Week 6: Hereditary renal tumor syndromes Flashcards by emma Wagner

What are the primary functions of the kidney?

-Waste removal
-Fluid and acid-base balance
-Regulate blood pressure
-Produce active form of vita D
-Control RBC production

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Most kidney cancer occurs in what part of the kidney?

The cortex

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T/F cancer in the medulla of the kidney is common

False, most occur in the cortex and cancer in the medulla is rare

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Cancers in the renal pelvis may be associated with what tumor predisposition syndrome?

Lynch syndrome

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What is the median age of diagnosis for renal cancer?

64 yrs

Unusual in individuals under 45yrs, rare in children

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Is renal cancer more common in men or women? Does it have higher incidence in any ancestry?

2-fold more common in men than women
-Higher incidence in African Americans and Native American populations

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What are some signs and symptoms associated with renal cancer?

-Hematuria (blood in urine)
-Flank pain
-Flank mass
-Weight loss
-Fatigue
-Anemia

Most renal cancer detected incidentally on imaging for vague abdominal complaints that may be unrelated

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What is the routine screening method for renal cancer?

There isn’t one

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What are the four types of treatment/surgical options for renal cancer?

Observation/active surveillance: masses <4cm, single focus, no extension
Partial nephrectomy: masses >4cm <7cm, multifocal, bilateral
Radical nephrectomy
Adjuvant therapy: for advanced stage disease and aggressive tumors

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What are some risk factors for kidney cancer?

-Smoking
-Hypertension
-Obesity
-Occupational exposures
-Advanced kidney disease
-Sickle cell
-Certain medications
-Family hx

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Approximately what percent of renal cancer is due to hereditary predisposition?

~4%

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What are paragangliomas? If someone is found to have one, should they undergo genetic evaluation?

PGL: neuroendocrine tumors of sympathetic or parasympathetic autonomic ganglia

Up to 40% of PGLs and PCCs may be due to hereditary predisposition so recommended that all patients with these tumors undergo genetic evaluation.

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What are pheochromocytomas? Should someone with a PCC undergo genetic evaluation?

PCC: neuroendocrine tumors of the adrenal gland

Up to 40% of PGLs and PCCs may be due to hereditary predisposition so recommended that all patients with these tumors undergo genetic evaluation.

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What are gastrointestinal stromal tumors (GISTs)?

-Rare tumors usually of gastrointestinal mesenchymal origin
-Most of pediatric GISTs show absent SDHB on IHC
-All pediatric GISTs need genetic risk evaluation

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What is the inheritance pattern, gene, and renal tumor type associated with von Hippel-Lindau?

-AD
-VHL gene
-Clear cell RCC, hemangioblastomas, pheochromocytomas

-Founder variant R200W found in Chuvash population, not associated with VHL in heterozygous state, associated with AR familial erythrocytosis type II

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When is it recommended to start screening for individual with VHL?

Typically before age 1

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What does management look like for VHL?

-RCC: “3cm rule”, active surveillance for tumors <3cm, nephron-sparing approach for larger tumors
-HIF2a inhibitor for adults whose disease does not require immediate surgery

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Name the gene, inheritance pattern, and tumor type associated with hereditary papillary renal cancer (HPRC)?

-Gene: MET
-AD
-Type I papillary RCC

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Name the gene, inheritance pattern, and tumor type associated with Birth-Hogg Dube?

-Gene: FLCN
-AD
-Chromophobe RCC, oncocytoma, hybrid, fibrofolliculomas

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What are the 3 discussed benign renal tumors?

-Angiomyolipomas (more common in females)
-Oncocytomas
-Renal adenomas

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Name the gene, inheritance pattern, and tumor type associated with tuberous sclerosis complex (TSC)?

-Gene: TSC1, TSC2
-AD (2/3 de novo)
-Angiomyolipomas, clear cell RCC

Name the gene, inheritance pattern, and tumor type associated with hereditary leiomyomatosis and renal cell carcinoma (HLRCC)?

-Gene: FH
-AD
-Type II papillary RCC, uterine and cutaneous leiomyomas

Name the gene, inheritance pattern, and tumor type/ pathology associated with hereditary paraganglioma and pheochromocytoma syndrome (hereditary PPGL)?

-Genes: SDHA, SDHB, SDHC, SDHD
-AD, paternal parent of origin transmission due to maternal imprinting
-Clear cell RCC, oncocytic RCC, paragangliomas, pheochromocytomas, GISTs

Name the gene, inheritance pattern, and tumor type associated with BAP1 tumor predisposition syndrome?

-Gene: BAP1
-AD
-Clear cell RCC, chromophobe RCC,
uveal/cutaneous melanoma, mesothelioma

Describe the increased cancer risk for HPRC and the recommended management

-Increased risk for multifocal and bilateral papillary renal tumors -Screening: abdominal MRI every 1-2yrs beginning at 30yr -Type 1 papillary renal cancer management: "3cm rule", active surveillance for tumors <3cm, nephron sparing approach for larger tumors -Therapeutic agents targeting MET pathway being developed

Birt-Hogg Dube has an increased risk for what type of non-kidney cancer?

Melanoma Management: skin exam every 6-12 months

Birt-Hogg Dube has a high risk for what pulmonary event?

-High risk for spontaneous pneumothorax -High risk for bilateral multifocal pulmonary cysts (70-85%) Management: avoid smoking, high ambient pressures, radiation exposure

Describe the renal cancer risk for Birt-Hogg Dube

-High risk for multifocal, bilateral tumors at young age, lifetime risk for renal tumor 25-35% -7-fold increased risk for RCC Management: abdominal MRI every 3yr beginning 20yr, RCC: "3cm rule", nephron-sparing approach for larger tumors

What is the leading cause of death for individuals with TSC?

CNS tumors leading cause of morbidity and mortality, renal disease second leading cause

T/F most cases of TSC are inherited

False! 2/3 cases de novo

Would you describe TSC as a localized, singular system disorder or a disorder with multisystem involvement?

-Multisystem involvement! -Highly variable phenotype, many cases underdiagnosed due to mild symptoms

A mutation in TSC1 or TSC2 produces a more severe phenotype? A mutation in which is more likely to be familial?

-TSC2 more severe and likely to be de novo -TSC1 more likely to be familial

A contiguous gene deletion of TSC2 and PKD1 on 16p result in what type of phenotype?

-Resulting phenotype of TSC and polycystic kidney disease (PKD) is severe -Usually evident in utero or diagnosed in infancy -Need to assess for PKD1 deletion if TSC2 deletion is identified

What does screening and management look like for TSC?

-Screening begins in infancy -Routine baseline EEGs and early screening for EEG abnormalities -Avoid contrast with brain MRI unless necessary -Abdominal MRI surveillance -mTOR inhibitors for treatment of TSC associated SEGA, LAM, AML

List the 3 primary clinical features of HLRCC

-Uterine fibroids: ~90% of females, typically seen at young age and require surgery -Cutaneous leiomyomas -RCC: highly aggressive papillary type 2 RCC that metastasizes early

What does management look like for HLRCC?

-Screening for renal tumors beginning at 8-10yr with annual abdominal MRI -Prompt surgical resection of renal tumors because such aggressive growth

Why is HLRCC an exception to the 3cm rule for management?

Because tumors are thought to metastasize very early and therefore should be resected widely and promptly

Mutations in what gene associated with PPGL syndrome are associated with risk for metastatic disease?

SDHB

GISTs, typically in the stomach, are associated with mutations in what two genes for hereditary PPGL?

SDHA and SDHC mutations

What is unique about the inheritance of hereditary PPGL?

-It is AD -SDHD displays a paternal parent of origin transmission due to maternal imprinting **tumor risk only if paternally inherited SDHD mutation***

What does screening and management look like for hereditary PPGL?

-Screening: beginning at age 6 annual biochemical and clinical surveillance, biennial full body MRI, consider endoscopic evaluation -Management: early detection and prompt surgical excision, active surveillance and non-surgical approaches are NOT appropriate

List some of the tumor risks for someone with BAP1 TPDS

-BAP1-inactivated melanocytic tumor (BMIT) -Uveal melanoma -Malignant mesothelioma -Cutaneous melanoma -RCC -Basal cell carcinoma -Possible increased risk for hepatocellular carcinoma, meningioma, thyroid, breast, lung, ovarian

T/F Sporadic tumors frequently have BAP1 mutations

True

What does management and screening look like for BAP1 TPDS?

-No consensus guidelines -UM: annual dilated eye exam with imaging -Annual full body dermatological exam -RCC: abdominal ultrasound or MRI Agents to avoid: -Arc-welding -Asbestos -Smoking -Prolonged sun exposure -Routine chest x-ray and CT

Inheritance, gene, info about microphthalmia-associated transcription factor (MITF)

-AD -Gene: MITF -3-5 fold increase for melanoma -POSSIBLE increased risk for renal cancer, studies not conclusive -No medical management recommendations to address possible increased risk for renal cancer

Clear cell RCC histology is associated with mutations in what genes?

VHL, BAP1, TSC1, TSC2, SDHA-D

Papillary type 1 RCC histology is associated with mutations in what gene?

MET

Chromophobe, hybrid, and oncocytoma RCC histology is associated with mutations in what gene?

FLCN

Papillary type 2 RCC histology is associated with mutations in what gene?

Oncocytic RCC histology is associated with mutations in what genes?

SDHB, SDHC, SDHD

Angiomyolipoma RCC histology is associated with mutations in what genes?

TSC1, TSC2

Why is identifying the renal cancer syndrome important for non-genetics care?

Hereditary cancer syndromes affect surgical management considerations!