Zhang Hong, Ophthalmology Department, Second Hospital of Tianjin Medical University, China
Abstract Orbital rhabdomyosarcoma is the most common orbital malignant tumor in childhood, with early age of onset, rapid disease development, difficult treatment and poor prognosis. The tumor mostly occurs before the age of 10 years and is more common in males. The tumor originates from mesodermal multipotential stem cells and histologically divides rhabdomyosarcoma into embryonal, glandular follicular and pleomorphic types. The most prominent clinical manifestations are unilateral rapidly developing ocular protrusion, eyelid and conjunctival congestion and edema, hard periorbital masses, advanced incomplete lid closure, and exposure keratitis. MRI shows a medium signal in T1WI and a high signal in T2WI, showing that intracranial spread is dominant. Diseases to be differentiated include subperiosteal hemorrhage, orbital cellulitis, dermatomal cyst, vascular tumor, vascular malformation, histiocytosis, leukemia, lymphoma, and neuroblastoma metastatic to the orbit. The current treatment principle is to preserve vision and prevent complications, and the treatment is supplemented by radiation and chemotherapy after tumor resection. The overall 5-year survival rate of orbital rhabdomyosarcoma is over 90%. Zhang Hong, Ophthalmology Department, Tianjin Medical University Sino-Singapore Eco-city Hospital
Keywords rhabdomyosarcoma, orbit, differential diagnosis
Orbital soft tissue tumors in children are different from adults in that they have histological and imaging characteristics. Most tumors originate from the mesoderm, and the most common malignant tumor is rhabdomyosarcoma, which occurs mostly in young children and has a rapid development and poor prognosis. Vascular diseases, including vascular tumors and developmental vascular malformations, can also occur in the orbit, with infantile hemangiomas being true tumors that occur in infancy with an abundant blood supply. The age of predilection for venous and lymphatic malformations or lymphangioleiomas is the same as for rhabdomyosarcoma. Fibrous tissue hyperplasia in infants or adolescents is a rare and aggressive histiocytic disease that presents as orbital bone destruction. These diseases are identical to rhabdomyosarcoma in that they both present clinically with ocular protrusion, but the treatment and prognosis are very different and therefore need to be differentiated with the help of imaging to facilitate the diagnosis and treatment of the disease.
Rhabdomyosarcoma is the most common mesodermal tumor in childhood, accounting for approximately 5% of childhood malignancies [1,2], and it is also the most common orbital malignancy in childhood, with a ratio of approximately 1:10 with retinoblastoma, the most common intraocular malignancy in childhood [3-5]. More than 1/3 of rhabdomyosarcomas originate from the head and neck, and those originating from the orbit account for about 25%-30% of head and neck rhabdomyosarcomas and 10% of all rhabdomyosarcomas [6-8]. Rhabdomyosarcoma from adjacent sites may also spread locally to the orbit, such as the nasopharynx, pterygopalatine fossa, infratemporal fossa, or paranasal sinuses, or may metastasize from distant sites to the orbit [7]. The most common histological type of rhabdomyosarcoma involving the orbit is the embryonal type.
While the previous view was that rhabdomyosarcoma originated from skeletal muscle, such as the intra-orbital extraocular muscle, it is now generally accepted that rhabdomyosarcoma originates from mesodermal multipotential stem cells capable of differentiating into skeletal muscle. This view explains why primary rhabdomyosarcoma can occur in sites where skeletal muscle is not present, such as the nasopharynx, paranasal sinuses, and bile ducts [4,8].
I. Pathogenesis and clinical features
Primary orbital rhabdomyosarcoma most commonly occurs before the age of 10 years, with a mean age of onset of 6-8 years [3,4,6], but can occur at any age, from infancy to 68 years [3], and the relatively rare adenoidal rhabdomyosarcoma usually occurs in older children or adolescents [4], and is more common in males, with a male to female ratio of approximately 5:3 [9].
The main clinical manifestations of rhabdomyosarcoma are rapidly progressive protrusion and displacement of the eyeball, in addition to swelling and congestion of the conjunctiva and eyelid, and incomplete lid closure, with an appearance similar to orbital cellulitis.
Transverse myxosarcoma is almost always unilateral, and Sohaib et al have reported one case of unilateral orbital multiple tumors. Most of the tumors occur outside or both inside and outside the muscle cones, most typically in the superior orbital quadrant or in the upper part of the orbit, where 33% to 53% of embryonal rhabdomyosarcomas occur, and adenoid rhabdomyosarcomas most often involve the lower part of the orbit [10].
Pathological features
Rhabdomyosarcoma is soft, fish-like, and light gray, pink or yellow in cut surface, with a mucus-like appearance due to the rich cellular stroma of the tumor. Smaller tumors have clear borders, and large tumors have irregular borders due to the invasion of the pseudocystic membrane of the tumor. There may be hemorrhage or cystic changes within the tumor [4,6].
Histologically rhabdomyosarcomas are classified as embryonal, glandular follicular and pleomorphic, but many tumors can include both subtypes. Most orbital rhabdomyosarcomas are embryonal and are common in young children. The glandular follicular type is less common in the orbit and the pleomorphic type is less common in children and even less common in the orbit [11].
Embryonal rhabdomyosarcoma is composed of elongated or spindle-shaped tumor cells with different degrees of differentiation, rich in eosinophilic cytoplasm, with a central nucleus that is densely stained and cells arranged in crossed or herringbone bundles. Bipolar cells rich in conical cytoplasm are more common, while long cells with eosinophilic cytoplasm in a tadpole shape are less common. About 60% of the tumors stained with trichrome or hematoxylin phosphotungstate stain, and crossed streaks were seen in the cytoplasm. These streaks are composed of bundles of actin and myosin filaments, suggesting a specific diagnosis of skeletal muscle differentiation. The surrounding stroma is lax and mucinous.
The less common glandular follicular pattern is characterized by a thin fibrovascular septum that divides the tumor into round or ovoid interstitial spaces with large, round or polygonal tumor cells containing abundant eosinophilic cytoplasm. The nuclei are large and cystic, and these cells are loosely adherent to the thin connective tissue septa [4].
III. Local spread and metastasis
Transverse myosarcoma is rapidly growing and aggressive, often invading adjacent bones and soft tissues; nowadays, extensive metastases are rarely seen due to early diagnosis.
Bone erosion is seen in 30%-40% of patients, invasion of paranasal sinuses is about 20%, and intracranial spread is relatively rare, about 3%. Local lymph node metastases are relatively rare except in advanced stages of the disease, due to the lack of lymphatic tissue in the posterior orbit. Distant metastases are mostly hematogenous, mostly to lung and bone [3], and orbital rhabdomyosarcoma leading to systemic metastases is less common than those to other sites.
Imaging features
Ultrasonography is not specific for orbital rhabdomyosarcoma, especially for those with intracranial spread, and B-mode ultrasound shows a round-like tumor with clear borders, low or moderate internal echogenicity and uneven distribution. Color Doppler ultrasound reveals abundant colored blood flow signals within the tumor [12,13].
CT and MRI play an important role in the preoperative evaluation, staging and follow-up of rhabdomyosarcoma and are suitable to show the aggressive behavior of the tumor. ct is most suitable to show bone involvement and MRI is advantageous to show intracranial spread. Continuous CT follow-up can show improvement or deterioration of bone involvement and the extent of tumor response to treatment, while MRI can observe tumor remnants and recurrence. Residual tumor after treatment predicts a poor prognosis [14].
Transverse myxosarcoma shows on CT as irregular ovoid shape outside the muscle cone with clear border and homogeneous tumor with the same density as extraocular muscle, calcification is seen in lesions with adjacent bone destruction, and the border is unclear when the tumor is large. Necrosis and hemorrhage within the tumor are uncommon, and if CT shows the tumor to be heterogeneous. Soft tissue thickening of the eyelid is often present whether or not the tumor has spread to the eyelid. The tumor is moderately or markedly enhanced after contrast enhancement injections. Occasionally, circumferential enhancement of the tumor is seen. Sometimes CT shows the tumor inextricably linked to the extraocular muscles, but often the muscles are displaced or obscured, and rarely there is muscle thickening. CT in about 40% of patients shows skeletal erosion or thinning, especially in larger tumors.
MRI shows orbital rhabdomyosarcoma with isosignal to muscle or brain tissue at T1WI and high signal at T2WI. Subacute hemorrhage within the tumor shows high signal in both T1WI and T2WI. Normal structures in the orbit may be obscured by the tumor. After injection of contrast intensifier, the tumor shows moderate or significant uniform and consistent enhancement. Ocular deformation or displacement is seen, but rarely invaded. MRI shows tumor spreading to adjacent paranasal sinuses or intracranially.
V. Differential diagnosis
Many benign and malignant tumors have similar clinical presentation and imaging features to rhabdomyosarcoma, but rhabdomyosarcoma should be considered first in children with unilateral onset and rapidly progressive ocular proptosis.
1. Subperiosteal hemorrhage Subperiosteal hemorrhage due to trauma is similar in appearance to rhabdomyosarcoma, especially on CT scan, because it can cause erosive changes as the hemorrhage subsides. Some patients are unaware that they have rhabdomyosarcoma and imaging after trauma is mistakenly attributed to trauma [9]. MRI is helpful in showing hematocrit signal changes.
Orbital cellulitis Orbital cellulitis and abscesses are similar to rhabdomyosarcoma and often present with rapid onset of eyelid swelling and protrusion of the eyeball, both of which can show orbital swelling and involvement of the adjacent paranasal sinuses. Enhanced MRI can differentiate between paranasal sinus secretions and tumors. In rare cases, rhabdomyosarcoma shows circumferential enhancement, similar to an abscess. Fever, leukocytosis, and inflammatory changes in the orbital fat on CT suggest orbital infection. In addition, orbital cellulitis is more common than rhabdomyosarcoma.
3. Dermatomal cysts Dermatomal cysts are the most common orbital tumors in childhood. If the cyst ruptures, the surrounding tissues develop an intense inflammatory response that clinically and imagingly resembles rhabdomyosarcoma. Imaging shows cystic changes with internal visible fat and calcification, features not present in rhabdomyosarcoma. Bone changes are mostly seen in dermatomal cysts, with bone depression formation visible at the zygomatic frontal suture, unlike the bone destruction seen in rhabdomyosarcoma [15].
Orbital vasculogenic tumors can occur in young children and can present with clinical manifestations similar to those of rhabdomyosarcoma. Capillary hemangioma is a benign tumor that is mainly due to abnormal proliferation of vascular endothelial cells. It develops at a younger age than rhabdomyosarcoma, usually within 1 year of age, and most children develop clinical signs within a few months of birth, although a very small number of rhabdomyosarcomas can occur in the neonatal period and should be differentiated. Capillary hemangiomas develop rapidly within 1 year of age, suggesting features of a malignant tumor. Hemangiomas are rich in blood vessels and the use of dynamic contrast-enhanced CT or MRI can help in the differential diagnosis. MRI can show flowing cavities around and within the lesion, suggesting features of a high-flow hemangioma. However, a few rhabdomyosarcomas are rich in blood supply and also show significant enhancement on enhanced CT or MRI. The diagnosis may be suggested by the presence of cutaneous hemangiomas of the same nature elsewhere in the child’s body.
Patients with orbital vascular malformations sometimes resemble malignant tumors in appearance [16]. The disease usually contains both lymphatic and venous components and develops in the same age group as rhabdomyosarcoma, often presenting for sudden eye protrusion, mostly due to bleeding or infection within the lesion, and is often misdiagnosed as rhabdomyosarcoma [6]. On imaging, the vascular malformation is cystic in nature and is often spaced into multiple luminalities with poorly defined lesion borders. Due to internal bleeding in cystic lesions, fluid planes are visible, which are extremely rare in rhabdomyosarcoma. Enhanced CT or MRI shows larger lesions that are not enhanced centrally and may have moderate enhancement around them, called circumferential enhancement. In contrast, rhabdomyosarcoma does not have circumferential enhancement. Venous vascular malformations may have venous stones, which may help in the differential diagnosis with rhabdomyosarcoma.
5. histiocytosis Langan cell histiocytosis is a histiocytic lesion with aggressive behavior occurring in children. orbital involvement accounts for 23% of systemic histiocytosis in children, and all invade the bone. Because the lesions originate in bone tissue and can spread directly to the orbit, the imaging presentation of orbital Langheim cell histiocytosis is extremely similar to that of rhabdomyosarcoma with bone invasion, except that the former has more significant bone destruction [17]. Both diseases can spread to the adjacent paranasal sinuses or to the skull. Histiocytosis is usually accompanied by uveitis and bone lesions elsewhere in the body. Transverse myxosarcoma can also reach the bones in case of systemic metastasis.
Leukemia and lymphoma account for approximately 10% of orbital tumors [9], with the most common orbital tumors being granulocytic leukemia (green tumor) and non-Hodgkin’s lymphoma, the former in young children and the latter in older children. Green tumors can be bilateral, whereas rhabdomyosarcomas are unilateral in the orbit. Peripheral blood pictures are helpful in suggesting a diagnosis of leukemia. The final differential diagnosis requires biopsy or bone marrow aspiration to confirm the diagnosis. Orbital lymphoma can be primary or part of a systemic lymphoma. Non-Hodgkin’s lymphoma is most likely to invade the orbit, and although it occurs most often in the elderly, it can also be seen in older children or adolescents. Unlike rhabdomyosarcoma, which often involves the lacrimal gland, MRI shows a low signal lesion in T2WI and casting-like changes with the eye, whereas rhabdomyosarcoma has a high signal in T2WI and compresses the eye with deformation [18].
7. neuroblastoma Metastatic neuroblastoma to the orbit is not uncommon and is similar to rhabdomyosarcoma bone invasion, and the finding of a primary tumor behind the retroperitoneum or mediastinum is highly suggestive of neuroblastoma [9].
VI. Treatment and prognosis
CT or MRI helps to stage the tumor, and staging is the most important treatment and prognosis indicator. The International Research Collaborative Group on Rhabdomyosarcoma divided orbital rhabdomyosarcoma into four groups, group 1 for tumor is relatively limited and can be completely resected; group 2 has residual tumor tissue on microscopic examination after surgery; group 3 refers to the residual tumor visible to the naked eye after biopsy; group 4 has distant tumor metastasis [7], and most orbital rhabdomyosarcomas are group 3 [4].
An open biopsy should be used to confirm the diagnosis, and fine needle aspiration biopsy should not be used as much as possible, especially for posterior orbital tumors, because needle aspiration biopsy cells are easily deformed and delay the diagnosis [6,14].
Until the early 1970s, orbital rhabdomyosarcoma was still treated by enucleation of the orbital contents, however, the prognosis remained poor, with a 5-year survival rate of approximately 20%. Therefore, the International Rhabdomyosarcoma Research Collaborative Group was formed to improve the treatment. Current treatment is mainly after incision or excisional biopsy, or surgical volume reduction, supplemented by radiation and chemotherapy. The 5-year survival rate for orbital rhabdomyosarcoma is now greater than 90%, and the overall 5-year survival rate for systemic rhabdomyosarcoma is approximately 70% [1,4]. The prognosis of different staging of rhabdomyosarcoma varies from about 94% for the embryonic type to poor prognosis for the glandular follicular type, with a 5-year survival rate of about 74% [1]. The current principles of treatment are preservation of vision and prevention of treatment complications, such as second tumors after radiation.
Factors with good prognosis include absence of distant metastases, primary site in the orbit and disease confined to the orbit, complete tumor resection under visual observation, patient age less than 10 years, histological typing of embryonic type, high hyperdiploid DNA component, and tumor less than 5 cm. the most important prognostic factor is response to treatment, and regular imaging allows observation of the effect of the tumor on treatment.
In conclusion, orbital rhabdomyosarcoma is the most common malignant tumor in childhood with rapid development and poor prognosis. Proficiency in the pathogenesis, clinical manifestations, imaging features, differential diagnosis and treatment principles of this disease can lead to early diagnosis, timely treatment and greatly improve the cure rate and survival of patients.