Clinical Review & Education
JAMA Dermatology Clinicopathological Challenge
Multiple Skin-Colored Papules With Diffuse Sclerosis Danielle S. Applebaum, BS; Seema Daulat, MD; Madeleine Duvic, MD
A man in his 60s presented with a 2-year history of progressive skin tightening and the formation of multiple asymptomatic papules symmetrically distributed on the extremities, face, and neck. He also developed mild dysphagia, intermittent voice hoarseness, and difficultyclosinghismouth,withdroolingwhileeating.Hereporteda9.1-kg weight loss owing to difficulty eating during the past year. Physical examination revealed diffuse hardening of the skin with multiple 1- to 3-mm white to skin-colored papules on the dorsal
A
aspect of the hands (Figure, A), arms, knees, posterior aspect of the neck, and posterior auricular area (Figure, B). There was decreased ability to pinch the skin on the forearms, and the oral aperture was slightly decreased at 3 cm. A 5-mm skin punch biopsy was performed on the right forearm for evaluation (Figure, C). What is your diagnosis?
B
C
Figure. A, Photograph of white to skin-colored papules on the dorsal aspect of the hands. B, Photograph of white to skin-colored papules on the posterior auricular area. C, Hematoxylin-eosin–stained section of skin punch biopsy specimen from the right forearm with cellular interstitial dermal proliferation of plump fibroblasts associated with increased dermal mucin and fragmented collagen bundles (arrowheads). Original magnification ×40.
jamadermatology.com
JAMA Dermatology August 2014 Volume 150, Number 8
Copyright 2014 American Medical Association. All rights reserved.
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893
Clinical Review & Education JAMA Dermatology Clinicopathological Challenge
Diagnosis Lichen myxedematosus
Microscopic Findings and Clinical Course Histopathologic examination revealed a cellular interstitial dermal infiltrate in the superficial and deep dermis with notable proliferation of plump fibroblasts, fragmented collagen bundles, and an increase in dermal mucin highlighted with colloidal iron stain. Serum protein electrophoresis revealed an IgG-λ monoclonal gammopathy (M-protein, 0.2 g/dL) with paraproteinemia (0.4 g/dL). A urine protein electrophoresis test was positive for IgG-λ Mproteinuria without Bence-Jones proteinuria. A bone marrow test was negative for malignant neoplasms, and results from thyroid studies were normal. To date, the patient’s disease is stable while he is receiving topical steroids (triamcinolone acetonide cream and clobetasol priopionate cream), bortezomib injections twice weekly, and pulsed dexamethasone, 40 mg weekly.
Discussion The group of disorders on the spectrum of lichen myxedematosus to scleromyxedema includes a localized form and a more generalized form, respectively.1,2 Rongioletti and Rebora3 described the histologic triad of scleromyxedema, which includes dermal mucin deposition, fibroblast proliferation, and fibrosis. Scleromyxedema, the most severe variant of lichen myxedematosus, is a rare disorder characterized by widespread cutaneous mucinosis (papular and scleroderma) and a monoclonal gammopathy in the absence of thyroid disease.1-6 This disorder affects adults in their 50s and 60s, with no sex predominance.2,6 Although scleromyxedema is often histologically indistinguishable from nephrogenic systemic fibrosis (NSF), with fibroblast proliferation and dermal mucin deposition, NSF commonly involves the fat, in contrast to scleromyxedema.4 ARTICLE INFORMATION Author Affiliations: Baylor College of Medicine, Houston, Texas (Applebaum); University of Texas, Houston (Daulat); MD Anderson Cancer Center, University of Texas, Houston (Duvic). Corresponding Author: Madeleine Duvic, MD, Department of Dermatology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1452, Houston, TX 77030 ([email protected]). Section Editor: Molly A. Hinshaw, MD; Assistant Section Editors: Soon Bahrami, MD; Nicole Fett, MD, MSCE; Anna K. Haemel, MD; Arni K. Kristjansson, MD; Lori D. Prok, MD. Published Online: June 11, 2014. doi:10.1001/jamadermatol.2014.14. Conflict of Interest Disclosures: None reported.
894
The pathogenesis of scleromyxedema remains unknown, and the relation to the paraproteinemia (seen in 80% of patients) is unclear.2,6 Although serum from patients with scleromyxedema stimulates dermal fibroblast proliferation in vitro, isolated IgG from these same patients fails to produce this same response, suggesting a role for a nonparaprotein factor in the pathogenesis of scleromyxedema.2,4,6 Clinically, patients can present with either widespread, small (2to 3-mm), waxy papules most commonly on the face, neck, upper trunk, forearms, hands (with sparing of the palms), and thighs or with generalized sclerosis.4-6 Patients may complain of decreased motility in their hands, mouth, and extremities.6 The papules, which are usually nonpruritic, may coalesce, forming sclerodermatous plaques without telangiectasia or calcinosis.3-6 Various signs have been described in patients with scleromyxedema, including leonine facies owing to glabellar infiltration,4,6 the “doughnut sign” owing to thickening of the proximal interphalangeal joint with central depression,3,4,6 and the “Shar-Pei sign” owing to deep furrowing of the back.1 In addition to their cutaneous symptoms, patients with scleromyxedema often have a number of extracutaneous manifestations.4,6 Common extracutaneous findings include dysphagia,2-4,6 upper gastrointestinal tract dysmotility,5,6 proximal muscle weakness,2-6 carpal tunnel syndrome, arthropathy,2,5,6 restrictive or obstructive lung disease,2,3,5,6 and neurological symptoms (dermatoneuro syndrome) characterized by fever, encephalopathy, seizures, and coma, often with an influenza-like prodrome.1,2,4-6 Although 80% of patients have a paraproteinemia, most often IgG-λ, only 10% of cases progress to multiple myeloma.2-4,6 No standardized treatment for scleromyxedema exists, and response to topical therapies has been limited.2,4 Promising results have been reported with systemic therapies including high-dose dexamethasone,1,2,6 intravenous immunoglobulins,1,2,4-6 low- or high-dose melphalan,1-6 photopheresis,2,3,5,6 thalidomide,1,4 and autologous stem cell transplant.1,2,5,6
Additional Contributions: Jonathan L. Curry, MD (Department of Pathology), and Donna Weber, MD (Department of Lymphoma/Myeloma), University of Texas, MD Anderson Cancer Center, Houston, assisted with this study. They are salaried employees. REFERENCES 1. Rongioletti F, Merlo G, Cinotti E, et al. Scleromyxedema: a multicenter study of characteristics, comorbidities, course, and therapy in 30 patients [published online February 26, 2013]. J Am Acad Dermatol. doi:10.1016/j.jaad.2013.01.007. 2. Rongioletti F. Lichen myxedematosus (papular mucinosis): new concepts and perspectives for an old disease. Semin Cutan Med Surg. 2006;25(2): 100-104.
3. Rongioletti F, Rebora A. Updated classification of papular mucinosis, lichen myxedematosus, and scleromyxedema. J Am Acad Dermatol. 2001;44(2): 273-281. 4. Yaqub A, Chung L, Rieger KE, Fiorentino DF. Localized cutaneous fibrosing disorders. Rheum Dis Clin North Am. 2013;39(2):347-364. 5. Donato ML, Feasel AM, Weber DM, et al. Scleromyxedema: role of high-dose melphalan with autologous stem cell transplantation. Blood. 2006; 107(2):463-466. 6. Cokonis Georgakis CD, Falasca G, Georgakis A, Heymann WR. Scleromyxedema. Clin Dermatol. 2006;24(6):493-497.
JAMA Dermatology August 2014 Volume 150, Number 8
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Nanyang Technological University User on 05/21/2015
jamadermatology.com
JAMA Dermatology Clinicopathological Challenge
Multiple Skin-Colored Papules With Diffuse Sclerosis Danielle S. Applebaum, BS; Seema Daulat, MD; Madeleine Duvic, MD
A man in his 60s presented with a 2-year history of progressive skin tightening and the formation of multiple asymptomatic papules symmetrically distributed on the extremities, face, and neck. He also developed mild dysphagia, intermittent voice hoarseness, and difficultyclosinghismouth,withdroolingwhileeating.Hereporteda9.1-kg weight loss owing to difficulty eating during the past year. Physical examination revealed diffuse hardening of the skin with multiple 1- to 3-mm white to skin-colored papules on the dorsal
A
aspect of the hands (Figure, A), arms, knees, posterior aspect of the neck, and posterior auricular area (Figure, B). There was decreased ability to pinch the skin on the forearms, and the oral aperture was slightly decreased at 3 cm. A 5-mm skin punch biopsy was performed on the right forearm for evaluation (Figure, C). What is your diagnosis?
B
C
Figure. A, Photograph of white to skin-colored papules on the dorsal aspect of the hands. B, Photograph of white to skin-colored papules on the posterior auricular area. C, Hematoxylin-eosin–stained section of skin punch biopsy specimen from the right forearm with cellular interstitial dermal proliferation of plump fibroblasts associated with increased dermal mucin and fragmented collagen bundles (arrowheads). Original magnification ×40.
jamadermatology.com
JAMA Dermatology August 2014 Volume 150, Number 8
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Nanyang Technological University User on 05/21/2015
893
Clinical Review & Education JAMA Dermatology Clinicopathological Challenge
Diagnosis Lichen myxedematosus
Microscopic Findings and Clinical Course Histopathologic examination revealed a cellular interstitial dermal infiltrate in the superficial and deep dermis with notable proliferation of plump fibroblasts, fragmented collagen bundles, and an increase in dermal mucin highlighted with colloidal iron stain. Serum protein electrophoresis revealed an IgG-λ monoclonal gammopathy (M-protein, 0.2 g/dL) with paraproteinemia (0.4 g/dL). A urine protein electrophoresis test was positive for IgG-λ Mproteinuria without Bence-Jones proteinuria. A bone marrow test was negative for malignant neoplasms, and results from thyroid studies were normal. To date, the patient’s disease is stable while he is receiving topical steroids (triamcinolone acetonide cream and clobetasol priopionate cream), bortezomib injections twice weekly, and pulsed dexamethasone, 40 mg weekly.
Discussion The group of disorders on the spectrum of lichen myxedematosus to scleromyxedema includes a localized form and a more generalized form, respectively.1,2 Rongioletti and Rebora3 described the histologic triad of scleromyxedema, which includes dermal mucin deposition, fibroblast proliferation, and fibrosis. Scleromyxedema, the most severe variant of lichen myxedematosus, is a rare disorder characterized by widespread cutaneous mucinosis (papular and scleroderma) and a monoclonal gammopathy in the absence of thyroid disease.1-6 This disorder affects adults in their 50s and 60s, with no sex predominance.2,6 Although scleromyxedema is often histologically indistinguishable from nephrogenic systemic fibrosis (NSF), with fibroblast proliferation and dermal mucin deposition, NSF commonly involves the fat, in contrast to scleromyxedema.4 ARTICLE INFORMATION Author Affiliations: Baylor College of Medicine, Houston, Texas (Applebaum); University of Texas, Houston (Daulat); MD Anderson Cancer Center, University of Texas, Houston (Duvic). Corresponding Author: Madeleine Duvic, MD, Department of Dermatology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1452, Houston, TX 77030 ([email protected]). Section Editor: Molly A. Hinshaw, MD; Assistant Section Editors: Soon Bahrami, MD; Nicole Fett, MD, MSCE; Anna K. Haemel, MD; Arni K. Kristjansson, MD; Lori D. Prok, MD. Published Online: June 11, 2014. doi:10.1001/jamadermatol.2014.14. Conflict of Interest Disclosures: None reported.
894
The pathogenesis of scleromyxedema remains unknown, and the relation to the paraproteinemia (seen in 80% of patients) is unclear.2,6 Although serum from patients with scleromyxedema stimulates dermal fibroblast proliferation in vitro, isolated IgG from these same patients fails to produce this same response, suggesting a role for a nonparaprotein factor in the pathogenesis of scleromyxedema.2,4,6 Clinically, patients can present with either widespread, small (2to 3-mm), waxy papules most commonly on the face, neck, upper trunk, forearms, hands (with sparing of the palms), and thighs or with generalized sclerosis.4-6 Patients may complain of decreased motility in their hands, mouth, and extremities.6 The papules, which are usually nonpruritic, may coalesce, forming sclerodermatous plaques without telangiectasia or calcinosis.3-6 Various signs have been described in patients with scleromyxedema, including leonine facies owing to glabellar infiltration,4,6 the “doughnut sign” owing to thickening of the proximal interphalangeal joint with central depression,3,4,6 and the “Shar-Pei sign” owing to deep furrowing of the back.1 In addition to their cutaneous symptoms, patients with scleromyxedema often have a number of extracutaneous manifestations.4,6 Common extracutaneous findings include dysphagia,2-4,6 upper gastrointestinal tract dysmotility,5,6 proximal muscle weakness,2-6 carpal tunnel syndrome, arthropathy,2,5,6 restrictive or obstructive lung disease,2,3,5,6 and neurological symptoms (dermatoneuro syndrome) characterized by fever, encephalopathy, seizures, and coma, often with an influenza-like prodrome.1,2,4-6 Although 80% of patients have a paraproteinemia, most often IgG-λ, only 10% of cases progress to multiple myeloma.2-4,6 No standardized treatment for scleromyxedema exists, and response to topical therapies has been limited.2,4 Promising results have been reported with systemic therapies including high-dose dexamethasone,1,2,6 intravenous immunoglobulins,1,2,4-6 low- or high-dose melphalan,1-6 photopheresis,2,3,5,6 thalidomide,1,4 and autologous stem cell transplant.1,2,5,6
Additional Contributions: Jonathan L. Curry, MD (Department of Pathology), and Donna Weber, MD (Department of Lymphoma/Myeloma), University of Texas, MD Anderson Cancer Center, Houston, assisted with this study. They are salaried employees. REFERENCES 1. Rongioletti F, Merlo G, Cinotti E, et al. Scleromyxedema: a multicenter study of characteristics, comorbidities, course, and therapy in 30 patients [published online February 26, 2013]. J Am Acad Dermatol. doi:10.1016/j.jaad.2013.01.007. 2. Rongioletti F. Lichen myxedematosus (papular mucinosis): new concepts and perspectives for an old disease. Semin Cutan Med Surg. 2006;25(2): 100-104.
3. Rongioletti F, Rebora A. Updated classification of papular mucinosis, lichen myxedematosus, and scleromyxedema. J Am Acad Dermatol. 2001;44(2): 273-281. 4. Yaqub A, Chung L, Rieger KE, Fiorentino DF. Localized cutaneous fibrosing disorders. Rheum Dis Clin North Am. 2013;39(2):347-364. 5. Donato ML, Feasel AM, Weber DM, et al. Scleromyxedema: role of high-dose melphalan with autologous stem cell transplantation. Blood. 2006; 107(2):463-466. 6. Cokonis Georgakis CD, Falasca G, Georgakis A, Heymann WR. Scleromyxedema. Clin Dermatol. 2006;24(6):493-497.
JAMA Dermatology August 2014 Volume 150, Number 8
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Nanyang Technological University User on 05/21/2015
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