Lecture 7.1: Vulva, Vagina, and Cervix

Question 1

Which descriptive clinical term refers to opaque, white, plaquelike epithelial thickening that may produce pruritus and scaling?

Answer 1

Leukoplakia

Question 2

Which cause of leukoplakia presents as smooth, white plaques of macules on the vulva that in time may enlarge and coalesce, producing a surface that resembles porcelain or parchment?

Answer 2

Lichen Sclerosus

Question 3

What is seen histologically with Lichen Sclerosus?

Answer 3

• Marked thinning of epidermis (parchment paper) + fibrosis/sclerosis of superficial dermis
• Excessive keratinization (hyperkeratosis)
• Chronic inflammatory cells in deeper dermis = band-like infiltrate

Question 4

Who is lichen sclerosus most commonly seen in; what are the risks of cancer?

Answer 4

• All ages, but most common in post-menopausal women
• NOT a premalignant lesion
• Slightly ↑ risk of developing SCC of the vuvlva

Question 5

Pathogenesis of Lichen Sclerosus is uncertain, but there is a higher frequency in association with what?

Answer 5

Autoimmune disorders

Question 6

Squamous cell hyperplasia (aka lichen simplex chronicus) results from what and how does it present?

Answer 6

• Presents as leukoplakia w/ leathery, THICK vulvar skin w/ enhanced skin markings
• Due to chronic rubbing or scratching

Question 7

Histological examination of Squamous cell hyperplasia (aka lichen simplex chronicus) will show what?

Answer 7

Thickening of the epidermis (acanthosis) and hyperkeratosis

Question 8

Is squamous cell hyperplasia (aka lichen simplex chronicus) pre-malignant?

Answer 8

Not premalignant; sometimes present at the margins of vulvar cancer

Question 9

Condyloma acuminatum are benign genital warts caused by what; are they pre-malignant?

Answer 9

• LOW oncogenic risk HPV, mainly types 6 and 11
• NOT pre-malignant

Question 10

What is seen on histological examination of condyloma acuminatum; which characteristic cytopathic change is seen in the surface epithelium?

Answer 10

• Papillary, exophytic, tree-like cores of stroma covered by thickened squamous epithelium
• Surface epi. shows koilocytic atypia = nuclear enlargement + hyperchromasia and a cytoplasmic perinuclear halo

Question 11

What are the 2 groups of SCC of the vuvla; which is related to HPV and what age group is more commonly affected by each?

Answer 11

• Basaloid and warty carcinomas related to HPV-16; less common and occur in younger women (peak in 50’s)
• Keratinizing SCC unrelated to HPV; more common; occur in older women (peak in 70’s)

Question 12

Basaloid and warty carcinomas and keratinizing SCC of the vulva arise from what precursor lesions?

Answer 12

• Basaloid and warty = classic vulvar intraepithelial neoplasia (VIN)
• Keratinizing = differentiated vulvar intraepithelial neoplasia (aka VIN simplex)

Question 13

The risk of progression from VIN to invasive basaloid and warty carcinomas is higher in whom?

Answer 13

• Women older than 45 y/o
• Immunosuppressed

Question 14

Keratinizing SCC of the vulva occurs most often in women with what underlying condition?

Answer 14

Older women w/ long-standing lichen sclerosus or SCC hyperplasia

Question 15

Higher frequency of what type of mutations are seen in differentiated VIN leading to keratinizing SCC of the vulva?

Answer 15

TP53

Question 16

What is the morphology upon presentation of classic VIN; what is seen microscopically?

Answer 16

• Presents as a discrete white (hyperkeratotic) or slightly raised, pigmented lesion
• Microscopically, shows epidermal thickening, nuclear atypia + ↑ mitoses and lack of cellular maturation

Question 17

Which carcinoma of the vulva is characterized by nests and cords of small, tightly packed cells that lack maturation often with a foci of central necrosis?

Answer 17

Basaloid carcinoma (HPV-16 assoc.)

Question 18

Which vulvar carcinoma is exophytic w/ papillary architectureand prominent koilocytic atypia?

Answer 18

Warty carcinoma

Question 19

Which carcinoma of the vulva is characterized by nests and tongues of malignant squamous epithelium w/ prominent central keratin pearls?

Answer 19

Keratinizing SCC

Question 20

Which type of VIN is characterized by marked atypia of the basal layer of the squamous epithelium and normal-appearing differentiation of the more superficial layers?

Answer 20

Differentiated VIN

Question 21

Which lesions of invasive carcinoma of the vulva are associated with an excellent prognosis (90% at 5-years)?

Answer 21

Lesions <2 cm

Question 22

What sharply circumscribed nodule most commonly presents on the labia majora or interlabial folds, and is often confused clinically w/ carcinoma due to its tendency to ulcerate?

Answer 22

Papillary Hidradenoma

Question 23

Papillary hidradenomas are histologically identical to what other tumor; what are the 2 layers of cells seen on the papillary projections?

Answer 23

• Identical to intraductal papilloma of the breast
• Upper layer = columnar secretory cells covering
• Deeper layer = flattened myoepithelial cells

Question 24

How does extramammary paget disease of the vulva typically present?

Answer 24

Itchy, red, crusted, maplike area usually on labia majora

Question 25

What do the cell of Paget disease of the vulva express which allows for immunostaining?

Answer 25

**Cytokeratin 7**

Question 26

Paget cells have pale cytoplasm containing mucopolysaccharide that can be stained with what 3 stains?

Answer 26

**PAS**, **Alcian blue**, or **macicarimine** stains

Question 27

How does Paget disease of the nipple differ from extramammary Paget disease in terms of underlying cancer association?

Answer 27

- **Paget** of the **nipple** = **100%** of pt's have underlying **ductal breast carcinoma** - **Extramammary** = typically **not** associated w/ underlying cancer and is **confined to the epidermis of vulvar** skin

Question 28

Septate, or double, vagina is accompanied by a double uterus (uterus didelphys) and is due to failure of what?

Answer 28

Failure of **müllerian duct** fusion

Question 29

What is vaginal adenosis and who is it most commonly seen in?

Answer 29

- Small patches of **residual glandular** **epithelium** from the **developing vagina** which persist into adult life and are seen as **red, granular** areas - Women exposed to **DES** in **utero**

Question 30

Where are gartner duct cysts found and what are they derived from?

Answer 30

- **Lateral walls** of the **vagina** and derived from **wolffian (mesonephric) duct rests** - **Fluid-filled** cysts occurring in submucosal location

Question 31

In rare instances DES-related vaginal adenosis has been associated with what type of cancer?

Answer 31

Clear cell carcinoma

Question 32

What is the greatest risk factor for SCC of the vagina?

Answer 32

**Previous carcinoma** of the **cervix** or **vulva**; associated w/ **high-risk HPVs**

Question 33

List 3 benign tumors of the vagina that most often occur in women of reproductive-age.

Answer 33

- **Stromal tumors** (stromal polyps) - **Leiomyomas** - **Hemangiomas**

Question 34

In which location of the vagina are invasive tumors most often seen?

Answer 34

**Upper** vagina along the **posterior wall** at the junction with the **ectocervix**

Question 35

Embryonal rhabdomyosarcoma (aka sarcoma botryoides) arises where in the female genital tract and most often in what age group?

Answer 35

- Rare **vaginal** tumor - Most often in **infants** and **children \<4 y/o**

Question 36

How do embryonal rhabdomyosarcoma (aka sarcoma botryoides) appear on presenation?

Answer 36

Clear, **polypoid**, round, **grape-like mass** emerging from vagina

Question 37

How do the tumor cells of embryonal rhabdomyosarcoma (aka sarcoma botryoides) and tumor appear histologically?

Answer 37

- Small and have **oval** nuclei, w/ **small protrusions of cytoplasm from one end**, resembling a **tennis racket** - Tumor cells beneath vaginal epi. **= crowded** in a **cambium layer** - **Deep regions** lie in **loose fibromyxomatous stroma** that is **edematous**

Question 38

What is the prognosis and complications associated with embryonal rhabdomyosarcoma (aka sarcoma botryoides)?

Answer 38

- Tend to **invade locally** = **death** by penetration into **peritoneal cavity** or by **obstruction** of the **urinary tract** - **Surgery** + **chemotherapy** offer best hope in cases diagnosed early

Question 39

What is the "transformation zone" of the cervix and why is this area clinically significant?

Answer 39

- Area where **columnar epithelium** (endocervix) meets the **squamous epithelium** (ectocervix) = **Squamocolumnar Jct.** - Contains area of **immature squamous metaplatic** epithelial cells which are **highly** susceptible to infections with **HPV**

Question 40

In which location do cervical precursor lesions and cancer develop?

Answer 40

**"Transformation zone" = Squamocolumnar Junction**

Question 41

What is the dominant microbial species found in the normal vagina and what is its function?

Answer 41

- **Lactobacilli** - Produce **lactic acid**, which maintain vaginal **pH \<4.5** - Produce **bacteriotoxic hydrogen peroxide** (H₂O₂)

Question 42

What are endocervical polyps, where do they arise and how do they appear?

Answer 42

- Common **benign** exophytic growths arising **within endocervical canal** - **Vary** from **small, sessile "bumps"** to **large polypoid masses** that may protrude through cervical os

Question 43

What is the clinical significance of endocervical polyps?

Answer 43

May be source of **irregular vaginal "spotting" (bleeding)** that arouses suspicion of some more ominous lesion

Question 44

What is the most important risk factor for the development of cervical cancer?

Answer 44

**HPV** especially **type 16** (**60%** of cases) and (**10%** of cases)

Question 45

Which viral protein of high-risk HPV impairs the ability of cells to repair DNA and which up-regulates expression of telomerase leading to cellular immortalization?

Answer 45

- **E6** inhibits **p53** and ↑ regulates expression of **telomerase** - **E7** inhibits **RB** + **p21** and **p27** = impairs ability of cell to repair DNA damage

Question 46

How do the E6 and E7 proteins of low-risk HPV impact cellular growth and survival?

Answer 46

- **E7** proteins bind **RB** with **lower** affinity; **E6** proteins **fail** to bind **p53** - Dysregulate growth and survival by interfering w/ **Notch** signaling pathway

Question 47

What is the position of HPV DNA in precursor lesions assoc. w/ high-risk HPVs and in condylomata assoc. w/ low-risk HPVs?

Answer 47

DNA is **extrachromosomal (episomal)**

Question 48

How does the squamous cell that HPV infects differ from the cell that HPV replicates in?

Answer 48

- **Infects** _immature_ squamous cells; **cannot** infect mature cells - **Viral replication** occurs in **_maturing_** squamous cells

Question 49

How does the position of the viral DNA of HPV change with malignant transformation?

Answer 49

Viral DNA is **integrated** _INTO_ **the host cel**l genome --\> ↑ expression of **E6** and **E7**

Question 50

How does the viral replication and cellular proliferation differ between low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL)?

Answer 50

- **LSIL** have **high** levels of **viral replication** and only **mild** alterations in the growth of host cells --\> **NOT** treated as **pre-malignant** - **HSIL** = **lower** rate of **viral replication** w/ ↑ cellular **proliferation** and ↓ or arrested epithelial maturation --\> **high risk** for progression to carcinoma

Question 51

Diagnosis of squamous intraepithelial lesions (pre-cursor lesions) is based on identification of what characteristics of nuclear atypia?

Answer 51

- Nuclear **enlargement** - **Hyperchromasia** (**dark staining**) - **Coarse** **chromatin granules** - Variation in **nuclear size** and **shape**

Question 52

Nuclear changes seen in squamous intraepithelial lesions often accompanied by what cytoplasmic finding?

Answer 52

Cytoplasmic **"halos"** + **nuclear alterations** = **koilocytic atypia**

Question 53

How does expansion of the immature cell layer in the normal basal location dictate the grading of a low vs. high-grade squamous intraepithelial lesion?

Answer 53

- **LSIL** = immature cells confined to the **lower 1/3** of the **epithelium** - **HSIL** = expansion to the **upper 2/3** of the **epithelial thickness**

Question 54

Staining for what cell markers highly associated with HPV infection is useful for confirmation of the diagnosis in equivocal cases of SIL?

Answer 54

**Ki-67** (marker of **actively dividing** cells) and **p16** (characterized **high-risk** infections)

Question 55

After SCC what is the second most common tumor type (15%) of the cervix and which 2 types represent only 5% of cases?

Answer 55

- **Adenocarcinoma** (**15%**) - **Adenosquamous** and **neuroendocrine** carcinomas (**5%**)

Question 56

Advanced cervical carcinoma spreads how and to where?

Answer 56

**Direct extension** to **contiguous tissues:** ## Footnote - **Paracervical soft tissue** - **Urinary bladder** - **Ureters** --\> hydronephrosis **- Rectum** **- Vagina**

Question 57

Lymphovascular invasion by advanced cervical carcinoma may cause distant metastases to what organs?

Answer 57

**Liver + Lungs + Bone marrow**

Question 58

Which cancer of the cervix is associated with a very poor prognosis?

Answer 58

**Small-cell neuroendocrine** tumors

Question 59

Most patients with advanced cervical cancer die due to what?

Answer 59

**Local tumor invasion** --\> ureteral obstruction, pyelonephritis, and uremia

Question 60

An abnormal Pap test should be followed up with what?

Answer 60

**Colposcopic exam** of the **cervix** and **vagina** to identify lesion

Question 61

What % of cervical cancer arise in women who were not in a regular screening program?

Answer 61

**50%**

Question 62

What is the significance of persistent HPV infections?

Answer 62

Persistent infection ↑↑↑ risk for cancer

Question 63

What % of LSIL regress, persist, and progress to HSIL within 2-year follow-up?

Answer 63

- **60% regress** - **30% persist** - **10%** progress to **HSIL**