Collision tumors are rare and may comprise components with different behavior, treatments, and prognosis. We report an unprecedented case of aggressive thyroid collision tumor containing widely invasive oncocytic carcinoma (OC), classical and hobnail (HPTC) variants of papillary carcinoma, and poorly differentiated carcinoma (PDTC). The patient underwent total thyroidectomy, radioactive iodine therapy, and within months progressed with local recurrence, and pulmonary metastases requiring neck dissection, external radiotherapy and systemic treatment with sorafenib. The rapid progression, dedifferentiated metastatic lesions, and failure to treatments resulted in the patient´s death. The great variety of histological types and the evolution of this case were a challenge for the management of metastatic disease. Widely invasive OC, HPTC and PDTC are considered to have a worse prognosis. HPTC has never been reported as a component of a collision tumor. HPTC and PDTC should call attention to a possible higher-grade transformation.

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Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal outcomes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent β-catenin activating mutations. Here, we demonstrated that ACC differentiation is maintained by a balance between nuclear, tissue-specific β-catenin-containing complexes and the epigenome. On chromatin, β-catenin bound master adrenal transcription factor SF1 and hijacked the adrenocortical super-enhancer landscape to maintain differentiation in CIMP-high ACC; off chromatin, β-catenin bound histone methyltransferase EZH2. SF1/β-catenin and EZH2/β-catenin complexes present in normal adrenals persisted through all phases of ACC evolution. Pharmacologic EZH2 inhibition in CIMP-high ACC expelled SF1/β-catenin from chromatin and favored EZH2/β-catenin assembly, erasing differentiation and restraining cancer growth in vitro and in vivo. These studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities.