Clear cell RCC accounts for approximately 70 % of all RCC [8]. The highest incidence occurs in the sixth and seventh decades but there is a wide age distribution, and males are affected twice as frequently as women. Presenting signs and symptoms include hematuria, abdominal pain or discomfort, scrotal varicocele, or generalized symptoms such as weight loss, fever, anorexia, or fatigue. Tumors are frequently identified incidentally by imaging for unrelated issues. Clear cell RCC is cortically based and are generally solitary, and multiple lesions should raise the consideration of von Hippel–Lindau disease caused by a germ-line mutation of the Von Hippel–Lindau (VHL) tumor suppressor gene at chromosome 3p25.

Clear cell RCC generally exhibits a round to lobulated growth pattern with pushing borders and formation of a fibrous pseudocapsule. High-grade clear cell RCC may have infiltrative margins. Low-grade tumors have a distinctive golden yellow appearance due to high lipid content that may be lost in higher grade tumors. Areas of hemorrhage, fibrosis and cystic degeneration are frequent. Clear cell RCC exhibits a sheet-like or nested growth pattern interspersed by a rich network of delicate thin-walled vessels. The cells within clear cell RCC typically have an abundant clear cytoplasm and prominent cell membranes. Higher grade tumors may lose this lipid production and show populations of cells having a more eosinophilic or granular appearance. Most clear cell RCCs show reactivity using antibodies against low-molecular-weight keratins, vimentin, RCC antigen, epithelial membrane antigen (EMA) carbonic anhydrase IX (CA IX), and CD10. Clear cell RCC is usually not positive for cytokeratin 7 (CK7) or alpha-methylacyl CoA racemase (AMACR), features that can be helpful separating clear cell from papillary RCC . CD117 and e-cadherin are negative in clear cell RCC in contrast to chromophobe RCC . Immunohistochemical stains may be useful in separating clear cell RCC from other subtypes on needle core biopsy specimens using a panel that includes CA IX, CD117, AMACR, CK7 and CD10 [9]. Genetic testing of clear cell RCC is characterized by structural alterations of the short arm of chromosome 3 (3p) resulting in the loss of genomic material at 3p21 and 3p12–14 or 3p25.

The outcome of patients with clear cell RCC is dependent on grade, stage, tumor size , coagulative tumor necrosis , and the presence of sarcomatoid and rhabdoid differentiation [10]. A number of clinical nomograms are available based on these features to predict outcome [11]. In regard to the three most common RCC subtypes, stage for stage and grade for grade, clear cell RCC has a worse outcome than papillary and chromophobe RCC (Fig. 23.3) [12].

Multilocular cystic RCC is an uncommon variant of clear cell RCC accounting for less than 2 % of RCC . This tumor is multicystic, and cysts are lined by cells with low grade nuclear features and clear cytoplasm in addition to small nests of clear cells in the cyst walls. Expansile nests of clear cells, however, disqualify a tumor from this diagnosis. The distinction of multilocular cystic RCC from a benign renal cortical cyst is made by the presence of multiple cell layers lining the cysts or more frequently and more dependably, by the presence of nests of clear cells in the cyst wall. Patients have an excellent outcome following tumor excision, and in our experience, none of these tumors has exhibited aggressive behavior.

Papillary type RCC is the second most common type of RCC, and accounts for 10 % of adult RCC [8]. The age distribution, male to female ratio, and presenting signs and symptoms are similar to patients with clear cell RCC. Papillary RCC (PRCC) is typically solitary, but multifocal or bilateral lesions are not uncommon, and rarely indicative of an inherited RCC syndrome. Grossly, PRCC is lobulated and circumscribed and frequently show degenerative changes with hemorrhage and friability. PRCC demonstrates a wide variety of morphologic features but are characterized by a papillary or tubulo-papillary growth pattern. Papillary structures are composed of fibrovascular cores that contain lipid-laden histiocytes. Some tumors have a more solid and tubular growth pattern mimicking metanephric adenoma. Psammomatous calcifications, areas of hemosiderin deposition (that can be present within the cytoplasm of tumor cells) and necrosis are also frequent findings.

The cells comprising PRCC can be quite variable showing a range of minimal to abundant eosinophilic, basophilic, or clear cytoplasm. This variability in cytoplasmic appearance has resulted in the categorization of PRCC into two types based in part on these cytoplasmic differences (Fig. 23.4) [13]. Tumors classified as type 1 are comprised of cells with a minimal amount of pale to basophilic cytoplasm and small oval nuclei with inconspicuous nucleoli. Cells of type 1 tumors tend to be distributed in a single layer along the papillary structures and commonly show lipid-laden macrophages and psammomatous calcifications. Type 2 tumors are comprised of cells with more abundant eosinophilic cytoplasm and larger, round nuclei with visible nucleoli, showing a pseudostratified organization along the papillary structures. Classifying a particular PRCC as type 1 or 2 can be problematic at times as there can be areas demonstrating features of both types within a single tumor. Cells with clear cytoplasm can be seen in PRCC , though generally they do not show the clarity of clear cell RCC but have a suggestion of granularity within the cytoplasm. The presence in a tumor with a papillary growth pattern of a significant proportion of cells with clear cytoplasm should raise the possibility of a translocation-associated RCC. Immunohistochemically, tumors are positive for low molecular weight keratin, RCC, CD10 and P504S, and CK7 is present in a significant proportion of PRCC with type 1 morphology. In cases of low-grade papillary RCC with basophilic features that resembles metanephric adenoma, WT-1 and CK7 are particularly helpful, as PRCC is WT1 negative and CK7 positive in contrast to metanephric adenoma. Immunohistochemistry (transcription factor E3/transcription factor EB, TFE3/TFEB) and molecular genetic analysis can be used to differentiate from translocation-associated tumors. The most reproducible genetic abnormality in PRCC is trisomy of chromosomes 7 and 17. Patients with PRCC have a better outcome grade for grade and stage for stage when compared to patients with clear cell RCC. Features predictive of outcome include tumor grade and stage. Although it is recommended to report the type of PRCC, the grade is a stronger prognostic feature than the type [14].

Clear cell PRCC (also known as clear cell tubulopapillary RCC) is a relatively recently described subtype of RCC that displays features of both clear cell and PRCC. This entity, along with other recently described entities addressed in this chapter, is covered in greater detail in Chap. 26 of this book. These tumors are typically circumscribed, encapsulated, and solitary although multiple tumors have been described in patients. They show areas of papillary, acinar, or tubular growth with a cystic component common. The cells have a small to moderate amount of clear cytoplasm and small, compact nuclei. A helpful diagnostic feature is the orientation of the nuclei towards the apical aspect of cells lining tubules or papillary structures. Unlike PRCC, clear cell papillary RCC does not contain clusters of lipid-laden histiocytes or exhibit necrosis.

Clear cell papillary RCC demonstrates a distinct immunophenotype. Tumor cells are strongly positive for CK7 and CA IX, and are typically negative for CD10 and AMACR [15]. Molecular studies have shown that clear cell papillary RCC represents an entity distinct from either papillary or clear cell RCC as it does not exhibit trisomy 7 or 17 or alteration of chromosome 3p. Based on reports thus far, clear cell papillary RCC is an indolent tumor. Nearly all tumors are low grade (ISUP grade 1 and 2) and low stage, and no reports of death have been reported although in our experience, rare tumors have acted aggressively.

Chromophobe RCC constitutes approximately 5–10 % of RCC [8, 10]. Signs and symptoms, age distribution and male to female ratio are similar to other RCC subtypes. Chromophobe RCC can be quite large and most are circumscribed, homogenous, and lack necrosis (Fig. 23.5). Higher stage tumors and tumors with necrosis should raise concern for sarcomatoid differentiation. Chromophobe RCC has a characteristic histologic appearance with solid growth and cells that have distinct cell membranes, abundant clear to eosinophilic cytoplasm with perinuclear clearing and irregular nuclei imparting a “plant cell” appearance to the tumor. Some tumors are composed of cells with eosinophilic cytoplasm, the so-called eosinophilic variant of chromophobe RCC. The nuclei in chromophobe RCC have a characteristic appearance and are particularly helpful in separating from other tumors, particularly oncocytoma. The nuclei have irregular wrinkled contours, often described as “raisinoid” or “koilocytotic” with condensed chromatin and inconspicuous nucleoli. Chromophobe RCC usually demonstrate reactivity with antibodies against pan keratins, CK7, CD117 and e-cadherin and are usually negative for CD10 and vimentin. The most common recurrent genetic abnormalities described in chromophobe RCC are losses of whole chromosomes 1, 2, 6, 10, 13, 17, and 21. Outcome for chromophobe RCC is similar to patients with papillary RCC. Features associated with outcome include stage, tumor necrosis , and presence of sarcomatoid component [10]. The ISUP recommends that tumors that share features of chromophobe and oncocytoma be designated as “hybrid” oncocytic chromophobe tumor and be classified as chromophobe RCC [3] .