Journal Vol.II No.2, March-April, 2007

91 Pages·2007·0.75 MB·English

1
Invest in Health- Build a Safe Future
P.S. Shankar Editorial
Governing Body Member, National Board of Examinations
Health is a precious and most Indonesia, China and Pakistan during been referred to as SARS. The disease
valuable possession that has 2006. This is an infectious disease caused causes flu-like symptoms initially,
been considered as the second by a highly contagious virus. The disease rapidly to be followed by respiratory
blessing, and vital principles of bliss. appears to have jumped the species problems, often serious leading to higher
Without health life is considered no life, barrier, infecting human and causing mortality.
and all our happiness lies in health. death. It necessitated culling of millions
SARS is a highly infectious disease caused
People all over the world have realized of chicken, ducks, geese and other birds
by a corona virus. It is transmitted by
the importance of health and the to prevent the spread of the disease. The
close contact with aerosolized droplets
following proverbs of different languages public health authorities were put on
and bodily secretions from an infected
highlight the importance given to health: high alert to prevent the occurrence of a
person. It causes diffuse alveolar damage.
Health is wealth (Kannada); Health is pandemic in human beings. The speed at
The person exhibits fever, cough,
better than wealth (English); From which this virus spread was
shortness of breath and difficult
bitterness of disease man learns the unprecedented.
breathing. There should be history of a
sweetness of health (Spanish); Good
There is a risk that humans could become close contact with a person who was
health or bad makes our philosophy
infected with both the avian and human known to have suffered from SARS
(French); Every healthy man is king
influenza virus at the same time. Avian within the past 10 days or travel within
(Gaelic); Wealth without health is half
flu virus could swap genetic material with past 10 days of onset of symptoms to
sickness (Italian); One can always be
human flu to produce a highly contagious places which have reported cases of the
healthy as long as one is not ill (Russian).
mutant. The parts of Asia affected by the disease. Prevention of SARS involves
Benjamin Disraeli had said ‘the health of outbreak of avian flu were put on strict avoidance of close contact with SARS
people is really the foundation upon measures of isolation and culling of patients. Persons suspected of having
which all their power as a State depend’. millions of chicken infected with a strain SARS must be isolated and should limit
World Health Organization (WHO) has of bird flu and isolation of persons their interactions outside hospital
given the slogan ‘Invest in health, build a thought to be infected. The 2006 settings. Quarantine of patients before
safe future’ for WHO Day on 7th April outbreak affected every country they spread disease, quarantine or close
2007. The slogan addresses to one of the contiguous either by land or sea. The monitoring of all the people they have
most vital concerns of the current times. entry of any poultry products were not come into contact with and a clampdown
Globalization and rapid travel allowed from those regions. The presence of social gatherings and travel are
surpassing the international time-zones of antibodies against H5N1 virus was important.
have enabled the easy spread of the new tested. The country should be vigilant
HIV/AIDS since 25 years has been racing
and existing diseases beyond the national about persons entering the country who
across nations, adversely impacting their
borders and have affected the collective appear to be presenting features of flu-like
economics and threatening their stability.
security. illness.
New diseases have appeared and old ones
Avian influenza and severe acute A mysterious form of highly contagious have re-emerged as epidemic/pandemic
respiratory syndrome (SARS) have pneumonia was reported in Guangdon prone diseases to present an acute threat
spread from one country and region to Province of People’s Republic of China to life. Climate change, natural disasters,
the next. Avian influenza (flu) epidemic in later part of 2002 and subsequently chemical and nuclear accidents and
swept across South Korea, Japan, Taiwan, spread to parts of South-east Asia during bioterrorism also hold the potential to
Vietnam, Thailand, Cambodia, Laos, the early months of 2003. The illness has threaten international public health
Journal of Postgraduate Medical Education, Training & Research 1
Vol. II, No. 2, March-April 2007
security. a campaign for preparedness against and challenges. WHO is assisting the
bioterrorism. Bioterrorism refers to the countries to strengthen their public
Global warming is occurring at an
use of chemical or biological weapons for health risks and challenges.
alarming speed due to combustion of
terrorism. Though the morbidity and
fossil fuels. It is associated with The revised and broadened international
mortality caused by bioterrorism have
anthropogenic emission of greenhouse health regulations 2005 are coming into
been very small compared to that
gases, air-borne particulates, nitrogen and effect in June 2007 to provide support to
produced by the use of other weapons,
sulphur dioxide. Global warming having the countries to stabilize global health.
there is need for preparedness against any
health impact has emerged as a public Under this international agreement the
possible bioterrorism.
health challenge. Global warming member states of WHO are obliged to
associated with rainfall, humidity, water- Natural disasters such as earthquake, prevent and control the spread of disease
logging, active photosynthesis of floods, cyclone, tsunami, and famine inside and outside their borders. They
vegetation, is changing the ecology of strike the globe frequently. WHO has have to maintain core surveillance and
many arthropod vectors transmitting defined disaster as ‘any occurrence that exhibit their capabilities to detect, assess,
diseases to human beings. Warmer causes damage, economic disruption, loss notify and report public health events to
temperatures increase mosquito and tick of human life and deterioration in health WHO and to respond to public health
vector overproduction, biting and services on a scale sufficient to warrant risks and public health emergencies. All
transmission of disease such as malaria, an extraordinary response from outside must keep in their mind about the closing
Rift Valley fever, and Lyme disease. the affected community or area’. There phrase found in many Latin letters: ‘ cura
Dengue fever and Chickungunya fever is ecologic disruption which exceeds the ut valeas’ (Guard your health).
spread by the mosquito, Aedes aegypti, capability of the affected community to
have widened their geographical make adjustments. The rescue and relief
boundaries in tropical regions. The faces many difficulties. In addition to
spread and activities of the sandflies, medical relief, quick removal and
vectors of Leishmaniasis, is strongly disposal of corpses, restoration of water
influenced by ambient temperature. supply, food and maintenance of Ancient Greece
There is an explosion of the mouse sanitation are important to prevent
population following heavy rainfall and widespread epidemics. The casualties are While surgeons are now
they may increase the chances of to be evacuated from the site as fast as considered to be
outbreak of Hantavirus pulmonary possible to a place where proper specialised physicians,
syndrome. treatment can be given on priority basis. the profession of surgeon and that
of physician had different
The climate change in the coming years William Mayo once said, ‘of all
historical roots. For example,
threatens human population with health cooperative enterprises public health is
Greek tradition was against opening
hazards by disrupting water and food the most important and gives the greatest
supplies, and increased spread of vector- returns’. Hence there is need for the body, and the Hippocratic Oath
borne diseases. It has called for reduction investment in health. Health emergencies warns physicians against the
of green house gas emissions by reducing cause global concerns and an effective practice of surgery. Specifically,
combustion of fossil fuels, development response requires international cutting persons laboring under the
of renewable energy technology, cooperation. This has been amply stone (i.e. lithotomy, an operation
establishment of stations equipped with exhibited by different nations following to relieve kidney stones) was to be
remote sensing and geographic tsunami disaster and outbreak of SARS. left to such persons as practice [it].
information system to monitor sea-level The WHO slogan highlights the vital need
Of course, most knowledge of
rise and extreme weather conditions. to invest in human resources and
surgery comes from dissecting
strengthen the health systems to enable
The dissemination of anthrax spores bodies, a science which was
the international community to
through US mails and the resultant repulsive to many healers.
effectively meet the public health risks
cutaneous and inhalation anthrax led to
2 Journal of Postgraduate Medical Education, Training & Research
Vol. II, No. 2, March-April 2007
2
Drug-Resistant Tuberculosis
P.S. Shankar Commentary
Governing Body Member, National Board of Examinations
Multi-drug resistant (MDR) including those living with human-
Table -1, Causes of resistance
tuberculosis (TB) is being immunodeficiency virus (HIV),
increasingly recognized in the Poor adherence to treatment virtually untreatable with the currently
recent years all over the world. The term Prescription of inappropriate available anti-tuberculosis drugs, and
refers to the disease due to M. tuberculosis combinations of drugs death becomes imminent.
that is resistant to the two most effective
Prescription of inadequate dosage of
The description of XDR-TB was first
current anti-tuberculosis drugs, isoniazid
drugs
given in early 2006 following a joint
and rifampicin with or without
Inappropriate rhythm of survey by World Health Organization
resistance to other drugs (poly-resistance)
administration (WHO) and the US Centres for Disease
1. It is an iatrogenic problem. Extensively
(Extremely) drug-resistant (XDR) Use of unreliable combinations Control and Prevention (CDC).
Resistance to anti-tuberculosis drugs is a
tuberculosis is caused by a strain of Addition of another drug to a failing
reflection of poorly managed
Mycobacterium tuberculosis resistant to regimen
tuberculosis. The care-giver, patient and
isoniazid and rifampicin (as in MDR- Erratic drug supply
drugs play a part in the emergence of
TB) in addition to any fluoroquinolones
Malabsorption of properly prescribed drug-resistant strains. The reasons
and at least one of the three injectable
drugs include incorrect drug prescribing
drugs such as capreomycin, kanamycin
practices by the care-giver, poor quality
and amikacin 2.
Drug resistance has to be suspected in a of drugs or erratic supply of drugs, and
Multi-drug resistant tuberculosis patient who continues to remain sputum- patient non-adherence.
positive after four months of regular
After dramatic outbreaks of multi-drug- Epidemiology of XDR-TB
treatment with an established short-
resistant tuberculosis in the early 1990s,
course chemotherapy regimen. A history The findings from a survey carried out
resistance became recognized as a global
of anti-tuberculosis treatment predicts by WHO and CDC on data from 2000 to
problem. MDR-tuberculosis (TB) now
the occurrence of MDR-TB. Non- 2004 has shown that XDR-TB is
threatens the inhabitants of the countries
compliance with the anti-tuberculosis encountered in at least 17 countries of the
in Asia, Africa, Europe and the Americas.
drugs therapy, and HIV-infection World. However its occurrence was
A new research finding from South
aggravate the situation. more frequent in the countries of former
Africa on an extensively drug-resistant
Soviet Union and Asia 5.
strain of M tuberculosis that causes Extensively drug resistant
tuberculosis is alarming the experts 3. The tuberculosis The survey has shown that in United
new strains of multi-drug resistant-, and States, 4% of isolates of MDR-TB met the
Looking at the emergence of extremely
extremely drug-resistant strains of criteria for XDR-TB. 15% of isolates of
drug resistant strains of tuberculosis
tubercle bacilli have emerged despite MDR tuberculosis in the Republic of
bacilli, the World Health Organization
availability of effective anti-tuberculosis, Korea were XDR strains. In Latvia, a
(WHO) has expressed concern and has
and it is due to their ineffective country with one of the highest rates of
called for urgent measures to strengthen
administration. They have great MDR-TB, 19% of MDR-TB cases met the
and to implement effectively the
significance for the public health field. criteria for XDR-TB (5). The data on the
prevention of the global spread of the
The causes of drug resistance are many recent outbreak of XDR-TB in an HIV-
deadly strains of tuberculosis. The newly
(Table- 1) 4. positive population in KwaZulu-Natal,
identified strains of XDR strains of
a province of South Africa has shown
tubercle bacilli leaves the patients,
Journal of Postgraduate Medical Education, Training & Research 3
Vol. II, No. 2, March-April 2007
alarmingly high rates of rapid death. Of polar group that does not demonstrate any resistant to all 8 second-line drugs tested
the 544 patients studied at a rural cell-mediated immunity. Between them and therefore, were denoted as XDR M
hospital, 221 had MDR-TB. Of them 53 are two intermediate groups, leaning tuberculosis. Retrospective analysis of
were defined as XDR-TB. Among them towards the reactive group and another the cases of XDR-TB showed that all of
44 had been tested for HIV and all of one leaning towards the un-reactive them belonged to 1 of 2 epidemiological
them were HIV-positive. 52 of 53 group. There is predominance of clusters, either a single-family cluster (4
patients died of tuberculosis on an lymphocytes and epitheloid cells to the cases) or a cluster of close contacts (8
average, within 25 days including those reactive group. The number of tubercle cases). The strains were identified as
getting benefit from anti-retroviral bacilli in the tissues and the level of belonging to the M tuberculosis super-
therapy 6. antibodies increase towards the un- families Haarlem I and East African
reactive group and there is rapid spread Indian.
Scarce drug-resistance data is available
of bacilli and lesions in the lungs and other
from Africa. While population Management
organs 8.
prevalence of drug-resistant TB appears
Early, accurate diagnosis and institution
to be low compared to Eastern Europe The studies on the immune defenses of
of effective treatment properly under
and Asia, drug-resistance in the region is people with tuberculosis have shown that
supervision for a proper duration are
on the rise. Given the underlying HIV the problem is not so much of an inability
essential in the control of tuberculosis.
epidemic, drug-resistant tuberculosis of the body’s defenses to deal with the
The treatment of patients whose
could have a severe impact on mortality organism but abnormally-regulated
organisms are resistant to the standard
in Africa and other countries and it defense mechanisms. Thus, in active
anti-mycobacterial agents poses many
requires an urgent preventive action. tuberculosis, the immune responses
difficulties. The tubercle bacilli and
rather than attacking the tubercle bacilli,
Immune defense mechanism their progeny remain viable and multiply
cause gross tissue destruction with the
in the presence of anti-mycobacterial
There is an increased resistance to re- formation of huge cavities in the lung as
agents in a concentration that would
infection in persons infected with well as causing systemic manifestations
normally destroy or inhibit their
tubercle bacilli either naturally from such as fever and wasting.
growth. Inadequate treatment select out
virulent strains of M tuberculosis or
Masjedi and co-workers from Iran drug-resistant strains which then
artificially following vaccination with
obtained sputum specimens from a total proliferate. Further inadequate and
attenuated, live tubercle bacilli. In
of 2030 patients with tuberculosis and improper treatment maintains the
addition, those infected develop a
digested, examined microscopically for vicious cycle leading to emergence of
delayed hypersensitivity to tuberculo-
presence of acid-fast bacilli and then strains that are resistant to other drugs
protein. These two changes-acquired
inoculated into Lowenstein-Jensen slants until creation of MDR and later XDR
resistance (tuberculo-immunity) and
by standard procedure 9. Testing of tuberculosis. Drug resistance poses a
tuberculin hypersensitivity- are specific
susceptibility to first-line anti- serious limitation to the successful
immunological reactions and are cell-
tuberculosis drugs was performed for treatment and control of tuberculosis.
mediated. These responses are acquired
1284 isolates of M. tuberculosis.
and develop only after the specific There is decreased clinical response,
Subsequently, the strains that were
antigenic stimulus. They play a key role persistence of acid-fast bacilli in the
identified as multi-drug resistant M
in the pathogenesis of tuberculosis 7. sputum, and radiological deterioration
tuberculosis (113 isolates) were subjected
even after continuous therapy for six
Lenzini and co-workers have established to susceptibility testing for second-line
months. These are indications that the
a spectrum of progressive human drugs. Spot-ligotyping and restriction
infecting organisms are resistant to the
tuberculosis on a clinical and fragment-length polymorphism were
drugs used in the treatment.
immunologic basis. 8 The patients are performed for strains that were
Inappropriate use of second-line anti-
categorized into four groups: one polar identified as XDR-M tuberculosis.
tuberculosis drugs in a patient for whom
group exhibits fully active cell-mediated
A total of 12 (10.9%) of 113 multi-drug first-line drugs are failing ends in XDR-
reactivity and the other un-reactive
resistant M tuberculosis strains were TB. The patient then spreads the infection
4 Journal of Postgraduate Medical Education, Training & Research
Vol. II, No. 2, March-April 2007
to individuals in close contact who receive a quick diagnosis and properly be administered for at least 18 months
acquires primary XDR-TB. selected drugs for adequate duration. It under strict monitoring supervision.
will facilitate to interruption of
XDR-TB poses a grave public health Increasing threat
transmission of drug-resistant organisms.
threat, especially in populations with
XDR-TB presents an increasing threat to
high rates of HIV infection and where WHO guidelines
global tuberculosis control. XDR-TB has
there are few health care resources.
WHO Guidelines for the Programmatic main implications for the management
Treatment regimens for drug-resistant
management of drug resistant of patients with HIV and for HIV
tuberculosis are less effective, more
tuberculosis include the following: control. High prevalence of HIV predicts
expensive and prolonged. Further the
extreme vulnerability to tuberculosis.
patient having drug resistant tuberculosis • strengthen basic TB care to prevent
Most crucial management issues in XDR-
poses public health danger of spread of the emergence of drug-resistance
TB treatment remain unanswered.
resistant organisms.
• ensure prompt diagnosis and Emergence of drug resistance is
The efficacy of treatment of resistant treatment of drug resistant cases to prevented by identifying cases of drug-
cases-both of MDR and XDR-TB- is cure existing cases and prevent susceptible disease and treating them with
worse than that of the original treatment. further transmission well tested regimens in a proper dosage
Hence, the initial intensive treatment for a proper duration. It has to be ensured
• increase collaboration between HIV
with proper chemotherapy has vital that the patient completes full course of
and TB control programs to provide
importance. Initial intensive treatment treatment till cured. There is need to
necessary prevention and care to co-
reduces the total bacterial population to treat patients with established MDR-TB
infected patients, and
such a low number that the risk of the with a complicated regimen including
emergence of resistant strains becomes • increase investment in laboratory second-line drugs, and followed for a
insignificant. The loss of sensitivity of infrastructure to enable better longer duration to prevent relapses and
tubercle bacilli to standard drugs is an detection and management of emergence of XDR-TB. Antiretroviral
undesirable and harmful phenomenon. resistant cases. drugs protect against tuberculosis by
restoring patients’ immuno-competence.
Drug resistance has to be suspected in a The patient with MDR-TB should be
patient who continues to remain sputum given at least four drugs which he/she has Conclusion
positive after four months of regular not received in the past or to which the
Retrospective cohort studies have shown
treatment with an established short- bacilli have demonstrated susceptibility
the emerging threat of extremely drug
course chemotherapy regimen. A history by laboratory testing 11. The chance of
resistant tuberculosis. Such a condition
of improper and inadequate anti- receiving at least two drugs having in
requires an aggressive treatment regimen
tuberculosis treatment predicts the vitro activity against tubercle bacilli are
and high-end dosing of drugs. The second-
occurrence of MDR-TB and of XDR-TB. greater if greater number of drugs, usually
line drugs have low potency and
Non-compliance with the therapy, and six or seven are used in the treatment.
increased toxicity. The treatment has to
HIV-infection aggravate the situation. However use of more number of drugs is
be carried out under direct observation
associated with greater toxicity, drug-
The treatment of MDR-TB and of XDR- to achieve compliance. High cost of
drug interactions and expense. The
TB poses many challenges to the treating treatment puts great hurdle in resource-
treatment of XDR-TB poses further
physician. The treatment is less effective, poor settings. Emergence of CDR-TB
problems as the organisms are resistant
more toxic and expensive. A detailed reflects a failure to implement the
to most of second-line of anti-tuberculosis
history of previous treatment for measures recommended in the WHO’s
drugs. The patients have to receive
tuberculosis has to be obtained. It should Stop TB Strategy 11. The strategy
individually tailored regimens
include the names of drugs-both first-line emphasizes the extensive use of DOTS
containing at least four drugs which they
and second-line-the dosage, duration and program, addressing HIV-associated
had not received previously or to which
regularity of intake. Drug susceptibility tuberculosis and drug resistance
they were known to be susceptible.
testing is necessary to ensure that patients strengthening health care system and
Second-line anti-tuberculosis drugs must
primary core services. Opportunities to
Journal of Postgraduate Medical Education, Training & Research 5
Vol. II, No. 2, March-April 2007
treat XDR-TB in developing countries 8. Lenzini L, Rottoli P, Rottoli L. The Mayos to establish the country’s first
has been made possible through Global spectrum of human tuberculosis. graduate program in clinical
fund to fight AIDS, TB and malaria, and Clin Exp Immunol 1977; 27: 230 medicine in 1915.
the Green Light committee for access to 9. Masjedi MR, Farnia P, Sorooch S, et
Each physician devoted attention to
second-line anti-tuberculosis drugs. More al. Extensively drug resistance
a particular area of medicine, and all
studies are needed to guide clinicians in tuberculosis: A 2-years of
physicians combined skills to
the management of this emerging surveillance in Iran. Clin Infect Dis.
provide superior patient care. This
problem. 2006; 43: 841-47
specialization led to the development
References 10. Iseman MD. Treatment of multi- of new surgical disciplines, including:
1. Veen J. Drug resistant tuberculosis: drug resistant tuberculosis N Engl J orthopedics, neurosurgery,
back to sanatoria, surgery and cod Med. 1993; 329: 784-91 ophthalmology, thoracic surgery,
liver oil? (Editorial) Eur Respir J 11. Roviglione MC, Uplekar MW. dental surgery and more.The Mayo
1995; 8: 1073 WHOs’ new Stop TB Strategy. brothers routinely visited other
2. Roviglione MC, Smith IM. XDR Lancet 2006; 267: 952-5 medical centers around the world to
tuberculosis-implications for global learn more about new procedures and
public health. N Engl J Med. 2007; ideas. They brought their findings
History of Surgery at
356: 656-9 back to Rochester to implement.
Mayo Clinic
This practice sparked a habit of
3. Emergence of XDR-TB. Geneva,
Surgery at Mayo Clinic began innovation at Mayo. For example,
World Health Organization
with the frontier practice of early Mayo surgical contributions
September 5, 2006
Dr. William Worrall Mayo. include the development of the low
4. Shankar PS. Multi-drug resistant
Dr. Mayo’s two sons, William J. and anterior resection for colon and
tuberculosis in Principles and
Charles H., assisted him in his rectal cancer, endoscopic injection of
Management of Tuberculosis, 3rd
practice at very early ages. Saint esphageal varices, and advances in
edn, New Delhi, Churchill
Marys Hospital opened in Rochester resection of the stomach for cancer.
Livingstone, 2002; 205-207
on Sept. 30, 1889 & Dr. Charlie In addition, many operating
5. Emergence of Mycobacterium removed a cancerous tumor of the techniques and instruments still in
tuberculosis with extensive eye, his first surgery, assisted by his use today were developed by Mayo
resistance to second-line drugs- brother and father. Between 1889 and Clinic surgeons, including the
worldwide, 2000-2004. Centres for 1905, the Mayos did all operations Balfour retractor, the Mayo stand,
Disease Control and Prevention at Saint Marys Hospital, themselves. the Mayo scissors, the Adson pickups,
(CDC) MMWE Morb Mortal Wkly To handle the growth of their the Harrington Behrens, and the
Rep 2006; 55: 301-305 practice, the Mayos opened a third Adson-Beckman retractors.Mayo
6. Gandhi NR, Moll A, Sturm AW, et operating room at Saint Marys in Clinic history includes more than a
al. Extremely drug-resistant 1905. century of innovations in the surgical
tuberculosis as a cause of death in treatment of patients, from the first
The Mayos maintained an “open-
patients co-infected with open-heart surgery in 1955 to the first
door” policy to other members of the
tuberculosis and HIV in a rural area total hip replacement in 1969 to the
medical profession. During
of South Africa. Lancet. 2006; 368: early use of robotic laparoscopic
operations, the brothers always
1575-80 surgery in 2002. Today, 255 Mayo
discussed their procedures for the
Clinic surgeons treat more than
7. Dannenberg AM Jr. Delayed-type benefit of visitors. Over the operating
76,000 surgical patients each year,
hypersensitivity and cell mediated tables, large adjustable mirrors
proving that the Mayo legacy of
immunity in the pathogenesis of provided a complete view of the
surgical teamwork and innovation is
tuberculosis. Immunol Today. operating field. This demand for
still alive.
1991; 1: 228-33 advanced medical training led the
6 Journal of Postgraduate Medical Education, Training & Research
Vol. II, No. 2, March-April 2007
3
Cancer Bladder Pathology & Natural History
Lt. Gen. S. Mukherjee Commentray
Armed Forces Medical College, Pune
About 70% of newly detected has a greater impact on the management Non muscle-invasive tumors are divided
cases are exophytic papillary of noninvasive tumors because most into noninvasive papillomas or
tumors confined largely to the muscleinvasive tumors (ie, greater than carcinomas (Ta), those invading the
mucosa (Ta) (70%) or less often to the T1) are G3. An alternative grading lamina propria (T1), and CIS. These
submucosa (T1) (30%). These tumors system of low or high grade has been tumors have previously been referred to
tend to be friable and have a high proposed, and it is our intent to transition as “superficial” tumors, an imprecise
propensity for bleeding. Their natural to this classification system over the next term which should be avoided. In some
history is characterized by a tendency to three years. We will retain the present cases, a papillary or T1 lesion will be
recur in the same portion or another part classification system for now since it is documented as having an associated in
of the bladder over time commonly used by practicing urologists. situ component (Tis). The standard
(a phenomenon termed A comparison of the different treatment in such cases is the repeat of
“polychronotropism”) and these classification systems is presented in the TUR. However, depending on the depth
recurrences can be either at the same stage Principles of Pathology Management. of invasion and grade, intravesical
as the initial tumor or at a more advanced therapy may be recommended. This
Papillomas are considered to be benign
stage. Papillary tumors confined to the suggestion is based on the estimated
tumors that closely resemble the normal
mucosa or submucosa are generally probability of recurrence (ie, a new
urothelium. Grade 1 papillary
managed endoscopically by complete tumor formation within the bladder) and
carcinoma in contrast can be recognized
resection. Progression to a more progression to a more advanced, usually
histologically because they have more
advanced stage may result in local invasive stage - events that should be
than the normal seven epithelial layers,
symptoms or, less commonly, symptoms considered independently.
normal polarity of the nuclei, and
related to metastatic disease. It is
minimal pleomorphism. Papillomas and Cystectomy is rarely considered for a Ta,
estimated that 10% to 70% of patients
G1, Ta carcinomas are managed almost G1 or G2 lesion. Intravesical therapy is
with a tumor confined to the mucosa will
exclusively by endoscopic means because used in two general settings: as
have a recurrence or a new occurrence of
they generally do not progress to a higher, prophylactic or adjuvant therapy
urothelial (transitional cell) carcinoma
more lethal stage. In contrast,Ta, G3 following a complete endoscopic
within 5 years. These probabilities of
tumors have a much higher chance of resection or, rarely, as therapy aimed at
progression vary as a function of the
progression to a more advanced stage. eradicating residual disease that could not
initial stage and grade. Refining these
be completely resected. This distinction
estimates for the individual patient is an Once stage and grade have been
is important, as most published data
area of active research. determined, treatment decisions are
reflect prophylactic or adjuvant use with
based on the depth of invasion and extent
Staging and grading the aim of preventing recurrence and/or
of disease. The treatment of bladder
delaying progression to a higher grade or
The most commonly utilized staging cancer entails the disciplines of urologic
stage. In many cases, intravesical therapy
system is the tumor, node, metastasis surgical oncology, radiation oncology,
is given to patients who do not require it
(TNM) system, as shown in. Bladder and medical oncology. For many of the
because the probability of recurrence or
carcinomas are graded as well complex strategies the involvement of
progression is low. Management of the
differentiated (G1), moderately multidisciplinary teams will optimize
different histologic subtypes of different
differentiated (G2), poorly results. The general principles for
grades is outlined below.
differentiated or undifferentiated (G3- surgery, chemotherapy and radiation
4). However, the determination of grade therapy are explained on respectively. Papilloma/Ta, G1 or G2
Journal of Postgraduate Medical Education, Training & Research 7
Vol. II, No. 2, March-April 2007
TUR without intravesical therapy is the period, with a full reevaluation at week sparing approaches.
standard treatment for Ta, G1 and Ta, 12 (ie, 3 months) after the start of therapy.
T1 disease
G2 tumors. Since patients diagnosed with Patients with Tis who have recurrent/
these tumors have a relatively high risk persistent disease at the 12-week (3- T1 lesions, those invading lamina
of recurrence, in addition to observation, month) evaluation can be given a second propria, are considered to be potentially
the panel also offers consideration of a course of BCG or MMC induction dangerous (usually T1G2 or G3) and
single dose of intravesicular therapy (no more than 2 consecutive have a high risk of both recurrence and
chemotherapy (not immunotherapy) courses). If a second course of BCG is progression. These tumors may occur as
within 24 hours of resection.Close given and there is residual disease at the solitary lesions or as multifocal tumors,
follow-up is needed, even though the risk second 12-week (3-month) follow-up, a with or without an associated in situ
of progression to a more advanced stage cystectomy should be strongly component. They, too, are treated with a
is low. As a result, these patients are considered. Depending upon prior complete endoscopic resection followed
advised to undergo a cystoscopy at 3 treatment, the extent of the disease, and by intravesical therapy (this is optional
months initially, and then at increasing the frequency of recurrences, intravesical for G1 or G2 lesions). Within the
intervals. If no recurrences develop therapy with the different intravesical category of T1 disease, two risk strata can
during the first year, the interval between agent (mitomycin, or less commonly be identified: low-risk (G1, G2, or
evaluations can be increased. Patients in valrubicin, alpha-interferon, or BCG solitary) and high-risk (G3 or multifocal
whom a recurrence is documented are plus alpha-interferon) is an alternative to lesions, tumors associated with vascular
treated with TURBT and adjuvant cystectomy. In some centers, however, invasion, or lesions that recur after BCG
therapy based on the stage and grade of these patients might still be candidates for treatment).
the recurrent lesion, and they are then investigational therapies. For patients
Low-risk disease
followed at 3-month intervals. with complete response at the follow-up
Intravesical therapy is recommended for cystoscopy, whether one or two courses After the initial TUR, patients with low-
patients who have a history of of induction therapy were administered, risk disease are observed or undergo
recurrences. maintenance therapy with BCG is intravesical treatment with BCG or
advised, although this recommendation mitomycin. Follow-up is similar to that
Ta, G3 disease
is not universal. Regardless of whether previously outlined above for Ta, G1-2
Tumors staged as Ta, G3 lesions are or not maintenance therapy is disease, with a urinary cytology and
considered to be high-grade papillary administered, patients with Tis should be cystoscopy recommended at 3-month
tumors with a relatively high risk of followed at 3-month intervals with a intervals for the first 2 years, repeated at
recurrence and progression towards urinary cytology and cystoscopy for the increasing intervals over the next 2 years,
more invasiveness. For this reason, in first 2 years, and if no recurrences are and annually thereafter. If cytology study
addition to observation, they are treated documented, every 6 months in the third is found positive despite the negative
with intravesical Bacillus Calmette- and fourth years and then annually. imaging and cytoscopy results, random
Guérin (BCG) or mitomycin (MMC), in Imaging of upper tract collecting system biopsies including TUR and prostate
the same manner as T1, G1-2 tumors with every 1 to 2 years is also recommended biopsy in male patients are
BCG being the preferred option for post- with or without urinary tumor markers recommended. Recurrent disease is
operative treatment. (category 2B) in selected cases. If treated as appropriate for the stage
progression to an invasive lesion is documented at the time of relapse.
Tis
documented at any point during follow-
High-risk disease
Primary Tis is a high-grade lesion that is up, a radical cystectomy is recommended.
believed to be a precursor of invasive Although controversial, patients who Patients with high-risk disease (T1, G3)
bladder cancer. Standard therapy for this present with recurrent superficial can be treated with a course of BCG
lesion is a complete endoscopic resection tumors prior to the documentation of a (preferred, category 1), mitomycin, or
followed by intravesical therapy with muscle-invading lesion are generally not radical cystectomy after a certain and
BCG. This is generally given once a week considered to be candidates for bladder- satisfied resection. If the complete
for 6 weeks, followed by a 4-6 week rest resection is uncertain based on the tumor
8 Journal of Postgraduate Medical Education, Training & Research
Vol. II, No. 2, March-April 2007
size and location, no muscle is shown in mass is appreciated at the time of the bladder-sparing approaches
the specimen, lymphovascular invasion, EUA, and (2) whether or not the tumor
Treatment of relapses is based on the
or inadequate staging is speculated, repeat has extended through the bladder wall.
extent of disease at the time of relapse,
resection of tumor or cystectomy Tumors that are organ-confined (T2)
with consideration given to the prior
followed by intravesical therapy with have a better prognosis than those that
treatment that a patient has received. Tis,
BCG (category 1) or mitomycin is have extended through the bladder wall
Ta, or T1 tumors are generally managed
recommended ( ). Evolving data suggest to the perivesical fat (T3) and beyond.
with intravesical BCG therapy. If there
that the preferred approach may be early Primary surgical treatment for T2
is no response, a cystectomy is advised. A
cystectomy if residual disease is found due lesions include radical cystectomy with
positive cytology with no evidence of
to the high risk of progression to a more the consideration of neoadjuvant
disease in the bladder should prompt
advanced stage. If highrisk disease is chemotherapy in selected patients, and
selective washings of the upper tracts and
managed conservatively and does not segmental cystectomy only in patients
an evaluation of the prostatic urethra. If
respond to BCG, a cystectomy should be with a single tumor (solitary lesion in a
the selective cytologies are positive,
performed. suitable location), and no any presence
patients are managed as described below
of CIS, nor previous multifocal bladder
Before any treatment is advised, the under treatment of upper tract tumors.
cancers. If no neoadjuvant chemotherapy
following workup procedures are Invasive disease is generally managed by
was given, post-operative adjuvant
recommended to determine the clinical radical cystectomy and a second attempt
chemotherapy is considered in those
staging. Laboratory studies such as at bladder preservation is not advisable.
patients based on the pathologic risk such
complete blood cell count (CBC) and All patients who relapse after bladder-
as positive nodes and pathologic T3
chemistry profile including alkaline sparing therapy and are being considered
lesions. If segmental cystectomy had been
phosphate need to be done, and the patient for radical cystectomy should be
performed, adjuvant RT or
should be assessed for the presence of evaluated for medical comorbidities and
chemotherapy based on pathologic risk
regional and/or distant metastases. This undergo a full restaging evaluation to
(positive nodes, positive margin, high-
evaluation should include a cystoscopy, ensure that there is no metastatic disease.
grade, and pathologic T3 lesions) should
EUA/TURBT, chest x-ray, bone scan in As is the case with primary cystectomy,
be considered. For patients with
patients with symptoms or elevated an exploratory laparotomy is performed
superficial muscle invasive T2 disease
alkaline phosphate, and evaluation of the first to ensure that there is no
and without hydronephrosis, bladder-
upper tracts with a CT or MRI scan of the involvement of the lymph nodes,
sparing treatment (category 2B) with
abdomen and pelvis. Some physicians omentum, or other organ sites. Even in
chemotherapy and radiation therapy
advocate performing magnetic resonance patients who have no extravesical spread,
may be possible following complete
imaging (MRI) to determine the depth of the morbidity of radical cystectomy can
TURBT. In highly selected patients with
invasion within the bladder and, in be significant although the operative
extensive comorbid disease or poor
particular, to ascertain whether a tumor mortality is low (1% to 3%). Although
performance status, chemotherapy as
has reached the perivesical fat (T3b). salvage cystectomy is the preferred
well as radiation therapy or TURBT is
Unfortunately, CT scans, ultrasound, or approach, it may not be possible for a
recommended. For those patients not
MRI cannot accurately predict the true patient who has received a full course
undergoing cystectomy, evaluation with
depth of invasion. (greater than 65 Gy) of external-beam RT
cystoscopy and tumor site re-biopsy is
and has bulky residual disease. For these
Organ-confined disease (T2a, necessary after the primary treatment.
patients, salvage chemotherapy is
T2b) Radical cystectomy is the standard
advised, generally with a regimen that is
treatment if tumor is found. Otherwise,
Surgical treatment with radical non-cross-resistant to the one that the
observation, further consolidation
cystectomy is still the most effective local patient has previously received. Those
chemotherapy with radiation, and/or
therapy in muscle invasive bladder treated with single-agent cisplatin can be
adjuvant chemotherapy alone is
cancer. Two critical issues exist in the consideredor a standard three- or four-
recommended.
management and prognosis of these drug regimen, whereas those who have
patients: (1) whether or not a palpable Relapses in the bladder after already received a three-drug (eg, MCV)
Journal of Postgraduate Medical Education, Training & Research 9
Vol. II, No. 2, March-April 2007
or four-drug (eg, M-VAC) regimen may palpable mass on EUA and no response is noted, chemotherapy with RT
be considered for therapy with paclitaxel, hydronephrosis. This approach should or a new chemotherapy regimen can be
gemcitabine, or ifosfamide, as outlined also be used in the context of an used. In highly selected T4a node-negative
below under salvage chemotherapy. If the investigational protocol, or be considered patients, surgery with or without
patient has not received RT, a course of for patients who are deemed unsuitable chemotherapy could be another
RT should be considered. Metastatic for surgery based on medical treatment option. If pelvic lymph nodes
disease is managed with salvage comorbidities. Evaluation with greater than 2 cm on imaging are
chemotherapy using a regimen to which cystoscopy, biopsy, or cytology study is documented, a biopsy is advised to
the patient has not been previously necessary following the bladder exclude nodal spread. Baseline renal
exposed. preservation treatment. If resectable function, the presence or absence of
tumor is found, surgical approach with cardiac disease, and overall performance
Non-organ-confined disease
cystectomy is considered. Patients with status must also be considered when
(T3a, T3b/T4a, T4b)
unresectable tumors undergo salvage making a treatment recommendation.
The primary surgical treatment for a therapy. If no tumor is detected, Patients with a good performance status
tumor that has extended beyond the observation, consolidation with and no significant comorbid disease may
confines of the bladder wall and that is chemotherapy and concurrent RT, or be considered for chemotherapy with or
still considered resectable, based on the adjuvant chemotherapy is recommended. without RT if their nodes are positive. If
mobility of the bladder, is radical The general approach to this bladder- complete response is obtained, patients
cystectomy with consideration of sparing strategy for these patients is may be managed with observation, boost
neoadjuvant chemotherapy, as outlined similar to that outlined previously under with RT, or surgery may be
previously. Except in highly selected bladder-sparing strategies in patients with contemplated. Chemotherapy options
cases (see below), bladder preservation is organ-confined disease. Patients are are discussed below under metastatic
not an option in such patients since the treated with a course of induction disease, whereas combined-modality
proportion rendered tumor-free using therapy (eg, RT with concurrent approaches using chemotherapy and RT
chemotherapy alone is generally less than chemotherapy, neoadjuvant are discussed above. For patients who
10%. Tumors that are pathologic stage chemotherapy alone or neoadjuvant cannot tolerate multidrug combinations
T3 or T4 with nodal involvement or chemotherapy plus RT with or without with radiotherapy, an alternative is to use
vascular invasion have a high risk concurrent chemotherapy) with a RT with a radiation sensitizer, such as
(greater than 50%) of systemic relapse deferred decision on management of the cisplatin, administered starting on day 1
and, therefore, may be considered for primary lesion. and day 21, or 5-FU with a variety of
treatment with adjuvant chemotherapy schedules. Patients are initially treated
T4a, T4b disease
or radiotherapy. The followup schema with 45 Gy of radiation to the pelvis and
is the same as that previously outlined for Patients with unresectable disease, bladder, with a boost of approximately
high-risk patients in the section on defined as a fixed bladder mass, or those 20 Gy to sites of disease within the
adjuvant chemotherapy. Owing to the with positive nodes prior to laparotomy bladder. In highly selected patients with
high risk of systemic relapse in this are considered for chemotherapy alone metastatic disease who have a complete
group, based on historical series using or chemotherapy with RT. An initial systemic response to chemotherapy,
surgery alone, a number of groups are stratification is based on the results of salvage surgery may be performed to
also investigating combined-modality transaxial imaging. For patients who render the patient disease-free. Data from
approaches using neoadjuvant show no nodal disease on CT scans, the several groups show that this aggressive
chemotherapy followed by surgery or treatment recommendation includes two approach can result in long-term
neoadjuvant chemotherapy and radiation to three courses of chemotherapy with or survival. Prior to exploratory surgery,
followed by surgery. If possible, these without RT followed by cystoscopy and metastatic disease must be excluded with
patients should be placed on clinical trials. CT scan. If the tumor has responded, appropriate imaging studies. If the
Bladder preservation can be considered options include surgery or consolidation exploration is negative for metastases
in selected cases in which there is no chemotherapy with or without RT. If no within the abdomen, salvage surgery can
10 Journal of Postgraduate Medical Education, Training & Research
Vol. II, No. 2, March-April 2007