Chapter 158. Scleredema and Scleromyxedema

Disorders characterized by excessive mucin deposition, increased collagen production, or fibrocyte hyperplasia are historically categorized as mucinoses, sclerosing disorders, and fibrosing disorders, respectively. The fibroblast is central in each of these conditions. Thus, shifting our focus from the fibroblast product (mucin, collagen, and fibrosis) to the cell of origin, the fibroblast and the mechanisms that stimulate specific fibroblast activities will provide better understanding of the histopathogenesis of these diseases and also lays a foundation for the development of more effective treatments for these incapacitating conditions. In some disorders, a singular fibroblast activity predominates, such as excessive mucin or collagen production [pretibial myxedema (see Chapter 151) and sclerodermoid disorders respectively (see Chapter 157)]. In others, a combination of excessive mucin and collagen production is observed (scleredema) or excessive mucin production and fibroblast hyperplasia occurs [scleromyxedema and nephrogenic systemic fibrosis (see Chapter 150)].

Fibroblasts are derived from CD34-positive hematopoietic precursors that originate in the bone marrow and populate the skin during development and wound repair. The chief role of the skin fibroblast is to deposit collagen, elastin, and ground substance, the major constituents of the dermis and pannicular septae and the substrate to which the epidermis and skin appendages attach (see Chapter 63).

The stimuli that cause fibroblasts to overproduce mucin or collagen or to proliferate or aberrantly immigrate into skin are varied. Infectious triggers, inflammatory states, diabetes mellitus, drugs, genetic mutations, and toxins as well as specific mediators such as eicosanoids, growth factors, cytokines, immunoglobulin-paraproteins, and other circulating factors have been implicated, but the precise mechanisms that result in fibroblast pathology (fibropathy) are poorly characterized. Some of these stimuli may recruit bone-marrow-derived fibroblast precursors to the skin; others may act directly on fibroblasts already residing in the skin.

This chapter will discuss scleredema and scleromyxedema. Other diseases relevant to cutaneous fibroblasts are discussed elsewhere in this textbook and listed in Table 158-1.

Historical Aspects

Scleredema was described by Buschke in 19021 and is also designated as scleredema of Buschke and scleredema adultorum, although the latter is a misleading term because children or adolescents can develop the condition.

Epidemiology

Scleredema is rare, although the precise incidence and prevalence are unknown. Men and women are affected with equal frequency. More than half of cases of scleredema occur in childhood or adolescence, most commonly after an upper respiratory tract infection.2 Streptococcal infection is most commonly identified, but other infectious agents have also been implicated. Disease development in adulthood in association with adult-onset diabetes mellitus is the second most common presentation of scleredema. Uncommonly, scleredema occurs in association with paraproteinemia or multiple myeloma, and this association possibly is becoming more common as other causes diminish in frequency with better treatment and management of underlying disease.

Pathogenesis

Type 1 collagen and hyaluronate appear to be the major fibroblast products that are increased in scleredema-affected skin.3–5 The precise mechanism(s) for increased collagen and glycosaminoglycan production in scleredema is not known. Stimulation of fibroblasts by serum factors or immunoglobulin may be related to the pathogenesis of scleredema, particularly cases associated with infectious agents or a paraproteinemia. Serum from a patient with scleredema associated with paraproteinemia was able to increase collagen production by cultured fibroblasts in vitro.6 However, the factor(s) involved has not been elucidated. Other soluble circulating cytokines and small molecule mediators likely also play critical roles.

Clinical Findings

The clinical findings of scleredema are distinctive. An acute onset of nonpitting induration of neck, shoulders, and upper back skin may be followed by involvement of the face and arms. Characteristically, the affected skin appears smooth and waxy, with tense dermal induration and prominent follicular ostia, at times imparting a “peau d'orange” appearance (Fig. 158-1). In general, however, skin changes are better felt on palpation than seen. The skin of the upper trunk (especially the back) is a favored site for scleredema, but more widespread involvement may be observed. The affected and unaffected skin blend imperceptibly. Scleredema involving the esophagus, bone marrow, nerve, liver, or salivary glands has been described rarely.7,8 However, investigations to identify internal organ involvement by scleredema are infrequently pursued. Patients may report symptoms of restricted motion of joints, the tongue, or eyes, as well as weak or tender muscles.

Histopathology

Punch biopsies of affected skin reveal a nontapered (square) appearance on low power. The proportion of dermis in dramatically increased in comparison to adjacent nonaffected skin (Fig. 158-2A). A decreased number or higher placement of eccrine units may be appreciated. Fibroblasts are normal in number and morphology. The collagen bundles are slightly thickened and separated from each other by subtle deposits of mucin. Stains for mucin (alcian blue, colloidal iron) are often used to identify the mucin deposits (Fig. 158-2B).

Prognosis and Clinical Course

Postinfectious scleredema usually abates in 1–2 years. Scleredema associated with adult-onset diabetes tends to be protracted, although some patients appear to improve with better glucose control. Gammopathy-associated scleredema is more chronic and can be resistant to many therapies.

Treatment

Antibiotics do not appear to affect the course of postinfectious scleredema. Treatment of the associated disease (e.g., improved glucose control or treatment of paraproteinemia) may lead to improvement. Ultraviolet A1 phototherapy has been reported effective in a few adult patients,9,10 as has psoralen plus ultraviolet A phototherapy.11 Treatment with methotrexate did not provide benefit in a series of cases of scleredema. Scleredema has responded to local radiotherapy or electron-beam irradiation. Scleredema associated with monoclonal gammopathy has responded to extracorporeal photopheresis.

Historical Aspects

Epidemiology

Lichen myxedematosus/scleromyxedema is a rare disease afflicting men and women with equal frequency and symptom onset in mid to later life.

Pathogenesis

The pathogenesis of scleromyxedema is unknown. Most patients with scleromyxedema have a monoclonal paraproteinemia, typically designated as monoclonal gammopathy of undetermined significance (MGUS). Rare patients meet criteria for multiple myeloma. Excessive hyaluronate production and fibroblast proliferation are observed, but support for a direct effect of the monoclonal protein on fibroblasts is lacking.15,16 Indirect mechanisms appear to include circulating cytokines, inflammatory mediators, and fibroblast precursor cell lineages that migrate from the blood, take up residence in the dermis and, in more extensive cases, in other tissues, and synthesize mucin.

Clinical Findings

Several distinct clinical presentations, and hence nosologic designations have been recognized. Although there is considerable clinical overlap and patients may show progression from limited to widespread involvement, it is useful to distinguish localized from generalized disease as well as patients that present with discrete papules from those with confluent plaques. The generalized lichenoid eruption consists of numerous minute (1–3 mm) papules scattered on the extremities and the trunk. Scleromyxedema presents with confluent lichenoid plaques. Individual lesions and plaques may exhibit marked erythema or hyperpigmentation. The face is involved in most cases, resulting in significant deformity, “bovine facies” (Fig. 158-3). The trunk and extremities are usually affected (Fig. 158-4A) and often results in decreased flexibility and range of motion in the involved areas (Fig. 158-4B).

A monoclonal paraproteinemia of undetermined significance, usually immunoglobulin-γ-κ type is identified in most patients. Paraproteinemia is less common in localized variants. Progression to multiple myeloma occurs rarely.

Muscle weakness, contractures, restrictive lung disease, upper airway involvement, pulmonary hypertension, esophageal dysmotility, and neurologic disorders (seizures, motor impairment, carpal tunnel syndrome, depression, memory loss, aphasia, peripheral neuropathy, and psychosis) have been reported in association with scleromyxedema. Thyroid function is normal by definition.

Histopathology

Regardless of the clinical presentation, the histopathologic findings of scleromyxedema are identical and demonstrate superficial to mid-dermal mucin deposition with admixed fibroblast proliferation (Fig. 158-5). Moreover, scleromyxedema is histologically distinct from other mucinoses as well as sclerosing and fibrosing conditions. Nephrogenic systemic fibrosis [(NSF), formerly nephrogenic fibrosing dermopathy] shows close histologic resemblance to scleromyxedema. However, the pannicular septae are the focus for histologic distinction: they are always involved in NSF and never involved in scleromyxedema. Moreover, scleromyxedema tends to be restricted to the upper half of the dermis and nephrogenic fibrosing dermopathy becomes more prominent in the lower dermis and then extends to pannicular septae. Although occasional multinucleated histiocytes with or without elastophagocytosis may be identified in biopsies of scleromyxedema, there is typically minimal associated inflammation. A highly unusual histologic presentation with a marked dermal granulomatous infiltrate was observed in association with fibromucinous deposition in a 56-year-old male with scleromyxedema.17 This unique case emphasizes the importance of correlating clinical and pathologic findings and raises the question if this patient may have had a second superimposed granulomatous disorder such as sarcoidosis in addition to scleromyxedema.

Prognosis and Clinical Course

Localized, “self-healing” variants are usually confined to the skin and self-limiting. However, prospective follow-up and caution is advised as some cases fitting criteria for localized disease have been associated with internal organ involvement or progression to more generalized disease (so called “atypical papular mucinosis”). Scleromyxedema usually follows a chronic and progressive clinical course and a poor outcome is expected. Respiratory failure, cerebral disease, and infection usually lead to a gradual decline and death.

Treatment

Melphalan had been used for decades to treat scleromyxedema with variable efficacy.18–20 Other therapies directed towards quantitatively reducing or ameliorating the effects of the paraproteinemia have shown variable results. Agents or therapies with reported efficacy include: glucocorticoids,21 intravenous immune globulin (IVIg),22 thalidomide,23 extracorporeal photophoresis,24 interferon alpha,25 combination chemotherapy,26 and PUVA.27 Partial to complete remission was achieved in 8 of 10 patients treated with IVIg.28 Autologous peripheral blood stem cell transplantation has resulted in dramatic remission of scleromyxedema in a number of patients with severe disease.29,30