tumor specific LC part II Flashcards
most common primary bone tumor in dogs,
osa - 85%
age demographic of osa
mostly older
few early 18 - 24 mths
Primary rib OSA tends to occur in younger adult dogs, with a mean age of 4.5 to 5.4 years
frequency of axial osa
75% of OSAs occur in the appendicular skel- eton with the remainder occurring in the axial skeleton
breeds at risk for osa
Saint Bernard, Great Dane, Irish Setter, Doberman Pin- scher, Rottweiler, German Shepherd, and Golden Retriever; however, size seems to be a more important predisposing factor than breed
> 40kg
males slightly more than females
ezrin - what is it, why care
Ezrin is a cellular protein belonging to the ezrin-radixin-moesin family and serves as a physical and functional anchor site for cytoskeletal F-actin fibers - cell adhesion and motility
during metastatic progression PKC directed ezrin phosphorylation leads to migration of canine OSA cells
Based on RT-PCR, six of the OSA cell lines what percent of primary OSA tumor samples overexpressed HER2;
40%
suggest neg prog for survival
mTOR pathway and cancer
contributes to growth, survival, and chemotherapy resistance
select the pathways that are active in osa cell lines
HH/notch
mTOR
wnt/b catenin
all 3
sub classifications of osa
osteoblastic, chondroblastic, fibroblastic, poorly differentiated, and telangiectatic
differentials for osa
fungal osteomyelitis
ihc for osa
not great ihc more so look at osteoid matrix
C-kit
vimentin?
cyto stain for osa
ALP
diagnostic rate of trephine bx of osa
dx rate of jamshidi
94% - increases risk o pathologic fracture
92% for tumor vs not and 82% for sp tumor type
frequency of second bone lesion at dx of osa
what dx method
7.8%
Nuclear scintigraphy was found to be the most useful modality for the detection of occult bone metastases - can get false +
stages of osa
stage 1 - low grade no mets
stage 2 - high grade not mets
stage 3 - lesions with regional or distant mets regardless of the grade
ezrin and osa
it has been demonstrated in murine preclinical models that ezrin is necessary for OSA metastases
ezrin staining in primary tumors was associated with a significantly shorter median DFI (116 days -4 mth ) compared with dogs with low primary tumor ezrin staining (188 days - 6 mths)
RON MET and OSA prognosis
expression of RON, but not MET, was prognostic for survival
Hepatocyte growth factor receptor (MET) and RON are members of the MET protooncogene family of receptor tyrosine kinases, and signaling through MET or RON promotes tumorigenesis and the formation of metastases
Survivin and osa
small protein belonging to the inhibitor of apoptosis family and participates in the processes of cell division as well as apoptosis inhibition
inhibits both caspase-dependent and -independent mediated apoptosis, and its expression can promote tumorigenesis
surviving sign decreases DFI
in what species do spontaneous brain tumors occur
humans, dogs and cats
most common primary brain tumors in dogs
meningioma 45%
glioma 40%
choroid plexus tumors 5%
ependymomas, primary central nervous system (CNS) lymphoma, primitive neuroecto- dermal tumors (PNETs), gliomatosis cerebri, and primary CNS histiocytic sarcoma (HS)
what percent of brain tumors are secondary brain tumors and what are the most common types
50%
HSA 29-35%
pituitary 11-25%
lymphoma 12-20%
met carcinoma 11 - 20%
There is a pro- pensity for PBTs in juvenile animals to be what type
neuroepithelial tumors of glial, neuronal, or embryonal origin
breeds over represented to form meningiomas
goldens, boxers, mini schnauzers, rat terriers
breed that gliomas are over represented
brachycephalic breeds - boxer Bostons bullmastiffs and English and French bulldogs
locus on what chromosome is strongly associate with glioma across many breeds
canine chromosome 26
single nucleotide variants in three neighboring genes DENR, CAMKK2, and P2RX7 that are highly associated with glioma susceptibility.
breakdown of feline primary intracranial tumors
70% of all tumors are primary
50% of primary bt are meningiomas
ependymomas, gliomas, and choroid plexus tumors, are infrequently reported
no breed or sex predilections
most common secondary brain tumors in cats
lymphoma 50%
pituitary tumors 30%
causes of clinical signs from brain tumors
hydrocephalus, intracranial hemorrhage, neuroinflammation, peritumoral edema
compensatory mechanisms when BT develop
decrease CSF production
shifting CSF into the spinal subarachnoid space
eventually autoregulatory mechanisms become overwhelmed and intracranial hypertension (ICH) develops - decrease in cerebral perfusion pressure
symptoms of brain tumors
new seizures that develop over the age of 5 in dogs
only 25% of cats will develop seizures - more commonly behavior changes - lethargy inappetence vestibular dysfunction
often will show signs of multifocal damage - even if its a solitary tumor due to the 2ndary effects
what percent of cats have multifocal brain tumor lesions
20%
occasional in dogs
distribution of canine oligodendroglioma
manifest with multifocal or diffuse leptomeningeal involvement
how do choroid plexus tumors metastasize
met within the CNS by “drop metastasis”
- cancer cells are exfoliated into the subarachnoid space or ventricular system and implanted distantly
differential diagnoses in dogs and cats with focal intra- cranial disease
multifocal or diffuse localization
anomalies/malformations, infectious or immune-mediated meningoencephalitis, traumatic brain injury, and stroke
metabolic disorders, neurodegenerative diseases, and meningoencephalitides
what percent of dogs also had other co-morbidities with brain tumors
3 - 23% rec cxr and aus
however these tests only changed dx in 1% and treatment in 8% of cases
clinically stable patients with a suspected brain tumor and unremarkable general physical examination, the authors do not routinely perform screening radiographs or AUS before MRI, but do recommend these procedures before brain tumor treatment
preferred modality for brain tumors and accuracy
MRI
70% accuracy of predicting the brain tumor type
what do meningiomas look like on imaging
broad-based skull attachment, have dis-
tinct tumor margins, hypointense T1, hyperintense T2, contrast on both
some have intratumoral fluid , mineralization, calvarial hyperostosis, or dural tail sign
Calvarial hyperostosis can result from tumor-
induced reactive osseous changes or tumor invasion into bone
Peritumoral edema is observed in more than 90% of canine meningiomas
what is the sn of mri at correctly identifying the intracranial meningiomas
dog?
cats?
60-100%
cannot distinguish grade or subtype
estimated to be 96% in cats
what does a glioma look like on imaging
originate within and may infiltrate and displace the neuropil
appear poorly marginated and may or may not demonstrate contrast enhancement
A “ring enhancing” pattern, in which a circular ring of contrast enhancement surrounds nonenhanc- ing abnormal tissue, is often associated with gliomas
not possible to reliably differentiate types of gliomas (astrocyto- mas from oligodendrogliomas) or accurately predict the grade of gliomas
what is the most common tumor type that is found in the intraventricular location
Choroid plexus tumors and ependymomas are the most common tumors found in an intraventricular location, and both of these tumors types often uniformly contrast enhance
rarely meningiomas arising from the tela choroidea of the third ventricle, oligodendroglioma, PNET, and central neurocytoma
can you discriminate between gr iii and gr I choroid plexus tumors
Identification of intraventricular or sub- arachnoid metastatic tumor implants on MRI studies is a reliable means to clinically discriminate grade III choroid plexus carcino- mas (CPC) from grade I papillomas (CPP)
what lesions can be occult on imaging studies of the brain
Lymphomatosis and gliomatosis cerebri
minimally invasive brain biopsy techniques
endoscopic-assisted, free-hand, and image-guided procedures
diagnostic in about 95% of tumors with AEs in 5%
most common grade of meningiomas in cats and dogs
The majority of feline meningiomas are grade I tumors
(grade II) meningiomas account for a sig- nificantly higher proportion (40%) of meningiomas in dog
Anaplastic (grade III) meningiomas are rare in humans, dogs and cats, and account for about 1% of all canine and feline meningiomas
palliative care for brain tumors
anti-epileptics, pain meds, steroids
Animals that have peritumoral vasogenic edema on MRI are more likely to respond favorably to corticosteroid treatment
animals without significant vasogenic edema may benefit also from the antiinflammatory and euphoric effects of corticosteroids; corticosteroid therapy alone may also tran- siently reduce the tumor burden in some cases
MST after palliative care of PBT
9 weeks, with a range of 1 to 13 weeks
supratentorial tumors treated pal- liatively have a better prognosis (MST 25 weeks) than those with infratentorial tumors (MST 4 weeks)
most common chemo to treat brain tumors
lomustine (CCNU), carmustine (BCNU), and temozolomide (TMZ), or the antimetabolite hydroxyurea, all of which penetrate the blood–brain barrier (BBB)
chemo has limited efficacy
should you use chemo for brain tumors
therapeutic responses to chemotherapeutic agents (such as bleomycin, carboplatin, CCNU, irinotecan, and TMZ), as well as mechanisms of chemo- resistance observed in canine glioma cell lines
but no survival benefit is seen in any study
treatment of feline supratentorial meningiomas
Cytoreductive surgery - located over the cerebral convexities, visibly well demarcated, and are not usually infiltrative into the underlying brain parenchyma
mst of feline meningiomas treated with sx
recurrence rate
MSTs ranging from 23 to 37 months
25% recurrence
When standard cytoreductive surgical techniques are used, the MST for canine meningiomas is
approximately 7 months
advanced surgical techniques (cortical resection, extirpation with an ultrasonic aspirator, or endoscopic assisted resection) have reports of 16 - 70 mths
mst RT + sx in dogs with meningiomas
16 to 30 months
average rate of surgical adverse events for PBT treatment is approximately
11%
Common causes of morbidity and early perioperative mortality for PBT sx
aspiration pneumonia, intracranial hemorrhage or infarction, pneumocephalus, medically refractory provoked sei- zures, transient or permanent neurologic disability, electrolyte and osmotic disturbances, and thermoregulatory dysfunction
biomarkers shown to have prognostic value in dogs with meningiomas treated with surgery and RT
survival was negatively correlated with VEGF expression
ST 25 mths with <75% VEGF
ST 15 mths with >75% VEGF
Progesterone receptor expression was positively correlated with survival (negative correlation with proliferative index)
91% survival at 2 years with PF > 24%
MSTs associated with RT treatment of extra- axial masses, the majority of which were presumptively diagnosed meningiomas
9 to 19 months
intraaxial masses ranges from 9 to 13 months
is rt useful for brain tumors
RT is effective at reducing tumor size, improving neurologic signs, and providing a sur- vival benefit in dogs and cats with pituitary tumors
risk of AE with rt treated brain tumors
10% of brain tumor cases treated with RT will experience treatment-related mortality or adverse effects
hypofractionated RT, delivery of a high dose per fraction resulted in the death of nearly of 15% of treated dogs because of suspected delayed radiation side effects
bacterially derived minicells were packaged with doxorubicin, targeted to EGFR using bispecific antibodies to EFGR, and administered intrave- nously to dogs with brain tumors
RR and AE?
Durable and objective tumor responses were seen in 24% of dogs and no significant toxicities were observed
What are prognostic factors for brain tumors?
Type of tx, neuro signs, location, histology, multi lesions
What are the different spinal tumors occurring and different locations?
Most extradural-OSA, HSA, STS; Intradural/extramedullary-meningioma; Intramedullary-glioma
What is the tx and outcome for spinal tumors?
Meningioma sx+RT-13-78months;
Nerve sheath 6months;
cats 180-1400days (6-47 mo)
Two most common tumors intramedullary spinal mets
TCC, HSA,
Expression of microRNAs in plasma and in extracellular vesicles derived from plasma for dogs with glioma vs dogs with other brain diseases
Results suggested that miR-15b and miR-342-3p have potential as noninvasive biomarkers for differentiating glioma from other intracranial diseases in dogs
what is the best way to determine volumetric criteria for evaluation of therapeutic response in dogs with intracranial gliomas
1D, 2D, contrast enhancing volumetric techniques and t2W tumor volumetric measurements all were comparable methods of determining tumor response
Reccomend t2w tumor volume calc due to simplicity, universal application, and superior performance
immune infiltration in gliomas
Low grade and high grade differed in # of FoxP3+ cells, Mac387+ cells, and CD163+ cells. More numerous in high grade
rt for presumptive gliomas
3 fx of 8-10 Gy one or more courses
636d - 21 mths (similar to fx rt)
- perfoming a 2nd course sig improved outcome - 258d (8.6 mo) vs 865d (28 mo)
- using chemo improved outcome
protooncogene highly expressed in canine gliomas
BMI1 - not associated with higher grade
inhibition activates the Rb pathway
Inter-pathologist agreement on diagnosis, classification and grading of canine glioma
Agreement on subtype and grade 66%, subtype only 80%, and grade only 82%
Agreement was similar for oligodendrogliomas and astrocytomas but lower for undefined gliomas
gliomas
Rt + temo
RR
MST
RT alone - RR 63.2%
RT + TMZ - RR 90.9%
MST palliation - 94 days
MST RT alone - 383 days
MST RT + TMZ 420 days (not statistically different)
TMZ did not improve outcomes
Positive prognostic factors for gliomas
tumor <5% of brain volume and normal mentation at presentation
location of worse outcome for canine gliomas
Subventricular zone more likely to develop mets and had shorter tumor specific survival 306 vs 719 days and a shorter TTP
Mri biomarker for oligodengrogliomas
T2-FLAIR mismatch sign as an imaging biomarker for oligodendrogliomas in dogs
Stereotactic Volume Modulated Arc Radiotherapy in Canine Meningiomas
rr
33 Gy given in 5 fx
ORR 65.5%
2 yr OS 74.3% and disease specific survival 97.4%
minimal se
CyberKnife stereotactic radiotherapy for treatment of primary intracranial tumors in dogs
mst
location based
tumor type influence
PFI 347d
MST 738d -25 mth (same as fx)
Cerebrum location pfi 357d
Cerebellum pfi 97 d
Brain stem pfi 266d
Tumor type was sig assoicated with mst - menigioma better than histiocytic
what imaging showed the best margins for different brain tumor types
glioma, HS, Meningioma
Meningioma and histiocytic - contrast had best margins
Glioma - T2 had best surgical margins
negative prognostic factor with brain tumor surgery
post op seizures
Solitary intraventricular tumors in dogs and cats treated with radiotherapy alone or combined with ventriculoperitoneal shunts
MST
Median survival time was 162 days rt alone vs 1103 days vps rt
Ventriculoperitoneal shunting led to rapid normalization of neurological signs and RT had a measurable effect on tumor volume. Combination of VPS/RT seems to be beneficial.
what percent of spinal tumors are extra dural
50% most coming from vertebrae - osa, chondrites, plasma, fibrosarcoma, hsa
Intradural-extramedullary tumors account for XX% of all tumors
35%
meningioma are most common
what percent of tumors are intra medullary
15%
most common spinal cord tumor in cats
lymphoma - cant be primary but more common secondary and part of multi centric disease
spinal cord lymphoma in cats - felv status
hx 90% were +
now 56%
ependymomas and nephroblastomas are more commonly seen in dogs of what age
younger than 6
breeds predisposed to nephroblastoma
GSD and goldens (<3yrs)
what percent of dogs with intramedullary tumros showed pain
68%
progression of signs in dogs with spinal cord tumors
acute decompensation is rare for primary intramedullary tumors compared to metastatic tumors
only get acute if pathologic vertebral fx hemorrhage or necrosis
cats with lymphoma treated with a combination of vincristine, cyclophosphamide, and prednisone had a complete remission rate of?
50% in 6 cats - 14 wk duration
MSTs for dogs with intraspinal meningioma treated with surgery alone
if RT is added?
6 to 47 months
postoperative RT in dogs with meningiomas increased the MST to approximately 45 months
dogs receiving RT took significantly longer to neurologically decline than dogs that did not
spinal meningioma in cats mst
6-17 mths
mst vertebral tumors for dogs
for cats
MST of 4.5 months in dogs with a variety of vertebral tumors
Cats with malignant vertebral tumors also have a guarded to poor long-term prognosis with surgical treatment, with a reported MST of 3.7 months
PNST arise from what cells
Schwann cells, perineurial cells, or intraneural fibroblasts
dont use the differentiation tho - just use malignant vs benign
cats mostly benign tumors
tend to not met
most commonly affected nerve with pnst
trigeminal nerve
caudal cervical spinal nerve roots c6-t2
Secondary pnst
lymphoma, malignant sarcomas, HS, and hamartomas, can occa- sionally involve peripheral nerves
neurolymphomatosis in cats
diffuse infiltra- tive peripheral nerve lymphoma
usually B cell
usually T cell in dogs
what % of PNST affect the brachial plexus
33%
mass can be palpable on pe
preferred tx method of PNST
surgery
PNST prognostic factors
Proximity to and invasion into the vertebral canal, which occurs in 45% of dogs
incomplete margins
mst of PNST dogs
hx poor - 6 mth
better if complete resection - 1303d ~43mo
use of VMAT RT inc to 8 mth
cats better but no number given
MSTs for dogs with trigeminal PNST treated with SRS or SRT
745 days and 441 days
What 2 tumor types is hemangiopericytoma classified as?
Peripheral nerve sheath and cutaneous perivascular wall (b/c people, but still has staining for nerves-S100+ & vimentin+
what component of the immunoglobulin causes clinical signs in myeloma related disorder
m component
diagnosis of MM
bone marrow or visceral organ plasmacytosis
osteolytic lesions
serum or urine myeloma proteins
what percent of dogs with MM respond to chemotherapy SOC and what’s general mst
dogs
cats
dogs:
>80% respond
MST 1.5 - 2.5 y
cats:
50-80% respond
MST 4-13 mths
Dog with multiple plasma cutaneous lesions
what is prognostic for multiple cutaneous plasma tumors
> 10 tumors
rec melphalan and pred
Dog with elevated iCa and elevated TP with normal albumin BM shows 10% plasma cells next step
malignancy profile
protein electrophoresis
start melphalan
Feline myeloma disease treatment of choice
CTX good but melphalan rr higher, - cyclophosphamide (250 mg/m2 PO or IV every 2–3 weeks) and prednisolone (1 mg/kg PO daily for 2 weeks and then every other day) protocol or a COP protocol or ctx 25 mg/cat twice weekly
melphalan and pred RR 70ish% but causes more significant myelosuppression
0.1 mg/kg once daily for 10 to 14 days, then every other day- Long- term continuous maintenance (0.1 mg/kg, once every 7 days) has been advocated or melphalan at 2 mg/m2, once every 4 days continuously
Withrow like ctx
What are risk factors for developing plasma cell tumors/MM?
Petroleum product, RT, viral (viral Aleutian dz of mink), chronic immune stimulation and implants (silicone gel), carcinogens (ag industry)
over expression of cyclin D1 and RTK dysregulation
What are some IHC for MM?
MUM1/IRF4, thioflavin T, CD79a
What are prognostic factors for MM?
Bence jones proteins, extensive boney lysis, hypercalcemia, renal disease, high peripheral neutrophil:lymphocyte ratio
What is the tx and outcome for solitary osseous plasma cell tumors and EMP?
Cutaneous/oral surgery can be curative; Visceral even with mets can still do well
What is the tx and outcome for MM?
CR%
Melphalan,
43%CR (happy if Ig decreases 50%)
MST 1.5yr
Which locations can progress to multiple myeloma in the dog/cat?
Dog- solitary osseous plasma cell tumor
Cat-cutaneous
what are the most common Ig in MM in dog?
cat?
dogs: IgA and IgG.
IgA maybe more than IgG
cats: IgG > IgA
5:1 ratio maybe be equal in another study
which Ig causes macroglobulinemia
IgM
Waldenström’s
single case of a B-cell lymphoma pro- gressing to MM exists in the dog
just know that
cytology of plasma cell
normal plasma cells to plasma blasts
bi/multinucleate cells often
increased size, multiple nuclei, clefted nuclei, anisocytosis, anisokaryosis, variable nuclear: cyto- plasmic ratios, decreased chromatin density, and variable nucleoli; nearly one quarter had “flame cell”
flame cell
eosinophilic cytoplasm of a plasma cell
light chain is called
bence Jone protein
what type of gammopathy with mm
typically monoclonal
but can have poly or biclonal
para neoplastic syndromes with MM
hyper viscosity syndrome
bone disease
hypercalcemia
bleeding diathesis
renal disease
immunodeficiency
cytopenia
heart failure
what percent of dogs have boney lesions with mm
dogs
cats
what bones
dogs:
25 - 66%
can be diffuse, or osteolytic lesions
cats:
8 - 65%
vertebrae, ribs, pelvis, skull, and the metaphyses of long bones
can use bisphosphonates
IgM (Waldenström’s) macroglobulinemia localized to what organs
rare in the bone
spleen, liver, lymphoid tissue
how does m component cause bleeding diathesis
epistaxis and gingival bleeding
M components may interfere with coagulation by
(1) inhibiting platelet aggregation and the release of platelet factor-3
(2) causing adsorption of minor clotting proteins
(3) generating abnormal fibrin polymerization
(4) producing a functional decrease in calcium
~50% of dogs have prolonged Pt and PTT
10% to 30% of dogs and up to one-quarter of cats have clinical evidence of hemorrhage
most common Ig to cause hyperviscocity
IgA
SE of Hyperviscosity
bleeding diathesis
neurologic signs (dementia, depression, seizure activity, coma),
ophthalmic abnormalities (dilated and tortuous retinal vessels, retinal hemorrhage retinal detachment),
increased cardiac workload with the potential for subsequent development of cardiomyopathy
cause of renal disease in MM
Bence Jones (light-chain) proteinuria, tumor infiltration into renal tissue, hypercalcemia, amyloidosis, diminished perfusion secondary to HVS, dehydration, or ascending urinary tract infections
frequency of bench Jone proteinuria
Bence Jones proteinuria occurs in approximately 25% to 40% of dogs and 40% of cats
immune suppression from mm in humans - how does it affect them
15 x more susceptible to infections
dec response to vaccines
% bone marrow affected to be MM
Normal marrow contains less than 5% plasma cells
Current recommendations require more than 20% marrow plasmacytosis to be present, although a 10% cutoff in cats has been recently recommended with special attention to cellular atypia
is pet scan helpful for mm
NO
predominant osteolytic activity with osteoblastic inactivity pres- ent, scans seldom give positive results and are therefore not useful for routine diagnosis
infectious causes of monoclonal gammopathy
ehrilichiosis
leishmaniasis
FIP
MGUS
dosing of melphalan
daily dosing with an initial starting dose of 0.1 mg/kg PO, once daily for 10 days, which is then reduced to 0.05 mg/kg PO, once daily continuously
pulse-dosing regimen uses melphalan at 7 mg/m2 PO, daily for 5 consecutive days every 3 week
with pred daily then EOD at 0.5mg/kg - taper off at 60 days
bone marrow toxicity of melphalan
can cause irreversible thrombocytopenia
how quick does mm respond
lab work 3- 6 wks
cs 3-4 wks
in cats 2-4 wks and 8 weeks for boney lesion
monitoring of mm
serum ig levels lag behind bence Jones
rec performing bence Jone test monthly until a good response is seen and then every 2-3 months after
Bortezomib for mm
proteasome inhibitor
shown to have activity against canine melanoma in cell culture and mouse xenograft models
not use din dogs for mm yet
one case report for feline mm - tolerated 0.7mg/m2
proteosomes normally break down misfolded proteins. by inhibiting them you all them to accumulate in the cell and then lead to apoptosis
1-, 2-, and 3-year survival rates of mm
81%, 55%, and 30%,
IgM macroglobulinemia tx and st
77% rr to chlorambucil mst 11 mths
location frequency of emps
86% skin
9 % oral cavity lips
4% gi
behavior of emps
Cutaneous and oral EMP in dogs are typically benign tumors that are highly amenable to local therapy
Colorectal EMPs tend to be of low biologic aggressiveness, and most do not recur after surgical excision
noncutaneous/nonoral EMP appears to be somewhat more aggressive in the dog
cutaneous plasmacytosis
biologically aggressive disease with treatment and outcomes more like MM
more than 10 and up to hundreds of lesions
chemotherapy recd
progression-free 153 d (5 mo)
MST 542 days (18 mo)
IHC panel for poorly differentiated round cell tumors
tryptase (mct), chymase (mct) , serotonin (mct), CD1a (HS), CD3(t cell), CD79a (b cell/plasma cell), CD18 (HS), and MHC class II (HS)
with naphthol AS-D chloroacetate stain
solitary osseous plasma cell tumor tx
surgery and RT
RT can be used alone (i.e., without surgery) in those cases where fractures are stable, as a palliative measure for bone pain, or in the case of vertebral SOP if the patient is ambulatory and stable
Emp recurrence rate and met rate
5% RR
2% met rate
clonality assay in canine B cell tumors targeting the immunoglobulin light chain lambda locus
20 of 23 cases of DLBCL showed clonality (87.0 %), whereas 8 of 30 cutaneous plasmacytomas were clonal (26.7 %)
most common location of SOP (solitary osseous plasmacytoma)
mst in one study
vertebrae
MST 912 d ~30 mo
MST with rt 1166d ~38 mo
Parotid Salivary Gland Extramedullary Plasmacytoma with Local Lymph Node Metastasis in a Dog
Response and outcome following radiation therapy of macroscopic canine plasma cell tumours
pRT ~30 Gy vs dRT ~48 Gy
95% had CR
improved pain
PFST 611 days, 20 mo
MST 771d 26 mo
Worse if PR only and pRT
canine oral extramedullary plasmacytoma
mst
MST 973 days - 2.7 yr
Histologic characteristics not associated with malignancy
variable tx - sx, rt, chemo
Hypoglobulinemia in a dog with disseminated plasma cell neoplasia
Diagnostic performance of routine electrophoresis versus species specific immunofixation for the detection of immunoglobulin paraproteins (M-Proteins) in dogs with multiple myeloma
Using species specific immunofixation with SPE improved m protein detection SN and SP
with morphologic features has sensitivity of 95.1% and specificity of 81.4%
what % improvement of M protein was beneficial to survival
Median survival was longer for dogs that attained ≥90% densitometric M-protein reduction (630 days-21 mths) than for those that did not attain at least 50% reduction in densitometric M-protein (284 days- 9 mth)
Cyclical 10-day dosing of melphalan for canine multiple myeloma
2 mg/m2 melaphalan q24 for 10 days followed by 10 days chemo break, 40 mg/m2 pred q24q10d then q48h,
well tolerated but shorter OST compared to pulse dose or daily dose
What specific bone marrow disorder is seen in FeLV+cats but rare in dogs?
Myelodysplasia-BM hyperplasia with maturation arrest/cytopenias, doesn’t always progress to leukemia
What is aleukemic leukemia?
Neoplastic blast in BM but not circulation
What missense mutations have been found in dog AML?
FLT3, CKIT, RAS
In AML classification AML-M1-7 which one do animals not develop?
AML-M3 promyelocytic
What syndrome is sometimes called preleukemia because it can progress?
Myelodysplasia
Which AML can look like MCT in circulation?
Basophil
What form of CLL is there circulating increased lymphocytes but no BM involved?
Tcell LGL, blast arise from spleen
What is Richters syndrome
CLL that progresses with blast in circulation
What mutations associated with disease are expressed on exon 8,9,11,17?
Exon 8-9-GIST, MCT, AML
exon11-GIST, MCT;
exon17-mastocytosis, leukemia/peop
what are the causes of the morphology seen here
acanthocytes
HSA*, osa, lsa
liver disease in people
English Bulldog CLL cell expression molecules
polyclonal b cell lymphocytosis
expressed lower class II MHC and CD25
splenomegaly, and hyperglobulinemia
get this younger than most breeds - 6 yrs vs 11 yrs
essential thrombocythemia
myeloproliferative neoplasia of platelets
chronic
platelet counts that are persistently greater than 600,000
chronic myelogenous leukemia
myeloproliferative neoplasia of granulocytes and/or monocytes
AML age/sex
typically 7-8 yo
can be as young as 7 mo
2:1 M:F
EPO
regulates erythroid proliferation and differentiation and is produced in the kidney, where changes in oxygen tension are detected
stem cell to rbc pathway
pluripotent sc -> hematopoetic sc -> blast forming unit E -> colony forming unit - E -> rbc
AML cell
blastic
what are the myeloproliferative neoplasms
polycythemia vera, CML, essential thrombocythemi, primary myelofibrosis
relative frequency of AML subtypes
42% monocytic leukemia (M5a, M5b), 33% myelomonocytic leukemia (M4), 13% myelo- blastic leukemia without differentiation (M1), 5% megakaryo- blastic leukemia (M7), and one each of myeloblastic leukemia with some differentiation (M2) and erythroleukemia (M6)
BCR–ABL translocation is reported in dogs with what type of leukemia
acute myeloblastic leukemia
raleigh chromosome 9->26
what mutation has been founding dogs with polycythemia vera
JAK2
polycythemia vera PCV
65 - 85%
Chronic Myelogenous Leukemia
similar to chronic neutrophilic leukemia in humans
total wbc typically > 100,000
Eosinophils and basophils may also be increased
hypersegmentation, ringed nuclei, and giant forms
MST 1 to 3 months, with some cases surviving up to 6 months or longer with aggressive treatment protocols
human Philadelphia chromosome is what in the dog
chromosomes 9 and 26, and BCR–ABL translocation,
termed the “Raleigh chromosome,”
what genetic chromosomal aberration has been seen in dogs with CML
chromosomes 9 and 26, and BCR–ABL translocation, termed the “Raleigh chromosome,”
variants of CML
chronic myelomonocytic leukemia and chronic monocytic leukemia (CMoL)
CML may terminate
in “blast crisis”
MST?
transformation from a
predominance of well-differentiated granulocytes to excessive
numbers of poorly differentiated blast cells
mst weeks to months
Basophilic leukemia
increased WBC count with a high proportion of basophils in peripheral blood and bone marrow
should be distinguished from mast cell leukemia (mastocytosis)
signs of essential thrombocythemia
Thrombosis and bleeding
>600,000 Plt
splenomegaly
r/o including inflammation, hemolytic anemia, iron deficiency ane- mia, malignancies, recovery from severe hemorrhage, rebound from immune-mediated thrombocytopenia, and splenectomy
myelofibrosis mechanism
breakdown of intramedullary megakaryocytes and subsequent release of factors that promote fibroblast proliferation or inhibit collagen breakdown may be the underlying pathogenesis of the fibrosis
myelofibrosis causes
- myeoproliferative disorders
- RT
- congenital hemolytic anemia
- idiopathic
- necrosis secondary to ehrlichiosis speticemia or drug toxicity ( estrogen, cephalosporin)
preleukemia
Myelodysplasia - cytopenias in two or three lines in the peripheral blood
myelodysplasia prognostic factors
poor prognostic factors include increased percentage of blast cells, cytopenias involving more than one lineage, and cellular atypia
myelodysplasia subtypes
MDS with excessive blasts (MDS-EB) - blast percentages are greater than 5% and less than 20% and progression to AML may occur
MDS with refractory cytopenia (MDS-RC) with blast percentages less than 5% and cytopenias in one or more lineages
MDS with erythroid predominance (MDS-ER) in which the M : E ratio is less than one and prognosis is poor
treatment of myelodysplasia
none usually if cytopenias are not bad - may need blood transfusion
human EPO has been given experimentally
treatment of thrombocythemia
one report - vincristine, Ara-C, cyclophosphamide, and prednisone - human med doesn’t know benefit
could use apoquel oclacitinib as a jak inhibitor
radiophosphorus in people has been reported
treat meant of CML
Imatinib mesylate (Gleevec), a tyrosine kinase inhibitor, is known to be an effective therapy for CML in humans
One dog with chronic monocytic leukemia treated with toceranib (Palladia) and prednisone therapy achieved a clinical remission
Hydroxyurea is the most effective agent for treating CML during the chronic phase.
initial dosage is 20 to 25 mg/kg twice daily. Treatment with hydroxyurea should continue until the leukocyte count falls to 15,000 to 20,000. Then the dosage of hydroxyurea can be reduced by 50% on a daily basis or to 50 mg/kg given biweekly or triweekly
humans use bisulfan alternatively
Vincristine and prednisone therapy resulted in a short remission in one dog
polycythemia vera treatment
The PCV should be reduced to 50% to 60% or by 1/6th of its starting value
Phlebotomies should be performed as needed, administering appropriate colloid and crystalloid solutions to replace lost electrolytes; 20 mL of whole blood/kg of body weight can be removed at regular intervals
chemotherapeutic drug of choice is hydroxyurea, an inhibitor of DNA synthesis. This drug should be administered at an initial dose of 30 mg/kg for 10 days and then reduced to 15 mg/ kg PO daily
Radiophosphorus (32P) has been shown to provide long-term control in people with PV
could consider JAK inhibition and use apoquel
treatment of AML
grave
doxorubicin, cyclophosphamide, vincristine, 6-thioguanine, and prednisone
cytosine arabinoside (Ara-C), 100 to 200 mg/m2, given by slow infusion (12–24 hours) daily for 3 days and repeated weekly, has been used, as well as several other variations using subcutaneous injections of Ara-C
rr of AML and MST
response rates to multiagent protocols are relatively high (50%–70%),
responses are not durable
MSTs 0.5 to 2 months
flow for myeloproliferative neoplasias
CD34+
negative for CD3, CD4, CD8, CD21, CD79, and IgG,
myeloperoxidase (MPO) and CD11b for myeloid cells
CD41 for megakaryoblasts
AML in dogs, most were CD45/CD18/CD34 positive
polycythemia vera vs absolute polycythemia
EPO concentrations in dogs with PV tend to be low or low-normal, whereas in animals with secondary absolute polycythemia, the levels are high
AML and bone marrow
If erythroid cells are less than 50% of ANC and the blast cells are greater than 20%, a diagnosis of AML or AUL is made.
If erythroid cells are greater than 50% of ANC and the blast cells are greater than 20%, a diagnosis of erythro- leukemia (M6) is made.
If rubriblasts are a significant proportion of the blast cells, a diagnosis of M6Er, or erythroleukemia with erythroid predominance, can be made.
ALP and AML
A recent study indicated that ALP was a useful marker for the diagnosis of AML if neoplastic cells express only CD34
A case of acute monocytic leukemia (AMoL or AML-M5) in an adult FeLV/FIV-positive cat
Blasts on cbc
Cd3 neg pax 5 neg dimly cd18 pos moderate pos for iba1
Monocytic differentiation
Treatment of myeloid neoplasia with doxorubicin and cytarabine in 11 dogs
mst
Median duration of remission in 7/11 responder 344 days (11 mo)
OST all dogs 369 day (12 mo)
A retrospective review of acute myeloid leukaemia in 35 dogs diagnosed by a combination of morphologic findings, flow cytometric immunophenotyping and cytochemical staining results
dx
ost
diagnosis : 20% blasts in bone marrow identified as myeloid based on morphology and flow and cytochemical stains
bi cytopenia 44%
pancytopenia 44%
ost 19 days - improved with chemo
dog with TCC on deramaxx which is true
a. Gi toxicity higher than piroxicam alone
b. when PD on deramaxx can add in chemotherapy and it is likely to improve disease
c. add gemcitabine
a. 17% of dogs had gastrointestinal signs with piroxicam alone - 6 dogs had to take holidays and only 2 resumed
19% of dogs had Gi signs with deramaxx alone bu the GI signs ere more mild and no dogs had to stop administration
b. MST 300 - 338 days; 10-11 mo (longest reported) were for the dogs who initially received cisplatin alone, and then when that treatment failed (due to toxicity or tumor progression) they received a COX inhibitor alone - opposite to the answer choice
c. gemcitabine and piroxicam 26% RR (CR/PR) 50% SD mst 230d
unsure what’s correct
TCC and risk of UTI
80%
staph positive culture - other is e.coli
female with urethral involvement increased risk
TCC firocoxib rr
20%
TCC stent facts
> 90% success, longer stent the higher the risk of incontinence
TCC BRAF sens and spec
Sn 80
Sp 100
complications with urethral stents
migration
incontinence
uti
where does tcc met in the spinal cord
intramedullary
- What is true of radiosensitivity and repair of sublethal RT-induced damage In TCC?
Surviving cell fractions at 2 Gy: 0.6
o ɑ/β low = higher dose/less fractionation indicated
K9 BRAF mutation in TCC
- mutation
- frequency
o Somatic mutation in V595E on Chr16
o Homologous to human V600E
o Present in 87% of invasive TCC
Which of the following are initiators for K9 TCC?
Somatic mutation of V595E
2,4-dichlorophenoxyacetic acid (2,4 D) (OR 4.4
tcc express what cancer promoting pathway
PDL1
literally so many studies showing this idk
What is the effect of combining piroxicam and CIS for tcc
Moderate to severe renal AE with TCC
what cox inhibitor was shown to not increase renal toxicity with cisplatin
firocoxib
TCC prioxicam alone
RR (pr/cr)
SD
PFI
MST
21% rr
59% sd
PFI 120 d - 4 mth
MST 244d - 8 mth
TCC deracoxib
RR (pr/cr)
SD
PFI
MST
RR 17%
SD 71%
PFI 133d - 4 mo
MST 323d - 11 mth
TCC Ferocoxib
RR (pr/cr)
SD
PFI
MST
RR 20%
SD 33%
PFI 105 d - 3.5 mo
MST 152 d - 5 mths
some received cisplatin after failure
TCC mitoxantrone + piroxicam
RR (pr/cr)
SD
MST
RR 35%
SD 46%
PFI 106 - 194d - 6 mo
MST 247 - 291 days - 10 mths
TCC vinblastine alone
RR (pr/cr)
SD
PFI
MST
RR 36%
SD 50%
PFI 122 - 143 ~4-5 mo
MST 147d - 531 d ~5-18mo
higher survival rates seen in dogs that received vinb alone and then once pd received piroxicam alone
TCC vinblastine piroxicam
RR (pr/cr)
SD
PFI
MST
PR 58%
SD 33%
PFI 199 d ~6.5 mo
MST 299 d ~10 mo
TCC vinb - folate conjugate
RR (pr/cr)
SD
MST
RR 56%
SD 44%
PFI 115d
MST 115 d - 4 mth
TCC cisplatin alone
RR (pr/cr)
SD
PFI
MST
RR 0 - 25%
SD 25-50%
PFI 84 - 124
MST 105-130 d - 3.5 - 4 mths
combo of several studies
dogs that did the best started on cisplatin and switched to Piroxicam or firocoxib
300-338 d
TCC cisplatin and piroxicam
RR (pr/cr)
SD
MST
RR 50% - 71%
SD 17% -28%
MST 246- 320 days ~8-10 mo
combo of two studies
TCC carbo alone - 12 dogs total
RR (pr/cr)
SD
MST
RR 0%
SD 8 dogs
PFI 41 d
MST 132 days
TCC prioxicam + carbo
RR (pr/cr)
SD
MST
RR 38%
SD 45%
PFI 73d
MST 161 d - 263d ~5-8.5 mo
TCC prioxicam + doxo
RR (pr/cr)
SD
PFI
MST
RR 9%
SD 60%
PFI 103d
MST 168 d
TCC 5 azacitadine
RR (pr/cr)
SD
MST
RR 22%
SD 50%
MST 203 d ~7mo
TCC leukeran metronomic 4 mg/m2
RR (pr/cr)
SD
PFI
MST
RR 3%
SD 67%
PFI 119 d ~4mo
MST 221d ~7 mo
Vinblastine/toceranib/COX inhibitor
RR
RR 33-55%
Cisplatin (60 mg/m2/ piroxicam/tavocept
RR
SD
MST
RR 27%
SD 73%
MST 253 d ~8.5mo
TCC firocoxib and cisplatin
RR (pr/cr)
SD
MST
RR 57%
SD 21%
MST 179 days - 6 mths
Psma = prostate specific membrane antigen
can this be used to distinguish between prostatic carcinoma and tcc?
NO PSMA was not differentially expressed
may be a target for treatment or dx of both disease
Irreversible Electroporation Balloon Therapy for Palliative Treatment of Obstructive Urethral Transitional Cell Carcinoma in Dogs
no complications noted
1/3 dogs had benefit
Usefulness of squash preparation cytology in the diagnosis of canine urinary bladder carcinomas
sn, sp, accuracy, npv, ppv
Se 98%
Sp 65%
Accuracy 89%
Npv 92%
Ppv 88%
cytologic findings on urinary bladder cancer cytology
absence of neutrophilic inflammation
presence of multinucleate cells
nuclear molding
Assessment of HER2 Expression in Canine Urothelial Carcinoma of the Urinary Bladder
HER2 expression in a subset of UC but also polypoid cystitis and normal bladder so not a good target
what’s better urine sediment or diagnostic catheterization?
SN and SP increased with diagnostic catheterization
BRAF mutation status and its prognostic significance tcc
BRAF status NOT associated with OST
most common variant was a V-to-E missense mutation in BRAF
Expression of receptor tyrosine kinase targets PDGFR-β,VEGFR2 and KIT in canine transitional cell carcinoma
PDGFR-b significantly expressed in TCC vs normal and cystitis
VEGFR2 stained but was similar across all tissue samples
minimal staining of kit
what are environmental exposure risks for tcc
Proximity to a farm and insecticide use were contributing factors to TCC risk
Low activity glutathione variants are unlikely to contribute as it does in humans
ct scans of patients with tcc revealed more what than traditional staging
boney mets and sternal lymphadenopathy
prognostic factors for tcc
boney mets, tcc location, sternal lymphadenopathy
mst of urethral vs bladder tcc
met rate of urethral vs bladdeer tcc
urethral 122 d - 4 mth , met rate 42%
bladder 420 d - 14 mth , met rate 6.3
palliative rt for cats with ucc
6 Gy weekly x 4 = 24Gy
Resolved symptoms in all cats minim AE grade 1 GI in one G2 urinary
Good tx option
most common location o bladder masses in cats
one study says trigone
Withrow says away from the trigone
met rate of tcc in cats
21%
pfs and mst in cats with tcc who had
surgery (partial cystectomy) and nsaids
pfs 113 d ~3.5 mo
mst 155 d ~5 mo
Withrow says 261 days ~ 8 mo from a smaller study
most common bladder tumors in cats
UCC
also mesenchymal, lymphoma, and others
mst cats with tcc treated with meloxicam
311 days ~10mo
what percent of urethral lesions are granulomatous/chronic active urethritis
24%
renal cancers in dogs
renal cell carcinoma (RCC), adeno- carcinomas, iUC, papillary cystadenocarcinomas, and less commonly, sarcomas
what para neoplastic syndrome is associated with renal cystuadenocarcinoma
nodular dermatofibrosis
what inherited msisense mutation is found in renal cystadenocarcinoma
FLCN (folliculin gene)
similar to Bird HOGG Dube in people
what renal tumor has been reported in young dogs and dogs of all ages
nephroblastoma
clinical signs of renal tumors
hematuria, pain in the area of the kidneys, a palpable abdominal mass, bone pain secondary to hypertrophic osteopathy, or other nonspecific signs such as GI upset or behavior changes
in a cat most common sign is weight loss
what paraneoplastic lab work abnormalities can you see with renal tumors
polycythemia vera from excessive epo production
anemia
hypercalcemia
elevated ALP
hypoalbuminemia
what is the treatment of choice for renal tumors
nephrectomy even for palliation
- must have ct, no mets, and normal renal functions
mst renal tumors
16 mth rcc
9 mth renal sarcoma
6 mths nephroblastomas
negative prognostic factors for rcc
high mitotic count >30 , high cox 2 expression, specific subtypes, fuhrman nuclear grade ( gr 1- 4)
mst for rcc based on mc
mc <10 1184d 40mo
mc >10<30 452d 15 mo
mc >30 187d 6mo
what subtypes are better or worse for rcc
mst clear cell - 87 days WORST ~3 mth
chromophobe, papillary, multilocular cystic
met rate at dx vs necropsy in renal tumors
16-34% at dx
88% of sarcomas at death
75% of nehphroblastomas at death
69% with carcinom
Excluding lymphoma, reported feline primary renal tumors include
tubular RCC, tubulopapillary RCC, sarcomatoid RCC, adenocarcinoma, adenoma, iUC, squamous cell carcinoma, leiomyosarcoma, nephroblastoma, and hemangiosarcoma
tubular and tubulopapillary RCC were most common
paraneoplastic syndrome in cats with renal tumors
polycythemia vera
treatment of renal tumros in cats
nephrectomy
chemo unknown benefit
most common grade of ucc in dogs
70% grade 3 (high grade) tumors, 29% grade 2 (intermediate grade) tumors, and 1% grade 1 (low grade)
non ucc bladder tumors
squamous cell carcinoma, adenocarcinoma, undifferentiated carcinoma, rhabdomyosarcoma, lymphoma, hemangiosar- coma, fibroma, and other mesenchymal tumors
% of ucc tumors in urethra? prostate?
urethra 56%
prostate 29%
% of ucc tumor with mets at diagnosis
nodal - 16%
distant mets - 14%
who staging ucc
T2 - 78%
T3 - 20%
% mets at necropsy dogs
58% distant mets
42% nodal mets
33% had both
sites of mets for ucc
lungs most common
liver, kidney, adrenal gland, spleen, bone, skin, heart, brain, GI, spinal
how many dogs with ucc have 2nd tumors at necropsy
13% including las, hsa, thyroid carcinoma, etc
% bone mets at necropsy
9% documented in records
14% when CT was used at euthanasia
other locations of uc besides the bladder
can occur in the abdominal wall, either through seeding from instruments and needles used in surgical and nonsurgical procedures, or through natural spread of transmural lesions along bladder ligaments.
UC in the abdominal wall is typically aggressive and poorly responsive to medical therapy
risk factor for ucc
exposure to older flea control , lawn chemicals, obesity, maybe cyclophosphamide, female gender, risk is higher in neutered dogs of any breed
** breed
risk was significantly lower in dogs that ate vegetables at least three times per week in addition to their dog food - carrots
IHC of tcc
uroplakin III
GATA 3
breeds associated with tcc
scottish terriers
shetland sheepdog
westie
beagle
dalmation
surgery for ucc
psi
mst
UC lesions away from the trigone
following chemo and nsaids
with or with out chemo
psi 235 d mst 348 d
subset of dogs with sx and piroxicam/deracoxib lived 722d - 749
what is the chance of tumor control for ucc by any means
75%
factors associated with advanced stage of ucc
younger - increased risk of nodal mets
prostate involvement - increased risk of distant mets
higher T stage - increased nodal and distant mets
when to treat a uti in a dog with ucc
A positive urine culture, with a low colony count in the absence of worsening clinical signs and supporting findings on urinalysis, is not an indication to treat with antibiotics
if a dog has new or progressive signs - perform a ua - if If the urinalysis reveals pyuria or the presence of intra- cellular bacteria -perform a culture
can treat with drug that will kill staph and E. coli - tms or clavamox
what abx have been associated with uti resistance after treatment for 30 days
amoxicillin, doxycycline, enrofloxacin
mst following urethral stent placement
20-78 days range 2 - 536 d - for prostate
frequency of incontinence with stents in tcc
25 - 39%
mst following ureteral stent placement
57 days range 7 - 337
transurethral carbon dioxide and near infrared diode laser ablation of uc complications
perfo- ration with iUC spread, transient postprocedural worsening of stranguria and hematuria, urethral stenosis, and infection
in a small study outcome was not better than medical management alone
rt SE for UC
chronic colitis, cystitis, and urethral strictures
improved with use of srt
newer study - mild and self-limiting and included colitis (38%), erythema or hyperpigmentation (19%), and stranguria (5%). Late complications included urethral stricture (9%), ureteral stric- ture (5%), or rectal stricture (5%).
mst IMRT for UC
654 d ~22mo
event free interval 317 d 10.5 mo
palliative rt for uc
10 daily f of 2.7 gy
mild colitis cystitis vaginitis and dermatitis
CR/PR 61%
SD 38%
how frequently do you monitor uc lesions
4-8 weeks
multiagent protocols for ucc
no benefit known
no known benefit of using a maintenance protocol
benefit of tavocept with cisplatin
less renal toxicity
but response was worse
can you avoid gi toxicity of piroxicam if you give gi protectants
no - one study showed they were worse
RCC prognostic with sx
a. 1 year
b. slightly more than 1 year
c. 6 months
b
mst with nephrectomy 16 months
Is c-kit ever mutated in feline tumors and if so what exon?
Yes, 68% higher than dogs, exon8
What two tumors stain positive for cytokeratin & vimentin?
Mesothelioma and synovial cell sarcoma, ovarian CA, RCC tubulopapillary
