Uterine cervix

The uterine cervix, also simply cervix, is the gateway to the uterine corpus. It is not infrequently afflicted by cancer -- squamous cell carcinoma. Prior to routine Pap tests it was a leading cause of cancer death in women in the Western world.

Polyps associated with the cervix are discussed the cervical polyp article.

Cytopathology of the uterine cervix is dealt with in the gynecologic cytopathology article.

Introduction

Overview

• Most cervix cancer is squamous cell carcinoma.
  • An effective screening test to detect this is the Pap test, which is dealt with in the gynecologic cytopathology article.
• The work-up of a suspicious Pap test is a colposcopic examination and biopsies, which are the topic of this article.

Indications for coloposcopic exam (based on the ASCCP Consensus Guidelines of 2001):

• High-grade squamous intraepithelial lesion (HSIL).
• Repeated low-grade squamous intraepithelial lesion (LSIL).
• Atypical squamous cells of undetermined significance (ASCUS) and a positive HPV test.
• ASC-H.
• Atypical glandular cells (AGC) not otherwise specified.
• Adenocarcinoma in situ (AIS).

Colposcopic examination

• Performed by gynecologists.
• Exam usually includes a search for acetowhite epithelium (AWE); this is accomplished by the application of acetic acid (to help identify lesions for biopsy).
  • Neoplastic cervical lesions are typically white.
  • Squamous metaplasia is also white.
• Cervical ectropian (AKA cervical eversion, AKA ectropian) = endocervical epithelium at external os, considered benign, grossly has a granulation tissue-like appearance.

Cervical specimens

Cytology

• Pap test - see gynecologic cytopathology.

Biopsies

The types of biopsies that are done are:

1. Cervical biopsies - prompted by abnormal Pap test, e.g. HSIL, to look for squamous cell carcinoma of the uterine cervix.
2. Endocervical curettage (ECC) - to work-up columnar dysplasia, e.g. endocervical adenocarcinoma/endometrial adenocarcinoma.

Surgical specimens

1. Loop electrosurgical excision procedure (LEEP).
   • AKA large loop excision of the transformation zone (LLETZ).
2. Radical trachelectomy - removal of the uterine cervix and parametria, preserves fertility.
3. Radical hysterectomy - advanced cervical carcinoma (Stage IA2 and Stage IB1), recurrent carcinoma.

Other

• Total abdominal hysterectomy - for non-cervical pathology, e.g. uterine leiomyomas, uterine adenomyosis.
• Radical hysterectomy - for endometrial carcinoma with endocervical involvement.

Normal histology

Features:

• The uterine cervix consists of non-keratinized squamous epithelium and simple columnar epithelium.
• The area of overlap (between squamous & columnar) is known as the "transformation zone".
  • Also known as "transition zone".

Notes:

• Considered from the perspective of histology:
  • The squamous component is referred to as the exocervix (or ectocervix).
  • The simple columnar (or glandular) component is referred to as the endocervix.

Images:

• Normal cervix (proteinatlas.org).

Negative LEEP

Main article: LEEP

Transformation zone - biopsy

Microscopic

Features:

• Small round cells.
• Usually no halos.
  • May be seen in pseudokoilocytes.
• No nuclear membrane irregularities.
• No nuclear hyperchromasia.

Images

• 

  NILM with pseudokoilocytes - intermed. mag. (WC)

• 

  NILM with pseudokoilocytes - high mag. (WC)

• 

  NILM with pseudokoilocytes - very high mag. (WC)

• 

  Benign stripped exocervix - high mag. (WC)

www:

• Normal cervix (flickr.com/euthman).
• CIN I versus normal (flickr.com/euthman).

Sign out

UTERINE CERVIX, BIOPSY: 
- TRANSFORMATION ZONE WITHOUT APPARENT PATHOLOGY.
- NEGATIVE FOR DYSPLASIA.

UTERINE CERVIX, BIOPSY:
- SQUAMOUS MUCOSA WITHOUT APPARENT PATHOLOGY.
- STRIPPED ENDOCERVICAL EPITHELIUM WITHOUT APPARENT PATHOLOGY.
- NEGATIVE FOR DYSPLASIA.

Endocervical glands

Microscopic

Features: Cervical glands normally have round nuclei and vaguely resemble the colonic mucosa.

Notes:

• If the nuclei are columnar think cancer! This is like in the colon-- columnar nuclei = badness.
  • Memory device: The Cs (Cervix & Colon) are similar.
• Endocervical epithelium (ECE) has a morphology similar to the epithelium of secretory phase endometrium (SPE):
  • ECE - grey foamy appearing cytoplasm.
  • SPE - eosinophilic cytoplasm.
    • Most useful feature to differentiate ECE and SPE is the accompanying stroma.

Sign out

UTERINE ENDOCERVIX, CURETTAGE: 
- ENDOCERVICAL MUCOSA AND STRIPPED ENDOCERVICAL EPITHELIUM WITHIN NORMAL LIMITS. 

Inflamed with squamous epithelium

UTERINE ENDOCERVIX, CURETTAGE:
- BENIGN STRIPPED ENDOCERVICAL EPITHELIUM AND SCANT INFLAMED ENDOCERVICAL MUCOSA.
- VERY SCANT SUPERFICIAL SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.

Squamous epithelium present

UTERINE ENDOCERVIX, CURETTAGE: 
- ENDOCERVICAL MUCOSA WITHIN NORMAL LIMITS. 
- SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.

Endometrium present

UTERINE ENDOCERVIX, CURETTAGE: 
- ENDOCERVICAL MUCOSA WITHIN NORMAL LIMITS. 
- SCANT NON-PROLIFERATIVE ENDOMETRIUM.

Inflamed

UTERINE ENDOCERVIX, CURETTAGE: 
- INFLAMED ENDOCERVICAL MUCOSA. 
- REACTIVE SQUAMOUS EPITHELIUM.
- NEGATIVE FOR MALIGNANCY.

UTERINE ENDOCERVIX, CURETTAGE:
- BENIGN INFLAMED ENDOCERVICAL MUCOSA.
- STRIPPED ENDOCERVICAL EPITHELIUM WITHIN NORMAL LIMITS.

No stroma present

UTERINE ENDOCERVIX, CURETTAGE: 
- STRIPPED ENDOCERVICAL EPITHELIUM WITHOUT APPARENT PATHOLOGY. 

Limited tissue

UTERINE ENDOCERVIX, CURETTAGE:
- ONE MINUTE FRAGMENT OF ENDOCERVICAL EPITHELIUM WITHOUT APPARENT PATHOLOGY,
SEE COMMENT.
- VERY SCANT SUPERFICIAL SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.

COMMENT:
The assessment is severely limited by the small amount of tissue. A re-biopsy
should be considered within the clinical context.

UTERINE ENDOCERVIX, CURETTAGE:
- ONE MINUTE FRAGMENT OF ENDOCERVICAL EPITHELIUM WITHOUT APPARENT PATHOLOGY,
SEE COMMENT.
- VERY SCANT SUPERFICIAL SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.

COMMENT:
The assessment is severely limited by the small amount of tissue. Clinical correlation is
suggested.

UTERINE ENDOCERVIX, CURETTAGE:
- BENIGN SQUAMOUS EPITHELIUM WITH METAPLASTIC CHANGE.
- VERY SCANT BENIGN ENDOCERVICAL EPITHELIUM, SUBOPTIMAL SAMPLING.

UTERINE CERVIX, BIOPSY:
- MINUTE FRAGMENTS OF SUPERFICIAL SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.
- SCANT MUCOUS AND INFLAMMATORY CELLS.
- SEE COMMENT.

COMMENT:
The assessment is severely limited by the small amount of tissue. A re-biopsy should be
considered within the clinical context.

Inadequate biopsy

• Unfortunately, inadequate biopsies are common.

Endocervix

Sign out

No endocervical epithelium

UTERINE ENDOCERVIX, CURETTAGE: 
- SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.
- NO ENDOCERVICAL EPITHELIUM IDENTIFIED.
- MUCOUS AND INFLAMMATORY CELLS.

No epithelium

UTERINE ENDOCERVIX, CURETTAGE: 
- MUCOUS AND INFLAMMATORY CELLS.
- NO EPITHELIUM IDENTIFIED.

No tissue

UTERINE ENDOCERVIX, CURETTAGE: 
- NO TISSUE PRESENT, SEE COMMENT. 

COMMENT: 
No tissue identified on gross or microscopy.

UTERINE ENDOCERVIX, CURETTAGE:
- NO TISSUE PRESENT, SEE COMMENT.

COMMENT:
No tissue identified on microscopy. No tissue is seen on inspection of the paraffin block.

Where to start

1. Identify epithelium - exocervical (stratified squamous), endocervical (simple columnar), both.
   • If there is both exocervix and endocervix --> transition zone.
2. Identify possible squamous lesions.
3. Identify possible endocervical lesions.

Benign entities of the cervix

The cervix is MANTLED:

• Mullerian papilloma/Mesonephric hyperplasia/Microglandular hyperplasia.
• Arias Stella reaction.
• Nabothian cyst.
• Tunnel cluster/Tuboendometrioid metaplasia.
• Lobular endocervical glandular hyperplasia.
• Endocervical polyp/Endocervicosis/Endometriosis/Ectopic prostatic tissue.
• Diffuse laminar endocervical hyperplasia.

Benign

Nabothian cyst

General

• Benign.
• Common.

Gross

• Bump.
• Pale colour.

DDx - clinical:

• Benign endocervical polyp.

Image

• 

  Nabothian cyst. (WC/euthman)

Microscopic

Features:

• Simple endocervical cyst.
  • Usually lined by endocervical epithelial cells - may be flattened.
    • Columnar morphology with large clear, apical vacuoles.
  • +/-Macrophages.
  • +/-Mucus.

Note:

• May be lined by tubal epithelium.
  • Cilia.
  • High NC ratio ~ 1:1.^{[citation needed]}

Image:

• Nabothian cyst (gfmer.ch).

Sign out

CERVICAL POLYP, REMOVAL:
- BENIGN POLYPOID FRAGMENT OF EXOCERVICAL MUCOSA WITH NABOTHIAN CYSTS AND 
BENIGN ENDOCERVICAL EPITHELIUM.

POLYPOID LESION ("CERVICAL POLYP"), EXCISION:
- POLYPOID NABOTHIAN CYST.

Tunnel cluster

General

• Benign.
• Not the same as microglandular hyperplasia.
• Considered a special type of nabothian cyst.

Microscopic

Features:

• Well-circumscribed lesion consisting of:
• Benign endocervical glands.
  • Dilated & filled with mucin or (less commonly) eosinophilic secretions.
  • Lining epithelium compressed/flattened (attenuated).
  • Gland architecture: branching, tortuous.
  • Scant intervening stroma.

Notes:

1. Usually no nuclear atypia and no mitotic activity.
2. Important only as one could possibly mistake it as minimal deviation adenocarcinoma, AKA adenoma malignum.

Images

• 

  Tunnel cluster - very low mag. (WC)

• 

  Tunnel cluster - low mag. (WC)

• 

  Tunnel cluster - intermed. mag. (WC)

• 

  Tunnel cluster - high mag. (WC)

• 

  Tunnel cluster - very high mag. (WC)

www:

• Tunnel cluster (surgpath4u.com).
• Tunnel cluster (ajronline.org).

Microglandular hyperplasia

Not to be confused with microglandular adenosis.

• Abbreviated MGH.
• AKA microglandular change.

Main article: Microglandular hyperplasia

Wolffian duct hyperplasia

General

• Benign.

Microscopic

Features:

• Abundant small tubules with a simple cuboidal epithelium.
• Round small bland nucleus.

DDx:

• Wolffian duct remnant.

Stains

• PAS-D+ve (cytoplasm).

Squamous metaplasia of the uterine cervix

• Abbreviated SMC.

Main article: Squamous metaplasia of the uterine cervix

Reactive squamous epithelium of the uterine cervix

• AKA reactive squamous epithelium.
• AKA reactive changes.

General

• Common.
• Individuals with persistent inflammation on Pap test may have occult SIL.

Microscopic

Features:

1. Inflammation - key feature.
   • Lymphocytes.
   • Plasma cells.
2. Mild nuclear enlargement. †
3. Nucleoli - important.

Note:

• † Normal squamous cell nuclei are approximately 8 μm.
  • Mild enlargement ~ 2-3x normal.
  • CIN I nuclei are ~ 3x normal (24 μm).

DDx:

• Cervical intraepithelial neoplasia I.
• Cervical intraepithelial neoplasia II.
• NILM.

IHC

• p16 -ve.

Sign out

UTERINE CERVIX, BIOPSY:
- REACTIVE SQUAMOUS EPITHELIUM.
- BENIGN ENDOCERVICAL GLANDS.
- NEGATIVE FOR MALIGNANCY.

COMMENT:
The squamous epithelium is negative for p16 staining. Ki-67 staining is predominantly in
the lower third of the epithelium.

Tubal metaplasia of the uterine cervix

• AKA tubal metaplasia, abbreviated TM.

General

• Benign.
• Mimics the appearance of AIS - especially at low power.

Microscopic

Features - like the fallopian tube:

• Nuclear crowding vis-à-vis benign endocervical epithelium (low power).
• Mixed cell population (high power):
  • Peg cells - "tall" and "skinny".
    • Columnar/golf tee-like appearance.
  • Ciliated cells - cilia, pale cytoplasm, round central nucleus.
  • Secretory cells - non-ciliated, basophilic cytoplasm, round small basal nuclei.

DDx:

• Endocervical adenocarcinoma in situ.

Image:

• Tubal metaplasia (nature.com).

IHC

Features:

• Vimentin +ve.
• CEA -ve/+ve.
• p16 -ve.^{[citation needed]}

Atrophy of the uterine cervix

• AKA cervical atrophy.
• AKA atrophy of the cervix.
• AKA cervix with atrophic changes.

Main article: Uterine cervix with atrophic changes

Radiation changes of the endocervical epithelium

Main article: Radiation changes

Main article: Radiation changes in cervical cytology

General

• Uncommon.
• Clinical history: radiation treatment for cervical carcinoma.

Microscopic

Features:

• Nuclear enlargement with a normal NC ratio.
• +/-Coarse chromatin.
• +/-Nucleoli.
• +/-Multinucleation - very common.
• Histiocytes - common.

Reactive endocervical cells

General

• Benign.

Microscopic

Features:

• Mild nuclear enlargement.
• +/-Multinucleation.

Notes: DDx of multinucleated endocervical cells:

• HSV.
• Benign endocervical cells.

Images

• 

  Multinucleated endocervix - high mag.

• 

  Multinucleated endocervix - very high mag.

• 

  Multinucleated endocervix - extremely high mag.

www:

• Reactive endocervical cells (surgpath4u.com).

Non-invasive

Cervical intraepithelial neoplasia

• Previously known as cervical intraepithelial neoplasia and cervical dysplasia.

Main article: Squamous intraepithelial lesion of the uterine cervix

Endocervical adenocarcinoma in situ

For the cytology see Gynecologic cytopathology#Endocervical adenocarcinoma in situ

• AKA adenocarcinoma in situ, abbreviated AIS.

Main article: Endocervical adenocarcinoma in situ

Cancer

Squamous cell carcinoma of the uterine cervix

Main article: Squamous cell carcinoma

• AKA cervical squamous cell carcinoma.

Main article: Squamous cell carcinoma of the uterine cervix

Adenocarcinoma of the uterine cervix

• AKA endocervical adenocarcinoma.
• AKA cervical adenocarcinoma.

Main article: Adenocarcinoma of the uterine cervix

Uncommon non-invasive

Stratified mucin-producing intraepithelial lesions of the cervix

• Abbreviated SMILE (Stratified Mucin-producing Intraepithelial LEsion).

General

• Rare.
• Often accompanied by cervical intraepithelial neoplasia and adenocarcinoma in situ.

Microscopic

Features:

• Stratified epithelium with:
  • Nuclear atypia.
  • Cytoplasmic clearing or vacuoles in lesions - through-out.

DDx:

• HSIL.
  • Mucin may be present superficially.

Images:

• SMILE (sunnybrook.ca).
• SMILE (sunnybrook.ca).

IHC

Features:

• Ki-67 high.
• Keratin 14 -ve.
• p63 +ve/-ve -- only basal if positive.

Uncommon types of cervical cancer

There are a number of uncommon type of cervical cancer.

Serous carcinoma of the uterine cervix

General

• Poor prognosis.
• Extremely rare.

Microscopic

Features:

• Like other serous carcinomas.

Adenosquamous carcinoma of the uterine cervix

Main article: Adenosquamous carcinoma of the uterine cervix

Clear cell carcinoma of the uterine cervix

Main article: Clear cell carcinoma of the uterine cervix

Small cell carcinoma of the cervix

Main article: Small cell carcinoma

• Like small cell carcinoma elsewhere.

DDx:

• Small cell carcinoma of the lung.
• Small cell carcinoma of the ovary, hypercalcemic type.

IHC

• HPV +ve.

Adenoid basal carcinoma

See also: Basal cell carcinoma.

General

• Good prognosis.

Microscopic

Features:

• Nests of cells with basaloid rim and squamoid center.
  • Basaloid cells look benign.

DDx:

• Ectopic prostate gland.

Image:

• Adenoid basal carcinoma (webpathology.com).

Glassy cell carcinoma

Main article: Glassy cell carcinoma

Villoglandular adenocarcinoma of the cervix

• AKA well-differentiated papillary villoglandular adenocarcinoma, AKA villoglandular papillary adenocarcinoma, AKA well-differentiated villoglandular adenocarcinoma.

General

• Rare.
• Younger patients and relatively good prognosis.
• Associated with HPV.
• May also arise from the endometrium.

Microscopic

Features:

• Papillary structures (nipple-like shapes with a fibrovascular core) that are long.
  • Nobody defines "long".
    • Perhaps - long >3:1 length:width.
• Covered by columnar (or cuboidal) epithelium.
• Intracellular mucin (focal).

DDx:

• Serous carcinoma of the cervix.

Images

www:

• VGA (webpathology.com).

• 

  VGA - very low mag. (WC)

• 

  VGA - intermed. mag. (WC)

• 

  VGA - very high mag. (WC)

Mucoepidermoid carcinoma of the uterine cervix

Main article: Mucoepidermoid carcinoma

General

• Controversial - not in the WHO.

Microscopic

Features:

• Squamous cell carcinoma-like with:
  1. No glands formation.
  2. Intracellular mucin.
     • Classically have mucous cells - cells with abundant fluffy cytoplasm and large mucin vacuoles - key feature.

Notes:

• Similar to the salivary gland tumour.

DDx:

• Cervical intraepithelial neoplasia, i.e. CIN II, CIN III.
• Adenosquamous carcinoma.

Stains

Mucin stains:

• Alcian blue stain
• Periodic acid-Schiff-diastase stain.

IHC

• CEA +ve.

Molecular

Like the salivary gland tumour:

• t(11;19) CRTC1/MAML2.

Mesonephric adenocarcinoma

General

• Arises from the mesonephric duct remnants.

Microscopic

Features:

• Nuclear atypia - key feature.
  • Nuclear crowding.
• Variable architecture:
  • Tubular, papillary, solid, retiform (net-like).

DDx:

• Mesonephric duct remnants.
• Cervical adenocarcinoma.
• Colorectal adenocarcinoma.
• Endometrioid adenocarcinoma.

IHC

Features:

• CK7 +ve.
• CD10 +ve.

Others:

• CK20 -ve.
• ER -ve.
• PR -ve.
• CEA -ve.

Minimal deviation adenocarcinoma of the uterine cervix

• AKA adenoma malignum.
• AKA minimal deviation adenocarcinoma, abbreviated MDA.

General

• Rare and difficult diagnosis.
  • Requires a deep sampling; thus, usually diagnosed on cone biopsy or hysterectomy.
• Associated with Peutz-Jeghers syndrome.
• Poor prognosis.

Microscopic

Features:

• Deep infiltrating glands - key feature.
  • Desmoplastic stroma - may be subtle.
  • Perivascular and/or perineural location.
• Minimal nuclear atypia.
• Abnormal gland morphology / loss of lobular (gland) architecture. †

Note:

• † Not a criterion required by all pathologists.

DDx:

• Adenocarcinoma of the uterine cervix - has "obvious" nuclear atypia.
• Tunnel cluster.

IHC

Features:

• CEA +ve.
• p16 -ve.

See also

• Vulvar intraepithelial neoplasia.
• Cervical polyp.
• Gynecologic cytopathology.
• Gynecologic pathology.

External links

• Interpretation altas for p16 staining (ups-tlse.fr).
• Cervical carcinoma (glowm.com).
• Treatments for CIN (obgyn.net).