This document discusses renal parenchymal neoplasms, specifically renal cell carcinoma. Some key points: - Renal cell carcinoma (RCC) accounts for about 70% of primary malignant renal tumors and occurs most commonly in the 6th-7th decades of life, with a male to female ratio of 2:1. - Risk factors for RCC include smoking, obesity, acquired cystic kidney disease, and certain hereditary conditions like Von Hippel-Lindau syndrome. - RCC is often asymptomatic until late stages but can present with hematuria, flank pain, or a palpable renal mass. Metastases most commonly occur in the lungs. - Clear cell R

1. Renal Parenchymal
Neoplasms
Lara Masri

3. Renal Cell Carcinoma
• Renal cell carcinoma (RCC) accounts for 2–5% of adult
cancers
• Constitutes approximately 70% of all primary malignant
renal tumors
• RCC occurs most commonly in the sixth to seventh
decades
• Male:female ratio of 2:1
• Arises mostly from the upper pole

4. Etiology
 Most renal cell carcinomas (RCCs) occur sporadically.
 Approx. 4% of renal cell carcinomas are associated with hereditary factors.
 Both forms show structural alterations of the short arm of chromosome 3 (3p) and
subsequent alterations of the VHL gene.
Risk factors for sporadic RCC
1. Male
2. Smoking  twofold increase in risk  major risk factor for RCC
3. Obesity
4. Sickle cell disease  Renal Medullary Carcinoma
5. Acquired cystic kidney disease
6. Renal pelvic stones
7. Hypertension
8. Immunodeficiency
9. Chronic hepatitis C infection
10. Occupational exposure to: Asbestos, solvents, cadmium

6. • The risk of developing RCC has been estimated to be >30 times higher
in patients receiving dialysis who have cystic changes in their kidneys
than in the general population.
• RCC occurs in 3–9% of patients with acquired cystic disease of the
kidneys.
• Renal cell carcinoma is associated with a wide spectrum of
paraneoplastic syndromes, including polycythemia, thrombocytosis,
hypercalcemia, cachexia, pyrexia, hypertension, and hepatic
dysfunction
• Hypercalcemia is the most common paraneoplastic complication in
renal cell carcinoma  13%  due to production of a parathyroid
hormone-related peptide (PTHrP)
• Stauffer syndrome is a constellation of signs and symptoms of
liver dysfunction that arises due to presence of renal cell carcinoma

7. Hereditary renal cell carcinomas
• Von Hippel-Lindau syndrome: is a familial cancer syndrome
o Approx. 40% of patients with VHL syndrome develop renal cell carcinomas
(usuallyclear cell RCC).
o central nervous system (CNS) hemangiomas, retinal agniomas, and
pheochromocytoma
• Tuberous sclerosis
o 5% of people with tuberous sclerosis develop renal cell carcinomas (usually clear cell
RCC).
o RCC occurs more commonly in women.
o Associated with AMLs, Seizures, Development Delay.
• Birt-Hogg-Dube syndrome
o Inherited autosomal dominant condition caused by a mutation in the folliculin (FLCN)
gene on chromosome 17.
o Characterized by
 Skin lesions: fibrofolliculomas, benign hamartomatous tumors of hair follicles
 Lung cysts , spontenous pneumothorax
 Renal cell carcinoma (usually chromophobic ceal cell RCC or oncocytic RCC)

9. • Succinate dehydrogenase kidney cancer (SDH-RCC)
 Autosomal Dominant
 caused by a mutation in any of three succinate dehydrogeanse subunits, B, C, or D.
 Patients develop clear cell RCC, chromophobe RCC, type 2 papillary RCC, and
oncocytomas, paragangliomas, pheochromocytomas.
 Hereditary leiomyomatosis and renal cancer syndrome (HLRCC)
o Autosomal dominant condition caused by a mutated fumarate dehydrogenase gene
(FH) located on chromosome 1
o Characterized by cutaneous and uterine leiomyomas
o 15% develop type 2 papillary RCC
 Hereditary papillary renal cell carcinoma (HPRCC)
o Autosomal dominant condition with a high penetrance
o Caused by activating mutations of the MET proto-oncogene located on the long arm
of chromosome 7
o Usually associated with type 1 papillary RCC

11. Clinical features
 Usually asymptomatic in the early stages
 Patients become symptomatic when the tumor has reached a large size (usually > 10 cm)
and/or if metastases are present.
 Constitutional symptoms Weight loss, fatigue, Fever, night sweats , Anemia
 Symptoms caused by primary tumor  7-10% of pts
 Hematuria  60% of RCC patients
 Flank pain
 Palpable renal mass
 Patients may also present with dyspnea, cough, and bone pain that are typically
symptoms secondary to metastases.
Hematuria
Flank Pain
Palpable mass

12. Pathogenesis
Renal cell carcinomas are vascular tumors that tend to spread
either by
direct invasion through the renal capsule into perinephric fat
and adjacent visceral structures .
direct extension into the renal vein.
Approximately 20–25% of patients show evidence of metastatic
disease at presentation.
The most common site of distant metastases is the lung.
However, liver, bone (osteolytic), ipsilateral adjacent lymph nodes
and adrenal gland, brain, the contralateral kidney, and
subcutaneous tissue are frequent sites of disease spread

13. ▶ Tumor Staging and Grading

15. Pathology
Renal cell carcinomas are adenocarcinomas that usually arise from the epithelial cells of
the proximal convoluted tubule.
Clear Cell Renal Cell Carcinoma:
 Relative frequency :70%
 Cell of origin: Proximal convuoluted tubule
 Etiology: Sporadic or inherited mutation of VHL gene on chromosome 3p
 Macroscopic appearance: Yellow or golden due to high intracellular lipid
concentration
 Microscopic appearance:
 Clear cells
 Polygonal cells arranged as cords or tubules (non-papillary growth)
 Clear, glycogen and/or lipid-filled cytoplasm
 Unifocal, unilateral growth
 Prognosis: Depending on tumor stage

16. Papillary RCC ( Chromophilic)
Relative frequency : 10-15%
Cell of origin: Proximal convuoluted tubule
Etiology: Trisomy 7, 17, Loss of Y chromosome
Macroscopic appearance: Yellow or golden due to high intracellular
lipid concentration
Microscopic appearance:
•Cuboidal, low columnar cells
•Cells grow in papillary formations
•Bilateral, multifocal growth possible
Prognosis:
• Type 1 papillary RCC: better than type 2 papillary RCC
• Type 2 papillary RCC: aggressive tumor with a poor prognosis

17. Chromophobe RCC
Relative frequency : 5%
Cell of origin: cortical collecting duct
Etiology: Hypodiploidy, Birt-Hogg-Dube syndrome
Macroscopic appearance: Yellow or golden due to high intracellular
lipid concentration
Microscopic appearance:
•Large polygonal cells with a prominent cell membrane
•Eosinophilic cytoplasm
•Perinuclear halo
Prognosis: Excellent

18. Oncocytic RCC
Relative frequency : 1%
Cell of origin: cortical collecting duct
Etiology: unknown
Macroscopic appearance: Yellow or golden due to high intracellular
lipid concentration
Microscopic appearance:
• Originate from oncocytomas
• Similar to chromophobic RCC, but without perinuclear halo
• Cells occur as tumor nests
Prognosis: Excellent

19. Collecting duct carcinoma (Bellini duct carcinoma)
Relative frequency : 1%
Cell of origin: Medullary Collecting duct
Etiology: unknown
Macroscopic appearance: Yellow or golden due to high intracellular
lipid concentration
Microscopic appearance:
• Hobnail pattern: irregularly arranged malignant glandular cells
within a fibrous stroma
• Medullary duct carcinoma: A variant that is associated with sickle
cell disease
Prognosis: Aggressive with poor prognosis

21. Diagnostics
Laboratory studies and urinalysis
 Urinalysis
o Can show frank and microscopic hematuria
o Measure albumin: creatinine ratio if proteinuria is detected.
 Laboratory studies
o CBC
 Abnormal hemoglobin levels  normochromic anemia in 30%
 ↑ WBC and/or ↑ platelets
 ↓ serum iron, TIBC
 ↑ ESR in 75%, ↑CRP ( could be prognostic of recurrence)
o CMP
 Hypercalcemia
 ↑ AST, ALT, and/or ALP
 ↑ BUN:creatinine ratio

22. Imaging
Imaging Classification for Renal Lesions

24. Workup based on imaging findings
Findings Next steps
•Bosniak I and II cystic mass •Follow-up is usually not required
•Bosniak IIF cystic mass
•Repeat imaging at 6 and 12 months,
then yearly for a total of 5 years.
•Refer to urology if there is any change
in appearance or > 3 mm growth per
year.
•Bosniak III or IV cystic mass
•Solid mass > 1 cm with no fat
•Obtain CBC, BMP, and urinalysis.
•Refer to urology for consideration of
further investigations (e.g.,
staging, biopsy).

25. Ultrasonography
 98% accurate in distinguishing simple cysts from solid lesions.
 Strict ultrasonographic criteria for a simple cyst include through transmission, a
well-circumscribed mass without internal echoes, and adequate visualization of
a strong posterior wall
 Contrast-enhanced ultrasound using microbubbles, rather than a contrast
agent, can better visualize renal parenchyma and blood flow within and around
the tumor.
 This is useful in patients who may not receive contrast because of a severe
allergy or chronic kidney disease.
 Intraoperative ultrasonography is also often used to confirm the extent and
number of masses in the kidney at the time of performing a partial
nephrectomy

27. CT scanning
• A typical finding of RCC on CT is a mass that is enhanced with contrast media.
• In general, RCC exhibits an overall decreased density in hounsfield units
compared with normal renal parenchyma.
• Identify macroscopic fat in a renal mass
• Stage the patient by visualizing the renal hilum, perinephric space, renal vein
and vena cava, adrenal glands, regional lymph nodes, and adjacent organs.
• A CT scan of the chest is indicated in patients with equivocal chest x-ray findings.
• Patients who present with symptoms consistent with brain metastases should
be evaluated with either head CT or MRI.

29. MRI
 Renal masses are isointense to moderately hypointense on T1-weighted phases
 Hyperintense on T2-weighted phases.
 Its primary advantage is in the evaluation of patients with suspected macroscopic
fat or renal vein and vena cava involvement with tumor thrombus
 The use of gadolinium-based contrast in MRI can avoid the risks of contrast
nephropathy .
 However, in those with severe renal insufficiency (eGFR < 30 mL/min), there is a
significant risk of nephrogenic systemic fibrosis with gadolinium.
 The primary disadvantage of MRI is higher cost, longer duration, and patient
discomfort during the study

32. Biopsy of Renal Masses
• Renal mass biopsy should be considered if a mass is concerning for
metastatic, hematologic, infectious, or inflammatory etiology
• Should not be considered in otherwise young and healthy patients
that would undergo intervention anyway or older, frail patients that
are not planning to undergo intervention
• Establishing a diagnosis in patients who are not surgical candidates,
selecting patients undergoing active surveillance for small renal
masses, and evaluating radiographically indeterminate lesions.
• Biopsy should be considered primarily in those patients in whom the
results would change management.
• Core biopsy is more sensitive and specific than fine-needle
aspiration and is preferred.

33. Treatment
Approach
• Local or locoregional disease: curative treatment intent
• Standard of care: nephrectomy (partial or radical)
• Consider adrenalectomy, lymph node dissection, and adjuvant therapy with sunitinib
• Metastatic disease: mostly palliative treatment intent but may be curative for patients
with a solitary metastasis or oligometastatic disease
• Targeted and/or immunotherapy
• In selected patients, surgery (i.e., cytoreductive nephrectomy, metastasectomy) or
other local therapies (e.g., embolization)
• Consider active surveillance for patients with:
1. Solid masses < 2 cm
2. Complex masses that are predominantly cystic
3. limited life expectancy
4. High surgical risk

34. Medical therapy
 Targeted Therapy
1. VEGF receptor tyrosine kinase inhibitor  Pazopanib , Sunitinib, Sorafenib,
Cabozantinib, Tivozanib, Axitinib, Lenvatinib
2. Anti-VEGF antibodies  Bevacizumab
3. mTOR inhibitors  Everolimus, Temsirolimus
 Immunotherapy
1. Anti-PD-1 antibodies  Pembrolizumab, Nivolumab, Avelumab
2. Anti-CTLA-4 antibodies  Ipilimumab
3. Cytokines  Interleukin 2 , Interferon alpha

35. Surgery
 The following applies to patients with solid renal masses or renal cysts with Bosniak
classification III or IV.
 The approach may be open, robotic, or laparoscopic.
 Partial nephrectomy:
o Absolute indications: patients with a T1a renal mass , a solitary kidney, bilateral
masses, familial RCC, preexisting chronic kidney disease, or proteinuria
o Relative indications: patients who are young and/or have a longer life expectancy,
multifocal masses, or comorbidities that impact renal function
 Radical nephrectomy
o Removal of the entire kidney along with the adrenal gland and
surrounding perinephric fat, with or without lymph node dissection
o Preferred in patients with increased oncological risk

36. Radiochemotherapy
 Radiation therapy is not typically used because RCC is usually
radioresistant.
 Conventional chemotherapy is not used to treat RCC because RCC is highly
resistant to most chemotherapeutic agents.
Local therapies
 Thermal ablation (e.g., cryoablation): may be appropriate for patients with
tumors ≤ 3 cm and/or high surgical risk
 Embolization of the primary tumor and/or metastases: for symptom
control in patients with nonresectable disease

37. Complications caused by paraneoplastic syndromes
1. Secondary hypercortisolism: due to ectopic ACTH release
2. Secondary polycythemia: due to ectopic erythropoietin (EPO) secretion
3. Hypertension: due to the release of renin
4. Hypercalcemia: due to the release of PTHrP (parathyroid hormone-related protein)
5. Leukemoid reaction: due to bone marrow stimulation
6. Limbic encephalitis
1. Memory loss
2. Psychosis
3. Depression
Complications caused by local spread
• Varicocele
 Rare, classically associated with left-sided RCC
 Malignant cells grow inside the left renal vein and occlude the ostium of the left
gonadal vein.
• Budd-Chiari syndrome: caused by involvement of the IVC
 Lower limb edema
 Ascites
 Hepatic dysfunction

39. Complications caused by metastatic disease
 Spread beyond the renal capsule affects the lymph nodes of the renal hilum and para-
aortic nodes.
 Hematogenous spread occurs via renal vein and IVC.
• Pulmonary metastases: most common site of metastases
• Hemoptysis
• Dyspnea
• Bone metastases: second most common site of metastases
• Bone pain
• Pathological fractures
Reactive amyloidosis
RCC accounts for 25 to 42% of all reported AA amyloidosis cases caused by solid organ
malignancies.
Clinical features
1. Nephrotic syndrome
2. Primary adrenal insufficiency
3. Hepatosplenomegaly
4. Malabsorption

41. Angiomyolipoma
 Definition: benign renal tumors that arise from perivascular epithelioid cells and consist
of blood vessels, smooth muscle, and mature fat cells
 Most common benign renal tumor, F > M (4:1)
 Etiology
o Sporadic  usually unilateral
o Associated with :
 Tuberous sclerosis (TSC)  45-80%  bilateral , asymptomatic
 Sporadic lymphangioleiomyomatosis

42.  Diagnostics
o Abdominal ultrasound: round, well-circumscribed, highly echogenic
(similar echogenicity to renal pelvis) renal tumor often located near the renal
capsule (cause bulging )
o Abdominal CT
 Tumor with macroscopic fat deposits
 No calcification
 Treatment: Surgical resection of the tumor is indicated for angiomyolipomas that
measure > 4 cm in diameter AND symptomatic
 If < 4 cm  follow up with yearly CT or US
 If > 4cm asymptomatic  follow up semiannual US

44. Oncocytoma
 Definition: benign epithelial tumor arising from the intercalated tubular cells in
the collecting duct, 3-5% of renal masses, males > females
 May occur in adrenal, thyroid, salivary, parathyroid gland.
 Pathology
o Macroscopy: smooth, clearly defined brown tumor with central stellate scar
o Microscopy
 Large acidophilic cells
 Excessive amount of mitochondria → acidophilic, granular
eosinophilic cytoplasm (oncocytes)
 Treatment
o Often resected in order to exclude RCC
o Surveillance
o Nephrectomy in case of increase in tumor size
 Prognosis: Oncocytomas are not invasive, but they may transform into a malignant oncocytic
RCC