A 79YearOld Man with Hematuria Chapter 9

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A 79-Year-Old Man with Hematuria- Chapter 9
Eugene G. Martin, Ph.D. Associate Professor of
Pathology Laboratory Medicine

• Based upon LABORATORY MEDICINE CASEBOOK. An
  introduction to clinical reasoning
• Jana Raskova, MD Professor of Pathology
  Laboratory MedicineStephen Shea, MD
  Professor of Pathology Laboratory
  MedicineFrederick Skvara, MD Associate
  Professor of Pathology Laboratory MedicineNagy
  Mikhail, MD Assistant Professor of Pathology
  Laboratory MedicineUMDNJ-Robert Wood Johnson
  Medical SchoolPiscataway, NJ

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History and Presentation

• 79 year old male with a history of hypertension
  is brought to the emergency room complaining of
  severe suprapubic pain associated with hematuria
• Rectal exam enlarged prostate
• Admitted, treated for pain and a work-up of
  hematuria was pursued.
• Initial BP 200/100 mmHg.
• BP decrease to 150/82 mmHg over a period of 48
  hrs.
• Intravenous pyelography, CAT scan and a surgical
  procedure were performed.

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HEMATOLOGY
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Urinalysis
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What does urinalysis show?What does it not show?

• Urinalysis shows
• Hematuria
• Pyuria
• Bacteriuria
• Hyaline casts - Reflects the presence of renal
  proteinuria. Formed in the distal tubules and
  collecting ducts. Not associated with postrenal
  proteinuria.
• Urinalysis DOES NOT show
• Cellular casts
• Significance
• Probably not acute glomerulonephritis cellular
  casts would be likely

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Post-Renal Proteinuria

• Post-Renal proteinuria
• The urine is contaminated with proteins during
  its passage along the genitourinary tract.
• The commonest causes are
• vaginal contamination
• urinary tract infection
• See WBC, Protein but few hyaline casts

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CHEMISTRY
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LDH 242. What is the significance?

• LDH sites of origin
• Heart, Liver, Sk. Muscle, RBCs, Kidney,
  Neoplasia, Lung, Lymphocytes
• Lactic dehydrogenase group of 5 different
  enzymes. Without characterizing LDH isoenzyme
  pattern, very little significance can be attached
  to a modest elevation.
• In malignancy the most common pattern is a
  non-specific elevation of all fractions with
  normal relationships between groups being
  preserved.

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Additional Studies
Electrolytes
Other
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Intravenous Pyelogram - Patient
2 cm filling defect
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Endoscopic Bladder Biopsy

• Note thinness of bladder mucosa
• 3-4 cells deep
• Nuclei regular
• Polarity maintained with basement membrane
• Bladder mucosa thickened by a papillary and solid
  transitional cell carcinoma
• Note - mitotic figures - loss of polarity
  - glandular metaplasia

NORMAL
PATIENT
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- Urine Cytology Transitional cell carcinoma
Inflammatory cells
Hyperchromatic, pleomorphic cells -
Nuclear/cytoplasmic ratio high - Nucl
chromatin distrib. Irregular - Nucl. Membrane
uneven
High-grade transitional cell carcinoma
Inflammatory cells
Normal transitional cells - Nucl. Chromatin
fine and evenly dispersed throughout
the nucleus
Normal
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Transitional cell carcinoma with glandular
metaplasia

• Bladder muscle fibers separated by invading tumor
  cells
• Glandular metaplasia evident note prominent
  vacuolization

Bladder muscle cells
Invading tumor cells
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Transitional Cell Carcinoma
Papillary Frond
Epithelial layer
Grade II
Normal
Increasing pleomorphism
Grade I
Thickened layer
Grade III
Grade II
Non papillaryincr. nuclear pleomorphismincr.
presence of prominent nucleoli
Pap or Non-Pap Moderate loss ofarchitecture Moder
ate pleomorphism
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Cell Cycle Analysis

• DNA content X-axis
• No. of cells of given staining intensity Y-axis
• G1D - G0/G1 phase of the diploid population
• G2D G0/G1 phase of the aneuploid population
• S phase Synthetic phase with intermediate
  DNA content

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DNA Ploidy/Cell Cycle Analysis

• Normal
• Diploid G1D DNA peak 95.4
• Small G2M population (2.1)
• Small S phase (2.5)

Normal

• Patient
• Diploid G1D DNA peak 87.7
• 2 distinct aneuploid populations (peaks)
• A1
• A2

Patient
Cell Number
DNA Content
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Urinary Tract Cytology

• Kidney Renal parenchymal cells
• Lower urinary tract (Bladder and Urethra)
• Transitional cells major epithelium of bladder
  and urethra
• Glandular cells trigone and dome of bladder
  prostate gland paraurethral glands cells from
  Brunns nest
• Squamous epithelium vaginal contamination in
  women distal penile urethra trigone of women,
  squamous metaplasia
• Upper urinary tract (Calyces, Renal Pelvis and
  Ureters)
• Transitional cells major epithelium of all 3
  sites
• Squamous epithelium squamous metaplasia

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Cytologic criteria of Malignancy

• Nuclear characteristics?
• Size ?r
• Shape Pleomorphic
• Nuclercytoplasmic ratio ?
• Membrane Unevenly thickened, often indented and
  angulated
• Chromatin Distribution irregular, size and
  shape vary. Sometimes course or clumped
• Number of nuclei May be multinucleated although
  this is not a reliable clue to malignancy
• Mitoses Abnormal mitoses, aneuploidy is a
  reliable criterion

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Cytology vs. urine markers

• Cystoscopy Gold standard
• Cytology
• High specificity (few false positives)
• Low sensitivity (many false negatives especially
  in superficial and low grade tumors
• Useful to ID high-grade bladder cancers and
  carcinoma in situ

• Urine Markers
• More sensitive, but less specific
• Useful at picking up low grade cancers
• Useful in monitoring for recurrence
• May significantly improve and simplify workup,
  diagnosis, and follow-up
• Evolving

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Urine Markers of Malignancy

• BTA stat test/BTA TRAK assays,
• NMP22,
• FISH,
• VysisUrovysion Immunocyt
• FDP
• Telomerase
• Hyaluronic Acid
• BLCA-4
• http//blcwebcafe.org/urinemarkers.asp
• http//www.clevelandclinic.org/urology/news/bladde
  r/vol5f.htm

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Case Summary

• Final Diagnosis
• Grade III Transitional Cell Carcinoma of the
  bladder
• Glandular metaplasia
• Right Hydronephrosis and Hydroureter
• Patient to undergo metastatic workup

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What is the answer AND why?

• ANSWER
• This patient has hematuria, pyuria and
  bacteriuria without any cellular casts. These
  findings indicate that the diagnosis of acute
  glomerulonephritis is least likely. Cystitis,
  bladder carcinoma and urethral infection are
  postrenal disorders and therefore do not lead to
  cast formation.

• 1. Based on the urinalysis of this patient the
  LEAST likely cause of his hematuria is
• A. acute glomerulonephritis
• B. cystitis
• C. bladder carcinoma
• D. urethral infection

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What is the answer AND why?

• 2. The presence of hyaline casts is best related
  to the patients
• A. hematuria
• B. proteinuria
• C. pyuria
• D. bacteriuria

• ANSWER
• Hyaline casts are composed of protein alone and
  pass through the urinary tract virtually
  unchanged.
• Since the cast formation occurs principally in
  the distal and collecting tubules, hyaline casts
  reflect the presence of a renal proteinuria.
• Post-renal proteinuria is not associated with
  hyaline cast formation.

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What is the answer AND why?

• 3. Urine cytology in this case is strongly
  suggestive of which of the following?
• A. pyelonephritis
• B. glomerulonephritis
• C. cystitis
• D. neoplasia

• ANSWER
• Urine cytology shows hyperchronic neoplastic
  epithelial cells consistent with transitional
  cell carcinoma.
• These cells would not be seen in cystitis or in
  pyelonephritis where acute inflammatory cells
  would be prominent.
• Acute inflammatory cells can also be seen in the
  urine cytology of patients with carcinoma, as in
  this case. In glomerulonephritis, abundant red
  blood cells might be encountered, but neoplastic
  cells are not a feature of that disease.

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What is the answer AND why?

• 4. This radiographic appearance suggests the
  presence of which of the following ?
• A. a filling defect in the bladder
• B. a possible blood clot in the bladder
• C. a possible neoplasm
• D. all of the above

• ANSWER
• All of the above
• The intravenous pyelogram shows a filling defect
  in the left portion of the urinary bladder. This
  could represent a blood clot or a neoplasm.

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What is the answer AND why?

• ANSWER
• The tissue depicted in the biopsy is a grade III
  transitional cell carcinoma of the bladder
• It shows invasion of the muscular bladder wall.
  While it is bladder tissue, it is neither normal
  or granulomatous.
• Malakoplakia is an inflammatory condition
  presenting as a plaque or a nodule that usually
  affects the genitourinary tract but may rarely
  involve the skin. Results from inadequate killing
  of bacteria by macrophages or monocytes that
  exhibit defective phagolysosomal activity.

• 5. The bladder biopsy shows
• A. normal bladder mucosa
• B. bladder mucosa and a granulomatous process
• C. a neoplastic process
• D. malakoplakia of the bladder

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What is the answer AND why?

• 6. All of the following statements concerning the
  lesion depicted are correct EXCEPT
• A. it is often recurrent
• B. it has been associated with p53 gene mutations
• C. it is often multicentric
• D. it arises only in the bladder
• E. it is thought to be clonal in nature

• ANSWER
• (D) The lesion is a transitional cell carcinoma.
• Transitional cell carcinoma arise in the renal
  pelvis, ureter, bladder or prostatic urethra.
• They are often recurrent and/or multicentric, but
  nevertheless are regarded as clonal in origin
  (ie. arising from a single cell).
• Their clonal character has been deduced on the
  basis of studies of p53 gene mutations and other
  molecular genetic studies.

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What is the answer AND why?

• 7. All of the following statements about lesions
  of this type are correct EXCEPT
• A. they have been etiologically associated with
  the therapeutic use of the anti-tumor agent
  cyclophosphamide
• B. they have been etiologically associated with
  nephropathy due to the prolonged use of
  phenacetin
• C. they have been etiologically associated with
  cigarette smoking
• D. they more often affect inhabitants of rural
  rather than those of urban areas
• E. they affect males predominantly

• ANSWER
• Epidemiologically, the male to female ratio of
  the incidence of transitional cell carcinoma is
  about 3 to 1, and the disease is more common in
  those who live in urban rather than rural areas.
• Transitional cell carcinoma has been associated
  with cigarette smoking, and with both phenacetin
  overuse and analgesic nephropathy in general.
  Treatment with cyclophosphamide, an antitumor and
  immunosuppressive agent, may cause severe
  cystitis and increase the risk of bladder cancer.

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What is the answer AND why?

• The histogram in Figure 9-7 shows both diploid
  and aneuploid DNA peaks. There are two aneuploid
  peaks, reflecting the presence of two aneuploid
  cell populations.
• The DNA content of the aneuploid populations is
  higher (a higher staining intensity points to a
  higher content of DNA) than that of a diploid
  population.
• The DNA index (DI) is a value given to express
  the aneuploid DNA content relative to the normal
  cell complement of DNA. The estimation of an S
  phase fraction, which is a measure of the
  proliferative activity of a given cell
  population, is complicated when two or more cell
  populations are present.
• Several studies have indicated that tumor
  recurrence and progression are more frequently
  seen in aneuploid bladder tumors.

• 8. All of the following statements about the DNA
  histogram are correct EXCEPT
• A. it depicts a diploid DNA peak
• B. it depicts an aneuploid DNA content
• C. with respect to DNA content, it depicts more
  than one abnormal cell population
• D. the abnormal cell population has a smaller
  amount of DNA per one cell than the normal cell
  population
• E. the estimation of the S phase fraction of
  the diploid cell population is complicated by the
  presence of the aneuploid DNA peaks

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What is the answer AND why?

• ANSWER
• (D) When first diagnosed, the majority of bladder
  cancers present as a single lesion, which is
  localized in the bladder.
• Hematuria is the most common and sometimes the
  only manifestation of bladder cancer.
• The cancer can cause urinary outflow obstruction,
  which would predispose the patient to
  pyelonephritis or hydronephrosis.

• 9. All of the following statements about this
  patients disease are correct EXCEPT
• A. hematuria is the most common clinical
  manifestation
• B. it may lead to pyelonephritis
• C. it may lead to hydronephrosis
• D. when first discovered, it is usually
  multifocal and localized outside the bladder in
  the majority of patients