Occult Esophageal Squamous Cell Carcinoma Presenting as Bone-Predominant Carcinoma of Unknown Primary: A Case Report of a p40-Negative Vertebral Metastasis

Background and Clincal significance: Esophageal squamous cell carcinoma (ESCC) classically presents with progressive dysphagia and weight loss, but atypical presentations may redirect the diagnostic workup before the esophageal primary is identified. We report a case illustrating the simultaneous convergence of three diagnostic pitfalls: absence of dysphagia, bone-predominant metastatic presentation initially managed as carcinoma of unknown primary (CUP), and negative p40 staining in a vertebral biopsy in a patient subsequently confirmed to have invasive mid-esophageal squamous cell carcinoma. CasePresentation: A 66-year-old African American man with dementia, active tobacco exposure, and prior alcohol use disorder presented with constipation, abdominal pain, melena, fever, nausea, vomiting, and progressive back pain. Dysphagia or odynophagia was not documented. CT of the abdomen and pelvis demonstrated diffuse lytic osseous metastases. During evaluation and palliation of symptomatic L2 disease, kyphoplasty and radiofrequency ablation were performed, and bilateral core biopsies showed poorly differentiated carcinoma that was AE1/AE3-positive but negative for p40, CK7, CK20, TTF-1, S100, GATA-3, PAX8, and NKX3.1, yielding an initial diagnosis of CUP. Subsequent chest CT revealed esophageal wall thickening with intraluminal debris. Esophagogastroduodenoscopy (EGD) identified a non-obstructive ulcerated mid-esophageal lesion, and biopsy confirmed invasive squamous cell carcinoma. Poor performance status precluded systemic therapy; palliative external-beam radiation was initiated after diagnosis but discontinued because of clinical deterioration, and the patient transitioned to hospice before passing several weeks after diagnosis. Melena is a gastrointestinal alarm feature, and the combination of gastrointestinal bleeding and an esophageal imaging abnormality warrants timely endoscopic evaluation even when dysphagia is not reported or the symptom history is unreliable. Negative p40 staining in a poorly differentiated, potentially decalcified bone specimen may reflect loss of lineage-marker expression, technical antigen degradation, or both. Tissue or plasma genomic profiling and emerging cell-free DNA methylation classifiers could complement the workup but would not replace direct biopsy of a radiographically suspicious esophageal lesion. Conclusions: In metastatic poorly differentiated carcinoma, lack of documented dysphagia should not exclude an esophageal primary, particularly in patients with cognitive impairment. A p40-negative bone biopsy does not rule out squamous lineage. Timely EGD and integrated clinicopathologic assessment are essential when clinical or imaging findings suggest esophageal involvement.