This document summarizes renal cell carcinoma (RCC). It originates in the renal cortex and arises mostly from the upper pole, accounting for 80-85% of primary renal tumors. RCC is classified based on morphology and genetics. Risk factors include smoking, obesity, and genetic syndromes. Symptoms include hematuria but often presents without symptoms. Diagnosis involves imaging like CT or MRI. Treatment of localized RCC is typically radical nephrectomy. For advanced or metastatic RCC, options include immunotherapy, targeted therapy, and radiation.

1. RENAL CELL CARCINOMA
-MANOJIT SARKAR
FINAL PROF
MLDMC&H

2. • Originates within the renal cortex.
• Arises mostly from the upper pole.
• Responsible for 80% to 85% of all primary renal
tumours.
• Transitional cell carcinomas of the renal pelvis are the
next most common (∼8%) renal neoplasms.
• Nephroblastoma or Wilms' tumor is common in
children (5%-6% of all primary renal tumors).

3. Classification of renal tumour
Benign
Cyst
Leiomyoma
Lipoma
Hemangioma
Angiomyolipoma
Adenoma
Juxtraglomerular cell tumour
Malignant
• RCC
• Transitional Cell Ca
• Oncocytoma
• Sarcoma
• Lymphoma
• Metastasis(Lung, Breast,
GIT,Prostate, Pancreas,
Melanoma)

4. Aetiology
• Males are affected twice as commonly as
females
• Peak incidence of sporadic RCC is 6th to 8th
decade.

5. Studies have shown associations with
Environmental
• urban dwelling
• low socio-economic status
• tobacco chewing
• smoking cigarettes, pipe, or cigars
• renal failure and dialysis (30-fold risk)
• obesity
• hypertension
• asbestos exposure
• the analgesic phenacitin
• thorium dioxide

6. Nutrition
• Asian migrants to Western countries are at
increased risk of RCC;
• Vitamins A, C, E, and fruit/vegetable
consumption are protective.

7. Anatomical risk factors include
Polycystic kidneys Horseshoe kidneys

8. Numerous conditions predispose to renal cell
cancer, including
• von Hippel-Lindau syndrome (cerebellar
hemangioblastomas, retinal angiomatosis, and
bilateral renal cell carcinoma),
• tuberous sclerosis, and
• acquired renal cystic disease developing in
patients with end-stage renal disease

9. Genetic
von Hippel Lindau (VHL) syndrome
• 50% of individuals with this autosomal dominant syndrome,
• characterized by phaeochromocytoma, renal and pancreatic
cysts, and cerebellar haemangioblastoma,
• develop RCC, often bilateral and multifocal.
• Patients typically present in 3rd, 4th, or 5th decades.
• VHL syndrome occurs due to loss of both copies of a tumour
suppressor gene at chromosome 3p.

10. • Inactivation of the VHL gene leads to effects on gene
transcription, including dysregulation of hypoxia
inducible factor 1 (HIF-1), an intracellular protein that
plays an important role in the cellular response to
hypoxia and starvation.
• This results in upregulation of vascular endothelial
growth factor (VEGF), the most prominent angiogenic
factor in RCC, explaining why some RCCs are highly
vascular.

11. • A papillary variant of RCC also has an autosomal dominant
familial component,
• characterized by trisomy 7 and 17,
• with activation of the c-MET proto-oncogene.
• c-MET encodes the receptor tyrosone kinase for
hepatocyte growth factor, which regulates epithelial
proliferation and differentiation in a wide variety of organs,
including the normal kidney.

12. Histologically, RCC is most often
• A Mixed Adenocarcinoma Containing Clear
Cells,
• Granular Cells, And,
• Occasionally, Sarcomatoid-appearing Cells.
The classifications of the subtypes of RCC are
based on morphology and cytogenetic
characteristics.

13. • Most RCCs are classified into 1 of the following
Histologic Subtypes:
• Conventional Clear Cell,
• Papillary (Chromophilic),
• Chromophobe,
• Collecting Duct,
• Neuroendocrine, And
• Unclassified.

14. Benign renal tumors are
• Papillary Adenoma,
• Renal Oncocytoma, And
• Metanephric Adenoma.

15.  Clear cells are rounded or
polygonal with abundant
cytoplasm, which contains
cholesterol, triglycerides, glycogen,
and lipids.
 The cells present in the papillary
(chromophilic) typecontain less
glycogen and lipids, and electron
microscopy reveals that the
granular cytoplasm contains many
mitochondria and cytosomes.
• Chromophobe-type
carcinomas contain large
polygonal cells with
distinct cell borders and
reticulated cytoplasm,
which can stain diffusely
withHale’s colloidal iron .

16.  Oncocytic RCC or oncocytomas
tend to have cytoplasm packed
with mitochondria, giving it a
granular appearance.
o Collecting duct tumors tend to
have irregular borders and a
basophilic cytoplasm with
extensive anaplasia
o likely to invade blood vessels
and cause infarction of tissue.
 Sarcomatoid cells are
spindle-shaped and form
sheets or bundles.
 This later cell type rarely
occurs as a pure form and is
most commonly a small
component of either the
clear cellor papillary cell
type (or both).

17. Clinical Findings
Symptoms and Signs
• Painless gross or microscopic hematuria throughout the urinary stream ("total
hematuria") occurs in 60% of patients.
• The degree of hematuria is not necessarily related to the size or stage of the
tumor.
• A triad of hematuria, flank pain, and a palpable flank mass suggests renal
cell carcinoma, fewer than 10% of patients will be present.
• Both pain and a palpable mass are late events occurring only with tumors that
are very large or invade surrounding structures or when hemorrhage into the
tumor has occurred.
• Symptoms due to metastases may be the initial complaint (eg, bone pain,
respiratory distress).

18.  Paraneoplastic syndromes are
common in renal cell carcinoma
and are often what suggests the
diagnosis.
These syndromes include
• hypercalcemia,
• erythrocytosis,
• hypertension, fever of unknown
origin,
• anemia, and
• hepatopathy (Stauffer's
syndrome).
 Renal cell carcinoma has a predilection
for producing occlusive tumor thrombi in
the renal vein and the inferior vena cava
(particularly from the right), manifested
by signs of lower extremity edema and
acute scrotal varicocele when occluding
the left renal vein.
 This phenomenon of inferior vena cava
thrombus occurs in approximately 5% to
10% of patients.
 Occasionally, the tumor thrombus
reaches up through the inferior vena cava
to the right atrium.

19. RCC is known to produce a multitude of other biologically
active products that result in clinically significant syndromes,
including
• adrenocorticotropic hormone (Cushing’s syndrome),
• enteroglucagon (protein enteropathy),
• prolactin (galactorrhea),
• insulin (hypoglycemia), and
• gonadotropins (gynecomastia and decreased libido; or
hirsutism, amenorrhea, and male pattern balding).

20. Laboratory Findings
• Microscopic urinalysis reveals hematuria in most patients.
• The erythrocyte sedimentation rate may be elevated but is
nonspecific.
• Elevation of the hematocrit and levels of serum calcium, alkaline
phosphatase, and aminotransferases occur in less than 10% of
patients. These findings nearly always resolve with curative
nephrectomy and thus are not usually signs of metastases.
• Anemia unrelated to blood loss occurs in 20% to 40% of patients,
particularly those with advanced disease.

21. Imaging Studies
• The diagnosis of renal cell carcinoma is often made by CT
(and, less frequently, by intravenous urography)
performed as an initial step in the workup of hematuria,
an enigmatic metastatic lesion, or suspicious laboratory
findings.
• Ultrasonography and CT scan often reveal incidental
renal masses, which now account for 50% of the initial
diagnoses of renal cancer in patients without
manifestations of renal disease.

22. • Plain abdominal x-rays may reveal a calcified renal mass, but only 20%
of renal masses contain demonstrable calcification. (Twenty percent of
masses with peripheral calcification are malignant; over 80% with
central calcification are malignant.)
• The initial technique for workup of hematuria is currently CT
urography; intravenous urography alone defines only 75% of renal
mass lesions.
• Differentiation of the most common renal mass (ie, a simple benign
cyst) can be made by the finding of a radiolucent center with a thin
wall and a sharp interface between the mass and the renal cortex (the
typical "beak sign" of a cortical cyst).

23. • Ultrasonography: Further definition of all renal masses
seen on intravenous urography is required. Occasionally,
some masses detected on CT require further
characterization by ultrasound. Abdominal
ultrasonography can define the mass as a benign simple
cyst or a solid mass in 90% to 95% of cases. Abdominal
ultrasound can also identify a vena caval tumor thrombus
and its cephalad extent in the cava.

24. • Isotope Scanning: Occasionally, a renal mass is suspected
on intravenous urography but is equivocal or not seen on
ultrasound. In these cases, a renal cortical isotope
scanning agent such as technetium-99m DMSA is helpful.
Isotope scans of a renal tumor or cyst show an area of
decreased uptake, whereas an area of increased uptake
indicates a renal "pseudotumor" or a hypertrophied
column of Bertin.

25. • CT Scan: CT scan is the diagnostic procedure of choice when a
solid renal mass is noted on ultrasound. CT scan accurately
delineates renal cell carcinoma in over 95% of cases. Over 80%
of tumors are enhanced by iodinated contrast medium,
reflecting their high vascularity.
CT scan is also helpful in local staging and can reveal tumor
penetration of perinephric fat; enlargement of local hilar lymph
nodes, indicating metastases; or tumor thrombi in the renal vein
or inferior vena cava. CT angiography can delineate the renal
vasculature, which is helpful in surgical planning for partial
nephrectomies.
• .

26. • MRI: MRI is not more accurate than CT and is much more
expensive.
• It is, however, the most accurate noninvasive means of
detecting renal vein or vena caval thrombi.
• MRI has become one of the primary techniques for staging
solid renal masses.
• Magnetic resonance angiography (MRA) has become
particularly useful for mapping the blood supply and the
relationship to adjacent structures in candidates for partial
nephrectomy

27. Other Diagnostic or Staging Techniques:
• Isotopic bone scanning is useful in patients with bone pain, elevated
alkaline phosphatase, or known metastases.
• Chest x-ray is sufficient if negative, but if equivocal, then CT scan of the
chest can be used to detect metastases.
• There are currently no tumor markers specific for renal cell carcinoma.
• Occasionally, aspiration cytology of the mass can be useful in an
enigmatic case.
• The diagnosis is most often made by noninvasive means, and needle
aspiration is required only in indeterminate cases (< 10%).

28. • Differential Diagnosis: A variety of lesions in the retroperitoneum and
kidney other than renal cysts may simulate renal cancer.
• These include lesions due to
• hydronephrosis,
• adult polycystic kidney disease,
• tuberculosis,
• xanthogranulomatous pyelonephritis,
• metastatic cancer from another primary cancer,
• angiomyolipoma or other benign renal tumors, or adrenal cancer and
• retroperitoneal lipomas, sarcomas, or abscesses.

29. • In general, the radiographic, MRI, or ultrasonographic
techniques described previously should make the differentiation.
• Hematuria may be caused by renal, ureteral, or bladder calculi;
renal pelvis, ureteral, or bladder tumors; or many other benign
conditions usually delineated by the studies described.
• Cystoscopy is obligatory in hematuric patients with a normal CT
scan or intravenous urogram to rule out disease of the bladder
and to determine the source of the hematuria.

31. TREATMENT
Localized disease—
• Surgical removal of the early-stage lesion remains the
only potentially curative therapy available for RCC
patients.
• Appropriate therapy depends almost entirely on the
stage of tumor at presentation and therefore requires a
thorough staging evaluation.
• The prognoses of patients with stages T1-T3a disease are
similar following radical nephrectomy.

32. • Radical nephrectomy is the primary
treatment for
localized RCC. Its goal is to achieve
the removal of tumor and to take a
wide margin of normal tissue.
• Radical nephrectomy entails en
bloc removal of the kidney and its
enveloping fascia (Gerota’s)
including the ipsilateral adrenal,
proximal one-half of the ureter, and
lymph nodes up to the area of
transection of the renal vessels.

33. • Preoperative renal artery embolization (angioinfarction) has been used
in the past as a surgical adjunct to facilitate radical nephrectomy,
• There is no conclusive evidence that preoperative embolization
actually decreases blood loss or facilitates surgery,
• Its use should be limited to patients with very large tumors in which
the renal artery may be difficult to reach early in the procedure.
• Additionally, this technique may be useful to palliate patients with
nonresectable tumors and significant symptoms such as hemorrhage,
flank pain, or paraneoplastic syndromes.

34. • RCC may invade renal vascular spaces and produce tumor thrombi extending into renal
veins, inferior vena cava, hepatic veins, and, occasionally, the right atrium.
• Between 5% and 10% of patients presenting with RCC have some degree of vena caval
involvement
• Patients presenting with involvement of the renal vein and vena cava below the hepatic
veins (T3bN0M0) but without evidence of regional or distant metastases have a
prognosis similar to patients with stage T2 disease when treated by radical excision.
• The surgical approach to the removal of caval thrombi depends entirely on the level of
cephalad extension.
• In general, these thrombi do not invade the wall of the cava and therefore can be
removed without resection of the caval wall.
• For tumor thrombi that have reached the level of the right atrium, the use of
cardiopulmonary bypass is typically required.

35. • Laparoscopic radical nephrectomy and partial nephrectomy can also
be accomplished successfully and safely.
• Laparoscopic radical nephrectomy is being used increasingly for
patients with localized renal tumors.
• This approach results in quicker recovery with efficacy comparable
to that of open radical nephrectomy and is now the approach of
choice in appropriate patients with <10 cm tumors and without
local extension or a renal vein or caval thrombus.

36. • For small exophytic lesions that do not
extensively involve the major vessels or urinary
collecting system, a partial nephrectomy (also
referred to as "nephron sparing surgery") can
be performed.
• Radiation therapy is an important method in
the palliation of patients with metastatic RCC.

37. Biologic response modifiers
• RCC "elicits an immune response, which
occasionally results in dramatic spontaneous
remissions.
• " This has encouraged a strategy of using
immunomodulating therapies, such as cancer
vaccines and interleukin-2 (IL-2), to reproduce
this response.

38. • Studies using partially purified human leukocyte
interferon in renal cancer were first reported in 1983,
with subsequent studies using human lymphoblastoid
interferon.
• More recently, recombinant interferon-alpha (r-IFN-α) is
used. Various doses and schedules of r-IFN-α have
demonstrated reproducible overall response rates of 10–
15% in advanced renal cancer.

39. • Interleukin-2 (IL-2), a T-cell growth factor, was
first identified in 1976.
• Recombinant IL-2 is the only agent approved by
the US Food and Drug Administration for
patients with advanced renal carcinoma.
• Controversy persists regarding the optimal dose
and schedule for IL-2 administration,

40. • Randomized trials comparing IFN-α, IL-2, and IL-
2 plus INF-α have demonstrated higher
objective response rates to the combination
therapy, with no difference in survival and
significantly higher toxicity associated with the
combination.

41. Newer biologic agents
• Another strategy is to restore the function of the VHL gene, which is to destroy proteins
that promote inappropriate vascularization.
• Oral agents such as Bevacizumab and Sunitinib can specifically inhibit receptors for
VEGF and PDGF thereby halting tumor angiogenesis and tumor progression.
• Bevacizumab, an antibody to VEGF, has significantly prolonged time to progression.
• Bevacizumab is a monoclonal antibody that binds and inactivates VEGF A. It has shown
the ability to yield partial responses, delay disease progression, and improve survival in
patients with advanced renal cancer.
• Sunitinib—an oral, small-molecule, multi-targeted (RTK) inhibitorand sorafenib — a
protein kinase inhibitor both interfere with tumor growth by inhibiting angiogenesis as
well as tumor cell proliferation.

42. • Temsirolimus (CCI-779) is an inhibitor of mTOR kinase (mammalian
target of rapamycin) that was shown to prolong overall survival vs.
interferon-α in patients with previously untreated metastatic renal cell
carcinoma with three or more poor prognostic features.
• Renal Cell Carcinoma Afinitor (everolimus) is an oral once-daily inhibitor
of mTOR indicated for the treatment of patients with advanced renal
cell carcinoma (RCC) after failure of treatment with sunitinib or
sorafenib.
• Treatment with tyrosine kinase inhibitors including nexavar, pazopanib,
and rapamycin have shown promise in improving the prognosis for
advanced RCC.

43. • Chemotherapy:Most of
the currently available
cytostatics are ineffective
for the treatment of RCC.
• Vaccine: Cancer
vaccines, such
as TroVax, have shown
promising results.

44. Follow up
• There is no universal agreement on the frequency or
studies required in the follow-up care of patients with
RCC.
• A stage-specific follow-up schedule is recommended for
patients who have undergone radical or partial
nephrectomy.
• Patients with stage T1 disease need less stringent follow-
up, with yearly chest x-rays and liver and renal function
tests.

45. • Those with stage T2 or T3 disease require more frequent
follow-up of at least 3-month or 6-month intervals in the
early postoperative period.
• Repeat CT scans of the abdomen should also be
obtained, especially in those who have undergone partial
nephrectomy, to rule out local recurrence.
• Patients with metastatic disease who are not undergoing
therapy need continued follow-up to provide appropriate
supportive care.