Mucinoses (Chapter 46)

- Made of what, produced by what
- what is the stain for mucin pathologically?
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Terms in this set (33)
Mucin is a component of the dermal extracellular matrix and is normally produced in small amounts by fibroblasts. It is a jelly-like, amorphous mixture of acid glycosaminoglycans (formerly referred to as acid mucopolysaccharides), which are complex carbohydrates composed of multiple repeating polysaccharide units (see Ch. 95). The acid glycosaminoglycans may be attached to both sides of a protein core (proteoglycan monomer), as in the case of dermatan sulfate and chondroitin sulfate, or they may be free, as in the case of hyaluronic acid, which is the most important component of dermal mucin.

Mucin is capable of absorbing 1000 times its own weight in water, playing a major role in maintaining the salt and water balance of the dermis.

For confirmation, special stains can be used, such as Alcian blue, colloidal iron or toluidine blue (Table 46.1). Furthermore, dermal mucin is PAS negative and, if composed of hyaluronic acid, hyaluronidase-sensitive.
The cutaneous mucinoses may be classified as primary, in which mucin deposition is the major histologic feature resulting in clinically distinctive lesions (Table 46.2), or secondary, in which mucin simply represents an associated histologic finding (Table 46.3). Primary mucinoses can then be divided into degenerative-inflammatory forms and hamartomatous-neoplastic types. The former are further subdivided into dermal and follicular forms, based upon the location of the mucin
1) Degenerative-inflammatory mucinoses
- Can be either dermal or follicular

a Dermal:
- Scleromyxedema
- Scleredema
- Lichen Myxedematosus
- Self healing cutanoues mucinoses
- Mucinoses related to Thyroid disfunction
- Reticular Erythematous
- Digital Mucous Cyst

b Follicular
- Follicular Mucinosis
- Urticaria like Follicular mucinoses

2) Hamartomatous-neopastic mucinoses
- Mucinous nevus
- Angiomyxoma
Scleromyxedema is a chronic idiopathic disorder characterized by numerous firm papules and areas of induration that are due to dermal mucin deposition in association with an increase in dermal collagen4. Nearly all patients also have a monoclonal gammopathy, and some may have systemic, even lethal, manifestations5. This entity must be distinguished from localized variants of lichen myxedematosus where the skin is the sole site of involvement (Table 46.4). There are, however, occasional patients who have an atypical constellation of findings and fall between scleromyxedema and localized lichen myxedematosus

Scleromyxedema is a fairly uncommon disease, affecting middle-aged adults of both sexes equally. The pathogenesis of scleromyxedema is unknown. The role of the associated monoclonal gammopathy remains a matter of debate. While most patients have a plasma cell dyscrasia paraprotein levels do not correlate with either the extent or the progression of the disease.
In scleromyxedema, numerous, 2-3 mm, firm, waxy, closely aligned papules develop in a relatively widespread symmetrical pattern. The
most common sites of involvement are the head and neck region, upper trunk, hands, forearms and thighs (Fig. 46.2). Papules are often arranged
in a strikingly linear array. The surrounding skin is shiny and indurated, i.e. sclerodermoid in appearance, and the glabella is typically involved with deep longitudinal furrowing. Severe involvement of the
face can result in a leonine facies (Fig. 46.3A). Deep furrowing can also occur on the trunk and extremities and is referred as the "Shar-Pei sign"

The mucous membranes and scalp are spared. As the condition progresses, erythematous and infiltrated plaques may appear with skin stiffening, sclerodactyly, and decreased motility of the mouth and joints. Overlying the proximal interphalangeal joints, a central depression surrounded by an elevated rim (due to skin thickening) can be seen and is referred to as the "doughnut sign". Mat and cuticular telangiectasias and calcinosis, as seen in systemic sclerosis, are absent.
Scleromyxedema is almost always associated with paraproteinemia. The monoclonal gammopathy is usually IgG and the light chains are more commonly lambda. Although a mild plasmacytosis may be observed in bone marrow biopsies, <10% of patients with scleromyxedema progress to symptomatic myeloma. Patients with scleromyxedema can have a number of internal manifestations, in particular muscular, neurologic, rheumatologic, pulmonary, renal and cardiovascular. Dysphagia, proximal muscle weakness due to myositis, disturbances of the CNS leading to unexplained coma, peripheral neuropathy, arthropathies, carpal tunnel syndrome, restrictive or obstructive lung disease, and scleroderma-like renal disease may accompany or follow the cutaneous manifestations5. While the predominantly sensory peripheral neuropathy typically affects older men and has an insidious onset, the dermato-neuro syndrome is a potentially life-threatening encephalopathy. This syndrome begins abruptly with a worsening of skin lesions, a flu-like prodrome, fever and seizures, and it can eventuate in an unexplained coma.
Scleromyxedema is characterized by a triad of microscopic features6:
• a diffuse deposit of mucin in the upper and mid reticular dermis
• an increase in collagen deposition
• a marked proliferation of irregularly arranged fibroblasts

The epidermis may be normal or thinned by the pressure of the underlying mucin and fibrosis; the hair follicles may be atrophic. A slight superficial, perivascular, lymphoplasmacytic infiltrate is often present. The elastic fibers are fragmented and decreased in number.

More recently, an interstitial granuloma annulare-like pattern was described7. Mucin may fill the walls of myocardial blood vessels as well as the parenchyma of the kidney, pancreas, adrenal glands, nerves, and lymph nodes. In the dermato-neuro syndrome, autopsy findings have not proved helpful in elucidating its underlying pathogenesis
The primary differential diagnosis for scleromyxedema is systemic sclerosis (scleroderma) and scleredema. The presence of papules, especially in linear arrays, is a very helpful clinical sign in distinguishing scleromyxedema. Additional entities in the sclerodermoid differential diagnosis should be excluded (see Ch. 43). For example, nephrogenic systemic fibrosis, which develops in individuals with renal impairment exposed to gadolinium-containing contrast media, may show mucin in biopsy specimens, but patients lack both facial involvement (commonly seen in scleromyxedema) and paraproteinemia

ddx of conditions with leonine facies
Lepromatous leprosy
Cutaneous lymphoma (T-cell, rarely B-cell)
Actinic reticuloid form of chronic actinic dermatitis
Leukemia cutis (specific cutaneous manifestations
of B-CLL)
Systemic amyloidosis
Lipoid proteinosis
Mastocytosis (nodular)
Multicentric reticulohistiocytosis
Progressive nodular histiocytosis
Recommendations are still based on case reports and open-label small case series. In the past, monthly courses of melphalan were often the therapy of choice, targeting the plasma cell dyscrasia. However, while this alkylating agent can result in some clinical improvement, it has also been implicated in 30% of the deaths secondary to its induction of hematologic malignancies and septic complications8. Other chemotherapeutic agents (e.g. cyclophosphamide, methotrexate, chlorambucil, 2-chlorodeoxyadenosine) have been tried, but with no better results and the risk of significant side effects.
IVIg, alone or in combination with systemic medications (see below), has gained widespread acceptance as first-line therapy for both cutaneous involvement and associated systemic manifestations, including the dermato-neuro syndrome9-10. Although long-lasting remissions after cessation of IVIg therapy have been reported, the response is usually not permanent and maintenance infusions are required5. Thalidomide (or lenalidomide) and/or systemic corticosteroids, standard therapies for multiple myeloma, are considered second-line treatments and are often administered in combination with IVIg11-12. Autologous HSCT represents third-line therapy, especially for individuals with disabling or potentially life-threatening disease13. Post-transplant recurrences can be treated with bortezomib plus dexamethasone14.

Additional therapies, including PUVA, UVA1, systemic retinoids, cyclosporine, electron beam radiation, plasmapheresis, and extracorporeal photochemotherapy, have all produced variable results. Dysarthria and a flu-like illness may herald the life-threatening coma, and the patient should be promptly admitted to the hospital for close observation. Occasionally, spontaneous improvement and clinical resolution, even after 15 years, have been described
In the localized variants of lichen myxedematosus, patients develop small, firm, waxy papules (or nodules and plaques produced by the confluence of papules) that are limited to only a few sites - usually the upper and lower extremities and/or trunk. The skin is the only site of involvement and these variants, in contrast to scleromyxedema, are not associated with sclerosis, paraproteinemia or systemic involvement nor are they associated with thyroid disease

The localized variants of lichen myxedematosus are subdivided into four subtypes:
• a discrete papular form
• acral persistent papular mucinosis
• cutaneous mucinosis of infancy
• a pure nodular form

Localized variants of lichen myxedematosus may be observed in association with HIV infection, exposure to toxic oil or L-tryptophan (historical), and hepatitis C viral (HCV) infection.
Clinical Features of lichen myxedematosusDiscrete papular lichen myxedematosus is characterized by 2-5 mm papules, numbering from just a few to hundreds and involving the limbs and trunk in a symmetrical pattern15 (Fig. 46.5). The affected skin is not indurated and the face is spared. The lesions progress slowly without systemic involvement. However, they rarely resolve spontaneously. To date, progression to scleromyxedema has never been proven. In acral persistent papular mucinosis, first described in 1986 by Rongioletti et al.16, multiple ivory to skin-colored papules develop exclusively on the dorsal aspect of the hands and extensor surface of the distal forearms (Fig. 46.6). A female predominance, with a female : male ratio of 3 : 1, has been noted. The lesions persist but without systemic manifestations17 In cutaneous mucinosis of infancy (syn. papular mucinosis of infancy), first described by Lum in 1980, firm opalescent papules appear on the neck (Fig. 46. 7), upper arms (especially the elbows), and trunk Nodular lichen myxedematosus is characterized by multiple nodules on the limbs and trunk, with a mild or absent papular componentDdx for localized lichen myxedematosusDifferential diagnosis Histologic examination of the skin helps to distinguish localized variants of lichen myxedematosus from several papular eruptions that can have a similar appearance, such as papular granuloma annulare, amyloidosis, colloid milium, molluscum contagiosum, papular elastorrhexis, and eruptive collagenomas. It is also important to differentiate these entities from scleromyxedema and the cutaneous mucinosis that can occur in the setting of autoimmune connective tissue diseasesTreatment for localized myxedematosusLocalized lichen myxedematosus does not require therapy, and a wait and- see approach is recommended. Topical application of corticosteroids, pimecrolimus or tacrolimus may be of some benefit15. One patient with associated HIV infection had a complete remission after treatment with oral isotretinoin. Spontaneous resolution may occur22, even in the setting of HIV infection.Self healing cutanoeus mucinosisAlthough previously considered a subtype of localized lichen myxedematosus, self-healing cutaneous mucinosis is best regarded as a distinct rare form of primary dermal mucinosis Self-healing cutaneous mucinosis is characterized by the following clinical presentations: (1) an acute eruption of multiple papules, sometimes coalescing into linear infiltrated plaques, on the face, neck, scalp, abdomen and thighs; and (2) mucinous subcutaneous nodules in periarticular areas and on the face, with periorbital swelling (Fig. 46.8). In addition, systemic symptoms (e.g. fever, arthralgias and muscle tenderness) may accompany the cutaneous lesions, but paraproteinemia, bone marrow plasmacytosis and thyroid dysfunction are not observed. Spontaneous resolution over a period of 1-8 months is characteristic, hence the name. Histologically, papular lesions show dermal mucin deposition with mild inflammation and a small increase in the number of fibroblasts, whereas nodules have deep mucinous deposits associated with bands of fibrosis and a prominent proliferation of fibroblast-like cells and gangliocyte-like cells mimicking proliferative fasciitis.Scleredema - PathogenesisScleredema is a symmetrical diffuse induration of the upper part of the body due to a thickened dermis and deposition of mucin. Pathogenesis: Scleredema is an unusual disease that affects all races. The form that is associated with diabetes mellitus is more prevalent in men, while other forms are seen more commonly in women. Irreversible glycosylation of collagen and resistance to degradation by collagenase may lead to an accumulation of collagen. Alternatively, enhanced stimulation by insulin, microvascular damage, and hypoxia may increase the synthesis of collagen and mucin. Streptococcal hypersensitivity (type I), injury to lymphatics, and paraproteinemia (type II) may also play a role.What are the three types of sclerodema, who do they affect, and clinical presentation Possible internal involvementClassically, there are three types of scleredema, although a simpler division into those with and those without diabetes has been suggested25. The first type affects primarily children and middle-aged women. It is preceded by fever, malaise, and an infection (usually streptococcal) of the upper or lower respiratory tract. The skin of the cervicofacial region suddenly hardens with extension to the trunk and proximal upper limbs. The face is expressionless and opening of the mouth and swallowing are difficult because of the involvement of the tongue and pharynx. This type usually resolves spontaneously. The second type shares the same clinical features as the first but has a more subtle onset, without a preceding illness. It persists for years. This type is more frequently associated with a monoclonal gammopathy. The third type occurs primarily in obese middle-aged men with insulin-dependent diabetes (scleredema diabeticorum). The onset is subtle and the involvement persistent. Erythema and induration of the posterior neck and the back are commonly observed (Fig. 46.9), as is a peau d'orange appearance of the skin. In those patients who also have cheiroarthropathy, the skin of the distal extremities may appear waxy, presumably due to increased amounts of glycosylated collagen. Occasionally, patients with limited site involvement, e.g. periorbital skin, have also been reported26. In all three forms, systemic manifestations such as serositis, myositis, dysarthria, dysphagia, parotitis, and ocular and cardiac abnormalities (e.g. ophthalmoplegia, congestive heart failure) may occur, but are unusual. Anecdotal associations include autoimmune diseases (e.g. rheumatoid arthritis, Sjögren syndrome, primary biliary cirrhosis, dermatomyositis), internal neoplasms (malignant insulinoma, gallbladder carcinoma, carcinoid, pituitary-adrenocortical neoplasm27), and HIV infection19. Except for limitation of movement, scleredema usually causes little morbidity. While postinfectious scleredema may clear within 6-24 months, scleredema associated with diabetes or a monoclonal gammopathy has a chronic unremitting course. Rarely, death may occur when internal organs are involved.Pathology of scleredemaThe principal alteration in scleredema is the thickening of the reticular dermis, with large collagen bundles separated from one another by clear spaces filled with mucin, resulting in fenestration of the dermis (Fig. 46.10). There is no increase in the number of fibroblasts, but the elastic fibers are reduced in number. At times, the mucin deposition can be so slight that multiple biopsies or staining of unfixed frozen sections are required to detect it. There is sometimes a sparse perivascular lymphocytic infiltrate. Direct immunofluorescence is usually negative, but deposits of IgG and C3 have been observed at the dermal-epidermal junction. Mucin also accumulates within skeletal muscle and the heart.Ddx of scleredema Treatment of scleredemaScleredema may be confused with scleroderma, but the absence of Raynaud phenomenon and cuticular and mat telangiectasias points to scleredema. Patients with scleromyxedema also have firm papules (often in a linear array) in addition to dermal induration as well as a proliferation of fibroblasts histologically. The other types of cutaneous mucinoses are usually distinguished on the basis of clinical findings. Additional entities in the sclerodermoid differential diagnosis should be excluded (see Ch. 43). Occasionally, because of associated erythema, patients with diabetes-associated scleredema are sometimes misdiagnosed as having cellulitis (usually by non-dermatologists). Therapy is unnecessary for scleredema associated with streptococcal infections because it is self-limited. Management of scleredema associated with diabetes or a monoclonal gammopathy is more difficult and no specific treatment is available. Phototherapy, in particular UVA1 and PUVA, is considered first-line therapy as it can stimulate fibroblasts to synthesize collagenase, thereby enhancing degradation of sclerotic tissue28. For scleredema associated with a plasma cell dyscrasia, bortezomib, a proteasome inhibitor commonly used to treat myeloma, may be effective29. Some, but not all, patients with diabetes-associated scleredema improve with strict glycemic control. Systemic and intralesional corticosteroids, intralesional hyaluronidase, antibiotics, methotrexate, cyclosporine, pulse therapy with cyclophosphamide plus oral corticosteroids, tamoxifen, and allopurinol30 have all been tried, with variable results. Electron beam radiotherapy, IVIg31, and extracorporeal photopheresis are additional reported therapies. In patients with limited mobility or respiratory difficulty, ultrasonic massage and physical therapy can be employed. Aggressive therapies should be limited to individuals with disabling disease or systemic manifestations.Mucinoses associated with altered thyroid function - What is the cause of localized myxedema - How common is it to see pretibial myxedemaLocalized (Pretibial) Myxedema - Localized or pretibial myxedema is characterized by cutaneous induration of the shins due to mucin deposition. It is often associated with hyperthyroidism (most commonly due to Graves disease), but may appear following treatment of the thyroid disease. - Graves disease is seven times more common in women than in men and its onset is usually during the third or fourth decade. Pretibial myxedema is one of the signs of Graves disease, along with goiter, exophthalmos - thyroid acropachy, and thyroid-stimulating immunoglobulins that recognize the thyroid-stimulating hormone (TSH) receptor. Overall, pretibial myxedema is found in 1-5% of patients with Graves disease, but in up to 25% of those with exophthalmos32. It can also appear in the setting of hypothyroidism following the treatment of Graves disease. Rarely, localized myxedema occurs in the setting of Hashimoto thyroiditis without thyrotoxicosis, and even in euthyroid patients.Localized myxedema - Clinical Presentation - PathologyLocalized myxedema presents as erythematous to skin-colored, but sometimes purple-brown or yellowish, waxy indurated nodules or plaques. A peau d'orange appearance is a characteristic finding (Fig. 46.11). The lesions are usually located on the anterolateral aspect of the lower legs or the feet. Localized myxedema can also present as a diffuse non-pitting edema of the shins or feet that evolves into elephantiasis. Even more rarely, localized myxedema affects the face, shoulders, upper extremities, lower abdomen, scars or donor graft sites. Large plaques are often painful and pruritic. When present, hypertrichosis and hyperhidrosis are confined to pretibial myxedematous skin. Apart from appearance and possible pain, associated morbidity is usually minimal. Entrapment of peroneal nerves by mucinous connective tissue may cause foot drop or faulty dorsiflexion Pathology: Large quantities of mucin are deposited within the reticular dermis, causing collagen bundles to separate and the dermis to thicken6. A subepidermal grenz zone of normal collagen is also observed. A perivascular and periadnexal lymphocytic infiltrate with mast cells is seen, as well as large stellate fibroblasts. Elastic fibers are reduced in number. There is often hyperkeratosis in addition to papillomatosis and hyperplasia of the epidermis.Localized myxedema - ddx - First line treatment - Treatment for severe elephantitis form - Does it improve with treatment of the thyroid disease?In addition to lichen simplex chronicus and hypertrophic lichen planus, pretibial myxedema should be distinguished from lymphedema, lipedema, and obesity-associated lymphedematous mucinosis. In the latter disorder, semi-translucent papules, plaques with woody induration, and occasionally vesicles develop on the shins of euthyroid, morbidly obese individuals with significant lower extremity edema. Histologically, mucin deposition is found within the superficial papillary dermis and around vessels, in addition to epidermal atrophy (with effacement of the rete ridge pattern), vertically oriented capillaries, and deposits of hemosiderin Corticosteroids, either applied under occlusive dressings or delivered by intralesional injection (e.g. triamcinolone 10-40 mg/cc), are considered first-line therapy32. For the severe elephantiasis form, medical treatments, including IVIg, rituximab, plasmapheresis and octreotide, at times combined with surgical procedures, have been of some benefit34-35. Unfortunately, skin grafting is usually followed by recurrence. Compression stockings and gradient pneumatic compression are useful for the associated lymphedema. Addressing risk factors such as obesity and smoking is recommended. Therapy for hyperthyroidism does not improve the cutaneous lesions and, often, localized myxedema develops after treatment has been instituted or completed. Localized myxedema may clear spontaneously after an average of 3.5 years.Generalized Myxedema - results from what? - clinical presentationDefinition Generalized myxedema is a manifestation of severe hypothyroidism in which mucin is deposited in the dermis, leading to waxiness of the skin. Pathogenesis Generalized myxedema is due to a quantitative or functional deficiency of thyroxine. Impaired degradation of mucin, rather than increased synthesis, has been suggested as the cause. The skin is pale, cool, waxy and dry; an absence of sweating can lead to acquired ichthyosis or eczema craquelé. A yellowish discoloration of the palms and soles due to carotenoderma may appear. Hair and nails are dry and brittle, and a diffuse non-scarring alopecia is common; alopecia of the lateral third of the eyebrows can also be seen. Purpura involving the extremities, blue telangiectatic fingertips, delayed wound healing, and xanthomas may be observed. Systemic manifestations include cardiomegaly, megacolon or bowel obstruction, psychiatric symptoms mimicking Alzheimer disease, serositis, carpal tunnel syndrome, and seventh nerve paralysis36.More Generalized Myxedema - diagnosis - treatmentPathology Mucin deposits, mainly perivascular and perifollicular, splay collagen bundles and may extend into the subcutaneous fat and nerves. Fibroblasts are not increased in number, but elastic fibers are reduced. Mucin deposits in the brain probably cause the psychiatric symptoms. Diagnosis and differential diagnosis The diagnosis is suspected clinically. Low levels of circulating free T4 confirm the diagnosis. The serum TSH level is high in primary hypothyroidism and low in secondary hypothyroidism. Myxedema does not seem to occur in secondary hypothyroidism. Treatment Early treatment is crucial for proper mental development of neonates with hypothyroidism, but it is also critical for the juvenile and adult forms. Measurement of serum levels of T4 and/or TSH is performed between 2 and 4 days of age in newborn screening panels, and treatment should be initiated within the first 2 weeks of life. Usually, symptoms subside with thyroxine administration and recur if it is discontinued. Even areas of hair loss regrow with proper treatment. If untreated, patients can die as a result of "myxedema coma".Reticular Erythematous Mucinosis - Most often seen in whom? - exacerbating factorsIntroduction and definition Reticular erythematous mucinosis (REM) is a disorder in which persistent, erythematous papules or plaques develop in the midline of the back or chest. The papules often have a reticular or net-like configuration. This disorder has some overlap with lupus erythematosus (LE) tumidus37-38. History Steigleder and colleagues coined the term "reticular erythematous mucinosis" in 1974. However, the initial description of similar cases appeared in 1960, when Perry and colleagues described three patients with plaque-like cutaneous mucinosis. Some authors regard these two entities as identical, while others view them as being on a continuum37. Epidemiology and pathogenesis REM is a rare disorder that occurs most often in middle-aged women, although men and children are not spared. It is seen worldwide and can be provoked or exacerbated by a wide range of factors, from heat and perspiration to oral contraceptives and pregnancy to radiation therapy. There is debate as to whether REM is a photoaggravated disorder. Familial cases suggest a genetic predisposition. Within endothelial cells and pericytes of lesional skin, tubuloreticular inclusions have been detected. Although these inclusions occur in viral infections, they can also be produced by high levels of interferon and are also found within endothelial cells in LE. Lastly, the fibroblasts of REM patients exhibit an abnormal overstimulation when exposed to exogenous IL-1.Clinical Features of REMClinical features Plaque-like cutaneous mucinosis and REM are probably different clinical presentations of the same rare syndrome. On the mid back or chest, pink to red macules and papules merge into reticulated and annular patterns (Fig. 46.13) or plaque-like lesions. They may be slightly pruritic and sometimes lesions spread to the abdomen. While sun exposure may worsen the eruption, it has also been reported to be beneficial. Provocative phototests (UVA and/or UVB) can sometimes reproduce REM lesions. In general, REM is not associated with systemic diseases or abnormal laboratory tests. However, there are reports of autoimmune diseases (e.g. LE), hypothyroidism, and more common internal malignancies in patients with REM37More REM - TreatmentPathology The epidermis is normal. Interstitial deposits of small amounts of mucin are seen in the upper dermis, along with a perivascular and, at times, perifollicular T-cell infiltrate6. Vascular dilation is present. Usually, direct immunofluorescence is negative, but, rarely, granular deposits of IgM, IgA and C3 have been seen at the dermal-epidermal junction38. Differential diagnosis In biopsy specimens of discoid lesions of LE there is involvement of the epidermis and deposits of IgG and C3 are found at the dermal-epidermal junction, and in lymphocytic infiltrate of Jessner, there is minimal, if any, dermal mucin. LE tumidus is very difficult to distinguish microscopically from REM. Both diseases have perivascular dermal infiltrates of T lymphocytes, primarily CD4+, plus increased dermal mucin. In REM, the mucin and the lymphocytes tend to be more superficial and the lymphocytes more scattered. In LE tumidus, plasmacytoid dendritic cells were found to be clustered whereas in REM they were fewer in number and appeared as single cells38. These findings aside, some authors view REM and LE tumidus as variants of the same disease and along a continuum with cutaneous LE. Seborrheic dermatitis and tinea versicolor may involve the central chest, but they have associated scale and can be diagnosed clinically, as can confluent and reticulated papillomatosis. Treatment Hydroxychloroquine or chloroquine (± quinacrine) are usually effective in clearing the lesions within 4-8 weeks. Results from other treatments such as topical and systemic corticosteroids, topical calcineurin inhibitors, oral antihistamines, tetracycline, cyclosporine, UVB irradiation, and pulsed dye laser are quite variable. Despite the potential for an exacerbation, improvement following UVA1 or UVB irradiation has been reported37. The lesions may clear spontaneously, even after 15 yearsPapulonodular Mucinosis secondary to connective tissue disease - Most commonly associated connective tissue disease? what others? - Lupus mucinosis occurs in what % of LE patients? -Papules, nodules and plaques secondary to mucin deposition may accompany or even antedate an autoimmune connective tissue disease, most commonly LE, and rarely dermatomyositis or scleroderma. Cutaneous lupus mucinosis occurs in 1.5% of patients with LE38. Only in Japan has a male predominance been observed. The lesions present as asymptomatic, skin-colored, at times erythematous, 0.5-2 cm papules and nodules (Fig. 46.14); rarely will they merge into large plaques. Tangential illumination can be used to enhance detection of the lesions. A central depression and pigmentation may be additional features. The back, V of the chest, and the upper extremities are the most common sites of involvement. In only a few reported patients was there a flare of the papulonodules after sun exposure. Cutaneous lupus mucinosis can antedate LE or begin concurrently. The clinical course may correlate, in some patients, with underlying disease activity. Approximately 75% of patients with LE who develop papular and nodular mucinosis have systemic involvement, primarily renal and articular. The minority have only skin involvement, usually discoid or subacute cutaneous LE lesions. Histologically, mucin abounds in the upper and mid dermis but may involve the subcutaneous fat as well. Sometimes, it is accompanied by a slight perivascular lymphocytic infiltrate. The epidermal changes of LE are absent, but linear or granular deposits of immunoglobulin and/ or C3 are detected at the dermal-epidermal junction. Cutaneous lesions of dermatomyositis often have dermal mucin histologically; rarely, patients develop erythematous nodules and plaques due to mucin deposition. The latter appear primarily on the trunk39 and usually follow the myositis. Papular and nodular mucinosis can also occur in association with systemic sclerosis40Treatment for papulonodular mucinosisTreatment Therapies for papular and nodular mucinosis are similar to those used for LE and dermatomyositis, i.e. sunscreens, topical corticosteroids, and oral antimalarials. For unresponsive cases, systemic corticosteroids can be prescribed. Intralesional corticosteroids may prove useful for reducing the size of large nodules and plaques.Follicluar mucinosisHistory, epidemiology and pathogenesis This uncommon inflammatory disorder, described in 1957 by Pinkus, has a predilection for children and for adults in the third and fourth decades of life. It is far from clear why dermal-type mucin is deposited selectively within an epithelial structure. Although follicular keratinocytes have been considered to be the source of the mucin, an etiologic role for cell-mediated immune mechanisms has been proposed43, including a reaction to persistent antigens such as Staphylococcus aureus. Clinical features Primary follicular mucinosis is an idiopathic benign form of the disease, apparently not linked to lymphoma43. Clinically, it presents as an acute or subacute eruption in children and young adults and is characterized by one or several pink plaques, often composed of grouped follicular papules. There may be associated scale, and lesions are limited to the face (Fig. 46.15A) and scalp and are associated with alopecia. Papulonodules (Fig. 46.15B), annular plaques, folliculitis, follicular spines, and acneiform eruptions have also been described43. A second type of follicular mucinosis, characterized by: (1) a more generalized distribution (extremities, trunk and face; Fig. 46.15C); (2) larger and more numerous plaques; (3) a chronic clinical course; and (4) occurrence in a slightly older age group41, is probably best regarded as a secondary follicular mucinosis associated with atopic dermatitis or cutaneous T-cell lymphoma, rather than a primary condition.Mucin accumulates within the follicular epithelium and sebaceous glands, causing keratinocytes to disconnect (Fig. 46.15D). In more advanced lesions, the follicles are converted into cystic spaces containing mucin, inflammatory cells, and altered keratinocytes. A perifollicular and intrafollicular infiltrate of lymphocytes, histiocytes and eosinophils is seen6. Differential diagnosis The differentiation between primary follicular mucinosis and mycosis fungoides-associated follicular mucinosis is very difficult6, and there is no single reliable criterion. Although the existence of a primary form of follicular mucinosis has been questioned by some authors (who consider it as an "indolent" localized form of cutaneous T-cell lymphoma44), features in favor of a primary form are the young age of the patient, a solitary plaque or limited number of lesions in the head and neck region, spontaneous resolution, and the absence histologically of epidermotropism and atypical lymphocytes. Detection of clonal T-cell gene rearrangements does not seem to help differentiate the two types43. Treatment There is no specific treatment. A wait-and-see approach is recommended for primary follicular mucinosis as many cases resolve spontaneously within 2-24 months. Topical, intralesional and systemic corticosteroids, antimalarials45, phototherapy (PUVA, UVA1), minocycline, dapsone, indomethacin, oral isotretinoin, interferon-α-2b, and orthovoltage irradiation have been reported to be beneficial. For secondary forms, treatment of the underlying disease is indicated. Longitudinal evaluation and assessment for cutaneous T-cell lymphoma is recommended for patients with presumed primary follicular mucinosis that is persistent or becomes more extensiveUrticaria like follicular mucinosisUrticaria-like follicular mucinosis is a very rare disorder that occurs primarily in middle-aged men. Pruritic urticarial papules or plaques appear on the head and neck within an erythematous "seborrheic" background. As lesions resolve, red macules persist for a few weeks. Hair-bearing regions may be involved, but neither follicular plugging nor alopecia is seen. Urticaria-like follicular mucinosis waxes and wanes irregularly over a period that can vary from a few months to 15 years. There are no associated systemic diseases. Response to natural sunlight has been inconsistent, but it has been beneficial in a small number of cases. As in primary follicular mucinosis, mucin-filled cystic spaces occupy hair follicles. In the upper dermis, lymphocytes and eosinophils are seen around blood vessels and hair follicles. In only a single patient to date were vascular C3 deposits seen by direct immunofluorescence. The prognosis is good, and based upon a limited number of case reports, antimalarials and dapsone were reportedly beneficial46A mucinous nevusA mucinous nevus (nevus mucinosus) is a benign hamartoma that can be congenital or acquired. It consists of a plaque that usually has a unilateral linear nevoid pattern47. Histologically, a diffuse deposit of mucin is seen in the upper dermis, and collagen and elastic fibers are absent within the mucinous area. The epidermis can be normal or it may be acanthotic with elongation of the rete ridges and hyperkeratosis, as in an epidermal nevus. The latter set of findings points to a combined hamartoma, in which features of an epidermal nevus are associated with those of a connective nevus of the proteoglycan type. The cellular component of a mucinous nevus consists of CD34+ fibroblasts and scarce factor XIIIa-positive dendritic cells.Superficial MyxomaSuperficial (Angio)Myxoma Superficial (angio)myxoma, also known as cutaneous myxoma, is an acquired benign neoplasm that is usually nodular and measures 1-5 cm in diameter. It favors the trunk, head and neck, and genital region; rarely, cutaneous myxomas have an acral location48. These tumors can be solitary, without any systemic abnormalities, or multiple. When multiple, they may be a manifestation of Carney complex (cutaneous myxomas, cardiac myxomas, numerous lentigines, multiple blue nevi, endocrine overactivity). Histologically, a cutaneous myxoma is a lobulated, well-defined lesion characterized by a mucinous matrix within the dermis and the subcutis, with variably shaped fibroblasts, mast cells, and a few collagen and reticulin fibers. Bizarre multinucleated cells and regular mitotic figures can be seen. The stromal cells are smooth muscle actin (SMA)-positive and factor XIII-negative49. Myxomas must be distinguished from cutaneous focal mucinosis, a reactive lesion which is usually <1 cm and ill-defined histologically; the latter does not have an epithelial component and the mucin deposits are in the dermis but not the subcutis. This differentiation is important as (angio)myxomas are true neoplasms, although benign, which can recur after incomplete excision.