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Prostate cancer with low PSA

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A high reading on a PSA blood test can pick up prostate cancer early. But not all prostate cancers have a high PSA. Some men are diagnosed with an aggressive prostate cancer but still have a very low PSA level. The journey for men whose PSA doesn’t rise with prostate cancer can be considerably more difficult. This week’s blog looks a new research regarding the characteristics of the tumours and outcomes for men with low-PSA high-grade prostate cancer.

What types of prostate cancer have low PSA levels?

Most cases of prostate cancer are called acinar adenocarcinoma. This long label refers to the specific type of cells that are growing out of control, forming tumours. When these prostate adenocarcinoma cells grow into tumours, they almost always produce high levels of PSA. This extra PSA protein can be detected in the blood, being an early warning of the cancer.

But there are some rare types of prostate cancer that do not always have a high PSA reading. Rare prostate cancers have been summarised in a research blog from last year.

Prostate cancers with low PSA

Adenocarcinoma: The vast majority of prostate cancers are classed as adenocarcinomas. These cancers develop from prostate gland cells. Although most of these tumours bring a rise in PSA levels, there are a some that do not.

Neuroendocrine prostate cancer:  Neuroendocrine cancer cells develop from normal (non-cancerous) neuroendocrine cells that are found in the prostate gland. These cells have features similar to nerve cells and cells that secrete hormones. The most common type of neuroendocrine prostate cancer is called small cell prostate cancer. But less than 1% of prostate cancers fit in this category. Small cell prostate cancer does not usually cause PSA levels to rise. Another rarer type of neuroendocrine prostate cancer is called large cell prostate cancer. Some cases of this cancer also have no rise in PSA level.

Ductal prostate cancer: Although rare, this is the second most common type of prostate cancer. It develops from prostate gland cells and is usually located near the prostate ducts. PSA levels are usually lower than expected and some men have no rise in PSA at the time they are diagnosed. For ductal prostate cancer, PSA levels are not a particularly good indication of the tumour stage, risk of return after treatment and presence of metastasis (tumours spread to far regions). A finger test (digital rectal exam) is usually ineffective at detecting ductal prostate cancer, as the prostate feels relatively normal despite the cancer.

Basal cell prostate cancer: These rare tumours usually don’t have high PSA levels. Very little is known about them.

Transitional cell prostate cancer: This form of cancer usually starts in the bladder then moves to the prostate. But some of these cancers start in the prostate, making them a rare form of prostate cancer. There are only a few recorded cases of transitional prostate cancer, so we don’t know much about it. Some of these cases have had low PSA levels.

Leiomyosarcoma: This rare type of prostate cancer is often aggressive. It mostly affects older men, but can also occur in younger men and sometimes children. Most cases of leiomyosarcoma have low PSA levels.

Rhabdomyosarcoma: Rhabdomyosarcoma is a rare type of prostate cancer that affects children and younger men. Rhabdomyosarcomas usually have a low PSA level.

How low-PSA cancers and rare prostate cancers are diagnosed?

Unfortunately for these rare types of prostate cancer, PSA tests and finger tests are usually unhelpful for early detection.

These rare types of prostate cancer are often diagnosed after symptoms occur. The symptoms may include painful urination, disrupted urination, painful ejaculation, blood in the urine or semen, or pain in the pelvic region. Unfortunately, some men with rare prostate cancers will be diagnosed at a late stage, when it has spread by metastasis. Symptoms of this spread could be pain, such as bone or abdominal pain. Other signs might be swollen lymph nodes or constipation. As these are rare cancers, it’s important to note that these symptoms could be a sign of any number of other conditions.

Challenges of having a rare cancer

Approximately 52,000 people are diagnosed with a rare cancer each year in Australia and around 25,000 people die from them. Rare cancers include over 200 different types of cancer. Over the last 20 years, the survival rates for rare cancers have only slightly improved. Research into rare cancers is also sparse compared to common cancers.

People who are diagnosed with a rare type of cancer are faced with many issues. They often find that few treatment options are available. They see clinicians who have very little experience in treating the cancer that they have. Very limited information is available to help them understand their own disease. Many people with rare cancers turn to treatments that are not government-funded or only available overseas. This creates a huge financial burden for them. People with rare cancers often face multiple difficult issues at the same time as they are fighting cancer.

When a man is diagnosed with a rare type of prostate cancer, this puts him in a similar situation to people with rare cancers. There is less information available to help him and his doctors only rarely see men with the same type of prostate cancer. However, there are many treatment options available. Treatments for the common type of prostate cancer are usually used by those with a rare type of the disease.

Research into prostate cancers with low PSA

More often than not, there is little research done for rare cancers. Governments and philanthropists who hand out grants wish to fund research that will help as many people as possible – that being more common diseases. People often donate to cancer research if they have been affected by the cancer. Therefore, the more common cancers will get more donations. Further, it’s difficult to study disease when there are very few cases. Scientists need to access tumour samples and large study groups of patients in clinical trials. This is more difficult for rare cancers. So more research into rare types of prostate cancer is urgently needed to improve outcomes for these men.

A very important scientific study on low-PSA high-grade prostate cancers was published last year. Researchers from The Dana Faber Cancer Institute and Harvard Medical School in the US led the study, which was published in a top journal, European Urology. This study took a very high-level approach, looking at numbers on a national scale. Although this type of study loses the story of the patient experience, bigger picture trends can highlight important needs in the community.

This aim of this study was to analyse low-PSA, high-grade prostate cancer. Men with these tumours are diagnosed with Gleason scores of 8 and over, but a low PSA level of less than 2.5ng/ml. The researchers did not include any men with small cell prostate cancer or tumours that have neuroendocrine features. These are the most common of the rare prostate cancer cases. So the prostate cancers included in this study are the more common adenocarcinoma type plus the very rare types.

The researchers started by using information from two very large American databases. The National Cancer Data Base (NCBD) has records of 70% of cancer cases in the US (494,793 people), and the Surveillance, Epidemiology and End Results (SEER) program has data on 28% of the US population (including 136,113 men with prostate cancer).

The first interesting finding from this study was that 5.6% of men with a Gleason grade of 8 – 10 had low-PSA prostate cancer. These were men with a PSA of 2.5ng/ml or less. This is unlikely to be just from rare prostate cancer, as it involves too many men. This result indicates that a subset of men with common adenocarcinoma tumours can have high-grade prostate cancer but a low PSA.

The researchers then studied death rates, where men had died from prostate cancer. This statistic is called prostate cancer specific mortality (PCSM). For men whose tumours were Gleason 7 or below, the higher the PSA level, the more likely they were to die of prostate cancer. But this pattern was not the same for men who had Gleason grade 8 or higher prostate cancer. The PCSM death rate rose when PSA rose for these men. But it was also relatively high for men with a low PSA level (2.5ng/ml or less) as well. In fact, men with a low PSA were just as likely to die from prostate cancer as men with the highest PSA levels. These results show that low-PSA high-grade prostate cancers are dangerous and have a relatively high chance of causing death.

Data on treatments for the low-PSA high-grade prostate cancers showed that, on average, treatment with hormone therapy (ADT) was less helpful than for men with high-grade prostate cancers and high PSA levels. So for many of these men, ADT was not a very effective treatment. Chemotherapy is hoped to be a good alternative to ADT for these men, but there was not enough information from these databases to know for sure. This should be a research priority.  

To finish the study, the researchers were able to perform genomic analysis on samples from 62 patients. They used a technique that examines genes that are switched on. From previous studies, they knew what types of gene were likely to be switched on in tumours with a small cell or neuroendocrine prostate cancer types. Their results showed that Gleason 8 or above tumours with low PSA were more likely to have a small cell or neuroendocrine pattern of gene usage. However, men diagnosed with small cell or neuroendocrine tumours were not part of this study. These results indicate that many of these tumours have features of small cell/neuroendocrine tumours, even though they were mostly diagnosed as adenocarcinomas.

The authors report two major clinical implications of their study:

  1. Existing clinical tools to predict the course of cancer do not take into account the high risk of dying from prostate cancer if PSA is low but Gleason score is high.
  2. The current paradigm for treating all men with high-risk localised prostate cancer is radiotherapy and ADT. This study suggests that men with low-PSA high-grade disease may not have good outcomes from this treatment. There is evidence that for some rare prostate cancers, chemotherapy is more effective than ADT. But we don’t know if this is the case for high-grade adenocarcinomas with low PSA. We urgently need better biomarkers as a way of finding these men, and clinical trials to determine the best course of treatment.

Another interesting question arises from this study – is low-PSA high-grade disease a separate type of prostate cancer? In medical speak, the question is: “Is low-PSA, high-grade prostate cancer a distinct clinical entity?” If this is the case, then considerable research effort needs to be directed towards addressing this aggressive type of prostate cancer. We need to detect this type of prostate cancer early and we need clinical trials for these men to test alternatives to ADT for treatment.

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