The Holy Organs Flashcards
Tumours Associated With Endometriosis
Polypoid endometriosis
Endometrioma
Seromucinous borderline tumour
Endometrioid carcinoma of ovary
Clear cell carcinoma
Rarely: mesonephric-like carcinoma, adenosarcoma, ESS, somatically derived YST.
NB:
Once seromucinous borderline tumour invades it is classed as an endometrioid carcinoma.
Need to do MMR on all endometrioid carcinomas, both ovary and endometrial.
Classification of Ovarian Tumours
Surface Epithelial:
Brenner, seromucinous borderline tumour / endometrioid, clear cell, SBT / LGSC, HGSC
Germ Cell:
Teratoma, yolk sac tumour, dysgerminoma, choriocaricinoma, embryonal carcinoma
Sex-Cord Stromal:
Fibroma, fibrothecoma, AGCT, JGCT, SCTAT, sclerosing stromal tumour, microcystic stromal tumour, signet ring stroma ltumour, Sertoli-Leydig cell tumours, steroid cell tumour
Metastases
Misc: Small cell carcinoma of hypercalcaemic type, FATWO, gonadoblastoma
Gynae Biomarkers
ER, PR, HER2
p53, p16
MMR proteins
Tumour Syndromes Associated with Gynae Neoplasms
Hereditary breast and ovarian cancer (BRCA1/BRCA2)
Lynch syndrome (endometrial & ovary)
PJS (SCTAT, HPV independent cervical adeno)
DICER1 (SCCOHT)
FIGO Staging Tube / Ovary / Peritoneum
Features to Include from Macro:
Intact / Ruptured (and timing of rupture)
Omental biopsy
Perintoneal washings
FIGO STAGING
I - Limited to one or both ovaries / fallopian tubes
- substaged based on surgical spill and positive washings
II - Extension / implants on uterus / pelvic tissues below brim
III - LN involvement / peritoneal disease outside pelvis
IV - Distant metastases incl: positive pleural cytology, extension to liver / spleen / intestine, extraabdominal organs
Molecular Classification of Endometrial Cancer
Based on TCGA data the PROMISE risk classifier divided endometrial carcinom into four molecular groups:
1. POLE mutated (ultramutated ) (PCR / NGS)
2. MMR deficient (hypermutated) (IPX)
3. p53 mutant (CN high / “serous like” (IPX)
4. p53 WT / CN low / NSMP
FIGO Staging Endometrial Carcinoma
I : Confined to uterine corpus
IA < 50% myometrial invasion
IB > 50% myometrial invasion
II : Invasion of cervical stroma
III: Local / Regional spread
IIIA uterine serosa and / or adnexal structures
IIIB: vaginal and / or parametrial involvement
IIIC: Pelvic and / or paraaortic nodes
IV: Invasion of bladder / bowel / distant metastases
FIGO Grading Endometrial Carcinoma
High grade by definition:
Serous
Clear cell
Carcinosarcoma
Dedifferentiated and undifferentiated carcinoma
Endometrioid carcinomas
Grade 1
< 5% solid, non glandular, non squamous growth
Grade 2
5 - 50% solid, non glandular, non squamous growth
Grade 3
> 50% solid, non glandular, non squamous growth
NB:
Can increase grade by one if there is significant cytologic atypia. Also, some authorities suggest using a binary grading system (low - grade 1 / 2 and high = grade 3).
Sentinel Lymph Nodes in Endometrial Carcinoma
(sn) prefix if sentinel node
(it) suffix if ITC’s only
(mi) suffix if micrometastasis
Size criteria same as breast i.e.
ITC’s = < 0.2mm or < 200 cells
Micrometastasis = 0.2 - 2mm
Macrometastasis = > 2mm
Nodal Staging: pTNM / AJCC
N1 = regional nodal micrometastasis
N2 = regional LN macrometastasis or paraaortic nodes
pM = metastases to inguinal lymph nodes
Syntopic Reporting Elements in Endometrial Cancer
Specimen type
Site and size of tumour
Histologic subtype
FIGO grade
FIGO staging - depth of myometrial invasion, involvement of cervical stroma, involvement of uterine serosa, adnexal structures, parametria and vagina
MELF pattern of invasion
LVI
Peritoneal washings
Omental biopsy
Immunomolecular classification and biomarkers:
MMR (+/- methylation profile) and p53
ER / PR
FIGO Staging Cervix
I - Strictly confined to cervix (extension to corpus allowed)
IA substage based on depth of stromal invasion (3, 5 mm)
IB substage based on greatest tumour size (2, 4 cm)
II: Into upper vagina or parametria
III: Into lower vagina, pelvic side wall, hydronephrosis, pelvic and paraaortic lymph nodes
IV: Beyond true pelvis, bladder or bowel mucosa, distant organs
Discordance Cervical Histology and Cytology?
Do levels and review cytology
Discuss at MDM
Consider lesion elsewhere in lower anogenital tract and need for re-examination or re-biopsy
All else fails need to consider and exclude a specimen mix up
Benign Mimics of HSIL on Cytology
Atrophy (basal / parabasal cells only)
High sampling (LUS post LLETZ)
Squamous metaplasia
Reactive atypia
Radiation atypia
Endometrial cells
Mimics of LSIL on Cytology
Reactive atypia (associated with infections e.g. Candida, BV, trichomonas)
HSV viral cytopathic effect
IUD cells - degenerative vacuolar changes
Tubal and tuboendometrioid metaplasia
Endometrial cells
Why is P16 positive in HSIL
HR HPV (subtypes 16 / 18) integrate into host genome
Production of viral oncoprotein E7 which binds to RB causing it to degrade
Without RB acting as a brake on the cell cycle, the CDKN2A gene can continue to produce p16 protein
When overexpressed p16 causes downstream effects on cellular proliferation and increased cell survival
NB: E6 viral oncoprotien binds to p53 with similar downstream effects
How does p57 help in the diagnosis of molar pregnancy?
Poor interobserver variability between CHM, PHM and hydropic abortus on histology alone. Can use p57 IPX and FISH to distinguish these.
Partial mole:
p57 positive (nuclear expression in at least 10% of villous stromal cells and cytotrophoblasts)
NB: p57 also positive in normal fetus / hydropic abortus
FISH shows triploidy in partial mole
Complete mole:
p57 negative
FISH shows diploidy (diandric)
P57 negative in CHM because p57 is a paternally imprinted, maternally expressed gene and complete moles are diandric (dispermy, empty ova)
What are the TORCH infections?
The acronym ‘TORCH’ has been used as a reminder of infections that cause congenital defects.
Toxoplasmosis
Others (syphilis, listeria, parvovirus B19, VZV, HIV)
Rubella
Cytomegalovirus (CMV)
Herpes (simplex) virus (HSV).
Features and Significance of CMV in Placenta
DNA virus that causes 10% of chronic villitis cases
Often no clinical symptoms.
Hearing and visual loss, neurologic deficit, IUGR
Macro:
Placenta may be large and edematous or small and fibrotic
Micro:
Lymphocytic or plasmacytic villitis with hyalinized villi
Hofbauer cell (fetal macrophage) hyperplasia
Rare intranuclear and cytoplasmic inclusions
Features and Significance of Listeria in Placenta
Gram positive bacteria strongly associated with stillbirth, premature delivery and sepsis
Macro: Small white nodules (microabcesses) scattered throughout parenchyma
Micro: Acute intervillositis with intervillous microabcesses; organisms identified with gram stain
Features and Significance of Syphilis in Placenta
Often associated with stillbirth or early neonatal death
Macro: Umbilical cord often normal but 36% have necrotizing funisitis; large oedematous disc
Micro: Immature, edematous villi with increased fetal erythroblasts, endarteritis and perivasculitis of stem vessels and lymphoplasmacytic villitis
Necrotizing funisitis or acute villitis have also been reported
Ancillary: Most cases with positive PCR have negative histology so do PCR of placental tissue if suspect syphilis
Positive stains: visualize spirochetes in cord using silver (Warthin-Starry) stain and / or Spirochete IPX
Synoptic Report for Vulval Cancer
Location & Laterality of Tumour
Uni / Multifocal
Macroscopic Size
Histologic Subtype of tumour: SCC-HPV associated, SCC HPV-independent, adenocarcinoma, carcinosarcoma, NEC, MINEN.
LVI / PNI
Neoadjuvant therapy
Additional findings: condyloma, VIN, dVIN, LSC
P16 immunohistochemistry
pTNM Staging (AJCC 8th):
pT1 Size of tumour (< / > 2cm) and depth of stromal invasion
pT2 Invasion into lower uretha / periurethal structures
pT3 Upper urethra / vagina / bladder / rectum
NB: no pT4
Sentinel Lymph Nodes in Breast
sn (ITC) = < 0.2mm or < 200 cells
sn (mi) > 0.2mm and < 2mm
macrometastasis >2mm
macro: size of largest deposit and ENE
Microinvasive Breast Carcinoma
Invasive carcinoma <1mm in size outside interlobar stroma
Usually arises in a field of DCIS
Can be single or multiple
Staged as pT1mi
Grading of Breast Cancer
Histologic grading is based on the Nottingham Score / Modified Bloom & Richardson Score
Tubule formation (1 - 3 points):
> 75% (1 point)
10 - 75% (2 points)
< 10% (3 points)
Nuclear pleomorphism (1 - 3 points):
Small, regular, uniform, similar to normal ductal epithelial cells, 2 - 3x RBC (1 point)
Moderate increase in size / variability (2 points)
Large nuclei, marked variation, often vesicular chromatin with prominent nucleoli (3 points)
Mitotic count (1 - 3 points)
Per 10 HPF, score dependent on microscopic field area
Total score
3 - 5 points: grade 1
6 - 7 points: grade 2
8 - 9 points: grade 3
Reporting Features for DCIS
Size of DCIS / In situ component
Nuclear grade
Architecture
Presence of necrosis (and calcifications)
Margins
Interpretation of HER2 IPX in Breast
+ Complete, strong membranous staining in >10%
Assessing invasive carcinoma cells
Number of cells staining, intensity of staining and whether or not it is complete membranous
Usually assessed on core biopsies (better fixation) but repeat if negative on resection specimen as can be heterogenous
0 = No staining or weak membranous staining in <10%
1+ = Faint / barely perceptible membranous staining in >10%
2+ = Weak to moderate complete membranous staining in >10%
Interpretation of HER2 ISH
Complicated - ideally use CISH or FISH dual fusion probe to compare ratio of number of HER2 gene loci to number of CEP17
(CEP17 = centromere chromosome 17, needed to quantify # of chromosomes present in each cell given aneuploidy is common)
Positive:
Single probe average HER2 copy number ≥ 6.0 signals/cell
Dual probe HER2/CEP17 ratio ≥ 2.0 with any average HER2 copy number or HER2/CEP17 < 2.0 with an average HER2 copy number ≥ 6.0 signals / cell
Reporting Elements in Invasive Breast Cancer
TUMOUR (pT)
Specimen type and laterality
Tumour focality
Tumour size (invasive and in situ)
(Size cutoffs 5, 10, 20 and 50mm)
Histologic Type
Histologic Grade (Nottingham score)
Involvement of skin (epidermis, dermis, dermal lymphovascular spaces)
Involvement of skeletal muscle
DCIS (size, grade, architecture, necrosis)
LVI and PNI
Post neoadjuvant treatment effect (tumour and lymph nodes)
Margins: invasive and in situ
Biomarkers: ER / PR / HER2
NODES (pN)
Sentinel versus non-sentinel
Sentinel nodes: Number involved, ITC, micro or macrometastases
Non sentinel: Number involved, size of largest deposit and ENE
METASTASES (pM)
Non regional lymph nodes, lung, liver, bone, brain
Treatment Response in Post NAT Breast
Loss of tumour may occur due to concentric shrinking of the tumour or as scattered loss / drop out of tumour cells
Tumour is replaced by loose fibrous tissue containing a variable infiltration of histiocytes, lymphocytes, giant cells, hemosiderin and vascular proliferation
Similar changes are seen in lymph nodes
Changes in normal breast tissue may include lobular atrophy, lobular cellular atypia and fibrous stromal involution
Classification Systems
Residual Cancer Burden (RCB 0 - IV)
- calculator on MD Anderson site
- submit entire maximum cross sectional area of tumour bed, and calculate % of tumour bed that contains residual cancer and % that is residual in situ.
- includes number of positive LN’s, size of largest deposit
Miller & Payne (1 - 5)
Myoepithelial Markers in Breast
p63 / p40
SMMHC
calponin / SMA
Tumour Syndromes Associated With Breast Cancer
BRCA1 / BRCA2
Cowden / PTEN Hamartoma Syndrome
Li-Fraumeni Syndrome
Peutz-Jegher Syndrome
Ataxia-Telangiectasia Syndrome
Hereditary diffuse gastric cancer syndrome (lobular)
Grading of Phyllodes Tumours
Criteria:
Stromal cellularity
Stromal overgrowth (> 4x field)
Stromal pleomorphism
Infiltrative border
Mitoses / 10 HPF
Presence of heterologous elements = malignant (except ALT)
Explain How You Would Cut Up this Specimen
- PPE, 3 points of ID, check MDM (imaging / biopsy results)
- Orient specimen, weigh and measure in 3D
- Ink ant / sup blue, ant / inf green and deep black
- Section from medial to lateral (removing HW in process), lay out slices, label and photograph
- Describe tumour, including size, circumscription, appearance of cut surface and measure to all margins.
- Block tumour: if DCIS (and small ish) all through otherwise Xray and block widely around biopsy clip / calcs. If invasive tumour usually 2 full faces of specimen and any other close margins (aiming 2 blocks / cm incl margins).
DDX Low Grade Spindle Cell Lesions in the Breast
Metaplastic Carcinoma: HMWCK / P63 / P40 positive
Stromal component of Phyllodes: CD34 +, usually ER positive
Fibromatosis: SMA positive, Nuclear beta catenin
Nodular Fasciitis: SMA positive, USP6 rearranged
Myofibroblastoma: SMA, Desmin, ER and CD34 positive
Type of VIN
HPV-Associated:
Younger women / immunocompromised, p16 block positive
Slower progression to SCC
Usually basaloid with peripheral palisading
HPV-Independent:
Older women, associated with LSC, p16 negative
Rapid progression to SCC
“dVIN” acanthosis, hyperparakeratosis, basal atypia with glassy pink cytoplasm. p53 parabasal, null, or cytoplasmic
When invasive -> Well differentiated, keratinising SCC
NAT Treatment Response in Ovarian Epithelial Tumours
CRS - chemotherapy response score
Assessed in omentum (and other sites) post NAT for HGSC
Score 1: No or minimal tumor response (mainly viable tumor with no or minimal regression-associated fibro-inflammatory changes, limited to a few foci);
Score 2: Partial tumor response (multifocal or diffuse regression associated fibro-inflammatory changes, with viable tumor ranging from diffuse sheets, streaks or nodules, to extensive regression with multifocal but easily identifiable residual tumor;
Score 3: Complete or near-complete response (mainly regression, with few irregularly scattered individual tumor cells or cell groups, all measuring <2 mm, or no residual tumor identified).
