Pam Harrison

September 07, 2017

CHICAGO — A rare neuroendocrine carcinoma of the breast might not be as uncommon as has generally been believed and can be missed unless stained specifically for neuroendocrine markers, new research suggests.

"Some of the cases we picked up just looked like high-grade ductal carcinoma, and there was no clear neuroendocrine differentiation in some of the tumors we are reporting on," said investigator Lubna Alattia, MD, a resident at Louisiana State University Health Sciences Center Shreveport.

"In fact, one of the tumors showed up as a spine metastases that did have neuroendocrine differentiation but the primary tumor did not; it just looked like a poorly differentiated ductal carcinoma," she told Medscape Medical News.

A neuroendocrine carcinoma of the breast is defined as a tumor in which at least 50% of the cells test positive for neuroendocrine markers. However, clinical features and morphology are not always distinct enough to distinguish these tumors from other subtypes of breast cancer, and the degree of neuroendocrine differentiation is usually low to moderate in these tumors.

One of the distinguishing features of these neuroendocrine cancers of the breast is that they do not respond to conventional chemotherapy.

"One of the distinguishing features of these neuroendocrine cancers of the breast is that they do not respond to conventional chemotherapy, so we're simply telling pathologists to be aware of neuroendocrine differentiation. It's rare, but even if there are a few cells or one foci, it's good to run the stain to see if this might be significant because it will affect the patient's response to therapy," Dr Alattia explained here at the American Society for Clinical Pathology 2017 Annual Meeting.

In their poster, Dr Alattia and her colleagues report on three patients who presented with primary breast tumors and subsequent skull and spinal masses. The first patient was 62 years of age and, at the time of presentation, the metastatic mass was 4.3 cm; the second patient was 61 years and the mass was 4.0 cm; and the third patient was 44 years and the mass was 2.0 cm.

After further analyses, the two older patients were found to have metastases in the spine and the younger patient was found to have a benign vascular lesion in the skull.

The first patient "was diagnosed with thoracic spinal cord metastatic breast cancer as the first manifestation of her disease," the investigators write. Subsequently, "lumpectomy revealed a high-grade invasive ductal carcinoma," they explain.

The second patient had estrogen receptor (ER)-positive ductal carcinoma not otherwise specified that had been refractory to conventional therapy during the 4 years before she developed a spinal mass. This mass showed a focal rosette formation that tested positive for neuroendocrine markers on further investigation.

When Dr Alattia's team retested the other two tumors for the presence of neuroendocrine markers, they confirmed that all three ER-positive breast cancers were, in fact, neuroendocrine carcinomas.

The investigators have recently identified a fourth patient who presented with metastatic disease to the brain, bringing the series to four cases in less than a year, at least three with confirmed metastases.

Adaptor Protein

Na/H exchanger regulatory factor 1, or NHERF1, is an adaptor protein recently shown to be involved in the progression of breast cancer, Dr Alattia explained.

"NHERF1 is not specific to this type of neuroendocrine cancer, but it's a new prognostic biomarker expressed in the breast," she said. It has yet to be proven whether this specific protein is the driver behind the enhanced metastatic potential of neuroendocrine tumors.

The team has retrospectively collected 30 breast metastases to the brain from patients seen in the past few years, said senior investigator Maria-Magdalena Georgescu, MD, PhD, medical director of neuropathology also at Louisiana State University Health Sciences Center Shreveport. They are in the process of analyzing these samples for NHERF1 to see if there is a relation between levels of expression and the metastatic potential of these tumors.

The behavior of the NHERF1 protein is somewhat paradoxic, Dr Georgescu told Medscape Medical News. When expressed in the plasma membrane, it acts more like a tumor suppressor; however, when expressed in the cytoplasm, it acts more like an oncogene.

Interestingly, two of the three tumors in this series stained very intensely for NHERF1 in the cytoplasm. In the third tumor, staining was limited to the polarized structures in the neuroendocrine neoplasm and mirrored the pattern of expression seen in neuroendocrine tumors.

The investigators plan to examine more patients, with a variety of neuroendocrine carcinomas, to see if metastatic potential is enhanced by the intrinsic

Different Clinical Behavior

Neuroendocrine tumors of the breast are a rare and aggressive malignancy that have a different clinical behavior and require a different treatment approach than that normally reserved for usual forms of invasive breast cancer, said Anubha Wadhwa, MD, assistant professor at the Medical College of Wisconsin in Milwaukee.

"Since its clinical and imaging features are nonspecific, it is usually up to the pathologist to make this astute diagnosis so that the right treatment can be given from the start," Dr Wadhwa told Medscape Medical News. "Pathologists need to be aware of the histologic features of this rare malignancy."

She said she agrees with the investigators that further studies are needed to evaluate NHERF1 expression in this tumor and establish whether it is, in fact, the driver of the enhanced metastatic potential.

"We also need to develop a good treatment plan to improve survival for these patients," she added.

American Society for Clinical Pathology (ASCP) 2017 Annual Meeting: Poster EP39. Presented September 6, 2017.

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