Clinical Reference / Dermatopathology: Practical & Conceptual / Jul – Sept 2006 | Vol. 12, No. 3 / Prurigo pigmentosa (Nagashima’s disease)—variations on a theme

Prurigo pigmentosa (Nagashima’s disease)—variations on a theme

Jul – Sept 2006 | Vol. 12, No. 3
Asgari, Masoud; Böer, Almut

Methods

We studied clinical lesions and findings in sections cut from formalin-fixed paraffin embedded biopsy specimens stained with hematoxylin and eosin in a total of 95 patients including those presented in our previous works on the subject. [3-6 ] Here, we present 34 new clinical pictures and photomicrographs taken from 12 new biopsy specimens in order to refine criteria for diagnosis of prurigo pigmentosa. We focus on features morphologic of the disease that were underemphasized in our previous publications. The spectrum of clinical manifestations of the condition is shown with emphasis on variations concerning the degree of involvement of the surface of the body, the amount of pigmentation, and on less common manifestations of the disease such as vesicular and pustular forms. The distinctive features of the disease histopathologically are pictured in a series of photomicrographs showing the variability of the disease at each stage of the process.

Introduction

Prurigo pigmentosa, a distinctive inflammatory disease described first by the Japanese dermatologist Masaji Nagashima in 1971 [1,2 ], remains rarely diagnosed outside Japan. Whereas more than 200 patients with prurigo pigmentosa have been reported on in Japan, less than 50 non-Japanese patients have come to notice as of today. In previous studies on the subject of prurigo pigmentosa, one of us (A.B.) along with coworkers elucidated the history of the disease and attempted to forge criteria for diagnosis of it both clinically and histopathologically. [3-6 ] Readers who want to learn more about the history of prurigo pigmentosa or who want to study clinical findings and photomicrographs of changes in specimens taken from our first series of patients are referred to these works for further information [3-6 ], one of them being available on this website. [3 ]

As a result of our previous publications on prurigo pigmentosa, we had the chance, during the last 4 years, to review an increasing number of clinical photographs and sections of biopsy specimens taken from patients diagnosed by colleagues with prurigo pigmentosa. In this article we seek to share with readers of this journal new material collected by us and we will highlight some features of the disease that were underemphasized in our previous publications. The patients shown here are of 5 different nationalities, namely, Japanese, German, Indonesian, Turkish, and Iranian.

Clinical presentation

Figures 1-5 and legends to them illustrate clinical findings in patients with prurigo pigmentosa. Patients presented themselves to us always with lesions centered on the trunk, distributed symmetrically and often involving the midline. The sites of predilection were the chest, the back, and the neck. Intermammary and submammary zones were involved more commonly than the clavicular site or the lateral side of the chest. When the back was affected, the shoulders and the upper part of the back were involved more often than the lower part of it or the lumbosacral region. Extraordinarily rarely, the forehead, the arms, or the abdomen are caught up in the process. We did not observe the mucous membranes to be affected in any of our patients. It is noteworthy that papules of prurigo pigmentosa tended to recur at the very same site where they had been present in a previous eruption. In a few patients the number of sites affected with the disease increased slowly over time.

Figs. 1A-H

Prurigo pigmentosa on the back. Lesions are distributed more or less symmetrically. Urticarial lesions are often scratched (1A). New papules ted to recur at the site of previous eruptions, as evidenced by netlike pigmentation (1B-E). At a late stage of the process, reticular pigmentation is all that is residual (1F-H).

Figs. 2A-H

Prurigo pigmentosa on the chest. Urticarial papules, as well as pigmented papules, are present together (2A-E). The degree of pigmentation varies markedly from patient to patient.

Figs. 3A-C

Prurigo pigmentosa on the neck. In all three patients urticarial papules predominate, whereas pigmented macules are virtually absent.

Figs. 4A-B

Prurigo pigmentosa on the arm is a rarety, only proximal parts of extremities being involved.

Figs. 5A-M

Lesions of prurigo pigmentosa close up. Urticarial papules, some of them scratched (5A and B); red papulovesicles (5C); papules and few pustules (5D); red papules, and netlike pigmented macules (5E-I); the degree of residual pigmentation varies markedly from patient to patient (5J-M).

Individual lesions captured in clinical photographs displayed were crusted red papules and smooth-surfaced pigmented macules in most instances. In only half of the patients, patchy erythema, urticarial papules, and urticarial plaques were seen. Papulovesicles, papulopustules, and erosions were present in a quarter of the patients, but frank pustules, vesicles, or bullae were seen in none of them. Urticarial lesions tended to be confluent and often assumed an arcuate or reticular shape. In all of the patients, lesions of different ages were seen together and the pattern of resolving lesions was netlike consistently.

The degree of pigmentation varied considerably among the patients studied by us. At the outset of an eruption of urticarial papules most patients did not show any sign of pigmentation, and even when the lesions resolved they left behind no pigment in some of the patients. When comparing the degree of postinflammatory hyperpigmentation, in more than a half of the patients it was only slight, and no more than 10 of them had marked pigmentation in reticular pattern. Even in a single patient, the degree of pigmentation is variable to a remarkable extent. Usually the pigmentation increased in darkness with the number of recurrences of eruption at the same site. When treatment was initiated early in the course of the disease, the postinflammatory hyperpigmentation was only slight.

Histopathologic features

In Figures 6-17, sections cut from biopsy specimens are presented along with legends that describe findings in them in detail.

Figs. 6A-D

Prurigo pigmentosa, early lesion. Sparse superficial perivascular dermatitis with edema of the papillary dermis (6A); neutrophils scattered in the epidermis accompanied by spongiosis (6B); few necrotic keratinocytes and some vacuolar alteration at the dermoepidermal junction, few neutrophils and nuclear dust of them in the epidermis (6C); sparse infiltrate of lymphocytes and neutrophils around vessels of the superficial plexus, melanophages are residual of a previous eruption at the same site (6D).

Figs. 7A-D

Prurigo pigmentosa, early lesion. Sparse superficial perivascular dermatitis with edema of the papillary dermis (7A); neutrophils scattered in the epidermis accompanied by spongiosis and few necrotic keratinocytes (7B and C); lymphocytes, neutrophils and an occasional eosinophil make up the infiltrate around the superficial plexus (7D).

Figs. 8A-D

Prurigo pigmentosa, early lesion. Moderately dense superficial and mid-dermal perivascular dermatitis (8A); aggregations of neutrophils have formed beneath the cornified layer and are accompanied by scattered neutrophils (8B), a few necrotic keratinocytes are present, too; at the same time when neutrophils tend to accumulate in the upper part of the dermis, lymphocytes can be found in the lower part of it (8C); lymphocytes predominate around the vessels of the superficial plexus whereas neutrophils and few eosinophils can be found in the interstitium (8D).

Figs. 9A-D

Prurigo pigmentosa, early lesion. Sparse superficial perivascular dermatitis with edema of the papillary dermis (9A); spongiosis is present in the epidermis along with few neutrophils, erythrocytes are extravasated in the papillary dermis (9B); aggregations of neutrophils have formed beneath the cornified layer (9C); lymphocytes, neutrophils and an occasional eosinophil make up the infiltrate around the superficial plexus (9D).

Figs. 10A-D

Prurigo pigmentosa, fully developed lesion. Moderately dense superficial and mid-dermal perivascular dermatitis (10A); reticular alteration together with scattered neutrophils and lymphocytes (10B); few necrotic keratinocytes are scattered in the adjacent epidermis which also shows slight spongiosis (10C); lymphocytes predominate the infiltrate in the dermis, but a few neutrophils and eosinophils are present, too (10D).

Figs. 11A-D

Prurigo pigmentosa, fully developed lesion. Superficial perivascular dermatitis with edema of the papillary dermis (11A); reticular alteration of the epidermis together with scattered neutrophils and numerous necrotic keratinocytes (11B); adjacent to the area of reticular alteration the epidermis shows spongionsis, few necrotic keratinocytes, and small collections of neutrophils beneath the cornified layer (11C); lymphocytes predominate the infiltrate in the dermis, but a few neutrophils and eosinophils are present, too (11D); melanophages are residual of a previous eruption at the same site.

Figs. 12A-D

Prurigo pigmentosa, fully developed lesion. Moderately dense superficial and mid-dermal perivascular dermatitis (12A); reticular alteration of the epidermis together with scattered neutrophils an numerous necrotic keratinocytes (12B); adjacent to the area of reticular alteration the epidermis shows spongionsis, few necrotic keratinocytes, and lymphocytes as well as neutrophils (12C); lymphocytes predominate the infiltrate in the dermis, but a few neutrophils and eosinophils are present, too (12D).

Figs. 13A-D

Prurigo pigmentosa, fully developed lesion. Moderately dense superficial and mid-dermal perivascular dermatitis (13A) with vesiculation due to marked reticular alteration; adjacent to the area of reticular alteration the epidermis shows spongionsis and collections of neutrophils (13B), a few necrotic keratinocytes are present here, too (13C); lymphocytes predominate the infiltrate in the dermis (13D).

Figs. 14A-D

Prurigo pigmentosa, fully developed lesion. Moderately dense superficial and mid-dermal perivascular dermatitis (14A) with complete necrosis of the epidermis (14B); adjacent to the area of necrosis en masse the epidermis shows neutrophils in small collections as well as scattered necrotic keratinocytes (14C); lymphocytes predominate the infiltrate in the dermis (14D).

Figs. 15A-C

Prurigo pigmentosa, periphery of a lesion. Superficial perivascular dermatitis with spongiosis of the epidermis (15A); few necrotic keratinocytes are present but practically no neutrophils; lymphocytes predominate the infiltrate in the dermis, but a few neutrophils and eosinophils are present, too (15C).

Figs. 16A-C

Prurigo pigmentosa, resolving lesion. Moderately dense superficial and mid-dermal perivascular dermatitis (16A); a layer of parakeratosis is present beneath orthokeratosis, some vacuolar alteration is seen in the basal layer accompanied by few lymphocytes (16B); ); lymphocytes predominate the infiltrate in the dermis (16C).

Figs. 17A-B

Prurigo pigmentosa, residual pigmented macule. No infiltrate of inflammatory cells is present in the dermis (17A); melanophages are present in number around vessels of the superficial plexus (17B).

In an early lesion of prurigo pigmentosa (Figs. 6-9) the pattern of the infiltrate is that of a sparse perivascular and interstitial dermatitis that most commonly is rather superficial but that may occasionally be mid-dermal or even deep, though it always is top heavy. The urticarial aspect of lesions at the outset of an eruption is caused by edema of the papillary dermis. The spectrum of changes histopathologically in evolving lesions of prurigo pigmentosa ranged from scattered neutrophils in the epidermis to poorly formed microabscesses and to large collections of neutrophils beneath the cornified layer. This variation was observable in lesions taken from different patients, and in different lesions taken from a single patient, and even in step sections of a single biopsy specimen taken from a fresh lesion in one patient. The degree of spongiosis ranged from slight to marked. As a rule, spongiosis was more prominent in evolving lesions than in resolving ones. Occasional necrotic keratinocytes were present in conjunction with scattered neutrophils and spongiosis in the epidermis even in very early lesions. Lymphocytes could be found sprinkled along the dermo-epidermal junction at the same time when neutrophils predominated in the upper layers of the epidermis. Sometimes, spongiotic vesicles housed neutrophils as well as few lymphocytes and eosinophils. Variable numbers of extravasated erythrocytes were encountered, too, they being evidence of the acuteness of the process.

When biopsies were taken from fully-developed lesions (Figs. 10-15), the infiltrate was moderately dense, it sometimes assumed a patchy lichenoid pattern, and lymphocytes in the dermis were more numerous. At first glance, it was often difficult to recognize neutrophils in the infiltrate because of the predominance and the density of lymphocytes, but they could be found always, as also was the case for nuclear dust of them. In the epidermis of sections of biopsy specimens taken from fully-developed lesions, ballooning and necrosis of kerationocytes was more prominent than spongiosis and lymphocytes in the lower part of the epidermis were numerous. Necrotic keratinocytes disposed as solitary units or in small clusters were a common finding, but necrosis en masse was present in but a few lesions, thereby causing an intraepidermal blister to come into being. In the upper part of an epidermis with changes such as these, neutrophils and nuclear dust of them were recognizable within aggregations of necrotic keratinocytes and also beneath the cornified layer in viable epidermis adjacent to necrotic epidermis. The cornified layer still was orthokeratotic and basket-woven at that stage of the process. In all sections studied by us, we could not find any hint of adnexal structures like eccrine glands and ducts, follicular epithelium, or nail matrix being involved in the process, but infundibular epidermis occasionally showed findings similar to those found in surface epidermis.

About half of the biopsy specimens that were made available to us were taken from resolving lesions (Fig. 16). The changes housed in sections of tissue taken from these specimens were those of a sparse infiltrate of lymphocytes in the upper part of the reticular dermis and the papillary dermis. Some lymphocytes were found along the dermo-epidermal junction and within the lower part of the epidermis. Necrotic keratinocytes were positioned as solitary units in the basal layer. The cornified layer was altered by parakeratosis and scale crust. Remnants of neutrophils could be found occasionally within the crust, and nuclear dust of neutrophils was present in the dermis, especially in the intersitial part of it. Melanophages positioned in the papillary dermis and the upper part of the reticular dermis ranged from few to many. In only a few patients lesions were biopsied at two different stages of the process, but when that was done, the findings in at least one of the specimens were diagnostic of the disease, capturing changes of an early or of a fully-developed lesion of prurigo pigmentosa.

Comment

The findings clinically and histopathologically in the patients presented here confirm, in general, what we found previously [3-6 ], but they demonstrate also the variation of morphologic presentations of a single pathological process. Table 1 lists criteria for diagnosis of prurigo pigmentosa as we perceive them now. Clues to a diagnosis of purirgo pigmentosa are summarized in Table 2.

Table 1 Criteria for diagnosis of prurigo pigmentosa (Adapted from: Böer A, Ackerman AB, Prurigo pigmentosa (Nagashima’s disease). New York City: Ardor Scribendi, Ltd., 2004 [5 ]).

Clinical Findings
Distribution of lesions Symmetrical, especially on the trunk
Sites of predilection Back, chest, neck
Sites rarely involved Proximal extremities, the upper extremities especially, forehead
Sites never involved Distal extremities, face, mucous membranes
Individual lesions Early lesions: Urticarial papules and plaques, often scratched. Fully developed lesions: Papules, papulovesicles, rarely papulopustules and frank vesicles. Resolving lesions: Crusted papules, scaly papules. Late lesions: Pigmented macules.
Arrangement of lesions Reticular
Subtle variations Pigmented macules may be absent entirely at the time of the first eruption of the disease and when a patient is of Caucasian skin type
Dynamic of the process Papules erupt in crops and subside within a week; recurrences at the same sites are common, often lesions of different ages being present together
Symptoms Pruritus of early lesions is often severe; resolving lesions are devoid of symptoms
Histopathologic findings
Early lesion Superficial perivascular infiltrate of neutrophils mostly; edematous papillary dermis; extravasated erythrocytes; spongiosis; neutrophils scattered in the epidermis; collections of neutrophils in the epidermis, especially beneath the cornified layer; neutrophils favor the upper part of the epidermis whereas lymphocytes are found, at the same time, in the lower part of the epidermis; eosinophils are an inconsistent finding, their numbers ranging form none to many; few necrotic keratinocytes may be present in the basal layer and the spinous zone even early in the course
Fully developed lesion Patchy lichenoid infiltrate; lymphocytes predominate; eosinophils as well as neutrophils are found in variable numbers, nuclear dust of neutrophils is often present; spongiosis is accompanied by ballooning; intraepidermal and subepidermal vesiculation is consequeent to reticular alteration and spongiosis; numerous necrotic keratinocytes and necrosis en masse are present sometimes
Late lesion Lymphocytes monopolize the infiltrate; the epidermis is slightly hyperplastic and parakeratotic; scale-crust is present sometimes; melanophages range from few to many; individual necrotic keratinocytes are encountered sometimes
Subtle variations Fetures of prurigo simplex may overlay signs diagnostic of prurigo pigmentosa because lesions are so itchy at the outset of an eruption

Table 2 Clues to the diagnosis of prurigo pigmentosa

Clinical clues •The impression of trunk-centered “scratched urticaria”
•Papulovesicles reminiscent of dermatitis herpetiformis devoid of herpetiform arrangement
•Wedge-shaped distribution of lesions on the back
•Reticular arrangement of lesions of different ages next to one another
Histopathologic clues •Spongiotic dermatitis with necrotic keratinocytes; spongiotic dermatitis with neutrophils predominating in the epidermis
•”Erythema-multiforme”-like changes together with neutrophils in collections beneath the cornified layer
•Reticular alteration together with clusters of necrotic keratinocytes, ballooning, vacuolar alteration, spongiosis, and a mixed cell infiltrate
•Basket woven orthokeratosis above reticular alteration or necrosis en masse of the epidermis

Lesions of prurigo pigmentosa are centered on the trunk consistently and they erupt in crops at one time, subsiding all within a week. Involvement of the distal extremities occurs never, and even involvement of proximal extremities is extraordinarily rare. The same is true for involvement of the face and the scalp. The arrangement of lesions is reticular, that kind of arrangement being the most typical feature of the disease. Individual lesions are urticarial papules at the outset of an eruption, but the urticarial aspect changes to smooth-surfaced red papules within hours, and those papules evolve occasionally and equally soon to papulovesicles. Vesicles may develop and they are a result of a combination of spongiosis with extensive ballooning and reticular alteration. Intraepidermal or subepidermal vesiculation, usually accompanied by necrosis en masse, is recognized histopathologically much more commonly than blisters are seen clinically. Collections of neutrophils are seen often histopathologically, especially directly beneath the cornified layer, but pustules are rarely seen clinically. Individual necrotic keratinocytes and clusters of them are a common finding in prurigo pigmentosa and they are often accompanied by spongiosis of the adjacent epidermis. Reticular alteration also is encountered relatively often in lesions of prurigo pigmentosa, and it comes into being by a combination of spongiosis, ballooning, and necrosis en masse. That combination of changes is reminiscent of the various appearances histopathologically of erythema multiforme, which also, at times, combines spongiosis with ballooning, vacuolar alteration, reticular alteration, individual necrotic keratinocytes, and necrosis en masse.

Lesions of prurigo pigmentosa resolve in a matter of days as crusted and scaly papules, which are slightly reddish in color. Crusted and scaly lesions are present for a few days only and eventually subside, leaving behind pigmented macules which may persist for months, and that is why crusted and scaly papules as well as pigmented macules are seen much more commonly in patients with prurigo pigmentosa than are urticarial papules and papulovesicles.

It is necessary to be fully aware of the dynamic of an eruption lasting no more than a week from beginning to end. By way of clinico-pathological correlation the disease can be diagnosed with confidence at any stage of the process, but features histopathologically are diagnosable with specificity much easier at the beginning and the summit of the eruption, than at a time when lesions resolve. If a patient is agreeable, at least two biopsy specimens should be obtained, one of which should be taken from an urticarial lesion that has been present less than two days. That procedure increases the chance of capturing features that are diagnostic enormously. Urticarial lesions are usually present for less than 48 hours and, therefore, a dermatologist is well advised to take the biopsies the day the patient seeks consultation for the first time rather than giving him or her a new appointment for biopsy a few days later. Most likely, the lesions will be on their way to involution at that date. If a specimen shows changes in the cornified layer such as parakeratosis or scale crust in a patient with clinical signs of prurigo pigmentosa, a resolving lesion has been biopsied and changes diagnostic of the disease cannot be expected in such a specimen. Lesions that show scratch marks should not be biopsied because excoriated lesions cannot be diagnosed with confidence.

Although the name prurigo pigmentosa was chosen by Masaji Nagashima because he was impressed by the pigmentation that occurred in his first collection of patients [1,2 ], pigmentation is, in our experience, often less impressive than is implied by the name of the disease. This fact becomes particularly relevant in diagnosis of the disease in Caucasions with fair skin, who rarely develop any postinflammatory hyperpigmentation. Even in Asians, among whom postinflammatory hyperpigmentation is a common finding, this could be observed by us, but much more commonly this is the case in fair-skinned Caucasians. One of the reasons why prurigo pigmentosa is diagnosed so extraordinarily rarely in Caucasians may be that the name of the disease is misleading. In Caucasians who have a light skin, reticular pigmentation cannot be used as a criterion for diagnosis because it may not actually occur. These patients present themselves with itchy red papules only, those lesions subsiding as scaly, slightly reddish macules within a week, leaving behind no residuum.

Conclusion

The criteria for diagnosis, as they have been set forth in our previous studies, enable patients with prurigo pigmentosa to be diagnosed with near surety, especially when biopsies are taken from early and fully-developed lesions. The combination of reticular alteration together with a combination of spongiosis, ballooning, and necrosis en masse, and associated with a mixed cell infiltrate in which neutrophils tend to cluster in the upper part of the epidermis, is highly distinctive of prurigo pigmentosa.

Pigmentation is no reliable criterion for the diagnosis of prurigo pigmentosa because it may be totally absent at the outset of an eruption. It also may be lacking entirely in Caucasian patients whose skin does not tend to develop postinflammatory hyperpigmentation. An explanation has yet to be found as to why lesions in prurigo pigmentosa are arranged typically in a netlike pattern, and the cause of the disease remains to be elucidated.

It has been assumed that prurigo pigmentosa occurs more commonly in the Japanese, but the fact that the patients shown here are of 5 different nationalities, namely, Japanese, German, Indonesian, Turkish, and Iranian, suggests that the disease has no ethnic proclivity and may be much underdiagnosed in countries in which the disease is not well known.

At last, we would like to encourage all colleagues who come to diagnose a patient with prurigo pigmentosa to share their observations with us. Much is still to be learned about the clinical course of the disease and about causative or genetic factors involved in the process, which only can be accomplished when a diagnosis of the condition is made with certainty.

Masoud Asgari, M.D., is a pathologist at Razi Center for Skin Lesions at the University of Medical Science in Tehran, Iran, and Almut Böer, M.D., is a dermatohistopathologist at the Dermatologikum Hamburg in Germany. This article was reviewed by Mary A. L. Tan, M.D., and Johannes Dayrit, M.D..Contact correspondingauthor via email: boer@dermatologikum.de.

References

1. Nagashima M, Ohshiro A, Shimizu N. A peculiar pruriginous dermatosis with gross reticular pigmentation. Japanese Journal of Dermatology 1971;81:38-39 (in Japanese).

2. Nagashima M. Prurigo pigmentosa – clinical observations of our 14 cases. J Dermatol 1978;5:61-67.

3. Böer A, Misago M, Wolter M, et al. Prurigo Pigmentosa: New observations and comprehensive review. Dermatopathol: Prac & Conc 2002; 8(3), available at: www.derm101.com.

4. Böer A, Misago N, Wolter M, et al. Prurigo pigmentosa: A distinictive inflammatory disease of the skin. Am J Dermatopathology 2003; 25:117-129.

5. Böer A, Ackerman AB. Prurigo pigmentosa (Nagashima disease). Textbook and Atlas of a Distinctive Inflammatory Disease of the Skin. New York City: Ardor Scribendi, Ltd., 2004.

6. Asgari M, Daneshpazhooh M, Chams-Davatchi C, Böer A. Prurigo pigmentosa: An underdiagnosed disease in patients of Iranian descent? J Am Acad Dermatol 2006, in press.