Iliff and Green [1] n = 174
Crawford [3] n = 572
Shields et al. [2] n = 250
Rootman [6] n = 241
Kodsi et al. [5] n = 340
Katowitz et al. [7] n = 243
Rhabdomyosarcoma
15
14
10
5
26
27
Leukemia/lymphoma
2
23
1
1
5
5
Langerhans
Cell histiocytosis
0
18
0
3
4
3
Soft tissue sarcomasa
6
9
2
5
9
5
Neuroblastoma
1
9
0
1
3
0
Retinoblastoma
6
1
9
0
14
1
Adenoid cystic carcinoma of lacrimal gland
0
0
1
2
0
0
Nasopharyngeal carcinoma
0
1
0
1
0
0
Esthesioneuroblastoma
0
0
0
0
1
1
Malignant schwannoma
0
0
0
0
0
1
Orbital melanoma
0
0
0
0
1
0
Medulloblastoma metastatic to optic nerve
0
0
0
1
0
0
Malignant teratoma
1
0
0
0
1
0
Metastatic astrocytoma
1
0
0
0
0
0
Total malignant tumors/% all orbital lesions in series
32/18.4%
75/13.1%
23/9.2%
19/7.9%
64/18.8%
43/17.7%
The incidence of a malignant orbital lesion as the cause of proptosis in a child or adolescent ranges from 7.9% to 18.8% (Table 36.1). The most common primary malignant orbital lesion in all US series is rhabdomyosarcoma, which accounts for 37.9% (97/256) of all pediatric malignant orbital lesions and 5.3% (97/1820) of all pediatric orbital lesions in the series listed in Table 36.1. Metastatic leukemia and lymphoma account for 14.5% of malignant orbital lesions, while orbital recurrences of retinoblastoma were found in 12.1% of the cases. A total of 28 individuals with Langerhans cell histiocytosis yielded a 10.9% occurrence rate among malignant lesions. A variety of primary and secondary non-rhabdomyosarcoma soft tissue sarcomas accounted for 14.1% of orbital malignancies. These are listed at the bottom of Table 36.1. Metastatic neuroblastoma was found in 5.5%, with most rare orbital entities each accounting for less than 1.5% of the total.
Using the information from these series, the clinical features of malignant orbital lesions combined with imaging studies can often lead the examiner toward an early and correct diagnosis even without a biopsy. However, unusual presentations, rapid progression with systemic features, or confusing clinical scenarios may require biopsy despite typical clinical features or imaging results. In certain disease states, biopsy may be required for staging or treatment decisions regardless of clinical or imaging results. In general, it is never wrong to err on a lesion biopsy, though lesions can be diagnosed with a high level of confidence with high-resolution MRI imaging (e.g., orbital venolymphatic malformation discussed in Chap. 35 and optic pathway glioma as discussed in Chaps. 14 and 35).
Primary Orbital Malignancies
Rhabdomyosarcoma
Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy occurring in children, accounting for nearly 5% of all childhood malignancies and 20% of soft tissue tumors [8]. As already outlined, it is also the most common primary orbital malignancy in children, representing approximately 40% of cases. There are approximately 250 cases of RMS diagnosed in the USA per year. Approximately 10%–15% of these occur in the orbit [9]. With these yearly estimates, there are most likely about 37 new cases of RMS that occur in the orbit in the USA per year. This lesion is so rare that in the Shields review of orbital tumors over a 30-year period, they report only 35 cases [10]. In our experience at the Children’s Hospital of Philadelphia (CHOP) , we see almost one new case of orbital RMS per year. This is helpful to keep in mind when reassuring families, but is in no way a comfort to the physician who must always remain vigilant when diagnosing orbital tumors. We once had a weekend on call at CHOP where we diagnosed two separate cases of orbital RMS in a single day!
Originally thought to arise from striated muscle, pluripotential mesenchymal cells appear to be the source of the malignant transformation in all types of childhood rhabdomyosarcoma [11, 12]. Seen even in the eighth decade, approximately 75% of primary orbital rhabdomyosarcomas, however, occur in the first decade of life with another 22% diagnosed in the second decade [11]. A bimodal age distribution has been identified based on tumor histology: embryonal and alveolar cell types occur in childhood, and the pleomorphic variety is more common in adulthood. Additionally, two peaks seem common in childhood, with ages 1 and 7 years on average accounting for the most common age presentations. Female slightly outweigh male preponderance 3:2. The average age at diagnosis is approximately 7 years, although the malignancy has been reported at birth and as late as 78 years of age [11, 13].
Rhabdomyosarcoma can involve the orbit as a primary tumor or through secondary invasion. In older reports, this differentiation was not often recognized because the histopathologic features of striated muscle cells gave the impression of a striated muscle tumor and kept researchers from recognizing that these tumors can arise from parameningeal sites and invade the orbit secondarily. The term parameningeal not only includes intracranial sites of origin but is used generally to include all non-orbital head and neck sites such as the retropharyngeal space, the sinuses, and the pterygoid fossa. Of the series mentioned, only Henderson acknowledges this difference in orbital presentation and found 17 cases of primary orbital RMS and 21 cases of secondary orbital involvement in his series [5]. Despite this difference in site of origin, diagnostic and treatment considerations with orbital involvement change little whether the tumor is of primary or secondary origin.
Classically, orbital rhabdomyosarcoma presents as a rapidly enlarging process with proptosis or globe dystopia, lid swelling, and inflammation in a previously healthy child (Fig. 36.1). Typically painless, the signs and symptoms worsen rapidly over a period of days, often mimicking a suspected traumatic injury, especially when edema and a rather consistent bluish or reddish/purple discoloration are present. Vision loss is an unusual feature early on except in secondary orbital RMS, where approximately 35% of patients present with vision worse than 20/200 secondary to apical involvement from these parameningeal tumors. Twenty-five percent of patients have a palpable orbital mass, and blepharoptosis is seen in about 20% of patients on presentation, which almost always accompanies the periorbital swelling. Less commonly, the primary site of presentation can occur in the eyelid, as seen in about 20% of cases where lid signs dominate the clinical presentation with a notable lack of proptosis and 7% of presentations can be subconjunctival with a visible, well-demarcated mass (the so-called botryoid type). Rarely, RMS can present as a slow, indolent process of intermittent swelling, tearing, or inflammation, delaying diagnosis and treatment [14]. Delays in diagnosis can also occur due to similar signs and symptoms shared by other pediatric orbital processes, including Langerhans cell histiocytosis, orbital cellulitis, metastatic neuroblastoma, ruptured dermoid cysts, granulocytic sarcoma, microcystic venolymphatic malformation, and idiopathic orbital inflammations. This differential diagnostic list should be kept in mind when faced with a child presenting with an acute, progressing orbital process.
Fig. 36.1
Rhabdomyosarcoma . (a) Clinical photograph of a 5-year-old boy with a 2-week history of left eyelid swelling and proptosis. (b) T2-weighted coronal MRI showing an irregular mass in the upper eyelid. (c) T1-weighted axial MRI shows an irregular mass filling the superior orbit. (d) Intraoperative photograph of tumor in the left superior orbit. An eyelid crease incision was made. The orbital septum was incised and reflected downward. Pathology and cytogenetic studies were performed on this mass, which was embryonal rhabdomyosarcoma
Four major categories of histopathologic appearance are used to classify orbital rhabdomyosarcoma: embryonal, alveolar, pleomorphic, and botryoid. This classification was first proposed by Horn and Enterline [15]. Very few tumors demonstrate pure histologic patterns, so the predominant pattern is used to define the histologic category. The major feature one uses to diagnose RMS is the presence of rhabdomyoblasts, which are small, densely eosinophilic, round cells with hyperchromatic nuclei and small nucleoli. Increasing degrees of differentiation reveal larger cells with abundant eosinophilic cytoplasm containing fibrillary material that can resemble a spider web (called spider cells) or can be shaped like tadpoles, spindles, or racquets. Strap cells can sometimes be identified (Fig. 36.2). A strap cell is a description of a primitive cell with an elongated cytoplasm resembling a strap as it presumably is differentiating toward development as a muscle fiber. Cross striations help to identify the most differentiated cells, which look like muscle fibers and can be found in about 50–60% of embryonal cell-type and around 30% of alveolar cell-type lesions (Fig. 36.2). Immunoperoxidase staining for myoglobin, periodic acid-Schiff (PAS) stain for glycogen, and electron microscopy for thin or thick myofilaments or Z-lines can further distinguish borderline lesions with indistinct features. The desmin stain is particularly useful in that it is very specific for rhabdomyosarcoma. It stains a specific filament present in the cytoplasm of this tumor and helps to differentiate it from other small cell tumors [16].
Fig. 36.2
Light microscopy of rhabdomyosarcoma of the orbit. (a) Strap cell (H and E stain, ×500) (Courtesy of Nasreen Sayed, MD). (b) Rhabdomyoblast with cross striations (small arrow) (Courtesy of Francis LaPiana, MD and AFIP). (c) Embryonal pattern of rhabdomyosarcoma with scant cytoplasm in cells (H and E stain). (d) Desmin stain of cells from same patient (×40) (Courtesy of Marta Guttenberg, MD)
The embryonal subtype is the predominant histopathologic pattern in about 65% of orbital rhabdomyosarcomas and demonstrates a mixture of myxoid and compact pleomorphic cellularity with abundant mitotic figures. If presenting as a subconjunctival mass and revealing this histologic pattern, it is referred to as a botryoid, reflecting the terminology used for other mucosa-related RMS, and accounts for about 7% of all orbital presentations [17]. Alveolar RMS demonstrates poorly differentiated tumor cells reminiscent of lung alveoli. Viable tumor cells are arranged at the periphery adherent to the septa with degenerative cells appearing to float freely in the center. Better-differentiated rhabdomyoblasts are less common in this cell type but can be found within the septa. It has been suggested that this cell type is seen more commonly in the inferior orbit and constitutes approximately 30–35% of cases of orbital RMS [16].
Pleomorphic rhabdomyosarcoma is the least common histologic variant, occurring primarily in adults and accounting for only 1–2% of orbital presentations. Variably sized, loosely arranged, deeply eosinophilic cells with many types of rhabdomyoblasts account for the pleomorphic name. Cross striations are rare, but glycogen is frequently present.
Older reports suggested a correlation between cell type and prognosis in orbital rhabdomyosarcoma [16]. Other authors find no significant difference in survivability based on histologic type but rather on site of origin: orbital versus parameningeal [18–21]. Patients treated with wide surgical excision alone or with a variety of other ancillary treatments prior to 1972 demonstrated only a 22% survival rate [17]. Presentation of primary orbital disease treated with incisional biopsy, with or without debulking, radiation, and chemotherapy, utilizing past Intergroup Rhabdomyosarcoma Study (IRS) criteria carries a 91% rate of local control and an 82% 2-year disease-free interval [18, 19]. Parameningeal RMS treated with radiation and chemotherapy after biopsy demonstrated a 61% 6-year survival rate in one series from Memorial Sloan Kettering Cancer Center, but only a 33% 4-year survival rate reported from 12 cases at the Mayo Clinic [16, 20]. It seems that the only reason for the improvement in the rates of local recurrence and survival for patients reported in the older versus newer literature is the choice of treatment rendered: wide local excision prior to 1972 versus radiation and chemotherapy.
The new IRS-V study combines group, stage, and histologic subtype to allocate patients to three different therapeutic protocols according to risk of recurrence. Low-risk patients have an estimated 3-year rate of 88%, intermediate-risk patients have an estimated 3-year failure-free survival rate of 55 ± 76%, and high-risk patients have a 3-year failure-free survival rate of <30% [22].
When evaluating a child with a suspected orbital rhabdomyosarcoma, review of the differential diagnosis list helps in guiding the initial work-up. A careful history and physical examination revealing symptoms or signs of sinus disease, upper respiratory infection, trauma, previous dermoid cyst, or manifestations of orbital lymphangioma can help direct the examination. This should be performed within 24 h due to the potentially rapid progression of these tumors and the attendant proptosis, corneal exposure, and vision loss that can ensue.
Thin-section computerized tomographic (CT) evaluation of the orbit and sinuses with contrast enhancement yields orbital and extraorbital localization of the process along with details of the surrounding bone to reveal any extraorbital spread or bony destruction that helps guide biopsy, surgical management, and systemic work-up [16]. This study modality, while more readily available, cannot easily differentiate rhabdomyosarcoma from other benign lesions and can sometimes be misleading and raise the suspicion for RMS. Magnetic resonance imaging (MRI) has become the ideal imaging modality to differentiate RMS from other lesions. Diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) mapping are additional studies performed during MRI that can further differentiate a lesion. Figure 36.3 shows four cases with orbital lesions that were referred with imaging for a presumed diagnosis of RMS. With the use of DWI imaging, the lesions were better identified for the risk for malignancy. All four lesions were biopsied, but only one of the four was in fact RMS. The role of orbital imaging in RMS is covered in more detail in Chap. 32. RMS on MRI is usually homogenous, well circumscribed, and within orbital soft tissues, not arising from the extraocular muscles. They are isointense to muscle on T1-weighted images and hyperintense on T2-weighted imaging. Contrast enhancement is best seen with fat-suppressed T1-weighted imaging. Often there is restriction seen on DWI.
Fig. 36.3
Four cases of presumed rhabdomyosarcoma. (a) Top left, case 1: 4-year-old boy with a rapid onset of painless proptosis. Bottom left, case 2: 5-year-old boy with rapid onset of ptosis with mild discomfort. Top right, case 3: 9-year-old boy with history of left upper eyelid edema and erythema, which did not improve with oral antibiotics. Bottom right, case 4: 8-year-old girl with painless proptosis that has progressed over 10 days. (b) Top left, case 1: axial CT shows an intraconal heterogeneous mass. Bottom left, case 2: axial CT showing an infiltrative superior orbital mass with bony lysis. Top right, case 3: T2-weighted axial MRI showing an infiltrative mass in the superolateral orbit. Bottom right, case 4: T1-weighted axial MRI showing an intraconal heterogeneous orbital mass. (c) Top left, case 1: additional imaging was obtained showing an intraconal, orbital mass with macrocysts and fluid levels. Because the patient had vision loss with an afferent pupillary defect, the patient underwent orbital biopsy. Pathology diagnosed with lesion as venolymphatic malformation. Bottom left, case 2: additional imaging was obtained showing a heterogeneous mass in the superior orbit on T1-weighted axial MRI. Biopsy of the orbit confirmed the diagnosis as Langerhans cell histiocytosis. The lesion was curetted and treated directly with methylprednisolone. Top right, case 3: orbital biopsy showed a lesion with acute inflammation only. Specimen culture grew methicillin-resistant Staphylococcus aureus (MRSA). Bottom right, case 4: orbital biopsy of the lesion confirmed the diagnosis of alveolar rhabdomyosarcoma . (d) Top left, case 1: normal diffusion noted on apparent diffusion coefficient mapping (ADC) associated with diffusion-weighted imaging (DWI) suggesting the lesion hypocellular and likely benign as seen in orbital venolymphatic malformation. Bottom left, case 2: restriction is noted on the ADC image derived from DWI imaging raising the suspicion of a malignant lesion. Top right, case 3: normal diffusion on the ADC image in a patient with MRSA orbital cellulitis. Bottom right, case 4: restriction on the ADC mapping image in orbital rhabdomyosarcoma
Evaluation by a pediatric oncologist to help stage the disease is important (see Chap. 13). Physical examination and ancillary studies for extraorbital spread, regional or distant lymphatic involvement, or possible metastasis to the lungs, bone marrow, or brain are important for staging the disease and for posttreatment metastatic evaluations. Table 36.2 lists the IRSG surgical-pathologic grouping system [22]. Table 36.3 is the IRSG staging system.
Group | Definition |
|---|---|
I | Localized tumor, completely removed with pathologically clear margins and no regional lymph node involvement |
II | Localized tumor, grossly removed with (a) microscopically involved margins; (b) involved, grossly resected regional lymph nodes; or (c) both |
III | Localized tumor, with gross residual disease after grossly incomplete removal or biopsy only |
IV | Distant metastases present at diagnosis |
Stage | Sites of primary tumor | Tumor size (cm) | Regional lymph nodes | Distant metastases |
|---|---|---|---|---|
1 | Orbit, non-PM head/neck; GU non-bladder/prostate; biliary tract | Any size | N0, N1 | M0 |
2 | All other sites | ≤5 | N0 | M0 |
3 | Any site | ≤5 >5 | N1 N0 or N1 | M0 |
4 | Any site | Any size | N0 or N1 | M1 |
If imaging studies demonstrate features consistent with rhabdomyosarcoma, orbital biopsy should be performed. This should occur with minimal delay as previously discussed. The imaging study and its demonstration of the position of the orbital lesion will reveal the best approach for biopsy, which is usually through an anterior lid crease incision for superior orbital lesions or through a transconjunctival or subciliary incision for lower orbital presentations. Adequate tissue for biopsy should be sent to pathology fresh for both frozen and permanent sectioning from which DNA can be obtained for cytogenetic studies.
In the last two decades, multiple gene mutations have been identified in RMS tumors. This has helped to aid in the diagnosis of these lesions, but has also shown the limitation of histologic evaluation as some lesions can be identified histologically as one subtype, but may have the genetics of a different RMS subtype, thus altering the staging of the tumor. This very thing occurred in one patient we recently followed. The patient underwent an incisional biopsy with pathologic assessment most consistent with embryonal RMS. However, subsequent molecular genetic testing of the biopsy specimen was positive for the PAX3/PAX7-FKHR chimeric gene, indicating that the tumor was actually an alveolar RMS . The patient received a more intensive chemotherapy regimen and also received proton beam radiotherapy. After chemotherapy and proton irradiation, the patient’s tumors shrank considerably, and she has remained in remission at over 3 years of follow-up. This patient is illustrative of the new tools available to the orbital specialist including both molecular genetic testing and proton beam irradiation for diagnosing and treating orbital RMS [23] (Fig. 36.4).
Fig. 36.4
Alveolar rhabdomyosarcoma. (a) An 8-year-old girl presents with painless proptosis that has progressed over 10 days. (b) 6-month status post-IRSG treatment protocol with chemotherapy and proton beam radiation. Ptosis with good levator function is noted on the left side. (c) 6-month status post-left modified Fasanella ptosis repair
A controversy still exists regarding whether more aggressive tumor debulking is indicated for RMS tumors that occur in the orbit alone. While some literature supports the benefit of overall survival with RMS tumor debulking [24], some oncologists and radiation therapists prefer simple biopsy alone followed by chemotherapy and radiation without debulking in an effort to decrease the risk of ocular and periocular iatrogenic injury [25]. It is thus important to work closely with an oncologist, radiation oncologist (and ideally a tumor board), in developing a specific management plan for each patient.
Armed with the tumor diagnosis from the histopathology specimen and the disease stage from the oncology evaluation, therapeutic chemotherapy and radiation regimens can be decided on. Most primary orbital RMS would fall under a group II staging, assuming no distant metastatic sites were found. Several regimens of radiation therapy and chemotherapy have evolved from the different stages of the Intergroup Rhabdomyosarcoma Study . Combination chemotherapy utilizing vincristine, actinomycin-D, and cyclophosphamide (VAC) coupled with local radiotherapy with a dosage range of 4500–5500 cGy yielded markedly improved local tumor control and survival for patients with rhabdomyosarcoma with primary orbital disease over surgical excision alone [19, 26]. Although primary orbital RMS treatment protocols for local control and survival are not related to cell type on histopathology, other extremity sites do have a variable prognosis based on histopathologic typing, as demonstrated in Table 36.4 [27]. These results have been the basis for changes in the treatment regimens in studies II and III of the IRS to improve survivability among the higher-risk cell types, especially alveolar and undifferentiated rhabdomyosarcoma [28, 29].
Table 36.4
Histopathologic risk classification for rhabdomyosarcoma (RMS)
I. Superior prognosis |
1. Botryoid RMS 2. Spindle cell RMS |
II. Intermediate prognosis |
1. Embryonal cell RMS |
III. Poor prognosis |
1. Alveolar RMS 2. Undifferentiated sarcoma |
IV. Subtypes whose prognosis is not presently evaluable |
1. RMS with rhabdoid features |
Significant morbidity can occur from these treatments in young children [30]. Cataracts are a nearly universal complication from the radiotherapy, with visual loss seen in nearly 80% of children treated with orbital rhabdomyosarcoma. Bony orbital hypoplasia results in about 50% of radiation-treated children, with resultant enophthalmos and ptosis, especially when treatment is required under 7 years of age. Keratitis sicca and conjunctival telangiectasia occur with dosages above 5000 cGy. The exact incidence of radiation optic neuropathy and retinopathy secondary radiation is difficult to evaluate due to the occurrence of dense cataracts, precluding adequate examination of the fundus to document these complications. As is seen in other childhood cancer survivors, those with RMS are now demonstrating secondary malignancies years after treatment [31]. Leukemias seem to be related to high doses of cyclophosphamide (>16.8 g/m2). Solid tumors have a tendency to arise in the irradiated field and correlate with actinomycin-D dosage of over 9.6 mg/m2, implicating it as a radiation inducer. In our experience, postradiation ptosis is a common occurrence and will necessitate a ptosis repair. This is ideally delayed for at least 3–6 months to observe if there is any improvement in eyelid height and levator function and to monitor for postradiation keratoconjunctivitis.
Rhabdomyosarcoma stands as a shining example of a cancer for which improved therapy has been fostered through large cooperative trials. Although the treatment of orbital RMS carries significant risks to the eye, survival is excellent, except in those children who present with distant disease. Challenges still exist in reducing the ocular side effects in this otherwise successful therapeutic protocol.
Ectomesenchymoma
This very rare soft tissue tumor is composed of both neuroectodermal and mesenchymal neoplastic elements. The embryologic origin of malignant ectomesenchymomas is the pluripotent migratory cells of neural crest, which give rise to all connective tissue of the globe and orbit [32]. It is often misdiagnosed initially as rhabdomyosarcoma. The presence of neuroectodermal elements helps the pathologist differentiate this lesion from rhabdomyosarcoma [33]. A 2002 review found only 60 reported cases of which only three occurred in the orbit. When the tumor’s predominant element is rhabdomyosarcoma, the treatment is tailored closely to the IRSG protocol for RMS with a similar prognosis. Figure 36.5 depicts our experience with a patient with this rare tumor [32].
Fig. 36.5
Ectomesenchymoma . (a) A 9-month-old with a left orbital tumor that was initially treated for RMS with chemotherapy was referred due to worsening proptosis while on chemotherapy. (b) Coronal MRI with heterogeneously T2 hyperintense and avidly enhancing mass lesion in the extraconal fat of the left orbit at the inferior and medial aspects of the orbit. An incisional biopsy was performed via a lateral canthal and swinging lower eyelid incision. Histopathology showed a malignant ectomesenchymoma. (c) A mixture of undifferentiated primitive small blue cells and more differentiated spindle and strap cells with bright red cytoplasm, consistent with embryonal rhabdomyosarcoma. In addition, scattered maturing ganglion cells are present. Immunostains reveal that the spindled and undifferentiated cells are strongly and diffusely positive for desmin, with approximately 30% displaying nuclear positivity for myogenin. Immunohistochemistry for PAX5 is negative. The ganglion cells and neuritic cell processes stain with NSE, S-100, PGP9.5, and synaptophysin. GFAP is negative. The presence of these neuronal elements in an otherwise typical embryonal rhabdomyosarcoma is consistent with ectomesenchymoma
Soft Tissue Sarcomas
Mesenchymal components of the orbit or other parts of the body that undergo malignant transformation are termed malignant sarcomas. Striated muscle, smooth muscle, connective tissue septa, fat cells, and the cartilage of the trochlea are the mesenchymal soft tissues in the orbit. Primary malignant degeneration in the pediatric population involving orbital mesenchyme is highly unusual. Large clinical series reviewing pediatric soft tissue sarcomas are dominated by rhabdomyosarcoma and often do not include information concerning the orbit as a primary site of neoplasm [34]. Most non-ophthalmic publications report these sarcomas under the more general category of head and neck sarcomas [35].
Table 36.1 includes data from over 1800 cases of pediatric orbital tumors reviewed at six institutions [1–7]. Thirty-six cases of non-rhabdomyosarcoma (non-RMS) soft tissue sarcomas primary to the orbit were identified, accounting for 2.0% of all pediatric orbital lesions seen at these institutions. These included ten undifferentiated sarcomas, five fibrosarcomas, five cases of Ewing sarcoma, five sarcomas secondarily invading the orbit from adjacent areas, four cases of alveolar soft part sarcoma, two chondrosarcomas, two osteosarcomas, one myxosarcoma, one lymphosarcoma, and one chondromyosarcoma. Only alveolar soft part sarcoma has been subjected to large series analysis to define the clinical parameters of the lesion.
No specific symptoms, signs, or imaging features occur with any regularity enabling identification of these lesions prior to biopsy. Wide surgical resection seems to be the preferred treatment for localized lesions, although IRS treatment regimens have been utilized with some success [35].
Alveolar soft part sarcoma is a malignant soft tissue tumor presumably of myogenic origin, affecting peripheral tissues more than head and neck regions [36]. In the study by Enzinger and Weiss of 143 cases from the AFIP, 27.3% involved the head and neck, with most found in the orbit and tongue [37]. Font and coauthors reported 17 cases involving the orbit [36]. Of these tumors, 9 were in children, with a 2:1 female preponderance and two-thirds involving the right orbit. All developed rapidly over a period of 1–3 months with proptosis, swelling, and dilated conjunctival vessels (Fig. 36.6). Imaging studies demonstrate a homogenous anterior orbital mass often displacing the globe and showing moderate enhancement with contrast administration. On biopsy, the tumor often appears well circumscribed and bleeds profusely secondary to the numerous vascular channels. It may appear to be encapsulated. Histologic analysis shows large polyhedral tumor cells lining fibrous trabeculations inside a pseudocapsule border, giving these tumors their characteristic alveolar appearance. PAS tissue preparations demonstrate positive-staining crystalline structures present in nearly all alveolar soft part sarcomas but not seen in any other tumors. Due to the large degree of tumor vascularity, distant metastases to the lung, bone, and brain are seen in about 33% of patients with extremity alveolar soft part sarcoma , whereas no reported cases with orbital presentation have had metastases on initial diagnosis. Surgical excision is the most common therapy because these tumors have demonstrated considerable radioresistance. Chemotherapy has been tried for metastatic disease with mixed results [38]. Long-term survival for these patients is poor, with universal fatality 20 years after diagnosis, although prolonged disease-free intervals are common [39].
Fig. 36.6
Alveolar soft part sarcoma . (a) Clinical photograph demonstrating an alveolar soft part sarcoma arising from the lateral orbit. (b) Axial CT scan with coronal reconstruction showing the intraorbital placement and features of the lesion in the patient in (a)
Angiosarcoma is a rare soft tissue sarcoma more commonly seen in adults [40]. The orbit is an unusual site for head and neck involvement but Hufnagel and colleagues were able to add 14 cases from the literature to their case of primary orbital angiosarcoma [41]. Ten of the fifteen patients were children in this series, which is unusual compared with other sites involved by angiosarcoma. Most patients present with a short history of proptosis with a posterior orbital location and with proptosis, eyelid swelling, and ptosis if the more typical anterosuperior lesion is seen. CT demonstrates a circumscribed mass with enhancement on contrast administration that may infiltrate surrounding structures. Biopsy demonstrates the characteristic angiomatous pattern with irregular lumina and clefts forming sinusoids lined by anaplastic endothelial cells. Due to the abundance of vascularity within the tumor, hematogenous metastases are common and give this tumor a poor prognosis. Treatment usually involves radical excision such as exenteration, since it appears that local control is important for long-term outcome due to its poorly circumscribed nature. Despite adding radiation and chemotherapy, only 10% of pediatric patients are alive after 3 years [41].
Mesenchymal chondrosarcoma is another rare malignancy showing a tendency to arise in bone, as one would expect by the well-differentiated cartilage seen in these tumors. Extraskeletal sites are uncommon but show a predilection for meninges, extremities, and the orbit [42]. These tumors show a peak incidence in the second and third decades of life. Its occurrence in females seems more prominent, and it presents with slow proptosis, diplopia, headache, and pain. CT may show an irregular mass with scattered calcifications and opacities where cartilaginous and bony differentiation occurs. Radical excision is the treatment of choice for these highly malignant tumors with poor prognosis [43]. In the series of ten cases reported by Guccion et al., only one patient survived more than 5 years, a child treated by exenteration for the orbital chondrosarcoma [42].
An important tumor not reported from any institution in Table 36.1 is the endodermal sinus tumor (also called yolk sac tumor or infantile embryonal carcinoma), a malignant neoplasm arising from persistent yolk sac endoderm (germ cells destined to become reproductive glands). These germ cells usually migrate through the mesentery to the genital ridge to become an undifferentiated gonad. Migrating germ cells may alight in aberrant midline locations such as the orbit, where they usually disappear with continued fetal development. Their persistence gives rise to extragonadal germ cell tumors of which endodermal sinus tumor is one malignant variant. Its name arose from histologic similarities among germ cell tumors involving the ovary and certain structures in rat placenta [44]. Typically seen around 1 year of age, proptosis is the main clinical feature in these rare pediatric orbital tumors. They are diagnosed earlier than other extranodal sinus tumors, presumably because of their orbital location, and so aggressive treatment, including surgical excision and triple drug chemotherapy, can result in long-term survival [45]. Clinical and histopathologic features may mimic RMS; immunoperoxidase staining localized to the cytoplasm of the tumor cells is positive for α-fetoprotein in this tumor, helping to differentiate it from RMS. It is suggested that loss of serum levels of α-fetoprotein can help monitor for tumor control as other extranodal sites register this potentially helpful change [46].
Perhaps the rarest of orbital tumors is the nonrenal malignant rhabdoid tumor . This is thought to be of primitive mesenchymal cell origin and typically arises in the kidney. When occurring in children in a nonrenal setting, this tumor is often lethal. One report of a congenital malignant rhabdoid tumor of the orbit has been reported [47]. Figure 36.7 is a similar case in a patient we biopsied.
Fig. 36.7
Congenital malignant orbital rhabdoid tumor . (a) A 4-day-old girl was seen in the NICU for a large orbital tumor. (b) Multiple subcutaneous masses palpable on the trunk and extremities. (c) T2-weighted MRD showing a huge lobulated heterogeneous mass with extensive vascularity involving the right side of the face and neck with right intraorbital extension and mass effect on the adjacent structures. (d) Histopathology densely cellular proliferation of cohesive epithelioid and focally spindle-shaped neoplastic cells. The neoplastic cells have enlarged, frequently eccentrically located ovoid, vesicular nuclei with irregular nuclear contours, conspicuous nucleoli, and a moderate amount of clear to eosinophilic cytoplasm. The tumor grows in a solid sheet pattern. Mitoses and apoptoses are readily seen. These findings and loss of INI-1 immunohistochemical expression are in keeping with a diagnosis of malignant rhabdoid tumor
The diagnosis of most non-RMS soft tissue sarcomas will be made on biopsy. Additional pathologic studies, as discussed in this section, should be done to help differentiate these tumors from rhabdomyosarcoma. With such limited numbers of cases, treatment decisions regarding degree and aggressiveness of surgical intervention, presurgical versus postsurgical chemotherapy, and the role and timing of radiation therapy will depend on pediatric oncology consultation, institutional experience, and the results of case reports showing treatment success. IRSG-style studies may prove beneficial for these rare orbital tumors.
Adenoid Cystic Carcinoma
Typically a primary epithelial lacrimal gland tumor in adults, several cases of this neoplasm have been reported in children [48–52]. Adenoid cystic carcinoma received its name based on the histopathologic features of closely packed cell aggregates separated by large ovoid spaces likening its low-power microscopic appearance to Swiss cheese. In adults, it is the most common epithelial malignancy involving the lacrimal gland. In children, it is the most common epithelial malignancy of the lacrimal gland, though extremely rare in children. The onset of symptoms typically precedes diagnosis by about 1 year, with progressive symptoms of proptosis, globe displacement, and orbital pain being the reasons for patients seeking ophthalmic evaluation. No specific deviations from this presentation are seen in children with adenoid cystic carcinoma compared with adults [50].
There are no specific imaging features that allow one to diagnose adenoid cystic carcinoma directly. Bony invasion is seen in about 33% of cases, but two pediatric cases reported by Rootman and Dolman showed only expansion without invasion, prompting these authors to speculate that perhaps this occurs due to the more pliable nature of bone in children [48]. Five histologic patterns are seen in this tumor: cribriform (Swiss cheese), solid (basaloid), sclerosing, comedocarcinoma, and tubular (ductal). All or several of these patterns may be present in one tumor, but one usually predominates. Gamel and Font reported only a 21% 5-year survival rate among adult patients, demonstrating a basaloid pattern on histopathology, whereas nonsolid patterns had a 71% 5-year survival [53]. Perineural invasion is accredited with being both the source of pain with these tumors and the reason for local and distant recurrence. Direct extension into the intracranial cavity, along with lung metastases, results in a nearly 100% mortality rate 20 years after tumor diagnosis [54]. Treatment consists of initial frozen section biopsy to confirm preoperative suspicions, followed immediately by en bloc excision of the lacrimal gland, tumor, and surrounding orbital bones with or without orbital exenteration in an attempt to resect any potential residual disease. Radiotherapy has been advocated, but two series show no increased survival with its use, although some reserve this modality for local recurrences after radical surgery [53]. It is estimated that the 15-year survival rate is a dismal 22% [53]. More recently Tse et al. have treated this lesion with intra-arterial chemotherapy as a neoadjuvant approach before definitive tumor excision [54]. This has also shown a good initial success in a pediatric patient who eventually underwent a lid-sparing exenteration [52].
Metastatic Orbital Malignancies
Orbital metastases must be strongly considered when faced with a potentially malignant orbital process in children. In Table 36.1, 87 cases were identified, with 14 of these originating from neuroblastoma and 37 occurring from leukemic/lymphomatous disorders. Other sources include 28 cases of Langerhans cell histiocytosis, 5 cases of Ewing sarcoma, 1 metastatic osteosarcoma, 1 metastatic astrocytoma, and 1 metastasis to the optic nerve from a medulloblastoma. Metastases are the second leading cause of a malignant disorder in the orbit of a child, just behind rhabdomyosarcoma.
Leukemic/Lymphomatous Disorders
It is hard to estimate the exact frequency with which hematopoietic malignancies involve the orbit in children (see Chap. 13). At the Hospital for Sick Children in Toronto , 1609 cases of childhood leukemia and 727 cases of childhood lymphoma were diagnosed between 1919 and 1981 [55]. Thirty-six of the leukemia cases had “significant” ophthalmic involvement, which included choroidal and retinal infiltration, optic nerve infiltration, anterior segment infiltration with glaucoma, iritis, iris mass and/or hypopyon, and orbital infiltration. It is not clear how frequent each of these actually occurred, due to a lack of examination in asymptomatic patients, but the highest percentage was seen in children with acute myeloblastic leukemia (8%) versus those with the acute lymphoblastic varieties (3%). Only three of the 727 lymphoma cases had ocular involvement: all 3 cases involved orbital infiltration by non-Hodgkin lymphomas. None of the 482 cases of Hodgkin disease had orbital or ocular involvement according to this 1983 survey, although an orbital pediatric series at the same institution published in 1967 indicated that 3 cases of orbital proptosis in children with Hodgkin disease had been seen [56] (Fig. 36.8).
Fig. 36.8
Optic nerve and orbital AML . (a) 8-year-old with vision loss and eyelid swelling with proptosis. (b) Right fundus photograph showing optic nerve infiltration and retinal venous occlusion. (c) T1-weighted MRI: the right intraorbital optic nerve is diffusely enlarged, with predominantly peripheral enhancement, abutting the optic nerve head, with convex contour into the ocular globe. There is also an enhancing infiltrate of the medial rectus
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