ELSEVIER
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RCR RADIOLOGY CASE REPORTS
Case Report
Multimodality local ablative therapy of 23 lung metastases with surgical resection and percutaneous cryoablation in a patient with Li-Fraumeni Syndrome: A case report
Jonathan A. Saenger, MDa,d.f, Ismail Tahir, MBBChBAOª, Manuela Födinger, MDd,e, Gregory M. Cote, MDPhDb, Ashok Muniappan, MDC, Florian J. Fintelmann, MDª,*
a Department of Radiology, Division of Thoracic Imaging and Intervention, Massachusetts General Hospital, Boston, MA, USA
b Department of Oncology, Massachusetts General Hospital, Boston, MA, USA
“Department of Surgery, Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA, USA
d Department of Radiology, Medical School, Sigmund Freud University, Vienna, Austria e Institute of Laboratory Diagnostics, Klinik Favoriten, Vienna, Austria
f Diagnostic and interventional Radiology, University Hospital Zurich, University Zurich, Switzerland
ARTICLE INFO
ABSTRACT
Article history: Received 4 June 2023 Accepted 20 July 2023
Keywords: Li-Fraumeni syndrome Cryoablation Thermal ablation Lung metastasis Leiomyosarcoma
Patients with Li-Fraumeni syndrome (LFS) are prone to develop a variety of malignancies due to insufficient activity of the encoded tumor suppressor protein P53, including adreno- cortical carcinoma, breast cancer, lung cancer, pancreatic cancer, and sarcoma. In the set- ting of LFS, local treatment options for lung metastases are limited to surgery and thermal ablation since radiotherapy and some systemic therapies predispose patients to additional future malignancies. We present the case of a 45-year-old woman with LFS with leiomyosar- coma metastases to both lungs who underwent bilateral wedge resections to treat a total of eight lung metastases followed by six percutaneous cryoablation sessions to treat 15 ad- ditional lung metastases over a period of 24 months. Our case demonstrates the option of multimodal local ablative therapies for lung metastases in patients with LFS, including per- cutaneous cryoablation.
@ 2023 The Authors. Published by Elsevier Inc. on behalf of University of Washington. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
# Acknowledgments: None.
Competing Interests: Dr. Fintelmann received salary support from the Wood Foundation for related research. The other authors have no relevant conflicts of interest to declare.
* Corresponding author. E-mail address: fintelmann@mgh.harvard.edu (F.J. Fintelmann).
https://doi.org/10.1016/j.radcr.2023.07.047
Introduction
Patients with Li-Fraumeni syndrome (LFS) show insufficient activity of the TP53-encoded tumor suppressor protein P53 [1- 3]. In healthy cells, TP53 regulates progression through the cell cycle by arresting cell growth, signaling DNA damage re- pair proteins, or initiating apoptosis [4]. Patients with LFS are prone to developing malignancies, including primary and metastatic lung cancer, adrenocortical carcinoma, breast can- cer, osteosarcoma, pancreatic cancer, and soft tissue sarcoma [1-3,5]. Traditional treatments for lung metastases include surgical resection, thermal ablation, radiation therapy, and systemic therapy, and surgical resection and thermal ablation for oligometastatic or oligoprogressive disease. However, ra- diation and some systemic therapies are not well suited in the setting of LFS [6]. Radiation therapy in patients with LFS has been linked to the development of secondary malignan- cies due to the inability of cells to recognize and repair double- strand DNA breaks generated by ionizing radiation [4,7-9]. The incidence of secondary tumors in a previous radiation field in patients with LFS is reported to be between 30% [10] and 37.5% [11].
Systemic therapy with genotoxic drugs can also cause iatrogenic cell damage and lead to secondary cancers [7,8,10,12,13]. While surgical resection of lung tumors is not contraindicated in the setting of LFS, the loss of lung func- tion may limit the number of tumors, number of times, and amount of lung that can be resected [14]. Also, even a cen- trally located small tumor may require a lobectomy or even pneumectomy [6].
Percutaneous cryoablation is a safe and effective thermal ablation technique that has been prospectively evaluated for treating lung metastases [15,16]. Cryoablation relies on image guidance to position one or more applicators through the skin into or adjacent to the targeted tumor(s). Necrosis is achieved with a series of freezing and thawing [6,17]. Moreover, cryoab- lation does not lead to a measurable decrease in functional performance and quality of life [16].
While thermal ablation has been recommended for pa- tients with LFS, cryoablation of lung metastases has not been described in this setting [3,18]. Here we present the case of a 45-year-old woman with LFS and sarcoma metastases to both lungs who underwent surgical resection and multiple percu- taneous cryoablation sessions.
Case report
A 45-year-old female with Brazilian heritage presented to the Emergency Department of our hospital after ten days of wors- ening right upper quadrant abdominal pain and mild nausea (Fig. 1). She described her pain as constant, exacerbated by moving her right arm, and worsening over two weeks. Com- puted tomography (CT) showed a 23 x 16 mm lobulated mass arising from the suprarenal inferior vena cava (IVC) associ- ated with a non-occlusive venous thrombus. The patient re- ported that her sister and her nephew had tested positive for a TP53 mutation (c.1010G>A; p. Arg337His) and that her
nephew had been previously diagnosed with choroid plexus carcinoma. Genetic testing revealed the same TP53 mutation in the patient in the R337H variant known to be a disease- causing founder variant in 0.2-0.3% in Southern Brazil. Sub- sequently, a high-grade leiomyosarcoma was resected from the IVC, and surveillance with whole-body MRI was recom- mended.
Two years later, a mammogram revealed calcifications in the right upper outer breast, and a needle biopsy showed atypical ductal hyperplasia. The patient opted for bilateral prophylactic mastectomy, and the final pathology was con- sistent with grade 3 ductal carcinoma in situ. Two months after the bilateral mastectomy and two years after resec- tion of the primary sarcoma, chest CT revealed eight enlarg- ing bilateral solid lung nodules measuring up to 16 mm in the posterior basal segment of the left lower lobe. The pa- tient was evaluated by thoracic surgery and underwent bilat- eral thoracoscopy-assisted wedge resections removing eight metachronous leiomyosarcoma metastases within the next eight months (Table 1). A left paraspinal mass and a scalp mass corresponding to additional leiomyosarcoma metas- tases were also surgically removed four months after the third wedge resection. The patient enrolled in chemotherapy-based clinical trials and also tried immunotherapy and monother- apy with off-label Lurbinectedin since previous phase II stud- ies had suggested potential benefits of Lurbinectedin for pa- tients with leiomyosarcoma (Fig. 1) [19].
While on systemic therapy and eight months after the third wedge resection, CT demonstrated six bilateral new and en- larging solid lung nodules measuring up to 9 mm, consis- tent with metachronous sarcoma lung metastases. The pa- tient was referred to a multidisciplinary clinic to discuss the option of thermal ablation. After image review and discussion with input from thoracic surgery, radiation oncology, and in- terventional radiology, percutaneous cryoablation was deter- mined to be the most appropriate treatment option for this young patient with excellent performance status to prolong survival while preserving quality of life.
The patient stopped systemic therapy one week before the cryoablation procedure and resumed five days afterward. For this and subsequent cryoablation procedures targeting lung metastases, the patient was positioned on the table of a CT scanner, and either moderate sedation or general anesthesia was administered, as previously described [20]. For the first of six cryoablation sessions, CT images obtained immediately before the ablation demonstrated an increase in the size of a 13 mm solid left pleural nodule (Fig. 2), which was treated with a 17.5 cm IcePearl 2.1 CX cryoprobe (Boston Scientific) using a triple freeze protocol (3 minute freeze, 3 minute pas- sive thaw, 7 minute freeze, 3 minute passive thaw, 10 minute freeze) followed by 2 minute active thaw. The patient under- went five additional cryoablation sessions two, three, four, eight, and ten months after the first ablation to treat 14 addi- tional lung metastases (Fig. 3). The patient experienced tran- sient intercostal neuritis after the fourth session because the ice ball encompassed the intercostal nerve during the treat- ment of a subpleural tumor (Common Terminology Crite- ria for Adverse Events [CTCAE] Version 5.0 Grade 1). No ad- ditional adverse events occurred following the cryoablation procedures.
IVC mass surgically removed
Whole Body MRI negative
Atypical Ductal Hyperplasia
Bilateral Mastectomy
Excision paraspinal and scalp mass
Resection of mediastinal mass and VATS L
VATS L
VATS R
VATS R
CAL
CAR
CAL
Initial ED Visit
Li-Fraumeni Syndrome Genetic Diagnosis
New Lung Nodules
CAL
CAR
CAR
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
50
52
54
56
58
60
62
64
Time in Months
CA
Lurbinectidin
Cryoablation
Irinotecan
VATS
Video-assisted
Clinical Trial
thoracoscopic surgery
Pembrolizumab
| Lesion number | Treatment session | Tumor size at time of treatment (mm) | Treatment intent | Tumor location (peripheral, intermediate, central) | Tumor location (lobe) |
|---|---|---|---|---|---|
| 1 | Wedge VATS Resection 1 | 15 | Eradication | Peripheral | LLL |
| 2 | 5 | Eradication | Peripheral | LUL | |
| 3 | Wedge VATS Resection 2 | 2 | Eradication | Peripheral | RUL |
| 4 | 7 | Eradication | Intermediate | RML | |
| 5 | Wedge VATS Resection 3 | 18 | Eradication | Peripheral | LUL |
| 6 | 16 | Eradication | Peripheral | LUL | |
| 7 | 4 | Eradication | Peripheral | LUL | |
| 8 | 9 | Eradication | Peripheral | LUL | |
| 9 | Cryoablation 1 | 13 | Eradication | Peripheral | LUL |
| 10 | Cryoablation 2 | 6 | Eradication | Intermediate | LLL |
| 11 | 8 | Eradication | Peripheral | LLL | |
| 12 | Cryoablation 3 | 7 | Eradication | Peripheral | RLL |
| 13 | Cryoablation 4 | 3 | Eradication | Intermediate | RLL |
| 14 | 7 | Eradication | Peripheral | RLL | |
| 15 | 8 | Eradication | Peripheral | RLL | |
| 16 | Cryoablation 5 | 4 | Eradication | Peripheral | LLL |
| 17 | 5 | Eradication | Peripheral | LLL | |
| 18 | 4 | Eradication | Peripheral | LLL | |
| 19 | 10 | Eradication | Peripheral | LLL | |
| 20 | 18 | Debulking | Central | LLL | |
| 21 | 9 | Eradication | Peripheral | LLL | |
| 22 | Cryoablation 6 | 7 | Eradication | Intermediate | RML |
| 23 | 7 | Eradication | Peripheral | RLL | |
| 20* | Wedge VATS Resection 3 | Partially ablated | Eradication | Central | LLL |
Abbreviations: LLL, left lower lobe; LUL, left upper lobe; RLL, right lower lobe; RML, right middle lobe; RUL, right upper lobe; VATS, video-assisted thoracoscopic surgery.
* This lesion was partially ablated due to proximity to the heart and resected 8 weeks later.
A
B
C
D
R
L
18
16
Lesions treated (mm)
4
VATS Resection #1
5
9
VATS Resection #2
VATS Resection #3 ☒
☐ Cryoablation #1
Cryoablation #2
13
Cryoablation #3
2
4
Cryoablation #4
4
5
Cryoablation #5
7
10
Cryoablation #6
VATS Resection of ☒ ablated lesion
7
7
3
18
8
7
6
15
8
9
7
Two months after the most recent cryoablation session the patient underwent resection of a 27 mm leiomyosarcoma metastasis located anterior to the heart combined with a fourth VATS resection targeting an 18 mm peridiaphragmatic left lower lobe nodule (metastasis #20, Table 1). This tumor was within 1 cm from the heart and had intentionally been partially treated with cryoablation. For the 14 ablated lung metastases treated with the goal of eradication, no local re- currence was observed at 16 months.
Discussion
This case highlights the option of multimodal local ablative therapy in a patient with LFS and multiple lung metastases. Surgical resection was combined with percutaneous cryoab-
lation since neither treatment modality increases the risk of secondary cancers, contrary to radiation therapy. Primary technical success was achieved for all treated lung metas- tases, and no local progression was observed. The only ad- verse event related to percutaneous cryoablation was tran- sient intercostal neuritis (CTCAE Grade 1).
Our experience with this case supports the safety and ef- ficacy of treating lung metastases with percutaneous cryoab- lation. Cryoablation is safe and particularly effective for sar- coma lung metastases smaller than 1 cm with local control rates of 99% and 98% at 1 and 2 years [20]. Cryoablation has dis- tinct advantages for patients with multiple lung metastases as it is (i) minimally invasive [20,21], (ii) preserves lung function [6], (iii) has lower complication rates than surgery [15], and (iv) is repeatable [22].
Prior studies showed that cryoablation of up to eight lung tumors in a single session is safe [20]. While data re-
garding the incidence of nerve injury due to percutaneous lung cryoablation are limited, [23] neuropathic pain following video-assisted thoracic surgery (VATS) has been described in about 25% of cases [24].
In general, the possibility of repeat percutaneous ablation is an important advantage compared with surgery and SBRT, since repeat pulmonary metastasectomy is associated with prolonged survival in patients with sarcoma [25]. Not only is the number of surgical interventions a patient can tol- erate limited by the lung parenchyma lost, but resection of even small central lung nodules may also require lobectomy or even a pneumonectomy [17,26]. On the contrary, no de- crease in lung function has been demonstrated following per- cutaneous thermal ablation, regardless of the tumor location. Therefore, percutaneous cryoablation provides the ability to control more pulmonary metastases than surgery alone [27]. Furthermore, cryoablation does not preclude subsequent sur- gical resection, as shown in this case of uneventful VATS fol- lowing multiple lung cryoablation sessions. Although local ab- lative therapies cannot provide a definitive cure for metastatic leiomyosarcoma, they may prolong survival [27]. In this young patient with excellent performance status, the combina- tion of surgery and thermal ablation-controlled disease bur- den while minimizing morbidity and preserving quality of life.
Patients with LFS are prone to developing multiple malig- nancies and management focuses on the surveillance, recog- nition, and early local treatment of emergent tumors [3,28]. Managing patients with LFS with lung metastases is com- plex and should involve a multidisciplinary team, including pulmonology, thoracic surgery, and interventional radiology [3,6,27]. This case report highlights the role of percutaneous lung cryoablation as a safe and effective treatment option for lung metastases in patients with LFS, where radiation is ide- ally avoided.
Authors’ contributions
Case report conception and design: J. Saenger, F. Fintel- mann; data collection: J. Saenger, G. Cote, A. Muniappan; draft manuscript preparation: J. Saenger, I. Tahir, F. Fintelmann. All authors reviewed the results and approved the final version of the manuscript.
Availability of data and materials
Not applicable.
Patient consent
Written informed consent for research and publication was obtained.
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