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Influence of Cryosurgery on Treatment Outcome of Low-grade Chondrosarcoma

Ahlmann, Elke R, MD*; Menendez, Lawrence R, MD, FRCS; Fedenko, Alexander N, MD; Learch, Thomas, MD§

Clinical Orthopaedics and Related Research®: October 2006 - Volume 451 - Issue - p 201-207
doi: 10.1097/01.blo.0000229293.98850.5d
SECTION II: ORIGINAL ARTICLES: Tumor
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Successfully managing low-grade chondrosarcomas with margins considered less than wide would minimize the need for extensive reconstruction. We report our experience using cryotherapy as an adjuvant to treat patients with low-grade intracompartmental chondrosarcomas. Ten consecutive patients had intralesional resections including curettage, cryo-surgery, and polymethylmethacrylate application. Eight of these patients required prophylactic skeletal stabilization. We retrospectively reviewed the outcomes for tumor recurrence, disease progression, and complications. The Musculo-skeletal Tumor Society rating scale was used to evaluate functional outcome, and the mean score was 27 points (range, 25-30 points). The mean age of the patients was 54.4 years (range, 29-83 years), and the average followup was 38.5 months (range, 24-60 months). Patients were treated for lesions of the femur (n = 3), humerus (n = 3), scapula (n = 2), tibia (n = 1), and acetabulum (n = 1). There was no evidence of recurrence or metastases. At the latest followup, all patients were well, however, one patient had hardware loosening. In this small group of patients, intralesional resection with adjuvant cryoablation provided an alternative to more radical procedures for low-grade intracompartmental chondrosarcoma.

Level of Evidence: Level IV Therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

From the *Department of Orthopaedics, Los Angeles County-University of Southern California Medical Center, Los Angeles, CA; the Department of Orthopaedics, the Department of Pathology, and the §Department of Radiology, Keck School of Medicine, University of Southern California, USC University Hospital, Los Angeles, CA.

Received: August 31, 2005

Revised: February 7, 2006; April 13, 2006

Accepted: June 1, 2006

Each author certifies that he or she has no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article.

Each author certifies that his or her institution has approved the reporting of these cases, that all investigations were conducted in conformity with ethical principles of research, and that informed consent was obtained.

Correspondence to: Elke R. Ahlmann, MD, Department of Orthopaedics, Los Angeles County-University of Southern California Medical Center, 1200 N. State Street, GNH 3900, Los Angeles, CA 90033. Phone: 323-226-7210; Fax: 323-226-4052; E-mail: ahlmann2002@yahoo.com.

Chondrosarcoma is the most common primary malignant bone neoplasm in patients older than 25 years, occurring in eight per one million people in the United States.29 A chondrosarcoma can begin as a primary malignant tumor or as a result of secondary malignant degeneration of a benign lesion such as an enchondroma or osteochondroma. As a group of tumors, chondrosarcomas have a variable and often unpredictable course, ranging from slow-growing lesions to aggressive metastasizing sarcomas. Prognosis depends on anatomic location, size of the lesion, and histologic grade.12,35

Some authors think appropriate treatment should be dictated by accurate staging and histologic grading.11,12,35 Chondrosarcomas are graded as Grade I (low grade), Grade II (intermediate grade), or Grade III (high grade) based on the histologic character of the intercellular background, degree of pleomorphism, mitotic activity, and frequency of lacunae containing multiple nuclei. The histo-logic grade is the most important prognostic indicator, with a 90% 5-year survival for patients with a Grade I tumor and a 40% to 60% 5-year survival for patients with Grades II and III tumors.12,13,35

Surgical resection has been the primary treatment of chondrosarcomas, as neoadjuvant and adjuvant therapies such as radiation and chemotherapy have been ineffective.11,18 They are reserved for recurrent disease, meta-static lesions, and unresectable tumors. Achieving an adequate surgical margin is the most important factor in successful treatment.6,32 Intermediate and high-grade tumors are treated locally with wide excision, and often with resultant endoprosthetic reconstruction.11,18 However, there is debate regarding the definition of adequate surgical margins in the treatment of low-grade chondrosarcomas. Some authors report preliminary successful treatment using curettage and cryosurgery,2,26,36 whereas others report margins considered less than wide may be inadequate and lead to an increased recurrence.6,13,18,34,38 Successful treatment of low-grade chondrosarcomas with less than wide resections would minimize the need for extensive reconstructive procedures and improve functional outcomes.

Curettage and cryotherapy are accepted adjuncts to surgical treatment of benign aggressive tumors,5,22,23 and may be effective in achieving local control of low-grade malignant lesions in properly selected patients. This surgical regimen may effectively treat localized intracompart-mental low-grade chondrosarcomas of the extremities without the morbidity associated with endoprostheses, structural allografts, or arthrodeses.

We sought to determine whether the local recurrence rate and disease progression of patients treated with intralesional resection and adjuvant cryoablation are comparable to those of more extensive resections. We additionally assessed the intermediate clinical and functional results regarding complications and functional outcome.

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MATERIALS AND METHODS

Through our oncology database, we identified 24 patients with low-grade extremity chondrosarcomas who had surgical excisions by one surgeon (LRM) from March 2000 to March 2003. From these 25 patients, we selected patients with intracompart-mental low-grade chondrosarcomas of bone treated with intralesional resection and adjuvant cryoablation and who had a minimum followup of 2 years. Patients with extracompartmental lesions extending into the soft tissues, patients with extraskeletal low-grade chondrosarcomas, and patients with less than 2 years followup were excluded from the study. This left 10 patients, eight men and two women, with a mean age at diagnosis of 54.4 years (range, 29-83 years) (Table 1). The average length of followup was 38.5 months (range, 24-60 months). The most common anatomic location was the proximal humerus (n = 3), followed by the glenoid of the scapula (n = 2), femoral neck (n = 2), distal femur (n = 1), proximal tibia (n = 1), and periacetabulum (n = 1).

TABLE 1

TABLE 1

All patients were referred to the senior author (LRM) for treatment. At presentation we obtained a detailed history, performed a physical examination, and obtained standard antero-posterior (AP) and lateral radiographs (Fig 1), magnetic resonance images (MRI) of the extremity, computed tomography (CT) scans of the chest, and radionuclide bone scintigraphy according to standard protocols to aid staging according to Enneking's classification system for malignant tumors.9 Magnetic resonance imaging is more accurate than CT in determining the extent of bone and soft tissue involvement.39 Computed tomography scans of the lesion were not obtained from the patients in this study, but they may be useful in determining the amount of cortical destruction. Patients also had total body bone scintigraphy to rule out evidence of secondary lesions or metastatic disease. All patients had one intracompartmental lesion at the time of presentation. The average lesion size as measured on preoperative radiographic studies was 10 cm (range, 4-20 cm). The lesions were differentiated from enchondromas as all patients were symptomatic and had pain directly at the site of the lesion, and plain radiographs showed evidence of cortical erosion.

Fig 1A

Fig 1A

We performed all surgery using standard principles without using extremity tourniquets. We used intraoperative fluoroscopic image intensification to accurately localize the lesion. The incisional biopsy was performed by drilling a large cortical window the size of the largest diameter of the lesion using a Midas Rex® burr (Midas Rex®, Fort Worth, TX). A specimen was removed with curettes and sent for intraoperative frozen section. All tumors were classified as Stage IA (low-grade, intracompartmental) according to the MSTS staging system9 after biopsy and surgical resection.

Additional surgery was performed if the results showed a low-grade chondrosarcoma. This consisted of thorough manual curettage while leaving a cavitary defect débrided of microscopic tumor tissue by the high-speed burr to remove any remaining neoplastic tissue.

After adequately retracting and protecting the surrounding soft tissues, neurovascular structures, and skin, we performed cryosurgical ablation using the CRYOcare® Smart23 system (Endocare Inc, Irvine, CA). This system uses argon gas (which has the advantage of freezing faster and colder than liquid nitrogen) to achieve a maximum temperature of −186°C. The osseous defect was filled with Surgilube® gel (Fougera®, Melville, NY) to provide conduction, and four to eight strategically placed probes (CRYOcare®, Endocare Inc) filled with argon were applied to rapidly freeze the cavity (Fig 2). Intralesional temperatures of approximately -160°C were maintained for 5 minutes with constant monitoring using thermocouples. The cavity then was allowed to slowly thaw by circulating helium gas through the probes while maintaining a temperature of 0°C for 5 minutes. Two cycles of fast-freeze slow-thaw were used to effectively extend the margin of resection.

Fig 2

Fig 2

If not used with caution, cryosurgery can injure the remaining bone and result in subsequent pathologic fracture. To prevent this complication, we used polymethylmethacrylate (PMMA) cement and internal fixation to the skeletal defect for additional structural support. Skeletal reconstruction with internal fixation was used in eight patients in whom stability was deemed compromised because of the extent and location of the resection. Our criteria for placing internal fixation were any lesion involving a lower-extremity weightbearing bone or a large cortical window in an upper extremity greater than 5 cm. The remaining osseous defect was packed with PMMA mixed with tobramycin for additional structural support. Five patients had intramedullary nailing, two had dynamic hip screws for prophylactic stabilization, and one patient with a periacetabular lesion had screws placed through the defect as a structural support for the bone cement (Fig 3). Two patients with scapula lesions did not have internal fixation. In one patient with a 20-cm tibial cortex resection, the reconstruction was augmented with a strip of cortical allograft cabled to the remaining bone using #5 fiber wire. Closed suction wound drains and perioperative antibiotics were routinely used. Patients were maintained at partial weightbearing for 6 weeks postoperatively.

Fig 3A

Fig 3A

All intraoperative frozen sections and permanent specimens were examined for histologic grade by a musculoskeletal-trained pathologist (ANF). Because of the difficulty in histologically distinguishing between enchondromas and low-grade chondrosarcomas, we retrospectively had a second blinded pathologist (AC) independently review the permanent slides. All study patients were confirmed to have been treated for low-grade chondrosarcomas. The diagnosis of low-grade chondrosarcoma was made based on the structural character of the intercellular background, the degree of pleomorphism, and replication activity (Fig 4).

Fig 4

Fig 4

Patients were followed up at regular intervals every 3 months for the first 2 years, every 6 months between 2 and 5 years after treatment, and yearly thereafter. We performed physical examinations, obtained plain radiographs, MR images of the surgical bed, CT scans of the chest, and specifically questioned patients about symptoms and complications at each visit. Functional evaluations were performed by administering the Musculoskeletal Tumor Society (MSTS) survey for functional outcome after the surgical treatment of musculoskeletal tumors.10 This survey equally weights pain, function, emotional acceptance, ambulatory supports, walking ability, and gait to obtain an overall numeric rating and a subjective rating of patient satisfaction.

From the patients' medical records, we recorded the time to local recurrence and disease progression, defined as the time to development of distant metastases. Additionally, postoperative complications and functional outcome scores were recorded. The results were compared with historical controls from the literature.

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RESULTS

No patients had locally recurrent disease at last followup. All patients were alive and well, and none had evidence of metastatic disease. No patients died as a result of tumor-related causes.

Only one complication occurred resulting in additional surgery. One patient had loosening of an intramedullary tibial nail and had surgery to insert distal interlocking screws. There were no pathologic fractures, neurovascular injuries, skin necrosis, or infections.

Functional outcome, as measured by the MSTS outcomes assessment, was consistently high for the 10 patients with an average of 27.3 points (range, 25-30 points). Overall, patients achieved 91% of their preoperative function. All patients participated in activities of daily living and occupation-related activities. Three patients experienced occasional mild pain relieved with nonnarcotic analgesics. Ambulatory supports were used by only one patient (Patient 8), an 88-year-old man who used a cane for balance. All patients stated they were very satisfied with the procedure and would have it again under similar circumstances.

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DISCUSSION

There is controversy regarding the extent of resection needed for adequate treatment of low-grade intracompart-mental chondrosarcomas. In the past, en bloc resection with wide surgical margins and skeletal reconstruction was advocated, often resulting in considerable morbidity and functional deficits.6,11,32 However, some authors suggested intralesional excision combined with cryosurgery provides equal tumor control to marginal excision and better function than wide resection.36 We did this study to determine if the local recurrence rate and disease progression in patients treated with intralesional curettage and cryoablation compares favorably with more extensive re-sections.

The limitations of this study include the presence of numerous confounding factors, a small study group, and limited followup. Although low-grade chondrosarcomas are slow-growing and often take a substantial amount of time to recur or metastasize, previous studies have shown the majority of patients who have inadequate surgery will experience local recurrence within 2 years.6,12 Therefore we limited the study to patients with a minimum of 2 years followup, resulting in a relatively small group. An additional problem with this disease in particular is the inherent difficulty in diagnosis of a low-grade chondrosarcoma. Controversy exists regarding the differentiation between enchondroma from low-grade chondrosarcoma because of their cytologic similarity.27 The misclassification of benign enchondromas as low-grade chondrosarcomas in studies evaluating local recurrence and metastasis rates can falsely improve results.27 When treating patients with this suspected disease, caution must be exercised before instituting treatment. The difficulty exists in obtaining certainty that these lesions are truly sarcomas. In such cases the histologic specimens should be examined by a trained musculoskeletal pathologist experienced in evaluating these tumors. Otherwise many patients with enchondromas may be overtreated with this surgical protocol. For this reason we only made the diagnosis of Grade I chondrosarcoma when the clinical and radiologic pictures were concurrent with the histologic diagnosis. We used the combined histologic and cytologic approach, which allows the benign enchondromatous pattern to be differentiated from a chondrosarcoma permeation pattern where cartilage permeates lamellar bone, infiltrates the Haversian systems, and replaces marrow fat.27 Therefore, we think classification of these lesions was correct and our results reflect the treatment of Grade I chondrosarcomas.

Limited intralesional procedures such as curettage alone are not adequate treatments for low-grade chondrosarcomas because of recurrence rates from 50% to 92%.11,32,35 Previous studies have shown intralesional re-section with adjuvant cryoablation may be an acceptable alternative to more extensive resections to decrease local recurrence and preserve function.26,36 A report of nine low-grade chondrosarcomas treated with curettage, cryo-ablation, bone grafting, and skeletal fixation revealed no local recurrences after a 26-month followup.36 Another study showed no local recurrences using curettage and cryoablation alone in seven patients after an average 6.5-year followup.26 Conversely, previous reports of patients with low-grade chondrosarcomas treated with wide excision showed 0% to 15% local recurrence rates, indicating more radical procedures are not necessarily curative.10,11,16 We think our study has the largest reported group of patients with Stage IA chondrosarcomas treated with intralesional resection with adjuvant cryoablation (Table 2). There were no local recurrences after an average 38.5-month followup, indicating our protocol may be a viable alternative to en bloc resection.

TABLE 2

TABLE 2

The success of cryoablation in treating giant cell tumors and aneurysmal bone cysts has been documented.22,23,25 Cytotoxic effects of cryoablation include thermal shock, denaturation of proteins, microvascular failure, and electrolyte changes.5,22 Previous studies have shown the zone of necrosis producing tumor cell death to range from 7 mm to 2 cm from the margin of resection depending on the number of freeze-thaw cycles.24,25

In addition to providing structural support, PMMA cement also can contribute to extending the surgical resection margins. Polymethylmethacrylate has been proposed to have tumoricidal properties because of the direct cytotoxic effects from the methylmethacrylate monomer and tissue hyperthermia from the exothermic polymerization process of the cement.7,16,17,19,20,30,31,37,40 The degree of local hyperthermia may be sufficient to produce a substantial zone of necrosis of neoplastic cells 1.3 to 2.8 mm from the bone-cement interface.3,4,15,21,28,41

The main complications associated with cryoablation include fracture, skin necrosis, transient nerve injuries, and infection.22,23,25,26,36 There is a 5.9% to 38% rate of pathologic fracture after cryosurgery in the absence of skeletal stabilization.22,26 We recommend routinely placing prophylactic internal fixation and cement in all lesions occurring in weightbearing bones and with large cortical windows in the upper extremity because of an increased risk for osteonecrosis as a result of cryoablation, which may lead to iatrogenic fracture. Our patients experienced no postoperative pathologic fractures despite cortical windows and defects of as much as 20 cm, which would have produced substantial stress risers.8,14,33 Postoperative fractures can be reduced by prophylactic internal fixation and supplemental cementation to provide immediate structural support after extensive resections.1

Cryoablation can result in skin, soft tissue, and nerve injuries if not used with caution. These complications occur in 1% to 3% of patients,22 and mainly are associated with the direct-pour and spray techniques of applying liquid nitrogen to a cavity without adequate retraction and protection of the surrounding structures. Using small thermal probes to circulate a freezing substance allows strategic application and computer-regulated temperature control.

The primary goals in treating patients with low-grade chondrosarcomas are to control disease and preserve function. This is especially important with periarticular tumors in which en bloc excision would result in resection of the native joint. Periarticular lesions occurred in eight of 10 patients, and joint function was preserved using our protocol. We avoided extensive resections and endoprosthetic reconstructions, which may have resulted in substantially greater disability and functional deficits. The overall functional outcome was excellent with MSTS questionnaire results indicating patients achieved 91% of premorbid function.

Low-grade intracompartmental chondrosarcomas treated with a protocol of curettage, cryoablation, bone cementation, and internal fixation seems to be a viable surgical alternative to more radical procedures. This allows for a reliable and durable solution while avoiding the morbidity of endoprosthetic reconstruction or amputation. There is strong clinical evidence to support intralesional resection with adjuvant cryoablation for treating Stage IA chondrosarcomas.

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Acknowledgment

We thank Adrian Correa, MD, for assistance in this study.

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References

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