Ch46: Mucinoses Flashcards
Mucin stains
Alcian blue, colloidal iron, toluidine blue
Mucin properties
- 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
Classification of Mucinoses
- Primary –> major histologic feature resulting in clinically distinctive lesions
- degenerative/inflammatory
- dermal
- dollicular
- hamartomatous/neoplastic
- degenerative/inflammatory
- Secondary –> mucin represents an associated histologic finding
- epithelial –> BCC, rarely malignancies
- dermal –> GA, lupus, neural tumours, etc
- follicular –> MF, eczematous dermatoses
Scleromyxoedema epidemiology
- nearly all patients have a monoclonal gammopathy
- uncommon
- middle aged
- M=F
Scleromyxoedema pathogenesis
- 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
Scleromyxoedema cutaneous findings
- 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
Scleromyxoedema non-cutaneous findings
- 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
Scleromyxoedema pathology
- 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
Leonine facies differentials:
- 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
Scleromyxoedema treatment
- 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
- IVIG, alone or wth systemic
- 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
Lichen Myxoedematosus subtypes
- 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 - 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 - Cutaneous mucinosis of infancy
- papules on neck, upper arms and trunk
- Can be linear - Nodular lichen myxoedematosus
- multiple nodules on the limbs and trunk
Lichen Myxoedematosus associations
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
Lichen Myxoedematosus pathology
- 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
Lichen Myxoedematosus Treatment
- watch and wait
- topical steroids or calcineurin inhibitors
- spontaneous resolution can occur, even in HIV
Self-Healing cutaneous mucinosis clinical
- 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
Self-Healing cutaneous mucinosis histology
- 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
Scleredema epidemiology
more prevalent in men
Scleredema pathogenesis
- 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
Scleredema clinical features and types
- 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
Scleredema pathology
- 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
Scleredema ddx
- Scleroderma (systemic sclerosis) however no Raynauds, telangiectasia
- Scleromyxoedema - firm papules, and fibroblasts proliferation
- Other cutaneous mucinoses
- Sclerodermoid differentials
- Cellulitis (usually by non-derms)
Scleredema rx
- 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
Localized pretibial myxoedema - what is it
Mucin deposition to the pretibial site, often associated with hyperthyroidism - most commonly due to Graves disease
Localized pretibial myxoedema epidemiology
- 7X more common in women than men
- Onset is usually during the third or fourth decade
Localized pretibial myxoedema pathogenesis
- 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
Localized pretibial myxoedema clinical
- 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