Paranasal sinus leiomyosarcoma after cyclophosphamide and irradiation ANIL K. LALWANI. MD. and MICHAEL J. KAPLAN. MD. San Francisco. California

Leiomyosarcoma is a rare complication of radiation and cyclophosphamide therapy. Paranasal leiomyosarcoma complicating irradiation and cyclophosphamide therapy in a 66-year-old man with a history of destructive nasoantral process is presented. This case highlights the difficult differential diagnosis. both clinically and histopathologically, in destructive lesions of the midface. The occurrence of rare induced second malignancies after irradiation or certain antineoplastic agents emphasizes the need for specific diagnosis.

From the Department of Otolaryngology-Head and Neck Surgery, University of California-San Francisco. Presented at the Annual Meeting of the American Rhinologic Society, New Orleans , La.• Sept. 22-23. 1989. Submitted for publication Oct . 3. 1989; accepted Oct. 31. 1989. Reprint requests: Anil K. Lalwani, MD, A717, 400 Parnassus, Department of Otolaryngology-Head and Neck Surgery. University of California-San Francisco. San Francisco. CA 94143.

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CASE REPORT

D. R. is a 66-year -old man with a history of a destructive nasoantral process treated with irradiation 6 years earlier, who presented to the otolaryngology-head and neck surgery service in January 1988 with epiphora, photophobia, and left facial and eye pain. The patient initially presented in April 1981 with nasal crusting. discharge, and sinus complaints . Sinus film showed opacification of the maxillary. ethmoid, and frontal sinuses, which failed to resolve with oral antibiotics . At surgery. a nasal "tumor" was noted and he underwent extensive exenteration. including septectomy, left Caldwell-Lac procedure , intranasal ethmoidectomy, and excision of the left lateral nasal wall. Biopsies were reviewed at Stanford and at the University of California-San Francisco and were interpreted as necrotizing granulomatous inflammation consistent with Wegener's granulomatosis or polymorphic reticulosis (PMR). There was no evidence of lymphoma or carcinoma. Creatinine, erythrocyte sedimentation rate (ESR), urinalysis, and chest radiograph were normal. Because his clinical presentation was more consistent with polymorphic reticulosis. he was treated

Fig, 1. High-grade leiomyosarcoma with numerous mitoses. (Hematoxylin-eosin stain; original magnification x 10.)

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Fig. 2. Coronal MRI of leiomyosarcoma infiltrating left orbit and antrum. Note tumor Involving medial rectus and inferior oblique muscles as well as penetration through lateral wall of the antrum.

with 5950 cOy of external beam radiation therapy between August 31. 1981, and October I. 1981. In February 1982, abrupt right vision loss developed . A dense central scotoma was found . Nasal and nasopharyngeal examination showed postoperative changes and crusting without any definite proliferative lesions. Orbital CT showed bony destruction of the ethmoid sinuses and orbital wall with impingement of the right optic nerve . Intranasal biopsies demonstrated acute and chronic inflammation . Serum creatinine. urinalysis. chest x-ray films. and pulmonary function tests were normal. He was empirically started on prednisone (60 mg daily) and cyclophosphamide (150 mg daily) with the clinical diagnosis of Wegener's granulomatosis . Within 7 days, his vision returned to normal and his symptoms of chronic facial pain and general malaise resolved . Cyclophosphamide was decreased to 100 mg per day and was subsequently discontinued in June 1982. Prednisone was tapered and discontinued in December 1985. CT scan of the orbits in August 1983 showed no progression of disease . Serial CT scan of the sinuses between October 1983 and January 1986 revealed unchanged soft tissue density in the paranasal sinuses without intracranial extension.

Fig. 3. Axial MRI demonstrates extension of tumor through anterior wall of the left antrum to Involve soft tissue of the cheek, Inferior to the orbit.

In January 1988. the patient presented with epiphora. photophobia , and left facial pain. He had a saddle nose deformity and a large fleshy intranasal mass. Otologic examination revealed a right tympanic membrane with granulation tissue and a thickened left tympanic membrane. Creatinine, liver function tests. ESR. urinalysis, and chest x-ray film were normal. CT scan of the paranasal sinuses demonstrated a large soft tissue mass filling the inferior nasal cavity and maxillary, sphenoid, ethmoid, and frontal sinuses with bony destruction involving the entire left maxillary sinus and medial wall of the right maxillary sinus. Additionally. there was soft tissue prominence in the region of the left pterygoid plate, suggesting posterolateral extension of the tumor. Temporal bone CT demonstrated abnormal fluid or soft tissue in the medial aspect of the right external ear extending into the right middle ear. Ossicles and scutum were intact. There was fluid or soft tissue in bilateral mastoid air cells without bony destruction . The patient underwent a transnasal biopsy and debulking of the nasal mass. which at surgery extended bilaterally along the floor of the nose and appeared attached to the remaining left medial wall of the antrum. Histologic examination revealed a high-grade leiomyosarcoma. with greater than 10 mitoses per high-powered field (Fig. I). Separate biopsies from the left posterior orbital floor. left anterior orbital floor. middle soft palate. sphenoid . rostrum, and maxillary sinus were all positive for leiomyosarcoma. The patient declined

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further surgical intervention, which was discussed in an effort to protect the uninvolved eye. In June 1988, because of progression of symptomsincluding facial pain, nasal obstruction, left infraorbital numbness and 40-lb. weight loss-palliative radiation therapy and chemotherapy was planned. Staging studies included chest cr, which showed normal lungs and adrenals with no evidence of hilar or mediastinal adenopathy. MRI showed a bulky soft tissue mass with osseous destruction involving the left maxillary sinus, nasal cavity, nasopharynx , inferior ethmoid and sphenoid, as well as medial left maxillary sinus. In addition, there was extension into the left infratemporal fossa, pterygoid fossa, left orbit, medial aspect of the right orbit, and through the left foramen ovale into the middle cranial fossa (Figs . 2, 3, and 4). Between June 14, 1988, and July 7, 1988, the patient received 2600 cGy to the sinuses, followed by two courses of cisplatin (120 mg/M') and adriamycin(60 mg/M') divided into two doses. In August 1988, MRI demonstrated no response to chemotherapy and radiation therapy and, in fact, revealed slight interval increase in the soft tissue mass, extending further posteriorly into the nasopharynx as well as more medially into the inferior ethmoid. Because of progression of disease while treatment was being received, no further chemotherapy or irradiation was planned. Because of marked exposure and conjunctival prolapse ectropion, a palliative procedure was performed in October 1988, consisting of anterior orbitotomy with tumor bulking and resection using CO, laser, tarsal ectropion correction with horizontal lid shortening, and winged tarsorrhapies. DISCUSSION

Granulomatous inflammation may be associated with autoimmune , neoplastic, infective, allergic, or idiopathic disorders . Differentiation among several entities associated with necrotizing granulomatous lesions affecting the upper respiratory tract remains difficult. The confusion between Wegener's granulomatosis (WG) and polymorphic reticulosis (PMR) results from superimposed inflammatory changes obscuring underlying pathologic tissue changes. The correct diagnosis is essential because the treatment is different and each is associated with significant morbidity. WG is a systemic disorder of unknown origin, characterized by necrotizing granulomatous vasculitis of the upper and lower respiratory tracts, systemic vasculitis, and glomeruloephritis.' In addition; there may be involvement of the skin, gastrointestinal tract , central nervous system, trachea, eyes or orbit, prostate, oropharynx. and ears . Initial clinical presentation may vary, but nonspecific nasal complaints such as nasal obstruction, crusting, drainage, and pain are common.

Fig. 4. Axial CT slightly inferior level compared to Figure 3, Note destruction of left pterygoid plate and anterior penetration through antrum Into soft tissue of the cheek.

Nasal examination is also nonspecific , showing friable mucosa, crusting , mass , and possibly nasal destruction. Sinus radiographs show nonspecific mucosal thickening. Systemic complaints of malaise. weakness, pallor, night chills, sweats and migratory arthralgias may be present. Anemia, elevated serum creatinine and ESR, abnormal urine sediment, and abnormal chest radiograph may be seen . Although eventual multipleorgan system involvement is far more common. local ized disease limited to the paranasal sinuses occurs and markedly increases the diagnostic dilemma. The consistently normal chest radiograph and ESR in this patient, for instance, added significantly to the diagnostic difficulty. Even in retrospect, his diagnosis before his leiomyosarcoma remains uncertain. Although a nasal biopsy demonstrating epitheliod necrotizing granulomas, vasculitis involving small arteries and veins, and acute and chronic inflammation of mucosa and submucosa with necrosis and ulceration would make the diagnosis of WG much easier, such a complete constellation of histologic findings is the exception . Granulomas and vasculitis are usually rarer in nasal biopsy than in pulmonary or renal biopsies .' PMR is a midface necrotizing disease, histopathologically characterized by dense infiltrate of lymphoid cells , with evolution into lymphoma common. Recent

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evidence suggests T-cell clonal expansion is a factor in its etiology. It is often difficult to distinguish from localized WG. They may be clinically distinguished by their presentation and course and response to therapy in addition to histopathologic features. Treatment of WG and PMR is very different. Clinically fulminant WG is treated with cyclophosphamide and prednisone. The role of cyclophosphamide in less extensive disease without renal involvement is controversial. Irradiation is often effective for local control in PMR, but continued monitoring for the development of lymphoma is important. This case points out the more feared late complications of treatment with cyclophosphamide or irradiation. This patient had received both radiation and systemic chemotherapy 6 to 7 years before the diagnosis of his sarcoma. It is widely recognized that sarcomas have appeared between 6 and 40 years after irradiation . .1 Leiomyosarcoma is a rare sarcoma postirradiation, with nine cases reported through 1987. 4 It has been seen after orbital irradiation for retinoblastoma,' mediastinal and neck irradiation for ganglioneuroblastorna,? and pelvic irradiation for benign and malignant pelvic disease." It is less well known that sarcomas are a potential sequella of cyclophosphamide treatment as well. Cyclophosphamide therapy for Hodgkins' disease" and Wilm's tumor has been associated with leiomyosarcoma of the bladder. Spindle-cell cancer of the bladder and renal immunoblastic sarcoma have been reported after cyclophosphamide therapy for WG. IO• 11 The prognosis of these sarcomas is poor, with treatment by radiation, chemotherapy, and surgery rarely being effective. This rare postirradiation postcyclophosphamide leiomyosarcoma highlights the difficult differential diag-

nosis, both clinically and histopathologically, in destructive lesions of the midface. The occurrence of rare induced second malignancies after irradiation or certain antineoplastic agents emphasizes the need for a specific diagnosis. REFERENCES

1. Komblut AD. Wolff SM. deFries HO. Fauci AS. Wegener's granulomatosis. Otolaryngol Clin North Am 1982; 15:673-83. 2. Batsakis JG, Luna MA. Midfacial necrotizing lesions. Sem Diagnostic Pathol 1987;4:90-116. 3. Weatherby RP, Dahlin DC. Ivins JC. Postradiation sarcoma of bone: review of 78 Mayo Clinic cases. Mayo Clin Proc 1981;56:294-306. 4. Korbi S, Meyer 0, Skalli O. Gabbiani G. Kapanci Y. Postirradiation leiomyosarcoma: case report with immunohistochemical studies. J Submicrosc Cytol 1987;19:365-9. 5. Font RL. Jurco S. Brechner RJ. Postradiation leiomyosarcoma of the orbit complicating bilateral retinoblastoma. Arch Ophthalmol 1983;101:1557-61. 6. Weiss KS. Zidar BL, Wang S. et al. Radiation-induced leiomyosarcoma of the great vessels presenting as superior vena cana syndrome. Cancer 1987;60:1238-42. 7. Meredith RF. Eisert DR. Kaka Z. Hodgson SE, Johnston GA Jr. Boutselis JG. An excess of uterine sarcomas after pelvic irradiation. Cancer 1986;58:2003-7. 8. Seo IS, Clark SA. McGovern FD. Clark DL, Johnson EH. leiomyosarcoma of the urinary bladder 13 years after cyclophosphamide therapy for Hodgkin's disease. Cancer 1985;55:1597603. 9. Oesterling IE, Eggleston JC. Jeffs RD. Leventhal BG. Anaplastic sarcoma arising in a mature metachronous bilateral Wilm's tumor after irradiation and chemotherapy: spontaneous versus induced malignant change. Cancer 1987;59:2000-5. 10. Chasko SB. Keuhnelian JG, Gutowski WT. Gray GF. Spindle cell cancer of bladder during cyclophosphamide therapy for Wegener's granulomatosis. Am J Surg Pathol 1980;4:191-6. II. Sant GR, Ucci AA Jr, Meares EM Jr. Renal immunoblastic sarcoma complicating immunosuppressive therapy for Wegener's granulomatosis. Urology 1983;21:632-4.

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Paranasal sinus leiomyosarcoma after cyclophosphamide and irradiation.

Paranasal sinus leiomyosarcoma after cyclophosphamide and irradiation ANIL K. LALWANI. MD. and MICHAEL J. KAPLAN. MD. San Francisco. California Leiom...
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