Localized lichen myxedematosus

INTRODUCTION — Lichen myxedematosus (LM; also called papular mucinosis) is a chronic idiopathic cutaneous mucinosis characterized by lichenoid papules, nodules, and/or plaques; mucin deposition and a variable degree of fibrosis in the dermis; and an absence of associated thyroid disease [1]. LM includes three clinicopathologic subsets (table 1) [1,2]:

●Localized LM – A localized papular form of LM with a benign course and lack of systemic involvement.

●Scleromyxedema – A diffuse/generalized papular and sclerodermoid form of LM associated with monoclonal gammopathy and systemic, potentially fatal, manifestations. (See "Scleromyxedema".)

●Atypical or intermediate forms of LM – LM with atypical features or overlapping features of localized LM and scleromyxedema.

Localized LM is divided into four subtypes that are differentiated based upon clinical and histopathologic features (table 2 and picture 1A-E). The four subtypes are:

●Acral persistent papular mucinosis (APPM)

●Discrete papular lichen myxedematosus (DPLM)

●Cutaneous mucinosis of infancy (CMI)

●Nodular lichen myxedematosus (nodular LM)

The clinical features, diagnosis, and management of localized LM will be reviewed here. Scleromyxedema and myxedema associated with thyroid disease are discussed separately. (See "Scleromyxedema" and "Pretibial myxedema (thyroid dermopathy) in autoimmune thyroid disease".)

EPIDEMIOLOGY — Epidemiologic data on localized LM are limited. Localized LM appears to be rare and less prevalent than scleromyxedema, though the frequency of this disorder is probably underestimated. Acral persistent papular mucinosis (APPM) is the most frequently reported variant of localized LM, with fewer than 50 reports of patients with APPM in the literature.

The primary populations affected by the various subtypes of localized LM differ. APPM usually develops in adults and is more frequent in women than men. In a literature review that evaluated reports of 32 patients with APPM, the mean patient age was 50 years (range 14 to 77 years) and 25 of the 32 patients (78 percent) were female. Discrete papular lichen myxedematosus (DPLM) affects adults of both sexes [3].

Nodular lichen myxedematosus (nodular LM) has primarily been reported in young adults [4] but has also occurred in a child [5]. Cutaneous mucinosis of infancy (CMI) is present at birth or appears in early infancy [5].

PATHOGENESIS — The pathogenesis of LM is unknown. The main hypothesis is that circulating cytokines known to stimulate glycosaminoglycan synthesis and fibroblast proliferation in the skin, such as interleukin (IL) 1, tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta, play a role [6]. In addition, it has been suggested that an intrinsic abnormality of fibroblasts in patients with LM may result in increased glycosaminoglycan synthesis [7].

Clinical observations suggest that other factors, such as viral infections (eg, HIV infection), surgery (eg, joint replacement) or other physical trauma, radiation therapy, and drugs, may stimulate mucin and collagen production, contributing to the development of localized LM [8,9]. In addition, discrete papular lichen myxedematosus (DPLM) has been described in the setting of toxic oil syndrome caused by contaminated rapeseed oil and L-tryptophan-associated eosinophilia-myalgia syndrome [10]. (See "Risk factors for and possible causes of systemic sclerosis (scleroderma)", section on 'Contaminated rapeseed oil' and "Risk factors for and possible causes of systemic sclerosis (scleroderma)", section on 'L-tryptophan'.)

A pathogenic mechanism that involves paraproteins acting as autoantibodies that stimulate fibroblasts to proliferate and overproduce mucin has been proposed for the scleromyxedema subtype of LM. However, localized LM is unlikely to share this mechanism, given the typical absence of associated paraproteinemia. A promoting role of TGF-beta and abnormally high secretion of IL-4, a profibrotic cytokine, has been associated with scleromyxedema, but a similar role for these cytokines in localized LM needs confirmation [11,12]. (See "Scleromyxedema", section on 'Pathogenesis'.)

A genetic predisposition to localized LM has been proposed based upon a report of a child with cutaneous mucinosis of infancy (CMI) whose father had similar cutaneous lesions during his childhood and a report of acral persistent papular mucinosis (APPM) in two sisters [13,14]. Such occurrences are rare; in general, a family history of localized LM is absent.

ASSOCIATED CONDITIONS — A variety of conditions have been linked to localized LM in case reports:

●Infection – There are multiple reports of discrete papular lichen myxedematosus (DPLM) occurring in association with HIV infection; HIV infection usually antedates the development of the skin lesions [15,16]. In addition, an association of DPLM with chronic hepatitis due to hepatitis C virus infection has been reported, most often in Japan [3].

●Monoclonal gammopathy and hypergammaglobulinemia – An absence of associated monoclonal gammopathy is a diagnostic criterion for localized LM, and the presence of monoclonal gammopathy in a patient with clinical and histologic findings consistent with localized LM is considered an atypical presentation (table 2). DPLM associated with monoclonal gammopathy has been reported [17]. In a case series of four patients with non-HIV-associated DPLM and monoclonal gammopathy, progression to scleromyxedema, multiple myeloma, or systemic involvement did not occur during a mean follow-up period of 34 months (range 6 to 72 months) [17].

Of note, most of the reported patients with HIV-associated DPLM have had associated polyclonal hypergammaglobulinemia [16]. Paraproteinemia has also been reported in a minority of patients with HIV-associated DPLM and may occur in relation to underlying HIV infection [16,18]. (See "HIV infection and malignancy: Management considerations", section on 'Plasma cell disorders'.)

●Other – Localized LM occurring in association with immunoglobulin A (IgA) nephropathy, joint replacement, or drug exposure, including biologic therapy (anti-tumor necrosis factor [TNF]-alpha and anti-interleukin [IL] 12/23), has been described in anecdotal case reports [9,19-21].

CLINICAL FINDINGS — The four subtypes of localized LM exhibit distinct clinical findings. Atypical LM can exhibit overlapping features of the subtypes (table 2) [22-24].

Acral persistent papular mucinosis — Acral persistent papular mucinosis (APPM) presents as multiple white to skin-colored, 2 to 5 mm, firm, waxy papules limited to the extensor surfaces of the hands, wrists, and sometimes forearms (picture 1A).

Discrete papular lichen myxedematosus — Discrete papular lichen myxedematosus (DPLM) usually manifests as waxy, skin-colored or reddish, 2 to 5 mm papules. The papules develop on the trunk and limbs in a symmetrical or asymmetrical pattern (picture 1B-C). The number of papules can vary from few to hundreds [1,3].

Cutaneous mucinosis of infancy — Cutaneous mucinosis of infancy (CMI) presents as firm, opalescent to skin-colored papules of less than 1 cm in diameter. The papules can be symmetrically distributed and densely grouped, linear and localized, or more generalized and arranged in rows or coalescing into plaques. The eruption is distributed over the trunk, neck, and extremities (picture 1D) [5].

Nodular lichen myxedematosus — Nodular lichen myxedematosus (nodular LM) presents with multiple firm, slightly elevated nodules (at least 1 cm in diameter) on the limbs and trunk (picture 1E). The nodules appear shiny and yellowish to skin-colored [2,5]. A mild papular eruption may also be present.

DIAGNOSIS — A diagnosis of localized LM is made based upon the detection of consistent clinical and histologic findings and the absence of findings suggestive of scleromyxedema or other diseases. The diagnostic criteria include [2]:

●Papular or nodular eruption consistent with one of the subtypes of localized LM

●Histologic findings of mucin deposition and variable degree of fibroblast proliferation

●Absence of gammopathy, thyroid disease, and systemic involvement

Skin biopsy — Although a diagnosis of localized LM may be suspected based upon the physical findings, a skin biopsy is required for diagnosis. A 4 to 5 mm punch biopsy provides a sufficient specimen from patients with papules or plaques. An incisional or excisional biopsy can be performed for nodular lesions. (See "Skin biopsy techniques".)

The expected histologic findings differ among the clinical subtypes of localized LM:

●Discrete papular lichen myxedematosus (DPLM) (picture 2) [25]:

•Diffuse deposition of mucin interspersed with large collagen bundles in the reticular dermis

•Variable degree of fibroblast proliferation

•Perivascular lymphocytic infiltrate (variably present)

●Acral persistent papular mucinosis (APPM) (picture 3) [25,26]:

•Focal dermal mucin deposition in the upper dermis with sparing of the subepidermal zone (Grenz zone)

•Lack of increase in dermal fibroblasts

●Cutaneous mucinosis of infancy (CMI) [5,25]:

•Focal, well-circumscribed deposit of mucin in the papillary dermis (mucin deposition may occur in the reticular dermis)

•Absence of fibroblast proliferation

•Perivascular mononuclear cell infiltrate in the superficial dermis

•Immunohistochemistry for CD1a, CD117, and CD68 is negative or noncontributory

●Nodular lichen myxedematosus (nodular LM):

•Collagen fibers separated by mucin deposition in the reticular dermis

•Variable degree of fibroblast proliferation

•Perivascular infiltrate of lymphocytes and plasma cells (variably present)

Deposition of mucin can be confirmed with an Alcian blue stain (pH 2.5) or colloidal iron stain.

Laboratory tests — Given the overlap in the clinical and histologic findings of localized LM and scleromyxedema, patients should be evaluated for monoclonal gammopathy, a characteristic associated finding in scleromyxedema. Laboratory testing should also be performed to distinguish LM from myxedema associated with thyroid disease.

Our initial laboratory work-up consists of the following tests:

●Serum protein electrophoresis and immunofixation

●Thyroid-stimulating hormone level

The results of these tests should be normal in patients with localized LM.

In addition, testing for HIV infection is often performed for patients with clinical and histologic findings consistent with DPLM given the association of DPLM with HIV infection. Testing for hepatitis B and C virus infection is also reasonable for patients with DPLM and risk factors or signs or symptoms of this disease. No other laboratory abnormalities are expected in patients with localized LM. (See 'Associated conditions' above and "Clinical manifestations and natural history of chronic hepatitis C virus infection", section on 'Clinical features'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of localized LM includes scleromyxedema and a variety of other cutaneous disorders:

●Scleromyxedema – Localized LM and scleromyxedema are considered to be on the same disease spectrum. Clinical, histologic, and laboratory findings aid in distinguishing these disorders. Clinically, the eruption of scleromyxedema is more diffuse and sclerodermoid (picture 4A-B). The classic histopathologic findings of scleromyxedema are a microscopic triad of mucin deposition, fibroblast proliferation, and fibrosis; rarely, an interstitial granuloma annulare-like pattern is detected. Unlike localized LM, scleromyxedema occurs in association with monoclonal gammopathy and can have a variety of extracutaneous manifestations. (See "Scleromyxedema".)

●Other disorders – The differential diagnosis of localized LM also includes cutaneous papular eruptions, particularly those that may present with white, skin-colored, or erythematous, smooth papules, plaques, or nodules, such as granuloma annulare, molluscum contagiosum, acrokeratoelastoidosis, lichen amyloidosis, lichen planus, and eruptive collagenoma as well as other forms of cutaneous mucinosis (eg, pretibial myxedema, reticulated erythematous mucinosis, follicular mucinosis). Review of the clinical findings and a skin biopsy distinguishes localized LM from these disorders.

Additional disorders in the differential diagnosis of cutaneous mucinosis of infancy (CMI) are self-healing juvenile cutaneous mucinosis (SHJCM) and mucinous nevus. SHJCM is characterized by an acute eruption of papules that may coalesce to form linear infiltrated plaques on the face, neck, scalp, abdomen, and/or thighs of children. Mucinous subcutaneous nodules on the face associated with periorbital swelling and on periarticular areas are sometimes predominant features. Patients can have systemic symptoms such as fever, arthralgias, weakness, and muscle tenderness. A skin biopsy will show a fibroblastic reactive proliferation involving the subcutaneous fat similar to nodular or proliferative fasciitis, with mucin deposited throughout the dermis and subcutis [27]. Spontaneous resolution typically occurs within a few weeks to several months.

Mucinous nevus is a congenital or acquired hamartomatous connective tissue nevus that manifests as a unilateral eruption of multiple brown to skin-colored papules or plaques in a linear or zosteriform arrangement [28]. The classic histopathologic findings are a band-like deposition of mucin that fills the upper dermis and loss of elastic fibers.

PROGNOSIS AND FOLLOW-UP — The cutaneous findings of localized LM may progress over time and generally persist. Spontaneous regression of discrete papular lichen myxedematosus (DPLM) has been reported in some patients with DPLM-associated HIV infection [29]. Although localized LM and scleromyxedema belong to a spectrum of disease, progression of localized LM to scleromyxedema has not been proven.

Given the benign and skin-limited nature of localized LM, clinical and laboratory follow-up is not needed for patients with typical disease presentations.

MANAGEMENT — Localized LM is a benign condition for which treatment is not required. We typically reassure patients regarding the benign nature of localized LM and do not initiate treatment.

However, the appearance of localized LM is bothersome for some patients and has led to attempts at treatment. There is no uniformly effective therapy. Treatments that have seemed beneficial for individual patients with discrete papular lichen myxedematosus (DPLM) or acral persistent papular mucinosis (APPM) include medical therapies (topical or intralesional corticosteroids and topical calcineurin inhibitors [30]) and destructive surgical therapies (dermabrasion, electrosurgery [31], carbon dioxide laser, erbium:yttrium aluminum garnet laser [32]). However, responses to these interventions vary, and surgical therapies are associated with risk for scarring. Partial or complete resolution of HIV-associated DPLM within several months after the initiation or a change in antiretroviral therapy has been documented in case reports [16]. In addition, a patient with DPLM had resolution of skin disease following combination antiviral therapy for chronic hepatitis C virus infection [33].

Improvement of nodular lichen myxedematosus (nodular LM) with intralesional corticosteroid injections or oral methotrexate has been described in case reports [4]. Given the benign course and the occurrence of cutaneous mucinosis of infancy (CMI) in young children, CMI generally is not treated.

SUMMARY AND RECOMMENDATIONS

●Localized lichen myxedematosus (LM) is a skin-limited form of LM characterized by lichenoid papules, nodules, and/or plaques; mucin deposition and a variable degree of fibrosis in the dermis; and an absence of associated monoclonal gammopathy, thyroid disease, or systemic involvement. Localized LM should be distinguished from scleromyxedema, a form of LM that presents with a diffuse/generalized papular and sclerodermoid eruption, monoclonal gammopathy, and the potential for systemic involvement (picture 4A-B). (See 'Introduction' above and "Scleromyxedema".)

●There are four subtypes of localized LM: acral persistent papular mucinosis (APPM), discrete papular lichen myxedematosus (DPLM), cutaneous mucinosis of infancy (CMI), and nodular lichen myxedematosus (nodular LM). APPM, DPLM, and nodular LM typically occur in adults. CMI is present at birth or develops in early infancy. DPLM can occur in association with HIV infection. (See 'Epidemiology' above and 'Associated conditions' above.)

●Atypical presentations of localized LM with monoclonal gammopathy or overlapping features of the different subtypes have been reported. (See 'Associated conditions' above.)

●The classic clinical manifestations of the subtypes of localized LM are (see 'Clinical findings' above):

•APPM – Multiple white to skin-colored, firm, waxy papules limited to the extensor surfaces of the hands, wrists, and/or forearms (picture 1A)

•DPLM – Multiple waxy, skin-colored or reddish papules on the trunk and/or limbs in a symmetrical or asymmetrical pattern (picture 1B-C)

•CMI – Firm, opalescent to skin-colored papules in a grouped, linear, or generalized distribution (picture 1D)

•Nodular LM – Multiple firm, shiny, yellowish to skin-colored nodules on the limbs and trunk (see 'Nodular lichen myxedematosus' above)

●A diagnosis of localized LM is made based upon review of the clinical, histologic, and laboratory findings. The diagnostic criteria include (see 'Diagnosis' above):

•Papular or nodular eruption consistent with one of the subtypes of localized LM

•Histologic findings of mucin deposition and variable degree of fibroblast proliferation

•Absence of gammopathy, thyroid disease, and systemic involvement

●In most patients, localized LM persists. Spontaneous resolution of HIV-associated DPLM has been reported. Progression to scleromyxedema does not appear to occur. (See 'Prognosis and follow-up' above.)

●Localized LM is a benign condition. Treatment is not necessary. A variety of medical and surgical treatments have been tried with variable results. (See 'Management' above.)