Rare Cancer Types and Syndromes

Paraganglioma

• a rare type of neuroendocrine tumor that arises from clusters of cells derived from the autonomic nervous system (head, neck and spine usually)

Can be either:

• Functional:

  • producing excess catecholamines→ HTN, sweating, rapid heartbeat

• Non-functional:

  • not producing hormones, usually asymptomatic

Functional Paraganglioma symptoms

• Excessive catecholamines (like norepinephrine)

• High blood pressure: preissnt or episodic

• Tachycardia/palpitations

• Excessive sweating

• Headaches

• Anxiety

• Flushing/pallor

• tremors

Pheochromocytomas

• paraganglioma tumor that develops in the adrenal glands

• ALWAYS FUNCTIONAL

  • produces excessive amounts of catecholamines (adrenaline and noradrenaline) cause high blood pressure, rapid heart rate, sweating and headaches

• Surgical removal of the tumor

MEN type 2B

RET

• Medullary Thyroid Cancer

• Marfanoid Habitus

• Mucocutaneus “GNs”(?)

Pheochromocytoma/Paraganglioma

MEN type 2A

-RET

• Medullary thyroid carcinoma

• Parathyroid hyperplasia

Pheochromocytoma/Paraganglioma

Paraganglioma-Pheochromocytoma Syndrome

Genes: SDHA, SDHAF2, SDHB, SDHC, SDHD, MAX, THEM127

Autosomal dominant

Maternal imprinting: SDHAF2, SDHD

• Tumors: Paragangliomas and Pheochromocytomas,

  • Gastrointestinal stromal tumors (GISTs): anywhere in the GI tract

  • Pulmonary Chondromas:

  • Clear cell renal cell carcinoma

  • Other tumors:

Multiple Endocrine Neoplasia Type 1

Gene MEN1 (tumor suppressor)

Inheritance : autosomal dominant

Diag criteria

• at least two: parathyroid, pituitary gland, gastro-intrapancreatic neuroendocrine tumor (GEP)

• at least one: Endocrine tumor and first-degree rel. with MEN1

Clinical Characteristics:

• Hyperparathyroidism: usually first (20-25yo) → leads to hypercalcemia by 50yo→causes the several symptoms

Symptoms

• CNS: PITUATARY ADENOMA

• GI:

• Skeletal increased risk factor

• Renal

• Cardiovascular

MEN1 Clinical Characteristics

• Primary hyperparathyroidism

  • Most common symptom

  • 90% is the first symptom

  • Age of onset 20-25yo

  • Hypercalcemia by 50yo→ increased bone fracture risk, HTN, hypercalciuria, short QT interval

• Tumors

  • Gastroenteropancreatic (GEP) Neuroendocrine tumors

  • Adrenocortical: nonfunctional

  • Anterior Pituitary Adenomas

    • growth hormone

    • Prolactin and Follicle stimulating hormone

    • Adrenotropic hormone: excess cortisol (Cushing disease)

• Skin

  • Facial angiofibroma’s

  • Collaenomas

MEN1 Medical Managment

• Screening starts very early—> the children of patients

Parayhtoird: imaing at 5yo

Pitoeraury: imaing 5yo

Multiple Endocrine Neoplasia Type 2

• Gene: RET (proto oncogene)

• Autosomal dominant

• MEN2A: 2 Features: medullary thyroid cancer, pheochromocytoma, parathyroid adenoma

• MEN2B: Marfanoid habitus, Early onset, MTC, PCC and ganglioneuromas —> bowel movement issues, renal agenesis etc (add from notes)

• FMTC: Presence of 4 or more cases of MTC over more than one generation in the absence of PCC

• Additional

Differntiing Multiple Endoceinre Neoplasias

MEN2 Managment Recommendations

• Medullary Thyroid cancer correlates with MEN2

• Prophylactic Thyroidectomy recommended: EXTREMLTY early (one variant is in 1st year, but other variants generally before 5yo)

Birt-Hogg-Dube Syndrome

• Gene: FLCN

• Inheritance: Autosomal Dominant

• one major or two minor

  • Major: 5 facial or truncal papules, 1 confirmed as fibrofolliculoma

  • Minor:

    • Early onset renal cell cancer (<50yo),

    • Multifocal/Bilateral renal cell cancer,

    • renal cell cancer with mixed chromophobe/oncolytic histology,

    • Multiple lung cyst (ETC)

Birt-Hogg Dube Beneing SKin Findings

• Fibrofollicuolmas: Hair follicle tumors present in 805 of patine >40yo

• Angiofibroma: vascualr tumor

• Acrochordon: skin tags

Birt Hogg Dube clincal symptoms

• Benign skin findings

• Pulmonary: Spontaneous pneumothorax (from LUNG CYSTS), lung nodules/cysts3

  • Often first symptom

  • age of onset: male 38yo, female 30yo

• Renal Cancers: oncocytoma + chromophobe hybrid, Clear Cell + Oncocytoma, Papillary carcinoma (less common)

Birt-Hogg-Dube Surivllance and Managment

• Surveillance: skin exams, annual Abdominal MRI/CT, annual thyroid ultrasound

• Avoiding: cigarette smoking, high ambient pressure (scuba diving)

Other Rare Tumor Predispition Syndromes

When to Suspect a herdiary renal cancer sydnrome?

• early onset RCC before 50

• bilateral or multi focal kidney tumors

• Fam hx of renal cancer or related cancers

• Associated syndromic features (skin lesions, lung cysts, fibroids)

Hereditary Leiomymatosis Renal Cell Cancer (HLRCC) syndrome: Inheritiance

• Fumarase (FH) gene

  • MONO (single) Allelic

  • JUST ONE PATHOGNEIC VARIANT necessary for condition

  • Autosomal Dominant, Highly Penetrant

Hereditary Leiomymatosis Renal Cell Cancer (HLRCC) syndrome: Clinical Findings

• Cutaneous Leiomytoma: Skin Fibroids,

• Uterine Leiomytoma: 100%, early diagnosis average 30yo, can cause pelvic pain and menstrual irregularity/heavy

  • larger, more numerous, younger age of onset that SPROADIC uterine fibroids

• Aggressive Renal Cell Carcinoma: 36-44yo

  • usually solitary

Hereditary Leiomymatosis Renal Cell Cancer (HLRCC) syndrome: Renal Cell Carcinoma

• 20% lifetime risk

• Aggressive forms of Renal Cell Carcinoma: Papillary Type 2

  • unlike other renal cancer syndromes, Papillary 2 is aggressive and metastasizes early

• usually solitary, or unilateral

Hereditary Leiomymatosis Renal Cell Cancer (HLRCC) syndrome: Managmet

• annual MRI of kidneys

• Dermalogical exam 1-2 years

• Regualr uterine

• Genetics followup

Von Hippel Lindau: Gene/inheritinace

VHL gene

Tumor suppressor

Autosomal domaiant with high pentrence

20% de novo mutation

Why id denovo rate important?

• No signs or symptoms in the family hisotry, than mabye the patient has a De Novo mutation ( IF THERE IS A HIGH DENOVO RATE)

VHL Syndrome organ involvement:

• Rentinal angioama (espcially young)

• HALLMARK: Multiple Hemangioblastoma

• Clear Cell Renal Cell caracmoa (before 40)

• Renal and Pancreatic cyts

• Pancreaic neuroencine tumors

• Adrenal or extra-adrenal pheochromocytoma

VHL: Hemangioblastoma symptoms

• Fluid buildup in brain that pushes on the brain

  • Dizziness,

  • headaches,

  • double vision,

  • vomit/swallowing difficulties

VHL: Pheochromocytoma symptoms

• “Fight or Flight”

  • HTN

  • Sweating

  • High heartrate

  • Anxiety/Panic

Hereditary Papillary Renal Cancer

• MET

• Proto-oncogene

• Autosomal dominant

• Penetrance 100%

• Associated cancer: RCC papillary type 1

Tuberous Sclerosis Complex (TSC)

• TSC1 (hamartin) and TSC2 (tuberin)

• Autosomal dominant

• De Novo rate 66%

• HEREDITARY RENAL CANCER SYMDOMRE

TSC Clinical features

• Skin

  • ASH leaf spots

• CNS: Tumors (leading casue of death)

• Kidney

  • Angiomyolipomas

  • Cysts

  • Renal disease (second leading cause of early death)

• Heart:

  • Rhabdomyomas,

  • Arrhytmias

• Lungs: (Fill in from Lecture slides)

TSC: Skin Manifestations

• Hypomelanimc macules (ASH LEAF SPOTS)

• Facial angiofibroma

• Shagreen patches

• Ungual fibromas

TSC: CNS Clincial Findings

• CNS tumors are leading cause of death in TSC

  • Brain lesions

  • Seizures

  • Intellcual diabltiy (AUTISM)

  • Developmantl Delay

Von Hippel-Lindau (VHL)

VHL

• Renal cell carcinoma

• Hemangioblastoma

• Pancreatic endocrine neoplasm

Pheochromocytoma/Paraganglioma

Hereditary Paraganglioma 3

SDHC

• GIST

Pheochromocytoma

Hereditary Paraganglioma 4

SDHB

• GIST

Pheochromocytoma

SDHB/SDHAF2

• “B” = Bad, “F”=Father

• A high risk of malignancy and extra-adrenal sympathetic PGLs

SDHD

• “D”= Dad

• Parent of origin effects (Deleterious effects from Dad)

What is a rare tumor?

• a tumor in organs that rarely develop malignances

• a tumor with dwan unusual/uncommon pathology/histology

  • Risk of inherited susceptibility is often increased in rare tumors compared to common tumor types

Challenges associated with Rare Tumors

• Patients may unaware of tumor’s pathology

• Patient (at times, referring) may not be aware of importance of reporting certain findings

• Limited information

• data prone to ascertainment bias: most striking cases idented, studied and reported

Fumarase Deficiency

• Bi-allelic (two pathogenic variants) of Fumarate Hydratase (FH) gene

• Also called Fumaric Aciduria

• Clinical symptoms

  • Severe neonatal and early infaitle encephalopathy

    • Poor feeding

    • Failre to thrive

    • hypotonia

    • seziures

    • dysmorpic facial features

SDHx genes

• SDHA + SDHB (responsible for Succinate to fumarate conversion)

• SDHC + SDHD (anchor enzyme to the membrane)

encode the 4 subunits of the SDH mitochondrial enzyme

Succinate dehydrogenase (SDH) enzyme converts succinate to fumarate: lack of activity results in oxidative stress

ASSOCIATED WITH HEREDITARY PGL-PHEO SYNDROME

SDHD, SDHAF2 and MAX

• Parent of origin pathogenic variant affects risk for Hereditary PGL-PHEO syndrome

  • Father: high risk of manifesting PGLs and PCCS

  • Mother: Low risk of manifesting (with exceptions)

  SDHD→ D = DAD

Overlap of features of MEN1, 2A, 2B

• Pituitary Adenoma: 1 only

• Pancreatic tumors: 1 only

• Parathyroid Hyperplasia: 1+2A

• Medullary Thyroid Carcinoma: 2A + 2B

• Pheochromocytoma: 2A+ 2B

• Mucosal neuromas: 2B only

• Marfanoid habitus: 2B only