Extensive adipocytic maturation can be seen in myxoid liposarcomas treated with neoadjuvant doxorubicin and ifosfamide and pre-operative radiation therapy
Authors: Wang Wei-Lien , Katz Daniela , Araujo Dejka M , Ravi Vinod , Ludwig Joseph A , Trent Jonathan C , Patel Shreyaskumar R , Lin Patrick P , Guadagnolo Ashleigh , Lòpez-Terrada Dolores , dei Tos Angelo Paola , Lewis Valerie O , Lev Dina , Pollock Raphael E , Zagars Gunar K , Benjamin Robert S , Madewell John E , Lazar Alexander J 
Published: December 2012

Abstract

Background
Trabectedin and thioglitazones have been documented to induce adipocytic maturation in myxoid liposarcoma; we have noted this in our experience as well. Intriguingly, we have also encountered this same phenomenon in myxoid liposarcomas exposed to various combinations of neoadjuvant doxorubicin and ifosfamide systemic chemotherapy with preoperative radiation, where the pathological effects have been less characterized. We examined the histological changes, including adipocytic maturation, associated with this treatment in patients with myxoid liposarcoma and evaluated for prognostic significance.

Methods
Twenty-two patients were identified with histologically confirmed myxoid liposarcomas (9 with variable hypercellular areas) who were treated with neoadjuvant doxorubicin (75-90 mg/m2/continous infusion over 72h every 3 week) and ifosfamide (2.5 g/m2 daily x 4 every 3 weeks) for 4-6 cycles. Twenty-one patients received pre-operative radiation including 5 with concurrent gemcitabine. Pre- and post-treatment MRI studies were compared for changes in tumor area, fat content and contrast uptake, with the latter two estimated as: none, <25%, 25-49% and >50%. Post-treatment specimens were evaluated for hyalinization, necrosis and adipocytic maturation. Clinical follow-up was obtained.

Results
Median age was 45 (26-72) years with a median tumor size of 11 (2-18) cm. All occurred in the lower extremities except for one case in the neck. As is common in myxoid liposarcoma, all had extensive treatment changes (>90%) with extensive hyalinization (n = 16; >90%) or prominent adipocytic maturation (n = 6; >50%) including 2 cases composed almost entirely of mature-appearing adipose tissue. Variable necrosis was identified (5-30%). MRI revealed a decrease in tumor area in all but one tumor (median, 65%), an increase in fat content in 7 tumors (n = 2, >50%;n = 2, 25-50%;n = 3,<25%), and a decrease in contrast enhancement in most tumors (n = 5, >50%; n = 9, 25-49%; n = 7, <25%). Median follow-up was 57 (12-96) months with 17 alive with no disease/metastases, 3 alive with disease and 2 dead of disease. Six patients developed metastases with median interval of 26 (22-51) months post resection. Four of 6 tumors with increased adipocytic maturation >50% on histology had increased fat detected by MRI (>25%). All 6 are alive but 2 developed metastases. In the remaining patients, 4 developed metastases with 14 alive and 2 dead of disease.

Conclusion
Myxoid liposarcoma exposed to neoadjuvant doxorubicin and ifosfamide and pre-operative radiation can have prominent adipocytic maturation similar to trabectedin treatment. Myxoid liposarcomas exhibit extensive treatment changes with prominent hyalinization being the most common histological change. Despite this, patients develop metastases regardless of adipocytic maturation. While of unclear significance, no patient with fatty maturation died of disease.