FormalPara Key Points

Primary localized cutaneous amyloidosis is a frequently encountered skin condition with a heterogeneous spectrum of clinical manifestations.

Classifying the clinical spectrum into geographic and morphological categories assists dermatologists in the timely recognition of the correct diagnosis.

1 Introduction

Amyloidosis refers to a group of conditions that share a common feature of abnormal deposition of eosinophilic misfolded proteins, amyloid fibrils, in various tissues [1]. It is divided into cutaneous and systemic forms based on localization but can be subgrouped based on biochemical structure [1, 2]. Primary localized cutaneous amyloidosis (PLCA) can be either keratinocyte derived in macular and lichen amyloidosis or immunoglobulin light chain derived in nodular amyloidosis. Secondary forms are also keratinocyte derived and can be seen in benign and malignant cutaneous tumors [1].

Primary localized cutaneous amyloidosis is a commonly encountered skin condition; hence, dermatologists can easily recognize the patches of skin of abnormal texture or color. Nonetheless, there are presentations that are atypical and need to be emphasized. In this review, we aim at focusing on the atypical morphology and distribution of keratinocyte-derived PLCA, to evaluate the histological features, associated differential diagnosis, and finally, to provide an updated management appraisal (Table 1).

Table 1 Review of the available therapeutic modalities of primary localized cutaneous amyloidosis
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2 Pathogenesis

Amyloid was described more than 150 years ago, initially thought to be a cellulose-like material and then discovered to be a protein, synthesized from more than 20 substances including keratin. Electron microscopy studies have shown that amyloid is made up of nonbranching fibrils that are arranged into β-pleated sheets but can also be found in alpha-helices. Amyloidosis manifests when these sheets are misfolded resulting in extracellular deposits [2].

Lichen amyloidosis was first recognized by Freudenthal when Congo red-positive hyaline bodies were noted within the epidermis and it was mistakenly thought to be extruded resulting in the cutaneous findings [2]. Better understanding of cutaneous amyloidosis was achieved once it was observed that the skin produced amyloid from degenerated basilar keratinocytes after exposure to psoralen and ultraviolet A [2]. Ultrastructural studies have corroborated those findings; degenerated tonofilaments were observed with amyloid filaments in some keratinocytes, implying the transformation of the degenerated filaments into amyloid [2].

When it comes to lichen and macular amyloidosis, the deposited substance was identified as keratinocyte-derived amyloid using immunofluorescence studies. These deposits were immunoreactive to antikeratin antibodies but not to antibodies against A protein, prealbumin, or fibronectin, other suspected precursors [2]. As for why these deposits form, the literature emphasizes the abnormal folding of proteins in the form of β-pleated sheets resulting in their extracellular presence. As mentioned, amyloid can be present in both the β-pleated and alpha-helical structures, although the former conformation predominates and is more likely to be present in PLCA. Similar to other proteins, several factors cause amyloid to accumulate in tissue [2]. First, it is proposed that when these proteins are produced in excess amounts, they tend to clump and fold into β-pleated sheets; however, even if produced in normal amounts, these proteins can develop abnormal structures under certain conditions such as low pH or the presence of metal ions or chaperones. Normally, these defective proteins are discarded through degrading mechanisms but if this fails, amyloid can deposit in tissue. Interestingly, this process is highly variable, and a lag phase is described where certain prerequisites are actually present, but the amyloid fibrils fail to form. This process can last from weeks to years, but once the first amyloid aggregation is formed, the development of the insoluble architecture soon follows [2]. With that said, the exact pathogenesis remains unclear, but it is considered to be multifactorial with both genetic and environmental risk factors associated with keratinocyte-derived amyloid formation [3].

When assessing if certain factors predispose individuals to develop PLCA, familial forms have been described. Primary localized cutaneous amyloidosis appears to be mainly sporadic but in about 10% of patients, an autosomal dominant inheritance pattern with variable penetrance can be observed [4]. In addition, PLCA is common in southeast Asia, South America, and the middle eastern region [3]. The racial susceptibility and familial aggregation suggest that underlying genetic factors must play a role in the pathogenesis of PLCA.

To date, oncostatin M receptor-beta and interleukin (IL)-31 receptor-alpha have been implicated in familial PLCA [5]. The exact link between these proteins and disease pathogenesis is not fully understood. Both receptors are members of the IL-6 cytokine receptor family, which work by JAK/STAT, MAPK, and PI3K/Akt signal transduction pathways. These receptors, through their cytokines (IL-6, IL-11, IL-27, and IL-31, and oncostatin M), play an important role in keratinocyte differentiation, proliferation, inflammation, and apoptosis, key elements in the pathogenesis of cutaneous amyloidosis [5, 6].

Oncostatin M receptor-beta is a component of both the OSM type II receptor and the IL-31 receptor. Oncostatin M receptor-beta unites with IL-31 receptor-alpha to form the IL-31 receptor [4, 7]. Autosomal dominant and recessive mutations in the fibronectin domain of oncostatin M receptor-beta have been reported in familial PLCA [5, 7, 8]. These studies suggest that missense mutations lead to aberrant IL-31 signaling, which is directly related to the clinical symptom of itch [7, 8]. The latter is plausible because IL-31 is also implicated in pruritic skin conditions such as prurigo nodularis. In addition, the IL-31 inhibitor, nemolizumab has been demonstrated to be useful in treating chronic pruritus in atopic dermatitis [6, 9].

In families with PLCA, aberrant IL-31 signaling may also cause downstream failure to induce expression of monocyte chemotactic protein-1. Monocyte chemotactic protein-1 is important in the recruitment of immune cells such as monocytes, which subsequently differentiate into macrophages when inflammation or injury is detected. The absence of monocyte chemotactic protein-1 results in failure to initiate the proper innate immunity response needed to establish a scavenging system and to clear cellular debris [10].

Further confirming the involvement of genetic factors, PLCA has been associated with syndromes such as pachyonychia congenita, familial palmoplantar keratoderma, and multiple endocrine neoplasia type 2A (MEN2A) [11, 12]. The strongest association has been noted with MEN2A; a rare autosomal dominant syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid tumors. This disorder is related to a germline mutation of the RET protooncogene, located on chromosome 10 [12]. Efforts to map the predisposing gene failed to provide direct evidence implicating RET in the pathogenesis of PLCA, but patients affected by this syndrome frequently report neurological itching on the upper back, even prior to the development of PLCA; a vital screening sign of this disorder. Review of the reported cases revealed that MEN2A-related PLCA seems to be more common in women and is the second most common manifestation of MEN2A, preceded only by medullary thyroid carcinoma [13]. As not all MEN2A patients have cutaneous amyloidosis, it is reasonable to assume that the gene of familial PLCA is separate but linked to the MEN 2A locus in the pericentromeric region of chromosome 10 [12].

3 Classical Clinical Variants

Classically, PLCA is divided into macular and lichen (Fig. 1), nonetheless, it is important to note that these entities represent the ends of a clinical spectrum. In fact, some lesions exhibit features of both macular and lichen amyloidosis, which is termed “biphasic amyloidosis” [1, 2, 14].

Fig. 1
figure 1

Cutaneous amyloidosis: classical macular (A), lichen (B), and both macular and lichen amyloid (C) together

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Macular amyloidosis is characterized by hyperpigmented grayish-brown patches either in a rippled or confluent pattern. The former being more evident upon stretching of the skin. This condition affects most commonly the upper back, especially the scapular area, followed by the extensor surfaces of the extremities. It is often accompanied by pruritus, but it can also be asymptomatic. Pruritus may even precede clinically evident lesions. In biphasic amyloidosis, papular lesions are seen on a background of hyperpigmentation [1, 2, 14].

Lichen amyloidosis is the most common form of PLCA. Initially, it presents as firm, discrete, hyperkeratotic, match-head to pea-sized, skin-colored or hyperpigmented, dome-shaped or hemispheric papules [14]. Later on, the lesions coalesce into plaques with a rippled pattern. An asymmetric distribution is occasionally noted early on. With time, the lesions progress to a symmetric pattern. The most common site involves the pretibial area but other extensor surfaces, such as thighs and forearms, can be affected.

4 Differential Diagnosis

Notalgia paresthetica shows a significant overlap with macular amyloidosis and should be entertained in the differential diagnosis. The former presents on the upper back and can have a rippled hyperpigmentation [15]. On histology, notalgia paresthetica demonstrates scattered melanophages but no amyloid deposits. When macular amyloidosis adopts a more diffuse form, it should be differentiated from post-inflammatory hyperpigmentation [16]. Other conditions to be ruled out are atrophic lichen planus [17], erythema dyschromicum perstans [18], drug-induced pigmentation [19], and frictional melanosis (Table 2) [20].

Table 2 Differential diagnosis of clinical variants of PLCA
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Once lichen amyloidosis is encountered, careful consideration should be given to lichen simplex chronicus and hypertrophic lichen planus. Both are characterized by chronic pruritic plaques often on the shins. However, histologically, none of these entities exhibit amyloid deposition. Other conditions to be entertained include papular mucinosis [21], pretibial myxedema [21], prurigo simplex/nodularis [22], colloid millium [14, 23], and elephantiasis nostras verrucosa (Table 2) [21]. The term “frictional amyloidosis” has been coined to describe a subgroup of patients in whom friction is the culprit to the production of macular and lichenoid lesions [2, 8, 24].

5 Histological Findings

Both macular and lichen amyloidosis display amyloid deposits restricted to the upper dermis, particularly the papillary dermis (Fig. 2). The special stains routinely employed in the detection of amyloid deposits are Congo red and Crystal violet [2, 25]. It is important to note that other stains might be used such as Thioflavin T, periodic-acid-Schiff method, and Sirius red to detect amyloid deposits [2, 25]. In lichen amyloidosis, the amyloid deposits may expand the papillae and displace the elongated rete ridges laterally. Features of chronic rubbing, such as acanthosis and orthohyperkeratosis, can be seen in the epidermis. These features are more pronounced in lichen amyloidosis compared with macular amyloidosis [2, 25].

Fig. 2
figure 2

Cutaneous amyloidosis: classical histopathology showing deposits (arrows) in the papillary dermis (hematoxylin and eosin ×200)

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6 Atypical Clinical Variants Based on Morphology

6.1 Amyloidosis Cutis Dyschromica

Amyloidosis cutis dyschromica has been reported as a rare form of PLCA (Fig. 3A). It is characterized by the presence of (1) reticular hyperpigmentation with hypopigmented macules distributed extensively, (2) minimal or no itching, (3) onset before puberty, and (4) focal subepidermal amyloid deposition [26]. It has been found to be a familial disorder with unknown pathogenesis. Environmental factors, particularly sun exposure, have been proposed as the underlying cause [26]. Some reports have highlighted the loss of glycoprotein nonmetastatic gene B as a possible etiology, in addition to associations with various disorders such as systemic sclerosis, systemic lupus erythematosus, and familial Mediterranean fever [27,28,29].

Fig. 3
figure 3

Cutaneous amyloidosis: dyschromic (A), poikilodermatous (B), and linear (C) presentations

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The differential diagnosis includes dyschromatosis universalis hereditaria [30], poikiloderma-like amyloidosis, and xeroderma pigmentosum (Table 3) [26, 31]. Amyloidosis cutis dyschromica can be distinguished from dyschromatosis universalis hereditarian histologically. Additional clinical features, such as poikilodermic lesions, short stature, and palmo-plantar keratoderma, point towards poikiloderma-like amyloidosis instead of amyloidosis cutis dyschromica [32]. A differentiating factor between xeroderma pigmentosum and amyloidosis cutis dyschromica is the marked photosensitivity present in the former.

Table 3 Differential diagnosis of clinical variants of amyloidosis cutis dyschromica
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6.2 Poikiloderma-Like Amyloidosis

Poikiloderma-like amyloidosis has been frequently reported in the literature (Fig. 3B). Two clinical forms have been described: the ordinary type and the poikiloderma-like cutaneous amyloidosis syndrome [32, 33]. The ordinary type presents with poikilodermatous lesions, and lichenoid papules, with or without blisters with an adult onset [32]. Poikiloderma-like cutaneous amyloidosis syndrome has an earlier onset and presents with multiple features including (1) poikilodermatous skin lesions, (2) lichenoid papules, (3) cutaneous amyloid deposits in the pigmented and lichenoid lesions, (4) light sensitivity, (5) short stature, and (6) other features such as blister formation or palmoplantar keratosis [33]. Based on the clinical presentation, it can be confused with true poikiloderma conditions such as poikiloderma atrophica vasculare [34], mycosis fungoides [35], connective tissue disorders, or genodermatoses (Table 4). This highlights the importance of a skin biopsy to be able to distinguish poikiloderma-like amyloidosis from the above-mentioned entities.

Table 4 Differential diagnosis of poikiloderma-like amyloidosis
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6.3 Bullous Amyloidosis (Keratinic Variant)

A bullous variant of lichen amyloidosis has been described in a few case reports [36,37,38]. Cases presented with pruritic lichenoid papules and vesicles. Based on the clinicopathological findings, a diagnosis of lichen amyloidosis was established. Note that familial forms of bullous amyloidosis were observed emphasizing the importance of genetic factors in the pathogenesis of PLCA [37]. Bullous amyloidosis without systemic involvement is a rare entity. Actually, most cases (88%) [38] described as bullous amyloidosis were later diagnosed as systemic amyloidosis [37]; therefore, careful attention should be given to patients presenting with bullous lesions.

6.4 Incontinentia Pigmenti Like

Macular amyloidosis has masqueraded as incontinentia pigmenti in several reports [39,40,41,42,43]. Patients would present in early infancy with diffuse Blaschkoid-arranged brownish patches that were initially erythematous. The lack of pruritus is a common feature of this entity [41]. It is important to note that vesicle or bulla formation is uncommon in this subtype; however, it has been reported [39]. Intriguingly, a familial inheritance of incontinentia pigmenti-like cutaneous amyloidosis has been suggested but not fully elucidated [40, 42].

6.5 Linear

Patients with linear macular amyloidosis exhibit a localized Blaschko-linear macular hyperpigmentation distribution [44] (Fig. 3C). The major clinical differential diagnosis to be entertained is nevoid hyperpigmentation. Furthermore, several acquired dermatoses distributed in a Blaschko-linear pattern should be considered such as psoriasis, lichen planus, and lichen striatus.

6.6 Nevoid

A case of asymmetric hyperpigmentation limited to the left side half of the body suggested a possible nevoid origin [45]. Therefore, it is important to keep in mind PLCA as a diagnosis in cases displaying bizarre patterns of hyperpigmentation.

6.7 Nodular Amyloidosis (Keratinic Variant)

Although the material in nodular amyloidosis is derived from immunoglobulin light-chains amyloid, an unusual type of nodular keratinocyte-derived amyloid has been reported with no systemic involvement [46]. The lesions displayed are numerous nodules coalescing into plaques on the lower extremities. Skin biopsy reveals typical characteristics of PLCA. Moreover, lipid chromatography tandem mass spectrometry analysis confirmed that the deposition was keratinocyte derived [46]. By being able to establish that the amyloid is keratinocyte derived, one can avoid an extensive systemic work-up. The differential diagnosis includes nodular amyloidosis [46], cutaneous lymphoid hyperplasia [47], pretibial myxedema [21], sarcoidosis [48], and granuloma annulare [49] (Table 5). All these conditions have distinctive histopathological findings.

Table 5 Differential diagnosis of nodular amyloidosis (keratinic variant)
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7 Atypical Variants of Amyloidosis Based on Distribution

The atypical variants of PLCA have been observed in unusual distributions such as on the ears, the anosacral area, and the face as well as a diffuse pattern.

7.1 Ear

Skin-colored pruritic papules on the ear were misdiagnosed as contact dermatitis unresponsive to topical corticosteroids. This prompted physicians to further evaluate the case with a skin biopsy, leading to the diagnoses of a variant of lichen amyloidosis of the auricular concha [50]. It is interesting to note that, although pruritus usually precedes the skin lesions in lichen amyloidosis [51], it was not found in half of the patients with the auricular concha involved. Moreover, using immunohistochemistry procedures, the amyloid expressed cytokeratin 34βE12, suggesting that the amyloid in amyloidosis of the ear is keratinocyte derived [52].

7.2 Anosacral

Although anosacral cutaneous amyloidosis was previously thought to be correlated with older age, patients developing the disease before the age of 60 years challenge this assumption [53]. It can easily be misdiagnosed as the clinical presentation is inconsistent [54]. Some patients showed also skin lesions on other parts of the body, whereas others presented with a solitary brownish scaly plaque in the gluteal area only [54]. Because of its wide clinical presentation, the differential diagnosis should include lichen simplex chronicus, post-inflammatory hyperpigmentation, senile gluteal dermatosis, or erythrasma [53].

7.3 Face

A single report of macular amyloidosis affecting the temple of patients has been recorded [55]. It was described as multiple discrete brownish macules on the temple that coalesced into a reticular pattern. Because of its uncommon location, lichen planus pigmentosus or other dyschromic dermatoses involving the face should be considered as well [55].

7.4 Diffuse

Diffuse reticulated rippled hyperpigmentation over the body (Fig. 4) and nails with mucosal involvement raised a possibility of a new entity of PLCA that does not fit previous types [32]. This variant was labeled as an atypical presentation of PLCA with some overlapping features of amyloidosis cutis dyschromica and poikiloderma-like amyloidosis. Other entities such as dermatopathia pigmentosa reticularis and Naegeli–Franceschetti–Jadassohn syndrome should be included in the differential diagnosis.

Fig. 4
figure 4

Diffuse cutaneous amyloidosis case with involvement of the trunk (A, B), extremities (C), and face (D)

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8 Therapeutic Modalities

The literature regarding PLCA treatment is scarce and limited to case series and case reports [8]. Despite the multitude of treatment options, no gold standard has been established as none are curative or uniformly effective and most therapies aim at breaking the itch-scratch cycle (Table 1) [8, 26, 28, 36, 37, 56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72]. Mild cases of PLCA respond, to some extent, to potent topical corticosteroids with an added benefit when given under occlusion or combined with a keratolytic agent [56]. Patients should be encouraged to avoid chronic friction, for example with towels and brushes, as they have been identified as potential precipitating or aggravating factors [8, 24]. Hydrocolloid dressings can serve as a mechanical barrier to protect the involved sites [8].

9 Conclusions

Primary localized cutaneous amyloidosis is a common disorder with well-known presentations easily discernable from other skin conditions. However, some forms of PLCA exhibit an atypical presentation whether in morphology or location. A physician’s awareness of specific PLCA manifestations provides an opportunity to establish early diagnosis and avoid unnecessary diagnostic testing. Hence, this review aims at providing physicians with the spectrum of PLCA cutaneous variants with emphasis on the atypical variants and to summarize available therapeutic options.