Gynae Path 2 Flashcards
What’s the distinction between high and low grade gynae cancers?
Surgical operation may differ:
Omentectomy
Lymphadenectomy
Adjuvant therapy may differ
Prognosis:
Recurrence free survival
grade 1, 95%
grade 2, 82% grade 3, 68%
Overall survival
grade 1, 89%
grade 2, 84%
grade 3, 63%
What is a Stage I Tumour confined to the corpus uteri?
IA No or less than half myometrial invasion
IB Invasion equal to or more than half of the myometrium
What is a stage 2 tumour?
Stage II Tumour invades cervical stroma
What is a Stage III Local and/or regional spread of the tumour?
IIIA Tumour invades the serosa of the corpus uteri and/or adnexa
IIIB Vaginal and/or parametrial involvement
IIIC Metastases to pelvic and/or para-aortic lymph nodes
IIIC1 Positive pelvic nodes
IIIC2 Positive para-aortic lymph nodes with or without positive pelvic lymph nodes
What is a Stage IV Tumour invades bladder and/or bowel mucosa, and/or distant metastases?
IVA Tumour invasion of bladder and/or bowel mucosa
IVB Distant metastases, including intra-abdominal metastases and/or inguinal lymph nodes
What is the TCGA classification?
Group 1: EEC with mutations in POLE (Polymerase E- ultramutated)
Group 2: EEC with MSI (hypermutated)
Group 3: EEC with low copy number alterations
Group 4: (serous-like) tumours show TP53 mutations
What are POLE mutant tumours?
These tumours often appear to be high-grade.
In the absence of the knowledge of their POLE gene mutation status, they would be mistakenly included into a category of tumours with bad prognosis.
POLE gene mutation confers a quite better prognosis.
So, the identification of this mutated subgroup is essential for better personalised treatment and prognosis analysis.
A fundamental cellular mechanism for preventing DNA alteration that are created largely during DNA replication
A fundamental cellular mechanism for preventing DNA alteration that are created largely during DNA replication
What is the Mismatch repair system?
Mutations or silencing by hypermethylation of one of the DNA mismatch repair genes results in MSI
Microsatellite instability (MSI): Alterations in the length of short, repetitive DNA sequences called microsatellites.
This results in an increase of the rate of mutations contributing to tumorigenesis, again with a high mutation burden.
What shows strong nuclear expression in tumour cells of endometrioid carcinoma.?
HMLH1 (A), PMS2 (B), MSH2 (C) and MH6 (D) show strong nuclear expression in tumour cells of endometrioid carcinoma.
What are hypersensitive to the immune checkpoint inhibitor, anti-PD-1, monotherapy?
EECs exhibiting POLE mutations and MSI are hypersensitive to the immune checkpoint inhibitor, anti-PD-1, monotherapy because,
these tumours are characterised by a high mutation load which produces more neo-antigens.
they have a higher number of tumour infiltrating lymphocytes.
What are Gp 4 tumours?
Composed mostly of SCs, but also include some EEC; many grade 3 but also some grades 1 and 2
What are the 4 patterns of p53 staining?
There are 4 main patterns of p53 staining:
Normal/wild-type
Complete absence
Overexpression
Cytoplasmic
What are leiomyomas?
Smooth muscle tumour of myometrium
Commonest uterine tumour
20% of women >35yrs
Lay term is fibroid
Usually multiple
May be intramural, submucosal or
subserosal
What are leiosarcomas?
Malignant counterpart of leiomyoma - rare
Usually solitary
Usually postmenopausal
Local invasion and blood stream spread
5yr survival 20-30%
What are endometrial stromal sarcomas?
Low grade, high grade and other Tumour types
What is endometriosis?
Presence of endometrial glands and stroma outside the uterus
Common – 10% of premenopausal women
Origin:
Metaplasia of pelvic peritoneum
Implantation of endometrium, retrograde menstruation
Ectopic endometrial tissue is functional and bleeds at time of menstruation > pain, scarring and infertility
Can develop hyperplasia and malignancy
What are the types of ovarian cysts?
Non neoplastic cysts:
Follicular and luteal cysts
Polycystic ovarian disease:
3-6% of reproductive age women
patients have persistent anovulation
obesity and hirsutism / virilism
Endometrioitc cyst
What is the classification of ovarian tumours?
Primary tumours
Epithelial tumours
Sex cord-stromal tumours
Germ cell tumours
Miscellaneous tumours
Secondary tumours
What is the Incidence and age of onset of epithelial tumours?
make up 65% of all ovarian tumours & 95% of malignant ovarian tumours
50% found in 45-65 age group
What is the Incidence and age of onset of germ cell tumours?
have bimodal distribution; one peak 15-21 year olds and one peak at 65-69
What is the Incidence and age of onset of sex cord stromal tumours?
most commonly seen in post-menopausal women but some sub-types peak in 25-30 year age group
What is the WHO classification of serous, mucinous and endometroid tumours?
Serous tumours
Benign: cystadenoma and adenofibroma
Borderline
Malignant:
Low-grade serous carcinoma
High-grade serous carcinoma
Mucinous tumours
Benign: cystadenoma and adenofibroma
Borderline
Malignant
Mucinous carcinoma
Endometrioid tumours
Benign: Endometriotic cyst, cystadenoma and adenofibroma
Borderline
Malignant
Endometrioid carcinoma
What is the WHO classification of clear cell, Brenner and seromucinous tumours?
Clear cell tumours
Benign: cystadenoma and adenofibroma
Borderline
Malignant
Clear cell carcinoma
Brenner tumours
Benign
Borderline
Malignant
Malignant Brenner tumour
Seromucinous tumours
Benign: cystadenoma and adenofibroma
Borderline
Malignant
Seroumucinous carcinoma
What are the benign epithelial tumours?
Serous Cystadenomas
Cystadenofibromas
Mucinous cystadenomas
Brenner tumour
What are benign epithelial tumours?
Tumours whose biologic behaviour cannot be predicted on histologic grounds
Tumours that have very low but definite metastatic potential
Morphologically similar tumours may behave differently
To date, there are no reliable histological or molecular predictive markers for the behaviour of these tumours
What is the epidemiology of malignant epithelial tumours?
Worldwide is the 6th most common cancer in women
2nd commonest female cancer causing death in women
Difficult to diagnosis at an early stage
Develops resistance to therapeutic agents
What are the RFs of malignant epithelial tumours?
Nulliparity, infertility, early menarche, late menopause.
Genetic predisposition: Family history of ovarian and breast cancers
Describe hereditary ovarian cancer
Up to 10% of epithelial ovarian cancer cases are familial
3 familial syndromes: All are transmitted in an autosomal dominant fashion
familial breast-ovarian cancer syndrome
site-specific ovarian cancer
cancer family syndrome (Lynch type II)
Familial breast-ovarian cancer and site-specific ovarian cancer syndromes
Associated with mutations of the BRCA1 and BRCA2; account for 90% of familial ovarian cancers
Hereditary ovarian cancer occurs at a younger age than sporadic
Carriers have 15 fold increase risk of ovarian carcinoma to non-carriers
> 90% cancers are of serous: ovarian, peritoneal, fallopian tube.
What is Lynch syndrome?
HNPCC is responsible for 3% of ovarian carcinomas
Ovarian cancers associated are mainly of the endometrioid and clear cell types
What has Molecular analysis has shown?
Molecular analysis has shown that different patterns of genetic aberrations underlie the development of the different histologic subtypes.
PTEN beta catenin KRAS TP53/ Rb PIK3CA BRAF
Describe High Grade Serous Carcinoma
Most common type of malignant tumours (80%)
Aggressive
Alteration in P53, in virtually all
BRCA1 or BRCA2 abnormalities (germline and somatic mutations; BRCA1 promoter methylation)
These genes encode proteins that play important roles in DNA repair (homologous recombination).
What is the Significance of Homologous Recombination Deficiency Testing?
Identification of hereditary cases.
Current data suggests that BRCA2 mutations confer an overall survival advantage compared with either being BRCA-negative or having a BRCA1 mutation in high-grade serous ovarian cancer.
BRCA mutation status has a major influence on response to chemotherapy.
Patients can benefit from targeted therapy by PARP inhibitors.
What are low grade serous carcinomas?
Distinct pathogenesis from high grade serous carcinoma.
Low grade, relatively indolent, arise de novo or from borderline ovarian tumours.
Mutations in KRAS, BRAF.
No association with BRCA mutations.
What are mucinous tumours?
Morphological features similar to mucinous tumours of the gastrointestinal tract.
KRAS mutations.
What are secondary ovarian tumours?
Metastatic colorectal carcinoma:
Ovaries, an anatomic site prone to involvement by metastatic colorectal adenocarcinoma.
4-10% of CRC go to ovary.
Ovarian lesions are identified prior to the primary tumor in 14-32% of cases.
Krukenberg tumours:
Bilateral metastases composed of mucin producing signet ring cells.
Most often of gastric origin or breast.
What are endometrial carcinomas?
10-20% associated with endometriosis, but most others thought to be derived from surface epithelium
Co-existence with endometrioid carcinoma in uterus common
Which mutations are associated with endometrial carcinomas?
CTNNB1 (38%-50%)
PTEN (15-20%)
KRAS and BRAF (4%-36%)
MSI (8-38%)
PIK3Ca in (20%)
P53 >60% and usually in high Endometriosis is a precursor
What is associated with Clear cell carcinoma?
Strong association with endometriosis
Molecular changes:
MSI (6-21%)
PTEN (6%)
P53 (8.3%)
BRAF (6.3%)
PIK3Ca (20-25%)
B-catenin (3%)
What are the sex cord stromal tumours?
Pure stromal tumours:
e.g. Fibroma, Thecoma, microcystic stromal tumour
Pure sex cord cells:
e.g. Adult type and juvenile granulosa cell tumour
Mixed sex cord-stromal tumours:
e.g. Sertoli Leydig cell tumour
Fibroblasts: Fibromas: benign, no endocrine production
Granulosa cells: Granulosa cell tumor variable behaviour, may produce estrogen
Thecal cells: Thecoma: benign, may secrete oestrogen, or rarely androgens
Sertoli-Leydig cells: Sertoli-Leydig cell tumor variable behaviour, may be androgenic
What are the Molecular Changes in Sex Cord-Stromal Tumours?
Adult type granulosa cell tumour (GCT):
97% of adult GCT show somatic mutation of the Forkhead transcription factor FOXL2, is a master transcription factor that regulates cell proliferation and apoptosis.
Microcystic stromal tumour:
FOXL2 mutation can be done in AGCT to confirm the diagnosis in cases where the diagnosis is in question.
Mutation in CTNNB1
What is Peutz Jeghers syndrome?
Peutz Jeghers syndrome:
Germline mutations of STK11
Sex cord stromal tumour with annular tubules
Cases occurring in PJS usually show indolent behaviour.
What is DICER1 syndrome?
DICER1 Syndrome
Germline mutation in DICER1, a gene encoding an RNAse III endoribonuclease.
Familial multinodular goitre with sertoli / leydig cell tumour, and tumour susceptibility includes pleuropulonry blastoma in childhood.
Found in up to 60% of seroli-Leydig cell tumours.
What are germ cell tumours in?
20% of ovarian tumours
95% benign
predominantly occur in first or second decade
What are dermoid tumours?
Benign
Solid or cystic
May show many lines of differentiation but all mature adult type tissues
Teeth and hair very common
What are immature teratomas?
Indicates presence of embryonic elements
Neural tissue particularly conspicuous
A malignant neoplasm that grows rapidly, penetrates the capsule and forms adhesions to the surrounding structures
Spreads in the peritoneal cavity by implantation
Metastasis to lymph nodes, lung, liver and other organs
Three tier grading system according to amount of primitive elements
What are Mature cystic teratoma with malignant transformation?
Malignant transformation is rare occurring in 2% of cases, usually in post menopausal women
Most frequently squamous cell carcinoma
Also carcinoid, thyroid carcinoma, basal cell carcinoma, malignant melanoma, intestinal adenocarcinoma, leiomyosarcoma, chondrosarcoma and angiosarcoma
What are Prognostic Factors in ovarian malignancies?
Stage of Disease
Tumour type
Tumor grade
Size of residual disease
Tumor response to therapy
