Chapter 25: Intro to Oncologic Surgery Flashcards
Generally speaking, what alterations results in the formation of cancer?
- Activation of tumor-promoting factors via oncogenes
or - Loss of innate tumor inhibitory effects via tumor suppressor genes (e.g. p53 “guardian of the genome”)
What are the (6) phenotypic characteristics of cancer cells?
- Self-sufficiency in growth signals
- Insensitivity to anti-growth signals
- Tissue invasion and metastasis
- Limitless replicative potential
- Sustained angiogenesis
- Evasion of apoptosis
Which forms of neoplasia have confirmed, true genetic heritability in animals?
- Osteosarcoma of Scottish Deerhounds
- Renal cystadenocarcinoma in GSD
- Nodular dermatofibrosis in GSD
List (5) biologic carcinogens in animals:
- FeLV and lymphoproliferative diseases
- Feline sarcoma virus and FSA (must also be infected with FeLV)
- Papillomavirus in puppies. Papilloma can lead to formation of SCC in rare cases
- Spircocerca lupi and esophageal sarcomas in dogs
- Transmissible venereal tumor by direct cellular transmission
List (5) physical carcinogens:
- Asbestos and mesothelioma in humans
- Injection-site sarcoma in cats
- Post-trauma ocular sarcomas
- Microchip-associated FSA
- TPLO metallurgy and canine OSA
List the four possible mechanisms which can transform genes into oncogenes:
- Retrovirus-mediated transduction
- Translocation mutation
- Amplification
- Proviral insertion
Translation of oncogenes leads to transcription of key proteins such as….
- Growth factors
- Growth factor receptors
- Cytoplasmic kinases/Ras
- Transcription factors
- Antiapoptotic proteins
What are Ras oncogenes?
Lead to production of membrane-associated proteins that have a key role in cell signalling leading to activation of various cell-proliferative pathways
What are the two forms of tumor suppressor genes?
- Gate keepers - Inhibit growth while promoting cell death (eg. p53)
- Care takers - Ensure DNA repair while maintaining genomic stability
p53 is one of the most common mutations. It is crucial for normal cell cycle and serves as a checkpoint for entry into apoptosis
In general, how do carcinomas, round cell tumors and sarcomas metastasize?
- Carcinomas and round cell tumors via lymphatics
- Sarcomas via hematogenous routes
How do metastatic cells survive in their new environment?
- Progressive hypoxia due to proliferation (need to be 100-200mcm from capillary bed for continued growth)
- Hypoxia activates hypoxia-induced factor (HIF1alpha), an oxygen-dependent transcription factor
- HIF-1a induced transcription of tumor-derived growth factors such as VEGF
- Growth factors lead to endothelial recruitment and eventual organization in capillaries
What factors need to be considered when choosing a biopsy?
- Invasiveness of procedure
- Potential for hemorrhage
- Seeding of tumor cells
- Will it change the treatment plan
How can nuclear scintigraphy be applied to dogs with OSA? What substance is used for this?
Technetium-99m hydromethylene diphosphate used for a whole body scan to detect asymptomatic synchronous or asymptomatic lesions
In one study, 7.8% of 399 dogs with appendicular OSA were diagnosed with a second asymptomatic lesion. Not good candidates for amputation
List some uses of nuclear scintigraphy:
- Technetium-99m hydromethyl diphosphate for OSA to detect multiple lesions or to define margins for limb-sparing
- Technetium-99m diethylenetriaminepentaacetic acid for GFR prior to nephrectomy
- Technetium-99m for thyroid tumors to identify metastatic or ectopic disease
- Indium-111 pentetreotide (somatostatin receptor scan) to identify primary and metastatic lesions in dogs with functional insulinomas
What is a PET-CT?
What are its limitations?
A radiopharmaceutical (F-fluorodeoxyglucose; FDG) is transported into and trapped inside tumor cells because it is not utilized in the glycolic pathway. Signal is higher in tumor cells as they have a higher uptake of glucose.
Limitations
- Not all tumors will have increased uptake
- Non-specific (inflammation reacts similarly)
- Not readily available
What size metastatic lesions can be seen on thoracic radiographs and CT?
- 6mm on radiographs
- 1mm on CT
What are the major potential side effects of doxorubicine and cisplatin?
- Doxorubicine can cause cardiotoxicity
- Cisplatin can cause nephrotoxicity
What are the 4 categories of tumor excision?
- Debulking
- Marginal
- Wide
- Radical
What are the general rules for lateral margins of soft tissue sarcomas, MCT and carcinomas?
- Sarcomas and MCT - 2-3cm lateral margins
- Carcinomas - 1cm usually sufficient
A study by Simpson et al revealed what regarding lateral margins for MCT excision?
- All grade 1 MCT were completely excised with 1cm margins
- Only 75% of grade 2 MCT were completely excised with 1cm margins, increasing to 100% with 2cm margins
2cm margins recommended for grade 1 and 2, not enough data to make recommendations for grade 3 so should aim for 3cm if possible
What are the 4 options when incomplete excision of an STS is achieved?
- No treatment
- Staged resection of the scar
- Wide scar revision
- Combination with radiation or chemo
78% of STS reported as incompletely excised do not have any evidence of residual tumor following further resection
Is lymph node size a predictor of metastasis?
No
A study of 100 dogs with oral malignant melanoma, 40% of dogs with normal-sized LN had metastasis and 49% of dogs with enlarged LN did not have metastasis
List 3 methods of identifying the sentinel lymph node:
- Lymphoscintigraphy
- Peritumoral injection of blue dye
- Intra-op cytology or histopath
What are some considerations regarding surgical technique for oncologic surgeries?
- Early hemostasis to prevent release of tumor emboli
- Careful handling to prevent exfoliation
- Structures adhered to the tumor should be resected en bloc if possible (57% rate of invasion in humans)
- Multifilament suture is associated with an increased risk of recurrence
- Ideally avoiding drains as can extend margins if resection if incomplete
- Reconstructive surgery is ideally done as a second procedure once histology results have confirmed clean margins
- Gloves and instruments changes prior to closure or between mass removals
What IHC markers are used for carcinomas and sarcomas?
- Cytokeratin (found in epithelial calls) stain for carcinomas
- Vimentin (found in mesenchymal cells) stain for sarcomas (and melanoma)
What proliferation markers can be used to help predict recurrence of incompletely excised grade 2 MCT?
- Ki67 (low vs high have signifcant prognosis)
- Proliferating cell nuclear antigen (PCNA) combined with Ki67 is prognostic for recurrence
What are the advantages and disadvantages of neoadjuvant radiation therapy?
Of adjuvant radiation therapy:
Neoadjuvant (prior to surgery) is theoretically more effective due to unimpaired vascular supply (better oxygenated, less hypoxic and therefore more radiosensitive)
- Irradiated skin is more likely to develop incisional complications
Radiation is much more effective against microscopic disease and there is no delay in surgery with adjuvant radiation
- Adjuvant radiation can also increase incisional complications, especially if started before 7 days post-op
Define “maximally tolerated dose” in chemotherapy:
Chemotherapy where toxicity, dosage and interval of treatment are based on phase I clinical trials. This data is not often available for vet patients and is extrapolated from human date. Drug doses delivered in vet med are typically half that in humans
Define metronomic chemotherapy:
Frequent, even daily, administration of chemotherapeutics at doses significantly below maximally tolerated dose, with no prolonged drug-free breaks
Aims to control or minimise angiogenesis and invasion rather than cytotoxicity
What are alkylating chemo agents?
- Non cell cycle specific, interfere with DNA replication and translation
- Loumustine (Histiocytic sarcoma, MCT). Severe hepatotoxicity 6%
- Cyclophosphamide (lymphoma). Furosemide can reduce occurrence of sterile hemorrhagic cystitis
What are microtubule inhibiting chemo agents?
- Cell cycle specific, affect spindle apparatus during mitosis
- Vincristine (lymphoma)
- Vinblastine (MCT)
- Vinorelbine (lymphoma, MCT, lung tumor)
Minimally myelosuppressive and well tolerated. Can cause paralytic ileus and extravasation phlebitis
Tell me about Doxorubicin?
- non cell cycle specific with multiple mechanisms of action
- Lymphoma, hemangiosarcoma, high grade STS, high grade carcinoma, OSA
- Can cause DCM like damage in dogs, renal insufficiency in cats
- Significant myelosuppression and GI toxicity
Tell me about platinum agents for chemo?
- Non cell cycle specific - caused binding of DNA, restricting replication and protein synthesis
- Carboplatin and cisplatin - OSA, rescue for other sarcoma and carcinomas
- Cisplatin fatal to cats! Fatal pulmonary edema
- Nephrotoxicity
Tell me about the role of bisphosphonates in chemo / cancer treatment?
- Inhibits osteoclast activity - palliative Tx for osteolytic disease from OSA, multiple myeloma and metastatic bone disease
- IV is preferred (low oral bioavailability, cause reflux)
- Pamidronate most common - approx 30% successful palliation
- Zoledronate - shorter infusion time, improved inhibition or resorption (100x potency), potential for less frequent treatment
What are the reported morbidity and mortality rates of chemotherapy patients as a whole?
- 15% require nonhospitalized medical attention
- 5% hospitalized
- 1% mortality rate
When is the bone marrow nadir with chemotherapeutics?
At what level is chemo delayed?
Typically 7 days with the exception of carboplatin which is 10-14 days
Chemo is delayed by 5-7 days if neutrophils are less than 1500-2000/uL and platelets less than 50,000/uL
If neuts under 1000, prophylactic antibiotics are initiated and future doses reduced by 20%
What is the most available form of immunotherapy?
Melanoma vaccine
DNA vaccine utilizing human tyrosinase DNA which shows an upregulation of antibodies in dogs against human tyrosinase. Clinical studies show mixed efficacy…
Tell me about tyrosine Kinase inhibitors in chemo?
- Target the ATP binding sites of membrane and cytoplasmic tyrosine kinases which are responsible for phosphorylation causing cell proliferation
- Toceranib (Palladia) for MCT in dogs - targets c-kit. Indicated for high grade or metastatic disease and work best on microscopic disease
What is the most common mechanism of acquired chemotherapeutic resistance?
Mutation in the canine MDR-1 gene (Collies, Shelties, Australian Cattle Dogs may already have this mutation)
Describe the process of metastasis:
- Cell detaches from primary tumor
- Migrates through surrounding tissues
- Intravasation into a microvessel
- Survival in circulation
- attachment to distant endothelial cell
- extravasation
- angiogenesis
- Proliferation
Malignant tumors may have what?
This means that the deep margin is what?
Satellite tumor cells outside the capsule
So deep margins are tumor-resistant fascial planes **
