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Myxomas and Angiomyxomas of the Orbit
Myxomas and Angiomyxomas of the Orbit A Clinicopathologic Study of 6 Cases Ahmed A. Hidayat, MD,1 Andrew Flint, MD,2 Lawrence Marentette, MD,2 Elise Torczynski, MD,3 Jerman M. Al-Qahtani, MD,4 Norman C. Ahl, MD,5 Victor M. Elner, MD, PhD2 Purpose: To report clinical and histopathologic features and biologic behavior of orbital myxomas and angiomyxomas. Design: Noncomparative retrospective case series. Participants: Patients with histopathologic diagnoses of orbital myxoma or angiomyxoma. Methods: Clinical metadata and features were obtained from the medical record. Neoplasms were studied by routine histopathology, special stains, and immunohistochemistry. Main Outcome Measures: Final diagnosis, based on histopathology, special stains, and immunohistochemistry, and clinical course from analysis of metadata and clinical features. Results: Three myxomas and 3 angiomyxomas were identified in 5 males and 1 female. Median age at presentation was 56 years (range, 4 – 69), with a follow-up ranging from 6 months to 8 years. Two angiomyxomas occurred in children ages 4 and 7 years whose tumors were locally aggressive and recurred. Recurrence also complicated one case of myxoma after incomplete excision. Pathologically, the tumors were poorly circumscribed. Histopathology showed them to be hypocellular, containing stellate and spindled cells in an abundant, loose, myxoid stroma rich in hyaluronic acid. Small blood vessels were rare in myxomas but abundant in angiomyxomas. Tumor cells were frequently immunoreactive for vimentin, CD34, and factor XIIIa. Conclusions: Myxomas rarely involve orbital tissue, and no angiomyxomas of the region have been previously reported. Angiomyxomas in children may be aggressive. Vascularity and bone involvement appear to be important prognostic features for recurrence. Complete resection with a margin of healthy tissue appears to be the treatment of choice. Tumor cell immunopositivity for vimentin, CD34, and factor XIIIa may assist in the histopathologic diagnosis. Ophthalmology 2007;114:1012–1019 © 2007 by the American Academy of Ophthalmology.
Myxomas are uncommon, benign, mesenchymal tumors that usually affect the skeletal muscles of the extremities, skin, subcutaneous tissues, heart, and genitourinary system.1,2 These tumors rarely arise in the orbit,3–15 eyelid,15–17 conjunctiva,18,19 and cornea,20,21 usually in the middle-aged without gender predilection. Ocular myxomas can be solitary lesions or a component of the Carney complex, Mazabraud syndrome, or McCune–Albright syndrome.15,16 When involving the conjunctiva and cornea, Originally received: April 4, 2006. Accepted: December 21, 2006. Manuscript no. 2006-405. 1 Department of Ophthalmic Pathology, Armed Forces Institute of Pathology, Washington, DC. 2 University of Michigan, Ann Arbor, Michigan. 3 Rush University Medical Center, Chicago, Illinois. 4 King Fahd Hospital of the University, Al-Khobar, Saudi Arabia. 5 Thomas-David Medical Centers, Tuscon, Arizona. Presented at: American Society of Ophthalmic Pathologists meeting, October 2004, New Orleans, Louisiana. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Correspondence to Victor M. Elner, MD, PhD, University of Michigan, Kellogg Eye Center, 1000 Wall Street, Ann Arbor, MI 48105. E-mail: [email protected].
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© 2007 by the American Academy of Ophthalmology Published by Elsevier Inc.
myxomas appear as well-circumscribed, yellow–pink, translucent, cystic and/or solid masses.15–21 Rare in the orbit, the main presenting symptom is proptosis.12 Computed tomography (CT) shows an infiltrative, enhancing soft-tissue mass.12 The rare orbital cases are subjects of case reports, usually without clinical follow-up information.3–15 Histopathologically, myxomas reported in the ocular region are characterized as hypocellular and hypovascular lesions with an abundant myxoid matrix that is rich in hyaluronic acid. Angiomyxomas, which are virtually unknown in the ocular region, are more aggressive and contain more blood vessels than typical myxomas. The angiomyxomas are designated as superficial angiomyxomas for dermal and subcutaneous variants and aggressive angiomyxomas for those located in the pelvic soft tissues and perineum.22–27 To our knowledge, angiomyxomas have not been described in the orbit. In this report, we describe the clinicopathologic features of 3 cases of orbital myxoma and 3 of angiomyxoma, with follow-up information.
Materials and Methods Six patients with histopathologic diagnoses of orbital myxomas or angiomyxomas were studied. For histopathologic evaluation, the following stains were available in all cases: hematoxylin– eosin, periodic acid–Schiff (PAS), Giemsa, and alcian blue at pH 2.5, the ISSN 0161-6420/07/$–see front matter doi:10.1016/j.ophtha.2006.12.022
Hidayat et al 䡠 Myxomas and Angiomyxomas of the Orbit last before and after treatment with hyaluronidase. For immunohistochemistry, the following immunostainings were done using an avidin– biotin–peroxidase technique: vimentin, CD34, factor XIIIa, smooth muscle–specific actin, desmin, S-100 protein, CD68, keratin, epithelial membrane antigen, progesterone receptor, and estrogen receptor. Follow-up clinical information was obtained on all patients. The institutional review board at the University of Michigan approved this study.
Clinical Data Clinical data are summarized in Table 1. The median age of 5 males and 1 female was 56 years (range, 4 – 69). Two of the patients with orbital angiomyxomas were children, 4 and 7 years old. Symptoms and signs, ranging in duration from 3 to 9 months, included proptosis, decreased visual acuity, partial loss of visual field, eyelid swelling, ptosis, afferent pupillary deficit, diplopia, and fullness on palpation. Radiologic findings were available in 4 cases. In case 2, magnetic resonance imaging showed a tumor that filled and expanded the left cavernous sinus, having extended from the left orbital apex, where it involved the superior and inferior rectus muscles and compressed the optic nerve. The radiologic diagnosis was meningioma; however, cavernous hemangioma and schwannoma were considered in the differential diagnosis. In case 3 (Fig 1), CT showed involvement of the entire inferior orbit by a mass that enhanced slightly with contrast. There was no evidence of bony involvement. In case 4 (Fig 2), CT revealed a right posterior, subperiosteal, superomedial, homogenous mass with erosion of the medial orbital wall as well as a right maxillary sinus retention cyst. Magnetic resonance imaging showed a 30⫻21⫻15-mm mass extending to the orbital apex and displacing the optic nerve. The tumor was isodense on T1- and bright on T2weighted images; it enhanced with contrast. In case 6, CT showed a 25-mm ovoid soft-tissue density with slight contrast enhancement, located extraconally in the superior lateral aspect of the left orbit. The mass indented the globe, causing proptosis as well as medial and downward displacement of the eye. The lesion appeared to arise in the lacrimal fossa and caused significant bony remodeling with frank bone destruction of the orbital ridge of the frontal bone. Radiologi-
cally, the mass was consistent with a lacrimal gland tumor, possibly epithelial or lymphomatous in origin. Plain skull films of the orbit showed a lytic lesion. Intraoperatively, the tumors were described as mucoid, bluish, cystic masses with thin capsules. Within the capsules, the tumors consisted of sticky, clear, mucinous material that closely resembled vitreous. Sometimes they appeared as fluctuant gelatinous cysts. In other instances, the tumors appeared as multiloculated cysts containing mucoid material. In case 2, the ill-defined angiomyxoid tumor was quite vascular and bled excessively during surgery. The tumor surrounded all cranial nerves within the cavernous sinus. The orbital tumors in patients 1, 5, and 6 were treated by simple local excision; however, the recurrence in case 6 necessitated removal of the lateral orbital roof. In case 2, transcranial orbitotomy was required for excision of the deep orbital portion of the tumor. Because the tumor involved the cavernous sinus, a second operation was performed 3 months later to resect this portion of the tumor. At surgery, cranial nerves within the sinus were enveloped by tumor, with severe compression of cranial nerve VII. The bones of the middle cranial fossa were soft and possibly infiltrated by the tumor. Although most of the tumor was resected, unresected residual tumor was left behind and the patient was treated with methotrexate. In case 3, lateral and anterior orbitotomies were performed to permit piecemeal tumor removal. In case 4, the initial treatment consisted of frontal orbitotomy and biopsy. This was followed by transcranial resection of the subperiosteal tumor and repair of the orbital roof with metal mesh. Because of recurrent progressive proptosis, lack of response to corticosteroids, and radiologically documented tumor regrowth that involved the orbital apex and ethmoid sinus, she underwent a unilateral subcranial orbitotomy 10 months later with partial ethmoid resection and dissection of tumor from around the optic nerve and cranial nerves at the superior orbital fissure, followed by repair with a contralateral vascularized pericranial flap. Four months later, a recurrent 5-mm tumor nodule in the cavernous sinus necessitated a frontal–temporal craniotomy with extradural resection of the anterior clinoid, inferior wall of the superior orbital fissure, and optic strut to provide access for complete resection of the cavernous sinus portion of the tumor. One month later, a right orbital exenteration extending to the pericranial flap covering the cavernous
Table 1. Orbital Myxomas and Angiomyxomas: Clinical Data of 6 Cases Case No.
Location
1
Left orbit
2
Left orbit, cavernous sinus, base of cranial fossa
3
Right orbit
4
Right orbit, ethmoid and maxillary sinuses, cavernous sinus
5 6
Age (yrs)
Gender
Duration (mos)
68
M
—
7
M
69
Signs and Symptoms
Treatment
Palpable mass
Simple local excision
9
Proptosis, loss of inferior VF, decreased visual acuity
M
4
4
F
9
Proptosis, lower lid swelling, palpable mass Proptosis, ptosis, afferent pupillary defect, decreased visual acuity
Transcranial orbitotomy for orbital tumor excision, dissection of tumor from cranial nerves, methotrexate Lateral and anterior orbitotomy for piecemeal tumor removal
Right orbit
48
M
—
Left orbit
67
M
3
Palpable mass Proptosis, diplopia
Frontal craniotomy, orbitotomy, ethmoid and maxillary sinuses for removal of tumor, oral corticosteroids, orbital exenteration Simple local excision Simple excision initially, orbitotomy with removal of lateral orbital roof for recurrence
Follow-up 4 yrs, alive and well 5 mos, 1 recurrence 7 yrs, alive and well 8 yrs, 3 recurrences
15 mos, alive and well 4 yrs, 3 recurrences
F ⫽ female; M ⫽ male; VF ⫽ visual field.
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Figure 1. Case 3. A, A 69-year-old man with right proptosis and eyelid fullness. B, Computed tomography shows a homogenous mass without bone involvement. C, Intraoperative photograph demonstrating a translucent cystic mass.
sinus, anterior and posterior ethmoidectomy, and sphenoidectomy were performed. A temporalis muscle flap was used to repair the posterior orbital and paranasal sinus defect. Due to suspicion of involved margins at the time of orbital exenteration, the frontal–temporal craniotomy was reopened, the cavernous sinus reexposed, and all the contents except for the carotid artery resected. An ethmoidal sinus recurrence 7 years after initial presentation required repeat ethmoidectomy for tumor resection. Follow-up clinical information was obtained in all patients and ranged from 5 months to 7 years (median, 6 years). In 1 of the 3 patients with orbital myxoma, 3 recurrences occurred after incomplete excision (case 6). Two of the 3 patients with orbital angio-
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myxomas developed recurrences (cases 2 and 4). The recurrences in patients with myxomas and angiomyxomas usually occurred in the first few months after incomplete excision of the lesions. At final follow-up, all 6 patients were alive and well. None of the patients had evidence of metastatic disease. No stigmata of the Carney complex were present in any of the 6 patients studied.
Microscopic Findings The light microscopic and immunohistochemical findings of the 6 tumors, 3 myxomas and 3 angiomyxomas, are summarized in Table 2. Three of the orbital tumors had been initially diagnosed as
Hidayat et al 䡠 Myxomas and Angiomyxomas of the Orbit myxoid liposarcoma, myxoid fibrous histiocytoma, and myxoid embryonal rhabdomyosarcoma; the remaining 3 tumors were initially diagnosed correctly as angiomyxoma (angiomyxofibroma) or myxoma. All of the myxomas were nonencapsulated, poorly circumscribed, hypocellular, and hypovascular. The abundant loose matrix was rich in hyaluronic acid and contained few collagen and reticulin fibers (Fig 3). Pseudocysts were observed in some lesions. The stellate and spindled tumor cells were sparse and showed mildly hyperchromatic and slightly pleomorphic nuclei. Intranuclear and intracytoplasmic vacuoles were frequently present (Fig 3). These vacuoles did not stain with alcian blue or PAS. No mitotic activity was seen in any of the tumors. Small blood vessels were rarely noted in myxomas. Mast cells and a few macrophages were observed in all tumors. The orbital angiomyxomas were quite similar to the myxomas, except for abundant small blood vessels (Fig 4). The elaborate arborizing vascular pattern, as seen in some sarcomas, was absent. Recurrent tumors showed similar histopathologic findings when compared with the primary lesion in each case (Fig 4). Immunohistochemically, tumor cells were immunoreactive for vimentin in 5 of 6 cases, CD34 (Fig 4) in 4 of 6 cases, and factor XIIIa (Fig 4) in 4 of 6 cases. Focal positivity for smooth muscle– specific actin was seen in 2 tumors. Immunoreactivity for progesterone receptor was found in 1 case. No immunoreactivity was detected for S-100 protein, desmin, cytokeratin, epithelial membrane antigen, or estrogen receptors in any case.
Discussion Myxomas of soft tissue are generally classified in 5 major categories: intramuscular (typical), cutaneous (superficial angiomyxoma), juxta-articular, nerve sheath (neurothekeoma), and aggressive angiomyxoma.1 However, these categories have not been applied to myxomas involving the ocular region, except for one recently reported case of superficial angiomyxoma of the eyelid.28 Histogenetically, Stout29 regarded myxoma as a tumor of primitive mesenchyme. Since then, proposed cells of origin include vascular endothelium, neural crest cells of the nerve sheath, dendritic cells, and fibroblasts or their precursors.30 –32 Whatever their origin, the tumor cells appear to be modified mesenchymal cells that produce excessive amounts of glycosaminoglycans rich in hyaluronic acid, but little collagen.2 We agree with other investigators19 that myxomas and angiomyxomas derive from cells similar to fibroblasts and are not primitive cells. Most ultrastructural studies, including those performed on conjunctival myxomas, show predominantly fibroblast or myofibroblastlike elongated tumor cells with prominent dilated rough endoplasmic reticulum, Golgi complexes, pinocytic vesicles, and intracytoplasmic microfilaments with focal densities.19,29,32 Orbital myxomas are rare tumors that may primarily involve the orbital soft tissue or adjacent bone or extend
4™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™ Figure 2. Case 4. A, A 4-year-old girl with right proptosis and eyelid fullness. B, Right proptosis evident on upgaze. C, Computed tomography shows a hemispherical mass involving bone superomedially in the orbital apex. D, Magnetic resonance imaging of a recurrent tumor showing isodensity with orbital fat. E, Magnetic resonance imaging with fat suppression showing a hyperintense recurrent tumor in the cavernous sinus.
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Ophthalmology Volume 114, Number 5, May 2007 Table 2. Orbital Myxomas and Angiomyxomas: Pathologic Data Case
Maximum Dimension/ Gross Appearance
1 2
20 mm 25 mm/vascularized
3
25 mm/bluish, cystic, filled with sticky material 30 mm/vascularized, soft, mucoid
4 5 6*
15 mm/multiloculated cyst containing mucoid material 25 mm
Initial Diagnosis Myxoid liposarcoma Myxoid embryonal rhabdomyosarcoma Myxoid fibrous histiocytoma Angiomyxoma Angiomyxofibroma Myxoma
Immunohistochemical Studies
Final Diagnosis
Vimentin ⫹, CD34 ⫺, factor XIIIa ⫹ Vimentin ⫹, CD34 ⫹, SMA ⫺, desmin ⫺
Myxoma Angiomyxoma
Vimentin ⫹⫹⫹, CD34 ⫹⫹⫹, factor XIIIa ⫹⫹⫹, SMA ⫹/⫺, S-100 ⫺, progesterone receptor ⫹, estrogen receptor ⫺ Vimentin ⫹⫹, CD34 ⫹⫹⫹, factor XIIIa ⫹⫹, SMA ⫹/⫺, CD68 ⫹, S-100 ⫺, desmin ⫺, EMA ⫺, GFAP ⫺, cytokeratin ⫺, progesterone receptor ⫺, estrogen receptor ⫺ Vimentin ⫹⫹, CD34 ⫹⫹, factor XIIIa ⫹⫹, SMA ⫺, desmin ⫺ Vimentin ⫺, CD34 ⫺, factor XIIIa ⫺, SMA ⫺, desmin ⫺
Myxoma Angiomyxoma Angiomyxoma Myxoma
EMA ⫽ epithelial membrane antigen; GFAP ⫽ glial fibrillary acidic protein; SMA ⫽ smooth muscle–specific actin. *Absence of any immunoreactivity, likely due to poor fixation and preservation of antigens.
from the paranasal sinuses to affect the orbit. Sixteen reports of myxomas involving the orbit have been published, all involving cases that arose in adults.3–15 Facial myxomas, arising from dental elements, also rarely involve children.33 These myxomas are slow-growing expansile lesions that are painless and may remain undetected for many years. The facial myxomas are benign, but may be locally invasive, cause bone destruction, and recur in up to 40% of cases.33 Angiomyxomas most frequently involve the dermis and are called superficial angiomyxomas or cutaneous angiomyxomas.34 –36 These superficial angiomyxomas also show a propensity for recurrence, also in up to 40% of cases.33 Recommended treatment of these lesions is complete excision, and metastases have not been reported.28,37 Aggressive angiomyxomas, first described by Steeper and Rosai in 1983,26 are uncommon variably myxoid neoplasms affecting predominantly the pelvic–perineal region of adults, with a female:male ratio of 6:1.38 This group of tumors shows distinctive vascularity, and they tend to recur at rates varying from 35% to 70%, often years after primary excision.22–27,38 In our series, the 3 cases of angiomyxomas were similar to reported aggressive angiomyxomas, except for the fact that they did not contain thick-walled blood vessels in addition to thin-walled vessels, which we did find. To our knowledge, aggressive angiomyxomas have not been reported in the orbit. In our series, 2 children (4 and 7 years old) had angiomyxomas that were locally aggressive orbital tumors that also involved the paranasal sinuses, cavernous sinus, and base of the skull, with rapid recurrences. We cannot rule
out the possibility that these 2 tumors arose in bone with secondary involvement of the orbit. The third case of orbital angiomyxoma affected an adult. The lesion was localized to the orbit and did not recur after complete excision. Contrary to conjunctival myxomas, the orbital myxomas and angiomyxomas were not well circumscribed, but infiltrative. Therefore, it appears that complete surgical excision with a margin of healthy tissue is the treatment of choice, as it is for conjunctival myxomas.15–21 Radiation therapy is probably not helpful for tumors such as these that originate from fibroblastic cells and display very low mitotic activity. In our series, 3 of the 6 tumors recurred without any evidence of distant metastases. The rapid clinical recurrence of 2 of the 3 orbital angiomyxomas we report is similar to the high recurrence rate of these vascularized tumors when they arise in other tissues.22–27,34 –36 Involvement of the soft orbital tissues alone was not followed by any recurrences, but infiltration of the bony wall of the orbit by the tumor, with or without involvement of the paranasal sinuses, resulted in recurrences in all 3 cases. Involvement of the bony wall of the orbit and/or adjacent sinuses was previously reported in 7 cases of facial myxoma.3,4,9,10,13,14 Many of these cases for which follow-up information was available showed recurrence.13,14 We conclude that vascularity and bone involvement areimportant prognostic factors predisposing to tumor recurrence. Myxomas and angiomyxomas were similar histopathologically except for the abundance of small blood vessels in the latter. Tumor cells of both lesions were sparse and stellate or
™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™3 Figure 3. Myxoma (case 3). A, Sparse spindled and stellate tumor cells in loose myxoid matrix (stain, hematoxylin– eosin; original magnification, ⫻320). B, Intranuclear vacuole in elongated tumor cell (stain, hematoxylin–eosin; original magnification, ⫻500). C, Infiltration of skeletal muscles by a myxoma containing mast cells (stain, hematoxylin– eosin; original magnification, ⫻320). Figure 4. Aggressive angiomyxoma (case 4). A, Recurrent tumor involving bone of medial orbital wall (stain, hematoxylin– eosin; original magnification, ⫻50). B, Myxoid orbital tumor with sparse cells and prominent vascularity (stain, hematoxylin– eosin; original magnification, ⫻100). C, Spindled and stellate myxoma cells, some with intracytoplasmic vacuoles, in vascularized myxoid matrix (stain, hematoxylin– eosin; original magnification, ⫻320). D, Intense alcian blue positivity at pH 2.5 that was greatly reduced by hyaluronidase treatment (original magnification, ⫻125). E, Immunoreactivity for factor XIIIa in tumor cells (peroxidase and hematoxylin counterstain; original magnification, ⫻500). F, Immunoreactivity for CD34 antigen in tumor cells (peroxidase and hematoxylin counterstain; original magnification, ⫻250).
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Ophthalmology Volume 114, Number 5, May 2007 spindled in shape. As previously reported for this type of tumor, we frequently observed small intranuclear18,19,25,34,35 and intracytoplasmic12,19,36 vacuoles in the cells. The intranuclear vacuoles are related invagination of the nuclear membrane by protrusion of the cytoplasmic matrix. We also noted scattered mast cells and occasional macrophages, which have been previously reported in myxomas and angiomyxomas.19,34,35 The abundant, basophilic, myxoid extracellular matrix was a regular feature of the myxomas and angiomyxomas and was responsible for the intraoperative findings of sticky, clear, viscous material composing much of the tumors. The matrix widely separated the tumor cells and contained fine fibrillary reticulin fibers and variable numbers of fibrous strands or trabeculae. Because the matrix is chiefly comprised of hyaluronic acid and chondrotin sulfate, it was positive with alcian blue at pH 2.5, which was sensitive to hyaluronidase treatment of tissue sections before staining.39 Our immunohistochemical studies showed frequent immunopositivity of the tumor cells for vimentin, CD34, and factor XIIIa. These immunologic markers may be useful in the diagnosis of myxomas and angiomyxomas. In previous reports, the tumor cells have been reported to be positive for vimentin and CD34, with infrequent immunostaining for smooth muscle–specific actin.12,32 The weak focal immunostaining for smooth muscle–specific actin that we observed in these tumors corresponds to the high variability reported for this antigen in myxomas and angiomyxomas in other tissues.40 In a previous study,36 the investigators sought and found immunoreactivity to factor XIIIa, in addition to vimentin and CD34. Factor XIIIa is a distinctive marker for dermal dendrocytes. It is thought that these dendrocytes, by virtue of their factor XIIIa content and activity, limit the accumulation of collagen in various fibrohistocytic lesions of the skin.41 Therefore, it is tempting to speculate that the subset of myxomas composed of factor XIIIa–positive cells is also largely devoid of collagen for the same reason. In one of our cases (case 6), no immunopositivity with any marker was found; this may have been due to poor fixation of the specimen. Accurate diagnosis of myxoma and angiomyxoma requires pathologists experienced in recognizing these tumors. In our series, tumors were initially diagnosed as myxoid liposarcoma, myxoid fibrous histiocytoma, and myxoid embryonal rhabdomyosarcoma (Table 2). Myxoid liposarcoma (myxoliposarcoma) relies on identification of lipoblasts and complex arborizing or plexiform vascular patterns.42,43 Like myxoliposarcoma, there are no recognized specific immunohistochemical markers for myxoid fibrous histiocytoma (myxofibrosarcoma), which requires regions demonstrating storiform cellular patterns and mixtures of plump and spindled cells.44 Myxoid embryonal rhabdomyosarcoma is usually highly cellular and composed of spindled and ovoid rhabdomyoblasts that can be identified by ancillary studies. Electron microscopy demonstrates characteristic intracytoplasmic actin and myosin filament arrays within the rhabdomyoblasts,45 whereas immunohistochemical staining for desmin, myogenin, nuclear MyoD, or other proteins confirms skeletal muscle differentiation.46 Benign tumors containing myxoid stroma should also be
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considered in the differential diagnosis of myxoma and angiomyxoma. Focal mucinosis is a rare subcutaneous, paucicellular, nodular lesion that may be related to myxoma. These tumors contain fibroblastic-appearing cells embedded in mucinous stroma; although staining for factor XIIIa, they are CD34 negative.47,48 Myxolipoma requires the presence of mature adipocytes without lipoblasts as well as spindled cells within myxoid stroma, which, if containing numerous blood vessels, changes the designation of the tumor to angiomyxolipoma.49 Neurofibromas contain admixtures of nerve fibers, Schwann cells, and fibroblasts in a fibrovascular stroma often containing mast cells. The tumors are immunoreactive for S-100 antigen. Nodular fasciitis demonstrates plump mitotically active stellate or spindleshaped fibroblastic cells in an edematous stroma that contains variable amounts of myxoid ground substance intermixed with the cells. These tumors show strong immunohistochemical reactivity with smooth muscle–specific actin and vimentin and electron microscopic features of fibroblasts and myofibroblasts, including abundant rough endoplasmic reticulum and parallel bundles of actinlike filaments with fusiform densities.50 Nerve sheath myxoma (neurothekeoma) demonstrates a distinct multinodular architecture with a peripheral fibrous border within which are small epithelioid Schwann cells arranged in corded, nested, or syncytiumlike aggregates intermixed with scattered spindled and stellate-shaped Schwann cells. The tumor cells demonstrate immunoreactivity for S-100 protein, glial fibrillary acidic protein, neuron-specific enolase, and CD57.30 Carney et al described a complex that includes myxomas, spotty pigmentation, and endocrine overactivity.41,51 Ophthalmic manifestations in the Carney complex include spotty pigmentation of the eyelids,16 pigmented lesions of the caruncle or conjunctival semilunar fold,16 and myxomas of the eyelids.15–17 We did not find any evidence of the Carney complex in our cases. Nevertheless, it is important to be aware of this complex because ocular myxomas in patients with this complex are at high risk for cardiac myxomas, which may cause significant morbidity and death.15–17,41 Echocardiography can detect these tumors, which may then be treated. Acknowledgment. The authors thank William E. Wilkens, MD, and Daniel McLachlan, MD, for contributing case 6.
References 1. Weiss SW, Goldblum JR. Benign soft tissue tumors and pseudotumors of miscellaneous type. In: Weiss SW, Goldblum JR, eds. Soft tissue tumors. 4th ed. St. Louis: Mosby, 2001:1419 – 81. 2. Allen PW. Myxoma is not a single entity: a review of the concept of myxoma. Ann Diagn Pathol 2000;4:99 –123. 3. Fuchs E. Myxoma orbitae. Klin Monstbl Augenheilkd 1914; 53:244 –5. 4. Kianski G, Lord BS. An unusual case of displacement of one eyeball due to myxoma of the frontal sinus. Lancet 1925;1: 126. 5. Lamb HD. Myxoma of the orbit with case report and anatomical findings. Arch Ophthalmol 1928;57:425–9. 6. Bistis J. Un cas de myxome de l’orbite. Arch d’Ophthalmol 1931;48:440 –2.
Hidayat et al 䡠 Myxomas and Angiomyxomas of the Orbit 7. Gifford SR. Multiple myxoma of the orbit. Arch Ophthalmol 1931;5:445– 8. 8. Blegnad O. Myxoma of the orbit. Acta Ophthalmol (Copenh) 1944;22:140. 9. Ardouin P. Le myxome du sinus maxillaire. Rev Laryngol Otol Rhinol (Bord) 1965;86:13–35. 10. Maria DL, Marwa V. Myxoma of the orbit. J All-India Ophthalmol Soc 1967;15:75– 6. 11. Krueger HR, Prolifrone JC, Baum G. Retrobulbar orbital myxoma and its detection by ultrasonography. J Neurosurg 1967;26:87–91. 12. Lieb WE, Wallenfang T. Myxoma of the orbit. a clinicopathologic report. Graefes Arch Clin Exp Ophthalmol 1990;228: 28 –32. 13. Candy EJ, Miller NR, Carson BS. Myxoma of bone involving the orbit [letter]. Arch Ophthalmol 1991;109:919 –20. 14. Maiuri F, Corriero G, Galicchio B, et al. Myxoma of the skull and orbit. Neurochirurgia 1988;31:136 – 8. 15. Kennedy RH, Flanagan JC, Eagle RC Jr, Carney JA. Carney complex with ocular signs suggestive of cardiac myxoma. Am J Ophthalmol 1991;111:699 –702. 16. Kennedy RH, Waller RR, Carney JA. Ocular pigmented spots and eyelid myxomas. Am J Ophthalmol 1987;104:533– 8. 17. Grossniklaus HE, McLean IW, Gillespe JJ. Bilateral eyelid myxomas in Carney’s complex. Br J Ophthalmol 1991;15: 251–2. 18. Mottow-Lippa L, Tso MO, Sugar J. Conjunctival myxoma: a clinicopathologic study. Ophthalmol 1983;90:1452– 8. 19. Pe’er J, Hidayat AA. Myxomas of the conjunctiva. Am J Ophthalmol 1986;102:80 – 6. 20. Lo GG, Biswas J, Rao NA, Font RL. Corneal myxoma: case report and review of the literature 1990;9:174-8. 21. Perez-Grossmann RA, Mesias LA, Contreras F, Spencer WH. Solitary corneal myxoma. Cornea 1997;16:498 –500. 22. Tsang WY, Chan JK, et al. Aggressive aniomyxoma: a report of four cases occurring in men. Am J Surg Pathol 1992;16: 1059 – 65. 23. Skalova A, Mical M, Husek K, et al. Aggressive angiomyxoma of the pelvioperineal region. Immunohistological and ultrastructural study of seven cases. Am J Dermatopathol 1993;15:446 –51. 24. Fetsch JF, Laskin WB, Lefkowitz M, et al. Aggressive angiomyxoma. a clinicopathologic study of 29 female patients. Cancer 1996:78:79 –90. 25. Granter SR, Nucci MR, Fletcher CD. Aggressive angiomyxoma, reappraisal of its relationship to angiofibroblastoma in a series of 16 cases. Histopathology 1997;30:3–10. 26. Steeper TA, Rosai J. Aggressive angiomyxoma of the female pelvis and perineum: report of nine cases of a distinctive type of gynecologic soft tissue neoplasm. Am J Surg Pathol 1983; 7:463–75. 27. Pierard GE, Arresse-Estrada J, Pierard-Franchimont C, DeleixheMauhin F. Is there a link between dendrocytes, fibrosis and sclerosis? Dermatologica 1990;181:264 –5. 28. Yuen HK, Cheuk W, Luk FO, et al. Solitary superficial angiomyxoma in the eyelid. Am J Ophthalmol 2005;139:1141–2. 29. Stout AP. Myxoma, the tumor of primitive mesenchyme. Ann Surg 1948;127:706 –9. 30. Fetsch JF, Laskin WB, Miettinen M. Nerve sheath myxoma: a clinicopathologic and immunohistochemical analysis of 57 morphologically distinctive, S-100 protein- and GFAP-positive, myxoid peripheral nerve sheath tumors with a predilection for the extremities and a high local recurrence rate. Am J Surg Pathol 2005;29:1615–24. 31. Landon G, Ordonez NG, Guarda LA. Cardiac myxoma: an immunohistochemical study using endothelial, histiocytic and
32. 33. 34. 35. 36.
37.
38.
39. 40.
41.
42. 43. 44. 45. 46.
47.
48. 49. 50. 51.
smooth muscle cell markers. Arch Pathol Lab Med 1986; 110:116 –20. Hashimoto H, Tsuneyoshi M, Daimaru Y, et al. Intramuscular myxoma. a clinicopathologic, immunohistochemical, and electron microscopic study. Cancer 1986;58:740 –7. Prasannan L, Warren L, Herzog CE, et al. Sinonasal myxoma. a pediatric case. J Pediatr Hematol Oncol 2005;27:90 –2. Allen PW, Dymock RB, MacCormac LB. Superficial angiomyxomas with and without epithelial components. Report of 30 tumors in 28 patients. Am J Surg Pathol 1988;12:519 –30. Wilk M, Schmoeckel C, Kaiser HW, et al. Cutaneous angiomyxoma: a benign neoplasm distinct from cutaneous focal mucinosis. J Am Acad Dermatol 1995;33:352–5. Fetsch JF, Laskin WB, Tavassoli FA. Superficial angiomyxoma (cutaneous myxoma). A clinicopathologic study of 17 cases arising in the genital region. Int J Gynecol Pathol 1997;16:325–34. Calonje E, Guerin D, McCormick D, Fletcher CD. Superficial angiomysoma: clinicopathologic analysis of a series of distinctive but poorly recognized cutaneous tumors with tendency for recurrence. Am J Surg Pathol 1999;23:910 –7. van Roggen JF, van Unnik JA, de Bruijn IH, Hogendoorn PC. Aggressive angiomyxoma: a clinicopathological and immunohistochemical study of 11 cases with long-term follow-up. Virchows Arch 2005;446:157– 63. Kindblom LG, Stener B, Angervall L. Intramuscular myxoma. Cancer 1974;34:1737– 44. Amezcua CA, Begley SJ, Mata N, et al. Aggressive angiomyxoma of the female genital tract: a clinicopathologic and immunohistochemical study of 12 cases. Int J Gynecol Cancer 2005;15:140 –5. Carney JA, Headington JT, Su WP. Cutaneous myxomas. a major component of the complex of myxomas, spotty pigmentation, and endocrine overactivity. Arch Dermatol 1986;122: 790 – 8. Sanberg, AA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: liposarcoma. Cancer Genet Cytogenet 2004;155:1–24. Dei Tos AP. Liposarcoma: new entities and evolving concepts. Ann Diag Pathol 2000;4:252– 66. Weiss SW, Enzinger FM. Myxoid variant of malignant fibrous histiocytoma. Cancer 1997;39:1672– 85. Erlandson RA. The ultrastructural distinction between rhabdomyosarcoma and other undifferentiated “sarcomas.” Ultrastruct Pathol 1987;11:83–101. Cessna MH, Zhou H, Perkins SL, et al. Are myogenin and myoD1 expression specific for rhabdomyosarcoma? A study of 10 cases, with emphasis on spindle cell mimics. Am J Surg Pathol 2001;25:1150 –7. Terui T, Aiba S, Tagami H. Solitary subcutaneous mucinosis surrounded by bizarre-shaped, factor XIIIa-positive cells with intranuclear vacuoles. J Cutaneous Pathol 1998; 25:271– 4. Wilk M, Schmoeckel C. Cutaneous focal mucinosis—a histopathological and immunohistochemical analysis of 11 cases. J Cutan Pathol 1994;21:446 –52. Lee HW, Lee DK, Lee MW, et al. Two cases of angiomyxolipoma (vascular myxolipoma) of subcutaneous tissue. J Cutaneous Pathol 2005;32:379 – 82. Sakamoto T, Ishibashi T, Ohnishi Y, Inomata H. Immunohistological and electron microscopical study of nodular fasciitis of the orbit. Br J Ophthalmol 1991;75:636 – 8. Wilkes D, McDermott DA, Basson CT. Clinical phenotypes and molecular genetic mechanisms of Carney complex. Lancet 2005;6:501– 8.
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Myxomas are uncommon, benign, mesenchymal tumors that usually affect the skeletal muscles of the extremities, skin, subcutaneous tissues, heart, and genitourinary system.1,2 These tumors rarely arise in the orbit,3–15 eyelid,15–17 conjunctiva,18,19 and cornea,20,21 usually in the middle-aged without gender predilection. Ocular myxomas can be solitary lesions or a component of the Carney complex, Mazabraud syndrome, or McCune–Albright syndrome.15,16 When involving the conjunctiva and cornea, Originally received: April 4, 2006. Accepted: December 21, 2006. Manuscript no. 2006-405. 1 Department of Ophthalmic Pathology, Armed Forces Institute of Pathology, Washington, DC. 2 University of Michigan, Ann Arbor, Michigan. 3 Rush University Medical Center, Chicago, Illinois. 4 King Fahd Hospital of the University, Al-Khobar, Saudi Arabia. 5 Thomas-David Medical Centers, Tuscon, Arizona. Presented at: American Society of Ophthalmic Pathologists meeting, October 2004, New Orleans, Louisiana. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Correspondence to Victor M. Elner, MD, PhD, University of Michigan, Kellogg Eye Center, 1000 Wall Street, Ann Arbor, MI 48105. E-mail: [email protected].
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© 2007 by the American Academy of Ophthalmology Published by Elsevier Inc.
myxomas appear as well-circumscribed, yellow–pink, translucent, cystic and/or solid masses.15–21 Rare in the orbit, the main presenting symptom is proptosis.12 Computed tomography (CT) shows an infiltrative, enhancing soft-tissue mass.12 The rare orbital cases are subjects of case reports, usually without clinical follow-up information.3–15 Histopathologically, myxomas reported in the ocular region are characterized as hypocellular and hypovascular lesions with an abundant myxoid matrix that is rich in hyaluronic acid. Angiomyxomas, which are virtually unknown in the ocular region, are more aggressive and contain more blood vessels than typical myxomas. The angiomyxomas are designated as superficial angiomyxomas for dermal and subcutaneous variants and aggressive angiomyxomas for those located in the pelvic soft tissues and perineum.22–27 To our knowledge, angiomyxomas have not been described in the orbit. In this report, we describe the clinicopathologic features of 3 cases of orbital myxoma and 3 of angiomyxoma, with follow-up information.
Materials and Methods Six patients with histopathologic diagnoses of orbital myxomas or angiomyxomas were studied. For histopathologic evaluation, the following stains were available in all cases: hematoxylin– eosin, periodic acid–Schiff (PAS), Giemsa, and alcian blue at pH 2.5, the ISSN 0161-6420/07/$–see front matter doi:10.1016/j.ophtha.2006.12.022
Hidayat et al 䡠 Myxomas and Angiomyxomas of the Orbit last before and after treatment with hyaluronidase. For immunohistochemistry, the following immunostainings were done using an avidin– biotin–peroxidase technique: vimentin, CD34, factor XIIIa, smooth muscle–specific actin, desmin, S-100 protein, CD68, keratin, epithelial membrane antigen, progesterone receptor, and estrogen receptor. Follow-up clinical information was obtained on all patients. The institutional review board at the University of Michigan approved this study.
Clinical Data Clinical data are summarized in Table 1. The median age of 5 males and 1 female was 56 years (range, 4 – 69). Two of the patients with orbital angiomyxomas were children, 4 and 7 years old. Symptoms and signs, ranging in duration from 3 to 9 months, included proptosis, decreased visual acuity, partial loss of visual field, eyelid swelling, ptosis, afferent pupillary deficit, diplopia, and fullness on palpation. Radiologic findings were available in 4 cases. In case 2, magnetic resonance imaging showed a tumor that filled and expanded the left cavernous sinus, having extended from the left orbital apex, where it involved the superior and inferior rectus muscles and compressed the optic nerve. The radiologic diagnosis was meningioma; however, cavernous hemangioma and schwannoma were considered in the differential diagnosis. In case 3 (Fig 1), CT showed involvement of the entire inferior orbit by a mass that enhanced slightly with contrast. There was no evidence of bony involvement. In case 4 (Fig 2), CT revealed a right posterior, subperiosteal, superomedial, homogenous mass with erosion of the medial orbital wall as well as a right maxillary sinus retention cyst. Magnetic resonance imaging showed a 30⫻21⫻15-mm mass extending to the orbital apex and displacing the optic nerve. The tumor was isodense on T1- and bright on T2weighted images; it enhanced with contrast. In case 6, CT showed a 25-mm ovoid soft-tissue density with slight contrast enhancement, located extraconally in the superior lateral aspect of the left orbit. The mass indented the globe, causing proptosis as well as medial and downward displacement of the eye. The lesion appeared to arise in the lacrimal fossa and caused significant bony remodeling with frank bone destruction of the orbital ridge of the frontal bone. Radiologi-
cally, the mass was consistent with a lacrimal gland tumor, possibly epithelial or lymphomatous in origin. Plain skull films of the orbit showed a lytic lesion. Intraoperatively, the tumors were described as mucoid, bluish, cystic masses with thin capsules. Within the capsules, the tumors consisted of sticky, clear, mucinous material that closely resembled vitreous. Sometimes they appeared as fluctuant gelatinous cysts. In other instances, the tumors appeared as multiloculated cysts containing mucoid material. In case 2, the ill-defined angiomyxoid tumor was quite vascular and bled excessively during surgery. The tumor surrounded all cranial nerves within the cavernous sinus. The orbital tumors in patients 1, 5, and 6 were treated by simple local excision; however, the recurrence in case 6 necessitated removal of the lateral orbital roof. In case 2, transcranial orbitotomy was required for excision of the deep orbital portion of the tumor. Because the tumor involved the cavernous sinus, a second operation was performed 3 months later to resect this portion of the tumor. At surgery, cranial nerves within the sinus were enveloped by tumor, with severe compression of cranial nerve VII. The bones of the middle cranial fossa were soft and possibly infiltrated by the tumor. Although most of the tumor was resected, unresected residual tumor was left behind and the patient was treated with methotrexate. In case 3, lateral and anterior orbitotomies were performed to permit piecemeal tumor removal. In case 4, the initial treatment consisted of frontal orbitotomy and biopsy. This was followed by transcranial resection of the subperiosteal tumor and repair of the orbital roof with metal mesh. Because of recurrent progressive proptosis, lack of response to corticosteroids, and radiologically documented tumor regrowth that involved the orbital apex and ethmoid sinus, she underwent a unilateral subcranial orbitotomy 10 months later with partial ethmoid resection and dissection of tumor from around the optic nerve and cranial nerves at the superior orbital fissure, followed by repair with a contralateral vascularized pericranial flap. Four months later, a recurrent 5-mm tumor nodule in the cavernous sinus necessitated a frontal–temporal craniotomy with extradural resection of the anterior clinoid, inferior wall of the superior orbital fissure, and optic strut to provide access for complete resection of the cavernous sinus portion of the tumor. One month later, a right orbital exenteration extending to the pericranial flap covering the cavernous
Table 1. Orbital Myxomas and Angiomyxomas: Clinical Data of 6 Cases Case No.
Location
1
Left orbit
2
Left orbit, cavernous sinus, base of cranial fossa
3
Right orbit
4
Right orbit, ethmoid and maxillary sinuses, cavernous sinus
5 6
Age (yrs)
Gender
Duration (mos)
68
M
—
7
M
69
Signs and Symptoms
Treatment
Palpable mass
Simple local excision
9
Proptosis, loss of inferior VF, decreased visual acuity
M
4
4
F
9
Proptosis, lower lid swelling, palpable mass Proptosis, ptosis, afferent pupillary defect, decreased visual acuity
Transcranial orbitotomy for orbital tumor excision, dissection of tumor from cranial nerves, methotrexate Lateral and anterior orbitotomy for piecemeal tumor removal
Right orbit
48
M
—
Left orbit
67
M
3
Palpable mass Proptosis, diplopia
Frontal craniotomy, orbitotomy, ethmoid and maxillary sinuses for removal of tumor, oral corticosteroids, orbital exenteration Simple local excision Simple excision initially, orbitotomy with removal of lateral orbital roof for recurrence
Follow-up 4 yrs, alive and well 5 mos, 1 recurrence 7 yrs, alive and well 8 yrs, 3 recurrences
15 mos, alive and well 4 yrs, 3 recurrences
F ⫽ female; M ⫽ male; VF ⫽ visual field.
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Figure 1. Case 3. A, A 69-year-old man with right proptosis and eyelid fullness. B, Computed tomography shows a homogenous mass without bone involvement. C, Intraoperative photograph demonstrating a translucent cystic mass.
sinus, anterior and posterior ethmoidectomy, and sphenoidectomy were performed. A temporalis muscle flap was used to repair the posterior orbital and paranasal sinus defect. Due to suspicion of involved margins at the time of orbital exenteration, the frontal–temporal craniotomy was reopened, the cavernous sinus reexposed, and all the contents except for the carotid artery resected. An ethmoidal sinus recurrence 7 years after initial presentation required repeat ethmoidectomy for tumor resection. Follow-up clinical information was obtained in all patients and ranged from 5 months to 7 years (median, 6 years). In 1 of the 3 patients with orbital myxoma, 3 recurrences occurred after incomplete excision (case 6). Two of the 3 patients with orbital angio-
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myxomas developed recurrences (cases 2 and 4). The recurrences in patients with myxomas and angiomyxomas usually occurred in the first few months after incomplete excision of the lesions. At final follow-up, all 6 patients were alive and well. None of the patients had evidence of metastatic disease. No stigmata of the Carney complex were present in any of the 6 patients studied.
Microscopic Findings The light microscopic and immunohistochemical findings of the 6 tumors, 3 myxomas and 3 angiomyxomas, are summarized in Table 2. Three of the orbital tumors had been initially diagnosed as
Hidayat et al 䡠 Myxomas and Angiomyxomas of the Orbit myxoid liposarcoma, myxoid fibrous histiocytoma, and myxoid embryonal rhabdomyosarcoma; the remaining 3 tumors were initially diagnosed correctly as angiomyxoma (angiomyxofibroma) or myxoma. All of the myxomas were nonencapsulated, poorly circumscribed, hypocellular, and hypovascular. The abundant loose matrix was rich in hyaluronic acid and contained few collagen and reticulin fibers (Fig 3). Pseudocysts were observed in some lesions. The stellate and spindled tumor cells were sparse and showed mildly hyperchromatic and slightly pleomorphic nuclei. Intranuclear and intracytoplasmic vacuoles were frequently present (Fig 3). These vacuoles did not stain with alcian blue or PAS. No mitotic activity was seen in any of the tumors. Small blood vessels were rarely noted in myxomas. Mast cells and a few macrophages were observed in all tumors. The orbital angiomyxomas were quite similar to the myxomas, except for abundant small blood vessels (Fig 4). The elaborate arborizing vascular pattern, as seen in some sarcomas, was absent. Recurrent tumors showed similar histopathologic findings when compared with the primary lesion in each case (Fig 4). Immunohistochemically, tumor cells were immunoreactive for vimentin in 5 of 6 cases, CD34 (Fig 4) in 4 of 6 cases, and factor XIIIa (Fig 4) in 4 of 6 cases. Focal positivity for smooth muscle– specific actin was seen in 2 tumors. Immunoreactivity for progesterone receptor was found in 1 case. No immunoreactivity was detected for S-100 protein, desmin, cytokeratin, epithelial membrane antigen, or estrogen receptors in any case.
Discussion Myxomas of soft tissue are generally classified in 5 major categories: intramuscular (typical), cutaneous (superficial angiomyxoma), juxta-articular, nerve sheath (neurothekeoma), and aggressive angiomyxoma.1 However, these categories have not been applied to myxomas involving the ocular region, except for one recently reported case of superficial angiomyxoma of the eyelid.28 Histogenetically, Stout29 regarded myxoma as a tumor of primitive mesenchyme. Since then, proposed cells of origin include vascular endothelium, neural crest cells of the nerve sheath, dendritic cells, and fibroblasts or their precursors.30 –32 Whatever their origin, the tumor cells appear to be modified mesenchymal cells that produce excessive amounts of glycosaminoglycans rich in hyaluronic acid, but little collagen.2 We agree with other investigators19 that myxomas and angiomyxomas derive from cells similar to fibroblasts and are not primitive cells. Most ultrastructural studies, including those performed on conjunctival myxomas, show predominantly fibroblast or myofibroblastlike elongated tumor cells with prominent dilated rough endoplasmic reticulum, Golgi complexes, pinocytic vesicles, and intracytoplasmic microfilaments with focal densities.19,29,32 Orbital myxomas are rare tumors that may primarily involve the orbital soft tissue or adjacent bone or extend
4™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™ Figure 2. Case 4. A, A 4-year-old girl with right proptosis and eyelid fullness. B, Right proptosis evident on upgaze. C, Computed tomography shows a hemispherical mass involving bone superomedially in the orbital apex. D, Magnetic resonance imaging of a recurrent tumor showing isodensity with orbital fat. E, Magnetic resonance imaging with fat suppression showing a hyperintense recurrent tumor in the cavernous sinus.
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Ophthalmology Volume 114, Number 5, May 2007 Table 2. Orbital Myxomas and Angiomyxomas: Pathologic Data Case
Maximum Dimension/ Gross Appearance
1 2
20 mm 25 mm/vascularized
3
25 mm/bluish, cystic, filled with sticky material 30 mm/vascularized, soft, mucoid
4 5 6*
15 mm/multiloculated cyst containing mucoid material 25 mm
Initial Diagnosis Myxoid liposarcoma Myxoid embryonal rhabdomyosarcoma Myxoid fibrous histiocytoma Angiomyxoma Angiomyxofibroma Myxoma
Immunohistochemical Studies
Final Diagnosis
Vimentin ⫹, CD34 ⫺, factor XIIIa ⫹ Vimentin ⫹, CD34 ⫹, SMA ⫺, desmin ⫺
Myxoma Angiomyxoma
Vimentin ⫹⫹⫹, CD34 ⫹⫹⫹, factor XIIIa ⫹⫹⫹, SMA ⫹/⫺, S-100 ⫺, progesterone receptor ⫹, estrogen receptor ⫺ Vimentin ⫹⫹, CD34 ⫹⫹⫹, factor XIIIa ⫹⫹, SMA ⫹/⫺, CD68 ⫹, S-100 ⫺, desmin ⫺, EMA ⫺, GFAP ⫺, cytokeratin ⫺, progesterone receptor ⫺, estrogen receptor ⫺ Vimentin ⫹⫹, CD34 ⫹⫹, factor XIIIa ⫹⫹, SMA ⫺, desmin ⫺ Vimentin ⫺, CD34 ⫺, factor XIIIa ⫺, SMA ⫺, desmin ⫺
Myxoma Angiomyxoma Angiomyxoma Myxoma
EMA ⫽ epithelial membrane antigen; GFAP ⫽ glial fibrillary acidic protein; SMA ⫽ smooth muscle–specific actin. *Absence of any immunoreactivity, likely due to poor fixation and preservation of antigens.
from the paranasal sinuses to affect the orbit. Sixteen reports of myxomas involving the orbit have been published, all involving cases that arose in adults.3–15 Facial myxomas, arising from dental elements, also rarely involve children.33 These myxomas are slow-growing expansile lesions that are painless and may remain undetected for many years. The facial myxomas are benign, but may be locally invasive, cause bone destruction, and recur in up to 40% of cases.33 Angiomyxomas most frequently involve the dermis and are called superficial angiomyxomas or cutaneous angiomyxomas.34 –36 These superficial angiomyxomas also show a propensity for recurrence, also in up to 40% of cases.33 Recommended treatment of these lesions is complete excision, and metastases have not been reported.28,37 Aggressive angiomyxomas, first described by Steeper and Rosai in 1983,26 are uncommon variably myxoid neoplasms affecting predominantly the pelvic–perineal region of adults, with a female:male ratio of 6:1.38 This group of tumors shows distinctive vascularity, and they tend to recur at rates varying from 35% to 70%, often years after primary excision.22–27,38 In our series, the 3 cases of angiomyxomas were similar to reported aggressive angiomyxomas, except for the fact that they did not contain thick-walled blood vessels in addition to thin-walled vessels, which we did find. To our knowledge, aggressive angiomyxomas have not been reported in the orbit. In our series, 2 children (4 and 7 years old) had angiomyxomas that were locally aggressive orbital tumors that also involved the paranasal sinuses, cavernous sinus, and base of the skull, with rapid recurrences. We cannot rule
out the possibility that these 2 tumors arose in bone with secondary involvement of the orbit. The third case of orbital angiomyxoma affected an adult. The lesion was localized to the orbit and did not recur after complete excision. Contrary to conjunctival myxomas, the orbital myxomas and angiomyxomas were not well circumscribed, but infiltrative. Therefore, it appears that complete surgical excision with a margin of healthy tissue is the treatment of choice, as it is for conjunctival myxomas.15–21 Radiation therapy is probably not helpful for tumors such as these that originate from fibroblastic cells and display very low mitotic activity. In our series, 3 of the 6 tumors recurred without any evidence of distant metastases. The rapid clinical recurrence of 2 of the 3 orbital angiomyxomas we report is similar to the high recurrence rate of these vascularized tumors when they arise in other tissues.22–27,34 –36 Involvement of the soft orbital tissues alone was not followed by any recurrences, but infiltration of the bony wall of the orbit by the tumor, with or without involvement of the paranasal sinuses, resulted in recurrences in all 3 cases. Involvement of the bony wall of the orbit and/or adjacent sinuses was previously reported in 7 cases of facial myxoma.3,4,9,10,13,14 Many of these cases for which follow-up information was available showed recurrence.13,14 We conclude that vascularity and bone involvement areimportant prognostic factors predisposing to tumor recurrence. Myxomas and angiomyxomas were similar histopathologically except for the abundance of small blood vessels in the latter. Tumor cells of both lesions were sparse and stellate or
™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™3 Figure 3. Myxoma (case 3). A, Sparse spindled and stellate tumor cells in loose myxoid matrix (stain, hematoxylin– eosin; original magnification, ⫻320). B, Intranuclear vacuole in elongated tumor cell (stain, hematoxylin–eosin; original magnification, ⫻500). C, Infiltration of skeletal muscles by a myxoma containing mast cells (stain, hematoxylin– eosin; original magnification, ⫻320). Figure 4. Aggressive angiomyxoma (case 4). A, Recurrent tumor involving bone of medial orbital wall (stain, hematoxylin– eosin; original magnification, ⫻50). B, Myxoid orbital tumor with sparse cells and prominent vascularity (stain, hematoxylin– eosin; original magnification, ⫻100). C, Spindled and stellate myxoma cells, some with intracytoplasmic vacuoles, in vascularized myxoid matrix (stain, hematoxylin– eosin; original magnification, ⫻320). D, Intense alcian blue positivity at pH 2.5 that was greatly reduced by hyaluronidase treatment (original magnification, ⫻125). E, Immunoreactivity for factor XIIIa in tumor cells (peroxidase and hematoxylin counterstain; original magnification, ⫻500). F, Immunoreactivity for CD34 antigen in tumor cells (peroxidase and hematoxylin counterstain; original magnification, ⫻250).
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Ophthalmology Volume 114, Number 5, May 2007 spindled in shape. As previously reported for this type of tumor, we frequently observed small intranuclear18,19,25,34,35 and intracytoplasmic12,19,36 vacuoles in the cells. The intranuclear vacuoles are related invagination of the nuclear membrane by protrusion of the cytoplasmic matrix. We also noted scattered mast cells and occasional macrophages, which have been previously reported in myxomas and angiomyxomas.19,34,35 The abundant, basophilic, myxoid extracellular matrix was a regular feature of the myxomas and angiomyxomas and was responsible for the intraoperative findings of sticky, clear, viscous material composing much of the tumors. The matrix widely separated the tumor cells and contained fine fibrillary reticulin fibers and variable numbers of fibrous strands or trabeculae. Because the matrix is chiefly comprised of hyaluronic acid and chondrotin sulfate, it was positive with alcian blue at pH 2.5, which was sensitive to hyaluronidase treatment of tissue sections before staining.39 Our immunohistochemical studies showed frequent immunopositivity of the tumor cells for vimentin, CD34, and factor XIIIa. These immunologic markers may be useful in the diagnosis of myxomas and angiomyxomas. In previous reports, the tumor cells have been reported to be positive for vimentin and CD34, with infrequent immunostaining for smooth muscle–specific actin.12,32 The weak focal immunostaining for smooth muscle–specific actin that we observed in these tumors corresponds to the high variability reported for this antigen in myxomas and angiomyxomas in other tissues.40 In a previous study,36 the investigators sought and found immunoreactivity to factor XIIIa, in addition to vimentin and CD34. Factor XIIIa is a distinctive marker for dermal dendrocytes. It is thought that these dendrocytes, by virtue of their factor XIIIa content and activity, limit the accumulation of collagen in various fibrohistocytic lesions of the skin.41 Therefore, it is tempting to speculate that the subset of myxomas composed of factor XIIIa–positive cells is also largely devoid of collagen for the same reason. In one of our cases (case 6), no immunopositivity with any marker was found; this may have been due to poor fixation of the specimen. Accurate diagnosis of myxoma and angiomyxoma requires pathologists experienced in recognizing these tumors. In our series, tumors were initially diagnosed as myxoid liposarcoma, myxoid fibrous histiocytoma, and myxoid embryonal rhabdomyosarcoma (Table 2). Myxoid liposarcoma (myxoliposarcoma) relies on identification of lipoblasts and complex arborizing or plexiform vascular patterns.42,43 Like myxoliposarcoma, there are no recognized specific immunohistochemical markers for myxoid fibrous histiocytoma (myxofibrosarcoma), which requires regions demonstrating storiform cellular patterns and mixtures of plump and spindled cells.44 Myxoid embryonal rhabdomyosarcoma is usually highly cellular and composed of spindled and ovoid rhabdomyoblasts that can be identified by ancillary studies. Electron microscopy demonstrates characteristic intracytoplasmic actin and myosin filament arrays within the rhabdomyoblasts,45 whereas immunohistochemical staining for desmin, myogenin, nuclear MyoD, or other proteins confirms skeletal muscle differentiation.46 Benign tumors containing myxoid stroma should also be
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considered in the differential diagnosis of myxoma and angiomyxoma. Focal mucinosis is a rare subcutaneous, paucicellular, nodular lesion that may be related to myxoma. These tumors contain fibroblastic-appearing cells embedded in mucinous stroma; although staining for factor XIIIa, they are CD34 negative.47,48 Myxolipoma requires the presence of mature adipocytes without lipoblasts as well as spindled cells within myxoid stroma, which, if containing numerous blood vessels, changes the designation of the tumor to angiomyxolipoma.49 Neurofibromas contain admixtures of nerve fibers, Schwann cells, and fibroblasts in a fibrovascular stroma often containing mast cells. The tumors are immunoreactive for S-100 antigen. Nodular fasciitis demonstrates plump mitotically active stellate or spindleshaped fibroblastic cells in an edematous stroma that contains variable amounts of myxoid ground substance intermixed with the cells. These tumors show strong immunohistochemical reactivity with smooth muscle–specific actin and vimentin and electron microscopic features of fibroblasts and myofibroblasts, including abundant rough endoplasmic reticulum and parallel bundles of actinlike filaments with fusiform densities.50 Nerve sheath myxoma (neurothekeoma) demonstrates a distinct multinodular architecture with a peripheral fibrous border within which are small epithelioid Schwann cells arranged in corded, nested, or syncytiumlike aggregates intermixed with scattered spindled and stellate-shaped Schwann cells. The tumor cells demonstrate immunoreactivity for S-100 protein, glial fibrillary acidic protein, neuron-specific enolase, and CD57.30 Carney et al described a complex that includes myxomas, spotty pigmentation, and endocrine overactivity.41,51 Ophthalmic manifestations in the Carney complex include spotty pigmentation of the eyelids,16 pigmented lesions of the caruncle or conjunctival semilunar fold,16 and myxomas of the eyelids.15–17 We did not find any evidence of the Carney complex in our cases. Nevertheless, it is important to be aware of this complex because ocular myxomas in patients with this complex are at high risk for cardiac myxomas, which may cause significant morbidity and death.15–17,41 Echocardiography can detect these tumors, which may then be treated. Acknowledgment. The authors thank William E. Wilkens, MD, and Daniel McLachlan, MD, for contributing case 6.
References 1. Weiss SW, Goldblum JR. Benign soft tissue tumors and pseudotumors of miscellaneous type. In: Weiss SW, Goldblum JR, eds. Soft tissue tumors. 4th ed. St. Louis: Mosby, 2001:1419 – 81. 2. Allen PW. Myxoma is not a single entity: a review of the concept of myxoma. Ann Diagn Pathol 2000;4:99 –123. 3. Fuchs E. Myxoma orbitae. Klin Monstbl Augenheilkd 1914; 53:244 –5. 4. Kianski G, Lord BS. An unusual case of displacement of one eyeball due to myxoma of the frontal sinus. Lancet 1925;1: 126. 5. Lamb HD. Myxoma of the orbit with case report and anatomical findings. Arch Ophthalmol 1928;57:425–9. 6. Bistis J. Un cas de myxome de l’orbite. Arch d’Ophthalmol 1931;48:440 –2.
Hidayat et al 䡠 Myxomas and Angiomyxomas of the Orbit 7. Gifford SR. Multiple myxoma of the orbit. Arch Ophthalmol 1931;5:445– 8. 8. Blegnad O. Myxoma of the orbit. Acta Ophthalmol (Copenh) 1944;22:140. 9. Ardouin P. Le myxome du sinus maxillaire. Rev Laryngol Otol Rhinol (Bord) 1965;86:13–35. 10. Maria DL, Marwa V. Myxoma of the orbit. J All-India Ophthalmol Soc 1967;15:75– 6. 11. Krueger HR, Prolifrone JC, Baum G. Retrobulbar orbital myxoma and its detection by ultrasonography. J Neurosurg 1967;26:87–91. 12. Lieb WE, Wallenfang T. Myxoma of the orbit. a clinicopathologic report. Graefes Arch Clin Exp Ophthalmol 1990;228: 28 –32. 13. Candy EJ, Miller NR, Carson BS. Myxoma of bone involving the orbit [letter]. Arch Ophthalmol 1991;109:919 –20. 14. Maiuri F, Corriero G, Galicchio B, et al. Myxoma of the skull and orbit. Neurochirurgia 1988;31:136 – 8. 15. Kennedy RH, Flanagan JC, Eagle RC Jr, Carney JA. Carney complex with ocular signs suggestive of cardiac myxoma. Am J Ophthalmol 1991;111:699 –702. 16. Kennedy RH, Waller RR, Carney JA. Ocular pigmented spots and eyelid myxomas. Am J Ophthalmol 1987;104:533– 8. 17. Grossniklaus HE, McLean IW, Gillespe JJ. Bilateral eyelid myxomas in Carney’s complex. Br J Ophthalmol 1991;15: 251–2. 18. Mottow-Lippa L, Tso MO, Sugar J. Conjunctival myxoma: a clinicopathologic study. Ophthalmol 1983;90:1452– 8. 19. Pe’er J, Hidayat AA. Myxomas of the conjunctiva. Am J Ophthalmol 1986;102:80 – 6. 20. Lo GG, Biswas J, Rao NA, Font RL. Corneal myxoma: case report and review of the literature 1990;9:174-8. 21. Perez-Grossmann RA, Mesias LA, Contreras F, Spencer WH. Solitary corneal myxoma. Cornea 1997;16:498 –500. 22. Tsang WY, Chan JK, et al. Aggressive aniomyxoma: a report of four cases occurring in men. Am J Surg Pathol 1992;16: 1059 – 65. 23. Skalova A, Mical M, Husek K, et al. Aggressive angiomyxoma of the pelvioperineal region. Immunohistological and ultrastructural study of seven cases. Am J Dermatopathol 1993;15:446 –51. 24. Fetsch JF, Laskin WB, Lefkowitz M, et al. Aggressive angiomyxoma. a clinicopathologic study of 29 female patients. Cancer 1996:78:79 –90. 25. Granter SR, Nucci MR, Fletcher CD. Aggressive angiomyxoma, reappraisal of its relationship to angiofibroblastoma in a series of 16 cases. Histopathology 1997;30:3–10. 26. Steeper TA, Rosai J. Aggressive angiomyxoma of the female pelvis and perineum: report of nine cases of a distinctive type of gynecologic soft tissue neoplasm. Am J Surg Pathol 1983; 7:463–75. 27. Pierard GE, Arresse-Estrada J, Pierard-Franchimont C, DeleixheMauhin F. Is there a link between dendrocytes, fibrosis and sclerosis? Dermatologica 1990;181:264 –5. 28. Yuen HK, Cheuk W, Luk FO, et al. Solitary superficial angiomyxoma in the eyelid. Am J Ophthalmol 2005;139:1141–2. 29. Stout AP. Myxoma, the tumor of primitive mesenchyme. Ann Surg 1948;127:706 –9. 30. Fetsch JF, Laskin WB, Miettinen M. Nerve sheath myxoma: a clinicopathologic and immunohistochemical analysis of 57 morphologically distinctive, S-100 protein- and GFAP-positive, myxoid peripheral nerve sheath tumors with a predilection for the extremities and a high local recurrence rate. Am J Surg Pathol 2005;29:1615–24. 31. Landon G, Ordonez NG, Guarda LA. Cardiac myxoma: an immunohistochemical study using endothelial, histiocytic and
32. 33. 34. 35. 36.
37.
38.
39. 40.
41.
42. 43. 44. 45. 46.
47.
48. 49. 50. 51.
smooth muscle cell markers. Arch Pathol Lab Med 1986; 110:116 –20. Hashimoto H, Tsuneyoshi M, Daimaru Y, et al. Intramuscular myxoma. a clinicopathologic, immunohistochemical, and electron microscopic study. Cancer 1986;58:740 –7. Prasannan L, Warren L, Herzog CE, et al. Sinonasal myxoma. a pediatric case. J Pediatr Hematol Oncol 2005;27:90 –2. Allen PW, Dymock RB, MacCormac LB. Superficial angiomyxomas with and without epithelial components. Report of 30 tumors in 28 patients. Am J Surg Pathol 1988;12:519 –30. Wilk M, Schmoeckel C, Kaiser HW, et al. Cutaneous angiomyxoma: a benign neoplasm distinct from cutaneous focal mucinosis. J Am Acad Dermatol 1995;33:352–5. Fetsch JF, Laskin WB, Tavassoli FA. Superficial angiomyxoma (cutaneous myxoma). A clinicopathologic study of 17 cases arising in the genital region. Int J Gynecol Pathol 1997;16:325–34. Calonje E, Guerin D, McCormick D, Fletcher CD. Superficial angiomysoma: clinicopathologic analysis of a series of distinctive but poorly recognized cutaneous tumors with tendency for recurrence. Am J Surg Pathol 1999;23:910 –7. van Roggen JF, van Unnik JA, de Bruijn IH, Hogendoorn PC. Aggressive angiomyxoma: a clinicopathological and immunohistochemical study of 11 cases with long-term follow-up. Virchows Arch 2005;446:157– 63. Kindblom LG, Stener B, Angervall L. Intramuscular myxoma. Cancer 1974;34:1737– 44. Amezcua CA, Begley SJ, Mata N, et al. Aggressive angiomyxoma of the female genital tract: a clinicopathologic and immunohistochemical study of 12 cases. Int J Gynecol Cancer 2005;15:140 –5. Carney JA, Headington JT, Su WP. Cutaneous myxomas. a major component of the complex of myxomas, spotty pigmentation, and endocrine overactivity. Arch Dermatol 1986;122: 790 – 8. Sanberg, AA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: liposarcoma. Cancer Genet Cytogenet 2004;155:1–24. Dei Tos AP. Liposarcoma: new entities and evolving concepts. Ann Diag Pathol 2000;4:252– 66. Weiss SW, Enzinger FM. Myxoid variant of malignant fibrous histiocytoma. Cancer 1997;39:1672– 85. Erlandson RA. The ultrastructural distinction between rhabdomyosarcoma and other undifferentiated “sarcomas.” Ultrastruct Pathol 1987;11:83–101. Cessna MH, Zhou H, Perkins SL, et al. Are myogenin and myoD1 expression specific for rhabdomyosarcoma? A study of 10 cases, with emphasis on spindle cell mimics. Am J Surg Pathol 2001;25:1150 –7. Terui T, Aiba S, Tagami H. Solitary subcutaneous mucinosis surrounded by bizarre-shaped, factor XIIIa-positive cells with intranuclear vacuoles. J Cutaneous Pathol 1998; 25:271– 4. Wilk M, Schmoeckel C. Cutaneous focal mucinosis—a histopathological and immunohistochemical analysis of 11 cases. J Cutan Pathol 1994;21:446 –52. Lee HW, Lee DK, Lee MW, et al. Two cases of angiomyxolipoma (vascular myxolipoma) of subcutaneous tissue. J Cutaneous Pathol 2005;32:379 – 82. Sakamoto T, Ishibashi T, Ohnishi Y, Inomata H. Immunohistological and electron microscopical study of nodular fasciitis of the orbit. Br J Ophthalmol 1991;75:636 – 8. Wilkes D, McDermott DA, Basson CT. Clinical phenotypes and molecular genetic mechanisms of Carney complex. Lancet 2005;6:501– 8.
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