Pulmonary Adenocarcinoma With Signet Ring Cell Features: A Comprehensive Study From 3 Distinct Patient Cohorts

Signet ring cells (SRCs) are best known in the setting of poorly differentiated adenocarcinomas of the gastrointestinal tract, especially the stomach, colon, and appendix. 1 SRCs are characterized by singly dispersed tumor cells with intracytoplasmic mucin and an eccentrically displaced nucleus.1 SRCs are a rare feature of primary pulmonary adenocarcinoma.2–6 Because of their rarity in primary tumors of the lung, metastatic disease is often considered in the differential diagnosis. If the differential diagnosis cannot be resolved on careful histologic examination, immunostains are often helpful, as primary pulmonary adenocarcinomas with SRCs frequently express thyroid transcription factor-1 (TTF-1) and CK7 but are usually negative for CK20 and CDX-2.2,7–9 Several studies have suggested that pulmonary adenocarcinomas with SRC features (SRC+) may have a more aggressive clinical course and may occur more frequently in nonsmoking patients.6,8,10,11 However, their comprehensive clinical and molecular characteristics are not well known because of a relative paucity of large series on pulmonary adenocarcinomas with SRC+. In addition, the diagnosis of SRC+ can be difficult, given the subjectivity in separating true SRC from morphologic mimics including cytoplasmic vacuolization, clear cell change, and degenerative changes such as tumor cell “ballooning.” Thus, one may have to question the findings of some previous studies that did not undergo a central review to confirm the diagnosis by careful histologic evaluation. SRC+ primary pulmonary adenocarcinomas have been associated with ALK gene rearrangement (ALK+).12–14 The EML4-ALK fusion was described in 2007 and occurs in 3% to 7% of pulmonary adenocarcinomas.15–17 More recently, chromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have been described as a rare (<3%) driver mutation in pulmonary adenocarcinomas, and the tumors with ROS1 rearrangement (ROS1+) have been shown to respond to crizotinib.18–20 Patients with ROS1+ tend to be younger and more likely to be never-smokers, similar to those with ALK rearranged tumors (ALK+).18,21 Whereas ALK+ lung adenocarcinomas with SRC+ have been widely reported, the incidence of ROS1+ in SRC+ lung adenocarcinomas is not well known. The main goal of our present study is to better characterize the clinicopathologic features of pulmonary adenocarcinomas with SRC+, including relationship to smoking status and clinical outcome, on the basis of a large number SRC+ cases confirmed by a careful histopathologic evaluation. In addition, we also examined the genetic abnormalities in SRC+ tumors including ALK, ROS1, and other genes known to be mutated in pulmonary adenocarcinomas, aligned with the patients’ smoking status.