Overview
This lecture introduces the vocabulary and classification systems used to describe neoplasms. It covers the meaning of neoplasia and related terms, the naming conventions for benign versus malignant tumours by tissue of origin, the systemic and local effects tumours can produce, histogenetic classification and grading, the mechanism and patterns of metastatic spread, and the principles of tumour staging (including TNM). It opens by posing the practical problem classification solves: how to tell tumours apart, compare treatment results, and know whether two growths are the same or different. A running clinical example (three patients, Jane, Jenny and Jill, each with a breast lump) is used throughout to link these concepts to outcome. Tumours have affected humans since antiquity: a Shang-dynasty skull (c. 1700-1050 BC) shows a destructive cranial/orbital lesion, offered as early evidence of tumour disease in the historical record.
Nomenclature and Basic Terms
- Neoplasia: Greek/Latin for “new growth”; growth that exceeds and is uncoordinated with normal tissue growth and persists after the stimulus that caused it stops. Encompasses both benign and malignant tumours. It is a genetic and epigenetic disease.
- Oncology: the branch of medicine dealing with tumours, their development, diagnosis, treatment and prevention. From Greek “oncos” = tumour/swelling.
- Tumour (tumor): from Latin “tumor” = swelling.
- Mass: the radiological term for a lump/tumour.
- A neoplasm is a clonal expansion of (stem) cells that have undergone neoplastic transformation, caused by a chemical, physical or biological agent that directly and irreversibly alters the cell genome. Tumour cells abort the normal cell cycle and divide excessively; these genomic changes are reflected in tissue morphology and identified microscopically as cellular dysplasia.
- Dysplasia: abnormal growth/tissue change reflecting these genomic alterations, seen microscopically as cellular dysplasia. Features: hyperchromatic nuclei, prominent nucleoli, enlarged nuclei, nuclear pleomorphism, higher mitotic rate.
- Benign lesions: dysplasia usually minimal.
- Pre-malignant/malignant lesions: dysplasia ranges from minimal to severe.
- Dysplasia may or may not progress to a malignant tumour.
- Framing questions posed for a growth: does size matter? Does invasion matter? Does necrosis matter? Does haemorrhage matter? Does spread to other organs matter? These are the features that classification, grading and staging (below) go on to formalise.
Purpose and Basic Framework of Classification
Classification exists to:
- Determine prognosis
- Determine who benefits from particular treatments
- Allow accurate exchange of information
- Facilitate epidemiological analysis
- Classification changes over time as knowledge improves.
Basic tumour classification has four components:
- Behavioural classification: benign vs malignant
- Histogenetic classification: tissue type and subtype
- Grade: differentiation (how well specialised)
- Stage: how far a malignant tumour has spread
Naming by Tissue of Origin
Nomenclature pairs a benign and malignant name for each tissue type:
| Tissue type | Benign | Malignant |
|---|---|---|
| Mesenchymal - fibrous tissue | fibroma | fibrosarcoma |
| Mesenchymal - smooth muscle | leiomyoma | leiomyosarcoma |
| Mesenchymal - bone | osteoma | osteosarcoma |
| Epithelial (glandular) | adenoma | carcinoma (adenocarcinoma) |
Melanoma, lymphoma and teratoma are named as exceptions to this pattern, that is, their names do not follow the standard benign/-oma versus malignant/-sarcoma or -carcinoma convention. [slide does not state the behaviour (benign/malignant) of each].
Benign vs Malignant Neoplasms
Benign:
- Less autonomous growth than malignant tumours
- Expand into surrounding tissue but are typically well demarcated, often with a fibrous capsule that eases surgical excision
- Usually do not spread to other sites
- Generally cause no great harm if adequately treated, but can still cause significant problems if they produce active substances, grow very large, rupture, or compress vital structures
- Well differentiated (resemble normal cells); not graded
Malignant:
- Greater degree of growth autonomy
- Invade local tissues (the hallmark of malignancy)
- Spread to other sites (metastasise)
- May be resistant to treatment
- Cause harm/death
- Differentiation ranges from well to moderately to poorly differentiated to undifferentiated/anaplastic
Summary comparison:
| Feature | Benign | Malignant |
|---|---|---|
| Differentiation | Resembles normal cells (well differentiated) | Dysplastic, differentiation varies, less resemblance to normal |
| Growth | Usually expansile | Invasive |
| Metastasis | None | Yes |
| Grading | Well differentiated (not graded) | Well / moderately / poorly differentiated / anaplastic |
| Effect on host | Harm from location or complication | Harm from location, complication, tumour product, or spread |
Systemic and Local Effects of Tumours
- Hormone production: both benign and malignant neoplasms can secrete hormones, e.g. pituitary adenoma (benign) producing growth hormone can cause acromegaly.
- Para-neoplastic syndromes: effects caused by tumour products or its presence, distinct from direct invasion or metastasis. Example: Cushing syndrome from neuroendocrine carcinoma of the lung producing corticotropin or corticotropin-like peptides. Other examples: hypercalcaemia, carcinoid syndrome, hypoglycaemia, and neuromyopathies (usually antibody-mediated). Cushing syndrome features include buffalo hump, hypertension, thinned skin, muscle wasting of the arms/legs, benign intracranial hypertension, cataracts, moon face with plethora, increased abdominal fat, avascular necrosis of the femoral head, easy bruising, and poor wound healing.
- Cachexia: a multi-organ syndrome of systemic inflammation and negative energy balance, producing irreversible wasting in the late stages of severe chronic illness such as cancer. Driven by cytokines (TNF, IL-1) from both the tumour and the host response; inflammatory cytokines signal in the CNS and peripheral tissues to increase catabolic and decrease anabolic processes.
- Local breast signs suspicious of malignancy: lump, ulceration, skin puckering, indrawn nipple, bloody nipple discharge, and peau d’orange (an orange-peel dimpled skin texture, illustrated by direct comparison to an orange peel). [slide does not give the mechanism]
Molecular/Genetic Subclassification
Molecular and genetic subclassification (applicable to both benign and malignant neoplasms) is used to:
- Predict response to systemic therapy
- Predict prognosis/risk of spread
- Determine tumour type or class via specific molecular events
- Aid differential diagnosis of malignancy
Examples given:
- Pituitary adenoma: growth hormone or oxytocin production
- Breast: oestrogen, progesterone and Her2 receptor status (guides Herceptin/hormonal treatment)
- Lymphoma: BCL2 expression
- Soft tissue sarcoma: CD99 expression
- Gastrointestinal stromal tumour: cKit/CD117 expression
- Melanoma: BRAF-inhibitor therapy target; copy number abnormalities help distinguish malignant from benign lesions
Worked Example: Breast Lesions (Fibroadenoma vs Carcinoma)
- Normal breast: epithelial cell bilayer (myoepithelial and epithelial layers, with columnar cell change in the epithelial layer) sitting on a basement membrane.
- Fibroadenoma (benign): well-circumscribed, round, bosselated mass on imaging and gross pathology. Microscopically, compressed/elongated glandular structures surrounded by dense fibrous stroma, which compresses epithelium into slit-like shapes.
- Breast carcinoma (malignant): invasive growth is the hallmark of malignancy. Imaging shows a spiculated mass with architectural distortion; gross pathology shows an irregular, infiltrative, stellate cut surface. Microscopically, infiltrative angulated glandular tubules invade through desmoplastic stroma and fat, with loss of normal lobular architecture.
Histogenetic Classification and Differentiation
Classifying by histogenetic type describes what tissue/differentiation pattern the tumour recapitulates:
- Adenocarcinoma: glandular differentiation, arising from and resembling glandular epithelium.
- Squamous cell carcinoma: squamous differentiation, arising from and resembling stratified squamous epithelium (may show keratinisation).
Even within one organ, several distinct histological subtypes exist. In breast:
- Adenocarcinoma subtypes: No Special Type (aka ductal), lobular, tubular, medullary, mucinous, cribriform.
- Squamous cell carcinoma subtypes: keratinising, non-keratinising.
Prognosis varies by subtype in breast adenocarcinoma:
- No Special Type (ductal) and lobular: worst prognosis
- Medullary and mucinous: intermediate prognosis
- Tubular and cribriform: most favourable prognosis
Tumour Grading
- Grading applies only to malignant tumours (benign tumours are well differentiated and resemble normal cells, so are not graded).
- Grading is based on how well a malignant tumour’s tissue is specialised/differentiated by light microscopy, using reproducibly detected factors such as cell morphology and proliferation rate.
- Grading criteria are specific to each tumour type (e.g. Bloom and Richardson criteria for breast).
- Grading matters for prognosis in many, though not all, malignant tumours; it is generally of less clinical significance than staging, except in soft tissue sarcoma, primary brain tumours, lymphoma and prostate cancer, where grading can matter more (especially for a small, localised tumour).
Adenocarcinoma differentiation grades:
- Well differentiated (approx. grade 1) - organised glandular structures
- Moderately differentiated (approx. grade 2)
- Poorly differentiated (approx. grade 3)
- Undifferentiated/anaplastic (approx. grade 3) - sheets of atypical cells, no glandular architecture
Breast carcinoma grade and survival:
| Grade | 5-yr survival | 7-yr survival |
|---|---|---|
| Grade 1 (tubular Ca) | 95% | 90% |
| Grade 2 | 75% | 63% |
| Grade 3 (ductal Ca) | 50% | 45% |
Metastasis
Definition: an auto-transplantation phenomenon in which transferred malignant cells grow into a satellite neoplasm remote from the primary tumour.
Steps required to develop a metastasis:
- Cells detach from the primary tumour
- Cells move through the extracellular matrix
- A transport system carries detached cells to a new site
- Cells survive the journey and attach at the new site
- Conditions at the new site must favour growth and multiplication
Each step in this “metastatic sequence” is subject to many influences, so a breakaway cell may fail to survive at any point; millions of cells are released into the circulation daily from a primary tumour, but only a few metastases actually form.
Typical secondary sites for malignant spread:
- Lymph nodes: especially carcinoma and lymphoma
- Liver: especially carcinoma from the colon
- Lung: most tumour types
- Bone: especially from prostate, lung, breast
- Brain: most tumour types
- Sarcoma: straight to blood and liver/lung
Organ-specific patterns of metastasis:
- To bone: bronchus/lung, kidney, breast, adrenal, thyroid, prostate
- To skin: bronchus, breast, melanoma
- To ovaries: breast, mucoid carcinoma of stomach and colon
- To gut: melanoma and lymphoma
Routes of Spread
- Lymphatic spread: to local lymphatic vessels, then the sentinel lymph node, then regional lymphatics, then more distant lymphatics. Histologically seen as tumour emboli within lymphatic channels. In the breast, drainage proceeds through axillary lymph nodes to supraclavicular nodes and nodes near the ribs/sternum.
- Peritoneal/cavity spread: secondary tumours of the peritoneum are quite common compared to primary tumours; can produce an “omental cake” studded with tumour nodules, and malignant cells can be identified cytologically in peritoneal fluid.
- Haematogenous spread: the primary tumour breaches the basement membrane, and transformed cells enter the circulation, interact with host lymphocytes and platelets, then egress into distant tissue to form a metastatic tumour. Within the circulation, tumour cells tend to aggregate in clumps; platelet-tumour aggregates may enhance survival and implantability. Adhesion to endothelium and egress through the basement membrane involves adhesion molecules (integrins, laminin receptors) and proteolytic enzymes.
Metastases by Site
- Lung: “cannonball” pattern of multiple round nodular opacities on chest X-ray; multiple pale nodules on gross pathology.
- Bone: increased tracer uptake on whole-body bone scan; gross haemorrhagic destructive lesions; histologically, bone trabeculae infiltrated by metastatic tumour cells. [flag: transcript notes an extra extracted token (“case36”) near this slide with unclear meaning; no clinical content depends on it]
- Liver: multiple low-attenuation lesions on CT; multiple pale nodules replacing normal liver tissue on gross pathology.
- Brain: multiple enhancing lesions with surrounding oedema on gadolinium-enhanced MRI; multiple haemorrhagic deposits on gross section.
- Intestine: transcript title reads “Metastases to Intestine” but the rendered slide shows no visible title text, so the organ is not confirmed; the image itself shows a dark haemorrhagic nodular lesion at a mucosal/skin surface. [flag: site uncertain]
- Lymphangitic (pulmonary lymphatic) spread: diffuse reticular/linear opacities on chest X-ray; thickened interlobular septa and peribronchovascular markings on CT, consistent with tumour infiltrating the pulmonary lymphatics.
Staging
- Staging indicates the patient’s likely prognosis and helps plan treatment; it is usually of greater clinical significance than grading (with the grading exceptions noted above).
- Staging is based on: (1) size of the primary neoplasm, (2) extent of spread to regional lymph nodes, (3) presence or absence of blood-borne metastases. It draws on clinical, radiological and surgical criteria (tumour size, regional lymph node involvement, presence of metastases).
- Staging systems and criteria are specific to each malignant tumour type and are combined by a multidisciplinary team using:
- Clinical staging: physical examination, blood tests, endoscopy, X-rays
- Radiographic staging: CT, MRI, arteriography, radioisotope scanning
- Surgical staging: surgical exploration of tumour extent
- Pathological staging: microscopic tissue examination to confirm malignancy
Simplified stage progression example (breast): Stage 1 = single mass; Stage 2 = mass plus adjacent/axillary nodal involvement; Stage 3 = mass plus more extensive nodal involvement; Stage 4 = advanced disease with metastases at distant sites (e.g. supraclavicular lymph nodes, bone, liver, lungs, brain). [slide heading pairs “Stage” with the Jane/Jenny/Jill vignette; the relationship between the two headings is not explained]
TNM Classification
The TNM system separately classifies:
- T: spread or size of the primary tumour
- N: nodal status
- M: presence of metastases
These are then grouped into an overall stage. The system is specific to each tumour type and has evolved with advances in diagnosis and treatment.
Breast stage and 5-year relative survival:
| Stage | 5-yr survival |
|---|---|
| 0 | 100% |
| I | 98% |
| IIA | 88% |
| IIB | 76% |
| IIIA | 56% |
| IIIB | 49% |
| IV | 16% |
Breast Cancer Pathology Report Contents
A breast cancer pathology report includes: tumour site and dimensions; histological tumour type and grade; hormone receptor status (oestrogen, progesterone, Her2, androgen); Ki67 proliferation index; lymph node status (x of y nodes involved); margin status (whether tumour reaches surgical margins); pathological stage; TNM descriptors (primary tumour pT, regional lymph nodes pN, with the year/edition of the staging system used); presence of any precancerous or other lesions. It is assessed jointly by pathologist, surgeon, radiologist and oncologist.
Clinical Vignette: Jane, Jenny and Jill
Three patients each presented with a breast lump, illustrating how classification, grading, staging and metastasis determine outcome:
- Jane, 19, a 10mm smooth, mobile, pea-sized, painless lump present 2 years: this was a fibroadenoma. Jane lived another 50 years and died of unrelated problems.
- Jenny, 43, a 10mm irregular, fixed, non-mobile lump pulling on the skin, noticed 3 weeks prior, with nipple discharge, not painful: this was adenocarcinoma (No Special Type), metastatic to lymph nodes, liver and lungs. Jenny lived 3 more years, dying very unwell, yellow in colour, and breathless once axillary lumps appeared.
- Jill, 62, a large ulcerated lesion with painful axillary lumps: adenocarcinoma metastatic to lymph nodes and brain. Jill died 1 week after presentation, with an ulcerated breast, a large axillary mass, and brain-metastasis symptoms (hallucinations, angry outbursts, inappropriate/blasphemous speech).
Next lecture (per the closing slide): Stage 0, pre-invasive cancer (in-situ neoplasia), e.g. cervical cancer and skin cancer.
Self-test
- Define neoplasia and explain what makes it “uncoordinated” growth.
- What is cellular dysplasia, and what microscopic features characterise it?
- List the four components of basic tumour classification.
- Give the benign and malignant name for a tumour of: fibrous tissue, smooth muscle, bone, and glandular epithelium.
- Name three tumour types that are exceptions to the standard benign/malignant naming pattern.
- Distinguish benign from malignant neoplasms in terms of growth pattern, invasion, and metastatic potential.
- Explain what a para-neoplastic syndrome is and give an example with its mechanism.
- Describe the pathophysiology of cancer cachexia.
- List local clinical signs in the breast suspicious of malignancy.
- Give two clinical uses of molecular/genetic subclassification of tumours, with an example each.
- Distinguish adenocarcinoma from squamous cell carcinoma in terms of tissue differentiation.
- Describe the four grades of adenocarcinoma differentiation, from best to worst differentiated.
- Why are benign tumours not graded?
- Describe the steps required for a tumour cell to successfully form a metastasis.
- List three organs that are common sites of metastasis and, for each, name a primary tumour type that classically spreads there.
- Describe the three main routes of metastatic spread and give one example of each.
- What three factors does cancer staging assess, and what does the TNM system stand for?
- Distinguish staging from grading in terms of what each measures and their relative clinical importance.
- Using the case of Jenny and Jill, explain how site and extent of metastatic spread affected their clinical course.
Answers
Reveal answers
- Neoplasia is new/abnormal tissue growth (benign or malignant) that exceeds and is uncoordinated with the growth of normal tissue, and persists in the same excessive manner after the stimulus that caused it has stopped; it is a genetic and epigenetic disease.
- Cellular dysplasia is the microscopic morphological change reflecting neoplastic transformation, marked by hyperchromatic nuclei, prominent nucleoli, enlarged nuclei, nuclear pleomorphism, and a higher mitotic rate; it is minimal in benign lesions and ranges from minimal to severe in pre-malignant/malignant lesions.
- Behavioural classification (benign vs malignant), histogenetic classification (tissue type/subtype), grade (differentiation), and stage (extent of spread).
- Fibrous tissue: fibroma / fibrosarcoma. Smooth muscle: leiomyoma / leiomyosarcoma. Bone: osteoma / osteosarcoma. Glandular epithelium: adenoma / carcinoma (adenocarcinoma).
- Melanoma, lymphoma, teratoma (any three) - named as exceptions to the standard naming pattern.
- Benign tumours grow expansile, are well demarcated (often capsulated), and do not metastasise; malignant tumours grow invasively into local tissue, can spread to other sites, may resist treatment, and can cause harm/death.
- A para-neoplastic syndrome is an effect produced by tumour products or the tumour’s presence, separate from direct invasion or metastasis; e.g. Cushing syndrome from a lung neuroendocrine carcinoma secreting corticotropin or corticotropin-like peptides, producing features such as moon face, buffalo hump, hypertension, thin skin, and muscle wasting.
- Cachexia is a multi-organ syndrome of systemic inflammation and negative energy balance causing irreversible wasting; tumour and host tissue both produce inflammatory cytokines (e.g. TNF, IL-1), which signal in the CNS and peripheral tissues to increase catabolic and decrease anabolic metabolism.
- Lump, ulceration, skin puckering, indrawn nipple, bloody nipple discharge, and peau d’orange (dimpled orange-peel skin appearance).
- Predicting response to systemic therapy (e.g. Her2 status in breast cancer guiding Herceptin/hormonal treatment) and predicting prognosis/risk of spread or aiding differential diagnosis (e.g. BRAF mutation status and copy number abnormalities in melanoma).
- Adenocarcinoma shows glandular differentiation, arising from and resembling glandular epithelium; squamous cell carcinoma shows squamous differentiation, arising from and resembling stratified squamous epithelium (sometimes with keratinisation).
- Well differentiated (~grade 1, organised glands) then moderately differentiated (~grade 2) then poorly differentiated (~grade 3) then undifferentiated/anaplastic (~grade 3, sheets of atypical cells with no glandular architecture).
- Because benign tumours are already well differentiated and resemble normal cells morphologically and functionally, so grading (a measure of loss of differentiation) does not apply.
- Cells detach from the primary tumour, move through the extracellular matrix, are transported to a new site, survive the journey and attach at the new site, and encounter conditions favourable for growth and multiplication there.
- Any three, e.g.: lymph nodes (carcinoma, lymphoma); liver (colon carcinoma); lung (most tumour types); bone (prostate, lung, breast); brain (most tumour types).
- Lymphatic spread (e.g. breast carcinoma to axillary/sentinel lymph nodes), haematogenous spread (e.g. tumour cells entering blood vessels to seed the liver or lung), and peritoneal/cavity spread (e.g. secondary peritoneal deposits forming an “omental cake”).
- Staging assesses: the size of the primary tumour, the extent of spread to regional lymph nodes, and the presence or absence of distant (blood-borne) metastases. TNM stands for Tumour (size/spread of primary), Node (nodal status), Metastasis (presence of metastases).
- Staging measures the anatomical extent of disease spread (tumour size, nodal involvement, metastases) and is generally the more clinically important prognostic indicator; grading measures how differentiated the tumour cells are histologically, and is usually secondary to staging except in tumours like soft tissue sarcoma, primary brain tumours, lymphoma, and prostate cancer.
- Jenny’s adenocarcinoma spread to lymph nodes, liver and lungs, causing jaundice-like colour change and breathlessness before death at 3 years; Jill’s adenocarcinoma spread to lymph nodes and brain, causing neuropsychiatric symptoms (hallucinations, personality change) before death within a week, showing that both the extent and the specific organs of metastatic spread determine the clinical course and speed of decline.