Adult Extrarenal Rhabdoid Tumor of the Lacrimal Gland John H. Ni[fenegger, MD, Frederick A. Jakobiec, MD, John W. Shore, MD, Daniel M. Albert, MD
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50-year-old man presented with a rapidly growing mass in the area of the right lacrimal gland. An initial erroneous histopathologic diagnosis of a pleomorphic adenoma made on a small-incisional biopsy was later corrected to a malignant rhabdoid tumor when a wide local excision of the tumor was performed. The tumor was composed predominantly of dyscohesive, globoid, and eosinophilic cells, which frequently contained cytoplasmic inclusions. These were demonstrated to be composed of whorls of intermediate vimentin filaments. The tumor cells expressed epithelial membrane antigen as well as cytokeratin. Ultrastructurally, they displayed intercellular junctions and interrupted segments of linear basement membrane material. These findings, together with the development of the lesion within the parenchyma of the lacrimal gland, are suggestive of an epithelial origin. The patient was treated with radical surgery and adjunctive radiotherapy and chemotherapy, which are the recommended treatment modalities for this highly malignant tumor. Ophthalmology 1992;99:567-574
Malignant rhabdoid tumor is a rare and highly aggressive renal tumor of infants with distinctive histopathologic and ultrastructural features. Since its original description, the rhabdoid phenotype has been recognized at a number of extrarenal sites in both children and adults, 1-17 which has led to many different histogenetic theories. We report the first adult orbital case that was unequivocally situated in the lacrimal gland and suggest its possible epithelial origin.
Clinical History A 50-year-old man had a 4-week history of right upper eyelid swelling. He had been previously treated for 1 month without resolution. On examination, the swelling was in proximity to the lacrimal gland and was believed to be dacryoadenitis, but it did not respond to topical and oral antibiotics. Two days before presentation at the Massachusetts Eye and Ear Infirmary Emergency Room, the
Originally received: October 3, 1991. Manuscript accepted: November 14, 1991. From the Massachusetts Eye and E,ar Infirmary, Department of Ophthalmology and Harvard Medical School, Boston. Reprint requests to Frederick A. Jakobiec, MD, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114.
patient experienced exacerbated pain and burning of the right eye, with an abrupt increase in upper and lower eyelid swelling and erythema (Fig 1). On initial examination at the Massachusetts Eye and Ear Infirmary, best corrected visual acuity was 20/50 in the affected right eye and 20/25 in the left. The patient was afebrile and had a palpable nontender mobile mass in the right upper lateral fornix. There were 3 mm of relative right proptosis, with intact extraocular motility. A contrast enhanced orbital computed tomographic study (Figs 2 and 3) revealed a rounded, superolateral soft tissue mass protruding beyond the orbital rim and extending posteriorly toward the orbital lobe of the lacrimal gland. The latter structure could not be definitely distinguished. There was no bone destruction. A presumptive clinical diagnosis of an inflammatory lesion was made, and a transcutaneous biopsy of the right lacrimal gland was performed. During surgery, a yellowwhite mass was incised in the lacrimal fossa. Frozen sections were interpreted as an atypical myxoid neoplasm, possibly a pleomorphic adenoma. The permanent sections were believed to be most consistent with a pleomorphic adenoma, although rare atypical cells were found. Over the ensuing week, the patient experienced a rapid increase of the upper eyelid swelling, with the tumor doubling in size and protruding through the palpebral fissure from the superolateral fornix (Figs 4 and 5). A right lateral
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Niffenegger et al . Rhabdoid Tumor of the Lacrimal Gland Top left, Figure 1. A 50-year-old man developed swelling of the right eyelids with some erythema and right proptosis over a 1-month period. Top right, Figure 2. A computed axial tomogram shows a somewhat rounded mass projecting anterior to the orbital rim. Second row left, Figure 3. The coronal projection of the mass discloses an oblong superoinferior shape without indentation of the contiguous bone or bone destruction. Second row right, Figure 4. One week after an incisional biopsy, the lid mass has dramatically increased.' Third row left, Figure 5. The upper eyelid was very taught, but on lid elevation, afleshy mass protruded into the visual axis from the superotemporal fornix . Third row right, Figure 6. Gross appearance of the excised mass via lateral orbitotomy displaying circumscription and partial encapsulation. The tongue of tissue on the right extended from the mass into the eyelid. Bottom left, Figure 7. The initial incisional biopsy was composed of spindle cells, focally merging into osteoidal regions, as revealed in the center of this field (hematoxylin-eosin; original magnification, XSO). Bottom right, Figure S. In scattered regions of the small initial incisional biopsy, small cords of more eosinophilic cells suggesting an epithelial aspect are separated in a mucinous matrix, leading to the mistaken diagnosis of a pleomorphic adenoma (hematoxylin-eosin; original magnification, X1S0).
(
orbitotomy exposed an extremely large tumor (Fig 6) extending from the lacrimal fossa region toward the superior orbital fissure and involving both the posterior and anterior surfaces of the tarsus of the upper eyelid. Histopathologic evaluation of the excised mass, coupled with immunohistochemical and electron microscopic studies, led to the diagnosis of a malignant extrarenal rhabdoid tumor. After a negative work-up for metastases and after evaluation of the cerebrospinal fluid for the absence of tumor cells, a right orbital exenteration was performed. Five weeks after exenteration, 4485 rad of radiotherapy were delivered in 25 fractions over 40 days. Six weeks after the completion of radiation therapy, the patient began systemic chemotherapy based on a protocol used in the National Wilms' Tumor Study, including cycles of actinomycin, doxorubicin, cyclophosphamide, and vincristine. Fifteen months after cessation of the chemotherapy, the patient has no evidence of either local recurrence or distant metastases.
Pathologic Findings The initial small-incisional biopsy (9 X 8 X 6mm) into the lacrimal gland contained masses of spindle cells, occasionally organized into fascicles, but more often dispersed in a looser myxoid stroma. Occasionally there were hyalinized stromal areas that merged into osteochondroidal zones (Fig 7). Interspersed in both the hyalinized and the looser areas were mononucleated eosinophilic cells, which sometimes formed delicate syncytia without ostensible tubule or lumen formation (Fig 8). These findings were responsible for the initial mistaken diagnosis of a pleomorphic adenoma. The second and more ample excision of the superotemporal and supraorbital mass grossly appeared to possess a partial capsule, had a soft texture with a variegated brown/pink coloration when trisected, and measured 30 X 40 X 25 mm. Histopathologically, the tissue showed a dramatically different architecture than that of the earlier incisional biopsy. A pseudocapsule was present on the anterior surface of the mass, but posteriorly it infiltrated
the orbital fat. Mucinious-trabecular (Fig 9), osteochondroidal (Fig 10), and lymphomatoid (Fig 11) patterns were seen focally. In most areas, however, among surviving elements of the lacrimal gland there were sheets ofloosely cohesive epithelioid cells with abundant eosinophilic to amphophilic cytoplasm (Fig 12). Occasionally, the diffuse proliferation was subdivided by variably thickened collagenous trabeculae (Fig 13). There was a paucity of capillary proliferation. The diffusely arranged cells possessed eccentrically placed vesicular nuclei with prominent central to paracentral nucleoli. Many of the tumor cells contained a prominent, globular, and eosinophilic cytoplasmic inclusion (Fig 14). Mitotic figures were numerous. In some areas, there were abrupt transitions between the globoid (rhabdoid) cells and more spindle-appearing cells. No cross striations were seen using the Masson-trichrome stain or the phosphotungstic acid-hematoxylin stain. Only a minimal amount of interstitial collagen was present between the sheets of tumor cells, but a faint deposition of argentophilic reticulin fibers was seen in some areas. The tumor cells stained negatively with the mucicarmine stain, and the Alcian blue stain revealed the presence of extracellular mucopolysaccharides in the myxoid regions. The exenterated orbital contents showed a small amount of residual tumor in the superolateral orbit away from the surgical margins, as well as within the anterior orbital fat and striated muscle of the upper eyelid. Immunohistochemical studies on fresh frozen and formalin-fixed paraffin-embedded tissue showed that the tumor cells were positive for vimentin (Fig 15), keratin (although only in frozen sections), and epithelial membrane antigen (Fig 16). The tumor stained negatively for desmin, muscle-specific actin, myoglobin, and neuron-specific enolase (Table 1). Focal patches of inflammatory cells within the lacrimal gland or in perivascular regions stained positively with Leu-7, and some of the lacrimal tissue stained positively with S-100 protein. Electron microscopy (Figs 17 and 18) showed that the tumor cells containing the cytoplasmic eosinophilic inclusions harbored masses of 80 to 100 angstrom wide, compactly arranged cytoplasmic filaments. Polyribosomes and monoribosomes, short segments of rough endo-
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Niffenegger et al . Rhabdoid Tumor of the Lacrimal Gland Top left, Figure 9. The larger specimen obtained at the time of lateral orbitotomy manifested several different histopathologic features. Shown here is a pseudoadenomatous or trabecular pattern in which cords of cells are separated by Aldan blue positive ground substance (hematoxylin-eosin; original magnification, X 120). Top right, Figure 10. Tumor cells on the left merge with an osteoidal region on the right (hematoxylin-eosin; original magnification, XI40). Second row left, Figure 11. Small lymphomatoid tumor cells with scant cytoplasm form elongated collections, occasionally in an Indian file configuration, separated by a myxoid interstitium (hematoxylin-eosin; original magnification, X220). Second row right, Figure 12. Most of the tumor was dominated by sheets of dyscohesive tumor cells with scant stroma that splayed apart preexisting elements of the lacrimal gland, as shown above (hematoxylin-eosin; original magnification, X60). Third row left, Figure 13. The diffuse and featureless proliferations of tumor cells were punctuated by collagenous septa that divided the tumor into variably sized lobules. Very little collagen deposition was found between the individual tumor cells (Masson stain; original magnification, X60). Third row right, Figure 14. Dyscohesive epithelioid or globoid cells occasionally exhibit a dominant cytoplasmic eosinophilic inclusion (hematoxylineosin; original magnification, X240). Bottom left, Figure 15. Immunohistochemical staining of the tumor cells demonstrates focal and diffuse collections of cytoplasmic vimentin filaments (immunoperoxidase reaction; original magnification, X220). Bottom right, Figure 16. The cell membranes of most of the tumor cells are positively identified to contain epithelial membrane antigen (immunoperoxidase reaction; original magnification, X220).
(
plasmic reticulum, scattered Golgi complexes, mitochondria, and monoparticulate glycogen were present. Adjacent cells were occasionally joined by rudimentary attachment sites; there was focal interrupted linear basement membrane deposition.
Discussion The malignant rhabdoid tumor was initially characterized in 1978 in a study that segregated it apart from Wilms' tumor of the kidney. IMalignant rhabdoid tumor is predominantly a renal entity, seen in the first year of life, and affects male infants more than females. 2-4 Extrarenal phenocopies that sometimes affect adults have been described in the orbit,5 brain,6 paravertebral soft tissues,?-9 pelvis, 10.11 inguinal soft tissues, 12 vulva, 13 bladder, 14 liver, 15 extremity,16 and facial skin. I? Among III renal examples in I study,IS 15 patients (13 .5%) developed brain tumors that were documented histopathologically to differ from malignant rhabdoid tumor. Most were diagnosed as medulloblastomas, but several displayed characteristics of primitive neuroectodermal tumors, ependymomas, or gliomas of the cerebellum or brain stem. Such tumors had a propensity to occur near the midline, either in the posterior fossa or just above the tentorium cerebelli. The diagnostic globular eosinophilic inclusions are reminiscent of spheroidal rhabdomyoblasts in rhabdomyosarcoma, except that immunohistochemical and ultrastructural studies fail to reveal any evidence of myoblastic differentiation in malignant rhabdoid tumor. 19 The inclusions are composed of compactions or whorls of intermediate cytoplasmic filaments that have proved to be vimentin. 3 Malignant rhabdoid tumor cells display only moderate pleomorphism, and multinucleation is decidedly rare; when such giant cells are prominent, they have been identified ultrastructurally and by immunohistochemical methods to be true histiocytic cells. IS .20 Besides creating
diffuse sheets of dyscohesive epithelioid cells, many other architectural patterns can be exhibited in malignant rhabdoid tumors, including sclerosing, cartilaginous and osteosarcomatous, alveolar, lymphomatoid, histiocytoid, spindled, hemangiopericytomatous, and, when capillaries are focally prominent, organoid or paragangliomatous. IS Several of these were exhibited by our tumor. Collections of extracellular mucin or central lobular necrosis can lead to pseudopapillary and pseudoglandular patterns. A trabecular pattern can be confused with adenocarcinoma or, when juxtaposed with sclerosing regions as in our case, with a pleomorphic adenoma. The tumor shows no clear-cut morphologic epithelial differentiation (lumens or secretions), despite the anomalous expression of epithelial membrane antigen and the co-expression of keratin with vimentin. ls This is the second reported example of a malignant rhabdoid tumor of the orbit. The rapidity of the clinical growth of the lacrimal mass certainly underscores its highly malignant character. This clinical course initially led to the clinical diagnosis of a dacryoadenitis, but, in retrospect, the globular rather than oblong shape of the mass on computed tomograms should have pointed to a noninflammatory malignant lesion. 21 .22 Rootman and colleagues5 reported the first orbital case in a 6-week-old male infant who had a rapidly progressive retrobulbar lesion. According to the article, their patient
Table 1. Immunohistochemical Studies of Adult Extrarenal Rhabdoid Tumor of the Lacrimal Gland Positive
Negative
Vimentin Keratin Epithelial membrane antigen
Desmin Muscle-specific actin Myoglobin Neuron-specific enolase
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Figure 17. Transmission electron microscopy demonstrates that the tumor cells are dispersed either singly or in small groups, up to 4 cells in profile, in a flocculent matrix (f) with occasional collagen fibrils (col). Cell membranes are often closely apposed; junctional complexes and basal lamina occur rarely. Nuclei (n) are slightly indented with prominent nucleoli (no). There are whorls of cytoplasmic fibrils (arrows) in many cells, as well as large glycogen deposits (gly). The large whorl at the upper left (arrow) is magnified in Figure 18, bottom. (m = mitochondria, rer = rough endoplasmic reticulum; original magnification, x4700.)
was alive 2 years after surgery with subtotal but extensive removal of the lesion, followed by radiotherapy and chemotherapy. The patient is still alive without local recurrence or metastasis after a total follow-up of 4 years (personal communication). Our adult patient has survived for 16 months after orbital exenteration coupled with adjunctive chemotherapy and radiotherapy. In comparison with kidney tumors, the orbital lesions are probably detected at an earlier stage when they were comparatively smaller and may have had a better prognosis when confined by intact bony perimeters than malignant rhabdoid tumors of other visceral sites. It is important to segregate malignant rhabdoid tumor
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from Wilms' tumor, as well as from rhabdomyosarcoma, as it is a decidedly more malignant neoplasm. In a large series of renal examples, there was a fatality rate greater than 80%, despite extensive local surgery, radiation therapy, and chemotherapy. 18 This may be attributable to the fact that vascular invasion is a prominent feature of the renal cases. Some authorities regard extrarenal and particularly adult malignant rhabdoid tumor as being "pseudo-rhabdoid" rather than true rhabdoid lesions, although the classic histopathologic and immunohistochemical findings are usually in evidence. 2 Subpopulations of rhabdoid cells can even be found with vimentin cytoplasmic positivity
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Rhabdoid Tumor of the Lacrimal Gland
Figure 18. Top. Group of rhabdoid cells dispersed in a flocculent matrix (f). These cells have extensive whorls and streams of intermediate filaments (arrows) and large glycogen deposits (gly) distributed in their cytoplasm. (n = nucleus, m = mitochondria, rer = rough endoplasmic reticulum). Center left. Basal lamina along a plasma membrane (PM), also a rare occurrence. Center right. Cell junction between two cells, a rare occurrence. Bottom. Large whorl of intermediate filaments in the cytoplasm of a cell illustrated in Figure 17. Top, original magnification, X10,800; center left, original magnification X89,250; center right and bottom, original magnification, x 4 1,000.
in less than I % of incontrovertible rhabdomyosarcomas, and they have been identified in many other soft tissue tumors and epithelial malignancies. 23 This has led to the hypothesis that, outside the kidney, rhabdoid cells may be of heterogeneous histogenetic origins. Nonetheless, the presence of rhabdoid cells in a neoplasm often confers a more aggressive clinical course. The presence of basement membrane material, epithelial membrane antigen, and the co-expression of cytokeratin along with vimentin suggests the possibility in
some cases of an epithelial ongm. The location of our patient's lesion in the lacrimal gland certainly reinforces such a suspicion. Many histogenetic theories have been championed, including a pluripotential mesenchymal cell that spawns malignant rhabdoid tumor in disparate parts of the body, as well as neural crest, primitive neuroectodermal, histiocytic, epithelial, or lymphohematopoietic progenitor cells. In summary, subpopulations of rhabdoid tumor cells have been discovered in cutaneous malignant melanoma
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(neural crest),24 a brain tumor (neuroectoderm),6 smooth muscle tumors (mesoderm),14,24 striated muscle tumors (mesoderm), 19 a primary tumor of the liver (endoderm), 15 and now in a tumor of the lacrimal gland (ectoderm). In the kidney, the rhabdoid tumor has a propensity to arise in the hilum, whereas Wilms' tumor arises more peripherally in the substance of the kidney. 18 Nonetheless, subpopulations of rhabdoid cells have now been identified in classic Wilms' tumors and even in renal cell carcinomas. 24 Therefore, the leading histogenetic theory at present is that malignant rhabdoid tumors may be a phenotypic expression of many different cellular lines. It would stand to reason that such expression also should be extended to epithelial structures, as we suspect occurred in the present case. Because of a combination of pleomorphic cellular features, malignant rhabdoid tumor when occurring in the lacrimal gland might be categorized among the malignant mixed tumors.
References I. Beckwith lB, Palmer NF. Histopathology and prognosis of Wilms tumor: results of the First National Wilms' Tumor Study. Cancer 1978;41:1937-48. 2. Weeks DA, Beckwith lB, Mierau GW. Rhabdoid tumor. An entity or phenotype? Arch Pathol Lab Med 1989;113: 113-4. 3. Haas lE, Palmer NE, Weinberg AG, Beckwith lB. Ultrastructure of malignant rhabdoid tumor of the kidney. A distinctive renal tumor of children. Hum Pathol 1981; 12: 646-57. 4. Schmidt 0, Harms D, Zieger G . Malignant rhabdoid tumor of the kidney. Histopathology, ultrastructure and comments on differential diagnosis. Virchows Arch [AJ 1982;398: 101-8. 5. Rootman 1, Damji KF, Dimmick lE. Malignant rhabdoid tumor of the orbit. Ophthalmology 1989;96: 1650-4. 6. Biggs Pl, Garen PD, Powers 1M, Garvin Al. Malignant rhabdoid tumor of the central nervous system. Hum Pathol 1987; 18:332-7. 7. Lynch HT, Shurin SB, Dahms BB, et al. Paravertebral malignant rhabdoid tumors in infancy. In vitro studies of a familial tumor. Cancer 1983;52:290-6. 8. Sotelo-Avila C, Gonzalez-Crussi F, deMillo D, et al. Renal and extrarenal rhabdoid tumors in children: a clinicopathologic study of 14 patients. Semin Diagn Pathol 1986;3: 151-63. 9. Balaton Al, Vaury P, Videgrain M. Paravertebral malignant rhabdoid tumor in an adult: A case report with immunocytochemical study. Pathol Res Pract 1987;182:713-8.
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10. Frierson HF lr, Mills SE, Innes Dl lr. Malignant rhabdoid tumor of the pelvis. Cancer 1985;55:1963-7. 11. Dervan PA, Cahalane SF, Kneafesy P, et al. Malignant rhabdoid tumor of soft tissue. An ultrastructural and immunohistochemical study of a pelvic tumor. Histopathology 1987;11:183-90. 12. Uchida H, Yokoyama S, Nakayama I, Zeze K. An autopsy case of malignant rhabdoid tumor arising from soft parts in the left inguinal region. Acta Pathol lpn 1988;38:108796. 13. Perrone T, Swanson PE, Twiggs L, et al. Malignant rhabdoid tumor of the vulva: is distinction from epithelioid sarcoma possible? A pathologic and immunohistological study. Am 1 Surg Pathol 1989; 13:848-58. 14. Harris M, Eyden BP, 10glekar VM. Rhabdoid tumor of the bladder: a histological, ultrastructural and immunohistochemical study. Histopathology 1987; 11: 1083-92. 15. Parham DM, Peiper SC, Robicheaux G, et al. Malignant rhabdoid tumor of the liver. Evidence for epithelioid differentiation. Arch Pathol Lab Med 1988; 112:61-4. 16. Kent AL, Mahoney DH lr, Gresik MV, et al. Malignant rhabdoid tumor of the extremity. Cancer 1987;60: 1056-9. 17. Dabbs Dl, Park HK. Malignant rhabdoid skin tumor: an uncommon primary skin neoplasm. Ultrastructural and immunohistochemical analysis. 1 Cutan Pathol 1988; 15: 109-15. 18. Weeks DA, Beckwith lB, Mierau GW, Luckey DW. Rhabdoid tumor of kidney. A report of III cases from the National Wilms' Tumor Study Pathology Center. Am 1 Surg Pathol 1989; 13:439-58. 19. Kodet R, Newton WA lr, Hamoudi AB, Asmar L. Rhabdomyosarcomas with intermediate-filament inclusions and features of rhabdoid tumors. Light microscopic and immunohistochemical study. Am J Surg Pathol 1991; 15:25767. 20. Gonzalez-Crussi F, Goldschmidt RA, Hsueh W, Trujillo WP. Infantile sarcoma with intracytoplasmic filamentous inclusions: a distinctive tumor of possible histiocytic origin. Cancer 1982;49:2365-75. 21. lakobiec FA, Yeo JH, Trokel SL, et al. Combined clinical and computed tomographic diagnosis of primary lacrimal fossa lesions. Am 10phthalmol 1982;94:785-807. 22. Yeo lH, Jakobiec FA, Abbott GF, Trokel SL. Combined clinical and computed tomographic diagnosis of orbital lymphoid tumors. Am J Ophthalmol 1982;94:235-45. 23. Tsuneyoshi M, Daimaru Y, Hashimoto H, Enjoji M. The existence of rhabdoid cells in specified soft tissue sarcomas. Histopathological, ultrastructural and immunohistochemical evidence. Virchows Arch [AJ 1987;411:509-14. 24. Weeks DA, Beckwith lB, Mierau GW, Zuppan CWoRenal neoplasms mimicking rhabdoid tumor of the kidney. A report from the National Wilms' Tumor Study Pathology Center. Am 1 Surg Pathol 1991;15:1042-54.
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50-year-old man presented with a rapidly growing mass in the area of the right lacrimal gland. An initial erroneous histopathologic diagnosis of a pleomorphic adenoma made on a small-incisional biopsy was later corrected to a malignant rhabdoid tumor when a wide local excision of the tumor was performed. The tumor was composed predominantly of dyscohesive, globoid, and eosinophilic cells, which frequently contained cytoplasmic inclusions. These were demonstrated to be composed of whorls of intermediate vimentin filaments. The tumor cells expressed epithelial membrane antigen as well as cytokeratin. Ultrastructurally, they displayed intercellular junctions and interrupted segments of linear basement membrane material. These findings, together with the development of the lesion within the parenchyma of the lacrimal gland, are suggestive of an epithelial origin. The patient was treated with radical surgery and adjunctive radiotherapy and chemotherapy, which are the recommended treatment modalities for this highly malignant tumor. Ophthalmology 1992;99:567-574
Malignant rhabdoid tumor is a rare and highly aggressive renal tumor of infants with distinctive histopathologic and ultrastructural features. Since its original description, the rhabdoid phenotype has been recognized at a number of extrarenal sites in both children and adults, 1-17 which has led to many different histogenetic theories. We report the first adult orbital case that was unequivocally situated in the lacrimal gland and suggest its possible epithelial origin.
Clinical History A 50-year-old man had a 4-week history of right upper eyelid swelling. He had been previously treated for 1 month without resolution. On examination, the swelling was in proximity to the lacrimal gland and was believed to be dacryoadenitis, but it did not respond to topical and oral antibiotics. Two days before presentation at the Massachusetts Eye and Ear Infirmary Emergency Room, the
Originally received: October 3, 1991. Manuscript accepted: November 14, 1991. From the Massachusetts Eye and E,ar Infirmary, Department of Ophthalmology and Harvard Medical School, Boston. Reprint requests to Frederick A. Jakobiec, MD, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114.
patient experienced exacerbated pain and burning of the right eye, with an abrupt increase in upper and lower eyelid swelling and erythema (Fig 1). On initial examination at the Massachusetts Eye and Ear Infirmary, best corrected visual acuity was 20/50 in the affected right eye and 20/25 in the left. The patient was afebrile and had a palpable nontender mobile mass in the right upper lateral fornix. There were 3 mm of relative right proptosis, with intact extraocular motility. A contrast enhanced orbital computed tomographic study (Figs 2 and 3) revealed a rounded, superolateral soft tissue mass protruding beyond the orbital rim and extending posteriorly toward the orbital lobe of the lacrimal gland. The latter structure could not be definitely distinguished. There was no bone destruction. A presumptive clinical diagnosis of an inflammatory lesion was made, and a transcutaneous biopsy of the right lacrimal gland was performed. During surgery, a yellowwhite mass was incised in the lacrimal fossa. Frozen sections were interpreted as an atypical myxoid neoplasm, possibly a pleomorphic adenoma. The permanent sections were believed to be most consistent with a pleomorphic adenoma, although rare atypical cells were found. Over the ensuing week, the patient experienced a rapid increase of the upper eyelid swelling, with the tumor doubling in size and protruding through the palpebral fissure from the superolateral fornix (Figs 4 and 5). A right lateral
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Niffenegger et al . Rhabdoid Tumor of the Lacrimal Gland Top left, Figure 1. A 50-year-old man developed swelling of the right eyelids with some erythema and right proptosis over a 1-month period. Top right, Figure 2. A computed axial tomogram shows a somewhat rounded mass projecting anterior to the orbital rim. Second row left, Figure 3. The coronal projection of the mass discloses an oblong superoinferior shape without indentation of the contiguous bone or bone destruction. Second row right, Figure 4. One week after an incisional biopsy, the lid mass has dramatically increased.' Third row left, Figure 5. The upper eyelid was very taught, but on lid elevation, afleshy mass protruded into the visual axis from the superotemporal fornix . Third row right, Figure 6. Gross appearance of the excised mass via lateral orbitotomy displaying circumscription and partial encapsulation. The tongue of tissue on the right extended from the mass into the eyelid. Bottom left, Figure 7. The initial incisional biopsy was composed of spindle cells, focally merging into osteoidal regions, as revealed in the center of this field (hematoxylin-eosin; original magnification, XSO). Bottom right, Figure S. In scattered regions of the small initial incisional biopsy, small cords of more eosinophilic cells suggesting an epithelial aspect are separated in a mucinous matrix, leading to the mistaken diagnosis of a pleomorphic adenoma (hematoxylin-eosin; original magnification, X1S0).
(
orbitotomy exposed an extremely large tumor (Fig 6) extending from the lacrimal fossa region toward the superior orbital fissure and involving both the posterior and anterior surfaces of the tarsus of the upper eyelid. Histopathologic evaluation of the excised mass, coupled with immunohistochemical and electron microscopic studies, led to the diagnosis of a malignant extrarenal rhabdoid tumor. After a negative work-up for metastases and after evaluation of the cerebrospinal fluid for the absence of tumor cells, a right orbital exenteration was performed. Five weeks after exenteration, 4485 rad of radiotherapy were delivered in 25 fractions over 40 days. Six weeks after the completion of radiation therapy, the patient began systemic chemotherapy based on a protocol used in the National Wilms' Tumor Study, including cycles of actinomycin, doxorubicin, cyclophosphamide, and vincristine. Fifteen months after cessation of the chemotherapy, the patient has no evidence of either local recurrence or distant metastases.
Pathologic Findings The initial small-incisional biopsy (9 X 8 X 6mm) into the lacrimal gland contained masses of spindle cells, occasionally organized into fascicles, but more often dispersed in a looser myxoid stroma. Occasionally there were hyalinized stromal areas that merged into osteochondroidal zones (Fig 7). Interspersed in both the hyalinized and the looser areas were mononucleated eosinophilic cells, which sometimes formed delicate syncytia without ostensible tubule or lumen formation (Fig 8). These findings were responsible for the initial mistaken diagnosis of a pleomorphic adenoma. The second and more ample excision of the superotemporal and supraorbital mass grossly appeared to possess a partial capsule, had a soft texture with a variegated brown/pink coloration when trisected, and measured 30 X 40 X 25 mm. Histopathologically, the tissue showed a dramatically different architecture than that of the earlier incisional biopsy. A pseudocapsule was present on the anterior surface of the mass, but posteriorly it infiltrated
the orbital fat. Mucinious-trabecular (Fig 9), osteochondroidal (Fig 10), and lymphomatoid (Fig 11) patterns were seen focally. In most areas, however, among surviving elements of the lacrimal gland there were sheets ofloosely cohesive epithelioid cells with abundant eosinophilic to amphophilic cytoplasm (Fig 12). Occasionally, the diffuse proliferation was subdivided by variably thickened collagenous trabeculae (Fig 13). There was a paucity of capillary proliferation. The diffusely arranged cells possessed eccentrically placed vesicular nuclei with prominent central to paracentral nucleoli. Many of the tumor cells contained a prominent, globular, and eosinophilic cytoplasmic inclusion (Fig 14). Mitotic figures were numerous. In some areas, there were abrupt transitions between the globoid (rhabdoid) cells and more spindle-appearing cells. No cross striations were seen using the Masson-trichrome stain or the phosphotungstic acid-hematoxylin stain. Only a minimal amount of interstitial collagen was present between the sheets of tumor cells, but a faint deposition of argentophilic reticulin fibers was seen in some areas. The tumor cells stained negatively with the mucicarmine stain, and the Alcian blue stain revealed the presence of extracellular mucopolysaccharides in the myxoid regions. The exenterated orbital contents showed a small amount of residual tumor in the superolateral orbit away from the surgical margins, as well as within the anterior orbital fat and striated muscle of the upper eyelid. Immunohistochemical studies on fresh frozen and formalin-fixed paraffin-embedded tissue showed that the tumor cells were positive for vimentin (Fig 15), keratin (although only in frozen sections), and epithelial membrane antigen (Fig 16). The tumor stained negatively for desmin, muscle-specific actin, myoglobin, and neuron-specific enolase (Table 1). Focal patches of inflammatory cells within the lacrimal gland or in perivascular regions stained positively with Leu-7, and some of the lacrimal tissue stained positively with S-100 protein. Electron microscopy (Figs 17 and 18) showed that the tumor cells containing the cytoplasmic eosinophilic inclusions harbored masses of 80 to 100 angstrom wide, compactly arranged cytoplasmic filaments. Polyribosomes and monoribosomes, short segments of rough endo-
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Niffenegger et al . Rhabdoid Tumor of the Lacrimal Gland Top left, Figure 9. The larger specimen obtained at the time of lateral orbitotomy manifested several different histopathologic features. Shown here is a pseudoadenomatous or trabecular pattern in which cords of cells are separated by Aldan blue positive ground substance (hematoxylin-eosin; original magnification, X 120). Top right, Figure 10. Tumor cells on the left merge with an osteoidal region on the right (hematoxylin-eosin; original magnification, XI40). Second row left, Figure 11. Small lymphomatoid tumor cells with scant cytoplasm form elongated collections, occasionally in an Indian file configuration, separated by a myxoid interstitium (hematoxylin-eosin; original magnification, X220). Second row right, Figure 12. Most of the tumor was dominated by sheets of dyscohesive tumor cells with scant stroma that splayed apart preexisting elements of the lacrimal gland, as shown above (hematoxylin-eosin; original magnification, X60). Third row left, Figure 13. The diffuse and featureless proliferations of tumor cells were punctuated by collagenous septa that divided the tumor into variably sized lobules. Very little collagen deposition was found between the individual tumor cells (Masson stain; original magnification, X60). Third row right, Figure 14. Dyscohesive epithelioid or globoid cells occasionally exhibit a dominant cytoplasmic eosinophilic inclusion (hematoxylineosin; original magnification, X240). Bottom left, Figure 15. Immunohistochemical staining of the tumor cells demonstrates focal and diffuse collections of cytoplasmic vimentin filaments (immunoperoxidase reaction; original magnification, X220). Bottom right, Figure 16. The cell membranes of most of the tumor cells are positively identified to contain epithelial membrane antigen (immunoperoxidase reaction; original magnification, X220).
(
plasmic reticulum, scattered Golgi complexes, mitochondria, and monoparticulate glycogen were present. Adjacent cells were occasionally joined by rudimentary attachment sites; there was focal interrupted linear basement membrane deposition.
Discussion The malignant rhabdoid tumor was initially characterized in 1978 in a study that segregated it apart from Wilms' tumor of the kidney. IMalignant rhabdoid tumor is predominantly a renal entity, seen in the first year of life, and affects male infants more than females. 2-4 Extrarenal phenocopies that sometimes affect adults have been described in the orbit,5 brain,6 paravertebral soft tissues,?-9 pelvis, 10.11 inguinal soft tissues, 12 vulva, 13 bladder, 14 liver, 15 extremity,16 and facial skin. I? Among III renal examples in I study,IS 15 patients (13 .5%) developed brain tumors that were documented histopathologically to differ from malignant rhabdoid tumor. Most were diagnosed as medulloblastomas, but several displayed characteristics of primitive neuroectodermal tumors, ependymomas, or gliomas of the cerebellum or brain stem. Such tumors had a propensity to occur near the midline, either in the posterior fossa or just above the tentorium cerebelli. The diagnostic globular eosinophilic inclusions are reminiscent of spheroidal rhabdomyoblasts in rhabdomyosarcoma, except that immunohistochemical and ultrastructural studies fail to reveal any evidence of myoblastic differentiation in malignant rhabdoid tumor. 19 The inclusions are composed of compactions or whorls of intermediate cytoplasmic filaments that have proved to be vimentin. 3 Malignant rhabdoid tumor cells display only moderate pleomorphism, and multinucleation is decidedly rare; when such giant cells are prominent, they have been identified ultrastructurally and by immunohistochemical methods to be true histiocytic cells. IS .20 Besides creating
diffuse sheets of dyscohesive epithelioid cells, many other architectural patterns can be exhibited in malignant rhabdoid tumors, including sclerosing, cartilaginous and osteosarcomatous, alveolar, lymphomatoid, histiocytoid, spindled, hemangiopericytomatous, and, when capillaries are focally prominent, organoid or paragangliomatous. IS Several of these were exhibited by our tumor. Collections of extracellular mucin or central lobular necrosis can lead to pseudopapillary and pseudoglandular patterns. A trabecular pattern can be confused with adenocarcinoma or, when juxtaposed with sclerosing regions as in our case, with a pleomorphic adenoma. The tumor shows no clear-cut morphologic epithelial differentiation (lumens or secretions), despite the anomalous expression of epithelial membrane antigen and the co-expression of keratin with vimentin. ls This is the second reported example of a malignant rhabdoid tumor of the orbit. The rapidity of the clinical growth of the lacrimal mass certainly underscores its highly malignant character. This clinical course initially led to the clinical diagnosis of a dacryoadenitis, but, in retrospect, the globular rather than oblong shape of the mass on computed tomograms should have pointed to a noninflammatory malignant lesion. 21 .22 Rootman and colleagues5 reported the first orbital case in a 6-week-old male infant who had a rapidly progressive retrobulbar lesion. According to the article, their patient
Table 1. Immunohistochemical Studies of Adult Extrarenal Rhabdoid Tumor of the Lacrimal Gland Positive
Negative
Vimentin Keratin Epithelial membrane antigen
Desmin Muscle-specific actin Myoglobin Neuron-specific enolase
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Figure 17. Transmission electron microscopy demonstrates that the tumor cells are dispersed either singly or in small groups, up to 4 cells in profile, in a flocculent matrix (f) with occasional collagen fibrils (col). Cell membranes are often closely apposed; junctional complexes and basal lamina occur rarely. Nuclei (n) are slightly indented with prominent nucleoli (no). There are whorls of cytoplasmic fibrils (arrows) in many cells, as well as large glycogen deposits (gly). The large whorl at the upper left (arrow) is magnified in Figure 18, bottom. (m = mitochondria, rer = rough endoplasmic reticulum; original magnification, x4700.)
was alive 2 years after surgery with subtotal but extensive removal of the lesion, followed by radiotherapy and chemotherapy. The patient is still alive without local recurrence or metastasis after a total follow-up of 4 years (personal communication). Our adult patient has survived for 16 months after orbital exenteration coupled with adjunctive chemotherapy and radiotherapy. In comparison with kidney tumors, the orbital lesions are probably detected at an earlier stage when they were comparatively smaller and may have had a better prognosis when confined by intact bony perimeters than malignant rhabdoid tumors of other visceral sites. It is important to segregate malignant rhabdoid tumor
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from Wilms' tumor, as well as from rhabdomyosarcoma, as it is a decidedly more malignant neoplasm. In a large series of renal examples, there was a fatality rate greater than 80%, despite extensive local surgery, radiation therapy, and chemotherapy. 18 This may be attributable to the fact that vascular invasion is a prominent feature of the renal cases. Some authorities regard extrarenal and particularly adult malignant rhabdoid tumor as being "pseudo-rhabdoid" rather than true rhabdoid lesions, although the classic histopathologic and immunohistochemical findings are usually in evidence. 2 Subpopulations of rhabdoid cells can even be found with vimentin cytoplasmic positivity
Niffenegger et al
Rhabdoid Tumor of the Lacrimal Gland
Figure 18. Top. Group of rhabdoid cells dispersed in a flocculent matrix (f). These cells have extensive whorls and streams of intermediate filaments (arrows) and large glycogen deposits (gly) distributed in their cytoplasm. (n = nucleus, m = mitochondria, rer = rough endoplasmic reticulum). Center left. Basal lamina along a plasma membrane (PM), also a rare occurrence. Center right. Cell junction between two cells, a rare occurrence. Bottom. Large whorl of intermediate filaments in the cytoplasm of a cell illustrated in Figure 17. Top, original magnification, X10,800; center left, original magnification X89,250; center right and bottom, original magnification, x 4 1,000.
in less than I % of incontrovertible rhabdomyosarcomas, and they have been identified in many other soft tissue tumors and epithelial malignancies. 23 This has led to the hypothesis that, outside the kidney, rhabdoid cells may be of heterogeneous histogenetic origins. Nonetheless, the presence of rhabdoid cells in a neoplasm often confers a more aggressive clinical course. The presence of basement membrane material, epithelial membrane antigen, and the co-expression of cytokeratin along with vimentin suggests the possibility in
some cases of an epithelial ongm. The location of our patient's lesion in the lacrimal gland certainly reinforces such a suspicion. Many histogenetic theories have been championed, including a pluripotential mesenchymal cell that spawns malignant rhabdoid tumor in disparate parts of the body, as well as neural crest, primitive neuroectodermal, histiocytic, epithelial, or lymphohematopoietic progenitor cells. In summary, subpopulations of rhabdoid tumor cells have been discovered in cutaneous malignant melanoma
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(neural crest),24 a brain tumor (neuroectoderm),6 smooth muscle tumors (mesoderm),14,24 striated muscle tumors (mesoderm), 19 a primary tumor of the liver (endoderm), 15 and now in a tumor of the lacrimal gland (ectoderm). In the kidney, the rhabdoid tumor has a propensity to arise in the hilum, whereas Wilms' tumor arises more peripherally in the substance of the kidney. 18 Nonetheless, subpopulations of rhabdoid cells have now been identified in classic Wilms' tumors and even in renal cell carcinomas. 24 Therefore, the leading histogenetic theory at present is that malignant rhabdoid tumors may be a phenotypic expression of many different cellular lines. It would stand to reason that such expression also should be extended to epithelial structures, as we suspect occurred in the present case. Because of a combination of pleomorphic cellular features, malignant rhabdoid tumor when occurring in the lacrimal gland might be categorized among the malignant mixed tumors.
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