蘭格罕細胞組織球增生症（Langerhans cell histiocytosis）是一種發生於兒童的腫瘤。雖然病理切片看起來是良性的，卻有惡性腫瘤般的臨床行為，也會侵犯其他組織。這種病雖然不治療會有致命危險，但絕大多數的病人經過適當治療都會完全康復。由於這種病與遺傳與感染無關，只要好好配合治療，都可以圓滿解決。
筆者記得當年考皮專時，錯的兩題之一就來自這個病，因此這次抱著訂正錯誤的心情完成了這個疾病的整理，希望對大家有幫助。
Carlo Gelmetti+鄭煜彬 整理
Introduction
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Histiocytoses包括那些細胞?
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Mononuclear phagocytes: monocytes(血)、macrophages(組織)、dendritic cells(組織)
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Monocytes的起源是哪裡的細胞?
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Pluripotential stem cells in bone marrow
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Histiocytes的本質是什麼?
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Connective tissue macrophages & dendritic cells
(nonlymphoid mononuclear cells)
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Dendritic cells是皮膚中的何種細胞變成的?
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Langerhans cells
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Dendritic cells和follicular dendritic cells來源的差異為何?
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Dendritic cells來自骨髓(hematopoietic origin)，follicular dendritic cells(位於淋巴結)來自結締組織(mesenchymal origin)
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Langerhans cells的型態、特殊胞器、細胞標記為何?
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型態： long cytoplasmic projections+ kidney-shaped nucleus.(腎形/咖啡豆的由來)
特殊胞器：Langerhans/ Birbeck granule(tennis racket)
標記：Langerin (CD207): 把抗原吃入Birbeck granules 並表現在外的受器
CD1a, S100, MHCII, CD4 and (adenosine triphosphatase, α-d-mannosidase, and peanut lectin)
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Langerhans cells遇到抗原會如何?
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移行到淋巴結，呈現抗原給naïve T cells
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Langerhans cells在骨髓的precursor還會變成哪些細胞(3)?
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Indeterminate cells: 不成熟的Lcs，缺Birbeck
Dermal dendritic cells: perivascular Lcs
Dermal macrophages:位於正常真皮, 發炎時增加
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Macrophage的細胞標記為?
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CD68
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Macrophage會分化成哪幾種giant cells(4)?
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Foreign body, epithelioid, Touton, & Langhans types.
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Langerhans Cell Histiocytosis(LCH/ histiocytosis X): Introduction, Epidemiology, Etiology and Pathogenesis
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LCH包括哪幾種歷史上的疾病?(4)
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Letterer–Siwe disease, Hand–Schüller–Christian disease, eosinophilic granuloma of bone, and Hashimoto–Pritzker disease(目前已捨棄此分類，但很多書籍仍會提到)
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LCH好發於那種族群?
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Male children, 1–3 y/o.
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Histiocytoses是指那些細胞的異常?
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Dendritic cells/ macrophages(mononuclear phagocyte system)增生與失控的活化。
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Histiocytoses有哪些候選的起因?
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viral infection, cytokine/adhesion molecules異常, gene缺陷。
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Histiocytoses屬於reactive or neoplastic disease?
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仍有爭議。
Reactive dz的理由(1)分化良好(2)和肉芽組織細胞相同 (3)會自動消失
Neoplasticdz的理由(1) 來自骨髓，有clonality (2) 有家族病例(3) 有染色體不穩定、p53異常(4) 合併myelodysplastic marrow.
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LCH: Clinical Findings
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Letterer–Siwe disease的急慢性、影響範圍、好發族群、良惡性如何?
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Acute, disseminated, multi-systemic form
Infants or newborns. (不治療會致命)
(等於Multisystem Disease, high/low risk groups)
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Hand–Schüller–Christian disease的急慢性、影響範圍、好發族群如何?
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Chronic, multifocal, single-systemic form
Childhood, progressive form
(等於Single-system Disease, Multiple site)
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Eosinophilic granuloma的急慢性、影響範圍、好發族群如何?
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Localized, benign form
(等於Single-system Disease, Single/Multiple site)
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Hashimoto–Pritzker disease的急慢性、影響範圍、好發族群如何?
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Localized,benign, self-healing form
Infants or newborns.
(等於Single-system Disease, Single site)
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目前學界如何分類?
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Single-system Disease：
Single site/localized: one bone, one lymph node, and skin
Multiple site: bones, lymph nodes
Multiple-system Disease: Disseminated disease
Low-risk group: skin, bone, lymph node, pituitary
High-risk group: hematopoietic system, lungs, liver, and spleen
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影響骨頭哪些部位時屬於CNS-risk lesions?
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頭骨前下方，即anterior & middle cranial fossae(不含頭蓋骨、posterior cranial fossa)
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LCH: Cutaneous Lesions
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LCH最早出現、最常見的病灶位於哪個器官?
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皮膚(因為Langerhans cell有強烈的epidermotropism)
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典型皮膚病灶的外觀為何?
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A 1–2 mm, translucent, rose-yellow, scaly papule(±vesicles, pustules, nodules, ulcer, crust)
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LCH皮膚病灶有哪四種types?
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Papules, vesiculopustules, xanthomatous, noduloulcerative
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皮膚的LCH最常位於何處?(3)
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Trunk
Skin fold(like intertrigo):retroauricular, axillary, & genital folds
Scalp( like seborrheic dermatitis or folliculitis, alopecia)
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LCH在那些地方容易融合成xanthomatous plaques?
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Medial chest, midback, and temporoparietal scalp (可參考Fitzpatrick's Dermatology in General Medicine圖147-4, C)
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LCH的nail change 包括哪些特徵?
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Nail fold/matrix
Paronychia→nail fold destruction→fragile lamina, longitudinal grooving
Nail bed
Subungual pustules→subungual hyperkeratosis, onycholysis, pigmented/purpuric striae
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Hashimoto–Pritzker disease有哪些別名?
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Self-healing LCH, self-healing reticulohistiocytosis, self-regressive cutaneous LCH(強調會自動消失)
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Hashimoto–Pritzker disease的臨床表現為何?
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Multiple/solitary firm, red to red–brown nodules→papulonodules with elevated borders+ulcer→ brown crusts→whitish atrophic scars
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Hashimoto–Pritzker disease類似那些疾病(2)?
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Infantile angiomas, chickenpox
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Hashimoto–Pritzker disease病程約多久?
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2–3 months (after birth)
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LCH的mucous membrane lesions有何特徵?
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Noduloulcerative lesions at perioral, gingival, perigenital, and perianal regions
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LCH發生於口腔會有那些症狀?
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嘴破：Pain, aphthae, gingival bleeding, candidiasis,
牙齒：teeth loss and premature eruption
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LCH: Non-cutaneous Lesions
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LCH會影響哪些器官?
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Bones, lungs, bone marrow, liver, spleen, and lymph nodes.
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皮膚之外LCH最常出現何處?
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Bone
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LCH易影響哪些骨頭?
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巨蝕(蝕骨)細胞多的骨頭(頭骨與受骨質疏鬆影響的骨頭)：skull, mandible, femur, pelvis, & spine
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LCH影響骨頭時易有那些症狀?
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Pain, tenderness, soft tissue swelling, deformation, fracture or medullar compression, bone marrow loss(三線都可能低)
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頭骨的那些部分常被LCH影響?
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Temporoparietal(map-like: osteolytic), maxillary, mastoid region
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LCH影響頭骨時會有那些疾病?
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CNS: 神經學症狀、seizures, ↑intracranial pressure
Eye: exophthalmos
腦垂腺：diabetes insipidus, growth retardation
Teeth: teeth loss & premature eruption
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骨頭病灶有哪些特徵時預後最好?
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Isolated bone lesions with beveled(斜角的) margins, without sclerosis(請參考下圖，表示病灶會和骨頭表面形成斜角)
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LCH常影響哪些人的肺部?
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The elderly
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LCH影響肺部有哪些症狀?
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Dyspnea, tachypnea with rib retraction, cough, cyanosis, and thoracic pain(S/S of Mediastinal compression and pneumothorax)
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LCH的胸部X光有什麼特徵?
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classic “honeycomb” appearance or amicronodular/reticulonodular pattern
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LCH對Pulmonary function tests結果有何影響?
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Restrictive lung disease(↓ pulmonary volume)
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肺部的LCH如何確診?
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Bronchoalveolar lavage中>5%是Langerhans cells
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LCH發生distension of the abdomen代表什麼問題?
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因Langerhans cell浸潤造成hepatosplenomegaly
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LCH對肝脾有什麼影響?
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Hepatosplenomegaly, liver fibrosis, biliary cirrhosis, liver failure
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LCH常影響哪處的淋巴結?
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Cervical lymph nodes(massive!)
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Aggressive form of LCH會有那些全身性症狀?
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Malaise, weight loss, failure to thrive, nausea, myalgia, arthralgia, and fever(全身性發炎的症狀)
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Laboratory Tests and Images
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LCH需做哪些實驗室檢查?
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腦垂腺：Electrolytes,UA, urine osmolality, Serum glucose level, TSH
肝臟：Liver function tests
骨髓：CBC, coagulation profile, T- & B-cell counts, T-cell subset analysis, Serum protein electrophoresis, ESR, CRP
其他檢查視受影響器官而定
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LCH需做哪些影像檢查?
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X ray, HRCT, gadolinium-enhanced MRI, bone scan, PET(做哪些部位視受影響器官而定)
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Histopathologic, Immunohistochemical, and Ultrastructural Evaluation | |
皮膚LCH不切片時如何檢查?
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Scraping early papules: 做cytologic examination
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LCH共通的特徵為何?
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Typical LCH cells: 4-5X larger than small lymphocytes, an irregular/vesiculated nucleus, kidney shaped, and abundant eosinophilic cytoplasm
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LCH有哪三種histologic patterns?
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(1) proliferative(early papules), (2) granulomatous(chronic stage)(3) xanthomatous(late lesions)
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Proliferative reaction的病理特徵為何?
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(1) epidermotropic lichenoid infiltration in the upper dermis(2) the epidermis is compressed, thinned, invaded, and destroyed (長太快，表皮被壓縮)
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Granulomatous reaction的病理特徵為何?
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(1) neutrophils, lymphocytes, and plasma cells(mixed infiltrate) (2)multinucleated giant cells(3) eosinophils
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Xanthomatous reaction的病理特徵為何?
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(1) foam cells (2) multinucleated giant cells (foreign-body type >Touton)(3) eosinophils
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Xanthomatous reaction在何種LCH的傳統分類會出現?
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Hand–Schüller–Christian disease(HSC)
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同一名病人會有幾種histologic patterns?
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1-3種都可能
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LCH的giant cells細胞質特徵為何?
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Acidophilic/ eosinophilic or a “ground glass” appearance
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LCH出現哪種標記代表有 good prognosis and limited disease?
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E-cadherin (frozen tissue samples優於paraffin-embedded tissue)
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Differential Diagnosis
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LCH須要和哪些疾病鑑別診斷?
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Papulosquamous: seborrheic dermatitis, guttate psoriasis, pityriasis lichenoides
Infections with vesicles/pustules: scabies, varicella, candidiasis
Infections with scales: tinea
Cell infiltration: non-LCH, hyperlipidemic xanthomatosis, urticaria pigmentosa, leukemia
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LCH發生於neonatal period常被誤診為哪些常見疾病?
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Eczema, miliaria, scabies, and varicella(因為脫屑紅疹合併水泡、膿泡)
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LCH在頭皮要和哪些疾病鑑別診斷?
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LCH在臉要和哪些疾病鑑別診斷?
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LCH在Intertriginous areas要和哪些疾病鑑別診斷?
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LCH在軀幹要和哪些疾病鑑別診斷?
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LCH的病灶偏紅時要和哪些疾病鑑別診斷?
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Infant: Diffuse neonatal hemangiomatosis, Blueberry muffin baby
Adult: Cherry angioma
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Complications
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LCH易有哪些感染?
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Candidiasis & dermatophytosis(especially LSD，因人類對真菌的免疫力來自Langerhans cells)
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LCH易伴隨哪些惡性腫瘤?
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Solid tumors (lung tumors, celiomesenteric neuroblastoma), lymphomas, or acute leukemia
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LCH和惡性腫瘤的因果關係為何?
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LCH可能只是惡性腫瘤造成的reactive process，或是LCH接受化放療後才產生惡性腫瘤
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Prognosis and Clinical Course
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哪些因子代表預後不佳(3)?
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an early-onset (< 2 y/o), extensive disease(lesions/ involved systems多), and organ failure
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哪些因子代表預後佳(5)?
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A small number of lesions, nodular lesions, prompt resolution, only one organ system (skin or bones), and adults
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病理特徵和預後有何關係?
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關係不大
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治療反應與預後有何關係?
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對一開始的治療反應越快/越好者預後較佳。
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xanthomatous lesions可能有何臨床意義?
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a disseminated aggressive form→a progressive chronic form(但許多人認為無關)
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哪些organ failure對預後有明顯影響?
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Liver, bone marrow(伴隨感染), and lung
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Diabetes insipidus出現與否對預後影響如何?
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沒有影響
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哪些身體檢查/實驗室數據出現時預後不好?
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Nail changes
Liver/spleen: jaundice, hepatic failure, hepatosplenomegaly(platelet & coagulation factor均降，易有purpura)
Bone marrow: thrombocytopenia, anemia
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Hypercalcemia在LCH代表哪兩種情形?
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Bone absorption or excess prostaglandin
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如何分辨neonatal/infant LCH是否為self-regressive cutaneous LCH?
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沒有辦法，只能持續觀察，看是否spontaneous regression/ multiorgan involvement。(可能的indicators：ulcer, necrosis, eosinophils, a solitary lesion, tendency to limb)
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Treatment: Single-system disease
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Single-system disease(bone/skin)的治療原則為何?
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Nonaggressive
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小孩皮膚的single-system disease的治療原則為何?
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Observation
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有哪些外用藥可用?
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Steroids (topical/IL), tacrolimus, imiquimod, nitrogen mustard(只限成人)
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全身性用藥有哪些選擇?
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Steroids, antimitotic drugs(chemical therapy),thalidomide, indomethacin
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非藥物治療有哪些選擇?
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Skin: PUVA/NBUVB/lacer; Bone: radiotherapy, curratage
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局部的periorificial eosinophilic granuloma可用何種方式治療?
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CO2 laser therapy(直接破壞)
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Children的bone lesions有哪些和成人相異的治療選擇?
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Oral indomethacin(1–2.5 mg/kg/day for 5-12months)
IL steroid: growth plate/teeth.(避免破壞正常結構)
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Treatment: Multiple-system disease
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Multiple-system disease最適合的化療為何?
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vinblastine±glucocorticoids(methylprednisolone)
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Multiple-system disease的ultiagent regimens包括哪些藥?
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Vincristine, cyclophosphamide, doxorubicin, and chlorambucil
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Refractory and advanced cases還可用哪些化療用藥?
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Cyclosporine, interferon-α2, and 2-chlorodeoxyadenosine (2-CdA, cladribine)
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承上，何種藥的效果較好?
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Cladribine(monotherapy即有良效)
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病人的哪些特性會影響Cladribine效果?
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Age：>2 y/o效果較好
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Cladribine會有哪些副作用?
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BMsuppression: transient neutropenia, T-cell suppression, absolute monocytopenia(抑制mononuclear phagocyte的結果)
Autoimmune hemolytic anemia, severe skin rashes
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Cladribine和預後有什麼關係?
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高風險病人若對cladribine效果不好，死亡率高
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