Rare Cancer Syndromes Flashcards
What are oncogenes?
normally encourage cell growth and have gain of function when mutated (flooding of cells with signal to divide)
usually missense mutations
Examples: MEN2-RET
What are tumor suppressor genes?
normally restrain cell growth and have loss of function when mutated (cells grow and divide uncontrollably)
deletions, trucations, and inactivating mutations
Examples: Retinoblastoma (RB1); TP53; BRCA1/2
What are missmatched repair genes?
when mutated, fail to correct NEA replication errors allowing mutations to accumulate in regulatory genes
Example: HNPCC
What is Retinoblastoma?
tumor of the retina (nervous tissue lining)
germline mutations in RB1 (13q14.1) or chromosome 12 deletions (5-7%)
most common intraocular malignancy in childhood (average age of dx 12-18 months old)
90% cure rate by enucleation and radiation
What is Li Fraumeni Syndrome?
AD
loss of function for TP53 gene
50% of malignancies occur before age 30
What symptoms are associated with Li Fraumeni Syndrome?
mimic all other cancer syndromes (pre-menopausal breast cancer, sacroma, leukemia/lymphoma, arenocortical carcinoma, brain tumors/childhood choroid plexus tumors, GI cancers, RCC, lung cancers, skin cancers, thyroid cancers)
What is the Chompert Criteria?
used to diagnose Li Fraumeni Syndrome- any one of the below:
proband with a LFS tumor before age 46 y/o AND at least one 1st/2nd degree relative with a LFS tumor before age 56 y/o or with multiple tumors
proband with multiple tumors, two of which are LFS tumor and the first occurred before age 46 y/o
proband ACC or CPC regardless of age
How is Li Fraumeni Syndrome managed?
women with TP53 mutations: breast cancer screening breast cancer risk reducing procedures men and women with TP53 mutations: annual physical exam annual skin exam annual whole body and brain MRI consider colonoscopy every 2-5 years beginning at 25 y/o additional screening based on family history of cancer avoid radiation and smoking decrease sun exposure and alcohol
List the PTEN related disorders.
Cowden Syndrome
Bannayan-Riley-Ruvalcaba Syndrome
PTEN Related Proteus Syndrome
What clinical features are associated with Cowden Syndrome?
multiple hamartomas* macrocephaly autism skin findings benign nodules, polyps, breast disease breast cancer (85%) thyroid cancer (35%) uterine/endometrial cancer (28%) colon cancer (9%) renal cancer (35%)
What clinical features are associated with Bannan-Riley-Ruvalcaba Syndrome?
childhood onset
hamartomatous polyps
lipomas
pigmented macules of glans penis
What are the NCCN major diagnostic criteria for PTEN related disorders?
two of the following breast cancer non-medulary thyroid cancer macrocephaly endometrial carcinoma
What are the NCCN minor diagnostic criteria for PTEN related disorders?
four of the following thyroid lesions IQ <75 uterine fibroids hamartoma polyps RCC lipomas GU malformation fibromas
What are the NCCN diagnostic criteria for children with PTEN related disorders?
macrocephaly plus 1 of the following autism/developmental delay derm features vascular features GI polyps
How are PTEN-related disorders managed?
surveillance (pediatric)
annual thyroid exam (US)
yearly skin check with physical exam
surveillance (adult)
yearly thyroid US and derm eval
women beginning at 30 y/o get monthly breast self-exams, yearly breast screening mammography/MRI, yearly transvaginal US or endometrial biopsy
men and women get colonoscopy beginning at age 35 y/.o and recurrent as per polyps found
What is Hereditary Diffuse Gastric Cancer?
AD
CDH1 gene mutants or deletion/duplications
What clinical manifestations are present in Hereditary Diffuse Gastric Cancer?
diffuse gastric cancer
lobular breast cancer
How is Hereditary Diffuse Gastric Cancer managed?
surveillance with endoscopy (contriversial)
total gastrectomy (prophylactic)
breast cancer screenings starting at age 35 y/o
consideration of prophylactic mastectomy
What is Peutz-Jegher Syndrome?
AD
STKII gene mutations and deletion/duplications
What clinical manifestations are associated with Peutz-Jegher Syndrome?
hamartomatous polyps in GI tract (mainly small intestine) or extra-intestinal (renal, pelvic, bladder, bronchus, gallbladder, nasal)
GI adenomas also noted
mucocutaneous pigmentation (fades in adolescence)
functional gonadal tumor (ovarian sex cord tumors or sertoli cell tumors)
heavy menses, precocious puberty, gynecomastia
How is Peutz-Jegher Syndrome managed?
screenings
stomach (start at 8 repeat every 3 years)
small intestine (start at 8 repeat every 3 years)
small intestine (begin at 8 and repeat every 3 years)
breast (self exam starting at 18 and repeat every 3 years; MRI begin at 35 and repeat annually)
ovary (begin at 18 and repeat annually)
cervix/uterus (begin at 18 and repeat annually)
pancreas (begin at 25 and repeat every 1-2 years)
testes (begin at birth and repeat annually)
What is Juvenile Polyposis Syndrome?
AD
BMPR1A or SMAD4 mutations (combined with HHT)
What clinical manifestations are associated with Juvenile Polyposis Syndrome?
hamartomatous polyps with normal epithelium, smooth surface, with inflammatory infiltrate, and mucus-filled cystic glands
increased risk for colon>stomach>upper GI>pancreatic cancer
What additional manifestations are associated with JPS/HHT?
telangiectasia
AV malformations
epistaxis
brain bleeds
What conditions are associated with Renal Cell Carcinomas?
Von Hippel Lindau (clear cell RCC) Brit-Hogg-Dube (mixed RCC) Hereditary Papillary RCC Hereditary Leiomyomatosis and RCC BAP1 associated tumor syndrome MITF Tuberous Sclerosis
What is Von Hippel Lindau Syndrome?
AD
VHL gene mutations and deletion/duplications
What clinical manifestations are associated with Von Hippel Lindau Syndrome?
hemangioblastomas (brain, spinal cord, retina --> headaches, emesis, gait issues, spinal cord compression, vision loss) endolymphatic sac tumors RCC pheochromocytoma epididymal and broad ligament cysts pancreatic necroendocrine tumors renal and pancreatic cysts
What is the protocol for screening in patients with Von Hippel Lindau Syndrome?
annual neuro, vision, hearing evals (begin at 1 y/o)
annual blood pressure check (begin at 1 y/o)
MRI of brain and spine (every 2 years starting at 16 y/o)
annual abdominal US switching to MRI at age 16
annual blood/urine metanephrine (start at age 5)
What is Brit-Hogg-Dube?
AD
FLCN mutations and deletion/duplications
What clinical manifestations are associated with Brit-Hogg-Dube Syndrome?
lung cysts and spontaneous pneumothorax renal tumors (mixed) cutaneous manifestations (acrochordons, fibrofolliculomas/trichodiscomas, perifollicular fibromas)
What are the clinical manifestations of Hereditary Leiomyomatosis RCC?
cutaneous leiomyomas (mean age 25) uterine leiomyomas (mean age 18-52) renal carcinomas (mean age 44)
What is Hereditary Leiomyomatosis RCC?
AD
mutations in the FH gene
List the kinds of thyroid cancers and what genes are associated with them.
papillary: FAP (APC), SDHB/SDHD, PTEN (rare)
follicular: PTEN
medulary: multiple endocrine neoplasia type 2 (RET)
What is Multiple Endocrine Neoplasms Type 1?
AD
MEN1 gene
usually non-cancerous
What clinical manifestations are associated with MEN1?
parathyroid adenomas (hyperparathyroidism)
pituitary
pancreas (neuroendocrine, gastrinomas, insulinomas)
adrenal hyperplasia
lung carcinoid tumor
What is Multiple Endocrine Neoplasms Type 2?
AD
RET gene mutations
Describe the subtypes of MEN2.
FMTC (adult)- medullary thyroid carcinoma only
MEN2A (early adult)- pheo, parathyroid adenoma, MTC
MEN2B (childhood)- pheo, mucosal neuroma, ‘marfanoid’, MTC, gangliomatosis
What is a paraganglioma?
tumor that arises from neuroendocrine tissue along paravert axis (from the base of the skull to the pelvis)
“sympathetic” cause chatecholamine excess
“parasympathetic” most often nonsecretory
What is a pheochromocytoma?
a subtype of paragangioma that is confined to the adrenal medulla
What symptoms are associated with Paragangliomas/Pheochromocytomas?
mass effect catecholamine hypersecretion (--> headache, HTN, episodic profuse sweating, palpitations, pallor, apprehension or anxiety)
What is the diagnostic criteria for Hereditary Paragangliomas/Pheochromocytoms?
any patient with a PGL/PCC (particularly if they are multiple, multifocal, recurrent, or early-onset)
family history of PGL/PCC
metastatic or extra-adrenal
What genes are associated with Hereditary Paraganglioma/Pheochromocytoma?
*SDHD (paternally inherited) SDHD (paternally inherited) SDHA SDHC MAX SDHAF2 TMEMI27
What is the screening protocol for patients with Pheochromocytoma/Paragangliomas?
start the following at age 10 y/o
24 hour urine metanephrine and catecholamine (following up with MRI/CT, 123I-MIBG, PET)
for SDHD/SDHC get imaging of skull base/neck every 2 years
for SDHB get imaging of abdomen/thorax/pelvis every 2 years
if GI symptoms are present, image for GIST
List the syndromes associated with melanoma.
CDK4 Cutaneous malignant melanoma Familial Atypical Multiple Mole Melamoma (CPKN2A) BAP1 Associated Tumor Syndrome BRCA1/2 Hereditary Retinoblastoma (RB1) Werner Syndrome Xeroderma pigmentosa
What is Nevoid Basal Cell Carcinoma Syndrome?
also called Garlin Syndrome
AD
PTCH1 or SUFU gene
What are the diagnostic criteria for Neviod Basal Cell Carcinoma Syndrome?
major: calcification of falx (<20 years), jaw keratocyst (2nd decade), multiple basal cell carcinomas
minor: polydactyly, childhood meduloblastoma, pleural cysts, macrocephaly, cleft lip/palate, vertebral/rib anomalies, fibromas (ovarian and/or cardiac), ocular (cataracts, retinal changes)
List the rare tumor types.
Carney comples
Gastrointestinal stromal tumors
Teratoid/rhabdoid tumor
What are DICER1 associated tumors?
benign and malignant neoplasia including: pleuropulmonary blastoma ovarian sex cord-stromal tumors cystic nephromas multinodular goiter and thyroid cancer ciliary body medulloepithelioma bothyroid-type embryonal hamartoma pituitary blastoma primative neuroectodermal tumor (PTEN) pineoblastoma
What developmental syndromes are associated with malignancies?
Down Syndrome
Noonan Syndrome
NF1
Beckwith Weidemann
What conditions incur greater risks for childhood cancers?
GATA2 deficiency (MDS) Fanconi Anemia (acute leukemia, meduloblastoma, hepatocellular carcinoma, nephroblastoma, solid tumors in adulthood)
What is Fanconi Anemia?
AR
FANCD1
biallelic with BRCA2 gene
What clinical manifestations are associated with Fanconi Anemia?
early onset leukemia
solid tumors (meduloblastoma and Wilms tumors)
birth defects (VACTERL spectrum)
positive chromosome fragility test
What is Constitutional Mismatch Repair Deficiency?
biallelic mutations in mismatch repair genes MLH1, MSH2, MSH6, or PMS2
What clinical manifestations are associated with Constitutional Mismatch Repair Deficiency?
childhood cancer predisposition syndrome hematologic malignancies brain/central nervous system tumors colorectal tumors multiple intestinal polyps other malignancies (embryonic tumors and rhabdomyosarcomas) cafe-au-lait macules
