Continuing Education Activity

Fibrosarcoma is defined as a neoplasm composed of fibroblasts with variable collagen production. This activity serves to provide a high-level overview of the topic of fibrosarcomas to allow medical practitioners to better understand the basic diagnosis and management. Furthermore, the activity serves to highlight the role of an interprofessional team member's management of this neoplasm, to optimize patient care.

Objectives:

• Identify the etiology of fibrosarcomas.
• Describe the evaluation of fibrosarcomas.
• Review the management options available for fibrosarcomas.
• Summarize how an interprofessional team can coordinate care to provide the best outcomes in patients with a fibrosarcoma.

Introduction

Fibrosarcomas are defined as a malignant neoplasm composed of fibroblasts that may have varying amounts of collagen production and a "herringbone" architecture. Adult fibrosarcomas have displayed a declining incidence over the past several decades as the classification of fibrosarcoma continually narrows, and other mesenchymal and non-mesenchymal tumors that mimic fibrosarcomas are more accurately diagnosed.[1][2] Fibrosarcomas can be sub-divided into two types: infantile or congenital fibrosarcomas, or adult-type fibrosarcomas. Infantile fibrosarcomas rarely metastasize, while adult-type fibrosarcomas are highly malignant.[3]

Etiology

Fibrosarcomas typically originate from fascia and tendons of soft tissue but can also occur in bones as a primary or secondary tumor within the medullary canal or the periosteum. Prior bone damage, whether from trauma or radiotherapy, may give rise to fibrosarcomas of the bone.[4][3]

Epidemiology

Adult fibrosarcoma is most common in middle-aged and older adults, and rarely occur in children. There is a slight predominance in male patients, and most commonly involves the deep soft tissues of the extremities, trunk, head, and neck.[5][2]

In a survey of adult fibrosarcomas, 80% were classified as "high-grade" (Grade 2 or 3), with 25% of the remaining low-grade lesions progressing to a high-grade sarcoma locally over time.

Pathophysiology

Fibrosarcomas derive from a mesenchymal cell origin, composed of spindle-cell fibroblasts with uncontrolled proliferation. Most frequently, fibrosarcomas originate from tendons and fascias of deep tissues, but may also occur within the medullary canal or the periosteum of bones. Pre-existing bone lesions or irradiated tissues may also give rise to secondary fibrosarcomas of the bone.[3]

Histopathology

Fibrosarcomas are a spindle cell type of soft tissue sarcoma, characterized by its fusiform oval nuclei, lance-shaped tapered cells, and unipolar or bipolar cytoplasm. Adult fibrosarcomas show a mild to moderate degree of pleomorphism. Neoplastic cells are arranged in long sweeping fascicles that form a classic "herringbone" pattern. Note that a high degree of pleomorphism should classify any tumor as an undifferentiated pleomorphic sarcoma. Fibrosarcomas display varying degrees of mitotic activity and have darkly staining nuclei with prominent nucleoli and scant cytoplasm. There is a variable amount of stromal collagen present within fibrosarcomas and may mimic fibromatosis in some tumors.

While histopathology is not sufficient to distinguish fibrosarcomas from other spindle-cell sarcomas, appropriate immunohistochemistry can greatly assist in diagnosis by identifying characteristic tumor markers. Furthermore, measurement of these markers on the cell surface or within the tumor environment is often critical in monitoring for treatment efficacy and tumor recurrence. 

Vimentin is a marker that is indicative of a mesenchymal cell origin and is often the only positively stained marker in the diagnosis of fibrosarcomas. One might also find alpha smooth muscle actin, muscle-specific actin, and desmin to be common myogenic markers, which often serve to represent myofibroblastic differentiation. 

In contrast, a positive S-100 protein marker would be indicative of a nerve sheath tumor, while CD31, CD34, and Factor VIII non-von Willebrand factor would suggest a vascular tumor rather than a true fibrosarcoma.[3][5][6]

History and Physical

Practitioners should inquire about the location, size, shape, and consistency of any soft tissue mass. Furthermore, providers should inquire about any local scar tissue, especially as a consequence of prior burn injuries. Similarly, the presence of prior vascular grafts, joint prosthetics, or other surgically implanted foreign materials should be noted. Previously irradiated tissues may be a risk factor for the development of a fibrosarcoma as are pre-existing dermatofibrosarcoma or well-differentiated liposarcoma.[3][7]

Additionally, the regional lymph node examination should be accompanied by a complete neurovascular examination. Fibrosarcomas typically arise in deep connective tissue rich with collagen, and thus, it is less common in the retroperitoneum, mediastinum, head, and neck. Fibrosarcomas generally are spherical with sharp demarcation from surrounding tissue and have a firm consistency on palpation. Fibrosarcoma tumors typically range from 3-8 cm in size.[3][8]

Fibrous tumors often have a very delayed diagnosis, as they arise from deep tissue and cause painless soft-tissue swelling. It is often not until symptoms arise from the local mass effect of a deep tumor that the lesion is identified and diagnosed. Impeded blood circulation, nerve compressions, or movement restriction is often present when diagnosing a fibrosarcoma.[3]

Late presentations of fibrosarcomas may be accompanied by weight loss and anorexia. Furthermore, pain associated with a deep soft tissue mass greater than 5 cm in size increases suspicion of malignancy, and warrants referral for further specialist evaluation.[3]

Evaluation

Radiographic imaging is the first diagnostic step when history and physical examination suggests a diagnosis of a malignant soft tissue tumor. Contrast-enhanced MRI is the preferred procedure to evaluate tumors of the extremities or pelvis and will provide information pertaining to a tumor's size, margins, signal density, degree of necrosis, and vascularization. CT Scans may also be employed to assess for tumors of the retroperitoneum or to identify any possible bony involvement. Fibrosarcomas appear as localized, nonspecific ovoid lesions with slightly irregular margins. One will see the displacement of surrounding tissue.[3]

If imaging suggests the presence of a soft tissue malignancy, a biopsy in the form of a core needle biopsy is warranted, as a fine needle aspiration (FNA) has been criticized as being unsuitable for providing an accurate initial diagnosis. FNA does, however, have utility in monitoring progression, as well as identifying tumor recurrence or metastasis if previous cytological studies are available for comparison. Finally, in tumors where minimally invasive biopsy techniques have failed or are untenable, more invasive surgical biopsies may be warranted. Excisional biopsy is generally recommended when you suspect a soft tissue sarcoma of 3 to 5 cm in size, whereas partial incisional biopsies are appropriate when tumor size exceeds 5 cm.[9][8][3]

Treatment / Management

Surgical excision is the mainstay of treatment for localized soft tissue sarcomas. Intramuscular tumors should have a compartmental en-bloc excision, and in this scenario, no additional radiation therapy would be indicated. If there is extracompartmental growth, or if the tumor does not reach the origin or insertion of the muscle, a wide-surgical resection would be appropriate, with the goal of obtaining tumor-free margins. Two centimeters of margin is generally recommended; however, there is a paucity of definitive evidence for the best safety margin. Surrounding structures such as nerves and vascular structures must always be taken into account.

For tumors that are high grade and larger than 5 cm, adjuvant radiation therapy is highly recommended. If clear margins are not obtained, reoperation is the most appropriate next step in management.

The utility of chemotherapy in the management of soft tissue sarcomas is unclear and, therefore, not generally recommended in standard treatment. Additionally, fibrosarcomas tend to form a co-resistance to drugs such as vincristine, vinblastine, and etoposide after the use of the first-line agent doxorubicin. Therefore, only patients with high-stage fibrosarcomas that require chemotherapy should be treated with anthracyclines as the first-line treatment. The addition of actinomycin D and ifosfamide may increase the response to treatment. That being said, an improvement in survival has only been demonstrated in 4-11% of sarcoma patients treated with standard chemotherapy.

Finally, intra-tumoral injections of matrix metalloproteinase inhibitors such as TIMP-1-GPI fusion protein has been shown to lead to a decreased tumor mass and growth. Furthermore, injection shows inhibition of cell migration as well as increased tumor cell apoptosis.[3][10]

Differential Diagnosis

By definition, a diagnosis for fibrosarcoma is a diagnosis of exclusion. Low-grade fibromyxoid sarcomas, sclerosing epithelioid fibrosarcomas, fibrosarcomatous dermatofibrosarcoma protuberans, and synovial sarcomas are all clinically distinct diagnoses that may be mistaken for a true adult fibrosarcoma.

While storiform areas may be present on histology in association with adult fibrosarcomas, storiform growth suggests the tumor arose from dermatofibrosarcoma protuberans. Furthermore, CD34 positive tumors likely represent fibrosarcomas arising from dermatofibrosarcoma protuberans or a fibrosarcoma progression from a single malignant fibrous tumor.

It is unlikely to find a fibrosarcoma within visceral organs, and these tumors likely represent cytokeratin-negative carcinomas. In the retroperitoneum, initially reported fibrosarcoma-like lesions frequently prove to be dedifferentiated liposarcomas.[5][2]

Medical Oncology

Adult fibrosarcoma is a very aggressive subtype of soft tissue sarcomas with a rate of recurrence of around 50%. Fibrosarcomas tend to respond poorly to chemotherapy which may be attributed to the intrinsic resistance to chemotherapeutic agents.[11]

There is limited data regarding histology-driven treatment for various subtypes of soft tissue sarcoma. The benefit of adjuvant chemotherapy in fibrosarcoma is debatable. Neoadjuvant treatment with MAID protocol has shown benefit in high-grade soft tissue sarcomas including fibrosarcomas, with a lower rate of recurrence, metastasis, and improvement of survival.[12][13]

In advanced or unresectable tumors, doxorubicin is the most commonly used chemotherapeutic agent and is usually considered the first-line drug with response rates ranging between 18 – 25%. There is no specific second-line therapy however some chemotherapeutic agents have shown benefit including ifosfamide with a response rate of around 25%  in pretreated soft tissue sarcomas including liposarcomas.[14][15]

The combination of gemcitabine and docetaxel has shown a response rate of 16.7% with an acceptable toxicity profile. Huiwen Ma et al reported a response rate of 25%, disease control rate of 82%, and better tolerance with apatinib, a VEGFR 2 inhibitor, when compared to standard second-line chemotherapy. [16][17] 

There is emerging data regarding the efficacy of immunotherapy in soft tissue sarcomas. The combination of chemotherapy with pembrolizumab has shown some promising results in phase ½ non-randomized trials. Further studies are warranted to explore its benefits in patients with soft tissue sarcomas including fibrosarcomas. [18][19]

Prognosis

As discussed above, 80% of adult fibrosarcomas were determined to be high-grade (Grades 2 or 3). Furthermore, 25% of the remaining low-grade lesions progressed to a local recurrence of high-grade sarcoma. These tumors were aggressive with many local recurrences as well as lymph and parenchymal metastases. The survival of adult fibrosarcomas is < 70% at two years, and < 55% at five years.[5][20][21]

Complications

As the mainstay of treatment for fibrosarcoma is surgical, complications are the same as any other surgery and include infection, bleeding, damage to surrounding tissues or structures, and even death. Adjuvant radiation therapy can further increase potential complications such as local fibrosis or increased risk of wound infection. In cases of high stage fibrosarcomas, chemotherapy may be used. Each chemotherapy agent carries its own risk profile, but doxorubicin, which is the mainstay of treatment, is classically associated with an increased risk of dilated cardiomyopathy.

Deterrence and Patient Education

Fibrosarcoma has a poor prognosis due to its aggressive disease course. To maximize outcomes, patients must seek medical treatment from trained specialists with an understanding of musculoskeletal tumors.

Optimal outcomes are seen when there is complete surgical tumor resection with histologically tumor-free margins, appropriate adjuvant treatment to surgical intervention to maximize treatment benefit, and minimize recurrence. There is the prevention of tumor invasion and metastasis. All patients should undergo routine medical screenings and should inquire with their primary care physician regarding any soft tissue masses they may have noticed on self-examination.[3]

Enhancing Healthcare Team Outcomes

The appropriate management of sarcomas, such as fibrosarcoma, is dependent on an interprofessional team of primary care physicians and specialists. As surgical excision is the mainstay of treatment for fibrosarcomas, a surgical team with experience in musculoskeletal oncology is important to optimize patient outcomes while minimizing risks and complications of surgery. A pathologist is required to assist in forming an accurate diagnosis of any sarcomatous lesion and help guide appropriate treatment. But most importantly, nurses and other medical staff must work in conjunction with the patient to ensure a patient-centered approach to care that meets all physical, psychological, and emotional needs of the patient. [Level 5]