Disturbances of Cell Growth & Neoplasia – Core Vocabulary

Disturbances of Normal Cell Growth

Atrophy (↓ size & weight)

• Definition: Reduction in organ/tissue mass due to decreased size and number of cells.
• Mechanisms: Reduced protein synthesis, increased proteolysis, autophagy.
• Types & Examples
  • Physiological
  – Ovary & breast after menopause.
  – Thymus after puberty.
  • Pathological
  – Generalized: chronic diseases, malnutrition, advanced malignancy.
  – Localized:
  – Disuse → skeletal muscle after immobilization.
  – Pressure → adjacent cells around amyloid deposits.
  – Vascular/Ischemic → myocardium in coronary atherosclerosis.
  – Neuropathic → denervated muscle.
  – Endocrine → genitalia & breast after oophorectomy.
  – Thermal → undescended testis.

Hypertrophy (↑ cell size)

• Definition: Enlargement of organ/tissue due to increased cell size (no new cells).
• Types
  • Physiological: gravid uterus; skeletal muscle in athletes/manual workers.
  • Pathological
  – Adaptive: LVH in aortic stenosis, gastric muscle in pyloric stenosis.
  – Compensatory: remaining kidney or lung after loss of the mate.

Hyperplasia (↑ cell number)

• Definition: Increased mass because of more cells; may coexist with hypertrophy.
• Types
  • Physiological: breast & genitalia at puberty.
  • Pathological
  – Hormonal: endometrium, breast (↑ estrogen).
  – Irritation/Inflammatory: lymphoid tissue after infection.
  – Compensatory: bone-marrow post-haemorrhage.

Metaplasia (cell type replacement)

• Definition: Reversible substitution of one adult cell type by another of same germ layer to cope with new stress.
• Forms
  • Epithelial
  – Squamous: respiratory epithelium in smokers; urinary bladder in bilharzial cystitis.
  – Intestinal: gastric glands around peptic ulcer.
  • Mesenchymal (Connective)
  – Osseous: fibroblasts → osteoblasts → bone in scars, calcified areas, myositis ossificans.

Dysplasia (disordered growth)

• Hallmarks: loss of uniformity, architectural distortion, pleomorphism, hyperchromatism, abnormal mitoses, N/C\,ratio \to 1:1.
• Etiology: chronic irritation; often accompanies hyperplasia/metaplasia.
• Sites: urinary bladder (bilharziasis), cervix, bronchi in heavy smokers.

Carcinoma in Situ (CIS)

• Early malignancy confined above basement membrane.
• Full-thickness atypia, loss of polarity, pleomorphism.
• Fate: invasive carcinoma within 5!\text{–}!10\;\text{yr}.
• Common in cervix, bladder, bronchi.

Neoplasia – General Concepts

Definition of Tumor / Neoplasm

Self-perpetuating (autonomous) mass produced by unlimited proliferation of abnormal cells.

Fundamental Characteristics

1. Uncontrolled proliferation – independent of body needs, persists during starvation.
2. No useful function – may even be harmful (ectopic hormones).
3. Two components
   – Neoplastic (monoclonal) parenchyma.
   – Non-neoplastic stroma & vessels (angiogenesis factor-driven).

Molecular Basis – “Four Gene Groups”

Classification of Tumors

A. Biological Behaviour

• Benign
• Malignant
• Intermediate / Locally malignant (locally aggressive, no metastasis) – e.g. basal cell carcinoma, giant-cell tumor of bone, adamantinoma, carcinoid, chordoma, craniopharyngioma.

B. Tissue of Origin (Histogenesis)

• Epithelial
• Mesenchymal
• Others (melanocytic, lymphoid, totipotent, etc.)

Nomenclature Highlights

• Carcinomas = malignant epithelial; named "prefix + carcinoma" (e.g. squamous cell carcinoma, adenocarcinoma).
• Sarcomas = malignant mesenchymal; named "prefix + sarcoma" (fibrosarcoma, osteosarcoma…).
• Exceptions: malignant melanoma, hepatocellular carcinoma, choriocarcinoma.

Benign vs Malignant – Detailed Comparison

Gross Features

Microscopy

• Benign: well-differentiated, minimal atypia, rare mitoses, scant vessels.
• Malignant: anaplasia (pleomorphism, hyperchromasia, ↑N/C ratio, abnormal mitoses, tumor giant cells), rich thin-walled vasculature, frequent necrosis.

Behaviour

• Benign: expansile, do not metastasize; problems arise in vital sites, obstruction, hormone production, or malignant transformation.
• Malignant: invasive & metastatic; recurrences common; major cause of death.

Causes of Cancer Death

1. Local destruction.
2. Metastatic organ failure.
3. Vital-centre damage (brain).
4. Luminal obstruction.
5. Cachexia, malnutrition, anemia (bleeding, marrow replacement, folate/iron deficiency, autoimmune hemolysis).
6. Toxemia/infection.
7. Para-neoplastic syndromes (≈10\%).

Spread of Malignant Tumors

Routes

1. Local invasion – ECM degradation (↓E-cadherin; ↑laminin/fibronectin receptors; metalloproteinases IV-collagenase, cathepsin D; pseudopodial migration).
2. Lymphatic – typical of carcinomas; subcapsular sinus → node replacement; lymphatic permeation causes edema (e.g. breast).
3. Hematogenous – typical of sarcomas; via venous invasion or thoracic duct; common metastasis sites: liver, lung, bone, brain (rare in muscle, spleen).
4. Transcoelomic – peritoneal, pleural, pericardial, CSF (e.g. ovarian, gastric → Krukenberg ovary).
5. Implantation – transluminal (urinary tract), surgical seeding.

Vascular Dissemination & Homing

• Tumor emboli → many destroyed by immunity; survivors coat with platelets → lodge in capillaries → extravasate → secondary growths.

Histological Classification (Selected Examples)

Epithelial Tumors

Mesenchymal Tumors

Precancerous (Premalignant) Lesions

1. Chronic inflammation: bilharzial cystitis, ulcerative colitis, atrophic gastritis, radiodermatitis, tertiary syphilis, lupus vulgaris.
2. Mechanical/stone irritation: gallstones, urinary calculi.
3. Hyperplasia/metaplasia: leukoplakia, endometrial & mammary hyperplasia.
4. Benign tumors: villous bladder papilloma, adenomatous GI polyps.
5. Others: liver cirrhosis, varicose & gastric ulcers, Paget bone disease, undescended testis, xeroderma pigmentosum.

Benign Epithelial Tumors (Papillomas & Adenomas)

Papilloma (exophytic on surface epithelium)

• Squamous cell papilloma: skin, mucosa (lip → anal canal).
• Transitional papilloma (urothelium): bladder/ureter; pre-malignant.
• Columnar papillomas
  • Duct papilloma (breast major ducts).
  • Mucous cell papilloma = adenomatous polyp (GIT).

Adenoma (glandular)

• Forms: simple/tubular, cystadenoma, papillary cystadenoma, fibro-adenoma (breast).
• Sites: endocrine/exocrine glands, mucosal glands (GIT, endometrium).
• Risk of malignant transformation varies (e.g. colonic villous adenoma).

Benign Mesenchymal Tumors – Key Points

Connective Tissue

• Lipoma: encapsulated yellow lobulated mass; anywhere subcutaneously (lipomatosis = multiple).
• Fibroma: firm grey mass; dermis, ovary; hyalinization/myxoid change possible.
• Chondroma: bluish lobulated cartilage nodules inside (enchondroma) or on bone surface; solitary vs Ollier's disease.
• Osteochondroma (exostosis): cartilage-capped bony outgrowth from epiphysis; multiple hereditary form; risk → chondrosarcoma.
• Osteoid osteoma: <2\,\text{cm} cortical nidus; severe nocturnal pain relieved by aspirin.
• Compact osteoma: ivory-like lesion in skull → cosmetic/pressure issues.
• Myxoma: gelatinous; heart (atrial) or jaw; may obstruct AV valves.

Muscle Tumors

• Leiomyoma (fibroid): most common female tumor; estrogen-dependent; subserous, intramural, submucous; whorled cut surface.
• Rhabdomyoma: rare, heart; may transform to rhabdomyosarcoma.

Vascular Tumors

• Hemangioma (capillary vs cavernous): congenital hamartoma; skin, oral mucosa, liver, spleen; macroglossia/macocheilia.
• Lymphangioma: cavernous channels with lymph; skin, tongue, spleen.

Peripheral Nerve Tumors

• Schwannoma (neurilemmoma): encapsulated eccentric to nerve; Antoni-A/B areas.
• Neurofibroma: fusiform expansion of nerve; solitary or NF-1.

Malignant Epithelial Tumors

Squamous Cell Carcinoma (SCC)

• Sun-exposed skin & any squamous mucosa; also metaplastic sites (bladder).
• Gross: fungating, ulcerative (raised everted edges), or infiltrative.
• Microscopy: keratinising "cell nests" graded by % keratinization (Broder I–IV).
• Spread: local → lymph → blood.

Adenocarcinoma

• Arises in glands & mucosa (breast, colon, pancreas, endometrium…).
• Patterns: infiltrative, polypoid, ulcerative, annular ("napkin-ring" colorectal).
• Histology from well differentiated acini to anaplastic solid sheets; variants: cystadenocarcinoma, papillary.
• Spread: local, lymph, blood (late), transcoelomic (GIT).

Mucin-Secreting Variants

• Mucinous (colloid): pools of extracellular mucin with floating glandular clusters.
• Signet-ring cell: intracellular mucin displacing nucleus; poor prognosis.

Transitional Cell Carcinoma (TCC)

• Urothelium (bladder > ureter > pelvis).
• Papillary (better) vs non-papillary infiltrative ulcers/masses.
• Metastasis via lymphatics; transluminal implantation possible.

Basal Cell Carcinoma (locally malignant)

• Sun-exposed facial skin above mouth-ear line.
• Palisading peripheral cells; variants include pigmented type.
• Invades locally; no metastasis.

Giant Cell Tumor (Osteoclastoma)

• Around knee; stromal mononuclear neoplastic cells + numerous reactive osteoclastic giant cells; egg-shell cortex; local recurrence common, rare metastasis.

Adamantinoma (ameloblastoma & tibial form)

• Mandible/maxilla or tibia; islands of odontogenic epithelium in fibrous stroma; local invasion.

Malignant Mesenchymal Tumors (Sarcomas)

• Liposarcoma – retroperitoneum; lipoblasts; myxoid, pleomorphic variants.
• Fibrosarcoma – herringbone spindle pattern; abundant vs scant collagen grades.
• Rhabdomyosarcoma – embryonal (sarcoma botryoides – grape-like masses in UB/vagina, children), alveolar, pleomorphic (strap cells).
• Leiomyosarcoma – uterus, GIT; eosinophilic spindle cells.
• Osteosarcoma, Chondrosarcoma, Angiosarcoma, etc. follow tissue nomenclature.

Pigmented Tumors

• Melanocytic Nevus (mole): junctional vs intradermal.
• Malignant Melanoma
  • Radial growth: lentigo-maligna, superficial spreading, acral lentiginous.
  • Vertical growth: nodular.
• High metastatic potential; staging via Breslow thickness.

Developmental & Embryonic Tumors

• Teratoma: tissues from all 3 germ layers; mature (ovarian dermoid cyst), immature, or specialized (e.g. struma ovarii).
• Embryonic (blastoma) tumors: neuroblastoma, medulloblastoma, retinoblastoma, hepatoblastoma, nephroblastoma (Wilms), embryonal rhabdomyosarcoma.
• Hamartoma: disorganized but mature tissue mass (lung, kidney, hemangioma, nevus).

Prognostic Factors

1. Tumor type & biology.
2. Stage (TNM): T0\text{–}4,\;N0\text{–}3,\;M0/M1 – best single predictor.
3. Histologic grade/differentiation.
4. Site & surgical accessibility.
5. Patient age.
6. Immune competence.
7. Early detection & therapy response.
8. Radio/chemo-sensitivity.
9. Hormone receptor status.
10. Growth fraction (cycling cells).

Diagnosis & Laboratory Aids

• Clinical exam, imaging (X-ray, US, CT, MRI).
• Pathology: biopsy (10% formalin), frozen section, FNA, exfoliative cytology.
• Ancillary: immunohistochemistry, EM, flow cytometry (DNA ploidy).

Tumor Markers (examples)

• AFP (hepatocellular, yolk sac).
• CEA (colon, pancreas).
• PSA (prostate).
• hCG (choriocarcinoma).
• Calcitonin (medullary thyroid).
• CA-125 (ovary).
  Use: diagnosis, therapy monitoring, relapse detection.

Oncogenes & Proto-oncogenes

• Proto-oncogenes: normal genes regulating growth/differentiation; become oncogenes via
  • Point mutation – RAS in lung/colon adenocarcinoma.
  • Translocation – t(8;14) MYC (Burkitt), t(9;22) BCR-ABL (CML).
  • Amplification – N!MYC (neuroblastoma), ERBB2 (HER2, breast).
• Result: autonomous growth signalling.

Etiology of Cancer (Carcinogenesis)

Chemical

• Polycyclic hydrocarbons (benzpyrene) – lung.
• Aromatic amines (β-naphthylamine) – bladder.
• Nitrosamines (bacterial) – stomach.
• Azo dyes – liver.
• Asbestos – mesothelioma.
• Aflatoxin B1 – hepatocellular carcinoma.

Physical

• UV (sun) – BCC, SCC, melanoma.
• Ionizing radiation – leukemia, thyroid, osteosarcoma, lung, skin.

Viral

• DNA: HPV 16/18 – cervical; HBV/HCV – liver; EBV – Burkitt, nasopharynx; HHV-8 – Kaposi.
• RNA (retroviruses): HTLV-I – T-cell leukemia/lymphoma; HIV via immunosuppression.

Hormonal Promotion

• Estrogen excess → endometrial & breast carcinoma.
• Androgen excess → prostate carcinoma.

Radiobiology

• Cellular effects: degeneration/necrosis, mitochondrial injury, enzyme inhibition, DNA single/double strand breaks, mitotic arrest.
• Tumor radiosensitivity
  • Sensitive: lymphoma, seminoma, Ewing sarcoma.
  • Responsive: SCC, BCC, breast carcinoma.
  • Resistant: osteosarcoma, melanoma.

High-Yield Self-Check MCQs (from lecture slides)

1. Hypertrophy = d) increase in cell size.
2. Benign tumors d) do not metastasize.
3. Hyperplasia = d) increase in cell number.
4. Metaplasia statements: only (d) Barrett’s oesophagus is correct; others false.
5. Dysplasia true features: b) abnormal mitosis, d) hyperchromatic nuclei, e) N:C \approx 1:1.
6. Benign neoplasm features: a) slow growth, e) innocent nature.

"Cheat-Sheet" Arabic Phrases from Slides (contextual)

• "زنقة الكلاب" – cramming just before exams.
• "مفيش وقت للإنهيار، ذاكر وانت بتعيط" – “No time to collapse; study while crying.”
  (Useful motivational quotes but not examinable!)