1- 2 - PATHOLOGY OF SKIN LESIONS Flashcards

Question

The superficial reactive unit is composed of

Answer 1

**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.

Answer 2

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.

Answer 3

Cutaneous spindle cell squamous carcinoma

Answer 4

Paget disease, extramammary Paget disease

Answer 5

Merkel cell carcinoma

Answer 6

Squamous cell carcinoma

Answer 7

Sweat gland neoplasms, Paget disease, extramammary Paget disease

Answer 8

Skeletal and smooth muscle tumors (leiomyoma)

Answer 9

Glomus tumor, leiomyosarcoma

Answer 10

Dermatoﬁbrosarcoma protuberans, trichoepitheliomas

Answer 11

Dermatoﬁbroma

Answer 12

Vascular tumors

Answer 13

Lymphatic endothelial marker

Answer 14

Infantile hemangiomas

Answer 15

Desmoplastic melanoma, Langerhans cell histiocytosis, granular cell tumor

Answer 16

Desmoplastic melanoma, blue nevus

Answer 17

Desmoplastic melanoma

Answer 18

Hematolymphoid proliferations

Answer 19

B-cell lymphomas

Answer 20

Atypical ﬁbroxanthomas, clear-cell hidradenoma, sebaceous tumors

Answer 21

Plasma cell, B-cell marker

Answer 22

Plasma cell marker

Answer 23

T-cell lymphomas

Answer 24

T-helper lymphocytic marker

Answer 25

Mantle cell lymphoma, chronic lymphocytic leukemia

Answer 26

Most commonly lost antigen in T-cell lymphoma

Answer 27

T-cell cytotoxic/suppressor marker

Answer 28

Anaplastic large cell lymphoma, lymphomatoid papulosis, chronic arthropod bites (scabies, tick)

Answer 29

Langerhans cell histiocytosis

Answer 30

Langerhans cells

Answer 31

B-cell lymphoproliferative disorders

Answer 32

Kaposi sarcoma

Answer 33

**acanthosis** **Figure 2-2 Acanthosis. The epidermis on the right side of this photomicrograph is thicker than normal because of a proliferation of keratinocytes.**

Answer 34

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.

Answer 35

**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).

Answer 36

**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.

Answer 37

**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.

Answer 38

**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.

Answer 39

**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.

Answer 40

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.

Answer 41

DERMALEPIDERMAL JUNCTION

Answer 42

**hemidesmosomes** These structural relationships correlate with complex molecular interactions that serve to bind the epidermis, basement membrane, and superficial dermis in a manner that promotes resistance to potentially life-threatening epidermal detachment. The basal lamina is not a rigid or impermeable structure because leukocytes, Langerhans cells, or other migratory cells pass through it without causing a permanent breach in the junction. After being destroyed by pathologic processes, the basal lamina is reconstituted; this represents an important phenomenon in wound healing and other reparative processes. Functionally, the basal lamina is part of a unit that, by light microscopy, appears as the periodic acid–Schiff–positive “basement membrane” and, in fact, represents the entire junction zone. This consists of the lamina lucida, spanned by microfilaments, and subjacent anchoring fibrils, small collagen fibers, and extracellular matrix. The junction zone is a functional complex that is primarily affected in a number of pathologic processes.

Answer 43

**blister formation** In these processes, the entire epidermis forms the roof of the blister, and the floor of the blister is composed of dermis without epidermal keratinocytes.

Answer 44

**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.

Answer 45

**below the basal lamina** These blisters look similar on hematoxylin and eosin (H&E) staining with the roof composed of intact epidermis. Reduced anchoring filaments and increased collagenase production result in dermolytic dermal–epidermal separation in recessive epidermolysis bullosa. Circulating autoantibodies directed against type VII collagen in anchoring fibrils are the cause of dermolytic blistering in acquired epidermolysis bullosa. Other disorders that result in dermolytic blistering include dermatitis herpetiformis, and porphyria cutanea tarda.

Answer 46

**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.

Answer 47

**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.

Answer 48

Interface and Lichenoid Dermatitis

Answer 49

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.

Answer 50

**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.

Answer 51

**reticular layer of the dermis** The dermis represents a strong fibroelastic tissue with a network of collagen and elastic fibers embedded in an extracellular matrix with a high waterbinding capacity. In contrast to the tightly interwoven fibrous components of this reticular layer of the dermis, the papillary dermis is composed of finer elastic fibers and collagen bundles that follow the structures they surround.

Answer 52

**perivascular** (angiocentric: around blood vessels), **periadnexal** (around hair follicles and/or eccrine glands)

Answer 53

(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.

Answer 54

**Periadnexal Pattern (Fig. 2-12)** Figure 2-12 Perifollicular pattern. In this example of folliculitis, inflammatory cells surround a follicle.

Answer 55

**Nodular or Diffuse Pattern (Fig. 2-13)** Figure 2-13 Nodular pattern. Dense aggregates of inflammatory cells are present in the dermis.

Answer 56

**Lymphocytes** Although lymphocytic infiltrates occur in the majority of inflammatory dermatoses, there are a number of pathologic processes in which lymphocytes predominate, and thus determine the histologic picture. Lymphocytic infiltrates are formed in inflammatory or proliferative conditions, and in proliferative conditions, may represent a benign or malignant process.

Answer 57

■ Lymphocytic cuffing of venules without involvement of the papillary dermis and the epidermis may occur in figurate erythemas, viral exanthema, and in drug eruptions. The infiltrates of chronic lymphocytic leukemia show a similar distribution pattern but are usually more pronounced. ■ Perivascular lymphocytic infiltrates with a mucinous infiltration of the nonperivascular connective tissue is often a clue to a differential diagnosis of lupus erythematosus or dermatomyositis. ■ Nodular lymphocytic infiltrates, often mimicking lymph node tissue, are typical of lymphocytoma cutis or cutaneous lymphoid hyperplasia. Atypical lymphocytic infiltrates involving both the superficial and deeper dermis, and cytologically characterized by pronounced pleomorphism of the cellular infiltrate, are characteristic of lymphomatoid papulosis, one of the spectrum of CD30+ lymphoproliferative disorders. This condition exemplifies the problems that arise when the histopathology of a lesion is used alone to determine whether a process is benign or malignant. Without knowledge of the clinical features and the course of disease, a definitive diagnosis is extremely difficult.

Answer 58

**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.

Answer 59

**Neutrophils** Neutrophil-rich infiltrates often imply an infectious etiology especially if neutrophils aggregate in the dermis forming an abscess. In contrast, there are many noninfectious neutrophilic processes in the skin, such as Sweet syndrome, pyoderma gangrenosum, urticaria, and vasculitis.

Answer 60

**granuloma**

Answer 61

**epithelioid cells** Granulomas usually lead to destruction of preexisting tissue, particularly elastic fibers, and in such instances result in atrophy, fibrosis, or scarring.

Answer 62

necrobiosis or fibrinoid or caseous necrosis, or it may result from liquefaction and abscess formation or from replacement of preexisting tissue by fibrohistiocytic infiltrate and fibrosis.

Answer 63

**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).

Answer 64

**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.

Answer 65

**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.**

Answer 66

**homogenization, thickening, and dense packing of the collagen bundles, and a narrowing of the interfascicular clefts within the reticular dermis** There is also a perivascular infiltrate of lymphocytes and plasma cells. Sclerodermoid changes may be found in the toxic oil syndrome and À-tryptophan disease, eosinophilic fasciitis, and mixed connective tissue disease.

Answer 67

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.

Answer 68

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).

Answer 69

**lobules of adipocytes and the intervening bands of fibrous connective tissue called septa** Inflammation of subcutaneous fat reflects either an inflammatory process of the fat lobules (lobular panniculitis) or a process arising in the septum (septal panniculitis). 8,9 There may or may not be associated vasculitis. Destruction of fat, be it of a traumatic or inflammatory nature, leads to the release of fatty acids that by themselves are strong inflammatory stimuli, attracting neutrophils and scavenger histiocytes and macrophages; phagocytosis of destroyed fat usually results in lipogranuloma formation.

Answer 70

**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.

Answer 71

**Lobular panniculitis** The lipid material derived from damaged adipocytes contains free and esterified cholesterol, neutral fats, soaps, and free fatty acids, which, in turn, exert an inflammatory stimulus. Histiocytic cells migrate into the inflamed fat, and phagocytosis leads to foam cell formation. Exogenous factors may affect the subcutaneous tissue. Traumatic panniculitis leads to necrosis of fat lobules and a reactive inflammatory and granulomatous tissue response. After the injection of oils or silicone, large cystic cavities may be formed. Oily substances may remain within the adipose tissue for long periods without causing a significant tissue reaction; oil cysts evolve that are surrounded by multiple layers of residual connective tissue, so that the tissue acquires a “Swiss cheese” appearance.

Answer 72

Panniculitis

Answer 73

**keratinocytes, melanocytes, Langerhans cells, and Merkel cells**

Answer 74

fibroblasts, endothelial cells lining vascular channels, smooth muscle cells, and nerve fibers.

Answer 75

(a) symmetry, (b) pattern of infiltration, (c) cytology, and (d) mitotic activity Although specific criteria may apply for certain tumor types, benign tumors generally demonstrate reasonably good symmetry if a vertical line is drawn through the center of the tumor.

Answer 76

Benign lesions are more likely to be well-circumscribed, whereas those with malignant potential often have a more infiltrative pattern into the surrounding tissue. Tumors that are benign tend to have cells with smaller, bland-appearing, and uniform nuclei compared to those that are malignant.

Answer 77

larger nuclei, nuclear pleomorphism, and sometimes prominent nucleoli are observed. Mitotic figures can be observed in benign lesions, but are more frequently seen in malignant tumors. Atypical mitotic figures (those that are asymmetric and/or multipolar) are also more likely to appear in the setting of a malignant tumor.

Answer 78

**hyperkeratosis, papillomatosis, and acanthosis (Fig. 2-21A)** **Figure 2-21 A, Verruca vulgaris showing hyperkeratosis, acanthosis and papillomatosis of the epidermis**

Answer 79

**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.**

Answer 80

Histologically, verrucae plana show **hyperkeratosis** and e**pidermal acanthosis**, but lack the **papillomatosis** seen in verrucae vulgaris. Koilocytes are observed in the granular layer of the epidermis.

Answer 81

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.

Answer 82

**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.

Answer 83

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.

Answer 84

**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.**

Answer 85

**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.**

Answer 86

**Keratoacanthoma** Multiple keratoacanthomas may arise spontaneously, in the context of genetic syndromes such as in Muir-Torre syndrome, or as a side effect of taking certain medications, notably the BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors sorafenib, vemurafenib, and dabrafenib. Microscopically, mature keratoacanthomas show a cup-shaped epithelial proliferation, exhibiting prominent acanthosis consisting of glassy keratinocytes. There is usually a central keratin-filled crater, and the epidermis extends medially over the crater to form a “lip.” The epithelial proliferation invaginates into the underlying dermis, which often displays solar elastosis. A characteristic finding of keratoacanthomas is the presence of neutrophilic microabscesses within the atypical epithelium. A lymphocyte-rich inflammatory infiltrate is frequently observed in the surrounding dermis. Involuting keratoacanthomas show atypia of the epidermis as described above, associated with a lymphocytic infiltrate at the base of the lesion and often the presence of dyskeratotic keratinocytes. This is accompanied by fibrosis of the surrounding stroma, which eventually forms a scar.

Answer 87

**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.

Answer 88

smaller, elongated islands of basaloid cells, as compared to the tumor lobules seen in nodular BCC, and may invade deeply into the dermis

Answer 89

similarly small, elongated islands, but in association with thickened collagen bundles These latter two histologic types, along with the micronodular type of BCC, which is composed of small tumor lobules in the dermis, represent the types of BCC at highest risk for aggressive behavior and local recurrence following surgery or other destructive treatment methods.

Answer 90

**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.

Answer 91

**Trichoblastoma** Trichoblastomas may be mistaken microscopically for BCCs, since they show lobules of basaloid epithelium situated in the dermis and demonstrate peripheral palisading. Unlike BCC, however, epidermal connections are not commonly observed in trichoblastomas. Another distinguishing feature compared to BCC is the stroma surrounding the basaloid islands, which is richer in fibroblasts and compacted, lacking mucinous ground substance. The stroma of trichoblastomas and trichoepitheliomas are therefore virtually identical in appearance. One variant of a trichoblastoma is the so-called trichoblastic fibroma, which shows similar epithelial and mesenchymal elements as trichoblastomas, but the basaloid islands in trichoblastic fibromas are smaller and the surrounding stroma is a more prominent feature.

Answer 92

**Syringoma** These epithelial islands are often described as having a “tadpole-like” appearance. The individual ducts show central lumina that are lined by 2 rows of bland epithelial cells. Occasionally, the epithelial cells have a clear cell morphology, which is the result of glycogen accumulation.

Answer 93

**sebaceous adenoma, sebaceous epithelioma, or sebaceous carcinoma**

Answer 94

**Sebaceous adenomas** The sebaceous cells predominate over the basaloid cells, so that most of the tumor is sebaceous in appearance. The cells are arranged in lobules and the tumor is well-circumscribed overall, lacking infiltrative growth patterns. Mitotic activity may be seen within the basaloid component of sebaceous adenomas.

Answer 95

**sebaceous epitheliomas** Like sebaceous adenomas, the basaloid compartment of the tumor may exhibit mitotic activity, and infiltrative growth is not observed. However, there may be some increased nuclear atypia compared to sebaceous adenomas.

Answer 96

**Sebaceous carcinomas** The tumor cells are frequently arranged in irregularly shaped lobules, and often show infiltration into the surrounding stroma. Mitoses are easily identified within the lesional cells.

Answer 97

**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.

Answer 98

**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

Answer 99

**Melanocytic bridging** **Figure 2-29 A, Dysplastic nevus displaying bridging of nests of melanocytes between adjacent epidermal rete pegs.**

Answer 100

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.

Answer 101

**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 .

Answer 102

**melanoma in situ** Invasive malignant melanoma usually involves the epidermis and the underlying dermis, although in a small number of cases, primary dermal melanomas are observed. Melanomas are classified as having a radial growth phase and/or vertical growth phase. Melanomas that have only a radial growth phase are those that are restricted to the epidermis, or the epidermis and the superficial dermis, in the absence of expansile tumor masses in the dermis. Vertical growth phase melanomas have dermal tumor masses that are larger than nests of melanocytes seen in the epidermis and/or have dermal mitoses.

Answer 103

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.

Answer 104

**Superficial spreading melanomas** The epidermis is thickened in superficial spreading melanoma and often atrophic in lentigo maligna melanoma. There is usually a greater degree of sun damage in the lentigo maligna type of melanoma. Acral lentiginous and mucosal lentiginous melanomas, similar to lentigo maligna melanomas, show a predominance of single melanocytes over nested growth along the dermal–epidermal junction. Pagetoid spread is seen but may not be extensive. By virtue of the sites of acral lentiginous and mucosal lentiginous melanomas, solar elastosis is minimal. Vertical growth phase melanomas are divided into those that have a radial growth phase and those that do not. Nodular melanomas are melanomas that have only a vertical growth phase. Whereas nodular melanomas harbor an intraepidermal component, the in situ melanoma does not extend significantly beyond the lateral borders of the dermal portion of the melanoma. The vertical growth phase component of melanomas that also have a radial growth phase may be conventional, or less commonly, desmoplastic or spindle cell in morphology. Conventional vertical growth phase melanomas demonstrate dermal cells that are similar in morphology to the overlying radial growth phase. Uniform cytologic atypia and mitoses are often found. Melanocytes in the dermis do not exhibit maturation as compared to intradermal nevi. Desmoplastic vertical growth phase melanomas are commonly found in association with lentigo maligna or mucosal lentiginous radial growth phases. Desmoplastic melanomas feature elongated, spindled nuclei set within a fibrotic stroma rich in thickened collagen bundles. Nuclear atypia may be subtle. One helpful clue to the diagnosis of desmoplastic melanoma is the presence of nodular lymphocytic aggregates in the dermis. Of note, desmoplastic melanomas have a distinct immunohistochemical staining profile compared to conventional melanomas; they are typically MART-1 negative and positive for S-100 and SOX10 stains.

Answer 105

**fibroblasts, endothelial cells, neural cells, and smooth muscle cells** These tumors may exhibit a spindle cell morphology, and certain morphologic clues are helpful in distinguishing the cell type of origin, and thus rendering an accurate diagnosis. For instance, smooth muscle cells have cigar-shaped nuclei with rounded, blunt ends that are accompanied by a perinuclear halo. Neural cells have wavy S-shaped nuclei with tapered ends. Cells that exhibit fibroblastic differentiation have elongated nuclei with tapered ends.

Answer 106

**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.**

Answer 107

**B, Higher power view of collagen wrapping.**

Answer 108

**(+) Factor XIIIa** **(-) CD34**

Answer 109

**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.”**

Answer 110

**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.

Answer 111

**Atypical Fibroxanthoma** The lesional cells harbor markedly enlarged nuclei, nuclear pleomorphism, and mitotic figures are easily identified. Despite this prominent cytologic atypia, AFXs are readily treated with local excision and only very rarely metastasize. A panel of immunohistochemical stains including CD34, pan-cytokeratin, p63, S-100, and CD10 may be helpful in distinguishing AFX from other spindle cell tumors, including dermatofibrosarcoma protuberans, spindle-cell SCC, and spindle-cell/ desmoplastic melanoma. Although CD10 is frequently positive in AFX, it is not a specific marker as it has also been reported to be positive in some carcinomas and melanomas. A biopsy of the surface of an undifferentiated pleomorphic sarcoma, a lesion with potential for metastatic disease, is indistinguishable from AFX.

Answer 112

**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.**

Answer 113

**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.

Answer 114

**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.

Answer 115

**SCHWANNOMAS** They are well-circumscribed but nonencapsulated lesions in the dermis, and are easily recognizable because there are two distinct patterns of tissue seen within them, namely **Antoni A and Antoni B** areas.

Answer 116

more cellular, with areas of palisading of nuclei in parallel to one another around a relatively an acellular extracellular matrix, also referred to as **Verocay bodies.**

Answer 117

demonstrate spindled cells within a looser and often myxoid extracellular matrix.

Answer 118

**LEIOMYOMA**

Answer 119

**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**

Answer 120

**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.

Answer 121

**leiomyosarcomas** **Figure 2-38 Leiomyosarcoma. The spindle cells show scattered enlarged atypical nuclei.**

Answer 122

**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.

Answer 123

* Pemphigus foliaceus * Subcorneal pustular dermatosis * Staphylococcal scalded-skin syndrome/bullous impetigo

Answer 124

* Spongiotic dermatitis * Herpes virus infection * Friction blister * Familial benign pemphigus (Hailey-Hailey Disease)

Answer 125

* Pemphigus vulgaris * Darier disease

Answer 126

* Epidermolysis bullosa * Epidermolysis bullosa acquisita * Bullous pemphigoid * Dermatitis herpetiformis * Porphyria cutanea tarda

Answer 127

**DARIER DISEASE** \*it is combined with dyskeratosis in the upper epidermal layers (Fig. 2-6) and a compensatory proliferation of basal cells

Answer 128

* Bullous Pemphigoid * Junctional forms of epidermolysis bullosa - due to hereditary impairment or absence of molecules important for dermal–epidermal cohesion.

Answer 129

intraepidermal vesicle, a small cavity filled with fluid