The expanding role of renal mass biopsy

Usage of renal mass biopsy has increased in recent years, ranging from selected clinical scenarios to routine implementation in some institutions. Major tasks for the field of diagnostic histopathology include discriminating primary renal cell cancers from other tumors, especially metastases, hematolymphoid tumors, and urothelial carcinoma. Within primary renal cell neoplasms, relevant distinctions include recognizing clear cell papillary renal cell carcinoma, which despite its resemblance to clear cell cancer is nonaggressive, as well as discriminating oncocytoma from chromophobe carcinoma. Helpful immunohistochemical markers include PAX8 for verification of primary renal cell lineage and carbonic anhydrase IX for support of clear cell subtype. Cytokeratin 7 is generally considered the best marker for discriminating oncocytoma from chromophobe renal cell carcinoma, showing only rare positive cells in oncocytoma and greater staining in chromophobe carcinoma. For metastatic tumors, attempting to discriminate clear cell from non-clear cell types may be important for treatment selection.     

Alpha-methyl CoA racemase expression in renal cell carcinomas

Alpha-methyl CoA racemase (AMACR), a new molecular marker for prostate cancer, has been recently reported to be one of the most highly expressed genes in papillary renal cell carcinomas (RCCs). We tested the diagnostic usefulness of AMACR antibody in a series of 110 renal tumors: 53 papillary RCCs (33 type 1, 20 type 2); 25 conventional RCCs; 6 chromophobe RCCs; 9 oncocytomas; 5 mucinous tubular and spindle tumors; 2 urothelial carcinomas; 7 angiomyolipomas; and 2 Bellini carcinomas. Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded tissue sections, with a primary prediluted rabbit monoclonal anti-AMACR antibody. Both type 1 and type 2 papillary RCCs exhibited cytoplasmic immunoreactivity for AMACR, with diffuse strong granular staining in 96.4% (53/55) of tumors, without correlation with type or nuclear grade. The 5 mucinous, tubular, and spindle cell carcinomas strongly expressed AMACR, and only 5 of 25 clear cell RCCs and 1 of 9 oncocytomas were focally reactive. The remaining 6 chromophobe RCCs, 5 urothelial carcinomas, and Bellini duct carcinomas showed no immunoreactivity for AMACR. Because high expression of AMACR is found in papillary RCCs (type 1 and 2) and in mucinous, tubular, and spindle cell carcinomas of the kidney, immunostaining for AMACR should be used in conjunction with other markers when histological typing of a renal tumor is difficult.     

Carbonic anhydrase IX expression in renal neoplasms: correlation with tumor type and grade

Carbonic anhydrase IX (CAIX), a hypoxia-induced protein, is expressed in some renal tumors. We evaluated its immunohistochemical expression in 317 primary and 42 metastatic renal neoplasms (186 clear cell, 52 papillary, 35 chromophobe, 47 unclassified, and 15 Xp11.2 translocation renal cell carcinomas [RCCs]; 26 oncocytomas; 2 metanephric adenomas; 1 urothelial carcinoma; 1 mixed epithelial and stromal tumor; and 1 angiomyolipoma); 7 neoplasms were unknown as to whether they were primary or metastatic. We also correlated expression with tumor type and grade. Variable staining was seen in clear cell, papillary, unclassified, and Xp11.2 translocation carcinomas. One chromophobe carcinoma had focal expression. No staining was seen with other tumors. An association was found between high expression and clear cell vs non-clear cell carcinomas with all cases (P < .01) and primary (P < .01) cases. An association between CAIX expression and grade (P < .01) in primary clear cell carcinomas was found. CAIX expression is more common in clear cell RCC than other renal tumor types and is associated with grade.     

Renal tumor with alpha b crystallin expression

In human, proximal convoluted tubules and thin limbs of Henle show expression of αB crystallin. Renal cell carcinoma also showed expression of αB crystallin in previous reports. We aimed to study the association between αB crystallin expression and renal cell carcinoma and urothelial carcinoma. Furthermore, we also investigated αB crystallin expression depending on the subtype of renal cell carcinoma and examined the relationship between αB crystallin expression and survival in patients with renal cell carcinoma. In our study, αB crystallin expression was different according to the type of tumor. A greater proportion of the clear cell type (52/77, 67.5%) and papillary type (4/4, 100%) showed reactivity compared to the chromophobe type (0/10, 0%). In the present study, a significantly greater number of renal cell carcinomas showed strong expression of αB crystallin (56/91, 61.5%) compared to urothelial carcinoma (P=7.967e-07). Therefore, αB crystallin might be a significant marker of renal cell carcinoma and might help to determine the type of renal tumor in cases of poorly differentiated kidney lesions and metastatic lesions. αB crystallin expression was not related to overall survival in univariate and multivariate models. In our study, alpha B crystallin could not be considered a prognostic marker of renal cell carcinoma.     

Clear cell papillary renal cell carcinoma: a review

The disease concept of clear cell (tubulo) papillary renal cell carcinoma (CCP-RCC) as a distinct subtype of renal cell carcinoma has been recently established. First described in the setting of end stage renal disease, this tumor type is more frequently recognized and encountered in a sporadic setting. In this article, we provide an overview of the recent understanding of this tumor. Macroscopically, tumors are well circumscribed with well-developed tumor capsule. Histologically, the tumor cells are cuboidal to low columnar cell with clear cytoplasm and papillary and tubulo-papillary configuration. Immunohistochemically, tumor cells generally show diffuse expression for cytokeratin 7, CA9 (cup-shaped pattern), HIF-1, GLUT-1 and high molecular weight cytokeratin, but negative for AMACR, RCC Ma and TFE3. CD10 is negative or focally positive in most tumors. Genetically, this tumor has no characteristics of clear cell RCC or papillary RCC. Prognostically, patients with CCP-RCC behave in an indolent fashion in all previously reported cases. In conclusion, although this tumor has been integrated into recent International Society of Urologic Pathology Classification of renal neoplasia, both aspects of disease concept and clinical behavior are yet to be fully elucidated. Further publications of large cohorts of patients will truly help understand the biologic potential and the molecular underpinnings of this tumor type.     

The evolution of collagen expression in sarcomatoid renal cell carcinoma

The development of a sarcomatoid morphotype is recognized as an extreme form of dedifferentiation in renal cell carcinoma and is associated with a poor prognosis. Although sarcomatoid renal cell carcinoma shows pronounced spindle cell morphology, clear cell renal cell carcinoma may show early spindle cell change with cellular elongation, and the prognostic significance of this is debated. To determine the relationship between sarcomatoid renal cell carcinoma and clear cell renal cell carcinoma showing early spindle cell change, we have investigated collagen expression using immunohistochemistry in these 2 tumor types. Both sarcomatoid renal cell carcinoma and early spindle cell change tumors showed pericellular interstitial expression of collagen types I and III, whereas sarcomatoid renal cell carcinoma also showed cytoplasmic expression of these collagen types. Expression of these collagen types in typical clear cell renal cell carcinoma was, in occasional cases, limited to faint and patchy staining in a pericellular interstitial distribution. Tumor cells did not stain for collagen type IV in sarcomatoid renal cell carcinoma, early spindle cell change, or typical clear cell renal cell carcinoma. In sarcomatoid renal cell carcinoma, there was diffuse pericellular expression of collagen type V and patchy pericellular expression of collagen type VI, whereas early spindle cell change tumors showed patchy pericellular staining with antibodies to collagen type V. Collagen type VI expression in early spindle cell change was largely confined to the vascular adventitia and areas of scarring, although very occasional foci of faint interstitial staining were also seen. In typical clear cell renal cell carcinoma, staining of collagen types V and VI was limited to the vascular adventitia and foci of desmoplasia, whereas no staining of tumor cell cytoplasm were seen. This study has shown that collagen expression of sarcomatoid renal cell carcinoma differs from that of early spindle cell change and provides validating evidence that these 2 morphotypes should not be considered together for classification purposes.     

Expression of carbonic anhydrase IX,PAX2 and PAX8 and their association with clinicopathologic characteristics in renal epithelial tumors北大核心CSCD

Objective: To study the expression of carbonic anhydrase IX (CAIX), PAX2 and PAX8 in different types of renal epithelial tumor and their association with clinicopathologic characteristics. Methods: Immunohistochemical study by EnVision method was performed in order to assess the expression of CAIX, PAX2 and PAX8 in 155 cases of renal cell carcinoma and 4 cases of metastatic clear cell renal cell carcinoma (CCRCC). Ninety-six cases of non-neoplastic renal parenchymal tissue adjacent to CCRCC, 8 cases of clear cell hepatocellular carcinoma and 2 cases of clear cell hidradenoma were used as controls. Results: CAIX was commonly expressed in CCRCC (94. 0%, 63/67), of which 77. 8% (49/63) showed strong positivity. CAIX was focally positive in papillary renal cell carcinoma, collecting duct carcinoma and urothelial carcinoma of renal pelvis. It was negative in chromophobe renal cell carcinoma, oncocytoma and adjacent non-neoplastic renal tissue. CAIX was also strongly expressed in the 4 cases of metastatic CCRCC. Focal expression of CAIX was demonstrated in the 8 cases of clear cell hepatocellular carcinoma and 2 cases of clear cell hidradenoma. The expression of CAIX in CCRCC did not correlate with tumor grading, clinical staging and presence of distal metastasis. On the other hand, PAX2 showed positive expression in different types of renal epithelial tumor, clear cell hepatocellular carcinoma and clear cell hidradenoma in various degrees. In contrast, PAX8 was commonly expressed in all types of renal epithelial tumor, with the exception of urothelial carcinoma of renal pelvis. PAX8 was not expressed in clear cell hepatocellular carcinoma and clear cell hidradenoma. Regarding diagnosis of CCRCC, CAIX demonstrated high sensitivity and specificity. PAX2 showed high specificity but low sensitivity. PAX8 was sensitive and specific in the diagnosis of renal epithelial tumor. Conclusions: CAIX is a useful immunohistochemical marker with high specificity and sensitivity in distinguishing CCRCC from other types of renal epithelial tumor and clear cell tumors of non-renal origin. PAX2 is a marker with high sensitivity and low specificity for diagnosis of renal epithelial tumors. PAX8 is typically expressed in renal epithelial tumors. The combined detection of CAIX, PAX2 and PAX8 is useful in the diagnosis and differential diagnosis of renal epithelial tumors.     

Oncocytic renal cell carcinoma having papillotubular growth: rare morphological variant of papillary renal cell carcinoma

Herein is described a unique renal cell tumor with previously unreported morphological and immunohistochemical features. The patient was a 78-year-old Japanese man. A huge left renal tumor was found on ultrasound during evaluation of left abdominal distention. The tumor was macroscopically characterized by a non-infiltrative border, pale yellow to grayish color, foci of hemorrhage and partial edematous change. Histologically the tumor had an extensive small tubular growth pattern often with papillary fronds mainly composed of oncocytic cells with deeply eosinophilic granular cytoplasm. Clear vacuolated cells were scattered among the oncocytic cells. The present case had an unusual immunohistochemical profile for all known types of renal cell tumors, but both the oncocytic cells and the clear vacuolated cells were strongly immunoreactive for α-methylacyl-coenzyme A racemase. It is concluded that the tumor may be a candidate for a rare variant of papillary renal cell carcinoma. Further cases having similar features are awaited for a definitive classification of this tumor as a previously undescribed tumor type.     

Decreased expression of mucin 18 is associated with unfavorable postoperative prognosis in patients with clear cell renal cell carcinoma

Background: MUC18 is correlated with tumor progression and metastasis in types of malignancy. But the role of MUC18 in clear cell renal cell carcinoma remains unclear. In this study, we aimed to investigate the expression of MUC18 and its correlation with clinical outcomes in clear cell renal cell carcinoma. Patients and Methods: Immunohistochemical staining was performed in samples from 288 patients with clear cell renal cell carcinoma. We used Kaplan-Meier method and Cox proportional hazard models to value the association between MUC18 expression and clinical outcome. Nomogram was constructed to predict overall survival at 5 and 8 years after nephrectomy. Results: MUC18 expression was significantly decreased in tumor compared to non-tumor tissue (P<0.001). Lower MUC18 expression in tumor predicted a shorter survival time (P=0.007). By multivariate cox analysis, MUC18 was defined as an independent prognostic factor (P=0.006). The nomogram performed better in predicting 5- and 8-year overall survival than the TNM stage alone in clear cell renal cell carcinoma. Conclusion: MUC18 is an independent prognostic factor for clear cell renal cell carcinoma and could be incorporated with the other parameters to predict 5- and 8-year overall survival for clear cell renal cell carcinoma patients.     

Renal cell carcinoma classification: what matters?

Renal cell carcinoma classification may seem to be increasing dramatically in complexity over the last 10 years. Although integration of morphology, immunohistochemistry, and molecular features continues to refine different tumor types and dissect subgroups from long-established categories of renal cancer, only a select subset of these distinctions are of highest importance for clinical management. In the metastatic setting, distinction of clear cell from non-clear cell renal cancer is important, as there are different treatment pathways for these two groups. Another select handful of tumor types are highly aggressive (sarcomatoid, medullary, collecting duct, and fumarate hydratase-deficient carcinomas), which may necessitate different therapy from other non-clear cell carcinomas. A few tumor types are highly favorable, especially chromophobe carcinoma and clear cell papillary carcinoma (which is likely to be reclassified as a “tumor” rather than carcinoma soon). Still other tumor histologies often imply a hereditary syndrome solely based on their diagnosis, particularly succinate dehydrogenase-deficient and fumarate hydratase-deficient cancers. Although several eosinophilic tumor types with subtly different features have been recently recognized, it is not clear at present that discriminating them from chromophobe carcinoma is critical, as behavior appears to be largely favorable. Therefore, although some aspects of surgical pathology rely heavily on molecular diagnostics, histologic pattern and select immunohistochemical markers can resolve the differential diagnosis in most renal neoplasms, without need for complex molecular analysis.     

Expression of EphA2 protein is positively associated with age,tumor size and Fuhrman nuclear grade in clear cell renal cell carcinomas

The receptor tyrosine kinase of EphA2 has been shown frequently overexpressed in various types of human carcinomas, which implicated that it plays important roles in carcinogenesis. Although EphA2 protein expression has been investigated in many types of human carcinomas, the relationship between the expression of EphA2 protein in clear cell renal cell carcinoma was not well documented. In the present study, using specific anit-EphA2 polyclonal antibody and immunohistochemistry, we evaluated EphA2 protein expression levels in clear cell RCC specimens surgically resected from 90 patients. Our results shows that EphA2 protein was positively expressed in all normal renal tubes of 90 samples (100%, 3+), which was expressed at low levels in renal cortex but high levels in the collecting ducts of the renal medulla and papilla. EphA2 was negatively or weakly expressed in 30 out of 90 samples (33.3%, 0/1+), moderately expressed in 24 samples (26.7%, 2+) and strongly expressed in 36 samples (40%, 3+). Expression of EphA2 was positively associated with age (P=0.029), tumor diameters (P<0.001) and Fuhrman nuclear grade (P<0.001). Our results indicate that EphA2 variably expressed in clear cell renal cell carcinomas. High expression of EphA2 was more often found in big size and high nuclear grade tumors, which indicated EphA2 protein may be used as a new marker for the prognosis of clear cell renal cell carcinoma.     

Distinct Cytoplasmic Expression of KL-6 Mucin in Chromophobe Renal Cell Carcinoma: A Comparative Immunohistochemical Study with Other Renal Epithelial Cell Tumors

The presence of cytoplasmic sialyl glycoproteins is a conspicuous feature in chromophobe renal cell carcinoma (RCC). We compared the immunohistochemical expression of sialyl glycoproteins in chromophobe RCC with that in other types of renal tumors. Formalin-fixed, paraffin-embedded tissues of surgically resected renal tumors (chromophobe RCC, 14 cases [10 cases of classic type and 4 cases of eosinophilic variant]; oncocytoma, 7 cases; and clear cell RCC, 9 cases) and kidneys from immature infants (4 cases) were immunostained with antibodies against sialyl glycoproteins (anti-KL-6 and anti-sialyl MUC1 antibodies). Cytoplasmic expression of KL-6 and sialyl MUC1 was distinctive in the chromophobe RCC and renal oncocytoma cells, and in the intercalated cells in collecting duct epithelia. Apical-surface staining of these sialyl glycoproteins was predominantly observed in clear RCC, in the epithelia of the distal tubule and collecting duct, and in the neonatal renal proximal tubule, but not in those of the adult renal proximal tubule. The above-mentioned observations provide additional evidence for similar phenotypic profiles of chromophobe RCC and renal oncocytoma, and the intercalated cells in collecting ducts and the oncofetal expression of sialyl glycoproteins in clear cell RCC. KL-6 is a potential tumor marker for renal tumors.     

Sarcomatoid conversion of clear cell renal cell carcinoma in relation to epithelial-to-mesenchymal transition

Approximately 8% of clear cell renal cell carcinoma cases contain regions of radically different morphology, demonstrating a mesenchymal appearance histologically resembling sarcomas. These biphasic neoplasms are called sarcomatoid clear cell renal cell carcinoma. Patients diagnosed with sarcomatoid clear cell renal cell carcinoma face a considerably worse prognosis due to an increased propensity for metastasis. In the present study we investigate whether the sarcomatoid conversion of clear cell renal cell carcinoma could be interpreted as linked to the process of epithelial-mesenchymal transition. Using 6 biphasic clear cell renal cell carcinoma cases we show that sarcomatoid clear cell renal cell carcinoma shares characteristic markers associated with loss of von Hippel-Lindau tumor suppressor with conventional clear cell renal cell carcinoma and also exhibits a markedly higher proliferative index. Furthermore the sarcomatoid elements demonstrate an enhanced expression of epithelial-mesenchymal transition related mesenchymal markers as compared with the clear cell renal cell carcinoma counterparts. We further selected a representative case, clinically demonstrating direct overgrowth of the sarcomatoid component into the liver and colon, for extended immunohistochemical characterization, resulting in a further set of positive and negative epithelial-mesenchymal transition markers as well as pronounced transforming growth factor β positivity, indicating that sarcomatoid clear cell renal cell carcinoma may be associated to epithelial-mesenchymal transition. Transforming growth factor β1 exposure of in vitro cultured primary clear cell renal cell carcinoma cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid clear cell renal cell carcinoma. Corresponding changes in RNA levels for key epithelial-mesenchymal transition markers were also seen. We therefore suggest that sarcomatoid clear cell renal cell carcinoma morphologically and immunohistochemically may represent a completed epithelial-mesenchymal transition and that transforming growth factor β1 could be an important driving force during the sarcomatoid transdifferentiation of clear cell renal cell carcinoma.     

Collecting duct carcinoma of the kidney: an immunohistochemical evaluation of the use of antibodies for differential diagnosis

Collecting duct carcinoma is a highly aggressive renal epithelial malignancy, although it accounts for less than 1% of the incidence of renal epithelial neoplasms. Differential diagnoses between collecting duct carcinoma, pelvic urothelial carcinoma with marked invasion to the renal parenchyma (invasive urothelial carcinoma), and papillary renal cell carcinoma is often challenging. In our current study, we examined the utility of using commercially available antibodies, in conjunction with lectin histochemistry, for such differential diagnoses. We examined 17 cases of collecting duct carcinoma, 10 cases of invasive urothelial carcinoma and 15 cases of papillary renal cell carcinoma (type 1, 6 cases; type 2, 9 cases) in these evaluations. Our results indicated that Ulex europaeus agglutinin 1, E-cadherin, and c-KIT were frequently positive in collecting duct carcinoma and invasive urothelial carcinoma, in comparison with papillary renal cell carcinoma, which had negative results for CD10 and α-methylacyl CoA racemase. We found, however, that collecting duct carcinoma showed positivity for high-molecular-weight cytokeratin and low-molecular-weight cytokeratin at a low frequency compared with invasive urothelial carcinoma, and that these distinctions need further careful evaluation. In addition, high-molecular-weight cytokeratin positivity was not a reliable marker for collecting duct carcinoma. We conclude that Ulex europaeus agglutinin 1 reactivity and positivity for E-cadherin and c-KIT are effective in distinguishing collecting duct carcinoma from papillary renal cell carcinoma, and that negative results for α-methylacyl CoA racemase and CD10 are potentially useful hallmarks of this distinction also. In contrast, a differential diagnosis for collecting duct carcinoma and invasive urothelial carcinoma will require careful examination of multiple routinely stained specimens, particularly in cases of in situ neoplastic lesions in the pelvic mucosa.     

Histopathologic approaches to the infiltrative renal mass

Most renal masses are round or oval, well-circumscribed, and demonstrate a well-defined interface from the normal renal parenchyma. However, a small subset of renal tumors exhibits an infiltrative pattern, with a poorly-defined interface with the renal parenchyma and entrapment of normal structures. These infiltrative renal malignancies generally show more aggressive clinical course and are associated with a poorer prognosis compared to the more typical renal neoplasms. Main differential diagnoses for a renal mass with infiltrative histology would include urothelial carcinoma, fumarate hydratase (FH)-deficient renal cell carcinoma (RCC), medullary RCC, metastatic cancer from another organ, and rare patterns of clear cell or papillary RCC. Non-epithelial processes may include lymphoma and various infectious, inflammatory, immune-mediated, and vascular mimics. Collecting duct carcinoma is extremely rare in modern practice and is essentially a diagnosis of exclusion once the previous considerations are thoroughly argued against. The aim of this review is to familiarize pathologists with the spectrum of entities that can present as infiltrative masses in the kidney, and to highlight the most relevant immunohistochemical or other tools to facilitate accurate diagnoses and appropriate patient management.     

Clear cell papillary renal cell carcinoma: Incidence,morphological features,immunohistochemical profile,and biologic behavior: A single institution study

This study was undertaken to determine the incidence and the clinicopathologic characteristics of those tumors that qualify as clear cell papillary renal cell carcinoma (CCPRCC) by the current definitions. From January 1, 2003 to April 30, 2013, a total of twenty-eight CCPRCC were identified (28/648, 4.3%). CCPRCC showed variable architectural patterns including cystic, papillary, tubular, and acinar. Irrespective of the architecture, the tumors were composed of cuboidal or columnar cells with clear cytoplasm, small vesicular, round or oval nuclei, and inconspicuous nucleoli. Variably thick bundles of smooth muscle actin-positive soft tissue encircled the whole tumors, forming a continuous pseudocapsule. CCPRCC strongly expressed PAX8, CA-IX, CK7, cytokeratin 34betaE12, and vimentin, and were negative for RCC, P504s/AMACR, and TFE3. On ultrastructural examination, CCPRCC showed short microvilli, cytoplasmic interdigitations, nuclear pseudoinclusions, and stromal myofibroblasts. To the best of our knowledge, this is first comprehensive ultrastructural study of CCPRCC in the literature. The major differential diagnostic considerations are clear cell renal cell carcinoma, multilocular cystic renal cell carcinoma, papillary renal cell carcinoma with clear cell changes, and Xp11.2 translocation renal cell carcinoma. CCPRCC seems to have a favorable prognosis. In the current series, none of the patients had local recurrence or metastatic disease.     

Parvalbumin is constantly expressed in chromophobe renal carcinoma.

Chromophobe renal carcinoma is composed of neoplastic cell showing several features similar to those found in the intercalated cells of the collecting ducts. Because the distal nephron expresses calcium-binding proteins playing a role in calcium homeostasis, we reasoned that these proteins could be expressed by chromophobe carcinoma and therefore represent a diagnostic marker. We studied the immunohistochemical expression of different calcium-binding proteins (parvalbumin, calbindin-D28K, and calretinin) in 140 renal tumors, including 75 conventional (clear cell) carcinomas, 32 chromophobe carcinomas, 17 papillary renal cell carcinomas, and 16 oncocytomas. Parvalbumin was strongly positive in all primary chromophobe carcinomas and in one pancreatic metastasis; it was positive in 11 of 16 oncocytomas and absent in conventional (clear cell) and papillary renal cell carcinomas, either primary or metastatic. Calbindin-D28K and calretinin were negative in all tumors, with the exception of two chromophobe carcinomas, four oncocytomas, and two papillary renal cell carcinomas showing inconspicuous calretinin expression. Our data demonstrate that parvalbumin may be a suitable marker for distinguishing primary and metastatic chromophobe carcinoma from conventional (clear cell) and papillary renal cell carcinoma. Moreover, they suggest a relationship between chromophobe renal carcinoma and renal oncocytoma and indicate that chromophobe carcinoma exhibits differentiation toward the collecting-duct phenotype.     

Onconeuronal antigen Cdr2 correlates with HIF prolyl-4-hydroxylase PHD1 and worse prognosis in renal cell carcinoma

Neoplastic expression of the onconeuronal cerebellar degeneration-related antigen Cdr2 in ovary and breast tumors is associated with paraneoplastic cerebellar degeneration (PCD). Cdr2 protein expression is normally restricted to neurons, but aberrant Cdr2 expression has mainly been described for breast and ovarian tumors. Previously, we found strong Cdr2 protein expression in the papillary subtype of renal cell carcinoma (pRCC) and showed that Cdr2 interacts with the hypoxia-inducible factor (HIF) prolyl-4-hydroxylase PHD1. High Cdr2 protein levels are associated with decreased HIF-dependent gene expression in cells as well as in clinical pRCC samples, providing a possible explanation why pRCCs are the most hypovascular renal tumors. Here, we demonstrate that strong Cdr2 protein expression in clinical samples from pRCC patients correlates with elevated PHD1 protein levels, suggesting that increased PHD1 activity attenuates HIF-dependent gene expression. Interestingly, survival analysis revealed a significant correlation between high levels of Cdr2 expression and worse patient outcome in clear cell (cc) RCC patients. These findings provide evidence that Cdr2 might represent an important tumor antigen in kidney cancer and possibly in other cancer types as well. In contrast to ovary and breast tumor patients who develop PCD, no Cdr2 auto-antibodies were detected in the serum of pRCC patients, which is in line with the fact that pRCC patients have not been reported to display paraneoplastic neurodegenerative syndromes. This suggests that, despite a shared target antigen, tumor immunity and autoimmunity only partially overlap, and also highlights to which extent immuno-surveillance against cancer can be clinically silent.