and neoplasia

Chapter 11 Carcinogenesis and neoplasia




GENERAL CHARACTERISTICS OF NEOPLASMS (TUMOURS)






Incidence of tumours


Malignant neoplasms—those that invade and spread and are therefore of greater clinical importance—develop in approximately 25% of the human population. The risk increases with age, but tumours can occur even in infancy (Fig. 11.1). The mortality rate is high, despite modern therapy, so that cancer accounts for about one-fifth of all deaths in developed countries. However, the mortality rate varies considerably between specific tumour types.



The relative incidence by diagnosis of various common types of cancer is shown in Fig. 11.2. Lung cancer is the most frequent malignant neoplasm in the UK and USA, and its importance is compounded by the extremely poor prognosis. In other countries other cancers are more common, and these differences often provide important aetiological clues.



For various reasons most epidemiological data on cancer incidence probably underestimate the true incidence. Not all tumours become clinically evident and, unless a thorough autopsy is performed, may never be detected. For example, autopsy surveys have revealed a higher than expected incidence of occult carcinoma of the prostate in elderly men, although these often minute lesions are probably of little clinical consequence. Cancer incidence may also be underestimated due to a failure of detection or diagnosis in countries and communities with poor health care.



Structure of tumours


Solid tumours consist of neoplastic cells and stroma (see below and Fig. 11.3). The neoplastic cells reproduce to a variable extent the growth pattern and synthetic activity of the parent cell of origin. Depending on their functional resemblance to the parent tissue, they continue to synthesise and secrete cell products such as collagen, mucin or keratin; these often accumulate within the tumour where they are recognisable histologically. Other cell products may be secreted into the blood where they can be used clinically to monitor tumour growth and the effects of therapy (p. 234).




Stroma


The neoplastic cells are embedded in and supported by a connective tissue framework called the stroma (from the Greek word meaning a mattress), which provides mechanical support and nutrition to the neoplastic cells. The process of stroma formation, called a desmoplastic reaction when it is particularly fibrous, is due to induction of connective tissue proliferation by growth factors in the immediate tumour environment.


The stroma always contains blood vessels which perfuse the tumour (Fig. 11.4). The growth of a tumour is dependent upon its ability to induce blood vessels to perfuse it, for unless it becomes permeated by a vascular supply its growth will be limited by the ability of nutrients to diffuse into it, and the tumour cells will cease growing when the nodule has attained a diameter of no more than 1–2mm (Fig. 11.5). Angiogenesis in tumours is induced by factors such as vascular endothelial growth factor (VEGF). This action is opposed by factors such as angiostatin and endostatin which have potential in cancer therapy.




Fibroblasts and the matrix they secrete give some mechanical support to the tumour cells and may in addition have nutritive properties. Stromal myofibroblasts are often abundant, particularly in carcinomas of the breast; their contractility is responsible for the puckering and retraction of adjacent structures.


The stroma often contains a lymphocytic infiltrate of variable density. This may reflect a host immune reaction to the tumour (Ch. 9), a hypothesis supported by the observation that patients whose tumours are densely infiltrated by lymphocytes tend to have a better prognosis.



Tumour shape and correlation with behaviour


The gross appearance of a tumour on a surface (e.g. gastrointestinal mucosa) may be described as sessile, polypoid, papillary, fungating, ulcerated or annular (Fig. 11.6). The behaviour of a tumour (i.e. whether it is benign or malignant) can often be deduced from its gross appearance: polypoid tumours are generally benign, i.e. unlikely to spread beyond the tissue of origin (Fig. 11.7); ulceration is more commonly associated with aggressive behaviour because invasion is the defining feature of malignancy (Fig. 11.8).





Ulcerated tumours can often be distinguished from non-neoplastic ulcers, such as peptic ulcers in the stomach, because the former tend to have heaped-up or rolled edges.


The shape of connective tissue neoplasms can be misleading. Although circumscription by a clearly defined border is one of the characteristics of benign epithelial tumours, some malignant connective tissue tumours are also well circumscribed.


Tumours are usually firmer than the surrounding tissue, causing a palpable lump in accessible sites such as the breasts. Extremely hard tumours are often referred to as ‘scirrhous’. Softer lesions are sometimes called ‘medullary’; they occur in the thyroid and breast.


The cut surfaces of malignant tumours are often variegated due to areas of necrosis and degeneration, but some, such as lymphomas and seminomas, appear uniformly bland.




CLASSIFICATION OF TUMOURS




Tumours are classified according to their behaviour and histogenesis (cell of origin).



Behavioural classification


The behavioural classification divides tumours into:




The principal pathological criteria for classifying a tumour as benign or malignant are summarised in Table 11.1. Some tumours, such as some ovarian tumours, defy precise behavioural classification, because their histology is intermediate between that associated with benign and malignant tumours; these are often referred to as ‘borderline’ tumours.


Table 11.1 Principal characteristics of benign and malignant tumours















































Feature Benign Malignant
Growth rate Slow Relatively rapid
Mitoses Infrequent Frequent and often atypical
Histological resemblance to normal tissue Good Variable, often poor
Nuclear morphology Often normal Usually hyperchromatic, irregular outline, multiple nucleoli and pleomorphic
Invasion No Yes
Metastases Never Frequent
Border Often circumscribed or encapsulated Often poorly defined or irregular
Necrosis Rare Common
Ulceration Rare Common on skin or mucosal surfaces
Direction of growth on skin or mucosal surfaces Often exophytic Often endophytic



Malignant tumours




Malignant tumours are, by definition, invasive. They are typically rapidly growing and poorly circumscribed. Histologically, they resemble the parent cell or tissue to a lesser extent than do benign tumours. Malignant tumours encroach on and destroy the adjacent tissues (Fig. 11.10), enabling the neoplastic cells to penetrate the walls of blood vessels and lymphatic channels and thereby disseminate to other sites. This important process is called metastasis and the resulting secondary tumours are called metastases. Patients with widespread metastases are often said to have carcinomatosis.


Not all tumours categorised as malignant exhibit metastatic behaviour. For example, basal cell carcinoma of the skin (rodent ulcer) rarely forms metastases, yet is regarded as malignant because it is highly invasive and destructive.


Malignant tumours on epithelial or mucosal surfaces may form a protrusion in the early stages, but eventually invade the underlying tissue; this invasive inward direction of growth gives rise to an endophytic tumour. Ulceration is common.


Malignant tumours in solid organs tend to be poorly circumscribed, often with strands of neoplastic tissue penetrating adjacent normal structures. The resemblance of the cut surface of these lesions to a crab (Latin: cancer) gives the disease its popular name. Malignant tumours often show central necrosis because of inadequate vascular perfusion.


The considerable morbidity and mortality associated with malignant tumours may be due to:










Histogenetic classification




Histogenesis—the specific cell of origin of an individual tumour—is determined by histopathological examination and specifies the tumour type. This is then incorporated in the name given to the tumour (e.g. squamous cell carcinoma).


Histogenetic classification includes numerous subdivisions, but the major categories of origin are:





Although some general differences exist between the main groups of malignant tumours (Table 11.2), individual lesions have to be categorised more precisely both in clinical practice and for epidemiological purposes. It is inadequate to label the patient’s tumour as merely having an epithelial or connective tissue origin; efforts must be made to determine the precise cell type. The classification of individual tumours is vitally important. Thorough histological examination of the tumour, sometimes using special techniques like genetic analysis and immunocytochemistry, detects subtle features that betray its provenance.


Table 11.2 Principal characteristics of carcinomas and sarcomas































Feature Carcinoma Sarcoma
Origin Epithelium Connective tissues
Behaviour Malignant Malignant
Frequency Common Relatively rare
Preferred route of metastasis Lymph Blood
In situ phase Yes No
Age group Usually over 50 years Usually below 50 years


Histological grade (degree of differentiation)


The extent to which the tumour resembles histologically its cell or tissue of origin determines the tumour grade (Fig. 11.11) or degree of differentiation. Benign tumours are not usually further classified in this way because they nearly always closely resemble their parent tissue and grading the degree of differentiation offers no further clinical benefit in terms of choosing the most appropriate treatment. However, the degree of differentiation of malignant tumours is clinically useful both because it correlates strongly with patient survival (prognosis), and because it often indicates the most appropriate treatment. Thus, malignant tumours are usually graded either as well, moderately or poorly differentiated, or numerically, often by strict criteria, as grade 1, grade 2 or grade 3.



A well-differentiated tumour more closely resembles the parent tissue than does a poorly differentiated tumour, while moderately differentiated tumours are intermediate between these two extremes. Poorly differentiated tumours are more aggressive than well-differentiated tumours.


A few tumours are so poorly differentiated that they lack easily recognisable histogenetic features. There may even be great difficulty in deciding whether they are carcinomas or lymphomas, for example, although immunocytochemistry and genetic analysis often enable a distinction to be made. Tumours defying precise histogenetic classification are often referred to as ‘anaplastic’, or by some purely descriptive term such as ‘spindle cell’ or ‘small round cell’ tumour. Fortunately, advances in diagnostic histopathology have resulted in considerably fewer unclassifiable tumours and these descriptive terms are rapidly becoming obsolete.



NOMENCLATURE OF TUMOURS




Tumours justify separate names because, although they are all manifestations of the same disease process, each separately named tumour has its own characteristics in terms of cause, appearance and behaviour. Accurate diagnosis and naming of tumours is essential so that patients can be optimally treated. A tumour that defies accurate classification is designated anaplastic; such tumours are always malignant.


The specific name of an individual tumour invariably ends in the suffix ‘-oma’. However, relics of this suffix’s former wider usage remain, as in ‘granuloma’ (an inflammatory aggregate of epithelioid macrophages), ‘tuberculoma’ (the large fibrocaseating lesion of tuberculosis), ‘atheroma’ (lipid-rich intimal deposits in arteries), and ‘mycetoma’ (a fungal mass populating a lung cavity) and ‘haematoma’ (mass of coagulated blood); these are not neoplasms.


There are exceptions to the rules of nomenclature that follow and these are a potential source of misunderstanding. For example, the words ‘melanoma’ and ‘lymphoma’ are both commonly used to refer to malignant tumours of melanocytes and lymphoid cells respectively, even though, from the rules of tumour nomenclature, these terms can be mistakenly interpreted as meaning benign lesions. To avoid confusion, which could be clinically disastrous, their names are often preceded by the word ‘malignant’. Similarly, a ‘myeloma’ is a malignant neoplasm of plasma cells.


The suffix for neoplastic disorders of blood cells is ‘-aemia’, as in leukaemia; but again, exceptions exist. For example, anaemia is not a neoplastic disorder.


Detailed descriptions of individual tumours are, in most instances, included in the relevant systematic chapters. Examples of tumour nomenclature are given below and, for reference, in Table 11.3.


Table 11.3 Examples of tumour nomenclature































































Type Benign Malignant
Epithelial    
Squamous cell Squamous cell papilloma Squamous cell carcinoma
Transitional Transitional cell papilloma Transitional cell carcinoma
Basal cell Basal cell papilloma Basal cell carcinoma
Glandular Adenoma (e.g. thyroid adenoma) Adenocarcinoma (e.g. adenocarcinoma of breast)
Mesenchymal    
Smooth muscle Leiomyoma Leiomyosarcoma
Striated muscle Rhabdomyoma Rhabdomyosarcoma
Adipose tissue Lipoma Liposarcoma
Blood vessels Angioma Angiosarcoma
Bone Osteoma Osteosarcoma
Cartilage Chondroma Chondrosarcoma
Mesothelium Benign mesothelioma Malignant mesothelioma
Synovium Synovioma Synovial sarcoma


Epithelial tumours


Epithelial tumours are named histogenetically according to their specific epithelial type and behaviourally as benign or malignant.




Malignant epithelial tumours


Malignant tumours of epithelium are always called carcinomas. Carcinomas of non-glandular epithelium are always prefixed by the name of the epithelial cell type; examples include squamous cell carcinoma and transitional cell carcinoma. Malignant tumours of glandular epithelium are always designated adenocarcinomas, coupled with the name of the tissue of origin; examples include adenocarcinoma of the breast, adenocarcinoma of the prostate and adenocarcinoma of the stomach.


Carcinomas should be further categorised according to their degree of differentiation: their resemblance to the tissue of origin.



Carcinoma in situ


The term carcinoma in situ refers to an epithelial neoplasm exhibiting all the cellular features associated with malignancy, but which has not yet invaded through the epithelial basement membrane separating it from potential routes of metastasis—blood vessels and lymphatics (Fig. 11.14). Complete excision at this very early stage will guarantee a cure. Detection of carcinomas at the in situ stage, or of their precursor lesions, is the aim of population screening programmes for cervical, breast and some other carcinomas. The phase of in situ growth may last for several years before invasion commences.



Carcinoma in situ may be preceded by a phase of dysplasia, in which the epithelium shows disordered maturation short of frank neoplasia. Some dysplastic lesions are almost certainly reversible. As there are other applications of the word ‘dysplasia’, as well as some difficulty in reliably distinguishing between carcinoma in situ and dysplasia in biopsies, the term is now less favoured. The term ‘intra-epithelial neoplasia’, as in cervical intra-epithelial neoplasia (CIN), is used increasingly to encompass both carcinoma in situ and the precursor lesions formerly known as dysplasia.





Miscellaneous tumours


Most tumours can be categorised according to the scheme of nomenclature already described. There are, however, important exceptions.



Teratomas


A teratoma is a neoplasm formed of cells representing all three germ cell layers: ectoderm, mesoderm and endoderm. In their benign form, these cellular types are often easily recognised; the tumour may contain teeth and hair, and, on histology, respiratory epithelium, cartilage, muscle, neural tissue, etc. In their malignant form, these representatives of ectoderm, mesoderm and endoderm will be less easily identifiable.


Teratomas are of germ cell origin. They occur most often in the gonads, where germ cells are abundant. Although all cells in the body contain the same genetic information, arguably in germ cells this information is in the least repressed state and is therefore capable of programming such divergent lines of differentiation. Supporting evidence for a germ cell origin for teratomas comes from karyotypic analysis of their sex chromosome content. Teratomas in the female are always XX, whereas only 50% of those in the male are XX and the remainder XY; this correlates with the sex chromosome distribution in the germ cells of the two sexes.


Ovarian teratomas are almost always benign and cystic; in the testis, they are almost always malignant and relatively solid. As germ cells in the embryo originate at a site remote from the developing gonads, teratomas arise occasionally elsewhere in the body, usually in the midline, possibly from germ cells that have been arrested in their migration. These extragonadal sites for teratomas include the mediastinum and sacro-coccygeal region.





Neuroendocrine tumours


Neuroendocrine tumours are derived from peptide hormone-secreting cells scattered diffusely in various epithelial tissues. These cells are sometimes referred to as APUD cells; this acronym signifies their biochemical properties (amine content and/or precursor uptake and decarboxylation). (For this reason, the tumours have been called ‘apudomas’.)


The name of those neuroendocrine tumours producing a specific peptide hormone is usually derived from the name of the hormone, together with the suffix ‘-oma’. For example, the insulin-producing tumour originating from the beta-cells of the islets of Langerhans is called an insulinoma. There are exceptions: for example, the calcitonin-producing tumour of the thyroid gland is called a ‘medullary carcinoma of the thyroid gland’ because it was described as a specific entity before calcitonin had been discovered.


Neuroendocrine tumours of the gut and respiratory tract that do not produce any known peptide hormone are called carcinoid tumours. The appendix is the commonest site, but, here, these tumours are usually an incidental finding of little clinical significance. Carcinoids arising elsewhere (the small bowel is the next commonest site) often metastasise to mesenteric lymph nodes and the liver. Extensive metastases lead to the carcinoid syndrome (tachycardia, sweating, skin flushing, anxiety and diarrhoea) due to excessive production of 5-hydroxytryptamine and prostaglandins.


Many neuroendocrine tumours are functionally active, and clinical syndromes often result from excessive secretion of their products (Table 11.4).


Table 11.4 Some neuroendocrine tumours and their associated clinical syndromes


















Tumour Clinical syndrome
Insulinoma Episodes of hypoglycaemia
Gastrinoma Extensive peptic ulceration of the upper gut (Zollinger–Ellison syndrome)
Phaeochromocytoma Paroxysmal hypertension
Carcinoid If metastases are present, flushing, palpitations and pulmonary valve stenosis

These neoplasms often pursue an indolent course, growing relatively slowly and metastasising late. Their behaviour cannot always be predicted from their histological features.


Some individuals inherit a familial predisposition to develop neuroendocrine tumours; they have a multiple endocrine neoplasia (MEN) syndrome (Ch. 17).





BIOLOGY OF TUMOUR CELLS




Contrary to past claims and an enduring hope, there is no therapeutically exploitable feature unique to neoplastic cells other than the general property of relative or absolute growth autonomy. Many of the other features have normal counterparts: mitotic activity is a feature also of regenerating cells; placental trophoblast is invasive; and the nucleated cells of the blood and lymph wander freely around the body, settling in other sites.


The autonomy of neoplastic cells is often relative rather than absolute. For example, approximately two-thirds of breast carcinomas contain oestrogen receptors; these tumours are better differentiated than receptor-negative breast carcinomas and they have a better prognosis. Furthermore, if women with oestrogen receptor-positive breast carcinomas are given tamoxifen (a drug that blocks the receptor) they survive longer than women with receptor-positive tumours who have not been treated in this way.


One of the many difficulties in studying tumours is their genetic instability, leading to the formation of many clones with divergent properties within one tumour. This is often reflected in the histology which may show a heterogeneous growth pattern, some areas appearing better differentiated than others. Clinically, this instability and consequent cellular heterogeneity is important because thereby some tumours resist chemotherapy; consequently, many chemotherapy regimes involve a combination of agents administered simultaneously or sequentially.






Metabolic abnormalities


Although tumour cells show a tendency towards anaerobic glycolysis, there are no metabolic abnormalities entirely specific to the neoplastic process. The known metabolic abnormalities of tumour cells are simply discordant with the normal physiological state of the tissue or host.


The surface of tumour cells is abnormal. Tumour cells are less cohesive. In many neoplasms, poor cellular cohesion is due to a reduction in specialised intercellular junctions such as desmosomes. This loss of adhesiveness enables malignant tumour cells to spread through tissues and detach themselves to populate distant organs.


Tumour cells may retain the capacity to synthesise and secrete products characteristic of the normal cell type from which they are derived, often doing so in an excessive and uncontrolled manner. In addition, tumours often show evidence of gene derepression. All somatic cells contain the same genetic information, but only a small proportion of the genome is transcribed into RNA and translated into protein in any normal cell. Most genes are repressed, and only those required for the function of the particular cell are selectively expressed. However, in many tumour cells, some genes become derepressed, resulting in the inappropriate synthesis of unexpected substances.



Tumour products


The major types of tumour product are:






Some tumour products are useful as markers for diagnosis or follow-up (Table 11.5). They can be detected in histological sections or their concentrations measured in the blood. Rising blood levels suggest the presence of tumour; falling levels indicate a sustained response to therapy (Fig. 11.16).


Table 11.5 Tumours secreting markers used in diagnosis or follow-up






































Tumour Marker Comment
Myeloma



Hepatocellular carcinoma Alpha-fetoprotein (AFP) Also associated with testicular teratoma
Gastrointestinal adenocarcinomas Carcinoembryonic antigen (CEA) False positives occur in some non-neoplastic conditions
Neuroendocrine tumours Peptide hormones (e.g. insulin, gastrin) Excessive hormone production may have clinical effects
Phaeochromocytoma Vanillyl mandelic acid (VMA) Metabolite of catecholamines in urine
Carcinoid 5-Hydroxyindole-acetic acid (5-HIAA) Metabolite of 5-hydroxytryptamine (5-HT) in urine
Choriocarcinoma Human chorionic gonadotrophin (hCG) In blood or urine
Malignant teratoma

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Jun 16, 2017 | Posted by in GENERAL SURGERY | Comments Off on and neoplasia

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