Discussion

Hereditary diffuse gastric cancer is an autosomal dominant cancer syndrome characterized by diffuse-type gastric carcinoma and invasive lobular breast carcinoma, caused by inactivating germline mutations in CDH1. Located on chromosome 16, CDH1 encodes E-cadherin, a transmembrane glycoprotein with cell-to-cell adhesion and cell signaling functions. A complete loss of E-cadherin function due to an inactivation of the second CDH1 allele, results in the initiation of neoplastic cells with signet ring cell phenotype. Prophylactic total gastrectomy is recommended for individuals with pathogenic CDH1 mutations.

Metastatic adenocarcinoma with signet ring cells are not always easily recognized in effusion cytology. A clear “second population” that is morphologically distinct from mesothelial cells or histiocytes may not be apparent. In these cases, a panel of immunomarkers is helpful for distinguishing histiocytes and/or reactive mesothelial cells from metastatic adenocarcinoma.

Histiocytic markers, CD68 and CD163, show dot-like granular or diffuse cytoplasmic immunoreactivity in histiocytes and are absent in both mesothelial and epithelial cells.

Mesothelial markers include WT1, calretinin, and D2-40 (also known as podoplanin). WT1 shows nuclear staining in mesothelial cells, but is also expressed in serous neoplasms of the gynecologic tract. D2-40 shows membranous pattern positivity in mesothelial cells. Calretinin shows nuclear and cytoplasmic staining in mesothelial cells but may also be positive in high-grade breast carcinomas.

Epithelial markers include claudin-4, MOC-31, Ber-EP4, and B72.3. Claudin-4 shows crisp membranous staining in epithelial cells and is absent in histiocytes and mesothelial cells. MOC-31 and Ber-EP4 show membranous staining in epithelial cells and in a subset of epithelioid mesotheliomas. In addition, the detection of intracytoplasmic mucin with a mucicarmine stain is helpful in distinguishing adenocarcinoma from mesothelial cells.

References:

  • Alshaikh S, Lapadat R, Atieh MK, et al. The utilization and utility of immunostains in body fluid cytology. Cancer Cytopathol. 2020;128(6):384-391.
  • Carneiro F, Huntsman DG, Smyrk TC, et al. Model of the early development of diffuse gastric cancer in E-cadherin mutation carriers and its implications for patient screening. J Pathol. 2004;203(2):681-687.
  • Elahi M, Lam H, Adams C, Li QK. Cytologic diagnosis and differential diagnosis of histiocytic signet ring cells in effusion specimens. Cytojournal. 2024;21:30. Published 2024 Sep 2.
  • Hansford S, Kaurah P, Li-Chang H, et al. Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA Oncol. 2015;1(1):23–32.
  • Husain AN, Colby TV, Ordóñez NG, et al. Guidelines for Pathologic Diagnosis of Malignant Mesothelioma 2017 Update of the Consensus Statement From the International Mesothelioma Interest Group. Arch Pathol Lab Med. 2018;142(1):89-108.
  • Sundling KE, Cibas ES. Ancillary studies in pleural, pericardial, and peritoneal effusion cytology. Cancer Cytopathol. 2018;126 Suppl 8:590-598.
  • van der Post RS, Vogelaar IP, Carneiro F, et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet. 2015;52(6):361-374.
  • Yu GH, De Frias DV, Horcher AM. Evaluation of histochemical methods for the detection of intracytoplasmic mucin in serous effusions. Cytopathology. 1999;10(5):298-302.