Leiomyosarcoma of the Conjunctiva VALERIE A. WHITE, MD, FRCPC, 1•2 KARIM F. DAMJI, MD, 1 JOHN S. F. RICHARDS, MD, FRCSC, 2 JACK ROOTMAN, MD, FRCSC1•2
Abstract: The clinical, light microscopic, immunohistologic, and ultrastructural findings of a leiomyosarcoma of the conjunctiva are presented. This tumor was diagnosed after a 26-year history and is the first to be adequately documented as having arise!) in the conjunctiva. Ophthalmology 1991; 98:1560-1564
Leiomyosarcoma, the malignant tumor of smooth muscle cells, most commonly arises in the uterus and gastrointestinal tract. 1 Within the ophthalmic literature, it has been reported rarely in the orbit. 2 We describe the clinical and pathologic features of a leiomyosarcoma that arose in the conjunctiva, the first to be adequately doc umented in this location.
CLINICAL HISTORY A 66-year-old man presented in March 1989 after re sults of penetrating keratoplasty and biopsy of "pseudo pterygia" ofthe left eye showed a histologically malignant spindle cell neoplasm involving both conjunctiva and cornea. He first experienced blurring of vision and irri tation in his left eye in 1963, 26 years previously. The eye was described as appearing "bloodshot" and he was treated with topical steroids for a presumed viral or allergic con junctivitis with initial success. A few months later, his symptoms recurred along with a white nodule at the lim b~s. Biopsy and review ofthe nodule at the Armed Forces Institute of Pathology resulted in the belief that it repre sented a squamous cell carcinoma of the conjunctiva with stromal invasion that was not completely excised. ReOriginally received: June 6, 1990. Revision accepted: May 23, 1991. 1 2
Departments of Pathology, Vancouver General Hospital and University of British Columbia, Vancouver. Department of Ophthalmology, Vancouver General Hospital and University of British Columbia, Vancouver.
Presented at the annual meeting of the Canadian Ocular Pathology Society, Calgal)l, Alberta, June 1989. Correspondence to Valerie A. White, MD, FRCPC, Department of Pa thology, Vancouver General Hospital, 855 W 12th Ave, Vancouver, BC, Canada V5Z 1M9.
1560
excision in 1964 showed no residual neoplasm. From 1964 to 1986, he continued to experience blurred vision, hy peremia, and intermittent ulceration, and was treated over these years with a variety oftopical medications including antibiotics, steroids, and idoxuridine, along with debride ment, cautery, contact lens, and patching for a presumed diagnosis of Herpes simplex keratitis. His visual acuity in the left eye in 1976 was 20/60. Examination at the Eye Care Center of the Vancouver General Hospital in 1986, after a 1-year period of wors ening symptoms, showed visual acuity of hand motions and intraocular pressure of 42 mmHg. The lower two thirds of the cornea showed stromal edema and scarring and masses were present at the limbus on both temporal and nasal sides, the "pseudopterygia." He was prescribed topical antiglaucoma medications, which controlled his pressure, and continued to receive topical steroids and occasional antibiotics. In 1987, he began to experience pain and discomfort in the eye and the cornea was de scribed as being elevated and vascularized. He underwent penetrating keratoplasty and biopsy of the limballesions in January 1989; results of pathologic examination showed a malignant spindle cell tumor, which is fully described below. The corneal graft became clear, but the surrounding conjunctiva remained elevated and hyperemic due to residual tumor (Fig 1). In April 1989, he underwent excision of large portions of nasal and temporal conjunctiva and biopsies of the margins of the lesions within superior and inferior conjunctiva and inferior rectus insertion. Tumor was found to be present in all specimens and at all resection margins_ After dis cussion with the patient, who believed that he could no longer tolerate the irritation and pain of his eye and, sec ondarily, because of residual conjunctival tumor, subtotal exenteration was performed a few weeks later. The pa tient's health had otherwise been excellent over these years and there was no evidence of metastatic disease on com plete physical and radiologic examination. The right eye
WHITE et al
•
LEIOMYOSARCOMA OF THE CONJUNCTIVA
vas normal. A computed tomography scan 6 months after showed no evidence of residual neoplasm. 1e remains well 2 years later.
~xenteration
>ATHOLOGY The first specimen consisted of a penetrating kerato 'lasty and biopsies of the limbal masses. The cornea ;howed a preserved but thinned epithelium. Between the ~pithelium and an intact Bowman's layer, there was a .;pindle cell neoplasm, which was thicker at one margin, ~xtending over the entire diameter of the cornea (Fig 2). The neoplasm was arranged in fascicles, showed pleo morphic cigar-shaped nuclei and eosinophilic cytoplasm jut no mitotic figures (Fig 3). The underlying stroma showed a focus ofperipheral neovascularization, but Des :::emet's membrane and the endothelium were normal. The biopsies of the limbal masses showed a more pleo morphic spindle cell neoplasm within the conjunctival substantia propria with similar appearing nuclei and three to four mitotic figures per ten high power fields (Fig 4). The overlying epithelium was intact. The conjunctival excisions showed similar features, again with numerous mitotic figures. The exenteration specimen showed resid ual neoplasm most extensively over the anterior nasal portion of the globe between the sclera and the intact overlying conjunctival epithelium (Fig 5). Here the fas cicular arrangement of the tumor was more evident in feriorly (Fig 6). The tumor extended on the scleral surface to the insertion ofthe inferior rectus muscle and superiorly to the fornix. There was malalignment of the donor cornea with stroma lying against conjunctival tumor and poor apposition of the ends of Descemet's membrane. Inferi orly, tumor was present in the substantia propria overlying Schlemm's canal and the episcleral venous plexus. Early peripheral anterior synechiae were present. There was no invasion of the globe, which showed normal intraocular structures, or extension to orbital resection margins. The anterior optic nerve showed Schnabel's cavernous optic atrophy. By the indirect immunoperoxidase method, numerous sections of tuq1or showed strong staining for vimentin (Biogenex Laboratories, San Ramon, CA, monoclonal 1/2000) (Fig 7) and muscle-specific actin (Enzo Diagnos tics, New York, NY, monoclonal 1/8000) (Fig 8) with moderate staining for alpha smooth muscle actin (Sigma Diagnostics, St. Louis, MO, monoclonal 1/8000) and weak staining for desmin (Sigma Diagnostics, monoclonal 1/500). Staining for keratin (Dako Corporation, Santa Barbara, CA, polyclonal1/500, predominantly against 52, 56, 58, kD subunits) was completely negative within the tumor while the overlying epithelium showed strong staining. There was no staining for S100 protein (Research Development Corporation, Toronto, Ontario, polyclonal 1/1000) and alpha-1-antichymotrypsin (Dako Corpora tion, polyclonal 1/200), except for occasional histiocytes within the tumor. Electron microscopy showed spindle shaped cells with oval convoluted nuclei and prominent nucleoli (Fig 9).
The cytoplasm showed subplasmalemmal thin filaments with dense bodies and occasional profiles of rough en doplasmic reticulum and Golgi bodies. The plasma membrane contained numerous pinocytotic vesicles and there was abundant external lamina (Fig 10). All cells showed similar features. The light microscopic, immu noperoxidase staining profile and electron microscopic findings were believed to be diagnostic of a leiomyosar coma involving the conjunctival substantia propria and subepithelial area of the cornea.
DISCUSSION The differential diagnosis in this unusual case was be lieved to rest between a spindle cell squamous carcinoma and a sarcoma, either a leiomyosarcoma or a malignant fibrous histiocytoma. The tumor was considered to be histologically malignant because of the high mitotic rate, nuclear pleomorphism, and extensive involvement of substantia propria. It was not believed to be a squamous carcinoma because of intact conjunctival and corneal ep ithelium, which showed no continuity with the tumor, lack of keratin staining, absence of tonofilaments and desmosomes on electron microscopy, and lack of an ag gressive course as reported in previous cases of invasive squamous cell carcinoma of the conjunctiva. 3- 5 A malig nant fibrous histiocytoma was ruled out because of lack of a storiform pattern and because of the monotonous appearance of cells with thin filaments and dense bodies and lack of histiocytic and fibroblastic features by electron microscopy. In a recent study, Azumi et al 6 showed that muscle-specific actin is a sensitive marker for leiomyo sarcoma, usually showing generalized expression, whereas desmin staining is more focal or may be negative in for malin-fixed tissue. Our case showed stronger and weaker generalized staining for muscle-specific actin and desmin, respectively. In addition, this case showed the electron microscopic features considered diagnostic for smooth muscle cells, including subplasmalemmal thin filaments with dense bodies, pinocytotic vesicles, external lamina, and convoluted nuclei. 7 Leiomyosarcoma of the conjunctiva must indeed be a rare neoplasm. In a review of2455 conjunctival specimens from the Johns Hopkins Eye Pathology Laboratory, Grossniklaus et al8 did not find a single case. We were only able to find one previously reported case in the literature. 9 This concerned a 20-year-old woman with xeroderma pigmentosum who also had numerous cutaneous squamous cell and basal cell carcinomas as well as melanomas. A limbal tumor, originally believed to be a leiomyoma on biopsy, recurred rapidly and exenteration showed a "mesenchymal malignancy, probably a leio myosarcoma," in addition to a small choroidal nevus. This tumor was reviewed by the Armed Forces Institute of Pathology, but the material was too poorly preserved for adequate electron microscopy and, at the present time, no tissue remains upon which to perform immunoper oxidase studies (personal communication, de Wolff Rouendaal, 1989). 1561
1562
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LEIOMYOSARCOMA OF THE CONJUNCTIVA
Fig I. Top lefi, photograph of patient's eye after penetrating keratoplasty. Notice hyperemic, elevated conjunctiva. Fig 2. Top right, margin of cornea shows spindle cell neoplasm between epithelium and Bowman's layer (hematoxylin-eosin; original magnification, X20). Fig 3. Second row lefi, higher power of margin of neoplasm on cornea shows fascicular arrangement of cells and pleomorphic, cigar-shaped nuclei (hematoxylin-eosin; original magnification, X50). Fig 4. Second row right, biopsy of limbal mass shows a more pleomorphic spindle cell neoplasm with numerous mitotic figures (hematoxylin-eosin; original magnification, X50). Fig 5. Third row lefi, whole mount of exenteration specimen shows residual tumor in nasal substantia propria, adherent to the sclera and elevating the epithelium. The tumor extends to the fornix superiorly and to the insertion of the rectus muscle inferiorly. Arrows denote the extent of tumor on the scleral surface. Notice Schnabel's cavernous optic atrophy (hematoxylin-eosin; original magnification, X 1.2). Fig 6. Third row right, high magnification from superior area of exenteration specimen shows fascicular arrangement of cells with pleomorphic nuclei and numerous mitotic figures (hematoxylin-eosin; original magnification, X50). Fig 7. Bottom lefi, strong staining for vimentin in corneal portion of tumor (indirect immunoperoxidase, hematoxylin; original magnification, X50). Fig 8. Bottom right, strong staining for muscle-specific actin in conjunctival portion of tumor (indirect immunoperoxidase, hematoxylin; original magnification, X50).
was available for five ofthe seven cases. Distant metastases developed in three patients, who died of tumor-related causes 12 to 67 months later. 14·15 Meekins' patient died at 5 months from a nontumor-related cause with no clin ical evidence of tumor recurrence. Only one patient was alive 42 months after excision of tumor with no evidence of recurrence or metastases. 216 · For a better understanding of our case, we turned to the more extensive literature of leiomyosarcoma of the skin. This is a superfically located, histologically malignant neoplasm that pursues a relatively benign course. Table 1 compares location, size, mitotic rate, and clinical out come of superficially and deeply located leiomyosarco mas.17-20 Although the more deeply located lesions tended to have a higher mitotic rate and worse cytology, the more important prognostic factors were location, size, and ad equacy of initial excision. The more superficial lesions, similar in location to the current case, were smaller, could
Fig 9. Low power electron micrograph shows spindle-shaped cells with oval, convoluted nuclei and prominent nucleoli (uranyl acetate, lead citrate; original magnification, X3250).
Other mesenchymal malignancies occurring at the lim bus have included a "pleomorphic fibrous histiocytoma of the comeosclerallimbus," which was treated primarily by enucleation, a fibrous histiocytoma and a fibrosarcoma of the limbus, which had aggressive courses necessitating numerous resections before eventual enucleation. 10- 12 The latter appeared histologically malignant and had invaded the underlying ciliary body, while the other histologically more benign appearing lesion had invaded the iris, pos sibly through a previous iatrogenic perforation. These three patients were alive at the time of follow-up from 18 months to 9 years after first presentation. A malignant fibrous histiocytoma involving substantia propria and or bit has been described 5 years after radiotherapy to the head and neck and chemotherapy for a diffuse small cleaved celllymphoma. 13 Leiomyosarcoma has rarely been reported to affect other ocular structures. Meekins et al2 recently presented a case of primary orbital leiomyosarcoma and reviewed six previously reported cases. Four patients experienced local recurrence after excision of the tumor. Follow-up
Fig 10. Higher magnification of cytoplasm showing subplasmalemmal thin filaments with dense bodies and numerous pinocytotic vesicles (ar row). Inset shows few profiles of rough endoplasmic reticulum and Golgi bodies with external lamina (arrow). (uranyl acetate, lead citrate; original magnification, X19,000; inset X26,500).
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Table 1. Comparison of Superficial and Deep Leiomyosarcomas No. of Cases
Size (em)
No. of Mitotic Figures
No. of Recurrerrces
No. of Metastases
No. of Deaths
Dermis Subcutaneous
65 15
0.4- 6 0.5-13
1->50/50 HPF 1->50/50 HPF
23/55 6/12
0/59 4/12
0/59 4/12
17
Dermis Subcutaneous
19 21
5 5
1-10/10HPF 1-10/10 HPF
9/17 6/20
2/17 8/20
2/17 8/20
18
Dermis Subcutaneous Deep fascia Skeletal muscle
3 9 2 11
1-1 .8 1.5-7.5 5, 7.5 7-25
1-38/10 HPF 2-36/10HPF 13, 49/10 HPF 2-105/10 HPF
2/3 4/9 1/2 4/11
NG
0/3 0/8 2/2 8/9
19
Retroperitoneum
36
7.5-35
1->20/10 HPF
NG
NG
23/30
20
Location
HPF
=
high power fields; NG
=
data not specifically given.
more often be completely excised, and infrequently caused death, despite numerous recurrences, whereas the deeper lesions were frequently fatal. Among these 145 patients, only 5 leiomyosarcomas involved the head and neck and none appeared in the conjunctiva. A similar situation has been found in the spectrum offibrohistiocytic neoplasms. Atypical fibroxanthoma is a cytologically malignant spin dle cell neoplasm usually confined to the dermis of the head. Despite its disturbing histologic appearance, it usu ally presents with a small size and pursues a benign course, although metastases have occasionally been reported. 21 •22 This contrasts with the aggressive course of malignant fibrous histiocytoma of the deep soft tissues. 1 In the present patient, it is difficult to know when the tumor first arose, due to the long history of pain and ir ritation, but it must have been present for several years, a feature in keeping with the protracted course of cuta neous leiomyosarcoma. 17- 19 Originally, we believed that the excision of tumor in 1963 may have represented the first indication of the present tumor, but these slides are not available for review now and examination of slides from the re-excision specimen of 1964 showed no residual neoplasm. We believed that the elevated intraocular pres sure could have been related to the presence of tumor involving the episcleral venous plexus, early peripheral anterior synechiae, or to the patient's many courses of topical steroids. In summary, we have reported an unusual tumor of the conjunctiva, which fulfills the diagnostic criteria for a leiomyosarcoma. The protracted course may relate to its superficial location and relatively small size as has been demonstrated with leiomyosarcoma of the skin.
REFERENCES 1. Enzinger FM, Weiss SW. Soft Tissue Tumors, 2nd ed. St. Louis: CV Mosby, 1988;402. 2. Meekins BB, Dutton JJ, Proia AD. Primary orbital leiomyosarcoma. A case report and review of the literature. Arch Ophthalmol1988; 106: 82-6. 3. Cohen BH, Green WR, Iliff NT, et al. Spindle cell carcinoma of the conjunctiva. Arch Ophthalmol 1980; 98:1809-13.
1564
Reference
4. Iliff WJ, Marback R, Green WR. Invasive squamous cell carcinoma of the conjunctiva. Arch Ophthalmol 1975;93: 119-22. 5. Wise AC. A limbal spindle-cell carcinoma. Surv Ophthalmol1967;12: 244-6. 6. Azumi N, Ben-Ezra J, Battifora H. lmmunophenotypic diagnosis of leiomyosarcomas and rhabdomyosarcomas with monoclonal anti bodies to muscle-specific actin and desmin in formalin-fixed tissue. Mod Pathol1988;1 :469-474. 7. Ghadially FN. Diagnostic Electron Microscopy of Tumours, 2nd ed. London: Butterworths, 1985;186-205. 8. Grossniklaus HE, Green WR, Luckenbach M, Chan CC. Conjunctival lesions in adults: a clinical and histopathologic review. Cornea 1987;6: 78-116. 9. de Wolff-Rouendaal D. Xeroderma pigmentosum with ophthalmological symptoms. Ophthalmologica 1976;173:290-1. 10. Urdiales-Viedma M, Moreno-Prieta M, Martos-Padilla S. Pleomorphic fibrous histiocytoma of the corneoscleral limbus [Letter). Am J Ophthalmol 1983;95:560-1. 11 . Litricin 0. Fibrous histiocytoma of the corneosclera. Arch Ophthalmol 1983;101 :426-8. 12. Delgado-Partida P, Rodriguez-Trujillo F. Fibrosarcoma (malignant fi broxanthoma) involving conjunctiva and ciliary body. Am J Ophthalmol 1972;74:479-85. . 13. Rootman J. Diseases of the Orbit: A Multidisciplinary Approach. Phil adelphia: JB Lippincott, 1988;351-3. 14. Terry TL. Sarcoma of eyelid . Metaplasia of leiomyosarcoma to round cell sarcoma after repeated attempted excisions. Arch Ophthalmol 1934;12:689-92. 15. Jakobiec FA, Howard GM, Rosen M, Wolff M. Leiomyoma and leio myosarcoma of the orbit. Am J Ophthalmol1975;80:1028-42. 16. Wojno T, Tenzel RR, Nadji M. Orbital leiomyosarcoma. Arch Ophthalmol 1983;101 :1566-8. 17. Fields JP, Helwig EB. Leiomyosarcoma of the skin and subcutaneous tissue. Cancer 1981;47:156-69. 18. Dahl I, Angervall L. Cutaneous and subcutaneous leiomyosarcoma. A clinicopathologic study of 47 patients. Path Europ 1974;9:307-15. 19. Hashimoto H, Daimaru Y, Tsuneyoshi M, Enjoji M. Leiomyosarcoma of the external soft tissues. A clinicopathologic, immunohistochemical, and electron microscopic study. Cancer 1986;57:2077-88. 20. Shmookler BM, Lauer DH. Retroperitoneal leiomyosarcoma: a clini copathologic analysis of 36 cases. Am J Surg Pathol 1983;7:269 80. 21 . Fretzin DF, Helwig EB. Atypical fibroxanthoma of the skin. A clinico pathologic study of 140 cases . Cancer 1973;31 :1541-52. 22. Helwig EB, May D. Atypical fibroxanthorna of the skin with metastasis. Cancer 1986;57:368-76.
Abstract: The clinical, light microscopic, immunohistologic, and ultrastructural findings of a leiomyosarcoma of the conjunctiva are presented. This tumor was diagnosed after a 26-year history and is the first to be adequately documented as having arise!) in the conjunctiva. Ophthalmology 1991; 98:1560-1564
Leiomyosarcoma, the malignant tumor of smooth muscle cells, most commonly arises in the uterus and gastrointestinal tract. 1 Within the ophthalmic literature, it has been reported rarely in the orbit. 2 We describe the clinical and pathologic features of a leiomyosarcoma that arose in the conjunctiva, the first to be adequately doc umented in this location.
CLINICAL HISTORY A 66-year-old man presented in March 1989 after re sults of penetrating keratoplasty and biopsy of "pseudo pterygia" ofthe left eye showed a histologically malignant spindle cell neoplasm involving both conjunctiva and cornea. He first experienced blurring of vision and irri tation in his left eye in 1963, 26 years previously. The eye was described as appearing "bloodshot" and he was treated with topical steroids for a presumed viral or allergic con junctivitis with initial success. A few months later, his symptoms recurred along with a white nodule at the lim b~s. Biopsy and review ofthe nodule at the Armed Forces Institute of Pathology resulted in the belief that it repre sented a squamous cell carcinoma of the conjunctiva with stromal invasion that was not completely excised. ReOriginally received: June 6, 1990. Revision accepted: May 23, 1991. 1 2
Departments of Pathology, Vancouver General Hospital and University of British Columbia, Vancouver. Department of Ophthalmology, Vancouver General Hospital and University of British Columbia, Vancouver.
Presented at the annual meeting of the Canadian Ocular Pathology Society, Calgal)l, Alberta, June 1989. Correspondence to Valerie A. White, MD, FRCPC, Department of Pa thology, Vancouver General Hospital, 855 W 12th Ave, Vancouver, BC, Canada V5Z 1M9.
1560
excision in 1964 showed no residual neoplasm. From 1964 to 1986, he continued to experience blurred vision, hy peremia, and intermittent ulceration, and was treated over these years with a variety oftopical medications including antibiotics, steroids, and idoxuridine, along with debride ment, cautery, contact lens, and patching for a presumed diagnosis of Herpes simplex keratitis. His visual acuity in the left eye in 1976 was 20/60. Examination at the Eye Care Center of the Vancouver General Hospital in 1986, after a 1-year period of wors ening symptoms, showed visual acuity of hand motions and intraocular pressure of 42 mmHg. The lower two thirds of the cornea showed stromal edema and scarring and masses were present at the limbus on both temporal and nasal sides, the "pseudopterygia." He was prescribed topical antiglaucoma medications, which controlled his pressure, and continued to receive topical steroids and occasional antibiotics. In 1987, he began to experience pain and discomfort in the eye and the cornea was de scribed as being elevated and vascularized. He underwent penetrating keratoplasty and biopsy of the limballesions in January 1989; results of pathologic examination showed a malignant spindle cell tumor, which is fully described below. The corneal graft became clear, but the surrounding conjunctiva remained elevated and hyperemic due to residual tumor (Fig 1). In April 1989, he underwent excision of large portions of nasal and temporal conjunctiva and biopsies of the margins of the lesions within superior and inferior conjunctiva and inferior rectus insertion. Tumor was found to be present in all specimens and at all resection margins_ After dis cussion with the patient, who believed that he could no longer tolerate the irritation and pain of his eye and, sec ondarily, because of residual conjunctival tumor, subtotal exenteration was performed a few weeks later. The pa tient's health had otherwise been excellent over these years and there was no evidence of metastatic disease on com plete physical and radiologic examination. The right eye
WHITE et al
•
LEIOMYOSARCOMA OF THE CONJUNCTIVA
vas normal. A computed tomography scan 6 months after showed no evidence of residual neoplasm. 1e remains well 2 years later.
~xenteration
>ATHOLOGY The first specimen consisted of a penetrating kerato 'lasty and biopsies of the limbal masses. The cornea ;howed a preserved but thinned epithelium. Between the ~pithelium and an intact Bowman's layer, there was a .;pindle cell neoplasm, which was thicker at one margin, ~xtending over the entire diameter of the cornea (Fig 2). The neoplasm was arranged in fascicles, showed pleo morphic cigar-shaped nuclei and eosinophilic cytoplasm jut no mitotic figures (Fig 3). The underlying stroma showed a focus ofperipheral neovascularization, but Des :::emet's membrane and the endothelium were normal. The biopsies of the limbal masses showed a more pleo morphic spindle cell neoplasm within the conjunctival substantia propria with similar appearing nuclei and three to four mitotic figures per ten high power fields (Fig 4). The overlying epithelium was intact. The conjunctival excisions showed similar features, again with numerous mitotic figures. The exenteration specimen showed resid ual neoplasm most extensively over the anterior nasal portion of the globe between the sclera and the intact overlying conjunctival epithelium (Fig 5). Here the fas cicular arrangement of the tumor was more evident in feriorly (Fig 6). The tumor extended on the scleral surface to the insertion ofthe inferior rectus muscle and superiorly to the fornix. There was malalignment of the donor cornea with stroma lying against conjunctival tumor and poor apposition of the ends of Descemet's membrane. Inferi orly, tumor was present in the substantia propria overlying Schlemm's canal and the episcleral venous plexus. Early peripheral anterior synechiae were present. There was no invasion of the globe, which showed normal intraocular structures, or extension to orbital resection margins. The anterior optic nerve showed Schnabel's cavernous optic atrophy. By the indirect immunoperoxidase method, numerous sections of tuq1or showed strong staining for vimentin (Biogenex Laboratories, San Ramon, CA, monoclonal 1/2000) (Fig 7) and muscle-specific actin (Enzo Diagnos tics, New York, NY, monoclonal 1/8000) (Fig 8) with moderate staining for alpha smooth muscle actin (Sigma Diagnostics, St. Louis, MO, monoclonal 1/8000) and weak staining for desmin (Sigma Diagnostics, monoclonal 1/500). Staining for keratin (Dako Corporation, Santa Barbara, CA, polyclonal1/500, predominantly against 52, 56, 58, kD subunits) was completely negative within the tumor while the overlying epithelium showed strong staining. There was no staining for S100 protein (Research Development Corporation, Toronto, Ontario, polyclonal 1/1000) and alpha-1-antichymotrypsin (Dako Corpora tion, polyclonal 1/200), except for occasional histiocytes within the tumor. Electron microscopy showed spindle shaped cells with oval convoluted nuclei and prominent nucleoli (Fig 9).
The cytoplasm showed subplasmalemmal thin filaments with dense bodies and occasional profiles of rough en doplasmic reticulum and Golgi bodies. The plasma membrane contained numerous pinocytotic vesicles and there was abundant external lamina (Fig 10). All cells showed similar features. The light microscopic, immu noperoxidase staining profile and electron microscopic findings were believed to be diagnostic of a leiomyosar coma involving the conjunctival substantia propria and subepithelial area of the cornea.
DISCUSSION The differential diagnosis in this unusual case was be lieved to rest between a spindle cell squamous carcinoma and a sarcoma, either a leiomyosarcoma or a malignant fibrous histiocytoma. The tumor was considered to be histologically malignant because of the high mitotic rate, nuclear pleomorphism, and extensive involvement of substantia propria. It was not believed to be a squamous carcinoma because of intact conjunctival and corneal ep ithelium, which showed no continuity with the tumor, lack of keratin staining, absence of tonofilaments and desmosomes on electron microscopy, and lack of an ag gressive course as reported in previous cases of invasive squamous cell carcinoma of the conjunctiva. 3- 5 A malig nant fibrous histiocytoma was ruled out because of lack of a storiform pattern and because of the monotonous appearance of cells with thin filaments and dense bodies and lack of histiocytic and fibroblastic features by electron microscopy. In a recent study, Azumi et al 6 showed that muscle-specific actin is a sensitive marker for leiomyo sarcoma, usually showing generalized expression, whereas desmin staining is more focal or may be negative in for malin-fixed tissue. Our case showed stronger and weaker generalized staining for muscle-specific actin and desmin, respectively. In addition, this case showed the electron microscopic features considered diagnostic for smooth muscle cells, including subplasmalemmal thin filaments with dense bodies, pinocytotic vesicles, external lamina, and convoluted nuclei. 7 Leiomyosarcoma of the conjunctiva must indeed be a rare neoplasm. In a review of2455 conjunctival specimens from the Johns Hopkins Eye Pathology Laboratory, Grossniklaus et al8 did not find a single case. We were only able to find one previously reported case in the literature. 9 This concerned a 20-year-old woman with xeroderma pigmentosum who also had numerous cutaneous squamous cell and basal cell carcinomas as well as melanomas. A limbal tumor, originally believed to be a leiomyoma on biopsy, recurred rapidly and exenteration showed a "mesenchymal malignancy, probably a leio myosarcoma," in addition to a small choroidal nevus. This tumor was reviewed by the Armed Forces Institute of Pathology, but the material was too poorly preserved for adequate electron microscopy and, at the present time, no tissue remains upon which to perform immunoper oxidase studies (personal communication, de Wolff Rouendaal, 1989). 1561
1562
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Fig I. Top lefi, photograph of patient's eye after penetrating keratoplasty. Notice hyperemic, elevated conjunctiva. Fig 2. Top right, margin of cornea shows spindle cell neoplasm between epithelium and Bowman's layer (hematoxylin-eosin; original magnification, X20). Fig 3. Second row lefi, higher power of margin of neoplasm on cornea shows fascicular arrangement of cells and pleomorphic, cigar-shaped nuclei (hematoxylin-eosin; original magnification, X50). Fig 4. Second row right, biopsy of limbal mass shows a more pleomorphic spindle cell neoplasm with numerous mitotic figures (hematoxylin-eosin; original magnification, X50). Fig 5. Third row lefi, whole mount of exenteration specimen shows residual tumor in nasal substantia propria, adherent to the sclera and elevating the epithelium. The tumor extends to the fornix superiorly and to the insertion of the rectus muscle inferiorly. Arrows denote the extent of tumor on the scleral surface. Notice Schnabel's cavernous optic atrophy (hematoxylin-eosin; original magnification, X 1.2). Fig 6. Third row right, high magnification from superior area of exenteration specimen shows fascicular arrangement of cells with pleomorphic nuclei and numerous mitotic figures (hematoxylin-eosin; original magnification, X50). Fig 7. Bottom lefi, strong staining for vimentin in corneal portion of tumor (indirect immunoperoxidase, hematoxylin; original magnification, X50). Fig 8. Bottom right, strong staining for muscle-specific actin in conjunctival portion of tumor (indirect immunoperoxidase, hematoxylin; original magnification, X50).
was available for five ofthe seven cases. Distant metastases developed in three patients, who died of tumor-related causes 12 to 67 months later. 14·15 Meekins' patient died at 5 months from a nontumor-related cause with no clin ical evidence of tumor recurrence. Only one patient was alive 42 months after excision of tumor with no evidence of recurrence or metastases. 216 · For a better understanding of our case, we turned to the more extensive literature of leiomyosarcoma of the skin. This is a superfically located, histologically malignant neoplasm that pursues a relatively benign course. Table 1 compares location, size, mitotic rate, and clinical out come of superficially and deeply located leiomyosarco mas.17-20 Although the more deeply located lesions tended to have a higher mitotic rate and worse cytology, the more important prognostic factors were location, size, and ad equacy of initial excision. The more superficial lesions, similar in location to the current case, were smaller, could
Fig 9. Low power electron micrograph shows spindle-shaped cells with oval, convoluted nuclei and prominent nucleoli (uranyl acetate, lead citrate; original magnification, X3250).
Other mesenchymal malignancies occurring at the lim bus have included a "pleomorphic fibrous histiocytoma of the comeosclerallimbus," which was treated primarily by enucleation, a fibrous histiocytoma and a fibrosarcoma of the limbus, which had aggressive courses necessitating numerous resections before eventual enucleation. 10- 12 The latter appeared histologically malignant and had invaded the underlying ciliary body, while the other histologically more benign appearing lesion had invaded the iris, pos sibly through a previous iatrogenic perforation. These three patients were alive at the time of follow-up from 18 months to 9 years after first presentation. A malignant fibrous histiocytoma involving substantia propria and or bit has been described 5 years after radiotherapy to the head and neck and chemotherapy for a diffuse small cleaved celllymphoma. 13 Leiomyosarcoma has rarely been reported to affect other ocular structures. Meekins et al2 recently presented a case of primary orbital leiomyosarcoma and reviewed six previously reported cases. Four patients experienced local recurrence after excision of the tumor. Follow-up
Fig 10. Higher magnification of cytoplasm showing subplasmalemmal thin filaments with dense bodies and numerous pinocytotic vesicles (ar row). Inset shows few profiles of rough endoplasmic reticulum and Golgi bodies with external lamina (arrow). (uranyl acetate, lead citrate; original magnification, X19,000; inset X26,500).
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VOLUME 98
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Table 1. Comparison of Superficial and Deep Leiomyosarcomas No. of Cases
Size (em)
No. of Mitotic Figures
No. of Recurrerrces
No. of Metastases
No. of Deaths
Dermis Subcutaneous
65 15
0.4- 6 0.5-13
1->50/50 HPF 1->50/50 HPF
23/55 6/12
0/59 4/12
0/59 4/12
17
Dermis Subcutaneous
19 21
5 5
1-10/10HPF 1-10/10 HPF
9/17 6/20
2/17 8/20
2/17 8/20
18
Dermis Subcutaneous Deep fascia Skeletal muscle
3 9 2 11
1-1 .8 1.5-7.5 5, 7.5 7-25
1-38/10 HPF 2-36/10HPF 13, 49/10 HPF 2-105/10 HPF
2/3 4/9 1/2 4/11
NG
0/3 0/8 2/2 8/9
19
Retroperitoneum
36
7.5-35
1->20/10 HPF
NG
NG
23/30
20
Location
HPF
=
high power fields; NG
=
data not specifically given.
more often be completely excised, and infrequently caused death, despite numerous recurrences, whereas the deeper lesions were frequently fatal. Among these 145 patients, only 5 leiomyosarcomas involved the head and neck and none appeared in the conjunctiva. A similar situation has been found in the spectrum offibrohistiocytic neoplasms. Atypical fibroxanthoma is a cytologically malignant spin dle cell neoplasm usually confined to the dermis of the head. Despite its disturbing histologic appearance, it usu ally presents with a small size and pursues a benign course, although metastases have occasionally been reported. 21 •22 This contrasts with the aggressive course of malignant fibrous histiocytoma of the deep soft tissues. 1 In the present patient, it is difficult to know when the tumor first arose, due to the long history of pain and ir ritation, but it must have been present for several years, a feature in keeping with the protracted course of cuta neous leiomyosarcoma. 17- 19 Originally, we believed that the excision of tumor in 1963 may have represented the first indication of the present tumor, but these slides are not available for review now and examination of slides from the re-excision specimen of 1964 showed no residual neoplasm. We believed that the elevated intraocular pres sure could have been related to the presence of tumor involving the episcleral venous plexus, early peripheral anterior synechiae, or to the patient's many courses of topical steroids. In summary, we have reported an unusual tumor of the conjunctiva, which fulfills the diagnostic criteria for a leiomyosarcoma. The protracted course may relate to its superficial location and relatively small size as has been demonstrated with leiomyosarcoma of the skin.
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1564
Reference
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