Familial Tumor Syndromes - associated tumors

Question 1

Cowden syndrome

Answer 1

Lhermitte-Duclos disease (LDD)
meningiomas

Question 2

Tuberous sclerosis complex

Answer 2

subependymal giant cell astrocytoma (SEGA)

Question 3

Li-Fraumeni Syndrome (5)

Answer 3

Astrocytoma** (most common)
ependymoma
choroid plexus tumors
medulloblastoma
oligodendroglioma

Question 4

Turcot Syndrome (2)

Answer 4

Medulloblastoma (very high risk for chidhood onset medulloblastoma) MRI q1-3 years in 1st decade
glioblastoma

Question 5

Nevoid Basal Cell Carcinoma Syndrome (Gorlin)

Answer 5

medulloblastoma
(facial dysmorphism and basal cell carcinoma)
get MRI for medullo up to age 8

Question 6

VHL

Answer 6

hemangioblastoma
posterior fossa location -most commons
endolymphatic sac tumor
(associated sudden hearing loss and vertigo)

Question 7

Cowden Syndrome

Answer 7

aka multiple hamartoma syndrome
AD
hamartoma of ectodermal, mesodermal and endodermal origin
(loss of function mut in phosphatase and tensin homolog (PTEN) on chrome 10q23
(now part of PTEN hamartoma tumor syndrome=spectrum)
loss of function -> overgrowth of benign and malignant tumors of breast, follicular thyroid, endometrium, skin, kidneys and GI hamartoma (or ganglioneuroma) colon
clinical manifestation seen by second decade of life (90%)

Question 8

Cowden syndrome diagnostic criteria

Answer 8

DX: 3 or more major (one must be macrocephaly, LDD or GI hamartomas) -or-
2 major and 3 minor

Major:
cancers: 1-breast, 2-epithelial-endometrial cancer, 3-follicular thyroid cancer, 4-GI hamartomas (incl ganglioneuroma-excludes hyperplastic polyps)
5-Lhermitte- Duclos disease (adults-cerebellar)
6-adult macrocephaly (>97th perc)
7-macular pigmentation of glans penis
8-mult mucocutaneous lesions: 1 trichilemmoma>bx proven; mult. Palmoplantar keratoses; oral papilloma (on tongue and gingiva, multiple; mult cutaneous facial papules

minor: autism, colon cancer, >3 esophageal glycogenic acanthoses, lipomas, MR/ID (IQ<75), papillary thyroid cancer, renal cell carcinoma, single GI hamartoma, testicular lipomatosis, vascular anomalies (mult intracranial dev venous anomalies)

Question 9

Lhermitte-Duclos Disease

Answer 9

associated with Cowden Syndrome/PTEN (1 of major dx criteria)
slow growing tumor contains dysplastic cells in cerebellum (aka dysplastic gangliocytoma)
classified with neuronal and mixed neuronal-glial tumors
IHC-activation or mTOR pathways (PTEN/AKT/mTOR)
histology: thickened and abnormal myelination of molecular layer in cerebellum, attenuated or absent Purkinje cells, infiltration of granular layer by dysplastic ganglions cells and variable vacuolization white matter)
MRI (imaging of choice) shows striated or laminar appearance of mass. t1-hypotense infrequent contrast

Question 10

Tuberous Sclerosis Complex

Answer 10

AD
TSC1 or TSC2-form regulatory complex for limiting activity of cell regulators or cell growth mTORcomplex 1 (mTORC1) by inhibiting small GTPase ras homolog
tumors include:
skin (hypomelantoic macules, angiofibromas, fungal fibromas)
brain: subependymal nodules, cortical dysplasia, SEGA
kidneys: angiomyolipomas, cysts, renal cell carcinomas
heart: rhabdomyomas
lungs: lymphangioleiomyomatosis
–
2nd most common neurogenetic tumor syndrome
benign hamartomas of eyes, brain, kidneys, lungs, skin and heart
epilepsy very common
also see neurodevelopmental abnormalities and neurocogntiive deficits
TSC2 has worse burden of disease and outcomes than 1 mut
—
common first manifestations: cardiac rhabdomyoma (in womb), hypopigmented macules, infantile spasms/seizures
—-

Question 11

TSC Dx Criteria

Answer 11

Major:
Hypomelanotic macules
angiofibromas (3 or more)
ungual fibromas (2 or more)
shagreen patch
retinal hamartomas (2 or more)
cortical tubers
subependymal nodules
cardiac rhabdomyoma
pulmonary lymphangioleiomyoma
angiomyolipomas (2 or more)

Minor:
confetti lesions
dental enamel pits (3 or more)
intraoral fibromas (2 or more)
retinal achromatic patch
multiple renal cysts
nonretinal hamratomas

Question 12

TSC imaging

Answer 12

cortical tubers, subependymal nodules (usually doesn’t enhance but do calcify)-> if enhance transform into subependymal giant cell astrocytoma. SEGA usually a formal of Monroe and can obstruct flow.
get MRI 1-3 years to age 25
surgery (curative) or everolimus 4.5 mg/m2 median duration is 32.4 months (mtor inhibitor) for growing/progression, after age 25 very slow growing. can monitor

Question 13

Li-Fraumeni Syndrome

Answer 13

AD / TP53 on chrom 17p13
cancer predisopostion syndrome
high penetrance *>70% men get cancer and >90% women
cancers
adrenocortical carcinoma (50%)
CNS (2-10%)
osteosarcoma (2-3%)
soft-tissue sarcomas (8-9%)
—
CNS tumors occurs before age 40
infiltrating astrocytoma most common
ependymomas
choroid plexus carcinomas
oligodendroglioma
medulloblastoma
supratent primitive neuroectodermal tumors
—-
**40% kids with choroid plexus tumor assoc with LFS
>10% kids with medulloblastoma -shh associated with LFS
—get annual MRIs

Question 14

Li_fraumeni diagnosis

Answer 14

all three classic criteria germline pathogenic variant TP53 on 17p13
-patient with sarcoma diagnosed before age 45
-1st degree relative with any cancer diagnosis before age 45
-1st or 2nd degree relative with any cancer diagnosis before age 45 or sarcoma dx at any age