Dermatitis (Eczema) 22

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Dermatitis (Eczema) 22

Ackerman and Ragaz (1982) started a major debate about the term “eczema”. Because of the difficulty in shortly and exactly defining what eczema really is they wanted the term to be expunged from the vocabulary of dermatology and dermatopathology and replaced by “dermatitis”. Eczema, a word with tradition, is to the author a clinical concept that encompasses a group of different skin conditions which, for the experienced eye, have a common characteristic trait making it pos- sible to discriminate them from other dermatoses. He- bra (Austrian dermatologist, 1816–1880) ingeniously expressed it: “eczema is which looks like eczema”

(Ackerman and Ragaz 1982). In modern literature the terms eczema and dermatitis are used as synonyms.

However, histopathologically, all kinds of eczema principally show the pattern of what pathologists call dermatitis. Thus it is not possible to distinguish differ- ent kinds of eczema by means of the histopathologic pattern, nor does the histopathologic pattern of der- matitis always represent a kind of eczema.

22.1 Clinical Appearance

As already mentioned there are clinically different types of dermatitis (eczema): allergic contact dermati- tis, irritant contact dermatitis, atopic dermatitis, num- mular dermatitis, seborrheic dermatitis and stasis der- matitis. Even mucous membranes may be affected.

22.1.1 Allergic Contact Dermatitis

Allergic contact dermatitis may be caused by a large number of allergens dealt with in the occupational sphere or in private life. It is a type IV delayed hyper- sensitivity reaction, the mechanism of which has been described in more detail (Sect. 4.5). Often allergens are haptens such as nickel, components of a locally applied remedy or cosmetics, or some kind of chemical added to clothing and shoes. The eruption may be acute to chronic. Acute lesions consist of local or widespread

erythematous and edematous areas, on which papules, vesicles and, occasionally, bullae appear. Vesicles and bullae burst and give rise to an oozing surface; later on, when the inflammation subsides, crusts cover the lesions. Chronic lesions are scaling and may also be fissured or thickened (lichenified) due to repeated rubbing or scratching. Eruptions sometimes show a mixed acute and chronic pattern. Often lesions are se- verely itching.

22.1.2 Irritant Contact Dermatitis

This kind of dermatitis is due to repeated contact with non-immunologic irritants and is a common cause of eczema on the hands of those involved in wet work.

Rather often the patient suffers from both contact der- matitis and irritant dermatitis.

22.1.3 Atopic Dermatitis

Atopic dermatitis occurs in genetically disposed indi-

viduals when they are subjected to one or several en-

vironmental factors, of which climate is the most im-

portant. Also food allergens or aeroallergens may be

of significance. Many of these patients also suffer from

allergic rhinitis, and/or asthma. The eruptions vary in

intensity and change with the age of the patient. The

disease is most common during early infancy and

childhood. In small children the lesions are located on

the face, scalp and extensor aspects of the extremities

and have the character of subacute to acute dermatitis

with erythema, papules, vesicles and oozing. Severe

itch is notorious and scratch marks are common. In

older children the flexural folds of the extremities are

affected and the pattern is that of a chronic lichenified

dermatitis. When the patient grows up the eruptions

in most cases disappear; however, patients with an

atopic disposition are more sensitive than non-atopic

individuals to exogenous irritants. They are inclined

to get irritant contact dermatitis and lichen simplex

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22 Dermatitis (Eczema) 156

chronicus. The latter is a plaque of severely itching der- matitis that most often occurs in adults

22.1.4 Nummular Dermatitis

By nummular dermatitis is meant spells of discrete, coin-shaped, erythematous plaques on the trunk and extremities, which remain for weeks to years. The pat- tern may be acute, subacute or chronic. The cause of nummular dermatitis is unknown.

22.1.5 Seborrheic Dermatitis

Seborrheic dermatitis appears in seborrheic areas and affects both infants and adults. The lesions are charac- terized by erythema covered with oily-looking scales.

The cause of seborrheic dermatitis is unknown. It is the most common skin lesion in HIV-infected indi- viduals and eruptions are often conspicuous.

22.1.6 Stasis Dermatitis

Stasis dermatitis appears on the lower legs in patients with insufficient return of the venous flow and is usu- ally located above the medial malleolus. Pigmentation due to deposition of iron pigment may be conspicu- ous.

22.1.7 Allergic Contact Stomatitis

Allergic contact stomatitis is rare, but may be caused for example by flavorings added to toothpastes, mouth washes, candy, chewing gum and food (Rietschel 2001). Stomatitis caused by chemical irritants is dis- cussed in Sect. 29.7).

22.2 Histopathologic Appearance

Histopathologically dermatitis may be described as acute, subacute or chronic; however, often one form merges into another.

22.2.1 Acute Dermatitis

In lesions of acute dermatitis fluid accumulates in the epidermis and gives rise to both intercellular and in- tracellular edema. Augmentation of the intercellular

fluid increases the distance between the keratinocytes and stretches the desmosomes (i.e., the filaments that serve as links between the keratinocytes). This makes the desmosomes visible in routinely stained sections;

the phenomenon is called spongiosis (Fig. 22.1a). In- tracellular edema is expressed as different-sized, clear spaces (vacuoles) in the cytoplasm. Large vacuoles compress the nucleus and displace it close to the cell membrane; the cell acquires the shape of a signet ring (Fig. 22.1a). The edema is patchy and, if not advanced, is reversible.

Progression results in disintegration of the kerati- nocytes. Intercellular edema causes rupture of the des- mosomes, and intracellular edema impairs vital intra- cellular cell structures, or disrupts the cell. In turn this leads to development of small cavities (vesicles), which may coalesce and form larger cavities (bullae). In the fully developed acute dermatitis there are tightly set vesicles and/or bullae (Fig. 22.1b). The vesicles/bullae contain clear fluid and lymphocytes. There are more or less dense infiltrates of lymphocytes in the dermal pa- pillae and in the subpapillary area and also a conspicu- ous papillary edema. Sometimes there are, in addition to lymphocytes, a variable number of eosinophils both in the dermis and epidermis. Now and then, so-called reticular degeneration appears, as also seen in herpes virus vesicles (Fig. 20.2a).

If the trigger of the dermatitis is eliminated, the inflammation subsides and the lesions heal without residue. However, an acute stage may pass over into a subacute stage.

Fig. 22.1 Dermatitis. a Inter- and intracellular edema and the beginning of vesiculation. The arrow indicates a keratinocyte with marked intracellular edema and the nucleus pressed to the cell membrane. To the right of this cell there are stretched desmosomes due to intercellular edema. b Acute dermatitis. There are densely set vesicles and papillary edema. c Subacute dermatitis. The rete ridges are thickened and irregularly elongated.

There is a fresh vesicle to the right and some older, filled with protein-rich exudate to the left (arrows). The crust is composed of parakeratotic keratin including exudate and inflammatory cells. dHealing lesion. The detached material (arrows) indicates earlier vesiculation. e Chronic dermatitis. The epidermis shows acanthosis together with hyper- and parakeratosis. f Psoriasi- form dermatitis. A papilla (arrowheads), walled off by slender rete ridges, contains thin-walled dilated vessels and is covered by a thin epidermis and a parakeratotic crust. In the papillary and upper dermis of all variants there are infiltrates of lymphocytes, some of which are migrating into the epidermis. H&E

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22.2.2. Subacute Dermatitis

Subacute dermatitis may start as such or, as mentioned above, may follow a spell of acute dermatitis. The epidermis is irregularly thickened and has unevenly lengthened and thickened rete ridges. This is called ac- anthosis. There are patches of spongiosis and intracel- lular edema and scattered vesicles, some of which may contain eosinophilic, protein-rich exudate (Fig. 22.1c).

As in acute dermatitis, lymphocytes migrate through the epidermis, a phenomenon called exocytosis. The surface is covered with a crust consisting of eosino- philic exudate and parakeratotic keratin (i.e., keratin containing nuclear remains). In the papillae and upper dermis there is edema, dilated venules, and sometimes proliferation of new vessels. The inflammatory cell in- filtrates mainly consist of lymphocytes, but there may be a fair admixture of eosinophils in both the dermis and epidermis.

Subacute dermatitis may contain vesicles with his- tiocyte-like cells in addition to small lymphocytes (Fig. 22.2). This phenomenon has been mistaken for Pautrier abscesses (see Glossary), appearing in my- cosis fungoides (LeBoit and Epstein 1990). Investiga- tions have shown that these cells are dendritic cells with a histochemical phenotype that is somewhat dif- ferent from that of Langerhans cells normally present in the epidermis and dermis. They are thought to be precursors of Langerhans cells, immigrated from the circulation and recruited to the site of inflammation by cytokines released by epidermal cells or associated T cells (Candiago et al. 2000).

Healing of vesicular dermatitis starts from the pre- served basic part of the epidermis. A more or less nor- mal-looking epidermis sheds a thick horny layer con- taining remnants of vesicles. Sometimes the presence of these residues is helpful in discriminating dermati- tis and psoriasis (Fig. 22.1d).

22.2.3 Chronic Dermatitis

The process starts as a chronic dermatitis or follows an acute or subacute phase of the disease. The course is protracted. The epidermis shows moderate to marked acanthosis and hyper- and parakeratosis (Fig. 22.1e).

There may be areas of inter- and intracellular edema, and rarely scattered small vesicles. The inflammatory cell infiltrates mainly consist of lymphocytes. Edema in the dermis is not prominent, but proliferation of new vessels may be seen. Sometimes the pattern is psoriasis-like and shows long, slender rete ridges and papillae, which are covered by a thin epidermis and

contain thin-walled dilated venules filled with eryth- rocytes (Fig. 22.1f; compare Fig. 23.1a).

In stasis dermatitis, there are in addition to a thickened and acanthotic epidermis numerous newly formed vessels, most marked at the level of the sweat glands, where also deposition of iron pigment is a characteristic phenomenon. Abnormal veins, demon- strated below in Case 3 (Fig. 22.3), are rarely observed.

Scratching and secondary infections may modify all histopathologic patterns described above (Figs. 29.1 and 29.2). Herpes simplex virus infection may be a se- rious complication in atopic dermatitis and is called eczema herpeticum.

22.3 Examples

Case 1. Subacute Dermatitis

A 38-year-old man presented with two nummular le- sions on the back.

Histologic investigation showed the pattern of sub- acute dermatitis with several small vesicles, which contained lymphocytes as well as a fair number of histiocyte-like cells with pale cytoplasm and one elon- gated and often indented nucleus. The dermal papillae were edematous and contained scattered histiocytes.

In the subpapillary area there were perivascular in- filtrates composed mainly of lymphocytes. Immuno- histochemical investigations revealed that the histio- cyte-like cells in the epidermis were positive for S-100 protein and CD1a and thus were Langerhans cells.

Also in the upper dermis many cells were positive for these markers; a few cells were positive for CD68, a marker of monocytes and macrophages (Fig. 22.2).

Case 2. Stasis Dermatitis

This patient presented with a 4×10 cm, well circum- scribed, and bluish-red eczematous patch on the me- dial aspect of the right lower leg. The lesion had slowly increased over 3 years and was resistant to treatment with corticosteroids. There were neither visible vari- cose veins nor edema, and stasis dermatitis was not suspected. Following surgery for varicose veins the skin lesion healed and did not return.

A biopsy specimen was taken and investigated at

three levels with many sections. In two sections at one

of the levels a large, tortuous, thick-walled, and dilated

venule was observed. Otherwise the pattern was that

of chronic stasis dermatitis (Fig. 22.3).

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Case 3. Subacute Stomatitis

The patient was 9 years old when a biopsy was taken from the buccal mucosa. From the age of 5 years he had had white lesions on the buccal mucosa and the tongue with no other symptoms. He was allergic to milk and egg.

Histologic investigation disclosed a thickened, but not keratinized epithelium with inter- and intracel- lular edema and small vesicles. Both epithelium and submucosa were diffusely infiltrated by lymphocytes and eosinophils. PAS staining did not reveal fungal structures (Fig. 22.4).

Fig. 22.2 Vesicular dermatitis with Langerhans cells. a A small vesicle contains lymphocytes and several histiocyte-like cells (arrows); ×400. b Close-up of the cells indicated in a (arrows);

×1000. H&E

Fig. 22.3 Stasis dermatitis. a The overview shows a conspicuously thickened, tortuous and branching vein located in the upper and middle part of the dermis. The epidermis is thickened and acanthotic. b Close-up of the part of the vessel located above the arrows ina. vG

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22.4 Differential Diagnosis

• Fungal infections. Fungal infections may clini- cally as well as histopathologically be mistaken for chronic, subacute or acute dermatitis (Fig. 13.1d).

Stomatitis has to be differentiated from Candida infection (Fig. 13.7). PAS staining is mandatory.

• Pityriasis rosea, possibly caused by some unknown infectious agent, may show the pattern of spongi- otic or vesicular dermatitis, but has a different clini- cal pattern and course than dermatitis.

• Incontinentia pigmenti, the first stage of which oc- curs in the neonatal period and shows the pattern of acute dermatitis with eosinophilia, is a heredi- tary disease.

• Langerhans cell histiocytosis (Sect. 21.2).

22.5 Erythroderma (Exfoliative Dermatitis)

Erythroderma or exfoliative dermatitis implies a generalized or nearly generalized dermatitis and is a complication that is common for several completely different dermatoses and skin conditions. It may thus develop from various kinds of eczema, other preexist- ing dermatoses such as psoriasis, lichen planus, pity- riasis rubra pilaris, and pemphigus foliaceus. It may also be provoked by drugs and, notably, may represent

the early stage of cutaneous T cell lymphoma. If no underlying cause is detected, the condition is called idiopathic erythroderma or the red man syndrome, a chronic disease, which may extend over years. The dis- ease affects all ages and is most common in men. The pathogenesis is unknown.

22.5.1 Clinical Appearance

From 80% to 90% of the body surface is involved. In the beginning of the disease the skin is highly ery- thematous and shiny, and sometimes oozing. Later powdery or flaky exfoliation usually appears. The con- dition is associated with a burning sensation and itch- ing (often severe). Dermatopathic lymphadenopathy may be present as well as systemic symptoms such as fever, elevated ESR, blood eosinophilia and increased levels of IgE antibodies (Sehgal and Srivastava 1986;

Thestrup-Pedersen et al. 1988).

22.5.2 Histopathologic Appearance

According to textbooks on dermatopathology and dermatology, the histopathologic pattern of erythro- derma is, depending on the phase of the disease, that of an acute, subacute, or chronic dermatitis (Lever

Fig. 22.4 Subacute stomatitis. a The epithelium is thickened, but not keratinized. It shows pronounced inter- and intracellular edema and also small vesicles. b Close-up of the vesicular area. H&E

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and Schaumburg-Lever 1990; Burton 1992; Freed- berg 1999). In investigations of larger series of un- known erythroderma, the discussion on histopathol- ogy has mainly dealt with the possibility of tracking the underlying disease (Thestrup-Pedersen et al. 1988;

Zip et al. 1993; Walsh et al. 1994; Botella-Estrada et al.

1994). The most common pattern seems to be that of a mild to moderate chronic dermatitis. In cases rep- resenting early T cell lymphoma, atypical T cells may be observed in the dermal inflammatory cell infiltrate and/or in the epidermis.

22.5.3 Example

Case 4. Erythroderma

A 71-year-old woman presented with penicillin-in- duced erythroderma.

A punch biopsy included the dermal–subcutane- ous interface. The epidermis was slightly irregular and spongiotic, and contained one single small vesi- cle. The latter contained a few lymphocytes and his- tiocyte-like cells (Langerhans cells?) The horny layer

Fig. 22.5 Erythroderma. a The epidermis is slightly irregular.

In the upper dermis there are dilated lymphatics, many extrava- sated red blood cells and a moderate number of lymphocytes.

b The epidermis contains a single small vesicle. In the upper

dermis there are red blood cells and newly formed vessels. c An area in the upper dermis, which contains a conglomeration of proliferating vessels. d Close-up shows both venules and capil- laries. H&E

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was normal. The papillary dermis was conspicuously edematous. The upper dermis contained, in addition to many dilated thin-walled vessels, prominent groups of newly formed vessels, and a rich amount of extrava- sated erythrocytes. In the upper half of the dermis there were small, mainly perivascular infiltrates of lymphocytes with a slight admixture of eosinophils (Fig. 22.5).

22.5.3.1 Comment

Erythroderma is on the whole a rare diagnosis and to obtain a biopsy specimen is uncommon. The experi- ence of the author is limited; however, in every case the author has been confronted with, the great dis- crepancy between the clinical and the microscopic appearance has been a surprise. This was the first re- action also in this case, before realizing that the most important changes affected the microvasculature. Be- sides dilated thin-walled vessels there was a marked proliferation of new vessels. Newly formed vessels are leaky and probably account for the massive extravasa- tion of erythrocytes in Case 4. If the presence of a high number of newly formed vessels in erythroderma is a criterion, it may explain the findings of Groves et al. (1995) indicating significantly elevated levels of the circulating adhesion molecules ICAM-1, VCAM- 1 and ELAM-1 (E-selectin) in erythroderma caused by psoriasis as well as by dermatitis (eczema). These CAMs may all be released from endothelial cells.

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