Renal cell carcinoma (RCC) is the predominant form of kidney cancer in adults, representing over 90% of such cases. The diagnosis and management of this disease depend on histology, the microscopic analysis of tissue. By examining the cellular structure of a tumor, pathologists can identify the specific type of RCC and assess its characteristics. This classification is fundamental for informing the course of treatment and provides a roadmap for oncologists.
The Process of Histological Examination
The journey from a suspected tumor to a definitive diagnosis begins with obtaining a tissue sample, either through a needle biopsy or surgical removal of the kidney, a procedure known as nephrectomy. This specimen is then preserved in a chemical called formalin to prevent decay. In the laboratory, the fixed tissue is embedded in paraffin wax, allowing for extremely thin slices to be cut by a microtome. These sections, often only a few micrometers thick, are then mounted on glass slides for staining.
The most common staining method is the Hematoxylin and Eosin (H&E) stain. This two-part process stains cell nuclei a purplish-blue, while eosin stains the cytoplasm and extracellular matrix in varying shades of pink. This color differentiation allows pathologists to distinguish between cellular components and observe the overall tissue structure.
Under the microscope, pathologists analyze the H&E-stained slides. They look for specific architectural patterns, such as how the cancer cells are arranged—whether in solid sheets, nested clusters, or finger-like projections. They also scrutinize the individual cells, noting their shape, size, and the appearance of their cytoplasm and nucleus.
Major Histological Subtypes of Renal Cell Carcinoma
The microscopic features observed during a histological examination allow pathologists to classify RCC into several distinct subtypes, each with a unique cellular appearance. Nearly 80% of diagnoses fall into the clear cell RCC (ccRCC) category. This subtype is characterized by cells whose cytoplasm appears clear or empty on H&E-stained slides because the preparation process washes out the abundant glycogen and lipids they contain. A hallmark of ccRCC is a rich, delicate network of branching blood vessels that weaves throughout the tumor.
Another common subtype is papillary RCC (pRCC), which accounts for 13-15% of cases. Its name derives from its characteristic growth pattern, forming finger-like projections called papillae. Pathologists distinguish pRCC into two types based on cellular features: Type 1 is composed of small cells with sparse, pale cytoplasm, while Type 2 features larger cells with more abundant pink cytoplasm and prominent nuclei.
A less frequent subtype is chromophobe RCC (chRCC), making up about 3-5% of kidney cancers. These tumors are composed of large, pale cells with distinct cell borders, sometimes described as having a plant-cell-like appearance. A characteristic feature of chRCC is the presence of wrinkled, “raisin-like” nuclei and a perinuclear halo, a clear space around the nucleus.
Beyond these three main subtypes, several rarer forms of RCC exist, each with its own histological profile. These include collecting duct carcinoma, a highly aggressive tumor arising from the kidney’s collecting ducts, and medullary carcinoma, an aggressive cancer associated with sickle cell trait. Accurate identification of these uncommon subtypes is important for determining the patient’s prognosis and management plan.
Grading Tumor Aggressiveness
Separate from identifying the tumor’s subtype is grading, which assesses the potential aggressiveness of the cancer cells based on their microscopic appearance. The standard for this is the World Health Organization/International Society of Urological Pathology (WHO/ISUP) grading system. This system, validated for clear cell and papillary RCCs, provides prognostic information by categorizing tumors into one of four grades.
The WHO/ISUP grading system focuses almost entirely on a specific feature within the cell’s nucleus: the nucleolus. The grade is determined by the prominence of these nucleoli when viewed under a microscope at specific magnifications. This approach replaced older, less precise systems that combined multiple nuclear features.
The four-tiered system is defined by clear criteria. Grade 1 tumors have nucleoli that are absent or inconspicuous and difficult to see even at high power (400x magnification). In Grade 2 tumors, the nucleoli become clearly visible at high power and are eosinophilic. The distinction for Grade 3 is that the nucleoli are very large and prominent, easily visible at low power (100x magnification).
Grade 4 is assigned to tumors that exhibit extreme nuclear irregularities, such as bizarre, giant, or multiple nuclei within single cells. This grade also includes tumors that have developed sarcomatoid or rhabdoid features. These terms describe cancer cells that have changed to resemble other types of aggressive cancers, indicating increased aggressive potential.
How Histology Guides Clinical Decisions
The tumor subtype and grade identified through histology directly influence clinical decision-making. This information helps predict the cancer’s behavior and response to treatment, allowing oncologists to tailor therapy. A tumor’s subtype can determine which treatments are most likely to be effective.
For instance, clear cell RCC is often characterized by abnormalities in the von Hippel-Lindau (VHL) gene. This leads to the overproduction of proteins that stimulate blood vessel formation. This biological characteristic makes ccRCC particularly responsive to targeted therapies that inhibit these pathways, as well as to immunotherapies.
In contrast, other subtypes like chromophobe or papillary RCC may not respond as well to these specific agents. This may prompt clinicians to consider different therapeutic strategies. This can include clinical trials for rarer tumor types.
The WHO/ISUP grade provides another layer of prognostic information. A higher grade is correlated with a more aggressive tumor and a greater likelihood of metastasis, regardless of the subtype. For example, a patient with a Grade 1 or 2 tumor may have a favorable prognosis if the cancer is localized and may be managed with surgery alone.
A diagnosis involving a Grade 3 or 4 tumor signals a higher risk of recurrence and spread. This finding often leads to recommendations for more aggressive treatment plans, which might include surgery followed by systemic therapy to target cancer cells that may have already escaped the kidney. The grade helps stratify risk, allowing clinicians to determine the intensity of follow-up surveillance and whether adjuvant therapy after surgery is warranted.