Birt–Hogg–Dubé Syndrome
Dongyou Liu in Handbook of Tumor Syndromes, 2020
In sporadic renal tumors, aggressive clear cell renal cell carcinoma (ccRCC) is the most common subtype (75%), followed by papillary RCC (pRCC, 10%), low-aggressive chromophobe RCC (chRCC, 5%), benign oncycotoma (5%), and other rare subtypes (<5%) [56]. This is in contrast to the BHD-associated renal tumors, where the majority are oncocytoma, chRCC, or hybrid chromophobe-oncocytoma type. Pavlovich et al. were the first to present a systematic pathologic analysis of BHD-associated renal tumors. They reviewed 130 renal tumors resected from 30 BHD patients, including 65 hybrid chromophobe-oncocytoma type (50%), 44 chRCC (34%), 12 ccRCC (9%), 7 oncocytoma (5%), and 2 pRCC (2%) [56]. In a cohort of French BHD patients, Benusiglio et al. reported a total of 124 patients in which 33 renal tumor (27%), 23 oncocytoma or hybrid chromophobe-oncocytoma type (70%), 3 ccRCC (9%), and 1 pRCC (3%) were identified histopathologically, while the remaining patients had no histopathological data [57]. This pattern is remarkably different from the histologic spectrum in sporadic renal tumors confirmed by several studies [35,42,58]. It is recommended by The International Society of Urological Pathology Tumor Panel that a diagnosis of BHD should be considered when a hybrid chromophobe-oncocytoma tumor is found [59]. Oncocytosis is observed histologically in about half of the BHD-associated tumors [60]. Renal oncocytosis is characterized by a spectrum of oncocytic changes that diffusely involve the renal parenchyma, and it is possibly a precancerous lesion [54,60,61].
Personalized Medicine in Hereditary Cancer Syndromes
II-Jin Kim in Cancer Genetics and Genomics for Personalized Medicine, 2017
Several TKIs have been widely studied as therapeutic agents for the treatment of VHL-associated RCC [47]. In a pilot study by Jonasch et al., 33% of RCCs showed a partial response, 67% were stable, and 10% progressed [47]. Multiple trials have been conducted to investigate the treatment of advanced clear cell renal cell carcinoma, most of which (80%) harbor mutations VHL gene. The TKIs studied in these trials include sorafenib, sunitinib, pazopanib, and axitinib, all of which have now been approved for the treatment of advanced clear cell RCC [48]. The role of these agents specifically in patients with VHL disease is less clear. It has been shown that patients with loss of functions (frameshift, nonsense, splice, and in-frame deletions/insertions) which are more characteristic of VHL disease have a better response rate to anti-VEGF therapy compared to wild-type VHL in patients with advanced RCC [49]. Sunitinib (Sutent) was being studied in a phase 2 clinical trial (NCI trial # NCT00330564) and preliminary results have showed partial response in 6 of 18 VHL renal lesions. The study was terminated due to slow accrual. Pazopanib is currently under clinical investigation in patients with VHL (NCI trial #NCT01436227 and NCT01436227).
Renal Cancer
Manit Arya, Taimur T. Shah, Jas S. Kalsi, Herman S. Fernando, Iqbal S. Shergill, Asif Muneer, Hashim U. Ahmed in MCQs for the FRCS(Urol) and Postgraduate Urology Examinations, 2020
Clear cell renal cell carcinoma accounts for 80%–90% of renal cancers. Loss of function of the VHL gene had been demonstrated in up to 95% of cases. These tumours are usually solitary but appear multifocally in 4% of cases and bilaterally in 3%. Microscopically CCRCC appear as clear cytoplasm cells due to their high content of glycogen and lipids. The growth pattern may be solid, tubular or cystic. CD10 expression has been observed in 94% of cases and CA9 in 90% of clear cell tumours.
Tumor microenvironment remodeling by an engineered oncolytic adenovirus results in improved outcome from PD-L1 inhibition
Published in OncoImmunology, 2020
Victor Cervera-Carrascon, Dafne C.A. Quixabeira, Joao Manuel Santos, Riikka Havunen, Sadia Zafar, Otto Hemminki, Camilla Heiniö, Eleonora Munaro, Mikko Siurala, Suvi Sorsa, Tuomas Mirtti, Petrus Järvinen, Markus Mildh, Harry Nisen, Antti Rannikko, Marjukka Anttila, Anna Kanerva, Akseli Hemminki
To understand how oncolytic virotherapy can enable responses to checkpoint inhibitors in solid tumors, three surgically removed tissues were studied. The tumor types (urothelial carcinoma: sample 1. Clear cell renal cell carcinoma: samples 2 and 3) are currently approved26 for anti-PD-L1 treatment or there are Phase III clinical studies showing evidence of benefit for the therapy27. These tumors were pathological grade 3 (sample 2) or 4 (samples 1 and 3) as evaluated from the hematoxylin and eosin staining (Figure 1a). Because one of the primary effects of the virally delivered cargo affects CD8 + T cells, their presence was also assessed (Figure 1b), showing two samples with an immune-excluded (“cold”) phenotype (Samples 1 and 2) and one with an immune-inflamed (“hot”) phenotype (sample 3). In addition, of relevance for anti-PD-L1 targeting, an assay to determine PD-L1 positivity was performed. This showed PD-L1 expression below 5% in immune cells in all samples, making them negative according to the test guidelines (Figure 1c).
Kidney carcinoid tumor: Histological, immunohistochemical and ultrastructural features
Published in Ultrastructural Pathology, 2018
Xin Gu, Minyu Cheng, Guillermo A Herrera
In the kidney, the majority of malignant epithelial tumors are conventional type clear cell renal cell carcinoma. Eosinophilic cytoplasmic change can be seen in both malignant and benign epithelial neoplasms. Differentiation of carcinoid tumor with uncommon growth pattern and cytologic appearance from clear cell renal cell carcinoma and other neoplasms is important for prognostic and therapeutic reasons.6,7 Awareness that renal carcinoid tumor may show uncommon histologic features that overlap with other renal neoplasms expands the differential diagnoses of renal neoplasms, especially in the kidney, many neoplasms may be presented with variable growth patterns and with uncommon cytologic alterations.8 A detailed study of the tumor morphology helps in the differential diagnosis and application of immunohistochemical studies is often necessary for confirm diagnosis. Nevertheless, in some case immunohistochemical reactions may be ambiguous and non-conclusive. For these cases, ultrastructural analysis of tumor cells will be necessary and ultrastructural analysis will provide more definitive morphological evidence in terms of cellular origin and differentiation.9,10
Identification of inhibitors targeting HIF-2α/c-Myc by molecular docking and MM-GBSA technology
Published in Journal of Receptors and Signal Transduction, 2021
Lijun Feng, Chuance Sun, Xiaohua Sun, Yang Zhao, Rilei Yu, Congmin Kang
Clear cell renal cell carcinoma (ccRCC) is one of the most dangerous adult malignances in the world, and the cause of ccRCC has become the research focus, recently. Most ccRCCs are associated with inactivation of the von Hippel-Lindau tumor suppressor gene (VHL), and it is also related to the expression of HIF-2α [1]. Hypoxia-inducible factor (HIF) is expressed in organisms and is a basic helix-loop-helix (bHLH) Per-ARNT-Sim (PAS) domain transcription factor. HIF includes HIFα (related protein HIF-1α, HIF-2α, and HIF-3α) and HIFβ (aryl hydrocarbon receptor nuclear translocator) subunits. HIFα and HIFβ formed heterodimers. Heterodimer complexes are involved in transcription and regulate the expression of genes related to hypoxia mechanisms [2]. In the case of sufficient oxygen in the cell, HIFα can be degrades by protease after a series of reactions [3]. However, under the conditions of hypoxia and VHL protein inactivation [4], HIF-α subunits quickly accumulated and entered the nucleus forming a dimer with HIF-1β. This dimer regulates the expression of multiple gene and is a key transcriptional regulator of neoangiogenesis [5–7]. The transcriptional activity of HIF-2α enhances the tumor’s adaptability, growth ability, and metastatic potential [8]. Interestingly, HIF-1α and HIF-2α behave in opposite ways in VHL-deficient RCCs: Overexpression of HIF-2α promotes an increase in the mass of RCC tumors, while increased expression of HIF-1α suppresses the tumor’s growth [9].
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