1. Hereditary tumours to be aware of Gerd JACOMEN Dept. of Pathology

2. What is the link?  Malignant tumours are caused by genetic changes  Hereditary diseases are genetically transmitted  Familial clusters of malignancies

3. Sporadic/Familial genetic changes  Mutation can be sporadic in 1 somatic cell: epigenetic  Mutation can be present in a germ cell: Germline mutation All cells derived from that cell will harbour the mutation Can be inherited or new

4. Familial tumours of the uterine corpus 95% are sporadic 5% are familial Lynch syndrome Variant: Muir-Torre syndrome Cowden syndrome BRCA1

5. HNPCC  Hereditary nonpolyposis colorectal cancer syndrome  Lynch  Autosomal dominant  Germline mutations in mismatch repair genes Genes that are responsible for correcting errors (mismatches) during DNA replication

6. Caretaker genes  Normal function: helps genome to be stable during replication  DNA Mismatch repair genes  Microsatellites: repetitive DNA sequences  Prone to replication errors  Normally corrected by Mismatch repair system

7. Microsatellite instability  Whenever Mismatch repair genes do not function  Result: microsatellites are no longer “stable” during replication  Hence: Microsatellite Instable  MSS, MSI-Low, MSI-High

8. Involved genes  MLH1, MSH2, MSH6, PMS2

9. Are all MSI-High tumours Lynch?  20-25% of all endometrial Ca are MSI-H  75% are sporadic: epigenetic silencing of MLH1 (promotor methylation)  Remaining cases: mostly Lynch associated  Ca 2% of all endometrial cancers! Age dependent: 9% in younger patients

10. Recognising is important  Patient and family have increased risk for malignancies  Genetic counseling/testing  Gynecologic malignancy is sentinel cancer in 50%

11. Features that raise suspicion  Familial anamnesis  Clinical  Gross  Histology

12. Familial anamnesis  Not only gynecologic malignancies  Not only females  Take your time!

13. Malignancy in Lynch  Increased risk of multiple malignancies Colon Endometrium Ovary Stomach Urinary tract Hepatobiliary tract Small intestine Brain

14. Clinical  Other malignancies?  Age  BMI

15. How to diagnose Lynch?  Def: germline mutation in DNA mismatch repair genes  Mutation analysis is definitive test  Expensive and time consuming  Patient consent needed  Screening!

16. Simple screening: immunohistochemistry  Using Ab against MLH1, PMS2, MSH2, MSH6: detection of MSI-H tumours Sensitivity 91% Specificity 83%

17. IHC result  Expression can direct mutational analysis  + staining with all 4 Abs: no further testing (except if clinical suspicious)

18. Importance of IHC result  Loss of MSH2 and/or MSH6 is virtually diagnostic for Lynch!  Loss of MLH1 or PMS2 can still be epigenetic (= not because of germline mutation)

19. Advantage of IHC as screening  Simple  Inexpensive  Readily available  Can direct gene sequencing

20. Disadvantages of IHC  Interpretation can be problematic  10% of germline mutations remain undetected by IHC  Loss of expression can be epigenetic = not Lynch, but sporadic

21. Breast Cancer and Lynch  Breast Cancer Research 2012,14:R90  Breast Cancer Research 2012,14:110

22. MSI in breast Ca  0-3% in sporadic breast Ca  > 50% of breast Ca in Lynch syndrome mutation carriers

23. Features of Lynch associated breast Ca  Same age  Same type  Same grade  Same stage  Same receptor and HER2 status  Same chemotherapy?

24. Which endometrial Ca should be stained?  < 50 ys  Non-endometrioid Ca < 60 ys  Lower uterine segment  Multicentric or heterogeneity  Peritumoral lymphocytes  TIL > 42/10 HPF  “hard to type” Ca  Familial/personal history

25. Hereditary tumours of ovary and fallopian tube  10% of all ovarian Ca are associated with inherited germline mutations  BRCA1/2  Lynch

26. Lifetime risk for mutation carriers  BRCA1: 66%  BRCA2: 10-20%  MLH1/MSH2: 3-12%  Global Western population <2%

27. BRCA1/BRCA2  Inherited mutations in BRCA1 or BRCA2 genes  BRCA1/BRCA2 act as tumour suppressor genes  Autosomal dominant

28. Tumour suppressor genes  Normal function: gene encodes for protein involved in control of normal cell cycle  Of each gene are 2 copies in a cell: 2 mutations are needed before the protein will not be encoded properly

29. 2 mutations: 1 in each allele  First: makes cell “vulnerable”  Mutation on second allele: no longer synthesis of normal protein  No longer normal function

30. Frequency of BRCA-mutation  0.3% of women is carrier of the mutation  2% of Ashkenazi jews

31. Histology of BRCA associated ovarian Ca  Type: Serous  Grade: High  Stage: Advanced  BRCA1 = BRCA2

32. What is not associated with BRCA?  Mucinous Ca If high grade/high stage: think of metastasis first!  Low grade serous  Borderline serous

33. BRCA1/2 associated ovarian/tubal Ca  Since high risk of Ca if carrier: prophylactic BSO  At age 35 ys, or after child-bearing is completed

34. Prophylactic BSO  Occult cancers  Tubal intraepithelial Ca

35. Occult cancers = Ca in absence of preoperative evidence of malignancy 4-10% of prophylactic BSO Can measure up to 5 cm

36. Where?  Most are located at tubal fimbriae  Due to oxidative stress at ovulation

37. Prognosis  Even little tumours may metastasise  Complete staging necessary as for serous Ca ovary

38. Precursor lesions  Tubal Intraepithelial Carcinoma (TIC)  In 8% of prophyactic BSO  + for p53  High Ki67 (>50%)

39. Prognosis  Uncertain  Some cases may metastasise  Chemotherapy not considered necessary

40. Precursor lesions of TIC  SCOUT  p53 signature  Proliferative p53 signature  Importance in routine setting unknown

41. p53 signature p53Ki67

42. BRCA1/2 and breast cancer  Lifetime risk of breast Ca if carrier: BRCA1: 70% BRCA2: 45% Other risk factors remain important

43. Histopathologic features of BRCA associated breast Ca  Invasive Ca of no special type (BRCA1)  Grade 3  Triple negative  p53 positive  Basal CKs positive

44. Hereditary diffuse gastric cancer  Families with diffuse gastric cancer and lobular Ca breast  Germline mutations of CDH1 gene (E-cadherin)

45. Diagnostic criteria ≥ 2 cases of diffuse gastric cancer in 1st or 2nd degree relatives, at least 1 diagnosed < age 50 or ≥ 3 cases of diffuse gastric cancer in 1st or 2nd degree relatives, regardless of age at diagnosis

46. Breast cancer in HDGC  Females in HDGC families are at increased risk of breast Ca Lifetime cumulative risk of 60% by age 80  Most are lobular Ca

47. Gastric biopsy of patient with lobular Ca

48. Atypical cells and signet cells in stroma

49. Diagnosis?  Lobular Ca breast and gastric diffuse Ca are similar  Metastasis?  2 separate primaries?  Treatment is completely different!

50. ER

51. Take home messages  Familial tumours can be encountered every day  High level of suspicion  Detection is important for genetic counseling

52. Take home messages 2  Familial anamnesis  Not limited to the same cancer  Not limited to gyneco/breast  Not limited to female members