4.4 Bladder cancer classification
Bladder cancer was earlier annotated with mutation recurrence in 32
genes114 and characterized with signature genetic
metabolism predispositions that includes; N-acetyl transferase editosome
due to “apolipoprotein B mRNA editing enzyme, catalytic
polypeptide-like” (APOBEC)-cytidine deaminases.10Profiling of 58-genes and genes fusion of 784 genes have identified
APOBEC signature mutations,115 that are highest in
bladder cancer due to overexpression of APOBEC3B genes than in all solid
tumours109 . However, cigarette smoking associated
gene (GSTM1-null) has been found more susceptible in females andFGFR3 mutation which is more frequent in non-muscle invasive
bladder cancer (NMIBC) types.10 Accurate association
of bladder cancer histological variants pathological features and
specific molecular mutational pattern might provide promising target for
developing therapy.116 So far, the European
Association of Urology has provided guidelines on identifying
evidence-based prognosis and progression115 as
different morphological subtype has different clinical course and
response to treatment.117 Lin and
colleagues102 recommend the use of radiomics and
transcriptomics in further identification of prognostic signature
markers for the different variants of bladder cancer.
The two main types of bladder cancer include the non-muscle-invasive
bladder cancer (NMIBCs), which is a low-grade
tumour,103,115 accounting for about 75% of all
diagnosed cases10,103 and has been associated with a
relative stable genomic FGFR mutation10,103 and
homozygous deletion of CDKN2A .118 Gene
expression profiling has identified 3 subtypes of NMIBCs from a luminal
to basal type marker progression shift from class 1 to class
3.119 Other type of bladder cancer is the
muscle-invasive bladder cancer (MIBC), although less frequently
diagnosed, it is genetically predisposed as unstable and divergent
type109,119. MIBC progress from a flat lesion and
gradually acquire gene mutations that promote cell proliferation and
survival120 and are associated with aneuploidyTP53 mutations.10,103 Other mutations observed
with MIBCs include p53 expression stability, upregulated cytokeratin 20
(CK20 ) and HER2 /neu genes and downregulated PTENexpression that is associated with upregulation of phosphatidylinositol
3-kinase (PI3K) pathway.10 Additionally, the common
RB1 deletion and 6P amplification are associated with MIBCs
development118 with an unfortunate less than 50%
5-year survival.103,117 However, the NMIBCs exhibits a
papillary growth pattern of low malignancy potential, however, they
requires an expensive clinical management which includes local resection
due to high tendency of recurrence.115,120
Nevertheless, the earlier anatomical based classification of bladder
tumour (NMIBC; Tis, Ta &T1 and MIB; T2, T3 & T4) had limitation in the
understanding of the diverse prognosis within same tumour
type.121 Several studies have speculated that tumour
heterogeneity might be associated with diagnosis, metastasis and
pre-existing treatment resistance especially in the case of
MIBCs.121 Therefore, for an optimized patient
precision therapeutic management, identification of an accurate
histopathological116,122 and specific transcriptomic
biomarkers are encouraged to be adopted.123 Based on
this, bladder cancer has been classified into urothelial carcinoma (UC),
urothelial carcinoma with variant (UCV), squamous cell carcinoma (SCC),
and adenocarcinoma (AD) subtypes.124,125Transcriptomics and other molecular techniques have led to the
identification of urothelial carcinoma (UC) that account for
75%116 or even up to 90%126 of the
bladder cancer. Whereas the remaining 25%, comprises of other
histological variants known as the nonurothelial
cancer.116 Invasive UC have a tendency to progress
into divergent variants of nonurothelial tumours through progressive
histological differentiation.126 Nonurothelial tumours
are also known to consist of different range of rare variants based on
the WHO 2016 classification that include the pure squamous, glandular,
neuroendocrine, sarcomatoid, micropapillary, plasmacytoid, microcystic,
clear cell and pure histological variants.116,117 The
pasmacytoid variant has been reported to have the worst overall survival
mean.116,124 In addition, other sub-populated tumours
with either the pure squamous cell or glandular differentiation are
shown not to be sensitive to adjuvant chemotherapy unlike their
counterpart that are populated with small cell carcinoma which are
however aggressive and sensitive to neo-adjuvant
chemotherapy.124
Moreover, UC is more prevalent in developed countries like Japan, North
America, Western countries,122 while squamous cell
carcinoma (SCC) and adenocarcinoma have a higher prevalence in countries
like Egypt.125 Zhang et al101 used
high-throughput transcriptomic profiling in cisplatin resistant UCs, to
unravel differential splicing in more than 300 genes with the specific
dysregulation in five candidate genes were validated with real time PCR.
These including upregulation of CDH1 , VEGFA , PTPRF ,CLDN7 genes and downregulation of MMP2 gene that are all
together involved in cell adhesion molecules (CAMs), focal adhesion and
bladder cancer progression pathways.101 In rare UC
cases, fusion transcripts associated with chromosomal region
rearrangements (17q25, 15q26.3 and 1p36.22) have been identified asSET9/CYHR, IGF1R/TTC23, SYT8/TNN12 and CASZ1/DFFA transcripts
respectively.47 Similarly, about 25-30% of UC of the
bladder possess histological variant which are predominantly populated
with SCC known as the urothelial carcinoma with variant
(UCV),125 which are associated with an enrichment ofMAPK signaling pathway121. Although SCC of the
bladder represent a small fraction (2%-5% in the United State) of
prevalence in the western countries based on the National Cancer
Database (NCDB), it attributes the worse prognosis both in terms of
stage-for-stage, grad, relapse and overall survival and to the
UC.116,127 Both the UC and SCC are derived from UCV
and have been demonstrated to have identical driving genes but
completely different transcriptional profiles.128 On
the other hand, SCC has also been attributed to be less responsive to
chemotherapy, thus its standard pre-existing treatment is still radical
cystectomy (RC) which might provide the maximal 5-year
survival.129 Unlike UC, SCC is shown to have a
negative expression of immune inhibitors biomarkers such as PD-L1, thus
its higher grade and aggressive association. Owyong et
al129 suggests the increase in the expression of
PD-L1might improve the immune response associated with treatment
outcome. Primary adenocarcinoma represents 0.5-2% of the all diagnosed
bladder cancer, like SCC it has a poor prognosis and has a weak TM
immunoexpression score than UC.130
On the other hand, small cell carcinoma (SmCC) is a rare bladder cancer
variant (less than 1% of all bladder diagnosis) and belongs to the
neuroendocrine carcinoma (NEBC) family, usually presented at a late
stage.126 Neuroendocrine carcinoma is somewhat similar
and sometimes intermingle with UC, although relatively rare (0.5-1.2%
of new cases) it is highly lethal with a 1-year survival
progression.126,131 Small cell carcinoma of the
bladder is associated with a depletion of CCND1 and an
amplification of CDKN2A genes whereas in UC, CDKN2A gene
is depleted while CCND1 gene is amplified.131This variant has neuronal marker signatures including upregulation ofNESTIN , TUBB2B , PEG10 gene with low or no
expression of basal or luminal biomarkers.131,132Another identified novel marker of SmCC is dysregulated PVT1-ERBB2
affecting ERBB2 gene expression which compliments the general MIBC
signature markers; TP53 and RB1 depletion,126,133and
are evident in their histological features.131Although SmCC/ NEBC may express basal or luminal biomarkers, a few of
them have a basal molecular feature which might explain their positive
response to chemotherapy126,132 or radiotherapy in
improving survival.132 Study by Shen and others, shows
that NEBC were sensitive to P13k inhibitor (GDC-0941) and FGFR inhibitor
(NVP-BGJ398). While Wang et al126 recommended
utilizing the common RB1 gene depletion as a potential therapeutic
target.