Branchioma is an uncommon benign neoplasm with an adult male predominance, typically occurring in the lower neck region. Different names have been used for this entity in the past (ectopic hamartomatous thymoma, branchial anlage mixed tumor, thymic anlage tumor, biphenotypic branchioma), but currently, the term branchioma has been widely accepted. Branchioma is composed of endodermal and mesodermal lineage derivatives, in particular epithelial islands, spindle cells, and mature adipose tissue without preexistent thymic tissue or evidence of thymic differentiation. Twenty-three branchiomas were evaluated morphologically. Eighteen cases with sufficient tissue were assessed by immunohistochemistry, next-generation sequencing (NGS) using the Illumina Oncology TS500 panel, and fluorescence in situ hybridization (FISH) using an RB1 dual-color probe. All cases showed a biphasic morphology of epithelial and spindle cells with intermingled fatty tissue. Carcinoma arising in branchioma was detected in three cases. The neoplastic cells showed strong AE1/3 immunolabeling (100%), while the spindle cells expressed CD34, p63, and SMA (100%); AR was detected in 40-100% of nuclei (mean, 47%) in 14 cases. Rb1 showed nuclear loss in ≥ 95% of neoplastic cells in 16 cases (89%), while two cases revealed retained expression in 10-20% of tumor cell nuclei. NGS revealed a variable spectrum of likely pathogenic variants (n = 5) or variants of unknown clinical significance (n = 6). Loss of Rb1 was detected by FISH in two cases. Recent developments support branchioma as a true neoplasm, most likely derived from the rudimental embryological structures of endoderm and mesoderm. Frequent Rb1 loss by immunohistochemistry and heterozygous deletion by FISH is a real pitfall and potential confusion with other Rb1-deficient head and neck neoplasms (i.e., spindle cell lipoma), especially in small biopsy specimens.

Bioptic Laboratory Ltd Pilsen Czech Republic

Department of Pathology and Laboratory Medicine University of Calgary Calgary Laboratory Services Foothills Medical Centre Calgary AB Canada

Department of Pathology and Molecular Pathology University Hospital Zurich Zurich Switzerland

Department of Pathology Faculty of Medicine in Pilsen Charles University E Benese 13 305 99 Pilsen Czech Republic

Department of Pathology Rutgers University New Jersey Medical School Newark NJ USA

Faculty of Medicine University of Zurich Zurich Switzerland

Head and Neck Pathology Consultations Woodland Hills CA USA

Institute of Pathology University Hospital Erlangen Friedrich Alexander University Erlangen Nürnberg Erlangen EMN Erlangen Germany

Molecular and Genetic Laboratory Bioptic Laboratory Ltd Pilsen Czech Republic

Pathology Department Regional Hospital Kolin JSC Kolin Czech Republic

School of Medicine and Pathology Queensland University of Queensland Brisbane Australia

School of Medicine and Pathology Queensland University of Queensland UQCCR Herston Australia

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