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Nodular primary localized cutaneous amyloidosis after trauma: A case report and discussion of the rate of progression to systemic amyloidosis
Nodular primary localized cutaneous amyloidosis after trauma: A case report and discussion of the rate of progression to systemic amyloidosis Andrew H. Kalajian, MD, Mark Waldman, MD, and Alfred L. Knable, MD Louisville, Kentucky Nodular primary localized cutaneous amyloidosis (NPLCA) has been associated with progression to systemic amyloidosis. The reported estimate of 50% progression to systemic amyloidosis has come under scrutiny as recent studies have suggested a significantly lower rate. Still, it is essential to consider systemic amyloidosis after making the diagnosis of NPLCA and to follow up patients longitudinally for possible progression to systemic disease. We present a case of a 24-year-old woman with NPLCA with onset after traumatic injury, review the literature, and discuss the proposed rate of progression of NPLCA to systemic amyloidosis. ( J Am Acad Dermatol 2007;57:S26-9.)
A
myloidosis is a spectrum of disease characterized by extracellular deposition of amyloid protein as nonfunctional beta-pleated sheets ranging from localized cutaneous to systemic disease. Localized cutaneous amyloid deposition is most commonly an incidental secondary reactive process associated with cutaneous tumors or after therapy with psoralen plus ultraviolet A1 and less commonly a primary phenomenon subdivided into lichenoid, macular, and nodular (tumefactive) types. Nodular primary localized cutaneous amyloidosis (NPLCA) is the least reported of the primary localized cutaneous amyloidoses and it is well accepted that a percentage of patients with NPLCA ultimately progress to systemic disease.1-5 No consensus has been reached regarding progression and previously accepted rates have recently come under scrutiny.4-6 NPLCA presents as single or multiple nodules of varying size in the sixth and seventh decades of life (mean age: 55 years, range: 20-87 years) and involves any cutaneous surface.4,6-10 There is no sex predilection.4-6,10 Cosmetic improvement can be achieved by surgical or shave excision, successive electrodessication and curettage, dermabrasion, From the Division of Dermatology, University of Louisville. Funding sources: None. Conflicts of interest: None declared. Previously presented at the 50th Annual Zola Cooper Dermatopathology Seminar, New Orleans, LA, November 2003; and CPC Challenge at the American Academy of Dermatology 62nd Annual Meeting in Washington, DC, February 2004. Reprint requests: Alfred L. Knable, MD, 310 E Broadway, Suite 200, Louisville, KY 40202. E-mail: [email protected]. 0190-9622/$32.00 ª 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2006.12.014
S26
and carbon-dioxide laser.5,11-14 Intralesional corticosteroids and cryosurgery are usually ineffective, with hemorrhage frequently complicating cryosurgery.11,13,14 As recurrences are common, the least invasive procedure yielding cosmetically acceptable results is the best option. We present a case of a 24-year-old woman with posttraumatic NPLCA and review the literature to discuss the rate of progression of NPLCA to systemic amyloidosis.
CASE REPORT A 24-year-old woman presented with a 3-year history of an asymptomatic, slow-growing nodule on her chin that recently began to enlarge rapidly and developed numerous satellite nodules. Initial onset followed local trauma from a thrown full beer can. She denied prior treatment and personal or family history of similar problems. Medical history was significant for degenerative disk disease, nephrolithiasis, and acetaminophen overdose. Review of systems revealed episodic flushing and palpitations, mild chest discomfort with deep inspiration, and occasional right-sided abdominal pain. She denied fevers, chills, nausea, vomiting, weight loss, cough, dysphagia, or odynophagia. Examination revealed a 1.5- 3 2.5-cm welldemarcated flesh-colored firm multilobed nodule with telangiectasia on the right aspect of her chin (Fig 1). Numerous smaller nodules (largest being 0.6 3 0.8 cm) were noted along her right mandible. No lymphadenopathy or hepatosplenomegaly were appreciated and her cardiac point of maximal impulse was nondisplaced. Biopsy specimen revealed complete dermal replacement by an acellular, amorphous, eosinophilic
J AM ACAD DERMATOL
Kalajian, Waldman, and Knable S27
VOLUME 57, NUMBER 2
Fig 1. Clinical appearance of 1.5- 3 2.5-cm nodule on right aspect of chin (A) with multiple smaller nodules along right mandible (B).
material with a paucity of adnexal structures, thickened vessel walls, and deposition surrounding the few remaining eccrine glands. A patchy focal infiltrate of plasma cells was present. Crystal violet stain was diffusely positive and Congo red staining revealed apple-green birefringence with polarized light. Immunohistochemical staining was positive for lambda light chain on amyloid and plasma cells, and negative for amyloid A, amyloid P, and kappa light chains. These findings are consistent with NPLCA (Fig 2). Systemic evaluation was negative or normal for complete blood cell count, comprehensive metabolic panel, urinalysis, serum protein electrophoresis, urine protein electrophoresis, chest radiograph, and electrocardiogram. The need for long-term follow-up was stressed and the patient was scheduled for surgical excision; however, she failed to return for further care.
DISCUSSION Amyloidosis has been classified according to the deposition of characteristic forms of amyloid fibril protein (Table I). The precise cause of NPLCA remains unknown, however, dermal amyloid L deposition is believed to derive from immunoglobulin light chains produced locally by light chain restricted clonally expanded plasma cells.2,4,6,15 Epidermal
damage is not thought to play any role in the development of NPLCA (as is well accepted in lichenoid and macular amyloidoses16,17); however, our patient relates a clear temporal relationship between local trauma and disease onset and several reports document cases of NPLCA lacking clonality and occurring in common sites of trauma.4,6,9,18 More data are needed before conclusions can be made regarding a causative role of epidermal damage in NPLCA. Cutaneous deposition of amyloid L occurring in both systemic amyloidosis and NPLCA appears histologically similar with the exception of a local plasma cell infiltrate present in NPLCA.1 Thus, it is essential to evaluate for systemic amyloidosis before making a diagnosis of NPLCA. It is then prudent to recognize that NPLCA can progress to systemic amyloidosis with congestive heart failure or arrhythmias accounting for death in 25% to 40% of such patients.19,20 Perhaps NPLCA should be considered a possible cutaneous manifestation of systemic amyloidosis, similar to petechiae and purpura (pinch purpura) found in 17% of cases of systemic amyloidosis.1 Brownstein and Helwig3 initially presented a series of 10 patients with NPLCA and 5 of these patients were later found to have systemic amyloidosis, after which a rate of progression of NPLCA to systemic amyloidosis of 50% has long been quoted in the literature. On review, it appears likely that some of the patients who Brownstein and Helwig3 classified as progressing to systemic disease actually had occult systemic amyloidosis at the time of initial diagnosis. In addition, recent studies have indicated that the rate of progression may be significantly lower. Northcutt and Vanover4 cited a rate of progression of 15% after review of 47 cases of NPLCA. Considering that this review included the original 10 patients reported by Brownstein and Helwig,3 this 15% likely still represents an overestimate. Katz,21 Woollons and Black,5,22 and Moon et al6 independently reported long-term follow-up of 15 patients with NPLCA, each demonstrating only one patient progressing to systemic amyloidosis. The patient of Moon et al6 who progressed may have had systemic disease initially, as demonstrated by a monoclonal protein present in her serum at the time of initial skin biopsy specimen. These most recent case series both report rates of NPLCA progression to systemic amyloidosis of 7% and although the sample sizes of these studies are small, the data indicate a rate of progression significantly lower than the previously accepted 50%, perhaps lower then 10%. Further studies should help clarify this issue. Regardless of the actual rate of progression, on making the diagnosis of NPLCA the diligent physician will undertake a thorough evaluation for systemic amyloidosis and follow up the
S28 Kalajian, Waldman, and Knable
J AM ACAD DERMATOL AUGUST 2007
Fig 2. Histologic evaluation reveals complete dermal replacement by acellular, amorphous, eosinophilic material (A), paucity of adnexal structures and thickened vessel walls (B), associated with patchy focal infiltrate of plasma cells (C). Immunohistochemical staining was positive for lambda light chain on amyloid and plasma cells (D). (A to C, Hematoxylin-eosin stain; original magnifications: A, 340; B, 3400; C, 3600. D, Immunohistochemical stain; original magnification: 340.)
Table I. Amyloid fibrils in amyloidosis Amyloid fibril protein
Amyloid L
Keratin derivative
Types of amyloidosis
Precursor substance
Immunoglobulin Systemic and light chains myeloma-associated amyloidosis Immunoglobulin Nodular primary light chains localized cutaneous amyloidosis Macular and lichenoid ? Keratin filaments primary cutaneous amyloidosis
patient longitudinally to monitor for progression to systemic amyloidosis. We are grateful to Dr Janine Malone for her dermatopathology assistance.
REFERENCES 1. Breathnach SM. Amyloid and amyloidosis. J Am Acad Dermatol 1988;18:1-16. 2. Kakani RS, Goldstein AE. Nodular amyloidosis: case report and literature review. J Cutan Med Surg 2001;5:101-4. 3. Brownstein MH, Helwig EB. The cutaneous amyloidoses, I: localized forms. Arch Dermatol 1970;102:8-19. 4. Northcutt AD, Vanover MJ. Nodular cutaneous amyloidosis involving the vulva: case report and literature review. Arch Dermatol 1985;121:518-21. 5. Woollons A, Black MM. Nodular localized primary cutaneous amyloidosis: a long-term follow-up study. Br J Dermatol 2001; 145:105-9. 6. Moon AO, Calamia KT, Walsh JS. Nodular amyloidosis: review and long-term follow-up of 16 cases. Arch Dermatol 2003; 139:1157-9. 7. Taylor SC, Baker E, Grossman ME. Nodular vulvar amyloid as a presentation of systemic amyloidosis. J Am Acad Dermatol 1991;24:139. 8. Helm TN, Danziger J, Helm KF. Bilateral plantar amyloidosis: a unique presentation of localized cutaneous amyloidosis. Cutis 1997;59:142-4.
J AM ACAD DERMATOL
Kalajian, Waldman, and Knable S29
VOLUME 57, NUMBER 2
9. Borrowman TA, Lutz ME, Walsh JS. Cutaneous nodular amyloidosis masquerading as a foot callus. J Am Acad Dermatol 2003;49:307-10. 10. Clement MI, Honavar M, Salisbury J, Neill S. Nodular localized primary cutaneous amyloidosis. Clin Exp Dermatol 1987; 12:460-2. 11. Vestey JP, Tidman MJ, Mclaren KM. Primary nodular cutaneous amyloidosiselong-term follow-up and treatment. Clin Exp Dermatol 1994;19:159-62. 12. Grattan CEH, Burton JL, Dahl MGC. Two cases of nodular cutaneous amyloid with positive organ-specific antibodies, treated by shave excision. Clin Exp Dermatol 1988;13:187-9. 13. Bart RS, Kopf AW. Tumor conference No. 56: Localized cutaneous nodular amyloidosis. J Dermatol Surg Oncol 1985;11:582-4. 14. Truhan AP, Garden JM, Roenigk HH. Nodular primary localized cutaneous amyloidosis: immunohistochemical evaluation and treatment with the carbon dioxide laser. J Am Acad Dermatol 1986;14:1058-62. 15. Kitajima Y, Seno J, Aoki S, Tada S, Yaoita H. Nodular primary cutaneous amyloidosis: isolation and characterization of amyloid fibrils. Arch Dermatol 1986;122:1425-30.
16. Black MM. The role of the epidermis in the histopathogenesis of lichen amyloidosis: histochemical correlations. Br J Dermatol 1971;85:524-30. 17. Black MM, Wilson Jones E. Macular amyloidosis: a study of 21 cases with special reference to the role of epidermis in its histogenesis. Br J Dermatol 1971;84:199-209. 18. Inazumi T, Hakuno M, Yamada H, Tanaka M, Naka W, Tajima S, et al. Characterization of the amyloid fibril from primary localized cutaneous nodular amyloidosis associated with Sjogren’s syndrome. Dermatology 1994;189:125-8. 19. Steciuk A, Dompmartin A, Troussard X, Verneuil L, Macro M, Comoz F, et al. Cutaneous amyloidosis and possible association with systemic amyloidosis. Int J Dermatol 2002;41: 127-32. 20. Touart DM, Sau P. Cutaneous deposition diseases, part I. J Am Acad Dermatol 1998;39:149-68. 21. Katz KA. Nodular localized primary cutaneous amyloidosis [correspondence]. Br J Dermatol 2002;147:400. 22. Woollons A, Black MM. Nodular localized primary cutaneous amyloidosis [reply from authors]. Br J Dermatol 2002; 147:401.
A
myloidosis is a spectrum of disease characterized by extracellular deposition of amyloid protein as nonfunctional beta-pleated sheets ranging from localized cutaneous to systemic disease. Localized cutaneous amyloid deposition is most commonly an incidental secondary reactive process associated with cutaneous tumors or after therapy with psoralen plus ultraviolet A1 and less commonly a primary phenomenon subdivided into lichenoid, macular, and nodular (tumefactive) types. Nodular primary localized cutaneous amyloidosis (NPLCA) is the least reported of the primary localized cutaneous amyloidoses and it is well accepted that a percentage of patients with NPLCA ultimately progress to systemic disease.1-5 No consensus has been reached regarding progression and previously accepted rates have recently come under scrutiny.4-6 NPLCA presents as single or multiple nodules of varying size in the sixth and seventh decades of life (mean age: 55 years, range: 20-87 years) and involves any cutaneous surface.4,6-10 There is no sex predilection.4-6,10 Cosmetic improvement can be achieved by surgical or shave excision, successive electrodessication and curettage, dermabrasion, From the Division of Dermatology, University of Louisville. Funding sources: None. Conflicts of interest: None declared. Previously presented at the 50th Annual Zola Cooper Dermatopathology Seminar, New Orleans, LA, November 2003; and CPC Challenge at the American Academy of Dermatology 62nd Annual Meeting in Washington, DC, February 2004. Reprint requests: Alfred L. Knable, MD, 310 E Broadway, Suite 200, Louisville, KY 40202. E-mail: [email protected]. 0190-9622/$32.00 ª 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2006.12.014
S26
and carbon-dioxide laser.5,11-14 Intralesional corticosteroids and cryosurgery are usually ineffective, with hemorrhage frequently complicating cryosurgery.11,13,14 As recurrences are common, the least invasive procedure yielding cosmetically acceptable results is the best option. We present a case of a 24-year-old woman with posttraumatic NPLCA and review the literature to discuss the rate of progression of NPLCA to systemic amyloidosis.
CASE REPORT A 24-year-old woman presented with a 3-year history of an asymptomatic, slow-growing nodule on her chin that recently began to enlarge rapidly and developed numerous satellite nodules. Initial onset followed local trauma from a thrown full beer can. She denied prior treatment and personal or family history of similar problems. Medical history was significant for degenerative disk disease, nephrolithiasis, and acetaminophen overdose. Review of systems revealed episodic flushing and palpitations, mild chest discomfort with deep inspiration, and occasional right-sided abdominal pain. She denied fevers, chills, nausea, vomiting, weight loss, cough, dysphagia, or odynophagia. Examination revealed a 1.5- 3 2.5-cm welldemarcated flesh-colored firm multilobed nodule with telangiectasia on the right aspect of her chin (Fig 1). Numerous smaller nodules (largest being 0.6 3 0.8 cm) were noted along her right mandible. No lymphadenopathy or hepatosplenomegaly were appreciated and her cardiac point of maximal impulse was nondisplaced. Biopsy specimen revealed complete dermal replacement by an acellular, amorphous, eosinophilic
J AM ACAD DERMATOL
Kalajian, Waldman, and Knable S27
VOLUME 57, NUMBER 2
Fig 1. Clinical appearance of 1.5- 3 2.5-cm nodule on right aspect of chin (A) with multiple smaller nodules along right mandible (B).
material with a paucity of adnexal structures, thickened vessel walls, and deposition surrounding the few remaining eccrine glands. A patchy focal infiltrate of plasma cells was present. Crystal violet stain was diffusely positive and Congo red staining revealed apple-green birefringence with polarized light. Immunohistochemical staining was positive for lambda light chain on amyloid and plasma cells, and negative for amyloid A, amyloid P, and kappa light chains. These findings are consistent with NPLCA (Fig 2). Systemic evaluation was negative or normal for complete blood cell count, comprehensive metabolic panel, urinalysis, serum protein electrophoresis, urine protein electrophoresis, chest radiograph, and electrocardiogram. The need for long-term follow-up was stressed and the patient was scheduled for surgical excision; however, she failed to return for further care.
DISCUSSION Amyloidosis has been classified according to the deposition of characteristic forms of amyloid fibril protein (Table I). The precise cause of NPLCA remains unknown, however, dermal amyloid L deposition is believed to derive from immunoglobulin light chains produced locally by light chain restricted clonally expanded plasma cells.2,4,6,15 Epidermal
damage is not thought to play any role in the development of NPLCA (as is well accepted in lichenoid and macular amyloidoses16,17); however, our patient relates a clear temporal relationship between local trauma and disease onset and several reports document cases of NPLCA lacking clonality and occurring in common sites of trauma.4,6,9,18 More data are needed before conclusions can be made regarding a causative role of epidermal damage in NPLCA. Cutaneous deposition of amyloid L occurring in both systemic amyloidosis and NPLCA appears histologically similar with the exception of a local plasma cell infiltrate present in NPLCA.1 Thus, it is essential to evaluate for systemic amyloidosis before making a diagnosis of NPLCA. It is then prudent to recognize that NPLCA can progress to systemic amyloidosis with congestive heart failure or arrhythmias accounting for death in 25% to 40% of such patients.19,20 Perhaps NPLCA should be considered a possible cutaneous manifestation of systemic amyloidosis, similar to petechiae and purpura (pinch purpura) found in 17% of cases of systemic amyloidosis.1 Brownstein and Helwig3 initially presented a series of 10 patients with NPLCA and 5 of these patients were later found to have systemic amyloidosis, after which a rate of progression of NPLCA to systemic amyloidosis of 50% has long been quoted in the literature. On review, it appears likely that some of the patients who Brownstein and Helwig3 classified as progressing to systemic disease actually had occult systemic amyloidosis at the time of initial diagnosis. In addition, recent studies have indicated that the rate of progression may be significantly lower. Northcutt and Vanover4 cited a rate of progression of 15% after review of 47 cases of NPLCA. Considering that this review included the original 10 patients reported by Brownstein and Helwig,3 this 15% likely still represents an overestimate. Katz,21 Woollons and Black,5,22 and Moon et al6 independently reported long-term follow-up of 15 patients with NPLCA, each demonstrating only one patient progressing to systemic amyloidosis. The patient of Moon et al6 who progressed may have had systemic disease initially, as demonstrated by a monoclonal protein present in her serum at the time of initial skin biopsy specimen. These most recent case series both report rates of NPLCA progression to systemic amyloidosis of 7% and although the sample sizes of these studies are small, the data indicate a rate of progression significantly lower than the previously accepted 50%, perhaps lower then 10%. Further studies should help clarify this issue. Regardless of the actual rate of progression, on making the diagnosis of NPLCA the diligent physician will undertake a thorough evaluation for systemic amyloidosis and follow up the
S28 Kalajian, Waldman, and Knable
J AM ACAD DERMATOL AUGUST 2007
Fig 2. Histologic evaluation reveals complete dermal replacement by acellular, amorphous, eosinophilic material (A), paucity of adnexal structures and thickened vessel walls (B), associated with patchy focal infiltrate of plasma cells (C). Immunohistochemical staining was positive for lambda light chain on amyloid and plasma cells (D). (A to C, Hematoxylin-eosin stain; original magnifications: A, 340; B, 3400; C, 3600. D, Immunohistochemical stain; original magnification: 340.)
Table I. Amyloid fibrils in amyloidosis Amyloid fibril protein
Amyloid L
Keratin derivative
Types of amyloidosis
Precursor substance
Immunoglobulin Systemic and light chains myeloma-associated amyloidosis Immunoglobulin Nodular primary light chains localized cutaneous amyloidosis Macular and lichenoid ? Keratin filaments primary cutaneous amyloidosis
patient longitudinally to monitor for progression to systemic amyloidosis. We are grateful to Dr Janine Malone for her dermatopathology assistance.
REFERENCES 1. Breathnach SM. Amyloid and amyloidosis. J Am Acad Dermatol 1988;18:1-16. 2. Kakani RS, Goldstein AE. Nodular amyloidosis: case report and literature review. J Cutan Med Surg 2001;5:101-4. 3. Brownstein MH, Helwig EB. The cutaneous amyloidoses, I: localized forms. Arch Dermatol 1970;102:8-19. 4. Northcutt AD, Vanover MJ. Nodular cutaneous amyloidosis involving the vulva: case report and literature review. Arch Dermatol 1985;121:518-21. 5. Woollons A, Black MM. Nodular localized primary cutaneous amyloidosis: a long-term follow-up study. Br J Dermatol 2001; 145:105-9. 6. Moon AO, Calamia KT, Walsh JS. Nodular amyloidosis: review and long-term follow-up of 16 cases. Arch Dermatol 2003; 139:1157-9. 7. Taylor SC, Baker E, Grossman ME. Nodular vulvar amyloid as a presentation of systemic amyloidosis. J Am Acad Dermatol 1991;24:139. 8. Helm TN, Danziger J, Helm KF. Bilateral plantar amyloidosis: a unique presentation of localized cutaneous amyloidosis. Cutis 1997;59:142-4.
J AM ACAD DERMATOL
Kalajian, Waldman, and Knable S29
VOLUME 57, NUMBER 2
9. Borrowman TA, Lutz ME, Walsh JS. Cutaneous nodular amyloidosis masquerading as a foot callus. J Am Acad Dermatol 2003;49:307-10. 10. Clement MI, Honavar M, Salisbury J, Neill S. Nodular localized primary cutaneous amyloidosis. Clin Exp Dermatol 1987; 12:460-2. 11. Vestey JP, Tidman MJ, Mclaren KM. Primary nodular cutaneous amyloidosiselong-term follow-up and treatment. Clin Exp Dermatol 1994;19:159-62. 12. Grattan CEH, Burton JL, Dahl MGC. Two cases of nodular cutaneous amyloid with positive organ-specific antibodies, treated by shave excision. Clin Exp Dermatol 1988;13:187-9. 13. Bart RS, Kopf AW. Tumor conference No. 56: Localized cutaneous nodular amyloidosis. J Dermatol Surg Oncol 1985;11:582-4. 14. Truhan AP, Garden JM, Roenigk HH. Nodular primary localized cutaneous amyloidosis: immunohistochemical evaluation and treatment with the carbon dioxide laser. J Am Acad Dermatol 1986;14:1058-62. 15. Kitajima Y, Seno J, Aoki S, Tada S, Yaoita H. Nodular primary cutaneous amyloidosis: isolation and characterization of amyloid fibrils. Arch Dermatol 1986;122:1425-30.
16. Black MM. The role of the epidermis in the histopathogenesis of lichen amyloidosis: histochemical correlations. Br J Dermatol 1971;85:524-30. 17. Black MM, Wilson Jones E. Macular amyloidosis: a study of 21 cases with special reference to the role of epidermis in its histogenesis. Br J Dermatol 1971;84:199-209. 18. Inazumi T, Hakuno M, Yamada H, Tanaka M, Naka W, Tajima S, et al. Characterization of the amyloid fibril from primary localized cutaneous nodular amyloidosis associated with Sjogren’s syndrome. Dermatology 1994;189:125-8. 19. Steciuk A, Dompmartin A, Troussard X, Verneuil L, Macro M, Comoz F, et al. Cutaneous amyloidosis and possible association with systemic amyloidosis. Int J Dermatol 2002;41: 127-32. 20. Touart DM, Sau P. Cutaneous deposition diseases, part I. J Am Acad Dermatol 1998;39:149-68. 21. Katz KA. Nodular localized primary cutaneous amyloidosis [correspondence]. Br J Dermatol 2002;147:400. 22. Woollons A, Black MM. Nodular localized primary cutaneous amyloidosis [reply from authors]. Br J Dermatol 2002; 147:401.