General Pathological Principles
Adequate understanding of the underlying pathophysiological disease processes associated with the range of obstetric and gynaecological presentations is essential for the rational evaluation of appropriate investigations, therapies and outcomes. Huge volumes of literature are available on almost all of the topics covered in this chapter, but the most important essential points are summarised in the sections below. A basic understanding of general pathological principles is covered in the first section of the chapter, with the pathologies of some important examples of obstetric and gynaecological entities described later.
Cellular Injury and Death
There is a limited cellular repertoire of response to injury from a variety of causes including hypoxia (lack of oxygen supply), ischaemia (lack of blood supply), metabolic insults, mechanical trauma, immunological reactions, infections and toxins. Such insults may cause either a temporary impairment of cellular function followed by complete recovery, structural cellular damage with survival but ongoing impairment or, if severe or prolonged, may result in widespread cell death. Control of cellular proliferation and death is also essential for normal tissue turnover regulation and all aspects of embryonic development. The maintenance of normal tissue architecture, whether normal or neoplastic, is dependent upon the balance between cellular proliferation and cell death. At the basic cellular level there are two major types of cell death which may occur in association with the type, severity and timing of insult, namely necrosis and apoptosis.
Necrosis essentially represents a process of severe widespread cellular damage with marked cell swelling and rupture of the membrane. It usually affects sheets of adjacent cells causing disruption of normal tissue architecture with release of mediators and associated inflammation; necrosis is always pathological. Apoptosis, in contrast, essentially represents the controlled or selective death of individual or selected cells within tissues, without significant tissue destruction or associated inflammatory response, and is an essential process in both embryonic development and normal tissue turnover. The process of necrosis is mediated within the cell by rising intracellular calcium concentration, with massive cellular swelling and uncontrolled activation of intracellular enzymes, whereas apoptosis is mediated by controlled activation of specific intracellular enzyme pathways (caspases, transglutaminases and endonucleases) which result in a controlled destruction of the cell and its subsequent phagocytosis and removal.
Response to Tissue Injury
Following injury due to any mechanism, at a tissue, rather than cellular, level, there are three basic tissue responses which may be stimulated depending on the type and severity of the insult: acute inflammation, wound healing and chronic inflammation.
Acute Inflammation
Acute inflammation is the common and stereotyped tissue response to injury from a wide range of insults. Five classical clinical features are described including redness, heat, swelling, pain and loss of function. The acute inflammatory response is mediated by the activation of a range of vasoactive and chemotactic pathways which result in local vasodilatation, with increased blood flow to the affected area resulting in redness and heat; increased vascular permeability, resulting in exudation of fluid into the interstitial tissue and swelling; and release of numerous mediators which recruit further inflammatory cells to the site and cause pain and loss of function. The primary inflammatory cell mediator of acute inflammation is the neutrophil in the early stage, followed by the macrophage with resolution. Huge numbers of mediators have now been described in association with acute inflammation including histamine, prostaglandins, leukotrienes, bradykinins and complement components in addition to an ever-expanding list of cytokines produced by the inflammatory cells themselves, such as interleukin and tumour necrosis factor families. With removal or reduction of the inciting agent, the later stages of acute inflammation merge imperceptibly with the process of tissue repair and wound healing described below. Fig. 6.1 shows acute inflammation in fetal membranes in a pregnancy complicated by chorioamnionitis.
Tissue Repair and Wound Healing
The process of tissue repair or healing may involve either regeneration of the tissue to its original state by replacement of dead or damaged cells by proliferation of cells of the same type, or repair and organisation, in which new connective or scar tissue replaces the original tissue. The type of process to occur depends upon the timing, severity and extent of the insult, in addition to the underlying characteristics of the tissues involved.
An example of this process is the healing of skin wounds. In wounds with closely opposed edges, healing can occur by first intention, in which an initial blood clot forms followed by cellular proliferation and migration of the marginal epidermis across the clot to bridge the defect with proliferation of blood vessels and fibroblasts into the wound edges in the underlying connective tissue to form loose granulation-type tissue which is then remodelled over time. In skin wounds in which the edges are widely separated (healing by secondary intention), there is similar, but more extensive, formation of granulation tissue but since the epithelial proliferation cannot rapidly bridge the defect, there is ongoing remodelling, with wound contraction secondary to the presence of myofibroblasts and replacement of the original tissue by scarring. The process of wound healing is further influenced by additional factors such as the local blood supply, the presence of infection or foreign bodies, excessive movement at the site or other systemic factors such as metabolic abnormalities. Defective wound healing may therefore result in either inadequate union and wound dehiscence or excessive production of scar tissue such as hypertrophic scars or keloid formation. It is clear that the control of the process of wound healing is complex and dependent upon large numbers of mediators such as transforming growth factor beta and epidermal growth factor, the manipulation of which may allow novel interventions in the future. It should also be noted that there are marked differences in the potential responses to injury between different tissues and at different stages in development, with fetal wound healing and remodelling, for example, occurring very rapidly.
Chronic Inflammation
Histologically, chronic inflammation is defined as an inflammatory process that is occurring simultaneously with attempted healing, rather than a simple sequential process following acute inflammation. It should therefore be noted that it may often be clinically impossible to distinguish between ongoing acute and chronic inflammation, the two potential mechanisms being persistence of a low-grade inflammatory stimulus that initially induced an acute inflammatory response, or a process involving chronic inflammation from its outset. The characteristic histopathological features of chronic inflammation are the presence of predominant mononuclear inflammatory cells, in particular lymphocytes, plasma cells and macrophages, in association with fibroblast proliferation. Many immunological diseases are associated with such chronic inflammatory responses from their outset. A specific type of chronic inflammation is termed granulomatous inflammation, which represents prominent collections of epithelioid macrophages within tissues as a consequence of either an immunological reaction or the presence of foreign organisms or material which cannot be digested and removed by macrophages ( Fig. 6.2 ). It should be noted that granulomatous inflammation and granulation tissue are entirely different processes.
Control of Cell and Tissue Growth or Differentiation
In normal tissue there is very strict control of cellular growth, proliferation, death and differentiation. Several types of abnormal tissue response may occur.
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Hyperplasia represents an increase in the number of cells in a tissue or organ, which may be physiological, such as during pregnancy, or pathological, such as with oestrogen-induced endometrial hyperplasia
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Hypoplasia is a reduction in cell number within an organ or tissue, which may also be physiological or pathological
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Atrophy represents a potentially reversible reduction in mass of the tissue, with atrophic cells usually being smaller than normal. This may also be physiological, such as in postmenopausal endometrial atrophy, or pathological, such as tissue atrophy following damaged nerve or blood supply
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Hypertrophy represents a potentially reversible increase in cell size, which may be physiological, such as the uterus in pregnancy, or pathological, such as myocardial hypertrophy in hypertension
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Metaplasia represents the change in cellular phenotype from one fully differentiated state to another, and usually occurs from stem cells in epithelia, the most common example being columnar to squamous metaplasia of the transformation zone of the cervix (see later)
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Epithelial dysplasia represents the presence of cytological changes associated with malignancy but in the absence of abnormalities of underlying tissue architecture with an intact basement membrane. For many tumours, there is thought to be a clear pathway of progression from low-grade to high-grade dysplasia through to invasive carcinoma, the primary example of which being cervical intraepithelial neoplasia (CIN) as a forerunner of invasive squamous cell carcinoma of the cervix (see later)
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Neoplasia represents the process of new growth of cells
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Tumour represents a distinct mass lesion, and hence not all tumours are neoplasms
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Tumours may be simply classified as benign or malignant, and primary (arising at the site) or secondary (metastatic from another site), with specific subtyping, grading and staging on the basis of clinical and histopathological features.
Neoplasms may be benign or malignant. In general terms, benign neoplasms are usually localised, do not exhibit local destructive infiltration, do not metastasise and are often composed of relatively well differentiated cells. Malignant neoplasms demonstrate local destructive invasion of the surrounding normal tissue and the ability to metastasise (grow at sites distant from the site of origin). Despite these apparently clear-cut definitions, in a range of clinical situations, the precise distinction between a benign and malignant neoplasm may be extremely difficult, although most of these are not of significance to the obstetrician and gynaecologist.
The terminology commonly used for many neoplasms implies their benign or malignant nature from the nomenclature. For example, benign mesenchymal neoplasms usually have the suffix ‘oma’, such as a leiomyoma, whereas malignant mesenchymal neoplasms usually have the suffix ‘sarcoma’, such as a leiomyosarcoma. Malignant epithelial neoplasms are termed carcinomas and many paediatric malignancies that mimic embryonal tissues are termed blastomas. Malignant neoplasms of haematological stem cells in the bone marrow are termed leukaemias, whereas other malignancies of lymphoid tissue are termed lymphomas. There are well described specific and detailed classification systems and staging systems (extent of spread) for all described malignancies from the World Health Organization (WHO) and, in the context of gynaecological malignancies, the International Federation of Gynecology and Obstetrics (FIGO).
Malignancies are defined histopathologically on the basis of abnormalities of tissue architecture and cytological features. There is loss of the normal well-defined microarchitecture, with destruction of the underlying basement membrane in the case of carcinomas, and invasion of the surrounding tissue by malignant cells. Cytological features of malignancy in general include abnormal nuclear shape and size, abnormal mitoses and an increased nuclear to cytoplasmic ratio. In addition, many malignant cells demonstrate reduced or abnormal differentiation. (It should be noted here that the cell of origin of a tumour is not necessarily the same as the phenotype to which it is differentiating.) Neoplasms are a consequence of abnormalities in the normal cellular proliferation and differentiation control mechanisms, the majority of which are associated with either activation of oncogenes or loss of function of tumour suppressor genes.
Histology and Pathology of the Genital Tract
The female genital tract essentially almost entirely develops from the müllerian duct system embryologically, with part paired and part fused areas, resulting in development of the fallopian tubes, uterus, cervix and upper vagina, in addition to the embryologically distinct ovaries. The female genital tract is lined by a range of different types of epithelium along its length ranging from vaginal squamous epithelium, through uterine columnar epithelium and tubal ciliated epithelium. The ovary is composed of a mixture of germ cells (oocytes) among ovarian stroma and covering epithelium. The range of pathologies encountered may therefore be related to any of the above elements depending on the specific site, age and other aetiological factors, with the most common tumours being related to the underlying histological structures.
The male genital tract is also composed of paired gonads, with germ cells surrounded by epithelium and connective tissue, connected to the external by a tubal system, but in males the müllerian ducts regress, the functional ductal system being developed from the wolffian system. Therefore, although the potential spectrum of pathologies which may affect male and female gonads is similar, the specific types and distributions of neoplasms significantly differ; for example, across all ages in males, testicular germ cell tumours in younger men represent the most common neoplasms, whereas the predominant neoplasm in females is ovarian carcinoma in older women.
Pathology of Gynaecological Tumours
The basic principles of neoplasia, tumorigenesis and benign versus malignant tumours have been introduced above. A wide variety of examples of such pathologies may be encountered in the female genital tract and the characteristic pathological features of some common examples are described below. Similar to most tumours in adults, by far the commonest group of malignant lesions are epithelial derived (carcinomas), the specific subtypes of which are primarily dependent on the type of epithelium normally present at that site, although it should be noted that, since the majority of the female genital tract is derived from müllerian structures, carcinomas developing at any point may essentially recapitulate any type of müllerian derived epithelium. Mesenchymal malignancies are rare at these sites but many of the benign neoplasms commonly encountered are derived from connective tissue components such as uterine fibroids (leiomyoma) arising from the myometrium.
Vulva
The vulva is covered by squamous epithelium, and squamous cell carcinoma accounts for more than 90% of malignancies at this site and about 5% of all female genital tract cancers. This is primarily a disease of elderly women and presents with an ulcerated or thickened area on the vulva. There is local invasion and lymphatic spread, first to the inguinal lymph nodes. In an analogous manner to the cervix (see below), preinvasive epithelial changes have now been recognised, and grading described, termed vulval intraepithelial neoplasia (VIN). In this condition, there are mitoses, often abnormal, above the normal basal layers in association with other features of cytological atypia such as nuclear pleomorphism and a high nuclear to cytoplasmic ratio, but with an intact basement membrane.
Vagina
The vagina is normally lined by non-keratinising squamous epithelium, and neoplasms of the vagina are rare. When they do occur, most are squamous cell carcinomas in elderly women, which usually present as an ulcerating or fungating mass lesion in the upper third, with local and lymphatic spread. In a similar manner to the cervix and vulva, vaginal intraepithelial neoplasia (VAIN) has also now been described, often in women with previous cervical malignancy, the process probably representing a premalignant ‘field change’. Glandular structures may sometimes be present in the subepithelial stroma of the vagina, termed vaginal adenosis, occurring either sporadically or in association with females exposed prenatally to diethylstilbestrol. Such adenosis is usually asymptomatic but may predispose to the development of clear cell adenocarcinoma of the vagina. In young girls, usually in the first 5 years of life, the vagina may also be a relatively common site of embryonal rhabdomyosarcoma, which develops in the subepithelial stroma and may present as a polypoid lesion with discharge.
Cervix
The normal ectocervix is covered by non-keratinising squamous epithelium, whereas the endocervix and endocervical canal is lined by columnar type epithelium. During puberty, the squamocolumnar junction may become situated onto the anatomical ectocervix, and the exposed endocervical epithelium undergoes squamous metaplasia forming the transformation zone. Due to this mixture of epithelial types present, squamous cell carcinoma, adenocarcinoma and sarcoma may all occur in the cervix, although the commonest neoplasm by far is squamous cell carcinoma affecting the area of the transformation zone. It is hypothesised that during the process of metaplasia the epithelium at this site shows increased susceptibility to oncogenic agents such as smoking and human papilloma virus (HPV) infection, and it is increasingly clear that infection with certain subtypes of HPV is a significant risk factor for the subsequent development of cervical carcinoma.
Abnormal changes in the epithelium of the cervix are often apparent many years before the development of invasive carcinoma, i.e., there are cytological abnormalities, but the changes are confined to the epithelium and have not breached the basement membrane. These pre-invasive changes are termed CIN, which may be graded according to increased severity of architectural and cytological changes, from grade 1 to grade 3. Invasive carcinoma of the cervix may follow high-grade CIN and initially spreads locally, often presenting as a fungating or ulcerated lesion, and then by lymphatic spread. The peak age for development of invasive squamous cell carcinoma of the cervix is around 60 years, with CIN developing around 20 years earlier.
Endometrium
The endometrium is composed of numerous glands set within a background stroma, the structure of which varies with age and throughout the menstrual cycle due to the sensitivity of the endometrium to the steroid hormones oestrogen and progesterone. Oestrogen, in the absence of progesterone, leads to proliferation of the endometrial epithelium, a normal finding in the first half of the menstrual cycle. Metaplasia of endometrial epithelium may occur but is extremely uncommon compared with metaplasia occurring in the cervix and is not required for the development of endometrial malignancy. As expected from the nature of its normal structure, the commonest malignancy at this site is endometrial adenocarcinoma, which again, due to its derivation from müllerian epithelium, may differentiate towards various epithelial phenotypes. The proposed precursor lesion of endometrial adenocarcinoma is endometrial hyperplasia which may occur in high oestrogen states, the risk being greatest for atypical complex hyperplasia in which there are both architectural and cytological abnormalities. Endometrial adenocarcinoma usually presents with abnormal vaginal bleeding in a peri- or postmenopausal woman and often remains confined to the uterus at presentation, although may spread locally or by lymphatics. Histologically, endometrial adenocarcinoma demonstrates abnormal, closely packed glandular structures with cytological abnormalities including nuclear enlargement, hyperchromasia and abnormal mitoses. Rarely, endometrial stromal sarcomas or malignant mixed müllerian tumours may occur with a malignant component derived from the stroma.
Myometrium
The connective tissue elements of the female genital tract only rarely give rise to neoplasms, the commonest by far being benign smooth muscle tumours of the myometrium (leiomyomata or fibroids). These occur as single or multiple intramyometrial lesions composed of interlacing bland spindle cells, which may show secondary changes such as infarction or myxoid degeneration. The other lesion that may commonly present as intramyometrial pathology, although not a true neoplasm, is adenomyosis, characterised by nests or nodules of endometrium within the myometrium (or at other extrauterine sites).
Ovary
The pathology of the ovary varies somewhat from the remainder of the female genital tract since, in addition to being covered with müllerian derived surface epithelium and containing a stromal component, the ovary also contains germ cells. The three major groups of primary tumour of the ovary may therefore be classified into those derived from epithelium, sex cord stromal tumours and germ cell tumours.
About 90% of malignant ovarian tumours are derived from the surface epithelium and are therefore carcinomas. Analogous to carcinomas from other sites in the female genital tract, ovarian carcinomas may differentiate along various pathways normally taken by müllerian epithelia, and hence may be serous, mucinous or endometrioid adenocarcinomas, although other rare types may of course also occur. Ovarian adenocarcinoma generally affects elderly women and, due to the lack of direct communication with a lumen, presentation is often with non-specific features, the disease being of advanced stage at diagnosis. Benign epithelial tumours may also occur (cystadenomas), and a group of epithelial tumours of intermediate malignancy have also been described (borderline tumours).
Sex cord stromal tumours represent neoplasms of specialised stromal cells, such as granulosa cells, Sertoli cells, theca cells and Leydig cells or specialised fibroblasts. Since these cells are often hormone-producing, such tumours may present with the consequences of abnormal hormone levels.
Germ cell tumours are relatively common in the ovary, especially in younger patients and represent a diverse group which may show minimal phenotypic differentiation, such as dysgerminomas, or extreme degrees of differentiation along all three embryonic pathways, such as mature teratomas. In addition, differentiation may be towards extraembryonic developmental elements such as trophoblast in choriocarcinoma ( Fig. 6.3 ) or yolk sac structures in yolk sac tumour. Teratomas are the commonest ovarian neoplasms, most being mature teratomas in which a wide range of well-differentiated histological tissue types are present with associated generally benign behaviour. Some teratomas may contain immature elements such as neuroepithelial tubules, with an increased risk of malignant behaviour, and other teratomas may contain frankly malignant elements such as embryonal carcinoma or yolk sac tumour. Pure malignant germ cell tumours of the ovary, such as pure yolk sac tumour, may also occur, and are the commonest ovarian malignancies in young children.
