Hereditary cancer miscellaneous

Question 1

Identify the pathology findings of the

renal cancer susceptibility syndromes.

Answer 1

Syndrome, Location, RCC Pathology

Von Hippel Lindau	
     Bilateral, multifocal, Clear cell
Hereditary Papillary
     Bilateral, multifocal, Papillary
Birt-Hogg-Dubé
     Bilateral, multifocal, Chromophobe, hybrid chromophobe/oncocytoma
HLRCC	
     Solitary, Type II papillary, clear cell

Question 2

Identify the syndromes that account for a hereditary

susceptibility to medullary thyroid cancer.

Answer 2

Hereditary Medullary Thyroid Cancer (MTC)
10% of all thyroid cancer is medullary
Approx 25% of MTC is hereditary and 75% is sporadic

MEN2A  =  ~20%
MEN2B  =  ~2%
FMTC  =  ~2%

Question 3

Identify the tumors associated with Von Hippel-Lindau (VHL) syndrome and the approximate prevalence of each.

Answer 3

CNS hemangioblastoma:(?) Prototypic lesion
Retinal hemangioblastoma: 70%
Clear cell renal carcinoma: 40%
Pheochromocytoma: (?)
Endolymphatic sac	: 10%

Question 4

When should RET mutation testing be performed?

Answer 4

RET mutation testing is appropriate for any patient diagnosed with:
Medullary thyroid carcinoma (MTC)
C-cell hyperplasia (carcinoma in situ of the thyroid)

RET testing should be performed, regardless of other symptoms

Patients with c-cell hyperplasia and negative RET testing should consider pursuing research-based testing, due to the extremely strong correlation between this finding and RET mutations

Question 5

What are the hallmark tumors or cancers

observed in Li-Fraumeni syndrome?

Answer 5

Sarcoma
Brain tumor
Breast cancer			      “SBBLA” syndrome
Leukemia
Adrenocortical carcinoma

Other:Choroid plexus tumor

Question 6

What hereditary cancer syndromes have skin

findings, and what are these lesions?

Answer 6

1. Cowden: Trichilemmomas, papillomatous papules, lipomas
2. Gardner: Soft tissue skin tumors (epidermal cysts)
3. Muir-Torre: Sebaceous carcinomas or adenomas, keratoacanthomas
4. Peutz-Jegher: Blue/black pigmentation around mouth and digits
5. Birt-Hogg-Dubé: Fibrofolliculomas
6. HLRCC: Cutaneous leiomyomata, Schwannomatosis Cutaneous schwannomas
7. Tuberous Sclerosis: Hypomelanotic macules, facial angiofibromas, shagreen patches, ungula fibromas
8. MEN 2B:Eyelid and oral neuromas
9. NBCCS: Pits on palms or soles
   10: Ataxia telangiectasia: Telangiectasias near surface of skin

Question 7

What hereditary cancer syndromes

are associated with breast cancer?

Answer 7

HBOC: 50-85%
Cowden syndrome: 25-50%
Li-Fraumeni syndrome:	>90% lifetime risk for female to develop any cancer type
Peutz-Jeghers syndrome: 54%
Hereditary diffuse gastric cancer: 39% (lobular-type)
Neurofibromatosis type 1	---
Bloom syndrome	---
Ataxia-telangiectasia	---

Question 8

Which hereditary cancer syndromes are caused

by mutations in tumor suppressor genes?

Answer 8

HBOC: BRCA1, BRCA2
HNPCC: MLH1,  MSH2
Li-Fraumeni syndrome:TP53
Retinoblastoma: RB1
Von Hippel-Lindau syndrome: VHL

Question 9

Tuberous-Sclerosis Complex (TSC)

Answer 9

A whole lot of funky growths
Inheritance: Autosomal dominant
Genes: TSC1, TSC2
Major features:
●Angiofibromas
●Cardiac rhabdomyoma
●Cortical dysplasias
●Hypomelanotic macules
●Lymphangioleiomyomatosis
●Multiple retinal nodular hamartomas
●Shagreen patch
●Renal angiomyolipoma
●Subependymal giant cell astrocytoma (brain tumor)
●Subependymal nodules
●Ungual fibromas
●Neuroendocrine tumors
    oPituitary adenoma
    oParathyroid adenoma
    oPancreatic adenoma
    oGastrinoma
    oPheochromocytoma
    oCarcinoids

Question 10

Tuberous Sclerosis: Minor features

Answer 10

●“Confetti” hypopigmented skin lesions
●Dental pits
●Intraoral fibromas
●Multiple renal cysts
●Retinal achromic patch

Question 11

Multiple Endocrine Neoplasia Type 1 (MEN1)

Answer 11

Inheritance: Autosomal dominant
Gene: MEN1
Associated tumors:
●Parathyroid
   oHyperparathyroidism
   oHypercalcemia
●Pituitary
   oProlactinoma
●Pancreatic neuroendocrine
    oGastrinoma
    oInsulinoma
    oGlucagonoma
●Carcinoid tumors
●Adrenocortical tumors
●Growths
    oAngiofribromas
    oCollagenomas
    oLipomas
    oMeningiomas
    oEpendymomas
    oLeiomyomas
Because of parathyroid tumors/adenomas, may manifest with primary hyperparathyroidism

Question 12

Multiple Endocrine Neoplasia Type 2 (MEN2)

Answer 12

Inheritance: Autosomal dominant
Gene: RET
●Proto-oncogene (not a tumor suppressor)
MEN2A
●Associated with GoF mutations
●Medullary thyroid cancer– Often before 35
●Pheochromocytoma
●Hyperparathyroidism
●Parathyroid adenomas
●May present with cutaneous lichen amyloidosis
Prophylactic thyroidectomy is recommended for mutation positive individuals

Question 13

MEN2B

Answer 13

MEN2B
●Associated with GoF mutations
●Early, aggressive medullary thyroid cancer
   oOften in childhood
   oThyroidectomy should occur before age 1 to avoid metastasis
●Pheochromocytoma
●Absence of parathyroid disease
●Marfanoid habitus (Kyphoscoliosis)
●Distinctive facies
    oHooded eyes
    oProminent lips
●Growths
    oMucosal neuromas
    oDiffuse ganglioneuromatosis of the digestive tract

Question 14

Familial Medullary Thyroid Cancer

Answer 14

●Associated with GoF mutations

●Medullary thyroid cancer without other symptoms of MEN2A/2B