Morphologic Heterogeneity of Carcinoma with Signet Ring Cell Features at Different Primary Sites

<b><i>Introduction:</i></b> Signet ring cells (SRCs) may be observed in carcinomas from multiple primary sites. Elucidating unknown primaries from metastases with SRCs represents a diagnostic challenge. This study examined morphologic characteristics of adenocarcinomas with SRCs from stablished primary sites and described objective features, which can aid in identifying the site of origin. <b><i>Methods:</i></b> The series encompasses 257 cases of adenocarcinomas with SRCs from gastroesophageal junction (GEJ, <i>n</i> = 38), stomach (<i>n</i> = 48), pancreatobiliary system (<i>n</i> = 16), colorectum (<i>n</i> = 40), appendix (<i>n</i> = 32), breast (<i>n</i> = 41), and lung (<i>n</i> = 42). H&amp;E sections were examined and scored using architectural and cytologic criteria. Morphometric analysis was performed using QuPath software. <b><i>Results:</i></b> Extracellular mucin was more abundant in GEJ, colorectal, and appendiceal carcinomas. Poorly cohesive morphology was the most frequent pattern in gastric and breast carcinomas. The cytoplasmic mucin/vacuole was predominantly clear and targetoid in breast carcinomas. Breast and gastric carcinomas showed the highest nuclear to cytoplasmic (N/C) <i>ratio</i>, whereas appendiceal carcinoma the lowest. <b><i>Conclusion:</i></b> Morphological evaluation (extracellular mucin, architectural patterns, and the nature of cytoplasmic mucin/vacuole) represents an important step to determine the cancer site of origin in adenocarcinomas with SRCs and guides further ancillary studies. Cytological morphometry may help further refine morphological criteria and facilitate the construction of digital-pathology algorithms.