breast and partial GYN CAP and Lester gross Flashcards
1
Q
Name 3 criteria distinguishing Well-Differentiated Endometrioid Endometrial Adenocarcinoma from EIN or Atypical Endometrial Hyperplasia
A
Irregular infiltration of myometrium associated with:
1) altered fibroblastic stroma (desmoplastic response)
2) loss of intervening stroma (confluent glandular, cribriform or labyrinthine pattern)
3) complex (villoglandular) or solid non-squamous epithelial growth
2
Q
What is the basis of the T stage for endometrial carcinoma?
A
- Myometrial invasion (< or >= 50% thickness)
- Other tissue invasion (cervical stromal tissue, serosal surface, adnexa, …)
T1 = confined to uterus, (a/b) depth of invasion 50%
T2 = involving cervix stromal connective tissue
T3 = Involving serosa, adnexa (a) or vagina, parametrium (b)
T4 = involving bladder/bowel
3
Q
What defines the 3 FIGO grading system used for endometrial carcinoma?
A
G1 = <=5% non-squamous solid growth pattern
G2 = 6 to < 50% non-squamous solid growth pattern
G3 = >50% non-squamous solid growth pattern
Severe cytologic atypia in the majority of cells (> 50%), which exceeds that which is routinely expected for the architectural grade, increases the tumor grade by 1.
4
Q
The FIGO (international federation of Gynecology and obstetrics) grading system for uterine corpus is designed specifically for which subtype of endometrial carcinoma?
A
Endometrioid Ca
Mucinous Ca
5
Q
Give 3 examples of endometrial carcinoma subtype which are NOT graded using the FIGO system.
A
All considered high-grade to start with:
- Serous Ca
- Clear cell Ca
- Transitional Ca
- Small cell neuroendocrine Ca
- Large cell neuroendocrine Ca
- Undifferentiated / dedifferentiated Ca
- Carcinosarcoma
- Mixed carcinoma (implies a serous or clear cell component)
- note that the squamous component of endometrioid carcinoma is not graded (parallels the glandular component)
6
Q
Compare to the general population, the prevalence of LUS endometrial carcinoma is significantly increase in which syndrome?
A
Lynch syndrome
7
Q
What are the 4 molecular subtype of endometrial carcinoma?
A
- POLE-ultramutated endometrioid carcinoma
- Mismatch repair–deficient endometrioid
carcinoma - p53-mutant endometrioid carcinoma
- no specific molecular profile (NSMP)
8
Q
Name 3 biomarkers which can be assessed in endometrial carcinoma
A
1) MMR proteins (universal, to be perform in all subtypes)
2) ER (in advance stage carcinoma, to predict response to endocrine therapy)
3) HER2 (for serous subtype)
9
Q
Which microscopic findings (pattern and IHC) do you expect for 1) endometrioid, 2) serous, 3) clear cell endometrial carcinoma
A
1) Endometrioid
- architecture: glandular, papillary, solid
- cell: differentiation is endometrioid, with some degree of squamous, mucinous or secretory
- loss ARID1A, PTEN, MMR
2) Serous
- architecture: glandular, complex papillae
- cell: high-grade feature
- abnormal p53, diffuse p16
3) Clear cell
- architecture: papillary, tubulocystic, solid
- cell: clear to eosinophilic cuboidal, polygonal, hobnail, or flat
- positive for HNF1beta, Napsin A, AMACR (P504S)
10
Q
In high-grade endometrial tumors, squamous differentiation strongly favors which histological subtype over the other?
A
Endometrioid Ca
11
Q
What IHC profile supports the diagnosis of undifferentiated endometrial carcinoma
A
Focal Pax8
Focal EMA
Focal Keratin
< 10% reactivity for neuroendocrine markers
vimentin +
ER, PR, ECAD -
May show MMR and/or BRG1 loss
12
Q
Name 3 prognostic factors deemed important for endometrial carcinoma and which you should report.
A
- histological subtype
- tumor grade
- LVI (for regional & distant recurrence, and survival)
- Lymph node status
- depth of myometrial invasion
- invasion of other tissues (stromal connective tissue of cervix, uterine serosal surface, adnexa, bladder, bowel)
- stage
13
Q
What is the minimal size recommended for a diagnosis of EIN?
A
1mm
14
Q
Which % of endometrial carcinoma are attributed to Lynch syndrome
A
3-5%
15
Q
According to NCCN guidelines, how does the grade of an endometrial carcinoma affects the accuracy of intraoperative evaluation of myometrial invasion (ie, assessment by gross examination of fresh tissue)?
A
As the grade of the tumor increases, the accuracy of intraoperative evaluation of myometrial invasion decreases (accuracy of 87% for G1, 65% for G2 and 30% for G3)
16
Q
When should you report on margins in hysterectomy for endometrial carcinoma?
A
Only when the cervix and/or paracervical-parametrial tissue is involved by carcinoma
17
Q
What are the only true margins (2) in total hysterectomy specimens?
A
Parametrial/paracervical soft tissue
Vaginal cuff
18
Q
Does peritoneal washing influence the FIGO stage (endometrial carcinoma)?
A
No (not considered as an independent risk factor; should still be reported)
19
Q
According to NCCN guidelines, what is the false-negative rate associated with endometrial biopsy?
A
10%
(thus, a negative result in a symptomatic individual should be followed by D&C)
20
Q
Name 2 mimics of lymphovascular space invasion (LVSI) in endometrial carcinoma evaluation
A
1) retraction
2) MELF (microcystic, elongated and fragmented) pattern of invasion
3) artifactual displacement of tumor cells
21
Q
Extent of LVSI is semi-quantitative in endometrial carcinoma. How is it quantified?
A
1) Low LVSI is < 3 vessel involvement
2) Extensive LVSI is >= 3 vessel involvement
22
Q
Loss of immunoreactivity for which immunostains (name 3) may be a helpful diagnostic tool when considering the diagnosis of EIN?
A
PAX2
PTEN
mismatch repair proteins
23
Q
Regarding gynecologic markers (ER, PR, etc), how do we report the results ?
A
1) intensity of immunoreactivity (weak, moderate, strong)
2) proportion of positive cells (%)
24
Q
Regarding breast/gynecologic ER receptor testing, list 5 causes of false-negative IHC.
A
- Exposure of tumor cells to heat (cautery during surgery)
- Prolonged cold ischemic time (antigenic degradation, should be 1 hour or less)
- Under or overfixation (at least 6 hours)
- Type of fixative (neutral-buffered formalin recommended, ER is degraded in acidic fixatives such as Bouin’s and B-5)
- Decalcification
- Nonoptimized antigen retrieval (or use of (weeks) old tissue sections
- Type of antibody
- Dark hematoxylin counterstain obscuring faintly positive diaminobenzidine (DAB) staining
- Artefact (crush or edge artefacts)
25
The breast carcinoma is triple negative. What can you rely on to ensure the result is a true negative? Name 3 parameters/factors.
1) Internal control (normal epithelial cells) should be positive
2) External control should be positive
3) Results should be concordant with those expected based on histological type and grade of the carcinoma
4) Tumoral cells are present on the stained section
5) Specimen handling was adequate (cold ischemic time, fixation time, etc.)
26
Regarding breast/gynecologic ER receptor testing, list 2 causes of false-positive IHC.
1) use of an impure antibody that cross-reacts with another antigen
2) misinterpretation of entrapped normal cells or an in situ component as invasive
3) image analysis devices that mistakenly count overstained nuclei
27
In breast/gynecologic ER receptor testing, what is the cutoff value (%) of positive cells that should be classified as receptor positive?
>= 1%
28
What type of biomarker is HER2 in breast?
Both prognostic (bad, marker of aggressivity) and predictive (to herceptin/transtuzumab therapy)
29
1) On which chromosome if HER2 located, 2) what is its general function, and 3) against which gene is it tested in FISH to assess for its amplification?
1) Chromosome 17
2) Tyrosine kinase receptor from the EGFR family (key role in signaling pathway regulating cell division, proliferation, differentiation, apoptosis)
3) CEP17 (HER2/CEP17 ratio > 2.0 usually)
30
1) On which chromosome is p53 located, 2) what is its general function, 3) what type of biomarker is it for the gynecologic tract, and 4) which endometrial carcinoma show abnormal p53 pattern?
1) Chromosome 17
2) Tumor suppressor protein that induces expression of p21, a cyclin-dependent kinase inhibitor that
is involved in the arrest of cellular proliferation at the G1 phase (key role for regulating cell proliferation, DNA repair, apoptosis and genetic stability)
3) diagnostic (for serous carcinoma), predictive (for targeted chemotherapy), prognostic (poorer outcomes)
4) Serous carcinoma (90%) and endometrioid carcinoma (10-40%)
31
What are the possible pattern of p53 IHC?
A) Wild type (nuclear expressed in a patchy fashion)
B) Abnormal-overexpressed (nuclear)
C) Abnormal-null
D) Abnormal-cytoplasmic (in addition to the nuclear staining)
32
Which 2 factors significantly affects p53 expression by IHC?
1) non-optimized antigen retrieval
2) use of archival (weeks old) tissue sections
33
Contrast Lynch syndrome, mismatch repair protein (MMR) and microsatellite instability (MSI)
Lynch syndrome is caused by germline mutations in MMR genes. Defects in MMR also cause MSI. MSI is an hallmark of Lynch, but is not specific to this syndrome.
To screen for Lynch, one may perform:
1) IHC, assessing MMR protein expression
2) DNA short tandem repeats analysis, assessing MSI*
3) Germline mutation analysis
Methods 1 and 2 are surrogate markers of Lynch. Option 3 should be performed by the genetic team.
* MSS / MSI-low / MSI-high can be viewed respectively as negative / equivocal / positive result indicating high-probability of Lynch syndrome. CAP recommends that if only MSI was performed, IHC should be done to identify the most likely gene to have a germline mutation.
34
1) Which MMR anomaly by IHC is most often due to a sporadic event, and 2) which additional test can you perform to distinguish sporadic vs germline event?
1) MLH1 loss, which is often due to hypermethylation of its promotor, an epigenetic sporadic event NOT indicative of Lynch
2) Methylation-specific real-time PCR can determine the presence of methylation; alternatively, the presence of BRAF V600E mutation would suggest a sporadic event (this mutation is NOT seen in Lynch)
35
What type of biomarker is ER/PR in breast?
Weak prognostic factor (negative prognosis if negative) and good predictive factor (to hormone therapy; ex.tamoxifen)
36
In breast, false-positive IHC results for HER2 may be due to... name 2 factors
1) Edge artefact
2) Overstaining (strong membrane staining of normal cells, may be due to improper antibody titration)
3) Cytoplasmic positivity (obscure membrane staining)
4) Misinterpretation of DCIS as invasive component (DCIS usually positive)
37
In breast, false-negative IHC results for HER2 may be due to... name 2 factors.
1) prolonged cold ischemic time
2) tumor heterogeneity
3) improper antibody titration
38
Name the possible scores and explain the criteria for the reported results of HER2 testing by IHC in **BREAST**.
39
Name the possible scores and explain the criteria for the reported results of HER2 testing by IHC in **GYNECOLOGIC**.
40
Name the possible scores and explain the criteria for the reported results of HER2 testing by IHC in **GASTRIC/GEJ**.
41
Name 2 reasons why the ISH of HER2 may fail
* Prolonged fixation in formalin (>1 week)
* Fixation in non-formalin fixatives
* Procedures or fixation involving acid (decalcification) may degrade DNA
* Insufficient protease treatment of tissue
42
Name 3 roles attributed to fixation (Lester).
- Harden tissue
- Inactive infectious agent (except Creutzfeldt-Jacob)
- Preserve tissue
- Stabilize tissue components
- Enhance avidity for dyes
43
Name 2 disadvantages associated with fixation (Lester).
- Alteration of protein structure
- Solubility of tissue components (lipids and carbohydrate are often lost)
- Shrinkage of tissue
- DNA and RNA degradation (especially those containing picric acid)
44
1) What amount of fixative is considered adequate for a given tissue; 2) what is the speed at which fixative penetrates the tissue; 3) what amount of time is usually required for adequate fixation in formalin; 4) at which temperature is formalin fixation usually performed? (Lester)
1) 15 to 20 times the volume of the tissue
2) 0.1cm per hour (but written 0.4 cm/24h elsewhere)
3) 6-8 hours
4) Room temperature (Note that temperature increases the rate of fixation and rate of autolysis; it must be monitored carefully)
45
Name 6 factors affecting the preservation of a biomolecule (DNA, RNA, protein, etc.). (Lester)
1) Patient factors: disease state, drug, other treatment (radiation)
2) Surgical factors: time at which tissue is removed from blood flow, time the specimen is removed from patient, exposure to surgical instrument (cutting, cauterizing), length of time of surgery, time under anesthesia
3) Transport factors: length of time of transport to path department, condition during transport (fresh or fixed)
4) Pathology factors: length of time to fixation, thickness of sections & adequacy of fixation, type of fixative, length of time in fixation prior to processing of paraffin blocks,
processing protocols (dehydration, clearing, impregnation), type of paraffin, length of time in paraffin, conditions of block storage, time since slides were cut.
46
Name 4 types of fixative and for each, list color, one advantage and one disadvantage (Lester).
1) Formalin: clear; A = cheap, fixes most tissue well, compatible with most histologic stains, preserves tissue for months, required for visualization of lacunar cells of CHL; D = slow penetration rate (0.4 cm/24h), overfixation can diminish immunoreactivity, dissolve uric acid crystals and calcium phosphate in breast.
2) Bouin's solution: yellow; A = sharp H&E staining, facilitate finding of LN (white on yellow background), prolonged fixation decalcify tissue; D= tissue brittle if fixed > 18h, colors specimen yellow, lyses RBC, dissolve iron and calcium deposits, contains PICRIC ACID which is EXPLOSIVE if dry and degrade DNA and RNA.
3) B-Plus: clear/blue; A = rapid fixation with excellent cytologic details, antigen preservation; D = same as formalin, contains ZINC which interferes with PCR.
4) Zenker's acetic fixative: orange; A = rapid fixation with excellent cytologic details, slowly decalcify tissue, lyses RBC, useful to demonstrate chromaffin reaction in pheochromocytoma; D = poor penetration, tissue brittle if fixed > 24h, dissolve iron, contains MERCURY which interferes with PCR, requires washing tissue before processing, and is TOXIC.
5) Glutaraldehyde: clear; A = excellent preservation of ultrastructure cellular details; D = penetrate slowly and poorly, refrigeration required for storage, false-positive PAS stains.
6) Alcohol: clear; A = many antigen well preserved, no special disposal method required; D = dissolve lipids and penetrates poorly.
47
Which fixative should you use for the following specimens (Lester):
1) Bone marrow biopsy
2) Gout specimen
3) Muscle biopsy
1) Bouin or Zenker fixative
2) Ethanol
3) Snap frozen and placed into glutaraldehyde
48
According to CLIA, what is the recommended retention times for (Lester):
1) Gross specimen (wet tissue)
2) Paraffin blocks
3) Glass slides of tissue sections
4) FNA slides
5) Surgical pathology report
1) until diagnosis issued
2) 2 years
3) 10 years
4) 5 years
5) 10 years
49
List 2 instances where the clinician should be contacted before rejecting specimen (Lester)?
1) Unlabeled or sub-optimally labeled specimens
2) Inappropriate, soiled or leaking containers
3) Empty container
4) Markedly degraded specimen
50
Considering the universally accepted anatomical position, what surface on the penis corresponds to the dorsal/posterior surface (Lester).
The upper surface (the penis is erected in the anatomical position, with the upper surface of the penis considered the dorsal or posterior part of the penis).
51
Give 3 possible explanation to finding fewer than expected lymph node on resection (Lester).
1) Pathology factors : prosector did not found them
2) Patient factor: elderly patient, prior surgery.
3) Treatment factors: radiation and chemotherapy can decrease the numbers
4) Surgical factors: specimen is small or doesn't contain enough lymph node to start with.
* Note that certain diseases (rheumatologic diseases, carcinoma with medullary features) are associated with nodular lymphoid hyperplasia, making the lymph node easier to see.
52
Name the 2 types of margins (Lester)
1) En face (parallel to the plane of resection)
2) Perpendicular to the plane of resection.
53
Name 1 advantage and 1 disadvantage of the en face margin, compare to the perpendicular one (Lester)
Advantages:
1) 10-100 fold greater surface area examined compared to perpendicular margin
2) Entire anatomic structure can be evaluated (ex. the complete circumference of a bronchus)
Disadvantages:
1) Exact distance of tumor from margin cannot be measured
2) Cautery impair interpretation
3) Pathologist less accustomed to it compared to perpendicular margin (may not interpret properly)
4) Type must be clearly specified in dictation because any tumor in the section is considered at the margin.
54
Name 1 advantage and 1 disadvantage of the perpendicular margin compare to the en face one (Lester)
Advantages:
1) Exact distance of the tumor from margin can de determined
2) Majority of pathologist are familiar with its interpretation compare to the en face
Disadvantage:
1) Very little tissue at margin is sampled in large resection
55
What characteristic color are you expecting for the following tumor (Lester)
1) ccRCC
2) Adrenal cortical lesions
3) Xanthogranulomatous inflammation
4) Steroid producing organs
5) Prior hemorrhage with oxidation, such as diffuse type giant cell tumor
6) Chloroma
1) Golden yellow, and hemorrhagic
2) Orange yellow
3) Yellow
4) Often pale or bright yellow
5) Green
6) Green
56
Following fixation, describe the 3 steps every tissue goes thru before being cut on a microtome (Lester)
1) Dehydration: water in tissue is replaced by .alcohol;
2) Clearing: alcohol replaced by clearing agent (xylene), rendering it receptive to infiltration;
3) Infiltration: xylene is replaced by paraffin or another embedding medium.
57
Name 2 methods of measuring with a microscope (Lester).
In increasing lower limit of accuracy (1mm to 0.01mm):
1) Direct measurement on slide (ink edges and measure with a ruler)
2) Estimation from field diameters
3) Vernier scale on stage
4) Ocular reticule (graticule)
58
What is the chromaffin reaction and in which circumstance would you use it (Lester) ?
To confirm the tumor is a pheochromocytoma, fresh tissue is immersed in potassium dichromate solution. The color of the tumor will turn to dark brown/black/purple due to oxidation of catecholamine.
59
What are the prognostic factors of breast DCIS?
1) Size (extent): associate with likelihood of recurrence
2) Nuclear grade
3) Necrosis
* Those 3 criteria guide management and are predictive of clinical outcomes
**Note that size (extent) has no local recurrence risk in mastectomy.
60
On which criteria are based the grading of breast DCIS?
6 nuclear features: nuclear size, pleomorphism, chromatin, nucleoli, polarization, mitoses
61
What is margin positivity in breast DCIS?
Ink on margin (0m)
Note: in report, clearly indicate which margins are located at less than 2mm from margin.
62
For which carcinoma is the CAP breast DCIS protocol intended?
DCIS, encapsulated papillary carcinoma without invasive carcinoma and solid papillary carcinoma without invasive carcinoma.
63
How should DCIS resection specimen be submitted?
In toto
64
Name 3 methods to estimate the volume of breast tissue involved by DCIS.
Reported as mm (+/- #blocks involved/examined), you can estimate the overall size by measuring:
1) DCIS in 1 block (if fits entirely in it)
2) Serial sequential sampling
3) Nonsequential sampling (x 4mm)
4) Margins
5) Gross lesion
65
Give 2 reasons why LN might be collected during a DCIS resection.
1) Extensive DCIS
2) Pathologic findings on prior biopsy suspicious for invasion (less than 1mm; if present, invasive CAP protocol should be used)
3) Imaging finding or clinical finding of a mass
4) Planned mastectomy (LN sampling does not alter morbidity of procedure)
66
When LN status are positive in DCIS resection, how do they usually present and what is the associated prognostic significance
As isolated tumor cells (ITC, <0.2mm or <200 cells), and they have no clinical significance
67
For which breast lesion is the breast phyllodes CAP protocol intended?
Malignant phyllodes only
68
What are the prognostic factor associated with breast malignant phyllodes?
Prognostic category is the same as AJCC stage for ST sarcoma of extremity and trunk, which is based on TNM.
69
What are criteria used to grade phyllodes tumor of breast?
Based on 5 features
1) stromal cellularity
2) stromal atypia
3) stromal overgrowth
4) tumor border
5) mitotic rate
Malignant requires: marked stromal cellularity, marked stromal atypia, stromal overgrowth, an infiltrative tumor border and ≥10 mitoses per 10 HPF.
*** Note that presence of malignant heterologous element OTHER than WELL-DIFFERENTIATED liposarcoma makes this a malignant phyllodes automatically.
70
What is margin positivity in malignant phyllodes tumor?
Ink on phyllodes (0mm)
71
What mandatory elements must be included in the report of a breast biopsy for invasive carcinoma?
1) Procedure
2) Laterality
3) Histologic type
4) Histologic grade
5) DCIS (with architectural pattern and necrosis)
72
What is required for a diagnosis of inflammatory breast carcinoma?
Combination of both clinical and pathological features:
1) Clinical features of inflammatory carcinoma : diffuse erythema and edema involving one-third or more of the breast
2) Pathological features : demonstration of an invasive carcinoma in the underlying breast parenchyma or at least in the dermal lymphatics
73
What are the prognostic factors for breast invasive carcinoma?
1) Size of invasive carcinoma (base of T stage; should combine imaging-gross-micro; report to the nearest mm)
2) LN status (especially metastasis > 2mm; for local recurrence and reduced survival; guides radiotherapy in stage IIa/b)
3) Dermal LVIs (high association with inflammatory breast)
4) LVI (associated with local recurrence and reduced survival)
5) Treatment effect (for disease free and overall survival)
6) Extensive intraductal component (associated with increase risk of local recurrence only if resection margins are + or not fully evaluated; this factor has less significance when DCIS is not close to margin; also, extent of DCIS has no local recurrence risk in mastectomy, only in breast-conserving surgery)
* Muscle invasion should be reported as an indication for postmastectomy radiation therapy.
74
How are breast invasive carcinomas graded?
Based on Nottingham grading system (G1 3-5, G2 6-7. G3 8-9):
1) tubule formation (score 1-3 : >= 75%, 10-75%, <10%)
2) nuclear pleomorphism (score 1-3: atypia and enlarged nuclei <1.5x, 1.5-2x, >2x)
3) mitotic rate (score 1-3: use table per field diameter and count 10 consecutive HPF in most mitotically active area)
* DCIS component is graded according to the 6 nuclear features mentioned in the CAP DCIS protocol
75
Name 3 high-penetrance breast cancer susceptibility genes
BRCA1
BRCA2
CDH1
PALB2
PTEN
TP53
76
Distinguish those 3 procedures: 1) simple mastectomy, 2) modified radical mastectomy, 3) radical mastectomy.
1) total mastectomy
2) total mastectomy + axillary content
3) total mastectomy + pectoralis major/minor muscle + axillary content
77
Patients with multiple foci of breast invasion may be divided into 6 groups. Name 4 of them.
1) Extensive carcinoma in situ with multiple foci of invasion
2) Invasive carcinoma with smaller satellite foci of invasion
3) Invasive carcinoma with extensive LVI
4) Multiple biologically separate invasive carcinomas
5) Invasive carcinomas after neoadjuvant therapy
6) Transection of a single carcinoma into multiple fragments
For patients with multiple ipsilateral invasive carcinomas, the T category assignment is based on the largest tumor
78
Regarding breast invasive carcinoma, define extensive intraductal component (EIC)-positive carcinomas.
Define in 2 ways:
1) DCIS is a major component within the area of invasive carcinoma and DCIS is also present in the surrounding breast parenchyma
or
2) There is extensive DCIS associated with an invasive carcinoma (primarily DCIS with small invasive component)
79
List the 4 criteria for LVI in breast resection.
1) LVI located outside the invasive foci
2) Tumor doesn't conforms exactly to the space
3) Space is lined by endothelial cells
4) Lymphatics are adjacent to blood vessels
80
In breast carcinoma resection, the extent of margin involvement is reported as extensive when which size is reached?
>= 5mm
81
Which pathological findings in breast carcinoma is susceptible to prompt or guide post-treatment radiation?
- Invasive carcinoma at deep margin (**presence of DCIS at the deep fascial margin is UNLIKELY to have clinical significance)
- Extensive DCIS present outside the area of invasive carcinoma
- Extension of carcinoma to skeletal muscle
- Lymph node positivity in stage IIA/IIB breast carcinoma
82
Sentinel lymph nodes are identified by the surgeon by uptake of radiotracer or dye or both. What maximal amount of lymph nodes can be removed for them to still be considered sentinel?
They are considered sentinel lymph nodes if less than six nodes are removed
83
List the 3 types of metastasis which can be found in lymph node for breast carcinoma resection, and give their defining characteristic.
1) Isolated tumor cells (ITC): < 200 cells or size =< 0.2mm
2) Micrometastasis: size >0.2mm to =< 2 mm
3) Macrometastasis: size > 2mm
84
What is T stage based on for the following BREAST lesions:
1) DCIS
2) Paget disease
3) Phyllodes
4) Invasive carcinoma?
1) In situ, so all Tis
2) In situ, so all Tis
3) Size
4) Size, skin and chest wall (intercostal muscle or deeper)
85
Name 4 favorable subtypes of breast carcinoma
Tubular carcinoma
Cribriform carcinoma
Mucinous carcinoma
Adenoid cystic carcinoma
Low-grade adenosquamous metaplastic carcinoma
Low-grade fibromatosis-like metaplastic carcinoma
86
List 6 types of neoplasms which should be staged as a uterine sarcoma
Adenosarcoma
Endometrial stromal sarcoma (LG and HG)
Undifferentiated uterine/endometrial sarcoma
NTRK-rearranged spindle cell neoplasm
Leiomyosarcoma
Rhabdomyosarcoma
Malignant perivascular epithelioid cell tumor (PEComa)
Uterine tumor resembling ovarian sex cord tumor
SMARCA4 deficient uterine sarcoma (SDUS)
Uterine inflammatory myofibroblastic tumor (IMT)
*** Rarely, angiosarcoma, liposarcoma and alveolar soft part sarcoma can also occur in the uterine corpus.
*** Carcinosarcoma is not. It should be considered as a carcinoma.
87
Name 2 important prognostic factors for uterine sarcomas
- Stage (for sarcoma, size and tumor extension to other organs is important; for adenosarcoma, depth of myometrial invasion and extension to other organs is important)
- Lymphovascular invasion
88
How is sarcomatous overgrowth defined in uterine sarcoma, i.e. adenosarcoma?
Pure sarcoma, usually high grade and without an epithelial component, occupying at least 25% of the tumor
89
List 3 criteria distinguishing ESS from endometrial stromal nodule (ESN)
- Depth of myometrial invasion >= 3mm
- LVI
- >= 3 foci of myometrial invasion of any depth
*** Minor marginal irregularity in the form of tongues < 3 mm is allowed for ESN
90
Name 1 molecular alteration found in low-grade endometrial stromal sarcoma
Genetic fusions (60%):
- JAZF1-SUZ12
- JAZF1-PHF1
- EPC1-PHF1
- MEAF6-PHF1
91
Name 1 molecular alteration found in high-grade endometrial stromal sarcoma
- **YWHAE-NUTM2A/B**
*You Will Have An Energetic - NUT Mix, 2A/B*
- **BCOR ITD**
*Internal tandem duplication*
- **ZC3H7B-BCOR**
92
According to NCCN guidelines, what are the 2 most common endometrial mesenchymal malignancy?
Leiomyosarcoma (accounts 40-50%) > Endometrial stromal sarcoma > undifferentiated uterine sarcoma
*note: carcinosarcoma is not considered a mesenchymal malignancy
93
According to NCCN guidelines, what is the most important prognostic factor for LG-ESS?
Stage
94
What are the 3 types of leiomyosarcoma, and list their diagnostic criteria
1) Spindle LMS : requires 2 of 3: tumor cell necrosis, marker atypia, >= 4 / mm2 (>= 10/10 HPF)
2) Epithelioid LMS : > 50% epithelioid, and 1 of 3: tumor cell necrosis, marked atypia, >= 1.6 / mm2 (>= 4/10 HPF)
3) Myxoid LMS: abundant myxoid stroma with 1 of 3: tumor cell necrosis, atypia, > 0.4 /mm2 (>1 /10HPF)
95
Which other mesenchymal uterine tumor must you exclude before rendering a diagnosis of undifferentiated uterine/endometrial sarcoma ?
All others, more specifically:
- Poorly differentiated Ca (IHC CK)
- Carcinosarcoma
- HG-ESS (molecular analysis to r/o gene fusion)
- NTRK sarcoma (NTRK molecular analysis or TRK IHC)
- Sarcomatous overgrowth in adenosarcoma
96
Name two specific IHC for PEComa (perivascular epithelioid cell tumor) and the criteria to classify it as malignant (5):
IHC+: HMB45**, MelanA, SMA, caldesmon, desmin, Cathepsin K**, TFE3 (if translocation present)
Malignant criteria (minimum 3/5):
- >= 5cm
- Mitoses > 1 / 50 HPF
- High nuclear grade
- Necrosis
- Vascular invasion
97
List the 4 types of rhabdomyosarcoma
Pleomorphic
Embryonal
Alveolar
Spindled
98
Which IHC defines or is very characteristic of the following tumor (name the most important one):
1) Inflammatory myofibroblastic tumor (IMT)
2) Alveolar soft part sarcoma
3) SMARCA4 deficient uterine sarcoma
4) NTRK-rearranged spindle cell neoplasm
5) PEComa
6) HG-ESS
1) ALK
2) TFE3
3) BRG1 loss (also show INI-1 loss if SMARCB1 loss)
4) TRK
5) HMB45 or cathepsin K
6) BCOR or cyclin D1
99
Name 2 important recommendations for sampling of an ovarian mass
- Thorough examination of ovarian surface, and sampling of any foci suspicious for involvement (influence treatment)
- Sample tumor adhesion and site of rupture
- Sample 1 section / cm of tumor largest dimension, and increase to 2 sections / cm for borderline serous or mucinous tumors
- Ovary and FT submitted in toto in suspicion of hereditary breast/ovarian cancer (4x increase in detection rate)
- FT in toto for high-grade serous carcinoma
- Sample to determine maximal depth of myometrial invasion for tumor present in uterus
- 5 to 10 sections of omentum for SBT, serous carcinoma and immature teratoma
- 4 to 6 sections of omentum following neoadjuvant chemo
- Unless tumor grossly evident, LN and staging biopsy specimen in toto
100
What are the prognostic factors for ovarian neoplasms?
- Tumor intact or ruptured (latter decrease progression free survival)
- Histologic type
- Histologic grade
- Chemotherapy response score (CRS)
101
Which type of tumor is most common in the ovary?
Epithelial tumor
102
Describe the criteria to assign the primary site of high-grade serous carcinoma (HGSC) as:
1) peritoneal
2) tubo-ovarian
3) ovary
4) fallopian tube
1) bilateral tubes and ovaries examined in toto, and negative for HGSC/STIC
2) bilateral tubes and ovaries unavailable for complete examination, and evidence of extrauterine HGSC
3) bilateral tubes examined in toto, separated from mass, and negative for mucosal HGSC/STIC
4) Tube with mucosal HGSC/STIC or inseparable from tubo-ovarian mass
103
How can you distinguish HGSC of tubo-ovarian versus endometrial origin? Name 2 criteria favoring an endometrial origin when HGSC is noted in both the ovaries and endometrium.
- Absence of extensive omental involvement
- Presence of SEIC (serous endometrial intraepithelial carcinoma)
- WT1 staining is weak/focal or negative
- tumor mainly present on ovarian surface or hilum
- multiple nodules on ovary
104
What are the most common ovarian cancer associated with hereditary breast and ovarian cancer and Lynch syndrome?
HBOC = HGSC
Lynch = CC and endometrioid tumors
105
What is the maximal depth of invasion allowed in serous borderline tumor with microinvasion or microinvasive low-grade serous carcinoma
< 5mm
106
How do LGSC and HGSC differ in terms of histology, IHC profile, risk factors, precursor lesion, response to chemotherapy and genetic events ?
* Histology: > 3fold nuclear size variation and > 12 mitoses / 10 HPF for HGSC
* IHC: p16 and p53 are strong and diffuse, and KI67 high in HGSC; ER and PR are high in LGSC
* Risk factor: >60yoa, family hx of breast/ovarian carcinoma and infertility for HGSC; elevated BMI for LGSC
* Protective factors: multiparity, breastfeeding, oral contraceptive, late menarche, early menopause for HGSC
* Precursor: STIC for HGSC, SBT for LGSC
* Response to chemo: responsive for HGSC, less responsive for LGSC
* Genetic events: TP53 mutation and high level of chromosomal instability (or CNV) in HGSC, MAPK pathway mutations (KRAS-BRAF-ERBB2) and low level of chromosomal instability (or CNV) in LGSC
Adv Anat Pathol. 2009 Sep; 16(5): 267–282.
https://doi.org/10.1530/ERC-21-0191
107
Name 4 morphologic criteria for STIC (serous tubal intraepithelial carcinoma)
1) nuclear enlargement
2) hyperchromasia
3) irregularly distributed chromatin
4) nucleolar prominence
5) mitotic activity
6) apoptosis
7) loss of polarity
8) epithelial tufting
108
Name the IHC profile of STIC
TP53 mutated (at least 12 consecutive epithelial cells expressing it), and ki67 > 10%
109
Metastatic mucinous carcinoma are more common than primary ovarian mucinous tumor. Name 3 possible site of origin for the metastasis, and one histologic feature favoring it
1) Endocervix (villoglandular growth with epithelial basal apoptosis and apical mitoses)
2) Appendix (mucinous dissection of stroma - pseudomyxoma ovarii - with incomplete gland formation and subepithelial cleft; pseudomyxoma peritoneii)
3) Colon (cribriform/garland growth with dirty luminal necrosis)
4) Stomach
5) Pancreaticobiliary (mimic primary ovarian)
6) Breast
110
List 4 criteria favoring a metastatic mucinous carcinoma over a primary mucinous ovarian carcinoma
Metastatic:
- Bilateral ovarian involvement
- Predominant surface an/or hilar involvement
- Nodular growth
- Infiltrative growth pattern (with desmoplastic stroma, or single cell infiltration)
- LVI
Primary
- size > 10-12 cm
- Expansile growth (>= 5mm cribriform glands with minimal intervening stroma without desmoplasia)
- PAX8, PAX2, CK7, CEA positive, and CDX2, SATB2 negative
- DPC4 expression (also in lower GIT and stomach, loss in pancreaticobiliary)
111
Name the 2 ovarian tumor categories most likely to metastasize
Ovarian epithelial carcinoma
Ovarian sarcoma
112
Give one molecular association for the following ovarian tumors:
1) LGSC
2) HGSC
3) Endometrioid and clear cell carcinoma
4) Clear cell carcinoma
5) Mucinous carcinoma
6) Malignant Brenner tumor
1) BRAF, KRAS, HER2 mutations
2) TP53 mutation; BRCA1, BRCA2
3) CTNNB1, ARID1A, PTEN mutations
4) ARID1A, PIK3CA mutations; deletion PTEN
5) KRAS, CDKN2A, TP53 mutations
6) PIK3CA mutation; MDM2 amplification
113
Give one molecular association for the following ovarian tumors:
1) Granulosa cell tumor, adult
2) Granulosa cell tumor, juvenile
3) Dysgerminoma, YST, EC
1) FOXL2 missense mutation
2) AKT1 and GNAS mutations
3) Chromosome 12 abnormalities (isochomosome 12p)
114
What is the minimal percentage of tumor required for reporting a second component (in the context of an ovarian mixed carcinoma)?
No minimal percentage
115
Regarding grading of ovarian epithelial carcinomas, which tumor are not graded?
Clear cell carcinoma
Carcinosarcoma
116
Regarding grading of ovarian germ cell tumors, which tumor are not graded ?
All tumors except immature teratoma (based on quantity of immature/embryonal elements, 3 tiers, <1, 1-3, >3 40x field)
117
Regarding grading of ovarian sex cord stromal tumors, how is Sertoli-Leydig cell tumor graded?
3-tier system, based on tubular differentiation (1 tubular, 2 lobular aggregate, 3 sarcomatous sheet)
118
Regarding ovarian tumors
1) What are the 2 types of noninvasive implants?
2) To which categories of ovarian tumors do they apply?
3) What distinguish them from invasive implants?
1) Epithelial and desmoplastic types
2) SBT and seromucinous borderline tumor
3) No retraction artefact around cell nests (seen in invasive implants of LGSC)
119
What are the criteria guiding the chemotherapy response score (CRS) for ovarian HGSC
Assessment of omentum shows:
CRS1: no/minimal tumor response = tumor with minimal fibroinflammatory changes
CRS2: appreciable tumor response amidst viable tumor = readily identifiable and regularly distributed tumor associated with fibroinflammatory changes
CRS3: Complete/near-complete response = no residual tumor or irregularly scattered tumor, or nodules up to 2 mm in maximum size
120
Which tumors are associated with endometriosis?
1) Endometrioid carcinoma
2) Clear cell carcinoma
3) Seromucinous borderline tumor (and benign)
4) Endometrioid stromal sarcoma (rarely)
5) Adenosarcoma (rarely)
6) Carcinosarcoma (rarely)
7) Squamous cell carcinoma (uncommon)
8) Mesonephric-like adenocarcinoma
121
List 2 examples of trophoblastic tumor requiring staging
1) Invasive hydatidiform mole
2) Gestational choriocarcinoma
3) Placental site trophoblastic tumor (PSTT)
4) Epithelioid trophoblastic tumor (ETT)
5) Mixed trophoblastic tumor
* Benign placental site lesions (exagerated placental site reaction - EPSR, and placental site nodule - PSN) should be reported separately and not staged
122
Name 2 particularities regarding the TNM staging of gestational trophoblastic tumor
1) pT stage stops at 2 : T1 confined to uterus, T2 extends to other genital structures (vagina, broad ligament, ovary, FT). Other involvement = metastasis
2) Absence of nodal category (no N stage; LN involvement is considered a metastasis, M1b)
3) M category comprises all distant metastasis, M1a = lung metastasis, M1b all other
123
The FIGO-modified WHO prognostic scoring index stratify women with gestational trophoblastic neoplasia in additiona to the stage group. 8 criteria or prognostic factors are used. Name 2 of them.
age
antecedent of pregnancy
interval months from index pregnancy
pretreatment serum hCG
Largest tumor size (including uterus)
Sites of metastasis
Number of metastasis
Previous failed chemotherapy
124
Regarding gestational trophoblastic tumor, which factor are important for prognosis and should be included in the report?
1) Largest tumor size
2) Sites of metastasis
3) Number of metastasis
4) Nodal involvement (very rare, extremely poor prognosis, considered a metastasis. No "N" stage)
5) Prior chemotherapy for known gestational trophoblastic tumor
125
Which IHC can be used to distinguish PSN from ETT?
Cyclin E
- Weak nuclear in PSN, intense diffuse nuclear (>50% of cells) in ETT
Other:
- Ki67 (>10% in ETT)
- PDL1 (highly expressed in ETT)
126
Which trophoblastic tumor and tumor-like lesions arise from:
A) implantation site intermediate trophoblast
B) chorionic-like intermediate trophoblast
A) EPSR and PSTT
B) PSN and ETT
EPSR: exagerated placental site reaction
PSTT: placental site trophoblastic tumor
PSN: placental site nodule
ETT: epithelioid trophoblastic tumor
127
Which IHC panel would you recommend to distinguish the non-molar trophoblastic lesions from one another?
IHC: beta-hCG, p63, hPL, CD146, KI67, cyclin E
Note:
* beta3-HSD and LMWCK confirms trophoblastic origin
* in the image, the (-) sign indicate (-, may sometime be (+))
128
What are the most common diagnostic errors in trophoblastic lesions ? Name 2
1. Misinterpretation of early complete hydatidiform mole as partial mole.
2. Over diagnosis of hydatidiform mole in tubal pregnancy because of florid appearance of normal early first-trimester trophoblastic proliferation.
3. Misdiagnosis of exuberant placental site nonvillous trophoblast as placental site trophoblastic tumor or choriocarcinoma.
4. Misdiagnosis of nonvillous trophoblast, often seen in the context of complete hydatidiform mole, as choriocarcinoma or placental site trophoblastic tumor
129
What does LAST stands for
Lower Anogenital Squamous Terminology
