Renal Cell Carcinoma: Implications of Histology

Renal cell carcinoma (RCC) is the most common kidney tumor worldwide.  In the United States, kidney cancer affects approximately 65k people and kills about 14k people per year.[1]  By definition, all RCC are adenocarcinomas -- meaning they derive from epithelium, or the lining, of the renal tubules that filter and conduct urine.  However, RCC represents several distinct entities including:

• Clear-cell RCC
• Papillary RCC
• Chromophobe RCC
• Collecting duct carcinoma
• Renal medullary carcinoma
• Translocation tumors
• Tubulocystic RCC
• Clear Cell (Tubulo) Papillary RCC
• Acquired Cystic Disease–associated RCC
• Multilocular Cystic Renal Cell Neoplasm of Low Malignant Potential (Multilocular Cystic RCC)
• Hybrid Oncocytic/Chromophobe Tumors

After a biopsy or surgery to remove a tumor, the pathology report will often define the tumor as one of these entities.  This blog will review the definitions and implications of some of the most common tumor histologies.

Clear-Cell Renal Cell Carcinoma

Clear-cell RCC under the microscope.

Clear-cell RCC is the most common RCC, accounting for 70-80% of all tumors.  Clear-cell RCC was formerly known as "conventional" RCC.  In general, they are well-cricumscribed, yellow and lobulated tumors.  They can have necrosis, hemorrhage or invade vascular structures around the kidney.  The cells of clear-cell RCC are full of glycogen, cholesterol and phospholipids which are washed out during the specimen processing - giving these cells their characteristics clear appearance.  Upwards of 75% of clear-cell tumors have a defect in the von Hippel-Lindau (VHL) gene on chromosome 3.  

Prognosis

Patients with clear-cell RCC have a worse prognosis, in general, when compared to patients with papillary or chromophobe RCC.  However, most systemic therapies are designed to target clear-cell RCC and therefore, most responses for immuno- and other systemic therapies have been in clear-cell RCC patients.  

Papillary Renal Cell Carcinoma

Papillary RCC accounts for 10-15% of RCC tumors, making it the second most common tumor subtype. Papillary RCC was previously known as "chromophilic" RCC.  Papillary RCC have a few important clinical correlations:

• commonly found in patients with end-stage renal disease
• commonly found in patients with acquired cystic disease
• often multifocal, upwards of 40% of papillary RCC are found in more than one site in the kidney

Papillary RCC (webpathology.com)

On imaging, they are often less intense than clear-cell or other "enhancing" tumors -- they can be mistaken for cysts.   While these are solid masses, like other forms of RCC, the cells grow in a papillary or tubular configuration, forming stalks of tumor cells rather than flat sheets.  There are two distinct patterns of growth under the microscope, in cytogenetics and molecular staining.

Papillary Type 1: 

• more common form
• dark cells with scant cytoplasm
• associated with Hereditary Papillary RCC Syndrome 

Papillary Type 2: 

• less common
• eosinophilic (red) cells with abundant cytoplasm
• sporadic forms of Papillary Type 2 are not necessarily dangerous
• these tumors are potentially aggressive when associated with the hereditary Leiomyomatosis and RCC Syndrome -- these tumors are now given their own distinction and are no longer lumped with Type 2 tumors.

Common cytogenetic abnormalities in papillary RCC are trisomy 7 and 17, and loss of the Y chromosome.

Prognosis

Most papillary RCC are low-grade and upwards of 80% are confined to the kidney.  While papillary RCC can still present with advanced and dangerous cancers, when compared to clear-cell RCC by stage and grade, papillary RCC is believed to have a better prognosis.  However, papillary RCC is generally not responsive to systemic and immuntherapies for advanced cancer.

Chromophobe Renal Cell Carcinoma

Chromophobe RCC represents only 3-5% of RCC.  Unlike clear-cell and papillary RCC, which derive from the proximal tubule of the nephron, chromophobe RCC derives from the collecting duct.  Under the microscope, chromophobe RCC cells are recognized by a perinuclear "halo" or clear cytoplasm around the nucleus; and microvesicles which can be seen with electron microscopy or with Hale's colloidal iron stain. The most common cytogenetic abnormality is loss of a whole chromosome (usually 1, 2, 6, 10, 13, 17, and 21).

Prognosis

In general, chromophobe RCC has a better prognosis than clear-cell RCC when localized and are most patients are diagnosed with a small, early-stage, low-grade tumor.  However, chromophobe cancers have a worse prognosis when present with advanced disease (sarcomatoid features or metastases) and are resistant to all current forms of immunotherapy.

Collecting Duct Carcinoma

As the name suggests, collecting duct carcinoma derives from the collecting duct (or Bellini's duct) of the nephron and are also known as Bellini tumors.  They account for less than 1% of RCC.  Collecting duct carcinoma often presents in younger patients with advanced disease and is unresponsive to most therapies, leading to a poor prognosis.

Renal Medullary Carcinoma

Also a rare and aggressive form of cancer, renal medullary carcinoma often presents in young, African-Americans with sickle-cell trait with a locally advanced tumor and metastatic disease.  The prognosis is poor.

Translocation Tumors

Translocation tumors are a relatively new diagnostic entity and describes a relatively common form of RCC in children.  While RCC is less than 5% of renal tumors in children (Wilms and neuroblastoma are much more common), >50% of the RCC are translocation tumors.  These tumors are rare in adults, but may be more common in patients exposed to chemotherapy for a prior malignancy.  Under the microscope, these tumors represent a combination of both clear-cell and papillary RCC.  The term "translocation" defines these tumors as they uniformly demonstrate chromosomal translocations involving the TFE3 transcription factor gene (maps to Xp11.2 locus).

Prognosis

As these tumors are a relatively new entity, data regarding outcomes is still premature.  Children have a relatively good prognosis, even with nodal (but not distant) metastases with >90% alive at about 5 years. Data suggests that adults have a worse prognosis, more often presenting with advanced disease and with an average survival of 1-2 years.  Interestingly, these tumors can metastasize 20 to 30 years after an initial diagnosis - so long-term follow-up is required.



[1] American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society; 2014.

Other Resources:
Campbell SC, Lane BR. "Malignant Renal Tumors" in Campbell-Walsh Urology, 10th Edition.  Wein, Kavoussi, Novick, Partin and Peters (Eds.).  Philadelphia: Elsevier, 2012. chapter 49, page 1413-1474.

Srigley JR, Delahunt B, Eble JN, Egevad L, Epstein JI, Grignon D, Hes O, Moch H, Montironi R, Tickoo SK, Zhou M, Argani P; ISUP Renal Tumor Panel.The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia.  Am J Surg Pathol. 2013 Oct;37(10):1469-89. doi: 10.1097/PAS.0b013e318299f2d1.