Papillary Renal Cell Carcinoma With Microcystic Architecture Is Strongly Associated With Extrarenal Invasion and Metastatic Disease

Abstract

Papillary renal cell carcinoma (PRCC) is wellrecognized as a morphologically and molecularly heterogenous group of kidney tumors with variable clinical behavior. Our goal was to analyze a unique histologic pattern of PRCC we have observed in routine practice to evaluate for potential clinical significance or distinct molecular signature. We identified 42 cases of PRCC showing a morphologically distinct architecture characterized by numerous epithelial-lined cysts containing the papillary tumor (herein called "microcysts"), which are typically separated by fibrous stroma. Of the initial 42 case test set with microcystic features, 23 (55%) were stage pT3a or higher. Most tumors had strong and diffuse cytoplasmic immunoreactivity for CK7 (93%, 37/40) and AMACR (100%, 40/40). Fumarate hydratase staining was retained in all cases tested (39/39). We performed next-generation sequencing on 15 of these cases with available tissue and identified chromosomal alterations commonly reported in historically "type 1" PRCC, notably multiple chromosomal gains, particularly of chromosomes 7 and 17, and MET alterations. However, alterations in pathways associated with more aggressive behavior (including SETD2, CDKN2A, and members of the NRF pathway) were also identified in 6 of 15 cases tested (40%). Given this molecular and immunophenotypic data, we subsequently reviewed an additional group of 60 consecutive pT2b-pT3 PRCCs to allow for comparisons between cases with and without microcysts, to assess for potential associations with other recently described histologic patterns (ie, "unfavorable architecture": micropapillary, solid, and hobnail), and to assess interobserver reproducibility for diagnosing architectural patterns and grade. Of the total combined 102 PRCCs, 67 (66%) had microcystic architecture within the intrarenal component but were commonly admixed with other patterns (39% had micropapillary, 31% solid, and 31% hobnail). Twentyseven cases (26%) had metastatic disease, and 24 of these 27 (89%) had microcystic architecture in the intrarenal tumor. Within the pT3 subset, 21 of 22 cases with metastases (95%) had extrarenal invasion as either individual microcysts in renal sinus fat or aggregates of microcysts bulging beyond the confines of the capsule. Backward elimination and stepwise regression methods to detect features significantly associated with adverse outcome identified solid architecture (hazard ratio [HR]: 6.3; confidence interval [CI]: 2.1-18.8; P = 0.001), hobnail architecture (HR: 5.3; CI: 1.7-16.7; P = 0.004), and microcystic architecture at the tumor-stromal interface (HR: 4.2; CI: 1.1-16.7; P = 0.036) as strongest. Of architectural patterns and grade, the microcystic pattern had a substantial interobserver agreement (κ score = 0.795) that was highest among the 6 observers. In summary, PRCCs with microcystic architecture represents a subset of historically "type 1" PRCC with a predilection for morphologically distinctive extrarenal involvement and metastatic disease. Microcysts co-vary with other "unfavora...

Papillary renal cell carcinoma: a single institutional study of 199 cases addressing classification, clinicopathologic and molecular features, and treatment outcome

“…The presence of tumor capsular invasion had a higher risk of progression (p = 0.044) and lack of tumor circumscription showed a significant association with PFS and CSS (p = 0.03 and p = 0.0002 respectively). In line with two recent studies that showed solid architecture or sheet-like growth as a significant prognostic indicator of PRCC ( 61 , 62 ), we found the presence of sheet-like growth pattern was also associated with both outcome measures (p = 0.015 for PFS and p = 0.005 for CSS). Aside from the solid/sheet-like growth pattern, hobnail, micropapillary, and microcystic features have also been identified to be of prognostic significance and often co-occur ( 61 , 62 ).…”

“…In line with two recent studies that showed solid architecture or sheet-like growth as a significant prognostic indicator of PRCC ( 61 , 62 ), we found the presence of sheet-like growth pattern was also associated with both outcome measures (p = 0.015 for PFS and p = 0.005 for CSS). Aside from the solid/sheet-like growth pattern, hobnail, micropapillary, and microcystic features have also been identified to be of prognostic significance and often co-occur ( 61 , 62 ). These histologic features represent important histologic patterns to be further validated for their independent prognostic values.…”

Renal Neoplasia Occurring in Patients With PTEN Hamartoma Tumor Syndrome

“…In our study, only 1 of 4 papillary RCCs (patient #6) showed classic morphology of historical type 1 papillary RCC, now regarded as the prototypical papillary RCC. Interestingly, this tumor also showed microcytic architecture, which has been recognized as a potentially aggressive histologic pattern of growth in papillary RCC 11 . None of the remaining 3 papillary RCCs in our cohort were compatible with other specific renal tumor entities characterized by papillary architecture within the WHO classification; therefore, they were felt best classified as within the spectrum of papillary RCC.…”

Cuproptosis-Related LncRNA-Based Prediction of the Prognosis and Immunotherapy Response in Papillary Renal Cell Carcinoma

“…Up to 80% of kidney tumors are renal cell carcinomas (RCCs); The most common type of RCC is clear cell renal cell carcinoma (ccRCC), occupying approximately 75% of all cases, followed by papillary renal cell carcinoma (pRCC) [ 1 , 2 ]. It has been reported that for 70% of patients with localized pRCC, the overall survival was 5 years, while with advanced pRCC, no treatment options were available [ 3 , 4 , 5 ]. About 75% of RCCs belong to ccRCCs, which have been studied most in terms of biomarkers and target therapies, resulting in few solutions for treating patients with pRCC [ 6 ].…”