278 CHAPTER 6 Urological neoplasia

Renal cell carcinoma: epidemiology and etiology

Renal cell carcinoma (RCC)—also known as hypernephroma (since it was erroneously believed to originate in the adrenal gland), clear cell carcinoma, and Grawitz tumor—is an adenocarcinoma. It is the most common of renal tumors, accounting for 85% of renal malignancies and 2% of all cancer deaths.

In the United States, 57,760 patients were diagnosed in 2009 and 12,980 patients died of RCC. RCC is the considered the most lethal of all urological tumors, approximately 40% of patients dying of the condition. Incidence has increased since the 1980s, when imaging such as ultrasound and CT scanning became more commonplace to investigate nonspecific abdominal symptoms.

The size of the masses has also decreased with time as more and more masses are discovered incidentally. It occurs in sporadic (common) and hereditary (rare) forms.

Etiology

Males are affected twice as commonly as females. Peak incidence of sporadic RCC is the sixth to eighth decade.

Environmental

Studies have shown associations with the following:

•Analgesic phenacetin use

•Asbestos exposure

•Family history in a firstor second-degree relative (relative risk of 2.9)

•Hypertension (1.4- to 2-fold risk)

•Low socioeconomic status

•Obesity

•Renal failure and dialysis (30-fold risk)

•Smoking cigarettes, pipe, or cigars (1.4- to 2.3-fold increased risk smoking cessation can reduce the relative risk by 20–50%)

•Tobacco chewing

•Urban dwelling

Nutrition is considered important: Asian migrants to Western countries are at increased risk of RCC; vitamins A, C, E, and fruit and vegetable consumption are protective.

Anatomical risk factors include polycystic and horseshoe kidneys.

Genetics

Clear cell renal cell carcinoma

This is associated with deletion of chromosome 3p and/or mutations of the VHL gene.

Von Hippel–Lindau (VHL) syndrome

Half of individuals with this autosomal dominant syndrome, characterized by pheochromocytoma, renal and pancreatic cysts, and cerebellar hemangioblastoma, develop RCC, often bilateral and multifocal. Patients typically present in third, fourth, or fifth decades.

RENAL CELL CARCINOMA: EPIDEMIOLOGY AND ETIOLOGY 279

VHL syndrome occurs from loss of both copies of a tumor suppressor gene at chromosome 3p25–26; this and other genes on 3p are also implicated in causing the common sporadic form of RCC.

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 up-regulation of vascular endothelial growth factor (VEGF), the most prominent angiogenic factor in RCC, which is why some RCCs are highly vascular.

Chromophobe RCC is a result of loss of chromosome 17.

Non-hereditary papillary RCC is linked with changes in both chromosome 7 and 17.

Hereditary papillary RCC (HPRCC)

HPRCC arises from mutation and activation of the met proto-oncogene on chromosome 7p34 and has an autosomal dominant familial component. c-MET encodes the receptor tyrosine kinase for hepatocyte growth factor, which regulates epithelial proliferation and differentiation in a wide variety of organs, including the normal kidney.

Birt-Hogg-Dubé (BHD) syndrome

This is a rare, autosomal dominant disorder caused by germ-line mutations in the BHD (FLCN) gene within the chromosomal band 17p11.2 and encodes for a tumor-suppressor protein, folliculin. BHD syndrome is characterized by the cutaneous triad of fibrofolliculomas (hamartoma of the hair follicle), trichodiscomas, and skin tags, along with a propensity for renal tumors.

The renal tumors are often chromophobe RCC or oncocytoma or hybrids of these tumors. A substantial number of patients will develop clear cell tumors as well. These tumors are more likely to be multiple and bilateral.

280 CHAPTER 6 Urological neoplasia

Renal cell carcinoma: pathology, staging, and prognosis

RCC is adenocarcinoma of the renal cortex, believed to arise from proximal convoluted tubule. It is usually tan colored and solid; 7–20% are multifocal, 10–20% contain calcification, and 10–25% contain cysts or are predominantly cystic. Smaller lesions are rarely grossly infiltrative. They are usually circumscribed by a pseudocapsule of compressed tissue.

Spread

•By direct extension to adrenal gland (7.5% in tumors >5 cm), through the renal capsule, into the renal vein (5% at presentation), inferior vena cava (IVC), right atrium

•By lymphatics to hilar and para-aortic lymph nodes

•Hematogenous to lung (75%), bone (20%), liver (18%), and brain (8%).

Histological classification of RCC

•Conventional (70–80%): arise from the proximal tubule; highly vascular; cells clear (glycogen, cholesterol) or granular (eosinophilic cytoplasm, mitochondria)

•Papillary (10–15%): papillary, tubular, and solid variants; 40% multifocal; small incidental tumors could equate with Bell’s legendary “benign adenoma”

•Chromophobe (5%): arises from the cortical portion of the collecting duct; possess a perinuclear halo of microvesicles

•Collecting duct (Bellini): rare; young patients; poor prognosis

•Medullary cell: rare; arises from calyceal epithelium; young, Black, sickle-cell sufferers; poor prognosis

The term sarcomatoid is used to describe an infiltrative, poorly differentiated variant of any type.

Genetic changes associated with RCC are described on p. 278. RCC is an unusually immunogenic tumor. Reports of spontaneous regression, prolonged stabilization, and complete responses to immunotherapy support this. RCC is also unusually vascular, overexpressing angiogenic factors, principally VEGF but also basic FGF and TGF-A.

Grading is by the Fuhrman system (1 = well-differentiated; 2 = moderately differentiated; 3 and 4 = poorly differentiated) based on nuclear size, outline, and nucleoli.

Staging is by the TNM (2002) classification following histological confirmation of the diagnosis (see Fig. 6.8 and Table 6.13). All cases rely on physical examination and imaging; the pathological classification (prefixed p) corresponds to the TNM categories. Staging is the most important prognostic indicator for RCC (see Box 6.5). Fuhrman grade and histological subtypes are also important.

RENAL CELL CARCINOMA: PATHOLOGY, STAGING, & PROGNOSIS 281

(a)

(d)

Figure 6.8 Renal cell carcinoma staging. (a) Primary tumor is limited to kidney (T1/T2). T1a is <4 cm and T1b is >4 cm but not >7 cm. T2 is >7 cm. (b) Primary tumor invades perinephric tissue but not beyond perinephric fascia or invades adrenal gland (T3a). (c) Primary tumor extends into renal veins or IVC below the diaphragm (T3b); above the diaphragm into right atrium or invades wall of vena cava (T3c); or outside perinephric fascia (e.g., into liver, bowel, or posterior abdominal wall) (T4). (d) N and M staging: involves multiple para-aortic or paracaval nodes; pulmonary, bone, or brain metastases (T1–4N2M1).

282 CHAPTER 6 Urological neoplasia

Box 6.5 Prognosis—5-year survival

Nomograms have been developed to predict risk of recurrence

Reprinted with permission from Kattan MW, Reuter V, Motzer RJ, Katz J, Russo P. (2001). J Urol 166(1): 63–67.

Table 6.13 TNM staging of RCC

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