Research Article
The Impact of Monoclonal Origin and Intraluminal Seeding Mechanism on Management of Non-Muscle Invasive Bladder Cancer: Needs for More Preoperative Adjuvant Intravesical Immune-and/or Chemo-Therapy
Imad Fadl-Elmula*
Department of Urology and Clinical Genetics, Assafa Academy, Sudan
*Corresponding author: Imad Fadl-Elmula, Department of Clinical Genetics, Assafa Academy, Khartoum, P. O. Box 12864 Cod 11111 Khartoum, Sudan
Published: 26 Feb, 2018
Cite this article as: Fadl-Elmula I. The Impact of
Monoclonal Origin and Intraluminal
Seeding Mechanism on Management of
Non-Muscle Invasive Bladder Cancer:
Needs for More Preoperative Adjuvant
Intravesical Immune-and/or Chemo-
Therapy. Clin Oncol. 2018; 3: 1420.
Abstract
Bladder cancer is a common disease, worldwide it is ranked as the seventh and the seventeenth most
frequent cancer worldwide in men and women respectively. Based on the histopathology (grading
and staging), bladder cancer can be classified into non-muscle invasive (superficial) and muscleinvasive
disease. The natural history of the superficial tumors differs from the muscle invasive
ones. Most non-muscle invasive tumors are characterized by multiplicity, high recurrence rate,
and heterogeneous natural history. According to many investigators, the multifocal nature of nonmuscle
invasive uroepithelial cancer, together with a propensity for recurrence (polychrono topicity)
is the results of intraluminal seeding of viable detached malignant cells that results in genetically
monoclonal multiple tumors. Thus, the intraluminal shedding and implantation of viable tumor
cells have been proposed as the mechanisms responsible for both synchronous and metachronous
multifocal bladder tumors. These findings are of considerable relevance for therapeutic strategies,
suggesting that complete endoscopic removal of the primary tumor is often not enough to treat
even non-muscle invasive bladder cancer because by, or during, the time of initial treatment, several
micro satellite tumors are already implanted in the bladder. Therefore, additional measures to
prevent tumor cell seeding and growth of the already implanted ones may reduce the recurrence
rate of non-muscle invasive bladder cancer.
The intraluminal seeding mechanism of synchronous and/or metachronous tumors enforces
more emphasis on intravesical adjuvant therapy in superficial bladder cancer, including the use of
intravesical chemo- or immunotherapy and long interval follow-up for those patients. Adopting
such therapeutic strategy may improve morbidity and mortality of superficial bladder cancer.
Introduction
Bladder cancer is a common disease, both in industrial and developing countries.
Cancer of the bladder is estimated to be the ninth most common cause of cancer worldwide and the
13th most numerous cause of death from cancer [1]. It is the 7th most common cancer in males and
the 17th most common in females worldwide [2]. Family history is associated with an approximately
two fold increased risk in cancer [3].
The disease is highly heterogeneous considering their natural history, histological, and
geographic characteristics. Although, 75–85% of patients with bladder cancer present with a disease
that is confined to the mucosa or submucosa, known as the non-muscle invasive bladder cancer
(NMIBC) [4], the disease still represents a major therapeutic challenge since 30% of urinary tract
TCCs are found as multiple tumors at the time of diagnosis, and 70% of the non-muscle invasive
bladder tumors recur after initial cystoscopic resection [5,6] of these recurrent cases, 80% remain
superficial throughout the life of the patient, whereas 16% to 25% eventually recur as higher grade
and/or stage tumor(s) [7,8]. A small percentage (10–15%) of all noninvasive (superficial) lesions will
progress to muscle-invasive disease, and genetic instability is crucial to this progression [9]. Even
tumors of same pathologic stage, may follow very different clinical courses. Current prognostic
markers (tumor grade, multiplicity, tumor shape, location, and presence of carcinoma in situ (Cis)
are of limited value [10] why it is difficult to predict the clinical course, especially for superficial
bladder tumors. However, the high rate of recurrence and disease progression may indicate
inadequate current therapeutic modalities.
The multifocal nature of bladder cancer, the tendency for
recurrence (polychrono topicity), and the dysplastic changes that
usually seen surrounding bladder tumors [11], have been interpreted
as evidence of field disease [12]. According to this field disease theory,
the entire epithelium is tumor-prone in the sense that multiple
polyclonal primary lesions are likely to emerge from it, either
synchronously or metachronously [13]. The alternative, monoclonal
view assumes a common clonal origin of all multiple and/or recurrent
tumors in each patient, implying that these macroscopically distinct
lesions develop as the result of intraluminal seeding of cancer cells
shed from the primary tumor. Support for the monoclonal hypothesis
has come from molecular, cytogenetic, and molecular cytogenetic
studies [14,-16]. Epidemiologic and clinical data have shown that
patients with ureteral or renal pelvis tumors have a higher (40%) risk
of having tumor(s) also of the bladder, and if carcinomas of both
the renal pelvis and the ureter are present, the probability of having
BC increases up to 75% of cases [17,18]. The proportion of patients
with non-muscle-invasive bladder cancer developing metachronous
upper urinary tract-TCC varies from 0.7 to 4% [19]. The present
report reviews the previous reports on clonal origin of multifocal
uroepithelial carcinoma and the implication of their findings on the
treatment and follows up of patients with non-muscular invasive
bladder cancer.
Material and Methods
Several reports on the clonal origin of multiple macroscopically
distinct uroepithelial tumor lesions (bladder tumors, ureteral tumors,
recurrent bladder tumors), obtained from the same patients have
been published. Those studies used various analysis techniques such
as cytogenetic analysis [15], comparative genomic hybridization
(CGH) technique [16], microsatellite markers to examine genetic
alterations [20,21], methylation patterns of the androgen receptor
gene (HUMARA) located at the X-chromosome [22,23], and CD44
alternative splicing patterns [24]. Other studies used molecular
analyzed of p53 tumor suppressor gene mutation by PCR-SSCP
and sequencing [14,25-27]. Loss of heterozygosity (LOH) assays
and X-chromosome inactivation [28], and most recently exome
sequencing [29].
In most of the studies, the synchronous and/or metachronous
multifocal tumors were carefully, separately collected and processed.
For studies using X-inactivation only tumors from female patients
were analyzed. The cytogenetic clonality criteria and the karyotype
descriptions were done according to the ISCN recommendation [30].
The Grading and staging were done according to WHO (1973) criteria
and the UICC (1978) tumor-node-metastasis (TNM) classification
system, respectively [31].
Results
The cytogenetic analysis of multiple tumors obtained from each
patient, including recurrent ones have shown consistent cytogenetic
monoclonality seen as almost identical karyotypes demonstrating
their common clonal origin. CGH Studies showed that all tumors
derived from the same patient shared a set of identical alterations
suggesting common clonal origin.
TP53 mutation analysis revealed identical TP53 mutations and
protein over expression in individual tumors in molecular studies.
The results provide further strong evidence for a monoclonal origin
of multifocal bladder cancer. It also suggests an intraepithelial
migration of tumor cells carrying specific chromosomal aberrations.
The same conclusion reached in studies using methylation analyses.
All tumors were monoclonal as indicated by unbalanced methylation.
Furthermore, same methylated allele has been detected in multiple
recurrent or multifocal tumors from any given patient, indicating
their identical clonal origin. Studies used loss of heterozygosity
(LOH) technique showed nearly identical pattern of allelic loss
indicating the common clonal origin. Phylogenetic analysis of high
confidence single nucleotide variants (SNV) demonstrated that the
sequenced multifocal bladder cancers arose from a clonal origin in
the tumors of each patient.
Discussion
Although studies investigated the clonal origin of bladder
cancer tumors have used various techniques, they reached the same
conclusion that multifocal uroepithelial tumors have a monoclonal
origin that arise via intraluminal seeding of viable cancer cells shed
from the original tumor. The results of all studies suggested that
the later lesions develop also from cells shed from so-called second
primary tumors, and according to genetic evolution, the seeding of
tumor cells is a comparatively late event that succeeds the acquisition
by them of multiple secondary genetic abnormalities [32,33].
Cystoscopic examination has a major limitation as a follow up tool
because tiny papillary tumors are easily overlooked, Cis, dysplasia,
and cases of microscopic recurrences cannot be detected [34]. Urine
cytology has low sensitivity for well-and moderately differentiated
cells that represent around 75% of all bladder cancer at diagnosis
[35]. Positive urine cytology ranged between 10% and 90% based on
the grade of the tumors [36]. Even when random biopsies are taken,
only 24% of the cases can be diagnosed. Based on FISH studies using
in the majority of the cases microscopic recurrences were detected
as malignant cell in urine samples collected from patient with
previous history of bladder cancer and present not so ever clinical
or radiological evidence of recurrent disease [37]. This may indicate
that in fact residual cancer following transurethral resection is more
than one would expect. However the logical question should be
whether all these so called micro-recurrences will give rise to clinical
recurrences. No present answer available but epidemiological data
suggesting this possibility. Another strong evidence arrived from
analysis of synchronous and metachronous tumors along the urinary
tract system showed monoclonal origin indicating the intraluminal
seeding mechanism as a mechanism responsible behind high rate
of recurrences and multifocality often seen in uroepithelial tumors
[24,26]. Epidemiological data revealed that an upper urinary tract
tumor is associated with a 75% probability of finding tumor(s) also in
the bladder, whereas the risk of developing a ureteral tumor following
the diagnosis of a bladder tumor is only 4% [18]. Studies investigated
the clonal origin of associated bladder tumor(s) with ureteral tumor
in the same patient concluded a downstream shedding of cancer
[15]. Thus such data argue against the regrowth of a new tumor at
a site different from the primary and instead favor the shedding and
intraluminal seeding hypothesis [16].
By ruling out the field cancerization view it is then clear that most
tumors including superficial papillary ones are in fact inadequately
treated. Clinical studies showed that after standard transurethral
resection, about 60%of superficial tumors recur as tumors of the
same grade and stage, whereas 25% relapse with more advanced and
aggressive forms of cancer [35].
Because intraluminal shedding and implantation of tumor cells is
the mechanism responsible for both synchronous and metachronous
multifocal uroepithelial carcinomas, it is beyond doubt that complete
endoscopic removal of the primary tumor is not enough in the
treatment of even non-invasive. In addition to endoscopic removal
of the superficial tumors, measures against the intraluminal seeding
of the cancer cells and their ability to divide should be taken,
perhaps in form of routine intravesical therapy of superficial bladder
cancer. Several clinical studies revealed that therapy with adjuvant
intravesical chemotherapy reduces the risk of tumor recurrence but
has no effect on the risk of progression [38]. This clinical observation
is in complete agreement with seeding notion. In addition to
chemotherapy, Immunotherapy with live BCG vaccine turned to be
an effective treatment of carcinoma in situ as long ago as 1976 [4], and
the vaccine is still the only intravesical agent capable to reduce both of
these risks in spite to its complication [4].
That intraluminal shedding and implantation of tumor cells is
the mechanism responsible for both synchronous and metachronous
multifocal bladder cancer may be of considerable relevance for
therapeutic strategies. Additional measures should be directed toward
stopping tumor cell seeding and the ability of already implanted
tumor cells to divide and growth. This implies more emphasis on
intravesical adjuvant therapy in superficial bladder cancer, including
the use of anti-inflammatory drugs, antagonists of cell adhesion,
and intravesical chemotherapy or immunotherapy with BCG. The
possibility of seeding viable cancer cells during the endoscopic
removal of the tumor suggest the avoidance of unnecessary trauma
to the urethelium during this procedure also seems stronger. The
practice of taking random bladder biopsies or removing a benign
prostate at the time of bladder tumor surgery seems illogical in this
perspective and should probably be avoided.
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