Renal Cell Carcinoma: Overview


A. Primary tumour (T)

Tx

Primary tumour cannot be assessed

T0

No evidence of tumour

T1a

Tumour ≤4 cm in maximal dimension, limited to the kidney

T1b

Tumour ≥4 cm but ≤7 cm

T1b

Tumour ≥7 cm and ≤10 cm in maximal dimension, limited to the kidney

T2a

Tumour more than 10 cm in maximal dimension limited to the kidney

T2b

Tumour more than 10 cm in maximal dimension, limited to the kidney

T3a

Tumour directly invades adrenal gland or perirenal and/or renal sinus fat but not beyond Gerota’s fascia

T3b

Tumour grossly extends into the renal vein or its segmental (muscle-containing) branches or invades the vena cava below the diaphragm

T3c

Tumour grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava

T4

Tumour invades beyond Gerota’s fascia (including continuous extension into ipsilateral adrenal gland)

B. Regional lymph nodes (N)

Nx

Lymph nodes cannot assessed

N0

No regional lymph node metastasis

N1

Metastasis in a single regional lymph node

N2

Metastasis in more than 1 regional lymph node

C. Distant metastasis

Mx

Distant metastasis not assessed

M0

No distant metastasis

M1

Distant metastasis



Additionally for clear cell RCC, the Fuhrman grading scheme for grading alterations to the nuclei can be used to give grades of I-IV (Table 17.2) that have been reported to correlate with prognosis, but the utility of the grading is less agreed on for other histological subtypes, though low grade and high grade can be used as one of the criteria to separate papillary RCC into types I and II. The vast majority of chromophobe RCC are low grade while oncocytomas are not graded. Within an individual stage, grade has prognostic value for clear cell RCC [3].


Table 17.2
Fuhrman grading


















F1

Nuclei are small (<10 μm) and round, with dense chromatin and inconspicuous nucleoli

F2

Nuclei are slightly larger (15 μm), with finely granular chromatin and small nucleoli

F3

Nuclei are 20 μm in size and may be oval in shape, with coarsely granular chromatin and prominent nucleoli

F4

Nuclei are pleomorphic, with open chromatin and single or multiple macronucleoli

An analysis of the incidence of RCC in the US from 1986 to 1998 based on SEER data reported stage at presentation to be 54 % localized (stage I or II), 21 % regional (stage III), 25 % advanced (stage IV) [4] (Table 17.3).


Table 17.3
Anatomic stage/Prognostic groups










































Stage

T

N

M

I

T1

N0

M0

II

T2

N0

M0

III

T1 or T2

N1

M0

T3

N0 or N1

M0

IV

T4

Any N

M0

Any T

Any N

M1


Reprinted Compton et al. [36]. With permission from Springer Verlag

Individuals with chromophobe RCC appear to have better survival rates than those with clear cell RCC. While individuals with a localized papillary RCC demonstrate a more favourable outcome than those localized clear cell RCC, this difference in tumour type has no apparent effect on the 5-year survival rates for extrarenal papillary RCC compared to extrarenal clear cell RCC [5].

Clear cell RCCs (CCRCC) have a higher propensity for vascular invasion than for lymphatic invasion, with malignant cells found within small intrarenal veins even in 18–29 % of organ-confined tumors [68]. Thus, for CCRCC, invasion into the renal sinus usually involves extension within the renal vein, leading to a higher propensity for distant metastasis than for loco-regional spread and involvement of the regional lymph nodes, which are more common pathways of spread in chromophobe and papillary RCC, respectively [7, 911].

The 5-year survival rate is high for patients with tumours limited to the kidney, 95 % in patients with T1 RCC and 88 % in patients with T2 RCC. However survival declines rapidly with the tumour invasion outside the kidney: patients with T3 RCC have a 5-year survival rate of 59 %, and those with T4 disease had a 5-year survival rate of 20 %.

The 5-year survival rates after radical nephrectomy for stage I and stage II RCC are approximately 94 and 79 % respectively, essentially the same as T1 and T2 RCC. Although renal vein involvement does not have a markedly negative effect on prognosis, the 5-year survival rate for patients with stage IIIB (T3b) renal cell carcinoma is 18 %. In patients with effective surgical removal of the renal vein or inferior vena caval thrombus, the 5-year survival rate is 25–50 %. Patients with regional lymph node involvement or extracapsular extension have a survival rate of 12–25 %. Unfortunately, 5-year survival rates for patients with stage IV disease are low (0–20 %).

Five survival prognostic factors for metastatic RCC patients have been used to categorize such patients into three tiered risk groups [12]. The prognostic factors were (1) low Karnofsky performance status (<80 %), (2) high serum lactate dehydrogenase (LDH) level (>1.5 times upper limit of normal), (3) low haemoglobin (below lower limit of normal), (4) high “corrected” serum calcium (>10 mg/dL) and (5) previous history of nephrectomy. Patients in the lowest risk group (zero risk factors) had a median survival of 20 months, while patients with intermediate risk (1 or 2 risk factors) had a median survival of 10 months and patients in the highest risk group (3 or more risk factors) had a median survival of only 4 months. Other factors reported to be associated with increased survival in patients with metastatic disease include the presence of only pulmonary metastases, the removal of the primary tumour and a good general performance status. Notably, a long disease-free interval between the initial nephrectomy and the first appearance of metastases is important, with progression-free survival at 3 and 6 months predicting better overall survival among patients with metastatic renal cell carcinoma [13].


Molecular Basis and Genetics of Renal Cell Carcinoma


Both inherited and acquired (somatic) genetic changes are implicated in the pathogenesis of familial RCC whereas somatic changes cause sporadic RCC. The best recognised inherited disorder predisposing to development RCC is von Hippel-Lindau (VHL) disease (see Chap. 3), resulting from the germline mutation or deletion of the VHL gene at chromosome 3p25 [14]. Affected individuals are at increased risk to tumours within multiple organ systems, including cysts and tumours of the kidney (lifetime risk of RCC >70 %), with a mean age at onset of 40 years. The patients frequently present with multifocal and/or bilateral RCC tumours and they are always of the CCRCC histologic type. Inherited constitutional chromosome 3 translocations can predispose to RCC (most commonly CCRCC). However, individuals who have an incidentally detected chromosome 3 translocation with no personal or family history of RCC are unlikely to be at high risk of RCC. Further major inherited disorders associated with RCC include: hereditary papillary renal carcinoma (HPRC), Birt-Hogg-Dubé (BHD) syndrome, hereditary leiomyomatosis renal cell carcinoma (HLRCC) and succinate dehydrogenase mutation associated renal cell carcinoma (SDH-RCC) [14, 15]. Also RCC may rarely complicate Tuberous Sclerosis (TS), and Cowden syndrome (Multiple hamartoma syndrome).

Hereditary papillary renal carcinoma and hereditary leiomyomatosis renal cell carcinoma are both associated with the development of papillary renal cell carcinoma (CCRCC) histologic types: type I with HPRC and type II with HLRCC. Birt-Hogg-Dubé syndrome predisposes to the development of a variety of histopathological subtypes including chromophobe, hybrid oncocytic, and CCRCC [16]. Succinate dehydrogenase mutation associated renal cell carcinoma also is not confined to a specific histologic type of RCC [17].

In addition there are patients with features of inherited non-syndromic RCC (e.g. family history of RCC, multifocality, bilaterality, and early age of onset) in whom no known genetic cause can be detected. Further investigation of these individuals should lead to the identification of novel hereditary RCC genes.


Clear Cell RCC


Clear cell RCC can be sporadic (>95 %) or familial (<5 %). Most sporadic RCC have somatic inactivation of the von Hippel Lindau (VHL) tumor suppressor gene located at chromosome 3p25 [18, 19] but VHL functions as a classical tumour suppressor gene in that inactivation of both alleles of the gene are required to initiate tumorigenesis. In sporadic RCC somatic mutation, loss or (less commonly) promoter methylation produce the two “hits” required for tumourigenesis whereas in patients with VHL disease the first “hit” is the germline VHL gene mutation and only one somatic hit is required for tumourigenesis.

The protein encoded by the VHL gene (pVHL) is a component of the elongin complex and is involved in targeting the hypoxia inducible factor alpha (HIFα) proteins for ubiquitination and subsequent degradation. Thus pVHL plays a critical role in the regulation of gene expression in response to oxygen levels. Inactivation of the VHL gene stabilises the levels of hypoxia-inducible factor-1α (HIF1α) and hypoxia-inducible factor-2α (HIF2α), which in turn activates expression of hypoxia response genes involved in the angiogenesis (e.g. vascular endothelial growth factor (VEGF)), cell proliferation (e.g. transforming growth factor alpha (TGFα)), apoptosis and other signalling pathways [20, 21]. Many recently introduced therapies for metastatic RCC target the tyrosine kinase receptors for HIF-regulated growth factors (e.g. VEGF). Though both HIF1 and HIF2 may be upregulated in pVHL-deficient clear cell RCC it appears that HIF2 is most responsible for promoting oncogenesis [21]. Amplification of, or activating mutations within, known proto-oncogenes is relatively infrequent in clear cell RCC though amplification of the MYC proto-oncogene on chromosome 8q can be detected in ~12 % of clear cell RCC [22]. Deletions of chromosome 3p occur in the majority of clear cell RCC and copy number loss on chromosomes 14, 8, 9, and 6 may be detected in 0–20 % [22]. Large scale candidate gene and exome sequencing studies of clear cell RCC have demonstrated that, after VHL inactivation, the most commonly mutated genes are those implicated in chromatin modelling/histone modification. Thus Varela et al. [23] undertook exome sequencing and found that the SWI/SNF chromatin remodelling complex gene PBRM1 demonstrated truncating mutations in 41 % of clear cell RCC. In addition SETD2, JARID1C, UTX and MLL2 have each been reported to be mutated in up to 5 % of clear cell RCC [24]. Interestingly, PBRM1 and SETD2 map to chromosome 3p21 an area of frequent allele loss in clear cell RCC that also contains the RASSF1A tumour suppressor gene that is frequently inactivated in sporadic clear cell and non-clear cell RCC.
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Jul 4, 2016 | Posted by in UROLOGY | Comments Off on Renal Cell Carcinoma: Overview

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