Acinar Atrophy Research Articles

Chronic sclerosing sialadenitis as one of the immunoglobulin G4-related diseases: a clinicopathological study of six cases from Central Europe

Chronic sclerosing sialadenitis (CSS) has been proposed recently to be a member of the group of IgG4-related diseases in Japanese and American series. The aim of our study was to validate these results in a cohort of European patients. Our CSS series included four females and two males, aged 32-76 years, all presenting with unilateral swelling of submandibular gland. Microscopically, all CSS-cases showed similar morphology with preservation of lobular architecture accentuated by cellular fibrous bands, dense lymphoplasmacytic inflammation and varied acinar atrophy. Ductal lymphocytes were detected in three cases. In five cases, the presence of intraductal secretory material accompanied by parenchymal neutrophils was observed. Obliterative phlebitis was seen in three cases. The inflammatory infiltrate was composed of T and B lymphocytes and polyclonal plasma cells. The median number of IgG-positive plasma cells per high-power field (HPF) was 157; median number of IgG4-positive plasma cells per HPF was 133. Median value of the IgG4:IgG ratio was 0.84. This is the first European series to demonstrate that CSS belongs to the family of IgG4-related disease. Unlike previous studies, in CSS we found rarely described ductal lymphocytes and parenchymal neutrophils. CSS displays consistent morphology with increased numbers of IgG4-positive plasma cells, and should be regarded as a member of the IgG4-related disease group.

Correlation of Histopathology, Islet Yield, and Islet Graft Function After Islet Autotransplantation in Chronic Pancreatitis

The number of islets available (yield) is an important predictor of insulin independence after islet autotransplantation (IAT) done at the time of total pancreatectomy to treat painful chronic pancreatitis. The aim of this study was to correlate histopathologic findings with islet yield and graft function. Pancreatic histopathology was examined in 105 adults who underwent pancreatectomy and IAT; postoperative insulin use was known in 53 cases. Histologic degree of fibrosis, acinar atrophy, inflammation, and nesidioblastosis were scored by a surgical pathologist. The correlation of histopathology with islet yield and graft function was evaluated. Patients received a median of 2968 islet equivalents per kilogram. Fibrosis and acinar atrophy correlated negatively with islet yield (P < G 0.001, r =0.67), as did inflammation (P < G 0.001, r =0.43). There was a positive correlation of islet yield (P < G 0.0001, r = 0.64) and a negative correlation of fibrosis (P = 0.006, r = 0.43) and acinar atrophy (P = 0.006, r = 0.42) with islet graft function. More severe histopathologic changes were associated with a lower islet yield and lower likelihood of insulin independence. Total pancreatectomy and IAT should not be delayed in patients with painful chronic pancreatitis refractory to medical therapy; otherwise progressive damage to the pancreas may limit islet yield and increase the risk of diabetes.

Adenoviral delivery of Tousled kinase for the protection of salivary glands against ionizing radiation damage

Oral complications of salivary hypofunction often afflict cancer patients undergoing radiotherapy for head and neck cancers. Dry mouth or xerostomia is an undesirable consequence of radiotherapy that compromises normal oral functions in addition to causing odynophagia and increasing the patient's risk of oral infections and dental caries. Radiation-induced xerostomia is irreversible, and palliative measures to provide symptomatic relief remain the mainstay of treatment. Previously, we identified a splice variant of a cellular kinase, Tousled-like kinase 1B (TLK1B), which when overexpressed protects normal epithelial cells against ionizing radiation (IR)-induced cell death. To address the need to protect salivary glands in patients undergoing regional radiotherapy, we investigated whether preemptive expression of TLK1B in salivary glands protects against IR. In stably-derived salivary cell lines in vitro, TLK1B expression increased cell survival after IR. Cells expressing exogenous TLK1B were less radiosensitive (A5-TLK1B, α/β=0.67 Gy; ParC5-TLK1B, α/β=4.3 Gy) compared to control cells (A5-BK, α/β=1.7 Gy; ParC5-BK, α/β=32.7 Gy). Using a recombinant adenovirus serotype 5 viral vector for TLK1B gene transfer into rat submandibular salivary glands in vivo, we demonstrated that TLK1B protects the saliva-secreting acinar cells and better preserves salivary gland function against IR relative to control glands. After a single fraction of 16 Gy, the decline in salivary function at 8 weeks was less pronounced in TLK1B-treated animals (40%) as compared to saline-treated controls (67%). Histopathological analysis demonstrated increase in acinar atrophy, decrease in acinar cell number, and increase in inflammatory infiltrate and fibrosis in irradiated control tissues relative to TLK1B-treated glands. These results show the radioprotective benefits of TLK1B and implicate its usefulness in the management of regional radiotherapy-induced xerostomia.

Caracterização histomorfológica da atrofia inflamatória proliferativa na próstata canina

A atrofia inflamatória proliferativa (PIA) é uma lesão prostática pré-maligna de grande ocorrência na próstata humana e, mais recentemente, também observada em cães. Esta pesquisa teve por objetivo verificar os aspectos histomorfológicos da PIA na próstata canina. Foram utilizadas 43 próstatas de cães adultos, de várias raças e portes, e com histórico ou não de doença prostática. Os focos de PIA apresentaram epitélio displásico, formado por ácinos atróficos e com mais de uma camada de células de morfologia atípica, especialmente anisocitose, anisocariose, citoplasma reduzido, núcleo volumoso e com nucléolo evidente. As alterações epiteliais eram sempre acompanhadas de infiltrado inflamatório intersticial periacinar predominantemente linfocitário. Foi observado um índice de 65% de PIA. Destes, 39% corresponderam à PIA com infiltrado inflamatório discreto, 42% à PIA com infiltrado moderado e 19% à PIA com infiltrado acentuado. Dessa forma, foi possível caracterizar a PIA prostática canina e constatar alta ocorrência dessa alteração nos cães examinados. Considera-se de grande importância a caracterização histomorfológica da PIA em cães, já que essa lesão vem sendo estudada na próstata humana quanto ao potencial pré-maligno. Ressalta-se ainda a possibilidade de utilização da próstata do cão como modelo experimental da PIA humana, considerando a semelhança dessa afecção prostática em ambas as espécies.

Caracterização imunofenotípica e avaliação quantitativa do infiltrado linfocítário junto às áreas de displasia epitelial da próstata de cães adultos sexualmente intactos

O estudo da próstata canina tem se tornado comum em razão da grande incidência de doenças prostáticas nessa espécie e das similaridades com as alterações apresentadas pela glândula prostática humana. Frente à alta frequência de displasias epiteliais acompanhadas de infiltrado linfocitário intersticial e atrofia acinar na espécie canina, o presente estudo teve como objetivos a caracterização imunofenotípica e a avaliação quantitativa desse infiltrado, utilizando marcadores para identificação de linfócitos T (anti-CD3) e B (anti-CD79a). Foram catalogadas 42 lesões displásicas classificadas em discreta (48%), moderada (38%) e acentuada (14%). O infiltrado linfocitário intersticial periacinar junto às áreas de epitélio prostático displásico constituiu-se predominantemente por linfócitos T (66%) e houve interação entre o grau histológico da displasia e o marcador imunoistoquímico, com oscilação na quantidade de células T e B intersticiais em função do grau da displasia epitelial.

Androgens and Integrins in Salivary Glands in Sjögren’s Syndrome

Laminin alpha1-chain normally induces intercalated duct progenitors to differentiate to acinar cells through integrin (INT) alpha1ss1 and alpha2ss1 receptors. Maintenance of acinar cells is impaired in Sjögren's syndrome (SS), which is also characterized by low levels of serum and salivary androgens. We hypothesized that androgens normally support salivary gland remodeling by upregulating either laminin alpha1 chain or its cellular alpha1 or alpha2 INT subunit-containing receptors. Intercalated duct and acinar human salivary gland (HSG) cells and labial salivary gland (LSG) biopsies from healthy controls and patients with SS were cultured without or with sex steroids. Laminin alpha1 chain and INT alpha1 and alpha2 subunits were studied using quantitative reverse-transcription real-time polymerase chain reaction and INT alpha1 and alpha2 subunits using immunofluorescence staining. INT alpha1-subunit and alpha2-subunit messenger RNA (mRNA) levels were increased in intercalated duct and acinar cells by DHEA and testosterone. In contrast, laminin alpha1-chain mRNA levels were not affected. The upregulating effect of DHEA on INT subunits was also seen at the protein level. DHEA also increased mRNA levels of both INT subunits in healthy but not SS LSG. Androgens increased INT alpha1 and alpha2 subunits in tubuloepithelial cells and in healthy LSG, but in SS salivary glands this androgen regulation was defective, which is likely to contribute to defective outside-in signaling, acinar atrophy, and ductal cell hyperplasia.

Conditional overexpression of TGF-β1 disrupts mouse salivary gland development and function

Transforming growth factor-β (TGF-β) signaling is known to affect salivary gland physiology by influencing branching morphogenesis, regulating ECM deposition, and controlling immune homeostasis. To study the role of TGF-β1 in the salivary gland, we created a transgenic mouse (β1glo) that conditionally overexpresses active TGF-β1 upon genomic recombination by Cre recombinase. β1glo mice were bred with an MMTV (mouse mammary tumor virus)-Cre (MC) transgenic line that expresses the Cre recombinase predominantly in the secretory cells of both the mammary and salivary glands. Although most of the double positive (β1glo/MC) pups die either in utero or just after birth, clear defects in salivary gland morphogenesis such as reduced branching and increased mesenchyme could be seen. Those β1glo/MC mice that survived into adulthood, however, had hyposalivation due to salivary gland fibrosis and acinar atrophy. Increased TGF-β signaling was observed in the salivary gland with elevated phosphorylation of Smad2 and concomitant increase in ECM deposition. In particular, aberrant TGF-β1 overexpression caused salivary gland hypofunction in this mouse model because of the replacement of normal glandular parenchyma with interstitial fibrous tissue. These results further implicate TGF-β in pathological cases of salivary gland inflammation and fibrosis that occur with chronic infections in the glands or with the autoimmune disease, Sjögren’s syndrome, or with radiation therapy given to head-and-neck cancer patients.

Heritability of Exocrine Pancreatic Insufficiency in German Shepherd Dogs

Several studies have revealed that exocrine pancreatic insufficiency (EPI) is an inherited disease in German Shepherd Dogs (GSDs). Pedigree analyses have suggested an autosomal recessive inheritance model. Test mating of 2 dogs with EPI. A sire and dam purebred GSD both with EPI and a litter of 6 puppies. Test mating and long-term follow-up of offspring. The pancreas was biopsied via laparotomy on 26 occasions. Serum trypsin-like immunoreactivity was measured. Study was approved by Animal Ethics Committee. During the 12-year study period only 2 of the 6 offsprings developed pancreatic acinar atrophy (PAA). In 1 puppy, end-stage PAA and in the other puppy partial PAA was diagnosed. PAA is not a congenital disease in GSDs. This study provided evidence that PAA is not inherited in a simple autosomal recessive fashion.

Correlation of Pancreatic Histopathologic Findings and Islet Yield in Children With Chronic Pancreatitis Undergoing Total Pancreatectomy and Islet Autotransplantation

The probability of insulin independence after intraportal islet autotransplantation (IAT) for chronic pancreatitis (CP) treated by total pancreatectomy (TP) relates to the number of islets isolated from the excised pancreas. Our goal was to correlate the islet yield with the histopathologic findings and the clinical parameters in pediatric (age, <19 years) CP patients undergoing TP-IAT. Eighteen pediatric CP patients aged 5 to 18 years (median, 15.6 years) who underwent TP-IAT were studied. Demographics and clinical history came from medical records. Histopathologic specimens from the pancreas were evaluated for presence and severity of fibrosis, acinar cell atrophy, inflammation, and nesidioblastosis by a surgical pathologist blinded to clinical information. Fibrosis and acinar atrophy negatively correlated with islet yield (P = 0.02, r = -0.50), particularly in hereditary CP (P = 0.01). Previous duct drainage surgeries also had a strong negative correlation (P = 0.01). Islet yield was better in younger (preteen) children (P = 0.02, r = -0.61) and in those with pancreatitis of shorter duration (P = 0.04, r = -0.39). For preserving beta cell mass, it is best to perform TP-IAT early in the course of CP in children, and prior drainage procedures should be avoided to maximize the number of islets available, especially in hereditary disease.

Chronic Pancreatitis in Mice by Treatment with Choline-Deficient Ethionine-Supplemented Diet

Although chronic pancreatitis is a risk factor for pancreatic ductal adenocarcinoma (PDA), the relationship between chronic pancreatitis and PDA remains obscure. A critical obstacle to understanding the role of chronic pancreatitis is the lack of animal models. To develop one such model, mice were fed long-term with a choline deficient ethionine-supplemented (CDE) diet. Histological evaluation revealed that chronic pancreatitis, characterized by acinar atrophy, fibrosis and well-developed tubular complexes (TCs), was observed after 24 weeks of CDE diet treatment. Furthermore, expression of epidermal growth factor receptor (EGFR) and its ligands; serine protease inhibitor Kazal type 3 (Spink3) and transforming growth factor alpha (TGF alpha) and activation of K-Ras (GTP-Ras formation), which are frequently observed in human PDA, were indeed observed in parallel with TCs formation. Neoplastic lesions were not found after 54 weeks of treatment, suggesting that a continuation of CDE diet or another insult is required for the development of PDA.

Ethanol consumption as inductor of pancreatitis

Alcohol abuse is a major cause of pancreatitis, a condition that can manifest as both acute necroinflammation and chronic damage (acinar atrophy and fibrosis). Pancreatic acinar cells can metabolize ethanol via the oxidative pathway, which generates acetaldehyde and involves the enzymes alcohol dehydrogenase and possibly cytochrome P4502E1. Additionally, ethanol can be metabolized via a nonoxidative pathway involving fatty acid ethyl ester synthases. Metabolism of ethanol by acinar and other pancreatic cells and the consequent generation of toxic metabolites, are postulated to play an important role in the development of alcohol-related acute and chronic pancreatic injury. This current work will review some recent advances in the knowledge about ethanol actions on the exocrine pancreas and its relationship to inflammatory disease and cancer.

Unilateral absence of submandibular gland secondary to stones. Aplasia versus early atrophy

Major salivary gland absence is a rare disorder. The cause of congenital absence of the salivary glands has not been determined, but it may be associated with ectodermal defects of the first and second branchial arches. Isolated absence of a unilateral submandibular gland is an unusual entity with less than ten cases reported in the literature. The etiopathogenesis of isolated absence of a major salivary gland without other developmental anomalies is still unclear. The formation of a sialolith within the remaining Wharton's duct, associated with isolated aplasia (versus atrophy) of a unilateral submandibular gland has been recently reported. We describe in this work two cases of sialolithiasis within the ipsilateral remaining Wharton's duct in patients with isolated absence of a unilateral submandibular gland. In the cases reported, absence of the submandibular gland may have been the result of the complete acinar atrophy secondary to an early obstruction of Wharton's duct.

New insights into alcoholic pancreatitis and pancreatic cancer

Pancreatitis and pancreatic cancer represent two major diseases of the exocrine pancreas. Pancreatitis exhibits both acute and chronic manifestations. The commonest causes of acute pancreatitis are gallstones and alcohol abuse; the latter is also the predominant cause of chronic pancreatitis. Recent evidence indicates that endotoxinemia, which occurs in alcoholics due to increased gut permeability, may trigger overt necroinflammation of the pancreas in alcoholics and one that may also play a critical role in progression to chronic pancreatitis (acinar atrophy and fibrosis) via activation of pancreatic stellate cells (PSCs). Chronic pancreatitis is a major risk factor for the development of pancreatic cancer, which is the fourth leading cause of cancer-related deaths in humans. Increasing attention has been paid in recent years to the role of the stroma in pancreatic cancer progression. It is now well established that PSCs play a key role in the production of cancer stroma and that they interact closely with cancer cells to create a tumor facilitatory environment that stimulates local tumor growth and distant metastasis. This review summarizes recent advances in our understanding of the pathogenesis of alcoholic pancreatitis and pancreatic cancer, with particular reference to the central role played by PSCs in both diseases. An improved knowledge of PSC biology has the potential to provide an insight into pathways that may be therapeutically targeted to inhibit PSC activation, thereby inhibiting the development of fibrosis in chronic pancreatitis and interrupting stellate cell-cancer cell interactions so as to retard cancer progression.

Effect of Radiotherapy on Non-Neoplastic and Malignant Prostate

Pathologists nowadays are frequently confronted with post-radiotherapy biopsies of the prostate. It is critical to recognize the changes of benign prostatic tissue with radiation effect, which include frequent acinar atrophy, acinar distortion, basal cell hyperplasia, decreased acinar/stromal ratio, and stromal fibrosis. The non-neoplastic irradiated prostate can have nuclear enlargement and bizarre nuclei, changes overlapping or exceeding those commonly seen in prostatic adenocarcinoma. The presence of high-grade PIN adjacent to acini in question favors a cancer diagnosis. Ceratin immunostains, particularly cytokeratin 34sE12, in conjunction with selected other markers, can help the pathologist determine whether residual cancer is present in the most difficult cases.

Usefulness of initial histological features for stratifying Sjogren's syndrome responders to mizoribine therapy

To evaluate the response of patients with SS to mizoribine therapy in relation to histological features of minor salivary glands. Forty patients definitely diagnosed as having SS were treated with mizoribine (150 mg/day). Thirty-four untreated patients matched for age, baseline salivary secretion, etc., served as controls. Salivary secretion volume (measured by the Saxon test) and serum IgG level were measured before and after 24 weeks of treatment. Each histological finding (lymphocytic infiltration, acinar atrophy and intralobular fibrosis) was graded at baseline and the therapeutic responses were compared with the grade at 24 weeks in both the groups. There was a significant increase of the salivary secretion volume after treatment with mizoribine as compared with the untreated control group. The effect of mizoribine on salivary secretion was more marked in patients having moderate lymphocytic infiltration and moderate or less severe acinar atrophy and intralobular fibrosis at baseline. Mizoribine was clinically effective in patients with SS whose minor salivary glands had moderate cell infiltration and were free of intralobular fibrosis. The drug was less effective in patients who presented intralobular fibrosis. Histological evaluation of the minor salivary glands may serve to predict the response of SS patients to mizoribine therapy.

In vitro secretion of hormones from the islets of pancreas with acinar atrophy--influence of digestion with collagenase.

The release of insulin, glucagon and somatostatin from islets isolated by microdissection, and islets isolated by aid of different duration of collagenase digestion from pancreases with exocrine atrophy was assessed. Prior collagenase digestion caused an increased release of insulin and glucagon, but not somatostatin; also, the non-suppressibility of glucagon secretion despite high glucose concentration in the medium was characteristic for those islets. Additional data suggest that in the absence of intrinsic pancreatic proteases the nature of the damage conferred by collagenase to islet B- and A-cells is different. In the light of action of epinephrine, an inhibitor of insulin secretion, possible mechanisms responsible for disturbed hormone release in the presence of proteolytic enzymes are discussed.

Isolated Solitary Ducts (Naked Ducts) in Adipose Tissue

The distinction of ductal adenocarcinoma from chronic pancreatitis remains one of the most difficult challenges in surgical pathology. The glandular units of invasive carcinoma are often well formed with well-polarized cells, appearing deceptively benign. Conversely, the ducts of chronic pancreatitis may be atypical and pseudoinfiltrative as a result of acinar atrophy and fibrosis. We recently noted isolated solitary ductal units (ISDs) in adipose tissue to be a reliable indicator of adenocarcinoma. In this study, the frequency of ISDs was investigated in 105 pancreatic resections with ductal adenocarcinoma and 32 with chronic pancreatitis only. ISD was defined as a solitary gland lying individually in adipose tissue, either directly abutting adipocytes or separated from them by only a thin rim of fibromuscular tissue. ISD was detected in 50/105 (47.6%) of pancreatic resections for ductal adenocarcinoma, but not in any resections with chronic pancreatitis only (specificity 100%; sensitivity 47.6%). Most of the ISDs were very well differentiated and cytologically bland. A small subset of these units represented vascular invasion, in which the carcinoma cells epithelialized the vessel lining, transforming the vessel into a duct-like structure, virtually indistinguishable from normal ducts or PanINs. The vascular nature of these units was verified by Elastic-Van Gieson stain and muscular markers highlighting the elastic lamina and muscular wall, respectively. ISDs were often located in histologic sections taken for the evaluation of the retroperitoneal margin and pancreatic-free surfaces where adipose tissue is more abundant. In conclusion, ISD lying in adipose tissue unaccompanied by other elements, present in 47.6% of pancreatic resections when peripancreatic soft tissues away from the tumor are sampled, is a very specific finding for carcinoma that may be instrumental in the diagnosis and staging of carcinoma as well as margin evaluation.

Pancreatic Regenerating Protein I in Chronic Pancreatitis and Aging

We investigated the relationship of pancreatic regenerating protein (reg) in models of acinar cell atrophy and aging, and the effect of reg I protein replacement on glucose tolerance.Rats underwent pancreatic duct ligation (PDL) and were followed through 12 months. Aging rats were studied at 12 and 20 months. Intraperitoneal glucose tolerance tests (IPGTTs) were performed, pancreatic reg I, reg I receptor, insulin gene expression, and reg I protein levels were measured. Pancreatic duct ligation and aged animals were treated with exogenous reg I protein and assessed for glucose metabolism.After PDL, chronic atrophic pancreatitis developed, with a progressive loss of acinar cells and pancreatic reg I. During aging, a similar depression of reg I gene expression was also noted. The reg I levels correlated with pancreatic insulin levels. Twelve months after PDL, IPGTT results were abnormal, which were significantly improved by administration of reg I protein. Aged animals demonstrated depressed IPGTT, which marginally improved after reg I administration. Anti-reg antibody administration to young rats depressed IPGTT to elderly levels.Depletion of the acinar product reg I is associated with the pathogenesis of impaired glucose tolerance of pancreatitis-associated diabetes and aging, and replacement therapy could be useful in these patients. Reg I is an acinar cell product, which affects islet function.

A review of hereditary diseases of the German shepherd dog

The German shepherd dog (GSD) is a preferred choice of many law enforcement and military agencies across the world. Unfortunately, the breed is afflicted with approximately 50 hereditary diseases. Seven major diseases afflicting the GSD are described herein: pancreatic acinar atrophy, megaesophagus, hip dysplasia, degenerative myelopathy, hemophilia A, von Willebrand disease, and hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis. Also included is a discussion of behavior, a characteristic thought to be inherited in the dog and often problematic in larger breeds such as the GSD. Current clinical and genetic research efforts pertaining to these diseases are reviewed.

Ellagic Acid Inhibits Pancreatic Fibrosis in Male Wistar Bonn/Kobori Rats

The key pathological features of chronic pancreatitis are chronic inflammation, acinar atrophy, and pancreatic fibrosis. We have previously shown that ellagic acid, a plant-derived polyphenol found in fruits and nuts, inhibited activation of pancreatic stellate cells, a major profibrogenic cell type in the pancreas, in vitro. Here we examined whether ellagic acid inhibited the development of pancreatic fibrosis in vivo. Ellagic acid was administered orally in the diet to ten-week-old male Wistar Bonn/Kobori rats, an experimental model of spontaneous chronic pancreatitis, for ten weeks. Ellagic acid (100 mg/kg body weight/day) attenuated pancreatic inflammation and fibrosis. The protective effects were confirmed by an increase in pancreatic weight and decreases in myeloperoxidase activity (an index of neutrophil infiltration), collagen content, transforming growth factor-beta1 expression, and the number of alpha-smooth muscle actin-positive cells (activated pancreatic stellate cells) and ED-1-positive cells (macrophages/monocytes). Ellagic acid inhibited the production of reactive oxygen species in pancreatic stellate cells in response to transforming growth factor-beta1 or platelet-derived growth factor. Our results suggest that ellagic acid might be a candidate for treatment of chronic pancreatitis.