Metastatic breast cancer simulating well-differentiated neuroendocrine neoplasms of visceral organs

A series of metastatic breast carcinoma (MBC) mimicking visceral well-differentiated neuroendocrine neoplasms has not previously been reported. We identified 5 consultation cases originally submitted as neuroendocrine neoplasms in women but that were found to be MBC on subsequent review. All 5 neoplasms demonstrated nested architecture and relatively uniform nuclei. Four patients had a known history of breast cancer (remote in 3 and concurrent in 1), but the metastases (3 liver, 1 lung) labeled for chromogranin and/or synaptophysin, prompting misdiagnosis as neuroendocrine neoplasm. In a fifth case, a liver metastasis in a patient with a known pancreatic endocrine neoplasm was originally thought to be of pancreatic origin; an occult concurrent primary breast cancer (PBC) was subsequently identified as the source. On further immunohistochemistry (IHC), all metastases evaluated were diffusely, strongly positive for estrogen receptor (5/5 cases) and GATA3 (4/4 cases). Three patients had previously received ineffective treatment for neuroendocrine carcinoma. Based on the consultation diagnosis, all 4 patients with follow-up received hormone therapy, which was effective in 3. In a separate tissue microarray cohort of paired PBCs and hematogenous MBCs, chromogranin and/or synaptophysin IHC labeling was typically negative and increased from the PBC to the MBC in only 5% of cases. In conclusion, although neuroendocrine differentiation is uncommon in breast cancer and does not commonly increase in metastases, MBC with neuroendocrine differentiation should be considered in patients with visceral neuroendocrine neoplasms of unknown primary site. Diffuse IHC labeling for estrogen receptor and GATA3 helps establish the correct diagnosis.