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Generalized Acquired Cutis Laxa Associated With Multiple Myeloma With Biphenotypic IgG- λ and IgA-κ Gammopathy Following Treatment of a Nodal Plasmacytoma FREE

H. Douglas New, MD; Jeffrey P. Callen, MD
[+] Author Affiliations

Author Affiliations: Division of Dermatology, University of Louisville, Louisville, Kentucky.


Arch Dermatol. 2011;147(3):323-328. doi:10.1001/archdermatol.2011.26.
Text Size: A A A
Published online

ABSTRACT

Background  Cutis laxa is a rare dermatosis that can be inherited or acquired. The acquired form is rare and has been associated with various conditions, including multiple myeloma, monoclonal gammopathy of undetermined significance, and heavy chain deposition disease.

Observations  We describe a 48-year-old man who developed generalized cutis laxa over a 4-year duration. There were no preceding skin changes except for a history of erythematous plaques with granuloma annulare–like features on his buttocks and lateral hips. He underwent treatment of an axillary lymph node plasmacytoma with surgery and radiation 4 years prior to his cutaneous changes and had been clinically monitored with a diagnosis of monoclonal gammopathy of unknown significance (MGUS). Cutaneous manifestations prompted a systemic evaluation demonstrating a persistent monoclonal IgG-λ M-spike on immunofixation electrophoresis and lytic bone lesions. He was later found to have biphenotypic IgG-λ and IgA-κ multiple myeloma.

Conclusions  Multiple myeloma, plasma cell dyscrasia, and heavy-chain deposition disease have been very rarely reported to be associated with acquired cutis laxa (ACL). Findings in our patient support the hypothesis that paraproteinemia is a cause of ACL through immunologic destruction of elastic fibers manifesting as granuloma annulare–like plaques. Evaluation for an underlying gammopathy is essential for the workup of a patient with new-onset ACL.

Figures in this Article

Cutis laxa (CL) is a rare dermatosis resulting in loose, wrinkled, redundant skin secondary to defects in dermal elastic tissue. When involving the face, patients classically have a “bloodhound-like” or “hound dog–like” appearance. Extracutaneous manifestations may also occur, including pulmonary emphysema, diverticulae of the gastrointestinal tract orgenitourinary tract, and cardiovascular defects. Cutis laxa may be inherited or acquired with acquired cutis laxa (ACL) having a later onset of disease, and more generalized involvement and is related to various different etiologies including medications, inflammatory diseases, infections, and hematologic disorders.1 We describe a 48-year-old man who developed ACL and granuloma annulare (GA)-like lesions as a paraneoplastic manifestation of early myeloma years after being treated for a lymph node plasmacytoma.

REPORT OF A CASE

A 48-year-old man was referred for evaluation of “recalcitrant” GA. At the time of referral, we noted a 4-year history of gradually developing loose, wrinkled skin of his face, chest, upper back, lateral hips, buttocks, and proximal upper extremities. There were no preceding cutaneous changes on his face and upper body; however, he developed asymptomatic erythematous plaques with GA-like features on his buttocks and hips. Eight years earlier, a nodal plasmacytoma was surgically excised from his left axilla. He received local radiation therapy at that time and was clinically monitored by an oncologist for the working diagnosis of monoclonal gammopathy of unknown significance (MGUS).

His medical history was otherwise unremarkable, and his medications included oral acitretin, 25 mg/d, and daily oral multivitamins: oral vitamin E, 400 IU; oral vitamin D, 2000 IU; omega-3 fish oil, 2000 mg; and B-complex vitamin supplements. Acitretin was added by the referring dermatologist 1 month prior to his initial presentation to us without improvement of his skin disease. His family history was unremarkable.

Physical examination demonstrated a healthy-appearing man who appeared older than his stated age. He had loose, sagging skin on the face and neck along with wrinkled, lax skin on the chest, upper back, proximal upper extremities, and the lateral aspects of his hips (Figure 1 and Figure 2). Granuloma annulare–like erythematous, nonscaly plaques were noted on his lower back, buttocks, and lateral hips in association with increased wrinkling (Figure 3).

Place holder to copy figure label and caption
Figure 1

Loose, sagging skin on the face and neck with “bloodhound-like” appearance.

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Place holder to copy figure label and caption
Figure 2

Right lateral hip with loose, wrinkly, redundant folds with faint erythema.

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Place holder to copy figure label and caption
Figure 3

Sacral area with nonscaly, somewhat annular, erythematous papules and plaques.

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METHODS

Findings from two 4-mm punch biopsy specimens of the patient's left hip and upper back revealed a normal epidermis anddermoepidermal junction with few lymphocytes and histiocytes around superficial blood vessels and interstitially in the upper dermis. A marked decrease in elastic fibers with elastophagocytosis by epitheloid cells and giant cells were observed (Figure 4 and Figure 5). Results from periodic acid–Schiff and giemsa stains were unremarkable. No evidence of amyloid was seen with crystal violet. No alteration of collagen or increased mucin deposition was appreciated. Initially, the biopsy specimen involving his left hip had been diagnosed as GA and that from his upper back as mid-dermal elastolysis. Further review of the specimens concluded that both biopsy specimens were more suggestive of dermal elastolysis consistent with ACL rather than GA.

Place holder to copy figure label and caption
Figure 4

A 4-mm punch biopsy specimen from the hip demonstrating paucicellular infiltrate of interstitial histiocytes with intracytoplasmic eosinophilic refractile elastic fiber fragments (hematoxylin-eosin, original magnification ×600).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5

Verhoeff–Van Giesen stain highlights histiocytic cells engulfing fragmented elastic fibers, as well as diminished elastic fibers in the surrounding dermis (original magnification ×600).

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Findings from a complete blood cell count, including differential, hepatic function panel, basic metabolic panel, fasting lipid profile, thyroid panel, anti-Ro/SSA antibody, anti-La/SSB antibody, antinuclear antibody, anti–double-stranded DNA antibody, serum ceruloplasmin, serum copper level, serum β-2 microglobulin, erythrocyte sedimentation rate, and echocardiogram were negative for disease or were within reference range. Serum levels of IgG, IgA, IgM, albumin, total protein, α1-globulin, α2-globulin, γ-globulin, and total globulin were also within reference range on serum protein electrophoresis (SPEP).

Immunofixation electrophoresis (IFE) revealed a stable monoclonal IgG-λ M-spike (0.5 g/dL vs 0.4 g/dL when evaluated the previous year). One year prior to his presentation, the patient had elevations of serum κ free light chain (FLC) level (118 mg/L; reference range, 3.3-19.4 mg/L) and serum λ FLC level (79.3 mg/L; reference range, 5.7-26.3 mg/L).

A bone marrow biopsy was performed, revealing 10% plasma cells. A skeletal survey was also performed, revealing multiple lucent bone lesions, less than 5 mm in size, in the patient's skull along with lytic rib lesions. Biphenotypic IgG-λ and IgA-κ multiple myeloma was subsequently diagnosed by the patient's oncologist.

Treatment with oral lenalidomide, 25 mg/d; dexamethasone, 40 mg/wk; oral pamidronate monthly; and aspirin, 81 mg/d, was initiated. The patient's hematologic markers and skeletal disease remained stable; however, his cutaneous laxity gradually progressed during 5 months on this regimen.

COMMENT

Acquired cutis laxa manifests as localized or generalized laxity and has been associated with inflammatory dermatoses (ie, urticaria, dermatitis herpetiformis, sarcoidosis, amyloidosis, systemic lupus erythematosus, erythema multiform), medication use (ie, penacillamine, penicillin, isoniazid), hypersensitivity reaction to insect bites and related to an underlying hematologic disorder (ie, multiple myeloma, lymphoma, immunoglobulin heavy-chain deposition disease, plasma cell dyscrasia).14 Acquired cutis laxa has also been reported in patients following cutaneous mastocytosis, Sweet syndrome in pediatric patients (Marshall syndrome), and interstitial granulomatous dermatitis.57 At least 10 patients have been described in the literature as having ACL associated with multiple myeloma (Table 1).816

Table Graphic Jump LocationTable 1 Summary of Acquired Cutis Laxa (ACL) Associated With Plasma Cell Dyscrasias

Our patient's cutaneous laxity distribution is consistent with descriptions of prior cases. In contrast to prior reports, this is the first case, to our knowledge, of ACL due to myeloma associated with the clinical presentation of GA-like plaques. It is also interesting to note that the face and upper body had only isolated skin laxity without preceding plaques. Histologic examination of the erythematous lesions showed marked elastolysis with elastophagocytosis by giant cells and lacked evidence of amyloid deposition. The pattern of elastic fiber destruction with engulfment by phagocytes can be a nonspecific finding but is characteristic of elastolytic giant cell granuloma, which occurs on sun-damaged areas in contrast to our patient. However, a papular variant with 2- to 3-mm skin-colored papules occurring on the chest, neck, back, and shoulders of a 43-year-old woman was recently described in association with a IgG-λ gammopathy.17

The patient's cutaneous changes prompted further systemic investigation leading to the diagnosis of early myeloma, which could improve his overall survival. It is theoretically possible that use of immunosuppressive agents may improve his gammopathy and decrease the progression of his cutaneous changes; however, the likelihood is very low given the outcomes of prior reported cases.

The exact pathogenesis of ACL is unclear. In the setting of myeloma, amyloid light chains are produced by plasma cells and are deposited in various organs leading to end-organ failure. Three of the cases1416 reviewed did show evidence of amyloid deposition with reduction and fragmentation of elastic fibers, and the patient described by Dicker et al16 with localized acrolocalized ACL had so much dermal amyloid deposition that elastic fibers could not be evaluated. In addition to amyloid deposition, immunoglobulin-heavy chain deposition has also been reported with ACL (Table 2).3,4,18 Unfortunately, we could not assess immunoglobulin deposition owing to lack of tissue. This hypothesis could be the basis for the cell-mediated destruction of elastic fibers in the gammopathy-associated cases of cutis laxa and the case of papularelastolytic giant cell granuloma recently described. However, it is difficult (if not impossible) to determine if the immune deposits are the primary event or a normal response to repair and “clean up” damaged tissue.

Table Graphic Jump LocationTable 2 Summary of Acquired Cutis Laxa Associated With Immunoglobulin Heavy Chain Deposition

In conclusion, ACL is a very rare entity described in the literature, and cases related to monoclonal gammopathy are even scarcer. We believe our case supports the theory that myeloma-associated immunoglobulin deposition on elastic fibers triggers a cell-mediated immune response leading to their destruction phagocytosis. In our patient, this resulted in decreased skin laxity and the development of plaques with a clinical presentation strikingly resembling GA. Clinicians should be aware of this association and evaluate for the presence of a gammopathy with immunofixation electrophoresis when a patient presents with ACL and/or GA-like plaques with histologic characteristics resembling the so-called elastolytic giant cell granuloma.

ARTICLE INFORMATION

Correspondence: Jeffrey P. Callen, MD, Division of Dermatology, University of Louisville, 310 E Broadway, Floor 2A, Louisville, KY 40202 (jefca@aol.com).

Accepted for Publication: July 14, 2010.

Author Contributions: Both authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: New and Callen. Acquisition of data: New and Callen. Analysis and interpretation of data: New and Callen. Drafting of the manuscript: New and Callen. Critical revision of the manuscript for important intellectual content: Callen. Administrative, technical, and material support: Callen. Study supervision: Callen.

Financial Disclosure: Dr Callen has received honorarium from Amgen, Abbott, Genentech, Centocor, Electrical Optical Sciences, Celgene, and Medicis. He serves on a safety monitoring committee for Celgene.

Disclaimer: Dr Callen is Associate Editor of the Archivesof Dermatology, but he was not involved in any of the decisions regarding review of the paper or its acceptance.

Additional Contributions: Janine Malone, MD, assisted with the dermatopathologic photographs and captions.

REFERENCES

Hu  QReymond  JLPinel  NZabot  MTUrban  Z Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. J Invest Dermatol 2006;126 (2) 283- 290
PubMed Link to Article
Riveros  CJGavilán  MFFrança  LFSotto  MNTakahashi  MD Acquired localized cutis laxa confined to the face: case report and review of the literature. Int J Dermatol 2004;43 (12) 931- 935
PubMed Link to Article
Harrington  CRBeswick  TCSusa  JSPandya  AG Acquired cutis laxa associated with heavy chain deposition disease. J Am Acad Dermatol 2008;59 (5) (suppl)S99- S101
PubMed Link to Article
Fernández de Larrea  CRovira  MMascaró  JM  Jr  et al.  Generalized cutis laxa and fibrillar glomerulopathy resulting from IgG deposition in IgG-lambda monoclonal gammopathy: pulmonary hemorrhage during stem cell mobilization and complete hematological response with bortezomib and dexamethasone therapy. Eur J Haematol 2009;82 (2) 154- 158
PubMed Link to Article
Mahajan  VKSharma  NLGarg  G Cutis laxa acquisita associated with cutaneous mastocytosis. Int J Dermatol 2006;45 (8) 949- 951
PubMed Link to Article
Hwang  STWilliams  ML McCalmont  THFrieden  IJ Sweet's syndrome leading to acquired cutis laxa (Marshall's syndrome) in an infant with alpha 1-antitrypsin deficiency. Arch Dermatol 1995;131 (10) 1175- 1177
PubMed Link to Article
Lucas  ABañuls  JMataix  J  et al.  Localized acquired cutis laxa secondary to interstitial granulomatous dermatitis. Clin Exp Dermatol 2009;34 (5) e102- e105
PubMed Link to Article
Turner  RBHaynes  HAGranter  SRMiller  DM Acquired cutis laxa following urticarial vasculitis associated with IgA myeloma. J Am Acad Dermatol 2009;60 (6) 1052- 1057
PubMed Link to Article
Scott  MAKauh  YCLuscombe  HA Acquired cutis laxa associated with multiple myeloma. Arch Dermatol 1976;112 (6) 853- 855
PubMed Link to Article
Cho  SYMaguire  RF Multiple myeloma associated with acquired cutis laxa. Cutis 1980;26 (2) 209- 211
PubMed
Ting  HCFoo  MHWang  F Acquired cutis laxa and multiple myeloma. Br J Dermatol 1984;110 (3) 363- 367
PubMed Link to Article
McCarty  MJDavidson  JMCardone  JSAnderson  LL Cutis laxa acquisita associated with multiple myeloma: a case report and review of the literature. Cutis 1996;57 (4) 267- 270
PubMed
Gupta  AHelm  TN Acquired cutis laxa associated with multiple myeloma. Cutis 2002;69 (2) 114- 118
PubMed
Yoneda  KKanoh  TNomura  SOzaki  MImamura  S Elastolytic cutaneous lesions in myeloma-associated amyloidosis. Arch Dermatol 1990;126 (5) 657- 660
PubMed Link to Article
Appiah  YEOnumah  NWu  HElenitsas  RJames  W Multiple myeloma-associated amyloidosis and acral localized acquired cutis laxa. J Am Acad Dermatol 2008;58 (2) (suppl)S32- S33
PubMed Link to Article
Dicker  TJMorton  JWilliamson  RMChick  J Myeloma-associated systemic amyloidosis presenting with acquired digital cutis laxa-like changes. Australas J Dermatol 2002;43 (2) 144- 146
PubMed Link to Article
Rongioletti  FBaldari  MBurlando  MParodi  A Papular elastolytic giant cell granuloma: report of a case associated with monoclonal gammopathy and responsive to topical tacrolimus. Clin Exp Dermatol 2010;35 (2) 145- 148
PubMed Link to Article
Tan  SPon  KBargman  JGhazarian  D Generalized cutis laxa associated with heavy chain deposition disease. J Cutan Med Surg 2003;7 (5) 390- 394
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1

Loose, sagging skin on the face and neck with “bloodhound-like” appearance.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2

Right lateral hip with loose, wrinkly, redundant folds with faint erythema.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3

Sacral area with nonscaly, somewhat annular, erythematous papules and plaques.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4

A 4-mm punch biopsy specimen from the hip demonstrating paucicellular infiltrate of interstitial histiocytes with intracytoplasmic eosinophilic refractile elastic fiber fragments (hematoxylin-eosin, original magnification ×600).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5

Verhoeff–Van Giesen stain highlights histiocytic cells engulfing fragmented elastic fibers, as well as diminished elastic fibers in the surrounding dermis (original magnification ×600).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1 Summary of Acquired Cutis Laxa (ACL) Associated With Plasma Cell Dyscrasias
Table Graphic Jump LocationTable 2 Summary of Acquired Cutis Laxa Associated With Immunoglobulin Heavy Chain Deposition

References

Hu  QReymond  JLPinel  NZabot  MTUrban  Z Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. J Invest Dermatol 2006;126 (2) 283- 290
PubMed Link to Article
Riveros  CJGavilán  MFFrança  LFSotto  MNTakahashi  MD Acquired localized cutis laxa confined to the face: case report and review of the literature. Int J Dermatol 2004;43 (12) 931- 935
PubMed Link to Article
Harrington  CRBeswick  TCSusa  JSPandya  AG Acquired cutis laxa associated with heavy chain deposition disease. J Am Acad Dermatol 2008;59 (5) (suppl)S99- S101
PubMed Link to Article
Fernández de Larrea  CRovira  MMascaró  JM  Jr  et al.  Generalized cutis laxa and fibrillar glomerulopathy resulting from IgG deposition in IgG-lambda monoclonal gammopathy: pulmonary hemorrhage during stem cell mobilization and complete hematological response with bortezomib and dexamethasone therapy. Eur J Haematol 2009;82 (2) 154- 158
PubMed Link to Article
Mahajan  VKSharma  NLGarg  G Cutis laxa acquisita associated with cutaneous mastocytosis. Int J Dermatol 2006;45 (8) 949- 951
PubMed Link to Article
Hwang  STWilliams  ML McCalmont  THFrieden  IJ Sweet's syndrome leading to acquired cutis laxa (Marshall's syndrome) in an infant with alpha 1-antitrypsin deficiency. Arch Dermatol 1995;131 (10) 1175- 1177
PubMed Link to Article
Lucas  ABañuls  JMataix  J  et al.  Localized acquired cutis laxa secondary to interstitial granulomatous dermatitis. Clin Exp Dermatol 2009;34 (5) e102- e105
PubMed Link to Article
Turner  RBHaynes  HAGranter  SRMiller  DM Acquired cutis laxa following urticarial vasculitis associated with IgA myeloma. J Am Acad Dermatol 2009;60 (6) 1052- 1057
PubMed Link to Article
Scott  MAKauh  YCLuscombe  HA Acquired cutis laxa associated with multiple myeloma. Arch Dermatol 1976;112 (6) 853- 855
PubMed Link to Article
Cho  SYMaguire  RF Multiple myeloma associated with acquired cutis laxa. Cutis 1980;26 (2) 209- 211
PubMed
Ting  HCFoo  MHWang  F Acquired cutis laxa and multiple myeloma. Br J Dermatol 1984;110 (3) 363- 367
PubMed Link to Article
McCarty  MJDavidson  JMCardone  JSAnderson  LL Cutis laxa acquisita associated with multiple myeloma: a case report and review of the literature. Cutis 1996;57 (4) 267- 270
PubMed
Gupta  AHelm  TN Acquired cutis laxa associated with multiple myeloma. Cutis 2002;69 (2) 114- 118
PubMed
Yoneda  KKanoh  TNomura  SOzaki  MImamura  S Elastolytic cutaneous lesions in myeloma-associated amyloidosis. Arch Dermatol 1990;126 (5) 657- 660
PubMed Link to Article
Appiah  YEOnumah  NWu  HElenitsas  RJames  W Multiple myeloma-associated amyloidosis and acral localized acquired cutis laxa. J Am Acad Dermatol 2008;58 (2) (suppl)S32- S33
PubMed Link to Article
Dicker  TJMorton  JWilliamson  RMChick  J Myeloma-associated systemic amyloidosis presenting with acquired digital cutis laxa-like changes. Australas J Dermatol 2002;43 (2) 144- 146
PubMed Link to Article
Rongioletti  FBaldari  MBurlando  MParodi  A Papular elastolytic giant cell granuloma: report of a case associated with monoclonal gammopathy and responsive to topical tacrolimus. Clin Exp Dermatol 2010;35 (2) 145- 148
PubMed Link to Article
Tan  SPon  KBargman  JGhazarian  D Generalized cutis laxa associated with heavy chain deposition disease. J Cutan Med Surg 2003;7 (5) 390- 394
PubMed Link to Article

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