Infantile Fibrosarcoma in Older Child at Right Lower Leg: A Case Report

Background

Approximately 8% of all pediatric malignancies are soft-tissue sarcomas (STS), generally split into rhabdomyosarcoma (RMS) and non-RMS-STS. Fibrosarcoma is a non-RMS-STS that affects adults and children, with the prognosis often being better for younger individuals [1]. Infantile fibrosarcoma (IFS) is a rare tumor, with the highest prevalence early in life, with over 75% of cases recorded in the first year of life and 15% in the second year of life [2,3]. Fewer than 15% have already been discovered at prenatal ultrasonography screening [4].

Nearly 50% of IFS cases occur in the extremities. IFS typically manifests with rapid initial growth, occasionally followed by a more indolent course, as a non-tender, poorly delimited mass that varies in size and consistency, and lacking sensitivity [3,6]. IFS has a lower likelihood of metastasis (10%), a greater chance of long-term survival (90% at 5 years), and more chemosensitivity than the adult variety of fibrosarcoma [5].

Primary tumors are deemed unresectable at diagnosis in 48–62% of cases, necessitating a multimodal approach with preoperative cytoreductive and local therapy, including conservative surgery. In recent decades, surgical excision has been the main treatment. Primary excision may involve an invasive and potentially painful procedure with a higher morbidity; therefore, surgical treatment may be needed in addition to chemotherapy and radiotherapy for some illnesses [6]. Because of its rarity, this report presents our experience treating a case of IFS.

Case Report

A 4-year-old girl was admitted to our hospital with a chief concern of a mass in the right lower leg 3 years ago. The mass initially resembled a mosquito bite but progressively grew to the size of a chicken egg 1 year ago. The mass was operated on 3 months ago in another hospital, with a diagnosis of hemangioma. After surgery, the mass proliferated. The family denied any history of drastic weight loss.

The vital signs showed an axillary temperature of 36.3°C, a pulse of 94 beats/minute, and respiration of 20 times/minute. O2 saturation was 99% on room air.

On physical examination, the local status of the right lower leg showed a single mass with dense-rubbery consistency that was fixed and tender. The circumference of the healthy lower leg was 17.5 cm, while the affected leg was 15.5 cm (Figure 1). The knee range of motion (ROM) was limited, with ROM knee flexion-extension 0–40°. Visual Analog Score (VAS) was 7/10.

Laboratory tests showed WBC count 11 610 leukocytes/μl, platelets 263 000/uL, hemoglobin 11.40 g/dL, C-reactive protein (CRP) 0.02 mg/Dl, alkaline phosphatase 250 U/L, and lactate dehydrogenase (LDH) 267 U/L.

A chest X-ray taken at admission showed no abnormalities. Plain radiography of the right cruris AP/lateral view was performed and revealed: (1) no visible misalignment between joints; (2) no osteolytic, osteoblastic, or fracture line lesions; (3) no visible joint space narrowing; (4) a soft-tissue mass is seen on the anterior 1/3 distal cruris of the right side; The conclusion is that there is a soft-tissue mass in the anterior side of the 1/3 distal right cruris, with no bone involvement (Figure 2).

A CT Angiography of the lower extremity showed: (1) a bulging soft-tissue mass, solid (38 HU), isodense, oval in shape, clear boundaries and regular edge extra-muscular measuring ±2.8×3.1×4.7 cm in the distal 1/3 region of the right cruris, which on contrast administration showed visible abnormal contrast enhancement, with the lesion appearing to be feeding from the anastomosis of the anterior tibial artery and the draining vein of the anterior tibial vein; (2) no stenosis/dilatation of the arteries and veins in the right lower extremity was seen. In conclusion, imaging showed a bulging, extra-muscular, soft-tissue mass in the distal 1/3 region of the right cruris, feeding from the anastomosis of the right anterior tibial artery and draining vein of the right anterior tibial vein (Figure 3).

A right cruris MRI examination without/with intravenous contrast was performed, which showed: (1) a soft-tissue mass with isointense TIWI, hyperintense, T2WI/PDFS, partially restricted DWI, strongly enhanced after the addition of contrast, flow void appearance (−), lobulated surface, size ±1.9×2.9×4.7 cm, involving cutaneous-subcutaneous fat of the anterior distal compartment of the right cruris; (2) the mass appeared to be attached to m. extensor hallucis longus, m. tibialis anterior, and m. extensor digitorum longus, and enclosing the capillaries around it. Deep down, there was peri-osseous enhancement; (3) no a/v involvement of the right tibialis anterior, a/v. right posterior tibialis; a/v. of the right peroneus, and nerves; (4) no bone marrow changes were seen in the right tibia or fibula; (5) no involvement of the right talocrural articular was seen. In conclusion, we found an aggressive, superficial, soft-tissue mass in the cutaneous-subcutaneous compartment of the distal anterior region of the right cruris, with suspicion of a reactive peri-osseus lesion (Figure 4).

The right cruris tissue biopsy showed the presence of spindle mesenchymal tumor dd infantile fibrosarcoma dd fibrosarcomatous dermatofibrosarcoma protuberans. Immunohistochemistry examination with EMA, Ki67, SMA, CD34, and desmin antibodies showed EMA-negative in tumor cells (Figure 5), Ki67-positive in 15% of tumor cell nuclei (Figure 6), SMA focal-positive in approximately 40% of the tumor cell cytoplasm (Figure 7), CD34 focal-positive in approximately 50% of the tumor cell cytoplasm (Figure 8), and negative desmin in the tumor cell cytoplasm (Figure 9). We were unable to exclude immunophenotype, infantile fibrosarcoma, or fibrosarcomatous dermatofibrosarcoma protuberans.

Another immunohistochemistry examination with S100 and CD68 antibodies showed focal-positive S100 results of approximately 40% in the nucleus and cytoplasm of tumor cells (Figure 10), CD68 stained patchy on the cell membrane of histiocytes between tumor cells (Figure 11), and TLE1-negative in tumor cells (Figure 12). In conclusion, the immunophenotype results were more consistent with infantile fibrosarcoma.

The patient underwent wide local excision. The excised tumor tissue was examined for pathological anatomy consistent with infantile fibrosarcoma with surgical margins distal (tumor-free with a distance of 7 mm), medial (tumor-free with a distance of 4 mm), lateral (tumor-free with a distance of 7 mm), proximal (there was still a tumor, no radical). The tumor’s edge and the muscle’s edge were 4 mm apart. The tumor was adjacent to the bone. The patient’s family chose to forego chemotherapy and radiotherapy and decided on palliative care.

Discussion

Most infantile fibrosarcomas are diagnosed in patients aged 2 years old, have a herringbone or fascicular development with dividing bundles of the spindle to oval-shaped cell lines, blended inflammatory processes, and hemangiopericytoma-like stag-horn vessels, and fulfil these allelic criteria: ETV6-NTRK3 fusion or translocations of the NTRK1, BRAF, and MET genes [7]. Adult fibrosarcoma is more aggressive than the infantile form and involves a complex treatment. The infantile form generally has a better prognosis than the adult form [8].

Fibrosarcomas originate from mesenchymal cells, which consist mainly of spindle cell fibroblasts with uncontrolled proliferation. There is, nevertheless, an astonishing histologic diversity; some can exhibit a poorly structured pattern of immature and even primitive mesenchymal cells, while others can contain a varying number of inflammatory cells admixed with mesenchymal cells [9]. Fibrosarcomas have been reported as most commonly originating in the tendons and deep fascial tissues, but may also occur within the medullary canal or the periosteum of the bone [8]. Fibrosarcoma typically develops in collagen-rich connective tissue regions and multiplies within a few weeks. A tumor with a deep location may go undiagnosed for an extended period. Various symptoms may develop when the invading tumor compresses the surrounding tissue and organs, including micturition difficulties, discomfort, impaired blood circulation, and limited movement [10].

Infantile fibrosarcoma (IFS) is more prevalent in boys (60%) and primarily affects the lower and upper distal extremities (72%). Clinically, the most frequent manifestation of IFS is a distal, growing mass with no distinct limits. In rare instances, the surface is necrotic or ulcerative, mimicking vascular malformations such as hemangioma, and histology reveals a hemangiopericytoma-like structure. In addition, IFS can manifest with significant bleeding from the tumor and mimic Kasabach-Merrit syndrome (the combination of a rapidly growing vascular tumor, thrombocytopenia, microangiopathic hemolytic anemia, and consumptive coagulopathy), resembling a kaposiform hemangioendothelioma [11]. This tendency of IFS to mimic other tumors may interfere with the correct diagnosis and is believed to be one of the reasons for its rarity.

The cytogenetic investigation using RT-PCR (real-time polymerase chain reaction) and FISH (fluorescent in situ hybridization) may identify several defects unique to congenital infantile fibrosarcoma. IFS demonstrated a unique reciprocal translocation, t(12;15)(p13;q25), resulting in ETV6/NTRK3 gene fusion. Via the adaptor IRS-1, the ETV6/NTRK3 protein is involved with many signalling cascades, including Ras-MAP kinase and PI3KAKT. Several cell lineages may be susceptible to its impact, including fibroblasts, hematopoietic cells, and breast epithelial cells. As a result, this translocation becomes a pathognomonic feature of infantile fibrosarcoma [9].

A novel therapeutic approach has been discovered that effectively treats patients based on particular genomic mutations, rather than their anatomical location. Several drugs, such as Larotrectinib, repotrectinib, entrectinib, crizotinib, selitrectinib, lestaurtinib, and others, have been developed to treat solid tumors that have neurotrophic TRK (NTRK) gene fusion by inhibiting tyrosine receptor kinase (TRK) [12–15]. A number of these pharmaceutical agents exhibit significant efficacy against various forms of cancer that bear TRK fusions, such as sarcoma, and across diverse age groups of patients. The utilization of neurotrophic tropomyosin receptor kinase (TRK) inhibitors that are targeted has been identified as a viable and precise therapeutic alternative for patients diagnosed with infantile fibrosarcoma (IFS) who possess the NTRK gene translocation. New therapeutic agents often elicit a prompt and substantial tumor reaction, giving a promising prognosis [16]. Cytogenetic investigation can detect any changes in certain chromosomes that may be a sign of a genetic disease or condition or some types of cancer. In cases of infantile fibrosarcoma, cytogenetic or molecular examinations do not always have to be performed [17].

On magnetic resonance imaging (MRI), infantile fibrosarcomas present as diverse soft-tissue masses with well-delineated or encroaching tumor boundaries. They may have fibrous streaks with a weak signal intensity. In both T1- and T2-weighted imaging, intralesional signal voids caused by vascular and hemorrhagic components may be hyperintense. T1 (usually hypointense to isointense to muscle), T2 (generally hyperintense signal intensity), and T1 C+ (Gd) are common signal characteristics (heterogeneous predominantly peripheral enhancement) [2].

Lymphadenectomy is typically unnecessary since IFS seldom metastasizes to lymph nodes, and there was no lymph node enlargement in our patient. Rather than radical ablative surgery, extensive local excision is the initial surgical procedure of choice for IFS patients. Complete excision with negative resection edges is the objective, although it is sometimes difficult to achieve because malignant tumors circumnavigate and penetrate neurovascular connections and can substitute muscle units. In this circumstance, delaying surgery is advised [5].

Positive postoperative margins have previously been identified as a significant predictive factor [5]. Our patient had positive proximal margins, although not radical. It has been found that children with entirely resected tumors have a 100% 5-year survival rate. However, those with disease remaining after resection and adjuvant treatment were reported to have a 76% 5-year survival rate [18].

Uncertainty remains as to whether chemotherapy is helpful for positive microscopic margins after surgical resection. A patient with a positive surgical boundary did not get adjuvant treatment in our research. Positive surgical boundaries after excision following neoadjuvant chemotherapy do not necessarily predict a poor prognosis [19]. In unresectable instances or cases where major ablative surgery is the only option, the pre-surgical chemotherapy is recommended to reduce tumor growth, followed by resection with no residual or micron-sized residual disease, especially if the tumor’s edges approach the neurovascular system [5].

Large lesions should be treated with neoadjuvant chemotherapy when total surgical excision during the initial procedure is difficult or would entail amputation [18,20]. Neoadjuvant chemotherapy has been recommended to reduce local recurrence and distant metastasis incidence [6,21]. The role of adjuvant chemotherapy following primary surgery is less well-defined. Vincristine, cyclophosphamide, actinomycin-D, and doxorubicin are the most commonly used chemotherapeutic medicines, while ifosfamide and etoposide are used to treat neonates. Radiotherapy is typically not recommended because it can inhibit growth; it is only appropriate for axial primary sites if total resection is impossible [5].

At the time of diagnosis, local relapse is more likely in children younger than 5 years of age. In contrast, distant metastases are more likely in children older than 10 years; the lung is the most common location for IFS metastases [5]. Lung metastases accounted for 20% of all distant metastases. The probability of a local recurrence is as high as 43%; it normally occurs within 1 year of the prior operation, although it can occur 5–31 years after the first resection [21].

Conclusions

Infantile fibrosarcoma (IFS) is an uncommon tumor in early childhood. Local excision is the first-choice treatment, with a good prognosis for IFS. Rather than radical ablative surgery, extensive local excision is the initial surgical procedure of choice for IFS patients. Delayed surgery is required if the malignant tumor cells surround and penetrate neurovascular bundles. Although local relapse is possible, metastases are rare in IFS.