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sarcoid), while ASMA/desmin expression in rhabdomyosarcoma can be very sparse. Factor VIII is a key marker able to highlight any endothelial cell
in the tissue. This antibody not only labels tumoural endothelial cells arising from blood vessels (e.g. haemangioma, haemangiosarcoma) but also the ones from lymphatic vessels (lymphangioma, lymphan- giosarcoma), in addition to normal endothelial cells: therefore, factor VIII alone is not able to distinguish from vascular tumour arising from blood or lymphatic vessels. In this regard, a recent paper suggests that PROX- 1 could represent a good candidate for labelling lym- phatic endothelial cells (Junginger et al., 2010 ). Melanomas are common neoplasms in horses. While in the ma-
jority of cases, this type of tumour is characterised by heavily mel- anised neoplastic cells, in some cases, they can be “amelanotic” (i.e. without melanin) and show a morphology overlapping with other tumours. The classic markers for melanocytes used for decades are S- 100 (whose positivity should be present in both nucleus and cy- toplasm) and Melan A; nonetheless, a paper describes PNL- 2 as the most sensible and specific marker for equine melanocytic tumour and raises some doubts regarding the Melan- A usefulness in the equine species (Ramos- Vara et al., 2014 ). There are multiple nervous system markers in equine pathol-
ogy. One of the most used ones remains the glial fibrillary acidic protein (GFAP) which labels glial cells. This antibody is usually em- ployed when dealing with CNS tumours, especially to confirm as- trocytomas. Olig- 2 is an antibody used to label oligodendrocytes (and oligodendrogliomas) in multiple animal species; in the horse, Olig- 2 IHC is seldom reported, suggesting it is a valid antibody also in the equine species (Cavasin et al., 2020 ). Neuronal markers valid in equine pathology include S- 100 (which is also considered a me- lanocytic one), PGP 9.5, synaptophysin and neuronal- specific eno- lase (NSE). Among these, synaptophysin seems the most reliable for neurons as S- 100, PGP 9.5 and NSE can be expressed by other cell types (especially S- 100) (Ramos- Vara et al., 2014 ). Similar concepts are applicable to the peripheral nervous system, where neurons and axons can be highlighted via NSE, synaptophysin, S- 100 and PGP 9.5, while Schwann ' s cells and perineurial cells can be highlighted via S- 100 and GFAP (Knottenbelt et al., 2016b ). Synaptophysin (and also other neuronal markers) are also considered very useful to aid the diagnosis of equine dysautonomia (grass sickness): indeed, synaptophysin is able to highlight neurons ' cytoplasm enhancing the ability of the pathologist to properly assess the neuronal shape and cytoplasm (Figure 2 ) (Waggett et al., 2010 ). As supported by the Hoerdemann et al. ( 2024 ), the researchers reached a diagnosis in a ganglioneuromatosis case, stressing the importance of IHC in equine pathology: the tumour presented by the authors, in absence of IHC, would have been indeed diagnosed as a generic mesenchy- mal tumour (such as gastrointestinal stromal tumour/fibrosarcoma, peripheral nerve sheath tumour) with no possibility of understand- ing its cellular origin. Lymphoid markers are commonly used in equine pathology, not
only to characterise lymphomas and other lymphoid neoplasia, but also to label immune cells in any study of equine immunology. CD3
ROCCHIGIANI and RESSEL
(T cell marker), Pax5, CD 79a, CD 20 and anti- BLA- 36 (B cell markers) are reported to work on equine tissue (Durham et al., 2013 ), although, in our experience, the best one for B marker remains Pax5. It is always a good practice to include, for any lymphoma suspect case, to include CD3 and at least two different B cell markers, as B cell lymphomas can arise from a specific stage of B cell maturation and, therefore, express only a fraction of B cell proteins. In our lab, we prefer Pax5 and CD20, as CD79a is commonly giving us faint signals on equine tissue (likely due to low cross- reactivity). Take into consideration, that in horses, as well as in other animal species, lymphomas may be nega- tive to both T and B cell markers, complicating such diagnosis. Rarer round cell tumours include mast cell tumours and histio-
cytic neoplasm. For these tumours, classic antibodies such as IBA- 1 (histiocytic neoplasms) and c- kit (mast cell tumour) are working very well in the equine species. C- kit is also used to diagnose gastroin- testinal stromal tumours (GISTs), which are mesenchymal neoplasms arising from the interstitial cells of Cajal, normally present within the gastrointestinal musculature. The key features of this tumour should be the positivity to c- kit and vimentin, while the tumour shows vari- able labelling to other mesenchymal markers, including ASMA and S- 100 (Knottenbelt et al., 2016c ). Despite the great utility, IHC does not represent a “ deus ex
machina ” able to solve any diagnostic challenge, having some limits: as an example, inflammation- driven dysplasia in epithelia can closely mimic carcinomas and there are no reliable IHC markers able to dis- tinguish these two entities, and decision remains in most cases, a domain of the old- fashioned morphology. IHC should be requested when a specific question needs an answer (e.g. an undifferentiated tumour is an epithelial or a mesenchymal one) and when such an an- swer cannot be answered via histological features alone. Considering that IHC in the equine species “started” approximately 50– 60 years ago, we have already a broad “arsenal” of antibodies employable to unravel many diagnostic dilemmas and we believe that many more IHC markers are awaiting to be discovered, as the pace of multidisci- plinary scientific progress accelerates.
FIGURE 2 Myenteric plexus from a horse with acute grass sickness. Synaptophysin immunohistochemistry highlights chromatolytic neurons. 40×. Image courtesy of Dr Emanuele Ricci.
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