Pathology

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.

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.

• 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

• Hypoplasia is a reduction in cell number within an organ or tissue, which may also be physiological or pathological

• 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

• 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

• 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)

• 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)

• Neoplasia represents the process of new growth of cells

• Tumour represents a distinct mass lesion, and hence not all tumours are neoplasms

• 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.