Profiles of the Epidermal/Dermal Area in some Vesicular/Bullous Dermatoses 27

Profiles of the Epidermal/Dermal Area in some Vesicular/Bullous Dermatoses 27

The profile of the epidermal/dermal area is sometimes helpful in the differential diagnosis.

27.1

Vesicular/Bullous Dermatitis (Eczema) In subacute and acute dermatitis (eczema) vesicles and bullae are located in the epidermis (Chapter 22). The basement membrane is not destroyed. When the caus- ing agent is removed or becomes weaker the epithe- lium is repaired. This is probably a rather fast process, which starts in the preserved surrounding epithelium.

A shedding horny layer, containing exudate, may then be the only sign indicating the possibility of acute/

subacute dermatitis (Figs. 22.1d and 27.1a).

27.2

Necrolytic Migratory Erythema

Necrolytic migratory erythema is a rare kind of erup- tion, which in most cases is due to a glucagonoma, a pancreatic tumor which secretes the polypeptide hormone glucagon, normally produced by cells in the pancreatic islets. The condition is called the glu- cagonoma syndrome which, in addition to the skin eruption and high serum levels of glucagon, includes other symptoms such as mild diabetes mellitus, weight loss, anemia, and stomatitis. Glucagonoma is a slowly growing tumor which may be benign or malignant.

The skin eruption appears often before the underly- ing tumor becomes evident. Occasionally necrolytic migratory erythema appears without the presence of a glucagonoma. In these cases the underlying disease may be another kind of tumor, liver disease, inflam- matory bowel disease, or malabsorption disorders (Tierney and Badger 2004).

The eruption consists of erythematous areas which become infiltrated and then vesicular and crusted.

They may be widespread, but are most common on the trunk and extremities and in periorificial areas. The lesions spread outwards and heal in the center, giving rise to annular or circinate figures. They wax and wane over periods of 7–14 days (Mallinson et al. 1974).

The characteristic histopathologic findings are multiple small areas of necrosis in different stages of development and repair, which are located above a preserved and sometimes hyperplastic basal cell layer (Fig. 27.1b). Above the epidermis one to three gen- erations of shed necrotic epithelium may be observed.

This is in contrast to toxic epidermal necrolysis, in which the whole epidermis becomes necrotic and sheds (Fig. 28.5d). In the dermis there are edema and infiltrates of inflammatory cells, mainly composed of lymphocytes (Mallinson et al. 1974; Pujol et al. 2004).

Chapter 27



Fig. 27.1 Profiles of the epidermal/dermal area. a Epidermal vesicular lesion during healing. The shed horny layer contains exudate and inflammatory cells. The underlying part of the epi- dermis is slightly hyperkeratotic and acanthotic and sparsely infiltrated by lymphocytes; H&E. b Necrolytic migratory ery- thema. The thin epidermis contains focal necroses of different ages. The small arrows indicate a fresh necrotic area above the basal cells and the large arrow an area of repair. A large necrotic flake covers the whole lesion; H&E. c Vesicular SLE. To the right there is a widened follicle with a keratin plug and to the left a subepidermal vesicle containing fibrinous exudate. Both the epidermis and the follicular epithelium are reduced to a few rows of cells. The upper dermis is edematous, but contains only a few inflammatory cells; vG. d Vesicular dermatomyositis. The pattern is very much the same as that demonstrated in c; H&E.

e Lichen sclerosus et atrophicus. The epidermis is very thin, but the horny layer is conspicuously thickened. To the right a small part of a plugged follicle is visible. Below a subepidermal cleft there is a hyaline zone. A part of the underlying band-formed infiltrate of lymphocytes is exposed in the left lower corner;

H&E. f Bullous pemphigoid. There is a subepidermal bulla. The

arrow indicates the beginning of restoration of the basement

membrane. Note also the degenerated roof of the bulla. H&E

211

27.1 Vesicular/Bullous Dermatitis (Eczema)

27 Profiles of the Epidermal/Dermal Area in some Vesicular/Bullous Dermatoses 212

27.2.1 Example

Case 1. Necrolytic Migratory Erythema

An 80-year old woman presented with coalescent an- nular lesions on the upper lip, forehead, trunk and thighs. The patient had recently had an operation for carcinoma of the breast and was thought also to be suffering from Sjögren syndrome (see Glossary). The lesions, which had progressed for some time, were considered an expression of lupus erythematosus.

However, an increased level of plasmachromogranin A was the reason, and even the possibility of a neuroen- docrine tumor was discussed. The patient died before further investigations could be done and autopsy was not performed, and thus the character of the underly- ing disease remained unclear.

The histologic investigation showed a thin epider- mis, which contained multiple areas of necrosis above the preserved basal cell layer. One to three generations of shed necrotic epithelium covered the epidermis.

There was a conspicuous subepidermal edema and rather dense perivascular infiltrates of lymphocytes (Fig. 27.1b).

27.3

Vesicular/Bullous Eruption in Systemic Lupus Erythematosus and Dermatomyositis Systemic lupus erythematosus (SLE) is an autoimmune disease which may involve several organs or tissues, differing with respect to numbers and combinations. A characteristic trait is the presence of a wide variety of circulating autoantibodies such as antinuclear and an- ticytoplasmic antibodies, antiphospholipid antibodies, antibodies against blood cells, and antibodies against various tissues such as gastric mucosa, muscle sarco- lemma and neurons (Bos and de Rie 2005). The skin lesions may be acute, subacute, or chronic. In acute erythematous eruptions subepidermal vesicles/bullae sometimes occur. In these cases there are also antibod- ies against a component in the basement membrane zone, mostly collagen IV (Georgi et al. 2001).

Histologic investigation shows a conspicuous de- struction of the epidermis including the basal cells. In some places there is only a hypertrophic horny layer, to which a sparse number of degenerated keratino- cytes are attached, above a vesicle or bulla filled with fibrinous exudate. However, inflammatory cells are re- markably few. Widened hair follicles and sweat gland orifices plugged with keratin are also typical.

Dermatomyositis is an autoimmune disease in

1 Courtesy of Dr. Ismini Vassilaki, Danderyd Hospital, Stockholm, Sweden

which groups of striated muscles and the skin are affected. The mechanism of the disease is unclear.

However, especially in elderly women, there is an as- sociation with malignant disease of internal organs.

Vesicular/bullous lesions appear occasionally. The his- topathologic pattern is the same as that seen in vesicu- lar/bullous lesions of SLE (McCollough and Cockerell 1998). Consequently, it is not possible to differentiate between the two diseases only by means of the histo- pathologic pattern of the vesicular/bullous lesions.

27.3.1 Examples

Case 2. SLE with Acute Vesicular Eruption

A 19-year-old man suffering from SLE had had a wide- spread and intensely erythematous skin eruption for 4 months. The disease course was short and fatal. Au- topsy revealed glomerulonephritis characteristic of SLE.

Histologic investigation of lesional skin showed subepidermal vesicles, the roof of which consisted of a thickened horny layer with the minor remains of regressively changed epidermis and the roof of mark- edly edematous tissue. Hair follicles were widened and filled with keratin (Fig. 27.1c).

Case 3. Dermatomyositis with Vesicles

A 65-year old woman had had slowly progressing and itching skin lesions for 4 months. The lesions had started on the face and spread to the trunk and ex- tremities. Investigation showed circinate, erythema- tous areas with peripheral scaling and central healing.

She also complained of weakness and soreness of the thigh muscles. Six years earlier she had been operated on for pulmonary carcinoma. The histopathologic pattern was very much similar to that seen in Case 2 (Fig. 27.1d).

27.4

Lichen Sclerosus et Atrophicus

Lichen sclerosus is a chronic and presumably autoim- mune disease. Autoantibodies against extracellular matrix protein and oxidative damage to lipids and DNA have been proved (Sander et al. 2004). The pri- mary efflorescence is a small whitish, round papule.

Papules coalesce into larger whitish areas with promi-

nent widened hair follicles and sweat gland orifices

filled with yellow or brown keratin plugs. Occasion-

ally vesicles or bullae appear. Details are best studied

on the upper trunk, but are most common and most

severe in the anogenital area in women, and on the

prepuce in men.

213

The histopathologic pattern is typical. As in lupus erythematosus and dermatomyositis, there is succes- sive destruction of the epidermis from the basal cell layer outwards, massive hyperkeratosis, and follicular plugging. Also in some areas the havoc in the epider- mis leaves the horny layer with only a few keratino- cytes attached that in combination with subepidermal edema gives rise to a vesicle or bulla. However, in contrast to vesicles/bullae in SLE and dermatomyosi- tis, the floor consists of a band of hyaline collagen tis- sue, beneath which there is a band-formed infiltrate of lymphocytes, sometimes with an admixture of plasma cells.

27.4.1 Example

Case 4. Lichen Sclerosus et Atrophicus

A 66-year-old woman had had non-itching lesions on the upper back for several years, which clinically as well as histologically were typical of lichen sclerosus et atrophicus (Fig. 27.1e).

27.5

Bullous Pemphigoid

In bullous pemphigoid, as mentioned above, circulat- ing autoantibodies directed against the hemidesmo- somes give rise to subepidermal bullae, the roof of which consists of epidermis and the floor of the papil- lary dermis (Sect. 25.4.1.2). Restoration of a new epi- dermis starts as early as after a few days (Lever 1965).

A change in morphology and function of the keratino- cytes in the perilesional epidermis (edges of the bulla and adnexal remnants) allow them to migrate over the denuded dermal area and at the same time reconstruct the basement membrane. When the whole dermal surface is covered by basal cells and a new basement membrane is formed the migration stops and the basal cells proliferate and differentiate normally (Falabella and Falanga 2001). The process takes some time and when completed no shed remains of the roof are left.

27.5.1 Example

Case 5. Bullous Pemphigoid

An 80-year-old woman had had bullae on the extremi- ties, partly developed on a nonerythematous base, for about 1 month.

The subepidermal bulla contained fibrinous exu- date and many eosinophils. In the dermis there were diffusely spread neutrophils and small perivascular in- filtrates of lymphocytes. At both ends of the bulla the

beginning of the restoration of a new basal cell layer was evident (Fig. 27.1f).

27.6 Comment

When the injury is located in the epidermis and the basement membrane is intact, the restoration time is short and shed epidermal remains, significant for the diagnosis, may be observed in the biopsy speci- men (Figs. 22.1d and 27.1a,b; see also biting lesions on the buccal mucosa and tongue, Fig. 29.6c,d). If the basement membrane or deeper parts of the basement membrane zone are injured, the restoration (if it oc- curs) takes more time, and thus shed remains are not found in a biopsy specimen from an active lesion.

In Case 1 the possible diagnosis was the subject of much discussion. The two diagnoses proposed were Sjögren syndrome associated with lupus erythemato- sus and necrolytic migratory erythema. In both dis- eases skin lesions and stomatitis may occur. However, the histopathologic pattern with focal areas of epithe- lial necrosis and shed flakes of necrotic epithelium ex- cludes lupus erythematosus and strongly supports the diagnosis necrolytic migratory erythema.

References

Bos JD, de Rie MA (2005) Lupus erythematosus. In: Bos JD (ed) Skin immune system. Cutaneous immunology and clinical immunodermatology. CRC Press, London, pp 545–552

Falabella AF, Falanga V (2001) Wound healing. In: Freinkel RK, Woodley DT (eds) The biology of the skin. Parthenon, New York, pp 281–297

Georgi M, Jainta S, Bröcker E-B, Zillikens D (2001) Autoan- tigens of subepidermal bullous autoimmune dermatoses (in German). Hautarzt 52:1079–1089

Lever WF (1965) Pemphigus and pemphigoid. Charles C.

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Mallinson CN, Bloom SR, Warin AP, Salmon PR, Cox B (1974) A glucagonoma syndrome. Lancet 2:1–5

McCollough ML, Cockerell CJ (1998) Vesiculo-bullous der- matomyositis. Am J Dermatopathol 20:170–174

Pujol RM, Wang C-YE, el-Azhary RA, Su WPD, Gibson LE, Schroeter AL (2004) Necrolytic migratory erythema. Clini- copathologic study of 13 cases. Int J Dermatol 43:12–18 Sander CS, Ali I, Dean D, Thiele JJ, Wojnarowska F (2004) Oxidative stress is implicated in the pathogenesis of lichen sclerosus. Br J Dermatol 151:627–635

Tierney EP, Badger J (2004) Etiology and pathogenesis of necrolytic migratory erythema. Review of the literature.

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