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.
What are associated with prognosis in subcutaneous mast cell tumors?
Mitotic index, multinucleation, and degree of tissue infiltration
What is the recommended treatment of low to intermediate grade mast cell tumors localized to the skin?
wide surgical excision is treatment of choice
Marginal excision (no gross residual disease) may be acceptable
Not all tumors with incomplete excisions will recur
What is the recommended treatment of high grade MCTs, intermediate grade MCTs with regional or distant metastases, or mucocutaneous / mucus membrane junction MCT?
chemotherapy and/or RT +/- surgery
How can prednisone help with mast cell tumors?
inhibits MC proliferation, induces tumor cell apoptosis in vitro, and decreases peritumoral edema and inflammation
What are the tyrosine kinase inhibitors used to treat mast cell tumors?
toceranib (Palladia)
masitinib (Masivet)
imatinib (Gleevec)
How does stelfonta (tigilanol tiglate) work?
newer treatment that involves intratumoral injection of a potent cellular signaling molecule which results in rapid destruction of the treated tumor by hemorrhagic necrosis and tumor sloughing
Which form of mast cell tumor is most amenable to cure with surgery?
Subcutaneous MCTs
What are some ancillary therapies for mast cell tumors?
important when systemic signs are present
- Antihistamines
- Antacids
- GI protectants
What are the three syndromes of mast cell tumors in cats?
cutaneous
- histiocytic and mastocytic
splenic/visceral
intestinal
What is the typical signalment of cats with mast cell tumors?
Mean age is 8-9 years
No sex predilection
Histiocytic type appears younger
- mean 2.4 years old
Siamese cats may be predisposed
What are histiocytic MCTs in cats?
predominantly found in young cats
Siamese cats predisposed
less common than the mastocytic subtype
presents as multiple, non-pruritic, firm, hairless, pink, and sometimes ulcerated SQ nodules
What are mastocytic MCTs in cats?
more common type
most commonly a solitary, raised, firm, well-circumscribed, hairless, white to pink/erythematous, dermal nodule up to 3cm diameter, with variable ulceration
- 20% may have multiple
some cats may present with what looks like discrete subcutaneous nodules (suggestive of panniculitis) or eosinophilic plaques
Pruritus is variable
typically on the head and neck
- base of the pinna
Oral cavity may be affected
Darier’s sign may be present
Which form of MCT in cats may be difficult to diagnose on cytology?
histiocytic form
MCs may comprise only 20% of the cells (the majority are histiocytes, followed by eosinophils and lymphocytes, potentially looking a lot like inflammation or granulomatous nodular panniculitis / dermatitis)
Where, internally, are mast cell tumors frequently found in cats?
spleen
What is the typical behavior of feline mast cell tumors?
in general, feline cutaneous MCTs behave in a more benign way than canine MCTs
How are feline mast cell tumors graded on histopathology?
histopathologic grading systems used in dogs are not reliable predictors in cats
Mitotic index in cats is often associated with higher risk
- but some may still be benign
mastocytic type of feline MCTs may be histopathologically categorized as compact (50-90% of cases) or diffuse (anaplastic)
- anaplastic may be more malignant
How is number of mast cell tumors important for cats?
Cats with one cutaneous MCT have a better prognosis for survival than those with 5 or more
cutaneous MCTs.
How is the histiocytic form of mast cell tumor treated in cats?
may spontaneously regress over 4-24 months
Conservative surgical resection or active surveillance (monitoring) can be pursued
How is the mastocytic form of mast cell tumor treated in cats?
If well-differentiated with low mitotic figures
- surgical excision
- Local recurrence is uncommon but possible.
Poorly differentiated / high mitotic figure MCTs
- treated like aggressive canine
mast cell tumors, with a combination of chemotherapy +/- RT +/- surgery
- Gleevec and lomustine have been used
What is the typical signalment of urticaria pigmentosa in dogs?
Only a small number of dogs overall
usually < 1 yr
a middle-aged dog was reported
What is the typical clinical appearance of urticaria pigmentosa in dogs?
non-pigmented
head, neck, trunk, perineum, and legs
May be up to 5cm
- single, multiple, or numerous
+/- Darier’s sign and pruritus
Other signs of MC degranulation
What is the typical histopathologic appearance of urticaria pigmentosa in dogs?
moderate to severe perivascular to diffuse, nonencapsulated and poorly demarcated infiltration of well-differentiated MCs in the dermis
What is the treatment of urticaria pigmentosa in dogs?
May spontaneously regress or progress to systemic signs
Excellent response has been noted with oral glucocorticoids, H1 blockers, and H2
blockers
What is the typical signalment of urticaria pigmentosa in cats?
Average age is <1 year
Devon Rex and Sphynx are predisposed
What are the 3 clinical presentations of urticaria pigmentosa?
(1) non-pigmented papules and wheals on the head, shoulders, ventral neck, and axillae, with pruritus
(2) non-pigmented maculopapular erythematous dermatitis with crusts and pruritus
(3) highly pruritic chronic dermatitis with bilaterally symmetrical linearly distributed, pigmented lesions on the flanks
(Darier’s sign is typically negative in all)
What is the typical histopathologic appearance of urticaria pigmentosa in cats?
moderate to severe perivascular to diffuse, nonencapsulated and poorly demarcated infiltration of well-differentiated MCs in the dermis, with numerous eosinophils
What has been found about c-kit mutations in dogs with urticaria pigmentosa?
No dogs had mutations in c-KIT exons 8 and 11
What is the primary differentials for urticaria pigmentosa in cats?
Dermatophytosis: has been reported in three cases that clinically mimicked MPCM but were diagnosed with histopathology
MC tumor: may initially present as papules but is typically not pruritic and found in older cats
What IHCs can be used for urticaria pigmentosa in cats?
Tryptase
KIT
What is the treatment for feline urticaria pigmentosa?
Prognosis is variable
May have spontaneous regression
- more likely with non-pigmented papules/wheals
May be progressive and aggressive
Systemic glucocorticoids, antibiotics (amoxicillin/clavulanic acid or doxycycline) and/or blackcurrant seed oil, and also antihistamines (hydroxyzine/cetirizine) in addition to shampoo or cyclosporine
What is disseminated / diffuse cutaneous mastocytosis?
Rare condition in dogs and cats
May involve c-kit mutation for dogs
Typically progresses to systemic
Poor response to treatment
- may lead to euthanasia
What is systemic mastocytosis with disseminated cutaneous mastocytosis?
Very rare condition in dogs and cats
Visceral form (splenic or intestinal) of feline MCTs has also been referred to as systemic
mastocytosis but this doesn’t met to skin
What are the cutaneous lymphoproliferative disorders in dogs and cats?
(1) Cutaneous lymphoma
(2) Cutaneous lymphocytosis
(3) Lymphomatoid granulomatosis
(4) Extranodal lymphoma with cutaneous involvement
(5) Reactive lymphoid hyperplasia
Where are neoplastic lymphocytes found in epitheliotropic lymphoma?
epithelial tissues of epidermis/hair
due to expression of specific integrins
Where are neoplastic lymphocytes found in non-epitheliotropic lymphoma?
neoplastic lymphocytes are found in the dermis and subcutis
What type of lymphocytes are found in epitheliotropic lymphoma?
most commonly have a T-cell origin, and B-cell tumors are rare
- dogs are usually CD3/CD8+ and γδ
- may have increased CD25+ T-cells
- humans are usually CD3/CD4+
What is thought to be a risk factor for epitheliotropic lymphoma?
chronic inflammation
FeLV may play a role in cats
How is COX-2 thought to play a role in cutaneous neoplasms?
increasing angiogenesis, invasiveness, and metastasis; inducing resistance to apoptosis; and suppressing immune responses
How are COX-2 inhibitors thought to have anti-neoplastic activity?
inhibition of PGE2 synthesis
What are Pautrier’s microabscesses?
discrete collections of neoplastic lymphocytes in the upper layers of the epidermis
Which anatomical location in cats has an especially poor prognosis for epitheliotropic lymphoma?
tarsus
MST of 190 days
What is associated with a poorer prognosis to cutaneous lymphoma?
f neoplastic lymphocytes in peripheral blood, thrombocytopenia, and poor initial chemotherapeutic response
The increased transcription of which cytokines is associated with epitheliotropic lymphoma in dogs?
Th-1 type cytokines IL-12 and IFN-gamma
Increased levels of which T-cell markers are associated with epitheliotropic lymphoma in dogs?
perforin and granzyme B
normally associated with CD8+ T-cells
What breeds of dogs are likely to be predisposed to epitheliotropic lymphoma in dogs?
English cocker spaniels, boxers, and golden retrievers
What are the 3 clinical forms of epitheliotropic lymphoma in dogs?
(1) mycosis fungoides
(2) pagetoid reticulosis
(3) Sezary syndrome
What is mycosis fungoides?
a form of epitheliotropic lymphoma in dogs
exfoliative erythroderma
depigmented mucocutaneous lesions
erosions or ulcers
solitary/multiple nodules or plaques
infiltrative oral mucosal disease
rare vesiculobullous variant
will have neoplastic lymphocytes in the dermis
What is Sezary syndrome?
progressive form of mycosis fungoides
skin lesions
develop leukemia
- Sezary cells
What is pagetoid reticulosis?
dogs have similar signs to mycosis fungoides
distinction is made histopathologically
neoplastic infiltrate is solely in the epidermis and adnexal structures
What is the prognosis of cutaneous lymphoma in dogs?
poor, ranging from a few months to 2 years (median survival time 6 months)
Is mucosal involvement of cutaneous lymphoma in dogs associated with a worse prognosis?
No
Mucosal lesions: MST 491 days
Skin lesions: MST 130 days
Where are lesions due to epitheliotropic lymphoma typically found in cats?
face, eyelids, mucocutaneous junctions, elbows, and trunk
Is epitheliotropic lymphoma or cutaneous non-epitheliotropic lymphoma more commonly associated with skin lesions?
epitheliotropic is more common in dogs
non-epitheliotropic is more common in cats
What type of lymphocyte is typically associated with cutaneous non-epitheliotropic lymphoma?
T-cell infiltrates are more common than B-cell
most are CD8+ or CD4-/CD8-
What is the typical histopathologic findings of cutaneous non-epitheliotropic lymphoma?
predominantly deep dermal and subcutaneous nonencapsulated masses
composed of sheets, clusters or nodular
- a bottom-heavy or base-wide
perivascular aggregates of relatively monomorphic cells
Grenz zone in superficial dermis
adnexal structures are typically not invaded
What are the typical clinical lesions of cutaneous non-epitheliotropic lymphoma?
single to multiple to diffuse dermal or subcutaneous nodules
can mimic panniculitis
typically rapidly progressive
- metastasis to draining lymph nodes
paraneoplastic hypercalcemia is possible
What is the relative prognoses of different types of lymphoma in the skin?
B-cell is best for dogs, worse for cats
cutaneous non-epitheliotropic lymphoma is better than epitheliotropic lymphoma
panniculitis-type T-cell non-epitheliotropic lymphomas in dogs is particularly aggressive
What is cutaneous lymphocytosis?
more common in cats than dogs
may be a more indolent, slowly progressive form of cutaneous lymphoma
- monoclonal lymphoid populations
stable or very slowly progressive disease
- might become malignant/systemic
- unknown if just initial misdiagnosis
What is the pathogenesis of cutaneous lymphocytosis in dogs?
Most lymphocytes are a/b T-cells
About half co-express CD8+ or are CD4-/CD8-There may be small aggregates of B-cells in the infiltrate
What is the typical clinical appearance of cutaneous lymphocytosis in dogs?
Dogs often present with multifocal erythema, alopecia, scale, and plaques
Nodules and papules have not been reported in dogs (unlike cats)
pruritus is rarely a feature
What is the most common treatment of cutaneous lymphocytosis in dogs?
Glucocorticoids
What is the pathogenesis of cutaneous lymphocytosis in cats?
Most infiltrating lymphocytes are CD18+, CD3+, and CD5+ T-cells
May be small aggregates of B-cells in the infiltrate
What is the typical clinical appearance of cutaneous lymphocytosis in cats?
single lesion of erythema, scale, and alopecia +/- crusting
Erythematous plaques, nodules, or papules may be seen
Pruritus is common
Lesions are most common over the thorax but can be seen anywhere, including the legs, pinnae, flank, and neck
What is the pathogenesis of cutaneous lymphocytosis in cats?
systemic or topical glucocorticoids
or chlorambucil or lomustine
What is lymphomatoid granulomatosis (angioinvasive lymphoma)?
rare lymphohistioticytic proliferative disorder
angio-invasive and angio-destructive, proliferation of large atypical lymphohistiocytic cells
- small lymphocytes, plasma cells, and histiocytes
may represent a form of atypical non-epitheliotropic T-cell lymphoma
systemic involvement is a consistent finding, primarily in the lung
- cats can have lungs, liver, spleen, eye, skin, and subcutis
combinations of CD3, CD20, and CD79 positivity in dogs
- mixed B and T cells in cats
poor prognosis - MST ~2 months
What is extranodal lymphoma with cutaneous manifestations?
can be a cause of otitis media/interna in cats
most are T-cell origin; 1 case was a non-B, non-T-cell lymphoma
Prognosis was poor for survival
What is lymphoid hyperplasia?
reported in one cat presenting with a unilateral erythematous, scaly, alopecic, swelling on the muzzle
was not neoplastic
What is hepatocutaneous syndrome?
complex disorder involving SND lesions, a distinct hepatopathy (hepatocutaneous‐associated hepatopathy, HCH), hypoaminoacidemia, and aminoaciduria
What is the treatment for hepatocutaneous syndrome?
IV‐AA infusions, high protein diets, traditionally commercial diets supplemented with whey protein +/- zinc supplementation
Somatostatin analogues (octreotidum) is used in people
What is the typical signalment of dogs with hepatocutaneous syndrome?
more commonly reported in small breed geriatric dogs and had a male predisposition
Cocker spaniel, Shetland sheepdog, Shih Tzu, and West Highland White terrier are predisposed
What is necrolytic migratory erythema typically associated with in humans?
pancreatic tumor that secretes glucagon (glucagonoma)
- not typical for dogs
Why is hypoacidemia thought to occur with hepatocutaneous syndrome?
elevated gluconeogenesis due to hyperglucagonemia (associated with pancreatic tumors) or heightened hepatic breakdown of amino acids (in cases of chronic liver disease) leads to decreased plasma amino acid levels and depletion of epidermal proteins
What are some clinical findings associate with hepatocutaneous syndrome?
anemia, microcytosis, elevated alkaline phosphatase activity, and hypoalbuminemia
What causes the Swiss cheese-like appearance of the liver on ultrasound with hepatocutaneous syndrome?
Vacuolar hepatopathy
- Glycogen-vacuolated hepatocytes
collapse of the areas of parenchyma surrounding the nodules rather than to the cirrhosis and/or nodular hyperplasia reported previously
What is the typical cutaneous lesions associated with hepatocutaneous syndrome?
Erosions, ulcers, crusts
Pawpads, MC junctions, oral cavity, pinna, pressure points
Horses hoof wall sloughing
Secondary infections are common
Pruritus may be minimal to intense
Often painful
What is the typical histopathologic appearance of hepatocutaneous syndrome?
diffuse parakeratotic hyperkeratosis, intracellular edema of the granular epithelial cells and basal cell hyperplasia
“red, white, and blue”
What are the reported causes of hepatocutaneous syndrome in dogs?
- Hepatic disease (>90%)
- vacuolar idiopathic, toxic, or metabolic
- Hypoaminoacidemia
- Glucagon producing tumors (pancreas)
What is feminization syndrome?
24-57% of dogs with a Sertoli cell tumor
shift of balance btw estradiol and testosterone
linear preputial dermatitis
signs of hyperestrogenism
What is the histopathological findings of paraneoplastic (thymoma)-associated exfoliative dermatitis?
cell-poor or rich interface dermatitis affecting the epidermis and the hair follicle with apoptosis of keratinocytes, satellitosis and a lymphocytic dermal infiltrate as well as reduced or absent sebaceous glands
- EM meets sebaceous adenitis
What is the pathogenesis of paraneoplastic (thymoma)-associated exfoliative dermatitis?
not fully understood, but aberrant auto-antigen-responsive T-cells are implicated
What are the clinical signs of paraneoplastic (thymoma)-associated exfoliative dermatitis?
Cutaneous lesions: severe exfoliation or scaling, hypotrichosis and erythema without pruritus
lesions usually start on the head and pinna, becoming generalized
Tend to precede the systemic signs
Anorexia, lethargy, cough, hypercalcemia, myasthenia gravis, keratoconjunctivitis sicca, polymyositis, thrombocytopenia, anemia, granulocytopenia
What is the treatment for paraneoplastic (thymoma)-associated exfoliative dermatitis?
Surgical resection is the treatment of choice if the thymoma is excisable
If able to be removed, prognosis is good and skin lesions improve within a few months
What species has paraneoplastic (thymoma)-associated exfoliative dermatitis been reported in?
Cats (classic), rabbits, goats
What has been reported as a cause of paraneoplastic alopecia in cats?
pancreatic carcinoma > biliary carcinoma, hepatic carcinoma or plasma cell tumor, or metastasizing intestinal carcinoma
What are the clinical signs of feline paraneoplastic alopecia?
acute, progressive symmetrical alopecia, easily epilated hairs and an underlying shiny and thin skin
Some cats groom excessively
leads to the postulation that thereby the stratum corneum is exfoliated leading to the shiny skin
Lesions affect mainly the limbs, flanks and the face but eventually become generalized
Foot pads are also affected and are either dry, crusted and fissured, or erythematous and moist
Secondary Malassezia-dermatitis is possible
What are the histopathologic findings associated with feline paraneoplastic alopecia?
absence of the stratum corneum, marked follicular telogenisation, miniaturization and atrophy
What is the prognosis of feline paraneoplastic alopecia?
In the vast majority of cases, the neoplasia has already metastasized so the prognosis is grave
Other than thymoma-associated exfoliative dermatitis, which immune-mediated diseases have been associated with neoplasia?
Paraneoplastic pemphigus (similar to PV)
Erythema multiforme/SJS
Sterile nodular panniculitis
What is an isthmic and inferior stem cell marker panel?
CK8, CK15, CK19, and CD34
What is survivin?
inhibits apoptosis and maintains stem cells
partial co-localization with CK15 in trichoepitheliomas and trichoblastomas
Which hair follicle tumors are derived from the inferior or lower isthmic segment?
Inferior tricholemmoma
Malignant trichoepithelioma
Trichoepithelioma
Pilomatricoma
Which hair follicle tumors are derived from the middle isthmic segment?
IKA
isthmic tricholemmoma
Which hair follicle tumor does not have keratinization?
Trichoblastoma
ribbons, medusoid, or trabeculae
*granular form has abrupt
Which hair follicle tumors come from hair germ origin?
Trichoblastoma
Which hair follicle tumor has all gradual (lamellar) keratinization?
Infundibular keratinizing acanthoma
- lamellar keratin
- trichohyalin granules
- +/- central pore (based on cut)
- mucin, cartilage/mineralization
Which hair follicle tumor has all abrupt keratinization?
Pilomatricomas
- ghost cells
- matrical cells (basaloid)
- +/- trichohyalin granules
- mineral, bone, melanin
- +/- amyloid
Which hair follicle tumor has mixed abrupt and gradual keratinization?
Trichoepitheliomas
- lamellae and ghost cells
- kerato- and trichohyalin granules
Which breed is predisposed to infundibular keratinizing acanthomas?
Norwegian Elkhounds overall
Young, male Norwegian Elkhounds and Keeshonds are predisposed to having numerous nodules (up to 40–50 nodules)
What is the histological appearance of infundibular keratinizing acanthomas?
Well-demarcated, dermal, cup-shaped lesions, consisting of a cyst that is filled with lamellar, concentric keratin, and has a central pore opening to the epidermal surface
What is the treatment for infundibular keratinizing acanthomas?
surgical excision +/- oral retinoids if many
infundibular keratinizing acanthoma
Which breed is predisposed to tricholemmomas?
Afghan Hounds may be predisposed
What are the histopathologic findings of tricholemmomas?
well demarcated, non-encapsulated tumors with a low mitotic rate
2 types - the isthmic and the inferior/bulb
- neither has granules
- isthmic have trichilemmal keratinization
- inferior has lobular groupings with small cells arranged in islands/nests/trabeculae
Which hair follicle tumors have no keratohyalin or trichohyalin granules?
tricholemmomas
Which breed is predisposed to pilomatricomas?
Most common in breeds with a continuously growing hair coat and anagen predominance
Esp Kerry Blue Terriers
Where do pilomatricomas arise from?
hair matrix of the hair bulb
What is the typical histopathologic findings of pilomatricomas?
well-circumscribed dermal/SC tumor
multiple cystic structures of variable size
- lined by small, basaloid (matrical) cells
- trichohyalin granules usually present
- frequently exhibit high mitotic activity
What are matrical carcinomas?
Pilomatricas that show invasive tendencies on histopathology
- may have distant metastasis
Canine inferior tricholemmoma.
A. Well-demarcated tumor in the deep dermis and subcutis with islands and trabeculae of neoplastic cells. H&E. 4×. B. Nests of neoplastic cells with vacuolated, peripherally palisading cells in the outer layer and multifocally more eosinophilic cytoplasm in the center (asterisk). Note that a distinct basement membrane surrounds each tumor cell aggregate (arrow). H&E. 40×
Canine pilomatricoma
A–C. Benign pilomatricoma. A. Multilocular, cystic structures of variable size lined by basaloid matrical cells. H&E. 2×. B. Small, basaloid matrical cells line the cyst and have abrupt keratinization. Ghost cells (arrow) are within the lumen. Note red trichohyalin granules (inset). H&E. 60×. C. Example of rupture of the tumor resulting in pyogranulomatous inflammation surrounding a large number of ghost cells. H&E. 20×. D–F. Malignant pilomatricoma. D. Unencapsulated, infiltrative, poorly circumscribed tumor. Note contiguity with epidermis, which is ulcerated. H&E. 2×. E. Infiltrative basaloid cell population. Note desmoplasia surrounding neoplastic cells. H&E. 20×. F. Neoplastic basaloid cells with numerous atypical mitotic figures (black arrows). Note single cell necrosis (white arrow). H&E. 40×.
Where do trichoblastomas arise from?
the primitive hair germ of embryonal follicular development
What is the breed and age predilection for trichoblastomas in dogs?
Poodles, Cocker Spaniels, and mixed-breed
→ long anagen?
4–10 y old
Male dogs appear predisposed
What is the typical age of onset for most hair follicle tumors in dogs?
Middle aged (not very geriatric)
Where are trichoblastomas typically found?
most common on the head and neck, especially at the base of ears
In cats this predisposition extends to the cranial half of the trunk
What are the 5 subtypes of trichoblastomas?
Ribbon or medusoid
Granular cell
Trabecular
Spindle
with ORS differentiation
What is the most common subtype of trichoblastomas in dogs?
Ribbon or medusoid
What is the most common subtype of trichoblastomas in cats?
Trabecular
What is the typical appearance of spindle trichoblastomas?
lima bean–like silhouette with a central indentation, a broad epidermal connection, and ulceration consists of basaloid epithelial cells arranged in islands, nests, and short trabeculae
What is the typical appearance of trichoblastomas with ORS differentiation?
composed of multiple lobules, trabeculae and areas of cystic degeneration as a result of acantholysis and drop-out of keratinocytes
Small keratinocytes form anastomosing cords which merge into small islands of cells or into trabeculae
Trichoblastoma
A, B. Canine ribbon trichoblastoma. Note ribbon-like columns radiating from central epithelial nests in B. H&E. 2× and 20×, respectively. C, D. Canine trabecular trichoblastoma. Note peripheral palisading of cells in D. H&E. 2× and 20×, respectively. E, F. Feline spindle trichoblastoma. Note spindle-shaped cells arranged in fascicles in F. H&E. 2× and 20×, respectively. G–I. Canine trichoblastoma with outer root sheath differentiation. Note cystic center (G) lined by glycogenated cells (H) and multifocal heavy melanization (I). H&E. 2× (G) and 20× (H, I), respectively.
What breed of dog is predisposed to trichoepitheliomas?
Bassett hounds
- Spayed female dogs may be
Persian cats
What is the histopathologic appearance of trichoepitheliomas?
well-circumscribed, usually non-infiltrative, unencapsulated tumors consisting of epithelial islands and cystic structures of variable size that show differentiation toward all 3 of the follicular segments
Have both keratohyalin and trichohyalin granules
Dystrophic mineralization may occur, but mineralization and osseous metaplasia are not prominent features
What are malignant epitheliomas?
Spayed females and the Basset Hound and Airedale Terrier breeds may be predisposed
Older dogs 8–12 y
Appears similar to the benign version but is more invasive and sketchy looking
What is the typical treatment of hair follicle tumors?
surgical excision
Canine trichoepithelioma
A–D. Benign trichoepithelioma. A. Well-circumscribed tumor consisting of cystic structures. Note area of inflammation as a result of rupture of the tumor (asterisk). H&E. 2×. B. Cysts are lined by squamous epithelium. H&E. 20×. C. Cysts are lined by both squamous epithelium and matrical cells. Note both blue keratohyalin and red trichohyalin granules (insets). H&E. 40×. D. Cysts lined by matrical cells have abrupt keratinization without a granular layer. Note ghost cells within the cyst (arrow). H&E. 60×. E, F. Malignant trichoepithelioma. E. Unencapsulated, infiltrative, poorly circumscribed tumor. Note contiguity with epidermis. H&E. 20×. F. Infiltrative basaloid cell population lining cyst-like structure filled with keratin and ghost cells. Note severe desmoplasia surrounding epithelial cells. H&E. 20×.
What is a trichofolliculoma?
More likely nonneoplastic, hamartoma-like lesions rather than true neoplasms
uncommon in dogs and rare in cats, also occurs in guinea pigs
usually appears as a well-circumscribed, unencapsulated dermal nodule composed of one or several, large, dilated primary HFs filled with keratin and hair shafts
Trichofolliculoma in a guinea pig
A. Well-demarcated, unencapsulated mass consisting of a few dilated, central primary hair follicles, surrounded by many secondary hair follicles. H&E. 2×. B. Secondary hair follicles radiate from the primary hair follicle in an arborizing pattern. H&E. 10×. C, D. Note various stages of maturation ranging from primitive hair germ (C) to fully developed hair follicles with a well-developed hair bulb and red trichohyalin granules (arrow). D. Note well-differentiated sebaceous glands in C and D (asterisks). H&E. 40× (C) and 20× (D).
What are dermoid cysts?
Focal reduplications of the skin resulting from incomplete separation of the cutaneous ectoderm and neuroectoderm during embryogenesis, and they include epidermis, dermis, and adnexal structures
Which breeds are predisposed to dermoid cysts?
Rhodesian Ridgebacks and Boxers are predisposed and often have multiple cysts on the dorsal midline
What age group is typically diagnosed with dermoid cysts?
Since they are developmental anomalies, young animals (<2 y old) are affected primarily
Where are dermoid cysts found?
dorsal midline and occasionally may extend to the spinal canal and attach to the dura mater
can also be found on the lateral neck or shoulder, particularly in cats
What are the histopathologic findings associated with dermoid cysts?
Can be either dermal or subcutaneous
are lined by squamous epithelium with prominent keratohyalin granules
contain lamellar keratin, hair fragments, and sometimes sebaceous secretions
Hair shafts are frequently present
What are the 5 types of follicular cysts?
Infundibular follicular cysts
Isthmus cysts
Matrical cysts
Hybrid cysts
Panfollicular cysts
What are infundibular follicular cysts?
Common in dogs and cats
lined by squamous epithelium with keratohyalin granules, and are filled by lamellar, often concentric keratin occasionally with a few sebaceous glands are attached
In Merino sheep, these cysts are often multiple and may progress to squamous cell carcinomas
What are isthmus follicular cysts?
In dogs and (rarely) in cats
The pattern closely resembles the isthmus ORS, with granules absent and the cyst is filled with amorphous, trichilemmal keratin
Siberian Huskies have a type that is flame follicle–like
What are matrical follicular cysts?
Mostly occur in dogs and cats
wall resembles the epithelium of the hair bulb, may have trichohyalin granules, and have abrupt keratinization
What are hybrid and panfollicular cysts?
Hybrid cysts are derived from 2 HF segments
Panfollicular cysts have differentiation to all 3 parts of the HF
What are keratomas?
cystic lesions in the hoof wall of the toe or, less frequently, the quarter or heel in simple or cloven-hoofed animals
often develop secondary to a traumatic injury
induce lameness and deformity of the hoof wall or sole and may be associated with distal phalangeal lysis
What are dilated pores of Winer?
rare, hair-follicle neoplasms recognized only in senior cats, primarily males and on the head
also found in a horse
Infundibular cyst
Isthmus cyst
Matrical cyst
Hybrid cyst
What is is overexpressed in equine squamous cell carcinomas to an extent compatible with gene mutation?
p53 gene
What inflammatory response is associated with squamous cell carcinomas in horses?
numerous CD3+ T-lymphocytes, CD79+ B-lymphocytes, immunoglobulin G+ plasma cells, and macrophages
What are basal cell tumors in horses?
a large group of neoplasms
numerous histopathologic “subclassifications”
most are benign
generally show differentiation toward follicular structures
- reclassified in dogs and cats
What are cystic apocrine gland dilations?
Best characterized as hamartomas
Two forms exist:
- cystic form in upper/mid dermis with poor association with hair follicles
- more diffuse form with cystically dilated apocrine glands associated with multiple hair follicles
middle-age or older dogs
less commonly, cats
Head and neck are the most common sites where these lesions develop
Appear as fluctuant dermal cysts or as translucent bullae
Complete excision is curative
What are apocrine gland adenomas?
dogs, cats, and rarely horses
form benign cysts
Two types:
- secretory (more common)
- ductular (less cystic)
Complete surgical excision is curative
What breeds are most at risk for apocrine gland adenocarcinomas?
For dogs: Treeing Walker Coonhounds, Norwegian Elkhounds, German Shepherd Dogs, and mixed-breed dogs are most at risk
For cats: Siamese may be predisposed
Where do apocrine gland adenocarcinomas tend to arise?
axillary and inguinal regions
How do apocrine gland adenocarcinomas tend to behave?
locally invasive and frequently metastasize to draining lymph nodes
Less commonly, skin and lung metastasis may occur
What dogs are most at risk for apocrine gland anal sac adenocarcinomas?
Older English Cocker Spaniels, Springer Spaniels, Dachshunds, Alaskan Malamutes, German Shepherd Dogs, and mixed-breed dogs are most at risk
What can apocrine gland anal sac adenocarcinomas be associated with?
humoral hypercalcemia of malignancy
causes anorexia, weight loss, polyuria and polydipsia, and mineralization of renal tissue with increased BUN and creatinine concentrations
How do apocrine gland anal sac adenocarcinomas tend to behave?
highly infiltrative into the pelvic canal
commonly (90%) metastasize to the sublumbar lymph nodes or to distant internal organs (40%)
What is the typical treament for apocrine gland anal sac adenocarcinomas?
Wide surgical excision, including involved lymph nodes, is the treatment of choice
Intracavitary chemotherapy with 5-fluorouracil mixed with the animal’s serum may help local control
Follow-up radiation therapy, intralesional chemotherapy, tyrosine kinase inhibitor, or systemic chemotherapy may increase the tumor-free interval
Few dogs are reported to live >1 year after the tumor has been recognized
What are eccrine gland tumors in dogs?
Extremely rare
Have only been identified in footpads of dogs and cats
Most are malignant and invasive with metastasis to draining lymph nodes
What are sebaceous gland hamartomas?
benign tumors
solitary lesions reported only in dogs
linear or circumscribed and several centimeters in length or diameter
usually identified shortly after birth.
What are sebaceous gland hyperplasias (senile sebaceous hyperplasias)?
benign tumors
represent a senile change in dogs and cats
In dogs: Manchester Terriers, Wheaten Terriers, and Welsh Terriers are at greatest risk
In cats: there is no breed predilection, but females develop these lesions more frequently than males
Location: skin of the head and abdomen are affected most commonly
What are sebaceous gland adenomas?
benign tumors
Seen in all domestic animals
Very common in older dogs and cats
For dogs: Coonhounds, English Cocker Spaniels, Cocker Spaniels, Huskies, Samoyeds, and Alaskan Malamutes are most likely breeds
frequently are clinically indistinguishable from sebaceous hyperplasias, but they tend to be larger (typically >1 cm)
For cats: Persians
What are sebaceous gland epitheliomas?
benign tumors
variant of sebaceous adenoma distinguished by lobules composed primarily of basal progenitor cells rather than mature sebocytes
occasionally be confused with sebaceous carcinomas
found in older dogs and rarely in cats.
Clinical appearance: ulcerated nodules that may be several centimeters in diameter
A papillated epidermal surface and pigmentation are variable findings
What are sebaceous gland adenocarcinomas?
recognized almost exclusively in dogs and cats
generally in middle-aged or older animals
For dogs: Cavalier King Charles Spaniels; Cocker Spaniels; and Scottish Terriers, Cairn Terriers, and West Highland White Terriers are most at risk
Sex: Male dogs/female cats may be predisposed
locally infiltrative and may metastasize
What are hepatoid gland tumors?
Arise from modified sebaceous glands around the anus (also present on the ventral midline, tail, and lumbar/sacral regions)
Intact male dogs are 3x more likely to develop them than female due to influence of androgen
adenomas versus adenocarcinomas
What are hepatoid gland adenomas?
Most common in senior dogs esp Siberian Huskies, Samoyeds, Pekingese, and Cocker Spaniels
90% are found in the perianal region
<95% of male dogs respond completely to castration
Excision or laser ablation surgery may be used, recurrence is common especially in females
Radiation therapy is also an option and has a 2-year cure rate of 69% for benign tumors
Cryosurgery or electroporation are additional therapeutic alternatives
- may cause fecal incontinence
What are hepatoid gland adenocarcinomas?
uncommon canine neoplasms
generally appear as nodular lesions affecting the perianal region
found in male dogs 10 times more commonly than in females
Siberian Huskies, Alaskan Malamutes, and Bulldogs are most likely to develop this tumor
have metastatic potential and often spread to regional lymph nodes
Treatment consists of wide surgical excision including involved lymph nodes and, possibly, subsequent radiation
- masitinib, toceranib, and other tyrosine kinase inhibitors may overcome chemoresistance, inhibit the proliferation of tumor cells, and prevent the emergence of metastasis
- Overall prognosis is guarded
What is the histologic appearance of canine hepatoid gland tumors?
groups of hepatocyte-like cells which in females regress to single islets, whereas in males they form glandular masses
What are fibrovascular papillomas?
“skin tags” or ACROCHORDONs
Fibrovascular in origin
May be proliferative response to trauma or focal furunculosis
Doberman and lab seem predisposed (large breeds)
Occur over bony prominences
Histopath: filiform to pedunculated, smooth, hyperkeratotic
Surgery vs benign neglect
What breed of dogs are predisposed to fibromas?
Boxers, Boston terriers, Dobermans, golden retrievers, fox terriers
What are the cytologic and histopathologic findings associated with fibromas?
FNA – small number of spindle shaped fibroblasts
Histo – whorls of interlacing bundles fibroblasts. May contain mucinous/myxomatous degeneration (fibromyxomas)
What are fibropruritic nodules?
Etiopathogenesis = unknown
Often seen in dogs >8y in GSD
Solitary/multiple firm/pedunculated alopecic nodules that vary in size 1-2cm
Mainly dorsal lumbosacral area – chronic flea bite
Histo – nodular dermal fibrosis, inflammation, eosinophilic, papillated
Control fleas/surgical excise
What is the histopathology of fibrosarcomas?
Histo – interwoven bundles of immature fibroblasts, moderate numbers of collagen fibers
What are fibromyxosarcomas?
fibrosarcomas associated with mucinous/myxomatous degeneration
What are myxomas and mycosarcomas
Rare neoplasm of older dogs (GSD and Dobermans) and cats from dermal and SC fibroblasts with abundant myxoid matrix with mucopolysaccharides
often infiltrative
What is the histopathology of myxomas and mycosarcomas?
stellate to fusiform cells in vacuolated basophilic stroma
What is nodular fascitiitis?
Rare benign, non-neoplastic growth affecting eyes/periocular are (but can occur elsewhere)
Proliferative inflammatory process from SC fascia – often misdiagnosed as a fibrosarcoma
Can be very invasive
Surgical excision is curative
What is the histopathology associated with nodular fascitiitis?
Histopath – poorly circumscribed proliferation of haphazardly growing fibroblasts with ground substance.
What genetic mutation is associated with Schwannomas?
Point mutation in HER2/neu oncogene
What are clinical signs of Schwannomas caused from?
Involve the nerve root as they exit the spinal canal and manifest in pain and paresis due to nerve root compression
What are Schwannomas histopathologically characterized by?
1) neurofibroma (faintly eosinophilic thin wavy fibres in loosely textured strands
2) neurilemoma – spindle-shaped cells with nuclear palisading and twisting bands with Antoni type A and B tissues
What are granular cell tumors?
Solitary firm, well circumscribed rare masses within the tongue but can occur in other locations
In cats can be on tongue, vuvla, tonsil, brain and digits
Generally benign and do not metastasize
What are granular cell tumors histopathologically characterized by?
circumscribed mass of ovioid to polyhedral cells with central or eccentric nuclei and pale cytoplasm containing eosinophilic granules
Granules are PAS, vimentin, and S100 positive
What dogs are predisposed to hemangiomas?
> 10y
Lightly pigmented Boxers, golden retrivers, GSD, English springer spaniel, Airedale etc.
What cat are predisposed to hemangiomas?
> 10y
M>F
What do hemangiosarcomas stain positive for?
Positive for vimentin, S100 protein, Factor 8-related antigen (vWf), type 4 collagen and laminin + CD31 (PECAM)
What dogs are predisposed to hemangiosarcomas?
Average of 10y in GSDs, goldens, BMDs, and Boxers
What tends to cause cutaneous hemangiosarcomas?
Chronic solar damage of ventral glarous skin of lightly pigmented dogs and pinna of white eared cats
What breeds are predisposed to lipomas?
Siames cats, cockers, dachshunds, Weimaraners, Doberman, Mini Schnauzer, Labradors
What are the histopathologic features of lipomas?
well circumscribed proliferation of normal-appearing lipocytes
Infiltrative lipomas may have a poorly circumscribed proliferation of normal lipocytes that infiltrate surrounding tissues
What are liposarcomas?
Occur >10y MALES in dachshunds, Shetland sheepdogs, Brittany Spaniels. Solitary > multiple
Malignant, infiltrative, but rarely metastasise
Red O stain for lipid in frozen tissue and to differentiate liposarcomas from other soft tissue sarcomas
Wide surgical excision is treatment of choice (1188 days)
What IHNs are cutaneous mast cell tumors positive for?
Vimentin, tryptase, KIT (CD117), Chymase, MCP1 and IL-8
What factors influence histocyte development?
Fms like tyrosine kinase ligand (FLT3)
GM-CSF
Stem cell factor
TNF-alpha
IL4
TGF-b
What do Langerhans cells express?
E-cadherin
C-type lectin (CD207)
CD1a
CD11c
MHC class II
What are interstitial dendritic cells?
APCs of the DERMIS
Occur in perivascular locations (except for brain)
Rapid turnover and are repopulated by a blood-borne precursor (monocyte) and by local self-renewal
What do interstitial dendritic cells express?
Thy-1 (CD90)
CD4
CD1a
CD11c
MHC class II
What are Langerhans cells?
Antigen presenting cells (APC) of epidermis
Internalization of langerin mediates formation of Birbeck granules
Subject to slow turnover and are maintained by self-renewal or renewal from a dedicated dermal precursor cell
- from CD14+ precursors
- require TGF-B and CCL20
- mature with IL-4 and GM-CSF
What markers do macrophages have?
class A scavenger receptors
- CD163 and CD 204
display neither E –cadherin or thy-1
What CD11s can be found in histiocytes?
CD11b – Macrophage + some dermal interstitial cells
CD11c – expressed by LC and interstitial DC
CD11d – Macrophages
What immunolabeling is reactive histiocytosis expected to be positive for?
CD204, Thy1 (CD90), MHCII, CD1a, CD4, CD18, and CD11c
What is responsible for presentation of peptides, lipids, and glycolipids from cutaneous dendritic cells to T cells?
CD1a molecules
MHC class I and class II molecules
What do splenic histiosarcomas express?
CD1a
CD11c
MHC class II
What do histiocytic sarcomas of lungs express?
CD1a
CD11c
MHC class II
What is the marker for the histocyte stem cell precursor?
CD34+
What happens to CD34+ monocytes under the influence of M-CSF?
they become macrophages
What happens to CD34+ monocytes under the influence of GM-CSF and IL-4?
Become dendritic cells
What is differentiation of Langerhans cells critically dependent on?
TGF-β1 stimulation
- from epidermal keratinocytes
What causes immature epidermal-resident LCs to target the skin?
MIP-3α or CCL20 that is produced there?
What does successful interaction of DCs and T cells in response to antigenic challenge involve?
orderly appearance of co-stimulatory molecules (B7 family – CD80 and CD86) on DCs, and their ligands - CD28 and cytotoxic T-lymphocyte antigen 4 (CTLA-4) on T cells.
What breed of dog is prone to multiple histiocytomas?
Shar Peis
What cells seem to be responsible for the regression of histiocytomas?
CD8+ T cells
mediate lysis of neoplastic histiocytes
What type of cell do cutaneous histiocytomas seem to arise from?
dermal precursors of LCs
do not arise directly from intra-epidermal LCs
What Langerhans cell markers fo cutaneous histiocytomas express?
CD1a and often E-cadherin
What skin homing receptors do T cells express under interstitial dendritic cell influence?
CLA/E-selectin
CCR4/CCL17
CCR10/CCL27
What do morphological descriptions of histiocytomas emphasize?
tropism of the tumor infiltrate for the superficial dermis and epidermis to create a “top-heavy” lesion
- may invade the epidermis as individual cells or nests of cells
Which markers do tumor histiocytes in canine histiocytoma express?
CD1a
CD11a/CD18
CD11c/CD18
CD44
CD45
MHC class II
E-cadherin
- may be limited to near the surface
+/- CD11b/CD18
+/- CD54
What do Langerhans cells use E-cadherin to do?
localize in the epidermis via homotypic interaction with E-cadherin expressed by keratinocytes
What is cutaneous Langerhans cell histiocytosis?
extensive skin involvement with multiple histiocytomas
Shar peis are over-represented
May regress or progress
What is a negative prognostic indicator in cutaneous Langerhans cell histiocytosis?
Lymphatic invasion
usually progresses to systemic lesions
- ex in lungs
What do histiocytic sarcomas tend to be derived from?
cells with the phenotypic profile of interstitial DCs
Where are interstitial dendritic cells found?
occur in all tissue except brain
do occur in the meninges and choroid plexi
Abnormalities in which suppressor gene loci have been found in Bernese mountain dogs and flat-coated retrievers with histiocytic sarcomas?
CDKN2A/B, RB1 and PTEN
What are the clinical signs of histiocytic sarcomas?
vague or depend on organ involved
What are the typical morphologic features of histiocytic sarcomas?
typically destructive mass lesions with a uniform, smooth cut surface and are white/cream to tan in color
composed of sheets of large, pleomorphic, mononuclear and multi-nucleated giant cells, which usually have marked cytological atypia and numerous bizarre mitotic figures
- may consist of spindle cells
Which markers do histiocytic sarcomas tend to express?
CD1a
MHC class II
CD11c/CD18
What does CD4 tend to indicate for histiocytes?
an activation phenotype
histiocytes in canine reactive histiocytoses regularly express CD4
What do (large cell) lymphocytes express that can make them difficult to tell apart from histiocytes?
CD18
What are the distinctive syndromes of the histiocytic sarcoma complex?
Hemophagocytic histiocytic sarcoma
Articular / periarticular histiocytic sarcoma
Central Nervous System Histiocytic Sarcoma
Dendritic cell leukemia
What are the clinical signs of hemophagocytic histiocytic sarcoma?
hemolytic anemia, thrombocytopenia
mild hyperbilirubinemia
coagulopathy
seems like IMHA
worst prognosis (MST 4wk)
diffuse splenomegaly
- DCs and macrophages
also in lungs and bone marrow
What are the clinical signs of auricular histiocytic sarcomas?
multiple tan nodules located beneath the synovial lining
usually has a inflammatory component
associated with CCLrs and trauma
cells are identical to perivascular iDCs
- not synovial fibroblasts
What are the clinical signs of central nervous system histiocytic sarcomas?
often originates in the leptomeninges
has many mixed inflammatory cells
- an atypical histocytes
Pembroke Welsh Corgis at risk
focal, solitary subdural masses
less common diffuse meningeal infiltrates
What is dendritic cell leukemia?
a form of histiocytic sarcoma
two reports in dogs
many atypical histiocytes in peripheral blood
DC lineage (CD1+ CD11c+ CD11d- MHCII+)
What marker is found on all histiocytes because it is a marker of APCs?
CD1a
What is the immunophenotypic expression pattern of systemic and cutaneous histiocytosis?
markers expected of DCs
- CD1a
- C11c/CD18
- MHC class II
- CD4 (a marker of DC activation)
- CD90 (Thy-1)
negative for E-cadherin
Which immunophenotypic involved in histiocytic neoplasms are not assessable in formalin fixed tissue sections?
CD1a, CD4 and CD11c
What is feline pulmonary Langerhans cell histiocytosis?
disease of aged cats (10 to 15 years),
causes progressive respiratory failure
- leading to euthanasia
obliteration of pulmonary parenchyma by infiltrating LCs
- particularly within terminal bronchioles
- Rads: diffuse, broncho-interstitial pattern
- Liver and pancreas spread possible
Which breed of dog may be predisposed to the histiocytic sarcoma complex and systemic reactive histiocytosis?
Bernese Mountain dogs
What is feline progressive histiocytosis?
originates from interstitial DCs
Middle aged to older cats
Solidary vs multiple nodules
- focused on head
- may have epitheliotropism
Low-grade neoplasia of iDCs
- initial indolent behavior
But poor long-term prognosis
- spontaneous remission does not occur
- may develop internal lesions
What is thought to be the cause of cutaneous and systemic histiocytosis?
believed to have an element of immune dysregulation in their pathogenesis
thought to be antigen driven
but no etiologic agent/antigen has been discovered
What is the histopathologic appearance of cutaneous and systemic histiocytosis?
activated dermal iDCs and T cells
- can be pleocellular
may have lympho-histiocytic vasculitis
lesions radiate from affected vessels and coalesce to form masses, especially in the deep dermis and panniculus
- “bottom-heavy” topography
What is cutaneous histiocytosis?
involves activated dermal iDCs and T cells
primarily involves skin and subcutis
multiple cutaneous and SC nodules
may wax and wane
What is systemic histiocytosis?
generalized histiocytic proliferative disease
tendency to involve skin, ocular and nasal mucosae, and peripheral lymph nodes
predominately affects young to middle aged dogs (2-8 years)
clinical signs vary
may have remissions and relapses
What neoplasia is readily confused with reactive histiocytosis?
Inflamed cutaneous non-epitheliotropic T cell lymphoma
Lymphoma can have variable CD3
- “CD3 antigen loss”
What can definitively differentiate between reactive histiocytosis and inflamed cutaneous non-epitheliotropic T cell lymphoma?
T cell receptor gamma (TRG) gene rearrangement analysis
What stains are lymphangiomas positive for and what can help differentiate them from hemangiomas?
positive for
- vimentin
- factor VIII-related antigen(vWF)
- CD31
negative
- laminin
- type IV collagen
absence of continuous basement membrane and pericytes
What is malignant fibrous histiocytoma?
“grab-bag” diagnosis that includes pleomorphic forms of several soft tissue sarcomas with histologic similarities in horses
Which phenotype of nonepitheliotropic cutaneous lymphoma in horses tends to have a long period of stability before progressing?
histiolymphocytic phenotype
What are pseudolymphomas?
disorders in which a histologic picture suggesting lymphoma stands in sharp contrast to benign biologic behavior
associated with reactions to sunlight, drugs, arthropods, contactants, and idiopathy
- usually ticks in horses
Which breeds of dog have the highest risk for developing subungual melanomas?
Schnauzer family (miniature and standard), Scottish terriers, Irish setters
What are the histopathology findings associated with melanomas?
characterized by atypical melanocytes in sheets, packets (nests and theques), and cords
The melanocytes may be predominantly epithelioid, spindle cell, or a combination of these two forms.
Rarely, the melanocytic proliferation may be distinctly perifollicular (pilar neurocristic melanoma)
Clear cell (balloon cell) melanomas have been described
What are the 5 histologic types of feline melanomas?
signet-ring - often amelanotic, thus need to confirm origin from other methods
epithelioid
balloon-cell - often amelanotic, thus need to confirm origin from other methods
mixed epithelioid or spindle
spindle
What is a melanoma in the veterinary context?
synonymous with a malignant proliferation of
melanocytes
What markers can be used to help diagnose melanomas?
Melan A, PNL2, TRP-1, TRP-2 combination
in situ hybridization for tyrosine gene
positive for vimentin
variably positive for S-100 protein and neuron-specific enolase
Cyclooxygenase 2 (COX-2) expression
-not normally expressed by melanocyte
What is proposed to be the mechanism of action of the dog oral melanoma vaccine?
The foreign tyrosinase produced by the vaccine is different enough from canine tyrosinase that it can break tolerance and be recognized by the dog’s immune system as a foreign protein inducing an active immune response leading to destruction of neoplastic melanocytes
What are the typical histopathologic findings associated with melanocytomas?
melanocytomas are characterized by melanocytes in sheets, packets, and cords.
The melanocytes may be predominantly epithelioid, spindle cell, or a combination of these two forms
Histologic subtypes
- junctional, compound, and dermal
Rarely, the melanocytic proliferation is distinctly perifollicular (pilar neurocristic melanocytoma)
Which breed of horse is predisposed to linear epidermal hamartomas?
Belgian horses
seen on the caudal aspect of the rear cannon bone areas
What are transmissible venereal tumors?
Round (or discrete) cell tumor, suspected to be of histiocytic origin
Canids only
may be affected by hormone - ovariohysterectomy can reduce size of tumor
Horizontally transmitted tumor (cellular mechanism of transmission)
Transmitted directly from dog to dog across MHC barriers through transplantation of viable tumor cells on damaged mucosal surfaces
Coitus is the classic mode of transmission - other social behaviors: sniffing, biting, licking, scratching
+/- thrombocytopenia and prolonged clotting times
What markers tend to be associated with trichoblastomas?
often express p27 in high levels; most express cytokeratin 8 and 18
What are the typical histopathologic findings associated with squamous cell carcinomas?
Cords of dysplastic keratinocytes within dermis, big keratin pearls
What is thought to be the cause of transmissible lymphoma in hamsters?
Hamster polyomavirus (papovavirus)
usually T lymphocytes
What causes enzootic lymphoma in cattle?
retrovirus
(bovine leukemia virus [BLV])
