PCM1 · NCRS · Lecture 27 · Renal Pathology 6

Renal Tumors & Bladder Diseases

This is a revision reference. It covers the material from the pre-reading and the class, and works through all eleven questions from the session with every option explained.

The opening case

The three questions from the pre-reading, with the reasoning from class.

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. 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.

Painless hematuria30 pack-years11 years, textile dyesNo mass on CTSterile cultureCreatinine 0.9

1. Where in the urinary tract is the bleeding most likely arising?

From the urothelium, which lines the tract continuously from renal pelvis through ureter and bladder to urethra. Erythrocytes without casts, without proteinuria and without dysmorphic forms rule out a glomerular source, and the absence of pyuria and a sterile culture rule out infection. Painless, visible, intermittent hematuria in an adult over 50 is urothelial malignancy until proved otherwise.

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

Urothelial carcinoma. Cigarette smoking is the single largest risk factor, and aryl amines from textile dyeing, rubber and paint work are the classic occupational exposure. Both reach the urothelium through the urine, so the whole lining is exposed at once. That field effect is why these tumors are frequently multifocal and why recurrence approaches 70% after resection.

3. Why does a normal CT not exclude malignancy?

Because one of the two morphological routes makes no mass at all. Flat carcinoma in situ spreads within the thickness of the urothelium without forming a papillary excrescence or a wall lesion, so cross-sectional imaging is normal and cystoscopy may show only reddened, granular mucosa. It is nevertheless high grade from the outset, and 50 to 75% of untreated cases progress to muscle-invasive disease. Only cystoscopy with biopsy, supported by urine cytology, will find it.

What happened to GraceCystoscopy showed patchy erythematous velvety mucosa with no papillary lesion. Biopsies from those areas and from normal-looking mucosa showed high-grade flat carcinoma in situ. She was treated with intravesical BCG and entered lifelong surveillance.

Renal tumors

Where each tumor comes from, and why age decides the list.

Origin. Every renal tumor is named for the cell it arises from, so the classification follows the nephron. Proximal tubular epithelium gives papillary adenoma and clear cell renal cell carcinoma. Intercalated cells of the collecting duct give oncocytoma and chromophobe carcinoma. Perivascular epithelioid cells give angiomyolipoma. Metanephric blastema, the embryonic tissue that should have been consumed making nephrons, gives Wilms tumor.

Tumor	Cell of origin	Age	Behavior
Papillary adenoma	Proximal tubule	Adult	Benign; under 15 mm by definition, usually incidental
Angiomyolipoma	Perivascular epithelioid cell	Adult	Benign; hemorrhage is the hazard
Oncocytoma	Intercalated cell	Adult	Benign; resected because imaging cannot exclude carcinoma
Renal cell carcinoma	Proximal tubule (clear cell)	6th–7th decade	Malignant; invades the renal vein
Wilms tumor	Metanephric blastema	Under 6 years	Malignant; the commonest renal tumor of childhood

Nephrectomy specimen: a golden-yellow renal cell carcinoma at the upper pole, with hemorrhage and a well-defined edge against normal cortex.

Telling the three benign tumors apart

All three are benign, and all three can appear as an incidental, well-circumscribed renal mass. Each one has a feature that identifies it.

Angiomyolipoma	Vessels, smooth muscle and fat, arising from perivascular epithelioid cells. A quarter to a half of patients with tuberous sclerosis have one, and it also occurs sporadically. The danger is spontaneous hemorrhage. Its vessels are thick-walled but not strong, because the wall has no internal elastic lamina.
Oncocytoma	A mahogany-brown cut surface with a central stellate scar. Large eosinophilic cells packed with mitochondria.
Renal papillary adenoma	Small, unencapsulated, papillary or tubulopapillary, with low-grade nuclei. Among the most common incidental findings at autopsy.

Remember thisAll three are benign. The one that causes trouble is angiomyolipoma, because it bleeds.

Angiomyolipoma: mature adipose tissue, thick-walled dysmorphic vessels and spindled smooth muscle, in varying proportions.

Renal cell carcinoma

Risk factors. Smoking roughly doubles the risk. Obesity, hypertension, unopposed estrogen therapy, heavy metals, chronic kidney disease and acquired cystic disease all contribute. Hereditary forms account for about 4%: von Hippel-Lindau disease, hereditary papillary carcinoma, and the syndrome associated with hereditary leiomyomatosis.

Clinical features. The classic triad of costovertebral pain, palpable mass and hematuria is uncommon, and its presence usually means advanced disease. Hematuria is the most reliable single clue. Constitutional symptoms are common, and because the tumor invades the renal vein it can present with a left-sided varicocele that fails to empty when the patient lies down. More than half of cases are now found incidentally on imaging performed for another reason.

Metastasis. Lung in more than 50%, bone in about a third, then regional lymph nodes, liver, adrenal and brain.

How one lost gene explains most of clear cell carcinoma

VHL protein normally tags hypoxia-inducible factor for destruction. When both VHL alleles are lost, HIF accumulates and the cell runs the hypoxia program while sitting in fully oxygenated blood. Almost every feature of the tumor follows from that single error.

↑ VEGF	Tumor angiogenesis. Renal cell carcinoma is among the most vascular of solid tumors, which is why anti-VEGF agents work in metastatic disease and why the tumor bleeds.
↑ Erythropoietin	Polycythemia, with a normal oxygen saturation and a raised serum erythropoietin. It resolves after nephrectomy.
↑ PDGF	Stromal proliferation and tumor growth.
Independent of HIF	PTHrP causes hypercalcemia by acting on bone and kidney. Renin causes hypertension. Steroid-like hormones cause feminization or masculinization. Amyloidosis and a leukemoid reaction also occur.

Remember thisRenal cell carcinoma is called one of the great mimics because any of these syndromes can appear long before the kidney causes a local symptom.

The genetic basis of the two commonest subtypes: clear cell carcinoma follows chromosome 3 deletion and loss of VHL, papillary carcinoma follows trisomy 7 and an activating MET mutation. The hereditary forms are bilateral and multifocal.

Clear cell renal cell carcinoma: nests of cells with clear cytoplasm, separated by a delicate branching vascular network.

Wilms tumor

Presentation. A large abdominal mass in a child under six, often with fever, weight loss and sometimes hematuria or hypertension. Ninety per cent occur before the age of six. The tumor is large, pale tan and soft on cut surface.

Two genes in Wilms tumor, doing two different jobs

Confusing WT1 with TP53 is the most common error in this topic, because one gene explains why the tumor exists and the other explains how it behaves once it does.

WT1 · 11p	Drives formation of the tumor. Wilms tumor may be syndromic or sporadic.
TP53	Drives anaplasia: nuclei at least three times the size of their neighbors, hyperchromatic, with atypical multipolar mitoses. Anaplasia predicts resistance to chemotherapy, which is why it is the most important adverse prognostic factor. Focal anaplasia does better than diffuse.

Remember thisTriphasic histology follows from the origin. The tumor arises from metanephric blastema, so it recapitulates nephrogenesis and shows blastemal, epithelial and stromal elements together.

Wilms tumor: blastemal sheets of small blue cells, abortive tubules and glomeruloid structures, and spindled stroma.

Anaplasia in Wilms tumor: markedly enlarged hyperchromatic nuclei and an atypical multipolar mitotic figure (green arrowhead).

The bladder before cancer

Congenital anomalies, and the two kinds of cystitis.

The two congenital anomalies named by objective 6036

Both are failures of a normal structure, and both cause disease years after the anatomy went wrong.

Urachal fistula	The urachus, which connects the fetal bladder to the allantois, stays fully patent. Urine discharges at the umbilicus in the newborn.
Urachal cyst	Only the central segment stays open, and the trapped segment becomes infected.
Diverticulum	An outpouching at a point of muscular weakness, congenital or acquired from outlet obstruction. Urine stagnates in it, so infection and calculi follow.
Also worth knowing	Vesicoureteral reflux is the most common and the most consequential anomaly, causing ascending pyelonephritis and renal scarring. Exstrophy leaves bladder mucosa exposed on the abdominal wall, where it undergoes metaplasia and is at risk of infection.

Remember thisEach anomaly matters because of what stagnant urine or exposed mucosa causes over the following decades.

The same complaint, eight months apart

Two women describe frequency, suprapubic pain and dysuria. The diagnosis depends on two things: how long the symptoms have lasted, and whether the urine culture grows bacteria.

Acute infectious cystitis	Days. Culture positive, usually Escherichia coli, then Proteus, Klebsiella and Enterobacter. Neutrophils and hyperemic mucosa. Biopsy is not required. Common in women because the urethra is short.
Chronic cystitis	Repeated or persistent infection, often on a background of obstruction, calculi or catheterization. Mononuclear infiltrate, fibrosis and a thickened wall.
Interstitial cystitis	More than six weeks of symptoms by definition. Cultures sterile. Cystoscopy shows mucosal fissures and punctate hemorrhages, and in the late ulcerative form a Hunner ulcer. Biopsy shows a non-specific infiltrate with increased submucosal mast cells, and it is mandatory.
Why mandatory	Flat carcinoma in situ produces an identical symptom complex, forms no mass, and is high grade. Between 50 and 75% of untreated cases progress to muscle-invasive disease.

Remember thisInterstitial cystitis is a diagnosis of exclusion. What is being excluded is a cancer that is almost invisible at cystoscopy.

Bladder cancer

Two morphological routes, and the boundary that decides treatment.

Classification. Bladder malignancies divide into epithelial, mesenchymal and secondary. Epithelial tumors are the great majority: urothelial carcinoma first by a wide margin, then squamous cell carcinoma at 3 to 7% in the United States, then adenocarcinoma, which is rare and arises in urachal remnants or in exstrophy. Mesenchymal tumors are leiomyoma and leiomyosarcoma. Secondary tumors reach the bladder by direct extension from cervix, uterus, prostate or rectum.

Risk factors. Cigarette smoking is the largest, accounting for roughly half of cases in men. Aryl amines from textile dyeing, rubber and paint work are the classic occupational exposure, with a latency of fifteen to twenty years. Cyclophosphamide, prior pelvic irradiation, long-standing calculi or catheters, and Schistosoma haematobium infection also raise risk. All of them reach the urothelium through the urine, which is why the whole lining is at risk and why these tumors are multifocal.

Clinical features. Painless hematuria is the presenting symptom in the great majority. Frequency, urgency and dysuria may accompany it. A tumor at a ureteric orifice obstructs it, producing hydronephrosis and, if bilateral or in a solitary kidney, renal failure.

The two routes to invasion: papillary lesions become higher grade as they grow into the lumen, while flat carcinoma in situ is high grade from the start.

The layer that decides the operation

The papillary route begins with a papilloma and passes through low-grade and then high-grade carcinoma before it invades. The flat route does not pass through those steps. Carcinoma in situ is high grade from the outset and invades directly. Both converge on the same staging question.

Above the muscularis propria	Non-invasive papillary tumors, flat carcinoma in situ, and tumors that have reached the lamina propria. Transurethral resection, then intravesical BCG when the tumor is high grade, multifocal or carcinoma in situ.
Into the muscularis propria	The detrusor muscle is invaded. Treatment becomes radical cystectomy, or cystoprostatectomy in men, or radiation with chemotherapy.
No muscle in the specimen	The tumor cannot be staged.
Either way	Recurrence reaches 70%, because the whole urothelium was exposed to the same carcinogens. Surveillance cystoscopy is lifelong.

Remember thisThe extent of invasion and spread at diagnosis is the single most important prognostic factor in bladder cancer.

Papillary urothelial carcinoma: delicate fronds, each with a fibrovascular core, covered by thickened disordered urothelium.

How a squamous carcinoma arises in a urothelial bladder

The bladder has no squamous epithelium, so a keratinizing squamous carcinoma cannot arise from the native lining. A whole adaptive step has to happen first.

Chronic irritation	Schistosoma haematobium ova deposited in the bladder wall, or long-standing calculi, or years of indwelling catheterization.
Squamous metaplasia	Adaptation. The epithelium is replaced by a tougher type better able to survive persistent injury.
Dysplasia and carcinoma in situ	Failure of that adaptation. The new epithelium loses control of its own growth.
Invasive carcinoma	Malignant squamous cells forming keratin pearls. Usually fungating or ulcerative, and usually invasive by the time it presents.

Remember thisCompare this with urothelial carcinoma, where smoking and aryl amines act on the native epithelium directly and no metaplastic step is needed.

The eleven questions

Every question from the session, with the reasoning behind each option.

Question 1 of 11Case 1 · Hematuria and a flank mass

A 65-year-old man has a 2-week history of recurrent hematuria and left flank discomfort. Examination shows a palpable mass in the left costovertebral angle, and ultrasonography shows a solid mass in the upper pole of the left kidney.

Which of the following characteristics of this patient is most useful in narrowing the differential diagnosis?

AIncorrect

The patient’s sex. Renal cell carcinoma is about twice as common in men, which shifts probability a little. It does not change which diagnoses belong on the list.

BCorrect

The patient’s age. Age splits the list in two before anything else does. In adults the benign lesions are papillary adenoma, angiomyolipoma and oncocytoma, and the malignant one is renal cell carcinoma. In children the malignant one is Wilms tumor. Almost nothing crosses over.

CIncorrect

The side involved. Side has no bearing on histology. Bilateral disease is a different matter, since it suggests a hereditary syndrome.

DIncorrect

The presence of flank discomfort. Pain indicates that the lesion is large or bleeding. It does not indicate what the lesion is, and the classic triad of pain, mass and hematuria is uncommon.

EIncorrect

The serum creatinine concentration. Creatinine measures how much kidney is still working. It is essential before iodinated contrast, and it says nothing about the nature of the mass.

Question 2 of 11Case 1 · Hematuria and a flank mass · continued

The mass measures 7 cm and is solid on ultrasonography. Serum creatinine is 0.9 mg/dL and the estimated glomerular filtration rate is 88 mL/min/1.73 m². He has no known allergy to iodinated contrast material.

Which of the following is the most appropriate next step in evaluation?

AIncorrect

Urine cytology. Cytology samples cells shed into the urine, so it detects urothelial tumors of the renal pelvis, ureter and bladder. A parenchymal renal mass does not shed into the urine, so a negative result would not reassure.

BIncorrect

Percutaneous renal biopsy. Biopsy is used selectively, when the result would change management: suspected lymphoma, a metastasis from a known primary, infection, or a patient being considered for ablation. It is not used for a typical solid mass in a fit adult, because it does not exclude carcinoma reliably enough to leave the mass in place.

CIncorrect

MRI of the abdomen without contrast. A defensible answer, and the right one when iodinated contrast is contraindicated. CT is preferred here because he has normal renal function and no allergy, and because CT is faster, more available, and stages chest and abdomen in one study.

DCorrect

Multiphase contrast-enhanced CT of the abdomen and pelvis. A solid renal mass needs high-quality multiphase cross-sectional imaging. CT shows the degree of enhancement, detects macroscopic fat, and defines renal vein, caval, nodal and distant spread in a single study.

EIncorrect

PET-CT scan. FDG is excreted in urine and accumulates in the collecting system, obscuring the kidney. PET-CT has a limited role in metastatic disease and none in characterizing a renal mass.

Question 3 of 11Case 1 · Hematuria and a flank mass · continued

Before surgery his hematocrit is 58% and serum erythropoietin is elevated, with an oxygen saturation of 98% on room air. Nephrectomy shows a golden-yellow tumor of clear cells. Six weeks later his hematocrit is 44%.

Which of the following best explains this patient’s hematologic findings?

AIncorrect

Compression of renal parenchyma causing local hypoxia. Compression reduces local blood flow and contributes to tumor-associated hypertension through renin. It does not explain this picture, because his oxygen saturation is normal and the marrow is therefore not answering real hypoxia.

BCorrect

Stabilization of HIF after loss of VHL function. Both VHL alleles are lost, so HIF escapes degradation and drives the hypoxia program in a cell sitting in fully oxygenated blood. Erythropoietin is one of its target genes, and removing the tumor removes the signal. The same pathway raises VEGF, which is why renal cell carcinoma is among the most vascular of solid tumors.

CIncorrect

Tumor secretion of parathyroid hormone-related protein. PTHrP is a genuine product of renal cell carcinoma, and it raises serum calcium by acting on bone and kidney. It has no erythropoietic action.

DIncorrect

An autonomous JAK2 V617F clone in the marrow. JAK2 V617F causes polycythemia vera, in which erythropoietin is characteristically low rather than elevated, and which nephrectomy would not correct.

EIncorrect

Chronic blood loss into the urinary tract. Blood loss lowers hemoglobin. His is elevated. In renal cell carcinoma, hematuria contributes to anemia far more often than to erythrocytosis.

Question 4 of 11Case 2 · A three-year-old with an abdominal mass

A 3-year-old boy is brought to the physician because of a 2-week history of an abdominal mass, recurrent fever and weight loss. Physical examination shows a firm mass in the left upper abdomen that does not cross the midline. Ultrasonography shows a solitary 9-cm mass arising from the lower pole of the left kidney. Biopsy shows blastemal, epithelial and stromal elements together.

Which of the following is the most likely diagnosis?

AIncorrect

Renal cell carcinoma. Renal cell carcinoma peaks in the sixth and seventh decades. In a 3-year-old it is vanishingly rare.

BIncorrect

Teratoma. Teratoma contains tissues from all three germ layers and arises at gonadal and midline sites, not within renal parenchyma.

CIncorrect

Pleomorphic adenoma. Pleomorphic adenoma is a salivary gland tumor. It does not occur in the kidney.

DCorrect

Nephroblastoma. Wilms tumor is the most common primary renal malignancy of childhood, with 90% of cases before the age of six. Blastemal, epithelial and stromal elements together, the triphasic pattern, are the hallmark, because the tumor arises from metanephric blastema and so recapitulates nephrogenesis.

EIncorrect

Neuroblastoma. This is the most difficult distractor. Neuroblastoma is the other common abdominal mass of childhood, but it arises from adrenal medulla or sympathetic chain, characteristically crosses the midline and displaces the kidney rather than arising within it, and is not triphasic. The mass here does not cross the midline.

Question 5 of 11Case 2 · A three-year-old with an abdominal mass · continued

Further review of the biopsy specimen shows cells with nuclei at least three times the diameter of adjacent nuclei, marked hyperchromasia, and atypical multipolar mitotic figures. These changes are present in several separate microscopic fields.

This additional finding most likely indicates a mutation in which of the following genes?

AIncorrect

WT1. WT1 on chromosome 11p drives formation of the tumor itself. It does not cause anaplastic change.

BIncorrect

Rb. Rb mutation causes retinoblastoma and predisposes to osteosarcoma. It has no role here.

CCorrect

p53. The finding is anaplasia, and it is associated with TP53 mutation. It is the most important adverse prognostic marker in Wilms tumor, because it predicts resistance to chemotherapy rather than simply looking aggressive. Anaplasia present in several separate fields is diffuse, which carries a worse prognosis than focal anaplasia.

DIncorrect

VHL. VHL drives clear cell renal cell carcinoma through the HIF pathway, as in Case 1. Wrong tumor and wrong age.

EIncorrect

RET. RET is associated with MEN2 and medullary thyroid carcinoma.

Question 6 of 11Case 3 · A newborn weeping from the umbilicus

A 3-week-old boy is brought to the physician because of intermittent clear discharge from the umbilicus for 1 week, which increases when he cries or strains. The fluid has a urea nitrogen concentration far exceeding that of serum, and ultrasonography shows a tubular tract running from the dome of the bladder to the umbilicus.

Which of the following best describes the etiopathogenesis of this condition?

AIncorrect

Failure of the vitelline duct to involute, leaving a tract to the ileum. A patent vitelline duct also discharges at the umbilicus, but the fluid is intestinal content rather than urine. The urea nitrogen concentration is what separates the two.

BCorrect

Failure of the urachus to obliterate, leaving a tract to the bladder. The urachus connects the fetal bladder to the allantois and normally obliterates before birth. Left fully patent it forms a urachal fistula, with urine discharging at the umbilicus, as here. Partly patent it leaves a urachal cyst, and the trapped segment becomes infected. The other anomaly named by objective 6036 is the diverticulum, an outpouching at a point of muscular weakness where urine stagnates, so infection and calculi follow.

CIncorrect

Failure of the processus vaginalis to close along the inguinal canal. A patent processus vaginalis produces an indirect inguinal hernia or a hydrocele. It runs toward the scrotum, not to the umbilicus, and the fluid would not be urine.

DIncorrect

Persistence of mesonephric duct remnants beside the developing gonad. Mesonephric duct remnants give Gartner duct cysts in the female and epididymal structures in the male. Neither communicates with the umbilicus.

EIncorrect

Abnormal branching of the ureteric bud during metanephric development. Ureteric bud abnormalities give duplex collecting systems and other ureteral anomalies, with no tract to the umbilicus.

Question 7 of 11Case 4 · One day of burning

A 34-year-old woman comes to the physician because of a 1-day history of fever, increased urinary frequency and burning on urination. She takes no medications. Physical examination shows suprapubic tenderness with no costovertebral angle tenderness. Urinalysis shows erythrocytes and pus cells, with positive leukocyte esterase and nitrites.

Which of the following is the most likely diagnosis?

AIncorrect

Glomerulonephritis. Glomerulonephritis presents with proteinuria, dysmorphic erythrocytes and red cell casts, hypertension and edema, not with lower urinary tract irritation. Her urine shows no casts.

BIncorrect

Pyelonephritis. Pyelonephritis produces loin pain and costovertebral angle tenderness, and often rigors and vomiting. Her tenderness is suprapubic, which localizes the problem to the bladder.

CCorrect

Cystitis. The triad of frequency, suprapubic pain and dysuria with pyuria in a young woman is acute cystitis. Escherichia coli is the most common organism, followed by Proteus, Klebsiella and Enterobacter. The short female urethra is why this is predominantly a disease of women, and diaphragm and spermicide use raises the risk further. Histology shows neutrophils and hyperemic mucosa, and biopsy is not required.

DIncorrect

Allergic interstitial nephritis. Allergic interstitial nephritis follows drug exposure and presents with rash, fever, eosinophilia and a rising creatinine. She is on no medications.

EIncorrect

Papillary necrosis. Papillary necrosis occurs in analgesic abuse, diabetes mellitus and sickle cell disease, and presents with sloughed papillae in the urine. It is not a one-day illness in a healthy young woman.

Question 8 of 11Case 4 · One day of burning · continued

Her symptoms recurred after treatment and persist. Three urine cultures have shown no growth. Cystoscopy shows mucosal fissures and punctate hemorrhages with no mass, and biopsy shows increased submucosal mast cells.

Before accepting a diagnosis of interstitial cystitis, the biopsy must exclude which of the following?

AIncorrect

Acute bacterial cystitis. Three sterile cultures over eight months exclude bacterial infection, and that is precisely what moved her out of the acute cystitis she had eight months ago.

BCorrect

Flat urothelial carcinoma in situ. Carcinoma in situ is high grade by definition, causes frequency, urgency, dysuria and suprapubic pain, and forms no mass, so it is clinically indistinguishable from interstitial cystitis. Untreated, 50 to 75% progress to muscle-invasive disease. Interstitial cystitis itself requires symptoms beyond six weeks, sterile cultures, fissures and punctate hemorrhages on distention, and mast cells in the submucosa, and the late ulcerative form shows a Hunner ulcer.

CIncorrect

Papillary urothelial carcinoma. A papillary tumor is exophytic and would have been seen at cystoscopy as frond-like projections into the lumen.

DIncorrect

Squamous cell carcinoma of the bladder. Squamous cell carcinoma is a mass-forming invasive tumor, usually ulcerated or fungating, and it would not have been missed at cystoscopy.

EIncorrect

Bladder diverticulum. A diverticulum is a structural outpouching visible on imaging. It causes stasis, infection and calculi, not this picture, and it is not a histologic diagnosis.

Question 9 of 11Case 5 · An invasive mass in the bladder wall

A 71-year-old man comes to the physician because of a 2-month history of malaise, weight loss and painless passage of blood in the urine. He has smoked for 45 years and worked for 20 years in a rubber processing plant. Cystoscopy shows a mass infiltrating the wall of the bladder, and a biopsy reveals high-grade urothelial carcinoma.

Which of the following pieces of information would most alter this patient’s prognosis?

AIncorrect

The size of the tumor. Size influences the risk of recurrence. It does not change the stage, and it is stage that carries the prognosis.

BCorrect

Invasion of the muscularis propria. The muscularis propria is the dividing line. Whether the tumor has reached it is what separates non-muscle-invasive from muscle-invasive disease, and that is what determines the stage. The extent of invasion and spread at the time of initial diagnosis is the single most important prognostic factor in bladder cancer. Nothing else on this list moves the tumor across that line.

CIncorrect

The number of pack years. Smoking is the leading risk factor and explains why he has this tumor. It says nothing about how the tumor will behave now that he has it.

DIncorrect

Multifocal tumor. Multifocality raises the risk of recurrence, which reaches 70% regardless because the whole urothelium was exposed to the same carcinogens. It does not change the stage.

EIncorrect

Results of urine cytology. Cytology confirms that a urothelial tumor exists somewhere in the tract. It says nothing about depth of invasion.

Question 10 of 11Case 5 · An invasive mass in the bladder wall · continued

Random biopsies from normal-appearing mucosa on the opposite wall show full-thickness cytologic atypia confined to the urothelium, with an intact basement membrane and no papillary architecture.

Which of the following is the most accurate statement about this second lesion?

AIncorrect

It is low grade and carries a low risk of progression. Grade climbs along the papillary route, from papilloma through low-grade to high-grade carcinoma. Flat carcinoma in situ does not climb, because it starts at the top.

BCorrect

It is high grade although it forms no mass. Flat carcinoma in situ is high grade by definition. It forms no mass, so cystoscopy can look near-normal or merely reddened, and 50 to 75% progress to muscle-invasive disease if untreated. This is the second of the two morphological routes: papillary lesions grow into the lumen as fronds with fibrovascular cores, while flat carcinoma in situ stays within the thickness of the urothelium.

CIncorrect

It represents reactive atypia following recent resection. Reactive atypia follows instrumentation and infection, but it is patchy and retains surface maturation. Full-thickness atypia with loss of maturation is not reactive.

DIncorrect

It has invaded the lamina propria. Invasion means the basement membrane has been breached. It is intact here, so this lesion is still confined to the urothelium.

EIncorrect

It is harmless while confined to the urothelium. Confinement is not reassurance. Carcinoma in situ is high grade from the start, and 50 to 75% progress to muscle-invasive disease.

Question 11 of 11Case 6 · Keratin pearls in the bladder

A 58-year-old man comes to the physician because of a 3-month history of painless passage of blood in the urine. He has never smoked and has never worked with dyes or rubber. As a child he swam daily in fresh water irrigation canals and recalls passing blood in the urine at that time. Urine culture shows no growth. Cystoscopy shows a fungating bladder mass with surrounding pale, thickened mucosa, and biopsy shows malignant squamous cells with keratin pearls.

Which of the following is the most likely risk factor for this presentation?

AIncorrect

Chronic bacterial cystitis caused by Escherichia coli. Escherichia coli causes acute cystitis, which resolves in days. Metaplasia is an adaptation to years of sustained injury, and the culture here shows no growth.

BCorrect

Chronic infection with Schistosoma haematobium. Schistosoma haematobium ova deposited in the bladder wall provoke chronic granulomatous inflammation. The urothelium turns squamous in response, that metaplastic epithelium becomes dysplastic, then carcinoma in situ, then invasive carcinoma with keratin pearls. The pale thickened mucosa around the tumor is the metaplasia itself. Freshwater exposure in an endemic region and childhood hematuria are the history to recognize, and where the parasite is endemic squamous carcinoma outnumbers urothelial carcinoma.

CIncorrect

Aryl amine exposure acting on the native urothelium. Aryl amines from textile, rubber and paint work drive urothelial carcinoma, acting on the native epithelium with no metaplastic step. He has had no such exposure, and this is Grace’s exposure rather than his.

DIncorrect

Carcinogens from cigarette smoke concentrated in urine. Smoking is the leading risk factor for urothelial carcinoma, again acting on the native epithelium directly. He has never smoked.

EIncorrect

Columnar metaplasia within a persistent urachal remnant. Columnar metaplasia in a urachal remnant is the background for the rare adenocarcinoma at the bladder dome. It produces glands, not keratin pearls, and this tumor is on the posterior wall.

Learning objectives

PATH.6035Distinguish the common renal tumors by age, etiology, risk factors, pathogenesis, clinical features and complications, including paraneoplastic syndromes and metastasis, and genetic basis.

PATH.6036Distinguish the common congenital anomalies of the bladder: urachal remnants and diverticulum.

PATH.6037Distinguish the two types of bladder inflammation, acute or chronic infectious cystitis and interstitial cystitis, by etiology, pathogenesis, clinical course and morphology.

PATH.6038Explain the risk factors, clinical features, classification and concept of microscopic staging of bladder cancer.

PATH.6039Distinguish morphologically the papillary and flat varieties of bladder cancer.