Langerhans’Caenldl : 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 . 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 -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- 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 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 -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 . 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 . 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 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, , 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- 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, , may be the result of production defects , 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 ings differ from LCHin that premature tooth loss gen- bones, the sella turcica, and mandible,as well as the ribs erally involves the mandibular primary incisors, which and pelvis are commonlyinvolved, y, 22 The relative fre- often have abnormally large pulp spaces.32 Fibrous dys- quency of organ system involvement is as follows: bone, plasia is a progressive expansile non-neoplastic bone 80%;skin, 60%;liver, spleen, lymphnodes, 33%;lungs, lesion that may result in primary tooth loss. Cheek 25%;orbit, 25%;and maxillofacial, 20%.s Initial physi- swelling produces the so-called "eyes-raised-to-heaven" cal findings often include skin rash, otitis media, fever, or cherub look that distinguishes this condition from

12 AmericanAcademy of PediatricDentistry PediatricDentistry - 18:1,1996 LCH.33 Papillon-Lef6vre syndrome is associated with LCH,who have an excellent prognosis, s Treatment of marked destruction of alveolar bone with premature single system disease is generally benign and may primary tooth loss. This condition is differentiated from include observation for spontaneous regression, LCHby the associated hyperkeratosis of the palms and radiation, surgical curettage, or intralesional infiltra- soles. B4 This brief list includes conditions commonly tion41 with steroids. included in the differential diagnosis for patients with Protocols for young children with disseminated dis- destructive periodontal disease and tooth loss in the ease are similar to those for childhood leukemia and primary dentition. employ chemotherapeutic agents such as The long-term dentofacial development of patients sulfate, vincristine sulfate, prednisone, methotrexate, treated for LCHhas not been reported. Sequelae for ,and 6-mercaptopurine.S,24, 41, 43 The patients with childhood leukemia are knownand cor- use of cyclosporineis also thought to be effective in com- relate to LCHpatients undergoing similar treatment bination therapy for children with milder forms of protocols. Chemoradiation’s influences on craniofacial LCH.s Although no chemotherapeutic regimen has been growth and dental development are age related and demonstrated as superior, evidence suggests that most significant for children younger than 5 years of , which is knownto be effective for malignan- age. 35 The incidence of salivary gland dysfunction, cies of / macrophageorigin, maybeuseful in enamel dysplasias, tooth / root agenesis, and alteration patients with vital organ involvement or those not re- of mandibular growth is greater in patients receiving spondingto moreconservative treatment, s, 41, 43, 44 combined radiation and .B6, 37 The long- These newer combination therapies are being recom- term dental managementof LCHpatients begins with mendedfor front-line therapy only for the severe mul- a review of the specific disease, location, and the thera- tisystem form of LCH.Significant morbidity, such as peutic protocol the child received. Displaced teeth and / second tumor development, may be associated with or developingfollicles with altered eruption patterns are aggressive therapy and should be reserved for patients commonfor children with a history of oral involve- with a poor prognosis and those with disease progres- ment.2s Parents should be aware of the possibility of sion while undergoingconservative therapy.41, 43 localized enamel defects, agenesis of roots and/or Young patients with disseminated LCHare at in- crowns, altered dentoalveolar growth, as well as ortho- creased risk for disease progression because of the con- pedic sequelae for those having undergonecraniofacial cern over radiation effects and reluctance to employthis radiation therapy. treatment modality in the younger age groups.41 Radia- tion therapy in children youngerthan 6 years of age has Medical managementand prognosisof LCH been associated with altered growth, adverse intellectual Prognostic indicators for LCHinclude: 1) age -- chil- effects, and arrested dental developmentas well as sec- dren less than 2 years generally have disseminated dis- ond tumor development.22 Radiation treatment of 600- ease and a poorer prognosis; 2) numberof sites involved 1500 cG in 200-cGdaily fractions is highly effective in -- multisystem disease carries a poorer prognosis; and children beyondthe age of such concerns or in solitary 3) organ dysfunction, which, if present, also results in lesions22,45 in very critical areas, suchas sella turcica. diminished outlook21,38Liver dysfunction at the time of diagnosis (indicated by hypoproteinemia or hyperbi- Case reports lirubinemia) as well as hemopoietic system involvement Case 1 (indicated by thrombocytopenia, neutropenia, and ane- A 15-month-old Hispanic female presented to mia) both are associated with a poorer outlook.24’ 39 The Medical Center Hospital emergency room in May of prognosis is particularly grave for children younger 1993 with chief complaints of diarrhea, diminished ap- than 2 years old who present with multiple organ in- petite, and refusal to walk because of ankle swelling. volvementand associated dysfunction.4° Mortality rates Clinical examination revealed significant hepatosple- for this group exceed 60%.6, 41 Second tumors such as nomegaly. The recent medical history consisted of ane- leukemia or thyroid carcinoma are potential complica- mia and recurrent otitis media. After medical evalua- tions for long-term suvivors.42 Older children with mul- tion, a provisional diagnosis of tisystem disease at presentation also demonstrate con- was made. This diagnosis was based largely on results siderable morbidity. Manydevelop chronic problems of liver and bone marrow aspiration. Lab such as liver dysfunction, diabetes insipidus, chronic values were as follows: WBC8,000/mm 3, Hb 8.2 g/dL, otitis, and learning disabilities that stem from the vari- MCV89.4 ~ g/dL, and platelets 145,000/mm3, The fact ous treatment modalities.", 24 that Birbeck’s granules had not been identified from the The heterogeneity of disease in patients with LCH initial liver biopsy, although not unusual, led to has made development of specific treatment protocols the provisional malignant histiocytosis diagnosis. The difficult. Often the particular therapeutic approach has child was placed on a regimen consisting of methylpred- little influence on the prognosis for infants presenting nisolone (10 kg/day) and vinblastine (0.1 mg/kg with disseminated disease, whohave a relatively poor weekly intervals). She was transferred to Santa Rosa prognosis, or those presenting with the mild form of Children’s Hospital.

PediatricDentistry- 18:1, 1996 AmericanAcademy of PediatricDentistry 13 Fig 1. CT scan of 16-month-old female that demonstrates right temporal bone involvement as well as expansion of the left alveolus surrounding the maxillary left primary first molar.

Fig 2. Periapical radiograph of this 27-month-old's maxillary left primary second molar indicates abnormal pulpal architecture and root anatomy. Dental examination revealed a soft tissue lesion in the maxillary left primary first molar area that seemed to surround the erupting first molar crown. A gingival biopsy was obtained and the involved tooth was ex- tracted. Electron microscopy revealed Birbeck's gran- ules from histiocytic cells of the oral lesion. Based on this information it was later determined that Birbeck's gran- ules also were present on a few sections of the original liver biopsy. CT scan of the skull confirmed the maxil- lary left posterior alveolar defect as well as involvement of the petrous portion of the right temporal bone (Fig 1). From these results, the diagnosis was changed to the LCH form of histiocytosis, which was important be- cause it has a significantly different prognosis than that of malignant histiocytosis. The child was continued on oral prednisone and vinblastine and rapid improvement of the organomegaly was observed. Radiation was given Fig 3. This lateral radiograph (A) demonstrates relapse of LCH in a 17-month-old male. Classic multiple radiolucent to the petrous bone using a linear accelerator. lesions of the skull are noted. Chemotherapy was res- At age 2.3 years — 12 months after the initial diag- umed and the patient followed with radiographic nosis — further intraoral pathology was noted. The resolution noted at age 3.1 years (B). The patient again maxillary disease resulted in alveolar bone destruction relapsed with significant radiographic changes (C) diag- with malformation of the maxillary left primary second nosed just 4 months after the previous film, age 3.5 years. molar as demonstrated on the periapical radiograph

14 American Academy ofPediatric Dentistry Pediatric Dentistry - 18:1, 1996 (Fig 2). The maxillary left primary second molar extrac- were found during the periodic dental evaluations from tion was accomplished during conscious sedation us- January 1994 to the time of this report. The patient con- ing midazolam and local anesthesia. Three months later, tinues on maintenance chemotherapy with vinblastine it became apparent radiographically and by physical awaiting radiographic resolution of the cranial lesions. examination that the lesion in the petrous portion of the He is currently in remission, 5.4 years after the initial temporal bone had not resolved and indeed seemed diagnosis, but with a guarded long-term prognosis. active. An excisional biopsy and mastoidectomy re- The presence of destructive periodontal disease vealed significant necrosis and residual disease. After and/or tooth loss during the primary dentition should healing, radiation with an additional 1000 cG was ad- alert the practitioner to the possibility of serious sys- ministered to the petrous bone. The patient has been temic disease. LCH is included in the differential diag- asymptomatic since that time (15 months). Mainte- nosis of such a condition, which may be the patients' nance therapy with dexamethasone and vinblastine is initial chief complaint. The diagnosis for LCH may be anticipated to continue until radiographic resolution of confirmed through immunofluorscence for the SI 00 the cranial lesions has occurred. protein (Fig 5). Sufficient gingival biopsy material, with or without tooth extraction, should be obtained for that Case 2 purpose. The two cases presented both had oral in- A 2-month-old male was referred to Santa Rosa volvement but a quite different presentation at the time Children's Hospital in September 1990 by his pediatri- of diagnosis. The first case involved maxillary involve- cian because of fever, anemia, and splenomegaly. The ment without mandibular association, which is rare. In family history revealed a maternal cousin had died of the second case, the impressive mandibular radiolucen- "histiocytosis X" in childhood. Physical examination cies were evident, yet the intraoral soft tissues were un- identified multiple small, flaky skin and scalp lesions. remarkable with no apparent dental involvement. The abdomen was enlarged with no lymphadenopathy noted. Lab values were as follows: WBC 10,600/mm3, Hb 9.1 g/dL, MCV 77 pg/dL, and platelets 137,000/ mm3. A diagnosis of Langerhans' cell histiocytosis was made based on skin biopsy of the abdomen and needle biopsy of the liver, both suggestive of LCH. No os- teolytic lesions were seen on a skeletal survey. Therapy was begun with six courses of intravenous etoposide and methylprednisolone and continued for 12 months. In December 1991, 3 months after discontinuation of therapy, the child presented with fever, otitis and skin rash. A skeletal survey demonstrated multiple lytic le- sion of the frontal and parietal bones (Fig 3A). Weekly chemotherapy was resumed using intravenous vinblas- tine and was continued until September of 1993. The Fig 4. Panoramic radiograph of the patient at 3.6 years of patient was followed with resolution noted radio- age depicts mandibular involvement often associated graphically (Fig 3B). with LCH. The numerous lytic lesions are apparent. In January 1994 the patient again relapsed and im- pressive lytic lesions were evident radiographically (Fig 3C). These as well as rib lesions were not present 4 months earlier. The panoramic radiograph of this now 3.6-year-old child demonstrates the multiple mandibu- lar lesions associated with LCH (Fig 4). Intravenous chemotherapy with vinblastine was reinstituted along with cranial radiation SOOcG to the base of the skull. The tumor board's decision was to avoid mandibular radia- tion. The concern related to diminished intellectual de- velopment and the adverse growth effects to the max- illa and mandible associated with cranial radiation in children of this age. Radiographic surveys in December 1994 revealed a marked improvement of the lytic lesions of the skull Fig 5. This gingival biopsy exemplifies the immuno- and mandible compared with those taken at the time of histochemical staining of LCH cells for S-100 protein relapse in early 1994. Despite the major mandibular in- (original magnification 25x). The reaction product is volvement, no periodontal involvement, mobility of diagnostic of LCH since the cytoplasm of normal teeth, alveolar expansion, jaw pain or facial swelling histiocytes does not stain in this manner.

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16 American Academyof Pediatric Dentistry Pediatric Dentistry - 18:1, 1996