The limitation of light microscopy in the study of mast cells prompted the employment of other imaging platforms. A platform that was widely used in the early sixties through mid-eighties was the electron microscopy. Using the RCA EMU-2A electron microscope, \citet{Smith_1957} studied mast cells isolated – via centrifugation – from the peritoneal fluid of adult male rodents. The cells were dehydrated with various alcohol concentrations before they were embedded in plastic and gelatin. Because of the poor quality in preserving the structural integrity of the mast cells, the authors attempted to optimise the preparatory procedures by using several fixative agents at different times of fixation as well as varying the pH of the fixative and adding modifications to the polymerisation of the embedding plastic. None of the modifications yielded significant improvements to the quality of the electron micrographs. However, the authors stressed that the mast cells that they obtained appeared similar to those isolated from skin, spleen, and liver that were prepared according to the method developed by \citet{14927794}. The embedded cells were cut into thin sections prior to imaging.
In addition to imaging normal mast cells, the effects of total body irradiation and intraperitoneal (IP) injection of heparin-binding agent – toluidine blue and protamine sulfate – and histamine-releasing agent, stilbamidine were investigated. The morphology of normal mast cells was described as observed under the electron microscope: large nucleus occupied by thread-like structures with empty spaces towards the interior, multiple round or oval-like electron-dense bodies with a diameter of 0.5-1.0 µ. Thread-like materials that resemble those in the nucleus were present inside these electron-dense structures (cytoplasmic granules), albeit they were thinner with fine granule-like particles attached to them. In cells treated with the heparin-binding agents and stilbamadine, the size of the granules and the inner structures remained unchanged. Each granule seemed to be surrounded by a halo of clear cytoplasm enclosed and separated from each other by the perigranular membrane. The authors attributed this change in the electron micrographs due to cell swelling as a result of the fluid-filled IP injection. The authors noted that although the treatment caused the cells to be turgid, it did not affect the integrity of the granules. Unlike the untreated and IP-injected mast cells, cells isolated from irradiated rodents had more electron-dense bodies that were much larger than the typical size range of a secretory granule with fewer reticular structures on the inside. The nucleus appeared elongated and deformed and together with the absence of intragranular structures, mirrored that observed under the light microscope, which is suggestive of cells undergoing apoptosis \citep{Smith_1957}.
The plasma membrane of rat peritoneal mast cells was reported to exhibit finger-like projections that protrude into the extracellular space \citep{Lagunoff_1972}. This structural component was also observed in rat mast cells in the tongue \citep{Enerb_ck_1974}. However, this microvillus-like folding of the membrane was absent in mast cells observed in the lamina propria of the gut mucosa. In addition to the smooth cell membrane, the morphology of these cells slightly differs from that observed in peritoneal (Lagunoff, 1972) and mesentery (Smith 2006) mast cells. Mucosal mast cells often exhibited irregularly-shaped nuclei with indentations \citep{Enerb_ck_1974}, and have fewer but larger granules as compared to tongue mast cells, which have numerous and fairly-uniform sized granules that are within the size range reported by Smith (1957). The intragranular structures between these two cells were observed to be relatively distinct such that most of the granules in tongue mast cells exhibited a homogeneous fine particulate appearance whereas those in mucosal mast cells were composed of coarse particles. Besides this, other mesenchymal and granular (mainly eosinophils) cell types as well as phagocytic immune cells, were typically found in contact or in close proximity to mucosal mast cells \citep{Enerb_ck_1974}. Lagunoff (1972) noted that these cells, which appeared smaller than peritoneal mast cells, were often found localised near nerves and blood vessels.Following electron microscopic studies on animal mast cells, \citet{Hibbs_1960} attempted to study the morphology of human mast cells under normal/untreated conditions. Tissue biopsies were obtained from digital and abdominal skin and subcutis, as well as the gastric mucosa. The samples were divided for imaging by light and electron microscopy where the tissue specimens were processed as described by Smith (1957) for imaging with the electron microscope. Because eosinophils and neutrophils were easily distinguished, granular cells that were not identified as either eosinophils or neutrophils were assumed to be mast cells. Two morphologically distinct cells were observed: One was spindle-shaped with an elongated nucleus and numerous tightly-packed granules wherein the internal structures were not visually apparent; the other type was round or ovoid with many cytoplasmic granules that were more widely distributed. Unlike the light microscope, at the highest magnification of X50 000 of the objective lens of the electron microscope, the authors were able to observe the intragranular structures in the ovoid cells. They appeared to consist of two components – fine particles and lamellar/scroll-like structures. Variations exist between cells with regard to the composition and localisation of these components such that the granules may be composed of mostly fine particles or lamellar or a mix of both. Similar to the skin and dermis, both cell types were observed in the gastric mucosa specimen. However, only the ovoid cells were found in the specimen obtained from a patient who received intensive adrenocorticosteroid treatment. Furthermore, only the lamellar structure of the granules could be observed; the other component was rarely found in these cells, which lead the authors to the hypothesis that the steroid treatment caused the fine particles to be released from the granules. The study also highlighted another advantage of electron microscopy – it enabled the identification of two cell types as distinct cells, which was not feasible via the light microscope \citep{Hibbs_1960}.