Chronic inflammation of the prostate
Chronic inflammation of the prostate is very common, affecting between 15% and 40% of adult men—depending on age groups and thresholds used. Inflammation is measured by counting the number of white blood cells in prostatic fluid using a microscope. White blood cells indicate that inflammation is present, usually meaning that our immune system is fighting a microbe. However, no microbes seem present in the prostate! The cause of chronic prostate inflammation has been a medical mystery for over a century.
X-rays of the lower back
There are many types of back pain, and telling them apart by analyzing symptoms is difficult. In the early 20th century, it was realized that ankylosing spondylitis (AS) could be seen on X-rays of the lower back. The most specific AS biomarker is degradation of the sacroiliac joint, which connects the spine and hip bone. This allowed studies to detect AS-type back pain using an objective method.
Using the two techniques described above, Visher conducted the first objective study linking prostate inflammation with AS-type back pain (Visher 1929). He tested the prostatic fluid of 500 young men admitted for any reason to the Veterans’ Hospital in Waukesha (Wisconsin): 87 men (17%) had a high white blood cell counts. Of these 87 men, 36 men had X-rays taken of their lower back, of which 20 showed signs of AS (55%). This greatly exceeded the expected rate.
King and Romanus (1953-1961)
In the 1950s, two European research groups replicated Visher’s work in large well-controlled studies (Mason et al 1958; Domeij et al 1958; Oates 1959; Catterall et al 1961): chronic prostate inflammation is very strongly associated with AS-type back pain.
Visher, King and Romanus suspected a microbe
Chronic inflammation usually means that the immune system is fighting a microbe. However, none of these groups managed to find such a microbe in the prostate, despite much effort. What they needed was modern technology. And they knew it:
“It is tempting to consider these [symptoms] as manifestations of one disease which is caused by genital infection [...] In this survey bacteriological and serological investigations failed to reveal a likely causative organism. [...] Progress in the diagnosis and treatment of this condition is hindered by the failure to find the causative organism [...] Further research into this aspect of the problem is urgently required, using new and improved techniques.” (Catterall 1961)
It wasn’t until the introduction of high-throughput DNA sequencing (in the 2010s) that Malassezia’s presence in the prostate and other internal organs was revealed. These fungi don’t grow well in culture, and are invisible under the microscope when standard staining techniques are used. Visher, King and Romanus had no chance of finding Malassezia with the technology they had.
Do prostate cancer and AS-type back pain have a common cause?
Prostate inflammation is strongly suspected of causing prostate cancer (Marzo et al 2007). Prostate inflammation and AS-type back pain are strongly associated. This does not in and of itself imply a common cause. However, four similarities between prostate cancer and spondyloarthropathies (including AS-type back pain) point to a shared infectious cause:
Similarity 1: sexual risk factors
Both spondyloarthropathies (Hall et al 1953; Csonka 1958; Ford 1964; Valtonen et al 1985; Kvien et al 1994; Butrimiene et al 2006; Savolainen et al 2009; Ostaszewska et al 2015) and prostate cancer (Key 1995; Dennis et al 2002) have clear sexual risk factors. This suggests they have a sexually acquired infectious cause, as occurred in cervical cancer before the discovery of oncogenic HPV strains (Strickler et al 2001).
Similarity 2: ubiquitous microbe
Both spondyloarthropathies and prostate cancer seem to be caused by a microbe which infects a very large fraction of the adult population. We know this because lifetime latent prostate cancer risk is ~70% (Sakr et al 1994; Powell et al 2010), and monozygotic twin concordance in ankylosing spondylitis is ~63% (Brown et al 1997). This means well over half of the adult population must be infected. This high prevalence excludes most microbes and all known STIs.
Similarity 3: intracellular microbe
Both spondyloarthropathies and prostate cancer seem to be caused by an intracellular microbe. In ankylosing spondylitis, we know this because HLA-B27 and ERAP1 variants increase disease risk (see here for details). In prostate cancer, we know this because PSP94 is only active within human cells (Sutcliffe et al 2014).
Similarity 4: immunity against fungi
Both spondyloarthropathies and prostate cancer have unambiguous links to immunity against fungi. In spondyloarthropathies, CARD9 variants and antibodies against fungi show this (see here for details). In prostate cancer, PSP94’s fungicidal activity shows this (Sutcliffe et al 2014).
Difference 1: age at onset
There is a very important difference between AS and prostate cancer: age at onset. AS usually begins between age 15 and 35, when the risk of acquisition of sexually transmitted infections is highest. Prostate cancer risk is negligible before the age of 45, and increases exponentially thereafter. Shouldn’t they both peak at the same time if they share the same infectious cause?
No! Stomach cancer caused by bacterium Helicobacter pylori takes decades to develop. Many mutations must accumulate within human cells before they become cancerous, and these don’t happen overnight! It takes decades of chronic inflammation before enough mutations have accumulated to cause cancer. This is why prostate cancer never develops in young men.
Prostate cancer and AS-type back pain are thought to be caused by chronic inflammation of the prostate. Researchers have suspected for more than a century that this inflammation is due to a chronic infection. However, they have so far failed to find a causative microbe. Prostate cancer and AS share four important properties which point to a common infectious cause: sexual risk factors, immunity against an intracellular infection, immunity against fungi and very high prevalence.
The only fungi that I could find in the prostate are Malassezia restricta and Malassezia globosa. These fungi are present on everyone’s skin from birth, so I dismissed them as contaminants for five years. This was a mistake. Malassezia cause AS-type back pain. The similarities listed above between AS-type back pain and prostate cancer mean that Malassezia are the most plausible etiological candidate for prostate cancer, by a wide margin.
NB: This post is based on Laurence et al 2018 (simplified for clarity).
Animated prostate cancer video: https://youtu.be/bNGvEU0TaHY