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Keywords:

  • kidney;
  • cytology;
  • renal cell carcinoma;
  • papillary;
  • tumor;
  • fine-needle aspiration

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

The papillary variant of renal cell carcinoma has distinctive pathologic and clinical features. Because the prognosis of patients with papillary renal cell carcinoma differs from that of patients with other variants of renal cell carcinoma, accurate diagnosis based on cytologic material may be important for appropriate clinical disease management.

METHODS

A retrospective analysis of cytologic material from 17 papillary renal cell carcinomas and 52 other renal neoplasms with histologic follow-up was performed to identify the relative sensitivity and specificity of different cytologic criteria for papillary carcinoma.

RESULTS

Foamy macrophages and intracytoplasmic hemosiderin were the most sensitive and most specific criteria for the diagnosis of papillary renal cell carcinoma. Foamy macrophages were present in 14 of 17 cases (82%), and intracytoplasmic hemosiderin was present in 13 of 17 cases (76%). Foamy macrophages and intracellular hemosiderin were each present in only 2 of 52 (4%) of nonpapillary tumors examined. Malignant cells were arranged in papillary groups with fibrovascular cores in only 6 of 17 cases (35%), including only 1 of 7 high grade tumors. Nuclear grooves were present in 9 of 17 cases (53%) but were common in only 2 cases. Psammoma bodies were present in only 1 case. Nucleoli and pleomorphism were prominent in high grade tumors. These features, in association with frequent abundant vacuolated cytoplasm, made it difficult to distinguish high grade papillary carcinoma from the clear cell variant of renal cell carcinoma. However, as with low grade tumors, the presence of intracytoplasmic hemosiderin and foamy macrophages were important clues to the diagnosis of 6 of 7 high grade tumors (86%).

CONCLUSIONS

Intracytoplasmic hemosiderin and foamy macrophages are the most sensitive and specific markers for both high and low grade papillary renal cell carcinoma, and they allow for the correct diagnosis in most cases. Cancer (Cancer Cytopathol) 1998;84:303-308. © 1998 American Cancer Society.

Papillary renal cell carcinoma (RCC), defined histologically as a malignant epithelial tumor of the kidney with a minimum of 50% papillary architecture1 and, more recently, by a combination of histologic and cytogenetic features,2 represents between 7% and 15% of renal carcinomas.1, 3 Compared with other subtypes of RCC, papillary RCC has distinctive pathologic and clinical features.1, 3-7 Tumors with low nuclear grade and low stage are associated with an excellent prognosis;1, 3, 6, 8 however, patients with high grade tumors have a more guarded prognosis. Compared with clear cell RCC, papillary RCCs are more often multifocal,9 yet this feature is predicted radiologically in less than half of cases.10 Accurate cytologic diagnosis may still be important for clinical management, particularly in considering a partial versus a radical nephrectomy.

There have been few reports regarding the fine-needle aspiration (FNA) diagnosis of papillary RCC.11, 12 Several criteria have been emphasized, including psammoma bodies, nuclear grooves, intracytoplasmic hemosiderin, foamy macrophages, and papillary tissue fragments. However, the relative sensitivity and specificity of these criteria are unknown. Herein, in an attempt to define further the most sensitive and specific cytologic criteria of this tumor, we report the cytologic features of 17 papillary RCCs and 52 nonpapillary tumors.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Seventeen cytologic specimens from patients with papillary RCC who had their tumors resected were identified in the files of Brigham & Women's Hospital and Children's Hospital, Boston. None of the 8 cases previously reviewed are included.13 All the resected primary tumors were composed of greater than 50% papillary architecture or were otherwise histologically and cytogenetically characteristic of papillary RCC.14 Cytologic material from 15 FNAs performed under radiologic guidance for a renal mass or during intraoperative consultation for a renal mass was reviewed. Two specimens were touch preparations performed during intraoperative consultation. Alcohol-fixed, Papanicolaou-stained direct smear preparation (Papanicolaou-stained ThinPrep, Cytyc Corporation, Boxborough, MA), air-dried, Diff-Quik-stained smears, and hematoxylin and eosin-stained cell block and direct smear material were examined. Of the 15 FNAs, both direct smears and ThinPrep preparations were made for 10, ThinPrep preparations were made for 3, and direct smears were made for 2. The following cytologic features were examined: cellularity, presence of clusters, single cells, papillary fragments, fibrovascular cores, spherules, necrosis, blood, intracytoplasmic hemosiderin (within tumor cells), macrophages, psammoma bodies, nuclear pleomorphism, nuclear pseudoinclusions, nuclear grooves, nucleoli, and cytoplasmic vacuoles. For comparison, the same cytologic features were examined in cytologic specimens (intraoperative aspirations and touch preparations) from histologically confirmed clear cell renal RCC (40 cases), oncocytoma (3 cases), chromophobe RCC (2 cases), metanephric adenoma (1 case), and angiomyolipoma (6 cases). Again, none of these cases previously reviewed are included.13

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Papillary RCC

Eleven patients were male and 6 were female. Their ages ranged from 12 to 79 years (mean, 55 years). Ten tumors were low grade (Furhman Grade 1 and 2) and 7 were high grade (Furhman Grade 3 and 4). Pertinent cytologic findings are summarized in Table 1. All specimens were cellular and composed predominantly of cohesive clusters and tissue fragments. Scattered single cells were present in all smears but were numerous in only two. One high grade tumor was composed nearly entirely of single cells with a few small clusters of cells. Papillary fragments with fibrovascular cores were identified in only 6 of 17 cases. Necrosis was not identified in any of the cases. Red blood cells were noted in all cases but were abundant in only 3. Macrophages were present in 14 of 17 smears and were numerous in 5 of these (Fig. 1 (33K)). Intracytoplasmic hemosiderin located in tumor cells was present in 13 of 17 smears and was abundant in 9 (Fig. 2 (22K)). There was excellent correlation between the presence of hemosiderin in cytologic and histologic material. Chromatin texture was fine in 16 of 17 smears and was coarse in 1 high grade tumor. Intranuclear pseudoinclusions were present in only three cases; they were frequent in two cases and rare in another. Nuclear grooves or creases were present in 9 of 17 cases; they were frequent in 3 cases and rare in 6 others (Fig. 3 (28K)). Cytoplasmic vacuoles, ranging from multiple fine to single large vacuoles, were noted in all cases and were a prominent feature in five cases. Psammoma bodies were seen in only one case and were numerous. An interesting finding in 9 of 17 cases was the presence of round balls or spherules of cells that ranged in size from 25 cells to hundreds of cells. These spherules had smooth outer contours and appeared hollow when the focus of the microscope was adjusted (Fig. 4 (27K)).

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Figure 1. A papillary renal cell carcinoma specimen is shown. Foamy macrophages are sensitive for the diagnosis of both high and low grade tumors (Papanicolaou stain, original magnification x400).

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Figure 2. In this high grade papillary renal cell carcinoma, intracytoplasmic hemosiderin can be seen (Papanicolaou stain, original magnification x800).

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Figure 3. This papillary renal cell carcinoma contains nuclear grooves, which, although present in approximately half of tumors, are often difficult to find (Papanicolaou stain, original magnification x800).

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Figure 4. Compared with papillary tissue fragments, smooth-bordered papillae seem to be a more specific feature of papillary renal cell carcinoma (Papanicolaou stain, original magnification x200).

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Table 1. Comparison of the Cytologic Features of Low Grade and High Grade Papillary Renal Cell Carcinomas
CriteriaNo. (%) of cases
Low grade papillary RCC (n = 10)High grade papillary RCC (n = 7)Total all cases (n = 17)
Papillae5  (50%)1  (14%)6  (35%)
Psammoma bodies1  (10%)0  (0%)1  (6%)
Foamy macrophages8  (80%)6  (86%)14  (82%)
Intracytoplasmic hemosiderin7  (70%)6  (86%)13  (76%)
Nuclear grooves6  (60%)3  (43%)9  (53%)

Cytologic Findings in Other Renal Neoplasms

The same cytologic features used to evaluate papillary RCC were examined in 52 renal neoplasms and are presented in Table 2. These data were used to determine the specificity of these criteria for the diagnosis of papillary RCC. True papillary fragments with rounded contours were not seen in any tumors. However, pseudopapillae with irregular, ragged outlines (Fig. 6 (79K)) were seen in 11 of 40 clear cell RCCs (27.5%). Psammoma bodies were seen in the 1 metanephric adenoma studied (100%). Foamy macrophages were seen in only 2 of 40 clear cell RCCs (5%) and no other tumors. Intracytoplasmic hemosiderin was seen in 2 of 40 clear cell RCCs (5%) but was not seen in any other tumors. Both tumors were cystic clear cell RCCs that had abundant hemosiderin within macrophages (nonfoamy) and rarely in tumor cells. In this study, we observed siderophages (nonfoamy) in five cases of clear cell RCC, of which two cases were associated with intracytoplasmic tumoral hemosiderin. Nuclear pseudoinclusions were seen in 5 of 40 clear cell RCCs (12.5%), 2 of 2 chromophobe RCCs (100%), and 4 of 6 angiomyolipomas (67%). Nuclear grooves were seen in 10 of 40 clear cell RCCs (25%), 1 of 2 chromophobe RCCs (50%), and 1 of 6 angiomyolipomas (17%), as well as in the 1 metanephric adenoma studied (100%). These data show that the most specific features were foamy macrophages and intracytoplasmic hemosiderin, both with a specificity of 96%.

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Figure 6. Papillary tissue fragments with irregular borders may be seen in both papillary renal cell carcinoma (A) and the clear cell variant (B) (H & E, original magnification x200).

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Table 2. Frequency of Various Cytologic Features of Renal Tumors Other than Papillary Renal Cell Carcinoma
CriteriaNo. (%) of cases
Clear cell RCC (n = 40)Oncocytoma (n = 3)Chromophobe RCC (n = 2)Angiomyolipoma (n = 6)Metanephric adenoma (n = 1)Total (n = 52)
Papillae0  (0%)0  (0%)0  (0%)0  (0%)1  (100%)1  (2%)
Psammoma bodies0  (0%)0  (0%)0  (0%)0  (0%)1  (100%)1  (2%)
Foamy macrophages2  (5%)0  (0%)0  (0%)0  (0%)0  (0%)2  (4%)
Intracytoplasmic hemosiderin2  (5%)0  (0%)0  (0%)0  (0%)0  (0%)2  (4%)
Nuclear grooves10  (25%)0  (0%)1  (50%)1  (17%)1  (100%)13  (25%)
Intranuclear cytoplasmic inclusions5  (12.5%)0  (0%)2  (100%)4  (67%)0  (0%)11  (21%)

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Papillary RCC represents between 7% and 15% of renal carcinomas.1, 3 By histologic definition, papillary RCC must be composed of at least 50% papillary architecture.1 More recently, a combination of histologic and cytogenetic criteria have been used to define this tumor.14 The most compelling evidence that papillary RCC is a distinct variant of RCC has been the demonstration of unique chromosomal abnormalities. Deletions in the short arm of chromosome 3 are identified in the majority of clear and granular cell RCCs, but are not observed in papillary RCC.4 Instead, a characteristic set of chromosomal trisomies, most commonly involving 7, 16, and 17, have been documented by karyotyping.5 Papillary RCCs are also distinguished by their immunohistochemical phenotype. Like other subtypes of RCC, papillary RCCs are immunoreactive for epithelial membrane antigen (EMA) and low molecular weight keratins. Unlike other RCCs, however, papillary RCC routinely exhibits strong immunoreactivity with antibodies to high-molecular-weight callus keratins (DAKO)7 and CK7.15 This observation applies to both low grade and high grade papillary RCCs. Papillary RCCs also have characteristic radiologic findings; they are often cystic and necrotic, and may appear hypodense on CT scan. Angiographically, papillary RCC often appears avascular or hypovascular.3

In 1976, Mancilla-Jimenez et al. published the first large series of papillary RCCs (34 cases) and found they were predominantly low stage tumors (85% Robson Stage I [AJCC Stage I and II]), and the overall 5-year survival was 84%.1 Mydlo and Bard studied 39 cases of papillary RCC and reported similar 5-year survival rates for both Stage I (87%) and Stage II (84%) patients, but a lower rate for Stage III patients (50%).3 More recently, Lager et al. found that tumors with low nuclear grade were associated with 100% disease specific 5-year survival, irrespective of stage; however, survival for patients with with high grade tumors was only 50% at a mean of 4 years of follow-up.8 In the largest series to date, which contained 62 papillary RCCs, pathologic stage was the only independently significant predictor of clinical outcome. However, there was a reasonable correlation between stage and nuclear grade.6 Based on these data, the prognosis of patients with low grade/low stage papillary RCC at 5 years of follow-up is excellent-probably even better than that for patients with comparable clear cell tumors. Patients with high grade/high stage papillary RCCs have a much more guarded prognosis.

Despite the widespread acceptance of papillary RCC as a distinct variant of RCC, very few reports about its cytologic features have been published.11, 12 In one of these series, there was no surgical pathology follow-up to confirm the FNA diagnosis.11 Furthermore, the sensitivities and specificities for different cytologic characteristics were not defined. In these studies, the authors concluded that papillary RCCs have distinctive cytologic features that allow for "confident diagnosis." Our experience, prior to examining this series, contrasted with these previous reports. In a study of accuracy of FNA in distinguishing subtypes of RCC, we found that the most common pitfall was misclassifying a papillary RCC, usually a high grade tumor, as a clear cell or sarcomatoid RCC.12 We undertook this survey of additional papillary RCCs to examine the cytologic spectrum of papillary RCC critically and define the most sensitive and specific criteria for its diagnosis.

The cytologic features emphasized in cytology texts and frequently referred to as "classic features" of papillary RCC were often absent in this series. For example, in this study, psammoma bodies were present in only one case and intranuclear pseudoinclusions were present in only three cases. Dekmezian et al. concluded that "the most distinguishing features, however, are nuclear; nuclear grooves are frequently evident, nuclear pleomorphism is unusual, and nucleoli are inconspicuous."12 Nuclear grooves, one of the most touted features of papillary RCC, were common in only 2 of our papillary RCC cases (they were rare in 6 and altogether absent in 7 cases) but were seen in 25% of other tumors. Despite the conspicuous absence of some "classic features" of papillary RCC, the diagnosis of low grade papillary RCC was not difficult when the entire spectrum of changes was evaluated. The malignant cells were often arranged in papillary groups with fibrovascular cores. The nuclei were bland and contained fine chromatin. Foamy macrophages and prominent intracytoplasmic hemosiderin were often seen. In this series, the most sensitive features for the diagnosis of low grade RCC were foamy macrophages and intracytoplasmic hemosiderin, with sensitivities of 82% and 76%, respectively. Both of these criteria were 96% specific. Although very helpful when present, nuclear grooves and psammoma bodies appear to be less sensitive and specific criteria for the diagnosis of papillary RCC.

Compared with low grade papillary RCC, the diagnosis of high grade papillary RCC is more challenging. Seven of 17 tumors in this series were high grade tumors. In the previous two cytologic series, Furhman grading was not reported, and these studies neither described nor illustrated high grade papillary tumors.11, 12 Papillary fragments with fibrovascular cores, which are perhaps the most specific cytologic feature of papillary RCC, were seen in only one high grade tumor in our series. Together with pleomorphism and frequent, prominent nucleoli, these tumors might easily be mistaken for a high grade clear cell variant of RCC (Fig. 5 (26K)). The most sensitive features for the diagnosis of high grade papillary RCC in this series were again intracytoplasmic hemosiderin deposition (present in 6 of 7 high grade tumors) and foamy macrophages (present in 6 of 7 cases). However, one case, a Grade 4 tumor, lacked papillary fragments, hemosiderin, and macrophages. This case serves to illustrate that accurate subtyping of some high grade papillary RCCs is probably not possible. However, it should be pointed out that making a distinction between high grade papillary RCC and clear cell RCC may not be as important as with low grade tumors, because the prognosis may not differ significantly.

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Figure 5. Some high grade papillary renal cell carcinomas (RCCs) are difficult to distinguish from the clear cell variant of RCC. We found the presence of foamy macrophages and intracytoplasmic hemosiderin to be the most sensitive diagnostic features of papillary RCC (Papanicolaou stain, original magnification x800).

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The presence of hemosiderin is fairly sensitive for the diagnosis of papillary RCC. We have also demonstrated that hemosiderin is relatively specific as well. Only 5% of clear cell RCCs showed intracytoplasmic hemosiderin. That intracytoplasmic hemosiderin is seen only rarely in clear cell RCC is also reflected in the scarcity of reported clear cell RCCs with this feature.16 Interestingly, there is cytogenetic evidence raising the possibility that these tumors are a distinctive subset of RCC and may be more closely related to papillary tumors than clear cell tumors at the cytogenetic level.16 It is important to emphasize that the intracytoplasmic hemosiderin specifically relates to tumoral hemosiderin, not hemosiderin within macrophages. Tumors that have intracytoplasmic (tumoral) hemosiderin are usually associated with hemosiderin within macrophages. We consider hemosiderin within macrophages less specific for the diagnosis of papillary RCC. It should also be kept in mind that pigment that closely resembles neuromelanin has been observed in a case of clear cell RCC and may be mistaken for hemosiderin and inadvertently lead to a misdiagnosis of papillary RCC.17 One criterion deserves further comment. As illustrated in Figure 6 (79K), the papillarylike structures with ragged irregular outlines were seen in 27.5% clear cell RCCs and are indistinguishable from similar structures seen in true papillary RCC. We believe that the presence of fingerlike papillae with bulbous, rounded ends and spherules are a more reliable criteria of papillary RCC. Spherules are simply the detached ends of these blunt-ended papillae. We did not observe these structures in any of the 40 clear cell RCCs in this study.

In conclusion, low grade papillary RCC has distinctive cytologic features that facilitate a specific diagnosis based on FNA. High grade papillary RCCs, however, may be difficult or impossible to distinguish from high grade clear cell RCCs by FNA, even with adequate cellularity. Intracellular hemosiderin and foamy macrophages are the two most helpful features in making this distinction. In difficult cases, if cell block material is available, immunohistochemical studies may be helpful in distinguishing papillary RCC from clear cell RCC.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES