Glomeruli and Tubular Cells

Normal elements are occasionally encountered, particularly when the radiologist is sampling a small lesion, and the needle excursions traverse normal kidney. It is vital not to misinterpret normal elements as tumor cells. Glomeruli (Fig. 15.1) are highly cellular globular structures that mimic the papillae of papillary RCC, especially at low magnification. Glomeruli lack atypia, but so do low-grade papillary RCCs. In contrast with papillary RCC, however, the cells in a glomerulus are not evenly distributed, but instead are much more dense in the center than at the periphery; most important, close inspection of the edges of a glomerulus reveals its distinctive capillary loops.

Proximal tubular cells have a round, bland nucleus; a small but easily seen nucleolus; and abundant, granular cytoplasm (Fig. 15.2A). The cells lack a well-defined cell border, and the granules often appear to be spilling out of the cells. They are very similar to the cells of an oncocytoma and chromophobe RCC. FNA preparations of both tumors, however, are usually more cellular, and their cells are frequently binucleate, often with some variation in cell and nuclear size and shape. Also, the cell borders of an oncocytoma and chromophobe RCC are usually sharply defined, whereas those of proximal tubular cells are torn and irregular.

Distal tubular cells are small, isolated or cohesive cells, with less cytoplasm than proximal tubular cells (Fig. 15.2B). Their cytoplasm is clear to slightly granular, and they have a small, round nucleus and an inconspicuous nucleolus. The cell borders are well defined, and the cytoplasm is not vacuolated.⁴³ Distal tubular cells are very similar to the malignant cells of a low-grade clear cell or papillary RCC. Aspirates of those tumors are usually more cellular, however, and the cells of low-grade papillary RCC form papillae and spherules, something distal tubular cells do not.

Oncocytoma

Oncocytoma, a benign tumor of oncocytes (cells with abundant granular cytoplasm), comprises 3% to 5% of all renal tumors44–50; rare metastases have been reported.⁵⁰ They have a wide age distribution, with a median size of 6 cm, and most are incidental findings in patients undergoing imaging studies for unrelated reasons. Radiologic findings, unfortunately, cannot be relied upon to make a confident diagnosis of oncocytoma. Histologically, tumor cells have abundant granular cytoplasm and uniform round nuclei, with small but distinct nucleoli equivalent to those of a Fuhrman grade 2.⁵¹ Occasional cases contain scattered large, sometimes bizarre nuclei, but mitoses are absent or very rare. Electron microscopy reveals abundant mitochondria, which account for the characteristically granular cytoplasm by light microscopy.⁵² The arrangement of the neoplastic cells in rounded nests is distinctive and contrasts with the trabeculae (ribbons) of a chromophobe RCC.⁵³ Cytogenetics reveals a mosaic of normal and abnormal karyotypes. The most common abnormalities are losses of chromosomes 1 and Y, but deletions and rearrangements also occur.⁵⁴ Unfortunately, these findings are nonspecific and therefore not useful for confirming the diagnosis of an oncocytoma.

Cytologically, smears from a well-sampled oncocytoma reveal numerous isolated cells with abundant, eosinophilic, granular cytoplasm; well-demarcated cell borders; and round nuclei with small or medium-sized nucleoli55–59 (Fig. 15.3A, B). In occasional cases, isolated pleomorphic or bizarre nuclei occur and can be quite alarming,⁵⁷ but these are thought to represent degenerative changes and are not indicative of malignancy. Necrosis is absent, and mitoses are either absent or very infrequent.

When examining cells with abundant granular cytoplasm from a kidney FNA, one should consider inadvertent sampling of the liver, which happens with FNAs of a right renal mass if the needle traverses the liver on its way to the kidney. Hepatocytes have abundant granular cytoplasm, but they often contain lipofuscin pigment and show more variation in nuclear and cellular size (see Fig. 13.1). If hepatocytes are the only finding, the sample is nondiagnostic (insufficient).

One also needs to exclude a RCC. Several different subtypes of RCC can have granular cytoplasm and therefore mimic an oncocytoma. Some clear cell RCCs are composed mostly of granular (rather than clear) cytoplasm. In comparison with the cells of an oncocytoma, those of a clear cell RCC, including the granular cell variant, are more cohesive, usually with more nuclear atypia and less uniformly granular cytoplasm. The rare eosinophilic variant of papillary RCC has a similar cytologic appearance to an oncocytoma, but papillae and foamy macrophages, typical of papillary RCC, are not features of oncocytomas. The cells of chromophobe RCCs have abundant granular cytoplasm, but it is usually less uniformly granular (there is often a patchy, perinuclear clearing), and they may have greater nuclear outline irregularity. Nevertheless, in any individual case the distinction between a chromophobe RCC and an oncocytoma can be extremely difficult on smear preparations alone. Tissue fragments in cell block sections, fortunately, are tremendously helpful: The cells of an oncocytoma are arranged in round nests (you can draw a circle around them) (Fig. 15.3C), whereas the cells of a chromophobe RCC are in endless trabeculae. Hale’s colloidal iron (HCI) stain is helpful because it usually shows diffuse cytoplasmic staining in chromophobe RCCs, and most oncocytomas are negative. Unfortunately, some oncocytomas show a positive staining reaction with HCI, but usually only focally and in an apical pattern,⁶⁰ and therefore care in interpreting the result is necessary (Figure 15.3D). Immunohistochemical markers might be helpful in the distinction between oncocytoma, chromophobe RCC, and clear cell RCC, but their reliability in routine practice is not yet known.⁶¹ To make the situation even more complicated, rare hybrid renal tumors composed of oncocytoma and chromophobe RCC do occur, either sporadically or in association with the Birt-Hogg-Dube syndrome⁶²; FNA findings depend upon the areas sampled.

If only smears were prepared, the wisest (and most honest) interpretation in most cases is “oncocytic neoplasm (oncocytoma versus chromophobe RCC),” with a note that, if clinically indicated, a partial nephrectomy should be considered. This may not satisfy the urologist, who was hoping for an unequivocal interpretation. It is unwise, however, to make a definitive diagnosis of oncocytoma without an assessment of tissue architecture with the help of a cell block or core needle biopsy, because a rounded (nested) architecture is essentially the only finding relatively specific for an oncocytoma. Virtually all the other features of oncocytoma can be mimicked by several subtypes of RCCs, not just the chromophobe RCC.

Renal Cortical Adenoma

Except for their size, renal cortical adenomas are histologically, immunohistochemically, and cytogenetically indistinguishable from low-grade papillary RCCs.63–64 Renal adenomas are by definition very small lesions, always less than 0.5 cm and usually less than 0.2 cm.⁶⁵ They are too small to be aspirated, and therefore the diagnosis “renal cell adenoma” is not appropriate for an FNA specimen.

Angiomyolipoma

Angiomyolipomas (AMLs) are benign mesenchymal tumors that arise from the so-called “perivascular epithelioid cell” and compose between 0.7% and 2.0% of all renal tumors. They occur in two distinct clinical settings.66–68 Approximately one half occur in young adults with tuberous sclerosis (TS), an autosomal dominant disease caused by mutation of one of the two TS-associated genes and manifested by mental retardation, seizures, and skin changes. In TS patients, the AMLs are usually multiple and bilateral. The other half are usually solitary and occur in young and middle-aged women with no known clinical syndrome. Some patients present with flank pain, but a majority of AMLs are detected incidentally during a radiologic work-up for an unrelated disorder. They vary widely in size and can be tiny or up to 20 cm in diameter. Large lesions can bleed, and some are resected to prevent this from occurring.

Histologically, an AML is composed of three elements: mature fat, blood vessels, and smooth-muscle cells. The latter can have moderate to marked atypia. Mature fat makes up the bulk of most AMLs, but these common, fatty AMLs are reliably identified by imaging studies, precluding the need for an FNA, except perhaps when well-differentiated liposarcoma is a consideration based on imaging findings.⁶⁹ FNA is needed only for the subset of AMLs that have very little adipose tissue (the “fat-free” or “low-fat” AMLs), which cannot be distinguished from a RCC by imaging alone. In virtually all cases, the neoplastic cells, most conspicuously the smooth muscle cells but also the lipid-distended fat cells, are immunoreactive for melanoma-related antigens like HMB-45 and MART-1 (Melan-A).^70–80 An uncommon subtype, the epithelioid AML, is composed of large epithelioid rather than spindle smooth muscle cells. Epithelioid AMLs have metastatic potential, but predicting which will behave in a malignant fashion is problematic.⁷⁰

AMLs can be diagnosed confidently by FNA, but they do have their challenges: specimens are usually paucicellular; the adipose tissue component is scant or nowhere to be found; and the thick vessels are rarely seen. The smooth muscle cells, sometimes with moderate-to-marked nuclear atypia, usually dominate the picture (Fig. 15.4A-C). Atypical spindle cells and their very large nuclei, if present, are usually interspersed among numerous much less atypical cells. The cytoplasm of the smooth muscle cells has a stringy or crystalline appearance, quite different from the vacuolated or granular cytoplasm of RCC. Scattered large, clear fat vacuoles can be present in the smooth muscle cells and impart a resemblance to RCC. The differential diagnosis includes sarcoma⁸¹ and sarcomatoid RCC. Immunostains for HMB-45 and MART-1 (i.e., Melan-A) are extremely helpful, because RCCs and most sarcomas are negative for these markers (Fig. 15.4D).

The cells of an epithelioid AML are round and range from medium-sized to huge; because of their abundant cytoplasm and enormous nucleoli, they resemble ganglion cells. Necrosis and mitoses can be seen. The differential diagnosis of an epithelioid AML includes clear cell RCC.20,80,82 Here, too, immunostains are extremely helpful in distinguishing an epithelioid AML from RCC.

Of note, AML is one of the lesions most likely to yield a sparsely cellular, difficult-to-interpret sample composed of rare spindle-shaped cells and stromal fragments. Nevertheless, it is often possible to demonstrate immunoreactivity for HMB45 and make a definitive diagnosis on this basis. For this reason, it is prudent to obtain immunostains on any atypical and/or paucicellular spindle cell or epithelioid cell lesion in the kidney.

Metanephric Adenoma

Metanephric adenoma (MA) is a rare, essentially benign kidney tumor,83–86 although the occasional case with metastases has been described.⁸⁷ It can be found at any age but most commonly occurs in women in the fifth decade. About one half are discovered incidentally; the rest are detected because of hematuria, flank pain, or polycythemia. They range from small to very large lesions and can measure up to 15 cm in diameter. Histologically, MA is composed of tight, uniform tubules lined by bland cells with small round nuclei and inconspicuous nucleoli. Mitoses are absent or very infrequent. Psammoma bodies are common. They resemble low-grade papillary RCCs and differentiated Wilms tumors. Unlike papillary RCC, they are negative for epithelial membrane antigen (EMA) and have a normal karyotype. Like Wilms tumor, MAs show nuclear immunoreactivity for Wilms tumor 1 (WT1).

On cytologic preparations, the cells form short tubules, tight balls, and loose sheets; they have scant cytoplasm, round monotonous nuclei, fine, even chromatin, and rare small nucleoli⁸⁸ (Fig. 15.5A-C).

Most Wilms tumors are easily distinguished from MA in that Wilms tumors are triphasic neoplasms that contain a blastemal component (small, closely packed, mitotically active cells) as one of their three constituents. An epithelial-predominant Wilms tumor, with little or no blastema, can be virtually impossible to distinguish from an MA,⁸⁹ although some claim—on the basis of histologic material—that the cells of a Wilms tumor are larger, with more hyperchromasia and mitoses.⁸³ Low-grade papillary RCCs have more cytoplasm than MA and, unlike MA, are positive for EMA and negative for WT1.64,83,90 Finally, because of the high nuclear-to-cytoplasmic ratio of MA cells, a metastasis should be considered. Most metastases are EMA-positive, and a metastasis is unlikely in the absence of a known or suspected primary tumor elsewhere.

Cystic Nephroma/Mixed Epithelial and Stromal Tumor

Cystic nephroma/mixed epithelial and stromal tumor is a benign cystic neoplasm, also known as multilocular cyst, that most commonly occurs as a solitary tumor in boys and middle-aged women. Although some argue that these are distinct tumors, many pathologists disagree, and the cytologic features are identical.91–92 It is composed of stroma and small cysts lined by atypical epithelium.⁶⁸ Although cystic, this lesion appears solid radiographically. FNA samples are usually misdiagnosed as either RCC, angiomyolipoma, or sarcoma.^29,93–94 Specimens are generally hypocellular, but contain some epithelial cells with clear to vacuolated cytoplasm, nuclear membrane irregularity, and prominent nucleoli.^95–96 Alternatively, specimens consist of large, pleomorphic spindle cells, admixed with cells with intracytoplasmic vacuoles simulating fat.⁹⁷ As a rule, complete excision is required to make the diagnosis. The only predictable cytologic feature is sparse cellularity. This adds support to the wisdom that hypocellular specimens with atypical cells should be reported as suspicious rather than positive.

Renal Abscess

Focal bacterial pyelonephritis and a renal abscess can appear masslike radiologically.1,98 Aspirates contain necrotic material and numerous neutrophils, sometimes with rare atypical cells that are easily confused with those of a clear cell RCC. The atypical cells are few in number, however, and in the context of abundant acute inflammation should be reported (at most) as suspicious for malignancy

Xanthogranulomatous Pyelonephritis

Xanthogranulomatous pyelonephritis is an atypical host reaction to a bacterial infection and usually presents as a mass lesion.²⁸ Histologically and cytologically, the lesion is composed of histiocytes and multinucleated giant cells. The histiocytes can form aggregates and resemble the cells of clear cell RCC, but they lack nuclear atypia, and their cytoplasm has a more microvacuolated appearance than that of typical RCCs. Differential immunoreactivity for EMA and CD68 is helpful in difficult cases.

Renal Infarct

Rarely, renal infarcts have a radiographic appearance suggestive of malignancy.⁹⁹ Specimens are sparsely cellular and composed of necrotic material, which can contain rare atypical cells resembling those of clear cell RCC. A diagnosis of malignancy should be avoided when the atypical cells are few in number, which is usually the case with renal infarcts.

Renal Cysts

Renal cysts are common. Of all renal lesions, 70% to 85% are cysts, and 50% of men over the age of 50 years have at least one cyst.100–101 A majority are benign, acquired, and solitary; only 1% to 4% of cysts are cystic RCCs,^102–108 usually of clear cell or papillary type.⁶⁸ The prognosis of a patient with a cystic RCC is generally excellent,^109–110 but metastases do occur,¹¹¹ and resection, either by partial or radical nephrectomy, is indicated.

The pretest probability that a renal cyst is malignant depends, in part, on the radiologic appearance. Cysts are classified according to the Bosniak system.112–117 Most lesions are category 1 (benign); category 4 lesions are frankly malignant and are resected directly; and categories 2 and 3 are indeterminate. Between 5% and 57% of indeterminate cysts are malignant. Because the pretest probability of malignancy is as high as 57%, many urologists believe that all indeterminate cysts should be resected.

How helpful is an FNA specimen that lacks atypical cells (contains only macrophages)? Does this result change the pretest probability of an RCC? Much of the data on this subject predates CT and MRI26,98,101,104–105,118–120 but implies that a negative diagnosis supports the diagnosis of a benign cyst. Closer examination, however, reveals that the vast majority of the lesions in these studies were simple cysts (Bosniak category 1 lesions) that would not be aspirated today. Unfortunately, no study has examined the sensitivity of FNA for Bosniak 2 and 3 lesions. Indirect evidence provides some insights. First, 10% of all RCCs yield a nondiagnostic or falsely negative FNA result.^{20,22,26,29,37,121–122} Second, most RCCs incorrectly interpreted as negative by FNA are cystic.³⁷ Third, most radiographically suspicious cysts prove to be RCC.^20,22,29 Finally, in the largest series of cystic RCCs (11 cases), only two cases had atypical cells on cytologic examination, and repeat aspirates in both patients were negative.¹²³ From these data, it can be inferred that the sensitivity of FNA for Bosniak category 2 and 3 cysts is low, and certainly no higher than 10% to 20%. Given that the pre-FNA probability is 5% to 57%, a negative FNA result (macrophages only) in this setting has little effect on the patient’s risk of disease and is best reported as nondiagnostic (Fig. 15.6).

Complicating the matter further is the fact that some benign cysts are virtually impossible to distinguish from an RCC by FNA. Patients on renal dialysis for renal failure often acquire cysts, and 9% develop RCC, often a multifocal tumor.124–127 Patients with adult polycystic kidney disease, an autosomal dominant disease, are also at an increased risk for developing RCC, which, like the tumors in renal dialysis patients, can be multifocal. In both settings, papillary hyperplasia occurs within the cysts,¹²⁸ and distinction between this hyperplasia and carcinoma is not possible by FNA. (Histopathologic criteria for this distinction are controversial as well.) The best approach is simply to avoid aspirating cysts in these patients.

When confronted by an FNA specimen of a cystic renal mass, the cytologist can be aided by a review of the imaging findings, especially with a radiologist who has expertise with renal cysts. Some urologists aspirate benign, Bosniak category 1 cysts merely for symptomatic relief. In this setting, where the radiographic probability of RCC is so low, one should take a very conservative approach in interpreting any atypical cells. If, on the other hand, the aspirate is performed for an indeterminate (Bosniak category 2 or 3) lesion and even a few atypical cells are seen, a suspicious diagnosis is appropriate (Fig. 15.7). If the result is nondiagnostic (macrophages only), an explanatory note can be helpful, such as “The findings are consistent with a cystic renal lesion. Because parenchymal elements have not been sampled, the possibility of a neoplasm cannot be excluded.”

Clear Cell Renal Cell Carcinoma

Clear cell (also called conventional) RCC accounts for 75% to 80% of all RCCs and is strongly associated with a variety of deletions on the short arm of chromosome 3 (3p), the site of the VHL gene.133–136 The average size of a clear cell RCC is 7 cm, but small tumors are being detected with increasing frequency due to the increasing use of cross-sectional imaging techniques. Size is not a determinant of malignancy, but the frequency of metastases does correlate with increasing size of the primary tumor. Necrosis, hemorrhage, cystic degeneration, and calcification are common; these features give the clear cell RCC its characteristic heterogeneous appearance on imaging studies. Histologically, clear cell RCC is composed of cells with abundant cytoplasm that is clear, granular, or a mixture of both. The clear and granular appearance is due to the presence of lipid and glycogen in the cytoplasm. A distinction used to be made between RCCs of predominantly clear or granular type, but this is no longer believed to have clinical relevance, and the granular type is now folded into the clear cell category. The tumor cells have a rich network of delicate, thin-walled blood vessels, which accounts for the contrast enhancement pattern on imaging studies and the frequent bloodiness of FNA samples.

Aspirates from a clear cell RCC are often very bloody. Smears can be highly cellular, but in fact sometimes reveal only blood; in such cases tissue fragments are often recovered in cell block sections. With cellular smears, the tumor cells are displayed as large tissue fragments and isolated cells. The malignant cells have abundant cytoplasm and thus a low nuclear-to-cytoplasmic ratio, with a round to slightly irregular, eccentrically placed nucleus26,28,43,137 (Fig. 15.8A and B). The eccentrically positioned, round nucleus gives the cells a plasmacytoid appearance (Fig.15.8C). The nucleus is sometimes so far off-center that it appears partially extruded. The size of the nucleolus depends on the grade of the tumor: small and inconspicuous in grade 1 tumors, progressively more prominent in grade 2, 3, and 4 tumors. Cytoplasm is thin and wispy, and cell membranes are poorly defined. Small cytoplasmic vacuoles are often peripherally placed, and the remaining, more granular, cytoplasm is central. Higher-grade tumors have more isolated cells, less cytoplasmic vacuolization, and, as mentioned, larger nucleoli (Fig.15.8D). Pink, strandlike fibrillary material, possibly basement membrane material, is seen with Romanowsky stains and is highly characteristic (see Fig. 15.8B). Cytologic preparations from roughly one half of RCCs demonstrate so-called transgressing vessels;¹³⁸ their diagnostic significance is unclear, however, as some other tumors show similar features. Low-grade tumors are challenging because fragments of the tumor are extremely cohesive: One encounters large, highly cellular aggregates in which the individual cells are difficult to identify. A careful search around the perimeter of these chunks reveals the characteristic cells. Grade 1 and 2 clear cell RCCs, sometimes a challenge to interpret correctly on direct smears, are often surprisingly straightforward on cell block sections, where the clear cell morphology is especially easy to recognize (Fig. 15.8E).

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