Esophageal neuroendocrine neoplasms (NENs) are uncommon type of esophageal malignancies. We describe the clinical course and molecular imaging features of the relatively rare esophageal malignancy (an aggressive poorly differentiated NEN) that was widely metastatic at the initial presentation. The patient underwent multiple cycles of chemotherapeutic regimens, employing cisplatin-etoposide and nanopaclitaxel-carboplatin and later on rechallenge with cisplatin-etoposide. There was observation of fluctuating disease course and differential characteristics of tumor lesions in terms of treatment response and recurrences with multiple cycles of chemotherapy. In view of the histopathology of high Mib-1 labeling index and dual tracer positron emission tomography-computed tomography (PET-CT) (flurodeoxyglucose [FDG] and 68Ga-DOTATATE) features, the patient was not a suitable candidate for 177Lu-DOTATATE PRRT and FDG PET-CT was the preferred imaging modality for both treatment response assessment and disease monitoring in this patient. The varying response among metastatic lesions in the same individual (with one lesion showing partial response and the other one demonstrating disease progression) was an additional noteworthy feature of the case.