IV. Malignant Tumors
After completing this tutorial the student will know the following about
malignant tumors of the urothelium:
- which are the common and important tumors
- the epidemiological features and predisposing factors
- what is meant by a "field effect"
- clinical and histologic features
- natural course and prognostic factors
Urothelial carcinomas are 3 to 4 times more common in males than
females. The incidence peaks at age 50 to 80 years.
Association between these cancers and occupational exposure to arylamines,
especially 2-naphthylamine (b -naphthylamine)
and benzidine, is well established.
Cigarette smoking increases risk. Estimates are that up to 80% of carcinomas
in men are related to smoking. The risk persists up to 10 years after cessation
of smoking and depends on the smoking habit and duration.
Chronic cyclophosphamide exposure increases risk by about 10 times.
Chronic inflammation, such as in chronic Schistosoma haematobium infestation,
staghorn calculus, recurrent infections and bladder extrophy, is an established
risk mainly in squamous cell carcinoma but also in transitional cell carcinoma.
Long term phenacetin use and Balkan nephropathy are implicated in transitional
cell carcinoma of the pelvis.
Transitional cell carcinomas (TCC) are often multifocal and synchronous (in
70% of newly diagnosed tumors) and may be accompanied by areas of dysplasia
up to carcinoma-in-situ (in more than 50% of newly diagnosed patients) either
in contiguous or remote areas. Metachronous recurrences occur in more than
60% of patients and are found at sites remote from the primary. These observations
have led to the concept of a "field effect" where exposure of the urothelium
to the same carcinogens at roughly the same concentration causing a "restless
epithelium" from which occasional cells become initiated and give rise to
independent clones of transformed cells. Subsequent promotion may lead to
multifocal tumors, which may be synchronous or metachronous.
About half of patients with tumors of the renal pelvis and ureter will have
or subsequently develop additional tumors in the bladder while only about
3% will develop contralateral upper urinary tract tumors. In contrast, only
about 3% of patients with bladder cancer ever develop upper urinary tract
tumors. These observations have led to the suggestion that the multifocal
nature of TCC may be due to intraluminal dispersion of single clones of viable
cells or lateral intraepithelial migration of cells from a single clone in
the case of primary bladder tumors. Recent evidence for this suggestion have
emerged from molecular analysis of individual tumors which indicate that multiple
synchronous and metachronous tumors are all derived from the same clone of
neoplastic cells. Subsequent acquisition of additional mutations in these
cells will then lead to tumors with different histologic features occurring
at different locations.
The commonest presentation of tumors arising from the urothelium is painless
hematuria. Flank pain or a palpable mass is less often the presenting sign
and usually indicate obstruction or advanced disease.
- Transitional Cell Carcinoma
Cancers of the pelvis and ureter account for less than 10% of tumors.
Transitional cell carcinoma may be papillary (exophytic) or non-papillary
(endophytic or flat) and invasive or non-invasive. Papillary tumors predominate
and consist of variably sized structures, which have slender stalks or are
sessile and have delicate fronds. Non-papillary tumors appear as flat ulcerations
surrounded by slightly raised infiltrated borders or as fungating, necrotic
Papillary transitional cell carcinoma of bladder. Exophytic masses fill the
lumen of this bladder.
Papillary transitional cell carcinoma of bladder. Multiple papillary excrescencies
fill the bladder lumen.
Papillary transitional cell carcinoma of the renal pelvis. An exophytic mass
fills a calyx.
Papillary transitional cell carcinoma of the ureter.
Histologically, the fronds of papillary tumors have thin connective tissue
cores covered by transitional epithelium showing various grades of cytologic
and architectural abnormalities. TCC is arbitrarily graded on a scale of I-III
based on the degree of cytologic and architectural abnormalities.
Grade I: These are papillary and are covered by thickened transitional
epithelium with cells, which may resemble normal urothelium.
Papillary transitional cell carcinoma grade I. Papillary frond covered by
epithelial layer of normal thickness on one side and a much thickened layer
on the other.
Grade II: May be papillary or non-papillary with moderate loss of
architecture and moderate nuclear pleomorphism.
Papillary transitional cell carcinoma grade II. Note the greater degree of
Another example of papillary transitional cell carcinoma grade II.
Grade III: Tumors show marked cellular pleomorphism and architectural
abnormalities and most are non-papillary. The neoplastic cells may be barely
recognizable as transitional.
Non-papillary carcinoma grade III. Note greater degree of nuclear pleomorphism
and presence of prominent nucleoli.
As would be expected grade correlates with invasiveness. Grade I papillary
tumors are almost always non-invasive while grade II papillary tumors may
be invasive or non-invasive. Most papillary tumors are grade I or II. Non-papillary
tumors are usually high grade and invade extensively and deeply into the bladder
wall. They presumably arise from high-grade carcinoma-in-situ (see below).
The pathologic stage of transitional cell carcinoma is a better prognostic
indicator than the histologic grade. There are several staging systems but
the Jewett system is used here:
- Jewett A - tumor confined to the mucosa and submucosa.
- Jewett B1 - tumor extends less than half way through muscle
- Jewett B2 - tumor extends more than half way but not completely
through muscle wall
- Jewett C - tumor is through muscle and into surrounding tissue
- Jewett D - lymph node metastases.
The natural history of transitional cell carcinoma is one of multiple recurrences
over long periods of time, with a tendency for subsequent tumors to show greater
anaplasia and to invade deeper. Recurrence rates increase with grade.
Question: Which hormone can be detected in the urine about 50% of
patients with grade III TCC?
- Transitional Cell Carcinoma-In-Situ (Non-Papillary, Flat)
In this entity, there is full-thickness malignant transformation of a flat,
non-papillary transitional epithelium.
Question: What is the difference between carcinoma-in-situ and invasive
Patients present with urinary frequency, dysuria or urgency. Microscopic
hematuria is very common but gross hematuria is present in an occasional patient.
The lesions are typically multifocal and are particularly common in patients
with multiple or recurrent tumors in the bladder or elsewhere in the urinary
tract. Foci are most frequent near tumors, but can occur in distant parts
of the bladder. The gross appearances range from normal looking to granular,
erythematous areas with no intraluminal projections.
The histologic picture is that of an epithelium of variable thickness showing
full-thickness cellular and architectural atypia in the form of nuclear pleomorphism
and lack of maturation respectively.
Transitional cell carcinoma-in-situ (right panel). Compare the degree of pleomorphism
with the normal transitional epithelium in the left panel.
The majority of patients with transitional carcinoma-in-situ will have invasive
carcinoma elsewhere in the bladder or will develop subsequent invasive carcinoma.
Invasive carcinoma developing from carcinoma-in-situ is typically high grade.
Question: Why should transitional cell carcinoma-in-situ be considered
a more aggressive lesion than papillary, non-invasive carcinoma?
- Squamous Cell Carcinoma
Pure squamous cell carcinoma accounts for up to 10% and 5% of tumors of the
renal pelvis and bladder respectively in most countries but in countries endemic
for schistosomiasis the proportion is much higher. Bladder diverticula and
extrophy are other predisposing factors. Pre-existing squamous metaplasia
with longstanding chronic inflammation is typically present and, presumably,
gives rise to the tumors.
Squamous metaplasia. Here stratified squamous epithelium replaces the normal
transitional epithelium of the bladder mucosa.
Squamous cell carcinoma of the bladder. Necrotic, hemorrhagic mass almost
fills the lumen of the bladder. Note the deep invasion of the bladder almost
to the perivessical fat.
Histologically, some are well-differentiated tumors exhibiting obvious squamous
differentiation with keratinization but many are poorly differentiated.
Squamous cell carcinoma with focal keratinization and necrosis.
Squamous cell carcinoma with focal keratinization and necrosis.
Although clinical behavior is similar to transitional cell carcinomas, the
prognosis is worse as patients usually present with advanced disease - about
95% show muscle invasion at time of diagnosis. About 70% of patients are dead
in one year.
Question: What histologic feature indicates squamous cell differentiation
in a tumor?
This is very rare and form less than 1% of tumors. They may arise in areas
of glandular metaplasia or in urachal remnants.
Glandular (colonic) metaplasia of bladder mucosal epithelium. This resembles
Adenocarcinoma of the bladder produces abundant mucin and the tumor surface
may be gelatinous. The tumors show histologic features similar to colonic
carcinomas and range from well-differentiated, gland forming neoplasms to
signet ring carcinomas.
Adenocarcinoma of the bladder.
Signet ring cell carcinoma of the bladder. Individual tumor cells are filled
with mucin pushing the nucleus to one side against the cell membrane.
These tumors have poor prognosis because patients present late.
Question: What histologic feature(s) are diagnostic of an adenocarcinoma?
- Undifferentiated carcinoma
These are tumors in which the neoplastic cells show neither transitional,
squamous or glandular differentiation. The tumor cells range from large polygonal
pleomorphic cells, through small cells to spindle sarcomatoid cells.
Undifferentiated carcinoma. Note the lack of differentiation and sarcomatoid
nature of the neoplastic cells.
Question: What is the role of urine cytology in the diagnosis of tumors
of the urinary tract?