High-grade angiosarcoma arising beside a pelvic orthopedic implant: a case report

Abstract

Introduction:

Angiosarcomas are very rare, malignant tumors of the endothelial lining of blood vessels and most present cutaneously, while only 10% present as deep soft tissue angiosarcomas. Literature is sparse regarding secondary deep soft tissue angiosarcoma, especially in cases that have formed surrounding a foreign body such as orthopedic implants.

Case:

A 59-year-old Caucasian male presented with a 1-year history of occasional headaches and non-intentional weight loss. One month prior to consult, he began to experience progressive pelvic pain on weight-bearing, up to 10/10 in severity, with associated swelling of the left leg. Further diagnostics revealed a hypervascular tumor on the anterior left hemipelvis, directly over his initial pelvic injury and orthopedic implants placed 33 years ago.

Clinical Discussion:

Biopsy revealed a high-grade angiosarcoma surrounding a stainless-steel 316L reconstruction plate adjacent to a titanium alloy (Ti-6Al-4 V) total hip arthroplasty. NextGen Genome sequence analysis done reveals tier II mutations (potential clinical significance) in the HOXB13 p.G84E and RPS6KB1 genes.

Conclusion:

Few published cases exist regarding secondary deep soft tissue angiosarcoma, and its peculiar presentation in our case arising at the juncture between two orthopedic implants of different compositions suggests a possible effect of galvanic corrosion, and warrants further study.

Introduction

Angiosarcomas are rare, aggressive, malignant tumors originating from the endothelial lining of blood vessels and have a high propensity for lymph node, liver, and lung metastasis. It most commonly presents as insidious long-standing pain, or multiple cutaneous bluish lesions in the elderly, and can present anywhere with a vascular lining, and at any age. Deep soft tissue angiosarcoma in bone, muscle, adipose tissue comprises only around 10% of angiosarcoma cases. Variable degrees of anaplasia can be seen upon histologic examination, and it strongly tests positive for endothelial markers CD31 and CD34, von Willebrand factor, and Vascular Endothelial Growth Factor on immunohistochemistry^[1^]. Management is primarily surgical wide resection to achieve local control followed by adjuvant radiotherapy and carries a poor prognosis due to its tendency for local recurrence and distant metastasis.

HIGHLIGHTS

• A 59-year-old Caucasian male presented with a 1-month history of progressive pelvic pain on weight-bearing, up to 10/10 in severity, with associated swelling of the left leg.

• Further diagnostics revealed a hypervascular tumor on the anterior left hemipelvis, directly over his initial pelvic injury and orthopedic implants placed 33 years ago.

• Biopsy revealed a high-grade angiosarcoma surrounding a stainless-steel 316L reconstruction plate adjacent to a titanium alloy (Ti-6Al-4V) total hip arthroplasty.

• NextGen Genome sequence analysis of the specimen done reveals Tier II mutations (potential clinical significance) in the HOXB13 p.G84E and RPS6KB1 genes.

Identified risk factors for cutaneous angiosarcoma include chronic lymphedema (Stewart-Treves Syndrome), radiation, exposure to chemicals such as arsenic and vinyl chloride, genetic familial syndromes, and, much less commonly reported in the literature due to scarcity of cases, a reaction related to foreign bodies such as orthopedic implants.

Case

A 59-year-old Caucasian male presented with a 1-year history of occasional headaches, non-intentional weight loss, and night sweats. One month prior to consult, he began to experience progressive pelvic pain on weight-bearing, up to 10/10 in intensity, with associated swelling of the leg. PET/CT scan revealed a hypervascular tumor on the anterior left hemipelvis, directly over his initial pelvic injury and implants, placed 33 years ago.

His past medical history includes ORIF with reconstruction plate and screws for a left hemipelvis fracture in 1991, and a total hip arthroplasty (THA) of the left hip for post-traumatic arthritis 6 months later (Fig. 1).

Figure 1.

Pre-amputation anteroposterior and lateral pelvic radiographs showing a pelvic reconstruction plate with screws made of stainless steel (316L), and a total hip arthroplasty implant of porous plasma-flame stem shaft (Zimmer), also made of titanium alloy (Ti-6Al-4V), Stelkast (SKT) acetabular shell, also made of titanium, and polyethylene inlay.

He admits to exposure to asbestos at work, but recalls no radiation exposure. His father underwent limb amputations from complications of diabetes, and his sister also underwent a limb amputation from peripheral arterial occlusion disease. He also has a known allergy to Phenprocoumon, a vitamin K antagonist.

A biopsy done in Graz revealed angiosarcoma, and chest and abdominal CT scan showed absence of metastatic spread. Since his tumor was localized to the pelvis (Fig. 2), no pre-operative chemotherapy nor radiation therapy was done.

Figure 2.

MRI showing the vascular soft tissue mass 28 × 20 × 20 cm (yellow arrows) over the site of initial pelvic injury and plate fixation.

The patient underwent a classical external hemipelvectomy in floppy lateral position, and a wide margin of resection was achieved (Fig. 3a,b). The entire surgery lasted for 1 hour and 30 minutes. The specimen was identified as an extensive hemorrhagic intrapelvic tumor along the iliac crest measuring 28 × 20 × 20 cm (Fig. 4a,b). Sections reveal that extensive tumor formations are detectable in the area surrounding the metal plate, revealing partly epithelioid and partly spindle-shaped tumor cells with irregular, pleiomorphic nuclei. A striking feature is diffuse erythrocyte extravasation between tumor cells, and hemosiderin-laden macrophages are also frequently observed. Focally accentuated mitoses are evident in over 20 cells per 10 HPF cells (Fig. 5a,b). A para-iliac lymph node size 2 × 1 × 1 cm was also resected and sent to histopathology and came out sarcoma-free. Histopathologic evaluation of the specimen sent confirmed poorly differentiated high-grade angiosarcoma. Pathology report indicated that the area where the tumor grew most destructively seems to have originated around the plate and screws on the side closest to the THA and that the surrounding tissues beyond the plate and screws, including the area of the THA itself, were sarcoma-free. The soft tissue and bone margins of the amputated limb were sarcoma-free.

Figure 3.

(A) Postoperative radiographs. (B) Clinical specimen showing the entire left hemipelvis and lower extremity have been amputated.

Figure 4.

(A) Gross pictures reveal the extent of the angiosarcoma (dark red, outlined by yellow arrows and its position relative to the radiograph), which appears to arise over and around the stainless-steel pelvic plate, particularly on the side closest to the titanium THA, and none on the side away from the THA. (B) View perpendicular to iliac wing showing the angiosarcoma is concentrated on the iliac side around the plate (yellow arrows), and there appears to be no tumor around the titanium THA implant (green arrow).

Figure 5.

Low-power field (A) and high-power field (B) microscopy showing wide necrotic, high-grade spindle cell partly epithelioid angiosarcoma in the pelvis.

Postoperatively, the patient underwent a debridement surgery and flap revision 1-week post-op and was discharged once resolved. He received no adjuvant chemotherapy nor radiotherapy because of negative resection margins.

NextGen Genome Sequencing Analysis was performed using the Illumina TruSight Oncology 500 (TSO500). Our patient has no Microsatellite instability and with low mutational burden. Tier II mutations based on the AMP classification (of potential clinical significance) were present in the HOXB13 p.G84E and RPS6KB1 genes. Specimen sent was formalin-fixed paraffin embedded tissue with 80% tumor purity estimate and a 5% variant allele frequency.

Discussion

There is a paucity of literature with regard to implants being a risk factor in secondary deep soft tissue angiosarcoma, mostly because of the rarity of angiosarcomas as a whole, as well as the difficulty to prove direct causality given the long period of time in between the traumatic incident and fixation, and the time of diagnosis.

Samargandi in 2024 presented a narrative review of cases wherein development of angiosarcoma was associated with foreign bodies such as vascular grafts, orthopedic metal plates and prosthesis, as well as shell splinter and bullets, surgical sponge/s, bone wax, and cardiac defibrillator. This review included 16 cases of metallic and other foreign materials from 1956 until 2012 from different authors and hospitals, 13 of whom (81.2%) were male, with an average age of 68.7 years (range 42–86), and an average interval to angiosarcoma development of 36.9 years (range 16–63), and these all align in the presentation of angiosarcoma in our patient. Ten of the 16 cases (62.5%%) in this narrative review had documented metastasis, and also 10 of 16 cases had recurrence among those who survived past 1 year^[2^]. This review also included 15 cases of orthopedic prosthesis associated with development of angiosarcoma from 1986 until 2021, 50% of which were male, with an average age of 74 years (range 55–85), and an average interval to angiosarcoma development of 14.5 years (range 1–31).

A proposed pathogenesis theory is that the presence of the foreign body could activate the chronic inflammatory pathway, leading to infiltration of neutrophils, monocytes, macrophages, and matrix proteins leading to fibrosis, evolving into a mature fibrous capsule surrounding the implant^[2^]; however, this is not currently a well-documented pathway for secondary angiosarcoma.

Our case also has the peculiarity of having two different implants applied merely months apart and are of different compositions, namely stainless steel (316L) and titanium alloy (Ti-6Al-4 V), with both being millimeters apart, but have no direct contact with each other.

One mechanism that we authors have not completely ruled out is galvanic corrosion between these two materials, and although there is no direct contact between the two implants, the bodily fluids such as hematoma and even bone could have served as a conductive environment linking the two implants. Since titanium is more noble and has a higher electrochemical potential, this could lead to corrosion of the less noble stainless steel, leading to its localized degradation and subsequent release of metal ions such as chromium, nickel, and iron into the surrounding tissue. These ions can theoretically cause adverse biologic reactions, including allergic responses and inflammation. This is of course, merely a hypothesis, as we have no direct way of proving this phenomenon; however, it is worth noting that the tumor was concentrated in the area of the stainless-steel plate that was closest to the titanium THA and that there was absence of the tumor on the other end of the plate on the side away from the titanium THA (Fig. 3).

Regarding trauma alone as a possible cause of secondary angiosarcoma, Banza et al reported a case of a 72-year-old African male presented with pain and a gross 5 × 7 cm swelling of the 1 year after sustaining a blunt injury from a baton strike. Radiographs appeared normal, but ultrasound studies showed heterogenous hemorrhagic tissue and necrosis. Puncture biopsy of the hematoma revealed moderately differentiated angiosarcoma and was managed with radiotherapy in another institution. Unfortunately, no genome sequencing was done in this case^[3^].

A comparative single-center analysis by Hillenbrand et al involving 18 cases of primary angiosarcoma and 10 cases of secondary angiosarcoma shows that 61.1% of primary angiosarcoma metastasized, while only 40% of secondary angiosarcoma metastasized. This supports our claim that our case is secondary in nature, as metastasis was not present in our patient. Local recurrence, however, was higher in secondary angiosarcoma at 50% and just 27.8% in primary^[4^]. As of writing, there has been no documented metastasis nor recurrence in our patient.

Tumor-only sequencing using the TSO 500 panel identified tier II variants in HOXB13 and RPS6KB1, tier III variants in ASXL2, FAT1, JAK3, P1K3R1, and TCF3, and a low tumor mutational burden.

According to a review article by Cao et al, angiogenesis genes have been confirmed to play a role in radiation-induced secondary angiosarcoma, particularly proto-oncogene MYC amplification located at chromosome 8q24 and was related to UV and sunlight exposure. FLT4 gene in chromosome 5q35 encodes for VEGFR3, and its gene amplification is present in 25% of secondary angiosarcomas. Less commonly, CIC gene, a transcriptional repressor on chromosome 19q13.1, was reported in 9% of patients with primary cutaneous angiosarcoma. Unfortunately, MYC and CIC were not available in the NextGen panel that was used, although FLT4 was included, but did not turn out to be present in our patient.

This appears to be the first documented case wherein a deep soft tissue angiosarcoma formed over time at a location where two implants were of varying compositions and that the postoperative specimen was documented on NextGen genome sequencing to have mutations in the HOXB13 p.G84E and RPS6KB1 genes.

Although we cannot make any direct conclusions as to the origins of the tumor, whether it may be from an effect of galvanic corrosion, from proximity to an implant, or by sheer coincidence in location, this paper adds to the growing body of information regarding deep soft tissue angiosarcomas, and the authors recommend that whenever possible, genome sequencing should also be done in similar cases, so we can make more solid associations in the future when more similar literature has been published.

The authors declare no conflicts of interest. All funding has come from the primary author himself. Ethical approval has been covered by the institution’s ethics committee. This case is currently not in consideration in any other journal. The patient has given his verbal and written consent in the writing of this paper. This work has been reported in line with the SCARE criteria^[5^].

Conclusion

We conclude that this case adds to the growing body of literature regarding a very rare phenomenon of development of angiosarcoma surrounding orthopedic implants, particularly in our case that involves implants of differing compositions in close proximity with each other, and further studies are warranted.

Although the authors cannot make solid recommendations in management without established proof that the tumor was indeed caused by galvanic corrosion, we deem it wise to choose orthopedic implants of similar composition over different ones, especially when used in close proximity with each other.

Ethical approval

Ethical approval has been given under Reference number: EK-Nr: 1364/2018 and covered by the corresponding body associated with the Orthopedics Tumor Department of the Allgemeines Krankenhaus Wien (Vienna General Hospital).

Consent

The patient himself is fully aware of the study and has given his full consent in the writing of this paper for publication. Written informed consent was obtained from the patient for publication.

Included in the files sent is his written consent in his participation in the research paper as well as willingness to share his medical information including pictures in the writing of the paper.

Sources of funding

I have no sources of funding other than my own personal finances.

Author contributions

P.M.: Primary/Corresponding author, Study design. R.W.: Contributed in writing the paper. G.H.: Surgeon, Data collection and analysis. P.F.: Surgeon; Data collection and analysis. A.S.: Pathologist; Data collection and analysis. N.C.: Data collection and analysis.

Conflicts of interest disclosure

None declared.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

All authors/co-authors are guarantors who have access to the data and take responsibility for the work.

Sources of support

Nil.

Provenance and peer review

Not commissioned; externally peer-reviewed.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon request.