Ch46: Mucinoses

Question 1

Mucin stains

Answer 1

Alcian blue, colloidal iron, toluidine blue

Question 2

Mucin properties

Answer 2

• component of dermal ECM
• normally produced by small amounts of fibroblasts
• amorphous mixture of acid glycosaminoglycans - complex carbohydrates composed of multiple repeating polysacchraide units
  
  • amino glycosaminoglycans may be attached to a protein core (chondroitin) or may be free (hyaluronic acid)
• absorbs 1000X its own weight in water
• stains: Alcian blue, colloidal iron, toluidine blue
  
  • Dermal mucin is PAS negative, and if composed of hyaluronic acid, hyaluronidase-sensitive
  • fixation in alcohol over formalin will improve dermal mucin detection
• what causes it to increase?
  
  • certain immunoglobulins/cytokines could promote upregulation of glycosaminoglycan synthesis
  • circulating autoantibodies have been associated with mucinosis
  • cytokines implicated: IL-1, TNF-alpha, TGF-beta

Question 3

Classification of Mucinoses

Answer 3

• Primary –> major histologic feature resulting in clinically distinctive lesions
  
  • degenerative/inflammatory
    
    • dermal
    • dollicular
  • hamartomatous/neoplastic
• Secondary –> mucin represents an associated histologic finding
  
  • epithelial –> BCC, rarely malignancies
  • dermal –> GA, lupus, neural tumours, etc
  • follicular –> MF, eczematous dermatoses

Question 4

Scleromyxoedema epidemiology

Answer 4

• nearly all patients have a monoclonal gammopathy
• uncommon
• middle aged
• M=F

Question 5

Scleromyxoedema pathogenesis

Answer 5

• Unknown
• plasma cell dyscrasia - however, paraprotein levels do not correlate with either the extent or progression of disease
• clinical remission has occurred following stem cell transplant –> bone marrow as possible source of circulating factors
• autoimmune phenomena suggested - have developed after intradermal injections of hyaluronic gel

Question 6

Scleromyxoedema cutaneous findings

Answer 6

• Cutaneous
  
  • 2-3 mm firm, waxy closely aligned papules develop in widespread symmetrical pattern
  • common sites: head, neck, upper trunk, hands, forearms, thighs
  • usually linear
  • surrounding skin shiny and indurated, glabella is typically involved
  • extensive –> leonine facies
  • Shar-Pei: deep furrowing on the trunk and extremities
  • erythema, oedema, brown discolouration
  • MM and scalp spared
  • as progresses –> skin stiffening, sclerodactyly, decreased motility
  • Doughnut sign - central depression surrounded by an elevated rim over the proximal IP joints
  • No telangiectasias or calcinosis, as you would see in systemic sclerosis

Question 7

Scleromyxoedema non-cutaneous findings

Answer 7

• Monoclonal gammopathy –> IgG and light chains (lambda most common)
• Mild plasmacytosis –> <10% progress to symptomatic myeloma
• Neuro - coma, peripheral neuropathy, arthropathies, carpal tunnel.
  
  • Dermato-neuro syndrome potentially life threatening: encephalopathy, worsening of skin lesions, flu-like prodrome, fevers, seizures, coma
  • Sensory peripheral neuropathy - older men, gradual onset
• Muscular - dysphagia, proximal mm weakness
• Resp - restrictive/obstructive lung disease
• Renal - sclerodermal like renal disease

Question 8

Scleromyxoedema pathology

Answer 8

• Triad:
  
  • Mucin in upper and mid-reticular dermis
  • Increase in collagen deposition
  • Marked proliferation of irregularly arranged fibroblasts (not seen in scleroderma)
• mucin may also fill walls of myocardial BV, kidney parenchyma, pancreas, adrenal glands, nerves, lymph nodes
• Epidermis may be normal or thinned
• Hair follicles may be atrophic
• Slight superficial, perivascular lymphoplasmacytic infiltrate
• Elastic fibres are fragmented and decreased in number
• Interstitial GA subtype has been described

Question 9

Leonine facies differentials:

Answer 9

• Deposition disorders
  
  • Scleromyxoedema
  • Leukaemia cutis
  • Systemic amyloidosis
  • Lipoid proteinosis
  • Sarcoidosis
• Infectious
  
  • Lepromatous leprosy
  • Leishmaniasis
• Malignancy
  
  • CTCL
  • CBCL
• Papulosquamous
  
  • Actinic reticuloid form of chronic actinic dermatitis
  • Mastocytosis
  • Multicentric reticulohistiocytosis
  • Progressive nodular histiocytosis
• Pachydermoperiostosis

Question 10

Scleromyxoedema treatment

Answer 10

• based on case reports and small case series
• Used to be melphalan as it targets plasma cell dyscrasias, but is has been implicated in 30% of the deaths secondary to its induction of haematologic malignancies and septic complications
• First line:
  
  • IVIG, alone or wth systemic
    
    • response often not maintained, requires ongoing infusions
    • For cutaneous, associated systemic, and dermato-neuro syndrome
• Second line:
  
  • thalidomide +/- systemic steroids (standard therapies for multiple myeloma)
• Third line:
  
  • Autologous HSCT - especially for individuals with potentially life-threatening or disabling disease
  • Post transplant recurrence - treat with bortezomib + dexamethasone
• Other things:
  
  • PUVA, UVA1
  • Systemic retinoids
  • Cyclosporin
  • Electron beam radiation
  • Plasmapharesis
  • extracorporeal photochemotherapy
• Dysarthria + flu like illness may precede dermato-neuro syndrome, and need to be admitted to hospital for observation

Question 11

Lichen Myxoedematosus subtypes

Answer 11

1. Discrete papular lichen myxoedematosus
   - 2-5 mm papules numbering from a few to a hundred, involving the limbs and trunk in a symmetrical pattern
   - affected skin not indurated, face is spared
   - progress slowly
2. Acral persistent papular mucinosis
   - multiple ivory to skin-coloured papules on dorsal aspect of hands and extensor surface of distal forearm
   - F>M 3:1
3. Cutaneous mucinosis of infancy
   - papules on neck, upper arms and trunk
   - Can be linear
4. Nodular lichen myxoedematosus
   - multiple nodules on the limbs and trunk

Question 12

Lichen Myxoedematosus associations

Answer 12

Other associations

• With HIV: most have hypergammaglobulinaemia
  
  • Can have papular form on trunk and limbs, or acral persistent papular mucinosis
  • 10% of those with HIV have an MGUS ?link to LM
• In toxic syndromes: been associated with toxic oil syndrome and L-tryptophan-associated eosinophilia-myalgia syndrome (related to contaminant in L-tryptophan containing products used as sedatives in the 80s) –> shares similar clinical features of LM, including constitutional sx, peripheral eos, hyperpigmentation and sclerodermoid appearance. Lesions resolve slowly
• With HCV: association with chronic HCV
• Atypical forms - intermediate between scleromyxoedema and localised lichen myxoedematosus

Question 13

Lichen Myxoedematosus pathology

Answer 13

• less characteristic than scleromyxoedema
• mucin in upper and mid-reticular dermis
• fibroblast proliferation is variable
• fibrosis - not too much, may be absent
• Acral persistent papular mucinosis –> mucin accumulates focally in the upper reticular dermis, fibroblasts not increased in number
• Cutaneous mucinosis –> mucin may be so superficial, may look énclosed’ by the epidermis

Question 14

Lichen Myxoedematosus Treatment

Answer 14

• watch and wait
• topical steroids or calcineurin inhibitors
• spontaneous resolution can occur, even in HIV

Question 15

Self-Healing cutaneous mucinosis clinical

Answer 15

• distinct rare form of primary dermal mucinosis
• Clinical presentations:
  
  • acute eruption of multiple papules, sometimes coalescing to form linear plaque, on face, neck, scalp, abdomen and thighs
  • Mucinous subcutaneous nodules in peri-articular areas and face, with peri-orbital swelling
  • Systemic symptoms: fevers, arthralgias, muscle tenderness
  • No evidence of paraproteinaemia, thyroid dysfunction, etc
  • Spontaneously resolve over 1-8 months

Question 16

Self-Healing cutaneous mucinosis histology

Answer 16

• dermal mucin deposition with mild inflammation, small increase in fibroblasts
• nodules: deep mucinous deposits associated with bands of fibrosis, and prominent fibroblast cell proliferation and gangliocyte like cells mimicking proliferative fasciitis

Question 17

Scleredema epidemiology

Answer 17

more prevalent in men

Question 18

Scleredema pathogenesis

Answer 18

• unsure
• either prevents collagen breakdown resulting in collagen accumulation
• or enhanced stimulation of insulin/microvascular damage/hypoxia may stimulate collage synthesis
• Also thought: streptococcal hypersensitivity, lymphatic injury and paraproteinaemia

Question 19

Scleredema clinical features and types

Answer 19

• suggested to divide into diabetes or not diabetes
  1. Type 1
• Children and middle-aged women
• Preceded: fever, malaise, infection (strep)
• Cervicofacial hardening, extension to trunk and proximal upper limbs
• Opening of mouth and swallowing difficult
• Usually resolves spontaneously
  2. Type 2
• Same as Type 1 but more subtle
• associated with monoclonal gammopathy
  3. Type 3 - Scleredoema diabeticorum
• Obese middle aged men with insulin-dependent diabetes
• subtle onset - erythema and induration of the posterior neck and back, peau dórange
• if have cheiroarthropathy - skin of distal extremities may appear waxy, presumably due to increased amounts of glycosylated collagen
• Can have limited site involvement –> peri-orbital
• Systemic manifestations:
  
  • serositis
  • myositis
  • dysarthria
  • dysphagia
  • parotitis
  • ocular and cardiac abnormalities
• Anecdotal associations: autoimmune diseases (RA, Sjogren, primary biliary cirrhosis, DM), internal neoplasms (malignant insulinoma, GB cancer, carcinoid, pituitary-adrenocortical neoplasm), HIV
• can have chronic unremitting course
• Little morbidity
• Post-infectious may clear within 6-24 months

Question 20

Scleredema pathology

Answer 20

• thickening of reticular dermis
• large collagen bundles separated from one another by clear spaces filled with mucin –> fenestration of the dermis
• elastic fibres reduced in number
• no increase in number of fibroblasts
• DIF usually negative, but deposits of IgG and C3 have been observed
• Obviously mucin deposits in skeletal muscle and heart as well

Question 21

Scleredema ddx

Answer 21

• Scleroderma (systemic sclerosis) however no Raynauds, telangiectasia
• Scleromyxoedema - firm papules, and fibroblasts proliferation
• Other cutaneous mucinoses
• Sclerodermoid differentials
• Cellulitis (usually by non-derms)

Question 22

Scleredema rx

Answer 22

• unnecessary unless associated with a strep infection
• self-limited
• if associated with DM or monoclonal gammopathy –> more difficult as no specific treatment
• First line:
  
  • Phototherapy - particularly UVA1 and PUVA –> stimulates fibroblasts to synthesize collagenase –> degrading the sclerotic tissue
• If associated with a plasma cell dyscrasia: bortezomib - proteasome inhibitor used to treat myeloma
• Others:
  
  • systemic and intralesional steroids
  • intralesional hyaluronidase
  • antibiotics
  • MTX
  • cyclosporine
  • cyclophosphamide + steroids
  • tamoxifen
  • allopurinol
  • electron beam radiotherapy
  • IVIG
  • ECP
• Ultrasonic massages and physical therapy

Question 23

Localized pretibial myxoedema - what is it

Answer 23

Mucin deposition to the pretibial site, often associated with hyperthyroidism - most commonly due to Graves disease

Question 24

Localized pretibial myxoedema epidemiology

Answer 24

• 7X more common in women than men

- Onset is usually during the third or fourth decade

Question 25

Localized pretibial myxoedema pathogenesis

Answer 25

• Sign of Graves disease - goitre, exophthalmos, thyroid acropachy, thyroid stimulating immunoglobulins
  
  • Found in 1-5% of patients with it
  • 25% in those with exophthalmos
• Seen in hypothyroidism following Graves treatment
• Rarely seen in Hashimoto thyroiditis without thyrotoxicosis
• Postulation: serum factor may incite fibroblasts to produce mucin
• Fibroblasts in the lower legs are more likely to be sensitive to serum factors
• Also implicated: insulin-like growth factor, trauma, lymphatic obstruction

Question 26

Localized pretibial myxoedema clinical

Answer 26

• Erythematous-skin coloured, but can be purple-brown or yellowish, waxy indurated nodules or plaques
• Peau d’orange: characteristic
• Anterolateral aspect of lower legs or the feet
• Can also present as diffuse non-pitting oedema of the shins or feet that evolves into elephantiasis
• Very rarely it can affect the face, shoulders, upper extremities, lower abdomen, scars or donor graft sites
• Large plaques can be painful and itchy
• Can get hypetrichosis and hyperhidrosis to the pretibial area
• Minimal associated morbidity –> entrapment of peroneal nerve at the worst resulting in foot drop