Clinical Oncology Flashcards
Superior vena cava obstruction
Aetiology
• Malignancy (80%): NSCLC (50%), SCLC (25%), NHL (10%), others e.g. germ cell tumors, CA breast, thymoma
• Non-malignant causes: thrombosis 2o to central venous catheters, infection (e.g. TB, syphilitic aortitis), indwelling cardiac device / pacemaker wire, aortic aneurysm, post-RT
Clinical features
• Symptoms: SOB (MC, >50%), cough (50%), hoarseness of voice
• Signs
o Dilated superficial veins over anterior chest wall
o Distended neck veins (60%) +/- facial and arm veins
o Facial edema (MC, >80%), neck and upper extremities with cyanosis
o Pemberton’s sign (fig.)
• Complications
o Laryngeal edema (lethal) - stridor
o Cerebral edema (lethal) - headache / lightheadedness / confusion
Investigations
• CXR: increased width of paratracheal soft tissue density (bilateral mediastinal LN)
• Duplex USG (‘B’ USG + Doppler) +/- digital subtraction venography
• CT thorax with contrast
• Investigations for underlying malignancy: o CBC D/C, clotting, LRFT, blood film, CaPO4, TFT
o Tumour markers: epithelial markers (CEA), germ cell markers (AFP, HCG, LDH)
o Obtain tissue diagnosis before empirical treatment (do not withhold if life-saving)
- Solid cancer: FNAC, lymph node biopsy, biopsy (EBUS/ EUS/ CT-guided/ open),
pleural tap, …
- Lymphoma: excisional biopsy of LN +/- BM biopsy
• Rule out co-existing pericardial effusion / cardiac tamponade / secondary pulmonary embolism
Management (SAQ!!)
• Resuscitation (ABC): prop up head elevation + protect airway + O2
• Urgent consult oncology
• IV dexamethasone 4mg Q6h (do NOT withhold to wait for the biopsy)
o Immediate RT (first-line): response rate ≥ 80%
o Chemotherapy: if RT not possible (e.g. very large tumour) / chemosensitive tumour (e.g. SCLC, teratoma, lymphoma) + haemodynamically stable
- Concern: fluid load might exacerbate symptoms
o SVC stenting (if other options exhausted): post-op DAPT for 3months
- Total SVC occlusion and SVC thrombus are not absolute C/I
• CVC thrombosis: anticoagulation + remove offending catheters
• SVC thrombus: consider thrombolysis (mechanical/pharmacological) + anticoagulation for 3-6mo or longer (LMWH and apixaban/rivaroxaban preferred over warfarin)
Complications of RT to thorax
• Pulmonary fibrosis
• RT-induced vasculitis (pulmonary vessels)
• Secondary malignancies: CA thyroid, secondary leukaemia
Y
Differential diagnosis of SOB in oncology
• Pericardial effusion ± cardiac tamponade (decreased BP)
• Pulmonary embolism
• Atelectasis
Anterior mediastinal mass
• Thyroid, thymus, teratoma, terrible lymphoma
Malignant pericardial effusion & cardiac tamponade
Clinical features
• Most common symptom: SOB
o Clinical symptoms depend on rate of fluid accumulation
• Signs:
o Beck’s triad: hypotension, elevated JVP, muffled heart sounds
o Others: pulsus paradoxus > 10mmHg, Kussmaul sign (rare), LL edema
Investigations
• ECG: small voltage, electrical alternans
• CXR: globular heart, but clear lung fields
• Echocardiogram (gold standard): systolic RA collapse à diastolic RV collapse à left chambers collapse;
distended IVC
Management
• Immediate resuscitation: O2, gentle IV fluids (pre-load), avoid diuretics / vasodilators (do NOT treat as CHF)
• Echo-guided pericardiocentesis and pigtail
o Send fluid for biochemistry, C/ST, cytology
• Treat underlying malignancy (usually CA lung / breast)
• Pericardial window if recurrent
Malignant hypercalcaemia
Aetiology (in order of frequency)
• PTHrP (humoral hypercalcaemia of malignancy): SQCC, RCC, TCC
• Bony metastasis (osteolytic): breast, MM, lymphoma, RCC
• Calcitriol secretion: Hodgkin’s lymphoma
• Ectopic PTH secretion: lung, ovary, HCC
Clinical features
Dehydration due to
• n/v
• Delirium
• Hypercalcaemia-induced nephrogenic DI
Investigations
• Corrected calcium – severity:
o Mild: ≥ 2.6
o Moderate ≥ 3
o Severe ≥ 3.5 or presence of renal (AKI), neurological (confusion), cardiac arrhythmias
• RFT
• ECG: shortened QT interval, prolonged PR interval, bradyarrhythmia
Management [MED-REN] (SAQ!!)
• Monitor I/O, RFT, CaPO4, cardiac monitoring
• Withhold Ca & vit D supplement, thiazide diuretics
• Rehydration: IV NS 2-3L/day, adjust against urine output > 2L/day
o No role for Lasix in acute Mx of severe malignant hyperCa
• Bisphosphonates (after correcting dehydration: ensure CrCl > 30)
o Example: pamidronate IV 60-90mg in 500ml NS over 2-4h / zoledronic acid IV 4mg over 15min
o Onset 24-72h (do NOT repeat dose until Day 7)
o MOA: inhibit bone resorption by osteoclasts
o Renal adjustment:
§ Lower dose, slower infusion rate
§ Switch to calcitonin if CrCl < 30
• Salmon calcitonin IM/SC: if need acute ¯Ca
o Onset: 2-3h
Clinical oncology 45
o Risk of tachyphylaxis after 2-3 days – ICU monitoring
• Hydrocortisone: only for steroid-sensitive cancers e.g. lymphoma, myeloma
o MOA: inhibit vit D conversion to calcitriol
• Denosumab SC: if refractory / cannot use bisphosphonates due to CKD
• ?Haemodialysis with low Ca dialysate
• Consult oncology: treatment of underlying cancer
Cord compression in oncology
Aetiology
• Extradural: vertebral body metastasis (90%) - CA prostate, breast, lung > MM, NHL, RCC
• Intradural: meningioma, schwannoma
• Intramedullary: astrocytoma, ependymoma
Sites of compression
Thoracic (70%), lumbosacral (20%), cervical (10%)
Clinical features
• Back pain (70-95%)(radicular pain —> hemithorax, radiate from back to front, with dermatone): exacerbated by cough/ lying down /
straining, followed by
• Neurological signs – appear in the order of:
o Motor weakness: 70% could walk at first
o Sensory level: unreliable – the sensory level
corresponds with nerve roots within 2 levels above or 4 levels below the compressed cord
o Sphincter dysfunction (“neurogenic bladder”): AROU
- Spinal cord: detrusor-sphincter dyssynergia
- Sacral nerve (e.g. conus): detrusor areflexia
- Peripheral nerve (e.g. cauda): hypo/areflexic bladder
• Autonomic dysreflexia if lesion above T6 (fig.): vasodilation above lesion & vasoconstriction below lesion, bradycardia, hypertension, spastic bladder
Cord compression
Site: above L1
Onset: acute
Pain: LBP + radicular pain
Pattern: LMN at affected level; UMN below affected level
Motor: Spinal shock, then spastic paralysis (pyramidal pattern), hyperreflexia
Sensory: sensory level, symmetrical
Automatic: spastic sphincters (AROU, constipation)
Investigations
• Initial: Plain XR spine, bloods (CBC, LRFT, CaPO4), tumor markers (e.g. PSA, CEA)
• Diagnostic:
o Anatomical: MRI whole spine with contrast (1/3 has >1 level of compression) —> CT myelography (if MRI contraindicated)
o Cancer: staging workup (PET-CT, bone scan), tissue diagnosis if N/A
Management
• Diagnose & treat ASAP: functional status at the time of treatment is the most important prognostic factor
• IV dexamethasone 4mg Q6h: reduce oedema around the lesion
• Supportive care: pain control, bowel care, Foley catheterisation, compression stockings, ± prophylactic LMWH
• Definitive treatment: surgery (consult ortho) or RT (consult oncology), considering
o Disease factor:
- Radiosensitivity of tumor
—> Sensitive e.g. prostate, breast, SCLC, MM, NHL
—> Resistant e.g. melanoma, sarcoma, RCC
- Need for definitive tissue diagnosis
- Patient fitness of surgery
o Mechanical factor:
- No. of compression
- Spinal column stabilit
Neutropenic fever
Definition
• Fever: oral temperature ≥ 38.3°C or ≥38°C for ≥1h
• Neutropenia: ANC < 0.5 or ANC < 1 with projected decrease to 0.5 within 48h
• Mortality 11% (50% if septic shock)
Risk factors
• Obstructions (lymphatics, GI tract, urinary tract, biliary tract)
• Presence of FB (stents, catheters)
• Rate of fall, absolute level (<0.5) and duration (≥7 days) of neutropenia
o Note: Neutrophil count usually nadir ~D14 after chemo, except Taxane (D4-5) or post-BM transplant (D21)
• Number and dose of chemotherapy used
• Types of cancer: haematological cancer, BM transplant, advanced stage
• Patient factors: advanced age, poor performance status, organ dysfunction
Pathogens
Culture positive only in 30%
• GN > GP, polymicrobial
• Fungal: PCP, candidiasis, aspergillosis
• TB: extra-pulmonary
Investigations
• Bloods: CBC d/c, LRFT, CaPO4 lactate
• Septic work-up: blood (peripheral site, each central line), urine, sputum, others if localising S/S (e.g. stool, CSF)
• Imaging: CXR (consolidation may be absent due to inability to mount inflammatory response)
Management
• Admit all patients
• Risk stratification: Is the patient in septic shock?
o High risk (inpatient): any of
- Anticipated prolonged (≥ 7 days) / profound (ANC < 0.1) neutropenia
- Medical co-morbidities e.g. haemodynamically unstable, deranged LRFT, altered mental state
- MASCC score < 21
o Low risk (outpatient – seldom in HK)
• Immediate blood culture x 1 set, then
• Empirical IV broad-spectrum anti-pseudomonal antibiotics for a course of at least 7 days
o IV Tazocin 4.5g Q8h ± gentamicin (if haemodynamically unstable)
o Other options: ceftazidime (Fortum), cefepime 2g Q12h, meropenem 1g Q8h, imipenem 500mg Q6h
• Adjust antimicrobials:
o Persistent fever > 2-3 days: antifungals, antivirals, TB, rarer organisms (e.g. mould)
o Suspected catheter-related infections, skin & soft tissue infections, known MRSA carriers: MRSA coverage (vancomycin / linezolid)
o ILI during flu season: empirical Tamiflu
o Thrush/ dysphagia: candida
o Abdominal pain/ diarrhoea (neutropenic enterocolitis/ typhilitis): CT abdomen, bowel rest, antibiotics with C. diff coverage (metronidazole)
Prevention of recurrent neutropenic fever
• Chemotherapy dose reduction: preferred if
other toxicities present
• Prophylactic antibiotics: oral Augmentin /
fluoroquinolones
• G-CSF (Filgrastim): decrease duration of
neutropenia, but not improve survival —> daily injection, 72 hrs after chemotherapy —> cannot exclude neutropenia but reduce the period of time
If breast cancer adjuvant chemotherapy —> GCSF given and not reduce dose of cytotoxic chemotherapy (study showed)
Tumour lysis syndrome
Pathophysiology
• Massive breakdown of tumour cells triggered spontaneously or by
chemotherapy
• High risk malignancies: Burkitt’s lymphoma, acute leukaemia
(ALL, AML, CML in blast crisis), SCLC
Risk factors
• Tumor factor: high tumor burden (LDH), high proliferating index,
high sensitivity to chemotherapy
• Patient factor: old age, impaired RFT
Clinical features & investigations:
Cairo-Bishop criteria for TLS:
Laboratory TLS – at least 2 of following
occurring from Day -3 to Day +7 of
chemotherapy despite prophylaxis:
• K ≥ 6 (or ↑25% baseline)
• urate ≥ 0.5 (or ↑25% baseline)
• PO4 ≥ 1.45 (or ↑25% baseline)
• Ca ≤ 1.75 (or ↓25% baseline)
Clinical TLS = Lab TLS + any of:
• Renal impairment: Cr ≥ 1.5 x ULN
• Cardiac arrhythmia
• Seizure
• Sudden death
Prophylaxis
• Avoid nephrotoxic drugs (NSAID, IV contrast)
• Adequate hydration (3-4L/day) ± diuretics to maintain high urine output (150ml/h)
• Urate lowering drugs prior to chemotherapy:
o Allopurinol: check HLAB-5801, need renal adjustment
o Febuxostat: expensive, for HLAB-5801 or poor RFT (not require renal adjustment unless severe), C/I: IHD
o ± Rasburicase: if high risk
• Urine alkalinization: NaHCO3 to keep urine pH ≥7 – not used now (lecture)
Management
• IV hydration to maintain renal perfusion (BP > 95) & high urine output (>70mL/h)
• Rasburicase 0.2g/kg/day if urate/ Cr not improving after 48h
o Check G6PD level
o allopurinol / febuxostat NOT for treatment
• Correct electrolyte disturbances (hyperK, hyperPO4, hyperuricemia, hypoglycemia) and treat arrhythmia:
o Do not replace Ca unless symptomatic (risk of nephrocalcinosis)
o Haemodialysis / Haemofiltration if necessary
- monitor I/O
Hyperviscosity syndrome
Aetiology
• Polycythaemia vera (MC)
• Myeloma: Waldenstrom’s macroglobulinaemia (WM), MM
• Leukaemia: AML, CML
o Hyperleukocytosis: WBC > 100
o Leukostasis: symptomatic hyperleukocytosis —> organ damage, tissue hypoxia and early death
Clinical features
• Neurological: headache, altered mental state, blurred vision (retinal haemorrhage), ICH
• Haematological: DIC, TLS
• Cardiorespiratory: SOB
Management
• TLS prophylaxis: IV hydration + allopurinol
• Reduce hyperviscosity by
o PV: venesection
o Myeloma: plasmapheresis
o Leukaemia: cytoreduction therapy (e.g. hydroxyurea, cytarabine, dexamethasone)
- ± leukapheresis (prophylactic leukapheresis offers no advantage over intensive induction chemo)
• Transfusion:
o Red cells: avoid if WBC > 50 (to prevent hyperviscosity), slow transfusion if absolutely required (e.g. Hb < 5)
o Platelet: transfuse if < 20 to prevent major bleeding or ICH
Renal cell carcinoma
- 70% clear cell carcinoma
Risk factor:
- < 1 year from diagnosis to treatment
- Karnofsky PS < 80%
- low hemoglobulin
- high calcium
- high platelet
- high neutrophil
Ix:
- CT-guided biopsy
- molecular diagnosis —>
1. PDL1 score
2. VHL positive
3. PIK3CAm positive
Mx:
- pembrolizumab (immunotherapy) + sunitinib (anti-VEGF)
- nephrectomy only if minimal extrarenal disease
Chemotherapy-induced toxicity
- Malignancy-induced nausea and vomiting (CINV)
—> prophylactic ondansetron - Alopecia
- Mucositis
- Bone marrow suppression
- Infertility
- Secondary malignancy
Anti-emetic prophylaxis
- HEC (cause CINV >90% patient ): 5HT3-RA, NK1-RA, corticosteroids +/- Do-RA
- MEC (cause CINV >30-90% patient ) : 5HT3-RA + corticosteroids +/- NK1-RA
- LEC (cause CINV >10-30% patient ): 5HT3-RA or corticosteroids or Do-RA
Prophylaxis for alopecia:
- reversible
- Scalp cooling cap
BM suppression:
- wbc reduced
- go to emergency if fever
Side effects of anti cancer therapies
Conventional cytotoxic: myelosuppression, alopecia, mucositis, nausea, and vomiting
Target agents: depends on what the agent is targeting
- Anti-EGFR: skin and mucosal toxicity
- Anti-VEGFR: toxicities are often associated with vascular system: hypertension, proteinuria, thromboembolic events
- Anti-HER2: cardiotoxicity
- TKIs: skin and mucosal toxicities (rash, stomatitis, diarrhioea)
- monoclonal antibodies: less skin and mucosal toxicities
Lung cancer classification
- Non-small cell carcinoma
- Adenocarcinoma - young female, non-smoker, peripheral location, TTF-1
- Squamous cell carcinoma - strongest relation to smoking, central location, P40, P63
- Large cell carcinoma - peripheral location - Small cell carcinoma - Strong relation to smoking, tend to metastasise early, central location, synaptophysin/chromogranin
Symptoms of CA lung
• Constitutional symptoms: malaise, weight loss, cachexia, loss of appetite
• Endobronchial growth: cough, haemoptysis, SOB, wheeze/stridor
• Regional spread:
o Pleura: pleural effusion, pleuritic chest pain
o Pericardium: pericardial effusion ± cardiac tamponade
o RLN / esophagus: hoarseness of voice, dysphagia
o Pancoast’s syndrome: Horner’s syndrome, brachial plexopathy, shoulder pain, small hand muscle wasting
o SVCO: puffy face, dilated chest veins, Pemberton’s sign
o Lymphangitis carcinomatosis
o Phrenic n. palsy (elevated hemidiaphragm)
Metastasis of CA lung
o Supraclavicular / Cervical LN
o Liver: hepatomegaly, dLFT
o Adrenal: glucocorticoid insufficiency (hypoglycaemia, dehydration, weight loss, weakness, fatigue, hypotension, muscle cramps)
o Bone: pathological #, hyperCa, bone pain, back pain, cord compression
o Brain: unilateral limb weakness, seizures
Paraneoplastic syndrome of CA lung
o Endocrine:
• SCC: PTHrP (hypercalcemia) – squamous cells cannot produce cholesterol, but peptides
• SCLC: ACTH (Cushing’s syndrome), ADH (SIADH), TSH (thyrotoxicosis), IGF-1 (hypoglycemia) –
small cells are derived from endocrine cells
o Neurological (SCLC): Lambert-Eaton myasthenic syndrome (LEMS), subacute cerebellar degeneration (anti-Hu, anti-Yo), sensory neuropathy (anti-Hu), limbic encephalopathy (anti-Hu, anti-Yo)
o Skeletal: hypertrophic osteoarthropathy (symmetric polyarthritis & proliferative periostitis of long bones)
o Cutaneous: acanthosis nigricans, dermatomyositis, thrombosis (Trousseau syndrome), gynaecomastia (ectopic hCG)
o Hematologic: hypercoagulable state, DIC
Ix of CA lung
• Bloods: CBC, RFT (SIADH, ectopic ACTH), LFT (ALT, ALP), CaPO4
o CEA: raised in 1/3 of adenoCA, good for pre-op and post-op monitoring
• Mandatory imaging:
o CXR: initial screening
o CT thorax with contrast (cover from neck to adrenals): look for distant metastasis, assess resectability (e.g. invasion into pulmonary artery/veins, ribs)
o 18-FDG PET-CT: standardized uptake value (SUV) ≥ 2.5 is highly suspicious
Central lesion: EBUS + transbronchial needle aspiration
Peripheral lesion: Ct-guided biopsy (Transthoracic needle aspiration)
S/E: Pneumothorax, hemothorax, missed lesion, pleural seeding, air embolism
• Further staging if indicated: MRI brain, bone scan, triphasic CT abdomen (liver), echo (heart)
• Molecular genetics: require lung tissue or plasma / urine (refer below for details)
o Current standard: EGFR mutation, ALK translocation, ROS1 rearrangements, PD-L1 expression
Staging of CA lung
TNM staging
T1: <3cm
T2: main bronchus / visceral pleura / atelectesis extend to Hilary region, 3-7cm
T3: atelectesis of entire lung, separate tumour nodule in Ipsilateral lobe, >7cm
T4: RLN invasion, separate tumour nodule in Ipsilateral side but different lobe
N1: hilar/peribronchial/pulmonary
N2: Ipsilateral mediastinal / subcarinal
N3: Contralateral mediastinum / supracalvicle
M1a: local intrathoracic spread (pleural effusion/pericardial effusion/contralateral lung)
M1b: extrathoracic spread
M1a/M1b = stage 4
N3 = stage 3b
T4 = at least stage 3a
N2 = stage 3a
N1= stage 2
NSCLC treatment
Stage 1 / 2 : Surgery/SBRT +/- adjuvent chemo
Stage 3a: Surgery + neoadjuvent chemoRT +/- targeted therapy/immunotherapy
Stage 3b / 4:
- ChemoRT: cisplatin + etoposide + full-dose IMRT (2Gy x 30 days)
± Targeted therapy/immunotherapy (refer below)
- Solitary brain metastasis: surgery + RT
- Palliative RT for complications (e.g. SVCO, cord compression)
- Supportive Tx: pleurodesis (MPE), bronchoscopic stenting, analgesics
NSCLC treatment of chemotherapy, targeted therapy and immunotherapy
Chemotherapy (usually 4 cycle)
• AdenoCA: cisplatin + pemetrexed
• SCC: cisplatin + gemcitabine
Targeted therapies (usually 3 years)
1. EGFR
Actionable mutations in 40-55% Asians (esp. non-smoking F): Exon 19 deletions, exon 21 L858R mutations
• 1st TKI: gefitinib (Iressa)*, erlotinib
• 2nd TKI (more potent, but more toxic): afatinib, dacomitinib
• S/E: acneiform rash (Mx: topical steroids), diarrhea, lung fibrosis, hepatotoxicity
Resistance: check EGFR secondary mutation at exon 20 T790M and other mutations (e.g. MET activation)
• T790M +ve (50%): use 3rd generation TKI (osimertinib) [AURA3, FLAURA], amivantamab (EGFR + MET), lazertinib, osimertinib + savolitinib (MET)
o Osimertinib: irreversible binding to C797 (new site), and improved CNS penetration
• T790M -ve: use afatinib / cetuximab / chemotherapy
- ALK
Detected by break-apart FISH in ≥15% of cells / IHC
• 1st generation TKI: crizotinib [PROFILE1014 study] – out already!
• 2nd generation TKI (more specific, more potent, cover more resistance, more CNS penetration):
o Alectinib [ALEX], brigatinib, lorlatinib
• S/E: n/v/d - ROS1
- Crizotinib, ceritinib, entrectinib, lorlatinib - Antibody-drug conjugate (ADC) targeting HER3 expression: patritumab-deruxtecan
HER2: trastuzumab deruxtecan - Immunotherapy
Targetable driver mutation absent: check PD-L1 expression level
• PD-L1 ≥ 50%: pembrolizumab monotherapy [KEYNOTE-024/042], atezolizumab monotherapy
• PD-L1 1-49%: pembrolizumab + platinum-based double chemotherapy [KEYNOTE189], atezolizumab
+ bevacizumab + chemotherapy [IMPOWER 150], nivolumab + ipilimumab + chemotherapy
[Checkmate 9LA]
• PD-L1 <1%: immunotherapy not useful
• S/E: ILD (Mx: early steroids), autoimmune endocrinopathies (thyroiditis, adrenal insufficiency)
SCLC treatment
Limited stage
- within 1 radiation port/ only on 1 side of chest
• Resectable (cT1-2N0M0): Primary surgery (lobectomy + mediastinal LN) + adjuvant chemotherapy
• Unresectable: chemoRT ± PCI
Extensive stage
beyond 1 radiation port/
• Chemotherapy ± PCI
• Chemotherapy: cisplatin + etoposide
• Prophylactic cranial irradiation (PCI): occult brain metastasis is frequent in SCLC without neurological symptoms
Lung metastasis
• Types
o Haematological spread: cannon-ball lesions
- Causes: CRESP (choriocarcinoma, RCC, endometrial CA, sarcoma, prostate carcinoma)
o Lymphatic spread: lymphangitis carcinomatosis
• Surgical resection possible if:
o Complete resection possible: Controlled primary & single metastasis
o Long disease-free interval
o Brain Met:
- Whole-brain RT (C/I: risk of brain stem herniation)
- Consult NeuroSurgery
Brain metastasis
Most common primary sites
• Lung
• Breast
• RCC
• Melanoma
Management
• Investigations: MRI with contrast
• High-dose dexamethasone (for peritumoural vasogenic oedema)
• Single brain met: surgery + stereotactic radiosurgery (SRS)
• Multiple brain met/ inoperable: Whole-brain RT (C/I: risk of brain herniation)
- Consult neurosurgery
Bone metastasis
Common tumour metastasis to bone:
Melanoma, breast, lung, RCC, prostate, thyroid
Types of bony metastasis
• Osteosclerotic/ osteoblastic: SCLC, prostate
• Osteolytic: MM, thyroid, RCC, NSCLC
• Mixed (MC): breast, GI
4 complications of bony metastasis
• Bone pain
• Pathological fracture
• Malignant hypercalcaemia
• Neurological symptoms, e.g. cord compression
Diagnostic tools
• Bone scan: 99mTc based skeletal scintigraphy, detect increased osteoblastic
activity, reasonably sensitive and specific for bone metastases in CA breast /
lung / prostate, but less sensitive for tumors with little osteoblastic activity (e.g. MM)
• Skeletal survey: poor sensitivity
• PET-CT scan (usually FDG-based): high sensitivity and specificity
General management
• Supportive: analgesics, osteoclast inhibitors (bisphosphonates, denosumab)
• Observation: if short life expectancy, asymptomatic but wide metastasis
• EBRT (external beam RT)
• Surgery: if impending pathological fracture or cord compression
CA breast common metastasis
Lung, bone, liver, brain
Triple assessment of CA breast
- Clinical assessment
—> history + PE - Radiological assessment
—> Mammogram (craniocaudal, mediolateral), USG breast (performed together with mammogram, assess axillary LN), ductogram (if have nipple discharge), MRI breast (if previous -ve) - Pathological assessment
—> core needle biopsy (performed if BIRADS 4+), FNAC (preferred if low risk, like non-palpable mass or equivocal MMG or simple cyst), excisional biopsy (when core biopsy reveals suspicion lesion but not diagnostic)
Pre-malignant lesions of breast
• If found on core biopsy: excisional biopsy MUST be performed to rule out malignancy
• malignancies contained within basement membrane
- Ductal carcinoma in situ
- usually univocal
- mammogram: microcalcifications
- precursor to invasive ductal carcinoma of the same breast
- higher risk to become malignant
- Mx:
—> BCS +/- RT (first-line)
—> Masetomy + SLNB
—> Adjuvant: tamoxifen/AI if ER/PR+ - Lobular carcinoma in situ (LCIS)
- usually multifocal and multicentic
- Precursor and marker of bilateral
invasive carcinoma (ductal/ lobular)
- Mx:
—> Classical LCIS: close observation
Non-classical LCIS (pleomorphic): more
aggressive à surgical excision
Classification, clinical features and risk factors of CA breast
Epidemiology
• Incidence in female: 1st; mortality: 3rd
• Median age 55 (younger than global data)
• Lifetime risk 1: 16
Classification
• Invasive ductal carcinoma (76%): urther subclassified into tubular, mucinous (good prognosis), metaplastic, inflammatory
(poor prognosis)
• Invasive lobular carcinoma (8%): E-cadherin mutation
• Others: ductal/lobular (7%), colloid (mucinous) (2.4%), tubular (1.5%), medullary (1.2%), papillary (1%)
Clinical features
• Breast mass: hard, irregular, fixed, non-tender, mostly at upper outer quadrant
• Nipple discharge: increased risk if unilateral, single duct, bloody
• Special types:
o Paget’s disease of nipple: invasion of nipple-areolar complex; unilateral
nipple eczema + nipple discharge
• Ix: triple assessment, nipple biopsy x Paget cells
o Inflammatory breast cancer (T4d): invasion of local lymphatic ducts; painful swollen breast with cutaneous edema involving at least 1/3 of breast (peau d’orange)
• Metastasis: bone, liver, lung, brain
Risk factors
• Unopposed oestrogen: obesity, early menarche, late menopause,
nulliparous, no breastfeeding, COC/ HRT
• Lifestyle: smoking, alcohol
• FHx in 1st deg relative (if young)
• Benign breast diseases (refer to table)
o Epithelial hyperplasia: atypical ductal / lobular hyperplasia (5x risk), sclerosing adenosis
o Benign tumour: intraductal papilloma, Phyllodes tumour
• Genetics (10%, AD)
o BRCA1/2: 85% lifetime risk, risk of CA breast (triple negative), ovary (BRCA1), male breast, prostate, pancreas, melanoma (BRCA2); Mx: prophylactic bilateral mastectomy, BSO, PARP1 inhibitor
o TP53 germline mutation: Li Fraumeni syndrome
o PTEN mutation: Cowden syndrome/ multiple hamartoma syndrome
o Peutz-Jeghers syndrome
BRCA1 gene mutation patient has higher possibility of triple negative CA breast
Male CA breast
• Incidence: M:F = 1:100
• Average age at diagnosis: 65
• Risk factors
o BRCA2 carriers
o Increased oestrogen:
oestrogen therapy, etc
o Radiation
o Klinefelter’s syndrome (XXY)
• Management: mastectomy + SLNB/
ALND (if clinically +ve LN)
Ix of CA breast
Investigations
• Triple assessment, including bilateral mammogram (for synchronous contralateral breast cancer)
• Bloods: LFT (liver met), CaPO4 (bone met)
• Tumour markers: CA15.3, CEA
• Staging: CXR, PET-CT, bone scan
TNM staging of CA breast
• Clinical staging: tumour size, chest wall invasion, axillary LN metastasis
• Pathological staging: core biopsy + sentinel LN assessment (see separate section)
Tumour (T)
T0: no evidence of primary tumour
- T1: tumour ≤ 2cm
• T1a: tumor ≤ 0.5cm
• T1b: 0.5cm < tumor ≤ 1cm
• T1c: 1cm < tumor ≤ 2cm
- T2: 2cm < tumor ≤ 5cm
- T3: tumour > 5cm
- T4: tumour of any size, with direct extension to
• T4a: chest wall (except pectoralis major alone)
• T4b: skin (ulceration, edema i.e. Peau d’orange) but not meeting criteria of
inflammatory CA breast
• T4c: both chest wall & skin
• T4d: inflammatory cancer (at least 1/3 of breast)
Node (N)
N0: no regional LN involvement
N1: movable ipsilateral axillary nodes
N2: fixed ipsilateral axillary nodes / internal mammary nodes only
• N2a: Level I/II axillary LN
• N2b: internal mammary LN without axillary LN
N3:
• N3a: Level III axillary LN only
• N3b: internal mammary LN + axillary LN
• N3c: supraclavicular LN
Metastasis (M)
M0: no distant metastasis
M1: with distant metastasis
Summary for staging
• T1N0 —> Stage Ia
• TxN1 —> at least Stage II
• T4Nx —> Stage IIIb
• TxN3 —> Stage IIIc
Terms
• Early: T1/T2, N0/N1
• Locally advanced: T4 or above
Number of axillary LN metastasis is the strongest prognostic factor
• N0: 5-year survival ~70%
• The more lymph nodes, the worse 5-year survival
Surgical Mx of CA breast
Surgery
- BCS + post-op RT
- Mastectomy (+/- skin flap) + Sentinel LN biopsy (clinically -ve LN) / Axillary LN dissection (clinically +ve LN)
Medical Mx of CA breast
• Patient factors: age, menopausal status, medical co-morbidities (esp. cardiac & renal), family / social
• Tumour factors: size, axillary LN status, ER/PR/HER2 status, tumor histology & grading (Ki67), resection margin, operation done (BCS vs MRM), genomic studies
Adjuvant therapy
1. RT
- Chemo
- Indications: positive LN, high risk CA (e.g. T2+), HER2+ if >1cm, Triple negative if >0.5cm
- Regimen: Anthracyclines + Cyclophosphamide x 4 cycles —> Taxanes x 4 cycles
• Each cycle is 3 weeks
• Add cabecitabine if received neoadjuvant
- S/E:
• General: n/v, alopecia, mucositis (oral, diarrhoea), BM suppression, infertility, leukemia
• A: cardiotoxicity (Mx: dexrazoxane)
• C: haemorrhagic cystitis, premature ovarian failure
• T: neuropathy, myalgia/ arthralgia - Hormonal therapy
- Indications: All ER/PR+ cases unless C/I
- Pre-menopausal at diagnosis : 10 years, otherwise 5 years
• Seletive estrogen receptr modulator (SERM)(e.g. tamoxifen): S/E weight gain, flushing, risk of CA corpus, VTE
• Aromatase inhibitor (e.g. letrozole, anastrozole, exemestane): post-menopausal only, S/E fracture, more effective than tamoxifen
• GnRH analogue: pre-menopausal, Combine with tamoxifen / exemestane: more
effective but more S/E
• Radiation / Oophorectomy (rarely done)
**NOT given concurrently with chemo: stop breast tissue proliferation —> affect uptake of chemo - Targeted therapy
- HER2 +ve (strong) (20-25% of CA breast)
—> Trastuzumab (Herceptin): IV infusion Q1mo x 12; S/E cardiotoxicity (not used concurrently with anthracycline), hypersensitivity reaction
- High risk BRCA carriers —> PARP inhibitors e.g. olaparib
- High risk ER +ve —> CDK4/6 inhibitors e.g. abemaciclib
Neoadjumant therapy
- Chemo +/- Herceptin (if HER2 +ve)
- indications: locally advanced disease that is inoperable, large operable tumour that may be converted from mastectomy to BCS
- Mark the location of tumor with metal clip / radioactive seed in case it becomes undetectable after Tx
Advantages of neoadjuvant Tx:
• Tumor shrinkage —> Reduce extent of surgery
• Provide prognostic information
• Allow addition of different adjuvant regimens
Disadvantages of neoadjuvant Tx:
• No proven benefit c.f. standard therapy
• May upstage if no response to treatment
Palliative therapy
1. Hormonal
- ER/PR +ve
- May be used with targeted therapy (HER2)
2. Bone Tx:
- Bone met
- Bisphosphonates, e.g. pamidronic acid
RANKL inhibitor, e.g. denosumab
3. Chemo
- organ met, e.g. liver, lung
4. RT
- brain metastasis, cord compression, SVCO
- steroids can also be given for brain met
Prostate cancer (overview, risk factors, clinical features)
Overview
• Adenocarcinoma arising in the peripheral zone of the gland
• 3rd MC cancer among males in HK, lifetime risk: 1/26, annual incidence: ~2300
• 1/3 is locally advanced / metastatic upon presentation
Risk factors:
• Advanced age
• Smoking
• FHx (age & number of FDR)
• Genetics: TMPRSS2-ETS fusion gene (50%)
Clinical features
• Incidental findings: abnormal DRE, elevated PSA
o DRE (only 25% palpable): asymmetrically enlarged irregular prostate, hard nodule, midline sulcus lost
• Obstructive LUTS (late findings - cancer arises in peripheral zone)
• Haematuria / haemospermia, new-onset erectile dysfunction
• Metastasis: bone (vertebra: via Batson’s venous plexus), liver, adrenal
Ix of CA prostate
• PSA (arbitrary cutoff at < 4 ng/mL)
o Higher level = greater chance of CA prostate & higher risk of advanced disease
Controversy of PSA
• Organ-specific but not tumor-specific
• Function of PSA: liquefy semen coagulum
• Upper normal limit should be age-related
• Factors affecting PSA level
o ↑PSA: CA prostate, BPH, AROU, UTI, vigorous cycling, recent ejaculation <48h, DRE
o ↓PSA: castration, 5α reductase inhibitors, prostate RT
• PSA screening:
o Not for age < 40 or >77 (with life-expectancy < 10 years)
o May be considered for age 55-77
o May be considered for age 40-55 with family history
• Prostate health index (PHI) if PSA 4-10 + normal DRE
o Components: total PSA, free PSA, P2PSA (cancer-specific)
o >35: proceed to prostate biopsy
• Prostate biopsy:
o Indications:
- Elevated PSA > 10
- Abnormal DRE
- PHI > 35
- Early CA prostate on active surveillance
- Abnormal MRI prostate (PI-RADS 4-5)
o Approach: transrectal (with TRUS or MRI), transperineal (TPUS or MRI)
- “Fusion biopsy”: combine MRI image with USG
o Check MSU 1 week prior to procedure: treat UTI if +ve
o Take 12-18 random systematic biopsies
o Complications:
- Bleeding: haematuria, PR bleed, haemospermia
- Infection (<0.5% for transperineal, ~5% for transrectal:
antibiotic prophylaxis with FQ required)
- AROU (1-2%): pain and swelling of prostate
o Grading: Gleason score (1-5, sum of 2 most common histological patterns)
- Further classified into 5 groups for prognostication: higher group = more likely to have non-organ-confined disease
• Multiparametric MRI prostate
o 3 sequences: T2-weighted, DWI with ADC (apparent diffusion coefficient), DCE (dynamic contrast-enhanced)
o PI-RADS system: score from 1-5
o Roles: determine need of biopsy in controversial cases (PI-RADS 4, 5 indicated); local staging
Staging of prostate cancer
AJCC 8th edition staging system
• Combined use of TNM, serum PSA level & Gleason group
• T staging
o T1: clinically undetectable (normal DRE)
o T2: palpable on DRE but confined to prostate
o T3: spread beyond prostatic capsule (e.g. T3b = seminal vesicle invasion)
o T4: invade to pelvic side wall
Staging workup: depend on risk stratification
Localised:
1. Low risk
- PSA < 10ng/ml
- GS < 7
- T1-2a
2. Intermediate risk
- PSA 10-20ng/ml
- GS = 7
- T2b
3. High risk
- PSA > 20ng/ml
- GS > 7
- T2c
Locally advanced
- any PSA
- any GS
- T3-4 or N+
• Low risk: Multiparametric MRI prostate
• High risk (e.g. PSA > 20, GS ≥ 8): PET-CT with PSMA (prostate-specific membrane antigen), c.f. FDG
o Superior to CT abdomen & pelvis + CXR + bone scan (Technetium-99 bone scintigraphy) – HA practice
Mx of local prostate cancer
Patient factor: age, co-morbidities
Disease factors: PSA, DRE findings, Gleason score
- Active surveillance
- Regular FU with serial DRE, PSA & biopsy for
Gleason score —> Offer RP/ RT only if worsen —> Avoid early Tx-related complications
- preferred in low risk localised disease
- limitations: disease progression; risk associated with repeated biopsy - Radical prostatectomy
- Robotic-assisted resection of prostate gland +
seminal vesicles + ampulla of vas deferens
± pelvic LN dissection in obturator & iliac
regions (only for staging in high risk; no
benefit in overall survival); Anastomosis of bladder neck & urethral stump
- preferred in young < 75yr, high risk disease
- early limitations: bleeding, UTI,
rectal injury (1%), ureteric injury
- late limitations: stress urinary incontinence (10%), erectile dysfunction (50%), anastomotic stricture (urethra, bladder neck), residual tumor / recurrence - Radiotherapy (EBRT / brachytherapy)
- Avoid risk of GA and surgery but equivalent
oncological control
- preferred in older
- limitations: ↓ Stress UI, similar ED c.f. RP
↑Irritative symptoms (FUN), radiation proctitis, radiation cystitis
Palliative approach for prostate cancer
Watchful waiting
- for life expectancy < 10yr
Mx of advanced / metastatic prostate cancer
Choice of treatment:
• Traditional approach: ADT monotherapy first —> add others if CRPC
• New approach: upfront chemohormonal therapy to destroy potential CRPC clones
- Androgen deprivation therapy (ADT)
• Surgical castration: bilateral simple orchidectomy (access via scrotal incision)
• Medical castration: traditionally use estrogens
- LHRH agonist (e.g. goserelin) + short-term
antiandrogen cover (e.g. flutamide x 4/52)
—> MoA: Downregulate gonadal axis (constant dose to mask normal LHRH pulsatility)
—> Dosing: Q3-6m (more convenient)
—> Pros: cheaper
- LHRH antagonist (e.g. degarelix)
—> Dosing: Q1m
—> Pros: faster onset, less CV risk
• S/E: osteoporosis, metabolic syndrome, thromboembolism, erectile dysfunction
- cord compression patient may preferred antagonist, to prevent the original flare up - Chemotherapy
- Add if patient young & fit with good RFT; improve survival if high-volume metastases
• Docetaxel
• Cabazitaxel - Androgen receptor targeted agents (ARTA)
• Abiraterone: CYP17 inhibitor, need maintenance steroids to prevent adrenal crisis
• Enzalutamide: potent multi-targeted AR antagonist
• Apalutamide - Others:
• Sipuleucel T: immunotherapy
• Radium 223: with bone-seeking element
• Lutetium-177 (177Lu)-PSMA
Castration-refractory prostate cancer (CRPC)
• Mechanisms:
o Adrenal production of minor androgens
o Tumor upregulation of androgen receptors
o Tumor cells produce ectopic androgens
Renal cell carcinoma (overview, pathology, risk factors, clinical features)
Overview
• Most common renal neoplasm (only 20% renal masses are benign: e.g. oncocytoma, angiomyolipoma)
• Prevalence of kidney cancers: RCC (MC)»_space; TCC renal pelvis > nephroblastoma (Wilm’s tumor)
Pathology
• Clear cell carcinoma (85%) – usually found in proximal tubule
• Others: papillary (10%), chromophobe, collecting duct (poor prognosis)
Risk factors
• Smoking, HT, obesity
• Occupation (petroleum)
• Genetics: von-Hippel-Lindau (VHL - AD, bilateral RCC), tuberous sclerosis, PKD
• Acquired cystic diseases (long-term HD/PD)
• Renal transplant on immunosuppressants
Clinical features: often asymptomatic until advanced disease
• Incidental finding on imaging (50-60%)
• Classical triad (10-20%): haematuria + flank pain + palpable renal mass
• Regional involvement: uniquely invade into renal vein, IVC, RA
o Left secondary varicocele: invasion to left renal vein
o LL edema, ascites, pulmonary embolism
• Metastasis: retroperitoneal LN, lung, bone, brain
• Paraneoplastic syndrome (common, 6-10%)
o Anemia (advanced disease), polycythemia, erythrocytosis
o Hypercalcemia (PTHrP)
o HT (ectopic renin)
o Cushing’s syndrome (ectopic ACTH)
moon face, hyperpigmentation, striae, thinning of skin, easy bruising, slow healing, infection, acne
o Hypoglycemia
o Gynaecomastia/amenorrhea/libido loss/baldness (ectopic gonadotrophin)
F: hirsuitism, irregular menses
M: ↓ libido/ fertility, erectile dysfunction
o hypercalcemia
o Pyrexia of unknown origin
o Stauffer’s syndrome: non-metastatic hepatic dysfunction; impaired LFT (ALP) in the
presence of a RCC (cholestasis)
o Acquired dysfibrinogenemia
Ix of RCC
• Diagnostic: CT abdomen with contrast —> nephrectomy for pathology
o Classical appearance: renal parenchymal mass with thickened irregular walls and contrast enhancement
o Role of USG: determine cystic vs solid (e.g. fat-filled – likely AML)
o Renal mass biopsy is usually NOT indicated: risk of bleeding, tumor seedling, false negative results (20%)
• Suspected lymphoma
• Metastatic RCC in poor surgical candidate (guide Tx)
• Suspected renal abscess
• Strongly enhancing extrarenal primary lesion (e.g. lung, liver,
colon, melanoma)
• Staging: CT T+A+P with contrast / PET-CT scan
• Prognostic: Fuhrman’s grading (nuclear size)
Ix:
- CT-guided biopsy
- molecular diagnosis —>
1. PDL1 score
2. VHL positive
3. PIK3CAm positive
Staging and Mx of RCC
TNM staging
• T1: ≤ 7cm (T1a: ≤4cm, T1b: 4-7cm), within kidney
• T2: > 7cm (T2a: 7-10cm, T2b: >10cm), within kidney
• T3: extend into perinephric tissues or major veins including IVC
• T4: extend beyond Gerota’s fascia (fibrous tissue that encapsulates kidney and adrenal gland) and/or into ipsilateral adrenal gland
Mx:
- pembrolizumab (immunotherapy) + sunitinib (anti-VEGF)
- nephrectomy only if minimal extrarenal disease
• Targeted therapy
o Sunitinib/ Softeinib
- Only for clear cell carcinoma
o Bevacizumab
- Anti-VEGF monoclonal antibody
- (also used in metastatic CRC)
o Temsirolimus/ Everolimus
- mTOR inhibitor
• Immunotherapy
o Interleukin-2
- S/E: fever, malaise, vomiting, diarrhoea
o Interferon alpha
o Lymphokine activated killer cells
• Radiotherapy for bone metastasis
Prognosis
• Early-stage kidney cancer: 5-year survival rates in excess of 90%
• ~10% of in distant metastases (poor prognosis)
CA esophagus (epidemiology, classifications, clinical features)
Epidemiology
• Common in male of 60-70, M:F = 3:1
• SCC most common in HK (90%) c.f. Western countries
• Prognosis poor: > 50% metastasis at presentation, 5-year survival is just 5-10%
Classifications:
1. Squamous cell carcinoma (Asia)
- Site: mostly in upper 2/3
- Risk factors:
Lifestyle: smoking, alcohol, hot drink,
nitrosamine, betel nut, corrosive / caustic injury
Oesophageal disorders: achalasia, Plummer-
Vinson syndrome^, long-standing esophagitis
Genetics: tylosis ( AD genetic disorder characterised by hyperkeratosis of palms & soles + oral leukoplakia)
- Mx: sensitive to chemoRT
- Adenocarcinoma (Caucasian)
- Sites: mostly in lower 1/3
- Risk factors: GERD, Barrett esophagus
- Mx: surgery, less sensitive to chemoRT
Tumour spread: Direct extension (e.g. tracheo-esophageal fistula), Vascular and lymphatics
Clinical features
• Painless progressive dysphagia (MC): ≥75% stenosis
• Odynophagia: usually due to extra-esophageal involvement
• UGIB: haematemesis, coffee ground vomiting, tarry stool, anemic symptoms
• Regurgitation / choking / aspiration pneumonia: due to esophageal obstruction
• Signs suggestive of locally advanced disease:
o Stridor / hoarseness of voice: vocal cord paralysis (usually left RLN palsy)
o Horner’s syndrome
o Respiratory symptoms: tracheo-esophageal fistula
o Hypercalcaemia: HHM - PTHrP (10%)
o Distant metastasis: Virchow’s node, liver (hepatomegaly + ascites), lung (hemoptysis, PE), bone
Ix of CA esophagus
• Diagnosis: OGD + biopsy: confirmatory histological diagnosis and pre-op assessment
• Staging work-up: EUS + PET-CT (neck + thorax + abdomen)
o Endoscopic ultrasound (EUS): best for T & N staging —> determine need of neoadjuvant chemoRT
• T: Assess depth of wall invasion: important to distinguish T1a vs T1b (need open surgery)
• N: EUS-guided FNAC of suspicious LN (hypoechoic, >1cm, spherical, homogenous)
• Can also implant metallic markers for delineation of RT
o CT whole body with contrast: for locoregional involvement (T3/4) and distant metastasis (M)
o PET-CT: similar sensitivity as CT for distant metastasis (M)
• Can also assess the metabolic activity after neoadjuvant chemoRT / detect recurrence
• May pick up additional signals (e.g. reactive hilar LN due to smoking)
o ± USG neck
o ± Diagnostic laparoscopy: recommended for OGJ tumors (adenoCA) for hepatic / peritoneal seeding
o ± Bronchoscopy: for cervical / upper thoracic tumors to detect tracheal invasion à may require stenting
before RT to prevent iatrogenic tracheo-esophageal fistula
• Others:
o CBC, LRFT, clotting
o Lung function (CXR, ABG, lung function test) for pre-op assessment
o Laryngoscopy: baseline vocal cord status
Mx of CA esophagus
• Tumor factor (staging)
• Patient factor: age, smoker, comorbidities, lung function (FEV1 > 1.5L), exercise tolerance (> 2 flight of stairs)
• Organ factor: method of reconstructing esophagus
Stage 0:
- Tis, N0, M0
Stage 1:
- T1, N0, M0
—> Tis/T1a (confined to mucosa): Endoscopic mucosal resection (EMR) / Endoscopic Submucosal dissection (ESD)
—> T1b (invades submucosa): esophagectomy
Stage 2:
- T2-3, N0, M0
- T1-2, N1, M0
Stage 3:
- T3, any N, M0
—> Operable SCC: neoadjuvant chemoRT + esophagectomy
—> Inoperable SCC: upfront chemoRT +/- esophagectomy (if downstaged)
—> Operable ADC: esophagectomy
—> Inoperable ADC: chemoRT
Stage 4:
- any T, any N, M1
—> Esophageal balloon dilation +/- stenting
—> Palliative chemoRT
- Esophagectomy
- Two-staged
- Three-staged - preferred for SCC - Neoadjuvant therapy
• Indication: locally advanced SCC – T2N1, T3N0, T3N1
• Regimen: 5-fluorouracil + cisplatin + 40 Gy RT
o 6-8 weeks for 2 courses —> wait 4 weeks and repeat PET-CT + OGD —> wait 4 weeks for surgery
• S/E: RT-induced fibrosis, worsened dysphagia - Primary ChemoRT
• Indication: inoperable SCC, not fit (e.g. poor lung function)
• Regimen: cisplatin + 5-fluorouracil + >50 Gy RT
Palliative treatments
• Endoscopic stenting:
• Endoscopic local ablation
• Nutritional support: NG tube / PEG tube / open gastrostomy / jejunostomy
• External radiotherapy / brachytherapy (intraluminal RT)
CA stomach (epidemiology, risk factors, classification, clinical features)
Epidemiology
• Incidence: ↓ trend (6th incidence, 4th mortality), but ↑ in Asia (Japan: diet-related)
• Cell type: adenocarcinoma (90%) > lymphoma (5%) > GIST, metastasis
• Site: distal stomach (antrum / pylorus) > cardia (↑ trend) > OGJ
Risk factors:
• Compensatory epithelial cell proliferation:
- H. pylori
- Chronic gastric reflux (e.g. Barrett’s esophagus): proximal CA
- Hx of gastric resection: bile reflux (e.g. Billroth II)
- Chronic atrophic gastritis: a/w pernicious anemia and Menetrier’s disease
• Environmental factors: smoking, smoked / pickled food, nitrosamines, alcohol
• Host factors: hereditary diffuse gastric carcinoma (HDGC: E-cadherin mutation), HNPCC, FAP, P-J syndrome
Classifications: Histological (Lauren classification)
- Intestinal type (well-differentiated, better Px)
Risk factors as above except FHx and HDGC
HER2+ve in 15%
Hematogenonus spread
Elderly male, distal stomach
- Diffuse type (undifferentiated, poorer Px)
Risk factors: HDGC
HER2-ve
Transmural and lymphatic spread
Young female, proximal stomach
Clinical features:
• Local: dyspepsia, early satiety, bloating, n/v, constitutional symptoms
• Complications: obstruction (dysphagia if proximal, GOO if distal), UGIB, perforation
• 4 routes of metastasis:
o Local spread: pancreas, transverse colon, liver, duodenum
o Lymphatic spread: peri-gastric / para-aortic
nodes, Virchow’s node, Sister Mary Joseph
nodule (periumbilical node), Irish node (left
axillary node)
o Haematogenous spread via portal venous
circulation: liver (hepatosplenomegaly,
jaundice) —> lung, bone and brain
o Transcoelomic spread: ascites, ovaries
(Krukenberg’s tumors), pouch of Douglas
(Blumer’s shelf)
• Paraneoplastic for GI adenoCA (e.g. gastric, pancreatic):
o Trousseau’s sign of malignancy (migratory
thrombophlebitis)
o Leser-Trelat sign: seborrheic keratosis
o Acanthosis nigricans
Ix of CA stomach
• Diagnostic: OGD + biopsy
o Obtain tissue diagnosis and evaluate extent of primary tumor
o Alternative: barium swallow (limited diagnostic value except for linitis plastica)
• Staging (TNM): most important prognostic factor is depth of tumor invasion
o CT abdomen + pelvis +/- thorax with contrast (thorax if proximal tumor e.g. cardia)
• Mandatory for M staging but not accurate for T & N
• Alternative: PET-CT – not too sensitive for CA stomach
o Endoscopic ultrasound (EUS): NOT mandatory for CA stomach (upfront surgery is advocated)
• More sensitive in T staging (e.g. differentiating T4a vs T4b) & N staging (e.g. perigastric LN)
• More operator-dependent and more invasive c.f. CT
o Staging laparoscopy + peritoneal lavage (routine)
• More accurate for peritoneal and liver metastasis c.f. CT
• Direct visualization +/- biopsy of suspicious lesions for frozen section
• Peritoneal washing for cytology to detect microscopic peritoneal metastasis
o CXR
• Tumor markers: CEA, CA125, CA19-9 – for monitoring recurrence and response to chemotherapy
• Pre-op bloods: CBC, LRFT, clotting
Mx of CA stomach
- Endoscopic treatment
- Endoscopic mucosal resection
- Endoscopic submucosal dissection - Gastrectomy with 15 lymph nodes resection
Non-surgical:
• Neoadjuvant chemotherapy: downstage the tumor to improve resectability rate
o HK: Upfront surgery is preferred – only consider if T3+ (not yet invade adjacent structures) / N+ (at least 1-2 lymph nodes)
o Regimen: FLOT (fluorouracil + leucovorin (folinic acid) + oxaliplatin + docetaxel) / Xelox if less fit
• Adjuvant chemotherapy: eradicate micro-metastasis
o Consider if T3+ / N+
o Regimen: 5-fluorouracil (or: capecitabine) +/-
oxaliplatin (i.e. Xelox) or TS-1
Palliative care
• Tumors considered unresectable if:
o Distal metastasis (e.g. multiple liver metastasis, peritoneal nodules, pelvic deposits, Virchow’s nodes)
o Extensive nodal involvement (D3)
o Invasion of major vessel, e.g. aorta, hepatic artery, coeliac axis, proximal splenic artery (not distal)
• Distal splenic a.: borderline resectable with LUQ exenteration
• Principles: relieve pain, nutrition, bleeding, obstruction, perforation
• Supportive treatments: transfusion, PPI, Fe supplement
• Endoscopic treatments
o Ethanol injection, adrenaline, clipping: for bleeding
o Metallic stenting: bypass obstructing tumor, but risk of re-stenosis by tumour ingrowth
• Palliative surgery
o Palliative resection: relieve bleeding / obstruction
o Palliative bypass (gastrojejunostomy / gastroenterostomy): more durable than stenting, but possible
impaired gastric emptying / bile reflux
• Palliative chemo +/- HER-2 inhibitor (if HER2 +ve) +/- ramucirumab (VEGFR2 antagonist)
• External beam radiotherapy (EBRT) for painful bone metastases
Ix for GIST
• OGD: mass with smooth margins and normal overlying mucosa (endoscopic Bx typically cannot establish Dx)
• Endoscopic ultrasound + fine needle aspiration (FNA)
o EUS: hypoechoic, homogenous lesions arising from 2nd-4th layer of GI wall
o Combined cytologic (histology: spindle cells) and IHC (CD117 + c-KIT mutation)
o Not mandatory – indicated if:
• Consider use of imatinib for unresectable / metastatic disease
• Consider neoadjuvant imatinib for large GIST
• GIST 1-2cm: obtain mitotic index risk stratification
• Percutaneous biopsy is NOT preferred: risk of tumour capsule rupture with peritoneal spread
• Staging: CT with contrast (MRI if at rectum or liver)
Mx of GIST
• Surgical resection: negative margins are adequate
o Indications: all GIST ≥ 2cm
o Approach: segmental resection (regional lymphadenectomy not required - rarely metastasized to LN)
• Explore abdomen during laparotomy to exclude liver / peritoneal metastases
• Avoid perforating capsule: chemo may be needed
• Tyrosine kinase inhibitor (first line: imatinib à acquired resistance: sunitinib)
o Adjuvant: in all high-risk cases e.g. perforated capsule
o Neoadjuvant: 3-6 month therapy for locally advanced/ metastatic (liver or peritoneal mets) potentially
resectable tumours (↓size & vascularity of tumors —> ↑organ preservation)
o Palliative: first-line treatment for metastatic GIST
Malignant potential of GIST depends
on AFIP prognostic model:
• Location (SB most likely
malignant)
• Size
• Mitotic index
• Tumor rupture
GIST
Metastasis: liver, peritoneum
Clinical features: incidental finding on OGD/CT
- GI bleed
- Abdominal pain
- Abdominal mass
Colorectal cancer (Risk factors, clinical features)
Risk factors
• Non-modifiable: age > 50, gender (male)
• Central obesity, sedentary lifestyle, diet (increased fat & red meat, reduced fibre), smoking
• GI: IBD (UC > CD), polyps
• Endocrine: DM, acromegaly (IGF-1 as growth factors for colonic mucosal cells)
• Family history: 25% have FHx; 10% have familial syndrome (FAP, Lynch syndrome)
• Protected factors: prolonged aspirin/ NSAID use
Clinical features
• Most commonly asymptomatic à detected by screening
• Different presentations between right-sided and left-sided lesions
Right-sided (Proximal): present later
- Tend to bleed (larger calibre, polypoid lesion)
- Iron deficiency anemia, dull vague abdominal pain, right-sided abdominal mass
- Not common to have change in bowel habits (stool is more liquid and colon more space on right side)
Left-sided (Distal): present earlier
- Tend to obstruct (smaller calibre, annular lesion)
- Change in bowel habits (tenesmus, reduced stool calibre, mucoid stool)
- Hematochezia, intestinal obstruction
• Metastasis:
o Direct spread: radial (implicated in resectability in rectal cancer)
o Lymphatic spread: Virchow’s node (Troisier’s sign)
o Haematogenous spread: liver (MC), lung (distal rectal tumour —> IVC —> lung)
o Transcoelomic spread: ovary (Krukenberg tumour), pouch of Douglas
Ix of CRC
• Bloods: CBC D/C (anemia), Fe profile, LFT (liver met), RFT
• Serum carcinoembryonic antigen (CEA): epithelial marker
o Cut-off: <4.7
o Low diagnostic ability: low sensitivity + low specificity for CRC
- Elevated in ~50% of CRC only: may be first-pass metabolized by liver
- False positive: pregnancy, smoking, TB, IBD, other carcinomas (e.g. GI tract, pancreas, breast)
o Post-op: take 4-6 weeks to return to normal
o Roles: prognostication, treatment monitoring and detection of recurrence (even if pre-op normal: can pick up non-portovenous distant metastases e.g. lung)
• Diagnostic: colonoscopy with biopsy (gold standard)
o Confirm diagnosis with histological evidence
o Exclude synchronous cancers (3-5%) and synchronous polyps (30-50%)
o Pre-op localization (esp. if tumor is very small): tattooing (inject ink to stain tumor)
• CT colonoscopy: when caecum cannot be reached by CLN
o Pros: similar diagnostic accuracy for tumors >1cm, extraluminal info, lower risk of perforation
o Cons: high radiation dose, not therapeutic (still need CLN to take biopsy)
• Double-contrast barium enema (DCBE): barium + air
o Superseded by CT colonography: risk of barium peritonitis
o Classical findings: “apple core” lesion – near-circumferential involvement of bowel walls
• Biomarker: for metastatic disease only
o KRAS & NRAS (signalling downstream of EGFR): mutated in 45% —> no response to anti-EGFR
o MMR: MMR-deficient/ MSI (microsatellite instability) —> PD-1 pathway inhibitors
Staging of CRC
Staging:
• Objectives
o Determine resectability
o Select patients for neoadjuvant therapy / local excision
o Most important prognostic factor
• Colon cancer:
o CT thorax + abdomen + pelvis with contrast: Most sensitive for T-staging, can also give N and M staging
o Alternative: PET-CT with contrast: better for detecting distant metastasis, also used for follow-up (localizing site of recurrence if ↑CEA)
o Other adjuncts: Bone scan, CXR and liver USG, liver MRI with contrast
• Rectal cancer:
o MRI pelvis: important for accurate T-staging for planning of neoadjuvant chemoRT
—> Assess extra-mucosal tumor invasion (EMTI): MRI is superior to CT in delineating mesorectal fat
—> Determine circumferential resection margin (CRM)
o Alternative: Endorectal ultrasound (EUS): only good for T staging, but operator-dependent and might not admit endoscope for obstructive tumors
• TNM staging:
o I: T1/2 N0
o II: T3/4 N0
o III: N1/N2
o IV: M1
Management overview
• Stage I: surgery + analysis of ≥12 LN
• Stage II: surgery +/- adjuvant chemo
(consider in high-risk stage II)
• Stage III: surgery + adjuvant chemo
(FOLFOX) +/- adjuvant RT (rectal
only) +/- neoadjuvant chemoRT (in
high risk rectal only*)
• Stage IV: chemo +/- surgery for
isolated liver metastasis
Mx of CRC
- Surgery
- right lesions: right-hemicolectomy
- left lesion: extended right, left hemi, sigmoidectomy, emergency: Hartmann’s operation - Adjuvant chemotherapy
o Options
• FOLFOX for 6 months: folinic acid + 5-fluorouracil + oxaliplatin
• Xelox for 3 months if lower risk (T1-3, N1):
o Indications: Stage 3 (N1+), high risk stage 2 (T4 tumor, lymphovascular invasion, poor histology)
Mx of rectal cancer
- Surgery
- local excision for T1N0 disease
- sphincter-preserving surgeries:
—> Indicated if: T2-4 + adequate pre-op sphincter function + adequate distal margins
—> Anterior resection / lower anterior resection + total mesorectal excision
- abdominal perineal resection: Indicated if ANY one of: poor pre-op sphincter function / failure to achieve negative distal margin / locally advanced or recurrent low-lying CA rectum - Neoadjuvant therapy
o 3 main indications
• Resectable but locally advanced disease: sterilize tumour bed, ↓ intra-op tumor spillage & ↓ local recurrence rate
• T3/T4 disease
• Nodal disease
• Threatened CRM (circumferential resection margin) (<2mm)
• Borderline resectable disease: downstage the tumor and ↑ resectability rate
• Low-lying tumor: downsize the tumor and ↑ sphincter preservation rate
Regimen:
5-FU based chemotherapy x 2 cycles
+ concurrent RT (50.4 Gy = 1.8 Gy
daily x 28 fractions)
—> Wait 8-10 weeks before surgery
—> 4 cycles of chemo as adjuvant
Disadvantages:
Max dose of RT for lifetime
Delay surgery
Remission after neoadjuvant chemoRT
• Clinical complete remission (CCR) ~20%: consider “watch and wait” for 3 years with MRI Q3m, flexible sigmoidoscopy Q3m, PET-CT / CT Q6m
• Pathological complete remission (PCR) ~15%: surgical specimen found to be tumor-free, may not require adjuvant chemo (case-by-case)
• Adjuvant chemotherapy: First-line is 5-FU based, other options include oxaliplatin, irinotecan, cetuximab
• Adjuvant radiotherapy: not common
Palliative Mx of CRC
Palliative management for colorectal cancer
• Palliative surgery
o Endoluminal stenting: for palliating obstruction / bridging therapy before elective surgery (avoid EOT)
• Not for distal rectal tumour (can cause tenesmus and pain)
o Palliative colostomy +/- tumor resection (palliative intent)
• Palliative radiotherapy: control local symptoms (e.g. pain, discharge, bleeding, incontinence) and bone pain
• Palliative chemotherapy for disseminated disease: oral capecitabine
Management principles of metastases
• Liver / Lung metastases: resect if possible (solitary metastasis, no other mets, controlled primary tumor)
o Refer to HBP for management of colorectal liver mets
Follow-up for CRC patients
Follow-up for colorectal cancer
• Aim: detect recurrence (40%) and metachronous tumors (new primary CA diagnosed 6mo afterwards)
• Follow-up interval:
o First 2 years: Q3m
o 3rd year: Q6m
o 4-5th year: yearly
o >5 years: considered to be in remission
• Investigations in each follow-up:
o CEA, rigid sigmoidoscopy, LFT
o CT TAP/ PET-CT Q1y
o Colonoscopy:
• Pre-op not full scope: within 6m of surgery (risk of synchronous tumour in CA rectum = 3-5%)
• Pre-op full scope: 1 year post-op, then at 3 years, 5 years, then Q5y
HCC Risk factors and clinical features
Overview
• MC primary liver cancer (80%) (intrahepatic cholangiocarcinoma 15%), 5th MC
cancer in HK, 3rd in mortality
cancer
• Patterns: solitary / multifocal / diffuse
• Histological subtype:
o Non-fibrolamellar: a/w HBV and cirrhosis
liver cirrhosis
o Fibrolamellar (FLC): a/w younger patients, not a/w HBV or cirrhosis;
Risk factors
• Any cause of cirrhosis: infection (HBV, HCV), metabolic (ALD, NAFLD, Wilson’s disease), immune (PBC, PSC)
o HBV infection carcinogenic in terms of cirrhosis + DNA damage induced by HBV DNA integration
• Smoking, alcohol (free radical production)
• Obesity, DM (liver involved in glucose metabolism)
• Chemical carcinogens, e.g. aflatoxin
Clinical features:
late presentation + absence of pathognomonic symptoms —> difficult diagnosis
• Local:
o RUQ pain +/- right shoulder pain (2o to Glisson’s capsule distension)
o Hepatomegaly
o Obstructive jaundice (invasion to biliary tree or compression of intrahepatic duct) – NOT common
o Constitutional symptoms: LOA, LOW
hepatorenal syndrome
• Paraneoplastic syndromes:
o Erythrocytosis (EPO secretion from tumour)
o Hypoglycaemia (high metabolic demands of tumour + IGF-2 secretion)
o Deranged LFT in cirrhotic patients: e.g. encephalopathy, coagulopathy, portal HT (ascites, edema, UGIB),
o Hypercholesterolemia (autonomous cholesterol synthesis)
o Hypercalcaemia (PTHrP secretion)
o Watery diarrhoea (VIP secretion)
o Cutaneous features: dermatomyositis, Leser-Trelat sign (explosive onset of multiple seborrheic keratoses)
• Ruptured HCC
• Metastasis: intrahepatic (via portal vein / hepatic vein), lung (MC), bone, brain, peritoneum, adrenals
Ix of HCC
• Bloods: CBC, clotting, LRFT, albumin
• Viral serology for underlying chronic hepatitis
o HBV: HBV DNA, HBsAg, HBeAg (↑risk of HCC)
o HCV: anti-HCV IgG, HCV RNA
• AFP: normal <6 (raised in 80%), level correlates with prognosis (risk of recurrence)
o False positive AFP: pregnancy, germ cell tumor / teratoma, liver cirrhosis, hepatitis,
• USG HBP: screening for HCC (any nodule that is not clearly hemangioma = HCC until proven otherwise)
o Mass < 1cm: repeat USG Q6m (rationale: tumor doubling time ~4 months)
o Mass ≥ 1cm: triphasic CT
• Triphasic CT scan (gold standard)
- Arterial phase: hyper dense
- Portovenous phase: washout
- Delayed phase: hypodense
• MRI liver with Primovist contrast (hepatospecific contrast) - if CT C/I or equivocal findings
o Typical features: high intensity on T2-weighted and low intensity on T1-weighted images
• Contrast-enhanced USG
• CT hepatic angiography: inject intraarterial contrast (e.g. SMA, hepatic a.)
• Post-lipiodol CT scan: HCC shows up on Day 10 due to lack of Kupffer cells to ingest lipiodol
• Percutaneous liver biopsy: Only done in inconclusive diagnosis and unresectable cases (e.g. differentiate primary from secondary tumors)
o Contraindications: bleeding tendency (e.g. INR > 1.2 despite vit K), thrombocytopenia (Plt < 50), high- grade biliary obstruction (risk of bile peritonitis)
o Risk of bleeding (hypervascular tumour), organ puncture, needle tract seeding of tumour
For staging:
• Imaging: triphasic CT, bone scan
o PET-CT: limited sensitivity as HCC does not take up FDG well and liver has high background metabolic activity —> require dual-tracer ([11C]-acetate + [18F]-FDG) - taken up by tumour cells at varying degrees
• TNM staging
For complications:
• CBC: low Hb, Plt (hypersplenism)
• Child-Pugh score (albumin, bilirubin, clotting, distended abdomen, encephalopathy)
Mx of HCC
- Liver resection
- Liver transplant
- Local ablation
• Roles: Potentially curative, bridge therapy to transplant, or palliative
• Radiofrequency ablation (RFA)
o Indications: small single tumour < 2cm (as alternative to resection – resection is preferred if 2-5cm), inoperable solitary HCC < 5cm, inoperable ≤3 nodules ≤3cm where transplant not feasible
o Route: percutaneous, open
o Contraindications: too close to major vessels / major bile ducts / diaphragm (if percutaneous)
o Complications: bile duct injury, thermal injury to surrounding tissues
• Other less commonly used: ethanol, microwave, high-intensity focused ultrasound (HIFU), cryotherapy - Trans-arterial chemoembolization
• Based on the premise that tumour is mainly supplied by hepatic artery
• Procedure:
o Selective intra-arterial administration of chemotherapy e.g. cisplatin, doxorubicin (drug-eluting beads)
• Emulsified with lipiodol: retain longer in HCC (no Kupffer cells to ingest)
o Partial embolization of major tumor artery with Gelfoam: ↓ clearance of chemo, promote tumor necrosis
• Indication: large (>5cm) + unresectable + Child A/B
• Contraindications: portal vein thrombosis (—> liver ischaemia), Child’s C, distant metastasis, AV shunt to hepatic vein (—> risk of PE)
• Complications:
o Post-embolisation syndrome (within 14 days): liver injury due to tumour lysis or ischaemic damage to normal liver tissue; S/S fever, RUQ pain, anorexia; resolve spontaneously after 1 week
o Liver failure: due to infarction of normal liver tissues
o Bile duct injury
o GI bleeding: cytotoxic reflux into other arterial supply to stomach
• Alterative: transarterial radioembolization (TARE) with 90Yttrium - Others
• Selective internal radiation therapy (SIRT): high-dose RT (3-6 fractions) to small inoperable HCC
• Sorafenib: multitargeted kinase inhibitor (e.g. Raf, VEGF, PDGF)
o Prolonged survival by 3 months [SHARP trial]
o Side effects: hand-foot syndrome (acral erythema)
o Alternatives: other TKI (e.g. regorafenib / lenvatinib), single-agents (e.g. doxorubicin, cisplatin), bevacizum - Immunotherapy
Pancreatic carcinoma
Types
• Ductal adenocarcinoma (90%)
• Cystic tumours, ampullary cell tumours, islet cell tumours: much better prognosis
• Metastasis: from RCC (MC), lung, breast
Sites: head (60%), body (15%), tail (5%), diffuse (20%)
Risk factors
• Smoking (3x risk)
• DM, chronic pancreatitis
• FHx
• Pre-malignant conditions e.g. pancreatic intraepithelial neoplasia (PanIN)
• Hereditary cancer syndromes e.g. Lynch
Clinical features
• Painless progressive obstructive jaundice (tumor at head)
• Severe epigastric pain radiating to the back (tumor at body/tail: retroperitoneal infiltration)
• Constitutional symptoms
• Symptoms of pancreatic insufficiency: e.g. steatorrhoea, maldigestion, malabsorption, new onset DM
• Acute pancreatitis / GOO
• Signs of metastasis: liver, peritoneum, lung, bone
• Paraneoplastic manifestations
o Trousseau syndrome: hypercoagulable state —> migratory superficial thrombophlebitis
o Paraneoplastic pemphigoid
Investigations
• Bloods: CBC, clotting, LFT (cholestatic pattern), RFT, glucose, amylase, lipase
• Tumor markers:
o CA19.9 (raised in 80%): prognostic marker + monitoring after Tx
• Low diagnostic value: not sensitive, not specific
• Other causes: HCC, cholangioCA, CA gallbladder, chronic pancreatitis, cholangitis
o CEA (raised in 30-60%)
• Imaging:
o USG (dilated bile ducts)
o CT abdomen with contrast (pancreatic protocol) – thin-sliced tri-phasic (arterial + pancreatic + portovenous phases)
• Double duct sign: dilated pancreatic duct + CBD
• Hypoattentuating mass within pancreas
• Determine resectability: encasement of SMA, hepatic artery, celiac trunk, SMV, PV
o +/- MRCP: delineate anatomy of biliary tree
• Tissue diagnosis: NOT mandatory if potentially resectable - only required if CT failed to demonstrate typical features, before chemotherapy, or suspected 2° mets to pancreas
o EUS-guided FNAC/biopsy preferred over percutaneous USG/CT-guided biopsy (↑risk of tumor seeding)
o ERCP brush cytology / biopsy: can also relieve jaundice by placing temporary stent
• Staging:
o CT T+A+P or PET/CT
o Intra-op laparoscopy (peritoneal metastasis often missed in imaging)
TNM staging
• Resectable: stage 0 - IIB
• Unresectable: stage III (T4) & IV
o Stage III: longer survival, more beneficial from systemic therapy
o Stage IV: shorter survival, less beneficial from systemic therapy
Curative treatment
Principle: Upfront pancreatectomy (+ local lymphadenectomy) + adjuvant chemotherapy (all cases) +/- RT
- Pancreaticoduodenectomy (Whipple’s operation)
- Adjuvant chemotherapy
• Indications: ALL resected CA pancreas
• Start within 12 weeks post-op
o FOLFIRINOX (folinic acid, 5-FU, irinotecan, oxaliplatin)
o Gemcitabine + capecitabine x 6 months
Nasopharyngeal carcinoma (Classifications, clinical features)
Epidemiology
• Southeast Asia: 25 per 100000
• Western countries: 2 per 100000
Risk factors
• Epstein-Barr Virus
• Family history
• Diet: preserved food, Salted fish
• Smoking
• ?HPV
Screening
• EBV DNA
• EBV VCA (viral capsid antigen)
Signs and symptoms
- nasal obstruction
- cranial nerve involvement (3,5,6,7 why not 6?)
- neck mass
- epistaxis
- serous otitis media
Hx: (new case)
- Ear
o Ear discharge
o Hearing impairment (conductive hearing loss): tumor compressing on Eustachian tube
o Tinnitus
o Ear ache
- Nose
o Nasal obstruction
o Postnasal drip
o Epistaxis or blood-stained discharge
- Throat
o Neck mass
o Dysphasia
o Dyspnoea
o Speech problem: hoarseness of voice
o Swallowing, choking
- Others
o Headache
o Facial numbness (CN 5)
o Visual impairment: diplopia (CN 3, 4, 6)
PE
- Cranial nerves
- Neck (LN)
- Side effects of RT: scars, oral mucositis, etc.
Classification
1. Keratinizing SCC
CN12 fasciculation Dental gap trismus
23
2. Non-keratinizing
- differentiated
- undifferentiated (most common in HK 95%)
3. Basaloid SCCC (extremely rare)
NPC Ix
Investigations
Bloods:
- CBC
- LFT (esp ALP)
- RFT: pre-chemo assessment (CrCl)
- Uric acid (if rapidly growing?)
- Serology (EBV DNA, EBV VCA); EBER (Epstein-Barr Virus Small RNA genes)
- (EBV IgA, IgG against VCA, early antigen, nuclear antigen)
Histology:
- Nasopharyngoscopy ± Bx
Imaging:
- USG + FNAC
- CT head & neck/MRI head & skullbase if intracranial extension suspected (fossa of
rosenmuller, pharyngobasilar fascia obliteration, tumor invasion to soft tissues, skull base, sinuses, LN mets)
o Or CT/MRI nasopharynx and neck (can also visualize cervical LN)
o May need thin slice, contrast imaging
- CT chest & upper abdomen (esp in px with high risk of distant metastasis I.e. Advanced nodal met N3)
- PET scan, bone scan
- Baseline audiogram
Staging for NPC
TNM staging
- bilateral cervical LN (N2) Stage III
- intracranial extension ± CNs involvement (T4) Stage IV
- Large cervical LN >6cm or supraclavicular fossa LN Stage IV
- N1 —> at least stage II
NPC Mx
- Radiotherapy (mainstay) (+ bilateral neck irradiation)
o Neuro - Carotid artery: stenosis, pseudoaneurysm, aneurysm (@ skull base: massive epistaxis), rupture
- Temporal lobe radionecrosis
• Memory loss, complex partial seizures - Autonomic dysfunction (sympathetic trunk at carotid body): fluctuating BP
- CN palsy (CN 8, 9, 10, 11, 12)
• Delayed bulbar palsy: dysarthria, dysphagia, tongue and palatal weakness, motor weakness of CN11 - Lhermitte’s syndrome
• ∵ reversible demyelination of ascending sensory neurons due to
inhibition of oligodendrocyte proliferation following RT of cervical or thoracic spine
o Endocrine
- panhypopituitarism (secondary)
• Growth hormone
—> Puberty cessation, fine wrinkles, obesity, muscle weakness
• ACTH cortisol (2° adrenal insufficiency)
o Anorexia, malaise, nausea, abdominal pain, postural hypotension, dizziness, hypoglycemia (hungry sensation, sweating)
o Addisonian crisis: convulsion, psychosis, hypoNa, hyperK, hyperCa, severe vomiting & diarrhea, low BP, syncope, slurred speech,
severe lethargy, hypoglycemia
• ADH (Diabetes insipidus)
o Polyuria, polydipsia, confusion
• Prolactin
o Galactorrhoea
• Thyroid
o Cold intolerance, weight gain, ↓ appetite, constipation, menorrhagia, depression, tiredness, lethargy, muscle aching &
cramps, thinning of hair
• Sex hormone
o Loss of libido, infertility, oligomenorrhea, loss of body hair, osteoporosis, erectile dysfunction
Primary hypothyroidism: fatigue, pretibial myxedema
o MSK
*Skull base osteoradionecrosis (osteomyelitis), *trismus
o Ear
- Otitis media effusion (Eustachian tube dysfunction)
- small vessel disease (complete conductive hearing loss)
- tinnitus
o Nasopharynx
Epistaxis: thinning of blood vessel wall
o Others
- Facial muscle fibrosis
- Xerostomia: dry mouth (salivary gland)
- skin changes (peeling), neck fibrosis/scarring
- mucositis: oral, GIT
- esophageal stricture
- poor nutrition, dehydration (gastrostomy tube insertion
- Secondary tumours, bone fibrosis
- Chemotherapy: for advanced cases
o Agents: cisplatin, 5-fluorouracil
o Pre-chemo: HT, DM, IHD, HBV, HCV, HIV, TB
o Chemo efficacy: initial symptoms
o Chemo S/E: renal impairment, neuropathy, emesis, neutropenia, hematological toxicity,
trismus (dental) - Concurrent chemoRT: for locoregionally advanced head and neck cancer to sensitive tumor to the effects of RT and thereby improve tumor control
- Molecular targeted agents (under research): Cetuximab, Bevacizumab
Early (Stage I): RT alone
Intermediate (Stage II): concurrent chemoRT
Advanced (Stage III, IVA & IVB): concurrent chemoRT ± adjuvant chemotherapy
Cervical cancer
Presentation:
- Routine pap smear
- Abnormal PVB (intermenstrual bleeding, post-coital bleeding, post-menopausal bleed)
- Constitutional S/S, pressure or mass symptoms (stage 4)
Dx
- Bx of cervical lesions if any
- Colposcopy if pap smear +Ve but no mass
- cone Bx or endocervical curettage
Ix
- USG: hydronephrosis +/- cystoscopy +/- sigmoidoscopy
Staging
- MRI pelvis (T staging) + MRI /CT (N staging) + PETCT (extrapelvic disease)
Mx:
- Hysterectomy +/- BSO
- Radiotherapy
Primary RT: all except stage 1A; not preferred in 1B/ 2A (morbidity»_space; surgery)
Concurrent chemoRT: tumor volume directed RT with additive weekly low dose cisplatin:
—> More effective, higher morbidity
—> For stage IB3; stage 2B or above
Technique: IMRT (reduce morbidity, same cure)
S/E:
Radiation proctitis, cystitis, ↑secondary cancer
Ovarian function, vaginal function (dyspareunia)
Chemo:
- Chemotherapy alone is for palliative Tx
- Regimen: Carbotaxol (Carboplatin + Taxol)
Target
- Metastatic disease: bevacizumab + chemotherapy
immunoTx
- antiPD1, antiPDL1 (nivolumab)
Risk factor
- HPV16-18; multiple sexual partners; smoking, OCP , old age, immunocompromised
Histology
- SQCC 80%, ADC 20%
Prognosis
- I II III IV —> 90, 70, 40, 8
FU Q4-6m PE: abdo exam (mass/ ascites) + LNs + speculum + PV + PR
Pap smear Q6m x 10yr
CA endometrium
Risk factor:
- Estrogen exposure, obesity, HT, DM, estrogen, TMX, PCOS
Histology:
- ADC 80% grade 1-3 (well to poorly differentiated)
Symptoms:
- PVB, PMB / IMB / menorrhagia
PE: general + abdomen + speculum + bimanual + PR +/- respi (pleural effusion)
Ix
- Dx: endometrial sampling / uterine curettage
- MRI A+P with contrast (better than CT, for soft tissue – myometrial & cervical invasion)
- PETCT in high grade tumor
Tx:
Stage 1A grade 1: mirena, PO progesterone
Stage I: TH +/- SO+ pelvic LN +/- para-aortic LN (Depending on grade)
II: THBSO + pelvic radiation + brachytherapy OR radical hysterectomy + BSO + pelvic +
para-aortic LN
III: THBSO + LN removal (no need full dissection) + adjuvant chemoRT
IV: palliative:
- hysterectomy BSO / local RT for bleeding S/S
- chemo (paclitaxel) +/- hormonal Tx
Adjuvant Tx
- Chemotherapy in stage III – IV or early stage high grade – carbotaxel
FU Q4-6months
- Symptoms, PE (LN, PV, PR, abdo, speculum x vaginal vault) PET CT if suspect
- Prognosis 5YS: 70% (80, 65, 30, 10)
CA ovary
Risk factor:
BRCA1/2, lynch syndrome
nulliparous, age of first child >35, early menarche late menopause, obese, HRT ~CA
breast
Protective:
- COCP , pregnancy. Breastfeeding, salpingectomy, sterilization
Histology
- Serous .» mucinous > endometroid > Clear cell > Transitional cell
Symptoms
- 75% present in advanced stage – pelvic mass, abdo mass, pelvic pain, bloating
PE: general exam + LN + respi (PE), abdomen (Ascites, mass), speculum, bimanual
PR (POD Nodularity, fixed pelvis / frozen pelvis)
Ix
USG (TAS / TVS)
Staging: CT A+P with contrast
Tumor marker: CA125, CA19.9 (mucinous)
Estimate RMI – risk of malignancy (USG + menopausal status + CA125)
Staging FIGO staging
I: tumor confined to ovary / fallopian tube
II: pelvic extension / peritoneal cancer
III: retroperitoneal LN / peritoneum macroscopic metastasis
IV: distant met (excluding peritoneal met) pleural effusion, extra-abdominal LNs
Tx
- Stage I&II
Staging laparotomy + debulking surgery (THBSO + omentectomy + peritoneal cytology +
RP LN assessment)
+ adjuvant chemo (carbotaxel carboplatin + paclitaxel) 6 cycles Q3 weeks
S/E: carboplatin: plt, nephrotoxicity, peripheral neuropathy
Paclitaxel: neutropenia, nephrotoxicity, peripheral neuropathy, alopecia
- Stage III-IV
Debulking surgery or neoadjuvant surgery + interval debulking surgery
Recurrence
- Chemo response depends on time to recurrence
—> Long time: re-try platinum agents
—> Short time: 2nd line chemo (Doxorubicin)
prognosis
- 90% > 70% > 60% > 17%
FU
- Symptoms + PE + CA125 suspicion: USG, CT T+A+P or PET CT
Hodgkin’s lymphoma
Presentation:
Painless LN enlargement (cervical > axillary); contiguous LN spread
50% present splenomegaly (usually NOT MASSIVE; due to REACTIVE; not infiltrate)
Infiltrative S/S:
● Pancytopenia symptoms
● Mediastinal involvement: SOB, SVCO
● Spinal cord compression
B symptoms (in advance disease)
Alcohol induced LN pain, pruritus
Ix
CBC
Excisional biopsy
Staging
Ann Arbor system
Mx
Stage I – II
RT (localised): involved field ER
●
S/E: second cancer, IHD, hypothyroid, lung fibrosis (Depending on field)
+/- chemotherapy
Advanced stage (III – IV, bulky II)
Chemotherapy
● ABVD: Adriamycin, bleomycin, vinblastine, dacarbazine
Consider autologous HCST
?+/- staging splenectomy
Non-Hodgkin lymphoma
Presentation:
Local: painless lymphadenopathy (B symptoms less frequent)
Extranodal involvement: skin (Sezary), GIT lymphoma, Waldeyer’s ring, HPSmegaly
Emergencies: SVCO, TLS, malignant hypercalcemia, pericardial effusion, IO, CNS
Diagnostic:
- excisional Bx of LN
- Immunophenotyping (flow, IHC); clonality (IGH mutation, cytogenetics); molecular genetics
- CBC D/C, PBS, DAT, TLS panel RFT + CaPO4 + urate, LDH, b2-microglobulin
- LFT, ESR
- IgG, IgA, IgM, SPE
Pre-treatment
- Hepatitis serology, TB, HIV, G6PD
- ABVD: lung function test
- Pregnancy test
Staging:
- BM aspiration & biopsy from bilateral iliac crest
- PET-CT (DLBCL), LP if high risk CNS involvement
Mx:
- Limited stage
Ann arbor I / II + no B symptoms + mass < 10cm: chemo + local RT
- Advanged stage III/ IV OR B symptoms OR mass >10cm: extended chemo +/- RT
Systemic chemotherapy R-CHOP + localized RT
- Rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisolone
- Pre-treatment
o R: Panadol + diphenhydramine premedication +/- H2 blocker (infusion
reaction)
o C: oral hydration + ↑voiding (hemorrhagic cystitis)
o H: avoid extravasation, ECHO
o O: neurotoxicity, paralytic ileus
- Monitoring: CBC D/C, RFT LFT, LVEF
Alternative: R-ICE; dose adjusted EPOCH-R (R CHOP E – etoposide)
Alternative: pembrolizuma
R-CHOP S/E
● R: Nausea, infection, infusion-related problems
● C: hemorrhagic cystitis, primary ovarian failure, alopecia, marrow
● H: cumulative cardiotoxicity; mucositis, myelosuppression, red urine
● O: peripheral neuropathy
● P: Cushing
● General: febrile neutropenia (10-20%) – consider prophylactic G-CSF
Monoclonal Ab: anti-C20, anti-CD30 (HL), anti-CD52
Targeted Tx
● BTK inhibitor: ibrutinib (B cell lymphoma)
● BCL2 inhibitor: venetoclax (CLL, follicular lymphoma)
● ALK inhibitor: crizotinib (anaplastic LCL)
Immunotherapy: bispecific T cell activator, PDL1
CAR-T cell
HSCT
3 cancers no need biopsy
HCC, prostate CA, testicular cancer
SVCO case
Young man
- lymphoma
- germ cell tumour
—> chemo sensitive
Look for laryngioedema
—> intubation
Take biopsy first before give steroid since if lymphoma —> excisional biopsy is important for architecture —> steroid may destroy it and affect diagnosis
Not goodly receive chemo
- mediastinum —> give RT for lymphoma for possible residual disease
- testis
- CNS —> intrathecal
- orbit
Delayed toxicity
- pneumonitis
- infertility (chemo)
- heart
- secondary malignancy, e.g. leukemia after high dose chemo
- CA thyroid
Central-located mass:
- SVCO
- tamponade
- RLN
- airway —> lung collapse
Peripheral-located
- pleural effusion
Superior sulcus (apical) (pancost tumour —> no SVCO since SVC already bifurcated)
- Horner’s syndrome
- T1 neuropathy —> brachial plexus
- dermatomal shoulder pain
Cord compression case
- check sensory level ** (MRI may give both old and new lesion)
- MRI to confirm diagnosis —> collapse of vertebrae / loss of pedicle (not TB not malignancy) (unstable spine) —> need surgery for spinal fusion
- but if radiosensitive like plasmacytoma —> RT first-line
Tumour lysis syndrome
- usually occur spontaneously (high risk malignancy)
—> burkitt’s lymphoma —> high LDH, expand in size very quickly , common presentation: extra-nodal sites: GI tract (bowel perforation / IO —> present to surgery)
DIC case
AML-M3
- give altra —> prevent DIC
* most patient die for DIC in 1-2 weeks
- then give chemo within 1 week
DIC
- fibrinogen decrease / increase
- D-dimer increase (elevation may not mean must DIC, but DIC must increase d-dimer)
OSLER
- Known you have cancer —> what cancer —> when occur?
- Treatment? Response? What doctor said?
—> landmark of the cancer
—> the earliest complaints can be vaguely asked
- Current presenting symptoms —> for PE
CA thyroid (classification and clinical features)
Classification
1. Papillary
- 85%
- Young adults
- Lymphatics spread
2. Follicular
- 10-15%
- Middle age (40-60)
- haematogenous spread
3. Anaplastic
- 1%
- Old > 60
- Lymphatics and haematogenous spread
4. Medullary
- 3%
- Sporadic: >50y; Familial: < 30y
- Lymphatics spread
Other rarer types: lymphoma (require core biopsy), SCC, poorly differentiated CA
Metastatic thyroid cancer
• Renal cell carcinoma (MC)
• Others: colorectal, lung, breast, uterine
Risk factors
• Female
• Family history of thyroid cancer
• Previous H&N irradiation e.g. childhood leukemia
• Familial syndrome, e.g. FAP (papillary), MENII (MTC)
• Hashimoto’s thyroiditis (thyroid lymphoma), iodine deficiency (follicular CA)
Note: Follicular adenoma is NOT a risk factor of follicular CA
Clinical features
• Palpable neck lumps
• Rapidly enlarging lumps: pain, HOV, stridor
• Multiple enlarged cervical LN
Ix and staging of CA thyroid
Investigations
• Bloods: TFT (normal), CaPO4 (parathyroid function), thyroid Ab and thyroglobulin (tumor marker)
• Thyroid USG: suspicious features (SHIT CME)
• FNAC: Bethesda system
• CT neck and chest: if locally advanced CA thyroid / bulky LN
• Pre-op workup for MTC
o Rule out familial disease (25%): FHx, 24h urine metanephrines, Ca & PTH
o Tumour markers: calcitonin (metatstatic if >500), CEA
o Workup for metastatic disease if calcitonin > 500: CT
T+A+P & bone scan
Staging of thyroid cancer
• Differentiated thyroid cancers: age-dependent
o Age <55: Stage I if M0, Stage II if M1, never Stage III/IV
o Age ≥55: Up to Stage IVB
• Anaplastic thyroid cancers: Stage IV automatically
• T staging:
o T1a: tumor ≤ 1cm
o T1b: 1cm < tumor ≤ 2cm
o T2: 2cm < tumor ≤ 4cm
o T3: >4cm but limited to thyroid
o T4: extrathyroidal extension
• N staging:
o N1a: Level VI / VII nodes
o N1b: Level I-V node
Mx of CA thyr
- Surgery
- Papillary / follicular
—> Total thyroidectomy
Indications: size > 4cm, gross extra thyroidal extension, LN positive, metastasis positive, familial disease, bilateral/multifocal
• Papillary CA tends to be multifocal
• Prevent local recurrence which may progress
• Allow post-op thyroglobulin monitoring
• Allow adjuvant RAI
—> Hemithyroidectomy
• Morbidities are lower, especially parathyroid & RLN injury
• Progression to undifferentiated CA is rare
• No evidence to show inferior prognosis
• Lifelong thyroxine replacement not required
• RAI is not required in most patients
- Medullary CA thyroid: total thyroidectomy (require prophylactic total thyroidectomy in high-risk MEN2 cases)
Choice of neck dissection
Terms: central compartment dissection (Level VI) vs lateral neck dissection (Level II-V)
1. Papillary CA thyroid:
• Therapeutic CCD / LCD if respective compartment +ve
• No role for prophylactic neck dissection
2. Follicular CA thyroid:
• Usually not required (haematogenous spread)
3. Medullary CA thyroid: often need to dissect one level up
• Prophylactic CCD for all patients
• Ipsilateral central LN +ve: + ipsilateral LCD
• Ipsilateral lateral LN +ve: + ipsilateral LCD (if calcitonin < 200), + bilateral LCD (if calcitonin > 200)
• Contralateral LN +ve: +bilateral LCD
Post-operative adjuvant treatments
- Remnant ablation:
o Residual thyroid tissue actually non-functional (require T4 supp anyway), but it interferes with post- op thyroglobulin monitoring and also cannot r/o residual malignancy!
- Radioactive iodine ablation (RAI):
- Pre-op give rTSH or withdraw T4 to promote 131I intake
- Low iodine diet x1 week
Similar to indication for total thyroidectomy (above):
• T3 / T4 disease
• N1 / M1 disease
• Aggressive histology: tall cell, columnar cell,
diffuse sclerosing, poorly differentiated PTC - External beam irradiation (EBRT)
Indications include:
• Positive surgical margins
• Incomplete resection (residual tumor left)
Thyroxine
o Roles: Replacement (prevent hypothyroidism) ± suppression (high TSH stimulates tumour growth)
- high risk: T4, M1/ incomplete resection —> TSH < 0.1mIU/L
- intermediate risk: T3, N1, aggressive histology, vascular invasion positive —> 0.1-0.5
- low risk: others —> 0.5-2.0
Disease monitoring:
o Neck USG Q6m
- Bloods: TSH, calcium, PO4 & thyroglobulin (on thyroxine suppression) Q3m - can be performed for both total/ hemithyroidectomy
• Total hemithyroidectomy: Tg < 0.2
• Hemithyroidectomy: Tg < 30
**thyroxine taken before breakfast and at least 1 hr apart from Ca+ since Ca+ affect thyroxine absorption
MEN disease
MEN1:
Pituitary adenoma
Parathyroid hyperplasia
Pancreatic tumour
MEN2a:
Parathyroid hyperplasia
Medullary thyroid carcinoma
Pheochromocytoma
MEN2b:
Mucosal neuroma
Mariano I’d body habitus
Medullary thyroid carcinoma
Pheochromocytoma
