Pathological Processes and Neoplasm Characteristics
Edema
Edema is the abnormal accumulation of fluid in the interstitium or body cavities due to an imbalance in fluid homeostasis.
Types of Edema
Types include pitting edema, caused by protein deficiency, increased hydrostatic pressure, increased capillary permeability, or fluid retention; and non-pitting edema, caused by lymphatic obstruction or hypothyroidism (myxedema).
Edema Pathogenesis
Pathogenesis involves decreased plasma oncotic pressure, increased capillary hydrostatic pressure, lymphatic obstruction, increased interstitial oncotic pressure, increased capillary permeability, and sodium and water retention.
Fluid Types in Edema
Fluid types are classified as transudate, which is low in protein and non-inflammatory, or exudate, which is high in protein and associated with inflammation.
Pulmonary Edema
Pulmonary edema results from heart failure or capillary injury, leading to fluid accumulation in alveoli, presenting as heavy, frothy lungs with hyaline membranes.
Cerebral Edema
Cerebral edema is life-threatening and includes vasogenic, cytotoxic, and interstitial types. It lacks lymphatic drainage and is regulated by the blood-brain barrier.
Clinical Relevance of Edema
Clinical relevance depends on the underlying cause, location, and severity. Edema can be localized or generalized.
Hemorrhages
Hemorrhage is the escape of blood from blood vessels, either externally or internally into tissues or body cavities.
Types of Hemorrhage
Types include external hemorrhage and internal hemorrhage into serous cavities (e.g., hemothorax, hemoperitoneum), hollow viscera, or tissues.
Hemorrhage Terminology
- Hematoma: Blood in tissue causing swelling.
- Petechiae: Pinpoint hemorrhages.
- Purpura: Small hemorrhages less than 1 cm.
- Ecchymosis: Large hemorrhages in skin or mucosa.
- Diapedesis: Microscopic red blood cell leakage due to congestion.
Etiology of Hemorrhage
Etiology involves trauma to vessel walls (e.g., labor injury), spontaneous rupture (e.g., aneurysm), inflammatory vessel damage (e.g., ulcers, vasculitis), neoplastic invasion (e.g., carcinoma), vascular diseases (e.g., atherosclerosis), and increased intravascular pressure (e.g., hypertensive retinal hemorrhage).
Clinical Effects of Hemorrhage
Clinical effects depend on the amount, speed, and site of blood loss, with rapid or large losses causing hypovolemic shock or death, especially if vital organs are involved.
Thrombosis
Thrombi Types by Location
Arterial thrombi are white, mural, and may cause infarction or gangrene.
Venous thrombi are red, occlusive, and may cause thromboembolism or edema.
Cardiac thrombi form in atria or valves and may embolize.
Capillary thrombi are tiny, seen in DIC or inflammation.
Thrombus Morphology
Gross: arterial (white, firm), venous (red, gelatinous), laminated (lines of Zahn).
Microscopy: alternating layers of platelets/fibrin and red blood cells in laminated thrombi.
Fate of Thrombi
Resolution via fibrinolysis (e.g., by plasmin, urokinase).
Organization into fibrous tissue and vessel wall integration.
Recanalization may restore blood flow through new channels.
Propagation enlarges thrombus, possibly occluding vessels.
Thromboembolism occurs if a thrombus fragment detaches and travels in circulation, causing distant obstruction.
Infarction
Infarction is the process of ischemic tissue necrosis, most commonly due to sudden arterial occlusion.
Etiology of Infarction
Etiology includes arterial thrombosis or embolism (most common), less commonly venous obstruction (stagnant hypoxia), or severe narrowing (e.g., atherosclerosis).
Infarction Types
Types are classified by:
Color: pale (anemic) or red (hemorrhagic)
Age: recent (fresh) or old (healed)
Infection: bland (non-infected) or septic (infected)
Infarction Pathogenesis
Pathogenesis involves early edema and hemorrhage, reversible injury (cloudy swelling), followed by coagulative necrosis, inflammation, and later granulation tissue and fibrosis.
Lung Infarct
Usually from embolism; wedge-shaped, hemorrhagic, often in lower lobes; microscopically shows coagulative necrosis, hemorrhage, hemosiderin, and fibrosis.
Kidney Infarct
Due to arterial occlusion; pale, wedge-shaped with base under capsule; microscopically shows ghost tubules, inflammatory border, and fibrotic healing.
Spleen Infarct
From splenic artery occlusion; pale, wedge-shaped with coagulative necrosis and inflammatory infiltration.
Liver Infarct
Rare due to dual supply; infarcts of Zahn (non-ischemic) show red-blue areas from reduced portal flow, chronic atrophy, and sinusoidal dilation.
Specific Granulomatous Inflammation
Chronic granulomatous inflammation is a type of chronic inflammation where the body attempts to wall off a persistent stimulus using granulomas.
Etiology of Granulomatous Inflammation
Infectious causes: tuberculosis, leprosy, syphilis, cat-scratch disease, actinomycosis
Immune-mediated diseases: sarcoidosis, Crohn’s disease, vasculitides
Foreign bodies: talc, beryllium, sutures
Mechanism of Granuloma Formation
Mechanism involves antigen-presenting cells activating CD4+ T cells → Th1 cells release IFN-γ → macrophage activation → formation of epithelioid cells and giant cells → granuloma.
Tuberculosis
Tuberculosis is caused by Mycobacterium tuberculosis.
Primary TB: Ghon complex = peripheral lung lesion + lymphatics + hilar nodes
Secondary TB: apical lung involvement; forms fibrocaseous lesions or cavities
Miliary TB: widespread small granulomas in multiple organs
Microscopically: granulomas with central caseation, epithelioid cells, Langhans giant cells, and fibrosis.
Syphilis
Syphilis is caused by Treponema pallidum.
Primary Syphilis: chancre with plasma cell-rich inflammation and endarteritis
Tertiary Syphilis: gumma with central necrosis, surrounded by lymphocytes, plasma cells, and giant cells
Leprosy
Leprosy is caused by Mycobacterium leprae.
Lepromatous Leprosy: diffuse skin lesions, foamy macrophages (lepra cells), high bacillary load
Tuberculoid Leprosy: granulomas with Langhans cells, nerve involvement, few bacilli
Other forms: pure neural, histoid, and reactional types (Type I and II reactions)
Sarcoidosis
Sarcoidosis is an immune-mediated granulomatous disease.
Non-caseating granulomas with epithelioid and giant cells
Asteroid bodies, Schaumann bodies, and birefringent crystals may be present
Lymphocyte-poor (“naked”) granulomas often seen
Actinomycosis
Actinomycosis is a bacterial infection by Actinomyces israelii.
Forms abscesses with sulfur granules (bacterial colonies with club-shaped ends)
Common forms: cervicofacial, thoracic, abdominal, pelvic
Cat-Scratch Disease
Cat-scratch disease is caused by Bartonella henselae.
Granulomatous lymphadenitis with neutrophilic abscesses and palisading histiocytes
Organisms visible with silver stains
Rheumatic Fever
Rheumatic fever (proliferative stage) occurs post-streptococcal infection.
Aschoff bodies: central fibrinoid necrosis, surrounding Anitschkow cells (caterpillar nuclei), lymphocytes, and plasma cells
Mainly affects heart valves (mitral > aortic) and myocardium
Immunodeficiency Diseases
Immunodeficiency diseases are a failure or deficiency of the immune system, leading to recurrent infections.
Types of Immunodeficiency
Primary Immunodeficiency: genetic/developmental (e.g., SCID, DiGeorge)
Secondary Immunodeficiency: acquired (e.g., HIV/AIDS)
Acquired Immunodeficiency Syndrome (AIDS)
AIDS (Acquired Immunodeficiency Syndrome) is caused by HIV (RNA retrovirus).
AIDS Epidemiology
Global pandemic; highest in Sub-Saharan Africa; ~35 million infected, 1.5 million deaths/year.
HIV Structure
Spherical, 100–140 nm; has core proteins (p24, p18), 2 RNA strands, reverse transcriptase; envelope with gp120 and gp41.
HIV Transmission Routes
Sexual (homo/heterosexual)
Blood (transfusions, IV drug use)
Perinatal (mother to child)
Occupational and other fluids
Stages of HIV Infection
Acute Stage: flu-like illness, high viremia, CD4+ drop, seroconversion in 3–6 weeks
Middle (Chronic) Stage: asymptomatic or lymphadenopathy, gradual CD4+ fall, high viral replication
Final (AIDS) Stage: CD4+ <200/μL, severe immunosuppression, opportunistic infections, malignancies
Clinical and Pathological Effects of HIV
Direct Viral Damage: lymphoid + CNS involvement
Opportunistic Infections: bacterial, viral, fungal, parasitic
Tumors: Kaposi’s sarcoma, lymphomas
Drug Effects: toxicity from HIV treatments
HIV Diagnosis
HIV detection: ELISA, Western blot, p24, RNA PCR
Immune monitoring: CD4+, CD8+ counts, immunoglobulins
Detect opportunistic infections, tumors
Neoplasm
Neoplasm is an abnormal, excessive, uncoordinated, purposeless, and autonomous growth of cells (benign or malignant).
Neoplasm Components
Neoplasms consist of two main components: parenchyma (the neoplastic cells) and stroma (the supportive connective tissue, vessels, and nerves).
Macroscopic Features of Neoplasms
Benign Neoplasms: spherical, encapsulated, firm, mobile
Malignant Neoplasms: irregular, poorly circumscribed, invasive, often with hemorrhage or necrosis
Microscopic Patterns of Neoplasms
Epithelial Tumors: acini, sheets, cords
Mesenchymal Tumors: separated by matrix (e.g., chondroma, osteosarcoma)
Hematopoietic Tumors: little/no stroma (e.g., leukemia, lymphoma)
Cytomorphology: Differentiation & Anaplasia
Differentiation: resemblance to normal tissue
Anaplasia: lack of differentiation
Benign Neoplasms: well-differentiated
Malignant Neoplasms: poorly to undifferentiated, anaplastic
Features of Anaplasia
Structural/tissue: disorganized architecture
Cellular: pleomorphism (size/shape), large nuclei, coarse chromatin
Nuclear changes: hyperchromasia, increased nuclear-cytoplasmic ratio, atypical mitosis
Angiogenesis and Tumor Stroma
Tumor stroma: connective tissue + vessels (no lymphatics)
Growth via basic fibroblast growth factor (BFGF)
Angiogenesis: new vessel formation via VEGF → essential for growth/metastasis
Tumors with excess stroma: desmoplastic (hard); soft = medullary
Inflammatory Reaction to Tumors
The inflammatory reaction is the host immune response (acute or chronic) involving lymphocytes, macrophages, and plasma cells attempting to destroy the tumor.
Benign Epithelial Tumors
Benign epithelial tumors are non-invasive, slow-growing, encapsulated, and resemble the tissue of origin.
Types by Epithelium of Origin
1. Papillomas
From surface epithelium (keratinizing/nonkeratinizing squamous, urothelium)
Example: Skin Papilloma (Verruca Vulgaris): small, cauliflower-like, hands/feet, caused by HPV
Microscopy: finger-like epithelial projections, fibrovascular cores, intact basement membrane
2. Adenomas
From glandular epithelium or mucosa
Variants: acinar, tubular, solid, papillary, mucinous, villous, cystic, etc.
Examples of Benign Epithelial Tumors
Fibroadenoma of Breast
Small, firm, white-grey, well-circumscribed
Intracanalicular: compressed, irregular ducts
Pericanalicular: round/oval ducts in proliferating stroma
Serous Papillary Cystadenoma of Ovary
Large, >5 cm, serous fluid, papillary structures, psammoma bodies
Ovarian Mucinous Cystadenoma
Large, multiloculated, mucin-filled cysts, lined by tall columnar cells with basal nuclei and mucus, no cilia
Malignant Epithelial Tumors
Malignant epithelial tumors, also known as carcinomas, invade and metastasize. They are arranged in nested or back-to-back glandular patterns with a common basement membrane and have a granular appearance.
1. Adenocarcinoma
From glandular epithelium
Example: Bowel Adenocarcinoma
Macroscopic Features: polypoid mass in proximal colon (bleeding), napkin-ring lesion in distal colon (obstruction)
Histology: irregular glandular lumens, invasion into submucosa/serosa, hyperchromatic nuclei, loss of goblet cells, grading G1–G3 based on differentiation
2. Urothelial Carcinoma
From urothelium (commonly bladder), high recurrence
Macroscopic Features: papillary (cauliflower-like), becomes firm, rough, invasive with progression
Histology: fibrovascular stalk covered with layers of urothelial cells, graded as low or high grade
Mesenchymal Tumors (Soft Tissue)
General Features of Mesenchymal Tumors
Cells in fascicles, oriented variably; secondary changes: hyalinization, ossification, teratogenesis, hemorrhage, myxoid, cystic.
Fibrohistiocytic Tumors
Fibroblast-like cells, phagocytic traits, CD68+; variants include dermatofibroma, sclerotic fibroma, giant cell fibroblastoma.
Fibromatosis
Fibrous tissue overgrowth, superficial (adults) or deep (juvenile), fascicles of spindle fibroblasts, collagen-rich (fibroma durum) or soft (fibroma mole).
Osteoma
Benign bone tumor, compact or trabecular, usually in frontal sinus, hard, asymptomatic, no Haversian canals, mature lamellar bone.
Chondroma
Benign cartilage tumor, distal bones/joints, firm, oval, semi-translucent, resembles hyaline cartilage with fibrous septa and chondrocytes.
Lipoma
Benign fat tumor, soft, oval, sharply demarcated, composed of mature adipocytes with fibrous septa, may have lipoblasts.
Rhabdomyoma
Benign striated muscle tumor, cardiac or extracardiac, types: adult, fetal, genital.
Leiomyoma
Benign smooth muscle tumor, uterus most common, oval, white, firm, spindle cells in bundles, cigar-shaped nuclei.
Hemangioma
Benign vascular tumor, skin/liver/mucosa, red/blue soft mass, dilated vessels with or without thrombi, types: capillary, cavernous, epithelioid.
Lymphangioma
Lymphatic malformation, thin-walled cysts (cystic hygroma), dermis or subcutis, dilated lymphatics, hemosiderin, endothelial cells with vesicles and junctions.
Malignant Mesenchymal Tumors
General Features of Malignant Mesenchymal Tumors
Not sharply demarcated, soft/fish-flesh appearance, hemorrhage, necrosis, hematogenous spread, grading based on differentiation, mitosis, necrosis, tumor cellularity.
1. Fibrosarcoma
Malignant fibroblast tumor
Macroscopic Features: white-tan, fleshy, necrotic, hemorrhagic
Histology: herringbone pattern, elongated nuclei, scant cytoplasm, variable collagen, mitosis, no giant cells
2. Chondrosarcoma
Malignant cartilage tumor
Macroscopic Features: pearly white/light blue, may calcify, contain cysts
Histology: cartilaginous matrix, well to poorly differentiated types, variants: clear cell, myxoid, mesenchymal
3. Osteosarcoma
Malignant bone tumor
Common Presentation: males <20 years, metaphyseal long bones (knees)
Macroscopic Features: large, destructive, infiltrative, grey-white with cysts/hemorrhage
Histology: osteoid matrix formation, pleomorphic osteoblasts, giant osteoclasts, associated with bone resorption
4. Liposarcoma
Malignant tumor from lipoblasts
Location: deep tissue (thighs, retroperitoneum)
Macroscopic Features: large nodular, grey-yellow, infiltrative
Malignant Mesenchymal Tumors (Continued)
Leiomyosarcoma
Malignant smooth muscle tumor
Location: uterus, vessels, retroperitoneum
Macroscopic Features: infiltrative, fleshy, hemorrhagic, necrotic
Histology: spindle cells, nuclear pleomorphism, mitoses, necrosis
Prognosis: poor, metastasizes, chemo- and radioresistant
Rhabdomyosarcoma
Skeletal muscle origin, common in children
Common Sites: head, neck, genitourinary tract
Types:
Embryonal (best prognosis): <5 yrs, head/neck, GU
Botryoid: grape-like in mucosa (vagina, bladder)
Spindle Cell: fascicular, paratesticular
Alveolar: round cells, extremities/trunk, poor prognosis
Anaplastic: pleomorphic, large nuclei, mitoses, adults
Sclerosing: rare, hyalinized stroma, eosinophilic cytoplasm
Synovial Sarcoma
Rare, near joints/tendon sheaths
Macroscopic Features: painless mass
Types: fibrous spindle cell + epithelial (biphasic)
Genetics: t(x;18)(p11.2;q11.2) translocation
Angiosarcoma
Malignant tumor of endothelial cells
Spread: via blood/lymph → metastasis
Macroscopic Features: red/dark lesion, poorly defined
Histology: spindle/epithelioid cells, red blood cell-filled capillaries, pleomorphism, mitoses, vacuoles
Variant: epithelioid can mimic melanoma/HCC
Benign and Malignant Melanocytic Tumors
Pigmented nevi are benign melanocytic proliferations.
Types of Pigmented Nevi
Epidermal Nevus: nests in epidermis
Junctional Nevus: nests at dermo-epidermal junction
Compound Nevus: nests at junction + dermis
Dermal Nevus: nests only in dermis
Malignant Melanoma
Malignant melanoma is a highly malignant tumor from melanocytes.
Macroscopic Features: variable color (black, brown, red), irregular borders, may ulcerate
Histology: nests/clusters or spindle-shaped cells, pleomorphic, large nuclei, eosinophilic nucleoli, loss of cohesion, +/- melanin (achromatic melanoma)
Melanoma Growth Phases
Radial Phase: lateral spread in epidermis/dermis
Vertical Phase: deep dermal invasion (nodular)
Clinical Types of Melanoma
Superficial Spreading Melanoma: from nevi, horizontal → vertical
Nodular Melanoma: aggressive, cauliflower-like
Lentigo Maligna Melanoma: sun-exposed skin, slow radial growth
Acral Lentiginous Melanoma: palms, soles, nail beds, vertical growth
Clark Levels of Invasion
Level 1: epidermis
Level 2: papillary dermis
Level 3: filling papillary dermis
Level 4: reticular dermis
Level 5: subcutis
Breslow Thickness
Depth is also measured by Breslow thickness.
Tumors of the CNS and PNS
Astrocytoma
Astrocytomas show narrow or diffuse infiltration. Pilocytic astrocytomas have a better prognosis and are often located in the cerebellum, optic nerve, or thalamus. Cells typically have hair-like processes.
Glioblastoma
Glioblastoma is the most common malignant brain tumor, often presenting as a butterfly lesion. It carries a poor prognosis, with survival typically around 15 months. Histologically, it is characterized by hyperchromatic, pleomorphic, and necrotic cells.
Meningioma
Meningiomas are benign tumors originating from the meninges. They are typically round, encapsulated, and compress the brain. Microscopic features include onion-skin whorls and psammoma bodies.
Schwannoma
Schwannomas are tumors, often affecting Cranial Nerve VIII. They exhibit two main patterns: Antoni A, characterized by palisading nuclei with Verocay bodies, and Antoni B, which shows a loose, myxoid pattern.
Neurofibroma
Neurofibromas are associated with Neurofibromatosis Type 1 (NF1), presenting with café au lait spots from birth and multiple tumors in nerves. Neurofibromatosis Type 2 (NF2) is associated with slow-growing tumors of Cranial Nerve VIII.
Neuroblastoma
Neuroblastoma is a malignant tumor originating from neural crest cells, often found in the adrenal gland, typically in children under 4 years old. Symptoms include abdominal pain, fever, and diarrhea. Histologically, it features “Homer-Wright” rosettes and hyperchromatic cells. It commonly metastasizes to bone and bone marrow.