Cutaneous Neoplasia and Paraneoplastic Syndromes Flashcards
What does interphase consist of?
G1: cell growth
S: DNA replication
G2: preparation for mitosis
What are the common places where the cell cycle becomes unregulated?
Loss of normal checkpoints
Overexpression of growth factors
Loss of signal to die
Loss of repair mechanisms in S phase
What are two major proteins that regulate the cell cycle?
cyclins
cyclin-dependent kinases (CDKs)
How can some cancers use telomerase?
Some cancer cells utilize telomerase to add telomeric sections to the ends of DNA during DNA replication, allowing these cancer cells to live and divide much longer than other somatic cells
What is p27?
a protein thought to maintain cells in G0 and which may be decreased in cancers like squamous cell carcinoma
What is the most common phase of the cell cycle for veterinary chemotherapeutic agents to work on?
S phase (DNA replication)
What stage of the cell cycle do antimetabolite chemotherapeutics work on?
S
What stage of the cell cycle do alkylating agent chemotherapeutics work on?
S
What stage of the cell cycle do cross-linking agent chemotherapeutics work on?
S
What stage of the cell cycle do topoisomerase inhibitor chemotherapeutics work on?
S
What stage of the cell cycle do antimicrotubule agent chemotherapeutics work on?
M
What stage of the cell cycle do signal transduction inhibitor chemotherapeutics work on?
the level of signal transduction that starts the cell cycle
When are cells most resistant to radiation therapy?
in S phase
In addition to making the tumor smaller, what can be a benefit of debulking surgery?
may stimulate cells to divide –>
may force them into a phase of the cell cycle more susceptible to other therapies.
What is a proto-oncogene?
are a group of normal genes in cells which can cause cells to become cancerous when the genes are mutated
- normally help cells grow and
divide or stay alive
Usually produce proteins that
- stimulate cell division
- inhibit cell differentiation
- halt cell death
What is an oncogene?
what a proto-oncogene is called once it has mutated
mutations are usually dominant and increase the level of activity
What is c-kit?
a proto-oncogene that encodes the receptor tyrosine kinase protein
- aka KIT, CD117, or mast/stem cell growth factor receptor (SCFR)
activating mutations lead to cancer
not restricted to mast cell tumors but is a prognostic indicator in them
What is the role of tyrosine kinase protein (KIT)?
a transmembrane cytokine receptor
on the surface of hematopoietic stem cells, interstitial cells, melanocytes, and mast cells
binds to stem cell factor (steel factor)
- forms a dimer
- activates its intrinsic activity
- leads to phosphorylation
- activation of signal cascades
promotes cell survival, proliferation, and differentiation
also involved in fibronectin adhesion, chemotaxis, and degranulation of mast cell tumors
What is c-myc?
a proto-oncogene
encodes a transcription factor that regulates the cell cycle
Aberrant expression c-myc is present in many feline and canine cutaneous tumors
What are tumor suppressor genes?
normal genes that slow down cell division or tell cells to die at the right time
- ex TP53 that encodes p53
- ex retinoblastoma protein
What is TP53?
a tumor suppressor gene
encodes for the p53 protein
- most frequently mutated
protein in all human cancers
regulates apoptosis in response to genotoxic or cellular stress
What is retinoblastoma protein (pRB)?
a tumor suppressor protein
- normally inhibits cell cycle progression until a cell is ready to divide
- papilloma E7 binds to and inhibits it
What are DNA repair genes?
normal genes that help fix mistakes made when the cell copies its DNA in cell division
If they can’t fix the cell, they trigger cell death
- ex BRCA in some breast cancers
What are 13 hallmarks of cancer?
(1) Genomic instability and mutation
(2) Replicative immortality
(3) Insensitivity to growth suppressive signals
(4) Ability to evade programmed cell death
(5) Reprogrammed energy metabolism
(6) Sustained angiogenesis
(7) Immune destruction evasion
(8) Tumor-promoting inflammation
(9) Self-sufficiency in growth signals/replicative immortality
(10) Tissue invasion and metastasis
(11) Phenotypic plasticity and disrupted differentiation
(12) Non-mutational epigenetic reprogramming
(13) The microbiome changes
How can energy metabolism differ between normal and neoplastic cells?
normal cells use oxygen to process glucose and produce energy
neoplastic cells can switch to aerobic glycolysis even in the presence of oxygen
- less efficient but faster
- makes several intermediate pecursors
other cancer cells can use lactate as main energy source
What are the most important inflammatory mechanisms that are corrupted by tumors?
NF-kappaB and inflammasome signaling
What mediates tumor tissue invasion and metastasis?
E-cadherin
integrins
other adhesion molecules
production of matrix-degrading proteases.
What are the paradigms of cancer metastasis?
Traditional: late-stage tumor shedding, after the tumor is of significant size
Parallel progression model: cells
disseminate from tumors early, possibly even before malignant conversion
What is the metastatic cascade?
(1) Invasion and migration
(2) Angiogenesis and intravasation
(3) Survival in the circulation and attachment to the endothelium
(4) Extravasation and colonization
What is considered the differentiating step between pre-cancerous neoplasia and malignant cancer?
Invasion through the basement membrane
How can angiogenesis facilitate metastasis?
enables the delivery of nutrients and oxygen
facilitates the removal of waste
immature new vessels are more permeable
- facilitating tumor intravasation
- enables transport to distant sites
- via vascular and lymph systems
What destroys most metastatic cells before they become distant tumors?
hemodynamic shear forces
red blood cell collisions
immune stresses
How do metastatic cells extravasate?
physical occlusion
- the cells get lodged in small microvasculature
adhesion after rolling
- via binding with E-selectin, P-selectin, ICAM-1, or VCAM-1
What are metastatic niches?
contain cell types and an extracellular matrix compatible for tumor cell survival and growth
What is the Cancer Immunosurveillance theory?
is that the immune system works to identify normal vs. transformed cells and constrain tumor growth
therefore, suppressing the immune system would increase the risk of neoplastic growth
How is cyclosporine is believed to be associated with the development of neoplasia?
- Inhibiting cytotoxic T cell-mediated anti-tumor immune surveillance
- Direct cellular effects (humans): morphological alterations, increased cell motility, and anchorage
independent (invasive) growth. - Mechanisms have not been elucidated entirely
What is the evidence for cyclosporine-based risk for neoplasia in small animals?
- An increased risk of neoplasia after feline renal transplantation and cyclosporine-based
immunosuppression has been reported - A dog developed multicentric lymphoma after being on cyclosporine for anal furunculosis for 4 weeks
- A dog developed multiple cutaneous hamartomas and squamous cell carcinoma in situ after being on long-term immunosuppressive therapy with prednisone and cyclosporine
What is the mechanism by which Apoquel is associated with the development of neoplasia?
by inhibiting JAK-1 receptor mediated signal transduction
results in an inhibition of cytokines (IL-2, IL-4)
subsequently reduce stimulation of cells of the innate tumor immunosurveillance system (gamma delta T-cells, NK cells)
How can cyclosporine be protective against some forms of cancer?
activation of p53 (e.g., bladder cancer, colorectal cancer, glioblastoma, and leukemia)
What is the theory by which oclacitinib may be part of combination therapeutic protocols with chemotherapy for certain types of canine cancers?
aberrant JAK / STAT signaling within hematologic and solid tumors can be a driver of tumor growth through effects on the local microenvironment, enhancing angiogenesis, immune suppression, and others
What is the evidence against immunosuppressive drugs causing neoplasia in dogs?
- There has been no increased prevalence of canine neoplasia reported in any cyclosporine published clinical trials compared to the general dog population.
- A retrospective study did not find that cyclosporine treatment for canine atopic dermatitis was a significant risk factor for cutaneous lymphoma.
- A retrospective study found no association between oclacitinib and the development of cutaneous tumors (benign or malignant) in dogs
What are the 4 ways to classify malignant tumors?
(1) broadly, by tissue, organ, and system
(2) by specific type
(3) histologic grade
(4) by spread (staging)
What are solid neoplasms subdivided into?
(1) Tumors of epithelial origin
(2) Tumors of mesenchymal origin
(3) Tumors of the blood (= leukemia)
(4) Tumors of lymphoid origin (= lymphoma)
Where do tumors of epithelial originate from?
epidermis, hair follicle, nailbed, or skin glands (sebaceous, apocrine, or eccrine glands)
What are carcinosarcomas?
rare neoplasms composed of admixed malignant epithelial and mesenchymal elements that metastasize together
What are the major mesenchymal cell types?
fibroblasts, mesothelium, endothelium, adipocytes, myoblasts, chondroblasts, and osteoblasts
What is the most common malignant neoplasms in cats?
tumors of mesenchymal origin
What are the common neoplasms of epithelia origin?
squamous cell carcinoma
apocrine/sebaceous gland tumors
tumors of hair follicles
What are the common mesenchymal tumors (related to dermatology)?
adipose tumors (lipoma/sarcoma)
muscle tumors (leiomyoma/sarcoma, rhabdomyoma/sarcoma)
blood and lymphatic vessel tumors (hemangioma/sarcoma, glomus tumors, lymphangioma/sarcoma)
peripheral nerve tumors
tumors of histiocytic or mastocytic origin
connective tissue tumors (myxoma/sarcoma, fibroma/sarcoma, hemangiopericytoma, sarcoid)
What is tumor grading based on?
combination of cytologic features (e.g., extent of cellular differentiation and dysplasia) and morphological-structural observations (e.g., mitotic count, necrosis)
What does increasing grade tend to be correlated with?
poorer or lack of differentiation
increasing grade correlates with more aggressive anticipated behavior, metastatic potential, and/ or potential for recurrence
What does tumor stage refer to?
extent of spread throughout the body
What is the TNM Classification of Malignant Tumors?
a widely used system for scoring tumor spread
size/extent of the primary tumor (T)
degree of spread to the LNs (N)
presence of distant metastases (M)
How do sarcomas tend to metastasize?
through blood
most commonly go to lungs
initial staging should include chest radiographs
How do carcinomas tend to metastasize?
tend to metastasize through blood and lymphatics
regional lymph nodes, lungs, liver, and/or spleen
staging includes aspirating the regional lymph node, chest radiographs, and abdominal ultrasound
What are sarcomas?
mesenchymal cancers
What are carcinomas?
epithelial cancers
How do round cell tumors tend to metastasize?
through the lymphatic systems
regional lymph nodes, liver and spleen
staging involves regional lymph node aspiration +/- abdominal ultrasound with liver/spleen aspiration
What are physical factors involved in the development of skin cancer in dogs and cats?
ionizing radiation
- squamous cell carcinoma
thermal injury
trauma
- fibrosarc or lymphoma (cats)
chemical injury
What are papilloma viruses associated with the development of in cats?
Bowenoid in situ carcinoma
squamous cell carcinoma
viral plaques
feline fibropapillomas (sarcoids)
What are papilloma viruses associated with the development of in dogs?
development of squamous cell carcinoma
What neoplasia is bilateral ischemic necrosis of the hindpaws associated with in cats?
May be associated with multicentric follicular lymphoma
What neoplasms is feline skin fragility syndrome associated with?
adrenal and other abdominal carcinomas
multicentric lymphoma
What common immunocytochemical stains are used for T cell neoplasias?
CD3
What common immunocytochemical stains are used for B cell neoplasias?
CD79a and CD20
What common immunocytochemical stains are used for epithelial neoplasias?
cytokeratin
What common immunocytochemical stains are used for mesenchymal cells neoplasias?
vimentin
What common immunocytochemical stains are used for melanocytic neoplasias?
Melan A
What are the cell grouping of epithelial tumors on cytology?
Intercellular junctions between
cells → cells are arranged in cohesive sheets or clusters
What are the morphologic features of epithelial tumors on cytology?
Round*, cuboidal, columnar, or polygonal
Cytoplasmic borders of individual cells are usually distinct.
- Tend to lose intercellular junctions/appear as discrete
round cells when poorly differentiated
If glandular tissue, may have
cytoplasmic vacuoles or
produce a cytoplasmic
product that displaces the nucleus.
What are the morphologic features of mesencymal tumors on cytology?
Spindle, stellate, or oval
Cytoplasmic margins are indistinct
Often embedded in ECM
What are the cell grouping of epithelial tumors on cytology?
No intercellular junctions → arranged individually or in non-cohesive aggregates
What is the degree of exfoliation of epithelial tumors?
Exfoliate well (typically)
What is the degree of exfoliation of mesenchymal tumors?
Exfoliate poorly
What are the cell grouping of round cell tumors on cytology?
Individualized in a monolayer
What is the degree of exfoliation of round cell tumors?
Exfoliate well
What are the cutaneous round cell tumors?
Mast cell tumor
histiocytic tumors
plasma cell tumors
transmissible venereal tumor
lymphoma
What is the appearance of melanocytic tumors on cytology?
mesenchymal but can adopt the appearance of epithelial, mesenchymal, or round cells
may or may not have intracytoplasmic pigmentation
What are the most common histochemical stains for small animal cutaneous tumors?
Toluidine blue and Giemsa
– used for mast cell tumors
Fontana Masson
– used for melanomas
What are the common IHCs used in histopathology for hemangiosarcomas?
factor VIII related antigen
- von Willebrand factor
claudin 5
CD31
laminin
type IV collagen
*= endothelial origin
What are the common IHCs used in histopathology for melanomas?
usually a “cocktail”
melan-A
PNL2
TRP-1 and TRP-2
+/- S100
What are the common IHCs used in histopathology for smooth muscle tumors?
smooth muscle actin
desmin
What are the common IHCs used in histopathology for skeletal muscle tumors?
myogenin D
sarcomeric actin
desmin
What are the common IHCs used in histopathology for mast cell tumors?
CD1117/c-kit
*can be helpful in prognostication
What are the common IHCs used in histopathology for plasma cell tumors?
MM-1/interferon regulatory factor-4 (MUM1/IRF4)?
What are the common IHCs used in histopathology for T cell lymphoma?
CD3
What are the common IHCs used in histopathology for B cell lymphoma?
CD79a
CD20
PAX5
What are the common IHCs used in histopathology for neuroendocrine tumors?
chromogranin A
synaptophysin
What are the common IHCs used in histopathology for histiocytomas?
CD18
CD204
IBA-1
What is a Polymerase Chain Reaction for Antigen Receptor Rearrangement (PARR) assay?
separates DNA by size to evaluate for clonal populations of B- and T-cells
How does PARR work?
If a cell becomes neoplastic, it no longer responds to growth controls –> it undergoes unlimited expansion
- the Ig or T-cell receptor genes in that population (depending on whether it is a B-cell or T-cell lymphoma) will be a single size
- reactive process should have multiple, different-sized, T-cell receptor and Ig genes
What are the applications of PARR?
*only in lymphoid cells
establish clonality in a sample that is cytologically or histologically ambiguous
compare two neoplasms arising at different times to determine whether they have the same clonal origin
How does flow cytometry work?
*most easily applied to fluid
- can also be cells in buffer method for counting/evaluating cells
cell suspension is passed through a detection laser
rapidly and simultaneously evaluates cellular granularity/size
input into a computer to analyze cell type
What are ablative therapies?
involves the physical removal of tumor tissue in bulk
- Conventional surgery
- Hyperthermia
- Cryotherapy
- Laser ablation
- Surgical diathermy
- Vascular or tumor ligation
What are the lasers used in veterinary dermatology?
carbon dioxide
neodymium-doped yttrium aluminium garnet (Nd:YAG)
diode lasers
What are cytotoxic therapies?
Chemotherapy
Photodynamic therapy (PDT)
Electrochemotherapy
Radiation therapy (RT)
What is oncologic chemotherapy?
the treatment of cancerous cells through cytotoxic medications
- typically prevent tumor cells from multiplying by interfering with their ability to replicate DNA
- can be utilized systemically or locally
How does photodynamic therapy work?
involves the use of light of appropriate activating wavelengths, oxygen, and a photosensitizer
- accumulates within a tumor
When excited, the photosensitizer reacts with molecular oxygen to create ROS that cause vascular stasis and necrosis, membrane damage, apoptosis, and inflammatory cascades
How does electrochemotherapy work?
involves electric pulses that cause reversible permeabilization of cell membranes, enabling entry of chemotherapeutic drugs or immunotherapies into cells
- electroporation
The primary indication is incompletely excised cutaneous and subcutaneous tumors
How does radiation therapy work?
involves the absorption of ionizing radiation into cells –> creates highly reactive free radicals that result in biologic damage that may kill the cell or render it incapable of reproducing
This is a treatment modality for solid tumors in animals
- soft tissue sarcomas
- mast cell tumors
- cutaneous lymphoma
What is fractionated RT?
involves the dividing of total RT dose into smaller doses (fractions) to cause less tissue injury and in some cases improve efficacy
What is brachytherapy?
a type of RT that utilizes radioactive implants
What are the adverse effects of radiation therapy on normal tissue?
acute
- mucositis
- erythema
- alopecia (temporary or permanent)
- desquamation
- lymphedema
- changes in pigmentation
- swelling
late (severe)
- rare, include fibrosis/necrosis
consequential
delayed
What is radiation recall?
poorly understood phenomenon wherein animals treated with chemotherapy after a course of RT develop a return of the radiation side effects like mucositis or skin desquamation
What is the percentage of malignant tumors in cats?
percentage of malignant skin tumors is higher in cats than dogs (70-82%)
What are the top skin tumors in dogs?
mast cell tumor (16.8%)
lipoma (8.5%)
histiocytoma (8.4%)
perianal gland adenoma (7.8%)
sebaceous hyperplasia/adenoma (6.5%)
squamous cell carcinoma (6%)
melanoma (5.6%)
fibrosarcoma (5.4%)
basal cell tumor (5%)
malignant peripheral nerve sheath tumor (4.3%)
papilloma (2.8%)
sweat gland adenocarcinoma (1.1%)
sebaceous adenocarcinoma (0.5%)
What are the top skin tumors in cats?
Basal cell tumors, mast cell tumors, squamous cell carcinoma, and fibrosarcoma account for ~70% of all feline skin tumors
basal cell tumor (23%)
mast cell tumor (16.5%)
fibrosarcoma (17.9%)
squamous cell carcinoma (10.4%)
miscellaneous (10.1%)
apocrine adenoma (3.4%)
lipoma (3.3%)
hemangiosarcoma (2.9%)
sebaceous adenoma (2.8%)
fibroma (2.7%)
hemangioma (1.7%)
melanoma (1.7%)
malignant fibrous histiocytoma (0.7%)
What are the differential diagnoses of plasma cells causing cutaneous tumor(s) in dogs and cats?
Solitary extramedullary cutaneous plasmacytoma
- 95%
Cutaneous plasmacytosis
- dogs only
Cutaneous metastasis from multiple myeloma
- <1% overall but up to 30% of cats with multiple myeloma
What are cutaneous plasma cell tumors?
found in both the dog and cat
part of a group of diseases called myeloma-related disorders
caused by clonal neoplastic populations of plasma cells
What are myeloma-related disorders?
cutaneous plasma cell tumors
multiple myeloma
non-cutaneous extramedullary plasmacytoma
macroglobulinemia
solitary osseous plasmacytoma
cutaneous plasmacytosis
plasma cell leukemia
When is staging important for cutaneous plasma cell tumors?
most important in cases of cutaneous plasmacytosis and multiple myeloma
- relatively high metastatic rates
less important for cutaneous or oral solitary extramedullary plasmacytomas
What can be found in the serum or urine of animals with cutaneous plasmacytosis and multiple myeloma?
M component
Where do extramedullary solitary plasmacytomas tend to occur in dogs?
mostly cutaneous (86%)
- limbs and head
oral cavity/lip membranes (9%)
gastrointestinal tract (4%)
other: spleen, genitalia, eye, third eyelid, liver, larynx, and trachea
Do extramedullary solitary plasmacytomas metastasize in dogs?
typically benign
tumors may develop nodal or distant metastases (2% cases), new cutaneous plasmacytomas at sites distant from the primary tumor (<2% cases), or monoclonal gammopathy or plasma cell leukemia.
What is the typical signalment of a dog with an extramedullary solitary plasmacytomas?
Median age is 9-10 years
breeds may be predisposed: Airedale terrier, boxer, cocker spaniel (English and American), German shepherd, West Highland white terrier, Yorkshire terrier
What is the treatment of extramedullary solitary plasmacytomas in dogs?
Conservative surgical excision is curative in most cases
Local recurrence rate 5%
Anecdotal success with cryotherapy, electrocautery ablation, and carbon dioxide laser ablation.
What are the clinical signs of extramedullary solitary plasmacytomas?
Solitary, smooth, raised pink, variably alopecic, up to 10cm diameter
Typically, no related systemic signs
What is the behavior of extramedullary solitary plasmacytomas in cats?
mostly cutaneous but can also occur elsewhere
May be benign but may also progress to systemic myeloma-related diseases
What is cutaneous plasmacytosis?
occurs in dogs only
Biologically aggressive
- outcomes similar to multiple myeloma
- Associated with
lymph node or abdominal viscera involvement in approximately 30% of cases
- May have monoclonal gammopathy
has multiple extramedullary cutaneous plasmacytomas
What is the treatment of cutaneous plasmacytosis in dogs?
Systemic chemotherapy is indicated: melphalan (treatment of choice), lomustine, prednisone
What is the M component?
accumulation of a single type of a whole immunoglobulin molecule or an immunoglobulin component
(like the Bence Jones protein)
- seen in multiple myeloma
- usually IgA or IgG in dogs
clinical signs of multiple myeloma are typically associated with the infiltration of bone or organs with neoplastic plasma cells
- bone disease
- bleeding diathesis
- hyperviscosity syndrome
- cytopenias secondary to myelophtisis
- cardiac failure
- hypercalcemia
- immunodeficiency/infections
- renal disease
- cryoglobulinemia
*usually bone marrow in dogs
*usually abdominal in cats
- occasional familial association
What are some cutaneous manifestations of cryoglobulinemia?
particularly on the extremities
erythema
purpura
ulcerations
punched out necrosis
What neoplasia is cryoglobulinemia seen with?
Multiple myeloma
What is the treatment of multiple myeloma in dogs?
aimed at reducing tumor cell mass and ameliorating the secondary systemic side effects they elicit
- melphalan (TOC)
- cyclophosphamide
- lomustine
- prednisone
- chlorambucil
Prognosis for long-term survival is generally good with chemotherapy (median survival time 540 days)
- complete remission typically doesn’t occur
What is the treatment of multiple myeloma in cats?
Treatment goals and options are similar to dogs, though melphalan is used less commonly
Prognosis for long-term survival is poorer than dogs (median survival time 4-13 months)
What are differential diagnoses for mast cell causing cutaneous tumors in dogs and cats?
- Mast cell tumors
- Urticaria pigmentosa
- Diffuse cutaneous mastocytosis
- Systemic mastocytosis with cutaneous involvement
What is the most common type of cutaneous tumor in dogs?
Cutaneous mast cell tumors
What is the most common malignant tumor in dogs?
Cutaneous mast cell tumors
How do cat cutaneous mast cell tumors behave?
quite different than their canine counterparts and in general have a benign behavior
In which animals have spontaneously regressing MCTs been reported?
young animals: cats, pigs, horses, humans, and one dog
What mediators are ultimately responsible for many of the clinical signs associated with MCTs?
Granule contents
heparin, chondroitin sulfate, biogenic amines (histamine), preformed tumor necrosis factor alpha (TNF-alpha), proteases (in the skin, primarily chymase and tryptase), acid hydrolases, cathepsin G, carboxypeptidase, and others
What do alterations in the oncogene encoding the KIT receptor (c-kit) do for for MCTs in dogs?
associated with 25-30% of intermediate- and high-grade MCTs and are linked to increased risk of local recurrence, metastasis, and tumor-related death
Why are tyrosine kinase inhibitors used for treatment of MCTs?
Stem cell factor is a growth factor which binds to the tyrosine kinase receptor KIT (c-kit) on mast cells
Where are mast cell tumors typically found in dogs?
most commonly in the dermal and subcutaneous tissues
usually solitary, but they may be multiple (11-14% affected dogs)
frequently trunk and perineal region (50%), limbs (40%), and head and neck (10%)
What is the etiology of mast cell tumors?
Etiology is unknown
Chronic inflammation may play a role
likely a role of genetic changes
- may involve alterations in p53
- expression of cyclin-dependent kinase inhibitors (p21, p27)
- estrogen and progesterone receptor expression and localization
- c-kit mutations
- others
What mutation can lead to survival, proliferation, and oncogenic transformation in canine MCTs?
A gain of function mutation in exon 8 or 11 of c-kit
- can develop without a c-kit mutation
is a negative prognostic indicator
What is the signalment of typical dogs with MCTs?
Mean age of dogs is 8-9 years
No sex predilection
Certain breeds may be predisposed: bulldog descendants (boxer, Boston terrier, English bulldog, pug), Labrador retriever, golden retriever, cocker spaniel, schnauzer, Staffordshire bull terrier, beagle, Rhodesian ridgeback, Weimaraner, and Chinese shar pei
Which breed of dog is most likely to develop less aggressive mast cell tumors?
bulldog descendants
Which breed of dog is most likely to develop more aggressive mast cell tumors?
shar peis
and at a younger age
can have multiple on the extremities that create gross distension and deformity of the legs
What is the typical clinical appearance of well-differentiated cutaneous MCTs?
typically solitary, small, slow growing, not ulcerated, and may be alopecic
What is the typical clinical appearance of poorly differentiated cutaneous MCTs?
usually rapidly growing, ulcerated, large, irritating, may cause inflammation or edema in surrounding tissues, and may cause small satellite nodules in surrounding tissues
What is the common history of cutaneous mast cell tumors?
waxing and waning size, which is associated with the intermittent release of mast cell granule contents which can cause edema and bleeding
What is the typical clinical appearance of subcutaneous mast cell tumors?
appear as quiet, subcutaneous swellings
- commonly mistaken for lipomas. (Personal tip: I have diagnosed several “lipomas” as MCTs or soft
tissue sarcomas. FNA any new mass, even if it looks lipomatous)
What are the paraneoplastic syndromes associated with mast cell tumors?
Darier’s sign
GI ulceration
- 35-83% on necropsy
Coagulation abnormalities
Delayed wound healing/dehiscence
Hypotension
Hypereosinophilia
What is Darier’s sign?
manipulation of the mast cell tumor during examination results in degranulation and subsequent wheal and flare in the surrounding tissues
How can mast cell tumors cause gastrointestinal ulceration?
histamine release from MCT granules acts on parietal cells via H2 receptors –> increased hydrochloric acid secretion and subsequent GI ulceration
- may also be an inhibition of normal gastrin feedback loops to
decrease gastric hydrochloric acid
histamine binding to H2 receptors also leads to increased gastrointestinal motility and capillary permeability, promoting intravascular thrombosis and mucosal ulceration
How can mast cell tumors cause coagulation abnormalities?
heparin release from MC granules can contribute to coagulation abnormalities
- may have normal normal presurgical coagulation parameters
How can mast cell tumors cause hypotension?
hypotension may result from vasodilation associated with the release of histamine, other vasoactive substances, and maybe prostaglandin D series
How can mast cell tumors cause delayed wound healing/dehiscence?
release of vasoactive amines and proteolytic enzymes by MCs can lead to suppression of fibroblast growth factor, reducing fibroplasia
How can mast cell tumors cause hypereosinophilia?
associated with the release of eosinophil chemotactic factors
What are the IHC stains for mast cell tumors?
vimentin (+)
tryptase (+)
KIT (CD117) (+)
chymase (+)
MCP-1(+)
IL-8 (+)
What is is the most consistent and reliable prognostic factor for cutaneous MCTs?
Histologic grade
- based on degree of MC differentiation
will not predict behavior of every tumor
*except subcutaneous mast cell tumors are not reliably graded by these systems
What is the Patnaik three-tiered grading system?
Grade I MCTs are low grade (well-differentiated)
- best type to have
- tend to not spread past skin
- surgery should be curative
- no chemotherapy is needed
- 80-90% do well after surgery
Grade II MCTs are intermediate grade
- somewhat unpredictable
- mitotic index may help
- < 5 had a MST of 70 months
- > 5 had a MST of 5 months
- 75% do well after surgery
Grade III MCTs are high grade (poorly differentiated)
- worst type to have
- behave invasively/aggressively
- to spleen/liver/bone marrow
- need more than surgery
- 55-96% are metastatic and die within in 1 year
Where do cutaneous mast cell tumors tend to spread to?
Metastasis is usually to local lymph nodes first, then to spleen and liver and other organs
What is the Kiupel two-tiered grading system of mast cell tumors?
Divide them into high and low
What factors have an influence on prognosis for mast cell tumors?
Histologic grade
Clinical stage
Location
Cell proliferation rate
Growth rate
Microvessel density
Recurrence
Systemic signs
Age
Breed
Sex
Tumor size
c-kit mutation
DNA copy number variation (CNV)
How can clinical stage be important for prognosis with cutaneous mast cell tumors?
Stages 0 and 1, confined to the skin without local lymph node or distant metastasis, have a better prognosis than higher stage disease
How can histological grade be important for prognosis with cutaneous mast cell tumors?
Strongly predictive of outcome. Dogs with undifferentiated tumors typically die of their disease after local therapy alone, whereas those with well-differentiated tumors are usually cured with appropriate local therapy
How can location be important for prognosis with cutaneous mast cell tumors?
Subungual, oral, and other mucus membrane sites are associated with more high-grade tumors and worse prognosis.
Preputial and scrotal tumors are also associated with worse prognosis.
Subcutaneous tumors have better prognosis.
Visceral or bone marrow disease usually carries a grave prognosis.
How can cell proliferation rate be important for prognosis with cutaneous mast cell tumors?
Mitotic index, relative frequency of AgNORs, and percent proliferating cell nuclear antigen, or Ki-67 immunopositivity are predictive of post-surgical outcome.
How can growth rate be important for prognosis with cutaneous mast cell tumors?
MCTs that remain localized and are present for prolonged periods of time (months or years) without significant change are usually benign.
How can microvessel density be important for prognosis with cutaneous mast cell tumors?
Increased microvessel density is associated with higher grade, a higher degree of invasiveness, and worse prognosis.
How can recurrence be important for prognosis with cutaneous mast cell tumors?
Local recurrence after surgical excision may carry a more guarded prognosis.
How can systemic signs be important for prognosis with cutaneous mast cell tumors?
The presence of systemic illness (hyporexia, vomiting, melena, GI ulceration) may be associated with a higher stage of disease.
How can age be important for prognosis with cutaneous mast cell tumors?
Older dogs may have shorter median disease-free intervals when treated with radiation therapy than younger dogs.
How can breed be important for prognosis with cutaneous mast cell tumors?
MCTs in boxers and other brachycephalic breeds tend to be of low or intermediate grade and a better prognosis.
How can sex be important for prognosis with cutaneous mast cell tumors?
Males have a shorter survival time than female dogs when treated with chemotherapy
How can tumor size be important for prognosis with cutaneous mast cell tumors?
Large tumors may be associated with worse prognosis after surgical removal and/or radiation
therapy
How can c-kit be important for prognosis with cutaneous mast cell tumors?
Activating mutations in c-kit are associated with a worse prognosis.
How can DNA copy number variation (CNV) be important for prognosis with cutaneous mast cell tumors?
Higher CNVs are associated with higher grade tumors and worse prognosis.