Repeated dedifferentiation of low-grade intraosseous osteosarcoma

Case Studies REPEATED DEDIFFERENTIATION OF LOW-GRADE INTRAOSSEOUS OSTEOSARCOMA AJ;JRA OGOSE, MD, TETSUO HOTTA, MD, IWAOEMURA, MD, SATOSHIIMAIZUMI,MD, MITSUHIRO TAKEDA,MD, AND SOICHIROYAMAMURA,MD

Low-grade inu'aosseous osteosarcoma is an u n c o m m o n bone tumor that is characterized by minimum cytological atypism and a much better prognosis than conventional osteosarcoma. This report describes a patient who had a low-grade osteosarcoma that mimicked fibrous dysplasia (FD). T h e tumor had an area of high-grade sarcoma at the initial diagnosis. Ten years after incomplete resection of FD-like

tumor, local recurrence with areas of high-grade tumor developed. This case illustrates the potential of dedifferentiation in low-grade intraosseous osteosarcoma. HUM PATHOL 31:615-618. Copyright © 2000 by W.B. Saunders Company Key words: low-grade osteosarcoma, dedifferentiafion.

The great majority of osteosarcomas are high-grade malignant neoplasm. Low-grade intraosseous osteosarcoma is less aggressive and has limited metastatic potential. It was found in only 1% to 5% of all osteosarcomas in large series. 1-~ Histologically, it is composed of spindle cells with only minimal at3qgia. The transformation of low-grade osteosarcoma into high-grade osteosarcoma (dedifferentiation) can be observed in recurrent tumors after incomplete treatment of the primary tumor. Although it is very rare, dedifferentiation may be also found at the time of presentation, as seen in parosteal osteosarcoma. 4 We herein describe a case of lowgrade intraosseous osteosarcoma of the humerus that showed dedifferentiated areas in both primary and recurrent tumors.

Pathological Findings

CASE REPORT

Clinical History, In 1986, a 33-year-old man was referred to the Orthopedic Department because of 2 months history of pain and swelling in the right upper arm. Plain radiogram showed an osteolytic lesion in the right humeral shaft with cortical destruction (Fig 1A). An incisional biopsy showed osteoblastic osteosarcoma with prominent proliferations of osteoclast-like giant cells. After 2 cycles of chemotherapy consisting of high-dose methotrexate, a wide excision was planned. The tumor was resected ~itla 5-cm bone margins from the osteolytic lesion, and vascularized intercalary fibtfla transfer was performed (Figs 1B, 2). The patient was given 8 additional courses of chemotherapy consisting of cisplatin and doxorubicin. Both osteotomy sites were archived fusion, and the patient was in good condition for 10 years. In January 1997, he had increasing pain in the right shoulder. Radiograms showed osteolytic lesions in the humeral head and proximal shaft (Fig 1C). An open biopsy on the humeral head showed recurrent osteosarcoma. After 2 courses of preoperative chemotherapy consisting of ifosfamide, wide excision and shoulder arthrodesis were performed with vascularized fibula transfer. Three additional courses of chemotherapy were performed. The patient is well with no evidence of disease 18 months after the last surgery. From the Department of Orthopedic Surgery and Pathology, Niigata UniversitySchool of Medicine, Niigata,Japan. Address correspondeqce and reprint reqtzests to Aldra Ogose, MD, Department of Orthopedic Surgery, Niigata University School of Medicine, A.sahimachi 1, Niigata 951-8510,Japan. Copyright © 2000 by W.B. SaundersCompany 0046-8177/00/3105-0013510.00/0 doi: 10.1053/hp.2000.6702

615

The initially resected tumor was composed of 2 different elements. The purely osteolytic lesion on the plain radiogram was composed of high-grade osteosarcoma. The tumor destroyed cortical bone and invaded surrounding soft tissue (Figs 2, 3A). These tumor cells had oval to short spindleshaped nuclei containing prominent nucleoli. Nucleolar pleomorphism, hyperchromatism, and many mitotic figures (10 per 10 high-power fields) were also observed. There were considerable loci of proliferations of osteoclast-like giant cells, tumor necrosis, and direct osteoid production by tumor cells (Figs 3B, C). Contrary to preoperative expectations, there was another tumor component surrounding the high-grade osteosarcoma. This tumor showed a fibrous dysplasia (FD)-like pattern and irregtflarly shaped seams of osteoid ~4th loosely arranged fibroblastic cell proliferation. The tumor showod btmdles of spindle-shaped, elongated cells of tmiform appearance with minimal atypia of nuclei (Figs 2, 3D). Mitotic figures were seldom observed. Although this fibrous tumor showed minimal cytological atypism, the tumor had an infiltration pattern of the bone marrow and cortical bones (Fig 3E). The proximal surgical margin was positive for the FD-like element (Fig 2). The recurrent tumor found in 1997 showed principally the same features as the primary t u m o r There were FD-like areas in the humeral head and the grafted fibula (Fig 2). A high-grade area was seen in the humeral head, and it invaded the surrotmding soft tissue. The FDqike area and high-grade sarcoma were sharply demarcated. The high-grade tumors had pleomorphic nuclei and many mitotic figures (Fig 3F). There was small focus of the high-grade tumor in the FD-like area of the grafted fibtfla (Fig 2, 3G). DISCUSSION Low-grade intraosseous osteosarcoma was first described as a distinct clinicopathologic entity in 1977. ~ Most of the

patients are young adults, and skeletal distribution is similar to the distribution seen in com,entional osteosarcoma, predominantly the femur and tibia, ll~ Althongh low-grade intraosseous osteosarcomas in the humerus are rarely reported, Kurt et al 2 found 2 cases that involved the humerus among 80 cases. Histologically, low-grade intraosseous osteosarcoma consists of spindle cells with little cytological atTpia. Mitotic figures are uncommon, and the cells are arranged in an interfacing pattern. The matrix frequently produces in the pattern of regnlar bony trabeculae simulating parosteal osteosarcoma. One third of the tumors have a desmoid appearance with scanty osteoid. In rare cases, the osteoid seams have the

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FIGURE 1. (A) Radiograph of the humerus shows an osteolytic lesion of the proximal shaft with cortical destruction. (B) The initial tumor was resected en bloc with 5-cm surgical margins from the osteolytlc lesion. The humerus was reconstructed with vascularlzed fibula transfer. (C) Radiograph of the recurrent tumor showed osteolytic lesions in both the humeral h e a d and the grafted fibula.

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high grade tumor

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FIGURE 2. Schema of the distribution of the FD-ilke and high-grade tumors in the primary and recurrent tumors. The proximal surgical margin of the primary tumor is positive, but the tumoral distribution in the humeral h e a d is unknown (#). There are large high-grade tumors in the humeral h e a d and a small focus In the grafted fibula in recurrent lesion (*).

616

CASE STUDIES

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FIOURE 3. CA) Low-power view of the junction of FD-Iike tumor (left) and high-grade osteosarcoma (right). Mitotic figures are easily found in high-grade osteosarcoma (arrows). (B) Lace-like osteoid production and Irregular-shaped osteoblastic cells In the high-grade tumor. (C) Considerable number of osteoclastlike giant cells with highly cellular fibroblastic cell proliferation. (D) The FD-like tumor is composed of loose fibrous stroma and irregularly shaped seams of osteoid, The cytologic atypis~ Is minimal. (E) Infiltration pattern of FD-Ilke tumor In the primary tumor. The cytological atyplsm Is minimal. (F) Marked nuclear pleomorphlsm of the high-grade element in the recurrent tumor. (G) High-power view of a small focus of dedifferentlatlon in the grafted fibula. The diameter of this area was 5 mm.

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Volume 31, No. 5 (May 2000)

classic Chinese character appearance of fibrous dysplasia,'-' as seen in this case.

tiation. To date, r a d i o g r a p h i c f i n d i n g s o f p a r o s t e a l osteosarc o m a are well r e c o g n i z e d , a n d p r e o p e r a t i v e clinical diagnosis is n o t difficult. T h e r e f o r e , parosteal o s t e o s a r c o m a is likely to b e r e s e c t e d e n bloc for t h e initial t r e a t m e n t . O n t h e o t h e r h a n d , t h e r a d i o g r a p h i c a p p e a r a n c e o f low-grade i n t r a o s s e o u s o s t e o s a r c o m a is highly variable, a n d p r e s u m p t i v e diagnosis is usually difficult. C u r e t t a g e is o f t e n p e r f o r m e d as t h e initial t r e a t m e n t , 5 a n d t h e m a t e r i a l s d o n o t c o n f i r m t h a t t h e r e is n o area o f d e d i f f e r e n t i a t i o n . A small focus o f d e d i f f e r e n t i a t i o n , as s e e n in t h e g r a f t e d fibula in this case, would b e o v e r l o o k e d if t h e materials were c u r e t t a g e d .

T h e differential diagnosis in this case involves fibrous dysplasia with s a r c o m a t o u s t r a n s f o r m a t i o n . However, sarcomas arising in fibrous dysplasia are u n c o m m o n w i t h o u t p r e c e d i n g r a d i a t i o n , l~ a n d t h e FD-like area in this case s h o w e d p e r m e a t i n g p a t t e r n . FD-like areas in t h e r e c u r r e n t t u m o r also s h o w e d p e r m e a t i o n a n d i n v a d e d t h e grafted fibula. A l t h o u g h cytological atypia was m i n i m a l a n d mitotic figures were seldom observed, permeating pattern of bone marrow and b o n e t r a b e c u l a e was t h e m o s t h e l p f u l f e a t u r e in diagnosis o f low-grade o s t e o s a r c o m a in this case. ~ T h e surgical m a r g i n s o f the initial excision was negative for h i g h - g r a d e area b u t positive for FD-like area at t h e p r o x i m a l m a r g i n . T h e r e c u r r e n c e o f t h e t u m o r was c o n f i r m e d 10 years later. T h i s l o n g clinical c o u r s e i n d i c a t e d t h a t t h e r e m n a n t FD-like t u m o r i n v a d e d t h e h u m e r a l h e a d a n d g r a f t e d fibula, a n d d e d i f f e r e n t i a t e d foci d e v e l o p e d . T h e p r e s e n t case h a d 3 d i f f e r e n t areas o f d e d i f f e r e n t i a t i o n , i n c l u d i n g t h e p r o x i m a l shaft in t h e initial tumor, t h e h u m e r a l h e a d , a n d t h e small focus in the g r a f t e d fibula in the r e c u r r e n t tumor. S u c h p h e n o m e n a i n d i c a t e t h a t d e d i f f e r e n t i a t i o n o f low-grade intraosseous o s t e o s a r c o m a is n o t u n c o m m o n in l o n g clinical course. D e d i f f e r e n t i a t i o n o f low-grade i n t r a o s s e o u s osteosarc o m a is usually s e e n in r e c u r r e n t tumors. Kurt et al 2 r e p o r t e d t h a t 11 o f 15 p a t i e n t s d e v e l o p e d local r e c u r r e n c e after i n a d e q u a t e surgery, a n d 4 o f t h e m h a d d e d i f f e r e n t i a t i o n . In t h e i r series, t h e r e were n o cases with d e d i f f e r e n t i a t i o n at t h e initial diagnosis. A similar risk o f d e d i f f e r e n t i a t i o n has b e e n n o t e d for parosteal o s t e o s a r c o m a . O k a d a et a113 r e p o r t e d t h a t 37 o f 226 p a t i e n t s with parosteal o s t e o s a r c o m a s d e v e l o p e d d e d i f f e r e n t i a t i o n . O f these 37 instances, 20 were r e c o g n i z e d at t h e time o f initial diagnosis. However, we f o u n d only 1 case o f low-grade i n t r a o s s e o u s o s t e o s a r c o m a with d e d i f f e r e n t i a t i o n at the time o f the initial diagnosis. 4 T h e r e a s o n for t h e d i f f e r e n t i n c i d e n c e s o f d e d i f f e r e n t i a t i o n at t h e initial diagnosis is unclear. O n e m u s t q u e s t i o n w h e t h e r t h e initial s a m p l i n g o f the t u m o r is a d e q u a t e to rule o u t t h e p r e s e n c e o f d e d i f f e r e n -

REFERENCES 1. Unni KK, Dahlin DC, McLeod RA, et al: Intt,'aosseouswell-differentiated osteosarcoma. Cancer 40:1337-1347, 1977 2. Kurt A-M, Unni KK, McLeod RA, et al: Low-grade intraosseous osteosat~ coma. Cancer 65:1418-1428, 1990 3. Bertoni F, Bacchini P, Fabbri N, et al: Osteosarcoma: Low-grade inu,'aosseous osteosarcoma, histologically resembling parosteal osteosarcoma. fibrous dysplasia, and desmoplastic fibroma. Cancer 71:338-345, 1993 4. Inemoto Y, Ushigome S, Fukunaga M, et al: Case report 679: Central low-grade osteosarcoma with foci of dedifferentiadon. Skeletal Radiol 20:379382, 1991 5. MirraJM: Primary, low-grade intramedullary variants, in MirraJM (ed): Bone Tumors. Philadelphia, London, Lea & Febiger, 1989, pp 359-383 6. Dorfman HD, Czerniak B: Well-differentiated intramedullary osteosarcoma, in Dorfman HD, Czerniak B (eds): Bone Tumors. St Louis, MO, Mosby, 1998, pp 205-217 7. Unni KK: Case report 136: Central low-grade osteosarcoma of tibia. Skeletal Radiol 6:65-67, 1981 8. Xipell JM, Rush J: Case report 340: Well differentiated intraosseous osteosarcoma of the left femur. Skeletal Radiol 14:312-316, 1985 9. Sundaram M, Herbold DR, McGuire MH: Case report 370: Lo~,-grade (well-differentiated)intramedullaryosteosarcoma.SkeletalRadio115:338-342,1986 10. Sire FH, Kurt A-M, McLeod RA, et al: Case report 628: Low-grade central osteosarcoma. Skeletal Radio119:457-460, 1990 11. Choong FM, Pritchard DJ, Rock MG, et al: Low-grade central osteogenic sarcoma. Clin Orthop 322:198-206, 1996 12. Ruggieri P, Sim FH, Bond JR" et al: Malignancies in fibrous dysplasia. Cancer 73:1411-1422, 1994 13. Okada K, Frassica FJ, Sim FH, et al: Parosteal osteosarcoma: A clinicopathological study.J Bone Joint Surg Am 76:366-378. 1994

CHRONIC RIGHT-SIDED MYOCARDITIS MIMICKING ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA PAUL J. MICHAELS, BS, JON A. KOBASHIGAWA, MD, JOHN S. CHILD, MD, AND MICHAEL C. FISHBEIN, MD

mogenic right ventricular dysplasia has therapeutic implications for the patient and relatives. HUM PATHOL 31:618-621. Copyright © 2000 by W.B. Saunders Company Key words: arrhythmogenic right ventricular dysplasia, right sided myocarditis, heart failure. Abbreviations: ARVD, arrhythmogenic fight ventricular dysplasia; AICD, automatic cardioverter defibrillator; MUGA, multigated acquisition.

Arrhythmogenic right ventricular dysplasia (ARVD) is a cause of right ventricular heart failure and has been implicated in some cases of sudden death in young adults. It is well known that a large majority of patients with ARVD have histological evidence suggestive of inflammation. Here we report a unique case of chronic myocarditis limited to the right ventricle and right side of the interventricular septum which presented clinically as ARVD. The fact that right sided myocarditis can clinically mimic the genetic disease of classic arrhyth-

From the Division of Anatomic Pathology and Division of Cardiology, University of California-Los Angeles, Los Angeles, CA. Address correspondence and reprint requests to Paul Michaels, Department of Pathology and Laboratory Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, A7-229 CHS, Los Angeles, California, 90095-1732. Copyright © 2000 by W.B. Saunders Company 0046-8177/00/3105-0014510.00/0 doi: 10.1053/hp.2000.6704

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Arrhythmogenic right ventricular dysplasia (ARVD) is a progressive heart muscle disease characterized by cardiac electrical instability with r e p l a c e m e n t o f t h e r i g h t v e n t r i c u l a r m y o c a r d i u m with v a r y i n g a m o u n t s o f a d i p o s e a n d fibrous tissue. 1"7 O v e r time ARVD progresses to diffuse r i g h t ventricular i n v o l v e m e n t a n d left v e n t r i c u l a r a b n o r m a l i t i e s , c u l m i n a t i n g in h e a r t failure. 1,6,7 ARVD has b e e n f o u n d to b e r e s p o n sible for severe v e n t r i c u l a r a r r h y t h m i a s in adults a n d s u d d e n d e a t h in y o u n g p e r s o n s , especially athletes. ~,4 T h e etiology o f