Case 4-2004 — A Nine-Month-Old Boy with an Orbital Rhabdomyosarcoma
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《新英格兰医药杂志》
Presentation of Case
Dr. Torunn Yock (Radiation Oncology): A nine-month-old male infant was referred to this hospital for treatment of an orbital rhabdomyosarcoma. The patient had been well until the age of six months, when excessive tearing developed. Over the next two days, his right eye was noted to be puffy and red. His pediatrician made a diagnosis of conjunctivitis. Topical treatment with a combination of bacitracin and polymixin B sulfate (Polysporin) had no effect, and two days later, proptosis developed (Figure 1A). The infant was referred to an ophthalmologist for evaluation and treatment of a possible orbital infection. A computed tomographic (CT) scan obtained nine days after the onset of symptoms (Figure 2A) revealed a mass involving the lateral orbital musculature, with no evidence of bony erosion or invasion. A magnetic resonance imaging (MRI) scan obtained the same day (Figure 2B and Figure 2C) showed a well-defined mass posterior and lateral to the globe, 2.2x1.5 cm; it displaced the optic nerve medially and involved the lateral and superior rectus and superior oblique muscles. The infant was admitted to a local hospital for a biopsy under CT guidance.
Figure 1. Photographs of the Patient.
At presentation (Panel A), there is striking proptosis of the right orbit. By the last day of proton radiation therapy (Panel B), the proptosis has resolved, and there is slight redness of the surrounding skin.
Figure 2. CT and MRI Scans Obtained at the Time of the Initial Evaluation.
A coronal CT image of the head, obtained without the use of contrast material, shows a large mass in the superolateral aspect of the right orbit (Panel A, arrows). The mass is indistinguishable from the superior rectus, the superior oblique, and the lateral rectus muscles as well as from the lacrimal gland, and it compresses the optic nerve. On an axial T1-weighted MRI scan, the mass is isointense relative to muscle (Panel B, arrow). On an axial T2-weighted MRI scan, it is slightly hyperintense relative to muscle (Panel C).
The patient and his family resided in Canada. He had been born at full term by normal, spontaneous vaginal delivery after an uncomplicated pregnancy. He had been well since birth. His two older brothers were well. There was no family history of childhood cancers. A paternal grandfather had died of lung cancer, and a maternal aunt had died of liver cancer.
On physical examination, the patient appeared to be well and was active. On the right side, there was proptosis with inferior and medial deviation of the eye, as well as bruising and edema of the eyelid. Eye movement was present but limited. There was no purulent discharge or conjunctival injection. The other findings on physical examination were normal.
A biopsy of the orbital mass disclosed embryonal rhabdomyosarcoma. CT scanning of the chest and abdomen, a bone marrow biopsy, and a lumbar puncture showed no evidence of metastatic disease. A bone scan showed increased uptake of tracer in the lateral aspect of the right bony orbit but no evidence of distant disease.
Six days later, combination chemotherapy with vincristine, dactinomycin, and cyclophosphamide was begun. One week after the initiation of chemotherapy, the proptosis markedly worsened. CT scanning revealed an enlarged tumor mass with areas of hypodensity, a finding consistent with the presence of necrosis. The increase in the size of the mass was thought to be due to edema from treatment-induced necrosis. Dexamethasone was administered, and the proptosis subsequently improved. Members of a tumor board at the local institution convened and recommended discontinuing the cyclophosphamide and instead administering vincristine and dactinomycin, followed by radiation therapy. Because of the patient's young age and the high risk of long-term side effects from standard photon radiation therapy, they recommended referral to this hospital so that proton radiation therapy could be considered.
The patient received three cycles of chemotherapy at the local hospital; the treatment was complicated by hepatic veno-occlusive disease and two episodes of febrile neutropenia. The mass decreased in size. Three months after the diagnosis, the patient was brought to this hospital for proton radiation therapy.
On evaluation in the clinic, the patient was pale but otherwise appeared to be well and was crawling actively. Examination of the head and neck revealed mild periorbital swelling of the right eye. There was no preauricular, supraclavicular, or cervical lymphadenopathy. The left eye was normal. The findings on physical examination were otherwise unremarkable.
Dr. Pamela W. Schaefer: The initial CT scan of the head, obtained without the use of contrast material (Figure 2A), reveals a large mass in the right superolateral aspect of the orbit. The mass is isodense in relation to muscle and is indistinguishable from the superior oblique, superior rectus, and lateral rectus muscles as well as the lacrimal gland. There is a thin layer of fat between the mass and the right optic nerve, but the mass compresses the optic nerve. The bones surrounding the orbit and the brain parenchyma appear to be normal. MRI scans obtained the same day show that, relative to muscle, the mass is isointense on T1-weighted imaging (Figure 2B) and slightly hyperintense on T2-weighted imaging (Figure 2C). The mass was densely and homogeneously enhanced after the administration of gadolinium. There was no abnormal enhancement in the adjacent bony structures or brain parenchyma.
The differential diagnosis of an orbital mass in a young patient includes rhabdomyosarcoma, eosinophilic granuloma (Langerhans'-cell histiocytosis), granulocytic sarcoma, lymphoma, and benign lesions, such as hemangioma and lymphangioma. Eosinophilic granuloma usually involves bone. In lymphoma and leukemia, there is usually, but not always, evidence of systemic involvement. Hemangiomas and lymphangiomas are usually bright on T2-weighted images.
Contrast-enhanced axial CT scans and gadolinium-enhanced MRI scans (Figure 3) obtained after chemotherapy show that the densely enhancing mass has markedly decreased in size. The mass effect on the adjacent orbital structures has decreased, as has the proptosis.
Figure 3. MRI Scans Obtained after Chemotherapy.
After chemotherapy, the right orbital mass is smaller, and the proptosis has lessened. On an axial T1-weighted image, the mass is isointense relative to muscle (Panel A). On an axial T2-weighted image, the mass is more hyperintense relative to muscle than it was before treatment (Panel B).
Pathological Discussion
Dr. Benjamin L. Hoch: Microscopical examination of the biopsy specimen from the orbital tumor disclosed sheets and fascicles of rounded and spindled cells with alternating cellular and myxoid regions. The tumor cells have elongated, hyperchromatic nuclei with tapered or blunt ends and eosinophilic fibrillary cytoplasm — features reminiscent of those of early fetal muscle cells (Figure 4A). Rhabdomyoblasts, which are larger, round-to-oval cells with abundant concentric, fibrillary cytoplasm, are scattered throughout the tumor (Figure 4B).
Figure 4. Biopsy Specimen of the Orbital Tumor.
Spindled tumor cells have elongated hyperchromatic nuclei with eosinophilic cytoplasm — features reminiscent of those of developing fetal muscle (Panel A; hematoxylin and eosin, x500). Large, round-to-oval cells with concentric, fibrillary cytoplasm exemplify the rhabdomyoblasts that are scattered throughout the tumor (Panel B; hematoxylin and eosin, x500). There is strong staining for desmin (brown), an intermediate filament expressed in myoid tumors (Panel C; immunoperoxidase stain, x500).
The diagnosis of round-cell and spindle-cell cancers of childhood rests on examination of morphologic features by light microscopy, followed in many cases by ancillary studies. The differential diagnosis on morphologic grounds includes Ewing's sarcoma or primitive neuroectodermal tumor, rhabdomyosarcoma, neuroblastoma, lymphoma or leukemia, poorly differentiated synovial sarcoma, congenital infantile fibrosarcoma, and desmoplastic small round-cell tumor, among others. In most cases, a panel of immunohistochemical stains with antibodies to muscle, neural, lymphoid, and epithelial markers, selected on the basis of the findings on microscopical examination, can help to distinguish among these tumors. In the rare case of a tumor for which the morphologic and immunohistochemical findings are equivocal, specific findings on electron microscopy or the detection of characteristic chromosomal translocations (Table 1) can provide a diagnosis.1
Table 1. Cytogenetic Abnormalities in Soft-Tissue Cancers of Childhood.
In this case, the morphologic features are typical of embryonal rhabdomyosarcoma.2 A limited immunohistochemical panel showed strong and diffuse staining of the tumor cells for desmin (Figure 4C) and muscle-specific actin, both of which are sensitive but not highly specific markers of rhabdomyoblastic differentiation; there was no staining for leukocyte common antigen, a lymphoid marker. This immunophenotype confirms the morphologic diagnosis of embryonal rhabdomyosarcoma.
The histologic subtype of the rhabdomyosarcoma is the most important prognostic information that the pathologist provides in this setting. The major subtypes of rhabdomyosarcoma are embryonal, alveolar, and pleomorphic. In general, embryonal rhabdomyosarcoma is associated with a more favorable prognosis than is alveolar rhabdomyosarcoma, so distinguishing between the two subtypes is critical. More than 80 percent of patients with alveolar rhabdomyosarcoma have one of two chromosomal translocations (Table 1), the detection of which can be useful in distinguishing alveolar from embryonal rhabdomyosarcoma. Some data suggest that the specific translocation may have prognostic importance within this category.3,4 Embryonal rhabdomyosarcoma can be further classified into three groups: conventional (as in this case), spindle-cell, and botryoid. The prognosis associated with the spindle-cell and botryoid forms is even more favorable than that associated with conventional embryonal rhabdomyosarcoma. In summary, this patient's tumor has the classic histologic features of conventional embryonal rhabdomyosarcoma.
Anatomical Diagnosis
Rhabdomyosarcoma of the orbit.
Discussion of Management
Options for Chemotherapy and Potential Problems
Dr. Alison M. Friedmann: This nine-month-old boy presented with severe proptosis caused by an embryonal rhabdomyosarcoma of the orbit. Rhabdomyosarcoma is the most common malignant tumor of the orbit in children, and it is typically manifested, as it was in this case, as rapidly progressive proptosis in a child who otherwise seems healthy. Other findings may include chemosis and edema of the eyelid, ophthalmoplegia, and conjunctival injection. The average (mean) age at diagnosis is seven years; the tumor is uncommon in infants. Three hundred fifty new cases are diagnosed each year in the United States; two thirds of them involve children nine years of age or younger (Table 2). Approximately 16 percent of the patients are less than three years old. There is a second, smaller peak during early-to-middle adolescence. The tumor is slightly more common in boys than it is in girls.
Table 2. Clinical Features of Rhabdomyosarcoma.
Rhabdomyosarcoma can arise virtually anywhere in the body, though there are distinct clinical patterns according to the age at presentation, the histologic subtype, and the site of the tumor (Table 2). Head and neck tumors, including those in parameningeal locations (the nasopharynx, paranasal sinuses, middle ear, or infratemporal fossa), tend to occur in children less than eight years of age and are usually the embryonal type. Tumors located in the trunk, the arms, or the legs occur more commonly in adolescents and are usually the alveolar type. Bladder and vaginal tumors tend to occur in infants and very young children and are the botryoid type of embryonal rhabdomyosarcoma, named for its characteristic gross appearance, like that of a cluster of grapes.
Only about 13 percent of patients with rhabdomyosarcoma have evidence of metastatic disease at the time of the diagnosis. The lung parenchyma is the most common site of metastasis, followed by bone marrow, bone, and locoregional lymph nodes. Staging procedures in new patients include CT or MRI studies of the primary site, CT scanning of the chest, bone scanning, examination of bone marrow aspirates and biopsy specimens, and (when the tumor is located in a parameningeal site) lumbar puncture.
Several factors have been found to be important predictors of outcome, and in current treatment strategies, patients are stratified according to risk in order to guide risk-adapted therapy. Risk factors include the site of the primary tumor (with the orbit being the most favorable location); the extent of the initial surgical resection (referred to as clinical "group"); the age at diagnosis, with infants and adolescents generally faring less well than children 2 to 10 years old; the histologic type; the tumor–node–metastasis (TNM) stage, which incorporates the site and size of the tumor, the status of the regional lymph nodes, and the presence or absence of metastases; and, most important, the response to therapy. In the future, the genetic features of the tumor cells may provide important prognostic information.3,4
The three treatment approaches are surgical resection, chemotherapy, and radiation therapy. Combination chemotherapy is the mainstay of treatment and is used to reduce the size of the primary tumor and to eradicate gross or microscopical metastases. Local control of the primary tumor, which is a prerequisite for long-term control of disease, is accomplished by surgery, radiation therapy, or both. In general, resection is performed if it will not impair function or cosmesis. Because of the location of most rhabdomyosarcomas, complete resection cannot be performed in most patients. Radiation therapy is typically used to control residual bulky or microscopical tumor, especially when the tumor is located in sites not amenable to surgical resection.
To make recommendations regarding optimal management for this patient, it is important to consider his overall prognosis. He is clearly in a favorable risk group, having a tumor of the embryonal type in an orbital location, with no lymph-node involvement or distant metastases. Resectability is not an important prognostic factor for orbital rhabdomyosarcoma, since these tumors are highly curable with a combination of chemotherapy and radiation therapy, and complete surgical resection is usually not attempted because of its adverse effects on both function and cosmesis.8 The only adverse prognostic feature in this case is the patient's very young age. I would estimate that this patient, who falls into a low-risk group, has about an 85 to 90 percent chance of long-term survival. Because we expect that his cancer will be cured, we must carefully consider the available approaches to treatment so that the cure comes at a cost that is as low as possible with respect to the late effects of treatment. In addition, the very young age of this patient makes him particularly vulnerable to untoward treatment effects.
The most straightforward aspect of treating this patient is to recommend that he receive combination chemotherapy. Early trials of single chemotherapeutic agents in patients with rhabdomyosarcoma showed that the most active drugs were vincristine, dactinomycin, cyclophosphamide, and doxorubicin. The combination of vincristine, dactinomycin, and cyclophosphamide was subsequently shown to result in greatly improved response rates.9
The largest cooperative clinical-trials group, the Intergroup Rhabdomyosarcoma Study Group (IRSG), has completed four sequential trials of treatment for rhabdomyosarcoma in more than 3500 patients.5,6,7,10 These trials, as well as those conducted by other international groups, have led to improved outcomes for patients, the identification of prognostic variables, and the development of risk-based therapies. The IRSG has established the combination of vincristine, dactinomycin, and cyclophosphamide as the standard chemotherapy regimen for most patients with rhabdomyosarcoma, although a subgroup of patients at low risk — like the patient under discussion — will fare very well with therapy consisting of just two drugs: vincristine and dactinomycin. This regimen, which can be given on an outpatient basis, is well tolerated, with acute toxic effects that are mild and late toxic effects that are minimal. Omitting cyclophosphamide, an alkylating agent, helps to eliminate the risks of infertility and secondary acute leukemia.
One study has suggested that chemotherapy may be unnecessary for localized orbital rhabdomyosarcoma.11 In a series of 24 patients treated with radiation therapy alone, the outcome seemed to be similar to that among patients treated with combined chemotherapy and radiation therapy in the IRSG studies. However, given that the late toxic effects of chemotherapy with vincristine and dactinomycin are negligible, that cure rates are still less than 100 percent, and that determining which patients can be treated successfully with radiation alone is difficult, chemotherapy remains the standard of care.
The more controversial question for this particular patient is whether radiation therapy should be given, especially when we take into account his very young age and his increased susceptibility to the untoward effects of radiation. Internationally, there is no clear consensus. In the United States, the standard approach is to administer radiation therapy for all orbital rhabdomyosarcomas that cannot be completely resected. This approach is based in part on the philosophy of maximizing disease-free survival after the initial treatment. The IRSG uses radiation therapy for patients with gross or microscopical residual tumor after surgery and has demonstrated the highest rate of relapse-free survival: 86 percent at 10 years in a group of patients similar to the patient in this case.8 However, the International Society of Pediatric Oncology (SIOP) has used radiation therapy much more sparingly, reserving it for patients with gross residual tumor or biopsy-proven microscopical residual tumor after chemotherapy.12 Although the rate of local recurrence is much higher with the SIOP approach (44 percent, vs. 8 percent with the IRSG approach), there is no difference in overall survival at 10 years, indicating that in many patients with local recurrence, retreatment can be successful. In addition to the benefits of omitting radiation therapy in a subgroup of patients, the costs of retreatment (with additional late sequelae from more chemotherapy) must be factored into this complicated equation.
For this patient, we followed the current IRSG approach for patients with stage I embryonal rhabdomyosarcoma of the orbit in whom there is gross residual tumor after an initial biopsy or surgical procedure (group III) and recommended chemotherapy with vincristine and dactinomycin and, for local control, radiation therapy.
Options for Radiation Therapy
Dr. Nancy J. Tarbell: The responsiveness of rhabdomyosarcoma to radiation therapy was established in the 1940s and 1950s.5,13 In the 1960s, Cassady and coworkers observed that in cases of orbital rhabdomyosarcoma, radiation therapy afforded better local control than exenteration.14,15 In IRSG trials, local control has been achieved in 94 percent of the patients who received radiation therapy and chemotherapy.16,17 However, the late effects of orbital radiation therapy are considerable (Table 3). 3,8,19 They result from the irradiation of normal tissues in the process of irradiating the tumor. When normal developing tissues are irradiated, they often do not continue to develop normally.19 The side effects of radiation are worse in younger patients than in older ones and increase as the dose and volume of radiation to a structure increase. Furthermore, radiation in children entails a risk of radiation-induced cancer within the treated field.20,21 At least in principle, the smaller the volume of tissue irradiated, the lower the risk of treatment-induced cancer and of impaired function of the ocular adnexal structures.
Table 3. Late Effects of Irradiation of the Orbit.
With the advent of better imaging by means of CT and MRI scanning, the ability to target therapy to the tumor volume has vastly improved. In conformal techniques, for example, MRI scans are anatomically registered to CT scans to allow precise targeting of tumors. Treatment involves the use of multiple fields, which converge on the tumor to deliver the total radiation dose. The latest technological advances in conventional radiation therapy consist of stereotactic CT-based techniques and intensity-modulated therapy. Both techniques rely heavily on accurate and reproducible patient-positioning systems, high-resolution three-dimensional CT-based imaging, and the use of sophisticated computers. Still, conventional photon radiation therapy always delivers a dose of radiation to the tissues superficial to the tumor (the entrance dose) as well as to the tissues at a deeper level than the tumor (the exit dose).
Protons have been used for the treatment of selected tumors in a few centers since the 1950s.22,23 The physical properties of protons result in a rapid loss of energy at the end of the range of the beam, so most of the energy is transferred to a small volume of tissue. With modulation of the beam, this peak of energy can be spread out over the entire target volume to produce a nearly uniform dose distribution. Thus, proton radiation therapy can deliver the desired dose of radiation to the tumor, but because the beam can be stopped at the distal edge of the lesion, no radiation is delivered to normal tissues beyond the tumor. There is still an entrance dose, but it is typically less than the entrance dose with photon radiation. These attributes make proton radiation particularly useful for treating tumors surrounded by normal tissues that are highly sensitive to the effects of radiation, such as the brain, and for treating tumors in children.
For many years, patients at this hospital who have intracranial and other head and neck tumors have been treated at the Harvard Cyclotron Laboratory, in a collaborative program.24,25,26 Experience here and elsewhere suggests that complications from the toxic effects of radiation can be reduced in children with the use of this technique, which also offers good tumor control.27,28 Recently, the installation of a proton-therapy facility at this hospital has expanded the number of patients who can be treated this way.
In the very young patient in the case under discussion, even the most sophisticated conformal techniques for photon irradiation would deliver a substantial exit dose to the brain and other normal tissues, placing him at increased risk for adverse effects such as developmental delay and a second tumor. Because this patient is so young and because his tumor is curable — in other words, because he will most likely live to experience the side effects of treatment — he is the ideal candidate for the most conformal form of external-beam irradiation available: proton radiation therapy.
He was given proton radiation at the standard total dose of 45 Gy, delivered at a rate of 1.8 Gy per fraction over a period of five weeks. There is minimal radiation to adjacent bone and brain with this approach. A photograph of the patient taken on the last day of proton radiation therapy (Figure 1B) shows nearly complete resolution of the proptosis and slightly increased pigmentation in the radiation portal; the pigmentation change resolves in two to four weeks.
Dr. Andrew E. Rosenberg (Pathology): Is there any way to predict what degree of facial asymmetry the child will have?
Dr. Tarbell: No. One of the key outcomes we measure as we follow patients with rhabdomyosarcoma is bony growth, as assessed by cephalometric and morphometric studies. In this child, we exposed a much smaller volume of tissue to radiation than we would have if we had used conventional photon radiation, but a small volume of bone still received the full dose of radiation. His young age renders him more susceptible to asymmetric facial growth than older children.
Dr. Nancy Lee Harris (Pathology): Can you tell us what additional treatment this patient received and describe the results of recent follow-up examinations?
Dr. Friedmann: He received two-drug chemotherapy for a total of 48 weeks. Fourteen months after the diagnosis, MRI showed only a very small, residual, soft-tissue mass that was enhanced with the use of contrast material. This residual mass has not changed in size and will be followed with the use of serial imaging studies.
We are indebted to Dr. Torunn Yock for preparing the case history and assisting in the preparation of the discussion of radiation therapy, and to the patient's family for providing photographs of the child and permitting their publication.
Source Information
From the Division of Pediatric Hematology–Oncology, Pediatric Service (A.M.F.), and the Departments of Radiation Oncology (N.J.T.), Radiology (P.W.S.), and Pathology (B.L.H.), Massachusetts General Hospital; and the Departments of Pediatrics (A.M.F.), Radiation Oncology (N.J.T.), Radiology (P.W.S.), and Pathology (B.L.H.), Harvard Medical School.
References
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Dr. Torunn Yock (Radiation Oncology): A nine-month-old male infant was referred to this hospital for treatment of an orbital rhabdomyosarcoma. The patient had been well until the age of six months, when excessive tearing developed. Over the next two days, his right eye was noted to be puffy and red. His pediatrician made a diagnosis of conjunctivitis. Topical treatment with a combination of bacitracin and polymixin B sulfate (Polysporin) had no effect, and two days later, proptosis developed (Figure 1A). The infant was referred to an ophthalmologist for evaluation and treatment of a possible orbital infection. A computed tomographic (CT) scan obtained nine days after the onset of symptoms (Figure 2A) revealed a mass involving the lateral orbital musculature, with no evidence of bony erosion or invasion. A magnetic resonance imaging (MRI) scan obtained the same day (Figure 2B and Figure 2C) showed a well-defined mass posterior and lateral to the globe, 2.2x1.5 cm; it displaced the optic nerve medially and involved the lateral and superior rectus and superior oblique muscles. The infant was admitted to a local hospital for a biopsy under CT guidance.
Figure 1. Photographs of the Patient.
At presentation (Panel A), there is striking proptosis of the right orbit. By the last day of proton radiation therapy (Panel B), the proptosis has resolved, and there is slight redness of the surrounding skin.
Figure 2. CT and MRI Scans Obtained at the Time of the Initial Evaluation.
A coronal CT image of the head, obtained without the use of contrast material, shows a large mass in the superolateral aspect of the right orbit (Panel A, arrows). The mass is indistinguishable from the superior rectus, the superior oblique, and the lateral rectus muscles as well as from the lacrimal gland, and it compresses the optic nerve. On an axial T1-weighted MRI scan, the mass is isointense relative to muscle (Panel B, arrow). On an axial T2-weighted MRI scan, it is slightly hyperintense relative to muscle (Panel C).
The patient and his family resided in Canada. He had been born at full term by normal, spontaneous vaginal delivery after an uncomplicated pregnancy. He had been well since birth. His two older brothers were well. There was no family history of childhood cancers. A paternal grandfather had died of lung cancer, and a maternal aunt had died of liver cancer.
On physical examination, the patient appeared to be well and was active. On the right side, there was proptosis with inferior and medial deviation of the eye, as well as bruising and edema of the eyelid. Eye movement was present but limited. There was no purulent discharge or conjunctival injection. The other findings on physical examination were normal.
A biopsy of the orbital mass disclosed embryonal rhabdomyosarcoma. CT scanning of the chest and abdomen, a bone marrow biopsy, and a lumbar puncture showed no evidence of metastatic disease. A bone scan showed increased uptake of tracer in the lateral aspect of the right bony orbit but no evidence of distant disease.
Six days later, combination chemotherapy with vincristine, dactinomycin, and cyclophosphamide was begun. One week after the initiation of chemotherapy, the proptosis markedly worsened. CT scanning revealed an enlarged tumor mass with areas of hypodensity, a finding consistent with the presence of necrosis. The increase in the size of the mass was thought to be due to edema from treatment-induced necrosis. Dexamethasone was administered, and the proptosis subsequently improved. Members of a tumor board at the local institution convened and recommended discontinuing the cyclophosphamide and instead administering vincristine and dactinomycin, followed by radiation therapy. Because of the patient's young age and the high risk of long-term side effects from standard photon radiation therapy, they recommended referral to this hospital so that proton radiation therapy could be considered.
The patient received three cycles of chemotherapy at the local hospital; the treatment was complicated by hepatic veno-occlusive disease and two episodes of febrile neutropenia. The mass decreased in size. Three months after the diagnosis, the patient was brought to this hospital for proton radiation therapy.
On evaluation in the clinic, the patient was pale but otherwise appeared to be well and was crawling actively. Examination of the head and neck revealed mild periorbital swelling of the right eye. There was no preauricular, supraclavicular, or cervical lymphadenopathy. The left eye was normal. The findings on physical examination were otherwise unremarkable.
Dr. Pamela W. Schaefer: The initial CT scan of the head, obtained without the use of contrast material (Figure 2A), reveals a large mass in the right superolateral aspect of the orbit. The mass is isodense in relation to muscle and is indistinguishable from the superior oblique, superior rectus, and lateral rectus muscles as well as the lacrimal gland. There is a thin layer of fat between the mass and the right optic nerve, but the mass compresses the optic nerve. The bones surrounding the orbit and the brain parenchyma appear to be normal. MRI scans obtained the same day show that, relative to muscle, the mass is isointense on T1-weighted imaging (Figure 2B) and slightly hyperintense on T2-weighted imaging (Figure 2C). The mass was densely and homogeneously enhanced after the administration of gadolinium. There was no abnormal enhancement in the adjacent bony structures or brain parenchyma.
The differential diagnosis of an orbital mass in a young patient includes rhabdomyosarcoma, eosinophilic granuloma (Langerhans'-cell histiocytosis), granulocytic sarcoma, lymphoma, and benign lesions, such as hemangioma and lymphangioma. Eosinophilic granuloma usually involves bone. In lymphoma and leukemia, there is usually, but not always, evidence of systemic involvement. Hemangiomas and lymphangiomas are usually bright on T2-weighted images.
Contrast-enhanced axial CT scans and gadolinium-enhanced MRI scans (Figure 3) obtained after chemotherapy show that the densely enhancing mass has markedly decreased in size. The mass effect on the adjacent orbital structures has decreased, as has the proptosis.
Figure 3. MRI Scans Obtained after Chemotherapy.
After chemotherapy, the right orbital mass is smaller, and the proptosis has lessened. On an axial T1-weighted image, the mass is isointense relative to muscle (Panel A). On an axial T2-weighted image, the mass is more hyperintense relative to muscle than it was before treatment (Panel B).
Pathological Discussion
Dr. Benjamin L. Hoch: Microscopical examination of the biopsy specimen from the orbital tumor disclosed sheets and fascicles of rounded and spindled cells with alternating cellular and myxoid regions. The tumor cells have elongated, hyperchromatic nuclei with tapered or blunt ends and eosinophilic fibrillary cytoplasm — features reminiscent of those of early fetal muscle cells (Figure 4A). Rhabdomyoblasts, which are larger, round-to-oval cells with abundant concentric, fibrillary cytoplasm, are scattered throughout the tumor (Figure 4B).
Figure 4. Biopsy Specimen of the Orbital Tumor.
Spindled tumor cells have elongated hyperchromatic nuclei with eosinophilic cytoplasm — features reminiscent of those of developing fetal muscle (Panel A; hematoxylin and eosin, x500). Large, round-to-oval cells with concentric, fibrillary cytoplasm exemplify the rhabdomyoblasts that are scattered throughout the tumor (Panel B; hematoxylin and eosin, x500). There is strong staining for desmin (brown), an intermediate filament expressed in myoid tumors (Panel C; immunoperoxidase stain, x500).
The diagnosis of round-cell and spindle-cell cancers of childhood rests on examination of morphologic features by light microscopy, followed in many cases by ancillary studies. The differential diagnosis on morphologic grounds includes Ewing's sarcoma or primitive neuroectodermal tumor, rhabdomyosarcoma, neuroblastoma, lymphoma or leukemia, poorly differentiated synovial sarcoma, congenital infantile fibrosarcoma, and desmoplastic small round-cell tumor, among others. In most cases, a panel of immunohistochemical stains with antibodies to muscle, neural, lymphoid, and epithelial markers, selected on the basis of the findings on microscopical examination, can help to distinguish among these tumors. In the rare case of a tumor for which the morphologic and immunohistochemical findings are equivocal, specific findings on electron microscopy or the detection of characteristic chromosomal translocations (Table 1) can provide a diagnosis.1
Table 1. Cytogenetic Abnormalities in Soft-Tissue Cancers of Childhood.
In this case, the morphologic features are typical of embryonal rhabdomyosarcoma.2 A limited immunohistochemical panel showed strong and diffuse staining of the tumor cells for desmin (Figure 4C) and muscle-specific actin, both of which are sensitive but not highly specific markers of rhabdomyoblastic differentiation; there was no staining for leukocyte common antigen, a lymphoid marker. This immunophenotype confirms the morphologic diagnosis of embryonal rhabdomyosarcoma.
The histologic subtype of the rhabdomyosarcoma is the most important prognostic information that the pathologist provides in this setting. The major subtypes of rhabdomyosarcoma are embryonal, alveolar, and pleomorphic. In general, embryonal rhabdomyosarcoma is associated with a more favorable prognosis than is alveolar rhabdomyosarcoma, so distinguishing between the two subtypes is critical. More than 80 percent of patients with alveolar rhabdomyosarcoma have one of two chromosomal translocations (Table 1), the detection of which can be useful in distinguishing alveolar from embryonal rhabdomyosarcoma. Some data suggest that the specific translocation may have prognostic importance within this category.3,4 Embryonal rhabdomyosarcoma can be further classified into three groups: conventional (as in this case), spindle-cell, and botryoid. The prognosis associated with the spindle-cell and botryoid forms is even more favorable than that associated with conventional embryonal rhabdomyosarcoma. In summary, this patient's tumor has the classic histologic features of conventional embryonal rhabdomyosarcoma.
Anatomical Diagnosis
Rhabdomyosarcoma of the orbit.
Discussion of Management
Options for Chemotherapy and Potential Problems
Dr. Alison M. Friedmann: This nine-month-old boy presented with severe proptosis caused by an embryonal rhabdomyosarcoma of the orbit. Rhabdomyosarcoma is the most common malignant tumor of the orbit in children, and it is typically manifested, as it was in this case, as rapidly progressive proptosis in a child who otherwise seems healthy. Other findings may include chemosis and edema of the eyelid, ophthalmoplegia, and conjunctival injection. The average (mean) age at diagnosis is seven years; the tumor is uncommon in infants. Three hundred fifty new cases are diagnosed each year in the United States; two thirds of them involve children nine years of age or younger (Table 2). Approximately 16 percent of the patients are less than three years old. There is a second, smaller peak during early-to-middle adolescence. The tumor is slightly more common in boys than it is in girls.
Table 2. Clinical Features of Rhabdomyosarcoma.
Rhabdomyosarcoma can arise virtually anywhere in the body, though there are distinct clinical patterns according to the age at presentation, the histologic subtype, and the site of the tumor (Table 2). Head and neck tumors, including those in parameningeal locations (the nasopharynx, paranasal sinuses, middle ear, or infratemporal fossa), tend to occur in children less than eight years of age and are usually the embryonal type. Tumors located in the trunk, the arms, or the legs occur more commonly in adolescents and are usually the alveolar type. Bladder and vaginal tumors tend to occur in infants and very young children and are the botryoid type of embryonal rhabdomyosarcoma, named for its characteristic gross appearance, like that of a cluster of grapes.
Only about 13 percent of patients with rhabdomyosarcoma have evidence of metastatic disease at the time of the diagnosis. The lung parenchyma is the most common site of metastasis, followed by bone marrow, bone, and locoregional lymph nodes. Staging procedures in new patients include CT or MRI studies of the primary site, CT scanning of the chest, bone scanning, examination of bone marrow aspirates and biopsy specimens, and (when the tumor is located in a parameningeal site) lumbar puncture.
Several factors have been found to be important predictors of outcome, and in current treatment strategies, patients are stratified according to risk in order to guide risk-adapted therapy. Risk factors include the site of the primary tumor (with the orbit being the most favorable location); the extent of the initial surgical resection (referred to as clinical "group"); the age at diagnosis, with infants and adolescents generally faring less well than children 2 to 10 years old; the histologic type; the tumor–node–metastasis (TNM) stage, which incorporates the site and size of the tumor, the status of the regional lymph nodes, and the presence or absence of metastases; and, most important, the response to therapy. In the future, the genetic features of the tumor cells may provide important prognostic information.3,4
The three treatment approaches are surgical resection, chemotherapy, and radiation therapy. Combination chemotherapy is the mainstay of treatment and is used to reduce the size of the primary tumor and to eradicate gross or microscopical metastases. Local control of the primary tumor, which is a prerequisite for long-term control of disease, is accomplished by surgery, radiation therapy, or both. In general, resection is performed if it will not impair function or cosmesis. Because of the location of most rhabdomyosarcomas, complete resection cannot be performed in most patients. Radiation therapy is typically used to control residual bulky or microscopical tumor, especially when the tumor is located in sites not amenable to surgical resection.
To make recommendations regarding optimal management for this patient, it is important to consider his overall prognosis. He is clearly in a favorable risk group, having a tumor of the embryonal type in an orbital location, with no lymph-node involvement or distant metastases. Resectability is not an important prognostic factor for orbital rhabdomyosarcoma, since these tumors are highly curable with a combination of chemotherapy and radiation therapy, and complete surgical resection is usually not attempted because of its adverse effects on both function and cosmesis.8 The only adverse prognostic feature in this case is the patient's very young age. I would estimate that this patient, who falls into a low-risk group, has about an 85 to 90 percent chance of long-term survival. Because we expect that his cancer will be cured, we must carefully consider the available approaches to treatment so that the cure comes at a cost that is as low as possible with respect to the late effects of treatment. In addition, the very young age of this patient makes him particularly vulnerable to untoward treatment effects.
The most straightforward aspect of treating this patient is to recommend that he receive combination chemotherapy. Early trials of single chemotherapeutic agents in patients with rhabdomyosarcoma showed that the most active drugs were vincristine, dactinomycin, cyclophosphamide, and doxorubicin. The combination of vincristine, dactinomycin, and cyclophosphamide was subsequently shown to result in greatly improved response rates.9
The largest cooperative clinical-trials group, the Intergroup Rhabdomyosarcoma Study Group (IRSG), has completed four sequential trials of treatment for rhabdomyosarcoma in more than 3500 patients.5,6,7,10 These trials, as well as those conducted by other international groups, have led to improved outcomes for patients, the identification of prognostic variables, and the development of risk-based therapies. The IRSG has established the combination of vincristine, dactinomycin, and cyclophosphamide as the standard chemotherapy regimen for most patients with rhabdomyosarcoma, although a subgroup of patients at low risk — like the patient under discussion — will fare very well with therapy consisting of just two drugs: vincristine and dactinomycin. This regimen, which can be given on an outpatient basis, is well tolerated, with acute toxic effects that are mild and late toxic effects that are minimal. Omitting cyclophosphamide, an alkylating agent, helps to eliminate the risks of infertility and secondary acute leukemia.
One study has suggested that chemotherapy may be unnecessary for localized orbital rhabdomyosarcoma.11 In a series of 24 patients treated with radiation therapy alone, the outcome seemed to be similar to that among patients treated with combined chemotherapy and radiation therapy in the IRSG studies. However, given that the late toxic effects of chemotherapy with vincristine and dactinomycin are negligible, that cure rates are still less than 100 percent, and that determining which patients can be treated successfully with radiation alone is difficult, chemotherapy remains the standard of care.
The more controversial question for this particular patient is whether radiation therapy should be given, especially when we take into account his very young age and his increased susceptibility to the untoward effects of radiation. Internationally, there is no clear consensus. In the United States, the standard approach is to administer radiation therapy for all orbital rhabdomyosarcomas that cannot be completely resected. This approach is based in part on the philosophy of maximizing disease-free survival after the initial treatment. The IRSG uses radiation therapy for patients with gross or microscopical residual tumor after surgery and has demonstrated the highest rate of relapse-free survival: 86 percent at 10 years in a group of patients similar to the patient in this case.8 However, the International Society of Pediatric Oncology (SIOP) has used radiation therapy much more sparingly, reserving it for patients with gross residual tumor or biopsy-proven microscopical residual tumor after chemotherapy.12 Although the rate of local recurrence is much higher with the SIOP approach (44 percent, vs. 8 percent with the IRSG approach), there is no difference in overall survival at 10 years, indicating that in many patients with local recurrence, retreatment can be successful. In addition to the benefits of omitting radiation therapy in a subgroup of patients, the costs of retreatment (with additional late sequelae from more chemotherapy) must be factored into this complicated equation.
For this patient, we followed the current IRSG approach for patients with stage I embryonal rhabdomyosarcoma of the orbit in whom there is gross residual tumor after an initial biopsy or surgical procedure (group III) and recommended chemotherapy with vincristine and dactinomycin and, for local control, radiation therapy.
Options for Radiation Therapy
Dr. Nancy J. Tarbell: The responsiveness of rhabdomyosarcoma to radiation therapy was established in the 1940s and 1950s.5,13 In the 1960s, Cassady and coworkers observed that in cases of orbital rhabdomyosarcoma, radiation therapy afforded better local control than exenteration.14,15 In IRSG trials, local control has been achieved in 94 percent of the patients who received radiation therapy and chemotherapy.16,17 However, the late effects of orbital radiation therapy are considerable (Table 3). 3,8,19 They result from the irradiation of normal tissues in the process of irradiating the tumor. When normal developing tissues are irradiated, they often do not continue to develop normally.19 The side effects of radiation are worse in younger patients than in older ones and increase as the dose and volume of radiation to a structure increase. Furthermore, radiation in children entails a risk of radiation-induced cancer within the treated field.20,21 At least in principle, the smaller the volume of tissue irradiated, the lower the risk of treatment-induced cancer and of impaired function of the ocular adnexal structures.
Table 3. Late Effects of Irradiation of the Orbit.
With the advent of better imaging by means of CT and MRI scanning, the ability to target therapy to the tumor volume has vastly improved. In conformal techniques, for example, MRI scans are anatomically registered to CT scans to allow precise targeting of tumors. Treatment involves the use of multiple fields, which converge on the tumor to deliver the total radiation dose. The latest technological advances in conventional radiation therapy consist of stereotactic CT-based techniques and intensity-modulated therapy. Both techniques rely heavily on accurate and reproducible patient-positioning systems, high-resolution three-dimensional CT-based imaging, and the use of sophisticated computers. Still, conventional photon radiation therapy always delivers a dose of radiation to the tissues superficial to the tumor (the entrance dose) as well as to the tissues at a deeper level than the tumor (the exit dose).
Protons have been used for the treatment of selected tumors in a few centers since the 1950s.22,23 The physical properties of protons result in a rapid loss of energy at the end of the range of the beam, so most of the energy is transferred to a small volume of tissue. With modulation of the beam, this peak of energy can be spread out over the entire target volume to produce a nearly uniform dose distribution. Thus, proton radiation therapy can deliver the desired dose of radiation to the tumor, but because the beam can be stopped at the distal edge of the lesion, no radiation is delivered to normal tissues beyond the tumor. There is still an entrance dose, but it is typically less than the entrance dose with photon radiation. These attributes make proton radiation particularly useful for treating tumors surrounded by normal tissues that are highly sensitive to the effects of radiation, such as the brain, and for treating tumors in children.
For many years, patients at this hospital who have intracranial and other head and neck tumors have been treated at the Harvard Cyclotron Laboratory, in a collaborative program.24,25,26 Experience here and elsewhere suggests that complications from the toxic effects of radiation can be reduced in children with the use of this technique, which also offers good tumor control.27,28 Recently, the installation of a proton-therapy facility at this hospital has expanded the number of patients who can be treated this way.
In the very young patient in the case under discussion, even the most sophisticated conformal techniques for photon irradiation would deliver a substantial exit dose to the brain and other normal tissues, placing him at increased risk for adverse effects such as developmental delay and a second tumor. Because this patient is so young and because his tumor is curable — in other words, because he will most likely live to experience the side effects of treatment — he is the ideal candidate for the most conformal form of external-beam irradiation available: proton radiation therapy.
He was given proton radiation at the standard total dose of 45 Gy, delivered at a rate of 1.8 Gy per fraction over a period of five weeks. There is minimal radiation to adjacent bone and brain with this approach. A photograph of the patient taken on the last day of proton radiation therapy (Figure 1B) shows nearly complete resolution of the proptosis and slightly increased pigmentation in the radiation portal; the pigmentation change resolves in two to four weeks.
Dr. Andrew E. Rosenberg (Pathology): Is there any way to predict what degree of facial asymmetry the child will have?
Dr. Tarbell: No. One of the key outcomes we measure as we follow patients with rhabdomyosarcoma is bony growth, as assessed by cephalometric and morphometric studies. In this child, we exposed a much smaller volume of tissue to radiation than we would have if we had used conventional photon radiation, but a small volume of bone still received the full dose of radiation. His young age renders him more susceptible to asymmetric facial growth than older children.
Dr. Nancy Lee Harris (Pathology): Can you tell us what additional treatment this patient received and describe the results of recent follow-up examinations?
Dr. Friedmann: He received two-drug chemotherapy for a total of 48 weeks. Fourteen months after the diagnosis, MRI showed only a very small, residual, soft-tissue mass that was enhanced with the use of contrast material. This residual mass has not changed in size and will be followed with the use of serial imaging studies.
We are indebted to Dr. Torunn Yock for preparing the case history and assisting in the preparation of the discussion of radiation therapy, and to the patient's family for providing photographs of the child and permitting their publication.
Source Information
From the Division of Pediatric Hematology–Oncology, Pediatric Service (A.M.F.), and the Departments of Radiation Oncology (N.J.T.), Radiology (P.W.S.), and Pathology (B.L.H.), Massachusetts General Hospital; and the Departments of Pediatrics (A.M.F.), Radiation Oncology (N.J.T.), Radiology (P.W.S.), and Pathology (B.L.H.), Harvard Medical School.
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