Renal & ureteric neoplasms
Epidemiology of renal neoplasms
A classification of kidney tumours is quite a difficult task. A simply
classification has been done by Barbaric (1994). This classification was based on
pathology (malignant, benign, or inflammatory tumours).
Benign renal tumours
Benign renal tumours arise from any of cell types in the kidney. The most
common benign lesions are renal cysts. 70% of asymptomatic renal masses are
simple cysts. They may be single or multiple and unilateral or bilateral.
Benign tumours include: adenoma, fibroma, renal oncocytoma, renal
angiomyolipoma, lipoma, myoma, lymphangioma, hemangioma.
Malignant renal tumours
Renal tumours account for around 3% of all neoplasias. Malignant tumours of
renal parenchyma are relatively uncommon but remain a problem in urological
oncology related to early diagnosis, innaccuracy of pre-operative staging and
toxicity of the treatment for metastatic disease.
Nephrocarcinoma is the generic category that includes adult parenchymatous
malignancies, primarily the classic hypernephroma. Relatively rare are
mesenchymal malignancies such as sarcomas, heman-giopericytomas, infiltrative
malignancies such as myeloma, and secondary or metastatic malignancies.
Renal cell carcinoma also defined as hypernephroma or Grawitz's tumour
originates from the proximal convoluted tubule and has an incidence of around 3,6
- 5,6 per 100.000 males and 1,7 to 3,4 per 100.000 females. The tumour mainly
affects adults aged 50 - 70 years with the male: female ratio of 3:1.
Renal cell carcinoma (RCC) is the most common malignant lesion of the
kidney with the percentage of around 90%, followed by Wilms' tumour, which is
the most common in childhood but is very rare in adults.
There are marked international variations in incidence of RCC, being high in
Northern Europe and North America, and low in Africa, Asia and South America.
There is some evidence of increasing incidence in males in the last years.
The disease can occur at any age. Despite the fact that RCC is the disease of
the adults, the tumour may well occur in children as several reports have shown.
Renal tumours have been a major subject of cytogenetic and molecular
genetic studies, which suggest that these findings may be useful clinically in
diagnosing renal tumours and metastases and indicating poor prognostic genetic
markers.
RCC like other cancers occurs in inherited and sporadic, non-inherited forms.
The hallmarks of familial renal cancer are that they occur at an early age, and
usually are bilateral and multifocal.
Tumours of the renal pelvis
Epithelial tumours of the renal pelvis have the same histologic morphology as
the ureter and bladder tumours, because they arise from urothelial cells.
Transitional and squamosus cell carcinomas of the renal pelvis can be induced
by the action of such substances as dibenzanthracen, benzpyrene,
methylcholantren, aflatoxin B, metabolites of certain chemical agents such as
benzidine. In carcinogenesis RNA viruses, inflammation, stone disease and
metaplasia also play a causative role.
Tumours of the renal pelvis are about 40 times more common in patients who
take large amounts of phenacetin. An association between ta-bacco use and
development of urothelial tumours of the renal pelvis is also shown.
The renal pelvis tumours are reltively rare. 7-8% of all renal tumours arise in
kidney pelvis and 6-12% of all malignant kidney tumours are transitional cell
carcinomas. The majority of these tumours develop in the elderly, namely in the 6
th to 8th decade and they mainly affect males with the male to female ratio 2-4: 1.
Pathology of renal tumours
Renal cell carcinoma (WHO)
Renal cell adenocarcinoma, hypernephroma, metanephroma, Grawitz tumour,
alveolar carcinoma, adenocarcinoma of kidney, adenocarcinoma renis, and clear
cell, dark cell, and granular cell carcinoma).
This cancer comprises up to 80% of renal cancer and is infrequent before the
fifth decade of life, with the pick incidence in the sixth decade of life. Renal cell
carcinoma (RCC) is rare in children. RCC occurs more frequently in men than in
women, and is rarely familiar. The strong association is seen between RCC and
syndrome of von Hippel and Landau. The etiology in humans is largely unknown
but RCC occurs more frequently in cigarette smokers.
Ultrastructural and immunologic studies clearly demonstrated that RCC arises
from the cells of proximal convoluted tubule. The clear tumour cells contain
abundant glycogen and lipid in their cytoplasm.
RCC arises usually in the upper pole of the kidney. In about 5% of all cases
RCC are multifocal and in 1% are bilateral. It is not uncommon that RCC is
presented initially with metastatic disease. Gross examination shows ovoid soft
mass. The cut surface may be grey, orange or golden yellow with foci of
hemorrhage, necrosis, cystic degeneration and sometimes calcifications. The small
RCC tumours are surrounded by pseudocapsule of fibrous tissue and atrophic renal
parenchyma. In late stage RCC penetrates its own pseudocapsule, renal fibrous
capsule and penetrates adjacent adipose tissue. The infiltrate of kidney pelvis and
hi-lar structures in cases presented with hematuria is seen; the infiltrate of renal
vein in cases presented with metastatic disease is common. Sometimes large RCC
goes without any metastases and small RCC tumours spread to lungs and then to
brain, liver and others organs.
Nephroblastoma (Wilms' tumour)
Nephroblastoma is the most common of the malignant abdominal tumours of
young children but accounts for only 6% of renal cancers in all ages. It may be
present at birth, 28% occur in the first year and over 96% occur before 6 years of
age. Rarely nephroblastoma arises in sites other than kidney such as inguinal canal
or within teratoma.
On gross examination the tumour is usually large (clinically it appears most
commonly as palpable abdominal mass), rounded, and dwarfing but not invading
the kidney until late. The cut surface revealed a soft, grey-white to cream coloured
tumour tissue foci of hemorrhage and necrosis.
Nephroblastoma is the malignant counterpart of embryonic rather than mature
tissue. Microscopically the typical nephroblastoma is composed of variable
amounts of metanephric blastema and its epithelial and stro-mal derivatives. The
blastema cells resemble: normal metanephros with small ovoid cells with scanty
cytoplasm and is arranged in nests or trabeculae. The epithelial element is usually
trabecular; sometimes the epithelium forms papillary structures or even glomerulilike structures. The stroma is heterogeneous and most often consists of spindle
cells of undetermined type, fibroblasts or smooth muscles. Sometimes foci of cartilage, adipose tissue and neural elements are seen. While most of nephro-blastomas
show the mixed pattern, the tumour may consist predominantly or entirely of
blastemal, epithelial or mesenchymal elements. Areas of leiomyosarcoma or
rhabdomyosarcoma and even neuroblastoma (with rosettes) or ganglion cells may
be present in nephroblastoma.
Malignant renal tumours
Renal cell carcinoma (RCC), clear cell carcinoma, Grawitz tumour
Renal cell carcinoma is a relatively rare tumour, accounting for approximately
3% of adult malignancies. RCC is more common among urban dwellers and is
more cmmon in males, with a male-to-female ratio of approximately 2:1. Familial
renal carcinoma has been reported. Patients with von Hippel-Lindau disease have a
higher incidence of this cancer polycystic kidney disease appear to be a
predisposition for development of the tumour, although this has not been firmly
established.
Renal carcinoma is a tumour of adults, occuring primarily in those in their
forties to sixties, but it may occasionally occur in younger age groups.
RCC is typically unilateral, but bilaterality, either synchronous or
asynchronous, occurs in approximately 2% of cases. Von Hippel-Lindau disease is
characteristically associated with the presence of multiple and bilateral renal
carcinomas.
The lump frequently extends into the renal vein as a thrombus, which may be
propagated for varying, distances into the inferior vena cava, even up to the right
atrium of the heart.
The more malignant and larger tumours can invade locally, with extension
into the surrounding muscles and direct invasion into adjacent organs.
Because of the long natural history of renal cell carcinoma and high
probability of late relapses or metastases, 10 to 15-year observation time has
become widely accepted to judge the effectiveness of therapy.
As far as symptoms is concerned, the classic triad of pain, hematuria and
flank mass is found in few patients and generally indicates advanced disease. RCC
arises from the proximal convoluted tubule and grows rather slowly; therefore it
can often achieve an enormous size without causing any symptoms. The most
frequent findings are pain (tumour invades surrounding areas or obstructs the
outflow of urine owing to hemorrhage and subsequent formation of blood clots) or
hematuria (as a result of invasion of the collecting system) secondary to the
primary tumour, but symptoms owing to metastatic disease probably occurs more
frequently. Raised erythrocyte sedimentation rate, weight loss, cachexia, fever,
night sweats, and the sudden development of a varicocele
Varicocele
in the male patient are not uncommon findings. Hypertension is due to
segmental artery occlusion or to elaboration of renin or renin-like substances.
The most dramatic syndrome is associated with nonmetastatic hepatic
dysfunction and is referred to as hepato-renal syndrome [Stauffer syndrome]
(abnormal liver function tests, white blood cell loss, fever, and areas of hepatic
necrosis without hepatic metastasis). Hepatic functions return to normal by
majority of patients after nephrectomy.
Hypercalcemia of rather obscure nature (skeletal metastases? production of
specific polypeptides?) and increased levels of erythropoietin were also noted by
some patients with RCC.
Sarcomas of the kidney constitute only about 1 to 3% of malignant tumours
of the kidney but increase in incidence with advancing age. The most common
symptoms are essentially those of a large renal carcinoma. Leiomyosarcomas, are
the most common variety. These tumours tend to compress and displace the kidney
rather than invade it. The survival in such lanes is extremely poor.
Lymphomas generally occur in the kidney only as a manifestation of the
systemic disease, often bilaterally. It can be silent or can produce he-maturia,
enlarged kidneys, and progressive renal failure.
Metastatic tumours from a variety of solid neoplasms are often localised in
the kidneys, because high blood flow and profuse vascularity of renal parenchyma
provide ahospitable environment for deposition and growth of malignant cells.
Metastases to the kidneys, because of dominating symptoms of basal disease, are
identified mostly at autopsy, and, in that sense, are of minimal clinical value.
Radiologic methods of study in renal tumours
1. Ultrasonography
This procedure should be initial in diagnosis of the urinary tract. This
examination is safe for the patient, noninvasive, repeatable and very efficient.
Ultrasonography allows to distinguish solid mass from the cyst. Probability of
detection of 3 cm tumour is 95%. The diagnostic capabilities of sonographic
Doppler analysis of blood flow allow noninvasive recognition of the vascular
pathology. The multiplanar capability of US demonstrates the extent of the tumour.
Although US is extensively used in the detection of renal neoplasm, it is less
accurate than CT or MRI in the staging of tumours. In 50% of patients the
retroperitoneal region may not be adequately visualised. US is also unable to detect
muscle inavasion.
2. Plain film
Plain film
Antero-posterio film must precede any contrast study of the urinary tract. The
film should include the entire area from the diaphragm to the pubic symphisis.
Plain film allows in many cases to suspect the presence of the tumour by:
• enlargement of whole or part of the kidney.
• changing of the shape of kidney, abnormal position of the organ
• presence of calcifications
3. Excretory Urography – IVP
Excretory Urography
This examination is sometimes required by clinicians to complete the
diagnosis of renal neoplasm. IVP is the type of dynamic examination which allows
to evaluate excretory functions of kidneys. In this examination we can observe all
kinds of must be done during so-called nephro-graphic phase. This is the period
when opacification of the renal parenchyma is at its best. Simple cysts or tumours
may be diagnosed by this method with 90% accuracy (3). Polar enlargement of a
kidney is one of the most frequent pyelographic changes. The renal outline may be
altered and markedly irregular. Calcification of renal carcinoma is not common but
may occur and may simulate renal lithiasis or calcifaction of a renal cyst. The
architecture of the collecting system varies from simple deformity of a calyx to
outright destruction of one or more calyces with their amputation.
4. Computed tomography
CT (Tumor of the kidney)
Over the past decade, CT has become the most widely used technique for
diagnosis and staging renal tumours, partially due to the very high overall accuracy
up to 90%, that has been achieved.
Indeterminated masses in US should be further evaluated by CT. A large
variability in the range of attenuation values exists because of necrosis,
hemorrhage, calcification, variable protein content and vascularity. Typically renal
tumours are solid in density, that is greater than a typical cyst. The margins of the
mass are usually irregular. The density of the mass may be homogeneous or non
homogeneous. The tumour can demonstrate local invasion into the fat within
Gerota's fascia and to the adjacent organs.
The reported accuracy rate for CT in staging renal tumours ranges between
72% and 98%.
Stage I tumours are defined on CT lying entirely within the kidney.
Stage II Tumour spread into the perinephric space. Renal capsular invasion is
difficult to diagnose. Recognised signs on CT include extending tumours to the
perinephric space, thickening of the perirenal fascia, soft tissue spreading into the
perirenal fat.
Stage III tumour spread to the venous system and lymph node involvement.
Detection of lymph node involvement on CT relies on detecting an increase in the
size of infiltrated node. The most important sign of venous tumour infiltration is a
persistent filling defect following intravenous contrast administration within the
renal vein or IVC.
Stage IV Tumour spread to adjacent organs and distant metastasis are well
demonstrated in CT and the specificity is almost 98%.
5. Magnetic Resonance Imaging
Due to its high tissue contrast and multiplanar imaging capabilities, MRI
provides a detailed display of renal anatomy. Recent technical developments
overcoming the problem of respiration motion artefacts and the use of
paramagnetic contrast agents have further improved the performance of MRI
which is now an alternative or complementary imaging modality to US, excretory
urography and CT. On plain MR images solid as well as cystic renal and pararenal
masses often present the same signal intensity as the adjacent renal tissue.
Therefore detection of such tumours is based only on the visible displacement or
alteration of organ contours. Delineation from the surrounding renal parenchyma is
successful with the aid of contrast enhanced examination. Additional techniques
such as fat suppression, provide further improvement of lesion detection, allowing
demonstration of small cyst or solid masses with diameters less than I cm. MRI is
highly sensitive in demonstrating hemorrhage, hemorrhagic cyst. Among solid
tumours of the kidney, MRI allows detection of only fat-containing angiomyolipoma accurately, other solid lesions show very similar SI patterns.
Advantages of MRI in staging of the tumour include direct imaging in sagittal and
coronal planes. MRI is faced with the same limitations as CT in identifying early
extension into the perinephric space. MRI is the best noninvasive method for the
assessment of tumour thrombi in the renal veins or in the inferior vena cava.
At present MRI and spiral contrast-enhanced CT have similar accuracy in
detecting lymph node and venous invasion. The choice between these techniques
will depend on several factors apart from accuracy, such as availability and cost.
Currently CT is the most widely used technique, with MRI kept in reserve to solve
particular problems.
6. Renal arteriography; aortography; phlebography an inferior vena
cavography
Visualisation of the renal arteries and renal veins may be accomplished
by:
• translumbar aortography
• percutaneous aortography
• selective renal arteriography
• percutaneous phlebography
It is dynamic study of arterial blood supply of the kidney and the tumour and
allows to show the pathology as well as anatomy. Visualisation of the renal veins
has become very important in the diagnosis of invasive malignancies of the
kidneys and their prognostic evaluation. During these examinations we can provide
embolisation of the tumour in nonoperative tumours or before the surgery.
Classification and principles of treatment of renal tumours
Clinical staging of renal tumours is very important in order to treat them
correctly. The objectives of the clinical staging ought to be the following:
1. evaluation of the local extension of the tumour
2. determination of the presence of distant metastases
3. determination of the presence of venous tumour thrombus Clinical staging
is important in order to decide on a therapeutical approach but surgical and
anatomopathological staging is equally important for our knowledge about
prognosis.
RCC
The UICC present TNM classification of RCC is following: Tl - tumour < 7
cm. in greatest dimension limited to the kidney T2 - tumour > 7 cm. in greatest
dimension limited to the kidney T3 - tumour extends into major veins or involve
adrenal or perinephric tissues but not beyond Gerota's fascia
T3a - tumour invades adrenal gland or perinephric tissues but not
beyond Gerota's fascia
T3b - tumour grossly extends into renal vein or vena cava
T3c - tumour grossly extends into vena cava above the diaphragm T4 tumour invades beyond Gerota's fascia NO - no regional lymph node metastasis Nl
- metastasis to a single regional lymph node N2 - metastasis in more than one
regional lymph node MO - no distant metastases Ml - distant metastasis
During the last decade it has been observed that patients with Tl and T2
tumours have similar survival and that 2,5 cm. cutoff does not adequatly
differentiate between stage Tl NO Mo and T2 NO MO. In 1997 TNM
classification of renal cell carcinoma the cutoff between Tl and T2 tumours was
increased to 7 cm.. The 1997 TNM classification resulted in a redistribution many
cases of RCC from stage T2 to stage Tl. This group represents 44% of all cases and
76% of stage T2 cases according to 1987 TNM classification. Many findings
suggest that increasing the cutoff from 2,5 cm. to 7 cm. alone does not greatly
affect outcome. The benefit of the 1997 TNM staging classification of RCC is a
potential cost savings. Some investigators postulate elimination of postoperative
abdominal CT for Tl NO MO patients and reduction in followup tests and visits.
The impact of these savings needs to be evaluated in prospective studies.
After all diagnostic steps, staging of the tumour according to TNM
classification may be done and then decision about form of the therapy may be
made, too.
Surgical therapy is the most effective management form of RCC.
In the case of local extension of the tumour at the time of diagnosis succesful
therapy in RCC is radical nephrectomy - removal of the entire tumourous kidney
including fatty capsule and adrenal gland within Gerota's fascia followed by lymph
node dissection. After radical nephrectomy the 5 - year survival rate increased to
52 - 60% compared with 33% for simple nephrectomy and 10 - year survival rate
from 7,1% to 49%. The operative mortality is 1 - 5%.
Distant metastases, at the time of diagnosis, are found in 30% of patients. The
indication for surgery in such cases is judged differently by various authors.
Popular is the opinion that removal of all neoplastic tissue is mandatory. sue is
mandatory. The hope for spontaneus regression of distant metastases after
nephrectomy should not influence the indication for surgery. In j these cases
nephrectomy is indicated if surgical removal of the metasta-ses is also planned. In
patients with more locally advanced disease complete excision of the tumour by
means of an extensive operation including if necessary liver lobectomy and
excision of the involved bowel, spleen or other organs will be performed.
It is very difficult to attain true radicality and surgery often is a compromise
between oncological radicality and debulking.
Even in the presence of distant metastases some of urologists proposed
aggresive therapy including tumour nephrectomy. In these cases a prolonged life
expectancy cannot be achieved.
As a palliative procedure in complications due to the tumour (hemorrhage,
pain, policythemia, hypercalcaemia) nephrectomy may be indicated.
Alternative procedure to palliative nephrectomy is embolisation of the
tumour. There are also immunological considerations that a positive effect on the
cellular immunity following tumour nephrectomy has been observed. In the case of
bilateral renal tumours or tumour in a solitary kidney, the decision may be very
difficult. In the case of bilateral tumours, the one side is removed radically but the
other side undegoes an organsaving operation. It should be done also on the
solitary kidney, if j anatomically possible.
Extracorporeal bench surgery and autotransplantation is another possibility.
Bilateral nephrectomy is indicated rarely because of the side effects and toxicity of
immunosupressive therapy or hemodialysis.
In the cases of more advanced metastatic disease other than surgical forms of
treatment such as radiotherapy, chemotherapy and immunother-apy may be used.
Surgical treatment of renal tumours
The basic form of the renal tumour treatment is surgery. In the present time
various modalities of surgical treatment are used: radical surgery -radical
nephrectomy, nephron - sparing surgery and palliative surgery.
Incision
The fundamental principles of radical surgery are following:
- choice of the best incision
- preliminary ligation of the renal artery
- lymphadenectomy
- complete excision of the tumour
- control and removal the tumour extending into the inferior vena cava
- excision of resectable distant metastases
The most popular parietal incision for radical nephrectomy are: xiphoumbilicus epigastric subcostal incision, transverse abdominal incision and thoracophreno-laparotomic incision.
Two last incisions give optimal exposure of inferior vena cava and are the
best approaches for right renal tumours (RCC) extending into the inferior vena
cava. Optimal parietal incisions allow to expose the main vessels: the vena cava
inferior, the abdominal aorta and allow to reach the renal artery at its origin.
The most important step of the radical nephrectomy is initial ligation of the
renal artery and then ligation of the renal vein. This procedure prevents the spread
of the tumour cells. The next steps are: the mobilization of the kidney, the division
of the ureter and exenteration of the renal lodge by,,en bloc" removal of the
kidney, adrenal and perirenal fat with Gerota's fascia. During radical nephrectomy
hi-lar, pericaval or periaortal lymphadenectomy is also performed.
The role of lymphadenectomy in renal cell carcinoma is controversial in the
context of oncological urology. The reported incidence of retroperitoneal lymph
node metastases ranges from 6% to 43,5%. The differences in the frequency of
nodal involvement may be explained by the extent of lymphadenectomy. Recently
the incidence of nodal metastases is minor because the diagnosis of RCC often
occurs in the early stage. However in 7% of patients with tumour confined to the
kidney (Tl, T2, M0) nodal metastases were seen.
Cumulative overall survival after radical nephrectomy and extended
lymphadenectomy was appreciated on 46% and 25% at 5 and 10 years
respectively.
In patients with tumour stage pTl NO M0 survival rates at 5 and 10 years of
80% and 50% respectively were noted, while in patients with tumour stage pT2 N 0
M0 survival rates were 68% and 59% at 5 and 10 years respectively.
Patients with tumour extending to perirenal fat (T3) have shown a 70%
survival rate at 5 years after radical nephrectomy. It is a significant improvement
compared to the 14% survival rate at 5 years after simple nephrectomy.
In patients with lymph node metastases survival rates of 52% and 26% at 5
and 10 years respectively were observed.
Lymphadenectomy, an integrating part of radical nephrectomy does not
increase operative mortality and morbidity, allows for improved surgical staging of
the tumour and lower frequency of local recurrences.
In the last years there have been some reports, which indicate that almost all
patients with lymphatic spread of RCC have additional distant metastases.
Therefore, the therpeutic effect of extensive retroperitoneal lymphadenectomy in
association with radical nephrectomy seems to be low.
However, limited lymph node dissection may be useful as a staging
procedure. Thus it seems rational that radical nephrectomy with lymphadenectomy
(extended or limited) is indicated in T2, T3 and in some T4 cases of RCC tumours.
Conservative surgery of renal tumours.
Renal cell carcinoma may develop synchronously in both kidneys in about 1,8
to 3% of cases.
Frequency of renal cancer in solitary kidney is not well known.The classic
indications for nephron sparing surgery are: bilateral renal tumours, tumour in
solitary kidney and in the case when radical nephrectomy would result in renal
insufficiency necessitating dialysis or transplantation.
Conservative surgery for RCC may be identified with two types of
procedures: enucleation of the tumours (tumourectomy) and partial nephrectomy.
Both these techniques may be performed in situ or ex situ. Usually, clamping of
the renal artery is unnecessary but if it was indicated regional hypothermia should
be considered.
Partial nephrectomy
The classic indications for conservative surgery of RCC are justifiable. In the
last years there has been a tendency toward wider application of kidney sparing
surgery. Elective kidney sparing surgery means that this form of conservative
treatment is used when the contralateral kidney is normal.
The arguments against elective nephron sparing surgery are following:
rradical nephrectomy for Tl and T2 RCC will probably be curative in 100%, the
chance of developing contralateral tumour is small, higher complications rate for
conservative surgery, the possibility of tumour recurrence, the possibility of
multifocal RCC in the kidney. An argument favoring nephron sparing surgery for
RCC is its efficacy in providing for cure of cancer in series of electively treated
patients. The criteria for the indications of elective nephron sparing surgery are
following: the tumour should be solitary, well demarcated on CT, the tumour
should be; well localized and easily resectable, the tumour size should not exceed
4,3 cm. in diameter (3-5).
Elective kidney sparing surgery in the case of small, low grade, well localized
RCC may be usually curative.
Approximately one third of patients with RCC have distant metastases at
diagnosis. In patients with multiple metastases survival is not positively affected
by their complete excision. In these cases surgical treatment of metastases has only
a pallitive role. In the case of solitary synchronous or metachronous metastasis the
complete removal of metastatic foci would significantly improve the probability of
longer survival. The patient with synchronous metastasis has worse prognosis if
compared to this with metachronous disease. The beneficial effects of excision of
metastatic renal cell carcinoma are limited and the cure of patients with me- j
tastatic disease is relatively uncommon.
Non-surgical treatment of renal tumours
Non-surgical treatment of renal cell carcinoma comprises irradiation,
transfemoral catheter embolisation of inoperable and symtomatic tumours,
cytostatic treatment of metastatic disease, hormonotherapy and immunotherapy.
Embolisation of the kidney
Transfemoral catheter embolisation of the kidney has the following
applications:
1. curative superselective erribolization in non malignant renal diseases
2. radiologic nephrectomy as the form of palliative embolisation of renal
tumours (bleeding, pain, paraneoplastic syndromes)
3. preoperative embolisation of renal tumours
Embolisation of the kidney is in the majority of cases only palliative
procedure and very seldom gives a curative effect.
Radiotherapy
In 1923 Waters observed that radiation could reduce the tumour mass of renal
cell carcinoma. For a long time it was thought that RCC is radio-resistent. The
value of pre- or postoperative radiotherapy for the prognosis of the patients with
RCC is still discussed. Postoperative radiotherapyn locally advanced renal tumours
is used in some oncological centers.
More often is indicated palliative radiotherapy of metastases. Bone pain from
metastases is well palliated in this way.
Hormonal therapy
Many reports from the 70's have indicated good response in patients with
RCC receiving progesterone or androgens. The gestagens: medroxypro-gesterone
and hydroxyprogesterone as well as testosterone were applied. The first optimistic
results in prospective studies have not been confirmed. On the other hand high
dose of progesterone treatment is nontoxic anabolic therapy which offers the
improvement of patient's general condition.
Chemotherapy
Many cytostatic drugs were used in the treatment of metastatic RCC. Positive
results of such treatment were observed in 10% patients. In many studies
vinblastine (VB) as a single drug or in combination with lomustine (LM, CCNU)
was the most effective with response rate from 15-30%. The continous infusional
chemotherapy with 5- fluoro-2-deoxyuridine (FUOR) gives a response rate of 2033% in patients with metastatic RCC.
In general results of combined chemotherapy are not superior to those
obtained by single drug treatment.
Immunotherapy
The biology of renal cell carcinoma is considered to be influenced by immune
system of the tumour host. Occasional spontaneous regressions of metastases are
arguments for this assumption.
Multiple modalities for active or passive immunotherapy were described. In
conventional immunotherapy of RCC were used following agents: BCG, transfer
factor (TF), polymerised tumour cells, tumour cells + Corynebacterium parvum,
immune RNA (I- mRNA), tumour necrosis factor (TNF), thymosine factor 5.
In the current opinion use these agents was largely unsuccessful.
The forms of adoptive immunotherapy are LAK and TEL treatment in solid
renal tumours.
Lymphokine activated killer cells (LAK) treatment gives a 31% response rate
(CR + PR) in RCC.
An alternative to the use of LAK cells generated from peripheral blood
lymphocytes is using the lymphocytes which infiltrate the tumour (TIL). LAK and
TIL adoptive immunotherapy has been criticised mainly on account of the toxicity
and expence.
In the present time the most often form of immunotherapy is the use of
biological response modifiers such as interferons and interleukins.
A large number of patients have been treated with interferons for advanced
RCC (interferon alfa, interferon beta and interferon gamma). Doses of interferons
ranged from 1 MIU dalily to 16 MIU daily although the majority of patients were
treated with 3 MIU daily or the same dose 3 times each week. Observed responses
rates ranged from 5 to 29%. There is no evidence that larger doses than 5-10 MIU
daily produce higher response rates.
The toxicity of IFN with increasing doses and prolonged treatment is higher.
Interleukin-2 (11-2) is produced by activated T cells. Some authors reported
the clinical result with 11-2 in RCC. It was used in intravenous infusions but
toxicity of such treatment was high.
Recently systemic immunotherapy with interleukin 2 (11-2), interferon alfa
(INF alfa) and 5-fluorouracyl gives promising results with response rate about 4048%. However, systemic immunotherapy is limited by severe side effects. Longlasting response is rare but only systemic com-i bined immunotherapy is the most
efficient in the treatment of metastaticj RCC.
Neoplasms of the ureter -epidemiology and pathology
Ureteric tumours are relatively uncommon and account for about 1% of all
urothelial tumours. Males are about 3 times more likely to suffer from ureteric
tumours than females. The peak incidence in men occurs in the 75 to 79-year-old
age range. According to Annual Cancer Statistic Review, the disease affects 10
white men per 100000 per year.
In families afflicted with Balkan endemic nephropathy, a much higher
incidence of upper urinary tract transitional cell carcinoma is seen. Petkovic (1975)
reported that the incidence rates for some villages affected by Balkan endemic
nephropathy were 100 to 200 times greater than for similar towns nearby.
The pathological analysis indicates that more than 90% of ureteric tumours
are transitional cell carcinomas. According to the current classification, three
grades of malignancy are distinguished. Grade I is characterised by the increased
number of epithelium layers but the separate cells are not much different from the
cells of normal urothelium. In tumours identified as grade II the urothelium is
thickened and the cell, which reveal various amounts of cytoplasm and diverse
sizes of nuclei, are patterned irregularly. Random arrangements of the cells, whose
nuclei differ considerably from one another in size and shape, are typical of grade
III tumours. Nevertheless they still can be recognised as transitional cell
carcinomas. The term anaplastic carcinomas refers to tumours that cannot be
recognised as urethelial as the pathological view is blurred.
Papilloma is a benign urothelial tumour. The tumour consists of fibrovascular stalks lined by normal urothelium. Such rumours are never anaplastic. They
are not invasive. Nor do they metastasise. But they are very uncommon. The
incidence of papilloma in the ureter is not more than 3%.
Inverted papillomas occur in the ureter as well as in the bladder. They are
usually benign but they may occur in association with other urothelial carcinomas.
Grainger et al. (1990) reported an 18% incidence of malignancy within inverted
papillomas of the ureter. Thus patients with inverted papillomas of the ureter
should be followed closely for upper urinary tract and bladder transitional cell
carcinomas.
In 1952 Melicow identified carinoma in situ. According to UICC, the name is
used to denote anaplasia of the superficial layers of urothelium without exophytic
growth or invasion.
Carcinoma in situ is often associated with low-differentiated tumours or it
may precede their development. Thus it requires early and aggressive treatment.
Squamous cell carcinomas are far less common in the upper urinary tract than
urothelial tumours. Their incidence varies from 0,7 to 7%. In the renal pelvis they
occur approximately six times more frequently than in the ureter. They can
originate from leucoplakia or straight from urothelium. Squamous cell carcinomas
are frequently associated with infected staghorn calculi that have been present for a
long duration. Squamous cell carcinomas are often invasive and soon metastasise.
Therefore their response to treatment is rather poor.
Adenocarcinoma in the ureter is extremely rare. As with squamous cell
carcinoma, adenocarcinoma usually is associated with calculi, long-term
obstruction and inflammation.
In 70% of cases adenocarcinomas excrete mucus. They usually infiltrate the
ureteric wall and metastasise early. The response to radiation or chemotherapy is
poor.
Nonepithelial tumours are hardly ever spotted. The following cases have been
described so far: leiomyosarcoma, carcinosarcoma, leiomyo-mas, neurofibromas,
plasmocytomas and angiosarcomas.
Symptomatology and diagnostic procedures of ureteric tumours
The most common symptom of upper tract urothelial tumours is gross or
microscopic hematuria. It occurs in about 75% of patients suffering from the
disease. Messing and Valencourt (1990) indicated that micro-hematuria was very
likely to be found in all cases of upper urothelial tumours provided a sufficient
number of urine examinations were carried out.
About 30% of patients complain of flank pain, which is usually dull and
lasting. Acute colic caused by massive bleeding from the tumour and resulting
obstruction of the collecting system by a blood clot is more typical of collecting
system tumour rather than of ureteral tumours. Prostration and invasion of
periureteric tissue are observed in patients with symptoms of advanced disease.
Occasionally the symptoms are due to metastasis. Nothing is usually found on the
physical examination. The tumour is perceived below the ribs or in the flank only
in very advanced stages of the disease. About 10-15% of patients are
asymptomatic. The tumour is diagnosed incidentally during an examination
undertaken for some other reasons.
Since symptoms characteristic of urothelial tumours are very scarce imaging
studies become particularly useful as diagnosing procedures.
Excretory
The most common radiological examination is excretory urography. Ureteric
tumours cause obstruction and nonvisualisation of the collecting system. In
extreme cases total loss of renal function is observed. The differential diagnosis
includes ureteric stricture, filling defect, radiolucent stone, blood clot, sloughed
renal papilla or fungus ball.
If excretory urography is not revealing due to loss of renal function caused by
the ureteric tumour retrograde urography is recommended. Contrast material
should be injected via a ureteric catheter. The ureteric orifice should be checked as
some bleeding might occur. Retrograde urography visualises the ureter below the
tumour and if the stricture is not total the assessment of the malignancy length is
possible. According to Murphy retrograde urography makes it possible to diagnose
the ureteric tumours in 75% of cases. Antegrade pyelography is not advisable in
patients suspected of having upper tract transitional carcinoma because th risk of
seeding tumour cells along the needle tract is considerable.
Computed tomography is less useful because of small volume of the tumour
mass. However, in some cases is helpful. Transiotional cell carcinomas are
recognised as soft tissue masses with an average density of 46 HU and a range of
10 - 70 HU. Uric acid stones, which are radiolucent on standard urography, are
opaque on CT scans because their radioden-sity is usually greater then 100 HU.
Neither ultrasonography nor NMR is performed as they do not offer any
material advantage over CT in the diagnosis and staging of patients with upper
tract urothelial tumours.
Recently endoscopic procedures have been used increasingly in the diagnosis
of ureteric tumours. Both rigid and flexible ureteroscopes are used. According to
Blute the correct diagnosis of ureteral tumours based on ureteroscopy was made in
90% of cases.
The procedure makes it possible to localise the tumour, to assess its
morphological features and to perform the biopsy. On the other hand ureteroscopy
is an invasive procedure requiring full anesthesia. The risk of potential
complications is high (Blute's sample: 7%). Even trivial amount of hematuria can
sufficiently cloud visibility, which makes the biopsy impossible. Small tissue fragments obtained by means of small endoscopic biopsy forceps may be difficult for
the pathologist to interpret. Thus diagnostic ureteroscopy should be reserved for
patients in whom the diagnosis remains in doubt after using conventional
diagnostic techniques.
Another noninvasive diagnostic procedure commonly performed is cytopathology. However with low grade tumours the cytology is read as normal in up
to 80% of patients. As with bladder cancers, there is a correlation between tumour
grade and positive cytology results. Thus in diagnosing primary tumours it is of
little help. The accuracy of the examination increases significantly the successive
tumour grades. In patients with grade III tumours the specificity of cytopathology
varies, according to different authors, from 60 - 87%. Ureteral catheterization for
collection of urine directly from the upper urinary tract provides more accurate
cytologic results, but is still associated with substantial false negative and false
positive findings. The drawback of cytology is its low specificity. False positive
results are obtained in patients with urinary stones. Hematuria, bacteriuria,
crystalluria and alkaline reaction of the urine make the assessment of the sample
difficult.
Finally, mention should be made about brush biopsy introduced by Gill.With
this technique, a fine brush mounted of the end of the guidewire is passed through
a ureteral catheter into the ureter. The lesion is sampled by moving the brush back
and forth within the catheter. Sheline reported that brush biopsy had a sensitivity of
91% and a specificity of 88%. As ureteroscopy has become easily available brush
biopsy is no longer as popular as it used to be but performed in some urological
centres due to the low complication rate.
Treatment of ureteric tumours
Ureteral tumours almost always produce symptoms and signs, that need
additional examinations and then allow to establish diagnosis in comparatively
short time. Diagnosed upper urinary tract urothelial tumours must be cured.
So far collecting data let to make following generalisation.
With low-grade and low-stage tumours good results are achieved either with
conservative or radical surgery. Intermediate tumours do better with radical
surgery. Bad results are observed in group patients with high-grade, high-stage
tumours irrespectively of chosen sort of treatment.
Traditional management of upper urinary tract urothelial tumours is
nephroureterectomy with excission of bladder's wall cuff, that surrounds orifice of
the ureter. If one performs this operation it is important not to open ureter and
avoid implantation of neoplasmatic cells into surrounding tissues. Cystotomy
anterior wall of bladder facilitates removal of distal and intramural part of the
ureter as well as minimalises the risk of injury the lower part of contralateral
ureter. 5-years survival rate in patients treated with total nephroureterectomy in
stage Tis, Ta, Tl was 91%, in stage T2 was 43%, in stage T3, T4 and Nl or N2 was
23%.
Conservative methods of surgery have become more popular since seventies.
They are used for low-grade, low-stage tumours of upper and middle or distal part
of the ureter. Partial nephrectomy is performed if tumour is localised in pelvis.
Local recurrences are observed in 25-40% of cases, more often in renal pelvis
tumours. Recurrent tumours are successful treated with repeat local excision.
Conservative methods are especially appropiate for patients with solitary kidney
(anatomically or functionally), bilateral or small low-grade tumours.
Upper urinary tract urethelial tumours are treated also endoscopically.
Ureteroscopic method is preferred.It allows not to disseminate neoplas-matic cells
to adjacent tissues, if one avoids perforation of the ureter wall. Low-grade tumours
are removed using ureteroscope. Patients should be in rigorous follow-up because
of high recurrence rate and mul-tifocality of ureteral tumours. Percutanous
treatment of renal pelvic tumours is accepted only if there is a small, solitary, lowgrade tumour and ureteroscopic access encounters problems. Percutanous method
needs full endoscopic control of ureter and bladder.
Instillation therapy with cytotoxic agents or BCG is nowadays experimental
method without determined indications and efficacy. This kind of treatment can be
indicated in patients with multiple, superficial tumours or carcinoma in situ, if
there is disturbed renal function or tumours are bilateral. For topical treatment
percutanous access (nephrostomy tube) rather then retrograde one (ureteral
catheter) is preferred. The first one reduces the number of complications.
Systemic chemotherapy according to M-VAC regimen, as in urothelial
bladder malignancies, can be potent in advanced (T3-T4) tumours. Durable
complete response was observed in 5-10% of patients. Small groups patients with
upper tract tumours make impossible the conduction of prospective, randomised
trials.
Adjuvant radiotherapy with doses of 37 to 60 Gy can minimalize the local
recurrence rate after total nephroureterectomy for high-stage and high-grade
tumours. Problems with radiotherapy are related to the possibility of injuring
neighboring organs and large surface of irradiation.
Positive cytolgic findings without endoscopic or radiographic evidence of
tumours should be only followed closely.
Epidemiology of the urinary bladder malignancies
Carcinoma of the bladder is the most frequent neoplasm of the urinary tract.
According to United States statistical data it is fourth most common neoplasm
among men (5,5% cases) and eight among women (2,3% cases). Carcinoma of the
bladder is three times more common among men then women.
Neoplasm of bladder can occur at any age of patients but it is most common
in elderly persons (55 years and older) and incidence of bladder cancer increases
directly with age. The median age at the time of diagnosis is, depending on the
country, 60-70 years. The neoplasm diagnosed at age below 30 years is usually
low-grade tumour with a good prognosis, but, as in older population, it depends on
stage and grade of the tumour.
The rise in incidence of bladder cancers is observed in the last 20 years.
This rise in incidence of bladder cancer is not dependent on better diagnostic
methods. Aging of society influences this incidence, but it is hard to explain fact,
that it refers only to men. In population of women, whose life expectancy is longer
then men, who are nowadays exposed to industrial and environmental carcinogenes
in the same extent, there is a declining incidence of bladder cancer of 2% annually.
Bladder cancer is diagnosed 1,5 to 2 times more common among whites then
among blacs, depending on gender. Carcinoma in the first group, although is
detected more often, in greater percentage is noninvasive. Among black bladder
cancer is diagnosed in more advanced form. It doesn't depend on delay in
establishing the diagnosis but is rather related to different, more aggressive biology
of neoplasm.
In 1995 50 500 new cases of bladder cancer were detected in United States.
The bladder cancer was the cause of death of 11 200 patient and this accounts for
2,6% all cancers death in man and 1,4% in women.
In the same time, in Poland, bladder cancer was diagnosed at 3828 persons (it
consists 2,8% of incidence of all malignancies) and was the cause of death of 2252
(it accounts for 3,6% all cancer deaths).
Five year survival rate is highest in white men (84%) and the lowest in black
women (51%). The difference in survival rate can be related to the fact, that in
blacks bladder cancer is seldom diagnosed in less advanced stage and more often
exists in more aggressive or other then urothelial form of malignancies, such as
squamous cell carcinoma or adenocarcinoma. The treatment last ones malignancies
is less effective then urothelial tumours. Additionally, economic conditions can
make inaccessible adequate specialistic treatment.
During last 50 years incidence rate of bladder cancer has increased of
approximately 50% but mortality has decreased of approximately 33%. It is hard to
state, to which factors - changing in the biology of cancer, earlier diagnosis, better
treatment or alteration in risk factors this phenomenon can be attributed.
Symptomatology and diagnostic procedures in urinary bladder tumours
Bladder tumours develop secretly. The first most common symptom is
hematuria of changeable intensity, often accompanied by bladder irritability,
urinary frequency, urgency and dysuria. No connection between the intensity and
frequency of hematuria and the stage of the tumour was found. Urinary tract
infection is observed in 30% of patients.
Pain appears in advanced stages of the tumour. When it is located in the
suprapubic region it signals that the tumour infiltrates the perivesical tissues. Flank
pain, often accompanied by fever, is due to the ureteral obstruction. As the
symptoms of bladder tumours are rather sparse, what seem fundamental in the
diagnosis are additional examinations.
Exretory urography
Urography with cystography are performed in all patients suspected of
bladder tumours. The procedures provide information about the renal function and
the morphology of the urinary tract. Ureterohydronephrosis signals the muscleinvasive growth of the tumour in 70-90% of cases.
Filling defects in the central part of the cystogram can indicate the papillary
growth of the tumour. Marginal filling defects are typical of flat tumours, which
are always invasive.
The most common method used in the diagnosis of bladder tumours is
ultrasonography.
Sonography
Sonography
Transabdominal sonography makes it possible to identify exclusively
exophytic tumours whose diameter exceeds 10 mm. Transurethral sonography is a
more discriminating method. It helps to determine the depth of the tumour invasion
into the bladder wall.
Cystoscopic view
The most revealing diagnostic procedure is cystoscopy. It shows the size of
the tumour, its appearance and its surrounding. If a biopsy is also applied the
histology of the tumour as well as its grade can be determined.
Biopsy (cystoscopic view)
The biopsy of non-affected parts of the bladder should be obtained in search
of carcinoma in situ.
The pathological stage of the tumour must be precisely estimated. This can be
achieved by means of transurethral resection.
After the procedure a pathologist checks the removed tissues
as well as the material taken from the place where the tumour was located. The
histological grade determined in this way is consistent with the grade of the tumour
removed during the cystectomy. The tumour grade is adequately estimated during
the transurethral resection in 96% of patients with superficial carcinomas. The
procedure is much less accurate when the tumour infiltrates the bladder muscle or
perivesical tissues. In such cases the differentiation between T2/T3a and T3b is
successful in 57% of patients. Bimanual examination is still useful as it helps to
approximate the local advancement of the tumour.
Computed tomography is of little use in the diagnosis of bladder cancers. CT
scanning is limited in accuracy because it can detect only gross extravesical
tumour extension. CT scans fail to detect nodal metastases in up to 40% of patients
having them.
Cytological examination is particularly useful for patients who underwent
treatment due to bladder cancer. It may also be used as a screening procedure for
people who are especially vulnerable to bladder cancers because of their
professions. The sensitivity of the method increases with the tumour grade. In grade
3 tumours it varies from 60 to 87%. The drawback of cytological examination is its
low specificity.
Classification and principles of the treatment of the urinary
bladder tumours
Staging of the urinary bladder tumours
In description of staging urinary bladder tumours system T (estimation of the
tumour), N (estimation of the regional lymph nodes metastases), M (estimation of
distant metastases) is commonly used. This system have been worked out by UICC
(International Union Against Cancer).
The following stages are distinguished.
Tumour estimation (T):
Ta - papillary, epithelial confined tumour,
Tis - flat, in situ carcinoma,
Tl - tumour invades lamina propria of urothelium
T2 - tumour invades superficial muscle layer (inner half),
T3a - tumour invades profound muscle layer (outer half),
T3b - tumour invades perivesical fat,
T4 - tumour invades pelvic viscera like rectum, pelvic walls, prostatic stroma
or uterus.
The symbol TO is applied, if tumour haven't been found in postcystec-tomy
specimen and Tx, if there is no data regarding bladder tumour.
Regional lymph nodes estimation
NO - there are no metastases in regional lymph nodes,
Nl - there is single positive node less then or equal to 2 cm in diameter,
N2 - there is single positive lymph node greater then 2 cm but less then 5 cm
in diameter, or multiple positive nodes less then 5 cm in diameter,
N3 - positive lymph nodes greater then 5 cm in diameter.
Symbol NX means, that status of nodes is unknown. Regional lymph nodes
are those located in pelvis minor, below the bifurcation of common iliac arteries
Metastases estimation
The presence of distant metastases (visceral or in lymph nodes above
bifurcation of the aorta) is recorded as Ml and the lack of them as MO. MX is used
if there is uncertainty regarding distant status.
In order to specify staging of the bladder tumour, besides clinical examination, USG and bimanual investigation of patients, following additional
procedures are performed:
1. transurethral diagnostic (primary) resection
2. transurethral ultrasonography
3. computed tomography of pelvis minor, retroperitoneum and liver
4. magnetic resonance of pelvis minor and bones - sites suspected of the
metastases,
5. chest radiograph.
Preoperative staging of bladder tumours is often underestimated (about 30%
of cases) or overestimated (about 10% of cases).
Strategy of the treatment of the urinary bladder tumours.
The discrimination between noninvasive tumours (Ta,Tl) and invasive ones
(T2-T4) is very important because of the difference in the treatment of them.
Additionally, on the method of treatment influences grading of neoplasmatic cells
atypia (symbol G).
Noninvasive tumours can be treated with preservation of the bladder. The
basic curative method is transurethral resection of the tumour. Beside diathermic
current recently energy of laser radiation is used to destroy neoplasmatic, former
photosensitized cells. In the case of recurrent, high grade tumours as well as the
prophylactic of recurrences, intravesical cytostatic (doxorubicin, mitomycin c,
thio-tepa) or immunostymu-lated agents (suspension of the tuberculosis germs
bacilli - BCG therapy) are used. Big tumours can be removed with a fragment of
bladder wall (partial cystectomy). High graded superficial tumours, early or often
recurrent, presenting progression of staging or grading are the indication to radical
cystoprostatectomy and urinary diversion in some urology departments.
The procedure of choice in invasive tumour of bladder is radical
cystoprostatectomy (including regional lymph nodes removal). For advanced forms
of disease the systemic chemotherapy, based on M-VAC regimen (metotrexat,
vinblastin, doxorubicin, cisplatin) is used as adjuvant (after surgery) or
neoadjuvant (before surgery) supported form of treatment. In highly selected group
of patients bladder-sparring methods are tested. Usually the combination of surgery
- transurethral resection or partial cystectomy - with radiation or/and systemic
chemotherapy are examined. Radiotherapy is the basic method of treatment in
certain countries. Results obtained with it are poorer regarding survival rate and
complications rate in comparing to radical cystoprostatecomy.
Patients with advanced bladder cancer may suffer mainly from pain and
intractable haematuria, if the bladder haven't been removed. Palliative external
radiotherapy is not recommended so as it is ineffective and produces many
complications. Massive haematuria, if transurethral ful-guration is insufficient,
may be treated with intravesical instalations under anesthesia of silver nitrate, 1%
alum and 4% formalin solutions. Transdermal embolisation of arterial vessels is
also recommended.
Surgical treatment of urinary bladder tumours
Three methods of surgical treatment are commonly used in bladder cancer.
These are: transurethral resection, partial cystectomy and radical
cystoprostatectomy. The choice of the appropriate procedure is determined by the
following factors: tumour stage, grade and multifocal growth. Such tests as DNA
flow cytometry, ABH blood group and Thomsen-Friedenreich (T) antigen
expression, DNA synthesising (S-phase) fraction and abnormalities in p53 gene are
less useful in every-day clinical practice.
Most authors believe that radical cystectomy is the treatment of choice in
invasive bladder cancer. What is identified as invasive cancer is the tumour which
infiltrates the bladder muscle. According to TNM classification (1989) it represents
stage T2-T4. Transurethral resections are performed in cases of superficial
caricinomas whereas radical cystectomy is reserved for invasive tumours. In
selected cases partial resection of the bladder is performed. However, the division
presented above is fairly simplistic. Local recurrence was observed in 50-80% of
patients with bladder cancer - stage Ta and Tl. In 25% of these the disease
progressed. Patients with cancer recognised as stage Tl and grade G3 were still
alive 5 years after the operation only in 50-60% of cases. It is a well-known fact
that noninvasive tumours which are confined to the lamina propria of the bladder,
usually regarded by urologists as superficial, may metastasise into the lymph
nodes. Smith and Whitmore reported that kind of development in 5% of patients
who had undergone radical cystectomy. Lerner diagnosed metas-tases in the lymph
nodes in 4% of patients with bladder cancer defined as stage pTa, pTis or pTl.
These findings suggest that carcinomas infiltrating lamina propria should be
treated as advanced, which means that they require procedures more radical than
transurethral resection. On the other hand, some urologists believe that
transurethral resection in association with chemotherapy can be an alternative to
radical cystectomy as it proves to be successful in the treatment of some patients,
even those with invasive bladder cancers.
Transurethral resection
Transurethral resection as primary therapy should be reserved for patients
who have small, solitary, low grade superficial carcinomas and bladder papillomas.
The operation is frequently performed in two stages. Stage I involves the resection
of the bladder tumour. Stage II is the resection of the scar resulting from the first
operation. The procedure makes it possible to remove deep layers of the bladder
muscle, which renders the treatment more radical. Transurethral resections are
performed in spinal anaesthesia. They are well tolerated and do not require a blood
supply. Patients do not stay in hospital longer than a few days after the operation.
The combination of transurethral resection with chemotherapy and irradiation was
introduced in order to save the bladder. However, the treatment proved to be less
successful than expected.
Partial resection of the bladder
Partial resection
Partial resection of the bladder is performed rarely. The treatment is reserved
for patients with solitary muscle-infililtrative tumours localised on top of the
bladder, far from the trigone or vesical neck. No evidence of carcinoma in situ can
be recognised in the remaining part of the bladder. A tumour-free margin of 1,5 to
2,0 cm must be obtained. The results for patients selected carefully for the
procedure were not inferior to those of cystectomy.
In order to improve the therapeutic results partial resection was combined
with chemotherapy. Herr and Scher reported that the combination gave five-year
survival in 64% of patients. All of them preserved their own well-functioning
bladder. Because of the multifocal growth of bladder cancer, patients undergoing
partial cystectomy must be followed by careful surveillance cystoscopies as
intravesical recurrences are common. Herr and Scher observed such recurrences in
46% of cases.
Radical cystectomy
Radical cystectomy in the treatment of bladder cancer has been performed for
more than a hundred years. The first operation of that type was carried out by
Bardenheuer in 1887. Ineffective anaesthesia, lack of antibiotics and problems with
urinary diversion were the reasons for the postoperative mortality rate of 50-60%
at the beginning of the century. In 1939 von Hinmen reported that 34,2% of
patients who had undergone cystectomy died directly after the operation. In the
60's the postoperative mortality rate was already 10%. Nowadays, in most
urological centres it is about 1%. The operation consists in the resection of the
bladder together with the prostate and seminal vesicles. Abdominal assess is used.
In female patients, the standard operation for invasive bladder cancer is an anterior
pelvic exenteration with wide excision of the bladder and urethra in continuity with
the uterus, fallopian tubes, ovaries, and anterior wall of the vagina.
The connection of the tumour stage with lymphatic metastases is commonly
known. In patients with tumours superficially infiltrating the bladder muscle lymph
node metastases were observed in 6-36% of cases. In patients with more advanced
carcinomas lymph node metastases were diagnosed in 50% of cases. These
findings made urologists try to improve the therapeutic results. Thus cystectomy
was combined with pelvic lymphadenectomy. The term radical cystectomy denotes
the operation involving a total resection of the bladder with the prostate and
seminal vesicles and pelvic lymphadenectomy.
Many authors used to believe that multifocal growth of the urothelial tumours
required preventive urethrectomy in addition to cystectomy.
As nowadays neobladders are commonly made, urethrectomy is performed
only when the tumour infiltrates the urethra. Even though cystectomy is a serious
and mutilating operation it is applied more commonly now because it has become
safer (lower mortality rate) and more comfortable to the patient. The implantation
of the ureters to the skin as well as the methods consisting in connecting the
urinary tract with the alimentary system have been superseded by new methods of
urinary diversion described by Bricker (1950), Couvelaire, Cibert and Carney.
Kock and Le-isinger described the method of making a continent urinary reservoir
called Kock-pouch. In 1985, urologists from Mainz described a new method of
making a continent urinary reservoir shaped from the coecumand the terminal part
of the ileum. The method was related to the operation performed by Gilchrist in the
50's. It is known as Mainz Pouch. Rowland from the University of Indianapolis
modified the operation in that the reservoir was made from the coecum and a part
of a colon. The modification is known as Indiana Pouch. Recently neobladders
joined to the urethra have been used. The operation makes it possible to avoid
urostomy, which mutilates the patient. However, neobladders cannot always be
made.
As cystestomy used to cause impotence in almost 100% of men, a number of
patients did not accept the operation. The nerve-sparing modification introduced by
Walsh reduced the risk of impotence as a side effect of cystectomy. The
modification consists in that vesical arteries and bladder pedicles are transected
immediately adjacent to the seminal vesicle and ureters to avoid injury to the
cephalad portion of the neurovascular bundles.
Mention should be made of the combination of cystectomy with radiotherapy.
This integrated therapy was introduced by Whitmore. The method was used in the
60's and 70's in many urological centres in the world. It was expected to improve
the therapeutic results in patients with bladder cancer as well as to reduce the
percentage of local recurrences after cystectomy. The bladder was irradiated with
40 Gy over the period of four weeks. The operation was performed four weeks
after the irradiation had been completed. 'Short' irradiation lasted for a week, the
dosage being 10-20 Gy. In those cases cystectomy was made a few days after the
irradiation. The results of the integrated therapy were promising. Whit-more
reported a significant drop in the percentage of local recurrences (37% vs. 16%)
over the period of 20 years. Five-year survival of patients with bladder cancer
increased during that time, too. The theoretical as-f sumption underlying the
therapy is that irradiation destroys tumour cells in the lymph nodes, thus
preventing their dissemination during the operation. In addition, radiotherapy may
diminish the mass of the tumours that were regarded as non-operative prior to the
irradiation.
However, a number of authors were rather sceptical about the superiority of
the integrated therapy over mere cystectomy. In 1984 Montie presented the
therapeutic results achieved over the period of 20 years in 99 patients who had
undergone radical cystectomy without prior irradiation. The percentage of local
recurrences in those patients was only 9% and five-year survival in T3, T4 tumours
was 40%. Similar results were observed by Mathur. When comparing the
integrated therapy (cystectomy + irradiation-16Gy) with radical cystectomy in the
analysis of 197 patients with bladder cancer, Skinner found no statistically
significant survival advantage in either of the methods. Thus the better results
reported widely have been attributed to better surgical techniques, better selection
for the operation, progress in anaesthesia and intensive care rather than to the
combination of cystectomy and radiotherapy. Nowadays the integrated therapy in
bladder cancer is not particularly common. Instead, radical cystectomy associated
with neoadjuvant or adjuvant chemotherapy is applied.
At present radical cystectomy appears to be the most effective therapeutic
option for patients with invasive bladder cancer. Five-year survival is assessed by
different authors as 30-54% of cases. However, the operation is dangerous,
technically difficult, for which the risk of perioperative morbidity is high.
What seems to be of primary importance is to determine strictly the
indications for the operation. These are:
1. invasive bladder cancer irrespective of the tumour grade,
2. recurrences of the tumour after transurethral resection, particularly when
the grade increases,
3. high grade tumours coexisting with carcinoma in situ,
4. multifocally growing superficial bladder cancers resistant to intrave-sical
chemo- or immunotherapy administered after transurethral resection,
5. recurrences of carcinoma in situ following chemo- or immunotherapy.
It seems that nowadays the radical treatment tends to be increasingly applied
even in early stages of bladder cancer. Current research on the biology of
neoplasms might help to determine the progression risk factors, which in turn will
make it possible to decide which patients require the resection of the bladder and
which can be administered a less aggressive treatment.
Radiotherapy of the urinary bladder tumours
Cure rates of up to 80% can be obtained with surgery for T1-T2 well
differentiated tumours where lymph node involvement is uncommon. Poorly
differentiated or multiple T1-T2 tumours may be treated by local radiotherapy to
the bladder and perivesical tissues with five- year survival rates of 40-60%.
Lymphatic involvement occurs in about 60% of patients with T3 tumours and
radiation is usually given to the whole pelvis. Five-years survival rates after
radiotherapy, however are less than 35%. External -beam radiotherapy is often first
line therapy in Great Britain and Europe, with salvage cystectomy reserved for
treatment failures. Analysis of clinical characteristics has defined several
prognostic factors that predict for local control freedom from metastasis and
survival in patients treated with definitive irradiation. Most series show that depth
of tumour's invasion defined by stage is an important prognostic indicator. Other
poor prognostic sign include tumour greater than 5 cm, residual disease after
TURB, and radiographic evidence of ureteral obstruction with hydronephrosis.
In an effort to improve local control rates with external - beam radiotherapy
for patient with invasive bladder cancer hyperfractionated treatment schedules
have been used. Edsmyr and coworker reported a Swedish trial of 168 patient with
T2 to T4 disease randomly assigned to receive either 1 Gy three times a day to a
total of 84 Gy or 2 Gy once a day to a total of 64 Gy. Both regimens were given
over 8 weeks with an imposed mid-course 2-week treatment interruption. The 5year survival for the group receiving 84 Gy was 37% and for those receiving 64 Gy
it was 16%. Patients with T3 disease particularly appeared to benefit from the
hyperfractionated schedule.
A study in Great Britain has tested an accelerated hyperfractionated regimen
in 24 patients with muscle invasive bladder cancer. Over a 22-day period, patients
received doses of 1.8 to 2.0 Gy per fraction to total doses of 54 to 64 Gy to the
bladder and 39.6 to 44 Gy to the whole pelvis. Local control was, 56% and
survival was 35% at 2 years.
Simulation and treatment
During simulation and treatment, the patient is supine and the bladder is
emptied to ensure reproducibility. At the time of simulation a Foley catheter is
inserted and 25 to 30 ml of radiopaque contrast material is instilled in addition to
10 to 15 ml of air for bladder visualisation. A rectal tube with barium contrast
medium is placed to visualise the rectum.
In general, a four- field box approach is used (Anterior posterior and lateral
fields) delivered through 6 to25 MV X-rays. A lot of favour the four field box
because of the ease of interpreting imaging films, the ease of making portal size
reductions, and the satisfactory dose distribution. Other techniques of irradiation
are possible e.g. anterior posterior, rotational, three-field portal arrangements. The
360-degree arc rotation technique was significantly associated with an increased
risk of severe complications.
Preoperative radiotherapy
The rationale for using this neoadjuvant irradiation is to reduce the incidence
of tumour bed failures and potential seeding of malignant cell from the operation.
Some of retrospective studies have suggested that the addition of preoperative
radiotherapy improves the overall outcome, other series have found no benefit
when results are compared with modern surgical series. Several prospective trials
that compared preoperative radiotherapy plus radical cystectomy to radical
cystectomy alone have demonstrated no significant differences between the
treatment arms in two studies of so called sandwich irradiation patients with
clinical B2, C, D disease received sequentially 5 Gy (single fraction)
preoperatively, radical cystectomy, and 45 Gy postoperatively. The 5- year disease
-free survival rate for these patients was only 20%.
Preoperative irradiation is recommended for T2, largo =4 cm tumours, highgrade lesions, T3 and resectable T4.
Complication of radiation therapy
Radiotherapy is generally well tolerated, most patients experience dy-suria,
urgency, urinary frequency, and diarrhea as acute self limiting symptoms. The
incidence of long -term complication is acceptable when proper treatment
techniques are used. In general, such complications become clinically manifest
within the first 3 years after radiotherapy. Shipley reported an 11% incidence of
chronic grade III-IV genitourinary complications among 35 patients with locally
advanced bladder cancer treated with conventional fractionated therapy.
Palliative Radiotherapy
- is for rapid relief of pain or hematuria with minimal incovenience to the
patient. This can be accomplished with a short course with a high dose per
fraction.: 17 Gy in 2 fractions over 3 days, 30 Gy in six fractions of two fractions
per weeks, 21 Gy in three fractions over 5 days. Many suffered acute side effects
including diarrhea, vesicovaginal fistulas, contracted bladders.
Brachytherapy
Interstitial treatment may be used alone, in combination with low or moderate
dose external irradiation, or to treat the suturejine in patients undergoing partial
cystectomy. In carefully chosen patients, the technique has provided excellent
tumour control and bladder function.
Experience with radium needle implants has been reported by Van der Werf
Messing from Rotterdam. 328 patients with T2 and 63 patients with T3 muscle
invasive bladder cancer were treated with preoperative radiation of three fractions
each at a dose of 3.5 Gy followed by radium. Results local recurrence at 5 years
was 16% for T2, and 28% for T3 tumours. Survival -56% of patients with T2, and
37% of those with T3 disease alive at 5 years. (Survival was similar to patients
undergoing definitive external-beam radiotherapy or cystectomy.)
Other isotopes using in the brachytherapy: cesium (Cs -137) iridium (Ir-192).
Mazeron treated 30 patients with T2 and 5 with T3 disease using a single fraction
of 8,5 Gy, followed by partial cystectomy and iridium implantation, and attained
excellent local control. Rozan reported a multicenter French experience that
included 98 patients with Tl, 66 with T2, 26 with T3a, 9 with T3b, and 1 with T4
disease treated by preoperative external beam radiation, partial cystectomy with
lymphadenectomy, and placement of an iridium implant into the tumour bed.
Preoperative radiation was targeted to the bladder in 44 patients and to the pelvis in
161 patients for a mean total dose of 11 Gy, and a mean dose per fraction of 5,4
Gy. Of the 36 tumour recurrences, 9 were located and the original site, and 19
occurred in a different site. They reported an overall 5- years survival of 67%.
Survival was 77% for pTl, 43% for pT3. Serious complications: hematuria - 8,
chronic cystitis -17, fistulas - 11 patients.
Local treatment of the urinary bladder tumours (chemotherapy and
BCG-therapy)
Introduction
Superficial bladder cancer has a high tendency to recur, and in significant
subset of patients, to progress. Analysis of the clinical risk factors of superficial
bladder cancer, such as stage, grade, size and multifocality is crucial tc predict the
course of the disease. The field of topical therapy can roughly be divided into the
chemotherapeutic and immunotherapeutic approaches.
Chemotherapeutic and immunotherapeutic agents have been used in the
therapeutic ablation of existing or residual tumours and in prophylaxis against their
recurrence. Intravesical therapy can also be used tc treat existing superficial
bladder tumours. Currently, this is reserved primarily for the management of
carcinoma in situ, which is often almost impossible to resect endoscopically in its
entirety or for the rare patieni with so many superficial tumours that endoscopic
resection is not feasible and cystectomy is either not appropriate or not desired by
the patients. With these exceptions, however, intravesical therapy is used primarily
in an adjuvant form, although this may often be threatening existent or persistent
disease that is just not yet detectable.
Adjuvant intravesical therapy or intravesical immunotherapy is indicated in
patients who are at a high risk for tumour recurrence by virtue olhaving multiple
tumours, recurrent tumours, high grade tumours associated with urothelial atypia,
or carcinoma in situ.
Intravesical chemotherapy
Since 1948, when Semple first used podophyllin in an attempt to reduce the
recurrence rate of superficial bladder cancer, many different agents have been
employed.
Generally, intravesical chemotherapy began in the 1960 with the introduction
of intravesical thiotepa. From many different substances used in treatment, only the
most frequently used and successful will be described. Table 1 summarises the
advantage and disadvantages of the compounds that have been studied for
chemotherapy and chemoprophylaxis.
All agents for intravesical chemotherapy are about equally effective. The
possible exception is that mitomycin may be marginally superior to thiotepa in the
treatment of patients with stage Ta tumours and for high-grade tumours. When
used as prophylaxis against tumours recurrence, recurrence rates have been
reduced to 30-44% compared with about 70% in controls. However, the study by
Pawinski et al.(9) reported on 2535 patients from the European Organisation for
Research and Treatment of Cancer (EORTC) and Medical Research Council
studies on chemotherapy with a median follow-up of 7,8 years, who were analysed
for the duration of disease-free interval and survival, with regard to recurrence, the
overall advantage of chemotherapy over TUR alone was 6%. Nowadays, little
evidence exist to indicate, that any type of intravesical chemotherapy prevents
progression to muscle invasion. From analysing a variety of randomised,
controlled studies that collected progression data, it appears that patients treated
with surgery alone and patients treated with both surgery and intravesical
chemotherapy experience roughly a 7% chance of developing muscle - invasive
disease .
Table 1: Advantages and disadvantages of therapeutic compounds used
in treatment of bladder cancer
Molecular
Name
Advantages
Disadvantages
Therapeutic use
weight
Systemic absorption leading
Thiotepa Small Inexpensive
to myelosuppression and
+/renal failure
Systemic side-effects;
Epodyl
Small Inexpensive
+/myelosuppression
AdriaMinimal
Large
Chemical cystitis; expensive
++
mycyn
absorption
Minimal
Epirubicin Large
Chemical cystitis; expensive
++
absorption
Mitomycin C
MitoxantronC
Minimal
Chemical cystitis, bladder
(absorption
ulceration; expensive
Minimal
Large
Chemical cystitis, expensive
absorption
Relatively
Local toxicity, BCG-itis
BCG
Large
inexpensive
(absorption)
Cytokines Relatively Effective Systemic toxicity; extremely
Interferon small
expensive
Large
++
++
+++
+
Intravesical Bacille Calmette-Guerin (BCG) therapy
For many years it has been known that patients dying of tuberculosis have a
very low incidence of incidentally discovered tumours at autopsy. In 1929 it was
suggested that response of the body to the tuberculosis bacillus might convey
benefit in preventing cancer.
In 1976 Morales et al. presented the first results of intravesical BCG
instillation in the treatment of superficial bladder tumours. Subsequently Lamm et
al. and Brosman, amongst others, reported successful prophylaxis of recurrent
bladder tumours with BCG instillations.
BCG is an attenuated strain of Mycobacterium bovis that has stimulatory
effects on immune responses. Several strains of BCG have been used including the
Pasteur, Tice, Armand-Frappier and Moreau strains. All are derived from the
original strain developed at the Pasteur Institute and the precise mechanism by
which BCG exerts remain unknown. The fact that intravesical therapy without
scarification or conversion of previously negative Mantoux test, is as effective as
in the other circumstances, suggests that it is a purely local mechanism. Some
studies suggests that one mechanism involves the release of cytokines into the
bladder, belonging to both the interferon and inrleukin families.
BCG is commonly given in three clinical settings: prophylaxis in tumour-free
patients, treatment of residual tumour in patients with papillary TCC and treatment
of patients with carcinoma in situ.
Intravesical BCG treatment, compared with many other instillations, does
sometimes cause major side-effects and patients must be seen regularly. Although
most patients only suffer bladder irritation, irreversible bladder contracture and
systemic BCG-itis may occur. Such severe symptoms requiring antituberculous
therapy occur in up to 6% of patients.
BCG is perhaps most useful in the treatment of patients with carcinoma in situ
In several studies BCG induced complete response rates in about 72% of patients
with ca. in situ. Intravesical BCG in conjunction with transurethral resection of the
prostate may be effective in the treatment of patients with carcinoma in situ
involving the prostatic urethral mucosa or prostatic ducts.
Conclusion
Because well-differentiated and moderately differentiated superficial tumours
recur after complete endoscopic resection in roughly 50% of patients but rarely
progress to more aggressive disease, it would make sense that intravesical therapy
be withheld in such patients until the frequency or multiplicity of recurrences
becomes so great that the expense, discomfort, or risk of repeated TUR exceeds
that of intravesical therapy. Alternatively, because high-grade lesions, particularly
Tis or stage Tl, have substantial risk of stage progression, intravesical therapy is
indicated immediately. Because only BCG has been shown to delay or prevent
progression it should be the first agent used.