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).
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

• 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".

Images:

• Normal cervix (proteinatlas.org).

Transformation zone - biopsy

Microscopic

Features:

• Small round cells.
• No halos.
• No nuclear membrane irregularities.

Images:

• 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. 

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.

No stroma present

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

Note:

• Some pathologists classify this as inadequate.

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.

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 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.

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:

• WC:
  • Tunnel cluster - intermed. 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.

General

• Associated with OCP use.

Microscopic

Features:

• 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:

• Adenocarcinoma in situ of the uterine cervix.
• Endometrial mucinous microglandular adenocarcinoma - very rare.
• Clear cell carcinoma of the uterine cervix.

Images:

• MGH (nature.com).
• MGH (sunnybrook.ca).

IHC

Features:

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

Others:

• p53 -ve.
• CEA -ve.
• p16 -ve (scattered cells +ve).^{[citation needed]}

Sign out

UTERINE ENDOCERVIX, CURETTAGE: 
- MICROGLANDULAR HYPERPLASIA. 
- SQUAMOUS EPITHELIUM WITH REACTIVE CHANGES AND METAPLASTIC CHANGES.

Micro

The sections show gland forming epithelium without nuclear atypia (no nuclear membrane irregularities, no coarse chromatin). The nuclei are less than 2x the size of a neutrophil, regularly spaced, pale staining and have small regular nucleoli visible with the 20x objective. No mitotic activity is apparent.

Fragments of reactive squamous epithelium with metaplastic changes are present. Benign superficial squamous epithelium is identified.

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.

General

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

Gross

• Acetowhite lesion.

Microscopic

Features:

• Uniform cell spacing - no crowding - key feature.
• Nuclei are uniform size and round.
  • Nucleoli present.
• 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.

DDx:

• CIN II - esp. for immature squamous metaplasia.
• CIN III.
• Squamous cell carcinoma of the uterine cervix.

Images:

• Squamous metaplasia - cervix (sciencephoto.com).
• Squamous metaplasia - bronchus (WC).
• Squamous metaplasia - cytology (techriver.net).
• Immature squamous metaplasia (eurocytology.eu).

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.
  • 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]}

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:

• LSIL (low-grade squamous intraepithelial lesion) = CIN I.
• HSIL (high-grade squamous intraepithelial lesion) = CIN II, CIN III.

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.

Gross

• Acetowhite lesion at colposcopy.

Microscopic

Cervical intraepithelial neoplasia I

Features - Cervical intraepithelial neoplasia (CIN) I:

• "Koilocytic atypia":
  • 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).

Note:

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

Image

• 

  CIN I. (WC/KGH)

www:

• CIN 1 (flickr.com/Qiao).
• CIN 1 (eurocytology.eu).

Cervical intraepithelial neoplasia II

Features - CIN II:

• 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.

Image:

• 

  CIN I. (WC/KGH)

Cervical intraepithelial neoplasia III

Features - CIN III:

• 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.
   • Nucleoli are common in reactive changes.
8. The most probably place for CIN is the posterior cervix (6 o'clock position) - risk is marginally increased.

DDx:

• CIN II.
• Squamous cell carcinoma of the uterine cervix.

Images

• 

  CIN I. (WC/KGH)

www:

• CIN III (flickr.com/euthman).
• CIN III (flickr.com/euthman).
• CIN III - several images (flickriver.com).

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.
  • 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:

• p16.
  • Diffuse strong staining involving at least all of the basal aspect of the epithelium = 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.
  • CIN I with p16 staining appears to have a higher risk of progression the p16 negative CIN I.

ECC - cannot grade

UTERINE CERVIX, BIOPSY:
- FRAGEMENTS OF SQUAMOUS EPITHELIUM SHOWING DYSPLASIA, SEE COMMENT.

COMMENT:
The fragments of squamous epithelium do not show full epithelial 
thickness. Thus, while dysplasia is apparent, it is not possible 
to distinguish low-grade from high-grade in this specimen. That said,
there is at least low grade-dysplasia. Follow-up is recommended with 
re-biopsy if clinically indicated.

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.

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

COMMENT:
CIN 3 is seen in 2 of 5 blocks and has a total linear extent of 17 millimeters.

Biopsy

LSIL

UTERINE CERVIX, BIOPSY:
- LOW-GRADE SQUAMOUS INTRAEPITHELIAL LESION (LSIL).
- NO ENDOCERVICAL EPITHELIUM IDENTIFIED.

UTERINE CERVIX, BIOPSY:
- LOW-GRADE SQUAMOUS INTRAEPITHELIAL LESION (LSIL).
- TRANSFORMATION ZONE PRESENT.

CIN 1

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

COMMENT:
The Ki-67 positive cells are confined to the lower aspect of the squamous epithelium.  
A p16 stain is negative.

At least CIN 2

UTERINE CERVIX, BIOPSY:
- AT LEAST CERVICAL INTRAEPITHELIAL NEOPLASIA 2 (MODERATE DYSPLASIA).
- TRANSFORMATION ZONE PRESENT.

UTERINE ENDOCERVIX, CURETTAGE:
- HIGH-GRADE SQUAMOUS INTRAEPITHELIAL LESION (HSIL).
- ENDOCERVICAL MUCOSA AND STRIPPED ENDOCERVICAL EPITHELIUM WITHIN NORMAL LIMITS.

COMMENT:
The HSIL is in keeping with CIN 2.

CIN 3

UTERINE CERVIX, BIOPSY:
- CERVICAL INTRAEPITHELIAL NEOPLASIA 3 (SEVERE DYSPLASIA).

COMMENT:
A p16 stains marks the full thickness of the epithelium and is strong.  A Ki-67 stain 
marks increased numbers of superficial epithelial cells.

Micro

CIN 1

The sections show the transformation zone. The squamous epithelium has cells with an increased nuclear size, nuclear hyperchromasia, perinuclear clearing and irregularities in the nuclear membrane. The nucleus-to-cytoplasm ratio is mildly increased. Occasional binucleation is identified. Mitoses are seen in the low third of the epithelium. Nucleoli are not apparent. No columnar dysplasia is identified.

CIN 3

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.

Biopsy

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. Nucleoli are not apparent. No invasion is identified.

No columnar dysplasia is identified.

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).

Gross

• Not apparent at colposcopy.

Microscopic

Features:

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:

• Tubal metaplasia.
• Arias-Stella reaction.
• Endometriosis.
• Lower uterine segment epithelium - esp. proliferative phase endometrium - mitoses rare, NC ratio normal, stroma different.
• Endocervical adenocarcinoma - often has paradoxical maturation... paler cytoplasm & nuclei than adjacent AIS.
• Metastatic adenocarcinoma.

Images:

• Endocervical adenocarcinoma in situ (techriver.net).
• Endocervical adenocarcinoma in situ (womenshealthsection.com).
• Endocervical adenocarcinoma in situ - cytology (techriver.net).

IHC

• p16 +ve.
• CEA +ve.
• Vimentin -ve.

Cancer

Squamous cell carcinoma of the uterine cervix

Main article: Squamous cell carcinoma

• 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.

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:

• Squamous metaplasia of the uterine cervix - if you can trace the squamous cells from a gland to the surface it is less likely to be invasive cancer.
• CIN III +/- endocervical gland involvement.

Images:

• Microinvasive cervical SCC - low mag. (sunnybrook.ca).
• Microinvasive cervical SCC - high mag. (sunnybrook.ca).
• Cervical SCC - low mag. (ucsf.edu).
• Cervical SCC - high mag. (uscf.edu).

Grading

Divided into:

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):

• <= 3 mm.
• Negative for vascular invasion.

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:

• Stromal changes - "desmoplastic stroma/desmoplastic reaction".
  • Fibrosis/streaming cells.
• Gland fusion.
• Glands too deep -- very fuzzy criterion.

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:

• Microglandular hyperplasia - NC ratio normal, no nuclear atypia.
• Endocervical adenocarcinoma in situ.
• Metastatic adenocarcinoma.

Images:

• Cervical adenocarcinoma - low mag. (WC).
• Cervical adenocarcinoma - intermed. mag. (WC).
• Cervical adenocarcinoma - high mag. (WC).

IHC

Features for diagnosis:

• p16 +ve.
• Ki-67 -- high.

Uterus vs. cervix:

• 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

• 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

General

• Uncomon.

Note:

• Glassy cell carcinoma is considered to be a subtype of adenosquamous carcinoma.

Microscopic

Features:

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

Images

• 

  Adenosquamous carcinoma - intermed. mag. (WC)

• 

  Adenosquamous carcinoma - high mag. (WC)

Clear cell carcinoma of the uterine cervix

• AKA cervical clear cell carcinoma.

General

• Associated with diethylstilbestrol exposure in utero.
• Less common in the cervix - when compared to other gynecologic sites.
  • More common in the endometrium.

Note:

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

Microscopic

Features:

• 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:

• Clear cell carcinoma of the endometrium - diagnosis based on clinico-radiologic correlation (IHC & histology not useful).
• Serous carcinoma of the endometrium.
• Serous carcinoma of the uterine cervix.

IHC

• Essentially considered to be like endometrial clear cell carcinoma.

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

General

• Rare.
• Rapid growth, poor prognosis.
• Considered a subtype of adenosquamous carcinoma.

Microscopic

Features:

• 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.

DDx:

• Adenosquamous carcinoma of the uterine cervix.
• Squamous carcinoma of the uterine cervix.

Images:

• WC:
  • GCC - low mag. (WC).
  • GCC - high mag. (WC).
• www:
  • GCC - low mag. (webpathology.com).
  • GCC - high mag. (webpathology.com).
  • GCC - several images (upmc.edu).

Stains

• PAS stain - marks plasma membrane.

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).
• WC:
  • 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.^{[citation needed]}

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).