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Dorchester Center, MA 02124
The female reproductive tract comprises the vulva, vagina, uterus, fallopian tubes and ovaries. As in other systems, a wide range of pathological conditions may occur in these organs. Malignant tumours and their precursor conditions are of major pathological importance. An interesting feature of the female genital tract is that there is a range of epithelial malignancies that can occur at almost any site in the tract. For example, serous adenocarcinoma is most commonly found in the ovary but can also present in the uterus and cervix.
The vulva is subject to many of the conditions affecting skin elsewhere in the body, including inflammatory conditions such as dermatitis and lichen planus (see Ch. 21 ), but is also an important site for sexually transmitted infections, including the chancre of primary syphilis. Many vulval inflammatory lesions lead to intense itching and the histological features of these conditions are therefore complicated by the effects of trauma from scratching (lichen simplex chronicus) . In some post-menopausal women, the vulval mucosa tends to become thickened and white as a result of epithelial atrophy and subepithelial fibrosis, a condition known as lichen sclerosus et atrophicus ( Fig. 17.1 ).
Benign tumours of the vulva are relatively uncommon and include Bartholin’s gland cysts, fibroepithelial polyps (skin tags), haemangiomas (see Fig. 11.8 ) and benign naevi. Hidradenoma papilliferum , a benign tumour of apocrine sweat gland origin, typically presents as a firm ulcerated nodule in the vulva and has a distinctive histological appearance of uniform apocrine cells arranged in papillary fronds and surrounded by a fibrous stroma ( Fig. 17.2 ).
The majority of malignant tumours arising in the vulva are well differentiated squamous cell carcinomas, similar to those of the skin and mucous membranes ( Figs 7.3 and 17.8 ). Squamous cell carcinoma of the vulva is preceded by epithelial dysplasia, known as vulval intraepithelial neoplasia (VIN) . There are now two recognised types of VIN: ‘usual type’ , which is associated with HPV infection, and ‘differentiated’ , which is associated with lichen sclerosus et atrophicus ( Table 17.1 and Fig. 17.3 ). Clinically, it can be difficult to differentiate these conditions from inflammatory lesions and biopsy is necessary for diagnosis.
|Usual Type VIN||Differentiated VIN|
|Age||Young women||Older women|
|Key histological features||Basaloid/warty: conventional dysplasia||Dysmaturation|
|Grading||Can be low or high grade dysplasia||Always high grade|
|Associations||High risk HPV||Lichen sclerosus et atrophicus|
Paget’s disease of the vulva or extramammary Paget’s disease (EMPD) is a rare vulval tumour that has an identical histological appearance to Paget’s disease of the breast (see Fig 18.13). In most cases, EMPD is confined to the epidermis but there are rare cases of an associated invasive primary vulval adenocarcinoma. EMPD can also arise secondary to adenocarcinomas in the nearby anus, rectum or bladder and this should be excluded clinically. Other rare malignant tumours of the vulva include basal cell carcinoma, malignant melanoma and adenocarcinoma arising in Bartholin’s glands.
Disorders of the vagina include infections such as Candida (see Fig.5.15) and Trichomonas (see Fig 5.20), cysts and endometriosis. Rarely, dysplasia can occur in the vagina, similar to that in the vulva, perianal region and cervix (vaginal intraepithelial neoplasia, VAIN) . Primary tumours of the vagina include squamous cell carcinoma and adenocarcinoma .
C cystic space E epidermis F fibrous stroma H hyalinised collagen In inflammation R rete pegs W well circumscribed edge
The cervix frequently exhibits chronic inflammatory changes, known as chronic cervicitis ( Fig. 17.4 ), which may also be associated with polypoid hyperplasia of the endocervical mucosa. This can result in the formation of a pedunculated polyp containing distended endocervical glands and stroma ( Fig. 17.5 ). Clinically, the most important lesions of the cervix are epithelial dysplasia of varying degrees of severity and squamous cell carcinoma . These related conditions and their pathogenesis are considered in detail in Figs 17.6 to 17.8 . Neoplastic, pre-invasive changes are termed cervical intraepithelial neoplasia or CIN . The terminology for grading these lesions is evolving and is discussed in Fig. 17.7 . Glandular dysplasia also occurs in the cervix and is known as cervical glandular intraepithelial neoplasia (CGIN) . CGIN and invasive adenocarcinoma of the cervix are less common than CIN and squamous cell carcinoma.
The understanding that most, if not all, invasive cervical carcinomas are preceded by a long period of pre-invasive neoplastic change in the cervix has led to a revolution in the treatment of cervical carcinomas. These changes are detectable on cytological examination of smears of the cervix, permitting early treatment and prevention of progressive disease. Cytological screening programmes in many countries have reduced the number of deaths from cervical carcinoma. Almost all cervical dysplasia and cancers are caused by persistent infection by oncogenic types of human papillomavirus (HPV), a very common sexually transmitted virus.
In most screening programmes, a positive cytology result is followed up with direct visualisation of the cervix by colposcopy along with a biopsy for definitive diagnosis. HPV testing is increasingly being used to help ‘triage’ those with positive cytology or to assess cytological smears in women who have had colposcopic treatment (test of cure). More recently, there is a drive to perform primary HPV testing on cervical smears so that only women with a positive HPV test would require cytological examination of their smear. This will potentially have major implications on cytology laboratory infrastructure and staffing.
In the UK, cervical smears taken as part of the national screening programme are reported based on guidelines from the British Association of Cytopathology. Biopsies and large loop excisions of the transformation zone (LLETZ) are reported using the World Health Organization (WHO) system. These classifications are described in further detail in Figs 17.6 and 17.7 ; however, it should be noted that both systems now also use a simplified two-tier classification (low or high grade) rather than the old three-tier classification (CIN 1/2/3, mild, moderate and severe dyskaryosis), allowing improved reporting consistency. In practice, many pathologists use both the old and new classifications in clinical reports.
The ectocervix is covered by stratified squamous epithelium while the endocervix has a lining of simple columnar mucin-secreting cells. The junction between the two varies during reproductive life with changes in the volume of the cervical stroma. This expands under the influence of hormones during each menstrual cycle, at menarche and during pregnancy and this causes eversion of the vaginal end of the endocervical canal, thus exposing some of the simple columnar epithelium to the vaginal environment. This exposed epithelium appears red in relation to the surrounding stratified squamous epithelium and hence became inaccurately known as a cervical erosion; more appropriate is the term cervical ectropion . Under the influence of the vaginal environment, the ectopic columnar epithelium may undergo squamous metaplasia (see Fig. 6.5) to form stratified squamous epithelium. This metaplastic area, known as the transformation zone , appears to be sensitive to the oncogenic effects of HPV. HPV can also infect other squamous cells in the vagina, vulva and perianal region, as well as at more distant sites such as the oesophagus (see clinical box ‘Human papillomavirus (HPV) and cancer’).
B basal atypia D dysplastic epidermis Di differentiated VIN Ep squamous epithelium F Nabothian follicle G gland In Invasive well differentiated squamous cell carcinoma J squamocolumnar junction K koilocytes Pa parakeratosis P polyp R elongated rete ridges
D dyskaryotic cells K koilocytes L lower third of epithelium M mitotic figures S cervical squamous cell
It is now well established that persistent infection with high risk types of HPV causes a number of cancers, including cervical, anal, vulval, penile and oropharyngeal cancers (OPSCC). HPV is transmitted via skin/mucous membrane contact during sexual activity and is usually asymptomatic. The majority of infections are cleared quickly by the host immune system. A small number remain persistent. There are over 100 types of HPV, which can be broadly divided into two categories:
High risk : There are at least 13 oncogenic types, the commonest being HPV 16 and 18.
Low risk : HPV 6 and 11 are the commonest and cause condyloma acuminata (genital warts) and respiratory papillomatosis.
High risk types of HPV possess viral genes, which can act as oncogenes (see Ch. 1 ). The early E6 and E7 genes are particularly important in carcinogenesis. For example, the E6 gene product is known to bind and inactivate p53 in the host cell. p53 has a key role in tumour suppression as it normally inhibits the cell cycle and promotes cell death if DNA damage is present. Its inactivation by the E6 protein can therefore allow unregulated proliferation of genetically abnormal cells, leading to dysplasia and cancer.
There are a number of factors that can increase the risk of persistent infection, development of pre-invasive changes (dysplasia) and subsequent cancer, including smoking, early first sexual contact, multiple sexual partners and immunodeficiency (HIV/AIDS).
PCR-based tests for detection of HPV are used in cervical cancer screening as a primary screening test or to guide further management. In general, HPV positive tumours respond better to chemoradiation and therefore these patients have better outcomes than those with HPV negative tumours. Immunohistochemistry for the HPV surrogate marker p16 can also be used in this setting.
HPV vaccination programmes are now established in many countries. In the UK, girls aged 12–13 years are vaccinated with a quadrivalent vaccine, which protects against HPV6, 11, 16 and 18, with cross protection against some other high risk types. However, it should be remembered that this will not prevent all cases of cervical cancer and attendance at cervical screening tests is still important.
E surface epithelium H HSIL/CIN3 M mitoses N normal vaginal mucosa S stroma T tumour
The uterine endometrium undergoes monthly cyclical changes under the influence of hormonal stimuli during the reproductive years, except during pregnancy. Before menarche and after the menopause, the endometrial glands and stroma are compact and inactive. At menarche, around the menopause and for the first few cycles after a pregnancy, the endometrium shows a mixture of inactive and normal functional patterns. Iatrogenic factors such as oral contraceptive drugs, other hormonal treatments and intrauterine contraceptive devices may also modify the appearance of the endometrium.
The myometrium is the site of one of the most common benign mesenchymal tumours, the leiomyoma ( Fig.17.10 ), often known as a fibroid. Leiomyoma must be differentiated from its much rarer malignant counterpart, leiomyosarcoma , as well as from tumours that are difficult to classify, known as smooth muscle tumours of unknown malignant potential (STUMP) .
The myometrium may also contain islands of ectopic endometrium known as adenomyosis ( Fig. 17.11A ), which can cause pain and other menstrual disturbances. Such ectopic endometrial tissue may also be found in various other sites throughout the pelvis and sometimes the abdominal cavity, where it is called endometriosis ( Fig. 17.11B ). In this case, it may respond to the normal cyclical hormonal changes resulting in bleeding into the tissues and consequent fibrosis.
Endometrial infection is uncommon but may be associated with retained products of conception after childbirth or miscarriage, pelvic inflammatory disease or with intrauterine contraceptive devices. Endometrial tuberculosis is rare in developed countries, but much more common in countries where TB is common. Localised areas of polypoid hyperplasia forming endometrial polyps are common and benign ( Fig. 17.12 ). Excessive or uncoordinated hormonal stimulation of the endometrium may produce endometrial hyperplasia ( Fig. 17.13B ), some variants of which are pre-malignant.
The most common malignant tumour of the endometrium is endometrioid carcinoma , an adenocarcinoma derived from endometrial glands ( Fig. 17.14A ). Other types of adenocarcinoma of the endometrium occur rarely, including tumours typical of the ovary such as serous and clear cell carcinomas ( Figs 17.14B and C ). Other rare tumours of the endometrium include endometrial stromal sarcoma and carcinosarcoma (previously known as malignant mixed Müllerian tumour, MMMT). Carcinosarcoma is a highly aggressive tumour showing a biphasic appearance with malignant epithelial elements in a sarcomatous stroma.
G endometrial gland M myometrium S endometrial stroma T tumour
A cytological atypia C cytoplasmic clearing D dilated gland E crowded malignant glands G endometrial gland F cell budding M myometrium P papillary architecture S endometrial stroma SM squamous morule SL slit-like spaces
There have been significant recent advances in the molecular understanding of EC. Current risk stratification is based on the histological subtype of EC, FIGO grade and stage. More recently, the Cancer Genome Atlas Classification has shown that at a genomic level, there are four main subtypes of EC that can predict outcome and potentially help guide clinical management, particularly in high grade tumours. Further studies have shown that immunohistochemical markers can also be used to demonstrate the same stratification. This could potentially be used in routine histopathology departments. The subgroups are listed below in order of outcome (best at the top). In the future, these molecular tests are likely to be part of the routine pathological assessment of ECs.
Ultramutation of POLE : This is a gene involved in DNA repair, and ultramutation is associated with an excellent outcome, regardless of stage or grade.
Microsatellite instability (MSI) high : This can occur in Lynch syndrome, somatic mutations and epigenetic alterations such as MLH1 hypermethylation (see Ch. 1 ).
Copy number low: This group of tumours lacks specific molecular signatures and typically show on endometrioid morphology.
Copy number high : Serous type carcinomas. TP53 mutation testing or immunohistochemistry can be used as a surrogate marker. These typically have a very poor prognosis.
Details of the various structural and functional abnormalities of the placenta, decidua, membranes and umbilical cord are generally outside the scope of this book; however, hydatidiform mole ( Fig. 17.15 ) and choriocarcinoma ( Fig. 17.16 ) are included as examples of disorders of placental growth. Ectopic pregnancy is discussed in Fig. 17.18 .
C cytotrophoblast H haemorrhage M tubal mucosa P purulent exudate S cistern Sy syncytiotrophoblast T trophoblast
The fallopian tubes may become infected by pyogenic bacteria, particularly Gonococcus and chlamydia species , resulting in acute inflammation known as acute salpingitis ( Fig. 17.17 ). This may be complicated by obstruction of the tubal lumen, leading to chronic suppurative inflammation and abscess formation. Along with tuberculosis of the fallopian tube, these conditions constitute an important cause of female infertility worldwide owing to obliteration of the tubal lumen. In developed countries, endometriosis ( Fig 17.11 ) is a common cause of infertility. Scarring of the tube and other disorders may prevent the free passage of a fertilised ovum into the endometrial cavity and implantation may occur in the tube leading to tubal ectopic pregnancy ( Fig. 17.18 ); this usually culminates in massive intraperitoneal haemorrhage caused by the placenta eroding through the tubal wall.
The ovary may be affected by a variety of non-neoplastic disorders including endometriosis ( Fig. 17.11 ), as well as being involved by chronic inflammation in the form of tubo-ovarian abscesses caused by primary infection of the fallopian tube ( Fig. 17.17 )
Under the influence of pituitary gonadotrophins, the ovary undergoes cyclical changes allowing for the development and release of a mature ovum at the mid-point of each monthly menstrual cycle and for the production of the ovarian hormones, which control the menstrual cycle. During the proliferative phase of the menstrual cycle, a number of follicles enlarge culminating in maturation of one follicle that discharges its single ovum into the fallopian tube (ovulation) . The follicle, until this time also responsible for production of oestrogens, now develops into the corpus luteum , responsible for producing progesterone until the beginning of the next menstrual cycle when the follicle atrophies to form the redundant, collagenous corpus albicans . This regular sequence of changes is normally only interrupted by pregnancy, in which case the corpus luteum persists until the end of the first trimester. On occasion, however, the sequence is arrested at some stage and small follicular or luteal cysts may form. Some small cysts may also form by inclusion of islands of surface ‘germinal’ epithelium of the ovary; these are known as epithelial inclusion cysts . These three types of cyst are shown in Fig. 17.19 .
B placental site reaction CV chorionic villi Ep epithelium G granulosa cells H haemorrhage L luteal cells M muscular wall of fallopian tube PC peritoneal cavity T trophoblast
Tumours may arise from each of the specialised elements that make up the ovary and may be classified into four broad groups based on the current WHO classification. These groups of tumours and their major subtypes are listed in Table 17.2 below.
Epithelial tumours : Tumours of the surface ovarian epithelium are the commonest and are defined by histological type and by prognosis (benign, borderline, malignant). These tumours range from benign (often cystic) to frankly malignant. Intermediate between these two ends of the spectrum are tumours with low malignant potential. This group is called borderline or atypical proliferating tumours . Classification of serous carcinoma into two distinct tumours (high and low grade) is important and is described in detail in Figs 17.20 and 17.21 and Table 17.3 .
|Serous carcinoma||High grade serous carcinoma||Low grade serous carcinoma|
|Frequency||Commonest malignant tumour of ovary||Uncommon|
|Genetics||Genetically unstable (high copy number alterations)||Genetically stable|
|Molecular||Majority TP53 mutations||RAS pathway mutations (KRAS/BRAF/ErbB2)|
|Origin||Fallopian tube (STIC)||Serous cystadenoma via serous borderline tumour|
|Clinical course||Aggressive, fast||Indolent, slow|
Sex cord stromal tumours : These tumours may develop from granulosa cells and theca cells ( Fig. 17.27 ), as well as from spindle cells of the ovarian stroma forming fibromas . These may produce oestrogenic hormones and cause endocrine effects such as endometrial hyperplasia ( Fig. 17.13 ).
Germ cell tumours : The classification and morphology of ovarian germ cell tumours is quite similar to those for testicular germ cell tumours (see Fig. 19.1).
Metastatic tumours : The ovary is a common site for metastatic carcinoma, which is frequently bilateral. A well-known example is the Krukenberg tumour in which there is infiltration of the ovary by mucin secreting adenocarcinoma of signet ring type (see Fig. 17.25 ); such tumours are usually derived from stomach or colon and probably reach the ovary by either transcoelomic or lymphatic spread. Tumours from other parts of the genital tract, including uterus and cervix, commonly involve the ovaries. Breast and pancreaticobiliary carcinomas also frequently metastasise to this site. The ovaries may also be involved by lymphoma.
B basement membrane N nuclear atypia S slit-like spaces
Classification of ovarian serous carcinomas into low and high grade reflects recent evidence showing that these two tumours are biologically and molecularly distinct diseases that develop two different pathways. As described in Fig. 17.22 , low grade serous carcinoma develops from the serous cystadenoma/serous borderline tumour pathway, whereas high grade serous carcinoma is thought to develop from STIC lesions in the distal fallopian tube ( Fig. 17.20 ).
TP53, a tumour suppressor gene , is mutated in almost all high grade serous carcinomas. Mutations can result in different types of protein expression in the nucleus, which can be detected by immunohistochemical stains. Overexpression is the commonest pattern, giving strong and diffusely positive staining. Null expression results in completely negative staining, which can be misinterpreted as ‘normal’. As low grade serous carcinomas do not harbour TP53 mutations, they show a ‘wild type’ or phenotypically normal expression pattern with variable staining of the nuclei. Rarely, high grade serous carcinomas can show cytoplasmic or wild type pattern of staining. These patterns are illustrated in Fig. 17.21 .
H hierarchical branches P psammoma bodies S stroma St stromal cell nuclei T tumour cells
B Call-Exner body C cystic spaces Cap capsule CS collagenous stroma G malignant glands L luteinised cells M micropapillary tumour Mu mucin N nests of transitional cells Sp spindle cells SR signet ring cells T tumour
G glial tissue Gan ganglion H hair follicles K keratin S sebaceous glands.
| Epithelial tumours
| Low grade serous: serous cystadenoma, serous borderline tumour (SBT), low grade serous carcinoma
High grade serous carcinoma
Mucinous: mucinous cystadenoma, borderline mucinous tumour, invasive mucinous carcinoma
Endometrioid: resembles endometrioid carcinoma of the uterus and may arise from endometriosis
Seromucinous: a new category, associated with endometriosis.
Brenner (transitional cell) tumour: almost all benign, rarely malignant
Clear cell: almost all malignant and high grade – may arise from endometriosis
Undifferentiated: too poorly differentiated to categorise
Neuroendocrine: large cell and small cell types
Granulosa cell tumour – adult type, juvenile type
Sertoli-Leydig cell tumour
| Germ cell tumours
| Mature teratoma (dermoid cyst): very common and benign
Immature teratoma: immature tissues, usually neuroepithelial elements
Dysgerminoma (testicular equivalent is seminoma)
Yolk sac tumour
| Metastatic tumours
| From stomach, colon, breast, uterus, cervix
May also be involved by lymphoma
|Site||Pathological condition||Main pathological features||Figure|
|Vulva||Lichen sclerosus et atrophicus||Thin/thick epithelium, band of hyalinised collagen under epithelium with underlying band of chronic inflammation||17.1|
|Dysplasia (VIN)|| Neoplastic epithelial cells confined to the epithelium.
VIN usual type and differentiated
|Hidradenoma papilliferum||Apocrine benign tumour with papillary architecture.||17.2|
|Invasive SCC||Similar to SCC at other sites||Like 17.8|
|Cervix and vagina||Chronic cervicitis||Chronic inflammation with papillary hyperplasia of the mucosa||17.4|
|Endocervical polyp||Dilated endocervical glands in an inflamed fibrous stroma||17.5|
|CIN||Atypical epithelial cells confined to the epithelium, either 3 grades, (CIN 1, 2 and 3) or 2 (LGSIL and HGSIL)||17.6 and 17.7|
|SCC||Similar to SCC at other sites||17.8|
|Adenocarcinoma in situ||Dysplastic cells lining pre-existing cervical glands||17.9|
|Adenocarcinoma||Adenocarcinoma - usually mucin-producing but rarely endometrioid or clear cell types|
|Uterus||Adenomyosis/endometriosis||Endometrial glands in the myometrium/at other sites||17.11|
|Endometrial polyp||Disorganised endometrial glands in fibrotic stroma||17.12|
|Endometrial hyperplasia: with/ without atypia||Proliferative endometrial glands with varying degrees of crowding and cytological atypia||17.13|
| Endometrial carcinoma
||Adenocarcinoma invading the endometrium or myometrium||17.14|
|Leiomyoma (fibroid)||Well defined nodule of smooth muscle cells in the myometrium||17.10|
|Placenta||Hydatidiform mole||Abnormal chorionic villi, often with cystic spaces and atypical proliferating trophoblast||17.15|
|Choriocarcinoma||Frankly malignant tumour consisting of layers of syncytiotrophoblast and cytotrophoblast||17.16|
|Fallopian tube||Acute salpingitis||Typical acute inflammation with plentiful neutrophils||17.17|
|Ovary||Benign, non-neoplastic cysts: epithelial inclusion cyst, follicular cyst, luteal cyst||Bland cysts lined by flattened epithelium, granulosa cells or luteinised granulosa cells||17.19|
| Epithelial tumours
|| Various types
| Sex-cord stromal tumours
| Germ cell tumours
|Metastatic tumours: primaries from gastric, colon, pancreas, kidney, others||Resembles primary tumour morphology||17.25|
A 46-year-old women presents with vulval itching and is found to have an erythematous, scaly plaque on the labia. The area is biopsied and is illustrated above. What is the diagnosis? Select ONE answer.