Investigations
Computed tomography (CT) demonstrates a well-circumscribed, nonenhancing, radiolucent mass that molds to the eye and other orbital structures. Bone invasion does not occur. On magnetic resonance imaging (MRI), T1-weighted images show a circumscribed mass isointense to fat and hypointense to muscle, whereas T2-weighted images show lipomas to be hyperintense to muscle and isointense to fat (Fig. 19.1B). The tumor is not enhanced with gadolinium. Ultrasonography shows a hypoechoic mass.
Pathology
Lipomas consist of mature lipocytes in delicate stroma, without increased vascularity. The lipocytes demonstrate slightly increased variation in size and shape compared with those in normal fat (Fig. 19.1C and D). Electron microscopy reveals cells with single, centrally positioned large lipid vacuoles and peripherally placed cytoplasm and nuclei.6 Also present are small spindle cells and preadipocytes, with smaller lipid vacuoles, that are often situated along the interstitial capillaries and are thought to be adipocyte precursors. These cells are more frequently seen in lipomas than normal fat.
Spindle cell/pleomorphic lipoma is a variant that occurs in the orbit, in which there is a variable admixture of spindle cells and rounded, pleomorphic cells containing hyperchromatic nuclei, sometimes multiple and arranged in a floretlike pattern. Other variants include angiolipoma, which is composed of mature adipose tissue with a proliferation of small-caliber vessels most common around the periphery, some of which contain microthrombi and perivascular mast cells, and fibrolipoma, which is fibroadipose tissue associated with conspicuous myxoid change and mild chronic inflammation.7,8 Adipocytes stain immunochemically for vimentin and variably for S-100 protein, leptin, and leptin receptor.
Management
Treatment for lipoma is surgical excision.
Lipoblastoma and Lipoblastomatosis
Lipoblastoma and lipoblastomatosis are rare, benign lipomatous tumors. They constitute 4% to 5% of pediatric adipose tumors and arise from uncontrolled proliferation of lipoblasts in white fat that continues in the postnatal period.3 Lipoblastomas differ from lipomas in that lipomas contain mature lipocytes, whereas lipoblastomas have lipocytes with different degrees of maturation.
Historical Background
The term “lipoblastoma” was first used by Jaffe in 1926 and “lipoblastomatosis” by Vellois in 1958 based on their observation of adipocytes in various stages of differentiation. They suggested that these tumors show developmental arrest of postnatal fat maturation.9 Some feel that the tumors are variants of the same entity, with lipoblastoma occurring as a well-circumscribed mass and lipoblastomatosis as a diffuse and infiltrative mass. Because these tumors do not metastasize, the term “infantile lipoma,” rather than lipoblastoma, was proposed, but it has not been widely adopted.10
Pathogenesis
Lipoblastoma is felt to result from expression of pleomorphic adenoma gene 1 (PLAG1), a developmental gene at 8q12, which leads to the production of its transcription factor protein causing escape from adipose maturation.11
Epidemiology
Approximately 70% to 90% of tumors occur in children less than 3 years of age. Males are affected 1.5 times more commonly compared with females.12 Although rare in the orbit and eyelids, most lipoblastomas arise in the extremities, trunk, abdomen, head, and neck where they spread locally but do not metastasize.
Clinical Features
Only three cases of orbital lipoblastoma can be found in the English language literature since 1966 – two in the eyelid and one in the anterior orbit, with an additional case of diffuse orbital lipoblastomatosis.13 These cases presented with symptoms of eyelid fullness and redness. The other associated symptoms were proptosis, globe displacement, extraocular motility disturbance, and diplopia. The lesions were reportedly palpable and anteriorly located.
Investigations
CT scans show eyelid thickening with a low-density mass. MRI shows a heterogeneous density with areas hypointense to fat in T1-weighted images and areas of increased intensity in T2-weighted images. The tumor heterogeneity reflects the fibrous architecture of the tumor.
Pathology
Grossly, the tumor appears pale yellow with myxoid and cystic foci. Histopathologically, lipoblastomatosis and lipoblastomas contain lobules composed of an admixture of mature adipocytes and multivacuolated lipoblasts demarcated by fibrous septae, an abundant myxoid stroma, and a sparse plexiform vascular network. The embryonic lipoblasts have varying degrees of maturation throughout the tumor. The cells are vacuolated with centrally located nuclei, without evidence of anaplasia or atypia. The myxoid stroma may contain undifferentiated spindle cells.
Cytogenetics plays an important role in diagnosis of lipoblastoma. Detection of chromosomal band 8q11-13 rearrangement has a sensitivity of 77% and specificity of 98% for diagnosis of lipoblastoma.14
Management
Treatment of lipoblastoma and lipoblastomatosis requires complete surgical excision. Meticulous surgical technique is required for resection of more infiltrative tumors to ensure complete excision with preservation of normal tissues.
Prognosis and Complications
Recurrence has been reported up to 50% of cases, evidently representing incomplete excision.15 Late recurrences have been reported, necessitating long-term follow-up.3,12 Although recurrent tumors may cause local dysfunction by transformation into more mature lipoma or fibrolipoma, malignant transformation has not been observed.
Lipodermoid (Dermolipoma)
Lipodermoids are congenital dysgenetic choristomas (healthy tissue growing in an abnormal anatomic location) that derive from the second branchial arch. They constitute 3% of all orbital lesions in adults and 5% in children. They may be associated with developmental anomalies such as Goldenhar syndrome, oculoectodermal syndrome, Emanuel syndrome, and encephalocraniocutaneous lipomatosis (Table 19.1).16–18
Table 19.1
Syndromes Associated With Dermolipomas
| Goldenhar Syndrome (Oculo-Auriculo-Vertebral Dysplasia) | Oculoectodermal Syndrome (Toriello Lacassie Droste Syndrome) | Encephalocraniocutaneous Lipomatosis | Emanuel Syndrome |
| A polymalformative syndrome caused by a defect in the development of the first and second branchial arches | Rare neurodevelopmental syndrome with multisystem involvement (eye, skin, central nervous system, and cardiovascular) | A rare unilateral neurocutaneous syndrome involving tissues from ectodermal and mesodermal origin (skin, eye, adipose tissue, and brain) | A rare imbalance of the chromosome 22, resulting in a polymalformative syndrome with microcephaly and psychomotor delay |
| Ocular manifestations: epibulbar dermoids | Ocular manifestations: epibulbar dermoids | Ocular manifestations: epibulbar or limbal dermoids, lipodermoids, scleral anomalies, ocular and palpebral colobomas, aniridia, microphthalmia, and calcification of the globe | Ocular manifestations: strabismus, myopia, ptosis, conjunctival tumors such as lipodermoids, and Duane anomaly |
| Associated with malformations of the ear and cervical vertebrae, craniofacial dysostosis, skeletal abnormalities renal, and cardiac abnormalities | Associated with aplasia cutis congenita, arachnoid cysts in the brain and seizure disorder, aortic coarctation, progressive bone cysts, hyperpigmented nevi, nonossifying fibromas, and giant cell tumors of the jaw | Associated with lipomatous hamartomas on the face and scalp, ipsilateral intracranial and intraspinal lipomas, aortic coarctation, progressive bone cysts, and jaw tumors | Associated with facial dysmorphism; renal, digestive, and neurologic abnormalities; upper respiratory infections caused by immunologic abnormalities |
Differential Diagnosis
Clinically, prolapsed orbital fat is the main differential diagnosis. Scleral adhesion, a paler color, and firm consistency are clinical features that distinguish lipodermoid from herniated orbital fat, which often shows lipid globules. Small fine hairs and keratinization are common clinical features of lipodermoids but are not seen with fat herniation.
Clinical Features
Dermolipomas are usually unilateral, but, rarely, both eyes may be involved. They are located subconjunctivally and can extend into the anterior orbit, where they sometimes affect the lateral rectus muscle, lacrimal gland, lateral canthal tendon or levator muscle, and aponeurosis. They most commonly involve the superotemporal fornix or lateral canthus and appear as a pink to yellow, soft, rounded mass.(Fig. 19.2A).19 Lipodermoids usually remain stable in clinical appearance but may show slow enlargement or progressive keratinization and hair growth (Fig. 19.2B). For these reasons and because of heightened awareness, patients may seek treatment in their teenage years.
Investigations
CT shows a well-defined, oval, low-density mass in the superotemporal quadrant with an attenuation similar to normal orbital fat. On MRI, the mass is isointense to extraocular muscles or orbital fat on T1- and T2-weighted sequences. The lesion does not enhance with gadolinium.
Histopathologic examination of lipodermoids shows mature adipose and thick bundles of dense collagenous tissue with overlying stratified squamous epithelium. Pilosebaceous units are commonly seen. Occasionally, cartilage, bone, or lacrimal glandular acini may be observed. When conjunctival epithelium is present, it is often irregularly thickened, although it may be thin and smooth.
Management
Most cases can simply be observed but symptomatic or disfiguring lesions can be treated with transconjunctival resection. Associated structures such as the lateral rectus, levator aponeurosis, lacrimal gland, and the lacrimal excretory ducts are prone to surgical damage and should be protected. Resection of the epithelium overlying the lipodermoid may result in forniceal scarring and restrictive strabismus. Resection should be conservative, given the potential risk of keratoconjunctivitis sicca, diplopia, or ptosis.
Prognosis
The prognosis for vision is usually excellent, and there is no malignant potential.
Liposarcoma
Epidemiology
Liposarcoma is the most common soft tissue (nonosteogenic) sarcoma in adults, comprising 20% of all sarcomas. It most commonly affects the thigh and the retroperitoneum but rarely involves the ocular region. Approximately 50 published cases of primary orbital liposarcoma have been reported in the PubMed database of English language publications through 2015.20 Metastatic orbital liposarcoma is even rarer.
The mean age of presentation for primary orbital liposarcoma is 32 years, with a range of 5 to 79 years. Some report equivalent gender distribution, whereas others find a female preponderance.21
Pathogenesis
Cytogenetic studies show that well-differentiated liposarcomas have abnormalities in chromosome 12, especially in the region 12q13-15, where a number of proto-oncogenes, including MDM2, CDK4, and HMGI-C, are amplified.22 MDM2 plays a role in cell proliferation, CDK4 is important in cell cycle regulation, and HMGI-C regulates adipocyte differentiation. In the other subtypes of liposarcoma, a p53 mutation is the most common abnormality. It is suggested that the MDM2 gene plays a role in the pathogenesis of liposarcoma by inhibiting p53. Additionally, the inactivation of the S-phase DNA damage checkpoint through mutations of p53 or MDM2 appears to be one of the factors in the pathogenesis of liposarcoma. Myxoid/round cell liposarcoma has a unique reciprocal translocation between chromosomes 12 and 16. This unique t(12 : 16)(q13;p11) reciprocal translocation leads to the formation of a chimeric CHOP-TLS gene.23 In 10% of tumors, an alternative t(12;22)(q13;q12) translocation involving CHOP and 5′ end of the EWS gene mapped to the q12 region of chromosome 22 has been noted.24 CHOP-TLS and CHOP-EWS chimeric proteins function as oncogenic transcription factors. In pleomorphic liposarcoma, complex chromosomal abnormalities with aneuploidy is observed. Low immunohistochemical expression of p27 in myxoid/round cell liposarcoma correlates with decreased survival.25
Clinical Features
The most common presentation of primary orbital liposarcoma is gradual onset of proptosis, followed by diplopia, vertical or horizontal displacement of the globe, lid swelling, decreased vision, signs of optic nerve compromise, and pain when the tumor is located near the orbital apex.21 The duration of symptoms ranges from several months to 7 years.
Investigations
On CT, orbital liposarcoma usually appears as a heterogeneous, lobulated mass. It is usually well-circumscribed but may be ill-defined.21 It enhances well and heterogeneously with contrast.
On MRI, orbital liposarcoma is isointense to hypointense to muscle on T1 images and hypointense compared with surrounding fat on T2 images (Fig. 19.3A and B). Dense septae can be observed within the lesion. It enhances diffusely with gadolinium. Enhancement is mild in myxoid liposarcomas and marked in pleomorphic liposarcomas (see Pathology below) and greater at the periphery.
Most orbital liposarcomas involve the intraconal space, followed by the superior orbit. It is rarely located medially, laterally, or inferiorly.
Pathology
On gross examination, liposarcomas appear as yellow to yellow-white soft/jelly like or firm/lobulated masses. They are thought to originate from primitive stromal cells in the intermuscular fascial planes or pluripotential mesenchymal cells around capillary-sized blood vessels.26
Classification
The World Health Organization (WHO) recognizes four subtypes of liposarcoma:
1. Atypical, well-differentiated – this form rarely metastasizes, but it recurs locally and causes local destruction
2. Myxoid/round cell – this form is locally aggressive and can metastasize
3. De-differentiated – this form is very aggressive and highly malignant
The atypical well-differentiated and myxoid forms are the most common subtypes and occur in the extremities. In the orbit, the most common subtype is myxoid/round accounting for more than 50% of tumors, followed by atypical well-differentiated and pleomorphic subtypes.21 The atypical well-differentiated subtype contains mature adipocytes with significant atypia and variable cell size.27 Vacuolated lipoblasts and hyperchromatic, multinucleated stromal cells are present in varying numbers28 (Fig. 19.3C and D). The myxoid/round-cell subtype contains uniform, round- to oval-shaped, primitive mesenchymal cells and small lipoblasts with signet-ring appearance as a result of nuclei displaced by large lipid droplets. This form has a myxomucinous stroma and intricate, arborizing vascular pattern within a variably fibrillar network. The de-differentiated subtype has lipoblasts that show abrupt histopathologic transition from low-grade, well-differentiated areas to high-grade patterns of pleomorphic sarcoma.28 The pleomorphic liposarcoma subtype is composed of pleomorphic multivacuolated lipoblasts in high-grade pleomorphic sarcoma (malignant fibrous histiocytoma-like sarcoma). Pleomorphic cells vary in shape from round to spindle-shape, with the latter type being arranged in fascicles.
Management
Tumor excision with wide surgical margins is the treatment of choice, often requiring orbital exenteration. Orbital exenteration with clear resection margin provides the best local control of primary liposarcomas. Incomplete resection poses a high risk of recurrence. If the tumor recurs, it may de-differentiate into a more malignant phenotype.
External beam radiotherapy is commonly used to treat tumor recurrences. Most of tumors are resistant to chemotherapy, but cytotoxic drugs are used for palliative treatment in metastatic disease.
Prognosis
The overall 10-year survival of liposarcomas ranges from 50% to 85%.20 Primary orbital liposarcomas have a favorable prognosis, as no cases have been reported to develop metastasis. Their better prognosis likely results from a combination of small tumor size at the time of diagnosis and more favorable tumor subtype.
Skeletal Muscle Tumors
Rhabdomyosarcoma
Epidemiology
Rhabdomyosarcoma is the most common malignant orbital tumor in children and the most common soft tissue sarcoma of the head and neck in childhood.29 It involves the genitourinary system (29%), parameningeal tissue (24%), extremities (15%), retroperitoneal space (13%), orbit (8%), and other head and neck sites (7%).30 In a review of population-based incidence, an annual 1.16% increase in incidence of head and neck rhabdomyosarcoma was seen between 1973 and 2007.31
Rhabdomyosarcoma may arise primarily in the orbit or invade from adjacent sinuses, as a proliferation of pluripotential mesenchymal cells that demonstrate striated muscle cell differentiation. Rarely, orbital rhabdomyosarcoma occurs as a result of distant metastasis. Constituting 4% of all pediatric malignancies and 10% of orbital tumors, it affects patients in the first decade of life, with mean ages for primary and secondary orbital rhabdomyosarcomas of 7 and 12 years, respectively.29,32 There is a male predilection, with a ratio of 5 : 3.29,32
Rhabdomyosarcomas are mostly sporadic but can be seen in some genetic cancer predisposition syndromes such as neurofibromatosis, Li-Fraumeni syndrome, Costello syndrome, Noonan syndrome, familial cancer syndrome, and Beckwith-Wiedemann syndrome.33
Clinical Features
Orbital rhabdomyosarcoma usually presents abruptly with progressive proptosis developing over days to weeks with associated ptosis, a palpable firm mass, and globe displacement, which is downward and outward because of the predilection of rhabdomyosarcoma for the superomedial orbit.34,35 When the eyelids are involved, bluish or reddish discoloration of the eyelid may mimic an acute infection or ecchymosis. Incidental trauma is said to delay diagnosis in many cases. If there is compression of the globe or of the optic nerve, choroidal folds and optic disk edema may be observed (Fig. 19.4A). The alveolar subtype has a predilection to inferior quadrants.
Secondary rhabdomyosarcoma originating from the adjacent paranasal sinuses can present with unilateral or bilateral orbital involvement. Orbital rhabdomyosarcoma can erode the skull base to involve the brain or metastasize to the lung, bone, or bone marrow.36
Investigations
On CT, rhabdomyosarcoma appears as a well-circumscribed, homogeneous, soft tissue mass in early stages. Later, the borders become irregular as a result of pseudocapsular invasion. The mass is isodense to muscle. However, extraocular muscles are rarely enlarged.36 Hemorrhage or necrosis causes heterogeneous radiodensity. It is usually located in the extraconal space in 37% to 87%, or both intraconal and extraconal spaces in 13% to 47%, of cases36 (Fig. 19.4B).
On MRI, the rhabdomyosarcoma appears as a homogeneous or heterogeneous irregular mass that is isointense to extraocular muscles and hypointense to orbital fat on T1-weighted images. It is hyperintense to both orbital fat and extraocular muscles on T2-weighted images.37 It shows moderate to marked enhancement with gadolinium. The tumor shows better delineation with fat suppression (Fig. 19.4B).
Pathology
Definitive diagnosis of rhabdomyosarcoma is based on surgical biopsy. Rhabdomyosarcomas are composed of cells with considerable pleomorphism and high mitotic activity. The cells contain enlarged hyperchromatic nuclei with variable amounts of amphophilic to eosinophilic cytoplasm (Fig. 19.4D).
Rhabdomyosarcomas are divided into embryonal, alveolar, pleomorphic, and botryoid subtypes based on clinical, genetic, and histopathologic features.
Embryonal rhabdomyosarcoma is the most common variant, comprising 50% to 70% of orbital rhabdomyosarcoma.36 It has highly cellular areas alternating with less cellular myxoid areas in a pattern of interlacing fascicles. Bipolar cells with tapered cytoplasmic processes and occasional larger eosinophilic cells with strap, ribbon, tadpole, or racquet shapes may be seen. The eosinophilic cytoplasm contains bundles of actin and myosin filaments, which sometimes form cross-striations that may be visible with Masson’s trichrome or phosphotungstic acid-hematoxylin histochemical stains. The embryonal subtype may affect the conjunctiva, anterior orbit, and eyelid. This is the classic histologic variant from which rhabdomyosarcoma derives its name.
The botryoid (from Greek botrus meaning “bunch of grapes”) variant of embryonal rhabdomyosarcoma has grossly visible grapelike protrusions and generally affects the mucosa of the genitourinary tract or conjunctiva.
Alveolar rhabdomyosarcoma constitutes 20% to 30% of orbital rhabdomyosarcoma, occurs in older children, and involves the inferior part of the orbit. Histopathologically, it is a highly cellular tumor and constitutes large primitive round cells with hyperchromatic nuclei, coarse chromatin, and prominent nucleoli. The tumor cells form ill-defined aggregates of loosely arranged, poorly differentiated malignant cells separated by thin fibrovascular septa into irregular ovoid spaces, resembling an alveolar pattern, which gives this subtype its name. Tumor giant cells contain multiple peripheral nuclei as a result of fusion of rhabdomyoblasts.
Unique chromosomal translocations, (2;9)(q35;q14) or (1;13)(p36;q14), resulting in the formation of two chimeric genes, PAX3-FKHR and PAX7-FHKR, are observed in more than 80% of alveolar rhabdomyosarcoma.38
Pleomorphic rhabdomyosarcoma is the least common variant and affects only adults with an average age of 56 years.39 It has numerous haphazardly arranged pleomorphic, undifferentiated cells. These cells are composed of variable proportions of rhabdomyoblasts in the polygonal, spindle, tadpole, and racketlike shape with dense eosinophilic cytoplasm and hyperchromatic nuclei.39
On histopathologic examination, cross-striations are common in more than half of embryonal rhabdomyosarcomas but rare in alveolar and pleomorphic rhabdomyosarcomas. On periodic-acid-Schiff stain, glycogen is seen in most of rhabdomyosarcoma subtypes. Immunohistochemical staining reveals strong vimentin reactivity, even in poorly differentiated tumor cells; desmin and muscle-specific actin in developing rhabdomyoblasts; and myoglobin, myosin, and creatine kinase M in well-differentiated cells.40 Immunoreactivities for desmin and muscle-specific actin are present in 95% to 100%, myogenin in 91%, MyoD in 91%, and myoglobulin in 28% of all rhabdomyosarcomas.39 However, MyoD and myogenin gene expression is driven by the fusion protein formed in alveolar rhabdomyosarcoma, and immunoreactivity for these two proteins is usually more regular and intense in alveolar rhabdomyosarcoma.41
Management
Suspected orbital rhabdomyosarcoma must be biopsied promptly and surgically debulked as much as possible without causing undue morbidity, although there is controversy over surgical debulking. This approach improves staging and tumor response to treatment.
Established chemoradiation protocols are extremely effective in treating this entity. Chemotherapy (vincristine, actinomycin D, and cyclophosphamide) and external beam radiotherapy are used. Based on the intergroup rhabdomyosarcoma study, patients with completely resected embryonal rhabdomyosarcoma do well without external beam radiotherapy42 (Table 19.2).
Prognosis
The Intergroup Rhabdomyosarcoma Study showed greater than 90% survival at 5 years for orbital rhabdomyosarcoma, with embryonal survival of 94% to 97% and alveolar survival of 74% at 5 years, respectively.40,41 Patients with group 1 orbital or eyelid tumors are usually cured with chemotherapy; those with group 2 disease almost always cured with additional postoperative radiotherapy. The worst prognosis is for patients who present with or develop metastasis, usually to the lung or bones, having a 3-year survival rate of 70%.
Fibrous Tumors
Nodular Fasciitis
Epidemiology
Nodular fasciitis has been variously designated as pseudosarcomatous fibromatosis, proliferative fasciitis, and nodular fibrositis.43 Nodular fasciitis occurs in all age groups, with an equal incidence in males and females. The majority of the reported cases have been in young adults between 20 and 40 years, and only nine cases have been reported in individuals less than 20 years of age.43 The entity has been frequently encountered in the subcutaneous fascia of the trunk and upper extremities. In infants and children, however, head and neck and periorbital tissues are more commonly involved.44
Nodular fasciitis is a reactive, benign proliferation of fibroblast and myofibroblasts, first described by Font and Zimmerman in 1966. 43,44 It rarely develops in the orbit, with only two cases identified an a large series of 1264 orbital space occupying lesions.43 It may affect the anterior ocular structures, including the eyelid, epibulbar surface, and corneoscleral limbus. Nodular fasciitis originating from the Tenon capsule45 and episclera have been reported.46
Pathogenesis and Etiology
Although trauma has been suggested as a trigger, most cases do not include history of trauma.48 In some studies, a high proportion of the proliferating cells were found to be in the S and G2 growth phases and as a polyclonal cellular expansion using HUMARA-methylation-specific polymerase chain reaction. This suggests a reactive rather than a neoplastic process.49
Clinical Features
Nodular fasciitis lesions are well circumscribed and fast growing and may show clinical signs of inflammation, including pain lasting 1 month or less.43,44 They present as superficial, palpable masses and can cause eyelid deformity. Only one case of nodular fasciitis has been reported posterior to the equator of the globe causing proptosis.50
Investigation
Although there are no distinctive features on CT and MRI, typically nodular fasciitis presents as well-defined, superficial soft tissue masses with moderate to marked enhancement and local bony erosion.51
Differential Diagnosis
Because the clinical features and the radiologic findings are nonspecific, some differential diagnoses include dermoid or epidermoid cyst, hemangioma, sarcoidosis, aggressive fibromatosis, dermatofibroma, fibrosarcoma, and malignant fibrous histiocytoma. In children, dermoid cyst, rhabdomyosarcoma, eosinophilic granuloma, metastatic neuroblastoma, and granulocytic sarcoma are also to be considered.
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