Case report
POEMS syndrome with an unusual dermatologic manifestation: immunopathology of skin lesions Xu Chen1, MD, Mei Ju1, MD, Min Li2, MD, PhD, Hong-Yan Wu3, B.S.Med, Xiu-Lian Xu4, MD, Hao Chen4, MD, Kun Chen5, MD, Juan-Qin Gong1, MD, Lin Lin1, MD, and Heng Gu1, MD
1 Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing, China, 2 Department of Pathology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China, 3Department of Pathology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China, 4Departments of Pathology, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China, and 5Physical Therapy, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
Correspondence Heng Gu, MD 12 Jiangwangmiao Street Nanjing 210042 China E-mail: [email protected] Conflicts of interest: None.
Introduction POEMS syndrome is an unusual multisystemic disease typically accompanied by monoclonal plasmacyte disorders. The principle features of this syndrome, from which its designation is derived, are polyneuropathy (P), organomegaly (O), endocrinopathy (E), M protein (M), and skin (S) changes.1 Hyperpigmentation, acrocyanosis, skin thickening, hypertrichosis, and glomeruloid hemangioma are the most common skin changes.2 We report one case of POEMS syndrome associated with a rare dermatologic manifestation and immunopathologic features. Case report A 45-year-old man was referred to our hospital in March 2011 with atropurpureus patches on the thighs, diffused hyperpigmentation, and skin thickening. He had noticed ª 2013 The International Society of Dermatology
a gradual development of skin thickening and hyperpigmentation on the extremities over the previous three years. In December 2010, symmetrical and painful erythemas emerged on both thighs and gradually enlarged and developed into atropurpureus patches over the subsequent three months. The subject's medical history included polyneuropathy and Castleman's disease of three years' duration, as well as hypothyroidism and dysinsulinism of two years' duration. He had been diagnosed with hydropericardium, hydrothorax, and ascites two years previously. No polytrichia, pruritis, or hyperhidrosis had been noted. The subject had no history of smoking, alcoholism, drug abuse, or exposure to toxic agents. Physical examination revealed diffuse hyperpigmentation, thickening, dryness, and scales of the skin. A symmetrical, sharply circumscribed, atropurpureus patch was noted on the extensor surface of each thigh; these measured 5 9 4 cm on the left thigh and 4 9 2 cm on International Journal of Dermatology 2014, 53, 1513–1519
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the right thigh. The skin lesions exhibited a necrotic scarlike appearance, surrounded by pruinosus livedo peripherally (Fig. 1). Neurologic examination indicated hypoesthesia, hypoalgesia, and diminished tendon reflexes. In addition, a decrease in muscular strength in the lower extremities was noted. Routine analysis of blood showed that blood platelet count was 578 9 109/l (normal range: 100–300 9 109/l). Other laboratory findings were normal. Serum immunofixation electrophoresis was positive for immunoglobulin G (IgG) type lambda of monoclonal protein, but urine immunofixation electrophoresis was negative for monoclonal protein. Serum kappa free light chain showed a value of 2.54 g/l (normal range: 0.93–2.42 g/l); the patient's lambda free light chain level was normal. Urine immunofixation electrophoresis showed elevated levels of kappa (122.0 mg/l; normal range: 0–7.1 mg/l) and lambda (37.7 mg/l; normal range: 0–4.4 mg/l) light chains. The patient's C-reactive protein (CRP) was 19 mg/ l (normal range: 0–10 mg/l). Serum calcium was 2.11 mM (normal range: 2.18–2.92 mM), and serum phosphorus was 1.42 mM (normal range: 0.73–1.34 mM). Bone marrow aspiration showed active bone marrow hyperplasia, as well as normal form and ratios for all myeloid cell series. Electromyography indicated peripheral neuropathy. Ultrasonography demonstrated hepatomegaly and splenomegaly. Serum liver enzymes and bilirubin were normal. Creatinine, urea nitrogen, uric acid, and lactate dehydrogenase were normal. Serologic tests for hepatitis, human immunodeficiency virus (HIV), and syphilis were negative. Tests for antinuclear antibody (ANA), circulating immune complex (CIC), complement 3 (C3), complement 4 (C4), rheumatoid factor (RF), and antistreptolysin O (ASO)
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indicated negative findings. Papilledema was not observed. Plain radiographs of the chest and abdomen indicated no lytic or sclerotic lesions within the scanned skeletons. The clinical, laboratory, and radiographic findings in this patient fulfilled the diagnostic criteria defined by Dispenzieri et al.2 for POEMS syndrome. A first skin biopsy (Fig. 2a, b) from the atropurpureus patch on the right thigh showed hyperkeratosis associated with parakeratosis, intracellular edema in some epidermal areas, acanthosis, and increased melanin at the dermo–epidermal junction. An increased number of blood vessels, comprising capillaries and venules, most of which had significantly dilated lumens, were recognized in the superficial dermis. Slight lymphocytic infiltration around the vessels was noted within the dermis. No plasma cells were noticed. The lesion, which clinically manifested hyperpigmentation, was biopsied for a second time (Fig. 2c, d) on skin adjacent to the site of the first biopsy. Findings showed an increase in melanin at the dermo–epidermal junction and no proliferative or dilated vessels in the dermis. No histologic changes indicating vasculitis or thrombosis were seen in either of the biopsy specimens. Six formalin-fixed, paraffin-embedded specimens from each of the two biopsies were used in immunohistochemistry (IHC) studies for, respectively, CD31 (JC70A [1 : 200]; Dako, Carpinteria, CA, USA), CD34 (QBEnd.10 [1 : 350]; Dako), vascular endothelial growth factor (VEGF) (VG1 [1 : 400]; Dako), IgG (polyclonal [1 : 1000]; Dako), kappa light chain (KP-53 [1 : 100]; Novocastra, Newcastle upon Tyne, UK) and lambda light chain (Hp-6054 [1 : 100]; Novocastra). The vessel walls in the dermis in both biopsies stained
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Figure 1 At presentation, the patient exhibited symmetrical, sharply circumscribed, atropurpureus patches on the extensor surface of each thigh. The lesions were necrotic and scar-like in appearance, surrounded by pruinosus livedo peripherally. Biopsy 1 was obtained from the atropurpureus patch on the right thigh (red arrow). Biopsy 2 was obtained from the clinically hyperpigmented lesion on skin (blue arrow) adjacent to the site of biopsy 1 International Journal of Dermatology 2014, 53, 1513–1519
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positive for VEGF, but the intensity of staining among collagen bundles in biopsy 2 was significantly lower than that in biopsy 1 (Fig. 3). In addition, positive staining for VEGF was seen on the vessel walls in the subcutaneous fatty tissue in biopsy 1 (Fig. 3a). The epidermis in both biopsies showed diffuse positive staining for VEGF at a lower intensity, without apparent difference. Immunohistochemistry studies for CD31 and CD34 revealed positive staining of the vessel walls in
Case report
both biopsies. However, a significantly greater quantity of vessels stained positive for CD31 and CD34 in biopsy 1 than in biopsy 2 (Fig. 4). Positive staining for kappa and lambda light chains, which were deposited mainly on the vessel walls, was seen in both biopsies. Interestingly, the deposition of lambda was greater than that of kappa in biopsy 1 (Fig. 5). Positive staining for IgG was observed on the vessel walls in the dermis and subcutaneous fatty tissue in biopsy 1 (Fig. 6). Both
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Figure 2 Full montage preparation of (a) biopsy 1 and (b) biopsy 2. Higher magnification shows (c) an increased number of blood vessels, most of which have significantly dilated lumens, in the superficial dermis in biopsy 1, and (d) no proliferative or dilated vessels in the dermis in biopsy 2. No thrombosis or vasculitis were found in either biopsy. [Hematoxylin and eosin stain; original magnification (a, b) 940, (c, d) 9200]
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Figure 3 Immunohistochemistry studies for vascular endothelial growth factor (VEGF) show (a, b) diffusely positive staining on the vessel walls and among collagen bundles in biopsy 1, and (c, d) positive staining on some vessel walls, but significantly less intense staining of infra-collagen bundles in biopsy 2. The epidermis in both biopsies was diffusely positive for VEGF at a lower intensity, without apparent difference. [3,3′-Diaminobenzidine (DAB) stain; original magnification (a, c) 940, (b, d) 9200] ª 2013 The International Society of Dermatology
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Figure 4 Immunohistochemistry studies for CD31 and CD34 showing a larger number of blood vessels positive for (a, b) CD31 and (e, f) CD34 in biopsy 1. Quantities of vessels positive for (c, d) CD31 and (g, h) CD34 were significantly lower in biopsy 2. [3,3′-Diaminobenzidine (DAB) stain; original magnification (a, c, e, g) 940, (b, d, f, h) 9200]
biopsies were negative for special staining of crystal violet reacting with amyloid. Discussion Skin changes in POEMS syndrome include hyperpigmentation, skin thickening, hyperhidrosis, edema, hypertrichosis, glomeruloid hemangiomata, Raynaud's phe‐nomenon (or acrocyanosis), flushing, and white nails.1–4 Among these skin manifestations, glomeruloid hemangioma is considered to be a distinctive cutaneous marker of POEMS syndrome,5–7 although a few cases of glomeruloid hemangioma without POEMS syndrome have been described.8,9 Further, some rare skin manifestations have been reported, including alopecia,10 pigmented plaque,11 multiple seborrheic keratosis, ichthyosis, livedo reticularis, vasculitis,12 and facial lipoatrophy.4 International Journal of Dermatology 2014, 53, 1513–1519
Barete et al.4 described infiltrated livedo in six of a total of 21 patients with POEMS syndrome, in some of whom skin lesions were associated with necrosis. The histology of three biopsy specimens obtained from patients with infiltrated livedo with necrosis manifested thrombosis without vasculitis within the deep dermal or hypodermal arterioles.4 Although the outline of one patient's skin lesion, a photograph of which was published in Barete et al.,4 was similar to the outlines of the lesions in the present patient, the histologic features of the skin lesions were significantly distinct. Findings in the present patient indicated no thrombosis but an increased number of blood vessels, most of which had significantly dilated lumens. Vascular endothelial growth factor, a selective mitogen for endothelial cells, is critical for vasculogenesis and angiogenesis, and the role of high serum VEGF in POEMS ª 2013 The International Society of Dermatology
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Figure 5 Immunohistochemistry studies for kappa and lambda light chains showing positive staining for (a–d) kappa and (e–h) lambda light chains, which were deposited mainly on the vessel walls, in (a, b, e, f) biopsy 1 and (c, d, g, h) biopsy 2. The deposition of lambda was greater than that of kappa in biopsy 1 (e vs. a). [3,3′-Diaminobenzidine (DAB) stain; original magnification (a, c) 9100, (b, d, f, h) 9200, (c, g) 940]
syndrome has been emphasized in several studies.1,2,13,14 Consequently, the overproduction of VEGF is speculated to be involved in the pathogenesis of some skin changes in POEMS syndrome.4 Yamamoto and Yokozeki7 discovered the increased expression of VEGF and its receptor, Flt-1, in glomeruloid hemangioma with POEMS syndrome. Although we did not assay serum VEGF in the present patient, our findings in IHC studies, which demonstrated expression of VEGF in both skin biopsies and at a higher intensity in biopsy 1, indicate that the rare skin manifestation in this case may correlate with abnormal VEGF levels. CD34 is expressed by both hematopoietic progenitors and ª 2013 The International Society of Dermatology
endothelial cells,15 and enhanced expression of CD34 indicates activating or developing endothelial cells16 and correlates with vasculogenesis. Significantly more blood vessels marked for CD34 and CD31 in biopsy 1 than in biopsy 2; these findings are in accordance with comparative studies of VEGF, which exhibited a significant difference between the two biopsies. Therefore, the occurrence of the rare skin manifestation in the present case may reflect the involvement of VEGF-mediated vasculogenesis or angiogenesis. In vitro and in vivo studies have demonstrated that keratinocyte-derived VEGF is a potent mitogen for dermal microvascular endothelial cells.17,18 Overproduction of International Journal of Dermatology 2014, 53, 1513–1519
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Figure 6 Immunohistochemistry studies for immunoglobulin G (IgG) showing (a, b) increased deposition of IgG on the vessel walls in the dermis and subcutaneous fatty tissue in biopsy 1 and (c, d) less deposition in biopsy 2. [3,3′-Diaminobenzidine (DAB) stain; original magnification (a, c) 940, (b, d) 9200]
VEGF in the psoriatic epidermis19 is considered to play an important role in the pathogenesis of psoriasis, in which the dermis exhibits angioproliferation. Accordingly, the abnormal expression of VEGF in epidermal keratinocytes in the present patient indicates that the paracrine or autocrine actions of VEGF may participate in vasculogenesis or angiogenesis in the dermis in POEMS syndrome. Abnormal elevated serum lambda or kappa free light chains can be observed in nearly all POEMS syndrome patients,20 and the laboratory findings in the present patient were in accord with this characteristic. Enomoto et al.21 reported one case of POEMS syndrome with lambda chain deposition in a hemangioma; however, studies of the deposition of light chains or immunoglobulin in skin lesions in POEMS syndrome are rare. Interestingly, deposition of light chains was discovered in both biopsies in the present patient, and we speculate that this deposition of light chains may reflect the VEGF-mediated enhanced permeability of vessels in high serum levels of free light chains. It is currently unclear whether the deposition of light chains plays a pathogenetic role in skin changes in POEMS syndrome. Deposition of light chains can be a causative factor of amyloid light-chain (AL) amyloidosis, and POEMS syndrome accompanied by AL amyloidosis has been reported, albeit rarely.22,23 However, special staining for amyloid in both biopsies was negative. The issue of whether light chains deposition will trigger the development of amylogenesis requires further observation. We describe a case of POEMS syndrome associated with a rare skin manifestation. Immunohistochemistry studies for VEGF, CD31, CD34, kappa, lambda, and IgG indicate that the unusual skin manifestation in the present International Journal of Dermatology 2014, 53, 1513–1519
patient may reflect the involvement of VEGF-mediated vasculogenesis, angiogenesis, and enhanced vessel permeability, as well as the deposition of light chains and IgG. References 1 Dispenzieri A. POEMS syndrome. Blood Rev 2007; 21: 285–299. 2 Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome: definitions and longterm outcome. Blood 2003; 101: 2496–2506. 3 Miralles GD, OFallon JR, Talley NJ. Plasma-cell dyscrasia with polyneuropathy. The spectrum of POEMS syndrome. N Engl J Med 1992; 327: 1919–1923. 4 Barete S, Mouawad R, Choquet S, et al. Skin manifestations and vascular endothelial growth factor levels in POEMS syndrome: impact of autologous hematopoietic stem cell transplantation. Arch Dermatol 2010; 146: 615–623. 5 Phillips JA, Dixon JE, Richardson JB, et al. Glomeruloid hemangioma leading to a diagnosis of POEMS syndrome. J Am Acad Dermatol 2006; 55: 149–152. 6 Tsai CY, Lai CH, Chan HL, et al. Glomeruloid hemangioma – a specific cutaneous marker of POEMS syndrome. Int J Dermatol 2001; 40: 403–406. 7 Yamamoto T, Yokozeki H. Increased expression of vascular endothelial growth factor and its receptor, Flt-1, in glomeruloid hemangioma associated with Crow– Fukase syndrome. J Eur Acad Dermatol Venereol 2007; 21: 417–419. 8 González-Guerra E, Haro MR, Fariþa MC, et al. Glomeruloid hemangioma is not always associated with POEMS syndrome. Clin Exp Dermatol 2009; 34: 800–803. 9 Piña-Oviedo S, López-Patiño S, Ortiz-Hidalgo C. Glomeruloid hemangiomas localized to the skin of the ª 2013 The International Society of Dermatology
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trunk with no clinical features of POEMS syndrome. Int J Dermatol 2006; 45: 1449–1450. Amichai B, Giryes H, Ariad S, et al. Alopecia as a rare cutaneous manifestation of POEMS syndrome. Br J Dermatol 1994; 131: 297–298. Feddersen RM, Burgdorf W, Foucar K, et al. Plasma cell dyscrasia: a case of POEMS syndrome with a unique dermatologic presentation. J Am Acad Dermatol 1989; 21: 1061–1068. Fishel B, Brenner S, Weiss S, et al. POEMS syndrome associated with cryoglobulinemia, lymphoma, multiple seborrheic keratosis, and ichthyosis. J Am Acad Dermatol 1988; 19: 979–982. Scarlato M, Previtali SC, Carpo M, et al. Polyneuropathy in POEMS syndrome: role of angiogenic factors in the pathogenesis. Brain 2005; 128: 1911–1920. D’Souza A, Hayman SR, Buadi F, et al. The utility of plasma vascular endothelial growth factor levels in the diagnosis and follow-up of patients with POEMS syndrome. Blood 2011; 118: 4663–4665. Suda J, Sudo T, Ito M, et al. Two types of murine CD34 mRNA generated by alternative splicing. Blood 1992; 79: 2288–2295. Ito A, Nomura S, Hirota S, et al. Enhanced expression of CD34 messenger RNA by developing endothelial cells of mice. Lab Invest 1995; 72: 532–538. Detmar M, Yeo KT, Nagy JA, et al. Keratinocytederived vascular permeability factor (vascular
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endothelial growth factor) is a potent mitogen for dermal microvascular endothelial cells. J Invest Dermatol 1995; 105: 44–50. Mirones I, Conti CJ, Martínez J, et al. Complexity of VEGF responses in skin carcinogenesis revealed through ex vivo assays based on a VEGF-A null mouse keratinocyte cell line. J Invest Dermatol 2009; 129: 730–741. Detmar M, Brown LF, Claffey KP, et al. Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med 1994; 180: 1141–1146. Stankowski-Drengler T, Gertz MA, Katzmann JA, et al. Serum immunoglobulin free light chain measurements and heavy chain isotype usage provide insight into disease biology in patients with POEMS syndrome. Am J Hematol 2010; 85: 431–434. Enomoto H, Takahashi T, Sato H, et al. POEMS syndrome with lambda chain deposition in hemangioma. Eur J Dermatol 2008; 18: 463–464. Adami F, Briani C, Binotto G, et al. Coexistence of primary AL amyloidosis and POEMS syndrome: efficacy of melphalan-dexamethasone and role of biochemical markers in monitoring the disease course. Am J Hematol 2010; 85: 131–132. Patier JL, Pinilla A, Rodríguez-Posada A, et al. Primary amyloidosis associated with osteosclerotic myeloma. Rev Clin Esp 2003; 203: 162–163.
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POEMS syndrome with an unusual dermatologic manifestation: immunopathology of skin lesions Xu Chen1, MD, Mei Ju1, MD, Min Li2, MD, PhD, Hong-Yan Wu3, B.S.Med, Xiu-Lian Xu4, MD, Hao Chen4, MD, Kun Chen5, MD, Juan-Qin Gong1, MD, Lin Lin1, MD, and Heng Gu1, MD
1 Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing, China, 2 Department of Pathology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China, 3Department of Pathology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China, 4Departments of Pathology, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China, and 5Physical Therapy, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
Correspondence Heng Gu, MD 12 Jiangwangmiao Street Nanjing 210042 China E-mail: [email protected] Conflicts of interest: None.
Introduction POEMS syndrome is an unusual multisystemic disease typically accompanied by monoclonal plasmacyte disorders. The principle features of this syndrome, from which its designation is derived, are polyneuropathy (P), organomegaly (O), endocrinopathy (E), M protein (M), and skin (S) changes.1 Hyperpigmentation, acrocyanosis, skin thickening, hypertrichosis, and glomeruloid hemangioma are the most common skin changes.2 We report one case of POEMS syndrome associated with a rare dermatologic manifestation and immunopathologic features. Case report A 45-year-old man was referred to our hospital in March 2011 with atropurpureus patches on the thighs, diffused hyperpigmentation, and skin thickening. He had noticed ª 2013 The International Society of Dermatology
a gradual development of skin thickening and hyperpigmentation on the extremities over the previous three years. In December 2010, symmetrical and painful erythemas emerged on both thighs and gradually enlarged and developed into atropurpureus patches over the subsequent three months. The subject's medical history included polyneuropathy and Castleman's disease of three years' duration, as well as hypothyroidism and dysinsulinism of two years' duration. He had been diagnosed with hydropericardium, hydrothorax, and ascites two years previously. No polytrichia, pruritis, or hyperhidrosis had been noted. The subject had no history of smoking, alcoholism, drug abuse, or exposure to toxic agents. Physical examination revealed diffuse hyperpigmentation, thickening, dryness, and scales of the skin. A symmetrical, sharply circumscribed, atropurpureus patch was noted on the extensor surface of each thigh; these measured 5 9 4 cm on the left thigh and 4 9 2 cm on International Journal of Dermatology 2014, 53, 1513–1519
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the right thigh. The skin lesions exhibited a necrotic scarlike appearance, surrounded by pruinosus livedo peripherally (Fig. 1). Neurologic examination indicated hypoesthesia, hypoalgesia, and diminished tendon reflexes. In addition, a decrease in muscular strength in the lower extremities was noted. Routine analysis of blood showed that blood platelet count was 578 9 109/l (normal range: 100–300 9 109/l). Other laboratory findings were normal. Serum immunofixation electrophoresis was positive for immunoglobulin G (IgG) type lambda of monoclonal protein, but urine immunofixation electrophoresis was negative for monoclonal protein. Serum kappa free light chain showed a value of 2.54 g/l (normal range: 0.93–2.42 g/l); the patient's lambda free light chain level was normal. Urine immunofixation electrophoresis showed elevated levels of kappa (122.0 mg/l; normal range: 0–7.1 mg/l) and lambda (37.7 mg/l; normal range: 0–4.4 mg/l) light chains. The patient's C-reactive protein (CRP) was 19 mg/ l (normal range: 0–10 mg/l). Serum calcium was 2.11 mM (normal range: 2.18–2.92 mM), and serum phosphorus was 1.42 mM (normal range: 0.73–1.34 mM). Bone marrow aspiration showed active bone marrow hyperplasia, as well as normal form and ratios for all myeloid cell series. Electromyography indicated peripheral neuropathy. Ultrasonography demonstrated hepatomegaly and splenomegaly. Serum liver enzymes and bilirubin were normal. Creatinine, urea nitrogen, uric acid, and lactate dehydrogenase were normal. Serologic tests for hepatitis, human immunodeficiency virus (HIV), and syphilis were negative. Tests for antinuclear antibody (ANA), circulating immune complex (CIC), complement 3 (C3), complement 4 (C4), rheumatoid factor (RF), and antistreptolysin O (ASO)
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indicated negative findings. Papilledema was not observed. Plain radiographs of the chest and abdomen indicated no lytic or sclerotic lesions within the scanned skeletons. The clinical, laboratory, and radiographic findings in this patient fulfilled the diagnostic criteria defined by Dispenzieri et al.2 for POEMS syndrome. A first skin biopsy (Fig. 2a, b) from the atropurpureus patch on the right thigh showed hyperkeratosis associated with parakeratosis, intracellular edema in some epidermal areas, acanthosis, and increased melanin at the dermo–epidermal junction. An increased number of blood vessels, comprising capillaries and venules, most of which had significantly dilated lumens, were recognized in the superficial dermis. Slight lymphocytic infiltration around the vessels was noted within the dermis. No plasma cells were noticed. The lesion, which clinically manifested hyperpigmentation, was biopsied for a second time (Fig. 2c, d) on skin adjacent to the site of the first biopsy. Findings showed an increase in melanin at the dermo–epidermal junction and no proliferative or dilated vessels in the dermis. No histologic changes indicating vasculitis or thrombosis were seen in either of the biopsy specimens. Six formalin-fixed, paraffin-embedded specimens from each of the two biopsies were used in immunohistochemistry (IHC) studies for, respectively, CD31 (JC70A [1 : 200]; Dako, Carpinteria, CA, USA), CD34 (QBEnd.10 [1 : 350]; Dako), vascular endothelial growth factor (VEGF) (VG1 [1 : 400]; Dako), IgG (polyclonal [1 : 1000]; Dako), kappa light chain (KP-53 [1 : 100]; Novocastra, Newcastle upon Tyne, UK) and lambda light chain (Hp-6054 [1 : 100]; Novocastra). The vessel walls in the dermis in both biopsies stained
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Figure 1 At presentation, the patient exhibited symmetrical, sharply circumscribed, atropurpureus patches on the extensor surface of each thigh. The lesions were necrotic and scar-like in appearance, surrounded by pruinosus livedo peripherally. Biopsy 1 was obtained from the atropurpureus patch on the right thigh (red arrow). Biopsy 2 was obtained from the clinically hyperpigmented lesion on skin (blue arrow) adjacent to the site of biopsy 1 International Journal of Dermatology 2014, 53, 1513–1519
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positive for VEGF, but the intensity of staining among collagen bundles in biopsy 2 was significantly lower than that in biopsy 1 (Fig. 3). In addition, positive staining for VEGF was seen on the vessel walls in the subcutaneous fatty tissue in biopsy 1 (Fig. 3a). The epidermis in both biopsies showed diffuse positive staining for VEGF at a lower intensity, without apparent difference. Immunohistochemistry studies for CD31 and CD34 revealed positive staining of the vessel walls in
Case report
both biopsies. However, a significantly greater quantity of vessels stained positive for CD31 and CD34 in biopsy 1 than in biopsy 2 (Fig. 4). Positive staining for kappa and lambda light chains, which were deposited mainly on the vessel walls, was seen in both biopsies. Interestingly, the deposition of lambda was greater than that of kappa in biopsy 1 (Fig. 5). Positive staining for IgG was observed on the vessel walls in the dermis and subcutaneous fatty tissue in biopsy 1 (Fig. 6). Both
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Figure 2 Full montage preparation of (a) biopsy 1 and (b) biopsy 2. Higher magnification shows (c) an increased number of blood vessels, most of which have significantly dilated lumens, in the superficial dermis in biopsy 1, and (d) no proliferative or dilated vessels in the dermis in biopsy 2. No thrombosis or vasculitis were found in either biopsy. [Hematoxylin and eosin stain; original magnification (a, b) 940, (c, d) 9200]
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Figure 3 Immunohistochemistry studies for vascular endothelial growth factor (VEGF) show (a, b) diffusely positive staining on the vessel walls and among collagen bundles in biopsy 1, and (c, d) positive staining on some vessel walls, but significantly less intense staining of infra-collagen bundles in biopsy 2. The epidermis in both biopsies was diffusely positive for VEGF at a lower intensity, without apparent difference. [3,3′-Diaminobenzidine (DAB) stain; original magnification (a, c) 940, (b, d) 9200] ª 2013 The International Society of Dermatology
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Figure 4 Immunohistochemistry studies for CD31 and CD34 showing a larger number of blood vessels positive for (a, b) CD31 and (e, f) CD34 in biopsy 1. Quantities of vessels positive for (c, d) CD31 and (g, h) CD34 were significantly lower in biopsy 2. [3,3′-Diaminobenzidine (DAB) stain; original magnification (a, c, e, g) 940, (b, d, f, h) 9200]
biopsies were negative for special staining of crystal violet reacting with amyloid. Discussion Skin changes in POEMS syndrome include hyperpigmentation, skin thickening, hyperhidrosis, edema, hypertrichosis, glomeruloid hemangiomata, Raynaud's phe‐nomenon (or acrocyanosis), flushing, and white nails.1–4 Among these skin manifestations, glomeruloid hemangioma is considered to be a distinctive cutaneous marker of POEMS syndrome,5–7 although a few cases of glomeruloid hemangioma without POEMS syndrome have been described.8,9 Further, some rare skin manifestations have been reported, including alopecia,10 pigmented plaque,11 multiple seborrheic keratosis, ichthyosis, livedo reticularis, vasculitis,12 and facial lipoatrophy.4 International Journal of Dermatology 2014, 53, 1513–1519
Barete et al.4 described infiltrated livedo in six of a total of 21 patients with POEMS syndrome, in some of whom skin lesions were associated with necrosis. The histology of three biopsy specimens obtained from patients with infiltrated livedo with necrosis manifested thrombosis without vasculitis within the deep dermal or hypodermal arterioles.4 Although the outline of one patient's skin lesion, a photograph of which was published in Barete et al.,4 was similar to the outlines of the lesions in the present patient, the histologic features of the skin lesions were significantly distinct. Findings in the present patient indicated no thrombosis but an increased number of blood vessels, most of which had significantly dilated lumens. Vascular endothelial growth factor, a selective mitogen for endothelial cells, is critical for vasculogenesis and angiogenesis, and the role of high serum VEGF in POEMS ª 2013 The International Society of Dermatology
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Figure 5 Immunohistochemistry studies for kappa and lambda light chains showing positive staining for (a–d) kappa and (e–h) lambda light chains, which were deposited mainly on the vessel walls, in (a, b, e, f) biopsy 1 and (c, d, g, h) biopsy 2. The deposition of lambda was greater than that of kappa in biopsy 1 (e vs. a). [3,3′-Diaminobenzidine (DAB) stain; original magnification (a, c) 9100, (b, d, f, h) 9200, (c, g) 940]
syndrome has been emphasized in several studies.1,2,13,14 Consequently, the overproduction of VEGF is speculated to be involved in the pathogenesis of some skin changes in POEMS syndrome.4 Yamamoto and Yokozeki7 discovered the increased expression of VEGF and its receptor, Flt-1, in glomeruloid hemangioma with POEMS syndrome. Although we did not assay serum VEGF in the present patient, our findings in IHC studies, which demonstrated expression of VEGF in both skin biopsies and at a higher intensity in biopsy 1, indicate that the rare skin manifestation in this case may correlate with abnormal VEGF levels. CD34 is expressed by both hematopoietic progenitors and ª 2013 The International Society of Dermatology
endothelial cells,15 and enhanced expression of CD34 indicates activating or developing endothelial cells16 and correlates with vasculogenesis. Significantly more blood vessels marked for CD34 and CD31 in biopsy 1 than in biopsy 2; these findings are in accordance with comparative studies of VEGF, which exhibited a significant difference between the two biopsies. Therefore, the occurrence of the rare skin manifestation in the present case may reflect the involvement of VEGF-mediated vasculogenesis or angiogenesis. In vitro and in vivo studies have demonstrated that keratinocyte-derived VEGF is a potent mitogen for dermal microvascular endothelial cells.17,18 Overproduction of International Journal of Dermatology 2014, 53, 1513–1519
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POEMS syndrome with unusual skin change
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Figure 6 Immunohistochemistry studies for immunoglobulin G (IgG) showing (a, b) increased deposition of IgG on the vessel walls in the dermis and subcutaneous fatty tissue in biopsy 1 and (c, d) less deposition in biopsy 2. [3,3′-Diaminobenzidine (DAB) stain; original magnification (a, c) 940, (b, d) 9200]
VEGF in the psoriatic epidermis19 is considered to play an important role in the pathogenesis of psoriasis, in which the dermis exhibits angioproliferation. Accordingly, the abnormal expression of VEGF in epidermal keratinocytes in the present patient indicates that the paracrine or autocrine actions of VEGF may participate in vasculogenesis or angiogenesis in the dermis in POEMS syndrome. Abnormal elevated serum lambda or kappa free light chains can be observed in nearly all POEMS syndrome patients,20 and the laboratory findings in the present patient were in accord with this characteristic. Enomoto et al.21 reported one case of POEMS syndrome with lambda chain deposition in a hemangioma; however, studies of the deposition of light chains or immunoglobulin in skin lesions in POEMS syndrome are rare. Interestingly, deposition of light chains was discovered in both biopsies in the present patient, and we speculate that this deposition of light chains may reflect the VEGF-mediated enhanced permeability of vessels in high serum levels of free light chains. It is currently unclear whether the deposition of light chains plays a pathogenetic role in skin changes in POEMS syndrome. Deposition of light chains can be a causative factor of amyloid light-chain (AL) amyloidosis, and POEMS syndrome accompanied by AL amyloidosis has been reported, albeit rarely.22,23 However, special staining for amyloid in both biopsies was negative. The issue of whether light chains deposition will trigger the development of amylogenesis requires further observation. We describe a case of POEMS syndrome associated with a rare skin manifestation. Immunohistochemistry studies for VEGF, CD31, CD34, kappa, lambda, and IgG indicate that the unusual skin manifestation in the present International Journal of Dermatology 2014, 53, 1513–1519
patient may reflect the involvement of VEGF-mediated vasculogenesis, angiogenesis, and enhanced vessel permeability, as well as the deposition of light chains and IgG. References 1 Dispenzieri A. POEMS syndrome. Blood Rev 2007; 21: 285–299. 2 Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome: definitions and longterm outcome. Blood 2003; 101: 2496–2506. 3 Miralles GD, OFallon JR, Talley NJ. Plasma-cell dyscrasia with polyneuropathy. The spectrum of POEMS syndrome. N Engl J Med 1992; 327: 1919–1923. 4 Barete S, Mouawad R, Choquet S, et al. Skin manifestations and vascular endothelial growth factor levels in POEMS syndrome: impact of autologous hematopoietic stem cell transplantation. Arch Dermatol 2010; 146: 615–623. 5 Phillips JA, Dixon JE, Richardson JB, et al. Glomeruloid hemangioma leading to a diagnosis of POEMS syndrome. J Am Acad Dermatol 2006; 55: 149–152. 6 Tsai CY, Lai CH, Chan HL, et al. Glomeruloid hemangioma – a specific cutaneous marker of POEMS syndrome. Int J Dermatol 2001; 40: 403–406. 7 Yamamoto T, Yokozeki H. Increased expression of vascular endothelial growth factor and its receptor, Flt-1, in glomeruloid hemangioma associated with Crow– Fukase syndrome. J Eur Acad Dermatol Venereol 2007; 21: 417–419. 8 González-Guerra E, Haro MR, Fariþa MC, et al. Glomeruloid hemangioma is not always associated with POEMS syndrome. Clin Exp Dermatol 2009; 34: 800–803. 9 Piña-Oviedo S, López-Patiño S, Ortiz-Hidalgo C. Glomeruloid hemangiomas localized to the skin of the ª 2013 The International Society of Dermatology
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trunk with no clinical features of POEMS syndrome. Int J Dermatol 2006; 45: 1449–1450. Amichai B, Giryes H, Ariad S, et al. Alopecia as a rare cutaneous manifestation of POEMS syndrome. Br J Dermatol 1994; 131: 297–298. Feddersen RM, Burgdorf W, Foucar K, et al. Plasma cell dyscrasia: a case of POEMS syndrome with a unique dermatologic presentation. J Am Acad Dermatol 1989; 21: 1061–1068. Fishel B, Brenner S, Weiss S, et al. POEMS syndrome associated with cryoglobulinemia, lymphoma, multiple seborrheic keratosis, and ichthyosis. J Am Acad Dermatol 1988; 19: 979–982. Scarlato M, Previtali SC, Carpo M, et al. Polyneuropathy in POEMS syndrome: role of angiogenic factors in the pathogenesis. Brain 2005; 128: 1911–1920. D’Souza A, Hayman SR, Buadi F, et al. The utility of plasma vascular endothelial growth factor levels in the diagnosis and follow-up of patients with POEMS syndrome. Blood 2011; 118: 4663–4665. Suda J, Sudo T, Ito M, et al. Two types of murine CD34 mRNA generated by alternative splicing. Blood 1992; 79: 2288–2295. Ito A, Nomura S, Hirota S, et al. Enhanced expression of CD34 messenger RNA by developing endothelial cells of mice. Lab Invest 1995; 72: 532–538. Detmar M, Yeo KT, Nagy JA, et al. Keratinocytederived vascular permeability factor (vascular
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endothelial growth factor) is a potent mitogen for dermal microvascular endothelial cells. J Invest Dermatol 1995; 105: 44–50. Mirones I, Conti CJ, Martínez J, et al. Complexity of VEGF responses in skin carcinogenesis revealed through ex vivo assays based on a VEGF-A null mouse keratinocyte cell line. J Invest Dermatol 2009; 129: 730–741. Detmar M, Brown LF, Claffey KP, et al. Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med 1994; 180: 1141–1146. Stankowski-Drengler T, Gertz MA, Katzmann JA, et al. Serum immunoglobulin free light chain measurements and heavy chain isotype usage provide insight into disease biology in patients with POEMS syndrome. Am J Hematol 2010; 85: 431–434. Enomoto H, Takahashi T, Sato H, et al. POEMS syndrome with lambda chain deposition in hemangioma. Eur J Dermatol 2008; 18: 463–464. Adami F, Briani C, Binotto G, et al. Coexistence of primary AL amyloidosis and POEMS syndrome: efficacy of melphalan-dexamethasone and role of biochemical markers in monitoring the disease course. Am J Hematol 2010; 85: 131–132. Patier JL, Pinilla A, Rodríguez-Posada A, et al. Primary amyloidosis associated with osteosclerotic myeloma. Rev Clin Esp 2003; 203: 162–163.
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