Intramedullary Well-Differentiated Osteosarcoma: Imaging and Pathologic Findings in a Group of 17 Patients

Background: Intramedullary well-differentiated osteosarcoma (IMWDOS) is rare and may easily be misdiagnosed. Objective: This study was to investigate the clinical, imaging and pathological features of IMWDOS for correct diagnosis. Materials and methods: Seventeen patients with IMWDOS were enrolled and the clinical, imaging and pathological data were analyzed. Results: There were 13 males and 4 females with an age range of 19-55 years (mean 32). The lesion was located at long bones in 16 patients and at the second region of acetabulum in one patient. Except for three patients with limited areas of lesions, all the other patients had wide areas of disease, and the lesion in long bones all involved the metaphysis area with possible extension towards the diaphysis. In imaging, the lesion usually had an unclear boundary with destruction of bone cortex, uneven thickness of the bone cortex, thick and coarse trabecula in the lesion, but few periosteal reaction and soft tissue masses. The lesion was histologically composed of spindle cells with slight atypia. Follow-up was performed 2-101 months (mean 37.7) in 14 cases, 10 years in one case and 26 years in the remaining two. At follow-up, 12 patients (12/17 or 70.6%) who had complete resection including amputation (n=2), wide excision (n=8) and endoprosthetic replacement (n=2) had no recurrence or metastasis. Among ve patients with curettage, three (3/17 or 17.6%) were recurrent with two deaths, and the third one died during post-operation chemotherapy. Conclusion: Intramedullary well-differentiated osteosarcoma tends to occur at the metaphysis of long bones especially at the distal femur involving a large area. Histological, clinical and imaging data have to be closely combined to reach the correct diagnosis. the radiological characteristics of well-differentiated osteosarcoma in eight found three patients to be misdiagnosed as benign lesions both pathologically and radiologically. The tumor margins were ill-dened in ve patients but well demarcated in the other three patients in radiograph. The bone response was both osteolytic and osteoblastic in seven patients but totally osteolytic in the remaining one, with expansile bone destruction in four patients. All patients had cortical thinning and discontinuity in imaging presentation, with extraosseous invasion in the soft tissue in six patients and active periosteal reaction in two. There were three common radiological features which strongly suggested malignancy: cortical discontinuity, ill-dened soft-tissue invasion and cloudlike tumor matrix. Histologically, the IMWDOS is basically a spindle-cell tumor with low cellularity, irregular production of bone and few mitotic gures. The IMWDOS is so well differentiated that it is hard to make a malignancy diagnosis based on limited biopsy specimen 4, 10 . The IMWDOS tumors are frequently demarcated as grey rm masses which have a brous whorled appearance typically localized in the medullary cavity in the metaphysis or meta-diaphysis area. In microscopic appearance, the tumors are hypo-cellular and composed of interlacing fascicles of spindle cells which showed mild cytological atypia with low mitotic activity. Typically, the IMWDOS tumor has a permeative growth pattern entrapping the native bone trabecula. An associated soft tissue mass may be present with the produced matrix being well differentiated. excision) all had recurrence within a mean of 3.9 years after the rst surgical operation and all underwent amputation. Four of the eleven patients died after 2-48 years after the diagnosis. Seventeen of the 80 patients had a wide excision as the initial treatment modality, with fteen patients still alive and free of disease at a mean follow-up of 4 years 1 . In our study, a total of 12 patients (12/17 or 70.6%) who had complete resection including amputation (n=2), wide excision (n=8) and endoprosthetic replacement (n=2) had no recurrence or metastasis at follow-up. Among ve patients with curettage in our study, three (3/17 or 17.6%) were recurrent with two deaths, and the third one died during post-operation chemotherapy. This conrmed that complete excision results in good recovery with no recurrence or metastasis.


Introduction
Osteosarcoma is a high-grade tumor usually developing in the intramedullary cavity of long bones in adolescents and young adults. Well differentiated osteosarcoma of the bone is rare and accounts for 1%-2% of all osteosarcomas with an equal gender distribution 1,2 . This type of bone osteosarcoma was rst described by Unni et al in 1977 3, 4 , and later the World Health Organization described it as low-grade central osteosarcoma (LGCOS) 5 . Unlike most osteosarcomas, LGCOS is less aggressive with limited metastatic potential and a good prognosis 4,6 . Nonetheless, the tumor may recur locally to exhibit greater malignancy with an increased potential for metastasis 7,8 , and the current standard treatment modality for LGCOS is wide resection with a negative margin. Although this disease is rare, the high differentiation and low malignancy contribute to a high rate of misdiagnosis initially, presenting similarly as brous dysplasia, giant cell tumors, and chondrosarcoma in the clinical manifestation. The di culty in managing patients with LGCOS lies in diagnosing the disease correctly, and the radiological appearance is often confused with that of brous dysplasia, desmoplastic broma, nonossifying broma, osteoblastoma and aneurysmal bone cysts 1,[9][10][11][12][13] . It is consequently vital to combine both histopathological and radiological ndings to reach a correct diagnosis. Our study analyzed the clinical, imaging and pathological ndings of seventeen patients with intramedullary well-differentiated osteosarcoma (IMWDOS) and presented our experience in diagnosing this disease.

Materials And Methods
This study was approved by the hospital ethics committee with all the patients given their written informed consent. The data of fteen patients with IMWDOS con rmed by histological examinations were collected between January 2000 and June 2017, and additional two patients with IMWDOS con rmed 26 years ago were also enrolled, with a total number of 17 patients ranging 19-55 (mean 32) years in age. There were 13 males and 4 females. Two patients were found to have IMWDOS because of trauma resulting in pathological fracture, and the rest 15 patients had bone pain, discomfort or restricted activity of the affected limb with aggravated symptoms at presentation. The duration of symptoms lasted for three years in one patient and 2-12 months (mean 8.2) in the rest. All patients had plain radiography, fourteen patients had preoperational computed tomography (CT) scanning, and nine patients had magnetic resonance imaging (MRI) of the affected areas. Pathological specimens in all patients were evaluated by two experienced pathologists for con rmation of the disease. All patients had post-operation follow-up, with 26 years in two patients, ten years in one and 2-101 months (mean 37.7) in the rest patients. Among sixteen patients with IMWDOS in the long bones, two patients had amputation of the limb with 26 years of follow-up, eight patients had endoprosthetic replacement of either allograft or autograft with a follow-up duration ranging 2-80 months (mean 23), one curettage patient had 10-year follow-up, and four patients had curettage with a post-operation follow-up of 13-45 months (mean 31.3). One patient with long bone IMWDOS had internal xation at the initial pathological fracture but endoprosthetic replacement four months later due to con rmed IMWDOS by pathological ndings with a follow-up duration of 101 months. The last patient had pelvic IMWDOS which was excised and followed up for 37 months.

Imaging presentations
The lesion was located in the tibial proximal, middle and distal segments with involvement of bula, the humerus proximal segment, the radius distal segment, the pelvis and acetabulum in seven patients. All the rest patients had the lesion in the femur, including the proximal segment in three patients and distal ends in the rest seven patients (Table 1 and Fig.1-6). In 16 cases with long bones diseases, the greatest diameter ranged 3.5-13.9 cm (mean 9.4), all involving the metaphysis region and nine cases having the lesion extending towards the diaphysis. The lesion was close to the lower joint surface (within 1 cm to the joint surface) in eight cases and across the joint surface in four cases. The lesion was primarily osteolytic in six patients (35.3%), osteoslerotic in two (11.8%) and mixed destruction in the rest (52.9%) ( Table 2). The lesion was clearly separated from surrounding bone in only one patient but unclearly in the rest. The bone cortex was destructed and discontinued in all but one patient (Table 3). In one patient, the discontinued cortex was only demonstrated by CT scanning (Fig.2-6). The endosteum was invaded with thinned cortex in all patient accompanied with some irregularly thickened cortex (Fig.1&2). The lesion grew eccentrically in two patients but involved the whole medullary cavity in the rest with in ltrating destruction on one side of the bone. The lesion was markedly expansive in six patients, non-expansive in three and eccentrically slightly expansive in the rest (Table 3). Bone septum was presented in the lesion in eight patients, with thick bone septum in six patients but thin septum in two. Variant ossi cation areas were shown in the lesion in 13 cases, and periosteal reaction was present in seven cases. One patient with the lesion in the middle and distal tibial segments had marked periosteal reaction with presence of Codman triangle, but the rest six patients had slight periosteal reaction. Except for the patient with the lesion in the distal radius segment and in the acetabulum which had apparent soft tissue masses (MRI showed more clearly in Fig.3, 4 and 6), the rest six patients had the lesion extending into surrounding soft tissue but with no apparent masses. In one patient with accompanied secondary aneurysmal bone cyst, MRI scanning showed apparent expansion with a uid-uid level. Pre-operation misdiagnosis was made in six patients as a benign lesion including brous dysplasia, aneurysmal bone cyst and giant cell tumor of bone in three patients, and the rest three patients all had a lesion of expansive growth with a relatively clear edge, which was diagnosed as a benign tumor. One lesion at the femoral proximal end was misdiagnosed as femoral head necrosis with cystic change.

Pathological ndings
Gross examination: Tissue specimen was obtained from all patients. The section was like sh esh in two cases and pale and rm in the rest with sand gravel feeling in part of the specimen. In 13 patients, the bone cortex was discontinued, and a soft tissue mass was demonstrated in three cases. In two cases with recurrence, the amputated segment of bone was located in the femur in one case and in the knee joint in the other, and the recurred tumor invaded the bone cortex, ankle cartilage, bula and surrounding soft tissue with a huge soft tissue mass.
Microscopic observation: The lesion was composed of brous tissue and osteoid tissue ( Fig.1 and 3). The brous cells were fusiform in alternate permutation with relatively the same in size. The cell nucleus was mild dysplasia with occasional mitotic images rather than pathological nuclear division. Almost all the lesions were in ltrative and invaded bone marrow. Variant tumorous osteoid tissue was observed in all the lesions with variant maturity. In seven cases, new bone trabecula was big and braided together, and in three cases, the tumorous osteoid tissue was like brous dysplasia. Few osteoblasts surrounded the osteoid tissue. Benign polykaryocytes were observed in four cases, and focal cartilage differentiation was demonstrated in two cases with one case having focal heterotype cartilage in the second recurrence. In three cases, the lesion was like desmoplastic bromas, and most of the lesion was composed of brous tissue with few cells, abundant collagen and few osteoid tissues, which was di cult to differentiate from collagen tissue. In two cases, the cellular components were increased with more heterotype cells, tumorous bone and cartilage (Table 1).

Effects and follow-up
Two patients (2/17 or 11.8%) had amputation of the affected long bone, with no recurrence or metastasis after follow-up for 26 years. Eight patients (47.1%) with endoprosthetic replacement had no recurrence or metastasis after a mean follow-up of 23 months. In ve patients with curettage (29.4%), two patients (11.8%) had recurrence and died at 20 and 28 months, respectively, one patient died from post-operation chemotherapy, and one patient (5.9%) had recurrence ten years later with the tibial lesion of destruction as big as 33.3 cm, apparent sclerosis, osteolysis and a soft tissue mass. In two patients (2/17 or 11.8%) with pathological fracture at presentation, the patients with the lesion at the humerus and the femur had endoprosthetic replacement with no recurrence or metastasis at follow-up of 101 months. In the case with the lesion at the acetabulum, recurrence occurred two years after excision, and then, the lesion recurred ve months later and was managed with resection of half pelvis and . No recurrence or metastasis was found eight months later.

Discussion
Most osteosarcomas are of high malignancy with marked cytological heterotype, whereas INWDOS is rare but has a more benign indolent course with a higher survival rate and less potential for metastasis 3,4,14 . Local excision of this disease is almost always associated with recurrence leading to a high-grade common osteosarcoma in 15% of the patients 1 . Consequently, it is crucial to distinguish the INWDOS from benign lesions and high-grade osteosarcomas.
In our study, we investigated the clinical, imaging and pathological data of 17 patients with IMWDOS. In this cohort of patients, the disease is more prevalent in the male than the female gender. This is quite different from the literature which has reported that the disease prevalence was equivalent in both genders 1 or slightly more in female than in male gender 4,5,14 . The age of the cohort in our study was greater than patients with common osteosarcoma, which is in line with the literature 3 . Most of the lesions were located in long bones except for one case which was at the pelvis. The femoral lesions accounted for 62.5% of all the patients while the distal end of the femur accounted for 70% of all the cases. All the lesions in the long bones involved the metaphysis or mainly located at the metaphysis except for one patient with the tibial lesion which tended to extend toward the diaphysis. This distribution of disease is quite different from what has been reported of the tumor predilection site in the literature 14 .
In imaging diagnosis, IMWDOS can be confused with brous dysplasia, desmophastic broma, nonossifying broma, osteoblastoma and aneurysmal bone cysts 1, 9-12, 15, 16 . The key to distinguish IMWDOS from benign tumors is to identify the invasive growth pattern, and the radiological characteristics are variable with a mixed osteolytic and osteoblastic appearance, as demonstrated in our study. Four radiological patterns of IMWDOS have been described by Andresen et al with a case cohort of 70 patients: osteolytic with varying amounts of thick and coarse trabeculation (31%), predominantly osteolytic with few thin incomplete trabecula (30%), densely osteosclerotic (24%) and mixed osteolytic and osteoslerotic (14%) 5 . The majority (52.9%) of radiographic patterns in our series were in line with the mixed osteolytic and osteosclerotic pattern, with the osteolytic pattern in only ve patients and the osteosclerotic in three.
Analysis of the imaging features in this group of patients, the imaging is characterized as expansile and osteolytic destruction with tumor bone inside the lesion, discontinued bone cortex, and uneven thickness of bone cortex, which are in line with the pathology of the tumor. The IMWDOS tumor has low malignancy, slow growth and expansile imaging presentation, which make it di cult to differentiate from benign tumors. However, benign tumors have consistent growth with even thickness of expansile cortex of bone, whereas the IMWDOS has uneven thickness of the bone cortex and discontinued cortex of bone, re ecting the invasiveness nature of low malignancy tumor to normal tissues.
Fibrous dysplasia, non-ossifying broma, osteoblastoma, or other benign tumors may be easily be misdiagnosed as IMWDOS (Table 3) 1, 9-12, 15, 16 . The key to differentiation from these benign tumors lies in recognition of the invasive growth pattern of IMWDOS because these benign tumors rarely present with cortical destruction or soft tissue masses. Some intermediate tumors like giant cell tumors, aneurysmal bone cyst, and desmoplastic broma should also be differentiated from IMWDOS, and these intermediate tumors have the following characteristics of expansile growth, complete bone shell, rare ossi cation or calci cation. Other malignant tumors should also be differentiated including chondrosarcoma, low-grade brosarcoma, common osteosarcoma, Ewing's sarcoma, lymphoma, and metastatic tumors. Chondrosarcoma, low-grade brosarcoma and IMWDOS are all of low grade malignancies. When chondrosarcoma is located within the medulla, the bone intima often presents scallop-like notch, and the lesion often has characteristic annular, semicircular and popcorn-like cartilage calci cation, with typical long cartilage lobular signal on T2WI. Low-grade brosarcoma also has invasive growth features but no ossi cation nor calci cation within the lesion. Common osteosarcoma, Ewing's sarcoma, and lymphoma have high malignancy and are characterized by bone destruction, periosteal reaction, soft tissue masses but rare expansion. Metastatic tumors often have multiple lesions besides the history of the primary tumor.
When the IMWDOS lesion is primarily osteolytic, it should be differentiated from giant cell tumors, aneurysmal bone cyst, non-ossifying broma, brous dysplasia, desmoplastic broma, and low-grade brosarcoma. When the IMWDOS lesion is primarily osteosclerotic, it should be differentiated from osteoblastoma and sclerosing osteosarcoma. In mixed lesions, it should be differentiated from brous dysplasia, desmoplastic broma, osteoblastoma, and chondrosarcoma.
In a study investigating the radiological characteristics of well-differentiated osteosarcoma in eight patients 14 , Ellis et al found three patients to be misdiagnosed as benign lesions both pathologically and radiologically. The tumor margins were ill-de ned in ve patients but well demarcated in the other three patients in radiograph. The bone response was both osteolytic and osteoblastic in seven patients but totally osteolytic in the remaining one, with expansile bone destruction in four patients. All patients had cortical thinning and discontinuity in imaging presentation, with extraosseous invasion in the soft tissue in six patients and active periosteal reaction in two. There were three common radiological features which strongly suggested malignancy: cortical discontinuity, ill-de ned soft-tissue invasion and cloudlike tumor matrix. Histologically, the IMWDOS is basically a spindle-cell tumor with low cellularity, irregular production of bone and few mitotic gures. The IMWDOS is so well differentiated that it is hard to make a malignancy diagnosis based on limited biopsy specimen 4,10 . The IMWDOS tumors are frequently demarcated as grey rm masses which have a brous whorled appearance typically localized in the medullary cavity in the metaphysis or meta-diaphysis area. In microscopic appearance, the tumors are hypo-cellular and composed of interlacing fascicles of spindle cells which showed mild cytological atypia with low mitotic activity. Typically, the IMWDOS tumor has a permeative growth pattern entrapping the native bone trabecula. An associated soft tissue mass may be present with the produced matrix being well differentiated.
Treatment modalities affect the prognosis of this disease. Wide resection with negative margins is the standard treatment with almost no recurrence at followup, whereas curettage or marginal excision was found to almost always lead to local recurrence with a 15% of recurrences being of high grade osteosarcoma 1 . Among 80 patients with low-grade intraosseous osteosarcoma 1 , eleven patients who had local surgical treatment (lesional curettage and marginal excision) all had recurrence within a mean of 3.9 years after the rst surgical operation and all underwent amputation. Four of the eleven patients died after 2-48 years after the diagnosis. Seventeen of the 80 patients had a wide excision as the initial treatment modality, with fteen patients still alive and free of disease at a mean follow-up of 4 years 1 . In our study, a total of 12 patients (12/17 or 70.6%) who had complete resection including amputation (n=2), wide excision (n=8) and endoprosthetic replacement (n=2) had no recurrence or metastasis at follow-up. Among ve patients with curettage in our study, three (3/17 or 17.6%) were recurrent with two deaths, and the third one died during post-operation chemotherapy. This con rmed that complete excision results in good recovery with no recurrence or metastasis.
There may be some limitations in this study, including a limited cohort of patients, which indicates the rarity of this disease, single center study, retrospective nature, Chinese ethnicity only and no comparison. However, this study also con rmed that wide excision with negative margins in most cases have a high chance of cure.
In conclusion, intramedullary well-differentiated osteosarcoma tends to occur at the metaphysis of long bones especially at the distal femur involving a large area. Histological, clinical and imaging data have to be closely combined to reach the correct diagnosis.

Declarations
Ethics approval and consent to participate: This study was approved by the ethics committee of the Third Hospital of Hebei Medical University, and all patients had given their signed informed consent to participate.
Consent for publication: All authors agreed to publish the paper in this journal.