—  SPECIALTY CONFERENCE  —

Genitourinary Pathology

Case 3 - Acquired Cystic Kidney Disease-Specific Renal Cell Carcinoma

Satish Tickoo
Joan & Sanford I. Wiell Medical College of Cornell University
New York, NY


Click on each slide thumbnail image for an enlarged view
Clinical History
A 68-year-old female on hemodialysis for chronic renal failure was found to have a 4 cm solid mass in her left kidney. Left simple nephrectomy was performed.


Case 3 - Figure 1 - Intermediate magnification view of the smaller tumor. Large eosinophilic cells arranged in cribriform, tubular and microcystic architecture. Numerous intratumoral oxalate crystals are present (open arrowheads).
Case 3 - Figure 2 - Higher magnification view of the smaller tumor showing the cytologic details, including Fuhrman's grade 3 nuclei, and abundant eosinophilic granular cytoplasm.
Case 3 - Figure 3 - The larger tumor with focal cribriform architecture. While most of the cells have eosinophilic granular cytoplasm, some cells in the lower half of the image show focal cytoplasmic clarity.


Case 3 - Figure 4 - An area of papillary growth pattern in the larger tumor.
Case 3 - Figure 5 - Focal clear cell (conventional) renal cell carcinoma-like features in the larger tumor.
Case 3 - Figure 6 - Marked cystic change in the residual renal parenchyma.

Gross Findings
The renal parenchyma was almost completely replaced by thin-walled cysts that did not communicate with the pelvicalyceal system. Most cysts contained pale-yellow clear fluid. Two masses, with the maximum diameters of 4.3 and 2.5 cm, respectively, were identified in the lower and the mid portions of the kidney. Both had a brown-tan cut surface, and the larger tumor showed large areas of hemorrhage and necrosis. While the larger tumor appeared solid, the smaller one had a spongy cut surface with multiple clear fluid-containing cysts ranging from less than 0.1 to 0.4 cm in size.

Microscopic Findings
Slide #1 has been prepared from the larger tumor, and #2 from the smaller one. Both share the common feature of areas with cribriform to (micro)cystic architecture, with cells containing abundant granular, eosinophilic (oncocytic) cytoplasm and Fuhrman's grade 3 nuclei. Some cells in these areas exhibit hobnailed appearance. The smaller tumor (slide #2) shows this morphology in almost its entirety, whereas the larger tumor (slide #1) has a more variegated morphology. The larger tumor also contains areas with papillary, as well as solid and acinar growth patterns. Some foci closely mimic clear cell (conventional) renal cell carcinoma, with clear to finely vacuolated cytoplasm. The central part of the tumor shows extensive necrosis. There is extensive calcium oxalate crystal deposition within both the tumors, and foci of calcification, including psammomatous type, are also present. The small amount of surrounding kidney in these sections shows multiple cysts, some lined by cells with eosinophilic cytoplasm and others by clear cells.

Diagnosis
Acquired Cystic Kidney Disease-Specific Renal Cell Carcinoma

Discussion
Acquired Cystic Kidney Disease (ACKD) is characterized by the development of multiple cysts in the kidneys of patients with End-Stage Renal Disease (ESRD), in the absence of congenital cystic disease. [1, 2] The prevalence and severity of ACKD progressively increases in patients on dialysis (both hemo- and peritoneal-dialysis), being present in 20% of the cases on 1-3 years of dialysis, and approximately 90% of the patients on dialysis for 5-10 years. [2, 3] Rarely, ACKD may develop in cases of ESRD who have never received any dialysis. [4]

There is almost a 100-fold increase in the prevalence of renal cell carcinoma in patients with ACKD as compared to the general population. [2, 5, 6] Renal tumors arising in ACKD have variably been reported to be papillary, clear cell (conventional), multilocular cystic, or chromophobe renal cell carcinomas, with papillary renal cell carcinoma being considered as the commonest subtype in most publications. [5, 7, 8]

In our initial experience, we found many tumors in the setting of ACKD difficult to classify and often not conforming to the usual and common subtypes of RCC. In a detailed morphologic evaluation of nephrectomy specimens from 43 cases of ESRD, the results of which were presented by us at the 2003 USCAP meeting, [9] we found that there are five distinct tumor subtypes that occur in this setting. Besides the usual papillary renal cell carcinoma (RCC), clear cell (conventional) RCC, and chromophobe RCC, we also found some tumors with clear cell cytology, but with extensive papillary architecture (tentatively designated as papillary clear cell RCC by us). However, the most common tumor subtype that we observed was what we designated as ACDK-specific RCC (AS-RCC). Two examples of this are represented in the submitted slides on this case. Among the 43 cases of ESRD, we found the AS-RCC to be the dominant tumor nodule in 15 cases, and in the setting of ESRD with ACKD AS-RCC formed approximately 50% of the tumors. Such tumors were observed only in the kidneys with ACDK and not in the other ESRD kidneys without ACKD. We have also never seen such a tumor in a non-ESRD setting.

AS-RCCs show a spectrum of morphologic features, but the presence of eosinophilic (oncocytic) cells with at least grade 3 nuclei, arranged in cribriform as well as tubular and cystic patterns, is a consistent finding. Areas with papillary and/or alveolar, solid-alveolar, or diffuse patterns may also be seen, and sometimes variable proportion of the tumor may have clear-cell cytology. Most tumors also possess intratumoral oxalate crystals. Because of these varied architectural patterns, it is not difficult to understand how many of these could be classified as clear cell or papillary RCC in small series of cases.

For example, in two of the more recent publications on small number of RCCs with intratumoral oxalate crystals, three tumors were classified as papillary RCC, and one was classified as clear cell RCC. [10, 11] Interestingly, all four of these cases were reported to have ACKD. On evaluation of the published illustrations, we believe that at least some of these qualify as AS-RCC. Similarly, the 'cribriform lesion,' and the 10 mm renal cell carcinoma with histological features 'indeterminate between papillary and clear cell types' illustrated by Cheuk et al [12] also appear to be similar to AS-RCC. It is not surprising that the molecular/genetic findings reported on a few renal tumors in ACDK have been confusing, at the best. Most such reports are based on the studies on a small number of cases. The largest series on 18 tumors by Hughson et al [13] reported trisomies of 7 and 17 in 5 of 14 'papillary RCCs,' loss of 3p in 1 of 2 'clear cell RCCs,' and neither trisomies nor 3p losses in 2 tumors designated as 'solid eosinophilic cell' carcinomas. We analyzed 12 cases by FISH for trisomies 7 and 17 as well as deletion of VHL gene, and found 1 of 2 papillary RCC with trisomy 7 and 17, 2 of 2 clear cell RCCs with VHL deletions, 1 of 2 chromophobe RCCs with monosomy of chromosome 17, and 4 papillary clear cell RCC with neither trisomy 7/17 nor 3p losses. Of the 4 AS-RCC tested, one showed a trisomy of 7/17 and another a monosomy 3, whereas all 4 lacked any VHL losses. Thus, it appears that most of the AS-RCCs are not only morphologically, but genetically as well, different from the usual clear cell or papillary RCC. However, the presence of trisomies 7 and 17 in occasional tumors [9, 12] suggests some still to-be-clarified relationship with papillary RCCs.

The recognition and proper classification of the tumors in the setting of ACDK, rather, in any setting, is essential for many reasons. We know that many renal tumors that bear superficial resemblance to each other are in fact clinically and biologically different entities (e.g., renal oncocytoma vs. chromophobe RCC- eosinophilic variant vs. clear cell RCC-eosinophilic variant). Proper morphologic separation, however, very frequently lets us predict the likely biologic behavior in each tumor. Additionally, and possibly more pertinent to the case under discussion, is the fact that it was the recognition of chromophobe renal cell carcinoma and its eosinophilic variant as distinct entities in the 1980s [14, 15] that has been a basis for the dramatic change in the way we understand and classify renal tumors now. Therefore, recognition is the first step towards any logical progress in understanding any tumor, be it its pathogenesis, biologic behavior, or management.

The biologic behavior of RCCs in ESRD is reported to be less aggressive than the RCCs in sporadic or non-ESRD setting. Only rare cases have been reported to metastasize. [16, 17, 18] A possible reason for this less aggressive behavior may be that these patients are usually under constant medical care, with radiological evaluations possibly picking up most tumors quite early. Thus, the mean tumor size in our series was 3.0 cm (median = 2.6). However, we did observe lymph node metastasis at presentation in 1 of our 15 cases of AS-RCC, and have recently found another case with large sarcomatoid areas. We, therefore, believe that AS-RCCs are not benign or hyperplastic nodules, but are another subtype of renal cell carcinoma; these tumors need to be recognized before any further progress can be made in understanding them.

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