Non-LCH (refer to Template For LCH) Flashcards
Classification
LANGERHANS
LCH
Erdheim-Chester disease/extracutaneous juvenile xanthogranuloma
Indeterminate cell histiocytosis
CUTANEOUS AND MUCOCUTANEOUS Juvenile xanthogranuloma Adult xanthogranuloma Solitary reticulohistiocytoma Benign cephalic histiocytosis Generalised eruptive histiocytosis Progressive nodular histiocytosis Xanthoma disseminatum Cutaneous Rosai-Dorfman disease Necrobiotic xanthogranuloma Multicentric reticulohistiocytosis Cutaneous histiocytosis not otherwise specified
MALIGNANT Histiocytic sarcoma Indeterminate cell sarcoma Langerhans cell sarcoma Follicular dendritic cell sarcoma
ROSAI DORFMAN DISEASE
Rosai Dorfman disease
Non cutaneous, non LCH not otherwise specified
HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE ACTIVATION SYNDROME
Non-LCH Classification
DENDRITIC CELL ORIGIN Juvenile xanthogranuloma Benign cephalic histiocytosis Generalised eruptive histiocytosis Papular Xanthoma Progressive nodular histiocytosis Xanthoma disseminatum Diffuse plane xanthomatosis Erdheim-Chester disease (systemic component predominates, but skin may be involved)
NON-DENDRITIC CELL ORIGIN Reticulohistiocytoma Familial sea-blue histiocytosis Hereditary progressive mucinosis histiocytosis Malakoplakia Necrobiotic xanthogranuloma Multicentric reticulohistiocytosis Rosai-Dorfman disease (Sinus histiocytosis with massive lymphadenopathy)
Juvenile xanthogranuloma
Benign proliferative disorder of histiocytes
Early infancy and childhood
May occur at birth
Single to multiple papules/nodules
Start as reddish yellow macules/papules
Enlarge and evolve into yellow brown patches/plaques with surface teles
Firm and rubbery consistency
Predilection sites
- Face
- Head, neck
- Upper torso
- Upper and lower extremities
EXTRACUTANEOUS (SYSTEMIC) INVOLVEMENT 50% have no skin lesions Commonly solitary mass in deep soft tissue (deep JXG) Liver Spleen Lung
CNS
- seizures, ataxia, increased intracranial pressure, subdural effusions —‘. Developmental delay, diabetes insipidus
Ocular
- < 1% with co-existing skin JXG
- usually unilateral
- erythema, irritation, photophobia —> acute hyphaema, glaucoma, blindness
COURSE
Benign course
Spontaneously regresses within 1-5 years (skin and most systemic lesions)
Ocular and CNS involvement lead to significant complications
ASSOCIATED DISEASES
NF1 —> higher risk of developing juvenile myelomonocytic leukaemia (JMML) esp with concurrent JXG
LCH (simultaneously or LCH first)
PATHOGENESIS
Dendritic cell origin
Unknown
Lipid abnormalities do not play any role
HISTO
Dense dermal infiltrate small slightly spindled histiocytes splaying collagen fibres
Touton giant cells (characteristic wreath of nuclei around homozygous eosinophilic centre, prominent xanthomatisation in the periphery)
Positive IHC - Factor XIIIa - CD68 - CD163 - CD14 - Fascin Negative IHC - S100 - CD1a
RX SINGLE AND ACCESSIBLE LESIONS
Most will resolve spontaneously —> does not require Rx —> warn parents occasionally resolution may result in a scar
Surgical excision
RX OCULAR JXG
Topical, intralesional, subconjunctival CS
Surgery to treat complications I.e. hyphaema, glaucoma
Chemo, RTX (Resistant cases)
Eye surveillance for high risk patients age <2 yrs
- baseline screening at Dx
- review every 3-6 months until age 2
RX SYSTEMIC JXG
No established standard Rx
LCH-based Rx but variable results
Benign cephalic histiocytosis
Self limiting histiocytic disorder
Many consider this as a clinical variant/milder form of JXG w/o systemic involvement
Young children
Asymptomatic
Erythematous brown macules/papules/nodules
Predilection sites
- Cheeks
- Spread to forehead
- Earlobes
- Neck
- Rare extension to trunk, upper limbs, buttocks
No mucosal involvement
HISTO
Identical to JXG
RX
Nil as self limiting
Generalised eruptive histiocytosis
Mainly affects adults
Asymptomatic
Rapid appearance of crop of lesions
Multiple Symmetrical small red brown papules
Predilection sites
- Face
- Trunk
- Arms
Sparing flexures
Rare mucosal involvement
Resolves spontaneously
Leaves macular area of PIH
Evolution to other non-LCH reported
Must be distinguished from eruptive histiocytomas assoc with hyperlipidaemia
Rebiopsy if lesions become
- xanthomatoid
- involves flexures
- systemic symptoms develop
HISTO
Monomorphic histiocytic cells in the upper and mid dermis
No giant cells or foam cells
+/- scattered lymphocytes
IHC identical to JXG with positive
- Factor XIIIa
- CD68
Negative IHC
- S100
- CD1a
RX Generally self limiting Often does not require Rx ? UVB ? PUVA Chloroquine Thalidomide Systemic CS
Papular xanthoma
Small yellow or reddish yellow papules/plaques
Both skin and mucous membranes
Predilection sites
- Back
- Head
COURSE/PROGNOSIS (differs in adults and children)
Adults
- mucosal involvement
- risk for disease progression
Children
- Spontaneous resolution starting after weeks to months, and complete in 1-5 years
- leaves anetoderma-like scarring
CLINICAL DDX
JXG
- papular xanthoma not assoc with systemic involvement or CALMS (NF1 association with JXG)
Xanthoma disseminatum
- papular xanthoma papules don’t coalesce and no predilection for flexures
HISTO Foamy histiocytes and giant cells upper and mid dermis Few inflammatory cells IHC positive - Factor VIIIa (except foamy cells which are negative) - CD68 IHC negative - S100 - CD1a
RX
Children —> no Rx as spontaneous resolution
Adults —> no effective Rx
Progressive nodular histiocytosis
Benign histiocytic disorder of unknown aetiology
Progressive appearance
Asymptomatic
Multiple lesions with 2 morphologies
- superficial yellow orange papules
- skin coloured or reddish-orange (due to overlying teles) deep subcutaneous nodules (spindled histiocytes on histo)
Random distribution
All over body
No predilection for flexures
Skin and mucosa
- conjunctiva
- oral cavity
- larynx
No tendency to spontaneous involution —> disfiguring with time
Not generally assoc with systemic involvement or other diseases
HISTO
No epidermal involvement or epidermotropism
Dermal
Early lesions
- Xanthomatised and scalloped histiocytes
- Some infiltrating lymphocytes
Older lesions
- Histiocytes spindled and arranged in storiform pattern
- Occasional giant cells
- No mitoses
IHC positive
- Factor XIIIa
- CD68
IHC negative
- S100
- CD1a
RX
Excision of large/painful lesions
Xanthoma disseminatum
Non-familial
Self-limiting histiocytosis
Proliferation of histiocytic cells in which lipid deposition is a secondary event
Male children and young adults
Erythematous yellow brown papules and nodules
Symmetrically distributed
- Scalp
- Face
- Trunk
- Proximal extremities
Become confluent —> xanthomatous plaques —> may become verrucous
Flexural involvement
EXTRACUTANEOUS INVOLVEMENT Lips Eye mucous membranes Upper resp tract I.e. pharynx, larynx, trachea, bronchus —> stridor Meninges —> usually transient diabetes insipidus, seizures, growth retardation Liver (rare) Spleen (rare) Bone marrow (rare)
COURSE/PROGNOSIS
Self limiting
May be locally destructive/disfiguring and persist for years
3 clinical patterns
- self healing form
- chronic progressive form
- progressive multiorgan form —> may be fatal
PATHOGENESIS
Thought to be reactive
Unknown inflammatory triggers
HISTO Early infiltration of dermis with - small spindle shaped histiocytes with iron and lipid - more foamy histiocytes in older lesions \+/- Touton giant cells in older lesions - lymphocytes - neuts - eos
IHC positive
- Factor XIIIa
- CD68
IHC negative
- S100
- CD1a
RX CO2 laser ablation Dermabrasion Electrocoagulation Surgical excision Systemic CS (unpredictable response) Chlorambucil (unpredictable response) AZA (unpredictable response) Cyclophosphamide (unpredictable response) Cladribine Lipid lowering agents I.e. simvastatin, rosiglitazone (needs further assessment)
Diffuse plane xanthomatosis
Rare
Non-lipaemic disease (serum lipids normal)
Multiple flat xanthomatous macules and plaques develop in assoc with underlying haematological disease
Large flat plaque-like xanthomatous skin lesions
Predilection sites
- Eyelids
- Neck
- Upper trunk
- Buttocks
- Flexures
Serum lipids usually normal
ASSOCIATED CONDITIONS **Monoclonal paraproteinaemia/gammopathy **Multiple myeloma CML CLL Acute monoblastic leukaemia Lymphoma Sezary syndrome Castleman disease
PATHOGENESIS
Result of perivascular deposition of lipoprotein-immunoglobulin complexes
Anti-lipoprotein antibodies formed against paraproteinaemia
Serum lipids may be raised, possibly d/t reduced clearance of lipoprotein-antibody complexes)
HISTO
Xanthomatous and inflammatory elements
Foamy macrophages in dermis with distinct perivascular accentuation
Variable degree mixed Inflammatory infiltrate
RX Underlying haematological disorder For Limited skin lesions - Excision - Chemoabrasion - Dermabrasion - Ablative laser I.e. Erbium:YAG
Reticulohistiocytoma
Localised variant of Multicentric reticulohistiocytosis
Non-neoplastic reactive process
Young adult males
Rarely in the newborn period
Solitary asymptomatic tumour
Papules and dome-shaped nodules
Anywhere on the body including genitalia
Oral mucosal lesions reported
HISTO
Nodules of large epitheliod histiocytes with abundant glassy eosinophilic cytoplasm
May have lacuna space-like clearing at the periphery and scalloped cytoplasm
Extends from papillary dermis to mid dermis
Lymphocytes
+/- eos
IHC variable
- Factor XIIIa
IHC positive
- CD68
- CD163
IHC negative
- S100
- CD1a
RX
Surgical excision
Necrobiotic xanthogranuloma
Multisystem histiocytic disease
Widespread infiltrated xanthomatous nodules and plaques
Strongly assoc with haematological malignancy that typically occurs ~ 2 yrs from onset of skin manifestations
CLINICAL FEATURES
Slowly progressive
Reddish yellow xanthomatous plaques/nodules
Infiltrative and destructive
Predilection sites - 80% Periorbital - Trunk - Limbs —> subcut nodules and xanthomatous plaques with atrophy and ulceration
Systemic symptoms
- Nausea
- Vomiting
- Fatigue
- Epistaxis
- Back pain
- Raynaud phenomenon
EXTRACUTANEOUS INVOLVEMENT Eyes - Conjunctivitis - Keratitis - Uveitis - Iritis - Proptosis - Blindness
ASSOCIATED DISEASES Monoclonal gammopathy - IgG-kappa MGUS - IgG-lambda - IgA Multiple myeloma Non-Hodgkin lymphoma CLL
PATHOGENESIS
Unknown
HISTO
Sheets or nodules of granulomatous masses in the dermis and extending to subcut tissue
Necrobiosis separate nodules
Numerous giant cells
- Touton
- Bizarre angulated giant cells
*Cholesterol clefts
Lymphoid nodules (some that develop germinal centres)
Perivascular plasma cells
Characteristic palisading cholesterol cleft granulomas
Characteristic xanthogranulomatous panniculitis
RX
Generally directed at assoc haem disorder —> may result in clearing of the skin
Skin-directed
- ILCS
- CO2 laser
Systemics
- IVIg
- Thalidomide
- Melphalan +/- prednisolone
- Chlorambucil
- Plasmapheresis
- Interferon-alpha
- Cyclophosphamide
- MTX
Multicentric reticulohistiocytosis
Nodular skin lesions + mucosal involvement + destructive symmetrical polyarthritis
Arthropathy usually precedes skin and mucosal infiltration
20% skin nodules appear first
Skin and joint can manifest concurrently
Middle aged adults
Firm brown or yellow papules and plaques
Rarely ulcerate
May Heal with scarring
Predilection sites
- predominantly Extensor surfaces esp hands, forearms
- Face
- Scalp
- Ears
- Hands
- Lower trunk (rare)
- Legs (rare)
Coral bead-like lesions around nail folds —> result in nail dystrophy
Systemic symptoms
- Fever
- Weight loss
- Malaise
EXTRACUTANEOUS INVOLVEMENT Mucosa - characteristically Lips and tongue - Mouth - Gingiva - Pharynx, larynx - Sclera
Destructive symmetrical polyarthritis
- Usually Hands
- Knees
- Shoulders
- Wrists
- Hips
- Ankles
- Feet
- Elbows
- Spine
- TMJ
- often remits spontaneously
- can progress to mutilating osteoarthropathy with disabling deformities
Heart (rare)
ASSOCIATED DISORDERS Malignancy (Multicentric reticulohistiocytosis precedes malignancy in most cases, and may relapse with recurrence of malignancy) - Gastric CA - Ovarian CA - Breast CA - Uterine CA - Multiple myeloma - Lymphoma - Melanoma
Latent TB
Active TB
Autoimmune
- SLE
- Sjogren syndrome
- Diabetes
PATHOGENESIS
Unknown
Generally considered to be reactive histiocytosis
COURSE/PROGNOSIS
Disease becomes quiescent in 7-8 years if no systemic malignancy
Crippling arthropathy
Skin scarring
Fatal cardiac involvement with widespread systemic involvement
Most children have self-limiting disease with non-deforming arthritis
HISTO Large eosinophilic cytoplasm-rich histiocytes and multinucleated giant cells with ground glass appearance in the dermis Interspersed inflammatory cells - histiocytes - lymphocytes - eosinophils
RX Rx underlying disease, though does not usually influence disease course Prednisolone MTX Cyclophosphamide CSA Leflunomide AZA Bisphosphonates Anti-TNF I.e. Etanercept, Infliximab, Adalimumab
Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy)
Self limiting non-neoplastic disorder characterised by abundant histiocytes in the lymph nodes throughout the body
Skin is most common extranodal site and found in isolation in 50%
Young adults
CLINICAL FEATURES
Bilateral painless cervical adenopathy
Other nodes may be involved
- Axillary
- Mediastinal
- Inguinal
Systemic symptoms
- Fever
- Malaise
- Night sweats
- Weight loss
Skin lesions
- Yellow, but may be violaceous or purple
- Reported macular erythema, papules, nodules, infiltrated plaques
- Scaling often present
- Telengiectasia
- No predilection of any sites
EXTRANODAL SITES BESIDES SKIN Head and neck with nasal cavity and parotid gland (commonest sites) Lung Breast Urogenital tract GIT Liver Pancreas Isolated intracranial disease attached to dura w/o extracranial LN —> headaches, seizures, numbness, paraplegia
ASSOCIATED DISORDERS/PREDISPOSING FACTORS
Autoimmune haemolytic anaemia
Rheum diseases
PATHOGENESIS
Aetiology unknown
Infectious or malignant process result in aberrant activation of the macrophage system —> excessive cytokine release
COURSE/PROGNOSIS
Unpredictable clinical course
Episodes of exacerbation and remission may extent over many years
Disease often self limiting
But 5-10% die from disease
Underlying immunological abnormalities —> worse prognosis —> more widespread nodal disease, higher fatality rate
IX Mild normochromic or hypochromic normocytic anaemia Leukocytosis Elevated ESR Low albumin Polyclonal gammopathy Hypergammaglobulinaemia Serum lipids normal
Consider CT chest (axillary, mediastinal LN, lung)
Consider MRI head (intracranial disease, head and neck LN)
HISTO SKIN
Dense upper dermal histiocytic infiltration with scattered multinucleated giant cells and plasma cells
HISTO INVOLVED LN
Massive sinus infiltration of large histiocytes advised with lymphocytes and plasma cells
Emperipolesis (phagocytosis of intact leukocytes, esp lymphocytes) but histiocytes that express S100
IHC positive
- CD68
- S100
IHC negative
- CD1a
RX
Only necessary when a vital organ is compromised or nodal enlargement leads to functional problems I.e. airway obstruction
Surgical excision/debunking of respectable lesions
Systemic CS (regrowth often occurs within short period of cessation)
IV Rituximab
Interferon-alpha + chemo
