Nodular Localized Cutaneous Amyloidosis

Back

Background

Localized cutaneous amyloidosis (LCA) refers to a condition characterized by the deposition of amyloid or amyloid-like proteins in the dermis. Localized cutaneous amyloidosis encompasses several conditions characterized by amyloid deposition, including macular amyloidosis and lichen amyloidosis. Nodular localized cutaneous amyloidosis (NLCA) is the rarest type of localized cutaneous amyloidosis and is distinct from the other two.

Gottron first reported nodular localized cutaneous amyloidosis in 1950. Since then, approximately 60 patients have been reported in the North American, European, and Asian literature. This entity also is termed amyloidosis cutis nodularis atrophicans or tumefactive amyloid. By definition, nodular localized cutaneous amyloidosis describes a primary disease of the skin, although lesions occasionally appear similar to the skin manifestations of systemic amyloidosis.

Pathophysiology

As a term, "amyloid" was used historically to define proteins that shared similar microscopic characteristics and affinity for certain stains. Research has revealed that "amyloid" proteins are heterogeneous. The various diseases characterized by deposition of "amyloid" proteins are similarly heterogeneous but have in common the deposits of fibrillar proteins characterized as "amyloid" in the dermis. In nodular localized cutaneous amyloidosis, the amyloid is believed to derive from local plasma cells, in contrast to lichenoid or macular amyloidosis, which have keratinocyte-derived amyloid.

In nodular localized cutaneous amyloidosis, plasma cells produce immunoglobulin light chains that are precursors to the amyloid fibril protein(s) termed amyloid L. Reports differ regarding the clonality of this population of plasma cells. In some instances, plasma cells have been monoclonal, suggesting that nodular localized cutaneous amyloidosis is a neoplastic disorder.[1] On the other hand, cutaneous plasma cell clonality has been observed in the absence of a monoclonal plasma cell population in the bone marrow.[1, 2] In other cases, plasma cells demonstrated polyclonality, which usually is a feature of a more reactive process.

Epidemiology

Frequency

United States

Incidence and prevalence of localized cutaneous amyloidosis in the United States are not known; however, the scarcity of reported patients with localized cutaneous amyloidosis indicates that the condition may be rare.

International

Despite a paucity of reported patients, localized cutaneous amyloidosis, although rare, is represented in the American, Asian, and European literature.

Mortality/Morbidity

Nodular localized cutaneous amyloidosis typically is benign and limited to the skin. However, lesions are more often persistent. Reported rates of progression to systemic disease are derived from case series with small numbers of patients; these rates vary from 7% to nearly 50%.[3, 4] Progression to fatal systemic amyloidosis has been reported, although this is a rare occurrence.[5] As many as 25% of reported cases have been associated with Sjögren syndrome. Some speculate that these 2 disorders have may have a shared pathogenesis.[6, 7, 8, 9, 10]

Case reports have also correlated nodular localized cutaneous amyloidosis with other autoimmune disorders such as CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia syndrome), primary biliary cirrhosis, rheumatoid arthritis, and systemic lupus erythematosus.[11] Other rare associations described in the case report literature include alcoholic cirrhosis[12] and severe atopic dermatitis.[13]

Race

Epidemiologic data can be difficult to establish when so few patients are reported. No specific racial, ethnic, or geographic group appears more prone than another to developing nodular localized cutaneous amyloidosis.

Sex

Of the first 13 patients described in the Japanese literature, 12 were women; however, this disproportionate ratio has not been seen consistently. In a subsequent series of 12 patients, the male-to-female ratio was equal. Other series have reported equal or nearly equal male-to-female ratios.

Age

Patients reportedly range in age from 33-86 years. The mean age of onset has been reported to be 55 years. Although numbers are small, reports indicate that nodular localized cutaneous amyloidosis is likely to occur during adulthood.

History

Patient history may include the following:

Physical

Physical examination may reveal the following:

Causes

The cause of nodular localized cutaneous amyloidosis is not known, although the amyloid protein is derived from a localized infiltrate of plasma cells.

Laboratory Studies

Normal serum protein electrophoresis and urine protein electrophoresis studies help to exclude multiple myeloma, which can also cause amyloid deposits made up of immunoglobulin light chains.

Positive antinuclear, anti-Ro, and anti-La antibodies suggest Sjögren syndrome.

Laboratory studies, such as CBC, serum chemistry profile, and liver function tests often were part of a general workup in several case reports of patients with nodular localized cutaneous amyloidosis. Nodular localized cutaneous amyloidosis does not cause any abnormal findings in these studies.

Urinalysis or 24-hour urine testing can be performed to check for protein. Proteinuria is not a feature of localized cutaneous disease but can be seen in systemic amyloidosis.

Imaging Studies

In some patients, imaging studies have included chest radiography, ECG, and abdominal ultrasonography.

Screening for amyloid within organs can be accomplished using scintigraphy with radioiodinated serum amyloid P component (ie, SAP scanning). This is a very sensitive test for detecting early systemic amyloidosis.

Procedures

Skin biopsy provides the definitive diagnosis. No special tissue preparation or handling is required before delivering the specimen to the laboratory. Special stains and immunohistochemistry are helpful.

An optimal biopsy specimen includes the epidermis, papillary dermis, and reticular dermis. The amyloid in nodular localized cutaneous amyloidosis is located in the reticular dermis and subcutaneous fat, and clearly differentiates nodular localized cutaneous amyloidosis from other forms of amyloidosis. A shave biopsy or other superficial sample may not include enough reticular dermis to complete the diagnosis.

Consider bone marrow biopsy with gene rearrangement studies (if available) to exclude multiple myeloma.

Histologic Findings

Despite their biochemical heterogeneity, all "amyloid" deposits demonstrate a similar light microscopic appearance. They are eosinophilic and homogeneous when stained with hematoxylin and eosin and viewed with standard optics. When stained with Congo red and viewed with polarized light, deposits exhibit a characteristic apple-green birefringence. Pagoda red is even more specific for amyloid, and staining with thioflavin T is very sensitive. In nodular amyloidosis, amyloid is not limited to the papillary dermis but is present in the entire dermis and may extend to subcutaneous fat. Amyloid deposition may be particularly prominent in walls of small blood vessels and surrounding individual lipocytes (see the images).



View Image

The bright pink homogeneous-appearing material seen is amyloid stained with Congo red. A distinguishing feature of amyloid in the skin is an affinity ....



View Image

Amyloid shows apple green when examined with polarized light.



View Image

This transmission electron micrograph of amyloid deposited in the tissue shows loosely interwoven straight filaments.

Plasma cells, which most likely produce the amyloid, occur within an adjacent and intermingled inflammatory infiltrate. They can be sparse or numerous (similar plasma cell infiltrate occurs in nodular pulmonary amyloidosis but usually is absent in cutaneous lesions of primary systemic amyloidosis). When eosinophilic amyloid material is exposed to potassium permanganate prior to staining with Congo red, the amyloid retains its congophilia, similar to systemic amyloidosis but in contradistinction to secondary amyloidosis. Kappa or lambda light chains (or both) may be present on immunohistochemical staining.[5]

When viewed with a transmission electron microscope, the apparently homogeneous deposits of amyloid are composed of loosely interwoven 6- to 10-nm–thick straight filaments. The amino acids of the filament proteins are arranged in a characteristic beta-pleated sheet tertiary structure. Amyloid deposits in the skin also contain small amounts of a plasma-derived, nonfibrillar, amyloid-P protein.

Medical Care

Various methods attempt to improve the appearance of the nodular localized cutaneous amyloidosis lesions, including topical and intralesional corticosteroids, cryotherapy, dermabrasion,[21] shaving, curettage and electrodesiccation, carbon dioxide laser,[22, 23, 24] and pulsed dye laser.[25] However, lesions frequently recur after treatment. Topical and intralesional corticosteroids and cryotherapy usually are not helpful. One attempt at cryotherapy produced pinpoint bleeding. Recently, a solitary report has described successful treatment with cyclophosphamide in a patient with both CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) and Sjögren syndrome.[26]  One patient responded to intralesional methotrexate.[27]

Rarely, patients with nodular localized cutaneous amyloidosis develop systemic amyloidosis or multiple myeloma years later, suggesting the need for follow-up care.

Surgical Care

Procedures may include the following:

None of these treatment methods totally eradicates lesions, which can recur.

What is nodular localized cutaneous amyloidosis (NLCA)?What is the pathophysiology of nodular localized cutaneous amyloidosis (NLCA)?What is the prevalence of nodular localized cutaneous amyloidosis (NLCA) in the US?What is the global prevalence of nodular localized cutaneous amyloidosis (NLCA)?What is the morbidity associated with nodular localized cutaneous amyloidosis (NLCA)?What are the racial predilections of nodular localized cutaneous amyloidosis (NLCA)?What are the sexual predilections of nodular localized cutaneous amyloidosis (NLCA)?Which age groups have the highest prevalence of nodular localized cutaneous amyloidosis (NLCA)?Which clinical history findings are characteristic of nodular localized cutaneous amyloidosis (NLCA)?Which physical findings are characteristic of nodular localized cutaneous amyloidosis (NLCA)?What causes nodular localized cutaneous amyloidosis (NLCA)?What are the differential diagnoses for Nodular Localized Cutaneous Amyloidosis?What is the role of lab tests in the workup of nodular localized cutaneous amyloidosis (NLCA)?What is the role of imaging studies in the workup of nodular localized cutaneous amyloidosis (NLCA)?What is the role of biopsy in the workup of nodular localized cutaneous amyloidosis (NLCA)?Which histologic findings are characteristic of nodular localized cutaneous amyloidosis (NLCA)?How is nodular localized cutaneous amyloidosis (NLCA) treated?What is the role of surgery in the treatment of nodular localized cutaneous amyloidosis (NLCA)?

Author

Nicholas V Nguyen, MD, Director of Pediatric Dermatology, Akron Children's Hospital

Disclosure: Nothing to disclose.

Coauthor(s)

Tracy Funk, MD, Fellow in Pediatric Dermatology, Department of Dermatology, The Children’s Hospital Colorado

Disclosure: Nothing to disclose.

Specialty Editors

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Disclosure: Nothing to disclose.

Warren R Heymann, MD, Head, Division of Dermatology, Professor, Department of Internal Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Catharine Lisa Kauffman, MD, FACP, Georgetown Dermatology and Georgetown Dermpath

Disclosure: Nothing to disclose.

Acknowledgements

Lauren Biesbroeck Washington University in St Louis School of Medicine

Disclosure: Nothing to disclose. Marion C Miethke, MD Clinical Assistant Professor, Department of Internal Medicine, Section of Dermatology, University of Washington

Disclosure: Nothing to disclose.

Gregory J Raugi, MD, PhD Professor, Department of Internal Medicine, Division of Dermatology, University of Washington at Seattle School of Medicine; Chief, Dermatology Section, Primary and Specialty Care Service, Veterans Administration Medical Center of Seattle

Gregory J Raugi, MD, PhD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

References

  1. Hagari Y, Mihara M, Hagari S. Nodular localized cutaneous amyloidosis: detection of monoclonality of infiltrating plasma cells by polymerase chain reaction. Br J Dermatol. 1996 Oct. 135(4):630-3. [View Abstract]
  2. Grunewald K, Sepp N, Weyrer K. Gene rearrangement studies in the diagnosis of primary systemic and nodular primary localized cutaneous amyloidosis. J Invest Dermatol. Oct 1991. 97(4):693-6. [View Abstract]
  3. Kalajian AH, Waldman M, Knable AL. Nodular primary localized cutaneous amyloidosis after trauma: a case report and discussion of the rate of progression to systemic amyloidosis. J Am Acad Dermatol. Aug 2007. 57(2 Suppl):S26-9. [View Abstract]
  4. Woollons A, Black MM. Nodular localized primary cutaneous amyloidosis: a long-term follow-up study. Br J Dermatol. Jul 2001. 145(1):105-9. [View Abstract]
  5. Moon AO, Calamia KT, Walsh JS. Nodular amyloidosis: review and long-term follow-up of 16 cases. Arch Dermatol. Sep 2003. 139(9):1157-9. [View Abstract]
  6. Inazumi T, Hakuno M, Yamada H. Characterization of the amyloid fibril from primary localized cutaneous nodular amyloidosis associated with Sjögren's syndrome. Dermatology. 1994. 189(2):125-8. [View Abstract]
  7. Srivastava M. Primary cutaneous nodular amyloidosis in a patient with Sjögren's syndrome. J Drugs Dermatol. Mar 2006. 5(3):279-80. [View Abstract]
  8. Yoneyama K, Tochigi N, Oikawa A, Shinkai H, Utani A. Primary localized cutaneous nodular amyloidosis in a patient with Sjögren's syndrome: a review of the literature. J Dermatol. Feb 2005. 32(2):120-3. [View Abstract]
  9. Konishi A, Fukuoka M, Nishimura Y. Primary localized cutaneous amyloidosis with unusual clinical features in a patient with Sjögren's syndrome. J Dermatol. Jun 2007. 34(6):394-6. [View Abstract]
  10. Meijer JM, Schonland SO, Palladini G, et al. Sjögren's syndrome and localized nodular cutaneous amyloidosis: coincidence or a distinct clinical entity?. Arthritis Rheum. Jul 2008. 58(7):1992-9. [View Abstract]
  11. Summers EM, Kendrick CG. Primary localized cutaneous nodular amyloidosis and CREST syndrome: a case report and review of the literature. Cutis. Jul 2008. 82(1):55-9. [View Abstract]
  12. Ueno M, Yamamoto T, Yamanaka M, Matsunaga T. Nodular amyloidosis in a patient with liver cirrhosis. Dermatol Online J. Jul 2011. 17(7):10. [View Abstract]
  13. Fujisawa T, Shu E, Ikeda T, Seishima M. Primary localized cutaneous nodular amyloidosis that appeared in a patient with severe atopic dermatitis. J Dermatol. Mar 2012. 39(3):312-3. [View Abstract]
  14. Wey SJ, Chen YM, Lai PJ, Chen DY. Primary sjögren syndrome manifested as localized cutaneous nodular amyloidosis. J Clin Rheumatol. Oct 2011. 17(7):368-70. [View Abstract]
  15. Lee DY, Kim YJ, Lee JY, Kim MK, Yoon TY. Primary localized cutaneous nodular amyloidosis following local trauma. Ann Dermatol. Nov 2011. 23(4):515-8. [View Abstract]
  16. Hicks BC, Weber PJ, Hashimoto K, Ito K, Koreman DM. Primary cutaneous amyloidosis of the auricular concha. J Am Acad Dermatol. Jan 1988. 18(1 Pt 1):19-25. [View Abstract]
  17. Mun KS, Pailoor J, Reddy SC. Primary localised deep cutaneous amyloidosis of the eyelid. Malays J Pathol. Dec 2005. 27(2):113-5. [View Abstract]
  18. Northcutt AD, Vanover MJ. Nodular cutaneous amyloidosis involving the vulva. Case report and literature review. Arch Dermatol. Apr 1985. 121(4):518-21. [View Abstract]
  19. Borowicz J, Shama L, Miller R. Nodular cutaneous amyloidosis. Skinmed. Sep-Oct 2011. 9(5):316-8. [View Abstract]
  20. Criado PR, Silva CS, Vasconcellos C, et al. Extensive nodular cutaneous amyloidosis: an unusual presentation. Br J Dermatol. Jul 2001. 145(1):105-9. [View Abstract]
  21. Lien MH, Railan D, Nelson BR. The efficacy of dermabrasion in the treatment of nodular amyloidosis. J Am Acad Dermatol. Feb 1997. 36(2 Pt 2):315-6. [View Abstract]
  22. Hamzavi I, Lui H. Excess tissue friability during CO2 laser vaporization of nodular amyloidosis. Dermatol Surg. Sep 1999. 25(9):726-8. [View Abstract]
  23. Truhan AP, Garden JM, Roenigk HH Jr. Nodular primary localized cutaneous amyloidosis: immunohistochemical evaluation and treatment with the carbon dioxide laser. J Am Acad Dermatol. Jun 1986. 14(6):1058-62. [View Abstract]
  24. Lesiak A, Rakowski A, Brzezinska A, et al. Effective treatment of nodular amyloidosis with carbon dioxide laser. Cutan Med Surg. Sep-Oct 2012. 16(5):372-4. [View Abstract]
  25. Alster TS, Manaloto RM. Nodular amyloidosis treated with a pulsed dye laser. Dermatol Surg. Feb 1999. 25(2):133-5. [View Abstract]
  26. Tong PL, Walker WA, Glancy RJ, et al. Primary localized cutaneous nodular amyloidosis successfully treated with cyclophosphamide. Australas J Dermatol. Feb 2013. 54(1):e12-5. [View Abstract]
  27. Raymond J, Choi J. Nodular cutaneous amyloidosis effectively treated with intralesional methotrexate. JAAD Case Rep. 2016 Sep 29. 2(5):373-376. [View Abstract]
  28. Bozikov K, Janezic T. Excision and split thickness skin grafting in the treatment of nodular primary localized cutaneous amyloidosis. Eur J Dermatol. May-Jun 2006. 16(3):315-6. [View Abstract]
  29. Breathnach SM. Amyloid and amyloidosis. J Am Acad Dermatol. Jan 1988. 18(1 Pt 1):1-16. [View Abstract]
  30. Carroll CB, Collison DW, Rodman OG Jr. Atrophic outpouchings of abdominal skin. Nodular cutaneous amyloidosis. Arch Dermatol. Feb 1996. 132(2):223-4, 226-7. [View Abstract]
  31. Helm TN, Danziger J, Helm KF. Bilateral plantar amyloidosis: a unique presentation of localized cutaneous amyloidosis. Cutis. Mar 1997. 59(3):142-4. [View Abstract]
  32. Horiguchi Y, Takahashi C, Imamura S. A case of nodular cutaneous amyloidosis. Amyloid production by infiltrating plasma cells. Am J Dermatopathol. Feb 1993. 15(1):59-63. [View Abstract]
  33. Huilgol SC, Ramnarain N, Carrington P, et al. Cytokeratins in primary cutaneous amyloidosis. Australas J Dermatol. May 1998. 39(2):81-5. [View Abstract]
  34. Kakani RS, Goldstein AE, Meisher I, Hoffman C. Nodular amyloidosis: case report and literature review. J Cutan Med Surg. Mar-Apr 2001. 5(2):101-4. [View Abstract]
  35. Masuda C, Hayashi M, Kameda Y, et al. Protein AL origin in amyloidosis cutis nodularis atrophicans. J Dermatol. Aug 1986. 13(4):280-4. [View Abstract]
  36. Masuda C, Mohri S, Nakajima H. Histopathological and immunohistochemical study of amyloidosis cutis nodularis atrophicans--comparison with systemic amyloidosis. Br J Dermatol. Jul 1988. 119(1):33-43. [View Abstract]
  37. Touart DM, Sau P. Cutaneous deposition diseases. Part I. Aug 1998. 39(2 Pt 1):149-71; quiz 172-4. [View Abstract]
  38. Trau H, Shpiro D, Schewach-Millet M, et al. Nodular cutaneous amyloidosis. Am J Dermatopathol. Aug 1991. 13(4):414-7. [View Abstract]
  39. Vestey JP, Tidman MJ, Mclaren KM. Primary nodular cutaneous amyloidosis--long-term follow-up and treatment. Clin Exp Dermatol. Mar 1994. 19(2):159-62. [View Abstract]

The bright pink homogeneous-appearing material seen is amyloid stained with Congo red. A distinguishing feature of amyloid in the skin is an affinity to take up Congo red stain.

Amyloid shows apple green when examined with polarized light.

This transmission electron micrograph of amyloid deposited in the tissue shows loosely interwoven straight filaments.

The bright pink homogeneous-appearing material seen is amyloid stained with Congo red. A distinguishing feature of amyloid in the skin is an affinity to take up Congo red stain.

Amyloid shows apple green when examined with polarized light.

This transmission electron micrograph of amyloid deposited in the tissue shows loosely interwoven straight filaments.