Limb Salvage by Repetitive Radical Surgery in Recurrently Spreading Myxofibrosarcoma: Case Report and Literature Review

Myxofibrosarcoma (MFS) is a rare and aggressive mesenchymal malignancy that primarily affects the extremities [1]. It constitutes approximately 5% of all soft tissue sarcomas and less than 1% of all malignant tumors in adults [2]. Originally classified in 1977 as a myxoid variant of malignant fibrous histiocytoma [3], MFS was redefined as a distinct entity following revisions to the World Health Organization (WHO) classification of bone and soft tissue tumors in 2002 and 2013 [4‒6]. It is often graded by the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) based on malignancy criteria (G1-3). The 5-year survival rate for MFS is around 75% [7]; however, metastases are frequently observed in high-grade tumors (G3). Despite radical surgical resection, MFS is notorious for its high local recurrence rate, often exceeding 60%, which presents significant challenges in clinical management.

Patients with MFS typically present with a painless mass, which can occasionally be misdiagnosed as a lipoma. Magnetic resonance imaging (MRI) is the preferred diagnostic modality, providing detailed visualization of the tumor’s characteristics. Confirmation of suspected malignancy is achieved through histopathological examination via biopsy. It is crucial to differentiate between superficial epifascial and deeper subfascial or intramuscular tumor locations, as this distinction influences treatment planning and prognosis. The histological heterogeneity and complex classification of MFS contribute to its diagnostic challenges.

Treatment strategies have evolved from primary amputation to a multimodal approach involving radical surgical resection and (neo)adjuvant radiotherapy, aimed at achieving local control and limb preservation [8]. This shift underscores the importance of multidisciplinary tumor boards in tailoring treatment plans based on comprehensive clinical, radiological, and histological evaluations.

MFS is characterized by a locally aggressive growth pattern, often exhibiting septum-like proliferations into surrounding tissues. This infiltrative behavior contributes to a high rate of local recurrence [2], posing significant challenges for surgeons and interdisciplinary tumor boards [9‒11]. Effective management of MFS often necessitates radical surgical resection, and when extensive tissue removal is required, free flap reconstruction becomes essential for addressing defects and facilitating functional restoration after the excision of critical muscle groups.

Reconstructive surgery should be tailored to the individual needs of each patient following tumor resection, as surgical excision often results in some degree of functional loss. Complex reconstruction may be necessary to restore function and optimize outcomes, ensuring that the reconstructive approach aligns with the specific anatomical and functional requirements of the patient.

We present a unique clinical case 7 of limb salvage in a patient suffering from recurrent and widely spreading MFS of the left lower leg. Having refused amputation as recommended elsewhere she received complete limb salvage, soft tissue and functional reconstruction and disease-free long-term survival was achieved by multiple radical resections (17 procedures in 3 years) and skin and soft tissue reconstruction by two subsequent free flaps despite the extent of the disease. Adjuvant radiotherapy was performed with a cumulative dosage of 60 gray (Gy). A short systematic review is presented to discuss the evidence for an aggressive surgical approach.

A 70-year-old athletic female patient, otherwise healthy, presented to our clinic with a residual undifferentiated pleomorphic soft tissue sarcoma measuring 6 × 3.5 × 2 cm, located distally and ventrally to the left fibular head (cT2 N0 M0, G2). She had previously undergone an R1 resection at another hospital and was advised to undergo amputation, which she refused.

We performed a radical resection, excising the skin, soft tissue, portions of the anterior tibialis and soleus muscles, and Hoffa’s fat pad. The resulting defect was covered using a microvascular free latissimus dorsi flap from the left side, measuring 25 × 15 cm, with end-to-end anastomoses to the anterior tibial artery and vein (Fig. 1). This approach provided adequate soft tissue coverage for subsequent adjuvant radiotherapy, which was administered at a cumulative dose of 60 Gy. Histopathological examination revealed the characteristic features of a cell-poor MFS (graded as intermediate) with prominent vascular architecture (Fig. 2).

During a routine follow-up 1.5 years later, MRI revealed a recurrence of the tumor on the medial aspect below the knee joint and in the medial thigh area. Histologically guided radical resections were performed until clear margins were achieved, including the resection of the pretibial fascia, resulting in a soft tissue and skin defect measuring 33 × 13 cm. Soft tissue reconstruction was accomplished using a free deep inferior epigastric perforator (DIEP) flap, with microvascular end-to-side anastomosis to the popliteal artery and accompanying vein (Fig. 3).

Nine months later, clinical follow-up and MRI scans identified another recurrence proximal to the previous resection area and DIEP anastomosis, as well as distally at the medial tibia. These were radically resected using local tissue for closure. Further recurrences occurred 9 and 15 months later in the medial lower leg, which were also radically excised after the patient definitively opted for full functional preservation of her leg. R0 resection was achieved by removing the gastrocnemius muscle, parts of the soleus muscle, and periosteal tibia. A final recurrence was detected 4 weeks later at the lateral femur condyle and was radically resected, with wound closure performed using local tissue. Ultimately, a stable R0 situation was achieved, with the patient remaining recurrence-free for over 9 years.

Histopathological findings showed a progressive decrease in differentiation with each recurrence (Fig. 2). After a total of 17 resections, defect coverage with two free flaps, and adjuvant radiotherapy (total dose of 60 Gy), the patient has been clinically and radiologically recurrence-free for 9 years. Her primary goal of maintaining full function in the affected leg was achieved through this multistage approach. At 80 years old, she actively engages in daily activities and sports such as hiking, aerobics, and water sports. She perceives limb salvage as a significant gift in her life. Given the rarity of such extensive multiple recurrences and the potential for intensive discussions regarding limb preservation, we conducted a systematic literature review.

A comprehensive literature search was conducted by the authors using the PubMed and Cochrane databases to identify relevant citations regarding surgical management strategies for highly aggressive MFS of the extremities. The search employed Medical Subject Headings (MeSH) terms, including “myxofibrosarcoma,” “recurrences,” “resection,” and “radiation therapy” (Diagram 1, Fig. 4).

Publications were considered eligible (Table 1) if they detailed surgical approaches for MFS management. The authors applied specific inclusion and exclusion criteria: only retrospective studies on human subjects published in English were included, as well as data-based analyses. A minimum mean follow-up period of 1-year post-surgery was required. Studies that reported on mixed tumor entities or were published in non-English languages were excluded. Bibliographic management was conducted using Zotero, and data extraction was performed manually and compiled using Microsoft Excel 16.45 (Albuquerque, NM, USA).

Oncological surgery for MFS, coupled with the reconstruction of functional capacity, presents a complex challenge for plastic surgeons. MFS is most commonly diagnosed in patients in their sixth to seventh decade of life. While it predominantly affects the lower extremities, accounting for 77% of cases, it can also occur in the trunk, comprising 12% of cases [17]. MFS is a malignant neoplasm characterized by a myxoid stroma and varying degrees of nuclear pleomorphism. Macroscopically, it presents as a multilobular tumor with a mucoid interface. Microscopically, it is predominantly composed of myxoid regions with low cellularity. These myxoid areas contain spindle-shaped and pleomorphic cells embedded within a mucopolysaccharide-rich matrix.

MFS exhibits a highly infiltrative growth pattern, characterized by septiform extensions into surrounding tissues, which complicates differentiation from adjacent structures. This infiltrative nature, particularly into muscle and adipose tissue, contributes to its high local recurrence rate, reported between 16% and 57%. The tumor’s diffuse, septum-like characteristics present significant challenges for surgical intervention, necessitating meticulous preoperative planning. In cases of unsuccessful resection, the local recurrence rate can range from 25% to 52%, underscoring the importance of achieving clear surgical margins [2].

The incidence of local recurrence in MFS is notably higher compared to other soft tissue sarcomas, with rates reported to be as high as 10% more according to Sanfillipo et al. [15]. In their retrospective study of 153 patients, Sanfillipo et al. [15] identified that the size and histologic grade of the primary tumor, along with the status of surgical margins, were independent predictors of patient survival. Achieving disease-negative microscopic margins during surgical resection is crucial for improving survival outcomes in patients with MFS.

The literature indicates that local recurrences in MFS are primarily predicted by the quality of surgical margins, while distant metastases are more closely associated with the histologic grade of the tumor. This correlation is due to the tendency for dedifferentiation in tumors that recur locally, as observed in our case (Fig. 3).

MFS often shows signal alterations along the muscle fascia in MRI (“tail sign”), which correspond to infiltrative growth of the tumor [18]. These changes are most prominently observed in T2-weighted MRI sequences, where the use of intravenous gadolinium enhances the delineation of tumor extension. Defining tumor margins and, consequently, resection boundaries based on imaging is a critical component of surgical planning. However, these margins cannot always be precisely determined preoperatively, necessitating the surgeon’s expertise to accurately differentiate between tumor and healthy tissue during the procedure. That is why unplanned, insufficient and incomplete excisions of an MFA prior to allocation to a specialized center have serious consequences for the affected patient. The 5-year survival rate is lower and the local recurrence rate higher than in patients with adequate interdisciplinary therapy.

In cases where a tumor infiltrates critical neurovascular structures, bones, or joints, and marginal resection is not feasible, primary amputation should be considered and thoroughly discussed with the patient to ensure complete oncological clearance. An alternative therapeutic modality is isolated limb perfusion (ILP), which has been utilized in recent years for the management of locally advanced or marginally resectable extremity soft tissue sarcomas. The objective of ILP is to convert a non-resectable tumor into a resectable one by enhancing the tumor capsule, thereby facilitating surgical excision. This approach primarily focuses on improving resectability rather than inducing significant tumor regression. Due to the associated high complication rate, ILP is reserved for select cases of locally advanced and non-resectable tumors. Nevertheless, radical resection remains the gold standard treatment when feasible, as it provides the best opportunity for complete tumor removal and optimal patient outcomes.

In a systematic review and meta-analysis, Neuwirth et al. [19] reported an overall limb salvage rate of 73.8% for patients undergoing treatment for highly aggressive MFS of the extremities. The median time to local (in-field) progression varied between 4 and 28 months, with a weighted median of 22.1 months. The superficial and infiltrative growth pattern of MFS often results in extensive soft tissue defects following surgical resection. These defects necessitate plastic-reconstructive interventions, such as local or free flap reconstruction, to achieve limb preservation and restore functional integrity. Recent advancements in sarcoma treatment have highlighted the potential of immunotherapy, particularly the use of pembrolizumab, an immune checkpoint inhibitor. This therapy has demonstrated a 43% reduction in relapse risk for certain soft tissue sarcomas, as shown in a clinical trial presented at the 2024 American Society of Clinical Oncology Annual Meeting. The trial involved 127 patients and indicated that integrating immunotherapy could significantly enhance survival rates for high-risk sarcoma patients, marking a critical evolution in treatment alongside traditional methods like surgery and radiation [20].

In our case, multiple local recurrences necessitated extensive resections, with free flap reconstructions playing a crucial role in achieving limb preservation until a recurrence-free state was attained. Notably, Ghazala et al. [11] is the only retrospective study detailing reconstructive procedures, reporting that 9 out of 50 patients underwent free flap coverage post-tumor resection, though the study did not provide specific data on local recurrence rates following such interventions. The most significant risk factor for recurrence is tumor-affected surgical margins. Therefore, particularly in high-grade MFSs, it is imperative to combine resection with radiotherapy, as microscopic residual tumor is found in 25–52% of cases even after surgical excision.

In the retrospective study by Teurneau et al. [16], it was observed that among patients who received radiotherapy, 9 out of 34 (27%) experienced local recurrence. Similarly, 6 out of 22 (27%) patients who did not receive radiotherapy also developed local recurrence. Notably, all 9 patients who experienced recurrence post-radiotherapy did so within the irradiated field, mirroring the findings in the current study. This underscores the complexity of managing local recurrences in MFS, highlighting the need for further investigation into optimizing radiotherapy protocols to enhance local control. Boughzala-Bennadji et al. [14] showed in their retrospective study that R0 resection and adjuvant radiation therapy were significantly associated with better local control and in the case of R1 resection, re-resection should be performed without hesitation.

Scar tissue, altered anatomical layers and the absence of a tumor mass indicate that it is more difficult to obtain a negative margin in recurrent Myxofibroarcoma than in primary tumors [10]. Randomized-controlled trials have shown that local control can be improved with the combination of surgery and radiotherapy, but no studies are found specifically for MFSs with a follow-up of >1 year.

Radiotherapy serves as a beneficial adjunct to surgical intervention, particularly for high-grade MFS, yet the cornerstone of effective treatment remains aggressive surgical strategies aimed at achieving R0 resection margins. Chemotherapy is primarily reserved for cases of metastatic MFS. To our knowledge, this is the first systematic literature review focusing on surgical approaches for recurrent MFS, illustrated by our case study featuring long-term follow-up after multiple resections, which exceed the extent of other published cases.

Our systematic review has several limitations. Notably, precise surgical techniques were infrequently reported, particularly regarding whether re-resection was performed in R1 situations or following reconstructive surgery. Kikuta et al. [13] provided some insight in their retrospective study, indicating that the number of surgeries, including the initial procedure for recurrent tumors during the follow-up period, averaged three, with a range of one to eight surgeries. This lack of detailed reporting on surgical interventions highlights a significant gap in the literature, which could impact the understanding and optimization of surgical strategies for recurrent MFS. Second, our study was limited to retrospective analyses, as there are no randomized-controlled trials specifically addressing MFS available in literature. This reliance on retrospective data may affect the robustness of the conclusions drawn, underscoring the need for prospective studies to better elucidate optimal management strategies for this malignancy.

Limb-sparing surgery in patients with MFS is achievable while preserving functionality through the integration of comprehensive treatment modalities. In this clinical case, regional and local recurrences were effectively managed using a multimodal approach centered on aggressive surgical intervention. This strategy resulted in long-term tumor-free survival and successful limb preservation. The case is of particular interest to the surgical community as it underscores the challenges associated with treating tumors characterized by morphologically undetectable margins and a dispersed growth pattern. Effective surgical management can be accomplished while maintaining functionality by employing the full spectrum of reconstructive microsurgical techniques, regardless of the patient’s age.

It is crucial to engage in shared decision-making with the patient and discuss findings within a multidisciplinary tumor board. Consideration must extend beyond functional maintenance or improvement to include cosmetic and psychological aspects. A meticulously crafted multidisciplinary surgical plan is essential. Limb-sparing procedures, coupled with soft tissue coverage post-oncological surgery, should not be restricted to patients with curative intent; those in a palliative stage of disease may also benefit from surgery in terms of pain reduction and enhanced quality of life. Given the complexity of a multidisciplinary approach, individualized treatment should be administered in specialized centers with expertise in musculoskeletal oncology.

The support of Hans Kreipe, Head of Pathology, in the workup of this difficult case is greatly appreciated.

Ethical Board of Hannover Medical School: An ethical approval was not required. This retrospective review of patient data did not require ethical approval in accordance with local/national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000544059).

The authors have no conflicts of interest to disclose.

This study was not supported by any sponsor or funder.

T.G. collection of data and writing the manuscript: F.L. provision of histological data, images, and conceptualization of the pathological section: N.D. manuscript revision: P.M.V. surgery, conceptualization of the manuscript, revisions, provision of clinical data and images, and provision final version of manuscript.

The data that support the findings of this study are not publicly available due to their containing sensitive personal information that could compromise the privacy of research participants but are available from the corresponding author [J.S.] upon reasonable request and with appropriate ethical approvals.