ENT Pathology Flashcards
DEFINITIONS:
- Acanthosis
- Keratosis
- Parakeratosis
- Hyperkeratosis
- Koilocytosis
- Ancantholysis
xxx
Acanthosis
- Thickening of the epidermal layer
Keratosis
- Presence of keratin on an epithelial surface
Parakeratosis
- Persistence of nuclei in the stratum corneum (keratin layer of the squamous epithelium)
Hyperkeratosis - Thick keratin layer
Koilocytosis - Large squamous cells with shrunken nuclei lodged inside large cytoplasmic vacuole (cytoplasmic vacuolisation) suggests viral infection
Acantholysis - Breakdown of the epithelial layer
TONSIL HISTOLOGY xxx
Specialized lymphoid tissue with an external lining of stratified squamous epithelium
- Forms part of the MALT (mucosa assoc lymphoid tissue) system
Histology:
- Lymphoid follicles with germinal centres covered by stratified squamous epithelial lining
- 55% B cells, 40% T cells, 5% Plasma cells
Epithelium: The epithelium covering most of the tonsil is stratified squamous epithelium Within the crypts it is single-layered and differentiation from the lymphoid tissue may be difficult (hence lymphoepithelium)
Function: Front-line immune defence and reinforce the mucosal immunity of the entire aerodigestive tract Induce secretory immunity and regulate secretory Ig
TONSIL HISTOLOGY - lymphoid compartments
4 lymphoid compartments:
- Specialised squamous epithelium (epithelium invaginates as the crypts - increase surface area to compensate for lack of afferents)
- Lymphoepithelium = epithelium + lymphocytes + macrophages + dendritic cells (APC)
- Captures foreign material from the epithelial surfaces - Parafollicular (T-cell rich)
- Dendritic cells present antigens on their cell surface via MHC-II molecules, interacting with CD4+ T cells (assisted by co-stimulatory molecules e.g. CD80) - Mantle zone = lymphocytic cap (ie. an outer ring of lymphocytes) around the germinal centre (B-cell predominant)
- Primed T cells interact with naive B cells with co-stimulatory CD-40 —> B cell proliferation and differentiation
- B cells migrate to the lymphoid follicle (forming germinal centres) - Germinal centres (B-cell rich)
- B cell proliferation, high affinity mutation, isotype switching and maturation
- Produces Plasma cells and memory B cells
Differences from lymph nodes:
- Non-encapsulated
- No afferent lymphatic channels
TONSIL HISTOLOGY - differences to lymph node
Differences from lymph nodes:
- Non-encapsulated
- No afferent lymphatic channels
note - lymph follicule = mantle zone + germinal centre
ADENOID
Embryology
Hyperplasia mechanism
Embryology
- Fusion of 2 lateral primordia
- Fully formed at 7mo
- Largest age 2-5 then involutes (NPx also grows)
Hyperplasia
Adenoid Hyperplasia
- Due to clonal expansion of immunocompetent cells
- Physiologic response to Ag exposure
ADENOID ANATOMY / HISTOLOGY xxx
Histo
- Nasal mucociliary blanket passes inhaled Ag over Ads - Only epithelium is sig diff from tonsils
1. Pseudostratified ciliated columnar epithelium rich in goblet cells, plicated to form numerous surface folds - Contains specialized membrane cells (M cells) that transport antigens from nasopharyngel lumen
- Ag taken up by M cells -> transported inwards -> exposed to APC
2. Parafollicular (T-cell rich) - Dendritic cells present antigens on their cell surface via MHC-II molecules, interacting with CD4+ T cells (assisted by co-stimulatory molecules e.g. CD80)
3. Mantle zone = lymphocytic cap around the germinal centre (B-cell predominant) - Primed T cells interact with naive B cells with co-stimulatory CD-40 — B cellproliferation and differentiation
- B cells migrate to the lymphoid follicle (forming germinal centres)
4. Germinal centres (B-cell rich) - B cell proliferation, high affinity mutation, isotype switching and maturation
- Produces Plasma cells and memory B cells
SKIN HISTOLOGY - epidermis - dermis
5 layers of the epidermis
- Stratum basale - germinal layer
- Stratum spinosum
- Stratum granulosum - cells have granules for keratinisation
- Stratum lucidim
- Stratum corneum- flattened fused cell remnants mainly keratin
Mnemonic: Come, Let’s Get Sun Burned (superficial to deep) OR Cows Like Grass So Bad
Dermis
The dermis is immediately below these 5 epidermal layers, and consists of collagen, elastic tissue and reticular fibers.
The layers of the dermis are the ‘papillary layer’ and the ‘reticular layer’ that is thicker and stronger.
Dermis contains: hair follicles, sebaceous glands, sweat glands, blood vessels and nerves
BCC SUBTYPES xxxx
BCC subtypes:
Nodular - Most common (raised, circular, appears pink and waxy and visable superficial capillary network). May also be nodulocystic (more cystic in appearance) or noduloulcerative (larger nodular BCC’s tend to ulcerate)
Superficial - Scarring and atrophy with a threadlike waxy border consisting of red scaling patches, they are also common and the least aggressive
Basosquamous - More aggressive tumour, often ulcerated with histologic features of SCC and BCC
Morpheaform - Most aggressive, present late as margins are indistinct and lesions look like scars, whitish/yellowish plaque
SCC VARIANTS xxx
- Classical SCC
-
Verrucous
- Exophytic, broad-based lesion with superficial spreading growth
- Blunt incursions, expansile advancing margin, may be a brisk lymphocytic response
- Can be destructive (muscle, cartilage, bone) -
Adenosquamous
- Uncommon, aggressive variant with poor prognosis
- Older males, larynx/hypopharynx
- Conventional SCC admixed with glanduloductal elements — Mucin +ve -
Basaloid
- High grade, aggressive variant. Middle aged males - OPx, larynx, HPx
- Hard tumours with central necrosis and superficial ulceration
- Infiltrative and deeply invasive
- Lobular arrangement of pleomorphic cells around a central cystic necrotic focus -
Papillary
- Similar to verrucous but lacks the surface keratinisation
- All H&N subsites, including larynx and hypo pharynx
- Atypical squamous cells overlying fibrovascular papillary stromal cores - Spindle cell Carcinosarcoma
- Elderly males, often Hx of RT
- Bimorphic tumour squamous component can be difficult to identify
- Areas of typical SCC
- Bizarre spindle cell sarcomatoid areas
- Upper respiratory tract sites
SMALL ROUND BLUE CELL TUMOURS xxxx
Neuroendocrine tumours
MR SLEEP:
Melanoma/Merkel cell carcinoma
Rhabdomyosarcoma
SNUC/Sarcoma/Small cell carcinoma
Lymphoma
Ewing’s Sarcoma
Esthesioneuroblastoma
PNET (primitive neuro-ectodermal tumour)
Need IHC for pathological differentiation
These are typically mesenchymal tumours which can look primitive on H&E
DYSPLASIA Definition
Defintion of dysplasia:
Abnormal maturation and differentiation of epithelium with features of an increased:
- Pleomorphism
- Nuclear-to-cytoplasmic ratio
- Loss of polarity
- Increased mitoses
- Loss of intercellular adherence (graded as mild, mod, severe)
DYSPLASIA Grades Malignant transformation rate Treatment
Mild Dysplasia = features limited to the lower 3rd of epithelium
Mod Dysplasia = features limited to 2/3rds of epithelium
Severe Dysplasia = features extend from 2/3rds to almost complete thickness (but not entire thickness)
Carcinoma in situ = the above changes, but it involves the entire thickness of the epithelium (doesn’t breach BM)
Malignant transformation rate….
- Mild dysplasia = 10%
- Severe dysplasia/CIS = 30-40% (mean time is 4 yrs)
Treatment
Severe dysplasia / Ca insitu = these lesions need treatment, excisional biopsy is preferred
Mild/mod dysplasia = predominantly reversible, hence close observation
GRANULOMA xxx
Definition: A group of epithelioid macrophages surrounded by a cuff of lymphocytes
Types: - Caseating vs non-caseating
Cause: - Immune vs foreign body reaction
Pic: non-caseating granuloma in pt with sarcoidosis
DEFINITIONS: - Leukoplakia - Erythroplakia xxxx
Leukoplakia: A white, mucosal-based keratotic plaque which cannot be wiped free from the underlying tissue
SCC risk = 5%
- If assoc with dysplasia, 7-fold increased malignant risk (1/3 progress, 1/3 stable,1/3 regress)
Erythroplakia: A red mucosal plaque that does not arise from any obvious mechanical or inflammatory cause and persists after removal of possible etiologic factors
SCC risk = 90%
NEUROENDOCRINE NEOPLASMS - def - classification
WICK’S CLASSIFICATION (Am J Clin Path, 2000)
Neuroendocrine tumours: Prognosis dependent on tumour type
-
Epithelial: stain with epithelial markers (cytokeratin, CEA, EMA)
a) Typical Carcinoid well-differentiated
b) Atypical (large cell) Carcinoid moderately differentiated
c) Small cell poorly differentiated -
Neural: don’t stain with epithelial markers (CK -ve)
- Paraganglioma
- Chief cells = NE markers (synaptophysin, chromagranin, CD57).
- Sustentacular cells = S-100
- Esthesioneuroblastoma
- Mucosal melanoma
- Meningioma
- Granular cell tumour
- Ewing’s sarcoma
- Neurofibroma, schwannoma
NEUROENDOCRINE NEOPLASMS - markers - prognosis
Neuroendocrine markers:
- Chromagranin A
- Neuron Specific Enolase (NSE)
- Synaptophysin
- CD-56
Prognosis:
Typical carcinoid = good prognosis. Neck dissection not warranted
Atypical carcinoid = aggressive. LN mets often present. ND warranted
Small cell = extremely poor prognosis. Like SCLC, consider it to be a systemic disease
COLLAGEN TYPES xx
Type 1: Skin, tendon, vascular ligature, organs, bone (main component of organic part of bone) - >90% of the body’s collagen is Type 1
Type 2: Cartilage
Type 3: Reticular collagen — found alongside Type 1
Type 4: Basement membrane
Type 5: Cell surfaces, hair, placenta
STREPTOCOCCAL SPECIES / CLASSIFICATION xxx
Based on their haemolysis patterns on blood agar plates
- a-haemolytic incomplete haemolysis — oxidises Fe — green
S. pneumoniae
S. viridans
- b-haemolytic complete haemolysis — rupture of RBCs — clear
Grp A — S. pyogenes
Grp B — S. agalactiae
Grouping of b-haemolytic streptococci via Lancefield groupings based on cell membrane carbohydrates
- g-haemolytic no longer classified as streptococcal species
Enterococcus fecalis
CUTANEOUS WOUND HEALING xxxxx
Healing by deposition of collagen and other ECM components —> scar formation
Primary intention = clean cut, minimal epithelial disruption —> thin scar
Secondary intention = large defect, epithelial distortion —> larger scar
Phases of wound healing:
- Inflammation - Platelet adhesion/aggregation — stops bleeding - Clot formation- scaffold for migrating cells (neutrophils in 1st 24 hours) - Inflammation
- Proliferation - Granulation tissue - 24-72 hours. New blood vessels + fibroblast proliferation - Migration of connective tissue cells - neutrophils replaced by macrophages, fibroblast migration, TGF-b is a key chemokine - Macrophages are the key cellular constituent for tissue repair - Re-epithelialistion - keratinocyte migration
- Maturation - ECM deposition - Type 1 collagen - Tissue remodelling - balance between ECM deposition and degradation - Wound contraction - myofibroblasts
FACTORS AFFECTING WOUND HEALING xxxx
Systemic factors and local factors
- Systemic - Nutrition —> Vit C (inhibits collagen synthesis) - Metabolic status —> DM (microangiopathy) - Circulatory status —> Atherosclerosis, varicose veins, lymphatic oedema - Hormones —> Glucocorticoids
- Local - Infection —> Persistent tissue injury and inflammation - Mechanical —> Early motion can delay healing - Foreign bodies —> Impede healing - Size/location/type of wound —> Face heals fast as highly vascular
PATHOLOGIC ASPECTS OF REPAIR xxxxx
-
Inadequate granulation tissue
- Dehiscence
- Ulceration -
Excessive formation of repair components - Hypertrophic scar Clinical features - Scar confined to wound - Rarely >1cm wide/thick - Arise within 4 weeks of injury and may regress within 1 year - Assoicated with excessive skin tension - May form contracture Histologic features - Excess collagen - fine and thin
- Keloid Clinical features - Grow beyond the wound border - Arise after months and may proliferate indefinitely - Pruritic, painful - Ear lobe, jawline, neck - Not associated with contracture - Increased in blacks Histologic features - Excess collagen - large and thick collagen fibers, increased ratio of type I to type III collagen - Exuberant granulation —> ‘proud flesh’ - Contracture —> exaggerated wound contraction (e.g. palms, soles, ant thorax) - Fibrosis —> excessive collagen deposition - Often in the face of persistent tissue damage
Tissue injury promotes a cellular and vascular response
- Stimulus removed: - Regeneration — restitution of normal structure - Repair — scar formation
- Stimulus persists: - Fibrosis — tisue scarring
HUMAN PAPILLOMA VIRUS - def - subtypes
Definition: is a DNA virus from the papillomavirus family that is capable of infecting humans.
Papillomaviruses are nonenveloped viruses of icosahedral symmetry with a capsid shell surrounding a genome containing double-stranded circular DNA.
>90 subtypes
High risk —> types 16, 18
Intermediate risk
Low risk —> types 6, 11 —> lower binding affinity for E6/E7 to p53/Rb
Their genome is divided into the following 3 major functional regions:
Early (E) region codes for 6 nonstructural genes, several of which are associated with cellular transformation.
Late (L) region codes for 2 structural proteins, L1 and L2, that form the capsid
Long control region is a noncoding region that regulates replication and gene function
In health: Cyclin-dependent kinases —> phosphorylation of Rb —> disassociates E2F —> promotes transcription of genes essential for the transition from G1 to S phase p16 (a cyclin dependent kinase inhibitor) —> inactivates the cyclin-dependent kinases (responsible for phosphorylation of Rb) —> hypophosphorylated Rb (E2F remains bound to Rb)—> inhibits cell cycle progression form G1 to S phase
HUMAN PAPILLOMA VIRUS - pathological detection - def p16 +ve
HPV detection:
- PCR - detects virus, doesn’t confirm integration to host genome
- ISH (in situ hybridization) - identifies viral DNA integrated into host genome
- p16 - indirect marker of integration and potential carcinogenesis (p16 is present in 92% of high-grade HPV, vs 15% of low grade HPV) - Inactivation of Rb by E7 —> increase cell cycle, and hence upregulation of p16
NOTE: loss of p16 is an early event in tobacco-related carcinogensis
Positive p16 staining means there is staining in >70% of cells
HUMAN PAPILLOMA VIRUS - pathogenesis
Pathogenesis:
Infects basal epithelial cells only (ie. keratinocytes of skin and mucosa) with DNA incorporated into the host cell
Contains 8 proteins
E1- initiates DNA replication
E2- transcription regulation
E4- viral release
E6- transforming protein, binds p53
E7- transforming protein, binds Rb
L1 and L2 for capsid production
NOTE: incorporation into host DNA —> deletion of E1 and E2 —> upregulation of E6 and E7
Low-risk HPV lesions - HPV genome exists as circular episomal DNA separate from the host cell nucleus
Malignant lesions - HPV genome is integrated into host cell genome and considered hallmark of malignant transformation
E6 - Promotes p53 degradation (rather than producing a mutated p53 - which is rare in HPV tumours) —> removes its ability to act as a guardian of the genome (G1/S cell cycle arrest, DNA repair, apoptosis)
E7 - Binds Rb —> Rb unable to bind E2F —> E2F free to promote transcription of genes essential for G1/S phase progression
Bound Rb —> loss of usuall negative feedback of p16 —> p16 overexpression
HERPES SIMPLEX VIRUS xxx
Tsanck cells: Viral nuclear inclusions in multinucleated giant cell formed by the fusion of acantholytic keratinocytes (viral lesions such as VZV, HSV, pemiphigus)
Acantholysis, Keratinocyte necrosis, ballooning degeneration Inflammatory cell infiltrate
Erythema multiform: - Symmetrical widespread target lesions - Start on hands and feet then spread towards trunk - Mild form of Stevens-Johnson syndrome — blisters, ulcers, eyey lesions - HSV, Mycoplasma, Carbamazepine, Sulfonamides, Ceclor
EPSTEIN BARR VIRUS - pathogenesis & testing
Heterophile antibodies are produced by EBV-infected B Lymphocytes - cross react to antigens occurring in several species that are not phylogenetically related. They agglutinate sheep or horse RBCs but don’t react with any EBV antigens
Pathogenesis: Infects both epithelial cells and B-lymphocytes
- Epithelial cells - Infected during active phase of infection, allowing for viral replication - Oropharyngeal epithelial cells ‘burst’ due to replication of EBV - Periodic reactivation of virus may occur without symptoms
- Memory B-lymphocytes - This is where latent EBV virus resides - Swollen LN’s are due to infection spreading to resting B-cells Investigations
Test for heterophile antibodies or for specific antibodies
Haematology- Lymphocytosis 12-25, >10% atypical - EBV = heteregenous enlarged lymphocytes, lymphocytosis of 12-25 - Acute myeloid leukaemia = homogenous enlarged lymphocytes, lymphocytosis of 50-100 - Atypical Lymphs seen in - Toxoplasmosis, acute HIV, Rubella, Hepatitis A, seroconversion illness - Thrombocytopenia is not uncommon in EBV mononucleosis
Biochem - Elevated transaminases (up in 2nd/3rd week, return to normal by 5th week)
Microbiology- Secondary bacterial infection in 30%
Immunology - Paul-Bunnell test: sheep glycoproteins from red cell membranes bind heterophile antibodies causing agglutination - False -ve 25% in 1st week and 5-10% in 2nd week
Monospot test - sensitivity 50% in children, 70-90% in adults (like the PB test, tests for heterophile antibodies - horse)
Antibody testing - Viral Capsid Antigen (VCA) present early at onset (used if heterophile ab tests are -ve but still clinical suspicion)
EPSTEIN BARR VIRUS - def - epidemiology - general - complications - management
B Lymphotrophic human DNA herpes virus (HHV-4)
Dual strategy of:
- Latency in B Lymphocytes (ie. like most herpes viruses causes a life-long latent infection)
- Intermittent replication in oropharyngeal epithelial cells to enable transmission
EBV associated diseases:
- Infectious Mononucleosis
- Burkitt’s Lymphoma
- Oral Hairy Leukoplakia
- Hodgkin’s Disease
- T-Cell Lymphomas
- Nasopharyngeal Carcinoma
- Smooth muscle tumours in HIV patients
Epidemiology
2 peaks of infection, age 1-6 and 14-20 — 80-90% of adults seropositive
- Developing countries = 99% seroconversion by 6 yrs
- Developed countries = 50% seroconvert in teens/early adulthood
Transmission via saliva containing infected squamous epithelial cells
Infectious mononucleosis occurs in 50% of seronegative 17-25 year olds who become infected with EBV, the other 50% seroconvert without symptoms.
Clinical Features: Incubation period typically of 4 wks from contact, then the prodrome starts of 2-5 days (note - antibody graph shows day 0 as the beginning of incubation)
General - Malaise, fevers/chills, sweating, headache, stiff neck, anorexia —> prodrome = 2-5 days
ENT - Pharyngitis/exudative tonsillitis, generealised lymphadenopathy, petechie of SP
Skin - Rash - occurs in nearly all patients (80-90%) given Amoxycillin (immune complex deposition in skin most likely mechanism)
GIT - Splenomegaly (50%), hepatomegaly (25%)
Eyes - Periorbital oedema seen in upto 30%
Complications of EBV Haem - haemolytic anaemia, splenic rupture, aplastic anaemia Neurological- encephalitis, CN palsies, GBS, seizures, sudden SNHL Liver - 90% have mild elevation of LFTs, jaundice in 10%, hepatic failure rare Cardiac - Pericarditis, myocarditis Respiratory - Airway obstruction, laryngitis, epiglottitis, tracheitis, quinsy
Management: Supportive care Antibiotics to cover secondary bacterial infection present in 30% Steroids - hasten resolution of pharyngitis, fever, haem abnormalities. Use selectively for severe tonsillitis Avoid contact sports for > 1 month in all confirmed EBV cases
HYPERSENSITIVITY REACTIONS xxx
-
IgE-mediated IgE (Type I) Antigen induces crosslinking of IgE bound to mast cells
- ie. Allergy, Anaphylaxis, Asthma, AFS -
Cytotoxic, antibody-dependent IgM, IgG (Type II) Cytotoxic hypersensitivity with ab directed against cell surface antigen causing cellular destruction
- Graves disease - Myasthenia gravis - Autoimmune haemolytic anaemia - Immune complex disease IgG (Type III) Immune complex mediated with ab-ag complexes depositing in distant tissues to cause inflammatory response - RA - SLE - Post-strep GN
- Delayed hypersensitivity/Cell-mediated T cells (Type IV) Cell-mediated hypersensitivity with sensitized Th1 cells or cytotoxic-T-cells - Mantoux - MS - Transplant rejection - Contact dermatitis
LYMPH NODE STRUCTURE xxx
Gross structure: - Surrounded by a fibrous capsule - Made up of lobules - Arranged side-by-side and radiating out from the hilum - Anchored to the hilum by its vascular roots
Zones of the node:
- Cortex outer - Composed of spherical follicles (2 types) - B cells migrate here - Activated B cells migrate to germinal centres Primary follicles: lymphoid follicles without a germinal centre Secondary follicles: lymphoid follicles with a germinal centre (contain activated B-cells)
- Paracortex - Area where T cells accumulate
- Medulla inner - Composed of cords. Between the cords are sinuses - Vessel-like spaces which separate the cords
Inputs/Outputs: - Afferent channels: multiple afferent channels bring lymph to the node peripherally - Efferent channel: single leaves the hilum of the node
Lymph flow: Afferent —> subcapsular sinus —> cortical sinuses —> medullary sinuses —> efferent vessels
CELL CYCLE xxx
Cell Cycle:
- Progression thru phases is controlled by cyclins and cyclin-dependant kinases, and their inhibitors
- CDK’s are expressed constitutively during cell cycle but in inactive form
- Cyclins activate CDK’s, and are synthesised during specific phases in cell cycle (decline rapidly after cell-cycle done)
- G1/S is the restriction point - controlled by p53 and Rb. p53 also works at S/G2 transition
G1 phase (gap phase btw mitosis and synthesis): Replication of cellular machinery (proteins, organelles needed for the S phase)
- Cyclin-D + CDK = complex that can phosphorylate Rb (on-off switch)
- If Rb+phos means that Rb is no longer bound to E2F (a transcription factor) and hence cell-cycle progression can occur
G1/S phase checkpoint: - E2F results in transcription of Cyclin-E
- Cyclin-E + CDK = moving thru G1/S checkpoint
- ie. the S phase is a point of no return hence G1/S checkpoint is most impt for identification of DNA damage.
S phase (synthesis): DNA synthesis with replication of chromosomal pairs - Now that moved thru checkpoint G1/S, Cyclin-E/CDK complex allows transcription of machinery for DNA synthesis
G2 phase (2nd gap phase btw synthesis and mitosis): DNA is double checked for errors
G2/M phase checkpoint: - Transition intiated by Cyclin-A/CDK complex to enter the M phase
- Monitors for completion of DNA replication and checks whether cell can safely divide (mitosis)
M phase: nuclear and cellular division into 2 cells - Cyclin-B/CDK complex causes the breakdown of nuclear envelop and initiates mitosis
- At end of the M-phase the phos groups on Rb are removed, therefore Rb+E2F complex is reformed halting cell-cycle again.
- Newly divided cells can exit to the G0 phase, or re-enter the G1 phase for continued division.
Gram stain xx
Gram +ve/-ve staining: +ve = purple, -ve = red
Primary stain applied (crystal violet) to a heat-fixed smear of a bacterial culture.
Iodide added (binds to crystal violet and traps it in the cell)
Rapid decolorization with alcohol or acetone, and
Counterstaining with safranin.
Differentiates bacteria by the chemical and physical properties of their cell walls by detecting peptidoglycan
Gram-positive bacteria —> retain the crystal violet dye
Gram-negative bacteria —> red or pink coloring (d/t safranin counterstain added after the crystal violet stain)
PEMPHIGUS VULGARIS x
A group of autoimmune mucocutaneous diseases characterised by intra-epithelial cleaving, which may be fatal
Pathogenesis: autoimmune disease = genetics + environment
Genetics: HLA Class 2 alleles
Desmoglein 3 = intercellular adhesion molecule of the cadherin family
Antibodies directed against Dsg3- IgG antibodies deposit in intracellular space and attack the extracellular component of Dsg
- Results in epithelial separation
Pathology: - Separation/cleavage of basal from suprabasal layers
- Basal layers remain attached to LP (‘tombstone’ appearance)
Pemphigus = staining in intercellular spaces
Investigations: - Biopsy (see next facet) - Direct immunofluorescence- anti-desmoglein 3 IgG - anti-Ds1antibodies present if skin also involved (Ds1 not present in mucosa)
PEMPHIGOID Mucous Membrane Cicatricial Pemphigoid x
A heterogenous group of autoimmune subepithelial vesiculobullous diseases
Pathogenesis: Formation of autoantibodies against molecular components of the BM zone
- bullous pemphigoid antigen 2, laminin 5, b1subunit of integrin
Pathology: Linear deposition of IgG and C3 in BM zone
Separation of mucosal epithelium from underlying LP in absence of significant inflammation
IF staining- linear continuous/homogenous staining of IgG, IgA and C3
Investigations: - Serum autoantibodies to epithelial basement membrane zone (uncommon). Alpha-6 integrin
- Epiligrin- rare antibody but assoc with internal malignancy - IgG immune deposits (common)
ORAL LICHEN PLANUS xx
Definition: Mucocutaneous disease of autoimmune immunologic origin, mediated by T cell reaction to surface antigens within epithelium. Commonly affects oral mucosa, skin, genital mucosa, scalp and nails. Affects 0.5-2% of the general population.
Aetiology: Immunologically-mediated Mosly idiopathic. Significantly greater anxiety/depression observed than in controls Assoc with systemic disease: sclerosing cholangitis, SLE, primary biliary cirrhosis, Sjogren’s disease
Pathogenesis: CD8+ T cell-mediated apoptosis of basal keratinocytes Fibrinogen deposition in these basal layers (diagnostic with direct immunofluorescence)
Pathology: - Lymphocytic infuiltrate in basal layer, Civatte bodies (degeneration of basal layer keratinocytes), liquafactive necrosis of basal cell layer, saw tooth appearance of Rete pegs - Fibrinogen deposition seen on immunofluorescence!!!!!!!!
Signs and Symptoms: Bilateral, multifocal lesions helps Dx - Bilateral white lesions in the buccal or lingual mucosa - Reticular - usually asymptomatic, lacy network (Wickham’s striae) symmetrically bilateral buccal mucosa - Plaque - multifocal, lateral/ventral tongue and buccal mucosa - Atrophic/Erythematous - reddened areas of mucosa, often coexists with reticular/erosive forms. Gingival mucosa (poor dental appliance hygiene sets up bacteria to create antigens) - Erosive - often superficial, can be deep/painful ulcers, covered with pseudomembrane, often have peripheral striae - As erosions heal, new areas develop - Bullous- rarest form. Bullae range in size up to 1cm. Transient bulla, then ruptures to leave painful ulceration. Assoc with other forms of OLP within the mouth, thus difficult Dx
Risk of malignant transformation for atrophic and erosive types (5% over ten years). Least common variants
LEUKOPLAKIA xx
Definition: Clinical not histopathological diagnosis A white mucosal lesion that cannot be rubbed or scraped off and that is not recognised as any other lesion
DDx- cheek/tongue biting, OLP, candida, drug reaction, amalgam tattoo, geographic tongue
Aetiology: Tobacco - disappearance of lesions within 1 year of cessation Trauma - frictional (denture, cheek biting, toothbrushing), chemical (smokeless tobacco, aspirin, peppermint/cinnamon) Microorganisms - Candida albicans, treponema pallidum UV radiation
Pathology: PRECANCEROUS LESION Macroscopically: Thin vs Thick
Histology: - Epithelium - hyperkeratosis, acanthosis, parakeratosis - Most are devoid of dysplasia. BUT full range of dysplasia can be present - Submucosa - variable chronic inflammatory cell infiltrate - Fungal stains may be positive. Primary cause vs secondary infiltration
- Most Common sites (account for >2/3) are: vermillion border of lower lip, buccal mucosa, gingiva
Risk of severe dysplasia +/- carcinoma is 4-30%
Risk factors for malignant transformation: - Site - FOM, tongue, vermillion border of lip - Long duration of leukoplakia - Homogenous thick leukoplakia - Surface granularity/verrucous appearance - Female - Absence of a smoking Hx - Presence of dysplasia
Prognosis: 30% of lesions disappear 30% improve 25% show no change 7.5% demonstrate local spread 6% progress to SCC
ORAL HAIRY LEUKOPLAKIA xx
Defintion: A distinctive asymptomatic white lesion of the oral mucosa
Aetiology:
- EBV-related
- Immunosuppressed patient (i.e. HIV mostly) - ie. requires EBV infection, replications, and expression of EBV latent genes, followed by immune escape (hence assoc with EBV + immunosupression)
Clinical features: - Often asymptomatic, occasionally symptoms of mild pain, dysesthesia, alteration of taste, and cosmetic concerns. - Side of the tongue with a corrugated or hairy appearance
Pathology: Hyperkeratosis
Irregular surface projections
Ballooning degeneration of subsurface layers
IHC: EBV Image = vertical corrugated keratotic ridges are seen.
ERYTHOPLAKIA xx
Defintiion: A red mucosal lesion that cannot be rubbed off or scraped off and that is not recognised as any other disease
More likely than leukoplakia to correlate to underlying severe dysplasia/carcinoma
- 90% have evidence of invasive carcinoma, carcinoma in situ or severe dysplasia
- >25% risk of carcinoma
Pathology: Most have at least severe dysplasia - Surface epithelium devoid of keratinisation - Non-specific submucosal inflammaton and dilated capillaries
Malignant transformation: 28%
Granular cell tumours xx
Definition: A neoplastic lesion of neural derivation with granularity due to the accumulation of secondary lysosomes in the cytoplasm.
Epidemiology: Rare F:M = 3:2 Middle aged Black persons 10% of individuals have multiple lesions Benign > malignant (rare < 2% of all granular cell tumors)
Aetiology: Unkown
Pathology (benign variant): Gross - Pale white/yellow, nonencapsulated, and variably (well to poorly) circumscribed nodules with solid, fleshy cut surfaces that are devoid of liquefaction, necrosis, or bleeding. The overlying skin or mucosa is thickened and may have a cobblestone appearance Histo - Eosinophilic cytoplasmic granules and small round nuclei with dense chromatin, +/- infiltrative margins. Squamous epithelium overlying the peripheral superficial lesions exhibit acanthosis and pseudoepitheliomatous hyperplasia. IHC - Stain +ve for S-100 protein, neuron-specific enolase, and NK1-C3
Classified as malignant if >3cm, locally destructive changes, cytologic features of malignancy (freq mitoses, vesicular nuclei with prominent nucleoli) or metastasis (lymph nodes or distant sites) or otherwise causes death.
Sx: Painless nodules with an insidious onset and slow growth rate Head, neck, trunk, extremities
Signs: Nonulcerated, painless nodule Solitary (may be multiple) <3cm Tongue (25%) Breast - common Parenchyma, subcutaneous tissue, and dermis (account for 15%) Small—>medium-sized cranial or spinal nerves, but neurologic deficit is rare Visceral involvement - mucosal or submucosal nodules in the esophagus, larynx, bronchi
Ix: CT/MRI
Mx: Benign - surgical excision Malignant - WLE - Chemo/RTx - not effective
Prognosis: Benign lesions - recurrence rate 2-8% if -ve margin, 20% +ve margin Malignant lesions - aggressive and difficult to eradicate with surgery. Local recurrences 32%, and metastases in 50% within 2 yrs 60% of patients die of the disease within 3 years of detection of the primary tumor. Ki-67 immunoreactivity of 10% or more tumor cells is an adverse prognostic factor.
What is dysplasia? What is the difference btw dysplasia and carcinoma in situ? What is the risk of malignant transformation rates for mild dysplasia, severe dysplasia/CIS? Treatment options? xxxx
Defintion of dysplasia: Abnormal maturation and differentiation of epithelium with features of an increased: - Nuclear-to-cytoplasmic ratio - Loss of polarity - Increased mitoses - Loss of intercellular adherence (graded as mild, mod, severe)
Mild Dysplasia = features limited to the lower 3rd of epithelium
Mod Dysplasia = features limited to 2/3rds of epithelium
Severe Dysplasia = features extend from 2/3rds to almost complete thickness (but not entire thickness)
Carcinoma in situ = the above changes, but it involves the entire thickness of the epithelium (doesn’t breach BM)
Malignant transformation rate….
- Mild dysplasia = 10%
- Severe dysplasia/CIS = 30-40% (mean time is 4 yrs)
Treatment Severe dysplasia / Ca in situ = these lesions need treatment, excisional biopsy is preferred Mild/mod dysplasia = predominantly reversible, hence close observation
What are the radiological malignancy criteria for regional neck disease? xxxx
o Minimal diameter of: 15mm for jugulodigastric nodes located in level, and 10mm for nodes located in other levels
o Minimum diameter of 8mm for retropharyngeal nodes
o Groups of 3 or more borderline nodes (ie. 1-2mm smaller)
o Any node with evidence of central necrosis
o Loss of tissue planes (fat planes)
What is acanthosis? What is hyperkeratosis? What is parakeratosis? xxxx
Acanthosis = diffuse epidermal hyperplasia (thickening of the skin)
- It implies increased thickness of the stratum basale and stratum spinosum
Hyperkeratosis = Hyperplasia of the stratum corneum associated with qualitative abnormality of the keratin
Parakeratosis = Persistence of nuclei in the stratum corneum (keratin layer of the squamous epithelium)
What does squamous mean? What does keratinizing mean? What does stratified mean? xxxx
Squamous cells = flat, scalelike or platelike cells
Stratified = cells arranged in layers
Pseudostratified = epithelium appears to be several layers (strata) of cells but cells are actually resting on the base layer (often ciliated and occurs only in mucosa)
Keratinizing = a protein that is waterproof, contained within squamous cells that are no longer alive, and contain no nucleus, continually lost from the surface of the epithelium, and only occurs on skin normally. i.e.. has a non-living outer surface
Non-keratinizing = squamous cells that don’t contain the keratin, and the cells are living at the surface (ie with nucleus)
What is a Carcinoma? xxxx
Carcinoma = a malignant growth made up of epithelial cells that are infiltrating surrounding tissues
What is a: Neoplasm? Hamartoma? Choristoma? xxx
Neoplasm (abnormal proliferation) - An abnormal mass of tissue that grows by cellular proliferation more rapidly than normal, and continues to grow after the stimuli that initiated the new growth ceases. May be either benign or malignant.
Malignant neoplasm / cancer - A neoplasm that tends to grow, invade, and metastasize.
Hamartoma (abnormal differentiation, but mature) - A non-neoplastic developmental anomaly of aberrant tissue differentiation that produces a mass of disorganised but mature tissue indigenous to the particular site
Choristoma - A non-neoplastic developmental anomaly of essentally normal itssue that is ectopic of its normal location (ie. ectopic endometrial tissue in lung)
IHC summary to be completed
Immunohistochemistry
- differentiation from other small blue cell tumours
- S100 -ve (classical for melanoma, Esthesio’s, SCUNC) - Synaptophysin -ve (classical for SCUNC)
- NSE -ve (neurone specific enolase) (classical for Esthesio’s, SCUNC)
- HMB-45, Vimentin -ve, Melan A (classical for melanoma)
- CD99 -ve (classical for Ewings Sarcoma)
- CK7, CK8, CK19 +ve (SNUC’s are consistently immunoreactive with epithelial markers for pankeratin and simple keratins)
HALLMARKS OF CANCER CELLS xxxx
- Self-sufficiency of growth signals - EGFR
- Insensitivity to growth inhibitory signals - Retinoblastoma
- Evasion of programmed cell death - p53
- Immortality - p53, Rb, telomerase activation
- Sustained angiogenesis - VEGF
- Tissue invasion and metastasis - Growth factors - EGFR - Intercellular adhesion molecules- integrins, c-adherins
GENERAL FEATURES OF SCC xxxxx
Normal mucosa/skin: - Reasonable thickness - Polarity or arrangement of cells - Intercellular bridges - Pale nuclei with a small nucleus in abundant pink cytoplasm - Nucleus/cytoplasmic ratio in strong favor of the cytoplasm - All cells/nuclei of approx the same size - Cell resemble fish scales or pavement blocks - Keratin at the surface if keratinizing
Malignancy features: - Hyperchromatism (dark nuclei, with clumping of chromatin) - Pleomorphism (cells of different sizes and shapes) - Abnormal mitosis - Keratin whorls appearing as roundish, eosinophilic (pink), lamellated ‘pearls’ - Loss of polarity - low-grade lesions: show maintainence of intercellular bridges, cells resembling those normally found, some adherance to polarity - moderate to poorly differentiated lesions: show significant deviation from normal and may not resemble squamous epithelium
Verrucous SCC
Verrucous - Locally destructive, not metastatic (v rarely) - M > F 60s, tobacco smoking / chewing - Exophytic, broad-based lesion with superficial spreading growth - Blunt incursions, expansile advancing margin, maybe a brisk lymphocytic response - Can be destructive (muscle, cartilage, bone) Mets rare - OC - buccal & HP MC > Larynx - RTx contraindicated (rare exceptions) —> anaplastic transformation - Excellent prognosis if neg margins on WLE
Histo - Well diff, minimal / absent dysplasia / church spire hyperkertosis
Papillary SCC
Papillary
- Similar to verrucous but lacks the surface keratinisation - All H&N subsites, including larynx (MC) and hypopharynx
- Atypical squamous cells overlying fibrovascular papillary stromal cores
- Prognosis - similar to conventional / slightly better
Spindel cell carcinosarcoma (SCC variant)
Spindle cell Carcinosarcoma - Elderly males, often Hx of RT - Bimorphic tumour - SCC & malignant stromal component - squamous component can be difficult to identify - Areas of typical SCC - Bizarre spindle cell sarcomatoid areas - Upper respiratory tract sites - Poor prognosis
Photo - left = spindle, right = SCC
