THE AMERICAN JOURNAL OF CLINICAL PATHOLOGY Vol. 52, No. 1 Copyright 1969 by The Williams & Wilkins Co. Printed in U.S.A. FRACTURE CALLUS ASSOCIATED WITH BENIGN AND MALIGNANT BONE LESIONS AND MIMICKING OSTEOSARCOMA LEONARD B. KAHN, M.B.B.CH., M.MED (PATH.), FRED W. WOOD, M.D., AND LAUREN V. ACKERMAN, M.D. Division of Surgical Pathology, Washington University School of Medicine, St. Louis, Missouri 63110 ABSTRACT Kahn, L. B., Wood, F. AV., and Ackerman, L. V.: Fracture callus associated with benign and malignant bone lesions and mimicking osteosarcoma. Am. J. Clin. Path., 52: 14-24, 1969. Reparative callus associated with ordinary fractures causes no problem to the pathologist and orthopedic surgeon, but fracture callus superimposed on benign and malignant bone lesions may cause considerable diagnostic difficulty to the surgeon, radiologist, and pathologist alike. Misinterpretation of this callus as osteosarcoma may lead to an unjustified amputation. We feel that this has not received adequate documentation in the literature, and we have thus presented some representative cases which help to clarify this problem. These include three benign lesions of bone and one metastatic lesion to bone. In three cases, fracture callus complicating the underlying disease process was sufficiently disturbing to cause the pathologist to seek other opinions, and in one case an amputation for metastatic disease was performed. The careful correlation of all available clinical, radiologic, and pathologic features of each case at the time of study of the biopsy was found to be the most important factor in preventing diagnostic errors. Reparative callus associated with the usual fracture does not cause any problem to the pathologist or the orthopedic surgeon because of the clinical history and obvious radiographic findings. During the past few years, we have seen a number of cases in which both benign and malignant bone lesions have been associated with callus. Portions of this callus have been submitted to various pathologists, and the bizarre pattern has either suggested osteosarcoma or been misinterpreted as osteosarcoma. As the callus may be associated with a benign tumor or lesion, such an error might lead to unjustified amputation. This potentially hazardous problem has not received adequate documentation in the literature. Although several authors 2 " 5 have referred to these diagnostic difficulties caused by reparative callus, the only detailed case descriptions we have found are those of Baker. 1 He reported on two cases of fragilitas ossium in which hyperplastic callus simulated osteosarcoma. We wish to present several representative recent cases which have been helpful in clarifying the problem for us. Received November 11,1968. 14 This problem arises when the surgical pathologist is presented with a biopsy from the site of an overt or occult pathologic fracture and is unaware of the clinical and radiologic features of the case. In many cases, the clinical and radiologic features are so distinctive of some underlying benign osseous lesion that no diagnostic difficulty should arise. In other cases the rapid rate of growth of a benign lesion may mislead the radiologist and pathologist into seriously considering a malignant process. The most difficult cases are those in which the callus formation masks the underlying process and causes the radiologist to diagnose an osteosarcoma. We will present four cases to illustrate some of these problems. REPORT OF CASES Case No. 1. K. B., a 9-year-old male, fell from a tree and injured his left knee in June 1966. Roentgenograms revealed an expansile cystic lesion of the medial aspect of the distal femoral metaphysis, with some periosteal new bone formation (Figs. 1 and 2). An open biopsy was performed, and this showed areas of disturbing osteoblastic
July 1969 FRACTURE CALLUS MIMICKING OSTEOSARCOMA 15 FIGS. 1 AND 2. Case 1. Anteroposterior and lateral roentgenogram showing an expansile, eccentric, radiolucent lesion involving the medial aspect of the distal femoral metaphysis. A fracture is seen in the lateral film at the lower end of the lesion. (Washington University illustrations (W. U.) G7-1344 and 67-1024.) proliferation and formation of osteoid seams (Figs. 3 and 4), as well as areas in which loose fibrous tissue and scattered multinucleate giant cells were seen (Fig. 5). A correct diagnosis of metaphyseal fibrous defect with superimposed fracture callus was made. The typical radiologic features in this case led to a confident diagnosis even in the presence of active reparative callus. Case No. 2. D. B., a Caucasian female aged 34 years, developed mild pain in the region of her left hip 6 months prior to her first hospital admission in 1961. A roentgenogram at that time showed an osteolytic lesion of the upper femoral shaft with well defined borders, intact cortex, and no periosteal reaction (Fig. 6). At operation, the surgeon noted that the lesion did extend beyond the cortical bone into the surrounding soft tissue, and he biopsied this most peripheral part of the lesion. A diagnosis of sarcoma was made on both the frozen and permanent sections and a hip disarticulation was recommended. An eminent bone pathologist was requested to review the slides and he concurred with this diagnosis, although he did not see the roentgenograms (Figs. S and 9). However, the patient refused treatment and was admitted to Barnes Hospital where the roentgenograms and slides were reviewed. It was thought that the lesion was probably an aneurysmal bone cyst complicated by the presence of fracture callus. This opinion was arrived at only because the histologic sections were studied together with the roentgenograms. The lesion was curetted and the diagnosis of aneurysmal bone cyst was confirmed (Figs. 10 and 11). Six years later, roentgenograms showed healing of the lesion (Fig. 7). In this case, the importance of a combined study of both roentgenograms and histology is obvious. The initial biopsy was taken from the presumed "invasive" margin of the lesion and showed only fracture callus. The
16 K A H N ET AL. %.K- FIG. 3 (upper). Case 1. Newly formed osteoid and osseous trabeculae of the fracture callus complicating the metaphyseal fibrous defect. The regular arrangement of these trabeculae, the presence of a lining rim of osteoblasts around the trabeculae, and the rather sparsely cellular intervening stroma are the features which enable the pathologist to diagnose callus without difficulty. Hematoxylin and eosin. X 90. (W. U. 68-412.) FIG. 4 (middle). Case 1. This higher magnification of Figure 3 shows an area of the most recently fornied osteoid seams. The osteoblasts within these seams show considerable atypism. This degree of atypism is common in newly formed, active callus. Hematoxylin and eosin. X 350. (W. U. 68-413.) FIG. 5 (lower). Case 1. This shows the loose fibrous tissue with scattered multinucleate giant cells from the metaphyseal fibrous defect. Hematoxylin and eosin. X 350. (W. TJ. 68-414.) Vol. 52
July 1969 FRACTURE CALLUS MIMICKING OSTEOSARCOMA 17 FIG. G (left). Case 2. Osteolytic lesion at the upper end of the femoral shaft. The lesion has well defined borders and no periosteal reaction. These features are more suggestive of a benign lesion than of a malignant tumor. (W. TJ. 61-7914.) FIG. 7 (right). Case 2. This shows healing of the aneurysmal bone cyst 6 years after its curettage. There is deformity of the femur indicating healing of a previous fracture. (W. TJ. 62-8760.) surgeon as well as the pathologists should have been alert to this possibility had more attention been given to the radiologic appearance of the lesion. Case No. S. J. F., a 15-year-old Caucasian female, developed gradually increasing pain in her left upper arm 4 months prior to admission. A radiologic diagnosis of osteosarcoma was made on the basis of a rapidly expansile, destructive lesion of the proximal metaphysis of the humerus, with extension into adjacent soft tissue (Fig. 12, A, B, C). An open biopsy of the lesion showed an abundance of irregular osteoid formation with osteoblastic proliferation, and this material was referred to Barnes Hospital for review (Figs. 14 and 15). At Barnes, it was suspected that florid callus formation was complicating an underlying bone lesion. The lesion was explored, and a soft mass containing many blood-filled spaces and partial 1 j' covered by a thin shell of cortical bone was found. Histologically, this showed the features of an aneurysmal bone cyst (Fig. 16). The lesion continued to enlarge during the next 2 months, and the left upper humerus with the cyst was completely excised (Fig. 13) and replaced by an endoprosthesis (Fig. 17). The patient was alive and well without recurrence of disease 9 years later. The rapid clinical progression of this lesion may have influenced the radiologist to consider this an osteosarcoma despite the rather characteristic "blow-out" appearance produced by aneurysmal bone cysts. The pathologist in turn was influenced by this radiologic opinion, and his difficulties were compounded by the active, bizarrelooking fracture callus. A subsequent thorough exploration of the lesion revealed its true nature.
FIG. 8 (upper left). Case 2. The cartilage and osteoid trabeculae in this fracture callus show some regularity in their arrangement, although this is much less obvious than in Case 1. The intervening stroma has uniformly distributed fibroblasts and well formed capillary vessels. Although these features are very suggestive of fracture callus, this was interpreted as osteosarcoma by an experienced bone pathologist. Hematoxylin and eosin. X 150. (W. U. 67-10002.) FIG. 9 (upper right). Case 2. At higher magnification, the atypical appearance of chondrocytes and osteoblasts is well illustrated. Hematoxylin and eosin. X 350. (W. U. 67-10003.) FIG. 10 (lower left). Case 2. This shows the typical appearance of an aneurysmal bone cyst. Hematoxylin and eosin. X 150. (W. U. 67-10000.) FIG. 11 (lower right). Case 2. Numerous large, multinucleate giant cells in the walls of the aneurysmal bone cyst. Hematoxylin and eosin. X 350. (W. U. 67-10001.) 18
July 1969 FRACTURE CALLUS MIMICKING OSTEOSARCOMA 19 F I G. 12. Case 3. A (left), December 19, 1959, 4 months after the onset of symptoms, there is a destructive metaphyseal lesion which has expanded into the surrounding soft tissue. B (middle), J a n u a r y 2, I960. C (right), February 22, 19(30: the configuration of calcification within the lesion suggests loculation. The thin, expanded cortex is well shown. (W. TJ. GO-2328,60-2329, and GO-2330.) F I G. 13. Case 3. Resected upper end of humerus showing the large aneurysmal bone cyst. (W. U. 67-10430.) Case No. 4- T. M., a 67-year-old man, was admitted to Barnes Hospital in October 1967, with a complaint of pain in the right upper thigh of 8 to 10 months' duration. A tender and fixed mass was present in the region of the lesser trochanter, and this extended into the soft tissues (Fig. IS). A radiologic diagnosis of osteosarcoma was made. A Craig needle biopsy showed a malignant tumor, type unclassified. An
20 KAHN ET Vol. 52 AL. FIG. 14 (left). Case 3. The biopsy shows the very cellular fibroblastic tissue with formation of irregular osteoid trabeculae from the fracture callus which complicates the aneurysmal bone cyst. The osteoid trabeculae are rather haphazardly arranged and are not lined by a uniform layer of osteoblasts. This appearance could readily be misinterpreted as osteosarcoma. Hematoxylin and eosin. X 150. (W. U. 67-9907.) FIG. 15 (right). Case 3. Higher magnification of Figure 14, showing extreme cellularity of the callus and moderate atypism of fibroblasts and osteoblasts. An irregular osteoid seam is seen in the left central area of the photomicrograph. Hematoxylin and eosin. X 350. (W. U. 67-9908.) unsuccessful search was made for an extraskeletal primary malignant tumor. This included a metastatic bone series, upper gastrointestinal series, barium enema, intravenous pyelogram, and chest and lumbar spine roentgenograms. A needle biopsy of the prostate was unremarkable. An open biopsy and frozen section of the lesion was performed, and a diagnosis of osteosarcoma was made (Figs. 20 and 21). The right hip was disarticulated. In the upper third of the shaft of the femur, several partially necrotic tumor nodules were found, some of which extended into the soft tissue of the thigh through an avulsion fracture of the lesser trochanter (Fig. 19). Abundant callus was present at the fracture site. Histologically, much reparative callus was seen in juxtaposition to nodules of metastatic carcinoma (Figs. 22 and 23). A chest roentgenogram taken at the time of discharge showed a small round mass in the left lung which had not been present on the admission films. This case illustrates most dramatically how readily the pathologist may err, when confronted with pieces of callus, especially when presented with a roentgenogram which he is led to believe shows a primary osteosarcoma. DISCUSSION Although it is not possible to determine the frequency with which fracture callus is misdiagnosed as a primary malignant bone tumor, several cases have been referred
July 1969 FRACTURE CALLUS MIMICKING OSTEOSARCOMA 21 J&-, FIG. 17. Case 3. Replacement endoprosthesis of upper end of humerus. (W. U. 60-2331.) FIG. 16. Case 3. Typical septa and cavernous spaces of an aneurysmal bone cyst. The osteoclast tj'pe giant cells in the septa are shown at higher magnification in the inset. Hematoxylin and eosin. X 150. (W. U. 67-9907.) Inset: Hematoxylin and eosin. X 350. (W. U. 67-9909.) to this institution in which such a diagnostic dilemma existed. The experience of most pathologists with primary bone lesions is small and they seldom have occasion to examine callus removed as biopsy material. In some cases, the radiologic and clinical features may be so distinctive of an underlying benign lesion that even an inexperienced pathologist would be unlikely to err if given material from an accompanying reparative callus. However, the clinician and radiologist may be so convinced of the "malignancy" of a benign lesion on the basis of its clinical behavior or radiologic appearances that the pathologist confronted with material from reparative callus could well diagnose it as osteosarcoma. The purely histologic differentiation of provisional callus from osteosarcoma is usually not difficult in that the obvious anaplasia of an osteosarcoma is not seen in reparative callus. The haphazard arrangement of the osteoid, woven bone and cartilage, and the presence of mitotic figures, are less helpful in this differentiation as these features may be conspicuous in both. Occasionally, however, this histologic differentiation may be extremely difficult, especially if a section has been taken only from the most recently formed callus. The plump, active-looking osteoblasts, the presence of mitotic figures, and the bizarre pattern of osteoid formation may then be misinterpreted as evidence of malignancy. Careful attention should be given to the presence or absence of obvious anaplasia in making this differentiation. When definite callus makes its appearance from about the 3rd week following the fracture, the recognition of this callus becomes easy. The osteoid and bony trabeculae are regularly arranged and are usually rimmed by a single layer of osteoblasts. Acknowledgments. Dr. Robert W. Brangle, Dr. Carl Rylander, and Dr. Leon Fox submitted cases to us.
FIG. 18 (upper). Case 4. Osteoblastic lesion in the region of thelesser trochanter of the femur. There is an osteoblastic invasive lesion in the intertrochanteric portion of the femur. The lesser trochanter is destroyed, and extensive soft tissue calcification is present. This was interpreted radiologically as an osteosarcoma. (W. U. 68-9391.) FIG. 19 (lower). Case 4. There is an avulsion fracture of the lesser trochanter. Pale, partially necrotic tumor nodules are seen in the bone adjacent to the fracture site. (W. U. 67-9065.) 22
w FIG. 20 (upper left). Case 4. This biopsy shows the bizarre-looking cartilage and osteoid tissue of the fracture callus which was misdiagnosed on frozen section as osteosarcoma. As in the biopsy from Case 2, the extreme cellularity and haphazard arrangement of the osteoid seams make differentiation from osteosarcoma very difficult. Hematoxylin and eosin. X 150. (W. U. 67-9900.) FIG. 21 (upper right). Case 4. The cellularity and pleomorphism of the cells in the fracture callus from Case 4 are shown at higher magnification. Hematoxylin and eosin. X 350. (W.U. 67-9901.) FIG. 22 (lower left). Case 4. Metastatic carcinoma in the upper left half of the photomicrograph and fracture callus in the right half of the photomicrograph. Hematoxylin and eosin. X 150. (W. U. 67-9904.) FIG. 23 (lower right). Case 4. Higher magnification of metastatic carcinoma seen in Figure 22. (VV. U. 67-9903.) 23
24 KAHN ET AL. Vol. 52 REFERENCES 1. Baker, S. L.: Hyperplastic callus simulating sarcoma in two cases of fragilitas ossium. J. Path. & Bact., 58:009-623,1946. 2. Brailsford, J. F.: The Radiology of Bones and Joints, Ed. 5. Baltimore: The Williams & Wilkins Company, 1953, pp. 610, 611, 780, 781, 788. 3. Dahlin, D. C: Bone Tumors, Ed. 2. Springfield, 111.: Charles C Thomas, Publisher, 1967, pp. 248, 249. 4. Evving, J.: Neoplastic Diseases, Ed. 4. Philadelphia: W. B. Saunders Company, 1940, p. 275. 5. Lichtenstein, L.: Bone Tumors, Ed. 3. St. Louis: The C. V. Mosby Company, 1905, pp. 360-308.