Course: IDPT 5005
University of Colorado Denver, School of Medicine
Francisco G. La Rosa, M.D. (Francisco.LaRosa@ucdenver.edu)
Associate Professor
TUMORS OF KIDNEY & URINARY TRACT
I.
LEARNING OBJECTIVES
1. List the most common benign and malignant tumors of the kidney and describe their most
important characteristics in regards to:
a. Incidence
b. Clinical features
c. Imaging features
d. Urinary findings
e. Gross pathology
f. Microscopic pathology
g. Staging and Prognosis
2. Understand the basic genetic differences between spontaneous and familial renal tumors.
3. Describe the most important benign and malignant tumors of the urinary tract, calyx, pelvis,
ureter, urinary bladder, and urethra.
II.
TUMORS OF THE KIDNEY
Both benign and malignant tumors occur in the kidney. With the exception of oncocytoma,
the benign tumors rarely cause clinical problems. Malignant tumors, on the other hand, are of great
importance clinically and deserve considerable emphasis. By far the most common of these
malignant tumors is renal cell carcinoma (RCC), followed by Wilms tumor, which is found in children
and will be discussed in a separate lecture, and finally urothelial tumors of the calyces and pelves.
Although some tumors that occur more commonly in adults may also occasionally be
encountered in children and vice versa, a broad separation of renal tumors according to patient age
is an arbitrary but widely accepted practice whose usefulness has been validated by many years of
experience. Most of the pathological categories of neoplasms have been documented as primary
tumors of the kidney, particularly in adults, but most tumors are carcinomas that conform to a rather
narrow range of histologic lesions differentiating in whole or in part toward renal tubular epithelial
structures.
A.
BENIGN TUMORS:
1. Renal Papillary Adenoma: Well circumscribed nodules within the cortex, 7 – 22 % at
autopsy, small (5 mm diameter). Surgically removed since they are considered “early
cancers.”
2. Renal Fibroma or Hamartoma (Renomedullary Interstitial Cell Tumor): Fibrous, less than 1
cm, within pyramids, no malignant tendency.
3. Angiomyolipoma: Vessels, smooth muscle and fat. 25 -50% in patients with tuberous
sclerosis.
4. Oncocytoma: Eosinophilic epithelial cells, numerous mitochondria, 5 – 15% of all renal
neoplasms. Some cases are familial.
5. Metanephric adenoma. Very rare, only one case in a child known to produce metastases.
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B.
MALIGNANT TUMORS:
In the broadest sense, most renal tumors could be classified as adenocarcinoma, but current usage
prefers the term renal cell carcinoma (RCC) to distinguish them. In the USA, renal cancer is the 7th
leading malignant condition among men and the 12th among women, accounting for 2.6 % of all
cancers. About 2% of cases of renal cancer are associated with inherited syndromes. In the USA,
more than 36,000 new cases of renal cancer are predicted to occur every year, many of which are
being discovered earlier because of the widespread availability of radiographic testing.
Nevertheless, more than 12,000 deaths from the disease are predicted to occur every year. RCC
arise from the renal epithelium and account for about 85 % of renal cancers. A quarter of the
patients present with advanced disease, including locally invasive or metastatic RCC. Moreover, a
third of the patients who undergo resection of localized disease will have a recurrence. Median
survival for patients with metastatic disease is about 13 months. Thus, there is a great need for
more effective surgical and medical therapies.
The biological behavior of RCC is generally malignant, but the few benign tumors in the group
cannot be distinguished by size alone. The classification of RCC has recently undergone revision,
based on correlative cytogenetic, genetic, and histologic studies of both familial and sporadic
tumors.
1. Clear Cell Carcinoma
 Incidence: Most common type, accounting for 70% to 80% of renal cell cancers (third most
common urologic malignancy, found in 3% of the adult population). Male to female ratio 3:1.
 Clinical:
o Hematuria.
o Renal mass may be incidental finding on imaging study.
o Arises in the renal cortex, has a propensity to invade the renal vein and can extend
into the inferior vena cava up to the heart.
o Regional lymph nodes may be enlarged. Hematogenous spread to lungs may occur,
too. Metastatic disease often as multiple nodules in the lungs.
 Imaging:
o Ball-like mass of renal cortex; tumor enhances less than normal parenchyma.
o Engorged, tumor-filled renal vein with extension to inferior vena cava.
o Look for metastatic disease.
 Pathology:
o Gross: Most often as single tumor (multifocal and bilateral in Von Hippel-Lindau
disease), somewhat spherical, yellowish gray mass, variegated appearance, focal
hemorrhage, 20% are cystic.
o Histology: In clear cell RCC three cell types are generally recognized -clear,
granular, and spindle. Most tumors are composed of clear cells, granular cells, or a
mixture of these two cell types. Nuclear grade of tumor cells is assigned according to
Fuhrman's criteria, and varies from 1 to 4. Nuclear grade in RCC is an important
independent predictor of survival; that is tumors of grades 1-2 carry a better
prognosis than tumors of grades 3-4. Spindle cell types or sarcomas tend to grow
and spread more quickly than the other kinds of RCCs. They can be associated with
any of subtype mentioned and this subtype portends poorer prognosis.
 Genetics:
o Current studies implicate the VHL gene in the development of both familial and
sporadic clear cell tumors.
a. Familial, associated with VHL (Von Hippel-Lindau) disease (4% of cases)
b. Most cases (95%) are sporadic.
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o

98% of tumors: loss of sequences on short arm chromosome 3 by deletion (3p-) or
by unbalanced chromosomal translocation (3;6, 3;8, 3;11) resulting in loss of
chromosome 3 spanning 3p12 to 3p26. This region harbors the VHL gene (3p25.3).
o A second nondeleted allele of the VHL gene shows somatic mutations or
hypermethylation-induced inactivation in about 80% of clear cell cancers, indicating
that the VHL gene acts as a tumor-suppressor gene in both sporadic and familial
cancers.
o VHL gene: encodes a protein that is part of a ubiquitin ligase complex involved in
targeting other proteins for degradation. Important among the targets of the VHL
protein is hypoxia-inducible factor-1 (HIF-1). When VHL is mutated, HIF-1 levels
remain high, and this constitutively active protein increases the transcription and
production of hypoxia-inducible, pro-angiogenic proteins such as VEGF and TGF-β1.
In addition, insulin-like growth factor-1, another VHL target, is upregulated. Thus,
both cell growth and angiogenesis are stimulated.
Prognosis: The average 5-year survival rate of patients with renal cell carcinoma is about
45% and up to 70% in the absence of distant metastases. With renal vein invasion or
extension into the perinephric fat, the figure is reduced to approximately 15% to 20%.
Nephrectomy has been the treatment of choice, but partial nephrectomy to preserve renal
function is being done with increasing frequency and similar outcome.
2. Papillary carcinoma (Chromophilic)
 Incidence: Represent 10% to 15% of renal cancers.
 Pathology:
o Gross: Unlike clear cell RCCs, papillary carcinomas are frequently multifocal.
o Histology: Papillary growth pattern.
 Genetics: Occurs in both familial and sporadic forms. Not associated with 3p deletions.
o Most common cytogenetic abnormalities are trisomies 7, 16, and 17 and loss of Y in
male patients in the sporadic form, and trisomy 7 in the familial form.
o The gene for the familial form has been mapped to a locus on chromosome 7 (MET
locus, a protooncogene that serves as the tyrosine kinase receptor for hepatocyte
growth factor). This gene has also been shown to be mutated in a proportion of the
sporadic cases of papillary carcinoma.
 Prognosis: Better than clear cell RCC.
3. Chromophobe Renal Carcinoma
 Incidence: Represents 5% of renal cell cancers
 Pathology: Cells with prominent cell membranes and pale eosinophilic cytoplasm, usually
with a halo around the nucleus. Histologic distinction from oncocytoma can be difficult.
 Genetis: multiple chromosome losses and extreme hypodiploidy. They are, like the benign
oncocytoma, thought to grow from intercalated cells of collecting ducts.
 Prognosis: Excellent compared with that of the clear cell and papillary cancers; similar to
oncocytomas.
4. Collecting Duct (Bellini duct) Carcinoma
 Incidence: Represents approximately 1% or less of renal epithelial neoplasms. They arise
from collecting duct cells in the medulla.
 Pathology: Nests of malignant cells enmeshed within a prominent fibrotic stroma, typically in
a medullary location.
 Genetics: A number of chromosomal losses and deletions have been described for this
tumor, but a distinct pattern has not been identified.
 Prognosis: Associated with aggressive behavior and poor prognosis. For the majority of
patients surgical treatment will not result in a cure. Previously recommended chemotherapy
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and/or immunotherapy appear to have a limited role in treatment of this disease, and early
detection may be the best method for prolonging patient survival.
5. Familial RCC:
 Incidence:
o Although they account for only 4% of renal cancers, familial variants have been
enormously instructive in studying renal carcinogenesis.
 Von Hippel-Lindau (VHL) syndrome: 1/2 to 2/3 of VHL patients:
o hemangioblastomas of the cerebellum and retina
o develop renal cysts and bilateral, often multiple, renal cell carcinomas (nearly all, if
they live long enough)
o Current studies implicate the VHL gene in the development of both familial and
sporadic clear cell tumors.
 Hereditary (familial) clear cell carcinoma, confined to the kidney, without the other
manifestations of VHL but with abnormalities involving the same or a related gene.
 Hereditary papillary carcinoma. This autosomal-dominant form is manifested by multiple
bilateral tumors with papillary histology. These tumors exhibit a series of cytogenetic
abnormalities and, as will be described, mutations in the MET protooncogene.
C.
STAGING MALIGNANT RENAL TUMORS
The most important factor in predicting prognosis is the stage. The stage describes the cancer's
size and how deeply it has spread beyond the kidney. The Staging System of the American Joint
Committee on Cancer (AJCC) is sometimes known as TNM system. The letter T followed by a
number from 1 to 3 describes the tumor's size and spread to nearby tissues. Higher T numbers
indicate a larger tumor and/or more extensive spread to tissues near the kidney. The letter N
followed by a number from 0 to 2 indicates whether the cancer has spread to lymph nodes near the
kidney and, if so, how many are affected. The letter M followed by a 0 or 1 indicates whether or not
the cancer has spread to distant organs (for example, the lungs or bones) or to lymph nodes that
are not near to the kidneys.
1. Stage I: The tumor is 7 cm (about 2 3/4 inches) or smaller, and limited to the kidney. There is
no spread to lymph nodes or distant organs.
2. Stage II: The tumor is larger than 7.0 cm but still limited to the kidney. There is no spread to
lymph nodes or distant organs.
3. Stage III: There are several combinations of T and N categories that are included in this
stage. These include tumors of any size, with or without spread to fatty tissue around the
kidney, with or without spread into the large veins leading from the kidney to the heart, with
spread to one nearby lymph node, but without spread to distant lymph node or other organs.
Stage III also includes tumors with spread to fatty tissue around the kidney and/or spread into
the large veins leading from the kidney to the heart, that have not spread to any lymph nodes or
other organs.
4. Stage IV: There are several combinations of T, N, and M categories that included in this
stage. This stage includes any cancers that have spread directly through the fatty tissue and the
fascia ligament-like tissue that surrounds the kidney. Stage IV also includes any cancer that has
spread to more than one lymph node near the kidney, to any lymph node not near the kidney, or
to any other organs such as the lungs, bone, or brain.
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T, N, M categories and stage groupings
T - Primary tumor:
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TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
T1: Tumor 7 cm or less, limited to kidney
T2: Tumor greater than 7 cm, limited to kidney
T3: Tumor extends into major veins/adrenal/perinephric tissue; not beyond Gerota's
fascia
T3a: Tumor invades adrenal/perinephric fat
T3b: Tumor extends into renal vein(s) or vena cava below diaphragm
T3c: Tumor extends into vena cava above diaphragm
T4: Tumor invades beyond Gerota's fascia
N - Regional lymph nodes:
 NX: Regional nodes cannot be assessed
 N0: No regional lymph node metastasis
 N1: Metastasis in a single regional lymph node
 N2: Metastasis in more than one regional lymph node
M - Distant metastasis:
 MX: Distant metastasis cannot be assessed
 M0: No distant metastasis
 M1: Distant metastasis
III.
TUMORS OF THE URINARY TRACT
About 95% of urinary tract tumors are of epithelial origin, the remainder being mesenchymal
tumors. Most epithelial tumors are composed of urothelial (transitional) type cells and are thus
interchangeably called urothelial or transitional tumors, but squamous and glandular carcinomas
also occur. A small number of benign neoplasias of the urinary tract are represented by small
tumors generally of mesenchymal origin. The two most common are fibroepithelial polyps and
leiomyomas. The fibroepithelial polyp is a tumor-like lesion that grossly presents as a small mass
projecting into the lumen. The lesion occurs more commonly in the ureters (left more often than
right) but may also appear in the bladder, renal pelves, and urethra. The polyp presents as a loose,
vascularized connective tissue mass lying beneath the mucosa.
A.
TRANSITIONAL CELL NEOPLASMS

Incidence: 80% patients between 50 -80 years. Male to female ratio 3:1. More frequent in
urban areas. Fifty to 80% of all bladder cancers are in smokers. Industrial exposure to
acrylamides (2-snaphthylamine). Schistosoma haematobium infections in Egypt and Sudan.
Exposure to radiation.

Clinical:
o Comprise more than 90% of tumors that arise from the urinary tract, other cell types
include squamous cell and adenocarcinomas.
o Clinical presentation includes hematuria and irritative bladder symptoms such as
dysuria, urinary frequency and urgency.
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o
o
o
o
The hematuria may be episodic, gross or microscopic. May be an incidental finding
on urinalysis.
TCC may arise from the renal calyces, pelvis, ureters, bladder, urethra and
urothelium lined ducts in the prostate.
The tumor can extend to the pelvic sidewalls and metastases can go to the lungs,
bones and liver.
The tumor can cause ureteral obstruction leading hydronephrosis, unilateral or
bilateral depending on its location.

Imaging:
o Multiple modalities, CT, MRI, cystography, IVP can demonstrate the tumor
o Tumors appear as filling defects in the urinary tract.
o Appearance depends on the size of the tumor and whether it is polypoid or sessile

Pathology: The gross patterns of urothelial cell tumors vary from purely papillary to nodular
or flat. The tumors may also be noninvasive or invasive. The level of invasion has prognosis
significance and can involve the lamina propria, muscularis propria, peri-cystic fat tissue and
other organs. Papillary lesions appear as red, elevated excrescences varying in size from
less than 1 cm in diameter to large masses more than 5 cm in diameter. Multicentric origins
may produce separate tumors. The histologic changes encompass a spectrum from benign
papilloma to highly aggressive anaplastic cancers. Overall, the majority of papillary tumors
are low grade. Most arise from the lateral or posterior walls at the bladder base.

Genetics: There is no familial tendency.

Prognosis: Depending on grade and stage.

Grading of Urothelial (Transitional Cell) Tumors (WHO/ISUP Grades):
- Urothelial papilloma (benign)
- Urothelial neoplasm of low malignant potential (Grade 0)
- Papillary urothelial carcinoma, low grade (Grade 1)
- Papillary urothelial carcinoma, high grade (Grades 2 and 3)

Staging of Bladder Carcinoma, AJCC/UICC (Depth of Invasion):
Noninvasive, papillary (Ta)
Carcinoma in situ (noninvasive, flat) (Tis)
Lamina propria invasion (T1)
Muscularis propria invasion (T2)
Microscopic extra-vesicle invasion (T3a)
Grossly apparent extra-vesicle invasion (T3b)
Invades adjacent structures (T4)

Therapy: BCG, Electrocautery, Surgery
REFERENCES
-
Chapters 20 & 21. Kumar, Robbins and Cotran: Pathologic Basis of Disease, 7th ed. WB
Saunders Co. Online: http://www.mdconsult.com/das/book/body/94286448-2/0/1249/0.html
Urological Pathology by William M. Murphy, Saunders, 2nd Edition, 1997, pp. 442-502
Herbert T. Cohen HT, McGovern FJ. Renal-Cell Carcinoma. N Engl J Med 2005;353:2477-90.
http://medinfo.ufl.edu/~bms5191/renal/renal.html
http://library.med.utah.edu/WebPath/RENAHTML/RENALIDX.html
http://www.uchsc.edu/pathology/smallgroups/renal/
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Disclaimers:
1. The primary goal of this chapter is to study the learning objectives outlined at the beginning of
this handout. The material to study is provided in the lectures, the handouts and the
recommended textbooks. All these sources provide the content over which you will be tested.
The lectures are intended to provide broad information of the material found in the textbooks and
handouts, and to give the students the opportunity to ask questions on subjects not clear in the
texts. The handouts do not seek to follow up the sequence of the lectures, and most importantly,
they are not a surrogate of the books.
2. The text presented in this handout has been edited by Dr. La Rosa from material found in your
books, from published articles and other educational works. This handout is solely for
educational purpose and not intended for commercial or pecuniary benefit (see USA Copyright
Law, Section 110, “Limitations on exclusive rights: Exemption of certain performances and
displays”). Reproduction and use of this handout can be done only for educational use.
[Download] the USA Copyright Law version, October 2009.
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