Uterine cervix

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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.
  • 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):[1]

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).
  • Cervical ectropian (AKA cervical eversion, AKA ectropian) = endocervical epithelium at external os, considered benign, grossly has a granulation tissue-like appearance.[4]

Cervical specimens

Cytology

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).
  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.[5]

Other

Normal histology

  • 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".[6]
    • Also known as "transition zone".

Images:

Negative 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

www:

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

Nabothian cyst

General

  • Benign.
  • Common.

Gross

  • Bump.
  • Pale colour.

DDx - clinical:

Image

Microscopic

Features:

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

Note:

Image:

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

Microscopic

Features:[10][11]

  • 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.[12]

Images

www:

Microglandular hyperplasia

Not to be confused with microglandular adenosis.
  • Abbreviated MGH.
  • AKA microglandular change.

Wolffian duct hyperplasia

General

  • Benign.

Microscopic

Features:

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

DDx:

Stains

Squamous metaplasia of the uterine cervix

  • Abbreviated SMC.

General

  • Benign process: columnar cells -> squamoid cells.
    • Biologic response to irritation and/or inflammation.

Gross

Microscopic

Features:

  • Uniform cell spacing - no crowding - key feature.
  • Nuclei are uniform size and round.
  • Distinct cell borders
  • +/-Intercellular bridges (due to edema) - common.
  • Adjacent/closely associated with columnar epithelium.
    • Columnar epithelium superficial in immature metaplasia.

Negatives:

  • No mitoses (think cancer/CIN if you see 'em).
  • Usually no hyperchromatism (think cancer/CIN if you see it).

Notes:

  • NC ratio high - possible to confuse with CIN III.
  • May have goblet cells - uncommon.[13]

DDx:

Images:

IHC

  • p16 weak-to-moderate patchy +ve -- checkerboard-like; not full thickness.
    • Strong diffuse full thickness positivity in HSIL and SCC.
  • Ki-67 - low proliferative rate.

Sign out

ECC

UTERINE ENDOCERVIX, CURETTAGE: 
- SQUAMOUS METAPLASTIC EPITHELIUM.
- VERY SCANT STRIPPED ENDOCERVICAL EPITHELIUM. 

Cervical biopsy

UTERINE CERVIX, BIOPSY: 
- SQUAMOUS METAPLASTIC EPITHELIUM.
- SCANT BENIGN ENDOCERVICAL GLANDS.
UTERINE CERVIX, BIOPSY: 
- SQUAMOUS METAPLASTIC EPITHELIUM.
- SCANT BENIGN ENDOCERVICAL GLANDS.
- NEGATIVE FOR DYSPLASIA AND NEGATIVE FOR MALIGNANCY.

Micro

The sections show stratified squamous epithelium. The cells are equally spaced and spaces are seen between the cells (edema).

The nuclei are not significantly enlarged (<3x resting lymphocyte diameter). No nuclear halos are apparent. The nuclear membranes are regular. Mild inflammation is present. Nucleoli are present focally.

No endocervical cells are identified.

Reactive squamous epithelium of the uterine cervix

  • AKA reactive squamous epithelium.
  • AKA reactive changes.

General

  • Common.

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.[15]
    • Mild enlargement ~ 2-3x normal.
    • CIN I nuclei are ~ 3x normal (24 μm).

DDx:

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:

Image:

IHC

Features:[16]

Atrophy of the uterine cervix

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

General

  • Common.
  • Post-menupausal.
  • Important to recognize and differentiate from HSIL.

Microscopic

Features:

  • Cells smaller.
  • Cytoplasm grey/blue.
  • No "dancing"/"sparkling" chromatin.
  • No mitoses.

DDx:

Images

www:

IHC

  • p16 -ve.
  • Ki-67 rare basal cells.

Sign out

UTERINE CERVIX, BIOPSY:
- SQUAMOUS MUCOSA WITH ATROPHIC CHANGES.
- BENIGN ENDOCERVICAL EPITHELIUM.
- NEGATIVE FOR DYSPLASIA.

COMMENT:
A p16 immunostain is negative. A Ki-67 immunostain marks rare basal cells.

Radiation changes of the endocervical epithelium

General

  • Uncommon.
  • Clinical history: radiation treatment for cervical carcinoma.[18]

Microscopic

Features:[18]

  • 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.[19]

Images:

Non-invasive

Cervical intraepithelial neoplasia

  • Previously known as cervical intraepithelial neoplasia and cervical dysplasia.

Endocervical adenocarcinoma in situ

For the cytology see Gynecologic cytopathology#Endocervical adenocarcinoma in situ
  • AKA adenocarcinoma in situ, abbreviated AIS.

General

  • Usually due to HPV.
  • May be found together with squamous neoplasias of the cervix.
  • AIS of the cervix is much less common than squamous dysplasia of the cervix/SCC of the cervix.
  • Generally, definitely diagnosed with an endocervical curettage (ECC).

Gross

  • Not apparent at colposcopy.

Microscopic

Features:[8]

  1. Nuclear changes - key feature:
    • Variable nuclear stratification.
      • Nuclear crowding/pseudostratification.
    • Nuclear enlargement.
      • Often cigar-shaped nuclei.
    • Coarse chromatin.
    • Small nucleolus or nucleoli.
  2. +/-Mitoses.
  3. +/-Reduced cytoplasmic mucin.
  4. Preservation of glandular architecture.
    • Normal gland spacing - lack of complexity ("lobular pattern").
    • Normal gland depth (subjective).

DDx:

Images:

IHC

  • p16 +ve.
  • CEA +ve.
  • Vimentin -ve.

Cancer

Squamous cell carcinoma of the uterine cervix

  • AKA cervical squamous cell carcinoma.

General

  • Most common type of cervical cancer.

Risk factors:

  • Low socioeconomic status.
  • Smoking.
  • Early first intercourse.
  • High risk partners.
  • Human papillomavirus (HPV) infection, esp. "high risk HPV".
    • HPV 16 closely assoc. with SCC.[22]

Microscopic

Features:

  • Squamous differentiation.
    • +/-Intracellular bridges.
    • Scant-to-moderate cytoplasm.
  • Penetration of basement membrane.
    • May be challenging to determine.
  • Nuclear atypia.

SCC of the cervix versus CIN III: Invasive cancer look for:

  • Eosinophilia.
  • Extra large nuclei, i.e. nuclei 5x normal size.
  • Stromal inflammation (lymphocytes, plasma cells).
  • Long rete ridges.
  • Numerous beeds/blobs of epithelial cells that seem unlikely to be rete ridges.
  • Desmoplastic stroma - increased cellularity, spindle cell morphology.

DDx:

Images:

Grading

Divided into:[26]

  1. Well-differentiated (keratinizing).
  2. Moderately differentiated (nonkeratinizing).
  3. Poorly differentiated.

Depth measurement

  • Basement membrane (where it invades) to deepest point.

Note:

  • Stage Ib - clinical diagnosis.
    • Definition of stage Ib: clinically visible.
FIGO

Microinvasive SCC as per FIGO:

  • Depth < 5 mm.
  • Width < 7 mm.
  • +/-Vascular invasion.
SGO

Microinvasive SCC as per The Society of Gynecologic Oncologists (SGO):

Note:

  • The SGO criteria the prefered by North American gynecologists.

IHC

  • Factor VIII - to look for LVI.

Sign out

Early invasive SCC - things to report:

  • Depth of invasion.
  • Length of tumour.
  • Number of blocks with tumour.
  • LVI.
  • Margins.
UTERINE CERVIX, BIOPSY:
- FRAGMENTS OF INVASIVE SQUAMOUS CELL CARCINOMA.
-- DEPTH OF INVASION AND LENTH OF TUMOUR CANNOT BE ASSESSED.
-- LYMPHOVASCULAR INVASION NOT APPARENT.

Adenocarcinoma of the uterine cervix

  • AKA endocervical adenocarcinoma.
  • AKA cervical adenocarcinoma.

General

  • Adenocarcinoma of the cervix is much less common than squamous dysplasia of the cervix/SCC of the cervix.
  • Arises from the endocervical glands.

Microscopic

Features:

Notes:

  • AIS changes - similar to colonic dysplasia.
  • AIS may occur together with CIN.
    • Not infrequently they (AIS, CIN) occur together - both are due, indirectly, to HPV infection.
  • May be difficult to be certain of invasion.
    • A feature suggestive of invasion is cytoplasmic eosinophilia.

DDx:

Images:

IHC

Features for diagnosis:

  • p16 +ve.
  • Ki-67 -- high.

Uterus vs. cervix:[27]

  • Cervix (typically): CEA +ve, p16 +ve.
    • ER -ve, PR -ve, vimentin -ve.
  • Uterus (typically): vimentin +ve, ER +ve, PR +ve.
    • CEA -ve, p16 -ve.

Uncommon non-invasive

Stratified mucin-producing intraepithelial lesions of the cervix

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

General

Microscopic

Features:[28]

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

DDx:

  • HSIL.
    • Mucin may be present superficially.[28]

Images:

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.[30]
  • Extremely rare.

Microscopic

Features:

Adenosquamous carcinoma

General

  • Uncomon.

Note:

Microscopic

Features:

  • Morphologic features of both squamous carcinoma and adenocarcinoma:
    • Adenocarcinoma: gland forming or mucin vacuoles.
    • Squamous carcinoma: abundant eosinophilic cytoplasm, central nucleus.

Images

Clear cell carcinoma of the uterine cervix

  • AKA cervical clear cell carcinoma.

General

  • Associated with diethylstilbestrol exposure in utero.[32]
  • Less common in the cervix - when compared to other gynecologic sites.[33]

Note:

  • HPV does not appear to be important in the oncogenesis;[35] however, this is not completely settled.[36]

Microscopic

Features:[36]

  • Like clear cell carcinoma elsewhere:
    • Clear cytoplasm - key feature.
      • May be absent!
    • Cells have large free/luminal surface area (hobnailing pattern) and small non-free surface.
    • Moderate-to-severe nuclear pleomorphism.
    • Tubular and/or cystic morphology.
      • May be (simple) papillary and/or solid.
  • Adenosis - typically adjacent.

DDx:

IHC

Small cell carcinoma of the cervix

  • Like small cell carcinoma elsewhere.

DDx:

IHC

  • HPV +ve.

Adenoid basal carcinoma

See also: Basal cell carcinoma.

General

Microscopic

Features:[37]

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

DDx:

Image:

Glassy cell carcinoma

General

Microscopic

Features:[40]

  • Epithelioid cells in sheets or cords.
  • Round/oval nucleus.
  • One or more prominent nucleoli.
  • Abundant finely vacuolated eosinophilic to amphophilic cytoplasm.
  • Distinct cell borders.
  • Inflammation - esp. eosinophils.[41]

DDx:

Images

www:

Stains

Villoglandular adenocarcinoma of the cervix

  • AKA well-differentiated papillary villoglandular adenocarcinoma,[43] AKA villoglandular papillary adenocarcinoma, AKA well-differentiated villoglandular adenocarcinoma.

General

  • Rare.
  • Younger patients and relatively good prognosis.[44]
  • Associated with HPV.
  • May also arise from the endometrium.[45]

Microscopic

Features:[46]

  • 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:

Mucoepidermoid carcinoma of the uterine cervix

General

  • Controversial - not in the WHO.[47]

Microscopic

Features:[48]

  • 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:

DDx:

Stains

Mucin stains:[48]

IHC

Molecular

Like the salivary gland tumour:

  • t(11;19) CRTC1/MAML2.[47]

Mesonephric adenocarcinoma

General

Microscopic

Features:[33]

  • Nuclear atypia - key feature.
    • Nuclear crowding.
  • Variable architecture:
    • Tubular, papillary, solid, retiform (net-like[49]).

DDx:

IHC

Features:[33]

  • CK7 +ve.
  • CD10 +ve.

Others:[33]

  • 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

Microscopic

Features:[54]

  • Deep infiltrating glands - key feature.
    • Desmoplastic stroma - may be subtle.
    • Perivascular and/or perineural location.
  • Minimal nuclear atypia.
  • Abnormal gland morphology[12] / loss of lobular (gland) architecture. †

Note:

  • Not a criterion required by all pathologists.[50]

DDx:[50]

IHC

Features:

See also

References

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