EXTRAORDINARY CASE REPORT
Granulomatous Scleromyxedema: Case Report and Literature Review Julia Shlyankevich, BS,* Galina Y. Stetsenko, MD, MHA,† Evan George, MD,‡ Dan M. Lantz, MD,† Nicholas R. Burwick, MD,§ and Jay C. Vary Jr, MD, PhD†
Abstract: Scleromyxedema is a rare and frequently disabling disease characterized by generalized waxy papules, skin induration, and cardinal histological features of dermal fibroblastic proliferation, thickened collagen, and mucin deposition. A monoclonal gammopathy is almost always present with rare progression to multiple myeloma. We describe the case of a 54-year-old man who presented with a rash in the setting of a new medication and histological features suggesting a granulomatous drug reaction. Despite discontinuation of the medication, the rash persisted and a second biopsy confirmed an interstitial granulomatous pattern. Serum protein electrophoresis identified the presence of a biclonal gammopathy leading to a diagnosis of granulomatous scleromyxedema. Review of the medical literature reveals only a handful of well-documented similar cases of this rare variant. It is important for pathologists and clinicians to be familiar with this condition to facilitate timely diagnosis and optimal clinical management of these patients. Key Words: scleromyxedema, lichen myxedematosus, monoclonal gammopathy (Am J Dermatopathol 2015;37:240–245)
INTRODUCTION Scleromyxedema is a chronic idiopathic disease characterized by widespread erythematous papules and progressive skin induration and tightening. Dermal mucin deposits, increased fibroblast proliferation, and marked collagen deposition are the key histological features.1 Paraproteinemia [usually immunoglobulin (Ig) with l light chain] is almost invariably present. We describe a 54-yearold man who presented with physical findings of scleromyxedema and interstitial granulomatous features on light microscopy. An initial diagnosis of interstitial granulomatous drug reaction was suggested, but the condition did not improve after discontinuation of the suspected medication, From the *School of Medicine, University of Washington, Seattle, WA; †Department of Medicine, Division of Dermatology, University of Washington, Seattle, WA; ‡Department of Pathology, University of Washington, Seattle, WA; and §Department of Medicine, University of Washington Medical Center, Seattle, WA; and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA. The authors declare no conflicts of interest. Reprints: Jay C. Vary Jr, MD, PhD, Department of Medicine, Division of Dermatology, University of Washington, Box 354697 4225 Roosevelt Way NE, Fourth floor, Seattle, WA 98105 (e-mail: [email protected]). Copyright © 2013 Wolters Kluwer Health, Inc. All rights reserved.
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allopurinol. On further evaluation, the patient was found to have biclonal IgA and IgG l light chain gammopathies by serum protein electrophoresis (SPEP). Integration of the physical findings, laboratory abnormalities, and histopathologic features led to a diagnosis of granulomatous scleromyxedema. This is the fifth such case documented in the medical literature, further supporting the existence of a granulomatous variant of scleromyxedema. We also discuss the differential diagnosis of cutaneous interstitial granulomatous disorders and summarize previous cases reported in the medical literature.
CASE REPORT A 54-year-old man presented with a 2-month history of an erythematous pruritic eruption involving the face, upper extremities, and torso. The rash started 1 week after the initiation of allopurinol for gout. A biopsy of lesional skin was performed and revealed a superficial dermal spindle cell proliferation associated with thickened collagen bundles and interstitial mucin deposits. A diagnosis of interstitial granulomatous drug reaction was favored. All medications, including allopurinol were discontinued. The patient was started on topical triamcinolone ointment and a prednisone taper with subsequent improvement of the symptoms. However, after completion of the taper and reinitiation of antihypertensives because of uncontrollable hypertension, small pruritic papules, erythema, and edema of the face and shoulders recurred. On presentation to our clinic, the patient reported a 3-month history of skin tightening and waxiness of his forehead, neck, back, torso, and arms. He had a decreased ability to open his mouth because of stiffness of the skin, intermittent swelling of the abdomen, mild shortness of breath, and hand and finger swelling with difficulty making a fist. Medical history was significant for Crohn’s disease in remission, hypertension, and controlled Graves disease after thyroid ablation and replacement therapy. Medications on presentation included atenolol, levothyroxine, hydrochlorothiazide, simvastatin, and losartan. Physical examination revealed exaggerated wrinkling of the glabella and firm skin on the sides of the nose, upper back, and shoulders (Fig. 1). Numerous 2- to 3-mm waxy papules were diffusely scattered over the upper shoulders. There was notable tightness along the labial commissures, with the ability to insert only 2.5 adjacent fingers between his incisors at maximal opening. His skin appeared xerotic and became noticeably flushed with minimal movement, demarcating areas of induration. Periorbital edema, telangiectasias, and calcinosis were absent. A cutaneous punch biopsy specimen from the right shoulder was performed. The most prominent abnormality was a band-like zone of stromal hypercellularity and thickened collagen bundles in the upper reticular dermis (Fig. 2A). Histiocytoid cells with abundant blue-gray cytoplasm and spindle cells surrounded thickened collagen Am J Dermatopathol Volume 37, Number 3, March 2015
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Am J Dermatopathol Volume 37, Number 3, March 2015
Granulomatous Scleromyxedema
FIGURE 1. Induration and erythema of the skin, waxy papules, and microstomia. Clinical photographs printed with the permission of the patient.
bundles, occasionally forming loose granulomas and cords, without necrobiotic foci (Fig. 2B). There was also a mild perivascular lymphoid infiltrate with rare plasma cells. Colloidal iron stains highlighted increased dermal mucin, which cleared with hyaluronidase digestion (Fig. 2C). Immunohistochemical staining for CD68 highlighted the lesional histiocytoid and spindle cells (Fig. 2D). The epidermis showed minimal alterations including mild compact hyperkeratosis and attenuation of the rete ridges. These histopathologic features were suggestive of interstitial granuloma annulare. Laboratory studies revealed a complete blood cell count and comprehensive metabolic panel within normal limits. Thyroid stimulating factor was mildly depressed but normalized on repeat labs. Anti-Scl70 and anticentromere antibodies were negative. SPEP was significant for a biclonal IgG and IgA l gammopathy. Urine analysis was negative for Bence–Jones proteins. Clinical features suggestive of scleromyxedema in conjunction with changes suggestive of interstitial granuloma annulare on light microscopy and biclonal gammopathy led to the diagnosis of granulomatous scleromyxedema. The patient was referred to the hematology–oncology service for further evaluation of a possible plasma cell dyscrasia. Subsequent bone marrow biopsy revealed Copyright 2013 Wolters Kluwer Health, Inc. All rights reserved.
normocellular marrow with a mild increase in plasma cells (8.5% by manual estimate). Flow cytometry demonstrated an abnormal plasma cell population with biclonal l light chain restriction indicative of plasma cell dyscrasia. Without the presence of hypercalcemia, renal insufficiency, anemia or lytic bone lesions, and less than 10% abnormal plasma cells in the bone marrow, the biclonal gammopathy was not sufficient to diagnose multiple myeloma. None of the cytogenic abnormalities associated with multiple myeloma were demonstrated in fluorescence in situ hybridization studies of bone marrow aspirate. The k–l serum-free light chain ratio was normal. Treatment was initiated for the patient given the presumed monoclonal gammopathy of unknown significance associated scleromyxedema, which has been reported to respond to anti–myelomabased therapy. Treatment consisted of lenalidomide 25 mg for 21 days of a 28-day cycle and dexamethasone 40 mg orally per week. The patient exhibited significant symptomatic improvement after 1 treatment cycle, including an increased ability to open his mouth, improved finger flexion, and softening of the facial skin. The papular skin eruption persisted on the upper extremities, whereas areas of thickening showed gradual improvement. Repeat SPEP showed an absence of an IgA spike and a progressive decrease in IgG l. www.amjdermatopathology.com |
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FIGURE 2. A, Superficial dermis with band-like cellular infiltrate (hematoxylin–eosin stain; original magnification: ·40). B, Epithelioid and spindled dermal infiltrate associated with thickened collagen bundles (hematoxylin–eosin stain; original magnification: · 200). C, Colloidal iron stain demonstrates increased dermal mucin (original magnification: ·100). D, CD68 stain highlighting the dermal infiltrate (original magnification: ·100).
DISCUSSION Scleromyxedema, also known as the generalized form of lichen myxedematosus (papular mucinosis), is an idiopathic, chronic, and disabling disease equally affecting middle-aged men and women.1,2 The diagnosis of scleromyxedema is made based on the compilation of clinical, laboratory, and histological studies. The characteristic skin findings consist of 2- to 3-mm, waxy, firm, dome-shaped, or flat-topped papules in a densely grouped, symmetrical, and linear arrangement. The lesions most commonly involve the dorsal hands, forearms, face, neck, upper trunk, and thighs.3 Nearby skin is often shiny in appearance and can progress to erythematous infiltrated plaques with skin stiffening, sclerodactyly, and decreased mobility of the mouth and joints, resembling scleroderma but with absent telangiectasias and calcinosis.1 Deep longitudinal furrowing of the glabella may also be present.1 Systemic involvement, which may include proximal myopathy, inflammatory polyarthritis, esophageal dysfunction, pulmonary and neurologic complications, is a common cause of morbidity and mortality in this disease.4 Scleromyxedema is almost always associated with a paraproteinemia, usually IgG with l light chains.4 Our patient presented with a biclonal IgG and IgA gammopathy, which is a rare phenomena observed in 2%–6% of patients with monoclonal gammopathy detected by SPEP.5 Biclonal gammopathy in the setting of scleromyxedema has only been reported twice in the literature.6,7 As with our patient, there may be a mild bone marrow plasmacytosis, and there is rare progression to multiple myeloma or other hematologic malignancies.1 The pathophysiology of scleromyxedema has not been elucidated; however, serum from patients with this disease
has been shown to stimulate abnormal fibroblast activation and proliferation and increased production of glycosaminoglycans.8 This did not occur with the purified IgG population, however, suggesting a causative soluble factor separate from the associated gammopathy. The characteristic histology of scleromyxedema is a triad of (1) increased mucin deposition in the upper and midreticular dermis, (2) proliferation of fibroblasts, often stellate and large, and (3) increased collagen deposition.2,4 In biopsy specimens wherein all of these histological alterations are fully developed, the overall pattern is relatively distinct from those observed in other disorders with increased dermal mucin and sclerotic collagen. The principal histological differential diagnostic consideration is the recently described entity of nephrogenic systemic fibrosis (NSF) (also known as nephrogenic fibrosing dermopathy).9 NSF tends to involve the entire thickness of the reticular dermis, whereas the histological alterations in scleromyxedema are usually limited to the midreticular and upper reticular dermis. Also, clinical NSF is usually seen in patients with renal insufficiency and exposure to gadolinium-based contrast agents. Scleroderma is also in both the histological and clinical differential diagnoses but is less likely with the presence of waxy papules and a gammopathy and the histological findings of increased mucin and histiocytic infiltrate concentrated in the upper reticular dermis. The interstitial granulomatous reaction pattern observed in our patient’s biopsies evokes a broader differential diagnosis including interstitial granuloma annulare, interstitial granulomatous drug reaction, granulomatous mycosis fungoides, superantigen id reaction, and interstitial granulomatous dermatitis. The last of these is associated with various
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Granulomatous Scleromyxedema
TABLE 1. Summary of Granulomatous Lichen Myxedematosus Case Characteristics Reference Stetsenko et al, 200812
Age/ Gender 56/M
Skin Findings
Extracutaneous Findings
Pruritic, generalized fleshcolored papules
Microstomia
Generalized hyperpigmentation and skin induration
Multiple joint contractures Sclerodactyly
Laboratory Results Monoclonal IgG k gammopathy
Dysphagia
Rongioletti et al, 201011
76/M
Flesh-colored papules on glabella, auricular, post-auricular area, and forearms Skin hardening and tightness of trunk and extremities
Esophageal dysmotility Weight loss Shortness of breath Microstomia Multiple joint contractures
Monoclonal IgG l gammopathy
Sclerodactyly
Bolton and Satter, 201213
42/M
Initially few yellow postauricular papules
None
Monoclonal IgG l gammopathy
None
Monoclonal IgG l gammopathy
Later, erythematous, waxy papules of arms and upper back
De Cambourg et al, 201214
55/M
Flesh-colored papules on erythematous and indurated base on extensor surfaces of hands and feet, inner thighs and hypogastric region
Histological Findings
Treatment
Follow-up
Diffuse band-like histiocytic infiltrate with abundant bluegray cytoplasm forming loose granulomas Epithelioid and spindled cytomorphology Patchy lymphocytic infiltrate Patchy mucin accumulation Factor XIIIa and CD68+
Thalidomide and dexamethasone
Improvement of skin thickening
Perivascular and interstitial infiltrate of epitheliod cells with abundant blue-gray cytoplasm in papillary and midreticular dermis Scattered lymphocytes Sparse giant cells Interstitial mucin deposition
IVIG
CD68+ *Interstitial infiltrate of spindled and epithelioid cells in upper to mid-dermis Sparse perivascular lymphoplasmacytic infiltrate Increased interstitial mucin Factor XIIIa and CD68+ Granulomas with altered eosinophilia of collagen fibers Basophilic stromal material Moderate inflammatory infiltrate surrounding necrotic collagen bundles CD68+ Diffuse dermal mucin deposits in later biopsies
Alive at 3 y
Excellent response including less difficulty opening the mouth after 1 cycle
No specific treatment
No specific treatment
Limited improvement thereafter Alive at 4 mo Lesions on postauricular area and back resolved Lesions on arms expanded and became confluent Skin involvement remained stable
Resolution of gammopathy
(continued on next page )
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TABLE 1. (Continued ) Summary of Granulomatous Lichen Myxedematosus Case Characteristics Reference Shlyankevich et al (Current study)
Age/ Gender 54/M
Skin Findings Pruritic, waxy papular rash on upper shoulders
Extracutaneous Findings Microstomia
Laboratory Results Biclonal IgG and IgA l gammopathy
Histological Findings
Treatment
Follow-up
Increased deposition of whorled collagen in dermis
Lenalidomide and dexamethasone
Decreased microstomia, improved finger flexion and softening of facial skin Resolution of IgA spike and decreased IgG Alive at 8 mo
Numerous histiocytic and spindled cells with abundant bluegray cytoplasm Erythema and induration of face, torso and upper extremities
Abdominal swelling Shortness of breath Hand and finger swelling
Mild perivascular lymphocytic infiltrate Increased dermal mucin CD68+
*Initial papules on post-auricular skin showed xanthogranulomatous features. Later, waxy papules had interstitial granulomatous pattern. Eventually, classic scleromyxedema histology. ANA, anti-nuclear antibody; M, male; IVIG, intravenous immunoglobulin.
autoimmune diseases and lymphoproliferative disorders. Attention to subtle histological clues such as vacuolar interface change, apoptotic keratinocytes, the presence of neutrophils or eosinophils, and lymphocytic nuclear atypia can be helpful.9,10 However, correlation with clinical dermatologic findings, medical history, and medication usage is usually required. Although granulomatous inflammation is not usually associated with scleromyxedema or other forms of lichen myxedematosus, 4 cases with an unusual granulomatous histological pattern have been previously reported.11–14 A summary of these cases is presented in Table 1. All reported cases were in males between the ages of 42 and 76 years, and skin biopsy findings initially interpreted as most suggestive of granuloma annulare. Two of these cases presented with a generalized form of lichen myxedematosus (scleromyxedema),11,12 1 with localized disease,13 and 1 with an intermediate form.14 Both patients with generalized disease presented with a pruritic papular rash and significant sclerodermoid induration. Monoclonal IgG gammopathies were present in both cases; however, one had l light chains11 and the other presented with k light chains.12 Nevertheless, the cutaneous eruptions and partial responses to treatment were similar. Histological specimens from both showed mucin deposition, increased fibroblasts, mild perivascular lymphocytic inflammation, and an interstitial histiocytic infiltrate, occasionally forming loose granulomas. Giant cells were sparse, and necrobiosis was not observed. The case reported by Bolton and Satter13 presented with a localized form of lichen myxedematosus and IgG l monoclonal gammopathy. Interestingly, biopsies at different points in time exhibited variable histological patterns; the first specimen had xanthogranulomatous changes, the second had an interstitial granulomatous reaction pattern, and later biopsies finally showed the typical features associated with scleromyxedema.
Similarly, in the case reported by De Cambourg et al,14 early biopsies were most consistent with granuloma annulare, whereas later biopsies showed more typical findings of scleromyxedema. Clinically, this patient presented with a widespread papular rash consistent with an intermediate (or atypical) form of lichen myxedematosus with an associated IgG l monoclonal gammopathy but lacked the generalized sclerodermoid eruption of scleromyxedema. The presence of paraproteinemia and typical clinical manifestations of lichen myxedematosus/scleromyxedema in the reported patients supports the hypothesis that the observed granulomatous infiltrates in this rare variant are likely in response to the monoclonal gammopathy or other factors related to the underlying plasma cell dyscrasia.12 Granulomatous cutaneous reactions have also been described in association with many types of neoplasms including a wide variety of hematolymphoid malignancies.15 Unfortunately, the molecular pathophysiology for these phenomena remain poorly understood. The role of multiple myeloma therapy in the treatment of scleromyxedema has shown promising clinical results.16 Importantly, our patient showed significant clinical improvement in terms of skin tightening and complete to near complete resolution of the IgA and IgG gammopathies, respectively, after the initiation of lenalidomide and dexamethasone therapy. The previously reported patient with granulomatous scleromyxedema in the setting of monoclonal gammopathy showed marked improvement with similar treatment as well.12 These results support the use of these multiple myeloma treatments in the management of patients with granulomatous scleromyxedema. In summary, the current case study and literature review lend further support to the existence of a granulomatous variant of scleromyxedema. This diagnosis should be considered in the setting of similar clinical and histological findings.
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REFERENCES 1. Ronglioletti F, Rebora A. Updated classification of papular mucinosis, lichen myxedematosus, and scleromyxedema. J Am Acad Dermatol. 2001;44:273–281. 2. Rongioletti F. Lichen myxedematosus (papular mucinosis): new concepts and perspectives for an old disease. Semin Cutan Med Surg. 2006;25:100–104. 3. Georgakis C, Falasca G, Georgakis A, et al. Scleromyxedema. Clin Dermatol. 2006;24:493–497. 4. Dinneen AM, Dicken CH. Scleromyxedema. J Am Acad Dermatol. 1995; 33:37–43. 5. Varettoni M, Corso A, Cocito F, et al. Changing pattern of presentation in monoclonal gammopathy of undetermined significance. A single center experience with 1400 patients. Medicine (Baltimore). 2010;89:211–216. 6. Gabriel SE, Perry HO, Oleson GB, et al. Scleromyxedema: a sclerodermalike disorder with systemic manifestations. Medicine (Baltimore). 1988;67: 58–65. 7. Manousaridis I, Loeser C, Goerdt S, et al. Managing scleromyxedema with intravenous immunoglobulin: acute worsening of scleromyxedema with biclonal gammopathy. Acta Dermatovenerol Alp Panonica Adriat. 2010;19:15–19. 8. Harper RA, Rispler J. Lichen myxedematosus serum stimulates human skin fibroblasts proliferation. Science. 1978;199:545–547.
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Granulomatous Scleromyxedema 9. Wheedon D. Skin Pathology. 3rd ed. Philadelphia, PA: Elsevier; 2010. 10. Magro CM, Crowson AN, Schapiro BL. The interstitial granulomatous drug reaction: a distinctive clinical and pathological entity. J Cutan Pathol. 1998;25:72–78. 11. Rongioletti F, Cozzani E, Parodi A. Scleromyxedema with an interstitial granulomatous-like pattern: a rare histologic variant mimicking granuloma annulare. J Cutan Pathol. 2010;37:1084–1087. 12. Stetsenko GY, Vary JC Jr, Olerud JE, et al. Unusual granulomatous variant of scleromyxedema. J Am Acad Dermatol. 2008;59:346–349. 13. Bolton JG, Satter EK. An interstitial granulomatous pattern in localized lichen myxedematosus with associated monoclonal gammopathy. J Cutan Pathol. 2012;39:395–398. 14. De Cambourg G, Joganah H, Cribier B. Atypical papular mucinosis with initial histological findings evocative of granuloma annulare. Ann Dermatol Venereol. 2012;139:58–62. 15. Rongioletti F, Cerroni L, Massone C, et al. Different histologic patterns of cutaneous granulomas in systemic lymphoma. J Am Acad Dermatol. 2004;51:600–605. 16. Canueto J, Labrador J, Roman C, et al. The combination of bortezomib and dexamethasone is an efficient therapy for relapsed/refractory scleromyxedema: a rare disease with new clinical insights. Eur J Haematol. 2012;88:450–452.
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Granulomatous Scleromyxedema: Case Report and Literature Review Julia Shlyankevich, BS,* Galina Y. Stetsenko, MD, MHA,† Evan George, MD,‡ Dan M. Lantz, MD,† Nicholas R. Burwick, MD,§ and Jay C. Vary Jr, MD, PhD†
Abstract: Scleromyxedema is a rare and frequently disabling disease characterized by generalized waxy papules, skin induration, and cardinal histological features of dermal fibroblastic proliferation, thickened collagen, and mucin deposition. A monoclonal gammopathy is almost always present with rare progression to multiple myeloma. We describe the case of a 54-year-old man who presented with a rash in the setting of a new medication and histological features suggesting a granulomatous drug reaction. Despite discontinuation of the medication, the rash persisted and a second biopsy confirmed an interstitial granulomatous pattern. Serum protein electrophoresis identified the presence of a biclonal gammopathy leading to a diagnosis of granulomatous scleromyxedema. Review of the medical literature reveals only a handful of well-documented similar cases of this rare variant. It is important for pathologists and clinicians to be familiar with this condition to facilitate timely diagnosis and optimal clinical management of these patients. Key Words: scleromyxedema, lichen myxedematosus, monoclonal gammopathy (Am J Dermatopathol 2015;37:240–245)
INTRODUCTION Scleromyxedema is a chronic idiopathic disease characterized by widespread erythematous papules and progressive skin induration and tightening. Dermal mucin deposits, increased fibroblast proliferation, and marked collagen deposition are the key histological features.1 Paraproteinemia [usually immunoglobulin (Ig) with l light chain] is almost invariably present. We describe a 54-yearold man who presented with physical findings of scleromyxedema and interstitial granulomatous features on light microscopy. An initial diagnosis of interstitial granulomatous drug reaction was suggested, but the condition did not improve after discontinuation of the suspected medication, From the *School of Medicine, University of Washington, Seattle, WA; †Department of Medicine, Division of Dermatology, University of Washington, Seattle, WA; ‡Department of Pathology, University of Washington, Seattle, WA; and §Department of Medicine, University of Washington Medical Center, Seattle, WA; and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA. The authors declare no conflicts of interest. Reprints: Jay C. Vary Jr, MD, PhD, Department of Medicine, Division of Dermatology, University of Washington, Box 354697 4225 Roosevelt Way NE, Fourth floor, Seattle, WA 98105 (e-mail: [email protected]). Copyright © 2013 Wolters Kluwer Health, Inc. All rights reserved.
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allopurinol. On further evaluation, the patient was found to have biclonal IgA and IgG l light chain gammopathies by serum protein electrophoresis (SPEP). Integration of the physical findings, laboratory abnormalities, and histopathologic features led to a diagnosis of granulomatous scleromyxedema. This is the fifth such case documented in the medical literature, further supporting the existence of a granulomatous variant of scleromyxedema. We also discuss the differential diagnosis of cutaneous interstitial granulomatous disorders and summarize previous cases reported in the medical literature.
CASE REPORT A 54-year-old man presented with a 2-month history of an erythematous pruritic eruption involving the face, upper extremities, and torso. The rash started 1 week after the initiation of allopurinol for gout. A biopsy of lesional skin was performed and revealed a superficial dermal spindle cell proliferation associated with thickened collagen bundles and interstitial mucin deposits. A diagnosis of interstitial granulomatous drug reaction was favored. All medications, including allopurinol were discontinued. The patient was started on topical triamcinolone ointment and a prednisone taper with subsequent improvement of the symptoms. However, after completion of the taper and reinitiation of antihypertensives because of uncontrollable hypertension, small pruritic papules, erythema, and edema of the face and shoulders recurred. On presentation to our clinic, the patient reported a 3-month history of skin tightening and waxiness of his forehead, neck, back, torso, and arms. He had a decreased ability to open his mouth because of stiffness of the skin, intermittent swelling of the abdomen, mild shortness of breath, and hand and finger swelling with difficulty making a fist. Medical history was significant for Crohn’s disease in remission, hypertension, and controlled Graves disease after thyroid ablation and replacement therapy. Medications on presentation included atenolol, levothyroxine, hydrochlorothiazide, simvastatin, and losartan. Physical examination revealed exaggerated wrinkling of the glabella and firm skin on the sides of the nose, upper back, and shoulders (Fig. 1). Numerous 2- to 3-mm waxy papules were diffusely scattered over the upper shoulders. There was notable tightness along the labial commissures, with the ability to insert only 2.5 adjacent fingers between his incisors at maximal opening. His skin appeared xerotic and became noticeably flushed with minimal movement, demarcating areas of induration. Periorbital edema, telangiectasias, and calcinosis were absent. A cutaneous punch biopsy specimen from the right shoulder was performed. The most prominent abnormality was a band-like zone of stromal hypercellularity and thickened collagen bundles in the upper reticular dermis (Fig. 2A). Histiocytoid cells with abundant blue-gray cytoplasm and spindle cells surrounded thickened collagen Am J Dermatopathol Volume 37, Number 3, March 2015
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Am J Dermatopathol Volume 37, Number 3, March 2015
Granulomatous Scleromyxedema
FIGURE 1. Induration and erythema of the skin, waxy papules, and microstomia. Clinical photographs printed with the permission of the patient.
bundles, occasionally forming loose granulomas and cords, without necrobiotic foci (Fig. 2B). There was also a mild perivascular lymphoid infiltrate with rare plasma cells. Colloidal iron stains highlighted increased dermal mucin, which cleared with hyaluronidase digestion (Fig. 2C). Immunohistochemical staining for CD68 highlighted the lesional histiocytoid and spindle cells (Fig. 2D). The epidermis showed minimal alterations including mild compact hyperkeratosis and attenuation of the rete ridges. These histopathologic features were suggestive of interstitial granuloma annulare. Laboratory studies revealed a complete blood cell count and comprehensive metabolic panel within normal limits. Thyroid stimulating factor was mildly depressed but normalized on repeat labs. Anti-Scl70 and anticentromere antibodies were negative. SPEP was significant for a biclonal IgG and IgA l gammopathy. Urine analysis was negative for Bence–Jones proteins. Clinical features suggestive of scleromyxedema in conjunction with changes suggestive of interstitial granuloma annulare on light microscopy and biclonal gammopathy led to the diagnosis of granulomatous scleromyxedema. The patient was referred to the hematology–oncology service for further evaluation of a possible plasma cell dyscrasia. Subsequent bone marrow biopsy revealed Copyright 2013 Wolters Kluwer Health, Inc. All rights reserved.
normocellular marrow with a mild increase in plasma cells (8.5% by manual estimate). Flow cytometry demonstrated an abnormal plasma cell population with biclonal l light chain restriction indicative of plasma cell dyscrasia. Without the presence of hypercalcemia, renal insufficiency, anemia or lytic bone lesions, and less than 10% abnormal plasma cells in the bone marrow, the biclonal gammopathy was not sufficient to diagnose multiple myeloma. None of the cytogenic abnormalities associated with multiple myeloma were demonstrated in fluorescence in situ hybridization studies of bone marrow aspirate. The k–l serum-free light chain ratio was normal. Treatment was initiated for the patient given the presumed monoclonal gammopathy of unknown significance associated scleromyxedema, which has been reported to respond to anti–myelomabased therapy. Treatment consisted of lenalidomide 25 mg for 21 days of a 28-day cycle and dexamethasone 40 mg orally per week. The patient exhibited significant symptomatic improvement after 1 treatment cycle, including an increased ability to open his mouth, improved finger flexion, and softening of the facial skin. The papular skin eruption persisted on the upper extremities, whereas areas of thickening showed gradual improvement. Repeat SPEP showed an absence of an IgA spike and a progressive decrease in IgG l. www.amjdermatopathology.com |
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FIGURE 2. A, Superficial dermis with band-like cellular infiltrate (hematoxylin–eosin stain; original magnification: ·40). B, Epithelioid and spindled dermal infiltrate associated with thickened collagen bundles (hematoxylin–eosin stain; original magnification: · 200). C, Colloidal iron stain demonstrates increased dermal mucin (original magnification: ·100). D, CD68 stain highlighting the dermal infiltrate (original magnification: ·100).
DISCUSSION Scleromyxedema, also known as the generalized form of lichen myxedematosus (papular mucinosis), is an idiopathic, chronic, and disabling disease equally affecting middle-aged men and women.1,2 The diagnosis of scleromyxedema is made based on the compilation of clinical, laboratory, and histological studies. The characteristic skin findings consist of 2- to 3-mm, waxy, firm, dome-shaped, or flat-topped papules in a densely grouped, symmetrical, and linear arrangement. The lesions most commonly involve the dorsal hands, forearms, face, neck, upper trunk, and thighs.3 Nearby skin is often shiny in appearance and can progress to erythematous infiltrated plaques with skin stiffening, sclerodactyly, and decreased mobility of the mouth and joints, resembling scleroderma but with absent telangiectasias and calcinosis.1 Deep longitudinal furrowing of the glabella may also be present.1 Systemic involvement, which may include proximal myopathy, inflammatory polyarthritis, esophageal dysfunction, pulmonary and neurologic complications, is a common cause of morbidity and mortality in this disease.4 Scleromyxedema is almost always associated with a paraproteinemia, usually IgG with l light chains.4 Our patient presented with a biclonal IgG and IgA gammopathy, which is a rare phenomena observed in 2%–6% of patients with monoclonal gammopathy detected by SPEP.5 Biclonal gammopathy in the setting of scleromyxedema has only been reported twice in the literature.6,7 As with our patient, there may be a mild bone marrow plasmacytosis, and there is rare progression to multiple myeloma or other hematologic malignancies.1 The pathophysiology of scleromyxedema has not been elucidated; however, serum from patients with this disease
has been shown to stimulate abnormal fibroblast activation and proliferation and increased production of glycosaminoglycans.8 This did not occur with the purified IgG population, however, suggesting a causative soluble factor separate from the associated gammopathy. The characteristic histology of scleromyxedema is a triad of (1) increased mucin deposition in the upper and midreticular dermis, (2) proliferation of fibroblasts, often stellate and large, and (3) increased collagen deposition.2,4 In biopsy specimens wherein all of these histological alterations are fully developed, the overall pattern is relatively distinct from those observed in other disorders with increased dermal mucin and sclerotic collagen. The principal histological differential diagnostic consideration is the recently described entity of nephrogenic systemic fibrosis (NSF) (also known as nephrogenic fibrosing dermopathy).9 NSF tends to involve the entire thickness of the reticular dermis, whereas the histological alterations in scleromyxedema are usually limited to the midreticular and upper reticular dermis. Also, clinical NSF is usually seen in patients with renal insufficiency and exposure to gadolinium-based contrast agents. Scleroderma is also in both the histological and clinical differential diagnoses but is less likely with the presence of waxy papules and a gammopathy and the histological findings of increased mucin and histiocytic infiltrate concentrated in the upper reticular dermis. The interstitial granulomatous reaction pattern observed in our patient’s biopsies evokes a broader differential diagnosis including interstitial granuloma annulare, interstitial granulomatous drug reaction, granulomatous mycosis fungoides, superantigen id reaction, and interstitial granulomatous dermatitis. The last of these is associated with various
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Granulomatous Scleromyxedema
TABLE 1. Summary of Granulomatous Lichen Myxedematosus Case Characteristics Reference Stetsenko et al, 200812
Age/ Gender 56/M
Skin Findings
Extracutaneous Findings
Pruritic, generalized fleshcolored papules
Microstomia
Generalized hyperpigmentation and skin induration
Multiple joint contractures Sclerodactyly
Laboratory Results Monoclonal IgG k gammopathy
Dysphagia
Rongioletti et al, 201011
76/M
Flesh-colored papules on glabella, auricular, post-auricular area, and forearms Skin hardening and tightness of trunk and extremities
Esophageal dysmotility Weight loss Shortness of breath Microstomia Multiple joint contractures
Monoclonal IgG l gammopathy
Sclerodactyly
Bolton and Satter, 201213
42/M
Initially few yellow postauricular papules
None
Monoclonal IgG l gammopathy
None
Monoclonal IgG l gammopathy
Later, erythematous, waxy papules of arms and upper back
De Cambourg et al, 201214
55/M
Flesh-colored papules on erythematous and indurated base on extensor surfaces of hands and feet, inner thighs and hypogastric region
Histological Findings
Treatment
Follow-up
Diffuse band-like histiocytic infiltrate with abundant bluegray cytoplasm forming loose granulomas Epithelioid and spindled cytomorphology Patchy lymphocytic infiltrate Patchy mucin accumulation Factor XIIIa and CD68+
Thalidomide and dexamethasone
Improvement of skin thickening
Perivascular and interstitial infiltrate of epitheliod cells with abundant blue-gray cytoplasm in papillary and midreticular dermis Scattered lymphocytes Sparse giant cells Interstitial mucin deposition
IVIG
CD68+ *Interstitial infiltrate of spindled and epithelioid cells in upper to mid-dermis Sparse perivascular lymphoplasmacytic infiltrate Increased interstitial mucin Factor XIIIa and CD68+ Granulomas with altered eosinophilia of collagen fibers Basophilic stromal material Moderate inflammatory infiltrate surrounding necrotic collagen bundles CD68+ Diffuse dermal mucin deposits in later biopsies
Alive at 3 y
Excellent response including less difficulty opening the mouth after 1 cycle
No specific treatment
No specific treatment
Limited improvement thereafter Alive at 4 mo Lesions on postauricular area and back resolved Lesions on arms expanded and became confluent Skin involvement remained stable
Resolution of gammopathy
(continued on next page )
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Shlyankevich et al
TABLE 1. (Continued ) Summary of Granulomatous Lichen Myxedematosus Case Characteristics Reference Shlyankevich et al (Current study)
Age/ Gender 54/M
Skin Findings Pruritic, waxy papular rash on upper shoulders
Extracutaneous Findings Microstomia
Laboratory Results Biclonal IgG and IgA l gammopathy
Histological Findings
Treatment
Follow-up
Increased deposition of whorled collagen in dermis
Lenalidomide and dexamethasone
Decreased microstomia, improved finger flexion and softening of facial skin Resolution of IgA spike and decreased IgG Alive at 8 mo
Numerous histiocytic and spindled cells with abundant bluegray cytoplasm Erythema and induration of face, torso and upper extremities
Abdominal swelling Shortness of breath Hand and finger swelling
Mild perivascular lymphocytic infiltrate Increased dermal mucin CD68+
*Initial papules on post-auricular skin showed xanthogranulomatous features. Later, waxy papules had interstitial granulomatous pattern. Eventually, classic scleromyxedema histology. ANA, anti-nuclear antibody; M, male; IVIG, intravenous immunoglobulin.
autoimmune diseases and lymphoproliferative disorders. Attention to subtle histological clues such as vacuolar interface change, apoptotic keratinocytes, the presence of neutrophils or eosinophils, and lymphocytic nuclear atypia can be helpful.9,10 However, correlation with clinical dermatologic findings, medical history, and medication usage is usually required. Although granulomatous inflammation is not usually associated with scleromyxedema or other forms of lichen myxedematosus, 4 cases with an unusual granulomatous histological pattern have been previously reported.11–14 A summary of these cases is presented in Table 1. All reported cases were in males between the ages of 42 and 76 years, and skin biopsy findings initially interpreted as most suggestive of granuloma annulare. Two of these cases presented with a generalized form of lichen myxedematosus (scleromyxedema),11,12 1 with localized disease,13 and 1 with an intermediate form.14 Both patients with generalized disease presented with a pruritic papular rash and significant sclerodermoid induration. Monoclonal IgG gammopathies were present in both cases; however, one had l light chains11 and the other presented with k light chains.12 Nevertheless, the cutaneous eruptions and partial responses to treatment were similar. Histological specimens from both showed mucin deposition, increased fibroblasts, mild perivascular lymphocytic inflammation, and an interstitial histiocytic infiltrate, occasionally forming loose granulomas. Giant cells were sparse, and necrobiosis was not observed. The case reported by Bolton and Satter13 presented with a localized form of lichen myxedematosus and IgG l monoclonal gammopathy. Interestingly, biopsies at different points in time exhibited variable histological patterns; the first specimen had xanthogranulomatous changes, the second had an interstitial granulomatous reaction pattern, and later biopsies finally showed the typical features associated with scleromyxedema.
Similarly, in the case reported by De Cambourg et al,14 early biopsies were most consistent with granuloma annulare, whereas later biopsies showed more typical findings of scleromyxedema. Clinically, this patient presented with a widespread papular rash consistent with an intermediate (or atypical) form of lichen myxedematosus with an associated IgG l monoclonal gammopathy but lacked the generalized sclerodermoid eruption of scleromyxedema. The presence of paraproteinemia and typical clinical manifestations of lichen myxedematosus/scleromyxedema in the reported patients supports the hypothesis that the observed granulomatous infiltrates in this rare variant are likely in response to the monoclonal gammopathy or other factors related to the underlying plasma cell dyscrasia.12 Granulomatous cutaneous reactions have also been described in association with many types of neoplasms including a wide variety of hematolymphoid malignancies.15 Unfortunately, the molecular pathophysiology for these phenomena remain poorly understood. The role of multiple myeloma therapy in the treatment of scleromyxedema has shown promising clinical results.16 Importantly, our patient showed significant clinical improvement in terms of skin tightening and complete to near complete resolution of the IgA and IgG gammopathies, respectively, after the initiation of lenalidomide and dexamethasone therapy. The previously reported patient with granulomatous scleromyxedema in the setting of monoclonal gammopathy showed marked improvement with similar treatment as well.12 These results support the use of these multiple myeloma treatments in the management of patients with granulomatous scleromyxedema. In summary, the current case study and literature review lend further support to the existence of a granulomatous variant of scleromyxedema. This diagnosis should be considered in the setting of similar clinical and histological findings.
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Granulomatous Scleromyxedema 9. Wheedon D. Skin Pathology. 3rd ed. Philadelphia, PA: Elsevier; 2010. 10. Magro CM, Crowson AN, Schapiro BL. The interstitial granulomatous drug reaction: a distinctive clinical and pathological entity. J Cutan Pathol. 1998;25:72–78. 11. Rongioletti F, Cozzani E, Parodi A. Scleromyxedema with an interstitial granulomatous-like pattern: a rare histologic variant mimicking granuloma annulare. J Cutan Pathol. 2010;37:1084–1087. 12. Stetsenko GY, Vary JC Jr, Olerud JE, et al. Unusual granulomatous variant of scleromyxedema. J Am Acad Dermatol. 2008;59:346–349. 13. Bolton JG, Satter EK. An interstitial granulomatous pattern in localized lichen myxedematosus with associated monoclonal gammopathy. J Cutan Pathol. 2012;39:395–398. 14. De Cambourg G, Joganah H, Cribier B. Atypical papular mucinosis with initial histological findings evocative of granuloma annulare. Ann Dermatol Venereol. 2012;139:58–62. 15. Rongioletti F, Cerroni L, Massone C, et al. Different histologic patterns of cutaneous granulomas in systemic lymphoma. J Am Acad Dermatol. 2004;51:600–605. 16. Canueto J, Labrador J, Roman C, et al. The combination of bortezomib and dexamethasone is an efficient therapy for relapsed/refractory scleromyxedema: a rare disease with new clinical insights. Eur J Haematol. 2012;88:450–452.
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