Langerhans cell histiocytosis differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

Overview

Langerhans cell histiocytosis must be differentiated from other diseases that cause bone pain, cutaneous lesions, hepatosplenomegaly, and palpable lymph nodes, such as cat-scratch disease, mastocytosis, sinus histiocytosis with massive lymphadenopathy.

Differentiating Langerhans cell histiocytosis from other Diseases

• Langerhans cell histiocytosis must be differentiated from other diseases that cause bone pain, cutaneous lesions, hepatosplenomegaly, and palpable lymph nodes, such as:

• Lymphoma
• Mastocytosis
• Cat-scratch disease
• Hypersensitivity reaction
• Acrodermatitis enteropathica
• Erdheim-Chester disease
• Wiskott-Aldrich syndrome
• Seborrheic dermatitis
• Sinus histiocytosis with massive lymphadenopathy
• Kimura disease
• Eosinophilic pustular folliculitis
• Erythema toxicum neonatorum
• Acropustulosis of infancy

Disease	Rash Characteristics	Signs and Symptoms	Associated Conditions	Images
Cutaneous T cell lymphoma/Mycosis fungoides	Premycotic phase: A scaly, red rash in areas of the body that usually are not exposed to the sun. This rash does not cause symptoms and may last for months or years. Patch phase: Thin, erythematous, eczema-like rash. Plaque phase: Small raised bumps (papules) or hardened lesions on the skin, which may be erythematous. Tumor phase: Tumors form on the skin. Infection secondary to ulcers.	Epidermal atrophy or poikiloderma Generalized itching (pruritus) Pain in the affected area of the skin Insomnia Red (erythematous) patches scattered over the skin of the trunk and the extremities Tumor-like lobulated outgrowths form on the skin in the latter phase of the disease Weight loss Lymphadenopathy Malaise and fatigue Anemia May progress to Sezary syndrome (skin involvement plus hematogenous dissemination)	Sezary syndrome
Pityriasis rosea	Pink or salmon in color, which may be scaly; referred to as "herald patch" Oval shape Long axis oriented along the cleavage lines Distributed on the trunk and proximal extremities Squamous marginal collarette and a “fir-tree” or “Christmas tree” distribution on posterior trunk Secondary to viral infections Resolves spontaneously after 6-8 weeks	Preceded by a prodrome of: Sore throat Gastrointestinal disturbance Fever Arthralgia	Infection by any of the following: HHV-6 HHV-7 HHV-8
Pityriasis lichenoides chronica	Recurrent lesions are usually less evenly scattered than in cases of psoriasis Brownish red or orange-brown in color Lesions are capped by a single detachable, opaque, mica-like scale Often leave hypopigmented macules	High fever Malaise Myalgias Paraesthesia Pruritus	Infection by any of the following: Epstein-Barr virus (EBV) Toxoplasma gondii Human immunodeficiency virus (HIV)
Nummular dermatitis	Multiple coin-shaped eczematous lesions Commonly affecting the extremities (lower>upper) and trunk May ooze fluid and become dry and crusty	Often appears after a skin injury, such as a burn, abrasion (from friction), or insect bite Lesions commonly relapse after occasional remission or may persist for long periods Pruritus	Associated with: Dry skin Emotional stress Allergens (rubber chemicals, formaldehyde, neomycin, chrome, mercury, and nickel) Staphylococcus infection Seasonal variation Alcohol Drugs Atopy
Secondary syphilis	Round, coppery, red colored lesions on palms and soles Papules with collarette of scales	Fever Generalized lymphadenopathy Sore throat Patchy hair loss Headache Weight loss Myalgia Fatigue	Associated with: Condylomata lata Corona verinata Positive VDRL test
Bowen’s disease	Erythematous, small, scaly plaque, which enlarges erratically over time Scale is usually yellow or white and it is easily detachable without any bleeding Well-defined margins	Pruritus Pain Bleeding lesions	Associated with: Erythroplasia of Queyrat (Bowen's disease of the penis) Squamous cell carcinoma Solar radiation and ultraviolet (UV) exposure Radiotherapy Immunosuppression Arsenic exposure Human papilloma virus (HPV) type 16 Merkel cell polyomavirus Sjögren’s syndrome
Exanthematous pustulosis	Numerous small, primarily non-follicular, sterile pustules, arising within large areas of edematous erythema	Fever Leukocytosis Intracorneal, subcorneal, and/or intraepidermal pustules with papillary dermal edema containing neutrophils and eosinophils	Associated with: Antibiotics (penicillins, sulfonamides, tetracyclines) Carbamazepine Calcium channel blockers (Diltiazem) Hydroxychloroquine
Hypertrophic lichen planus	Classically involves shin and ankles and is characterized by hyperkeratotic plaques and nodules covered by a scale Lesions may transform into hyperkeratotic thickened, elevated, purplish or reddish plaques and nodules	Chronic pruritus Scaling May be asymptomatic	Associated with Hepatitis C virus infection
Sneddon–Wilkinson disease	Flaccid pustules that are often generalized and have a tendency to involve the flexural areas Annular configuration	Pruritus May be asymptomatic	Associated with: Monoclonal gammopathy, usually an IgA paraproteinemia Crohn's disease Osteomyelitis Adalimumab
Small plaque parapsoriasis	Erythematous plaques with fine scaly surface May present with elongated, finger-like patches Symmetrical distribution on the flanks Known as digitate dermatosis	Lesions may be asymptomatic May be mildly pruritic May fade or disappear after sun exposure during the summer season, but typically recur during the winter	May progress to mycosis fungoides
Intertrigo	Red and fleshy looking lesion in skin folds Itching Oozing May be sore	Pruritus Musty odor	Associated with: Infections (Fungal, bacterial, viral) Allergies Diabetes Obesity
Langerhans cell histiocytosis	Scaling and crusting of scalp	Pathological fractures Visceromegaly (hepatomegaly, spleenomegaly) Chronic cough Dyspnea Lymphadenopathy	Associated with: Diabetes insipidus Pancytopenia
Tinea manuum/pedum/capitis	Scaling, flaking, and sometimes blistering of the affected areas Hair loss with a black dot on scalp in case of tinea capitis	Pruritus KOH preparation of the lesions confirms fungal infection	Associated with: Diabetes Immunosupression Intimate contact with infected person May lead to asthma exacerbation
Seborrheic dermatitis	Papulosquamous, scaly, flaky, itchy, and red rash found particularly at sebaceous gland-rich areas of the body	Pruritus	Associated with: AIDS Stress Fungal infection Fatigue Sleep deprivation Change of season Parkinson's disease Biotin deficiency

Langerhans cell histiocytosis must be differentiated from other diseases that cause bone pain, edema, and erythema.

Disease	Findings
Soft tissue infection (Commonly cellulitis)	History of skin warmness, swelling and erythema. Bone probing is the definite way to differentiate them.
Osteonecrosis (Avascular necrosis of bone)	Previous history of trauma, radiation, use of steroids or biphosphonates are suggestive to differentiate osteonecrosis from ostemyelitis. MRI is diagnostic.
Charcot joint	Patients with Charcot joint commonly develop skin ulcerations that can in turn lead to secondary osteomyelitis. Contrast-enhanced MRI may be diagnostically useful if it shows a sinus tract, replacement of soft tissue fat, a fluid collection, or extensive marrow abnormalities. Bone biopsy is the definitive diagnostic modality.
Bone tumors	May present with local pain and radiographic changes consistent with osteomyelitis. Tumors most likely to mimic osteomyelitis are osteoid osteomas and chondroblastomas that produce small, round, radiolucent lesions on radiographs.
Gout	Gout presents with joint pain and swelling. Joint aspiration and crystals in synovial fluid is diagnostic for gout.
SAPHO syndrome (Synovitis, acne, pustulosis, hyperostosis, and osteitis)	SAPHO syndrome consists of a wide spectrum of neutrophilic dermatosis associated with aseptic osteoarticular lesions. It can mimic osteomyelitis in patients who lack the characteristic findings of pustulosis and synovitis. The diagnosis is established via clinical manifestations; bone culture is sterile in the setting of osteitis.
Sarcoidosis	It involves most frequently the pulmonary parenchyma and mediastinal lymph nodes, but any organ system can be affected. Bone involvement is often bilateral and bones commonly affected include the middle and distal phalanges (producing “sausage finger”), wrist, skull, vertebral column, and long bones.
Langerhans' cell histiocytosis	The disease usually manifests in the skeleton and solitary bone lesions are encountered twice as often as multiple bone lesions. The tumours can develop in any bone, but most commonly originate in the skull and jaw, followed by vertebral bodies, ribs, pelvis, and long bones.

Differential diagnosis

Langerhans cell histiocytosis must be differentiated from other cavitary lung lesions.

Causes of lung cavities	Differentiating Features	Differentiating radiological findings	Diagnosis confirmation
Malignancy (Primary lung cancer)	Elderly male or female Chronic smokers Presents with a low-grade fever, absence of leukocytosis, systemic complaints weight loss, fatigue Absence of factors that predispose to gastric content aspiration, no response to antibiotics within 10 days Hemoptysis is commonly associated with bronchogenic carcinoma	A coin-shaped lesion with thick wall(>15mm) is seen on CXR with less ground glass opacities Bronchoalveolar lavage cytology shows malignant cells	Biopsy of lung
Pulmonary Tuberculosis	Mostly in endemic areas Symptoms include productive cough, night sweats, fever, and weight loss	CXR and CT demonstrates cavities in the upper lobe of the lung	Sputum smear positive for acid-fast bacilli and nucleic acid amplification tests (NAAT) is used on sputum or any sterile fluid for rapid diagnosis and is positive for mycobacteria.
Necrotizing Pneumonia	Any age group Acute, fulminant life threating complication of prior infection >100.4 °F fever, with hemodynamic instability Worsening pneumonia-like symptoms	CXR demonstrates multiple cavitary lesions Pleural effusion and empyema are common findings	CBC is positive for causative organism
Loculated empyema	Children and elderly are at risk Pleuritic chest pain, dry cough, fever with chills Dullness to percussion decreased breath sounds, and reduced vocal resonance on examination	Empyema appears lenticular in shape and has a thin wall with smooth luminal margins	Thoracocentesis
Granulomatosis with polyangiitis (Wegener's)	Women are more commonly effected than man Kidneys are also involved Upper respiratory tract symptoms, perforation of nasal septum, chronic sinusitis, otitis media, mastoiditis. Lower respiratory tract symptoms (e.g. hemoptysis, cough, dyspnea) Renal symptoms, hematuria, red cell casts	Pulmonary nodules with cavities and infiltrates are a frequent manifestation on CXR	Positive for P-ANCA Biopsy of the tissue involved shows necrotizing granulomas
Rheumatoid nodule	Elderly females of 40-50 age group Manifestation of rheumatoid arthritis Presents with other systemic symptoms including symmetric arthritis of the small joints of the hands and feet with morning stiffness are common manifestations	Pulmonary nodules with cavitation are located in the upper lobe (Caplan syndrome) on X-ray	Positive for both rheumatoid factor and anticyclic citrullinated peptide antibody.
Sarcoidosis	More common in African-American females Often asymptomatic except for enlarged lymph nodes Associated with restrictive lung disease Erythema nodosum Lupus pernio (skin lesions on face resembling lupus) Bell palsy Epithelioid granulomas containing microscopic Schaumann and asteroid bodies	On CXR bilateral adenopathy and coarse reticular opacities are seen CT of the chest demonstrates extensive hilar and mediastinal adenopathy Additional findings on CT include fibrosis (honeycomb, linear, or associated with bronchial distortion), pleural thickening, and ground-glass opacities.	Biopsy of lung shows non-caseating granuloma
Bronchiolitis obliterans (Cryptogenic organizing pneumonia)	Rare condition and mimics asthma, pneumonia and emphysema It is caused by drug or toxin exposure, autoimmune diseases, viral infections, or radiation injury People working in industries are at high risk Presents with fever, cough, wheezing, and shortness of breath over weeks to months	Common appearance on CT is patchy consolidation,often accompanied by ground-glass opacities and nodules.	Biopsy of the lung Pulmonary function tests demonstrate low fev1/fvc
Langerhans cell Histiocytosis	Exclusively afflicts smokers, with a peak age of onset of between 20 and 40 years Clinical presentation varies, but symptoms generally include months of dry cough, fever, night sweats, and weight loss Skin is involved in 80% of the cases, scaly erythematous rash is typical	Thin-walled cystic cavities are the usual radiographic manifestation, observed in over 50% of patients by either CXR or CT scans.	Biopsy of the lung