Cutaneous amyloidosis (overview)L99.0; E85.4

Gutmann 1923-1928; Freudenthal 1926-1930; Gottron 1950; Palitz 1952;

Rare, non-systemic, localized, chronic skin disease, usually associated with itching, caused by deposition of amyloid (amylum = starch) in the dermis. See also keratin amyloidosis. The skin lesions of this amyloid type must be distinguished from the skin lesions of the systemic am yloidoses (other amyloid types/AS-AL amyloidoses) and the very rare hereditary amyloidoses.

Localized (non-systemic) cutaneous amyloidoses are divided into:

• Localized (primary) cutaneous amyloidoses (Wang WJ et al 2001).
  • Lichen amyloidosus (amyloid K) - most common localized cutaneous amyloidosis (~ 60%).
  • Macular cutaneous amyloidosis (amyloid K) (~ 10%).
  • Biphasic forms with macular and lichenoid amyloidosis (~20%)
  • Nodular cutaneous amyloidosis (amyloidosis cutis nodularis atrophicans/ (amyloid L) (~1%)
  • Familial primary localized cutaneous amyloidosis (mutations in oncostatin M receptor-beta) (~<7%)
  • Anosacral cutaneous amyloidosis (very rare, so far only seen in Asians; combination with diabetes mellitus described)
  • Special clinical forms (poikilodermic, vitiliginous or vesicular forms)
• Localized (secondary) cutaneous amyloidoses
  • Amyloidoses in actinic (permanent) lesions (also after PUVA therapy/Amyloid K)
  • Amyloid deposits (amyloid K) in benign and malignant tumors (basal cell carcinoma/50%; spinocellular carcinoma, seborrheic keratoses, actinic keratoses)
  • "Friction amyloidosis": Cutaneous amyloidosis due to constant scratching and scrubbing of certain skin areas with hard brushes or other objects (nylon brush macular amyloidosis)/amyloid K. There are pathogenetic relationships to notalgia paraesthetica.
  • X-linked reticular pigment disorder (rare syndrome characterized by recurrent infections and sterile multiorgan inflammation (mutation in POLA1 gene encoding the catalytic subunit of DNA polymerase-alpha (Pol-α) (Starokadomskyy Pet al. 2019).

Primary cutaneous amyloidoses have variable incidences worldwide. A frequent occurrence is observed in the Asian population (Singapore, Taiwan, Thailand). Macular amyloidosis seems to be clustered in South America (Ollage W et al. 1990).

The exact etiopathogenesis of cutaneous amyloidoses is not known. In principle, it can be assumed that the cutaneous amyloidoses are clinical variants of an identical pathologic process that is currently not well understood. It has been hypothesized that signaling disturbances via the oncostatin M-type II recept or and/or the interleukin (IL)-31 receptor lead to apoptosis of keratinocytes and subsequent amyloid deposition and pruritus (Arita K et al. 2008; Weidner T et al. 2017).

The amyloids of cutaneous amyloidoses (lichen amyloidosus and macular amyloidosis) represent a group of heterogeneous proteins that are ultrastructurally similar or react similarly on histologic staining. Due to their reaction with monoclonal antibodies directed against all cratin filaments, these amyloids are referred to as amyloid K.

Biochemistry: Probably in apoptotic keratinocytes, the alpha-helical structure of keratins is converted into a ß-folded sheet structure. These misfolded proteins cannot be cleared by macrophages and remain as keratin amyloid (amyloid K) in the papillary dermis.

Immunology: It is widely accepted that the amyloid in both the lichenoid and macular forms of cutaneous amyloidosis is of epidermal origin. This distinguishes these variants from the amyloid of nodular cutaneous amyloidosis, which consists almost exclusively of monoclonal immunoglobulin light chains of the kappa or lambda type (amyloid L).

Cytokeratins are released from the perished and apoptotic basal keratinocytes. This concerns mainly cytokeratin 5, but also cytokeratins 1, 10 and 14. The released cytokeratins have an antigenic effect and induce an antibody reaction. At the same time, the accumulation of amyloid P components occurs. After phagocytosis by macrophages or fibroblasts, enzymatic conversion to amyloid K, a non-degradable substance, occurs.

Furthermore, the expression of amyloid precursors by monoclonal or polyclonal plasma cells is discussed, whose proliferation is triggered by amylogenic proteins, e.g. keratin, immunoglobulins, insulin or beta2-microglobulin.

While primary cutaneous amyloidoses are mainly sporadic, in some cases a familial clustering with autosomal dominant inheritance can be observed. Causes include mutations in OSMR(Oncostatin M receptor-beta/Arita K et al. 2008), which are responsible for 10% of primary, localized, cutaneous amyloidoses, particularly within certain geographic regions, such as South America and Southeast Asia.

W:M=1.2:1.0; average age at first medical examination 57 years (24-87 years)

Amyloid is characterized by:

• Blue staining after contact with and dilute sulfuric acid.
• Eosinophilia in conventional HE staining
• Green-yellowish to red staining and birefringence in polarized light after staining with Congo red
• Electron microscopy by a meshwork of unbranched fibrils and by a non-fibrillar component (serum amyloid P component) common to all types of systemic and localized amyloid
• Beta-fold sheet structure, detectable by X-ray diffraction
• Differently associated protein types (detectable by laser microdissection of amyloid deposits followed by mass spectrometry)

Primary, cutaneous (non-systemic) amyloidoses are classified under localized amyloidoses (E85.4), which can affect not only the skin but also other organs. The localized amyloidoses should be separated from the systemic amyloidoses.

In organ-specific localized amyloidoses, particular local conditions, as well as the deposition of different amyloids from different protein precursors, play a determining pathogenetic role:

• Keratin amyloid in non-systemic cutaneous amyloidosis (see below Keratin amyloidoses).
• Islet amyloid polypeptides (deposits in the beta cells of the islets of Langerhans) in diabetes mellitus type II
• Components of precalcitonin as amyloid in tumors and metastases
• Native transthyretin as senile cardiac amyloid in myocardium of the elderly
• Aggregated Aß peptide in Alzheimer's disease (Alzheimer plaques)

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12. Venkataram MN et al (2001) Frictional amyloidosis: a study of 10 cases. Australas J Dermatol 42:176-179.

13. Wang WJ et al (2001) Clinical and histopathological characteristics of primary cutaneous amyloidosis in 794 Chinese patients. Zhonghua Yi Xue Za Zhi (Taipei) 64:101-107.

14. Weidner et al (2017) Primary localized cutaneous amyloidosis: A systematic treatment review. Am J Clin Dermatol 18:629-642.