February 26 (Mon)



February 26 (Mon)

Path – 11AM

Dr. Mira

Landry / Wilson

P022611.doc

Scribe for hire: James Morgan

And now for something completely different…

THE CERVIX

Side Note: Dr. Mira covered a lot of stuff today. So pull up the his website, look at the pictures, sit back, relax, and learn…



I. Intro…the basics of cervixology:

A. Part of the uterus, divided into two sections

1. Endocervix (w/columnar cells)

a. mucus secreting epithelium that has crypts (endocervical glands)

2. Vaginal (w/squamous cells)

a. needed to constantly replace this area subjected to lower pH

B. Squamocolumnar junction

-where squamous and glandular epithelium meet

1. at birth, is at the os (fig 24-2a)

2. reproductive age (fig 24-3a)

3. after giving birth, the junction is everted ( it is exposed to the lower pH and the naked eye (fig 24-2b)

a. this leads to the production of a transformation zone (24-2c) because of:

1) epidermidalization (ingrowth of squamous epithelium)

2) squamous metaplasia (intrinsic squamous differentiation of subcolumnar reserve cells)

4. from the post-birth to menopause, this junction begins to move cephalad

a. after menopause, it is usually inverted and ( not visible anymore (fig 24-3b)

5. This zone of proliferation and change is the place where pre/cancerous lesions may appear (see further down)

CERVICAL INFLAMMATION

I. Acute Cervicitis (benign lesion)

A. Pathogenesis

1. At menarche, estrogens ( maturation (glycogen production) of cervical squamous epith (along with vaginal squamous)

a. cells shed ( glycogen = substrate for endogenous bacteria (streptococci, enterococci, E. coli, staphylococci)

b. bacterial growth (’s pH

c. this leads to transformation of cervical columnar to squamous epithelium (see above also)

d. this is a normal process that occurs in all women

2. This inflammation of the cervix can also be caused by:

a. Trauma

b. Other infections

-Candidal / Trichomonal spread (from vaginitis)

-STD involving the cervix (gonorrhea, chlamydia, herpes)

-post partum infections (staphylococci, streptococci)

c. even clinical manipulation

II. Chronic Cervicitis (fig 24-15)

A. In all sexually active women

B. Pathogenesis

1. severe and chronic stromal inflammation (PMN, mononuclear cells) leading to the loss of:

a. epithelial lining (ulcer/erosion)

b. epithelial repair (dysplasia of repair or reparative atypia)

C. Caused by: STD’s & Other Diseases

1. Chlamydia ( follicular cervicitis w/lymphoid follicles (fig 24-16)

2. Herpes

a. large multinucleated cells

b. peripheral margination of chromatin = glassy appearance

3. TB

a. granulomas w/central necrosis

b. multinucleated giant cells w/nuclear proliferation toward surface of cell

D. Secondary Changes

1. Nabothian Cyst (benign)

a. when the squamous overgrowth (transformation) occurs, can cover a columnar crypt ( obstruction ( mucus filled cyst (Nabothian cyst)

b. micro: dilated lakes of mucus compress the epithelium

2. Microglandular Hyperplasia

a. proliferation of endocervical glands (filled w/PMNs)

b. eventually ( Squamous metaplasia (b/c inflammation)

c. frequent w/women using oral contraceptives

E. Random other stuff

1. Mesonephric Duct remnants (rests)

a. lateral cervix ( can become cystic

III. Endocervical Polyps (Benign)

A. General

1. Inflammatory polyps occurring in 2-5% of women

2. May cause irregular vaginal spotting / bleeding

a. polyp is very vascular even on the tip

3. Vary in size, may protrude through cervical OS

4. Simple curettage / excision is curative

B. Types

1. Decidual

a. growth (polyploid) of stromal decidual reaction

b. associated w/intra- or extrauterine gestation

c. made of subepithelial stroma

-mesodermal and mullerian (responds same as endometrium)

-can transform into decidua

d. the perineum can develop decidual reaction during pregnancy

-reaction called Leiomymatosis Peritoneal Disseminata

2. Fibrous

3. Glandular

a. usually present w/polyp protruding through cervical os (pedunculated)

b. very stressing to pt b/c looks similar to more serious diseases

1) looks like malignant tumor of endometrium, leiomyoma (myometrium)

2) must do Bx (biopsy) to determine what it is

C. Differential Dx of protrusion from cervix like a polyp

1. Pedunculated mucosal myoma (originate in myometrium – leiomyoma)

2. Endometrial Carcinoma

a. develops on endometrial polyps

b. can be malignant

3. so anything that protrudes through endocervical mucosa and into cervical canal should be excised and examined

4. one last protrusion:

a. uterine prolapse – try not to get them confused (the entire cervix has fallen out of the vagina so shouldn’t be too hard too tell the difference)

D. Micro (fig 24-17)

1. Stroma (in general - inflamed, fibrotic)

a. large blood vessels

- thick walled, fibrotic vessel

- branch toward distal end of polyp

b. glands

-proliferation (usually peripheral)

-papillary endocervicitis (endothelial papillary growth)

2. epithelium

a. acute/chronic inflammation

b. squamous metaplasia

-when polyp gets into vagina and the epithelium changes

INTRAEPITHELIAL AND INVASIVE SQUAMOUS NEOPLASIA

I. Risk Factors for Cervical Dysplasia / Carcinoma

A. Early age at 1st intercourse

B. Multiple sexual partners

C. Male partner w/multiple previous sexual partners

-characteristics of this guy include:

1. congenital carcinoma (esp. squamous cell CA of the penis)

2. ( socioeconomic status

3. ( sexual partners

4. poor hygiene

D. HPV (oncogenic infection)

1. Evidence linking HPV to CA

a. HPV DNA in 85% cervical CA; in 90% cervical condylomata and dysplasias

b. HPV Types 6, 11, 42, 44 = assoc w/condylomata (low risk)

-have free episomal viral DNA

c. HPV Types 16, 18, 31, 33 = assoc w/ advanced dysplasias and invasive CA (high risk)

-have capacity to transform cells in culture (E6, E7 viral oncogenes)

-E6 binds tumor suppressor p53 (ceases to function)

E. 15% of cervical CA = non-HPV associated

F. Other STDs that may lead to cervical dysplasia or cancer

1. Herpes

2. Chlamydia

3. Gonorrhea

4. Syphilis

5. Trichomonas

II. Cervical Dysplasia and CIN (fig 24-18)

A. Classification of CIN

|( grade SIL |CIN I (fig 24-20b) |HPV, condyloma (May only need to be followed w/PAP smears) |

| | |Mild Dsyplasia (May require topical or local Tx) |

| |

|( grade SIL |CIN II (fig 24-20c) |Moderate Dysplasia |SIL = Squamous Intraepithelial Lesion |

| | | |CIN = Cervical Intraepithelial Neoplasia |

| | | |

| |CIN III |Severe Dysplasia | |

| | | | |

| | |Carcinoma-in-situ (fig 24-20d) | |

A. Pathogenesis and pathology of infection with HPV (in basal cells and immature squamous metaplastic cells)

1. latent infection (many do not ( dysplasia for at least 10yrs)

a. no viral expression

b. epithelium = NL

1) benign condyloma – virus proliferation independent of host cell

2. Virus begins to proliferate (condylomata)

a. faster than NL cells

b. changes seen on surface of epithelium

c. Atypical koilocytes = ABN nucleus and perinuclear halo (fig 24-19)

*hallmark of condyloma (atypical koilocyte)

-Hyperkeratosis = thickened keratin layer (no nuclei)

-Parakeratosis = hyperkeratosis w/nuclei

3. Dysplasia (with or w/o viral DNA integration) (histologically = diagnosis and stage)

a. Mild (CIN I)

- begins w/proliferation of basal cells that fail to mature

- koilocytotic atypia (lower 1/3 epith cells) w/perinuclear halos

- large, hyperchromatic nuclei

- disorganized cells (loss of polarity)

b. Moderate (CIN II)

- progressive atypia = lower ½ ( 2/3 of epith.

- ABN mitotic figures

c. Severe (CIN III)

- almost entire layer

- hyperchromatic, ( mitotic figures, ( N/C ratio

d. Carcinoma-in-situ (CIN III)

- full thickness atypia w/loss of maturation

- viral DNA integrated

- can be followed by invasive carcinoma

4. Dysplasia (cytologically = for screening) fig 24-21

a. HPV Condyloma

- Koilocytes

- Nucleus: binucleation, perinuclear halo

- Chromatin: hyperchromatic, coarse, granular, fills nucleus

- Cytoplasm: thickened, pushed to periphery

- Membrane: wavy, demarcated

b. Mild dysplasia

- Nucleus: 3-5 x’s NL size,

- Chromatin: hyperchromatic, coarse, granular, some euchromatic spaces

- Cytoplasm: abundant (~ 1 nucleus diameter thick)

- Membrane: smooth

c. Moderate dysplasia

- Nucleus: 5-7x’s NL in relation to cytoplasm ((N/C ratio)

- Chromatin: coarse, irreg. distribution, hyperchromatic

- Membrane: nuclear membrane irregularity

d. Severe dysplasia

- Nucleus: takes up almost entire cell ((’r N/C ratio)

- Membrane: well delineated margins

- Cell size: ( drastically

e. Carcinoma-in-situ

- Nucleus: same as severe, maximal (N/C ratio

- Membrane: no margins seen

5. From book, of those exposed to HPV, 50% are ( risk ( 10% of those have persistent ( grade CIN ( 1.3% become carcinoma ( 0.4% die

C. Diagnosis of Dysplasia

1. 1st perform PAP smear (can detect most cervical dysplasias)

-PAP can be on Simprep® (test kit that you can do in the clinic)

a. out of 1 million diagnoses of dysplasia, only 1.5% ( carcinoma (mostly b/c of early detection and Tx)

2. If PAP = ABN, then Bx and check histologically

-look w/colposcopy (( power microscope that you use w/speculum to Bx proper area)

a. Cytologically,

CIN I(CIN III (as progresses, so does N/C ratio)

3. if demonstrates dysplasia, then Tx

a. Mild dysplasia = close follow-up

b. Moderate and severe = cervical conization (cutting a cone of tissue out) or hysterectomy

II. Squamous Cell Carcinoma ()

A. Epidemiology, Clinical

1. Peak age = 40-45 y/o

a. though not rare to see in 25 y/o, and in situ dysplasia in teens

b. conversion from in situ ( invasive = ~10yrs

2. Sx = similar to other cervical CA

a. most prominent = post-coital bleeding

b. leukorrhea, coital pain, dysuria

3. 5 Year Survival Rates (FYS)

|Stage |FYS |

|I |80-90% |

|II |75% |

|III |35% |

|IV |10-15% |

|Death usually due to local extension of tumor, not METS |

|(metastases) |

B. Types (fig 24-22)

1. Exophytic

a. 80% of

b. projects above the surrounding mucosa

c. has infiltrative components

d. polyploid andenocarcinoma

2. Ulcerative

a. has infiltrative components

b. more common in cervical adenocarcinoma (except polyploid andenocarcinoma)

3. Infiltrative

C. Micro (Dr. Mira starting speeding things up here)

1. will see keratin pearls

a. if they are there, then tumor is still differentiated = good

III. Other carcinomas of the Cervix

A. Adenocarcinoma

1. General

a. 3-7% of cervical CA ((’ing)

b. most present w/vaginal bleeding

c. little worse prognosis than

B. Small Cell Undifferentiated Carcinoma

1. Similar to Oat Cell Carcinoma of lung (histologically)

2. Early METS and ( mortality

3. Usually infiltrative

4. Both RadioTx and ChemoTx sensitive

IV. Staging of Cervical Carcinomas

|Stage |5 Year Survival Rate |Definition |

|0 |100% |Carcinoma-in-situ (CIN III) |

|I |80-90% |Carcinoma confined to cervix |

|II |75% |Beyond the cervix, but not to pelvic wall or lower 1/3 of vagina |

|III |35% |Extension onto pelvic wall, involving lower 1/3 of vagina |

|IV |10-15% |Extension beyond true pelvis or involvement of the bladder or rectal mucosa, distant METS |

“Where there are no oxen, the manger is empty, but from the strength of an ox comes an abundant harvest”

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