Spectrum of Radiological Findings of Hereditary Renal Cell Cancer Syndromes S. Mojdeh Mirmomen, Moozhan Nikpanah, Faraz Farhadi, Les R. Folio, Andrew J. Dwyer, Elizabeth C. Jones, Jana Lovell, Ramaprasad Srinivasan, Adam Metwali, W. Marston Linehan, Ashkan A. Malayeri Radiology and Imaging Sciences, National Institutes of Health Urology Oncology Branch, National Institutes of Health Introduction Renal cell carcinoma (RCC) affects nearly 60,000 people and causes over 14,000 deaths annually in the United States. RCC is not a single disease; rather, it is made up of a number of different types of cancers, each with a different histology, a different clinical course and different driver mutations. We present the most common hereditary renal cell cancer syndromes (HRCC) with their renal and extra-renal radiologic manifestations on CT and MRI. Teaching Objectives: To identify the different histologic subtypes of RCC seen in genetically defined HRCCs. To describe the genomic features of the more common HRCC. To compare renal and extra-renal radiologic manifestations of HRCCs on CT and MRI. Birt-Hogg-Dubé (BHD) Syndrome Genomic Findings: BHD is an autosomal dominant syndrome caused by germline mutations in the tumor suppressor gene FLCN (chromosome 17), which encodes for folliculin. Mutations in the FLCN gene may disrupt the mammalian target of rapamycin (mTOR) signaling pathway, leading to dysregulated cell growth. Renal Findings: A variety of renal tumor subtypes can manifest in BHD syndrome, including oncocytic hybrid tumors (mixed pattern of oncocytomas and chromophobe tumors), chromophobe RCCs, oncocytomas, ccRCCs, and papillary RCCs. Like other HRCC syndromes, BHD-related renal tumors tend to be bilateral and multifocal. Although oncocytic hybrid tumors and chromophobe RCCs are typically less aggressive than RCCs of other HRCC syndromes, metastatic forms have been reported, indicating necessity of surveillance imaging. Extra-Renal Findings: Extra-renal manifestations of BHD include fibrofolliculomas, acrochordons, and pulmonary cysts. Fibrofolliculomas develop in patients between 30 to 40 years of age as multiple, white to flesh-colored, smooth papules on the scalp, face, neck, and upper trunk. Acrochordons (i.e. skin tags) are small furrowed papules appearing on the eyelids, neck, and axilla. Pulmonary cysts may present as spontaneous pneumothoraces. Imaging Findings: Patients with BHD demonstrate solid enhancing renal masses and cysts (unrelated to the tumors). Lung imaging shows multiple cysts and occasional pneumothoraces. The lung cysts are well circumscribed, round, air-filled structures, more often in the lower than in the upper lobes. Lung cysts accompanied by renal tumors limit the likely diagnosis to BHD syndrome and TSC. However, the final diagnosis depends on other features, such as the presence of typical skin lesions, intracerebral lesions, or angiomyolipoma (diagnosis of TSC). Tuberous sclerosis (TS) Genomic Findings: TS is an autosomal dominant disorder caused by mutations in the TSC1 or TSC2 genes. TSC1 (chromosome 9) and TSC2 (chromosome 16) encode for hamartin and tuberin, respectively. It is hypothesized that TSC genes are tumor suppressor genes, and that deficiency of tuberin or hamartin leads to constitutive mTOR signaling, resulting in uncontrolled cell growth and protein synthesis. Renal Findings: Renal disease is the leading cause of mortality in TS. The most common renal manifestations are cysts and angiomyolipomas (both lipid-poor and lipid-rich). Unlike the sporadic form of angiomyolipoma (AML), AMLs in TS are often multiple and bilateral with a higher incidence and severity in women. AMLs can develop acute life-threatening hemorrhages. While the majority of renal lesions in TS are AMLs, RCCs have been reported in 1-3% of patients with TS. RCC subtypes in TS include ccRCC (most common), papillary, chromophobe, and oncocytomas. Extra-Renal Findings: Other causes of mortality in TS include pulmonary lymphangioleiomyomatosis and subependymal giant cell astrocytomas. Dermatological manifestations include skin hamartomas, facial angiofibromas, subungual fibromas, Shagreen patches, and ash-leaf spots. Additional manifestations include hamartomas of the brain, retina, and viscera, cardiac rhabdomyomas, cerebral sclerosis, rectal polyps, sclerotic bone lesions, and thyroid adenomas. Imaging Findings: Typical, lipid-rich AMLs can be readily differentiated from RCCs due to the fat attenuation and signal within them on CT and MRI respectively. In contrast, differentiation of lipid-poor AML from renal cell cancer can be challenging on contrast-enhanced MRI and CT. Non-fatty AMLs can demonstrate higher attenuation than surrounding renal parenchyma on unenhanced scans. Despite their large size, they are commonly uniform in enhancement. Identification of lung cysts and multiple bone islands on CT should suggest the diagnosis of TSC-LAM complex. Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) Syndrome Genomic Findings: HLRCC is a rare autosomal dominant syndrome caused by mutations in the fumarate hydratase (FH) gene. Functional FH protein converts fumarate to malate in the citric acid cycle. Inactivated FH results in the accumulation of fumarate, which may contribute to tumorigenesis through the accumulation of HIFα and impaired DNA repair. Renal Findings: The majority of RCCs in HLRCC syndrome occur early in life and are histologically classified as type II papillary RCCs. Other HLRCC-related RCCs can range from tubulopapillary to collecting duct RCCs. HLRCC-related RCCs tend to present as solitary and unilateral lesions; this presentation is distinct from the common presentation of multiple, bilateral masses in other inherited RCC syndromes. HLRCC tumors are also aggressive and can metastasize even when smaller than 3cm. Extra-renal Findings: Cutaneous and uterine leiomyomas are the most common extra-renal manifestations in HLRCC syndrome, developing in about 76% of patients. Cutaneous leiomyomas are benign tumors typically presenting as multiple firm, dermal papules and nodules on patients between 20 and 40 years of age. Uterine leiomyomas, which occur in more than 90% of women with HLRCC, are benign tumors that typically develop prior to age 30. In women with HLRCC syndrome, uterine leiomyomas are commonly numerous, large, and symptomatic, frequently requiring hysterectomy at a young age. Imaging Findings: HLRCC-related RCCs tend to be hypovascular on CT and MRI and have cystic components. As tumors become larger, they become more solid and vascular and less differentiable from more common type of renal cell cancers - the ccRCC. Von Hipple-Lindau (VHL) Syndrome Genomic Findings: VHL is an autosomal dominant disorder caused by germline mutations in the tumor suppressor gene VHL on chromosome 3. The VHL gene encodes for the VHL protein (pVHL), which targets hypoxia-inducible factor (HIF)-1α for proteasomal degradation. Mutation of the VHL gene results in HIFα accumulation and increased expression of angiogenic factors including vascular endothelial growth factor (VEGF) and erythropoietin. These factors promote angiogenesis and proliferation of endothelial cells that account for the highly vascular tumors, particularly hemangioblastomas and RCCs. Renal Findings: Bilateral and multifocal RCCs, specially clear cell RCC (ccRCC) type is the most common renal neoplasm in VHL syndrome. ccRCCs present as slow-growing, hypervascular cystic, solid, or mixed cystic-solid lesions. The proportion of solid component and the size of tumors determine the risk of metastasis and the time to initiation of therapy. Tumors greater than 3cm are resected. Extra-renal Findings: Extra-renal findings in patients with VHL disease include : CNS hemangioblastomas are the most common tumor in VHL patients and are the major cause of morbidity despite their benign features. Multifocal and bilateral retinal hemangioblastoma. Although asymptomatic at early stages, these tumors can lead to vision loss without prompt treatment. Bilateral endolymphatic sac tumors are unique to VHL syndrome and present with symptoms of hearing loss, tinnitus, and disequilibrium. Pancreatic neuroendocrine tumors and cysts (histologically; serous cystadenomas) are often asymptomatic and slow growing. Pheochromocytomas; can present with symptoms of catecholamine excess when large in size. Multifocal and bilateral pheochromocytomas are possible in VHL syndromes. Epididymal and broad ligament cystadenomas are benign tumors arising from the epididymal duct and broad ligament and typically present as multiple and bilateral tumors. Imaging Findings: Clear cell renal cell carcinomas (ccRCCs) are often hypervascular and can be differentiated from the background renal parenchyma. Pancreatic cysts can be readily evaluated with T2 weighted MRI images, while neuroendocrine tumors of the pancreas are best imaged on arterial phase CT or T1 weighted MRI images. A B 35 year old female with VHL. Multiple hyperenhancing hemangioblastomas of the cerebellum (arrows) (A) and retina (arrowheads) (B). 25 year old male with HLRCC. Note cystic lesion within the right kidney with fine enhancing nodules at the wall (arrows). 40 year old female with HLRCC. Large mass within the left kidney with cystic and enhancing solid components (arrow)(A). Notice several metastasis the liver (A) and multiple uterine fibroids (arrows)(B). 51 year old female with BHD syndrome. Multiple bilateral enhancing masses of the kidneys (arrows)(A and B) with central scaring identified. Pathology was consistent with hybrid oncocytic/chromophobe RCCs. Multiple cysts were seen with a small loculated pneumothorax (arrow heads) at the base of the left lower lobe. Imaging findings of a patient with tuberous sclerosis. Axial CT shows a fat containing mass in the left kidney (arrow) (A), which is confirmed on T2 fat saturated MRI image (B). Numerous thin wall lung cysts is shown on CT of the chest as part of the complex (C). Succinate dehydrogenase (SDH)-deficient RCC syndrome Genomic Findings: Hereditary paraganglioma and pheochromocytoma is an autosomal dominant syndrome caused by SDH deficiency. Mutations in 3 of the 4 SDH genes (SDHB, SDHC, and SDHD) have been associated with this syndrome. SDH catalyzes the oxidation of succinate to fumarate in the citric acid cycle. Similar to FH mutations in HLRCC, SDH mutations contribute to tumorigenesis through the accumulation of HIFα.  Syndrome VHL HPRC BHD TSC HLRCC SDH-associated Renal Cancer Gene association C-MET FLCN TSC-1 TSC-2 FH SDH-B SDH-C SDH-D Chromosome locus 3p25.3 7q31.3 17p11.2 9q34 16p13 1q42.3-q43 1p36 1q23 11q23 Clinical Findings   Imaging Findings Renal lesions spectrum varies from simple cysts to complex cysts with solid components and completely solid lesions Hypovascular on contrast-enhanced CT. The change in enhancement before and after contrast is as little as 10-15 HU. Solid renal masses that enhance significantly after IV contrast and cysts. Multiple pulmonary cysts with well-defined, round, air-filled structures in the lower lobes. Non fatty AML with higher attenuation than surrounding renal parenchyma on unenhanced scans. Solitary and unilateral hypovascular RCC on CT and MRI. Complex cystic or solid enhancing renal masses. Oncocytomas demonstrate central scaring and progressive enhancement. 31 year old female with VHL. Numerous cystic lesions of the kidneys and pancreas identified (A and B). Note mostly solid lesion within the right kidney compatible with ccRCC(arrow) (B). Renal Findings: Patients with germline SDH mutations can develop RCCs of various histologic subtypes, including ccRCC, chromophobe RCC, and oncocytomas. RCCs associated with SDH mutations are aggressive and present earlier than the general population, typically by age 30. Since RCC may be the only clinical manifestation in this syndrome, testing for SDH mutations in patients with early-onset, bilateral, multifocal ccRCC or chromophobe RCC is warranted. Extra-renal Findings: Extra-renal manifestations associated with SDH mutations include pheochromocytomas, gastrointestinal stromal tumors, and paragangliomas that can develop anywhere along the paravertebral axis. Imaging Findings: RCCs in SDH mutation are usually solid, the aggressive forms have necrotic components. Paragangliolmas on the other hand, demonstrate rather distinct imaging and location features that help to differentiate them from other forms of malignancies. These features include T2 signal hyperintensity and avid arterial enhancement on MRI and CT. A B 25 year old male with VHL. Enhancing mass within the left scrotum (arrow) compatible with cystadenoma. 29 year old male with SDH-B mutation. T2 hyper- intense lesion (arrow)(A) with avid enhancement (arrow) (B) in the aortopulmonary window was confirmed to be a paraganglioma. Hereditary Papillary Renal Carcinoma (HPRC) Syndrome Genomic Findings: HPRC syndrome is an autosomal dominant disorder caused by a missense mutation in c-MET, a proto-oncogene, located on chromosome 7. c-MET encodes the hepatocyte growth factor receptor (HGFR), a tyrosine kinase receptor. Mutations in the c-MET gene result in constitutive activation of HGFR, causing aberrant cellular proliferation, invasion, and angiogenesis. Renal Findings: Affected patients develop bilateral, multifocal type I papillary RCCs. Papillary RCCs are slow growing and can present early (2nd or 3rd decade) or late (after 5th decade). Imaging Findings: HPRC renal tumors are often hypo-enhancing on contrast-enhanced CT. Therefore, they might be mistaken for cysts if density measurements are not performed carefully. In HPRC renal lesions, the change in enhancement before and after contrast is as little as 10-15 HU. Since papillary RCC is hypoechoic, ultrasound can easily miss papillary lesions in HPRC patients. On MRI, the pRCCs are distinctly hypoenhancing with homogenous restricted diffusion, demonstrating as dark on ADC maps. 60 year old male with SDH-B mutation. Large T2 hyperintense and enhancing mass within the antrum of the stomach compatible with GIST (arrow)(A and B). Also noted an enhancing mass within the anterior mid-portion of the right kidney with a central scar, likely an oncocytoma (arrow)(C). A B C Conclusion: References: pRCC, Papillary renal cell carcinoma; chRCC, chromophobe renal cell carcinoma; ccRCC, clear cell renal cell carcinoma; LAM, Lymphangioleiomyomatosis; AML, angiomyolipoma; SDH, succinate dehydrogenase; GIST, gastrointestinal stromal tumor; VHL, Von Hipple-Lindau; HLRCC, Hereditary leiomyoma renal cell carcinoma; BHD, Birt-Hogg-Dube; HPRC, Hereditary papillary renal cancer; TSC, Tuberous sclerosis complex; FH, Fumarate hydratase Hereditary and genetically defined RCCs are a small group of renal cell cancers with diverse histopathological subtypes and syndromic manifestations. The renal and extra-renal manifestations of these syndromes are often the source of severe comorbidities. In addition, patients life expectancy can be affected by other factors including; delayed diagnosis, early-age onset and predisposition to other malignancies. In this education exhibit, we aimed to enhance radiologists’ knowledge of the imaging findings of HRCCs. We hope that better understanding of the genomic basis of HRCCs in combination with imaging findings will create an opportunity to develop prevention and treatment strategies that improve the lives of our patients. 42 year old male with HPRC. Several bilateral hypoenhancing masses of the kidneys (arrows) with homogenous restricted diffusion on ADC maps.