Abstract

The incidence of kidney cancer is gradually increasing, with a rate of 2–3% per decade. The kidney develops various kinds of neoplasms, some of which are associated with familial cancer syndromes. Such cases have provided clues to identify the cancer-responsible genes. In 2004, the World Health Organization published a new classification system of renal neoplasms, incorporating recent knowledge obtained in the cytogenetic and molecular biological fields, i.e. genes responsible for each histologic subtype (von Hippel-Lindau for clear cell renal cell carcinoma, c-met for papillary renal cell carcinoma type 1, etc.). Subsequently, the Japanese classification system in ‘the General Rule for Clinicopathological Study of Renal Cell Carcinoma’ has been revised as the 4th edition, according to the World Health Organization system. Several novel subtypes have been introduced, i.e. mucinous tubular and spindle cell carcinoma, and Xp11.2/TFE3 translocation-associated renal cell carcinoma. Even after the publication of the classification, other novel subtypes have emerged, i.e. acquired cystic disease-associated renal cell carcinoma and tubulocystic renal cell carcinoma. Additionally, some of the subtypes seem to form families based on morphological transition, immunohistochemical features and gene expression profile. In future, the classification of renal cell carcinoma should be reorganized on the basis of molecular biological characteristics to establish personalized therapeutic strategies.

INTRODUCTION

The mortality of kidney cancer accounts for 2.2% of cancer deaths in the world and 2.4% in Japan (1). Although its incidence is not necessarily high, the kidney develops various kinds of neoplasms, some of which are associated with familial cancer syndromes (2). Among them, renal epithelial tumors encompass various malignant and benign tumors. Renal epithelial neoplasms have been considered to originate from terminally differentiated tubular epithelial cells via some cell injury followed by acquisition of stem cell properties. Depending on the specific microanatomical site of origin, each type of renal cell carcinoma (RCC) shows unique morphology and property.

In 2004, the World Health Organization (WHO) published a new classification system of renal neoplasms, incorporating recent knowledge obtained in the cytogenetic and molecular biological fields (3). In Japan, ‘General Rules for Clinical and Pathological Studies on Cancers’ have been used as the guidelines of pathological reporting of each cancer and for renal cell carcinoma, the ‘General Rule for Clinical and Pathological Studies on Renal Cell Carcinoma (RCC)’ (4). After the publication of the third edition in 1999, it has not been revised even though new morphological and molecular biological aspects have been found. In 2010, the Japanese classification system in ‘the General Rule for Clinical and Pathological Studies on Renal Cell Carcinoma (RCC)’ (4) has been revised as the fourth edition, based on the WHO system of 2004. During the improvement of the classification system, novel histologic types were introduced. The RCC associated with Xp11.2 translocations bears translocation involving the TFE3 gene, predominantly occurs in younger generations and shows relatively indolent clinical outcomes. Mucinous tubular and spindle cell carcinoma is composed of slender tubules and spindle cell fascicles with a mucinous stroma, occurs predominantly in middle-aged female, and is favorable in prognosis. Renal medullary carcinoma is so far limited in the African population bearing the sickle cell trait (5), and neuroblastoma-associated RCC is secondary malignancy occurring after treatment for neuroblastoma (6). The so-called ‘granular cell RCC’ previously used has reclassified into chromophobe, papillary RCCs and other kinds of renal neoplasms such as oncocytoma and epithelioid angiomyolipoma. As shown in Table 1, the Japanese classification system of RCC has been revised based on the WHO classification. However, there are several subtypes emerging after the publication of the most current classification, i.e. tubulocystic carcinoma, acquired cystic disease (ACD)-associated RCC, etc. (7). Further understanding of renal neoplasm requires the elucidation of relationships between these subtypes including the newly emerging subtypes thereafter.

Table 1.

Alteration in the classification of renal epithelial tumors in the ‘General Rules for Clinical and Pathological Studies on Renal CellCarcinoma’ with newly emerging subtypes and putative groups

3rd edition (1999.12.) 4th edition (2011.4) Newly emerging subtypes (modified from ref. 7Putative groups of the subtypes 
Benign adenoma 
 Papillary/papillotubular  adenoma Clear cell type RCC Tubulocystic carcinoma Clear cell RCC group 
 Oncocytoma Multilocular cystic RCC ACD-associated RCC  Clear cell RCC 
 Metanephric adenoma Papillary RCC Thyroid follicle-like carcinoma  Multilocular cystic RCC 
 Chromophobe RCC Clear cell papillary RCC  
Malignant RCC Collecting duct carcinoma of Bellini Oncocytic papillary RCC Papillary RCC group 
 Clear cell RCC Renal medullary carcinoma Leiomyomatous renal carcinoma  Papillary RCC 
 Granular cell RCC RCC associated with Xp11.2 translocations/TFE3 gene fusions RCC associated with 6p21 translocations/TFEB gene fusions  Mucinous tubular and spindle cell carcinoma 
 Chromophobe RCC RCC associated with neuroblastoma   Tubulocystic carcinoma 
 Spindle cell carcinoma Mucinous tubular and spindle cell carcinoma   ACD-associated RCC 
 Cyst-associated RCC RCC, unclassified   
 RCC derived from the cyst Papillary adenoma  Chromophobe RCC/oncocytoma group 
 Cystic RCC Oncocytoma   Chromophobe RCC 
 Papillary RCC    Oncocytoma 
 Collecting duct carcinoma  of Bellini Appendix   Hybrid oncocytic/chromophobe tumor 
  Metanephric adenoma   
Miscellaneous  Dialysis-associated renal tumors  Collecting duct carcinoma group 
 Diaysis-associated RCC  Spindle cell carcinoma   Collecting duct carcinoma of Bellini 
    Renal medullary carcinoma 
   Translocation-associated RCC groupa 
    RCC associated with Xp11.2 translocations/TFE3 gene fusions 
    RCC associated with 6p21 translocations/TFEB gene fusions 
3rd edition (1999.12.) 4th edition (2011.4) Newly emerging subtypes (modified from ref. 7Putative groups of the subtypes 
Benign adenoma 
 Papillary/papillotubular  adenoma Clear cell type RCC Tubulocystic carcinoma Clear cell RCC group 
 Oncocytoma Multilocular cystic RCC ACD-associated RCC  Clear cell RCC 
 Metanephric adenoma Papillary RCC Thyroid follicle-like carcinoma  Multilocular cystic RCC 
 Chromophobe RCC Clear cell papillary RCC  
Malignant RCC Collecting duct carcinoma of Bellini Oncocytic papillary RCC Papillary RCC group 
 Clear cell RCC Renal medullary carcinoma Leiomyomatous renal carcinoma  Papillary RCC 
 Granular cell RCC RCC associated with Xp11.2 translocations/TFE3 gene fusions RCC associated with 6p21 translocations/TFEB gene fusions  Mucinous tubular and spindle cell carcinoma 
 Chromophobe RCC RCC associated with neuroblastoma   Tubulocystic carcinoma 
 Spindle cell carcinoma Mucinous tubular and spindle cell carcinoma   ACD-associated RCC 
 Cyst-associated RCC RCC, unclassified   
 RCC derived from the cyst Papillary adenoma  Chromophobe RCC/oncocytoma group 
 Cystic RCC Oncocytoma   Chromophobe RCC 
 Papillary RCC    Oncocytoma 
 Collecting duct carcinoma  of Bellini Appendix   Hybrid oncocytic/chromophobe tumor 
  Metanephric adenoma   
Miscellaneous  Dialysis-associated renal tumors  Collecting duct carcinoma group 
 Diaysis-associated RCC  Spindle cell carcinoma   Collecting duct carcinoma of Bellini 
    Renal medullary carcinoma 
   Translocation-associated RCC groupa 
    RCC associated with Xp11.2 translocations/TFE3 gene fusions 
    RCC associated with 6p21 translocations/TFEB gene fusions 

ACD, acquired cystic disease; RCC, renal cell carcinoma.

aPossesses intimate relationship with angiomyolipoma and epithelioid angiomyolipoma.

This review aims to introduce the recent state of histopathologic classification of the renal neoplasms, especially of RCC with molecular biological features, and to provide information on the relationship between the subtypes including newly emerging ones.

CLEAR CELL RCC AND THE VON HIPPEL-LINDAU GENE

Clear cell RCC is the most common epithelial renal neoplasm, which accounts for 70–80% of RCCs. The tumor predominantly occurs in seventh and eighth decades, and the male to female ratio is 2–3:1. The classical symptomatic trias is hematuria, lumbago and lumbodorsal tumor. Radiologically, the tumor is hypervascular. Grossly, the tumor is generally well demarcated from the renal parenchyma, and characteristically yellowish white in color. Hemorrhage and necrosis are frequent.

Histologically, the clear cell RCC is composed of alveolar architectures of the tumor cells (Fig. 1). Between the tumor cell nests, fine vascular networks are observed. The tumor cells are uniform in size, and possess pyknotic and small-sized nuclei and watery clear cytoplasm. The tumor is considered to be derived from the proximal tubular epithelial cells based on the ultrastructural and immunohistochemical investigations. Immunohistochemically, the tumor cells are positive for CD10, CD15, carbonic anhydrase IX and RCC-marker, which are also positive in the proximal epithelium. Its prognosis is dependent on the pathologic stage, nuclear grades and on the presence or absence of sarcomatoid element (8).

Figure 1.

Clear cell RCC, representative histology (H&E).

Figure 1.

Clear cell RCC, representative histology (H&E).

More than half of sporadic clear cell RCC possesses molecular abnormalities of the von Hippel-Lindau (VHL) tumor suppressor gene (9–12), of which product protein negatively regulates hypoxia-inducible factor (HIF) via ubiquitin-proteasome-mediated degradation (13). Subsequently, HIF and the downstream molecules, vascular endothelial growth factor (VEGF) and platelet-derived growth factor show excessive function in clear cell RCC to cause abnormally enhanced angiogenesis (Fig. 2). Therefore, the suppression of angiogenesis via the VHL-HIF-VEGF pathway is expected to provide a sophisticated therapeutic strategy of clear cell RCC (14). Based on this fact, sorafenib and sunitinib are reported to improve the survival periods comparing those in the cytokine era (15). Simultaneously, HIF enhances the transcription of GLUT-1, erythropoietin and CXCR4 chemokine receptor genes, resulting in the formation of glycogen-rich clear cytoplasm, paraneoplastic polycythemia and increased tumor cell motility, respectively (Fig. 2B). These events can interpret the characteristics of clear cell RCC.

Figure 2.

The function of pVHL. (a) The physiological function of pVHL. Under a normoxic condition, pVHL forms a ubiquitin ligase complex with elongin B, elongin C, Cul2 and VBP to degrade HIFs 1α and 2α to suppress unnecessary cellular response to hypoxia. Under a hypoxic condition, pVHL and the partners do not degrade the HIFs. HIFs 1α or 2α forms a heterodimeric transcription factor with constitutively expressed HIF1β to induce hypoxic response. (b) In the cases of VHL-mutated RCCs, truncated pVHL failed to form a ubiquitin ligase complex and hypoxic response is constitutively accelerated. Accordingly, abnormal angiogenesis and polycythemia are induced by abnormally expressed VEGF and erythropoietin, respectively.

Figure 2.

The function of pVHL. (a) The physiological function of pVHL. Under a normoxic condition, pVHL forms a ubiquitin ligase complex with elongin B, elongin C, Cul2 and VBP to degrade HIFs 1α and 2α to suppress unnecessary cellular response to hypoxia. Under a hypoxic condition, pVHL and the partners do not degrade the HIFs. HIFs 1α or 2α forms a heterodimeric transcription factor with constitutively expressed HIF1β to induce hypoxic response. (b) In the cases of VHL-mutated RCCs, truncated pVHL failed to form a ubiquitin ligase complex and hypoxic response is constitutively accelerated. Accordingly, abnormal angiogenesis and polycythemia are induced by abnormally expressed VEGF and erythropoietin, respectively.

Multilocular cystic RCC is composed of tumor cells with clear cytoplasm lining the delicate cystic walls. This subtype is considered as a variant of clear cell RCC based on the cellular morphology and frequent VHL mutation. Multilocular cystic RCC is distinguished from conventional clear cell RCC, because of its indolent behavior and excellent clinical outcomes (16). Consequently, excessive treatment should be avoided for this subtype, unlike conventional clear cell RCC.

PAPILLARY RCC AND RELATED SUBTYPES

Papillary RCC is defined as a subtype of RCC, in which papillary architectures is a predominant component. This subtype is considered to relate with newly emerging subtypes, mucinous tubular spindle cell carcinoma, tubulocystic carcinoma and ACD-associated RCC, mainly based on the cDNA expression profiling and immunohistochemistry.

Papillary RCC accounts for 7–15% of all the RCC. The age of the patients are similar to clear cell RCC (52–66 years old) and the male to female ratio is 1.8–3.8:1. The initial symptom is also similar to clear cell RCC, and frequently detected with abdominal ultrasonography during health check-up (17).

Grossly, the tumor is well demarcated from the renal parenchyma. The capsule might be thick and firm. The cut surface is golden yellow and muddy. Hemorrhage and necrosis are frequent.

Microscopically, the tumor is predominantly composed of papillary architectures of tumor cells as its definition. The cores contain small blood vessels and fibrous tissue. According to the cellular atypism, papillary RCC is subclassified into two subtypes, that is, type 1 and type 2 (18). Tumor cells of type 1 papillary RCC are small in size, and possess small round nuclei and pale to basophilic cytoplasm (Fig. 3a). The nuclear atypism is mild. Tumor cells are arranged in a monolayered manner. In contrast, tumor cells of type 2 are moderate to large in size, and possess larger nuclei with marked atypism and eosinophilic cytoplasm (Fig. 3b). The tumor cells are arranged in a pseudostratified manner. Type 2 tumor shows more unfavorable clinical outcomes than type 1 (17,18).

Figure 3.

Papillary RCC type 1 (a) and type 2 (b), and of probably relating subtypes (c–e), representative histology. (c) Mucinous tubular and spindle cell carcinoma. (d) ACD-associated RCC. (e) Tubulocystic RCC. The tumor is composed of various-sized cysts lined with tumor cells (H&E).

Figure 3.

Papillary RCC type 1 (a) and type 2 (b), and of probably relating subtypes (c–e), representative histology. (c) Mucinous tubular and spindle cell carcinoma. (d) ACD-associated RCC. (e) Tubulocystic RCC. The tumor is composed of various-sized cysts lined with tumor cells (H&E).

Immunohistochemically, the tumor cells are characteristically positive for α-methyl acyl CoA racemase (AMACR) and CD10 (19). Generally, papillary RCC shows the immunophenotypes resembling the proximal tubular epithelial cells. Cytogenetically, trisomy or tetrasomy 7, trisomy 17 and loss of Y chromosome are characteristic to papillary RCC. Additionally, familial type 1 cancer is reported to bear gain-of-function mutation of c-met and familial type 2 loss-of-function mutation of fumarate hydratase (FH) gene (20).

Mucinous tubular and spindle cell carcinoma (MTSCC) is a newly introduced subtype. MTSCC occurs predominantly in middle aged to elderly females. Most of the cases are detected incidentally. Radiologically, the tumor is well demarcated and hypovascular, without necrosis or hemorrhage.

Grossly, the tumor is well demarcated, and elastic to firm in consistency. The cut surface is milky white and homogenous in color. Hemorrhage and necrosis are absent.

MTSCC is composed of tubular architectures of cuboidal epithelial cells and fascicles of spindle cells. The tumor cells possess small round nuclei and scanty clear cytoplasm (Fig. 3c). Generally, its prognosis is favorable, except for few cases. Because the tumor cells partly possess immunophenotypes similar to those of the distal tubular and collecting ductal epithelial cells, MTSCC is initially referred as low-grade collecting duct carcinoma. However, cDNA profiling indicates an intimate relationship with papillary RCC. Additionally, similar immunophenotypes including positivity with AMACR has been reported (21,22), although different karyotypic abnormalities between them have been also observed (23).

The clinical outcomes are generally favorable. Consequently, pathological diagnosis should be precise to avoid excessive treatment. However, there are several case reports of aggressive cases of MTSCC (24).

In patients with long-term hemodialysis, the morbidity of RCC increases from 5- to 6-folds, comparing with non-dialysis patients. The ages of initial diagnosis are younger by 5–10 years, comparing with non-dialysis group. The male-to-female ratio is 5–6:1. Characteristically, the kidneys present marked parenchymal atrophy with multiple cysts, the so-called ACD of the kidney. Together with the unusual histology, dialysis-associated RCC is considered to possess a unique carcinogenic mechanism and clinicopathological characteristics to be clarified (25). Tickoo et al. (26) reviewed 261 tumors occurring in end-stage renal disease cases. They reported that approximately half of the cases examined could be classified into the subtypes listed in the WHO classification. The rest of the cases were classified into two groups: (1) ACD-associated RCC composed of solid and microcystic architectures of granular tumor cells (Fig. 3d) and (2) clear cell-papillary RCCs (not described in this review). At least, ACD-associated RCC seems to bear chromosomal abnormalities different from the other RCC subtypes (27). Several gene profile studies on ACD-associated RCC revealed features similar to papillary RCC, as well as morphologic transition and immunohistochemical similarities (AMACR and CK7).

Tubulocystic RCC, a new subtype not included in the recent classification, forms a well-circumscribed mass composed of pure tubular and cystic architectures. The wall of the tubules and cysts are lined with tall columnar epithelial cells (Fig. 3e). Their nuclei are large with prominent nucleoli and the cytoplasm is eosinophilic and granular (28). Immunohistochemically, the tumor cells are positive for AMACR and CK7, like papillary RCC. Originally, this subtype had been recognized as low-grade collecting duct carcinoma as presented in the atlas published by the Armed Forces Institute of Pathology (29). Generally, this subtype usually occurs in patients older than 60 years (34–94 years old) with a strong male predominance (7:1).

Described as above, the papillary RCC is a prototype of a larger family of subtypes. Actually, composite tumors are reported, which possess a papillary RCC element with gradual transition to mucinous tubular and spindle cell carcinoma as well as to tubulocystic carcinoma. ACD-associated RCC has been diagnosed as ‘papillary RCC’, but frequently histological transition to papillary RCC is noted.

CHROMOPHOBE RCC AND ONCOCYTOMA

Chromophobe RCC accounts for ∼5–10% of RCC, and characteristically possesses cloudy and reticular cytoplasm. Since the first report in human by Thoenes et al. (30), investigators have clarified different characteristics of chromophobe RCC from the clear cell RCC.

The chromophobe RCC occurs in somewhat younger generation, comparing with clear cell RCC. Male and female are equally involved. Clinical presentation is mainly renal tumor detected with ultrasonography on routine health check-up. However, abdominal palpable tumor might be an initial presentation, because of its huge size.

Grossly, the tumor is generally well demarcated from the surrounding parenchyma, and forms a large homogenous mass with beige color. Necrosis or hemorrhage is scarce.

Histologically, the tumor is composed of solid cell sheets, trabecular and glandular architectures of the tumor cells. The tumor cells are large in size and polygonal in shape. The cytoplasmic rims are accentuated to give a ‘plant cell-like’ appearance. The nuclei are irregular in configuration, which are frequently referred as ‘raisin like (rasinoid)’. Characteristically, the cytoplasm is weakly eosinophilic and cloudy or reticular (typical variant). Occasionally, tumor cells with eosinophilic granular cytoplasm (eosinophilic variant) might be intermingled. Eosinophilic variant frequently gives difficulties in differential diagnosis between oncocytoma. Although the nuclei are scored as high grade in atypism, chromophobe RCC possesses a more favorable prognosis than clear RCC (31) (Fig. 4a). However, chromophobe RCC is known to develop a sarcomatoid change in a higher frequency than the other subtypes (32,33). The tumor cells are diffusely positive for colloid iron staining. Ultrastructurally, the cytoplasm is filled with numerous microvesicles probably derived from mitochondrial membrane. In eosinophilic variant, mitochondria are more abundant.

Figure 4.

Chromophobe RCC and oncocytoma. (a) Chromophobe RCC, representative histology. (b) Oncocytoma, representative histology (H&E).

Figure 4.

Chromophobe RCC and oncocytoma. (a) Chromophobe RCC, representative histology. (b) Oncocytoma, representative histology (H&E).

Immunohistochemically, the tumor cells are positive for epithelial membrane antigen (EMA), E-cadherin (34) and c-KIT (35,36). These markers are positive in those of the distal tubular and collecting ductal epithelial cells, which are the origin of chromophobe RCC.

Chromophobe RCC shows non-random multiple chromosome loss (37). The gene responsible for chromophobe RCC is not identified. The FCLN gene, responsible for Birt-Hogg-Dubé syndrome, is a candidate (described later) (38). Several studies have been performed on the alteration of the FCLN gene in renal neoplasms, but the results are not consistent (39).

Oncocytoma is a benign neoplasm of the kidney, which is composed of solid cell sheets of uniform and round tumor cells. The cytoplasm is characteristically eosinophilic and granular.

The patients of oncocytoma show a peak in the seventh decade. The gender deviation has not been described. Most of the cases are incidentally found during abdominal ultrasonography during health check-up. Radiologically, the tumor presents a spoke-wheel like vasculature on angiography. All the cases are successfully treated by radical or partial nephrectomy.

Grossly, the tumor is well demarcated from the renal parenchyma without capsule formation. The cut surface is mahogany in color with a frequent central scar.

Microscopically, the tumor is composed of cell nests with an edematous stroma. The tumor cells are uniform and small in size. Notably, their cytoplasm is characteristically eosinophilic and granular (Fig. 4b), which coincide with numerous mitochondria. The immunohistochemical characteristics of the tumor cells show positivities for E-cadherin, c-kit and mitochondrial antigen, similar to those of chromophobe RCC (reviewed in ref. 40)

Because of various similar features, differential diagnosis between chromophobe RCC and oncocytoma is frequently challenging. The pathobiological features shared by these tumors (13) are as follows: (i) morphological similarities, i.e. eosinophilic and granular cytoplasm, (ii) mitochondrial abnormalities are suggested, i.e. vesicles probably derived from the mitochondria in chromophobe RCC and numerous mitochondria present in oncocytoma, (iii) similar lectin histochemical and immunohistochemical results (34) and (iv) mitochondrial DNA alteration reported by some investigators (41). To make a differential diagnosis of these two, the notable points were listed in Table 2.

Table 2.

Differential diagnosis between chromophobe RCC and oncocytoma (ref. 3,31,34)

 Chromophobe RCC Oncocytoma 
Gross findings Beige, homogenous Mahogany, central scar 
Microscopic findings 
 Architecture Solid sheet-like, tubular, cystic Alveolar, organoid, solid, tubular 
 Nuclei Cleaved, rasinoid Round 
 Cell boundary Definite Obscure 
 Stroma Hypovascular Edematous or hyalinized 
 Colloidal iron stain Diffusely positive Negative or positive limited to the apical surface 
Immunohistochemistry   
 CD82 Positive Negative 
 CK7 Diffusely positive Focally positive or negative 
 S100A1 Negative Positive 
Electron microscopy Numerous microvesicles Abundant mitochondria 
 Cytogenetics Multiple chromosome loss Normal; deletion #1 and/or #14; translocation involving #11q12–13 
 Chromophobe RCC Oncocytoma 
Gross findings Beige, homogenous Mahogany, central scar 
Microscopic findings 
 Architecture Solid sheet-like, tubular, cystic Alveolar, organoid, solid, tubular 
 Nuclei Cleaved, rasinoid Round 
 Cell boundary Definite Obscure 
 Stroma Hypovascular Edematous or hyalinized 
 Colloidal iron stain Diffusely positive Negative or positive limited to the apical surface 
Immunohistochemistry   
 CD82 Positive Negative 
 CK7 Diffusely positive Focally positive or negative 
 S100A1 Negative Positive 
Electron microscopy Numerous microvesicles Abundant mitochondria 
 Cytogenetics Multiple chromosome loss Normal; deletion #1 and/or #14; translocation involving #11q12–13 

#, chromosome.

Recent reports demonstrated the existence of hybrid tumor containing elements of chromophobe RCC and oncocytoma (42). Furthermore, both tumors develop in BHD syndrome, an autosomal dominant-inherited familial tumor syndrome, which shows fibrofolliculoma of the head and neck, spontaneous pneumothorax caused by the rupture of pneumatocele and multiple renal tumors (43). The responsible gene, Folliculin, FLCN is a tumor-suppressor gene located in chromosome 17p11.2, encoding a protein named as folliculin (38). Although the exact roles of folliculin in renal carcinogenesis remains to be elucidated, recent studies revealed that folliculin is involved in AMPK and mTOR signaling pathways, and that artificial Flcn inactivation in the murine kidney generates severe polycystic changes in the kidney (44,45). Considering these facts, FCLN mutation in this case caused abnormal cell growth in the kidney resulting in renal epithelial tumors. Consequently, the FLCN gene is expected to play some role in the development of chromophobe RCC and oncocytoma (46).

TRANSLOCATION-ASSOCIATED RCCS

Recently, RCCs occurring in the childhood and young generation are known to bear characteristic chromosomal translocations involving transcription factor enhancer genes, TFE3 on Xp11.2 and TFEB on 6p21.

The Xp11.2/TFE3 translocation-associated RCCs are mostly composed of papillary or nested patterns of the tumor cells with clear and weakly eosinophilic cytoplasm. The nuclear atypism is higher than conventional clear cell RCC. Microcalcification and psammoma bodies are frequent (Fig. 5a). Radiologically, these tumors are hypovascular. Their prognoses are reported to be mostly indolent even though their clinical stage might be advanced. However, it could be aggressive, especially when occurring in elderly patients (47).

Figure 5.

Translocation-associated RCCs. (a) RCC associated with Xp11.2 translocations/TFE3 gene fusions, representative histology and (b) 6p21/TFEB translocation-associated RCC. Note the microcystic structure containing smaller cells with matrix substance.

Figure 5.

Translocation-associated RCCs. (a) RCC associated with Xp11.2 translocations/TFE3 gene fusions, representative histology and (b) 6p21/TFEB translocation-associated RCC. Note the microcystic structure containing smaller cells with matrix substance.

Although this kind of tumors has been diagnosed as clear cell RCC or papillary RCC (see bellows), Argani et al. (48) reported that these tumors bear chromosomal translocation involving #Xp11.2 and several kinds of partners (Table 3). As the results of translocation, TFE3 fuses with ASPS/PRCC17, PMF and CLTC. In cases of inversion, a fusion gene, TFE3-NonO is generated. TFE3-ASPS/PRCC17 is also formed in the alveolar soft part sarcoma, a malignancy occurring in the limb skeletal muscle of the young generation (49). Whatever the partner gene is, the fusion gene product (chimeric protein) has a sustained turnover than the native TFE3 protein. Subsequently, immunohistochemical staining for TFE3 shows nuclear staining in the translocation RCCs, which is a diagnostic hallmark of TFE3-translocation RCCs as well as in alveolar soft part sarcoma (50).

Table 3.

Translocations identified in Xp11.2/TFE3- and 6p21/TFEB-translocation-associated RCCs (ref. 47–52)

Translocation Resultant fusion genes 
t(X;17)(p11.2;q21.2) PRCC-TFE3 
t(X;1)(p11.2;p34) PSF-TFE3 
t(X;17)(p11.2;q25.3) ASPL/RCC17-TFE3 
t(X;17)(p11.2;q23) CLTC-TFE3 
inv(X)(p11.2;q12) NonO-TFE3 
t(6;11)(p21:q13) TFEB-α 
Translocation Resultant fusion genes 
t(X;17)(p11.2;q21.2) PRCC-TFE3 
t(X;1)(p11.2;p34) PSF-TFE3 
t(X;17)(p11.2;q25.3) ASPL/RCC17-TFE3 
t(X;17)(p11.2;q23) CLTC-TFE3 
inv(X)(p11.2;q12) NonO-TFE3 
t(6;11)(p21:q13) TFEB-α 

On the other hand, RCC with t(6;11)(p21.1;q12) chromosome translocation generates the TFEB (transcription factor enhancer B)—α fusion gene (51,52). TFE3 and TFEB form a transcription factor family together with the microphthalmia transcription factor (MiTF) and TFEC, called the MiTF/TFE transcription factor family. Therefore, these translocation-associated RCCs seem to have an intimate relationship with each other (53). This subtype is composed of papillary or solid architectures surrounding the basement membrane-like matrix in the center. The tumor cells show the so-called biphasic morphology, that is, larger and smaller ones. The larger cells possess large vesicular nuclei and voluminous clear cytoplasm and the smaller cells small round nuclei and scanty cytoplasm similar to that of lymphocytes (Fig. 5b). Immunohistochemically, the tumor cells show aberrant nuclear positivity for TFEB protein and cytoplasmic positivity for cathepsin K (54). Characteristically, the tumor cells frequently present positivity for melanoma markers, i.e. melanosome-associated antigen (detected by HMB45 antibody), but negativity for epithelial markers, i.e. cytokeratin and epithelial membrane antigen (55,56). Although its prognosis is generally indolent, more cases should be evaluated before a conclusion is established.

Both TFE3 and TFEB belong to a transcription family, MiTF/TFE family. MiTF is the master regulator of melanocyte differentiation. Together with the positive reaction with HMB45 (an antibody raised against a melanosome-associated antigen) and positivities of melanocyte markers (Melan A, tyrosinase, MiTF), the translocation-associated RCCs seem to possess some relationship with melanoma. Furthermore, melanotic cases have been reported.

On the other hand, angiomyolipoma and epithelioid angiomyolipoma are non-epithelial tumors, which are frequently associated with tuberous sclerosis (TSC) and bears the aberrations of TSC-responsible genes, TSC-2 and TSC-1. They are known to be positive for melanocyte markers. Whereas the former is composed of dysmorphic thick-walled blood vessels, leiomyomatous spindle cells and mature fat, the latter purely composed of highly atypical polygonal cells with epithelioid arrangements, mimicking carcinoma. Therefore, some of epithelioid angiomyolipoma is considered to be misdiagnosed as high-grade RCC, before the establishment of epithelioid angiomyolipoma by Eble et al. (53). Both conventional and epithelioid angiomyolipoma show immunoreactivities with melanocyte markers, i.e. melanosome-associated antigen detected by HMB45, MiTF, Melan A and tyrosinase (55). Interestingly, TFE3- and TFEB-translocation-associated RCCs are composed of polygonal cells with an epithelioid arrangement, which mimic epithelioid angiomyolipoma. Translocation-associated RCCs occasionally show melanin production and deposition as well as epithelioid angiomyolipoma. Together with the morphological findings and similar immunohistochemical natures, epithelioid angiomyolipoma and translocation-associated RCCs might form a disease family, which should be evaluated in future.

CONCLUSION

Recent advances in molecular biology have altered the classification of renal epithelial tumors. Especially, excessive function of HIF-VEGF pathway provides a molecular target therapy for clear cell RCC. For other subtypes, tailored medicine will be established.

Whether all the tumors with a specific gene abnormality show same morphology should be elucidated in future. If the common pathway is involved, different kinds of tumors could develop. For example, abnormalities both of TSC2 and of FCLN are expected to cause excessive function of the mTOR pathway. However, the former causes angiomyolipoma and epithelioid angiomyolipoma, whereas the latter causes chromophobe RCC, oncocytoma and hybrid chromophobe/oncocytic tumor.

Finally, tumors with low-grade malignancy have emerged (mucinous tubular and spindle cell carcinoma, ACD-associated RCC, tubulocystic RCC), for which excessive treatment should be avoided. For renal epithelial tumors, precise histological diagnosis is required based on the molecular biological knowledge to establish individualized therapeutic strategies.

Funding

Our original works cited in this review were supported by grants-in-aid from the Japanese Ministry of Education, Culture, Sports and Science and from the Yokohama Foundation for Promotion of Medicine.

Conflict of interest statement

None declared.

Acknowledgements

The authors acknowledge Ms Tamiyo Taniguchi and Sayuri Kanaya for their assistance.

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