Medical management of langerhans cell histiocytosis from diagnosis to treatment

Figures & data

Table 1. Differential diagnosis for manifestations of langerhans cell histiocytosis.

Involvement	Manifestation	Possible other condition
Skin	Vesicles and bullae (most common in early infancy)	Erythema toxicum Herpes simplex Chickenpox infection
	Dermatitis (most frequently scalp, diaper or axilla, may occur up to late infancy)	Seborrheic dermatitis (eczema; usually no petechiae and marked scaling)
	Nodules	Mastocytosis Juvenile xanthogranuloma Neuroblastoma Infant leukemia
	Pruritus (more common), Petechiae (uncommon)	Scabies (other family members may be affected) [62] Dermatopathic nodes and dermatopathic lesions [63]
Bone	Vertebra plana	Ewing sarcoma Septic osteomyelitis Chronic relapsing multifocal osteomyelitis (CRMO) Leukemia Lymphoma Aneurysmal bone cyst Juvenile xanthogranuloma Myeloma (only described in adults) Osteoporosis
	Temporal bone	Chronic otitis media Mastoiditis Cholesteatoma Soft tissue sarcoma
	Orbit	Acute infection (preseptal cellulitis) Dermoid cyst Rhabdomyosarcoma Neuroblastoma Pseudoinflammatory tumor
	Other lytic lesions of the long bones	Parasitosis like difilariosis [64] Osteomyelitis Chronic relapsing multifocal osteomyelitis Aneurysmal bone cyst Bone angiomatosis (Gorham disease) Fibrous dysplasia Atypical mycobacterial infection Osteogenic sarcoma Ewing's sarcoma
Lung	In particular systemic symptoms and cavitated pulmonary nodules	Pneumocystis Carinii cavitated infection Mycobacterial or other pulmonary infections Sarcoidosis Bronchiolar-alveolar carcinoma (only described in adults) Lymphangio-Leiomyosarcoma (only described in young adult women) Septic emboli
Pituitary	Central diabetes insipidus	Dysgerminoma Idiopathic central diabetes insipidus [65,66]
Liver	Jaundice with direct hyperbilirubinemia Hypoalbuminemia	Chronic destructive cholangitis Metabolic disease Hepatitis Neoplasia obstructing biliary tract Inherited deficient conjugation of bilirubin Toxic (Reye syndrome) Chronic inflammatory bowel disease Neonatal hemochromatosis
Anemia Thrombocytopenia	Hematophagocytic syndrome with hepato splenomegaly	Familial Hemophagocytic Lymphohistiocytosis [67]

Table2. Definition of organ involvement in langerhans cell histiocytosis.

Criteria
Bone involvement
General bone involvement: All radiological documented lesions, usually considered as LCH lesions
An abnormality on Tc Bone scan or an MRI hypersignal, not correlated with symptoms, and not correlated with an X-ray image is not considered bony disease!
Skin involvement
Any rash documented by histological examination
or any lesion (erythematous and crusted macules, papules or nodules, with or without ulceration, or petechiae, or seborrhea-like picture) compatible with the diagnosis, if LCH is confirmed by biopsy of another organ
Mucosae involvement
Oral involvement with lesions in the oral mucosa, gums
Genital or anal involvement
Pituitary involvement
Any pituitary hormone deficiency
or tumor appearance in the hypothalamic pituitary axis
Ear involvement
Ear involvement with external otitis, otitis media or otorrhea
Hematopoietic involvement
Mild
Hemoglobin between 10 and 7 g/dl (not due to other causes, e.g., iron deficiency)
Or thrombocytopenia with platelets between 100,000 and 20,000/mm^3
Severe
Hemoglobin < 7 g/dl. Exclude iron deficiency or other causes
Or platelets < 20,000/mm^3
Liver involvement (the patient can show a combination of these symptoms)
Enlargement > 3 cm below the costal margin at the mid-clavicular line, confirmed by ultrasound
or dysfunction documented by: hyperbilirubinemia > 3 times normal, hypoalbuminemia (< 30 g/dl), γ GT increased > 2 times normal, ALT(SGPT) - AST(SGOT) > 3 times normal, ascites, edema
or intra hepatic nodular mass
Spleen involvement
> 3 cm below the costal margin at the mid-clavicular line, confirmed by ultrasound
Lung involvement
Typical imaging (nodules or cysts) on CT scan
Any atypical aspect needs to be explored by BAL or biopsy in order to have histopathological/cytological diagnosis
Central nervous system (CNS) involvement
Tumoral: All intracerebral expansive lesions predominantly affecting the brain or meninges
Neurodegeneration on MRI: MRI imaging compatible with neurodegenerative disease^1, i.e., abnormal signal intensity localized in the dentate nuclei or cerebellum or cerebral atrophy not explained by corticosteroids
Clinical neurodegeneration: Presence of suggestive symptoms (either cerebellar syndrome or learning difficulty) with compatible MRI imaging
Eye involvement
Orbital involvement with proptosis or exophthalmos
Anatomic involvement of the eye

Table 3a. Langerhans cell histiocytosis – systemic score [29].

Variable	Modality	Score
Bone (a)	Pain	1
	No pain	0
Bone (b)	Compressing other organs (orbit or spine)	2
	No compression	0
Fever (> 38.5 °C)	Yes	1
	No	0
Lung: iconography	Pneumothorax	2
	Interstitial lesion on chest X-ray film or lung CT scan	1
	Normal chest X-ray film or lung CT scan	0
Lung: function	Mechanical ventilation or PFT > 50%	5
	Supplemental oxygen or PFT between 50 to 80%	2
	No dysfunction, no cyanosis, no supp. Oxygen	0
Skin: area	25%	2
	5 – 25%	1
	Below 5%	0
Soft tissue tumor (including CNS)	5 cm max diameter	2
	2 – 5 cm max diameter	1
	0 – 2 cm max diameter	0
Nodes (> 2 cm)	Yes	1
	No	0
Liver	Below umbilicus	2
	Enlarged above umbilicus	1
	Not enlarged	0
Spleen	Below umbilicus	2
	Enlarged above umbilicus	1
	Not enlarged	0
Liver (enzymes)	> 10 N	2
	3 N to 10 N	1
	< 3 N	0
Liver (gamma GT)	> 10 N	2
	3 N to 10 N	1
	< 3 N	0
Albumin	Perfusion required in past week	3
	No perfusion but < 30 g/l	1
	> 30 g/l	0
Platelet: requirements in past week	More than 2 transfusions	4
	1 or 2 transfusions	3
	Low platelet count, no transfusion	2
	Normal count	0
Red cells: requirements in past week	More than 2 units	4
	1 or 2 units	3
	Hb below 10 g/dl, no transfusion	1
	Hb equal or above10 gr/dl	0

The score is calculated after collection of the clinical information, a chest X ray, a complete blood count, albumin level, SGOT, SGOT and gamma GT.

N: Maximal normal value for the laboratory.

Table 3b. Lung score evaluated by the high-resolution CT scan.

Estimation of the proportion of cysts by field:			Estimation of the proportion of nodules by field:
0 no nodules			0 no nodules
1 < 25% or rare			1 < 25% or rare
2 25 – 50% or intermediate			2 25 – 50% or intermediate
3 > 50% or high			3 > 50% or high
	Right	Left		Right	Left
Upper			Upper
Medium			Medium
Lower			Lower

To establish this score, the chest was divided into six fields: upper, medium and lower and left and right. For each field, and both for nodules and for cysts, the score was 0 if no lesion, 1 if the proportion of lesions was between 1 and 25% of the surface (or consider as rare), 2 if the proportion of the lesions was between 26 and 50% (or consider as intermediate) and 3 if the proportion of lesions was above 50% (or consider as high) [30,31]. This score correlates with lung function.

Table 3c. Score sequel [32].

	Score
Hormones DI	3	Panhypopituitarism and/or hypothalamic syndrome not correctable with hormone replacement
	2	Partial anterior pituitary deficiency and diabetes insipidus on replacement therapy
	1	Diabetes insipidus on replacement therapy
	0	No pituitary deficiency
Cerebellar syndrome [33]	3	Severe ataxia (scale > 40) or other motor disability
	2	Moderate ataxia (scale 20–40)
	1	Mild ataxia (scale < 20)
	0	No ataxia
Intellectual deficiency	3	Severe learning difficulty (IQ < 70) and/or severe behavioral/psychological problems impairing function and not correctable by treatment
	2	Moderate learning difficulty (IQ 71–79) and/or behavioral/psychological problems correctable by treatment
	1	Mild learning difficulty (IQ 80–89) and/or mild behavioral/psychological problems not requiring treatment
	0	No intellectual deficiency
Ear function	3	Severe bilateral hearing loss, not correctable with aids
	2	Moderate bilateral hearing loss, partially correctable by aids
	1	Mild bilateral or moderate/severe unilateral loss correctable with aids
	0	No hearing loss or mild unilateral hearing loss, no aids required
Lung = dyspnea NYHA	3	Patients who should be at complete rest, confined to bed or chair; any physical activity brings on discomfort and symptoms occur at rest./requiring lung transplant
	2	Patients with marked limitation of activity; they are comfortable only at rest
	1	Patients with slight, mild limitation of activity; they are comfortable with rest or with mild exertion
	0	Patients with no limitation of activities; they suffer no symptoms from ordinary activities
Dysmorphie facial - teeth	3	Gross facial or orthodontic abnormality and/or scarring requiring repeated or major surgery
	2	Moderate facial or orthodontic abnormality and/or scarring correctable with surgery
	1	Mild facial or orthodontic abnormality and/or scarring not requiring any surgery
	0	No abnormality
Liver	3	Liver function extremely poor/requiring liver transplant
	2	Moderate liver function decrease/jaundice permanent
	1	Mild cholangitis – no liver dysfunction
	0	No liver dysfunction
Obesity	3	Pathological obesity – BMI > 35
	2	Obesity – BMI 30 – 35
	0	BMI < 30
Vision	3	Bilateral blindness – not correctable
	2	Mild bilateral blindness or unilateral severe blindness
	1	Mild unilateral blindness
	0	No abnormality
Other: in text

This score can be applied at each follow-up visit and is correlated with quality of life.

Talanin NY, Smith SS, Shelley ED, Moores WB. Cutaneous histiocytosis with Langerhans cell features induced by scabies: a case report. Pediatr Dermatol 1994;11:327-30

 PubMed Web of Science ®Google Scholar

Geissmann F, Nosjean MC, Dezutter C, Accumulation of immature Langerhans cells in human lymph nodes draining chronically inflamed skin. J Exp Med 2002;196:417-30

 PubMed Web of Science ®Google Scholar

Perret-Court A, Coulibaly B, Ranque S, Intradural dirofilariasis mimicking a Langerhans cell histiocytosis tumor. Pediatr Blood Cancer 2009;53:485-7

 PubMed Web of Science ®Google Scholar

Favara BE, Jaffe R, Egeler RM. Macrophage activation and hemophagocytic syndrome in langerhans cell histiocytosis: report of 30 cases. Pediatr Dev Pathol 2002;5:130-40

 PubMed Web of Science ®Google Scholar

Donadieu J, Piguet C, Bernard F, A new clinical score for disease activity in Langerhans cell histiocytosis. Pediatr Blood Cancer 2004;43:770-6

 PubMed Web of Science ®Google Scholar

Nanduri VR, Pritchard J, Levitt G, Glaser AW. Long term morbidity and health related quality of life after multi-system Langerhans cell histiocytosis. Eur J Cancer 2006;42:2563-9

 PubMed Web of Science ®Google Scholar

Trouillas P, Takayanagi T, Hallett M, International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci 1997;145:205-11

 PubMed Web of Science ®Google Scholar