Uterine cervix

The cervix, or uterine cervix to be more precise, 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.

Introduction

• 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".
• Most cervix cancer is squamous cell carcinoma.

Common benign

Nabothian cyst

• Simple endocervical cyst.
  • Lined by endocervical epithelial cells.
    • Columnar morphology with large clear, apical vacuoles.

Image:

• Nabothian cyst (gfmer.ch).

Tunnel cluster

• Benign proliferation of endocervical glands
• Important only as one could mistake minimal deviation adenocarcinoma for it. (???)

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.

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.

Mnemonic: The Cs (Cervix & Colon) are similar.

Cervical intraepithelial neoplasia (CIN)

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) + followup.

LEEP = Loop Electrosurgical Excision Procedure (LEEP) Procedure.

• 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.

Histologic changes in CIN I, CIN II and CIN III

• CIN I = cytoplasmic halos (koilocytic atypia), atypical cells close to basement membrane only.
  • 3:1 enlargement of nucleus vs. normal
  • Binucleation may be seen (cytopathic effect of HPV)
• 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.
• CIN III = same changes as in CIN II + outer third (or full thickness).

Ref.:

Notes:

• Hyperchromasia is a very useful feature for identifying CIN (particularly at low power, i.e. 25x).
• Kiolocytes are the key feature of CIN I.
• Kiolocytes are not considered to be part of a CIN II lesion or CIN III lesion.
• Large irregular nuclei are not required for CIN II... but you should think about it.
• Some mild changes at the squamo-columnar junction are expected.
• Look for the location of mitoses...
  • If there is a mitosis in the inner third (of the epithelial layer) = at least CIN I.
  • If there is a mitosis in the middle third (of the epithelial layer) = at least CIN II.
  • If there is a mitosis in the outer third = CIN III.
• Nucleoli are usually NOT present in CIN.
  • Nucleoli are common in reactive changes.

Kiolocytes versus benign squamous

Kiolocytes:

• 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.

Cervix cancer grading

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

Ref.:

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

Pitfalls:

• Squamous metaplasia.
  • If you can trace the squamous cells from a gland to the surface it is less likely to be invasive cancer.

See: http://www.nature.com/modpathol/journal/v15/n3/pdf/3880520a.pdf

Squamous metaplasia

Squamous metaplasia is a response to inflammation...

• Nuclei are uniform size and round.
• Intercellular bridges are often seen/edema is often seen.
• Uniform cell spacing, i.e. NO crowding.
• NEGATIVES:
  • No mitoses (think cancer/CIN if you see 'em)
  • Usually no hyperchromatism (think cancer/CIN if you see it)

Notes:

• It is possible to confuse CIN III with squamous metaplasia.

IHC:

• p16 (poor man's test for HPV).
• Ki-67 (proliferation marker).

Adenocarcinoma

• Adenocarcinoma of the cervix/adenocarcinoma in situ (AIS) of the cervis is much less common than squamous dysplasia of the cervix/SCC of the cervix.
• AIS/adenocarcinoma arises can arise from the endocervical glands.

AIS

• Diagnosis of AIS dependent primarily on nuclear changes:
  • Nuclear crowding.
  • Nuclear hyperchromasia.
  • Cigar-shaped nuclei.
  • +/-Mitoses.
• Cytoplasm.
  • Hyperchromasia.

Invasive

• Invasive adenocarcinoma
  • May be difficult to be certain.
  • 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.

IHC

Uterus vs. cervix:

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

See also

• Vulvar intraepithelial neoplasia.
• Cervical polyp.