Diagnostic Approach to Hereditary Renal Cell Carcinoma

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1 Genitourinary Imaging Review Gupta et al. Hereditary Renal Cell Carcinoma Genitourinary Imaging Review Shiva Gupta 1 Hyunseon C. Kang Dhakshina Moorthy Ganeshan Tharakeswara Kumar athala Vikas Kundra Gupta S, Kang HC, Ganeshan D, athala TK, Kundra V Keywords: chromophobe renal cell carcinoma, clear cell renal cell carcinoma, hereditary renal cell carcinoma syndromes, medullary renal cell carcinoma, papillary renal cell carcinoma, renal cell carcinoma DOI: /JR Received July 18, 2014; accepted without revision ugust 20, ased on a presentation at the Radiological Society of North merica 2013 annual meeting, Chicago, IL. 1 ll authors: Department of Diagnostic Radiology, University of Texas M. D. nderson Cancer Center, Unit 1473, 1515 Holcombe lvd, Houston, TX ddress correspondence to S. Gupta (sgupta6@mdanderson.org). JR 2015; 204: X/15/ merican Roentgen Ray Society Diagnostic pproach to Hereditary Renal Cell Carcinoma OJECTIVE. The purpose of this article is to discuss the histopathologic features, genetics, clinical presentation, and imaging of hereditary renal cancer syndromes. CONCLUSION. Hereditary renal cell carcinoma syndromes can be diagnosed with a pattern-based approach focused on the predominant histologic renal cell carcinoma subtype and associated renal and extrarenal features of each syndrome. R enal cell carcinoma (RCC) is the third most common urologic cancer and accounts for 2 3% of adult malignancies [1, 2]. In the United States, incidence of kidney and renal pelvis cancer is on the rise, with an estimated 63,920 new cases and 13,860 new deaths by these cancers in [1, 3, 4]. Hereditary renal cancer syndromes account for approximately 2 5% of RCCs [5 7]. The autosomal dominant inheritance in most of these syndromes results in a predisposition to the development of renal tumors [2, 5]. Several hereditary renal cancer syndromes occur equally in men and women, but some syndromes occur more often in women. These renal tumors tend to be multiple and distributed bilaterally and occur at a relatively young age [2]. Understanding the ontogeny, histopathogenesis, and biologic behavior of these hereditary RCCs has led to improvements in diagnosis, treatment plans, and prognosis [8]. We provide an up-to-date discussion of these characteristics. We also introduce a patternbased approach to the diagnosis of hereditary RCC syndromes that focuses on the predominant histologic RCC subtype for each syndrome (adapting the Heidelberg classification of renal cell tumors [9]) and the associated renal and extrarenal imaging findings. Histopathologic Subtypes of Renal Cancers ccording to the 2004 World Health Organization classification of renal tumors, histologic subtypes of RCC include clear cell, papillary, chromophobe, collecting duct, medullary, and unclassified. Clear cell RCC is the most common histologic type, accounting for approximately 70 75% of RCCs [8, 10, 11]. Clear cells, which arise from the proximal convoluted tubular epithelium, are grossly yellow-tan owing to lipid content but appear clear after staining owing to their glycogen-rich content [8]. Granulosa and spindle cells may also be present in clear cell RCCs [8]. The vascular appearance of this cancer subtype is due to its characteristic network of small, thin-walled, sinusoidlike blood vessels [10, 11]. The multilocular cystic form of clear cell RCC consists of septated, variably sized cysts lined by a monolayer of epithelial cells that contain serous or hemorrhagic fluid [10, 11]. The papillary histologic subtype accounts for 10 15% of RCCs [10, 11]. Within these tumors, the papillae have fibrovascular cores with foamy macrophages and associated cholesterol crystals [11, 12]. Papillary RCCs are subclassified into two subtypes basophilic type I and eosinophilic type II [13]. These subtypes have similar clinical and histopathologic patterns, except that type I has a substantially higher cancer-specific survival rate than does type II [14 16]. This may be explained by the higher frequency of lymphovascular invasion associated with type II papillary RCC [16]. Macroscopically, papillary RCCs exhibit hemorrhagic, necrotic, and cystic degeneration [10, 11]. The chromophobe subtype comprises approximately 4 6% of RCCs [11]. Chromophobe cells are thought to arise from the intercalated cells of the collecting system [17]. JR:204, May

2 Gupta et al. Chromophobe cells have a reticular cytoplasm with a perinuclear halo and a more peripheral cytoplasm rich in mitochondria [8]. Gross examination shows that these solid tumors are tan-brown with a mildly lobulated but well-circumscribed surface [11]. Collecting duct carcinoma accounts for approximately % of RCCs in Western countries [18]. It consists of dilated tubules and papillary structures lined by a unilayer of cells that have eosinophilic, basophilic, or amphophilic cytoplasm with high-grade nuclei and is commonly associated with a desmoplastic reaction [18, 19]. Cytoplasmic and luminal mucin is a differentiating feature [19]. One may find foamy macrophages lining the papillae or inflammatory cells infiltrating the surrounding stroma [19]. Macroscopically, these masses are infiltrative, firm, and gray-white [19]. This carcinoma is considered a highly aggressive tumor; more than 50% of cases involve metastatic disease [19]. Medullary carcinoma accounts for less than 1% of RCCs and is histologically similar to collecting duct carcinoma, exhibiting both a desmoplastic reaction and mucin production [20]. However, unlike collecting duct carcinomas, medullary carcinomas contain cribriform glands [18]. In patients with sickle cell trait, hypoxia in the renal medulla often leads to transitional cell proliferation within the terminal collecting ducts and papillary epithelium [20]. It is thought that the epithelial proliferation leads to the development of medullary carcinomas [20]. Grossly, these carcinomas are tan-gray and have a firm, rubbery consistency [18]. Unclassified RCCs account for as many as 7% of RCCs, according to the 2004 World Health Organization classification [10]. However, over the last several years, some of these rare tumors have been characterized as being related to hereditary RCCs. Some benign renal masses are worth discussing, given their association with certain RCC syndromes. ngiomyolipoma is a renal hamartoma that contains vascular, lipomatous, and myeloid components. ngiomyolipomas larger than 4 cm are at increased risk of hemorrhaging. ngiomyolipomas are commonly seen in patients with tuberous sclerosis. Oncocytomas, which are associated with irt-hogg-dubé syndrome, account for 2 3% of renal tumors. Composed of granular eosinophilic cytoplasm, oncocytoma cells grow away from a central avascular scar [8]. TLE 1: Hereditary Syndromes ssociated With Finding of Multiple or ilaterally Distributed Tumors With Features of Clear Cell Renal Cell Carcinoma (RCC) Hereditary RCC Syndrome to Rule Out von Hippel Lindau syndrome Tuberous sclerosis complex Succinate dehydrogenase complex subunit associated RCC (rare) Familial clear cell RCC (rare) Chromosome 3 translocation RCC (rare) ssociated Lesion Renal and pancreatic cysts Pancreatic serous cystadenoma Pancreatic neuroendocrine tumor Pheochromocytoma Spinal and cerebellar hemangioblastomas Renal angiomyolipoma Renal cyst Oncocytoma Other RCC subtype Pulmonary lymphangioleiomyomatosis Cortical tubers (brain) Subependymal giant cell astrocytoma Cardiac rhabdomyoma Pheochromocytoma, paraganglioma Other RCC subtype Oncocytoma No associated lesion Pathogenesis of Renal Cell Carcinoma in Hereditary Renal Cell Carcinoma Syndromes Much progress has been made in finding the underlying pathogenetic mechanism of several hereditary RCC syndromes (Fig. 1). key component is hypoxia-inducible factor (HIF), which is composed of three alpha subunits (HIF-1α, -2α, and -3α) and a single beta subunit (HIF-1β). Under normoxic conditions, HIF-α binds to the von Hippel Lindau (VHL) tumor suppressor protein [21]. Targeting of this complex by the proteasome pathways leads to apoptosis [5, 21]. Under hypoxic conditions, prolyl-hydroxylation of proline residues within the oxygen-dependent degradation domain of HIF-α is inhibited; the result is accumulation of HIF-α and dimerization with HIF-1β [5, 21]. The HIF-α HIF-1β complex activates hypoxia-inducible genes, including those that prevent apoptosis and activate angiogenesis [5, 21]. Mutations in fumarate hydratase and succinate dehydrogenase (SDH) result in accumulation of fumarate and succinate, stabilization of HIF-1α, and activation of hypoxia-inducible genes [5, 22]. The mammalian target of rapamycin (mtor) pathway regulates angiogenesis and cell growth and is affected by several upstream regulators. mplification of mesenchymal epithelial transition (MET) transmembrane tyrosine kinase activates the phosphatidylinositide 3 kinase (PI3K) pathway. Normally, the PI3K pathway inhibits the mtor pathway, but mutations in PI3K can lead to dysregulation of the mtor pathway. Mutations in the TSC1, TSC2, and HD genes can also activate the mtor pathway [5]. Hereditary Syndromes ssociated With Clear Cell Renal Cell Carcinoma Sporadic clear cell RCC is multiple in approximately 4% of cases and bilateral in 3% of cases of clear cell RCC [5]. Several hereditary renal syndromes are predominantly associated with clear cell RCC, including VHL syndrome, tuberous sclerosis complex, SDH complex subunit (SDH)-associated RCC, constitutional chromosome 3 translocation, and familial clear cell RCC (Table 1). Clear cell RCC exhibits strong heterogeneous enhancement on both CT and MR images that is similar to, if not greater than, that of the renal cortex. Specifically, on CT images, clear cell RCC enhancement is greater than 80 HU in the corticomedullary phase and greater than 60 HU in the excretory phase [23]. On MR images, clear cell RCC can exhibit drop JR:204, May 2015

3 Hereditary Renal Cell Carcinoma out of signal intensity on T1-weighted outof-phase images compared with T1-weighted in-phase images owing to the presence of intracellular lipid content. Von Hippel Lindau Syndrome VHL syndrome is the most common hereditary RCC syndrome. In Europe and North merica, the prevalence of VHL syndrome is 1 in 36,000 40,000 [8]. VHL syndrome has greater than 90% penetrance at 65 years of age [7]. mong patients with VHL syndrome, RCC develops in 25 40% [5] at an average age of 39 years, much earlier than the average age of 61 years for the presentation of sporadic RCCs [7]. Genetics Germ-line mutation of the VHL tumor suppressor gene located on the 3p25-26 locus is the cause of the syndrome. multiprotein complex (VHL protein, Cullin 2, Rbx 1 [or Roc1], NEDD8, and elongin and C) normally targets HIF-1α and HIF-2α for proteasome-mediated degradation under normoxic conditions [24]. However, in a hypoxic environment, the VHL protein does not bind to HIF-α, thus preventing its degradation. HIF-α accumulation in turn regulates several processes, such as inhibiting apoptosis and promoting angiogenesis and tumor cell proliferation. Clinical and imaging features Patients with VHL syndrome (Figs. 2 and 3) present with multiple and bilateral renal lesions, including as many as 600 tumors and 1100 cysts per kidney [7, 25]. lthough hundreds of tumors and cysts may be found in each kidney, only some can be seen on imaging, and even fewer are clinically significant. Metastases can be seen if solid clear cell RCCs are left untreated, particularly if the RCCs are larger than 3 cm [8]. Several organs in addition to the kidneys are affected by VHL syndrome. Cerebellar and spinal hemangioblastomas, which present as enhancing nodules, can cause neurologic defects and secondary syringomyelias. Retinal angiomas are avidly enhancing lesions that can cause blindness if left untreated. Endolymphatic sac tumors are heterogeneously enhancing and cause central cystic changes with associated surrounding erosive changes in the bony labyrinth of the inner ear. In severe cases, endolymphatic sac tumors can cause complete deafness. In the abdomen, the most commonly visualized extrarenal lesions are pancreatic serous cystadenomas, which can present with exocrine insufficiency, abdominal pain, decreased appetite, or a combination of these signs and symptoms. Serous cystadenomas classically have a honeycomb appearance due to numerous small cysts and thin septations with a fibrous or calcified central scar that may or may not be enhancing. Pancreatic neuroendocrine tumors and pheochromocytomas occur in less than 8% of patients with VHL syndrome [8]. The average life expectancy of a patient with VHL syndrome is less than 50 years [26]. Tuberous Sclerosis Tuberous sclerosis has an incidence at birth of 1 in ,000. Most cases of tuberous sclerosis are a result of spontaneous mutation [8]. pproximately 30% are inherited as autosomal dominant disorders with near-complete penetrance and variable expressivity [7]. RCC develops in only 1 4% of patients with tuberous sclerosis [7]. Genetics Two genes account for most cases of tuberous sclerosis TSC1 and TSC2. TSC1 is found on the 9q34 locus, codes for the protein hamartin, and accounts for 20% of sporadic and 50% of familial cases of tuberous sclerosis [7, 8, 27, 28]. TSC2, which is believed to be associated with a more aggressive form of tuberous sclerosis, is found on the 16p13.3 locus and encodes for tuberin [7, 8, 28]. Hamartin and tuberin bind to each other [7, 8, 28] to inhibit downstream pathways of mtor [7]. TSC2 is closely associated with PKD1, a gene responsible for autosomal dominant polycystic kidney disease [29]. nother condition that shares genetic abnormalities similar to those of tuberous sclerosis is lymphangioleiomyomatosis, which is a mosaic form of tuberous sclerosis with associated pulmonary cysts, renal cysts, angiomyolipomas, and retroperitoneal and pelvic lymphangiomas [7]. Clinical and imaging features Tuberous sclerosis is associated with several neurologic and ocular findings, including cortical tubers, giant cell astrocytomas, and retinal hamartomas. Dermatologic findings include facial angiofibromas, fibrous forehead plaques, subungual fibromas, and shagreen patches. dditional features of tuberous sclerosis include renal angiomyolipomas and cysts, cardiac rhabdomyomas, pulmonary lymphangioleiomyomatosis, rectal polyps, bone islands and cysts, thyroid adenomas, and renal cancers [8] (Figs. 4 and 5). ngiomyolipomas are the most common and distinguishing renal lesions in tuberous sclerosis, occurring in 70 80% of tuberous sclerosis patients older than 10 years [7]. The distribution of these lesions is multiple and bilateral. ngiomyolipomas can cause hematuria, mass effect, hypertension, and renal insufficiency [8]. cute hemorrhage is the most concerning risk associated with angiomyolipoma, particularly if the angiomyolipoma is larger than 4 cm. The numerous renal cysts can cause pain, infection, and renal insufficiency, particularly in cases associated with polycystic renal disease. RCCs occur in 1 4% of tuberous sclerosis patients and usually present at an average age of 28 years in a multiple, bilateral pattern [7, 30]. The principal RCC associated with tuberous sclerosis is clear cell, although papillary and chromophobe RCCs and oncocytomas may also occur [7, 8]. ngiomyolipomas and cysts can be differentiated on CT images by the presence of low attenuation corresponding to fat in angiomyolipomas and the lack of enhancement of cysts. However, one third of patients with tuberous sclerosis present with nonfatty angiomyolipomas. oth lipid-poor angiomyolipomas and renal cancers are avidly enhancing, making it difficult to differentiate the two. In addition, it is important to be aware that angiomyolipomas can extend into the inferior vena cava and local lymph nodes, mimicking malignancy [8]. Renal Cell Carcinoma ssociated With Succinate Dehydrogenase Complex Subunit Genetics Germline mutations affecting SDH subunits, C, and D are associated with a risk of development of paragangliomas and pheochromocytomas [31]. Germline mutations in SDH are specifically associated with RCC. Clinical and imaging features Patients with germline mutations in SDH present with clinical characteristics typical of paragangliomas or pheochromocytomas (Fig. 6). Several subtypes of RCC are associated with SDH mutation, including clear cell and chromophobe RCCs (Fig. 6). Oncocytomas can also be seen [7, 31]. Constitutional Chromosome 3 Translocation Genetics Translocations of the third chromosome (3:2, 3:8, 3:11, and 3:6) are associated with tumors that express somatic mutations in the VHL gene [8, 32]. The location at which the translocated segment breaks from the short arm of chromosome 3 is the site of functional mutation [8]. This break is not at the VHL gene locus (3p25) [8]. Clinical and imaging features Patients with translocation of chromosome 3 express noncystic tumors similar to clear cell carcino- JR:204, May

4 Gupta et al. mas that tend to be avidly enhancing. lthough these patients have somatic mutations of the VHL gene, they do not express manifestations of VHL syndrome [8]. Unless the patient or a family member of a chromosome 3 translocation carrier has a history of clear cell RCC, annual renal surveillance is not necessary [7]. Familial Clear Cell Renal Cell Carcinoma Familial clear cell RCC is defined as clear cell RCC found in two or more family members without constitutional chromosome 3 translocations or the presence of a syndrome [7]. Genetics Familial clear cell RCC is thought to be the result of multigenic inheritance, that is, inheritance specified by a combination of multiple genes [7]. Clinical and imaging features Within the family of the affected individual, at least one member has had a single clear cell RCC at between 50 and 70 years of age. Hereditary Syndromes ssociated With Papillary Renal Cell Carcinoma Several syndromes are associated with multiple or bilateral papillary RCC (Table 2). Papillary RCCs generally exhibit mild homogeneous and, rarely, no enhancement, making these tumors difficult to differentiate from hyperdense cysts on CT [33]. On MRI, these carcinomas generally are T2 hypointense and are hypoenhancing relative to normal renal parenchyma on contrast-enhanced images [33]. Hereditary Papillary Renal Cell Carcinoma Hereditary papillary RCC is a condition in which affected individuals are predisposed to well-differentiated type 1 papillary RCC. Genetics The hereditary papillary RCC gene is located at the 7q locus. Missense mutations at the tyrosine kinase domain of the MET protooncogene activate the MET protein and promote the development of papillary RCC [8, 34]. Unlike the sporadic type, hereditary papillary RCC is associated with trisomy 7 with duplication of the mutant MET allele [7]. Clinical and imaging features The main clinical feature of hereditary papillary RCC is detection of a germline mutation of the c- MET gene. ecause papillary renal cancers are slow growing, they do not present until later in life (50 70 years of age) or at autopsy [7, 8]. There is 90% likelihood that patients with hereditary papillary RCC will have RCC by 80 years of age [7]. Renal lesions may range from microscopic papillary adenomas to carcinomas, and some TLE 2: Hereditary Syndromes ssociated With Finding of Multiple or ilaterally Distributed Tumors With Features of Papillary Renal Cell Carcinoma (RCC) Hereditary RCC Syndrome to Rule Out Hereditary papillary RCC Hereditary leiomyomatosis RCC Hereditary hyperparathyroidism jaw tumor syndrome Papillary thyroid carcinoma with papillary renal neoplasia Phosphatase and tensin homologue hamartoma tumor syndrome patients can have as many as 3400 adenomas in a single kidney [7]. Papillary RCCs are usually hypovascular type 1 papillary carcinomas, which enhance only HU after IV contrast administration. On MRI, these lesions may become enhanced by only 15% on contrast-enhanced images relative to unenhanced images. On ultrasound images, the lesions may be isoechoic to background renal parenchyma [8]. In addition, one has to be careful to differentiate these lesions from cysts, which can coexist with hereditary papillary RCC. ssociated Lesion Renal cysts Renal cysts Uterine and skin leiomyomas Parathyroid adenomas or carcinomas Ossifying jaw fibromas Polycystic kidneys Renal hamartomas, cortical adenomas Late-onset Wilms tumor Papillary thyroid cancer Papillary renal adenomas reast cancer Thyroid cancer Hereditary Leiomyomatosis With Renal Cell Carcinoma Hereditary leiomyomatosis with RCC was initially characterized in Finland when a member of a family with multiple cutaneous leiomyomatosis and uterine leiomyomas was found to have papillary RCC at a young age [8]. This hereditary syndrome is traditionally most commonly associated with type 2 papillary RCC [7, 8]. Genetics Hereditary leiomyomatosis with RCC is an autosomal dominant inherited mutation of the fumarate hydratase gene with incomplete phenotype penetrance. The fumarate hydratase gene, located on the 1q42.3-q43 locus, is a catalyst in the Krebs cycle, converting fumarate to malate [7, 8]. Heterozygous germline mutations of this gene result in stabilization of HIF through the accumulation of fumarate and the creation of a pseudohypoxic environment, resulting in the production of tumor-promoting factors [35]. Clinical and imaging features Type 2 papillary renal cancers present as a single hypovascular lesion in as many as 20% of patients with hereditary leiomyomatosis with RCC [7, 8]. These lesions can become more vascular as they enlarge and tend to be aggressive, with high nuclear grade and metastases regardless of size [7, 8]. This metastatic disease frequently ends in death within 5 years [7]. Renal cysts may also be present [7, 8]. Patients usually manifest skin leiomyomata and uterine fibroids at the age of years. Cutaneous leiomyomas are skin-colored or brownish red papules or nodules that measure cm. These painful (to pressure and low temperature) lesions have a variable extent and tend to occur on the trunk and limbs. lthough these lesions are usually benign, they can undergo malignant transformation [7]. Uterine leiomyomas in patients with hereditary leiomyomatosis with RCC often cause menorrhagia and pelvic pressure and pain, necessitating hysterectomy before 30 years of age. Like cutaneous leiomyomas, uterine leiomyomas usually are benign but in rare instances undergo malignant transformation. Hereditary Hyperparathyroidism Jaw Tumor Syndrome Genetics The gene associated with hereditary hyperparathyroidism jaw tumor syndrome, the hyperparathyroidism type 2 gene, is found on the 1q24 32 locus. This gene normally serves as a tumor-suppressor gene, inhibiting the c-myc protooncogene [7]. Inhibition of the hyperparathyroidism type 2 gene leads to autosomal dominant expression of the hereditary hyperparathyroidism jaw tumor syndrome JR:204, May 2015

5 Hereditary Renal Cell Carcinoma Clinical and imaging features Patients are predisposed to the development of primary hyperparathyroidism from solitary or multiple parathyroid adenomas (which can recur after resection). In 15% of patients, parathyroid carcinoma causes hyperparathyroidism. s a result, patients can present with hypercalcemia in childhood to the late teenage years [36]. Patients may also present with ossifying jaw fibromas [7], which are usually found incidentally and may cause dentition distortion [36]. pproximately 15% of patients with this syndrome have variable renal manifestations, including polycystic kidneys, renal hamartomas, lateonset Wilms tumor, renal cortical adenomas, and RCC. Papillary RCC has been described in only one patient [37]. To our knowledge, association with other subtypes of RCC has not been reported, but this syndrome remains a part of the growing family of hereditary RCCs. In addition, benign and malignant uterine abnormalities including endometrial hyperplasia, adenomyosis, leiomyomas, adenofibromas, and adenosarcomas are found in as many as 75% of women with this syndrome [7, 38]. Papillary Thyroid Carcinoma With ssociated Papillary Renal Neoplasia Genetics Familial papillary thyroid carcinoma is an autosomal dominant inherited condition associated with benign nodular thyroid disease [39]. The phenotype of familial papillary thyroid carcinoma and papillary renal neoplasm is linked to the 1q21 locus [7, 37]. Clinical and imaging features Papillary thyroid carcinoma has a genetic component in approximately 5% of cases; women are affected twice as often as men [7, 39]. Evaluation of families with hereditary papillary thyroid carcinoma has shown an association with papillary RCC, multifocal papillary adenomas, and, less commonly, renal oncocytoma [7, 37] (Fig. 7). TLE 3: Hereditary Syndromes ssociated With Finding of Multiple or ilaterally Distributed Tumors With Features of Chromophobe Renal Cell Carcinoma (RCC) Hereditary RCC Syndrome to Rule Out irt-hogg-dubé syndrome Tuberous sclerosis complex Succinate dehydrogenase complex subunit associated RCC (rare) Phosphatase and Tensin Homologue Hamartoma Tumor Syndrome Genetics Phosphatase and tensin homologue (PTEN) hamartoma tumor syndrome is associated with germline mutations of the PTEN tumor-suppressor gene linked to the 10q23 locus and leads to increased cell proliferation and reduced cell death [40]. Clinical and imaging features Women have PTEN hamartoma tumor syndrome twice as often as men do. This syndrome is associated with Cowden, annayan-riley-ruvalcaba, and other syndromes and phenotypically presents with hematuria. This syndrome is associated with papillary RCC, commonly in the fifth decade of life. This syndrome also may be associated with breast and thyroid cancer [40]. Hereditary Syndromes ssociated With Chromophobe Renal Cell Carcinoma Chromophobe RCC exhibits homogeneously weak enhancement on CT and MR images and is often highly aggressive. The lesions tend to be large (classically > 7 cm) and often contain calcifications [41]. Chromophobe RCC in hereditary renal syndromes is usually associated with other RCC subtypes, such as clear cell RCC in tuberous sclerosis and papillary RCC in SDH-associated RCC. nother commonly discussed but rare syndrome, irt-hogg-dubé syndrome, is associated with several RCC subtypes, predominantly chromophobe (Table 3). ssociated Lesion Oncocytomas Fibrofolliculomas Pulmonary cysts Other RCCs Renal angiomyolipomas Renal cysts Oncocytomas Other RCC subtypes Pulmonary lymphangioleiomyomatosis Cortical tubers (brain) Subependymal giant cell astrocytomas Cardiac rhabdomyomas Pheochromocytomas, paragangliomas Other RCC subtypes Oncocytomas irt-hogg-dubé Syndrome Genetics irt-hogg-dubé syndrome has an autosomal dominant inheritance pattern. The HD gene is found at the 17p11.2 locus and normally encodes for a tumor suppressor protein called folliculin. In irt-hogg-dubé syndrome, the gene becomes biallelically inactivated in RCC by second-hit mutations. This causes a mutation in folliculin and dysregulation of the mtor pathway [8, 42]. Clinical and imaging features irt-hogg- Dubé syndrome is associated with several different types of lesions (Fig. 8). For example, fibrofolliculomas are benign 2- to 4-mm skin papules that arise from hair follicles and are found on the scalp, face, neck, and upper trunk, usually during the third to fourth decade of life. crochordons, commonly known as skin tags, occur on the eyelids, neck, and axillae. Pulmonary cysts occur more commonly in the lower lobes and are found in as many as 70% of patients with irt-hogg-dubé syndrome. Spontaneous pneumothorax can be found in as many as 25% of patients with this syndrome [8]. Renal tumors of various subtypes are found in 15 30% of patients with irt-hogg-dubé syndrome. The most common subtype is hybrid chromophobe RCC oncocytomas (50%), although nonhybrid chromophobe RCC and oncocytomas can also be found in 34% and 5% of irt-hogg-dubé syndrome patients. Clear cell RCC is found in as many as 9% and papillary RCC in as many as 2% of patients with irt-hogg-dubé syndrome [8]. Hereditary Syndromes ssociated With Medullary Renal Cell Carcinoma Medullary RCC develops in young patients (11 39 years) with the sickle cell trait and is most commonly found in people of frican descent. Genetics The gene for β-globin is located on the short arm of chromosome 11. Cytogenetic testing of JR:204, May

6 TLE 4: Renal Lesions ssociated with Hereditary Renal Cell Carcinoma (RCC) Syndromes Syndrome Clear Cell RCC Papillary RCC Chromophobe RCC Medullary RCC Oncocytoma ngiomyolipoma Other Von Hippel Lindau syndrome Frequent association Cysts Tuberous sclerosis Frequent association Some association Some association Some association Frequent association Cysts SDH-associated RCC Frequent association Some association Some association Chromosome 3 translocation Frequent association Familial clear cell RCC Frequent association Hereditary papillary RCC Frequent association Cysts (type I) Hereditary leiomyomatosis RCC Frequent association (type II more than type I) Some association Polycystic, hamartomas, late-onset Wilms tumor, cortical adenomas Hereditary hyperparathyroidism jaw tumor syndrome Frequent association Some association Papillary adenomas Papillary thyroid carcinoma with associated papillary renal neoplasia renal medullary carcinoma tissue in patients with the sickle cell Gupta et al. trait has shown monosomy 11 in 66% of cases [2]. The exact genetic factor involved in the pathogenesis remains unknown. PTEN hamartoma tumor syndrome Frequent association irt-hogg-dubé syndrome Some association Some association Frequent association Frequent association Sickle cell trait Frequent association Note SDH = succinate dehydrogenase complex subunit, PTEN = phosphatase and tensin homologue. Clinical and Imaging Features Renal medullary carcinoma is a highly aggressive cancer with a poor prognosis. The mean survival period after diagnosis is only 15 weeks. It often presents with microhematuria. Renal medullary carcinomas are centrally located infiltrative tumors and are often associated with caliectasis (Fig. 9). These tumors are heterogeneous with intratumoral hemorrhaging or necrosis [11]. Conclusion Radiologists may be the first to suggest the diagnosis of a hereditary RCC syndrome, which should be suspected if a patient has multiple RCCs or bilaterally distributed or early onset (< 50 years) RCC. pattern-based approach incorporating imaging features of the predominant tumor subtype (Table 4) with certain associated findings may help radiologists differentiate the various hereditary RCC syndromes. References 1. Pascual D, orque. Epidemiology of kidney cancer. dv Urol 2008; : Choudhary S, Sudarshan S, Choyke PL, Prasad SR. Renal cell carcinoma: recent advance in genetics and imaging. Semin Ultrasound CT MR 2009; 30: Jemal, Siegel R, Ward E, et al. Cancer statistics. C Cancer J Clin 2006; 56: Siegal R, Ma J, Zou Z, Jemal. Cancer statistics. C Cancer J Clin 2014; 64: xwijk PH, Kluijt I, de Jong D, Gille H, Teertstra J, Horenblas S. Hereditary causes of kidney tumors. Eur J Clin Invest 2010; 40: Pfaffenroth EC, Linehan WM. Genetic basis for kidney cancer: opportunity for disease-specific approaches to therapy. Expert Opin iol Ther 2008; 8: Verine J, Pluvinage, ousquet G, et al. Hereditary renal cancer syndromes: an update of a systematic review. Eur Urol 2010; 58: Choyke PL, Glenn GM, Walther MM, Zbar, Linehan WM. Hereditary renal cancers. Radiology 2003; 226: Kovacs G, khtar M, eckwith J, et al. The Heidelberg classification of renal cell tumors. J Pathol 1997; 183: Eble JN, Sauter G, Epstein JI, Sesterhenn I, eds. Word Health Organization classification of tumors: pathology and genetics of tumours of the urinary system and male genital organs. Lyon, France: IRC Press, Prasad SR, Humphrey P, Catena JR, et al. Common and uncommon histologic subtypes of renal cell carcinoma: imaging spectrum with pathologic correlation. RadioGraphics 2006; 26: min M, Corless CL, Renshaw, Tickoo SK, Kubus J, Schultz DS. Papillary (chromophil) renal cell carcinomas: histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 62 cases. m J Surg Pathol 1997; 21: Delahunt, Eble JN. Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol 1997; 10: Mejean, Hopirtean V, azin JP, et al. Prognostic factors for the survival of patients with papillary renal cell carcinoma: meaning of histological typing and multifocality. J Urol 2003; 170: Pignot G, Elie C, Conquy S, et al. Survival analysis of 130 patients with papillary renal carcinoma: prognostic utility of type 1 and type 2 subclassification. Urology 2007; 69: Waldert M, Haitel, Marberger M, et al. Comparison of type I and II 1036 JR:204, May 2015

7 Hereditary Renal Cell Carcinoma papillary renal cell carcinoma (RCC) and clear cell RCC. JU Int 2008; 102: Störkel S, Steart PV, Drenckhahn D, Thoenes W. The human chromophobe cell renal carcinoma: its probable relation to intercalated cells of the collecting duct. Virchows rch Cell Pathol Incl Mol Pathol 1989; 56: lgaba F, kaza H, Lopez-eltran, et al. Current pathology keys of renal cell carcinoma. Eur Urol 2011; 60: ose D, Das RN, Chatterjee U, anerjee U. Collecting duct carcinoma: a rare malignancy. J Cancer Res Ther 2013; 9: Prasad SR, Humphrey P, Menias CO, et al. Neoplasms of the renal medulla: radiologic-pathologic correlation. RadioGraphics 2005; 25: Haase VH. The VHL/HIF oxygen-sensing pathway and its relevance to kidney disease. Kidney Int 2006; 69: Pollard PJ, riere JJ, lam N, et al. ccumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 2005; 14: Sheir KZ, El-zab M, Mosbah, El-az M, Shaaban. Differentiation of renal cell carcinoma subtypes by multislice computerized tomography. J Urol 2005; 174: Ohh M. Ubiquitin pathway in VHL cancer syndrome. Neoplasia 2006; 8: Pause, Lee S, Lonergan KM, Klausner RD. The von Hippel Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. VHL HIF-α HIF-α degraded HIF-β FH, SDH HIF-α HIF-α HIF-β complex Hypoxia c-met P13K pathway TSC1, TSC2 HD mtor pathways ngiogenesis Cell proliferation and apoptosis prevention Proc Natl cad Sci US 1998; 95: Friedrich C. Genotype-phenotype correlation in von Hippel-Lindau syndrome. Hum Mol Genet 2001; 10: Kwiatkowska J, Jozwiak S, Hall F, et al. Comprehensive mutational analysis of the TSC1 gene: observations on frequency of mutation, associated features, and nonpenetrance. nn Hum Genet 1998; 62: van Slegtenhorst M, Nellist M, Nagelkerken, et al. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet 1998; 7: Martignoni G, onetti F, Pea M, Tardanico R, runelli M, Eble JN. Renal disease in adults with TSC2/PKD1 contiguous gene syndrome. m J Surg Pathol 2002; 26: Washecka R, Hanna M. Malignant renal tumors in tuberous sclerosis. Urology 1991; 37: Ricketts C, Woodward ER, Killick P, et al. Germline SDH mutations and familial renal cell carcinoma. J Natl Cancer Inst 2008; 100: van Kessel G, Wijnhoven H, odmer D, et al. Renal cell cancer: chromosome 3 translocations as risk factors. J Natl Cancer Inst 1999; 91: Egbert ND, Caoili EM, Cohan RH, et al. Differentiation of papillary renal cell carcinoma subtypes on CT and MRI. JR 2013; 201: Schmidt L, Duh FM, Chen F, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 1997; 16: ehnes CL, Schlegel C, Shoukier M, et al. Hereditary papillary renal cell carcinoma primarily diagnosed in a cervical lymph node: a case report of a 30-year-old woman with multiple metastases. MC Urol 2013; 13:3 36. Szabó J, Heath, Hill VM, et al. Hereditary hyperparathyroidism jaw tumor syndrome: the endocrine tumor gene HRPT2 maps to chromosome 1q21-q31. m J Hum Genet 1995; 56: Richard S, Lidereau R, Giraud S. The growing family of hereditary renal cell carcinoma. Nephrol Dial Transplant 2004; 19: radley KJ, Hobbs MR, uley ID, et al. Uterine tumours are a phenotypic manifestation of the hyperparathyroidism-jaw tumour syndrome. J Intern Med 2005; 257: Malchoff CD, Sarfarazi M, Tendler, et al. Papillary thyroid carcinoma associated with papillary renal neoplasia: genetic linkage analysis of a distinct heritable tumor syndrome. J Clin Endocrinol Metab 2000; 85: Mester JL, Zhou M, Prescott N, Eng C. Papillary renal cell carcinoma is associated with PTEN hamartoma tumor syndrome. Urology 2012; 79: Kim JK, Kim TK, hn HJ, Kim CS, Kim KR, Cho KS. Differentiation of subtypes of renal cell carcinoma on helical CT scans. JR 2002; 178: aba M, Hong S, Sharma N, et al. Folliculin encoded by the HD gene interacts with a binding protein, FNIP1, and MPK, and is involved in MPK and mtor signaling. Proc Natl cad Sci US 2006; 103: Fig. 1 Chart shows mutations in von Hippel Lindau (VHL), fumarate hydratase (FH), and succinate dehydrogenase (SDH) result in activation of hypoxia pathway, leading to accumulation of hypoxia-inducible factor α (HIF-α) and ultimately angiogenesis and cell proliferation while inhibiting apoptosis. Mutations in phosphatidylinositide 3-kinase (PI3K ) pathway, TSC1, TSC2, and irt-hogg-dubé (HD) genes lead to activation and dysregulation of mammalian target of rapamycin (mtor) pathway, which cross-talks with HIF pathway and also stimulates cell proliferation and angiogenesis while inhibiting apoptosis. JR:204, May

8 Gupta et al. E C Fig year-old woman with von Hippel Lindau syndrome. D, CT images show renal (black arrow) and pancreatic (white arrow, ) cysts. Patient had right hypervascular renal cell carcinoma that is enhancing from unenhanced () to corticomedullary (C) phase and washed out in nephrogenic phase (D). E, Contrast-enhanced T1-weighted MR image shows patient also has cerebellar hemangioblastoma (arrow). D 1038 JR:204, May 2015

9 Hereditary Renal Cell Carcinoma Fig year-old woman with von Hippel Lindau syndrome who presented with left clear cell renal cell carcinoma., CT image shows left clear cell renal cell carcinoma (white arrow) and right adrenal pheochromocytoma (black arrow)., CT image obtained 4 years after shows pancreatic neuroendocrine tumors (arrow). C Fig year-old woman with tuberous sclerosis who presented with multiple angiomyolipomas., Non fat-saturated T1-weighted MR image shows hyperintense angiomyolipomas (arrows)., Fat-saturated T1-weighted MR image shows angiomyolipomas (arrows) are hypointense. C, xial contrast-enhanced T1-weighted fat-saturated MR image also shows perivascular epithelioid cell tumor (arrow) in pelvis. JR:204, May

10 Gupta et al. Fig year-old woman with tuberous sclerosis. xial CT image shows pulmonary cysts (arrows), which can also be seen in patients with lymphangioleiomyomatosis. Fig year-old man with left carotid body tumor and history of resection of right jugulotympanic glomus tumor., CT image shows left carotid body tumor (paranglioma, arrow)., CT image obtained 2 years after shows left renal enhancing solid mass (arrow), which proved at biopsy to be clear cell renal cell carcinoma. Patient was reported to have succinate dehydrogenase complex subunit mutation positive type 4 hereditary paraganglioma syndrome. Fig year-old woman with papillary thyroid carcinoma. and, CT images show papillary thyroid carcinoma (arrow, ) associated with papillary renal cell carcinoma (arrow, ) JR:204, May 2015

11 Hereditary Renal Cell Carcinoma C E Fig year-old woman with irt-hogg-dubé syndrome who presented with multiple bilateral renal lesions. D, Unenhanced (), corticomedullary (), nephrographic (C), and excretory (D) phase CT images show multiple bilateral renal lesions (arrows) with delayed enhancement of central scar in one lesion. Pathologic examination showed these lesions to be hybrid chromophobe renal cell carcinoma oncocytomas. E, CT image also shows multiple basilar pulmonary cysts (arrows). Fig year-old woman with sickle cell trait who was found to have incidental renal mass during cesarean delivery. and, Unenhanced () and corticomedullary () phase CT images show relatively hypovascular, infiltrating medullary renal mass (arrow) that was centrally located. D JR:204, May