Chest Wall

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2017, Case 40, and is atypical lipomatous tumor of the chest wall.

Sections reveal a well-circumscribed tumor composed of lobules of mature adipocytes showing variation in cell size. The lobules are separated by fibrous septae containing spindle stromal cells with hyperchromatic, atypical nuclei. Few cells with cytoplasmic vacuoles consistent with lipoblasts are identified. These features are consistent with a diagnosis of atypical lipomatous tumor (ALT).

ALT is a mesenchymal neoplasm with adipocytic differentiation and intermediate biologic potential; it accounts for about 40% of all liposarcomas, representing the most common variant of liposarcoma in adults. ALT occurs in middle age to elderly adults and does not favor a gender. Common sites of involvement are the extremities followed by retroperitoneum, paratesticular area, mediastinum, and head and neck.

ALT is synonymous with well-differentiated liposarcoma (WDL); however, in the (2013) World Health Organization classification of soft tissue tumors only the ALT diagnosis is retained. The authors point out that the choice to use ALT versus WDL is dependent on the tumor location and resectability and not on the histological features. Tumors arising on the limbs or trunk, where complete resection is achievable, are diagnosed as ALT. At these sites, complete excision is usually curative and thus a diagnosis of sarcoma is not warranted. On the other hand, for tumors arising in the retroperitoneum, mediastinum, or spermatic cord, complete excision is often impossible. Such tumors are characterized by uncontrollable recurrences, which may lead to death even in the absence of distant metastases. For such tumors, the term WDL is usually employed to reflect the potential for disease progression.

Gross examination usually reveals a large, well-circumscribed mass with a yellow to white lobulated cut surface. Areas of fat necrosis and hemorrhage may be seen in large lesions. Rarely, an infiltrative pattern may be encountered.

Histologically, ALT can be divided into three subtypes: lipoma-like, sclerosing, and inflammatory. The lipoma-like ALT is composed predominantly of mature fat, which in contrast to the fat of a benign lipoma demonstrates variation in cell size. A variable number of spindle cells with atypical, hyperchromatic nuclei and multivacuolated lipoblasts are noted. Of note, the presence of lipoblasts is not required for a diagnosis of ALT.

The sclerosing form of ALT is more common in the retroperitoneum and paratesticular area. It is characterized by atypical stromal cells with hyperchromatic nuclei set in a collagenous stroma. Lipogenic areas are limited and can be missed on a small sample. Often ALT show mixed features of both lipoma-like and sclerosing subtypes.

The inflammatory subtype of ALT is less common and occurs more often in the retroperitoneum; it is characterized by a dense lymphoplasmacytic infiltrate associated with features of lipoma-like or sclerosing ALT.

By cytogenetic analysis, ALT demonstrate giant marker and ring chromosomes containing amplified sequences of chromosome 12q13-q15 spanning the locus for several genes including MDM2 and CDK4. ALT show overexpression of MDM2 and CDK4 by immunohistochemistry, which can be used as a diagnostic tool in separating them from lipomas. However, immunohistochemical stains for MDM2 and CDK4 are not entirely specific for ALT as they may be encountered in the nuclei of histiocytes within areas of fat necrosis and rarely in spindle cell/pleomorphic lipomas. Evaluation for MDM2 amplification by FISH is a more sensitive and specific test to diagnose ALT.

Clinical behavior of ALT is dependent of location. They have propensity for local recurrence but do not metastasize. Local recurrence is much less common in tumors involving the extremities compared to mediastinal and groin tumors. A proportion of ALT undergo dedifferentiation (about 5% of tumors involving the extremities and 10% to 15% of mediastinal tumors). Dedifferentiation occurs in persistent tumors after an average time of 7 to 8 years. Dedifferentiated liposarcomas are considered fully malignant tumors with a potential to metastasize.

The differential diagnosis of ALT includes benign lipomatous tumors such as spindle cell/pleomorphic lipoma (SC/PL) or other types of liposarcoma such as dedifferentiated liposarcoma (DL), myxoid liposarcoma (ML), and pleomorphic liposarcoma (PL).

SC/PL is a subcutaneous tumor with a predilection for the posterior neck, back, and shoulders. Originally, spindle cell and pleomorphic lipomas were described as separate entities; however, in more recent classifications they are considered as one entity due to the considerable overlap in clinical, histologic, and cytogenetic features. SC/PLs are characterized by an admixture of mature adipose tissue and bland spindle cells associated with thick “rope-like” collagen fibers. In addition, the classic pleomorphic lipomas contain multinucleated giant cells with a concentric arrangement of hyperchromatic nuclei around an eosinophilic cytoplasm (floret-like giant cells). As opposed to ALT, SC/PLs lack lipoblasts and atypical stromal cells, and do not show MDM2 amplification.

DL is defined as an ALT/ WDL associated with a usually high-grade, non-lipogenic sarcoma. Rarely, DL may demonstrate a low-grade sarcoma or a lipogenic high-grade sarcoma. While the low-grade lipogenic component of DL is indistinguishable from ALT, the presence of a non-lipogenic sarcomatous component of variable grade helps in differentiating DL from ALT.

ML is a malignant lipogenic tumor composed of lipoblasts and immature spindle cells in a myxoid stroma with a characteristic branching vascular pattern admixed in various proportions with a uniform round, non-lipogenic cell component. As opposed to ALT, ML lacks MDM2 and CDK4 gene amplification and demonstrates recurrent translocations t(12;16) and t(12;22) resulting in FUS-DDIT3 and EWSR1-DDIT3 gene fusions, respectively.

PL is a high-grade sarcoma containing pleomorphic lipoblasts. The high-grade histology of the sarcomatous component distinguishes PL from ALT.

1. Which of the following histologic features is required for the diagnosis of atypical lipomatous tumor (ALT)?
   
   
   1. Atypical stromal cells
   2. Circumscription
   3. Floret-like giant cells
   4. Lipoblasts
   5. Lymphoplasmacytic infiltrate
2. Which of the following IHC stains is useful in differentiating ALT from spindle cell/pleomorphic lipoma?
   
   
   1. CD31
   2. Desmin
   3. ERG
   4. MDM2
   5. S100
3. Which of the following statements is MOST accurate about ALT?
   
   
   1. ALT are not known to undergo dedifferentiation.
   2. ALT can be differentiated from well-differentiated liposarcomas by histologic examination.
   3. ALT have a high metastatic potential.
   4. ALT located on the extremities are characterized by a good prognosis.
   5. Mediastinal ALT can be easily resected completely.

1. Doyle LA. Sarcoma classification: An update based on the 2013 World Health Organization classification of tumors of soft tissue and bone. Cancer. 2014;120:1763-1774.
2. Dei Tos AP, Pedeutour F. Atypical lipomatous tumour. In: Fletcher CDM, Bridge JA, Hogendoorn FM, eds. WHO Classification of Tumours of Soft Tissue and Bone. Lyon, FR: International Agency for Research on Cancer, 2013; 33-36.
3. Jo VY, Fletcher CDM. WHO classification of soft tissue tumours: an update based on the 2013 (4th) edition. Pathology. 2014;46:95-104.
4. Sirvent N, Coindre JM, Maire G, et al. Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR. Am J Surg Pathol. 2007;31:1476-1489.
5. Weaver J, Downs-Kelly E, Goldblum JR, et al. Fluorescence in situ hybridization for MDM2 gene amplification as a diagnostic tool in lipomatous neoplasms. Mod Pathol. 2008;21:943-949.

Aleodor A. Andea, MD, MBA
Surgical Pathology Committee
University of Michigan
Ann Arbor, MI

1. Atypical stromal cells (a)
2. MDM2 (d)
3. ALT located on the extremities are characterized by a good prognosis. (d)