Introduction
Amyloidosis can be classified as systemic with involvement of various organ systems and localized in which deposits are limited to a single organ. Dermatologists likely encounter amyloidosis as a primary cutaneous form or rarely as cutaneous manifestations seen in systemic forms. Primary localized cutaneous amyloidosis refers to a group of conditions characterized by deposition of extracellular homogenous hyaline material in the skin, particularly, the papillary dermis, without any systemic involvement.[1] Lichen amyloidosis, macular amyloidosis, and nodular amyloidosis are different subtypes of primary localized cutaneous amyloidosis (PLCA).
The condition can present as a relatively innocuous skin disfigurement on one hand and a progressive life-threatening systemic disease with multiorgan involvement on the other hand.
History
Rudolf Virchow first introduced the term amyloid in 1854, after observing that amyloid behaved like starch after staining with iodine. Gutmann first described the clinical features of lichen amyloidosis and named the disease, “amyloidosis cutis nodularis et disseminate.” “Lichen amyloidosis” was coined by Freudenthal in 1930.[2,3]
Macular form of cutaneous amyloidosis was first described by Palitz and Peck in 1952.[4]
Epidemiology
The primary localized cutaneous amyloidosis is prevalent worldwide. Majority of cases are sporadic, but about 10% of cases have been reported to be familial.[1,5]
It is quite common in Southeast Asian countries, China, and South America.[6,7] Macular and Lichen amyloidosis are seen more frequently in skin types III and IV with a female preponderance. The age of onset ranges between 21 and 50 years.[8]
Classification
Amyloidosis is broadly classified into two types, systemic and cutaneous [Table 1]. The source of amyloid in cutaneous form is generally near the affected site, whereas it is secreted in the blood and deposited in various organs in systemic type.
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Table 1: Clinical classification of amyloidosis.
Etiopathogenesis
Structure
Amyloid is comprised of three components. Major component is the amyloid fibrils, a loose network of unbranched fibrils, about 10 to 15 nm in diameter. The fibrillar protein determines the type of amyloid and the associated systemic disease.[9] Important ones include AL (immunoglobulin light chain) responsible for primary systemic amyloidosis, type AA (serum amyloid A) implicated in secondary systemic amyloidosis and type ATTR (transthyretin) causing familial amyloidotic polyneuropathy.[10] Second non-fibrillar component is amyloid P, identical to serum amyloid protein (SAP) constituting about 15% of amyloid deposits and the third component is the ground substance comprised of glycosaminoglycans and apoE lipoprotein mainly.
Precise pathogenesis of PLCA has not been elucidated fully, but various factors like genetic predisposition,[11] friction,[12,13,14] sunlight,[14] atopy,[15] and Epstein Barr virus[16,17] have been implicated. Amyloid in macular and lichenoid variants is derived from keratinocytes, as they are positive for cytokeratin K5.[18] Two pathogenic mechanisms have been proposed, regarding the origin of amyloid in PLCA. The fibrillar theory proposes that the tonofilaments of apoptotic keratinocytes undergo filamentous degeneration and are deposited into the dermis. These are phagocytosed by histiocytes and fibroblasts and modified into amyloid material.[18] According to the secretory theory, degenerated basal keratinocytes secrete amyloid material which then drops into the dermis through damaged lamina densa.[19] The amyloid in nodular amyloidosis is derived from plasma cells, because it is composed of immunoglobulin light chains (in contrast to cytokeratins seen in MA and LA), similar to the systemic forms of amyloidosis.[18,20]
Primary localized cutaneous amyloidosis
In primary localized cutaneous amyloidosis, amyloid deposits are seen in previously normal skin, with no evidence of deposits in internal organs.[1] More common macular and lichen amyloidosis share same pathogenic mechanisms.[18]
Pathogenic mutations in the oncostatin M receptor (OSMR) gene and interleukin-31 receptor A (IL-31RA) are believed to be the major cause for familial type of PLCA.[21,22] Higher frequency of OSMR mutation was reported in sporadic type of PLCA also. Higher mutation rates in OSMR genes were observed in familial type of PLCA and in female patients, when compared to male patients of PLCA.[23,24]
Friction or oft repeated trauma by towels, nylon scrubbers, and clothes has been implicated in the causation of MA, and is described as friction amyloidosis or nylon friction dermatitis.[12,25,26]
Frequent involvement of sun-exposed areas, and exacerbation of the melanosis on exposure to sunlight could point to sunlight as one of the possible contributory factors in PLCA.[14] Other risk factors implicated in the etiology include female gender,[27,28,29] atopy,[15] and race.[30] Its predilection among certain races, the familial occurrence in about 10% and its association with multiple endocrine neoplasia type 2A points to genetic susceptibility in the etiology.[31,32]
PLCA has been described in associations with various immune disorders that include: systemic sclerosis,[33,34,35,36] CREST syndrome,[37] rheumatoid arthritis,[38] systemic lupus erythematosus,[38,39] primary biliary cirrhosis,[40] autoimmune cholangitis,[41] Kimura’s disease,[42,43] ankylosing spondylitis, and autoimmune thyroiditis.[44] IgA nephropathy and sarcoidosis were also reported to be associated with PLCA, and it was proposed that atypical and extensive PLCA in association with immune disorders could be a subset of cutaneous amyloidosis, thus supporting immune dysregulation as a cause in PLCA.[45]
Three types of PLCA are described.
Macular amyloidosis (MA) 35%
Lichen amyloidosis (LA) 35%, and
Nodular amyloidosis
Biphasic amyloidosis (15%) describes the presence of both the macular and papular variants in the same patient.[46]
Clinical features
Macular amyloidosis
Macular amyloidosis usually presents in adults and comprises of about 1/3rd cases of PCLA. It clinically presents as small, brownish macules with a characteristic reticulated or rippled pattern, which may coalesce to form poorly circumscribed hyperpigmented areas.[29] The most common site of involvement is the upper back, especially the interscapular area [Figure 1]. Extensor surfaces of the extremities [Figure 2], like forearm and shin, are involved quite frequently.[27,29,47] Face, neck, breast, and areas adjacent to bony prominences also may be involved, especially when nylon scrubbers are used while bathing.[12] Anosacral amyloidosis has been described in Japanese and Chinese patients. Amyloidosis of the auricular concha[48] and temple area has been described.[49] It occurs more frequently in women and generally has an earlier age of onset.[8,50]
Figure 1: Typical involvement of the interscapular area in macular amyloidosis.
Figure 2: Macular amyloidosis involving the extensor Legs.
Histopathologically, mild epidermal hyperkeratosis is sometimes seen. Irregularly scattered eosinophilic amyloid globules can be visualized in papillary dermis. Melanophages occasionally are seen in the periphery of these deposits [Figure 3].[51]
Figure 3: Macular amyloidosis − basket-weave orthokeratosis, basal hyperpigmentation, pigment incontinence, and amyloid deposits in the upper dermis. Congo red staining (×100).
Patients seek medical attention for pigmentation and the troublesome pruritus. Pruritus ranges from mild to moderate and may be absent in about 20% of cases.[27]
Though the rippled and reticulate pattern is the most common presentation, many unusual forms, like poikilodermatous,[52,53,54] diffuse,[55] bullous,[56] nevoid,[57] linear,[58] amyloidosis cutis dyschromica,[59] incontinentia pigmenti like,[60] are reported.
Lichen amyloidosis (LA)
It accounts for about 35% cases of primary cutaneous amyloidosis.[7] It is seen more frequently in men and manifests at a later age, around 5th or 6th decade. Sites most often involved are the shins and extensor forearms [Figure 4]. It can involve upper back and thighs less frequently.[61] Initial lesions are discrete, intensely pruritic, firm, hyperkeratotic papules, arranged in linear or grouped pattern. They may coalesce later to form hyperpigmented rough plaques. Pruritus is intense and Koebner’s phenomenon may be seen.[62,63] The constant itching and scratching are believed to induce LA.[64] Cutaneous small-fiber neuropathy and hyper-responsiveness, and over expression of IL-31 receptors in the skin is thought to be the reason for pruritus in it.[65]
Figure 4: Lichen amyloidosis involving the shins.
Histologically, epidermis shows acanthosis, papillomatosis, and hyperkeratosis. Rete ridges are elongated [Figure 5].[51] Basal keratinocytes may show hyperpigmentation and vacuolar degeneration. Large globular deposits of eosinophilic amyloid in papillary dermis are noted. Melanophages outside the deposits are seen more frequently than in MA.[66,67,68]
Figure 5: Lichen amyloidosis − compact orthohyperkeratosis, acanthosis, and amorphous amyloid deposits with melanin granules in the dermal papillae H&E ×400.
Lichen amyloidosis may be associated with multiple endocrine neoplasia type 2A, primary biliary cirrhosis, systemic lupus erythematosus, and Sjogren syndrome.
Both the variants, macular and lichen have a protracted course, and have not been reported to progress to systemic amyloidosis.
Dermoscopic features
The most common dermoscopic finding of MA was a central hub, which could be either white or brown, surrounded by various configurations of pigmentation, including fine streaks, leaf-like extensions, and a noncircular thick pedal projection with a smooth border [Figure 6].[51]
Figure 6: Dermoscopic picture of macular amyloidosis − venation like extension of pigmentation from white central hub.
The central hub in LA was found to be either white or scar-like surrounded by brownish dots or a rim of white collarette [Figure 7].[51]
Figure 7: Dermoscopic picture of lichen amyloidosis − whitish scar-like center surrounded by some brownish dots (arrows) or a rim of white collaret (arrowhead).
Nodular amyloidosis (NA)
Nodular amyloidosis is very rare and the source of amyloid is believed to be local plasma cells. The precursor protein in NA is Amyloid L, in contrast to K5 cytokeratin associated with MA and LA. Nodular amyloidosis presents as a single or multiple waxy nodules or infiltrated plaques on the face, trunk, and usually extremities.[69,70,71] About 25% of cases have been reported to be associated with Sjogren syndrome leading to speculation of a shared pathogenesis between these two conditions.[72,73,74,75,76]
Other autoimmune disorders reported to be associated with NA include primary biliary cirrhosis, rheumatoid arthritis, systemic lupus erythematosus, and CREST syndrome.[77] The cause of NA is not known but some patients give a history of preceding trauma.[78,79,80]
In nodular amyloidosis, amyloid is not limited to the papillary dermis but is present in the entire dermis, and seen even extending into the subcutaneous fat and also involves the blood vessels. A perivascular infiltrate of plasma cells[81] contiguous to the deposits implies local synthesis of amyloid L, the precursor protein of NA.
NA, though considered a localized clonal plasma cell disorder is known to progress to systemic amyloidosis. Northcutt and Vanover[71] estimated the rate of progression to be 15%, after studying a cohort of 47 PLCA patients. Therefore, a long-term follow-up in patients with NA is advisable.
Dermoscopic features
It shows a distinct pattern from MA or LA. The features include linear and serpentine vessels over an orange-yellow background or structureless yellow background interspersed with whitish spots.[82,83,84]
Diagnosis of amyloidosis
The demonstration of amyloid in the skin or other organs provides conclusive proof of amyloidosis [Table 2].
Table 2: Investigations for the diagnosis of amyloidosis.
Investigations performed for the diagnosis include the following:
H & E stain − Sections show small, amorphous globules of eosinophilic material in papillary dermis along with pigmentary incontinence and epidermal changes like hyperkeratosis, acanthosis, hypergranulosis, and parakeratosis.
Special stains − Amyloid stains orange-red with Congo red staining[85] and shows a typical apple-green birefringence under polarized light, a phenomenon called dichroism.[86,87] Other stains which can detect amyloid include PAS, crystal violet, methyl violet, Thioflavin T,[87] and cotton dyes like Pagoda red and Dylon stain.[1,20]
In many instances the amount of amyloid deposit is too scanty to be demonstrated and repeat biopsies are recommended to improve the rate of detection and proper categorization.[78,88]
Immunohistochemistry
Antibodies directed against various amyloid fibril proteins help in accurately diagnosing the type of amyloidosis. Macular and lichen amyloidosis are positive for antibodies against cytokeratin K5, and antibodies directed against immunoglobulin light chains are specific for nodular and systemic AL amyloidosis.[89]
Electron microscopy − It provides conclusive proof of the presence of amyloid, wherein typical aggregates of 7 to 10 nm non branching fibrils of amyloid are visualized.[89]
X-ray crystallography and infrared spectroscopy reveal the characteristic cross-β-pleated sheet configuration.[90]
Direct Immunofluorescence − DIF is another valuable adjunctive test to confirm cutaneous amyloidosis. Both macular and lichen amyloidosis show positive immunofluorescence with IgM, C3, and IgA in basement membrane zone and papillary dermis. They may fluoresce in oval, amorphous, or colloid pattern. The results obtained by DIF are comparable to Congo red staining.[91,92,93,94,95]
Management
Cutaneous amyloidosis is a recalcitrant condition, refractory to most of the treatment options available. A wide range of treatment options are employed in the treatment of PLCA. None of these modalities is uniformly effective. Treatment is directed towards the two major problems of pruritus and hyperpigmentation. Since pruritus is believed to induce amyloid deposits, it is important to break the itch-deposition-itch cycle and thus many therapies are directed against pruritus.
Medical management
In mild cases of LA, potent topical steroids alone, or under occlusion or in combination with salicylic acid may help. Intralesional steroids have been tried in localized disease.[96]
Topical DMSO was reported to be effective in MA, LA, and biphasic amyloidosis.[97,98] Intermittent therapy was found to be sufficient as maintenance treatment after reduction of pruritus with daily application of topical DMSO. There was significant reduction of pruritus, pigmentation, and papules.[99] The side-effects of therapy were contact urticaria, desquamation, burning sensation, and garlic-like breath odor. Other authors found treatment with DMSO to be unsatisfactory, with only transient and partial results.[100,101]
Phototherapy is an alternative safe option in the management of PLCA. NbUVB therapy was reported to be very effective in both MA and LA.[102,103] PUVA, topical psoralen with Ultraviolet A was also found to be of benefit, especially with regards to the resolution of pruritus in LA.[104] Topical tacrolimus 0.01% and topical corticosteroids were used to enhance the response of NbUVB.[105,106] Re-PUVA, a combination of acitretin with bath PUVA, was used with success to reduce the pruritus and the papules in LA.[107]
Retinoids − Oral etretinate, 1 mg/kg/day,[108,109,110] acitretin, 0.5 mg/kg/day,[111,112,113,114] were reported to reduce pruritus and flatten the papules in LA. Four to six months treatment is required to see results.[114] Oral isotretinoin[115] and alitretinoin,[116] were successfully used in LA. Tocoretinate, a hybrid compound of retinoic acid and tocopherol, was shown to be beneficial in both LA and MA lesions in a case series involving 10 patients.[117] Topical calcipotriol,[118] topical tacrolimus 0.1%,[119] oral low dose cyclophosphamide,[120] oral cyclosporin,[43,121,122] have been tried with varying degrees of success.
Chemical peels like 15% Trichloracetic acid and 50% Glycolic acid have been found to be beneficial in both MA and LA.
Laser treatments:
CO2 and Nd:YAG lasers are both effectively used in PLCA. Esmat et al.[123] reported a significant reduction in pigmentation, thickness of the lesions, itching, and amyloid deposits in a study population of 25 patients of LA and MA after using fractional ablative CO2 laser. Good improvement with reduction in itching with CO2 laser was demonstrated by Norisugi et al.[124] in two patients of LA on the legs.
Ostovari et al.[125] treated a group of 20 female patients suffering with MA using Q switched Nd:YAG laser and showed an effective reduction of pigmentation in all. They concluded that 532 nm was more efficacious than 1064 nm, Liu et al.[126] showed very good results in a patient of LA by using Q-switched frequency doubled Nd:YAG (532 nm) laser.
Pulsed dye laser has been shown to be beneficial in MA,[127] LA,[128] and NA.[129]
Surgical management
Surgical procedures are generally preferred for NA and sometimes for LA. Various procedures like dermabrasion,[130] scraping with a scalpel,[131] electrodesiccation,[132] have been tried with clearance of LA lesions.
Future directions
Small-fiber neuropathy has been found in patients with lichen amyloidosis, which leads to a reduction in intraepidermal nerve fibers. Increased epidermal expression of IL31 receptors further renders the remaining cutaneous nerve fibers to become hypersensitive and leads to the pruritus in LA.[65,133] IL 31 has been demonstrated to be a mediator of pruritus and therefore, Nemolizumab, a humanized antibody against IL31RA has the potential to become a treatment option for patients with PLCA.[23] Capsaicin may achieve an anti-prurigenic effect by overstimulating and exhausting the cutaneous histamine-sensitive and mechanosensitive C and Aδ fibers.[134] Zeidler et al.[135] demonstrated impressive results in two patients of LA with the help of 8% capsaicin patch. Another possible area of research could be development of therapies aimed at the OSMR β expressing cutaneous nerves.[23]
What is new
The role of dermoscopy and immuno-fluorescence in the diagnosis of cutaneous amyloidosis is becoming more important. The dermoscopic features of nodular amyloidosis have been delineated recently. Recent developments like changes in the epidermal nerve fiber density which is altered in amyloidosis and the role of C fibers in the pathogenesis of PCLA are important contributory factors in the etiology. This recent understanding could lead to novel and more effective targeted approach towards amelioration of this recalcitrant condition. The role of OSMR β expressing cutaneous nerves as another area of interest is highlighted.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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