Liposarcoma

Etiology

The cause of liposarcoma is still unknown. The American Cancer Society has identified some apparent risk factors for soft tissue sarcomas; however, multiple cases exist where patients have no apparent risk factors for the disease. The exact genetic mutation leading to these malignancies is still under investigation. Liposarcoma risk factors identified by the American Cancer Society include radiation (especially radiation therapy used to treat other malignancies), certain family cancer syndromes, damage/trauma to the lymphatic system, and exposure to toxic chemicals. It is important to note that liposarcomas do not develop from lipomas, which are completely benign. 

Epidemiology

Overall, liposarcoma occurrence in the United States is less than 20% of all soft tissue sarcomas. The average age of diagnosis is 50 years of age, although case reports of childhood-onset have been noted.[6] According to the American Cancer Society, liposarcoma is the most common soft tissue sarcoma worldwide. No other predilection for liposarcoma is known. There is no significant association with race or gender. A slight male predominance has been reported in some studies. Liposarcoma of the esophagus is exceedingly rare. The most common esophageal cancer in the United States is adenocarcinoma and worldwide is squamous cell carcinoma. Overall, sarcoma only accounts for 0.5% of all esophageal neoplasms.[7] Among those, only 40 cases of esophageal liposarcoma have been reported.[5] According to these published cases, esophageal liposarcoma tends to occur in the middle to elderly male patients (age range 38 to 83 years, with an average of 62 years; male to female ratio = 4 to 1).[5]

Pathophysiology

Liposarcoma is a complex tumor, and its pathophysiology can be best explained by dividing it into three subtypes (according to the World Health Organization (WHO) classification from 2002). These include well-differentiated and dedifferentiated liposarcoma (WDLPS/DDLPS), myxoid and round cell liposarcoma (MLS and RCL), and pleomorphic liposarcoma (PLS).  WDLPS/DDLPS will have a diagnostic giant marker and ring chromosome, which affects uncontrolled cell proliferation.[8] For MCL and RCL, reciprocal translocation occurs between chromosomes 12 and 16, leading to the fusion of genes DDIT3 and FUS and subsequently activating some downstream targets such as PPARgamma2 and C/EBPalpha, promoting cell cycle proliferation.[8] Pleomorphic liposarcoma is the most complex and least-understood of these. Mutations in various tumor suppressor pathways like p53, NF1, RB1 lead to many gains and account for the aggressive nature of this tumor.[9]

Histopathology

The most common type of esophageal liposarcoma is the well-differentiated type, characterized histologically by mature adipocytes with a variable amount of fibrous stroma containing atypical nuclei. It has three main subtypes, the lipoma-like subtype, the sclerosing subtype, and the inflammatory subtype. The lipoma-like subtype frequently has lipoblasts and scattered atypical cells. This type closely mimics benign lipoma. The sclerosing subtype has abundant fibrous areas with scant lipogenic components. The inflammatory subtype has chronic inflammatory infiltrate, with a predominance of B cells. These cells can pose a diagnostic challenge as inflammatory infiltrate can obscure the adipocytes.

The second most common type of esophageal liposarcoma is myxoid liposarcoma (MLS), subdivided into low-grade and high-grade tumors. Low-grade MLS have low cellularity with bland nuclei and a rich, prominent network of curving capillaries, resembling a chicken-wire pattern. High-grade MLS are markedly hypercellular with solid sheets of round cells comprising at least 5% of the tumor.

The least common type of esophageal liposarcoma is the pleomorphic type, which has marked pleomorphic cells occupying at least 65% of the tumor and at least focal areas of typical liposarcoma.

History and Physical

The history and presentation of liposarcoma are based on the location of the tumor. The most common location for liposarcoma is in the extremities, followed by the retroperitoneum, and, least often, in the esophagus. Myxoid liposarcoma of the extremities presents as a deep mass in the lower extremity. Case reports of primary subcutaneous mass have been reported as well.[10] Most patients with liposarcoma have no symptoms. Symptoms develop only when the tumor grows large enough to exert a mass effect on surrounding structures. These symptoms include pain/tenderness, edema, or functional loss due to impingement of neurovascular bundles. Other reported symptoms include paresthesias, varicose veins, fatigue, weight loss, nausea, and vomiting. Liposarcoma of the retroperitoneum can grow undetected until late stages due to the obscurity of symptoms. Nonspecific abdominal symptoms are the only known symptoms, with the tumor often growing to several pounds or kilograms before diagnosis. 

On physical examination, liposarcoma appears as a non-tender, palpable mass. Patients with retroperitoneal disease may present with diffuse abdominal distention. 

The most common esophageal liposarcoma site is the upper esophagus, which explains most of the symptoms associated with this neoplasm. Patients usually present with progressive dysphagia and weight loss.[5] In some cases, when the size of the tumor is large, patients also present with polyp/mass protruding from the mouth.[11] Regurgitation of food can occur. Shortness of breath and cough due to the compression of the trachea are less common symptoms.[7]

Evaluation

Different radiology diagnostic modalities such as barium swallow, computed tomography (CT) scan, magnetic resonance imaging (MRI) and esophagogastroduodenoscopy, can be used to diagnose liposarcoma. Although none of these techniques is specific, CT scan and MRI can help narrow down the differential diagnosis as both modalities can detect the percentage of a lipomatous component of the tumor. Higher fat content is associated with benign lipoma, while less fat is consistent with atypical lipoma or sarcoma. A definitive diagnosis can only be achieved by tissue examination. In the majority of the cases, complete resection of the tumor is needed for a correct diagnosis.[5]

Most liposarcomas have well-defined and often lobulated margins. Well-differentiated liposarcomas are hyperintense on T2-weighted images, with minimal enhancement using intravenous contrast. Myxoid liposarcomas are homogeneous, which may have a pseudo-capsule on imaging. Pleomorphic liposarcomas have heterogeneous internal structures. Myxoid and pleomorphic tumors show significant enhancement with intravenous contrast on radiologic imaging. 

Pre-operative open biopsy with a subsequent histologic and immunohistochemical evaluation of the specimen is crucial for treatment planning. Specialized stains are used to differentiate liposarcomas from leiomyosarcoma, rhabdomyosarcoma, etc. 

Treatment / Management

Surgical excision is the mainstay of treatment.[1] Wide and deep surgical excision, adjuvant radiation, and/or chemotherapy may be necessary for high-grade lesions. However, liposarcoma response to chemotherapy is not well documented. Therefore, chemotherapy in liposarcomas remains experimental. Radiation therapy may be a valuable adjunct to surgery, especially in the myxoid subtypes. For esophageal liposarcoma, surgery can be either a minimally invasive endoscopic submucosal resection or an aggressive partial or total esophagectomy.[12] There are some case reports of using adjuvant radiation therapy to decrease the rate of recurrence. However, the role of adjuvant chemo and radiation therapy is controversial, and long-term follow-up is recommended due to the high rate of recurrence.[5](B3)

Differential Diagnosis

There are some other benign or neoplastic lesions in the esophagus clinically and microscopically mimicking liposarcoma. First is the typical lipoma, which is composed of benign mature adipose tissue and lacks lipoblasts or any atypical nuclei. Second is the fibroepithelial polyp, which is usually characterized histologically by fibrovascular cores with overlying non-keratinizing squamous epithelium. Although large polyps may have adipose tissue with myxoid areas, closely mimicking myxoid or well-differentiated liposarcoma, they can be ruled out by immunohistochemical stains (fibroepithelial polyp stains negative for either CDK4 or MDM2). Leiomyoma/leiomyosarcoma and gastrointestinal stromal tumor are two other entities that can mimic liposarcoma. Leiomyoma/leiomyosarcoma are composed of intersecting bundles of smooth muscle cells with characteristic nuclei with blunt ends and are immunohistochemically positive for actin and desmin. Gastrointestinal stromal tumor cells are also spindle-shaped but show immunoreactivity to CD34 and c-Kit (CD117).[9]

Staging

Localized malignant tumors of the extremities, as well as the retroperitoneum, are divided into 4 stages according to the Enneking oncologic staging system: IA, IB, IIA, and IIB. Metastatic high-grade intra-compartmental tumors are characterized as stage IIIA tumors, and extra-compartmental malignant tumors are characterized as stage IIIB. These stages are dependent on the tumor classification according to the familiar TNM staging system. In addition to the tumor extent (T), lymph node involvement (N), and presence of metastasis (M), the staging of sarcomas is also dependent on its grade. The French or FNCLCC system is predominantly used to classify sarcomas based on the degree of differentiation, mitotic count, and presence/degree of tumor necrosis. 

Prognosis

The prognosis of liposarcoma depends on several factors. The most important correlation with survival is associated with histologic subtypes, the grade of the tumor, the tumor's location, and the status of surgical margins.[4] A well-differentiated liposarcoma has been reported to have a 50% recurrence rate with no risk of distant metastasis and an excellent five-year survival rate (75% to 100%). In comparison, myxoid and pleomorphic liposarcomas have a higher percentage of recurrence (up to 80%) and a poor to intermediate survival rate (ranging from 4 to 107 months). Undifferentiated liposarcoma has a higher risk of distal metastasis. Positive surgical resection margin is associated with high local recurrence rates and poor survival. Although there are some case reports of using adjuvant radiation therapy to decrease the rate of recidivism, the role of adjuvant chemotherapy and radiation therapy is under debate without a clear consensus. 

Complications

Long-standing esophageal liposarcoma can have serious complications, such as dysphagia and consequent anemia and weight loss, regurgitation-associated aspiration, asphyxiation, and respiratory failure.[13] Other complications of liposarcoma of the extremities and retroperitoneum include local mass effects of the peritoneal cavity, retroperitoneal structures, and neurovascular bundles of the limbs.