26 Malignant Pediatric Tumors Doris Hadjistilianou and Zeynel A. Karcioglu

ased on several large series published during the Orbital RMS accounts for about 10 to 20% of all past three decades, the incidence of orbital ma- the rhabdomyosarcomas. Males are more affected than Blignancies in children and adolescents ranges females, and the mean age at diagnosis is 8 years. A from approximately 8 to 18% of all orbital lesions in history of trauma is frequently associated with the this age group.1–6 The most common orbital malig- clinical presentation of the tumor.11,12 The histo- nancy in the United States and western European se- pathologic types include embryonal, alveolar, spindle ries is rhabdomyosarcoma, which accounts for ap- cell, and botryoid tumors (Box 26.1). The embryonal proximately 40% of all pediatric orbital malignant type is the most common; the alveolar is less com- tumors. In the developing countries and the underde- mon and carries the worst prognosis (Figures 26.1 and veloped regions of the world, however, the most com- 26.2).13 Another type of RMS, called the pleomorphic mon orbital malignancies in the pediatric group are not type, is extremely rare in the orbit. Tumor location primary malignant tumors, but secondary and meta- correlates with histology: embryonal and differenti- static lesions, such as , Burkitt’s lym- ated types are more commonly located in the supero- phoma, and leukemias.7–10 Other tumors, including nasal quadrants, whereas the alveolar type originates mesenchymal malignancies (Ewing’s sarcoma, os- within the inferior orbit.14 teogenic sarcoma, fibrosarcoma, alveolar soft part sar- Orbital RMS can present insidiously, mimicking coma, malignant ), fibrohistiocy- other lesions clinically and radiologically. The most toses (Langerhans cell histiocytosis), lacrimal gland characteristic presenting features of orbital RMS are a tumors (adenoid cystic carcinoma), and secondary met- fairly rapid onset and progression of proptosis and dis- astatic tumors ( and esthesioneuroblas- placement of the globe (Box 26.2). The upper inner toma) also develop within the pediatric orbit, leading quadrant is the most common site of origin. Intracra- to proptosis, extraocular motility disorders, and com- nial extension and invasion of the paranasal sinuses pressive optic neuropathy. Although it is a low-grade are rather uncommon at presentation, whereas malignancy, (grade I and II astrocy- changes in the adjacent bone have frequently been toma) should also technically be considered to be a ma- reported.15 lignant lesion of the pediatric orbit. The best way of arriving at a diagnosis is to sus- This chapter details the more commonly encoun- pect rhabdomyosarcoma whenever one observes the tered primary and secondary malignant tumors of the clinical presentation of a rapidly progressive unilateral pediatric orbit, including rhabdomyosarcoma, orbital exophthalmos in a child. However, RMS may also pre- myeloid sarcoma (granulocytic sarcoma), neuroblas- sent as a palpable nodular subconjunctival or lid mass toma, and the optic nerve glioma. Other tumors, listed with edema of the lids and conjuctiva (Figure 26.3). by way of introduction, are covered elsewhere in this Symptoms depend on the origin and site of the tumor book (Chapters 5, 15, 17, 18, and 22). mass. Posterior tumors rapidly develop edema of the optic disk, choroidal folds, and some degree of oph- thalmoplegia (Figure 26.4). When RMS is situated in PRIMARY TUMORS the inferior and anterior portions of the orbit, it often causes obvious chemosis and swelling of the eyelids. The superior nasal quadrant of the orbit is the most Orbital Rhabdomyosarcoma common site of origin of this tumor.13 Once considered to be a very rare malignancy, orbital Once ophthalmologists believed that orbital RMS rhabdomyosarcoma (RMS) has emerged as the most arose from the extraocular muscles; now, however, it common malignant mesenchymal orbital tumor of is accepted that the condition develops from undif- childhood. It accounts for about 5% of all cancers in ferentiated mesenchymal cells that have the capacity the pediatric population. Rhabdomyosarcoma of the to differentiate into striated muscle.16 The clinical dif- neck and the head usually appears in the first decade ferential diagnosis includes most causes of proptosis of life. in childhood. The important lesions to be considered

304 CHAPTER 26: MALIGNANT PEDIATRIC TUMORS 305

BOX 26.1. Proposed Classification for Childhood Rhabdomyosarcoma

I. Superior prognosis a. Botryoid RMS b. Spindle cell RMS II. Intermediate prognosis a. Embryonal RMS III. Poor prognosis a. Alveolar RMS b. Undifferentiated sarcoma IV. Subtypes whose prognosis cannot be evalu- A ated at present

include benign and malignant conditions such as cap- illary hemangioma, dermoid cyst, , eo- sinophilic granuloma, and metastatic neuroblastoma (Box 26.3).17,18 Computed tomography (CT) and magnetic reso- nance imaging (MRI) play important roles in the pre- operative evaluation to determine location and size and also in evaluating residual or recurrent disease. Particular attention should be given to the presence of bone erosion and intracranial extension.19 CT dem- B onstrates a moderately well-defined homogeneous or- FIGURE 26.2. Photomicrographs of embryonal rhabdomyosar- bital mass isodense to the extraocular muscles, which coma. (A) Light microscopy shows a mixture of pleomorphic ma- lignant cells, some of which are elongated and tadpole shaped. (B) often shows enhancement after contrast administra- Electron microscopy is invaluable to identify the myofilaments tion; bone destruction is relatively frequent and can (white arrows) and Z bands (black arrows) (B). N: nucleus.

FIGURE 26.1. Light micro- scopic appearance of embryonal (A) and alveolar (B) histopathology patterns. In the embryonal type, relatively well-differentiated “strap” cells contain intracytoplasmic cross-striations that correspond to myosin and A B actin filaments. The alveolar pattern, on the other hand, presents a distinctive architecture in which the cells are interspersed within a branching network of connective tissue trabeculae. In many areas, a single layer of tumor cells adheres to the fi- brous septae, and in other areas, loosely cohesive cells occupy the spaces within the fibrous skeleton. Immuno- histochemical stains reveal positivity for desmin (C) and actin (D) within the cytoplasm C D of rhabdomyosarcoma cells. 306 PART FIVE: PEDIATRIC ORBITAL TUMORS AND PSEUDOTUMORS

BOX 26.2. Orbital Rhabdomyosarcoma: Clinical Presentation

Proptosis Globe displacement Blepharoptosis Palpable mass Conjunctival and eyelid swelling Pain Ophthalmoscopic findings Optic disk edema Choroidal folds Venous tortuosity

FIGURE 26.4. Large posterior tumor causing marked proptosis of the left eye with choroidal folds of the fundus.

be appreciable (Figure 26.5). On T1-weighted MR im- ages the tumor may appear iso- to hyperintense to the extraocular muscles and hypointense with respect to the orbital fat. On proton density and T2-weighted MR images, hypointensity, isointensity, and even hyper- intensity with respect to both extraocular muscles and orbital fat may be appreciable (Figure 26.6). On T1- weighted, contrast-enhanced MR images, rhab-

BOX 26.3. Differential Diagnosis of Orbital RMS

Orbital cellulitis Orbital abscess Dermoid cyst Lymphangioma Eosinophilic granuloma Capillary hemangioma Burkitt’s lymphoma Chloroma (myeloid sarcoma) FIGURE 26.3. Symptoms of rhabdomyosarcoma depend on the site and the growth rate of the tumor. This patient’s tumor involved Metastatic neuroblastoma the superior medial orbit, upper eyelid, and conjunctiva. CHAPTER 26: MALIGNANT PEDIATRIC TUMORS 307

TABLE 26.1. Staging by the Intergroup Rhabdomyosarcoma Study Group.

Group Description I Completely resected localized disease implying gross impression resection and microscopic confirmation of complete resection with absence of regional lymph node involvement Ia Confirmed to muscle or organ of origin Ib Contiguous involvement outside the muscle or organ of origin II Residual disease and/or regional lymph node involvement IIa Grossly resected localized tumor with microscopic residual disease and no evidence of gross residual tumor or regional lymph node involvement IIb Completely resected regional disease with no microscopic residual tumor FIGURE 26.5. Axial CT image shows a rather well-circumscribed IIc Grossly resected regional disease with microscopic homogeneous mass, isodense to the extraocular muscles in the su- residual tumor perior portion of the right orbit. III Incomplete resection with biopsy or gross residual disease IV Distant metastatic disease present at onset domyosarcomas show moderate to marked enhance- ment, even though in some cases a highly vascular in- ternal architecture mimicking a capillary hemangi- oma may be demonstrated.20 recently, ifosfamide and etoposide following conser- The staging of RMS proposed in the third Inter- vative surgery and combined with radiotherapy (5000 group Rhabdomyosarcoma Study is summarized in cGy) allow a survival rate of 90%. Table 26.1.20 The simplification of this classification The role of surgery in the management of orbital by Shields et al. can also be applied to cases of orbital RMS is still controversial. Some centers perform ex- RMS.21 Exenteration was the standard surgical treat- tensive surgery while others prefer to do incisional bi- ment for orbital rhabdomyosarcoma up to the 1970s. opsy only. The surgical approach should be planned Orbital exenteration is now confined to the treatment according to the clinical and radiographic findings. of patients with recurrent disease.21 The poor prog- When possible, a complete or near complete tumor ex- nosis for children with orbital rhabdomyosarcoma fol- cision is suggested without damaging vital structures lowing orbital exenteration suggested the use of ra- (optic nerve and/or extraocular muscles) (Figures 26.8 diotherapy. In fractionated doses, 4000 cGy offered and 26.9). If the suspected orbital RMS is located deep satisfactory tumor control.22 Chemotherapy, intro- in the orbit, an incisional biopsy is appropriate. Fine- duced subsequently, also succeeded in reducing these needle aspiration biopsy is usually unrepresentative lesions (Figure 26.7). Vincristine, actinomycin D, and, and may be misleading. Advances in chemotherapy and radiotherapy have significantly improved survival rates. The excellent survival rate has allowed following survivors for many years and observing the late effects of radiotherapy on both facial growth (bony hypoplasia of the orbit and facial asymmetry) and visual function (cataracts, ker- atopathy, retinopathy).23,24 The challenge for the future should be to identify the characteristics of patients who can safely be treated with primary chemotherapy alone to reserve radiotherapy for the remaining patients in an attempt to reduce late effects.25–27 Further reduction in radia- tion sequelae may derive from the use of three- dimensional conformal radiation therapy techniques, by minimizing the inclusion of normal structures in the treated volume.28 FIGURE 26.6. Axial T1-weighted MR image of a rhabdomyosar- coma in a patient with type 1. The tumor shows isodensity with respect to the muscles and hypodensity with re- spect to the orbital fat. The belly of the lateral rectus muscle is in- Optic Nerve Glioma volved with the tumor, which extends posteriorly into the superior orbital fissure. In this case, the greater wing of the sphenoid bone Optic pathway account for 0.6 to 1.2% of all was absent because of neurofibromatosis. intracranial tumors (see Chapter 7).29 The incidence 308 PART FIVE: PEDIATRIC ORBITAL TUMORS AND PSEUDOTUMORS

FIGURE 26.7. Axial T1-weighted, fat-suppressed MR images with contrast reveal an orbital tumor before chemotherapy (A) and after- ward (B). The tumor, which was proven to be an alveolar rhabdomyosarcoma, shows marked reduction of enhancement after therapy.

is 1 in 100,000 patients, with 90% presenting in the first two decades and 65% in the first 5 years of life. First reported by von Graefe in 1864, gliomas of the anterior visual pathways constitute about 1 to 5% of all childhood intracranial tumors.30 The majority of these tumors, including optic nerve gliomas, are low- grade . Some present spheri- cal or cylindrical swollen cell processes called Rosen- thal fibers, which stain eosinophilic (Figure 26.10). The astrocytic nature of the tumor can be confirmed using immunohistochemical techniques with antibod- ies against glial fibrillary acidic protein (GFAP, MW A 15 kDa).31 Although this protein may also be present in some , increased GFAP expression is typical for astrocytic tumors.32 Optic gliomas commonly occur in neurofibro- matosis type 1 (NF1) and belong to the diagnostic cri- teria of NF1.33–35 The incidence of optic gliomas in children with NF1 is as high as to 15 to 20%, with symptomatic vi- sual loss in approximately 20% of affected patients (Figure 26.11). Bilateral gliomas are most often seen in patients with NF1 (Figure 26.12). The optic nerve B alone is involved in 24% of cases and the chiasm in 76% of cases; invasion of the midbrain is documented in 46% of patients.35,36 The most important prognostic factor is age at presentation. Early-onset optic gliomas (Ͻ6 years) grow rapidly and must be followed closely.37,38 Pri- mary symptoms include deterioration of visual acuity and progressive visual field defects. However, patients with NF1 seem to have a less aggressive variant of glioma. Neuro-ophthalmic aspects of optic nerve glioma are also covered in Chapter 7.39,40 The clinical course of optic pathway gliomas is re- C lated to the extent at diagnosis and histopathologic FIGURE 26.8. Superior orbital rhabdomyosarcoma before (A) and after (C) treatment, which consisted of debulking (B), chemother- pattern (Figure 26.13). In pediatric patients with NF1 apy, and radiation treatment. and optic pathway gliomas, the likelihood of visual CHAPTER 26: MALIGNANT PEDIATRIC TUMORS 309

FIGURE 26.9. (A) Rhabdomyosar- coma of the superior orbit and the upper lid is removed (B) through a lid crease incision. Note the well- delineated myxoid tumor with a grayish-white glistening surface that appears to be “fleshy” like a lymphoma (C,D).

loss depends on the extent and location of the tumor follow-up of optic pathway gliomas to evaluate sta- as determined by MRI and is particularly associated bility or progression should include a high-resolution with postchiasmal structure involvement.40 MRI study. This is particularly helpful to evaluate the There is still controversy regarding the growth of intracranial extent of optic nerve glioma.44,45 optic gliomas and potential extension posteriorly to CT and MRI are important to establish the tumor the chiasma. Hoyt and Baghdassarian suggested that extension, to plan treatment, and to allow radiologic optic gliomas represent congenital hamartomas with growth potential in the first years of life.41 Progres- sion usually occurs in the first year of presentation.42 However, the variable and unpredictable course of these tumors makes standardization of treatment strategies difficult. Optic gliomas may undergo spon- taneous regression. In a recent study, Parsa et al. doc- umented spontaneous regression and tumor shrinkage in 12 patients with optic glioma. Regression was ob- served in patients with and without NF1.43 Accurate

FIGURE 26.11. (A) Patient with neurofibromatosis type 1 has cu- taneous of the forehead and slight proptosis of the FIGURE 26.10. Histopathologic appearance of an optic nerve right eye secondary to a unilateral optic nerve glioma. (B) Note the glioma that is composed of proliferating fibrillary astrocytes show- missing greater wing of the sphenoid bone (arrow) on axial CT ing different degrees of pleomorphism. image. 310 PART FIVE: PEDIATRIC ORBITAL TUMORS AND PSEUDOTUMORS MR-images fusiform lesions show high signal, while large lobulated tumors tend to have a more hetero- geneous signal. A double-intensity “tubular thick- ening,” with kinked and elongated optic nerves, sug- gests but does not prove glioma in patients with NF1 (Figure 26.14). Enlargements of the chiasm and the optic tracts are signs of intracranial involvement. T1-weighted MR images after gadolinium adminis- tration usually show variable enhancement; when the tumor is large, the center of the mass shows a marked enhancement, but the periphery is not en- hanced (consistent with ectactic or hyperplastic FIGURE 26.12. Bilateral optic nerve gliomas in neurofibromatosis arachnoid around the nerve). Differential diagnosis type I. Axial T2-weighted MR image shows enlargement of both op- tic nerves (arrows), which presents as isointense to the gray matter of optic nerve glioma should include idiopathic op- and as surrounded by hyperintense cerebrospinal fluid. tic neuritis, sarcoidosis, demyelinating disease, and optic nerve sheath .47,48 Treatment strategies include observation only, sur- and clinical follow-up. The tumor causes fusiform gery, irradiation, chemotherapy, or a combination of enlargement of the optic nerve. On CT the tumor these modalities. An “observation” policy may be ap- presents an enlarged, fusiform, not calcified optic plied in children with anterior tumors and absence of nerve mass with frequent kinking and cystic areas.46 signs of progression. Uniform and marked enhancement after contrast Surgical resection is successful in tumors confined administration is commonly observed. On T1- to an optic nerve. Radiotherapy is usually reserved for weighted MR images, the tumor is usually isoin- patients with progression after surgery and for opti- tense to the cerebral gray matter. On T2-weighted cohypothalamic gliomas. Chemotherapy is at an ex- perimental stage. Chemotherapy of optic nerve glioma is further covered in Chapter 34.49,50

A

B FIGURE 26.14. (A) Axial and (B) sagittal T1-weighted MRI images FIGURE 26.13. (A) A young child with mild proptosis of the left show tubular thickening of the left optic nerve showing elongation eye and a minimum pallor of the temporal disk (B) secondary to a and kinking at midorbit secondary to optic nerve glioma. The pa- unilateral optic nerve glioma. tient did not have neurofibromatosis. CHAPTER 26: MALIGNANT PEDIATRIC TUMORS 311 SECONDARY AND METASTATIC TUMORS BOX 26.4. Orbital Neuroblastoma: Clinical Presentation Neuroblastoma Proptosis Neuroblastoma is the most common extracranial solid Periorbital ecchymosis (“panda bear” eyes) tumor of childhood, accounting for 8 to 10% of all Ptosis childhood cancers. It represents a malignant neoplasm Globe displacement of primitive neuroblast and is the most common met- Blindness (rare) astatic orbital tumor, affecting children at a mean age of 2 years.51 Neuroblastoma arises in the abdomen, thoracic, cervical, and pelvic regions, and metastases occur by hematogenous spread. Ophthalmic manifestations are mosis are typical; ptosis and globe displacement are common, frequently resulting from periorbital soft rather common. Symptoms are bilateral in 20 to 50% tissue infiltration of the tumor.52,53 The most com- of cases (Box 26.4). Orbital involvement is almost ex- mon sign of orbital metastic neuroblastoma is pro- clusively associated with disseminated disease, while ptosis and periorbital ecchymosis (“panda bear eyes”), Horner syndrome and opsoclonus are frequently asso- followed by unilateral Horner syndrome and opso- ciated with localized neuroblastoma, particularly in clonus (Figure 26.15). Proptosis and periorbital ecchy- the mediastinum.54 Horner syndrome, secondary to tumor in the cervical sympathetic chain, may be the presenting sign. On a retrospective review of children, ophthalmic involvement in neuroblastoma was present in 80 of 405 cases (20%). The most common site of origin was the abdomen.51 At CT, a soft tissue mass inhomogeneously en- hancing with associated lytic bony erosions is appre- ciable (typically involving the zygomatic bone adja- cent temporal orbit). At MRI, the tumor often is isointense to the extraocular muscles, but intratu- moral hemorrhages may lead to variable appearance both on T1- and T2-weighted images, depending on the degree of hemoglobin catabolism. After gadolin- ium administration, variable degrees of enhancement are encountered. Histopathologically, neuroblastoma can be distinguished from most of the neurogenic tumors of the orbit by the presence of neurosecre- tory dense-core granules, detected by electron mi- croscopy, and by positive -specific enolase (NSE) activity, demonstrated by immunohistochem- istry. Immunohistochemistry helps to differentiate a neuroblastoma from other small-cell tumors such as rhabdomyosarcoma, retinoblastoma, Ewing’s sar- coma, and lymphoma.55,56 The prognosis in neuroblastoma is influenced mainly by age, stage, and site of origin. In children di- agnosed during the first year of life, the 2-year relapse- free survival rate is 75%; it drops to 12% after the age of 2 years.57 The survival rate in neuroblastoma has improved little in the past two decades; about 70% of the patients present with disseminated disease at the time of diagnosis. Early diagnosis is an important fac- FIGURE 26.15. (A) Bilateral ecchymosis of the eyelids and perior- tor influencing the prognosis. The ophthalmologist bital skin of a patient with metastatic abdominal neuroblastoma of may play a major role in the diagnosis of the disease, both orbits and brain. (B) Multiple metastatic nodules in orbits and brain are shown in T-1 weighted axial MRI image. (Courtesy of Dr. since 20% of the patients present with ophthalmo- Robert A. Gordon of New Orleans, Louisiana.) logic involvement.51 The treatment consists of mul- 312 PART FIVE: PEDIATRIC ORBITAL TUMORS AND PSEUDOTUMORS tiagent chemotherapy; combinations of cisplatin, teni- ulocytic sarcoma (myeloblastoma or chloroma) is a poside, vincristine, and cyclophosphamide have been very uncommon manifestation of acute myelocytic employed. Radiotherapy doses vary according to the leukemia and presents as a focal soft tissue mass (Fig- age (1500–4000 cGy) Orbital metastasis has a poor ure 26.16). prognosis; the 3-year survival rate is 11%. The term chloroma (green tumor) is derived from the greenish coloration of this lesion, which is due to the myeloperoxidase in cells of granulocytic lineage. Orbital Myeloid Sarcoma On occasion, granulocytic sarcoma presents as an iso- (Granulocytic Sarcoma) lated soft tissue mass prior to the development of sys- The orbit may be affected in all types of leukemia, but temic disease. Correct diagnosis of the solitary lesion it has a greater propensity to be involved in acute is important because it leads to early implementation myeloid leukemia (AML). Mass formation, however, of chemotherapy.59 is quite rare; diffuse infiltration is more common. The While most childhood orbital tumors, such as lym- tumor may appear before, after, or concomitant with phangioma, rhabdomyosarcoma, capillary hemangi- hematologic evidence of leukemia.58 oma, dermoid cyst, and optic nerve glioma are uni- The most frequent clinical manifestations include lateral, bilateral orbital involvement is observed in exophthalmos, ptosis, edema, and chemosis of the eye- metastatic neuroblastoma and myeloid sarcoma.60 lids, with pain. Diagnosis is established by clinical and Orbital myeloid sarcoma occurs in young children laboratory findings, imaging studies and biopsy. Gran- and is quite rare among the orbital tumors of child- hood, accounting for only 1 of 250 cases.3 On the basis of a review, Shields et al. calculated that about 88% of the patients with proptosis seen by an ophthalmologist have no history of leukemia at the time of presentation.60 Myeloid sarcomas are most common in certain subtypes of AML, in particular, M5a (monoblastic), M5b (monocytic), M4 (myelomonocytic), and M2 (myeloblastic with maturation).61 There appears to be a very strong association of orbital myeloid sar- coma with AML cases demonstrating a t(8;21) translocation, which is associated with a good prog- nosis.62,63 At T1-weighted MRI, granulocytic sar- coma is slighthy hyperintense to gray matter, mus- cle, and bone marrow. At T2-weighted imaging, it is isointense to white matter, muscle, and bone mar- row.64 CT shows the mass to be isodense to mus- cle. This tumor trends to mold to contiguous struc- tures and demonstrates relatively little bony destruction.65 Orbital myeloid sarcoma preferen- tially involves the lateral orbital wall. Imaging ap- pearance, clinical history, and location can suggest the correct diagnosis, allowing prompt treatment be- fore the development of systemic disease.66

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Tumorlike Conditions in the Orbit