랑게르한스 세포 조직구 증식증

[문형철]

깊은 이해를 가능케 한 현대과학, 현대의학에 감사하며

랑게르한스세포조직구증식증

[ Langerhans cell histiocytosis , ─細胞組織球增殖症 ]

단구·대식세포계의 조직구가 여러 장기에서 증식하여 증세를 일으키는 질환.

조직구증X라고도 한다. 단구·대식 세포계의 조직구가 증식을 일으켜 여러 장기에 침범하여 질환을 일으키는 증후군이다. 전신을 침범하는 질환으로 장기 침범의 정도에 따라 다양한 증세가 나타나는데, 하나 또는 여러 증세가 동시에 나타나기도 한다. 주로 피부·뼈·간·폐 ·골수 등에 침범한다. 나이가 어릴수록, 침범된 기관이 많을수록, 기관장애가 많을수록, 조직학적으로 섬유화나 괴사가 많을수록 그 예후가 좋지 않다. 원인은 확실하게 알려져 있지 않으나 면역학적인 측면에 의해 발생하는 것으로 추정된다. 

환자의 50％ 정도는 요붕증·성장장애·만성폐질환·지능장애·간경변·신경장애 등이 후유증으로 남을 수 있다. 또갑상선암, 급성 골수성백혈병, 림프종, 간암 등 2차성 악성 종양이 드물게 발생할 수도 있다. 뼈 주사 검사 등으로 병소를 확인할 수 있다. 그 증세는 다음과 같다. 

① 자주 나타나는 전신 증세로는 열·설사가 나타나는데 아이의 경우 보채며 기운이 없다. 소아 환자의 80％ 정도는 뼈에 병변이 나타나는데, 특히 두개골이 구멍뚫린 것 같거나 지도 모양의 병소가 보이는 등 두개골 이상이 가장 많이 나타난다. ② 척추뼈에 침범하면 척추 허탈을 일으킨다. ③ 장골에 침범하면 골절을 초래할 수 있다. ④ 피부 증세로는 습진과 비슷한 구진, 다발성 발진, 육아종성 궤양 등이 몸통이나 이마에 특징적으로 나타난다. 

⑤ 폐에 침범하면 빈호흡·호흡곤란·기침·폐기종·늑막삼출 등의 증세가 나타난다. ⑥ 간에 침범하면 간비종대·저단백혈증·부종·복수·과빌리루빈혈증 등의 증세가 나타난다. ⑦ 안구 주위의 이상조직이 증식하여 안구 돌출이 양측성으로 나타난다. ⑧ 뇌하수체와 시상하부가 침윤되면 요붕증, 성장장애, 사춘기 지연 현상 등이 나타난다. ⑨ 장에 침범하면 단백실조성장염을 일으킨다. 
 
치료는 뼈에만 병변이 나타난 경우에는 외과적인 절제나 단순한 소파술로도 효과가 있다. 자연적으로 치유되는 경우도 있고 방사선 조사에도 잘 반응하며 치료 시작 후 5개월 정도에는 현저한 효과가 나타난다. 뇌실질·뇌막·요붕증·폐·내장을 침범한 경우에도 방사선 치료가 효과가 있다. 그러나 뼈에 국한된 경우에도 다른 부위의 골격에 병소가 생길 가능성이 있고 재발하기도 한다. 

미만성인 경우에는 화학요법이 필요하다. 수혈·항생제 투여 등 일반적인 요법을 시행하면서 스테로이드·빈블라스틴·빈크리스틴·사이클로포스파마이드·메토트렉세이트와 같은 약을 단독 또는 복합적으로 투여한다. 그러나 이렇게 치료를 하여도 경과가 좋지 않은 경우가 많아서 골수이식을 하는 경우도 있다.

Langerhans cells are dendritic cells (antigen-presenting immune cells) of the skin andmucosa, and contain large organelles called Birbeck granules. They are present in all layers of the epidermis, but are most prominent in the stratum spinosum.^[2] They also occur in thepapillary dermis, particularly around blood vessels,^[2] as well as in the mucosa of the mouth,foreskin, and vagina.^[3] They can be found in other tissues, such as lymph nodes, particularly in association with the condition Langerhans cell histiocytosis (LCH).

Langerhans cell histiocytosis (LCH) is a rare disease involving clonal proliferation of Langerhans cells, abnormal cells deriving from bone marrow and capable of migrating from skin to lymph nodes. Clinically, its manifestations range from isolated bone lesions to multisystem disease. LCH is part of a group of clinical syndromes called histiocytoses, which are characterized by an abnormal proliferation of histiocytes (an archaic term for activated dendritic cells and macrophages). These diseases are related to other forms of abnormal proliferation of white blood cells, such asleukemias and lymphomas.

The disease has gone by several names, including Hand–Schüller–Christian disease, Abt-Letterer-Siwe disease, and histiocytosis X, until it was renamed in 1985 by the Histiocyte Society.^[1]

The disease spectrum results from clonal accumulation and proliferation of cells resembling the epidermal dendritic cells called Langerhans cells, sometimes calledDendritic Cell Histiocytosis. These cells in combination with lymphocytes, eosinophils, and normal histiocytes form typical LCH lesions that can be found in almost any organ.^[2]A similar set of diseases has been described in canine histiocytic diseases.

LCH is clinically divided into three groups: unifocal, multifocal unisystem, and multifocal multisystem.^[3]

Unifocal[edit]

Unifocal LCH, also called Eosinophilic Granuloma (an older term which is now known to be a misnomer), is a slowly progressing disease characterized by an expanding proliferation of Langerhans Cells in various bones. It is a monostotic (involving only one bone) or polyostotic (involving more than one bone) disease. It typically has no extraskeletal involvement, but rarely an identical lesion can be found in the skin, lungs, or stomach. When found in the lungs, it should be distinguished from Pulmonary Langerhans cell hystiocytosis—a special category of disease most commonly seen in adult smokers.^[4] This primary bone involvement helps to differentiate Eosinophilic Granuloma from other forms of Langerhans Cell Histiocytosis (Letterer-Siwe or Hand-Schüller-Christian variant.^[5]

Multifocal unisystem[edit]

Seen mostly in children, multifocal unisystem LCH is characterized by fever, bone lesions and diffuse eruptions, usually on the scalp and in the ear canals. 50% of cases involve the pituitary stalk, leading to diabetes insipidus. The triad of diabetes insipidus, exopthalmos, and lytic bone lesions is known as the Hand-Schüller-Christian triad. Peak onset is 2–10 years of age.

Multifocal multisystem[edit]

Multifocal multisystem LCH, also called Letterer-Siwe disease, is a rapidly progressing disease in which Langerhans Cell cells proliferate in many tissues. It is mostly seen in children under age 2, and the prognosis is poor: even with aggressive chemotherapy, the five-year survival is only 50%.^[6]

Pulmonary Langerhans Cell Histiocytosis (PLCH)[edit]

Pulmonary Langerhans Cell Histiocytosis (PLCH) is a unique form of LCH in that it occurs almost exclusively in cigarette smokers. It is now considered a form of smoking-related interstitial lung disease. Some patients recover completely after they stop smoking, but others develop long-term complications such as pulmonary fibrosis and pulmonary hypertension.^[7] PLCH patients, families, and caregivers are encouraged to join the NIH Rare Lung Diseases Consortium Contact Registry. This is a privacy protected site that provides up-to-date information for individuals interested in the latest scientific news, trials, and treatments related to rare lung diseases.

Preval‎ence[edit]

LCH usually affects children between 1 and 15 years old, with a peak incidence between 5 and 10 years of age. Among children under the age of 10, yearly incidence is thought to be 1 in 200,000;^[8] and in adults even rarer, in about 1 in 560,000.^[9] It has been reported in elderly but is vanishingly rare.^[10] It is most preval‎ent in Caucasians, and affects males twice as often as females.^[11] In other populations too the preval‎ence in males is slightly more than in females.^[12]

LCH is usually a sporadic and non-hereditary condition but familial clustering has been noted in limited number of cases. Hashimoto-Pritzker disease is a congenital self-healing variant of Hand-Schüller-Christian disease.^[13]

Pathophysiology[edit]

The pathogenesis of Langerhans cell histiocytosis (LCH) is a matter of debate. There are ongoing investigations to determine whether LCH is a reactive (non-cancerous) or neoplastic (cancerous) process. Arguments supporting the reactive nature of LCH include the occurrence of spontaneous remissions, the extensive secretion of multiple cytokines by dendritic cells and bystander-cells (a phenomenon known as cytokine storm) in the lesional tissue, favorable prognosis and relatively good survival rate in patients without organ dysfunction or risk organ involvement.^[14][15]

On the other hand, the infiltration of organs by monoclonal population of pathologic cells, and the successful treatment of subset of disseminated disease using chemotherapeutic regimens are all consistent with a neoplastic process.^[16][17][18] In addition, a demonstration, using X chromosome–linked DNA probes, of LCH as a monoclonal proliferation provided additional support for the neoplastic origin of this disease.^[19] While clonality is an important attribute of cancer, its presence does not prove that a proliferative process is neoplastic. Recurrent cytogenetic or genomic abnormalities would also be required to demonstrate convincingly that LCH is a malignancy.

Activating mutation of a protooncogen in the Raf family, the BRAF gene, was detected in 35 of 61 (57%) LCH biopsy samples with mutations being more common in patients younger than 10 years (76%) than in patients aged 10 years and older (44%).^[20] This study documented the first recurrent mutation in LCH samples. Two independent studies have confirmed this finding.^[21][22] Presence of this activating mutation could support the notion to characterize LCH as myeloproliferative disorder.

Signs and symptoms[edit]

CT scan showing LCH infiltratingperi-orbital tissue (arrowed).

A patient with Hand–Schüller–Christian disease which is a subtype of Langerhans Cell Histiocytosis.

LCH provokes a non-specific inflammatory response, which includes fever, lethargy, and weight loss. Organ involvement can also cause more specific symptoms.

• Bone: The most-frequently seen symptom in both unifocal and multifocal disease is painful bone swelling. The skull is most frequently affected, followed by the long bones of the upper extremities and flat bones. Infiltration in hands and feet is unusual. Osteolytic lesions can lead to pathological fractures.^[23]
• Skin: Commonly seen are a rash which varies from scaly erythematous lesions to red papules pronounced in intertriginous areas. Up to 80% of LCH patients have extensive eruptions on the scalp.
• Bone marrow: Pancytopenia with superadded infection usually implies a poor prognosis. Anemia can be due to a number of factors and does not necessarily imply bone marrow infiltration.
• Lymph node: Enlargement of the liver in 20%, spleen in 30% and lymph nodes in 50% of Histiocytosis cases.^[24]
• Endocrine glands: Hypothalamic pituitary axis commonly involved.^[25] Diabetes insipidus is most common.^[26] Anterior pituitary hormone deficiency is usually permanent.^[27]
• Lungs: some patients are asymptomatic, diagnosed incidentally because of lung nodules on radiographs; others suffer from chronic cough and shortness of breath.^[28]
• Less frequently gastrointestinal tract, central nervous system, and oral cavity.^[29]

Diagnosis[edit]

Micrograph showing Langerhans Cell Histiocytosis. H&E stain.

Diagnosis is confirmed histologically by tissue biopsy. Hematoxylin-eosin stain of biopsy slide will show features of Langerhans Cell e.g. distinct cell margin, pink granular cytoplasm. Presence of Birbeck granules on electron microscopy and immuno-cytochemical features e. g. CD1 positivity are more specific. Initially routine blood tests e.g. full blood count, liver function test, U&Es, bone profile are done to determine disease extent and rule out other causes. Radiology will show osteolytic bone lesions and damage to the lung. The latter may be evident in chest X-rays with micronodular and interstitial infiltrate in the mid and lower zone of lung, with sparing of the Costophrenic angle or honeycomb appearance in older lesions. MRI and CT may show infiltration in sella turcica. Assessment of endocrine function and bonemarrow biopsy are also performed when indicated.

• S-100 protein is expressed in a cytoplasmic pattern^[30][31]
• peanut agglutinin (PNA) is expressed on the cell surface and perinuclearly^[32][33]
• major histocompatibility (MHC) class II is expressed (because histiocytes are macrophages)
• CD1a^[30]
• langerin (CD207), a Langerhans Cell–restricted protein that induces the formation of Birbeck granulesand is constitutively associated with them, is a highly specific marker.^[34][35]

Treatment[edit]

Guidelines for management of patients up to 18 years with Langerhans cell histiocytosis has been suggested.^{[36][37][38][39]} Treatment is guided by extent of disease. Solitary bone lesion may be amenable through excision or limited radiation, dosage of 5-10 Gys for children, 24-30 Gys for adults. However systemic diseases often require chemotherapy. Use of systemic steroid is common, singly or adjunct to chemotherapy. Local steroid cream is applied to skin lesions. Endocrine deficiency often require lifelong supplement e.g. desmopressin for diabetes insipidus which can be applied as nasal drop. Chemotherapeutic agents such as alkylating agents, antimetabolites, vinca alkaloids either singly or in combination can lead to complete remission in diffuse disease.

Prognosis[edit]

Excellent for single-focus disease. With multi-focal disease 60% have a chronic course, 30% achieve remission and mortality is up to 10%.^[40]

In popular culture[edit]

In the 10th episode of season 3 of House entitled "Merry Little Christmas", the primary patient is a girl with dwarfism who has a variety of symptoms, who is ultimately diagnosed with Langerhans cell histiocytosis.^[41]

Nomenclature[edit]

Langerhans cell histiocytosis is occasionally misspelt as "Langerhan" or "Langerhan's" cell histiocytosis, even in authoritative textbooks. The name, however, originates back to its discoverer, Paul Langerhans.^[42]

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