Chapter 33 - Miscellaneous Tumors Flashcards
What tumor suppressor gene is inactivated in >50% of canine HSA?
PTEN
What angiogenic growth factors and receptors have been identified in cHSAs?
Compared to hemangiomas, HSA are strongly positive for what?
VEGF, bFGF, angiopoietins-1 and -2, and their R.
Suggests potential for autocrine stimulation leading to dysregulated proliferation and survival.
PDGFR-B
Increased activity of what signaling pathway has been identified in canine HSA?
NOTCH
Inhibition via y-secretase inhibitors suppresed cell growth
In the dog, what is the most common site for HSA? What are other frequent sites? How about cats?
Spleen
Right atrium, skin, SQ, liver
Cats: cutaneous and visceral are evenly distributed
How does HSA look histologically?
What IHC stains can be requested to dx HSA?
Immature, pleomorphic endothelial cells forming vascular spaces containing variable amounts of blood and thrombi.
An IHC panel is more useful than any marker on its own, as they are not all always expressed and are not specific.
Von Willebrand factor (factor VIII-related antigen
CD31/PECAM)
Other markers that could be used:
- CD117 (KIT)
- Claudin 5
- VEGFA and its receptor Flk-1 - no difference when compared to non-neoplastic endothelial cells
- Ang 2 - may be useful
- Tie 2 - less reliable
How does HSA metastasize? What are the most common places in dogs? Cats?
Hematogenously or through transabdominal implantation following rupture
Dogs: liver, omentum, mesentery, lungs
Cats: liver, omentum, diaphragm, pancreas, lungs
What forms of HSA are an execption to the classic malignant behavior of visceral HSA?
Cutaneous or dermal HSA without any histologic evidence of subdermal infiltration
Approximately what percentage of dogs with splenc HSA will also have right atrial involvement?
25%
What is the most common metastatic brain tumor?
HSA
What morphology of red blood cells has been associated with HSA (2)?
Other blood work abnormalities (3)?
Which is a poor prognostic indicator?
Shistocytes - microangiopathic hemolysis
Acanthocytes - ON THE TEST! (both present in 10%)
Thrombocytopenia - 75-95% - poor PI
Coagulation abnormalities consistent with DIC 50%
Neutrophilic leukocytosis
A 1992 study revealed that thoracic radiographs had a ___% sensitivity and ___% negative predictive value for detecting pulmonary manifestations of HSA.
78% sensitivity
74% NPV
Echocardiogram in dogs with pericardial effusion secondary to right atrial HSA have a visible mass in what % of cases?
65% to 90%
What % of dogs that have a splenectomy for HSA developed arrhythmias? When do these typically resolve? Influence on prognosis?
24%
24 to 48 hours after surgery
Negative prognostic indicator
What chemo durgs have been used in HSA?
Doxorubicin, methotrexate, vincristine, cyclophosphamide, ifosfamide
Doxo + cyclo versus doxo + cyclo + d L-MTP-PE (immunoT)
The MST in the dogs that did not receive L-MTP-PE was ___, compared to ___ for dogs that received it.
Approximately ___% of the dogs in the L-MTP-PE experienced “long term” survival.
6 months vs 9 months
40%
Form of immunotherapy unavailable in USA
Palladia administration to dogs with stage I or II splenic HSA after doxorubicin (q2w) chemotherapy completion.
Overall DFI and MST vs DFI and MST in dogs that received Palladia?
What % of dogs receiving Palladia developed mets?
Overall DFI 140
Palladia DFI 160
Overall MST 170
Palladia MST 170
~5.6m
80%
Did NOT work at all, same numbers as with everything else
MST and DFI for metronomic chemotherapy with etoposide, cyclophosphamide, and an NSAID for K9 HSA as a first line therapy? Thalidomide?
Thalidomide 1-yr SR when used as a first line?
Do they improve MST when administered post doxorubicin completion?
6m - etoposide, cyclo, NSAID
5.6m - thalidomide; stage II MST 10m vs stage III 40d
Thalidomide 1-yr SR 33%
Overall MST for dogs with splenic HSA that receive surgery alone is ___ months.
<1m - 3m
Even with the addition of chemotherapy, < than ___% of dogs with HSA make it to 1 yr.
Surgery plus doxorubicin-based chemo results in a MST to ___ to ___ months.
10%
5 - 6m
What drug when used in a metronomic fashion has been shown to improve TTM and MST?
Thalidomide in addition to doxorubicin and cyclophosphamide
TTM and MST not reached
Overall, what is the MST of cardiac HSA when treated with surgery alone, chemo alone, and sx + chemo?
Sx alone: MST 1-4m
Chemo alone: MST 3.8m
Sx + chemo: MST 5.4m
In cats with visceral HSA, what is the prognosis?
What is the local recurrence rate of feline cutaneous and subcutaneous HSA following sx?
Poor60 to 80%
From what cell do thymomas originate?
What are the different histologic types and which one is the most common in dogs?
Thymic epithelial cells
Histologic types:
- Differentiated epithelial -> most common one
- Lymphocyte rich
- Clear cell type
Infiltration of thymomas by which cell is positively correlated with improved survival in both dogs and cats?
Lymphocytes
What is the most common form of thymomas in cats and how does int influence prognosis?
Cystic
How are thymomas classified as benign or malignant?
Degree of invasiveness
Ability to surgically excise them
(Rather than histologic features)
What is the metastatic rate of thymomas in dogs and cats?
Dogs - rare
Cats with cystic thymoma - 20%
What are the 3 most common differentials for mediastinal masses?
Lymphoma, thymoma, ectopic thyroid tumor
Other: branchial cysts, rare sarcomas, metastatic neoplasms
Explain the maturation process of T lymphocytes
Thymic cortex -> maturation of T lymphocytes
Thymic medulla -> composed of epithelial cells/thymocytes
TCL precursors express CD34. When TCL precursors enter the thymic cortex, they loose expression of CD34, and express CD5 and CD3. They then evolve from double negative cells, to double positive CD4+ and CD8+ cells. When they leave the thymus, they loose co-expression and are committed to either a CD4+ or CD8+ lineage.
Paraneoplastic syndromes are reported to occur in ___% of dogs with thymoma.
What are some reported PNS?
When can these tend to occur?
67%
PNS:
- Myasthenia gravis
- Exfoliative dermatitis
- Erythema multiforme
- Hypercalcemia
- T-cell lymphocytosis
- Anemia
- Polymyositis
At presentation, later in the course of the disease, after tumor removal
Myasthenia gravis occurs in up to ___% of dogs with thymomas and has also been reported in cats.
Concurrent megaesophagus and aspiration pneumonia is present in ___% of dogs with MG.
What % of cats with MG have mediastinal masses?
40% (both first answers)
50% of cats with MG have mediastinal masses
What 3 CBC abnormalities may be seen in dogs with thymoma?
Anemia, thrombocytopenia, and lymphocytosis
Hypercalcemia as a PNS in dogs with thymoma can occur in up to ___% of cases and is secondary to production of what?
34%
PTH-rp
What confirmatory test should be done if MG is suspected?
Demonstration of serum antibodies against ACH receptors (MG Ab titers)
Tensilon test with edrophonium, an ultra short acetylcholinesterase inhibitor agent (anticholinesterase)
How do cytologic samples from thymoma tumors look like?
What % of samples contain epithelial cells?
Neoplastic to normal epithelial cells, large numbers of mature small lymphocytes, ocasional mast cells. Usually normal appearing epithelial cells vs thymic carcinoma.
60%
Non-diagnostic samples are common due to presence of only lymphocytes and no epithelial cells
How can a thymoma be differentiated from lymphoma or thymic carcinoma?
Flow cytometry. IHC not helpful
More than 80% of thymic lymphocytes should co-express CD4 and CD8.
Thymoma >10% of lymphocytes co-express CD4 and CD8
LSA <2% of lymphocytes co-express CD4 and CD8
Carcinoma <1% of lymphocytes co-express CD4 and CD8 and samples usually have a low lymphocyte count (<40%)
What is the standard of care treatment for thymomas?
No standard of care or studies comparing different treatments
What is the MST in dogs and cats with thymoma that undergo surgical resection?
Perioperative mortality in both spp?
Dogs: MST 1.7-2 years
Cats: MST 4-5 years
Perioperative mortality 20%
ORR of RT in dogs and cats with thymoma?
ORR 50-75%,
Dogs MST 8
Cats MST 2 yrs
Some px treated with RT alone, other with sx, RT, and chemo.
What % of dogs and cats eventually die from their thymoma?
Dogs - 40%
Cats - 20%
Positive (1) and negative (6) prognostic factors identified in px with thymoma?
PPI - degree of lymphocyte infiltrate = improved ST in both dogs and cats
NPI dogs for a shorter ST: Presence of another tumor at dx Lack of surgical excision Incomplete histologic excision Masaoka stage III+ PNS: hypercalcemia, MG Tx with adjuvant chemo or RT
PNS did NOT affect ST in another study
What is a TVT and how does it spread?
Horizontally transmitted infectious histiocytic tumor usually spread through damaged mucosal epithelium from coitus, licking, biting, and sniffing
What are the most common sites of involvement for TVT?
Genital mucosa, nasal and oral cavities, SQ tissues, eyes
External genitalia - caudal aspect of the penis in males, posterior vagina or vestibule in females
Also nasal and oral cavities
Spontaneous regression with TVT’s is seen secondary to what? When does it occur? At what point in time is it not likely to not regress on its own?
Immune responses against the tumor
3-6 months
9 months
TVT’s are seen in dogs of what age usually?
2 to 5 yrs
Metastasis in TVT can be seen in ___ to ___% of cases. What are the most common places?
5 to 17%
Draining lymph nodes (inguinal, tonsillar, iliac), SQ, skin, eyes, oral mucosa, liver, spleen, BM
Some of these may represent autotransplantation
How is TVT cytologically described?
For what IHC does it stain positive (4)?
Round cell tumor with many discrete clear cytoplasmic vacuoles
Vimentin, lysozyme, alpha-1-antitrypsin (AAT), macrophage specific ACM1, GFAP
What intracellular bacteria has been associated with TVT cells?
Leishmania
Can be co-transmitted along with the tumor
In addition to cell-mediated immunity, what other immune response does TVT also elicits?
Humoral immune response demonstrable by antibodies against TVT antigens
During which phase are high numbers of lymphocytes and mast cells are seen to be infiltrating TVT’s?
R (regression) phase - lymphocytes
P (progressive) phase - mast cells
A complete response is seen in ___ to___% of dogs with TVT when treated with single agent ____ once weekly for 3 to 6 treatments.
Resistant cases can be treated with which chemotherapy drug or what other treatment modality?
Vincristine ORR 90 to 95%
Doxorubicin, RT
Surgery for TVT’s has an overall local recurrence of ___ to ___%.
30 to 75%
What % of dogs with a splenic mass and hemoabdomen have HSA (range)?
60-70%
What % of NON-ruptured splenic masses are benign vs malignant?
Presence of what finding on US was suggestive of malignancy?
Benign - 70%
Malignant - 30%
Hypoechoic nodules
Out of dogs with concurrent splenic and hepatic masses, what % had benign vs malignant dz? What % of malignant masses were HSA?
Benign 27%
Malignant 48%
77%
Dogs with splenic masses that weigh more than ___kg are more likely to have HSA.
> 27.8kg
When comparing the site and cause of spontaneous hemoabdomen, dogs weighing < ___kg were more likely to be bleeding from which organ vs dogs weighing > than ___kg.
< 20kg liver
> 20kg spleen
Although there is no difference in cytology of pericardial effusion in dogs with HSA vs other tumors, dogs with HSA have elevated levels of what when compared to dogs with idiopathic effusions?
Troponin I
If > 0.25 ng/mL more likely to be cardiac HSA
What % of dogs with splenic HSA and grossly abnormal looking livers have HSA metastasis?
50%
What is the sensitivity and specificity of gross dark lesions on the liver in dogs with splenic HSA?
85% for both
What % of dogs undergoing laparoscopy for splenic HSA have to convert to open laparotomy?
What influenced this?
27%
Heavier body weight was significantly associated with conversion; OR 1.6
Splenic mass, BCS, were not
Doxorubicin q2 weeks MST for stage I, II, and III canine visceral HSA?
I - 8.5m
II - 7m
III - 3.5m
Doxorubicin ORR for gross cardiac and non-cardiac HSA?
Cardiac - ORR 40%, biologic response 70%
Non cardiac - ORR 40 to 50%
VAC for canine HSA ORR, CR, PR and overall MST?
Any difference in ST depending on stage?
ORR 90%, CR 43%, PR %43
Overall MST 6m, if CR 9m (lived longer than PR)
No
Doxo and concurrent cyclophosphamide administration can result in what in dogs with HSA?
Shorter ST
Alternated CCNU and doxo for K9 HSA MST? 1-yr SR?
5m
16% 1-yr survival rate
Ifosfamide MST for K9 HSA?
5m
What chemotherapy drug has been shown to inhibit HSA cell migration and induce apoptosis in vitro?
Paclitaxel
What 2 chemical compounds have been shown to enhance cell kill when combined with doxorubicin vs doxo alone in cell lines?
Tetrathiomolybdate - Cu binding agent that may reduce resistance
Resveratrol - naturally occurring polyphenolic compound in red wine; induces autophagy via activation of MAPK
What is allogenic LDC vaccination for dogs with HSA?
In what did it result?
AE?
Cationic liposome and DNA complex, which is an immune stimulant added to vaccines, combined with pooled cells from 2 HSA cell lines.
8 doses were administered along with doxorubicin chemo
Vaccine elicited strong humoral immune response to a control antigen and most dogs also mounted an Ab response against canine HSA cell lines
DFI 150d MST 180d (6m)
17% GI AE; diarrhea most common
How does Yunnan Baiyao work for HSA (3)?
Increased activity of caspases 3 and 7
Increased clot strength on TEG
Improved DFI in dogs with HSA
When dogs with stage II HSA are treated with alternating CCNU and doxo, how does the MI influence ST?
MI <11 MST 9.7m
MI 11-20 MST 7m
MI > 21 MST 3.8m
Identified negative prognostic factors in dogs with splenic HSA (5)?
Sx alone Higher stage Mets at dx MI (<11 MST 10m, 11-20 MST 7m, >21 4m) Administration of allogenic blood products
MST of K9 retroperitoneal sarcoma?
3 yrs
K9 renal HSA tx with sx alone or sx + chemo overall MST?
Negative PI?
9m
NPI - hemoperitoneum shorter MST 2m
K9 nodal HSA tx with sx alone or sx + chemo overall MST?
> 260-600
Cutaneous HSA most common signalment, location, and predisposed breeds (9)?
Light pigmented dogs with thin coats
Ventral abdomen and preputial region most common location
Breeds: Whippets, Salukis, bloodhounds, beagles, white bulldogs, English pointers, Staffies, Italian greyhound Dalmatian
Histopathology consistent with UV-associated solar dermatosis is detected in what % of dogs with skin HSA?
70%
What % of dogs with dermal and hypodermal or IM HSA have mets at diagnosis?
Dermal - 2%
Hypodermal/IM - 32%
Overall MST in dogs with dermal HSA (stage I) HSA when treated with sx?
Up to what % can develop metastasis? Risk factors for metastasis(2)?
2 to 2.7 yrs
30-35%
SQ involvement 2x more
Non-predisposed breeds with invasive tumors
Identified prognostic factors for ST in dogs with dermal HSA?
Longer MSTs seen in: predisposed breeds, ventral abdominal location, solar induced changes
Shorter MSTs seen in: hemoabdomen, mets development, non-predisposed breeds with larger tumors
Overall MST in dogs with SQ/IM (together) HSA when treated with sx and chemo?
If aggressive local therapy is pursued for these, what is the reported DFI and MST for SQ and IM tumors?
Metastatic rate?
5.7-10m; often large and invasive
With aggressive and good local control:
SQ - DFI 4.2yr MST 3.2
IM DFI 8.8m, MST 9
60% develop mets
ORR and median duration of response for doxorubicin in the gross dz setting in dogs with cutaneous HSA?
ORR 40%
53d (1.7m)
How is the location distribution of HSA in cats?
Equally distributed between visceral and cutaneous forms
In cats, what are the most common locations for visceral HSA and how is it distributed?
What % has multifocal disease?
Liver 35% Small intestine 31% Large intestine 31% Abdominal LN 31% Mesentery 27% Spleen 23%
77% multifocal disease
What % of cats with visceral HSA have pulmonary mets at diagnosis?
33%
When compared to dogs, how does cutaneous/SQ HSA behave in cats? Major concern with it?
Behaves similar to other STS
Local recurrence in; 60-80%
MST of cutaneous vs SQ feline HSA?
Cutaneous - not reached
SQ - 384d (12.8m)
Prognosis and MST of visceral HSA in cats?
77d
Negative PI in cats with HSA?
SQ location (vs cutaneous)
Visceral form (poor progn and high met rate)
MI>3 (MST 2m)
Incomplete tumor excision (MST 9m)
Most common cardiac neoplasm in dogs and cats?
Dogs - HSA #1, followed by aortic body tumors (chemodectoma, paraganglioma)
Cats - lymphoma #1
What % of pericardial effusion in dogs is causes by cancer? Most common causes (3)?
60%
HSA, aortic body tumors, mesothelioma
What are the 2 most common EKG abnormalities seen in dogs with cardiac tumors?
Accelerated idioventricular rhythm #1
VPC #2
Where are aortic body tumors derived from? IHC?
Neural crest
IHC: positive for NSE, chromogranin A, synaptophysin, S100
Loss of chromogranin A and S100 can be seen in what type of aortic body tumor?
Grade III paragangliomas
What % of aortic body tumors and right auricular masses are unresectable?
Almost all of ABT and ~50% of RA tumors
MST of dogs with RA HSA treated with sx?
3m
Is there a difference in outcome in dogs with neoplastic pericardial effusion when a pericardectomy vs a pericardial window is performed?
No
MST of dogs with cardiac/pericardial mesothelioma when treated with a pericardiectomy?
10-15m; can be less, not a lot out there, usually palliative; IC chemotherapy can be beneficial
Negative PI in dogs with cardiac HSA?
Thrombocytopenia
Tumor size of >4.7cm
Not treating with chemo
MST for aortic body tumors with medical management vs pericardiectomy?
Medical management: 40d to 4.3m
Pericardiectomy: 2yrs
MST of pericardial HSA, mesothelioma, and lymphoma?
HSA - 16d
Mesothelioma 15m with surgery
Lymphoma - 5m with chemo
What is mesothelioma? Risk factor? Where can they arise?
Rare neoplasm that derives from mesoderm involving the cells lining the coelomic cavities; arises from the surface serosal cells of the pleural (> 90% of cases), peritoneal, and pericardial cavities and from the tunica vaginalis of the testis
Can arise in the thoracic or abdominal cavity, pericardial sac, vaginal tunics of the scrotum
Asbestos - induces neoplastic transformation: chromosomal rearrangements, loss of TSG, generation of ROS by macs, increased GF, chronic inflammation
“Grossly”, how does mesothelioma look?
Cytologically, how do mesothelial cells look?
Histologically, what are the 3 ways they can be classified and which one is most commonly seen?
Diffuse nodular masses that cover the surface of body cavities (depends on histo type)
Similar to epithelial cells
Epithelial, mesenchymal, biphasic (combination)
Epithelial most common
What can cause an increase in proliferation of mesothelial cells?
What can cause an increase in proliferation of mesothelial cells?
What variant of the mesenchymal form of mesothelioma can be seen in male or German Shepherd dogs?
Sclerosing: resembles a sarcoma
What is the metastatic rate of mesothelioma?
True metastasis is rare, fluid accumulation results in exfoliation and implantation of cells, this results in seeding and multiple tumor formation
What is a CT finding that can be seen in px with mesothelioma?
Pleural thickening
How can you rule out mesothelioma in a px with pericardial effusion?
Normal fibronectin concentration; usually increased with MSA
What is required for mesothelioma dx?
Biopsy
Local penetration of IC chemotherapy?
2-3mm; consider debulking sx for large masses before IC
What is the MST of dogs with malignant neoplastic effusions when treated with IC carbo or mitoxantrone?
11m
What is used in dogs with TVT to confirm a diagnosis?
LINE-c-myc sequence with PCR
All TVT cells share c-myc oncogene rearrangement; a long interspersed nuclear element (LINE1) is present 5’ to the first exon
LINE-1 can disrupt transcriptional regulation of downstream genes, potentially initiating oncogenic activity
How is the karyotype of TVT cells vs normal host cells?
Normal dogs have 78 chromosomes and all but 2 are acrocentric (the 2 sex chromosomes)
TVT cells have a rearranged karyotype consisting of 57-59 chromosomes, including 15-17 submetacentric (resulting from fusion) chromosomes and 40-42 acrocentric chromosomes
TVT cells are aneuploid but exhibit stable and similar karyotypes in samples from different regions
A recent study of cytokine expression in dogs with TVT revealed changes in which cytokines (6)?
The majority of the samples evaluated were in which phase?
TGF-B - normal to reduced expression; may be associated with VCR resistance
IFN-y - decreased expression
IL-6 - decreased expression
CXCR4 - decreased expression; may be associated with lack of metastasis
VEGF - high expression
P phase
What is the most important change in P phase in dogs with TVT?
Down-regulation of MHC class I B-2 microglobulin and class II expression through TGF-B1 tumor secretion
This allows for immune system tumor evasion and decreased NK recognition
What are the 2 most common cranial mediastinal tumors in dogs?
Lymphoma #1
Thymoma #2
What % of dogs with thymoma have concurrent unrelated tumors?
27%
What % of dogs with thymoma have a polyclonal PCR result?
92%
MG in dogs with thymoma failed to resolve or required medications for tx in what % of the cases?
50%
Blood monocytes can differentiate into macrophages or dendritic cells based on what factors?
Macrophages - M-CSF
DC - M-CSF and IL-4
All leukocytes express what integrin receptor?
CD11/CD18
What cells express CD1a, CD11c, CD11b, and CD11d?
CD1a - all dendritic cells
CD11c - LC cells and DC
CD11b - macs and a subset of dermal interstitial DC
CD11d - macs of the splenic red pulp and bone marrow
What is FLT3?
Receptor is expressed on hematopoietic CD34+, CD117+ stem cells
FLT3 ligand is a growth factor for immature myeloid cells and stem cells and can expand CD34+ cells in vitro and in vivo
It synergizes with other growth factors and aids in development of DC and NK cell differentiation
In humans, FLT3 receptor is also expressed at high levels in a spectrum of hematologic malignancies including 70% to 100% of acute myelogenous leukemia (AML) of all French-American-British (FAB) subtypes, B-precursor cell acute lymphoblastic leukemia (ALL), a fraction of T-cell ALL, and chronic myelogenous leukemia (CML) in lymphoid blast crisis.
IBA-1 is expressed on what cells?
Ionized calcium binding adapter molecule 1
Expressed in all histiocytic cells and disorders
Can be used to ddx a histiocytoma from a plasmacytoma
What cell markers are used to dx cutaneous histiocytoma?
Positive for: CD1a, CD11c, MHC class II, E-cadherin, MUM1
Negative for Thy-1 and CD4 - markers of activated DC
What is the cell of origin of cutaneous histiocytoma, histiocytic sarcoma, hemophagocytic histiocytic sarcoma, cutaneous Langergans cell histiocytosis, and reactive histiocytosis (cutaneous and systemic forms)?
Histiocytoma - Langerhans cell
Histiocytic sarcoma - interstitial DC
HHS - macrophage
Cutaneous Langergans cell histiocytosis - Langerhans cell
Reactive histiocytosis - activated interstitial DC
What IHC marker can be used to differntiate a plasmacytoma from a histiocytoma?
Iba-1 - stains all histiocytic cells
MUM1 - multiple myeloma protein is expressed on both cutaneous histiocytoma and plasmacytoma
What are the histiocytic disorders?
Cutaneous histiocytoma
Cutaneous Langerhans cell histiocytosis
Reactive histiocytosis (cutaneous and systemic forms)
Histiocytic sarcoma (different locations)
Erythrophagocytic histiocytic sarcoma
What is cutaneous Langergans cell histiocytosis?
Langerhan cell disorder of the skin and +/- draining lymph nodes and internal organs
Most commonly seen in Shar-peis (35% of the cases) and usually limited to the skin in this breed
Delayed regression; >10m - does not occur if LN mets
50% euthanized due to lack of regression or complications from ulcerations
Systemic histiocytosis is familial in what breed? What is SH?
Bernese Mountain Dogs
Similar to cutaneous reactive histiocytosis, but involves the mucus membranes and organs.
Long-term therapy is common; combination of steroids and other immunosuppressants
Prolonged clinical course that rarely results in death
What breeds are predisposed to developing HS (4)?
Bernese Mountain dog, Rottweilers, Flat-Coated retrievers, Miniature Schnauzers
HS accounts for ___% of deaths in BMD and FCR.
15%
What are the different HS forms (4)?
Localized: -Splenic -Periarticular/synovial -Pulmonary; Min. Schnauzers may be over represented -CNS Disseminated
Identified risk factors in BMD vs FCR
BMD:
- 225x higher risk of HS
- 17x more likely to die from tumor causes
- 2x as likely as FCR to develop disseminated dz
- FCR 7x more likely than BMD to have localized dz
- Prev orthopedic dz increases risk of HS in BMD, but risk is lower in those receiving medications for >6m
Dogs with PAHS are ___ more likely to have had prior joint disease in the tumor-affected joint.
13.4x
After revision, what tumor has been classified as the most common primary synovial tumor?
HS
Histiocytic sarcoma arises from ___ and EHS arises from___.
Histiocytic sarcoma - dendritic cells
EHS - macrophages
What tumor suppressor genes are commonly affected in BMD and FCR with HS, suggesting a genetic predisposition?
CDKN2A/B deletions in 63%
PTEN deletions in 40%
RB1 - FCR 2x more likely to have deletions vs BMD
TP53 - FCR 2x more likely to have gain of function mutations vs BMD
Recently, what a gain of function mutation was identified in BMD with HSA?
PTPN11 gene exon 3 mutation
Substitution of E76K at the SH2 domain of the SHP2 gene encoded by PTPN11
BMD with HS had a higher prevalence of this mutation (37%) compared to other breeds with HS (9%)
Dogs with PTPN11 E76K mutation had increased AKT, ERK 1/2, and AKT
What marker is sensitive and specific for histiocytic sarcoma?
CD204
Cytoplasmic stain
A class A macrophage scavenger receptor that should be expressed on normal tissue macrophages, but not interdigitating DC of lymphoid tissue or Langerhans cells (CH is CD204-)
50/50 HS samples were positive, including EHS
It also stains normal tissue macrophages but these can be distinguished from tumor based on lack of malignancy characteristics
What is the immunophenotype of HS cells?
Positive for: CD11c/CD18, Iba-1, CD1, MHC class II, ICAM-1, CD45, CD80, CD86, CD90, CD204
Serum biomarkers in BMD with HS?
High ferritin (not necessarily outside the reference range)
Lower total WBC count
MCP-1 (monocyte chemoattractant protein)
MST and metastatic rate for synovial and periarticular HS in digs with therapy? Is one better than the other?
MST with amputation 6m
91% metastatic rate
Periarticular may have a longer MST - 391d
MST of primary CNS HS? MRI characteristics?
3d
Forebrain most common location
Solitary extra-axial mass with moderate to marked CE
Iso or hypointense on T2 (vs meningioma, hyperintense)
Diffuse marked enhancement of the meninges is common
Overall MST and PFS with therapy for primary pulmonary HS in dogs?
Metastatic rate at dx?
Overrepresented or predisposed breeds?
MST 4-8m
PFS 7m
46% intrathoracic mets, 16% pulmonary mets
Corgis, Min Schnauzers
Negative prognostic factors in dogs with pulmonary HS (3)?
Clinical signs - PFS only
Intrathoracic mets - PFS & MST
Lack of sx
Negative prognostic factors on multivariate analysis for dogs with histiocytic sarcoma (4)? On univariate (1)?
Multivariate:
- Thrombocytopenia
- Disseminated dz
- Palliative therapy
- Concurrent use of steroids
Univariate:
-Elevated survivin levels- also associated with chemoresistance
MST of dogs with disseminated HS?
2 to 2.8m (<3m)
ORR, duration of response, and MST of responders in dogs with measurable HS treated with CCNU?
Negative PI (4)?
ORR 46%
Duration of response 2.8 to 3.2m
MST6m
Negative PI (all associated with EHS):
- Anemia
- Thrombocytopenia
- Hypoalbuminemia
- Spenic involvement
MST of localized HS treated with sx, CCNU, and +/- RT?
19m
ORR, PFS of responders, and MST of alternating CCNU/doxo q 2 weeks for dogs with different forms of histiocytic sarcoma (disseminated or not)?
ORR 58%
PFS and MST 6m
ORR, clinical benefit, PFS of responders for DTIC as a rescue therapy for measurable HS in dogs?
ORR 18%
Clinical benefit 47%
PFS of responders 70d (2.3m)
ORR, biological response, median TTP of dogs epirubicin/CCNU as a first line therapy vs epirubicin alone in dogs with measurable HS?
What % required dose reductions? DLT?
ORR 29% first line with CCNU
ORR 19% rescue (rescue vs first line with CCNU)
Biological response 71%
TTP 2m
MST 6m
30% due to GI toxicity primarily
ORR of clodronate (bisphosphonate) in dogs with measurable HS?
40% experienced tumor regression
Periarticular HS treated with RT alone vs CCNU and RT?
RT alone - 6m
CCNU and RT - 7m
Blood work abnormalities that can be seen with EHS (4)?
Regenerative anemia - 94%
Hypoalbuminemia - 94%
Thrombocytopenia - 88%
Hypocholesterolemia - 70%
MST of dogs with EHS?
days to 1-2m
What IHC can be used to differentiate EHS from disseminated HS?
CD11d (macrophages from the splenic red pulp and BM)
In cats, how does HS typically occur? What locations are most commonly affected (3)?
Usually multifocal or disseminated; localized form is rare
Spleen, liver and BM involvement
What is feline progressive histiocytosis? Most common locations?
Initially occurs in skin and progresses over time to involve multiple organs (LN, lungs, abdominal viscera)
Multiple firm, haired or hairless, dermal papules or nodules, that can coalesce into plaques and become ulcerated
Head, feet, legs
Unresponsive to steroids, effective medical tx not available; can consider removal of solitary masses, but development of more is expected
Disease progresses over months to years (median 13.4m)
IHC for feline progressive histiocytosis?
CD1a, CD1c, CD11b, CD18, MHC II +/-, E-cadherin +/- (may be lost as tumor progresses)
87% express PDGFR-b (of FPH and HS)
Almost all cats surviving more than 300d had high PDGFR-b expression
What is malignant fibrous histiocytoma?
Tumors with histologic characteristics of both histiocytes and fibroblasts
How can MFH be differentiated from other histiocytic tumors?
Positive for vimentin, desmin, S-100
Negative for CD18 and CD11
Splenic fibrohistiocytic nodules is a term no longer used and has been reclassified to other dzs, with the most common ones being stromal sarcomas, HS, and complex nodular hyperplasia.
What is the MST of splenic stromal sarcomas and splenic HS?
Stromal splenic sarcoma - MST 488d
Splenic HS - MST 2.4m
What % of dogs with localized HS have the pulmonary form?
31%
What is the PFS and MST of dogs with pulmonary histiocytic sarcoma treated with CCNU chemo alone?
PFS 3m
MST 4m
What is the PFS and MST of dog with pulmonary HS treated with surgery and CCNU?
PFS 9m
MST 12.5m
