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Renal Cell Carcinoma

  1. Most common histopathology is clear cell cancer.
  2. Clear cell cancer originate from proximal tublar cell.
  3. Most common site is upper pole of kidney.
  4. Renal cell carcinoma represents 2-3% of all cancers and 2% of all cancer deaths; 90-95% of neoplasms arising from the kidney.
  5. 9th most common male malignant tumor; 13th most common female malignant tumor.
  6. The tissue of origin for renal cell carcinoma is the proximal renal tubular epithelium. Renal cancer occurs in both a sporadic (nonhereditary) and a hereditary form.
  7. Most common gene associated is VHL gene (in 90%).
  8. Familial and sporadic forms of renal cell carcinoma are associated with structural alterations of the short arm of chromosome 3 (3p).
  9. This condition occurs most commonly in the fourth to sixth decades of life.
Most important prognostic factor of renal cancer based on (AIIMS May 09)
A. Size of tumour                 
B. Pathological staging                         
C. Nuclear Grading               
D. Histologic type
Ans. B Pathological staging

  1. Predominant sex: Male > Female (3:1)
  2. Synonyms: Hypernephroma/ Grawitz's tumor/ Hypernephroid cancer
    1. Most of the carcinogens that cause renal cancer are unknown.
    2. Smoking (Most common risk factor), obesity, long-term use of phenacetin and acetaminophen, presence of kidney stones, and exposure to cadmium, thorotrast, petroleum products, and other industrial chemicals are important risk factors for developing renal cancer.
    3. Hypertension may be associated with increased incidence of Renal cell carcinoma.
    4. Whether polycystic kidney disease is associated with RCC remains controversial; however, acquired renal cystic disease, which typically occurs in patients with chronic renal failure on hemodialysis, is strongly associated with RCC.
    5. The relationship between benign renal adenomas and RCC is controversial.
  3. Hereditary syndromes associated with renal cell carcinoma are:
    1. Von Hippel-Lindau (VHL) syndrome: VHL disease is transmitted in an autosomal dominant familial multiple- cancer syndrome, in which there is predisposition to a variety of neoplasms, including the following:
      1. Renal cell carcinoma with clear cell histology
      2. Pheochromocytoma
      3. Pancreatic cysts and islet cell tumors
      4. Retinal angiomas
      5. Central nervous system hemangioblastomas
      6. Endolymphatic sac tumors
      7. Epididymal cystadenomas
    2. Hereditary papillary renal carcinoma (HPRC): an autosomal dominant inheritance pattern in which individuals who are affected develop bilateral, multifocal papillary renal carcinoma.
    3. Familial renal oncocytoma (FRO): individuals can develop bilateral, multifocal oncocytoma or oncocytic neoplasms in the kidney; associated with Birt-Hogg-Dube syndrome (BHDS), a hereditary cutaneous syndrome.
    4. Hereditary renal carcinoma (HRC).
  4. History:
    The classic triad of flank pain, hematuria, and flank mass is infrequent (10%) and is indicative of advanced disease.
    Most common presentations Hematuria (40%)/ Flank pain (40%)/ Palpable mass in the flank (25%)

Cell type

Feature Cells of origin
Clear cell Most common PCT
Chromophilic B/L & multifocal PCT
Chromophobic Indolent course Cortical collecting duct
Oncocytic Rarely metastatic Cortical collecting duct
Collecting duct Very aggressive Medullary collecting duct
  1. Other signs and symptoms
    1. Weight loss (33%)/ Fever (20%)/ Hypertension (20%)/ Hypercalcemia (5%)/ Night sweats/ Malaise/ Varicocele, usually left sided, (2% of males)
    2. Paraneoplastic syndromes, including hypercalcemia, erythrocytosis, and nonmetastatic hepatic dysfunction
    3. (Stauffer syndrome). Polyneuromyopathy, amyloidosis, anemia, fever, cachexia, weight loss,
    4. Dermatomyositis, increased sedimentation rate, and hypertension also are associated with renal cell carcinoma.
  2. Physical:
    1. Pain, Lump & Hematuria is regarded as triad for RCC.
    2. Gross hematuria with vermiform clots suggests upper urinary tract bleeding.
    3. Hypertension, supraclavicular adenopathy, and abdominal mass with bruit.
    4. Approximately 30% of patients with renal carcinoma present with metastatic disease. Physical examination should include thorough evaluation for metastatic disease. Organs involved include:
      1. Lung (75%)/ Soft tissues (36%)/ Bone (20%)/ Liver (18%)/ Cutaneous sites/ Central nervous system
      2. Varicocele and findings of paraneoplastic syndrome raise clinical suspicion for this diagnosis.
      3. Most common site of distant spread lung soft tissue bone liv
  1. Lab Studies:
    1. Laboratory studies in the evaluation of renal cell carcinoma should include a workup for paraneoplastic syndromes. Initial studies are as follows:
      1. Urine analysis
      2. CBC with differential count
      3. Electrolytes
      4. Renal profile
  2. Liver function test
  3. Calcium
  4. Erythrocyte sedimentation rate
  5. Prothrombin time
  6. Activated partial thromboplastin time
  1. Imaging Studies:
    1. Contrast-enhanced CT scanning has become the imaging procedure of choice for diagnosis and staging of renal cell cancer.
    2. FNAC not required if operable case.
    3. CT imaging can differentiate cystic masses from solid masses and supplies information about lymph nodes and renal vein and inferior vena cava involvement.
    4. Ultrasound examination provides excellent staging and diagnostic information. Ultrasound provides accurate anatomic detail of extrarenal extension of tumor, adrenal or lymph node involvement, and infiltration of adjacent viscera.
    5. Renal arteriography is used in cases where nephron sparing nephrectomy is planned.
    6. When inferior vena cava involvement is suspected, either inferior venacavography or MRI is used. MRI is currently the preferred imaging technique.
    7. Inferior vena cava involvement is important in planning the vascular aspect of the operative procedure.
    8. A bone scan is recommended for bony symptoms with elevated alkaline phosphatase.
    9. Histologic Findings (The Mainz Classification of Renal Cell Tumors): Renal cell carcinoma has 5 histological subtypes, as follows: clear cell (75%), chromophilic (15%), chromophobe (5%), oncocytoma (3%), and collecting duct (2%). 
Extra Edge:
RCC: Paraneoplastic Syndromes (20%)
  • Raised ESR: MC paraneoplastic manifestation
  • Hypercalcemia:
    • Due to production of PTH-rp
    • Only paraneoplastic syndrome in which medical therapies are proven useful.
    • Hypertension (Renin production from tumor)
    • Polycythemia (Erythropoietin production from tumor)
  • Stauffer's syndrome:
    • Non-metastatic hepatic dysfunction due to raised IL-6Q leading to increased ALP, PT and bilirubin
    • Hepatic function normalizes after nephrectomy
  • Others are: Cushing syndrome, hypoglycemia, anemia, gynecomastia, amenorrhea
  • Diagnostic IOC: CT (95% accurate)
  • MRI is most accurate non-invasive investigation for detecting tumor thrombus in renal vein or IVC. Distinguishes tumor thrombus from bland thrombus
  • Inferior venocavogram is most sensitive and specific but invasive means to detect involvement of IVC.
  • Renal arteriography is done before renal sparing surgery (partial nephrectomy), but 3-D helical cr is also sufficient.
  • Specific plain X-ray finding is central calcification,
FNAC is not routinely done in RCC, indications are:
  • Suspected secondaries
  • Suspected lymphoma
  • Clinical suspicion of renal abscess
  • To prove pathological diagnosis in disseminated or unresectable disease
  1. Renal Adenoma
    1. Small renal epithelial neoplasms are commonly and incidentally found during autopsies.
    2. Many investigators believe that these lesions lack the ability to progress to RCC and are benign. However, since the same lesions are not uncommonly associated with concomitant
    3. Microscopically, histopathologic features of both greatly overlap, and almost any histologic pattern described in RCC can be encountered in benign adenomas.
    4. Although it is acknowledged that many of these small renal neoplasms are probably benign, they should be considered potentially malignant, regardless of their size.
  2. Renal Oncocytoma
    1. Renal oncocytoma (5% of the tumors); is derived from tubular epithelium). While most tumors are incidentally found, they can present as a mass or with hematuria.
    2. Histologically tumor cells exhibit large and finely granular cytoplasm, uniform round nuclei, clumped chromatin and small nucleoli.
    3. Conservative surgery is considered an adequate treatment since true oncocytomas are always benign.
    4. Renal oncocytoma has a characteristic central white fibrous scar.
    5. Although rare, necrosis may occur and Hemorrhage is common.
    6. Bilaterally or multicentricity are common.
  3. Staging:
    The Robson modification of the Flocks and Kadesky system:
    1. Stage I - Tumor confined within capsule of kidney
    2. Stage II - Tumor invading perinephric fat but still contained within the Gerota fascia
    3. Stage III - Tumor invading the renal vein or inferior vena cava (A), or regional lymph-node involvement (B), or both (C)
    4. Stage IV - Tumor invading adjacent viscera (excluding ipsilateral adrenal) or distant metastases
The rate of 5-year survival varies by stage:                           
  1. >90% for stage I
  2. 85% for stage II
  3. 60% for stage III
  4. 10% for stage IV.
  1. ​Surgical Care:
    1. Surgical resection remains the only known effective treatment for localized renal cell carcinoma, and it also is used for palliation in metastatic disease.
    2. Radical nephrectomy, which is the standard procedure today for treatment of localized renal carcinoma, involves complete removal of Gerota's fascia and its contents, including a resection of kidney, perirenal fat, and ipsilateral adrenal gland, with or without ipsilateral lymph node dissection.
    3. Partial nephrectomy for tumor upto 4 cm localized at either pole of kidney.
    4. Radiation therapy may be considered as the primary therapy for palliation in patients whose clinical condition precludes surgery.
    5. Palliative radiation therapy is commonly used for local or symptomatic metastatic disease, such as painful osseous lesions and brain metastasis, to halt potential neurologic progression.
    6. The probability of cure is directly related to the stage or degree of tumor dissemination, so the approach is curative for early stage disease.
    7. The treatment options for renal cell cancer are surgery, radiation therapy, chemotherapy, hormonal therapy, immunotherapy, or combinations of these.
    8. Options for systemic therapy are limited, and no hormonal or chemotherapeutic regimen is accepted as a standard of care.
    9. Renal cell carcinoma is an immunogenic tumor, and spontaneous regressions have been documented. Many immune modulators, such as interferon, IL-2, lymphokine-activated killer (LAK) cells plus IL-2, tumor-infiltrating lymphocytes, and nonmyeloablative allogeneic peripheral blood stem-cell transplantation have been tried.
    10. Renal cell carcinoma is refractory to most chemotherapeutic agents because of multidrug resistance mediated by p-glycoprotein.
  2. Recent Advances:
    1. Targeted therapy (tyrosin kinase inhibitor)Sorafenib, Sunitinib: It is gold standard for metastatic renal cell cancer.
    2. RCC is found to be immunogenic tumor & spontaneous regression documented with IL-2, BCG vaccination, (lymphokine activated killer cells)
    3. Tersirolimas – Inhibits serine / threonine kinase
    4. Everolimus – Serine threonine kinase inhibitors Vaccine trials are in early stage of development.
A child was operated for Wilms tumor partial nephrectomy was done. On HPE nephroblastomatosis tissue was found in the periphery, around tumour. It denotes:- (AIIMS Nov 09)
A. Mutation in insulin like growth factor                                   
B. Possibility of having bilateral enlargement
C. Nephroblastoma cell in the lymph node                                               
D. Denny Drash syndrome
Ans. B. Possibility of having bilateral enlargement

Wilms Tumor
  1. Wilms' tumor can arise from both germline and somatic mutations, and can occur in the presence or absence of a family history.
  2. Nearly 97% of Wilms' tumors are sporadic in that they occur in the absence of a heritable or congenital cause or risk factor.
  3. When a heritable risk factor is identified, the affected children often present at an earlier age, and are frequently bilateral.
  4. In addition, there is an increased incidence of Wilms' tumor in certain overgrowth conditions, particularly Beckwith-Wiedemann syndrome and hemihypertrophy.
  5. The WAGR syndrome has been shown to result from the deletion of one copy each of the Wilms' tumor gene, WT1, and the adjacent aniridia gene, PAX6, on chromosome 11p13.
  6. Beckwith-Wiedemann syndrome is an overgrowth syndrome that is characterized by visceromegaly, macroglossia, and hyperinsulinemic hypoglycemia. It arises from mutations at the 11p15.5 locus.
    1. Wilms tumor (WT) is the fifth most common pediatric malignancy and the most common renal tumor in children.
    2. Incidence is approximately 0.8 cases per 100,000 persons.
    3. Etiology: The tumor may arise in 3 clinical settings, (1) sporadic, (2) association with genetic syndromes, and (3) familial. The etiology essentially remains unknown.
Sporadic Wilms tumor
  1. Beckwith-Wiedemann syndrome (Macrosomia, Macroglossia, Pancreatic duct hyperplasia, adrenocortical cytomegaly, Omphalocele hemihypertrophy, linear fissure in lobule of external ear)
  2. Hemihypertrophy
  3. Congenital aniridia
  4. WT, aniridia, genitourinary malformations, and mental retardation (WAGR syndrome)
  5. Denys-Drash syndrome (WT, pseudohermaphroditism, and glomerulopathy)
  6. Trisomy 18 mutation
  7. Pathophysiology: The pathophysiology of WT is characterized by an abnormal proliferation of the metanephric blastema.
  • Clinical: The mean age at diagnosis is 3.5 years.
  1. The most common feature at presentation is an abdominal mass.
  2. Lump, Pain & Fever is regarded as triad for Wilms.
  3. Abdominal pain occurs in 30-40% of cases.
  4. Other signs and symptoms include hypertension, fever from tumor necrosis, hematuria, and anemia.
  5. Major congenital anomalies include genitourinary anomalies (WAGR and Denys-Drash syndromes- 5%); ectopic, solitary, horseshoe kidney; hypospadias and cryptorchidism; hemihypertrophy & organomegaly (Beckwith-Wiedemann syndrome- 2%); aniridia (1%).
  • Investigation
  1. Imaging Studies
    1. Ultrasound
      1. Initial diagnosis of a renal or abdominal mass, possible renal vein or inferior vena cava (IVC) thrombus
      2. Information regarding liver and other kidney
    2. Computed tomography scan – Investigation of choice
      1. Differential diagnosis of a kidney tumor versus adrenal tumor (neuroblastoma)
      2. Liver metastases
      3. Status of opposite kidney
      4. Lymph node assessment
      5. Status of chest with respect to metastases
    3. Histologic Findings:
      WT arises from the primitive embryonal renal tissue and contains epithelial, stromal, and blastemal elements.
      1. Favorable histology (FH): 90% of cases. All 3 histological elements are present. The cure rate is close to 90%.         
      2. Occasionally, foci of cartilaginous, adipose, or muscle tissue may appear (ie, teratoid WT).
      3. Unfavorable histology (UH): 10% of the cases. Focal or diffuse anaplasia, clear cell carcinoma of the kidney (bone-metastasizing renal tumor of childhood), and rhabdoid tumor of the kidney are present.
  • Staging:
  1. Stage I: The tumor is limited to the kidney and is excised completely.
  2. Stage II: The tumor extends beyond the kidney but is excised completely. Capsular penetration, renal vein involvement, and renal sinus involvement also may be found. A biopsy of the tumor is performed, and local spillage occurs.
  3. Stage III: Residual intra-abdominal tumor (nonhematogenous) exists after the completion of surgery. Lymph node findings are positive, or peritoneal implants are found. The resected specimen has histologically positive margins, or the tumor has been spilled into the abdominal cavity.
  4. Stage IV: Hematogenous or lymph node metastasis has occurred outside the abdomen or pelvis.
  5. Stage V: Synchronous bilateral involvement has occurred. Each side is assigned a stage from I to III, and histology is based on biopsy findings.
  • Treatment
  1. Surgical therapy is option of choice.
  2. According to the NWTSG protocol, the first step in the treatment of WT is surgical staging followed by radical nephrectomy and regional lymph node dissection or sampling are performed (If the disease is unilateral).
  3. If bilateral disease is diagnosed, nephrectomy is not performed but biopsy specimens are obtained.
  4. If the tumor is unresectable, biopsies are performed and the nephrectomy is deferred until after chemotherapy, which will shrink the tumor in most cases.
  5. Contiguous involvement of adjacent organs frequently is overdiagnosed.
  6. With bilateral WT (5% of cases), surgical exploration, biopsies from both sides, and accurate surgical staging (including lymph node biopsy of both sides) are performed. This is followed by 6 weeks of chemotherapy that is appropriate to the stage and histology of the tumor. Then, reassessment is performed using imaging studies, followed by definitive surgery with
    1. Unilateral radical nephrectomy and partial nephrectomy on the contralateral side;
    2. Partial nephrectomy for tumor upto 4 cm localized at either pole of kidney.
    3. Unilateral nephrectomy only, if the response was complete on the opposite side. This approach dramatically reduces the renal failure rate following bilateral WT therapy.
      1. Postoperative details: Postoperative chemotherapy and radiotherapy protocols are based on the surgical staging and follow the guidelines of the NWTSG.
      2. PROGNOSIS: With the advent of multimodal therapy, the overall cure rate approaches 80-85%. Cases with diffuse anaplasia and stage III or IV that recur in spite of the complex therapy have a bad prognosis. 
A 45 yr old male with solitary kidney is detected to have 4 cm exophytic mass involving lower pole of the kidney. Which of the following would be most appropriate line of Rx? (AIPG 2011)
A. Follow-up with ultrasound                        
B. Radical Nephrectomy with hemodialysis
C. Partial nephrectomy                                  
D. Radical Nephrectomy with immediate renal transplant
Ans. C. Partial nephrectomy.

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