New observations and comprehensive review

Jul – Sep 2002 | Vol. 8, No. 3
Ackerman, A. Bernard; Böer, Almut; Kiryu, Hiromaro; Misago, Noriyuki; Wang, Xiao-Dong; Wolter, Manfred

Historical Perspective

Nagashima (Figure 1), a Japanese dermatologist, and two of his colleagues, Oshiro and Shimizu, were the first to publish, in 1971, an account of their experience with “A peculiar pruriginous dermatosis with gross reticular pigmentation,” for which they proposed the name “prurigo pigmentosa” 1. The original article was written in Japanese and that may be the chief reason the disease seems subsequently to have been recognized more often in Japan than elsewhere. Between 1967 to 1969, Nagashima and his associates observed eight patients, all of them Japanese, who suffered from a malady that presented itself in repeatable fashion. In their seminal article they pointed out what they regarded to be characteristic features of the disease clinically, summarizing them as follows (translated from the Japanese):

Fig. 1

Masaji Nagashima. Professor Nagashima was the first, along with his coworkers, to describe “A peculiar pruriginous dermatosis with gross reticular pigmentation” (prurigo pigmentosa). He did that in the Japanese Journal of Dermatology for 1971.

“. . . we accumulated eight cases of a disease which we could not diagnose and which were characterized by a highly pruritic red rash which left behind reticular pigmentation. . . . The lesions had an urticarial aspect and often were scratched. The red, highly pruritic rash tends to recur and when it remits leaves a coarse reticular pigmentation. The back, neck, and clavicular region are favorite sites. Young females are most often affected.” Nagashima et al., 1971, Japanese Journal of Dermatology1

Nagashima and his coworkers referred to the condition as “an ignored clinical entity”. They illustrated the clinical features by way of 12 photographs (Figures 2AD) that showed clearly how similar was the eruption as it presented itself in all of the patients reported on. Sections of tissue from biopsy specimens (Figures 3AB) were seen to exhibit the following findings (translated from the Japanese):

“In biopsies taken from the rash, spongiosis, vesiculation, and exocytosis of inflammatory cells was seen. The basal cell layer showed vacuolization. The papillary dermis was edematous and contained dilated blood vessels. A dermal perivascular infiltrate consisting of lymphocytes and some neutrophils could be observed. The pigmented lesions showed pigmentation of the basal layer and a dermal perivascular infiltrate of lymphocytes.” Nagashima et al., 1971, Japanese Journal of Dermatology1

The following photographs (Fig. 2 AD) from Nagashima”s original article in 1971 show how similar is the eruption of prurigo pigmentosa in each of his patients. Lesions are distributed somewhat symmetrically on the trunk. The upper part of the back (Fig. 2A), the neck (Fig. 2B), and the lower part of the back (Fig. 2C) are sites of predilection. In each of the photographs, the lesions can be seen to have become confluent in foci and, by virtue of that, to have assumed a reticular pattern.

Fig. 2A

Prurigo pigmentosa on the upper part of the back. (Reproduced with permission from Nagashima M, Ohshiro A, Shimizu N: A peculiar pruriginous dermatosis with gross reticular pigmentation, Japanese Journal of Dermatology 1971;81:38-39).

Fig. 2B

Prurigo pigmentosa on the neck. (Reproduced with permission from Nagashima M, Ohshiro A, Shimizu N: A peculiar pruriginous dermatosis with gross reticular pigmentation, Japanese Journal of Dermatology 1971;81:38-39).

Fig. 2C

Prurigo pigmentosa on the lower part of the back. (Reproduced with permission from Nagashima M, Ohshiro A, Shimizu N: A peculiar pruriginous dermatosis with gross reticular pigmentation, Japanese Journal of Dermatology 1971;81:38-39).

Fig. 2D

Prurigo pigmentosa. Reticular pattern formed by lesions after they have become confluent (Reproduced with permission from Nagashima M, Ohshiro A, Shimizu N: A peculiar pruriginous dermatosis with gross reticular pigmentation, Japanese Journal of Dermatology 1971;81:38-39).

The following photomicrographs (Fig. 3A and 3B) appeared in the article of Nagashima et al. in 1971.

Fig. 3A

Prurigo pigmentosa. There is slight spongiosis and a hint of ballooning, in addition to a sparse superficial infiltrate of lymphocytes. The histopathologic findings pictured here are hardly representative of a fully developed lesion of prurigo pigmentosa, which for Nagashima was a red papule. (Reproduced with permission from Nagashima M, Ohshiro A, Shimizu N: A peculiar pruriginous dermatosis with gross reticular pigmentation, Japanese Journal of Dermatology 1971;81:38-39).

Fig. 3B

Prurigo pigmentosa. This photomicrograph also comes from the article of Nagashima et al. in 1971. Many melanophages are situated in the papillary dermis and in the upper part of the reticular dermis in company there with a sparse perivascular infiltrate of lymphocytes. These findings are consonant with a clinical lesion of prurigo pigmentosa at the end stage of the disease, namely, when only pigmented macules are residual (Reproduced with permission from Nagashima M, Ohshiro A, Shimizu N: A peculiar pruriginous dermatosis with gross reticular pigmentation, Japanese Journal of Dermatology 1971;81:38-39).

Although Nagashima and his collaborators thought the histopathologic findings were non-specific, they classified the pruritic papules among the “pruriginous dermatoses” and suggested the name “prurigo pigmentosa” for the condition; that designation captured only the itching and the peculiar netlike pigmentation that was residual. In their judgment, the differential diagnosis included confluent reticulated papillomatosis of Gougerot and Carteaud, erythema dyschromicum perstans (“ashy dermatosis”), pigmented contact dermatitis, lichen pigmentosus, urticaria pigmentosa, and prurigo melanotica (the latter being a disorder first recorded by Pierini and Borda and associated with cirrhosis2), the link among those various maladies being marked pigmentation clinically. Nagashima et al. emphasized the uniquences of prurigo pigmentosa and stressed that all of the diseases in their differential could be excluded by virtue of attributes they deemed to be characteristic of prurigo pigmentosa. The authors sought to manage the eruption with antihistaminics, antiserotonins, and corticosteroids administered systemically, but none of those medications proved to be effective.

After the initial article by Nagashima et al., prurigo pigmentosa came to be recognized in Japan increasingly and, soon thereafter, several reports of patients affected by it appeared in the Japanese literature. By 1978, over 40 patients with prurigo pigmentosa, including those of Nagashima and his fellow workers, had been recorded. At that time, Nagashima elected to publish his findings in a forum that would attract more attention internationally. The article, in English, was published in 1978 in The Journal of Dermatology and was titled, “Prurigo pigmentosa-clinical observations of our 14 cases”. The stated purpose of Nagashima was “to report on this new clinical entity. . . as no such entity has ever been noted. . . in other countries” 3. He described the clinical features of the condition in these words:

“The primary lesions of the disease are a few slightly-raised reddish papules, ranging in size from a millet seed to a half-grain of rice. . . . The papules, accompanied by severe pruritus, evolve to urticarial papular lesions by the stimulus of scratching. The size of each papule then becomes enlarged, and sometimes two or three of them coalesce. . . . These urticarial papular lesions begin to subside spontaneously in two or three days along with disappearance of the pruritus, and the conditions usually improve in about a week. However, the pigmentation is left in the lesions, and the papules may recur. . . . The pigmented spots,. . . because of repeated occurrence of the reddish papules, tend to coalesce and to show a motted, gross reticular or marble-like appearence. . . . Because of the absence of recurrences, the pigmentation gradually clears.”. . .

“When repeated attacks occur in short succession, tiny excoriations, crusts and scales . . . are found. . . . Sometimes the lesions may be covered by polymorphous eczematous features.” Nagashima, 1978, The Journal of Dermatology3

The findings in sections of tissue from biopsy specimens were summarized by Nagashima thus:

“Reddish papules: . . . exocytosis, inter- and intracellular edema, and liquefaction degeneration of the basal cell layer. Marked spongiosis or spongiotic bullae are not constant features. . . In the upper and middle portion of the dermis, varying degrees of edema, dilation of the blood vessels and perivascular round cell infiltration were found. . . . Pigmented lesions: . . . moderate to marked incontinence of pigments and mild perivascular round cell infiltration in the dermis.” Nagashima, 1978, The Journal of Dermatology3

For Nagashima, the findings histopathologically in both the epidermis and the dermis were “non-specific and not diagnostic”, which prompted him to conclude that diagnosis of prurigo pigmentosa should be made on the basis of clinical features characteristic of it.

In regard to therapy of prurigo pigmentosa, Sugawara et al. had commented in 1973, in an abstract written in Japanese, about a “dramatic response . . . in one patient [with prurigo pigmentosa to] 100 mg of diamino-diphenyl-sulfone [dapsone]”4. By dint of experience with four patients, Nagashima confirmed the effectiveness of dapsone in the treatment of prurigo pigmentosa, but he could not explain the mechanism of action of it, stating simply that “. . . the reason for successful treatment with DDS (diamino-diphenyl-sulfone, dapsone) is as yet unknown, [although] this drug is recommended as useful for the disease”. Dobson abstracted the essence of Nagashima’s article for The Year Book of Dermatology of 1979 and opined that the very good response to dapsone indicated that patients with prurigo pigmentosa probably had an unusual variant of dermatitis herpetiformis 5. Dobson recommended, therefore, that studies employing immunofluorescence be carried out routinely when a diagnosis of prurigo pigmentosa was suspected. No such studies had been performed by Nagashima.

Once the disease gained attention through publications about it in journals whose readership was international, and especially after Coterill and his coworkers, in the British Journal of Dermatology in 1981, shared their experience with two patients with prurigo pigmentosa, those being the first with the disease remarked on in the West 6, the number of reports of the condition in other countries began to increase, albeit slowly. An article by Teraki, Nagashima, and other Japanese colleagues appeared in the British Journal of Dermatology in 1991 7, and it received more attention than had been given the original one in English by Nagashima in 1978. Whereas only six non-Japanese patients with prurigo pigmentosa were identified in the decade before 1992, 18 non-Japanese patients have come to notice as of today, an indication that the disease is more prevalent outside Japan than was thought previously. The non-Japanese patients were said to be Chinese8,9, Tunesian10,11, western European6,12,13, middle European14,15, Italian16-18, Portuguese19, Spanish20, Moroccan21, Turkish22, and both Caucasian23,24 and African Americans25 living in the United States. Interestingly, five of the non-Japanese patients were Sicilian, and three of them had been diagnosed incidentially in the course of an undertaking devoted to “Skin pathology findings in a cohort of 1500 adult and elderly subjects”26 Siragusa and Schepis, who studied the Sicilian patients, speculated that prurigo pigmentosa might be a disease that was more common than appreciated but underdiagnosed, or a disease of Sicilians especially.

In little more than 30 years, over 200 patients with prurigo pigmentosa have been reported on in Japan, many of them in presentations at conferences (as evidenced by a search in Centra Revuo Medicine, Japan). In the literature of dermatology written in Japanese, more than 70 patients have been presented since Nagashima’s original article appeared in 1971. Preponderance of Japanese patients in the literature given to prurigo pigmentosa is more explicable on the basis of greater awareness of the disease in Japan than on ethnologic proclivity of the disease for Asians.

The fact that prurigo pigmentosa is diagnosed rarely in the West is evident by even casual perusal of most standard textbooks of dermatology, dermatopathology, and general pathology, only few of which even mention the disorder2730, and half of those that do refer to it make no reference to Nagashima’s publications in 1971 and 197829,30. A clinical photograph of the disease was pictured in only one volume, that is, the Textbook of Dermatology edited by Rook, Wilkinson, and Ebling27. Histopathological findings of prurigo pigmentosa are given short shrift, no more than a paragraph, in the forementioned textbooks and, in general, are said to be those of a non-specific, somewhat lichenoid tissue reaction with a superficial perivascular infiltrate of lymphocytes mainly, interface changes, and, in hyperpigmented lesions, melanophages.

At the 22nd Colloquium of the International Society of Dermatopathology that convened in Stresa, Italy, in October 2001, a question was raised about whether prurigo pigmentosa truly is a distinct entity, clinically and histopathologically. The work presented here was joined in an effort to answer that question. The new observations that follow are based on study of 25 patients with prurigo pigmentosa, most of whom had numerous exacerbations and recurrences of the disease over the course of up to 10 years. A review of the subject that then follows concerns 178 patients of more than 10 nationalities and includes every patient who has been reported on to date in the medical literature of the English language (search by medline), as well as the vast majority of patients published in the literature of dermatology written in Japanese.

Clinical Features

Attributes of prurigo pigmentosa said to be typical of it clinically can be conveyed best and most compellingly by quoting directly from articles dedicated to the subject. What follows are quotations from the principle articles that appeared subsequent to the first publication by Nagashima:

“. . . reddish papules, some excoriated, and marked reticulate hyperpigmented motteling.” Cotterill et al., 1981, British Journal of Dermatology6

“The eruption subsided in 1 week or ten days, leaving residual pigmentation, but new papules broke out . . . accompanied by severe itching.” Yamasaki et al., 1981, The Journal of Dermatology31

“. . . itchy reddish papules, which evolved into marked reticulate pigmentation. . . . In the pigmented area there were some reddish raised papules. . . . coalescing to form a reticulate pattern.” Miyakawa et al., 1984, Dermatologica32

“Many reddish papules . . . were distributed as dots on the reticular pigmentation.” Shimizu et al., 1985, Journal of the American Academy of Dermatology33

“Intensly puritic eruptions . . . The rash always subsided a week later leaving a reticulate pigmentation.” Harms et al., 1986, Dermatologica12

“. . . there were erythematous scaling papules confined to the reticulate areas of pigmentation, the intervening skin being clinically normal . . . ” Cox et al., 1987, British Journal of Dermatology8

“. . . puritic rash, of sudden onset, with erythematous . . . and. . . . hyperpigmented papules . . . The lesions were 2-3 mm in diameter and a hyperpigmented reticulate pattern was observed between the papules.” Schepis et al., 1996, British Journal of Dermatology16

“. . . mottled erythema, reticular pigmentation, small red papules and small blisters . . . some scratch marks. . . .” Murao et al., 1996, British Journal of Dermatology34

“. . . multiple itchy painful, vesicular lesions erupting in a disseminated pattern” Kubota et al., 1998, European Journal of Dermatology35

In articles about prurigo pigmentosa that appeared after Nagashima’s two seminal reports, pictures of lesions clinically are shown in about 80 patients and, although some of those photographs are wanting in quality, almost all of them correspond well with illustrations that appeared in the articles of Nagashima (Figures 4 AH). Descriptions of the clinical aspects, the chronological sequence of individual lesions, and the course of the disease itself are strikingly similar in all articles that have dealt with those matters about prurigo pigmentosa during the past 30 years. Among the 178 patients reported on in articles reviewed by us, detailed description of clinical features was given in 168 of them. Erythematous macules distributed either in patchy or random fashion were noted in 22 patients. In almost all patients, intensely pruritic erythematous papules, 2 to 4 millimeters in diameter, were dominant; in 58 patients those papules were thought to be urticarial. Plaques were said to be present in 68 patients and those lesions were characterized as being “wheal-like” in 11 patients. Frank vesicles were claimed to have occurred in some patients25,3544, but pustules16,37 or bullae 35,44 were noted in very few of them. Signs of excoriation were apparent in 35 patients, crusts in 32, and scales in 27. In time, the lesions resolved, leaving as residuum a reticular pattern of pigmentation. The process was typified by exacerbation and remission.

What precedes immediately (Figs. 4 AH) are clinical photographs of prurigo pigmentosa that appeared subsequent to the publication of the seminal article of Nagashima. They show features very similar to those pictured by Nagashima and his colleagues. The neck, back, and chest are favored sites. When lesions become confluent, a reticular pattern comes into being consistently.

Fig. 4A

Prurigo pigmentosa. Papules, tiny crusted erosions, and reticular hyperpigmentation on the neck, shoulders, and upper two thirds of the back, where there is a hint of the lesions being distributed in a wedge shape. (Reproduced with permission from Murao K, Urano Y, Uchida N, Arase S: Prurigo pigmentosa associated with ketosis, British Journal of Dermatology 1996;134:379-380)

Fig. 4B

Prurigo pigmentosa. The eruption is rather symmetrical on the back. Discrete papules are apparent at the periphery of the broad zone in which papules have become confluent. Large zones of sparing, as seen here, are common. (Reproduced with permission from Aso M, Miyamoto T, Morimura T, Shimao S: Prurigo pigmentosa successfully treated with minocycline, British Journal of Dermatology 1989;120:705-708)

Fig. 4C

Prurigo pigmentosa. The papules are so numerous that they cover the back densely, but despite the effluorescence, a reticular pattern still is discernable. (Reproduced with permission from Shimizu H, Yamasaki Y, Harada T, Nishikawa T: Prurigo pigmentosa, Journal of the American Academy of Dermatology 1985;12:165-169)

Fig. 4D

Prurigo pigmentosa. The inter- and submammary zones are affected often in prurigo pigmentosa. Note also the extensive involvement of the breast and the abdomen where papules, vesicles, and erosions are distributed in a wedge shape. (Reproduced with permission from Matsunaga J, Hattyoume N, Tagami Y: Prurigo pigmentosa with intraepidermal vesicles containing many dyskeratotic cells and neutrophils, Rinsho Derma (Tokyo) 1989;31:273-276).

Fig. 4E

Prurigo pigmentosa. The shoulders, neck, and chest are affected by papules arranged in a netlike pattern. Note the zone of sparing in the middle of the chest. (Reproduced with permission from Cox NH: Prurigo pigmentosa, British Journal of Dermatology 1987;117:121-124).

Fig. 4F

Prurigo pigmentosa. Involvment of the face by prurigo pigmentosa is rare, but when that happens the forehead is the site most likely to be affected. (Reproduced with permission from Miyakawa S, Kurihara S, Nishikawa T: Prurigo pigmentosa affecting the forehead, Dermatologica 1984;169:135-137).

Fig. 4G

Prurigo pigmentosa. A netlike pattern is stereotypical for lesions of prurigo pigmentosa (Reproduced with permission from Cox NH: Prurigo pigmentosa, British Journal of Dermatology 1987;117:121-124).

Fig. 4H

Prurigo pigmentosa. The netlike pattern of prurigo pigmentosa is repeatable. (Reproduced with permission from Degarve B, Guilhou JJ, Guillot B: Prurigo pigmentosa, Ann. Dermatol. Venereol. 1994;121:46-49).

In only 13 articles1,3,12,31,39,4552 was mention made of the duration of individual papules, namely, two days to one week. The netlike pigmentation was said to have persisted for weeks and even months. Scarring was rare and developed mostly as a consequence of the effects of excoriation. No reference was made ever to involvement of mucous membranes, hair, or nails.

The lesions of prurigo pigmentosa were distributed symmetrically (146/168), the center of the trunk being the favorite site for them. Other sites of preference were the chest (108/168) and the back (129/168), neck (66/168), lumbosacral region (62/168), abdomen (43/168) and shoulders (40/168). When involvement of the chest was specified (53/108), the anterior chest was affected most commonly (35/53), especially the intermammary region (12/35).15, 47,51,5355 The lateral aspect of the chest was affected in 15 patients and the submammary region in four of them.19,22,42,43 In some patients, the arms were involved (21/168), and the legs (5/168)16,18,25,31,40 and the forehead very uncommonly (6/168).8,17,32,5658

Lesions of prurigo pigmentosa tended to recur and did that in at least 112 of the 168 patients. The interval of freedom from new lesions was from weeks to months, or even years. In most instances, a patient had had the disease for months, at least, before a correct diagnosis was made clinically. In articles pertinent to the subject, a meaningful history is provided for 157 patients, 81 of them having had the disease somewhere between more than a year and up to 10 years1,3,4,612,18,20,2225,3133,36,45,4752,54,55,58,6075 before diagnosis was rendered accurately. Forty one patients recounted that the eruption had recurred for several months before precise diagnosis was accomplished. 1,3,4,6,21,22,31,37,39,40,4345,50,51,53,55, 56,62,64,6971,75,76,7880,8284 Only in 35 patients was the disease diagnosed correctly within days or a few weeks from the time of onset of signs and symptoms.15,34,35,37,38,41,42,48,51,56,62,7274,77,8388

In the report of Nagashima et al.,3 12 female and two male patients had prurigo pigmentosa, a ratio of 6:1, whereas Teraki et al. found the female:male ratio of the disease to be 4:17. One hundred and twenty two females and 56 males with prurigo pigmentosa now have been reported on, a convincing indication of preponderance in females. The mean age at the time of diagnosis was 25 years, females being younger (mean: 24 years) than males (mean: 27 years) when the diagnosis was made. No family history of prurigo pigmentosa was obtained in any patient. Never has the disease been diagnosed demonstrably in either prepubescent children or the elderly.

In sum, prurigo pigmentosa presented itself most often as an eruption distributed symmetrically on the trunk, with predilection for the upper part of the back, neck, shoulders, sacrum, and abdomen. Patients often tell of having had lesions for several months prior to seeking consultation, the individual lesions being short-lived, red, urticarial papules, plaques, and papulovesicles that resolved with pigmentation in reticular arrangement. Lesions were intensly pruritic and, as a consequence, evidences of excoriation, including hemorrhogic crusts, were common. Recurrences are the rule. The disease manifested itself initially in young adults mostly. Females are affected about twice as often as males.

Critique

Of course, lesions of prurigo pigmentosa must appear first as erythematous macules, rather than as papules, and, moreover, it is unlikely in the extreme that any of the papules actually subside completely in two days (only urtica involutes that quickly and the papules of prurigo pigmentosa are urticarial, not urtica). The pigmentation is post inflammatory, that is, a residuum of the effects of the infiltrates of inflammatory cells on the epidermis, from whence melanin is lost to macrophages in the upper part of the dermis; red papules resolve as pigmented macules. In order for pigment to appear in reticular pattern, weeks, at least, must go by and the phenomenon can be explained not only by the fact that the urticariaal papules erupt in a somewhat reticulated pattern, but by the reality that each crop of papules in a recurrent eruption, upon involuting, contributes to the netlike pattern of pigmentation.

As the number of reports of patients with prurigo pigmentosa increased, the ratio of females to males has declined continually, that is, from 6:1 recorded by Nagashima in 19783 to 2:1 when data from all of the articles published to date are pooled. Prurigo pigmentosa still appears to be more common in females, but sex, alone, cannot be used as a criterion for diagnosis or in differential diagnosis.

None of the authors of articles have commented on the lack of appropriateness of the name “prurigo pigmentosa”, a designation that fails to enlighten because it is but one of hundreds of diseases of the skin that are itchy and resolve with pigmentation. Neither should prurigo pigmentosa be conceived of simply as one of the “pruriginous dermatoses”, which, in actuality, are not a distinct group of inflammatory diseases but rather variations on the theme of lichen simplex chronicus. Prurigo pigmentosa is a distinctive inflammatory skin disease that arises sui generis.

Our Observations

All of our patients, six Japanese males (mean age at the time of diagnosis 30 years) and 19 females (mean age at the time of diagnosis 26 years), sixteen of those women being Japanese, one Turkish, one Italian, and one German, told of a pruritic eruption that occurred on the trunk in the absence of a prodrome. The lesions were situated on the back (Figures 5AI) and the neck (Figures 6AD) mostly. In some patients the distribution of lesions on the back was wedge-shaped, seeming to cut a swath through the length of the center of the back, the apex of the wedge being caudal. In other patients lesions spared the upper part of the back and formed the negative image of a wedge on the lower part of the back. The chest was affected in 14 patients (Figures 7AH), whereas the clavicular region (Figures 8AC) and the abdomen was caught up in the process in but a few patients. In two patients, the upper extremities where involved. Large zones of sparing are an expected finding in prurigo pigmentosa. In most of the patients (21/25), the eruption recurred, 13 of them attesting to several recurrences over months, and 8 telling of many recurrences over years. The interval between episodes in these patients was as short as two weeks and as long as three years. The number of anatomic sites involved in the process increased, albeit slowly, in 9 patients. As but one example, the Turkish women had no lesions on the face for 10 years, but after that period of time she developed lesions on the forehead.

Photographs of lesions of prurigo pigmentosa on the back (Figs. 5AI), neck (Figs.6AD), chest (Figs. 7AH), and clavicular region (Figs. 8AC) as they presented themselves in our patients are presented in the following figures in a sweep from extensive to paltry involvement.

Fig. 5A

Prurigo pigmentosa on the back: Red urticarial papules, many of which have become confluent to form plaques.

Fig. 5B

Prurigo pigmentosa on the back: Erythematous urticarial papules and plaques on the back, especially the upper part of it. Note also pigmented macules.

Fig. 5C

Prurigo pigmentosa on the back: Erythematous papules and plaques in company with crusts. Scales as well as pigmented macules are present mostly on the lower part of the back. The upper part of the back is largely spared.

Fig. 5D

Prurigo pigmentosa on the back: Red papules have become confluent to form plaques in a netlike pattern and in asymmetrical fashion.

Fig. 5E

Prurigo pigmentosa on the back: Netlike pigmentation in the lumbar region represents the postinflammatory stage of prurigo pigmentosa.

Fig. 5F

Prurigo pigmentosa on the back: Many red papules and tiny vesicles are discrete, but others have become confluent, the latter resulting in formation of an incipient reticular pattern.

Fig. 5G

Prurigo pigmentosa on the back: The midline of the mid portion of the back is affected by red papules and pigmented macules arranged in a netlike pattern and distributed in patchy fashion.

Fig. 5H

Prurigo pigmentosa on the back: Reticular pigmentation in a wedge shape on the back, a consequence of resolution of urticarial papules. Some red papules have appeared newly.

Fig. 5I

Prurigo pigmentosa on the back: Most of the red papules and pigmented macules on the back are discrete, but some have become confluent.

Fig. 6A

Prurigo pigmentosa on the neck. Red papules and pigmented macules have become confluent to create a netlike pattern (picture kindly provided by Dr. Teraki, Tokyo).

Fig. 6B

Prurigo pigmentosa on the neck. Some red papules are discrete, whereas others have become confluent to form plaques and lesions that are linear and arcuate.

Fig. 6C

Prurigo pigmentosa on the neck. Discrete red papules and ill defined plaques characterized by a jaggered outline.

Fig. 6D

Prurigo pigmentosa on the neck. Discrete red papules and papules have joined to form an arc.

Fig. 7A

Prurigo pigmentosa on the chest. Red papules and pigmented macules arranged in netlike fashion (picture kindly provided by Dr. Teraki, Tokyo).

Fig. 7B

Prurigo pigmentosa on the chest. Discrete red papules and confluence of them to form a reticular pattern.

Fig. 7C

Prurigo pigmentosa on the chest. Many red papules have become confluent, of a reticular pattern being the result. The pigmented macules are the residuum of red papules that involuted.

Fig. 7D

Prurigo pigmentosa on the chest. Pink macules, some of which have become confluent to assume a netlike outline

Fig. 7E

Prurigo pigmentosa on the chest. Some bright red papules are discrete, whereas others have become confluent to form plaques with figurate shapes, chief among those being arciform. Crusts atop some papules.

Fig. 7F

Prurigo pigmentosa on the chest. Some orange-red papules are discrete and others have become confluent to form a plaque whose border is scalloped.

Fig. 6G

Prurigo pigmentosa on the chest. Slightly violaceous papules, some of them discrete and others having become confluent to assume arciform and pyramidal shapes.

Fig. 7H

Prurigo pigmentosa on the chest. Most of the papules pictured here are discrete, but some have become confluent. The erosions are secondary to excoriation.

Fig. 8A

Prurigo pigmentosa of the clavicular region. Papules and papulovesicles, most of which have become confluent to form plaques, are covered by crusts that, in large part, resulted from excoriation.

Fig. 8B

Prurigo pigmentosa of the clavicular region. Confluence of orange papules has resulted in hints of a reticular pattern and in ill defined plaques.

Fig. 8C

Prurigo pigmentosa of the clavicular region. Only a few dull pink papules are discrete, most of them having become confluent to create a somewhat netlike pattern at a site immediately above the clavicle.

In each of the patients, individual papules were extremely pruritic and, at the outset, hivelike. Some papules assumed an arcuate or linear shape. The papules tended to cluster and became confluent, thereby causing a netlike pattern to come into being (Figures 9 AE). Occasionally, a blotchy pattern could be observed. In the course of the disease in 7 patients, tiny vesicles and/or pustules appeared amidst the papules. In the process of resolution, lesions flatten. As lesions subside, they sport crust and scale, but when they no longer are active, they become pigmented macules whose surface is smooth. As a result of confluence of papules, the pattern of pigmentation in prurigo pigmentosa was reticular consistently; when new papules developed between pigmented macules and more recent lesions eventually resolved, new foci of pigmentation appeared and a netlike pattern emerged. The more numerous the recurrences, the more striking is the reticular pattern of pigmentation. As a result of recurrences, different stages in the “life” of lesions of prurigo pigmentosa may be present concurrently. The clinical picture in most of the patients is complicated by signs of rubbing and scratching.

The following photographs (Figs. 9 AE) show the pattern of lesions in prurigo pigmentosa.

Fig. 9A

Prurigo pigmentosa, pattern of lesions. Netlike pattern formed by confluence of red papules, some of which are crusted consequent to excoriation.

Fig. 9B

Prurigo pigmentosa, pattern of lesions. A reticular pattern has developed from linkage of pigmented macules that represent the residuum of papules that involuted

Fig. 9C

Prurigo pigmentosa, pattern of lesions. Incipient reticular pattern as a consequence of confluence of red papules and papulovesicles just beginning.

Fig. 9D

Prurigo pigmentosa, pattern of lesions. Blotchy and reticular pattern formed by confluence of rust-colored papules and smooth-surfaced and scaly pigmented macules.

Fig. 9E

Prurigo pigmentosa, pattern of lesions. Plaques in blotchy pattern as a consequence of confluence of them.

The chronological sequence of the eruption as it presented itself on the back of three of our patients is pictured in Figures 1012. Close up views of lesions from different patients are presented in chronological order in Figures 13 AF.

Fig. 10A

Prurigo pigmentosa in a young Turkish woman. Very early stage manifested as an eruption of urticarial papules distributed symmetrically and in a wedge shape on the back.

Fig. 10B

Prurigo pigmentosa in a young Turkish woman. Later stage as evidenced by resolution of papules, some of them covered by crust. The reticular pattern is a consequence of resolution of urticarial papules. Note also newly developed red papules on the upper part of the back and on the shoulders.

Fig. 10C

Prurigo pigmentosa in a young Turkish woman. End stage of the process with pigmented macules in reticular pattern being distributed in wedge.

Fig. 10D

Prurigo pigmentosa in a young Turkish woman. An eruption, only a few days old, developed at the same site that papules have resolved as pigmented macules.

Fig. 10E

Prurigo pigmentosa in a young Turkish woman. More than a year later, yet another eruption of urticarial papules appeared. A reticular pattern has begun to come into being in the lumbosacral region.

Fig. 10F

Prurigo pigmentosa in a young Turkish woman. Still another recurrence of papules situated amidst pigmented macules that bear testimony to papules having once been present at those very sites.double space

Fig. 11A

Prurigo pigmentosa in a young Japanese woman. Eruption of red papules in the vicinity of pigmented macules that represent the residuum of a previous eruption. Most of the papules are arranged in a wedge.

Fig. 11B

Prurigo pigmentosa in a young Japanese woman. Pigmented macules are all that remain of what once was an eruption of urticarial papules.

Fig. 12A

Prurigo pigmentosa in a young Japanese man. Eruption of reddish papules and vesicles in a distribution that is the negative image of a wedge.

Fig. 12B

Prurigo pigmentosa in a young Japanese man. After less than two weeks, papules and vesicles have resolved as pigmented macules.

Fig. 13A

Individual lesions of prurigo pigmentosa in chronological sequence. Pink macules, urticarial papules, and urticarial plaques.

Fig. 13B

Individual lesions of prurigo pigmentosa in chronological sequence. Urticarial papules and plaques, one of the papules having been excoriated.

Fig. 13C

Individual lesions of prurigo pigmentosa in chronological sequence. Urticarial papules and plaques, vesicles, and erosions.

Fig. 13D

Individual lesions of prurigo pigmentosa in chronological sequence. Urticarial papules and plaques, papulovesicles, and vesicles.

Fig. 13E

Individual lesions of prurigo pigmentosa in chronological sequence. Papulovesicles, vesicles, crusts, and scales. Note the reticular pattern.

Fig. 13F

Individual lesions of prurigo pigmentosa in chronological sequence. Crusted and scaly papules in company with pigmented macules.

Fig. 13G

Individual lesions of prurigo pigmentosa in chronological sequence. Pigmented macules and patches covered by scales. The reticular pattern is preserved.

Fig. 13H

Individual lesions of prurigo pigmentosa in chronological sequence. Smooth-surfaced pigmented macules and patches in a vaguely reticular pattern.

Differential Diagnosis Clinically

During the active stage of prurigo pigmentosa, the main differential diagnosis is dermatitis herpetiformis. Other diseases which at that stage must be included in the differential diagnosis are linear IgA dermatosis and acute lupus erythematosus. When, in contrast, the condition is quiescent and typified by pigmentation in reticular pattern, the differential diagnosis consists of confluent and reticulated papillomatosis of Gougerot and Carteaud on one hand and macular amyloidosis on the other. Similarities and differences clinically between dermatitis herpetiformis and prurigo pigmentosa are summarized in Table 1. The major criteria for distinguishing pertinent diseases in the differential diagnosis of prurigo pigmentosa follow.

Table 1 Clinical Attributes of Dermatitis Herpetiformis and Prurigo Pigmentosa

Similarities Dermatitis herpetiformis Prurigo pigmentosa
Distribution Symmetrical Symmetrical
Shoulders affected commonly Shoulders affected commonly
Eruption involves the trunk often Eruption involves the trunk virtually always
Sacrum often affected Sacrum often affected
Buttocks often affected Buttocks sometimes affected
Arrangement Lesions often confluent Lesions often confluent
Lesions of different ages seen next to one another Lesions of different ages seen next to one another
Individual lesions: Red urticarial papules Red urticarial papules
early Intensely pruritic Intensely pruritic
Individual lesions: fully developed Vesicles common Vesicles sometimes
Individual lesions: Erosions Erosions
Late Crusts Crusts
Not pruritic Not pruritic
Differences Dermatitis herpetiformis Prurigo pigmentosa
Distribution Not centered on the trunk Centered on the trunk
Not in the center of the back In the center of the back
Upper part of the back involved rarely Upper part of the back involved consistently
Not wedge shaped or the “negative image” of a wedge on the back Often wedge shaped or the “negative image” of a wedge on the back
Neck sometimes affected Neck almost always affected
Sternal and inframammary regions, and abdomen not involved Sternal and inframammary regions, and abdomen involved
Extremities affected often Extremities affected seldom
Extensor surfaces of extremities favored Flexor surfaces favored, if extremities are involved at all
Scalp affected often Scalp not affected
Face not affected Forehead sometimes affected
Arrangement Lesions almost always grouped in herpetiform fashion Lesions grouped, but not in herpetiform fashion
Lesions not in reticular pattern Lesions often in reticular pattern
Papules round Papules round, linear, and arcuate
Individual lesions: early Urticarial papules grouped Urticarial papules often not grouped at first
Individual lesions: Vesicles often Papulovesicles and vesicles occasionally
fully developed Pustules never Pustules occasionally
Tense bullae episodically Bullae practically never
Individual lesions: No scales Scales
late Pigmentation episodically Pigmentation the rule
Pigmentation patchy Pigmentation in reticular pattern

The distribution of lesions and the morphologic attributes of lesions may be very similar in dermatitis herpetiformis and prurigo pigmentosa. Papules in both diseases are red and exceedingly pruritic, that symptom inducing, invariably and inevitably, animated scratching that results in complications such as erosions, ulcerations, and crusts. Red urticarial papules in dermatitis herpetiformis, like those of prurigo pigmentosa, are distributed symmetrically. The shoulders and sacral region are favorite sites in both conditions. In contrast to prurigo pigmentosa, however, dermatitis herpetiformis often has a predilection for the buttocks and extensor surfaces of the extremities, as well as for the scalp. Lesions in dermatitis herpetiformis are grouped (herpetiform) but tend to remain discrete, whereas in prurigo pigmentosa the grouping is not truly herpetiform and the lesions are much more given to confluence, thereby resulting in a netlike pattern. Vesicles are common in dermatitis herpetiformis, but they are rare in prurigo pigmentosa. Unlike the situation in dermatitis herpetiformis, papules in prurigo pigmentosa tend to be distributed in the shape of a wedge that extends from the upper part of the back to the lower part of it, and sometimes those papules assume arcuate and linear shapes. Scales are common in prurigo pigmentosa, but not in dermatitis herpetiformis. Prurigo pigmentosa resolves with pigmentation in characteristic reticular pattern, whereas pigmentation in dermatitis herpetiformis occurs in herpetiform pattern.

No association with glutensensitive enteropathy has been recorded ever in prurigo pigmentosa, unlike the situation in dermatitis herpetiformis, where such an association is common.

Linear IgA dermatosis shares some clinical features with dermatitis herpetiformis. In contrast to prurigo pigmentosa, however, linear IgA dermatosis often involves the scalp and the extensor surface of the limbs. Involvement of mucosae is common in linear IgA dermatosis, but never has been recorded in prurigo pigmentosa. Linear IgA dermatosis and prurigo pigmentosa can be differentiated from one another, too, by the presence of blisters in the former but hardly ever in the latter. In linear IgA dermatosis, lesions often are clustered in cockadelike fashion, whereas that is not the case for prurigo pigmentosa. Postinflammatory hyperpigmentation may occur in linear IgA dermatosis, just as it may in dermatitis herpetiformis, but not in a reticular pattern so typical of prurigo pigmentosa.

Acute lupus erythematosus sometimes presents itself in a manner similar to that of prurigo pigmentosa with an eruption of red macules, papules, and plaques on the neck and chest, usually in photodistribution. A “butterfly blush” typical of acute lupus erythematosus has never been mentioned in a report of prurigo pigmentosa. Lesions in lupus erythematosus often are subtle patches and plaques, whereas those in prurigo pigmentosa are small papules. Bullous lupus erythematosus is characterized by large, as well as small, blisters, whereas, for practical purposes, frank blisters hardly ever occur in prurigo pigmentosa and when they do they are tiny vesicles. In contrast to lesions of prurigo pigmentosa, those in acute lupus erythematosus are not pruritic, but at times are associated with paraesthesia and a sensation of “burning”. Postinflammatory hyperpigmentation may be seen in patients with acute lupus erythematosus, but in patchy, rather than reticular, pattern.

In confluent and reticulated papillomatosis of Gougerot-Carteaud, which seems to be a variant of acanthosis nigricans, lesions are distributed symmetrically and with predilection for the sternal and inframammary regions, sites that also may be involved in prurigo pigmentosa. The papillomatosis consists of gray or brown, smooth-surfaced papules that may become confluent to form a reticular pattern akin to that of prurigo pigmentosa. The preferred site for the confluent and reticulated papillomatosis of Gougerot-Carteaud is the anterior trunk. The distribution of lesions in a patient with prurigo pigmentosa is the trunk, particularly the center of it, shoulders, extremities, and, episodically, forehead.

Macular amyloidosis may present itself in a fashion like that of prurigo pigmentosa, that is, pigmentation distributed symmetrically in reticular pattern on the upper part of the back, but there is no tendency for a sweep in wedge shape along the midline, and the lesions themselves are neither urticarial nor scaly. Macular amyloidosis in contrast to prurigo pigmentosa, is not an inflammatory disease.

Histopathologic Findings

The findings of authors who, after Nagashima’s original article in 1978, reported on changes in sections of tissue from specimens of prurigo pigmentosa are communicated in the quotations, verbatim, that follow.

“. . . a small focus of epidermal thinning, marked parakeratosis, focal spongiosis, dermal papillary edema, dilation of superficial blood vessels and perivascular lymphocyte cuffing. Moderate numbers of melanin laden macrophages . . . ” Cotterill et al., 1981, British Journal of Dermatology6

“. . . mild hyperkeratosis . . . and an increase of melanin granules in the basal cell layer”

“. . . mild acanthosis, elongation of the rete ridges, . . . partial spongiform edema, exocytosis and liquefaction degeneration of the basal cell layer, . . . increase in melanophages” Yamasaki et al., 1981, The Journal of Dermatology31

“. . . intercellular edema, liquefaction degeneration of the basal layer and neutrophlic exocytosis. In the atrophic epidermis, necrosis with abscess formation and numerous dyskeratotic cells were observed. There was a moderate perivascular neutrophilic infiltration in the early biopsy and a lymphohistiocytic infiltration in the second biopsy. Pigment laden macrophages were numerous.” Harms et al., 1986, Dermatologica12

“. . . hyperkeratosis, a decreased stratum granulosum, mild spongiosis, large numbers of dyskeratotic keratinocytes throughout the epidermis, focal liquefaction degeneration of the basal layer, pigmentary incontinence, and a superficial perivascular lymphoid infiltrate” Cox et al., 1987, British Journal of Dermatology8

“moderate regular acanthosis with a superficial and mid-dermal perivascular mononuclear cell infiltrate. There were mild intercellular edema and parakeratosis. While the granular layer was focally diminished, hypogranulosis was not prominent. . . . moderate exocytosis of small round mononuclear cells . . . mild basal vacuolation, dyskeratosis and papillary dermal melanophages. The perivascular infiltrate contained eosinophils” Joyce et al., 1989, Archives of Dermatology23

“Four stages . . . Urticarial papules: . . . slight spongiosis, migration of neutrophils and slight degeneration of the basal layer . . . urticarial erythema: . . . marked spongiosis, infiltration of lymphocytes, many dyskeratotic cells and liquefaction degeneration of the basal cell layer . . . dilatation of superficial blood vessels and perivascular round cell infiltration . . . Erythema with pigmentation: . . . acanthosis. . . deposits of melanin in the upper dermis. . . reticular pigmentation:. . . marked incontinence of pigments and mild perivascular round cell infiltration in the upper dermis.” Arai et al., 1992, American Journal of Dermatopathology89

“. . . focal spongiosis, exocytosis of mononuclear cells, focal liquefaction degeneration of the basal cell layer, dyskeratotic keratinocytes and a perivascular infiltrate of lymphoid cells. . . . exocytosis of neutrophils and subcorneal abscesses were also observed in an early lesion” Sakamoto et al., 1992, European Journal of Dermatology46

“Stage I: Urticarial papules: epidermis: mild spongiosis, mild infiltrate of neutrophils; dermis: superficial infiltrate of neutrophils, superficial and mid-dermal infiltrate of lymphocytes. Stage II: Urticarial erythema: epidermis: epidermal hyperplasia, microabscesses, spongiosis, vesicles, dyskeratotic cells, liquefaction degeneration of the basal cell layer; dermal: elongation of rete ridges, dilatation of vessels, dermal infiltrate consisting of lymphocytes and eosinophils. Stage III: Pigmented erythema: epidermal: . . . dyskeratotic cells, dermal: melanophages, dilatated blood vessels, mild infiltrate of lymphocytes. Stage IV: . . . . Dermal melanophages” Fujita et al.,1994, Nishinihon Hifuka (translated from the Japanese) 51

“. . . spongiotic vesicles and perivascular lymphohistiocytic infiltrate in the upper dermis.” Murao et al., 1996, British Journal of Dermatology34

Nagashima et al., in their original publication about prurigo pigmentosa, noted only “nonspecific” findings histopathologically. This was true, too, for other authors who commented on changes in sections of tissue as they were scrutinized by conventional micoscropy. In the articles reviewed by us, biopsy specimens were obtained from 153 patients with prurigo pigmentosa and the findings encountered most often in sections of tissue were said to be these: “acanthosis” (44/153), “spongiosis” (104/153), “spongiotic vesicles” (34/153) “necrotic keratinocytes” (66/153), “intraepidermal lymphocytes” (71/153), “lymphocytes at the dermo-epidermal junction” (56/153), “liquefaction degeneration of the basal layer” (63/153), “perivascular lymphoid infiltrate in the upper dermis” (148/153), “dilatation of superficial blood vessels” (46/153), “papillary edema” (45/153) and “pigmentary incontinence” (89/153). “Necrosis” of parts of the epidermis was noted in lesions from but a few patients (7/153: 8,12,39,40,44,57,66). “Hyperpigmentation of the basal layer” of the epidermis was observed in 6 of 153 patients.6,16,31,45,53

Only a few of the articles addressed the matter of the chronologic sequence1,3,12,19,32,33,40,46,51,64,89 of changes in individual lesions of prurigo pigmentosa as they were judged histopathologically. Nagashima et al., in their article written in Japanese in 1971, recorded “spongiosis”, “vesiculation”, “exocytosis” and a dermal infiltrate of lymphocytes and a few neutrophils in early lesions,1 whereas in Nagashima’s article written in English in 1978,3 “liquefaction degeneration of the basal layer” was stressed as being striking in early lesions and “pigmentary incontinence” in later ones. The latter findings were what prompted him to characterize the histopathological changes “lichenoid”. Signs of lichenoid infiltration were remarked on by several authors subsequently,8,9,21,23,25,33,59,83 though other observers noted fewer changes at the dermo-epidermal interface than did Nagashima.6,23

Photomicrographs of prurigo pigmentosa that have appeared in published articles are pictured now in Figs. 14 AI. The diversity of changes histopathologically is related directly to the dynamic of the process, which is extraordinary. The findings in the photomicrographs are arranged in what we regard to be the sequence of changes as a lesion of the disease develop over time, that chronological course being either very rapid (14 AE) or much less rapid (FI).

Fig. 14A

Prurigo pigmentosa. This spongiotic dermatitis with neutrophils and an edematous papillary dermis was shown in a photomicrograph that appeared in the article by Fujita et al. in 1994. The authors designated these changes “Stage I” of the disease. (Reproduced with permission from Fujita Y, Kasuoka K, Arai A, Iwasaki M: Prurigo pigmentosa – Statistical examination of 23 cases based on the histological and immunhistochemical studies, Nishinihon Hifuka 1994; 56(4):749-757).

Fig. 14B

Prurigo pigmentosa. This spongiotic dermatitis with neutrophils is associated with obscuration of the dermo-epidermal junction by both inflammmatory cells and vacuolar alteration. The epidermis is topped by a normal cornified layer whose configuration is basket woven, an indication that the changes pictured here are at an early phase in the process. The photomicrograph comes from the article by Harms et al. in 1986. (Reproduced with permission from Harms M, Mérot Y, Polla L, Saurat JH: Prurigo pigmentosa: 3rd non-Japanese case, Dermatologica 1986;173:202-204).

Fig. 14C

Prurigo pigmentosa. In addition to a superficial perivasular and interstitial infiltrate composed largely of neutrophils but also of lymphocytes, there are marked edema of the papillary dermis, prominent spongiosis, intraepidermal abscesses, and epidermal hyperplasia. That the process is early in its course can be told by a cornified layer that still is normal. These findings were pictured by Sakamoto et al. in 1992. (Reproduced with permission from Sakamoto T, Tokura Y, Tikigawa M: Prurigo pigmentosa, a case report with immunhistological observations, Eur J Dermatol 1992;2:161-163).

Fig. 14D

Prurigo pigmentosa. A spongiotic vesicle that houses neutrophils, nuclear “dust” of neutrophils, and lymphocytes is apparent in the lower half of the epidermis, and above it the number of necrotic keratocytes is so great that the upper half of the epidermis is nearly entirely necrotic. The papillary dermis is severely edematous. Because the cornified layer is normal these changes must have evolved very rapidly. This photomicrograph was shown by Omichi and coworkers in 1999. (Reproduced with permission from Omichi M, Kuramochi A, Tsuchida T: A case of prurigo pigmentosa with bulla formation, Rinsho Derma (Tokyo) 1999;41:1901-1904).

Fig. 14E

Prurigo pigmentosa. The vesicle that houses lymphocytes mostly, but also neutrophils and some “dust” of them, came into being by virtue of extensive spongiosis and slight ballooning. The upper part of the epidermis is necrotic. These changes were depicted by Matsunaga et al. in 1989. (Reproduced with permission from Matsunaga J, Hattyoume N, Tagami Y: Prurigo pigmentosa with intraepidermal vesicles containing many dyskeratotic cells and neutrophils, Rinsho Derma (Tokyo) 1989;31:273-276).

Fig. 14F

Prurigo pigmentosa. The character of the inflammatory cells pictured cannot be assessed accurately in this photomicrograph, but those cells are present around venules of the superficial plexus and in the slightly spongiotic, hyperplastic epidermis, where they are joined by numerous necrotic keratocytes disposed as solitary units and arranged in clusters. Note also the presence of parakeratosis. The photomicrograph appeared in an article by Cox in 1987 (Reproduced with permission from Cox NH: Prurigo pigmentosa, Br J Dermatol 1987;117:121-124).

Fig. 14G

Prurigo pigmentosa. Lymphocytes are situated around venules of the superficial plexus, along the dermo-epidermal junction, and within an epidermis that contains scant spongiosis but many necrotic keratocyes as solitary units, in clusters, and, in foci, en masse. Besides the basket-woven appearance of the cornified layer, there is a focus on the right of parakeratosis. This picture accompanied the publication of Teraki et al. in 1991 (Reproduced with permission from Teraki Y, Shiohara T, Nagashima M, Nishikawa T: Prurigo pigmentosa: role of ICAM-1 in the localization of the eruption, Br J Dermatol 1991;125:360-363).

Fig. 14H

Prurigo pigmentosa. This interface dermatitis associated with spongiosis, ballooning, many necrotic keratocytes, and mounds of parakeratosis resembles closely changes of pityriasis lichenoides et varioliformis acuta (Mucha-Habermann-disease), but the fact that the dermal infiltrate is made up of neutrophils, as well as lymphocytes, compels to a diagnosis of prurigo pigmentosa. This illustration appeared in an article by Dijkstra et al in 1987. (Reproduced with permission from Dijkstra JWE, Bergfeld WF, Taylor JS, Ranchoff RE: Prurigo pigmentosa – a persistent lichenoid reaction to bismuth? Int J Dermatol 1987;26(6):379-381).

Fig. 14I

Prurigo pigmentosa. Melanophages in number in the upper part of the dermis beneath a slightly hyperplastic epidermis are indicative of a lesion that has involuted largely. Fujita et al., who pictured these findings in 1994, thought that they represened “Stage IV” of the disease. (Reproduced with permission from Fujita Y, Kasuoka K, Arai A, Iwasaki M: Prurigo pigmentosa-Statistical examination of 23 cases based on the histological and immunhistochemical studies, Nishinihon Hifuka 1994; 56(4):749-757).

Arai et al., in 1991, presented a poster at the 12th Colloquium of the International Society of Dermatopathology in Lübeck, Germany, in which they called attention to neutrophils in the epidermis as being typical of the earliest lesion in 19 patients with prurigo pigmentosa.89 Already in 1986, Harms et al. had noted neutrophils in the epidermis of early lesions of prurigo pigmentosa12 (see Fig. 14B), but they interpreted the findings as being “nonspecific.” In 1989 Matsumaya et al. found neutrophils and eosinophils, as well as subcorneal pustules, in the epidermis of a patient with prurigo pigmentosa39 and, in 1992, Sakamoto et al.46 (see Fig. 14C) stated that “marked infiltration of neutrophils into the epidermis seems to be a characteristic feature of the early prurigo pigmentosa”. Despite that acknowledgement, those coworkers designated the reaction “lichenoid” histopathologically.

In 1994, Fujita and Arai et al. wrote again of their findings histopathologically in 23 patients with prurigo pigmentosa, this time in the Japanese journal Nishinihon Hifuka (The Nishinion Journal of Dermatology)51 (see Fig. 14 A). Early lesions, which the authors called “Stage I” of the disease, were described by them as showing mild spongiosis, a mild infiltrate of neutrophils in the epidermis, and an infiltrate of neutrophils in the superficial dermis. What the authors termed “Stage II” of prurigo pigmentosa was characterized by epidermal hyperplasia, microabscesses, spongiosis, vesicles, dyskeratotic cells, liquefaction degeneration of the epidermal basal layer, elongation of rete ridges, dilation of vessels, and an infiltrate in the dermis that consisted of lymphocytes and eosinophils. In later lesions, dubbed by them “Stage III”, they told of dyskeratotic cells in the epidermis and of melanophages, dilated blood vessels, and a mild infiltrate of lymphocytes in the dermis, and in still later lesions, “Stage IV”, of melanophages only in the dermis (see Fig. 14I).

A few neutrophils in the dermal infiltrate of “early lesions” of prurigo pigmentosa were recognized not only by Nagashima et al. in 1971, but later by other authors,12,46,51,54,55,82,89 among them Ohihara, Nagashima, and coworkers in 1996, who observed lymphocytes and neutrophils within follicular epithelium and around it72. Prominent infiltrates of eosinophils in company with neutrophils in the epidermis and the dermis have been mentioned in several reports about prurigo pigmentosa.15,23,4244,46,49,51,54,55,74,77,81,82,89

The results of direct immunofluorescence were provided in 21 patients with prurigo pigmentosa, that procedure having been performed for the purpose of excluding dermatitis herpetiformis. The results always were either nonspecific14,25,37 or negative. 6,12,13,17,1921,23,24,32,33,42,60,76,90

Immunhistochemical studies were recorded in seven articles about prurigo pigmentosa,7,38,40,46,51,61,73 but it is difficult to interpret the results of them. Teraki et al. noted similarities to changes in fixed drug eruption, particularly in regard to expression of ICAM-1. Moreover, they told of CD8+ cells at the dermo-epidermal junction7, a finding observed also by Fujita and Arai et al.51, but not by Sakamoto et al., who found T lymphocytes at the dermo-epidermal junction to be CD4+46, and who spotted CD8+ T lymphocytes in early lesions especially.

Few lesions of prurigo pigmentosa have been studied by electron microscopy and, on the whole, those findings, too, have been said to be “nonspecific.”10,16,17,33,40,53,56 For the most part, they merely confirm what is seen by conventional micoscropy, namely spongiosis, damage to basal cells of the epidermis, and a superficial perivascular infiltrate of lymphocytes. Schepis et al. claimed to have seen signs of acantholysis in basal keratocytes, an increased number of melanocytes at the dermo-epidermal junction, and melanin granules in basal keratocytes.16,17 Other authors observed numerous melanophages in the upper part of the dermis.10,33

In short, most of those who studied sections of tissue from biopsy specimens of prurigo pigmentosa by conventional micoscropy recorded only “nonspecific” findings, namely, spongiosis, slight interface changes, a superficial perivascular infiltrate of lymphocytes and melanophages, epidermal hyperplasia, ortho- and parakeratosis, erosions, and crusts. Some, however, took note in early lesions of neutrophils in the upper part of the dermis and in the epidermis.

Staining by direct immunofluorescence is nonspecific or negative.

Differential Diagnosis Histopathologically

At an early stage of the disease, the differential diagnosis of prurigo pigmentosa consists only of urticaria and leukocytoclastic vasculitis early in the course of it. Later in the process, the differential diagnosis must include dermatitis herpetiformis, linear IgA dermatosis, acute lupus erythematosus, eruptive psoriasis, and a pustular expression of dermatophytosis. At the stage when lymphocytes come to predominate and obscure the dermo-epidermal junction, Mucha-Habermann disease has to be taken into account. Table 2 summarizes histopathologic attributes shared by dermatitis herpetiformis and prurigo pigmentosa, and the findings that enable those diseases to be distinguished from one another. Criteria for differentiation of the aforementioned diseases from prurigo pigmentosa follow now.

Table 2 Histopathological Attributes of Dermatitis Herpetiformis and Prurigo Pigmentosa

Similarities Dermatitis herpetiformis Prurigo pigmentosa
Earl lesion Infiltrate superficial perivascular and interstitial Infiltrate superficial perivascular and interstitial
Neutrophils predominate, especially in the interstitium; lymphocytes present perivascularly Neutrophils predominate, especially in the interstitium; lymphocytes present perivascularly
Neutrophils at the dermo-epidermal junction Neutrophils at the dermo-epidermal junction
Nuclear “dust” of neutrophils Nuclear “dust” of neutrophils
Edema of the papillary dermis Edema of the papillary dermis
Fully developed lesion Infiltrate superficial perivascular and interstitial Infiltrate superficial perivascular and interstitial
Neutrophils and eosinophils in the papillary dermis Neutrophils and eosinophils in the papillary dermis
Nuclear “dust” of neutrophils Nuclear “dust” of neutrophils
Subepidermal vesicles and bullae common Subepidermal clefts and vesicles sometimes
Late lesion Erosions Erosions
Crusts Crusts
Differences Dermatitis herpetiformis Prurigo pigmentosa
Early lesion Neutrophils primarily in the papillary dermis Neutrophils scattered in the interstitium of the papillary and part of the upper reticular dermis
Small collections of neutrophils at the tip of dermal papillae Neutrophils scattered in the papillary dermis and rarely in collections there
No inflammatory cells in the epidermis Neutrophils scattered throughout the epidermis
No spongiosis Slight spongiosis
No necrotic keratocytes Individual necrotic keratocytes
Fully developed lesion No abscesses in the epidermis Abscesses in the upper part of the viable epidermis
Acantholytic cells within blisters and just above neutrophils situated in the lower portion of the epidermis No acantholytic cells
No necrotic keratocytes within the epidermis Individual necrotic keratocytes, and foci of necrosis in the upper part of the epidermis.
No necrosis en masse Necrosis en masse of the upper epidermal layers episodically
Neutrophils and eosinophils predominate; lymphocytes are present but not in lichenoid pattern Lymphocytes and eosinophils predominate both in the patchy lichenoid pattern and in lower part of the epidermis.
No interface changes Ballooning and necrosis of basal keratocytes; vacuoles seem to form between keratocytes
No spongiosis Slight or marked spongiosis; spongiotic vesicles sometimes
Subepidermal blister not a consequence of interface changes but of marked edema of the papillary dermis Subepidermal blister a consequence of changes at the dermo-epidermal junction and of marked edema of the papillary dermis
Fibrin in subepidermal spaces No fibrin beneath the epidermis
No extravasated erythrocytes in the papillary dermis Erythrocytes extravasated in the papillary dermis
No crusts as a rule Crusts containing neutrophils and few lymphocytes
Late lesion Blisters intra-epidermal as a consequence of re-epithelization No blisters
Eosinophils often outnumber neutrophils in the dermal infiltrate Mixed infiltrate of lymphocytes, few neutrophils, and few eosinophils
No alteration of cornification Parakeratosis
No epidermal hyperplasia Slight epidermal hyperplasia
No spongiosis Slight spongiosis
No epidermal hyperpigmentation Epidermal hyperpigmentation
Melanophages sometimes Melanophages nearly always
Direct Immunofluorescence Granular deposits of IgA at the tip of dermal papillae Non-specific or negative

Both a true hive and an urticarial papule of prurigo pigmentosa are characterized at an early stage by a sparse perivascular and interstitial infiltrate that consists mostly of neutrophils. In contrast to the situation in prurigo pigmentosa, however, the papillary dermis and the dermo-epidermal junction of urtica are spared by the infiltrate.

In leukocytoclystic vasculitis, as in prurigo pigmentosa, an early lesion is typified by a perivascular and interstitial infiltrate of neutrophils especially, in company with nuclear “dust” of neutrophils. In leukocytoclastic vasculitis, however, the amount of “dust” is greater by far.

In both dermatitis herpetiformis and prurigo pigmentosa, an early lesion is typified by a superficial perivascular and interstitial infiltrate made up mostly of neutrophils. In contrast to dermatitis herpetiformis, neutrophils in prurigo pigmentosa are present in the epidermis; in variable numbers when sufficient in number, they tend to form abscesses. The products of those neutrophils cause keratocytes to become necrotic, first as solitary units, then in clusters, and, at times, en masse. As a rule, the epidermis is spared in dermatitis herpetiformis. Unlike the situation in prurigo pigmentosa, dermatitis herpetiformis is typified by the presence of neutrophils at the tip of dermal papillae, in subepidermal spaces, and in subepidermal vesicles. Although spongiotic vesicles may occur in the epidermis of prurigo pigmentosa, they do not do that in dermatitis herpetiformis. In a later lesion, eosinophils predominate in the infiltrate of dermatitis herpetiformis, whereas in prurigo pigmentosa the infiltrate, as a rule, harbors relatively few eosinophils. Last, unlike the situation in prurigo pigmentosa, dermal papillae and subepidermal clefts at the side of a vesicle house of dermatitis herpetiforms neutrophils, nuclear “dust” of neutrophils and band forms. That is not the case in prurigo pigmentosa. Deposits of IgA in dermal papillae are characteristeristic of dermatitis herpetiformis, but no such deposits appear in prurigo pigmentosa. For that reason, staining by direct immunofluorescence is helpful in differentiation of the two diseases.

Linear IgA dermatosis displays histopathologic findings indistinguishable from those of dermatitis herpetiformis. The criteria just mentioned for differentiation histopathologically of dermatitis herpetiformis from prurigo pigmentosa are applicable equally to linear IgA dermatosis. Dermatitis herpetiformis and linear IgA dermatosis differ from one another, not only clinically, but in regard to the results of studies that employ methods of immunofluorescence. Direct immunofluorescence reveals deposits of IgA in dermal papillae of dermatitis herpetiformis, whereas granular deposits of IgA in linear array are present at the basement membrane zone of linear IgA dermatosis, No such findings by immunofluorescence are observed in prurigo pigmentosa.

Acute lupus erythematosus is marked by neutrophils in the upper part of the dermis, along the dermo-epidermal junction, and in the lower part of the epidermis, findings that are somewhat similar to those in prurigo pigmentosa. In prurigo pigmentosa, however, neutrophils are not confined to the lower part of the epidermis; intraepidermal abscesses form often in the middle and upper part of the viable epidermis. Neither spongiosis nor intraepidermal vesiculation occurs in acute lupus erythematosus, but both spongiosis and spongiotic vesicles may be discernible readily in prurigo pigmentosa. Mucin sometimes may be increased in amount in the reticular dermis of lesions of acute lupus erythematosus, but not in that of prurigo pigmentosa. Direct immunofluorescence may reveal deposits of immunoglobulins and complement factors at the dermo-epidermal junction in a lesion of acute lupus erythematosus, but not in prurigo pigmentosa.

Eruptive (guttate) psoriasis exhibits neutrophils at all levels of the epidermis, as is the case, too, for prurigo pigmentosa at an early stage of the process. In contrast to prurigo pigmentosa, however, lesions of eruptive psoriasis display discrete collections of neutrophils in the spinous zone (Munro’s microabscesses) and/or in poorly circumscribed collections (spongiform pustules of Kogoj) there and in the granular zone. In guttate psoriasis, neutrophils also may be found at the summit of mounds of parakeratosis that are staggered in the cornified layer; that is not the case for prurigo pigmentosa.

The findings in a pustular expression of dermatophytosis may be just like those in eruptive psoriasis, the only difference between them being hyphae that reside in the cornified layer of a lesion of the infection by a superficial fungus.

In Mucha-Habermann disease, as in a fully developed lesion of prurigo pigmentosa, a patchy lichenoid infiltrate of lymphocytes often obscures the dermo-epidermal junction and lymphocytes are present in the epidermis in company with individual necrotic keratocytes or clusters of them, ballooning, and spongiosis. The infiltrate in the dermis of Mucha-Habermann disease, unlike the situation in prurigo pigmentosa, tends to be wedge-shaped, both deep as well as superficial, and made up entirely of lymphocytes.

Treatment

What follows are direct quotations in regard to therapy of prurigo pigmentosa.

“. . . regressed within a week on dapsone 100 mg daily. The rash promptly reappeared 2 weeks after the dapsone was stopped.” Cotterill et al., 1981, British Journal of Dermatology6

“. . . with sulfisomezole 2 g/d . . . the itchiness subsided and the red papules disappeared, leaving only pigmentation.” Yamasaki et al., 1981, The Journal of Dermatology 31

“The . . . eruption disappeared . . . without any treatment, but the patient continues to suffer. . . eruptions. . . every season.” Miyakawa et al., 1984, Dermatologica 32

“Dapsone, 50 mg daily, was given for 4 months with very good results. Three weeks after stopping dapsone, a new eruption appeared. Treatment with potassium iodide, 500 mg/day, was tried inducing a control of the active lesions. . . . No recurrence was observed during this period but 14 days after stopping potassium iodide,” Harms et al., 1986, Dermatologica12

“With a dose of minocycline 100-200 mg daily, the pruritus, papules and erythema rapidly disappeared within a few days or up to a week. Although prurigo pigmentosa is likely to recur. . . in two of our cases. . . a long remission was obtained with minocycline.” Aso et al., 1989, British Journal of Dermatology60

“Ten days following oral minocycline, . . . , the eruption subsided. . . . It was possible that our patient responded well to dapsone and minocycline through suppression of the function of neutrophils infiltrating in the early lesion.” Sakamoto et al., 1992, European Journal of Dermatology46

“Because minocycline is not available in Turkey our first patient was treated with doxycycline. Her skin lesions resolved and did not recur . . . The skin lesions of the second patient resolved spontaneously . . . ” Gürses et al., 1999, International Journal of Dermatology 22

“. . . 300 mg roxythromycin daily for two weeks. Three days later the erythema disappeared, and 5 days later, the pruritus disappeared. . . . all 4 patients showed a very good response to this agent [macrolide antibiotics]. Yazawa et al., 2001, Dermatology56

The remarkably beneficial effect of diamino-diphenyl-sulfone (dapsone, DDS) in prurigo pigmentosa, testified to by Sugawara et al. in 1973,4 was proved to be true in at least 27 other patients. Six additional patients responded well to other sulfonamides, such as sulfimethoxazole. In an abstract of Tashiro published in 1979, minocycline was said to be effective in prurigo pigmentosa.93 In articles reviewed by us, minocycline was reputed to be efficacious in 46 patients; three other patients responded to doxycycline. Harms et al. claimed to have observed remission of prurigo pigmentosa consequent to administration of potassium iodide,12 Yazawa et al. was the first to call attention to macrolide antibiotics as being helpful in prurigo pigmentosa.56

No improvement of prurigo pigmentosa derives from antihistamines or from corticosteroids administered topically or systemically. Only a few patients with prurigo pigmentosa have been purported to have recovered fully in the absence of any treatment at all, but follow up of those patients, when it was provided, was as short as two months and only as long as 15 months.15,21,22,25,65

In brief, prurigo pigmentosa usually responds to dapsone, sulfonamides, and minocycline, but not to corticosteroids and antihistamines.

Cause

Several authors have commented about worsening of prurigo pigmentosa in the spring and summer,1,3,8,9,11,31,32,45,51,66,67,74 but those statements are anecdotal. Sunlight was thought to be influential,8,21 but testing for photosensitivity failed, consistently, to confirm that impression. Nagashima et al. were the first to suggest that sweating could provoke an eruption of prurigo pigmentosa,1,3 but that thesis has yet to be proved. Friction from clothing also has been claimed to worsen matters.3,79 Nagashima, in 1978, proposed that “friction from clothing may act not as a contact allergen but as a nonspecific mechanical stimulus”; that, too, remains speculation.

H. Pinkus thought that “new environmental factors” might be responsible for prurigo pigmentosa.106 None, though, have been identified as truly being causative. Other students of the subject have suggested that prurigo pigmentosa could be akin to pigmented contact dermatitis caused by the optical whitener, Tinopal (a combination of 1-(3-chlorphenyl)-3-phenyl-pyrazoline and 1-(3-chlorphenyl)-3-(4-chlorphenyl)-pyrazoline).3,107 Comprehensive patch tests, including to optical whiteners, were carried out in 16 patients with prurigo pigmentosa,1,3,6,11,1953,108 but only in two patients were there positive reactions to chromium,11,108 an indication that the disease is not related to contact allergens.

Although Nagashima, in 1978, noted “no systemic changes” in his patients with prurigo pigmentosa,1,3 reports recently, including one of Teraki and Nagashima et al.,62 claimed that an association existed between nutrition and prurigo pigmentosa. Note has been taken of eruptions of prurigo pigmentosa that seemed to coincide with dieting, weight loss, anorexia nervosa,53 and implementation of vegetarian cuisine.76 Diabetes mellitus also has been implicated as a factor. Thirty patients with prurigo pigmentosa were said to have ketonuria, either as a consequence of diabetes mellitus35,62,75,8386,88 or of dieting.34,41,43,53,62,7274,80,81,90 Teraki et al. stressed that while “The eruption [of prurigo pigmentosa] cleared when the ketosis diminished”, serum levels of glucose seemed to have no influence on the disease.62 Nutrition appeared to improve the condition in patients who dieted, and insulin was said to expedite regression of lesions in patients with diabetes. Most patients with prurigo pigmentosa, however, do not have ketosis or diabetes. No mention was made ever about any disorders of the gastrointestinal tract in patients with prurigo pigmentosa, unlike the situation in dermatitis herpetiformis, where an association with glutensensitive enteropathy is established. A few reports tell of a relationship between prurigo pigmentosa and other diseases, but those seem to be coincidental.1,3,6,15,23,87

In sum, friction, heat, sunlight, sweating, and allergic contact sensitization have been said to be connected in some way to induction of prurigo pigmentosa, as have been diabetes mellitus and ketonemia. No compelling evidence exists on behalf of any of these propositions.

Dpc0803a03 - Quiz 1