Alveolar Soft Part Sarcoma

The Union for International Cancer Control (UICC) or American Joint Committee on Cancer (AJCC) TNM system can be used.

The ASPSCR1-TFE3 fusion protein localizes to the nucleus, where it functions as an aberrant transcription factor, causing c-Met overexpression and activation of c-Met signaling, rendering ASPS cells sensitive to c-Met inhibition in vitro and in vivo. A recent clinical trial of the c-Met inhibitor crizotinib in ASPS reported disease stabilization in most patients, but tumor shrinkage was uncommon. Finally, a mouse model of ASPS driven by conditional expression of an ASPSCR1-TFE3 transgene highlighted the exquisite dependence of ASPS on lactate for growth, which may be linked to its frequent occurrence in muscle and its high expression of the lactate transporter MCT1 and its associated protein, CD147. Cytogenetically, ASPS is defined by a specific alteration, der(17)t(X;17)(p11;q25). Because the der(X) resulting from the t(X;17)(p11;q25) is rarely retained, the der(17)t(X;17) may be described in some cases as add(17)(q25), if the quality of the banding is not sufficient to allow for positive identification of the additional material as coming from the short arm of chromosome X. This translocation results in the fusion of the TFE3 transcription factor gene (from Xp11) with ASPSCR1 (also known as ASPL) at 17q25.3. Depending on the TFE3 intron involved in the genomic rearrangement, ASPSCR1-TFE3 fusion transcripts can differ by the presence or absence of one additional exon of TFE3.

Tumors vary from 1.2 to 24 cm (median: 6.5 cm). They are partially circumscribed and consist of multiple soft fleshy nodules and fibrotic bands. The center of larger lesions often shows hemorrhage or necrosis.

ASPS is composed of large polygonal cells with well-defined cell borders, eosinophilic granular cytoplasm, a rounded central/eccentric vesicular nucleus, and a prominent nucleolus. The cells are arranged in a uniform organoid or nest-like pattern, showing central discohesion resulting in the characteristic alveolar pattern. A rich sinusoidal capillary vasculature is seen throughout; this often encircles tumor nests and imparts a hemangiopericytomatous appearance focally. Vascular invasion is very common. Cytoplasmic clearing, rhabdoid cells, a pseudoglandular pattern, or cystic change with myxoid material may be seen. Nuclear pleomorphism, hyperchromasia, giant cells, mitosis, necrosis, calcification, lymphocytic infiltrate, and xanthomatous features are uncommon. Small cells, non-alveolar growth, and inconspicuous vessels are particularly seen in lingual tumors. Many tumors show intracytoplasmic rod-like/rhomboid crystalline structures, focally or diffusely, in a sheaf-like or stacked configuration. These crystals and the intracytoplasmic granules are PAS-positive/diastase-resistant and are immunoreactive for MCT1 and CD147. ASPS shows nuclear immunoreactivity for TFE3. Immunopositivity for cathepsin K (100%) is also typical. Calretinin (46%) and focally desmin (50%) can be detected.

In cytological preparations, smears reveal large cells, mainly distributed singly, with granularity or vacuoles.

ASPS is not formally graded but is regarded as high-grade by definition. Local recurrence occurs in 11–50% of cases. Metastases involve the lungs, liver, bone, brain, and (rarely) lymph nodes, often ≥ 10 years after diagnosis. The overall survival rate is 82% at 2 years and 56% at 5 years. Negative prognostic factors include older age, tumor size > 10 cm, distant metastasis at diagnosis, and a primary site in the trunk. Tumors detected early, at a completely resectable stage, such as lingual ASPS, have a better prognosis.

Demonstration of TFE3 rearrangement or ASPSCR1-TFE3 fusion transcripts may be diagnostically helpful. Although the presence of the ASPSCR1-TFE3 fusion appears to be highly specific and sensitive for ASPS among sarcomas, the same gene fusion is also found in a small but unique subset of renal cell carcinomas, often affecting young patients.

Essential: eosinophilic polygonal cells in an organoid/nested pattern; rich sinusoidal capillaries and intracytoplasmic crystals (in some cases); TFE3 nuclear expression by immunohistochemistry (strong and diffuse).

Desirable: demonstration of TFE3 gene rearrangement or ASPSCR1-TFE3 fusion (in selected cases).