Neoplasms of the Kidney ▪ Von Hippel Lindau (VHL) syndrome
**most common malignant tumor: renal cell carcinoma, Wilms tumor, and
urothelial carcinoma of the calyces and pelvis
BENIGN NEOPLASMS
A. Renal Papillary Adenoma
• Small discrete adenomas arising from renal tubular epithelium
o Found commonly (7-22%) at autopsy
o MC papillary (“papillary adenomas”)
• Morphology
o < 1.5 cm d
o Present invariably within the cortex and appear grossly as
pale-yellow gray discrete well-circumscribed nodules
o Complex branching papillomatous structures with
numerous complex fronds
▪ Cells may also grow as tubules, glands, cords, and
sheets
▪ Cuboidal to polygonal shape
▪ Regular small central nuclei
▪ Scanty cytoplasm
▪ No atypia
o By histologic criteria, these tumors do not differ from low
grade papillary RCC and share some immunohistochemical
and cytogenic features (trisomy 7 and 17) with papillary
cancers
o Tumor size – prognostic (> 3 cm metastasize)
B. Angiomyolipoma
• Consists of vessels, smooth muscle, and fat from perivascular
epithelioid cells
• Present in 25-50% patients with tuberous sclerosis
o Disease caused by loss of function mutations in the TSC1 or
TSC2 tumor suppressor genes
o Characterized by lesions of the cerebral cortex that produce
epilepsy and intellectual disability, skin abnormalities, and
unusual benign tumors (eg heart)
• Susceptible to spontaneous hemorrhage
C. Oncocytoma
• Epithelial neoplasm composed of large eosinophilic cells with
small round benign-appearing nuclei that have large nucleoli
o Numerous mitochondria
• Arise from intercalated cells of collecting ducts
• 5-15% of renal neoplasms
• Grossly tan or mahogany-brown, homogenous, and well-
encapsulated with a central scar in 1/3 cases
o Up to 12 cm diameter
• Familial cases are multicentric (not solitary)
MALIGNANT NEOPLASMS
A. Renal Cell Carcinoma
• Epidemiology and Etiology
o 3% of all newly diagnosed cancers in the US and 85% of
renal cancers in adults
o 65000 new cases per year and 13000 deaths
o MC in elderly (6th-7th decade), males > females
o Most significant risk factor: tobacco
o Other risk factors: obesity (in women), hypertension,
unopposed estrogen therapy, and exposure to asbestos,
petroleum, and heavy metals
o Increased risk in patients with ESRD, CKD, acquired cystic
disease, and tuberous sclerosis
o MC sporadic, but unusual forms of AD familial cancers occur
(MC in younger individuals)
- 1/2 to 2/3 patients with VHL develop renal cysts
and bilateral multiple RCCs
- VHL gene implicated in both familial and sporadic
clear cell carcinomas
▪ Hereditary leiomyomatosis and renal cancer cell
syndrome
- AD; d/t mutation of FH gene – expresses fumarate
hydratase
- Cutaneous and uterine leiomyomata and
aggressive papillary carcinoma (metastatic)
▪ Hereditary papillary carcinoma
- AD; multiple bilateral papillary tumors
- MET proto-oncogene mutation
▪ Birt-Hogg-Dube syndrome
- AD; mutation of BHD gene – expresses folliculin
- Skin (fibrofolliculomas, trichodiscomas, and
acrochordons), pulmonary (cysts or blebs), and
renal tumors
• Classification
1. Clear cell carcinoma
o MC (70-80%) of renal cell cancers
o Cells with clear/granular cytoplasm; non-papillary
o Familial or sporadic (95%)
o 98% associated with loss of sequences on the short arm of
chromosome 3
▪ Deleted regions harbors the VHL gene
▪ A second non-deleted allele of the VHL gene shows
somatic mutations or hypermethylation-induced
inactivation
- VHL acts as a TSG in both sporadic and familial
cancers
▪ VHL gene – encodes a protein that is part of a ubiquitin
ligase complex involved in targeting other proteins for
degradation
- 1 important target: hypoxia inducible factor 1
(HIF-1)
- When VHL is inactive, HIF-1 levels remain high and
cause inappropriate expression of genes
promoting angiogenesis (VEGF) and genes
stimulating cell growth (IGF-1)
- HIF collaborates in complex ways with the
oncogenic factor MYC to reprogram cell
metabolism in ways that favor growth
o Mutations in genes regulating histone modifications
(epigenome dysregulation)
2. Papillary carcinoma
o 10-15% of renal cancers
o Papillary growth pattern
o Familial or sporadic
o Trisomy 7 and 17
▪ Sporadic: loss of Y in male patients
▪ Familial: trisomy 7
- Gene: MET (encoder of tyrosine kinase receptor
for hepatocyte growth factor / scatter factor
which mediates growth, cell mobility, invasion,
and morphogenetic differentiation)
o MC multifocal
3. Chromophobe carcinoma
o 5% of renal cancers
 o Composed of cells with prominent cell membrane and pale
eosinophilic cytoplasm (usually with a halo around the
nucleus)
o Cytogenetics: multiple chromosome losses and extreme
hypodiploidy
o Grow from intercalated cells of collecting ducts (d/dx:
benign oncocytoma)
o Excellent prognosis
4. Xp11 translocation carcinoma
o Genetically distinct subtype of RCC
o Occurs in young patients
o Translocations of TFE3 gene located at Xp11.2
▪ Overexpression of TFE3 transcription factor
o Cells with clear cytoplasm and papillary architecture
5. Collecting (Bellini) duct carcinoma
o < 1% of renal epithelial neoplasms
o Arise from collecting duct cells in the medulla
o Malignant cells forming glands enmeshed with a prominent
fibrotic stroma
o D/dx: medullary carcinoma – morphologically similar; seen
in patients with sickle cell trait
• Morphology
o RCCs may arise in any portion of the kidney (MC affect the
poles)
o Sarcomatoid changes arise infrequently in all types of RCC
(ominous)
o Clear cell carcinomas
▪ MC arise from PCT epithelium
▪ Solitary unilateral
▪ Bright yellow-gray-white spherical masses of variable
size that distort the renal outline
- Yellow – prominent lipid accumulation
- Gray-white – necrosis and foci of hemorrhagic
discoloration
▪ Margins sharply defined and confined within the renal
capsule
▪ Growth pattern varies from solid to trabecular
(cordlike) or tubular
▪ Cells have a rounded or polygonal shape and abundant
clear/granular cytoplasm (with glycogen and lipids)
▪ Delicate branching vasculature
▪ Cystic and solid areas
▪ Mostly well-differentiated but some have nuclear
atypia with bizarre nuclei and giant cells
▪ With enlargement, may bulge into the calyces and
pelvis and eventually fungate through the walls of the
collecting system to extend into the ureter
▪ (+) tendency to invade the renal vein – may grow as a
solid column of cells extending up to the IVC and
sometimes the right side of the heart
o Papillary carcinomas
▪ Arise from DCT
▪ Multifocal and bilateral
▪ Hemorrhagic and cystic (especially when large)
▪ Tumor is composed of cuboidal or low columnar cells
arranged in papillary formations
▪ Interstitial foam cells are common in papillary cores
▪ +/- Psammoma bodies
▪ Stroma scanty but highly vascularized
o Chromophobe renal carcinoma
▪ Pale eosinophilic cells often with perinuclear halo
▪ Arranged in solid sheets with a concentration of the
largest cells around the blood vessels
o Collecting duct carcinoma
▪ Rare; irregular channels lined by highly atypical
epithelium with a hobnail pattern
• Clinical Features
o Classic: costovertebral pain, palpable mass, and hematuria
▪ All 3 are seen in only 10% cases
o Most reliable clue: hematuria
▪ Usually intermittent and may be microscopic – tumor
may remain silent until it reaches a size of > 10 cm,
wherein it is associated already with constitutional sx
(fever, malaise, weakness, weight loss)
- Increasingly detected incidentally
o RCC – one of the great mimics in medicine – diversity of
symptoms not related to the kidney
▪ Constitutional symptoms
▪ Syndromes d/t abnormal hormone production
(polycythemia, hypercalcemia, hypertension, hepatic
dysfunction, feminization, masculinization, Cushing
syndrome, eosinophilia, leukemoid reactions, and
amyloidosis)
▪ Tendency to metastasize widely before giving rise to
any local s/sx
- In 15% new patients with RCC, (+) radiologic
evidence of mets at time of presentation
- MC mets to lungs (>50%), bones (33%), and
regional LNs, liver, adrenals, and brain
▪ 5-yr SR: 70-100% in the absence of distant mets (60%
with renal vein invasion or extension into perinephric
fat)
• Treatment
o Radical nephrectomy – treatment of choice
o Nephron-sparing surgery recommended for T1a tumors (<
4cm) and large tumors when technically feasible
o Drugs that inhibit VEGF and various tyrosine kinases are
used as an adjunct to therapy for metastatic disease
B. Urothelial Carcinoma of the Renal Pelvis
o 5-10% of primary renal tumors originate from the
urothelium of the renal pelvis
▪ Range from apparently benign papillomas to invasive
urothelial (transitional cell) carcinomas
o Renal pelvic tumors usually become clinically apparent
within a relatively short time, because they lie within the
pelvis, and by fragmentation, produce noticeable
hematuria
▪ Invariably small when discovered
▪ May block urinary outflow and lead to palpable
hydronephrosis and flank pain
o Urothelial tumors may occasionally be multiple, involving
the pelvis, ureters, and bladder
▪ In 50% renal pelvic tumors, there is a pre-existing or
concomitant bladder urothelial tumor
▪ Histology: foci of atypia or carcinoma in situ in grossly
normal urothelium remote from the pelvic tumor
o Increased incidence in individuals with Lynch syndrome
o Infiltration of the wall of the pelvis and calyces is common
▪ Despite their apparently small, deceptively benign
appearance, prognosis is poor
▪ 5-yr SR: 50-100% for low-grade non-invasive lesions,
and 10% for high-grade infiltrating tumors