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

  • Most cervix cancer is squamous cell carcinoma.
  • The work-up of an abnormal Pap test is a colposcopic examination and biopsies, which are the topic of this article.

Cervical specimens

Cytology:

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.[1]

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".[2]
    • Also known as "transition zone".

Endocervical glands

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

  • If the nuclei are columnar think cancer! This is like in the colon-- columnar nuclei = badness.

Memory device: The Cs (Cervix & Colon) are similar.

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

Inflamed

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

Inadequate biopsy

  • Unfortunately, inadequate biopsies are common.

Endocervix

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No stroma

UTERINE ENDOCERVIX, CURETTAGE: 
- STRIPPED ENDOCERVICAL EPITHELIUM WITHOUT APPARENT PATHOLOGY. 
- ASSESSMENT LIMITED AS NO DEFINITE ENDOCERVICAL STROMA IS PRESENT.

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 tissue 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 (common)

Nabothian cyst

General

  • Benign.
  • Common.

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:

Tunnel cluster

General

Microscopic

Features:[5][6]

  • 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.[7]

Images:

Microglandular hyperplasia

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

General

Microscopic

Features:[4]

  • Cytologically benign - important.
    • Usually cuboidal morphology.
    • Typically clear cytoplasm.
  • Crowded small glands (classic), reticular or solid.

Significant negatives:

  • Nuclear atypia absent.
  • NC ratio not significantly increased.

DDx:

Images:

IHC

Features:[12]

  • Ki-67 ~ 0.5% cells.
  • Vimentin -ve.
  • PR +ve ~ 60% of cases.
  • ER +ve/-ve.

Others:[12]

  • p53 -ve.
  • CEA -ve.

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

General

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

Microscopic

Features:

  • Uniform cell spacing - no crowding - key feature.
  • Nuclei are uniform size and round.
  • Distinct cell borders
  • +/-Intercellular bridges (due to edema) - common.

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 CIN III.

DDx:

Images:

IHC

  • p16 +ve - in SCC; a poor man's test for HPV.
  • Ki-67 - stains a large number of cells; proliferation marker.

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

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.[13]
    • Mild enlargement ~ 2-3x normal.
    • CIN I nuclei are ~ 3x normal (24 μm).

DDx:

IHC

  • p16 -ve.

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

Non-invasive

Cervical intraepithelial neoplasia

CIN I, CIN II and CIN III redirect to here.
  • Abbreviated CIN.

General

  • Refers to changes in squamous epithelium.

Grades (squamous intraepithelial neoplasia):

  • CIN I = mild dysplasia.
  • CIN II = moderate dysplasia.
  • CIN III = severe dysplasia.

Bethesda system:

Treatment

  • LSIL: nothing, as usually regress.
  • HSIL: excision (e.g. cone, LEEP, laser) + follow-up.

Loop electrosurgical excision procedure (LEEP):

  • Used for squamous lesions -- pathologist typically gets several pieces.

Cone:

  • Used for endocervical lesions, i.e. adenocarcinoma in situ (AIS).
  • Pathologist gets a ring or donut-shaped piece of tissue.

Microscopic

Cervical intraepithelial neoplasia I

Features - Cervical intraepithelial neoplasia (CIN) I:[14]

  • "Koilocytic atypia":[15]
    • Cytoplasmic halos.
    • Nuclear enlargement >=3:1 enlarged nucleus:normal nucleus.
    • Nuclear membrane irregularities.
    • Nuclear hyperchromasia.
    • Coarse chromatin.
    • Binucleation may be seen (cytopathic effect of HPV).[16]

Note:

  • Atypical cells usually close to basement membrane.
    • May be seen, focally, in the upper layers.[15]

Cervical intraepithelial neoplasia II

Features - CIN II:[14]

  • Increased nuclear-cytoplasmic ratio, loss of polarity, incr. mitoses, hyperchromasia.
    • If there are large nuclei... you should seen 'em on low power, i.e. 25x.

Cervical intraepithelial neoplasia III

Features - CIN III:[14]

  • Same changes as in CIN II + outer third (or full thickness).

Notes:

  1. Hyperchromasia is a very useful feature for identifying CIN (particularly at low power, i.e. 25x).
  2. Koilocytes are the key feature of CIN I.
  3. Koilocytes are not considered to be part of a CIN II lesion or CIN III lesion.
  4. Large irregular nuclei are not required for CIN II... but you should think about it.
  5. Some mild changes at the squamo-columnar junction are expected.
  6. Look for the location of mitoses...
    • If there is a mitosis in the inner third (of the epithelial layer) = think CIN I.
    • If there is a mitosis in the middle third (of the epithelial layer) = think CIN II.
    • If there is a mitosis in the outer third = think CIN III.
  7. Prominent nucleoli are not present in CIN.[15]
    • Nucleoli are common in reactive changes.[17]
  8. The most probably place for CIN is the posterior cervix (6 o'clock position) - risk is marginally increased.[18]

Koilocytes versus benign squamous

Koilocytes:

  • Perinuclear clearing.
  • Nuclear changes.
    • Size similar (or larger) to those in the basal layer of the epithelium.
    • Nuclear enlargement should be evident on low power, i.e. 25x. [19]
    • Central location - nucleus should be smack in the middle of the cell.

Notes:

  1. Both perinuclear clearing and nuclear changes are essential.
  2. Benign cells have a small nucleus that is peripheral.

IHC

Features:[20]

  • p16.
    • Diffuse, strong positive staining = CIN II or CIN III.
    • Patchy, weak positive staining = CIN I or squamous metaplasia.
  • Ki-67.
    • Several positive cells above basal layer suggests CIN II or CIN III.

Notes:

  • Both p16 and Ki-67 are usually negative in CIN I -- 75% of cases.[21]
    • CIN I with p16 staining appears to have a higher risk of progression the p16 negative CIN I.[22]

Images:

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LEEP

UTERINE CERVIX, LOOP ELECTROSURGICAL EXCISION PROCEDURE (LEEP):
- CERVICAL INTRAEPITHELIAL NEOPLASIA 2 (MODERATE DYSPLASIA).
- DEEP, ENDOCERVICAL AND EXOCERVICAL MARGINS NEGATIVE FOR INTRAEPITHELIAL NEOPLASIA.
UTERINE CERVIX, LOOP ELECTROSURGICAL EXCISION PROCEDURE (LEEP):
- CERVICAL INTRAEPITHELIAL NEOPLASIA 3 (SEVERE DYSPLASIA).
- DEEP, ENDOCERVICAL AND EXOCERVICAL MARGINS NEGATIVE FOR INTRAEPITHELIAL NEOPLASIA.

Biopsy

UTERINE CERVIX, BIOPSY:
- CERVICAL INTRAEPITHELIAL NEOPLASIA 3 (SEVERE DYSPLASIA).
UTERINE CERVIX, BIOPSY:
- CERVICAL INTRAEPITHELIAL NEOPLASIA 1 (MILD DYSPLASIA).
- TRANSFORMATION ZONE PRESENT.

Micro

The sections show the transformation zone.

The squamous epithelium has an increased nuclear-cytoplasmic ratio, loss of polarity, mitoses and nuclear hyperchromasia extending to the superficial third of the epithelium. Mitoses are seen in the upper third of the epithelium. No nucleoli are present. No invasion is identified.

The columnar epithelium has focal involvement by the squamous lesion. There is no columnar dysplasia. The margins are negative for dysplasia.

Alternate

The sections show fragments of transformation zone.

There is dysplastic squamous epithelium with coarse chromatin, nuclear hyperchromasia, nuclear enlargement, irregular nuclear membranes, and an increase nuclear-to-cytoplasmic ratio. Mitotic activity is abundant focally (5 mitoses/0.2376 mm*mm). The dysplastic squamous epithelium does not show appreciable maturation toward the surface (CIN 3). The dysplastic squamous epithelium is not associated with stroma; thus, the presence/absence of invasion cannot be assessed. Small nucleoli are seen rarely.

There is benign squamous epithelium. Scant benign stripped endocervical epithelium is present.

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).

Microscopic

Features:[4]

  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.
    • Normal gland depth (subjective).

DDx:

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.[24]

Microscopic

Features:

  • 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:

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.

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Early invasive SCC - things to report:

  • Depth of invasion.
  • Length of tumour.
  • Number of blocks with tumour.
  • LVI.
  • Margins.

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.

DDx:

Images:

IHC

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

Microscopic

Features:

Adenosquamous carcinoma

Features:

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

Image: Adenosquamous carcinoma - high mag. (WC).

Clear cell carcinoma of the uterine cervix

  • AKA cervical clear cell carcinoma.

General

  • Associated with diethylstilbestrol exposure in utero.[31]
  • Less common in the cervix - when compared to other gynecologic sites.[32]

Note:

  • HPV does not appear to be important in the oncogenesis;[34] however, this is not completely settled.[10]

Microscopic

Features:[10]

  • 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:[35]

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

Image:

Glassy cell carcinoma

General

  • Rare.
  • Rapid growth, poor prognosis.[36]

Microscopic

Features:[37]

  • 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.[38]

DDx:

Images:

Stains

Villoglandular adenocarcinoma of the cervix

  • AKA well-differentiated papillary villoglandular adenocarcinoma,[40] AKA villoglandular papillary adenocarcinoma, AKA well-differentiated villoglandular adenocarcinoma.

General

  • Rare.
  • Younger patients and relatively good prognosis.[41]
  • Associated with HPV.
  • May also arise from the endometrium.[42]

Microscopic

Features:[43]

  • 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:

Mucoepidermoid carcinoma of the uterine cervix

General

  • Controversial - not in the WHO.[44]

Microscopic

Features:[45]

  • 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:[45]

IHC

Molecular

Like the salivary gland tumour:

  • t(11;19) CRTC1/MAML2.[44]

Mesonephric adenocarcinoma

General

Microscopic

Features:[32]

  • Nuclear atypia - key feature.
    • Nuclear crowding.
  • Variable architecture:
    • Tubular, papillary, solid, retiform (net-like[46].

DDx:

IHC

Features:[32]

  • CK7 +ve.
  • CD10 +ve.

Others:[32]

  • 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:[51]

  • Deep infiltrating glands - key feature.
    • Desmoplastic stroma - may be subtle.
    • Perivascular and/or perineural location.
  • Minimal nuclear atypia.
  • Abnormal gland morphology[7] / loss of lobular (gland) architecture. †

Note:

  • Not a criterion required by all pathologists.[47]

DDx:[47]

IHC

Features:

See also

References

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  3. Nucci, MR. (Oct 2002). "Symposium part III: tumor-like glandular lesions of the uterine cervix.". Int J Gynecol Pathol 21 (4): 347-59. PMID 12352183.
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