Iatrogenic cardiac papillary fibroelastoma: A study of 12 cases (1990 to 2000)

Iatrogenic Cardiac Papillary Fibroelastoma: A Study of 12 Cases (1990 to 2000) ANIL N. KURUP, MD, HENRY D. TAZELAAR, MD, WILLIAM D. EDWARDS, MD, ALLEN P. BURKE, MD, RENU VIRMANI, MD, KYLE W. KLARICH, MD, AND THOMAS A. ORSZULAK, MD Cardiac papillary fibroelastoma (PFE) is a rare, benign, slowgrowing tumor of the endocardium. Whether it represents a reactive tumoral lesion or a true neoplasm remains a matter of debate. However, an anecdotal association of PFEs with previous cardiac surgery has been reported. The current study was undertaken to determine the frequency and nature of iatrogenic events associated with PFEs and to provide a comprehensive review of the topic. The study group comprised 12 cases seen between 1990 and 2000, with specimens from 7 women and 5 men. Six developed postoperatively and 6 developed after thoracic irradiation. The 9 Mayo cases represented 18% of all surgically excised PFEs during the study period. The mean age at operation was 54 years (range, 29 to 79 years). The mean interval between the iatrogenic event and excision of the tumor

was 18 years (range, 9 to 31 years). In 58% of cases, the presence of multiple tumors was either confirmed pathologically (41.7%) or strongly suggested by echocardiography (16.6%). Among patients who had undergone previous cardiac surgery, PFEs were found in the chamber closest to the procedure. Similarly, in patients who had received radiation therapy, tumors developed in the left atrium, in the right ventricle and atrium, and on the tricuspid valve within the radiation field. In conclusion, iatrogenic PFEs may be relatively common among all such tumors, are frequently multiple, and often involve nonvalvular endocardial surfaces. HUM PATHOL 33:1165-1169. Copyright 2002, Elsevier Science (USA). All rights reserved. Key words: iatrogenesis, cardiac neoplasm, papillary fibroelastoma. Abbreviations: PFE, papillary fibroelastoma.

Cardiac papillary fibroelastoma (PFE), a benign tumor of the heart, is the most common tumor of cardiac valves and the third most common primary cardiac tumor, after myxoma and fibroma.1-4 Grossly, it resembles a pom-pom or sea anemone, with multiple papillary fronds. It generally occurs singly and is typically found on the atrial aspect of atrioventricular valves or either side of the semilunar valves, although it has been reported on all endocardial surfaces, including papillary muscles, tendinous cords, and the septa or free walls of each cardiac chamber.1,4-6 PFEs were once considered rare, incidental findings most often diagnosed at autopsy. However, because of the widespread use of echocardiography, they are being diagnosed during life with increasing frequency.7,8 Embolization of a tumor or an attached thrombus may cause cardiac, pulmonary, or neurologic symptoms, and prolapse of a tumor into a coronary ostium may cause sudden death.1,9,10 Accordingly, prophylactic tumor excision, even in asymptomatic patients, is considered by many to be the treatment of choice.1,10,11 The histogenesis of PFE remains controversial. They have been considered neoplasms, hamartomas, organized thrombi, and unusual endocardial responses

to infection or hemodynamic trauma.2,4 Anecdotal evidence suggests that iatrogenic factors, such as previous cardiac surgery, may play a role in tumor development.12 The current study was undertaken to determine the frequency and characteristics of PFEs associated with iatrogenic factors.

From the Mayo Medical School and the Divisions of Anatomic Pathology, Cardiovascular Disease, and Cardiovascular Surgery, Mayo Clinic, Rochester, MN, and the Armed Forces Institute of Pathology, Washington, DC. Accepted for publication September 9, 2002. Address correspondence and reprint requests to Dr. Henry Tazelaar, Hilton 11 (Pathology), Mayo Clinic, 200 First Street SW, Rochester, MN 55905. This is a US government work. There are no restrictions on its use. 0046-8177/02/3312-0003$0.00/0 doi:10.1053/hupa.2002.130105

PATIENTS AND METHODS The available clinical records of all patients with a pathologically confirmed diagnosis of papillary fibroelastoma, made at Mayo Clinic Rochester or the Armed Forces Institute of Pathology (AFIP) between January 1, 1990 and December 31, 2000, were reviewed for evidence of a possible iatrogenic cause. For this study, potential causes included thoracic irradiation and open-heart surgery (specifically septal myectomy, cardiac valve replacement, or congenital heart defect repair). For each patient in the study, the following data were abstracted from the clinical chart: age at time of pathologic diagnosis, gender, suspected iatrogenic cause, interval between the procedure and tumor excision, other significant cardiac disease as defined by echocardiography or cardiac catheterization, and tumor size and location. Pathologic materials (reports, photographs, and slides stained with hematoxylin and eosin and Verhoeff-van Gieson stain) were reviewed, and the diagnosis of PFE was confirmed for all study cases. Four of the cases in this series (cases 4, 5, 8, and 12) have been published previously in a review of the echocardiographic features of PFE,8 and 1 case (case 4) in a review of surgically excised cardiac neoplasms.3

RESULTS General Features The clinical database of Mayo Clinic Rochester contained 51 cases of pathologically confirmed PFE

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TABLE 1. Clinical and Pathologic Features of Iatrogenic Cases of Cardiac Papillary Fibroelastoma (PFE) Age and Case Sex 1 2

35 M 47 F

Current Procedure AVR, PVR Septal myectomy, PFE excision

Previous Procedure VSD enlargement for DILV Septal myectomy

3

49 F

4

52 M

5

65 M

6

79 M

Septal myectomy, MVR

7

29 F 42 M

Endomyocardial Irradiation for HD biopsy Cardiac Irradiation for NHL transplantation

49 F 57 F

Autopsy

8

9 10 11 12

67 F 75 F

AVR, MVR, septal Septal myectomy myectomy, PFE excision PFE excision Repair of VSD and double-chamber RV Autopsy MVR

Endomyocardial biopsy LAA and PFE excision PFE excision

AVR

Interval Between Procedure and PFE (years)

Other Significant Heart Disease

PFE Location

18

DILV, AR, PR

2

LVOT, AV

17

HCM, arrhythmia/cardiac arrest requiring pacemaker and AV nodal ablation HCM, MR, old AV repair

2

LV septum

20

⬎40

LV, MV

PFE Size (mm) 8 ⫻ 7 ⫻ 7 LVOT, 3 ⫻ 3 ⫻ 1 AV 20 ⫻ 10 ⫻ 8 (aggregate)

2 to 12 in greatest dimension 7 ⫻ 6 ⫻ 2 LVOT, 3 ⫻ 2 ⫻ 1 LVOT, 7 ⫻ 3 ⫻ 2 AV NA

18

TR, old TV infective endocarditis

3

LVOT, AV

NA

Infundibular stenosis, LVOT obstruction, old partial RV and PV excision for polyvalvular dysplasia RHD with MS/MR, TR, AR/AS, LVOT obstruction, CAD, CHF Constrictive pericarditis

1

LVOT

2

LV septum

1*

RA

NA

1

LA

2

1

RV free wall

16

16

Irradiation for HD

22

Ischemic heart disease, CHF, old CABG and coronary endarterectomy CHF, constrictive pericarditis TR, MR, old constrictive pericarditis and pericardectomy TR, MR

Irradiation for breast carcinoma

17

Constrictive pericarditis

Irradiation for breast carcinoma Irradiation for breast carcinoma

No. of Tumors

13

9 31

1* 1 1

3 ⫻ 4 ⫻ 5 (aggregate)

NA

TV tendinous 28 ⫻ 17† cords/papillary muscles, RV free wall and RVOT LA 8⫻3⫻1 TV atrial surface, anterior leaflet

21 ⫻ 15 ⫻ 3

Abbreviations: AR, aortic regurgitation; AS, aortic stenosis; AV, aortic valve; AVR, aortic valve replacement; CABG, coronary artery bypass graft; CAD, coronary artery disease; CHF, congestive heart failure; DILV, double inlet left ventricle; HCM, hypertrophic cardiomyopathy; HD, Hodgkin’s disease; LA, left atrium; LAA, left atrial appendage; LVOT, left ventricular outflow tract; MR, mitral regurgitation; MS, mitral stenosis; MV, mitral valve; MVR, mitral valve replacement; NA, not available; NHL, non-Hodgkin’s lymphoma; PR, pulmonary regurgitation; PV, pulmonary valve; PVR, pulmonary valve replacement; RA, right atrium; RHD, rheumatic heart disease; RV, right ventricle; RVOT, right ventricular outflow tract; TR, tricuspid regurgitation; TV, tricuspid valve; VSD, ventricular septal defect. *Only one PFE was biopsied, but multiple tumors were detected by echocardiography (one additional tumor suspected in the right ventricle in each case). †Measured by transthoracic echocardiography only.

within the 11-year search period. A review of the clinical charts revealed likely iatrogenic etiologies in 9 cases (18%). Three cases were identified at the AFIP, yielding a study population of 12 cases. Clinical Features The study group was comprised of 7 women and 5 men (Table 1). The mean age at the time of tumor excision was 54 years (range, 29 to 79 years). Six patients had thoracic irradiation as the likely iatrogenic factor (3 for lymphoma and 3 for breast carcinoma). In 6 cases of PFE after open-heart surgery, 2 patients had valve replacement, 2 had a septal myectomy for hypertrophic cardiomyopathy, and 2 had repair of congenital heart defects. The mean interval between the iatrogenic event and PFE excision was 18 years (range, 9 to 31 years) and did not differ between postoperative and postirradiation cases. All of the patients had concomitant heart disease; 7 had dysfunction of 1 or more valves. Four (33%) had mitral valve disease, 4 (33%) had tricuspid regurgita-

tion, 3 (25%) had aortic valve disease, and 1 (8%) had pulmonary regurgitation. Two patients had hypertrophic cardiomyopathy, and 1 patient had severe ischemic heart disease requiring transplantation. Four of the 6 patients who had received thoracic irradiation also had constrictive pericarditis. Pathologic Features Five patients (41.7%) had more than 1 pathologically confirmed PFE. Two other cases (16.6%) had multiple PFEs detected by echocardiography, but only 1 tumor excised and confirmed pathologically. Hence in 58% of cases the tumors were likely multiple. Among the other 42 cases of PFEs excised at the Mayo Clinic, only 8 were multiple, with the difference between iatrogenic and noniatrogenic cases being statistically significant (P ⬍0.01; ␹2 test). PFEs were located in the left ventricle or on the left-sided valves in all patients who underwent previous open-heart surgery. In contrast, PFEs developed in these locations in no patients with thoracic irradiation.

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open-heart surgery or thoracic irradiation in some patients. Including the 12 cases in this series (Table 1) and 10 cases from the literature (Table 2), 22 pathologically confirmed cases of iatrogenically induced PFEs have been reported.5, 12-20 These cases involved 15 women and 7 men, with a mean age at tumor excision of 54 years (range, 27 to 75 years). Sixteen patients (73%) had undergone previous open-heart surgery, and 6 (27%) had received thoracic irradiation. Among the postoperative cases, PFEs occurred in 5 after subaortic septal myectomy, in 5 after valve repair, in 4 after valve replacement, and in 2 after repair of congenital heart defects. Tumor Size and Number

FIGURE 1. Papillary fibroelastoma identified on endomyocardial biopsy (Case 7). Muscle fragment on left and papillary fibroelastoma on right with multiple fronds.

Rather, PFEs developed in the left atrium in 2 patients, in the right ventricle in 2 patients, in the right atrium in 1 patient, and on the tricuspid valve in 1 patient. Patients 8 and 11 (Table 1) had received 4000 cGy and 3600 cGy irradiation, respectively, that included the right-sided chambers and left atrium but little of the left ventricle. Tumor size varied widely, with the largest measuring 28 mm and the smallest measuring 2 mm. Histologically, however, all of the tumors appeared similar, consisting of a central dense core of elastin and collagen surrounded by a layer of loose myxoid tissue and lined by endothelium contiguous with adjacent endocardium. Mural thrombus was not identified in any case. Figure 1 shows the characteristic features in a PFE identified on endomyocardial biopsy. A Unique Case Case 3 is an extreme example of multiple papillary fibroelastomas (Fig 2). While monitoring the progression of hypertrophic cardiomyopathy and mitral valve insufficiency in a 49-year-old woman, transthoracic and transesophageal echocardiography revealed 2 intracavitary left ventricular masses. One of these masses was located along the ventricular septum at the mitral contact site, and the other was on the posterior mitral leaflet. The patient had undergone a septal myectomy in 1979. In 1999, she underwent revision of the septal myectomy and replacement of her mitral and aortic valves. At operation, more than 40 separate tumors were identified attached to and within the trabeculations, along the folds of the papillary muscles, at the junction of the papillary muscles and tendinous cords, and along the cords themselves.

Among the 22 cases, tumor size varied from 2 mm to 32 mm in greatest dimension. Typically, noniatrogenic PFEs are ⬍10 mm in size, although tumors as large as 50 mm have been reported.2,21 In the iatrogenic cases, there was no apparent correlation between tumor size and tumor location, iatrogenic factor, or interval between iatrogenic factor and pathologic diagnosis. Overall, 80% to 90% of pathologically proven PFEs occur as a single lesion.2,8 Among the 51 surgically excised PFEs from Mayo Clinic Rochester, 34 of 42 (81%) noniatrogenic tumors were single, but only 3 of 9 (33%) iatrogenic tumors were single, a statistically significant difference. Two additional cases of multiple iatrogenic PFEs have also been described, including 1 of the current cases from the AFIP (Table 1) and 1 case reported by Levinsky et al.18 Iatrogenic Origin of Papillary Fibroelastoma The pathogenesis of PFEs is controversial. Various gross, microscopic, and molecular characteristics of PFE have caused the lesions to be described as neoplasms, hamartomas, organized thrombi, and unusual endocardial responses to trauma.2 The histochemical presence of fibrin, hyaluronic acid, and laminated elas-

DISCUSSION General Features The results of this study strongly suggest an association between the development of PFEs and previous

FIGURE 2. Gross photograph of multiple papillary fibroelastomas developing 17 years following open-heart surgery (case 3).

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TABLE 2. Ten Previously Reported Cases of Iatrogenic PFE Case

Reference

Age and sex

Current Procedure

Previous Procedure

13

Lichtenstein et al (1979)14

52 M

PFE resection, VSD repair, infundibular resection

Pulmonary valvulotomies

14

Cha et al (1981)5

54 F

MVR, AVR, TV plasty

Lower RV near junction of papillary muscles and septum MV Papillary muscle commissurotomy and AV

15

Levinsky et al (1981)18

27 F

AVR

Septal myectomy

16

De Virgilio et al (1989)13

48 F

17

Lee et al (1993)19

57 F

MVR and PFE excision MVR, PFE excision

18

Takahashi et al (1993)15

68 F

MVR

19

Allen et al (1996)16

57 M

PFE excision

20

Herrera et al (1998)17

55 F

21

Cesena et al (1999)12

63 F

Prosthetic MV excision and replacement, PFE excision MVR

MV MV, LV commissurotomy Septal myectomy LV septum, LVOT, AV, cords of MV MV Posteromedial commissurotomy papillary muscle and tendinous cords of MV Myomyectomy Posteromedial papillary muscle of MV MVR MV

22

Taniyasu et al (2000)20

60 F

MVR and PFE Excision

Location

AV, MV

Interval (years)

Size (mm)

22 and 20

12 ⫻ 10 ⫻ 6

PS, VSD

About 10

15 ⫻ 16 ⫻ 32

8

15 AV, 5 AV, 5 MV

20

5 ⫻ 10

15

NA

RHD with MS/MR, AR, TR HCM, CHF, AR, iatrogenic VSD RHD with MS/MR MR

13

8⫻7

10

15 ⫻ 15

9

20 ⫻ 10 ⫻ 10

RHD, cerebral embolism

RHD with MS, cerebral embolism MR

MV commisurotomy

MV at transition between cusp and cords

12

20

MVR

LVOT

15

13 ⫻ 10

Concomitant Heart Disease

MS

HCM

Abbreviations: PS, pulmonary stenosis; CVA, cerebrovascular accident; AR, aortic regurgitation; AS, aortic stenosis; AV, aortic valve; AVR, aortic valve replacement; CABG, coronary artery bypass graft; CAD, coronary artery disease; CHF, congestive heart failure; DILV, double inlet left ventricle; HCM, hypertrophic cardiomyopathy; HD, Hodgkin’s disease; LA, left atrium; LAA, left atrial appendage; LVOT, left ventricular outflow tract; MR, mitral regurgitation; MS, mitral stenosis; MV, mitral valve; MVR, mitral valve replacement; NA, not available; NHL, non-Hodgkin’s lymphoma; PR, pulmonary regurgitation; PV, pulmonary valve; PVR, pulmonary valve replacement; RA, right atrium; RHD, rheumatic heart disease; RV, right ventricle; RVOT, right ventricular outflow tract; TR, tricuspid regurgitation; TV, tricuspid valve; VSD, ventricular septal defect.

tic fibers within the fronds supports the hypothesis that PFEs may be related to organizing thrombi.22-25 Evidence favoring the hamartoma hypothesis includes a histologic appearance suggesting the proliferation of miniature tendinous cords rather than organizing thrombi, as well as apparent congenital PFEs associated with other congenital cardiac anomalies.21,23,26 Based on the presence of dendritic cells and cytomegalovirus in some PFEs, a recent study proposed that PFEs may be related to a chronic form of viral endocarditis.27 The current investigation of iatrogenic cases supports the concept that at least some PFEs represent posttraumatic tumors. The trauma may be either mechanically induced or radiation induced. Such PFEs in this and other studies occur in close proximity to the iatrogenic process. All of the 16 postoperative cases of PFE reported occurred in the cardiac chamber most closely associated with the site of surgery. Furthermore, in 2 of 6 patients who received radiation therapy and in whom detailed information was available, PFEs developed only in cardiac chambers within the irradiated field (Tables 1 and 2). PFEs also resemble age-related Lambl’s excrescences, which are thought to result from

chronic, repetitive low-grade trauma of valve closure.2 Many of the patients with iatrogenic PFEs had concomitant heart disease, which often caused hemodynamic abnormalities in the heart. Repetitive hemodynamic injury may play a role in the development of PFEs in rheumatic heart disease,8,12,13,15,22,28,29 hypertrophic cardiomyopathy,8,16,18,19 mitral valve prolapse,7,30,31 atrial septal defect,32 and other congenital heart defects.21,23,33,34 The possibility of PFE development stemming from radiation damage to the endocardium also seems plausible. Radiation-induced heart disease includes pericardial effusions, acute or chronic pericarditis, constrictive pericarditis, endocardial and myocardial fibrosis, valvular dysfunction, coronary artery disease, and obstruction involving the vessels of the cardiac conduction system.35-37 PFEs may represent a delayed manifestation of radiation-induced injury to the endocardium and may occur concurrently with other forms of radiation damage, such as pericarditis. Such PFEs have displayed a long latency period after radiation exposure, ranging from 9 to 31 years in the current study. Lesions were consistently located within the irradiated field. In

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general, cardiac tissue has an intermediate sensitivity to radiation, with a tolerance dose of approximately 4000 cGy.35 Whether the relationship between radiation exposure and PFE development is dose-dependent remains to be shown. Several other types of tumors have proven or suspected environmental causes. Factors known to contribute to tumor development include ionizing radiation, asbestos, pesticides and other chemical agents, and oncogenic viruses. Trauma is frequently implicated in the development of soft tissue sarcomas, and there are some reports of sarcoma developing in the vicinity of plastic or metal implants.38 Cicatricial changes after surgery, fractures, or thermal or acid burns may also lead to tumorigenesis of the affected soft tissue. One study noted a spectrum of preneoplastic histologic changes in the capsules surrounding the implantation site of biomaterials.39 Similarly, surgical trauma and a reaction to prosthetic material (eg, valves) may lead to endocardial changes and subsequent PFE development. The results of this study suggest that patients who undergo open-heart surgery for valve replacement, congenital defect repair, or septal myectomy or who receive thoracic irradiation are at longterm risk for the development of PFEs. Acknowledgment. The authors thank Paula J. Schomberg, MD, Mayo Radiation Oncology, for reviewing the medical histories of the 4 Mayo Clinic patients who were irradiated elsewhere and determining the cumulative radiation dosage and the affected cardiac chambers in the 2 patients who had received radiotherapy at Mayo Clinic Rochester.

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13. de Virgilio C, Dubrow TJ, Robertson JM, et al: Detection of multiple cardiac papillary fibroelastomas using transesophageal echocardiography. Ann Thorac Surg 48:119-121, 1989 14. Lichtenstein HL, Lee JC, Stewart S: Papillary tumor of the heart: Incidental finding at surgery. HUM PATHOL 10:473-475, 1979 15. Takahashi A, Kitaura K, Murayama Y, et al: A case of papillary fibroelastoma of the heart found 13 years after open mitral commissurotomy. Jpn J Thorac Cardiovasc Surg 41:2121-2125, 1993 16. Allen KB, Goldin M, Mitra R: Transaortic video-assisted excision of a left ventricular papillary fibroelastoma. J Thorac Cardiovasc Surg 112:199-201, 1996 17. Roman Herrera L, Pech Escalante CM, Martinez Enriquez A, et al: A papillary fibroelastoma of the left ventricle in the presence of a mitral valve prosthesis: A case report and review of the literature. Arch Inst Cardiol Mex 68:232-238, 1998 18. Levinsky L, Srinivasan V, Gingell RL, et al: Papillary fibroelastoma of aortic and mitral valves following myectomy for idiopathic hypertrophic subaortic stenosis. Thorac Cardiovasc Surg 29: 187-191, 1981 19. Lee KS, Topol EJ, Stewart WJ: Atypical presentation of papillary fibroelastoma mimicking multiple vegetations in suspected subacute bacterial endocarditis. Am Heart J 125:1443-1445, 1993 20. Taniyasu N, Akiyama K, Iba Y, et al: Papillary fibroelastoma in association with thrombosis on a mechanical valve. Jpn Circ J 64:797-799, 2000 21. Flotte T, Pinar H, Feiner H: Papillary elastofibroma of the left ventricular septum. Am J Surg Pathol 4:585-588, 1980 22. Almagro UA, Perry LS, Choi H, et al: Papillary fibroelastoma of the heart: Report of six cases. Arch Pathol Lab Med 106:318-321, 1982 23. Pomerance A: Papillary “tumours” of the heart valves. J Pathol Bacteriol 81:135-140, 1961 24. Schiller AL, Schantz A: Papillary endocardial excrescence of the right atrium: Report of two cases. Am J Clin Pathol 53:617-621, 1970 25. Fishbein ML, Ferrans VJ, Roberts WC: Endocardial papillary elastofibromas. Arch Pathol Lab Med 99:335-341, 1975 26. Raeburn C: Papillary fibro-elastic hamartomas of the heart valves. J Pathol Bacteriol 65:371-373, 1953 27. Grandmougin D, Fayad G, Moukassa D, et al: Cardiac valve papillary fibroelastomas: Clinical, histological and immunohistochemical studies and a physiopathogenic hypothesis. J Heart Valve Dis 9:832-841, 2000 28. Kalman JM, Lubicz S, Brennan JB, et al: Multiple cardiac papillary fibroelastomas and rheumatic heart disease. Aust N Z J Med 21:744-746, 1991 29. Bedi HS, Sharma VK, Mishra M, et al: Papillary fibroelastoma of the mitral valve associated with rheumatic mitral stenosis. Eur J Cardiothorac Surg 9:54-55, 1995 30. Shapira OM, Williamson WA, Dugan JM: Papillary fibroelastoma of the mitral valve. Cardiovasc Surg 1:599-601, 1993 31. Stellin G, Bortolotti U, Valfre C, et al: Mural papilloma of the left ventricle and floppy mitral valve: Report of an unusual association. Texas Heart Inst J 10:89-92, 1983 32. Watanabe T, Hosoda Y, Kikuchi N, et al: Papillary fibroelastoma of the tricuspid valve in association with an atrial septal defect: Report of a case. Surg Today 26:831-833, 1996 33. Jacobsson E: Two cases of so-called myxofibroma of the heart valves, producing clinical symptoms and congenital vitium. Ann Paediat 161:1-12, 1943 34. Anderson KR, Fiddler GI, Lie JT: Congenital papillary tumor of the tricuspid valve: An unusual cause of right ventricular outflow obstruction in a neonate with trisomy E. Mayo Clin Proc 52:665-669, 1977 35. Fajardo LF, Berthrong M, Anderson RE: Radiation Pathology. New York, NY, Oxford University Press, 2001, pp 155-192 36. Oh KY, Shimizu M, Edwards WD, et al: Surgical pathology of the parietal pericardium: A study of 344 cases (1993-1999). Cardiovasc Pathol 10:157-168, 2001 37. Veinot JP, Edwards WD: Pathology of radiation-induced heart disease: A surgical and autopsy study of 27 cases. HUM PATHOL 27:766-773, 1996 38. Weiss SW, Goldblum JR: Enzinger and Weiss’s Soft Tissue Tumors, 4th ed. St. Louis, MO, Mosby-Year Book, 2001, pp 2-4 39. Kirkpatrick CJ, Alves A, Kohler H, et al: Biomaterial-induced sarcoma: A novel model to study preneoplastic change. Am J Pathol 156:1455-1467, 2000

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