Q1. C
Q2. A
Q3. B

Metaplastic thymoma

This presentation is most consistent with a diagnosis of metaplastic thymoma. Metaplastic thymomas are an extremely rare variant of primary thymic epithelial tumors (ie. thymomas) which are characterized by a biphasic histomorphology and a generally benign clinical course.

There are fewer than 100 cases of metaplastic thymoma documented in the medical literature. There is a slight female predilection (M:F ratio = 1:1.5) and the median age of affected individuals is 50 years. These tumors most commonly present with non-specific symptoms (ex. cough) or incidentally with a rounded, solid anterior mediastinal mass on imaging. Myasthenia gravis is not typically associated with these tumors, although isolated case reports of ocular myasthenia gravis in patients with metaplastic thymomas containing multiple intratumoral lymphoid aggregates can be found in the literature. Definitive treatment is complete surgical resection. Recurrence or malignant transformation is exceptionally rare and has only appeared in the literature in isolated case reports.

Correct diagnosis can typically be made upon recognition of the tumor’s classic biphasic morphology on H&E. Metaplastic thymomas generally lack the overly lobulated architecture and thick, fibrous septae which are characteristic of other thymoma subtypes. They are composed of solid-to-trabecular areas of darker epithelioid cells which merge, abruptly or subtly, with lighter areas of fibroblast-like spindle cells with ample cytoplasm. Nuclear irregularities and grooves may be seen, but mitosis are rare or absent. The epithelial component is highlighted by keratins (AE1/AE3 shown in Figure 6) and p40 (not shown), while the spindle cells are negative for p40 and may or may not demonstrate keratin positivity. The spindle cells are consistently positive for vimentin but have been reported to variably demonstrate loss of EMA, whereas EMA is retained in the epithelioid components. Tdt-positive lymphocytes are generally absent, but may be seen at the edge of tumor in adjacent thymic remnants (Figure 2, see upper lefthand corner of image).

More recently, studies investigating the molecular oncogenesis of this tumor subtype have identified rearrangements involving MAML2 and YAP1 in 77-100% of cases. This yields a YAP1::MAML2 fusion gene which combines exon 1 or exons 1-5 on YAP1 with exons 2-5 on MAML2. While presence of this fusion can be confirmed through sequencing or fluorescence in situ hybridization studies, these are generally not considered necessary for rendering the diagnosis. Furthermore, because the fusion gene results from an intrachromosomal inversion on chromosome 11, the split signal from a break apart FISH study may be easily missed resulting in a false-negative interpretation. Recurrent YAP1-MAML2 fusions have been reported in poroma, porocarcinoma, and pediatric NF2-wildtype meningiomas. While understanding of the fusion’s functions remains incomplete, it’s believed to be associated with increased YAP1 signaling and increased activation of the Hippo signaling cascade. Notably, metaplastic thymomas are consistently negative for the GTF2I c.74146970T>A mutation commonly seen in type A and type AB thymomas.

Take-home message for trainees: Don’t automatically assume a spindle cell neoplasm in the mediastinum equates to a type A thymoma or a high grade (sarcoma or carcinosarcoma) neoplasm. Awareness of this entity and recognition that it lacks the features of high grade malignancies (frequent mitoses, prominent coagulative necrosis, significant nuclear atypia, focal heterologous differentiation) will prevent misdiagnosis and potentially unnecessary adjuvant treatments.

den Bakker, MA. Unusual thymoma subtypes. Diagnostic Histopathology. 2022 Dec 16;29(2):105-113.
Liu B, Rao Q, Zhu Y, et al. Metaplastic thymoma of the mediastinum A clinicopathologic,
immunohistochemical, and genetic analysis. Am. J. Clin. Pathol. 2012;137:261–269.

Marx A, Chan JKC, Chalabreysse L, et al. The 2021 WHO classification of tumors of the thymus and mediastinum: what is new in thymic epithelial, germ cell, and mesenchymal tumors? J. Thorac. Oncol. 2022;17:200–213.

Vivero M, Davineni P, Nardi V, et al. Metaplastic thymoma: a distinctive thymic neoplasm characterized by YAP1-MAML2 gene fusions. Mod Pathol. 2020 Apr;33(4):560-565.

Zhao J, Zhao R, Xiang C, et al. YAP1-MAML2 fusion as a diagnostic marker for metaplastic thymoma. Front Oncol. 2021;11:692283.

Emily Shaffer, DO
Cardiothoracic Pathology Fellow ’23-‘24
NYU Langone, New York, NY