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Lymph Node Metastases: Observed And Occult - The Next Wave Of Attack
(September 2003)
Despite the current
trend of detection of prostate cancer at an earlier stage, about 15 to 40%
of men (estimates vary) with apparently localized disease will have cancer
recurrence. Localized cancer transforms into metastatic cancer as PC cell
mutations endow cells with new capabilities - to mention only a few - that
effect disassociation from the primary tumor, dissolve collagen barriers
that prevent cell migration, and create PC cell receptors that respond to
the cytokine tug from lymph nodes and the blood stream.
A well done study was
reported by Bader and colleagues from the University of Bern (J UROL,
March, 2003),"Disease Progression and Survival of Patients with Positive
Lymph Nodes after Radical Prostatectomy. Is there a chance of Cure?" By
performing meticulous extended lymphadenectomies in 367 men with
apparently localized disease and examining the lymph nodes in 3 mm slices
they observed metastases in 25% of cases. No immunohistochemical stains
were used. They cleared the tissue from the external iliac vein to the
internal iliac artery and from the femoral canal to the bifurcation of the
iliac vessels. A median of 21 nodes (range 6- 50) were retrieved per case,
substantially more than are removed in the less aggressive limited
resection, which variously yields fewer nodes and finds positive nodes in
about 7-12% of cases. The pathologic tumor stage ('97 TNM) and the percent
with positive nodes were collated: pT1-pT2b - 13% positive nodes, pT3a -
25%, and pT3b 49%. They subdivided the cases into groups having one, two,
or >2 positive nodes. At a median follow-up of 45 months the men in the 1,
2, and >2 nodes positive groups developed asymptomatic PSA rise in 18, 30,
and 24% respectively, and symptomatic progression in 44, 60, and 62%.
Their conclusion: 1) more nodes harbor metastases than customarily
discovered at limited lymphadenectomies, and 2) "In lymph node positive
prostate cancer, time to asymptomatic PSA increase, time to symptomatic
tumor progression, and time to tumor specific death significantly
correlate with the number of lymph node metastases."
Additionally, more
sensitive detection techniques reveal micrometastatic deposits that
routine H&E staining miss. Shariat in Cancer Research, Aug, 2003, using
immunohistochemistry for cytokeratins and PSA, and RT-PCR for kallikrein
(closely associated with PSA) found cancer in 7% of H&E negative nodes
from pT3N0 patients. Martinez-Pineiro (European Urology Apr, 2003) using
the RT-PCR technique found tags indicating mRNA for PSA in 39.5% (57/145)
of "pN0" nodes, which were negative with immunohistochemical staining.
Undetected nodal positivity must be one of the important factors leading
to treatment failure in clinically localized prostate cancer.
Current research
efforts are being directed toward identifying cells within the prostate
which are members of a population of which some may already have escaped
the gland, or cells which, while still in the prostate, display features
that indicate the potential to metastasize. Dr. Don Malins, PhD, DSc at
the Pacific Northwest Research Institute, Seattle, is developing the use
of Fournier transform infrared spectroscopy on fresh prostate tissue to
analyze the extent of oxidative and other damage to DNA (a surrogate for
mutation) and is able to identify a characteristic pattern of damage
associated with metastatic disease. Wang (JNCI, May 7, 2003) presents one
of many studies wherein high-density tissue microarrays are used to
identify patterns of gene expression associated with disease progression.
Dr. Alvin Liu and
colleagues at the Institute for Systems Biology, Seattle, is approaching
this issue by homing in on PC cell surface phenotype markers and has
identified two cluster designations (CD), CD26 and CD10, which are
associated with metastatic spread or the potential to spread. Evaluation
for these CDs can be performed with flow cytometry on fresh tissue, a
technique that is easily performed in a good clinical laboratory.
With more accurate
information about PC cell behavior - information whose accuracy will in
time exceed observational data and the probability estimates based upon
currently clinical parameters - comes the desire for effective early
intervention. Currently, the clinical management debate revolves around
the timing of hormone deprivation, early or late, or a whether a combined
chemo-hormonal regimen is appropriate. The next wave, however, will be the
early application of effective vaccine therapy; or treatment based on
therapeutic antibodies, radiolabled or not, against appropriate CD
targets. Stay tuned.
BOTTOM LINE:
More accurate information about prostate cancer cell behavior will lead to
a clearer definition of management choices.
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