Well-Differentiated Liposarcoma

Well differentiated liposarcoma is a locally aggressive, non-metastasising adipocytic neoplasm with amplification of MDM2 and CDK4 at 12q13-15. The same entity is called atypical lipomatous tumour when it arises in the limbs, trunk or other sites where complete excision is feasible, and well differentiated liposarcoma in the retroperitoneum, mediastinum or spermatic cord.

It is the commonest liposarcoma subtype, making up 40% to 45% of liposarcomas. Liposarcoma accounts for 15% to 20% of soft tissue sarcomas. Peak age is 50 to 70, and the sites are deep thigh, retroperitoneum, paratesticular region and trunk.

No inherited syndrome is established, and risk factors are unknown.

Pathophysiology. Supernumerary ring or giant marker chromosomes carry amplified MDM2, CDK4 and HMGA2. MDM2 inhibits p53, and CDK4 drives cell cycle progression. MDM2 amplification by FISH, or nuclear MDM2 and CDK4 positivity, defines the diagnosis.

Histology. Mature adipocytes with variable size, atypical hyperchromatic stromal cells and lipoblasts in some cases. Variants are lipoma like, sclerosing, inflammatory and spindle cell types.

Behaviour. Metastasis is essentially absent unless dedifferentiation occurs. Dedifferentiation risk is under 2% in limb tumours and up to about 20% in retroperitoneal tumours over long follow up. Local recurrence is about 10% to 15% after marginal limb excision and up to 40% to 80% over 10 years in the retroperitoneum, where death comes from uncontrolled local disease.

• Slowly enlarging painless deep mass in the thigh or buttock. Retroperitoneal tumours grow silently to a very large size.
• Retroperitoneal symptoms: abdominal distension, early satiety, discomfort, change in bowel habit, urinary symptoms, oedema of the leg, and a palpable mass.
• Paratesticular tumours present as a scrotal or inguinal swelling.

Red flags.

• Rapid growth, new pain, or a new non-fatty enhancing nodule within a fatty mass (dedifferentiation).
• Obstruction, bleeding, hydronephrosis or venous compression.

• MRI (limb) or CT with contrast (retroperitoneum): fat containing mass (over 75% fat) with thick septa or small non-fatty nodules. A simple lipoma lacks septal enhancement.
• Percutaneous core biopsy (for any fatty mass over 10 cm, deep or with septa) with MDM2 FISH or MDM2 and CDK4 immunohistochemistry. Biopsy is done in a way that allows the tract to be removed at surgery.
• Retroperitoneal staging: CT abdomen and pelvis. Chest CT is not essential for pure well differentiated tumours.
• Baseline renal function (split function if nephrectomy is anticipated).

Differential diagnosis.

• Lipoma and lipoma variants (spindle cell, pleomorphic, hibernoma)
• Dedifferentiated liposarcoma
• Other liposarcoma subtypes
• Angiomyolipoma and adrenal myelolipoma
• Teratoma
• Retroperitoneal fat necrosis or fatty hernia

Limb and trunk (atypical lipomatous tumour). Marginal or wide excision, preserving function, with complete excision of the tumour with its pseudocapsule. Radiotherapy is not routine. Recurrences are re-excised.

Retroperitoneal. Surgery by an experienced sarcoma centre, with en bloc resection of adjacent organs (kidney, colon, psoas) as needed, aiming at complete resection with negative margins. Preoperative radiotherapy (50.4 Gy in 28 fractions) is considered, since the benefit in local recurrence is seen mainly in this subtype. Postoperative radiotherapy is not advised for retroperitoneal disease because of toxicity.

Paratesticular. Radical inguinal orchidectomy with high ligation of the cord and wide excision of scrotal soft tissue.

Systemic therapy. Response rates are low. It is reserved for unresectable symptomatic progression, with the decision made by a sarcoma multidisciplinary team. Agents targeting CDK4 and MDM2 remain investigational.

Monitoring. Retroperitoneal: CT or MRI every 3 to 6 months for 2 to 3 years, then every 6 months to year 5, then annually, with lifelong follow up because recurrence occurs beyond 10 years. Limb: MRI at 6 to 12 months intervals for 5 years, then annually.

Referral and escalation.

• All deep fatty tumours over 5 cm or with septal or nodular enhancement are referred to a sarcoma centre before excision.
• Re-excision of a tumour excised without prior imaging or biopsy is planned by the sarcoma team.
• Urgent review for bowel or ureteric obstruction.

Special groups.

• Older adults: surgery for symptomatic limb or retroperitoneal disease, with observation of small asymptomatic lesions after discussion.
• Mediastinal and spermatic cord sites need site specific surgical teams.