Recurrent YAP1-TFE3 Gene Fusions in Clear Cell Stromal Tumor of the Lung

Abstract

Clear cell (hemangioblastoma-like) stromal tumor of the lung (CCST-L) is a recently described distinctive rare pulmonary neoplasm of unknown histogenesis and molecular pathogenesis. Only 7 cases have been reported in 2 recent studies, although additional cases might have been reported under the heading of extraneural pulmonary hemangioblastoma. We herein describe 4 CCST-L cases, 3 of them harboring a YAP1-TFE3 fusion. The fusion-positive tumors occurred in 3 women, aged 29, 56, and 69 years. All presented with solitary lung nodules measuring 2.3 to 9.5 cm. Histologically, all tumors showed similar features being composed of relatively uniform medium-sized epithelioid to ovoid cells with clear cytoplasm and small round monomorphic nuclei. Scattered larger cells with enlarged hyperchromatic nuclei and marked pleomorphism were noted in 2 cases. The tumors were associated with a hypervascularized stroma with variable but essentially subtle resemblance to capillary hemangioblastoma and perivascular epithelioid cell tumor (PEComa). Immunohistochemistry was negative for all lineage-specific markers. Targeted RNA sequencing showed a YAP1-TFE3 fusion in 3 of 4 cases. All 3 tumors showed homogeneous nuclear TFE3 immunoreactivity. Two patients were disease free at 36 and 12 months. The third patient had biopsy-proven synchronous renal and hepatic metastases, but extended follow-up is not available (recent case). The fourth case lacking the fusion affected a 66-year-old woman and showed subtle histologic differences from the fusion-positive cases, but had comparable TFE3 immunoreactivity. CCST-L represents a distinctive entity unrelated to hemangioblastoma and likely driven by recurrent YAP1-TFE3 fusions in most cases. The relationship of our cases to the recently reported "hemangioblastoma-like" CCST-L remains to be determined. Analysis of larger series is paramount to delineate the morphologic spectrum and biological behavior of this poorly characterized entity.

FIGURE 1

Preoperative CT (A) and PET-CT (B) of case 1 show a well-circumscribed tumor nodule in the left upper lobe of the lung.

FIGURE 2

Representative images of clear cell stromal tumor of the lung (CCST-L). At low-power, the tumors are closely associated with the bronchial tree and look well circumscribed peripherally (A). Confluent central areas of ischemic-type necrosis are seen (B). At low-power, areas with moderate cellularity and vaguely nested pattern with scattered small lymphocytes in the background are seen (C). At high power, the stroma is sparse and the cytology was clear cell to flocculent and pale with histiocytoid appearance (D).

FIGURE 3

Potentially misleading features in CCST-L include thick-walled pericytoma-like vessels (A), scattered bizarre hyperchromatic lobulated likely degenerative nuclei (A, B), spindling with scattered monocular cells resembling inflammatory myofibroblastic tumor (C), entrapped pseudovascular alveolar spaces (D), and prominent entrapment of regenerative alveolar epithelium mimicking salivary-type biphasic lesion (E). Periodic Schiff stain highlights prominent cytoplasmic glycogen (F).

FIGURE 4

By immunohistochemistry, the neoplastic cells of CCST-L lacked expression of any lineage markers but expressed diffusely vimentin (not shown) and TFE3. Note strong, diffuse and homogeneous TFE3 immunoreactivity limited to the neoplastic cells highlighting also the scattered bizarre nuclei (in A) and sparing the entrapped alveolar glands (in B).

FIGURE 5

IGV split-screen view of read alignments of the identified YAP1-TFE3 fusion event of case 1 and 2. Shown are the breakpoints in the YAP1 (left) and the TFE3 locus (right), respectively. Alignments whose mate pairs are mapped to the fusion sequence on the other chromosome are colored ocher. All other alignments are colored grey, green, red and brown.

FIGURE 6

FISH (Case 3) showing break-apart signals for both TFE3 (A) and YAP1 (B), in keeping with gene rearrangements (red, centromeric; green, telomeric).

FIGURE 7

The fusion-negative case showed endobronchial location (A) and a variably collagenized (B) to sparse (C) stroma. The cells had predominantly well-defined borders and clear cell (C); note scattered hyalinized or thin-walled vessels. TFE3 immunoreactivity comparable to other cases was observed in this tumor which lacked a fusion by NGS testing (D).