Neoplasia and carcinogenesis

Stroma

The neoplastic cells are embedded in and supported by a connective tissue framework called the stroma (from the Greek word meaning a mattress), or tumour microenvironment, which provides mechanical support, intercellular signalling 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 fibroblast proliferation by growth factors elaborated by the tumour cells. These cells have subtly altered properties and are sometimes called cancer-associated fibroblasts . Cancer-associated fibroblasts and the matrix they secrete give some mechanical support to the tumour cells and may in addition have nutritive, intercellular signalling and enzyme-secreting properties. Stromal myofibroblasts may be abundant, particularly in breast cancers, where their contractility is responsible for the puckering (e.g. overlying skin) and retraction of adjacent structures (e.g. nipple).

The stroma always contains blood vessels which perfuse the tumour. 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 will cease expanding when the nodule has attained a diameter of no more than 1 to 2 mm ( Fig. 10.4 ). Angiogenesis in tumours is induced by factors secreted by tumour cells such as vascular endothelial growth factor (VEGF). This action is opposed by factors such as angiostatin and endostatin which have potential in cancer therapy.

The stroma often contains a lymphocytic infiltrate of variable density. This may reflect a host immune reaction to the tumour ( Ch. 8 ), a hypothesis supported by the observation that patients whose tumours are densely infiltrated by lymphocytes tend to have a better prognosis and some are more amenable to immunotherapy, such as immune checkpoint inhibitors.

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, exophytic/fungating, ulcerated or annular ( Fig. 10.5 ). The behaviour of a tumour (i.e. whether it is benign or malignant) often correlates with its gross appearance: polypoid tumours are generally benign, that is, unlikely to spread beyond the tissue of origin ( Fig. 10.6 ); ulceration is more commonly associated with destructive invasive behaviour, which is the defining feature of malignancy ( Fig. 10.7 ). Ulcerated tumours can often be distinguished from nonneoplastic ulcers, such as peptic ulcers in the stomach, because the former tend to have heaped-up irregular 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 due to stromal fibrosis, causing a palpable lump in accessible sites, such as the breasts. The cut surfaces of malignant tumours are often variegated due to areas of necrosis, haemorrhage, fibrosis and degeneration, but some, such as lymphomas and seminomas, appear uniformly bland.

Benign tumours

Benign tumours remain localised. They are slowly growing lesions that do not invade the surrounding tissues or spread to other sites in the body. They are often enveloped by a thin layer of compressed connective tissue (i.e. encapsulated).

When a benign tumour arises in an epithelial or mucosal surface, the tumour grows away from the surface, because it cannot invade, often forming a polyp which may be either pedunculated (stalked) or sessile (sitting on the surface); this noninvasive outward direction of growth creates an exophytic lesion ( Fig. 10.9 ). Histologically, benign tumours closely resemble the parent cell or tissue, with only mild nuclear changes.

Although benign tumours are, by definition, confined to their site of origin, they may cause clinical problems due to:

• pressure on adjacent tissues (e.g. benign meningeal tumour causing epilepsy)

• obstruction to the flow of fluid (e.g. benign epithelial tumour blocking a duct)

• production of a hormone (e.g. benign thyroid tumour causing thyrotoxicosis)

• transformation into a malignant neoplasm (e.g. adenomatous polyp progressing to an adenocarcinoma)

• anxiety (because the patient fears that the lesion may be something more sinister).

Malignant tumours

Malignant tumours are, by definition, invasive. They are typically rapidly growing with an irregular margin (not circumscribed). Histologically, they resemble the parent cell or tissue to a lesser extent than do benign tumours. Malignant tumours invade into and destroy the adjacent tissues (see Fig. 10.9 ), 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 have irregular margins, often with tongues 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. Malignant neoplastic cells show a greater degree of atypical nuclear changes, with enlargement of the nucleus, more variability in nuclear size, shape and chromatin clumping (pleomorphism), and darker staining (hyperchromasia).

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

• pressure on and destruction of adjacent tissue

• formation of secondary tumours (metastases)

• blood loss from ulcerated surfaces

• obstruction of flow (e.g. malignant tumour of the colon causing intestinal obstruction)

• production of a hormone (e.g. adrenocorticotropic hormone [ACTH] and vasopressin [ADH] from some lung tumours)

• other paraneoplastic effects causing weight loss and debility

• anxiety and pain.

Histological grade (degree of differentiation)

The extent to which the tumour resembles histologically its cell or tissue of origin determines the tumour grade ( Fig. 10.10 ) or degree of differentiation. Benign tumours are not usually further classified in this way because they nearly always closely resemble their parent tissue. However, the degree of differentiation of malignant tumours is clinically useful both because it correlates strongly with patient survival (prognosis), and because it may indicate the most appropriate treatment. Thus malignant tumours are usually graded either as well, moderately or poorly differentiated, or numerically, 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 recognisable histogenetic features and are referred to as ‘anaplastic’. There may even be great difficulty in deciding whether they are carcinomas or lymphomas, for example, although immunohistochemistry and molecular pathological clonality analysis often aid this distinction.

Benign epithelial tumours

Benign epithelial tumours are either:

• papillomas

• adenomas.

A papilloma is a benign tumour of nonglandular or nonsecretory epithelium, such as transitional or stratified squamous epithelium ( Fig. 10.11 ). An adenoma is a benign tumour of glandular or secretory epithelium ( Fig. 10.12 ). The name of a papilloma or adenoma is incomplete unless prefixed by the name of the specific epithelial cell type or glandular origin; examples include squamous cell papilloma, transitional cell papilloma, colonic adenoma and thyroid adenoma.

Malignant epithelial tumours

Malignant tumours of epithelium are always called carcinomas . Carcinomas of nonglandular 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.

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. 10.13 ). 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 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 with milder nuclear changes. 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 ‘ intraepithelial neoplasia’ , as in cervical intraepithelial neoplasia (CIN), is used increasingly to encompass both carcinoma in situ and dysplasia.

Benign connective tissue and mesenchymal tumours

Benign mesenchymal tumours are named after the cell or tissue of origin suffixed by ‘-oma’, as follows:

• lipoma : benign tumour of the lipocytes of adipose tissue

• rhabdomyoma : benign tumour of striated muscle

• leiomyoma : benign tumour of smooth muscle cells

• chondroma : benign tumour of cartilage

• osteoma : benign tumour of bone

• angioma : benign vascular tumour.

Malignant connective tissue and mesenchymal tumours

Malignant tumours of mesenchyme are always designated sarcomas , prefixed by the name that describes the cell or tissue of origin. Examples include:

• liposarcoma : malignant tumour of lipocytes

• rhabdomyosarcoma : malignant tumour of striated muscle

• leiomyosarcoma : malignant tumour of smooth muscle

• chondrosarcoma : malignant tumour of cartilage

• osteosarcoma : malignant tumour of bone

• angiosarcoma : malignant vascular tumour.

As with carcinomas, sarcomas can be further categorised according to their grade or degree of differentiation ( Fig. 10.14 ).

Teratomas

A teratoma is a neoplasm of germ cell origin that forms cells representing all three germ cell layers of the embryo: 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, and so on. In their malignant form, these representatives of ectoderm, mesoderm and endoderm may appear more immature and can be less easily identifiable.

Teratomas 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. 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 sacrococcygeal region.

Embryonal tumours: the ‘blastomas’

Some types of tumour occur almost exclusively in the very young, usually in those below 5 years of age, and bear a histological resemblance to the embryonic form of the organ in which they arise. Examples include:

• retinoblastoma , which arises in the eye and for which there is an inherited predisposition

• nephroblastoma or Wilms tumour , which arises in the kidney

• neuroblastoma , which arises in the adrenal medulla or nerve ganglia and occasionally ‘matures’ into a harmless benign ganglioneuroma

• hepatoblastoma , which arises in the liver.

Mixed tumours

Mixed tumours show a characteristic combination of cell types. The best example is the mixed parotid tumour (pleomorphic salivary adenoma); this consists of glands embedded in a cartilaginous or mucinous matrix derived from the myoepithelial cells of the gland. Another common mixed tumour is the fibroadenoma of the breast, a lobular tumour consisting of epithelium-lined glands or clefts in a loose fibrous tissue matrix.

Endocrine tumours

Endocrine tumours are derived from hormone-secreting cells scattered diffusely in various epithelial tissues. Many endocrine tumours are functionally active, and clinical syndromes often result from excessive secretion of their products. The nomenclature of these tumours has been confusing in the past — they were previously thought to have some neural origin and so were called neuroendocrine tumours and were also referred to as APUDomas; this acronym signifies their biochemical properties (amine content and/or precursor uptake and decarboxylation). The best current term is endocrine but neuroendocrine is still widely used.

The name of those endocrine 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 (causes episodic hypoglycaemia). A gastrinoma secretes gastrin, causing Zollinger–Ellison syndrome with extensive peptic ulceration. 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. Phaeochromocytomas of adrenal medulla secrete adrenaline and noradrenaline, causing paroxysmal hypertension.

Endocrine tumours of the gut and respiratory tract that either do not produce any known peptide hormone or a mixture of peptide hormones are called carcinoid tumours , though neuroendocrine or endocrine tumour might be better terms. 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 (serotonin) and prostaglandins. 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 endocrine tumours; they have a multiple endocrine neoplasia (MEN) syndrome ( Ch. 17 ).

Hamartomas

A hamartoma is a tumour-like lesion, the growth of which is coordinated with the individual; it lacks the autonomy of a true neoplasm. Hamartomas are always benign and usually consist of two or more mature cell types normally found in the organ in which the lesion arises. A common example occurs in the lung, where a hamartoma typically consists of a mixture of cartilage and bronchial-type epithelium (the so-called ‘adenochondroma’; Ch. 14 ). Pigmented naevi of skin or ‘moles’ ( Ch. 24 ) may also be considered as hamartomatous lesions, although many contain mutations in neoplasia-associated genes and some may develop neoplastic features. Their clinical importance is:

• hamartomas may be mistaken for malignant neoplasms, on a chest x-ray for example

• hamartomas are sometimes associated with clinical syndromes that may include tumour formation, as, for example, in tuberous sclerosis ( Ch. 26 ) or dysplastic naevus syndrome ( Ch. 24 ).

Cysts

A cyst is a fluid-filled space lined by epithelium. Some cysts are neoplasms, others are not, but because they may have local effects similar to those produced by true tumours and some tumours are typically cystic, it is pertinent to consider them here. Common types of cyst are:

• neoplastic (e.g. cystadenoma, cystadenocarcinoma, cystic teratoma)

• congenital (e.g. branchial and thyroglossal cysts) due to embryological defects

• parasitic (e.g. hydatid cysts due to Echinococcus granulosus)

• retention (e.g. epidermoid and pilar cysts of the skin)

• implantation (e.g. as a result of surgical or accidental implantation of epidermis).

Tumour products

The major types of tumour product are:

• substances appropriate to their cell of origin (e.g. keratin from a squamous cell carcinoma, steroid hormones from an adrenocortical adenoma)

• substances inappropriate or unexpected for their cell of origin (e.g. ACTH and ADH from small cell carcinomas of the lung), an example of a paraneoplastic syndrome

• fetal reversion substances (e.g. carcinoembryonic antigen from adenocarcinomas of the gastrointestinal tract, alpha-fetoprotein from liver cell carcinomas and testicular teratomas)

• substances required for growth and invasion (e.g. autocrine growth factors, angiogenic factors, collagenases).

Some tumour products are useful as markers for diagnosis or follow-up ( Table 10.4 ). 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. 10.15 ). Release of tumour-derived DNA as cell-free DNA fragments into the blood may also be detected as tumour markers (e.g. mutated oncogenes or TSGs).

Invasion

The invasiveness of malignant neoplasms is determined by the properties of the neoplastic cells within them. Factors influencing tumour invasion are:

• decreased cellular adhesion

• secretion of proteolytic enzymes

• abnormal or increased cellular motility.

Altered expression of adhesion molecules (e.g. E-CADHERIN) can allow decreased cell-cell adhesion in carcinomas. Integrin receptors become dispersed around the tumour cell to allow altered tumour cell-matrix adhesion. Cellular motility is abnormal in that the cells are not only more mobile than their normal counterparts (which may not move at all) but also show loss of the normal mechanism that arrests or reverses normal cellular migration: contact inhibition of migration.