Histiocytoses Flashcards
What is the progenitor cell for all histocytoses?
CD34
What are the groups of histiocytes?
- Langerhans
- Macrophage/mononuclear
- Dendritic
- Type 1: Papillary dermal dendrocytes, factor 13a positive
- Type 2: Reticular dermal dendrocytes, CD34 positive
What is the gene identified in LCH and what percentage have it?
BRAFV600E
What are the 4 rough groups of LCH?
Letterer-Siwe
Congenital self-healing reticulohistiocytosis
Hand-Schuller-Christian
Eosinophilic granuloma
Clinical findings of Letterer-Siwe
- <1 year of age
- 1-2 mm pink papules, pustules or vesicles in scalp, flexural areas, neck, perineum, etc
- Scale, crust and impetiginisation common findings
- Coalesce and become tender –> cause fissures in intertriginous regions
- Ddx: seborrheic dermatitis, diaper dermatitis, arthropod bites, varicella
Clinical findings of Hand-Schuller-Christian Disease
- 2-6 years of age
- Triad: diabetes insipidus (infiltration of posterior pituitary), bone lesions (80%) and exophthalmos
- 30% have skin lesions –> when early they are more like Letterer-Siwe, when later become more like xanthomatous
- You will have a hard time fixing the DI with radiation, but they can be treated with symptomatic vasopressin
Clinical findings of Eosinophilic Granuloma
- localized variant
- rarely have skin involvement
- usually have an asymptomatic granulomatous lesion of the bone
Clinical features of Congenital self-healing reticulohistiocytosis
- Limited to skin, rapidly self-healing
- First few days of life
- Characteristic wide-spread red to purplish brown papulonodules that have a nascular appearance
- After several weeks the lesions crust and involute
Prognosis of LCH?
Association with malignancies - particularly haematological
Varies depending on sites involved
Those with CD34 progenitor cells with BRAFV600E mutation has a poorer prognosis
Immunostains for LCH
- Positive for: S100, CD1a, Langerin (CD207) - then less done but: fascin, ATPase, peanut lectin, alpha-D-mannosidase
- Negative: Factor 13a, CD68, CD163, HAM56
Histological findings of LCH
- Epidermis:
- May be come LCH cell infiltrate
- Interface changes
- Dermis:
- LCH cell proliferation in the papillary dermis- these look like large cells with kidney shaped nuclei
- Mixed cells: eosinophils, neutrophils, lymphocytes, mast cells, plasma cells
- Secondary changes: haemorrhage, necrosis, crusting
Investigations for LCH
- Biopsy first
- Evaluate:
- Haematological - FBC, blood smear, haem referral
- Pulmonary - referral and CXR
- Renal - urine, UEC
- Skeletal - X-ray if suspicious
Treatment of LCH
- Limited disease - skin only:
- topical steroids, antibiotics, nitrogen mustard, imiquimod and NBUVB
- Extensive cutaneous:
- Case reports only: thalidomide, azathioprine, methotrexate
- Reserve: BRAF inhibitor - vemurafenib, allogenic haematopoietic stem cell transplant
- Multi-system: vinblastine + prednisone
When to use systemic treatment?
- Multi-system LCH
- Single-system LCH with multifocal bone lesions
- Single system in special sites - i.e. vertebral
- Single system with at risk CNS lesions
JXG Epidemiology
- Very common non-LCH
- M:F - 1.5:1
- ?more common in Caucasian
- rare in adults
JXG pathophysiology
- suggested that is a histiocytic reaction to a traumatic or infectious stimulus
- some suggest that generalised eruptive histiocytoma, benign cephalic histiocytosis and JXG may represent different expressions of the same disorder
JXG Cutaneous manifestations
Two forms:
- Small nodular/micronodular
- pink-red brown dome shaped papules, 2-5 mm in diameter
- widely scattered on upper body
- rapidly become yellow
- Large nodular
- solitary
- 1-2 cm in diameter
- These 2 forms can coexist
- Commonly head and neck, oral is rare
- Prognosis:
- limited to skin, self-limiting and benign
- Regress within 3-6 years
- Residual: hyperpigmentation, atrophy, anetoderma
JXG extra-cutaneous manifestations and associations
- Extra-cutaneous:
- Eye most commonly
- usually unilateral
- develops in <0.5% of patients with cutaneous lesions
- occurs before 2 years of age, and often affects the iris
- Hyphoema (haemorrhage into anterior chamber) and glaucoma can lead to blindness
- Then lung
- Other: visceral, bone, CNS (diabetes insipidus)
- Eye most commonly
- Associations:
- CALMs
- Juvenile monomyelocytic leukaemia
- NF1
- ‘Triple’ association: JXG, MM leukaemia and NF1
- Other forms of leukaemia –> CLL, B cell lymphoma
JXG Histology
- Well-demarcated, dense infiltrate of histiocytes within the superficial dermis in small lesions, in large lesions going to the subcutaneous fat
- Loss of rete ridges
- Mature lesions: Touton giant cells –> foamy xanthomatous appearnce
- Scattered lymphocytes, eosinophils and plasma cells
JXG Immunostains
- think non Langerhan:
- HAM56
- CD68
- Factor 13a
- Negative: CD1s, CD207 and sometimes S100
JXG Treatment
- No treatment required
- Cosmetic –> remove
- Ophthal review
- If systemic:
- Chemotherapy regimes
- Radiotherapy
- High dose systemic steroids
- Cyclosporin
NXG pathophysyiology
- ?paraproteinaemia is primary inciting agent or a cofactor in eliciting a giant cell granulomatous reaction
- normolipic plane xanthoma exist along a spectrum given both assocation to paraproteinaemia
NXG Clinical
- Multiple, asymptomatic indurated papules/nodules/plaques with a yellow hue
- Peri-orbital region most common
- 50% –> ophthalmic involvement: orbital mass, ectropion, ptosis, conjunctival lesions, keratitis, scleritis, uveitis
- Paraproteinaemia - IgG monoclonal gammopathy in 70% of cases
- Other findings: hepatosplenomegaly, raised inflammatory markers, lymphopaenia, low complement, underlying plasma cell dyscrasia i.e. multiple myeloma
- Overall good survival - 100% at 10 years
NXG Histology
- Normal epidermis and superficial dermis
- Palisading xanthogranuloma in mid-dermis to panniculus
- Granulomas: histiocytes, foam cells, lymphoid follicles, plasma cells, giant cells with zones of necrobiosis
- Cholesterol clefts
- Both Touton giant cells and large, bizarre foreign body giant cells
- Stains: positive for lysozyme, CD68 and CD11b (these are non LCH stains)
NXG DDx
- NLD
- Normolipiemic plane xanthomas
- Xanthelasma
- Non-LCH disorders such as JXG
- Foreign body granulomas
- Sarcoidosis
NXG Treatment
- Treat underlying cause
- Resolution or improvement of skin lesions seen in some treated with low dose chlorambucil, melphalan or cyclophosphamide
- Surgical excision –>40% recurrence rate
Indeterminate cell histiocytosis pathogenesis
- Unknown
- believed to be variation of one of the other non-LCH disorders
- association with haematologic malignancies - mast cell leukaemias, AML and low grade B cell lymphoma
Indeterminate cell histiocytosis clinical
- Commonly involves the trunk and extremities, but can occur elsewhere
- Forms:
- Generalized - firm, red-brown papules, <1 cm
- Solitary - single, soft erythematous lesion
- Can ulcerate
- As progress, become brown-yellow
- Waxes and wanes
- Extra-cutaneous:
- corneal and conjunctival
- visceral involvement has been reported so need close monitoring
Indeterminate cell histiocytosis histopath
- Monomorphous infiltrate of histiocytes
- Histiocytes have oncocytic appearance
- Epidermotropism less common
- Touton giant cells
- Immunophenotype:
- Positive for S100,m CD1a, CD68, CD163, HAM56, lysozyme, alpha-1 antitrypsin, HLA-DR, CD11c, CD4b and factor 13a
- Negative for CD207 - Langerin
ICH ddx
- Generalised eruptive histiocytoma, JXG, congenital self-healing reticulohistocytosis
- Benign cephalic histiocytosis
- Eruptive syringomas, UP, lymphomatoid papulosis
ICH treatment
- self-limited or non-progressive
- really bad –> chemotherapy
- reports of thalidomide, isotretinoin, MTX, NBUVB, PUVA, TSEB
- Given can get visceral - requires long term follow up
Benign cephalic histiocytosis epi
- ~ 60 cases reported worldwide
- occurs by age 1, always within first 3 years of life
Benign cephalic histiocytosis pathogenesis
- Unknown
- similar immunohistochemical profile to JXG
- maybe just park of a spectrum with JXR and eruptive histiocytoma
Benign cephalic histiocytosis clinical
- 2-5 mm, pink-red and red-brown macules nad papules initially on the face, and then appear on the ears and neck, very occasionally spreads elsewhere
- eventually flatten, leaving a residual hyperpigmentation
- one report of diabetes insipidus, otherwise really healthy
Benign cephalic histiocytosis histo
- Three patterns:
- Dermal papillary
- Diffuse
- Lichenoid
- Histiocytes - can be pleomorphic, round, regular
- can have Touton giant cells
- Markers: CD11b, CD11c, CD14b, CD68, HAM56, factor 13a –> usually only stain for CD68 and CD163 though
Benign cephalic histiocytosis ddx
- UP
- LCH
- JXG
- Eruptive histiocytoma
- Indeterminate cell histiocytosis
Benign cephalic histiocytosis treatment
- generally a self limiting disorder
- regular examination
Generalized Eruptive Histiocytoma epi, path, clinical
Epidemiology
- Very rare
- 3rd-6th decade of life, kids <4 years
Pathogenesis
- not known
- may be on same spectrum as benign cephalic or an eraly, indeterminate stage of non-LCH
Clinical
- Recurrent crops of red to brown papules –> hundreds of papules less than 1 cm in diameter, on trunk, proximal extremities and occasionally on the face
- Usually symmetric, and mucosal surfaces occasionally involvemed
- Resolution within months - PIH or small scars
- In kids may be more xanthomatous
Generalized eruptive histiocytoma histo, ddx, rx
Histo
- Sup-mid dermis - nearly uniform infiltrate of histiocytes with a few lymphocytes, rarely lichenoid
- Xanthomatous cells are rare, but can see spindled
- Stains: lysozyme, alpha-1 antitrypsin, CD11b, CD14b, CD68 and Factor 13a
Ddx
- LCH
- UP
- Eruptive syringomas
- Papular GA
- Non-LCH disorders
Rx
- None rewuired
- Occasionally roaccutane, cryotherapy, PUVA
- Rarely leukaemia
Reticulohistiocytosis epi
- predominantly Caucasian adults
- multicentric: super uncommon, occurring in women in their 40s
- Giant cell: young adults
Reticulohistiocytosis pathogenesis
- unknown
- suggested TB
- ?after trauma
Giant Cell Reticulohistiocytosis clinical
- single, asymptomatic yellow-red nodule
- patients are otherwise healthy
- spontaneously resolves
Multicentric Reticulohistiocytosis clinical - cutaneous
- Cutaneous and mucous membrane
- Pink, red-brown to yellow papules
- Acral, head, hands, fingers, ears, articular regions
- Papules and nodules: oral, pharyngeal, nasal mucosae
- Rare: leonine facies, photodistribution, nail changes
Multicentric Reticulohistiocytosis clinical - extracutaneous
- Arthropathy
- 6-8 year course of symmetric, erosive arthritis –> 45% develop arthritis mutilans
- Other:
- Hyperlipidaemia, positive TB, vasculitis, autoimmune
- 25-30% associated malignancy
- Rarely, monoclonal gammopathies, cryoglobulinaemia
- Heart, eye, lungs, thyroid, liver, kidney, bone marrow, etc
- Spontaneously remits within 5-10 years
Reticulohistiocytosis Histology
- Circumscribed, non-encapsulated dermal and synovial infiltrate of multinucleate histiocytes
- Histiocytes have eosinophilic ground glass, they are more angulated in appearance
- Can have plasma and eosinophils
- For solitary, have more neutrophils, spindle cells and greater frequency of xanthomatous changes
- Stain: CD68, CD11b, CD45, HAM56, negative for S100 and Mac387
Reticulohistiocytosis Ddx
- Solitary nodule –> super broad ddx, adult xanthogranuloma
- Multicentric:
- rheumatoid arthritis
- dermatomyositis
- other histiocytoses: generalized eruptive histiocytosis, Rosai-Dorfman
Reticulohistiocytosis Rx
- Surgical excision
- Systemic: NSAIDs, steroids, MTX, cyclophosphamide, TNF alpha blockers
