Papillary renal cell carcinoma

In 2014, PRCC was first acknowledged as a renal tumor subtype by the World Health Organization (WHO) considering its distinct genetic, molecular and histologic characteristics. Type 1 Papillary Renal Cell Carcinoma Type 1 PRCC, also known as a renal tumor caused by a genetic predisposition of hereditary papillary renal cancer syndrome, compromises approximately 25% of all PRCCs. In the perspective of immunochemistry, it has a profile of strong CK7 and alpha-methyl acyl-CoA racemase (AMACR) expression at most focal CA-IX expression. Histologically, its epithelium is composed of relatively small-sized simple cuboidal cells lined in a single layer. These cells are well-characterized by basophilic cytoplasm. Due to its solid growth, an extremely compact papillary architecture is often observed. In general, the nuclei of type 1 PRCC belong to grade 1-2 of the Fuhrman system. Foamy macrophages are inside of papillary fibrovascular cores. File:Histopathology of papillary renal cell carcinoma type 1, grade 2, with variable density.jpg|Type 1 PRCC, this case being more compact at right. Type 2 Papillary renal cell carcinoma Accounting for 25% of PRCCs, type 2 PRCC is the pathological subtype that is most commonly associated with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. When compared to type 1, it shows more variation in protein expression mostly by loss of CK7. In a gross examination, it shows papillae covered by large cells abundant in eosinophilic cytoplasm. Its large spherical nuclei on papillary cores are arranged in a pseudo-stratified manner. Unlike type 1 PRCC, foamy macrophages and psammoma bodies are less common in case of type 2. The majority of type 2 PRCC has high Fuhrman grade nuclei with prominent nucleoli. == Signs and symptoms ==

Due to its asymptomatic nature, PRCC is often undetectable, and the majority of cases are incidentally diagnosed during the radiological workup of unrelated diseases. Since early diagnosis is relatively uncommon, PRCC patients may experience symptoms caused by the metastatic spread to secondary sites. Specifically, metastasis occurs most frequently in the lungs followed by bone and the brain, exhibiting a wide range of symptoms including bone pain to a persistent cough. == Causes ==

Currently, the exact cause of PRCC remains unclear. Possible risk factors have been identified that contribute to PRCC development, which include genetic mutations, hereditary syndrome, renal injuries, and lifestyle factors. Germline mutation of c-MET oncogene and fumarate hydratase gene elevates the risk of type 1 and type 2 PRCC respectively through distinct signaling pathways. Regarding hereditary conditions, patients with hereditary papillary renal cancer syndrome showed a greater risk of type 1 PRCC, whereas those with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome have an increased risk of type 2 PRCC. Moreover, patients who experienced chronic kidney diseases or acute kidney injury exhibited a higher incidence of PRCC. Additionally, other risk factors such as smoking, obesity, and high blood pressure can influence the pathogenesis of PRCC. == Pathogenesis ==

. CDKN2A is a tumor suppressor gene, while loss of its expression results in enhanced tumorigenesis and metastasis. Moreover, mutation of gene involved in chromatin remodeling (SETD2, BAP1, or PBRM) may lead to higher rate of TFE3/TFEB fusion. Additionally, CIMP papillary renal cell carcinoma tumors exhibited somatic FH gene mutation, which is closely associated with HLRCC syndrome. == Diagnosis ==

Currently, cross-sectional imaging with computed tomography (CT) and magnetic resonance imaging (MRI) is known as the best option for diagnosing papillary renal tumors. and hemorrhage compared to chromophobe RCC. Solid, small PRCC tumors (<3 cm in diameter) are more easily viewed on nephrographic, excretory phase images rather than on unenhanced, corticomedullary phase images. Specifically, PRCC exhibits hypointensity due to its dense collagenous matrix or deposition of calcium and hemosiderin within the tumor. Such visual features help PRCC to be differentiated from clear cell RCC, which has heterogeneously higher single intensity shown on T2-weighted images. Currently recommended by the WHO, this four-tiered WHO/ISUP grading system has also been validated for PRCC. == Treatment ==

First-line treatment for metastatic PRCC has not been standardized. Thus, similar treatment approaches for clear cell RCC have been used for PRCC, even though it has a distinct tumor histology. Surgery Nephrectomy or nephron-sharing partial nephrectomy is widely recommended to reduce the risk of metastasis by eliminating all or part of the kidney. Sunitinib, sorafenib, and axitinib are TKIs with anti-vascular endothelial growth factor (VEGF), which inhibit cellular signaling by targeting multiple receptor tyrosine kinase. Everolimus and temsirolimus are used in deregulating the mTOR pathway. Specifically, mTOR inhibitors have crucial roles in regulating cell growth, cell proliferation and metabolism of highly active tumor cells. Considering that MET gene mutation is one oncogenic pathway of PRCC, MET inhibitors like tivantinib and volitinib are currently being investigated as a new targeted therapy option. == Prognosis ==

The five-year survival rate of PRCC has been reported as 82-90%, which is slightly higher than that of other kidney cancers. The reduced survival rate has been positively correlated to several factors, which are high nuclear grade and stage, vascular invasion, DNA aneuploidy, and more. Patients with type 1 PRCC have significantly improved survival rates than those with type 2, which is a reflection of its lower TNM stage with a well-encapsulated tumor. Compared to other common types of RCC, PRCC exhibits a relatively lower risk of tumor recurrence and cancer-related death after nephrectomy. Specifically, the cancer-specific survival rate at five years following surgery with PRCC has reached up to 91%, while clear cell RCC and chromophobe RCC were 72% and 88%, respectively. == Epidemiology ==

Among different histologic subtypes of RCC, PRCC is the second most predominant type and accounts for 10-15% of all renal tumors. In the case of the United States, it is estimated that the incidence of PRCC will rise to 3,500 to 5,000 cases annually. The mean age at presentation is identified as 52–66 years old; however, no statistically significant difference was found in the incidence of PRCC between the younger (40 years). In terms of racial variation, several studies have proven that people with African or Afro-Caribbean ancestry tend to have higher chances of being diagnosed with PRCC. According to the National Cancer Database, PRCC was more common in the Non-Hispanic Black population (38.9%) when compared to other races – Asian American (18.0%), Non-Hispanic White (13.2%), and Hispanic White populations (6.1%). == See also ==