A generalized, non-pruritic variant of lichen amyloidosis: a case report and a brief review.

Lichen amyloidosis (LA) has been considered a highly pruritic dermatosis, and the deposition of fibrillar material has generally been considered to be secondary to the scratching. Focal epidermal damage and chronic scratching have been implicated as the pathogenetic factors in the occurrence of LA, although they may not be able to explain the occurrence of a widespread variant of this dermatosis. There are few case reports describing the occurrence of a non-pruritic variant of LA. We hereby report a case of non-pruritic, generalized variant of lichen amyloidosis.

What was known?

1. According to many standard dermatology textbooks, lichen amyloidosis is considered to be a highly pruritic dermatosis.

2. Chronic scratching leading to focal epidermal damage has been implicated as a possible factor leading to keratinocyte degradation and amyloid deposition.

3. Few case reports of non-pruritic and generalized variant of lichen amyloidosis exist, suggesting that factors other than scratching may be responsible for amyloid deposition.

Introduction

Amyloidosis is the extracellular deposition of any unrelated proteins leading to changes in tissue architecture and function.[1] Lichen amyloidosis (LA) is a subtype of primary localized cutaneous amyloidosis (PLCA), wherein there is deposition of amyloid in previously apparently normal skin with no evidence of deposits in internal organs. Other subtypes of PLCA include the macular variant and the rare tumefactive form.[2] LA has been considered a highly pruritic dermatosis, and the deposition of fibrillar material has generally been considered to be secondary to the scratching induced by other subjacent pruritogenic processes.[3] There are few case reports describing the occurrence of a non-pruritic variant of LA.[34] The widely believed theory is that in predisposed individuals, focal epidermal damage and filamentous degeneration of keratinocytes is followed by apoptosis and conversion of filamentous masses into amyloid material in the papillary dermis.[5] Chronic scratching is considered to be the trigger for precipitating epidermal trauma, leading to keratinocyte degeneration. The above-mentioned theories wherein focal epidermal damage and chronic scratching have been implicated may not be able to explain the occurrence of a widespread, non-pruritic variant of this dermatosis, as seen in our patient.

Case Report

A 62-year-old man presented with complaints of multiple dark eruptions involving his lower limbs, back, chest, and parts of the upper extremities. The lesions appeared 10 years ago on the lower limbs and progressed to involve the other parts of the body over the past 3 years. There was no history of itching, trauma, chronic scratching or friction, no systemic symptoms and no similar complaints in other family members. On examination, multiple, discrete, hyperpigmented, papules were present on the shins, [Figure 1] and similar smaller papules were seen on the upper back, chest, abdomen, upper arms and few on the thigh and gluteal region [Figure 2a and b]. Histopathological examination revealed a hyperplastic epidermis and globular masses in the dermal papillae [Figure 3]. Congo red staining revealed amorphous, eosinophilic deposits in the papillary dermis [Figure 4]. Routine laboratory investigations including complete blood count, blood sugar levels, renal, hepatic, urinary analysis, and thyroid function tests were within normal limits.

Figure 1

Discrete, follicular and non follicular, hyperkeratotic, brown papules on shin

Figure 2

(a) Small, brown, papules on arms and upper chest (b) similar, discrete, papules on the upper back

Figure 3

Hyperplastic epidermis and pink masses in papillary dermis (H and E, ×200)

Figure 4

Amorphous eosinophilic deposits in the papillary dermis (Congo red, ×400)

A diagnosis of lichen amyloidosis was made on the basis of clinicopathological findings, and the patient was given topical clobetasol propionate and salicylic acid combination along with oral acitretin 25 mg/day.

Discussion

Virchow introduced the term “amyloid” (starch-like) to designate an amorphous material that had resemblance to starch or cellulose. LA forms the most common subtype of primary localized cutaneous amyloidosis (PLCA), and occurs more commonly in males, during the 5th and 6th decade of life. It is defined as a chronic pruritic disorder characterized by multiple, grouped, hyperkeratotic, brownish, papular lesions mainly located on the shins, back, forearms, or thighs. The papules at times may coalesce to form plaques resembling hypertrophic lichen planus, lichen simplex, or nodular prurigo. The lesions may localize to a single area or may involve various body sites. The most commonly affected area is the pre-tibial region,[6] although presentation of LA has been reported on the abdominal or chest wall, the auricular concha,[78] the anosacral region,[9] the scalp, and the interscapular region; in the latter, lichen amyloidosis occurs in association with MEN type 2a syndrome.[10] LA may rarely manifest itself as a bullous variant[11] in a “thermosensitive” pattern[12] or localizing itself to the sites of varicose veins on the lower extremities.[13]

Even though various theories have been proposed regarding the origin of amyloid in LA,[14151617] the reason remains unclear. Most recently, Clos et al.[18] have proposed a mixed theory, based on their investigation of the role of prefibrillar amyloids (oligomers) in amyloidogenesis. They were able to detect prefibrillar amyloids in the basal cell layer of the epidermis and in surrounding cells within the dermis and believe that these fibrils may have a role in eventual amyloid fiber formation.

Genetic factors, viral factors as well as chronic friction due to scratching are said to be possible causes of LA.[19] PLCA is sporadic in most cases although some individuals do show evidence for genetic susceptibility, and 10% of the cases are known to exhibit autosomal dominant inheritance.[20] Epstein–Barr virus-encoded RNA has been detected in Chinese patients of PLCA.[21] There has been considerable debate regarding whether pruritus acts as a causative factor in LA or is the result of amyloid deposition. Pruritus is a varying symptom in lichen amyloidosis and a non-pruritic variant exists, which accounts for 20% of the PLCA cases.[34] Weyers et al.[22] suggested that the deposition of amyloid in LA is not the cause but the result of itching and scratching, and this was based on several different factors. They concluded that LA represents a variant of lichen simplex chronicus (LSC) and prurigo nodularis (PN) as there is enough evidence to show that LA is a result of scratching, although an additional unknown factor may be playing a role, which explains the absence of amyloid accumulation in the papillary dermis in most cases of LSC and PN. Kibbi et al.[23] noticed an absence of pruritus in 4 cases in there group of 15 patients with LA and stated that the cause of the pruritus associated with the dermatosis remains unexplained. Kuligowski and Chang[4] reported a single case of non-itchy LA and stressed on the fact that the absence of pruritus should not lead to the exclusion of the diagnosis of LA, provided the other criteria are fulfilled. A study carried out in Hispanic patients revealed a significant decrease in the amount of nerve fibers in the epidermis and the dermoepidermal junction in LA lesions as compared to controls. The neurohypoplasia may result in the hypersensitivity of the remaining nerve fibers, thereby leading to pruritus, although the cause for the damaged nerve fibers remained unknown.[24] Recent data from a Chilean family with PLCA brought to light the occurrence of heterozygous missense mutations in the fibronectin-III domains of oncostatin M receptor b (OSMRb) encoded by the OSMR gene in cases of familial PLCA. It has been demonstrated that mutant OSMRb, when stimulated by oncostatinM or IL-31 or both these cytokines, leads to keratinocyte apoptosis (with subsequent amyloid deposition), a reduced number of cutaneous nerves (possible apoptosis) and, in most individuals, pruritus.[25]

The epidermis in LA shows irregular acanthosis and hyperkeratosis. The amyloid deposits are large enough to expand the dermal papillae and are usually confined to the papillary dermis and usually do not involve the vasculature or adnexal structures.[226] Weyers et al.[2227] demonstrated in their study that deposits of amyloid were nearly always confined to areas that also showed typical signs of LSC. In another report, the authors concluded that in cases presenting with persistent skin lesions simulating lichen simplex chronicus, amyloid should be specifically looked for in biopsy material.[28] Pretibial pruritic papular dermatitis (PPPD) is a distinct entity, which has striking clinical resemblance with LA, consisting of discrete, roundish, extremely pruritic papules with a smooth surface caused by the delicate and persistent rubbing of pretibial skin, although the histopathological findings do not reveal any amyloid deposition.[29] Amyloid cannot be detected in clinically normal skin of patients with LA.[3031] Special stains used for the histologic demonstration of amyloid include methyl violet, the PAS method, substantive cotton dyes such as Congo red or Sirius red, and thioflavin T. Amyloid fibrils display a beta-pleated sheet configuration on X-ray diffraction crystallography, which is responsible for their ability to bind Congo red (Congophilia) and exhibit an apple-green birefringence under polarized light. Immunohistochemical staining of the amyloid deposits with antikeratin antibody (EAB-903), suggesting their epidermal origin.[32] Immunofluorescence in LA reveal IgG, IgM, C3, and light chains, which are believed to be passively absorbed into the globular aggregates.[33] On electron microscopy, the amyloid of LA is composed of amyloid filaments, normal and degenerated tonofilaments, and lysosomes.[6]

Even though numerous studies have tried to gain an insight into the cause of pruritus in LA, there is still no single theory which explains the occurrence of pruritus in this common dermatosis. In view of our case and few prior case reports,[3423] which highlight the absence of pruritus in cases of LA, we would urge dermatologists to consider the diagnosis of LA, even in the absence of pruritus. One must consider a biopsy for long-standing, hyperkeratotic, papular lesions; present not only on the pre-tibial region but even elsewhere, which are resistant to conventional treatment. The hypothesis that chronic scratching leads to epidermal trauma, which further leads to amyloid deposition, may not be able to explain the occurrence of generalized lesions or multifocal lesions as in our case. Generalized LA has been previously reported in the literature,[34353637] wherein pruritus was reported in all the cases, although one of the cases was associated with hypertrophic lichen planus[35] and the other with chronic urticaria.[37] We conclude that a non-itchy variant of LA does exist and that chronic scratching may be an initiating event in most but not in all cases of LA. The occurrence of the non-itchy variant with multi-focal involvement has not been previously reported to our knowledge. We speculate the role of genetic factors that predispose the individual to the non-itchy variant of this dermatosis.

What is new?

1. The diagnosis of lichen amyloidosis should not be excluded in the absence of pruritus.

2. Certain genetic factors may predispose an individual to this non-itchy variant.

3. There is now evidence showing that neurohypoplasia and certain genetic mutations may have a role in the pruritus experienced in lichen amyloidosis.