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