CHAPTER 12 Kidney, adrenal and retroperitoneum proper
Clinical aspects
The place of FNAC in the investigative sequence
By the 1960s, Scandinavian workers had already demonstrated the value of FNAC in the diagnosis of solid renal masses.1–3 Since then, several series of kidney tumors investigated by FNAC have been published, reporting good results.4–8 Two recent developments have had an important influence on the practice of FNAC in this area. Advances in radiological imaging technique, particularly computed tomography (CT), have considerably increased diagnostic accuracy, reducing the need for a preoperative tissue diagnosis by needle biopsy. On the other hand, the revised classification of renal tumors and the definition of new subtypes with different behavior and prognosis have produced a greater need for specific preoperative tumor typing to allow more conservative surgical treatment in selected cases.9 Immunophenotyping and cytogenetics play an increasing role in this context, and FNB is an ideal, minimally invasive way of providing cell material for such studies. The most rational approach to diagnosis seems to be the combination of radiological imaging and FNB in the same session.10
Generally accepted indications for FNB of solid renal masses are:
For a review of the indications and usefulness of FNAC of lesions in the kidney based on current experience, see Puttaswamy et al.15
With regard to the adrenal, FNAC has mainly been used to investigate lesions detected by abdominal CT in the preoperative work-up of potentially resectable lung tumors. Mass lesions found incidentally by upper abdominal CT examination, so-called ‘incidentalomas’, may be primary adrenal tumors, metastatic malignancies or non-neoplastic lesions, with an approximately equal probability of neoplasms being metastatic or primary.16,17 The efficacy of image-guided FNB in the diagnosis of adrenal lesions has been demonstrated in several studies.18–21 Appropriate radiological and biochemical investigations may reduce the need for biopsy.13
For tumors of the retroperitoneum proper, percutaneous image-guided FNB is a valuable supplement to preoperative radiological investigations. For example, the distinction between tumor recurrence and retroperitoneal fibrosis as the cause of ureteric obstruction in patients treated for cancer of this region is of great clinical importance.22,23 In advanced inoperable disease, a cytological diagnosis may be a sufficient basis for palliative radiotherapy or chemotherapy without the need for a formal surgical biopsy. Cytological diagnosis of primary soft tissue tumors of the retroperitoneum is difficult and a type-specific diagnosis may not be possible, but the exclusion of metastatic malignancy or lymphoma is of clinical value. If smears prove to be non-diagnostic on immediate checking, a core needle biopsy can be performed in the same session.
Abdominal and retroperitoneal lymphadenopathy are a common targets for image-guided FNB, to distinguish metastatic malignancy, malignant lymphoma and reactive lymphadenopathy.24,25 In metastatic malignancy the cytology often suggests the site and type of the primary tumor. FNB is a valuable supplement to lymphangiography or CT in the preoperative staging of urogenital cancer.26,27
FNAC in the investigation of renal, adrenal and retroperitoneal lesions in the paediatric age group is presented in Chapter 17.
Accuracy of diagnosis
In a literature review of 1585 cystic and solid renal and adrenal masses, the false-positive rate was 2.3% if cases reported as suspicious of malignancy were included. The diagnostic sensitivity was 86% for 603 malignant tumors, specificity was 98% and the predictive value of a positive result was 96%.4 More recent series recorded similar levels of accuracy.5–1028 The commonest causes of false-negative diagnosis are insufficient diagnostic cells in cystic tumors, small tumors, or large tumors with extensive necrosis and hemorrhage. False-positive diagnoses have been recorded in angiomyolipoma, in inflammatory processes such as pyelonephritis with regenerative epithelial atypia, and in infarcts.29,30
Large series of FNB of adrenal lesions have been reported, but histologic correlation is often lacking. Only two incorrect diagnoses were made in 81 primary adrenal lesions reported from M. D. Anderson Cancer Center.17 Others have reported similar results and a 100% specificity for the diagnosis of malignancy.18–2031 Tumor size is an important parameter in the diagnosis of adrenal tumors, underlining the importance of clinical and radiological correlation.32
The accuracy of image-guided FNB of abnormal retroperitoneal lymph nodes has been analyzed in the context of staging urogenital cancer.23,33 FNB may reveal metastatic involvement of nodes that appear radiologically normal.
Complications and contraindications
The complications of puncture of renal cysts were analyzed in a large number of cases accumulated from several institutions in the USA by Lang in 1977.34 Hemorrhage, infection and pneumothorax did occur after puncture, but the rate was low and was reduced by experience and technical modifications. Complications have been recorded in about 0.4% of FNB of solid renal masses.4,27 A few cases of tumor seeding in the needle track following FNB of renal cell carcinoma have been reported.28,35 The risk is considered higher for transitional cell carcinoma.28,36 Needle size is not always specified in the reports and some involved core needle biopsy.37 This serious complication is extremely rare but should not be ignored.38 Infarction of renal cell carcinoma following FNA has been reported.39
There is a documented risk of causing a hypertensive crisis by needling adrenal pheochromocytoma.40,41 The expertise and facilities to deal with such an event must therefore be immediately available at the procedure, which should only be performed in major hospitals.42
Technical considerations
The biopsy technique is described in detail in Chapters 2 and 3. Image guidance is the routine, even in palpable masses, to ensure representative samples avoiding necrosis, cystic change, hemorrhage and major vessels. The parallel use of air-dried, MGG/Diff-Quik-stained and wet-fixed Pap-stained smears is recommended. Cell blocks are often of great value and are better suited for immunohistochemical studies than smears. The pros and cons of FNB and core needle biopsy (CNB) in renal tumors have been discussed in a review by Volpe et al.,28 concluding that the methods are complementary. We feel that FNB, correctly carried out, is less traumatic and less costly than CNB and should be the first line of investigation. Immediate checking of samples during the procedure allows the selective use of CNB.
Cytological findings
Normal structures; cortical pseudotumor (Figs 12.1 and 12.2)3
Non-neoplastic epithelial cells and other components of renal cortical tissue may be sampled by FNB in three different ways: (1) The needle may inadvertently sample normal tissue adjacent to the target; (2) focal hyperplasia of renal cortical tissue, either as a mass at the convexity (cortical pseudotumor) or as a rounded expansion of a medullary pyramid (inversion of renal lobule or lobular dysmorphism), may mimic an avascular solid tumor radiologically; (3) an ectopic kidney may be radiologically mistaken for a neoplasm.43 Smears from non-neoplastic renal tissue may be surprisingly cellular, suggestive of a low-grade renal cell tumor, a possible pitfall for the inexperienced observer. The hallmark of non-neoplastic renal cortical tissue is the coexistence in smears of tubular epithelial cells from different parts of the nephron looking distinctly different. Glomeruli are not always found.
Large epithelial cells from the proximal convoluted tubules usually dominate the smears. The cytoplasm is abundant, pale eosinophilic (gray–violet in MGG), finely granular with indistinct cell borders. Nuclei are round, central, relatively small and uniform, with small indistinct nucleoli. Cytoplasmic vacuolation is not a feature of normal tubular epithelial cells. Single cells and stripped nuclei may be seen but most of the cells form monolayered sheets. The nuclei are often arranged in rows. Cells of intermediate size, from the distal convoluted tubules, also lack distinct cell borders. The smaller tubular epithelial cells from the loop of Henle and from the collecting tubules have scanty, dense cytoplasm and distinct cell borders and form monolayered sheets or short tubular segments (Fig. 12.1). Some of the cells contain coarse, dark, cytoplasmic granules, probably lipofuscin. Aggregates of tubular epithelial cells may include strands of pink (MGG) hyaline material, contributing to the resemblance to renal cell tumors. Glomeruli are seen as rounded tissue fragments of tightly cohesive, small, spindly endothelial cells with indistinct cytoplasm and strands of stroma. They have a lobulated shape similar to glomeruli in tissue sections, but more or less distorted by smearing (Fig. 12.2).44
Benign and inflammatory conditions
Renal cysts (Fig. 12.3)
The diagnosis of simple renal cyst is usually made by US examination alone and cytological confirmation is not often necessary, but the aspirated fluid is often routinely submitted for cytological examination. The fluid is typically thin, clear, containing small numbers of degenerate epithelial cells and macrophages, but the number of cells can occasionally be surprisingly large. Macrophages in air-dried smears may appear atypical with moderately enlarged irregular nuclei, and may be clustered (Fig. 12.3).45 This could raise a suspicion of a cystic tumor, but if the radiological features are typical of a cyst and if the aspirated fluid is clear, there is no cause for concern. On the other hand, if the aspirate contains old blood and/or necrotic debris, a cystic neoplasm has to be excluded by further investigations, even if no tumor cells are found in the smears. Carcinoma within the wall of an apparently solitary simple cyst is a rare but well-recognized event in which the malignant component can be missed by needle biopsy.46,47 Accurate radiological guidance is essential.
Cystic nephroma (multilocular renal cyst) (Figs.12.4, 12.5)
Cystic nephroma is most common in children and is related to Wilms’ tumor, but also occurs in adults. In adults, tumors of this type are now often reclassified as other entities unrelated to nephroblastoma. It is included here as a cystic lesion of the kidney. Cytological findings have been reported in a number of single cases.48–51 Aspiration yields mainly cyst fluid. The cell content of the fluid is fairly low, but the cells often appear atypical and may be mistaken for cystic renal cell carcinoma. The atypical cells, which are both clustered and single, represent the hobnail type of epithelial cells lining the cystic spaces (Fig. 12.4). In one reported paediatric case, the cytology showed features mimicking a malignant small round cell tumor.52 The cystic spaces are separated by septa of solid connective tissue, which is usually densely fibrous with no blastema and which does not contribute cells to the smears.
In one of our adult cases, smears contained highly cellular tissue fragments of spindle cells in addition to epithelial cells of hobnail type (Fig. 12.5B). The histological counterpart was multifocal thickening of cyst walls and septa by cellular stroma of spindle cells reminiscent of ovarian cortex. The possibility of a mixed epithelial and stromal tumor of the kidney,53 a recently defined entity that was previously regarded as adult mesoblastic nephroma or as a variant of cystic nephroma with cellular stroma, was therefore considered. However, this lesion should also contain an epithelial component of immature tubules, which was not present in our case. Morgan and Greenberg reported a similar case with spindle cells of smooth muscle type, incorrectly diagnosed as angiomyolipoma.50
Xanthogranulomatous pyelonephritis3,54
Macrophages in FNB smears from xanthogranulomatous pyelonephritis can be numerous and look quite atypical, and can be mistaken for malignancy. They have a vacuolated cytoplasm and the nuclei appear enlarged and irregular, particularly in air-dried smears. Chronic inflammatory processes involving adipose tissue in other sites in the retroperitoneum can show a similar cytological pattern (Fig. 12.6). The clinical and radiological findings, the generally inflammatory character of the smear, and the recognition of the ‘atypical’ cells as histiocytes (easier in alcohol-fixed smears) point to the correct diagnosis.
Angiomyolipoma of kidney (Figs 12.7–12.11)55–58
Fig. 12.11 Angiomyolipoma
Tissue sections; same case as Fig. 12.10. (A) Typical pattern (H&E, IP); (B) Round cell pattern (H&E, HP).
The cytological findings are fairly characteristic. Aspirates tend to be bloody but contain a variable number of tissue fragments, syncytial cell clusters and single cells. The cells have elongated or spindle-shaped nuclei, some with truncated ends. Their size and shape are moderately variable. Nuclear chromatin is bland and mitoses are rare. The abundant fragile eosinophilic cytoplasm appears as a background to the nuclei, and cell borders are generally not visible (Fig. 12.8). Large fat vacuoles and some adipocytes are intimately associated with the spindle cells. Strands of endothelial cells and short segments of small vessels are often, but not always present in smears (Fig. 12.7). Tallada et al. found vascular structures in only one of four cases.56
Some angiomyolipomas include highly cellular areas composed predominantly of epithelioid cells of leiomyoblastic type with rounded nuclei (Figs 12.10 and 12.11).59 Nuclear enlargement, anisokaryosis and hyperchromasia of moderate degree may be present and be mistaken for a low-grade renal cell tumor. Several false-positive diagnoses have been reported in the literature.4,5,30,55 However, the cytoplasm of smooth muscle cells is not granular or vacuolated but pale eosinophilic, and the nuclear chromatin is bland. Some typical spindle-shaped nuclei can usually be found also in predominantly round cell areas. A background of fat droplets and adipocytes is usually seen in angiomyolipoma, whereas strands of basement membrane material with adhering tumor cells are characteristic of renal cell tumors. Prominent nuclear atypia and pleomorphism can occur also in angiomyolipoma of the usual spindle cell type raising a suspicion of malignancy (Fig. 12.9). Correlation with clinical and radiological findings and immunostaining (EMA, SMA, HMB-45) is helpful in atypical cases.55
Heavy admixture with blood is common and can make a cytological diagnosis difficult. In such cases, a cell block preparation may contain diagnostic tissue fragments including a vascular component.60 CNB has been successfully used in some cases to confirm the diagnosis.
Renal cell tumors4,5,9,18,61,62
The current classification of renal cell tumors (WHO 2004) includes the following entities:
Clear cell renal cell carcinoma (Figs. 12.12–12.16)
Criteria for diagnosis
About three-quarters of renal cell tumors (RCC) are histologically of the classic clear cell type. Although the clear cell appearance is not well reproduced in cytological preparations, the findings in low- and intermediate-grade tumors are fairly characteristic. Cells have abundant, pale eosinophilic, granular and vacuolated cytoplasm, and cell borders are generally distinct. The cells are relatively cohesive, forming sheets and solid, trabecular or pseudopapillary aggregates. There are variable numbers of single cells and stripped nuclei due to cytoplasmic fragility. Cell cohesion is reduced and single cells are more common in less well-differentiated tumors. The cells are polygonal and have a low nuclear:cytoplasmic ratio. Nuclei are rounded, relatively small and uniform in low-grade tumors (Fig. 12.12), and are enlarged and of variable size, shape and chromatin pattern in intermediate and high-grade tumors (Fig. 12.13). Nucleoli are hardly visible in low-grade tumors, and are large to very large in high-grade tumors. The pattern is less characteristic at the poorly differentiated end of the spectrum, but some cells with abundant pale vacuolated cytoplasm can usually be found (Fig. 12.14). A characteristic feature in smears is tumor cells adhering to strands of stromal material staining pink with MGG, probably derived from the wall of sinusoidal blood vessels (Fig. 12.13). This pseudopapillary pattern must not be mistaken for true papillae. Intranuclear cytoplasmic inclusions can be found in about one-third of RCCs. Intracytoplasmic hyaline eosinophilic globules have been observed but can be found also in large cell carcinomas of other sites.63 Finally, fresh and altered blood, necrotic material and foamy or hemosiderin-containing macrophages are commonly present in the background.
The cytology of RCC, at least of low or intermediate grade, is usually characteristic enough to be recognized also in FNB samples from metastatic sites (Fig. 12.15).64,65 Co-expression of cytokeratin and vimentin by the tumor cells, and positive staining for RCC antigen and CD10, although not specific, can be helpful in the identification of unsuspected metastatic RCC.66,67 Higher specificity has been claimed for two new markers, PAX-2 and H2AX.68
Malignant cells of granular cell type are most commonly seen focally in clear cell carcinoma but occur also in other types of RCC. A separate granular cell variant is no longer recognized. Cells of this type usually have high-grade nuclear morphology. The cytoplasm is abundant, but eosinophilic and finely granular rather than vacuolated (Fig. 12.16).69
Multilocular cystic renal cell carcinoma is a rare subtype of clear cell carcinoma with a generally very good prognosis.70 Conservative, nephron-sparing surgery may be suitable for this tumor, but to our knowledge the potential of preoperative diagnosis by needle biopsy has not yet been documented.
Papillary renal cell carcinoma
Criteria for diagnosis
Ten to fifteen percent of RCCs are of the papillary type (Figs 12.17 and 12.18).71,72 The cells of the type 1 variant are small with a small amount of dense cytoplasm showing no obvious vacuolation or granularity. Nuclei are small, uniform and bland-looking, and nucleoli are inconspicuous. Intranuclear vacuoles occur. True papillary fragments are often prominent in smears. Psammoma bodies are commonly found. Numerous vacuolated macrophages are a characteristic component when present and intracytoplasmic hemosiderin is often seen.73,74 Distinction of type 1 from renal cortical adenoma is mainly based on size. Metastases have been observed from tumors as small as 1 cm75 and tumors larger than 5 mm are now classified as RCC. A conservative approach and radiological follow-up may be an option in very small, incidentally discovered tumors, but if FNB findings are of a clear cell pattern or high nuclear grade the tumor should probably be regarded as RCC regardless of size. Metanephric adenoma also enters the differential diagnosis (see below).
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