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
Basaloid SCC
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 - May be assoc HPV
Adenosquamous SCC
Adenosquamous
- Uncommon, aggressive variant with poor prognosis
- Older males, larynx/hypopharynx
- Conventional SCC admixed with glanduloductal elements —> Mucin +ve
SCC VARIANTS xxxx
- Classical SCC
- Verrucous
- Adenosquamous
- Basaloid
- Papillary
- Spindle cell
NASOPHARYNGEAL CARCINOMA - def - aetiology - path categories
Carcinoma of the nasopharynx demonstrating evidence of squamous differentiation
Aetiology:
Genetics: 8x risk in a 1st degree relative. HLA subtypes- A, B and D subgroups
EBV exposure and reactivation
Environment: salted fish (contains nitrosamines)
Pathology: WHO Classification
- Keratinising (25%) Pattern consistent with other H&NSCC. <5% in endemic areas
- Non-Keratinising (75%) EBV-related, aggressive, radiosensitive, good prognosis
a) Differentiated
b) Undifferentiated - >90% in endemic areas
NASOPHARYNGEAL CARCINOMA - histo - immunohistochem - other tests
Histology:
Keratinising SCC - Epitheliod looking, ‘scale’ like or layered, keratin seen, intercellular bridges
Non-keratinising, Undifferentiated (MC) - Round nuclei, prominent eosinophilic (pink) nucleoli, dispersed nuclear chromatin, scant eosinophilic cytoplasm - Cells do not form ‘scale’ patterns or layers
Non-keratinising, Differentiated - Squamous cells seen (ie. epitheliod looking, ‘scale’ like or layered) - No keratin seen
IHC: High molecular weight cytokeratin, EBV-latent membrane protein
Other diagnostic tests: Serology - IgA to viral capsid antigen (VCA), IgG/IgA to Early antigens (EA)
BRANCHIAL CLEFT CYST xxx
Pathology:
Cyst lining: stratified squamous epithelium (90%) or respiratory epithelium
Cystic contents: fluid contains cholestrol crystals and keratin
They may also contain lymphoid tissue as well, salivary tissue
Image = Stratified squamous epithelium
THYROGLOSSAL DUCT CYST xxx
Pathology:
- Cyst lining: Respiratory epithelium-lined
- May contain squamous metaplasia (esp if recurrent infection)
- Thyroid follicles present in 60%
PAPILLARY THYROID CANCER xxx
A malignant epithelial neoplasm with evidence of follicular cell differentiation typically with papillary structures and characteristic nuclear features
MC thyroid malignancy (60-80%)
Multicentric, lymphotropic
FNA: nuclear features are diagnostic - Nuclear enlargement and pleomorphism - Powdery chromatin pattern - Intranuclear incusions, nuclear grooves/indentations (coffee beans) and nuclear overcrowding/overlapping (‘basket of eggs’) - Chromatin margination
Pathology: - Papillary growth pattern with fibrovascular core - Psammoma bodies - Intratumoral fibrosis - Orphan Annie cells (optically clear appearing nuclei with chromatin margination) - Nuclear features as per FNA
Aggressive variants: not independent risk factor for poor prognos - Diffuse sclerosing - Tall cell - Columnar cell - Poorly differentiated, anaplastic
Classification: - Microcarcinoma - <1cm, no capsule invasion, no LN mets - Intrathyroid - 1-4cm, confined to gland - Extrathyroid - decreased survival
These variants present with features recognised by other staging systems to be associated with worse prognosis, rather than being an independent predictor of poor prognosis
FOLLICULAR THYROID CANCER xxx
Definition: A malignant epithelial tumour showing follicular cell differentiation without architectural or cytonuclear features of papillary thyroid carcinoma (5-15% of all thyroid ca’s)
10-20% of thyroid malignancies - Iodine-deificient - Cowden’s disease, irradiation
FNA - Limited as unable to demonstrate capsular invasion or angioinvasion - The hallmarks of diagnosis
Pathology: - Encapsulated tumours - Follicular growth rather than papillary - Uniform-appearing colloid-filled follicles - Uniform growth pattern (ie. if a variety then think papillary ca) - Key features: capsular invasion, angioinvasion
Patholgogical Classification Minimally invasive = limited capsule invasion only or angioinvasion (<4 vessel, small calibre vessel) Widely invasive = complete capsule invasion or >4 vessel invasion or large calibre vessel or invasion to adjacent thyroid parenchyma Hurtle cell ca = poorer histological variant of follicular ca (defined as presence of oncocytes ie. eosinophilic grannular cytoplasm due to mitochondria)
FNA diagnosis limited — Ca requires capsular or angio-invasion
Prognosis: - Minimally invasive = excellent (no mets — 70-100%, mets — 50%) - Widely invasive = poor (25-45% — metastatic propensity)
HURTHLE CELL CARCINOMA xxx
A variant of FTC
Follicular cancer with oncocytic cells
Oncocytes = Epithelial cell characterized by an excessive amount of mitochondria, resulting in eosinophilic (pink), granular cytoplasm. Oncocytes can be benign or can undergo malignant transformation.
Same division as FTC:
- Minimally invasive
- Widely invasive
Prognosis worse than conventional FTC: Older patients Increased frequency of malignancy (compared with non-oncocytic follicular neoplasms) Redued RAI uptake Increased extra-thyroidal spread
5-year survival: 30-70% Picture: Cytoplasmic oxyphilia
MEDULLARY THYROID CARCINOMA xxx
A tumour of the C-cells of the thyroid
RET protoncogene mutation (10q11.2)
- Sporadic (70%) vs Familial (30%)
- Familial = MEN2A, MEN2B, Familial MTC
FNA: - Increased cellularity with single cells or small cell clusters - Round/oval cells, spindle-shaped, pleomorphic nuclei, coarse chromatin pattern and abundant eosinophilic cytoplasm - Nuclear inclusion and eccentrically placed in cell - Extracellular homogenous eosinophilic to pale orange amorphous clumps/spheres/rods seen = amyloid (congo red stains confirms) - Follicular pattern, papillary structures and colloid is not seen
Pathology: - Looks like paraganglioma with nest-like structure - Pink amyloid stroma (congo red —> apple green birefringence) - IHC: neuron specific enolase, synaptophysin, chromagranin - i.e. neuroendocrine tumour - Calcitonin
HASHIMOTO’S THYROIDITIS xxx
Picture: Diffuse involvement of the thyroid gland in which mature lymphocytes, with/without germinal centres are present
Associated with thyroid lymphoma
DE QUERVAIN’S THYROIDITIS xxx
Subacute granulomatous thyroiditis
Viral cause — malaise, fever, thyroid pain + tremor/heat intolerance
- Thyroid gland = very tender, firm, irregular
Lasts 12-16/52 — period of hypothyroidism (gland unable to produce hormones)
Management: NSAIDs, b-blocker Prognosis: thyroid damage and recurrence rare
Picture: - Thyroid follicles replaced with neutrophils and multi-nucleated giant cells - Colloid still present (floating within neutrophilic cell infiltrate)
MERKEL CELL CARCINOMA xxx
Definition: Rare but aggressive neuroendocrine tumour arising from the mechanoreceptor Merkel cells of the skin
Aetiology: UV radiation exposure and immunosuppression appear important
Pathology A small round blue cell tumour - Arises from Merkel cells in the skin (mechanoreceptors) - Undifferentiated malignant small cell infiltration in dermis and subcutaneous tissues - Generally doesn’t involve epidermis - May be separated from epidermis by a rim of papillary dermis - Grenz zone
IHC: - Cytokeratin 20 (CK-20) positive —> differentiates from metastatic neuroendocrine small cell cancer of the lung —> Characteristic perinuclear dot pattern - Neuroendocrine markers may be positive: chromagranin, synaptophysin
BASAL CELL CARCINOMA xxx
Definition: Slow-growing, locally invasive malignant epidermal skin tumour
Epidemiology: MC skin cancer: 800/100,000
Aetiology:
Genetics: Xeroderma pigmentosa - failure of fibroblast repair of DNA damage Gorlin’s syndrome - mutliple BCCs, palmar pits, jaw cysts, rib abnormalities, calcification of falx cerebri, characteristic facies (frontal bossing, hypoplastic maxilla, broad nasal root, ocular hypertelorism) - PTCH gene 9q22, AD inheritance
Environment: UVB > UVA
Pathology: BCC subtypes: nodular, superficial, basosquamous, pigmented, sclerosing Arise in continuity with basal cell layer of epidermis or from the adnexae Uniform hyperchromatic (eosinophilic) cells with nuclear pallisading towards edges of tumour nests
IHC: Bcl2, 60% androgen receptor +ve
CUTANEOUS MELANOMA xxx
Pathologic subtypes: Small, blue cell tumour, may see Melanin in tissues, otherwise IHC Dx
- Superficial spreading 65-75%- pre-existing naevus, radial growth for years prior to development of vertical growth phase
- Nodular 10-15%- blue-black raised nodule. MC mucosal melanoma. most invasive, poorest prognosis 3. Lentigo maligna melanoma- seen in background of chronic solar damage as Hutchinson’s melanocytic freckle (LM) —5% progress to LMM
- LM = melanoma in situ
- Subclinical and extensive involvement of periphery — difficult excision margins - Desmoplastic - neurotropic <1%- locally aggressive, highly aggressive. 75% arise in H&N
IHC: S-100, tyrosinase (both sensitive, not specific) Melan A, HMB-45, Vimentin (specific, not sensitive — 15% won’t stain for these 3)
MUCOEPIDERMOID CARCINOMA xxx
Most common primary malignant epithelial salivary gland neoplasm composed of an admixture of epidermoid, mucous and intermediate cells
Cellular components:
- Mucous cells - pale-staining, foamy cytoplasm, peripherally -placed nuclei - Associated with cyst formation
- Epidermoid cells - nests/solid areas in conjunction with mucous cells (absence of keratin and intercellular bridges differentiates it from adenosquamous)
- Intermediate cells - small basal cells and larger polygonal cells
Growth patterns: papillary, cystic, glandular, duct-like, solid sheets, cords
Grade: Low grade = increased mucinous High grade = increased epithelial
AFIP grading system uses the following criteria to determine grading: - Intracystic component <20% (i.e. mostly solid) — 2 points - >4 mitotic features per 10 HPFs — 3 points - Cellular anaplasia — 4 points - Necrosis — 3 points - Neural invasion — 2 points - Low grade = 0-4, intermediate = 5-6, high > 7 - Mortality: low = 0%, high = 45%
IHC: - Mucinous = PAS, mucin - Epithelial = cytokeratin, EMA
Management: - Low grade - local Rx alone. PORT only if +ve margins - High grade - local Rx + ND + PORT
ADENOID CYSTIC CARCINOMA xxx
Malignant epithelial salivary gland neoplasm of myoepithelial and epithelial cells characterised by tendancy to invade nerves and assume a protracted/relentless course
10% of all malignant salivary gland tumours
- 50% of minor salivary gland tumours
Pathology: - Unencapsulated, infiltrating neoplasm - Neurotropism and invasion beyond the gland (e.g. skeletal muscle) - Microcysts
Growth patterns:
- Tubular- least aggressive, may have some cribriform areas
- Cribriform- ‘swiss-cheese’ pattern, may include tubular areas, <30% solid tumour, most common (See Picture)
- Solid- >30% solid within a cribriform background, most aggressive
IHC: - Ductal cells - CK, S-100, EMA, CEA - Myoepithelial cells - S-100, Smooth muscle actin/myosin
Management:
Surgery + RT - RT alone does not cure ACC (50% have early relapse within 18/12) - Surgery alone rarely averts local recurrence - Only Rx neck if involved (rarely) Chemo - palliation only. Symptomatic relief or rapid growth characteristics - Response rates are low and effects are short-lived
Targeted therapy - Imatinib is a c-kit tyrosine kinase inhibitor (c-kit known to be an important protoncogene in ACC) - Cetuximab- contradictory responses seen
Prognosis: Worse prognosis if SMG (more neck disease, higher recurrence) Tendancy for late recurrence (>10 years). Worse if sinonasal disease - Local failure and distant metastasis (rarely nodal disease) Slow growing tumours, indolent but relentless course
ACINIC CELL CARCINOMA xx
Malignant salivary gland neoplasm with a variety of histologic growth patterns, some cells characterised by cytoplasmic (Zymogen) granules
Epidemiology: - Male prepondernace - Present in 3rd decade
Pathology: multiple cell types and growth patterns common - Variable cytologic components: Recapitulate the serous acinar cells of normal salivary tissue - Acinar cells- pathognomonic - Polyhedral, small dark eccentrically placed nuclei - Abundant basophilic cytoplasm with granular cytoplasm (Zymogen granules) - Intercalated, duct-like cells - Vacuolated cells - Clear cells - Reactive lymphoid stroma - Growth patterns- microcystic vs papillary-cystic vs solid vs follicular - Picture = solid and cystic pattern coexisting - Neurotropism - Invasion of adjacent tissue
IHC: PAS-D (Zymogen granules). Other markers nonspecific
Management: - Surgery primary Rx - PORT if +ve margins or metastatic disease
Prognosis: - Generally indolent disease - 1/3 get recurrence (often within 5 years)
POLYMORPHOUS LOW GRADE ADENOCARCINOMA xx
Malignant salivary gland characterised by cytologic uniformity, histologic diversity, infiltrative growth pattern and low metastatic potential
Low metastatic potential, second MC intraoral salivary malignancy (after MEC)
- 60% involve palate (esp hard/soft palate junction)
Pathology: Cytologic uniformity, histologic diversity, infiltrative growth pattern - Well-circumscribed but unencapsulated - Polymorphic appearance between and within tumours - Solid, glandular, cribriform, ductal, tubular - I.e. many different components to the tumour (see picture- multiple growth patterns)
CARCINOMA EX-PLEMORPHIC ADENOMA xx
Epithelial salivary gland malignancy with histologic evidence of arising within a pre-existing pleomorphic adenoma
Pathology: - Histologically high-grade, overtly infiltrative masses - Mostly high-grade adenocarcinoma (other: SCC, MEC, salivary duct carcinoma) - Need residual evidence of pleomorphic adenoma
- 3 types with deteriorating prognosis:
- Within a pleomorphic adenoma
- Within 1.5cm of a pleomorphic adenoma
- Beyond the adenoma
Picture: pleomorphic adenoma on right = myxochondroid stroma and hypo cellular compared with carcinoma on left = densely cellular
AETIOLOGY OF BENIGN SALIVARY GLAND NEOPLASIA xx
Benign salivary gland neoplasms:
- Monomorphic - Warthin’s, basal cell adenoma, canalicular adenoma, myoepithelioma
- Pleomorphic
Aetiology proposed to be either:
- Bicellular reserve theory - Intercalated duct origin — adenomatoid (pleo, oncoctyoma, Warthin’s, acinic cell ca, adenoid cystic ca) - Excretory cell origin — epidermoid tumours (SCC, MEC)
- Multicellular theory - Each neoplasm arises from a distinctive cell type
PLEOMORPHIC ADENOMA xx
Benign, epithelial-derived tumour composed of both epithelial and mesenchymal cells
MC benign salivary gland neoplasm
Aetiology: Radiation PLAG1
Pathology: morphologic variability seen within a single neoplasm - Encapsulated, well-demarcated tumour (low T1, high T2) Multiple components 1. Epithelial- flat cuboidal cells line the ducts 2. Myoepithelial- spindle-shaped hyperchromatic cells 3. Stromal (5 elements) - myxoid, chondroid, fibrous, vascular, osseous - Myxoid tumours more delicate, easily damaged capsule — prone to recurrence
Risk of malignant transformation 10% over 10 years - SM gland - Older patient - Size >4.5cm - Duration
MONOMORPHIC ADENOMA xx
Benign salivary gland neoplasms characterised by a lack of the mesenchymal-like stromal component seen in pleomorphic
Pathology: - Composed exclusively of the epithelial component - Most commonly epithelial tumours (basal cell adenomas, canalicular cell adneoma) - May be composed solely of myoepithelial components (myoepithelioma) - Lacks the mesenchyme-like stromal component
WARTHIN’S TUMOUR xx
Benign salivary gland tumour with easily recognisable histologic features:
- papillary, cystic, bilayered oncocytic epithelial component and lymphoid follicles
2nd MC salivary gland neoplasm. Lights up on Technitium scan
Older men assoc with smoking
Bilateral in 10%, multicentric in 10%
Pathology: Papillary cystadenoma lymphomatosum - Neoplastic transformation of entrapped salivary duct epithelium within intra and periparotid LNs during embryogenesis - Papillary and cystic lesion composed of epithelial and lymphoid components - Epithelium = bilayered granular eosinophilic cells - Oncocytic cells- high mitochondrial content - Lymphoid = lymphoid follicles with germinal centres
- Without the lymphoid component = oncocytoma
Misdiagnosis of Warthin’s: SCC or Acinic Cell Carcinoma
NECROTISING SIALOMETAPLASIA xx
Definition: A benign, self-healing reactive inflammatory process of minor salivary glands of the palate that may be clinically and histologically mistaken for malignancy
Pathology: - Trauma —> interruption of minor salivary gland vascular supply —> ischaemia - Deep crater-like ulcerative lesion - Ischaemic appearance with reactive background and preservation of surrounding salivary gland architecture - Squamous metaplasia in ducts, retains lobular architecture
- Classic misdiagnosis is MEC (or SCC)
LYMPHOMA Reed-Sternberg cells x
Key cell is the Reed-Sternberg cell. Classic Reed-Sternberg cell is 20 to 50 microns in size, with acidophilic or amphophilic cytoplasm, large bilobed or multilobed nucleus with vesicular or coarse chromatin. A large, round, eosinophilic central nucleolus is always present.
LYMPHOMA Rye classification x
Pathology: Neoplastic proliferation of RS cells - Large cells (>45micrometre diameter) with abundant cytoplasm - Multiple nuclei or a single nucleus with multiple nuclear lobes, each with large inclusion-like nucleolus - ‘Owls eyes’
Surrounded by host inflammatory cells- lymphocytes, plasma cells, neutrophils, eosinophils - Predominantly B cell origin
Other conditions in which Reed-Sternberg cells are seen: - Infectious mononucleosis - Solid-tissue cancer - Large-cell NHLs
WHO now classifies 2 types only:
- Classical
- Nodular Sclerosing
- Lymphocyte-rich
- Lymphocyte depleted
- Mixed cellularity
- Nodular lymphocyte predominant Hodgkin’s lymphoma (NLPHL)
Therapy and prognosis guided by Ann Arbor staging
RANNULA xx
Pathogenesis: Sublingual gland duct obstruction —> mucus extravasation —> pseudocyst formation
Plunging ranula:
- Boutonierre deformity- button-hole dehiscence in mylohyoid
- Intact mylohyoid — extravasates more postero-lateral around back end of mylohyoid
- Ectopic sublingual gland- may lie below plane of mylohyoid — vulnerable to external trauma (i.e. a plunging rannula may develop without the oral component)
Pathology: No Epithelial Lining Pseudocyst within neck - wall contains granulation tissue with fibroblasts, small vessels, mixed (acute/chronic) inflammatory cell infiltrate, incl foamy histiocytes Salivary gland: dilated ducts, fibrosis, acinar atrophy, chronic inflammation
Image = pooling mucus, and foamy histiocytes
CHONDRODERMATITIS NODULARIS CHRONICUS HELICIS (CDCH) xxx
Idiopathic non-neoplastic ulcerative lesion of the auricle
Aetiology: - Unknown, theories include……cold exposure, actinic damage, local trauma, pressure necrosis
Clinical: - M in late middle to older age
- Spontaneoulsy occuring unilateral painful nodule, intensely tender 2ndary to perichondrial involvement
Pathology: - Involved epidermis is ulcerated - Base of ulcer = granulation tissue, oedema, fibrinoid necrosis - Granulation tissue and inflammatory infiltrate extends to and involves perichondrium and cartilage - Central portion of epidermis is ulcerated - Adjacent epithelium shows acanthuses, hyper and parakeratosis and pseudoepitheliomatous hyperplasia - Base of ulcer shows grannulation tissue, fibrinoid necrosis and inflammatory changes
DDx: BCC or SCC common misdiagnosis
Treatment: - Surgical excision is treatment of choice and is curative (wedge excision) - Steriod injection may help in a minority of pts
KERATOACANTHOMA xxx
Likely to be a form of SCC characterised by spontaneous resolution
Clinical course is characteristic: - Begin as a small papule that rapidly enlarges —> erythematous nodule with a central keratotic plug - Continued growth over 4-8 weeks, then remains stable - Exquisitely tender - Fleshy rim then recedes —> keratotic horn - Central plug then falls out and lesion resolves
Pathology: - Central crater surrounded by hyperkeratosis, parakeratosis, acanthuses - Crater then filled with hyperkeratotic material
Management: Current management is early excision, rather than waiting for resolution
RELAPSING POLYCHONDRITIS xxx
Rare systemic, relapsing disease characterised by progressive degeneration of cartilage structures throughout the body
Aetiology: Presumed autoimmune
Autoantibodies to Type II collagen
Pathogenesis: Initial neutrophil infiltration, cartilage loss, later infiltration by histiocytes, plasma cells and lymphocytes, atrophic cartilage with cystic spaces/gelatinous areas
Pathology: Inflammatory infiltrate around cartilage erosion and replacement by fibrous tissue
Diagnostic criteria = McAdam criteria (see Staging System cards)
EXOSTOSIS xxx
Localised overgrowth of bone - a reactive lesion consisting of a compact proliferation of layers of bone
Differential Diagnosis from Osteoma: Broad-based
Multiple (4, 7, 11 o’clock positions)
Dense lamellae of periosteal bone — dense solid bone on CT
Pathology: - ‘Onion-skin’ appearance - Thin periosteum + skin overlying it - Lack of marrow spaces and trabecular architecture
Pathogenesis: Cold water —> vasoconstriction of periosteal vessels —> reflex vasodilation and new bone formation
OTOSCLEROSIS xxx
Hereditary disease of the human otic capsule bone characterised by localised, abnormal bone remodelling
Autosomal dominant with incomplete penetrance and variable expressivity
Pathogenesis: 2 stages
- Active (otospongiosus) - increased cellularity/vascularity (spongiotic, disorganised bone), bone remodelling, sheets of CT replace bone, enlarged marrow spaces with large vessels +ve Schwartze - continuous active resorption and remodelling
- Inactive (otosclerosis) - dense sclerotic bone formation with few recognisable Haversian systems in areas of previous resorption Path features of otosclerotic plaques - bone resorption, new bone formation, increased vascularity, CT stroma
Blue mantles of Manasse - early feature, more basophilic than normal bone as new bone is rich in amorphous ground substance and deficient with collagen (but over time this is replaced with collagen causing dense sclerotic bone)
PAGET’S DISEASE Osteitis deformans xxx
Definition: A progressive disease of unknown aetiology characterised by exuberant bone remodelling
Genetic - there is AD inheritance - Sequestsome 1 (SQSTM1) p62 scaffold protein in NF-kB pathway ? viral - paramyxovirus identified in Pagetic osteoclasts
ie. viral etiology in genetically susceptible individuals
Pathogenesis/Pathology: 3 Histologic Stages:
- Osteolytic phase - excessive osteoclastic activity resulting in bone resorption
- Mixed phase - new bone formation predominates over bone resorption - deposition of bone adjacent to areas of bone resorption
- Osteoblastic phase - Increased new bone, dense irregular masses showing mosaic pattern (cement lines)- as per picture
Sarcomatous transformation in 1% (osteosarcoma)
CHOLESTEATOMA xxxx
A progressive, locally destructive disorder resulting from accumulation of keratinising squamous epithelium within the middle ear or other pneumatised portions of the temporal bone
Pathology: Cystic mass with a surrounding inflammatory reaction.
3 components:
- Cyst = keratin
- Matrix = keratinising stratified squamous epithelium 3. Perimatrix = inflammatory infiltrate/granulation tissue - Proteases and collagenases contribute to local destruction - May have cholesterol clefts also at periphery (hence term ‘cholesteatoma’)
MIDDLE EAR ADENOMA xxx
Benign glandular neoplasm arising from the middle ear mucosa
Rare neoplasm. Can be mistaken for metaplasia of glands in CSOM
Pathology: - Grey-white to red-brown lesion, appears as a relatively avascular soft tissue density - Unencapsulated tumour - Individual or back-to-back growth - Glands = single layer of cuboidal/columnar epithelium
LANGERHAN’S CELL HISTIOCYTOSIS xxx
Formerly Histiocytosis X
Unchecked proliferation of pathologic Langerhan’s cells
2nd-3rd decade of life
Most lesions are osseous based- incl middle ear and temporal bone
Pathogenesis: Clonal proliferation of Langerhan’s cells (a cellular comonent of the dendritic cell system) Isolated vs systemic proliferation
Encompasses:
- Eosinophilic granuloma - single focus (intraosseous), benign, excellent prognosis - Local curettage +/- low dose RT
- Hand-Schuller-Christian disease - multifocal incl extra osseous + systemic features (DI, exophthalmos) - Low dose chemo for systemic symptoms
- Letterer-Siwe disease - diffuse involvement, fever, rash, LNpathy, hepatosplenomegaly - Poor prognosis, high mortality- high-dose chemo, + RT, BM transplant
Pathology: Proliferation of Langerhan’s cells - sheets, nests, clusters
- Nuclei features show longitudinal nuclear groove (as for PTC), and kidney shaped nuclei
- Inflammatory cell infiltrate (eosinophils seen mainly in eosinophilic granulomas but not other types)
Electron Microscopy: elongated granules are referred to as ‘Birbeck’s’ granules and are seen in the cytoplasm of Langerhan cells
IHC: S-100, CD1A
PARAGANGLIOMA xxxx
Benign neoplasm arising from the extra-adrenal neural crest-derived paraganglia
Genetics = Succinyl dehydrogenase subunit mutations (Krebs cycle) Ch 11q23 ie.
SDH is a mitochondrial enzyme complex with impt role in oxidative phosphorylation and intracellular oxygen sensing and signaling
- SDH-D = MC (PGL1 locus), SDH-C also assoc with PGs (PGL3 locus)
- SDH-B = Phaeochromocytoma
- SDH-A = Necrotising encephalomyelopathy
AD with maternal imprinting (SDH-A and SDH-D is with imprinting). SDH-C and SDH-B are without imprinting.
Germline mutations of genes encoding SDHB and SDHC predispose to paraganglioma syndromes (SDHC is very rare)
Pathology: Gross = encapsulated, well-circumscribed, ovoid, rubbery or firm Nests of Zellballen - Formed by the sustentacular cells, surrounded by prominent vasculature
IHC: based on cell type: Chief cells - Round or oval with uniform nuclei, dispersed chromatin, abundant eosinophilic, granular or vacuolated cytoplasm - IHC staining with……chromagranin, synaptophysin, NSE Sustentacular - Represent modified schwann cells (supporting cells) - Located at periphery of cell nests as spindle-shaped (ie. like Antoni A/B cells of AN), basophilic-appearing cells - S-100, GFAP (glial fibrillary acidic protein)
Note image = predominantly chief cells with their round/oval uniform nuclei and dispersed chromatin, granular or vacuolated cytoplasm. There is a fibrovascular stroma. The Sustentacular cells are ‘spindle shaped’ and basophilic (often difficult to see on light microscopy)
VESTIBULAR SCHWANNOMA xxxx
Definition: A benign tumour affecting the Schwann cells of CN VIII
95% sporadic (unilateral), 5% NF-2
Chromosome 22q12- Merlin (TSG) gene product — 2-hit hypothesis
Mostly affects SVN, arise at Rednik-Obersteiner line (neurilemmal-neuroglial junction where nerve acquires a sheath)
Pathology: S-100 positive - strongly and diffusely, NSE/chromogranin/synaptophysin -ve!
Antoni A - densely packed cells with spindle-shaped, darkly staining nuclei (See picture: whirled appearance with nuclear pallisading = Verocay body) Antoni B - loosely packed cells with vacuolated pleomorphic cells, myxoid stroma (myxoid = ‘mucin like’) also
MENINGIOMA xxx
Benign neoplasm arising from arachnoid cells forming the arachnoid villi (meningoepithelial cells)
- Related to dural venous sinuses
2nd MC CPA lesion, F>M, 5th decade, previous RT, 18% of IC tumours
- May be ectopic in the middle ear or access middle ear by direct spread
- May be assoc wtih NF-2
MC sites: Parasagittal Falx Olfactory groove Tuberculum sellae Sphenoid ridge Petrous face (CPA) Tentorium/lateral ventricle/Clivus
Imaging: CT - Hyperostosis in 75% (tumour invades the bone also) MRI - Broad-based lesion, iso/hypointense T1, mod Gad-enhancement (95%) i.e..not as bright as AN, variable T2 (typically ‘cellular’ therefore less bright than acoustics which have a higher ‘water’ component) - Dural tail in 60% (seen on gad scan)
Pathology: - Lobular firm mass. Tumour nests separated by a variable amount of fibrous tissue - Psammoma bodies may be present - Nuclei may have a punched-out appearance
WHO Grading:
- Benign (90%) - Slow growing, don’t metastasise. May increase during pregnancy
- Atypical (7%) - More aggressive. Increased mitotic index (4 per HPF)
- Anaplastic (3%) - Very aggressive (>20 mitoses/HPF)
4 histologic variants: - Syncytial - Fibroblastic - Transitional (comb of syncytial and fibroblastic) - Angioblastic
IHC: Vimentin and EMA +ve (-ve for synaptophysin, chromagranin) - Can extend into bone via Haversian canals
Management: - Total resection is aim - Can do subtotal resection — adjuvant RT or combined approach (e.g. anterior transnasal approach)
ENDOLYMPHATIC SAC TUMOUR xxx
Rare but distinct neoplasm arising from the endolymphatic sac epithelium
Sporadic vs von Hippel Lindau - vHL = AD multisystem disorder - cerebellar haemangioblastomas, retinal angiomas, renal cysts, clear cell RCC, other visceral tumours - vHL gene: Ch 3p25 (tumour suppressor gene) - 1/3 of vHL tumours are bilateral
Pathogenesis: 2-hit hypothesis for the vHL TSG
Pathology: low-grade adenocarcinoma Variable papillary-glandular appearance - Covered by single row of low cuboidal cells - Have a vascular nature
May mimic other tumours - thyroid (papillary), renal/prostate (clear cell Ca), choroid plexus papilloma IHC: Cytokeratin, vimentin, epithelial membrane antigen, S-100, NSE
CHOLESTEROL GRANULOMA xxx
Aetiology: - Represents the a foreign body granulomatous response to cholesterol crystals derived from the rupture of red blood cells with breakdown of the lipid layer of the erythrocyte cell membrane
Pathology: - Empty grooves surrounded by hemosiderin laden macrophages and foamy histiocytes +/- multinucleated giant cells (FB granuloma) - Cholesterol dissolves in tissues — needle-shaped clefts (ie. fluid of cyst consists of breakdown products of blood that consists of cholesterol crystals) - Stromal response to haemorrhage ie. surrounding fibrous capsule - Need to exclude a primary pathology (tumour, cholesteatoma)
- Granulomas (FB)
- Foamy histiocytes
- Haemosiderin ladden macrophages
- Cholesterol clefts
- Fibrous capsule Image = granulation tissue, multinucleated giant cells, clefts of cholesterol crystals and fresh haemorrhages
CHORDOMA xxx
Malignant lesion arising from remnants of the notochord
- Destructive midline mass
Epidemiology: - M>F, 2:1 - Peak incidence in the 8th decade, and rare before the age of 40
Embryology: - Notochord develops at 3-4/40 then disappears by 7/40 - Function = is a dorsal organizer region ie. determines the dorsal-ventral axis of neural tube (notochord is ventral to the neural tube), L and R asymmetries, and arterial-vs-venous fates of early blood vessels - Pathway: Exits sphenoid to primitive pharynx then re-enters basiocciput and descends through the centre of vertebral bodies (has a ‘serpentine’ course thru BOS). Thornwaldt cysts are due to this pathway of communication btw nasopharynx/notocord. - Persists as the nucleus pulposus of intervertebral discs - Chordoma = arise from vestiges of notochord along its path (not from nucleus pulposus) - 35% of chordomas are in the skull base (50% sacrococcygeal, 15% spinal)
Presentation: Upper brainstem — CN II, hemianopia etc (like pituitary lesion) Lower branistem — Lower cranial nerves incl XII - Metastasis - do occur ie. lung/liver/bone but take place late in disease process and don’t contribute significantly to overall mortality
MRI: ‘honeycomb’ appearance, variable T1 (may be areas of high T1 signal), high T2, marked Gad enhancement (indistinguishable from chondrosarcoma on radiology - except chondrosarcoma’s are paramedian and chordomas are midline)
Pathology: - Pseudo-encapsulated tumour (fibrous outer layer that commuicates with internal septations of lesion) - Lobular growth pattern, exophytic - Physalliferous cells — ‘soap bubble’ appearance with vacuolisation of cytoplasm displacing nuclei peripherally, may have chondroid features
IHC: S-100, cytokeratin, EMA +ve ie. epithelial markers +ve (differentiates from chondrosarcoma)
Chondrosarcoma vs Chordoma: - lack of ‘soap bubbles’ - have islands of cartilage (ie. may appear like chondroid chordomas), - lack epithelial antigens on IHC. - Chodrosarcomas are ‘mesenchymal origin lesions’ vs chordomas are epithelial orgin lesions
Presentation: Ophthalmoplegia (VI in Dorellos, III, IV. VI in cavernous sinus) or H/A Recurrence — 5% 5-year survival
Treatment: - Generally chordomas and chondrosarcomas are considered chemoresistant and relatively radio resistant, hence mainstay is surgical excision - Complete surgical excision of skull base lesions is almost impossible and assoc with high morbidity, therefore often sugical decompression followed by adjuvant RT (proton beam)
CHONDROSARCOMA xxx
Definition: A mesenchymal tumour (hence Vimentin staining) arising from petro-occipital cartilage rests
Classification:
Primary - chondrosarcoma in absence of other features Secondary - associated with anchondroma, Olliers disease (multiple cartilage tumours)
MC Sites:
- Larynx
- Petrous apex- arise from cartilage rests: petro-sphenoid and petro-occipital
- Maxillofacial
Radiology: key is to differentiate from chordoma CT: destructive, lateral lesion, chondroid calcifications MRI: ‘popcorn’ appearance, low T1, high T2, heterogenous Gad enhancement
Pathology: Biphasic tumour:
- Cellular area = undifferentiated, small round cells
- Cartilage = relatively bland appearing
High grade vs low grade - Cellularity, pleomorphism, mitoses and multinucleated cells IHC: Vimentin, CD99, NSE - Negative for epithelial markers
CHONDROSARCOMA - grading disease
The grading of chondrosarcomas is done on the basis of cellularity and atypia. Mitotic figures are uncommon and are not used in the grading.
The tumor shown in the photomicrograph is a Grade 2 chondrosarcoma given the cellularity and pronounced atypia. Between 30% and 40% of all chondrosarcomas are Grade 2.
TYMPANOSCLEROSIS xxx
Acellular hyaline and calcified deposits accumulate within the TM and submucosa of the middle ear
Aetiology: - Complication of otitis media or trauma - VTs — 60% (lower for myringotomy alone- 15%)
Pathogenesis: Destructive process within connective tissue —> degeneration of collagen and subsequent dystrophic calcification and tympanosclerosis
Pathology: - Hyalinization of subepithelial connective tissues - TM — limited to the lamina propria - ME — most frequent in attic, assoc with ligaments of the malleus head and incus body - Calcification most often present - Osteoneogenesis can occur —> ossicular fixation
Management: suggest conservatism as likely variable outcomes - Smyth et al — 79% hearing restoration with OCR - Used a two-stage technique - Teufert et al — 60% success in ABG closure to less than 20dB (average pre-op ABG was 30dB) - Gormley et al — 7% improved to within 20dB
NEUROFIBROMA xxx
Definition: A benign nerve sheath tumour in the peripheral nervous system
Epidemiology: - Most are single and not assoc with a syndrome - Assoc with NF1 and very rarely NF2 - Localized cutaneous form is MC, plexiform is often assoc with NF1 - NF1 pts often affected as children, and get all types (cutaneous and plexiform)
Pathophysiology: Biallelic inactivation of the NF-1 gene (17q11.2) that codes for neurofibromin - RAS-inhibitor which mediates cell growth signaling pathways Two-hit hypothesis - Inherited mutation present in NF-1 means only a single hit required to produce a neoplasm
Pathology: Arises from non-myelinating Schwann cells - Non-myelinating Schwann cells encapsulate small diameter PNS axons with their cytoplasmic processes - Myelinating Schwann cells cover large diameter (>1pm) PNS axons with myelin In contrast to Schwannomas, although arising from Schwann cells they incorporate many additional types of cells - Fibroblasts, perineural cells, endothelial cells, mast cells - Residual nerve fibers are interspersed in tumour (unlike schwannoma which is eccentric to nerve) - Histology shows spindle cells with wavy nuclei - IHC = S100 +ve
Subtypes:
- Dermal - Single peripheral nerve in the skin - 3 types: discrete cutaneous, discrete subcutaneous, deep nodular - Arise in teenage years, often assoc with onset of puberty - Increase in size and number through adult life
- Plexiform - Multiple nerve bundles - skin or more internal nerve bundles - Difficult to remove completely because they extend through multiple layers of tissue
Clinical Features: - Typically solitary, unless assoc with NF1 - NF1 features = cafe-au-lait spots, axillary freckling, >2 neurofibromas, 1 plexiform NF, optic nerve gliomas - Localised cutaneous = are soft, polypoid, painless, slow-growing mass - Diffuse cutaneous = plaquelike thickenings of dermis - Localised intraneural = asymptomatic lump, can cause neuropathic pain or tingling
Prognosis: - Localised cutaneous don’t undergo malignant change - Diffuse cutaneous and intraneural NF’s rarely undergo malignant transformation - Plexiform neurofibromas are the MC to undergo malignant transformation
DERMOID xxx
Definition: Benign developmental cystic anomaly arising from ectoderm and mesorderm (no endoderm)
Epidemiology: 34% of all dermoids occur in H&N Most often present 1st decade of life
Aetiology: Ectodermal differentiation of multipotential cells trapped at the time of closure of the anterior neuropore (hence along midline of neck). Result of entrapment of epithelial and dermal (i.e.. layer just beneath epithelium) elements along embryonic lines of fusion (ie. Median and paramedian)
Pathology: Lined by stratified squamous epithelium Cutaneous adnexal structures (hair shafts, sebaceous glands, eccrine glands, apocrine glands) in the fibroconnective tissue wall Cyst filled with keratin Rupture results in florid foreign body giant cell reaction
Typically midline, usually sub mental - Attached to and move with overlying skin
Vascular anomalies xx
Features: Vascular tumours vs Vascular Malformations
Vascular Tumours - HOI not present at birth vs Congenital haemangioma present at birth (RICH vs NICH) - Rapid proliferation, then involution - Endothelial hyperplasia with active growth - Multilayered basement membrane - Rapidly dividing endothelial cells - Pathology shows syncytial masses with and without lumina - GLUT-1 receptors present (HOI)
Vascular Malformations - Present at birth - Growth matches that of child - Endothelial cell hypertrophy (not hyperplasia) - Single layer basement membrane, flat quiescent endothelium - Non-dividing endothelial cells - Pathology shows abnormal dilatation of vascular channels - GLUT-1 receptor absent
LYMPHATIC MALFORMATION xxx
A low flow vascular malformation
Embryology/Pathogenesis:
- Centripedal theory - Lymphatic channels fail to grow from lymphatics to venous system - Retain proliferative growth potential without connection to normal lymphatic system
- Centrifugal - Endothelial fibrillar membrane proliferation from walls of the cyst, penetrate surrounding tissue along lines of least resistance
Pathology: Multiple dilated lymphatic channels - Lined by single layer of flattened endothelium - contains proteinacous fluid and lymphocytes - Intervening stroma - fibrous connective tissue, muscle (smooth/striated), lymphoid aggregates
Subtypes: Macrocystic (>2cm3)
Microcystic (<2cm3)
Mixed
INVERTING PAPILLOMA xxxx
Definition: One of 3 types of Schneiderian papilloma (fungiform/exophytic, cylindrical/columnar, inverting) Schneiderian Papilloma - a benign tumour arising from ectodermally derived Scheiderian mucosa of the sinonasal tract (ie. nasopharynx is endodermal derived) Schneiderian Membrane - histologically distinct in that it is ‘mucoperiosteum’. i.e.. a bilaminar membrane with ciliated columnar epithelial cells on the internal side, and periosteum on the osseous side.
Epidemiology: Exophytic (fungiform or septal) = 50%, Inverting = 47%, Oncocytic (Cylindrical) = 3% Up to 4% of all nasal tumours, M>F (i.e.. just like Antrochoanal polyps), 5th-6th decade
Pathogenesis/Pathology: General Features of Schneiderian Papillomas - All show squamous epithelium (arising from normal respiratory epithelium) - All have intra-epithelial mucin and mucocytes Inverted type - Prolif of epithelium with finger-like inversions into underlying stroma (but not through basement membrane!!!!) - Assoc with chronic inflam cells, goblet cells and intra-epithelial mucin microcysts (PAS +ve) Exophytic papilloma - Exophytic type of growth, found mainly on the nasal septum - Squamous epithelium arranged in papillary fronds Cylindrical/oncocytic papilloma - Multilayered epithelium with an eosinophilic cytoplasm
Malignant transformation 5-15% - features assoc with malignant transformation:
- Hyperkeratosis
- Plasma cells
- Bilateral disease
- > 2 mitotic features
PYOGENIC GRANULOMA xxxx
Rapidly growing lesion characterised by proliferation of capillaries in a lobular architecture
aka Lobular Capillary Haemangioma — other haemangiomas are rare in the sinonasal tract
A submucosal lesion with thickening of the overlying epithelium
Trauma, hormonal (OCP, pregnancy)
Pathologic features: smooth, lobulated polypoid red mass
- Lobular capillary proliferation - ectatic vessels with RBCs within them - Lobular architecture differentiates it from granulation tissue
- Loose CT stroma
- Inflammatory cell infiltrate - granulation tissue and mixed chronic inflam cell infiltrate
No true cytologic atypia
OSTEOMA xxxxx
Definition: Benign, bone-forming tumours almost exclusive to the craniofacial skeleton
M>F, any age, often asymptomatic, frontal>ethmoid>max>sphenoid
Sharply delineated radio-opaque lesion confined to bone or protruding into a sinus
Sporadic or assoc with Gardner’s syndrome (AD, intestinal polyposis, soft tissue lesions, multiple craniofacial osteomas)
Submucosal proliferation of dense, mature, predominantly lamellar bone
Pathology: Histologically divided into 3 categories
- Ivory - compact, dense bone. Minimal fibrous tissue, no evidence of Haversian systems
- Mature - spongy, mature bone. Conspicuous fibrous tissue, fibroblasts, collagen
- Mixed - components of both ivory and mature
FIBROUS DYSPLASIA xxxx
Definition: Genetically-based developmental anomaly of bone-forming mesenchyme Benign, idiopathic non-neoplastic bone disease, normal medullary bone replaced by structurally weak fibrosseous tissue
Mutation of GNAS1 gene Ch20q13.2 (codes for a subunit of G-protein)
Epidemiology: Diagnosed in 1st-2nd decade of life
Classification:
- Mono-ostotic
- Poly-ostotic
- MaCune-Albright syndrome (triad of polyostotic fibrous dysplasia, endocrine dysfunction, cutaenous hyperpigmentation)
Clinical Features: No specific symptoms, just as a space occuping lesion within the nasal obstruction +/- sinus drainage and obstruction
Pathogenesis: Defect of bone caused by a defect in osteoblastic differentiation and maturation that leads to replacement of normal bony tissue by fibrous tissue of variable cellularity and immature woven bone. All bone components present but don’t differentiate to mature structure Well-circumscribed, intramedullary lesions, expand/distort bone Replacement of medullary bone by fibrous tissue +/- bone metaplasia Chinese characters = curvilinear trabecular of woven bone surr by mod fibroblastic prolif
- Pagetoid 56% (ground-glass)
- Sclerotic 23% (least active)
- Cystic 21% (most active)
No osteoblasts at the edges — differentiates from ossifying fibroma
Malignant transformation to osteosarcoma- Mono = low, Poly = 0.5%, MAS = 4%
Investigations:
CT scan = early phases is assoc with a high density of fibrous tissue, and radiolucency or lytic appearance, as amount of bony tissue increases get a ground glass appearance
MRI scan = signal reported as variable on T2 weighted sequences, T1 shows hypointensity, nonhomogenous enhancement with gadolinium.
Treatment:
Surgery - To relieve symptoms of visual impairment if compression of optic nerve, and open sinuses if causes concern - Radiotherapy contraindicated because of risk of malignancy
Medical - Bisphosphonates to inhibit osteoclastic activity if assoc with disfigurement
OSSIFYING FIBROMA xxx
Definition: A true benign neoplasm Well-demarcated, slow-growing, benign fibro-osseous neoplasm composed of fibrocellular tissue mixed with variable osseous component
Epidemiology: - Presents in 3rd-4th decade - More common in black women
Pathology: Origin from periodontal ligament (ie mandible is most common site) Randomly distributed mature lamellar bone spicules rimmed by osteoblasts mixed with a fibrous stroma
Osteoblastic rim differentiates it from Fibrous Dysplasia
Psammomatoid (active) OF:
Investigations: CT - unifocal lesion, sharply defined, smooth/corticated borders - Early lesions = cyst-like - Later lesions = radio-opaque mass surrounded by radiolucent rim
Management: Observation - small, asymptomatic lesion Surgery - complete excision more easily obtained than FD -Aim should be radical resection as lesions have high replase rate (44% for ethmoid lesions) with aggressive behaviour if reoccur with invasion of adjacent vital structures
Natural History/Prognosis: Excellent prognosis with surgical excision - Recurrent tumours can be aggressive No known malignant potential
PSAMMOMATOID OSSIFYING FIBROMA xxx
Variant of ossifying fibroma
- Typically occurs in sinonasal tract (ethmoid, supraorbital ridge)
- 1st/2nd decade, M>F, ethmoid or supra-orbital, single or multiple
- Very aggressive
Pathology: Similar to OF but also psammomatoid bodies - Bony spicules/spherules admixed with fibrous stroma - Psammomatoid bodies - central blue-black appearance surrounded by pink-appearing rim and with concentric laminations - Stroma is composed of spindle-shaped or polyhedral cells with basophilic nuclei and scant cytoplasm
Management: Surgical excision (recurrence rel to incomplete excision).
No malignant potential
HAEMANGIOPERICYTOMA xxx
A type of soft tissue sarcoma that originates in the pericytes in the walls of capillaries
Middle age, M=F
- A rare sinonasal neoplasm (1%) but 25% of HPC occurs in sinonasal tract
Pathology: - Macroscopically - beefy red, soft, fleshy/friable masses - Submucosal, circumscribed but unencapsulated cellular tumour - Diffuse growth pattern - Single cell type surrounding endothelial-lined vascular spaces - Uniform, elongated cells with hyper chromatic nuclei - Vessels have a ‘staghorn’ configuration (‘antler-like’)
IHC: Actin, Vimentin
SINONASAL SCC xxx
Malignant epithelial neoplasm arising from the surface epithelium with squamous cell differentiation
MC sinonasal malignancy. Max > nasal > ethmoid >> sphenoid/frontal
Risk factors: - Nickel exposure (250x), textile dust, prior IP
Subtypes:
Keratinising (85%) - Intercellular bridges, hyperchromatic nuclei, mild-mod atypia, low mitotic rate - Well, mod, poorly differentiated carcinomas — more differentiated- less keratinisation, more nuclear atypia/mitoses - ‘Mosaic tile’ arrangement - Keratin pearl formation, surface keratinisation - Dysplasia of overlying surface epithelium may also be seen - Stromal invasion: cohesive nests or cords
Non-keratinising (15%) - Elongated cells, nuclear pleomorphism, increased N:C, loss of polarity - Papillary or exophytic growth pattern with downward growth as well - Can be confused for inverting papilloma - stromal invasion may be difficult to demonstrate - Hypercellular neoplasm - pleomorphism, hyperchromasia, increased N:C, loss of polarity, atypical mitoses - Variants are rare
Overall 5 year survival = 60% - Nasal cavity do better than maxillary sinus (earlier diagnosis)
SINONASAL ADENOCARCINOMA xxx
Definition: Malignant glandular epithelium tumour of the sinonasal tract
Epidemiology: M>F = 4:1, 5th-7th decades
Aetiology: Hard wood - 500x risk (wood dust particles rather than chemicals used) - Ebony, oak and beech. Only present in 25% of AdenoCa - Arise in olfactory cleft when assoc with hard wood - Generally T3/T4 at presentation, neck involvement <10%
Pathology:
Non-Salivary gland origin
- Intestinal-Type (ITAC) - Barnes classification: Papillary, colonic, solid, mucinous, mixed - Papillary least agressive, solid/mucinous worst prognosis - Hard wood = papillary and colonic
- Non-intestinal, non-salivary sinonasal adenocarcinoma - Low-grade (ethmoid) vs high-grade (maxillary) - No known occupational associations
Salivary gland origin - Adenoid cystic MC (MEC, acininc cell less common)
Histology:
- ITAC - so called as may have features of intestinal mucosa (ie. villi, paneth cells, enterochromaffin cells, muscularis mucosa) - Barnes classification- papillary, colonic, solid, mucinous, mixed - IHC: cytokeratin CK-20 (as for colon carcinoma), CDX2 Papillary types (MC, least aggressive) - papillary archietecture with tubular glands, minimal atypia Colonic (MC) - tubuloglandular architecture, rare papillae, increased nuclear pleomorphism/mitosis Solid (poor prognosis) - Loss of differentiation with solid and trabecular growth, marked increase in small cuboidal cells and nuclear pleomorphism/mitosis Mucinous - prominent mucus production, similar to colonic adenocarcinomas Mixed - mixture of the above type
- Non-salivary, non-ITAC Seromucinous - Low-grade = ethmoid, high grade = maxillary - No known occupational exposures
- Salivary gland origin - Adenoid cystic is MC in sinonasal tract, identical to other salivary origins histologically ie. cribriform/tubular/solid variants, tumours composed predominantly of abluminal myoepithelial cells and luminal duct lining cells, perineural invasion is high - MEC and acinic cell are less common
Ohngren’s line for prognosis (angle of mandible to medial canthus)
NOTE: adjacent image is ITAC colonic subtype
SINONASAL UNDIFFERENTIATED CARCINOMA (SNUC) xxx
Definition: Highly aggressive and clinicopathologically distinctive carcinoma of uncertain histogenesis, presenting with locally advanced disease (WHO definition)
Rare, rapid onset of symptoms
No known aetiologic agents
Extensively infiltrative at presentation- includes orbit, brain
- Also regional and distant (liver, lung, bone)
Pathology: Squamous and glandular differentiation not present - Hypercellular, variable patterns: nests, lobules, trabeculae, sheets - Pleomorphic tumour cells- similar to large cell Ca or nasopharyngeal Ca or ‘Western’ type (small nuclei, hyperchromatic with pink cytoplasm). Often polygonal - Frequent necrosis - LVS and PNI is common - IHC: - 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)
ESTHESIONEUROBLASTOMA xxx
Malignant neuroectodermal neoplasm thought to arise from the olfactory basal reserve cell
Bimodal age distribution, no known aetiologic agents
Pathology: Cell of origin is the olfactory basal reserve cell The great imposter - can be confused with other undifferentiated sinonasal cancers
Hyams tumour grading: I-IV, generally divided I/II vs III/IV Grade I/II vs III/IV Pleomorphism slight vs prominent/marked Mitosis/necrosis absent/slight vs prominent/marked Neurofibrillary matrix prominent/present vs absent Rossettes are the hallmark! present vs absent Calcification variable vs absent Lobular growth pattern with rosettes - circumferential grouping of cells around the neurofibrillary matrix IHC - Neuron-specific enolase, S-100, chromogranin (-ve for cytokeratin, epithelial markers CEA/EMA)
More on rossettes - Homer-Wright- pseudorosettes Hyams I-II (central hub composed of fibre-like process) - Flexner-Wintersteiner - true rosettes Hyams III-IV (central hub has a lumen)
MUCOSAL MELANOMA xxx
Definition: Neural crest-derived neoplasms originating from melanocytes and demonstrating melanocytic differentiation
Sinonasal tract is an uncommon site, adults, M>F
Nasal cavity (septum, LNW) more common than sinuses (max>eth) No known aetiologic agents
Pathology: can appear very similar to other tumours — need IHC - Surface ulceration common - Epithelioid or spindle cells, often mixed - Variable growth patterns- solid, organdie, nested, trabeculated, alveolar - Cells: round, marked pleomorphism, increased N:C, hyperchromatic nuclei
IHC: S-100, HMB-45, Vimentin, Melan A - Gold-standard for diagnosis
SINONASAL LYMPHOMA xxx
Heterogenous group of haematolymphoid malignancies
NHL is MC (B cell mostly)
NK/T cell lymphoma - Men, age = 6th decade, MC in Asian populations - EBV associated (strongly) - Destructive process of the mid face- septum, palate, orbit - Pathology: granulomatous picture may mimic Wegeners - Angiocentric and angioinvasive lymphoid infiltrate - Atypical PMN cells
Lipford classification
- Perivascular infiltrate of lymphocytes, plasma cells 2. Increasing atypical lymphoid cells with focal necrosis 3. Obvious lymphoma with vascular destruction + extensive necrosis
Disease stages
Prodromal - clear rhinorrhea, NAO
Ulcerative - purulent rhinorrhea, ulceration, septal perforation, bone/cartilage destruction
Terminal - malaise, fever, sloughed off tissue, gross midface destruction, death
B-cell lymphoma - low-grade — nasal mass assoc with airway obstruction - high-grade — non-healing ulcer, CN palsies, facial swelling, epistaxis, pain, orbital involvement
IHC: - CD-45 = Common leukocyte antigen - B-cell = CD-20 - Ki67 = Proliferative index (affects prognosis and treatment) - T-cell = CD-3 - NK-cell = CD-56
RHABDOMYOSARCOMA xxxx
Malignant tumour of skeletal muscle phenotype
40% occur in H&N, 20% in sinonasal tract
- MC sarcoma in childhood
Pathology: Spindle cells with hyperchromatic nuclei Myxoid stroma Botryoid type —> polypoid gross appearance Cambian layer = submucosal hypercellular layer
Pathologic Subtypes:
- Embryonal - Botryoid (in picture on this facet), Spindle cell
- Alveolar - fibrous septae separate clusters of loosely cohesive groups
- Pleomorphic
IHC: desmin, actin, fast myosin, myoglobin, MyoD1
JUVENILE NASAL ANGIOFIBROMA xxxx
Definition: A vascular tumour of the nasopharynx arising in adolescent males characterised by vascular spaces embedded in a fibrous stroma
Adolescent males 10-25 years old
Hamartoma - Composed of tissue elements normally found at the site but growing in a disorganised mass. Benign focal malformation rather than malignant tumour
Hormonal influences controversial - ? relationship to estrogen receptor positivity, Genetic changes (Chr 17), Proangiogenic growth factors (VEGF, TGF-b), p53
Pathogenesis: Myofibroblast is the cell of origin Arises from superior margin on SP foramen (trifurcation of palatine bone, horizontal ala of vomer, root of pterygoid process)
Pathology: Vascular spaces with dense stroma Well-circumscribed, lobulated, purple-red mass, with intact mucosa Two components microscopically
- Fibrous stroma - spindle-shaped cells in dense collagen stroma
- Vessels - irregular vascular channels (capillary-large venules) = Staghorn vessels (pathognomonic) with loss of muscular layer.
IHC: smooth muscle actin, vimentin
NASAL POLYPOSIS xxx
Pathology: Surface epithelium intact (ciliated pseudo stratified)
Oedematous stroma
Absence of mucoserous glands
Mixed chronic inflammatory infiltrate - eosinophils vs neutrophils, plasma cells, lymphocytes ‘Pseudogranuloma’- small patches of stromal non-oedematous collagen with inflammatory cells aggregated around periphery
Nerves absent- decreased secretion, abnormal vasc perm with oedema
ANTROCHOANAL POLYP xxxx
Pathology: Similar to inflammatory polyp - No glands in the core - No inflammatory response - Increased fibrosis + squamous metaplasia of the surface epithelium
Has a cystic stalk attachment to antrum!
NASAL GLIOMA xx
Midline lesion
Need to exclude intracranial extension
Pathology: Fibrillary pattern with large astrocyte cells IHC: GFAP- Glial Fibrillary Acidic Protein
MUCOCELE xxx
Definition: A chronic epithelial-lined (pseudostratified columnar), mucus containing sac filling the sinus, capable of expansion, typically caused by sinus outflow obstruction (ie. if sinus isn’t expanded then it is just an obstructed sinus)
Epidemiology: - Rare. All ages, equal gender distribution Aetiology: 1/3 have no predisposing factor Surgery and trauma most common
Pathogenesis: Consequence of obstruction and inflammation. 3 main theories
- Pressure erosion
- Cystic degeneration of glandular tissue
- Active bone resorption and regeneration
Events - Obstruction of sinus outflow - Chronic inflam - cytokine production, upregulation of vasc adhesion molecules - Osteoclastic bone resorption, fibroblast proliferation
Pathology: - Cyst lined with flattened pseudostratified ciliated columnar epithelium — i.e. near normal respiratory epithelium - Supports not needing to remove the mucocele lining - Reactive bone changes adjacent to cyst epithelium (neo-osteogenesis)
Picture: herniation of cyst into submucosal tissue adjacent bony wall of sinus
Structure & function of cilia
Each cilium has an array of longitudinal microtubules arranged as 9 doublets formed in an outer circle around a central pair (2)
Main structural protein of doublets = tubulin.
Radial spokes connect the outer doublets with a central sheath of protein around the central pair
Inner and outer dynein arms, are attached to the A subunit of each microtubule doublet.
Dynein, a type of ATPase, provides energy for microtubule sliding and the longitudinal displacement of adjacent microtubular doublets, resulting in ciliary bending.
The protein nexin links the outer microtubular doublets
Because nexin links maintain axonemal relationships while the basal bodies anchor the microtubules, the sliding of the outer microtubule results in bending of the cilium.
PRIMARY CILIARY DYSKINESIA xx
Definition: A rare group of disorders causing defects in the action of cilia lining the respiratory tract, fallopian tube and flagella of sperm
Epidemiology: Rare, autosomal recessive
Assoc Syndromes:
Kartagener’s: triad of situs invertus, CRS and bronchiectasis - > 1/2 of patients with PCD will have full triad due to loss of functional cilia in embryonic period
Young’s syndrome: CRS + obstructive azoospermia - Motile cilia and normal CTFR gene separate it from CF and PCD
Pathology: Ultrastructural defects affecting proteins in the outer and/or inner dynein arms which give cilia their motility - DNAI1 and DNAH5 code for outer dynein arm proteins (38% of cases) Results in severe mucociliary impairment
Look for missing outer or inner dynein arms or both!
CHORDOMA xx
Low-intermediate grade malignant tumour arising from the embryonic remnants of the notochord
Notochord normally disappears by 7/40
- May persist: sacrococcygeal, skull, verebra (C>L>T)
Craniocervical chordomas: dorsum sella, clivus, nasopharyngeal
Pathology: - Pseudo-encapsulated tumour separated into lobular growth pattern by fibrous CT - Epithelioid cells with vesicular nuclei and abundant, vacuolated-appearing cytoplasm - Physaliferous cells = ‘soap-bubble’ appearance with vacuolization of cytoplasm displacing nuclei peripherally
IHC: S-100, cytokeratin +ve, EMA +ve
PALATE - development
Face develops from 4-8/40, Palatogenesis = 5-12/40 Face develops from neural crest cells that migrate to form the facial mesenchyme
At 4/40: 5 processes form around the stomodeum - Frontonasal process (cranial neural crest cells) - Bilateral maxillary processes (arch I) - Bilateral mandibular process (arch I)
Thickenings appear on each side of the frontonasal process- the nasal placode - On each side of the placode forms the medial and lateral nasal processes (5/40) - The nasal pit lies between these (also 5/40)
The maxillary process then grows under the lateral nasal process to fuse with the already fused medial nasal processes - The primary palate (7/40) - (primary palate formed from fusion of median nasal prominences)
PALATE - - Primary step and fusion
Primary palate = central maxillary alveolar arch (4 incisors) and hard palate anterior to incisive foramen - Medial nasal prominence — philtrum, medial upper lip, nasal tip, columella
- Max prominences — lateral lip and then fuses with MNP
Behind the primary palate, the maxillary processes form palatal shelves (6/40)
- These grow towards each other, initially facing downward
- The medial edge epithelium then rapidly elevate over hours during 7/40 to fuse in the midline and allow the mesenchyme to flow across the palate
Palatal fusion progresses anterior-posterior - Incisive foramen at 8/40, completed by 12/40 (uvular fusion)
Nasal septum fuses with both primary and secondary palates - In unilateral cleft, it fuses with the normal side only
Nose formed from: MNP = tip, collumella and LNP = alar and FNP = nasal bridge
