The most characteristic feature of clear cell RCC in both resection and biopsy specimens is the presence of delicate, intricately branching, richly vascular fibrous septae (Fig. 3.1A-D) that surround solid acini, alveoli, tubules, cysts, or papillary/pseudopapillary structures. Many tumors show a combination of these growth patterns in variable proportions (Fig. 3.2A-F, eFigs. 3.1 and 3.2). The rich capillary vascular network is retained in almost all but some high-grade, sheet-like, and sarcomatoid areas. Thus, this diagnostic hallmark of the characteristic vascularity should be the initial focus of attention in the diagnosis of clear cell RCC, and more so in needle core biopsies. In general, architectural pattern is loosely associated with grade (discussed later) because most low-grade lesions have

an acinar growth, whereas higher grade areas are more likely to exhibit solid, pseudopapillary, or sarcomatoid features (Fig. 3.2E,F). Tumors exhibiting a pseudopapillary growth pattern, which must not be confused with the true papillary growth pattern typically seen in papillary RCCs, are characterized by pseudopapillae lacking true fibrovascular cores. In our experience, pseudopapillations are particularly more common in core biopsies, especially at their edges, as these are the areas most prone to


lose the direct support and compression provided by the walls of biopsy needle on delivery from the needle. Such pseudopapillations occur more often in high-grade tumors, as they are less likely to have closely arranged fibrovascular septations and, therefore, abundant internal architectural support (Fig. 3.3). Occasionally, the biopsy may yield what at initial evaluation appears as fibrous tissue only. This often represents the biopsy needle
hitting a scar within the tumor. However, single or small clusters of cells— resembling small lymphocytes with scant clear cytoplasm—may often be noted dispersed within the fibrosis (Fig. 3.4A,B). These very frequently represent rare tumor cells that are still viable within scar tissue and must be investigated further, particularly with the help of immunohistochemical stains. The results on immunohistochemical staining in such material are frequently surprising as well as gratifying (Fig. 3.4C). Many of the tubules and acini show intraluminal hemorrhage—a characteristic but not specific finding in clear cell RCC (Fig. 3.5). This feature is common even at metastatic sites and should lead to the workup for a possible renal primary. Areas of necrosis, sometimes extensive (Fig. 3.6A), and hemorrhage are some other not uncommon histologic findings seen in core biopsies. Some tumors contain an inflammatory infiltrate, often predominantly lymphocytic in nature (Fig. 3.6B). Calcifications and osseous metaplasia, as well as intracytoplasmic hyaline globules or Paneth-like coarse granules (eFigs. 3.3 and 3.4) may also be seen in occasional biopsies.

Besides the pure clear cell cytology in many tumors, the majority of clear cell RCCs show a mixture of cytoplasmic features in various proportions, that is, combination of cells with clear and granular eosinophilic cytoplasm (Fig. 3.7A). The cytoplasmic features often correlate with tumor grade; low-grade (grade 1 or 2) lesions almost always contain clear cytoplasm, whereas the cytoplasm of higher grade lesions is more likely to be variably eosinophilic and granular (Fig. 3.7B). Some grades 3 and


4 lesions may altogether lack clear cytoplasm (Fig. 3.7C). Grade 4 lesions contain bizarre, pleomorphic and/or multilobulated, and multiple nuclei (Fig. 3.7D); cells with rhabdoid features (Fig. 3.7E); or spindle cells (sarcomatoid areas) (Fig. 3.7F).

As a biopsy represents only a minute proportion of the tumor, and because the tumors often show morphologic heterogeneity, nuclear


grade in biopsy often does not correlate with the final grade on resection specimen (7,44,45). Therefore, if the nuclear grade is provided, it should be qualified by a statement similar to “… in this limited material.” As is intuitive however, high nuclear grade in the biopsy tends to correlate with high grade on resection specimen as well (7,45).

Among the immunohistochemical stains that are reported to be most useful in the differential diagnosis of clear cell RCC from other renal primary tumors on needle core biopsies, carbonic anhydrase IX (CA-IX) shows diffuse and strong membranous reactivity within more than 90% tumors (eFig. 3.5), including in its sarcomatoid components in a significant proportion of cases (20,46,47,48,49). CD10 is also often positive (membranous), but cytokeratin 7 (CK7), CD117, and racemase (AMACR) are generally negative.

However in our experience, AMACR tends to label some clear cell RCCs more than focally in needle core biopsies. Immunohistochemistry and molecular studies in renal and adrenal tumors are described in greater details in Chapter 13.