Oncology: Hereditary Cancer Syndromes

General Syndromes

Syndromes

  • Li-Fraumeni Syndrome
  • PTEN Hamartoma Tumor Syndromes:
    • Cowden Syndrome
    • Bannayan-Riley-Ruvalcaba Syndrome
    • Cronkhite-Canada Syndrome
  • Peutz-Jeghers Syndrome
  • Ataxia-Telangiectasia
  • Von Hippel Lindau Syndrome
  • Muir-Torre Syndrome
  • Hereditary Diffuse Gastric Cancer
  • Neurofibromatosis Type 1
  • Neurofibromatosis Type 2
  • Tuberous Sclerosis
  • Colorectal Cancer & Polyposis Syndromes
    • Familial Adenomatous Polyposis (FAP)
    • Lynch Syndrome (Hereditary Nonpolyposis Colon Cancer/HNPCC)
    • Juvenile Polyposis Syndrome (JPS/Familial Juvenile Polyposis)
    • MUT Y Homolog (MUTYH)-Associated Polyposis (MAP)
    • Serrated Polyposis Syndrome (SPS)/Hyperplastic Polyposis Syndrome (HPS)

Li-Fraumeni Syndrome

  • Mutation: p53
    • CHEK2 Has Also Been Associated
  • Often See Multiple Childhood Tumors
  • Strongest Associations: Mn
    • Sarcomas (Osteosarcoma & Soft Tissue Sarcoma)
    • Breast Cancer
    • Brain Cancer
    • Leukemia
    • Adrenocortical Tumors
  • Other Increased Risks: Melanoma, Stomach, Colon, Pancreas, Esophagus, Lung, Gonadal Germ Cell & Wilms’ Tumor
  • Definition (Must Have All):
    • Proband Diagnosed with Sarcoma Before Age 45
    • First-Degree Relative Diagnosed with Any Cancer Before Age 45
    • Additional First- or Second-Degree Relative with Either a Sarcoma at Any Age or Any Cancer Before Age 45
  • Surveillance:
    • Breast MRI Every Year, Starting at Age 20
    • Brain MRI Every Year, Starting at Age 18 (From Birth if High-Risk p53 Variant)
    • Colonoscopy Every 2-5 Years, Starting at Age 18-25 (*Debated)

PTEN Hamartoma Tumor Syndromes

  • Mutation: PTEN Mn
  • Cowden Syndrome
    • Most Common PTEN Syndrome
    • Associations: Diffuse Hamartomas Throughout the GI Tract Mn
      • Breast
      • Endometrium
      • Kidney
      • Colorectal
      • Thyroid
    • Surveillance:
      • Physical Exam Every Year, Starting at Age 18
      • Thyroid US Every Year, Starting at Age 7
      • Colonoscopy Every 5 Years, Starting at Age 35
      • Renal US Every 1-2 Years, Starting at Age 40
      • Breast MRI or Mammogram Every Year, Starting at Age 30-35
      • Random Endometrial Bx Every 1-2 Years
  • Bannayan-Riley-Ruvalcaba Syndrome
    • Associations:
      • GI Polyposis (Hamartomas)
      • Hemangiomas
      • Pigmented Penile Macules
      • Macrocephaly
      • Mental Retardation
  • Cronkhite-Canada Syndrome
    • Associations:
      • GI Polyposis (Hamartomas)
      • Alopecia
      • Cutaneous Hyperpigmentation
      • Onychodystrophy (Dystrophic Nails)
Peutz-Jeghers Syndrome
  • Mutation: STK11 Mn
  • Associations:
    • GI Hamartomas
      • Small Bowel (60-90% Most Common) – Classically in the Jejunum
      • Stomach (15-30%)
      • Colon (50-64%)
    • Melanin Spots of Buccal Mucosa
    • Breast Cancer
    • Uterine/Cervical Cancer
    • Testicular Cancer
    • Pancreatic Cancer
  • Diagnosis: (≥ 2 Of):
    • ≥ 2 Peutz-Jeghers-Type Hamartomatous Polyps of the GI Tract
    • Mucocutaneous Hyperpigmentation
    • Family History of Peutz-Jeghers
  • Surveillance:
    • Baseline Triple-Endoscopy at Age 8 (Colonoscopy, EGD & Video Capsule)
      • If Polyps Founds: Repeat Every 2-3 Years
      • If Polyps Not Found: Repeat at Age 18 & Every 2-3 Years After
    • Breast MRI Every Year, Starting at Age 30
    • EUS or MRCP Every 1-2 Years, Starting at Age 30-35
    • Pelvic Exams:
      • Testicular Exam Every Year Starting at Age 10
      • Pelvic/Pap Smear Every Year Starting at Age 18-21
  • No Indication for Prophylactic Colectomy

Melanin Spots of Buccal Mucosa 1

Ataxia-Telangiectasia

  • Mutation: ATM
  • Associations:
    • Progressive Cerebellar Degeneration
    • Oculocutaneous Telangiectasia
    • Immunodeficiency
    • Neurologic Vasculo-Cutaneous Findings
    • Breast Cancer
    • Leukemia
  • Surveillance:
    • Breast MRI Every Year, Starting at Age 25

Von Hippel-Lindau Syndrome

  • Mutation: VHL Gene (Upregulation of VEGF)
  • Autosomal Dominant
  • Associations:
    • CNS Tumors (Cerebellar Hemangioblastomas)
    • Retinal Hemangioblastomas
    • Clear Cell RCC (Most Common Cause of Death)
    • Pheochromocytoma
  • Surveillance:
    • Physical Exam Every Year, Starting at Birth
    • Eye/Retinal Exam Every 6-12 Months, Starting at Birth
    • Plasma/Urinary Metanephrines Every Year, Starting at Age 5
    • MRI Brain & Spine Every 2 Years, Starting at Age 11
    • Audiology Assessment Every 2 Years, Starting at Age 11
    • US/MRI Abdomen Every 1-2 Years Starting at Age 15

Muir-Torre Syndrome

  • Mutation: MLH1, MSH2, MSH6 or PMS2
    • MUTYH Has Also Been Associated (Type 2)
  • Associations:
    • Sebaceous Skin Tumors
    • Visceral Cancers:
      • Colorectal Cancer – Most Common Visceral Tumor
      • Urogenital Tract
    • Breast Cancer
    • Pancreatic Cancer
    • Gastric Cancer
    • Lung Cancer

Hereditary Diffuse Gastric Cancer

  • Mutation: Cadherin 1 (CDH1)
    • CTNNA1 Less Commonly Associated
  • Associations:
    • Gastric CA
    • Breast CA
  • Prophylactic Surgery:
    • Recommended Prophylactic Total Gastrectomy Between Ages 18-40 Years
      • May Consider Earlier Surgery for Family History of Gastric Cancer Prior to Age 25
    • Consider Prophylactic Mastectomy
  • Surveillance:
    • Colonoscopy Every Year if Gastrectomy Refused/Deferred
    • Breast MRI Every Year, Starting at Age 30

Neurofibromatosis Type 1

  • Mutation: NF1
  • Associations:
    • Café au Lait Spots – Flat Hyperpigmented Macules
      • Appear in Childhood & Fade Later in Life
    • Neurofibromas & CNS Tumors
    • Iris Hamartomas (Lisch Nodules)

Neurofibromatosis Type 2

  • Mutation: NF2
  • Associations:
    • Bilateral Vestibular Schwannomas – Most Common
    • Intracranial Meningiomas
    • Spinal Tumors
    • Cataracts
    • Cutaneous Tumors & Plaques

Tuberous Sclerosis

  • Mutation: TSC1 or TSC2
  • Associations:
    • Ash Leaf Spots
    • Fascial Angiofibroma of the Malar Regions
    • CNS Hamartomas
    • Tuberous Sclerosis-Associated Neuropsychiatric Disorders (TAND):
      • Epilepsy
      • Cognitive Deficits
      • Autism
      • Behavioral Problems
    • Cardiac Rhabdomyoma
    • Kidney Tumors

Colorectal Cancer & Polyposis Syndromes

  • Other Syndromes:
    • Familial Adenomatous Polyposis (FAP)
    • Lynch Syndrome (Hereditary Nonpolyposis Colon Cancer/HNPCC)
    • Juvenile Polyposis Syndrome (JPS/Familial Juvenile Polyposis)
    • MUT Y Homolog (MUTYH)-Associated Polyposis (MAP)
    • Serrated Polyposis Syndrome (SPS)/Hyperplastic Polyposis Syndrome (HPS)
  • *See Oncology: Colorectal Cancer & Polyposis Syndromes

Cafe au Lait Spots 2

Ash Leaf Spots 3

Comparisons

Breast & Endometrial Cancer

Breast Endometrium Colorectal Other
Li-Fraumeni X CNS, Adrenal, Sarcoma, Leukemia & Many Others
ATM X Leukemia & Vaso-Cutaneous Findings
Hereditary Diffuse Gastric Cancer X Breast Cancer
Cowden X X X Thyroid & Kidney
Peutz-Jeghers X X X Melanin Spots, Pancreas & Testicle
Muir-Torre X X X Other Urogenital Tract & Sebaceous Skin Tumors
HNPCC X X
Other Considerations
  • VHL Has Neither Colorectal or Breast Cancer
  • Pancreatic Cancer Primarily in Peutz-Jeghers or Li-Fraumeni

Mnemonics

Li-Fraumeni Syndrome

  • Also Known as SBLA Syndrome
  • S – Sarcoma
  • B – Breast & Brain
  • L – Leukemia
  • A – Adrenocortical

PTEN Hamartoma Tumor Syndromes

  • “Brr!” (B.R.R.) Cold “Canada” “Cows” are Kept Out in Pens (PTEN)
  • Cowden Syndrome
  • Bannayan-Riley-Ruvalcaba Syndrome
  • Cronkhite-Canada Syndrome

Cowden Syndrome Associations 4

Peutz-Jeghers Syndrome

  • Mutation: STK11
  • Buccal Mucosa Spots Look Like a Mouth Filled with “Skittles” – STK11

References

  1. Sarhan A. Wikimedia Commons. (License: CC BY-SA-4.0)
  2. Rim JH, Chung HJ, Shin S, Park SJ, Choi JR. Isodicentric Chromosome 15 Syndrome in a Korean Patient With Café-au-lait Spots. Ann Lab Med. 2015 Jul;35(4):474-6. (License: CC BY-NC-3.0)
  3. van Geel N, Speeckaert M, Chevolet I, De Schepper S, Lapeere H, Boone B, Speeckaert R. Hypomelanoses in children. J Cutan Aesthet Surg. 2013 Apr;6(2):65-72. (License: CC BY-NC-SA-3.0)
  4. @RadOncMnemonics. Twitter.