Renal cell carcinoma C64

Grawitz was the first to describe clear cell renal carcinoma in 1883, which has since also been referred to as "Grawitz tumor". In the 19th century, terms such as "hypernephroma" and "hypernephroid carcinoma" appeared, which are now considered obsolete (Wittig 2012). Robson was the first to describe radical nephrectomy as a curative procedure for localized renal cell carcinoma in 1969 (Doehn 2020).

Renal cell carcinoma (RCC or RCC) is a heterogeneous group of tumors that have specific histopathological, genetic and clinical characteristics. They can be benign or highly malignant and occur unilaterally or bilaterally (Kasper 2015).

RCC is classified according to histopathological criteria and taking into account molecular characteristics as defined by the WHO in 2016 (Ahrens 2020) and is categorized as follows:

• Clear-cell renal cell carcinoma: Accounting for 60%–70% of cases, it is the most common type of tumor.
• Papillary carcinoma: This accounts for 5%–15% of cases and tends to involve multifocal and bilateral kidney involvement.
• Chromophobe carcinoma: Chromophobe carcinoma is found in 5%–10% of cases and is characterized by an unremarkable clinical course.
• Oncocytoma: This is also rare, accounting for 5%–10% of cases, and is generally considered benign. It can also occur as a hybrid tumor in conjunction with a chromophobic carcinoma. Oncocytomas can also be precursors of a chromophobic carcinoma (Kraus 2014).
• Ductus Bellini carcinoma: Ductus Bellini carcinoma (also known as collecting duct carcinoma) is very rare, accounting for < 1% of cases, and is highly aggressive (Kasper 2015).

Described as a separate tumor entity in earlier WHO classifications:

• Medullary carcinoma: Medullary carcinoma occurs very rarely and is highly aggressive (Golbeck 2013). It is found exclusively in patients with sickle cell anemia (Herold 2020).
• Multilocular cystic renal cell carcinoma: This tumor is closely associated with clear cell RCC (see above). It is only mildly malignant. No cases of metastasis have been reported to date (Golbeck 2013).

An additional classification is the Vancouver Classification of the International Society of Urological Pathology (ISUP). It applies in particular to new categories of epithelial tumors, such as:

• tubulocystic renal cell carcinoma
• papillary renal cell carcinoma (type 1 and type 2)
• clear cell renal cell carcinoma
• translocation-associated renal cell carcinoma
• Renal cell carcinoma associated with acquired cystic kidney disease
• Renal cell carcinoma associated withhereditary leiomyomatosis(Doehn 2020)

Tumor classification

According to the Union for International Cancer Control (UICC) 2017, RCCs are classified as follows: 

T

• T 0: Primary tumor not detectable
• T 1: Tumor up to 7 cm in size and confined to the kidney
• T 1a: Less than 4 cm in size
• T 1b: 4–7 cm in size
• T 2a: Tumor > 7 cm – 10 cm
• T 2b: > 10 cm in size
• T 3a: Invasion into the renal vein or perirenal infiltration
• T 3b: Invasion of the vena cava below the diaphragm
• T 3 c: Invasion of the vena cava above the diaphragm
• T 4: Penetration of Gerota’s fascia

N

• N 0: No evidence of lymph node metastases
• N 1: Evidence of metastasis in 1 regional lymph node
• N 2: Evidence of metastasis in more than 1 lymph node

M

• M 0: No evidence of distant metastases
• M 1: Evidence of distant metastases

TNM staging system of the Union for International Cancer Control (UICC, 2010):

Stage I: T1 N0 M0

Stage II: T2 N0 M0

Stage III: T1 N1 M0

                     or: T2 N1 M0

                     or: T3 N0 M0

                     or: T3 N1 M0 

Stage IV: T1 N2 M0

                      or: T2 N2 M0

                      or: T3 N2 M0

                      or: T4 N0 M0

                      or: T4 N1 M0

                      or: T4 N2 M0

                      or: any T, any N, M1

Venous invasion in RCC: Here, a distinction is made between four different levels:

• Level I: The tumor extends to the renal vein
• Level II: The tumor extends below the liver to the vena cava
• Level III: The tumor extends below the diaphragm into the intrahepatic vena cava. A two-cavity procedure is required for clamping.
• Level IV: A tumor thrombus is present above the diaphragm. This necessitates a two-cavity procedure with a heart-lung machine. (Manski 2020) 

Renal cell carcinoma accounts for approximately 2%–4% of all malignant neoplasms in adults (Delecluse 2020) and, at 90%, is the most common malignant kidney tumor in adults (Manski 2020).

RCC typically grows unilaterally, but in 1% of cases it can also be bilateral (Herold 2020).

Medullary RCC is found on the right side in approximately 75% of affected individuals (Golbeck 2013).

The cause of RCC is as yet unknown. However, several risk factors are known to promote disease. These include:

• Smoking (2 x higher risk (Keller 2010)
• secondary renal cysts in chronic renal insufficiency (this increases the risk by a factor of 30 [Keller 2020])
• terminal renal failure
• tuberous sclerosis (autosomal dominant inherited phakomatosis [Pantelis 2007])

(Kasper 2015)

• Analgesic- nephropathy due to several years of use of mixed analgesics or NSAIDs (with the exception of ASA).

(Wolf 2020)

• occupational pollutants such as:
  • Cadmium
  • Trichloroethylene
  • asbestos (Keller 2010)
• Obesity especially in women (Keller 2010)
• Phacomatoses such as:
  • Neurofibromatosis
  • tuberous sclerosis
  • Sturge- Weber- Krabbe disease (Keller 2010 / Ertl- Wagner 2007)

A familial cluster is found in about 4% of all RCC. For first- or second-degree relatives, the risk of also developing RCC increases by a factor of 2 - 4 (Doehn 2020).

RCC originates from the epithelium of various segments of the nephron in mature renal parenchyma (Manski 2020): 

• clear cell renal cell carcinoma originating in the proximal tubule
• papillary RCC of the proximal tubule
• Oncocytoma of the cortical collecting duct
• chromophobe carcinoma, also originating from the cortical collecting duct
• Ductus Bellini carcinoma originating from the medullary collecting duct in the renal medulla (Kasper 2015)

Germline mutations can be detected in 1%–4% of all RCC cases.

Currently, four molecularly defined syndromes are known to be associated with an increased risk of developing RCC:

• Hippel-Lindau syndrome(in this autosomal dominant hereditary multisystem disorder, RCC is found in approximately 30% of cases [Herold 2020])
• Birt-Hogg-Dubé syndrome
• Hereditary leiomyomatosis and renal cell carcinoma
• Hereditary papillary renal cell carcinoma (Doehn 2020)

Also seen in: 

• CNS hemangioblastoma (a rare benign tumor of the posterior fossa or other parts of the nervous system [Dützmann 2018])
• Retinal angiomatosis (Herold 2020)

RCC can occur at any age, but the incidence increases significantly with age (Kasper 2015). An exception is medullary RCC, the average age of which is 19 years (Golbeck 2013).

The male sex is affected twice as often as the female sex (Kasper 2015).

The peak age of disease is 68 years for men and 71 years for women (Doehn 2020).

The leading clinical symptoms of RCC are:

Haematuria : Haematuria is found in about 60% of all patients. It is caused by a herniation of the renal pelvis, which occurs relatively early in RCC (Herold 2020).

Abdominal pain: occurs in about 40 % (Herold 2020).

Palpable tumour in the flank area: If the tumour is already palpable, it is usually inoperable (Herold 2020).

However, these typical symptoms exist in only 10 % - 20 % of patients. Further symptoms can be:

• unclear fever
• weight loss
• Anemia

varicocele, especially of the left testis (if it breaks into the left renal vein (Kasper 2015)

paraneoplastic syndromes: they are caused by tumor-induced hormone production, such as

• hypertension (due to renin)
• hypercalcemia (due to parathyroid hormone-related protein = PTHrP)
• Polyglobulia (due to erythropoietin)
• Stauffer's syndrome (liver dysfunction caused by the tumor with increased AP)

The above-mentioned symptoms usually occur only facultatively or only at a late stage.

Initially, the symptoms are mostly unspecific or rather point to a systemic disease. This is why RCC is also referred to as the "urological chameleon" (Ganten 2002). However, most RCC (60 % - 70 %) are still discovered as an incidental finding during sonography, as no typical symptoms are present in the early stages. (Herold 2020)

Metastasis: Ifmetastasis has already occurred, the following symptoms may also exist, for example:

• Icterus
• Cough
• Dyspnoea
• bone pain
• neurological deficits (Manski 2020)

Inspection and Physical Examination

• Occasionally, a palpable, breath-shiftable abdominal mass at the lower pole of the kidney
• primarily a left-sided varicocele that does not resolve when lying down (Keller 2010)
• Hypertension (Herold 2020)

Sonography: Tumours with a diameter of approx. 2 cm or more can be visualised by sonography (Keller 2010).

Benign tumours, such as angiomyolipoma, are increasingly presented echogenically as a smoothly delineated mass, whereas renal cell carcinoma and oncocytoma both show an inhomogeneous echo pattern (Kuhlmann 2015).

Visualization of possible metastases to the liver (Manski 2020).

Further investigations should be performed to clarify the dignity of the tumor and metastases (see below). (Keller 2010)

Color duplex sonography: In RCC, a basket-like displacement of the intrarenal vessels can be visualized, which is also referred to as a so-called parenchymal hump or pseudotumor (Keller 2010).

Chest X-ray: A chest X-ray should be performed to exclude pulmonary metastases. If tumors > 3 cm are found or if pulmonary symptoms exist, a chest CT is recommended for further diagnosis (Manski 2020).

CT abdomen. CT can be used to:

• the renal function of the opposite side can be assessed
• a lymphadenopathy of > 1 cm indicates a lymphogenic metastasis (Manski 2020)
• For the planning of organ-preserving surgery, the vascularisation of the tumour can be visualised with the aid of contrast medium:
  • papillary renal cell carcinoma is less vascularized
  • the clear cell tumor is stronger
  • a benign tumor presents hypo- or avascular (Kuhlmann 2015).

CT- Thorax: In case of radiological evidence of > 3 cm pulmonary metastases or pulmonary symptoms, a CT of the thorax should be performed (Manski 2020).

MRI: According to the guideline, an additional MRI should always be performed if the tumor shows vein involvement or protrudes into the inferior vena cava, as an MRI can be used to more accurately assess tumor extension (Doehn 2020).

Accurate determination of invasion is important for surgical planning (Manski 2020). The exact staging s. b. Venous invasion in RCC under "Classification."

In addition, MRI is required in patients with known contrast allergy (Kuhlmann 2015).

Cranial MRI: Cranial MRI should be performed in cases of suspected brain metastases (Manski 2020).

Bone scintigraphy: Bone scintigraphy is indicated in:

• advanced RCC
• elevated AP
• Bone pain
• Evidence of other metastases (Manski 2020).

Fine-needle biopsy: A preoperative fine-needle biopsy should be performed as a punch-cylinder biopsy under ultrasound or CT control if it would influence the choice of therapy (Doehn 2020). This may be the case, for example, in the presence of:

• Renal abscess
• Lymphoma
• metastases
• before systemic therapy in advanced stages of the disease. If there is no histopathological finding so far, a biopsy from the primarius or from the metastasis is recommended (Doehn 2020). (Manski 2020)

Biopsy of cystic tumors is considered contraindicated because the probability of detecting the solid portions (and thus the possibility of excluding a malignant tumor) in a cystic tumor is too low (Doehn 2020).

False negative histology is found in 5%-15% (Manski 2020).

The following laboratory abnormalities may exist in RCC:

• Anemia
• Erythrocytosis (found in about 3% at the time of initial diagnosis) (Kasper 2015).
• Thrombocytosis
• Hypercalcemia
• Liver dysfunction (also without liver metastases as so-called "Stauffer syndrome", see above "Clinical picture" [Herold 2020])
• Increase in alkaline phosphatase
• Disorders of hormone balance (e.g. erythropoietin, glucagon, PTHrP, renin, ACTH-like hormone, gonadotropins, insulin) (Keller 2010)
• increased inflammation values
• impaired blood coagulation (Manski 2020)

To date, there are no molecular markers in RCC that could provide evidence of metastasis (Doehn 2020).

Differential diagnosis of hematuria:

• Nephrolithiasis (Herold 2020)

Differential diagnosis to renal tumor are e.g.:

• inflammatory tumors:
  • Abscess
  • xanthogranulomatous pyelonephritis
  • infected renal cyst
  • rheumatic diseases with granuloma formation
  • tuberculosis
• Tumors of immature renal parenchyma:
  • Wilms tumor
  • sarcoma
• Tumors of mature renal parenchyma:
  • adenoma
• Tumors of the renal pelvis:
  • Papilloma
  • Urothelial carcinoma
  • Adenocarcinoma
  • Squamous cell carcinoma
  • cystic kidney tumours
• renal tumors of the vascular system:
  • Hamartoma
  • Hemangioma
  • Lymphangioma
  • Angiomyolipoma
• Mesenchymal renal tumors:
  • Fibroma
  • Fibrosarcoma
  • Lipoma
  • Liposarcoma
  • Leiomyoma
  • Leiomyosarcoma
• Renal tumors of the nervous system:
  • Neuroblastoma
  • Schwannoma
  • Sympathicoblastoma
• perirenal tumors:
  • retroperitoneal sarcoma
  • Lymphoma
  • Neuroblastoma
  • Lymph node metastasis (e.g. from testicular tumours)
  • Teratoma
• renal metastases from:
  • Bronchial carcinoma
  • breast carcinoma
  • gastrointestinal carcinoma
  • malignant melanoma
  • lymphoma (Manski 2020)

Metastases

Metastasis primarily occurs via the hematogenous route—usually first to the lungs—and subsequently to the bones, adrenal glands, liver, and central nervous system. 

Lymphogenous metastasis occurs via the regional lymph nodes, the cisterna chyli, or the thoracic duct, with local metastasis occurring only as a final stage (Keller 2010).

Metastases from renal cell carcinoma are frequently found in the following areas (Keller 2010):

• Lungs and mediastinum (55%)
• Regional lymph nodes, such as those at the renal hilum, abdominal, para-aortic, and paracaval (34%)
• Liver (33%)
• Skeletal system (32%)
• Adrenal glands (19%)
• contralateral kidney (11%)
• CNS (6%)
• In the oral cavity, primarily the gums (in approximately 23% of cases, oral cavity metastases are the first sign of a malignant process. Metastases of RCC in the oral cavity occur in 8.5% of women and 11% of men (Wittig 2012).

The treatment of renal cell carcinoma is primarily surgical and is also carried out depending on the stage (for tumour classification, see "Classification"). Neoadjuvant therapy is not clinically relevant.

In certain cases, the following can be used:

• Immunotherapy (e.g. in the case of multiple metastases)
• radiotherapy (e.g. for bone metastases)
• ablative procedures such as cryo- or radiofrequency ablation for small RCC and high comorbidity or limited life expectancy) (Doehn 2020).

Clear cell RCC: Clear cell RCC is almost completely resistant to common cytotoxic or cytostatic agents.

In advanced stages or in the presence of metastases, human monoclonal antibodies (such as a combination of pembrolizumab plus axitinib) can be used for first-line therapy (Doehn 2020).

Multiple metastases: For multiple metastases, palliative therapy (with the exception of metastatic clear cell RCC [Doehn 2020]) is possible with:

- giogenesis inhibitors e.g. Bevacizumab combined with Interferon- alpha

- rosine kinase inhibitors, so-called VEGFR inhibitors, e.g. sorafenib, sunitinib

- TOR inhibitors such as temsirolimus, everolimus

- mune checkpoint inhibitors such as PD-1 inhibitor Nivolumab (Herold 2020)

Bone metastases: In this case, treatment can be carried out with bisphosphonates or local radiotherapy (Herold 2020).

Stage I (see "Classification"): Currently, organ-preserving partial kidney resection is considered the standard for patients in stage I or T1. Depending on the anatomical conditions, this can be performed open or laparoscopically (Kasper 2015). In laparoscopic procedures, blood loss is generally lower and the inpatient stay shorter (Doehn 2020).

Stage ≥ II (see "Classification"): From stage II and higher, radical nephrectomy is the standard procedure.

The operation is performed using the so-called no-touch technique, i.e. before manipulation of the kidney, the blood vessels supplying and draining the kidney are cut off. In radical nephrectomy, the kidney with perirenal fat capsule, Gerota's fascia, ipsilateral adrenal gland, ureter and the spermatic and ovarian vessels are resected en bloc, as well as the paracaval and paraaortic lymph vessels and any cone from the vena cava (for stages of vein invasion, see "Classification"). (Herold 2020)

Bilateral tumors: In bilateral tumors, the primary goal should be partial renal resection. If this is not possible, it is recommended to perform partial resection on the technically simpler side first. The residual function of the operated kidney should be evaluated p.o. after about one month.

If the function is sufficient, a tumor nephrectomy can be performed on the other side.

If function is insufficient, the options are imperative partial kidney resection or tumor nephrectomy followed by dialysis. (Manski 2020)

Lymphadenectomy: Systematic lymphadenectomy is not recommended with unremarkable preoperative imaging and unremarkable intraoperative findings (Doehn 2020).

Solid distant metastases: Solid distant metastases from e.g. liver or lung can also be surgically removed or minimally invasively destroyed (Herold 2020).

Multiple metastases: see above "Internal therapy".

Note: If there are contraindications to surgery, local ablative procedures such as radiofrequency or crypto-ablation can be used (see above "Therapy, general" (Herold 2020).

Preoperatively and postoperatively, various formulas can be used to calculate the risk of recurrence.

For example, preoperative formulas include:

• Cindolo formula
  • ≤ 1.2 = low risk with a 2- and 5-year recurrence-free rate of 96% and 93%, respectively.
  • > 1.2 = high risk with a 2- and 5-year recurrence-free rate of 83% and 68%, respectively.
• Yaycioglu- Formula
  • ≤ 3 = low risk with a 2- and 5-year relapse-free rate of 98% and 92%, respectively.
  • > 3 = high risk with a 2- and 5-year recurrence-free rate of 67% and 57%, respectively (Doehn 2020).

Postoperative formulas include, for example:

• UCLA Integrated Staging System (UISS- Model).
  • Stage I: 2- and 5-year recurrence-free rates of 96% and 94%, respectively (equivalent to TNM I).
  • Stage II: 2- and 5-year recurrence-free rates of 89 % and 67 % respectively (corresponds to TNM I, II, III)
  • Stage III: 2- and 5-year recurrence-free rate of 66 % and 39 % respectively (corresponds to TNM III and IV))
  • Stage IV: 2- and 5-year recurrence-free rate of 42 % and 23 % respectively (corresponds to TNM IV)
  • Stage V: 2- and 5-year relapse-free rate of 9 % and 0 %, respectively (corresponds to TNM IV) (Doehn 2020 / Kraus 2014).

A good prognosis has:

• papillary renal cell carcinoma
• multilocular cystic renal cell carcinoma (Golbeck 2013)
• oncocytoma (Kraus 2014)

A poor prognosis:

• clear cell RCC
• Ductus Bellini carcinoma
• Renal medullary RCC (in this case, distant metastases are already found at initial diagnosis in about 95% of cases [Golbeck 2013]). (Herold 2020)

Mortality: The prognosis of RCC is relatively favorable compared to other malignancies. In men, the relative 5-year survival rate is 75% and in women 77%. Depending on the tumor stage, the 5-year survival rate is:

• Stage I: 97 %
• Stage II: 87 %
• Stage III: 60 % without lymph node involvement / 30 % with lymph node involvement (Herold 2020)
• Stage IV: 30 % if solitary metastases removed, < 5 % in all other cases (Herold 2020) (Doehn 2020).

Metastatic RCC: Prognosis is markedly variable in metastatic RCC. Patients have a poor prognosis if the following factors are present:

• No nephrectomy
• KPS (Karnofsky Performance Status) < 80
• low Hb value
• high corrected calcium
• abnormally high LDL levels

Patients had a median survival at:

• no factor of 24 mon.
• 1 - 2 factors by 12 mon.
• ≥ 3 factors by 5 mon (Kasper 2015).

Depending on the stage of the disease, patients are divided into 3 different groups:

• 1. Low risk pT1a / b, cN0, cM0, G1 - 2
• 2. medium risk (Intermediate risk)
  • pT1a / b, cN0, cM0, G 3
  • pT2 c / pN0, cM0, G1 - 2
  • ablative therapy or R1-situation (residual tumor) of a low-risk carcinoma
• 3. High risk
  • pT2 c / pN0, cM0, G3
  • pT3 - 4 and / or pN + (Doehn 2020)

Since even in early stages of RCC sonography, excretory urogram and angiography do not allow reliable staging, the following procedure is recommended:

1. patients with Low risk: In these patients the following examinations should be performed at intervals of 3, 6, 12, 18, 24, 36 and 48 months:

• clinical examination
• Determination of laboratory parameters such as blood count, creatinine, CRP, ESR (the increase in nonspecific inflammatory parameters may indicate metastasis).
• Sonography of the abdomen in examinations where no CT or MRI is performed
• CT or MRI of the abdomen pelvis and bone window (after 3, 12, 24 and 48 months)
• CT or MRI of the thorax (after 12, 24 and 48 months) (Doehn 2020)

2. patients with intermediate risk: The examinations that are performed in patients with low risk are also performed. However, the time intervals are different: 3, 6, 12, 18, 24, 36, 48, 60, 84, 108 months.

CT of the thorax should be done at 6, 12, 24 months and then at each subsequent examination.

CT of the abdomen at (3), 12, 36, 60 months and then at each subsequent examination. (Doehn 2020)

Patients with high risk: The examinations that are carried out in patients with low risk are also carried out here. The time intervals are as for intermediate risk 3, 6, 12, 18, 24, 36, 48, 60, 84, 108 months. However, CT of the thorax should be performed for the first time at 6 months and then at each subsequent examination. CT of the abdomen is recommended at (3), (6), 12, 24, 60 months and subsequently at each subsequent examination. (Doehn 2020)

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