Langerhans’Caenldl histiocytosis: case reports literature review Robert J. Henry, DDS, MS EdwardA. Sweeney,DMD angerhans’ cell histiocytosis (LCH), formerly logic presence of Langerhans’ granules (also called knownas histiocytosis X, is one of a group of Birbeck’s granules).14 Birbeck’s granules are rod-shaped L poorly understood diseases of histiocytes. The ultrastructural organelles that may have a vesicular clinical spectrum of disease ranges from the chronic, portion giving it a so called "tennis racquet" appearance localized form to an acute leukemia-like disease with a under electron microscopy. 14-16 The presence of fatal outcome.Alfred Handwas the first to report a case Birbeck’ss,17 granules is pathognomonicof LCH. of histiocytosis in 1893.1Later, in 1941, Farber described Although the etiology of LCHhas not been estab- this condition when reporting the overlap amongdis- lished, several theories exist regarding this disease. eases that wouldlater be termed histiocytosis X.2,3 Since Pathologic Langerhans’ cells are thought to be derived that time, numerouscase reports have appeared in the from precursor cells or through alteration of normal dental literature, each having a diverse focus and using histiocytes.16, is The mechanismby whichthis prolifera- inconsistent terminology. The purpose of this review tion and accumulation takes place remains unknown. article is to enhance the understanding of LCHand to Viruses have been implicated as inciting agents in LCH report two cases of very young children demonstrating but their involvementremains theoretical, s, 16 Consider- skull and jaw lesions. able effort has been madeto assess the role of the im- LCHpreviously has been considered a reactive munesystem in the etiology of LCH.The bulk of evi- polyclonal disease of immuneregulation and not a true dence for this theory relates to abnormal thymic neoplasm. More recent evidence, however, has demon- biopsies of patients with LCH,particularly those with strated4-6 clonal proliferation, a key neoplastic feature. multisystem involvement. Findings such as thymus in- LCHafflicts young children primarily, some adoles- volvement and macrophageactivation in the childhood cents, and a few young adults. The classic presentation histiocytoses seem to support an immunesystem eti- involves7 lytic lesions of bone, particularly of the skull. ology.16,19, 20 However,the fact that there seemsto be The pathophysiology of LCHinvolves histiocytes -- no histologic difference betweenpatients with localized cells derived from monocytes of the granulocyte/mac- disease and those with multisystem involvement has rophage series after extravascular diapedesis. Histio- prompted someto suggest that the above findings may cytes function either as antigen-processingcells, phago- be secondary occurrences in the disease process21 cytic cells, or as antigen-presenting cells, s Langerhans’ Newer x-linked polymorphic DNAprobes have dem- cells are specialized histiocytes with immunefunctions onstrated that LCHis a highly variable monoclonal similar to other dendritic cells and macrophages. neoplastic disorder whose specific etiology remains Langerhans’ cells function immunologicallyby present- unestablished.6 ing antigen to T lymphocytes.9’ 10 In LCH,these cells undergo pathologic change and appear histologically Classification within an inflammatory background with a varied mi- The term histiocytosis X was a generic term devel- croscopic appearancethat necessitates additional analy- oped as a result of similarities in the pathophysiology sis in order to establish a diagnosis.TM 12 The numberof amongthe diseases of histiocytes as well as the shared Langerhans’ cells may be scarce and mixed with mac- clinical and histologic features. B, 22 Letterer-Siwe syn- rophages, lymphocytes,eosinophils, giant cells, neutro- drome was an earlier term used to describe an acute phils and plasma cells whenviewed under light micros- disseminated multisystem disease process of the reticu- copy. 13 Pathologic Langerhans’ cells are characterized loendothelial system that typically affected children by the presence of antigenic surface markers that react younger than 3 years of age. Hand-Sch~iller-Christian with a specific monoclonalantibody and by the histo- syndrome was used to describe an intermediate, PediatricDentistry- 18:1, 1996 AmericanAcademy of PediatricDentistry 11 chronic, disseminated form of the disease that gener- organomegaly, anemia, and diabetes insipidus. TM 22, 25 ally affected children older than 3. Theclassic triad as- Pituitary and pulmonary involvement also is common, sociated with Hand-Sch611er-Christian disease, which particularly in males.2° Thedifferential diagnosis relates often did not occur together, included exophthalmos, to the particular organ system involved and includes diabetes insipidus, and multiple bone lesions of the someof the following conditions: juvenile xanthogranu- skull, the second two largely due to sella turcica in- loma, chronic osteomyelitis, interstitial pneumonia,scle- volvement. The mildest form of diseases of histiocytes rosing cholangitis, dermatopathic lymphadenopathy, was termed eosinophilic granuloma and presented as odontogeniccysts, and periodontal disease.11, 22 solitary bonylesions of the ribs, pelvis, or mandibleand Oral involvementis a frequent finding. Ten to twenty usually afflicted older children and young adults. percent of initial symptomsare nonspecific oral findings Hashimoto-Pritzker syndromeis yet another term that that include: gingival enlargement, oral ulceration, was used to describe a congenital form of the disease mobility of teeth with alveolar expansion, jaw pain, fa- thatu, presented with deep subcutaneous skin lesions, cial swelling, as well as the classic intraosseous lesions 16 Numerousother terms also were utilized to describe ands, scoopedout radiolucencies of the alveolar process, diseases of histiocytes, which often confused the diag- 22, 26, 28. Children with multiple organ and bone lesions nosis. By 1987, it was widely established that the Langer- commonlyhave mandibular involvement with destruc- hans’ cell was pathognomonicof diseases of histiocytes tive radiolucencies, alveolar bone loss, and teeth that and that classification should nowbe determined on the appear to be "floating in air". 22 Mandibularlesions are cellular basis of the disease.21 TheInternational Histio- commonlyassociated with maxillary involvement, but cyte Society in 1987 established a classification of his- rarely is maxillary disease seen without mandibular tiocytoses into three groups as follows: radioluciencies I. Langerhans’cell histiocytosis Dental considerations II. Histiocytoses of mononuclear phagocytes other than Langerhans’ cells LCHis included in the differential diagnosis for chil- ~,17,21 dren presenting with advanced periodontal disease III. Malignanthistiocytic disorders2 and/or bone loss in the primary dentition. As men- Even though this classification does not reflect re- tioned, oral involvement is commonin LCHand may cent neoplastic evidence, it is universally accepted. The be the initial chief complaint. Other entities with simi- vast majority (99%) of patients are diagnosed with the lar presentations mayinclude: prepubertal periodonti- type I or II variety. 23 The diagnostic criteria for a de- tis, leukemia, neutropenia, hypophosphatasia, fibrous finitive diagnosis for type I (LCH)is the presence dysplasia, and Papillon-Lef6vre syndrome. Prepubertal Birbeck’s granules and is utilized by the International periodontitis is associated with the microorganismAc- Histiocyte Society for establishing a positive diagnosis tinobacillus actinomycetemcomitans(Aa) and mayresult of LCH27Amore recent method for LCHdiagnosis is in mobility and tooth loss by age 3. Differentiation from the positive immunostaining for $100 protein and the LCHis based on the limited gingival inflammation with CDlaantigen, s,lB,2° This review will focus on the type I marginal bone loss and demonstration of Aa from sub- variety, LCH. gingival culture. 29 Acute myelogenousleukemia (AML) may present with gingival hypertrophy and appear as Clinical presentation LCH.AML accounts for 15%of childhood leukemia and Approximately .200 new cases of LCHare diagnosed is distinguished from LCHby systemic symptomsthat each year in the US2~ Children from I to 15 years of age generally lead to confirmation of leukemia through are the most commonlyafflicted. The peak incidence is bone marrowaspiration. B° Various neutropenic disor- from 2 to 4 years of age, and a predilection for black ders also mayresult in significant gingival inflamma- patients has been reported21,24 Pathologic Langerhans’ tion and alveolar bone loss. Reducedneutrophil counts cells infiltrate various organs such as bone, skin, liver, may be the result of bone marrow production defects spleen, lung, and brain and mayresult in a variety of or neutrophil destruction and generally are associated clinical signs and symptomsdepending on the degree with systemic findings such as splenomegalyand infec- of individual organ infiltration and functional compro- tion.3~ Distinction from LCHis based on laboratory data. mise. The clinical course of LCHvaries considerably Hypophosphatasia is characterized by low serum alka- depending on the extent and numberof organs involved line phosphatase levels and excessive excretion of as well as the age of the patient at the time of diagnosis. phosphoethanolaminein the urine. The classic oral find- Bones of the skull, particularly orbital and temporal