Chromophobe renal cell cancer - review of the literature and potential methods of treating metastatic disease

Renal cell carcinoma (RCC) is rather a rare neoplasm (in Poland about 3% of all tumors). According to the most recent National Cancer Register in Poland, 2150 men and 1501 women were diagnosed with renal cancer in 2004 [1].

Approximately 200,000 new cases of RCC are diagnosed annually worldwide, while the number of deaths caused by RCC approaches 100,000. Cure can be obtained in 70-90% of patients in the TNM stage I, in 55-70% of patients in stage II, in 20-30% of patients in stage III, and in less than 10% in stage IV [2].

The 2004 World Health Organization (WHO) classification of RCC recognized several subtypes of RCC. Most common subtypes are: clear cell RCC (70%), papillary RCC (10-15%), chromophobe RCC (4-6%), collecting duct carcinoma (about 1%) and unclassified RCC (4-5%) [3, 4].

Chromophobe RCC (ChRCC) is diagnosed mainly in 6th decade of life. An incidence of ChRCC is similar in both men and woman [5]. 86% of ChRCCs are diagnosed in stage 1 or 2 [3]. Renal vein invasion is seen in about 5% of cases [5].

Incidence of metastatic disease in chromophobe renal cell carcinoma is 6-7% [6, 7].

In summary of 28 cases based on 7 reports, most common metastatic sites were liver (39%) and lung (36%) [6].

Chromophobe RCC was first described in patients by Thoenes in 1985 [8].

Macroscopically, ChRCC is a solitary, circumscribed, and not capsulated mass with a homogeneous light brown cut surface. The median tumor size of ChRCC is 6.0 cm, and it is larger than that of other subtypes [7].

Microscopically, it contains of large, polygonal cells with prominent cell membrane [5]. Cytoplasm is pale and resistant to staining with hematoxylin and eosin. ChRCC cells have irregular nuclei with perinuclear clear halo. The tumor blood vessels have thick walls and are eccentrically hyalinized [3].

Chromophobe RCC is a heterogeneous group including classic type, eosinophilic type and mixed type. Eosinophilic variant (containing greater than 80% eosinophilic cells) has areas similar to renal oncocytomas (nested, alveolar or sheetlike architecture with eosinophilic granularity, perinuclear clearing, peripheral accentuation of cytoplasm) and it is often bilateral (11%) and multifocal (22%). Classic type of chromophobe RCC (containing greater than 80% pale cells) is associated with necrosis or sarcomatoid change. It has alveolar or sheetlike architecture and cytoplasm with flocculent "soap-bubble" appearance. Chromophobe RCCs with mixed histology have variable architecture (containing admixture of pale and eosinophilic cells) [6].

Microscopic tumor necrosis and sarcomatoid change are known to be aggressive with a high potential for distant metastases [6].

One of the diagnostic criteria of ChRCC is Hale colloidal iron [5], another are intracytoplasmatic microvesicles between 250-400 nm in diameter [9] (Figure 1- Chromophobe renal cell carcinoma, HE, 200×; Figure 2 - Positive reaction showing the presence of colloidal iron in cytoplasm of ChRCC, 400×).

They can be demonstrated by electron microscopy, which is not used routinely in diagnosis of chromophobe RCC.

The main diagnostic criteria of chromophobe RCC is morphology coupled with characteristic immunophenotype (diffuse CK7, and KIT positivity).

Prognosis in ChRCC is better than in other types of RCC. Five- and 10-year DFS for chromophobe RCC was 83.9% and 77.9%, respectively [12]. The median time from nephrectomy to metastasis detection, and from metastasis detection to death were twice as long for ChRCC than for other subtypes of RCC (papillary, clear cell RCC) [7].

In univariate analysis: sarcomatoid change (p < 0.001), microscopic necrosis (p = 0.019), tumor size (p = 0.025), pT stage (3.4 vs. 1.2; p = < 0.001), broad alveolar growth (p = 0.012), vascular invasion (p = 0.020), and Fuhrman nuclear grade (grade 4 vs.3 vs 2; p < 0.001) were associated with aggressive ChRCC behavior. Independent predictors (Multivariable Cox Regression) of aggressive ChRCC included: pT stage (pT 3.4 vs. pT 1.2; p = 0.025, relative hazard 3.4), sarcomatoid change (p = 0.013, relative hazard 4.7) and microscopic necrosis (p = 0.020, relative hazard 3.5) [6]. Other factors like: age, sex, histologic subtyping by clear, eosinophilic or mixed cell types, tubulocystic pattern, degenerate or symplastic atypia were not predictors of chromophobe RCC behavior.

The patients with aggressive phenotype of chromophobe RCC may be candidates for adjuvant therapies as they become available [6].

ChRCCs are hyperechogenic in ultrasound examination, CT imaging or MRI demonstrate homogeneous enhancement. A spoke-wheel pattern of contrast enhancement is characteristic for ChRCC and for onkocytoma [13]. Most of ChRCCs are sporadic, but sometimes they are associated with BHD (Birt-Hogg-Dubè) syndrome [14].

BHD syndrome is an autosomal dominant disorder that includes: benign skin tumor (skin tags, fibrofolliculomas), renal epithelial neoplasms (ChRCC, oncocytoma) and spontaneous pneumothorax. Renal tumors are often multifocal and bilateral. BHD gene encodes potential tumor suppressor protein - folliculin on 17p11 [15].

ChRCCs is characterized by length polymorphism such as loss of chromosomal material involving chromosomes: 1, 2, 3p, 6, 10, 13, 17p, 17q and 21 [16, 17]. It may be helpful in distinguishing between clear, papillary and chromophobe subtypes of RCC.

KIT (CD117) is a type III receptor tyrosine kinase that plays a role in intracellular signal transduction in several cell types. It regulates apoptosis, cell differentiation, proliferation, chemotaxis, and adhesion. Pathologic activation of KIT through gain-of-function mutations leads to neoplasia of KIT-dependent and KIT-positive cell types in different systems: Cajal cells - gastrointestinal stromal tumors (GISTs), myeloid cells - myeloid leukemia. In addition, many tumors have positive KIT immunoreactivity: small cells carcinomas, adenoid cystic carcinoma, chromophobe, thymic and sometimes ovarian and breast carcinomas [18].

In normal tissue of kidney KIT showed weak immunoreactivity only in the cytoplasm of distal tubules [19]. From all RCCs, KIT gene product was detected (overexpression) in membrane of cells ChRCC (88-100%) [19, 20]. This is in agreement with histogenetic origin of chromophobe RCC from distal tubules.

KIT expression in classic variant is more often than eosinophilic variant (82% vs. 67%) [21].

Thus, immunohistochemical detection of KIT expression appears to be useful in diagnosis and treatment of ChRCC.

Yamazaki et al. reported upregulation of c-kit gene expression in ChRCCs. The mechanism for the overexpression of KIT in ChRCC is unknown. They suggested that the KIT signal pathway in ChRCCs could be activated in an autocrine way [19]. In summary 70 cases, based on 4 reports investigators were unable to detect activating mutations within exon 17 of the c-kit gene [19–22]. Absence of c-kit mutation could be argue for potential effectiveness of imatinib therapy in patients with metastatic ChRCCs.

Now we have three potentially active and targeted agents against CD 117: imatinib, dasatinib and nilotinib.

Currently, we do not have any effective treatment for the metastatic disease apart from surgical procedures. Overexpression of CD117 on cellular membranes of ChRCC could be a potential target for kinase inhibitors like: imatinib, dasatinib, nilotinib. The potential targets for other kinase inhibitors (sunitinib and sorafenib) in ChRCC seem to be VEGFR and PDGFR. In conclusion, these observations are the basis for formulating research hypotheses which should be verified in prospective studies.