• ↓ Alkaline phosphatase

Etiology: AR – hereditary deficiency of alkaline phosphatase

Clinical: 4 subtypes

1. Congenital type (present at birth): 75 % mortality
2. Early infantile type (appears within 1st 6 months of life): 50 % mortality. It causes:
   • Renal calcinosis
   • Cranial synostosis
   • Delayed motor development
   • Premature teeth loss
3. Late infantile type (appears within 6 – 24 months of life): few skeletal defects limited to irregular ossification, some rickets-like changes and premature teeth loss.
4. Adult type (rare!!!): bone pain, pathological fractures, childhood history of rickets.

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Etiology:

1. Removal of gland:
   • During thyroidectomy
   • Radical neck dissection
   • Resection of parathyroid mass/nodes
2. Congenital gland aplasia
3. Idiopathic gland atrophy
4. Primary adrenal insufficiency (usually with mucocutaneous candidiasis)

Clinical: Related to hypocalcemia

• Neuromuscular:
  • Tetany
  • Chvostek sign (facial nerve spasms)
  • Trousseau sign
  • Parkinson like movements
  • Papilloedema
• CNS: Emotional instability, anxiety, depression, hallucination, psychosis
• Eyes: Cataracts due to lens calcification
• CVS: Long QT interval
• Dental: General hypoplasia, failure of eruption

NB: Pseudohypoparathyroidism: Failure of 2nd messenger cAMP to respond to PTH

• Type 1: Albright syndrome
• Type 2: Defect in cAMP target tissue

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• Increased PTH
• PTH increases Ca²⁺ levels in blood
• Hormonal disorder:
  • Increased serum PTH
  • Increased alkaline phosphatase
  • Multiple bone lesions + osteoclastic multinucleate cells

Etiology/clinical subtypes:

1. Primary

• Benign tumors (75-80%) (adenoma)
• Gland hyperplasia (10-15%)
• Malignant tumors (<5%) (adenocarcinoma)

2. Secondary:

• Renal failure – compensatory reaction to low Ca²⁺ levels – therefore deceased kidney function – decreased vitamin D metabolism and decreased Ca²⁺ absorption and metabolism from blood
• Vitamin D deficiency
• Malabsorption

3. Hereditary: AD trait – mutation in HRPT2 (endocrine tumor suppressor gene) chromosome 1

• *Ectopic glandular tissue
• Short stature
• Distorted face
• Mental retardation
• Cardiac defects

Clinical:

1. Brown tumor (Brown color due to hemorrhage)
2. Kidney stones
3. Metastatic calcification
4. Osteoporosis
5. Fibroblastic/giant cell tumors of bone
6. Neural dysfunction due to fluctuating Ca²⁺ levels
7. Serum Ca²⁺ level increased > 16-17 mg/dl
8. Increased alkaline phosphatase

Symptoms:

• Pain
• Renal dysfunction
• Fatigue
• Weakness
• Brittle bones
• Bone swellings
• Nausea
• Arrythemia
• Parathyroid crisis
• Coma

Radiology:

• Loss of lamina dura
• “Pepper pot skull” = osteopenia → stippling patterns
• Radiolucent cyst like areas
• Multiloculated appearance
• Subperiosteal resorption

Histology:

• High osteoclastic activity: Demineralization of bone – starts at subperiosteal and endosteal surface of cortex – replaced with fibrous CT – containing microcysts (osteitis fibrosa cystica)
• Brown tumor: Vascular intrabony lesions (sinusoids filled with blood) + osteoclastic giant cells)

Management:

1. Surgery – Parathyroidectomy
2. Palliative care
3. Hormonal replacement and vitamins

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• Increased GH, ACTH and TSH
• Rare metabolic condition characterized by bony and soft tissue overgrowth and metabolic hypersecretion

Etiology: Benign pituitary adenoma – chronic hypersecretion of GH, ATCH and TSH

NB: If hypersecretion occurs prior to closure of epiphyseal growth plates, gigantism will occur

Clinical:

A) Systemic:

1. Hyperhidrosis (increased sweating)
2. Hirsutism (masculinization)
3. Impotence
4. Muscle weakness
5. Paresthesia
6. Carpal tunnel syndrome
7. Sleep apnoea
8. Hypertension
9. Heart disease

B) Bone:

1. New periosteal bone formation
2. Cartilaginous hyperplasia
3. Frontal bossing
4. Nasal bone hypertrophy

C) Oral:

1. Mandibular prognathism (increase in mandibular condyle)
2. Acquired malocclusion
3. Macroglossia

Lab: In serum, increased GH, ACTH, TSH and testosterone

Management:

• Transsphenoidal surgery
• Radiotherapy
• Bromocriptine (dopamine activator)

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Endocrine system

Secretion of hormones act on tissues as:

1. Autocrine (same cell)
2. Paracrine (cells in immediate vincity)
3. Endocrine (distant cells via blood)

Hormones divided into:

1. Signaling molecules (1st messengers act on cell surface receptors)
   • Peptides – Growth hormone, insulin
   • Amino acid derived molecules – epinephrine, histamine
2. Steroids (diffuse across cell membrane and interact with intracellular receptors)
   • Estrogen
   • Progesterone
   • Glucocorticoids
   • Thyroxine
   • Retinoic aid

Feedback inhibition: Increased activity of target-tissues → act as stimulus to down regulate secretary glands

Major pituitary function – controlled by hypothalamus

Anatomical region	Cell type	Hormones secreted	Target organ
Anterior pituitary/adenohypophysis	Somatotrophs	Growth hormone (GH)	All body systems
	Lactotrophs	Prolactin	Breasts
	Corticotrophs	1.Adrenocorticotropic hormone (ACTH) 2.Proopiomelanocortin 3.Melanocyte stimulating hormone (MSH) 4.Endorphins 5.Lipotropin	Adrenal glands Melanocytes Brain cortices Adipocytes
	Thyrotrophs	Thyroid stimulating hormone (TSH)	Thyroid glands
	Gonadotrophs	1.Follicle stimulating hormone (FSH) 2.Luteinizing hormone (LH)	Ovaries
Posterior pituitary/neurohypophysis	Glial cells/pituicytes	Oxytocin	Uterus, breasts
		Vasopressin	Liver (glycogen breakdown)
		Antidiuretic hormone (ADH)	Renal system for fluid/electrolyte balance

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1. Acromegaly
2. Hyperparathyroidism
3. Hypoparathyroidism
4. Hypophosphatasia
5. Hypothyroidism
6. Infantile cortical hyperostosis – Caffey’s disease
7. Osteitis deformans – Paget’s disease
8. Osteogenesis imperfecta
9. Osteoporosis
10. Osteopetrosis
11. Renal osteodystrophy and rickets
12. Scurvy

Bone disease of unknown etiology:

• Langerhans cell histiocytosis

a) Radiotherapy

1. Radiation mucositis

• Etiology:
  • Radiation > 3500-4000 rads
  • Usually develops in 2nd week of radiotherapy
• Clinical:
  • Reddening of oral mucosa
  • Pseudomembrane and greyish white slough
• Histology:
  • Ulceration/atrophy of surface epithelium
  • Attenuated stratum spinosum
  • Inflammation of submucosa
• Management:
  • Soothing mouth rinse
  • Pain relief

2. Osteoradionecrosis

• Etiology: High dose of radiation – impaired vascularity of jaw bones – complicated by proximity of normal oral flora
• Clinical: Gross necrotic lesion
• Histology:
  • Death of osteocytes, osteoblasts and endothelial cells within bone
  • 2ry infection – purulent discharge
• Management:
  • Prophylactic treatment
  • Resection of dead bone
• More under osteomyelitis

3. Temporary complications

1. Focal alopecia
2. Dermatitis of overlying skin
3. Pain
4. Dysgeusia (altered taste)
5. Candidiasis
6. Erythema
7. Mucositis

4. Permanent complications

1. Xerostomia
2. Cervical caries
3. Telangiectasia (dilated blood vessels)
4. Epithelial atrophy
5. Focal hyperpigmentation
6. Osteoradionecrosis

b) Chemotherapy

• Local toxicity
• Myelosuppression
• GIT toxicity
• Alopecia
• Pulmonary fibrosis
• Cardiotoxicity
• Nephrotoxicity
• Neurotoxicity

c) Surgical therapy

1. Short term:

1. Bleeding
2. P/O pain and paresthesia
3. Infection
4. Prolonged convalescence (recovery from illness)
5. Wound dehiscence

2. Long term:

1. Loss of mastication
2. Loss of speech function
3. Gross disfigurement
4. Graft rejection

Post-operative complications:

• Skin flap necrosis
• Hematoma
• Salivary fistula – due to trauma, presents as an opening in the suture line below the lobule of the ear
• Facial nerve paralysis – temporary or permanent
• Numbness of ear – injury to great auricular nerve
• Mucocele
• Xerostomia
• Frey’s syndrome

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Frey’s syndrome

Gustatory sweating syndrome – patient sweats when they see food

Etiology: Post-op growth of the interrupted preganglionic parasympathetic nerve branches to the parotid into the more superficial sweat glands

Diagnosis:

• History
• Starch iodine test:
  • Paint the affected skin with iodine, dust the skin with starch
  • Feed the patient
  • Appearance of bluish discoloration of overlying skin due to reaction between starch and iodine in the presence of moisture (sweat)

Management:

• Parasympatholytic creams such as glycopyrrolate lotion or scopolamine cream
• Apply anti-perspirant to avoid sweating
• Jacobsen’s neurectomy via tympanotomy approach

Preventive measure: Elevating skin flap and placing tissue such as fascia, dermis, or creating SCM muscle flap. For large defects use regional flaps such as pectoralis major flap

Etiology of oral cancer

1. Familial/hereditary/genetic factors

2. Occupation: Exposure to nitrosamines, polycyclic aromatic hydrocarbons, oncogenic viruses

3. Solar irradiation: UVB exposure – angular cheilitis, lip cancer

4. Atmospheric pollution: Benzene trichloroethylene in traffic emissions

5. Immunosuppression

6. Tobacco consumption (toxins): Aromatic hydrocarbons eg. Benzene, tobacco specific nitrosamines

7. Alcohol consumption:

• Increase permeability of oral mucosa to other carcinogens especially tobacco
• Poor oral hygiene – intraoral metabolism of alcohol to acetaldehyde by bacterial alcohol dehydrogenases
• Damage liver – decrease detoxification of carcinogens
• Secondary nutritional deficiency eg. B12

8. Other culture specific habits: Toombak, betel plant, areca nut

9. Virus: EBV, HPV 2, 6, 16, 18, 57 (deactivate p53 by E6 proteins)

10. Diet: Lack of antioxidants and vitamin A, C, E

11. Poor oral hygiene: Chronic irritation

12. Autoimmune: Oral lichen planus

13. Infections: Syphilis, chronic candidiasis

Pathogenesis of oral cancer – Multistep hypothesis

Accumulation of a series of genetic changes that lead to:

• Loss of cell growth control
• Increased cell motility
• Induction of neo-angiogenesis

Mutations of specific oncogenes and tumor suppressor genes – leads to selective growth advantage – enhances clonal expansion of malignant cells

1. Change in expression of tumor suppressor gene – p53

• 50% of OSCC
• p53 is a key regulator of G1-S cell cycle checkpoint
• Dysfunction of it’s encoded proteins – uncontrolled proliferation of cells

2. Dysregulation of it’s other cell cycle proteins

• Cyclin D1
• MDM2
• p16ink4a
• p27Kip1

3. Overexpression of anti-apoptotic proteins – evade apoptosis

• Bcl-2
• Bcl-x
• Bid
• Bax

4. Maintenance of telomere length – Increased replicative life span of neoplastic clones

5. Other oncogenes

• Growth factors – FGF
• Growth factor receptors – ErbB1 and ErbB2 
• Signal transducing proteins – Ras
• Nuclear regulatory proteins – Myc
• Overexpression of angiogenic proteins – angiogenesis:
  • VEGF
  • FGF
  • IL-8

6. Invasiveness

• Cadherins
• Catenin
• Matrix metalloproteinases

7. Non antigenicity

• HLA proteins
• TGF-β  immune suppressors
• FasL (for T cells)

Clinical presentation of orofacial tumors

Tumor morphology:

• Papillary
• Ulcerative
• Deeply infiltrative

Common symptoms:

1. Progressive swelling/enlargement, cortical expansion, asymmetry
2. Sudden tooth mobility/migration of teeth without apparent cause
3. Persistent/referred pain
4. Paresthesia/dysesthesia of tongue or lips
5. Soft tissue ulceration – non healing, persistent (>14 days), indurated, necrotic base, rolled margin
6. Lymphadenopathy – rare in pediatrics
7. Red/White lesions – precursors
8. Induration of tongue – fixed to underlying tissues
9. Airway obstruction – respiratory distress
10. Dysphagia
11. Chronic ear ache
12. Trismus
13. Alteration/blurring of vision
14. Unusual oral bleeding
15. Dysphonia – prolonged vocal hoarseness

Lymph node levels:

Level I: Submental, submandibular

Level II: Cranial jugular (deep cervical) nodes – Skull base to hyoid

Level III: Medial jugular (deep cervical) nodes – Hyoid to cricoid

Level: IV: Caudal jugular (deep cervical) nodes – Cricoid to clavicle

Level V:

• Supraclavicular nodes (posterior triangle)
• Dorsal cervical (superficial cervical) nodes along accessory nerve

Level VI: Prelaryngeal and paratracheal nodes

Other nodes:

• Parotid nodes
• Occipital nodes
• Buccal nodes
• Retroauricular nodes
• Retropharyngeal nodes

Investigations

Systemic investigations:

1. Chest xray
2. Full blood screen
3. Blood group and cross match
4. Clotting assays
5. U&E
6. LFT
7. Blood gases
8. ECG

Primary site:

1. Clinical examination
2. OPG
3. Lesional biopsy
4. Nodal biopsy
5. Endoscopy – Nasal, esophageal, bronchial
6. MRI and CT scan
7. Diagnosis and treatment of any dental problem

TNM classification of lip and oral cavity carcinomas

• Assessed by CT, MRI and palpating

T = Primary tumor	N = Regional lymph nodes	M = Metastases
TX: Cannot be assessed	NX: Cannot be assessed	MX: Cannot be assessed
T0: No evidence	N0: No regional lymph node metastases	M0: No distant metastases
Tis: Carcinoma in situ	N1: Metastasis to 1 ipsilateral lymph node, ≤ 3cm in diameter	M1: Distant metastasis present
T1: ≤ 2cm in diameter	N2: Metastasis of > 3cm, ≤ 6cm in diameter
T2: > 2cm, ≤ 4cm in diameter	N2a: Single ipsilateral lymph node
T3: > 4cm in diameter	N2b: Multiple ipsilateral lymph node
T4: Invades into adjacent structures	N2c: Bilateral/contralateral lymph node
	N3: Metastases to lymph node > 6cm in diameter

Stage	TNM groups
0	Tis, N0, M0
I	T1, N0, M0
II	T2, N0, M0
III	T3, N0, M0 T1/T2/T3, N1, M0
IVa	T4, N0/N1, M0 Any T, N2, M0
IVb	Any T, N3, M0
IVc	Any T, any N, M1

Mode of management:

• Stage 0, I, II – Surgery (wide excision)
• Stage III, IV – Surgery to also include neck dissection (selective, modified, radical) + adjuvant therapy (chemo and radiotherapy)

Oral squamous cell carcinoma

• Malignant epithelial neoplasm
• Non healing ulcer
• Exhibits squamous differentiation – characterized by:
  • 1. Keratinization
  • 2. Presence of intercellular bridges
• Consists of solid sheets, cords, islands or individual malignant cells

Modes of spread:

• Lymphatic
• Intravascular
• Local soft tissue infiltration
• Bone infiltration
• Perineural spread

Histology:

• Keratin pearls
• Epithelial dysplasia, characterized by:
  • Cellular pleomorphism
  • Hyperchromatic nuclei
  • Abnormal mitosis
  • Individual cell keratinization
  • Loss of cohesion
• Malignant epithelium invades CT and underlying muscles

Premalignant lesions:

• Leukoplakia
• Erythroplakia
• Lichen planus
• Nicotine stomatitis
• Oral submucous fibrosis
• Frictional keratosis
• Actinic cheilitis

Management: Surgery, chemotherapy, radiotherapy

Broder’s system

Histological grades of oral cancer:

Grade	Differentiation	Resemblance to original stratified squamous epithelium	Intercellular bridges	Keratinization	Mitotic figures	Atypical mitosis	Multinucleated cells	Cellular and nuclear pleomorphism
I	Well differentiated	Closely	Present and of varying proportions	Present	Few	Rare	Rare	Minimal
II	Moderately differentiated	Intermediate	Less conspicuous	Less	More	Seen	Seen	More
III	Poorly differentiated	Slight	Extremely scarce	Rarely present	Frequent activity	Frequent	Frequent	More and obvious

• Low grade: Well and moderately differentiated tumors
• High grade: Poorly/undifferentiated tumors

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B cell malignancy – abnormal production of monoclonal immunoglobulin

Subtypes

1. Multiple
2. Solitary
3. Extramedullary

Clinical

• Increased malignant plasma cells – replace bone marrow and erode bone, therefore pancytopenia
• Develop in vertebrae, ribs, pelvis, skull
• Localized pain
• Pain aggravated by exercise, relieved by rest
• Mandible – Paresthesia of lip, loose teeth
• Swelling
• Numbness
• Weightloss
• Weakness
• Anemia
• Bleeding
• Infection
• Amyloidosis (10%) – amyloid deposition reason for macroglossia
• Osteoporosis and pathological fractures

Radiology

• Sharply punched out, non corticated radiolucencies

Diagnosis

• Full blood screen:
  • Anemia
  • Rouleaux formation
• IgA and IgG proteins in serum (electrophoresis)
• Bence-Jones proteinuria (in urine)
• PBF – Plasma cells
• Stains for amyloid – Congo red, thioflavin T
• Immunochemistry for λ light chain
• Bone marrow biopsy

NB: Amyloidosis also seen in osteomyelitis and CEOT

Histology

• Monotonous proliferation of neoplastic plasma cells
• Peripheralization of chromatin – clock face appearance Picture

Differential diagnosis

• Langerhans cell histiocytosis
• Lymphoma
• Metastases

Management

• Combination chemotherapy
• Poor prognosis

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• Highly aggressive B-cell lymphoma

Etiology

• Translocation from chromosome 8 to chromosome 14
  • Chromosome 8 – locus of c-myc oncogene
  • Chromosome 14 – locus of Ig heavy chain
• Can also be t(8:22) or t(2:8) translocation
• Agents: EBV and malaria

Epidemiology

• Children and adolescents (50% childhood malignancy in Africa)
• 3-8 year olds
• M:F = 2:1

Clinical

• Doubling time is 25 hours and 100% growth fraction, therefore be quick to diagnose
• Rapidly expanding intraoral mass
• Pain and paresthesia

3 main clinical forms:

1. Endemic:

• Equatorial Africa
• Malaria as a co-factor
• 95% associated with EBV infection
• 50% have jaw involvement
• Involves mandible, abdominal viscera, kidney, adrenal glands, ovaries

2. Sporadic:

• Outside Africa
• Affects young adults
• Involves ileocecum and peritoneum
• Abdominal mass due to ileocecal involvement

3. Immunodeficiency associated:

• HIV
• Organ transplant patients (Immunosuppressant drugs)

Diagnosis

• Incisional biopsy
• Immunochemistry – Monoclonality of lymphocytes
• Ki67 staining (proliferation marker) – all cells in various stages of cell cycle
• Immunofluorescence (EBV and CD21)

Histology

• Monomorphic sheets of densely packed neoplastic lymphocytes
• High mitotic index: 100% cells in active division
• “Starry sky” appearance:
  • B lymphocytes – Sky
  • Macrophages – Stars – pale foamy cytoplasm

Radiology

• Floating teeth appearance (due to osteolysis)

Management

1st line drugs: (CHOP)

• Cyclophosphamide
• Adriamycin
• Vincristine
• Prednisolone

2nd line drugs:

• CHOP regimen + Procarbazine/cytarabine

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Clinical:

• Both Hodgkin’s and NHL – Present as nodal/ extra nodal lesions.
• Frequently in HIV positive patients
• Arises in single node/ chain of nodes – spreads to contiguous lymphoid tissues

Hodgkin’s lymphoma:

• Malignant lymphoma with presence of Reed Sternberg cells
• Reed Sternberg cells arise from B lymphocyte lineage – have mutations that render it incapable of producing complete immunoglobulin chains
• 50% of HL are associated with Epstein-Barr virus

Predisposing factors NHL:

• HIV
• EBV
• H. pylori
• Gluten enteropathy

Diagnosis

• Bone marrow biopsy, PET scan, CT scan, Chest xray

Jamshidi needle – bone marrow biopsy in iliac crest

• Normochromic normocytic anaemia
• Leucocytosis
• Eosinophilia
• Raised ESR and C-reactive protein
• Bone marrow involvement in late disease
• Serum lactate dehydrogenase is raised

Histology

• Reed Sternberg cells: binucleate “mirror image” neoplastic giant cells. Not present in NHL

Histological patterns:

• A) Classical type:
  • Nodular sclerosis
  • Mixed cellularity
  • Lymphocytic predominance
  • Lymphocyte depletion
• B) Lymphocyte predominance

Ann Arbor classification for Hodgkin’s and NHL

Class I I/IE	– 1 node – 1 extra lymphatic site/organ
Class II II/IIE	– 2+ nodes on same side of diaphragm – Contiguous extra lymphatic organ/tissue
Class III III/IIIS/IIIE/IIIES	– Nodes on both sides of the diaphragm – Contiguous extra lymphatic organ/tissue – Extra lymphatic site – Spleen involvement
Class IV	– Multiple foci – 1+ extra lymphatic organ

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Diffuse large B-cell lymphoma

• Most common form of NHL

Clinical:

• Rapid enlarging mass nodal or extranodal
• Includes Waldeyer’s ring and oropharyngeal lymphoid tissues – tonsils and adenoids
• Liver and spleen can also be affected
• Extra nodal: GIT, Skin, Bone, Brain
• Aggressive but curable

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