Abstract
Background: We present the case of a recurrent malignant phyllodes tumor of the breast, after mastectomy and radiotherapy, in which electrochemotherapy (ECT) was applied to the tumor bed, to achieve better local control. Case Report: A 66-year-old woman with a large malignant phyllodes tumor of the right breast with a size of 40 cm underwent right radical mastectomy and right axillary lymph node sampling. One month after surgery, with histologically clear margins, the woman presented with multiple small oval masses in the upper portion of the chest wall, indicating rapid disease progression. A second radical excision with clear margins was performed, followed by adjuvant radiotherapy. Two months after the end of treatment, a new 3-cm mass was present in the right axillary extension. The patient underwent a third extensive debulking surgery. At the end of the resection, ECT was applied on the tumor bed along the extensive skin flaps and resection margins. After eight months of follow-up, breast magnetic resonance imaging and total body computed tomography showed disease recurrence in the anterior portion of the right serratus muscle and in the lungs bilaterally. The area undergoing previous ECT showed no disease recurrence. The patient received two lines of palliative chemotherapy. She died 28 months after diagnosis. At the time of death, the large area treated with ECT was geometrically spared from local disease progression. Conclusion: This case report suggests the potential efficacy of ECT at the operating bedside to increase local control in aggressive malignancies.
Phyllodes tumor is a rare fibroepithelial neoplasm that accounts for less than 1% of all breast cancers and usually presents in adult women (35-55 years). It can be benign or malignant and often manifests as circumscribed, rapidly growing, mobile masses, sometimes in association with nonspecific symptoms, such as dilated skin veins, nipple retraction, skin ulcers, palpable axillary lymphadenopathy, or discoloration of the skin (1). Complete and wide local excision is often curative with a reduced risk of local recurrence when margins are larger than 1 cm (2). Mastectomy is often required due to the large size of these tumors. The local recurrence rate of malignant phyllodes tumors of the breast is ≥15% for patients with tumors >2 cm treated with lumpectomy alone and with tumors >10 cm treated with mastectomy alone. In addition, the risk of local recurrence increases with increasing tumor size and decreasing free surgical margin thickness (3). Adjuvant therapy mainly includes radiotherapy, which has been found to reduce local recurrence, whereas chemotherapy does not seem to provide any clinical benefit (4).
Electrochemotherapy (ECT) is a combination therapy in which the effect of a cytostatic drug is enhanced via electroporation. The electroporation mechanism enables the drug to deliver its cytotoxic effect directly into the cell, where it penetrates, in some cases, reversing cancer drug resistance (5). There is already strong evidence in the literature showing ECT as a safe, effective, and non-invasive loco-regional treatment for breast cancer recurrence on the chest wall when it is not suitable for surgical resection and/or when systemic therapy is ineffective or contraindicated (5-7). However, there is no evidence on the role of ECT as a concomitant treatment to radical surgery, to be applied at the surgical bedside, aimed at treating any residual microscopic foci of disease distributed beyond the margins of surgical resection.
Here, we present an extended indication to ECT applied to the surgical bedside for malignant phyllode tumor recurrence of the breast after mastectomy and radiotherapy. Informed consent was obtained from the patient involved in the study.
Case Report
A 66-year-old woman came to our observation in March 2021 for a large polylobate solid formation of the right breast of 40 cm in maximum diameter with purplish discoloration from initial superficial ischemia, dense subcutaneous vascular network, and with a nipple-areola complex distended but sliding on the deep plane, free from infiltrative elements (Figure 1A).
Voluminous polylobated solid formation of the right breast of 40 cm (A). Right mastectomy (B-C).
The patient reported that about 30 years earlier a small mass had appeared in her right breast, with slow growth. Three months earlier, however, it had begun to grow rapidly. She also reported significant weight loss in the last month. At the time of diagnosis, the patient weighed 40 kg and was 150 cm tall. No axillary or supraclavicular lymphadenopathy bilaterally, and no distant metastases were found on total body computed tomography (CT). The patient underwent right radical mastectomy and right axillary lymph node sampling (Figure 1B and C); breast reconstruction was delayed according to the patient’s desire. The operating time was 4 h; blood loss was 500 ml, no intra-operative complications occurred. Final histology showed a high-grade, malignant phyllodes tumor (60 mitoses/10 HPF, ki67 proliferation index equal to 55%), with a diameter of 39 cm, without axillary lymph node metastases. The surgical resection margins were close but tumor-free (deep margin distance <1 mm, superficial margin distance 2 mm, radial margin distance >5 mm), as was the skin. After multidisciplinary discussion, the patient was addressed to adjuvant radiotherapy treatment. During postoperative follow-ups, the patient underwent dressings and multiple chest wall ultrasound-guided drainage of small subcutaneous serous collections. One month after surgery, before starting radiotherapy, the patient underwent the last clinical and ultrasonographic evaluation of the right chest wall with the finding, in the upper portion, of minute oval masses suggestive of local disease progression. A second radical excision was performed. Final histology showed a high-grade malignant phyllode tumor (100 mitoses/10 HPF) with a morphological appearance similar to the previous lesion. Surgical resection margins were tumor-free (deep margin distance <1 mm).
After negative evaluation on total body CT scan and ultrasound of the right chest wall, the patient underwent adjuvant radiation treatment. A 6 MV linear accelerator was used on the chest wall. The planned dose was 2.87 Gy per fraction with a total dose of 40 Gy. Tolerance was good (G2 erythema). Two months after the end of the radiotherapy, the patient presented a 3 cm mass in the right axillary extension, fixed in the deep plane (Figure 2A). Ultrasound showed a 32 mm oval, globular, vascularized formation. CT scan did not reveal distant metastases. Aiming to achieve a longer local control, given the experience in our institution with palliative care of recurrent superficial cancer (6-7), the multidisciplinary board discussed and approved the choice to combine standard debulking surgery with ECT, providing a novel modality of application on the residual surgical bedside, after disease resection. The patient then underwent a third large debulking surgery, removing the recurrence with large macroscopically free margins and, after resection, ECT was additionally applied on the tumor bed and along all resection margins, in the absence of macroscopic residual disease.
Recurrence in the right axilla (A). Electrochemotherapy treatment with grid drawing of the area to be electroporated (B-C). Vision of the treated area at discharge on the seventh post-operative day (D).
Twenty-one mg of Bleomycin was infused intravenously over 5 min; 8 min after infusion, single-pass ECT of the entire previously defined area was performed for 115 pulses every 16 min (Figure 2B and C).
Given the large area to be electroporated, to avoid treating the same tissue segment multiple times, the procedure was performed under the guidance of a grid pattern that divided the entire treatment area into multiple small square areas. A fixed-geometry hexagonal electrode (mod. H-30-ST) was used, which was dipped in methylene blue dye. As electroporation proceeded, the treated area was tattooed with blue, and was thus recognizable compared to the untreated area.
During the postoperative course, the patient developed grade I erythema in the right upper hemithorax and upper third of the arm, which was treated with prophylactic antibiotic therapy and cortisone cream with resolution of symptoms. The patient was discharged on the sixth postoperative day (Figure 2D).
After eight months of negative follow-up, a breast magnetic resonance imaging and total body CT showed disease recurrence in the right anterior serratus muscle, bordering the area treated with ECT, and multiple bilateral lung metastases.
Despite this, the area that had previously undergone ECT showed no disease recurrence. The patient received palliative chemotherapy. She was treated with first-line trabectedin-based chemotherapy for three cycles with disease progression to bilateral lung and thrombotic involvement of the pulmonary vein. Second-line therapy with Pazopanib was administered, with further disease progression at the level of the chest wall muscles and lungs. The patient died in February 2023, 28 months after diagnosis. At the time of death, the large area treated with ECT was geometrically spared, and there were no signs of recurrence.
Discussion
This case report highlights the challenges in managing high-grade malignant phyllodes tumors, which are rare breast tumors with unpredictable behavior. The initial management of the patient with radical mastectomy and axillary lymph node sampling, followed by complementary radiotherapy treatment, was appropriate for the high-grade nature of the tumor. However, the two early disease recurrences in the upper outer thorax (two months after surgery) and in the right axillary extension (two months after the end of the radiotherapy) may suggest that surgical treatment alone and the addition of adjuvant radiotherapy was not effective in eradicating the tumor. The decision to combine standard debulking surgery with electrochemotherapy applied to the tumor bed and resection margins in the absence of macroscopic disease represented an innovative approach to the management of this aggressive and highly recurrent disease, which succeeded in avoiding at least local recurrence. Indeed, the treated field remained geometrically preserved from the recurrence, which instead affected tissues of the serratus anterior muscle, just outside the boundary of the treated region, with subsequent spread of the disease to distant sites (the lungs).
Malignant phyllodes tumor of the breast is a rare type of breast cancer that begins in the connective tissue of the breast. It can grow quickly and has the potential to spread to other parts of the body. Treatment for malignant phyllodes tumor typically involves surgery to remove the tumor, with or without radiation therapy and chemotherapy (8). ECT is a novel treatment approach that combines the use of electric pulses and chemotherapy to improve local control of tumors. ECT works by delivering a series of electric pulses to the tumor, which temporarily permeabilizes the tumor cell membrane and allows for increased uptake of chemotherapeutic agents (9). This results in increased cytotoxicity and improved local control of the tumor. ECT has been shown to be effective in the treatment of a variety of solid tumors, including breast tumors (10).
To the best of our knowledge, there are no studies to date evaluating the efficacy of ECT in the absence of macroscopic disease, i.e., applied to the surgical bed after disease excision to increase local control.
From this first experience, which was successful in halting the rapid sequence of local recurrences, allowing prolonged local control over time (until death). Although limited to the treatment field only, regardless of disease progression in regions other than the treated one, we can deduce two considerations: the first is that a microscopic persistence of disease after surgical excision, on the bed and margins, must be assumed, on which ECT must act; the second is that the use of ECT should have determined in this patient the activation of the immune system. In malignant phyllodes tumor, evidence suggests that the immune system plays a role in tumor development and progression. Studies have shown that the tumor microenvironment in malignant phyllodes tumor contains a variety of immune cells, including T cells, B cells, and macrophages. The presence of these immune cells is associated with a better prognosis, suggesting that they may play a role in limiting tumor growth (11). Recent studies have shown that ECT can cause an immune response in the treated area, which can help destroy cancer cells. The electrical pulses used in ECT can cause cell death and the release of tumor-associated antigens, which can be recognized by immune cells. This can activate immune cells to migrate to the site of treatment and attack the cancer cells. Moreover, ECT can cause immunogenic cell death (ICD), a type of cell death that triggers an immune response. ICD can release danger signals that activate immune cells to attack the cancer cells. This can enhance the immune response and improve the effectiveness of ECT (12). This suggests that ECT may be a useful approach for local control of high-grade malignant phyllodes tumors.
In the case of malignant phyllodes tumor of the breast, only one study has investigated the use of ECT in 12 patients with recurrent breast cancer, including one patient with a malignant phyllodes tumor. The study found that ECT was effective in controlling local recurrence in this patient; however, it was applied directly to the disease, and not to the surgical bed, as in our case (13). Notably, the recurrence of the disease in the lungs bilaterally and in the right serratus anterior muscle nine months after the ECT treatment suggests that the approach may not be entirely effective in eradicating the disease, which uses several routes of spread including blood.
In conclusion, this case report emphasizes the need for continued research into the optimal management of high-grade malignant phyllodes tumors, the importance of multidisciplinary discussion in managing complex cases but, more importantly, it raises the need to test the effectiveness of applying ECT to the surgical bed even in other locally aggressive diseases as well, in order to increase local control. Further research is needed to verify feasibility and safety of this novel ECT application combined with surgery.
Acknowledgements
This publication was supported by the MoH – Ricerca Corrente 2023.
Footnotes
Authors’ Contributions
Conceptualization: G.C.; Data curation: S.B., B.A.; Methodology: S.M.F.; Supervision: L.T.; Validation: G.G.; Writing - original draft: G.C., S.M.F.; Writing - review & editing: G.S. and G.G.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
- Received October 4, 2023.
- Revision received November 16, 2023.
- Accepted November 20, 2023.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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