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RENAL CELL CARCINOMA

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RENAL CELL CARCINOMA Powered By Docstoc
					Renal cell carcinoma
   Renal cell carcinoma (RCC) accounts for
    roughly 2.5% of adult cancers and constitutes
    approximately 85% of all primary malignant
    renal tumors
   In the United States in 2002, an estimated
    31,800 new cases of adenocarcinoma of the
    kidney were diagnosed, and 11,600 deaths
    occured from this disease (Jemal et al, 2002).
   RCC occurs most commonly in the fifth to
    sixth decade
    Has a male-female ratio of 2:1.
   There appears to be an increase in the
    incidence of all stages of RCC over the past
    few decades (Chow et al, 1999; Hock, Lynch,
    and Balaji, 2002)
Etiology

   Cigarette smoking is the only risk factor
    consistently linked to RCC by both
    epidemiologic case-control and cohort
    studies (La Vecchia et al, 1990), with most
    investigations demonstrating at least a 2-fold
    increase in risk for the development of RCC
    in smokers (Yu et al, 1986).
   Exposure to asbestos, solvents, and
    cadmium has also been associated with an
    increased incidence of RCC (Mandel et al,
    1995).
   RCC occurs in two forms-
   Inherited
   Sporadic
Various types of Hereditary RCC -

   Von Hippel-Lindau disease –This is a
    relatively rare autosomal dominant disorder
    that occurs with a frequency of 1 per 36,000
    population
   familial cancer syndrome in which affected
    individuals have a predisposition to have
    tumors develop in multiple organs, including
    cerebellar hemangioblastoma, retinal
    angiomata, and bilateral clear cell RCC
   RCC develops in about 50% of patients
    with von Hippel–Lindau disease and is
    distinctive for its early age at onset, often
    in the third, fourth, or fifth decade of life,
    and for its bilateral and multifocal
    involvement
Hereditary papillary renal carcinoma

   Hereditary papillary renal carcinoma -
    characterized by a predisposition to develop
    multiple bilateral renal tumors with a papillary
    histologic appearance
   Studies of families with HPRCC
    demonstrate an autosomal dominant
    mode of transmission
Hereditary leiomyomatosis and renal
cell cancer (HLRCC) syndrome
   In 2001, Launonen and colleagues
    described a new familial renal cancer
    syndrome in which patients commonly
    develop cutaneous and uterine
    leiomyomas and type 2 papillary RCC
   Renal tumors in this syndrome are
    unusual for familial RCC in that they are
    often solitary and unilateral, and they are
    more likely to be aggressive than are
    other forms of familial RCC
   Penetrance for RCC is lower than for the
    cutaneous and uterine manifestations, with
    only a minority (20%) of patients developing
    RCC
Other etilogic factor

   Acquired cystic disease of the kidneys -
    multiple bilateral cysts in the native kidneys of
    uremic patients
   The risk of developing RCC has been
    estimated to be greater than 30 times higher
    in patients receiving dialysis who have cystic
    changes in their kidney than in the general
    population (Brennan et al, 1991).
Pathology

   RCC originates from the proximal renal
    tubular epithelium
   These tumors occur with equal frequency in
    either kidney and are randomly distributed in
    the upper and lower poles
   Most sporadic RCCs are unilateral and
    unifocal.
    Bilateral involvement can be
    synchronous or asynchronous and is
    found in 2% to 4% of sporadic RCCs,
    although it is considerably more common
    in patients with von Hippel–Lindau
    disease or other familial forms of RCC
   RCCs originate in the cortex and tend to grow
    out into perinephric tissue, causing the
    characteristic bulge or mass effect that aids
    in their detection by diagnostic imaging
    studies
   Grossly, the tumor is characteristically yellow
    to orange because of the abundance of lipids,
    particularly in the clear cell type
   RCCs do not have true capsules but may
    have a pseudocapsule of compressed renal
    parenchyma, fibrous tissue, and inflammatory
    cells
   Histologically, RCC is most often a mixed
    adenocarcinoma containing clear cells,
    granular cells, and, occasionally,
    sarcomatoid-appearing cells
Classification of the subtypes of RCC
based on morphology and cytogenetic
characteristics-
1) Conventional clear cell,
2) Papillary (chromophilic),
3) Chromophobe,
4) Collecting duct,
5) Neuroendocrine,
6) Unclassified
Pathogenesis

   RCCs are vascular tumors that tend to
    spread either by direct invasion through the
    renal capsule into perinephric fat and
    adjacent visceral structures or by direct
    extension into the renal vein
    Approximately 25–30% of patients have
    evidence of metastatic disease at
    presentation
   The most common site of distant metastases
    is the lung
   liver, bone (osteolytic), ipsilateral adjacent
    lymph nodes, adrenal gland, brain, the
    opposite kidney, and subcutaneous tissue
    are frequent sites of disease spread
Robson Tumor Staging

    Stage I:—Tumor is confined within the kidney parenchyma
     (no involvement of perinephric fat, renal vein, or regional
     lymph nodes).
    Stage II:—Tumor involves the perinephric fat but is
     confined within Gerota's fascia (including the adrenal).
    Stage IIIA:—Tumor involves the main renal vein or inferior
     vena cava.
    Stage IIIB:—Tumor involves regional lymph nodes.
    Stage IIIC:—Tumor involves both local vessels and
     regional lymph nodes.
    Stage IVA:—Tumor involves adjacent organs other than
     the adrenal (colon, pancreas, etc).
    Stage IVB:—Distant metastases
TNM Classification

Tx                   Tumor can’t be assessed
T0                   No evidence
T1a                  Tumor <= 4 cm , confined
                     to kidney
T1b                  Tumor > 4 , <7 cm
T2                   Tumor > 7 cm but confined
                     to kidney
T3a                  Tumor invades adrenal,
                     perinephric fat but not
                     gerotas fascia
T3b   Tumor extends into renal
      vein or vena cava below
      the diaphragm

T3c   Tumor extends into vena
      cava above the diaphragm
      or invades the wall of vena
      cava
T4    Tumor invades beyond the
      Gerota’s fascia
Nx   Regional nodes can not
     be assessed


N0   No node metastasis



N1   Metastasis in single
     regional node


N2   Metastasis in more than
     one regional LN
Mx   Distant metastasis cannot
     be assessed



M0   No distant metastasis




M1   Distant metastasis present
Staging

Stage 1   T1N0M0
Stage 2   T2N0M0
Stage 3   T1 or T2, N1, M0
          T3 , N0 or N1 , M0
Stage 4   T4, any N , M0
          Any T , N2 , M0
          Any T, any N , M1
Symptoms and Signs

   triad of gross hematuria, flank pain, and a
    palpable mass occurs in only 10–15%
   Sixty percent of patients present with gross or
    microscopic hematuria
   Pain, an abdominal mass, or both are seen in
    approximately 40% of patients
   Symptoms secondary to metastatic disease,
    such as dyspnea and cough, seizure and
    headache, or bone pain from lung, brain, and
    bone metastases, respectively, lead to a
    diagnosis in up to 30% of patients
Paraneoplastic Syndromes

   RCC is associated with a wide spectrum of
    paraneoplastic syndromes including
    erythrocytosis, hypercalcemia, hypertension,
    and nonmetastatic hepatic dysfunction.
    Overall, these manifestations can occur in
    10–40% of patients with RCC
paraneoplastic erythrocytosis

   RCC is the most common cause of paraneoplastic
    erythrocytosis, which is reported to occur in 3–10%
    of patients with this tumor
   the elevated erythrocyte mass is physiologically
    inappropriate and may result either from enhanced
    production of erythropoietin from the tumor or as a
    consequence of regional renal hypoxia promoting
    erythropoietin production from nonneoplastic renal
    tissue
Hypercalcemia

   reported to occur in up to 20% of patients
    with RCC
   due to production of a parathyroid hormone–
    related peptide that mimics the function of
    parathyroid hormone (Strewler et al, 1987) or
    other humoral factors such as osteoclast-
    activating factor, tumor necrosis factor, and
    transforming growth factor-alpha (Muggia,
    1990).
Hypertension

   reported in up to 40% of patients
   renin production by the neoplasm has been
    documented in 37%
   The excess renin and hypertension
    associated with RCC are typically refractory
    to antihypertensive therapy but may respond
    after nephrectomy (Gold et al, 1996).
Stauffer syndrome

   reversible syndrome of hepatic dysfunction in
    the absence of hepatic metastases
    associated with RCC. Hepatic function
    abnormalities include elevation of alkaline
    phosphatase and bilirubin, hypoalbuminemia,
    prolonged prothrombin time, and
    hypergammaglobulinemia
    tends to occur in association with fever,
    fatigue, and weight loss and typically resolves
    after nephrectomy
   adrenocorticotropic hormone (Cushing
    syndrome),
   enteroglucagon (protein enteropathy),
    prolactin (galactorrhea),
    insulin (hypoglycemia), and
    gonadotropins (gynecomastia and
    decreased libido; or hirsutism, amenorrhea,
    and male pattern balding
Laboratory Findings

   anemia, hematuria, and an elevated
    sedimentation rate are frequently observed.
Intravenous Urography

   Calcification overlying the renal shadow is an
    important diagnostic finding because its
    presence significantly increases the
    probability of cancer (Daniel et al, 1972).
Ultrasonography

   noninvasive, relatively inexpensive technique
    able to further delineate a renal mass seen
    on IVU
   98% accurate in defining simple cysts
   Extension of tumor thrombus into the inferior
    vena cava can also be determined by
    ultrasonography.
CT Scanning

   shown to be more sensitive than US or IVU
    for renal cancer detection
   A typical finding of RCC on CT is a mass that
    becomes enhanced with the use of
    intravenous contrast media
   method of choice in staging the patient by
    visualizing the renal hilum, perinephric space,
    renal vein and vena cava, adrenals, regional
    lymphatics, and adjacent organs
Renal Angiography

   Angiography is capable of demonstrating
    neovascularity and arteriovenous fistulas as
    well as renal vein and vena caval tumor
    involvement
   carries a small but real risk of complications,
    including hemorrhage, pseudoaneurysm
    formation at the puncture site, arterial emboli,
    and contrast-related nephrotoxicity
Radionuclide Imaging

   Determination of metastases to bones is
    most accurate by radionuclide bone scan
    There is evidence that patients without bone
    pain and with a normal alkaline phosphatase
    level have a very low incidence of bone
    metastases (Henriksson et al, 1992), and
    thus a routine bone scan is not necessary in
    such patients.
Magnetic Resonance Imaging

   MRI is equivalent to CT for staging of RCC
   Its primary advantage is in the evaluation of
    patients with suspected vascular extension
   MRI is superior to CT in assessing inferior
    vena caval involvement
   MR angiography can also be used to
    delineate the vascular supply before planned
    nephron-sparing surgery.
Positron Emission Tomography (PET)

   This technique allows the measurement of
    systemically administered biochemical agents
    such as 18-fluoro-2-deoxyglucose (FDG),
    which can accumulate in the kidney
   it may be useful in monitoring response to
    systemic therapy in those with metastatic
    disease
   FDG-PET may also be more accurate than
    routine CT scanning in detecting disease
    recurrence or progression
Fine-Needle Aspiration

   limited role in the evaluation of RCC
   Fine-needle aspiration of renal lesions is the
    diagnostic approach of choice in those
    patients with clinically apparent metastatic
    disease who may be candidates for
    nonsurgical therapy
   Other settings in which fine-needle aspiration
    may be appropriate include establishing a
    diagnosis in patients who are not surgical
    candidates, differentiating a primary RCC
    from a renal metastasis in patients with
    known primary cancers of nonrenal origin,
    and evaluating some radiographically
    indeterminate lesions
Instrumental and Cytologic Examination

   Patients presenting with hematuria should be
    evaluated with cystoscopy
   although urine cytologic study is rarely helpful
    in the diagnosis of RCC, cytologic study of
    urine with renal pelvis washing is frequently
    diagnostic in renal pelvis tumors
Treatment
Localized Disease ( Stage 1 & 2 )

   Surgical removal of the early-stage lesion
    remains the only potentially curative therapy
    available for RCC patients
   Radical nephrectomy is the primary treatment
    for localized RCC
   goal -achieve the removal of tumor and to
    take a wide margin of normal tissue
Radical nephrectomy

    Encompasses the basic principles of early
    ligation of the renal artery and vein, removal
    of the kidney outside Gerota's fascia,
    excision of the ipsilateral adrenal gland, and
    performance of a complete regional
    lymphadenectomy from the crus of the
    diaphragm to the aortic bifurcation
   Removal of the adrenal is unnecessary if the
    tumor is not in the upper pole, because
    adrenal involvement is uncommon in this
    instance.
Laparoscopic radical nephrectomy

   Laparoscopic radical nephrectomy has
    emerged as a less morbid alternative to
    open surgery in the management of low-
    to moderate-volume (8 to 10 cm or
    smaller), localized RCCs with no local
    invasion, renal vein involvement, or
    lymphadenopathy
   The likelihood of local recurrence after radical
    nephrectomy is 2–3%
   Repeat resection of isolated local recurrence
    can be curative and yield a survival benefit
   There is no evidence that postsurgical
    radiation therapy to the renal bed, whether or
    not residual tumor is present, contributes to
    prolonged survival.
Nephron-Sparing Surgery

   Approach to the patient with either bilateral
    RCC or disease in a solitary kidney differs
    from the standard approach of radical
    nephrectomy
   Radical nephrectomy in these patients or in
    those with solitary kidneys obviously commits
    patients to long-term dialysis or renal
    transplantation and the morbidities of these
    conditions
   Partial nephrectomy with an adequate
    parenchymal margin remains the preferred
    treatment.
   Partial nephrectomy and wedge resection
    with an adequate margin of normal
    parenchyma is increasingly being used as
    primary surgical therapy for patients with
    tumors less than 4 cm in size, even in the
    presence of a normal contralateral kidney
   It is now considered the approach of choice
    in patients with small (< 4 cm), incidentally
    discovered renal tumors that are peripherally
    located.
   Cryoablation, high-intensity focused US, and
    radiofrequency ablation are the other types of
    treatment that are used
   The long-term effectiveness of these
    emerging technologies remains to be
    determined.
TREATMENT OF LOCALLY
ADVANCED RENAL CELL
CARCINOMA
Inferior Vena Caval Involvement

   One of the unique features of RCC is its
    frequent pattern of growth intraluminally into
    the renal venous circulation, also known as
    venous tumor thrombus
   The absence of metastases in many patients
    with vena caval extension is an intriguing
    aspect of this cancer's behavior
   Overall, involvement of the IVC with RCC
    occurs in 4% to 10% of patients
   Venous tumor thrombus should be suspected
    in patients with a renal tumor who also have
    lower extremity edema, isolated right-sided
    varicocele or one that does not collapse with
    recumbency, dilated superficial abdominal
    veins, proteinuria, pulmonary embolism, right
    atrial mass, or nonfunction of the involved
    kidney
Staging of the level of IVC thrombus is as
follows
   I- adjacent to the ostium of renal vein
   II- extending up to the lower aspect of the
    liver
    III- involving the intrahepatic portion of the
    IVC but below the diaphragm
    IV-extending above the diaphragm
   MRI is a noninvasive and accurate
    modality for demonstrating both the
    presence and the cephalad extent of vena
    caval involvement and has become the
    preferred diagnostic study at most
    centers
   Renal arteriography remains a useful
    preoperative study in patients with RCC
    involving the inferior vena cava because
    in 35% to 40% of cases, distinct
    vascularization of a tumor thrombus is
    observed
   Approximately 45% to 70% of patients with
    RCC and IVC thrombus can be cured with an
    aggressive surgical approach including
    radical nephrectomy and IVC thrombectomy
   Patients presenting with involvement of the
    renal vein and vena cava below the hepatic
    veins (stage IIIA or T3aN0M0) but without
    evidence of regional or distant metastases
    have a prognosis similar to patients with
    stage II (T2) disease when treated by radical
    excision
   In general, 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.
Locally Invasive Renal Cell Carcinoma

   These include aggressive types of RCC
    result in occasional patients presenting with
    large primary tumors that invade adjacent
    structures
   Such patients usually present with pain,
    generally from invasion of the posterior
    abdominal wall, nerve roots, or
    paraspinous muscles
   Extended operations with en bloc resection of
    adjacent organs is indicated
   Complete excision of the tumor, including
    resection of the involved bowel, spleen, or
    abdominal wall muscles, is the aim of therapy
Disseminated Disease
Surgery

    Radical nephrectomy was primarily used as
    a palliative procedure in the setting of
    metastatic disease for managing patients with
    severe hemorrhage or unremitting pain
   Patients presenting with a solitary metastatic
    site (synchronous metastases) that is
    amenable to surgical resection may be
    candidates for combined nephrectomy and
    removal of the metastatic foci
Radiation Therapy

   Important method in the palliation of patients
    with metastatic RCC.
   RCC is a relatively radioresistant tumor
   Effective palliation of metastatic disease to
    the brain, bone, and lungs
Hormonal Therapy

   There are numerous uncontrolled trials of use
    of progestational, androgenic, and
    antiestrogenic agents in RCC in literature
   Recent studies in large numbers of patients
    have shown response rates of 1–2%, with
    responses typically being partial and of brief
    duration (Kjaer, 1988).
Chemotherapy

   RCC is among the most chemotherapy-
    resistant epithelial cancers
Biologic Response Modifiers

   Recombinant interferon-alpha used in various dose
    and schedules has demonstrated reproducible
    overall response rates of 10–15% in advanced renal
    cancer (Pastore et al, 2001).
   Interferon-alpha is commonly administered 3–5 days
    per week as a subcutaneous injection. Patients
    most likely to have a clinical benefit from interferon
    therapy are those who have minimal tumor burden
    (ie, primary kidney tumor removed), lung or nodal
    metastases only, and an excellent performance
    status.
   Interleukin-2 (IL-2), a T-cell growth factor
   Recombinant IL-2 is the only agent approved
    by the US Food and Drug Administration for
    patients with advanced renal carcinoma
   overall response rates of IL-2 is in the 15%
    range
   Randomized trials comparing interferon-
    alpha, IL-2, and IL-2 plus interferon-alpha
    have demonstrated higher objective response
    rates to the combination therapy, with no
    difference in survival and significantly higher
    toxicity associated with the combination
    (Negrier et al, 1998).
Follow-Up Care

   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
Prognostic Factors

   Pathologic stage has proved to be the
    single most important prognostic factor
    for RCC
   Lymph node involvement has long been
    recognized as a dire prognostic sign
    because it is associated with 5- and 10-
    year survival rates of 5% to 30% and 0% to
    5%, respectively
   Systemic metastases portend a
    particularly poor prognosis for RCC, with
    1-year survival of less than 50%, 5-year
    survival of 5% to 30%, and 10-year
    survival of 0% to 5%
   Another significant prognostic factor for
    RCC is tumor size
TUMOR SIZE   5 YEAR SURVIVAL



Upto 5 cm    84 %



5 – 10 cm    50%



> 10 cm      0%
   Other important prognostic factors for
    RCC include nuclear grade and histologic
    subtype
Prognosis

Stage       5 year survival

1           91-100 %

2           74-96%

3           59-70 %

4           16-32
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