langerhans cell histiocytosis lch - europa · euro histio net guidelines march 2011, version 1.1...

Euro Histio Net Guidelines March 2011, Version 1.1

of 18

LANGERHANS CELL HISTIOCYTOSIS (LCH)

GUIDELINES FOR DIAGNOSIS, CLINICAL WORK-UP AND TREATMENT DURING CHILDHOOD

Euro Histio Net Work Group for LCH Guidelines: Riccardo Haupt (Leader and Editor)1, Itziar Astigarraga2, Jean Donadieu3, Maarten Egeler4, Gritta Janka5, Rima Jubran6, Dragan Micic7, Milen Minkov8, Vasanta Nanduri9, Carlos Rodriguez-Galindo10, Stefaan Van Gool11, Johannes Visser12, Sheila Weitzman13

1 Istituto G. Gaslini in Genova, Italy; 2 Hospital de Cruces, Barakaldo, Spain; 3 Reference Centre for Histiocytosis at Hopital Trousseau, Assistance Publique – Hopitaux de Paris, France; 4 Leiden University Medical Center, Leiden, The Netherlands; 5 University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 6 Children's Hospital of Los Angeles, Los Angeles, California, USA; 7 Mother and child Health Institute of Serbia “Dr Vukan Cupic”, Belgrade, Serbia; 8 Children’s Cancer Research Institute, St. Anna Children’s Hospital, Vienna, Austria; 9 Watford General Hospital, Watford, UK; 10 Dana Farber Cancer Institute, and Children’s Hospital Boston, Massachusetts, USA; 11 University Hospital Gasthuisberg, Leuven, Belgium; 12 University Hospitals of Leicester, LRI Children’s Hospital, Leicester, United Kingdom; 13 Hospital for Sick Children, Toronto, Ontario, Canada METHODS AND PROCESS OF DEVELOPMENT

These guidelines were designed and established by an international group of physicians who have been involved in the study and management of histiocytic disorders for several years. They are active members of the international medical society of histiocytoses “Histiocyte Society” (HS), of the European national societies of Hematology/Oncology, and of their res-pective national groups for the study and treatment of these diseases. Drafts were commented by the entire group and redrafted by the guidelines editor. Final agreement was consensual.

In summary, the following guidelines are an adap-tion of different international and national guidelines and recommendations documents: • Langerhans Cell Histiocytosis – Evaluation and

Treatment Guidelines of the Histiocyte Society • LCH – Recommendations for therapeutic care of

Langerhans Cell Histiocytosis, French Study Group for Histiocytosis of the French Society for Pediatric Haematology and Immunology (SHIP) and the French Society for Children’s and Adults’ Cancer and Leukemia (SFCE)

• Langerhans Cell Histiocytosis (LCH) – Guidelines for Diagnosis and Therapy in Paediatric Haema-tology and Oncology, developed by the Histiocyte Society and the German Society for Paediatric Oncology and Haematology (GPOH) for the German Study Group for the Scientific Medical Societies (AWMF)

The contents of these documents were systema-tically reviewed and updated where new evidence was available in scientific articles published in peer-reviewed journals in the years till 2010.

PURPOSE AND RESTRICTIONS

The guidelines detailed herein have been developed for use as recommended practices in the evaluation and treatment of children (up to 18 y.) not formally enrolled in cooperative national or international studies or clinical trials. (For study and trial protocols see Hwww.histio.netH and Hwww.histiocytesociety.orgH) They are intended for physicians and other health care providers from the following medical fields: dermatology, gastroenterology, haematology, hepa-tology, immunology, internal medicine, oncology, oto-laryngology, pneumology, and radiology.

Please note that these guidelines are based on the best available evidence from clinical research, on extensi-ve and systematic literature review, and on expert opi-nions. They are intended to provide guidance in order to improve diagnosis, clinical work-up, and treatment. The recommendations cannot replace the physician’s own professional judgment based on the patient’s special clinical circumstances. Due to the diversity of clinical course of LCH, even recommendations which are established as standard of care may need to be critically appraised in an individual case. We suggest that you never hesitate to contact LCH experts in case that the clinical course raises questions or doubts. Whenever possible patients should be enrolled in ongoing clinical trials.

In LCH like in other rare diseases, research questions are rarely addressed in prospective studies of adequate designs and high quality. Therefore, available data are insufficient and not necessarily consistent. In some circumstances as clinical presentation and clinical course of the disease, data are evidence based, but the evidence on some aspects of LCH, like clinical work-up and therapeutic strategies, is still limited and mostly based on expert opinion. Based on the mentioned considerations, these guidelines report the level of agreement between experts (see table 1, page 2).


of 18

TABLE OF CONTENTS

1. GENERAL CONSIDERATIONS 2. DIAGNOSIS

2.1. Biopsy and Histological Examination 2.2. Diagnostic Criteria

3. PRETREATMENT CLINICAL EVALUATION 3.1. Complete History 3.2. Complete Physical Examination 3.3. Laboratory and Radiographic Evaluation 3.4. Specific Clinical Scenarios and Recom-

mended Additional Testing 3.5. Definition of Organ Involvement

3.5.1. Possibly Involved Organs 3.5.2. Risk Organs 3.5.3. “Special Sites”

3.6. Head MRI in LCH Patients 3.6.1. Technique 3.6.2. Frequency of MRI Surveillance

4. STRATIFICATION 4.1. Clinical Classification

4.1.1. Single System LCH (SS-LCH) 4.1.2. Multisystem LCH (MS-LCH)

4.2. Differential Diagnosis

5. TREATMENT 5.1. Management Algorithms 5.2. Local Therapy or Careful Observation 5.3. Systemic Therapy

5.3.1. Front Line Treatment 5.3.2. Evaluation of Response 5.3.3. Maintenance Therapy 5.3.4. Salvage Therapy

5.4. Treatment Options in Case of Reactivation 5.4.1. Reactivation of Single System Disease 5.4.2. Reactivation after Systemic Therapy

6. MONITORING FOR PERMANENT CONSEQUENCES 6.1. Diabetes insipidus 6.2. Hormone Deficiency

6.2.1. Growth 6.2.2. Puberty 6.2.3. Suggested Investigations for delayed

Growth / Puberty 6.3. Orthopaedic 6.4. Ears 6.5. Oral Tissue and Jaw 6.6. Neurological 6.7. Lungs 6.8. Liver 6.9. Associated Malignancies 6.10. Follow-up – Required Tests and Frequency

7. REFERENCE LIST

1. GENERAL CONSIDERATIONS

The disease may affect any organ or system of our body, but those more frequently affected are the bone (80% of cases), the skin (33%), and the pitui-tary (25%). Other organs often involved are the liver, spleen, the hematopoietic system and the lungs (15% each). Finally, the lymph nodes (5-10%) and the central nervous system excluding the pituitary (2-4%) are the other possible localization sites of the disease (see other pages of the web portal). Clinical manifestations of the disease vary depen-ding on the organ or system affected, ranging from an isolated lesion as in the skin or in the bone or in the lung in adults, to a more severe clinical manifest-tation affecting the same tissue in multiple sites, or several organs. Thus, the clinical course may vary from self-limiting and self-healing disease to a rapidly progressive one, that might lead to death. Another important aspect of this disease is that between 30 and 40% of affected patients may develop permanent consequences that in some cases may severely affect quality of life either during the acute illness, or later in life. Examples are neuroendocrine deficits (e.g. diabetes insipidus), orthopedic sequelae (e.g. scolio-sis, vertebra plana), chronic lung dysfunction, neuro-logic or neuropsychological deficits, sclerosing cho-langitis, teeth loss, and deafness. Treatment options vary depending on disease extent and severity at onset, and on the response to front-line treatment. Thus, after diagnosis is confirmed, it is important to have the diagnostic and the clinical work-up performed according to uniform guidelines.

Table 1 Determination of the Level of Agreement

AGREEMENT CRITERIA

+ According evidence and/or general agreement

Discussed evidence and/or discussed recom- mendation, but no strong objections

– Conflicting evidence and/or divergence of opinion


of 18

2. DIAGNOSIS 2.1. BIOPSY AND HISTOLOGICAL EXAMINATION

The diagnosis of LCH should be based on histolo-gical and immunophenotypic examination of a biop-sy of lesional tissue. Biopsy should be taken from the most accessible organ: skin if involved; while in case of multiple skeletal involvement, the bony le-sion that is most easily accessible should be chosen for biopsy. The main diagnostic feature is the mor-phologic identification of the characteristic LCH cells, but positive staining of the lesional cells with CD1a and/or Langerin (CD207) is required for defi-nitive diagnosis [Chikwava & Jaffe, 2004; Lau et al, 2008; Swerdlow et al, 2008;Valladeau et al, 2000]. Electron microscopy is no longer recommended since it has been shown that the expression of Langerin fully correlates with the presence on electron microscopy of Birbeck granules, which were previously one of the criteria required for definitive diagnosis. There are, however, very few exceptions as the fact that in organs such as liver Birbeck granules are not present and CD1a and/or Langerin may be negative.

When tissue sample is taken from a bone lesion, curettage of the center of the lesion is usually suffi-cient for pathologic diagnosis and also may trigger the initiation of a healing process. Complete excision of bone lesions is not indicated since it may increase the size of the bony defect and the time to healing; it might also result in permanent skeletal defects.

In very few circumstances, when the only lesion in-volves particular structures and the risk of biopsy outweighs the need for a definitive diagnosis, the risk/ benefit of biopsy should be carefully considered. This is the case in patients with isolated involvement of a vertebral body without adjacent soft tissue affection, as in case of “vertebra plana” or the isolated involvement of the odontoid peg.

The “vertebra plana” radiologic imaging is due to a lesion in the vertebral bone that leads to collapse of the vertebral body. However, if the decision to skip or postpone a biopsy is met, every effort should be made to consider other clinical conditions that might lead to a similar radiological finding, such as Ewing sarcoma, non Hodgkin lymphoma of the bone, osteomyelitis (see also 4.2. Differential diagnosis). Appropriate additional investigations should be per-formed in order to exclude other diseases with a great deal of certainty. In particular in case of vertebra plana,

a spinal MRI within two weeks is mandatory and a further multidisciplinary work up (including ortho-pedic surgeon and hemato-oncologist) is preferable in order to exclude a malignant tumor. Patients with-out histologically confirmed diagnosis need to be carefully monitored by appropriate imaging at least for the next 6 months in order to re-consider the need for biopsy and its justification (e.g. to exclude malignancy). Another possible, but rare situation is that of pituitary deficit (e.g. diabetes insipidus) and/or neurological impairment with a small and not easily accessible lesion on head or spinal MRI. The same approach of close monitoring and re-assessment of the need for biopsy is recommended.

2.2. DIAGNOSTIC CRITERIA

The diagnosis is clinicopathologic and should only be made in the correct clinical setting to prevent mis-diagnosis in the presence of normal reactive Langer-hans cells particularly in regional lymph nodes.

The two levels of certainty of LCH diagnosis which are generally agreed upon are shown in table 2.

Table 2 Diagnostic Criteria of LCH

► DEFINITIVE = Based on microscopic examination and at least one of

the following immunological staining: ♦ Langerin (CD 207) positivity ♦ CD1a positivity ♦ Presence of Birbeck granules on electronic

microscopy.

► PRESUMPTIVE (OR COMPATIBLE) = Based only on clinico-radiological evidence, without

biopsy, as in case of: ♦ Typical bone lesion (in a difficult to reach region)

with/without diabetes insipidus ♦ Pulmonary lesions on CT scan with typical cysts and

nodules in a smoker (however, biopsy should be considered in order to reach a more definitive diagnosis)


of 18

3. PRETREATMENT CLINICAL EVALUATION

The following patient evaluation is recommended only for patients with definite diagnosis of LCH and for those with presumptive LCH in whom a biopsy is deferred for the above mentioned reasons. In all other cases we suggest either consulting the referral center of your country or sharing the histological slides with other reference or specialized centers.

3.1. COMPLETE HISTORY

After having made an LCH diagnosis, it is important to collect further baseline information in order to decide on the therapeutic approach. A complete his-tory should include special reference to the nature and duration of symptoms. Specific symptoms to be actively looked for are: pain, swelling, skin rashes, otorrhea, irritability, fever, loss of appetite, diarrhea, weight loss or poor weight gain, growth failure, polydipsia, polyuria, changes in activity level, dyspnea, smoke exposure, and behavioral and neurological changes.

3.2. COMPLETE PHYSICAL EXAMINATION

Complete clinical examination considering the symp-toms described in section 3.1 should be performed and the symptoms documented.

This history and examination should be performed at each follow-up visit in order to assess response to therapy, investigate for possible disease progression or reactivation, as well as to detect sequelae.

3.3. LABORATORY AND RADIOGRAPHIC EVALUATION

Currently there is no specific biological marker of disease activity, however there is general agreement that biochemical and imaging evaluation at diagno-sis and in case of disease reactivation should in any case include the examinations shown in table 3.

3.4. SPECIFIC CLINICAL SCENARIOS AND RECOMMENDED ADDITIONAL TESTING

After having performed the baseline clinical evalu-ation, certain scenarios might require additional testing. Recommended laboratory investigations, imaging or specialized clinical assessments are shown in table 4, page 5.

Table 3 Laboratory and radiographic evaluation

►FULL BLOOD COUNT ♦ Hemoglobin ♦ White blood cell and differential count ♦ Platelet count

►BLOOD CHEMISTRY ♦ Total protein ♦ Albumin ♦ Bilirubin ♦ ALT (SGPT) ♦ AST (SGOT) ♦ Alkaline phosphatase ♦ γGT ♦ Creatinine ♦ Electrolytes

►ERYTHROCYTE SEDIMENTATION RATE (ESR)

►ABDOMINAL ULTRASOUND (in particular for young children) ♦ Size and structure of liver and spleen ♦ Abdominal lymph-nodes

►COAGULATION STUDIES ♦ INR/PT ♦ APTT/PTT ♦ Fibrinogen

►CHEST RADIOGRAPH (CXR)

►SKELETAL RADIOGRAPH SURVEY1, 2

1 Note that other imaging techniques as bone Tc scan, PET scan or MRI are not an alternative to the standard skeletal survey. The real value of these images in LCH is still under study. In particular information from bone scan should not be considered for evaluation of disease extent and decision-making. PET scan has proven to be the most sensitive functional test used in the identification of LCH lesions and in evaluating patient response to therapy. However, it is currently expensive and not widely available (Phillips et al, 2009). 2 It is not recommended to change the method of bone evalua-tion (skeletal radiograph), as it may lead to discrepancy between assessments. It is important also to consider the ALARA prin-ciple (As Low As Reasonably Achievable) for ionizing radiation and, if possible, during follow up, limit the evaluation to the anatomic region initially involved.


of 18

Table 4 Specific Clinical Scenarios: Recommended Additional testing

Agree-ment

► HISTORY OF POLYURIA OR POLYDIPSIA ♦ Early morning urine specific gravity and osmolality + ♦ Blood electrolytes + ♦ Water deprivation test if possible + ♦ MRI of the head (see 3.6. for details) +

► BICYTOPENIA, PANCYTOPENIA, OR PERSISTENT UNEXPLAINED SINGLE CYTOPENIA

♦ Any other cause of anemia or thrombocytopenia has to be ruled out according to standard medical practice. If no other causes are found, the cytopenia is considered as LCH-related.

+

♦ Bone marrow aspirate and trephine biopsy to exclude causes other than LCH.1

+

♦ Hemophagocytic biological feature (coagulation, including factor I / fibrinogen, triglycerides, and ferritin) to evaluate macrophage activation and hemophagocytic syndrome. 2

+

►LIVER DYSFUNCTION ♦ Consult a hepatologist and consider liver MRI that is

preferable to retrograde cholangiography in case of frank liver dysfunction (liver enzymes > 5 fold normal / bilirubinemia > 5 fold normal range)

+

♦ Liver biopsy is only recommended if there is clinically significant liver involvement and the result will alter treatment (i.e. to differentiate between active LCH and sclerosing cholangitis)

+

►LUNG INVOLVEMENT In case of abnormal Chest X Ray or symptoms/signs suggestive for lung involvement, or lung findings not characteristic of LCH or suspicion of an atypical infection:

♦ Lung high resolution computed tomography (HR-CT) or preferably low dose multi-detector HR-CT if available. Note that cysts and nodules are the only images typical of LCH; all other lesions are not diagnostic. In children already diagnosed with MS-LCH (see 4.1) low dose CT is sufficient in order to assess extent of pulmonary involvement, and reduce the radiation burden.

+

♦ Lung function test (if age appropriate) + ♦ Bronchoalveolar lavage (BAL): > 5% CD1a + cells

in BAL fluid may be diagnostic of LCH in a non-smoker

3

♦ Lung biopsy (if BAL is not diagnostic) +

►SUSPECTED CRANIOFACIAL BONE LESIONS INCLUDING MAXILLA AND MANDIBLE

♦ MRI of head (see 3.6.) including the brain, hypothalamus-pituitary axis and all craniofacial bones. If MRI not available, CT of the involved bone and the skull base is recommended

+

►VERTEBRAL LESIONS (EVEN IF ONLY SUSPECTED) ♦ MRI of spine to exclude spinal cord compression and

to assess for soft tissue masses +

►VISUAL OR NEUROLOGICAL ABNORMALITIES ♦ MRI of head (see 3.6. for details) + ♦ Neurological assessment + ♦ Neuropsychometric assessment +

►SUSPECTED OTHER ENDOCRINE ABNORMALITY (i.e. short stature, growth failure, hypothalamic syndro-mes, precocious or delayed puberty)

♦ Endocrine assessment (including dynamic tests of the anterior pituitary and thyroid)

+

♦ MRI of head (see 3.6. for details) +

► AURAL DISCHARGE OR SUSPECTED HEARING IMPAIR-MENT / MASTOID INVOLVEMENT

♦ Formal hearing assessment + ♦ MRI of head (see 3.6. for details) or HR-CT of

temporal bone +

► UNEXPLAINED CHRONIC DIARRHEA, FAILURE TO THRIVE, OR EVIDENCE OF MALABSORPTION

♦ Endoscopy + ♦ Biopsy +

1 The clinical significance of CD1a positivity in the bone marrow remains to be proven. An isolated finding of histiocytic infiltration on the bone marrow with no cytopenia is not a criterion for diagnosis or reactivation (McClain et al, 1983; Minkov et al, 2007). 2 Hemophagocytic syndrome with macrophage activation is a common finding in patients with hematological dysfunction (Favara et al, 2002; Galluzzo et al, 2010). 3 See discussion in references (Tazi et al, 2000; Vassallo et al, 2000)


of 18

3.5. DEFINITION OF ORGAN INVOLVEMENT

3.5.1. Possibly Involved Organs

After the diagnosis of LCH has been made, involve-ment of other organs should be evaluated and defined according to the clinical, biological or radiological criteria shown in table 5.

3.5.2. Risk Organs

Based on previous experience, disease involvement in the hematopoietic system, spleen, or liver is a marker of a less favorable prognosis, even of mortality if the patient doesn’t respond to standard therapy [Gadner et al, 2001; Gadner et al, 2008; Minkov et al, 2002].

There is general agreement that lung involvement can also considerably worsen the prognosis and therefore is a risk for the patient [Tazi et al, 2000; Vassallo et al, 2000]. However, it is also generally agreed that lung involvement is no “risk organ involvement” in reference to the clinical trials for LCH. Additionally, lung involvement itself does not always justify systemic treatment (see 5.2). Thus lung involvement alone is no longer a criterion for inclusion in the “risk” disease category of the LCH clinical trials.

The risk organs are marked in table 5.

3.5.3. “Special Sites”

Disease in some sites which are marked as “Special Sites” in table 5 requires additional consideration.

In certain situations, such as odontoid peg and vertebral lesions with intraspinal soft tissue extension, lesions are located in functionally critical anatomical sites. These lesions may cause immediate risk to the patient because of the potential for disease progression and the hazards of attempting local therapy. Isolated disease in these “Special Sites” may justify systemic therapy, but does not require prolonged therapy once the immediate risk of neurologic compression is over. These lesions need to be distinguished from other bone lesions.

Other “Special Sites” are craniofacial bone lesions that are associated to diabetes insipidus. They are detailed in table 5, section “Bone”. Recent knowledge suggests that involvement or disease reactivation of these bones is statistically associated with diabetes insipidus which can either be present at diagnosis or develop later (Donadieu et al 2004b; Grois et al 2006; Haupt et al 2004).

CNS involvement although rare may have serious consequences. The natural history is not well under-stood and appropriate preventative and treatment options are not established. Therefore these patients need careful attention and follow-up and their management should be discussed with an expert. (Grois et al, 2006).

Table 5 Criteria for Organ Involvement Definition in Langerhans Cell Histiocytosis

Involvement Criteria Agree-ment

Special Site

Risk Organ

♦ General bone involvement: All radiological documented lesions, which are not mentioned below, confirmed by histological examination of the most accessible lesion.

+

♦ Craniofacial bone involvement: Lesions in the orbital, temporal, mastoid, sphenoidal, zygomatic, or ethmoidal bones; the maxilla or paranasal sinuses; or cranial fossa; with intracranial soft tissue extension.

+

♦ Vertebral involvement without soft tissue extension, e.g. vertebra plana, is not regarded as “Special Site” lesions.

+

♦ Vertebral involvement with intraspinal soft tissue extension or lesions in the odontoid peg is regarded as “Special Site” lesions.

+

► BONE

An abnormality on Tc Bone scan or a MRI hypersignal, not correlated with symptoms, or with an X ray image is not considered bony disease! +

► SKIN ♦ 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.

+


of 18

Table 5 Criteria for Organ Involvement Definition in Langerhans Cell Histiocytosis

Involvement Criteria Agree-ment

Special Site

Risk Organ

♦ Mild: (both of the following categories should be present) - Hemoglobin between 10 g/dl and 7 g/dl (not due to other causes, e.g.

iron deficiency) +

- Thrombocytopenia with platelets between 100.000 and 20.000/mm3. + ♦ Severe: (both of the following categories should be present) - Hemoglobin < 7 g/dl. Exclude iron deficiency. +

► HEMATOPOIETIC

- Platelets < 20.000/mm3 +

► SPLEEN ♦ > 3 cm below the costal margin at the mid clavicular line, confirmed by ultrasound +

♦ 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 - AST> 3 times normal, ascites, edema.

+

or Intra hepatic nodular mass +

► LIVER

The patient can also show a combination of these symptoms.

♦ Typical imaging (nodules or cysts) on CT scan. + ( )1 ► LUNG Any atypical mass needs to be explored by BAL or biopsy in order to have histopathological / cytological diagnosis +

♦ Oral involvement with lesions in the oral mucosa, gums. + ► MUCOSAE

♦ Genital or anal involvement +

► EYE ♦ Orbital involvement with proptosis or exophthalmos. +

► EAR ♦ Ear involvement with external otitis, otitis media, or otorrhea. +

♦ Any pituitary hormone deficiency. + ► PITUITARY or Tumor appearance in the hypothalamic pituitary axis. +

♦ Tumoral: All intracerebral expansive lesions predominantly affecting the brain or meninges.

+

♦ Neuro degeneration on MRI: MRI imaging compatible with neuro degenerative disease2, i. e. abnormal signal intensity localized in the dentate nuclei or cerebellum or cerebral atrophy NOT explained by corticosteroids.

+

► CNS

♦ Clinical neuro degeneration: Presence of suggestive symptoms (either cerebellar syndrome or learning difficulty) with compatible MRI imaging.

+

1 See 3.5.2 2 The term radiological neurodegeneration has been coined to describe a certain pattern of MRI findings, but this terminology

may be misleading as it does not necessarily correlate with histopathology.


of 18

3.6. HEAD MRI IN LCH PATIENTS

3.6.1. Technique

The MRI protocol must be able to investigate the entire brain, the hypothalamus-pituitary axis and all craniofacial bones. The aim of the MRI is to syste-matically seek any neuro-degenerative involvement and/or tumorous lesion and meningeal involvement.

The use of intravenous contrast (Gadolinium chelates) is mandatory.

The following protocol is recommended: - Axial and sagittal T1 w. slices of the entire brain - Fine T1 w. sagittal slices focused on the pituitary

gland (3 mm / 0.3 mm or below) - Axial T2W. and FLAIR w. slices (except age < 1

year) of the entire brain

It is not recommended to use the option “contrast by magnetic transfer”. If it is nevertheless done, the same technique has to be used every time and this information has to be specified on the report.

After injection of Gadolinium: o MRI scan according to data obtained on the first

series by (T1 w. slices): � Fine sagittal slices of the pituitary � Coronal slices of the brain

o Additional sequences may be taken if indicated. 3.6.2. Frequency of MRI surveillance

Suggestion for further surveillance in case of posi-tive findings at MRI:

1. If a lesion has been identified in the CNS it is suggested to repeat the examination after 6 weeks (in symptomatic patients and those with tumorous lesions) and 3 months. Further images should be decided on the basis of the results of the first two examinations.

2. In case of clinical hypothalamic dysfunction or neuro degenerative findings on MRI, even without symptoms, it is suggested to perform a second MRI after one year and then at 2, 4, 7, and 10 years. If after 10 years there is no clinical deterioration, further MRI is recommended only upon clinical indication.

4. STRATIFICATION

4.1. CLINICAL CLASSIFICATION

4.1.1. Single System LCH (SS-LCH)

One organ/system involved (uni- or multifocal):

►Bone: unifocal (single bone) or multifocal (> 1 bone)

►Skin

►Lymph node (not the draining lymph node of another LCH lesion)

►Lungs

►Hypothalamic-pituitary / Central nervous system

►Other (e.g. thyroid, thymus)

For the definition of organ involvement see 3.5.

4.1.2. Multisystem LCH (MS-LCH)

Two or more organs/systems involved:

► With involvement of “Risk Organs” (Hemato-poietic system, spleen, and/or liver)

► Without involvement of “Risk Organs”

For the definition of organ involvement see 3.5.

Note: Other systems have also been proposed in order to classify disease extension. In particular the so called “activity score” has been proposed [Donadieu et al, 2004a] and is still in use in some countries such as in France. This system provides a score (0 no activity, up to 5 maximum activity) for each organ or system possibly affected by LCH. The score can be measured at diagnosis as at any follow-up visit. A total score > 6 is considered as unfavorable, as well as any worsening of previous scores.


of 18


of 18

5. TREATMENT

5.1. MANAGEMENT ALGORITHMS

Treatment recommendations are based on site and extension of the disease.

Figure 1 Management of Langerhans Cell Histiocytosis and Local Treatment or Careful Observation


of 18

Figure 2 Management of Langerhans Cell Histiocytosis and Systemic Treatment


of 18

5.2. LOCAL THERAPY OR CAREFUL OBSERVATION

In case of single system LCH (SS-LCH) with unifocal bone involvement only local therapy and follow-up is recommended. In some cases, careful observation can be sufficient. Decision on the most appropriate approach should be based on the pre-sence or not of clinical symptoms and or complaints, on the size and localization of the disease, on the presence on imaging of healing signs. For multifocal bone LCH and for bony lesions in “special sites”, systemic therapy should be discussed; see 5.3.

Local therapy in case of unifocal bony lesions might consist of a simple biopsy. As mentioned before, curettage of the center of a bone lesion is usually sufficient for pathologic diagnosis and may also trigger the initiation of a healing process. Complete excision of bone lesions is not indicated and may increase the size of the bony defect (destroy the bone matrix), the time to healing, and result in permanent skeletal defect. At the moment of biopsy, intralesional injection of steroid has been suggested as a measure to accelerate the healing process. Depending on lesion size, dosages of 40 - 160 mg of methylpredni-solone have been used. The efficacy of this practice however has not been assessed in randomized trials.

Supportive treatment like an orthopedic corset should be considered in some situations with spinal instability that might compromise spine development and increase risk of scoliosis. Vertebra plana “per se” is not an indication for orthopedic corset, and only appropriate and expert physiotherapy should be considered. The decision with regards to orthopedic or physiotherapy option has to be taken in agreement with an orthopedic surgeon.

In case of a single system LCH (SS-LCH) with skin lesions, local therapy – like topical treatment – and follow-up is recommended. Topical caryolisine (nitrogen mustard ointment) is the best documented treatment option, but its applicability is limited as it requires precautions and trained staff for application [Hadfield et al, 1994; Sheehan et al, 1991]. Moreover this topical oinment is not largely available (no commercial preparation at all). Topical steroids are often suggested in standard textbooks but their effi-cacy has never been proved. Moreover, most LCH patients with cutaneous involvement (either isolated or within the frame of MS-LCH) are diagnosed after unsuccessful treatment with local steroids. Therefore, at the moment there is no evidence to advocate this treatment option.

All newborns and young infants with skin-only LCH require careful observation in order to detect possible cases of progression to multisystem risk disease. Those patients who remain with skin only LCH pro-bably do not need therapy except for symptoms such as pain or ulceration. Systemic therapy should only be used in these patients under extreme circumstances.

In case of lung involvement, systemic therapy is not necessarily justified. Smoking withdrawal and stop-ping exposure to cigarette smoke is always mandato-ry. However, isolated lung involvement can be very challenging due to the risk of severe acute complica-tions as pneumothorax, or acute cardiopulmonary arrest. Therefore, treatment in experienced center is strongly recommended.

Radiotherapy is no longer recommended due to the long term sequelae.

5.3. SYSTEMIC THERAPY

Systemic therapy should be considered in case of the following disease category:

MS-LCH with/without involvement of “risk organs”

Systemic therapy has also been suggested in case of other particular situations, but this is not universally accepted:

SS-LCH with “special site” lesions SS-LCH with multifocal bone lesions (MFB)

Some investigators consider these last two scenarios as an indication for systemic therapy, while others treat only in case of lesions that may have clinical consequences. Consider discussing this with your reference centre.

Over the years, several international protocols for MS-LCH treatment have been designed within the framework of the Histiocyte Society. Study patients were recruited from many countries worldwide and results have been reported in the literature [Gadner et al, 2001; Gadner et al, 2008; Minkov et al, 2002]. From the previous studies, the main conclusions are: • Standard treatment is based on steroids and

vinblastine (VBL). • Prolonged treatment (i.e. for 1 year) reduces the

risk of disease reactivations. • Clinical response after the first 6 weeks of treat-

ment is a good marker of further disease evolution. New international protocols will be opened to patient accrual (Hwww.histio.netH and Hwww.histiocytesociety.orgH).


of 18

5.3.1. Front Line Treatment

Front line treatment of MS-LCH is based on: • Vinblastine (VBL) 6 mg/m2 i.v. bolus once every

7 days (once a week) for 6 weeks, along with • Prednisone at 40 mg/m2/day given orally in three

divided doses for 4 weeks and then tapered over the following 2 weeks

After the first 6 weeks of treatment, disease status should be re-evaluated and treatment continued accordingly.

5.3.2. Evaluation of Response

In case of good response (especially in the risk organs) to VBL and steroid, treatment should be continued for 6 further weeks with: • VBL 6 mg/m2 i.v. bolus (once a week), along with • Prednisone at 40 mg/m2/day given orally in three

divided doses for 3 days every week Maintenance therapy up to a total of 12 months must follow and is described below.

Evaluation of response may be difficult in some patients especially those with bone lesions and multisystem involvement where there may be regression in some lesions with progression of disease in others. A disease activity score has been published [Donadieu et al, 2004a] and may be a useful tool to assess disease response, especially in case of systemic disease.

Response at 6 weeks is particularly important and if there is evidence of progressive disease in a patient with hematological and or hepatic dysfunction at this stage it is suggested to consider early switch to salvage therapy (see 5.3.4).

LCH may be quite unpredictable and recurrences or reactivations of the disease may occur. In the case of clinical suspicion for disease progression or reac-tivation, complete evaluation as recommended in the previous section 3. has to be performed in order to make decisions on further treatment strategy. 5.3.3. Maintenance Therapy

New study protocols will be needed in order to get reliable data about the optimum duration of main-tenance therapy, which depends on the severity of the disease. Given that the risk of reactivations is high in many forms of LCH, treatment should continue up to a total of 12 months with: • VBL 6 mg/m2 i.v. bolus every 3 weeks, along with • Prednisone at 40 mg/m2/day given orally in three

divided doses for 5 days

5.3.4. Salvage Therapy

Refractory disease in patients with hematological and or liver dysfunction is a rare but life threatening situa-tion [Minkov et al, 2002; The French Langerhans' Cell Histiocytosis Study Group, 1996]. Such patients need to be referred to a trained team. Therapeutic options (although evidence quite limited) may con-sider the chemotherapy combination of 2-Cda and Ara-C [Bernard et al, 2005; McClain 2005] or hematopoietic stem cell transplant after reduced intensity conditioning regimen [Steiner et al, 2005].

5.4. TREATMENT OPTIONS IN CASE OF REACTIVATION

5.4.1. Reactivation of Single System Disease

The choice of treatment options is based on the same principles as for initial disease.

The options for reactivations of SS-LCH (skin, bone, other) include

I. Wait and watch approach

II. Local therapy (as above)

III. Indomethacin for bony disease

IV. Vinblastine (VBL) + steroid (as above)

Radiotherapy is no longer recommended due to the long-term sequelae.

In case of a multisystemic reactivation of a SS-LCH, treatment should follow the options for MS-LCH including systemic therapy (see 5.3. and 5.4.2.).

5.4.2. Reactivation after Systemic Therapy

I. If the reactivation is after completion of treat-ment, re-induction with VBL + steroid may be effective and there may be no need to switch to alternative therapy. If however, the disease is not responsive we suggest discussion with the reference centre for your country.

II. If reactivation occurs while on treatment, 2nd line strategies should be discussed with your reference centre, taking into account disease severity and the respective risk for unfavorable outcome.


of 18

6. MONITORING FOR PERMANENT CONSEQUENCES Although LCH is a mostly benign and treatable disease, it can result in sequelae affecting various tissues involved. Some may be present or even precede diagnosis, while other may become manifest later. It is thus important to keep monitoring these patients at least until growth is completed and possibly into adult life. The most common long-term consequences are endocrine and growth, auditory, and orthopedic. Neurocognitive, pulmonary and liver sequelae are rare but cause major morbidity.

The frequency of investigations and tests that are recommended are shown in table 7 at the end of this section 6.

A scoring system for sequelae has been developed in order to observe the evolution [Nanduri et al, 2006].

6.1. DIABETES INSIPIDUS

Diabetes insipidus (DI) is the most frequent endocri-nopathy associated to LCH with incidence ranging between 15 to 50% of cases. It is due to involvement of posterior pituitary gland and may become mani-fest either before, concurrently or after LCH diag-nosis. It is thus important to always investigate thirst and polyuria in LCH patients, even many years after diagnosis. In case of symptoms investigate accor-ding to previous section 3.4.

6.2. HORMONE DEFICIENCY

Growth hormone deficiency is the most frequent anterior pituitary hormone loss and is seen in up to 10% of patients. Other problems include delayed puberty and rarely panhypopituitarism. Measurement of height and weight and assessment of puberty is therefore recommended every 6 months or 1 year until growth is completed.

6.2.1. Growth

Ideally, standardized equipment, such as a Harpen-den stadiometer or other similar stadiometer should be used, and by the same operator. Measurements must be plotted onto appropriate growth charts (National growth charts if available, or WHO charts) and assessed in relation to parents’ heights. Serial measurements should be plotted. Standard deviation (SD) scores for age, sex and country should be calculated where possible and plan for investigations as below.

Indications for investigation of growth:

Criteria for investigation are taken from the Consensus guidelines of the GH Research Society [Growth Hormone Research Society., 2000]. If SD score are available: a) Any child with severe short stature defined as a

height more than 3SD below the mean b) Height more than 1.5 SD below mid-parental

height c) Height more than 2 SD below the mean and a

height velocity > 1SD below mean for age d) In the absence of short stature, a height velocity

more than 2SD below the mean over 1 year or 1.5 SD over 2 years

If SD scores are not available: a) Any child between the ages of 2 and 10 years

who is growing at less than 5 cms per year (this child has a low height velocity, and will drop below the expected percentile with time)

b) Any child whose height is well below the expec-ted percentile for parents’ heights

c) Children with excessive weight gain in relation to height

d) Any child who does not have an adequate pubertal growth spurt despite onset of puberty

6.2.2. Puberty

Assess puberty according to Tanner stages starting from age 8 years in girls and 9 years in boys.

Indications for investigation of puberty: a) Delayed onset of puberty (B2 > 13 years in girls,

P2, T2 > 14 years in boys) b) Delayed onset of periods (menarche) in girls (>

14 years) c) Precocious puberty (B2 < 8 years in girls, P2,

T2 < 9 years in boys) d) Arrest or regression of pubertal development (a

child who starts pubertal development at correct time, but then does not progress or has loss of secondary sexual characteristics).

6.2.3. Suggested Investigations for delayed Growth /

Puberty

1. Bone age assessed on X ray 2. Anterior pituitary function tests (in those with

poor growth / delayed puberty depending on the suspected deficit)

a. Stimulation of GH secretion using Insulin, Glucagon or Arginine stimulation test


of 18

b. Gonadotropin releasing hormone/luteinizing hormone releasing hormone (GnRH, LHRH) test to assess LH and FSH secretion in case of suspicion of hypogonadotropic hypogona-dism

c. Thyroid function test d. Cortisol levels

3. MRI scan of head as in 3.6. (if there is any hor-mone deficiency)

4. Bone mineral density (DEXA) scan needs to be monitored in patients with GH deficiency, de-layed puberty, panhypopituitarism

5. Consider karyotype analysis in girls with de-layed puberty and short stature as they might have Turner syndrome.

6.3. ORTHOPAEDIC

Lesions of the vault of the skull and the long bones of the limbs usually heal without major problems. However, when vertebrae are affected scoliosis may become manifest later in life, in particular during periods of rapid growth such as puberty. Children should be assessed clinically at least annually in par-ticular during puberty in order to identify any early signs of scoliosis. They should be referred to the orthopaedic surgeon in order to start preventative physical therapies (e.g. orthopaedic corset/ brace, or neck collar) in order to manage this proactively.

If facial bones are affected by the disease, facial asymmetry may become manifest as the child grows and reconstructive surgery may be required.

6.4. EARS

Subjects with disease involvement of the middle or inner ear and the temporal bone should be monitored with audiometry at diagnosis and at end of treatment and reassessed at start of school and if any new symptoms develop. Early diagnosis and interven-tional strategies such as hearing aids can avoid deterioration of school performance and signifi-cantly improve outcome.

6.5. ORAL TISSUE AND JAW

Subjects with LCH involvement of gums and jaw should be monitored for dental development and growth of the jaw, as they might need orthodontic surgery.

6.6. NEUROLOGICAL

Children with multisystem LCH are at risk of develo-ping late neuropsychological sequelae, in particular cerebellar ataxia and learning difficulty. All children with multisystem LCH should be regularly followed up clinically. In those children where there is a sig-nificant history or clinical neurological abnormality further investigations should be performed as below. a) Neuropsychological tests – IQ, memory and

attainment b) Cerebellar function assessment according to the

Ataxia rating scales [Schmahmann et al, 2009; Trouillas et al, 1997].

c) MRI of the head 6.7. LUNGS

In those children with a history of lung involvement spirometry should be performed regularly and if abnormal may need X ray and HR-CT of chest.

The dangers of smoking should be explained and smoking avoided. 6.8. LIVER

Liver involvement is rare, but can have serious mor-bidity. Only those with abnormal liver function might need further investigation including ultrasound scan of liver or cholangiography. 6.9. ASSOCIATED MALIGNANCIES

There is a recognized association between LCH and malignancies [Haupt et al, 2005]. The malignancies may precede, occur concurrently or follow the diagnosis of LCH and should be considered at every clinical visit. Acute leukemia should be considered in patients who develop signs of bone marrow involvement or hepatosplenomegaly. Acute lymphoblastic leukemia and lymphoma more often occur prior to the diagnosis of LCH but may be diagnosed within 5 years after LCH.

Myeloid leukemias usually follow LCH especially in those patients exposed to etoposide, alkylating agents and/or radiotherapy. With the current treatment strategy it is expected that these types of secondary malignancy will hopefully be exceptional.

Solid tumours may precede, occur concurrently or follow the diagnosis of LCH. Most of those that followed LCH developed in a previous radiation field e.g. sarcoma, skin cancer, thyroid cancer.


of 18


of 18

7. REFERENCE LIST

Bernard,F., Thomas,C., Bertrand,Y., Munzer,M., Landman,P.J., Ouache,M., Colin,V.M., Perel,Y., Chastagner,P., Vermylen,C., & Donadieu,J. (2005) Multi-centre pilot study of 2-chlorodeoxy-adenosine and cytosine arabinoside combined chemotherapy in refractory Langerhans cell histiocytosis with haematological dysfunction. Eur.J Cancer, 41, 2682-2689.

Chikwava,K. & Jaffe,R. (2004) Langerin (CD207) staining in normal pediatric tissues, reactive lymph nodes, and childhood histiocytic disorders 191. Pediatr.Dev.Pathol., 7, 607-614.

Donadieu,J., Piguet,C., Bernard,F., Barkaoui,M., Ouache,M., Bertrand,Y., Ibrahim,H., Emile,J.F., Hermine,O., Tazi,A., Genereau,T., & Thomas,C. (2004a) A new clinical score for disease activity in Langerhans cell histiocytosis. Pediatr.Blood Cancer, 43, 770-776.

Donadieu,J., Rolon,M.A., Thomas,C., Brugieres,L., Plantaz,D., Francois,E.J., Frappaz,D., David,M., Brauner,R., Genereau,T., Debray,D., Cabrol,S., Barthez,M.A., Hoang-Xuan,K., & Polak,M. (2004b) Endocrine involvement in pediatric-onset Langerhans' cell histiocytosis: a population-based study. J.Pediatr., 144, 344-350.

Favara,B.E., Jaffe,R., & Egeler,R.M. (2002) Macrophage activation and hemophagocytic syndrome in langerhans cell histiocytosis: report of 30 cases. Pediatr Dev.Pathol., 5, 130-140.

Gadner,H., Grois,N., Arico,M., Broadbent,V., Ceci,A., Jakobson,A., Komp,D., Michaelis,J., Nicholson,S., Potschger,U., Pritchard,J., & Ladisch,S. (2001) A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr, 138, 728-734.

Gadner,H., Grois,N., Potschger,U., Minkov,M., Arico,M., Braier,J., Broadbent,V., Donadieu,J., Henter,J.I., McCarter,R., & Ladisch,S. (2008) Improved outcome in multisystem Langerhans cell histiocy-tosis is associated with therapy intensification. Blood 111, 2556-62.

Galluzzo,M.L., Braier,J., Rosenzweig,S.D., Garcia de Davila,M.T., & Rosso,D. (2010) Bone marrow findings at diagnosis in patients with multisystem langerhans cell histiocytosis 25. Pediatr.Dev.Pathol., 13, 101-106.

Grois,N., Potschger,U., Prosch,H., Minkov,M., Arico,M., Braier,J., Henter,J.I., Janka-Schaub,G., Ladisch,S., Ritter,J., Steiner,M., Unger,E., & Gadner,H. (2006) Risk factors for diabetes insipidus in langerhans cell histiocytosis. Pediatr.Blood Cancer, 46, 228-233.

Growth Hormone Research Society (2000) Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society. J Clin Endocrinol Metab. 85:3990-3)

Hadfield,P.J., Birchall,M.A., & Albert,D.M. (1994) Otitis externa in Langerhans' cell histiocytosis-the successful use of topical nitrogen mustard. Int.J.Pediatr.Otorhinolaryngol., 30, 143-149.

Haupt,R., Nanduri,V.R., Calevo,M.G. & Egeler,R.M. (2005) Late effects of Langerhans cell Histiocytosis and the association of LCH with malignancy. In Histiocytic Disorders in Children and Adults. Histiocytic Disorders in Children and Adults. (ed. by W. S. Egeler RM) Cambridge University Press.

Haupt,R., Nanduri,V., Calevo,M.G., Bernstrand,C., Braier,J.L. Broad-bent,V, Rey,G., McClain,K.L., Janka-Schaub,G. & Egeler,R.M. (2004) Permanent Consequences in Langerhans Cell Histiocytosis Patients: A Pilot Study From the Histiocyte Society - Late Effects Study Group. Pediatr.Blood Cancer, 42, 438-444

Lau,S.K., Chu,P.G., & Weiss,L.M. (2008) Immunohistochemical expression of Langerin in Langerhans cell histiocytosis and non-Langerhans cell histiocytic disorders. 110. Am.J.Surg.Pathol., 32, 615-619.

McClain KL. Drug therapy for the treatment of Langerhans cell histio-

cytosis. Expert Opin Pharmacother. 2005 Nov;6(14):2435-41 McClain,K., Ramsay,N.K., Robison,L., Sundberg,R.D., & Nesbit,M., Jr.

(1983) Bone marrow involvement in histiocytosis X. Med.Pediatr.Oncol., 11, 167-171.

Minkov,M., Grois,N., Heitger,A., Potschger,U., Westermeier,T., & Gadner,H. (2002) Response to initial treatment of multisystem Langerhans cell histiocytosis: an important prognostic indicator. Med.Pediatr Oncol., 39, 581-585.

Minkov,M., Potschger,U., Grois,N., Gadner,H., & Dworzak,M.N. (2007) Bone marrow assessment in Langerhans cell histiocytosis 12. Pediatr.Blood Cancer, 49, 694-698.

Nanduri,V.R., Pritchard,J., Levitt,G., & Glaser,A.W. (2006) Long term morbidity and health related quality of life after multisystem Langerhans cell histiocytosis. Eur.J Cancer, 42, 2563-2569.

Phillips M, Allen C, Gerson P, McClain K. (2009) Comparison of FDG-PET scans to conventional radiography and bone scans in management of Langerhans cell histiocytosis. Pediatr Blood Cancer. 52:97-101

Schmahmann,J.D., Gardner,R., MacMore,J., & Vangel,M.G. (2009) Development of a brief ataxia rating scale (BARS) based on a modified form of the ICARS 10. Mov Disord., 24, 1820-1828.

Sheehan,M.P., Atherton,D.J., Broadbent,V., & Pritchard,J. (1991) Topical nitrogen mustard: an effective treatment for cutaneous Langerhans cell histiocytosis. J.Pediatr., 119, 317-321.

Steiner,M., Matthes-Martin,S., Attarbaschi,A., Minkov,M., Grois,N., Unger,E., Holter,W., Vormoor,J., Wawer,A., Ouachee,M., Woessmann,W., & Gadner,H. (2005) Improved outcome of treatment-resistant high-risk Langerhans cell histiocytosis after allogeneic stem cell transplantation with reduced-intensity conditioning. Bone Marrow Transplant., 36, 215-225.

Swerdlow,S.H., Campo,E., Harris,N.L., Jaffe,E.S., Pileri,S.A., Thiele,J., & Vardiman,J.W. (2008) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Fourth Edition. 252, pp. 358-360. IARC press, Lyon.

Tazi,A., Soler,P., & Hance,A.J. (2000) Adult pulmonary Langerhans' cell histiocytosis. Thorax, 55, 405-416.

The French Langerhans' Cell Histiocytosis Study Group (1996) A multi-centre retrospective survey of Langerhans' cell histiocytosis : 348 cases observed between 1983 and 1993. Arch Dis Child, 75, 17-24.

Trouillas,P., Takayanagi,T., Hallett,M., Currier,R.D., Subramony,S.H., Wessel,K., Bryer,A., Diener,H.C., Massaquoi,S., Gomez,C.M., Coutinho,P., Ben,H.M., Campanella,G., Filla,A., Schut,L., Timann,D., Honnorat,J., Nighoghossian,N., & Manyam,B. (1997) 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, 145, 205-211.

Valladeau,J., Ravel,O., Zutter-Dambuyant,C., Moore,K., Kleijmeer,M., Liu,Y., Duvert-Frances,V., Vincent,C., Schmitt,D., Davoust,J., Caux,C., Lebecque,S., & Saeland,S. (2000) Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules. 20. Immunity., 12, 71-81.

Vassallo,R., Ryu,J.H., Colby,T.V., Hartman,T., & Limper,A.H. (2000) Pulmonary Langerhans'-cell histiocytosis. N.Engl.J Med., 342, 1969-1978.

langerhans cell histiocytosis lch - europa · euro histio net guidelines march 2011, version 1.1...

Documents