (Fig. 2-37A).
piloleiomyoma
Figure 2-37 A, Pilar leiomyoma exhibiting fascicles of spindled cells in the reticular dermis
The cells are pink in color and elongated, with cigar-shaped nuclei that have tapered ends (Fig. 2-37B). While mitoses are sometimes observed, the mitotic rate is generally very low.
Figure 2-37 B, Higher power view of pilar leiomyoma. The spindled cells have cigar-shaped nuclei with blunt ends
appears as a well-circumscribed nodule in the deep reticular dermis and subcutaneous fat (Fig. 2-37C).
Angioleiomyoma
C, Angioleiomyoma, showing characteristic deeply seated well-circumscribed nodules in the deep reticular dermis.
A central vascular lumina may be seen, in addition to smaller vascular channels amid bundles of smooth muscle.
Similar to their benign counterparts, ________ may be derived from pilar muscle or vascular smooth muscle. These malignant tumors may display atypical, enlarged nuclei, increased cellularity, frequent mitoses, and/or infiltrative growth patterns (Fig. 2-38).
leiomyosarcomas
Figure 2-38 Leiomyosarcoma. The spindle cells show scattered enlarged atypical nuclei.
Reactive units of the Skin
Reactive units of skin
- The superficial reactive unit (SRU) comprises the epidermis (E), the junction zone (J), and the papillary body (PB, or papillary dermis) with the superficial microvascular plexus.
- The dermal reactive unit (DRU) consists of the reticular dermis (RD) and the deep dermal microvascular plexus (DVP).
- The subcutaneous reactive unit (S) consists of lobules (L) and septae (Sep).
- A fourth unit is the appendages (A; hair and sebaceous glands are the only appendages shown). HF, hair follicle.
a disease that is characterized by both ACANTHOLYSIS AND DYSKERATOSIS
DARIER DISEASE
*it is combined with dyskeratosis in the upper epidermal layers (Fig. 2-6) and a compensatory proliferation of basal cells
