Home > Skin nontumor > Amyloidosis

Skin nontumor

Dermal collagen and elastic tissue alterations and metabolic disorders

Amyloidosis


Ani Toklu, M.D.
Carina Dehner, M.D., Ph.D.

Last author update: 27 February 2025
Last staff update: 27 February 2025

Copyright: 2002-2025, PathologyOutlines.com, Inc.

PubMed Search: Amyloidosis

Ani Toklu, M.D.
Carina Dehner, M.D., Ph.D.
Page views in 2024: 12,159
Page views in 2025 to date: 9,156
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Immunofluorescence description | Immunofluorescence images | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Practice question #1 | Practice answer #1 | Practice question #2 | Practice answer #2
Cite this page: Toklu A, Dehner C. Amyloidosis. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/skinnontumoramyloidosis.html. Accessed August 27th, 2025.
Definition / general
  • Amyloidosis is characterized by extracellular deposition of amorphous material that has fibrillar morphology and is composed of insoluble misfolded autologous proteins
  • Amyloid deposition can involve a solitary site or multiple organs
Essential features
  • Characterized by extracellular deposition of misfolded autologous proteins arranged in a fibrillary form
  • Amyloid deposits appear as amorphous eosinophilic material on H&E and show characteristic staining with Congo red yielding apple green birefringence under polarized light
  • Amyloidoses with skin involvement are clinically classified into 2 main groups: systemic and localized; further subclassification is mainly based on the etiology, type of amyloid protein involved and pattern of deposition
  • Systemic amyloidosis needs to be ruled out by clinical history and laboratory tests for diagnosis of primary localized cutaneous amyloidosis
ICD coding
  • ICD-O: 9769/1 - immunoglobulin related amyloidosis (AL amyloidosis)
    • Systemic AL amyloidosis
    • Localized AL amyloidosis
    • Heavy chain AL amyloidosis
  • ICD-11: 5D00.0 - AL amyloidosis
Epidemiology
  • Primary and myeloma associated systemic amyloidosis
  • Secondary systemic amyloidosis
  • Hereditary / familial amyloidosis
    • Mainly associated with multisystemic diseases and autoinflammatory conditions (familial Mediterranean fever, Muckle-Wells syndrome, familial cold autoinflammatory syndrome, familial autoimmune polyneuropathy) (Best Pract Res Clin Rheumatol 2003;17:929)
  • Amyloid elastosis, very rare
  • Macular amyloidosis, lichen amyloidosis and biphasic amyloidosis
    • Adult population is affected, macular amyloidosis in a slightly younger population compared to lichen amyloidosis
    • Macular amyloidosis affects female patients more than male patients (J Dermatol 1999;26:305)
    • Lichen amyloidosis and macular amyloidosis are the most frequent types of primary localized cutaneous amyloidosis
    • More common in Southeast Asia, South America and Middle East (skin phototype III - V); rare in Europe and North America (Clin Dermatol 1990;8:20, Australas J Dermatol 2023;64:e121)
  • Nodular amyloidosis (NA)
    • Rare
    • Adult population, sixth decade is most common
    • No clear gender predilection
  • Familial primary cutaneous amyloidosis
  • Secondary localized cutaneous amyloidosis
    • Associated with many cutaneous neoplasms such as squamous cell carcinoma in situ, melanocytic nevi, basal cell carcinoma
  • Reference: Calonje: McKee’s Pathology of the Skin, 5th Edition, 2019
Sites
  • Primary and myeloma associated systemic amyloidosis → head and neck, face, periorbital area, hands, flexural regions and rarely genitalia (Clin Cosmet Investig Dermatol 2023;16:987)
  • Hemodialysis associated amyloidosis → mostly on buttocks (Plast Reconstr Surg Glob Open 2023;11:e5039)
  • Lichen amyloidosis → predilection for extensor surfaces of the extremities, torso
  • Macular amyloidosis → trunk; predilection for interscapular area (often overlying skin affected by notalgia parasthetica) (J Clin Med 2023;12:7672)
  • Nodular amyloidosis → predilection for acral areas but can occur in any site including face, extremities, torso and genitalia (Arch Dermatol 2003;139:1157)
Pathophysiology
  • Primary and myeloma associated systemic amyloidosis
    • Amyloid derived from immunoglobulin light chains (AL), kappa or lambda
  • Secondary systemic amyloidosis
  • Hereditary / familial amyloidosis
  • Amyloid elastosis
  • Macular amyloidosis, lichen amyloidosis and biphasic amyloidosis
    • Keratin derived amyloid, amyloid K (AK) resulting from degenerated keratinocytes
  • Nodular amyloidosis
Etiology
  • Lichen amyloidosis and macular amyloidosis
    • Keratinocyte theory: repeated minor trauma, friction, prolonged exfoliation and scratching cause damage to the epidermis, keratinocyte degeneration and release of keratin protein that subsequently gets phagocytosed by macrophages to be disposed; however, the disposal mechanism is disrupted for unclear reasons and keratin derived amyloid is formed
    • Lichen amyloidosis is reported to be associated with autoimmune disorders, MEN2a syndrome (10% of lichen amyloidosis patients), chronic EBV infection and HIV infection have been documented (Thyroid 2002;12:1149, Acta Derm Venereol 1998;78:399, Ann Intern Med 1989;111:802)
  • Nodular amyloidosis
    • Has been associated with trauma and autoimmune disease but the exact mechanism is unknown (Int J Mol Sci 2023;24:7378)
    • Results from local and usually clonal plasma cells producing immunoglobulin light chains
  • Insulin injections may lead to secondary localized cutaneous amyloidosis (Indian J Endocrinol Metab 2015;19:174)
  • Long term hemodialysis, infections and inflammation may lead to secondary systemic amyloidosis (J Dermatol 2005;32:410)
Clinical features
  • Amyloidoses with skin involvement are clinically classified into 2 main groups: systemic and localized
    • Systemic amyloidoses: primary, myeloma associated, secondary, hereditary / familial, amyloid elastosis
    • Localized amyloidoses: lichen and macular amyloidosis, nodular, secondary, familial primary
  • Cutaneous involvement in primary systemic amyloidosis
  • Macular amyloidosis and lichen amyloidosis (Dermatology 2022;238:579)
    • Most common symptom: pruritus (lichen amyloidosis > macular amyloidosis)
    • Lichen amyloidosis → small and waxy hyperpigmented papules
    • Macular amyloidosis → hyperpigmented (or less commonly hypopigmented), ill defined macules coalescing into a patch or thin plaque
  • Nodular amyloidosis
    • Usually asymptomatic
    • Single or multiple pink-brown waxy nodules that can coalesce, sometimes with atrophic or ulcerated surface
    • Association with autoimmune conditions, primarily Sjögren syndrome (up to 25% of nodular amyloidosis patients) and CREST syndrome (J Dermatol 2005;32:120, Cutis 2008;82:55, J Clin Rheumatol 2011;17:368)
  • Other rare, localized forms
    • Poikilodermatous amyloidosis (includes amyloidosis cutis dyschromica) → reticulate hyperpigmentation with hypopigmented lesions all over the body (Dermatopathology (Basel) 2022;10:20)
    • Anosacral amyloidosis, keratinic variant of bullous amyloidosis, incontinentia pigmenti-like amyloidosis, linear macular amyloidosis, keratinic variant of nodular amyloidosis
  • Reference: Calonje: McKee’s Pathology of the Skin, 5th Edition, 2019
Diagnosis
  • Essentially based on clinical findings and histopathologic evidence of amyloid deposition in tissues
  • Requires sampling of the tissue, histopathological examination and confirmation by Congo red staining
  • Electron microscopy is another confirmatory method but less frequently used due to limited availability and high cost
  • Immunofluorescence
    • Direct immunofluorescence using thioflavin T can be used as a complimentary method to Congo red staining in primary localized cutaneous amyloidosis (J Clin Diagn Res 2017;11:WC01)
    • Examination of Congo red stained tissue by fluorescent microscopy can help to overcome the limitations of light microscopic examination (Hum Pathol 2014;45:1766)
  • Immunohistochemistry
    • Using antibodies against amyloidogenic proteins
    • Helps discriminate between the amyloid proteins
  • Lipid chromatography tandem mass spectrometry: definitive typing of amyloid (J Nippon Med Sch 2024;91:261)
  • Systemic amyloidosis can be diagnosed by
    • Blind abdominal fat pad aspiration biopsy (preferred method)
    • Blind abdominal skin punch biopsy (J Cutan Pathol 2021;48:1342)
      • Highly sensitive for diagnosis of AL (primary) amyloidosis (most common type of amyloid in systemic amyloidosis in developed countries)
      • Specific for diagnosing AA (secondary) amyloidosis
      • Sensitivity improved with adequate depth (> 10 mm) and diameter (> 6 mm) of biopsy (J Cutan Pathol 2021;48:1342)
Laboratory
  • Diagnosing localized cutaneous amyloidosis requires absence of systemic involvement (Int J Mol Sci 2023;24:9409)
  • Clinical work up to rule out primary systemic amyloidosis (Clin Cosmet Investig Dermatol 2023;16:987)
    • Complete blood count with differential
    • Comprehensive metabolic panel (including ALP and cardiac biomarkers) allows assessment for organ involvement by systemic amyloidosis, such as heart, kidney and liver
    • Urinalysis and urine protein electrophoresis (UPEP) 
      • Elevated urine free light chains, presence of clonal light chains on UPEP
      • Proteinuria by 24 hour urine protein test and elevated albumin to creatinine ratio are suggestive of kidney involvement of systemic amyloidosis (Clin Chem Lab Med 2022;60:386)
    • Serum protein electrophoresis (Clin Cosmet Investig Dermatol 2023;16:987)
    • Presence of clonal immunoglobulins (M spike) in systemic disease
    • Possibly bone marrow biopsy and aspirate - to rule out involvement by plasma cell neoplasm
Radiology description
Radiology images

Images hosted on other servers:
Nodular amyloidosis (MRI)   Nodular amyloidosis (MRI)

Nodular amyloidosis (MRI)

Nodular amyloidosis (PET)

Nodular amyloidosis (PET)

Prognostic factors
  • Lichen amyloidosis: complete clinical remission is not usually achieved (World J Clin Cases 2023;11:2549)
  • Nodular amyloidosis
    • High rate of local recurrence even after excision, affected by the extent of the lesion
    • Systemic work up and long term follow up are recommended due to increased risk of progression to systemic amyloidosis (in ~7 - 50% patients) (Br J Dermatol 2001;145:105)
Case reports
Treatment
  • Systemic amyloidosis
    • Treatment of the underlying condition (e.g., plasma cell neoplasm, inflammatory condition, infection)
  • Primary localized cutaneous amyloidosis
    • Treatment not required, usually for cosmetic purposes and relief of associated symptoms
    • Macular, lichen and biphasic amyloidosis
      • Treatment for pruritus and cosmetic purposes topical or intralesional corticosteroids, antihistamines, emollients, topical tacrolimus, phototherapy, laser therapy, retinoids, cyclosporine, cyclophosphamide and thalidomide (Am J Clin Dermatol 2017;18:629)
    • Nodular amyloidosis
      • Surgical excision, dermabrasion, laser therapy, electrodesiccation and curettage, intralesional steroid injection and cryosurgery (Ann Dermatol 2023;35:S30)
Clinical images

Images hosted on other servers:
Lichen amyloidosis - symmetric hyperpigmented macules

Lichen amyloidosis:
symmetric
hyperpigmented
macules

Nodular amyloidosis, pink-brown nodules

Nodular amyloidosis: pink-brown nodules

Nodular amyloidosis salmon colored waxy nodule

Nodular amyloidosis: salmon colored waxy nodule

Macular amyloidosis hyperpigmented macules

Macular amyloidosis: hyperpigmented macules

Macular amyloidosis scapular region

Macular amyloidosis: scapular region

Facial involvement

Microscopic (histologic) description
  • Amyloid appears as eosinophilic amorphous material in all types of amyloidosis
  • Systemic amyloidosis
    • Large masses of fissured amyloid deposits in the dermis and subcutis
    • Prominent perivascular amyloid deposition (Cureus 2023;15:e48346)
    • Deposits are also seen in arrector pili muscles, adnexal structures and subcutaneous fat
    • Flattened epidermis
  • Localized cutaneous amyloidosis
    • Macular amyloidosis
      • Limited quantity of small globular amyloid deposits in the papillary dermis with close proximity to the dermoepidermal junction (Australas J Dermatol 2001;42:176)
      • Associated pigment incontinence and melanophages
      • Mild chronic perivascular inflammatory infiltrate in the superficial dermis
      • Epidermal changes are minimal and may include
        • Hyperkeratosis
        • Acanthosis
        • Basal vacuolar change
        • Colloid bodies
    • Lichen amyloidosis
      • Similar to macular amyloidosis; however
        • Greater quantity of amyloid deposits in the papillary dermis with widened dermal papilla
        • Pronounced epidermal changes, including
          • Hyperkeratosis
          • Acanthosis
          • Hypergranulosis
          • Basal vacuolar change
          • Colloid bodies
      • Associated pigment incontinence and melanophages (Clin Exp Dermatol 2023;48:261, J Clin Med 2023;12:7672)
    • Nodular amyloidosis
      • Extensive deposition of amyloid in the dermis and subcutis (Ann Dermatol 2023;35:S30)
      • Prominent in deep perivascular and periadnexal areas
      • Associated plasma cell infiltrate
      • Rare foreign body giant cells and calcifications
  • References: Calonje: McKee’s Pathology of the Skin, 5th Edition, 2019, Elston: Dermatopathology, 3rd Edition, 2018, Patterson: Weedon’s Skin Pathology, 5th Edition, 2020
Microscopic (histologic) images

Contributed by Ani Toklu, M.D. and Carina A. Dehner, M.D. Ph.D.
Amyloid

Amyloid

Perieccrine amyloid deposition

Perieccrine amyloid deposition

AL amyloidosis in deep dermis

AL amyloidosis in deep dermis

Intradermal neoplasm intermixed with amyloid   Intradermal neoplasm intermixed with amyloid

Intradermal neoplasm intermixed with amyloid

Amyloid deposition underlying squamous cell carcinoma in situ

Amyloid deposition underlying SCC in situ


Macular amyloidosis

Macular amyloidosis

Pigment incontinence, melanophages, mild epidermal changes   Pigment incontinence, melanophages, mild epidermal changes

Pigment incontinence, melanophages, mild epidermal changes

Lichen amyloidosis   Lichen amyloidosis

Lichen amyloidosis

Perieccrine amyloid deposition

Perieccrine amyloid deposition


Congo red apple green birefringence   Congo red apple green birefringence

Congo red apple green birefringence

Cytokeratin AE1 / AE3

Cytokeratin AE1 / AE3

Congo red

Congo red

Lambda in situ hybridization

Lambda in situ hybridization

Virtual slides

Images hosted on other servers:
Abdominal fat pad biopsy, H&E

Abdominal fat pad biopsy

Abdominal fat pad biopsy, Congo red

Abdominal fat pad biopsy, Congo red

Lichen amyloidosis

Lichen amyloidosis

Nodular amyloidosis

Nodular amyloidosis

Cytology description
Immunofluorescence description
Immunofluorescence images

Images hosted on other servers:
Amorphous pattern with IgM, IgG, IgA, C3

Amorphous pattern with IgM, IgG, IgA, C3

Positive stains
  • Congo red
    • Most commonly used special stain; considered gold standard
    • Brick red staining, apple green birefringence with polarization
    • Staining is not always strongly positive, false negative results due to limited presence of amyloids, thin tissue sections (ideal thickness: 8 - 10 μm) or technical variability (Biosci Rep 2019;39:BSR20181415)
    • Positive staining is not specific for amyloid; can stain hyaline deposits in colloid milium and lipid proteinosis or elastin and collagen fibrils
    • Lower sensitivity in macular amyloidosis (J Clin Diagn Res 2017;11:WC01)
    • Higher sensitivity can be achieved in combination with alternative methods including immunohistochemistry, Congo red fluorescence and immunofluorescence (Hum Pathol 2014;45:1766)
  • Thioflavin T
    • Very sensitive but requires fluorescence microscopy; yellow-green fluorescence (Biochim Biophys Acta 2010;1804:1405)
    • Limited specificity; stains cartilage, elastic fibers and mucopolysaccharides
  • Crystal violet, methyl violet
    • Metachromatic staining (purple-red in a blue background) in amyloid and acid mucopolysaccharides
    • Not commonly used due to overall low specificity and sensitivity compared to Congo red (Biosci Rep 2019;39:BSR20181415)
    • Most sensitive for keratin derived amyloid
  • Cotton dyes such as pagoda red, scarlet red, RIT cardinal red no. 9 (Arch Dermatol 1984;120:1184)
    • Bright orange color
    • Pagoda red most specific but rarely used
  • PAS stains glycogen and mucopolysaccharides
    • Not commonly used for amyloid detection due to lack of specificity
  • Van Gieson stain can be used to differentiate colloid milium (stains yellow) from amyloidosis (stains pink)
  • Cytokeratin
  • Immunoglobulin light chains
    • Positive staining with either kappa or lambda (more often) light chains in the amyloid fibrils in nodular amyloidosis and cutaneous involvement of primary systemic amyloidosis
    • Light chain restriction seen in the lesional plasma cells in nodular amyloidosis and systemic amyloidosis associated with plasma cell dyscrasia
  • AA, A beta 2 microglobulin
  • C4d
Negative stains
Electron microscopy description
  • Long nonbranching straight rod shaped filaments with variable length, a diameter of 6 - 10 nm and random arrangement without bundle formation (Ann Dermatol 2023;35:S376)
Electron microscopy images

Images hosted on other servers:
Amyloid fibrils

Amyloid fibrils

Mesh-like pattern

Mesh-like pattern

Molecular / cytogenetics description
  • In situ hybridization (ISH) for immunoglobulin light chains kappa and lambda as an alternative method to IHC to demonstrate light chain restriction in plasma cells
    • Light chain restriction is expected in nodular amyloidosis or cutaneous involvement by systemic amyloidosis associated with plasma cell dyscrasia
  • Polymerase chain reaction and gene rearrangement studies can confirm clonality of the plasma cells in nodular amyloidosis (Br J Dermatol 1996;135:630)
    • Not required for diagnosis, infrequently used for diagnostic purposes
Videos

Lichen amyloidosis

Macular amyloidosis

Nodular amyloidosis

Sample pathology report
  • Skin, abdomen, biopsy:
    • Amyloid deposits in papillary dermis and around eccrine glands, consistent with cutaneous amyloidosis (see comment)
    • Comment: There are amorphous, pink deposits with clefting in the papillary dermis and around eccrine glands. The deposits are strongly positive with Congo red and negative for cytokeratin 34 beta E12. The kappa in situ hybridization was negative while lambda in situ hybridization identified a clonal infiltrate of plasma cells. Further studies (mass spectrophotometry) are pending.
    • Addendum: Mass spectrophotometry detected a peptide profile consistent with AL (lambda) type amyloid. These findings support amyloid deposition associated with plasma cell proliferation. Correlation with clinical and laboratory findings is recommended to distinguish systemic from localized AL amyloidosis.

  • Skin, left pretibial region, biopsy:
    • Lichen amyloidosis (see comment)
    • Comment: H&E sections reveal hyperkeratosis, slight epidermal hyperplasia and dyskeratotic cells in the epidermis. There are melanophages in the papillary dermis, a sparse perivascular lymphocytic inflammatory infiltrate and small, discrete globules of amorphous material in the papillary dermis. The material is positive for cytokeratin AE1 / AE3 and Congo red stain with apple green birefringence under polarized light. These findings support the above diagnosis.

  • Skin, right lateral heel, biopsy:
    • Squamous cell carcinoma in situ with papillary dermal amyloid deposition (see comment)
    • Comment: Extensive, pink, amorphous deposits in the papillary dermis underlying squamous cell carcinoma in situ is highlighted by Congo red staining. This likely represents secondary localized cutaneous amyloidosis; however, another form of cutaneous amyloidosis could also be considered. Clinical correlation is recommended.
Differential diagnosis
Practice question #1
Amyloidosis


A 56 year old woman presents with persistent pruritic and hyperpigmented papules on her shins. A skin biopsy is performed and histopathologic examination reveals deposits in the papillary dermis that are positive for Congo red staining. What is the primary component of the deposits observed in this type of amyloidosis?

  1. β2 microglobulin
  2. Immunoglobulin light chains
  3. Keratin derived amyloid
  4. Serum amyloid A protein
  5. Transthyretin
Practice answer #1
C. Keratin derived amyloid. The patient's diagnosis is most consistent with lichen amyloidosis based on the given clinical and histopathologic findings. In lichen amyloidosis, the amyloid deposits are derived from degenerated keratinocytes. Answer A is incorrect because β2 microglobulin derived amyloid is associated with dialysis related amyloidosis. Answer B is incorrect because immunoglobulin light chains are associated with AL amyloidosis that may be seen in primary systemic amyloidosis, nodular amyloidosis or in association with plasma cell dyscrasia. Answer D is incorrect because serum amyloid A protein is related to AA amyloidosis, commonly related to systemic inflammatory conditions. Answer E is incorrect because transthyretin is associated with ATTR amyloidosis, which rarely affects skin.

Comment Here

Reference: Amyloidosis
Practice question #2
A 77 year old woman with multiple, waxy, translucent papules on her periorbital region complains of fatigue and easy bruising. Physical examination is remarkable for macroglossia. A skin biopsy is performed, showing perivascular amyloid deposits in the dermis. Which of the following findings would be most consistent with primary systemic amyloidosis associated with plasma cell dyscrasia?

  1. Elevated serum amyloid A levels
  2. History of Sjögren syndrome
  3. Low serum complement levels
  4. Monoclonal spike on serum protein electrophoresis
  5. Positive antinuclear antibody (ANA) test
Practice answer #2
D. Monoclonal spike on serum protein electrophoresis. The presence of a monoclonal spike (M spike) on serum protein electrophoresis is indicative of a monoclonal immunoglobulin seen in plasma cell dyscrasias. This is expected to be seen in primary systemic amyloidosis (AL amyloidosis) where the amyloid deposits are composed of immunoglobulin light chains. Answer A is incorrect because elevated serum amyloid A levels are associated with AA amyloidosis, resulting from chronic inflammation. Answer B is incorrect because Sjögren syndrome has been reported to be associated with nodular amyloidosis. Answers C and E are incorrect because positive ANA test and low serum complement levels are commonly seen in autoimmune conditions and are not related to primary systemic amyloidosis associated with plasma cell dyscrasia (Clin Cosmet Investig Dermatol 2023;16:987).

Comment Here

Reference: Amyloidosis
Back to top
Home > Skin nontumor > Amyloidosis
Image 01 Image 02