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Classifying Histologic Subtypes of Renal Cell Carcinoma

Classifying Histologic Subtypes of Renal Cell Carcinoma


With the advent of advanced imaging technology and increased use of new technology, the incidence of renal tumors has risen in the past 30 years. A review of the Surveillance, Epidemiology and End Results (SEER) database has shown that the incidence of renal cell carcinoma (RCC) has increased significantly by as much as 4% in some populations.1 Most of the renal tumors diagnosed as a result of increased imaging are of lower stage, namely T1 tumors with no evidence of metastasis or nodal involvement.2 The disease has shown a lack of stage migration, with overall mortality constant over the past three decades. This has led urologists to review and rethink their approach to RCC on several points. Has the disease itself changed? Do we need to refine our techniques in treating RCC? How can we improve prognoses? ?

Histologic typing?

To answer the first question, one should look at renal pathology. The evolution of renal pathology has greatly enhanced our understanding of renal tumors. With more tumors for evaluation, histologic typing and grading of renal tumors has become more standardized. In addition to standardizing pathologic subtypes, the increased incidence of renal tumors has led to a better understanding of the histologic subtypes of RCC. Furthermore, molecular genetics and immunohistochemistry have proved to be invaluable in the subclassification of RCC, allowing clinicians to better predict the natural history of the disease and to make prognoses. We will review the histologic subtypes of RCC, including new subtypes recognized in the 2004 World Health Organization classification of renal tumors. We will describe their appearance, prevalence, prognosis, and association with genetic syndromes, and review new advances in genetics and molecular biology that allow pathologists and urologists to distinguish among subtypes.?

While many renal tumors are "incidentalomas," it is important to recognize both the risk factors for and symptoms of RCC. First, as with bladder cancer, smoking is a significant risk factor. Other risk factors include obesity,3 renal failure, and hemodialysis.4 The genetic basis of several subtypes of RCC has been elucidated and will be discussed with each pathologic subtype.?

Renal tumors were recognized as distinct entities starting in the early 19th century, though these tumors were poorly characterized and the distinction between benign and malignant tumors was often unclear. Throughout the 1800’s, autopsy studies clarified the difference between malignant and benign tumors, whose status was confirmed on histologic evaluation. Through the first half of the 20th century, urologists and pathologists began to understand the distinction between benign and malignant neoplasia as well as histologic, structural, and genetic differences between the different subtypes of malignant tumors.5?

RCC pathology prior to 1997 was divided into two categories: clear cell and granular cell carcinoma, with several descriptors associated with each category. In 1986, a European consensus group convened in Mainz, Germany to standardize the classification of renal neoplasms. The group decided that cell cytology and genetics should determine classification, with subcategories defined by histology and tumor architecture. This classification system proved unwieldly and was not used widely outside of Europe.6?

In 1997, consensus meetings were held in Rochester, Minn., and Heidelberg, Germany to re-evaluate and standardize the classification of renal tumors. These two consensus meetings defined the more common classifications of RCC in wide use today. Histologic appearance and architecture were used instead of tumor genetics.?

Clear cell RCC ?

Clear cell RCC is the most common histologic subtype of malignant tumors of the kidney. This histology accounts for 75% of renal masses that are evaluated.7,8 Clear cell RCC derives from the proximal tubular epithelium and, in the majority of cases, has a clear cytoplasm with a large prominent nucleus. Bilateral tumors are rare, occurring in only 0.5% to 3.0% of cases. Two well-described methods are used to further characterize clear cell RCC. First and most commonly, the Fuhrman grading system is used to classify RCC (See Table 1). Fuhrman grading was first described in 1982 and has been used to both describe renal tumors and make prognoses. Fuhrman grading has prognostic significance, with higher Fuhrman grades predicting a worse clinical outcome.9 The second method is chromosomal analysis. Clear cell RCC often has distinct genetic abnormalities, with the loss of the 3p chromosome as well as a frequent loss of chromosome 9p.?

Clear cell RCC is associated with von Hippel-Lindau (VHL) disease. It is the evaluation of this genetic abnormality that has led to some of the more significant advances in the treatment of clear cell carcinomas. VHL disease is an autosomal dominant disease with a prevalence of 1 in 36,000 in the United States.10 The clinical manifestations include the development of clear cell RCC, pheochromocytomas, retinal angiomas, and central nervous system hemangioblastomas. The genetic abnormality associated with VHL disease is the loss of chromosomes at 3p25-26. Through careful study of the cytogenetics of VHL patients, the gene at this locus was found to be a tumor suppressor gene associated with familial clear cell carcinomas as well as a large majority of sporadic RCC.?

The VHL protein sequenced by this gene was found to complex with the hypoxia-inducible factor (HIF-1) to promote the degradation of HIF-1. HIF-1 regulates production of multiple proteins, including vascular-endothelial growth factor (VEGF) and other cell regulatory proteins that are normally kept in check but which are significantly elevated in times of hypoxia, starvation, and stress. The investigation of this and other pathways in the HIF-1 cascade has led to a better understanding of the pathophysiology of RCC and the development of inhibitors of these pathways that have shown promise in the treatment of clear cell RCC.11 It is from these pathways that sunitinib and sorafenib were developed; these medications show great promise as targeted therapy for clear cell RCC. ?

Clear cell RCC is known to have an aggressive course, but one variant recognized by the WHO 2004 classification—multilocular cystic RCC—has an indolent course with a favorable clinical outcome. Multilocular cystic RCC’s are well circumscribed masses that are characterized by multiple non-communicating cysts separated by thick fibrous septae, which are often hyalinized. The cysts are lined with clear cells; however, they more commonly show an attenuated lining.12 The hallmark for a multilocular cystic RCC diagnosis is the presence of small nests of clear cells within the cyst wall. While VHL mutations are noted in multilocular cystic RCC, it earned separate classification due to its indolent course and low malignancy potential. Clear cell renal cell carcinoma are positive for CAIX (carbonic anhydrase IX), vimentin, CD10, and RCC antigen by immunohistochemistry ?

Papillary RCC?

The second most common variant, papillary RCC, has a well-defined genetic abnormality associated with it, much like clear cell RCC. Approximately 10%-15% of renal masses are papillary RCC, with a small portion of these related to the familial syndrome. To review the characteristics of papillary RCC, we first should examine the histologic and structural appearance of papillary tumors. Papillary RCC was not considered a distinct subclassification of RCC until the Heidelberg and Rochester consensus meetings. Furthermore, in 2004, WHO officially recognized the distinction between the two types of papillary RCC. ?

Papillary RCC is derived from the distal convoluted tubules. As the name implies, papillary RCC is composed of a single or pseudostratified layer of cells arranged around a fibrovascular core to create the characteristic papillae. These tumors are notable for the presence of aggregates of foamy macrophages within the papillae and could also have psammoma bodies. These characteristics are common to both subtypes of papillary RCC. Papillary type I and type II are distinguished mainly by histologic and cytologic criteria. Type I tumors are more common and are composed of small cells characterized by their scanty basophilic cytoplasm and low nuclear grade. The fibrovascular cores of the papillae are lined with a single layer of cells. In contrast, type II tumors are composed of large cells with eosinophilic cystoplasm and higher grade nuclei with pseudostratification along the fibrovascular core. Fuhrman grading has been shown to provide good prognostic information regarding these tumors. Therefore, with higher Fuhrman grades, type II papillary RCC has a worse prognosis than type I, though both of these tumors have a more optimistic prognosis than clear cell RCC.13 Genetic analysis of papillary tumors has revealed a definitive genetic characteristic. In papillary RCC, tumors do not display the loss of the 3p allele, but instead show multiploidy at chromosomes 7 and 17. In males, papillary tumors are also notable for the loss of the Y chromosome. Hereditary papillary RCC is associated with alterations in the c-met oncogene, also located on chromosome 7, but trisomy of chromosomes 7 and 17 are also identified in tumors associated with this syndrome.14 Papillary renal cell carcinoma is positive for CK7 and racemase by immunohistochemistry.?

Chromophobe RCC?

First described in 1985, chromophobe RCC accounts for approximately 5% of renal tumors.15 This RCC subtype has a better prognosis than either clear cell or papillary RCC, but it is worth noting that metastases from chromophobe RCC have been reported. Chromophobe RCC derives from the intercalated cells of the collecting duct epithelium. Chromophobe RCC is characterized by sheets of large plant-like pale to eosinophilic cells with abundant cytoplasm. In its classic­al form, it is notable for its nuclear features characterized by perinuclear halos, binucleation, and raisinoid nuclei. In its eosinophilic variant, Chromophobe RCC can be difficult to distinguish from oncocytoma, which is considered a benign renal neoplasm. Staining for Hale’s colloidal iron distinguishes between these two neoplasms, with chromophobe showing diffuse staining in a reticular pattern while oncocytoma provides only patchy staining.16?

In addition, the use of an immunohistochemical panel of staining, such as CK7, C-Kit, and Pax-2, aids in the distinction, where chromophobe RCC is predominantly positive for CK7 and C-kit and negative for pax-2, and oncocytomas are CK7 and C-kit negative or focally positive and pax-2 positive.17 ?

With respect to genetic analysis, chromophobe RCC is frequently associated with chromosomal losses and hypodiploidy, such as the loss of chromosome 1 and 17, though losses of chromosomes 2,6,10, and 21 have been noted.18 Birt-Hogg-Dube also is associated with a chromosome 17p11.2 deletion and is characterized by skin lesions, renal tumors, and spontaneous pneumothorax.19 Half of the tumors in the Birt-Hogg-Dube patients have features of both chromophobe RCC and oncoytoma and have been referred to as the "hybrid oncocytic tumors." While clear cell, papillary, and chromophobe RCC were well established subtypes of RCC prior to the 2004 WHO reclassification, the following subtypes were better characterized recently: collecting duct carcinoma (CDC), renal medullary carcinoma, and mucinous tubular and spindle-cell carcinoma. It is worth noting, however, that these tumors represent only approximately 10% of all renal tumors evaluated. ?

Collecting duct carcinoma?

CDC was first recognized as a subtype of renal carcinoma in 1986.20 Similar to chromophobe RCC, CDC, as the name implies, derives from the collecting duct cells in the medulla. Unfortunately, most tumors are symptomatic and patients often present with advanced stage disease, with more than one third of patients presenting with metastatic disease. These tumors tend to have a male predominance (2:1). ?

CDC is characterized by infiltrating, irregular tubules and papillae of varying dimensions in a desmoplastic stromal reaction. CDC nearly always has multi­-?ple mitotic figures with high Fuhrman grade nuclei. Collecting duct carcinoma ?does not have a specific staining pattern and is positive for CEA, peanut ?lectin agglutinin and Ulex europaeus agglutinin. It can also be positive for cyto­-keratin 34BE12 and CK7. Unlike other renal carcinomas, however, CDC does not have a clear genetic karyotype. Although individual cases have displayed either trisomy of some chromosomes or loss of heterozygosity of others, there is no ?clear consensus.22 ?

Renal medullary carcinoma?

Renal medullary carcinoma was first reported to be a distinct variant of renal tumors in 1995.23 This type of carcinoma is also derived from the renal ?collecting duct and is considered by some to be an even more aggressive variant of CDC. It is found with overwhelming predominance in younger patients, particularly African Americans, with the mean age at presentation of 19 years. Male predominance has been reported at 2:1. Nearly all reported cases of renal medullary carcinoma are associated with sickle cell disease and in some cases sickle cell trait. Patients are symptomatic upon presentation with hematuria, flank pain, abdominal pain, and weight loss. Unfortunately, 95% of patients present with metastatic disease and prognosis is poor, with a mean survival of 18 weeks after diagnosis.24 ?

The pathologic appearance of medullary carcinoma reveals an infiltrative, poorly differentiated carcinoma with solid sheets of tumor cells and a significant desmoplastic response. Sickled red blood cells are often noted within the tumor. Medullary carcinoma shows a similar pattern of immunostaining as collecting duct carcinoma. Like CDC, medullary carcinoma has proved difficult to characterize on genetic analysis, with significant alteration in gene number. While some work is promising, there has been no established genetic profile for medullary carcinoma.?

Mucinous tubular and spindle-cell carcinoma?

Mucinous tubular and spindle-cell carcinoma is a new addition to the WHO renal tumors classification. It is a rare tumor that is postulated to be of collecting duct and possibly loop of Henle origin. The current classification provides a description of the tumor by naming its three components: tubules, spindle cells, and mucinous stroma. Patients with these tumors have a range of ages at presentation. The mean age is 53 years. The tumors, which demonstrate a female predominance, frequently behave in a non-aggressive fashion, though several cases have demonstrated nodal involvement and metastases.?

Microscopically, mucinous tubular and spindle-cell carcinoma is composed of tightly packed elongated tubules, some with a spindle-cell appearance, in a bubbly mucinous stroma. The nuclei of tumor cells tend to appear low grade and uniform. Associated foam cells and psammoma bodies are often present. Immunohistochemical staining of this tumor is positive for CK7, racemase, and RCC antigen. Genetic analyses have suggested that trisomy of chromosome 7 and 17 as well as loss of chromosomes 1, 4, 6, 8, and 13 are characteristic of this type of tumor though its genetic profile is poorly defined at present.27?

Renal translocation carcinomas?

Included in the 2004 WHO reclassification are renal translocation carcinomas, which have recently been identified as a distinct subset of renal carcinoma. These tumors were often classified as clear cell variants since they tend to form papillae lined with clear cells resembling conventional clear cell RCC. Most patients present at a young age (between late childhood and early adulthood) and are symptomatic, presenting with hematuria, flank pain, an abdominal mass, or fever. These tumors tend to be large, with the histology described above.28 Genetic analysis shows that these tumors are associated with alterations to the Xp11.2 gene. These alterations include both translocation and fusion of the genes coding for the microphthalmia transcription factor subfamily, which includes both transcription factors E3 and EB. The proteins overexpressed by these genetic alterations can be identified on immunohistochemical staining and help in diagnosing Xp11.2 translocation tumors. These tumors are rare but they tend to be aggressive, particularly when they occur in adults, and therefore need to be clearly defined.29 ?

Emerging subtypes?

Several new and emerging types of renal tumors are being identified that will most likely become part of the standard classifications of RCC. These include tumors associated with end-stage renal disease and tumors with hybrid histology.30 The clinical significance of these tumors remains to be seen and are beyond the scope of this review. ?


Our knowledge of renal tumors has expanded greatly since the first consensus conference in Mainz and those in Heidelberg and Rochester and will only continue to expand as more renal tumors are identified and evaluated. With greater knowledge of tumor genetics and immunohistochemistry, we will improve our ability to make prognoses and to target therapy appropriately to those who would benefit most. n?


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2. Jayson M, Sanders H. Increased incidence of serendipitously discovered renal cell carcinoma. Urology. 1998;51:203-205.?

3. Dhote R, Thiounn N, Debré B, Vidal-Trecan G. Risk factors for adult renal cell carcinoma. Urol Clin North Am. 200431:237-247.?

4. Ishikawa I, Saito Y, Shikura N, et al. Ten-year prospective study on the development of renal cell carcinoma in dialysis patients. Am J Kidney Dis. 1990;16:452-458.?

5. Delahunt B, Thornton A. Renal cell carcinoma. A historical perspective. J Urol Pathol. 1996;4:31-49. ?

6. Thoenes W, Störkel S, Rumpelt HJ, Moll R. Cytomorphological typing of renal cell carcinoma–a new approach. ?Eur Urol. 1990;18 Suppl 2:6-9.?

7. Störkel S, Eble JN, Adlakha K, et al. Classification of renal