Prostate cancer is usually highly androgen-dependent and exquisitely responsive to
androgen deprivation therapy (ADT). In addition, prostate-specific antigen (PSA) production
is positively regulated by androgens.[1] Although PSA is classically elevated in high-grade disease, some patients present
with the inharmonious scenario of high-grade disease and low PSA. Low-PSA, high-grade
disease may represent a unique entity with underlying dedifferentiated biology, and
as such may respond poorly to the current standard treatments, particularly ADT and
is associated with high rates of prostate cancer-specific mortality.
As a general rule, low-PSA-producing, high-grade prostate cancer is neuroendocrine
prostate cancer, including the small-cell variant, which represents an aggressive
hormone-resistant entity.[2],[3],[4],[5] In patients diagnosed pathologically as having either large cell or small cell neuroendocrine
carcinoma, the prognosis is even poorer. As an example, in a series of 241 cases identified
from the Surveillance, Epidemiology, and End Results (SEER) database over a 30-year
period, 60% had metastatic disease at presentation. The 1, 2, and 5-year survival
rates for the entire series were, respectively, 48%, 28%, and 14%.[6] Mahal et al. analyzed differences in values for 62 prostate cancer transcriptomic signatures in
the decipher genomics resource information database; including signatures related
to prognosis,[7] androgen receptor (AR) signaling,[8] and neuroendocrine/small-cell prostate cancer.[9] After manifold testing adjustment, Gleason 8–10 tumors with PSA ≤2.5 ng/ml were
more likely to be associated with neuroendocrine/small-cell genomic signatures and
less likely to be associated with an AR signaling signature compared to Gleason 8–10
tumors with PSA >2.5 ng/ml (both P = 0.046). No such association was seen for Gleason
≤7 tumors.
Imperative differences in the clinical and prognostic characteristics of these patients
are illustrated by an analysis that included almost 500,000 men with T1-4N0M0 prostate
cancer from the National Cancer Database (NCDB) and 136,000 men from the SEER database.
In the by and large NCDB series, 0.7% of patients had Gleason 8–10 disease and a PSA
≤2.5 ng/dL. Among those with Gleason 8–10 disease, 6% had a PSA ≤2.5 ng/dL.[10] In the SEER record, prostate cancer-specific mortality was higher for men with a
PSA ≤2.5 ng/dL and Gleason 8–10 adenocarcinomas compared with the reference group
of those with a PSA 4.1–10.0 ng/dL at diagnosis (hazard ratio [HR] 2.70), and it was
similar to that for men with high-grade disease and a PSA >20 ng/dL (HR 2.56 compared
with the reference group). The adjusted prostate cancer-specific mortality rate at
47 months after diagnosis was 14.0% in the high-grade, low-PSA subset, compared with
4.9% in those with a PSA >2.5 ng/dL.[11]
Among men with high-grade disease and a low PSA treated with radiation therapy, the
use of androgen deprivation therapy was associated with an overall survival benefit
for those with a PSA >2.5 ng/dL but not for those with a PSA ≤2.5 ng/dL.[12]
Given the biological heterogeneity of prostate cancer and its multifocality, it is
hypothesized that tumors with a higher Gleason grade have a higher chance for occurrence
of a clonal shift in the original tumor that may express the features of other prostate
cancers, including biological aggressiveness, and that such tumors may be associated
with to be deficient in PSA production. The phenomenon of prostate cancer progression
with unrelated PSA elevation may be explained by the proliferation of cell lines that
either cannot produce PSA or are poorly differentiated prostate cancer cells that
have lost their capacity to express PSA. In addition, these findings also highlight
the potential difficulties with detecting this unique aggressive entity, which would
not necessarily be diagnosed with PSA screening as the PSA levels would typically
be below the threshold to biopsy. Thus, it is likely that such patients with aggressive
cancers could be diagnosed based on some combination of clinical symptoms, presentation,
digital rectal examination, imaging, and PSA kinetics.
Since low-PSA, high-grade disease tends to be late-presenting given that low PSA does
not typically prompt a biopsy, the development of supplementary biomarkers to aid
in early detection of aggressive and poorly differentiated disease is necessary. Furthermore,
whether low-PSA, high-grade tumors are a heterogeneous entity with a mixture of tumor
types such as aggressive neuroendocrine and more standard-risk prostate adenocarcinoma
would need to be determined in developing new approaches to this disease. In a study
by Sella et al., on 18 patients with clinically progressive androgen-independent prostate cancer
with low PSA levels, each patient demonstrated elevation of at least one tumor marker,
such as CA 19-9, CEA, CA 125, and CA 15-3. The tumor cells were immunoreactive for
neuroendocrine markers in all specimens. They found that a low serum PSA level and
progressive androgen-independent prostate cancer was characterized by a high proportion
of lytic bone disease, visceral metastasis, the histological features of small cell
or poorly differentiated prostate cancer and sensitivity to cisplatin-based chemotherapy.[13] Nishio et al. also reported that serum CEA, CA 19-9, and CA 15-3 were elevated in patients with
metastatic prostate cancer who had normal serum PSA levels.[14]
Although the clinical presentation of these prostate cancers when they present with
localized disease is similar to that of other prostate cancers, metastases often occur
early in the natural history, and symptoms can be due to distant disease. In addition,
a range of laboratory abnormalities have been reported with the small cell variant,
including paraneoplastic syndromes such as Cushing's syndrome, peripheral neuropathy,
membranous nephropathy, and hypercalcemia.
In moving toward the treatment guidelines, one hypothesis is that patients with low-PSA,
high-grade disease may be the group that would benefit the most from addition of chemotherapy
to standard hormonal therapy for high-risk localized disease, on the basis of new
randomized evidence showing the benefit of chemoradiotherapy in localized high-risk
disease.[15],[16] While docetaxel has been favored as the chemotherapy of choice for high-risk localized
disease, a platinum-based agent could also be considered in the setting of a clinical
trial given the neuroendocrine expression features. It has been demonstrated that
neuroendocrine prostate cancer has significant over expression and amplification of
specific markers, and there are ongoing phase 2 studies evaluating the efficacy of
targeted inhibition in the metastatic setting (NCT01799278). Depending on the results
of this study, the expansion of targeted inhibition for patients with low-PSA, high-grade
disease in an investigative setting may be appropriate. Finally, it should be noted
that an alternative surveillance strategy to PSA monitoring that involves imaging
may be needed.
The optimal management of patients with high-grade, low-PSA prostate cancer has not
been well defined, and the clinical observations in these patients suggest that the
standard approach to high-risk and very high-risk disease may not be optimal. Clinicians
should be aware of these findings, and these patients should be considered for additional
molecular markers, systemic staging, and clinical trials studying the use of chemotherapy
and other novel agents for very high-risk prostate cancers.
