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Angiosarcoma arising in association with vascular Dacron grafts and orthopedic joint prostheses: clinicopathologic, immunohistochemical, and molecular study
Angiosarcoma Arising in Association with Vascular Dacron Grafts and Orthopedic Joint Prostheses: Clinicopathologic, Immunohistochemical and Molecular Study Abbas Agaimy MD, Ofer Ben-Izhak MD, Thomas Lorey MD, Marcus Scharpf MD, Brian P. Rubin MD, PhD PII: DOI: Reference:
S1092-9134(16)30002-8 doi: 10.1016/j.anndiagpath.2016.01.002 YADPA 51047
To appear in:
Annals of Diagnostic Pathology
Please cite this article as: Agaimy Abbas, Ben-Izhak Ofer, Lorey Thomas, Scharpf Marcus, Rubin Brian P., Angiosarcoma Arising in Association with Vascular Dacron Grafts and Orthopedic Joint Prostheses: Clinicopathologic, Immunohistochemical and Molecular Study, Annals of Diagnostic Pathology (2016), doi: 10.1016/j.anndiagpath.2016.01.002
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ACCEPTED MANUSCRIPT Angiosarcoma Arising in Association with Vascular Dacron Grafts and Orthopedic Joint Prostheses: Clinicopathologic, Immunohistochemical and
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Molecular Study.
Abbas Agaimy, MD1, Ofer Ben-Izhak, MD2, Thomas Lorey, MD3, MD, Marcus Scharpf, MD4,
Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, University
Hospital, 91054 Erlangen, Germany.
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Brian P. Rubin, MD, PhD5.
2
Department of Pathology, Rambam Health Care Campus, 31096 Haifa, ISRAEL.
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Institute of Pathology, Caritas-Krankenhaus, Bad Mergentheim gGmbH, 97980 Bad
Mergentheim, Germany.
Institute of Pathology, University Hospital, 72076 Tübingen, Germany
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Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland,
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OH 44195, USA.
Address page proofs, correspondence, and requests for reprints to:
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Abbas Agaimy, MD
Pathologisches Institut Universitätsklinikum Erlangen Krankenhausstraße 8-10 91054 Erlangen, Germany Telephone: +49-9131-85-22288 Fax: +49-9131-85-22613 Email: [email protected] Short running title: Prosthesis-associated angiosarcoma Conflict of interest: none to declare. Funding: none. 1
ACCEPTED MANUSCRIPT ABSTRACT Angiosarcoma may rarely arise in close proximity to inert foreign body material including
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vascular grafts and metal joint prostheses. 16 such cases have been reported since 1972 but mostly in the radiological or surgical literature without detailed histological or molecular
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analyses. We herein describe the clinicopathologic and molecular features of 2 new cases and reanalyzed 3 previously reported cases of angiosarcoma that developed in association
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with Dacron grafts for vascular repair (n=3) or related to orthopedic metal prostheses for joint replacement (n=2). All patients were males aged 50-84 (median, 71). Mean time to development of angiosarcoma was 9 years (range, 4.6-17). Symptoms were recurrent
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bleeding/ loosening of prosthesis for suspected infection (in the joint prosthesis cases) and fatigue, weight loss, and abdominal symptoms in the Dacron-associated cases. Four patients
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died of disease within 1-24 months (mean, 8). One patient was alive after radical surgery,
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radiochemotherapy and embolization of pulmonary metastases (17 months). Histologically, all tumors were high-grade epithelioid neoplasms with a predominant solid growth pattern
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and variable vasoformation. All tumors expressed CD31, ERG, FLI-1 and variably pancytokeratin (diffuse in 3 cases) but none expressed D2-40, MDM2 or CDK4. FISH analysis revealed no MDM2 or CDK4 alterations. MYC was expressed in all cases, but only 1 case was MYC-amplified by FISH. Angiosarcomas are exceedingly rare fatal complications of longstanding metal and Dacron prostheses. Awareness of their morphology and frequent cytokeratin expression is necessary to avoid misdiagnosis as metastatic carcinoma. Limited awareness of their existence explains delayed clinical diagnosis in most of cases. Absence of MDM2/CDK4 alterations underlines their distinction from intimal-type sarcomas. Keywords: angiosarcoma; Dacron graft; joint prosthesis; joint replacement; metal; foreign body; MYC. 2
ACCEPTED MANUSCRIPT INTRODUCTION Soft tissue sarcomas are uncommon (<1% of all cancer types). Angiosarcomas are even rarer
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representing <2% of all soft tissue sarcomas [1]. They mainly arise in the skin and superficial
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soft tissue and less frequently in deep soft tissue and bones [1]. Cutaneous angiosarcomas show a predilection for the head and neck skin and they mainly affect the elderly [2]. On the hand,
deep-seated
angiosarcomas
mainly
originate
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other
in
the
extremities,
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retroperitoneum and trunk with a wide age range (5-97 yrs) [3]. Rarely, angiosarcomas may develop within visceral organs such as breast [4], liver [5], spleen [6], heart [7], kidney [8], gastrointestinal tract [9], urinary bladder [10], and abdominal and thoracic cavity including serosal membranes [11-13]. As is with soft tissue sarcomas in general, the vast majority of
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angiosarcomas arise de novo without underlying systemic diseases or predisposing
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conditions. However, a subset of angiosarcomas arise in a background of previous irradiation for malignant diseases, in particular, after breast-conserving surgery and adjuvant irradiation
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for breast cancer, prostate cancer and others (secondary or post-radiation angiosarcomas)
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[4,10]. Furthermore, angiosarcomas have been increasingly recognized to occur in specific predisposing clinicopathological circumstances including well documented cases related to exposure to chemical agents (liver angiosarcomas after thorotrast injection [5]), bullet and other war injuries [14], laparotomy sponge and other synthetic material left behind at surgical exploration [14,15], breast implants [16], injection-site [17], gouty tophus [18] within chronic expanding hematomas [19], chronic lymphedema of diverse etiology [20], venous graft used as arterial bypass [21] and arteriovenous fistulae created for hemodialysis in patients with terminal renal failure [22]. Rare cases developed on a background of solid organ transplantation [23].
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ACCEPTED MANUSCRIPT Angiosarcomas arising in association with Dacron grafts for vascular repair or related to orthopedic metal prosthesis for joint replacement are rare with a total of 16 single case
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reports published between 1972 and 2015 [24-40]. However, with two exceptions [28,40], all
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cases have been reported in the orthopedic, surgical or radiological literature and hence, detailed histopathological and immunohistochemical analyses were not provided. We herein
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describe two new cases of angiosarcomas arising in association with prostheses, reanalyzed
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three previously reported cases and reviewed the literature to look for similar cases to delineate their major clinicopathological features.
MATERIALS AND METHODS
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Case 1-3 have been reported previously [28,32,38,39]. Case 4 and 5 were retrieved from the
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pathology departments of two of the authors (A.A & B.P.R.). Tumor specimens were fixed in buffered formalin overnight and embedded routinely for histological examination.
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Immunohistochemical stains were performed on freshly cut 3-µm paraffin sections using a
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fully automated slide preparation system (“Benchmark XT System”, Ventana Medical Systems Inc., 1910 Innovation Park Drive, Tucson, Arizona, USA) and the following antibodies: pancytokeratin (clone KL-1, 1:200, Immunotech), CK7 (OV-TL, 1:1000, Biogenex), CK20 (KS20.8, 1:50, Dako), ERG (clone EPR3864, prediluted/ready to use, Ventana Medical Systems), FLI-1 (clone G146-222, 1:200, BD Pharmingen™), podoplanin (clone D2-40, 1:50, Zytomed), high molecular weight cytokeratin (clone 34ßE12, 1:50, Dako), SMARCB1 (MRQ27, 1:50, Zytomed), TP53 (clone DO-7, 1:50, Dako), MYC (clone EP121, 1:100, Epitomics, California, USA), MDM2 (clone IF1, 1:50, CalBiochem) and CDK4 (clone DCS-156, 1:100, Zytomed).
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ACCEPTED MANUSCRIPT To detect amplifications of the MDM2, CDK4 and MYC gene loci, fluorescence in situ hybridization (FISH) was performed on freshly cut sections prepared from formalin-fixed
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paraffin-embedded tumor tissue blocks using ZytoLight Dual Color Probes (ZytoVision,
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Bremerhaven, Germany) with standard protocols according to the manufacturer`s instructions. Fifty tumor cell nuclei were assessed and cases with a ratio of >2 were
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considered amplified.
RESULTS
All patients were males aged 50-84 (median, 71; table 1). Three patients received Dacron grafts for vascular repair of the infrarenal aorta (2 cases) or of the right common iliac artery
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(one). Two patients received total hip endoprothesis for degenerative joint disease.
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Mean time to development of angiosarcoma was nine years and was similar for those with Dacron and joint prostheses (range, 4.6 to 17 yrs). Symptoms were unexplained recurrent
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bleeding/revision of prosthesis for suspected infection (in the joint prosthesis cases) and
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fatigue, unexplained weight loss and/or abdominal pain in patients with Dacron-associated intra-abdominal angiosarcoma. Treatment was surgical resection and/or palliative radiochemotherapy in four patients. One patient refused any palliative therapy and he died postoperatively from uncontrolled bleeding. Multiple pleural metastases were found at autopsy. Four patients died of disease (either with extensive metastatic disease or due to disease complications) within 1-24 months (mean 8 months). One patient was alive after radical surgery, radiochemotherapy and embolization of pulmonary metastases (last followup 17 months).
Pathological findings
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ACCEPTED MANUSCRIPT Angiosarcoma was closely associated with the implanted foreign body and formed a periprosthetic mass or capsule like tissue variably encasing the prosthesis material or lining
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the original vascular lumen in the cases of Dacron grafts. A variable degree of osteolysis was
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seen on imaging of the joint prosthesis- associated cases (Fig. 1). Grossly, all tumors showed extensive hemorrhage closely mimicking expanding hematoma or infection at the time of
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revision. Histologically, tumor tissue was seen forming a capsule-like layer surrounding the
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joint capsule (Fig. 2A) or lining the original vascular lumen (Fig. 2B). All tumors were highgrade epithelioid neoplasms with predominant solid morphology and variable vasoformative component (Fig. 2C-E). The tumor cells were large with polygonal or rounded vesicular nuclei and prominent, centrally located nucleoli. The vasoformative component was generally
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minor and comprised <20% of the neoplasm (Fig. 2C). The solid tumor areas were strikingly
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reminiscent of poorly differentiated adenocarcinoma as several tumor cells contained empty intra-cytoplasmic vacuoles that occasionally looked like signet ring cells or abortive gland
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formation (Fig. 2D). A corded pattern with voluminous cytoplasm occasionally containing
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single erythrocytes within vacuoles was seen as well (Fig. 2E). All cases showed variable stromal sclerosis with hemosiderin deposits as evidence of recurrent bleeding (Fig. 2F). Mitotic activity ranged from 10 to 35/10 high power fields (median, 18/10 HPFs). By immunohistochemistry (table 2), all tumors expressed CD31 (Fig. 3A) with a distinctive membranous pattern and a staining intensity similar to that seen in normal vessels. In addition, all tumors showed strong nuclear expression of ERG (Fig. 3B) and FLI-1, but none expressed D2-40. D2-40 highlighted prominent permeation of lymphatic vessels (Fig. 3C). Strong and diffuse expression of pancytokeratin was seen in 3 cases with a remarkable intensity similar to staining in epithelial neoplasms (Fig. 3D). Cytokeratin occasionally highlighted neoplastic cells lining the joint capsule (Fig. 3E) or the original vessel. Cytokeratin
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ACCEPTED MANUSCRIPT 7 was focally expressed in one case (case 4). None of the tumors expressed CK20 or high molecular weight cytokeratins. TP53 was expressed in <10% of tumor cells in all cases.
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Nuclear SMARCB1 expression was intact in all cases. None of the tumors expressed CDK4 or
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MDM2. Moderate to strong diffuse expression of MYC by immunohistochemistry was seen in 4/5 cases (Fig. 3F) and focal expression in one case. FISH analysis revealed no copy
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number changes of MDM2 or CDK4 in all four evaluable cases. MYC amplification was
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detected by FISH in 1/4 evaluable cases (case 2; Fig. 4).
DISCUSSION
Sarcomas comprise 89% of malignant tumors developing at the site of total hip arthroplasty
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[41]. The majority of these sarcomas (75%) develop within the soft tissues and the
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remainder within bone [41]. Histologically, undifferentiated pleomorphic sarcoma (MFH) is the most frequent sarcoma type encountered in this setting (65%). Of those developing
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within bones harboring metal-implants, osteosarcoma is the most common variant [42].
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Prosthesis-associated sarcomas are highly aggressive with 77% of patients dying within one year after diagnosis [41].
This is the first pathological study devoted to angiosarcomas originating in association with orthopaedic joint prosthesis and Dacron vascular grafts. In this study we describe two new cases of this rare entity, re-evaluate three other cases reported previously in brief and review 13 additional cases reported in the English language literature between 1972 and 2015. Including the current cases, a total of 18 angiosarcoma cases associated with implanted surgical foreign body material have been documented in the literature (table 3 & 4). The type of foreign body in reported cases including our cases was woven Dacron vascular grafts (7 cases), joint replacement endoprothesis (6 cases) and implanted internal 7
ACCEPTED MANUSCRIPT metal fixation for long bone fractures (5 cases). Affected patients were 15 males and 4 females. All were adults with an age range of 48-84 years. The time interval between
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implantation of the foreign material and development of the angiosarcoma ranged from 3.5-
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52 years. Notably, the mean time varied significantly for the different prosthesis types: 8.9 years for Dacron vascular grafts, 17 years for joint endoprothesis and 35 years for implanted
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internal metal fixation for long bone fractures. Of 18 patients with information regarding
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metastases, 16 developed wide spread metastases at different sites including regional nodes, peritoneum, liver, brain, lung, pleura and others. Twelve patents died of disease within 2 years (half of them died within the first postoperative month and all but one died within one year). Only 2 patients survived longer without disease (one for 3 years and one
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died at 10 years of unrelated cause). Notably, both long term survivors had angiosarcomas
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related to implanted internal metal fixation for long bone fractures and both were treated by radical hemipelvectomy (case 6 and 8). It is noteworthy that, the diagnosis of
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angiosarcoma in several cases (including our cases) was significantly delayed as a neoplasm
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was not suspected clinically and, instead, pseudoaneurysm, graft infection and osteomyelitis were the main consideration in most patients prior to tissue biopsy. Diagnosis was thus delayed in most cases by a few months to two years. It is noteworthy that, all cases showed variably extensive areas of old granulation tissue with stromal sclerosis and hemosiderin deposits as evidence of recurrent bleeding. Such findings might be misinterpreted as reactive changes on limited biopsy material thus rendering a false negative diagnosis on biopsy.
The vast majority of previous reports do not include detailed histopathological, immunohistochemical or molecular analysis of the tumor as they have been mainly
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ACCEPTED MANUSCRIPT described from surgical or radiological view points. However, all tumors were reportedly poorly differentiated epithelioid angiosarcomas. This is confirmed by our detailed illustration
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of the five cases presented in this report. All showed solid epithelioid growth of
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undifferentiated large polygonal cells closely mimicking poorly differentiated carcinoma. However, all cases showed at least focal minor vasoformation representing a clue to the
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correct diagnosis which was then confirmed by immunohistochemistry. Strong and diffuse
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expression of pancytokeratin seen in three of our cases and focal expression in the other two cases represents a potential source of confusion which could have resulted in misinterpretation as carcinoma, given that some primitive vasoformative areas closely resembled abortive gland formation. Rare angiosarcomas may show profound signet ring-
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like cell appearance [43]. None of our cases expressed D2-40 as a marker of lymphatic
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endothelial lineage. In line with previous studies, strong nuclear expression of ERG and FLI-1 represents highly sensitive adjunct markers for confirming endothelial differentiation in such
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poorly differentiated angiosarcomas.
In contrast to soft tissue sarcomas in general, angiosarcoma may develop either as a primary neoplasm of unknown etiology or secondary to several specific etiological factors. For example, 25% of hepatic angiosarcomas in a previous review were associated with known etiologic factors (exposure to vinyl chloride monomer, Thorotrast, inorganic arsenic and treatment with androgenic anabolic steroids).5 In another study, 4/80 (5%) angiosarcomas of soft tissue were associated with synthetic foreign material: one originated at the site of an inguinal hernia repair (6 years earlier), one case each was associated with synthetic iliac artery graft and a femoral-popliteal bypass graft and one abdominal wall angiosarcoma followed a history of an abdominal brace for unspecified reason. However, a detailed
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ACCEPTED MANUSCRIPT description of these cases was not provided [3]. While post-radiation angiosarcomas but not atypical vascular lesions (AVL) of the breast skin have been uniformly linked to MYC
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amplification [44,45], recent studies have shown MYC to be amplified in a subset of
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cutaneous angiosarcomas unrelated to previous irradiation [46]. In one study, MYC status showed 100% concordance with protein expression by immunohistochemistry in secondary
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angiosarcomas and AVL lesions [47]. Our results are in line with these recent studies. We
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observed a 2+/3+ MYC protein expression in 4/5 cases but only one of them showed MYC amplification by FISH. Thus it is likely that MYC plays a role in the pathogenesis of prostheses-associated angiosarcomas. Alternative mechanisms are possibly responsible for the upregulation of MYC expression seen in our cases and in other angiosarcoma cases
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expressing MYC but lacking MYC amplification [46]. Absence of MDM2 and CDK4
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amplification in all 3 Dacron-associated vascular angiosarcomas in this study argues against a molecular pathogenesis analogous to intimal sarcomas of large vessels.
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Regarding the etiological role of implanted foreign material in the pathogenesis of
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angiosarcoma, it is unclear whether the metal prosthesis acts as an inert body (as reported for a variety of non-metal foreign bodies complicated by angiosarcoma [15]), or if specific mechanisms related to the biophysical properties of the metal are implicated. To date, no specific type of joint prosthesis has been implicated to be associated with increased risk of malignancy. A large epidemiological study from Finland suggested a higher risk of soft-tissue sarcoma in the metal-on-metal cohort than in the non-metal-on-metal cohort [48]. However, based on the low number of reported sarcoma cases (46 cases reported between 1974 and 2003) compared to the total population of hip arthroplasty, the authors of the same study postulated that chronic, particle-induced inflammation around the prosthesis does not seem to increase the risk for carcinogenesis [48]. When diagnosing an implant-associated
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ACCEPTED MANUSCRIPT angiosarcoma, it is important to exclude other underlying conditions known to be associated with a risk of angiosarcoma such as previous irradiation, Maffucci syndrome and other
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genetic disorders. Furthermore, it is important to exclude a pre-existing neoplasm that might
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have necessitated graft implantation. However, based on the highly aggressive clinical course of angiosarcomas in this series with most of patients dying of disease within one year
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of diagnosis and based on the observation of a very long latency between graft/prosthesis
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implantation and angiosarcoma diagnosis (mean, 9 year), it is very unlikely that angiosarcoma was pre-existent before implantation of the foreign material. Alterations in the blood flow and/or turbulence might be implicated in the Dacron graft-associated cases.
no foreign material [22].
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In line with such a hypothesis, angiosarcomas have been reported in vessels with shunts but
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In summary, we report in detail the clinicopathological features of five angiosarcomas
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associated with Dacron vascular grafts or orthopedic joint prosthesis and reviewed the clinicopathological features of an additional 14 previously reported cases. This study
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highlights the predominance of epithelioid morphology and the highly aggressive clinical course of angiosarcoma in this setting as well as the frequent delay in diagnosis due to the confusing clinical presentation. Considering angiosarcoma in cases with unexpected late loosening of hardware or infection and unexplained bleeding around the prosthesis is mandatory for timely diagnosis as radical local treatment is the only hope of long-term survival in patients with localized disease.
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ACCEPTED MANUSCRIPT ACKNOWLEDGEMENT
The authors are grateful to A. Müller, MD (Kliniken Dr. Erler, Nürnberg) for supplying clinical
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data and M. Lell, MD (Erlangen) for providing imaging data on case 4.
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ACCEPTED MANUSCRIPT Figure 1 Imaging findings in joint prosthesis-associated angiosarcomas from case 5 (A; CT) and case 4
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Figure 2
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soft tissue component and variable osteolytic changes.
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(B; MRI) showed large masses encasing the femur neck and the prosthesis with an extensive
Representative histological images from prosthesis-associated angiosarcomas. A (case 5) and
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containing single erythrocytes (case 2). F: All cases showed variable fibrosclerosis with
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Figure 3
Representative images of immunohistochemical features
of prosthesis-associated
angiosarcomas. All cases expressed CD31 with distinctive strong membranous pattern (A, case 4). ERG was expressed strongly in the nuclei of tumor cells in all cases (B, case 1). D2-40 highlighted lymphatic vessel permeation but the neoplastic cells were negative (C, case 1). Pancyokeratin was strongly expressed in 4 cases and focal in one case (D, case 4), occasionally highlighting tumor cells lining the joint capsule (E, case 4). Moderate to diffuse nuclear MYC expression was seen in 4 cases (F, case 2).
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84 M
Infrarenal aorta
Dacron graft
8 years
Follow-up DOD (6 mo)
Recurrence & lung MTS (12 mo); DOD (24 mo) Died postoperative. Lymph nodes & vertebral MTS
Solid Surgery epithelioid, sclerotic areas 4 78 M Hip, encasing Total hip 17 years. Solid Palliative DOD shortly after the joint endoprosthesis Revised after epithelioid, diagnosis prosthesis 14 yrs sclerotic areas 5 55 M Left Bilateral hip 8 years Anastomosing Surgery + Lung MTS hemipelvis replacement vessels, RCT ANED (17 mo) contiguous epithelioid cell with prothesis features ANED=alive with no evidence of disease; CIA, common iliac artery; DOD= died of disease; F=female; M= male; mo=month; MTS= metastasis; RCT= radiochemotherapy.
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Table 1: Clinicopathologic features of prosthesis-associated angiosarcomas (n=5)*. No Age/ Site Foreign body Time to Histology Treatment Gender type angiosarcoma 1 71 M Aortobifemoral Dacron graft 8 years Solid Palliative bypass. tumor epithelioid, chemotherapy between graft +gaping & original right vessels CIA 2 50 M Infrarenal Dacron graft 4.6 years Solid Surgery + aorta epithelioid chemotherapy
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<10 %+ <10 %+
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Nor mal Nor mal
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Table 2: Immunohistochemical and molecular findings in prosthesis-associated angiosarcomas (n=5). MD CDK Ca Pa CK34ß C CK CD ER FL D MD CD MY TP5 INI M2 4 se nE12 K7 20 31 G I-1 2- M2 K4 C 3 1 CK 4 IHC IHC IH IHC IH FIS FIS 0 C C H H 1 ++ ++ ++ ++ ++ <10 inta NR NR + + %+ ct 2 +( ++ ++ ++ ++ <10 inta Nor Nor F) + + + %+ ct mal mal
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Table 3: Clinicopathologic features of reported angiosarcomas associated with Dacron vascular grafts (n=7). N Authors/ye Age/ Foreign Interval to Symptom Histological Treatme Follow-up o ar Gender body type/ angiosarco s pattern nt underlying ma disease/ cause 1 Fehrenbach 67 M Dacron 12 yrs Progressi Angiosarco Resectio Penile MTS er et al, graft, infrave right ma n of the (4 mo), 1981 renal aortic foot pain graft then wideaneurysm spread MTS & death (10 mo) 2 Weiss et al, 56 M Dacron 3.5 yrs Increasin Epithelioid Resectio Liver MTS 1991 graft, infrag pain angiosarco n & new (11 mo), renal aortic and a ma Dacron, alive with aneurysm mass irradiati disease on 3 Ben-Izhak 71 M Dacron graft 8 yrs Pain, Epithelioid Biopsy, synchronou et al, 1999 aortobifemo nausea, angiosarco palliativ s peritoneal (current; ral vomiting, ma e MTS, DOD case 1) weight treatmen (6 mo) loss t 4 Okada et 50 M, Dacron 17 yrs Cerebral Epithelioid Biopsy Presented al, 2004 Marfan graft, aortic symptom angiosarco of brain with root s ma MTS multiple brain MTS. DOD (2 wks) 5 Umscheid 50 M Dacron, 4.6 yrs Fatigue, Epithelioid Resectio Local et al, 2007 Klinefelt infrarenal weight angiosarco n + CT recurrence (current; er aortic loss, abd. ma & lung case 2) aneurysm pain MTS (1 yr), DOD (2 yrs) with widespread MTS 6 Almeida et 60 F Dacron 9 yrs Dyspnoea Angiosarco Biopsy Initial al, 2011 graft, right , fatigue, ma & wideatrium weight palliativ spread loss e RCT MTS, died 3 wks later 7 Schmehl et 84 M Dacron, 8 yrs Fatigue, Epithelioid Resectio Died of al, 2012, infrarenal weight angiosarco n complicatio Brendle et aortic loss, abd. ma ns postop al, 2011 aneurysm pain with lymph (current; nodes & case 3) vertebral MTS ANED=alive with no evidence of disease; CT= chemotherapy; DOD= died of disease; DOOC= died of other cause; F=female; ICD= intracardiac device; M= male; mo=month; MTS= metastasis; postop= postoperative; PUO= pyrexia of unknown origin; RCT= radiochemotherapy; TEP= total endoprothesis; yrs= years.
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Table 4: Clinicopathologic features of reported angiosarcomas associated with orthopedic metal prostheses (n=11). N Authors/ye Age/ Foreign body Interval to Symptoms Histological Treatment Follow-up o ar Gende type/ angiosarco pattern r underlying ma disease/ cause 1 Dube & 84 M Metal plate 26 yrs Swelling & Epithelioid Local Local Fisher, (type 316 calf pain angiosarcom resection, then recurrence 1972 stainless a amputation (7 mo); steel), left DOD (11 tibia, mo) with farming inguinal accident node, lung & brain MTS 2 van der 72 F Bilateral hip 11 yrs Loosening Epithelioid Biopsy NA List et al, TEP for of TEP, angiosarcom 1988 congenital malaise, a hip dysplasia progressive pain 3 Ferrari et 48 M Intramedulla 31 yrs Pain & mass Angiosarco Hip ANED al, 2001 ry nail in distal ma disarticulation (3yrs) fixation, left thigh, fever & CT distal thigh fracture (accident) 4 McDonald 70 M Fixation with 52 yrs Gradual Angiosarco Wide resection Iliac & et al, 2002 plate, screw onset of a ma with + CT paraaortic & bone graft, mass epithelioid node MTS proximal areas (postop), thigh lung MTS fracture right (7 mo), (accident) DOD (12 mo) 5 McDonald 71 M Fixation with 41 yrs Pain & large Angiosarco Hemipelvecto DOOC 10 et al, 2002 plate, screw thigh mass ma my years later & bone graft, proximal thigh fracture (accident) 6 Albert et 85 F Total 10 yrs Knee pain Epithelioid Biopsy, then Synchronou al, 2009 arthroplasty, after a fall angiosarcom mid-thigh s lung and right knee a amputation regional node MTS, sudden death 1 mo later 7 Mallick et 84 F Bilateral hip 30 yrs Painful right Angiosarco Biopsy & Deterioratin al, 2009 TEP revised hip ma (not palliative g, inguinal 10 &11 yrs illustrated, radiotherapy node ago with type not involved, no ceramic & specified) extended titanium follow-up 8 Drexler et 72 M Tibial 25 yrs Degenerativ Epithelioid Above-knee Synchronou al, 2010 plateau left (removed e change, angiosarcom amputation, s MTS knee after 1 yr pain, a then irradiation proximal stainless due to bleeding femur & steel plate. irritation pelvis motor accident 9 Fabbri et 80 M Hip TEP 27 yrs, 6 yrs Progressive Epithelioid Open reduction DOD al, 2011 later loss of angiosarcom & fixation, shortly of uncemented function, a then wide spread Lord pain, amputation bilateral prosthesis fracture lung MTS for aseptic failure
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Current (case 4)
78 M
Hip TEP
17 yrs, revised after 14 yrs
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Current (case 5)
55 M
Bilateral hip replacement
8 yrs
Loosening, recurrent uncontrollab le bleeding Loosening, bleeding
Epithelioid angiosarcom a
Biopsy and supportive
DOD shortly after diagnosis
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Epithelioid Resection + Lung MTS angiosarcom RCT ANED (17 a mo) ANED=alive with no evidence of disease; CT= chemotherapy; DOD= died of disease; DOOC= died of other cause; F=female; ICD= intracardiac device; M= male; mo=month; MTS= metastasis; postop= postoperative; PUO= pyrexia of unknown origin; RCT= radiochemotherapy; TEP= total endoprothesis; yrs= years.
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S1092-9134(16)30002-8 doi: 10.1016/j.anndiagpath.2016.01.002 YADPA 51047
To appear in:
Annals of Diagnostic Pathology
Please cite this article as: Agaimy Abbas, Ben-Izhak Ofer, Lorey Thomas, Scharpf Marcus, Rubin Brian P., Angiosarcoma Arising in Association with Vascular Dacron Grafts and Orthopedic Joint Prostheses: Clinicopathologic, Immunohistochemical and Molecular Study, Annals of Diagnostic Pathology (2016), doi: 10.1016/j.anndiagpath.2016.01.002
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ACCEPTED MANUSCRIPT Angiosarcoma Arising in Association with Vascular Dacron Grafts and Orthopedic Joint Prostheses: Clinicopathologic, Immunohistochemical and
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Molecular Study.
Abbas Agaimy, MD1, Ofer Ben-Izhak, MD2, Thomas Lorey, MD3, MD, Marcus Scharpf, MD4,
Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, University
Hospital, 91054 Erlangen, Germany.
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1
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Brian P. Rubin, MD, PhD5.
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Department of Pathology, Rambam Health Care Campus, 31096 Haifa, ISRAEL.
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Institute of Pathology, Caritas-Krankenhaus, Bad Mergentheim gGmbH, 97980 Bad
Mergentheim, Germany.
Institute of Pathology, University Hospital, 72076 Tübingen, Germany
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Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland,
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OH 44195, USA.
Address page proofs, correspondence, and requests for reprints to:
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Abbas Agaimy, MD
Pathologisches Institut Universitätsklinikum Erlangen Krankenhausstraße 8-10 91054 Erlangen, Germany Telephone: +49-9131-85-22288 Fax: +49-9131-85-22613 Email: [email protected] Short running title: Prosthesis-associated angiosarcoma Conflict of interest: none to declare. Funding: none. 1
ACCEPTED MANUSCRIPT ABSTRACT Angiosarcoma may rarely arise in close proximity to inert foreign body material including
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vascular grafts and metal joint prostheses. 16 such cases have been reported since 1972 but mostly in the radiological or surgical literature without detailed histological or molecular
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analyses. We herein describe the clinicopathologic and molecular features of 2 new cases and reanalyzed 3 previously reported cases of angiosarcoma that developed in association
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with Dacron grafts for vascular repair (n=3) or related to orthopedic metal prostheses for joint replacement (n=2). All patients were males aged 50-84 (median, 71). Mean time to development of angiosarcoma was 9 years (range, 4.6-17). Symptoms were recurrent
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bleeding/ loosening of prosthesis for suspected infection (in the joint prosthesis cases) and fatigue, weight loss, and abdominal symptoms in the Dacron-associated cases. Four patients
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died of disease within 1-24 months (mean, 8). One patient was alive after radical surgery,
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radiochemotherapy and embolization of pulmonary metastases (17 months). Histologically, all tumors were high-grade epithelioid neoplasms with a predominant solid growth pattern
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and variable vasoformation. All tumors expressed CD31, ERG, FLI-1 and variably pancytokeratin (diffuse in 3 cases) but none expressed D2-40, MDM2 or CDK4. FISH analysis revealed no MDM2 or CDK4 alterations. MYC was expressed in all cases, but only 1 case was MYC-amplified by FISH. Angiosarcomas are exceedingly rare fatal complications of longstanding metal and Dacron prostheses. Awareness of their morphology and frequent cytokeratin expression is necessary to avoid misdiagnosis as metastatic carcinoma. Limited awareness of their existence explains delayed clinical diagnosis in most of cases. Absence of MDM2/CDK4 alterations underlines their distinction from intimal-type sarcomas. Keywords: angiosarcoma; Dacron graft; joint prosthesis; joint replacement; metal; foreign body; MYC. 2
ACCEPTED MANUSCRIPT INTRODUCTION Soft tissue sarcomas are uncommon (<1% of all cancer types). Angiosarcomas are even rarer
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representing <2% of all soft tissue sarcomas [1]. They mainly arise in the skin and superficial
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soft tissue and less frequently in deep soft tissue and bones [1]. Cutaneous angiosarcomas show a predilection for the head and neck skin and they mainly affect the elderly [2]. On the hand,
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retroperitoneum and trunk with a wide age range (5-97 yrs) [3]. Rarely, angiosarcomas may develop within visceral organs such as breast [4], liver [5], spleen [6], heart [7], kidney [8], gastrointestinal tract [9], urinary bladder [10], and abdominal and thoracic cavity including serosal membranes [11-13]. As is with soft tissue sarcomas in general, the vast majority of
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angiosarcomas arise de novo without underlying systemic diseases or predisposing
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conditions. However, a subset of angiosarcomas arise in a background of previous irradiation for malignant diseases, in particular, after breast-conserving surgery and adjuvant irradiation
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for breast cancer, prostate cancer and others (secondary or post-radiation angiosarcomas)
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[4,10]. Furthermore, angiosarcomas have been increasingly recognized to occur in specific predisposing clinicopathological circumstances including well documented cases related to exposure to chemical agents (liver angiosarcomas after thorotrast injection [5]), bullet and other war injuries [14], laparotomy sponge and other synthetic material left behind at surgical exploration [14,15], breast implants [16], injection-site [17], gouty tophus [18] within chronic expanding hematomas [19], chronic lymphedema of diverse etiology [20], venous graft used as arterial bypass [21] and arteriovenous fistulae created for hemodialysis in patients with terminal renal failure [22]. Rare cases developed on a background of solid organ transplantation [23].
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ACCEPTED MANUSCRIPT Angiosarcomas arising in association with Dacron grafts for vascular repair or related to orthopedic metal prosthesis for joint replacement are rare with a total of 16 single case
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reports published between 1972 and 2015 [24-40]. However, with two exceptions [28,40], all
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cases have been reported in the orthopedic, surgical or radiological literature and hence, detailed histopathological and immunohistochemical analyses were not provided. We herein
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describe two new cases of angiosarcomas arising in association with prostheses, reanalyzed
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three previously reported cases and reviewed the literature to look for similar cases to delineate their major clinicopathological features.
MATERIALS AND METHODS
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Case 1-3 have been reported previously [28,32,38,39]. Case 4 and 5 were retrieved from the
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pathology departments of two of the authors (A.A & B.P.R.). Tumor specimens were fixed in buffered formalin overnight and embedded routinely for histological examination.
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Immunohistochemical stains were performed on freshly cut 3-µm paraffin sections using a
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fully automated slide preparation system (“Benchmark XT System”, Ventana Medical Systems Inc., 1910 Innovation Park Drive, Tucson, Arizona, USA) and the following antibodies: pancytokeratin (clone KL-1, 1:200, Immunotech), CK7 (OV-TL, 1:1000, Biogenex), CK20 (KS20.8, 1:50, Dako), ERG (clone EPR3864, prediluted/ready to use, Ventana Medical Systems), FLI-1 (clone G146-222, 1:200, BD Pharmingen™), podoplanin (clone D2-40, 1:50, Zytomed), high molecular weight cytokeratin (clone 34ßE12, 1:50, Dako), SMARCB1 (MRQ27, 1:50, Zytomed), TP53 (clone DO-7, 1:50, Dako), MYC (clone EP121, 1:100, Epitomics, California, USA), MDM2 (clone IF1, 1:50, CalBiochem) and CDK4 (clone DCS-156, 1:100, Zytomed).
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paraffin-embedded tumor tissue blocks using ZytoLight Dual Color Probes (ZytoVision,
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Bremerhaven, Germany) with standard protocols according to the manufacturer`s instructions. Fifty tumor cell nuclei were assessed and cases with a ratio of >2 were
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considered amplified.
RESULTS
All patients were males aged 50-84 (median, 71; table 1). Three patients received Dacron grafts for vascular repair of the infrarenal aorta (2 cases) or of the right common iliac artery
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(one). Two patients received total hip endoprothesis for degenerative joint disease.
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Mean time to development of angiosarcoma was nine years and was similar for those with Dacron and joint prostheses (range, 4.6 to 17 yrs). Symptoms were unexplained recurrent
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bleeding/revision of prosthesis for suspected infection (in the joint prosthesis cases) and
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fatigue, unexplained weight loss and/or abdominal pain in patients with Dacron-associated intra-abdominal angiosarcoma. Treatment was surgical resection and/or palliative radiochemotherapy in four patients. One patient refused any palliative therapy and he died postoperatively from uncontrolled bleeding. Multiple pleural metastases were found at autopsy. Four patients died of disease (either with extensive metastatic disease or due to disease complications) within 1-24 months (mean 8 months). One patient was alive after radical surgery, radiochemotherapy and embolization of pulmonary metastases (last followup 17 months).
Pathological findings
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the original vascular lumen in the cases of Dacron grafts. A variable degree of osteolysis was
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seen on imaging of the joint prosthesis- associated cases (Fig. 1). Grossly, all tumors showed extensive hemorrhage closely mimicking expanding hematoma or infection at the time of
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revision. Histologically, tumor tissue was seen forming a capsule-like layer surrounding the
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joint capsule (Fig. 2A) or lining the original vascular lumen (Fig. 2B). All tumors were highgrade epithelioid neoplasms with predominant solid morphology and variable vasoformative component (Fig. 2C-E). The tumor cells were large with polygonal or rounded vesicular nuclei and prominent, centrally located nucleoli. The vasoformative component was generally
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minor and comprised <20% of the neoplasm (Fig. 2C). The solid tumor areas were strikingly
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reminiscent of poorly differentiated adenocarcinoma as several tumor cells contained empty intra-cytoplasmic vacuoles that occasionally looked like signet ring cells or abortive gland
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formation (Fig. 2D). A corded pattern with voluminous cytoplasm occasionally containing
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single erythrocytes within vacuoles was seen as well (Fig. 2E). All cases showed variable stromal sclerosis with hemosiderin deposits as evidence of recurrent bleeding (Fig. 2F). Mitotic activity ranged from 10 to 35/10 high power fields (median, 18/10 HPFs). By immunohistochemistry (table 2), all tumors expressed CD31 (Fig. 3A) with a distinctive membranous pattern and a staining intensity similar to that seen in normal vessels. In addition, all tumors showed strong nuclear expression of ERG (Fig. 3B) and FLI-1, but none expressed D2-40. D2-40 highlighted prominent permeation of lymphatic vessels (Fig. 3C). Strong and diffuse expression of pancytokeratin was seen in 3 cases with a remarkable intensity similar to staining in epithelial neoplasms (Fig. 3D). Cytokeratin occasionally highlighted neoplastic cells lining the joint capsule (Fig. 3E) or the original vessel. Cytokeratin
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Nuclear SMARCB1 expression was intact in all cases. None of the tumors expressed CDK4 or
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MDM2. Moderate to strong diffuse expression of MYC by immunohistochemistry was seen in 4/5 cases (Fig. 3F) and focal expression in one case. FISH analysis revealed no copy
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number changes of MDM2 or CDK4 in all four evaluable cases. MYC amplification was
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detected by FISH in 1/4 evaluable cases (case 2; Fig. 4).
DISCUSSION
Sarcomas comprise 89% of malignant tumors developing at the site of total hip arthroplasty
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[41]. The majority of these sarcomas (75%) develop within the soft tissues and the
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remainder within bone [41]. Histologically, undifferentiated pleomorphic sarcoma (MFH) is the most frequent sarcoma type encountered in this setting (65%). Of those developing
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within bones harboring metal-implants, osteosarcoma is the most common variant [42].
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Prosthesis-associated sarcomas are highly aggressive with 77% of patients dying within one year after diagnosis [41].
This is the first pathological study devoted to angiosarcomas originating in association with orthopaedic joint prosthesis and Dacron vascular grafts. In this study we describe two new cases of this rare entity, re-evaluate three other cases reported previously in brief and review 13 additional cases reported in the English language literature between 1972 and 2015. Including the current cases, a total of 18 angiosarcoma cases associated with implanted surgical foreign body material have been documented in the literature (table 3 & 4). The type of foreign body in reported cases including our cases was woven Dacron vascular grafts (7 cases), joint replacement endoprothesis (6 cases) and implanted internal 7
ACCEPTED MANUSCRIPT metal fixation for long bone fractures (5 cases). Affected patients were 15 males and 4 females. All were adults with an age range of 48-84 years. The time interval between
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implantation of the foreign material and development of the angiosarcoma ranged from 3.5-
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52 years. Notably, the mean time varied significantly for the different prosthesis types: 8.9 years for Dacron vascular grafts, 17 years for joint endoprothesis and 35 years for implanted
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internal metal fixation for long bone fractures. Of 18 patients with information regarding
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metastases, 16 developed wide spread metastases at different sites including regional nodes, peritoneum, liver, brain, lung, pleura and others. Twelve patents died of disease within 2 years (half of them died within the first postoperative month and all but one died within one year). Only 2 patients survived longer without disease (one for 3 years and one
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died at 10 years of unrelated cause). Notably, both long term survivors had angiosarcomas
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related to implanted internal metal fixation for long bone fractures and both were treated by radical hemipelvectomy (case 6 and 8). It is noteworthy that, the diagnosis of
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angiosarcoma in several cases (including our cases) was significantly delayed as a neoplasm
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was not suspected clinically and, instead, pseudoaneurysm, graft infection and osteomyelitis were the main consideration in most patients prior to tissue biopsy. Diagnosis was thus delayed in most cases by a few months to two years. It is noteworthy that, all cases showed variably extensive areas of old granulation tissue with stromal sclerosis and hemosiderin deposits as evidence of recurrent bleeding. Such findings might be misinterpreted as reactive changes on limited biopsy material thus rendering a false negative diagnosis on biopsy.
The vast majority of previous reports do not include detailed histopathological, immunohistochemical or molecular analysis of the tumor as they have been mainly
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of the five cases presented in this report. All showed solid epithelioid growth of
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undifferentiated large polygonal cells closely mimicking poorly differentiated carcinoma. However, all cases showed at least focal minor vasoformation representing a clue to the
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correct diagnosis which was then confirmed by immunohistochemistry. Strong and diffuse
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expression of pancytokeratin seen in three of our cases and focal expression in the other two cases represents a potential source of confusion which could have resulted in misinterpretation as carcinoma, given that some primitive vasoformative areas closely resembled abortive gland formation. Rare angiosarcomas may show profound signet ring-
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endothelial lineage. In line with previous studies, strong nuclear expression of ERG and FLI-1 represents highly sensitive adjunct markers for confirming endothelial differentiation in such
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poorly differentiated angiosarcomas.
In contrast to soft tissue sarcomas in general, angiosarcoma may develop either as a primary neoplasm of unknown etiology or secondary to several specific etiological factors. For example, 25% of hepatic angiosarcomas in a previous review were associated with known etiologic factors (exposure to vinyl chloride monomer, Thorotrast, inorganic arsenic and treatment with androgenic anabolic steroids).5 In another study, 4/80 (5%) angiosarcomas of soft tissue were associated with synthetic foreign material: one originated at the site of an inguinal hernia repair (6 years earlier), one case each was associated with synthetic iliac artery graft and a femoral-popliteal bypass graft and one abdominal wall angiosarcoma followed a history of an abdominal brace for unspecified reason. However, a detailed
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ACCEPTED MANUSCRIPT description of these cases was not provided [3]. While post-radiation angiosarcomas but not atypical vascular lesions (AVL) of the breast skin have been uniformly linked to MYC
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amplification [44,45], recent studies have shown MYC to be amplified in a subset of
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cutaneous angiosarcomas unrelated to previous irradiation [46]. In one study, MYC status showed 100% concordance with protein expression by immunohistochemistry in secondary
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angiosarcomas and AVL lesions [47]. Our results are in line with these recent studies. We
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observed a 2+/3+ MYC protein expression in 4/5 cases but only one of them showed MYC amplification by FISH. Thus it is likely that MYC plays a role in the pathogenesis of prostheses-associated angiosarcomas. Alternative mechanisms are possibly responsible for the upregulation of MYC expression seen in our cases and in other angiosarcoma cases
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expressing MYC but lacking MYC amplification [46]. Absence of MDM2 and CDK4
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amplification in all 3 Dacron-associated vascular angiosarcomas in this study argues against a molecular pathogenesis analogous to intimal sarcomas of large vessels.
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Regarding the etiological role of implanted foreign material in the pathogenesis of
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angiosarcoma, it is unclear whether the metal prosthesis acts as an inert body (as reported for a variety of non-metal foreign bodies complicated by angiosarcoma [15]), or if specific mechanisms related to the biophysical properties of the metal are implicated. To date, no specific type of joint prosthesis has been implicated to be associated with increased risk of malignancy. A large epidemiological study from Finland suggested a higher risk of soft-tissue sarcoma in the metal-on-metal cohort than in the non-metal-on-metal cohort [48]. However, based on the low number of reported sarcoma cases (46 cases reported between 1974 and 2003) compared to the total population of hip arthroplasty, the authors of the same study postulated that chronic, particle-induced inflammation around the prosthesis does not seem to increase the risk for carcinogenesis [48]. When diagnosing an implant-associated
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ACCEPTED MANUSCRIPT angiosarcoma, it is important to exclude other underlying conditions known to be associated with a risk of angiosarcoma such as previous irradiation, Maffucci syndrome and other
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genetic disorders. Furthermore, it is important to exclude a pre-existing neoplasm that might
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have necessitated graft implantation. However, based on the highly aggressive clinical course of angiosarcomas in this series with most of patients dying of disease within one year
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of diagnosis and based on the observation of a very long latency between graft/prosthesis
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implantation and angiosarcoma diagnosis (mean, 9 year), it is very unlikely that angiosarcoma was pre-existent before implantation of the foreign material. Alterations in the blood flow and/or turbulence might be implicated in the Dacron graft-associated cases.
no foreign material [22].
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In line with such a hypothesis, angiosarcomas have been reported in vessels with shunts but
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In summary, we report in detail the clinicopathological features of five angiosarcomas
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associated with Dacron vascular grafts or orthopedic joint prosthesis and reviewed the clinicopathological features of an additional 14 previously reported cases. This study
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highlights the predominance of epithelioid morphology and the highly aggressive clinical course of angiosarcoma in this setting as well as the frequent delay in diagnosis due to the confusing clinical presentation. Considering angiosarcoma in cases with unexpected late loosening of hardware or infection and unexplained bleeding around the prosthesis is mandatory for timely diagnosis as radical local treatment is the only hope of long-term survival in patients with localized disease.
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ACCEPTED MANUSCRIPT ACKNOWLEDGEMENT
The authors are grateful to A. Müller, MD (Kliniken Dr. Erler, Nürnberg) for supplying clinical
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data and M. Lell, MD (Erlangen) for providing imaging data on case 4.
REFERENCES
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1. Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, eds. (2013) World Health Organisation classification of Tumours of Soft Tissue and Bone (4th edn). Lyon, IARC Press, 2013, pp.80-82. 2. Albores-Saavedra J, Schwartz AM, Henson DE, et al. Cutaneous angiosarcoma. Analysis of 434 cases from the Surveillance, Epidemiology, and End Results Program, 1973-2007. Ann Diagn Pathol 2011;15:93-7. 3. Meis-Kindblom JM, Kindblom LG. Angiosarcoma of soft tissue: a study of 80 cases. Am J Surg Pathol 1998;22:683-97.
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15. Ben-Izhak O, Kerner H, Brenner B, et al. Angiosarcoma of the colon developing in a capsule of a foreign body. Report of a case with associated hemorrhagic diathesis. Am J Clin Pathol 1992;97:416-20.
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16. Saunders ND, Marshall JS, Anderson RC. A case of chest wall angiosarcoma associated with breast implants. J Thorac Cardiovasc Surg 2007;134:1076-7. 17. Cheng H, Allen PW. Selected case from the Arkadi M. Rywlin international pathology slide seminar: injection-site high-grade angiosarcoma, subcutis, left buttock region. Adv Anat Pathol 2011;18:329-32.
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18. Folpe AL, Johnston CA, Weiss SW. Cutaneous angiosarcoma arising in a gouty tophus: report of a unique case and a review of foreign material-associated angiosarcomas. Am J Dermatopathol 2000;22:418-21.
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19. Burgert-Lon CE, Riddle ND, Lackman RD, et al. Angiosarcoma Arising in Chronic Expanding Hematoma: Five Cases of an Underrecognized Association. Am J Surg Pathol 2015;39:1540-7.
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20. Miettinen M, Lehto VP, Virtanen I. Postmastectomy angiosarcoma (Stewart-Treves syndrome). Light-microscopic, immunohistological, and ultrastructural characteristics of two cases. Am J Surg Pathol 1983;7:329-39.
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21. Nocturne G, Sellam J, Miquel A, et al. Is sarcoma a complication of arterial femoropopliteal bypass? Joint Bone Spine 2010;77:358-60. 22. Oskrochi Y, Razi K, Stebbing J, et al. Angiosarcoma and Dialysis-related Arteriovenous Fistulae: A Comprehensive Review. Eur J Vasc Endovasc Surg 2015 Oct 5. pii: S10785884(15)00627-9. doi 23. Chen X, Lagana SM, Poneros J, et al. Cytological diagnosis of angiosarcoma arising in an immunosuppressed patient 6 years after multi-visceral transplantation: a case report and literature review. Diagn Cytopathol 2014;42:884-9. 24. Dube VE, Fisher DE. Hemangioendothelioma of the leg following metallic fixation of the tibia. Cancer 1972;30:1260-6. 25. Fehrenbacher JW, Bowers W, Strate R, et al. Angiosarcoma of the aorta associated with a Dacron graft. Ann Thorac Surg 1981;32:297-301. 26. van der List JJ, van Horn JR, Slooff TJ, et al. Malignant epithelioid hemangioendothelioma at the site of a hip prosthesis. Acta Orthop Scand 1988;59:328-30.
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ACCEPTED MANUSCRIPT 27. Weiss WM, Riles TS, Gouge TH, et al. Angiosarcoma at the site of a Dacron vascular prosthesis: a case report and literature review. J Vasc Surg 1991;14:87-91.
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28. Ben-Izhak O, Vlodavsky E, Ofer A, et al. Epithelioid angiosarcoma associated with a Dacron vascular graft. Am J Surg Pathol 1999;23:1418-22.
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29. Ferrari D, Pignatti G, Bertoni F, et al. Angiosarcoma of bone following intramedullary nail fixation. Orthopedics 2001;24:795-7.
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30. McDonald DJ, Enneking WF, Sundaram M. Metal-associated angiosarcoma of bone: report of two cases and review of the literature. Clin Orthop Relat Res 2002;396:206-14.
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31. Okada M, Takeuchi E, Mori Y, et al. An autopsy case of angiosarcoma arising around a woven Dacron prosthesis after a Cabrol operation. J Thorac Cardiovasc Surg 2004;127:18435. 32. Umscheid TW, Rouhani G, Morlang T, et al. Hemangiosarcoma after endovascular aortic aneurysm repair. J Endovasc Ther 2007;14:101-5.
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33. Albert A, Lootvoet L, Lejeune E, et al. Angiosarcoma around a knee arthroplasty. Report of a case and literature review. Acta Orthop Belg 2009;75:549-53.
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34. Mallick A, Jain S, Proctor A, et al. Angiosarcoma around a revision total hip arthroplasty and review of literature. J Arthroplasty 2009;24:323.e17-20.
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35. Drexler M, Dolkart O, Amar E, et al. Late recurrent hemarthrosis following knee arthroplasty associated with epithelioid angiosarcoma of bone. Knee 2010;17:365-7.
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36. Almeida NJ, Hoang P, Biddle P, et al. Primary cardiac angiosarcoma: in a patient with a dacron aortic prosthesis. Tex Heart Inst J 2011;38:61-5. 37. Fabbri N, Rustemi E, Masetti C, et al. Severe osteolysis and soft tissue mass around total hip arthroplasty: description of four cases and review of the literature with respect to clinico-radiographic and pathologic differential diagnosis. Eur J Radiol 2011;77:43-50. 38. Brendle C, Müller M, Pfannenberg C. Epitheloides Angiosarkom nach Endovaskularprothese als seltene Differenzialdiagnose zur Protheseninfektion. Rofo 2011;183:567-8. 39.Schmehl J, Scharpf M, Brechtel K, et al. Epithelioid angiosarcoma with metastatic disease after endovascular therapy of abdominal aortic aneurysm. Cardiovasc Intervent Radiol. 2012;35:190-3. 40. Smith SC, Bernacki KD, Haft JW, et al. Internal cardiac defibrillator implant-associated angiosarcoma presenting as suspected implant pouch infection. Cardiovasc Pathol 2013;22:105-8. 41. Visuri T, Pulkkinen P, Paavolainen P. Malignant tumors at the site of total hip prosthesis. Analytic review of 46 cases. J Arthroplasty 2006;21:311-23. 14
ACCEPTED MANUSCRIPT 42. Keel SB, Jaffe KA, Petur Nielsen G, et al. Orthopaedic implant-related sarcoma: a study of twelve cases. Mod Pathol 2001;14:969-77.
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43. Salviato T, Bacchi CE, Luzar B, et al. Signet ring cell angiosarcoma: a hitherto unreported pitfall in the diagnosis of epithelioid cutaneous malignancies. Am J Dermatopathol 2013;35:671-5.
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44. Manner J, Radlwimmer B, Hohenberger P, et al. MYC high level gene amplification is a distinctive feature of angiosarcomas after irradiation or chronic lymphedema. Am J Pathol 2010;176:34-9.
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45. Mentzel T, Schildhaus HU, Palmedo G, et al. Postradiation cutaneous angiosarcoma after treatment of breast carcinoma is characterized by MYC amplification in contrast to atypical vascular lesions after radiotherapy and control cases: clinicopathological, immunohistochemical and molecular analysis of 66 cases. Mod Pathol 2012;25:75-85. 46. Shon W, Sukov WR, Jenkins SM, et al. MYC amplification and overexpression in primary cutaneous angiosarcoma: a fluorescence in-situ hybridization and immunohistochemical study. Mod Pathol 2014;27:509-15.
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47. Fernandez AP, Sun Y, Tubbs RR, et al. FISH for MYC amplification and anti-MYC immunohistochemistry: useful diagnostic tools in the assessment of secondary angiosarcoma and atypical vascular proliferations. J Cutan Pathol 2012;39:234-42.
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48. Mäkelä KT, Visuri T, Pulkkinen P, et al. Cancer incidence and cause-specific mortality in patients with metal-on-metal hip replacements in Finland. Acta Orthop 2014;85:32-8.
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ACCEPTED MANUSCRIPT Figure 1 Imaging findings in joint prosthesis-associated angiosarcomas from case 5 (A; CT) and case 4
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soft tissue component and variable osteolytic changes.
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(B; MRI) showed large masses encasing the femur neck and the prosthesis with an extensive
Representative histological images from prosthesis-associated angiosarcomas. A (case 5) and
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B (case 3) showed neoplastic tissue lining and encasing the original structures (joint capsule in case 5 and original vascular lumen in case 3). C: variable vasoformation was seen but usually represented a minor component (image from case 5). D: solid growth of large
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epithelioid cells with cytoplasmic vacuoles mimicking abortive gland formation (Case 4). E: corded pattern with voluminous cytoplasm and occasional primitive vasoformation
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containing single erythrocytes (case 2). F: All cases showed variable fibrosclerosis with
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entrapped hemosiderin pigment, which could lead to interpretation as reactive tissue and thus a false negative biopsy (image from case 4).
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Figure 3
Representative images of immunohistochemical features
of prosthesis-associated
angiosarcomas. All cases expressed CD31 with distinctive strong membranous pattern (A, case 4). ERG was expressed strongly in the nuclei of tumor cells in all cases (B, case 1). D2-40 highlighted lymphatic vessel permeation but the neoplastic cells were negative (C, case 1). Pancyokeratin was strongly expressed in 4 cases and focal in one case (D, case 4), occasionally highlighting tumor cells lining the joint capsule (E, case 4). Moderate to diffuse nuclear MYC expression was seen in 4 cases (F, case 2).
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occasional cluster-formation indicating MYC amplification (CEN8: orange signals).
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84 M
Infrarenal aorta
Dacron graft
8 years
Follow-up DOD (6 mo)
Recurrence & lung MTS (12 mo); DOD (24 mo) Died postoperative. Lymph nodes & vertebral MTS
Solid Surgery epithelioid, sclerotic areas 4 78 M Hip, encasing Total hip 17 years. Solid Palliative DOD shortly after the joint endoprosthesis Revised after epithelioid, diagnosis prosthesis 14 yrs sclerotic areas 5 55 M Left Bilateral hip 8 years Anastomosing Surgery + Lung MTS hemipelvis replacement vessels, RCT ANED (17 mo) contiguous epithelioid cell with prothesis features ANED=alive with no evidence of disease; CIA, common iliac artery; DOD= died of disease; F=female; M= male; mo=month; MTS= metastasis; RCT= radiochemotherapy.
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Table 1: Clinicopathologic features of prosthesis-associated angiosarcomas (n=5)*. No Age/ Site Foreign body Time to Histology Treatment Gender type angiosarcoma 1 71 M Aortobifemoral Dacron graft 8 years Solid Palliative bypass. tumor epithelioid, chemotherapy between graft +gaping & original right vessels CIA 2 50 M Infrarenal Dacron graft 4.6 years Solid Surgery + aorta epithelioid chemotherapy
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* Cases 1-3 have been reported previously (see table 3).
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+( F)
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++ + ++ +
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Norm al Norm al
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<10 %+ <10 %+
MYC FISH
Nor mal Nor mal
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Table 2: Immunohistochemical and molecular findings in prosthesis-associated angiosarcomas (n=5). MD CDK Ca Pa CK34ß C CK CD ER FL D MD CD MY TP5 INI M2 4 se nE12 K7 20 31 G I-1 2- M2 K4 C 3 1 CK 4 IHC IHC IH IHC IH FIS FIS 0 C C H H 1 ++ ++ ++ ++ ++ <10 inta NR NR + + %+ ct 2 +( ++ ++ ++ ++ <10 inta Nor Nor F) + + + %+ ct mal mal
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Table 3: Clinicopathologic features of reported angiosarcomas associated with Dacron vascular grafts (n=7). N Authors/ye Age/ Foreign Interval to Symptom Histological Treatme Follow-up o ar Gender body type/ angiosarco s pattern nt underlying ma disease/ cause 1 Fehrenbach 67 M Dacron 12 yrs Progressi Angiosarco Resectio Penile MTS er et al, graft, infrave right ma n of the (4 mo), 1981 renal aortic foot pain graft then wideaneurysm spread MTS & death (10 mo) 2 Weiss et al, 56 M Dacron 3.5 yrs Increasin Epithelioid Resectio Liver MTS 1991 graft, infrag pain angiosarco n & new (11 mo), renal aortic and a ma Dacron, alive with aneurysm mass irradiati disease on 3 Ben-Izhak 71 M Dacron graft 8 yrs Pain, Epithelioid Biopsy, synchronou et al, 1999 aortobifemo nausea, angiosarco palliativ s peritoneal (current; ral vomiting, ma e MTS, DOD case 1) weight treatmen (6 mo) loss t 4 Okada et 50 M, Dacron 17 yrs Cerebral Epithelioid Biopsy Presented al, 2004 Marfan graft, aortic symptom angiosarco of brain with root s ma MTS multiple brain MTS. DOD (2 wks) 5 Umscheid 50 M Dacron, 4.6 yrs Fatigue, Epithelioid Resectio Local et al, 2007 Klinefelt infrarenal weight angiosarco n + CT recurrence (current; er aortic loss, abd. ma & lung case 2) aneurysm pain MTS (1 yr), DOD (2 yrs) with widespread MTS 6 Almeida et 60 F Dacron 9 yrs Dyspnoea Angiosarco Biopsy Initial al, 2011 graft, right , fatigue, ma & wideatrium weight palliativ spread loss e RCT MTS, died 3 wks later 7 Schmehl et 84 M Dacron, 8 yrs Fatigue, Epithelioid Resectio Died of al, 2012, infrarenal weight angiosarco n complicatio Brendle et aortic loss, abd. ma ns postop al, 2011 aneurysm pain with lymph (current; nodes & case 3) vertebral MTS ANED=alive with no evidence of disease; CT= chemotherapy; DOD= died of disease; DOOC= died of other cause; F=female; ICD= intracardiac device; M= male; mo=month; MTS= metastasis; postop= postoperative; PUO= pyrexia of unknown origin; RCT= radiochemotherapy; TEP= total endoprothesis; yrs= years.
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Table 4: Clinicopathologic features of reported angiosarcomas associated with orthopedic metal prostheses (n=11). N Authors/ye Age/ Foreign body Interval to Symptoms Histological Treatment Follow-up o ar Gende type/ angiosarco pattern r underlying ma disease/ cause 1 Dube & 84 M Metal plate 26 yrs Swelling & Epithelioid Local Local Fisher, (type 316 calf pain angiosarcom resection, then recurrence 1972 stainless a amputation (7 mo); steel), left DOD (11 tibia, mo) with farming inguinal accident node, lung & brain MTS 2 van der 72 F Bilateral hip 11 yrs Loosening Epithelioid Biopsy NA List et al, TEP for of TEP, angiosarcom 1988 congenital malaise, a hip dysplasia progressive pain 3 Ferrari et 48 M Intramedulla 31 yrs Pain & mass Angiosarco Hip ANED al, 2001 ry nail in distal ma disarticulation (3yrs) fixation, left thigh, fever & CT distal thigh fracture (accident) 4 McDonald 70 M Fixation with 52 yrs Gradual Angiosarco Wide resection Iliac & et al, 2002 plate, screw onset of a ma with + CT paraaortic & bone graft, mass epithelioid node MTS proximal areas (postop), thigh lung MTS fracture right (7 mo), (accident) DOD (12 mo) 5 McDonald 71 M Fixation with 41 yrs Pain & large Angiosarco Hemipelvecto DOOC 10 et al, 2002 plate, screw thigh mass ma my years later & bone graft, proximal thigh fracture (accident) 6 Albert et 85 F Total 10 yrs Knee pain Epithelioid Biopsy, then Synchronou al, 2009 arthroplasty, after a fall angiosarcom mid-thigh s lung and right knee a amputation regional node MTS, sudden death 1 mo later 7 Mallick et 84 F Bilateral hip 30 yrs Painful right Angiosarco Biopsy & Deterioratin al, 2009 TEP revised hip ma (not palliative g, inguinal 10 &11 yrs illustrated, radiotherapy node ago with type not involved, no ceramic & specified) extended titanium follow-up 8 Drexler et 72 M Tibial 25 yrs Degenerativ Epithelioid Above-knee Synchronou al, 2010 plateau left (removed e change, angiosarcom amputation, s MTS knee after 1 yr pain, a then irradiation proximal stainless due to bleeding femur & steel plate. irritation pelvis motor accident 9 Fabbri et 80 M Hip TEP 27 yrs, 6 yrs Progressive Epithelioid Open reduction DOD al, 2011 later loss of angiosarcom & fixation, shortly of uncemented function, a then wide spread Lord pain, amputation bilateral prosthesis fracture lung MTS for aseptic failure
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Current (case 4)
78 M
Hip TEP
17 yrs, revised after 14 yrs
11
Current (case 5)
55 M
Bilateral hip replacement
8 yrs
Loosening, recurrent uncontrollab le bleeding Loosening, bleeding
Epithelioid angiosarcom a
Biopsy and supportive
DOD shortly after diagnosis
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Epithelioid Resection + Lung MTS angiosarcom RCT ANED (17 a mo) ANED=alive with no evidence of disease; CT= chemotherapy; DOD= died of disease; DOOC= died of other cause; F=female; ICD= intracardiac device; M= male; mo=month; MTS= metastasis; postop= postoperative; PUO= pyrexia of unknown origin; RCT= radiochemotherapy; TEP= total endoprothesis; yrs= years.
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