Histiocytic Disorders

Question 1

Classification of Histiocytic disorders

Answer 1

-Dendritic cell proliferation
Langerhans Cell Histiocytosis LCH

-Macrophage proliferation
   Juvenile Xanthogranuloma
    Erdheim-Chester disease
    Rosai- Dorfman disease 
    Hemophagocytic lymphohistiocytosis

-Histiocytic malignancies

Malignant histiocytosis
Histiocytic sarcoma
AML M7

Question 2

LCH

Answer 2

Histology: Brubeck granules on electron microscopy, factor XIII
CD207+, CD1a, histiocytes among inflammatory infiltrate
Molecular- BRAF- V600E Ras- RAF- Mek-erk

Median age at presentation 2.4 yr
Very rare in African/ American

Question 3

LCH disease categories

Answer 3

Risk based on organ involvement

• HR- liver, BM, spleen
• Multisystemic LR
• Single system LR

CNS risk -
Lesions in skull and pituitary
Risk of developing neurodegeneration

Question 4

LCH therapy

Answer 4

Front line therapy-

Skin alone 
- oral MTX, VBL/Pred, hydroxyurea 
Low risk ( bone+/- skin, LN, CNS risk)
- VBL/ pred 12 mo
High Risk
-VBL/pred/6-MP
Radiotherapy
- only for spine, femur or non- CNS risk isolated bone lesions

Question 5

LCH outcomes

Answer 5

Low Risk
Mortality 0%
EFS 50%

High risk

10% mortality
EFS - 50%

Question 6

Rosai- Dorfman

Answer 6

Disorder of macrophage proliferation

Emperipoleisis

Viable lymphocytes trafficking through histiocytes cD163+ and S 100A+

Presents with massive lymphadenopathy
AA children

Question 7

RDD treatment

Answer 7

Observation
Steroids
Clofarabine

Question 8

Juvenile Xanthogranuloma

Answer 8

CD163+
Usually limited to the skin 
Can have tumors everywhere 
Can have disseminated AML LIKE DISEASE 
ASSOCIATED WITH NF1
Mutation in MAPK genes

Question 9

HLH

Answer 9

Too much inflammation
T- cell dysfunction

50% will survive if treated
If not treated or recognize they will not survive

Question 10

HLH diagnostic criteria

Answer 10

5 of 8 
Fever
Splenomegaly
Cytopenias ( at least 2 cell lines)
Hypertriglyceridemia or hypofibrinogenemia
Hemophagocytosis
Ferritin >500
Elevated s-IL-2
Decreased NK cell activity
Gene mutations

Question 11

Genes associated with HLH

Answer 11

PRF1- FHL2
UNC13D- FHL3
STX11- FHL4
RAB27A- Griscelli syndrome 
STXBP2- FHL5
AP3B1- Hermansky- Pudlack2
SHD1A - XLP1
XIAP- XLP2
ITK, CD27- T cell dysfunction

Question 12

HLH EVALUATIONS

Answer 12

Evaluate cytotoxic function
- NK CELL FUNCTION
CD107 mobilization assay

• Perforin, XLP protein ( xiap, sap) expression
• Targeted sequencing or whole genome sequencing

Virus, bacteria, fungal search
Focus on herpes viruses
Evaluate for malignancy
Evaluate for autoimmune disease

Damage from activation
CBC,

Question 13

Treatment of high risk multisystemic LCH?

Answer 13

Induction (6 weeks): VBL and prednisone
Can be repeated if partial response
Continuation (12 months): VBL, prednisone, 6MP

Question 14

What is the outcome of HR multisystemic LCH as per LCH III?

Name 1 important prognostic factor

Answer 14

OS: 84%, reactivation rates 27%

Response to therapy at 6 weeks