Langerhan cell Histiocytosis

Slide 1King Chulalongkorn Memorial Hospital
DIAGNOSIS OF LCH
• Langerin (CD 207) – immunohistochemistry
• Birbeck granules - electron microscopy is no longer needed
Langerhans Cell Histiocytosis (LCH): Guidelines for Diagnosis, Clinical work-up, and Treatment for Patients Till the Age of 18 Years Riccardo Haupt, MD, Milen Minkov, MD, Itziar Astigarraga, MD and for Euro Histio Network. Pediatr Blood Cancer 2013;60:175-184
• CD207(+) cell and CD3(+) T cells were isolated from LCH lesions to determine cell- specific gene expression.
• Compared with control epidermal CD207(+) cells, the LCH CD207 (+) cells yielded 2113 differentially expressed genes.
• Several novel genes whose products activate and recruit T cells to sites of inflammation, including SPP1 (osteopontin), were highly overexpressed in LCH CD207(+) cells.
• Furthermore, several genes associated with immature myeloid dendritic cells were overexpressed in LCH CD207(+) cells.
• This study support a model of LCH pathogenesis in which lesions do not arise from epidermal LCs but from accumulation of bone marrow-derived immature myeloid dendritic cells that recruit activated lymphocytes.
Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells
Allen CE, Li L, Peters TL et al. J Immunol. 2010;184(8):4557-67
clinical
% OF TOTAL CASES
Classification use in the LCH IV Histiocyte Society Protocol
Group Definition
‘High-risk’ patients (at least one Spleen, liver or haematological ‘risk organ’ involved) dysfunction
Multivisceral system without Any organs involved but no spleen,
‘risk organs’ liver or haematological dysfunction
Single system One-organ system*
Risk organs involvement definition
• Hematopoietic involvement: (+/- BM involvement~CD1a +) – At least 2 of the following:
1. Anemia: o Hemoglobin <10 g/dl
o Infants <9.0 g/dl
2. Leukocytopenia: WBC <4,000/μL
3. Thrombocytopenia: platelets <100,000/μL
• Spleen involvement: enlargement >2 cm BCM in the MCL by PE
• Liver involvement: ≥ 1 of the following 1. Enlargement >3 cm BCM in the MCL by PE
2. Dysfunction i.e. hypoproteinemia <55 g/L, hypoalbuminemia <25 g/L, not due to other causes
3. Histopathological findings of active disease
LCH-IV study protocol
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0 2 4 6 8 10 12 14 16 18 20
years
Hem Only
2 RO
3 RO
Liver Only
Lung Only
Spleen Only
0 RO
Provided by Vienna Data Center
1. Positive CD1a confirmed the presence of LCH cells in 3/22 (14%) samples.
2. Hemophagocytosis and poor outcome were significantly more common in patients with bilineage and trilineage cytopenias.
3. Myelofibrosis, megakaryocytic dysplasia, and emperipolesis were common findings.
Galluzzo ML, Braier J, Rosenzweig SD, Garcia de Davila MT, Rosso D. Pediatr Dev Patho. 2010 Mar-Apr; 13(2) : 101-6.
Bone marrow findings at diagnosis in patients with multisystem langerhans cell histiocytosis
CNS-Risk Lesions
Skull base Mastoid Temporal Maxilla Sphenoidal Ethmoidal Zygomatic bone Orbits
With intracranial extension or could not be excised
3 x risk of CNS disease
Indications for Systemic Therapy
Response to Initial Treatment of Multisystem Langerhans Cell Histiocytosis : An Important Prognostic Indicator. Milen Minkov, MD, Nicole Grois, MD, Andreas Heitger, MD, et al Med Pediatr Oncol 2002; 39 : 581-585.
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P ro
b ab
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o f
su rv
iv al
Log-rank test
Responder Intermediate
p = 0.165
p <0.001 p = 0.034
years from response evaluation
Rapid response and mortality in the 4 treatment arms of LCH-I & II
Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification Helmut Gadner, Nicole Grois, Ulrike Pötschger, et al Blood, 2008 111 : 2556-2562.
Rapid Response Mortality
(VBL vs VP16) (VBL + VP16)
A B A B
LCH-III Preliminary Results
OS >80% Difference in reactivation rates
No differences A vs. B (+ MTX) - 2 yr RR 6 mo ~ 45%
- Response - 2 yr RR 12 mo ~ 30%
- Reactivation rates Longer duration is beneficial
Multifactorial Further improvement is needed
- Second course of induction
General design of the upcoming Langerhans cell histiocytosis (LCH)-IV study
Group 2 : SS-LCH (MFB and/or ‘CNS-risk’ lesions)
LCH-long-term follow-up (late effects)
LCH registry and classification
Progression, reactivation in non-risk organs
Lack of response, Progression in risk organs
NAD
(randomized for duration and addition of mercaptopurine)
SS-LCH other than Group 2
‘Wait and watch’ or
Recurrent LCH 20-50% of patients
• Low risk: SS-MFB, MS RO- – Disease reactivation 1/3 of patients
– Response well to 2nd line therapy
– 6-MP and MTX, indomethacin, bisphosphanate, BRAF inhibitor, cladribine
• High risk: RO+ – Poor response to standard therapy
Monsereenusorn et al., Expert Opinion on Orphan Drugs. 2016; 4(10): 1057-68.
MS-LCH without risk organ involvement MS-LCH with risk organ involvement
1. Cladribine
bone)