Hereditary Urogenital Cancer Syndromes
Melanie Corbman1 and Eric Fowler2
1 Eastern Regional Medical Center, Cancer Treatment Centers of America, Philadelphia, PA, USA
2 Midwestern Regional Medical Center, Cancer Treatment Centers of America, Zion, IL, USA
Urogenital malignancies are in the cancer spectra of multiple hereditary cancer syndromes. Some diagnoses are strongly associated with inherited risks for cancer, while others are less predictive of a mutation. This chapter will utilize case presentations to emphasize the importance of personal and family histories in cancer genetics risk assessments, explore some of the challenges and uncertainties associated with genetic counseling and testing, and highlight selected controversies in urogenital cancer genetics.
Case study 126.1 The urological oncologist on staff asks you to meet with a 45-year-old male patient who has been diagnosed with bilateral multifocal, extensive chromophobe and oncocytic renal cell tumors and underwent bilateral partial nephrectomies. The patient had multiple skin-colored papules on his face and reported a large lipoma under his right arm. The patient has a history of smoking. The patient reports the following family history:
Sister, age 42, was recently diagnosed with bilateral renal cell cancer and had similar papules on her face. Sister, age 45, is unaffected with cancer but reported that she had testing for Von Hippel–Lindau (VHL) syndrome due to family history and tested negative. Father died at age 48 from complications of a collapsed lung. Father had similar skin lesions and a history of smoking. Paternal grandfather had renal cell cancer. There are no cancers reported in the maternal family.
1. Considering the patient’s personal and family history, what genetic syndromes would be in your differential?
VHL syndrome Birt–Hogg–Dubé syndrome (BHDS) No genetic syndrome, since smoking can explain risk for renal cell cancer and pneumothorax One of the primary features of BHDS is skin-colored papules on the face, neck, and trunk that typically develop in the 20s–30s, and become larger and more numerous with age. Histologically, fibrofolliculomas are the most predictive of and associated with BHDS. Bilateral and multiple cystic pulmonary lesions, pneumothorax, and renal tumors such as chromophobe and oncocytoma (or hybrids of the two) further characterize the syndrome. BHDS can be diagnosed based on clinical findings or molecular genetic testing, with mutations in the FLCN gene being detected in almost 90% of people with the condition. BHDS is an autosomal dominantly inherited condition, with children and siblings of an affected individual having a 50% chance of being affected. Significant intra- and interfamilial variation has been documented.
2. The patient has limited medical insurance. The patient was referred to the dermatologist, who confirmed the diagnosis of BHDS. Would there be any reason for the patient to have genetic testing?
Yes, to confirm the diagnosis Yes, to provide information to family members No; the patient already has his diagnosis With the information provided by the dermatologist to confirm the patient’s diagnosis, the patient is more likely to get coverage for the molecular genetic testing. The results of the testing will enable him to get coverage to screen for the other manifestations of BHDS and for his family members to have testing. If a mutation is identified in the patient, family members can have site-specific testing for the identified mutation.
3. If the patient’s sons and sister, who have no symptoms, have genetic testing and find out that they test positive, should they have any screening for BHDS?
Yes; there are recommended evaluations for individuals who test positive No; they have no symptoms, so they do not need to have unnecessary tests No; a person who has annual medical exams does not need to have any additional testing Individuals who have been diagnosed with BHDS or those who have been found to carry a FLCN mutation should be monitored by physicians familiar with the syndrome. The following evaluations are recommended:
Dermatologic evaluation and punch biopsies of skin lesions High-resolution computed tomography (HRCT) or computed tomography (CT) of the chest and lungs to monitor for pulmonary cysts. A clinical suspicion of pneumothorax should result in immediate chest X-ray and CT and subsequent management. Abdominal and pelvic CT scan or magnetic resonance imaging (MRI) to monitor for renal tumors. Consideration of renal ultrasound to differentiate between cystic and solid lesions.
Case study 126.2 A 52-year-old African American and Native American female patient presented with iron deficiency anemia (large submucosal and extrinsic mass in the fundus with ulceration) and weight loss. CT of the abdomen was concerning for renal cell carcinoma with primary carcinoma of the pancreas versus renal cell carcinoma, and cystic adenoma of the pancreas. The patient underwent left-sided nephrectomy and tolerated the procedure well. The pathology showed clear cell carcinoma with sarcomatoid features (30%), stage III T3N0M0.
The patient reported the following family history:
Brother, age 60, recently diagnosed with pancreatic cancer, with a son who died of a hemangioblastoma of the spinal cord at age 40 Sister, age 57, with a history of three strokes and nephrectomy Brother with nephrectomy at age 53 for renal cell carcinoma Sister, age 45, recently diagnosed with an abdominal mass Brother died at age 29 of a cerebrovascular accident Mother died at age 67 of a brain stem tumor The patient has two sons, 26 and 21, and one daughter, 25, who are unaffected.
1. What hereditary cancer syndromes would you consider based on this patient’s personal and family history?
VHL syndrome Lynch syndrome Hereditary leiomyomatosis and renal cell cancer (HLRCC) VHL is associated with hemangioblastomas of the central nervous system and retina, clear cell renal cell carcinoma and renal cysts, endolymphatic sac tumors, and pheochromocytoma. Hemangioblastomas in the cerebellum can be the cause of such signs and symptoms as headaches, gait abnormalities, vomiting, and ataxia. Some people with VHL present initially with vision loss due to retinal hemangioblastomas. The leading cause of mortality in people with VHL is clear cell renal cell carcinoma, occurring in about 70% of affected individuals. Pheochromocytomas should be suspected as a possible cause of hypertension in people with VHL. Mild to severe hearing loss can be caused by endolymphatic sac tumors.
VHL is an autosomal dominant condition. Children and siblings of an individual who tests positive have a 50% risk to have the condition. Approximately four out of five of people with VHL have an affected parent, while one in five affected individuals are the first case in their families.
2. The patient stated that her family has been given a clinical diagnosis of VHL. Since the family already has the diagnosis, is there a benefit to performing genetic testing in this family?
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