Fluorouracil plus leucovorin induces submandibular salivary gland enlargement in rats

The administration of 5-fluorouracil (FU) and leucovorin (LV) to rats induced a previously unreported sialoadenitis-like toxicity. Four different treatment regimens were used: daily-times-5 iv or ip injections of LV (200 mg/kg) followed 30 minutes later by FU (27.5 mg/kg or 35 mg/kg). These treatments resulted in 3 severity levels of systemic toxicity indicated by changes in body weight. In addition to the well known FU+LV-induced diarrhea, myelosuppression, and stomatitis, facial edema, and enlargement of the submandibular salivary gland were consistently seen. Facial edema occurred almost exclusively in rats that subsequently underwent excessive weight loss and were euthanized. The submandibular, but not parotid or sublingual, salivary gland was enlarged and the severity of this effect changed in a bell-shaped relationship with respect to increasing FU+LV induced loss of body weight. Histologic examination of affected glands established the occurrence of bacterial infection, sialoadenitis and destruction of gland tissue. This paper provides the first known documentation of FU+LV treatment-induced selective pathology of the submandibular salivary gland. The selectivity of this toxicity, apparently not normally seen in humans, to the submandibular salivary gland of the rat is of interest and its mechanism warrants further investigation.     

Perivascular nerves in the rat submandibular salivary gland.

Perivascular nerves in the rat submandibular salivary gland have been studied using a variety of histochemical procedures coupled with electron microscopy. Two principal nerve types, adrenergic and cholinergic, appear to predominate and are localized principally around arterioles. Venules are rarely innervated. The possibility that a non-adrenergic non-cholinergic nerve population might influence blood flow is discussed critically in the light of anatomical and physiological findings.     

Stereological study on the submandibular gland in hypothyroid rats.

Most research done on hypothyroidism has focused on physiological and biochemical aspects of the tissues, whilst there has been little work on tissue morphology especially on salivary glands. The present study has used hypothyroid Wistar rats as a model for investigating the effects of hypothyroidism on submandibular gland structure. Two groups of Wistar rats were studied. One was made hypothyroid with methimazole and the second was an untreated euthyroid group (control). They were euthanised after 10 weeks. Submandibular glands were removed and studied. Systematic random transverse sections were obtained from submandibular glands and subjected to morphometric analysis. Volume density and absolute volume of granular, striated and excretory ducts and interlobular connective tissue were estimated by point counting. Volume-weighted mean particle volume of serous and mucous acini was also determined by unbiased stereology. Absolute volume of granular ducts in the submandibular gland of hypothyroid rats was reduced by approximately 50% (p<0.009) whilst that of the striated and excretory ducts and interlobular connective tissue was unaffected. Volume of serous acini was also significantly (p<0.03) lower in hypothyroid rats. These changes suggest that hypothyroidism has an effect on submandibular gland structure, and that this effect occurs mostly in two major exocrine compartments (granular duct and serous acinus) of the gland.     

Identification of immunosuppressive fractions from the rat submandibular salivary gland.

It had previously been suggested that the submandibular gland (SMG) of mice and rats may contain in vivo immunosuppressive factor(s). To identify such factor(s), we used a multi-step purification procedure of rat SMG extracts. Gel filtration chromatography of the SMG crude extract resulted in two pools of fractions with significant effects on lymphocyte reactivity in the in vitro concanavalin A (Con A) bioassay. Of these two pools, only the one with lower molecular weight resulted in the prolongation of murine skin allograft survival, the suppression of the delayed-type hypersensitivity (DTH) response to picryl chloride and the decrease in number of direct (IgM) plaque-forming cells against sheep red blood cells. Fractionation of this low molecular weight (LMW) pool through hydrophobic interaction chromatography resulted in three protein fractions designated A, B and C. Of these fractions only fraction A produced significant suppression of the DTH response. Further purification of fraction A with anion exchange chromatography produced two fractions with immunosuppressive activity in the DTH response. One fraction demonstrated on SDS-PAGE a single component of 40,000 MW, while the other had two components of 30,000 and 40,000 MW respectively.     

Suppression of immune responsiveness by a submandibular salivary gland factor.

Both tissue extracts prepared from submandibular salivary glands of male mice and epidermal growth factor isolated from these glands depressed the delayed type hypersensitivity response to 2,4-dinitro-1-fluorobenzene in mice. Extirpation of the submandibular salivary glands from male mice did not alter the delayed type hypersensitivity response. The role of salivary gland factors, particularly epidermal growth factor, in influencing the immune response has been discussed.     

Ultrastructural study of acinar and intercalated duct organization of submandibular and parotid salivary gland

According to some current hypotheses, the morphology and organization of the intercalated duct/acinar interface of salivary gland have implications for the induction of tumors in this organ. However, this region has received limited detailed investigation. To study the organization of the terminal ductal segments of salivary gland, conventional transmission electron microscopy of human parotid and submandibular glands and canine submandibular gland was combined with 3-dimensional observations of polymer casts of the canine submandibular ductal system; the latter were prepared by retrograde injection of acrylic resin via the main excretory duct with subsequent digestion of the gland tissue. The division of intercalated ducts, into first- and second-order branches, and acinar arrangement is more complex than previously suggested. The entire surface of each elongated second-order intercalated duct is covered with acini projecting in all directions. In the human gland, some acini abut directly on the intercalated duct surface, whereas others are connected by a short stalk of intercalated duct cells; in comparison with canine submandibular gland, the latter may be a modification producing a third-order of the intercalated duct unit. All of these features combine to produce a highly efficient secretory apparatus with a large proportion of acinar cells to each intercalated duct.     

Reaction of the rat submandibular salivary gland to injury to the contralateral gland

After burns of resection of the submandibular salivary gland the intact contralateral gland in rats responds by increased proliferative activity. The number of mitoses reached a maximum 72 h after injury in the case of burns and 48 h after resection. Burns of the salivary gland cause lasting but weak compensatory hypertrophy of the contralateral gland. Hypertrophy of the gland is accompanied by an increase in size of the cells and nuclei, the area of which rises by 10 and 17% respectively. Resection of the salivary gland causes an increase in weight of the intact gland only in the early period of observation; by the 30th and 45th days after the operation the weight of the experimental glands was not significantly different from the control. Differences in compensatory growth of the intact glands observed after two types of injury of the contralateral gland evidently depend on the quantity of tissue breakdown products and the duration of their presence in the body.Department of Biology and General Genetics, Moscow Medical Stomatological Institute. (Presented by Academician of the Academy of Medical Sciences of the USSR A. P. Avtsyn.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 82, No. 9, pp. 1108–1110, September, 1976.     

Elastic fibers in the duct system of the rat submandibular salivary gland.

The submandibular salivary gland originates from the floor of the mouth whose mucosa contains elastic fibers. Therefore, such fibers were sought in the duct system of the derivative organ. In adult rats, light microscopy has indeed revealed fine, circumferential, elastic fibers near the basement membrane of the duct epithelium. In the larger extralobular ducts, they were separated from several layers of longitudinal elastic fibers by a capillary-rich zone sparse in elastic fibers except for fine angular ones. More peripherally, larger angular-appearing fibers were frequently present near the submandibular parasympathetic ganglia in the duct wall. As duct diameter decreased, elastic fiber size and number diminished. Intralobularly, the smaller striated ducts, granular and intercalated ducts, and acini generally lacked such fibers. Electron microscopy of the extraglandular portion of the main duct revealed fibrils extending from both fibroblasts and elastic fibers that were close to the epithelium. Microfibrils coursed from them toward the lamina densa. Anchoring filaments joined the lamina densa to the basal plasma membrane of the epithelium. Elastic fibers also appeared to connect to both capillaries and collagen via finer intermediate structures. These associations might permit dynamic interactions of fibroblasts, fibers, smaller fibrillar components, vasa, and the duct epithelium. This interplay could occur during feeding and grooming when tongue protrusion and neck extension stretch the submandibular duct and the gland itself. As a result, the tensile forces engendered could modify cell geometry and the calibers of the larger ducts' lumens and intercellular spaces, thus affecting the flow and composition of salivary secretion.     

Cutaneous metastasis from a myoepithelial carcinoma of submandibular salivary gland

Myoepithelial carcinoma is a rare malignant tumor of salivary gland with locally aggressive nature and potential for distant metastasis. It is composed of tumor cells with myoepithelial differentiation showing varied cytomorphology. Lungs and kidneys are the commonest sites for distant metastasis. Cutaneous metastasis of myoepithelial carcinoma is very rare. In this report, we described cutaneous metastasis of myoepithelial carcinoma arising from submandibular gland. Diagn. Cytopathol. 2015;43:53–56. © 2014 Wiley Periodicals, Inc.     

Langerhans' cells in a pleomorphic adenoma of submandibular salivary gland

Large numbers of round and dendritic cells similar to Langerhans' cells of normal epidermis and other epithelia were seen within a pleomorphic adenoma of the submandibular salivary gland. These cells, which were present only in areas of non-cornifying epidermoid metaplasia, exhibited Birbeck granules with isolated terminal vesicles, cytoplasmic microfilaments, microtubules, and a few poorly developed intercellular junctions.     

Regeneration of submandibular salivary gland autografted in the rat tongue

Autologous SMG fragments were implanted in tongues of male rats which were sacrificed 15–20 min, 24 hr, 72 hr, 1 week, or 8 weeks after implantation. The tongues were excised, fixed, and processed for light and electron microscopy. In addition, some rats were injected with [³H]-thymidine 1 hr before sacrifice and the labeling indices (L.I.) of the salivary epithelial and interstitial cells were calculated. Twenty-four hours after implantation, SMG autografts showed massive central necrosis with some acini and ducts surviving at the periphery of the lobules. There was marked infiltration of the autografts with neutrophils and macrophages. Also the basal laminae surrounding the necrotic acini and ducts remained intact. The morphology of the autografts after 72 hr was similar to that after 24 hr except that there was additional necrosis and acini and ducts could no longer be identified in the autografts. By 1 week after implantation, the autografts showed lobular morphogenesis, ductal branching, and revascularization. At this time, the regenerating salivary epithelium appeared undifferentiated with no evidence of secretory granules. The L.I. of interstitial and ductlike structures showed significant increases over control values at 1 week after implantation, and then declined toward control levels by 3 weeks after implantation. By 8 weeks after implantation, there was evidence of acinar and striated ductal cytodifferentiation in two autografts. The results emphasize the potential of SMG autografts to regenerate subsequent to severe tissue necrosis.     

Recovery of rat submandibular salivary gland function following removal of obstruction: a sialometrical and sialochemical study

Functional recovery of the rat submandibular gland following ligation of the main excretory duct was examined. Rat submandibular glands were ligated for 1, 4 and 8 weeks using a micro-clip with a plastic tube. Micro-clips were removed and glands were allowed to recover for periods of 8, 16 and 24 weeks. Submandibular glands were stimulated with autonomimetic drugs (methacholine and isoprenaline) and salivas were collected from atrophic or de-ligated and contralateral control glands. Glands recovered almost full size (92% of control gland) following 24 weeks of de-ligation. Saliva volume secreted by ligated/de-ligated (RSM) and control (LSM) glands were similar with different doses of agonists. Protein output expressed per gram of tissue wet weight was similar from both ligated/de-ligated and control glands with all doses of agonist. Sodium and chloride levels were higher from de-ligated glands than contralateral control glands. Protein electrophoresis showed similar profiles of salivary proteins in all samples with some minor differences. Acinar cells in de-ligated glands showed a normal morphology, as indicated by light microscopy, whilst granular ductal cells were fewer and contained fewer secretory granules. Sodium potassium ATPase staining of striated ducts in de-ligated glands was similar to that of control glands. It can be concluded that rat submandibular glands can regenerate following severe atrophy and secrete normal amounts of saliva containing broadly a full profile of secretory proteins. In contrast to acinar cells, ductal cells appear not to recover full function.     

Chromogranin B-like immunoreactivity in the mouse submandibular salivary gland during postnatal development.

Presence and distribution, developmental changes, and molecular features of chromogranin B proteins within the submandibular salivary glands of male mice were investigated by 2-dimensional electrophoresis and PAP immunostaining. Chromogranin B-like immunoreactivity was detected in the juxta-acinar (JA)) cells of the submandibular salivary gland during the first week of postnatal development. During the 2nd and 3rd weeks, chromogranin B-like immunoreactivity reached the plateau level, while its reduction seemed to be occurred in correspondence to the appearance of the granular convoluted tubule cells, in which they did not show any chromogranin B-like immunoreactivity. Up to 7 weeks of age, chromogranin B-like immunoreactivity was substantially decreased, but not completely. A few JA cells, chromogranin B-like immunoreactive, retained even in the adult morphologically matured submandibular salivary gland of mice. A predominant protein which can be revealed by 2-dimensional electrophoresis and by immunocytochemistry, was chromogranin A. Chromogranin C was not detected in any cell type of the submandibular salivary gland of mice from early postnatal period up to 35 d of age. Physiological significance and possible function as well as an application of these findings were discussed.     

Expression of c-erbB-2 oncoprotein in salivary gland tumours: an immunohistochemical study.

Sections of formalin-fixed, paraffin-embedded primary salivary gland tumours were stained with a monoclonal antibody to the c-erbB-2 oncoprotein to determine the incidence and significance of expression of this protein. The series of 131 tumours comprised 33 cases of pleomorphic adenoma, 2 of malignant mixed tumour, 1 oxyphil adenoma, 31 Warthin's tumours, 4 basal cell adenomas, 6 mucoepidermoid carcinomas, 14 acinic cell carcinomas, 19 adenoid cystic carcinomas, 3 squamous carcinomas, and 18 poorly differentiated adenocarcinomas. Positive staining, as defined in previous studies, was present in five tumours (three cases of poorly differentiated adenocarcinoma, one mucoepidermoid carcinoma, and one adenoid cystic carcinoma). A review of the medical records of all patients did not disclose any clear difference between the clinical behaviour of positive and negative cases over a period of follow-up that ranged from 18 to 120 months. The findings of this study indicate that the protein product of the c-erbB-2 proto-oncogene is infrequently expressed in salivary gland tumours, and when it is localized on the tumour cell surface membrane, there is no clear evidence that this determines the biological behaviour of the tumour.     

Neonatal cystic choristoma in submandibular salivary gland simulating cystic hygroma

A congenital cystic malformation occurred in the submandibular salivary gland of a neonate. The embryogenesis and differential diagnosis are discussed. Since it seems to be a product of endodermal heterotopic differentiation or entrapment of foregut epithelial rests in the submandibular gland, it is classified as a cystic choristoma.