Female genital tract

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Inflammation, infection and non-neoplastic disease221

21.2 Dysplasia and neoplasia223
21.3 Pathology related to pregnancy227

Self-assessment: questions228
Self-assessment: answers229

Chapter overview
The female genital tract comprises the vulva, vagina, uterus, cervix, fallopian tubes and ovaries. Infections in this region are common. Many are relatively trivial, but pelvic inflammatory disease can cause infertility or serious intra-abdominal sepsis. Infection with certain subtypes of human papilloma virus (HPV) predisposes to dysplasia and malignancy in the cervix. Carcinoma of the ovary is the fifth most frequent cause of female cancer mortality in the UK, and often presents at an advanced state. In contrast, the cervical cytology screening programme has allowed early diagnosis of premalignant and invasive cervical carcinomas in many cases, with a consequential fall in mortality from cervical cancer of approximately 40%. Disorders relating specifically to reproductive function include endometriosis, ectopic pregnancy and hydatidiform mole.

21.1. Inflammation, infection and non-neoplastic disease

Learning objectives
You should:

• know the common female genital tract infections
• know about human papilloma viruses (HPV)-associated diseases
• understand the pathology of endometriosis.

Genital tract infection

Common causes include:

• bacteria – Gardnerella, Neisseria gonorrhoeae, Chlamydia
• viruses – HPV, herpes simplex type 2
• fungi – Candida albicans
• protozoa – Trichomonas vaginalis.

Gardnerella

Gardnerella is a common cause of vaginitis.

Neisseria gonorrhoeae

N. gonorrhoeae can infect the cervix, endometrium, fallopian tubes and ovaries.

Chlamydia trachomatis

C. trachomatis is an intracellular pathogen that causes urethritis, cervicitis and lymphogranuloma venereum (genital ulceration with suppurative and granulomatous inflammation of pelvic, inguinal and rectal lymph nodes). Transmission to neonates during vaginal delivery can cause conjunctivitis and pneumonia.

Staphylococcus

Toxic shock syndrome is a rare but serious infection caused by exotoxins produced by Staphylococcus aureus. It is associated with tampon use and presents with fever, diarrhoea and vomiting, rash and shock. Occasionally it can be fatal.

Human papilloma virus

This infects squamous epithelia at many body sites (see Table 37). Low-risk subtypes cause genital warts (condylomata acuminata); high-risk subtypes are associated with the development of cervical carcinoma. HPV changes are frequently seen in association with cervical dysplasia on tissue biopsy. HPV serotyping using the polymerase chain reaction is likely to play an important part in future cervical cancer screening programmes. Cytological features associated with HPV infection include irregular enlarged hyperchromatic nuclei surrounded by poorly staining cytoplasm (these features are known as koilocytosis), multinucleation and abnormal keratinisation.
Table 37 HPV subtype disease associations
HPV subtype Associated lesions
1, 2, 4, 7 Benign squamous cell papillomas (viral warts)
5, 8 Cutaneous squamous cell carcinoma
6, 11 Benign anogenital warts (condylomata acuminatum)
16, 18 High-grade cervical epithelial dysplasia
(31, 33, 35) (CIN) and squamous carcinoma

Herpes simplex type 2

Infection is relatively common in young women. Ulcerating vesicles develop on the vulva, vagina or cervix several days after sexual contact. Spontaneous healing occurs but latent infection leads to recurrent attacks. Neonatal transmission during vaginal delivery can cause severe systemic infection and neonatal death. Herpes simplex 2 is also associated with cervical carcinogenesis.

Trichomonas vaginalis

Trichomatosis is a sexually transmitted infection and causes a foamy discharge, itching, dysuria and dyspareunia. Trichomonas, Candida and herpes virus infections may be identified incidentally on cytological examination of routine cervical screening smears (see below).

Pelvic inflammatory disease

Pelvic inflammatory disease (PID) describes a chronic upper genital tract infection that presents as pelvic pain, fever and vaginal discharge. Causative organisms include gonococci and Chlamydia, although other bacteria can cause PID following termination of pregnancy or spontaneous vaginal delivery. Actinomycosis is a common infection in users of contraceptive coils. Infection spreads from the lower genital tract to the fallopian tubes and ovaries. Complications include tubo-ovarian abscess, pyosalpinx, peritonitis, intestinal obstruction and infertility.

Chronic endometritis

Chronic endometritis is identified microscopically by the presence of plasma cells in the endometrium. Chronic endometrial infection occurs:

• in association with intrauterine contraceptive devices (IUD, ‘coil’)
• in patients with chronic PID
• in association with retained products of pregnancy
• in tuberculosis – diagnosis can be difficult as cyclical endometrial shedding prevents the formation of typical caseating granulomas
• without other associated factors (15%).
Treatment depends on the underlying cause – antibiotics, removal or replacement of the IUD or endometrial curettage to remove retained gestational tissue.

Lichen sclerosus

Lichen sclerosus a chronic inflammatory skin condition that most commonly affects the vulva. Classically, the surface keratin is thickened, the epidermis is atrophic and the dermis is abnormally fibrotic. There is an increased risk of developing squamous cell carcinoma.

Endometriosis

Endometriosis a common condition in which endometrial glands and stroma are present in organs other than the uterus (Box 28 and Figure 57). Typical sites of endometriosis include the ovaries, fallopian tubes, uterosacral ligaments, Pouch of Douglas and cervix, but it can occur throughout the peritoneum and even within distant organs such as the lung. The process is not neoplastic but the mechanism(s) by which endometrial tissue establishes itself in these extrauterine sites remains uncertain. Theories include:

• endometrial metaplasia
• retrograde flow through the fallopian tube at menstruation
• implantation after surgery
• bloodstream spread of viable endometrial fragments.
Box 28

Symptoms related to cyclical bleeding and subsequent inflammation:

• pain, often dyspareunia or dysmenorrhoea
• ovarian cysts (‘chocolate cysts’ containing altered blood)
• infertility (fallopian tube involvement)
• haematuria (bladder endometriosis)
• intestinal obstruction
• endometriotic nodules in abdominal surgical scars.
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Figure 57

Endometriotic foci may show proliferative and secretory activity in response to oestrogen and progesterone, in the same way as normal uterine endometrium. Endometriosis in the ovary is associated with clear cell adenocarcinoma (see below). The presence of endometrial glands and stroma within the myometrium is called adenomyosis.

Polyps

Polyps are benign polypoid proliferations of glandular epithelium and stroma. They can arise in the endocervix and endometrium and may cause abnormal vaginal bleeding. Endometrial polyps occur most frequently after the menopause, and the incidence is increased in breast carcinoma patients receiving treatment with tamoxifen.

Ovarian cysts

Benign follicle (‘follicular’) and corpus luteum cysts are very common, but sometimes raise clinical suspicion of malignancy if seen on an ultrasound scan. Multiple bilateral follicular cysts, associated with ovarian enlargement, menstrual irregularities, hirsutism, obesity and infertility, are features of polycystic ovarian disease. The underlying cause seems to be abnormal release of pituitary hormones.

21.2. Dysplasia and neoplasia

Learning objectives
You should:

• understand the principles and practice of the NHS Cervical Screening Programme
• have sufficient knowledge of neoplastic disease of the female genital tract to interpret histopathology reports of these tumours.
Dysplasia means abnormal growth. Dysplastic epithelium shows morphological changes of neoplastic cells but without evidence of invasion (Figure 58). Dysplastic changes include:

• increased nuclear to cytoplasmic ratio
• nuclear pleomorphism (variation in size and shape)
• nuclear hyperchromatism (increased intensity of staining)
• abnormal mitoses
• abnormal cellular crowding
• failure of epithelial maturation.
Epithelial dysplasia occurs throughout the lower female genital tract:

• vulval intra-epithelial neoplasia (VIN)
• vaginal intra-epithelial neoplasia (VAIN)
• cervical intra-epithelial neoplasia (CIN)
• cervical glandular intra-epithelial neoplasia (CGIN)
• atypical endometrial hyperplasia.
The intra-epithelial neoplasia of squamous epithelium in the vulva, vagina and cervix (VIN, VAIN and CIN) is numerically graded from 1 to 3, according to the severity of dysplastic changes. Thus, CIN 1 is low-grade cervical dysplasia in which the cellular abnormalities are confined to the lower third of the squamous epithelium. In CIN 3 (high-grade dysplasia, also called carcinoma in situ), the entire thickness of the epithelium is abnormal, showing cytological features of malignant cells. However, there is no invasion of the atypical cells beyond the epithelial basement membrane and so there is no capacity for local spread or distant metastasis. CGIN describes dysplasia of endocervical glandular epithelium, and is classified as either low or high grade.
Only atypical hyperplasia is regarded as a high-risk premalignant change. Like other adaptive tissue changes, hyperplasia remains under the control of the eliciting stimulus. If the oestrogen excess is neutralised, for example by exogenous progesterone administration, the hyperplasia will regress. Even early stage endometrial carcinoma may be effectively treated in some cases with progestogens rather than surgery.

Cervical screening

The ability to recognise the abnormal cells from dysplastic cervical epithelium forms the basis of the NHS Cervical Screening Programme. All women between the ages of 25 and 65 are invited to have a cervical smear examination every 3–5years. A brush is used to gently remove cells from the surface of the cervix, ensuring that the cervical os is adequately visualised and the transformation zone is sampled. The cells are examined under the microscope for nuclear changes – enlargement, chromatin abnormalities and nuclear membrane irregularities – which might indicate a dysplastic or malignant lesion. The cytological changes are called dyskaryosis and graded as mild, moderate or severe. The screening programme was originally intended to identify dyskaryosis in the squamous epithelial cells, but it is possible to detect endocervical glandular abnormalities in some cases. Smears that show changes of HPV infection in the absence of dyskaryosis are still regarded as abnormal and warrant further follow-up, in view of the association between HPV and cervical neoplasia. Cytological abnormalities that do not amount to unequivocal dyskaryosis may be described as ‘borderline’, and again these changes require more regular follow-up smears to exclude significant disease.
The success of the programme depends on the detection and treatment of women with asymptomatic dysplastic lesions (CIN and CGIN) before they progress to invasive carcinoma. The degree of dyskaryosis in the cervical smear is an indication of the likely severity of dysplasia in the epithelium. High-grade smear abnormalities or persistent low-grade changes require colposcopic examination of the cervix by a gynaecologist, with tissue biopsy for histological confirmation of dysplasia (Figure 59). Treatment by laser, cold coagulation or tissue resection is followed up with regular smears, until it is safe for the patient to return to routine recall.
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Figure 59

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