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PATHOLOGY of the URINARY TRACT - Coggle Diagram
PATHOLOGY of the URINARY TRACT
normal urothelium
7 layers
this concept is useful to understand if there is something wrong!
basal cells at the bottom and above the umbrella layer
it this is preserved, the lesion is benign by definition
the different cellular layers do not have the same IHC markers
superficial layers: low molecular weight cytokeratins (CK18, 20)
basal layers: high molecular
weight cytokeratins (CD5, 10, 14);
basal markers (p63)
this epithelial lining is a transitional epithelium
the lamina propria changes in thickness depending on the organ
very well represented in the bladder
very thin in the ureter
muscularis mucosa is not complete, differently from GI tract
this is the reason why it is not used for diagnostic or staging purposes
keep in mind the difference between bladder and ureter
they are made up of the same layers, but different thicknesses are observed
this explains why bladder cancer is diagnosed earlier as compared to ureteral cancer
ureter
congenital anomalies
atresia
duplication or ectopia
diverticula
inflammation
generally, moving to the bladder
tumors
obstructions
intrinsic (calcula, uretral tumors)
lithiasis
frequent
test Ca++ and hyperparathyroidism (secondarily, also uric acid, dietary factors, tubular acidosis, intestinal Ca++ uptake, gout, leukemia, proteus infections
complications: inflammation, hemorrhage, ulcers, infections
extrinsic (extraperitoneal fibrosis, pregnancy, endometriosis, extra-ureteral tumors)
bladder
paraphysiological anomalies
CYSTITIS CYSTICA and
CYSTITIS GLANDULARIS
no alterations typical of cancer; the lesion located submucosally, but the urothelium is normal
in the lamina propria of the bladder, Von Brunn urothelial nests can be seen and they correspond to nests of normal-looking urothelial cells
when a degenerative process occurs, they
start having a lumen (cystitis cystica)
this condition may progress to cystitis glandularis when intestinal / glandular metaplasia is acquired
SQUAMOUS METAPLASIA
non-keratinizing
more common in females
(pre- or post-menopausal)
keratinizing
more frequent
evolution of chronic inflammatory processes
anterior wall
possible precursor of SCC
GLANDULAR METAPLASIA
linked to cystitic cystica; possible
precursor of adenocarcinoma
the maturation may be complete (transformation in glandular epithelium, typical of the intestinal wall) or incomplete
sometimes associated with neuroendocrine cells
likely to become the site of origin of NE-differentiated cancers in the bladder
NEPHROGENIC METAPLASIA / ADENOMA
stroma with tubular / papillary epithalial structures
hamartomatous appearance
blunt appearance, no atypia, arranged in cystic spaces covered by tubular or papillary structures
no possibility of evolution
clearly visible at macroscopy
congenital anomalies
EXTROPHY
anomaly in the development of the abdominal wall and bladder, resulting in the external exposure of the bladder mucosa
there is a change in the type of epithelium:
from urothelium to glandular metaplasia
increased risk of infections and AC
CONGENITAL DIVERTICULA
primary alterations of the bladder wall
when they are congenital, there is a complete wall involvement (similar to normal bladder wall)
in acquired diverticula, the muscular layer is not present and they are mainly caused by obstruction: only urothelium and lamina propria are seen
VESICOURETERAL REFLUX
normally, the anatomy of the ureter allows the creation of a sort of obstruction of the lumn during urination, thus preventing the reflux
reflux occurs in the presence of abnormal angles between ureters and bladder due, for example, to an underlying infection
URACHAL REMNANTS
glandular structures, possible umbilical fistula and risk for AC
usually, the epithelium covering the urachus is totally lost in adult life
some remnants can be seen in the bladder dome, with residual glandular structures
obstructions
PROSTATIC HYPERTROPHY
most common cause in men
STENOSIS
congenital
acquired
multiple
false
variable size
calcula
inflammation
squamous metaplasia
INFLAMMATION
infective and non-infective,
specific and non-specific
inflammation is very frequent, especially in females of reproductive age
spread
ascending: most frequent, E. Coli, Proteus, Klebsiella, Enterobacteria, diabetes, calcula, stagnation, catheter
descending / hematogenous: TBC, Candida, Schistosoma
pathology
macro: mucosal edema and bleeding (hemorrhagic cystitis) or exudative forms
micro: granulocytes, RBCs, ulcers
if chronic evolution: lymphocytes and plasma cells + follicles (follicular cystitis)
complications: perivesicular abscess, fistulae, peritonitis
specific forms
interstitial cystitis (CD117):
full thickness
unknown etiology (AID?)
middle-aged females
posterior wall/dome
chronic infiltrate
mast cells and fibrosis
clinically associated with pain and impairment of abladder function
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malacoplakia (CD68, Von Kossa):
foamy histiocytes (full of debris from phagocytosis)
PAS+ with Michaelis-Gutmann bodies (laminar, Ca++)
--> microscopic calcifications
unknown etiology (inadequate phagocytosis)
immunocompromised patients (unbalanced stimulation of the immune system, together with inadequat processes of phagocytosis
in the urogenital tract, not only the bladder
eosinophilic cystitis
polypoid (catheterization)
radiation-induced cystitis
only clinical, not histological
granulomatous cystitis
TBC-related
following BCG treatment: it resembles a tuberculosis, but more productive and with more pronounced necrosis
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NEOPLASMS
epidemiology
95% are urothelial carcinomas
5% are soft tissue tumors or
other carcinoma histotypes
increasing incidence, high mortality
M>F 3:1
mean age: 50-80 ys
risk factors:
genetic susceptibility
dietary factors
smoking
environmental pollution
infections (schistosoma)
occupational exposure (aromatic amines, polycyclic aromatic hydrocarbons, chlorinated hydrocarbons
clinical presentation
HEMATURIA
ALWAYS INVESTIGATE! It may be totally benign or the first sign of something severe
obstructive symptoms
mainly related to tumors of the urethra, not of the bladder
recurrent infections
sometimes asymptomatic
macroscopy
with invasion
without invasion
flat
exophytic growth (papillary)
histological types
invasive / noninvasive the basal membrane (confined or not to the urothelium)
non-invasive
urothelial dysplasia
increase/decrease in thickness, significant cytological and architectural atypia, but not sufficient for a carcinoma diagnosis; potential precursor of carcinoma
it may be associated with infections, endoluminal therapies, etc.
DD: AUS, reactive atypia, urothelial carcinoma in situ
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similar to squamous lesions of the oral cavity or in the cervix
pts with urothelial dysplasia is at risk of developing cancer
urothelial papilloma
<1% of bladder tumors, made of true papillary protrusions of the urothelium with no increase in the number of layers (<7 layers)
cells have no cytological atypia;
papillae should be less than 2 cm
inverted papilloma
polypoid, normal superficial urothelium with endophytic growth of nests of urothelial cells with no atypia and with no involvement of the detrusor muscle; it probably originates from von Brunn nests
there are no papillary formations since it grows in the lamina propria; the growth in the lamina propria has a pseudo-invasive pattern, but without the involvement of the muscular wall
papillary urothelial neoplasm of low malignant potential
increase of the layers
increase in cellularity
alteration of the urothelium (totally different from that in papilloma)
conserved polarity: maturation of the urothelial cells, well-identifiable basal/superficial layers, basally-located mitotic figures
IHC for p53 is performed, but no overexpression is detected
non-invasive papillary urothelial carcinoma
low grade
high grade
in the past, three grades existed, but the distinction in only two grades (low or high) is much more indicative, in particular from a clinical point of view and to better understand how to proceed with therapy
absence of infiltration of the basal membrane with marked cytological and architectural atypia, fusion of papillae, loss of polarity, increased mitotic rate with superficial mitoses, p53++
urothelial carcinoma in situ
the only flat non-invasive!
absence of papillary growth, marked cytological and architectural atypia (lack of polarization), p53+++
if papillae are present, the lesioin cannot be urothelial carcinoma in situ!
diagnosis may be difficult
usually there is a chronic inflammation of the lamina propria associated with in situ urothelial carcinoma, with edema and ulcerations
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urothelial hyperplasia
(uncertain malignant potential)
increased stratification, flat or pseudopapillary
(no fibro-vascular stalk), no cytological atypia
mind the vascular stalk!!!
invasive
independently if it has a papillary or a flat structure, it infiltrates the basal membrane
variants:
with squamous differentiation
with glandular differentiation
nested
microcystic
micropapillary
lymphoepithelioma-like
plasmacytoid
giant cells
lipid-rich
sarcomatoid
with trophoblastic differentiation
clear cell
undifferentiated
either low- or high-grade on the basis of the risk of developing metastases
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in general, diagnosis is based on macroscopy and microscopy
IHC is needed in the case of metastasis suspect
there are no reliable markers: the most frequently positive one is GATA3, but it is also associated with paragangliomas, parathyroid tumors and breast cancer
pure histological variants
squamous cell carcinomas
squamous cell metaplasia can exist in the urothelium (substrate for developing SCC)
the pure type is infrequent (1-3%)
more prevalent in Egypt and North Africa (associated with infection by Schistosoma)
it may follow chronic infections and inflammation
adenocarcinomas
it is a pure glandular carcinoma, very rare (2%)
it can be of all histological variants present in all kinds of adenocarcinoma (mucinous, clear cell, signet ring)
location: dome of the bladder (due to the transformation of the urachal remnants) or association with exstrophy
it can be the evolution of intestinal metaplasia in cystitis glandularis
DD: pure adenocarcinoma of the bladder is similar to any other kind of adenocarcinoma
neuroendocrine tumors
carcinoids (well-differentiated form) are rare
the most frequent is the small cell carcinoma (mixed form)
soft tissue tumors
since the most represented connective tissue in the bladder is skeletal muscle, rhabdomyosarcoma may develop
the muscle in the bladder is not a completely skeletal one, but it is a specialized smooth muscle
the usual rhabdomyosarcoma type is the adult form, but there is a pediatric form that is the same type of rhabdomyosarcoma described in the lower tract for females, embryonal or botyroid rhabdomyosarcoma
staging
clinical
muscle invasive and non-muscle invasive (superficial)
important because the big diffrence in prognosis depends on invasion of the muscular wall
pathological
invasioin is intended as the penetration of the basal membrane in pathological terms
T1: invasion of the lamina propria
T2: invasion of the muscularis propria in its inner half (T2a) or outer half (T2b)
T3: invasion of the perivascular soft tissue microscopically (T3a) or macroscopically (T3b)
what is not invasive is coded in different ways if related to the papillary group of lesions or flat lesions:
Ta for non-invasive papillary urothelial carcinoma
Tis for urothelial carcinoma in situ
staging on the lymph nodes is not based on the size, buit on the number and the location:
N1 and N2 are pelvic metastases (single or multiple)
N3 are metastases outside the pelvis
prognostic factors
clinical
multicentricity, size >3 cm, stage, associated CIS
pathological
grade, vascular invasion, histological aggrssive types, type of infilatration, status of margins
in non-invasive forms, the main prognostic factor is histological grading
in invasive lesions from T2, there are no clear-cut prognostic factors
molecular pathogenesis
it has a therapeutical meaning in particular because we have drugs directed against specific molecular alterations
genomic information
mutation or genetic defects that are most commonly present in bladder cancer
there are two different lines of progression:
one for papillary lesions
one for flat lesions
the importance of dividing papillary lesions from flat lesions resides in the fact that they have different molecular backgrounds and molecular pathways of progression
papillary line of lesions:
RAS or FGFR3 mutations
flat lesions:
p53 expression alteration
molecular classification
muscle invasive bladder cancer classification is based on gene expression profiling
luminal gene: differentiated cluster of cells
basal squamous gene cluster: more undifferentiated or divergently differentiated into squamous differentiation
neuronal gene cluster: neuroendocrine differentiated cancers
immune gene over-represented cluster: mixture of histologies all put together
diagnostic flow
urinary cytology
neither specific nor sensitive
in urothelial carcinoma in situ it is easier to obtain a positive result because of the typical disepithelization
it is possible to say that urinary cytology is quite sensitive in the case of high-grade tumors, but this is not enough to make it a good screening test
it is not very specific because a lot of situations may mimic urothelial carcinoma
in the case of carcinoma, there are also multi-chromosomal changes
FISH test has started to be used to detect gains (ch3 and ch17) or losses (e.g. 9p21)
it is sometimes used as a follow-up test for urothelial carcinoma patients
cystoscopy + biopsy
second step for diagnosing cancer
surgery
macroscopy
histological typing
grading / staging
resection margins
NEUROLOGICAL BLADDER
CYSTOCELE
common cause in women