Hereditary Renal Cancer 239 15 Hereditary Renal Cancer Toshiyuki Miyazaki and Mutsumasa Takahashi CONTENTS 15.1 Introduction 15.1 Introduction 239 15.2 Histologic Subtypes of Renal Cancer 240 15.3 von Hippel-Lindau Disease 241 Renal cancer is diagnosed in over 30,000 Ameri- 15.3.1 Clinical Features 241 cans each year, accounting for approximately 15.3.2 Genetics 243 12,000 deaths annually. Smoking, obesity, and occu- 15.3.3 Imaging and Management 243 pational exposure have been implicated in the devel- 15.4 Hereditary Papillary Renal Cancer 248 opment of renal cancers but, in general, their cause 15.4.1 Clinical Features 248 Moyad 15.4.2 Genetics 248 remains obscure ( 2001). Although heredi- 15.4.3 Imaging and Management 249 tary renal cancer makes up only about 4% of the 15.5 Hereditary Leiomyoma Renal Cell Carcinoma 249 total number of cases, this percentage is expected 15.5.1 Clinical Features 249 to increase as a more complete understanding of 15.5.2 Genetics 250 the genetic causes of cancer is elucidated (Gago- 15.5.3 Imaging and Management 250 Dominguez 15.6 Birt-Hogg-Dubé Syndrome 251 et al. 2001). 15.6.1 Clinical Features 251 Increasing knowledge of hereditary renal cancer 15.6.2 Genetics 251 syndromes has provided insights into the mecha- 15.6.3 Imaging and Management 251 nisms of cancer development in the general popula- 15.7 Familial Renal Oncocytoma 252 tion and has assisted efforts to prevent and treat renal 15.7.1 Clinical Features 252 cancers. These cancers include von Hippel-Lindau 15.7.2 Genetics 252 15.7.3 Imaging and Management 252 disease, hereditary papillary renal cancer, hereditary 15.8 Medullary Carcinoma of Kidney 253 leiomyoma renal cell carcinoma, Birt-Hogg-Dubé 15.8.1 Clinical Features 253 syndrome, hereditary renal oncocytoma, familial 17.8.2 Genetics 253 renal oncocytoma, medullary carcinoma of kidney, 17.8.3 Imaging and Management 253 and tuberous sclerosis (Table 15.1; Choyke at al. 15.9 Tuberous Sclerosis 253 15.9.1 Clinical Features 253 2003). The most common cell type in renal cancer 15.9.2 Genetics 253 is the clear cell carcinoma, followed by papillary 15.9.3 Imaging and Management 254 (types 1 and 2), chromophobe carcinoma, and onco- 15.10 Translocation of Chromosome 3 254 cytoma (Amin et al. 2002). Medullary carcinoma and 15.11 Familial Renal Cancer 254 duct of Bellini cancers are rare. Over the past 5 years, 15.12 Conclusion 254 References 255 hereditary renal cancer syndromes have been associ- ated with one or more of these cancer cell types. Many of the genes responsible for these syn- dromes have been discovered and research is under- way to explain the molecular pathways that guide tumor development. A more complete picture of the mechanisms underlying the development of tumors of varying cell types is emerging. T. Miyazaki, MD Hereditary cancers are typically multifocal and Chairman, Department of Radiology, Arao City Hospital, 2600 bilateral, and the radiologist is often the first to raise Arao, Arao city 864-0041, Japan M. Takahashi, MD the possibility of a hereditary cause for a particular Emeritus Professor, Department of Radiology, Kumamoto renal cancer (Table 15.2). It is therefore important University, International Imaging Center, 1-2-23 Kuhonji, to be familiar with the expanding list of diseases Kumamoto city 862-0976, Japan known to predispose to renal cancers. 240 T. Miyazaki and M. Takahashi 15.2 Histologic Subtypes of Renal Cancer Before considering the individual hereditary renal cancer syndromes, it is important to review the char- bromas of skin, of skin, bromas acteristics of the different cell types of renal cancer. Renal cancers can be subclassified into a variety of cell types (Fig. 15.1; Storkel et al. 1997). Clear cell carcinomas are the most frequent type of renal cancer, accounting for approximately 75% angiomas, pancreatic cysts, neuro- cysts, pancreatic angiomas, endocrine of tumors the pancreas, pheochromocytoma mothoraces CNS tubers, angiofi CNS tubers, rhabdomyomas cardiac of renal cancers. The term “clear cell carcinoma” encompasses the clear cell variant, the granular cell et al. 2003) et al. variant, and mixed cell types. The high glycogen content within the cytoplasm of clear cell cancer Choyke cells accounts for their lucent appearance on con- ventional histologic stains. When glycogen is less abundant, the cytoplasm is darker and the cells are termed “granular.” A delicate but rich and perme- able vascular supply is often seen throughout these tumors, although regions of necrosis, fibrosis, or hemorrhage are avascular or hypovascular. Clear Other renal tumor types tumor Other renal abnormalities Associated Clear cell, papillary, oncocytoma papillary, Clear cell, pneu- cysts, lung Fibrofolliculomas, chromophobe, oncocytomachromophobe, cell carcinomas are thought to arise from the proxi- mal tubular epithelium of the kidney. The second leading type of renal cancer is termed “papillary,” or sometimes “chromophil,” renal cancer, and accounts for 10–15% of all renal cancers. There are two subtypes of papillary renal cell carcinoma, types 1 and 2, which are distinguished by tumor archi- tecture and cellular morphology. Both types share a Predominant renal tumor tumor renal Predominant type neoplasm hepatocyte growth factor. (With permission from permission from (With hepatocyte growth factor. common papillary structure: a fibrovascular core with HGF tumor cells lining the surface of each papilla (Fig. 15.1; Kovacs et al. 1997). Type 1, or basophilic renal cancer, usually is considered clinically low grade and has a Frequency Frequency of cancer (%) 15–302 type Papillary None leiomyomas and uterine Cutaneous 1–2 Clear cellfavorable papillary, angiomyolipoma, Cysts, prognosis. This tumor is composed of fronds of fibrovascular papillary and tubular structures cov- ered by cells with scanty cytoplasm and small oval nuclei. Foamy macrophages, which are thought to represent a host immune response, are often present central nervous system, nervous system, central within the interstitium, and psammoma bodies also CNS are frequently present. Despite the apparent vascular- ity on histology, type 1 papillary renal tumors typically enhance poorly on CT or during renal angiography. product) 1q42-43, “FH,” (fumarate “FH,” 1q42-43, hydratase) 16p13 “TSC2,” (tuberin) 16p13 “TSC2,” Type 2 papillary tumors, or eosinophilic renal cancers, bear a superficial resemblance to type 1 tumors in that the basic frond-like architecture is present but they may not be related at a biologic level. Type 2 papillary renal cancers consist of papillae covered by large cells with abundant eosinophilic cytoplasm and large nuclei with prominent nucleoli. Type 2 papillary tumors Hereditary renal cancers in adults. in adults. cancers renal Hereditary often are more clinically aggressive than type 1 papil- lary tumors and can enhance more intensely. Papillary tumors also are thought to arise from the proximal Table 15.1. Table Syndrome (gene name,” “gene Gene, von Hippel-Lindau disease Hippel-Lindau von (pVHL)“VHL,” 3p26, 28–45 Clear cell Cysts retinal CNS hemangioblastomas, Birt-Hogg-Dubé syndromeBirt-Hogg-Dubé (folliculin)“BHD,” 17p11.2, 8–15 oncocytic Chromophobe, Hereditary papillaryHereditary cancer renal receptor) (HGF “c-MET,” 7q34, 19 cell renal leiomyoma Hereditary carcinoma Papillary type1 oncocytoma renal Familial Unknown None Unknown Oncocytoma None None dysfunction Renal Medullary carcinoma of kidney carcinoma Medullary sclerosisTuberous 11p (hamartin) “TSC1,” 9q34 tubular epithelium. Unknown carcinoma Medullary None Sickle trait cell Hereditary Renal Cancer 241 Table 15.2. Summary of six patients with renal cell carcinoma in von Hippel-Lindau disease. ML multilocular, UL unilocular, CNS central nervous system, ND not detected Case no./ Pathologic find- Structure Size (cm) CNS Non-CNS age (years)/ ings gender 1/71/F Right, ML cystic Cystic 5×4×4.5 ND Pancreas cysts UL cystic Tubular ø1.3 UL cystic Tubular ø1.2 Solid Tubular ø1.0 Left, ML cystic Tubular 3.5×3×3 ML cystic Tubular ø2.0 Solid Tubular ø3.0 2/65/F Right, ML cystic Alveolar ø4.5 ND Pancreas cysts Solid Alveolar ø3.0 Renal cysts, bilateral Left, solid Alveolar ø3.5 Solid Alveolar ø2.0 3/60/M Right, ML cystic Tubular 8×7×7 ND Pancreas cysts Left, ML cystic Tubular 5×5×4 Renal cysts, bilateral Adrenal tumor, right 4/47/M Right, solid Cystic ø2.3 Hemangioblastoma Pancreas cysts Left, ML cystic Cystic 5×5×4 (lumbar) Renal cysts, bilateral ML cystic Cystic ø3.2 ML cystic Cystic ø2.5 5/36/M Right, solid Alveolar ø5.0 Acoustic neurinoma, ND Solid Papillary ø5.0 left Solid Papillary ø1.5 Left, ML cystic Alveolar ø8.0 Solid Tubular ø0.8 6/22/M Right, solid Alveolar > tubular ø2.0 Hemangioblastoma Renal cysts, bilateral Solid Alveolar > tubular ø1.3 (cervical, lumbar) Solid Alveolar > tubular ø0.9 Left, solid Alveolar > tubular ø1.5 Solid Alveolar > tubular ø0.16 The chromophobe carcinoma, so-named because Collecting duct carcinoma includes the medul- of its resistance to staining with typical histologic lary carcinoma of kidney associated with sickle cell stains such as hematoxylin and eosin, is the third trait and duct of Bellini tumors. Medullary carci- most common type of renal cancer, accounting for noma is characterized histologically by irregular about 5% of renal tumors. Chromophobe carcinoma channels lined by highly atypical epithelium that can be stained with Hale’s colloidal iron, which yields sometimes have a “hobnail” appearance. The chan- a homogeneous blue cytoplasmic stain (Nagashima nels are found in an inflamed desmoplastic stroma 2000). In routine histologic sections the cytoplasm (Figenshau et al. 1998; Davidson et al. 1995). Both tends to condense near the cell membrane producing medullary renal cancer and duct of Bellini tumors a halo around the nucleus. The cytoplasm is rich in are clinically aggressive neoplasms. Medullary car- mitochondria much as in oncocytoma (Erlandson cinoma and its variants arise from the collecting et al.