Dr. Terencia, Dr Neeraj /Dr.Manoj Unni/Dr. Rema(Dept of Clinical Hematology), Dr. C Jayakumar, AIMS, Kochi
One year old child, admitted for evaluation of maculopapular skin with intense pruritus
lesions and oul smelling umbilical discharge noticed since 1.5 months of age, worsened since past 6 months.
First child of NCM with uneventful perinatal history
He had history of recurrent URI/LRTI requiring oral antibiotics in the past +.
History of pitting and onycholysis of all fingers of hands and feet for which he received antifungals.. He also had poor appetite and significant FTT( well thriving till 6 months of age ). All these complaints were managed on an outpatient basis with no hospitalisations in the past.
There was no history of oral thrush/ delayed cord fall/ recurrent diarrhea/ colitis/ pyoderma/ skin abcess/ polyuria/ seizures.
Differential Diagnosis: –
1.Inborn error of immunity
2. Common variable immunodeficiency
3. Langerhans cell histiocytosis (LCH)
4. Juvenile xanthogranuloma (JXG)
5.Myeloproliferative disorder
6.Malignancy
Child was malnourished, afebrile with stable vitals
No PICCLE
Sparse brittle hair +
No clear BCG scar
Hypopigmented Maculopapular rashes over the face and back with ?central prominence
Scalp seborrhea+
Extensive onycholysis of all 20 finger nails +
Foul smelling discharge from ears
Systemic Examination-Within normal limits.
Initial labs showed neutrophilic leukocytosis, w and thrombocytosis(Hb-8.5g/dl, TC-30.1ku/ml, PLT-750ku/ml) and CRP-(C-reactive protein) : 9.59 mg/L.
Peripheral smear was normal and LFT showed mild transamintis.
Figure 1- CXR showed diffuse reticulonodular opacities- ? TB ?malignancy ? disseminated infection.
Gastric aspirate MTB panel was negative. In view of recurrent infections beginning from early infancy, the first possibilityconsidered was Inborn error of immunity with predisposition to fungal infections – includingDOCK 8 deficiency , CARD 11 deficiency, IL-17 pathway defects( Chronic mucocutaneous candidiasisis). Immunoglobluin profile, basic lymphocytic subset analysis (LSSA) and preop serology were done and negative. In view of Onychomycosis, Nail scrapings were sent and was positive for Candida parapsillosis and hence was started anti-fungals.
Pus culture of the ear swab had shown Serratia marcescens(Moderate growth) and Staphylococcus aureus (Moderate growth) CMV quantitative PCR was normal .
USG abdomen, showed altered liver echotexture wit ill- defined and rounded focal lesions scattered in both lobes- ? disseminated fungal infection Skin biopsy
showed epidermis of rete pegs with thinly preserved granular layer and basket weave keratin.
Mild spongiosis seen. There was a focal area where epidermis is thinned and papillary dermis is expanded medium sized rounded epithelioid cells with moderate eoisnophilic cytoplasm and ovoid indented nuclei; some showing nuclear grooves. Few multinucleate cells seen. Exocytosis seen. The rest of the dermis showed perivascular lymphohistiocytes and few similar appearing cells in the interstitium. Immuno histo chemistry (IHC), shown the CD 1a,S100 and fascin- Positive ,CD68 -Shows perinuclear dot like staining ,Cyclin D1 showed focal nuclear staining .Morphology with IHC was consistent with LCH.
The clinical features of rash+ scalp seborrhea+ reticulonodularshadows on xray + liver lesions+ skin biopsy IHC fitted in with multisystem LCH.
Currently child is on chemotherapy with vinblastine, 3 cycles over which the child had tolerated well.
Histiocytic disorders – Langerhans cell histiocytosis (LCH) is a malignant histiocytic disorder of myeloid origin
Although rare, LCH is the most common neoplastic histiocytic disorder.
LCH is most common in children from one to three years old.
●Pathophysiology – LCH is a clonal disorder driven activation of the MAPK-ERK signaling pathway, which offers a treatment opportunity for some patients; BRAF V600E mutation is present in more than half of cases.
●Clinical manifestations – Symptoms, affected organ systems, and disease tempo vary widely.
LCH can present as a single site or multiple sites of disease in one organ system or it can present in multiple organ systems simultaneously or sequentially. The distinction between single-system and multisystem LCH affects prognosis and management.
•Single-system LCH – Unifocal or multifocal involvement of bone, skin, lungs, and central nervous system (CNS).
•Multisystem LCH – Two or more organs/systems are involved. It is especially important to identify involvement of critical (“risk”) organs: CNS, heart, liver, and spleen, which affects prognosis and treatment choices.
●Sites of involvement – Lytic bone lesions, eczematous or papular rash, or pituitary involvement causing arginine vasopressin deficiency (AVP-D) are the most common manifestations; clinical findings in various organs are described above.
●Evaluation – The extent of disease is evaluated with history and physical examination, laboratory studies, imaging, and biopsy.
•Imaging – Patients ≥2 years should have whole-body fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT). Other imaging is guided involved sites; examples include magnetic resonance imaging (MRI) for brain lesions or CT, MRI, or ultrasound for abdominal symptoms.
•Pathology – Demonstration of CD1a+, CD207+ Langerhans cells (picture 6) in a heterogeneous inflammatory infiltrate. Biopsy of an osteolytic bone lesion or skin lesion is generally preferred.
●Diagnosis – LCH should be suspected in a patient of any age with an unexplained lytic bony lesion, skin rash, AVP-D, pituitary mass, or respiratory symptoms.
The diagnosis is based on pathologic evidence of LCH in the setting of suggestive clinical and imaging features.
Management – Management of Langerhans cell histiocytosis(LCH) is guided
•Single-system versus multisystem disease, Involvement of central nervous system (CNS) or a critical (“risk”) organ (bone marrow, liver, or spleen), Unifocal versus multifocal/extensive disease, Symptoms, Age – Preferred systemic treatment for children (≤20 years),.
Single-system disease
•Bone-only – Classification is described above.
-Single bone – Curettage provides tissue diagnosis and treatment. Radiation therapy (RT) may be used for selected adults, but not children
-Multiple bones – For ≥2 bone lesions, lesion ≥5 cm, femoral or vertebral involvement, or CNS-risk bone (ie, orbit, mastoid, temporal, sphenoid), treatment involves systemic therapy.
Surgery or RT may be added in selected cases.
•Skin-only – Topical steroids or mustard, or oral hydroxyurea, methotrexate, thalidomide, or lenalidomide can be effective.
Multisystem – Multisystem disease requires systemic therapy.
•Children – For initial systemic treatment of children with LCH, we suggest induction therapy with vinblastine plus prednisone (V-P), rather than other chemotherapy regimens or a targeted agent.
Treatment response guides further management; continuation therapy is 12 months for response to V-P.
-No CNS or risk organ involvement – For multisystem LCH in adults with no CNS or risk organ involvement, we suggest single-agent cytarabine or cladribine, rather than combination chemotherapy or a targeted agent
-CNS or risk organ involvement – For adults with BRAF V600E-mutated LCH and involvement of CNS or a risk organ, we suggest a BRAF inhibitor (eg, vemurafenib, dabrafenib), rather than systemic chemotherapy
Take home message- Among children, LCH is limited to one organ system in approximately 55 percent of cases and the remainder present with multisystem disease. Acute disseminated multisystem disease is most often seen in children <3 years, while involvement of a single organ is more common in older children and adults. Hence LCH should be suspected and evaluated for when a child especially when less than 3 years of age presents with an unexplained lytic bony lesion, skin rashes, AVP-D, pituitary mass, recurrent infections or respiratory symptoms.