Small cell? Or neuroendocrine cancer?

AparicioDr. Ana Aparicio is an Associate Professor in the Department of Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas.

Prostatepedia spoke with her about rare but highly aggressive forms of prostate cancer.

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How did you become involved in such a specialized subset of prostate cancer research?

Dr. Aparicio: I was very frustrated by the fact that we treat homogeneously a disease that we perceive in the clinic to be heterogeneous. It drives me crazy that different people walk into the clinic with different diseases and yet we do the same thing to each and every one of them. This ends up meaning that many large Phase III trials are an enormous resource expense. It’s difficult to advance the field. I had remarkable responses for patients with Yervoy (ipilimumab) and yet the Phase III trial was negative. I felt like that was wrong. We should be smarter about what we’re doing. We need to understand the heterogeneity of prostate cancer and incorporate that understanding into clinical trials. Otherwise, it’s going to take us 200 years to make a difference in this disease.

I think of it in the following way. I take all of the prostate cancers and peel away the most aggressive ones. I then look to see how that relates to the rest of the disease. If we peel back in that way, we will start to understand the disease.

So then the work you’re doing can potentially change not only how we treat patients, but also how we design clinical trials?

Dr. Aparicio: Yes.

What is neuroendocrine prostate cancer?

Dr. Aparicio: Neuroendocrine prostate cancer is a histological definition of a prostate cancer variant. The prostate is composed of glandular tissue. When a pathologist looks at your garden-variety prostate cancer under the microscope, she sees it is composed of groups of glands. That is why it’s called adenocarcinoma: adeno meaning of or relating to the glands, carcinoma referring to the cancer arising from epithelial tissue. It’s cancer and not normal prostate tissue, but you can still recognize the glandular structures. Prostate adenocarcinomas respond very well to hormonal therapies.

On the other hand, small-cell prostate cancers basically look like sheets of cancer cells under the microscope. There is no glandular formation of any sort. These are small, round cells that have small amounts of cytoplasm (the gel-like material surrounding the nucleus) so their nuclei look very prominent. Small-cell cancers often express neuroendocrine markers, which are a type of protein expressed by a number of different tissue types and in a number of different cancers. Neuroendocrine markers are in no way specific to small-cell prostate cancers, but because the small-cell prostate cancers express them frequently, the other name that is given for small-cell prostate cancers is ‘poorly differentiated neuroendocrine prostate carcinoma.’ Many garden-variety prostate adenocarcinomas (those composed of groups of glands) also express these neuroendocrine markers. Again, the word neuroendocrine is not specific to small-cell cancers. Small cell refers to sheets of cells that are small with little amounts of cytoplasm.

The presence of small-cell cancer morphology on a surgical specimen or a biopsy is often associated with atypical clinical features for prostate cancer and a poor response to hormone therapies.

Garden-variety prostate adenocarcinomas most often spread to the bone and make round sclerotic (hardening) or osteoblastic bone metastases that show on a CT scan like a white patch.

In contrast, small-cell prostate carcinomas are often associated with what we call lytic (relating to disintegration) bone metastases, which show on a CT scan like a dark, punched-out hole. And that’s when the carcinomas go to the bone because they often don’t even show up in the bone. Men with small-cell cancer morphology can have exclusive visceral metastases, meaning their cancer has only gone to the liver, lymph nodes, or lung. They might also have bulky tumor masses, including bulky and symptomatic primary prostate tumors or bulky liver or lymph node masses. While they don’t respond well to hormonal therapies, small-cell prostate cancers often respond to chemotherapy.

A problem we ran into was that we would often find these atypical clinical features that I just described, but under the microscope where we expected to find small-cell prostate carcinoma morphology to justify chemotherapy, we didn’t. What happens when we see those atypical clinical features, but the biopsy doesn’t show small-cell morphology? Our experience shows that those people don’t do well with hormone therapies. In other words, when we do a biopsy and we find small-cell carcinoma morphology, we know that those cancers need to have chemotherapy sooner rather than later, as opposed to treatment with hormonal therapy. They need early chemotherapy as well; so we coined the term aggressive variant prostate cancers, which are tumors that share clinical features with small-cell cancers but may have different morphologies under the microscope. When we do a biopsy, they might look like adenocarcinoma, but they behave like small-cell cancer.

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