Lichen Myxedematosus: A Unique Paraneoplastic Mucinous Sclerosing Dermopathy

Our patient was a 59-year-old Caucasian woman who presented with a progressive eruption on her arms, ears, shoulders, and legs characterized by localized areas of induration exhibiting a peau d’orange surface change with supervening coalescing papules (Figure 1). The patient stated that the rash was not associated with pain or pruritus. She had occasional right hip pain that was attributed to osteoarthritis. She denied any difficulty swallowing. Her past medical history included hypertension and hypercholesterolemia for which she received lisinopril and atorvastatin.

The patient underwent two sets of biopsies. The first skin biopsy procured from the left elbow region suggested a diagnosis of granuloma annulare with an interstitial or an incomplete necrobiotic pattern. A subsequent biopsy in 2021 was consistent with lichen myxedematosus (LM).

Given the diagnosis of LM, subsequent serologic workup was noteworthy for a monoclonal gammopathy of IgGλ-restricted isotype.

The biopsy specimen demonstrated a marked increase in dermal cellularity and connective tissue matrix, changes that were apparent in the superficial half of the reticular dermis. Interstitial hypercellularity was reflected by many well-differentiated spindled and histiocytoid-appearing cells coursing through the dermis unaccompanied by any additional inflammatory cell components such as lymphocytes, eosinophils, plasma cells, and neutrophils. There was a prominent and conspicuous increase in mesenchymal mucin. Amidst the mesenchymal mucin, there was supervening significant sclerosis, the latter characterized by a haphazard disposition of widened collagen bundles within the dermis (Figure 2). A CD34 preparation was extensively positive; many of the stromal spindled and histiocytoid-appearing cells showed a positive reaction while the smooth muscle actin stain was negative. The stromal spindled and histiocytoid-appearing cells were also focally positive for Factor XIIIa, CD4, and CD68 (Figure 3) emphasizing their monocyte ontogeny. The CD138 preparation did not highlight any plasma cells. A congo red stain and crystal violet stain were negative.

The overall clinical presentation and morphologic findings on biopsy were characteristic for LM, a distinct form of cutaneous mucinosis with specific clinical and histologic features.^1,2 The classification of LM and its relationship to other known cutaneous mucinous conditions, most notably myxedema, was addressed in the seminal paper by Montgomery and Underwood in 1953.³ They emphasized that there was no association with endocrine disturbances. Falling under the umbrella of LM are papular mucinosis (PM) and scleromyxedema (SME). PM is represented by the generalized and localized variants without any induration of the skin or association with systemic disease, whereas SME is a more extensive pattern of skin involvement hallmarked by significant skin induration with the potential for extracutaneous disease.³

The histologic findings supportive of the diagnosis of LM included a fairly striking interstitial infiltrate of fibroblasts associated with haphazard bundles of sclerotic collagen accompanied by abundant mucin within the superficial half of the dermis. The spindle cells demonstrated the classic phenotype seen in this entity, whereby there was variable staining for CD4, CD68, factor XIIIa, and CD34, indicative that these cells were fibrocytes possibly of myeloid monocytic derivation and had likely differentiated into wound culture-like fibroblasts with the capability of elaborating connective tissue matrix.¹

Monocyte-derived dendritic cells (MoDCs) are highly malleable cells capable of differentiating into other MoDCs, but also they can become fibroblasts and hence produce collagen, hyaluronic acid, and peptidoglycans with the immediate precursor monocyte-derived cells representing the fibrocyte. This trandifferentiation can be inhibited by serum amyloid P.⁴

Differentiating between generalized and localized SME vs localized and generalized PM requires correlation with the extent of potential cutaneous and extracutaneous involvement by this sclerosing mucinous process and the presence or absence of a monoclonal gammopathy.

In certain cases of LM, there is an association with a monoclonal gammopathy typically seen in SME and rarely reported in PM. In 1969, the first association of a plasma cell dyscrasia with SME was reported.⁵ Several biochemical peculiarities of monoclonal immunoglobulins in patients with SME were reported in case reports or short series, such as IgGλ overrepresentation, cationic migration, and partial deletion.⁶ In this case, given the background of peau d’orange induration along with establishment of an IgGλ-restricted restricted monoclonal gammopathy, the combined clinical findings in concert with the pathology  is consistent with a diagnosis of localized SME as opposed to PM.^1,7-10

SME was first recognized in the early part of the 20th century as a disease that resembled scleroderma. Patients can initially present with significant induration especially involving the face and fingers (hence resembling scleroderma). However, due to the nodular pattern of fibrosis and mucin deposition, the face can acquire a leonine-like quality while the indurated fingers can show the so-called donut sign characterized by  a central depression surrounded by a raised and infiltrative area.¹¹

The induration of SME has the distinctive orange peel (ie, a peau d’orange) appearance that was well exemplified by our case and is then followed by superimposed papules. The papules exhibit a linear arrangement and follow the lines of cleavage as well as lymphatics. These cutaneous findings are confirmed histologically after diagnosis. Invariably, SME is associated with a monoclonal gammopathy.^12,13

The histologic findings in SME are similar to those encountered in the cutaneous confined papular variant, which is unassociated with skin induration and have already been discussed. To summarize, there is a haphazard disposition of thickened collagen bundles accompanied by mucin in the superficial to mid-portions of the dermis. The classic scleroderma fibroblast phenotype revealed by the acquisition of smooth muscle staining with a loss of CD34 is not seen, and instead the fibroblasts strongly express CD34 and fail to show immunoreactivity for smooth muscle actin.^12,14,15

While SME is histomorphologically indistinguishable from PM, the extent of cutaneous involvement is more dramatic and extensive. Clinically, there is significant induration and sclerosis of the skin with relative lack of mobility of the skin similar to that encountered in scleroderma. The mucin deposited within the dermis is a mixture of hyaluronic acid and proteoglycans including decorin and bigylcan. In addition, there is versican, which is an unusually large proteoglycan that contains chondroteinsulfate that is key in absorbing water. Versican is also implicated in other sclerosing conditions such as keloid, taxane-induced scleroderma, and systemic scleroderma.¹⁶ In some instances, there may be a supervening granulomatous pattern of inflammation defining granulomatous SME.¹⁷

In the setting of SME as opposed to PM, extracutaneous disease can occur in sites such as the central nervous system (CNS), muscle, joints, heart, and eyes, the latter presenting as cataracts and chorioretinitis. Unlike PM where extracutaneous disease has not been described, systemic manifestations can occur albeit uncommon, and the affected organs can lead to protean clinical manifestations. Joint involvement is not uncommon. Muscle involvement as well as neurologic complications, including encephalopathy, have been documented. While the cutaneous biopsies demonstrate a very striking and reproducible picture of irregular fibrosis and mucin deposition, extracutaneous organs do not show similar findings. For example, in patients with extensive CNS disease, their brain at autopsy will exhibit gliosis and demyelination. The actual histologic findings in the setting of cardiac involvement are poorly documented but the clinical assessments include inflammatory cardiomyopathy, congestive cardiomyopathy, and myocardial infarction.¹⁸

The criteria for PM are as follows:

• Papular or nodular/plaque eruption in the absence of underlying plaque-like skin induration, which may be generalized or localized
• Histologic confirmation
• Absence of thyroid disease with a monoclonal gammopathy being very uncommon

PM is subdivided into five types: a discrete 3opular form involving any site; acral persistent PM involving only the extensor surface of the hands and wrists; self-healing PM, of a juvenile and an adult type; PM of infancy; and a nodular form. Conventional adult cases of PM usually affects adults aged 30 to 50 years. The dominant localization of the lesions is dorsum of the hands, arms, and upper trunk with relative sparing of the trunk, face, and neck. In PM of infancy, the lesions are scattered or grouped and exhibit a widespread distribution on the skin. There is no association with any underlying cutaneous endocrine disorder or monoclonal gammopathy. Histologically, there is an increase in mucin without any supervening sclerosis.¹⁹

The fibroblasts are the presumptive source of mucopolysaccharides in LM. It has been postulated the patients with LM regardless of subtype have a chemotactic factor in their serum that leads to the migration of fibrocytes into the skin with the subsequent elaboration by these cells of collagen and hyaluronic acid.²⁰ In one study, there was confirmatory evidence that the serum induced the proliferation of fibroblasts, though the amount of glycosaminoglycan was not significantly increased per cell.²¹ It is important to note that removal of the abnormal paraprotein is not uniformly associated with the potent fibroblastic stimulating properties of the serum, indicative of a serum factor other than the abnormal paraprotein.

In addition to SME, other fibrosing reactions can be associated with an underlying plasma cell dyscrasia, most notably scleroderma and eosinophilic fasciitis, whereby biopsies may show an infiltrate of well-differentiated light chain restricted plasma cells.²² There is a striking degree of overlap histologically with nephrogenic systemic fibrosis, and, in fact, the pathogenesis of nephrogenic systemic fibrosis could provide a clue into the underlying mechanisms leading to the distinct cutaneous manifestations of LM.²³ Nephrogenic systemic fibrosis was recognized in 2000 as a unique fibrosing dermopathy resembling SME but occurring in patients on hemodialysis.²⁴

It was soon recognized that this condition had the potential for extracutaneous organ involvement with a similar pattern of fibrosis developing in the skeletal muscle, diaphragm, lung, and heart and that it was closely linked with gadolinium radiocontrast exposure. The etiologic role of gadolinium in its pathogenesis was made by Grobner in 2006.²⁵ The gadolinium cannot be adequately excreted in patients with renal insufficiency, leading to higher levels. There are increased levels of gadolinium+3, which then accumulates in tissue serving as a potent upregulation of matrix production by fibroblasts largely attributable to increased chemotaxis of fibrocytes into the skin from the peripheral blood stream. Patients at risk are those with renal
insufficiency. Patients present with lower extremity symmetrical bilateral edema, which progresses to brawny induration with a peau d’orange appearance and joint contractures. Once there is stabilization of renal function, the fibrosis can at least stabilize and possibly spontaneously regress.²⁶ Fibronectin, chemokine receptors 2 and 7, and oxidative stress are implicated in nephrogenic systemic fibrosis. Both the C-C chemokine receptor 2 (CCR2) and its ligand the monocyte chemoattractant protein 1 are held to be key instigators in the pathogenesis of cutaneous and extracutaneous fibrosis in the setting of nephrogenic systemic fibrosis.²⁷ Neoplastic plasma cells can produce CCR2, providing a potential common pathophysiologic link between SME and nephrogenic systemic fibrosis.²⁸

In summation, the patient in this brief vignette is a classic textbook depiction of LM associated with an underlying monoclonal gammopathy. The preferred designation in this case would be localized cutaneous SME, given the underlying induration of the skin with its peau d’orange quality and the identification of a monoclonal gammopathy. One might argue that the lack of obvious extracutaneous disease and of more extensive skin disease would suggest a diagnosis of PM over SME. There is no reason to believe that this patient has any of the extracutaneous stigmata associated with this disorder.

The exact mechanism by which matrix-producing fibrocytes destined to become fibroblasts migrate to specific areas of the skin to produce classic cutaneous lesions of SME is possibly reflective of an unidentified serum factor that creates a microenvironment that is conducive to the migration of  matrix producing cells into the skin.From a practical perspective, when a pathologist has a biopsy showing the distinctive histologic changes of LM, the diagnosis is best kept under the general umbrella of LM and then a subsequent further categorization as SME or PM would be based on the extent of cutaneous disease, possible extracutaneous organ involvement, and establishment of a monoclonal gammopathy.

Dr Magro is a distinguished professor of pathology and laboratory medicine in the department of pathology at Weill Cornell Medicine in New York City, NY, and section editor of The Dermatopathologist in The Dermatologist. Dr Goldman is a clinical instructor in dermatology at Weill Cornell Medicine and founder of Goldman Dermatology in New York City, NY.

Disclosure: The authors report no relevant financial relationships.