Therapeutic Strategies for Hereditary Kidney Cancer.

The study of hereditary forms of kidney cancer has vastly increased our understanding of metabolic and genetic pathways involved in the development of both inherited and sporadic kidney cancers. The recognition that diverse molecular events drive different forms of kidney cancers has led to the preclinical and clinical development of specific pathway-directed strategies tailored to treat distinct subgroups of kidney cancer. Here, we describe the molecular mechanisms underlying the pathogenesis of several different types of hereditary renal cancers, review their clinical characteristics, and summarize the treatment strategies for the management of these cancers.

Sudden Vision Loss in a Patient With Renal Cell Carcinoma: A Potential Indicator of Choroidal Metastasis.

Choroidal metastasis of renal cell cancer (RCC) is an exceptionally rare clinical occurrence. In most cases, sudden vision loss is the first symptom. Here we present the case of a 52-year-old male with papillary RCC first diagnosed in 2018. Three years later, a bronchoscopy with endobronchial ultrasound (EBUS) identified suspicious infracarinal lymph nodes. A biopsy confirmed metastasis from RCC, leading to the initiation of systemic first-line therapy with cabozantinib monotherapy. The patient confirmed an excellent response with complete remission. In 2023, the patient reported for the first time a bilateral decrease in vision. Initial management with corrective lenses was unsuccessful. Further staging indicated metastases in the liver, spleen, and adrenal gland. Consecutively, the therapy was switched to lenvatinib and pembrolizumab. Two months later, an ophthalmologic examination due to persisting vision loss confirmed bilateral choroidal metastases. The systemic therapy was continued, and the patient's vision significantly improved. In 2024, the patient developed immune-associated pneumonitis, initially treated with prednisolone. The pulmonary situation became worse. A CT scan confirmed additional metastases in the lung with lymphangiosis carcinomatosis. Due to a poor performance status, no further systemic therapy has been initiated to date. In conclusion, this case highlights the rarity of choroidal metastases in RCC and the challenges of diagnosis. Ophthalmologic examination in RCC patients experiencing sudden vision loss is essential to detect these specific metastases as soon as possible. Comprehensive documentation and awareness of these rare metastatic manifestations are essential to improving diagnostic accuracy and patient outcomes.

Checkpoint inhibitors in metastatic papillary renal cell carcinoma.

Papillary Renal Cell Carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC) and a distinct entity, although heterogenous, associated with poor outcomes. The treatment landscape of metastatic pRCC (mpRCC) relied so far on targeted therapies, mimicking previous developments in metastatic clear-cell renal cell carcinoma. However, antiangiogenics as well as mTOR inhibitors retain only limited activity in mpRCC. As development of immune checkpoint inhibitors (ICI) is now underway in patients with mpRCC, we aimed at discussing early activity data and potential for future therapeutic strategies in monotherapy or combination. Expression of immune checkpoints such as PD-L1 and infiltrative immune cells in pRCC could provide insights into their potential immunogenicity, although this is currently poorly described. Based on retrospective and prospective data, efficacy of ICI as single agent remains limited. Combinations with tyrosine-kinase inhibitors, notably with anti-MET inhibitors, harbor promising response rates and may enter the standard of care in untreated patients. Collaborative work is needed to refine the molecular and immune landscape of pRCC, and pursue efforts to set up predictive biomarker-driven clinical trials in these rare tumors.

Pathology and systemic therapy of non-clear cell renal cell carcinoma: an overview.

Introduction: Non-clear cell renal cell carcinoma (nccRCC) represents a highly heterogenous group of kidney cancer entities. As most clinical trials predominantly include patients with clear cell RCC (ccRCC), nccRCC treatment guidelines are mainly extrapolated from recommendations in ccRCC. Here, we review and elucidate current data on the pathologic classification and treatment of nccRCC.Areas covered: This article gives an overview of the WHO classification of RCC, showing the histological diversity of nccRCC and focusing particularly on entities first characterized since 2016, their specific molecular behavior and their role as indicators for hereditary cancer syndromes. In this context, we discuss the available data on nccRCC treatment oprtions such as tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, cytotoxic chemotherapy, and immune checkpoint inhibitors.Expert opinion: Although nccRCCs are relatively uncommon, entities of this type account for a subgroup of up to 20-25% of all RCCs. Advances in histopathology and molecular genetics, together with evidence gained from retrospective and prospective clinical data, have improved understanding of these tumors in recent years. Nevertheless, selective trials of current and novel therapies including new targeted agents in patients with nccRCC are urgently needed to further improve treatment guidelines.

Are immune checkpoint inhibitors a valid option for papillary renal cell carcinoma? A multicentre retrospective study.

BACKGROUND: Papillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC). Pivotal studies evaluating immune checkpoint inhibitors mostly excluded nccRCC. The aim of this retrospective and multicentre study was to evaluate the activity of programmed death-1 (PD-1)/ programmed death-ligand 1 (PD-L1) inhibitors specifically in metastatic pRCC. METHODS: The primary end-point was time to treatment failure (TTF). Secondary endpoints included objective response rate (ORR), overall survival (OS) and treatment-related adverse events (TRAEs). RESULTS: From 02/2016 to 01/2019, 57 patients with pRCC were included. Histology included 16 (28%) type 1 pRCC, 34 (60%) type 2 pRCC and 7 (12%) unclassified pRCC. Treatment with immune checkpoint inhibitors was used in the first-line setting in 4 patients (7%), in the second-line setting in 32 patients (56%) and in the third-line setting or more in 21 patients (37%). With a median follow-up of 12 months (95% confidence interval [CI]: 9.9-21.0), the median TTF was 3.1 months (95% CI: 2.7-5.0). Among the 55 patients evaluable for ORR, best response was complete response/partial response in 6 patients (11%), stable disease in 18 patients (33%) and progressive disease in 31 patients (56%). The median OS was 14.6 months (95% CI: 9.0- not reached). TRAEs of grade III-IV were noted in 6 patients (10%) leading to treatment discontinuation, and no grade V TRAEs were observed. CONCLUSION: PD-1/PD-L1 inhibitors exhibit limited activity as monotherapy in this pRCC population, which remains an unmet need. Our findings underline the need for further prospective clinical trials evaluating immune checkpoint inhibitor combinations in patients with pRCC.

Hereditary leiomyomatosis and renal cell cancer (HLRCC): A case report.

Hereditary leiomyomatosis and renal cell cancer is a rare, inherited disease caused by mutations in the fumarate hydratase gene. It is characterized by cutaneous leiomyomas, uterine leiomyomas, and/or renal cell cancer. We present the case of a 42-year-old woman with a heterozygous missense mutation (p.M195T) in the fumarate hydratase gene. Although the patient did not have cutaneous leiomyoma and she had no family history of hereditary leiomyomatosis and renal cell cancer, the presence of early onset symptomatic uterine leiomyoma and type 2 papillary renal cell cancer confirmed the diagnosis of hereditary leiomyomatosis and renal cell cancer.

Construction of immune-related risk signature for renal papillary cell carcinoma.

The kidney renal papillary cell carcinoma (KIRP) is a relatively rare type of kidney cancer. There has been no investigation to find a robust signature to predict the survival outcome of KIRP patients in the aspect of tumor immunology. In this study, 285 KIRP samples from The Cancer Genome Atlas (TCGA) were randomly divided into training and testing set. A total of 1534 immune-related genes from The Immunology Database and Analysis Portal (ImmPort) were used as candidates to construct the signature. Using univariate Cox analysis, we evaluated the relationship between overall survival and immune-related genes expression and found 272 immune-related genes with predicting prognostic ability. In order to construct an efficient predictive model, the Cox proportional hazards model with an elastic-net penalty was used and identified 23 groups after 1000 iterations. As a result, 15-genes model showing more stable than other gene groups was chosen to construct our immune-related risk signature. In line with our expectations, the signature can independently predict the survival outcome of KIRP patients. Patients with high-immune risk were found correlated with advanced stage. We also found that the high-immune risk patients with higher PBRM1 and SETD2 mutations, increasing chromosomal instability, together with the gene set enrichment analysis (GSEA) results showing intensive connection of our signature with immune pathways. In conclusion, our study constructs a robust 15-gene signature for predicting KIRP patients' survival outcome on the basis of tumor immune environment and may provide possible relationship between prognosis and immune-related biological function.

Malignant Transformation in Mature Cystic Teratomas of the Ovary: Case Reports and Review of the Literature.

Malignant transformation occurs in 1.5-2% of mature cystic teratomas (MCT)s of the ovary and usually consists of squamous cell carcinoma, whereas other malignancies are less common. Diagnosis and treatment represent a challenge for gynecologic oncologists. The preoperative detection is very difficult and the diagnostic accuracy of imaging examinations is uncertain. The tumor is usually detected post-operatively based on histopathologic findings. This paper reviewed 206 consecutive patients who underwent surgery for a histologically-proven MCT of the ovary between 2010 and 2017. Malignant transformation occurred in 3 (1.5%) of them, and consisted of squamous cell carcinoma in one, type 2 papillary renal carcinoma in one, and papillary thyroid carcinoma in another one. The paper reported the clinical, radiological and histological features of these cases and reviewed the literature data on the treatment options.

Determinants and prognostic implications of malignant ascites in metastatic papillary renal cancer.

OBJECTIVE: To describe the incidence of ascites in metastatic papillary renal cell cancer (pRCC), identify the factors associated with its development and evaluate its prognostic effect on the survival of these patients. METHODS: A retrospective evaluation of the medical records of patients with metastatic pRCC seen at National Cancer Institute (2000-2014) was undertaken. Logistic regression to identify predictors of the development of malignant ascites and Kaplan-Meier analysis to estimate survival was done. RESULTS: Overall, 106 consecutive patients with metastatic pRCC were identified; sufficient data were available in 100 patients to enable assessment of ascites. Further, 20% had evidence of malignant ascites. Median age at diagnosis of ascites was 48.0 years (26.1-76.6 years) and median time to development of ascites from initial diagnosis of metastatic disease was 16.0 (0-73.3) months. There was no significant difference in the incidence of ascites between patients with hereditary and sporadic pRCC (P = 0.803) or among patients with different subtypes of pRCC (P = 0.456). Elevated platelet-lymphocyte ratio predicted development of malignant ascites in our cohort (P = 0.009). Median overall survival was shorter for patients who developed ascites [25.0 (10.2-39.8) months] compared with patients who did not develop this complication [42.5 (30.5-54.4) months, P = 0.041]. CONCLUSION: To our knowledge, this is the first systematic evaluation of the incidence, predictors, and prognostic effect of ascites in metastatic pRCC. Malignant ascites is a common manifestation of metastatic pRCC and is associated with a shorter overall survival. An elevated platelet-lymphocyte ratio predicts a higher risk of developing malignant ascites.