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Of a total of 928 primary esophageal cancers, 16 cases of "undifferentiated" esophageal carcinoma were isolated. The topographic and age distributions as well as the clinical presentation and evolution of these tumors were basically similar to those of the usual esophageal squamous carcinoma. By light microscopy, the tumors were comprised exclusively or predominantly of small, round-to-fusiform cells. The cytoplasm appeared scanty and the nuclei were comparatively large and hyperchromatic. Mitotic activity was prominent. Four of the sixteen neoplasms showed occasional foci of squamous differentiation. Argyrophilic cells were seen in all cases, although their number and distribution were variable. Occasional mucosubstance droplets were present in 2 cases. Argentaffin and amyloid stains were negative in all tumors. Ultrastructural studies revealed variable numbers of granules consisting of a dense core, a pale halo, and a single, delimiting membrane; these measured between 80 and 220 nm in diameter. Four of the sixteen cases displayed conspicuous tonofilament bundles and rare keratohyalin granules. The predominant ultrastructural common denominator of these tumors was the presence of characteristic neurosecretory-type granules; thus, their classification as neuroendocrine carcinomas would appear justified. Nevertheless, the abundant tonofilaments and the rare keratohyalin granules and mucosubstance droplets seen in several cases indicate that some of these epithelial cancers possess and express variable capabilities toward multidirectional differentiation.

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The existence of epithelial cells displaying synchronous features of exocrine and endocrine differentiation has been well established. Sporadic descriptions of neoplasms comprising or including such cells have also been recorded. The authors investigated eight carcinomas (lung, two; stomach, two; colon, one; appendix, one; esophagus, one; and pancreas, one). By conventional light microscopy, all eight neoplasms appeared as moderately to well-differentiated adenocarcinomas. Mucosubstance stains showed positive material within well-defined lumina and as intracytoplasmic droplets. Argyrophil stains were positive in seven of the eight neoplasms. The esophageal tumor was a predominantly solid carcinoma; it compromised small to intermediate cells with focal mucosubstance positivity and squamous pearls. By electron microscopy, all these carcinomas including cells displaying variable complements of neurosecretory granules, which were concentrated in the basal pole or in cytoplasmic processes. The granule population was often heterogeneous. The pancreatic carcinoma also showed typical zymogen granules. In all cases, many of the neoplastic cells had true lumina or intracytoplasmic lumina, as well as arrays of filaments; secretory granules were also observed in cells with true or intracytoplasmic lumina. Immunohistochemical studies revealed in all cases either serotonin or one of a spectrum of neuropeptides. Five tumors contained more than one immunoreactive material. The authors conclude that synchronous exocrine and endocrine differentiation may be comparatively frequent in a spectrum of tumors that may be properly termed "amphicrine" carcinomas. This demonstrable heterogeneity of malignant cell populations, however variably expressed, may prove to have considerable significance in the diagnosis and management of these neoplasms.