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| REVIEW ARTICLE |
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| Year : 2015 | Volume
: 2
| Issue : 1 | Page : 1-7 |
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Epidermal reaction patterns
Aanchal Panth, M Ramam
Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India
| Date of Web Publication | 16-Jul-2015 |
Correspondence Address:
Dr. Aanchal Panth
Department of Dermatology and Venereology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2349-6029.160977
Changes in the epidermis serve as important histopathological clues to the diagnosis of skin disorders. These peculiar changes are referred to as epidermal reaction patterns. Certain epidermal reaction patterns such as acantholytic dyskeratosis, epidermolytic hyperkeratosis, cornoid lamellae and papillomatosis point towards a specific diagnosis and hence it is important to recognise them. In this article, we have reviewed the histopathological appearance of these reaction patterns as well as their etiology and the conditions in which they are seen. Keywords: Acantholytic dyskeratosis, cornoid lamellae, epidermolytic hyperkeratosis, papillomatosis
How to cite this article:
Panth A, Ramam M. Epidermal reaction patterns. Indian J Dermatopathol Diagn Dermatol 2015;2:1-7 |
| Introduction | |  |
Epidermal reaction patterns represent a group of conditions in which distinctive and recognizable histopathological changes occur primarily in the epidermis. Several inflammatory reaction patterns including psoriasiform, lichenoid, spongiotic and vesicobullous reactions show conspicuous involvement of the epidermis. However, these patterns will not be the focus of this article. Instead, we will consider conditions that are marked by changes confined almost completely to the epidermis and in which inflammatory infiltrates do not play a significant part. Some have referred to these patterns as minor epidermal reaction patterns. [1]
| Epidermolytic Hyperkeratosis | | |
The term epidermolytic hyperkeratosis (EHK) is used to describe a distinctive histologic pattern of a pathologic epidermal process [2] and was coined by Frost and Van Scott in 1966. [3] Ackerman [2] in 1970 described the classical features of epidermolytic hyperkeratosis which include a compact hyperkeratosis, variously sized clear spaces around nuclei in the stratum spinosum and stratum granulosum, a reticulate, lightly staining, amphophilic material forming indistinct cellular boundaries with a markedly thickened granular zone containing an increased number of small and large, irregularly shaped, basophilic keratohyalin-like bodies and amorphous eosinophilic trichohyalin-like bodies. Dyskeratosis occurs which results in intracellular eosinophilic globules. Intraepidermal bulla may occur as a result of separation of edematous cells. [4] These changes are seen mainly in the upper epidermis but focally dip lower into the lower layers [Figure 1]a and b. Changes in the surfaces epidermis may also extend into the follicular epithelium. [5] | Figure 1: (a) Epidermolytic hyperkeratosis: There is hyperkeratosis with focal areas of keratinocyte degeneration. (×10) (b) Epidermolytic hyperkeratosis: There is a vacuolar and granular degeneration pf keratinocytes with pink trichohyaline and blue keratohyaline granules. Some keratonocytes are dyskeratotic. (×400)
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Epidermolytic hyperkeratosis may involve the entire length of the epidermis or be interrupted by skip areas of normal epidermis. The extent of involvement correlates fairly well with the clinical presentation of disease: extensive involvement is seen in extensive disease, viz. epidermolytic ichthyosis and limited involvement in mosaic disease presenting as epidermolytic epidermal nevus.
Abnormal clumping in suprabasal keratinocytes is seen on immunohistochemistry with monoclonal antibodies against K1 and K10. [5] Electron microscopy reveals keratin filaments in suprabasal keratinocytes aggregated into large perinuclear clumps of tonofilaments. [6]
Till recently, the term epidermolytic hyperkeratosis was used as a clinical label for the condition also known as bullous ichthyosiform erythroderma. A few years ago, the condition was renamed epidermolytic ichthyosis. It is a rare disorder of keratinization inherited in an autosomal dominant pattern. It was first described by Brocq in 1902 [7] and is a heterogenous condition with widely variable severity. [8] It presents at birth as flaccid blistering, peeling, erosions and generalized erythema which improves after first year of life. It is replaced by thick, dark, keratotic scales which are preset over the entire skin and are more prominent in skin flexures.
Epidermolytic hyperkeratosis is seen in a variety of hereditary skin diseases, including ichthyosis hystrix of Curth-Macklin, and ichthyosis bullosa of Siemens, [9] linear epidermal nevus of EHK, [10] melanocytic nevus, [11],[12] solar keratosis, [13] nevus comedonicus, [14] progressive systemic sclerosis, [15] leukoplakia (oral and genital), [16],[17] squamous cell and basal cell carcinoma. [18] Localized lesions in the male and female external genitalia have been described. [19],[20] It may also be seen as an incidental finding in a variety of disorders. [21]
Epidermolytic hyperkeratosis occurs as a result of mutations in keratin 1 and 10, genes of which are located on chromosomes 12q13.3 and 17q21.2. [22] Keratin 1 and 10 are expressed in the suprabasal keratinocytes and hence, mutations in these keratins cause keratinocytes to weaken which lead to vacuolar changes in the upper layers of the epidermis. [23]
| Cornoid Lamellation | | |
Cornoid lamellation is a reaction pattern which was first described by Mibelli in 1893 and is characterised by the presence of a narrow parakeratotic column. [24] Porokeratosis is the prototype disorder in which this pattern is seen. Lamellar bodies, which contain lipid substances that function as a permeability barrier of the horny layer, [25] also have acid hydrolase which causes desquamation of horny cells. [26],[27] Stacking of cornoid lamella horny cells may result from decreased number of lamellar bodies which brings about a defect of desquamation. Increase in p53 expression has been observed. [28]
Cornoid lamellation is a change that is confined to the edge of clinical lesions and it is essential that the margin of the papule or plaque be biopsied. Some have recommended the use of gentian violet to highlight the keratotic borders, though this is not usually required. [29]
Cornoid lamellation is characterized by a thin column of parakeratotic cells that extends through the surrounding orthokeratotic stratum corneum and to some extent above and below it. There is a marked decrease in or loss of the granular zone beneath the column of parakeratosis [Figure 2]a and b. Of considerable diagnostic significance is the presence of dyskeratosis or vacuolization of cells in the underlying spinous layer, just beyond the lower end of the parakeratotic column and serves to distingish the cornoid lamella from other ordinary columns of parakeratosis. [30] The parakeratotic column is often oriented slightly obliquely with its tip slanting inwards. The papillary dermis beneath the column shows dilated capillaries with a moderately dense lymphocytic infiltrate. Multiple enlarged cornoid lamellae have been described in linear porokeratosis [31] and in penoscrotal porokeratosis. [32] The changes of cornoid lamellation restricted to the hair follicle have been reported. [33] | Figure 2: (a) Porokeratosis: A slanting column of keratin invaginates the epidermis. (×40) (b) Porokeratosis: There is focal hypogranulosis. The parakeratotic column extends between keratinocytes with a few dyskeratotic keratinocytes beneath it. (×100)
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Ultrastructurally, there is a decrease in keratohyaline granules and lamellar bodies underneath the cornoid lamella. [34] Dyskeratotic cells beneath the cornoid lamella have vacuolated cytoplasm. Some of these vacuoles were noted to be due to vacuolated mitochondria. The cells in the parakeratotic column were flattened, more compact and had electron dense cytoplasm. [26] The homogenous eosinophilic appearance of cornoid lamella seems to be due to stacking of ultrastructurally compact horny cells. [34]
Porokeratosis is the prototype disorder in which cornoid lamella is observed. Wade and Ackerman [30] observed that cornoid lamellation occurred in conditions other than porokeratosis such as seborrheic keratoses, verruca vulgaris, scar, milia, solar keratosis, squamous cell carcinoma in situ and basal cell carcinoma. It can also be seen in inflammatory disorders such as psoriasis, lichen planus like keratosis, dermatomyositis, keratosis lichenoides chronica, Grover's disease and Fox Fordyce disease. [35]
The cornoid lamella is thought to be formed by a genetically determined mutant clone of atypical epidermal keratinocytes. [36] Abnormal distribution pattern of -SH groups and SS linkages have been seen in the cornoid lamella. The -SH groups were seen to irregularly and abruptly disappear at the bottom of cornoid lamella. [37] Involucrin, a marker of terminal differentiation of epidermal keratinocytes was over expressed beneath the cornoid lamella and it had irregular appearance and disappearance. [38] There is also a tendency to rapid or incomplete keratinization of keratinocytes forming the cornoid lamella.
| Acantholytic Dyskeratosis | | |
Acantholytic dyskeratosis is characterized by the presence of suprabasal acantholysis along with acantholytic and dyskeratotic cells. This reaction pattern is seen in a variety of conditions with varied clinical presentations.
Darier's disease
There is epidermal hyperkeratosis with a suprabasal cleft with areas of acantholysis [Figure 3]a. Dyskeratotic cells in the viable epidermis are referred to as corps ronds and those in the stratum corneum as grains. [39] Corp ronds are larger cells with irregular eccentric nuclei surrounded by a clear halo with brightly eosinophilic cytoplasm usually present in the granular layer. [40] Grains are more eosinophilic flatter structures with scanty cytoplasm and abundant keratohyaline granules seen in the upper layers of the stratum granulosum [Figure 3]b. These changes are well developed in the keratotic papules of this condition. In hypopigmented macules and the acrokeratosis-like verrucous papules on acral skin, changes are subtle and may require multiple sections to be examined. | Figure 3: (a) Darier's disease: There is a suprabasal cleft with overlying compact hyper-and parakeratosis Dyskeratotic cells are seen. (×100) (b) Corps ronds, having irregular nuclei with eosinophilic cytoplasm are noted in the cleft. (×40)
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Hailey- Hailey disease
There is an intraepidermal cleft with suprabasal acantholysis with spongiosis. The extensive loss of intercellular connections with partial coherence of cells gives the characteristic "dilapidated brick wall appearance" [41] [Figure 4]. Dyskeratotic cells are not common in Hailey Hailey disease. There is loosening of the structure of the entire epidermis. There are instances when it is difficult to distinguish pemphigus from Hailey Hailey. The latter has a parakeratotic cap in the area of the suprabasal cleft while pemphigus does not. | Figure 4: Hailey-Hailey disease More Details: There is prominent acantholysis throughout the epidermis ("dilapidated brick wall appearance") with overlying parakeratosis. (×200)
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Flexural Darier's disease that is localized exclusively to body folds may create clinical and histopathological confusion. Keratotic papules and significant dyskeratosis help identify Darier's disease.
Warty dyskeratoma
There is a central well -defined cup-shaped keratin-filled crater. [42] A suprabasal split with villi formation is seen containing dyskeratotic cells [Figure 5]a. There is proliferation of stratified squamous epithelium with acantholysis along with presence of keratin pearls [43] [Figure 5]b. Warty dyskeratomas present as non-descript nodules and are practically impossible to recognize before a biopsy is undertaken. | Figure 5: (a) Warty dyskeratoma: Endophytic epidermal proliferation with hyperkeratosis and suprabasal clefting in broad foci (b) Warty dyskeratoma: The epidermal lining shows suprabasal clefts with many dyskeratotic cells (corps ronds). (×400)
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Grover's disease
There is hyperkeratosis, acanthosis and parakeratosis. Alternating vertical orthokeratosis and parakeratosis may be seen. There is focal acantholysis with dyskeratotic cells. Spongiotic changes may also be seen. The papillary dermis shows perivascular infiltrate of lymphocytes and histiocytes with variable number of eosinophils. [44]
This is a disease of older Caucasian men and is practically unknown in the dark skinned. It presents as itchy, erythematous papules on the back and the rest of the trunk. The eruption is often quite chronic, persistent and troublesome.
Galli-Galli disease
The main feature of this disorder is acantholysis but dyskeratosis has been reported in a few cases. [45] There are digitate downgrowths of slender, elongated and interconnected rete ridges and thinning of the suprapapillary epidermis. Follicular epithelium also shows these changes, sometimes more prominently than the surface epidermis.
Clinically, the condition is indistinguisable from Dowling Degos disease and presents with mottled pigmentation in the flexures accompanied by pigmented follicular pits.
Ultrastructurally, the cells in the basal and prickle cells are vacuolated in Darier's disease. [46] There is a normal or slightly increased amount of aggregated tonofilaments in these precursors of corps ronds in lacunae. These become mature corps ronds by further vacuolization when in the granular layer. On the other hand, vacuolated cells of the lower malpighian layer may develop premature aggregation of tonofilaments that compress the preexisting vacuoles into slits and give rise to intra-lacunar grains. There is acantholysis and presence of microvillar changes consisting of elongation, thinning, branching, clubbing and detachment, which precede intercellular space widening and changes in tonofilament and desmosomes in Hailey Hailey disease. [47] In the basal layer, there are thickened bundles of straight or wavy tonofilaments and whorled tonofilaments in granular layer. There is persistence of tonofilaments in stratum corneum. Similar features are seen in warty dyskeratoma. There are poorly developed tonofilaments in the basal cells, and the structure of desmosomes appear normal in Grover's disease. [48] There is an increase in the number of desmosomes in the spinous layer indicating compensation of defective desmosomal function.
The cause for acantholytic dyskeratosis in Darier's disease is attributed to ATP2A2 gene mutation [49] while in Hailey-Hailey to ATP2C1 gene mutation. [50] These changes have also been seen in mosaic variety of these disorders. [51],[52]
The changes of acantholytic dyskeratosis may be generalized as in Darier's disease, systematized process as in a variant of epidermal nevus, transient as seen in Grover's disease, solitary as in warty dyskeratoma or may be an incidental finding. Papular lesions in the vulva have also shown these changes. [53]
| Papillomatosis | | |
The term "papillomatosis" is used when the epidermal surface shows undulations and projections. The extent of papillomatosis may vary from small elevations to tall projections. The term 'church-spiring' is used to denote tall elevations resembling the steeple of churches. Epidermal hyperkeratosis and acanthosis may be present along with papillomatosis. Not uncommonly, pityrosporon yeasts are found in the stratum corneum of biopsies taken from the upper trunk. Inflammatory infiltrates are absent in the pattern as defined for this purpose, though they may be noted in some stages of some of the diseases that have this histopathological appearance. It is the the most common epidermal reaction pattern and is seen in a wide variety of conditions. However, in spite of its lack of specificity, it is a useful histopathological appearance to recognize because it provides a starting point to narrow down the differential diagnoses for the group of disorders characterized primarily by epidermal hyperplasia.
Some conditions that show papillomatosis are verruca vulgaris, [54] acrokeratosis verruciformis, [55] epidermodysplasia verruciformis, [56] verruca plana [Figure 6], seborrheic keratosis, [57] stucco keratosis, [58] arsenical keratosis, [59] acanthosis nigricans [60] [Figure 7] confluent and reticulated papillomatosis, [61] epidermal nevus [62] and verrucous carcinoma. [63] | Figure 6: Verrucca plana: Undulating papillomatosis with overling parakeratosis is noted. There are many koilocytes in the upper epidermis
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Since the pattern is shared by several disparate diseases, clinico-pathologic correlation is key to reaching a specific diagnosis. Individual papules in the different conditions resemble each other and it is their arrangement and localization that help in making the diagnosis, more easily in some diseases than in others. The degree of verrucosity can vary greatly from barely elevated papules to greatly keratotic ones.
Each of these patterns is noted in specific diseases described above. They may also occur as incidental findings at the edge of unrelated lesions such as melanocytic nevi, [64],[65] as focal lesions, [66] in follicular epithelium and as palmo-plantar lesions. In these settings, the diagnosis is usually discovered only after biopsy as the clinical presentation is non-descript.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
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