Abstract
Introduction
Primary vascular leiomyosarcomas are incredibly rare and have a poor prognosis. The purpose of this study was to analyze the surgical outcomes of patients with primary inferior vena cava (IVC) leiomyosarcoma.
Methods
We performed a retrospective review of IVC leiomyosarcoma resections performed at a single tertiary care hospital from 2014 to 2023. A total of 13 cases were analyzed, including 10 women and 3 men. The presenting symptoms, tumor characteristics, operative management, postoperative complications, and survival rates were assessed for each patient.
Results
The median patient age was 59 years (quartile [Q]1, 52 years; Q3, 68 years). The median tumor size was 7.0 cm (Q1, 6 cm; Q3, 12 cm). The median mitotic rate was 6 per 10 high-power fields (Q1, 2.5; Q3, 15.5). All 13 patients underwent grossly negative tumor resection, with 9 (69%) having microscopically negative margins (R0). No patient had lymph node involvement. The IVCs were managed with ligation in four patients for tumors already occluding the IVC and bovine pericardial patch angioplasty in seven patients or primary repair in two patients for patent IVCs. Concomitant right nephrectomy was performed in seven patients. Left renal vein ligation was performed in three patients, but no left nephrectomies were performed. Significant postoperative complications included one patient with lower extremity compartment syndrome, two patients with severe leg swelling, and one patient with arm swelling. The 30-day mortality rate was zero. Using the Kaplan-Meier product limit method, disease-specific survival was estimated to be 93%.
Conclusions
Surgical resection is a feasible and effective oncologic treatment option for patients with IVC leiomyosarcoma. The IVC can be safely managed by ligation, primary repair, or patch angioplasty, depending on the prior patency of the IVC.
Keywords: IVC leiomyosarcoma, IVC ligation, IVC patch angioplasty, IVC primary repair, Perirenal tumors, Renal vein ligation, Retroperitoneal sarcoma
Article Highlights.
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Type of Research: A single-center, retrospective cohort study
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Key Findings: A total of 13 patients were analyzed in this study, all of whom were found to have primary inferior vena cava (IVC) leiomyosarcoma and underwent surgical resection. All 13 patients underwent grossly negative tumor resection, with 9 (69%) having microscopically negative margins (R0). The IVCs were managed with ligation in four patients for tumors already occluding the IVC and bovine pericardial patch angioplasty in seven patients or primary repair in two patients for patent IVCs. The 30-day mortality rate was zero. Using the Kaplan-Meier product limit method, disease-specific survival was estimated to be 93%.
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Take Home Message: Surgical resection is a feasible and effective oncologic treatment option for patients with IVC leiomyosarcoma with excellent long-term outcomes.
Vascular leiomyosarcomas are rare tumors, primarily arising from the inferior vena cava (IVC) and constituting <0.001% of adult malignancies.1 Primary leiomyosarcoma arising from the IVC is a rare, medial, smooth muscle cell-derived malignancy.2 It appears to affect middle-age women more than other populations.3 In comparison to other retroperitoneal sarcomas, primary IVC leiomyosarcomas are more aggressive.1 Primary IVC leiomyosarcomas are also challenging to manage due to their size and location.4
Surgical resection with clear margins is the mainstay of treatment of this rare malignancy.4, 5, 6, 7 Reported case series favor aggressive operative management, informed by the reasonable long-term survival of patients.4, 5, 6 Dzsinich et al8 were one of the first groups to suggest that excision with venous reconstruction could prolong survival for those with this rare malignancy. Hollenbeck et al4 reported the largest case series to date with 25 patients and showed that surgical resection is feasible and associated with improved survival. A series by Mingoli et al9 indicated that extended venous resection, including either retroperitoneal tissue or vena cava to achieve grossly negative margins, of IVC leiomyosarcoma does not affect the local recurrence rate or long-term outcomes. However, it remains that most individuals diagnosed with unresectable metastatic leiomyosarcoma are usually deemed incurable, with the predominant management being palliative with the aim of reducing the tumor burden, alleviating symptoms, and enhancing quality of life.10
Regarding neoadjuvant chemotherapy, doxorubicin-based chemotherapies are the preferred first-line options.11 They have been shown to improve the time to local and distant recurrence and overall recurrence-free survival for patients with localized, resectable soft tissue sarcoma.12 The efficacy of radiotherapy, although commonly used as neoadjuvant therapy, is not well-defined in the literature. Currently, no data-driven protocol is available for the treatment of primary IVC leiomyosarcoma. Therefore, the objective of this study is to analyze the IVC leiomyosarcoma resections performed at Duke University Hospital to delineate an institutional operative algorithm.
Methods
This study was reviewed and deemed exempt by the Duke University Medical Center institutional review board (identification no. Pro00113518). All patients who underwent surgical resection of a primary IVC leiomyosarcoma at our tertiary referral center between January 2014 and July 2023 were reviewed. Only patients with a pathologic diagnosis confirming primary leiomyosarcoma originating from the IVC were included. The demographics, clinical presentation, tumor characteristics, operative management, postoperative complications, and survival rates were obtained from the medical records. Perioperative mortality was defined as death occurring within 30 days after surgical resection. Disease-specific survival was assessed using the Kaplan-Meier estimate.
Results
Thirteen patients underwent surgical resection of primary IVC leiomyosarcoma between January 2014 and July 2023. The median age of the patients was 59 years (quartile [Q]1, 52 years; Q3, 68 years). The population was predominantly female (n = 10). The most common presenting symptoms included abdominal pain (n = 5) and back pain (n = 3). Less common symptoms were chest pain and leg swelling. One diagnosis was incidental during a lymphoma workup. The patient demographic information is summarized in Table I.
Table I.
Patient characteristics
| Characteristic | Median (Q1, Q3) or No. (%) |
|---|---|
| Age, years | 59 (52, 68) |
| Gender | |
| Male | 3 (23) |
| Female | 10 (77) |
| Presenting symptoms | |
| Abdominal pain | 5 (38) |
| Back pain | 3 (23) |
| Leg swelling | 2 (15) |
| Chest pain | 2 (15) |
| Incidental | 1 (8) |
| Comorbidities | |
| Hypertension | 7 (54) |
| Obesity (BMI >30 kg/m2) | 10 (77) |
| Type 2 diabetes mellitus | 2 (15) |
| Coronary artery disease | 1 (8) |
| Complications | |
| LE compartment syndrome | 1 (8) |
| Leg swelling | 2 (15) |
| Arm swelling | 1 (8) |
| Follow-up interval | 3.25 (0.94, 5.25) |
BMI, Body mass index; LE, lower extremity; Q1, quartile 1; Q3, quartile 3.
The median tumor size was 7.0 cm (Q1, 6 cm; Q3, 12 cm). The median mitotic rate was 6 per 10 high power fields (Q1, 2.5; Q3, 15.5). Nine patients underwent complete resection of the tumor with negative margins, both microscopically and grossly (R0 resection). Four patients had microscopically positive IVC margins after surgical resection (R1). Of the 13 tumors, 15% were grade 1, 46% were grade 2, 8% were grade 3, and 31% were ungraded because the patients had already received neoadjuvant chemotherapy or radiotherapy. The primary tumor (T) stage was T1 for 23%, T2 or T2b for 46%, and T3 or T4 for 31%. The regional lymph node (N) stage was NX for 38%, indicating that cancer in nearby lymph nodes could not be measured, and N0 for 62%, indicating no cancer in the nearby lymph nodes. Finally, for distant metastasis (M), of those reported, 30% were MX, indicating that metastasis could not be measured. Otherwise, metastasis was not reported in the pathology findings, although cases of leiomyosarcoma recurrence are discussed three paragraphs onward. The pathological characteristics are summarized in Table II. The predominant preoperative imaging modality for all 13 patients was computed tomography (CT). All the tumors were staged with cross-sectional imaging of the chest, abdomen, and pelvis. Preoperatively, every case was discussed by the multidisciplinary tumor board, with frequent input from surgical oncology, urologic oncology, and vascular surgery. The neoadjuvant chemoradiotherapy regimens varied and included total neoadjuvant chemotherapy (n = 4), total adjuvant chemotherapy (n = 1), total neoadjuvant radiotherapy (n = 6), and total adjuvant radiotherapy (n = 3).
Table II.
Pathologic characteristics
| Characteristic | Median (Q1, Q3) or No. (%) |
|---|---|
| Tumor size, cm | 7.0 (6, 12) |
| Mitotic rate, mm2 | 6.0 (2.5, 15.5) |
| Resection margins | |
| R0 | 9 (70) |
| R1 | 4 (30) |
| Grade | |
| 1 | 2 (15) |
| 2 | 6 (46) |
| 3 | 1 (8) |
| Ungraded | 4 (31) |
| Stage | |
| T | |
| T1 | 3 (23) |
| T2, T2b | 6 (46) |
| T3, T4 | 4 (31) |
| N | |
| NX | 5 (38) |
| N0 | 8 (62) |
| M | |
| MX | 4 (30) |
Q1, Quartile 1; Q3, quartile 3.
All 13 patients underwent complete gross resection of the tumor. Nine patients underwent R0 resection and four underwent R1 resection. None of these four patients with microscopically positive IVC margins had local or regional recurrence. Management of the IVC included resection with primary repair with Prolene suture (n = 2) or bovine pericardial patch angioplasty (n = 7), infrarenal ligation (n = 3), or suprarenal ligation (n = 1). One patient required cardiopulmonary bypass during resection because the tumor thrombus extended to the cavoatrial junction. Due to involvement of the right renal vein, seven patients underwent right nephrectomy, none of whom experienced a significant decline in renal function (defined as a 50% reduction in creatinine clearance). The operative management is summarized in Table III.
Table III.
Operative management and perioperative outcomes
| Variable | No. (%) |
|---|---|
| IVC | |
| Suprarenal IVC ligation | 1 (8) |
| Infrarenal IVC ligation | 3 (23) |
| Patch angioplasty (bovine pericardial patch) | 7 (54) |
| Primary repair | 2 (15) |
| Left renal vein ligation | |
| Yes | 3 (23) |
| No | 10 (77) |
| Nephrectomy (right side) | |
| Yes | 7 (54) |
| No | 6 (46) |
| Estimated blood loss, mL | |
| <300 | 6 (46) |
| >300 | 6 (46) |
| Length of stay, days | |
| <3 | 8 (62) |
| >3 | 5 (38) |
IVC, Inferior vena cava.
The median follow-up was 3.25 years (Q1, 0.94 year; Q3, 5.25 years). One patient who underwent infrarenal IVC ligation experienced bilateral lower extremity edema secondary to bilateral deep vein thromboses (DVTs). Another patient who underwent infrarenal IVC ligation experienced bilateral lower extremity compartment syndrome and underwent bilateral fasciotomies. The patient who underwent suprarenal IVC ligation also underwent right nephrectomy and ligation of the left renal vein with the remaining venous drainage via the adrenal, gonadal, and lumbar veins. This patient had 2+ bilateral lower extremity pitting edema, which improved quickly with furosemide (Lasix; Pfizer) diuresis and compression stockings, and continued to have adequate left renal function, without a need for hemodialysis after resection. All three of these patients and the fourth patient who underwent IVC ligation were discharged with therapeutic anticoagulation. Aspirin was given to all patients who underwent primary repair and patch angioplasty. Another patient who had undergone IVC patch angioplasty experienced right upper extremity swelling, secondary to a DVT extending from the patient's right brachiocephalic vein to internal jugular vein, after which therapeutic enoxaparin was started. To date, no patient has developed local recurrence; however, four patients developed metastatic recurrence found on subsequent surveillance imaging.
Of these four patients with metastatic recurrence, one each developed pulmonary and gastric metastasis at 4 years after the initial surgery, pulmonary and hepatic metastasis 13 months after surgical resection, pulmonary metastasis at 10 months postoperatively, and hepatic metastasis at 2 years postoperatively. All four patients with recurrence had had microscopically negative margins. Using the Kaplan-Meier product limit, the disease-specific survival was estimated to be 93%.13
Discussion
Although literature on cases involving leiomyosarcoma of the IVC is scarce, reported series have demonstrated that surgical resection of IVC leiomyosarcomas is associated with improved survival.4, 5, 6 Our series substantiates this with complete oncologic resection and no perioperative mortality. Additionally, we delineate an institution algorithm by which to manage these complex cases.
After tumor resection, the IVC can be managed using a variety of methods. These include primary repair, patch angioplasty, interposition tube grafting, and ligation. At our institution, reconstruction is the preferred method if the IVC is patent on preoperative imaging. CT venography is used for preoperative planning. In cases of IVC occlusion with well-developed collateral vessels, ligation is preferred, because the patients are already tolerating IVC occlusion. This also avoids the morbidity associated with placement of the tube graft that would be required for in-line reconstruction. Whenever primary repair would lead to >50% IVC narrowing, patch angioplasty is preferred and was the most common type of repair in this cohort. An interposition graft is used when there is circumferential or near circumferential involvement of the IVC. Preoperative and postoperative CT imaging for a patient managed with patch angioplasty is shown in Fig 1. None of these patients in our cohort experienced significant postoperative complications. Other studies have demonstrated that primary repair or patch angioplasty is typically well tolerated with minimal postoperative lower extremity edema.4 The next most common management strategy in our series was ligation of the IVC (four patients). One patient developed lower extremity compartment syndrome and one developed bilateral lower extremity DVTs. It is possible that these complications could have been avoided with in-line reconstruction with an interposition graft. Case reports of suprarenal IVC involvement have used expanded polytetrafluoroethylene tubes.14 They have demonstrated some effectiveness as a viable management technique for the IVC, although a thick pseudo-intima often developed in these grafts, reducing the cross-sectional area of the original lumen.15,16 Also, some patients subsequently develop thrombosis and persistent severe lower extremity edema.4 Another technique, although rarely reported in the literature, is autologous reconstruction of the IVC, with use of the superficial femoral vein and fascio-peritoneal patch repair reported.17,18 The one patient in our series who underwent suprarenal IVC ligation had adequate residual left renal drainage via the adrenal, gonadal, and lumbar veins (Fig 2) and did not have significant renal failure or leg swelling.
Fig 1.
Preoperative and postoperative computed tomography (CT) scan of a patient with inferior vena cava (IVC) leiomyosarcoma managed with patch angioplasty.
Fig 2.
Postoperative computed tomography (CT) scan of a patient with inferior vena cava (IVC) leiomyosarcoma managed with right nephrectomy, suprarenal IVC ligation, and left renal venous drainage via the adrenal, gonadal, and lumbar veins.
Regardless of the reconstruction technique, survival remains the critical consideration. A pooled analysis performed by Wachtel et al19 of 377 patients diagnosed with leiomyosarcoma of the IVC identified factors that influence overall survival, with the presence of clear surgical margins emerging as one of the most notable determinants. Given negative margins and excellent postoperative outcomes of the patients in our series, our group also recommends operative management for those affected by leiomyosarcomas of the IVC. The literature suggests that the use of intraoperative frozen section analysis is of limited utility and unlikely to change the course of resection. However, it can be used to assess the vessel margins in vascular leiomyosarcoma.20 At our institution, we do not routinely use analysis of frozen margins in the surgical treatment of IVC leiomyosarcoma but rather to determine the extent of resection needed for grossly negative margins based on close inspection of the preoperative imaging studies.
All the patients reported in our case series underwent CT imaging of the chest, abdomen, and pelvis before surgery. CT was repeated at 6-month intervals for surveillance for 5 years. At our institution, we do not typically use positron emission tomography for preoperative staging, although studies have shown positron emission tomography avidity corresponds to both higher tumor grades and maximum tumor size.21
Compared with other reported case series, our outcomes are more favorable. There were no perioperative deaths and limited morbidity despite challenging surgical resections. We attribute these results to careful preoperative planning within our multidisciplinary team. Our 3-year survival rate of 100% is the highest reported, as is our percentage of R0 resections.4, 5, 6 Our IVC surgical management technique was most frequently patch angioplasty, which is distinct from other series with a leading management technique of ligation and replacement with a polytetrafluoroethylene prosthesis.4,5 The IVC of a patient managed with patch angioplasty is shown in Fig 3. Advancements in vascular surgery operative techniques and conduit options could perhaps result in more IVC management options.
Fig 3.
Inferior vena cava (IVC) of a patient with IVC leiomyosarcoma after patch angioplasty.
Although we favor complete surgical resection for all patients without metastatic disease, there is further potential to consider additional therapies as an additive measure. Many trials aimed at assessing adjuvant chemotherapy for soft tissue sarcomas encompass various histologic subtypes, which complicates subtype-specific recommendations.22 Likewise, the efficacy of radiotherapy for retroperitoneal sarcoma remains elusive. The STRASS (surgery with or without radiation therapy in untreated nonmetastatic retroperitoneal sarcoma) trial, conducted by the European Organization for Research and Treatment of Cancer, assessed how preoperative radiotherapy combined with surgery compares with surgery alone for patients with primary retroperitoneal sarcoma and found no significant differences in outcomes.23 Historically, neoadjuvant radiotherapy was given frequently at our institution; however, following the STRASS trial, upfront resection is now our standard practice. In the current series, patients underwent a variety of case-specific neoadjuvant and adjuvant chemoradiotherapy regimens. Going forward, some of these patients might be eligible for STRASS II (randomized phase III study of neoadjuvant chemotherapy followed by surgery versus surgery alone for patients with high risk retroperitoneal sarcoma), a trial aimed at investigating the effect of preoperative chemotherapy for patients with high-risk retroperitoneal sarcoma, and, thus, will receive preoperative chemotherapy. As adjuvant and neoadjuvant therapies are discovered, combining novel oncologic technologies in tandem with intentional surgical management could potentially improve survival.
Study limitations
The findings of our case series must be considered in the context of several key limitations. First, the present study was descriptive and retrospective. Additionally, the number of patients reported in the case series was small, limiting the conclusions that can be drawn. There were no control groups for comparison in terms of outcomes. A promising future area of study would be a multicenter collaboration to gain additional data to inform the best oncologic care for these patients.
Conclusions
Surgical resection with grossly negative margins of IVC leiomyosarcoma can be done safely and is the only potentially curative treatment of this rare disease. The algorithm presented in this report is as follows: if preoperative imaging indicates a patent IVC, excision and reconstruction is the preferred method. For cases with IVC occlusion, excision and ligation is preferred. This algorithm leads to successful oncologic resection with excellent survival rates. Multi-institutional, prospective studies are needed to determine the oncologic efficacy and longevity of these approaches.
Author contributions
Conception and design: HS, SC, DB, YK, KS, ZW
Analysis and interpretation: HS, SC, DB, ZW
Data collection: HS, DB, ZW
Writing the article: HS, SC, ZW
Critical revision of the article: HS, SC, DB, YK, KS, ZW
Final approval of the article: HS, SC, DB, YK, KS, ZW
Statistical analysis: Not applicable
Obtained funding: Not applicable
Overall responsibility: ZW
Disclosures
None.
From the Eastern Vascular Society
Footnotes
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest.
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