Cervix

Question 1

Follicular Cervicitis

Answer 1

• Caused by Chlamydia Trachomatis
• Treat with doxycycline

Risk factors:
* Sexually active
* OCP use
* Pregnancy

Micro:
* Lymphoid germinal centres in sub mucosa
* Plasma cells
* Reactive epithelial atypia

Question 2

Endocervical Polyp

Answer 2

• Usually multigravidas in 4th to 6th decades
• Usually incidental findings
• Can present with vaginal bleeding

Macro:
* Rounded/elongated
* Smooth/lobulated surface
* Most commonly single
* Can measure from millimeters to a few centimeters

Micro:
* Varying amounts of squamous oit endocervical epithelium
* Depends on proximity to cervical os.
* Stroma consists of fibroconnective tissue
* Thin and thick walled vessels

Question 3

Microglandular hyperplasia

Answer 3

• Benign non-neoplastic endocervical glandular proliferation

Clinical:
* Incidental finding
* Women of reproductive age
* Associated with OCP, pregnancy and postpartum condition

Macro:
* polypoid lesions
* single or multiple

Micro:
* Crowded glands
* Variable amount of mucin
* Focal squamous metaplasia
* Signet ring cells may be present
* Neurophils are commonly present in the glandular lumina
* Stoma separating glands shows acute and chronic inflammatory cells

IHC:
* CEA generally negative
* Mucin +ve

Question 4

Tunnel Clusters

Answer 4

• Incidental finding
• Lobular aggregates of benign endocervical glands in cervical wall

Two Types:
Type A
* Small noncystic glands
* May show gastric metaplasia in up to 15% of cases

Type B
* Cystically dilated glands

• No risk of recurrence or malignant transformation

IHC:
* PAX2+
* Alcian blue/PAS +ve in Type A if gastric metaplasia present
* CEA focal or -ve

Question 5

Mesonephric remnants/hyperplasia

Answer 5

• Embryonic remnants of mesonephric ducts
• Usually incidental
• Typically in lateral cervical wall

Micro:
* Small tubules lined by low columnar to cuboidal cells without cillia
* Surrounded by prominent smooth muscle
* Oesinophilic material in lumens in characteristic

IHC:
* CD10+ (Luminal, patchy)
* Calretinin+
* GATA3+

• CEA -ve
• ER/PR -ve
• P16 -ve

Question 6

Lobular Endocervical Glandular Hyperplasia (LEGH)

Answer 6

• Benign condition
• Metaplastic process
• NOT related to high risk HPV
• Typically –> upper endocervix and inner half of cervical wall.

Molecular:
* Can be associated with Peutz-Jeghers Syndrome
* Germline STK11/LKB1 mutations

Micro:
* Well demarcated lesion
* Lobular/Acinar architecture
* Composed of central crypt, sometimes with cystic dilation
* Surrounded by smaller, round shaped glands and cysts arranged in a floret-like pattern
* Lined by columnar cells with basal nuclei
* Mild nuclear atypia

IHC:
* CEA -ve
* ER and PR -ve

Question 7

Diffuse Laminar Endocervical Hyperplasia

Answer 7

• AKA nonspecific hyperplasia
• Usually incidental finding

Micro:
* Diffuse proliferation of medium sized, closely packed glands
* Well differentiated, mucious glands
* Inner third of cervical wall
* Sharply demarcated
* Basal nuclei
* Chronic inflammation
* Stromal oedema
* No significant cytological atypia

IHC:
* CEA -ve

Question 8

Low Grade Squamous Intraepithelial Lesion (LSIL)/CIN1

Answer 8

Includes:
* Flat, low grade squamous intraepithelial lesion/CIN 1
* Exophytic/Papillary LSIL (condyloma)

Cause:
* Low grade –> HPV 6, 11 (low risk), HPV 16, 18 (high risk)
* Koilocytes in upper layers are characteristic
* Majority of LSIL regress spontaneously

Question 9

High Grade Squamous Intraepithelial Lesion (LSIL)/CIN 2 and 3

Answer 9

• High risk HPV driven pre-cancerous lesion
• HPV 16 is most common
• Also HPV 18

Micro:
CIN 2:
* Superficial cytoplasmic maturation in the upper third of mucosa
* High rate of regression

CIN 3:
* Marked, full-thickness atypia
* Increased mitotic activity and atypical mitoses
* Highest risk of progression to SCC

Treatment:
Surgical excision –> unless pregnant or CIN 2 in <25yo

Staining:

p16 IHC
* Good surrogate test fot HPV in anogenital carcinomas/pre-malignant lesions.
* Positive p16 –> strong continuous nuclear and cytoplasmic staining
* Negative p16 –> cytoplasmic only staining

HPV ISH
* High specificity
* Relatively low sensitivity compared to p16 IHC

Question 10

LAST Project

Answer 10

• Lower Anogenital Squamous Terminology

Recommendations for p16 IHC:
* To distinguish HSIL from mimickers –> atrophy, Immature metaplasia
* Morphological CIN 1 vs 2
* Professional disagreement on diagnosis when HSIL is in consideration
* Biopsies showing LSIL or lesser in patients at high risk for missed HSIL based on prior pap or HPV testing

Warning:
* HPV independant p16 overexpression seen in ovarian and uterine serous carcinomas

Question 11

Adenocarcinoma in situ

Answer 11

• AKA High grade cervical glandular intraepithelial neoplasia (HG-CGIN)
• Precursor for invasive endocervical adenocarcinoma.
• Associated with high risk HPV
• Seen in 3rd or 4th decade

Micro:
* Normal glandular architecture is preserved
* High N:C ratio
* Mitotic activity and apoptotic bodies

IHC:
* p16+
* CEA+
* Mucin+

Question 12

Types of cervix Ca

Answer 12

SCC
75-80%
HPV-associated

Adenocarcinoma
20-25%

• HPV associated (90%)
  -Usual type endocervical adenocarcinoma
  -Intestinal type
  -Signet ring cell type
  -Villoglandular carcinoma
• Non-HPV associated (10%)
  -Gastric type endocervical adenocarcinoma
  -Clear cell carcinoma
  -Mesonephric carcinoma

Question 13

Squamous Cell Carcinoma of Cervix

Answer 13

Can be microinvasive or invasive

Risk Factors:
* HPV
* HIV
* Smoking
* Younger age at first sexual intercourse
* Greater number of sexual partners
* OCP >5yrs
* 4+ full term pregnancies
* STIs

Macro:
* Microinvasive: Red papule, White plaque or irregular ulcerated lesion
* Invasive: Exophytic papillary mass or endophytic ulcer. Usually solitary

Micro:
* Usually associated with high grade dysplasia or CIS
* Full-thickness involvement of epithelium or cervical glands
* Pleomorphic, high N:C ratio and mitotic activity
* Variable degree of squamous differentiation including keratin pearls

Microinvasive:
* Tumour depth <3mm
* Measured from basal layer of overlying surface epithelium to deepest invasion by tumour
* If invasion present only adjacent to an involved gland –> measure from top of gland to deepest invasion.

Invasive:
* Greater than 3mm in depth of invasion
* Generally greater than 7mm in diameter

Types:
* Keratinising
* Non-Keratinising
* Basaloid
* Verrucous
* Warty
* Papillary
* Lymphoepithelioma-like carcinoma

IHC:
* p16
* Cytokeratin and p63 positive
* CEA focally positive
* Mucin negative

Question 14

Endocervical Carcinoma

Answer 14

HPV-Associated:

• 80% of cases
• Younger patients (4th decade)
• Smaller tumour, Lower stage, Negative margins
• Better prognosis

Mutations:
* PIK3CA
* KRAS

Micro:
* Floating mitotic figures/apoptotic bodies visible on scanning magnification.
* Silva pattern relevant for prediciting LN involvement
* Positive for p16 and HPV ISH

Non-HPV-Associated:

• 20% of cases
• Older patients (5th decade or higher)
• Larger tumour size, Higher stage, Propensity for positive margins
• Poor prognosis

Mutations:
* TP53
* KRAS
* ERBB2
* STK11

Micro:
* Lack of floating mitotic figures/apoptotic bodies visible on scanning magnification.
* Silva pattern NOT relevant
* Usually negative for p16 and HPV ISH

• Referral to hereditary cancer program for suspected Peutz-Jegher Syndrome

Question 15

Gastric type adenocarcinoma

Answer 15

• Non-HPV
• Negative for p16
• Gastric type differentiation
• Clear to eosinophilic cytoplasm
• Nuclear atypia
• Atypical glands extend below the normal level expected for benign endocervical glands
• Grading is not recommended –> even well-differentiated tumours behave aggressively
• worse prognosis

Minimal Deviation Adenocarcinoma:

• A well-differentiated gastric type adenocarcinoma.
• Ususally sporadic
• Can be associated with Peutz-Jeghers –> Germline STK11 mutation

Micro:

• Diagnosis made on the basis of abnormal location of these glands –> deep in the wall of the cervix (>5mm)
• Increased number of glands at the surface
• Stomal desmoplasia may be present
• Tumour cells have tall apical mucin
• May have foamy cytoplasm
• Basally located nuclei
• Variable mitotic activity
• May have intestinal differentiation –> Goblet cells, paneth0like neuroendocrine cells

IHC:
* p16 negative
* p53 aberrant/mutant –> diffuse or completely absent
* CEA/mCEA –> Diffuse or focal
* CK7 +
* PAX8 +

Question 16

Clear Cell Carcinoma

Answer 16

• Not associated with high-risk HPV

Micro:
* Micture of tubulocystic, papillary and/or solid architecture.
* Clear/eosinophillic flat or cuboidal cells

Clinical:
Arise in two distinct settings:

1) Sporadic tumours in the endocervix
2) Tumours arising in association with in utero dithystilbestrol (DES) exposure

Question 17

Mesonephric Adenocarcinoma

Answer 17

• Rare
• Non-HPV associated
• Derives from Mesonephric/Wolffian remnants

Micro:
* Variety of morphological patterns
* Mucin-free cuboidal epithelium
* Elevated mitotic activity

Molecular:
* KRAS mutations

IHC:
* GATA3 +ve
* CD10 (luminal) +ve
* PAX8 +ve
* P16 -ve
* ER -ve

Question 18

FIGO Staging (2018)

Answer 18

I: Confined to the cervix
IA1: stomal invasion <3.0mm
IA2: stromal invasion >3.0 but <5.0mm
IB1: <2cm
1B2: >2cm but <4cm
IB3: >4cm

II: Extension beyond the uterus but not to the pelvic wall or to the lower third of the vagina

IIA: Limited to the upper 2/3 of the vagina without parametrial involvement

IIA1: Lesion ≤ 4 cm in largest dimension
IIA2: Lesion > 4 cm in largest dimension

IIB: Parametrial involvement but not up to the pelvic wall

III: Extension to the pelvic wall and/or involves the lower third of the vagina and/or causes hydronephrosis or a nonfunctioning kidney and/or involves pelvic and/or para-aortic lymph nodes

IIIA: Extension to lower third of the vagina but not to the pelvic wall

IIIB: Extension to the pelvic wall and/or causes hydronephrosis or a nonfunctioning kidney (unless known to be due to another cause)

IIIC: Involves pelvic and/or para-aortic lymph nodes, regardless of tumor size and extent

IIIC1: Only metastasis to pelvic lymph nodes

IIIC2: Metastasis to para-aortic lymph nodes

IV: Extension beyond the true pelvis or biopsy-proven involvement of the bladder or rectal mucosa

IVA: Spread to adjacent pelvic organs

IVB: Spread to distant organs

FIGO IA1 –> local excision
FIGO IA2 and IB –> radical trachelectomy or hysterectomy

• Involvement of vascular/lymphatic spaces should not change the staging
• Omental mets and inguinal lymph nodes indicate distant spread —> staged as IVB