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Other Hereditary Cancer Syndromes
Revised May 20, 2011
Content in this section includes:
- Background
- Features of the following hereditary cancer syndromes:
- Referral criteria for the above syndromes are described in the Referrals section of this site.
Background
- Family histories of cancer can be classified as:
- sporadic (70-75%), or
- multifactorial/familial (20-25%), or
- hereditary (5-10%)
- Some of the syndromes described in this section are associated with pre-malignant or non-malignant lesions, in addition to specific types of cancer.
- Only those individuals with personal or family history that suggests an inherited predisposition should be referred to the Hereditary Cancer Program. See Assessing Family History for examples.
- There are many rare hereditary cancer syndromes that are not described in this section. Referral to the Hereditary Cancer Program is indicated for any person from a family with a confirmed mutation in a gene associated with a specific hereditary cancer syndrome.
Familial Adenomatous Polyposis (FAP)
top Referral Criteria
- The most common hereditary polyposis syndrome, explains 1% of colorectal cancers
- Associated with mutations in the APC gene
- Inherited in an autosomal dominant manner (20-25% de novo)
- Characterized by > 100 adenomatous polyps in the colon, typically identified before age 40
- Progression to malignancy is inevitable without colectomy
- Additional features may include: gastric polyps, duodenal adenomatous polyps, osteomas, dental abnormalities (e.g. supernumerary teeth), CHRPE, soft tissue tumours (epidermoid cysts and fibromas), desmoid tumours, and other associated cancers
- An attenuated form of FAP exists (AFAP):
- 10-100 colorectal adenomas, with a tendency to rectal-sparing
- delay in onset of adenomatosis and bowel symptoms
- delay in onset of colorectal cancer and death
- lifetime penetrance of colorectal cancer appears to be high, however, cancer does not seem to develop in all affected patients
- more limited expression of the extracolonic FAP features
- gastric and duodenal adenomas frequently encountered
- Gardner syndrome: association of colonic adenomatous polyposis, osteomas, and soft tissue tumors (epidermoid cysts, fibromas, desmoid tumors)
- Turcot syndrome: association of colonic adenomatous polyposis and CNS tumors, usually medulloblastoma
Other polyposis: MYH-associated polyposis (MAP)
top Referral Criteria
- Associated with mutations in the MYH gene
- Inherited in an autosomal recessive manner
- Multiple (15-100) colonic adenomas, usually present later in life
- Challenging to distinguish from FAP/AFAP
- Increased risk for colon cancer, predominantly left-sided
- Polyps are predominantly small, mildly dysplastic, tubular or tubulovillous adenomas with few hyperplastic polyps
Juvenile Polyposis (JPS)
Juvenile polyps are hamartomas. The typical JPS polyp is unilobulated and pedunculated, spherical in shape with a smooth outer surface. Lacks a smooth muscle core and shows an internal dense inflammatory response. Dilated, mucus-filled cystic glands are seen in the lamina propria.
- Clinical diagnosis is made if any of the following is present:
- >5 juvenile colorectal polyps in one individual
- Multiple juvenile polyps of the upper and lower GI tract in one individual
- Any number of juvenile polyps and a family history of juvenile polyp
- Increased risk for colorectal cancer, with other malignancies reported (gastric, duodenal and pancreatic)
- Congenital anomalies have been reported in 11-20% of individuals with JPS
Peutz-Jegher (PJS)
top
Peutz-Jegher polyps are broad based, lobulated hamartomas. A central core of smooth muscle extends in a tree-like manner (“arborisation”) into the superficial epithelial layer. Epithelial misplacement can occur and appear as "pseudocarcinomatous" invasion.
- Associated with mutations in the STK11(LKB1) gene
- Characterized by:
- pigmented mucocutaneous macules (pathognomonic on lips, perioral region and buccal mucosa; may fade after age 25), and
- GI hamartomatous polyps (most often in small intestine; also in colon, stomach, rectum)
- Increased risk for carcinomas of the GI tract, breast and pancreas
- Non-malignant tumours include ovarian sex cord tumours and testicular tumours
Hereditary diffuse gastric cancer (HDGC)
top Referral Criteria
Diffuse gastric cancer is typically a poorly differentiated adenocarcinoma that infiltrates into the stomach wall causing thickening of the wall (linitis plastica) without forming a distinct mass. Also referred to as signet ring carcinoma or isolated cell type carcinoma.
- Autosomal dominant susceptibility to diffuse gastric cancer
- Associated with CDH1 gene mutations
- Estimated cumulative risk of gastric cancer by age 80 years is 67% for men and 83% for women (average age of onset is 38 years, with a range of 14-69 years)
- Women also have a 39% lifetime risk for lobular breast cancer
- Colorectal cancer may also be reported in some HDGC families
Hereditary paraganglioma (PGL)/pheochromocytoma (PCC) syndromes
top Referral Criteria
- PGL1 – associated with SDHD mutations
- Characterized by primarily head and neck PGLs, often multifocal, with fewer PCC and abdominal PGLs reported
- Sex-dependent disease transmission, penetrant only when inherited from father
- PGL3 – associated with SDHB mutations
- Characterized by primarily functional PGLs in the abdomen, pelvis and thorax (extra-adrenal), also PCCs, fewer head and neck PGLs
- Increased malignant po
- tential and possible increased risk for extra-paraganglial neoplasias
- PGL4 – associated with SDHC mutations
- Rare, appear to predispose primarily to head and neck PGLs
Multiple endocrine neoplasia Type 1 (MEN1, Wermer syndrome)
top Referral Criteria
- Autosomal dominant condition
- Associated with mutations in the MEN1 gene
- Class triad of pituitary tumours (2/3 microadenomas), parathyroid neoplasia and pancreatic endocrine neoplasia
- Primary hyperparathyroidism is the most common manifestation and usually the first sign
- Neuroendocrine carcinomas of the pancreas (islet cell tumours):
- gastrinomas, insulinomas
- less commonly VIPomas, glucagonomas, somatostatinomas
- Other associated findings may include: foregut carcinoids, skin tumours, adrenal cortical lesions, thyroid adenoma, pheochromocytomas, ependymomas and leiomyomas.
Multiple endocrine neoplasia Type 2 (MEN2A, MEN2B)
- Autosomal dominant condition
- Associated with mutations in the RET gene
- Most common clinical subtype is MEN2A:
- Medullary thyroid carcinoma (MTC), pheochromocytoma and hyperparathyroidism (HPT)
- Least common subtype is MEN2B:
- MTC, pheochromocytomas along with marfanoid habitus, ganglioneuromas of the mucosae and medullated corneal nerve fibres
- Tumour development is on average ten years earlier than MEN2A
von Hippel Lindau syndrome (VHL)
top Referral Criteria
- Autosomal dominant condition
- Associated with mutations in the VHL gene
- Most frequent manifestations include: hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pancreatic and epididymal cysts, pheochromocytoma
- Less frequent findings include: pancreatic tumours, broad ligament cystadenomas and endolymphatic sac tumors
Li-Fraumeni syndrome (LFS)
top Referral Criteria
- Rare condition
- Associated with mutations in the TP53 gene, inherited in autosomal dominant manner
- Predisposes to multiple primary cancers, ~20% of which occur before the age of 20 years
- Typical malignancies include:
- sarcomas (bone and soft tissue)
- female breast cancer
- brain tumours
- adrenocortical carcinomas
- leukemia
- Other cancers have also been reported (eg colorectal, melanoma, pancreatic, lung)
- Male cancer risk is 70-90% over a lifetime, with approx 45% chance by age 45
- Female cancer risk is nearly 100%, with approx 84% chance by age 45 (primarily breast cancer)
- Considerable variability with respect to age of cancer onset and tumour type has been reported
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