Renal Tumors & Bladder Diseases

This flipped classroom covers tumors of the kidney and the diseases of the urinary bladder.

Threading case

Grace Whitfield, 54

A 54-year-old woman comes to the physician because of three episodes of painless passage of visible blood in the urine over the past month. She has had no fever, no urinary frequency or burning on urination, and no flank or abdominal pain. She has smoked one pack of cigarettes daily for thirty years and worked for eleven years in a textile dyeing plant. Her temperature is 98.4°F, pulse is 78/min, respiratory rate is 14/min, and blood pressure is 128/76 mmHg. Examination shows no abdominal or flank mass and no costovertebral angle tenderness. Urinalysis shows numerous erythrocytes with no casts, no proteinuria and no pyuria; urine culture is sterile. Serum creatinine is 0.9 mg/dL. Contrast-enhanced CT of the abdomen and pelvis shows normal kidneys and no bladder mass.

Before reading, note your initial thinking

Q1. Where in the urinary tract is the bleeding most likely to be arising?

Q2. Which malignancy does her exposure history make most likely?

Q3. Why does a normal CT not exclude malignancy?

Notes

Learning objectives covered

PATH.6035PATH.6036PATH.6037PATH.6038PATH.6039

Renal Tumors: origin and classification

Distinguish the common renal tumors by age, and name the three benign lesions of adults.

Where each tumor comes from

Click a numbered cell of origin

Click a number to see which tumor arises from that cell.

Classification by age and behavior

	Benign	Malignant
Adults	Renal papillary adenoma · Angiomyolipoma · Oncocytoma	Renal cell carcinoma
Children	—	Wilms tumor (nephroblastoma)

The three benign tumors

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Angiomyolipoma

What makes a benign tumor dangerous?

Composition

Vessels, muscle and fat

Angio, myo and lipo, arising from perivascular epithelioid cells. Present in 25 to 50% of patients with tuberous sclerosis, and also sporadic. Its vessels are thick-walled but not strong: the wall has no internal elastic lamina, so it bleeds.

↩

Oncocytoma

Why remove a benign tumor?

Recognition

Mahogany-brown, central scar

Large eosinophilic cells packed with mitochondria, forming a well-circumscribed mass with a central stellate scar.

↩

Renal papillary adenoma

Benign or malignant?

Definition

Benign, and usually incidental

Small unencapsulated papillary or tubulopapillary lesions with low-grade nuclei. Among the most common incidental findings at autopsy.

Associated syndrome

Tuberous sclerosis. A quarter to a half of these patients have an angiomyolipoma, and in them the tumors tend to be multiple and in both kidneys. This is why the association matters: more lesions mean more opportunities for bleeding.

Label the histology

Angiomyolipoma · H&E

Click each numbered marker to identify the component

Click a marker to identify each component.

Self-check

Attempt before revealing.

1

Angiomyolipoma contains three tissue types. Which one accounts for its main clinical risk, and why?

Answer

The vascular component. The vessels are thick-walled but not strong. A thick wall would normally mean a tough vessel, and these lack an internal elastic lamina, so they rupture. The danger in this benign tumor is spontaneous retroperitoneal hemorrhage.

Back to Grace

Her examination makes a large renal tumor unlikely. It does not exclude a small one, and it says nothing at all about the tract below the kidney.

Decision point

If Grace were 3 years old rather than 54, which tumor would be the most likely diagnosis, and from which cell would it arise?

Explanation

Notes

Learning objective covered

PATH.6035

Renal Cell Carcinoma

Trace how loss of VHL shapes the appearance and behavior of clear cell RCC.

Peak age

6th–7th decade

Sex

2:1 M:F

Leading risk factor

Tobacco

Familial

~4%

Also: obesity, especially in women; hypertension as an independent factor; and occupational exposure to petroleum products and heavy metals.

The VHL pathway

VHL on chromosome 3p tags HIF for destruction. Lose both alleles and HIF accumulates, so the cell behaves as though it lacks oxygen even though the blood supply is normal.

The VHL pathway

Tap any node to see what it does

Scroll the diagram sideways to see all of it

Tap any node above to see details.

Histological subtypes

Major subtypes

Subtype	Genetics	Histology
Clear cell	3p loss, VHL	Nests of clear cells; yellow gross
Papillary	Trisomy 7 and 17, loss of Y, MET	Papillary; bilateral in hereditary form
Chromophobe	Multiple chromosome losses	Pale cells, prominent borders

Sporadic and hereditary forms of the two commonest subtypes. Clear cell carcinoma follows chromosome 3 deletion and loss of VHL, whether sporadic or inherited, and the hereditary form is bilateral and multifocal. Papillary carcinoma follows trisomy 7 and 17 with loss of Y in the sporadic form, trisomy 7 alone in the hereditary form, and an activating MET mutation in both.

RCC · Gross

Nephrectomy specimen. Large solitary tumor with hemorrhage, necrosis and a yellow cut surface from lipid-rich clear cells. Note invasion of the renal vein, which can extend as a solid column into the inferior vena cava and rarely the right atrium.

RCC histology low and high magnification

Clear Cell RCC · H&E

Histology. Left: nests of pale tumor cells separated by thin sinusoidal vessels. Right: large polygonal cells with clear cytoplasm, where glycogen and lipid dissolved out during processing.

Clinical features

Presentation

The classic triad is costovertebral pain, palpable flank mass and hematuria. All three together are uncommon, and hematuria is the most reliable single clue. Constitutional symptoms are common: fever, malaise, weakness, weight loss. Metastasis goes to lung in over 50% and bone in 33%, then regional nodes, liver, adrenals and brain.

Paraneoplastic syndromes

RCC is considered one of the great mimics in medicine. Abnormal hormone production lets it produce a diversity of systemic symptoms not related to the kidney.

↩

Polycythemia

Which hormone, and why this tumor?

Mechanism

Ectopic erythropoietin

Stabilized HIF transcribes EPO, so the marrow makes red cells the body does not need. Elevated hematocrit with normal oxygen saturation. Resolves after nephrectomy.

↩

Hypercalcemia

Which hormone?

Mechanism

Ectopic PTHrP

PTHrP mimics PTH at bone and kidney. Presents as confusion, constipation, polyuria or bone pain.

↩

Hypertension

Which hormone?

Mechanism

Ectopic renin

Tumor-derived renin activates the renin-angiotensin-aldosterone system, independent of renal artery stenosis.

↩

Feminization / masculinization

Which hormones?

Mechanism

Adrenal-steroid-like hormones

Gynecomastia in men, virilization in women. Uncommon, and the presentation gives no hint that the problem is in the kidney.

Self-check

Attempt before revealing.

2

Why is clear cell RCC yellow on the cut surface, and why do its cells look empty on H&E?

Answer

The cells are loaded with lipid and glycogen. That gives the intact specimen its golden color, and when those contents dissolve out during processing the cytoplasm is left optically clear on the slide.

Back to Grace

Thirty pack-years raises RCC as well as bladder cancer, since tobacco is the leading risk factor for both. What separates them in Grace is that RCC bleeds from a mass in the parenchyma, and her contrast CT reports normal kidneys.

Decision point

Loss of VHL makes clear cell RCC behave as though it were hypoxic. Which downstream consequence explains why these tumors are so vascular?

Explanation

Notes

Learning objective covered

PATH.6035

Wilms Tumor (Nephroblastoma)

Recognize the three tissue types of the childhood tumor, and what changes prognosis.

Peak age

< 6 years

90% of cases

Incidence

~1 in 10,000

Key gene

WT1 · 11p

Gross: large, well circumscribed and solitary, soft and homogeneous, pale tan to gray. Compare with RCC, which is golden-yellow, heterogeneous, and invades the renal vein.

Wilms Tumor · Gross

Nephrectomy specimen. A single large mass with a soft, fleshy, pale tan cut surface, sharply demarcated from the rim of residual kidney. The cut surface is pale rather than the golden-yellow of renal cell carcinoma.

Label the triphasic histology

Wilms Tumor · H&E

Click each numbered marker before reading the table

Click a marker to identify each component.

The three components

Component	Appearance	Represents
Blastemal	Sheets of small round blue cells, high N:C ratio	Undifferentiated metanephric blastema
Epithelial	Glandular and tubular structures	Differentiating tubular epithelium
Stromal	Spindle-cell connective tissue	Mesenchymal stroma of the developing kidney

Wilms anaplasia histology with green arrowhead

Wilms Tumor · Anaplasia

Anaplasia. Nuclei at least three times the size of their neighbors, with atypical multipolar mitotic figures. Associated with TP53 mutation, and the most important adverse prognostic marker because it predicts resistance to chemotherapy. Focal anaplasia does better than diffuse.

Self-check

Attempt before revealing.

3

Why does triphasic histology make embryological sense, and which gene decides the prognosis?

Answer

The tumor arises from metanephric blastema, the cell population the whole kidney develops from, so it recapitulates nephrogenesis in disordered form: blastema, epithelium differentiating toward tubules, and mesenchymal stroma. Prognosis turns on TP53, whose mutation produces anaplasia and so chemoresistance. WT1 drives tumor formation and has no role in anaplastic change.

Notes

Learning objective covered

PATH.6035

Diseases of the Urinary Bladder

Explain the congenital anomalies, the two kinds of cystitis, and how bladder cancer is staged.

Congenital anomalies

Anomaly	Significance
Urachal fistula	Fully patent urachus. Urine leaks from the umbilicus in the newborn.
Urachal cyst	Partially patent; the central segment stays open, and the trapped segment becomes infected.
Diverticulum	Outpouching at a point of muscular weakness. Urine stagnates, so infection and calculi follow.
Vesicoureteral reflux	The most common and most serious anomaly. Causes ascending pyelonephritis and renal scarring.
Exstrophy	The anterior wall fails to close, so the bladder communicates with the abdominal wall. The exposed mucosa undergoes metaplasia and is at risk of infection.

Cystitis

Predisposed by female sex, diabetes, instrumentation, calculi and outlet obstruction. Most common organisms are the coliforms: E. coli first, then Proteus, Klebsiella and Enterobacter. Symptoms are frequency, suprapubic pain and dysuria, with fever, chills and microscopic hematuria.

Infectious vs interstitial

Feature	Acute infectious	Interstitial
Etiology	Bacterial, fungal or parasitic	Unknown; chronic pelvic pain syndrome
Duration	Days	More than six weeks by definition
Urine culture	Positive	Negative
Cystoscopy	Erythema and edema	Mucosal fissures, punctate hemorrhages
Histology	Neutrophil infiltrate	Non-specific; submucosal mast cells increased
Biopsy	Not routinely needed	Required, to exclude carcinoma in situ

Do not miss this

Why the biopsy is mandatory. Flat carcinoma in situ produces the same symptoms and forms no visible mass, so it is clinically indistinguishable from interstitial cystitis. Interstitial cystitis is a diagnosis of exclusion, and what is being excluded is a high-grade cancer.

Bladder neoplasms

Age

50–80 years

80% of patients

Sex

3:1 M:F

Leading risk factor

Cigarette smoking

Leading prognostic factor

Stage at diagnosis

Three categories: epithelial (urothelial carcinoma, squamous cell carcinoma, adenocarcinoma), mesenchymal (leiomyoma, leiomyosarcoma) and secondary, by direct extension from cervix, uterus, prostate or rectum. Risk factors for urothelial carcinoma: smoking above all, then industrial aryl amines, analgesic abuse, irradiation and Schistosoma haematobium. Presentation is painless hematuria; a tumor at the ureteral orifice can obstruct it and cause hydronephrosis or pyelonephritis.

Work through the sequence

Progression through the bladder wall

1 of 6

Two routes to invasion. The papillary route above, the flat route below.

Papillary vs flat

Feature	Papillary	Flat (CIS)
Gross	Finger-like fronds into the lumen	Red velvety patch, or invisible
Grade	Often low; climbs over time	High grade by definition
Behavior	High recurrence; a minority invade	50–75% progress to muscle-invasive

Papillary Urothelial Carcinoma

Cystoscopy and histology. Left: frond-like projections into the lumen. Right: fibrovascular cores lined by transitional epithelium, with mitotic figures arrowed at high power. This is a non-invasive papillary urothelial neoplasm.

Squamous cell carcinoma

Three to seven percent of bladder cancers in the United States, far more where urinary schistosomiasis is endemic. Histology is squamous carcinoma as elsewhere in the body, with keratin pearls. The bladder has no squamous epithelium of its own, so the sequence runs: chronic irritation → squamous metaplasia → dysplasia → carcinoma.

Self-check

Attempt before revealing.

4

Squamous carcinoma needs a metaplastic step first. What is the equivalent change for bladder adenocarcinoma, and where does it arise?

Answer

Columnar metaplasia. It arises where mucosa is chronically exposed or chronically irritated, as in a urachal remnant or in exstrophy. The principle is the same as the squamous route: the epithelium is first replaced by a different type, and that new epithelium is what becomes malignant.

Back to Grace

A 54-year-old smoker with aryl amine exposure, painless visible hematuria, sterile urine and normal imaging. One lesion fits all of it: high grade, forming no mass, invisible on CT.

Decision point

Cystoscopy in Grace shows no mass, only a red velvety patch on the posterior wall. Biopsy shows high-grade malignant cells filling the full thickness of the urothelium, with an intact basement membrane. Which of the following best describes this lesion and how it behaves?

Explanation

Notes

Learning objectives covered

PATH.6036PATH.6037PATH.6038PATH.6039

Summary

Return to the three questions you set aside at the start, and write your answers before class.

Threading case

Grace Whitfield, 54

A 54-year-old woman comes to the physician because of three episodes of painless passage of visible blood in the urine over the past month. She has had no fever, no urinary frequency or burning on urination, and no flank or abdominal pain. She has smoked one pack of cigarettes daily for thirty years and worked for eleven years in a textile dyeing plant. Her temperature is 98.4°F, pulse is 78/min, respiratory rate is 14/min, and blood pressure is 128/76 mmHg. Examination shows no abdominal or flank mass and no costovertebral angle tenderness. Urinalysis shows numerous erythrocytes with no casts, no proteinuria and no pyuria; urine culture is sterile. Serum creatinine is 0.9 mg/dL. Contrast-enhanced CT of the abdomen and pelvis shows normal kidneys and no bladder mass.

Now answer with what you have read

Attempt each one before revealing.

1

Where in the urinary tract is the bleeding most likely to be arising?

Answer

The collecting system: renal pelvis, ureter, bladder or urethra. The urinalysis is what excludes a glomerular source. Glomerular bleeding is microscopic and comes with proteinuria, dysmorphic red cells and red cell casts, usually alongside edema, hypertension and a rising creatinine. Grace has erythrocytes with no casts, no proteinuria, a normal blood pressure and a creatinine of 0.9 mg/dL. Her bleeding is painless, visible and intermittent, and in an adult that means a tumor until proved otherwise. The sterile culture and absent pyuria argue against cystitis.

2

Which malignancy does her exposure history make most likely?

Answer

Urothelial carcinoma. Both exposures point there and both reach the tissue the same way. Tobacco is its leading risk factor, and the aryl amines used in dye and rubber manufacture, 2-naphthylamine and benzidine, are the classic occupational cause. Each is absorbed, metabolized and excreted in urine, so the urothelium is in contact with the carcinogen for as long as the urine stays in the bladder. That route is also why the damage affects the whole surface rather than one site: tumors are multifocal, and recurrence reaches 70%. Tobacco raises renal cell carcinoma too, but there the carcinogens arrive in blood at the tubular epithelium, and her kidneys are normal on CT.

3

Why does a normal CT not exclude malignancy?

Answer

CT finds most tumors because they form a mass, which is to say a lesion large enough to change the contour or the thickness of an organ wall. Flat carcinoma in situ is only a few cell layers thick and lies flat within the urothelium, so it alters neither, and the scan has nothing to resolve. It is high grade all the same. At cystoscopy it may show only a red velvety patch, or nothing at all. A normal CT therefore excludes a mass, and excluding a mass is not the same as excluding a cancer. This is why painless hematuria in an adult is investigated with cystoscopy, urine cytology and biopsy rather than imaging alone, and the same reason interstitial cystitis cannot be diagnosed without a biopsy.

Compare them side by side

Renal and bladder tumors compared

Tumor	Age	Origin	Gross	Genetics	Signature clue
Angiomyolipoma	Adult	Perivascular epithelioid cell	Contains fat	TSC1 / TSC2	Tuberous sclerosis; spontaneous hemorrhage
Oncocytoma	Adult	Intercalated cell	Mahogany-brown, central scar	—	Benign, but resected because imaging cannot exclude RCC
Clear cell RCC	6th–7th decade	Proximal tubule	Golden-yellow; renal vein	3p loss, VHL	Paraneoplastic syndromes; clear cytoplasm
Wilms tumor	< 6 years	Metanephric blastema	Large, pale tan, soft	WT1 · 11p	Triphasic histology; anaplasia means TP53
Urothelial carcinoma	> 60 years	Urothelium	Papillary fronds, or flat	—	Painless hematuria; smoking; multifocal
Squamous cell carcinoma	> 60 years	Metaplastic squamous	Fungating or ulcerative	—	Keratin pearls; schistosomiasis

Before the session

You have covered where each tumor comes from, the VHL pathway behind clear cell RCC, the triphasic tumor of childhood, and the boundary in the bladder wall that decides treatment. Grace’s case opens the class.

Thank you!

Notes

Learning objectives covered

PATH.6035PATH.6036PATH.6037PATH.6038PATH.6039