Introduction
Langerhans cell Histiocytosis is a challenging disease and may be manifested in a variety of ways, ranging from a spontaneously regressing solitary lesion of bone to a multisystem life threatening disorder. Lichtenstein considered eosinophilic granuloma of bone, letterer-siwe disease and Hand Schuller- Christian disease as related manifestations of a single nosologic entity with a pathologic common denominator and proposed use of the term "histiocytosis X" to refer to them collectively. Some forms require little, if any treatment, and others need aggressive therapy. Various hypotheses have been explored - principally, whether LCH is a clonal disorder, a cytokine mediated cellular proliferation of Langerhans cells, or a reactive process following a viral infection.
What are histiocytes?
Histiocytes are tissue macrophages, components of the mononuclear phagocytic cell system. They proliferate in inflammatory states; chronic hemolytic disease, storage disorders, and in some cases a graft-versus-host disease or severe combined immuno-deficiency. Histiocytes also apparently proliferate autonomously or in response to unidentified stimuli in the syndromes of histiocytosis X and malignant histiocytosis.
Classification of histiocytosis syndromes Class I- Langerhans cell histiocytosis, Class II - Histiocytosis of mononuclear phagocytes other than Langerhans cells, a) Hemophagocytic lymphohistiocytosis b) Sinus histiocytosis with massive lymphadenopathy c) Juvenile Xanthogranuloma d) Reticulohistiocytoma. Class III - Malignant histiocytic disorders, a) Acute monocytic leukemia b) Malignant histiocytosis c) True histiocytic lymphoma.
Histiocytosis X as related manifestations of single entity
1. Eosinophilic granuloma of bone: localized disease in bone.
2. Hand Schuller Christian disease: subchronic or chronic disease with mostly the triad of "geographic skull", exophthalmous, and diabetes insipidus.
3. Letterer-siwe disease: acute or subacute disseminated disease.
Signs and symptoms
It can occur in persons ranging in age from newborn to elderly; the peak incidence occurs between 1 and 4 years. Bone Lesions: Found almost in all patients with restricted or extensive LCH. Painful swelling is the most common sign, skull being the bone affected most often. This is followed by long bones of the upper extremities and then flat bones. Radiograph typically reveals single or multiple irregularly margined lytic lesions. Skin: There are generally first signs of LCH and frequently become manifest as scaly, erythmatous, seborrhea like brown to red papules, especially pronounced in inter-triginous zones. Lymph nodes: Cervical lymph nodes are affected most often and may reach massive size. Bone marrow: Langerhans cells do not appear to be a normal constituent of the bone marrow, although other dendritic cells can be seen. Pancytopenia and/or leucoerythroblastic reaction caused by bone marrow dysfunction is usually associated with poor prognosis. Liver and Spleen: Hepatosplenomegaly is the indication of presence of organ involvement by LCH or it may indicate obstructive disease caused by enlarged nodes in the porta hepatis. It may also reflect kupffer cell hypertrophy and hyperplasia as an indicator of generalized activation of the cellular immune system. Lungs: Cough, tachypnea/dyspnea, cyanosis, pneumothorax, or pleural effusion are attributable to the disease rather than to superimposed infection. Increasing number of cysts form honeycomb lungs and in later stages large bullae. GIT: Vomiting, diarrhea with or without blood, and protein losing enteropathy. Malabsorption leads to failure to thrive. In most cases there is radiographic evidence of alternating dilated and stenotic segments in the small and large bowel. Thymus: Thymic enlargement may be obvious on chest Xray studies, but its role in LCH is debatable. Endocrine Glands: Diabetes insipidus, the most common endocrinopathy, can occur before, concurrently with or subsequently to the development of lesions in extracranial sites. Growth retardation resulting from anterior pituitary involvement and growth hormone deficiency is seen in some patients. CNS: Progressive ataxia, dysarthria, nystagmus, hyperreflexia, dysdiadochokinesia, dysphagia, blurred vision or cranial nerve deficits can develop, at times years after the original diagnosis of LCH.
Categorization of LCH patients 1. Restricted Langerhans cell histiocytosis, a) Biopsy proved skin rash without any other site of involvement, b) Monostotic lesions, with or without diabetes insipidus, adjacent lymph node involvement, or skin rash, c) Polyostotic lesions, consisting of lesions in several bones or more than two lesions in one bone, with or without diabetes insipidus, adjacent lymph node involvement, or skin rash. 2. Extensive Langerhans cell histiocytosis, a) Visceral organ involvement, with or without bone lesions, diabetes incipidus, adjacent lymphnode involvement, and/or skin rash, but without signs of organ dysfunction of any of the following organ systems: lung, liver, or hemopoietic system, b) Visceral organ involvement, with or without bone lesions, diabetes incipidus, adjacent lymphnode involvement, and/or skin rash, but with signs of organ dysfunction of any of the following organ systems: lung, liver, or hemopoietic system.
Diagnosis: - Hematoxilin-eosin-stained Langerhans cells typically have moderate amount of homogenous, pink, granular cytoplasm and distinct cell margins. Definitive diagnosis rests on demonstration of the immunocytochemical features of the Langerhans cell or on electron microscopic demonstration of Birbeck granules in the cytoplasm. Besides the presence of Birbeck granules, CD1a positivity is the other requirement for definitive diagnosis.
Therapy: - Age of the patient, the duration and tempo of the disorder, the extent of organ system involvement, and the degree of life-threatening impairment of hepatic, pulmonary, and hematopoietic functions. Systemic therapy is clearly indicated for multi focal or disseminated disease, where as local measures such as surgical curettage or limited radiation therapy may suffice for solitary lesions. Histiocytosis X is ordinarily a chronic disease, generally lasting for a period of 3 to 5 years, but some times continuing for 10 or more years. It is also liable to recur even after several years of apparent cure. Many agents can produce complete remission in histiocytosis X, including alkylating agents, antimetabolites, Vinca alkaloids, and corticosteroids. Their administration, as single agents and in combination, continuously or intermittently, is successful in producing improvement in the majority of affected children. Because of the comparative ease of administration and excellent tolerance, the Vinca alkaloids should be considered first line therapy for histiocytosis X.
Detailed regimen of therapy and follow up are beyond the scope of the article.
Recent Advances:- Although the cause is still unknown, investigative research in three major fields is on.
LCH: a neoplastic or a reactive clonal disorder?
LCH: a cytokine-mediated disorder?
LCH: a viral disease? |
