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Keywords:

  • chordoid sarcoma;
  • myxoid chondrosarcoma;
  • bone;
  • cytogenetics

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

BACKGROUND

Chondrosarcoma of bone is a well recognized, relatively common clinicopathologic entity. Morphologically distinct soft tissue chordoid sarcoma (CS), or extraskeletal myxoid chondrosarcoma, is a relatively rare tumor that has generally been documented in extraosseous soft tissues.

METHODS

The clinical and pathologic features of two patients with biopsy-proven CS from the pathology files of the Mayo Clinic and St. Thomas's Hospital were evaluated. Routine hematoxylin and eosin-stained slides were reviewed in both cases. Sections from both were examined immunohistochemically using the avidin-biotin-peroxidase technique and employing commercially available antibodies to the following antigens: S-100 protein, cytokeratin (AE1/AE3), epithelial membrane antigen (EMA), CD31, and factor VIII. Appropriate positive and negative controls were utilized throughout these procedures. Cytogenetic analysis was performed on fresh samples obtained from one tumor. Clinical data were obtained from the patients' medical records.

RESULTS

The two cases of primary CS of bone arose from the right distal femur and right scapula, respectively, in 2 men ages 48 and 76 years, respectively. Morphologically, the tumors were lobulated, multinodular, and comprised of a uniform population of rounded to slightly spindled cells. Nuclei were hyperchromatic with inconspicuous nucleoli and surrounded by clear, vacuolated to eosinophilic cytoplasm. Neoplastic cells were arranged in anastomosing chords, strands, and, less often, nests and pseudopapillary structures embedded in an abundant, mostly hypovascular, mucinous matrix. Foci of hemorrhage and cystic degeneration were present in both tumors. No well developed hyaline cartilage or neoplastic osteoid was observed. Immunohistochemically, one neoplasm showed focal positivity for S-100 protein but was uniformly negative for cytokeratin (AE1/AE3), factor VIII, and CD31. The other tumor showed no immunopositivity with cytokeratin, EMA, or S-100 protein. Cytogenetic analysis in the latter tumor revealed a nonrandom reciprocal chromosomal translocation, t(9;22)(q22-31;q11-12). Both patients developed local recurrences and widespread distant metastases. Wide surgical excision was the primary mode of therapy. One patient died of tumor.

CONCLUSIONS

Skeletal CS is an extraordinarily rare neoplasm with a distinct morphology. Although follow-up data were limited to only four examples, including two from the literature, the clinical course appears worse than that for usual chondrosarcoma of bone. Wide surgical resection appears to represent the best mode of therapy. The role of chemotherapy and radiation therapy has not been clearly defined. Cancer 1997; 79:1903-10. © 1997 American Cancer Society.

Chordoid sarcoma (CS), also known as extraskeletal myxoid chondrosarcoma, is a relatively rare but well characterized tumor that usually arises in the deep soft tissues of the extremities.1, 2 Although myxoid degeneration is a common and often helpful finding in typical-appearing-chondrosarcomas of bone, morphologically distinct CS of osseous origin, to the authors' knowledge, has not been fully defined as a distinct clinicopathologic entity. To prevent confusion with the former, the authors have avoided the term myxoid chondrosarcoma in this article.

Regarding extraskeletal CS, Enzinger and Weiss, in their standard textbook of soft tissue tumors, state, "Since a morphologically identical tumor also occurs in bone, X-ray examination, CT scan, or magnetic resonance imaging may be necessary to establish its soft tissue origin."3 Nevertheless, the authors provide no references to substantiate the claim of a "morphologically identical tumor" in bone and no further information is given. Regarding the differential diagnosis of chordoma, Fechner and Mills mention myxoid chondrosarcoma as arising "in the soft tissues or bones" but, likewise, provide no references.4 In a small series of "chordoid sarcomas" Wick et al. described three examples of skeletal myxoid chondrosarcoma.5 However, it is unclear whether or not these tumors represented true CS or simply typical-appearing osseous chondrosarcomas with myxoid degeneration. The light microscopic description implied that the "neoplastic cells were set in distinct lacunar spaces," more characteristic of typical bone chondrosarcomas with myxoid changes than CS. Unfortunately, no radiographic or light microscopic illustrations of the skeletal myxoid chondrosarcomas were provided.5 Of several other major skeletal bone pathology textbooks, none recognizes osseous CS as a distinct clinicopathologic entity.6-9

In 1959, Lichtenstein and Bernstein described four neoplasms that may have represented skeletal CS.10 The tumors arose from the foot bones in three cases (astragalus, calcaneus, and metatarsal) and the finger phalanx in a fourth. The authors designated these tumors as "solitary chondroblastic sarcomas." Although the microscopic description appears to coincide with the current study cases, only one of the microphotographs, in the authors' opinion, is convincing for CS.10 Indeed, one of these tumors, which arose in the middle phalanx, may have represented a low grade chondroblastic osteosarcoma. The authors are aware of only isolated bona fide case report examples of primary CS of bone arising within the calcaneus, scapula, and femora.11-14

To better define the clinical and pathologic features of this rare neoplasm, the authors report herein two cases of skeletal CS and review the literature. In addition, they also discuss its clinical behavior, both within the skeleton and extraosseous soft tissues, in comparison to usual chondrosarcoma of bone.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Paraffin embedded tissue blocks and sections were retrieved from the pathology files of the Department of Anatomic Pathology, Mayo Clinic, (Case 1), Rochester, Minnesota, and the Department of Histopathology, St. Thomas's Hospital, London, United Kingdom (Case 2). Sections measuring 4-6 μm in thickness each were cut and stained with hematoxylin and eosin. Sections from both were also examined immunohistochemically utilizing the avidin-biotin-peroxidase complex and employing commercially available antibodies to the following antigens: S-100 protein (polyclonal, 1/2; Dako, Carpinteria, CA), cytokeratin (monoclonal, AE1/AE3, 1/100; Boehringer Mannheim, Indianapolis, IN), EMA (monoclonal, E29, 1/1000; Dako), CD31 (monoclonal, JC/70A, 1/20; Dako), and factor VIII (polyclonal, 1/8000; Dako). Appropriate positive and negative controls were utilized throughout these procedures.

Cytogenetic analysis was performed on fresh tumor samples obtained from Case 2. After disaggregation with collagenase, the tumor samples were characterized by standard G-banding after short term culture. The cytogenetics of this case have been previously reported. However, the bone origin was not appreciated at the time the specimen was collected, because the tumor was reported as extraskeletal.15

Plain film radiographs for Case 2 were not available for publication.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Case 1

A 48-year-old man presented to an outside institution reporting right knee pain of approximately 4 months' duration. He was initially diagnosed with degenerative joint disease and placed on crutches. Shortly thereafter, he fell, sustaining a fracture of his right distal femur. Conventional X-rays were obtained, revealing a permeative and destructive lesion of the right distal femur with concentric soft tissue extension and associated with pathologic fracture. A magnetic resonance imaging scan confirmed these findings (Fig. 1). Physical examination revealed a soft tissue mass in the right popliteal fossa and a second smaller (1-2 cm) mass involving the scalp. Incisional biopsy was performed, establishing the diagnosis of CS of the right distal femur with metastasis to the scalp. Subsequently, the patient was referred to St. Luke's Medical Center/Rush University. Due to the size of the neoplasm and probable involvement of neurovascular structures in the popliteal fossa, a right above-the-knee amputation was performed. Preoperatively, a chest computed tomographic scan showed no evidence of metastatic disease. Approximately 8 months after amputation, local recurrences developed in the soft tissues of the right thigh and scalp; cervical spine metastasis was also documented. He was given local radiation therapy and chemotherapy. At last clinical contact, approximately 13 months after amputation, the patient was alive but had widespread metastatic disease involving multiple sites including the lung, abdomen, lymph nodes, and bone.

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Figure 1. (A) Plain film radiographs and (B) magnetic resonance imaging reveal an ill-defined, permeative, and destructive lesion within the distal femur and an associated soft tissue mass.

Case 2

A 76-year-old man presented to an outside institution with an 18-month history of an enlarging, nonpainful right axillary mass. Conventional radiographs and computed tomographic scans revealed a mass associated with virtual complete destruction of the scapula and extensive extraosseous soft tissue extension. The epicenter of the tumor appeared to be within the scapula. The radiologist's interpretation suggested a primary bone sarcoma. Incisional biopsy was performed and the patient was referred to St. Thomas's Hospital for definitive therapy. Subsequently, he underwent a right radical forequarter amputation and excision of a portion of the chest wall. Postoperatively, he received radiation therapy. Approximately 22 months after radical surgery, he developed local chest wall recurrence, principally in the supraclavicular fossa. The remainder of his clinical course was complicated by widespread distant metastases. The patient died of tumor 59 months after initial presentation.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Pathologic Findings

Grossly, both tumors were gray-white, lobulated, markedly gelatinous, and focally showed red-brown, hemorrhagic, and cystic areas. No evidence of calcification or ossification was observed. The neoplasm from the patient in Case 1 measured 8 cm × 6 cm × 4 cm and extended from the femoral metadiaphysis to within 1 cm of the articular end (epiphysis) of the distal femur. No involvement of the joint cavity was present. Gross dissection in Case 2 revealed that the vast majority of the scapula had disappeared and was replaced by a lobulated mass, 22 cm × 15 cm × 10 cm. Only the superior 2.5 cm and medial 4 cm of the scapula (i.e., L-shaped) were intact and recognizable. The neoplasm had largely replaced the subscapular, infraspinotus, and posterior aspect of the deltoid muscle.

Microscopically, both tumors were also similar, being multinodular and lobulated. The appearances were essentially identical to CS in soft tissue. The degree of cellularity ranged from moderate to marked with a tendency, in some places, toward increased cellularity at the periphery of the nodules (Fig. 2). Individual neoplastic cells were usually arranged in short cohesive chords and linear strands within an abundant extracellular mucinous matrix (Fig. 3). The anastomosing chords often exhibited a "lace-like" appearance. Less frequently, tumor cells formed whorled aggregates, nests, and pseudopapillary structures, mimicking a mucinous adenocarcinoma (Fig. 4). Although blood vessels were present, they were not usually prominent. Cytologically, the tumor cells ranged from round, epithelial-like to bipolar spindled shapes. The nuclei were remarkably uniform, hyperchromatic, and surrounded by a thin rim of eosinophilic cytoplasm. Vacuolated cells were also frequently observed (Fig. 5). Mitotic activity was variable, ranging from <1 to 10 mitotic figures per 10 high-power fields in the most cellular areas. Well developed neoplastic hyaline cartilage and malignant osteoid were not observed in either tumor. Both tumors clearly showed extensive permeation and destruction of bone with foci of residual lamellar bone entrapping, characteristic of a primary bone sarcoma (Fig. 6).

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Figure 2. Case 2. Low-power view of chordoid sarcoma showing a multinodular pattern with individual nodules separated by fibrous tissue septa. Note the tendency for increased cellularity at the periphery of some of the nodules (H & E, original magnification ×20).

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Figure 3. Case 1. Anastomosing chords and strands of uniform-appearing tumor cells represented the most frequent pattern (H & E, original magnification ×100).

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Figure 4. Case 2. Some areas showed whorled chords and strands of tumor cells arranged in pseudopapillary configurations. (H & E, original magnification ×100).

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Figure 5. Case 1. Less frequently, cells with intensely vacuolated cytoplasm were present. Multivacuolated physaliferous cells were not observed in either tumor (H & E, original magnification ×200).

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Figure 6. Case 1. Infiltrating tumor cells arranged in cellular anastomosing chords, strands, and "lace-like" patterns entrapping residual bony trabeculae, have virtually completely replaced the bone marrow elements (H & E, original magnification ×40).

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Immunohistochemically, the neoplastic cells from Case 1 showed focal positivity for S-100 protein but were uniformly negative for cytokeratin (AE1/AE3), factor VIII, and CD31. The neoplastic cells from Case 2 showed no immunopositivity for S-100 protein, cytokeratin (AE1/AE3), or epithelial membrane antigen.

Cytogenetic analysis performed on Case 2 revealed a reciprocal translocation between chromosomes 9 and 22, t(9;22)(q22-31;q11-12).

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Extraskeletal myxoid chondrosarcoma was probably first described in 1953 by Stout and Verner, who reported a small series of morphologically similar-appearing cases, all of which arose in the extremities of adults.16 However, in 1972 Enzinger and Shiraki, in a series of 34 cases, first established extraskeletal myxoid chondrosarcoma or CS as a distinct clinicopathologic entity.1 Despite numerous additional case reports and series of extraskeletal CS,2, 17-24 to the authors' knowledge, only isolated rare bona fide case examples of skeletal CS have been clearly documented.11-14 The clinical features of the patients in the current study, as well as those reported in the literature, are summarized in Table 1.

Table 1. Clinical Features of Chordoid Sarcoma of Bone: A Literature Review
ReferenceAge/GenderLocationFollow-up (yrs)Status
  1. M: male; F: female; NA: not available; AWD: alive with disease; DOD: dead of disease; M: metastasis; R: local recurrence.

Steiner et al.11,, 3072FLeft calcaneus8.5AWD, M, R
Martinez-Tello et al.129MRight femurNANA
Fu and Kay1325MLeft femur6AWD, M, R
Gill et al.1466MScapulaNANA
Kilpatrick et al. (current series)48MRight femur1AWD, M, R
 76MRight scapula5DOD, M, R

Microscopically, extraskeletal CS is a distinctly lobulated, multinodular tumor comprised of a uniform population of rounded to slightly spindled cells, frequently arranged in anastomosing chords, strands, nests, and, less commonly, pseudopapillary structures.1, 2 By definition, the tumor cells are embedded in an abundantly mucinous, mostly hypovascular matrix. Cytologically, the nuclei show minimal to absent pleomorphism and are typically surrounded by a thin rim of clear, vacuolated to eosinophilic cytoplasm. Sometimes the cytoplasm contains hyaline "rhabdoid" inclusions.20 In contrast to typical chondrosarcoma of bone, well developed hyaline cartilage is rarely present in extraskeletal CS. Both of the cases in the current study exhibited these classic light microscopic features. Well developed neoplastic hyaline cartilage and malignant osteoid were not recognized in either tumor.

The radiographic findings were similar in both cases and showed changes characteristic of a primary bone malignancy. Furthermore, the permeative radiographic appearance with an associated soft tissue mass was indistinguishable from that usually observed in osteosarcoma or fibrosarcoma of bone origin. As a general rule, benign and malignant soft tissue tumors do not generally affect adjacent bone. Extensive bone destruction associated with an adjacent soft tissue mass is indicative of a primary bone tumor.25 When a soft tissue tumor affects adjacent bone, it usually causes minor cortical destruction; the bulk of the tumor, or epicenter, is observed in the soft tissues. In both cases in the current study, the epicenter of the tumor mass was associated with and extensively destroyed the presumed bone of origin. Subperiosteal spread was also noted in the tumor from the femur. The radiographic features of several rare primary bone tumors, more commonly associated with extraskeletal soft tissue origin, have also been described and appear similar to that observed in the current study cases.26-29 It should be pointed out that extraskeletal CS may cause focal erosion of adjacent bones, especially the small bones of the hands and feet.30, 31 In these examples, the epicenter of the tumor remained in the soft tissues.

The differential diagnosis for CS of bone includes mainly metastatic mucinous adenocarcinoma, epithelioid hemangioendothelioma, and chordoma. Because occasional examples of CS may show immunopositivity for cytokeratin, a thorough clinical and radiologic examination is best for excluding metastatic adenocarcinoma.23 Like CS, epithelioid hemangioendothelioma may exhibit uniform populations of neoplastic cells arranged in chords and strands embedded in a mucinous to chondroid-appearing matrix.32, 33 Vacuolated cells may be observed in both CS and epithelioid hemangioendothelioma; however, in epithelioid hemangioendothelioma, the vacuolation represents primitive vascular lumina and therefore, may contain red blood cells. Immunohistochemically, CS often expresses S-100 protein but is uniformly negative for factor VIII and CD31.2, 3 The latter two immunohistochemical markers are virtually always positive in epithelioid hemangioendothelioma. One of the current study cases (Case 1) showed focal positivity for S-100 protein, but was negative for cytokeratin, factor VIII, and CD31. The other (Case 2) showed no immunopositivity for S-100 protein, cytokeratin, or epithelial membrane antigen.

Chordomas most frequently arise in the sacrum, sphenooccipital region, and spine of middle-aged to older adults.34 Unlike CS, extremity involvement by chordoma is, for all practical purposes, nonexistent. Microscopically, chordomas are lobulated and comprised of strands, chords, and syncytia of uniform-appearing tumor cells within a hypovascular, mucinous matrix. Cytoplasmic vacuolation is common and, when abundant, the cells are termed physaliferous cells. Hyaline cartilage is rarely observed except in the sphenooccipital region, the so-called chondroid chordoma.34 Based solely on microscopic features, distinction between CS and chordoma may be difficult. The less common vacuolated areas of CS may closely resemble that observed in chordoma. However, diagnostic physaliferous cells are absent in CS and cytoplasmic vacuolation tends to be focal rather than diffuse, as observed in chordoma. Although both chordoma and CS are multilobulated, this feature tends to be more distinct in CS. By electron microscopy, the ultrastructural features of CS and chordoma are distinct, with the latter containing small, membrane bound, glycogen inclusions.5 Immunohistologically, S-100 protein positivity may be observed in both, but keratin and epithelial membrane antigen immunopositivity are more characteristic of chordoma.2, 23, 34, 35 Clinical correlation (i.e., anatomic site) is of the utmost importance. When available, cytogenetic analysis may also be helpful because extraskeletal CSs typically show a nonrandom reciprocal translocation of chromosomes 9 and 22, t(9;22)(q22-31;q11-12) with the EWS/TEC gene fusion product.14, 15, 36 To the authors' knowledge, only one example of skeletal CS involving the scapula of a 66-year-old man has been reported to contain this unique cytogenetic finding.14 One of the cases in the current study (Case 2), which involved the scapula in a 76-year-old man, also had this classic translocation. These two reported cases appear to provide compelling evidence that extraskeletal CS does have a skeletal counterpart. It should also be pointed out that a rare case of dedifferentiated chondrosarcoma reportedly showed a similar nonrandom translocation involving a more distal region of chromosome 9q, t(9:22)(q34;q11-12).37

Most initial reports have suggested that, aside from the differences in morphologic appearance, the biologic behavior of extraskeletal CS is appreciably different from that observed in classic chondrosarcoma of bone, the latter being distinctly more aggressive.1, 18, 24 However, recent investigators have not substantiated this claim. In a series of 10 patients with extraskeletal CS and long term clinical follow-up (>10 years), Saleh et al. documented 7 deaths (70%) due to metastatic tumor.38 The duration of survival for the patients who died ranged from 4 to 17 years. Nine patients (90%) developed distant metastasis and 5 patients (50%) had local recurrences. A second larger study, also with long term clinical follow-up, confirmed these findings; although survival was prolonged, local recurrences and even distant metastases occurred frequently (48% and 46%, respectively).39 Alternatively, the rates of local recurrence and distant metastases in chondrosarcomas of bone range from 20-45% and 14-20%, respectively.8, 40 Because these rates are reflective of all bone chondrosarcomas, regardless of histologic grade and mode of therapy (i.e., curettage vs. resection), the actual rates of local recurrence and distant metastasis are probably considerably lower for most cases. The relationship between histopathologic grade and clinical behavior of typical chondrosarcoma of bone has been well established.41 In the Mayo Clinic experience, as many as 60% of cases of osseous chondrosarcomas are low grade (Grade 1 of 3) type.8 Grade 1 chondrosarcomas of bone, although frequently associated with local recurrence if not adequately excised, rarely, if ever, develop metastases in the absence of dedifferentiation.40, 42 Only a minority of chondrosarcomas of bone represent the metastasizing Grade 3 type.

Clearly, the prognosis of most examples of extraskeletal CS is considerably worse than that observed in the vast majority of skeletal chondrosarcomas. Based on the clinical follow-up in the two cases in the current series and a review of the literature, it also appears that CS of bone is clinically more aggressive than typical skeletal chondrosarcoma. In one previously reported primary bone CS, the patient developed a local recurrence necessitating a below-the-knee amputation and distant metastases to the right groin, lung, and left thigh occurred 8.5 years after the initial diagnosis.11, 30 In a second reported example involving the left proximal femur of a 25-year-old man, the patient developed a local recurrence necessitating a hip disarticulation 4 years after initial diagnosis, distant metastases developed 2 years later.13 Despite wide surgical resection, both patients in the current study developed local recurrences and distant metastases; 1 patient died of tumor approximately 5 years after the initial diagnosis.

In summary, extraskeletal CS is a rare neoplasm with a distinct morphologic appearance and, ultimately, aggressive clinical behavior. Rare examples may also occur in bone and, based on a limited amount of data, appear to have a predilection for the femur and arise in older male patients. Although male gender, large tumor size, older age, and distant metastases are significantly associated with poor survival in patients with extraskeletal CS, histologic grading and proliferation markers appear to have no prognostic value.39 Whether or not such clinical and pathologic parameters have prognostic importance in skeletal CS is currently unclear. Because the prognosis for both skeletal and extraskeletal CS appears similar and worse than that typically observed with classical chondrosarcoma of bone, distinction between CS and chondrosarcoma of bone is essential. Because of its potentially high rate of local recurrence and distant metastasis, wide surgical resection appears to represent the best mode of therapy in CS, whether it is skeletal or extraosseous. The role of chemotherapy and radiation therapy has not been firmly established and will necessitate identification of a larger number of cases.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES