RENAL CELL CARCINOMA

Dr. Arkaprovo Roy (MS)ASSISTANT PROFESSOR, SURGERY

MALDA MEDICAL COLLEGEWEST BENGAL

INDIA

• 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).

Classification of renal tumourBenign

CystLeiomyomaLipoma Hemangioma AngiomyolipomaAdenoma Juxtraglomerular cell tumour

Malignant

• RCC• Transitional Cell Ca• Oncocytoma• Sarcoma• Lymphoma• Metastasis(Lung, Breast,

GIT,Prostate, Pancreas, Melanoma)

Aetiology

• Males are affected twice as commonly as females

• Peak incidence of sporadic RCC is 6th to 8th decade.

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

Nutrition• Asian migrants to Western countries are at

increased risk of RCC;• Vitamins A, C, E, and fruit/vegetable

consumption are protective.

Anatomical risk factors include

Polycystic kidneys Horseshoe kidneys

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

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.

• 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.

• 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.

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.

• Most RCCs are classified into 1 of the following

Histologic Subtypes: • Conventional Clear Cell,• Papillary (Chromophilic), • Chromophobe, • Collecting Duct, • Neuroendocrine, And • Unclassified.

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

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 .

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).

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).

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.

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).

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.

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.

• 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).

• 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.

• 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.

• 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.

• .

• 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

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%).

• 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.

• 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.

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.

• 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.

• 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.

• 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.

• 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.

• 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.

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.

• 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.

• 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,

• 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.

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.

• 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.

• Chemotherapy:Most of the currently available cytostatics are ineffective for the treatment of RCC.

• Vaccine: Cancer vaccines, such as TroVax, have shown promising results.

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.

• 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.