Hereditary tumours to be aware of

Gerd JACOMENDept. of Pathology

What is the link?

Malignant tumours are caused by genetic changes

Hereditary diseases are genetically transmitted

Familial clusters of malignancies

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

Familial tumours of the uterine corpus

95% are sporadic5% are familial

Lynch syndromeVariant: Muir-Torre syndrome

Cowden syndromeBRCA1

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

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

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

Involved genes

MLH1, MSH2, MSH6, PMS2

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

Recognising is important

Patient and family have increased risk for malignancies

Genetic counseling/testing

Gynecologic malignancy is sentinel cancer in 50%

Features that raise suspicion

Familial anamnesis Clinical Gross Histology

Familial anamnesis

Not only gynecologic malignancies

Not only females

Take your time!

Malignancy in Lynch

Increased risk of multiple malignanciesC

olon

Endometrium

Ovary

Stomach

Urinary tract

Hepatobiliary tract

Small intestine

Brain

Clinical

Other malignancies? Age BMI

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!

Simple screening: immunohistochemistry

Using Ab against MLH1, PMS2, MSH2, MSH6: detection of MSI-H tumours Sensitivity 91% Specificity 83%

IHC result

Expression can direct mutational analysis

+ staining with all 4 Abs: no further testing

(except if clinical suspicious)

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)

Advantage of IHC as screening

Simple Inexpensive Readily available Can direct gene sequencing

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

Breast Cancer and Lynch

Breast Cancer Research 2012,14:R90

Breast Cancer Research 2012,14:110

MSI in breast Ca

0-3% in sporadic breast Ca

> 50% of breast Ca in Lynch syndrome mutation carriers

Features of Lynch associated breast Ca

Same age Same type Same grade Same stage Same receptor and HER2 status Same chemotherapy?

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

Hereditary tumours of ovary and fallopian tube

10% of all ovarian Ca are associated with inherited germline mutations

BRCA1/2 Lynch

Lifetime risk for mutation carriers

BRCA1: 66% BRCA2: 10-20% MLH1/MSH2: 3-12%

Global Western population <2%

BRCA1/BRCA2

Inherited mutations in BRCA1 or BRCA2 genes

BRCA1/BRCA2 act as tumour suppressor genes

Autosomal dominant

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

2 mutations: 1 in each allele

First: makes cell “vulnerable”

Mutation on second allele: no longer synthesis of normal protein

No longer normal function

Frequency of BRCA-mutation

0.3% of women is carrier of the mutation

2% of Ashkenazi jews

Histology of BRCA associated ovarian Ca

Type: Serous Grade: High Stage: Advanced

BRCA1 = BRCA2

What is not associated with BRCA?

Mucinous Ca If high grade/high stage: think of

metastasis first! Low grade serous Borderline serous

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

Prophylactic BSO

Occult cancers Tubal intraepithelial Ca

Occult cancers

= Ca in absence of preoperative evidence of malignancy

4-10% of prophylactic BSO

Can measure up to 5 cm

Where?

Most are located at tubal fimbriae

Due to oxidative stress at ovulation

Prognosis

Even little tumours may metastasise

Complete staging necessary as for serous Ca ovary

Precursor lesions

Tubal Intraepithelial Carcinoma (TIC)

In 8% of prophyactic BSO

+ for p53 High Ki67 (>50%)

Prognosis

Uncertain

Some cases may metastasise

Chemotherapy not considered necessary

Precursor lesions of TIC

SCOUT p53 signature Proliferative p53 signature

Importance in routine setting unknown

p53 signature

p53 Ki67

BRCA1/2 and breast cancer

Lifetime risk of breast Ca if carrier: BRCA1: 70% BRCA2: 45%Other risk factors remain important

Histopathologic features of BRCA associated breast Ca

Invasive Ca of no special type (BRCA1)

Grade 3 Triple negative p53 positive Basal CKs positive

Hereditary diffuse gastric cancer

Families with diffuse gastric cancer and lobular Ca breast

Germline mutations of CDH1 gene (E-cadherin)

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

Breast cancer in HDGC

Females in HDGC families are at increased risk of breast CaLifetime cumulative risk of 60% by age

80

Most are lobular Ca

Gastric biopsy of patient with lobular Ca

Atypical cells and signet cells in stroma

Diagnosis?

Lobular Ca breast and gastric diffuse Ca are similar

Metastasis? 2 separate primaries?

Treatment is completely different!

ER

Take home messages

Familial tumours can be encountered every day

High level of suspicion Detection is important for genetic

counseling

Take home messages 2

Familial anamnesis Not limited to the same cancer Not limited to gyneco/breast Not limited to female members