Pediatrícs

Original article

Craniofacial and skull base findings in in pediatric patients

Daniel Forlino (1), Patricio Manzone (2), Matilde Cristina Gomel (2), María Beatriz Nicoli (2), Cesy Pedrini (3)

Resumen Abstract La histiocitosis de células de Langerhans (HCL) es una Craniofacial and skull base findings in Langerhans entidad poco frecuente, con una incidencia anual de cell histiocytosis in pediatric patients. 2,6 a 5,4 por millón de niños en la población general. Langerhans cell histiocytosis (CLH) is an uncommon entity, Tiene manifestaciones óseas (lesiones osteolíticas soli- of unknown etiology, with an incidence of 2.6 at 5.4 per tarias o múltiples en huesos planos, largos e irregula- 1,000,000 children/year in the general population. It may res) o multisistémicas. have bone manifestations (solitary or multiple osteolytic Se describen los hallazgos imagenológicos de una serie lesions in flat, long and irregular bones) or multiorgan man- retrospectiva de 17 pacientes pediátricos, de 1 a 12 ifestations. We report the radiological findings in retrospec- años de edad, con histiocitosis de células de tive series of 17 pediatric patients aged 1 to 12 years old, Langerhans en el macizo facial y la base del cráneo. with CLH in craniofacial and skull base. Las manifestaciones incluyeron lesiones osteolíticas y Radiological findings included osteolytic and soft tissue masa de partes blandas, que ocupaban las cavidades lesions occupying the orbit, sinuses, tympanic cavity and adyacentes, como la órbita, los senos paranasales, la mastoid. In the mandible, reabsorption of the alveolar ridge caja timpánica y la mastoides. En el maxilar inferior with the appearance of floating teeth was observed. puede provocar reabsorción del reborde alveolar con The anatomical complexity of the area studied required eval- apariencia de dientes flotantes. uation by CT and MRI with contrast. La complejidad anatómica del área de estudio requie- LCH disease should be considered in the differential diag- re su valoración mediante tomografía computada (TC) noses of craniofacial and skull base lesions, especially in y resonancia magnética (RM) con contraste. pediatric patients. La histiocitosis de células de Langerhans debe conside- Keywords. Histiocytosis. Pediatric. Craniofacial. Skull rarse dentro de los diagnósticos diferenciales de las base. lesiones del macizo facial y la base del cráneo, especial- mente en pacientes pediátricos. Palabras clave. Histiocitosis. Pediatría. Macizo facial. Base del cráneo.

INTRODUCTION LCH affects the facial bones and base of the skull in 6% to 27% of patients (7-14). Langerhans cells histiocytosis (LCH), formerly known In a review of bone histiocytosis performed in 480 as Histiocytosis X, is a rare disorder of unknown etio- patients, the skull and maxilofacial bones were affec- logy with an annual incidence of 2.6 to 5.4 cases per ted in 7.5% of cases, except for the jaw, which had an 1.000.000 children in the general population, with incidence of 0.2% (7). In addition, in a review perfor- peak incidence occurring in children between 1 and 3 med at the Mayo Clinic in 263 patients (including chil- years old. It may occur at any age with a slight male dren and adults), the rate of involvement was 15% for predominance (1-8). Patients may present with soli- the jaw, 6.8% for the orbit, 6% for the maxilla and 27% tary or multiple bone lesions, or with multisystem for the skull, without differentiating between the cal- involvement. Solitary lesions have a good prognosis varia and the skull base (8). In an additional review of and may even resolve spontaneously. The presence of 100 patients with cranial and intracranial manifesta- multiple or multisystem lesions may have a severe tions of LCH, lesions occurred in the mandible in 15% and even lethal course. of cases, in the skull base (temporal and sphenoid Favara et al. proposed a new classification, based on bone) in 13% of cases and in the maxilla in 8% (10). the origin of histiocytic disorders and their biological Our aim has been to retrospectively review the loca- behavior (9) (Chart 1). tion and characteristics of the lesions caused by LCH

(1) Diagnóstico por Resonancia Magnética S.A Recibido: octubre 2011; aceptado: octubre 2012 (1) Cátedra de Diagnóstico por Imágenes, Facultad de Medicina, UNNE. Received: october 2011; accepted: october 2012 (2) Hospital Pediátrico Avelino Castelán, Resistencia, Chaco. ©SAR (3) Hospital Pediátrico Juan Pablo II, Corrientes, Corrientes. doi: 10.7811/rarv77n1a07 Correspondencia: Dr. Daniel Forlino - [email protected]

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in maxillofacial bones, skull base, and calvaria, to ment, 2 had solitary bone lesions and 15 had multiple include this condition into differential diagnoses in bone lesions; 9 (52%) had multisystem involvement. pediatric patients. Radiologically, lesions were osteolytic. In the acute phase, margins were smooth, poorly defined, non- sclerotic and of beveled appearance, and in the chro- MATERIALS AND METHODS nic phase (or after treatment) margins were sclerotic and acquired a geographic appearance. We rarely We performed a retrospective review of imaging stu- observed small bone isolated fragments within the dies obtained in 17 pediatric patients (11 boys and 6 area of osteolysis, mimicking areas of bone sequestra girls) with histopathology diagnosis of LCH and cra- as in osteomyelitis. Only mandibular lesions were niofacial and skull base lesions. The mean age was 3.3 associated with laminar periosteal reaction. years (range: 1-12 years) and all patients were evalua- CT allowed a better visualization of bone involvement ted by plain radiograph (x-ray) and contrast-enhan- in anatomically complex structures, such as the facial ced computed tomography (CT) with helical scanner. bones and the skull base (especially the petrous tem- In 4 cases, volume rendering reconstructions were poral bone). The soft tissue component of the tumor performed and in half of these cases findings could be appeared homogeneous, isodense to muscle in con- correlated with those of bone scans. Eight patients of trast- and non-contrast enhanced images. the series were also evaluated by contrast-enhanced The methylene diphosphonate bone scan showed magnetic resonance imaging (MRI) using a 1.5 T MRI high radiotracer uptake in the facial bones and the scanner. skull base in all patients of our series. However, it was possible to identify concomitant lesions in the calvaria as photon negative areas. RESULTS In the MRI, the soft tissue component appeared as an heterogeneous and variable pattern (hypo-, iso- or Locations of lesions in our series of patients are shown hyperintense) on T1-weighted images, while on T2- in Table 1. weighted images and STIR, it was hyperintense, hete- The most common association was the base of the rogeneous and with a high uptake of the contrast petrous temporal bone and the greater wing of the agent. Enhancement of neighboring structures, such as sphenoid bone in 5 patients (29.4%). Of the total num- the dura mater, fasciae and muscles was also observed. ber of patients with craniofacial and skull base involve- Diffusion imaging, performed in one patient in the

Chart 1: Histiocytic diseases (9).

Histiocytic diseases

Dendritic cell-related Langerhans cell histiocytosis Secondary processes and related disorders Solitary histiocytomas of various dendritic cell phenotypes

Macrophage-related Hemophagocytic syndromes - Primary hemophagocytic lymphohistiocytosis - Secondary hemophagocytic syndrome * Infection-associated * Malignancy-associated * Rheumatic disease-associated * Others Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) Solitary histiocytoma with phenotype

Malignant disorders

Monocyte-related Leukemias * Monocytic leukemia M5A and B * Acute myelomonocytic leukemias M4 * Chronic myelomonocytic leukemia Extramedullary monocytic tumor or sarcoma.

Dendritic cell-related

Macrophage-related histiocytic sarcoma

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Chart 2: Usefulness of diagnostic imaging methods in LCH with craniofacial and skull base involvement.

RX Identification of osteolytic lesions.

CT High resolution and sensitivity for identification of osteolytic lesions in complex anatomical areas. Identification of intracranial and extracranial soft tissue tumor component.

NM Radiotracer uptake in active disease (false negatives: 16-35%).

MRI Marked enhancement of soft tissue tumor component and infiltration after the intravenous injection of gadolinium Assessment of the pituitary stalk, meninges and brain parenchyma

PET/CT Monitoring of active disease and response to treatment.

Table 1: Location of the LCH lesions in the seventeen patients evaluated.

Pat. Nº Age and Petrous Orbits Mandible Maxilla Other Multisystem gender temporal and skull bone involvement bone base lesions

1 F 2 years 2 month x - -

2 M 1 years 7 month x x Calvaria -

3 F 4 years x Calvaria -

4 M 8 years 2 month x - Lymph nodes

5 F 2 years x x x x Calvaria, spine Lymph nodes, lung, and long and liver, spleen and CNS flat bones

6 M 2 years x Calvaria and Lymph nodes, liver, spine spleen and CNS

7 F 2 years 4 month x x Calvaria Lung and CNS

8 M 2 a 4 month x Calvaria Liver, spleen and skin

9 M 1 year x x Calvaria, spine Lymph nodes, liver, and flat bones spleen and skin

10 M 1 year x - Lymph nodes, lung and skin

11 F 1 year 6 month x x Spine Lymph nodes, lung, liver, spleen, skin and CNS

12 M 5 years x x Calvaria and - long bones

13 M 1 year 9 month x Calvaria -

14 F 1 year x Calvaria, spine Lymph nodes and and flat bones lung

15 M 2 years 6 month x x Calvaria -

16 M 12 years x Calvaria -

17 M 3 years x - -

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series, showed a slightly heterogeneous behavior, dings are similar to those of otomastoiditis or otitis of with small restricted diffusion areas. The extent of the external auditory meatus, or the middle ear, and bone marrow involvement, without osteolysis, was therefore diagnoses may be delayed. Patients with better documented with STIR techniques. Chart 2 large lesions had conducting deafness caused by audi- shows the usefulness of diagnostic imaging methods tory ossicle chain erosion. None of the patients had for craniofacial and skull base LCH. vertigo, facial nerve paralysis or neurosensorial deaf- ness, although these symptoms have been reported in the literature (10). DISCUSSION The predominant imaging finding is involvement of the petrous bone base with osteolysis of the squama of the Monoclonal growth of bone marrow-derived temporal bone, mastoid, tympanic cavity, external audi- Langerhans cells rapidly progresses from the central tory canal and, less frequently, auditory ossicle chain portion of the bone and expands and produces oste- erosion. This is associated with soft tissue masses, sho- olysis of the cortical bone or tables of compact bone, wing a homogeneous/heterogeneous pattern on CT occupying neighboring spaces and cavities. and MRI (Figs. 1 and 2). This finding has been observed The higher rate of lesions in the petrous temporal in 8 patients (2 of them with bilateral involvement). bone, sphenoid bone and orbits in patients with mul- Differential diagnosis should include otomastoiditis tisystem LCH observed in our series is consistent with with abscess, primary tumor (such as rhabdomyosar- findings from multicenter studies reported in the lite- coma) and metastasis. rature (14, 15). The lesions found in the studied population are sum- marized below, based on their location: Orbits and skull base

Ten patients had lesions in orbital walls and/or the Temporal bone skull base, but only one corresponded to eosinophilic granuloma. All others had orbital involvement in the In agreement with our series, temporal bone involve- context of multisystem LCH. ment has been reported in 15-61% of all pediatric Orbital involvement by LCH accounts for 1-2% of all patients with histiocytosis during the course of mul- orbital tumors and commonly manifests as eosinophi- tisystem forms (16-18). The most common symptom lic granuloma (19, 20). Orbital involvement occurs by was otorrhea, with no response to medical treatment. osteolytic lesions in orbital walls, especially in the roof Presenting symptoms also include adjacent soft-tissue and posterolateral wall, with involvement of the grea- mass or lesions in the external auditory canal (eczema ter wing of the sphenoid bone. The soft tissue compo- or rash), which may be misleading because these fin- nent of the tumor extends into the orbit with predomi- a c

b

Fig. 1: One-year old boy with multiorgan LCH and masses in the bilateral mastoid region of 2 months duration. Non-contrast enhanced axial (a) and coronal (b) CT scan obtained with bone window at the level of the petrous temporal bone. Extensive soft tissue masses with marked osteolysis of the mastoid, middle ear and external ear, with ossicle chain erosion and extension to the temporal squama in both petrous portions (*). (c) CT follow-up two years after the initiation of treatment, with marked reduction of lesions.

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a b

c d

Fig. 2: Same patient of figure 1. MRI images: (a) T1-weighted axial view, (b) T2-weighted coronal view. Enlarged lymph nodes in the neck ( ). (í). (c)Diffusion, (d) T1-weighted coronal view with contrast at the level of the petrous temporal bone. (*) Heterogeneous soft tis- sue masses at the base of both petrous bones, isointense with brain parenchyma on T1-, T2- and diffusion-weighted images surrounding the cartilaginous portion of the external auditory canal (coarse arrow).Deformation of the skin contour and displacement of the auricle.(d) Marked contrast-enhancement and thickening of a bilateral dural tail in the middle cranial fossa ( ). nantly extraconal location (Figs. 3 and 4), and it may lesions on bone scan is variable, depending on osteo- invade the extrinsic eye muscles and the lacrimal blastic activity (Fig. 5). gland, causing compression and displacement of the LCH may also involve the pituitary stalk, with the eyeball. It rarely causes infiltration of the intraconal- consequent syndrome of diabetes insipidus in 5% to retrobulbar space, surrounding the optic nerve, and 50% of patients (8-15). MRI findings are characterized infiltrates the Inferior orbital fissure and the infratem- by the loss of the spontaneous hyperintense signal of poral fossa (15). the posterior pituitary and thickening of the pituitary Osteolysis of the greater wing of the sphenoid bone stalk on T1-weighted images 10, 11, 15). Less fre- acquires a "punched out" beveled appearance on CT. quently, infiltration of the brain and cerebellum The soft tissue component of the tumor grows occurs. In our series, 30% of patients had diabetes insi- towards the middle cranial fossa, with dural and pidus and none of them had involvement of the brain extradural location, and dural tail. The appearance of parenchyma.

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ab

c

Fig. 3: Boy aged 8 years and 2 months with a mass in the outer and upper margin of the left orbit, proptosis and cervical lymphadeno- pathy. CT images: (a) Coronal CT soft-tissue window image of the orbits, without contrast; (b) and (c) Axial CT bone window image of the orbital roof. (*) Osteolytic lesion of the roof and lateral wall of left orbit, with soft tissue mass isodense to brain parenchyma, compres- sing and displacing the eyeball. ac

b

Fig. 4: Same patient as in Figure 3. Coronal MRI: (a) T1-weighted images, (b) STIR and (c) Contrast-enhanced, fat-saturated, T1-weight- ed images. (*) Heterogeneous and hyperintense mass on T1- and T2-weighted images on the roof and lateral wall of left orbit. The mass enhances after contrast administration, with extradural intracranial location.

Clinically, patients exhibit a mass in the orbital margin Jaw and maxilla and upper eyelid with proptosis and swelling in the temporal region (19-21). Jaw involvement has basically two forms: one is the Involvement of the body of the sphenoid and foramen focal osteolytic lesion in the vertical tubular portions of magnum with osteolysis of the occipital bone is very rare the mandible, and in the horizontal portion with (10) (Figs. 6 and 7). In this series, it occurred in 3 patients. resorption of the alveolar ridge, producing the radiolo- The most important differential diagnoses are orbital cellu- gical appearance of “floating teeth” (6, 7, 24) (Figs. 8 and 9). litis with abscess, rhabdomyosarcoma, metastatic disease Gingival bleeding and inflammation is one form of from neuroblastoma, leukemic infiltration/lymphoma (21-23). clinical evidences. In our series, 3 patients had focal

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a b

c d

Fig. 5: Multiorgan LCH. (a) and (b) Child age 1 year and 7 months: (a) Axial CT bone window image of the orbit. Osteolysis of the gre- ater wing of the right sphenoid bone of beveled appearance (thin arrows); (b) Contrast-enhanced axial CT of the orbit. Thickening and dural tail in the sphenoid bone (coarse arrows). (c) and (d) Another 5-year-old patient: (c) contrast-enhanced CT. Simultaneous involve- ment of the right orbit and left temporal bone (*). The latter shows extradural intracranial extension with no significant osteolysis ( ). (d) Bone scan: view from the vertex with photon positive areas in facial bones ( ) and photon negative areas in the calvaria (*).

lesions of the vertical portion and one patient showed Bone scan is scarcely useful because photon positive alveolar ridge resorption (with a torpid progress and areas persist after healing (14, 25, 26). loss of almost all teeth). Four patients had maxillary Other imaging methods used and reported in the lite- involvement with occupation of the maxillary sinuses rature include somatostin receptor scintigraphy using by soft tissue tumor and wall osteolysis. Lesions may 111In-DTPA-D-Phe1-octreotide, which depicts the also invade the nasal cavity, zygomatic bone and active sites of disease and thus can help in monitoring maxillary alveolar ridge (see Fig. 6c). the response to treatment (27). Whole-body magnetic Differential diagnoses include sinusal or dental infec- resonance imaging is a diagnostic alternative for tions, with osteomyelitis, fibrodysplasia, hyperpa- assessing the extent of skeletal and extraskeletal rathyroidism, Ewing's sarcoma, metastasis and leuke- lesions of LCH in patients with multisystem involve- mic infiltration/lymphomas (6). ment (except for pulmonary lesions) (26). Follow-up of patients was performed by CT and MRI. Positron emission tomography (PET-CT) with fluoro-

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a b

c d

Fig. 6: Girl aged 1 year and 6 months with multisystem LCH. (a) Skull profile x-ray, (b) Axial CT bone window image of the skull base. Extensive osteolytic lesion of the sphenoid bone, involving the body and right greater and lesser wings ( ). (c) Axial CT scan at the level of the maxilla. Central osteolytic lesion of the right zygomatic bone (*) and of the left maxilla, with the nasal cavity and sinus being occupied by a soft tissue mass surrounding tooth germs (white arrows). (d) Anterior view of the skull on bone scan. Intense uptake of the tracer in both maxillae, skull base and walls of the right orbit ( ). deoxyglucose (18 FDG) can detect metabolically acti- References ve lesions with uptake values (SUV) greater than 2. It is currently used for monitoring the response to treat- 1. Schmidt S, Eich G, Geoffray A, et al. Extraosseous ment (11, 23, 25). Langerhans cell histiocytosis in children. Radiographics 2008; 28:707-26 2. Lieberman PH, Jones CR, Steinman RM, et al. Langerhans CONCLUSION cell (eosinophilic) granulomatosis. A clinicopathologic study encompassing 50 years. Am J Surg Pathol 1996; 20:519-52. 3. Bhatia S, Nesbit ME Jr., Egeler RM, Buckley JD, Mertens A, Diagnosis of LCH should be considered in the presen- Robison LL. Epidemiologic study of Langerhans cell his- ce of craniofacial and skull base osteolytic lesions with tiocytosis in children. J Pediatr 1997; 130:774-84. soft tissue components in pediatric patients, ruling 4. Alston RD, Tatevossian RG, McNally RJ, Kelsey A, Birch JM, out the various differential diagnoses according to Eden TO. Incidence and survival of childhood Langerhans topography. cell histiocytosis in Northwest England from 1954 to 1998.

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a b

Fig. 7: One-year-old girl with multisystem LCH. (a) CT with 3D reconstruction, posterior view: osteolytic lesion in the occipital bone, involving the posterior margin of the foramen magnum (*). (b) T1-weighted sagittal image: Hypointense heterogeneous mass in the occi- pital bone, without intracranial involvement (*). a b

Fig. 8: Twelve-year-old boy with multisystem LCH. (a) and (b) Front and lateral x-ray views of facial bones. Extensive osteolytic mandibu- lar lesion involving the alveolar ridge with floating teeth appearance ( ). Involvement of maxillae is also observed.

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Fig. 9: Six-year-old boy with mandibular eosinophilic granuloma: (a) Coronal CT bone window image at the level of the vertical portion of the mandible; (b) CT with 3D reconstruction of facial bones, right lateral view. (*) Osteolytic lesion of the right vertical portion of the man- dible, with soft tissue mass, extending towards the masseter muscle with laminar periosteal reaction ( ).

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The authors declare no conflicts of interest.

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