Genetics + Chemo Flashcards
What is the Retinblastoma proteins
Tumour suppressor protein that is dysfunctional in several major cancers (Protein name abbreviated pRb; gene name RB or RB1).
Prevents excessive cell growth by inhibiting cell cycle progression.
If an oncogenic protein binds to and inhibits pRb
this can lead to cancer.
Protein is encoded by the RB1 gene on Chr 13. If both alleles are mutated early in life the protein is inactivated and results in the dev of retinoblastoma.
Astd with:
Retinoblastoma
Lung Ca
Bladder breast osteosarcoma and melanoma.
What is Pancytoketarin AE1 and AE3
Keratin cocktail that detects CK1 - 8, 10, 14 - 16 and 19, but does not detect CK17 or CK18
Confirm or rule out epithelial nature of tissue, tumors or components of tumors (example: breast ductal lavage foam cells are not epithelial, Diagn Cytopathol 2002;27:261)
Identify metastatic carcinoma in lymph nodes (Gynecol Oncol 2007;105:683, J Clin Pathol 2006;59:518), bone marrow (Int J Cancer 2007;120:1603) or at frozen section (Acta Histochem Cytochem 2011;44:133) by immunohistochemistry or (uncommonly) flow cytometry
What was the FIRES study and what were its pertinent findings
The FIRES study was a prospective study of 385. It aimed to identify the sensitivity and negative predictive value of sentinel lymph node biopsy in presumed early stage endometrial cancer. (Lancet Oncology Mar 2017).
Indocyanine green 1mL to lateral cervix. sentinal nodes identified and taken and then completion lymphadenctomy - pelvicin all and paraaortic in 74% (robotic OT)
Overall - sensitivity 97% of +ve nodes were identified by the sentinal nodes
negative predictive value 99.6% ( only one pt had +ve nodes with -ve sentinal nodes)
What proportion of Endometrial Cancer is attributable to Obesity and lack of physical activity
70% ( American Cancer Society 2018)
What is the SNL detection rate of Indocyanine green? How does that compare to Blue + Tc-99
detection rate of SLN biopsy was
97.3% (143/147) for women in the Tc99m + BD group and 96.9% (189/195) for women in the ICG group (p = 0.547).
bilateral mapping rate for ICG was
84.1%-significantly higher with respect to the
73.5% obtained with Tc99m + BD (p = 0.007).
NO DIFFERENCE in sensitivity and false -ve rate in women with LND and SNL Algorithm.
Overall same detection rate but higher bilateral rate in Indocyanine Green.
In Endometrial cancer. What % of women will have +ve Para-aortic nodes when the pelvic nodes are -ve
1.5%
Chiang 2011
OBJECTIVE:
To describe and review the incidence of para-aortic (PA) nodal metastasis in completely staged endometrial cancer patients who are negative for pelvic nodal metastasis.
METHODS:
Using an institutionally maintained database, we identified all patients with endometrial cancer from 2002 to 2006 who had both pelvic and aortic nodal dissections and determined the rate of isolated para-aortic nodal metastasis in non-malignant (i.e. negative) pelvic nodes.
RESULTS:
201 endometrial cancer patients were surgically treated at our institution from 2002 to 2006. 171 patients had both pelvic and PA nodes removed during surgery, and specimens examined by a pathologist. Only 2 (1.2%) had PA nodes that tested positive for malignance (i.e. positive PA nodes) with pelvic nodes that tested negative for malignancy (i.e. negative pelvic nodes). The final International Federation of Gynecology and Obstetrics (FIGO) grade for the endometrial tumor cells in the two patients was “G1” with endometrioid adenocarcinoma and “G3” with endometrioid adenocarcinoma and mucinous differentiation, respectively.
CONCLUSION:
Based on the very low incidence of patients inflicted with endometrial cancer that have positive para-aortic lymph nodes (PALNs) with negative pelvic nodes found both in our literature review (1.5%) and in our own study (1.2%), the addition of PA lymphadenectomy in all patients was found to have minimal diagnostic and therapeutic value. At the present, the role of complete PA lymphadenectomy in all patients with endometrial cancer should be re-examined. Individualized algorithms should be developed based on risk factors and status of pelvic nodes.
What is Cowden Syndrome
AKA Multiple Harmatoma syndrome is an Autosomal Dominant inherited condition characterised by:
- Benign overgrowth (harmatomas)
- increased risk of Br, Thyroid, Uterine cancer + others
Risk about 1: 200,000
Astd with mutations in PTEN on 10q23.3
What is the PTEN gene mutation
Phosphatase and Tensin Homolog is encoded by the PTEN gene.
PTEN acts as a TUMOUR SUPPRESSOR GENE - through the action of its phosphatase protein prude. This phosphatase involved in the regulation o the cell cycle, preventing cells from growing and dividing too rapidly.
Mutations lead to a reduction or loss of activity. This leads to increased cell proliferation and reduced cell death. These are common in prostate CA (~70% of cases) as well as glioblastoma, endometria Ca.
What % of +ve lymph nodes have palpable/macroscopically abnormal nodes at OT
Fewer than 10% of pts with lymph nodes metastases have grossly enlarged lymph nodes.
Creaseman WT et al., Surgical pathologic spread patterns of endometrial CA 1987
in GOG-33 What % of women with presumed stage I endometrial carcinoma had more advanced disease
9% of women had pelvic nodal disease, 6% had para-aortic nodal disease, 5% had disease that had spread to the adnexa and 6% had other extrauterine metastases at the time of OT.
GOG-33
The surgical pathologic features of 621 patients with Stage I carcinoma of the endometrium are
presented. All patients were treated with primary surgery consisting of total abdominal hysterectomy,
bilateral salpingo-oophorectomy, selective pelvic and paraaortic lymphadenectomy and peritoneal cytology. An appreciable number of patients (144-2296) with Stage I cancers have disease outside of the
uterus (lymph node metastasis, adenexal disease, intraperitoneal spread and/or malignant cells in
peritoneal washings). Multiple prognostic factors particularly grade and depth of invasion are related to
extrauterine disease. This study adds credence to the primary surgical approach with individualized
postoperative therapy as indicated.
Cancer 60:2035-2041. 1987.
What % of Tumour grade is upgraded after final histology for endometrial Ca after Pipelle and D&C
Pipelle - 26% upgraded
D&C 10%
Daniel AG. Accuracy of office and operating room curettage in the grading of endometrial Ca Obstet Gyn 1998
Larson et alk. Comparison of D&C and office endometrial biopsy in predicting final histopathologic grade in ENdomerial Ca Obstst Gynael 1995
What is a POLE mutation and how is it relevant
POLE - encodes a polymerase that plays a major role in DNA synthesis and nucleotide and base excision repair. ALtered in 6.4% of endometrial Cancers. Astd with very high mutation burden
How often is there a HER2/neu mutation in Uterine Serous Adenocarcinoma
~ 40%
How often are HGSC of the ovary MSI-H
~ 1.5 %
How often do Endometrial andenocarcinoma have POLE mutations
~ 5 % (6.4%)
What are the Amsterdam II criteria for Lynch Syndrome?
3 or more relatives with verified lynch syndrome associated cancers - CRC, Endometrial, TCC of the Ureter or renal pelvis, small bowel)
- 1 of whom is a 1st degree relative of the other 2 and in whom FAP has been exluded.
- 2 generations are involved
- 1 or more cancers were diagnosed < 50 yo.
“3-2-1 rule” (3 affected members, 2 generations, 1 under age 50)
The sensitivity and specificity of Amsterdam II criteria for a diagnosis of Lynch syndrome are 22 and 98 %, respectively.
What are the Bethesda criteria for testing of MSI in colorectal cancer attempting to identify Lynch syndrome.
Testing for MSI should be conducted if:
- CRC @ < 50 yo
- Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors, regardless of age.
- CRC with MSI-H like histo @ < 60 yo ( tumour infiltrating lymphocytes. Crohn’s-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern.)
- CRC in pt with >/= relative with a HNPCC related tumour, with one < 50 yo.
- CRC in pt with >/= 2 or more 1st or 2nd degree relatives with HNPCC related tumours regardless of age.
Sensitivity and specificity are 82 & 77% respectively.
FOXL2
Forkhead box2. PLays an important role in ovarian development and function and regulares granulosa cell differntiation.
Found in adult granulosa cell tumours - not in juvenile granulosa cell tumorus or other ovarian cancers. Astd with sex determination, eyebrow thicknes.s, Blepharophimosis-ptosis-epicanthus inversus syndrome
DICER1
Regulates gene expression and acts as a tumour suppressor. Autosomal dominant. increased risk of Sertoli-Leydig cell tumours - probably a majority of patients but not clear. all should be tested for. Also early childhood lung Ca.
BRIP1
BRCA Interacting Protein 1. Chr 17
~ 10 - 15 %
? increased lifetime risk for breast cancer, including triple-negative breast cancer.
PALB2
Partner And Localizer of BRCA2. Chr 16
PALB2 works together with BRCA2 to repair damaged DNA.
Ca Risk - by 80yrs
Br Female - 53%
Br male 1%
OVarian 5%
Pancreatic 2-3%
Consider RRSO after age 50 years unless there are early ovarian cancers in the family. The age of RRSO may be individualised based on family history
In the Kuchenbaecker study, the risk of Br Ca up to the age of 80 in women with BRCA 1 mutation?
72%
In the Kuchenbaecker study, the risk of Br Ca up to the age of 80 in women with BRCA 2 mutation?
69%
