Pediatric Liposarcoma

Liposarcoma is one of the least frequent nonrhabdomyosarcoma soft tissue sarcomas to occur in childhood; it comprises less than 5% of all soft tissue sarcomas in childhood.[1, 2] Surgical excision is the primary treatment, and prognosis depends on the histologic subtype and degree of resection. For patients with residual disease, radiotherapy has been used.[1]

Liposarcoma is a lipogenic tumor of large deep-seated connective tissue spaces. The 3 major locations in which liposarcomas are found are the lower extremities, the retroperitoneal region, and the shoulder area. The favored sites of occurrence in the lower extremities include the popliteal fossa and medial thigh. The most common retroperitoneal location is the perineal region. Occasionally, tumors may originate in the subcutis of shoulder, neck, and facial areas. Children tend to have a higher incidence of lower extremity tumors.[3]

Three distinct subgroups based on clinicopathologic and cytogenetic features have been identified: well-differentiated/dedifferentiated, myxoid/round-cell, and pleomorphic.

Well-differentiated/dedifferentiated liposarcoma has amplification of region 12q13–15, which includes the genes MDM2 and CDK4.[4]  Next generation sequencing identified 27 mutations in addition to amplification of MDM2 and CDK4. Two of these mutations, NF2 and EGFR, were driver mutations and potentially actionable.[5]

Myxoid liposarcoma has the translocation t(12;16)(q13;p11.2). This involves fusion of the transcription factor gene CHOP (DDIT3), which is essential for adipocytic differentiation, to the translocated in liposarcoma (TLS) or FUS gene on chromosome 16.[6] In about 2% of cases, a variant translocation t(12;22)(q13;q12) that involves fusion of CHOP (DDIT3) with the EWSR1 gene on chromosome 22 is noted. These cytogenetic abnormalities have also been reported in the more aggressive round-cell liposarcoma; myxoid and round-cell liposarcoma form a spectrum with regard to disease aggressiveness.[7]

Pleomorphic liposarcoma lacks identifiable translocations or gene amplification and was characterized by its clinical and pathologic aggressiveness. The introduction of molecular biological analysis suggests that many of these tumors express MDM2 and CDK4 and may better be described as dedifferentiated liposarcoma.[8]

In retrospective review of 331 liposarcoma samples, the use of molecular techniques in addition to standard histology resulted in a change in the type of liposarcoma diagnosed in approximately one-quarter of patients.[8]

Frequency

United States

In children, liposarcomas are rare and comprise fewer than 5% of soft tissue sarcomas.

Overall, less than 150 cases of childhood liposarcoma have been reported in the literature, usually in the second decade of life.[9, 10] At a large New York Cancer Hospital, 18 cases of liposarcoma were reported in patients aged 22 years or younger over a period of 4 decades.[11] A multi-institutional study reviewed 82 patients younger than 22 years diagnosed over a 27-year period.[12]

Mortality/Morbidity

Due to its rarity, survival data for liposarcoma patients are often extrapolated from small series or from adult data. As with other childhood nonrhabdomyosarcoma soft tissue sarcomas, outcome is linked to various prognostic factors, including stage and grade. Complete surgical resection is crucial. The estimated 5-year overall survival rates are impacted by histologic subtype and are as follows:[8]

• Pleomorphic tumors - 40%

• Round-cell tumors - 40%

• Myxoid tumors - 80%

• Well-differentiated tumors - 80-100%

Local recurrence following resection is common and may be avoided by wide excision or adjuvant radiation. Thus, an extremity location, which allows aggressive surgery, is a favorable prognostic feature as opposed to a retroperitoneal location.

Metastatic spread varies but commonly occurs to the lungs in high-grade pleomorphic tumors.[13] Lymphatic spread is not seen. Myxoid liposarcoma is often considered intermediate grade but may still metastasize in 10-35% patients, sometimes to extrapulmonary soft tissue sites, such as the retroperitoneum or chest wall[14] or even brain and spine.[15]

Race

No racial predilection is apparent.

Sex

In the several small series reported, gender predominance varies; assessing an accurate male-to-female ratio is not currently possible.

Age

Overall, the average age at presentation is 50 years. Liposarcomas are rarely seen in the teenage years and are almost never found in patients younger than 8 years. Earlier reports of liposarcoma in infancy are now mostly thought to be lipoblastomatosis.[3]

Presentation varies, but the tumor usually presents as a painless slow-growing lesion. Only 10-15% patients have a painful rapidly growing mass or functional limitations. Depending on the location and involvement of adjacent structures in the extremity, weakness or limitation of motion may be observed. Rarely, nonspecific symptoms, such as weight loss, fatigue, and lassitude, may also be observed.

Fascial compartmentalization may cause soft tissue sarcomas to adopt awkward discoid and fusiform shapes rather than smooth round forms. A fairly well-circumscribed palpable mass slowly increasing in size over many months appears to be the first manifestation of disease in many patients.

Pain is not often a prominent manifestation. Diffuse abdominal enlargement may be observed in patients with retroperitoneal disease. Characteristics of the primary tumor, such as size, texture, and mobility, are important to note. The neurovascular status of the involved extremities distal to the tumor should be evaluated. Palpation of draining lymph nodes usually does not reveal disease.

Although the precise etiology of liposarcomas is not yet defined, the presumed origin likely involves terminal dedifferentiation of mesenchymal cellular components. For myxoid/round-cell liposarcomas, the TLS-CHOP oncoprotein plays a key role in tumor formation.[16, 17] No specific causative environmental factors have been identified because of the rarity of these tumors.

CT scanning and MRI of the primary tumor may provide complementary findings in patients with liposarcoma.[18] CT scanning is superior to MRI in detailing cortical bone erosion and tumor mineralization.

MRI is useful in providing views of the long axis of the limb and can sometimes depict the fatty nature of the tumor. Different subtypes exhibit varying signal characteristics.[19] For example, myxoid liposarcomas have low signal on T1W, high signal on T2W, and thickened septa on postcontrast images. Round-cell liposarcomas and pleomorphic liposarcomas lack characteristic fat signal and look similar to other soft tissue sarcomas.

Angiography may reveal malignancy based on prominent vascularity and, thus, may be of value in planning surgical resection.

Fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging may also reveal malignancy, based on intensity of FDG activity.[20] It is also useful to diagnose bone metastases and might be more sensitive than bone scanning.[21]

Chest radiography may be used as initial screening for pulmonary metastases; however, the definitive modality used to detect pulmonary metastases is chest CT scanning. CT scanning of the chest and abdomen may be needed to evaluate for extrapulmonary metastatic spread, which may be seen with myxoid liposarcoma.

The diagnostic procedure of choice is open biopsy. Minimally invasive procedures have been advocated, such as fine needle aspiration; however, experience with these modalities is limited, and results have been equivocal.

For superficially located small fatty tumors, excisional biopsy is recommended for diagnosis.

For larger (>3 cm) and deeper tumors, diagnosis and treatment may involve open incisional biopsy followed by definitive resection.

Gross appearance can widely vary from tumor to tumor. Usually, the tumor displays smooth, lobulated, or nodular masses that are both encapsulated and freely movable. Upon section, fine fibrous septa can be observed dividing the tumor into smaller lobules. Areas of necrosis and recent and old hemorrhage are not infrequent. Calcification and ossification are uncommon.[22]

Several histologic subtypes are recognized; the 4 primary subtypes are well-differentiated, myxoid, round cell, and pleomorphic. Myxoid is the most common subtype. In a series of 82 patients younger than 22 years, myxoid liposarcomas accounted for 70-90% of tumors analyzed. This histologic finding is the very important since most myxoid subtypes are low-grade tumors with an excellent prognosis.[12]

Well-differentiated liposarcomas are low-grade lesions composed of a heterogeneous organization of univacuolate adult lipocytes, chronic inflammatory cells, and fibrous connective tissue. This fibrous matrix harbors an arrangement of fat-storing stellate-shaped cells. Neoplastic cells with large hyperchromatic and pleomorphic nuclei are scattered within the region. Fat necrosis and mitosis usually are not observed. However, 10% are dedifferentiated, with a pattern of a densely cellular spindle-shaped sarcoma without fat accumulation and a clinically aggressive course.

Myxoid liposarcomas occur in various forms based on the degree of cellularity. Basic features of this subtype include (1) proliferating lipoblasts in various stages of differentiation, (2) delicate plexiform capillary patterns, and (3) a myxoid matrix containing abundant hyaluronidase-sensitive acid mucopolysaccharides. The least cellular pattern is a low-grade tumor harboring small spindle-shaped cells. These cells surround a plexiform vascular pattern that contrasts with a background of extracellular acid mucopolysaccharide. The most cellular pattern is that of a round-cell liposarcoma containing densely packed uniformly round cells that overcrowd the plexiform vasculature. In reality, most myxoid-type lesions have a mixture of the above features.

Round-cell liposarcomas are associated with an aggressive clinical course and a high frequency of metastases. These are high-grade tumors, and their primary feature is an excessive proliferation of uniform and rounded cells with little intercellular myxoid material. Occasionally, cells are arranged in branching rows and strands along abortive capillaries, resulting in a trabecular and adenoid appearance. Large pale polyhedral cells often give a hypernephroid appearance to the tumor.

Pleomorphic liposarcomas are high-grade lesions and display a disorderly growth pattern, a large degree of cellular pleomorphism, and several bizarre giant cells. Large giant cells may be observed harboring numerous lipid droplets of varying size, giving a moruloid appearance to the cells. Nucleoli vary in occurrence. Numerous small polygonal, round, and spindle-shaped lipoblasts can be observed intermingled with giant cells.

Staging for childhood soft tissue sarcomas follows the standard American Joint Committee on Cancer (AJCC) system, which is of limited value. Liposarcomas do not spread to regional lymph nodes, and lymph node dissection is not indicated. Careful imaging is crucial in staging to assess size and presence or absence of metastases. Considering the possibility that a retroperitoneal or chest wall lesion may have a primary in the lower limb is important.

Grade or histologic subtype impacts significantly on prognosis, and an experienced pathologist needs to be involved. Myxoid liposarcomas that have more than 5-20% round-cell component have a worse outcome.

The AJCC staging system is as follows:

• G1 - Low grade

• G2 - Intermediate grade

• G3 - High grade

• T1a - Noninvasive (< 5 cm)

• T1b - Noninvasive (>5 cm)

• T2a - Invasive (< 5 cm)

• T2b - Invasive (>5 cm)

• N1 - Regional nodes involved

• M1 - Distant metastases

Three main modalities exist:

1. Surgery - remains the most important modality and the importance of a complete excision is critical

2. Chemotherapy - pre- or post-surgery

3. Radiation - also pre- or post-surgery

Chemotherapy has been shown to be active in these tumors, but its role needs to be defined in clinical trials. Italian studies showed that the use of neoadjuvant multiagent chemotherapy could decrease the size of the tumor and allow a complete resection.[23]  The role of post-operative chemotherapy has not been defined.

Adult studies have shown some promise in using trabectedin, an unconventional alkylating agent derived from Caribbean sea squirt, which showed a 45% reduction in disease progression compared to dacarbazine in a Phase III study in patients with advanced liposarcoma and leiomyosarcoma who had failed prior therapy.[24]  Unfortunately trabectedin as a single agent has not shown a benefit in pediatric trials.[25]

With better understanding of molecular biology of liposarcoma, targeted therapies have been identified. MDM2 inhibitors such SAR40538 and CDK4 inhibitors such as NVP-LEE011 have shown promise.[26]

Postoperative radiotherapy may be administered.

Surgical objectives include obtaining an accurate histologic diagnosis, minimizing the chance of local recurrence, achieving the best possible functional and anatomic result, and maximizing the probability of survival. Surgery should be performed at a children's cancer center with significant experience dealing with these rare tumors.

Open biopsy must be meticulously performed to avoid hematoma, tumor cell spillage, and postoperative infection. The incision must be oriented so that the biopsy site can be completely encompassed in the definitive resection. A longitudinal incision parallel with the fiber direction of the underlying muscle is used. Under ideal conditions, the surgeon performing the definitive resection also should perform the initial biopsy. Sometimes, performing the incisional biopsy and resection is possible during the same procedure, provided that the frozen section is definitive.

The 3 main techniques of surgical resection used in patients with liposarcoma include simple excision, wide en bloc resection, and amputation. The type of resection used is determined by the tumor's histology and by the anatomic findings at the time of surgery.[27]

If the lesion appears to be grossly and histologically consistent with lipoma or well-differentiated liposarcoma, simple excision is acceptable.

If the mass contains areas suggestive of low-grade liposarcoma with clear margins, simple marginal excision can be curative. When evidence suggesting high-grade liposarcoma is present, either a wider resection of the tumor bed may be performed or adjuvant radiotherapy may be added.

If preoperative studies (CT scanning, MRI, biopsy specimen analysis) suggest a high-grade lesion, either wide en bloc resection or amputation can be planned. Avoid shelling out a high-grade tumor because microscopic disease is left behind. In patients in whom amputation is under serious consideration (either as an initial procedure or following a limb-sparing operation), preoperative education is imperative.

In upper extremity tumors, axillary dissection is not performed unless the nodes feel abnormal.

For lesions in which malignancy is strongly suspected or in which a previous incisional biopsy has revealed liposarcoma, consultation with pediatric oncologist is recommended prior to the definitive surgical procedure.

Adjuvant therapy may be indicated in patients in whom excision is incomplete or when close margins are noted along with concern about microscopic residual disease. Consultation with a radiation oncologist is recommended.

Consultation with a physical therapist and referral for rehabilitation may be appropriate, depending on the site of the primary and the degree of surgical resection performed.

The role of adjuvant chemotherapy in soft tissue sarcomas is not clearly defined. Despite the fact that these tumors can respond to chemotherapy,[28] a definitive survival advantage for patients with incompletely resected tumors who are treated with combination chemotherapy has not been established.[23]

Doxorubicin and ifosfamide appear to be the most effective cytotoxic agents for nonrhabdomyosarcoma soft tissue sarcomas. Trabectedin has been shown to delay time to progression.[29, 30] In this setting, chemotherapy is investigational and consultation with a pediatric oncologist who has experience with nonrhabdomyosarcoma soft tissue tumors is required.

Another medical treatment option is sunitinib, a tyrosine kinase inhibitor. A clinical trial of sunitinib in relapsed or refractory disease showed some promising data. More than 40% of patients demonstrated responses, particularly those with liposarcoma, leiomyosarcoma, and malignant fibrous histiocytoma.[31]

Consideration for adjuvant therapy for liposarcoma should be based on the degree of residual disease left behind.

If microscopic disease remains following surgery, postoperative radiation therapy should be administered. External beam radiation doses can range from 4000-6500 centiGray, with dosing to be determined in consultation with a radiation oncologist. In children, long-term effects of radiotherapy, such as skeletal and soft tissue deformation, effects on growth, and risk of neoplastic transformation, should be weighed against the child's current physiologic status and potential for remission from liposarcoma.

If macroscopic disease remains following surgery, radiotherapy, chemotherapy, and second-look surgery should all be considered.

Prognosis depends on the stage, histologic subtype or grade, anatomic location of the tumor, tumor size, and the overall treatment regimen used.

Five-year survival rates range widely vary, depending on histologic subtype.

Based on histologic characteristics alone, myxoid lesions, which occur commonly in children, have 5-year survival rates approaching 80%.

In contrast, rare highly-aggressive pleomorphic lesions have 5-year survival rates around 20%

With any histologic subtype, local recurrence is common and is related to the completeness of surgical excision. If metastases occur, they typically involve the lungs, but unusual extrapulmonary soft tissue sites such as retroperitoneum or chest wall may be involved.