PathCrap Flashcards
When a RANZCR path question says “describe” they want?
When a RANZCR path question says “describe” they want
epi, macro, micro, bio beh.
Endometrial ca Type I (not molecular subtypes)
Histo and IHC
Precursors: Atypical endometriod hyperplasia, endometriod intraepithelial lesions.
Endometriod adenocarcinoma:
Invasive malignant glandular tissue w/non-squarmous solid component and desmoplastic response (increasing %solid increases FIGO grade I-III)
Severe nuclear atypia increase Grd by 1.
Differntiated from atypical hyperplasia by complex architecture: Cribiform, papillary, labrinthyine
IHC not necessary. ER/PR! (unlike type 2), PAX8, CK7, vimentin.
Mucinous carcinoma is rare and included in type 1.
WHO classification of endometrial Ca:
By tumour lineage:
Epithelial: precursor lesions (i.e. endometrial hyperplasia), endometroid adenocarcinoma, papillary serous, clear cell, mucinous, neuro-endocrine tumours
Mesenchymal: leiomyoma (fibroid), leiomyosarcoma, stromal sarcoma, rhabdomyosarcoma
Mixed epithelial/ mesenchymal: adenomyoma, atypical polypoid adenomyoma, adenofibroma,
adenosarcoma, carcinosarcoma
Other:
- Misc: adenomatoid tumours, neuro-ectodermal tumour, germ cell tumour
- Mets = breast, melanoma
Endometrial Ca Type 2:
10-20% of Cas: clear cell, papillary serous (10%).
Papillary: high grd anaplastic cells in complex papillary, glandular, or solid growth pattern (other features: necrosis, psammoma bodies, myometrium invasion, vascular invasion).
Bio beh: poor prog.
Correlates well with CA-125
p53+, p16+ (often strong and diffuse), AE1/AE3 and CK7+, PAX8+, MSH1/
MLH2/ MLH6/ PSM2 (can be loss in ~ 10% cases). CK20-, ER/PR-
Clear Cell (1-5%): papillary, tubule-cystic, or solid architecture with clear
cytoplasm (due to glycogen content) and ‘hob-nailing’
What are psammoma bodies?
Where do they occur?
Round microscopic calcifications forming concentric calcifications.
Brain:
- Prolactinoma
- Meningioma
- Melanocytic schwannoma
Thyroid:
- Papilliary Carcinoma!!!
Lung:
- mesothelioma
Endometrium:
- Papilliary serous carcinoma
Ovaries:
- both benign and malignant.
Approach to determining IDH status and additional tests that might trigger:
Upfront glioma IHC: IDH R132H, ATRXloss, p53
Step 1:
Immunohisto chemistry for most (>85%) common IDHmutant IDH1 R132H.
If present, then not GBM
If negative
Step 2:
Genotyping to detect Mutation
This step can be omitted if elderly (no absolute cut-off, but age>55 very low chance of mut if IHC-v
(also consider not testing if necrosis)
Endometrial Cancer molecular markers - prognostic and predictive value for each, how to they change staging?
POLEmut - Good prognosis - low risk spread.
P53abn - poor prognosis
MMRd=MSI - Intermediate prognosis, if coupled with POLEmut then over-rides p53. MMRd has predictive value - benefit from immune checkpoint inhibitor.
NSMP= No Specific Molecular Profile = Copy number low = default grouping where no POLE mut, TP53abn, or dMMR/MSI-H = intermediate prognosis.
Changes early stage:
POLEmut endometrial carcinoma, confined to the uterine corpus or with cervical extension, regardless of the degree of LVSI or histological type becomes stage “1AmPOLEmut” = 1A
p53abn - Upstages any stg II to stg IIC “IICp53abn”
What are the aggressive and non-aggressive subtypes of endometrial Ca?
Non-aggressive histological types are composed of low-grade (grade 1 and 2) EECs.
Aggressive histological types are composed of high-grade EECs (grade 3), serous, clear cell, undifferentiated, mixed, mesonephric-like, gastrointestinal mucinous type carcinomas, and carcinosarcomas.
Give the epidemiology of pit adenoma.
Basic Histo
How may staining be used to differentiate subtypes of pit adenoma?
Very common up to 17% at autopsy
M=F
70% of clinically detected disease is functional.
Genral histo: mono-morphic cells w/ salt-pepper chromatin.
The most common functional: Lactotroph (PRL) and somatotroph (GH) are Acidophilic/eosinophils.
The less common:
Basophilic (reddish blue/ purple) –
corticotroph (ACTH), gonadotroph (FSH/LH), thyrotroph (TSH)
Non-functioning - chromophobic!
Symptoms of a corticotrophic pit adenoma:
How would you investigate?
Cushing’s disease (as opposed to syndrome):
Central/ truncal obesity, plethoric moon face, buffalo hump, purple striae/ skin marks, acne, hirsutism, proximal muscle wasting.
Systemic: hypertension, glucose intolerance, osteoporosis, impotence, amenorrhea/ oligomenorrhea
Corticotroph
▪ Serum ACTH level
▪ 24-hour urine free cortisol
▪ Late night salivary cortisol level
▪ Dexamethasone suppression test: take 1mg dexamethasone 11pm, and blood test for
cortisol in morning (>10ng/mL = Cushing’s)
Lactotoph pit adenoma Sx:
How would you investigate?
How about for a somatotroph?
Women: galactorrhea, oligomenorrhea, infertility
Men: hypogonadism, erectile dysfunction, infertility, galactorrhea (rare)
Lactotroph: serum prolactin (>100ng/mL = macroadenoma; 30-100ng/mL = microadenoma)
Somatotroph: serum GH, IGF-1 (insulin-like growth factor)
▪ Glucose tolerance test (early morning fasting blood glucose; drink 75g glucose; then repeat blood glucose at 1 hour and 2 hour post)
Medical approach to lactotrophs:
How about the others?
Prolactinoma – initial treatment D2-agonist = cabergoline o May gradually withdrawn every 2-3 years to assess remission
o 90% response, 10% unresponsive/ intolerant
- GH-oma: somatostatin analogue (Octreotide) while waiting for surgery/ radiotherapy
- ACTH-oma (Corticotroph): ketoconazole
- TSH-oma: somatostatin analogue (Octreotide)
What immunohistochemical features allow you to distinguish between non small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and mesothelioma. (1 mark)
NSCLC:
Aden IHC= TTF-1, Ck7, Napsin-A.
SCC = CK5/6, p63+, TTF-1 -ve.
SCLC: synaptophysin and chromgranin+, CK7-ve and TTF-1-ve.
Mesothelioma: WT1+ve, ALSO CK5/6+, TTF1-ve, Ck7 negative.
Under the WHO classification of non-cranial germcell tumours, which NSGCTs are not derived from the typical origin?
WHO classifies into 1) Derived from in-situ disease (2) unrelated to in situ neoplasm (3) Sex cord stromal tumour.
Spermatocytic seminoma (derived from differentiated spermatogonia) and yolk sac tumour (pre pubertal) are not derived from in-situ germ cell neoplasm, just like teratomas.
Which tumours have Shiller-Duval bodies? What other features, what is the critical IHC?
Yolk sac AKA endodermal sinus tumour
* Most common paediatric GCT, 80% <2yo; may presents in mediastinum in adult, chemo- resistant
* Not associated cryptorchidism or GCNIS
!!!!!!!
* Serum marker:
elevated AFP (95-98% of cases),
~ 25% have elevated Beta-HCG
- Macro: soft solid tumour with mucinous/gelatinous appearance
- Micro: microcystic and reticular pattern, sieve-like/ lace-like appearance (due to intracytoplasmic vacuoles and merging of cells), Schiller-Duval bodies pathognomic (glomeruli-like endodermal sinuses).
The most aggressive Germ cell tumour?
BioBeh
Serum marker
Macro
Micro
Pure choriocarcinoma is rare, often seen as component of mixed NSGCT
* Haematogenous spread, may haemorrhage (present with haemoptysis with lung mets, haematemesis and melena with GI mets, anaemia, haemorrhagic brain mets)
* a/w gynaecomastia (10%), or hyperthyroidism
* Serum marker: very high Betea-HCG (in thousands; in all cases; level correlates w/ prog/tumour burden), AFP always normal!!!
* Macro: usually does not cause testicular enlargement, only small palpable testicular nodule; friable, haemorrhagic, necrotic
* Micro: 3 cell types:
o syncytiotrophoblastic (large, multinucleated cells with smudgy chromatin)
o cytotrophoblastic (round/ polygonal, sharp cell borders, clear
cytoplasm, single nucleus)
o intermediate trophoblastic (clear cytoplasm, large than cytotrophoblast with single nuclei)
IHC:
o B-HCG+ve (from syncytiotrophoblast), SALL4+, EMA+ve, cytokeratin +ve o OCT3/4- (+ in classic seminoma/ embryonal ca), CD117- (+ in classic seminoma), CD30- (+ in embryonal)
How do Mantle and Marginal Cells differ in the broad categories of lymphoma to which each belongs
Both NHL
Marginal = Low grade NHL. Pre germinal centre (inter folicullar area).
Mantle = intermediate grade NHL. Post germinal centre (perifollicular area).
Remember:
- Bone marrow (pre cursor B-cell Lymphoblastic leukaemia) ->
Lymphoid tissue:
-Pre = inter follicular space (mantle cells)
-Follicular = Germinal centre (centroblast->centrocyte) = Follicular, DLBCL, Burkitts or Hodgkins ->
- Post germ cell = perifollicular = Marginal, some DLBCL, plamacytoma.
Give examples of germinal and non-germinal centre lymphomas:
- Bone marrow (pre cursor B-cell Lymphoblastic leukaemia) ->
Lymphoid tissue:
-Pre = inter follicular space (mantle cells)
-Follicular = Germinal centre (centroblast->centrocyte) = Follicular, DLBCL, Burkitts or Hodgkins ->
- Post germ cell = perifollicular = Marginal, some DLBCL, plamacytoma.
Bad prognostic cytogenetics/gene fusions for sarcomas:
A general non-prognostic cytogenetic traint of liposarcomas:
- EWS-FL11 fusion transcript for Ewing sarcoma
- SS18-SSX fusion transcript for synovial sarcoma (=worse)
- FOXO1 translocation for alveolar rhabdomyosarcoma
Liposarcoma (e.g 40% of sarcomas are well diff liposarc)
MDM2 (12q15) is consistently amplified/ over-expressed
Lauren histological classification vs WHO (what are the categories?)
3 types of adenocarcinoma? Which is most aggressive?
Another way to subtype gastric cancer
Lauren: Intestinal vs diffues types
WHO:
AdenoCas: Tubular, papilliary, mucinous (>50% mucin producing)
Poorly cohesive carcinoma (with signet ring cell)
- Rare variants
o adeno-squamous
o choriocarcinoma
The Cancer Genome Atlas (TCGA) project recently uncovered four molecular subtypes of gastric cancer: Epstein-Barr virus (EBV), microsatellite instability (MSI), genomically stable (GS), and chromosomal instability (CIN).
The pathogenesis of bladder cancer points to 2 pathways after what event?
What are the tumours/histologies belonging to each cell type (mention recurrence rates):
Initial event = chromosome 9 deletion (both p and q)
80% Hyperplasia pathway (HRAS and EGFR mutations): Papilloma (largely benign 5%recurrence), Papillary urothelial neoplasm of low malignant potential (PUNLMP), and Non-invasive Papillary carcinoma = Ta High grade 70% recur!! - 15% Progress to Invasive HG (folowing p53 and Rb mutations).
20% Dysplasia pathway (Dysplasia->Cis->HG invasive)
1) Dysplasia, p53 and Rb (HPV-like) muts lead to:
2) 20% of dysplasia transform into CIS.
NB: CIS is flat!!!! and erythematous on Macro. Histo nucler pleo increased N:c and mitotic rate.
Invasive H-Grade - 50% metastasize.MOlecular events includer E and N cadherin loss, increased VGEF
What % of bladder cancers are invasive?
What are the subtypes how common is each?
For the most common type, grading is based on?
Give macro and micro and IHC:
25% of tumours
95% are invasive urothelial, 5% are SCC.
Macro: either flat, ulcerated, or papillary (sessile/ ulceration suggests HG)
Micro: atypical cells (spindle, pyramidal) invading basement membrane Grading: HG vs LG
based on: cytological atypia (polarity, nuclear size/ pleomorphism/ hyperchromatism), and
mitotic figure
IHC: CK7+, CK20+, HMWCK+ (marker of urothelial origin), GATA3+, p63
For invasive urothelial carcinoma, WHO say there are how many subtypes? One subtype is divided into multiple further subtypes, which is that?
Why is that relevant?
16.
Urothelial carcinoma with divergent differentiation
o Squamous differentiation
o Glandular differentiation
o Trophoblastic differentiation
o Müllerian differentiation
An SCC with any component of conventional urothelial carcinoma is not an SCC but a “Urothelial carcinoma with Squamous differentiation”
How can IHC differentiate:
Urothelial carcinoma from SCC and prostate adenoCa
UC: GATA 3+, HMWCK+, CK7
SCC: CK 5/6, p63+, GATA3-
PrCa: PSMA, PSA, AMARC, PROSTEIN. CK7 negative.
For bladder SCC:
Epidem
RFs
Macro
Histo
IHC
Epidem: Rare - <5% of primary bladder cancers.
RFs: Chronic irritation/inflammation (e.g. long term IDC, chronic UTIs, caculi, neurogenic bladder), smoking, schistosomias infection (in endemic areas), previous bladder SCC, radiation.
Macro (not asked): Appear white due to keratin, bulky, polypoid, necrotic.
Histo: Must not show component of conventional urothelial carcinoma (if present, tumour should be classified as urothelial carcinoma with squamous differentiation)!!! Keratin and intracellular bridging.
IHC: CK 5/6, p53, GATA and HMWCK -ve
Epi/Biobeh of ductal adenocarcinoma of the prostate and PSA
Histology:
3% of prostate cancer
Periuthral disease may cause haematuria.
More likely to have distant disease at Dx
Mets including to unusual sites (e.g. the dick).
Similar mortality rate to Gleason score 8 - 10
PSA can be highly variable, but on average lower than acinar.
More likely to have a PSA < 4.0 ng/mL;
Histo:
Frequently mixed with acinar adenocarcinoma
Tall columnar cells with pseudostratified nuclei.
Patterns include cribriform, papillary, solid and prostatic intraepithelial neoplasia-like pattern
c. Describe the WHO classification system for meningioma. (3.5)
Grade I to III. Is based on the presence or extent of Mitosis, Atypia, Invasion and Necrosis.
Grd I: (80% of mengiomas): NO Mitosis, no necrosis, No brain invasions. These are hypocellular. 13 Subtypes: Fibroblastic most common.
Grd II: (10%): Brain invasion OR frequent mitoses (>4/10xHPF) OR 3 or more atypical cellular features: Hyper-cellularity, high N:C ration, prominent nucleoli, pattern-less growth of focal necrosis.
There are 3 subtypes (ACC): Atypical (most common), Clear Cell, Chordoid
Grd III (<=5%): Very frequent mitosis (>20),OR melanoma, carcinoma, sarcoma features. Also 3 sub-types (RAP): Rhabdoid Anaplastic Papillary.
Molecular classification: TERT promotor mutation or CDKN2A/B may be grade III.
Meningioma
Macro
Micro
IHC
Well circumscribed, attached to dura, can be lobulated, separates easily from brain (separated by arachnoid plane)
Micro:
* Syncytial cells with indistinct cell membrane
* lobulated architecture (meningothelial whorls)
* may contain psammoma bodies
* May have morphology features of mitoses, atypia, brain invasion, necrosis (‘MAIN’)
IHC
* Vimentin + (strong) (expressed in mesencymal cells)
* EMA+ (may be weak/ focal, 70%) * S100+
* PR+ (70% of cases) – however, hormonally manipulation not proven to be effective)
SWOG S9005 (Ji 2015 JCO) – mifepristone (n=80) vs. placebo (n=84) in unresectable meningioma; no difference in PFS and OS between arm
Epi for meningioma
- 30% of primary intracranial neoplasm
- Most common benign intracranial tumour in adult
- F: M 2:1 for all meningioma; 1:1 for anaplastic meningioma
b. Describe the microscopic features of a Gleason Grade 3 prostate adenocarcinoma (2m)
c. List the immunohistochemical stains that may help differentiate between benign and malignant tissues in the prostate biopsy (1m)
Grade 3:
- Small glands, discrete/ separate (i.e. not fused), no cribriform glands, no comedonecrosis
IHC benign v.s Malig:
1) Malignant loose basal cells and become HMWCK -ve
2)p63 Expressed in basal cell nuclei
- malignant = loss of basal cell → p63 IHC negative
3) AMACR - +ve in prostate cancer. Expressed on Apical portion
Describe the Gleason Scoring system for prostate cancer. Include mention of any differences between
how the pathologists assigns the Gleason score on prostate biopsy specimens and a radical prostatectomy specimen (2m)
For both Bx and RRP specimens a primary (most prevalent) and secondary score (most aggressive or 2nd most common - see below) are reported. For RRP specimens a tertiary score is also reported - namely the 3rd most prevelent score. constituting <5% (if present).
Grading is based on the extent and quality of glandular fromation and the presence of necrosis as follows:
Gleason 1-2 - Non maligant glandular tissue
Gleason 3: Small glands, with no comedo necrosis or solid component.
4: Slit like glandular lumens, fused glands, cribiform architecture
5: Solid architecture, comedo necrosis
ISUP grades
- ISUP GG1 = Gleason 3+3
- ISUP GG2 = Gleason 3+4
- ISUP GG3 = Gleason 4+3
- ISUP GG4 = Gleason 8 (4+4, 3+5, 5+3) - anything that adds to 8
- ISUP GG5 = Gleason 9 (4+5/ 5+4/5+5) - anything>=9
Describe each of the skin SCC precursor lesions. The give macro and micro. Same for SCC
Actinic keratosis (solar keratosis)
o pre-malignant dysplastic lesion, a/w build-up of excess keratin o 1% progress to SCC, but 80% of SCC arise from them
o Macro: brown rough sand-paper from excess keratin, ‘cutaneous horn’
o Micro: cytologic atypia of basal cells with hyperplasia, intracellular bridges, thickened stratum corneum,
due to excess keratin production
Bowen’s disease (SCC in situ) o 3% progress to SCC
o Macro: sharply defined red macule/ papule/ plaque
o Micro: atypical cells in all layers of epidermis but does not invade basement membrane (cf: actinic
keratosis where dysplasia limited to basal layer of epidermis)
SCC
o Macro: nodular, ulcerative, varying amount of hyperkeratosis
o Micro: atypical cells (variable cellular differentiation, descriptors of anaplasia), intracellular bridges,
infiltrates dermis (WD – keratin pearls; PD – focal necrosis, no keratin)
IHC: CK5/6+ve, AE1/3+ve, p63+ve,
!!EMA +ve (cf: EMA -ve in BCC)
DDx Keratokanthoma.
For BCC:
Micro/macro IHC.
Differentiate from SCC
Micro:
Monotonous basoloid cells (large nuclei, scant cytoplasm), no intercellular bridge
Architecture = Palisading peripheral cells, peripheral clefting, fibroblastic stroma
IHC: BCL2+ve, p63+ve,
EMA-ve (cf EMA+ve in SCC), CK20-ve
Macro and Micro description of PTC (papillary thyroid cancer):
Solid, grey white tumour, firm, invasive with ill-defined margins (<10% surrounded by complete capsule).
Dx based heavily on distinct nuclear features:
▪ Changes in nuclear size and shape: large ovoid nuclei, nuclear elongation
▪ Irregularities of nuclear membranes: abundant
nuclear grooves (from infolding of nuclear membrane), highly irregular nuclear contour
▪ *Chromatin pattern: empty appearance of nucleoplasm, ground-glass nuclei (Orphan-Annie nuclei. i.e. empty looking)
o Papillary Architecture
o Presence of psammoma bodies (rounded, concentrically laminated calcification, from necrosis) in 50% of cases
Basic epidemiology and clinical presentation of follicular thyroid:
(15%) (arise from follicular cells)
Epi: 75% women, older age than PTC (peak 40-60y/o), rare in children
Clinical:
o Associated with iodine deficiency (response to RAI, except Hurtle cell variants)
o Usually solitary ‘cold’ nodule on radionuclide scan
Micro description of FTC (follicular thyroid cancer):
Dx is a bit of a contasting with PTC findings:
o Trabecular or solid pattern of follicles (small, normal, or large size)
o No nuclear features of PTC
o Capsular invasion: capsule is typically thickened and irregular, needs penetration through the capsule
(full thickness), may have reactive pseudo-capsule around invasion edge
o Vascular invasion: vessel within or beyond capsule, tumour covered with endothelium, attached to
wall/ with thrombus
o May have nuclear atypia, focal spindled area, low mitotic figures (<1 per 10HPF)
o No necrosis, usually no squamous metaplasia, no psammoma bodies, no/ rare lymphatic invasion
Essential features of Paget’s disease of breast:
Epi
Common presentation
What is it?
Molecular feature
Uncommon (1-4% of Breast cancers) clinical presentation of breast cancer
Most often presents as an eczematous / erythematous change of the nipple areolar skin
Cutaneous manifestation is due to tumor cells involving the epidermis and disrupting intercellular junctions
Underlying high grade ductal carcinoma in situ (DCIS) or invasive carcinoma is present in > 95% of patients
Majority of Paget cells and associated underlying carcinoma are HER2+
For gene expression profiling (3m)
i. Describe the 21-gene recurrence score (OncotypeDx), and the Amsterdam 70-gene profile (Mammaprint)
ii. Discuss the predictive importance of the above profiles
OncotypeDx
- Developed in the NSABP-B18 and B20 cohort
- Based on 21-gene DNA micro-array
- Used in women with ER+, N0 who have endocrine therapy
- Predict risk of distant metastases and benefits from adjuvant chemotherapy
- Stratified into 3 groups based on risk score – low (<18), intermediate (18-30), high (>30)
Mamma Print (Amsterdam-70) - RCT prognostic validation - despite clinical high risk, low genomic risk pts have 95% distant met free survival without chemo
PAM50
Describe the basal like subtype of breast cancer (2m)
When a RANZCR path question says “describe” they want epi, macro, micro, bio beh.
Epi
- 15-20% of breast cancer - Young patients,
- a/w BRCA1 mutation
Micro:
High proliferation rate
Usually grade 3, high mitotic indices, with necrosis, pushing borders, conspicuous LVI
Molecular/IHN
Tripple negative
p53 often mutated
HMWCK +
Biological behaviour
List the risk factors for triple negative breast cancer
- Younger patients
- p53 mutation
- BRCA mutation carriers
- Gynae: early menarche, early age at first pregnancy
- More commonly a/w pregnancy-related breast cancer, inflammatory breast cancer
Discuss breast cancer risk for:
Li-Fraumini
Lynch
Other cancers:
Fi-Frau -90% by age 60
Lynch - 5%, unless PMS2 - then 25%
Fi-frau:
- Sarcoma (soft tissue and bone)
- Brain cancer
- Leukaemia
- Adrenal cancer
Lynch:
- Colorectal cancer
- Endometrial cancer
- Ovarian cancer
- Gastric cancer
Key pathological features of Invasive lobular carcinoma:
Include key mutational risks
10 to 15% of cases overall, more common in women 45-55, estrogen exposure appears a greater risk factor (e.g. HRT),
CDH1 mutation increase risk of lobular but not ductal cas,
BRAC2 increases risk of both : rubbery texture, poorly visible on mammogram (better w/ MRI).
“Indian filing” histology,
Often bilateral/multicentric,
>80% ER+,
spreads to unusual locations such as meninges, serosal surfaces, BM, ovary, and RP - ?WHY????
Key pathological features of Invasive ductal carcinoma:
Incidence, imaging
Macro
Micro
IHC
Bio beh
80% cases. Often well seen on mammogram.
Macro:
Firm mass (cartilagenous feeling) irregular mass with desmoplastic reaction, advanced can show teathering to sking (dimpling of the skin surface).
Micro:
Invasive malignant epithelial cells with degree of tubule formation suggestive of grade (more = lower) along with nuclear pleomorphism and mitotic rate. Surrounded by desmoplastic stroma. Lack characteristic feature suggestive of special type.
IHC:
Ck7, E-cadherin +, 60% ER+, 60%PR+, 25%HER2
The driver mutations and their frequencies for NSCLC:
EGFR Exon 19, and 21 33% (Osimertinib, older getfitinib)
KRAS - 25% (not yet targeted)
Alk - 5% - Mutually exculsive w/EGFR (alectinib)
ROS-1 - 1% crixotinib
BRAF V600E 1%
What sarcoma is the most commonly induced radiation sarcoma? What is the second?
How are sarcomas graded?
RT induced sarcoma: osteosarcoma (21%), Undifferentiated pleomorphic sarcoma, (17%), angiosarcoma (15%)
GRADING (FNCLCC) – based on: Differentiation + mitotic count + necrosis
For sarcomas give the most common subtypes in:
1) Children and adolescents
2) Adults
Children and adolescents
rhabdomyosarcoma and synovial sarcoma;
Adults:
1) Undifferentiated pleomorphic sarcoma, 25%
2) liposarcoma, 15%
3) leiomyosarcoma,
~5% myxofibrosarcoma and synovial sarcoma
Key cytogenetics for:
Liposarcoma
Leiomyosarcoma
Synovial
Rhabdo
Fibrosarcoma
Lipo - MDM2 overexpressed especially in de-differentiated lipo
do (12q13) FISH test
Leio - Most common Li-Fraumini = TP53
Synovial t(X:18)(p11:q11) involving genes SS18, and either SSX1, SSX2:
o SS18-SSX1 inhibit Snail gene,
o SS18-SSX2 inhibit Slug gene
(X,18)
Rhabdo:
FOXO1 translocation for alveolar rhabdomyosarcoma
Fibrosarcoma = anueploidy.
Tumour prognostic factors for soft tissue sarcoma:
Location of tumour – retroperitoneal (compared to extremities) = poorer (often may not be completely resected)
- Grade (take into account differentiation, mitotic count, and tumour necrosis) – higher grade = worse
- Differentiation – differentiated (compared to well-differentiated) = more likely to have distant mets
- Myogenic differentiation = increased risk of distant mets
- Histological subtype – e.g. leiomyosarcoma = higher propensity for distant mets
-Cyto gentics: e.g SS18-SSX1/2
For each of the following subtypes of soft tissue sarcoma, write brief notes on the key histological features and any critical chromosomal abnormalities
i. Fibrosarcoma (1m)
ii. Well-differentiated liposarcoma (1m)
iii. Synovial sarcoma (1m)
iv. Leiomyosarcoma (1m)
Fibrosarcoma:
Highly cellular fibroblast proliferation in herringbone pattern,
cyto = anueploidy
WD Lipo:
Mature adipocytes with variable size - Bizarre and hyperchromatic stromal cells within fibrous stroma
Cyto= MDM2 amplification
Synovial:
2 subtypes: spindle cell only (monophasic) or biphasic, spindle-epithelial. Chromosomal translocation t(X:18)(p11:q11), involving SS18, and SSX1/ SSX2
Leimyosarcoma:
intersecting fascicles of spindle cells
- Elongated ‘cigar-shaped nuclei
- Necrosis common in large tumour
- Mitotically active
No key cytogentics, but most common Li-Fraumini (p53) associated.
ii. What are the risk factors and biological behaviour for Type 1 endometrial carcinoma? (3)
Type 1: Estrogen exposure: early menache, late menopause, null parity. Obsesity/low exercise, tamoxifen (2-3x risk). Poly cystic ovarian syndrome, estrogen producing tumours (e.g Ovarian granulosa)
Genetic: Lynch Syndrome (mutations in MMR genes: MSH1, MLH2, MLH6, PMS2, or EPCAM gene silencing), Cowdens syndrome (PTEN). Protective: OCP (>6months associated w/decreased risk), child birth, Smoking
Biobeh: Slower growing than type 2, 2/3 present early due to bleeding. Endometrial spread including to ovaries and cervix/vagina and myometrial invasion. Risk of nodal spread increases with degree of invasion (including LVI), early haematogenous spread rare. Distant met sites: Lung (most common), bone, liver, brain.
ii. What are the risk factors and biological behaviour for Type 2 endometrial carcinoma? (3)
Type 2: No clear risk factors. Age>70 most commonly occur in atrophy uterus. Less clear risk factors, modern research suggest estrogen exposure is also a risk.
BioBeh: Aggressive local growth (compared to Type 1), Early spread to nodes and peritoneum (requires Bx at surgery) and higher rate of systemic spread. Distant met sites: Lung, bone, liver, brain.
Mechanisms for path resistance to immunotherapies:
1) Receptor/target mutations decreasing or preventing monoantibody binding
2) Bypassing mutations - e.g. signal transduction pathway amplifications, receptor independent signalling.
Lynch syndrome most common cancers (in order)
Colorectal 50%
Endometrial 33%
10%Ovarian
5% Gastric.
5% Pancreas
Turcotts - CRC + GBM
Compare and contrast the features of Primary Mediastinal B Cell Non-Hodgkin’s Lymphoma (NHL) and Classical (Nodular Sclerosing) Hodgkin’s Lymphoma affecting the mediastinum: (3)
i. Clinical
ii. Histological; and
iii. Immunohistochemical
Clinical;
Mediastinal BNHL: Often presents late/bulky with symptoms of mass effect (e.g. cough, dyspnoea, SVC obstruction), can present B symptoms (fever, night sweats, wt loss). Tends to occur in adults mean age 35, F>M. Extra-mediastinal involvement uncommon at time of Dx.
Classic HL: Tends to occur in younger patients mean age 25. M=F. Mediastinum involvement common. As above may present with Sx of bulky disease/mass effect, B Sx - Also Pel-Ebstein fevers (alternating weeks of high-fever, and no fever).
Histological:
M.NHL: Intermediate size malignant B-cells, densely packed (more so than HL) and or clustered. Clear cell change (abundant cytoplasm), prominent scelerosis (may mimic HL).
Classic HL: Nodules within broad bands of sclerosing collagen along with eosinophils, plasma cells, atypical mononuclear cells and Reed-Sternberg cells.
IHC:
M.NHL: CD19, CD 20, PAX 8, BCL2, and BCL 6 may be present
C.HL: CD15, Cd30
For a suspected glioma, what are the upfront IHC tests?
Key molecular differences between astro and oligo. What feature may upgrade and astro to astro IV?
Upfront glioma IHC: IDH R132H, ATRXloss, p53
Astro: ATRXloss p53
Oligo: ATRX retained 1p19q codeleted
Astro grd III -> IV is CDK2NA/B, necrosis, or microvascular proliferation
Besides IDH status, what other features are needed to Dx GBM
What is normal role of MGMT?
IDH?
IDH + at least 1 of:
Endothelial proliferation
Necrosis
Microvascular profliferation
TERT mut
EGFR mut
MGMT - rescues cells from alkylating agent induced damaged (e.g. tamzolomide).
IDH: 2 roles - glucose metabolism, oxidative damage control.
List all the potential molecular features of a glioma, their significance (Dx, prog, pred)
IDH - obvious.
ATRX mut/retained - Differentiate astro from oligo. Not prognostic.
MGMT - predeictive and independently prognostic (unmethylated is poor)
H3K27M - associated with midline glioma and por prognosis (often unmethylated)
1p19q - oligodenroglioma if 1p19q + IDHmut. Codel is a good prognostic and predictive feature.
BRAF V600E - BRAF + histo consistent = pilocytic astro, Good prognostic and predictive (response to verafinib)
