Review
PERFORATING DERMATOSES: A CLINICOPATHOLOGIC REVIEW AMIR H. MEHREGAN, M.D. From the Department of Dermatology and Syphilology, Wayne State University School of Medicine, Detro'it and Pinkus Dermatopathology Laboratory, Monroe, Michigan
The phenomenon of transepithelial elimination was proposed in 1968,' supported by observation of this process in various pathologic states. In eczematous dermatitis leukocytes, erythrocytes and occasionally mast cells transmigrate into the epidermis through a break in the basement membrane and are carried up within the intercellular spaces. In a similar fashion, mononuclear cells enter the epidermis to form Pautrier microabscesses in mycosis fungoides. Hansen bacilli and spirochetes may be found moving upward through the epidermis and into the surface keratin layer. Imbibition of the elastic fibers occurs in the process of epidermal repair in wound healing. Globes of amyloid may be taken into the epidermis in lichen amyloldosus and macrophages or giant cells are often taken up by the proliferating epithelium in various types of chronic granulomatous inflammation.
calcium chloride, the epidermis shows areas of pseudoepitheliomatous hyperplasia engulfing masses of calcified material and occasionally forms channels through which particles of calcified material are moved to the surface. In a similar situation, small fragments of bony tissue may be eliminated through an area of epidermal disruption. With this introduction to the process of transepithelial elimination, in the following pages various cutaneous disorders are discussed in which the process of perforation and elimination of various tissue components plays a major role in the basic pathologic mechanism. These include perforating granuloma annulare, perforating follicuiitis, elastosis perforans serpiginosa and reactive perforating collagenosis.
ln the condition known as black heel,^ small foci of hemorrhages are moved from the tips of the papillary bodies into the epidermis and are found in the thick keratin layer of this area. In all these situations the reaction of the epidermis is minimal and no major disruption of the epidermal structure is observed. The epidermis, however, reacts more actively when larger particles are to be taken in and eliminated. In calcinosis cutis, nodular type or secondary to contact with
Perforating Granuloma Annulare The initial observation of perforation and transepidermal elimination of necrobiotic connective tissue in a patient with disseminated papular form of granuloma annulare^ was soon confirmed by subsequent reports by Owen and Freeman^ and by Izumi'* and others.^^ ^ This phenomenon occurs when the area of necrobiosis and surrounding palisading granuloma is located sufficiently high to
Address for reprints: Amir H. Mehregan, M.D., Pinkus Dermatopathology Laboratory, P.O. Box 360, Monroe, Ml 48161.
19
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Fig. 1. Perforating granuloma annularo shows necrobiotic tissue in the area of perforation and in the upper corium where it is surrounded by palisading granuloma (H-E X 180).
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•
Mehregan
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have a direct effect on the overlying epidermis. At the periphery of the area of perforation, the epidermis may exhibit some degree of pseudoepitheliomatous hyperplasia. Necrobiotic connective tissue is found within the area of perforation as well as in the upper corium, where it is surrounded by the palisading type of lymphohistiocytic granuloma (Fig. 1). Perforating Folliculitis From 1967 to 1969, an increasing number of patients was observed with discrete inflammatory follicular lesions involving the extensor surfaces of the extremities and the buttocks (Fig. 2). The erythematous follicular papules showed central plugs of keratinous material, often giving an impression of follicular pustules.^ The eruption appeared to be related to some chemical in clothing. We suspected free formaldehyde and were able to demonstrate formaldehyde in the cloth material tested by Schiff's reagent. However, we were not successful in eliciting an allergic reaction in skin tests. The reaction appeared to be a primary irritant of follicular type. The reaction pattern is that of follicular hyperkeratosis and retention of the hair shaft in the dilated follicle. Secondary breakdown of the follicular wall occurs most likely due to mechanical irritation of the curled-up hair. This is followed by pseudoepitheliomatous proliferation of the follicular epithelium and intake of inflammatory cells, collagen and elastic fibers into the follicular cavity, forming a large plug** (Fig. 3). Whatever factor that was responsible for the production of this tissue reaction appears to have been gradually eliminated. In the past 3 years the number of cases observed has been greatly re-
Fig. 2. Perforating folliculitis is characterized by discrete follicular lesions with a central keratinous plug.
duced. Cases of this type have been described as examples of Kyrle's hyperkeratosis follicularis et parafollicularis in cutem penetrans.5'" In my opinion, Kyrle's disease is not a distinctive clinicopathologic entity but represents a histologic pattern of tissue reaction produced by variety of conditions, including perforating foliiculitis, hypertrophie Darier's disease, keratosis pilaris, etc. Elastosis Perforans Serpiginosa This connective tissue disease is a good example in the group of perforating disorders exhibiting the process of transepithelial elimination of the elastic fibers. The cutaneous lesions appear during the second decade of life and in their most common location over the back or sides of neck are characterized by discrete keratotic papules arranged into a circle or showing serpiginous configuration (Fig. 4). Histologic sections show an increase in the number of dermal elastic fibers and accumulation of the elastotic
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Fig. 3. Perforating follicuiitis shows an area of disruption of the follicular wall through which some fragments of connective tissue and inflammatory cells are entering into the follicular cavity (H-E X 135).
Fig. 4. Elastosis perforans serpiginosa is composed of discrete keratotic papules forming a circular lesion.
•r'
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Fig. 5. Elastosis perforans serpiginosa shows a perforating channel containing inflammatory cells and brightly eosinophilic elastic fibers (H-E X 180).
material within the papillary bodies. The reaction of the epidermis or the follicular wall is characterized by foci of pseudoepitheliomatous hyperplasia and formation of perforating channels through which some brightly eosinophilic elastic fibers mixed with inflammatory cells are eliminated (Fig. 5). The eosinophilic elastic fibers may be recognized in hematoxylin-eosin sections and when observed in scraping material taken from
the keratotic papular lesions, they may resemble fungous mycelia.^ An interesting feature is the association of elastosis perforans serpiginosa in one fourth of the cases with several types of hereditary disorders and disorders of the connective tissue such as mongoloid idiocy, EhlersDanlos syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum and Marfan's syndrome. Recently, 2 cases have been reported
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Fig. 6. Reactive perforating collagenosis is characterized by development of small pinhead size papules and well developed umbilicated lesions.
by Guilaine et al.^i and by Pass and his colleagues'2 of the development of elastosis perforans serpiginosa in patients with Wilson's disease under treatment with penicillamine. It has been postulated that the mechanism may involve a local copper deficiency and a decrease in the amount of mature cross-linked elastin and an increase in tropoelastin. Reactive Perforating Collagenosis Reactive perforating collagenosis was described in 1967" as a distinctive form of cutaneous reactivity to superficial trauma. The eruption appears during infancy and persists into adult life. In response to superficial trauma, the primary lesion appears as pinhead-size keratotic papules, which are discrete or arranged in a line suggesting Koebner
Jan.-Feb. 1977
Vol. 16
phenomenon. The lesions gradually increase in size and become centrally umbilicated (Fig. 6). A fully developed lesion shows a central core of leathery plug which cannot be removed without bleeding. The lesions reach their maximum size of 5 to 10 mm within a 4-week period and then begin to regress. In this stage the central plug wears off and the lesions flatten out, leaving behind macular spots of hypopigmentation. The entire cycle will take place within a 6to 8-week period. The cutaneous lesions may be produced experimentally by superficial trauma.i-* The histologic changes may be reconstructed as follows. The first microscopic changes observed in a pinhead-sized keratotic papule are characterized by an area of basophilic staining of the papillary connective tissue and atrophy of the suprapapillary plate (Fig. 7). The basophilic collagen bundles are gradually taken into the epidermis through the intercellular spaces and foci of epidermal disruptions.15 Extruded material mixed with keratinized cells forms a leathery plug within a cup-shaped area of epidermal depression (Fig. 8). As more material is eliminated, the central plug becomes larger until the supply of deformed connective tissue is exhausted. The process of transepithelial elimination is then terminated and the epidermis begins to regenerate, closing the areas of interruptions. The parakeratotic core in the center of the lesion is gradually eliminated. Twenty-one patients with reactive perforating collagenosis have been described in 8 publications."-20 There are in addition 7 unpublished cases in our file making a total of 28 patients reviewed. In this series are 4 pairs of sib-
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• Mehregan
25
Fig. 7A. Top, an early pinhead size lesion shows degenerated collagenous tissue in a widened dermal papilla (H-E X 180). Fig. 7B. Bottom, shows foci of epidermal disruption and transepidermal elimination of collagen bundles (H-E X 225). = • : — ..
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Fig. 8A. Top, fully developed umbilicated lesion of reactive perforating collagenosis containing a central leathery plug (H-E X 60). Fig. 8. Bottom, a healing lesion of reactive perforating collagenosis shows regeneration of epidermis and elimination of the central plug (H-E X 60).
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lings. Other familial cases include 2 families reported by Kanan^'' from Kuwait in which 7 members had this condition, ln another family from India reported by Nair and colleagues,''' 5 members were involved. Reactive perforating collagenosis appears to be a hereditary disease but the mode of its inheritance has not yet been properly evaluated. We have an unpublished observation of an adult and there is another patient^' with the cutaneous lesions of reactive perforating collagenosis, which occurs in adult patients with chronic renal disease undergoing dialysis. This is similar to elastosis perforans serpiginosa, which develops in patients with Wilson's disease receiving penicillamine. Here, we have agajn a condition which appears to be hereditary but produced under an unrelated pathologic state. These observations may provide a chance for investigation and a clue to the basic molecular changes responsible for the abnormal reactivity of the connective tissue in these 2 histologically related conditions. References
-^...-...c;:.:.-::" .;•'= .r:.:-; s>,i;.-
PERFORATING DERMATOSES: A CLINICOPATHOLOGIC REVIEW AMIR H. MEHREGAN, M.D. From the Department of Dermatology and Syphilology, Wayne State University School of Medicine, Detro'it and Pinkus Dermatopathology Laboratory, Monroe, Michigan
The phenomenon of transepithelial elimination was proposed in 1968,' supported by observation of this process in various pathologic states. In eczematous dermatitis leukocytes, erythrocytes and occasionally mast cells transmigrate into the epidermis through a break in the basement membrane and are carried up within the intercellular spaces. In a similar fashion, mononuclear cells enter the epidermis to form Pautrier microabscesses in mycosis fungoides. Hansen bacilli and spirochetes may be found moving upward through the epidermis and into the surface keratin layer. Imbibition of the elastic fibers occurs in the process of epidermal repair in wound healing. Globes of amyloid may be taken into the epidermis in lichen amyloldosus and macrophages or giant cells are often taken up by the proliferating epithelium in various types of chronic granulomatous inflammation.
calcium chloride, the epidermis shows areas of pseudoepitheliomatous hyperplasia engulfing masses of calcified material and occasionally forms channels through which particles of calcified material are moved to the surface. In a similar situation, small fragments of bony tissue may be eliminated through an area of epidermal disruption. With this introduction to the process of transepithelial elimination, in the following pages various cutaneous disorders are discussed in which the process of perforation and elimination of various tissue components plays a major role in the basic pathologic mechanism. These include perforating granuloma annulare, perforating follicuiitis, elastosis perforans serpiginosa and reactive perforating collagenosis.
ln the condition known as black heel,^ small foci of hemorrhages are moved from the tips of the papillary bodies into the epidermis and are found in the thick keratin layer of this area. In all these situations the reaction of the epidermis is minimal and no major disruption of the epidermal structure is observed. The epidermis, however, reacts more actively when larger particles are to be taken in and eliminated. In calcinosis cutis, nodular type or secondary to contact with
Perforating Granuloma Annulare The initial observation of perforation and transepidermal elimination of necrobiotic connective tissue in a patient with disseminated papular form of granuloma annulare^ was soon confirmed by subsequent reports by Owen and Freeman^ and by Izumi'* and others.^^ ^ This phenomenon occurs when the area of necrobiosis and surrounding palisading granuloma is located sufficiently high to
Address for reprints: Amir H. Mehregan, M.D., Pinkus Dermatopathology Laboratory, P.O. Box 360, Monroe, Ml 48161.
19
20
INTERNATIONAL JOURNAL OF DERMATOLOGY
Jan.-Feb. 1977
Vol. 16
Fig. 1. Perforating granuloma annularo shows necrobiotic tissue in the area of perforation and in the upper corium where it is surrounded by palisading granuloma (H-E X 180).
No. 1
PERFORATING DERMATOSES
•
Mehregan
21
have a direct effect on the overlying epidermis. At the periphery of the area of perforation, the epidermis may exhibit some degree of pseudoepitheliomatous hyperplasia. Necrobiotic connective tissue is found within the area of perforation as well as in the upper corium, where it is surrounded by the palisading type of lymphohistiocytic granuloma (Fig. 1). Perforating Folliculitis From 1967 to 1969, an increasing number of patients was observed with discrete inflammatory follicular lesions involving the extensor surfaces of the extremities and the buttocks (Fig. 2). The erythematous follicular papules showed central plugs of keratinous material, often giving an impression of follicular pustules.^ The eruption appeared to be related to some chemical in clothing. We suspected free formaldehyde and were able to demonstrate formaldehyde in the cloth material tested by Schiff's reagent. However, we were not successful in eliciting an allergic reaction in skin tests. The reaction appeared to be a primary irritant of follicular type. The reaction pattern is that of follicular hyperkeratosis and retention of the hair shaft in the dilated follicle. Secondary breakdown of the follicular wall occurs most likely due to mechanical irritation of the curled-up hair. This is followed by pseudoepitheliomatous proliferation of the follicular epithelium and intake of inflammatory cells, collagen and elastic fibers into the follicular cavity, forming a large plug** (Fig. 3). Whatever factor that was responsible for the production of this tissue reaction appears to have been gradually eliminated. In the past 3 years the number of cases observed has been greatly re-
Fig. 2. Perforating folliculitis is characterized by discrete follicular lesions with a central keratinous plug.
duced. Cases of this type have been described as examples of Kyrle's hyperkeratosis follicularis et parafollicularis in cutem penetrans.5'" In my opinion, Kyrle's disease is not a distinctive clinicopathologic entity but represents a histologic pattern of tissue reaction produced by variety of conditions, including perforating foliiculitis, hypertrophie Darier's disease, keratosis pilaris, etc. Elastosis Perforans Serpiginosa This connective tissue disease is a good example in the group of perforating disorders exhibiting the process of transepithelial elimination of the elastic fibers. The cutaneous lesions appear during the second decade of life and in their most common location over the back or sides of neck are characterized by discrete keratotic papules arranged into a circle or showing serpiginous configuration (Fig. 4). Histologic sections show an increase in the number of dermal elastic fibers and accumulation of the elastotic
22
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Fig. 3. Perforating follicuiitis shows an area of disruption of the follicular wall through which some fragments of connective tissue and inflammatory cells are entering into the follicular cavity (H-E X 135).
Fig. 4. Elastosis perforans serpiginosa is composed of discrete keratotic papules forming a circular lesion.
•r'
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Mehregan
23
Fig. 5. Elastosis perforans serpiginosa shows a perforating channel containing inflammatory cells and brightly eosinophilic elastic fibers (H-E X 180).
material within the papillary bodies. The reaction of the epidermis or the follicular wall is characterized by foci of pseudoepitheliomatous hyperplasia and formation of perforating channels through which some brightly eosinophilic elastic fibers mixed with inflammatory cells are eliminated (Fig. 5). The eosinophilic elastic fibers may be recognized in hematoxylin-eosin sections and when observed in scraping material taken from
the keratotic papular lesions, they may resemble fungous mycelia.^ An interesting feature is the association of elastosis perforans serpiginosa in one fourth of the cases with several types of hereditary disorders and disorders of the connective tissue such as mongoloid idiocy, EhlersDanlos syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum and Marfan's syndrome. Recently, 2 cases have been reported
24
INTERNATtONAL JOURNAL OF DERMATOLOGY
Fig. 6. Reactive perforating collagenosis is characterized by development of small pinhead size papules and well developed umbilicated lesions.
by Guilaine et al.^i and by Pass and his colleagues'2 of the development of elastosis perforans serpiginosa in patients with Wilson's disease under treatment with penicillamine. It has been postulated that the mechanism may involve a local copper deficiency and a decrease in the amount of mature cross-linked elastin and an increase in tropoelastin. Reactive Perforating Collagenosis Reactive perforating collagenosis was described in 1967" as a distinctive form of cutaneous reactivity to superficial trauma. The eruption appears during infancy and persists into adult life. In response to superficial trauma, the primary lesion appears as pinhead-size keratotic papules, which are discrete or arranged in a line suggesting Koebner
Jan.-Feb. 1977
Vol. 16
phenomenon. The lesions gradually increase in size and become centrally umbilicated (Fig. 6). A fully developed lesion shows a central core of leathery plug which cannot be removed without bleeding. The lesions reach their maximum size of 5 to 10 mm within a 4-week period and then begin to regress. In this stage the central plug wears off and the lesions flatten out, leaving behind macular spots of hypopigmentation. The entire cycle will take place within a 6to 8-week period. The cutaneous lesions may be produced experimentally by superficial trauma.i-* The histologic changes may be reconstructed as follows. The first microscopic changes observed in a pinhead-sized keratotic papule are characterized by an area of basophilic staining of the papillary connective tissue and atrophy of the suprapapillary plate (Fig. 7). The basophilic collagen bundles are gradually taken into the epidermis through the intercellular spaces and foci of epidermal disruptions.15 Extruded material mixed with keratinized cells forms a leathery plug within a cup-shaped area of epidermal depression (Fig. 8). As more material is eliminated, the central plug becomes larger until the supply of deformed connective tissue is exhausted. The process of transepithelial elimination is then terminated and the epidermis begins to regenerate, closing the areas of interruptions. The parakeratotic core in the center of the lesion is gradually eliminated. Twenty-one patients with reactive perforating collagenosis have been described in 8 publications."-20 There are in addition 7 unpublished cases in our file making a total of 28 patients reviewed. In this series are 4 pairs of sib-
No. 1
PERFORATING DERMATOSES
• Mehregan
25
Fig. 7A. Top, an early pinhead size lesion shows degenerated collagenous tissue in a widened dermal papilla (H-E X 180). Fig. 7B. Bottom, shows foci of epidermal disruption and transepidermal elimination of collagen bundles (H-E X 225). = • : — ..
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Fig. 8A. Top, fully developed umbilicated lesion of reactive perforating collagenosis containing a central leathery plug (H-E X 60). Fig. 8. Bottom, a healing lesion of reactive perforating collagenosis shows regeneration of epidermis and elimination of the central plug (H-E X 60).
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lings. Other familial cases include 2 families reported by Kanan^'' from Kuwait in which 7 members had this condition, ln another family from India reported by Nair and colleagues,''' 5 members were involved. Reactive perforating collagenosis appears to be a hereditary disease but the mode of its inheritance has not yet been properly evaluated. We have an unpublished observation of an adult and there is another patient^' with the cutaneous lesions of reactive perforating collagenosis, which occurs in adult patients with chronic renal disease undergoing dialysis. This is similar to elastosis perforans serpiginosa, which develops in patients with Wilson's disease receiving penicillamine. Here, we have agajn a condition which appears to be hereditary but produced under an unrelated pathologic state. These observations may provide a chance for investigation and a clue to the basic molecular changes responsible for the abnormal reactivity of the connective tissue in these 2 histologically related conditions. References
-^...-...c;:.:.-::" .;•'= .r:.:-; s>,i;.-
