HLH, LCH

Question 1

what cells are histiocytes

Answer 1

macrophages
dendritic cells
monocytes

Question 2

LCH has mutations in what pathway, and most common mutation

Answer 2

Ras-MEK-ERK
50-60% BRAF V600E
15% MAP2K1

Question 3

LCH peak incidence

Answer 3

1-4yo

Question 4

LCH RF

Answer 4

none well defined
FHx cancer or thyroid
thyroid disease
perinatal infection
parental solvent/dust exposure
Hispanic
low SES
unvaccinated

Question 5

LCH HR organs

Answer 5

liver, spleen, BM

Question 6

LCH organ involvement manifestations

Answer 6

bone (80%): lytic lesions; see CNS risk lesions
Skin: scaly rash
BM: cytopenias
endocrine: pituitary symptoms

Question 7

LCH CNS Risk lesions

Answer 7

facial bones
anteiror/middle cranial fossae: temporal, orbit, sphenoid, ethmoid, zygomatic

Question 8

LCH risk of DI

Answer 8

15% of all LCH
50% will progress to other pituitary deficiencies

Question 9

LCH Tx by risk, and px

Answer 9

single system
- skin: observe; topical steroid; PO MTX/MP/HU
- bone: curettage +- intralesional pred; RT

LR multisystem - EFS 50%, OS 100%
(including bone only w CNS risk lesion)
- vinblastine + pred x 12 mo

HR multisystem - EFS 50%, OS 90%
- vinblastine + pred + 6MP x12mo

Salvage
- chemo: cytarabine, VCR, clofarabine, MEK inhibitor
- HSCT (rare)

Question 10

LCH long term complications

Answer 10

hearing loss (13%)
ortho (20%)
DI (15%)
hypopituitarism
neurodegeneration

Question 11

1o HLH etiology

Answer 11

Familial:
- Perforin = PRF1 (30-40%)
- Syntaxin 11 = STX11 (5-25%)
- STXBP2 (5-25%)
- MUNC13-4 (20-40%)

Immune deficiencies
- XLP1
- XLP2
- Chediak Higashi (LYST)
- Griscelli (RAB27A or MYO5A)
- Hermansky-Pudlak Syndrome 2 and 9
- XMEN syndrome
- CD27 deficiency
- CGD

Question 12

2o HLH etiology

Answer 12

Infection
- EBV > CMV, parvo, HHV8, adenovirus
- fungal, bacterial, parasitic
malignancy: lymphoma
rheum: SLE, HIA
metabolic

Question 13

HLH dx criteria

Answer 13

Known genetic defect

5 of
- Fever >38.5
- splenomegaly
- bicytopenia: Hb <90, Plt <100, Neut <1
- hyperTG (fasting 3+) or hypofibrinogenemia (<1.5)
- hemophagocytosis (BM, spleen, LN, liver)
- decreased/absent NK activity
- ferritin 500+ (most sens/spec >10 000)
- increased sIL-2R = CD25 (>2400)

Question 14

HLH tx

Answer 14

tx underlying condition

HLH-94:
Induction (8w): dex and etoposide; CNS+ IT MTX/HC
Continuation (1y): CSA; Dex/etop q2w

HSCT for 1o, R/R, CNS disease, persistent abnormal NK function

Salvage: campath, ATG, anakinra, ruxolitinib, emapalumab (anti INFg)

Question 15

HLH prognosis

Answer 15

1o: 5yOS 59%
2o: 5yOS 64%
HSCT: 5yOS 66%

Question 16

LCH immunophenotype

Answer 16

CD1a, CD207, S100, vimentin, CD68, HLA-DR

Absent B/T markers (except CD4), CD30

Question 17

LCH neurodegenerative syndrome epi and manifestations

Answer 17

1-4%
tremor, ataxia, dysarthria, h/a, visual change, cognitive/behavioural, psychosis

Question 18

LCH workup

Answer 18

BW
UA (r/o DI)
biopsy involved skin, bone, LN
BMA/B if <2yo or cytopenias
PET
skeletal survey - CT head best for skull

Question 19

how to treat bone only LCH with CNS risk lesion

Answer 19

CNS risk lesion: facial bones; anterior/middle cranial fossae: temporal, orbit, sphenoid, ethmoid, zygomatic

Tx as LR multisystem
- vinblastine + pred x12mo

Question 20

Result of LCH-II and -III

Answer 20

LCH-II: no benefit of added etop
LCH-III: no benefit of added MTX

Question 21

Describe pathophys of HLH

Answer 21

lack of normal downregulation of activated macrophage/lymphocytes leads to excess cytokine release, causing inflammation and tissue destruction

Question 22

Important HLH cytokines

Answer 22

IFNg: activates macrophage/NK

Immune activation: TNFa, IL-1, -2 (CD25), -6, -18

Question 23

Rosai-Dorfman disease definition, presentation, tx

Answer 23

= sinus histiocytosis with massive lymphadenopathy
rare non-Langerhans histiocytosis associated with lymphoma or autoimmunity (SLE, AIHA)

presentation: bilateral massive painless cervical LN; 43% extranodal disease, 19% multisystemic

observe unless symptomatic
- resect
- multiorgan: steroid, chemo