Papillary renal cell carcinoma (PRCC) is a malignant, heterogeneous tumor originating from renal tubular epithelial cells of the kidney, which comprises approximately 10-15% of all kidney neoplasms. Based on its morphological features, PRCC can be classified into two main subtypes, which are type 1 (

basophilic Basophilic is a technical term used by pathologists. It describes the appearance of cells, tissues and cellular structures as seen through the microscope after a histological section has been stained with a basic dye. The most common such dye is ...

) and type 2 (

eosinophilic Eosinophilic (Greek suffix -phil-, meaning ''loves eosin'') is the staining of tissues, cells, or organelles after they have been washed with eosin, a dye. Eosin is an acidic dye for staining cell cytoplasm, collagen, and muscle fibers. ''Eosi ...

). As with other types of renal cell cancer, most cases of PRCC are discovered incidentally without showing specific signs or symptoms of cancer. In advanced stages,

hematuria Hematuria or haematuria is defined as the presence of blood or red blood cells in the urine. “Gross hematuria” occurs when urine appears red, brown, or tea-colored due to the presence of blood. Hematuria may also be subtle and only detectable w ...

flank pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a more ...

, and

abdominal mass An abdominal mass is any localized enlargement or swelling in the human abdomen. Depending on its location, the abdominal mass may be caused by an enlarged liver (hepatomegaly), enlarged spleen (splenomegaly), protruding kidney, a pancreatic mass, ...

are the three classic manifestation. While a complete list of the causes of PRCC remains unclear, several risk factors were identified to affect PRCC development, such as genetic mutations, kidney-related disease, environmental and lifestyle risk factors. For pathogenesis, type 1 PRCC is mainly caused by MET gene mutation while type 2 PRCC is associated with several different genetic pathways. For diagnosis, PRCC is detectable through computed tomography (CT) scans or magnetic resonance imaging (MRI), which commonly present a small homogeneous hyposvascular tumor.

Nephrectomy A nephrectomy is the surgical removal of a kidney, performed to treat a number of kidney diseases including kidney cancer. It is also done to remove a normal healthy kidney from a living or deceased donor, which is part of a kidney transplant pro ...

or partial nephrectomy is usually recommended for PRCC treatment, often accompanied with several targeted molecular therapies to inhibit metastatic spread. PRCC patients are predominantly male with a mean age of 52–66 years. When compared to conventional

clear cell renal cell carcinoma Clear-cell renal-cell carcinoma (CCRCC) is a type of renal-cell carcinoma. Genetics Cytogenetics * Alterations of chromosome 3p segments occurs in 70–90% of CCRCCs * Inactivation of von Hippel–Lindau disease ( VHL) gene by gene mutation a ...

(RCC), the prognosis of non-metastatic PRCC is more favorable, whereas a relatively worse outcome was reported in patients with

metastatic disease Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

. Globally, the incidence of PRCC ranges between 3,500 to 5,000 cases, while it greatly varies depending on gender, age, and race/ethnicity.

Classification

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. It is further divided into type 1 and type 2 based on morphological features.

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 Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellul ...

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. Other morphological characteristics include intracellular hemosiderin and foamy macrophages placed inside of papillary fibrovascular cores or psammoma bodies. In general, the nuclei of type 1 PRCC belong to grade 1-2 of the Fuhrman system. File:Histopathology of papillary renal cell carcinoma type 1, high magnification.jpg, A micrograph of type 1 PRCC, illustrating features of small basophilic cells with scarce cytoplasm. A single layer of cells are surrounding the basal membrane. 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 Reed's syndrome is a rare inherited condition characterised by multiple cutaneous leiomyomas and, in women, uterine leiomyomas. It predisposes for renal cell cancer, an association denominated hereditary leiomyomatosis and renal cell cancer, an ...

(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. Its clinical manifestations are similar to those of clear cell RCC, which are the classical triad of renal cell carcinoma (

and palpable

; only 6-10% of patients) or even nonspecific symptoms including

fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...

fever Fever, also referred to as pyrexia, is defined as having a body temperature, temperature above the human body temperature, normal range due to an increase in the body's temperature Human body temperature#Fever, set point. There is not a single ...

, and

anorexia Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gre ...

. Since early diagnosis is relatively uncommon, PRCC patients may experience symptoms caused by the metastatic spread to secondary sites. Specifically,

metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

occurs most frequently in the lungs followed by bone and the brain, exhibiting a wide range of symptoms including

bone pain Bone pain (also known medically by several other names) is pain coming from a bone, and is caused by damaging stimuli. It occurs as a result of a wide range of diseases or physical conditions or both, and may severely impair the quality of life. ...

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 c-Met, also called tyrosine-protein kinase Met or hepatocyte growth factor receptor (HGFR), is a protein that in humans is encoded by the ''MET'' gene. The protein possesses tyrosine kinase activity. The primary single chain precursor protein is ...

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 Reed's syndrome is a rare inherited condition characterised by multiple cutaneous leiomyomas and, in women, uterine leiomyomas. It predisposes for renal cell cancer, an association denominated hereditary leiomyomatosis and renal cell cancer, and ...

(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

Different molecular mechanisms are involved in PRCC development, which further result in distinct histologic features and clinical outcomes. Type 1 PRCC is caused by a genetic mutation or a gain in chromosome 7 where the MET gene is positioned, resulting in the promotion of oncogenic pathways in renal epithelial cells. Typically, the MET gene is upregulated for renal tissue repair and regeneration by encoding the receptor tyrosine kinase c-MET of

hepatocyte growth factor Hepatocyte growth factor (HGF) or scatter factor (SF) is a paracrine cellular growth, motility and morphogenic factor. It is secreted by mesenchymal cells and targets and acts primarily upon epithelial cells and endothelial cells, but also acts o ...

. However, activation of the oncogenic pathway in the MET gene will manifest invasion, anti-apoptosis, angiogenesis, and metastasis. Type 2 PRCC is associated with irregularity of several signaling pathways, which includes

CDKN2A CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. It is ubiquitously expressed in many tissues and cell types. The gene codes for two proteins, including the INK4 family ...

silencing, mutation in chromatin-modifying genes, and a GpG island methylator phenotype (CIMP). CDKN2A is a tumor suppressor gene, while loss of its expression results in enhanced

tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...

and metastasis. Moreover, mutation of gene involved in chromatin remodeling (

SETD2 SET domain containing 2 is an enzyme that in humans is encoded by the ''SETD2'' gene. Function SETD2 protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active c ...

BAP1 BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) is a deubiquitinating enzyme that in humans is encoded by the ''BAP1'' gene. ''BAP1'' encodes an 80.4 kDa nuclear-localizing protein with a ubiquitin carboxy-terminal hydrolase (U ...

, or PBRM) may lead to higher rate of

TFE3 Transcription factor E3 is a protein that in humans is encoded by the ''TFE3'' gene. Function TFE3, a member of the helix-loop-helix family of transcription factors, binds to the mu-E3 motif of the immunoglobulin heavy-chain enhancer and is ex ...

TFEB Transcription factor EB is a protein that in humans is encoded by the ''TFEB'' gene. Function TFEB is a master gene for lysosomal biogenesis. It encodes a transcription factor that coordinates expression of lysosomal hydrolases, membrane protei ...

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 A computed tomography scan (CT scan; formerly called computed axial tomography scan or CAT scan) is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers ...

(CT) and

magnetic resonance imaging Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...

(MRI) is known as the best option for diagnosing papillary renal tumors. CT scan of PRCC in a 54-year-old woman

Computed tomography (CT)

Contrast-enhanced computed tomography (CT) is most commonly used to identify the subtypes of RCC. PRCC can be differentiated from other types of RCC due to its distinguishing features, displaying a small hypovascular renal tumor on T2 weighted images. Typically, PRCC tends to appear homogeneous while clear cell RCC is likely to be in a heterogeneous form when the tumor is less than 3 cm in diameter. Comparatively, in cases of tumors larger than 3 cm in diameter, PRCC is generally heterogeneous with areas of

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...

and

hemorrhage Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...

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.

Magnetic resonance imaging (MRI)

Magnetic resonance imaging Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...

(MRI) is recommended instead of CT for patients with an allergy to iodinated contrast materials. As some renal tumors do not enhance significantly on CT, MRI examination is required to be performed with more sensitive contrast enhancement. On MRI, the distinct features of PRCC are fibrous capsules and homogeneously low single intensity on both T1- and T2-weighted 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. PRCC displays the smallest tumor-to-cortex enhancement at corticomedullary and nephrographic phases when juxtaposed with clear cell and chromophobe RCCs.

Grading System

Histopathology of papillary renal cell carcinoma type 1 grade 2, very high magnification, annotated

The WHO/ISUP system is histological tumor grading system for renal cell carcinoma, suggested by the International Society of Urologic Pathologists (ISUP) in 2012 to diagnose tumor grades based on nucleolar prominence. Currently recommended by the WHO, this four-tiered WHO/ISUP grading system has also been validated for PRCC. Earlier, the Fuhrman system was largely used, and was similarly based on nuclear features.Table 3
from:

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

or nephron-sharing partial nephrectomy is widely recommended to reduce the risk of metastasis by eliminating all or part of the kidney. Surgery procedures for PRCC depend on the patient's status and are very similar to procedures performed on RCC patients.

Targeted Therapy

Several medications that target molecular pathways in RCC have been possible options for advanced and metastatic PRCC. Among different medications,

tyrosine kinase inhibitors A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosph ...

(TKIs) and

mammalian target of rapamycin The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MTOR'' gene. ...

(mTOR) inhibitors are effective in inhibiting

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...

, blocking growth and suppressing spread of the tumor.

Sunitinib Sunitinib, sold under the brand name Sutent, is a medication used to treat cancer. It is a small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and i ...

sorafenib Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer ( hepatocellular carcinoma), FLT3-ITD positive AML and r ...

, and

axitinib Axitinib, sold under the brand name Inlyta, is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models and has shown partial responses in clini ...

are TKIs with anti-

vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...

(VEGF), which inhibit cellular signaling by targeting multiple receptor tyrosine kinase.

Everolimus Everolimus, sold under the brand name Afinitor among others, is a medication used as an immunosuppressant to prevent rejection of organ transplants and as a targeted therapy in the treatment of renal cell cancer and other tumours. It is the 40 ...

and

temsirolimus Temsirolimus, sold under the brand name Torisel, is an intravenous drug for the treatment of renal cell carcinoma (RCC), developed by Wyeth Pharmaceuticals and approved by the U.S. Food and Drug Administration (FDA) in May 2007, and was also appro ...

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. Other targeted agents such as MET inhibitors,

epidermal growth factor receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The epidermal growth factor recept ...

(EGFR) inhibitors, and

monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ca ...

, are also promising treatment approaches for PRCC. Foretinib is one example of a multikinase inhibitor targeting c-MET. Considering that MET gene mutation is one oncogenic pathway of PRCC, MET inhibitors like

tivantinib Tivantinib (ARQ197; by Arqule, Inc.) is an experimental small molecule anti-cancer drug. It is a bisindolylmaleimide that binds to the dephosphorylated MET kinase ''in vitro''. (MET is a growth factor receptor.) Tivantinib is being tested clinica ...

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. Generally, PRCC is more prevalent among men than women, while the reported sex ratio (M: F) varies from 1.8:1 to 3.8:1. 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) and older adult groups (>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%).

References

External links

{{DEFAULTSORT:Renal Cell Carcinoma Kidney cancer