Hello from a new contributor!

Hey everyone! Just wanted to pop in and introduce myself as a new contributor to this blog. Currently, I’m in my second year of residency and will therefore be subjecting you all to a whole lot of gen path! I’ll do my best to add interesting papers and odd tidbits that aren’t related to phase I, too.


Hope to see you in the comments!


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Taking it up a Notch

Yikes. Phase 1 is upon us. Less than a month to go, how are you all feeling for it? Personally, I’m not feeling great…but I do have a pretty detailed study plan (see upcoming post for a boards prep plan!) that’s helping to ease my worries. I’m going to be going through some of the important pathways and try to break them down into small nuggets of (hopefully) less painful gen path content.

First up, Notch signaling.

(Taken from Zacharioudaki E and SJ Bray. 2014. Tools and methods for studying Notch signaling in Drosophila melanogaster. Methods 68(1):173-182)

So the Notch gene is a highly conserved, it’s important not only during embryogenesis (developmental decisions including differentiation of tissue types) but in life after-birth too (regulating homeostasis, cancer development, immunity). Essentially, the Notch pathway has three over-arching functions (1) lateral inhibition, (2) lateral induction, and (3) lineage decisions. Lateral inhibition is when a bunch of multipotent cells that are adjacent develop a hierarchy of function so they do not all become the same cell type. On the other hand, lateral induction is when cells of one population determines the outcome of another cell population. Lastly, lineage decisions occur during asymmetric division. This allows daughter cells to develop into different populations of cells depending on Notch pathway modulators and expression.

Although this pathway has many functions, there actually aren’t any second messengers and the mechanism is pretty straightforward (thank goodness). Essentially, a ligand binds to the Notch receptor (a heterodimeric, single-pass transmembrane protein) which releases cleaved Notch into the cytoplasm.  The cleaved Notch is then translocated to the nucleus where it targets certain transcription genes (via interaction with CBF1/Suppressor of Hairless/Lag-1, depending on the species/scenario we’re talking about).  This was a description of canonical Notch signaling, non-canonical exists too and has different ligands and end-points than canonical signaling.

The cool thing about not having second messengers is that there is an important relationship between the amount of ligand that binds Notch and the response the cells undergoes.

As far as test questions seem to go, most of the focus (at least on practice questions) seems to be on the role Notch plays in regulating angiogenesis. So we’ll dive into that.

Both Notch (binding to the Dll4 ligand) and VEGF-A (binding to VEGF2 Receptor, mostly) are critical for angiogenesis and have opposing effects. Notch/Dll4 has inhibitory effects, limiting sprouting of vessels (even to the point of down regulating VEGF2R expression). VEGF expression actually induces Dll4 expression (negative feedback!) which helps to ensure that supporting cells and endothelial cells don’t occlude the new vessels being created.

Typically, VEGF expression is higher in the leading cell than in the cells closer to the sprout (where it’s coming from the parent vessel). There are a lot more details in Zachary and McGavin on the nitty gritty of angiogenesis (EPCs, BMP, PDGF, oh my!), but the information above is the basics on Notch/Dll4 involvement in the process.

Questions, comments, and corrections are welcome in the comments!


  1. Andersson ER, R Sandberg, and U Lendahl. 2011. Notch signaling: simplicity in design, verstaliiy in function. Development. 138:3593-3612
  2. Siekmann AF and ND Lawson. 2007. Notch signalling and the regulation of angiogenesis. Cell Adhesion and Migration. 1:2, 104-106
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Unusual tumor of the zygomatic arch in a Dog

HISTORY: 10 year old female spayed Japanese Chin developed a mass on the right zygomatic arch. Radiographs showed regions of bone lysis and proliferation and invasion of the right temporalis muscle.


The zygomatic bone is effaced by an expansile locally infiltrative, poorly cellular neoplasm of mesenchymal cells arranged in small whorls and streams in an abundant sclerotic collagenous stroma with ossification of the stroma and remodeling forming marrow spaces in the central regions. Neoplastic cells have indistinct cell borders, scant cytoplasm, and are fusiform. Nuclei are flattened, ovoid, and often hyperchromatic, with some at the periphery having finely stippled chromatin. At the leading edge of the tumor the reactive bone forms a shell around the tumor, and is being lysed as the tumor expands and infiltrates. In some areas the neoplasm infiltrates and expands the surrounding skeletal muscle, and forms small whorls which advance out from the main mass.

1509180018 zygomatic 2x2

Low power view of zygomatic arch tumor, showing some connection to the bone in the lower left corner, and the extension into the muscle into the upper left corner. The mass is haphazardly ossified, and interspersed with dense hypocellular fibrous tissue.

1509180018 zygomatic 10x1

High power magnification at one edge of the tumor where it was less ossified, showing a hypocellular whorling mass of fibrous tissue eroding the surrounding reactive bone to the right of the image. This shell of reactive bone is indicative of a moderately growing mass. Slower growing tumors may have lamellar bone at the periphery while more rapidly growing tumors efface any reactive bone.

1509180018 zygomatic 10x2

Moderate magnification of the center of the mass, in a region where the fibrous tumor is effacing islands of reactive woven bone. The woven bone is bordered by flattened to plump osteoblasts and loose connective tissue, but in some areas the fibroblastic tumor erodes them. In the center there is a whorl of fibrous tumor with a small area of mineralization. This is deceptive, as it can be interpreted as bone produced by the tumor. But in this case, this is simply mineralization of a dense collagenous stroma, which can occur in the right microenvironment.

1509180018 zygomatic 20x1

High magnification view of a region of mineralizing tumor stroma. Notice the blending of collagen fibers of the tumor with the surrounding bone, and in the center the slight stippling of basophilic stroma indicating small areas of mineral deposition that are independent of osteoblasts.


Right zygomatic arch: Low grade sclerosing fibrosarcoma with osseous metaplasia


This is an uncommon tumor which most likely arose from either the periosteum or medullary cavity of the zygomatic bone.  Differentials included were benign fibro-osseous tumors such as ossifying fibroma, or fibrous dysplasia, however the bone produced seemed to be eroded by the tumor stroma as it advanced, and did not seem to be produced by it. The central regions of osseous metaplasia were formed by calcification of the haphazard collagenous fibers produced by the tumor, which can be seen using polarized light microscopy.  As the tumor matrix mineralized it then became fair game for the resident osteoclasts and osteoblasts to begin laying down reactive woven osteoid thereby forming the ossified portions of the tumor. The remodeling that has occurred is a factor of the prolonged time course and slow growth rate of this tumor.

A google search for the term sclerosing fibrosarcoma will find a medical diagnosis of “sclerosing epithelioid fibrosarcoma”, which has a particular histological appearance that this tumor did not share. The term “sclerosing fibrosarcoma” is more a descriptive term, and one given to me Dr Roy Pool from Texas A&M when I consulted him on this tumor. Perhaps this may become a distinctive entity in veterinary medicine as more cases are described and recognized. The biological behavior appears to be less aggressive than other fibrosarcomas of bone, and should be differentiated from the highly aggressive entity of the “histologically low-grade, biologically high-grade fibrosarcoma” of the mandible and maxilla.

The closest human analog to this tumor is the desmoplastic fibroma, but again the histological appearance is distinctive.  The word “desmoplastic” refers to the abundnat collagen fiber content in this tumor which resembles connective tissues and shows no mineralization (desmos: A bond, fastening or chain; ie desmitis -inflammation of a tendon). The tumor in this bone does not share this type of collagenous fiber arrangement.

Initially, prior to histopathology, I was expecting a multilobular tumor of bone (MLTB; Multilobular osteochondrosarcoma) given the location. These tumors appear to be associated with bone symphyses and suture lines (skull, hard palate, maxilla, mandible, zygomatic bone). The microscopic architecture is usually characteristic, however it is said that as these become high grade this architecture is lost. Differentiating a high grade MLTB from an osteo- or chondrosarcoma can be difficult, but in my experience there are regions of spindle cell sarcomatous sheets and bundles that are not seen in chondrosarcoma, and there is no convincing bone produced. This probably reflects the fibro-osseous origin of the tumor. Nevertheless the tumor in this case is very low grade, and had no features in common with a MLTB.

If anyone has seen a similar tumor in the skull or long bones I would appreciate hearing about it.


Desmoplastic fibroma of bone: A report of 8 cases and review of the literature. J Bone Joint Surg Am. 1985 Jun;67(5):732-47.

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VetPath Services

It’s been so long since my last post. Partly because I was keeping busy examining racehorse breakdowns for New York. You can see the results of these exams here.


Since then I’ve traveled to Brisbane for 6 months, and worked at Idexx. As fun as it was to work in Brisbane, when VetPath Services, in Stone Ridge, NY opened a position I couldn’t pass up the opportunity.

Let me tell you about VetPath Services, and why this lab is the preferred choice of our clients.

  • Experience: Jim Walberg founded this lab after years of experience in diagnostic pathology labs, and his expertise extends into many areas within anatomical and clinical pathology, dermatopathology, gastrointestinal diseases, bone diseases and oral tumors, primate pathology, and lab animal pathology. Check out Jim‘s and my blurb at the website. Add to this my own experience in bone and joint pathology, oral and dental and nasal diseases, as well as well-rounded knowledge of skin disease, GI, liver, renal, and reproductive diseases.
  • Quality: Jim and I review every slide that comes out of the lab, and take direct part in trimming complex cases, processing fluids, and reviewing reports. It is rare to find such quality control in a busy diagnostic lab, and this often results in delays, errors, or miscommunication.
  • Consistency: Jim and I work together to review complex cases and those that require additional expertise. Its rare to find a lab with consistent diagnoses between pathologists. We strive to come to agreement on difficult and complex cases, and can offer a wealth of advice on additional testing that can help make the diagnosis.
  • Availability: Just call and ask to speak to me or Jim and we can assist you in any way you need, from deciding what samples to biopsy, assessing gross lesions at necropsy, and submitting samples, or determining additional testing. We are available to discuss your patients, and offer any professional advice within the scope of our practice of diagnostic pathology.

I’m looking forward to many great years getting to know the clients of VetPath Services.

I will continue to post interesting cases I’ve collected from Kansas, Cornell, Brisbane, and Stone Ridge, and I am working on adding a more extended Orthopedic Path section, as well as oral tumors, and nasal disease sections. Stay tuned….

Brian G. Caserto


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Diagnosis- What’s your diagnosis #6

What’s your diagnosis #6

See original post here

Continue for Diagnosis…

History: a 15 month old Angus steer went down acutely and was euthanized.

Gross findings were unremarkable.


Brain: In the gray and white matter of the caudal cerebrum, midbrain, and cerebellar peduncle there are multifocal perivascular infiltrates of lymphocytes and fewer neutrophils. There are randomly scattered multifocal areas of necrosis with moderate numbers of neutrophils, lymphocytes, macrophages, microglia and astrocytes (microabscesses). There is a single arteriole with a predominantly eosinophilic infiltrate with fewer lymphocytes.

Brainstem:  There are bilaterally symmetric focal areas of severe necrosis with large numbers of macrophages, neutrophils, lymphocytes, and a few multinucleated giant cells. The meninges are multifocally thickened with moderate numbers of lymphocytes and macrophages. Within areas of necrosis are large expanses of spongiosis with myelin sheath swelling, axonal spheroid formation and digestion chambers with Gitter cells (foamy macrophages).

Brain: At low power there are multifocal areas of necrosis and suppurative inflammation, and perivascular cuffing

Brain: At high power the neuropil is fragmented, and neurons are not visible, instead there is cell debris and neutrophils and increased numbers of glial cells including microglia

Brain: Some areas have large macrophages, or reactive astrocytes with abundant eosinophilic cytoplasm which are cleaning up and repairing the damaged neuropil

Brain: Some areas have focal gliosis, which is interpreted as a region of healing (glial scarring)

Brain: Perivascular cuffing ins prominent in some areas; cells consist of lymphocytes, macrophages and some neutrophils.

Brainstem: At low power there are areas of spongiosis (clear spaces; swollen myelin sheaths).

Brainstem: At higher power there is loss of axons, and numerous clear spaces containing large eosinophilic spheroids (swollen damaged axons), and Gitter cells in axonal spaces.

Morphologic Diagnosis:

Brain and brainstem: Meningoencephalitis, necrotizing, suppurative, multifocal, severe, with lymphocytic cuffing


Immunostaining revealed the presence of Listeria monocytogenes in the CNS microabscesses.

Brain, Immunohistochemistry: The red foci indicate positive staining for Listeria monocytogenes

Diagnosis: Listeriosis


Listeria sp are Gram-positive facultative anaerobic bacilli found in the environment. It is hardy, and able to survive in temperatures ranging from 4-45 degrees C. It is an intracellular pathogen of macrophages, neutrophils,  and epithelial cells. Virulence factors include the surface protein internalin,  which internalizes with E-cadherin to overcome the intestinal, placental, and blood brain barriers. It also has a cholesterol-binding hemolysin to lyse phagosomes and escape into the cytoplasm. The organism proliferates in the host cytoplasm and migrates against the cell membrane to form protrusions that can be taken up by other cells. It can use the host cell actin filaments to help cell-cell transfer.

Disease syndromes usually dont overlap. Infection can cause abortions, septicemia, and encephalitis. Septicemia Listeriosis occurs in fetuses, neonates and young large animals up to 1 year of age resulting in generalized visceral abscesses.  Encephalitis is almost solely found in adult ruminants, and may be sporadic or associated with outbreaks.  Listeria can grow in spoiled silage that is incompletely fermented. It invades the oral mucosa and invades the trigeminal nerves traveling to the brain.  Lesions not seen in this case include vasculitis.

Of the competing differentials most can be confirmed by histopathology.

BSE: Histologic lesions include vacuolation of brainstem neurons and immunohistochemical confirmation is possible.

Polioencephalomalacia: Characteristic laminar cortical necrosis, with possible mild endothelial hypertrophy, and perivascular histiocytic cells. The same lesion occurs with thiamine deficiency and lead toxicity.

Rabies: Characteristic Negri bodies (eosinophilic intracytoplasmic inclusions) in neurons with perivascular lymphocyte cuffing.

Urea/Ammonia toxicity: There are no characteristic histologic lesions that I am aware of. In horses ammonia toxicity causes Type II Alzheimer cells, which are a type of reactive astrocyte. This has not been described as a feature of cattle with ammonia toxicity. The alkaline rumen pH may have made this a consideration.  7.4 is pretty alkaline for the rumen, and may indicate the presence of ammonia, the by product of urea metabolism by rumen flora.

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