Gynaecological pathology Flashcards
DX:
CIN II
NB: cytoplasmic maturation in upper 1/3 and abrupt transition from dysplastic sqamous epithelium to benign columnar epithelium.
DX:
Histol features:
DX: CIN II/HSIL
Histo features: diffuse nuclear enlargement, hyperchromasia, and membrane irregularities with persistent cytoplasmic maturation at the upper 1/3 of the epithelium, consistent with HSIL/CIN II. Note the increased mitotic activity in the lower and middle thirds.
DX:
Histo features:
DX: CIN III
Histo features: A low magnification showing HSIL/CIN III involving the underlying endocervical glands. Notice that the involved glands have smooth, round borders and lack a desmoplastic stromal reaction, features not typical of invasive SCC.
Dx:
Key histol features?
Dx: HSIL/CIN III
Histo: Lacks maturation
DX:
Histo features:
DX: CIN III
Histo features: HSIL with superficial keratinization. Note the diffuse nuclear atypia and increased mitotic activity throughout all layers of the epithelium.
DX:
Features:
DX: HSIL/CIN II (upper half) and invasive SCC lower half.
Histo features:
- Diffuse basaloid appearance (CIN III)
- Reverse maturation (invasive SCC)
A lesion looks like HSIL/LSIL. Name other Ddx.
Reactive squamous epithelium
Immature squamous metaplasia and atrophy
Pseudostratified mucinous intraepethilial lesion
Adenosquamous carcinoma in situ
Placental implantation site/plaque
Early invasive SCC
Dx:
Histo features:
Dx: LSIL
Features: Hyperchromatic nuclei and perinuclear halos with irregular contours in the upper layers
DX:
Histo features:
Dx: HSIL
Histo: full thickness loss of maturation and atypia. Mitoses seen across all layers. Apoptoses seen (arrow)
Cervix
Dx:
Dx: Immature exophytic LSIL
Slender Papillae and Surface Maturation
Immature exophytic LSIL is composed of slender papillae with some surface maturation.
Dx:
Dx: basal atypia with abnormal mitoses indicative of HSIL
DX:
Hx:
Dx: Pseudostratified Mucinous Intraepithelial Lesion (SMILE)
Histo:
- involves the full thickness epithelium.
- at medium or high power, cells contain abundant pale cytoplasm, some with intracytoplasmic vacuoles.
Dx
Adenosquamous carcinoma
DDX for endometrial hyperplasia with atypia?
Technical artifacts
Endometrial polyp
Atypical polypoid adenomyoma
Endometrial hyperplasia without atypia
Endometrioid adenocarcinoma
Endocervical adenocarcinoma in situ (“colonization of endometrial glands”)
Serous endometrial glandular carcinoma
Describe molecular/genetic mutations wrt atypical endometrial hyperplasia?
Monoclonal expansion
Inactivation of PTEN (TSG), most frequent
Microsatellite instability (20-25%) (Lynch and Cowden syndrome)
KRAS activating mutations (~15%)
CTNNB1 mutations ( 25-30%)
MLH1 epigenetic activation (15-20%)
Dx:
Histo feature exemplified:
Dx: atypical endometrial hyperplasia with squamous metaplasia
Histo feature: Morules (squamous metaplasia)
50F bx from left ovary.
Dx?
Histo features:?
Bonus: common genetic mutation?
Dx: granulosa cell tumour
Histo: Microfollicular growth pattern (Call–Exner bodies) composed of monotonous tumour cells with nuclear grooves and folds and scant cytoplasm disposed around spaces filled with hyalinized material.
Bonus: Nearly all adult granulosa cell tumours harbour a recurrent somatic FOXL2 missense mutation
25F
Incidental finding of 1.5cm RIF well-circumscribed mass.
Dx? histo features?
Dx: Brenner tumour
Benign epithelial-stromal tumor with nests of transitional-type epithelium embedded in fibromatous stroma. The transitional type epithelium shows abundant pale to clear cytoplasm.
Which stain could you use to differentiate adult granulosa cell tumour from fibroma or thecoma?
Reticulin
Which gene is commonly mutated in adult granulosa cell tumour?
Nearly all adult granulosa cell tumours harbour a recurrent somatic FOXL2 missense mutation
Uterine lesion
Dx? IHC?
PEComa is most commonly composed of epithelioid cells with variable eosinophilic to clear cytoplasm. Shows myomelanocytic differentiation.
IHC: HMB45 (99%); SMA (80%); desmin (80%); caldesmon (76%).
TFE3 translocated associated PEComa: HMB45 and TFE3 strong and diffuse staining.
3 main algorithms have been proposed for predicting behavior
Nongynecologic specific criteria (Am J Surg Pathol 2005;29:1558):
Benign: < 5 cm, noninfiltrative, no high grade atypia, mitoses ≤ 1/50 high power fields (HPFs), no necrosis, no lymphovascular invasion (LVI)
Uncertain malignant potential: nuclear pleomorphism / multinucleated giant cells or > 5 cm
Malignant: 2+ features (> 5 cm, noninfiltrative, high grade atypia, mitoses > 1/50 HPFs, necrosis, LVI)
Gynecologic specific criteria (Am J Surg Pathol 2014;38:176):
Benign / uncertain malignant potential: < 4 features (≥ 5 cm, high grade atypia, mitoses > 1/50 HPFs, necrosis, LVI)
Malignant: ≥ 4 features
Modified gynecologic specific criteria (adopted by the WHO 2020) (Am J Surg Pathol 2018;42:1370)
Uncertain malignant potential: < 3 features (> 5 cm, high grade atypia, mitoses > 1/50 HPFs, necrosis, LVI)
Malignant: ≥ 3 features
Recurrences can occur years after original diagnosis
Ovarian lesion
Dx?
Criteria for subtype?
Micropapillary serous borderline tumour.
Need a minimum of 5mm to qualify as micropapillary (or cribriform subtype). Micropapillae - lining stromal cores, 5 x as long as they are wide.
What are the SET patterns of ovarian HGSC.
Describe the demographic.
Significance.
Solid, endometrioid-like, transitional.
Cases are much more frequently a/w germline BCRA 1/2 mutations (50% of cases).
These patients are generally younger (c.f conventional HGSC), are a/w lower frequency of STICK, and have more favourable prognosis.
Serous borderline tumour
Define stromal microinvasion
stromal microinvasion < 5 mm in greatest dimension in any single focus with small cell clusters / individual cells with abundant dense eosinophilic cytoplasm or small papillae within clear lacunar spaces, cytologically similar to the non-invasive component of SBT.
peritoneal bx.
Dx and description of criteria.
Epithelial-type non-invasive implants associated with ovarian serous borderline tumour
Complex papillary architecture is present within an epithelium-lined space. Non-invasive implants that display hierarchically branching papillae or detached clusters of cells not associated with stroma are designated as epithelial implants.
Name the two types of implants a/w ovarian SBT?
Epithelial and desmoplastic.
Non-invasive implants that display hierarchically branching papillae or detached clusters of cells not associated with stroma are designated as epithelial implants.
Desmoplastic implants consist of single cells or clusters of cells embedded in reactive-appearing (granulation tissue–like or fasciitis-like) or desmoplastic stroma that predominates over the epithelial component and appears tacked on to the peritoneal surface. The epithelium frequently blends into the surrounding stroma. If a desmoplastic implant is present on the ovarian surface or within the cyst of an ovarian SBT, the term “autoimplant” is used.
peritoneal biopsy. Ovarian mass.
Dx?
Criteria
Desmoplastic non-invasive implants associated with ovarian serous borderline tumour. (Low-grade simple glands with slight epithelial stratification are present within abundant desmoplastic stroma.)
How to diagnose partial hydatiform molar pregnancy?
When 3 of the following 4 features are well developed.
1. Two populations of villi (large hydropic and smaller fibrotic)
2. Enlarged, irregular, dysmorphic villi with trophoblast inclusions
3. Enlarged villi with cisterns (at least 3mm)
4. Syncytiotrophoblast hyperplasia/atypia
Partial hydatiform moles
Genetic composition?
Usually diandric triploidy (2 paternal, one maternal) or digynic (2 maternal, one paternal)
complete mole, microscopic features
No direct or indirect evidence of fetus
All villi are enlarged with central cisterns
Mixed trophoblast proliferation is circumferential but may be discontinuous
Implantation site with markedly abnormal invasive trophoblasts
Very early complete mole. Microscopic features.
No direct or indirect evidence of fetus
All villi are enlarged with central cisterns
Mixed trophoblast proliferation is circumferential but may be discontinuous
Implantation site with markedly abnormal invasive trophoblasts
Describe the silva classification and what it is use.
Subepidermal bulla
Discuss the ddx with eosinophils
Bullous pemphigoid
What does the antibody target?
BP230 (protein in hemidesmosome)
Pemphigoid gestationis
Antibody directed against which protein?
BP180 (in hemidesmosome)
Epidermolysis bullosa aquisita
antibody against which protein?
collagen VII
Subepidermal bulla with neutrophils
DDx
Bullous SLE
type of antibody against which protein
IgG against collagen VII
Cx biopsy.
Dx?
Adenocarcinoma in situ.
Essential: pseudostratified, hyperchromatic nuclei with easily identified apical mitotic figures and karyorrhexis.
P16
Which gene encodes this protein.
Mechanism of action?
Gen: Tumor suppressor protein encoded by CDKN2A gene (9p21.3)
MOA: Prevents progression into S phase of cell cycle.
Protein expression often increased in aging cells, which eventually drives cell death and apoptosis
Negative IHC in tumors with loss of p16 protein function / expression
Immunohistochemical positivity commonly considered a surrogate marker for oncogenic HPV infection
Inactivation of Rb by the viral E7 oncoprotein following viral integration into host genome leads to overexpression of p16
serous borderline ovarian tumour
Criteria for microinvasion?
Stromal microinvasion defined as < 5mm in any largest dimension.
Patterns of microinvasion include: small clusters of cells or individual cells within stroma, small papillae within clear lacunar spaces cytologically similar to the non-invasive component. No desmoplasia should be present. These cells may sometimes be within lymphatic spaces -> This pattern is diagnosed as SBT with microinvasion.
LGSC
Who dx criteria?
Essential: invasive serous tumour with small nests, glands, papillae or micropapillae, and inverted macropapillae, frequently free-floating within unlined clear spaces; low-grade cytological atypia (< 3-fold variation in nuclear size); low mitotic activity.
Ovarian lesion
Dx?
IHC:
LGSC:
This example exhibits an inverted macropapillary pattern of invasion. The macropapillae are surrounded by unlined clear spaces. Scattered small papillae, clusters, and individual cells are also present.
IHC: Diffusely + for PAX8, CK7, ER and WT1.
CK20-, p16 patchy +, p53 WT
clear cellc ca vs HGSC vs endometrioid
IHC ?
WT1, napsin A, and ER together are recommended for distinction from high-grade serous carcinoma and napsin A and PR for distinction from endometrioid carcinoma.
Ovarian clear cell ca
IHC:
CCC typically positive for PAX8, Napsin A, HNF1B, and negative for WT1, ER and PR.
mucinous borderline ovarian tumours
a/w which other diagnoses?
brenners tumour
dermoid cysts
in mucinous borderline tumours (of the ovary)
What is the difference between microinvasion and microinvasive carcinoma?
Microinvasion is defined by small foci of stromal invasion (which may be multiple), comprising single cells or small groups of cells, measuring < 5 mm in greatest linear extent, and showing the same degree of cytological atypia as the borderline tumour. The presence of marked cytological atypia in such small invasive foci warrants a diagnosis of microinvasive carcinoma
mucinous carcinoma
Can arise from which entities?
MBT, brenner tumour or mature cystic teratoma
Endometrioid adenocarcinoma (of uterus)
Grading?
G1: </= 5%
G2: 6-50%
G3: > 50%
Solid non-glandular, non-squamous growth.
The presence of severe cytological atypia in the majority of cells (> 50%) increases the grade by one level, but serous ca should be excluded in cases with nuclear atypia that is out of proportion to the architecture.
partial mole
dx criteria & aetiology
PHM is triploid gestation with 2 paternal genomes and 1 maternal genome (diandric triploidy)
Triploidy can also be composed of 2 maternal genomes and 1 paternal genome (digynic triploidy): These are not associated with PHM
Morphology alone is generally diagnostic for PHM when at least 3 of 4 following features of PHM are well developed
2 populations of villi (large hydropic and smaller fibrotic)
Enlarged, irregular, dysmorphic villi with trophoblast inclusions
Enlarged villi with cisterns (at least 3 mm in size)
Syncytiotrophoblast hyperplasia/atypia
Nonmolar triploidy (digynic triploidy) may show some of these features but not significant syncytiotrophoblast hyperplasia
29F postcoital bleeding. cx bx
dx?
cervical deciduosis
Image: Decidual change is characterized by large, rounded cells with abundant pale eosinophilic cytoplasm, large bland nuclei with prominent nucleoli
leiomyoma
histological subtypes
- cellular leiomyoma
- Leiomyoma with bizarre nuclei (symplastic leiomyoma) (but mitotic count low, < 2mitoses/mm2)
- FH–deficient: staghorn vasculature, alveolar-pattern oedema, scattered bizarre nuclei, ovoid nuclei sometimes arranged in chains, eosinophilic cytoplasmic (rhabdoid) inclusions, and prominent eosinophilic nucleoli surrounded by perinucleolar haloes. Can be somatic or germline mutations
- Mitotically active leiomyomas - usu in women of repro age. 2.5–6 mitoses/mm2 (equating to 6–14 mitoses/10 HPF of 0.55 mm in diameter and 0.24 mm2 in area). No cytological atypia or tumour cell necrosis. extensive sampling important +++
- Hydropic leiomyoma has conspicuous zonal, watery oedema, which separates tumour cells into thin and delicate cords or nests and may surround thick-walled vessels in a perinodular pattern
- Leiomyoma with apoplectic changes displays multiple stellate zones of haemorrhage surrounded by a hypercellular rim of cells – some with eosinophilic cytoplasm, pyknotic nuclei, and increased mitoses. may be associated with a myxoid background. Most importantly, away from these areas, the smooth muscle cells have a banal appearance, imparting overall a zonation phenomenon. These changes are induced by progestogen therapy and pregnancy; there may be hydropic change and cells with a deciduoid or signet-ring appearance.
- Lipoleiomyoma has variable numbers of mature adipocytes admixed with the smooth muscle cells.
- Epithelioid leiomyomas display round or polygonal cells with appreciable eosinophilic granular or clear cytoplasm
- Myxoid leiomyoma is a well-circumscribed and hypocellular tumour with cells widely separated by myxoid acid-mucin stroma (Alcian blue–positive)
- Dissecting leiomyoma shows irregular dissection by nodules of bland smooth muscle cells of the myometrium, often with conspicuous hydropic change
- Diffuse leiomyomatosis is characterized by innumerable, poorly circumscribed hypercellular nodules of bland smooth muscle cells diffusely involving the myometrium
uterus lesion
dx?
lipoleiomyoma
uterin lesion
dx?
Key features exemplified in image?
epithelioid leiomyoma
The tumour cells are polygonal, with eosinophilic or clear cytoplasm and lack of cytological atypia.
uterin lesion
dx
Key features exemplified
myxoid leiomyoma
Cytologically benign spindle cells are widely separated by myxoid stroma.
uterin lesion
dx
features displayed in image
Dissecting leiomyoma
Nodules of tumour with hydropic change infiltrate the myometrium.
uterine lesion
dx
features displayed in image
FH deficient leioymoma
Cellular tumour with scattered bizarre cells and staghorn blood vessels.
uterine lesion
dx
feature displayed in image
Leiomyoma with bizarre nuclei
The cells with bizarre nuclei have a diffuse distribution within the tumour; they display smudged nuclear chromatin and some nuclear pseudoinclusions. Karyorrhectic nuclei (often mistaken for atypical mitoses) are seen.
uterine lesion
dx
Key features displayed in image?
Fumarate-hydratase deficinet leiomyoma
Prominent oedema with an alveolar-like morphology.
uterin lesion
dx
key features displayed in image
celllular leiomyoma
The tumour is composed of “blue” cells with very scant cytoplasm, mimicking a stromal tumour. There are associated thick blood vessels and cleft-like spaces.
pagets disease of vulva
IHC: primary vs secondary
Primary and secondary EMPD: CAM5.2, CEA, EMA positive; ER, PR, MART-1/melan-A, tyrosinase, MITF, and HMB-45 negative; rarely S100 positive
Primary: CK7, GCDFP-15, MUC1, MUC5, GATA3 positive
Secondary anorectal: CK20, CDX2, MUC2 positive
Secondary urothelial: CK7, CK20, GATA3, p63, uroplakin-3 positive
Secondary cervical: p16 positive
53F cervical lesion, PMB
Dx
Dx criteria
IHC
mesonephric adenocarcinoma
Mostly occur in lateral cervical wall, not a/w HPV
classic pattern is tubular, with back-to-back tubules lined by cuboidal cells with lumina filled with dense eosinophilic secretions (PAS-positive and mucicarmine-positive) { 7573674 }. The ductal (pseudoendometrioid) pattern consists of angulated glands lined by columnar cells.
Distinction from benign mesonephric remnants and hyperplasia is based on architectural crowding, haphazard infiltrative growth, elevated mitotic activity, intraluminal necrotic debris, and nuclear atypia
Essential: an admixture of architecture patterns; optically clear nuclei with grooves; p16 is not diffuse.
Desirable: association with adjacent mesonephric remnants and/or mesonephric hyperplasia; positivity for GATA3 and/or TTF1; negativity for ER and napsin A; HPV negativity.
No grading system applicable to MNAC
IHC: (+) GATA3, PAX8, and CD10 (luminal staining pattern); completely (-) ER; usu (-) napsin A/AMACR. Can be (+) TTF1 (rarely) and calretinin. p53 is wildtype. p16 is not diffuse and HPV is not detected
Image: Classic tubular and ductal patterns. The tubules are lined by cuboidal cells and contain dense eosinophilic secretions, as well as focal intraluminal necrotic debris. The ductal pattern comprises angulated glands that are lined with columnar cells.
52F cervical mass
Dx
Key dx features
IHC
Px
Cervical adenocarcinoma, gastric type
Essential: abundant pale eosinophilic to clear cytoplasm and distinct cell borders (gastric phenotype) or well-formed glands in a haphazard distribution and minimal atypia (minimal deviation); destructive invasion and moderate to severe nuclear atypia (gastric-type); negative ER/PR.
Desirable: negative or patchy p16 and/or negative HPV testing; neutral-type mucin (pinkish-red on Alcian blue / PAS staining); abnormal p53 staining in ~50%.
IHC: PAX8, CAIX, CEA, and CK7 are usually positive; CK20 and CDX2 may be focally positive; ER and PR are usually negative. p16 is either negative or patchy in most cases; however, overexpression can be seen. Abnormal p53 (overexpression or null) is seen in about 50% of cases.
Px: aggressive
Image: Tumoural glands are composed of mucinous cells with ample granular to foamy cytoplasm and distinct cell borders.
left fallopian tube
dx
Origin
Key features
IHC
Adenomatoid tumor
of mesothelial origin
Can arise in uterus, fallopian tubes, ovaries…
Variably sized slit-like, tubular, and cystic spaces that may have papillae, lined by mesothelial cells; tumours arising in the peritoneum have no invasion into the adjacent tissue. Usually, there are thread-like bridging strands within the luminal spaces.
IHC: tumour cells express calretinin, WT1, D2-40, cytokeratin AE1/AE3, and CAM5.2;intact/retained nuclear expression of BAP1, in contrast to mesothelioma, which frequently demonstrates loss of nuclear BAP1 expression
endometrioid adenocarcinoma of uterus
grading
EEC is graded using FIGO grading criteria: grade 1, 2, and 3 tumours, respectively, exhibit ≤ 5%, 6–50%, and > 50% solid non-glandular, non-squamous growth. The presence of severe cytological atypia in the majority of cells (> 50%) increases the grade by one level, but serous carcinoma should be excluded in cases with nuclear atypia that is out of proportion to the architecture { 21993268 }. Binary grading { 30550484 } is recommended, whereby grade 1 and 2 tumours are classified as low-grade and grade 3 tumours as high-grade. In low-grade EEC, endometrioid differentiation can be diagnosed on routine histology. In high-grade tumours, squamous differentiation strongly favours EEC over other histological endometrial carcinoma types.
HGSC vs LGSC (ovary)
Histo features:
IHC panel to distinguish:
LGSC: invasive serous tumour with small nests, glands, papillae or micropapillae, and inverted macropapillae, frequently free-floating within unlined clear spaces; mild to moderate atypia, with < 3-fold variation in nuclear size, occasionally with a central nucleolus { 15087669 }. Mitotic figures are present, usually 1–2 mitoses/mm2, equating to 3–5 mitoses/10 HPF of 0.55 mm in diameter and 0.24 mm2 in area (with as many as 5 mitoses/mm2, equating to 12 mitoses/10 HPF of 0.55 mm in diameter and 0.24 mm2 in area) { 15087669 }. Psammoma bodies are often present. Necrosis is rare.
IHC: Tumours are typically diffusely positive for CK7, PAX8, ER, and WT1; p16 expression is patchy and p53 exhibits wildtype immunoreactivity
HCSC: tumours typically exhibit solid, papillary, labyrinthine (with slit-like spaces), glandular, or cribriform architecture. Nuclei are large and markedly atypical (nuclear size variability of > 3-fold), with high mitotic activity, typically > 5 mitoses/mm2 (equating to > 12 mitoses/10 HPF of 0.55 mm in diameter and 0.24 mm2 in area), including atypical mitoses. Necrosis and multinucleated cells are common. Morphological patterns: microcystic architecture with intraluminal and intracytoplasmic mucin, cytoplasmic clearing, and (very rarely) signet-ring cells { 11603214 }; follicular pattern; and spindle cells.
Homologous recombination–deficient tumours frequently display variant architecture, which includes SET (solid, endometrial-like, transitional) pattern
IHC: Approximately 90% of tumours demonstrate nuclear expression of WT1 (usually diffuse) and approximately 95% exhibit an abnormal pattern of p53 expression (mutation-type labelling) represented by strong diffuse staining in at least 80% of cells, no expression (with an intact internal control), or (rarely) diffuse cytoplasmic staining with weak nuclear staining { 27840695 ; 30059451 }. CK7, CA125, and PAX8 are typically positive and ER is frequently expressed. p16 demonstrates strong diffuse immunoreactivity in ≥ 50% of tumours { 26974996 ; 24336157 ; 26173002 }. CK20, CEA, HNF1β, and napsin A are typically negative in these tumours, while PTEN and ARID1A expression is retained
endometrioid adenocarcinoma of uterine corpus
grading
FIGO grading criteria: grade 1, 2, and 3 tumours, respectively, exhibit ≤ 5%, 6–50%, and > 50% solid non-glandular, non-squamous growth
ovarian mass
dx
essential + desireable dx criteria
Thecoma
Essential: predominant population of stromal cells with bland ovoid to round nuclei with appreciable pale-grey cytoplasm.
Desirable: reticulin surrounding individual cells; positivity for inhibin, calretinin, and other sex cord markers.
chemotherapeutic response score
Describe
serous borderline tumour (ovarian)
micropapillary subtype- criteria
The micropapillary/cribriform subtype has elongated micropapillae without stromal cores (at least 5 times longer than wide) that directly emanate from large papillae (the so-called Medusa head appearance) and/or small punched-out cribriform spaces. An area of pure micropapillary/cribriform growth measuring ≥ 5 mm is required for the tumour to be classified as the micropapillary/cribriform subtype.
The nuclear features should not be high-grade, and mitoses are infrequent.
serous borderline tumour (ovary)
Microinvasion definition
Stromal microinvasion is defined as invasion < 5 mm in greatest dimension in any single focus. Patterns of microinvasion include small clusters of cells or individual cells with abundant dense eosinophilic cytoplasm within stroma, as well as small papillae within clear lacunar spaces cytologically similar to the non-invasive component. No desmoplasia should be present.
However, if the morphology resembles low-grade serous carcinoma (LGSC) and invasion measures < 5 mm in greatest dimension in any single focus, the tumour should be classified as microinvasive LGSC
HGSC (ovary)
Morphology
tumours typically exhibit solid, papillary, labyrinthine (with slit-like spaces), glandular, or cribriform architecture.
Nuclei are large and markedly atypical (nuclear size variability of > 3-fold), with high mitotic activity, typically > 5 mitoses/mm2.
Necrosis and multinucleated cells are common.
Homologous recombination–deficient tumours frequently display variant architecture, which includes SET (solid, endometrial-like, transitional) patterns.
Essential: serous tumour with solid (with slit-like spaces), papillary, glandular, or cribriform architecture; large, markedly atypical nuclei (nuclear size variability of > 3-fold); high mitotic activity; both fallopian tubes should be grossly visible in their entirety and contain no serous tubal intraepithelial carcinoma or mucosal HGSC after being examined in total using a SEE-FIM (sectioning and extensively examining the fimbriated end) protocol.
Desirable (in selected cases): WT1 immunoreactivity; mutation-type p53 expression.
47F ovarian mass
dx?
IHC
Frequent genetic (molecular) mutation
Adult granulosa cell tumour
IHC: Reticulin stain highlights reticulin fibres around tumour nests, unlike in fibroma and thecoma (where there is staining around individual cells)
Tumours are typically positive for FOXL2, calretinin, inhibin (although staining may vary in distribution and intensity), and SF1. ER, pancytokeratin, CD99, and WT1 are frequently positive.
Molecular: characteristic FOXL2 point mutation
Serous borderline micropapillary variant
diagnostic criteria
The micropapillary/cribriform subtype has elongated micropapillae without stromal cores (at least 5 times longer than wide) that directly emanate from large papillae (the so-called Medusa head appearance) and/or small punched-out cribriform spaces. An area of pure micropapillary/cribriform growth measuring ≥ 5 mm is required for the tumour to be classified as the micropapillary/cribriform subtype { 15897738 ; 28248817 }. The cells have a high N:C ratio and the nuclei are small and uniform, with small nucleoli. The nuclear features should not be high-grade, and mitoses are infrequent.
Borderline serous carcinoma with microinvasion vs microinvasive ca
diagnostic criteria, patterns of invasion
Stromal microinvasion is defined as invasion < 5 mm in greatest dimension in any single focus. Patterns of microinvasion include small clusters of cells or individual cells with abundant dense eosinophilic cytoplasm within stroma, as well as small papillae within clear lacunar spaces cytologically similar to the non-invasive component. No desmoplasia should be present. These cells may sometimes be within lymphatic spaces . This pattern is diagnosed as SBT with microinvasion. However, if the morphology resembles low-grade serous carcinoma (LGSC) and invasion measures < 5 mm in greatest dimension in any single focus, the tumour should be classified as microinvasive LGSC, and extensive sampling should be performed to exclude larger foci of invasion.
Below: Small nests and individual tumour cells with abundant eosinophilic cytoplasm (arrows) are present within spaces devoid of epithelial lining in the stroma. This is the most common pattern of microinvasion.
Dx differences between ovarian…
Mucinous cystadenoma
Borderline mucinous tumour
Microinvasion vs microinvasive carcinoma
Intraepithelial carcinoma
Mucinous carcinoma
Benign, essential: tumour with cysts and glands lined by benign mucinous epithelium with no architectural complexity or cytological atypia.
Borderline, essential: tumour with gastrointestinal-type mucinous epithelium lining cysts with variable degrees of epithelial stratification, tufting, and villous or slender filiform papillae, in at least 10% of the tumour; low-grade nuclear atypia (except if intraepithelial carcinoma); absence of stromal invasion (except if microinvasion or microinvasive carcinoma). NB: A component of benign mucinous cystadenoma is often present. NB: The presence of focal or patchy marked cytological atypia, often associated with mitotic activity, warrants a diagnosis of intraepithelial carcinoma in these tumours.
Microinvasion is defined by small foci of stromal invasion (which may be multiple), comprising single cells or small groups of cells, measuring < 5 mm in greatest linear extent, and showing the same degree of cytological atypia as the borderline tumour
The presence of marked cytological atypia in such small invasive foci warrants a diagnosis of microinvasive carcinoma
Carcinoma, essential: mucinous tumour with cytological atypia and expansile/confluent and/or infiltrative/destructive invasion, measuring at least 5 mm in linear extent.
(Carcinomas are characterized by two different patterns of invasion: expansile/confluent and infiltrative/destructive, each measuring at least 5 mm in linear extent. The two patterns may coexist; however, the expansile/confluent pattern is more common. The expansile/confluent invasive pattern displays marked glandular crowding, with little or absent intervening stroma, creating a labyrinthine appearance. Papillary and cribriform areas may be present. The infiltrative/destructive pattern is characterized by irregular glands, nests, and single cells with malignant cytological features, often in a desmoplastic stroma. An infiltrative pattern, in particular in the setting of bilateral ovarian involvement, should raise suspicion for metastatic mucinous carcinoma and prompt evaluation for an extraovarian source)
Below: mucinous borderline tumour with intraepithelial carcinoma
Ovarian borderline mucinous tumour and carcinoma
IHC
diffusely positive for CK7 and variably positive for CK20, CEA, and CDX2 { 16931958 }. CA19-9 is often diffusely positive; CA125, WT1, napsin A, vimentin, ER, and PR are usually negative. PAX8, usually focal and weak, is positive in a subset of tumours { 31239549 }. p53 may show wildtype or mutation-type staining; p16 is usually negative or focally positive (non–block-type immunoreactivity) { 17460447 ; 30062862 }. Diffuse strong positivity for SATB2 can be seen in mucinous tumours associated with mature teratomas
Ovarian mass
dx
Common mutation
feature displaying
Mucinous carcinoma
KRAS
The tumour exhibits expansile/confluent growth (c.f destructive/infiltrative growth), with anastomosing/labyrinthine architecture and minimal to absent stroma.
Below: The tumour exhibits infiltrative/destructive growth, with irregularly shaped glands arranged haphazardly within altered stroma.
uterine lesion
dx
IHC
adenomatoid tumour
IHC (+): AE1/AE3, CK7, CAM5.2, calretinin, D2-D40, WT1
IHC (-): desmin, PAX8,
p16
What is it and when should you use this in terms of cervical dysplasia?
What is positivity?
Tumor suppressor protein encoded by CDKN2A gene (9p21.3)
Prevents progression into S phase of cell cycle
Inhibits cyclin D dependent protein kinases (CDK4 and CDK6) therefore maintaining Rb in its hypophosphorylated state which prevents its dissociation from E2F transcription factor
Protein expression often increased in aging cells, which eventually drives cell death and apoptosis (Exp Cell Res 1997;237:7)
Protein function is silenced or lost in many non HPV related tumors by epigenetic or genetic abnormalities, including promoter CpG methylation or less commonly by mutations
Immunohistochemical positivity commonly considered a surrogate marker for oncogenic HPV infection
Inactivation of Rb by the viral E7 oncoprotein following viral integration into host genome leads to overexpression of p16 p16 immunohistochemistry is not recommended as a routine adjunct assessment when the biopsy interpretation is negative, CIN I or CIN III. Strong and diffuse block staining for p16 supports a categorization of precancerous disease. Any identified p16 positive area must meet H&E morphologic criteria for a high grade lesion to reinterpreted as such. Positive staining is defined as "block" staining: strong nuclear and cytoplasmic expression in a continuous segment of cells (at least 10 - 20 cells)
ovarian mass
corpus luteum cyst
HSIL (VIN), HPV-associated vs dedifferentiated VIN
p53 staining
53 immunostaining usually shows a wildtype pattern, but accentuated p53 staining may be seen { 29254796 }. If p53 expression is increased, it typically spares the basal layer, with the strong expression confined to suprabasal cells, in contrast with the basal staining seen in differentiated VIN.
vulval lesion
dx
Key histological features
Associated conditions
IHC
VIN-HPV independent (aka deVIN)
Characterized by atypia of the basal and parabasal keratinocytes in an otherwise well-differentiated epithelium. The epidermis shows parakeratosis and can be atrophic or acanthotic with elongated and anastomosing rete ridges. Abrupt abnormal keratinization in the form of abortive keratin pearls, or dyskeratosis, is a characteristic feature. The atypical cells are enlarged and eosinophilic, with large vesicular nuclei, macronucleoli, and prominent intercellular bridges. Basal hyperchromasia and atypical mitoses are frequent. Extension into skin appendages is rare (c.f. VIN-HPV associated).
lichen sclerosus or lichen planus
IHC:
Desirable: p16 negativity; abnormal p53 immunostaining.
Below: Differentiated VIN with unusual features. Abnormal p53 staining characterized by nuclear positivity and overexpression in the basal layer with prominent suprabasal extensio (can also have null staining).
vulval lesion
dx?
IHC:
VIN, HPV-independent
p16 and p53
p53
describe aberrant patterns of staining in serous carcinoma
What is p16?
How does it become over-expressed in HPV related lesions
Cyclin dependent kinase inhibitor strongly expressed ruing infection of intermediate-higih risk HPV types
HPV blocks Rb (by viral protein E7) which causes a bulid-up of p16 nin HPV associated tumours. However if Rb is just mutated (not “blocked”) this could cause p16 to increase and lead to overexpression by IHC
endometrial adenocarcinoma
describe the molecular classificaiton
Pole ultra-mutated
MSI hypermutated
copy number low
copy number high
Hysterectomy for prolapse
section from tube
Dx?
Salpingitis isthmica nodosa (i.e. adenomyosis of the Fallopian tubes)
Glands lined by normal tubual epithelium and completely surrounded by smooth muscle
fallopian tube
Dx?
Salpingitis isthmica nodosa
Ovarian mass, 20F
dx
IHC
Genetic assocations
Dx: Sertoli-Leydig cell tumour
IHC:
Sertoli cells: positive for sex cord markers sex cord markers α-inhibin, calretinin, SF1, WT1, and FOXL2, also for pancytokeratin/vimentin.
Leydig cells: typically show either no or only minimal staining for FOXL2 and WT1, but they usually express α-inhibin and melan-A.
Dicer 1 syndrome
35F incidental finding cervix
Dx?
IHC?
Dx: mesonephric rests/(mesonephric hyperplasia)
Hyperplasia of mesonephric ducts is characterized by a glandular population similar to mesonephric remnants but larger, more irregular and haphazardly distributed with increase in lobule size and extensive involvement of the cervix
Small round mesonephric tubules are often deep within cervical wall and extend to cervical surface. No back to back glandular crowding, no nuclear atypia, no angiolymphatic invasion, no perineural invasion
IHC:
(+) CD10, calretinin, GATA3
(-) p53, ER, CEA
below, Glandular lumen is usually filled with a dense eosinophilic PAS positive, diastase resistant material; mucinous or ciliated cells are not identified
IHC to differentiate HGSC, LGSC, endometrioid carcinoma, CCC, Mucinous carcinoma.
TCCG molecular subtypes of endometrioid carcinoma and typical features
ovarian mass.
Dx;
IHC:
Seromucinous borderline tumour
IHC: The epithelial cells are generally positive with PAX8, ER, and PR and usually WT1-negative; p53 exhibits wildtype immunoreactivity.
ovarian mass 70F
Dx:
IHC:
Borderline brenner tumour
IHC: (+) p63, GATA3, (-) ER/PR, WT1; p53 WT.
Describe there three main aetiologies of extramammary pages and how you’d sort them
- Most commonly, it is an intraepithelial adenocarcinoma, which is derived from a multi potential cell in the epidermis, adnexa, or anogenital mammary-like glands; 2. it may represent pagetoid extension or metastasis to the skin by a carcinoma nearby, such as a primary adenocarcinoma of the cervix or the Bartholin gland or a transitional cell carcinoma of the bladder or urethra; 3. it may become an invasive adenocarcinoma arising from intraepithelial adenocarcinoma.
bilateral ovarian masses, 35F
Dx:
Key features:
Syndromic associations
Sex cord tutor with annular tubules
Key features:
Variably size round nests of sharply delineated simple and complex tubules containing basement membrane-like material, which may also be present around the tubules
Sertoliform tubules are classified as annular by their arrangement as small concentric secondary ring shaped acini peripherally arranged around the circumference of a larger tubule
Tall cells with ample amount of pale cytoplasm and basally located round nuclei
Often with antipodal nuclear distribution within the tubules
Peutz-Jeghers syndrome
LMS - subtypes and diagnostic criteria
59F PMB, unilateral ovarian mass discovered incidentally on USS
Macro: well circumscribed.
DX:
Key features:
DDx:
Dx: thecoma
clinically: May present with estrogenic or androgenic manifestations
Key features:
cells showing ovoid to round nuclei and pale gray cytoplasm (c.f. fibroma cells which usually spindled)
syncytial appearance
minimal nuclear atypia
Hyaline plaques
Reticulin shows a pericellular pattern
Cytoplasmic lipid vacuoles may be present but are not essential
DDx:
Fibroma (spindled cells producing collagen; Occurs in ~25% of patients with nevoid basal cell carcinoma syndrome (Gorlin syndrome)
Granulosa cell tumour (reticulin stain shows nested pattern; harbors FOXL2 mutation)
Sclerosing stromal tumor
Pseudolobular growth pattern with cellular nodules separated by dense collagenous or edematous connective tissue (Cancer 1973;31:664)
Staghorn vessels
In below image, thecoma cells (left) merge with fibroma cells (right)
which syndrome should you think of in a young pt with bilateral ovarian fibromas?
Occurs in ~25% of patients with nevoid basal cell carcinoma syndrome (Gorlin syndrome)
features of leydig cell tumor
Benign steroid cell tumor composed of polygonal cells with abundant eosinophilic cytoplasm and Reinke crystals
33F hysterectomy for menorrhagia. Cx
Dx?
Mesonephric hyperplasia.
Mesonephric duct remnants appear as groups of round glands and tubules, lined by simple flat to low cuboidal epithelium.
IHC mucinous carcinoma of the ovary.
CK7+; v+ for CK20/CEA/CDX2. CA19-9 is often diffusely positive; CA125, WT1, napisn A, vimentin, ER and PR are usu negative.
PAX8 usually focally weak.
NB: diffuse strong + for SATB2 can be seen in mucinous tumours a/w mature teratomas.
ovaries
Familial ovarian cancer syndromes
Hereditary breast and ovarian cancer syndrome and lynch syndrome
Germline mutations in BRCA1 or BRCA2, which encode proteins involved in high-fidelity repair of double-strand DNA breaks, accoutn for 95% of cases of HBOCS, and these pts have an estimated 45% lifetime risk of developing ovarian carcinoma….with the risk being hihgher in patietns with BRCA1 mutationsthan those iwht BRCA2 mutations. In HBOCS, patients are at increased risk of developing HGSC but not at significantly increased risk of developing other histotypes of ovarian carcinoma, borderline tumors, germ fcell tumors or sex-cord-stromal tumors. Of patietns newly diagnosed with HGSC, 15-20% will have a germline BRCA1 or BRCA2 mutation.
LS a/w 8-10% lifetime risk of developing ovarian carcinoma, and the carcinomas that arise in patients with Lynch syndrome are of those histotypes associated with endometriosisi (I.e. endoemtrioid and clear cell).
essential dx features low grade stromal sarcoma and helpful IHC
proliferative-phase endometrial stromal-type tumour cells permeating the myometrium, with or without LVSI.
IHC: CD10 (diffuse expression), ER/PR+; focal + for cyclin D1.
Tumours may be positiv for wide-spectrum keratins.
grading immature teratoma
graded based on the no. of LPF containing aggregated amounts of immature neuroepithelium in any one slide.
molecular alterations HG vs LG stromal sarcoma
HG: Tumours harbour YWHAE-NUTM2A/B fusions, ZC3H7B-BCOR fusions , or BCOR ITD.
LG: JAZF1-SUZ12 being most common
molecular classification of endometrioid carcinoma + features
