Tumor Syndromes

Question 1

What is the gene and inheritance pattern of Basal cell nevus syndrome (Gorlin syndrome)

Answer 1

PTCH (patched tumor suppressor protein)

AD

Question 2

What is the underlying pathophysiology in basal cell nevus syndrome (Gorlin syndrome)?

Answer 2

Patched normally inhibits smoothened (when uninhibited signals intracellularly and activates GLI1/2 which is a transcription factor to promote transcription of genes involved in cellular growth) –> basal cell nevus syndrome results from a mutation in the Patched gene

Question 3

What are the major criteria of Basal cell nevus syndrome (Gorlin syndrome)?

Answer 3

Needs 2 for confirmation (or one major and 2 minor)

• >2 BCC or 1 before the age of 20
• Palmoplantar pits (>3)
• Odontogenic keratocyts of the jaw, histologically proven
• Calcification of the falx cerebri
• Medulloblastoma
• First degree relatives with Basal cell nevus syndrome (Gorlin syndrome)

Question 4

What are the minor criteria for Basal cell nevus syndrome (Gorlin syndrome)?

Answer 4

Rib anomalies (bifid most commonly, also fused, or markedly splayed)

• Cleft lip/palate
• Skeletal anomalies (pectus excavatum or pectus carinatum, polydactyly, syndactyly, kyphoscoliosis, Sprengel deformity, or other vertebral anomalies
• Macrocephaly
• Ovarian/cardiac fibroma
• Lyphomesenteric cysts
• Ocular abnormalities (strabismus, hypertelorism, congenital cataracts, glaucoma, and colobomas

Question 5

What are the clinical findings in Basal cell nevus syndrome (Gorlin syndrome)?

Answer 5

Multiple, early-onset (usually around puberty), BCC [*Note: these can look like nevi milia, SK). These also favor sun-exposed areas like the face, neck and upper torso, but can occur in non-sun-exposed skin too

• Medulloblastoma usually presents in the first 3 yrs of life
• The palmoplantar pits are present in childhood
• The odontogenic keratocyst of the jaw need to be histologically proven, usually asymptomatic and then present late in the first decade of life
• All abnormalities listed as minor criteria (they like to test on bifid ribs, frontal bossing, ovarian/cardiac fibroma) can occur
• Also, can see an increased risk of fibrosarcoma, rhabdomyosarcoma, cryptorchidism, gynecomastia, agenesis of corpus callosum, ovarian fibromas, and cardiac fibromas

Question 6

What is the treatment of Basal cell nevus syndrome (Gorlin syndrome)?

Answer 6

Standard BCC treatments plus you can use targeted therapy with vismodegib (acts as an artificial patched, inhibits smoothened

Question 7

What syndromes are associated with increased basal cells?

Answer 7

Gorlin, Bazex-Dupré-Christol, Rombo, Brooke-Spiegler, xeroderma pigmentosum, and Schöpf-Schulz-Passarge

Question 8

What is the gene and the mode of inheritance for Birt-Hogg-Dubé syndrome?

Answer 8

BHD gene (folliculin)

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Question 9

When do the manifestations of Birt-Hogg-Dubé begin?

Answer 9

Third decade or later

Question 10

What are the cutaneous findings of Birt-Hogg-Dubé?

Answer 10

Fibrofolliculomas, trichodiscomas, and acrochordons

• Clinically these looks like multiple tiny skin-colored to white papules on the face

Question 11

What is the histology of the fibrofolliculomas’s / trichodiscomas seen in Birt-Hogg-Dubé?

Answer 11

These have slender strands of basophilic cells radiating from a follicular unit, surrounded by a fibrous stroma, can have a “bat-wing” appearance

Question 12

What are the systemic findings in Brooke-Spiegler syndrome?

Answer 12

Salivary and parotid gland tumors

Question 13

What are the extracutaneous findings in Birt-Hogg-Dubé?

Answer 13

Renal cell carcinoma and spontaneous recurrent pneumothorax (w/ lung cysts and bullous emphysema)

Question 14

What is the gene and mode of inheritance for Brooke-Spiegler syndrome?

Answer 14

Gene: CYLD (tumor suppressor, is a deubiquitinating enzyme which interacts w/ NEMO to downregulate NFkappaB expression)

• AD

Question 15

What are the skin findings in Brooke-Spiegler syndrome?

Answer 15

Presents in adolescence/early adulthood

• Cylindromas (Papules/nodules on scalp)
• Trichoepitheliomas (skin-colored to white small facial papules)
• Spiradenomas (Painful nodules on head/neck and elsewehre)
• Multiple BCC
• Can also see malignant degeneration into cylindro- and spiradenocarcinoma

Question 16

What is the gene and mode of inheritance for multiple endocrine neoplasia (MEN) syndrome I (MEN1)?

Answer 16

MEN1 gene mutation (menin)

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Question 17

What are the tumors seen in multiple endocrine neoplasia (MEN) syndrome I (MEN1)?

Answer 17

3 p’s

Pituitary (prolactinoma most common)

• Parathyroid (can present w/ kidney stones from calcium/phosphate derangements as the tumor is hyperplasia/adenoma)
• Pancreas (Zollinger elison sometimes, stomach ulcers) [tumors are usually islet cell hyperplasia, adenomas, or carcinoma]

Question 18

Cutaneous findings in multiple endocrine neoplasia (MEN) syndrome I (MEN1)?

Answer 18

Can look like tuberous sclerosis: facial angiofibromas, gingival papules, hypopigmented macules and CALM

Question 19

What is the gene and mode of inheritance for MEN IIA?

Answer 19

RET proto-oncogene

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Question 20

What neoplasias are seen in MEN IIA?

Answer 20

Parathyroid hyperplasia (not in IIB)

• Medullary thyroid carcinoma (everyone)
• Pheochromocytoma

Question 21

What are the skin findings in MEN IIA?

Answer 21

Lichen amyloidosis and macular amyloidosis

This get’s asked a bit

Question 22

What is the gene and mode of inheritance for MEN IIB?

Answer 22

RET gene as well

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Question 23

Skin findings in MEN IIB?

Answer 23

Remember that this is also called multiple neuroma syndrome, so:

• Mucosal neuromas on tongue/lips
• thickened lips
• Marfanoid habitus

Question 24

What are the endocrine findings in MEN IIB?

Answer 24

Ganglioneuromatosis –> megacolon, diarrhea, and constipation

Question 25

What is the gene and mode of inheritance for Cowden syndrome (multiple hamartoma syndrome)?

Answer 25

PTEN - AD

Question 26

What is the pathophysiology of Cowden syndrome (multiple hamartoma syndrome)?

Answer 26

PTEN is a tumor suppressor gene, loss of it leads to a proliferation of cutaneous/GI/mucosal/thyroid/breast tissues

Question 27

What syndrome is PTEN also mutated in?

Answer 27

Bannayan-Riley-Ruvalcaba which is like Cowden syndrome + pigmented macules on the glans penis, lipomas, macrocephaly, and mental retardation. Some rarer forms of Proteus syndrome can also be PTEN but usually AKT1

Question 28

What are the cutaneous findings in Cowden syndrome (multiple hamartoma syndrome)?

Answer 28

**Sclerotic fibromas**, **facial tricholemmomas** (skin-colored to light brown small papules), **punctate palmoplantar keratoses, keratotic papules (acral keratoses)** [These acral keratoses occur on the **dorsal** hands/feet/forearms/legs], **lipomas**, skin tags, and inverted follicular keratoses

Question 29

What are the oral findings in Cowden syndrome (multiple hamartoma syndrome)?

Answer 29

Small skin-colored grouped papillomas leading to a "cobblestone" appearance on the lips and gingival/buccal/labial mucosa - These are effectively fibrofolliculomas of the mouth

Question 30

What are the thyroid findings in Cowden syndrome (multiple hamartoma syndrome)?

Answer 30

Goiter, adenomas, and carcinoma (f**ollicular carcinoma most commonly**)

Question 31

Breast findings in Cowden syndrome (multiple hamartoma syndrome)?

Answer 31

Fibrocystic disease, fibroadenomas, and adenocarcinoma (**most common malignancy in Cowden's overall,** up to 50% of female pts)

Question 32

What are the GI findings in Cowden syndrome (multiple hamartoma syndrome)?

Answer 32

Hamartomatous polyps along GI tract, low risk of malignancy

Question 33

In general what cancers are seen in Cowden syndrome (multiple hamartoma syndrome)?

Answer 33

**#1 Breast cancer (in women)** - Follicular thyroid cancer - Endometrial carcinoma (10% of female pts) - GU carcinomas/cysts

Question 34

What MSK abnormalities can be seen w/ Cowden syndrome (multiple hamartoma syndrome)?

Answer 34

Craniomegaly (80% of pts), adenoid facies, kyphoscoliosis, bone cysts, large hands/feet

Question 35

What is Lhermitte-Duclos disease?

Answer 35

Dysplastic gangliocytoma of the cerebellum Presents w/ overgrowth of cerebellar ganglion cells leading to ataxia, seizures and increased intracranial pressure ## Footnote *this is pathognomonic criterion for Cowden's*

Question 36

What is the gene involved and the method of inheritance for Gardner syndrome?

Answer 36

APC gene (adematous polyposis coli) AD

Question 37

Pathogenesis of Gardner syndrome?

Answer 37

APC is a tumor suppressor gene that regulates Beta-catenin

Question 38

What are the cutaneous manifestations of Gardner syndrome?

Answer 38

Epidermoid cysts (classically w/ pilomatricoma changes), fibromas (in the skin subcutaneous and mesentery/retroperitoneal areas), lipomas

Question 39

What are the GI manifestations of of Gardner syndrome?

Answer 39

Premalignant polyposis throughout the GI tract - Also see desmoid tumors, locally aggressive but don't metastasize female\>male can occur post-surgically after resection and these can lead to obstruction ## Footnote *Huge increase in the risk of adenocarcinoma, especially high in the colon/rectum where 100% of affected pts get it*

Question 40

What are the ocular manifestations of Gardner syndrome?

Answer 40

congenital hypertrophy of retinal pigment epithelium (CHRPE; 70%)

Question 41

What are the other tumors that can be seen in Gardner syndrome?

Answer 41

Osteomas (skull/mandible/maxilla; 80% of pts, painless), odontomas of teeth, supernumerary teeth, papillary thyroid carcinoma in women, hepatoblastoma, adrenal adenomas, sarcomas, pancreatic carcinomas, and brain tumors

Question 42

What is Turcot syndrome?

Answer 42

Gardners but w/ glioblastomas and medulloblastomas

Question 43

What is the treatment for Gardner syndrome?

Answer 43

Prophylactic colectomy when polyp formation is first evident, usually in the 2-3rd decade