Classification and Clinical Data
Based on the new classification, renal carcinomas (previously classified as clear cell, granular cell, papillary, tubulopapillary, or sarcomatoid types) are included in the category of conventional RCC, and account for approximately 60% of all renal tumors.
Clinically, RCC is considered the great imitator (Ochsner et al, 1973
). The classic symptoms
at the time of diagnosis are hematuria, flank pain, and a palpable mass,
each of which occurs in less than 50% of cases (Ritchie et al, 1983
). Nonspecific symptoms
may include fever, night sweats, weight loss, hypertension,
and, rarely, erythrocytosis, anemia, and hypercalcemia
(Skinner and deKernion, 1978
; Brodsky and Gavnick, 1989
). A significant percentage of cases are asymptomatic incidental findings
diagnosed by abdominal US or CT during workups for other diseases (Konnack and Grossman, 1985
; Thompson and Peck, 1988
; Porena et al, 1992
Figure 40-6 Conventional renal cell carcinoma (RCC). A. Gross picture of a 2-cm conventional RCC in the inferior pole of left kidney. The tumor was asymptomatic, an incidental finding on imaging. Note the golden-yellow cut surface. B. Histology: conventional RCC, clear cell type. Note the microtubule or acinar pattern and multiple nuclei in many cells. This is a grade 1 tumor. C. RCC with predominantly granular cells. The gross appearance is dark yellow to brick red. This large tumor (16 cm in diameter) presented as a left abdominal mass and flank pain. D. Histology of conventional RCC with predominantly granular cells. Note the presence of cytoplasmic vacuoles containing fat and glycogen. The nuclei are larger and some irregularly shaped, with visible nucleoli; therefore, this is a grade 2 tumor. E. Conventional RCC with predominantly sarcomatoid growth. The gross appearance is fleshy white. F. Histology of spindly (sarcomatoid) RCC.
The behavior of RCCs is unpredictable. In some patients, the primary tumor is occult and the patient is seen because of metastatic disease, commonly in the bone, lung, liver, or subcutaneous tissue. In other patients, metastases of RCC may occur many years after nephrectomy. Unexpected sites of metastases that can mimic a primary tumor are the thyroid, ovary, salivary gland, and, rarely, pancreas (see appropriate chapters). Finally, RCC in metastatic sites may express a morphologic pattern that is very different from the primary tumor, with the spindle-cell pattern being the most common. The recognition of metastatic renal cancer is often a diagnostic challenge.
A diagnostically valuable immunohistochemical feature
of RCCs is the simultaneous expression of intermediate filaments for keratin
(mainly types 8 and 18) and vimentin
(Pitz et al, 1997
). Although similar phenomena may occasionally be seen in other cancers, notably thyroid carcinoma,
this feature is very helpful in determining the renal origin of metastatic foci in various organs (Domagala et al, 1988
Surgically resected RCCs vary in size, from very small (2-3 cm in diameter) to very large (20 cm or more). The colors
of the cut surface of the tumors show a reasonable correlation with histologic patterns. Thus, golden-yellow
tumors (Fig. 40-6A,B
) are usually composed of clear cells, brickred
tumors (Fig. 40-6C,D
) are granular or oncocytic, and sarcomatoid tumors are fleshy-white
). The tumor may invade the calyces and the renal pelvis, in which case the voided urine cytology may be positive
(see Chap. 23
). RCCs have a tendency to invade the renal veins and thence the vena cava. Hemorrhage, extensive necrosis, and cavity formation
within the tumor occur frequently.
Most renal carcinomas show a mixture of histologic and cytologic patterns of growth, as summarized in Table 40-4
Although any tumor may be composed of more than one cell type,
the most common renal carcinoma
is the clear cell type with a classic growth pattern
in solid sheets or cords.
This is particularly true for relatively small tumors. Gland formation
may occur. A rich network of capillaries and larger blood vessels is present. The cytoplasm
of tumor cells contains lipid and glycogen,
and the nucleus is disproportionately small
In some of these tumors, the dominant type is a cancer cell with denser, more granular and eosinophilic cytoplasm,
and more conspicuous nuclear abnormalities.
These tumors were formerly classified as the granular cell type of RCC
). They must be distinguished from chromophobe carcinoma, oncocytoma, and rare cases of CDC that may contain similar cells (see below).
TABLE 40-4 MORPHOLOGIC VARIANTS OF CONVENTIONAL RCC
Acinar or glandular
Solid or alveolar
Undifferentiated small cell
Some tumors are composed partly or wholly of spindly cancer cells
), mimicking a variety of sarcomas (sarcomatous type of RCC
). According to a large study by de Peralta-Venturina et al (2001)
, the sarcomatous change is most common in the conventional type of RCC, but it may also occur in other types of renal cancer,
such as papillary, chromophobe, and collecting duct carcinomas.
Many of the patients in that study had tumors of high stage, and their prognosis was less favorable than that of tumors without this component.
Some tumors may be composed partly or wholly of very poorly differentiated large or small cancer cells. Such poorly differentiated tumors are sometimes difficult to classify (see below).
Aspirates of RCC often contain much blood
and may show considerable necrosis
with cell debris (the latter is particularly evident in tumors with cystic degeneration).
Within this background, abundant tumor cells, often anchored to capillaries,
are usually seen. The types of tumor cells
observed in conventional RCC in FNA smears are listed in Table 40-4
. It must be stressed that various types of cancer cells are often simultaneously present in the same patient. The cytologic classification of these tumors is usually based on the dominant cell type in smears, but is not always representative of the tumor type on histologic examination
(Renshaw et al, 1997b
). As mentioned above, a simultaneous expression
is very helpful in determining the renal origin of tumors (Domagala et al, 1988
Aspirates of RCC usually show loosely cohesive flat groups of cancer cells
with clear cytoplasm with poorly defined cell borders and many single cells. The tumor cells may also be seen anchored along capillaries, resulting in a pseudopapillary appearance (Fig. 40-7A
). The clear cancer cells are large
(much larger than benign tubular cells) and have abundant clear or faintly blue delicate cytoplasm
that is often filled with numerous small vacuoles
containing lipid and glycogen but not mucin
). The vacuoles are better seen in air-dried smears processed with hematologic stains. Phagocytosed hemosiderin
may be seen. The nuclei are relatively small, but still much larger than those of benign tubular cells.
They are only slightly pleomorphic,
haphazardly placed, usually hyperchromatic,
and contain readily visible nucleoli.
Figure 40-7 FNA appearance of conventional RCC with a mixture of clear and granular cells. A. Loosely cohesive flat groups of large cancer cells. Many single cells are present. B. High magnification reveals abundant, finely vacuolated cytoplasm and relatively small, hyperchromatic nuclei in large cancer cells of various configurations. C. Adjacent field shows predominantly granular cancer cells with eosinophilic cytoplasm. D. Another example of a renal smear showing side-by-side cancer cells with clear and granular cytoplasm.
conventional RCCs, composed predominantly of clear cells, the FNA smears fixed in 95% ethanol
may show numerous well-preserved nuclei stripped of cytoplasm (“naked” nuclei)
). This phenomenon is caused by dissolution of the cytoplasmic lipids in alcohol, resulting in cytoplasmic disintegration. “Naked” nuclei may also be observed in metastatic renal cancers. Some of these nuclei contain prominent ruby-red nucleoli, consistent with renal origin.
conventional RCCs, the malignant nature of the cells is usually quite evident (Fig. 40-8C,D
). The cancer cells have large nuclei with prominent, sometimes ruby-red nucleoli, and relatively scanty cytoplasm that is either clear or eosinophilic and granular. It is usually easy to recognize such tumors, and the only point of differential diagnosis may be metastatic carcinomas, which have a different clinical and radiologic presentation.
As illustrated in Figure 40-7
, most conventional RCCs show a mixture of clear cells and granular (oncocytic) cells
in an ample FNA sample. The granular cancer cells have an eosinophilic, granular cytoplasm, are usually smaller and more uniform than the clear cells,
and have larger and more atypical nuclei,
and hence a higher N/C ratio. Cytoplasmic granules,
reflecting numerous mitochondria,
are well visualized in air-dried smears processed with hematologic stains. In H&E- or Papanicolaoustained smears the granules are intensely eosinophilic
). In some cases, the granular cells are predominant, but so long as some clear cells are also present in the smears, the diagnosis of a conventional RCC is favored.
The eosinophilic cells may resemble hepatocytes,
which may be obtained in a misdirected FNA smear and mistaken for granular cells of RCC. Normal hepatocytes do not show the nuclear abnormalities seen in granular cancer cells. Lipofuscin and bile, when present in the cytoplasm, provide additional clues to the hepatic derivation of these cells. Weir and Pitman (1997)
noted that the characteristic vascular pattern observed in
well-differentiated hepatomas was absent in RCC (see Chap. 38
Figure 40-8 FNA of low- and high-grade renal carcinomas. A.
FNA of a small RCC (shown in Fig. 40-6A
) shows numerous well preserved “naked” nuclei, with some cells still retaining their eosinophilic granular cytoplasm. B.
Histology of the same case shows a low-grade (grade 1) conventional RCC, clear cell type. C,D.
Cells of a high-grade RCC with clear, scanty cytoplasm forming a cluster. B.
Corresponding histology is from metastasis to the liver (core biopsy).
Somewhat similar cells may be observed in two relatively uncommon renal tumors: the oncocytoma
and chromophobe renal carcinoma. Table 40-5
is a summary of salient clinical, cytologic, and ancillary characteristics of renal tumors with granular cytoplasm.
The very rare collecting duct carcinoma is not included in this table. All of these tumors are discussed below. In addition, Reuter (1999)
has reported that rare cells with granular cytoplasm may occur in angiomyolipoma and metastatic melanoma.
Among the uncommon cell types of conventional RCCs are undifferentiated cancer cells. This term implies the presence of clearly malignant cells of variable shapes and sizes with prominent nuclear abnormalities,
but no specific features of RCCs. The cells occur singly or in very loosely structured aggregates, and are sometimes very large and multinucleated. In our experience, the pleomorphic cells with very large nuclei
are relatively uncommon in renal FNA and always indicate the presence of a high-grade tumor (Fig. 40-9A
). The interpretation of such cells depends on the company they keep.
In the presence of at least some classic cancer cells with clear or granular cytoplasm, the most likely diagnosis is RCC. If the pleomorphic cells occur alone,
the possibility of a metastatic carcinoma
from an extrarenal site must be entertained.
In still other types of tumors, some of the undifferentiated cancer cells are quite small and occur singly and in small clusters
). These cells, which have relatively large hyperchromatic nuclei and scanty, clear cytoplasm,
may occur in conventional RCC and may be accompanied by clear or granular cancer cells. However, similar cells may also be found in Wilms’ tumor, metastatic small cell carcinoma, and a large cell lymphoma.
The interpretation depends entirely on the smear pattern,
which is quite different in each of these entities (see below).
In some conventional RCCs and in carcinomas composed of spindly cells, the cancer cells tend to be elongated or spindly
and may be similar to fibroblasts.
They have delicate, finely vacuolated, abundant, faintly granular cytoplasm and pleomorphic ovoid to elongated nuclei, usually with prominent nucleoli
). Such cells correspond to areas of the primary tumor that are composed of elongated cells (see Fig. 40-6F
), and may also occur in metastatic foci, mimicking a sarcoma
(Koss et al, 1992
TABLE 40-5 RENAL CELL TUMORS WITH GRANULAR CYTOPLASM
Chromophobe RCC (ChRCC)
RCC With Predominant Granular Cells
Not known but common in higher grade lesions (all variants 60%)
Average tumor size and location
6 cm (central stellate scar in 1/3), often subcapsular
Large (9 cm), cortical
5.5 (recent series)-8 cm (older series); more common in upper pole
Predominantly isolated cells or small aggregates
Some single cells
Loose clusters and single cells, bare nuclei
Cell size and cytoplasmic characteristics
Very large, uniform, low N/C ratio
Homogeneous, dense pink granular cytoplasm
Large, pleomorphic with high N/C ratio
Dense pink granular cytoplasm with perinuclear pale zones
Medium, uniform to pleomorphic, high N/C ratio.
Sometimes vacuolated pink granular cytoplasm
Uniform, small and round (8-10 μm),
Finely granular chromatin
Uniform to pleomorphic (10-15 μm)
Notched nuclear contour
Large (15-20 μm) relatively uniform
Fine chromatin, large nucleoli
Stain for lipid and glycogen negative
LMW keratin positive
Hale’s colloidal iron stain positive
LMW keratin negative
Stain for lipid and glycogen positive in some cells
LMW keratin negative
EMA, epithelial membrane antigen; LMW, low molecular weight; N/C ratio, necleocytoplasmic ratio.