Halal and Kosher Vitamin D products

An Overview:
Dynamic Contrast Enhanced Imaging of
Prostate Cancer
Isabelle Chrysanthou-Baustert
April 2006
Imaging philosophy
For many years, medical imaging focused on the anatomy of the body by
taking a picture of the organs. Latest techniques allow us to investigate
physiological and even molecular features of the imaged tissue. The
interpretation of such images requires thus a thorough understanding of the
imaging technique as well as a deep understanding of the biology and
physiology of the healthy and diseased organ.
The switch to these new techniques represents a steep learning curve. To
assist in this task we present some basic anatomy and physiology of the
normal prostate. The many different types of diseases that are relevant make
it difficult to give a complete picture in a couple of lines. Thus a summary of
the most important findings is presented here. References to more detailed
publications are also given.
A note of care:
MRI and in particular dynamic contrast enhanced (DCE) MRI is very sensitive
to benign or malignant conditions of the tissue. This has increased the
numbers of false positive radiological assessments. The false positive issue
becomes even more critical when screening a population, i.e. when scanning
a population which has a high probability of not having a malignant problem.
Researchers developing computer aided diagnostic tools have been pushed
to change the investigation paradigm. The question now asked is “show me
what is normal” rather than “let me find the tumour”.
Molecular and cellular research is in its infants shoes and the myriads of new
findings in this field is lacking full understanding and is not correlated with
radiological appearances.
In practice, a radiologist is left with only little information from clinical studies
to take decisions as to what could the diagnosis be.
Basic Anatomy
Several systems of terminology are available. With respect to MRI imaging,
the zonal anatomy has mostly replaced lobar anatomy and in young men four
zones can be differentiated: (1) peripheral zone (PZ), (2) transition zone (TZ),
(3) central zone (CZ), and (4) anterior fibromuscular stroma (AFS) zone.
The nonglandular anterior fibromuscular stroma (AFS) is an anterior
band of fibromuscular tissue contiguous with the bladder muscle and
the external sphincter.
The peripheral zone (PZ) contains about 70% of the glandular tissue
and forms the external layer of the prostate predominant at the apex
and the posteriolateral side.
The central zone (CZ) surrounds the ejaculatory ducts.
The transition zone (TZ) is central and less prominent in younger men.
With increasing age, the TZ may become the dominant zone (hypertrophy)
reducing the visibility of the CZ on T2 images and compressing the PZ.
Therefore, the term central zone is often used to define the TZ hypertrophy
clearly visible on ultrasound and MRI. The TZ, PZ, and the AFS are clearly
defined on T2 MRI. Two papers explaining the anatomy of the prostate for
imaging and radiotherapy treatment planning have recently been published
(1) (2).
The neurovascular bundles contain the cavernous nerves responsible for
potency. They are located in close proximity to the prostate gland on the
posterolateral surface. Branches of the neurovascular bundles enter the
prostate at the base (superior pedicle) and the apex (inferior pedicle)
posterolaterally. They represent the main route of extraprostatic spread of
cancer as they enable cancer cells to bypass the anatomical barrier of the
prostate capsule. Extracapsular extension in the absence of perineural
invasion is uncommon and is usually associated with large, high-grade
tumors. Extracapsular extension most commonly occurs on the posterolateral
surface of the prostate near the region of the neurovascular bundles. The
distance from the prostate capsule to the neurovascular bundle is 2 to 5 mm
at the apex (inferior pedicle) and 10 to 15 mm at the base (superior pedicle)
on the posterolateral surface of the prostate.
Basic physiology
From a molecular point of view, the prostate gland consists of a duct system
composed of epithelial cells overlying a fibromuscular stroma (3). The lining of
the prostatic ducts is found to vary depending on how central they are
positioned within the gland, making up the different zones. Indeed, the cells of
the stroma vary from almost exclusively fibroblast distally to almost wholly
smooth muscle at the proximal end of the ducts. The specific competences of
these regions are not only due the structure, abundance and variety of the
stromal cells, but also due to the growth factors they generate and impose
upon themselves.
To get a flavour of the complexity of the cellular physiology we have
researched the two most common diseases and present a summary below.
Benign prostatic hyperplasia (BPH)
It is thought that BPH is a mesenchymal disease and results from the
reawakening of embryonic inductive interactions between the prostatic stroma
and epithelium (4). BPH is a truly hyperplastic process characterized by an
increase in the total cell population, which is due to cellular proliferation and
escape from the normal apoptotic process. BPH can progress to carcinoma,
but it is rare. It seems that epithelial cells within BPH maintain their normal
restriction to the basal cells. At an early stage, BPH is characterised by the
hyperplasia of mainly stromal tissues around the urethra with excessive
growth localised to the points where the ejaculatory ducts enter into the TZ of
the prostate (5). As the prostate grows larger during BPH, hyperplasia of
glandular tissue might predominate. In general, the heterogeneous nature of
BPH nodules in different prostatic areas makes generalisation difficult. In
addition, tissue composition of BPH can change with time. The histological
appearance of epithelium in BPH is flattened with a decrease in mean
epithelial height compared to normal TZ. In addition the intraluminal space is
increased in BPH by 125%. The lymphatic vessels density has been reported
to be higher in BPH than in normal areas. Microvesseldensity (MVD) is lower
in BPH than in cancer (6).
Prostate Cancer (CaP)
The activation of carcinoma is reported to be due to a genomic alteration in
which the host microenvironment plays a key role (7). Indeed, it has been
found that factors from the host rather than from the tumour can contribute
angiogenesis and tumour formation. Growth factors produced by all cells of
the organ act in a paracrine and autocrine way to promote the ability of cancer
cells to acquire altered behaviours, e.g. progression to androgen
independency and osteomimicry (leading to metastasis) (8). Unlike in BPH,
CaP involves proliferation not only of the basal epithelial cells but also of e.g.
luminal epithelial cells. Extracellular matrix remodelling and angiogenesis are
prerequisites for cancer growth and metastasis. Indeed, an increase in
microvessel density is seen in CaP (9). Several papers report no correlation
between MVD and Gleason score (6) (10). On the other hand, a recent
investigation reports destruction of lymphatic vessel in CaP but not at the
tumour periphery (6).
Epidemiology and molecular research are gathering increasing evidence that
recurrent prostate inflammation may initiate and promote cancer development
Imaging Prostate
An overview of T1, T2 and DCE characteristics of prostatic tissue is given in
Appendix 1.
T2 images
MRI provides the most accurate information about the anatomy and location
of tumour compared to other imaging modalities like US and CT. So far it has
the highest staging accuracy of any diagnostic imaging technique available.
The detection T3b tumours invading the seminar vesicles could make a
significant difference in planning radiotherapy treatment. Its routine use
though in staging of all prostate cancers remains controversial, because of a
wide range of reported accuracies. Diagnostic imaging requires knowledge as
well as acquired skills and undoubtedly the experience of the radiologist plays
a key factor in prostate MRI interpretation (12).
Prostate is best seen on T2-weighted images. The normal PZ shows high
signal intensity on T2 images. It is surrounded by a slim low signal intensity
rim representing the prostate capsule. The TZ and CZ present with lower and
more heterogeneous signal intensities than the PZ.
Prostate cancer usually induces lower signal intensity than the healthy
surrounding tissue, but these changes are not entirely specific to cancer, as
benign conditions such as haemorrhage, prostatitis, and the sequelae of
radiation or hormone treatment produce a similar signal drop.
MRI should not be performed during 4-6 weeks after biopsy to avoid
diagnostic misinterpretations due to haemorrhage.
The diagnosis of cancer in the CZ and TZ is more complex because of the
difficult differentiation with nodules of hyperplasia. Confluent areas of low
signal intensity are most useful findings, suggesting central gland cancers.
While wedge shape diffuse extension without mass effect are indicative of
benignity (13).
There are acknowledged limitations in the detection and staging of cancer on
T2 images: cancer is not always identified in the PZ as a low intensity and the
detection of cancer in the CZ and TZ is a bigger problem mainly due to
inhomogeneous signal intensities due to the hyperplastic nodlues.
T1-weighted images do not show the internal architecture of the prostate, but
the information can be used to to assess post-biopsy haemorrhage within the
prostate as well as aiding interpretation of the integrity of the prostate capsule.
Dynamic Contrast Enhanced images
Dynamic contrast enhanced (DCE) imaging has been introduced to
investigate the neovascularisation (angiogenesis) which is necessitated for
the growth of any new tissue i.e. cancer (14). DCE MRI has the potential to
detect cancer and any other disease involving angiogenesis. Since the
beginning of DCE MRI in the early 1990, imaging research has progressed
and spatial and temporal resolutions have been optimised to produce the best
results possible.
When investigating DCE MRI data, the PZ and the TZ are assessed
separately, due to their difference in anatomy, physiology and most probable
disease generation.
In the PZ, clinical studies report a higher accuracy of CaP detection with
dynamic parameters from DCE MRI compared to T2 images (15) (16) (17).
Kim presents good results with a wash-in rate, while Engelbrecht reports
highest discrimination between normal and malignant with relative peak
enhancement (tumour peak enhancement normalised to normal tissue peak
enhancement in PZ and CZ resp.).
Discrimination between benign and malignant in the inner part of the TZ on
the basis of DCE MRI alone remains a challenge. Additional information about
PSA and prostate size might aid differential diagnosis (17). Compared to PZ
tumours of similar size and grade, TZ cancers are associated with a
favourable prognosis due to natural barriers to extension (eg, urethra, anterior
fibromuscular stroma, fibrous plane between TZ and PZ) and inherent biologic
Interesting new work by Noworolski (18) gives indication about enhancement
pattern of stromal and glandular BPH in the CZ. According to her paper,
combined with T2 images a discrimination between CaP and BPH would be
possible (cf the table above).
DCE MRI is particularly suited to assist decision making in cases of suspected
extracapsular extension. The enhancement pattern at the prostate edge itself
might confirm or reject the suspicion of the radiologist.
After radiotherapy, prostate tissue demonstrates diffuse low signal intensity on
T2 images. Recurrent tumour show poor contrast and cannot be distinguished
from the post radiotherapy fibrosis. Rouviere (19) has shown that contrast
enhanced MRI increase diagnostic accuracy from 0.60 to 0.79.
Padhani (20) has investigated the effects of androgen deprivation on DCE
MRI. He reports a reduction in tumour volume and vascularisation due to
fibrosis induced by androgen deprivation.
Villeirs GM, K LV, De Neve WJ, De Meerleer GO. Magnetic resonance
imaging anatomy of the prostate and periprostatic area: a guide for
radiotherapists. Radiother Oncol 2005;76(1):99-106.
McLaughlin PW, Troyer S, Berri S, Narayana V, Meirowitz A, Roberson
PL, Montie J. Functional anatomy of the prostate: implications for
treatment planning. Int J Radiat Oncol Biol Phys 2005;63(2):479-491.
Farnsworth WE. Prostate stroma: physiology. Prostate 1999;38(1):6072.
Lee KL, Peehl DM. Molecular and cellular pathogenesis of benign
prostatic hyperplasia. J Urol 2004;172(5 Pt 1):1784-1791.
Untergasser G, Madersbacher S, Berger P. Benign prostatic
hyperplasia: age-related tissue-remodeling. Exp Gerontol
Trojan L, Michel MS, Rensch F, Jackson DG, Alken P, Grobholz R.
Lymph and blood vessel architecture in benign and malignant prostatic
tissue: lack of lymphangiogenesis in prostate carcinoma assessed with
novel lymphatic marker lymphatic vessel endothelial hyaluronan
receptor (LYVE-1). J Urol 2004;172(1):103-107.
Gonzalgo ML, Isaacs WB. Molecular pathways to prostate cancer. J
Urol 2003;170(6 Pt 1):2444-2452.
Chung LW, Baseman A, Assikis V, Zhau HE. Molecular insights into
prostate cancer progression: the missing link of tumor
microenvironment. J Urol 2005;173(1):10-20.
Schlemmer HP, Merkle J, Grobholz R, Jaeger T, Michel MS, Werner A,
Rabe J, van Kaick G. Can pre-operative contrast-enhanced dynamic
MR imaging for prostate cancer predict microvessel density in
prostatectomy specimens? Eur Radiol 2004;14(2):309-317.
Kiessling F, Lichy M, Grobholz R, Heilmann M, Farhan N, Michel MS,
Trojan L, Ederle J, Abel U, Kauczor HU, Semmler W, Delorme S.
Simple models improve the discrimination of prostate cancers from the
peripheral gland by T1-weighted dynamic MRI. Eur Radiol
Nelson WG, De Marzo AM, DeWeese TL, Isaacs WB. The role of
inflammation in the pathogenesis of prostate cancer. J Urol 2004;172(5
Pt 2):S6-11; discussion S11-12.
Carey BM. Imaging for prostate cancer. Clin Oncol (R Coll Radiol)
Cruz M, Tsuda K, Narumi Y, Kuroiwa Y, Nose T, Kojima Y, Okuyama
A, Takahashi S, Aozasa K, Barentsz JO, Nakamura H.
Characterization of low-intensity lesions in the peripheral zone of
prostate on pre-biopsy endorectal coil MR imaging. Eur Radiol
Folkman J. The role of angiogenesis in tumor growth. Semin Cancer
Biol 1992;3(2):65-71.
Kim JK, Hong SS, Choi YJ, Park SH, Ahn H, Kim CS, Cho KS. Wash-in
rate on the basis of dynamic contrast-enhanced MRI: usefulness for
prostate cancer detection and localization. J Magn Reson Imaging
Engelbrecht MR, Huisman HJ, Laheij RJ, Jager GJ, van Leenders GJ,
Hulsbergen-Van De Kaa CA, de la Rosette JJ, Blickman JG, Barentsz
JO. Discrimination of prostate cancer from normal peripheral zone and
central gland tissue by using dynamic contrast-enhanced MR imaging.
Radiology 2003;229(1):248-254.
Hara N, Okuizumi M, Koike H, Kawaguchi M, Bilim V. Dynamic
contrast-enhanced magnetic resonance imaging (DCE-MRI) is a useful
modality for the precise detection and staging of early prostate cancer.
Prostate 2005;62(2):140-147.
Noworolski SM, Henry RG, Vigneron DB, Kurhanewicz J. Dynamic
contrast-enhanced MRI in normal and abnormal prostate tissues as
defined by biopsy, MRI, and 3D MRSI. Magn Reson Med
Rouviere O, Valette O, Grivolat S, Colin-Pangaud C, Bouvier R,
Chapelon JY, Gelet A, Lyonnet D. Recurrent prostate cancer after
external beam radiotherapy: value of contrast-enhanced dynamic MRI
in localizing intraprostatic tumor--correlation with biopsy findings.
Urology 2004;63(5):922-927.
Padhani AR, MacVicar AD, Gapinski CJ, Dearnaley DP, Parker GJ,
Suckling J, Leach MO, Husband JE. Effects of androgen deprivation on
prostatic morphology and vascular permeability evaluated with mr
imaging. Radiology 2001;218(2):365-374.
Buckley DL, Roberts C, Parker GJ, Logue JP, Hutchinson CE. Prostate
cancer: evaluation of vascular characteristics with dynamic contrastenhanced T1-weighted MR imaging--initial experience. Radiology