Acquired Cystic Disease–Associated Renal Cell Carcinoma: Review of Pathogenesis, Morphology, Ancillary Tests, and Clinical Features

Where once PRCC was thought to be the most frequent malignancy associated with ACKD, ACD-RCC is now believed to represent the most commonly occurring RCC in patients with ACDK.^3,5  The range of patients affected by ACD-RCC is very narrow, and by definition the tumor is only diagnosed in the context of patients with ACKD due to ESRD. Compared with the general population, the risk of developing RCC in ACKD is increased by more than 100-fold.⁵  Patients with RCC most often are asymptomatic and the disease is frequently found incidentally on routine imaging,⁵  whereas a minority of patients with RCC present with microscopic hematuria or flank pain.^2,6  Significant hematuria and hematoma formation was found in 17% of nephrectomies performed for ACKD; such massive hemorrhage can obscure radiographic and macroscopic identification of RCCs arising in a cystic background.⁵  Renal cell carcinoma developing in a background of individuals with ACKD tends to occur among those of younger age and predominantly male sex.⁵ 

The incidence of RCC in ACKD increases with duration of dialysis and ranges from 1.6% to 8%.⁷  Although recent studies found that ACD-RCC was more likely to occur 10 to 20 years after dialysis, compared with CCRCC tumors which generally developed within 10 years of initiating dialysis,^4,6,8  this association was not confirmed in another study of renal epithelial neoplasms in patients with ESRD.³  Inoue and colleagues⁹  found that neoplasms associated with ACKD (PRCC, ACD-RCC, and CCPRCC) grouped by genetic clustering had a greater number of cases occurring more than 20 years after dialysis compared with tumors that were genetically similar to sporadic CCRCC.

This increased risk is also true for individuals who have undergone kidney transplantation. In patients with renal transplant, presence of ACKD was the single most important risk factor for the development of RCC. Additionally, male sex, African American race, age of 65 years or older, longer duration of pretransplantation dialysis with an interval of greater than 4.6 years, donor age of at least 50 years, and allograft rejection within the first year of transplant were also risk factors for RCC.¹⁰ 

Acquired cystic disease–associated RCC is a lesion arising from the cells of the proximal nephron. Immunophenotypic characterization has determined the neoplastic cell expresses proximal tubule markers, such as CD10, RCC marker, α-methyl-acyl-coenzyme A (AMACR; also known as racemase or P504S), and GST-α, but it may also aberrantly express distal tubule markers, such as BerEP4.^2,11  Isoform characterization of cadherin by immunohistochemistry has also shown that ACD-RCC cells are derived from proximal tubules that express N-cadherin but lack E-cadherin, a marker of distal tubule differentiation.^11,12  It has been suggested that the proximal tubule phenotype may contribute to the deposition of calcium oxalate crystals that are characteristic of ACD-RCC.² 

The pathophysiologic mechanisms underlying epithelial hyperplasia and tumorigenesis of ACD-RCC are still under investigation. Cellular damage due to a chemically altered microenvironment secondary to ESRD is thought to lead to carcinogenesis. Damage resulting from uremia associated with ESRD has been thought to promote ACKD even before dialysis has been initiated.¹³  In order to protect against oxidative stress associated with dialysis, cancer cells may acquire antioxidative properties by increasing expression of peroxiredoxins and thioredoxins. Eventual dysregulation of these antioxidant enzymes may provide neoplastic cells with a protective property against free radicals associated with dialysis, and may promote tumor survival.¹⁴  COX-2, a marker of oxidative stress, was significantly more increased in ACD-RCC compared to sporadic CCRCC.⁸ 

The precursor lesion of ACD-RCC is still a subject of ongoing investigation, but researchers have strongly suggested its relation to calcium oxalate deposition and cyst development in ESRD.^{5,8,9,11–13}  Sule and colleagues²  hypothesize that increased serum oxalate, proximal tubular phenotype, and lower levels of calcium oxalate inhibitors may promote deposition. Calcium oxalate may cause tubular damage by obstruction and formation of reactive oxygen species, but lack of changes in tumor cell proliferation and apoptosis between RCCs with crystals and those without suggests they may not play a primary role in tumorgenesis.²  According to Truong and colleagues,⁵  the degree of epithelial hyperplasia and atypia is vastly greater in acquired rather than hereditary cystic disease. Acquired cystic disease–associated RCC has been found to be associated with cysts lined by foamy and eosinophilic cells rather than clear cells. The presence of multiple renal cysts and close association of these specific cyst types with ACD-RCCs suggest a sequential progression from cyst to carcinoma.^12,13  Similarly, atypical cysts lined by cells with eosinophilic cytoplasm and large nucleoli were always found in association with ACD-RCC.¹¹  The presence of atypical cysts and oxalate deposition is significantly greater in ACD-RCC compared with CCRCC and is believed to be related to the longer duration of dialysis occurring with ACD-RCC.⁸  Furthermore, atypical cysts, in contrast with simple cysts, have been found to have similar genetic changes.^9,15  Clustered microcystic lesions and papillary adenomas have less frequently been proposed as precursor lesions.³  Based on the reported literature, cysts with epithelial proliferation or atypia may represent the likely precursor lesion for ACD-RCC.

The kidneys in which ACD-RCC is diagnosed have features of typical ESRD, including atrophic kidneys with corticomedullary junctions obscured by diffuse, small cortical cysts.^5,12,16  The lesion may be solitary or multifocal, and it may be found in association with atypical cysts, adenomas, or additional neoplasms.^3,5  Bilaterality is seen in more than 20% of cases.³  The tumor is generally circumscribed^2,3,17  and often arises in a cyst.^3,8  Size is variable but averages approximately 3 cm in greatest dimension.^2,3  Thick, fibrous capsules can be present in larger tumors.³  The cut surface ranges from yellow-tan^2,8,12  or white,¹⁸  to brown.¹⁷  Focal hemorrhage and necrosis have been described.^2,3  An example of the macroscopic pathology is shown in Figure 1.

Histologically, ACD-RCC has a variable papillary, tubulocystic, microcystic, macrocystic, solid, and cribriform architecture (Figure 2). Cribriform is the unique pattern to help distinguish this entity from other neoplasms with predominant papillary structure. The lining cells are typically large, with eosinophilic, granular cytoplasm and ill-defined cell membranes, and they less frequently have clear cell appearance (Figure 3). Intracytoplasmic microlumen formation or vacuoles contribute to the cribriform pattern and have been proposed as a distinguishing feature of ACD-RCC.¹⁹  The dysplastic nuclei are characteristically high grade with prominent nucleoli (Fuhrman grade 3). Syncytial growth is also observed.¹¹  Similar to PRCC, foamy cells have been identified within the tumor, but immunophenotypic evidence has determined these cells to be neoplastic rather than foamy histiocytes, as are seen in PRCC.¹⁹  Sarcomatoid differentiation is uncommon in ACD-RCC and has only been described in a handful of cases to date.^{3,4,12,16,18,20}  Rhabdoid features have been described in a single case report.¹⁶ 

One of the most prominent, but not pathognomonic, histologic features of ACD-RCC is the deposition of polarizable calcium oxalate crystals within the tumor and parenchyma (Figures 4 and 5). Intratumoral crystals are present within the neoplastic epithelium and stroma and also within the renal parenchyma or other cysts, but the crystals fail to elicit a foreign-body giant cell–type reaction.^2,3  The crystals exhibit multicolored birefringence and stain by Pizzolato method; they do not stain by von Kossa and alizarin red stains, and they are not visualized by periodic acid–Schiff, trichrome, and silver stains.²  The amount ranges from few to many, and crystals may be completely absent.^3,11,19  More often than not, crystals are detected exclusively in ACD-RCC.^3,13,21  Additionally, the landmark study describing calcium oxalate deposition in RCCs with ACDK documented 1 CCRCC with crystal deposition, but this tumor was also associated with an ACD-RCC in the same kidney and the contralateral kidney.²  Enoki et al⁸  quantified the percentage of crystals found in tumoral and nontumoral tissue in ACD-RCC compared with CCRCC and determined that intratumoral crystal deposition was exclusive to ACD-RCC. They also identified 2 cases of CCRCC with nontumoral crystals associated with atypical cysts.⁸ 

Fine-needle aspiration has been a useful tool in the evaluation of potential metastatic disease in patients with a history of ACD-RCC. Cytologic evaluations correlate with the original histopathology of nephrectomy specimens: aspirates are cellular with papillary or cribriform architecture and have similar cytologic features, including granular, eosinophilic cytoplasm with intracytoplasmic vacuoles, and centrally located nuclei with finely granular chromatin and prominent nucleoli.²¹ 

Because of the scarcity of information and the presence of characteristic morphologic features, the utility of immunohistochemistry in the diagnosis of ACD-RCC is limited.^4,22  As more and more cases are published, a distinctive immunophenotypic pattern for ACD-RCC has emerged. A summary of results from the available immunohistochemical analyses in the literature is displayed in the Table. The most common pattern of expression of ACD-RCC is positivity for CD10, RCC marker, and AMACR (Figure 6). Cytokeratin 7 (CK7) is focally expressed in a subset of cases (Figure 7). Cytokeratin stains for AE1/AE3 and CAM5.2^11,12,23  are generally positive, whereas high–molecular weight cytokeratin (CK903) is negative. Proliferation index determined by Ki-67 is low (2.85%–6.2%).^3,8 

Immunoreactivity for the following markers is described in case reports or small series: BerEP4,¹¹  PAX8,¹²  p53,¹²  mitochondria,^12,24  vinculin,³  MIA,^18,24  and S100.¹⁷  In contrast, CA9,^13,19  MOC31,¹¹  c-kit,¹⁹  VEGFR-2,¹⁹  PDGFR-α,¹⁹  and TFE¹⁸  were not detected. Variable results were obtained for epithelial membrane antigen, vimentin,^20,23  PAX 2,^19,24  CD57,^8,19  and GST-α.¹¹  Cadherin expression in ACD-RCC has determined the presence of N-cadherin,¹²  the absence of E-cadherin,^11,12  and subsets with reactivity for kidney-specific cadherin.^2,19 

The genetic mechanisms underlying the carcinogenesis of ACD-RCC are complex, and even samples taken from different tumors within the same individual are not identical.^9,11  The genetic abnormalities reported to be associated with ACD-RCC are summarized in the Table. The most common abnormalities include gains in chromosomes 3, 7, and 16. To a lesser extent, gains have been observed in chromosomes 1, 2, 5, 6, 8 to 12, 17 to 19, X, and Y. Losses are infrequently observed but have been described in chromosomes 2, 3, 16, and Y. Mutations in the von Hippel-Lindau (VHL) gene have not been detected.^25,26 

Cytogenetic changes described in ACD-RCC with more aggressive features overlap with standard ACD-RCC but exhibit more complexities. Sarcomatoid differentiation has been associated with molecular changes with advanced polysomy of chromosomes 3 and 16, trisomy 9, and loss of Y chromosome,¹²  monosomy of chromosomes 3, 9, and 16,²⁴  and loss of chromosomes 1p, 2q, 9, and 14.²⁷  An additional case with sarcomatoid and rhabdoid features demonstrated gains of 16 and X with losses of chromosomes 6, 9, 14, 15, 22, and Y.¹⁶  Prior evidence associates alterations of chromosomes 15 and 22 exclusively with mucinous tubular and spindle cell carcinoma; however, current studies indicate these changes are not as specific as once thought.¹⁶  These variations, in addition to copy number changes in chromosomes 9 and 14, are recurrent molecular abnormalities detected in ACD-RCC with sarcomatoid features and likely account for the aggressive behavior of these tumors.

Studies have attempted to evaluate the molecular characteristics of ACD-RCC in relation to known changes associated with CCRCC and PRCC. Cluster analysis using DNA copy number alteration by comparative genomic hybridization grouped 16 ACD-RCCs with PRCC (cluster B), compared with only a single case of ACD-RCC grouped with CCRCC (cluster A). The study demonstrated CCRCC and PRCC in patients with ESRD were similar to their respective sporadic counterparts, but also that patients in cluster B had a significant association with ACKD and longer duration of dialysis. No significant copy number alteration differences were detected between cases of ACD-RCC and CCPRCC.⁹  Papillary RCC and ACD-RCC undoubtedly have overlapping morphologic, immunophenotypic, and molecular findings; yet, despite cytogenetic similarities with PRCC, there are differences to suggest the molecular pathway to ACD-RCC is indeed unique. Acquired cystic disease–associated RCC differs from PRCC in that PRCC has greater frequency of 1q gains⁹  and lacks gains of chromosome 3¹¹  and chromosome X.^11,12 

Similar genetic lesions have also been identified in precursor lesions, including gains in chromosomes 7, 12, 16, 17, 19, 20, and Y.^9,15  Hes et al²⁸  assessed the premalignant potential of nonneoplastic renal parenchyma in patients with ESRD and detected similar chromosomal aberrations in foci of hyperplastic and dysplastic tubules, including gains in chromosome 7 and 17, and loss of Y; unfortunately, assessment for 3p loss could not be evaluated because of weak probe signal. This is further evidence that the epithelial hyperplasia of atypical cysts is the likely precursor lesion of ACD-RCC.

Because papillary architecture is variably present in many cases of ADC-RCC, these tumors are commonly misdiagnosed as type 2 PRCC. The presence of clear cell areas with solid and acinar architecture may lead to confusion with CCRCC. Although CCRCC and type 2 PRCC can occur in the same clinical setting of ACKD with ESRD, and the morphologies of these entities overlap, careful attention to subtle differences, such as the presence of cribriform architecture and intratumoral calcium oxalate crystals, is essential in deciphering the correct diagnosis. A summary of differentiating features of these tumors by comparison of clinical data, morphology, immunohistochemistry, and molecular studies is shown in the Table.

The key defining features of ACD-RCC lacking in the other entities is the mixture of eosinophilic and clear cells, cribriform morphology, and presence of polarizable calcium oxalate crystals. The combination of papillary, cribriform, and/or tubulocystic features of ACD-RCC is more complex than in classic CCRCC, and the eosinophilic cells and high-grade nuclei are uncharacteristic of CCRCC.

Separating ACD-RCC from PRCC based on morphology is difficult, especially with PRCC type 2, because both have papillary architecture and large eosinophilic cells with high-grade nuclei. Helpful features to distinguish these differential diagnoses are the foamy macrophages, psammoma bodies, and glassy hyaline globules that can be associated with PRCC but are not seen in ACD-RCC. Papillary RCC also lacks cribriform appearance and is not associated with polarizable calcium oxalate crystals.

Clear cell PRCC is an important differential diagnosis because of the variable papillary and tubulocystic features. Despite the architectural similarities, the papillary cores of CCPRCC are lined by low-grade cells with a characteristic subnuclear vacuolar appearance due to the reversed polarity of nuclei away from the basement membrane.

Renal neoplasm with eosinophilic cells should also enter the differential diagnosis, which includes entities such as oncocytoma, chromophobe RCC, tubulocystic carcinoma, unclassified RCC with rhabdoid differentiation, and MiT family translocation RCC.²⁹ 

In general, RCC associated with ACKD is considered to be less aggressive than sporadically occurring RCC, and ACD-RCC is considered to have a good prognosis.^5,6,20  In transplant patients, the less aggressive nature of RCCs is believed to be a result of frequent monitoring. Transplant patients tend to be younger by approximately 10 years, to present with a smaller tumor size and papillary histology, to have a lower pathologic tumor stage (pT1a), and to have fewer metastases compared with nontransplant patients, who tend to have classic CCRCC and a graver prognosis.³⁰ 

Data regarding prognosis and outcomes are conflicting and are limited by the relatively low number of cases with patient follow-up. Acquired cystic disease–associated RCC has the same tumor stage, proliferation rate, apoptotic rate, and patient survival compared with CCRCC.²  One study determined that ESRD-associated RCC patients tended to have better survival than those with sporadic RCC, with the exception of 2 patients with ACD-RCC with sarcomatoid features, 1 of whom died of metastatic disease 34 months after diagnosis.³  Of 23 cases with follow-up, including sporadic and ESRD-associated RCC, metastatic disease occurred in 2 cases of ACD-RCC with sarcomatoid differentiation.³  This is in contrast to a study including 8 ACD-RCCs with no metastatic disease on follow-up.²⁰  Rhabdoid and sarcomatoid differentiation in RCC neoplasms should be reported regardless of the extent, whereas the percent of tumoral necrosis, if present, should be specified.²²  The incidence of sarcomatoid differentiation increases with duration of dialysis, especially for more than 20 years, and these patients have significantly decreased disease-free survival.⁶  Metastatic disease without sarcomatoid features was reported in 2 cases months following initial diagnosis.²¹  Additionally, a quarter (4 of 16) of patients with long-term dialysis therapy and ACD-RCC had a similar rate of aggressive disease in the form of metastasis, recurrence, and death compared with sporadic CCRCC.⁸  These findings suggest that in addition to sarcomatoid differentiation, other potential features account for the more aggressive behavior among the generally favorable ESRD-associated RCCs.

Standard treatment for ACD-RCC is nephrectomy, either partial or total. Targeted therapy in RCC primarily focuses on known signaling pathways in CCRCC, and chemotherapeutic agents have not been evaluated specifically for ACD-RCC. Among the current literature, a single report mentions use of sunitinib in a case of metastatic ACD-RCC that did not respond to therapy.¹⁹  Multiple recommendations for radiographic surveillance have been proposed, but a defined interval has not been established.¹⁰  Imaging for masses or large cysts is recommended for patients with ESRD, and frequent screening is recommended especially after 10 or more years of dialysis.⁶ 

Acquired cystic disease–associated RCC is currently recognized by the ISUP/Vancouver classification of renal neoplasia,³¹  and has been formally acknowledged in the current World Health Organization classification.³²  In summary, ACD-RCC is a neoplasm found exclusively in AKCD of ESRD, with a unique morphology characterized by complex papillary and cribriform architecture, eosinophilic cytoplasm, and high-grade nuclei. Intratumoral calcium oxalate crystal deposition is a frequent and fairly specific feature. Although diagnosis can be established by hematoxylin-eosin–stained sections, a distinctive immunophenotypic pattern of AMACR, CD10, and RCC Ma positivity with CK7 negativity can assist in evaluating the differential diagnosis. Similarly, molecular genetic studies have unveiled the recurrent pattern of gains in chromosomes 3, 7, and 16, whereas gains in chromosomes 9 and 14 are associated with more aggressive sarcomatoid features. The etiology of this tumor centers on epithelial hyperplasia and atypical cyst formation, but the underlying mechanism contributing to tumorigenesis requires additional research. Information about outcome, prognosis, and targeted therapy is still continuing to unfold.