Urinary Tract Tumors

• Arises from renal tubular cells
• 2-3% of all adulthood cancers
• 40% of patients die of cancer
• Most common in the 6th and 7th decade
• M:F is 2:1

Aetiology

• Multifactorial
• Majority of cases are sporadic, NCI reported 4% as familial
• Life style, environmental, and genetic predispositions identified

Risk Factors

• Cigarette smoking
• Obesity
• Hypertension
• Medications - diuretics, phenacetin
• Preexisting renal conditions - stones, cysts, infections
• Diabetes Mellitus
• Reproductive and hormonal factors
• Physical activities
• Diet and beverages
• Occupation
• Genetic

Pathology: Histologic Types/Classification of RCC

• Clear Cell RCC
• Papillary RCC
• Chromophobe RCC
• Oncocytomas
• Collecting Duct Carcinoma

Pathology: Staging- TNM Staging System

• By AJCC & IUCC
• Most widely used for staging all variants
• Correlates very well with prognosis
• Revised in 2010
• Tumors limited to the kidney are classified as T1 or T2 based on the size
• T3 tumors extend into the renal vein or perinephric tissues but not beyond Gerota’s fascia
• T4 tumors extend beyond Gerota’s fascia
• Node & distant metastases are simply classified as absent or present

TNM Staging System

×

TNM Staging System

Clinical Presentations

• Asymptomatic in >50%
• Incidental diagnosis on imaging studies
• 25% at presentation have advanced locoregional or metastatic disease
• 1/3rd of patients post-surgery for localized disease will relapse
  • Symptoms could be local or systemic
• Classic triad of flank pain, mass, and haematuria occur in <10%
• Varicocele – left (11%)
• IVC involvement
• Non-specific symptoms

Investigation

• Angiography
  • Generally supplanted by MRI Angiography
  • Used for preoperative tumor embolization
• IVU
  • Indicated for haematuria
  • Lacks sensitivity and specificity for detection of parenchymal renal lesion
• MRI
  • Superior to CT for evaluation of IVC involvement
  • Useful when USS & CT are nondiagnostic or in cases of contrast allergy or renal impairment
• FNAC/Biopsy
  • Generally not done
• Chest X-ray/Chest CT
• FBC
• BUE + Cr
• Urinalysis
• LFT
• Serum ALP
• etc

Treatment

• Surgery is the mainstay of treatment
• However, there are other available options
• What is done is dependent on the clinicopathologic stage at presentation as:
• Localised disease
• Locally advanced disease
• Metastatic disease

Treatment Modalities

• Surgery
  • Open
  • Laparoscopic
  • Ablative
• Hormonal therapy
• Immunotherapy
• Targeted Therapy
• Combination therapy

Radical Nephrectomy

• Open or laparoscopic
• No evidence to favor specific approach
• Suitable for localized disease

Indications for Open Radical Nephrectomy

• Large tumor with regional adenopathy
• Involvement of IVC or right atrial extension
• Metastatic RCC for cytoreductive nephrectomy
• Where partial nephrectomy is no longer possible

Follow-up After Nephrectomy

• This is to determine presence of recurrence and the need for additional therapy
• Risk for recurrence:
  • 7% T₁N₀M₀
  • 20% T₂N₀M₀
  • 40% T₃N₀M₀
• 6-monthly clinical assessment
• Annual CT scan for 3-10 years
• Surgical excision is preferred choice

Locally Advanced RCC

• Disease involving IVC, right atrium, liver, bowel, or posterior abdominal wall
• An aggressive surgical approach – multidisciplinary surgical team

Adjuvant Therapy

• Immunotherapy
• Targeted Therapy
• Radiotherapy

Metastatic RCC

• Approximately 25% of patients with RCC have metastasis at presentation
• 30% of other patients progress to this stage after nephrectomy
• Prognosis is generally poor
• There is improved prognosis in patients with:
  • Good performance status
  • Tumor nephrectomy
  • Single organ solitary metastasis
  • Absence of tumor thrombus

Prognosis

• Pathologic stage
• Nuclear grade
• Histologic subtype
• Tumor size
• Systemic symptoms
• Metastatic burden
• Performance status

• Histological BPH represents an inescapable phenomenon for the aging male population.
• Approximately 90% of men will develop histologic evidence of BPH by 80 years of age.
• Significant problem due to the aging population and associated cost of treatment.
• 50% of men will develop BPH.
• 50% of these will develop bothersome LUTS.
• Prevalence in middle-aged and elderly men: 11-65%
• BPH is not life-threatening but interferes with quality of life.

Pathology

• BPH is nodular hyperplasia and not diffuse hyperplasia.
• Affects the transitional and periurethral zones of the prostate.
• Increase in cell number caused by epithelial and stromal proliferation or impaired programmed cell death leading to cellular accumulation.
• Often the hyperplasia is multinodular, coalescing to form adenomata.
• Adenomata from the transitional zone form the lateral lobes while adenomata from the periurethral zone form the middle lobe.

BPH

×

BPH

• Most common cancer in men, and 2nd greatest cause of cancer mortality in men
• Disease awareness has grown in the past 2 decades
• Currently, 1 in 6 men will be diagnosed with CAP
• PSA playing a role in detection and follow-up

Carcinoma of the Prostate

Most common malignancy in males after middle age

• In western countries lifetime risk of microscopic prostate cancer: 30%
• Uncommon before 50 years Post mortem:
  • 14% of all males over 50 years
  • 80% of all males over 70 years
• No geographical or racial difference in incidence of post-mortem

Risk Factors

• Not well known
• Hereditary - One 1st line relative – Risk doubles
• 2 or more 1st line relatives – risk x 10 True hereditary Ca-P (9%) – 3 or more relatives involved or at least 2 with early Staged disease (i.e. < 55 yrs).
• Race
  • Highest in Negroes
  • Least in the Orients

Histological Types

1. Adenocarcinoma –> 90%
   • Conventional – Majority of cases
   • Mucinous
   • Neuroendocrine
   • Small cell
2. Transitional – usually from the prostatic urethra.
3. Squamous cell
4. Sarcoma
5. Lymphomas

2-5 Above do not produce PSA

Staging and Grading

Staging - TNM

Grading - Gleason score (2-10)

Gleason grade (1–5)

2 - least aggressive
10 - most aggressive

Spread – Local, Blood, Lymphatics

• Local – Prostatic urethra, bladder, seminal vesicles.
• Blood – Hips, vertebrae
• Ca – P commonest site of bony metastasis, followed by breast, kidney, bronchus, thyroid.
• Ca – P metastasize early to the vertebrae because of the valveless vein of Batson that connects with the vertebral veinous plexus.

Diagnosis / Clinical Staging

Clinical Features

1. Asymptomatic – From routine screening, PSA, DRE, TRUSS
2. Local disease – Lower urinary tract symptoms Obstructive, Irritative
3. Local Invasion – Urethra – Haematuria, dysuria Trigone – hydroureters, hydronephrosis Pelvic nerves – pain, erectile dysfunction Rectum – Bleeding, constipation
4. Metastatic Disease
   • Vertebrae - Low back pain
   • Pathological fractures
   • Lymphnode enlargement – Lower limb edema
   • Cerebral metastases
   • Skin
   • Liver, lungs etc

DRE

• Gland may be normal
• Hard nodule – hallmark
• Asymmetric enlargement
• Heterogeneous consistency – hard, soft, firm areas.
• Distorted or absent median sulcus
• Involvement of lateral structures - winging.
• Palpable seminal vesicles
• Adherence of rectal mucosa

PSA

• Organ specific but not disease specific.
• Most likely responsible for the stage migration.
• No universally accepted value. Recommended values:
  • Total - < 4ng/ml; 4 – 10 ng/ml, > 10ng/ml
  • Free / Total - Very useful in patients with PSA between 4 – 10
  • 0.15 – Recommended, PPV = 76%
  • The lower the f/t PSA, the greater the risk of cancer
• PSA Density - Takes care of overlap between Ca-P & BPH. Recommended value - > 0.15 highly suggestive of Ca – P.
• PSA Velocity - Rate of change of PSA with time.
  • At least 3 measurements within 2 years.
  • > 0.75 ng/ml – suggestive of Ca –P.
• Age Specific PSA:
  • sensitivity in younger men
  • specificity in older men
  • 40 – 49 – 2.5 ng/ml
  • 50 – 59 – 3.5 ng/ml
  • 60 – 69 – 4.5 ng/ml
  • 70 – 79 – 6.5 ng/ml
• PSA Doubling Time
  • Useful in differentiating local recurrence from metastatic disease in patients previously treated for early Ca – P.
  • < 6 months – Metastases
  • > 6 months – Local recurrence

Trans Rectal Ultrasound (TRUS)

• Classic Feature: Hypoechogenic area in peripheral zone.
• Hyperechogenic / Normoechogenic lesions Are also common
• Not very useful in direct screening
• Main use in needle biopsy.

Prostate Biopsy

1. Digitally guided FNAB
2. TRUSS guided transrectal core needle biopsy - gold standard.
   • Sextant to 12 cores recommended.
   • The greater the number of cores, the greater the success rate.

Treatment

Natural History – 75% of men with diagnosis of Ca-P without treatment will die from the Disease.

LOCALISED DISEASE: T1 – T2m No MO.

1. Watchful Waiting – Ideal for an asymptomatic man, life expectancy <10 yrs, low Gleason score. Evidence suggests greater risk of death from Ca-P when compared with treated groups.
2. Radiation Therapy
   • External beam: Outcome almost as good as surgery. Contraindicated in patients with colo-rectal disease and bladder outlet obstruction. 3D conformal radiotherapy – Now gold standard.
   • Brachytherapy: In very small tumors. Cure difficult to assess since tumor cells die gradually. Positive biopsies may not indicate failure, likewise a high PSA. Late toxicity eg bladder, erectile, bowel problems years after therapy.
3. Radical Prostatectomy
   • Gold standard. Retropubic or Transperineal or laparoscopic.
   • Not indicated in patients with short life expectancy.
   • Prostate gland including the capsule, Periprostatic fascia, ejaculatory duct, seminal vesicles and prostatic urethra. Walsh nerve sparing technique - lower risk of erectile dysfunction.
   • Bleeding, Incontinence, Erectile dysfunction, Urethral stricture, rectal injury.
4. Others
   • Cryo Surgery - Less bleeding, Similar complications as RP
   • High Intensity Focused Ultrasound (HIFU)
   • LASER
   • Hormonal Manipulation – Occasional patient who declines radical therapy or unfit for radical therapy.

Advanced Disease

Hormonal Manipulation – Gold standard

• Elimination of testicular testosterone
• Eliminates > 90% of circulating testosterone.
  • Bilateral orchidectomy – Gold Standard
  • LHRH agonist - Like above. Expensive. Flare phenomenon – Use antiandrogen for first 6 weeks. Never use alone in patients with impending paraplegia
  • Andropause – main side effect: impotence, loss of libido, less muscle bulk and bone density, hot flushes, etc.

Oestrogens – Mechanism - reduce LHRH secretion, direct reduction in Leydig cell function, and direct androgen inactivation.

• Diethylstilbestrol – Inexpensive, significant CVS morbidity. 1mg-5mg
• Phosphorylated form – less toxicity

LHRH Antagonist – No flare phenomenon. Rapidly acting. Lack of depo preparation delayed clinical introduction. Depo forms now available. Soon to replace LHRH agonists

Antiandrogens – Compete with androgen at the receptor level. Inferior to orchidectomy as monotherapy

• Non-steroidal – Flutamide, bicalutamide. Less effect on Libido.
• Steroidal – Cyproterone acetate – Greater side effect on Libido. Expensive. Less effective than orchidectomy.

Progestogens – Medroxyprogesterone acetate.

Maximal Androgen Blockade (MAB)

Combination of orchidectomy (or LHRH agonist or oestrogen) and antiandrogens.

• Blocks both testicular and extratesticular androgens.
• Doubtful superiority over orchidectomy alone.

Minimal Androgen Blockade (MIB)

• Finasteride - 5 alpha-reductase inhibitor – reduces intraprostatic DHT.
• PLUS
• Antiandrogen – Competes with remaining DHT for receptors. Keeps serum testosterone normal, hence no side effects associated with testosterone.

Treatment Failure

For post RP & RR patient – defined as a rising PSA after treatment with curative intent.

• Options - Individualized: RP, RR, Hormone manipulation or Watchful Waiting

Hormone Refractory Disease – Invariably occurs in patients managed by androgen deprivation. Most patients die within 1 year.

Definition:

1. Serum testosterone at castrate level.
2. 3 consecutive rises in PSA 2 weeks apart.
3. Antiandrogen withdrawal for at least 4 weeks.
4. PSA progression despite secondary hormonal manipulations.
5. Progress of osseous or soft tissue lesions.

Options:

1. Give antiandrogens – if not initially given
2. Withdraw antiandrogens.
3. High dose antiandrogens
4. Oestrogens – Estramustine
5. Ketoconazole
6. Aminoglutethimide
7. Strontium-89 - Bone metastases
8. Bisphosphonates - bone metastases
9. Hemibody radiation
10. Docetaxel therapy
11. Mitoxantrone
12. Steroids
13. Supportive care

Prevention / Screening

1. PSA / DRE / TRUSS
2. Diet - Vitamin D, Selenium, fat intake
3. Chemoprevention – Finasteride for high-risk groups

• Rare
• Most are malignant
• Transitional cell carcinoma usually
• Risk factor: smoking
• Mostly presenting with hematuria
• Diagnosis: IVP, Ureteroscopy + biopsy, CT Urography
• Treatment: Surgery (Nephroureterectomy), Chemotherapy, Radiotherapy