Learning Objectives
After completing this course, the reader will be able to:
Describe histologic features associated with sarcomatoid renal cell carcinoma.
Outline current surgical approaches to ...treating sarcomatoid renal cell carcinoma.
This article is available for continuing medical education credit at CME.TheOncologist.com
Recent advancements in the molecular characterization of renal cell carcinoma altered the classification system and now kidney cancer is divided into several distinct histologic subtypes. Although once a separate histologic category, sarcomatoid renal cell carcinoma is no longer considered a separate tumor type because it can occur with all histologic subtypes. Limited research on tumors with sarcomatoid change has led to minimal progress in the understanding and treatment of these tumors. Because the sarcomatoid variant of renal cell carcinoma can account for approximately one in six cases of advanced kidney cancer, we hope to familiarize clinicians with these tumors by describing the historic background, histologic features, molecular characterization, diagnosis, prognosis, treatment strategies, and active clinical trials of this aggressive type of tumor.
摘要
肾细胞癌分子定性的最新进展改变了分类系统，目前肾癌可分为几个不同的组织学亚型。肉瘤样肾细胞癌一度是独立的组织学类别，但因可见于所有组织学亚型，现已不再列为独立的肿瘤类型。肉瘤样变肿瘤的研究有限，对这些肿瘤的了解和治疗进展缓慢。肾细胞癌的肉瘤样变异型约占晚期肾癌的1/6，我们因此希望通过描述此类侵袭性肿瘤的历史背景、组织学特征、分子定性、诊断、预后、治疗策略和进行中的临床试验，使医生能熟悉此类肿瘤。
The historic background, histologic features, molecular characterization, diagnosis, prognosis, treatment strategies, and active clinical trials of the sarcomatoid variant of renal cell carcinoma are described.
Aerobic glycolysis in cancer cells, also known as the 'Warburg effect', is driven by hyperactivity of lactate dehydrogenase A (LDHA). LDHA is thought to be a substrate-regulated enzyme, but it is ...unclear whether a dedicated intracellular protein also regulates its activity. Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. A flexible loop within the amino terminus of FLCN controls movement of the LDHA active-site loop, tightly regulating its enzyme activity and, consequently, metabolic homeostasis in normal cells. Cancer cells that experience the Warburg effect show FLCN dissociation from LDHA. Treatment of these cells with a decapeptide derived from the FLCN loop region causes cell death. Our data suggest that the glycolytic shift of cancer cells is the result of FLCN inactivation or dissociation from LDHA. Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.
Traditional cancer treatments have been associated with substantial morbidity for patients. Focused ultrasound offers a novel modality for the treatment of various forms of cancer which may offer ...effective oncological control and low morbidity. We performed a review of PubMed articles assessing the current applications of focused ultrasound in the treatment of genitourinary cancers, including prostate, kidney, bladder, penile, and testicular cancer. Current research indicates that high-intensity focused ultrasound (HIFU) focal therapy offers effective short-term oncologic control of localized prostate and kidney cancer with lower associated morbidity than radical surgery. In addition, studies in mice have demonstrated that focused ultrasound treatment increases the accuracy of chemotherapeutic drug delivery, the efficacy of drug uptake, and cytotoxic effects within targeted cancer cells. Ultrasound-based therapy shows promise for the treatment of genitourinary cancers. Further research should continue to investigate focused ultrasound as an alternative cancer treatment option or as a complement to increase the efficacy of conventional treatments such as chemotherapy and radiotherapy.
Hereditary cases account for about 5% of all cases of renal cell carcinoma (RCC). With advances in next-generation sequencing, several new hereditary syndromes have been described in the last few ...years.
To review and summarise the recent preclinical and clinical literature in hereditary renal cancer.
A systematic review of the literature was performed in November 2018 using PubMed and OMIM databases, with an emphasis on kidney cancer, genetics and genomics, clinical criteria, and management.
Several autosomal dominant hereditary RCC syndromes have been described, including those related to germline pathogenic variants in VHL, MET, FH, TSC1/TSC2, FLCN, SDHA/B/C/D, BAP1, CDC73, and MITF. Clinical spectrum of SDH, BAP1, and MITF is still being defined, although these appear to be associated with a lower incidence of RCC. FH and likely BAP1 RCC are associated with more aggressive disease. Preclinical and clinical studies show that using systemic therapy that exploits specific genetic pathways is a promising strategy.
There are several well-described hereditary RCC syndromes, as well as recently identified ones, for which the full clinical spectrum is yet to be defined. In the new era of precision medicine, identification of these syndromes may play an important role in management and systemic treatment selection.
This review covers updates in the diagnosis and management of familial kidney cancer syndromes. We describe updates in testing and management of the most common syndromes such as von Hippel-Lindau, and hereditary leiomyomatosis and renal cell carcinoma. We also provide insights into recently described familial kidney cancer syndromes.
In the last few years, there have been significant advances in our knowledge about the familial kidney cancer syndromes, with updated recommendations on work-up and management. Additionally, there are more recently described familial kidney cancer syndromes that may be under-recognised.
Inactivation of the TCA cycle enzyme, fumarate hydratase (
FH), drives a metabolic shift to aerobic glycolysis in
FH-deficient kidney tumors and cell lines from patients with hereditary ...leiomyomatosis renal cell cancer (HLRCC), resulting in decreased levels of AMP-activated kinase (AMPK) and p53 tumor suppressor, and activation of the anabolic factors, acetyl-CoA carboxylase and ribosomal protein S6. Reduced AMPK levels lead to diminished expression of the DMT1 iron transporter, and the resulting cytosolic iron deficiency activates the iron regulatory proteins, IRP1 and IRP2, and increases expression of the hypoxia inducible factor HIF-1α, but not HIF-2α. Silencing of HIF-1α or activation of AMPK diminishes invasive activities, indicating that alterations of HIF-1α and AMPK contribute to the oncogenic growth of FH-deficient cells.
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► Loss of
FH drives a glycolytic shift and reduces AMPK levels in HLRCC tumor cells ► Reduced AMPK levels in
FH−/− cells activate ACC and rpS6 and decrease p53 levels ► Reduced AMPK levels in
FH−/− cells decrease DMT1 levels and increase IRP activities ► Reduced iron uptake and activation of IRPs increase levels of HIF-1α but not HIF-2α
ABSTRACT Purpose: To review the current literature regarding variant (non-clear) histology of renal cell carcinoma (RCC) and the clinical management of these renal tumors. Material and Methods: A ...PubMed database search was performed in May 2020 focusing on variant RCC, its diagnosis and associated syndromes, tumor characteristics, and options for management. Results: A broad range of pathological, clinical and diagnostic characteristics amongst non-ccRCC variants were found to have an impact on the overall management of these tumors. The imaging modalities, frequency of surveillance, and timing for intervention were found to be dependent on the type of genetic alterations, type of histology, and tumor growth rates. The timing and type of surgery as well as the systemic therapy are tailored to the specific tumor type and patient. Conclusion: The findings of this review suggest that clinical management should be considered and adjusted for patients with non-ccRCC histological variants based on tumor subtype and genetic alterations.
Purpose Recently, a new renal cell cancer syndrome has been linked to germline mutation of multiple subunits ( SDHB / C / D ) of the Krebs cycle enzyme, succinate dehydrogenase. We report our ...experience with the diagnosis, evaluation and treatment of this novel form of hereditary kidney cancer. Materials and Methods Patients with suspected hereditary kidney cancer were enrolled on a National Cancer Institute institutional review board approved protocol to study inherited forms of kidney cancer. Individuals from families with germline SDHB , SDHC and SDHD mutations, and kidney cancer underwent comprehensive clinical and genetic evaluation. Results A total of 14 patients from 12 SDHB mutation families were evaluated. Patients presented with renal cell cancer at an early age (33 years, range 15 to 62), metastatic kidney cancer developed in 4 and some families had no manifestation other than kidney tumors. An additional family with 6 individuals found to have clear cell renal cell cancer that presented at a young average age (47 years, range 40 to 53) was identified with a germline SDHC mutation (R133X) Metastatic disease developed in 2 of these family members. A patient with a history of carotid body paragangliomas and an aggressive form of kidney cancer was evaluated from a family with a germline SDHD mutation. Conclusions SDH mutation associated renal cell carcinoma can be an aggressive type of kidney cancer, especially in younger individuals. Although detection and management of early tumors is most often associated with a good outcome, based on our initial experience with these patients and our long-term experience with hereditary leiomyomatosis and renal cell carcinoma, we recommend careful surveillance of patients at risk for SDH mutation associated renal cell carcinoma and wide surgical excision of renal tumors.
The objectives of revision vaginoplasty are to optimize vaginal function and cosmesis, however this is considerably more challenging when correcting a previous complication and operating in a more ...hostile field with paucity of local tissue available for transfer. We describe a case of neovaginal revision with robotic assistance following complete obliteration.
The patient was a 23 year old transgender female who underwent combined penile and urethral inversion vaginoplasty in 2017. The initial postoperative course was complicated by unrecognized rectovaginal fistula formation which subsequently required two repairs. The complicated post op course impaired her ability to perform vaginal dilations which eventually led to vaginal stenosis and ultimately complete obliteration. The patient underwent reconstruction with a combined perineal and robotic approach. The surgical steps included: 1) repurposing excess urethral tissue for eventual contribution to the anterior neovaginal wall and vestibule 2) meatal repositioning and urethroplasty 3) robotic assisted dissection of a plane between the prostate and rectum for implantation of the neovagina 4) repurposing excess scrotal skin as flaps contributing to the posterior neovaginal wall 5) revision clitoroplasty.
The patient was discharged on postoperative day 1 and vaginal packing removed on day 7. At two month follow-up she was performing vaginal dilations (3.5cm dilator) without difficulty or pain. At six months she was found to have a vaginal depth of 12 cm, and a normal urinary stream. On global response assessment survey she rated herself as “markedly improved”. At 18 months follow up she reported successful penetrative intercourse and reported a sensate clitoris and labia majora.
Revision vaginoplasty using a combined perineal and robotic approach using local remnant tissue is a feasible option to correct for neovaginal obliteration with excellent aesthetic and functional outcomes.
To explore the current role of lymph node dissection (LND) in the management of nonmetastatic localized renal cell carcinoma (RCC).
There is currently no proven benefit of LND in the setting of RCC, ...and its role remains controversial because of conflicting evidence. Patients who may benefit from LND are those at greatest risk of nodal disease, but the tools used to predict nodal involvement are limited due to unpredictable retroperitoneal lymphatics. The indications, templates, and extent of LND are also not standardized, adding to the ambiguity of current guidelines surrounding its use.
A PubMed search of the literature from January 2017 to December 2022 was conducted using the search terms "renal cell carcinoma" or "renal cancer" in combination with "lymph node dissection" or "lymphadenectomy". Case studies and editorials were excluded, whereas studies investigating the therapeutic effect of LND were classified as either demonstrating a benefit or no benefit. References of the studies and review articles were also searched for notable studies and findings that were outside the five-year literature search. The studies in this review were restricted to the English language.
Only a number of studies in recent years have found an association between the extent of LND and increased survival. Most studies do not indicate an associated benefit, and some even suggest a negative effect on survival. Most of these studies are retrospective.
The therapeutic value of LND in RCC is still unclear, and although prospective data are needed, its declining rates and emerging new therapies make this unlikely. A better understanding of renal lymphatics and improved detection of nodal disease may help determine the role of LND in nonmetastatic localized RCC.
The extracellular molecular chaperone heat shock protein 90 (eHSP90) stabilizes protease client the matrix metalloproteinase 2 (MMP2), leading to tumor cell invasion. Although co-chaperones are ...critical modulators of intracellular HSP90:client function, how the eHSP90:MMP2 complex is regulated remains speculative. Here, we report that the tissue inhibitor of metalloproteinases-2 (TIMP2) is a stress-inducible extracellular co-chaperone that binds to eHSP90, increases eHSP90 binding to ATP, and inhibits its ATPase activity. In addition to disrupting the eHSP90:MMP2 complex and terminally inactivating MMP2, TIMP2 loads the client to eHSP90, keeping the protease in a transient inhibitory state. Secreted activating co-chaperone AHA1 displaces TIMP2 from the complex, providing a “reactivating” mechanism for MMP2. Gene knockout or blocking antibodies targeting TIMP2 and AHA1 released by HT1080 cancer cells modify their gelatinolytic activity. Our data suggest that TIMP2 and AHA1 co-chaperones function as a molecular switch that determines the inhibition and reactivation of the eHSP90 client protein MMP2.
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•Stress-inducible TIMP2 is a bona fide co-chaperone of extracellular HSP90 (eHSP90)•TIMP2 regulates HSP90 chaperone function and interaction with client MMP2•Secreted co-chaperones TIMP2 and AHA1 displace each other on the eHSP90:MMP2 complex•TIMP2-AHA1 competition impacts client MMP2 activity and matrix gelatinolysis
Hundreds of intracellular proteins depend on molecular chaperone heat shock protein 90 (HSP90) and its co-chaperones to properly function. Baker-Williams et al. identify two secreted co-chaperones that act as a molecular switch to inhibit and reactivate extracellular HSP90 (eHSP90) client matrix metalloproteinase 2 (MMP2). This mechanism impacts matrix degradation.
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