Fibrosarcoma

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.[3][4]

Epidemiology

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

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 high-grade sarcoma locally over time. Fewer than 5% of all primary bone tumors and only 10% of musculoskeletal sarcomas are fibrosarcomas. Men are somewhat more likely than women to have bone fibrosarcoma. There is no known racial preference. The bony fibrosarcoma of the femur and tibia are the most common sites for lesions, followed by the humerus. These pathological lesions are typically metaphyseal in origin and appear from the second to the seventh decade of life.[6][7]

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. Preexisting bone lesions such as bone infarcts, chronic osteomyelitis, Paget disease, and irradiated tissues may also give rise to secondary fibrosarcomas of the bone.[3]

Histopathology

Fibrosarcomas are soft tissue sarcoma spindle cells characterized by 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 (see Images. Soft Tissue Fibrosarcoma).

A variable amount of stromal collagen is present within a fibrosarcoma, which may mimic fibromatosis in some tumors. Atypical spindle cells, the herringbone pattern, and varying amounts of collagen formation are all histological characteristics of bony fibrosarcoma.

Myxofibrosarcoma encompasses a spectrum of malignant fibroblastic tumors featuring myxoid stroma, varying degrees of pleomorphism, and distinctive curvilinear vasculature. It is characterized by its low-grade nature, exhibiting both fibrous and myxoid regions, a whorled growth pattern, low cellularity, unremarkable fibroblastic cells, and the presence of curvilinear or arcuate vessels (see Image. Myxofibrosarcoma).

While histopathology is insufficient to distinguish fibrosarcomas from other spindle-cell sarcomas, appropriate immunohistochemistry can greatly assist in diagnosis by identifying characteristic tumor markers. Furthermore, measuring these markers on the cell surface or within the tumor environment is often critical in monitoring treatment efficacy and tumor recurrence.[8] 

Vimentin is a marker 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, often representing myofibroblastic differentiation. In contrast, a positive S-100 protein marker would indicate 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][9]

History and Physical

Clinicians should inquire about the location, size, shape, and consistency of any soft tissue masses. Furthermore, clinicians should inquire about any local scar tissue, especially due to prior burn injuries. Similarly, prior vascular grafts, joint prosthetics, or other surgically implanted foreign materials should be noted. Previously irradiated tissue may be a risk factor for the development of fibrosarcoma, as are preexisting dermatofibrosarcoma or well-differentiated liposarcoma.[3][10]

Additionally, the regional lymph node examination should accompany a complete neurovascular examination. Fibrosarcomas typically arise in deep connective tissue rich with collagen; 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 cm to 8 cm in size.[3][11]

Fibrous tumors often have a very delayed diagnosis, as they arise from deep tissue and cause painless soft-tissue swelling. It is usually 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 are 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]

The most frequent presentation of bony fibrosarcoma is chronic dull pain with or without soft tissue swelling. Patients with tumors around joints usually present with a limited and painful range of motion.[12]

Evaluation

Radiographic imaging is the first diagnostic step when history and physical examination suggest a diagnosis of a malignant soft tissue tumor. Contrast-enhanced magnetic resonance imaging (MRI) is the preferred procedure to evaluate tumors of the extremities or pelvis and will provide information about 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. The displacement of surrounding tissue will be demonstrated.[3]

If imaging suggests the presence of a soft tissue malignancy, a core needle biopsy is warranted, as a fine needle aspiration (FNA) has been criticized as unsatisfactory for making an accurate initial diagnosis. However, FNA has utility in monitoring progression and identifying tumor recurrence or metastasis if previous cytological studies are available for comparison. Finally, more invasive surgical biopsies may be warranted in tumors where minimally invasive biopsy techniques have failed or are untenable. Excisional biopsy is generally recommended when you suspect a soft tissue sarcoma of 3 cm to 5 cm in size, whereas partial incisional biopsies are appropriate when tumor size exceeds 5 cm.[3][11][13]

A fibrosarcoma's radiological appearance is comparable to an osteoid osteogenic sarcoma. Fibrosarcoma of bone usually appears irregular in shape and is osteolytic in nature. The periosteal reaction is minimal, however, the lesion has a moth-eaten appearance. These sarcomas are intramedullary and typically metaphyseal but can extend to the diaphysis. Technetium-99m bone scanning reveals a hot spot around the pathological area. MRI may be the most appropriate modality for determining the lesion size, neurovascular involvement, and extraosseous extent of fibrosarcoma.[14]  

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 extra-compartmental growth, or if the tumor does not reach the origin or insertion of the muscle, a wide-surgical resection would be appropriate to obtain tumor-free margins. Two centimeters of margin is generally recommended; however, no definitive evidence exists for the best safety margin. Surrounding structures such as nerves and vascular structures must always be considered.[15](B3)

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 managing 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 using 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 to 11% of sarcoma patients treated with standard chemotherapy. Similarly, fibrosarcoma of bone is treated with multiagent chemotherapy with wide resection. These tumors have a high rate of recurrence. [12]

Finally, intratumoral injections of matrix metalloproteinase inhibitors such as TIMP-1-GPl fusion protein have been shown to lead to a decreased tumor mass and growth. Furthermore, injection shows inhibition of cell migration and increased tumor cell apoptosis.[3][16](B2)

Differential Diagnosis

The diagnosis of 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.[2][5]

Medical Oncology

Adult fibrosarcoma is a very aggressive subtype of soft tissue sarcomas with a recurrence rate of approximately 50%. Fibrosarcomas tend to respond poorly to chemotherapy, which may be attributed to their intrinsic resistance to chemotherapeutic agents.[17]

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 the MAID protocol, an integrated chemoradiation program, has shown benefits in high-grade soft tissue sarcomas, including fibrosarcomas, with a lower rate of recurrence and metastasis and an improvement in survival.[18][19][20]

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% to 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.[21][22]

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%, a disease control rate of 82%, and better tolerance with Apatinib, a VEGFR 2 inhibitor, compared to standard second-line chemotherapy.[23][24] 

There is emerging data regarding the efficacy of immunotherapy in soft tissue sarcomas. Combining chemotherapy with pembrolizumab has shown some promising results in phase 1/2 nonrandomized clinical trials. Further studies are warranted to explore its benefits in patients with soft tissue sarcomas, including fibrosarcomas.[25][26]

Staging

Netherlands Committee on Bone Tumours (1966) [27]

• Grade 1- Well-differentiated tumor
• Grade 2- Moderately differentiated tumor
• Grade 3- Poorly differentiated tumor

Prognosis

As discussed above, 80% of adult fibrosarcomas are determined to be high-grade (Grades 2 or 3). Furthermore, 25% of the remaining low-grade lesions progress to a local recurrence of high-grade fibrosarcoma. These tumors are aggressive, with many local recurrences as well as lymph and parenchymal metastases. The survival of adult fibrosarcomas is <70% at 2 years and <55% at 5 years. In comparison to intraosseous fibrosarcoma, soft-tissue fibrosarcoma is regarded to have a better prognosis.[5][28][29]

Complications

As the mainstay of treatment for fibrosarcoma is surgical, complications are the same as any other surgery, including 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, the mainstay of treatment, is classically associated with an increased risk of dilated cardiomyopathy.[30]