Cancer syndromes Flashcards
What features on a FH should make you suspicious for HBOC
breast ca dx before the age of 50
male breast ca
ovarian ca
triple negative breast cancer histology
multiple primary breast cancers in either one or both breasts
combination of pancreatic cancer and/or prostate ca with breast and/or ovarian ca
AJ ancestry
two or more relatives with breast ca, one dx at or before 50yo
three or more relatives with breast ca at any age
FM with a known BRCA1/BRCA2 variant
What are the most common AJ PVs in BRCA1/BRCA2
BRCA1 c.68_69delAG
BRCA1 c.5266dupC
BRCA2 c.5946delT
What testing should be ordered for HBOC
multigene panel with BRCA1/BRCA2 with sequence analysis and del dup concurrently
for AJ ancestry, targeted analysis to start which account for 99% of all PVs identified
10-15% of variants are genomic rearrangements, make sure this testing is also ordered
If there is a known BRCA1/2 PV in a family, when is it still ok to order more testing other than the targeted testing
- individuals of AJ descent who may consider also testing for the three founder variants in addition to the familial variant
- individuals with known BRCA1/2 PV on one side of the family with characteristics of HBOC or another inherited cancer syndrome on the other side of the family should consider multigene panel testing which will also pick up the familial variant
What proportion of HBOC is made of BRCA1 PVs and BRCA2 PVs
BRCA1: 66%
BRCA2: 34%
What cancers are you at risk for if you have a BRCA1 PV and what is the lifetime risk
Breast: 50-70% by 70yo
Contralateral breast: 20-30% w/in 10yrs; 40-50% w/in 20yrs
Male breast: 1-2%
Ovarian: 39-44%
Prostate: 29% by 85yo
Pancreatic: 1-3%
What cancers are you at risk for if you have a BRCA2 PV and what is the lifetime risk
Breast: 45-69%
Contralateral breast: 20-30% w/in 10yrs; 40-50% w/in 20yrs
Male breast: 6-8%
Ovarian: 11-17%
Prostate: 60% by 85yo
Pancreatic: 3-5% by 70
elevated risk for melanoma of the skin and eye
What is the histology of tumors associated with HBOC
Triple negative breast cancer
BRCA2 tumors tend to be ER/PR +
serous adenocarcinomas of the fallopian tubes (rather than the ovaries)
male breast cancer tends to be high grade, hormone receptor + with lymph node metastases
BRCA1/2 among the most common known genetic causes of hereditary pancreatic ductal adenocarcinoma
How is breast and ovarian cancer tx if you have HBOC
Consider bilateral mastectomy as a primary sx tx of breast cancer bc of elevated rate of ipsilateral and contralateral breast cancer
PARP inhibitors given their role in DNA repair could lead to lethality of tumor cells (also called olaparib, which can also be used for ovarian ca tx)
How should you prevent cancer if you have HBOC
Consider prophylactic bilateral mastectomy
chemoprevention w tamoxifen reduces the risk for breast cancer by ~60% (higher rates of endometrial cancer and thromboembolic episodes though)
breast feed for a cumulative total or more than one year to reduce risk of breast cancer
consider prophylactic salpingo-oophorectomy which leads to a 80% reduction in ovarian cancer mortality
50% reduction in risk of ovarian ca associated with oral contraceptive use
What surveillance is recommended for women with HBOC
monthly self breast exam, CBE q6-12mos beginning @25yo, mammogram starting @30yo, breast MRI @25yo or earlier if cancer was dx in family member before 30yo
no screening for ovarian cancer
skin exam w derm
MRCP/EUS in asymptomatic ppl with a FH of pancreatic cancer and based on mutation status
What surveillance is recommended for men with HBOC
monthly self breast exam @35yo, CBE @35yo
serum PSA and digital rectal exam @40yo
skin exam w derm
MRCP/EUS in asymptomatic ppl with a FH of pancreatic cancer and based on mutation status
Is HBOC testing recommended for minors
No, bc surveillance is not recommended to start until 25yo
What is the mechanism of dz for HBOC
BRCA1 colocalized with BRCA2 and RAD51 at sites of DNA damage and activates RAD51 mediated homologous recombination repair of DNA ds breaks
LOF
How is the dx of Lynch syndrome established
in a proband with a heterozygous PV or deletion
recommended to start with a multigene panel that includes MLH1, MSH2, MSH6, and PMS2 as well as EPCAM deletion analysis AND DNA methylation studies of MLH1 promoter since it can be caused by constitutional inactivation of MLH1 by methylation of its promoter (usually in all tissues and is most often simplex)
Not often recommended by can also do serial single gene testing based on IHC results indicating that LOF of a particular MMR gene is most likely but this correlation is not 100%
What proportion of Lynch syndrome is attributed to PVs in which genes
MLH1: 15-40%
MSH2: 20-40%
MSH6: 12-35%
PMS2: 5-25%
EPCAM: <10%
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1+, MSH2+, MSH6+, PMS2+
MSI: MSS
Sporadic cancer
cancer due to other hereditary cancer syndrome
no further lynch testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1+, MSH2+, MSH6+, PMS2+
MSI: MSI High
sporadic cancer
Germline MMR gene PV
Germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
MSI: MSI high
sporadic cancer
germline MMR gene PV
IHC
if IHC not available, consider germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1-, MSH2+, MSH6+, PMS2-
sporadic cancer
germline MLH1 PV
germline PMS2 PV (rare)
targeted BRAF and/or MLH1 promoter methylation testing on tumor tissue
If BRAF/MLH1 methylation is normal, germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1-, MSH2+, MSH6+, PMS2-
BRAF V600E: Pos
OR
Immunohistochemistry: MLH1-, MSH2+, MSH6+, PMS2-
BRAF V600E: Neg
MLH1 promotor methylation: Pos
sporadic cancer
germline MLHI PV (rare)
Constitutional MLH1 epimutation
If early onset cancer or significant FH of cancer: germline MMR gene testing
If not, no additional testing
For early onset only: constitutional MLH1 epimutation testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1-, MSH2+, MSH6+, PMS2-
BRAF V600E: Neg
MLH1 promotor methylation: Neg
Germline MLH1 PV
Germline PMS2 PV (rare)
sporadic cancer
Germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1+, MSH2-, MSH6-, PMS2+
Germline MSH2/EPCAM PV
Germline MSH6 PV (rare)
sporadic cancer
Germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1+, MSH2+, MSH6+, PMS2-
Germline PMS2 PV
Germline MLH1 PV (rare)
sporadic cancer
Germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1+, MSH2-, MSH6+, PMS2+
Germline MSH2/EPCAM PV
sporadic cancer
Germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1+, MSH2+, MSH6-, PMS2+
Germline MSH6 PV
Germline MSH2/EPCAM PV
sporadic cancer with tx effect
Germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
If applicable, consider MSI analysis or repeat IHC on nontreated tumor
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1-, MSH2+, MSH6+, PMS2+
Sporadic cancer: MLH1 promotor methylation or somatic MLH1 or PMS2 PV
Germline MLH1 PV
Germline PMS2 PV
Targeted BRAF and/or MLH1 promoter methylation testing on tumor tissue
If BRAF and MLH1 methylation normal: germline MMR gene testing or paired germline/tumor tissue MMR gene testing
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
Based on the following tumor testing results, give plausible etiologies and additional testing options for Lynch syndrome
Immunohistochemistry: MLH1-, MSH2-, MSH6-, PMS2-
Germline MMR gene PV
Sporadic cancer
Targeted BRAF and/or MLH1 promoter methylation testing AND germline MMR gene testing or paired germline/tumor tissue MMR gene testing (often incl MLH1 methylation testing)
If germline testing negative and paired germline/tumor tissue not done, consider tumor tissue MMR gene testing
What cancer types are you at risk for if you are a female with a PV in MLH1
Any (78%)
CRC (44%)
Endometrium (35%)
Ovary (11%)
Stomach (8%)
Small bowel (8%)
Ureter, kidney (3%)
Urinary bladder (3%)
Brain (2%)
Breast (11%)
What cancer types are you at risk for if you are a male with a PV in MLH1
Any (64%)
CRC (53%)
Stomach (16%)
Small bowel (16%)
Ureter, kidney (4%)
Urinary bladder (5%)
Prostate (7%)
Brain (1%)
What cancer types are you at risk for if you are a female with a PV in MSH2
Any (77%)
CRC (42%)
Endometrium (46%)
Ovary (17%)
Stomach (10%)
Small bowel (10%)
Ureter, kidney (13%)
Urinary bladder (7%)
Brain (2%)
Breast (13%)
What cancer types are you at risk for if you are a male with a PV in MSH2
Any (71%)
CRC (46%)
Stomach (16%)
Small bowel (16%)
Ureter, kidney (16%)
Urinary bladder (9%)
Prostate (16%)
Brain (4%)
What cancer types are you at risk for if you are a female with a PV in MSH6
Any (62%)
CRC (20%)
Endometrium (41%)
Ovary (11%)
Stomach (2%)
Small bowel (2%)
Ureter, kidney (6%)
Urinary bladder (1%)
Brain (1%)
Breast (11%)
What cancer types are you at risk for if you are a male with a PV in MSH6
Any (28%)
CRC (12%)
Stomach (4%)
Small bowel (4%)
Ureter, kidney (2%)
Urinary bladder (4%)
Prostate (5%)
Brain (2%)
What cancer types are you at risk for if you are a female or male with a PV in PMS2
Any (22%)
CRC (3%)
Endometrium (13%)
Ovary (3%)
Stomach (4%)
Small bowel (4%)
Prostate (5%)
Breast (8%)
What cancer types are you at risk for if you are a female or male with a del in EPCAM
CRC: 75%
Endometrium: 12%
What histology is consistent with Lynch syndrome
CRCs with MSI tend to have better prognosis than MSS tumors, potentially reflecting active anti-tumor immune response; risk of metachronous CRC can be as high as 43% for those with MLH1/MSH2 PVs
endometrial cancers with MSI show better prognosis
ovarian cancer is typically of endometrioid histologic subtype
gastric cancers tend to present as intestinal-type adenocarcinoma, located to the duodenum and jejunum
urinary tract cancers are transitional carcinomas of the ureter, renal pelvis, and kidney
brain: glioblastoma makes up more than half; then astrocytoma (22%), oligodendroglioma (9%)
sebaceous neoplasm: sebaceous adenomas, sebaceous epitheliomas, sebaceous carcinomas, and keratoacanthomas (all are typically MSI high)
What are the features of Muir Torre syndrome
describes individuals presenting with the combination of sebaceous neoplasms of the skin and one or more visceral malignancies, commonly those seen in lynch syndrome
Is an uncommon variant OF lynch syndrome
What are the features of Turcot syndrome
individuals presenting with CRC or one or more colorectal adenomas in addition to tumors of the CNS caused by PVs in one of the MMR genes or an APC PV
APC PVs are more commonly associated with medulloblastoma; PVs in MMR genes are commonly associated with glioblastoma
What are the features of constitutional mismatch repair deficiency
rare childhood cancer predisposition syndrome caused by biallelic PVs in MLH1, MSH2, MSH6, or PMS2
have CRC or cancer of the small intestine prior to the second decade of life (colonic adenomas were the most frequent finding, cutaneous phenotype similar to NF1, nearly all with cafe au lait macules; hematologic cancers and brain tumors)
What is the genotype/phenotype seen in pts with Lynch syndrome
risk for extracolonic cancers is dependent on the size of the del. 3’ EPCAM deletions have been shown to confer a lower risk for extracolonic cancers, whereas deletions that extend into MSH2 confer extracolonic cancer risks similar to intragenic MSH2 PV
Describe the difference between the molecular differences of sporadic CRC and lynch syndrome associated CRC
sporadic MMR deficient tumors commonly occur in older females; show lack of MLH1 protein expression due to MLH1 promoter methylation and are strongly associated with the CpG island methylator phenotype and serrated route of carcinogenesis
BRAF-related: Somatic BRAF PVs occur in 15% of all CRC and, in rare instances, may be identified in tumor tissue from individuals with Lynch. Prevalence of BRAF PVs in MSI-high CRCs also increased with age; BRAF testing is cost-inefficient for screening in those with MSI-high CRCs dx before 50yo
Somatic MLH1 promoter methylation: 10-15% of CRCs are MSI high or MMR deficient due to somatic methylation of the promoter region of MLH1 that silences gene expression in the tumor tissue, rather than due to Lynch (more effective than BRAF testing); individuals in whom a Lynch syndrome associated germline PV is not identified and who have somatic MLH1 promoter methylation are likely to have sporadic cancer
What is the management for pts with Lynch syndrome
CRC: colonoscopy beginning at 20-25yo or 2-5yrs before earliest CRC dx in family
Endometrial cancer: educate females about symptoms (abnormal uterine bleeding, postmenopausal bleeding); eval of symptoms including endometrial bx q1-2yrs; screening should begin between 30-35yo
Ovarian cancer: educate females about symptoms (pelvic/abdominal pain, bloating, difficulty eating, urinary frequency)
Gastric and duodenal cancers: consider upper endoscopy beginning at 40yo q3-5yrs for those with FH of gastric cancer and Asian ancestry
Distal small bowel: consider capsule endoscopy and small bowel enterography in symptomatic individuals
Urinary tract cancers (renal pelvis, ureter, and/or bladder): consider urine cytology to identify microscopic hematuria in those with a FH beginning between 30-35yo
Pancreatic cancer: consider EUS/MRCP at 50yo in those with a FH
What are the tx options for pts with Lynch syndrome
adenomas of colon: complete endoscopic polypectomy w f/u colonoscopy q1-2yrs
CRC: segmental or extended colonic resection; for those with rectal adenocarcinoma, proctectomy or total proctocolectomy is indicated
other tumors: management as in general population
prophylactic hysterectomy and bilateral salpingo-oophorectomy can be considered after childbearing is completed
prophylactic colectomy is generally not recommended since screening is effective
aspirin therapy has been shown to decrease the risk of CRC
Why may a parent with Lynch not have cancer
incomplete penetrance, variable age of cancer development, cancer risk reduction from screening or prophylactic sx, or early death
What is the molecular pathogenesis of Lynch syndrome
PVs in genes involved in the MMR pathway which functions to identify and remove single-nucleotide mismatches or insertions and deletion loops
germline dels with EPCAM, which is not an MMR gene, can disrupt the MMR pathway by inactivating the adjacent MMR gene, MSH2, even though MSH2 itself has not been mutated
What are some laboratory considerations for Lynch syndrome
EPCAM: only large dels that include the last exon of EPCAM are causative of Lynch; other EPCAM variants are NOT associated with Lynch
MLH1: most instances of MLH1 promoter methylation are simplex, but a few families w inherited hypermethylation have been reported; MLH1 promoter methylation is not detectable by either sequence analysis or dup/del analysis of MLH1
PMS2: molecular analysis is more complex due to the presence of multiple pseudogenes; Long range PCR, cDNA sequencing, or specific solutions to NGS testing can help distinguish between the pseudogenes and PVs
How is the dx of Li Fraumeni syndrome established
proband who meets ALL THREE classic LFS criteria AND/OR has a germline PV in TP53
Classic criteria
1. proband with sarcoma before age 45
2. first degree relative with any cancer dx before 45
3. first or second degree relative with any cancer before 45yo or a sarcoma dx at any age
How are germline and somatic PVs in TP53 distinguished? How can they be acquired somatically?
Identification of low-level mosaicism for TP53 in leukocytes is suggestive of a postzygotic PV due to clonal hematopoiesis of indeterminate potential related to aging, cytotoxic txs, underlying hematologic malignancy or premalignancy, or circulating tumor cells
Evals include:
analysis of cultured skin fibroblasts for identified TP53 PV
molecular genetic testing of all offspring to determine if the TP53 PV was transmitted
molecular genetic testing of other FMs to determine if the TP53 PV is segregating with cancer in the family
What is the name of the criteria for Li Fraumeni syndrome
Chompret criteria; 30% will have a TP53 PV
What cancers is someone with Li Fraumeni at risk for
lifetime cancer risk for men is 70%; women is 90%
Five main types: adrenocortical carcinomas (6-13% before age 5), breast cancer (27-31%, most common cancer in women with TP53 PV, occurs prior to menopause), central nervous system tumors (9-14% of cancers typically before 40yo), osteosarcomas (3-16% by 30yo), soft-tissue sarcomas (17-27%, most common LFS cancer in children)
avg onset of first cancer in men is ~17yo; for women it is ~13yo although when including breast cancer it is 28yo
~50% risk of developing a second cancer 10yo after first dx
What are the common histologies associated with Li Fraumeni syndrome
Breast: triple positive; more likely to be ductal and have malignant phyllodes tumors
CNS tumors: glioblastomas and astrocytomas are the most common type; medulloblastomas are typically the sonic hedgehog subtype and display chromothripsos (numerous clustered chromosome rearrangements occurring in malignant cells)
Soft-tissue sarcomas: rhabdomyosarcomas and other soft-tissue sarcomas; rhabdomyosarcomas often before 5yo and are often nonalveolar tumors with diffuse anaplasia
leukemias/lymphomas: in 2-4%, usually primary and secondary leukemias, especially ALL, AML, and myelodysplastic syndrome; ALL often exhibits a low hypodiploid state with 32-39 chroms
What needs to be considered for pregnant women with a fetus at risk for a TP53 mutation
the pregnant mother of a fetus heterozygous for a pat inherited TP53 PV is at risk for choriocarcinoma or another gestational trophoblastic disease (occurrence of cancer in the placental tissue that can spread to other tissues)
What are genotype-phenotype correlations in Li Fraumeni syndrome
individuals with LFS who carry dominant negative PVs (mutated p53 protein interferes with the function of the wild type p53 protein)
TP53 founder variant p.Arg337His common in southern Brazil is associated with a high risk of childhood onset ACC, up to 55%; mat inheritance of p.Arg337His was identified in 72% of individuals, suggesting preferential selection
What genetic modifiers exist for Li Fraumeni syndrome
p.Arg72 polymorphism: higher levels of p53 degradation and earlier onset of first cancer
MDM2 c.14+309T>G: higher levels of p53 degradation and earlier onset of first cancer
microRNA R-605 variant: ten year accelerated mean age of tumor onset
16bp dup polymorphism in intron 3 (PIN3): appears to be protective, older ages of first cancer dx
shortened telomere length: accelerated tumor development (anticipation) in families
How are cancers in Li Fraumeni tx/managed
radiation therapy is avoided if possible to reduce the risk of secondary malignancies. however, tx efficacy should be prioritized above concerns regarding risk of subsequent malignancies (radiation may be needed to provide best chance of cure)
women encouraged to consider bilateral mastectomy to reduce risk of developing second primary breast cancer
adults should have colonoscopies
avoid sun, tobacco, other carcinogens
What is the recommended surveillance for Li Fraumeni
All cancers: complete physical exam (q3-4mo birth to 18yo; q6mo >18yo), whole body MRI annually for all ages
ACC: u/s of abdomen and pelvis q3-4mo birth to 18yo; serum total testosterone, dehydroepiandrosterone sulfate and androstenedione if u/s is unsatisfactory
Breast ca: CBE (q6-12mo from 20-25yo), Breast MRI (annually, 20-30yo); Mammogram (30-75yo)
CNS tumors: neurologic exam and brain MRI annually for all ages
upper endoscopy and colonoscopy q2-5yrs starting at 25yo
annual dermatologic exam starting at 18yo
sarcomas: whole body MRI/ u/s of abdomen and pelvis
Should children be tested for TP53 PVs if they have a FH
YES it is recommended that predictive testing be offered to individuals at birth (via cord blood) or soon after birth
special consideration should be given to education of the children and their parents prior to genetic testing and older children and adolescents should be given the option of assenting to the test
What is the molecular pathogenesis of TP53 and special lab considerations
encodes p53 which has been termed the guardian of the genome since it is involved with DNA replication/repair, epigenetic patterning of the genome, cell cycle arrest, apoptosis, etc. PVs ultimately lead to genomic instability and malignant transformation. It is the most frequently mutated gene in human cancer
TP53 missense variants are the variants most commonly identified and tumors and they present challenges in germline interpretation
How is Cowden syndrome dx via a scoring system
takes into account phenotype and age at dx has been developed
in adults, clinical threshold score of 10 or more leads to recommendation for referral to genetics
In children, macrocephaly and one or more of the following leads to the consideration of PHTS:
autism or DD
dermatologic features including lipomas, trichilemmomas, oral papillomas, or penile freckling
vascular features (arteriovenous malformations or hemangiomas)
gastrointestinal polyps
pediatric-onset thyroid cancer or germ cells
What are pathognomonic features of Cowden syndrome
Adult Lhermitte-Duclos dz (presence of a cerebellar dysplastic gangliocytoma)
mucocutaneus lesions: facial trichilemmomas, acral keratoses, papillomatous lesions, mucosal lesions
How is a clinical dx of Cowden syndrome made
If an individual meets any ONE of the following criteria:
Pathognomonic mucocutaneous lesions including one of the following:
Six or more facial papules, of which three or more must be trichilemmomas
Cutaneous facial papules and oral mucosal papillomatosis
Oral mucosal papillomatosis and acral keratoses
Six or more palmoplantar keratoses
Two or more major criteria
One major and three or more minor criteria
Four or more minor criteria
Major criteria
Breast cancer
Epithelial thyroid cancer (non-medullary), especially follicular thyroid cancer
Macrocephaly (occipital frontal circumference ≥97th percentile)
Endometrial carcinoma
Minor criteria
Other thyroid lesions (e.g., adenoma, multinodular goiter)
Intellectual disability (IQ ≤75)
Hamartomatous intestinal polyps
Fibrocystic disease of the breast
Lipomas
Fibromas
Genitourinary tumors (especially renal cell carcinoma)
Genitourinary malformation
Uterine fibroids
How is the dx of Cowden syndrome established in a family
other relatives are considered to have a clinical diagnosis of CS if they meet any one of the following criteria:
A pathognomonic criterion
Any one major criterion with or without minor criteria
Two minor criteria
History of Bannayan-Riley-Ruvalcaba syndrome
What molecular testing should you order for PTEN
sequence analysis then del dup
also perform sequence analysis of the PTEN promoter region for variants that decrease PTEN gene expression (10%)
What is Cowden syndrome
a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium; renal cell carcinoma and colorectal carcinoma present too
What is Bannayan-Riley-Ruvalcaba syndrome
congenital disorder characterized by macrocephaly, intestinal polyposis, lipomas, vascular malformations, and pigmented macules of the glans penis
What is PTEN-related Proteus syndrome
complex, highly variable disorder involving congenital malformations and overgrowth of multiple tissues
Describe the features associated with Cowden syndrome
90% have some clinical feature by late 20s, by the 4th decade, 99% of individuals develop the mucocutaneous features as well as acral and plantar keratoses; usually have macrocephaly and dolichocephaly
harmartomatous and mixed GI polyps that confer a risk for CRC
high risk for breast, thyroid, renal, and endometrial cancers, risk for multifocal and bilateral cancer increased; 7-fold increase risk of developing a second primary malignant neoplasm
What are the histologic features associated with Cowden syndrome
glycogenic acanthosis (in colon, small mounds of glycogen stores) have a high likelihood of finding a PTEN PV
breast: 67% risk of benign breast dz; 85% lifetime risk for female breast ca with 50% penetrance by 50yo
thyroid dz: benign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas up to 75% of individuals; lifetime risk for epithelial thyroid ca is ~35%, onset at 37yo (FOLLICULAR HISTOLOGY)
endometrial: benign uterine fibroids are common; lifetime risk for endometrial cancer is ~28% starting at late 30s-40s
GI neoplasias: 90% are found to have polyps (ganglioneuromatous polyps, hamartomatous, and juvenile polyps); lifetime CRC is 9% starting at late 30s
RCC: estimated to be 35% by 20s w the predominant histology being papillary RCC
lifetime risk for cutaneous melanoma is ~6%
rare CNS tumor, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos dz) may be pathognomonic
What are the common features associated with Bannayan-Riley-Ruvalcaba syndrome
in addition to the features of CS, high birth weight, DD, ID, myopathic process in proximal muscles, joint hyperextensibility, pectus excavatum, scoliosis
have same cancer risks of CS
GI polyps may be occasionally be associated with intussusception but rectal bleeding and oozing of “serum” is more common; these polyps NOT believed to increase risk for CRC
What are the common features associated with PTEN related Proteus syndrome
progressive segmental or patchy overgrowth of diverse tissues of all germ layers affecting the skeleton, skin, adipose tissue, and CNS
develops and progresses rapidly beginning in the toddler period causing severe overgrowth and disfigurement
striking predisposition to DVT and pulmonary embolism
What genetic modifiers exist for Cowden syndrome
germline KLLN epimutation: ~30% of individuals with CS do NOT have a PTEN PV and have a germline KLLN methylation epimutation resulting in downregulation of KLLN; have a greater prevalence of breast and RCC than do those with a germline PV
susceptibility genes: individuals without PTEN PVs harbor germline variants in SDHB and SDHD in 10% of persons with CS; ~10% are found to harbor a germline PIK3CA or AKT1 PVs; ~3%-6% have germline heterozygous SEC23B PVs, which are particularly associated with thyroid carcinoma and enhanced ribosome biogenesis
What is the recommended surveillance for pts with PTEN Hamartoma Tumor syndrome
annual comprehensive physical exam at 18yo or 5yrs before youngest age of dx
breast: @18, SBE; @25, CBE q6-12mo; @30-35, annual mammogram with consideration of breast MRI; discuss mastectomy as needed
thyroid u/s: starting at age of dx, annual thyroid u/s
kidney: @40, consider renal u/s q1-2yrs
endometrium: consider ca screening @35yo; consider endometrial bx screening q1-2yrs; transvaginal u/s in postmenopausal women as needed; discuss hysterectomy on completion of childbearing
colon: @35, colonoscopy q5yrs
dermatologic: annual exam
developmental: consider psychomotor assessment in children, brain MRI if symptomatic, eval for early intervention
What is the recommended cancer tx for Cowden/Bannayan-Riley-Ruvalcaba syndrome
mucocutaneous lesions: observation, removal only if malignancy is suspected
DD: support services, early intervention
breast dz/neoplasia: refer to breast specialist
thyroid dz: u/s, perform total thyroidectomy if suspicious for malignancy
endometrial dz: multiple fibroids are tx w total abdominal hysterectomy
Should minors be tested for PTEN if there is a FH
YES
given the possible early dz presentation in individuals with BRRS and PTEN-related proteus syndrome
What is the de novo rate for Cowden/Proteus syndrome
10-44%/ virtually all
What is the molecular pathogenesis for PTEN
downregulates the PIK3/AKT pathway
nearly 40% of PVs are in exon 5 which encodes the phosphate core motif
~76% of germline PVs in PTEN predict truncated protein, haploinsufficiency, or dysfunctional protein; many missense variants are functional null and act as dominant negatives
PTEN has a highly homologous pseudogene on chrom 9
What are the cancer risks associated with a heterozygous ATM PV
breast (20-30%), 4% for second breast cancer w/out bilateral mastectomy (annual breast MRI @30-35, start mammo @40- insufficient evidence for risk reducing mastectomy)
pancreatic (5-10%) (screen if FH)
ovarian (2-3%)
When should a dx of APC-associated polyposis be suspected
any of the following:
multiple CR adenomatous polyps (at least 10-20 cumulative)
FH of the above, known APC PV, and/or extracolonic features of APC-associated polyposis conditions
hepatoblastoma
multifocal/bilateral congenital hypertrophy of the retinal pigment epithelium (CHRPE)
desmoid tumor
cribriform-morular variant of papillary thyroid cancer
others: early onset CRC w few to no adenomatous polyps, dental abnormalities, osteomas, odontomas, epidermoid cysts, duodenal adenomas and cancer, gastric fundic gland polyposis, gastric cancer, pancreatic cancer, small bowel carcinoma, and/or medulloblastoma
How is the dx of APC-associated polyposis established
heterozygous PV in APC
classic FAP: > or =100 CR adenomas OR multiple but less than 100 adenomas and a relative with confirmed classic FAP
attenuated FAP: relative with confirmed AFAP AND/OR <100 CR adenomas OR >100 CR adenomas at an advanced age (>40yo)
GAPPS: PV in promotor 1B of APC AND: gastric polyps restricted to the body and fundus, >100 polyps in the proximal stomach or >30 polyps in a first degree relative w GAPPS; predominantly fundic gland polyps and some gastric adenomas; no evidence of CR or duodenal polyposis
What molecular testing should be ordered for someone with suspected APC-associated polyposis
single gene testing with del/dup; del/dup should also include the analysis of APC regulatory regions (promoter 1B) if APC PV is not identified with initial testing
~20% of simplex cases are somatic mosaic for an APC PV
What clinical features are associated with classic FAP
adenomas by 2nd-3rd decade w avg age of dx at 16yo
by 35yo, 95% of affected individuals have polyps which rapidly increase in number
100s-1000s typically observed
93% w CRC by 50yo
inter and intrafamilial phenotypic variability common
What clinical features are associated with AFAP
Characterized by fewer CR polyps (avg ~30) but a significant risk for CRC
< or = 100 CR adenomas at > or = 25yo
occur more proximally in the colon than FAP
avg age of CRC dx is 50yo
cumulative risk for CRC by 80yo is 70%
What extra-colonic features can be present in pts with FAP
small bowel, duodenal cancer (adenocarcinoma/carcinoma, 4-8%)
pancreas (adenocarcinoma, ~1%)
thyroid (papillary w cribriform pattern, 1-12%; female to male ratio of 80:1)
CNS (usually medulloblastoma, ~1%)
Liver (hepatoblastoma, ~2%; 750-7500x higher than general pop, majority before 3yo)
stomach (adenocarcinoma, ~1.3% in West but higher in Asian cultures)
non-malignant findings
osteomas (60-80%): bony growths typically on skull and mandible
dental anomalies (30-75%): unerupted teeth, congenital absence of one or more teeth, supernumerary teeth
CHRPE(80%): discrete, flat, pigmented lesions of the retina; isolated ones can be seen in the general population
benign cutaneous lesions
desmoid tumors (10-30%): clonal proliferations of myofibroblasts but do not metastasize. 65% are in the abdomen/abdominal wall which can compress organs or complicate abdominal sx
adrenal masses: 2-4x more prevalent than general pop
What predictors would put a pt at higher risk to develop desmoid tumors
APC PV 3’ of codon 1399
FH of desmoid tumors (highest magnitude of risk)
female gender
previous abdominal sx
What are the clinical features associated with GAPPS
proximal gastric fundic gastric polyps and intestinal-type gastric adenocarcinoma, typically without significant duodenal or colorectal polyps; have 13-25% lifetime risk for gastric carcinoma
What are the common regions for APC variants
78% of those meeting criteria for AFAP (extracolonic manifestations are rare) had a PV in:
1. the 5’ end of APC, 2. the alternative spliced region of exon 9, 3. 3’ codon of 1595
whole gene deletions typically associated with FAP
What are the only cancer syndromes with 100% penetrance
Classic FAP; Peutz-Jegher syndrome; VHL; hereditary retinoblastoma
What is the recommended surveillance for individuals with FAP
CR adenomas: Colonoscopy q1-2yrs at 10-15 for classic FAP and late adolescence in attenuated; for those w total colectomy w IPPAA: endoscopy of ileal pouch q1-2yrs; for those w subtotal colectomy w ileorectal anastomosis, surveillance of remaining rectum q1-2yrs or more frequent if high polyp burden; in ppl w total colectomy w end ileostomy, ileoscopy q1-2yrs
small bowel polyps/ca: EGD w complete visualization of ampulla of Vater q6mo-5yts at 20-25 depending on duodenal adenoma burden
thyroid: palpation of thyroid, u/s q2-5yrs in late adolescence
CNS tumors: neuro exam annually beginning at dx
hepatoblastoma: liver palpation, abdominal u/s, serum AFP q3-6mo during 1st 5yrs of life
gastric polyps and ca: EGD q6mo-5yrs beginning at 20-25; if neoplastic polyps, consider annual exams
desmoid tumors: abdominal palpation, MRI/CT annually
When is molecular genetic testing offered to someone with suspected FAP/ a FH of it
generally offered to children at risk by 10yo
some parents/pediatricians may consider hepatoblastoma screening from infancy to 5yo in affected offspring
testing for AFAP can wait until late adolescence, so no testing until then
What is the de novo rate for FAP
25%
Parent w somatic and germline mosaicism for APC variant may be mildly/minimally affected. Majority (65%) of individuals with APC somatic mosaicism have between 20-100 adenomas (AFAP), 30% have FAP phenotype and 5% have no adenomas
When should molecular genetic testing should be considered for hereditary diffuse gastric cancer
dx of DGC and pathologically confirmed in situ signet ring cells and/or pagetoid spread of signet ring cells
dx of DGC and a FH of 2 1st or 2nd degree relatives with DGC or LBC
Dx of DGC and a personal or FH of cleft lip/palate
How is the clinical dx of hereditary diffuse gastric cancer established
in a proband with diffuse gastric cancer confirmed on endoscopic bx AND one of the following:
a FH of one or more 1st or 2nd degree relatives with gastric cancer
a personal and/or FH of one individual with DGC dx before 40yo
a personal and/or FH of DGC and LBC, one dx before 50yo
How is the molecular dx of hereditary diffuse gastric cancer established
identification of a heterozygous PV in CDH1
sequence analysis of CDH1 is performed first then del/dup
What are the clinical features associated with hereditary diffuse gastric cancer
age of onset ~38yo
symptoms in the late state may include abdominal pain, nausea, vomiting, dysphagia, postprandial fullness, loss of appetite, and weight loss; tumor spread or metastasis may lead to an enlarged liver, jaundice, ascites, skin nodules, and fractures
increased risk for LBC (lifetime risk 42%, avg onset @53)
What is the prognosis for pts with hereditary diffuse gastric cancer
when sporadic, 5yr survival rate can be > 90%; survival rate drops below 30% when the dx is made at a late stage
bc early detection of DGC is difficult, survival of individuals with CDH1 PVs is believed to be the same as in individuals with sporadic DGC
What pathology is associated with hereditary diffuse gastric cancer
loss of the E-cadherin protein causes the individual tumor cells to grow and invade neighboring structures
no tumor mass is formed
malignant cells have a distinctive signet ring appearance
How is hereditary diffuse gastric cancer tx
total gastrectomy is recommended, cure rates ~40%
prophylactic total gastrectomy (PTG) is recommended rather than endoscopic surveillance due to the observation of early gastric cancers in PTG samples; generally not recommended until individual’s growth period is complete
all individuals have intermediate as well as long term complications: rapid intestinal transit, diarrhea, eating habit alterations, weight loss
prophylactic mastectomy may be considered in women heterozygous for CDH1 PV
adjuvant therapy
H pylori infection is tx in the standard manner (if present)
What is the recommended surveillance for hereditary diffuse gastric cancer
endoscopy: diffuse gastric cancer is difficult to detect at an early, treatable stage bc the lesions tend to spread in the submucosa
at-risk individuals who are not ready to undergo PTG should be screened with the Cambridge protocol: detailed 30min upper endoscopy q6-12mo s multiple random bx and bx of subtle lesions; screening beginning 5-10yrs prior to the earliest ca dx in the family
mo SBE @20yo; CBE q6-12mo @30; bilateral breast MRI annually @30yo
colonoscopy q3-5yrs @40yo or 10yrs prior to the youngest age
What cancer risks are associated with PVs in ATM
c.7271T>G associated w high penetrance breast cancer
others are associated with moderate penetrance and increased risks for other types of tumors such as pancreatic and prostate cancer
What cancer risks are associated with PVs in PALB2
Breast cancer in less than or = 58%; ovarian cancer, male breast cancer, pancreatic cancer
What cancer risks are associated with PVs in BARD1
Breast cancer
What cancer risks are associated with PVs in BRIP1
epithelial ovarian cancer, possible increased risk for breast cancer
What cancer risks are associated with PVs in CHEK2
Breast cancer
What cancer risks are associated with PVs in RAD51D/RAD51C
Ovarian cancer, possibly breast cancer (particularly ER/PR negative breast)
What are the histopathologic features of Juvenile polyposis syndrome
juvenile polyps are hamartomas that develop from an abnormal collection of tissue elements normally present at this site. proliferative characteristics of adenomas are typically not seen in juvenile
How is the dx of Juvenile polyposis syndrome
established in a proband with any one of the following:
more than five juvenile polyps of the colon or rectum
multiple juvenile polyps of the upper and lower GI tract
any number of juvenile polyps and a FH of juvenile polyps
identification of a heterozygous PV in BMPR1A/SMAD4
What molecular testing should be ordered for the dx of Juvenile polyposis syndrome
BMPR1A and SMAD4 concurrent testing with sequence analysis w analysis of the promoter regions and del/dup
can also do serial single gene testing: sequence and del dup of SMAD4 then sequence and del dup of BMPR1A
if both are negative, test for PTEN
consider CMA; dels of 10q22-q23 including BMPR1A and or PTEN may be associated with additional clinical features w or wout juvenile polyposis OR with severe early onset JPS
What clinical features are associated with Juvenile polyposis syndrome
predisposition to hamartomatous polyps in the GI tract (stomach, small intestine, colon, and rectum); some are sessile and others are pedunculated
# of polyps in individuals varies, most have polyps by 20yo
in juvenile polyposis of infancy, associated w contiguous del of BMPR1A and PTEN, polyps develop within the first few yrs and are accompanied w hypoproteinemia, protein-losing enteropathy, diarrhea, anemia, and FTT
What cancer risks are associated with Juvenile polyposis syndrome
most juvenile polyps are benign but malignant transformation can occur
incidence of CRC by 35yo is 22%; by 60yo it approaches 68%
incidence of gastric cancer is 21% in those with gastric polyps
relative risk for CRC is ~34%
What are the clinical features associated with JPS/HTT
have variable findings of JPS and HTT; most individuals have one or more clinical findings of HTT
epistaxis (childhood); telangiectasias (after 30yo); pulmonary AVMs (birth-50s); hepatic AVM (20s-50s); intracranial AVMs (11-18); aortopathy (~24yo); intrapulmonary shunting on echo (5-59yo)
What are some general genotype-phenotype correlations in Juvenile polyposis syndrome
individuals w SMAD4-related JPS are more likely to have a personal or FH of upper GI polyps; gastric ca almost exclusively in those w SMAD4 JPS
CRC more frequently than other cancers in BMPR1A related JPS
What is the recommended tx for Juvenile polyposis syndrome
colonoscopy w endoscopic polypectomy
partial or total gastrectomy/colectomy in those w many polyps to alleviate symptoms
iron repalcement and RBC transfusion as needed
What is the recommended surveillance for individuals with Juvenile polyposis syndrome
assess for rectal bleeding, anemia, abdominal pain, constipation, diarrhea, or changes in stool at each visit
colonoscopy/upper endoscopy q3yrs @15yo or earlier if symptomatic; w/out germline PV, recommend q5yrs
What screening could be done in a pt who is 15 but refuses molecular testing in someone with a FH of JPS
CBC and lower intestinal tract endoscopy
What is the de novo rate for Juvenile polyposis syndrome
50%
How is the clinical dx of Peutz-Jehger syndrome established
proband must have one of the following:
2 or > histologically confirmed PJS-type hamartomous polyps
any # of PJS-polyps detected in an individual with a FH of PJS in at least one close relative
mucocutaneous pigmentation in an individual who has a FH of PJS
any # of PJS-type polyps in an individual who also has characteristic mucocutaneous pigmentation
How is the molecular dx of Peutz-Jehger syndrome established
heterozygous PV in STK11
sequence then del/dup
if no STK11 PV is identified, testing of an alternative DNA source for somatic mosaicism should be considered
What are the clinical features associated with Peutz-Jehger syndrome
association of GI polyposis and mucocutaneous pigmentation; variable expressivity is common
PJS-type hamartomatous polyps can occur anywhere in the GI tract but occur most commonly in the small intestine (greatest in jejunum, ileum, then duodenum); adenomas also appear w increased prevalence throughout the GI tract
polyps can cause significant complications (bowel obstruction, rectal prolapse, severe GI bleeding with secondary anemia needing multiple emergency sx. intussusception (50% by 20yo)
natural hx of polyps in a family may be a predictor of severity for offspring
mucocutaneous pigmentation: melanocytic macules- dark blue/brown spots around the mouth, eyes, nostrils, perianal area, buccal mucosa; hyperpigmented MM on the fingers
females are at increased risk for ovarian sex cord tumors with annular tubules and mucinous tumors of the ovaries and fallopian tubes, typically benign
males occasionally develop large cell calcifying Sertoli cell tumors of the testes; may secrete estrogen and can lead to gynecomastia, advanced bone age
What are the cancers associated with Peutz-Jehger syndrome
Overall: 83% by 70
CRC: 39% by 40s
Stomach: 29% by 30s-40s
Small bowel: 13% by late 30s
Breast: 30-55% by late 30s-50s
Ovarian (mostly SCTAT): 21% by 28yo
Cervix (adenoma malignum): 10% by 30s-40s
Uterine: 9% by 43yo
Pancreas: 11-36% by 40s-50s
Lung: 7-17% by 47yo
What tx is available for pts with Peutz-Jehger syndrome
prophylactic polypectomy of polyps >1cm is performed to: decrease risk of bleeding, anemia, obstruction, and intussusception AND reduce the risk of cancer
video capsule endoscopy for better visualization of the small-bowel polyps
What is the recommended surveillance for children/adolescents with Peutz-Jehger syndrome
colonoscopy and upper endoscopy at 8yrs; if neg, rpt at 18yo; if polyps detected, endoscopy q1-3yrs
small bowel exam by video capsule endoscopy q1-3yrs @8yo
exam for precocious puberty in females annually @8yo
testicular exam, exam for feminizing changes, testicular u/s if indicated annually @10yo
What is the recommended surveillance for adults with Peutz-Jehger syndrome
colonoscopy and upper endoscopy at 18yo q2-3yrs
small bowel exam by video capsule endoscopy @18yo q2-3yrs
CBE 2x/yr @30yo; mammo/breast MRI @30yo
pelvic exam and pap smear annually @18-20
pancreatic imaging w endoscopic u/s or MRI/MRCP annually @30-35yo
testicular u/s if indicated annually @10yo
What percentage of affected individuals with Peutz-Jehger syndrome have an affected relative
~65-70%
How is STK11 implicated in sporadic lung and cervical cancer
PVs are observed in 1/3 of all non-small cell lung cancers (STK is the 3rd most commonly mutated gene)
appear to be frequent in male smokers of N European background and are associated w poorly differentiated tumors
sporadic PVs in STK11 are observed in at least 20% of cervical cancers
What are the clinical features of FAMMM syndrome
most present in children and teenagers
presenting features is usually a high total body nevi count (>50) w some having an atypical appearance resembling melanoma on the back, chest, buttocks, breasts, and scalps
melanomas as early as the 2nd-3rd decade of life
CDNK2A PVs (AD) have a 90% risk of developing melanoma by 80yo and 20% increased risk of developing pancreatic cancer by the age of 75yo
RARELY associated w breast ca, esophageal ca, and sarcomas
What % of pts with FAMMM do not have a molecular dx? How can the clinical dx be established?
60%
dx criteria: high total body nevi count (>50), nevi w certain histologies (lentiginous pattern, nuclear atypia), melanomas in 1 or more first or second degree relative
What is the recommended surveillance for FAMMM
screening for melanoma should begin at 10yo w total body skin eval w the use of dermoscopy
clinical skin exams or self-exams should then be performed q6mos
in families w a hx of pancreatic cancer or a CDNK2A PV, MRI/MRCP offered starting at 40yo
How is the clinical dx of Carney complex made
established in a proband w two or more major dx criteria:
Spotty skin pigmentation with typical distribution (lips, conjunctiva and inner or outer canthi, vaginal and penile mucosa)
Myxoma * (cutaneous and mucosal)
Cardiac myxoma *
Breast myxomatosis * or fat-suppressed MRI findings suggestive of this diagnosis
Primary pigmented nodular adrenocortical disease (PPNAD) * or paradoxic positive response of urinary glucocorticosteroid excretion to dexamethasone administration during Liddle’s test
Acromegaly as a result of growth hormone (GH)-producing adenoma *
Large cell calcifying Sertoli cell tumor (LCCSCT) * or characteristic calcification on testicular ultrasound
Thyroid carcinoma * or multiple, hypoechoic nodules on thyroid ultrasound in a child younger than age 18 years
Psammomatous melanotic schwannoma (PMS) *
Blue nevus, epithelioid blue nevus *
Breast ductal adenoma *
Osteochondromyxoma *
Family history of CNC consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations)
How is the molecular dx of Carney complex established
sequence analysis and del/dup of PRKAR1A
What are the clinical features associated w Carney complex
skin pigment abnormalities: pale brown to black lentigines that increase in # and appear anywhere; epithelioid-type blue nevi, combined nevi, cafe au lait macules, depigmented lesions
cutaneous/mucosal myxomas: appear between birth and 40s; occur on any part of the body except the hands and feet, typically on the eyelids, external ear canal, and nipples
cardiac myxomas: occur at a young age causing symptoms- intracardiac obstruction of blood flow, embolic phenomenon, heart failure, sudden death
breast myxomas: bilateral, in females after puberty
Primary pigmented nodular adrenocortical disease (PPNAD): overproduction of cortisol, most frequent observed endocrine tumor in the 2nd-3rd decade of life; results in Cushing syndrome w central obesity, moon facies, hirsutism, HTN, weakness, easy bruising, psychological disturbance
Somatomammotrophy hyperplasia/GH-producing adenoma: clinically evident acromegaly is a relatively frequent manifestation
Large cell calcifying Sertoli cell tumors (LCCSCT): in 1/3 of affected males within the first decade, almost always benign
Thyroid tumors: multiple thyroid nodules; carcinomas, both papillary and follicular
Psammomatous melanotic schwannoma (PMS): rare tumor of the nerve sheath, malignant degeneration in ~10%, frequently found in the nerves of the GI tract
pancreatic tumors of varying histology
benign breast ductal adenomas
What are the common causes of death in pts with Carney complex
most will have a normal life span
complications of cardiac myxomas, metastatic or intracranial PMS, thyroid carcinoma, and metastatic pancreatic and testicular tumors
What are the recommended tx’s for pts with Carney complex
cardiac myxoma: sx excision before development of heart complications
cutaneous/mammary myxoma: sx excision
Cushing syndrome: bilateral adrenalectomy
Pituitary adenoma: transsphenoidal sx
thyroid adenoma: sx resection for cancerous adenomas
LCCSCT: Orchiectomy for boys w aggressively growing tumors; for those whose tumors are not growing, tx w aromatase inhibitors
Psammomatous melanotic schwannoma: sx to remove primary or metastatic lesions
What is the recommended surveillance for pts with Carney complex
cardiac myxomas: echo annually at childhood
urinary free cortisol levels annually in adolescence for PPNAD
serum IGF-1 annually in adolescence for pituitary tumors
thyroid u/s annually beginning in adolescence
testicular u/s annually in childhood to monitor for tumors
What is the de novo rate for Carney complex
70% have an affected parent, 30% de novo
How is the clinical dx of Birt-Hogg-Dube established
one major or two minor criteria are necessary for the dx
major criteria
5 or more fibrofolliculomas/trichodiscomas with at least one confirmed histologically
identification of a PV in FLCN
minor criteria
multiple lung cysts with or without spontaneous primary pneumothorax
early onset renal cancer (<50yo)
multifocal/bilateral renal cancer
renal cancer of mixed chromophobe and oncocytic histology
first degree relative with BHDS
how is the molecular dx established for Birt-Hogg-Dube
sequence analysis then del dup of FLCN
Describe the clinical features present in pts with Birt-Hogg-Dube
cutaneous manifestations: multiple small skin-colored opaque whitish or yellowish dome shaped papules (fibrofolliculomas) between 2nd-4th decade in more than 80% of affected; increase in size, number, and distribution w age affecting the face, neck, and upper trunk; women have smaller and fewer lesions than men
acrochordons (skin tags) typically on the neck, axillae, and larger skin folds; angiofibromas, oral papules, multiple epidermal cysts, cutaneous melanoma (multiple desmoplastic melanoma and choroidal melanoma)
pulmonary cysts: lung cysts in more than 80% of adults; irregular shape and variable, does not exhibit signs of proliferation
spontaneous recurrent pneumothorax: typically the first manifestation, overall prevalence of recurrence is ~20-35%
renal cell carcinoma: tends to be bilateral and multifocal; prevalent in 19-35% of affected; most common tumor is a hybrid of oncocytoma and chromophobe but can also be clear cell carcinoma; can also have multiple nodules in the area surrounding tumors
can also have: parotid tumors (Salivary glands), thyroid cancer/ goiter, colorectal polyps
What is the recommended tx for pts with Birt-Hogg-Dube
fibrofolliculomas are benign and do not need tx other than for cosmetic purposes
tx of pneumothorax is the same for the general pop; lung cysts are not tx and most show normal lung function
crucial to detect renal tumors before they exceed 3.0cm bc sparing sx is the tx of choice whenever possible; if less than 3.0cm, they are monitored by periodic imaging
watch for rapidly growing lesions and symptoms: pain, blood in urine, atypical presentations
What is the recommended surveillance for Birt-Hogg-Dube
derm exam q6-12mo for possible risk of melanoma
Lung CT only for 1. those w suspected pneumothorax, 2. prior to scheduled flight/anesthesia
abdominal/pelvic MRI annually starting @20yo
consider thyroid u/s annually
colonoscopy early (10yrs) if there is a FH of CRC
What should pts with Birt-Hogg-Dube avoid
cigarette smoking (lung ca risk); high ambient pressures, which may precipitate spontaneous pneumothorax
How is the dx of Xeroderma Pigmentosum established
based on clinical findings and/or identification of biallelic PVs in DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, POLH, XPA, or XPC
order multigene panel
What are the most common genes causing Xeroderma Pigmentosum
ERCC2 (15%); POLH (23.5%); XPA (30%); XPC (27%)
What are the clinical findings associated with Xeroderma Pigmentosum
Cutaneous findings: more than 1/2 have a hx of acute sunburn rxn on minimal UV exposure, numerous freckle-like hyperpigmented macules appear on sun-exposed skin, starts between 1-2yo, limited to sun-exposed areas, poikiloderma (constellation of hyper and hypopigmentation, atrophy, and telangiectasia), premalignant actinic keratoses, accelerated photoaging
ocular abnormalities: first decade of life, findings are usually limited to the anterior, UV exposed portions of the eyes (conjunctiva, cornea, lids); dry eyes, epithelioma, SCC, melanoma are common, may be more severe in heavily pigmented individuals, benign conjunctival inflammatory masses obscure the cornea, photophobia, severe keratitis, corneal opacification, neovascularization, atrophy of the skin of the lids (can result in complete loss of the lids), lentigines, freckling on the lids, and lash loss are also common
neurologic findings (30%): progressive neurologic abnormalities that worsen slowly; may be early in infancy or delayed until second decade of life; may be mild (isolated hyporeflexia) or severe (acquired microcephaly, progressive ID, SNHL, spasticity, ataxia, seizures), reduced nerve conduction velocity
cutaneous neoplasms: usually in the first decade of life due to sun-induced DNA damage (50% w skin ca by 10yo); BCC >10,000 Fold risk, age of onset ~9yo; cutaneous melanoma median age of onset ~22yo
other: oral cavity neoplasms (SCC of the tip of the tongue), lung cancer in those who smoke (since DNA repair system is damaged in this condition), 34-fold increase in internal neoplasms; women at risk for early menopause, may require ART for pregnancy (usually have PVs in XPC); risk for thyroid nodules/carcinoma
What is the life expectancy for someone with Xeroderma Pigmentosum
median age of death is ~29yo w neurodegeneration and ~37 w/out neurodegeneration
cause of death is usually: skin cancer, neurologic deterioration, and internal cancer
What are the recommended tx for pts with Xeroderma Pigmentosum
premalignant lesions: freeze w liquid nitrogen
larger area of skin damage: topical 5-FU
recurrent skin cancers: best tx w Mohs sx
active development of large numbers of new tumors: oral isotretinoin to prevent new neoplasms
metastatic melanoma and invasive SCC: systematic chemo
hematologic malignancies: standard chemo, BMT not successful
internal manifestations: standard therapy, small dose X-ray if absolutely necessary
thyroid nodules: bx of suspicious nodules, thyroidectomy if cancer identified
neoplasms of eyelids, conjunctiva, and cornea: sx tx, topical 5-FU
severe keratitis: corneal transplantation
hearing loss: use of hearing aids, cochlear implants
premature menopause: hormone replacement therapy
What is immediately necessary in a patient w suspected Xeroderma Pigmentosum
tx depends on early dx and IMMEDIATE aggressive avoidance of sun and other UV exposure
clinical suspicion should prompt immediate sun-protective measures
bc the cells of individuals with XP are hypersensitive to UVA, UVB, and UVC, it is useful to measure UV light in an individual’s surroundings w a light meter so that high levels of environment UV can be identified and eliminated if possible
serum vitamin D levels should be monitored and dietary supplementation w oral vitamin D is recommended for ppl w low serum concentration of vitamin D
What is the recommended surveillance for pts with Xeroderma Pigmentosum
skin: exam q3-12mo; caregivers should look for suspicious lesions on skin q1wk
eyes: exam for damage assessment q6mo
neurologic: exam q12mo for symptomatic pts
hearing: audiograms q6-12mo
female reproduction: lab assessment for POI q12mo starting @18
If a women with Xeroderma Pigmentosum were to become pregnant, what do they need to be counseled on?
isotretinoin and acitretin are used as skin ca chemo agents in those who are actively developing large numbers of skin ca; KNOWN TO BE TERATOGENIC
may take a long time to be eliminated from the body (3yrs)
How is the clinical dx of MEN1 established
proband w:
2 or > endocrine tumors including parathyroid, anterior pituitary, and well-differentiated neuroendocrine tumors of the GEP tract OR
one of the three endocrine tumors above AND a first degree relative w MEN1
What are the parathyroid and anterior pituitary clinical features associated with MEN1
Primary hyperparathyroidism: often mild, most common associated endocrinopathy and first clinical feature in 90% between 20-25yo; all w hypercalcemia by 50%, may manifest as rickets and osteomalacia in pediatric pop; pathology: multiglandular parathyroid dx w enlargement of all the parathyroid glands, rather than a single adenoma is typical; parathyroid carcinoma is RARE
Anterior pituitary adenomas: first clinical manifestation in 25% of simplex cases and 10% of familial; occurs significantly more in women than men; symptoms depend on the pituitary hormone produced:
PRL-secreting adenoma: amenorrhea and galactorrhea (reduction of libido or impotence)
ACTH-secreting adenoma: hypercortisolism (Cushing dz)
GH-secreting adenoma: giantism in children, acromegaly in adults
FSH-secreting adenoma: reduced libido, erectile dysfunction
What is the pathology associated with anterior pituitary tumors in with MEN1
65-85% of pituitary adenomas are macroadenomas; significantly larger and more often invasive than sporadic pituitary tumors
malignant degeneration of MEN1-associated pituitary tumors is infrequent
What are the endocrine tumors of the gastroenteropancreatic (GEP) tract clinical features associated with MEN1
~40% have gastrinomas; > 90% occur in the duodenum; typically, multiple small gastrinomas are observed in the submucosa with diffuse hyperplastic changes of gastrin cells and multifocal microgastrinomas which are characteristic of MEN1; 70-85% are metastatic to regional lymph nodes at the time of dx; 15% show aggressive tumor growth (pancreatic ones are more aggressive than duodenal ones)
Insulinoma: tumors responsible for hyperinsulinism are usually 1-4cm in diameter; single tumor in the setting of multiple islet macroadenoma, almost always benign
glucagonoma: can be associated with other tumors, but are very rare; ~80% are malignant and metastasize to the liver
What are the carcinoid, adrenocortical, and non-endocrine tumors associated with MEN1
Carcinoid: thymic, bronchial, type II gastric enterochromaffin-like carcinoids in 3-10%; only tumors to exhibit male to female ratios; thymic carcinoids in females to males of 20:1 and bronchial in females to males of 1:4; tend to be multifocal and may occur synchronously or over time; thymic carcinoids are aggressive and highly lethal, most bronchial carcinoids are not aggressive; significantly increased risk of death in those with thymic carcinoids
Adrenocortical tumors: involve one or both glands, usually found incidentally on CT; most are nonfunctioning but 10% demonstrating hormonal secretion leading to Cushing dz exists; rarely results in malignancy, 1% will have adrenocortical carcinoma
Non-endocrine tumors: facial angiofibromas (85%), collagenomas (70%), lipomas (30%), cafe au lait macules, leiomyomas, adenomas of the thyroid, goiters, thyroid carcinomas in 25%
What is the life expectancy for MEN1
significantly increased risk for premature death
malignancies account for ~30% of deaths in individuals
How are the clinical features of MEN1 tx?
1 hyperparathyroidism: parathyroidectomy is the tx of choice; subtotal parathyroidectomy suggested as the initial tx; total parathyroidectomy w auto-transplantation may also be reserved for those w extensive dz either at first or at repeat sx; those who are asymptomatic can delay sx and have regular assessment for symptom onset
Anterior pituitary adenomas:
PRL-secreting adenoma: dopamine agonists, transsphenoidal sx and radiotherapy reserved for drug resistant tumors
GH-secreting adenoma: transsphenoidal sx for those causing acromegaly, effective in 50-70% of cases; somatostatin analogs
ACTH-secreting adenoma: excision of the adenoma, radiotherapy to reduce the production of ACTH
non-functioning adenoma: sx using a transsphenoidal approach
Well-Differentiated Endocrine Tumors of the GEP Tract:
gastrinoma: proton pump inhibitors or H2 receptor blockers to reduce gastric acid output; tumors are usually microscopic and scattered throughout the neuroendocrine tissue, successful sx outcome rare; long term symptom free f/u after excision of a lymph node gastrinoma is the only reliable criterion for the dx of a primary lymph node tumor
pancreatic tumors: sx usually indicated for insulinoma and most others; unresectable tumors or advanced metastatic ca can be treated w somatostatin analogs, chemo, inhibitors of tyrosine kinase, or inhibitors of mammalian target of rapamycin
Carcinoid tumors: long-acting somatostatin analogs can control the secretory hyperfunction associated w carcinoids; risk for malignant progression of the tumor remains unchanged; tx is sx removal if possible
Adrenocortical tumors: sx is suggested for adrenal tumors >4cm
pheochromocytoma occurs rarely in MEN1, appropriate to measure urinary catecholamines prior to sx to dx and tx a pheochromocytoma and thus avoid dangerous and potentially lethal BP peaks during sx
What is the recommended surveillance for pts w MEN1
parathyroid tumors: measure calcium and PTH annually @5yo
anterior pituitary adenomas: serum concentration of prolactin, IGF-1, fasting glucose and insulin annually @5yo; Head MRI q3-5yrs @5yo
well-differentiated endocrine tumors of the GEP tract: measurements for pancreatic neuroendocrine tumors annually @8yo; fasting serum gastrin concentration annually @20yo; consider abdominal CT, MRI, EUS q3-5yrs @20yo
carcinoid tumors: consider chest MRI, CT, SRS octreotide scan annually @15yo
non-endocrine tumors: skin exam consider annually as needed
What is the recommended surveillance for 1st degree relatives of pts w MEN1
parathyroid tumors: measure calcium and PTH annually @10yo
anterior pituitary adenomas: serum concentration of prolactin annually @5yo
well-differentiated endocrine tumors of the GEP tract: fasting serum gastrin concentration annually @20yo; EUS annually @20yo
What is the de novo rate for MEN1
~90% have an affected parent, 10% de novo
What is the molecular pathogenesis for MEN1? Special lab considerations?
tissue-specific roles in DNA replication and repair; suspected to repress tumorigenesis
biallelic inactivation of MEN1, by a germline heterozygous loss of function variant and an acquired somatic loss of function variant
coding region of MEN1 includes exons 2-10; no PVs have been found in exon 1, and this exon is usually excluded from genetic testing
How is the clinical dx of MEN2 made
MEN2A: occurrence of two or more specific endocrine tumors (MTC, pheochromocytoma, parathyroid adenoma/hyperplasia) in a single individual or in close relatives
FMTC: families with two or more individuals with MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia
MEN2B: presence of early-onset MTC, mucosal neuromas of the lips and tongue, as well as medullated corneal nerve fibers, distinctive facies w enlarged lips, marfanoid body habitus
How is the molecular dx of MEN2 made
single gene testing (sequence and del/dup (although no del/dups have been reported)
can also do select exon testing for those with suspected MEN2A/FMTC bc majority of PVs occur in exons 10,11, and 13-16
targeted analysis for RET PVs p.Met918Thr and p.Ala883Phe can be considered in those with suspected MEN2B
What are the clinical phenotypes associated w MEN2
MTC typically presents at a young age and is often associated w C-cell hyperplasia (CCH) as well as multifocality or bilaterality; includes neck mass or pain prior to 35yo; plasma calcitonin concentration high and diarrhea implies poor prognosis; 70% w palpable mass have cervical lymph node metastases; 20-30% w MTC have germline RET PVs; MTC and CCH are suspected in the presence of an elevated plasma calcitonin; all individuals w an MTC-predisposing RET variant who have not undergone prophylactic thyroidectomy demonstrate biochemical evidence of MTC by 35yo; 50% w MTC who have undergone total thyroidectomy and neck nodal dissections have recurrent dz; MTC originates in calcitonin-producing cells of the thyroid gland
Pheochromocytomas are often bilateral, rarely metastasize, but can be lethal bc of intractable HTN or anesthesia-induced hypertensive crises; nearly always adrenal; suspected when biochemical screening reveals elevated excretion of catecholamines and catecholamine metabolites in plasma/urine, consistently producing epinephrine or epi AND norepinephrine
Parathyroid abnormalities can range from benign adenomas to clinically evident hyperparathyroidism w hypercalcemia and kidney stones; elevated serum calcium occurs simultaneously w elevated or high-normal parathyroid hormone
What are the distinct cancer phenotypes associated with the three forms of MEN2
MEN2A: 70-80% of individuals w MEN2; MTC is generally the first manifestation; pheochromocytomas (dx at earlier age, subtler symptoms, bilateral) usually present after or concomitantly; hyperparathyroidism is typically mild and may be due to a single adenoma or hyperplasia (most have no symptoms); small number of families have cutaneous lichen amyloidosis
FMTC: 10-20%; MTC is the only clinical manifestation of FMTC; is a variant of MEN2A w decreased penetrance of pheochromocytoma and HPT
MEN2B: 5%; early development of an aggressive form of MTC in all affected individuals; those who do not undergo thyroidectomy before age 1yr are likely to develop metastatic MTC at an early age; pheochromocytomas in 50%, 1/2 are multiple and often bilateral, may die from a cardiovascular hypertensive crisis perioperatively; NOT associated with an increased risk for clinically significant parathyroid dz; distinctive facies: presence of mucosal neuromas on the tongue, palate, or pharynx; lips become prominent over time, neuromas of the eyelids, thickened corneal nerves; 40% have diffuse ganglioneuromatosis of the GI tract (abdominal distention, megacolon, constipation, diarrhea); 75% have a marfanoid habitus (w kyphosis/lordosis, joint laxity, decreased subcutaneous fat)
What is the recommended tx for MEN2 based on genotype
prophylactic thyroidectomy is the primary preventive measure for those w a germline PV in RET; age at which sx is performed is based on the codon position:
Highest risk (MEN2B, p.Met918Thr): as soon as possible in 1st yr of life
High risk: less than 5yo
Moderate risk: lesser gain of function variants: may delay after 5yo if criteria are met (normal calcitonin, annual neck u/s, FH of less aggressive MTC)
What is the general recommended tx for MEN2
prior to any sx to avoid intraoperative catecholamine crisis: If PCC is detected, adrenalectomy before thyroidectomy to avoid intraoperative catecholamine crisis
MTC: sx removal of thyroid and lymph node dissection; parathyroidectomy is not typically performed at time of thyroidectomy unless their is evidence of HPT; consider RET-selective inhibitors in those w metastatic dz
Hypothyroidism following thyroidectomy: HRT
PCC: tx of HTN prior to adrenalectomy often w alpha and beta adrenergic receptor blockade; resection by adrenalectomy
parathyroid adenoma/hyperplasia: for those dx w HPT at time of thyroidectomy, resection of visibly enlarged parathyroid glands, subtotal parathyroidectomy, total parathyroidectomy
When should molecular testing be offered to family members in a proband with a RET PV (MEN2)
MEN2A: at risk children by age 5; finding of MTC in the thyroid of a 12mo suggests even earlier if possible
FMTC: Same for MEN2A
MEN2B: as soon as possible after birth
If PV is not known: neck u/s and calcitonin levels for MTC; Annual albumin calcium for HPT; Annual plasma free metanephrines for pheos
What is the de novo rate for MEN2
MEN2A: 5%
FMTC: None
MEN2B: 50% (majority are paternal in origin)
What is the mechanism of dz for MEN2
GAIN of function
What are the laboratory findings consistent with a dx of PGL/PCC
elevated metanephrine or precursor epi (adrenaline)
elevated normetanephrine or precursor norepinephrine (noradrenaline)
elevated dopamine and its major metabolite 3-methyoxytyramine
How is the dx of hereditary PGL/PCC established
proband w a personal or FH of paraganglioma or pheochromocytoma and a germline heterozygous PV
What molecular testing should be ordered for suspected hereditary PGL/PCC
multigene panel including MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, and TMEM127
Single gene testing not often used but can be pursued based on the following:
SDHB in an individual w metastatic pheo or paraganglioma
SDHD in individuals w head and neck paragangliomas (account for 40-50% of HNPGLs)
How can tumor immunohistochemistry be used for hereditary PGL/PCC
may suggest an underlying PV
any component of the mito respiratory chain complex 2 is inactivated, the entire complex becomes unstable resulting in degradation of SDHB subunit. Therefore, negative staining appears to occur when a germline PV in SDHA, SDHB, SDHC, or SDHD is accompanied by inactivation of the normal allele
What are the clinical features associated with hereditary PGL/PCC
paragangliomas
head and neck paragangliomas: associated w the parasympathetic NS and do not secrete catecholamines or other hormones; most do not metastasize
paragangliomas in the LOWER mediastinum, abdomen, and pelvis: associated w the sympathetic NS and usually secrete catecholamines, higher risk of metastasizing
pheos are catecholamine secreting paragangliomas confined to the adrenal medulla; metastatic dz is less likely
majority of GISTs are associated w SDHA/SDHC; most occur in the stomach and are multifocal
pulmonary chondromas for those with PVs in SDHx genes
Clear cell RCC in those with PVs in SDHB/SDHD
What is the etiology of the tumors in hereditary PGL/PCC
arise within the paraganglia- collections of neural crest cells distributed along the paravertebral axis from the base of the skull to the pelvis
adrenal paragangliomas= pheos
what is the best imaging modality for visualization of hereditary PGL/PCC
CT
MRI is a better option for those whom radiation exposure must be limited
Where are the most common metastatic sites for hereditary PGL/PCC
bone, lung, liver, lymph nodes
What genes are associated with what phenotypes in hereditary PGL/PCC
MAX: pheos
SDHA: Pheos and paragangliomas
SDHFA2: HNPGLs
SDHB: higher morbidity/mortality, strongly associated w extra-adrenal sympathetic paragangliomas, increased risk of metastatic dz; less frequently pheos and parasympathetic paragangliomas
SDHC: HNPGLs
SDHD: HNPGLs, 75% w multifocal primary paragangliomas
TMEM127: pheos, HNPGLs, extra adrenal paragangliomas, CCRCC
What is the penetrance for SDHA/SDHB in hereditary PGL/PCC
SDHA: 50% by 70yo
SDHB: 25-55% by 60yo
What is the recommended surveillance for pts w hereditary PGL/PCC by gene
SDHA/SDHC/SDHD (start at 6-15yo): clinical assessment for manifestations of tumors (annually); metanephrines for secreting PGLs/PCC (q2yrs in childhood, annually in adults); whole body MRI (q2-3yrs); EGD for those w unexplained anemia and GI symptoms (as needed)
SDHB (start at 6-10yo): clinical assessment for manifestations of tumors (annually); metanephrines for secreting PGLs/PCC (q2yrs in childhood, annually in adults); whole body MRI (q2-3yrs); EGD for those w unexplained anemia and GI symptoms (as needed)
MAX/SDHAF2/TMEM127 (start at 6-8yo): clinical assessment for manifestations of tumors (annually); metanephrines for secreting PGLs/PCC (q2yrs in childhood, annually in adults); whole body MRI (q2-3yrs); EGD for those w unexplained anemia and GI symptoms (as needed)
What genes have a parent of origin effect in hereditary PGL/PCC
PATERNAL EFFECT
SDHD, SDHAF2, possibly MAX
What is the molecular pathogenesis of hereditary PGL/PCC? What are molecular considerations?
tumor suppressor genes; somatic second-hit variants in tumors include chromosomal rearrangements, recombination, SNVs, epigenetic changes that result in allelic inactivation
SDHA/SDHC/SDHD have pseudogenes
Describe the Dutch and Danish criteria for VHL
DUTCH
positive FH: 1 VHL related tumor AND a 1st or 2nd degree relative w dx of VHL; negative FH: More than or equal to 2 VHL related manifestations
clinical criteria include: retinal HB, CNS HB, RCC, Pheo, PNET, ELST paraganglioma, multiple kidney cysts, multiple pancreatic cysts are specific to this criteria
DANISH
positive FH: 1 VHL related tumor AND a 1st degree relative w dx of VHL; negative FH: More than or equal to 2 HBs OR 1 HB and 1 VHL related manifestation
clinical criteria: see above
What are the clinical features associated with VHL
Hemangioblastomas: CNS hemangioblastoma is the prototypic lesion of VHL, 80% will develop in the brain, 20% in the spinal cord; increased growth was associated w male sex, symptomatic tumors, hemangioblastoma-associated cysts and germline dels remain the main cause of death
brain hemangioblastomas: pituitary stalk is most common site, clinical symptoms depend on the site of the tumor; spinal: present w pain, sensory and motor loss may develop w cord compression; retinal: may be the initial manifestation and may occur in childhood in 70%, mean age of detection ~25yo, probability of these associated w vision loss increases w age
renal lesions: multiple, bilateral renal cysts are common; renal cell carcinoma (clear cell), 70% of individuals affected by 60yo, leading cause of mortality (PVs in VHL are the most common cause of RCC)
pheos: more likely to be identified incidentally, at a younger age; can be unilateral or bilateral and are often small and multifocal
paragangliomas: often nonfunctional (non-secreting)
pancreatic lesions: most are simple cysts and have no malignant potential; 6-17% have neuroendocrine tumors of the pancreas but are not typically hormonally active
endolymphatic sac tumors: 10-16% of individuals, some instances unilateral or bilateral heating loss is the initial clinical manifestation, typically sudden and often severe to profound; rarely malignant
epididymal and broad ligament cystadenomas: relatively common in males, if bilateral can cause infertility
How do you identify the molecular dx of VHL
Sequence analysis of VHL coding region, intron 1, flanking sequences, and del/dup
What are the four general phenotypes in VHL
type 1: retinal angioma, CNS hemangioblastoma, RCC, pancreatic cysts, and neuroendocrine tumors; low risk for pheos
type 1B: complete or partial del that extends 5’ of VHL to include BRK1 have a significantly reduced risk of RCC and pheos
Type 2: pheos, retinal hemangioblastomas, CNS hemangioblastoma, high risk for pheos
2A: pheos, retinal hemangioblastomas, CNS hemangioblastoma; low risk for renal cell carcinoma
2B: pheos, retinal hemangioblastomas, CNS hemangioblastoma, pancreatic cysts, neuroendocrine tumors; high risk for RCC
2C: risk for pheos only
What are targeted and general tx for VHL
Pazopanib for advanced RCC
Belzutifan for those with VHL and CCRCC, alters the biology of cells lacking the VHL protein
most hemangioblastomas can be sx removed safely
preoperative arterial embolization for expansive spinal hemangioblastomas, sx intervention for cysts in the spinal cord is recommended
retinal hemangioblastomas are followed closely to avoid blindless, although spontaneous regression has occurred
RCC should be tx w cryoablation and radiofrequency ablation instead of sx resection for small RCCs; kidney transplantation has been successful gor those that require bilateral nephrectomy
pheos should be sx removed, active surveillance for pheos smaller than 2cm can be safe
pancreatic neuroendocrine tumors should be sx removed if there is a high risk of metastases
consider sx removal of slow growing endolymphatic sac tumors with consideration for total deafness; early intervention associated w preservation of hearing and vestibular function
What is the recommended surveillance for pts with VHL
Clinical exam annually
brain and total spine MRI q2yrs @11
ophthalmology exam annually @1yr
MRI of abdomen q2yrs @15
BP annually, plasma/urine metanephrines annually @5
audiology exam q2-3yrs @11yo, MRI of internal auditory canals in asymptomatic ppl 15-20yo
What is the de novo rate in VHL
20%
How is the dx of hereditary retinoblastoma established
proband with retinoblastoma or retinoma and a FH of retinoblastoma
MAJORITY do not have a FH of the disorder, and therefore need a heterozygous PV in RB1
What testing should be ordered for pts w a FH of hereditary retinoblastoma? without a FH?
FH: sequence analysis and del dup of RB1
no FH: same as above on blood; if tumor tissue is available, perform sequence and del dup on that sample; if PVs are identified, test DNA from blood, if no PVs are identified, methylation analysis of RB1 promoter; no hypermethylation, then DNA from tumor is tested for amplification of MYCN
CMA for individuals w retinoblastoma w DD or other congenital anomalies
What clinical features are associated with hereditary retinoblastoma
leukocorcia (white pupillary reflex), strabismus, dx before 5yo
60% have unilateral w an avg dx at 24mo, tumor is usually unifocal, in most persons without a FH, the tumor is large and it is not possible to determine if a single tumor is present
40% have bilateral w a mean age of dx of 15mo; both eyes may show multiple tumors (trilateral if bilateral retinoblastoma and a pinealoblastoma develop
can also have benign retinal tumors (retinoma)
pinealoblastomas: occur in the “retina-like” tissue in the pineal gland of the brain; rare and usually fatal
other tumors: most common secondary neoplasms include osteosarcoma, soft tissue sarcoma, or melanoma; tumors usually in adulthood or adolescence
How does hereditary retinoblastoma usually present in the clinical setting
Neg FH and unilateral retinoblastoma (60%)
Neg FH and bilateral retinoblastoma (30%)
+ FH and unilateral or bilateral retinoblastoma (~10%)
chrom dels involving 13q14, often associated w DD and birth defects
What is the tx for hereditary retinoblastoma
goals are to preserve life then sight
options include: enucleation, cryotherapy, laser, chemo, radiation, last resort should be external beam radiotherapy (if possible, it is avoided)
included in care: ophthalmology, pediatric oncology, pathology, and radiation oncology
What is the recommended surveillance for pts w RB1 germline PV, persons w/o a germline PV but with unilateral retinoblastoma, persons w retinoma?
RB1 germline PV: eye exam under anesthesia, then without once they can be cooperative
persons w/o a germline PV but with unilateral retinoblastoma: clinical eye exam, eye u/s
persons w retinoma: retinal exams, photographic imaging to detect any change early
What is the risk to a sib if their sib has hereditary retinoblastoma
+FH, bilateral retinoblastoma= 50%
-FH, bilateral retinoblastoma=2%
-FH, unilateral, multifocal retinoblastoma= 1-2%
-FH, unilateral and unifocal retinoblastoma= ~1%
What prenatal screening can be done to determine if a fetus will have congenital retinoblastoma
If RB1+, u/s exam may be used to identify medium-sized intraocular tumors; delivery of the fetus ~36wks GA may be recommended as 30% will have tiny vision-threatening tumors
if no RB1 PV has been found, can do fetal MRI but are not sensitive enough to identify small retinoblastoma tumors
How is the dx of hereditary leiomyomatosis and renal cell cancer established
PV in FH, sequence then del/dup
CMA to detect large del/dups
What are the clinical features associated with hereditary leiomyomatosis and renal cell cancer
cutaneous leiomyomas: firms skin colored papules and nodules at ~30yo, tend to increase in size and # w age; painful or sensitive to light touch and/or cold temperatures
uterine leiomyomas (fibroids): have more fibroids and onset at a younger age than women in general pop; usually large and numerous and associated with irregular menses, menorrhagia, or pain; often undergo hysterectomy or myomectomy
renal cancer: typically unilateral and solitary, symptoms may include lower back pain, hematuria, palpable mass although many are asymptomatic; typically type 2 papillary
can have pheos and paraganglioma
What are the tx recommendations for pts with hereditary leiomyomatosis and renal cell cancer
cutaneous lesions: sx excision is considered standard; have a high rate of recurrence and meds can be used for pain relief
uterine fibroids: require medical and/or sx intervention earlier, sx options include myomectomy and hysterectomy
renal tumors: sx excision of renal malignancies appears to require earlier and possibly more extensive sx; due to metastatic potential, lymph node detection may be considered
What is the recommended surveillance for pts with hereditary leiomyomatosis and renal cell cancer
cutaneous leiomyoma: full skin exam annually after first dx
uterine leiomyoma: gynecologic consult annually @20yo or at first exam in symptomatic ppl
renal tumors: MRI w contrast is preferred but can do CT annually @8yo
no guidelines for pheos/paragangliomas
How is the clinical dx of TSC established
2 major findings OR 1 major and 2 minor findings
MAJOR
> or = 3 angiofibromas or fibrous cephalic plaques
cardiac rhabdomyoma
multiple cortical tuber and/or radial migration lines
lymphangioleiomyomatosis (LAM)*
multiple retinal nodular hamartomas
> or = 2 renal angiomyolipomas*
shagreen patch
subependymal giant cell astrocytoma (SEGAs)
> or = 2 subependymal nodules
> or = 2 ungual fibromas
these two together are not dx
MINOR
sclerotic bone lesions
confetti skin lesions
> or = 3 dental enamel pits
> or = 2 intraoral fibromas
multiple renal cysts
nonrenal hamartomas
retinal achromic patch
What sex tends to be more mildly affected in TSC
Females
What are the leading cause of morbidity and mortality in TSC? What causes the most disfigurement?
CNS tumors; angiofibromas
What are the clinical features associated w TSC
80% w seizures, KNOWN CAUSE OF INFANTILE SPASMS
~50% have ID/DD and leading cause of death is complication of severe ID
Renal dz is the second leading cause of death; benign angiomyolipomas: life-threatening bleeding, ESRD; renal cysts: PKD, ESRD; Malignant angiomyolipomas and RCC: 2-5% incidence, avg age of dx 28-30yo, immunologic staining for HMB-45 for angiomyolipomas and cytokeratin for RCC recommended
individuals w TSC associated LAM may present w shortness of breath or hemoptysis, some progress to death
What is TSC-Associated Neuropsychiatric disorder
TAND
Behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties
all pts should be evaluated since these disorders can contribute significantly poorer outcomes
What are genotype/phenotype correlations seen in TSC
TSC2 produces a more severe phenotype, @ greater risk for: renal malignancy, ID, ASD, decreased IQ, infantile spasms
infants w cardiac rhabdomyomas have a 75-80% chance of being affected w TSC
What are the surveillance recommendations associated with TSC
CNS: brain MRI q1-3yrs in asymptomatic individuals <25yo to monitor for new SEGA occurrence; routine EEG in asymptomatic individuals q6wks until 12mo then q3mo up to 24mo; annual TAND exam
Renal: MRI of abdomen q1-3yrs to assess for progression of angiomyolipomas and renal cystic dz
Pulmonary: screening for LAM for women >18yo or those w respiratory symptoms, high resolution CT of the lungs q5-7yrs through menopause
Derm: annual skin exam
Dental: exam @ least q6mo
Ophthalmology: annual exam
What txs are available for TSC
mTOR inhibitors for SEGAs (might still need neurosx)
Vigabatrin for infantile spasms. Possible mTOR inhibitor use for intractable seizures
mTOR inhibitors for growing renal angiomyolipoma (nephrectomy avoided due to increased incidence of complications and increased risk for future renal insufficiency and ESRF, and poor prognosis that results from chronic kidney dz
estrogen use is contraindicated due to possible involvement of proliferation of LAM cells, causing it to get worse
What is the de novo rate for TSC? What is the molecular pathogenesis of TSC1/TSC2
2/3 de novo rate
TSC1 + TSC2 encode hamartin and tuberin respectively, which work together to regulate cell growth. Regulators of the mTOR/AKT pathway
causes an abnormal gene product
What guidelines are used to determine who should have MSI tumor testing in Lynch syndrome? What criteria is used to determine who are high risk candidates for Lynch and what are they?
Bethesda
Amsterdam II criteria: 1+ lynch related cancer dx under 50; 2 successive generations affected, 3+ FH w lynch related cas (2 one must be a FDR or the other two)
