Journal of Surgical Oncology 47:75-78 (1991)
REFINEMENTS IN TECHNIQUE Open Biopsy Without Wound Closure for Skeletal Neoplasms KATHRYN E. CRAMER, MD, AND HERBERT S. SCHWARTZ, MD From the Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, Tennessee
During the past several years, the indications for limb salvage in musculoskeletal neoplasms have been expanded. As a result, interest in the topic of diagnostic biopsy has been renewed. Post biopsy hematoma formation and the iatrogenic spread of cancer cells has led to universally accepted guidelines for biopsy technique. These include meticulous hemostasis and wound closure. A technique of open biopsy without wound closure in which the biopsy site in a long bone with contained neoplasm remains open and hematoma allowed to drain into the dressings is outlined. A discussion of the theoretical advantages and disadvantages of this technique is presented. KEYWORDS:hematoma, tumor, bone
INTRODUCTION The iatrogenic spread of cancer in humans has been the subject of discussion for more than a century [1-4]. Human and animal studies have demonstrated increased numbers of cancer cells in the blood after surgical manipulation (biopsy) of a primary tumor [5-81. No investigations conclusively demonstrate that an increased number of tumor cells in the blood are adversely correlated with survival. This is in part due to the poor understanding of the biology of metastases. Brostrom et al. [9] conducted a retrospective study examining the effect of biopsy on survival of patients with osteosarcoma. These investigators concluded that the performance of a biopsy, followed shortly by amputation, had no adverse effect on survival. Three canine studies in the past decade have addressed the issue of tracking the iatrogenic spread of hematoma after open bone biopsy [ 10-121. Generally, biopsyinduced hematoma spreads intraosseously and in the adjacent soft tissues further than one might anticipate. The concept of the potential detrimental effects of local hematoma spread after open bone biopsy was appreciated many years ago at this institution. A novel biopsy technique was randomly employed to combat hematoma spread in which the incision and biopsy tract were left open at the termination of the surgical procedure. This paper describes the “open” open biopsy technique, reports on six case studies with long-term follow-up, and 0 1991 Wiley-Liss, Inc.
outlines the theoretical advantages and disadvantages of this alternative method of skeletal biopsy.
MATERIALS AND METHODS The hospital charts and clinic records for all patients treated at a single institution for a musculoskeletal neoplasm between 1960 to 1984 were reviewed. Seventyseven patients had sufficient records to review; of these, six were biopsied and treated definitively at our institution using the biopsy technique detailed below. The hospital charts, pathology reports, and radiographs of these six patients were reviewed in detail, and data regarding age, sex, location of the lesion, diagnosis, biopsy date and technique, definitive treatment, recurrence of lesion, and outcome were recorded. Complications related to the biopsy procedure were also noted (Table I). The biopsy technique used for these six patients differed significantly from that for the rest of the patients reviewed in that, after obtaining the biopsy specimen from the lesion, the biopsy sites were left open, then dressed and allowed to drain freely into the dressings. A Penrose drain or gauze wick was occasionally placed into Accepted for publication February 19, 1991. Address reprint requests to Dr. Herbert S. Schwartz, Department of Orthopaedics and Rehabilitation, T-43 1 1 MCN, Vanderbilt University Medical Center, Nashville, TN 37232-2550.
76
Cramer and Schwartz
TABLE I. “Open” Open Biopsy Technique: Patient Data Patient Data
#2
#I
#6
32 F Distal femur
12116/70 Low-grade chondrosarcoma None Wound infection 3/18/71 5/4/73 Resection, Curettage, autoclave ICBG, RT replantation, fixation
2/4/80 Periosteal OGS
1 O/ 18/82 GCT
2/15/78 Parosteal OGS
21 M Proximal humerus 2117/82 Parosteal OGS
None
None
None
2/17/78 Adjuvant chemotherapy, AK amputation
6130175, NED
6/6/90, NED
3 soft tissue recurrences 10/20/82 En bloc resection, proximal fibula transfer; 3 local excisions 4130187, NED
2/24/82 En bloc resection with fibula graft and ICBGshoulder fusion 8/87, NED
Bx date Pathology
Follow-up
#5
34 F Distal radius
27 M Distal femur
Rx date Rx
#4
18 F Midshaft tibia
Age Sex Location
Comp. (Bx)
#3
18
F Proximal humerus 5/2/73 GCT
12/14/84, NED
2/7/80 AK amputation, adjuvant chemotherapy
the wound, but no attempt was made to seal the medullary cavity or to close the wound with sutures. This technique, hereafter referred to as the “open” open biopsy technique, was used without rigid indications by the acknowledged author, who had an active oncology practice.
RESULTS The six patients that underwent biopsy with the “open” open technique had different diagnoses with lesions in different locations, as shown in Table I. All were under 35 years of age, and all had long bone lesions. All had aggressive benign or malignant neoplasms. With the exception of one patient (#4), all patients were operated on by the same surgeon. Three patients had five, and three patients, 10-year follow-up documentation. Nontumor complications related directly to the biopsy occurred in one patient (#l), who developed a grampositive wound infection at the biopsy site that required local wound care and antibiotics to clear. This subsequently delayed the patient’s definitive procedure. At 5-year follow-up he was doing well, with no evidence of recurrence. One patient (#4) sustained a tumor-related complication. With that exception, all other patients were alive and well at the final follow-up visit, with no evidence of recurrence. This patient (#4), had a radiographically aggressive giant cell tumor of her distal radius resected and a reconstruction utilizing autogenous fibular graft. She had three histologically documented local soft tissue recurrences that were excised; however, she had no evidence of metastatic spread or graft involvement at final follow-up.
12/88, NED
DISCUSSION The biopsy has been described as “the most crucial procedure” in the diagnosis of musculoskeletal lesions [ 131. Renewed interest in the biopsy procedure has been spurred by recent advances in the treatment of musculoskeletal lesions and the potential for limb salvage in many lesions that previously were only amenable to amputation. Adjuvant chemotherapy, radiation therapy, and better methods of fixation, along with the wider availability of allograft bone have all led to an improved prognosis for patients with musculoskeletal tumors. The biopsy procedure, when performed correctly, provides sufficient material for diagnosis and does not compromise the outcome for the patient [ 141. In a multicenter study reviewing biopsy complications, Mankin et al. [ 151 found a 17% incidence of problems related to the biopsy involving the skin, soft tissue, or bone, which altered the optimum treatment plan for the patient and a 10% incidence of nonrepresentative or technically poor biopsy specimens. The technique for open biopsy has been well described [ 13-16]; generally, meticulous hemostasis and surgical wound closure without drains is recommended. These recommendations have been universally accepted in the years following their publication in 1982. The group of patients in this study all underwent biopsy prior to the widespread acceptance of these recommendations. The biopsy procedure in these patients generally followed the standard recommendations with the exception that, although hemostasis was achieved, the wounds were not closed and were allowed to drain freely into the sterile dressings. The theoretical advantage of this is that there
Open Biopsy
is no hematoma accumulation and the potential for local spread should be diminished. An investigation of hematoma formation following bone biopsy using an animal model found that when the cortex of the bone was plugged with methylmethacrylate, no extraosseous hematoma was evident and very little hematoma was formed when the cortical window was left open and the surgical wound drained [lo]. However, a large intramuscular hematoma developed when the biopsy site was left open and the fascia and skin were closed. In a follow-up study [ 111, radioactive microspheres were used to simulate tumor cells, and various methods of wound closure were studied. A cortical window was created and a measured quantity of microspheres was placed into the canal. The canal was then either plugged with methylmethacrylate or left open, and all surgical wounds were closed. Local and distant spread of the microspheres was measured at 4 days. In the animals in which the window was left open, spread of the microspheres was limited to the adjacent tissue and regional lymph nodes. In the animals in which the window was plugged with methylmethacrylate, there was little or no local spread of the microspheres; however, there was significant uptake of the microspheres in the lung. In one group of animals, the canal was not plugged, but a penrose drain was placed prior to closure to facilitate drainage; however, this did not appear to reduce the spread of tumor cells in the soft tissue adjacent to the biopsy site. An explanation for this may be the process of tumor embolism and spread via the interstitial compartment in addition to local extension as elaborated by Scanlon [ 171. A recent canine experiment assessed the biopsyinduced intraosseous hematoma extent after open skeletal biopsy and meticulous wound closure [ 121. Hematoma freely communicated with the intramedullary space as determined by pathologic confirmation at autopsy and, while magnetic resonance imaging (MRI) accurately reflected the spread of hematoma, it underestimated its extent. In light of the above studies, one might theorize that allowing the wound to drain freely into the dressings, without closure, would decompress the intramedullary canal and permit hematoma egress, preventing its soft tissue accumulation. This potentially would decrease both local and distant spread; and, since the biopsy site would be excised en bloc (albeit, larger) during the definitive procedure, there would be no contamination of uninvolved structures. The “open” open biopsy technique, therefore, has theoretical advantages. Conversely, it also has disadvantages, such as the possibility of infection (as seen in one patient), which would compromise definitive therapy with allograft or fixation devices. This would not be expected to be a significant risk if the definitive procedure were carried out within 2 or 3 days;
77
however, the risk is present and would be increased with any delay in the definitive procedure. In addition, free-flowing hematoma will penetrate tissue planes, creating the possibility of tumor seeding in dependent areas. This also occurred in one patient. One might also argue that an open wound has more metabolic and nutritional demands; many of these patients may already be compromised in this respect. Another potential disadvantage may be that the continued flow of tumor cells over larger soft tissue planes may allow more tumor cells to be spread interstitially, picked up by the lymphatic system and spread to regional nodes as compared to a wound which is primarily closed.
CONCLUSION The biopsy procedure is pivotal in the diagnosis and treatment of musculoskeletal lesions. Current recommendations for biopsy technique include meticulous hemostasis and wound closure to prevent hematoma formation. The “open” open biopsy theoretically could decrease the amount of local and regional tumor spread by eliminating hematoma formation. The disadvantages include the risk of infection, increased metabolic and nutritional demand, and the possibility of inducing iatrogenic local or regional spread of tumor cells. With only six patients and an array of pathologic lesions, no conclusions can be drawn regarding this technique or its effectiveness; however, its theoretical goals remain worthy of achievement. ACKNOWLEDGMENT We wish to thank Dr. Arthur L. Brooks for his conceptual direction and guidance. REFERENCES I . Gerster AG: On the surgical dissemination of cancer. NY Med J 4 1233-236, 1885. 2. Ward GR: The blood in cancer with bone metastases. Lancet 1:67&677, 1913. 3. Mayo WJ: Grafting and traumatic dissemination of carcinoma in the course of operations for malignant disease. JAMA 60512513, 1913. 4. Knox LC: The relationship of massage to metastases in malignant tumors. Ann Surgery 75: 129- 142, 1922. 5 . Engell HC: Cancer cells in the blood. A five to nine year follow-up study. Ann Surg 149:457461, 1959. 6. Peterson FA, Janes JM, Kelly PJ, Pease GL: Isolation of osteogenic sarcoma cells from peripheral blood after biopsy: An experimental report and clinical note. Proc Mayo Clin 35:443447, 1960. 7. Ross OP, Brennhovd JO, Masselt OT, Efskind J , Liverud K: Invasion of tumour cells into the bloodstream caused by palpation or biopsy of the tumor. Surgery 59:691495, 1966. 8. Marsh MC: Tumor massage and metastases in mice. J Cancer Res I1:101-107, 1927. 9. Brostrom LA, Harris MA, Simon MA, Coperman DR, Nilsonne U: The effect of biopsy on survival of patients with osteosarcorna. J Bone Joint Surg 61B:209-212, 1979. 10. Robertson WW, Janssen HF, Pugh JL: The spread of tumorcell-sized particles after bone biopsy. J Bone Joint Surg 66A:1243-1247, 1984. 11. Robertson WW, Janssen HF: Hematoma formation after bone biopsy: A canine model. South Med J 76:966-968, 1983.
78
Cramer and Schwartz
12. Schwartz HS, Shockley TE, Lennington WJ, Mackey ES Jr: The significance of skeletal magnetic resonance imaging after open bone biopsy. J Orthop Res 9:120-130, 1991. 13. Simon MA: Biopsy of musculoskeletal tumors. J Bone Joint Surg 64A: 1253-1257, 1982. 14. Enneking WF: The issue of the biopsy. J Bone Joint Surg 64A:1119-1120, 1982. 15. Mankin HJ, Lange TA, Spanier SS: The hazards of biopsy in
patients with malignant primary bone and soft-tissue tumors. J Bone Joint Surg 64A:1121-1127, 1982. 16. Clark CR, Morgan Sonstegard DA,strength, MatthewsBone LS: The effect of biopsy shapeC,and on bone surg 59Al213-217, 1977. 17. Scanlon EF: The process of metastasis. Cancer 55:1163-1166, 1985.
REFINEMENTS IN TECHNIQUE Open Biopsy Without Wound Closure for Skeletal Neoplasms KATHRYN E. CRAMER, MD, AND HERBERT S. SCHWARTZ, MD From the Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, Tennessee
During the past several years, the indications for limb salvage in musculoskeletal neoplasms have been expanded. As a result, interest in the topic of diagnostic biopsy has been renewed. Post biopsy hematoma formation and the iatrogenic spread of cancer cells has led to universally accepted guidelines for biopsy technique. These include meticulous hemostasis and wound closure. A technique of open biopsy without wound closure in which the biopsy site in a long bone with contained neoplasm remains open and hematoma allowed to drain into the dressings is outlined. A discussion of the theoretical advantages and disadvantages of this technique is presented. KEYWORDS:hematoma, tumor, bone
INTRODUCTION The iatrogenic spread of cancer in humans has been the subject of discussion for more than a century [1-4]. Human and animal studies have demonstrated increased numbers of cancer cells in the blood after surgical manipulation (biopsy) of a primary tumor [5-81. No investigations conclusively demonstrate that an increased number of tumor cells in the blood are adversely correlated with survival. This is in part due to the poor understanding of the biology of metastases. Brostrom et al. [9] conducted a retrospective study examining the effect of biopsy on survival of patients with osteosarcoma. These investigators concluded that the performance of a biopsy, followed shortly by amputation, had no adverse effect on survival. Three canine studies in the past decade have addressed the issue of tracking the iatrogenic spread of hematoma after open bone biopsy [ 10-121. Generally, biopsyinduced hematoma spreads intraosseously and in the adjacent soft tissues further than one might anticipate. The concept of the potential detrimental effects of local hematoma spread after open bone biopsy was appreciated many years ago at this institution. A novel biopsy technique was randomly employed to combat hematoma spread in which the incision and biopsy tract were left open at the termination of the surgical procedure. This paper describes the “open” open biopsy technique, reports on six case studies with long-term follow-up, and 0 1991 Wiley-Liss, Inc.
outlines the theoretical advantages and disadvantages of this alternative method of skeletal biopsy.
MATERIALS AND METHODS The hospital charts and clinic records for all patients treated at a single institution for a musculoskeletal neoplasm between 1960 to 1984 were reviewed. Seventyseven patients had sufficient records to review; of these, six were biopsied and treated definitively at our institution using the biopsy technique detailed below. The hospital charts, pathology reports, and radiographs of these six patients were reviewed in detail, and data regarding age, sex, location of the lesion, diagnosis, biopsy date and technique, definitive treatment, recurrence of lesion, and outcome were recorded. Complications related to the biopsy procedure were also noted (Table I). The biopsy technique used for these six patients differed significantly from that for the rest of the patients reviewed in that, after obtaining the biopsy specimen from the lesion, the biopsy sites were left open, then dressed and allowed to drain freely into the dressings. A Penrose drain or gauze wick was occasionally placed into Accepted for publication February 19, 1991. Address reprint requests to Dr. Herbert S. Schwartz, Department of Orthopaedics and Rehabilitation, T-43 1 1 MCN, Vanderbilt University Medical Center, Nashville, TN 37232-2550.
76
Cramer and Schwartz
TABLE I. “Open” Open Biopsy Technique: Patient Data Patient Data
#2
#I
#6
32 F Distal femur
12116/70 Low-grade chondrosarcoma None Wound infection 3/18/71 5/4/73 Resection, Curettage, autoclave ICBG, RT replantation, fixation
2/4/80 Periosteal OGS
1 O/ 18/82 GCT
2/15/78 Parosteal OGS
21 M Proximal humerus 2117/82 Parosteal OGS
None
None
None
2/17/78 Adjuvant chemotherapy, AK amputation
6130175, NED
6/6/90, NED
3 soft tissue recurrences 10/20/82 En bloc resection, proximal fibula transfer; 3 local excisions 4130187, NED
2/24/82 En bloc resection with fibula graft and ICBGshoulder fusion 8/87, NED
Bx date Pathology
Follow-up
#5
34 F Distal radius
27 M Distal femur
Rx date Rx
#4
18 F Midshaft tibia
Age Sex Location
Comp. (Bx)
#3
18
F Proximal humerus 5/2/73 GCT
12/14/84, NED
2/7/80 AK amputation, adjuvant chemotherapy
the wound, but no attempt was made to seal the medullary cavity or to close the wound with sutures. This technique, hereafter referred to as the “open” open biopsy technique, was used without rigid indications by the acknowledged author, who had an active oncology practice.
RESULTS The six patients that underwent biopsy with the “open” open technique had different diagnoses with lesions in different locations, as shown in Table I. All were under 35 years of age, and all had long bone lesions. All had aggressive benign or malignant neoplasms. With the exception of one patient (#4), all patients were operated on by the same surgeon. Three patients had five, and three patients, 10-year follow-up documentation. Nontumor complications related directly to the biopsy occurred in one patient (#l), who developed a grampositive wound infection at the biopsy site that required local wound care and antibiotics to clear. This subsequently delayed the patient’s definitive procedure. At 5-year follow-up he was doing well, with no evidence of recurrence. One patient (#4) sustained a tumor-related complication. With that exception, all other patients were alive and well at the final follow-up visit, with no evidence of recurrence. This patient (#4), had a radiographically aggressive giant cell tumor of her distal radius resected and a reconstruction utilizing autogenous fibular graft. She had three histologically documented local soft tissue recurrences that were excised; however, she had no evidence of metastatic spread or graft involvement at final follow-up.
12/88, NED
DISCUSSION The biopsy has been described as “the most crucial procedure” in the diagnosis of musculoskeletal lesions [ 131. Renewed interest in the biopsy procedure has been spurred by recent advances in the treatment of musculoskeletal lesions and the potential for limb salvage in many lesions that previously were only amenable to amputation. Adjuvant chemotherapy, radiation therapy, and better methods of fixation, along with the wider availability of allograft bone have all led to an improved prognosis for patients with musculoskeletal tumors. The biopsy procedure, when performed correctly, provides sufficient material for diagnosis and does not compromise the outcome for the patient [ 141. In a multicenter study reviewing biopsy complications, Mankin et al. [ 151 found a 17% incidence of problems related to the biopsy involving the skin, soft tissue, or bone, which altered the optimum treatment plan for the patient and a 10% incidence of nonrepresentative or technically poor biopsy specimens. The technique for open biopsy has been well described [ 13-16]; generally, meticulous hemostasis and surgical wound closure without drains is recommended. These recommendations have been universally accepted in the years following their publication in 1982. The group of patients in this study all underwent biopsy prior to the widespread acceptance of these recommendations. The biopsy procedure in these patients generally followed the standard recommendations with the exception that, although hemostasis was achieved, the wounds were not closed and were allowed to drain freely into the sterile dressings. The theoretical advantage of this is that there
Open Biopsy
is no hematoma accumulation and the potential for local spread should be diminished. An investigation of hematoma formation following bone biopsy using an animal model found that when the cortex of the bone was plugged with methylmethacrylate, no extraosseous hematoma was evident and very little hematoma was formed when the cortical window was left open and the surgical wound drained [lo]. However, a large intramuscular hematoma developed when the biopsy site was left open and the fascia and skin were closed. In a follow-up study [ 111, radioactive microspheres were used to simulate tumor cells, and various methods of wound closure were studied. A cortical window was created and a measured quantity of microspheres was placed into the canal. The canal was then either plugged with methylmethacrylate or left open, and all surgical wounds were closed. Local and distant spread of the microspheres was measured at 4 days. In the animals in which the window was left open, spread of the microspheres was limited to the adjacent tissue and regional lymph nodes. In the animals in which the window was plugged with methylmethacrylate, there was little or no local spread of the microspheres; however, there was significant uptake of the microspheres in the lung. In one group of animals, the canal was not plugged, but a penrose drain was placed prior to closure to facilitate drainage; however, this did not appear to reduce the spread of tumor cells in the soft tissue adjacent to the biopsy site. An explanation for this may be the process of tumor embolism and spread via the interstitial compartment in addition to local extension as elaborated by Scanlon [ 171. A recent canine experiment assessed the biopsyinduced intraosseous hematoma extent after open skeletal biopsy and meticulous wound closure [ 121. Hematoma freely communicated with the intramedullary space as determined by pathologic confirmation at autopsy and, while magnetic resonance imaging (MRI) accurately reflected the spread of hematoma, it underestimated its extent. In light of the above studies, one might theorize that allowing the wound to drain freely into the dressings, without closure, would decompress the intramedullary canal and permit hematoma egress, preventing its soft tissue accumulation. This potentially would decrease both local and distant spread; and, since the biopsy site would be excised en bloc (albeit, larger) during the definitive procedure, there would be no contamination of uninvolved structures. The “open” open biopsy technique, therefore, has theoretical advantages. Conversely, it also has disadvantages, such as the possibility of infection (as seen in one patient), which would compromise definitive therapy with allograft or fixation devices. This would not be expected to be a significant risk if the definitive procedure were carried out within 2 or 3 days;
77
however, the risk is present and would be increased with any delay in the definitive procedure. In addition, free-flowing hematoma will penetrate tissue planes, creating the possibility of tumor seeding in dependent areas. This also occurred in one patient. One might also argue that an open wound has more metabolic and nutritional demands; many of these patients may already be compromised in this respect. Another potential disadvantage may be that the continued flow of tumor cells over larger soft tissue planes may allow more tumor cells to be spread interstitially, picked up by the lymphatic system and spread to regional nodes as compared to a wound which is primarily closed.
CONCLUSION The biopsy procedure is pivotal in the diagnosis and treatment of musculoskeletal lesions. Current recommendations for biopsy technique include meticulous hemostasis and wound closure to prevent hematoma formation. The “open” open biopsy theoretically could decrease the amount of local and regional tumor spread by eliminating hematoma formation. The disadvantages include the risk of infection, increased metabolic and nutritional demand, and the possibility of inducing iatrogenic local or regional spread of tumor cells. With only six patients and an array of pathologic lesions, no conclusions can be drawn regarding this technique or its effectiveness; however, its theoretical goals remain worthy of achievement. ACKNOWLEDGMENT We wish to thank Dr. Arthur L. Brooks for his conceptual direction and guidance. REFERENCES I . Gerster AG: On the surgical dissemination of cancer. NY Med J 4 1233-236, 1885. 2. Ward GR: The blood in cancer with bone metastases. Lancet 1:67&677, 1913. 3. Mayo WJ: Grafting and traumatic dissemination of carcinoma in the course of operations for malignant disease. JAMA 60512513, 1913. 4. Knox LC: The relationship of massage to metastases in malignant tumors. Ann Surgery 75: 129- 142, 1922. 5 . Engell HC: Cancer cells in the blood. A five to nine year follow-up study. Ann Surg 149:457461, 1959. 6. Peterson FA, Janes JM, Kelly PJ, Pease GL: Isolation of osteogenic sarcoma cells from peripheral blood after biopsy: An experimental report and clinical note. Proc Mayo Clin 35:443447, 1960. 7. Ross OP, Brennhovd JO, Masselt OT, Efskind J , Liverud K: Invasion of tumour cells into the bloodstream caused by palpation or biopsy of the tumor. Surgery 59:691495, 1966. 8. Marsh MC: Tumor massage and metastases in mice. J Cancer Res I1:101-107, 1927. 9. Brostrom LA, Harris MA, Simon MA, Coperman DR, Nilsonne U: The effect of biopsy on survival of patients with osteosarcorna. J Bone Joint Surg 61B:209-212, 1979. 10. Robertson WW, Janssen HF, Pugh JL: The spread of tumorcell-sized particles after bone biopsy. J Bone Joint Surg 66A:1243-1247, 1984. 11. Robertson WW, Janssen HF: Hematoma formation after bone biopsy: A canine model. South Med J 76:966-968, 1983.
78
Cramer and Schwartz
12. Schwartz HS, Shockley TE, Lennington WJ, Mackey ES Jr: The significance of skeletal magnetic resonance imaging after open bone biopsy. J Orthop Res 9:120-130, 1991. 13. Simon MA: Biopsy of musculoskeletal tumors. J Bone Joint Surg 64A: 1253-1257, 1982. 14. Enneking WF: The issue of the biopsy. J Bone Joint Surg 64A:1119-1120, 1982. 15. Mankin HJ, Lange TA, Spanier SS: The hazards of biopsy in
patients with malignant primary bone and soft-tissue tumors. J Bone Joint Surg 64A:1121-1127, 1982. 16. Clark CR, Morgan Sonstegard DA,strength, MatthewsBone LS: The effect of biopsy shapeC,and on bone surg 59Al213-217, 1977. 17. Scanlon EF: The process of metastasis. Cancer 55:1163-1166, 1985.
