PastExamQs&FuckingAnswers Flashcards
Write a short note on the biological behavior and histopathological features of Phyllodes tumour of the breast
Biological behaviour:
- Can grow slowly then rapid increase in size
Behaviour depends on grading:
o Benign: very low risk of recurrence (and recurrence may be benign as well), does not metastasize,
o Borderline: between benign and malignant
o Malignant – 30% risk of local recurrence, 10% risk of distant recurrence
Histopathological features:
- Leaf-like epithelial pattern
- Graded into benign, border, or malignant based on: stroma atypia/ cellularity/ overgrowth,
mitotic count, tumour border, malignant heterologous elements
A 35 year old female has a right mastectomy and axillar dissection for an invasive breast cancer.
a. List the factors in the pathology report that are required for you to make a decision on the recommendation for adjuvant radiation therapy. Indicate how each of these factors influences your decision to recommend adjuvant radiation therapy in this patient.
Especially in LN+ve patients, metanalysis demonstrates PMRT confers a locoregional recurrence and BCa-specific mortality reduction. In addition - The SUMREMO trial would consider CWRT in the following:
T3, close margin, T2N0grd 3, T2N0 with LVSI.
Therefore in report:
Tumour size >= T3 (50mm)
ALND: nodes positive, also nodes harvested (<=10 should consider nodal RT), ECE = RT, Nodes >=4 do RT, strongly consider>1, also micromets.
Hormone status: tripple negative
Grade = 3 and T2 = CWRT in SUPREMO
LVSI = consider RT is tumour T2
Margin status: <1mm
Multifocal disease.
The analyses of gene expression is being increasingly used in invasive breast cancer. Describe the 21 gene
recurrence score (Oncotype Dx) and the Amsterdam 70 gene profile (Mammaprint). Explain the utility of these (4m)
Oncotype:
Prognostic and predicitive (which non-locally advanced N0 pts benefit from chemo).
- Developed in the NSABP-B18 and B20 cohort
- Based on 21-gene DNA micro-array
- Used in women with ER+, N0 who have endocrine therapy
- Predict risk of distant metastases and benefits from adjuvant chemotherapy
- Stratified into 3 groups based on risk score – low (<18), intermediate (18-30), high (>30)
Mammaprint:
Based on 70-gene profile (DNA microarray) Prognostically validated in early breast (<T2=2-5cm) regardless of hormone status
(See also PAM50 and the EXPERT trial)
a. List the subtypes of non-Hodgkin lymphoma which occur within the hollow organs of the gastro-intestinal tract
(2m)
Follicular
Marginal - MALT
DLBCL
Mantle cell
Primary gastro-intestinal T cell lymphoma
A 40 year old man presents with a mass in the anterior mediastinum (4m)
i. What is your differential diagnosis for this mass?
Non-malignant:
Thymic cyst/congenital
Reactive nodes
Malignant Ddx:
Lymphoma: E.g mediastinal DLBCL, follicular lymphoma
Nodal met/or met: e.g from primary lung/skin (e.g melanoma)
Sarcoma
Seminoma/nonSem Germ cell tumour
A 40 year old man presents with a mass in the anterior mediastinum (4m)
ii. Describe the different approaches to obtaining a histological diagnosis for this mass, including specimen handling, plus advantages and disadvantages of each method described
CT-guided Bx - Advantages: Less resources (theatre time/staff), does not require GA. Disadvantages: Operator dependent, may be challenging, with high-risk anatomy (e.g SVC) nearby. No direct visualisation of mass.
EBUS - Advantage: Less chance of miss (compared to CT), can be done as a day day case, with less risk than operative Bx. Disadvantages: FNA therefore no architectural info, limited sample- insufficient for flow cytometry. Not all mediastinal lesions accessible by EBUS.
Medianoscopy and Bx (generally preferred), Adv: Direct visualisation, more tissue for full work up. Disadv: Operative risks and resources (GA, surgeon, theatre staff etc), where resources limited may delay Dx.
Open excision Biopsy: Adv: Highest chance of obtaining tissue, may be therapeutic. Disadv:Higherst risk, longest recovery and most resource intensive.
Compare and contrast the histological features of primary mediastinal B cell lymphoma and seminoma?
How could ancillary techniques be used to distinguish this entities?
Med BCL: Diffuse or clustered growing B-Cell neoplasm characterised by intermediate sized nuclei
Seminoma: Large round cells, “fried egg” nuclei
I
IHC B cell: +ve CD 19, 20, PAX8
IHC seminoma: +ve C-KIT, PLAP
A 70 year old man presents with a palpable cervical lymph node.
a. List the differential diagnosis (1m)
b. Regarding follicular lymphoma, describe the (2m)
i. Microscopic features
ii. Immunohistochemical profile
i. Microscopic features
B-cell neoplasm, forming follicles of centrocytes (smaller, cleaved nuclei) and centroblasts (larger, non cleaved lymphoid cells).
ii. Immunohistochemical profile
Pan B-cell marker: CD 19,20,21,79 and PAX8
Germinal centre markers: BCL-2, BCL-6, CD 10
Negative for T-cell marker: CD 3 and 5.
How is follicular lymphoma graded? (2m)
Grading from 1 to 3 based on density (#/HPF) of centroblasts: grd 1<5/hpf, grd 3>15/hpf. Grd 3 is incurable, grd 3B is centrocytes only (forming solid sheets)
Describe a prognostic scoring system used in follicular lymphoma (2m)
FLIP-2 (B-BLAH-N)*, similar to IPI for DLBCL, used to stratify into low (0-1) risk factor, intermediate and high (>2) RFs.
FLIPI-2: Bone Marrow Involvement, Beta2 Microglobulin> upper lim normal (ULN), Age>60, anaemia (Hb<120). And nodes>6cm. Don’t forget nodes!!!
Where RF are:
(B) Beta2 microglobuin >ULN,
(B)Bone marrow involvement,
(L)LDH>ULN,
(A)Age>60, [
(H) [Hb]<120.
10yr OS for low, int, and high risk are: 80, 50, 20 (%) respectively
The majority of follicular lymphoma have a translocation. Name the translocation. Describe 2 laboratory methods that can be used to assess whether the translocation is present (1m)
t(14,18) in 80-90%.
1) Cytogenetics via FISH for presence of translocation in chromosome (detected by flurescent probe)
2) IHC Over-expression of BCL2 protein from t(14:18) translocation Localisation of protein antigen by fluorescent-tagged antibody through antigen- antibody interaction
What is the natural history of low grade follicular lymphoma (2m)
Generally indolent (within above prognostic Risk categories)
Excellent LC with RT (>90%) with distant failure likely
10-year PFS 50%; 10-year OS 50%
30-50% risk of transformation to DLBCL
A 62 year old male presents with a six month history of increasing shortness of breath. Ten years ago he received chemotherapy and radiation therapy for a diffuse large B cell mediastinal lymphoma.
a. What are the possible causes for his shortness of breath? (3 marks)
Break into Disease related, treatment related, other causes:
Disease: Recurrence with mass effect (e.g/ SVC obstruction, trachial/bronchi compression potentially lobar collapse).
Treatment:
- CTx related (doxorubicin): Heart failure/ valvular disease
- RT-related
Lung: lung fibrosis, Secondary lung malignancies e.g. mesothelioma
Heart: valvular dysfunction, cardiac arrhythmia, heart failure
Other: name the systems: Resp: LRTI/COPD, CVS: Valv/failure/silent MI, Metabolic/Renal: Renal failure, oedma, Haem: anaemia.
In general, what strategies can be used to manage breathlessness in terminal cancer patients? (2 marks)
Pharmacology
- Opioid
- Sedative agents (midazolam/ benzodiazepam)
- Dexamethasone
- anti-secretory (hyoscine, atropine, glyco-pyronium bromide)
Non- pharmacology
- supplemental oxygen
- positioning (slight head elevation)
- manage secretion (suction)
- ascitic tap
- pastoral care/ single room
A 28 year old woman presents with a 6-month history of lethargy, progressive shortness of breath and non- productive cough. A chest CT scan demonstrates an 8cm mass in the anterior mediastinum. A core biopsy is performed. Histopathology demonstrates a diffuse large B-cell lymphoma
a. What further investigations would you organize (1m)
To complete IPI (LAKES) need LDH, determine stage and number of extra nodal sites. Also the below:
Blood test
FBE/ UEC/ CMP
Prognostic factors – LDH
B-HCG – exclude pregnancy
HIV
Hep B/ C – likely require rituximab, which may reactive HepB/C
Tissue Additional:
immunophenotyped from mediastinal biopsy
- C-MYC/ BCL2/ BCL6 for double/ triple hit phenotype
BMAT – ? marrow involvement
Imaging - CT and FDG PET scan
- Echo-cardiogram (baseline cardiac function prior to R-CHOP)
A 28 year old woman presents with a 6-month history of lethargy, progressive shortness of breath and non- productive cough. A chest CT scan demonstrates an 8cm mass in the anterior mediastinum. A core biopsy is performed. Histopathology demonstrates a diffuse large B-cell lymphoma
Staging investigations demonstrate no disease outside of the mediastinum.
What would you recommend as management for this patient now? Justify your answer (2m)
Assuming Stage I/II:
Bulky (>5cm or 7.5cm) should be treated with 6 cycles of R-CHOP (increased if activeated centre or dbl/trppl hit, e.g. x8 cycles). A PET should be perfomed post treatment. And adjRT ISRT 30-36Gy should be considered for increased event free survival (though not PFS/OS), I would not strongly recommend this, but would offer discussion.
UNFLODER RCT: Adjuvant radiotherapy for bulky disease after x6 R-CHOP, included sub analysis of primary mediastinal BCL for which EFS was only benefit. For partial responders on PET, adjRT may improve EFS to the degree of complete responders.
Interestingly RT may be associated with less secondary maligancy risk than other treatments (e.g. CAR T cell 4-6%).
A 28 year old woman presents with a 6-month history of lethargy, progressive shortness of breath and non- productive cough. A chest CT scan demonstrates an 8cm mass in the anterior mediastinum. A core biopsy is performed. Histopathology demonstrates a diffuse large B-cell lymphoma
Staging investigations demonstrate no disease outside of the mediastinum.
If her management was to include radiation therapy, describe a suitable technique and dose prescription for delivering this treatment (3m)
Adjuvant EBRT for improved EFS, to a total of 30gy/15#, 5#s/week, VMAT technique 6Mv photons.
Pre sim: pregnancy test, PPI/antemetics as needed
Sim: as usual.
2mm slice CT4, fusion with diagnostic PET
Planned on MIP and checked against all phases of breathing cycle.
Volumes: GTV = residual disease on CT and PET
CTV = GTV + extent of disease on pre-treatment CT/PET. Respecting anatomic boundaries except where invasion.
PTV = CTV + 5mm.
OARS -
MHD <4gy
Lung V20 Gy ≤30%
Breast mean dose <4Gy
Esophagus/Spine ALARA principle
Daily CBCT matched to bone with soft tissue review.
A 22 year old female presents with cough and shortness of breath. A chest x-ray shows a widened mediastinum.
Further investigation confirms a 10cm mediastinal mass with no evidence of disease elsewhere. i. What are the 4 most likely differential diagnoses in this patient? (1m)
ii. How will your proceed to obtain histological diagnosis (2m)
i. What are the 4 most likely differential diagnoses in this patient? (1m)
- Lymphoma (Hodgkin’s lymphoma, diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma)
- Germ cell tumour (teratoma)
- Thyroid malignancies
- Thymoma/ thymic cancers
Dx =
- CT-guided core biopsy
- Alternative with EBUS
A fit 46 year old female is referred for investigation of a 5cm lesion of the proximal humerus demonstrating full thickness cortical erosion in areas. Biopsy demonstrates a monoclonal plasma cell infiltrate.
a. What further investigation would you perform? Justify your answer (4m)
For a diagnosis IMWG requires all following criteria be met:
1)Bx-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
2)Normal bone marrow with no evidence of clonal plasma cells
3)Normal skeletal survey and MRI (or CT) of the spine and pelvis, except for the primary solitary lesion
4) Absence of end-organ damage = CRAB (hypercalcemia, renal failure, anemia, and osteolytic bone lesions), that can be attributed to a lympho-plasma cell proliferative disorder
Other:
- Beta2-microglobulin, albumin, LDH (for staging)
In general, what is the role of surgery in the management of solitary bone plasmacytoma (SBP)? (1m)
May have role in surgical fixation for stabilisation, where there is risk of vertebral instability, or risk of pathological fracture. Assess by SINS (“greater than or equal to 8 you should fix8”) and Mirel’s scores respectivly.
What is the Mirel scoring system? Include in your answer its component and how it is used (3m)
Each of 4 components scored 1-3, where prophylactic Long bone fixation should be considered @8, and indicated at>=9.
A) Pain 1=mid 2 mod 3 severe
B) Location: Upper limb 1, LL 2, intertroch 3
C) Lesion: Blastic =1, Mixed 2, Lytic 3
D) Cortex involved <1/3=1, >2/3=3
What is the risk of this patient (medullary plasmacytoma) progressing to multiple myeloma in the next 10 years?
Almost all will transform to MM – 50% in 5 years, 80-90% in 10 years
If the patient progressed to multiple myeloma, what would you discuss with this patient regarding the natural history of the disease with treatment and their prognosis
Incurable; alternate between remission and relapse Depending on stage
o MedianOS:Stage1~5yr,Stage2~4yr,Stage3~2yr
Compare multiple myeloma and plasmacytoma in terms of: (6m)
i. Pathological definition
MM:
Malignant proliferation of clonal plasma cells, requires 3 criteria:
- >10% abnormal clonal plasma cells on
bone marrow biopsy
- M-protein >3g/dL on SPEP/ UPEP
- Presence of CRAB end organ failure
Solitary plasmacytoma
- Presence of abnormal clonal plasma cells in one site (bone, or extramedullary)
Compare multiple myeloma and plasmacytoma in terms of: (2m)
ii. Clinical presentation
MM
CRAB end organ failure
- Hypercalcaemia
- Renal failure
- Anaemia
- Bone pain
PM
No CRAB features
Bone: bone pain, vertebral compression fracture Extramedullary (site dependent) e.g. nasal obstruction, epistaxis
Compare multiple myeloma and plasmacytoma in terms of: (6m)
iii. Biological behaviour
MM
OS 6 months without treatment
- Incurable; alternate between relapse/
remission
Survival based on stage: MedianOS Stage1~5yr, Stage2~4yr, Stage3~2yr
PM
- 90% local control with radiotherapy
- Risk of MM transformation
o Bone: 80% 10 year for bone
o Extramedullary: 20-30% at 10-year
c. Briefly describe the factors associated with poor prognosis for patients with multiple myeloma (2m)
Patient:
Increasing age
Poor performance status
Tumour
R-ISS factors
- high Beta2-microglobulin
- high LDH
- low albumin
- high risk cytogenetic abnormalities (t(4:14), del 17p, t(14:16) Other
- high CRP
- plasma-blastic morphology
- bone marrow infiltration
Treatment
fitness for systemic therapy/ bone marrow transplant
Regarding Hodgkin’s lymphoma:
a. Briefly describe the epidemiology (2m)
Describe the microscopic and immunohistochemical features (2m)
- Relatively uncommon, ~10% of lymphoma
- Male predominance
- Bimodal: mid-20s, and 60s
Micro
- 1-2% of tumour volume are Reed-Sternberg cells (classic diagnostic cell, binucleated with prominent nucleoli, well-demarcated nuclear membrane, and eosinophilic cytoplasm with perinuclear halo)
- The rest are tumour infiltration of lymphocytes, eosinophils, and plasma cells
IHC CD15+, CD30+, PAX8+
Regarding Hodgkin’s lymphoma:
List the factors associated with an adverse prognosis (2m)
Early stage (Stage I-II )
GHSG/ EORTC (slight differences) ‘A-MEEN’ Presence of any of the following factors = unfavourable
- Mediastinal mass : thoracic ratio >1/3
- Extranodal site
- ESR (>30 if B symptoms, >50 if no B symptoms)
- Nodal region >3 (GHSG), or >4 (EORTC)
- Age >50 (EORTC)
Advanced stage (Stage III-IV)
‘ALL-SHAM’
- Age >45
- Leucocytosis,
- Lymphocytopenia
- Stage IV,
- Hb<105
- Albumin<4
- Male
A 22 year old man presents with a painless mass in the right inguinofemoral region. He denies any other symptoms and examination is otherwise unremarkable. A core biopsy of the 3x5cm mass reveals nodular sclerosing Hodgkin’s disease. A staging CT and PET scan show no disease elsewhere.
a. Assuming that there are no adverse prognostic features, discuss the treatment options available for this man,
including the advantages and disadvantages of each approach (4m)
This man has Stage 1A (early favourable) right inguinal nodular HL
Option 1
2 x ABVD + INRT 20Gy (GHSG HD10)
Advantages
Similar outcomes (PFS/ OS) compared to 4xABVD and INRT 30Gy
- Less treatment and less toxicities
Disadvantages
Data mainly in pre-PET era
Option 2 (preferred)
PET-adapted approach
2xABVD then interim PET staging (EORTC H10)
a) - If PET negative, option of further 1xABVD, or RT
- Spare the late s/e of RT (e.g. 2nd malignancies),
- No difference in OS compared to
- In the event of progression, there are
good salvage options
Disadvantage
BUT! Lower PFS with omission of RT
b)If PET positive, - Improve PFS and OS compared to consider 2xBEACOPP + ISRT 30Gy
BUT
BEACOPP more toxicity than ABVD
A 22 year old man presents with a painless mass in the right inguinofemoral region. He denies any other symptoms and examination is otherwise unremarkable. A core biopsy of the 3x5cm mass reveals nodular sclerosing Hodgkin’s disease. A staging CT and PET scan show no disease elsewhere.
A decision is made to treat this patient with combined chemo-radiation therapy.
b. Describe in detail a suitable radiation therapy technique and dose prescription (3m)
I will offer him involved node radiotherapy to the right inguinal nodal mass a total dose of 20Gy in 10# with curative intent;
Name the histopathology and molecular subtypes of medulloblastoma
hISTO
- Desmoplastic/ nodular (15%)
- Extensive nodularity
- Classic (80%)
- Large cell/ anaplastic
Mol:
Group 1 (WNT)
- Group 2 (SHH)
- Group 3
- Group 4
For medulloblastoma - What is the clinical importance of molecular staging (1m)
- Better risk stratification/ prognostication
- Allow for development of biomarker-driven clinical trials, to allow de-intensification of treatment
Describe the microscopicof classical medulloblastoma
(1m)
- Densely cellular and undifferentiated small round cells, (carrot-shaped hyperchromatic
nuclei) - Classically a/w Homer-Wright rosettes (rings of neuroblasts surrounding eosinophilic neutrophils)
Describe the immunohistochemistry features of classical medulloblastoma
(1m)
- Beta catenin associated with WNT
- Neuron specific enolase (NSE) +ve
- Synaptophysin +ve,
- Chromogranin +ve
- GFAP -ve (+ve in glioma)
Describe the cytogenetics of classical medulloblastoma
(1m)
- WNT activated – Beta-catenin
- SHH activated – PTCH1 mutation
- MYC amplification/ gained
Discuss the pathological features of the desmoplastic variants of
medulloblastoma (1.5m)
Nodular architecture
2 important features giving desmoplastic appearance
* Reticulin fibres with densely packed undifferentiated cells with moderate pleomorphism
* Reticulin free zone (pale island)
Pathological
features
* Pathologic activation of SHH pathway, caused by SUFU and PTCH1 mutation in young
adult and PTCH1 and SMO mutation in adult
Discuss the biological behaviour of the desmoplastic variants of
medulloblastoma (1.5m)
- Most common site = cerebellar hemisphere (cf other medulloblastoma which occur most
commonly at midline e.g. vermis) - Can spread locally, or through CSF
- Associated with good prognosis
An 8-year-old girl is referred following gross total resection of a classic, non-WNT (wingless type), non-SHH posterior fossa medulloblastoma. She has an uncomplicated post-operative course. There is no overt disease elsewhere and no malignant cells in the cerebrospinal fluid.
a. What risk category is this patient in? Outline a management plan for this risk category (2m)
I will treat this patient as per SJMB protocol
Risk category Average risk (age>3, no residual, no anaplastic variants, no mets, CSF no malignant cells)
Management Adjuvant RT + adjuvant chemo (4x VCP)
An 8-year-old girl is referred following gross total resection of a classic, non-WNT (wingless type), non-SHH posterior fossa medulloblastoma. She has an uncomplicated post-operative course. There is no overt disease elsewhere and no malignant cells in the cerebrospinal fluid.
b. Describe a suitable radiation therapy technique and dose fractionation regiment for her treatment. Dose constraints to organs at risk are not required to be given (5m)
I will offer this patient cranio-spinal irradiation to a dose of 23.4Gy in 13 fraction followed by tumour bed boost to a dose of 30.6Gy/17# (to total dose of 54Gy/30#) (1.8Gy/#, 5#/ week). VMAT technique with 6MV photon- 3 isocentres (cranial, upper spinal, lower spinal), junction at 4cm depth, no feathering.
Pre-SIM
* Ensure recovery from surgery
SIM
* Positioning: supine, arms on side, head towards gantry
* Immobilisation: on vac bag/ body cradle, thermoplastic mask
* CT simulation: 3mm slice planning CT from vertex to mid-thigh
* Fusion: with pre-op MRI, post-op MRI
Target volume:
* Phase 1: CSI 23.4Gy/13# (entire intracranial/ spinal subarachnoid volume)
o CTVcranial = Entire brain, covering cribriform plate, and optic nerve
o CTVspine = Thecal sac expand laterally to intervertebral foramina; inferior level must be determined on
MRI (usually ~ S1-2)
o PTVcranial = CTVcranial + 3mm
o PTVspine = CTVspine + 5mm lat + 10mm AP + 10mm SI
* Phase 2: Tumour bed boost 30.6Gy/17#
o GTV: surgical cavity + post-op residual disease
o CTV30.6: GTV + 5mm
o PTV30.6: CTV30.6 + 3mm
Plan evaluation:
* Ensure CTV D98>98%, and PTV D98>95%,
* Minimise hotspot: D2<105% of prescribed dose
* Homogenous 16Gy covering entire vertebra body
Treatment verification
* daily kV matched to bone, 2mm tolerance for cranial (optic nerve/ chiasm), 4mm tolerance elsewhere
Additional
* Weekly FBE monitoring (given entire vertebral marrow irradiation)
For medulloblastoma: What are the potential radiation therapy side effect of the treatment you have prescribed? (3m)
Acute:
* Neurological – headache, N+V,
* GI symptoms – N+V, diarrhea,
esophagitis,
* Bone marrow suppression – need
weekly blood
* Skin – alopecia, dermatitis
* General – fatigue
Late:
* Neurocognitive – ‘I M-ABLe’ – IQ, Memory, Attention, Behaviour,
Learning)
* Neuro-endocrine deficits (pituitary dysfunction) – GH deficiency,
hypothyroidism, gonadal dysfunction
* Hypoplasia of occipital bone (high dose boost region)
* Hearing loss (from RT and chemo)
* Eye – cataract
* Alopecia
* Cerebrovascular – aneurysm/ stroke
* 2
nd malignancy (meningioma)
Spinal RT
* Spinal cord damage
* Hypothyroidism
* Musculoskeletal – impaired soft tissue/ bone growth/ reduced siting
height
* Cardiovascular – MI, arrhythmia
* Infertility
* Second malignancy (bowel and bladder cancer)
For Merkel cell carcinoma, describe the epidemiology, risk factors and pathological features (3m)
Epi
Rare primary neuroendocrine cancer of the skin
Mean age ~70
M:F ~2:1
Risk factors
UV radiation
Increasing age
Light skin
Merkel cell polyoma virus (MCPyV)
Immunosuppression – organ transplant, CLL, myeloma
Histology
Macro: red fleshy firm nodules
Micro: small round blue cells, frequent mitoses
IHC: synaptophysin+, chromogranin+, CK20+, CK7-, EMA+
Describe the role of viral carcinogen in the pathogenesis of Merkel cell carcinoma (1.5m)
- Merkel cell polyoma virus (MCV) is implicated
- MCV is integrated into Merkel cell tumour, which then require continued MCV oncoprotein expression to survive
- The integrated viral genomes have tumour-specific pattern of tumour antigen gene mutation that incapacitates viral DNA replication
A 58 year old man presents after local excision of a 3cm Merkel cell carcinoma from the upper right lateral arm
(over the deltoid).
There is a positive radial margin of 0.2mm and there is prominent lymphovascular space invasion.
a. What further information do you require to determine a management plan for this patient? (3m)
This is at least a T2 (3cm) Merkel cell carcinoma, with close surgical margin and LVI:
Hx -
Sx: tempo/ progress of primary lesion; any associated lymphoedema/ radiculopathy
- RFs: immunosuppression (organ transplant/ CLL), sun-damaged skin
- Fitness for RT: ECOG performance status, previous RT to the arm or contra-indications for
RT (which will dictate suitability for RT)
Ex - Other skin lesions, axillary/ supraclavicular lymphadenopathy (which will dictate treatment
volume)
Ix - CT C/A/P and FDG PET (routinely done, but not actually MBS funded) for assessment of
lymphadenopathy and distant mets, which will dictate treatment volume (nodal coverage and
dose) and intent (curative/ palliative)
Tx - Discussion with surgeon regarding feasibility for further resection to achieve good margin
(>3cm)
A 58 year old man presents after local excision of a 3cm Merkel cell carcinoma from the upper right lateral arm
(over the deltoid).
There is a positive radial margin of 0.2mm and there is prominent lymphovascular space invasion.
What management options are available for this patient? What would you recommend? Justify your answer
(4m)
Re-excision, node biopsy and adj RT to primary + nodal irradiation (axilla and
SCF)- Preferred recommendation
- Considered radio-sensitive disease
- Excellent local control/ distant control/ OS (>70%)
- Reduce risk of nodal recurrence (compared to no nodal irradiation)
- Avoid surgical morbidities
RT alone to primary (without elective
nodal irradiation)
- Will require SLNBx prior to RT, and if negative sentinel LN, can consider omitting nodes (in patients with T1 disease)
- In this case (T2 disease), higher risk of nodal recurrence with omission (~ 60% risk nodal recurrence)
RT + chemo - RT with concurrent weekly carboplatin
- TROG single arm study to improve LC/ PFS/ OS with concurrent chemo, compared to historical control w/o chemo (no actual evidence that outcomes superior to RT alone)
- However, associated with more chemo-related toxicity (30% febrile neutropenia)
Surgery (WLE +/-ND)
- Further re-excision, aiming for at least 3cm margin
- Morbid surgery (and will need graft)
- Avoid radiotherapy
A 42-year-old man, previously treated with chemotherapy for acute myeloid leukaemia, is referred following relapse
for total body irradiation prior to a bone marrow transplant.
a. What wold you explain to the patient about the rationale for total body irradiation and possible acute side effects that he may experience (3m)
Rationale:
1)Bone marrow ablation
(2) Immune suppression to prevent Grf vs Host
(3) Residual tumour ablation
(4) Sanctuary sites (e.g. testes/brain).
Acute SEs:
Nausea/vomitting (within 2-4 days), parotiditis (common 2-4 days post), dry eyes/xerostomia (up to a month), dysguisa, fatigue, erythema, epilation.
Describe a suitable radiation therapy technique and dose fractionation schedule for TBI. Justify your answer
DOSE PRESCRIPTION
* 12Gy in 6 fractions, 2 Gy per fraction, 2 fractions per day, over 3 days
* Prescribed to a single point at midline of the patient (usually umbilicus)
* (Other dose options: 2Gy/1#, 13.2Gy/11#, 4Gy/2#)
Pre-SIM
* MDM discussion
* Fertility preservation referral
SIMULATION
* Position: supine, upper arms on side resting on 4cm polystyrene (maximise lung shielding from lateral beam),
and hand resting on abdomen
* Planning CT: 3mm slice covering the entire body length (from vertex to mid-thigh)
TARGET VOLUME
* Entire body contour
TECHNIQUE
* 4-field equally weighted MV photons AP/PA and opposing lateral, with extended SSD (4m) and largest practical
field size
* 6/10/18 MV (avoid 18MV if possible)
Alternate APPA and oppose lateral for each fraction (e.g. APPA for fraction 1, 3, 5, lateral for fraction 2, 4, 6)
Lateral field Position:
* patient lie supine, small sponge under head, knee fix,
* Upper arm resting on 4cm polystyrene (to reduce lung dose)
* Hand resting on abdomen
* Trolley turn around for the opposing lateral field treatment
Compensator/ bolus (‘beam spoiler’) – (because of skin-sparing effect of photon)
* Super-flab – on lateral and anterior surface of neck + chest (to reduce dose to lung)
* Perspex – as head frame compensator, and from mid-thigh inferiorly (thicker from mid knee
inferiorly)
AP/PA field Position:
As above but:
* patient lie on side, head sponge under head, patient’s torso support with pillow (on beam exit side),
towel and pillow between legs
* Patient facing linac head for AP, and turned around, facing away from linac head for PA
Verification:
Physics QA prior to treatment
- Light field – TBI laser run along the incident surface of patient’s pelvis, coverage of whole body within the light
field
- TLD for dose verification on each body site of interest
What dose would you generally prescribe for TBI? How would you verify this? (2m)
Verification:
Physics QA prior to treatment
- Light field – TBI laser run along the incident surface of patient’s pelvis, coverage of whole body within the light
field
- TLD for dose verification on each body site of interest
Describe the technical difficulties that arise in TBI, and how these are overcome? (2m)
POTENTIAL TECHNICAL ISSUES
1) Large field
* Extended SSD (4m), may need special bunker set up/ trolley arrangement
2) Dose in-homogeneity
* Assumption that whole body is a block of homogenous density
* Varying body thickness and separation along the patient’s length – need ‘beam spoiler’ e.g. Perspex head compensator/ below thigh, and super-flab around anterior/ lateral neck
* Uneven tissue density in body (lung/ bone/ soft tissue) – take into account in treatment planning process
3)Treatment verification
* Only based on crude verification – that patient in line with the laser ligh
What physical and pharmacological measures should be employed when a patient attends for TBI treatment in radiation facility (1m)
Physical measures
- choose appropriate standing (up to 3omins) vs. lying technique.
Pharmacological measures
- Anti-emetic pre-treatment
- Dexamethasone
- Pre-med lorazepam
Intermediate and late side effects of TBI:
Intermediate
* Somnolence syndrome
* Pneumonitis (common – occurs in 50% of cases, and fatal in 50% of those with pneumonitis)
* Pancytopenia
Late
* Gland: Xerostomia, dysgeusia, sicca syndrome (dry eye/ dry mouth)
* Sterility/ need for hormone replacement (very common)
* Cataract (30-40%)
* Thyroid dysfunction (common) – hypothyroidism, thyroiditis
* Decreased bone mineral density
* 2nd malignancies (5% at 15 years)
A number of regimens have been developed in which TBI is replaced with additional chemotherapy agents.
What advantages and disadvantages of this approach? (2m)
Advantages of chemo
- Avoid RT toxicity and late effects of RT
- RT may be contraindication in some patients
o Connective tissue disorders, or radiosensitivity syndrome
o Previous high dose to lung
o Concern re: lung toxicity
- TBI not widely available
Disadvantages of chemo
- Depends on blood supply for delivery of chemotherapy
- influenced by variability in drug absorption, metabolism, biodistribution, or clearance
kinetics – may cause renal/ liver toxicity
- May not penetrate sanctuary sites e.g. testis and brain
- Chemo-resistant clones may be better treated with RT
a. A well 40-year-old female presents with intermenstrual bleeding. Clinical
examination reveals a 5 cm mass arising from the cervix. Biopsy confirms
squamous cell carcinoma.(1)
i. List and explain the components of an Examination under Anaesthetic (EUA).
Components of EUA to determine extent of disease:
Pt in lithotomoy position
1) External examination and palpation: of vulva, vagina, cervix, bimanual examination, DRE.
2) Internal examination:
Speculum examination and or hysteroscopy +/- biopsy.
Cystoscopy and/or proctoscopy may also be included.
a. A well 40-year-old female presents with intermenstrual bleeding. Clinical
examination reveals a 5 cm mass arising from the cervix. Biopsy confirms
squamous cell carcinoma.(1)
ii. Discuss the relative benefits of various imaging modalities
USS (not needed) benefits: Commonly available, results may help speed up further workup, no radiation (e.g. if pregnancy), can detect tumour and suspicious soft tissue changes (e.g. parametrium)
MRI: Best resolution of soft tissues allowing pre-op staging of tumour invasion, and nodal involvement.
CT staging: For systemic staging, local disease and hydronephrosis. More accessible than PET
PET CT – Sensitive for local and systemic disease, allows more accurate staging
In general, list the prognostic features that influence local control and survival in cervical cancer.
Patient: Functional status, immune suppression, older age (>60), socioeconomic status, smoking status, Hb<110
Tumour: Nodal status and T stage (i.e. invasive higher risk recurrence and systemic spread), M stage (ie. Survival and approach to local control), LVI, DOI, tumour differentiation (poor vs well diff). Cell histology: in order worse to best prog small cell, adenosquarmous, adenoCa, SCC (basaloid SCC most aggressive SCC subtype).
Treatment: Overall treatment time (aim complete within 8 weeks, or <7 weeks), concurrent chemo (OS benefit), brachy boost available (OS benefit).
This patient is diagnosed with a squamous cell carcinoma of the cervix with a 2cm para-aortic lymph node at the level of the third lumbar vertebrae (FIGO Stage IIIC2). Definitive chemoradiation is recommended.
For the external beam component describe in detail
i. Target volumes.
TARGET volumes for EBRT phase
GTVp = primary on imaging (CT/PET/MRI), GTVn = Involved nodes on imaging
CTV55 = GTVn +1cm.
CTV45= (GTVp + 1cm), cervix, uterus, upper ½ vag, parametrium.
PTV45 = CTV45 +1.5cm to account for bladder/rectum varaiation.
CTVpelvis 45 = GTVn + Obturator, external, internal iliacs. Include inguinal nodes if lower 1/3 vag involved. Consider common if high risk. Extended field - 2cm above highest positive node.
This patient is diagnosed with a squamous cell carcinoma of the cervix with a 2cm
para-aortic lymph node at the level of the third lumbar vertebrae (FIGO Stage
IIIC2). Definitive chemoradiation is recommended.
For the external beam component describe in detail
ii. Dose fractionation schedule.
Dose: Curative intent EBRT VMAT technique, 6Mv photons, to primary and pelvis 45Gy/25#s, boost involved node to 55/25, 5#s/week. Prescribed to D50.
This patient is diagnosed with a squamous cell carcinoma of the cervix with a 2cm para-aortic lymph node at the level of the third lumbar vertebrae (FIGO Stage
IIIC2). Definitive chemoradiation is recommended.
For the external beam component describe in detail
ii. Organs at risk.
Rectum, small bowel, bladder, lumbar plexus, cauda equina, large bowel, femoral head, potentially kidney.
For soft tissue sarcoma:
a. Describe the pathogenic risk factors (2m)
- Genetic predisposition (5%) – e.g. NF(NF-1), Familial Rb (Rb-1), Li-Fraumeni (p53, 17p13), Gorlins (PTC -> PTCH in Shh), the inbred Triad of Carneys (c-Kit - so GIST).
- Prior radiotherapy e.g. undifferentiated pleomorphic sarcoma, angiosarcoma
- Chronic iritation/inflammation
- Carcinogen exposure
- Viral infection HIV/ HHV8 for Kaposi sarcoma
For soft tissue sarcoma:
b. Describe the biological behaviour (2m)
Local
- Locally invasive
- Grow along path of least resistance initially (e.g. within muscle fascia/ compartment),
before eventually invade nerve/ vessels
Nodal Haematogenous Outcomes
- Nodal spread is rare (<5%) – higher in certain histology (CARE i.e. clear cell, angiosarcoma, rhabdomyosarcoma, epithelioid)
METS
- Most common route of spread is haematogenous
- Most common site lung> bone> bone marrow> liver> brain - depends on subtype (e.g. Myxoid Liposarc and angiosarc can go to skin)
Outcome: Depends on grade, nodal and met involvement, operable status and subtype (e.g. 30% 5yr OS for Leiomyosarcoma).
Clinical Features of Melanoma:
Epidemiology of Melanoma:
CLINICAL FEATURES (ABCDE)
* Asymmetry
* Border irregular
* Colour
* Diameter
* Evolve (mole evolve over time)
Mean age 50
2nd most common cancer in NZ
M>F
Regarding Lentigo Maligna or Hutchinson’s Melanotic Freckle, describe its (2.5):
i. Epidemiology and common locations.
Ii. Macroscopic appearance.
Iii. Biological behaviour.
iv Microscopic appearance
10% of all melanomas
Most common in elderly european population (age>70)
Most common sites are head and neck, and arms.
Ii. Macroscopic appearance.
At first, often resembles freckles or brown marks (lentigines). Becomes more distinctive and atypical in time, often growing to several centimetres over several years or decades. Like other flat forms of melanoma, can be recognised by ABCDE rule
Macro: freckle-like pigmented macule
Micro: lentiginous growth (continuous single cells at base of epidermis), often in
atrophic epidermis, ill-defined borders
Iii. Biological behaviour.
Can be slow growing over many years. 5-10% of cases develop invasive melanoma, which may result in itchiness, pain, thickening or ulceration of the lesion.
iv. Micro = Lentigenous spreading in sheet of cells at base of dermis, often occuring in atrophic skin. Not invading through basement layer.
Describe the BRAF signalling pathway and its significance in the development of cutaneous melanoma. Include in your answers the incidence of BRAF mutations and list its two most common variants.
BRAF is an intracellular part of the receptor tyrosine kinase signal transduction pathway. Where Growth factor (E.g. EGFR) binds the extracellular domain of RTK, leading to signal transduction via the following molecules: RAS (NRAs mutations 20% of melanomas) followed by RAF (BRAF mutations in 50% of melanomas) followed by MEK and ERK. Mutations in this pathway lead to increased cell growth/proliferation and apoptosis evasion, leading to increased potential for malignant transformation. Of the BRAF mutations BRAF 600E and 600K are most common (70 and 20% respectively) - can be target by BRAF inhibitors (Eg Debrafinib).
Regarding Superficial Spreading Melanoma, describe its (2.5):
i. Epidemiology and common locations.
Ii. Macroscopic appearance.
Iii. Biological behaviour.
iv Microscopic appearance
Most common subtype of melanoma - accounting for 70%
M>F
25% from existing dysplastic naevus, 75% de novo
a/w intermittent sun exposure of affected skin, light skin (Fitzpatrick skin type), younger group, a/w naevi
Macro: As per other superfical spreading can be identified by ABCDE
Micro: Radial (non-invasive) and pagetois growth components.
IHC+ve S100, SOX10, Melanin-A
IHC -ve EMA (i.e distinguish from Merkel)
Molecular: BRAF V600E or K, NRAS, kit unlikely for this subtype
Biobeh:
25% from existing dysplastic naevus, 75% de novo
Often long period of radial/superficial growth with fast appearance of nodules/invasive disease.
Less likely to spread via lymphatics/haem/skin than nodular melanoma.
For testicular germ cell tumours, describe:
a. The risk factors for their development (2.5m)
For testicular germ cell tumours, describe:
a. The risk factors for their development (2.5m)
* Cryptorchidism (abdominal cryptorchid testis higher risk than inguinal cryptorchid testis)
* Intratubular germ cell neoplasia (ITGCN)
* Testicular development disorders/ gonadal dysgenesis (e.g. Klinefelter syndrome)
* Family history
* Hypospadias
* Previous contralateral testicular cancer
* White race
* HIV
For testicular germ cell tumours, give the related serum tumour markers and their clinical application (5m)
General applications: Are not suited to screening (lack sens/spec), can help point to a Dx at initial work-up (e.g. AFP raised the not seminoma), along with disease extent, Monitoring for residual/progression.
AFP: If elevated not a seminoma, often elevated in embryonal (60%) and yolk sac (almost always)
BetaHCG - both seminomas ~10% (execpt spermatocytic) and NSGCTs may have raised levels - especially choriocarcinomas.
A 30 year old man undergoes an orchidectomy. Histology demonstrates pure seminoma.
a. What factors would you take into consideration when deciding on a management plan for this patient? (2m)
Patient
Fitness for treatment
- Radiotherapy (connective tissue disorders/ inflammatory bowel disease, horse-shoe kidney) Compliance with surveillance if opt for no adjuvant treatment
Fertility/ family planning
Patient’s preference
Tumour
Stage of disease – nodes involvement and size of node (Stage II)
Treatment
Previous abdominal/ pelvic RT
Outline the evidence for Mx approach to stage 1 (LVI negative) seminoma:
Surviellance: Retrospective data (relapse rate ~ 20%) Mortality 0.2% (due to effective salvage therapies)
TE19: 1-2 cycles Cyclophos vs Par-aortic RT (20/10). Both decrease recurrence to 5%, Chemo may be less toxic.
1)Describe a suitable technique and dose prescription for stage 1 seminoma post surgery:
2) Justify the target volume described above (1m)
Adj Para-aortic strip EBRT to reduce risk recurrence from 20% to 5%.
20Gy in 10 fractions, 2Gy per fractions, 5#s/wk VMAT technique, 6MV photons prescribed to D50
Pre-SIM
- Fertility counselling/ sperm banking
SIM
- Position: supine, arms up, head towards gantry
- Immobilisation: vac bag, knee fix, ankle support
- Additional: Clamshell for testicular shielding
- Planning CT: 3mm slice CT from mid thorax to mid-thigh Target volumes
IVC and aorta from 2cm below sup pole of kidney to bifurcation, expanded by 2cm (trimmed to boundaries), PTV 0.5cm.
- No hotspot of >107% in the field
- Review OAR DVH
o Kidney: Dmean<8Gy (=V8Gy<50%)
o Testicle: ALARA < 0.5Gy Treatment verification:
- Daily kV matched to bone, with 3mm tolerance
Justify vols:
MRC study showed that in patients with Stage 1 seminoma, there is no differences in relapse and OS between patients who had PA strip RT vs. dog-field RT
A 66-year-old man presents with a 3-week history of mid epigastric pain, 5% weight loss and fatigue. A GP orders an ultrasound which demonstrates a 4cm mass in the head of pancreas. History and examination is otherwise unremarkable.
a. How would you further evaluate this patient and justify your answer (2m)
Hx:
Symptoms: duration and tempo of pain, LOW, fatigue, nausea/ vomiting
- Address any acute symptoms e.g. analgesia for pain, anti-emetic for n+v
Risk factors: history of pancreatitis, cigarette smoking, obesity, diabetes, alcohol, family history or any genetic mutations e.g. BRCA
Fitness for treatment:
- General: ECOG, comorbidities
- Surgery: cardio/respiratory function
- Radiotherapy: connective tissue disorders/ previous chest/ abdo RT
Ex:
Jaundice
Abdominal examination – any palpable hepatosplenomegaly
Lymphadenopathy
Tests:
Bloods: LFTs (bili obstruction, mets, suitable for chemo), Lipase (pancreatitis), CA19.9, protein/alb (malnutrition), Baseline pretreatment FBC/U&E
Imaging:
- CT pancreatic protocol
- MRI (abdomen/ pelvis)/ MRCP
- FDG PET
Tissue diagnosis:
- EUS (preferred method) – better yield, safe, lower risk of peritoneal seeding (but risk of false negative)
- ERCP – may be useful if symptomatic obstructive jaundice requiring stenting
In general, what factors might determine whether a patient with pancreatic cancer is suitable for resection? (2m)
The critical things are arterial contact (none with coliac axis, sma or common hepatic), and venous (at most limited contact with SMV or portal vein).
Patient factors
Tumour factors:
- No distant mets
- No arterial tumour contact with coeliac axis, SMA, and common hepatic artery
- No radiographic evidence of SMV or portal vein contact, or <180degree contact without vein contour irregularity
This woman (left thigh HG myxoid) is discussed in a multi-disciplinary sarcoma meeting and a recommendation of preoperative radiation therapy is made.
c. Describe a suitable radiation treatment technique and dose prescription for this patient. (2m)
I will recommend pre-operative radiotherapy to the left thigh lesion to a total dose of 50.4Gy in 28 fractions, 1.8Gy per fractions, 5 fractions per week to Left thigh sarcoma. RT technique
- VMAT with 6MV photon with partial arc, prescribed to D50.
Pre-SIM
- MDM discussion
SIM:
- Position: supine, slight frog leg, arms on chest, head towards gantry
- Immobilisation: vac bag
- Planning CT: 3mm slice CT from mid abdomen to below knee
Fusion: MRI and FDG PET
Target volume:
- GTV = visible disease based on planning CT, and fused MRI/ FDG PET (T1 sequence + contrast)
- CTV = GTV + 1.5cm radial expansion + 4cm sup-inf expansion (include all oedema on T2 sequence)
- PTV = CTV + 1cm expansion
Plan evaluation
- Tumour coverage: PTV D98>95%
- Minimise hotspot: PTV D2< 105%, ensure no hotspot outside of PTV
- Ensure sparing of a strip of skin/ subcutaneous tissues for lymphatic drainage
- Review OAR DVH
o Weight bearing bone: Dmax< TD, <50% of circumferences of bone< TD, avoid dose across joint
Treatment verification
- daily CBCT, matched to bone with soft tissue review, ensuring tumour covered within PTV
Compare Ewings and Osteosarc in terms of:
X-ray/ CT
features (1.5m)
Ewings:
Lytic destructive lesions
Located at diaphysis
‘moth-eaten’, ‘onion-skinning’
Codman’s triangle
Osteosarc:
Sclerotic lesions
Located at metaphysis
‘sun-burst’ pattern (new bone formation)
Codman’s triangle
Compare Ewings and Osteosarc in terms of:
Aetiology/ risk
factors (1m)
Ewings: no known risk. Young age, European ancestry.
Osteo: Rb mutation (next most common event after the eye). Li-Fraumeni, previous RT, Paget’s disease.
Compare Ewings and Osteosarc in terms of:
Microscopic
histopathology
(3m)
Ewings: Small round blue cells
Homer-Wright pseudo-rosettes
Osteosarc: Malignant osteoid
High grade spindle cells
No small round blue cells
Compare Ewings and Osteosarc in terms of:
IHC markers (1m)
Ewings: EWS FLI1+, CD99+,
Osteosarc: Histo Dx. CD99+ (like Ewings)
Compare Ewings and Osteosarc in terms of:
How is response to neo-adjuvant chemotherapy assessed histologically in both tumours (1.5m)
Ewings:
* Assessed by extent of % of tumour necrosis (% of viable tumour cells)
Osteo:
* Huvos grading (based on degree of necrosis (G1-2 = poor response; G3-4 = good response)
o Grade 1: no treatment effect (<50% necrosis)
o Grade 2: 50-89% necrosis
o Grade 3: 90-99% necrosis
o Grade 4: 100% necrosis, no viable tumour
Clinical implications
o Predict LC and survival, independent of complete resection
o May guide decision on adjuvant radiotherapy
o No evidence for intensification of adjuvant chemotherapy in poor responders
For malignant mesothelioma:
i. What is the main risk factor and briefly how does that cause carcinogenesis?
ii. Name a few other risk factors
> 90%:
- Asbestos exposure
- Carcinogenesis:
2 Pathways:
1. Asbestos causes ROS mediated DNA strand breaks and mutation leading to malignant transformation via increased mutation rate.
- Pleural macrophages
- Further mesothelia DNA damage through release of ROS and TNF alpha.
- Chronic inflammation providing tumour promoting environment.
Other RFs:
- Previous thoracic radiotherapy
- Viral oncogene – Simian virus (SV-40)
- Genetic susceptibility – loss of expression of BAP1, homozygous deletion of CDKN2A like grd4 Astro
- Other mineral fibres e.g. erionite
Describe the main histological subtypes and immunohistochemistry of mesothelioma (2m)
- Epithelioid – cuboidal columnar cells, with psammoma body, favourable prognosis
- Sarcomatoid – spindle cells, poor prognosis
- Mixed/ biphasic – mixed of epithelioid and sarcomatoid features (at least 10% of each)
- CK5/6 +
- Calretinin +
- WT1+
- TTF1-
- Napsin-A-
Describe the options that are available for the management of pleural effusions in the setting of malignant
mesothelioma. What are the advantages and disadvantages of each approach (4m)
From least to most invasive:
1) Observation - Reasonable option if
asymptomatic/ depends on
severity of effusion BUT
- Non-invasive
BUT, may be symptomatic down the
track
2) Pleural tap
(thoracentesis)
- Invasive (relatively)
- U/S guided tap BUT
- More likely to re-accumulation
- Risk of infection
- Risk of pneumothorax
3) Indwelling pleural
catheter (pig-tail)
- Patient can self-drain at regular
interval e.g. every 2nd day or
when symptomatic BUT:
- Risk of infection
- Dislodgement
- Risk of pneumothorax
4) Talc pleurodesis - Reduce risk of re-accumulation
of pleural fluid BUT:
- More invasive
- Risk of infection
- Risk of pneumothorax
- Inflammatory like symptom
5) Pleurectomy + decortication
Discuss the role of the following in the systemic therapy of GBM. What are the main toxicities of these agents:
(3m)
i. Temozolomide
ii. Bevacizumab
TMZ:
- Improve OS when given concurrent/ adjuvant
with definitive RT (Stupp)
- Can be used instead of RT in elderly patients
with MGMT methylation (as per NOA-08 and
Nordic study)!!!!!!
Tox: Myelosuppression - especially thromobocytopenia, also neutropenia.
Bevacizumab:
PFS benefit in order of 3mths
NO role in definitive setting when combined with STUPP.
Tox:
GI bleeds, bowel perf, wound break down, kidney injury.
What are the most important molecular and/ or genetic markers in high grade glioma and outline their
prognostic and predictive significance:
1) IDH:
- Presence of IDH more likely to re-present secondary HG glioma i.e. progression from LG
glioma
- Prognosis – IDH mutation = more favourable outcomes - now defines GBM (if any of: necrosis, TERTmut, EGFRmut, microvasc prolif).
- Predictive – IDH mutation = better response to chemoRT
2) MGMT meth: epigenetic silencing of DNA repair protein (esp due to alkylating agents).
- Prognostic - better outcomes indep of treatment
- Predictive - Response to Tx esp/ TMZ
3) H3K27M: associated with midline glioma.
Prognostic: assoc poor prog.
4) CDKNA2 - upgrades a grd III astro to IV
5) TERT mutation - Prognostic worse outcome in IDHwt
6) EGFRmut - worse outcomes
A patient with GBM has standard definitive Mx.
What is the expected survival outcomes of your recommended treatment (1m)
Expected median OS ~ 14 months (as per EORTC/ Stupp study).
Nat Hx = 4-6months from Dx
Stupp: 14 months
Sub-analysis and other studies suggest 26months for methylated.
d. In general, how may radiation necrosis be distinguished from progressive high grade glioma? (2m)
Needs to be discussed in MDM, or ideally specialised neuroradiologist.
MRI:
Progression (and pseudo) looks like ring-enhancement, whereas Necrosis tends to have “Cut Pepper” appreance.
DWI: Prog has restriction, High FA, lower ADC
Nec has: no restriction, Lower FA, Higher ADC
Spect/PET: Prog has increased metabolic activity.
a. A 57-year-old female presents with seizures. She is otherwise well, ECOG0, with unremarkable examination. MRI brain shows periventricular enhancing posterior cerebral mass without significant mass effect and biopsy confirms primary CNS lymphoma.
List the investigations you would request.(1.5)
How would they know its PCNSL from a Bx only? Assume an eye exam is an investigation (and not an exam). Bloods: LDH, FBC, U&E, HepB/C, HIV (Aids defining). Tissue: BMAT to confirm PCNSL. Lumbar puncture/CSF protein. Imaging: Spinal MRI, PET/CT staging (8%have systemic disease)
a. A 57-year-old female presents with seizures. She is otherwise well, ECOG0, with unremarkable examination. MRI brain shows periventricular enhancing posterior cerebral mass without significant mass effect and biopsy confirms primary CNS lymphoma.
b.What are the key patient and tumour related prognostic factors in this disease? (1)
Patient: Age >60, KPS, co-morbidties that may limit aggressive therapy (including stem cell transplant), morbidity/neurology associated with tumour
Tumour: Response to induction chemo/pre-transplant therapy, systemic spread.
There is no staging just a prognostic score (Poor DEAL): Protein in CSF, Deep brain involved, ECOG>1, age>60, LDH>ULN
Fit well 57F with primary CNS lymphoma.
c. Outline the preferred initial treatment for this patient. What is the disadvantage of (initial radiation therapy? (2)
Is this fit and well patient not considered “elderly” (age <60).
Induction: High-Dose Methotrexate + Rituxumab + Alkylating agent (e.g. TMZ)
Initial radiotherapy prevents selecting a dose based on chemo response (thereby over treating some patients) (ie. Complete response dose 23.4/13, vs 39/26)
Fit well 57F with primary CNS lymphoma.
d. Following initial induction chemotherapy, a complete response is achieved. What are the options for consolidation therapy? Summarise the highest evidence for
each consolidation strategy. (3.5)
CR (age<60)
After above (and if feasible) +/- further chemo (HD-ARAC) then Autologuos Stem Cell Transplant (ASCT) - highest chance of cure. Phase 2 PRECIS trial a complex chemo regime then ASCT is better than Ritux HDmtx and some other stuff then 23.4/13WBRT. Better = improved event free survival, and less neurotoxic.
Or
After above (and if feasible) +/- further chemo (HD-ARAC) then WBRT 23.4Gy/13#. Chemo + WBRT improves PFS (phase 3 RCT) compared to chemo alone
If Elderly: WBRT 23.4/13, alcylating agent maintenance or wait and watch are all potential options,
Fit well 57F with primary CNS lymphoma.
d. Following initial induction chemotherapy, a PARTIAL response is achieved. What are the options for consolidation therapy? Summarise approaches (3.5)
High dose Ifosphamide
Or
WBRT 23.4/13 then boost residual to 45/25
Broadly, with treatment what are the expected outcomes for PCNSL?
Outcomes based on risk factors (PoorDEAL):
Protein elevated CSF
Deep brain structures involved
ECOG>1
Age>60
LDH elevated
0-1 RFs: 2yr 80%
2-3 50%
4 or more 20%
A 39 year old woman present with PR bleeding and a 4cm mass in the anal canal
a. How you would further evaluate this patient (Hx and Ex)? Justify your answer
Hx:
Symptoms: duration and tempo of PR bleeding, pain, urinary symptoms, incontinence,
symptoms of anaemia
- Risk factors: history of other HPV related cancers (vulva/ vagina/ cervical cancer), sexual
history, history of HIV, smoking
- Fitness for treatment: ECOG performance status, comorbidities, previous pelvic RT,
inflammatory bowel disease, contraindication for RT
- Fertility/ family planning
Ex: Peri-anal/ perineal/ vulva skin changes (risk of field cancerisation)
- PR examination – determine extent of tumour and sphincter function
- PV examination – to exclude vaginal involvement
- Abdominal examination for lymphadenopathy (inguinal LN)
A 39 year old woman present with PR bleeding and a 4cm mass in the anal canal
a. How you would further evaluate this patient - Investigations only! ? Justify your answer
Blood test: FBE/ UEC/ CMP/ LFT, HIV (CD4 if HIV+), Beta-HCG
- Imaging:
o MRI pelvis allow better evaluation of local extent of primary tumour
o CT A/P to evaluate extent of local disease and nodal disease
o FDG PET scan to evaluate distant disease
- Tissue diagnosis:
o Examination under anaesthesia + colonoscopy + biopsy of primary
o FNA/ excisional biopsy of palpable/ abnormal inguinal node
o Cystoscopy if bladder involvement
A patient has a biopsy proven squamous cell carcinoma of the distal anal canal. Investigations reveal a 2cm
right internal iliac node. The decision is made to treat with concurrent chemotherapy and radiation therapy
b. Describe dose fractionation schedule (technique next slide)
This is a T2N1a anal SCC, and assuming this patient is fit for curative intent chemoradiotherapy, I will offer:
Definitive chemo to a total dose of 54Gy in 30 fractions with concurrent 5FU/ MMC
Chemo: 5FU/ MMC (MMC IV D1 12mg/m2 + 5FU infusion 1000mg/m2/day D1-4 week 1 and 5)
A patient with a 2cm anal mass has a biopsy proven squamous cell carcinoma of the distal anal canal. Investigations reveal a 2cm
right internal iliac node. The decision is made to treat with concurrent chemotherapy and radiation therapy
b. Technique (dose ect other slide)
Node positive treat like bulky (>4cm). 54/30, 45/30 to nodes
T2N2 (some would not give higher dose to nodes<3cm).
Pre-SIM
- Fertility referral
- Medical oncology referral
- Full bladder/ empty rectum
SIM
- Position: supine, heads towards gantry, arms on chest
- Immobilisation: vacbag, knee fix, ankle support
- Addition: anal marker
- Planning CT: 3mm slice planning CT from iliac crest to mid-thigh
Fuse: staging MRI and PET
Target volume delineation
- GTVp and GTVn based on clinical examination/ MRI/ PET
- CTV54 = GTVp + 2cm + entire anal canal - - CTV54n = GTVn + 1cm isotropic
- CTV45 = CTV54 + elective nodal area (mesorectum + pre-sacral space + ischio-rectal fossa + internal iliac LN +
external iliac LN + inguinal) - !!! I would strongly consider treating the next echelon (common ilacs).
Verification daily CBCT w/soft tissue rev
OARS see below.
OARS for pelvis (anal, cervix)
Small bowel loop V30Gy<200c, Dmax<50Gy
Large Bowel loops = same as small bowel.
Rectum V40Gy <60%(e.g. cervix)
Bladder: V40Gy< 30% (or 35%), V50Gy<5%
External genitalia: V40Gy< 5%
Femoral head/neck: V30Gy< 50%
Kidneys: Mean dose <15Gy
Anal SCC: Outline your follow-up program for this patient (1m)
Clinical review ~ 4 weeks post RT to ensure resolution of acute toxicity
3Months:
- Clinical review (DRE + endoscopic surveillance)
- MRI/ PET 3 month post completion of treatment to ensure CMR and tumour shrinkage, if still residual metabolic
activity, repeat PET in another 3 months
Ongoing clinic review (DRE/exam/Hx, protoscopy).
3 monthly 1st year,
6 monthly 2nd year, annually until 5 years
Post anal SCC defiintive ChemoRT:
If there is residual disease palpable on digital rectal examination at first post-treatment review, how would
you manage this? (2m)
- Reassure patient that complete response can take months (or more)
- Surgical review for endoscopic visualisation +/- biopsy if concern for clinical progression
- If clinically no progression, will review again at 3 month post-completion of treatment with staging MRI and FDG
PET scan + clinical examination
List the malignant tumour arising from the tissues of the endometrium (3m)
- Epithelial
o Endometrial adenocarcinoma
o Uterine serous papillary carcinoma o Clear cell carcinoma
o Undifferentiated adenocarcinoma o Small cell carcinoma - Mesenchymal
o Uterine sarcoma – carcinosarcoma, leiomyosarcoma (LMS), stromal sarcoma - Uterine melanoma
- Uterine lymphoma
- Trophoblastic carcinoma
- Germ cell tumour - ? teratoma
Discuss the evaluation of pathological information of various types in relation to the management of adenocarcinoma of the uterus. (4m)
Mangement (ideally after TAH+BSO+LN sampling) is stage directed:
With key factors:
Invasion (myometrial, stroma, pelvis), favourable (endometriod endometrial adeno grd I-II) vs aggressive subtype (grd III, papilary serous, clear cell, small cell), grade (FIGO Grade=%solid non squarm), LVSI (focal vs extensive, extensive is now stage 2), Node status (+ve = at least stg III), molecular - POLEmut downstages Stg1any to 1A. P53abn any II to IIC.
Stg1A = <50%myo, grd I-II non agressive, no/focal LVI = observation
Stg1B = >50%myo and otherwise 1A = VBT (PORTEC2)
Stg1C = Pelvic RT alone (or consider VBT) PORTEC2
II-IV: ChemoRT + adjuvant chemo (PORTEC3) + VBT if cervix stroma involvement
Briefly describe the macroscopic and microscopic features of uterine serous carcinoma
Macro: Arise on the surface of polyps on background of atrophic endometrium.
Micro: Features of necrosis, with Psamomma bodies!! Typically myo and vasc invasive. Complex architecture - papillary, glandular, solid. IHC: ER/PR-, Ck 7+ CK20-
How does uterine serous carcinoma differ in its mode of spread from endometroid carcinoma (1m)
Endo:
Less aggressive
Spread to lymph nodes and ovaries
Serous:
More aggressive
Spread to peritoneum (need peritoneal Bx) and nodes
Describe the FIGO histological grading system for endometroid adenocarcinoma (2m)
Based on the degree of glandular differentiation, which is described as % non-squamous solid growth pattern
G1 5% non-squamous solid growth pattern
G2 6-50% non-squamous solid growth pattern
G3 >50% non-squamous solid growth pattern (i.e. more sold, less glandular)
What is Lynch syndrome?
Hereditary non-polyposis colorectal cancer (HNPCC):
Autosomal dominant
Caused by germline mutation in any one of the mismatch repair gene s(MSH2, MLH1, MSH6, PSM2), or deletion of the last few exons of the gene EPCAM that results in epigenetic silencing of MSH2
Associated with 20-80% risk CRC, >30% risk of endometrial cancer, 20%Ovarian, 10% urinary tract, 1-5% pancreas, gastric.
How do you test for Lynch syndrome in a hysterectomy specimen?
If specimen is deficient for MMR protein then perfom PCR: MLH1, MSH2, MSH6, PMS2, and EPCAM
A fit 70 year old woman is referred to you following TAH+BSO for a FIGO Stage IB Grade 3 endometroid carcinoma of the uterus (the tumour is confined to the uterus and invades through more than half of the myometrium). Pelvic node dissection has not been performed. - What further treatment would you recommend? Justify your answer (2m)
Give target volumes.
Grd 3 now (new staging) makes stg 1C (assume POLEmut -)
As per PORTEC 3 and GOG 249: Pelvic EBRT alone for LCR benefit 3yr (reduce recurrence from ~15-20% to 5% or less).
45/25 to:
CTVp = upper half vaginal + parametrium + para-vaginal soft tissue.
ITVp = Consider ITV defined as the combined volume of CTVp in both the fused empty and full bladder CT scans
CTVnodes: external (and obturator) and internal and presacral - just like cervix dont do common iliacs.
PTV=CTVs+ 1cm.
Isolated vaginal recurrence of endometriod endometrial adenoC with no metastatic disease
- Describe a suitable radiation technique and dose prescription for this woman’s treatment (4m)
Observation data supports:
Pelvic RT to a dose of 45Gy in 25#s, 1.8Gy/#, 5#/wk (concurrent weekly cisplatin 40mg/m2) followed by adjuvant vaginal vault brachytherapy 28Gy/4.
- Immobilisation: vac bag, knee fix, ankle support
- Planning CT: 2mm slice mid-abdo to mid-thigh, w/full and empty bladder. Fusion: with all available imaging (MRI and PET)
Target volume: - GTV = gross recurrence on vaginal apex based on imaging and clinical examination
- CTV45 = GTV + 1cm + parametrium + paravaginal soft tissue + at risk nodal group (i.e. obturator, internal iliac,
external iliac, pre-sacral LN) - ITV45 = CTV45 contoured on full and empty bladder scan
- PVT45 = ITV45 +1cm
This patients has Stage IB Grade 2 endometroid adenocarcinoma.
Assuming there are no other adverse features, what would you estimate her risk of vaginal and nodal recurrence to be?
Vaginal recurrence ~15%
Nodal recurrence ~10%
(for own notes: PORTEC-2 – 5-yr VR 2% and 5-r LRR 5%)
This patient has Stage IB Grade 2 endometroid adenocarcinoma.
Outline the potential further management option for this patient. Indicate your preferred option and justify your answer. Outline the potential toxicities of your treatment.
Intermediate Risk:
Vaginal vault brachytherapy (VBT) (preferred option)
- Preferred option as per PORTEC 2
- No differences in vaginal recurrence, disease free survival and compared to pelvic
external beam RT but associated with lower toxicity
Toxicity:
- Acute: procedural discomfort, vaginal mucositis
- Late: vaginal atrophy/ dryness/ stenosis, cystitis, proctitis, 2nd malignancy
Adjuvant pelvic external beam RT: Would use if other risk fctors - i.e stage Ic = RT alone (PORTEC3)
Observation: Same OS, but higher %15 LR (name numbers for ball cancer)
Mx options for endometrial recurrence post adj RT:
MDM discussion
Referral to medical oncology (the 3 Ps)
- Medroxyprogesterone (Provera) if ER/PR+ve
- Palliative chemotherapy if fit for chemo
- Pembro - PFS benefit for stg IV
Palliative care
- for psychosocial support and ongoing symptom management
A fit 70 year old woman presents with post-menopausal bleeding. She is diagnosed with endometrial cancer and undergoes a total abdominal hysterectomy and bilateral salpingo-oophrectomy. Pathology demonstrates a Grade 3 endometroid adenocarcinoma with 10 of 12mm myometrial invasion and lymphovascular invasion. Cervical stromal involvement was noted. 9 pelvic nodes were negative for disease (FIGO 2021 Stage II disease).
a. What are the possible treatment options for the management of this patient? Provide the rationale for the preferred option
Concurrent chemoRT (cisplatin) 48.6Gy/27# + vaginal brachytherapy (BT) 10Gy/2# (given cervical stromal involvement) + adjuvant chemotherapy (carboplatin/ paclitaxel) (based on PORTEC-3) – my preferred option
- improves overall survival, failure free survival, and reduce distant metastases
- Pt is in lower risk group than PORTEC-3, but should have discussion regarding the risk/benefits of concurrent and adj chemo.
Adj chemoRT + VBT, no adj chemo - inferior outcomes compared to full PORTEC-3, but spare some toxicities of
adj chemo.
Adj pelvicRT alone (no chemo)
- inferior oncological outcomes compared to full PORTEC-3 regimen; however reasonable option to reduce the risk of LR
Adj VBT alone 21Gy/3#
- not inferior to pelvic RT alone (with lower toxicity as per PORTEC-2);
If contraindicated for RT
- refer to med onc for discussion re: adjuvant chemo alone (GOG-258)
- pt actually slightly lower risk than GOG-258
Observation, with close clinical surveillance –reasonable risk of LR (?30%)
Endometrial Stg II.
A decision is made to deliver pelvic radiation therapy with a vaginal brachytherapy boost. Describe a suitable technique and dose fractionation schedule (4m)
I will offer this patient pelvic external beam radiotherapy to a total dose of 45/25 1.8Gy/#, 5#/ week and vaginal vault brachytherapy boost 10Gy/2#, 2#/ week.
CTVp = upper half vaginal + parametrium + para-vaginal soft tissue
* ITVp = combined volume of CTVP as contoured on full bladder and empty bladder scan, taking into account
bladder/ rectal position
* CTVn = at risk nodal group (obturator, external iliac, internal iliac and pre-sacral node)
* PTV = ITVp and CTVn +1cm
Technique: VMAT technique with 6MV photon Concurrent chemotherapy: cisplatin 50mg/m2 3-weekly.
Vaginal vault brachytherapy component
* Position: supine, use largest vaginal cylinder that will fit comfortably to minimise air pocket
* Target volume: upper half of vagina
* Dose/fractionation: 10Gy/ 2#, 5Gy/#, 2#/ week
* Technique: HDR brachytherapy with Iridium-192 radioactive source, prescribed to 5mm from surface.
Vaginal stenosis is a common complication following treatment for gynaecological cancer. Describe potential prevention and treatment strategies (2m)
- Use of topical oestrogen cream – may promote vaginal mucosa epithelial regeneration
- Use of vaginal dilator, start 2-4 weeks post completion of treatment, 2-3 times/ week, for 5-10 minutes each time
– break down adhesion and stretch vaginal wall to maintain patency - Maintain regular sexual intercourse in women who are still sexually active
A 40yro is referred following incomplete resection of a function pit adenoma (lactotroph) involving the right cavernous sinus. What would be critical in your history and examination?
Cranial examination: detailed focus on CNIII, CNIV, CNVI and V1 and V2.
Also optic chiasm
Sx:
Prolacinaemia: impotence/decreased sex drive (Galactorrhoea extremly rare in males)
Diplopia (e.g abducens palsy or CNIII palsy)
Bumping into things (may suggest bitemopral hemanopia = chiasm)
Scalp/forhead/facial numbness.
Ex:
Fields: e.g temporal hemanopia
Eyemovements: CNIII - Down and out, CNIV, Abducens = diplopia.
Sensation: V1 and V2
What is the role of external beam radiation therapy in heterotopic ossification of the hip? Include in your answer: (3m)
The indications for treatment
The optimal timing of treatment
The target volumes and
Dose fractionation schedules
What are the alternatives to radiation therapy?
Indication - Recurrent HO
Timing - <24 hour pre-op, or <72 hour post-op
Target volume - HO bone island + 1-1.5cm margin to PTV
Dose fractionation - 7Gy/1# , AP/PA dose to midline, spare a strip of soft tissue
Alternative - Surgery followed by NSAID (indomethacin 75-100mg/day) for 7-14 days post-op
List tumours that arises in the sellar region (1.5m)
Benign:
- Pituitary adenoma,
- Rathke cleft cyst
- Craniopharyngioma
- arachnoid cyst
- cavernous sinus cyst
Malig
- Pituitary carcinoma
- Glioma
- Malignant Craniopharyngioma
- Germ cell tumour
- Chordoma
- Metastases
Compare pituitary tumour arising from somatotroph and corticotroph in regards to:
i. Clinical features (1.5m)
ii. Laboratory findings (1m)
Somatotroph:
Headache/ bilateral hemianopia
- Acromegaly, frontal bossing,
macroglossia, prognathism, spade- like hand, LV hypertrophy, enlarged visceral, hypertension, diabetes/ insulin resistance
Corticotroph:
- Headache/ bilateral hemianopia
- Cushing’s disease (hypertension, central obesity,
moon face, buffalo hump, hirsutism, weak muscle strength, skin striae/ stretch marks) osteoporosis, impotence, oligomenorrhea
Labs Somato:
- Elevated GH/ IGF-1
labs Cortico:
- Elevated 24 hour urine cortisol
- Elevated serum cortisol on dexamethasone suppression test
- Elevated cortisol on late salivary test
c. What is the pituitary ‘stalk effect’?
Hyperprolactinaemia from tumour mass at the pituitary gland/ stalk that block delivery of dopamine from hypothalamus to prolactin secreting cells in the pituitary
Describe the pharmacological management of the three most common functional pituitary tumours (2m)
Prolactinoma - Dopamine agonist (bromocriptine, carbergoline)
- >50% will show reduction in prolactin, and 80% will show >25% reduction in volume
GH-oma - Somatostatin analogue e.g. Octreotide (while awaiting surgery) - GH receptor antagonist (pegivsomant)
ACTH-oma - Ketoconazole
A 30-year-old female presents with headache and diplopia. A CT brain shows a 2.5cm sellar mass with involvement of the cavernous sinus.
a. What further information from her physical examination
- Visual field testing – bilateral hemianopia
- Cranial nerve examination (for assessment of CN involvement from cavernous sinus
extension III, IV V1, V2, VI) - Signs of hormone hypersecretion
o Lactotroph – hypogonadism, galactorrhea,
o Somatotroph – acromegaly (frontal bossing, macroglossia, prognathism (projecting
lower jaw), large hand and feet, coarse skin, enlarged viseral
o Corticotroph – Cushing’s syndrome (weight gain, truncal obesity, moon face, buffalo
hump, striae), hypertension, glucose intolerance, osteoporosis o Gonadotroph – precocious puberty
o Thyrotroph – tremor, palpitation, fine brittle hair
What would you tell the patient about the expected outcome of radiation to a partially resected non-function pit adenoma? What potential treatment toxicities would you discuss with her? (2m)
Local control Radiographic response based on size ~90-100%
Acute:
- Fatigue
- Skin dermatitis, alopecia
- CNS: headache, nausea, vomiting, worsening neurology
- Eye: corneal irritation, dry eye Late:
- pan-hypo-pituitarism (most important) – up to 80% at 10 years
- optic chiasm injury
- cerebrovascular event
- 2nd malignancy (e.g. meningioma)
A decision is made to give adjXRTpartially resected non-function pit adenoma. Describe a suitable radiation therapy technique and dose fractionation schedule. (4m)
Make it SRS
Stereotactic radiosurgery of 16Gy (20Gy functional, 25/5 SRT) in 1# to improve LC
Pre-SIM
- Baseline hormonal profile
- Baseline ophthalmology + neurology + endocrinology review
- Post-op MRI SIM
- Position: supine, arms down, head towards gantry
- Immobilisation: thermoplastic mask/ stereotactic frame, vac bag, knee fix, ankle support
- Planning CT: 1mm slice planning CT with IV contrast Fusion: diagnostic and post-op MRI
Target volume:
- GTV = residual tumour on post-op MRI
- CTV = GTV
PTV = GTV + 1mm (3mm if SRT)
Oars for treating something in the middle of the chest (e.g. esophagus):
Spinal cord Dmax 45Gy,
Lungs V20Gy<20%,
Heart Kidney V40Gy<20%, consider split renal function if mean dose to one kidney >15Gy,
Liver V30Gy<30%,
Large bowel V15Gy<120cc.
a. With regards to Barrett’s oesophagus, describe:
i. Macroscopic and microscopic appearance (1m)
Macro:
red velvet-like “salmon flesh”
Microscopic
- Metaplasia: Replacement of non-keratinized stratified squamous epithelium with ‘intestinal- type’ columnar epithelium with goblet cells
- Dysplasia: nuclear polychromasia, irregular nuclear size and shape, prominent nucleoli, high N: C ratio, increased mitotic activity
a. List common posterior fossa tumours in children (1m)
BEAM (Brain stem glioma, Ependymoma, Astrocytoma, Medulloblastoma)
b. What are the microscopic features of classic ependymoma (2m)
- Cellular neoplasm with sheet like growth pattern
- Presence of perivascular pseudo-rosette (ependymal cell surrounding vascular lumen, which creates a nucleus
free zone around the lumen) - Ependymal rosette (present in ~ 10% of cases)
IHC: GFAP+ (i.e.glial origin), EMA+(i.e. endothelial differentiation), S100+, vimentin +
a. With intracranial germ cell tumour (ICGCT) in adults, what are the most common symptoms and physical
examination findings? (2m)
Usually arise from proximal 3rd ventricle more commonly than pineal:
Pineal - Compression of 3rd ventricle -> hydrocephalus, Nearby structures include optic pathway (LGN, radiations) causing visual Sx.
Suprasellar:
Classic triads: diabetes insipidus + precocious puberty + visual deficit (bitemporal hemianopia)
Hypothalamic/ pituitary dysfunction
* Diabetes insipidus due to reduced ADH
* GH abnormalities: delayed/ precocious puberty
* Isolated GH deficiency
* Hypothyroidism
* Adrenal insufficiency Ophthalmologic abnormalities
Regarding ependymoma of the spine. Outline: (2.5m)
i. Epidemiology
ii. Clinical presentation
i. Epidemiology – uncommon, bimodal age distribution (<5y/o, and 30-40 y/o)
ii. Clinical presentation – chronic back/ sacral/ lower leg pain; 1⁄4 may present with leg weakness or
sphincter dysfunction
Regarding ependymoma of the spine. Outlines: (2.5m)
iii. Histological subtypes and their common locations
iii. Histological subtypes and their common locations
Cervical/thoracic: spinal ependymoma, myc-amplified spinal ependymoma, subependymona, tancytic ependymoma.
Lower cord: myxopapillary ependymoma.
- G1: Myxopapillary ependymoma – more commonly in spinal cord/ filum terminale
- G1: Sub-ependymoma – most common in 4th ventricle
- G2: Classic ependymoma - intracranial
- G2: Tancytic subtype – usually in spinal cord
- G3: Clear cell subtype – usually supratentorial
- G3: Anaplastic ependymoma – intracranial
- G4: Ependymo-blastoma - treat like glioblastoma
Briefly discuss the prognostic factors in ependymoma (2m)
Pt: Age - see agreesive subtypes and spine location more common in adults (e.g. spinal myxopapillary ependymoma).
age <3 may limit options - but in some cases GTR + chemo equivalent to GTR+immeadiate RT
Males worse outcome
Tumour: Grade/aggressive subtype - anaplastic or worse ependymal-blastoma. Genetic: 1q gain, unfavourable molecular sub type.
Treatment: STR or worse unresectable.
A 36-year-old man presents with a 4 week history of progressive headaches and nausea. MRI brain demonstrates a mass arising from the 4th ventricle typical of an ependymoma causing early obstructive hydrocephalus.
a. Describe how you would further investigate and manage the patient. Justify your answer (2m)
Ix:
* Complete whole spine MRI for staging
* Lumbar puncture to ensure no spinal/ CSF mets (when safe i.e. when no increased ICP) !!!!!!! Can do 2 weeks post surg.
Mx:
Manage acute symptoms – analgesia, dexamethasone, ondansetron for headache/ nausea/ vomiting
Neurosurgical opinion:
- Shunting if required/ concern re: increased ICP
- Gross total resection of mass for tissue diagnosis and treatment
The patients undergoes surgical resection. Histology shows anaplastic ependymoma WHO Grade III. Post-op MRI shows minimal residual disease in the posterior fossa. Staging is otherwise clear
b. What treatment would you recommend for this patient? Include in your answer a suitable radiation therapy
technique and dose fractionation schedule including normal tissue dose constraints (3m)
Adj RT to the tumour bed alone to a total dose of 59.4Gy in 33 (if grd II then 54/30), 1.8Gy/#, 5#/week to reduce LRR. Aim to start RT within 6-week post-op. VMAT technique, 6MV photons prescribed to D50. Aim PTV D98% > 95%PD.
- CTV59.4 = surgical bed + post-op residual disease + 1cm, clipped at anatomical boundaries
- PTV = CTV + 5mm expansion
What investigation would you perform on a patient with a suspected Intracranial GCT? Justify your answer (3m)
Blood
AFP/ B-HCG (germinoma usually normal AFP/ HCG; NGGCT usually elevated)
Imaging
MRI whole brain/ spine: Spine mets are common in some subtypes (e.g. yolk sac).
Tissue diagnosis
Surgery for tissue diagnosis. Resection extent (if any), Subtype and grade guide management/dose.
What radiation therapy volumes you recommend for adult intra-cranial germinoma vs. non-germinoma tumour (3m)
Germinoma (1.5Gy/#)= WVRT+Boost, unless mets then CSI + GTV boost
NGGCT (1.5Gy/#)= CR/Pr = WVRT+Boost, unless mets or no response then CSI + GTV boost
WVRT = entire ventricle (include lateral, 3rd and 4th ventricle) and supra-sellar cistern + pineal cistern + pre-pontine cistern
CSI = CSI = entire brain parenchyma + thecal sac (down to ~ S2 level based on MRI)
Tumour bed boost =
GTV + 1cm = CTV CTV + 3mm = PTV
What radiation irradiation doses would you recommend for adult intra-cranial germinoma vs. non-germinoma tumour (3m)
Dose depends on response to chemo and presence of Mets.
Germinoma always 1.5Gy/#, and boost always 12Gy:
CR: 30/20 (18Gy whole vent, 12 boost)
PR: 36/30 (24 whole vent, 12Gy boost)
Met: CSI 24/16 Boost 45/25 (GTV+met)
NGGCT 1.8/Gy:
CR/PR: 30.4Gy/17 whole vent.
If non-response after chemo: CSI 36Gy/20#, 1,8Gy/#
Tumour bed boost to total 54Gy/30#
Bladder cancer: List the findings that should be included in the cystoscopy and histopathology reports.
Cystoscopy findings: Site, size, description of lesion (e.g. seated, flat), number of sites involved, tis/Cis, UO involved, Extent of Macroscopic resection, Overt muscle invasion/perforation, tissue taken.
Histo: Whether sample includes mucosa and muscle, macroscopic description of tissue and number samples collected, Histo: Tumour description and type and grade, extent of muscle/mucosal invasion, IHC as below.
ii. List the common immunohistochemical stains used to identify urothelial
carcinoma.
IHC: HMWCK+ (marker of urothelial origin), CK7+ Ck5/6 -ve
b. List the risk factors for the development of carcinoma of the bladder. (2)
Older age (>70),
smoking,
chronic inflammation (e.g stones, recurrent UTI, permanent catheters)
Immunsupression,
previous bladder cancer,
radiation exposure,
chemical exposure (e.g. cyclophosphamide),
congenital urogenital malformations.
Describe 2 potential pathogenesis pathways for the development of multifocal bladder cancers. In what other tumour sites can this phenomenon occur? (3)
Monoclonal cell pathway: Transformation of a single cell, with further genetic alterations/mutations with replication progressing through hyperplasia or in-situ disease to invasive cancer with potential for INTRA-EPITHELIAL SPREAD and INTRA-LUMINAL SEEDING to multiple sites with ongoing growth.
Field-cancerization: Repeat cell injury/cytoxic exposure (e.g. recurrent UTI, chronic inflammation from IDC, cyclophosphamide), leading to genetic (e.g chromosome 9 deletion in bladder Ca) and epigenetic changes in cells at multiple sites (progressing through hyperplasia or dysplasia). Each such cell with increased probability of malignant transformation to invasive disease and therefore multiple sites (multifocal) of cancer. Besides bladder, Head and Neck, and oesophagus are other examples of field cancerisation.
d. Regarding squamous cell carcinoma of the bladder, describe the: (2.5)
i. Potential pathogenesis.
SCC common pathogenesis: chronic inflammation/IRRITATION (e.g. permanent IDC), leading to increased proliferation and abnormal maturation of transitional cells with squamous metaplasia, the accumulation of mutations including p53 and gain of function mutations leading to increased growth, cell death evasion, further mutations and malignant transformation.
