Patozone

Anatomy and histology

Grossing

Arias-Stella Reaction

Atrophy

Basal cell hyperplasia

Hyper- / para-keratosis

Endometriosis

Herpes Simplex Virus (HSV)- cervicitis

Metaplasia

Diffuse Laminar Endocervical Glandular Hyperplasia

Lobular Endocervical Glandular Hyperplasia

Microglandular hyperplasia

Radiation-induced atypia

Reactive / Reparative Squamous Atypia

Endocervical polyps

Endometrial hyperplasia

Endocervicosis

Epithelioid Trophoblastic Tumor

Mesonephric hyperplasia

Nabothian cyst

Placental site nodule

Tunnel clusters

Rhabdomyosarcoma

• Sarcoma botryoides

Squamous Intraepithelial Lesions (SIL)

Superficially Invasive Squamous Carcinoma

Squamous cell carcinoma

Adenosquamous carcinoma

Adenocarcinoma In Situ (AIS)

Superficially Invasive Adenocarcinoma

Invasive Adenocarcinoma

Basaloid Squamous Carcinoma

Lymphoepithelioma-Like Carcinoma

Neuroendocrine carcinoma

Papillary Squamous Cell Carcinoma

Spindle Cell (sarcomatoid) carcinoma

Transitional Cell Carcinoma

Verrucous Carcinoma

Arias-Stella Reaction

Found in up to 2/5 pregnancies, or in pts on OCPs or idiopathic

- affects superficial or deep glands and can be local or diffuse

- usually a focal finding, when seen in curetting is assoc c intrauterine and ectopic gestations

Micro: big cells that can look red or c big vacuoles or hobnailed, irreg nuclei sometimes hyperchromatic

- can form papillary tufts or cribriform

- low mits, rare pseudoinclusions in nucleus, occasional decidualization of stroma

- can mimic AIS or clear cell ca

Atrophy

Altered squamous maturation 2/2 hormonal deficiency (menopause or prepuberty)

Micro: can produce several patterns:

Typical: thin epithelium c lack of maturation c uniform basal and parabasal cells and inc NC, dense chromatin, no /  rare mits, little-mild pleomorphism

Atrophy with partial maturation: cytoplasmic glycogen and large evenly spaced nuclei and scattered mits

Pseudokoilocytosis (aka postmenopausal squamous atypia) hyperchromatic nuclei c even chromatin, binucleation, and cytoplasmic halos c more uniform size and shape than HPV

IHC: Ki67 <20% in basal 1/3, <5% in middle 1/3 and absent in superficial cells (vs in SIL)

- negative: p16 (vs SIL)

Follicular cervicitis

Assoc c chlamydia infx

- see tingible body macrophages in lymph nodes

Tubal Metaplasia

Replacement of endocervical epithelium c epithelium of salpinges (somewhat unordered secretory, ciliated or peg cells) involving glands and surface epithelium, which may branch with hypercellularity of surrounding stroma

- low mits (vs endocervical AIS)

- may produce mucous grossly

- DES related?

- beware of tubal variant of adenocarcinoma in situ, which is ciliated

IHC: (+) p16 (can be problematic in the workup of glandular lesions in the cervix)

DDx: endocervical AIS

Microglandular hyperplasia

common, mostly in women of reproductive age (assoc c progesterone [OCPs and preg]), and up to 1/20 postmenopausal

- can grossly look like an erosion, polyp or friable raised area on the cervix

- may favor adenocarcinoma if large amt of tissue in bx (ie 3 blocks), lack of subnucleolar vacuoles, transition to other forms of endometrial adenoca, assoc c foamy stromal cells and + vimentin in cytoplasm

Micro: closely packed glands c variable shape and size c acute and chronic inflam c little intervening stroma, giving it a cribriform appearance

- epithelial lining is cuboidal to columnar c uniform nuclei c focal atypia, rare mits and produces mucin pools, possibly signet rings

- no nucleoli, can have different degrees of sq metaplasia

IHC: (+) p63 in reserve cell component, mucin

- neg: cytoplasmic vimentin (vs adenoca), p16 (though can be strongly but patchy positive, in which case doesn't co-localize MIB or cyclin E and not assoc c HPV infx), CD10

- CEA not helpful (neg in adenoca and microglandular hyperplasia)

Endocerical Polyps

Common b9 exophytic growths that arise in endocervical canal

- can be bumps or large polypoid masses that can protrude through cervical os

Micro: loose fibromyxoid stroma covered c mucous secreting endocervical cells

- usually assoc c inflam

Epithelioid Trophoblastic Tumor (ETT)

- malignant gestational trophoblastic neoplasm (GTN) derived from the chorionic-type intermediate trophoblast

- rarest trophoblastic neoplasm, ETT typically occurs in reproductive-age females (mean age: 30 to 40 years) following term pregnancy, spontaneous abortion, or hydatidiform molar gestation.

-- The latency period between a gestational event and the development of ETT can range from months to years.

ETT frequently develops in the lower uterine segment or cervix (approximately 50% of cases)

- serum beta-hCG is usually mildly to moderately elevated (less than 2500 mIU/mL).

Micro:  nodular growth of epithelioid cells with abundant eosinophilic cytoplasm and round nuclei with mild to moderate atypia.

-- see geographic necrosis, hyaline material surrounding neoplastic cells, and calcifications

IHC:  (+) GATA3, alpha-inhibin, and p63,

- negative SALL4, ER, TTF1, p16, and PAX8

Px:  Most cases of ETT are confined to the uterus and treated adequately with hysterectomy alone,

- up to 30% of cases develop metastases.

- FIGO stage remains the best predictor of outcome.

- lung is the most common metastatic site for ETT

DDX: Squamous cell carcinoma- Immunohistochemically, SCC should lack expression for HLA-G and H3D3B1, though it can stain positively for GATA3 and p63 which is a diagnostic pitfall. Some data support the use of CK18 (positive in ETT, negative in SCC). Most cervical SCC is HPV-driven, so diffuse p16 positivity would support the diagnosis of SCC of the cervix over ETT in the appropriate clinical context.

- Placental site stromal tumor: PSTT demonstrates a more infiltrative growth pattern, lacks the characteristic hyaline material of ETT, and is diffusely positive for hPL

Nabothian cyst

Normal finding caused by obstruction of crypt opening by squamous epithelium thus dilating endocervical glands

- usually superificial but can go deep

- can cause acute/chronic cervicitis

Micro: uniform architecture, no stratification, mits, or atypia

- can cause reactive changes if rupture

Tunnel clusters

Common, b9, incidental, assoc c multiple prior pregnancies, close to endocervical canal

- caused by localized prolif of endocervical glands c side channels growing out through them

Type A (non-cystic): well-circumscribed, pseudoinfiltrative, oval to pointed gland lumens, smaller cuboidal amphophilic or mucinous columnar, c big nuclei c mild nuclear atypia, florid glandular hyperplasia, and big nucleoli, minimal mits

- assoc c type B

Type B (cystic): larger glands c cystic dilation arranged in lobules, lined by bland flat to cuboidal cells c no mits

Micro: looks b9 c minimal atypia

IHC: (+)

- negative intracytoplasmic CEA

Squamous Intraepithalial Lesions (SIL)

2-tiered HPV-assoc SIL system based on LAST-project by CAP-ASCCP, which can then be broken down into more specific lesions

Risk factors: young at first intercourse, multiple sexual partners, cigarette smoking, immunocompromised, poor hygiene,

- HPV 6, 11, (low risk)

- HPV 16, 18, 31, 33, 35 (high risk)

- HPV vaccine available up to nonavalent (has 9 MC stands), and is approved for females from 9-26 yo

Low-Grade SIL (LGSIL or LSIL)

Has cytopathic HPV effect and mild-moderate cellular changes in the lower 1/3 of squamous epithelium

- assoc c HPV 6 and 11

- koilocytes formation assoc c viral E4 expression

-- productive infection (early and late gene expression) with non-integration of viral DNA

- early onset of juvenile respiratory papillomatosis

- ~3/5 regress, only ~1/1000 progress to carcinoma

Micro: koilocytes have marked nuclear variation (>3x variation), hyperchromasia, and irregular nuclear membranes ("raisinoid")

- cytoplasmic clearing is non-specific (can be reactive)

- basal layer loses its picket-fence pattern

IHC: 1/3 of LSIL are block p16+

High-Grade SIL (HGSIL or HSIL)

Includes CIN2+3

- CIN2 has mod-marked atypia in bottom 2/3 of squamous epithelium

- CIN3 has moderate-marked atypia in full thickness of the epithelium

- transforming infx c high-risk HPV types in high-grade intraepithelial lesions produce inc levels of E6 which binds p53 and E7 viral oncoprotein which binds and inactivates Rb causing upregulation of p16 by disruption of the negative-feedback loop

- integration of viral DNA

-- must be careful bc 2% of all b9 cases and 38% of low-grade lesions have shown positivity, and also up to 28% of high-grade lesions have been shown to be p16 negative

- p16 positivity in LG lesions may predict transformations to a HG lesions

Thin SIL [2] (historically called thin dysplasia):

Morphologically, these are immature intraepithelial lesions less than 10 cells thick. If a lesion is unequivocally SIL with significant immature abnormal basal proliferation or mitosis above the basal cells, it is designated as HSIL. If there is doubt about the nature of the proliferation (e.g., immature metaplasia versus SIL) then p16 staining can be used

Dysplasia extending into the endocervical glands (Gland-duct involvement??) [2]:

In general, grading of lesions extending into the

endocervical glands can be performed as with surface lesions. If the abnormal basal proliferation fills the gland with no or minimal evidence of maturation, this should be classified as high grade. However, it is important to be aware of the possibility of tangential sectioning of epithelial basal layers that may make accurate grading difficult or impossible.

IHC: (+) Ki67 in upper epithelial layers (although Ki67 can be expressed in the upper epithelial layers of LG lesions, and so should not be used to differentiate bwt the two)

- p16 (can be negative in low-risk HPV types but should be strongly positive in high-risk HPV types)

- p16 can help ddx bwt LSIL and HSIL

-- HSIL has strong diffuse block staining

- despite this, 1/3 of LSIL has p16 block positivity, and rare HSILs may not have block positivity (up to 30% are p16 negative)

ProExC, made of topoisomerase IIa (TOP2A) and Minichromosome Maintenance Protein 2 (MCM2) stains HG lesions and has reported 90% sensitivity and 79% PPV for HSIL

BIOMARKERS IN HPV-ASSOCIATED LOWER ANOGENITAL SQUAMOUS LESIONS [2]

1. p16 IHC is recommended when the H&E morphologic differential diagnosis is between precancer (–IN 2 or –IN 3) and a mimic of precancer (e.g., processes known to be not related to neoplastic risk such as immature squamous metaplasia, atrophy, reparative epithelial changes, tangential cutting).

2. If the pathologist is entertaining an H&E morphologic interpretation of –IN 2 (under the old terminology, which is a biologically equivocal lesion falling between the morphologic changes of HPV infection [low-grade lesion] and precancer), p16 IHC is recommended to help clarify the situation. Strong and diffuse block-positive p16 results support a categorization of precancer. Negative or non–block-positive staining strongly favors an interpretation of

low-grade disease or a non–HPV-associated pathology

3. p16 is recommended for use as an adjudication tool for cases in which there is a professional disagreement in histologic specimen interpretation, with the caveat that the differential diagnosis includes a precancerous lesion (–IN 2 or –IN 3).

4. WG4 recommends against the use of p16 IHC as a routine adjunct to histologic assessment of biopsy specimens with morphologic interpretations of negative, –IN 1, and –IN 3.

a. SPECIAL CIRCUMSTANCE: p16 IHC is recommended as an adjunct to morphologic assessment for biopsy specimens interpreted as

<=–IN 1 that are at high risk for missed high-grade disease, which is defined as a prior cytologic interpretation of HSIL, ASC-H, ASC-US/HPV-16þ, or AGC (NOS).

Pseudo-GDI? Cervical LSIL (CIN 1). Low-grade squamous intraepithelial lesion extends into an endocervical gland neck. When the full thickness of the abnormal epithelium is seen, the interpretation is straightforward. In areas with tangential sectioning (arrow), care must be taken not to overcall HSIL. Medium power, H&E [2]

Superficially Invasive Squamous Carcinoma

- aka Microinvasive squamous carcinoma

Defined as invasive carcinoma that [2]:

- is no a grossly visible lesion, AND

- Has an invasive depth of <3 mm from the basement membrane and the point of origin, AND

- Has a horizontal spread of <7 mm in maximal extent, AND

- Has been completely excised

Tongues of SCC breaking through the BM

- usually are better differentiated than in HSIL

- can be mimicked by inflam blurring the epithelial-stromal interface and tangentially cut endocervical glands, crushed epithelium and placental site nodules

- retraction artifact can be difficult to ddx from vascular invasion

Can be staged based on SGO or FIGO systems

- SGO: stromal invasion <3 mm below BM and doesn't invade blood vessels or lymph vessels

- FIGO: stage 1A: microscopic invasion; stage 1A1: invades <3 mm deep and <7 mm horizontally; stage IA2: invades >3 mm, < 5 mm deep and < 7 mm horizontally

- measured from the BM of HSIL to deepest invasive focus (should report depth of invasion in mm)

- in LEEPs or cold knife specimens also report # of foci, horizontal spread, presence / absence of vascular invasion, margin status

In cases of SISCCA, the following parameters should be included in the pathology report [1]:

- The presence or absence of LVI.

- The presence, number, and size of independent multifocal carcinomas (after excluding the possibility of a single carcinoma).

Micro: inc red cytoplasm, loss of nuclear polarity, sometimes keratin production

- usually present c florid HSIL in surface epithelium and deep endocervical glands, luminal necrosis in HSIL-involved glands, and aberrant intraepithelial squamous differentiation

- patterns of invasion: ragged/irreg cancer cell nests, epithelial reduplication, stromal epithelial nests, round tumor nests extending past glands, irreg nests c keratin production, stromal desmoplastic response, nests adjacent to medium-sized vessels

- can be graded by degree of differentiation as: intermediate > poorly > well

- can mimic clear cell ca c lots of glycogen

- worse px if contains mucin (confirm c IHC)

Small cell carcinoma

asdf

Stratified Mucin-Producing Intraepithelial lesion (SMILE)

carcinoma with cells that appear to by a hybrid of squames and mucinous columnars

SMILE IHC: Ki67 high, block p16, MUC+, neg IMP3 and CK14-

Adenocarcinoma in Situ (AIS)

Seen in rep age women (avg 30 yo)

- assoc c High Risk HPV, esp type 16 and 18

- many that present c AIS have cervical IN (CIN), or squamous intraepithelial neoplasia (SIN), or hx CIN/SIL

- seen close to SC junction, can be multifocal

- involvement of deep glands more obvious, but can involve superficial glands

Micro: cells crowded or stratified, large nuclei c dark coarse chromatin, little nucleoli, var stratification, inc (freq) mits; apoptotic bodies seen

- usually an abrupt transition from normal epithelium (clear demarcation of different glands)

- several subtypes: endocervical (MC), endometrioid, intestinal (gastric2), tubual, adenosquamous, clear cell

- calling something dysplastic glands not very good

- IHC: (+) p16 (strong, diffuse), Ki67 (>30%),

-- negative: nuclear PAX2 (loss of expression), ER/PR

- HPV ISH helps to show is HPV-driven process

DDx: Benign endometrial epithelium (reactive changes, tuboendometrial metaplasia, proliferative endometrial epithelium, endometrium / cervical endometriosis) are usually p16 neg although can have patchy p16 immunoreactivity (not diffuse tho)

- Paired box 2 (PAX2) has diffuse positivity in b9 cervical tissue (including tubal metaplasia, lobular endocervical glandular hyperplasia, and b9 mesonephric proliferations)

- b9 conditions have low Ki67

- ER and vimentin show diffuse positivity in endometrial epithelium and CD10 highlights endometrial stroma

NOTE: mesonephric AC and gastric-type AC are NOT assoc c high-risk HPV and therefore lack p16 immunoreactivity in most cases

- mesonephric AC usually positie for CD10, PAX8, vimentin and CEA, and can rarely have diffuse p16+

Clear cell AIS

cuboid, polygonal or flat cells c clear to red cytoplasm, big nuclei, inc mits

Endocervical AIS

moderate cytoplasm c dec mucin (vs normal endometrial gland)

Endometrioid AIS

no mucin, lots of pseudostritification, big nuclei, inc mits

Intestinal AIS

has goblet cells c large round cytoplasmic vacuole

Adenoma Malignum

- aka minimal deviation adenocarcinoma

- Assoc c Peutz-Jeghers syndrome (~1/20)

- well-differentiated form of cervical AC with gastric differentiation (?) [1]

- non-HPV related subtype of cervical AC

Grossly has friable mucosa or mass

Micro: pleomorphic neoplastic glands are lined by mucin-producing, columnar cells with basally located nuclei. - glands are variable in shape and size and sometimes surrounded by desmoplastic response

- sometimes vascular / lymph invasion

- rare mits, no HPV assoc

- IHC: (+) CEA, p53

-- neg: PAX2 (loss of expression)

Glassy Cell Carcinoma

Poorly diff variant of adenosquamous carcinoma in younger females that grows fast and is more aggressive

Grossly has a barrel-shaped uterus (which is elongated and thickened

- Micro: nests/sheets of big cells c big nucleoli and lots o mits. ground glass cytoplasm, lots of inflam c eos and plasma cells

- IHC: (+) p53, 34BE12, CAM5.2, MUC1/2. CEA, var ER/PR and Her2

- should r/o poorly diff sqca and lymepi-like ca