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Female reproductive system
Introduction
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.
Disorders of the vulva and vagina
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.
Table 17.1
Vulval intraepithelial neoplasia.
| 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 |
| Immunohistochemical markers | p16 | p53 |
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 .
Key to Figures
C cystic space E epidermis F fibrous stroma H hyalinised collagen In inflammation R rete pegs W well circumscribed edge
Diseases of the uterine cervix
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.
Cervical dysplasia and cancer
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’).
Key to Figures
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
Key to Figures
D dyskaryotic cells K koilocytes L lower third of epithelium M mitotic figures S cervical squamous cell
Human Papillomavirus (HPV) And Cancer
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.
Key to Figures
E surface epithelium H HSIL/CIN3 M mitoses N normal vaginal mucosa S stroma T tumour
Disorders of the uterus
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.
Key to Figures
G endometrial gland M myometrium S endometrial stroma T tumour
Key to Figures
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
Molecular Aspects of Endometrial Cancer (EC)
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.
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Ultramutation of POLE : This is a gene involved in DNA repair, and ultramutation is associated with an excellent outcome, regardless of stage or grade.
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Microsatellite instability (MSI) high : This can occur in Lynch syndrome, somatic mutations and epigenetic alterations such as MLH1 hypermethylation (see Ch. 1 ).
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Copy number low: This group of tumours lacks specific molecular signatures and typically show on endometrioid morphology.
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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.
Placental disorders
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 .
Key to Figures
C cytotrophoblast H haemorrhage M tubal mucosa P purulent exudate S cistern Sy syncytiotrophoblast T trophoblast
Diseases of the fallopian tubes
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.
Disorders of the ovary
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 )
Non-neoplastic cysts
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 .
Key to Figures
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 of the ovary
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 .
Table 17.3Serous carcinoma.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).
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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.
Key to Figures
B basement membrane N nuclear atypia S slit-like spaces
P53 and Serous Carcinoma
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 .
Key to Figures
H hierarchical branches P psammoma bodies S stroma St stromal cell nuclei T tumour cells
Key to Figures
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
Key to Figures
G glial tissue Gan ganglion H hair follicles K keratin S sebaceous glands.
Table 17.2
Overview of ovarian tumours.
| Tumour type | Subtype |
|---|---|
| Epithelial tumours ~70% |
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 |
| Sex-cord-stromal tumours ~20% |
Fibroma Thecoma Fibrothecoma Granulosa cell tumour – adult type, juvenile type Sertoli-Leydig cell tumour |
| Germ cell tumours ~5% |
Mature teratoma (dermoid cyst): very common and benign Immature teratoma: immature tissues, usually neuroepithelial elements Dysgerminoma (testicular equivalent is seminoma) Yolk sac tumour Choriocarcinoma |
| Metastatic tumours ~5% |
From stomach, colon, breast, uterus, cervix May also be involved by lymphoma |
Table 17.4
Chapter review.
| 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 |
17.3 | |
| 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
|
17.20–17.23 Like 17.14 Like 17.14 17.23 17.24 |
|
Sex-cord stromal tumours
|
|
17.26 17.27 |
|
Germ cell tumours
|
|
17.28 Like 19.4 Like 19.7 17.16 |
|
| Metastatic tumours: primaries from gastric, colon, pancreas, kidney, others | Resembles primary tumour morphology | 17.25 |
Apocrine secretion. (A) H&E (MP); (B) H&E (HP).
Apocrine glands are confined to a few localised areas, mainly in the axilla and groin. The secretory component is located in deep reticular dermis or subcutis and a duct system carries the secretion to be discharged into the upper part of the hair follicle above the sebaceous duct. Apocrine gland secretions in humans have no defined function but, in other mammals, they are responsible for scent production, used in territory marking and as a sexual attractant. The secretory portion of the gland S is of the coiled tubular type with a widely dilated lumen. The secretory cells are usually low cuboidal with eosinophilic cytoplasm. The budding appearance B of the apical cytoplasm of some cells gave rise to the belief that the mode of secretion was of the apocrine type, but recent evidence suggests that this appearance may be due to a fixation artifact and that the original interpretations were erroneous. Like eccrine sweat glands, apocrine glands have a discontinuous layer of myoepithelial cells My between the base of the secretory cells and the prominent basement membrane. Their duct Da is histologically similar to that of eccrine sweat glands. Apocrine glands do not become functional until puberty and, in women, undergo cyclical changes under the influence of the hormones of the menstrual cycle.
Reproduced from Young, B., O’Dowd, G., Woodford, P., Wheater’s Functional Histology, 6th edition. Copyright 2014, Elsevier Ltd.
Endocervix. (A) H&E (LP); (B) H&E (MP).
As seen in micrograph (A) , the mucus-secreting epithelial lining of the endocervical canal is thrown into deep furrows and tunnels, giving the appearance in two dimensions of branched tubular glands, hence the rather inaccurate term endocervical glands . The columnar mucus-secreting cells lining the ‘glands’ are shown at higher magnification in micrograph (B) . Note the leucocytic infiltrate in the superficial stroma and the presence of leucocytes in the endocervical mucus on the surface. Some inflammation is considered to be normal at this site. During the menstrual cycle, the endocervical epithelium undergoes cyclical changes in secretory activity. In the proliferative phase, rising levels of oestrogen promote secretion of thin, watery mucus which permits the passage of spermatozoa into the uterus around the time of ovulation. Following ovulation, the cervical mucus becomes highly viscid, forming a plug that inhibits the entry of microorganisms (and spermatozoa) from the vagina. This is particularly important should pregnancy occur.
Reproduced from Young, B., O’Dowd, G., Woodford, P., Wheater’s Functional Histology, 6th edition. Copyright 2014, Elsevier Ltd.
Cervical cytology (Papanicolou) (HP).
The cervical stroma is influenced by ovarian hormones, particularly oestrogens, which soften the tissues by reducing collagenous cross-linkages and increasing uptake of water by the ground substance. At its most extreme, this provides the means by which the cervix stretches, thins and dilates in late pregnancy and during parturition. To a much lesser extent, similar changes occur during the normal menstrual cycle. One effect of this is that the volume of the cervical stroma varies during each cycle, causing eversion of the columnar epithelium near the squamocolumnar junction and exposing it to the vaginal environment. This ectropion is known colloquially as ' cervical erosion '. This induces the growth of stratified squamous epithelium ( squamous metaplasia ) over the exposed area, considered a normal variant in women of reproductive age. The importance of this transformation zone is that it may undergo malignant change, causing cancer of the cervix.This area can be studied by scraping cells from the surface using various types of spatula or brush, smearing them on a glass slide and staining them by the Papanicolaou method (the cervical smear or 'Pap test'). This technique is known as exfoliative cytology and is demonstrated here from a normal healthy cervix. The surface cells of the stratified squamous epithelium have small, contracted nuclei and are stained pink due to the cytoplasmic keratin. Deeper cells have plump nuclei of normal appearance, and the cytoplasm is stained blue/green. An adequate Pap smear should also contain some endocervical cells (demonstrating that the transformation zone has been sampled), as well as cervical mucin and inflammatory cells. A more recent development of the cervical smear suspends the exfoliated cells in a special alcohol-based fixative medium and then layers them evenly onto a glass slide, a technique known as liquid-based cytology . This gives superior visibility of the cells and improves the ability of the cytologist to see abnormal cells. Various computerised technologies are also becoming available to screen the slides and detect abnormal cells.
Reproduced from Young, B., O’Dowd, G., Woodford, P., Wheater’s Functional Histology, 6th edition. Copyright 2014, Elsevier Ltd.
Uterine cervix H&E (LP).
The uterine cervix protrudes into the upper vagina and contains the endocervical canal , linking the uterine cavity with the vagina. The function of the cervix is to admit spermatozoa to the genital tract at the time when fertilisation is possible, i.e. around the time of ovulation. At other times, including pregnancy, its function is to protect the uterus and upper tract from bacterial invasion. In addition, the cervix must be capable of great dilatation to permit the passage of the fetus during parturition. As seen in this micrograph, the endocervical canal EC is lined by a single layer of tall columnar mucus-secreting epithelial cells. Where the cervix is exposed to the more hostile environment of the vagina V , the ectocervix , it is lined by thick stratified squamous epithelium as in the vagina and the vulva. The cells of the ectocervix often have clear cytoplasm due to their high glycogen content (not apparent in this specimen). The junction J between the ecto- and endocervical epithelium is quite abrupt and is normally located at the external os, the point at which the endocervical canal opens into the vagina.The main bulk of the cervix is composed of tough collagenous tissue containing a little smooth muscle. At the squamocolumnar junction, the cervical stroma is often infiltrated with leucocytes, forming part of the defence against ingress of microorganisms.
Reproduced from Young, B., O’Dowd, G., Woodford, P., Wheater’s Functional Histology, 6th edition. Copyright 2014, Elsevier Ltd.
Myometrium. (A) H&E (MP); (B) H&E (HP).
The main bulk of the uterus consists of smooth muscle, the myometrium , which is composed of interlacing bundles of long slender fibres arranged in ill-defined layers. This is readily seen in micrograph (A) , which contains bundles of fibres in transverse T , longitudinal L and oblique sections O . Within the muscle, there is a rich network of arteries and veins which are supported by collagenous supporting tissue. Micrograph (B) shows detail of the smooth muscle cells at high magnification, highlighting the closeness with which the muscle fibres are packed. During pregnancy, in response to increased levels of oestrogens, the myometrium increases greatly in size, mainly by increasing cell size ( hypertrophy ), although some increase in cell numbers ( hyperplasia ) due to cell division may also occur. At parturition, strong contractions of the myometrium are reinforced by the action of the hormone oxytocin , secreted by the posterior pituitary. These contractions expel the fetus from the uterus and also constrict the blood supply to the placenta, thus precipitating its detachment from the uterine wall.
Reproduced from Young, B., O’Dowd, G., Woodford, P., Wheater’s Functional Histology, 6th edition. Copyright 2014, Elsevier Ltd.
Leiomyoma. The uterus is distorted by a large white, circumscribed tumour with a lobular, whorled cut surface in keeping with a leiomyoma. The adjacent myometrium is compressed. Leiomyomas can be found within the myometrium (intramural), extend into the endometrial cavity (submucosal) or extend towards the serosa (subserosal).
Reproduced from Cooke, R., Stewart, B., Colour Atlas of Anatomical Pathology, 3rd edition. Copyright 2004, Elsevier Ltd.
Endometriotic cyst of ovary (endometrioma). The ovaries are the most common site for endometriotic deposits. The ovary pictured has been sliced in half to show a large cyst containing dark brown altered blood. The term ‘chocolate cyst’ refers to the dark brown appearance of the cyst contents.
Reproduced from Cooke, R., Stewart, B., Colour Atlas of Anatomical Pathology, 3rd edition. Copyright 2004, Elsevier Ltd.
Endometrial carcinoma. The uterus has been opened anteriorly. The tumour fills and expands the endometrial cavity and has a fleshy appearance with areas of haemorrhage. No definite myometrial invasion is seen. Two small white, smooth nodules are present in the myometrium in keeping with leiomyomata (fibroids).
Reproduced from Cooke, R., Stewart, B., Colour Atlas of Anatomical Pathology, 3rd edition. Copyright 2004, Elsevier Ltd.
Early placenta. (A) H&E (LP); (B) H&E (MP); (C) H&E (HP).
This series of micrographs illustrates, at increasing magnification, a placenta at about 6 weeks gestational age. Nucleated fetal erythrocytes E , which in humans persist until 9 weeks gestational age, can be seen in the capillary in micrograph (C) . At low magnification in micrograph (A) , the main feature is the large numbers of villi V projecting into the lacuna system L that, in vivo, would be filled with maternal blood. Some villi show evidence of branching. Solid cores of cytotrophoblast and intermediate trophoblast I can be seen extending away from the villi to form new branches. With further magnification in micrograph (B) , the villi are seen to have a core of primitive mesenchyme M . The villi are invested by trophoblast, comprising an inner layer of cytotrophoblast cells C and a broader outer syncytiotrophoblast layer S . In some areas, solid buds of trophoblast can be seen forming new branches. The specimen is a little broken up as it is derived from a curettage specimen following incomplete spontaneous abortion. Micrograph (C) focuses on the margin of a villus at high magnification, the cellular preservation being again less than ideal due to its origin from a spontaneous miscarriage. The syncytiotrophoblast layer S can be distinguished from the single layer of cytotrophoblast cells C , which are smaller. The mesenchymal cells MC are large with extensive branching cytoplasmic processes and the intercellular matrix is myxoid due to its high content of glycosaminoglycans.
Reproduced from Young, B., O’Dowd, G., Woodford, P., Wheater’s Functional Histology, 6th edition. Copyright 2014, Elsevier Ltd.
Fallopian tube. (A) H&E (LP); (B) H&E (MP); (C) H&E (HP); (D) Azan (HP).
At the time of ovulation, the infundibulum moves so as to overlie the site of rupture of the Graafian follicle. Finger-like projections called fimbriae extending from the end of the tube envelop the ovulation site and direct the ovum into the tube. Movement of the ovum along the tube is mediated by gentle peristaltic action of the longitudinal and circular smooth muscle layers of the oviduct wall. This is aided by a current of fluid, propelled by the action of the ciliated epithelium lining the tube. The mucosal lining of the Fallopian tube is thrown into a labyrinth of branching longitudinal folds, a feature that is most prominent in the ampulla (A) , which is the usual site of fertilisation. Note also in this micrograph, the muscular wall M and the vascular supporting tissue of the serosa S , which is continuous with the broad ligament BL . The serosal layer and broad ligament have a surface lining of mesothelium. The muscular wall has two layers, an inner circular and an outer longitudinal , not discernible at this magnification. Micrograph (B) focuses on one of the mucosal folds of the ampulla. These have a branching core of vascular supporting tissue ST and are invested by a single layer of tall columnar epithelial cells E . Micrograph (C) shows the tip of a mucosal fold at high magnification. The columnar cells of the epithelium are of three types: ciliated , non-ciliated secretory and intercalated cells . The non-ciliated cells produce a secretion that is propelled towards the uterus by the wave-like beating of the cilia of the ciliated cells, carrying with it the ovum. This secretion probably also has a role in the nutrition and protection of the ovum. The intercalated cells may be a morphological variant of the secretory cells. The ratio of ciliated to non-ciliated cells and the height of the cells undergo cyclical variations under the influence of ovarian hormones. The ciliated cells are generally shorter than the secretory cells, making the epithelial surface somewhat irregular in outline. Scattered intraepithelial lymphocytes are also present. Micrograph (D) employs a method that stains the secretory cells blue. Note that the collagen of the supporting tissue core of the mucosal fold is also stained blue.
Reproduced from Young, B., O’Dowd, G., Woodford, P., Wheater’s Functional Histology, 6th edition. Copyright 2014, Elsevier Ltd.
Mucinous cystadenoma. The cut surface of the cyst is multilocular. Some of the locules contain gelatinous mucoid material. Importantly, there are no papillary or solid components within the cyst.
Reproduced from Cooke, R., Stewart, B., Colour Atlas of Anatomical Pathology, 3rd edition. Copyright 2004, Elsevier Ltd.
Mature cystic teratoma (dermoid cyst). Dermoid cysts are typically cystic and solid with a smooth outer surface. The opened cyst pictured contains soft yellow sebaceous material and hair. A small white tooth is also seen.
Reproduced from Cooke, R., Stewart, B., Colour Atlas of Anatomical Pathology, 3rd edition. Copyright 2004, Elsevier Ltd.
Questions
Chapter 17 Question 1
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.
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