Renal Cell Carcinoma in the Era of Precision Medicine: From Molecular Pathology to Tissue-Based Biomarkers

Renal cell carcinoma (RCC) is not a single entity but includes various tumor subtypes that have been identified on the basis of either characteristic pathologic features or distinctive molecular changes. Clear cell RCC is the most common type of RCC and is characterized by dysregulation of the von Hippel Lindau/hypoxia-inducible factor pathway. Non–clear cell RCC represents a more heterogeneous group of tumors with diverse histopathologic and molecular features. In the past two decades, the improved understanding of the molecular landscape of RCC has led to the development of more effective therapies for metastatic RCC, which include both targeted agents and immune checkpoint inhibitors. Because only subsets of patients with metastatic RCC respond to a given treatment, predictive biomarkers are needed to guide treatment selection and sequence. In this review, we describe the key histologic features and molecular alterations of RCC subtypes and discuss emerging tissue-based biomarkers of response to currently available therapies for metastatic disease.

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Decreased Expression of Inhibitor of Caspase-Activated DNase (ICAD) in Renal Cell Carcinoma – Tissue Microarray of Human Samples

Journal of Kidney Cancer and VHL ◽

10.15586/jkcvhl.2016.47 ◽

2016 ◽

Vol 3 (1) ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Retnagowri Rajandram ◽

Azad H. A. Razack ◽

Keng Lim Ng ◽

Glenda C Gobe

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Tissue Microarray ◽

Renal Cell ◽

Clear Cell ◽

Normal Kidney ◽

Down Regulation ◽

Caspase Activated Dnase ◽

Clear Cell Rcc ◽

Metastatic Rcc

Although primary localised tumours of renal cell carcinoma (RCC) can be treated relatively successfully with surgery, metastatic RCC has poor prognosis because of late diagnosis and resistance to therapies. In the present study, we were interested in profiling the protein expression of “inhibitor of caspase-activated DNase” (ICAD), an apoptosis inhibitor, in kidney cancer and its paired normal kidney. Immunohistochemistry with automated batch staining and morphometry using digital pathology were used to compare ICAD in 121 RCC specimens with their paired normal kidney tissue. Tissue microarray of formalin-fixed, paraffin-embedded archival tissue was used. Intensity and localisation of ICAD were compared between normal and cancer samples, and against grading within the cancers. The results demonstrated that, in this cohort, ICAD was highly expressed in the proximal tubular epithelium of normal kidney, and significantly decreased in clear cell RCC tissue (p < 0.05) as well as other subtypes of RCC (p < 0.01) compared with normal kidney. There was a tendency towards nuclear localisation of ICAD in clear cell RCC, but not in other subtypes of RCC. No significant association was found between ICAD intensity and grade of RCC. In summary, down-regulation of ICAD occurs in RCC. ICAD normally inhibits DNA fragmentation and apoptosis; thus, its down-regulation was unexpected in a cancer known for its resistance to apoptosis. However, these RCC samples were from primary, not metastatic, RCC sites, and down-regulated ICAD may be part of a progressive pathway that promotes RCC metastasis.

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Tumor Microenvironment Features as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors (ICI) in Metastatic Clear Cell Renal Cell Carcinoma (mccRCC)

Cancers ◽

10.3390/cancers13020231 ◽

2021 ◽

Vol 13 (2) ◽

pp. 231

Author(s):

Audrey Simonaggio ◽

Nicolas Epaillard ◽

Cédric Pobel ◽

Marco Moreira ◽

Stéphane Oudard ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Tumor Microenvironment ◽

Cell Carcinoma ◽

Renal Cell ◽

Immune Checkpoint Inhibitors ◽

Clear Cell ◽

Checkpoint Inhibitors ◽

Predictive Biomarkers ◽

Cell Renal Cell Carcinoma ◽

Genomic Signatures

Renal cell carcinoma (RCC) is the seventh most frequently diagnosed malignancy with an increasing incidence in developed countries. Despite a greater understanding of the cancer biology, which has led to an increase of therapeutic options, metastatic clear cell renal cell carcinoma (mccRCC) still have a poor prognosis with a median five-years survival rate lower than 10%. The standard of care for mccRCC has changed dramatically over the past decades with the emergence of new treatments: anti-VEGFR tyrosine kinase inhibitors, mTOR Inhibitors and immune checkpoint inhibitors (ICI) such as anti-Programmed cell-Death 1 (PD-1) and anti-anti-Programmed Death Ligand-1 (PD-L1) used as monotherapy or as a combination with anti CTLA-4 or anti angiogenic therapies. In the face of these rising therapeutic options, the question of the therapeutic sequences is crucial. Predictive biomarkers are urgently required to provide a personalized treatment for each patient. Disappointingly, the usual ICI biomarkers, PD-L1 expression and Tumor Mutational Burden, approved in melanoma or non-small cell lung cancer (NSCLC) have failed to distinguish good and poor mccRCC responders to ICI. The tumor microenvironment is known to be involved in ICI response. Innovative technologies can be used to explore the immune contexture of tumors and to find predictive and prognostic biomarkers. Recent comprehensive molecular characterization of RCC has led to the development of robust genomic signatures, which could be used as predictive biomarkers. This review will provide an overview of the components of the RCC tumor microenvironment and discuss their role in disease progression and resistance to ICI. We will then highlight the current and future ICI predictive biomarkers assessed in mccRCC with a major focus on immunohistochemistry markers and genomic signatures.

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Emerging Therapies for Advanced Clear Cell Renal Cell Carcinoma

Journal of Kidney Cancer and VHL ◽

10.15586/jkcvhl.v7i4.156 ◽

2020 ◽

Vol 7 (4) ◽

pp. 17-26

Author(s):

Alexander T. Toth ◽

Daniel Cho

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Checkpoint Inhibitors ◽

Standard Of Care ◽

Small Subset ◽

Front Line ◽

Cell Renal Cell Carcinoma ◽

Clear Cell Rcc

Multiple combinational regimens have recently been approved and are now considered the standard of care for patients with advanced clear cell renal cell carcinoma (RCC). Several additional combinational regimens are deep in clinical assessment and are likely to soon join the crowded front-line therapeutic landscape. Most of these regimens are combinations of agents already approved as single-agents in RCC including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors. While these new front-line regimens are associated with reliably high response rates and prolonged survival, complete and durable remissions remain limited to a small subset of patients and the vast majority of patients continue to require subsequent therapy. The need for the continued development of novel agents in RCC persists and efforts have focused on agents targeting the molecular biology of clear cell RCC and novel immunotherapies including cytokines. In this review, we discuss the progress in the development of these novel therapies in the context of the evolving standard of care for patients with advanced clear cell RCC.

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Intraluminal Polypoid Metastasis of Renal Cell Carcinoma in Gallbladder Mimicking Gallbladder Polyp

Archives of Pathology & Laboratory Medicine ◽

10.5858/2009-0453-oa.1 ◽

2010 ◽

Vol 134 (7) ◽

pp. 1003-1009

Author(s):

Xueping Fang ◽

Nilesh Gupta ◽

Steven S. Shen ◽

Pheroze Tamboli ◽

Chusilp Charnsangavej ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

English Literature ◽

Polypoid Lesion ◽

Gallbladder Polyp ◽

Term Survival ◽

Clear Cell Rcc ◽

Metastatic Rcc

Abstract Context.—Metastatic renal cell carcinoma (RCC) in gallbladder is rare with only 18 cases published in the English literature. Objectives.—To review the clinicopathologic characteristics of metastatic RCC in gallbladder and to correlate the findings with clinical outcomes. Design.—We report 4 additional cases of intraluminal polypoid metastasis of RCC in gallbladder and reviewed all reported cases, to our knowledge, of metastatic RCC in gallbladder in the English literature. Results.—Most of the patients (19 of 22; 86%) were men. The ages at presentation ranged from 39 to 84 years with a median age of 61.5 years. All cases showed an intraluminal polypoid/pedunculated mucosal mass mimicking a gallbladder polyp. Histologically, all cases were clear cell RCC with most of the tumors either confined to gallbladder mucosa (67%) or involved both mucosa and muscular layer (27%). The longest interval between nephrectomy and the development of gallbladder metastasis was 27 years. Conclusions.—Metastatic clear cell RCC should be considered in the differential diagnosis of polypoid lesion of the gallbladder with clear cell morphology. Solitary metastasis of RCC in gallbladder correlated with better survival, and simple cholecystectomy for solitary metastatic RCC may provide patients with favorable long-term survival.

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Emerging Therapies for Advanced Clear Cell Renal Cell Carcinoma

Journal of Kidney Cancer and VHL ◽

10.15586/jkcvhl.2020.156 ◽

2020 ◽

Vol 7 (4) ◽

pp. 17-26

Author(s):

Alexander T. Toth ◽

Daniel C. Cho

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Checkpoint Inhibitors ◽

Standard Of Care ◽

Small Subset ◽

Front Line ◽

Cell Renal Cell Carcinoma ◽

Clear Cell Rcc

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Immune Checkpoint Inhibition in Advanced Non-Clear Cell Renal Cell Carcinoma: Leveraging Success from Clear Cell Histology into New Opportunities

Cancers ◽

10.3390/cancers13153652 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3652

Author(s):

Kevin Zarrabi ◽

Emily Walzer ◽

Matthew Zibelman

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Targeted Therapies ◽

Immune Checkpoint ◽

Renal Cell ◽

Clear Cell ◽

Checkpoint Inhibitors ◽

Rapid Development ◽

Cell Renal Cell Carcinoma ◽

Clear Cell Rcc

Renal cell carcinoma (RCC) is a histologically heterogeneous disease with multiple subtypes. Clear cell RCC (ccRCC) represents the most common histology and has thus been easiest to study in clinical trials. Non-clear cell RCC (nccRCC) represents about 25% of RCC tumors, with fewer treatment options available, compared to ccRCC, and with poorer outcomes. Non-clear cell RCC tumors are histologically diverse, with each subtype having distinct molecular and clinical characteristics. Our understanding of nccRCC is evolving, with a gradual shift from treating nccRCC as a single entity to approaching each subtype as its own disease with unique features. Due to the scarcity of patients for study development, trials have predominantly combined all nccRCC subtypes and re-purposed drugs already approved for ccRCC, despite the decreased efficacy. We are now in the early stages of a potential paradigm shift in the treatment of nccRCC, with a rapid development of clinical studies with a focus on this subset of tumors. Investigators have launched trials focused on the molecular drivers of tumorigenesis using targeted therapies. Harboring the immunogenicity of some nccRCC subtypes, and based on promising retrospective studies, clinicians have also devised multiple trials using immune checkpoint inhibitors (ICIs), both alone or in combination with targeted therapies, for nccRCC subtypes. We highlight the promising completed and ongoing studies employing ICIs that will likely continue to improve outcomes in patients with nccRCC and propose future potential immunotherapeutic avenues.

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Two Cases of Sporadic Eosinophilic Solid and Cystic Renal Cell Carcinoma in Manitoba Population

International Journal of Surgical Pathology ◽

10.1177/1066896921993229 ◽

2021 ◽

pp. 106689692199322

Author(s):

Seyed Mohammad Mohaghegh Poor ◽

Shivani Mathur ◽

Karl Kassier ◽

Janetta Rossouw ◽

Robert Wightman ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Preoperative Imaging ◽

Renal Neoplasm ◽

Renal Masses ◽

Cystic Renal Cell Carcinoma ◽

Eosinophilic Cytoplasm ◽

Clear Cell Rcc

Two sporadic cases of eosinophilic solid and cystic renal cell carcinoma (ESC RCC), at our institution, are presented in this study to contribute to the growing literature on this novel renal neoplasm. The first patient was a 38-year-old female with two synchronous renal masses measuring 3.5 and 1.9 cm on preoperative imaging. The second patient was a 44-year-old female with an incidental renal mass measuring 4 cm. Both patients underwent uncomplicated radical nephrectomies. The 1.9 cm mass in the first patient was consistent with clear cell RCC. The dominant mass in the first patient and the tumor in the second patient had microscopic and macroscopic findings in keeping with ESC RCC including a tan appearance, abundant eosinophilic cytoplasm, and CK20+ and CK7− staining. Both patients had an uncomplicated course following surgery with no evidence of local recurrence or distant metastatic disease for 1 and 2 years for the first and second patient accordingly. These cases contribute to a growing body of literature regarding ESC RCC including, to our knowledge, the first reported case of synchronous ESC RCC and clear cell RCC. Further research about this novel renal neoplasm is needed.

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Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms22126290 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6290

Author(s):

Hye-Won Lee

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Imaging Techniques ◽

Predictive Biomarkers ◽

Effective Control ◽

Extrinsic Factors ◽

Medical Needs

Advanced imaging techniques for diagnosis have increased awareness on the benefits of brain screening, facilitated effective control of extracranial disease, and prolonged life expectancy of metastatic renal cell carcinoma (mRCC) patients. Brain metastasis (BM) in patients with mRCC (RCC-BM) is associated with grave prognoses, a high degree of morbidity, dedicated assessment, and unresponsiveness to conventional systemic therapeutics. The therapeutic landscape of RCC-BM is rapidly changing; however, survival outcomes remain poor despite standard surgery and radiation, highlighting the unmet medical needs and the requisite for advancement in systemic therapies. Immune checkpoint inhibitors (ICIs) are one of the most promising strategies to treat RCC-BM. Understanding the role of brain-specific tumor immune microenvironment (TIME) is important for developing rationale-driven ICI-based combination strategies that circumvent tumor intrinsic and extrinsic factors and complex positive feedback loops associated with resistance to ICIs in RCC-BM via combination with ICIs involving other immunological pathways, anti-antiangiogenic multiple tyrosine kinase inhibitors, and radiotherapy; therefore, novel combination approaches are being developed for synergistic potential against RCC-BM; however, further prospective investigations with longer follow-up periods are required to improve the efficacy and safety of combination treatments and to elucidate dynamic predictive biomarkers depending on the interactions in the brain TIME.

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Immune-Related Meningoencephalitis following Nivolumab in Metastatic Renal Cell Carcinoma

Case Reports in Oncology ◽

10.1159/000513001 ◽

2021 ◽

pp. 1051-1058

Author(s):

Lisa B.E. Shields ◽

Mohammad S. Alsorogi ◽

Nataliya Mar ◽

Arash Rezazadeh Kalebasty

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Checkpoint Inhibitors ◽

Rare Complication ◽

Psoas Muscle ◽

High Dose ◽

Lower Extremity Weakness ◽

Left Psoas Muscle ◽

Metastatic Rcc

While immunotherapy with nivolumab is promising for patients with renal cell carcinoma (RCC), overactivation of the immune system can lead to serious side effects. Immune-related meningoencephalitis without a viral or microbial etiology is a rare complication that may occur in patients treated with checkpoint inhibitors (CPI). Herein, we report a 66-year-old man who underwent a partial nephrectomy which revealed a papillary RCC with clear cell component. Three years later, an abdomen and pelvic CT revealed metastatic lesions in the left psoas muscle and in the left 12th rib. The patient was treated with pazopanib which was discontinued after 2 weeks due to significant hepatic and renal toxicity. He subsequently started sunitinib. Two months later, a chest, abdomen, and pelvic CT demonstrated progressive metastatic RCC in the retroperitoneal mass of the left psoas muscle and paraspinal musculature as well as a left renal mass. The patient was treated with 7 cycles of the CPI nivolumab. He was subsequently hospitalized for 3 weeks after experiencing bilateral lower extremity weakness, lethargy, several falls, hyperthermia, confusion, and gait abnormalities. A CSF analysis demonstrated a lymphocyte pleocytosis with elevated protein and no bacterial or viral growth. The patient was treated with high-dose steroids after which his symptoms resolved. Chest, abdomen, and pelvic CT scans over the next 3 years revealed no evidence of metastatic disease, reflecting a progression-free survival of 40 months. We highlight the unique case of a patient with metastatic RCC who experienced immune-related meningoencephalitis following immunotherapy with nivolumab. Medical oncologists should be alert to the potential development of immune-related encephalitis in patients treated with nivolumab and should promptly diagnose and treat this concerning condition. The excellent oncologic outcome of this case emphasizes the need for continued aggressive measures for management of CNS toxicity resulting from CPI therapy.

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Detection of a peritumoral pseudocapsule in patients with renal cell carcinoma undergoing robot-assisted partial nephrectomy using enhanced MDCT

Scientific Reports ◽

10.1038/s41598-021-81922-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Makoto Toguchi ◽

Toshio Takagi ◽

Yuko Ogawa ◽

Satoru Morita ◽

Kazuhiko Yoshida ◽

...

Keyword(s):

Computed Tomography ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Partial Nephrectomy ◽

Renal Cell ◽

Clear Cell ◽

Robot Assisted ◽

High Attenuation ◽

Papillary Rcc ◽

Clear Cell Rcc

AbstractTo investigate the detection of peritumoral pseudocapsule (PC) using multi-detector row computed tomography (MDCT) for tumors resected by robot-assisted laparoscopic partial nephrectomy (RAPN) for T1 renal cell carcinoma (RCC). Study participants included 206 patients with clinical T1 RCC who underwent RAPN between October 2017 and February 2018. Two radiologists who were blinded to the pathological findings evaluated the computed tomography (CT) images. Radiological diagnosis of a PC was defined by a combination of observations, including a low-attenuation rim between the tumor and renal cortex in the cortico-medullary phase and a high-attenuation rim at the edge of the tumor in the nephrogenic or excretory phase. A PC was detected on CT in 156/206 tumors (76%) and identified by pathology in 182/206 (88%) tumors including 153/166 (92%) clear cell RCC, 13/14 (93%) papillary RCC, and 7/16 (44%) chromophobe RCC. In the whole cohort, CT findings showed a sensitivity of 81.3% (148/182), specificity of 66.7% (16/24), and positive predictive value of 94.9% (148/156). When the data were stratified according to pathological subtypes, MDCT was observed to have a sensitivity of 86.9% (133/153) and specificity of 61.5% (8/13) in clear cell RCC, sensitivity of 38.5% (5/13) and specificity of 100% (1/1) in papillary RCC, and sensitivity of 44.4% (4/7) and specificity of 66.7% (6/9) in chromophobe RCC. A low or high-attenuation rim around the tumor in the cortico-medullary or nephrographic-to-excretory phase indicates a PC of RCC, though the accuracy is not satisfactory even with 64- or 320-detector MDCT.

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