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Chondromyxoid fibroma of bone: A clinicopathologic review of 278 cases
Chondromyxoid Fibroma of Bone: A Clinicopathologic Review of 278 Cases CHEN TU WU, MD, CARRIE Y. INWARDS, MD, SABINA O'LAUGHLIN, MD, MICHAEL G. ROCK, MD, JOHN W. BEABOUT, MD, AND K. KRISHNAN UNNI, MB, BS In a study of the clinical, radiographic, and pathological features of chondromyxoid fibroma, the tumor was slightly more c o m m o n in men, usually in the second decade of life. Almost half of the tumors involved the long bones, although the ilimn and the small bones were also c o m m o n sites. Roentgenograms showed a sharply marginated, lobulated, lucent defect in the metaphysis. The tumor involved the medullary bone in an eccentric fashion, and the cortex was thinned and expanded. Periosteal reaction and soft tissue extension were uncommon. Mineralization was identified in 13% of the lesions. Histologically, the tumors were almost always arranged in lobules, winch were prominent (macrolobular) or somewhat indistinct (mi-
crolobular). The tumor cells were spindle-shaped or stellate and arranged in a myxoid matrix. Calcification was seen in more than one third of the cases but was rarely prominent. Hyaline cartilage and chondroblastoma-like areas were not uncommon. Approximately 18 % of tumors showed bizarre nuclei. Permeation of bony trabeculae was uncommon. Treatment was conservative surgical removal; approximately one fourth of the patients had recurrence. HUM PATHOL 29:438-446. Copyright © 1998 by W.B. Sannders Company Key words: chondromyxoid fibroma, chondroblastoma, fibrous dysplasia, chondrosarcoma.
C h o n d r o m y x o i d fibroma is a rare, benign t u m o r of b o n e that represents fewer than 1% of all benign a n d malignant tumors of bone. 1 T h e World Health Organization defines it as "a benign t u m o r characterized by lobulated areas of spindle-shaped or stellate cells with a b u n d a n t myxoid or c h o n d r o i d intercellular material separated by zones of m o r e cellular tissue rich in
MATERIALS AND METHODS
s p i n d l e - s h a p e d o r r o u n d cells with a v a r y i n g n u m b e r o f m u l f i n u c l e a t e d g i a n t cells o f d i f f e r e n t sizes. ''2 L a r g e p l e o m o r p h i c cells m a y b e p r e s e n t a n d c a n r e s u l t in c o n f u s i o n with c h o n d r o s a r c o m a . C h o n d r o m y x o i d f i b r o m a was first d e s c r i b e d by Jaffe a n d L i c h t e n s t e i n 3 in 1948. I n t h e i r files, t h e a u t h o r s s e p a r a t e d this n e o p l a s m f r o m c h o n d r o s a r c o m a , r e a l i z i n g t h a t t h e clinical b e h a v i o r was t h a t o f a b e n i g n process. A l t h o u g h s o m e cases o f m a l i g n a n t t r a n s f o r m a t i o n have b e e n r e p o r t e d in t h e l i t e r a t u r e , 4-6 t h e clinical b e h a v i o r is t h a t o f a b e n i g n n e o p l a s m , a n d it s h o u l d t h e r e f o r e b e d i f f e r e n t i a t e d f r o m m a l i g n a n t tumors, especially c h o n d r o s a r c o m a . 1 T h e h i s t o l o g i c a l similarities o f c h o n d r o m y x o i d f i b r o m a to c h o n d r o b l a s t o m a w e r e p o i n t e d o u t by D a h l i n 7 in t h e early 1950s. B e c a u s e o f its rarity, c h o n d r o m y x o i d f i b r o m a s still cause d i a g n o s tic difficulties f o r p a t h o l o g i s t s . We h a d t h e o p p o r t u n i t y to review 278 e x a m p l e s o f c h o n d r o m y x o i d f i b r o m a c o l l e c t e d f r o m t h e Mayo Clinic files a n d o u r c o n s u l t a t i o n files. We t h o u g h t t h a t a s t u d y o f s u c h a l a r g e n u m b e r o f cases w o u l d h e l p us to b e t t e r u n d e r s t a n d t h e r o e n t g e n o g r a p h i c features, clinical p r e s e n t a t i o n , a n d h i s t o l o g i c a l s p e c t r u m o f this r a r e n e o p l a s m .
A total of 327 cases with a diagnosis of chondromyxoid fibroma were reviewed. Included were cases from the Mayo Clinic files (between 1905 and the end of 1993) and our consultation files (between 1950 and 1993). Fifteen of the Mayo Clinic cases were seen before the original description of chondromyxoid fibroma in 1948. 3 All of these tumors had been reclassified by Dr D.C. Dahlin as chondromyxoid fibroma before this study. The original diagnoses were three giant cell tumors, two chondrosarcomas, and one each as osteochondrosarcoma, cellular fibrochondromyxoma, fibromyxochondroma, chondromyxoma, fibrochondroma, chondroma, grade 2 osteosarcoma, fibromyxosarcoma, c h o n d r o m a with chondrosarcoma, and grade 1 myxosarcoma. Histological slides from 301 cases and roentgenograms from 192 cases were available for review. After review, 23 cases were excluded because they did not fulfill the diagnostic criteria for chondromyxoid fibroma. Of these 23 cases, 20 were reclassified: 10 as chondroblastoma, two as hemangioendothelioma, two as giant cell reaction, and one each as chondrosarcoma, enchondroma, soft tissue chondroma, periosteal chondroma, metaphyseal fibrous defect, and congenital fibromatosis. The remaining three cases were too atypical to be further classified. The series thus comprised 278 cases, 38 from the Mayo Clinic files and 240 from our consultation files. Seventy-two of these cases have been reported previously.4
RESULTS A g e a n d Sex T h e 278 tumors o c c u r r e d in 145 male and 132 female patients f r o m 6 to 87 years of age (average, 31.1
From the Section of Surgical Pathology, and the Departments of Orthopedics and Diagnostic Radiology, Mayo Clinic and Mayo Foundation, Rochester, MN. Accepted for publicationJuly 21, 1997. Address correspondence and reprint requests to Carrie Y. Inwards, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Copyright © 1998 by W.B. Saunders Company 0046-8177/98/2905-000358.00/0
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years). I n f o r m a t i o n a b o u t sex was n o t available f o r o n e p a t i e n t a n d a b o u t age f o r six p a t i e n t s . T h e p e a k i n c i d e n c e was in t h e s e c o n d a n d t h i r d d e c a d e s o f life. P a t i e n t s in t h e s e two d e c a d e s f o r m e d 50% o f t h e e n t i r e g r o u p . A p p r o x i m a t e l y 72% o f t h e p a t i e n t s w e r e y o u n g e r t h a n 40 years. P a t i e n t s with i n v o l v e m e n t o f t h e s m a l l b o n e s o f t h e h a n d s a n d feet, p a t i e n t s with r e c u r r e n t
CHONDROMYXOID FIBROMA OF BONE (Wu et al)
tumors, and patients with lesions containing atypical cells t e n d e d to be somewhat younger. The average ages in these groups were 25.6, 22.6, and 22.5 years, respectively. Patients with lesions of the phalanges of the fingers were even younger, with an average age of 17 years. Information about age, sex, and skeletal distribution is given in Figure 1.
bones. T h r e e lesions each (20%) were in the frontal bones, the sphenoid, and the mandible. Two tumors (13.3%) involved the occipital bone and one each (6.7%) the zygoma, the maxilla, the ethmoid, and the calvarium. R a d i o g r a p h i c Features
Radiographs or prints of radiographs were available for review in 192 cases. In one instance, no lesion could be identified on the radiographs; therefore, 191 tumors were evaluated. Fifty-three percent of the tumors involved the long bones, in which they were usually eccentric (Fig 2). Sixty-eight percent of these tumors involved only the metaphysis. Fourteen tumors involved the metaphysis and epiphysis, and six involved the metaphysis and diaphysis. One tumor involved all three segments. Thus, the metaphysis was involved with t u m o r in 88% of long bone tumors. Eleven tumors were purely diaphyseal, and one t u m o r was purely epiphyseal. In the flat bones, the pelvis was the most frequently involved region. Twenty-two tumors were located in the ilium, and half of these involved the crest area (Fig 3). Thirty-six tumors involved the bones of the hands and feet, and 28 of these were in the feet. The most frequently involved b o n e was the metatarsal (Fig 4). In the small tubular bones, the metaphysis was involved in 84% of the cases. O f interest, the epiphysis was involved in conjunction with the metaphyses in approximately 42% of the tumors. Four tumors involved the entire tubular bone. O f the 191 tumors evaluated, 87% had a purely lucent matrix. Twenty-five tumors showed some degree of mineralization, which varied from slight to marked. In most cases, the mineralization was in the form of clumps of calcification, as usually seen in cartilage tumors. However, in a few instances there appeared to be ossification in the tumor matrix. The cortex was thinned in approximately 90% of tumors, and the cortex was e x p a n d e d in approximately
Location
Information about location within the skeleton was available in 277 cases; 130 lesions (46.9%) involved the long bones, 84 (30.3%) the flat bones, 48 (17.3%) the bones of the hands and feet, and 15 (5.4%) the skull and facial bones. O f the 130 long bone lesions, 72 (55.4%) were located in the tibia, 25 (19.2%) in the femur, 14 (10.8%) in the fibula, eight (6.2%) in the humerus, seven (5.4%) in the ulna, and four (3.1%) in the radius. Involvement of the small bones of the feet was five times more c o m m o n than involvement of the bones of the hands, and the skeleton o f the lower limbs was involved 5.6 times as frequently as that o f the u p p e r limbs. Eighty-four lesions occurred in the flat bones. O f these, 38 (45.2%) were in the ilium (including five centered in the acetabulum), 22 (26.2%) in the ribs, 10 (11.9%) in the vertebrae, seven (8.3%) in the scapula, two (2.4%) each in the sacrum and the ischium, and one (1.2%) each in the clavicle, the sternum, and the pubis. Information about exact location in the vertebra was available for six tumors. O f these, three involved the body, two the posterior elements, and one both the body and the posterior elements. Forty-eight lesions involved the bones of the hands and feet. O f these, 17 (35.4%) involved the metatarsal bones, 14 (29.2%) the phalanges of the toes, nine (18.8%) the tarsal bones (five in os calcis and two cases each in the cuneiform and the navicular), five (10.4%) the phalanges of the finger, and three (6.3%) the metacarpals. Fifteen of the tumors involved the skull and facial
12-
Males Females Unknown
145 132 1
~ 0 ~L--3 1 - - ~ 2
10-
Total
278
22--~1
14~
7--~
-3
-5
FIGURE 1. Skeletal and age distribution for chondromyxoid fibroma of bone,
Cases
8-
(%)
6
14
4
f (1)**
2 0
y////y////I/.////V///JV///YJ///7////~///~///~///~//~//~//~//~//~///~///~
1 ' 2
' 3
' 4
' 5
' 6 ' 7 ' 8 ' 9 '
Age in decades *Bilateral involvement; **no information on specific location in the femur; ***no information on specific location in the tibia; another lesion has no record of which bone was involved (total of 278 lesions) 439
t
-- 20
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--7
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-7
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FIGURE 2. Chondromyxoid fibroma in the most common region, the proximal tibia, with a Iobulated lucent defect.
85% of cases. In approximately 50% of cases, a portion of the cortex was absent. Rarely, there was an area of cortical thickening associated with the tumor. Pathological fracture was present in only three instances. T h e margins of the t u m o r were sharp in 179 (94%) instances, and there was a sclerotic rim in 59% of the tumors. Fifty-eight p e r c e n t had a lobulated outline (Fig 5). In 9% of the tumors, the margin was considered poorly defined. Periosteal new b o n e f o r m a t i o n was present over the surface of the t u m o r in 16 cases. In 16 instances, there was periosteal new b o n e at the margins of the t u m o r ( C o d m a n ' s triangle). Thus, periosteal new b o n e f o r m a t i o n is unusual. In 65 cases, there was evidence of soft tissue
FIGURE 3, Computed tomographic image of an expanded lesion in the ilium with considerable matrix mineralization.
440
FIGURE 4. Metatarsal bone with fusiform expansion involving much of the bone. The lesion is surrounded by sclerotic bone and appears benign.
extension of the tumor. In a n o t h e r 29 cases, the films available did not allow for a j u d g m e n t to be made. Histopathological Features
As the n a m e indicates, c h o n d r o m y x o i d fibromas show a variety of histological features. T h e frequencies of the different histological characteristics studied are listed in Table 1. T h e classic histological feature of a c h o n d r o m y x o i d fibroma is stellate or spindle-shaped cells a r r a n g e d in lobules in a myxoid background. However, a lobulated growth pattern was seen in only 86.7% of the tumors. T h e tumors showed a " m a c r o l o b u lar" or a " m i c r o l o b u l a r " pattern. T h e lobules in the
FIGURE 5. Tl-weighted magnetic resonance image showing a Iobulated lesion in the distal metaphyseal region of the femur. There are cortical destruction and slight soft tissue extension.
CHONDROMYXOID FIBROMA OF BONE (Wu et al) TABLE | .
Histological Features of C h o n d r o m y x o i d Fibroma Percentage of Cases
Features Lobular pattern Macrolobular Microlobular Both Hyaline cartilage Giant cells Pleomorphic nuclei Mitoses Chondroblastoma areas Aneurysmal bone cyst areas Calcification Reactive new bone formation Permeation pattern Soft tissue extension Liquefaction change Hyalinization Necrosis Foam cells
Total
Long Flat Hands Skull and Bones Bones and Feet Facial Bones
46.4 16.9 23.4 18.7 56.8 18.3 11.2
50.8 16.2 23.8 17.7 61.5 20.8 10.8
41.7 17.9 25.0 15.5 48.8 10.7 9.5
54.2 8.3 20.8 31.3 66.7 31.3 12.5
13.3 46.7 20.0 6.7 33.3 0 20.0
8.3
9.2
7.1
10.4
0
8.6 35.3
11.5 31.5
10.7 36.9
0 33.3
0 66.7
15.1 9.0 30.6 38.8 2.9 11.9 2.2
18.5 7.7 30.8 35.4 1.5 13.1 2.3
11.9 11.9 25.0 44.0 7.1 10.7 3.6
12.5 6.3 43.8 35.4 0 12.5 0
13.3 13.3 20.0 53.3 0 6.7 0
m a c r o l o b u l a r pattern, seen u n d e r low power, had a hypocellular center and condensation of the nuclei toward the periphery, giving rise to hypercellularity. In the microlobular pattern, the lobulafion was m u c h less distinct, a n d several lobules fit into an area occupied by a lobule o f the m a c r o l o b u l a r pattern. O f the tumors, 46.4% showed a m a c r o l o b u l a r pattern (Fig 6) and 16.9% a microlobular pattern (Figs 7, 8, and 9). In 23.4% of the tumors, a mixture of both microlobules and macrolobules was seen. O f all tumors, 13.3% did not show a distinct lobular growth pattern. Approximately 40% of the tumors had a microlobular growth pattern, either alone or in combination. A microlobular
FIGURE 7. A microlobular pattern with more cellular fibroid tissue surrounding Iobules of various sizes and shapes.
FIGURE 6. Typical appearance of a macrolobule in chondromyxoid fibroma. Spindle-shaped or stellate tumor cells condense into a more cellular zone at the periphery of the Iobule.
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pattern was seen m o r e c o m m o n l y in lesions involving the skull and facial bones (approximately two thirds of the cases). A m a c r o l o b u l a r p a t t e r n was seen in approximately one third of the lesions in this location. T h e t u m o r cells within the lobules of chondromyxold fibroma were either spindle-shaped or stellate (Fig 10). T h e t u m o r cells s e e m e d e m b e d d e d in a myxoid matrix. T h e matrix a p p e a r e d slightly blue-stained. T h e neoplastic cells occasionally h a d a b u n d a n t pink cytoplasm, resulting in an epithelioid appearance. Chondromyxoid fibromas without a distinctive lobular pattern were identified because of similar cells in these tumors. The interlobular tissue was cellular and c o m p o s e d of oval or spindle-shaped cells. Benign multinucleated giant cells were present between the lobules in 56.8% of the lesions. In 8.3% of the lesions, cells with oval nuclei and longitudinal grooves simulated the a p p e a r a n c e of a c h o n d r o b l a s t o m a (Fig 11). These cells were located in the cellular, interlobular areas. Areas of well-developed hyaline cartilage were present in 18.7% of the tumors (Fig 12). Such hyaline cartilage was present m o r e c o m m o n l y in lesions involving the small bones of the hands and feet. Calcification was e n c o u n t e r e d in 35.3% of the tumors. It was either granular or in the f o r m of chunks within the lobules (Fig 13). This kind of calcification was a c o m m o n feature in lesions involving the skull and facial b o n e s (66.7%) and lesions involving the ribs (45.5%). Only 13.5% of tumors in children y o u n g e r
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were usually sparse (one to three per 10 high-power fields). Atypical mitotic figures were not found. The myxoid matrix in chondromyxoid fibroma is usually solid, pale blue, and without the more extensive liquefactive changes associated with the myxoid change in chondrosarcomas. However, focal liquefactive change was seen in 38.8% of the cases. Cyst formation (6.1%), necrosis (11.9%), foam cells (2.2%), and areas of hyalinization (2.9%) were unusual findings. Lesions of the skull and facial bones were more likely to show liquefactive change (53.3%) and cyst formation (13.3%). T u m o r cells with bizarre cytological features were noted in 18.3% of the lesions (Fig 16). The nuclei were enlarged and hyperchromatic and showed pleomorphism. However, there was no change in the nucleocytoplasmic ratio, because the cytoplasmic content also was increased. T h e nuclei commonly showed vacuolization resembling that in bizarre nuclei of other benign neoplasms. Lesions involving the small bones of the hands and feet had a higher percentage of atypical cells. Nine tumors (3.2%) had an atypical appearance for chondromyxoid fibroma. The patients were younger (average age, 26.7 years), and the tumors commonly showed calcification. T h e diagnosis was based primarily on recognition of the typical cytological features of the t u m o r cells. The lobulation was less distinct, and the tumors t e n d e d to show heavy hyalinization (Fig 17). Only one contained hyaline cartilage. FIGURE 8. broma,
Hypocel[ular microlobules in chondromyxoid fi-
than 15 years showed calcification. Reactive new bone formation was present in 15.1% of the lesions. These bony trabeculae were woven and appeared either in the interlobular areas or at the p e r i p h e r y of the tumor. Bone formation was never p r o m i n e n t e n o u g h to suggest a bone-forming neoplasm. Secondary aneurysmal b o n e cyst occurred in only 8.6% of the tumors. Permeation of trabecular bone (9%) (Fig 14), permeation of the cortex (0.4%), and soft tissue extension (30.6%) were some u n e x p e c t e d findings in this benign neoplasm. We are not aware of a r e c u r r e n t tumor in the 25 patients who had permeation. This includes three patients treated at the Mayo Clinic who had follow-up o f 14, 27, and 268 months. Cortical permeation was seen in only one tumor. Soft tissue extension was m u c h more common, and this seemed to be caused by a pushing margin rather than true permeation (Fig 15). Permeation of bone was more c o m m o n in lesions of the skull and facial bones (13.3%) than in the lesions involving the small bones of the hands and feet (6.3%). Conversely, lesions o f the hands and feet showed more tendency for soft tissue extension (43.8% v 20.0%). Soft tissue extension was also a c o m m o n feature in lesions involving the ribs (40.9%). In one of the rib tumors, an a d h e r e n t segment of the lung had to be resected. Mitotic figures, usually present in more cellular interlobular areas, occurred in 11.2% of tumors. They 442
FIGURE 9. A lessweLl-defined microlobular pattern characterized by myxoid [obules fused with neighboring Iobules.
CHONDROMYXOID FIBROMA OF BONE (Wu et al)
FIGURE 10. High-power appearance of chondromyxoid fibroma showing stellate cells with round-to-oval nuclei and cytoplasmic extensions.
FIGURE 11. An area resembling chondroblastoma in an otherwise typical chondromyxoid fibroma arising in the metaphysis of the tibia.
c o m a developed in the proximal tibia 6 years after t r e a t m e n t of a c h o n d r o m y x o i d fibroma, which included radiation. This patient also died of disease.
Treatment and Follow-Up
No a t t e m p t was m a d e to get information a b o u t t r e a t m e n t in consultation cases. Most patients had b e e n treated with curettage or excision. We know o f 32 patients who had local recurrence. The t u m o r r e c u r r e d once in 23 patients and twice in seven patients. O n e patient had three recurrences, and one had five. T h e interval between first diagnosis and first r e c u r r e n c e r a n g e d f r o m 5 m o n t h s to 10 years (average, 38.4 months). T h e first r e c u r r e n c e was n o t e d within 1 year of t r e a t m e n t in 37.9% of the patients. T h e average age of the patients with r e c u r r e n c e was 22.6 years, and 40.6% of the patients were y o u n g e r than 15 years. T h e average age of the Mayo Clinic patients with r e c u r r e n t tumors was 17.6 years. T h e r e c u r r e n c e rate in the Mayo Clinic patients was 26.3%. Only 10% of the tumors in these patients had mitotic activity. However, 28.1% of all r e c u r r e n t lesions a n d 30% of lesions in Mayo Clinic patients with r e c u r r e n c e showed soft tissue t u m o r nodules. Malignancy arising in c h o n d r o m y x o i d fibroma was i d e n t i f e d in two lesions. O n e patient, a 45-year-old man, had a grade 4 malignant fibrous histiocytoma 5 m o n t h s after diagnosis of c h o n d r o m y x o i d fibroma of the pubis. T h e patient died with metastasis; at autopsy, b o t h c h o n d r o m y x o i d fibroma and malignant fibrous histiocytoma were present in the pubic bone. In the second patient, a 58-year-old woman, a grade 3 fibrosar-
DISCUSSION C h o n d r o m y x o i d fibromas are extremely unusual neoplasms of bone; approximately 400 cases are re-
FIGURE12. Hyaline cartilage in a macrolobule bordered by typical fibromatoid cells.
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FIGURE 13. Irregularly shaped plaquelike calcification in loose myxoid stroma.
ported in the literature. Until the end of 1993, only 45 examples of chondromyxoid fibroma were in the Mayo Clinic files of a total of 11,087 b o n e tumors. 1 In the same period, there were 119 examples of chondroblastoma in the Mayo Clinic files. The relative rarity of this lesion explains the diagnostic difficulties still encountered. We were able to review a fairly large series of cases of chondromyxoid fibroma from the Mayo Clinic and consultation files. This kind of retrospective study has limitations. Obviously, information about treatment and follow-up are incomplete in consultation cases. Hence, recommendations about treatment cannot be made on the basis of such a study. Nevertheless, we thought that a study of reentgenograms and histological material from a large series would be beneficial. We h o p e d to learn the spectrum of roentgenographic and histological features in chondromyxoid fibroma. The age and sex distributions of the patients in this series are very similar to those reported in the litera-
FIGURE 15. Soft tissue extension usually has a Iobular pushing border without a desmoplastic reaction. The patient was doing well 2 years after surgery.
ture. 4,8q5 In the literature, the ages of patients with chondromyxoid fibroma have ranged from 3 to 70 years. In the current series, the age range was 6 to 87 years, not too dissimilar to what has been reported. The only unusual finding was that patients with involvement of the phalanges of the fingers t e n d e d to be somewhat younger. The proximal tibia is the most c o m m o n site of involvement in all large r e p o r t e d series. This site was followed by the ilium, the ribs, the distal femur, the metatarsals, and the lower tibia. In any large consultation series, unusual locations may dominate. Nevertheless, the relatively c o m m o n involvement of the metatarsals is noteworthy. T h e metatarsals were relatively frequently involved in the Mayo Clinic series also, in sharp contrast to the rarity of involvement of the metacarpals. Within a long bone, chondromyxoid fi-
FIGURE 16. Bizarre tumor cells containing large, irregularly shaped, hyperchromatic nuclei with degenerative intranuclear vacuoles surrounded by abundant cytoplasm. The patient had no recurrence 13 months after surgery.
FIGURE 14. Chondromyxoid fibroma entrapping fragments of trabecular bone.
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CHONDROMYXOID FIBROMA OF BONE (Wu et aJ)
FIGURE | 7. Hyalinized matrix in an otherwise typical chondromyxoid fibroma, The tumors cells are compressed and a p p e a r pyknotic.
b r o m a classically involves the metaphysis. It may abut the epiphyseal plate. Two lesions involved the diaphysis of the tibia. Zillmer a n d D o r f m a n n also described an example involving the diaphysis. T h e classic histological feature of c h o n d r o m y x o i d fibroma is lobularity with condensation of the neoplastic cells at the p e r i p h e r y of the lobules. T h e lobules are typically easily seen on low power, especially because of the condensation of the nuclei at the p e r i p h e r y and the giant cells and m o n o n u c l e a r cells in the m o r e cellular areas. In this study, however, this m a c r o l o b u l a r pattern was seen in only 70% o f the cases. A lobular pattern, m u c h less distinct than that classically described, which could be t e r m e d a microlobular pattern, was seen in a large percentage of cases. Frequently, the tumors showed areas of m a c r o l o b u l a r pattern and o t h e r areas of microlobular pattern. Approximately I 7 % of the tumors showed microlobular growth pattern alone. Just over 13% of the tumors showed no lobular pattern whatsoever. T h e diagnosis in these cases was m a d e with the c o m b i n a t i o n of r o e n t g e n o g r a p h i c features a n d identification of the m o n o n u c l e a r cells quite typically seen in c h o n d r o m y x o i d fibroma. T h e neoplastic ceils in c h o n d r o m y x o i d fibroma are either spindle-shaped or stellate, as described in the literature. F e c h n e r and Mills 14also highlighted the pink staining of the cytoplasm of some of these cells. Although the n a m e " c h o n d r o m y x o i d f i b r o m a " suggests that there is c h o n d r o i d differentiation in the neoplasm, it is unusual to find hyaline cartilage of the type seen in a c h o n d r o m a or a chondrosarcoma. However, it occurred focally in approximately 19 % of the cases. In an earlier study f r o m the Mayo Clinic, Rahimi et al4 p o i n t e d out that microscopic foci of calcification are present in m o r e than one fourth of the cases of c h o n d r o m y x o i d fibroma. T h e incidence in the literature has varied considerably. Zillmer and D o r f m a n n r e p o r t e d a 14% incidence, and Gherlinzoni et a113 f o u n d calcification in 11%, whereas Schajowicz and Gallardo a5 m e n t i o n e d that it was seen in only 1 of 44
445
cases. This finding is i m p o r t a n t because, typically, roentg e n o g r a m s in c h o n d r o m y x o i d fibroma are purely lucent without mineralization. T h e calcification seen microscopically probably is not sufficient to be recognized on roentgenograms. C h o n d r o m y x o i d fibromas occurring on the surface of b o n e show considerable calcification on roentgenograms. These cases are rep o r t e d separately and have not b e e n discussed in this report. 16 Reactive new b o n e f o r m a t i o n was f o u n d in 7% of the cases described by Rahimi et al. 4 However, Zillmer and D o r f m a n 11 n o t e d no reactive new b o n e f o r m a t i o n in their series of cases. In this series, reactive new b o n e f o r m a t i o n was seen in 15% of the cases. This new b o n e f o r m a t i o n was present in the m o r e cellular areas between lobules of the neoplasm. Mitotic figures are considered to be rare to absent in c h o n d r o m y x o i d fibroma, s,9,~1,14 It has even b e e n suggested that lack of mitoses should be a useful criterion in differentiating c h o n d r o m y x o i d fibroma f r o m chondrosarcoma. T h e c u r r e n t study indicates that mitotic figures may be present in m o r e than 10% o f cases of c h o n d r o m y x o i d fibroma. They are n o t abundant (one to three per 10 high-power fields) and are usually seen in the m o r e cellular areas at the p e r i p h e r y of lobules and the interlobular tissue. Atypical mitotic figures are not seen in c h o n d r o m y x o i d fibroma. Therefore, mitosis cannot be used as a criterion to separate c h o n d r o m y x o i d fibroma f r o m chondrosarcoma. C h o n d r o m y x o i d f i b r o m a s classically are welld e m a r c a t e d lesions. Indeed, the edges a p p e a r lobulated a n d pull away f r o m the s u r r o u n d i n g bone, emphasizing lack of p e r m e a t i o n into s u r r o u n d i n g tissues. In this study, however, p e r m e a t i o n was seen in 9% of the cases. P e r m e a t i o n took the f o r m of t u m o r filling up m a r r o w cavity and e n t r a p p i n g preexisting b o n y trabeculae. This feature is n o t generally recognized with chondromyxoid fibromas. More surprisingly, this p e r m e a t i o n did not p o r t e n d r e c u r r e n c e of the lesion. We are not aware of a r e c u r r e n t t u m o r in the 25 cases showing p e r m e ation. This g r o u p includes three patients who had b e e n treated at the Mayo Clinic and for w h o m we have follow-up information for 14, 27, and 268 months. P e r m e a t i o n is m u c h m o r e c o m m o n in the small or flat bones, such as the skull, the jaw bones, and the small bones of the hands and feet. This occurrence is not surprising. Many o t h e r benign lesions show a p p a r e n t p e r m e a t i o n when involving such bones. Care has to be taken n o t to diagnose malignant disease on the basis of this criterion, especially when small a n d flat bones are involved. Soft tissue extension was seen in m o r e than 30% of the tumors. This soft tissue extension was m o r e likely to be expansion of the lesion into soft tissue rather than true permeation. This, too, was m o r e c o m m o n in the small bones of the hands and feet and the ribs. Indeed, in one rib lesion, the t u m o r was a d h e r e n t to lung. Cells in chondromyxoid fibroma can show pleomorphisrn. T h e t e r m " p l e o m o r p h i s m " is probably better than "cytological atypia." T h e nuclei tend to be large and bizarre, a p p e a r i n g without alteration in the nucleocytoplasmic ratio. T h e details of the nuclei are usually
HUMAN PATHOLOGY
Volume 29, No. 5 (May 1998)
not crisp, and they may a p p e a r vacuolated. This kind of bizarre a p p e a r a n c e is similar to that seen in some neoplasms, such as n e u r i l e m m o m a , and after radiation. Although this may lead to a mistaken diagnosis of malignant disease in a limited sample, attention to the overall picture should prevent this error. T h e differential diagnosis involves chondrosarcoma, chondroblastoma, and fibrous dysplasia. Chondrosarcomas with a lobulated growth p a t t e r n and spindling of the nuclei are generally easily identifiable as malignant. T h e r o e n t g e n o g r a p h i c features in these tumors are almost invariably those of an aggressive tumor. C h o n d r o m y x o i d fibromas are almost invariably associated with a benign r o e n t g e n o g r a p h i c appearance. Alt h o u g h lobulated c h o n d r o s a r c o m a s have condensation of nuclei at the p e r i p h e r y of the lobules, the center of the lobules is also hypercellular c o m p a r e d with the a p p e a r a n c e in c h o n d r o m y x o i d fibroma. Fibrous dysplasia can a p p e a r quite myxoid. T h e cells in fibrous dysplasia lack the epithelioid a p p e a r a n c e seen in chondromyxoid fibromas. If there is lobulation, fibrous dysplasia should be ruled out. If there is no lobulation, as may h a p p e n rarely with c h o n d r o m y x o i d fibroma, r o e n t g e n o g r a p h i c features may be of p a r a m o u n t importance. Chondroblastomas and c h o n d r o m y x o i d fibromas share m a n y similarities. Indeed, some tumors show features of both. Fortunately, the distinction is not of clinical significance. In these instances, we tend to use the t e r m " c h o n d r o m y x o i d f i b r o m a " if the lesion is metaphyseal and " c h o n d r o b l a s t o m a " if the lesion is epiphyseal. Because of the nature of this study, it is impossible to m a k e any statement a b o u t t r e a t m e n t and prognosis. We are not aware of any metastasis f r o m chondromyxoid fibroma. In this series, there are two well-docum e n t e d examples of malignant transformation, one with and one without radiation. We know of local r e c u r r e n t t u m o r in at least 32 patients. O n e patient h a d up to five recurrences. With the r e c u r r e n t tumor, soft tissue implantation may occur. 17-2° N o t included in this series are two most unusual tumors that a p p e a r to be p r i m a r y in soft tissues. O n e lesion involved the soft palate, f o r m i n g a 3.4-cm nodule. R o e n t g e n o g r a m s did not show any involvement of bone. T h e second lesion, in a 35-year-old woman, was an irregularly surfaced neoplasm, 2.5 × 2.5 × 1.0 cm, s u r r o u n d e d completely by fat and located at the anterolateral aspect of the anal sphincter between the anus
446
and the vagina. In this case, also, there was no connection between the n e o p l a s m and any bone.
REFERENCES 1. Unni KK: Dahlin's Bone Tumors: General Aspects and Data on 11,087 Cases (ed 5). Philadelphia, PA, Lippincott-Raven, 1996 2. Schajowicz F, Ackerman LV, Sissons HA: Histological typing of bone tumours. International Histological Classification of Tumours, No. 6. Geneva, Switzerland, World Health Organization, 1972 3. Jaffe HL, Lichtenstein L: Chondromyxoid fibroma of bone: Distinctive benign tumor likely to be mistaken especially for chondrosarcoma. Arch Patho145:541-551, 1948 4. Rahimi A, Beabout JW, Ivins JC, et ah Chondromyxoid fibroma: A clinicopathologic study of 76 cases. Cancer 30:726-736,1972 5. Iwata S, Coley BL: Report of six cases of chondromyxoid fibroma of bone. Surg Gynecol Obstet 107:571-576, 1958 6. Sehayik S, Rosman MA: Malignant degeneration ofa chondromyxoid fibroma in a child. CanJ Surg 18:354-357, 1975 7. Dahlin DC: Chondromyxoid fibroma of bone, with emphasis on its morphological relationship to benign chondroblastoma. Cancer 9:195-203, 1956 8. Mirra JM, Picci P, Gold RH: Bone Tumors: Clinical, Radiologic, and Pathologic Correlations. Philadelphia, PA, Lea & Febiger, 1989 9. Huvos AG: Bone Tumors: Diagnosis, Treatment, and Prognosis (ed 2). Philadelphia, PA, Saunders, 1991 10. Campanacci M: Bone and Soft Tissue Tumors. NewYork, NY, Springer-Verlag, 1990 11. Zillmer DA, Dorfman HD: Chondromyxoid fibroma of bone: Thirty-six cases with clinicopathologic correlation. HUM PATHOL 20:952-964, 1989 12. Kreicbergs A, Lonnquist PA, Willems J: Chondromyxoid fibroma: A review of the literature and a report on our own experience. Acta Pathol Microbiol Immunol Scand [A] 93:189-197, 1985 13. Gherlinzoni F, Rock M, Picci P: Chondromyxoid fibroma: The experience at the Istituto Ortopedico Rizzoli. J Bone Joint Surg Am 65:198-204, 1983 14. Fechner RE, Mills SE: Atlas of Tumor Pathology, Tumors of the Bones and Joints. Third series, Fascicle 8. Washington, DC, Armed Forces Institute of Pathology, 1993 15. Schajowicz E Gallardo H: Chondromyxoid fibroma (fibromyxoid chondroma) of bone: A clinico-pathological study of thirty-two cases.J Bone Joint Surg Br 53:198-216, 1971 16. Robinson LH, Unni KK, O'Laughlin S, et al: Surface chondromyxoid fibroma of bone. Mod Pathol 7:10A, 1994 (abstr) 17. Kyriakos M: Soft tissue implantation of chrondromyxoid fibroma. AmJ Surg Pathol 3:363-372, 1979 18. Mikulowski P, Ostberg G: Recurrent chondromyxoid fibroma. Acta Orthop Scand 42:385-390, 1971 19. HeydemannJ, Gillespie R, Mancer F,2 Soft tissue recurrence of chondromyxoid fibroma.J Pediatr Orthop 5:725-727, 1985 20. Troncoso A, Ro JY, Edeiken J, et al: Case report 798: Recurrent chondromyxoid fibroma in connective tissue of leg. Skel Radio122:445-448, 1993
crolobular). The tumor cells were spindle-shaped or stellate and arranged in a myxoid matrix. Calcification was seen in more than one third of the cases but was rarely prominent. Hyaline cartilage and chondroblastoma-like areas were not uncommon. Approximately 18 % of tumors showed bizarre nuclei. Permeation of bony trabeculae was uncommon. Treatment was conservative surgical removal; approximately one fourth of the patients had recurrence. HUM PATHOL 29:438-446. Copyright © 1998 by W.B. Sannders Company Key words: chondromyxoid fibroma, chondroblastoma, fibrous dysplasia, chondrosarcoma.
C h o n d r o m y x o i d fibroma is a rare, benign t u m o r of b o n e that represents fewer than 1% of all benign a n d malignant tumors of bone. 1 T h e World Health Organization defines it as "a benign t u m o r characterized by lobulated areas of spindle-shaped or stellate cells with a b u n d a n t myxoid or c h o n d r o i d intercellular material separated by zones of m o r e cellular tissue rich in
MATERIALS AND METHODS
s p i n d l e - s h a p e d o r r o u n d cells with a v a r y i n g n u m b e r o f m u l f i n u c l e a t e d g i a n t cells o f d i f f e r e n t sizes. ''2 L a r g e p l e o m o r p h i c cells m a y b e p r e s e n t a n d c a n r e s u l t in c o n f u s i o n with c h o n d r o s a r c o m a . C h o n d r o m y x o i d f i b r o m a was first d e s c r i b e d by Jaffe a n d L i c h t e n s t e i n 3 in 1948. I n t h e i r files, t h e a u t h o r s s e p a r a t e d this n e o p l a s m f r o m c h o n d r o s a r c o m a , r e a l i z i n g t h a t t h e clinical b e h a v i o r was t h a t o f a b e n i g n process. A l t h o u g h s o m e cases o f m a l i g n a n t t r a n s f o r m a t i o n have b e e n r e p o r t e d in t h e l i t e r a t u r e , 4-6 t h e clinical b e h a v i o r is t h a t o f a b e n i g n n e o p l a s m , a n d it s h o u l d t h e r e f o r e b e d i f f e r e n t i a t e d f r o m m a l i g n a n t tumors, especially c h o n d r o s a r c o m a . 1 T h e h i s t o l o g i c a l similarities o f c h o n d r o m y x o i d f i b r o m a to c h o n d r o b l a s t o m a w e r e p o i n t e d o u t by D a h l i n 7 in t h e early 1950s. B e c a u s e o f its rarity, c h o n d r o m y x o i d f i b r o m a s still cause d i a g n o s tic difficulties f o r p a t h o l o g i s t s . We h a d t h e o p p o r t u n i t y to review 278 e x a m p l e s o f c h o n d r o m y x o i d f i b r o m a c o l l e c t e d f r o m t h e Mayo Clinic files a n d o u r c o n s u l t a t i o n files. We t h o u g h t t h a t a s t u d y o f s u c h a l a r g e n u m b e r o f cases w o u l d h e l p us to b e t t e r u n d e r s t a n d t h e r o e n t g e n o g r a p h i c features, clinical p r e s e n t a t i o n , a n d h i s t o l o g i c a l s p e c t r u m o f this r a r e n e o p l a s m .
A total of 327 cases with a diagnosis of chondromyxoid fibroma were reviewed. Included were cases from the Mayo Clinic files (between 1905 and the end of 1993) and our consultation files (between 1950 and 1993). Fifteen of the Mayo Clinic cases were seen before the original description of chondromyxoid fibroma in 1948. 3 All of these tumors had been reclassified by Dr D.C. Dahlin as chondromyxoid fibroma before this study. The original diagnoses were three giant cell tumors, two chondrosarcomas, and one each as osteochondrosarcoma, cellular fibrochondromyxoma, fibromyxochondroma, chondromyxoma, fibrochondroma, chondroma, grade 2 osteosarcoma, fibromyxosarcoma, c h o n d r o m a with chondrosarcoma, and grade 1 myxosarcoma. Histological slides from 301 cases and roentgenograms from 192 cases were available for review. After review, 23 cases were excluded because they did not fulfill the diagnostic criteria for chondromyxoid fibroma. Of these 23 cases, 20 were reclassified: 10 as chondroblastoma, two as hemangioendothelioma, two as giant cell reaction, and one each as chondrosarcoma, enchondroma, soft tissue chondroma, periosteal chondroma, metaphyseal fibrous defect, and congenital fibromatosis. The remaining three cases were too atypical to be further classified. The series thus comprised 278 cases, 38 from the Mayo Clinic files and 240 from our consultation files. Seventy-two of these cases have been reported previously.4
RESULTS A g e a n d Sex T h e 278 tumors o c c u r r e d in 145 male and 132 female patients f r o m 6 to 87 years of age (average, 31.1
From the Section of Surgical Pathology, and the Departments of Orthopedics and Diagnostic Radiology, Mayo Clinic and Mayo Foundation, Rochester, MN. Accepted for publicationJuly 21, 1997. Address correspondence and reprint requests to Carrie Y. Inwards, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Copyright © 1998 by W.B. Saunders Company 0046-8177/98/2905-000358.00/0
438
years). I n f o r m a t i o n a b o u t sex was n o t available f o r o n e p a t i e n t a n d a b o u t age f o r six p a t i e n t s . T h e p e a k i n c i d e n c e was in t h e s e c o n d a n d t h i r d d e c a d e s o f life. P a t i e n t s in t h e s e two d e c a d e s f o r m e d 50% o f t h e e n t i r e g r o u p . A p p r o x i m a t e l y 72% o f t h e p a t i e n t s w e r e y o u n g e r t h a n 40 years. P a t i e n t s with i n v o l v e m e n t o f t h e s m a l l b o n e s o f t h e h a n d s a n d feet, p a t i e n t s with r e c u r r e n t
CHONDROMYXOID FIBROMA OF BONE (Wu et al)
tumors, and patients with lesions containing atypical cells t e n d e d to be somewhat younger. The average ages in these groups were 25.6, 22.6, and 22.5 years, respectively. Patients with lesions of the phalanges of the fingers were even younger, with an average age of 17 years. Information about age, sex, and skeletal distribution is given in Figure 1.
bones. T h r e e lesions each (20%) were in the frontal bones, the sphenoid, and the mandible. Two tumors (13.3%) involved the occipital bone and one each (6.7%) the zygoma, the maxilla, the ethmoid, and the calvarium. R a d i o g r a p h i c Features
Radiographs or prints of radiographs were available for review in 192 cases. In one instance, no lesion could be identified on the radiographs; therefore, 191 tumors were evaluated. Fifty-three percent of the tumors involved the long bones, in which they were usually eccentric (Fig 2). Sixty-eight percent of these tumors involved only the metaphysis. Fourteen tumors involved the metaphysis and epiphysis, and six involved the metaphysis and diaphysis. One tumor involved all three segments. Thus, the metaphysis was involved with t u m o r in 88% of long bone tumors. Eleven tumors were purely diaphyseal, and one t u m o r was purely epiphyseal. In the flat bones, the pelvis was the most frequently involved region. Twenty-two tumors were located in the ilium, and half of these involved the crest area (Fig 3). Thirty-six tumors involved the bones of the hands and feet, and 28 of these were in the feet. The most frequently involved b o n e was the metatarsal (Fig 4). In the small tubular bones, the metaphysis was involved in 84% of the cases. O f interest, the epiphysis was involved in conjunction with the metaphyses in approximately 42% of the tumors. Four tumors involved the entire tubular bone. O f the 191 tumors evaluated, 87% had a purely lucent matrix. Twenty-five tumors showed some degree of mineralization, which varied from slight to marked. In most cases, the mineralization was in the form of clumps of calcification, as usually seen in cartilage tumors. However, in a few instances there appeared to be ossification in the tumor matrix. The cortex was thinned in approximately 90% of tumors, and the cortex was e x p a n d e d in approximately
Location
Information about location within the skeleton was available in 277 cases; 130 lesions (46.9%) involved the long bones, 84 (30.3%) the flat bones, 48 (17.3%) the bones of the hands and feet, and 15 (5.4%) the skull and facial bones. O f the 130 long bone lesions, 72 (55.4%) were located in the tibia, 25 (19.2%) in the femur, 14 (10.8%) in the fibula, eight (6.2%) in the humerus, seven (5.4%) in the ulna, and four (3.1%) in the radius. Involvement of the small bones of the feet was five times more c o m m o n than involvement of the bones of the hands, and the skeleton o f the lower limbs was involved 5.6 times as frequently as that o f the u p p e r limbs. Eighty-four lesions occurred in the flat bones. O f these, 38 (45.2%) were in the ilium (including five centered in the acetabulum), 22 (26.2%) in the ribs, 10 (11.9%) in the vertebrae, seven (8.3%) in the scapula, two (2.4%) each in the sacrum and the ischium, and one (1.2%) each in the clavicle, the sternum, and the pubis. Information about exact location in the vertebra was available for six tumors. O f these, three involved the body, two the posterior elements, and one both the body and the posterior elements. Forty-eight lesions involved the bones of the hands and feet. O f these, 17 (35.4%) involved the metatarsal bones, 14 (29.2%) the phalanges of the toes, nine (18.8%) the tarsal bones (five in os calcis and two cases each in the cuneiform and the navicular), five (10.4%) the phalanges of the finger, and three (6.3%) the metacarpals. Fifteen of the tumors involved the skull and facial
12-
Males Females Unknown
145 132 1
~ 0 ~L--3 1 - - ~ 2
10-
Total
278
22--~1
14~
7--~
-3
-5
FIGURE 1. Skeletal and age distribution for chondromyxoid fibroma of bone,
Cases
8-
(%)
6
14
4
f (1)**
2 0
y////y////I/.////V///JV///YJ///7////~///~///~///~//~//~//~//~//~///~///~
1 ' 2
' 3
' 4
' 5
' 6 ' 7 ' 8 ' 9 '
Age in decades *Bilateral involvement; **no information on specific location in the femur; ***no information on specific location in the tibia; another lesion has no record of which bone was involved (total of 278 lesions) 439
t
-- 20
[~**-~*
--7
2-14-..
-7
HUMAN PATHOLOGY
Volume 29, No. 5 (May 1998)
FIGURE 2. Chondromyxoid fibroma in the most common region, the proximal tibia, with a Iobulated lucent defect.
85% of cases. In approximately 50% of cases, a portion of the cortex was absent. Rarely, there was an area of cortical thickening associated with the tumor. Pathological fracture was present in only three instances. T h e margins of the t u m o r were sharp in 179 (94%) instances, and there was a sclerotic rim in 59% of the tumors. Fifty-eight p e r c e n t had a lobulated outline (Fig 5). In 9% of the tumors, the margin was considered poorly defined. Periosteal new b o n e f o r m a t i o n was present over the surface of the t u m o r in 16 cases. In 16 instances, there was periosteal new b o n e at the margins of the t u m o r ( C o d m a n ' s triangle). Thus, periosteal new b o n e f o r m a t i o n is unusual. In 65 cases, there was evidence of soft tissue
FIGURE 3, Computed tomographic image of an expanded lesion in the ilium with considerable matrix mineralization.
440
FIGURE 4. Metatarsal bone with fusiform expansion involving much of the bone. The lesion is surrounded by sclerotic bone and appears benign.
extension of the tumor. In a n o t h e r 29 cases, the films available did not allow for a j u d g m e n t to be made. Histopathological Features
As the n a m e indicates, c h o n d r o m y x o i d fibromas show a variety of histological features. T h e frequencies of the different histological characteristics studied are listed in Table 1. T h e classic histological feature of a c h o n d r o m y x o i d fibroma is stellate or spindle-shaped cells a r r a n g e d in lobules in a myxoid background. However, a lobulated growth pattern was seen in only 86.7% of the tumors. T h e tumors showed a " m a c r o l o b u lar" or a " m i c r o l o b u l a r " pattern. T h e lobules in the
FIGURE 5. Tl-weighted magnetic resonance image showing a Iobulated lesion in the distal metaphyseal region of the femur. There are cortical destruction and slight soft tissue extension.
CHONDROMYXOID FIBROMA OF BONE (Wu et al) TABLE | .
Histological Features of C h o n d r o m y x o i d Fibroma Percentage of Cases
Features Lobular pattern Macrolobular Microlobular Both Hyaline cartilage Giant cells Pleomorphic nuclei Mitoses Chondroblastoma areas Aneurysmal bone cyst areas Calcification Reactive new bone formation Permeation pattern Soft tissue extension Liquefaction change Hyalinization Necrosis Foam cells
Total
Long Flat Hands Skull and Bones Bones and Feet Facial Bones
46.4 16.9 23.4 18.7 56.8 18.3 11.2
50.8 16.2 23.8 17.7 61.5 20.8 10.8
41.7 17.9 25.0 15.5 48.8 10.7 9.5
54.2 8.3 20.8 31.3 66.7 31.3 12.5
13.3 46.7 20.0 6.7 33.3 0 20.0
8.3
9.2
7.1
10.4
0
8.6 35.3
11.5 31.5
10.7 36.9
0 33.3
0 66.7
15.1 9.0 30.6 38.8 2.9 11.9 2.2
18.5 7.7 30.8 35.4 1.5 13.1 2.3
11.9 11.9 25.0 44.0 7.1 10.7 3.6
12.5 6.3 43.8 35.4 0 12.5 0
13.3 13.3 20.0 53.3 0 6.7 0
m a c r o l o b u l a r pattern, seen u n d e r low power, had a hypocellular center and condensation of the nuclei toward the periphery, giving rise to hypercellularity. In the microlobular pattern, the lobulafion was m u c h less distinct, a n d several lobules fit into an area occupied by a lobule o f the m a c r o l o b u l a r pattern. O f the tumors, 46.4% showed a m a c r o l o b u l a r pattern (Fig 6) and 16.9% a microlobular pattern (Figs 7, 8, and 9). In 23.4% of the tumors, a mixture of both microlobules and macrolobules was seen. O f all tumors, 13.3% did not show a distinct lobular growth pattern. Approximately 40% of the tumors had a microlobular growth pattern, either alone or in combination. A microlobular
FIGURE 7. A microlobular pattern with more cellular fibroid tissue surrounding Iobules of various sizes and shapes.
FIGURE 6. Typical appearance of a macrolobule in chondromyxoid fibroma. Spindle-shaped or stellate tumor cells condense into a more cellular zone at the periphery of the Iobule.
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pattern was seen m o r e c o m m o n l y in lesions involving the skull and facial bones (approximately two thirds of the cases). A m a c r o l o b u l a r p a t t e r n was seen in approximately one third of the lesions in this location. T h e t u m o r cells within the lobules of chondromyxold fibroma were either spindle-shaped or stellate (Fig 10). T h e t u m o r cells s e e m e d e m b e d d e d in a myxoid matrix. T h e matrix a p p e a r e d slightly blue-stained. T h e neoplastic cells occasionally h a d a b u n d a n t pink cytoplasm, resulting in an epithelioid appearance. Chondromyxoid fibromas without a distinctive lobular pattern were identified because of similar cells in these tumors. The interlobular tissue was cellular and c o m p o s e d of oval or spindle-shaped cells. Benign multinucleated giant cells were present between the lobules in 56.8% of the lesions. In 8.3% of the lesions, cells with oval nuclei and longitudinal grooves simulated the a p p e a r a n c e of a c h o n d r o b l a s t o m a (Fig 11). These cells were located in the cellular, interlobular areas. Areas of well-developed hyaline cartilage were present in 18.7% of the tumors (Fig 12). Such hyaline cartilage was present m o r e c o m m o n l y in lesions involving the small bones of the hands and feet. Calcification was e n c o u n t e r e d in 35.3% of the tumors. It was either granular or in the f o r m of chunks within the lobules (Fig 13). This kind of calcification was a c o m m o n feature in lesions involving the skull and facial b o n e s (66.7%) and lesions involving the ribs (45.5%). Only 13.5% of tumors in children y o u n g e r
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were usually sparse (one to three per 10 high-power fields). Atypical mitotic figures were not found. The myxoid matrix in chondromyxoid fibroma is usually solid, pale blue, and without the more extensive liquefactive changes associated with the myxoid change in chondrosarcomas. However, focal liquefactive change was seen in 38.8% of the cases. Cyst formation (6.1%), necrosis (11.9%), foam cells (2.2%), and areas of hyalinization (2.9%) were unusual findings. Lesions of the skull and facial bones were more likely to show liquefactive change (53.3%) and cyst formation (13.3%). T u m o r cells with bizarre cytological features were noted in 18.3% of the lesions (Fig 16). The nuclei were enlarged and hyperchromatic and showed pleomorphism. However, there was no change in the nucleocytoplasmic ratio, because the cytoplasmic content also was increased. T h e nuclei commonly showed vacuolization resembling that in bizarre nuclei of other benign neoplasms. Lesions involving the small bones of the hands and feet had a higher percentage of atypical cells. Nine tumors (3.2%) had an atypical appearance for chondromyxoid fibroma. The patients were younger (average age, 26.7 years), and the tumors commonly showed calcification. T h e diagnosis was based primarily on recognition of the typical cytological features of the t u m o r cells. The lobulation was less distinct, and the tumors t e n d e d to show heavy hyalinization (Fig 17). Only one contained hyaline cartilage. FIGURE 8. broma,
Hypocel[ular microlobules in chondromyxoid fi-
than 15 years showed calcification. Reactive new bone formation was present in 15.1% of the lesions. These bony trabeculae were woven and appeared either in the interlobular areas or at the p e r i p h e r y of the tumor. Bone formation was never p r o m i n e n t e n o u g h to suggest a bone-forming neoplasm. Secondary aneurysmal b o n e cyst occurred in only 8.6% of the tumors. Permeation of trabecular bone (9%) (Fig 14), permeation of the cortex (0.4%), and soft tissue extension (30.6%) were some u n e x p e c t e d findings in this benign neoplasm. We are not aware of a r e c u r r e n t tumor in the 25 patients who had permeation. This includes three patients treated at the Mayo Clinic who had follow-up o f 14, 27, and 268 months. Cortical permeation was seen in only one tumor. Soft tissue extension was m u c h more common, and this seemed to be caused by a pushing margin rather than true permeation (Fig 15). Permeation of bone was more c o m m o n in lesions of the skull and facial bones (13.3%) than in the lesions involving the small bones of the hands and feet (6.3%). Conversely, lesions o f the hands and feet showed more tendency for soft tissue extension (43.8% v 20.0%). Soft tissue extension was also a c o m m o n feature in lesions involving the ribs (40.9%). In one of the rib tumors, an a d h e r e n t segment of the lung had to be resected. Mitotic figures, usually present in more cellular interlobular areas, occurred in 11.2% of tumors. They 442
FIGURE 9. A lessweLl-defined microlobular pattern characterized by myxoid [obules fused with neighboring Iobules.
CHONDROMYXOID FIBROMA OF BONE (Wu et al)
FIGURE 10. High-power appearance of chondromyxoid fibroma showing stellate cells with round-to-oval nuclei and cytoplasmic extensions.
FIGURE 11. An area resembling chondroblastoma in an otherwise typical chondromyxoid fibroma arising in the metaphysis of the tibia.
c o m a developed in the proximal tibia 6 years after t r e a t m e n t of a c h o n d r o m y x o i d fibroma, which included radiation. This patient also died of disease.
Treatment and Follow-Up
No a t t e m p t was m a d e to get information a b o u t t r e a t m e n t in consultation cases. Most patients had b e e n treated with curettage or excision. We know o f 32 patients who had local recurrence. The t u m o r r e c u r r e d once in 23 patients and twice in seven patients. O n e patient had three recurrences, and one had five. T h e interval between first diagnosis and first r e c u r r e n c e r a n g e d f r o m 5 m o n t h s to 10 years (average, 38.4 months). T h e first r e c u r r e n c e was n o t e d within 1 year of t r e a t m e n t in 37.9% of the patients. T h e average age of the patients with r e c u r r e n c e was 22.6 years, and 40.6% of the patients were y o u n g e r than 15 years. T h e average age of the Mayo Clinic patients with r e c u r r e n t tumors was 17.6 years. T h e r e c u r r e n c e rate in the Mayo Clinic patients was 26.3%. Only 10% of the tumors in these patients had mitotic activity. However, 28.1% of all r e c u r r e n t lesions a n d 30% of lesions in Mayo Clinic patients with r e c u r r e n c e showed soft tissue t u m o r nodules. Malignancy arising in c h o n d r o m y x o i d fibroma was i d e n t i f e d in two lesions. O n e patient, a 45-year-old man, had a grade 4 malignant fibrous histiocytoma 5 m o n t h s after diagnosis of c h o n d r o m y x o i d fibroma of the pubis. T h e patient died with metastasis; at autopsy, b o t h c h o n d r o m y x o i d fibroma and malignant fibrous histiocytoma were present in the pubic bone. In the second patient, a 58-year-old woman, a grade 3 fibrosar-
DISCUSSION C h o n d r o m y x o i d fibromas are extremely unusual neoplasms of bone; approximately 400 cases are re-
FIGURE12. Hyaline cartilage in a macrolobule bordered by typical fibromatoid cells.
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FIGURE 13. Irregularly shaped plaquelike calcification in loose myxoid stroma.
ported in the literature. Until the end of 1993, only 45 examples of chondromyxoid fibroma were in the Mayo Clinic files of a total of 11,087 b o n e tumors. 1 In the same period, there were 119 examples of chondroblastoma in the Mayo Clinic files. The relative rarity of this lesion explains the diagnostic difficulties still encountered. We were able to review a fairly large series of cases of chondromyxoid fibroma from the Mayo Clinic and consultation files. This kind of retrospective study has limitations. Obviously, information about treatment and follow-up are incomplete in consultation cases. Hence, recommendations about treatment cannot be made on the basis of such a study. Nevertheless, we thought that a study of reentgenograms and histological material from a large series would be beneficial. We h o p e d to learn the spectrum of roentgenographic and histological features in chondromyxoid fibroma. The age and sex distributions of the patients in this series are very similar to those reported in the litera-
FIGURE 15. Soft tissue extension usually has a Iobular pushing border without a desmoplastic reaction. The patient was doing well 2 years after surgery.
ture. 4,8q5 In the literature, the ages of patients with chondromyxoid fibroma have ranged from 3 to 70 years. In the current series, the age range was 6 to 87 years, not too dissimilar to what has been reported. The only unusual finding was that patients with involvement of the phalanges of the fingers t e n d e d to be somewhat younger. The proximal tibia is the most c o m m o n site of involvement in all large r e p o r t e d series. This site was followed by the ilium, the ribs, the distal femur, the metatarsals, and the lower tibia. In any large consultation series, unusual locations may dominate. Nevertheless, the relatively c o m m o n involvement of the metatarsals is noteworthy. T h e metatarsals were relatively frequently involved in the Mayo Clinic series also, in sharp contrast to the rarity of involvement of the metacarpals. Within a long bone, chondromyxoid fi-
FIGURE 16. Bizarre tumor cells containing large, irregularly shaped, hyperchromatic nuclei with degenerative intranuclear vacuoles surrounded by abundant cytoplasm. The patient had no recurrence 13 months after surgery.
FIGURE 14. Chondromyxoid fibroma entrapping fragments of trabecular bone.
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CHONDROMYXOID FIBROMA OF BONE (Wu et aJ)
FIGURE | 7. Hyalinized matrix in an otherwise typical chondromyxoid fibroma, The tumors cells are compressed and a p p e a r pyknotic.
b r o m a classically involves the metaphysis. It may abut the epiphyseal plate. Two lesions involved the diaphysis of the tibia. Zillmer a n d D o r f m a n n also described an example involving the diaphysis. T h e classic histological feature of c h o n d r o m y x o i d fibroma is lobularity with condensation of the neoplastic cells at the p e r i p h e r y of the lobules. T h e lobules are typically easily seen on low power, especially because of the condensation of the nuclei at the p e r i p h e r y and the giant cells and m o n o n u c l e a r cells in the m o r e cellular areas. In this study, however, this m a c r o l o b u l a r pattern was seen in only 70% o f the cases. A lobular pattern, m u c h less distinct than that classically described, which could be t e r m e d a microlobular pattern, was seen in a large percentage of cases. Frequently, the tumors showed areas of m a c r o l o b u l a r pattern and o t h e r areas of microlobular pattern. Approximately I 7 % of the tumors showed microlobular growth pattern alone. Just over 13% of the tumors showed no lobular pattern whatsoever. T h e diagnosis in these cases was m a d e with the c o m b i n a t i o n of r o e n t g e n o g r a p h i c features a n d identification of the m o n o n u c l e a r cells quite typically seen in c h o n d r o m y x o i d fibroma. T h e neoplastic ceils in c h o n d r o m y x o i d fibroma are either spindle-shaped or stellate, as described in the literature. F e c h n e r and Mills 14also highlighted the pink staining of the cytoplasm of some of these cells. Although the n a m e " c h o n d r o m y x o i d f i b r o m a " suggests that there is c h o n d r o i d differentiation in the neoplasm, it is unusual to find hyaline cartilage of the type seen in a c h o n d r o m a or a chondrosarcoma. However, it occurred focally in approximately 19 % of the cases. In an earlier study f r o m the Mayo Clinic, Rahimi et al4 p o i n t e d out that microscopic foci of calcification are present in m o r e than one fourth of the cases of c h o n d r o m y x o i d fibroma. T h e incidence in the literature has varied considerably. Zillmer and D o r f m a n n r e p o r t e d a 14% incidence, and Gherlinzoni et a113 f o u n d calcification in 11%, whereas Schajowicz and Gallardo a5 m e n t i o n e d that it was seen in only 1 of 44
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cases. This finding is i m p o r t a n t because, typically, roentg e n o g r a m s in c h o n d r o m y x o i d fibroma are purely lucent without mineralization. T h e calcification seen microscopically probably is not sufficient to be recognized on roentgenograms. C h o n d r o m y x o i d fibromas occurring on the surface of b o n e show considerable calcification on roentgenograms. These cases are rep o r t e d separately and have not b e e n discussed in this report. 16 Reactive new b o n e f o r m a t i o n was f o u n d in 7% of the cases described by Rahimi et al. 4 However, Zillmer and D o r f m a n 11 n o t e d no reactive new b o n e f o r m a t i o n in their series of cases. In this series, reactive new b o n e f o r m a t i o n was seen in 15% of the cases. This new b o n e f o r m a t i o n was present in the m o r e cellular areas between lobules of the neoplasm. Mitotic figures are considered to be rare to absent in c h o n d r o m y x o i d fibroma, s,9,~1,14 It has even b e e n suggested that lack of mitoses should be a useful criterion in differentiating c h o n d r o m y x o i d fibroma f r o m chondrosarcoma. T h e c u r r e n t study indicates that mitotic figures may be present in m o r e than 10% o f cases of c h o n d r o m y x o i d fibroma. They are n o t abundant (one to three per 10 high-power fields) and are usually seen in the m o r e cellular areas at the p e r i p h e r y of lobules and the interlobular tissue. Atypical mitotic figures are not seen in c h o n d r o m y x o i d fibroma. Therefore, mitosis cannot be used as a criterion to separate c h o n d r o m y x o i d fibroma f r o m chondrosarcoma. C h o n d r o m y x o i d f i b r o m a s classically are welld e m a r c a t e d lesions. Indeed, the edges a p p e a r lobulated a n d pull away f r o m the s u r r o u n d i n g bone, emphasizing lack of p e r m e a t i o n into s u r r o u n d i n g tissues. In this study, however, p e r m e a t i o n was seen in 9% of the cases. P e r m e a t i o n took the f o r m of t u m o r filling up m a r r o w cavity and e n t r a p p i n g preexisting b o n y trabeculae. This feature is n o t generally recognized with chondromyxoid fibromas. More surprisingly, this p e r m e a t i o n did not p o r t e n d r e c u r r e n c e of the lesion. We are not aware of a r e c u r r e n t t u m o r in the 25 cases showing p e r m e ation. This g r o u p includes three patients who had b e e n treated at the Mayo Clinic and for w h o m we have follow-up information for 14, 27, and 268 months. P e r m e a t i o n is m u c h m o r e c o m m o n in the small or flat bones, such as the skull, the jaw bones, and the small bones of the hands and feet. This occurrence is not surprising. Many o t h e r benign lesions show a p p a r e n t p e r m e a t i o n when involving such bones. Care has to be taken n o t to diagnose malignant disease on the basis of this criterion, especially when small a n d flat bones are involved. Soft tissue extension was seen in m o r e than 30% of the tumors. This soft tissue extension was m o r e likely to be expansion of the lesion into soft tissue rather than true permeation. This, too, was m o r e c o m m o n in the small bones of the hands and feet and the ribs. Indeed, in one rib lesion, the t u m o r was a d h e r e n t to lung. Cells in chondromyxoid fibroma can show pleomorphisrn. T h e t e r m " p l e o m o r p h i s m " is probably better than "cytological atypia." T h e nuclei tend to be large and bizarre, a p p e a r i n g without alteration in the nucleocytoplasmic ratio. T h e details of the nuclei are usually
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not crisp, and they may a p p e a r vacuolated. This kind of bizarre a p p e a r a n c e is similar to that seen in some neoplasms, such as n e u r i l e m m o m a , and after radiation. Although this may lead to a mistaken diagnosis of malignant disease in a limited sample, attention to the overall picture should prevent this error. T h e differential diagnosis involves chondrosarcoma, chondroblastoma, and fibrous dysplasia. Chondrosarcomas with a lobulated growth p a t t e r n and spindling of the nuclei are generally easily identifiable as malignant. T h e r o e n t g e n o g r a p h i c features in these tumors are almost invariably those of an aggressive tumor. C h o n d r o m y x o i d fibromas are almost invariably associated with a benign r o e n t g e n o g r a p h i c appearance. Alt h o u g h lobulated c h o n d r o s a r c o m a s have condensation of nuclei at the p e r i p h e r y of the lobules, the center of the lobules is also hypercellular c o m p a r e d with the a p p e a r a n c e in c h o n d r o m y x o i d fibroma. Fibrous dysplasia can a p p e a r quite myxoid. T h e cells in fibrous dysplasia lack the epithelioid a p p e a r a n c e seen in chondromyxoid fibromas. If there is lobulation, fibrous dysplasia should be ruled out. If there is no lobulation, as may h a p p e n rarely with c h o n d r o m y x o i d fibroma, r o e n t g e n o g r a p h i c features may be of p a r a m o u n t importance. Chondroblastomas and c h o n d r o m y x o i d fibromas share m a n y similarities. Indeed, some tumors show features of both. Fortunately, the distinction is not of clinical significance. In these instances, we tend to use the t e r m " c h o n d r o m y x o i d f i b r o m a " if the lesion is metaphyseal and " c h o n d r o b l a s t o m a " if the lesion is epiphyseal. Because of the nature of this study, it is impossible to m a k e any statement a b o u t t r e a t m e n t and prognosis. We are not aware of any metastasis f r o m chondromyxoid fibroma. In this series, there are two well-docum e n t e d examples of malignant transformation, one with and one without radiation. We know of local r e c u r r e n t t u m o r in at least 32 patients. O n e patient h a d up to five recurrences. With the r e c u r r e n t tumor, soft tissue implantation may occur. 17-2° N o t included in this series are two most unusual tumors that a p p e a r to be p r i m a r y in soft tissues. O n e lesion involved the soft palate, f o r m i n g a 3.4-cm nodule. R o e n t g e n o g r a m s did not show any involvement of bone. T h e second lesion, in a 35-year-old woman, was an irregularly surfaced neoplasm, 2.5 × 2.5 × 1.0 cm, s u r r o u n d e d completely by fat and located at the anterolateral aspect of the anal sphincter between the anus
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and the vagina. In this case, also, there was no connection between the n e o p l a s m and any bone.
REFERENCES 1. Unni KK: Dahlin's Bone Tumors: General Aspects and Data on 11,087 Cases (ed 5). Philadelphia, PA, Lippincott-Raven, 1996 2. Schajowicz F, Ackerman LV, Sissons HA: Histological typing of bone tumours. International Histological Classification of Tumours, No. 6. Geneva, Switzerland, World Health Organization, 1972 3. Jaffe HL, Lichtenstein L: Chondromyxoid fibroma of bone: Distinctive benign tumor likely to be mistaken especially for chondrosarcoma. Arch Patho145:541-551, 1948 4. Rahimi A, Beabout JW, Ivins JC, et ah Chondromyxoid fibroma: A clinicopathologic study of 76 cases. Cancer 30:726-736,1972 5. Iwata S, Coley BL: Report of six cases of chondromyxoid fibroma of bone. Surg Gynecol Obstet 107:571-576, 1958 6. Sehayik S, Rosman MA: Malignant degeneration ofa chondromyxoid fibroma in a child. CanJ Surg 18:354-357, 1975 7. Dahlin DC: Chondromyxoid fibroma of bone, with emphasis on its morphological relationship to benign chondroblastoma. Cancer 9:195-203, 1956 8. Mirra JM, Picci P, Gold RH: Bone Tumors: Clinical, Radiologic, and Pathologic Correlations. Philadelphia, PA, Lea & Febiger, 1989 9. Huvos AG: Bone Tumors: Diagnosis, Treatment, and Prognosis (ed 2). Philadelphia, PA, Saunders, 1991 10. Campanacci M: Bone and Soft Tissue Tumors. NewYork, NY, Springer-Verlag, 1990 11. Zillmer DA, Dorfman HD: Chondromyxoid fibroma of bone: Thirty-six cases with clinicopathologic correlation. HUM PATHOL 20:952-964, 1989 12. Kreicbergs A, Lonnquist PA, Willems J: Chondromyxoid fibroma: A review of the literature and a report on our own experience. Acta Pathol Microbiol Immunol Scand [A] 93:189-197, 1985 13. Gherlinzoni F, Rock M, Picci P: Chondromyxoid fibroma: The experience at the Istituto Ortopedico Rizzoli. J Bone Joint Surg Am 65:198-204, 1983 14. Fechner RE, Mills SE: Atlas of Tumor Pathology, Tumors of the Bones and Joints. Third series, Fascicle 8. Washington, DC, Armed Forces Institute of Pathology, 1993 15. Schajowicz E Gallardo H: Chondromyxoid fibroma (fibromyxoid chondroma) of bone: A clinico-pathological study of thirty-two cases.J Bone Joint Surg Br 53:198-216, 1971 16. Robinson LH, Unni KK, O'Laughlin S, et al: Surface chondromyxoid fibroma of bone. Mod Pathol 7:10A, 1994 (abstr) 17. Kyriakos M: Soft tissue implantation of chrondromyxoid fibroma. AmJ Surg Pathol 3:363-372, 1979 18. Mikulowski P, Ostberg G: Recurrent chondromyxoid fibroma. Acta Orthop Scand 42:385-390, 1971 19. HeydemannJ, Gillespie R, Mancer F,2 Soft tissue recurrence of chondromyxoid fibroma.J Pediatr Orthop 5:725-727, 1985 20. Troncoso A, Ro JY, Edeiken J, et al: Case report 798: Recurrent chondromyxoid fibroma in connective tissue of leg. Skel Radio122:445-448, 1993