Recurrent KRAS mutations are early events in the development of papillary renal neoplasm with reverse polarity

Al‐Obaidy, Khaleel I; Saleeb, Rola; Trpkov, Kiril; Williamson, Sean R.; Sangoi, Ankur R.; Nassiri, Mehdi; Hes, Ondřej; Montironi, Rodolfo; Cimadamore, Alessia; Acosta, Andrés; Alruwaii, Zainab; Alkashash, Ahmad; Hassan, Oudai; Gupta, Nilesh; Osunkoya, Adeboye O.; Sen, Joyashree D.; Baldrige, Lee Ann; Sakr, Wael; Idrees, Muhammad T.; Eble, John N.; Grignon, David J.; Cheng, Liang

doi:10.1038/s41379-022-01018-6

Cited by 17 publications

(22 citation statements)

References 21 publications

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“…In agreement with previous studies, the 16 PRNRPs in our cohort presented mostly with an incidentally identified mass during the imaging study and showed a slight male predilection, and had small tumor size, low TNM stage, low WHO/ISUP nuclear grade, and a favorable prognosis at follow-up, without any recurrence, metastasis, or tumor-related death after surgical excision (13- 19,22,23). Although most are solitary tumors, previous studies have demonstrated that a subset of PRNRPs may have multiple tumors as defined by presence of ≥2 unilateral or bilateral tumors, particularly for those with small size which are usually clinically undetectable (13,22,23). Gross examination showing an encapsulated and cystic PRNRP with a soft and friable, intracystic polypoid mass.…”

Section: Discussionsupporting

confidence: 91%

“…only Raspollini et al (35) reported a case of clear cell RCC harboring KRAS mutation. Several previous studies have documented that KRAS mutation was absent in clear cell RCC, PRCC (both types 1 and 2), chromophobe RCC, and clear cell papillary RCC (14,15,23). According to TCGA database, mutation of KRAS occurred in 0.7% (2/279) of PRCCs and 0.2% (1/451) of clear cell RCCs (14)(15)(16).…”

Section: Discussionmentioning

confidence: 99%

“…We speculate that infarct formation in this case is related to intralesional hemorrhage and cystic degeneration, which leads to the increased pressure in the cystic cavity, further resulting in ischemic infarction of the tumor. However, it should be mentioned that the cysts are commonly filled with proteinaceous fluid or blood clots and may contain floating degenerated cell debris with hemosiderin deposition, which may be confused with necrosis; however, true tumor type coagulative necrosis is never present in PRNRPs (23).…”

Section: Discussionmentioning

confidence: 99%

“…KRAS mutation was identified in 57%-93% of PRNRPs in previous studies (14 -16, 18, 19, 22, 23), with an overall frequency of 85% and the most common KRAS mutation being p.G12V (54%), as documented by Wei et al (19). One KRAS-mutated PRNRP was reported to harbor a G12A/V/D complex mutation (23). only Raspollini et al (35) reported a case of clear cell RCC harboring KRAS mutation.…”

Section: Discussionmentioning

confidence: 99%

“…A recently published paper by Wei et al(19) comprehensively reviewed the 100 reported cases of PRNRP and emphasized that this tumor was frequently a cystic tumor and at least a partially cystic change can be noted in 62% cases. Additionally, Al-Obaidy et al(23) documented cystic expansion with intracystic papillary proliferation in 7 of their 16 clinically detected (≥5 mm) neoplasms. In line with these results, in our cohort, 14 cases displayed at least a partially cystic appearance and 5 larger tumors were predominantly cystic, frequently with intracystic polypoid or papillary masses protruding into the cystic spaces.…”

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confidence: 99%

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Papillary renal neoplasm with reverse polarity: A clinicopathological and molecular genetic characterization of 16 cases with expanding the morphologic spectrum and further support for a novel entity

et al. 2022

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Papillary renal neoplasm with reverse polarity (PRNRP) is a recently described, rare renal tumor that differs clinically, morphologically, and molecularly from papillary renal cell carcinoma (RCC). To further characterize the pathological spectrum of this rare tumor, in this study, we retrospectively identified 16 cases of PRNRP from three institutions to comprehensively investigate the clinicopathological and molecular genetic features, using immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH), and targeted next-generation sequencing (NGS). The patients included nine men and seven women, with age ranging from 47 to 80 years (median = 67.5 years, mean = 65 years). The tumor size ranged from 0.4 to 9.5 cm in the greatest dimension (median = 1.8 cm, mean = 2.6 cm). Most tumors (12/16) were incidentally identified by imaging studies. By AJCC stage, 15 were categorized as pT1 and 1 was pT2. Follow-up showed no recurrences, metastases, or disease-related deaths in all the 16 patients. Grossly, 14 cases demonstrated at least a partially cystic appearance. Microscopically, all PRNRPs except 1 (case 13) were composed predominantly of thin, branching papillary architecture covered by a single layer of cuboidal cells with finely granular cytoplasm, and low-grade nuclei typically located toward the apical surface away from the basement. Case 13 consisted mostly of solid, densely packed tubules with only a minor papillary component (5%). Other commonly seen histological features included hyalinized or edematous papillae (n = 11), lymphocyte aggregation in fibrovascular cores (n = 10), mast cell infiltration (n = 8), and intralesional hemorrhage (n = 7). Uncommonly seen histological features included lymphoid cuff (n = 4), hemosiderin deposition (n = 5), foci of clear cell change (n = 4), intracytoplasmic vacuoles (n = 4), eosinophilic hobnail cells (n = 2), and infarct-type necrosis (n = 1). Two PRNRPs were concurrent with ipsilateral clear cell papillary RCC and clear cell RCC, respectively. By IHC, the tumors were consistently positive for GATA3, CK7, and PAX8. Fourteen out of 16 tumors showed a basolateral-membranous E-cadherin expression pattern, and 12/16 cases were positive for 34βE12.The expression of AMACR, CD10, and vimentin was either absent or only weak and focal. By targeted NGS, 13/14 evaluated PRNRPs harbored KRAS missense mutations involving c.35G>T resulting in p.G12V (7/13), c.35G>A resulting in p.G12D (4/13), and c.34G>T resulting in p.G12C (2/13). By FISH, 1/15 had gains of chromosomes 7 and 17, and 2/8 male cases had deletion of chromosomes Y. In conclusion, our study confirms that PRNRP is an indolent renal cell neoplasm with unique morphology, consistent immunohistochemical profile, and recurrent KRAS mutation. Our study expands the morphologic spectrum of PRNRP and provides further evidence supporting it as a novel entity.

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Section: Discussionsupporting

confidence: 91%