Patient Presentation
A 56-year-old Hispanic woman presented with numerous hyperkeratotic, hyperpigmented, small, firm papules that were coalescing into symmetric plaques on the bilateral distal arms and legs. She also complained of multiple brown reticulated macules distributed symmetrically over her upper back. The patient indicated that her lesions were very pruritic and had slowly appeared and spread over a period of 1 year. Her past medical, family, and social histories were non-contributory. A skin biopsy of the leg papule was done to confirm diagnosis.
Diagnosis:Biphasic Amyloidosis
In 1838, Schleiden first introduced the term “amyloid” to describe plant starch.1 In 1854, Virchow adopted the term to describe tissue deposits that stained similarly to cellulose stained with iodine.2 These deposits were described as being waxy on gross examination and amorphous and hyaline on light microscopy. Gutmann first described a patient with clinical features of lichen amyloidosis in 1928.2 Freudenthal instituted the term “lichen amyloidosis” in 1930.1,2 Macular amyloidosis was first described by Palitz and Peck in 1952.3
“Amyloidosis” refers to a group of disorders that have in common the abnormal extracellular deposition of a family of proteins. These proteins are biochemically unrelated but share characteristic staining properties (e.g., apple-green birefringence on examination with polarized light after Congo red staining).4 Amyloidosis is typically categorized into either general (systemic) or organ-limited (localized). Within each of these categories, there are several subtypes that vary in the actual protein involved, as well as in specific anatomical sites of deposition (Table 1, below).
For the purpose of this discussion, we will focus on forms of amyloidosis that commonly have clinically evident cutaneous findings, which include primary systemic, myeloma-associated, and primary localized cutaneous amyloidosis (PLCA).
Epidemiology
The epidemiology of systemic amyloidosis is difficult to define because it is often misdiagnosed or undiagnosed. The incidence is estimated to be between 1,275 to 3,200 new cases per year.5 The disease occurs most commonly in elderly men with a mean age of onset of 65.4,6
Overall, lichen and macular amyloidosis occur more frequently in individuals with Fitzpatrick skin types III and IV.1 Lichen amyloidosis is more common in people of Chinese descent. Macular amyloidosis is common in Central and South American countries — especially those close to the equator — as well as Middle Easterners and non-Chinese Asians. Women are two times as likely as men to be affected with nodular localized amyloidosis, and are most often between 60 and 70 years of age.4 Nodular localized amyloidosis is the least common of the PLCA subtypes.4
Clinical Features
Mucocutaneous lesions in patients with systemic and myeloma-associated amyloidosis are seen in 40% or less of cases and occur in various forms.6 (See Table 2, above.) The most common lesion is pinched purpura, which occurs in 15% to 17% of patients and results from amyloid infiltration of blood vessel walls.4 Purpura is common in flexural areas and may appear in response to trauma or strain as during a Valsalva maneuver.4,6
Waxy, smooth, and shiny papules, nodules, and plaques are the most common skin finding in primary amyloidosis. They are typically skin- or amber-colored and may have a hemorrhagic appearance. Flexural areas are common sites of predilection and are usually asymptomatic.6 Lesions may also be found on the central face, lips, tongue, and buccal mucosa.6 Furthermore, the coalescing facial plaques may give a leonine appearance.4 Other less-common skin lesions that have been reported in association with systemic amyloidosis are bullae, alopecia, and cutis laxa.4
Nodular localized cutaneous amyloidosis may present with firm, subcutaneous nodules ranging from a few millimeters to several centimeters in size. These nodules are indistinguishable from those that can be found in primary systemic and myeloma-associated amyloidosis and are commonly asymptomatic.4,6 They are brown, pink, and waxy and often have overlying telangiectasias.4 Sites of predilection include the limbs, face, trunk, or genitalia, and it is more common to find multiple nodules rather than a single one.
Macular amyloidosis presents as brownish patches, most commonly on the inter-scapular region of the upper back. Other reported sites of involvement include the trunk, extremities, or buttocks. Small papules may coalesce to form a symmetrical rippled pattern.4 Unusual forms of macular amyloidosis include a poikiloderma-like form and a nevoid-like diffusely hyperpigmented form.6 These patches are pruritic and persist over many years.4
Lichen amyloidosis manifests as small, red-brown hyperkeratotic pruritic papules distributed over the shins and possibly spreading to the dorsa of the feet, distal arms, and the thighs.4
The coexistence of lichen amyloidosis and macular amyloidosis in an affected patient is termed “biphasic amyloidosis,” a phenomenon that has led some to regard the two presentations as variants of a single pathologic process.6 A biphasic whorled form of cutaneous amyloidosis following Blaschko’s lines has been reported.7
Histopathology
Amyloid is an eosinophilic hyaline substance with a fibrillar substructure. Approximately 16 distinct fibril proteins have been described, six of which have relevance to skin disease (Table 3).8
While amyloid ultrastructure differs among the various types described, the proteins share many histochemical properties such as characteristic staining. Amyloid stains pink with hematoxylin and eosin and metachromatically with crystal violet.8 Congo red selectively stains amyloid; in some cases of primary systemic amyloidosis and early localized amyloidosis, there has been low affinity for the substance, leading to false-negative reports.8 Crystal violet has been found to be more reliable than Congo red in sun-damaged skin, the latter having been also reported to lead to false-positives. Thioflavine T- stained amyloid appears bright yellow-green upon fluorescence,8 but false-positives may occur with stromal hyaline deposits, collagen fibers, and colloid bodies in lichen planus.9 Positive staining with antibodies to cytokeratin distinguishes amyloid keratin protein (AK) — found in macular and lichen amyloidosis — from amyloid light chain protein (AL) — found in nodular cutaneous amyloidosis and primary amyloidosis.10
Monoclonal anti-sera can be used to demonstrate a non-fibrillar protein derived from a normally circulating human glycoprotein called amyloid P component, which is found in all cutaneous amyloid deposits.8 Commercially available anti-sera exist for each of the six types of cutaneously relevant amyloid mentioned above.8 These specific anti-sera are suggested to be more reliable than the above-mentioned special stains.9
Primary Systemic and Myeloma-Associated
Amyloid deposits in the papillary dermis produce the papular lesions seen in primary systemic and myeloma-associated amyloidosis.8 A more diffuse amyloid infiltration of the dermis, sometimes extending into the subcutaneous tissue, produces a nodular plaque.8 In the subcutaneous tissue, amyloid deposits may be seen encircling individual fat cells forming “amyloid rings.”8 Histopathologic examination of hemorrhagic lesions reveals involvement of dermal blood vessels, while examining areas of alopecia reveals infiltration of the pilosebaceous units. Attenuation of the epidermis may be seen overlying large deposits.8 Pigmented cells are usually absent, and inflammatory cells are scarce.8
PLCA
In one study of 794 Chinese patients with PLCA, the most common histopathological findings in the epidermis were hyperkeratosis, irregular acanthosis with thinning of rete ridges, and expansion of dermal papillae by amyloid deposition.11 In both macular and lichen amyloidosis, globular amyloid deposits, which often include pigmented cells, can be visualized in the papillary dermis.8 The deposits may be separated from the overlying epidermis by a thin layer of dense collagen, or may be found in contact with or interspersed between the basal cells.8 The epidermis contains occasional apoptotic bodies and basal vacuolar change also occurs.8 In lichen amyloidosis, epidermal hyperkeratosis and acanthosis — similar to that seen in lichen simplex chronicus — is very prominent.8
In our patient, histopathologic exam of skin biopsied from the right shin revealed epidermal hyperkeratosis and acanthosis, and the papillary dermis demonstrated amyloid deposition with positive Congo red and crystal violet stains.
Differential Diagnosis
The differential diagnosis for macular amyloidosis includes notalgia paresthetica, post-inflammatory hyperpigmentation, pityriasis versicolor, atrophic lichen planus, erythema dyschromicum perstans, phototoxic contact dermatitis, and drug-induced pigmentation.1
The two primary differential diagnoses for lichen amyloidosis are lichen simplex chronicus and hypertrophic lichen planus. Other considerations are prurigo simplex, prurigo nodularis, papular mucinosis, pemphigoid nodularis, epidermolysis bullosa pruriginosa, and underlying scleroderma.1
Differential diagnoses to consider with nodular amyloidosis include cutaneous sarcoidosis, lupus vulgaris, and granuloma annulare.1
When histological confirmation of a non-AK amyloid is obtained, the differential diagnosis includes primary systemic amyloidosis, myeloma-associated amyloidosis, secondary amyloidosis, senile amyloidosis and various forms of hereditary amyloidosis.4
Pathogenesis
Primary Systemic and Myeloma Associated
Amyloid deposits found in primary systemic amyloidosis and myeloma-associated amyloidosis are designated AL and are composed of abnormal immunoglobulin light chains, fragments of light chains, or both.6 The light chains are derived from circulating immunoglobulin originating from an occult plasma cell dyscrasia (primary systemic) or an overt dyscrasia as in myeloma.4
PLCA
PLCA is divided into three types:
1. nodular
2. macular
3. lichen.
Most cases of PLCA are sporadic, but familial cases have been reported, suggesting a genetic basis may exist.11
Nodular amyloidosis is considered to be a cutaneous plasmacytoma, which locally produces immunoglobulin that forms amyloid deposits indistinguishable from the AL type found in primary and myeloma-associated amyloidosis.4 On occasion, nodular amyloidosis may contain AK protein likewise, so appropriate stains are necessary for diagnosis and prognosis.
The fibrillar component of amyloid deposits found in macular and lichen amyloidosis is designated AK, but it has yet to be definitively characterized.8 Two hypotheses for the origin of AK include first the “fibrillar body theory.” Proposed by Hashimoto, it suggests that degenerated keratin is the substrate. The less-popular “secretion theory” of Yamagihara et al proposed that disrupted basal cells secrete the amyloid substance, which is assembled at the dermo-epidermal junction.4,8,12,13
Trauma — including chronic rubbing, brushing, and scratching — has been proposed as a contributing factor to AK deposition.8,14 Scratching as a stimulating factor for lichen amyloidosis may possibly explain its uncommon occurrence with HIV-associated papular pruritus and refractory atopic dermatitis.8 Lichen amyloidosis has been associated with chronic Epstein-Barr virus infection and multiple endocrine neoplasia (MEN) IIa (Sipple syndrome.)4,8 Nodular amyloidosis has been reported in association with Sjogren’s syndrome.4
Clinically insignificant, microscopic amyloid deposits (secondary amyloidosis) occur as a secondary phenomenon in association with various skin conditions, including basal cell carcinoma, Bowen’s disease, squamous cell carcinoma, seborrheic keratosis, and disseminated superficial actinic porokeratosis. Localized amyloid deposits are also a common finding in patients with Alzheimer’s disease.4
Management
The prognosis for systemic amyloidosis is poor, especially for primary and myeloma-associated types. Cardiac and renal failures are the major causes of death, and patients require a multidisciplinary approach. Difficulty in assessing any response to therapy exists due to a lack of reliable methods to quantify amyloid in an individual patient. There is poor correlation between organ amyloid load and clinical improvement.4,15
Patients with a clinical picture of localized nodular amyloidosis should also be approached in a multidisciplinary manner. They require initial evaluation with biopsies, immunoglobulin studies, and radiographic imaging to rule out occult paraproteinemia and systemic disease.4 A thorough medical history and physical examination should be conducted to look for signs of congestive heart failure, hepatomegaly, peripheral neuropathy, and autonomic dysfunction. Echocardiogram, nerve conduction studies, and abdominal ultrasound, may be warranted.2,16
Fewer than 15% of patients with true localized nodular lesions progress to systemic disease (especially if the amyloid is AL type). Regular follow-up of these patients is recommended.17 Nodular amyloid lesions have been treated with surgical excision as well as with the carbon dioxide laser and pulsed dye laser with good outcomes, although recurrences can be seen.18,19,20
The patients with macular and lichen amyloidosis are mainly managed by dermatologists. Positive outcomes in treating lichen and macular amyloidosis have been reported using PUVA, UVB, topical dimethyl sulfoxide (DMSO), dermabrasion, systemic retinoids (etretinate and acitretin), potent topical steroids under occlusion, intra-lesional steroids, pulsed dye laser, and Nd:YAG laser.14, 21,22, 23, 24, 25, 26,27
With the exception of the dermabrasion study, which followed seven patients over 5 years, the reports are anecdotal. Etretinate and DMSO have a minimal role in alleviating pruritus associated with lichen amyloidosis.28,29,30 Oral anti-histamines are generally ineffective at reducing pruritus.4
Our patient was treated with a combination of intralesional corticosteroids, potent topical corticosteroids and systemic antihistamines with moderate improvement of pruritus, which was her main presenting complaint.
Patient Presentation
A 56-year-old Hispanic woman presented with numerous hyperkeratotic, hyperpigmented, small, firm papules that were coalescing into symmetric plaques on the bilateral distal arms and legs. She also complained of multiple brown reticulated macules distributed symmetrically over her upper back. The patient indicated that her lesions were very pruritic and had slowly appeared and spread over a period of 1 year. Her past medical, family, and social histories were non-contributory. A skin biopsy of the leg papule was done to confirm diagnosis.
Diagnosis:Biphasic Amyloidosis
In 1838, Schleiden first introduced the term “amyloid” to describe plant starch.1 In 1854, Virchow adopted the term to describe tissue deposits that stained similarly to cellulose stained with iodine.2 These deposits were described as being waxy on gross examination and amorphous and hyaline on light microscopy. Gutmann first described a patient with clinical features of lichen amyloidosis in 1928.2 Freudenthal instituted the term “lichen amyloidosis” in 1930.1,2 Macular amyloidosis was first described by Palitz and Peck in 1952.3
“Amyloidosis” refers to a group of disorders that have in common the abnormal extracellular deposition of a family of proteins. These proteins are biochemically unrelated but share characteristic staining properties (e.g., apple-green birefringence on examination with polarized light after Congo red staining).4 Amyloidosis is typically categorized into either general (systemic) or organ-limited (localized). Within each of these categories, there are several subtypes that vary in the actual protein involved, as well as in specific anatomical sites of deposition (Table 1, below).
For the purpose of this discussion, we will focus on forms of amyloidosis that commonly have clinically evident cutaneous findings, which include primary systemic, myeloma-associated, and primary localized cutaneous amyloidosis (PLCA).
Epidemiology
The epidemiology of systemic amyloidosis is difficult to define because it is often misdiagnosed or undiagnosed. The incidence is estimated to be between 1,275 to 3,200 new cases per year.5 The disease occurs most commonly in elderly men with a mean age of onset of 65.4,6
Overall, lichen and macular amyloidosis occur more frequently in individuals with Fitzpatrick skin types III and IV.1 Lichen amyloidosis is more common in people of Chinese descent. Macular amyloidosis is common in Central and South American countries — especially those close to the equator — as well as Middle Easterners and non-Chinese Asians. Women are two times as likely as men to be affected with nodular localized amyloidosis, and are most often between 60 and 70 years of age.4 Nodular localized amyloidosis is the least common of the PLCA subtypes.4
Clinical Features
Mucocutaneous lesions in patients with systemic and myeloma-associated amyloidosis are seen in 40% or less of cases and occur in various forms.6 (See Table 2, above.) The most common lesion is pinched purpura, which occurs in 15% to 17% of patients and results from amyloid infiltration of blood vessel walls.4 Purpura is common in flexural areas and may appear in response to trauma or strain as during a Valsalva maneuver.4,6
Waxy, smooth, and shiny papules, nodules, and plaques are the most common skin finding in primary amyloidosis. They are typically skin- or amber-colored and may have a hemorrhagic appearance. Flexural areas are common sites of predilection and are usually asymptomatic.6 Lesions may also be found on the central face, lips, tongue, and buccal mucosa.6 Furthermore, the coalescing facial plaques may give a leonine appearance.4 Other less-common skin lesions that have been reported in association with systemic amyloidosis are bullae, alopecia, and cutis laxa.4
Nodular localized cutaneous amyloidosis may present with firm, subcutaneous nodules ranging from a few millimeters to several centimeters in size. These nodules are indistinguishable from those that can be found in primary systemic and myeloma-associated amyloidosis and are commonly asymptomatic.4,6 They are brown, pink, and waxy and often have overlying telangiectasias.4 Sites of predilection include the limbs, face, trunk, or genitalia, and it is more common to find multiple nodules rather than a single one.
Macular amyloidosis presents as brownish patches, most commonly on the inter-scapular region of the upper back. Other reported sites of involvement include the trunk, extremities, or buttocks. Small papules may coalesce to form a symmetrical rippled pattern.4 Unusual forms of macular amyloidosis include a poikiloderma-like form and a nevoid-like diffusely hyperpigmented form.6 These patches are pruritic and persist over many years.4
Lichen amyloidosis manifests as small, red-brown hyperkeratotic pruritic papules distributed over the shins and possibly spreading to the dorsa of the feet, distal arms, and the thighs.4
The coexistence of lichen amyloidosis and macular amyloidosis in an affected patient is termed “biphasic amyloidosis,” a phenomenon that has led some to regard the two presentations as variants of a single pathologic process.6 A biphasic whorled form of cutaneous amyloidosis following Blaschko’s lines has been reported.7
Histopathology
Amyloid is an eosinophilic hyaline substance with a fibrillar substructure. Approximately 16 distinct fibril proteins have been described, six of which have relevance to skin disease (Table 3).8
While amyloid ultrastructure differs among the various types described, the proteins share many histochemical properties such as characteristic staining. Amyloid stains pink with hematoxylin and eosin and metachromatically with crystal violet.8 Congo red selectively stains amyloid; in some cases of primary systemic amyloidosis and early localized amyloidosis, there has been low affinity for the substance, leading to false-negative reports.8 Crystal violet has been found to be more reliable than Congo red in sun-damaged skin, the latter having been also reported to lead to false-positives. Thioflavine T- stained amyloid appears bright yellow-green upon fluorescence,8 but false-positives may occur with stromal hyaline deposits, collagen fibers, and colloid bodies in lichen planus.9 Positive staining with antibodies to cytokeratin distinguishes amyloid keratin protein (AK) — found in macular and lichen amyloidosis — from amyloid light chain protein (AL) — found in nodular cutaneous amyloidosis and primary amyloidosis.10
Monoclonal anti-sera can be used to demonstrate a non-fibrillar protein derived from a normally circulating human glycoprotein called amyloid P component, which is found in all cutaneous amyloid deposits.8 Commercially available anti-sera exist for each of the six types of cutaneously relevant amyloid mentioned above.8 These specific anti-sera are suggested to be more reliable than the above-mentioned special stains.9
Primary Systemic and Myeloma-Associated
Amyloid deposits in the papillary dermis produce the papular lesions seen in primary systemic and myeloma-associated amyloidosis.8 A more diffuse amyloid infiltration of the dermis, sometimes extending into the subcutaneous tissue, produces a nodular plaque.8 In the subcutaneous tissue, amyloid deposits may be seen encircling individual fat cells forming “amyloid rings.”8 Histopathologic examination of hemorrhagic lesions reveals involvement of dermal blood vessels, while examining areas of alopecia reveals infiltration of the pilosebaceous units. Attenuation of the epidermis may be seen overlying large deposits.8 Pigmented cells are usually absent, and inflammatory cells are scarce.8
PLCA
In one study of 794 Chinese patients with PLCA, the most common histopathological findings in the epidermis were hyperkeratosis, irregular acanthosis with thinning of rete ridges, and expansion of dermal papillae by amyloid deposition.11 In both macular and lichen amyloidosis, globular amyloid deposits, which often include pigmented cells, can be visualized in the papillary dermis.8 The deposits may be separated from the overlying epidermis by a thin layer of dense collagen, or may be found in contact with or interspersed between the basal cells.8 The epidermis contains occasional apoptotic bodies and basal vacuolar change also occurs.8 In lichen amyloidosis, epidermal hyperkeratosis and acanthosis — similar to that seen in lichen simplex chronicus — is very prominent.8
In our patient, histopathologic exam of skin biopsied from the right shin revealed epidermal hyperkeratosis and acanthosis, and the papillary dermis demonstrated amyloid deposition with positive Congo red and crystal violet stains.
Differential Diagnosis
The differential diagnosis for macular amyloidosis includes notalgia paresthetica, post-inflammatory hyperpigmentation, pityriasis versicolor, atrophic lichen planus, erythema dyschromicum perstans, phototoxic contact dermatitis, and drug-induced pigmentation.1
The two primary differential diagnoses for lichen amyloidosis are lichen simplex chronicus and hypertrophic lichen planus. Other considerations are prurigo simplex, prurigo nodularis, papular mucinosis, pemphigoid nodularis, epidermolysis bullosa pruriginosa, and underlying scleroderma.1
Differential diagnoses to consider with nodular amyloidosis include cutaneous sarcoidosis, lupus vulgaris, and granuloma annulare.1
When histological confirmation of a non-AK amyloid is obtained, the differential diagnosis includes primary systemic amyloidosis, myeloma-associated amyloidosis, secondary amyloidosis, senile amyloidosis and various forms of hereditary amyloidosis.4
Pathogenesis
Primary Systemic and Myeloma Associated
Amyloid deposits found in primary systemic amyloidosis and myeloma-associated amyloidosis are designated AL and are composed of abnormal immunoglobulin light chains, fragments of light chains, or both.6 The light chains are derived from circulating immunoglobulin originating from an occult plasma cell dyscrasia (primary systemic) or an overt dyscrasia as in myeloma.4
PLCA
PLCA is divided into three types:
1. nodular
2. macular
3. lichen.
Most cases of PLCA are sporadic, but familial cases have been reported, suggesting a genetic basis may exist.11
Nodular amyloidosis is considered to be a cutaneous plasmacytoma, which locally produces immunoglobulin that forms amyloid deposits indistinguishable from the AL type found in primary and myeloma-associated amyloidosis.4 On occasion, nodular amyloidosis may contain AK protein likewise, so appropriate stains are necessary for diagnosis and prognosis.
The fibrillar component of amyloid deposits found in macular and lichen amyloidosis is designated AK, but it has yet to be definitively characterized.8 Two hypotheses for the origin of AK include first the “fibrillar body theory.” Proposed by Hashimoto, it suggests that degenerated keratin is the substrate. The less-popular “secretion theory” of Yamagihara et al proposed that disrupted basal cells secrete the amyloid substance, which is assembled at the dermo-epidermal junction.4,8,12,13
Trauma — including chronic rubbing, brushing, and scratching — has been proposed as a contributing factor to AK deposition.8,14 Scratching as a stimulating factor for lichen amyloidosis may possibly explain its uncommon occurrence with HIV-associated papular pruritus and refractory atopic dermatitis.8 Lichen amyloidosis has been associated with chronic Epstein-Barr virus infection and multiple endocrine neoplasia (MEN) IIa (Sipple syndrome.)4,8 Nodular amyloidosis has been reported in association with Sjogren’s syndrome.4
Clinically insignificant, microscopic amyloid deposits (secondary amyloidosis) occur as a secondary phenomenon in association with various skin conditions, including basal cell carcinoma, Bowen’s disease, squamous cell carcinoma, seborrheic keratosis, and disseminated superficial actinic porokeratosis. Localized amyloid deposits are also a common finding in patients with Alzheimer’s disease.4
Management
The prognosis for systemic amyloidosis is poor, especially for primary and myeloma-associated types. Cardiac and renal failures are the major causes of death, and patients require a multidisciplinary approach. Difficulty in assessing any response to therapy exists due to a lack of reliable methods to quantify amyloid in an individual patient. There is poor correlation between organ amyloid load and clinical improvement.4,15
Patients with a clinical picture of localized nodular amyloidosis should also be approached in a multidisciplinary manner. They require initial evaluation with biopsies, immunoglobulin studies, and radiographic imaging to rule out occult paraproteinemia and systemic disease.4 A thorough medical history and physical examination should be conducted to look for signs of congestive heart failure, hepatomegaly, peripheral neuropathy, and autonomic dysfunction. Echocardiogram, nerve conduction studies, and abdominal ultrasound, may be warranted.2,16
Fewer than 15% of patients with true localized nodular lesions progress to systemic disease (especially if the amyloid is AL type). Regular follow-up of these patients is recommended.17 Nodular amyloid lesions have been treated with surgical excision as well as with the carbon dioxide laser and pulsed dye laser with good outcomes, although recurrences can be seen.18,19,20
The patients with macular and lichen amyloidosis are mainly managed by dermatologists. Positive outcomes in treating lichen and macular amyloidosis have been reported using PUVA, UVB, topical dimethyl sulfoxide (DMSO), dermabrasion, systemic retinoids (etretinate and acitretin), potent topical steroids under occlusion, intra-lesional steroids, pulsed dye laser, and Nd:YAG laser.14, 21,22, 23, 24, 25, 26,27
With the exception of the dermabrasion study, which followed seven patients over 5 years, the reports are anecdotal. Etretinate and DMSO have a minimal role in alleviating pruritus associated with lichen amyloidosis.28,29,30 Oral anti-histamines are generally ineffective at reducing pruritus.4
Our patient was treated with a combination of intralesional corticosteroids, potent topical corticosteroids and systemic antihistamines with moderate improvement of pruritus, which was her main presenting complaint.
Patient Presentation
A 56-year-old Hispanic woman presented with numerous hyperkeratotic, hyperpigmented, small, firm papules that were coalescing into symmetric plaques on the bilateral distal arms and legs. She also complained of multiple brown reticulated macules distributed symmetrically over her upper back. The patient indicated that her lesions were very pruritic and had slowly appeared and spread over a period of 1 year. Her past medical, family, and social histories were non-contributory. A skin biopsy of the leg papule was done to confirm diagnosis.
Diagnosis:Biphasic Amyloidosis
In 1838, Schleiden first introduced the term “amyloid” to describe plant starch.1 In 1854, Virchow adopted the term to describe tissue deposits that stained similarly to cellulose stained with iodine.2 These deposits were described as being waxy on gross examination and amorphous and hyaline on light microscopy. Gutmann first described a patient with clinical features of lichen amyloidosis in 1928.2 Freudenthal instituted the term “lichen amyloidosis” in 1930.1,2 Macular amyloidosis was first described by Palitz and Peck in 1952.3
“Amyloidosis” refers to a group of disorders that have in common the abnormal extracellular deposition of a family of proteins. These proteins are biochemically unrelated but share characteristic staining properties (e.g., apple-green birefringence on examination with polarized light after Congo red staining).4 Amyloidosis is typically categorized into either general (systemic) or organ-limited (localized). Within each of these categories, there are several subtypes that vary in the actual protein involved, as well as in specific anatomical sites of deposition (Table 1, below).
For the purpose of this discussion, we will focus on forms of amyloidosis that commonly have clinically evident cutaneous findings, which include primary systemic, myeloma-associated, and primary localized cutaneous amyloidosis (PLCA).
Epidemiology
The epidemiology of systemic amyloidosis is difficult to define because it is often misdiagnosed or undiagnosed. The incidence is estimated to be between 1,275 to 3,200 new cases per year.5 The disease occurs most commonly in elderly men with a mean age of onset of 65.4,6
Overall, lichen and macular amyloidosis occur more frequently in individuals with Fitzpatrick skin types III and IV.1 Lichen amyloidosis is more common in people of Chinese descent. Macular amyloidosis is common in Central and South American countries — especially those close to the equator — as well as Middle Easterners and non-Chinese Asians. Women are two times as likely as men to be affected with nodular localized amyloidosis, and are most often between 60 and 70 years of age.4 Nodular localized amyloidosis is the least common of the PLCA subtypes.4
Clinical Features
Mucocutaneous lesions in patients with systemic and myeloma-associated amyloidosis are seen in 40% or less of cases and occur in various forms.6 (See Table 2, above.) The most common lesion is pinched purpura, which occurs in 15% to 17% of patients and results from amyloid infiltration of blood vessel walls.4 Purpura is common in flexural areas and may appear in response to trauma or strain as during a Valsalva maneuver.4,6
Waxy, smooth, and shiny papules, nodules, and plaques are the most common skin finding in primary amyloidosis. They are typically skin- or amber-colored and may have a hemorrhagic appearance. Flexural areas are common sites of predilection and are usually asymptomatic.6 Lesions may also be found on the central face, lips, tongue, and buccal mucosa.6 Furthermore, the coalescing facial plaques may give a leonine appearance.4 Other less-common skin lesions that have been reported in association with systemic amyloidosis are bullae, alopecia, and cutis laxa.4
Nodular localized cutaneous amyloidosis may present with firm, subcutaneous nodules ranging from a few millimeters to several centimeters in size. These nodules are indistinguishable from those that can be found in primary systemic and myeloma-associated amyloidosis and are commonly asymptomatic.4,6 They are brown, pink, and waxy and often have overlying telangiectasias.4 Sites of predilection include the limbs, face, trunk, or genitalia, and it is more common to find multiple nodules rather than a single one.
Macular amyloidosis presents as brownish patches, most commonly on the inter-scapular region of the upper back. Other reported sites of involvement include the trunk, extremities, or buttocks. Small papules may coalesce to form a symmetrical rippled pattern.4 Unusual forms of macular amyloidosis include a poikiloderma-like form and a nevoid-like diffusely hyperpigmented form.6 These patches are pruritic and persist over many years.4
Lichen amyloidosis manifests as small, red-brown hyperkeratotic pruritic papules distributed over the shins and possibly spreading to the dorsa of the feet, distal arms, and the thighs.4
The coexistence of lichen amyloidosis and macular amyloidosis in an affected patient is termed “biphasic amyloidosis,” a phenomenon that has led some to regard the two presentations as variants of a single pathologic process.6 A biphasic whorled form of cutaneous amyloidosis following Blaschko’s lines has been reported.7
Histopathology
Amyloid is an eosinophilic hyaline substance with a fibrillar substructure. Approximately 16 distinct fibril proteins have been described, six of which have relevance to skin disease (Table 3).8
While amyloid ultrastructure differs among the various types described, the proteins share many histochemical properties such as characteristic staining. Amyloid stains pink with hematoxylin and eosin and metachromatically with crystal violet.8 Congo red selectively stains amyloid; in some cases of primary systemic amyloidosis and early localized amyloidosis, there has been low affinity for the substance, leading to false-negative reports.8 Crystal violet has been found to be more reliable than Congo red in sun-damaged skin, the latter having been also reported to lead to false-positives. Thioflavine T- stained amyloid appears bright yellow-green upon fluorescence,8 but false-positives may occur with stromal hyaline deposits, collagen fibers, and colloid bodies in lichen planus.9 Positive staining with antibodies to cytokeratin distinguishes amyloid keratin protein (AK) — found in macular and lichen amyloidosis — from amyloid light chain protein (AL) — found in nodular cutaneous amyloidosis and primary amyloidosis.10
Monoclonal anti-sera can be used to demonstrate a non-fibrillar protein derived from a normally circulating human glycoprotein called amyloid P component, which is found in all cutaneous amyloid deposits.8 Commercially available anti-sera exist for each of the six types of cutaneously relevant amyloid mentioned above.8 These specific anti-sera are suggested to be more reliable than the above-mentioned special stains.9
Primary Systemic and Myeloma-Associated
Amyloid deposits in the papillary dermis produce the papular lesions seen in primary systemic and myeloma-associated amyloidosis.8 A more diffuse amyloid infiltration of the dermis, sometimes extending into the subcutaneous tissue, produces a nodular plaque.8 In the subcutaneous tissue, amyloid deposits may be seen encircling individual fat cells forming “amyloid rings.”8 Histopathologic examination of hemorrhagic lesions reveals involvement of dermal blood vessels, while examining areas of alopecia reveals infiltration of the pilosebaceous units. Attenuation of the epidermis may be seen overlying large deposits.8 Pigmented cells are usually absent, and inflammatory cells are scarce.8
PLCA
In one study of 794 Chinese patients with PLCA, the most common histopathological findings in the epidermis were hyperkeratosis, irregular acanthosis with thinning of rete ridges, and expansion of dermal papillae by amyloid deposition.11 In both macular and lichen amyloidosis, globular amyloid deposits, which often include pigmented cells, can be visualized in the papillary dermis.8 The deposits may be separated from the overlying epidermis by a thin layer of dense collagen, or may be found in contact with or interspersed between the basal cells.8 The epidermis contains occasional apoptotic bodies and basal vacuolar change also occurs.8 In lichen amyloidosis, epidermal hyperkeratosis and acanthosis — similar to that seen in lichen simplex chronicus — is very prominent.8
In our patient, histopathologic exam of skin biopsied from the right shin revealed epidermal hyperkeratosis and acanthosis, and the papillary dermis demonstrated amyloid deposition with positive Congo red and crystal violet stains.
Differential Diagnosis
The differential diagnosis for macular amyloidosis includes notalgia paresthetica, post-inflammatory hyperpigmentation, pityriasis versicolor, atrophic lichen planus, erythema dyschromicum perstans, phototoxic contact dermatitis, and drug-induced pigmentation.1
The two primary differential diagnoses for lichen amyloidosis are lichen simplex chronicus and hypertrophic lichen planus. Other considerations are prurigo simplex, prurigo nodularis, papular mucinosis, pemphigoid nodularis, epidermolysis bullosa pruriginosa, and underlying scleroderma.1
Differential diagnoses to consider with nodular amyloidosis include cutaneous sarcoidosis, lupus vulgaris, and granuloma annulare.1
When histological confirmation of a non-AK amyloid is obtained, the differential diagnosis includes primary systemic amyloidosis, myeloma-associated amyloidosis, secondary amyloidosis, senile amyloidosis and various forms of hereditary amyloidosis.4
Pathogenesis
Primary Systemic and Myeloma Associated
Amyloid deposits found in primary systemic amyloidosis and myeloma-associated amyloidosis are designated AL and are composed of abnormal immunoglobulin light chains, fragments of light chains, or both.6 The light chains are derived from circulating immunoglobulin originating from an occult plasma cell dyscrasia (primary systemic) or an overt dyscrasia as in myeloma.4
PLCA
PLCA is divided into three types:
1. nodular
2. macular
3. lichen.
Most cases of PLCA are sporadic, but familial cases have been reported, suggesting a genetic basis may exist.11
Nodular amyloidosis is considered to be a cutaneous plasmacytoma, which locally produces immunoglobulin that forms amyloid deposits indistinguishable from the AL type found in primary and myeloma-associated amyloidosis.4 On occasion, nodular amyloidosis may contain AK protein likewise, so appropriate stains are necessary for diagnosis and prognosis.
The fibrillar component of amyloid deposits found in macular and lichen amyloidosis is designated AK, but it has yet to be definitively characterized.8 Two hypotheses for the origin of AK include first the “fibrillar body theory.” Proposed by Hashimoto, it suggests that degenerated keratin is the substrate. The less-popular “secretion theory” of Yamagihara et al proposed that disrupted basal cells secrete the amyloid substance, which is assembled at the dermo-epidermal junction.4,8,12,13
Trauma — including chronic rubbing, brushing, and scratching — has been proposed as a contributing factor to AK deposition.8,14 Scratching as a stimulating factor for lichen amyloidosis may possibly explain its uncommon occurrence with HIV-associated papular pruritus and refractory atopic dermatitis.8 Lichen amyloidosis has been associated with chronic Epstein-Barr virus infection and multiple endocrine neoplasia (MEN) IIa (Sipple syndrome.)4,8 Nodular amyloidosis has been reported in association with Sjogren’s syndrome.4
Clinically insignificant, microscopic amyloid deposits (secondary amyloidosis) occur as a secondary phenomenon in association with various skin conditions, including basal cell carcinoma, Bowen’s disease, squamous cell carcinoma, seborrheic keratosis, and disseminated superficial actinic porokeratosis. Localized amyloid deposits are also a common finding in patients with Alzheimer’s disease.4
Management
The prognosis for systemic amyloidosis is poor, especially for primary and myeloma-associated types. Cardiac and renal failures are the major causes of death, and patients require a multidisciplinary approach. Difficulty in assessing any response to therapy exists due to a lack of reliable methods to quantify amyloid in an individual patient. There is poor correlation between organ amyloid load and clinical improvement.4,15
Patients with a clinical picture of localized nodular amyloidosis should also be approached in a multidisciplinary manner. They require initial evaluation with biopsies, immunoglobulin studies, and radiographic imaging to rule out occult paraproteinemia and systemic disease.4 A thorough medical history and physical examination should be conducted to look for signs of congestive heart failure, hepatomegaly, peripheral neuropathy, and autonomic dysfunction. Echocardiogram, nerve conduction studies, and abdominal ultrasound, may be warranted.2,16
Fewer than 15% of patients with true localized nodular lesions progress to systemic disease (especially if the amyloid is AL type). Regular follow-up of these patients is recommended.17 Nodular amyloid lesions have been treated with surgical excision as well as with the carbon dioxide laser and pulsed dye laser with good outcomes, although recurrences can be seen.18,19,20
The patients with macular and lichen amyloidosis are mainly managed by dermatologists. Positive outcomes in treating lichen and macular amyloidosis have been reported using PUVA, UVB, topical dimethyl sulfoxide (DMSO), dermabrasion, systemic retinoids (etretinate and acitretin), potent topical steroids under occlusion, intra-lesional steroids, pulsed dye laser, and Nd:YAG laser.14, 21,22, 23, 24, 25, 26,27
With the exception of the dermabrasion study, which followed seven patients over 5 years, the reports are anecdotal. Etretinate and DMSO have a minimal role in alleviating pruritus associated with lichen amyloidosis.28,29,30 Oral anti-histamines are generally ineffective at reducing pruritus.4
Our patient was treated with a combination of intralesional corticosteroids, potent topical corticosteroids and systemic antihistamines with moderate improvement of pruritus, which was her main presenting complaint.
